RENAL

NORMAL STRUCTURE AND FUNCTION OF KIDNEY

Basic kidney processes – allows rapid changes
• Filtration
• Reabsorption: active transport
• Secretion of erythropoietinm renin and prostaglandins
• Excretion of waste products of metabolism
• Regulate body’s concentration of water, salt and other electrolytes
• Control acid-base balance

Glomerular corpuscle
• Afferent and efferent arteriole
• Capillaries in Bowman’s capsule

Gross Anatomy of Kidney

• Located in retroperitoneum
o Upper pole – opposite 12th thoracic vertebra
o Lower pole – opposite 3rd lumbar vertebra
• Normal: 11 cm in length
o Adult male: 125-170 gm
o Adult female: 115-150 gm
• Hilus: renal artery and vein, lymphatics, nerve plexus and renal pelvis
• Brick-red surface, generally smooth
o Occasionally tiny cysts that form
o Some may have persistence of fetal lobulations from early kidney development
• Translucent capsule – retracts easily in normal state but in inflammatory state (chronic
pyelonephritis) becomes thickened and fibrotic
• Renal parenchyma
o Cortex – tan-brown: 1.2-1.5 cm
o Medulla – broken into 8-18 striated conical segments = renal pyramids
 Base of pyramid: corticomedullary junction
 Apex of pyramid extends towards pelvis – forms papilla
 Single pyramid + overlying cortex = lobe
 Outer zone
• Outer stripe: pars recta (terminal straight portions of proximal
tubule)
• Inner stripe: TALH and collecting tubules
 Inner zone = papilla
• Collecting ducts, thin limbs and loops of Henle and vasa recta
• Surface of papilla – 10-25 small openings (area cribrosa) = distal
ends of collecting ducts
o Medullar rays: collecting tubules, pars recta and TALH
 Faint striations from medulla to cortical surface
• Calyces receive urine

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Blood Supply
• 0.5% of total body weight and 25% of cardiac output
• Cortex receives 90% of renal circulation
o Medulla receives only 10% of renal circulation and at lower pressures relative to
cortex
 Prone to papillary necrosis – sickle cell anemia, analgesic abuse
• Renal artery divides into branches – segmental arteries – interlobar arteries (course
between renal pyramids) – give rise to arcuate arteries at corticomedullar junction –
interlobular arteries (straight course to periphery)
o Cortical tissue between two interlobular arteries and contains a central medullary
ray = kidney lobule
o Interlobular arteries give rise to afferent arterioles – each supplies 1 glomerulus
o Afferent arteriole enters glomerular tuft and forms 20-40 capillary loops
o Efferent arterioles of superficial cortical nephrons leave glomerular tuft and form
rich vascular network of interstitial capillaries that encircle cortical tubules
o Efferent arterioles of deeper (juxtamedullary) nephrons give rise to vasa recta
which descend as straight vessels to supply medullary tubules
o Vascular supply of tubules = postglomerular
 Glomerulus disorder (acute glomerulonephritis/glomerulosclerosis) will
reduce amount of blood reaching efferent arteriole and hence cause
secondary damage to the tubules and interstitium by reducing the blood
supply
• End-arteries without interanastomoses
o Vasculitis/hypertension = damage to vessels of kidney
o Profound ischemic effects upon glomeruli and tubules, leading to
glomerulosclerosis and tubular atrophy

Cortex made up of glomeruli and numerous tubules

Two groups of neprhons
• Inner – glomeruli near C-M junction
• Outer – near outer region of cortex

Proximal tubule
Pars recta
Thin limb of Henle
TALH
Distal convoluted tubule
Collecting duct
• Medulla: vasa recta (capillaries), thin limbs and collecting ducts
• Inner stripe of outer medulla: MTAL and collecting duct

Major Compartments of Kidney

1. Glomerulus = filtering unit of nephron – 1 million per kidney
a. Glomerulus disease – immunologically mediated
b. Glomeruli surrounded by proximal tubules

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c. Very inapparent interstitium: only seen when expanded by edema, inflammation
d. Glomerular tuft = capillary inside Bowman’s space
e. Macula densa = specialized portion of proximal tubule – next to arterioles
(vascular poles)
f. Each kidney has 2 million nephrons – minute but designed to maximize surface
area
g. Cellular components
i. Glomerular endothelial cell
1. GBM defines each individual capillary
2. 1 per capillary
3. Deep to capillary = mesangial cell
4. Nucleus and cell body close to mesangium
5. Highly fenestrated epithelium
6. Glomerular capillary wall: type IV “spider” collagen
a. Large interstices ideal for filtering capillary wall
b. Forms chicken-wire mesh
c. Allows for loose association of lamin and heparan sulfate,
concentrated in laminae rarae
d. Impart net negative charge to capillary well – restrict
passage of negatively charged proteins, like albumin
e. Discriminates between molecules based on size and charge
7. Three main substructures
a. Lamina rara interna
b. Central lamina densa
c. Lamina rara externa
8. Filtration slit diaphragm – bridges pore between foot processes
a. Consists of “anatomic zipper”
b. Each delimits a pore = 40 x 140 angstroms
c. Albumin = 36 angstroms
d. If produce antibody to nephrin, localizes just to area of
filtration slit diaphragm
e. If mutated = congenital nephrotic syndrome
i. Babies develop proteinuria in utero
f. Contribute to 50% of resistance of glomerular capillary
wall
g. Very important for size selectivity
ii. Mesangial cell – specialized smooth muscle cell
1. Actin-myosin filaments that tether GBM: forms microtendons
2. Hold mesangial angles firm against outside forces
3. Continuous with smooth muscle in afferent and efferent arteriole
4. Control anastomoses between afferent and efferent arterioles
5. Two arteriole system designed to maintain high pressures in
capillary bed = driving force for filtration
6. Supports ramifying capillary bed
7. Surrounded by matrix
8. Normal state – shouldn’t have more than 3 mesangial cells in
cross-section

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 9. In response to AII, mesangial cells close off anastomoses between
capillary beds
10. Contraction – PLC, release of Ca2+: inflammatory and fibrogenic
cytokines
a. Important in glomerulonephritis
11. Relaxation – cAMP, cGMP
12. Also have monocyte liked features: able to phagocytoses
a. May be important in glomerulonephritis
b. Autocrine/paracrine system
iii. Visceral epithelial cell (podocyte)
1. Outside of capillaries – line internal aspect of urinary space
2. Large cells
3. Foot process = insert onto GBM
4. Neighboring foot processes come from different cells –
interdigitating system
5. Critical for balancing high hydrostatic pressure of glomerular
capillary
6. Contractile elements within podocyte
7. Receptors for vasoactive agents
8. Glycoprotein 330 – present on surface of clarthrin coated pits
a. Antigenic domain
b. Formation of immune complexes
iv. Parietal epithelial cell – lines outside of Bowman’s space
1. Bowman’s capsule reflects internally onto glomerular tuft and is
continuous with GBM
h. Glomerular filtration = K x A [Hydrostatic pressure – Oncotic pressure]
i. K = permeability, A = surface area
1. Maximize surface area for filtration
ii. Glomerular capillary hydrostatic pressure = 40-50 mmHg
iii. Glomerular capillary oncotic pressure = 15-25 mmHg
iv. Bowman’s space hydrostatic pressure = 10-15 mmHg
v. EFP = 10-15 mmHg (effective filtration pressure)
vi. Mesangial cell – able to fine tune system by altering surface area available
for filtration: close and open capillary beds
1. Glomerulotubular feedback
i. Efferent arteriole
i. Juxtamedullary nephron – breaks into rete mirabile which feeds blood to
tubules: tubules receive post-glomerular circulation
1. Any disease that effects glomerulus will reduce amount of blood
getting to efferent arteriole and cause ischemia in tubules
2. Interanatomic dependence
ii. Internephron – arteriole courses down as vasa recta – closely paired to
tubules
1. Interstitial capillaries – low pressure system for absorption of
filtrate
2. Tubules: disease – toxic, ischemic
3. Interstitium – disease also toxic or ischemic

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 4. Blood vessels – kidneys receive 25% of cardiac output
a. Cortex – high pressure system
i. Cortical arterioles vulnerable to hypertension
b. Medulla – low pressure system: papilla vulnerable to necrosis
c. Hypertension and intravascular coagulation: thrombotic microangiopathies
d. Renal artery does not piece kidney directly
e. Segmental branches – divide into interlobar arteries
f. As they reach corticomedullary junction, arch = arcuate arteries
g. Straight segments = interlobular arteries
h. Afferent arterioles arise from here
i. Each glomerulus receives blood from single afferent arteriole – no anastomoses to
protect glomerulus from injury: can develop glomerulosclerosis, tubular atrophy
and interstitial fibrosis – interdependence
j. Final common pathway of many different renal diseases = “end stage kidney”

ACUTE RENAL FAILURE

• Acute renal failure occurs when there is an abrupt decline in GFR
o Rapid deterioration in renal function reflected by rise in urea and creatinine
 Normal BUN (blood urea nitrogen) < 20 mg/dl
• May rise by 10-20 mg/dl per day
 Normal Creatinine < 1.2 mg/dl
• May rise by 1-2 mg/dl per day
o Azotemia - high level of nitrogenous waste products in blood due to failure of
kidney’s excretory ability
o Uremia – severe multiorgan system disease caused by inability of kidney to
excrete waste products
o Caused by:
 Decreased renal perfusion (pre-renal azotemia)
 Damage to components of kidney (intrinsic acute renal failure)
 Obstruction of outflow of urine from kidney (post-renal azotemia)
• Acute Tubular Necrosis – most common cause of intrinsic acute renal failure
o May result from nephrotoxic or ischemic damage to kidney
o Decrease in GFR that results may be due to:
 Tubular obstruction
 “Back leak” of filtrate
 Afferent arteriolar vasoconstriction
 Alterations in glomerular permeability to passage of filtrate
• As kidney function declines (reflected by decreasing GFR), need to lose 50% before see
change in serum levels of substances e.g. creatinine
• Creatinine – filtered but not absorbed in secreted – rises with decreasing GFR
• Acid – kidney can compensate for acid very efficiently
• K – doesn’t change until very end

Steady State and Glomerular Filtration Rate (GFR)

• Creatine released by muscle – coverted to creatinine
• Good way to measure GFR

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 • Plasma creatinine concentration x GFR = Urine creatinine concentration x urine
volume
• GFR = Urine Creatinine Concentration x Urine Volume
Plasma Creatinine
• Sudden decline in GFR – serum creatinine will rise and urine creatinine will drop
o New steady state: serum creatinine elevated but urine creatinine more normal

Acute Renal Failure

Epidemiology of ARF
• Rapid worsening of renal function (days) – acute decline in GFR
• Oliguria: urine output < 400 cc/day
o 400 ccs necessary to excrete body’s daily waste products
o Non-oliguric patients – better outcome and less fluid and electrolyte problems
o Anuria < 100 ml/day
• No real change in mortality over past 50 years
o Obstetric renal failure – much less common
o Medical causes have gone up – ventilators, IV antibiotics and IV pressors
• 19.4% mortality with ARF – 7.2% of those admitted to hospital
o As creatinine goes up, mortality rate rises as well

Etiology of ARF
• Pre-renal (hemodynamic) – cut off blood supply to kidney
o Drop in BP or vasculature catastrophe
o Extracellular volume depletion characterized by overt or postural hypotension,
decreased venous pressure, decreased skin turgor, dry mucous membranes,
decreased sweating
 Intravascular volume depletion
• Due to loss of body fluids: hemorrhage, GI loss (diarrhea),
sweating and renal losses
• Due to sequestration of body fluids outside vasculature: burns,
ascites, pancreatitis, crush injuries
 Decreased renal perfusion due to vasodilation
• Sepsis, antihypertensive medication
 Heart failure – cardiomegaly, S3 gallop rhythm, neck vein distention, rales
on lung auscultation and edema
o Other cause:
 Hepatorenal syndrome – advanced liver failure
• Prerenal azotemia
• Kidneys are morphologically normal – work ok in transplant
• Slow and steady decline in kidney function
• Mortality 100%
• Complete drop in kidney blood supply – intense vasoconstriction
causing decrease in RBF and GFR
• Urine sodium very low – kidneys absorbing a lot of Na

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 • Portal hypertension – splanchnic vasodilation – drop in arterial
filling, setting up vasoconstrictive mechanism – leads to renal
vasoconstriction
• Treatment: splanchnic vasoconstriction
 Prevention of compensation:
• NSAIDS – constriction of afferent arterioles and drop in GFR due
to inhibition of PGE production in conditions of avid salt retention
(heart failure, cirrhosis, nephrotic syndrome) or chronic reduction
in GFR
• ACE Inhibitors/ARB – take away squeeze in efferent arterioles by
blocking AII; abrupt decline in GFR in patients with renal artery
stenosis and volume-depleted patients with chronic GFR reduction
o Renal vasoconstriction and increased Na absorption are hallmarks
o When blood pressure going to kidney drops, kidney resistant to losing function
 Renal blood flow remains constant between 60-160 mmHg
o Higher plasma blood flow = high filtration rate
o In volume depletion or heart failure, decrease in RBF > than decrease in GFR
 Due to constriction of efferent arterioles (AII)
 Increase in filtration fraction (GFR/RBF)
 Increase in protein concentration of post-glomerular peritubular
capillary
 Therefore, increased resorption of Na and water in proximal tubule
because absorption of fluid from proximal tubule is related to protein
concentration of peritubular capillary
o Dilation of afferent arterioles – better pressure going to glomerulus (PGEs)
o Often with oliguria
 Renal vasoconstriction and increased filtration fraction associated with
increased absorption of salt in proximal tubule
 Aldosterone sercretion also stimulated – increased resorption from
collecting ducts
 Urinary salt excretion will be very low – important for diagnosis
o BUN – normally 10-20 mg/dl
 More fluid than normal is absorbed due to increased filtration fraction
 Concentration of less permeable solutes rises in lumen of proximal tubule
 Increase in concentration = increase in driving force for reabsorption of
solutes
 Also, the slower the flow rate in the distal nephron, the more urea is
absorbed
 Also, increase expected from decrease in GFR
 More than would be expected just from GFR
• Plasma creatinine inversely proportional to GFR
• Normal blood urea: creatinine ratio = 10-15:1
• Pre-renal azotemia: 20:1
• Intra-renal (parenchyma)
o Vascular
 Thrombotic microangiopathy

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 • Fibrin deposition in microvasculature
• Intravvascular hemolysis, thrombocytopenia and organ dysfunction
• Associated disorders: malignant HTN, HUS/TTP, scleroderma
renal crisis, preclampsia, drugs (cyclosporine, tacrolimus,
mitomycin, clopidrogel) – toxicity to endothelial cells leading to
fibrin depositon (local activation of coagulation cascade)
• Differential diagnosis: DIC – abnormal coagulation profile
 Atheroembolic disease
• ARF precipitated by angiography
• Often eosinophilia and low complement
• Multi-organ dysfunction, livedo reticularis, blue toes
• Generally irreversible – low inflammatory pathways leading to
fibrosis
o Glomerular
 Rapidly progressive glomerulonephritis
• Inflammation of glomerular capillary walls
• Usually immune phenomenon
o Immune complexes deposited in glomerulus – post-
infectious, SLE, IgAN, SBE, cryoglobulinemia
o Antibody against glomerular basement membrane
o Vasculitis producing necrosis and inflammation –
Wegner’s, microscopic PAN
• Key: urine – significant proteinuria, RBC, RBC casts
• Systemic findings
 Crystal induced ARF
• Crystals – poorly soluble in urine unless well hydrated
• If don’t pick up diagnosis, can cause permanent kidney damage
• Uric acid (tumor lysis)
• Oxalate (ethylene glycol) - antifreeze
• Methotrexate
• Acyclovir
• Sulfonamides
• Indinavir
• Phospho Soda – Fleet’s enema
o Interstitial
 Acute Interstitial Nephritis
• Triad of fever, skin rash and eosinophilia – sign of allergy; rising
creatinine
• Eosinophiluria
• Drugs: penicillin, cephalosporins, diuretics, NSAIDS, dilantin
• Usually completely reversible upon withdrawing drug
• ? glucocorticoids
o Tubular
 Acute Tubular Necrosis – most common

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• Tubular cells damaged – leads to kidney failure
o Concentrating ability of tubule is defective
o Isothenuria – urinary sodium concentration high
o BUN will be normal (no increased reabsorption of Na and
water)
• Any patient with prolonged ischemia to kidney
o Prolonged and severe decreased renal perfusion
o May follow hypotensive episodes during anesthesia,
surgery or other traumatic events
o Ischemia may cause decrease in permeability of glomerular
capillary filter, decrease in GFR for any given driving force
o May also cause tubular cell necrosis
 Flattened necrotic epithelium
• Depletion of intracellular glycogen
• Clumping of nuclear chromatin
• Swelling of ER
• Mitochondria swell
• Swelling, decrease in pH and accumulation
of intracellular Ca
 Sloughed necrotic cells in lumen – intra-renal
tubular obstruction
 Leakiness of tubule caused by ischemic damage -
interstitial edema compresses tubule, aggravating
obstruction
• Persistence of GFR decline may involve RAS
o ATN – high plasma renin levels
o Excessive delivery of salt to macula densa increases renin
production of juxtaglomerular cells
o Very high local levels of AII produce afferent arteriolar
vasoconstriction and decreases GFR
• Endogenous toxins – hemoglobin (mismatched blood transfusion),
myoglobinuria, light chains (clone of plasma cells – myeloma)
• Exogenous toxins – antibiotics (gentamycin), IV constrast,
chemotherapy, organic solvents, heavy metals
• Clinical: severe oliguria followed by period of increased urine
output and gradul improvement in GFR
o May not be oliguria, especially with drugs – associated with
lower morbidity and mortality
• Radiocontract nephropathy
o Risk factor: diabetic nephropathy, CRI, multiple myeloma,
pre-renal azotemia (renal hypoperfusion)
o Onset of oliguria within 24 hours
o Peak creatinine in 4-5 days followed by recovery in
majority
o Urine sodium concentration and FENa have been low (20

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 mEq/L and < 1 %), implicating vasoconstriction
o Differential diagnosis: atheroembolic disease
o Development of new constrast agents with lower osmotic
load (nonionic contrast)
• Heme pigment
o Intravascular hemolysis – hemoglobin released into plasma
o Trauma
o Decline in hematocrit, absence of serum haptoglobins,
elevated LDHG and urine positive for “blood”
o Mechanism uncertain: vasoconstriction, precipitation etc.
o Biggest risk factor = volume depletion
o If aggressively hydrate, may prevent ARN
• Myoglobulinuria
o Massive rhabdomylosis associated with trauma or nonn-
traumatic, crush injuries
o Tender swollen limbs or fascial compartments, dehydration
and dark urine
o Large increases in plasma levels of uric acid, K and
phosphorous (depression in Ca)
o Tremendously elevated levels of plasma muscle enzymes
(creatinine phosphokinase and aldolase)
o Dipstick positive for heme and myoglobin in urine
• Aminoglycosides
o Progressive azotemia in face of high urinary sodium
concentration and FENa and preserved urinary volume
o Dose-related, incidence depends on clinical setting
o Onset several days after treatment
o Recovery usually complete within 3 weeks if recognize
problem and stop drug
o Monitor drugs levels and kidney function
o Progressive volume expansion (due to oliguria) can be very bad
 In the past, most patients with ATN died with severe volume overload
o Danger of hyperkalemia with ATN
 Regulation of plasma K concentration dependent on high efficiency with
which kidney excretes K – flow rate very important
 The higher the flow rate, the more K is excreted
 Intracellular K is also released by diseases associated with tissue injury
(surgery, trauma, rhabdomyolysis or ischemia_
o Uremic Syndrome
 Patient in hypercatabolic state with rapid turnover of proteins
 Neurological abnormalities: confusion, convuolsions, coma
 Metabolic abnormalities: acidosis
 Low resistance to infection, defective coagulation state
• Post-renal (obstructive)
o Back-up of pressure – prevents kidney from functioning
o Consider obstruction in every patient with ARF

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 o Sites of obstruction leading to ARF: bladder neck obstruction (most common –
due to prostate enlargement) and bilateral ureters
 Renal stones and prostatic hypertrophy = common causes
o Leads to increase in hydrostatic pressure above obstruction
 Increase in intratubular pressure and pressure in Bowman’s space will
decrease net ultrafiltration pressure, leading to decreased GFR
 Increase in hydrostatic pressure in collecting system
• Permeability of tubule to sodium increases
• Prevents tubule from decreasing luminal sodium concentration to
minimal level
• Also, rate of active sodium absorption is decreased throughout
nephron
• Increased salt excretion
• High urinary salt concentration in presence of oliguria is typical
of post-renal azotemia
o If obstruction is bilateral (bilateral ureteral renal stones or prostatic hypertrophy),
there will be anuria
o Ureteral obstruction associated with influx of macrophages and T lymphocytes
into kidney – production of thromboxane by cells may modulate part of changes
in hemodynamics and GFR
o Urine volume variable
o Diagnosis: renal USG or bladder catheterization

• Top Five Causes of ARF

o Decreased renal perfusion
o Medications
o Radiographic constrast media
o Postoperative
o Sepsis

• Acute vs. Chronic Renal Failure

o Previous creatinine
o Chronic symptoms: nocturia, foamy urine
o Small kidneys on USG
o Renal osteodystrophy – evidence of bone damage on x-ray
o Broad casts on urine analysis – if acute renal failure, no time for kidney to
undergo hyperplasia

• Pre-renal ARF vs. ATN

o Pre-renal: kidneys functionally normal – urine Na levels very low
o Damaged kidney (ATN) – waste urine Na; can see how well kidneys can
concentrate urine
• Urine Microscopy
o Red cell casts: glomerular disease
o WBC casts: interstitial inflammation – allergic nephritis

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 o Muddy casts: ATN
o Broad casts: chronic renal failure

Treatment and prevention

• Supportive care
o Acid-base/electrolyte balance
o Fluid balance
o Nutrition
o Review of drugs
o Dialysis: HD, PD, continuous modalities
• Indications for dialysis:
o Volume overload
o Hyperkalemia
o Metabolic acidosis
o Uremia
o Pericarditis
o Bleeding – uremia effects platelet function and can cause bleeding
o (Intoxications)

Course and Outcome of ATN

• If don’t die, good prognosis
• Over 80% of survivors have normal renal function

Pathogenesis of ATN: GFR Effects

• Drop in glomerular filtration
• Afferent arteriolar constriction – drops perfusion
• Cells dying – obstruct flow of urine
• Cells dying – leakage of filtrate
• Tubuloglomerular feedback – in distal nephron, sense leakage of Na
o Sends signal to juxtaglomerular apparatus
o Shut down kidney to retain salt
• Reactive oxygen species
o Source: xanthine dehydrogenase, NADH oxidase
• Preventive strategies
o Hydration
o Bicarbonate
o N-acetyl cysteine
o Isoosmolar constrast
• Nothing shown to reverse ATN

VOLUME REGULATION

• Marked volume depletion can lead to hypotension and shock

• Extreme expansion of intravascular volume causes transudation of salt and water into
interstitial space, resulting in edema

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Remember that volume and tonicity are separate and distinct – analyze separately

Objectives
• Volume regulation is a function of salt content regulation
o Water accounts for 60% of body weight
o If regulate only water content without changing salt content, result = fluctuations
is osmolality with consequent deleterious changes in cell volume
o Regulating salt content by adjusting amount of NaCl excreted regulates
extracellular volume
o Thirst and kidney’s regulated excretion of water maintain serum osmolality within
narrow limits
• Edematous states reflect pathophysiology of salt content regulation
• Mechanisms of normal volume regulation mediate pathophysiology of edematous states

Clinical Case Presentation

• SOB, DOE, Fine respiratory rales present in both lung bases – pulmonary edema
• Rheumatic fever – etiology of CHF
• Pedal edema, increase in abdominal girth and body weight – peripheral edema
• Why edema? – increase in weight, not just mere redistribution
o Not just water – if water, would be massive dilution
o Gain of fluid = gain of salt
o Concentration of salt (Na = 140) – remains basically the same
o Volume = content, NOT tonicity
 CHF: salt content increases dramatically
 Adding/subtracting of water = tonicity regulation

70 kg subject
• Total body water – 42 L – 60% of body weight
o 2/3 intracellular
o 1/3 extracellular 14 L – kidney regulates volume of extracellular space by
regulating salt content
 2/3 interstitial 9 L
 1/3 intravascular

Congestive Heart Failure

• Salt driven expansion of ECF volume
• Intake exceeded excretion
• NaCl and water retention
• Why edema?
• Why ECFV expansion?
• Why Na retention?
• Why is renal salt excretion impaired? = fundamental question

Change in circulation volume stimulates change in Na excretion

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 • In steady state, renal salt excretion = salt intake
• Sharp increase in input: intake > excretion until reach new steady state
o Positive balance – net gain of salt
o 1 liter of water to dilute 9 grams of salt – weight rises by 1 kg
o Retention of water – smaller output of concentrated urine
o On each successive day of higher intake of Na, smaller fraction of dietary intake
retained as excretion of Na progressive increases over 3-5 days to match new
intake
• High sodium diet: higher intake = higher excretion
• Sudden decrease in intake: negative salt balance continues for several days
o Lose 1 liter of water to maintain tonicity

Summary: change in dietary salt intake, introduction of new NaCl source (such as IV fluids) or
development of new NaCl losses (as from vomiting or diarrhea) results in change in NaCl
content since initially salt excretion is unchanged
• Change in NaCl content leads to change in water content via mechanisms that regulate
osmolality
• Change in volume is sensed (afferent limb) and effector mechanisms (efferent limb)
change NaCl excretion until net input matches net ouput = new steady state

If water intake changed and dietary Na constant

• If water intake increases, water output increases rapidly
• Tonicity alterations not well tolerated – body responds promptly

Volume = salt content issue

• Salt determines volume status of patient

• Change in dietary salt intake

o Oral, IV
o Vomiting, diarrhea
• Change in Na content since initially urine Na is unchanged
• Change in extracellular volume
• Change in volume sensed (afferent limb)
• Change in urinary salt excretion by efferent limb that re-establishes steady state

Review of Normal Physiology

Afferent Limbs – decreased extracellular volume

Stretch receptors detect volume change associated with change in NaCl content
• Renal volume receptors
o Juxtaglomerular apparatus – sensor that releases renin when perfusion pressure
reduced: AII activated, reducing salt excretion
• Peripheral vascular volume receptor
o Carotid/aortic arch – increased sympathetic outflow
o Increased sympathetic tone of renal vasculature decreases salt excretion

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 o Renal sympathetics and catecholamines released from adrenal medulla stimulate
renin release
• Atria – decreased atrial natriuretic peptide (ANP)
o Released from secretory granules
o ANP: increases NaCl excretion and peripherally vasodilates

Efferent limbs – act to change salt excretion

Glomerular hemodynamics affect proximal tubular reabsorption
• 140 mEq/L x 200 L/day = 28,000 mEq/day of Na
• We filter but reabsorb almost everything
• Capillaries – hydrostatic pressure extrudes filtrate
• Efferent arteriole branches into peritubular capillaries around proximal tubule

• Normal
o GC: glomerular filtration driven by [hydrostatic pressure – oncotic pressure] x
constant
 Protein left behind at higher and higher concentration – increasing oncotic
pressure which opposes hydrostatic pressure
 When hydrostatic pressure = oncotic pressure – filtration pressure
equilibrium
o PTC: oncotic pressure > hydrostatic pressure
 Resistance vessel = efferent arteriole – lower hydrostatic pressure in
peritubular capillary than in glomerular capillary
 Because of filtration pressure equilibrium, peritubular capillary oncotic
pressure will be high – greater than hydrostatic pressure
 Oncotic forces in peritubular capillary favors reabsorbtion of fluid from
extracellular space of tubules
• GFR/RBF = filtration fraction
• Volume depletion – cardiac output decreases
o Increase in AII after renin increases: constriction of efferent arteriole
o GC: raise hydrostatic pressure
 Renal plasma flow falls because of increased resistance
 Reach filtration pressure equilibrium earlier
o PTC: efferent arteriole has increased tone – greater drop in pressure
 Also oncotic pressure still high
 Enormous gradient for reabsorption
• GFR preserved at expense of increased filtration fraction – concentration of protein
greater

Proximal Tubule
• Leakiness of tubular cells – cannot maintain large gradients of concentration or electrical
potential
• Resorption of filtered fluid occurs by active transport of sodium from tubule lumen into
peritubular space
• Na and water travel down concentration gradient into cell

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 • Active transport of Na and passive following of water into intercellular space
o Local hypertonicity of this area
o Can return to tubular lumen
o Starling forces: volume depletion with high peritubular oncotic pressure
 Increased driving force for reabsorption: higher protein concentration and
lower hydrostatic pressure than normal capillary
 Determines balance between back leak and reabsorption
Note: significant decrease in GFR associated with Na retention

RAS
• Angiotensinogen converted to AI by renin – released from JGA in response to
hypotension or to extracellular volume depletion in absence of hypotension
o Beta-adrenergic innervation, PGE2, low plasma K and increased Na delivery to
macula densa also stimulate renin release
• AI converted by ACE to AII
• AII
o Peripheral vasoconstriction
o Aldosterone release
o Thirst
o Sympathetic
o Ion transport

Angiotensin II conserves Na
• Constricts efferent arteriole
o Increases glomerular capillary hydrostatic pressure
o But flow if decreased due to increased resistance – GFR unchanged
o Lower RBF results in filtration pressure equilibrium at earlier point in glomerular
capillary = decreased area of filtration
 GFR little changed despite increased pressure
 GFR = Kf [Hydrostatic pressure – Oncotic pressure]
 Kf = area x permeability
o Since RPF is decreased, FF increased = increased albumin concentration in
peritubular capillary
 Normal FF = 25%
o Therefore, increased peritubular capillary oncotic pressure
o Proximal tubule Na resorption increases
o Increased reabsorption of salt and water will result in higher concentration of
many solutes in tubular fluid, such as urea
 If these solutes are also slightly resorbable, they will diffuse out of tubule
to a larger extent that normal
 BUN will rise to higher level than simply predict by reduction in filtration
rates – elevated BUN: creatinine ratio
• Increased proximal tubule Na transport - increased activity of NaH exchange
• Increased aldosterone by stimulation of zona glomerulosa of adrenal cortex
o Aldosterone also stimulated by elevated K and ACTH
o Increase in number of open Na channels in luminal membrane

16
 o Since cell sodium is low, increased permeability will lead to increased entry of
sodium and consequently increased exit at basolateral surface via Na-K ATPase
which is also sitmulated by aldosterone
o Increased distal Na reabsorption – 50-100 mEq/day
o Small amount but amount that normally escapes reabsorption – critical effect on
renal salt excretion
o Absence of aldosterone (Addison’s disease): patients develop negative salt
balance with severe salt depletion and shock unless intake compensates

Sympathetic outflow
• Activation of sympathetic NS leads to salt retention
• Vasoconstriction of afferent arteriole – decreases RBF and GFR: retain salt
o Similar to pre-renal azotemia
• Renin and subsequent angiotensin II release
• Direct effect on Na reabsorption – local release of adrenergic hormones

Atrial Natiuretic Peptide

• Released from atria in response to volume overload with atrial distention or after atrial
tachyarrhythmias
• Peripheral vasodilator
• Inhibits renin, aldosterone release
• Decreases afferent arteriolar tone
• Increases GFR and amount of Na available for excretion
• Redistributes renal blood flow (in dogs)
• Decreases distal Na reabsorption (terminal collecting duct)

Natriuretic Hormone
• Inhibits Na transport by mechanism similar to digitalis: binding to and inhibiting NaK
ATPase
• Role unclear

Endothelium-derived relaxing factor

• EDRF synthesized and released from endothelial cells = NO
• Potent vasodilator
• Effect on GFR not known

Endothelin
• Released from endothelial cells
• Potent vasoconstrictor and enhances aldosterone release

Autoregulation
• Minimal effect of renal artery pressure on renal blood flow and GFR
• Myogenic reflex to maintain pressure
Tubuloglomerular Feedback
• Inverse relationship of single nephron GFR distal to nephron (macula densa) perfusion

17
 rate
• When a lot of salt appears in nephron, reduction in GFR – conserve salt
Glomertubular Balance
• Proportional relationship between amount of Na delivered to segment and absolute Na
reabsorption

Volume Regulation in Disease

• Mechanism of salt excretion frequently deranged in disease – mostly excessive salt
retention
• Patients on normal diet fail to excrete daily salt intake – develop expansion of
extracellular volume = edema
• Either failure to filter (acute and chronic renal failure) or excessive tubular reabsorption
(congestive heart failure, cirrhosis and nephrotic syndrome)

Application of insights to pathophysiology of edema in CHF

1st phase
• Ligature at vena cava – simulates CHF: low flow state ~ acute MI
• Sudden decrease in cardiac function
• Drop in pressure – harbinger of shock
• Afferent limb: sympathetic outflow – increase in HR
o Renin activity increases – AII and aldosterone also increase
• Efferent limb: increased reabsorption of salt due to efferent arteriolar vasoconstriction
o Filtration fraction always elevated because decline in RBF > decline in GFR
o This is major cause of salt retention in congestive heart failure
• Also effect of aldosterone, but patients with Addison’s who have severe myocardial
damage can develop edema, indicating that proximal mechanism for Na retention is
sufficient
• Extracellular volume expands (interstitial edema) – plasma volume rises
o Indication of plasma volume increases: hematocrit falls
o Weight rises due to retention of salt and water
o Drops to lower Starling curve
 Increased intravascular volume - Increased LVEDP (improved position on
Starling curve with improved CO)
 May lead to pulmonary edema
2nd phase
• Increased extracellular volume restores cardiac output and arterial filling to near normal
levels
• Sympathetic outflow decreases with increased volume
o HR decreases
o Renin, aldosterone decreases
o Urine salt excretion starts to rise – new steady state
o Volume expansion persistent – improves position on Starling curve
o Weight stays up
• New MI

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 o Worse Starling curve – no amount of fluid retention can suppress afferent/efferent
limb
o Perpetual salt retention – never re-establish steady state
o Give diuretic – increase salt excretion and may bring back into balance
3rd phase
• Cure – heart transplant
• HR, renin, aldosterone goes down
• Excretion of retained salt – drop in weight due to negative salt balance

Renal Mediated Volume Disorders

• Edematous states
o GFR derangement – e.g. toxic ATN
 Renal failure
o Tubular reabsorption
 CHF, cirrhosis, nephrosis
• ECF depleted states
o Hypoaldosteronism – can’t handle last mEq of sodium
o Osmotic diuresis (DM) – large flux of glucose carries with it salt/water
o Diuretic abuse
o (not diarrhea – kidney will put out low amount of salt)
Pre-renal state:
• Urine sodium
o Glimpse into how salt being processed
o Low in conditions where renin/AII/aldosterone high
o Fooled: defect in salt handling – e.g. patient with CHF who takes diuretic
• BUN/creatinine ratio
o Elevated: indicates efferent arteriolar tone and FF increased
o Back-leak of BUN – not available for excretion
o Proxy for AII elevation
o Can also be raised by: GI bleeding, glucocorticoid excess causing muscle
breakdown
o Possible to be pre-renal and not have elevated ratio – starving for protein

Cirrhosis
• Cirrhosis uniformly associated with disturbances in salt excretion and subsequent
development of edema and ascites
• Disruption of normal liver architecture with consequent obstruction to flow of portal
blood through liver and activation of hepatic volume receptor
• Most likely, defect one of increased intraheptic pressure (e.g. in sinusoids)
• Kidney retains Na but GFR, RBF, renin and AII all normal – must be distal mechanism
• Total plasma volume increased – but capacity of splanchnic bed is larger in cirrhotics
than in normal individuals
• If extrasplanchnic plasma volume is depleted or effectively depleted due to vasodilation
and increased capacity, then mechanism for salt retention is the same as that induced by
simple extracellular volume depletion

19
 • If plasma volume is increased, salt retention is “primary” – simple, uncomplicated
cirrhosis
• As cirrhosis advances,
o Progressive portal hypertension contributes to excessive transudation of fluid into
peritoneal cavity
o Synthetic function of liver deteriorates – serum albumin concentration falls – low
oncotic pressure results in transudation of fluid into interstitial space
o Vasodilation occurs with severe hepatic failure = effective extrasplanchnic plasma
volume depletion
o Volume depletion from any of these causes would promote salt retention by
increase in AII and aldosterone

Summary of Edema and Ascites

• Imbalance of hydrostatic and oncotic forces across relevant capillary membranes
• Initial volume expansion (increased hydrostatic pressure) in cirrhosis favors transudation
= edema and ascites
• Portal hypertension – further increase hydrostatic pressure
• Albumin enters ascitic fluid: decrease in oncotic pressure increases ascites
• Hypoalbuminemia results in a general decline in oncotic pressure, contributing to
transudation of both ascites and peripheral edema
• Transudation results in volume depletion etc.

Nephrotic Syndrome and Glomerulonephritis

• Immunologic injury to glomerulus results in proteinuria and salt retention
• If proteinuria is severe = nephrotic syndrome
o Heavy proteinuria (> 3 grams/day)
o Hypoalbuminemia
o Edema
o Hypercholesterolemia
o Common causes = lipoid nephrosis, typically seen in children
 GFR normal
 Increase in glomerular permeability to protein
 Hypoalbuminemia results from excess protein excretion
 Plasma oncotic pressure reduced and plasma volume reduced because of
transudation
 Elevation of renin, angiotensin and aldosterone
• Also patients with nephrotic syndrome with normal/expanded plasma volume and low
renin
o Retain salt – may be primary salt retention causing expansion
o Inability to excrete salt load = common in advanced glomerulonephritis

Interaction of AII and Prostaglandins

• In patients with extracellular volume depletion or with edematous disorders, treatment
with NSAIDS results in salt retention and renal failure
• Inhibit PGE synthesis, which antagonizes effect of AII on efferent arteriole

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 • Without PGE, RBF falls, FF rises and GFR will fall too if AII high enough
o Result = salt retention

PHARMACOLOGY DIURETICS

Diuretics
• Inhibitors of sodium reabsorption – saluretics, not aquaretics
o Entry into cell – down electrochemical gradient
 Na channel or Na coupled solute carriers
o Exit into blood by Na:K ATPase – located in basolateral membrane of renal
tubular cells
 Inhibits by cardiac glycosides digoxin and ouabain
• May be called “water pills”
• Rapid increase in salt excretion – associated with loss of weight (only if salt intake does
not change)
• Used to treat salt-retaining states: CHF, cirrhosis, renal failure, salt-sensitive hypertension
and severe head trauma

Consequences on extracellular volume of failure to remain in salt balance

• Severe salt-retaining state, urine sodium < 10 mEq/day
• 70 kg person has 15 L of extracellular volume
• Average American consumes 6 grams (250 mEq) of Na per day
• Equivalent of 1.9 L of isotonic NaCl
• Even a “no salt” diet – 2 grams Na = 87 mEq Na = 600 mls isotonic NaCl
• Failure to maintain salt excretion equal to intake leads to rapid accumulation of salt and
water and thus inevitably to volume overload
• Treatment of volume overload must focus on both intake and outputs

Sodium absorbed in every segment of nephron

• PCT – 60-80%
• TALH – 15%
• DCT – few %
• CD – remaining %

Proximal Tubule
• Leaky epithelium – site of reabsorption of 70% of glomerular filtrate
• Most of lumen transported out of lumen via co and counter-transporters
• 20% of filtered Na resorbed during process of bicarbonate reabsorption
• Na enter cells by Na+:H+ exchange
• Part of acidification mechanism of kidney – requires presence of carbonic anhydrase
o Present in cytoplasm: converts CO2 and H2O to H2CO3, which splits into HCO3
and H+
 H+ pumped out into tubular lumen via Na:H exchanger
 HCO3- pumped out into blood via HCO3:Cl exchanger
o Present in luminal membrane

21
  When hydrogen ion secreted, interacts with HCO3 in tubular fluid to be
converted into CO2 and water
o Carbonic anhydrase inhibitors – derived from sulfonamides
 Acetazolamide
 Absorbed orally, readily filtered
 Inhibit both forms – inhibit H+ secretion – lose NaHCO3 in urine
 Increases delivery of NaCl and NaHCO3 out of PCT
 Weak diuretics – Na may be reabsorbed more distally
 Rarely used clinically as diuretics
 Used for correction of high HCO3 (metabolic alkalosis) in blood
• In general, treatment of underlying condition more efficient
 Also used for treatment of glaucoma because the formation of aqueoud
humor by ciliary processes is dependent on activity of carbonic anhydrase
• Inhibition of carbonic anhydrase = reduction of intraocular pressure
 May cause metabolic acidosis
• However, efficacy of drugs reduced in setting of metabolic acidosis
– limits severity
• Dumped into intracellular space
• Drawn into peritubular capillary – oncotic pressure in peritubular capillary important
regulator of Na reabsorption
• Mannitol – also works in proximal tubule = osmotic diuretic
o Sugar that is filtered by glomerulus but not reabsorbed by tubule
o Osmotically active agent: hold water in tubule
o Promote free water clearance more than transport inhibiting agents
o Administered IV – used following head trauma to reduced intracerebral swelling
o Osmotic diuresis – more important as pathological condition (diabetes)
 Saturation of glucose transport capability of proximal tubule
 Glucosuria leads to polyuria – often presenting complaint

TALH – thick ascending limb of loop of Henle: 10-20% of filtered Na

• Transporter on luminal membrane: Na:K:2Cl forced into cells
• K channel which allows K secretion into lumen
• Membrane of TALH generally impermeable to water – two essential functions:
o Can generate dilute urine because absorb Na but not water
o Generate hypertonic medulla – also necessary condition for concentrating urine in
collecting duct in presence of ADH (absorb water in collecting duct)
• Furosemide, bumetanide and ethacrynic acid – inhibit cotransporter
o Oral absorption and protein bound in plasma
o Readily filtered
o Secreted by proximal tubule organic acid transporter – can give small doses:
concentration of diuretic in proximal tubule and TALH will be higher than in
blood
 Inhibited by probenecid
• Inhibits Na:K:2Cl cotransporter
o Highly effective because distal tubule has relatively limited ability to increase its

22
 Na resorption
o Inhibits dilution and concentration of urine (see above)
 By preventing Na and Cl from making medulla hypertonic, reduce ability
of collecting duct to absorb water from filtrate to make concentrated urine
 Loop diuretics promite isosomotic diuresis, limiting abilutty of medullary
collecting duct to respond to volume depletion
 Results in loss of additional 1-2 L of water
 Makes it easy to over-diurese patient
o Promote Ca and Mg excretion – also absorbed in TALH
 May lead to symptomatic hypocalcemia and hypomagnesemia (often
missed because not rountinely measured)
 Hypercalcemia can be treated with saline hydration and forced diuresis
with loop diuretics
o Cause vasodilation and venodilation – especially following IV administration
 Immediate efficacy in acute treatment of pulmonary edema even prior to
initiation of diuresis
• Causes:
o Volume depletion – hypovolemia: excess diuresis – results in pre-renal
azotemia
o Hypokalemia
 Loop diuretics block K absorption
 Aldosterone stimulation from hypovolemia also contributes – increased
urine flow from isomotic diuresis creates potential for K wasting
o Metabolic alkalosis: consequence of volume depletion
 Increased AII and aldosterone
 Aldosterone + hypokalemia promote increased H+ secretion
 Metabolic alkalosis results – can be corrected by reversing hypokalemia
and volume depletion
o Hearing loss: seen with very high doses
o Allergic interstitial nephritis

Bartter’s Syndrome: genetic disease resembling chronic Furosemide use

• Chronic volume depletion: postural hypotension
• High renin and aldosterone
• Metabolic alkalosis
• Mutations in one of following genes:
o NKCC: furosemide-sensitive Na:K:2Cl co-transporter
o ROMK: K channel
o CLC-Kb: chloride channel

Distal Tubule
• TSC: Na:Cl co-transporter – thiazide sensitive: early part of distal tubule
• Mild diuretics because DT only responsible for small amount of filtered Na
• Gentle – preferred for chronic diuretic use
• Oral absorption, readily filtered
• Secreted by organic anion transporter in proximal tubule

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 • Inhibits NaCl cotransporter (TSC) in distal tubule
o Increases delivery of NaCl out of distal tubule
 Less pronounced effects vs. loop diuretics because less sodium is
reabsorbed in distal tubule and . . .
o Inhibits dilution but not concentration of urine
 Preventing ability to remove NaCl – action of drug
 In order to effect concentration, medulla must be effected
 Distal convoluted tubule is in cortex but not medulla – doesn’t contribute
to concentration of medulla
 Patient can compensate as volume depletion develops by concentrating
urine
o Decreased calcium excretion: may be due to Na:Ca exchangers or may be due to
Ca channels requiring hyperpolarization of cells: decreased Na concentration
• Can cause:
o Volume depletion: mechanism of action
o Hypokalemia: K excretion dependent on collecting duct
 Increased flow of urine in collecting duct = increased excretion of K
o Glucose intolerance and hypercholesterolemia: rare – mechanism unclear
o Hyponatremia
 Act on diluting segment – inhibit ability to form dilute urine
 Do NOT inhibit ability to concentrate urine – necessary for formation of
hyponatremia
 Restricted free water clearance + salt restriction and free water intake –
may result in severe hyponatremia
 May be due to volume depletion, which increases ADH
o Less likely to cause metabolic alkalosis because they are less potent and therefore
less able to induce hypovolemia
o Decrease renal excretion of calcium but enhance magnesium excretion
 Used to treat patients with hypercalciuria and recurrent calcium salt renal
caliculi

Gitelman’s Syndrome: genetic disease resembling chronic thiazide use

• Mild volume depletion
• Hypocalciuria
• Hypomagnesiuria
• Mutations in TSC

Collecting Tubule – site of action of aldosterone

Two cell types:
• Principal cell
o Na absorption: ENaC – epithelial Na ion channel
 Amiloride sensitive
 Na passes down electrochemical gradient into distal tubular cells
 Pumped out of cells via Na-K ATPase
o Water absorption: Aquaporin 2 – influenced by ADH
o K secretion: ROMK

24
 • Intercalated cell
o H transport: H+ ATPase

Amiloride/Triamterene
• Oral absorption
• Readily filtered
• Inhibits ENaC – block channel from apical side
o Normally, ENaC makes lumen negative vs. cell
• Reduces lumen negative membrane potential which results in:
o Inhibition of H+ secretion
o Inhibition of K+ secretion
 Can’t be pulled into lumen by negative potential
• Can cause hyperkalemia

Aldosterone action in collecting duct

• Binds to MR
• Increases opening of ENaC and K channel
• Increases activity of H+ ATPase
• High aldosterone associated with increased Na absorption and volume overload
• Low aldosterone associated with hyperkalemia, acidosis, decreased Na absorption and
volume depletion

Spironolactone
• Aldosterone antagonist
• Oral absorption
• Readily filtered
• Competes with aldosterone for binding to its receptor
• Reduces activity of ENaC and H+ ATPase
o Since most of salt has been reabsorbed before this segment, these drugs are only
moderately effective diuretics
• Reduces lumen negative membrane potential
o Inhibition of H+ and K+ secretion
• Can cause hyperkalemia – potassium sparing
o Main site of K+ excretion
o Can be combined with other diuretics to modify their hypokalemia
• Primary agent in treatment of ascites due to hepatic cirrhosis
o Fluid retention due in part to secondary hyperaldosteroneism due to decreased
hepatic metabolic of aldosterone

Hyperaldosteronism
• Volume depletion or heart failure
• Treatment with aldosterone antagonists improves survival of patients with heart failure
• Mild hyperkalemia may be protective?

Complications of Diuretic Use

25
 • Diuretics cause increased salt excretion and hence excessive use results in ECF volume
depletion
• Volume depletion causes increased renin, AII and aldosterone which can lead to
hypokalemia, metabolic alkalosis and hyperuricemia (???)

• Specific complications
o Acetazolamide – metabolic acidosis by inhibiting carbonic anhydrase
o Thiazides can cause hypercalemia by increasing Ca absorption may cause
hyperglycemia
o Loop diuretics - hearing impairment and increase Ca excretion in urine

Resistance to Diuretics
• If increase dose of diuretic, initial increase in salt excretion and then stop responding
• During prolonged use of loop diuretics, increased delivery of Na to more distal segments
in conjunction with increased aldosterone levels results in hypertrophy of sodium
transport epithelium downstream from loop
o More sodium reabsorbed distally
o Can administered drug combination
• Decreased delivery
o Excessive diuresis results in volume depletion, causing high renin, AII and
aldosterone
o High AII increases filtration fraction and stimulates NaCl absorption in proximal
tubule, thereby reducing amount of Na delivered to site of action of diuretics
o Most diuretics relatively rate: effect 1-2% of transport rate
o If amount of fluid decreased, won’t be able to get much diuresis
o High AII – also high aldosterone level: will be more reabsorption in collecting
duct
o Can treat by using diuretics that work more distally as well

Vasopressin
• Synthesized in supraoptic and paraventricular nuclei of hypothalamus
• Secreted from neurohypophysis
• Secretion closely regulated, mainly by plasma osmolarity
o Osmoreceptors in neurohypophysis monitor osmolarity
o Rises in osmolarity trigger ADH secretion
o Other stimuli for secretion: severe hypotension and nausea
• Binds to V2 receptor in collecting tubule
• Increases production of cAMP
• Increases water permeability of apical membrane = greater water resorption
• Causes fusion of vesicles containing aquaporin 2 with apical membrane
• Absorb water and excrete concentrated urine
• Also potent vasoconstrictor stimulating rise in blood pressure
• Rising ADH levels also stimulate thirst
• New drugs – aquaretics
o Block vasopressin receptor

26
 o Allow dilute urine to be excreted

Disorders of ADH
1. Diabetes Insipidus - polyuria with inability to concentrate urine
a. Neurogenic DI: failure to secrete ADH
i. Therapy: synthetic analog of ADH (desmopressin)
ii. 1200 x the antidiuretic activity but only 0.4 x the vasopressor activity
iii. More selective V2 receptor agonist and longer duration of action
iv. Cannot be administered orally: sensitive to trypsin
v. Administed intranasally or parenterally
vi. Can be administered 1-2 times/week to control polyuria
vii. Side effect: free water intoxication and hyponatremia due to inability to
excrete free water
b. Nephrogenic DI: failure of kidney to respond to ADH
i. Develop water wasting leading to volume depletion and hypernatremia
ii. Hyperosmolarity stimulates thirst and patient drinks to replete losses,
avoiding further dehydration
iii. Patient’s osmolarity then reset to that of thirst threshold
iv. Treatment: salt restriction and thiazide diuretics – reduce urine volumes by
> 50%
v. May induce mild salt depleted state which stimulates increased proximal
resorption of glomerular filtrate
vi. Less volume delivered to proximal tubule, reducing volume excreted
2. Inappropriate ADH secretion
a. Result in development of hyponatremia and hypo-osmolarity
b. Secretion of ADH may be excessive but “appropriate and regulated” given
underlying pathology (heart failure, cirrhosis)
c. ADH may also be uncoupled from regulatory processes = syndrome of
inappropriate ADH secretion (SIADH)
i. Associated with cancers, pulmonary diseases and CNS disorders
d. Hyponatremia is life-threatening
e. Correction: slow infusion of hypertonic saline accompanied by loop diuretics to
avoid volume overload
i. If renal failure, hemodialysis necessary
f. Therapy
i. Water restriction: 500-1500 cc/day
ii. Demeclocycline – tetracycline derivative can be used to induce
pharmacologic nephrogenic DI
1. CI in patients with cirrhosis
2. Inhibits stimulation of cAMP induced by vasopressin in renal
tissue
3. Prevents ADH induced increase in water permeability in collecting
duct, reducing water reabsorption and increasing water excretion

NEPHROTIC SYNDROME

Nephrotic syndrome

27
 • Heavy proteinuria (> 3-3.5 g/day)
o Normal: 150-200 mg/day
o Actually, 1 g of protein (low MW) in present in the glomerular filtrate in
Bowman’s space
o Final urinary concentration only 100 mg due to ability of tubules to reabsorb 90%
of filtered protein
o Proteinuria is responsible for other metabolic consequences
o Mild glomerular injury: highly selective proteinuria (just albumin)
o More severe damage: nonselective proteinuria
• Hypoalbuminemia – due to urinary loss
• Edema
o Fluid shift from vascular to interstitial space as a result of reduced oncotic
pressure of plasma
o Exacerbated by increased renal retention of salt and water because of stimulation
of RAS by low effective renal plasma flow
• Hyperlipidemia
o Liver responds to decreased oncotic pressure by increased protein synthesis of
protein, including albumin and lipoproteins
o Lipiduria – lipoproteins filtered
 Can be detected by examination of urinary sediment for
• Refractile lipid bodies (maltese crosses)
• Fat-filled casts (oval fat bodies)
o Increased atherosclerosis
• Hypercoagulability – due to increased fibrinogen and factors 5, 7, 8 and 10 and urinary
loss of antithrombin III
• Infections – hypogammaglobulinemia due to urinary loss of IgG
• Altered drug metabolism – albumin is important depot for host of drugs; prone to OD
• Negative nitrogen balance, malnutrition, stunted growth

Etiology of Proteinuria
• Damage to GBM
o Defective glomerular filter can permit increased permbeality to proteins the size
of albumin and larger
o All disorders causing nephrotic syndrome have pathology at this level
o Proteinuria can be extreme (> 20 gm/day)
• Damage to tubules
o Tubulo-interstitial diusease (pyelonephritis or allergic interstitial nephritis) may
o Proteinuria rarely exceeds 1-2 gm/day
• Increased plasma concentration of low-molecular weight proteins
o Multiple myeloma: increased amounts of light chain proteins produced by
neoplastic plasma cells freely filtered because of their low MW
o High concentration – overwhelms ability of tubule to reabsorb
o Also seen secondary to massive necrosis of muscle = myoglobinuria

28
Proteinuria
• Most common: albuminuria
• > 3 grams/day
• Strong detergent – frothy
o Add acid – causes precipitate
• Oval fat bodies in urine: tubular cells that have tried to reabsorb protein
• Maltese cross appearance
• Prevalence in proteinuria: > 300 mg/day – 10.6% of population
• Prevalence of microalbuminuria: 30-300 mg/day – 1.1%
o Function and age and disease (diabetes, hypertension)
• Both size and charge are important barriers to filtration
• Prognostic implications of persistent proteinuria:
o Causes decline in kidney function over time
• Why does high level of protein excretion lead to kidney failure?
o Physical damage to kidney
o Protein in glomerular space causes podocyte malfunction and loss of
microvascular endothelium
o Lead to production of cytokines that lead to scarring = glomerulosclerosis
o Protein also causes damage at level of tubulointerstitial disease
 Activation of complement at surface of tubular cells
 Attract leukocytes and neutrophils to interstitium
 Pro-inflammatory, pro-fibrotic system
 Leads to tubulointerstitial fibrosis – single most important predictor of
progressive kidney failure

Hypoalbuminemia
• Due to proteinuria and increased albumin catabolism in pro-inflammatory state of
glomerular disease
• The lower the albumin, the more symptomatic – edematous

Edema
• May present with facial (children) or lower extremity (adults) edema
• If serum albumin low = low onoctic pressure – leak fluid into interstitial space
• Increased Na retention (primary) – high hydrostatic pressure
• Altered permeability of endothelium

Hyperlipidemia
• Liver very sensitive to low oncotic pressure
• Liver responds by reeving up production of all proteins, including lipoproteins
• Loss of LPL in urine

Other Manifestations
• Hypercoagulability
o Loss of anticoagulants like ATIII in urine
o Platelets very sticky

29
 o Increased fibrinogen
• Infections: hypogammaglobulinemia
• Altered drug metabolism due to hypoalbuminemia
• Malnutrition due to protein loss

Treatment Principles
• Treatment of primary disease
o Immunosuppressive therapy
 Corticosteroids
 Chemotherapy
 Antimetabolites
 Cyclosporine/Tacrolimus
o Immunomodulators
 Anti-complement (MAC)
 IV Ig
 Levamisole
• Symptomatic treatment
o Diuretics for edema
o Anti-hyperlipidemic agents
 Statins
 Bile acid binding resins
 Ezetimibe
o Anticoagulants
o Dialysis for acute renal failure
• Reduction of proteinuria/slowing progression
o Blood pressure reduction
 Higher mean arterial pressure = worse kidney function (lower GFR)
 Need to be aggressive: 130/85
o Inhibition of RAAS
 ARBs
 ACE inhibitors – very powerful and important agents in treating
proteinuria
• Greater drop in protein = less decline in GFR
• Basis of damage from AII
o Efferent arteriole sensitive to AII
o Diabetic nephropathy – release of AII with hyperglycemia
o Hyperfiltration – elevated intraglomerular pressure
o Sets into motion pro-fibrotic cytokines (NFKB etc.)
o Result: scarring

Nephrotic Syndrome: Etiology by Age

• Primary nephrotic syndrome
o Minimal change disease: highly steroid responsive
 > 90% of patients under 4 years
 Treat with steroids before biopsy
o Focal segmental glomerulonephritis

30
 o Membranous glomerulonephritis
• Adult age group: not able to predict based on age
o First to renal biopsy, then treat accordingly

Case 1. Minimal change disease

• 8 y.o. child with swelling of eyes and ankles
• 4+ proteinuria, BUN and creatinine normal
• Albumin low (2.2 g/dl), serum cholesterol high (400), 24 hour urine protein 6.0 g/day
• Peak incidence between 2-6 years
• Characterized by abrupt onset of nephrotic syndrome with higher selective proteinuria
(albumin)
• Course is non-progressive – typically remitting and relapsing but steroid responsive
o Used to be called lipoid nephrosis – kidneys looked filled with lipid
o Saw lipid in tubules – actually, tubular lipid is nonspecific finding due to
nephrotic syndrome and lipiduria
o Also known as Nil disease and childhood nephrosis
o Lipiduria is by-product of liver’s response to hypoalbuminemia leading to
hyperlipidemia
o Can’t see anything wrong with glomeruli by light microscopy
o No evidence of immune deposits by immunofluorescence
o EM: no electron dense deposits
o Pathogenesis:
 Podocytes undergo effacement or fusion
 Highly differentiated foot process architecture is lost
 Swath of cytoplasm over surface of capillaries
 Loss of filtration slit diaphragms – large vesicles in podocytes because
water needs to get through; protein also gets through this way
• Circulating factor acting as toxin to podocyte – this toxin is not known
o Animal model: puromycin aminonucleoside nephrosis
o Primary defect = charge-selective barrier to protein filtration
o Theoretically due to either
 Reduction in anionic sites in lamina are interna and externa (at level of
heparan sulfate proteoglycans)
 Reduction in sialoprotein coat (glycocalyx) on surface of podocytes
 Either would lead to reduction in glomerular capillary wall’s negative
charge
 Reduced electrostatic barrier to negatively charged proteins (albumin)
• Evidence for immunologic derangements
o Viral infections may precede onset or recruescences
o May follow recent immunizations
o Altered in vitro response to mitogens
o Circulating lymphocytotoxins
o Low IgG, elevated IgM
o Atopy
o Increased HLA B-12

31
 o Association with Hodgkin’s disease and other lymphoproliferative disease
• Current theory: lymphokines or other soluble lymphocyte products may act at a distance
to increase glomerular permeability – permeability factor toxic to podocytes?
• Most cases are idiopathtic
o Occasionally may be due to drug reaction in response to NSAIDS
• Treatment and course
o Prednisone 1 mg/kg
o Furosemide prescribed for edema
o 3 weeks later: patient edema-free
o Urine dipsticks for protein negative
o Predinisone tapered and stopped by third month
• 80% of remission in first 4 weeks in children, by 16 weeks 99%
• If don’t go into remission, focal segmental sclerosis
• Adults: 60-70% go into remission by 2 months

Case 2. Focal segmental glomerulosclerosis (FSGS)

• 19 y.o. female college student gains 12 lbs. and has lower extremity edema.
o Can be seen in any age group
o Most common cause of primary nephrotic syndrome in African-American adults
o Accounts for < 10% of nephrotic syndrome
• Physician finds 4+ albuminemia
• Labs
o Creatinine 1.0 mg/dl
o Albumin 2.0 mg/dl – quite low
o Cholesterol 425 mg/dl – high
o 18 g proteinuria/day – very high
o Serologic tests negative
• Corticoid treatment without improvement
o Idiopathic - may occur secondary to permeability factors ~ minimal change
disease
• Renal biopsy
o Sclerosis = collagenization of glomerulus
o Focal = involving some glomeruli and not others
o Segmental = only part of glomerular tuft
o Is this progression of minimal change disease or different disease?
 Related but in many patients can present as separate entities from outset
 FSGS progresses to renal failure (not steroid responsive), higher incidence
of nonselective proteinuria, hematuria, hypertension
 Time course to renal failure = 5-15 years (mean)
o Sclerosis – term used to described collagenization involving GBM (collagen IV)
o Closes down capillaries – secondary loss of filtration
o Often hyaline deposists (entrapped plasma proteins) in areas of sclerosis
o Can spread to involve entire glomerular tuft
o Immunofluorescent staining: IgM and complement (C3) – not pathogenic for
disease, but gets trapped in areas of sclerosis

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 o ECM: collapse of GBM, overlying podocytes severly damaged: foot process
effacement and detatchment – heavy proteinuria that is less selective
o Global sclerosis – loss of efferent arteriolar blood supply will effect tubules
o Permeability factors – not well characterized
o Not all patients have primary focal sclerosis (no underlying etiology)
 Can also be pattern of renal injury that occurs in variety of settings
 Renal agenesis – hyperfiltration in solitary kidney: can progress to
sclerosis over time
 Reflex nephropathy – lose renal mass; hyperfiltration in remaining
nephrons
 Any chronic renal disease
 Obesity – overworked kidney: discordance between body mass and renal
mass
• Loss of functioning nephrons leads to increased glomerular capillary volume
o Elevated glomerular capillary pressures and flow rates = hyperfiltration
o Increased capillary pressure and radius (compensatory glomerular hypertrophy)
o Leads to microaneurysms
o Segmental capillary collapse and mesangial sclerosis
o Visceral cell detachment and progressive glomerular sclerosis
• HIV-associated nephropathy (also associated with heroin use) – secondary form
o Caused by HIV infection of visceral epithelial cells
o Leads to collapsing form of sclerosis – retraction of glomerular capillary walls and
marked visceral cell hypertrophy
o Also severe tubulointerstitial damage with formation of tubular “microcysts”
 Make the glomeruli largers
o More rapid time course to renal failure (2-4 months)
o HIV-1 may be infecting podocytes and tubular epithelial cells
• Treatment of Idiopathtic FSGS
o Immunosuppression can work for some patients
o Steroids – less than 50% respond; many of these are pediatric
o Cyclosporine
o Cyclophosphamide
o Mycophenolate
o Plasmapheresis – for very severe disease; can lead to sharp reduction in
proteinuria
o Symptomatic – furosemide and atorvastatin, lisinopril, low dose steroids and
cyclosporine
o Protein remained at 10-15 g/day
o Creatinine began to increase
o Receive living donor transport
o Relapse – started plasma exchange: factor in recipients body (permeability factor)
effecting donor kidney

Case 3. Membranous glomerulopathy

• 67 Caucasian male develops ankle edema and weight gain
• 12 g proteinuria

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• Albumin 1.4
• Cholesterol 635
• GFR normal
• Most common cause of nephrotic syndrome in Caucasian adults
o Peak incidence in 5th decade
o Presents with insidious onset of proteinuria (often associated with nephrotic
syndrome)
 Renal insufficiency may develop in chronic stages
o Serum complements normal; no evidence of elevated circulating immune
complexes
o 25% remit, 50% have persistent proteinuria and 25% progress to renal failure
o No proliferation or inflammatory cell infiltration of glomerulus
o Diffuse and global thickening of membranes seen in H & E – all glomeruli are
affected uniformly
o Due to basement membrane spikes
o Between spikes, presence of deposits – stain with IgG and C3
o EM: each deposit = electron-dense immune deposits
 Subepithelial – beneath visceral epithelium
o GBM very leaky to protein
o Overlying podocytes have foot process fusion – mantle of cytoplasm formed over
deposits (nonspecific ultrastructual finding seen in glomerular proteinuria of many
etiologies_
o Foot process effacement with transport vesicles and podocyte hypertrophy
 Increased transport of protein and water in droplets within visceral
epithelial cytoplasm
o Immune-mediated disease
• Pathogenesis:
o Most cases are idiopathtic/primary – 60%
o Infections: hepatitis B and C, secondary and congenital syphilis, malaria,
schistosomiasis
o Drugs: gold, penicillamine, captopril
 May be able to reverse by stopping drug
o Collagen vascular disease: SLE, Hashimoto’s thyroiditis, rheumatoid arthritis
o Neoplasia: carcinoma – lung, breast, colon and stomach
 May remit if carcinoma resected
• Etiology in humans in unknown
• Model = Heymann Nephritis
o Fractionated material from renal cortex – proximal tubular and brush border
antigens
o Would cause rats to develop nephritis – serum from these animals could cause
nephritis in other animals
o Develop antibody to gp 330; this antigen is from the brush border of tubule cells –
also cross-reacts with identical antigen presence on base of foot processes in
clathrin-coated pits
o Antigen-antibody complexes form in situ
o These are capped and shed into surface of subepithelial space, forms subepithelial

34
 deposits – give rise to same granular pattern of staining as in human disease
o Complement important for injury
 Immune complexes activate complement – C5b-C9
 Secondary podocyte activation leads to generation of reactive oxygen
species and proteases by podocyte
 Lipid peroxidation and damage of GBM
 Leads to altered permeability and proteinuria
o In secondary forms of membranous glomerulopathy (SLE, infections), antigen is
most likely non-glomerular
 Formation of subepithelial deposits in secondary membranous
glomerulopathy may be favored by presence of cationic antigen which has
affinity for negative charge sites in glomerular capillary wall
• Post-biopsy course
o All serologic tests normal
o Normal colonoscopy and CT abdomen/chest
o 3 days after admission, develops dull back ache and then becomes acutely short of
breath
o Chest x-ray normal
o ABG: pH = 7.45, pCO2 = 30, pO2 = 60 on room air
 Normal x-ray with hypoxia = pulmonary embolism
o CT angiogram requested
o Multiple branches of pulmonary vein filled with clots
o From dislodged renal thrombosis
Renal Vein Thrombosis
• Dangerous complication of nephrotic syndrome – seen almost exclusively in patients with
nephrotic sundrome due to membranous glomerulopathy
o Rarely associated with FSGS and amyloidosis
• Any nephrotic patient is hypercoagulable – very common
• May be unilateral or bilateral, acute or chronic
• If gradual, there may be no overt clinical manifestations related to kidney but on
angiographic studies, increased collateral venous cirulcation
• Acute renal vein thrombosis – flank pain
o If severe, may be hematuria, hemorrhagic infarction and rupture of kidney
o Treat patient with heparin followed by warfarin
o Patient given furosemide and low Na diet
o Atorvastatin added
• Treatment of membranous nephropathy
o Clinical course variable
 20-30% spontaneous remission rate
 60% renal survival at 15 years
o Predictors of poor prognosis
 Persistent proteinuria
 Reduced GFR
• If persistent proteinuria, institute immunosuppressive therapy
• Patient refused steroids – treated with cyclosporine and mycophenolate

35
 • 6 months later, urine protein excretion = 1.0 g/24 hours
o Cyclosporine tapered and stopped
o Continued on MMF, ramipril and atorvastatin
o Warfarin discontinued

Case 4. Diabetic glomerulosclerosis/nephropathy

• Most common cause of nephrotic syndrome worldwide – most common renal disease
leading to dialysis and transplantation
• Type 1 DM since 19 – 38 y.o, woman
• Severe retinopathy and multiple admissions for labile blood sugars
• Proteinuria – 3.2 grams
• Serum creatinine 1.5 mg/dl
• 22 lb weight gain and pitting edema to thighs
• BP 160/102 – uncontrolled
• Fundus exam – proliferative diabetic retinopathy
o Progressive thickening of capillary and arteriolar basement membrane
(microangiopathy) – present in every organ; greatest in retina and kidneys
o Increased in matrix material throughout all compartments of kidney
o Thickening of GBM, mesangial matrix and Bowman’s capsule
o Thickening of vessel walls – arteriosclerosis and arteriolar hyalinosis
o Affects all glomeruli equally and all parts of glomerular tufts
o Intercapillary sclerosis
o May be diffuse diabetic glomerulosclerosis
 Glomeruli normal in cellularity
 Diffuse thickening of GBM
 Uniform mesangial sclerosis (expansion of mesangial matrix)
 Altered glomerular capillary walls abnormally permeable to proteins,
leading to proteinuria and nephrotic syndrome
o Similar to nodular diabetic glomerulosclerosis
 Mesangial sclerosis can be even more pronounced – nodular sclerosis
 Nodules can give rise to glomerulocapillary microaneurysms (dilation of
glomerular capillaries, similar to process in retina)
 Kimmelstiel-Wilson disease
 Can encroach on capillary lumen – progression to global sclerosis
 Weakening of GBM where reflects of mesangium
 Retinopathy and nephropathy tend to develop together
 Hyaline material frequently forms in sclerosing glomeruli in both forms
• Insudation of plasma proteins into thickened BM
• Appear as waxy, homogeneous, eosinophilic material containing
focal lipid droplets
o Increasing severity of glomerular and vascular lesions eventually leads to
progressive interstitial fibrosis and tubular atrophy
o EM: not immune complex mediated
 Metabolic disorder causing thickening basement membrane and mesangial
sclerosis

36
  Membranes thick but abnormally permeable to plasma proteins
• Can occur in both type I and II DM
o Occurs in 50% of patients with both types of disease
• Pathogenesis
o Thickening of basement membranes in glomerulus, renal tubules
o Similar mechanism to retina, muscles, arterioles, Schwann cell membranes
(neuropathy), heart and major vessels – premature atherosclerosis and
cardiomyopathy
• Basic defect = non-enzymatic glycosylation of basement membrane
o Can also occur in non-structural proteins: hemoglobin A1c
o Formation of advanced-glycosylation end products (AGEs)
o Accumulation of circulating plasma proteins – defective mesangial clearing and
mesangial sclerosis
o Decreased sialic acid content – more cationic charge of GBM – proteinuria
o Increased disulfide bonding in GBM collagen – decreased GBM thickening and
increased synthesis – GBM thickening
• Major cause of end stage renal disease
o Kidney can be nearly normal size – increased laying down of matrix material that
expands volume despite loss of function
• Type 1 Diabetes
o Patients predictably present in ketoacidosis
o Stage 1: Early supranormal filtration through kidney glomerulus – high GFR due
to AII
 Mesangial expansion
o Stage 2: laying down of protein – GFR returns to normal
o Stage 3: microalbumin assay can detect problem – level of protein excretion rises:
insipient nephropathy
 Microalbuminuria
o Stage 4: urine protein levels rise and GFR decreases
 More sclerosis – overt proteinuria with declining kidney function
o Stage 5: dialysis/renal transplant
 End-stage kidney may be nearly normal in size – increased quantity of
basement membrane material laid down in all compartments of kidney
• 1/3 of patients with diabetes get microalbuminuria
o 1st manifestation – appears 10 years after onset of DM
• 1/3 of these get diabetic nephropathy
o Hypertension and renal insufficiency usually don’t develop until 20-30 years after
onset
• Can’t reverse once proteinuria starts – role of aggressive intervention
o Overt nephropathy: hypertension control, ACEIs/ARBs – slow progression of
kidney damage
• Treatment
o Furosemide and thiazide
o Pravastatin
o Reduction of proteinuria – ramipril

37
 o Over 6 years – hemodialysis; needs kidney transplant

Armanni-Ebstein lesion
• Frequently found at autopsy in juvenile-onset diabetics dying of ketoacidotic diabetic
coma
• Clearing of cytoplasms of pars recta of proximal tubule as a result of marked glycogen
deposition
• Rarely seen today with improved blood glucose control

Important Renal Complications of DM

• Pyelonephritis and papillary necrosis
• Diabetics have increased incidence of kidney and other UTIs
o Altered immunity
o Increased thickness of GBM (interfering with leukocyte migration)
o Increased incidence of UTI due to neurogenic bladder
• Papillary necrosis
o Often complicates pyelonephritis in diabetics
o Both arteriosclerosis and diabetic glomerulosclerosis may reduce blood supply to
papillary tips, making them more vulnerable to ischemia and necrosis

Case 5. Amyloidosis
• 66 y.o. housewife with severe rheumatoid arthritis for 22 years develops edema
• Labs:
o 9 g proteinuria/day
o Serum creatinine 1.2 mg/day
o Serologic tests negative
o Creatinine clearance of 100 cc/min – intact
• Biopsy:
o Deposition of eosinophilic amorphous material within glomerular tuft
o Deposits composed of 10-12 nm randomly oriented nonbranching fibrils
o Mimics FSGS in appearance but paler than normal matrix material
o Deposits first within mesangium – over time obliterates glomerulocapillary
lumena
o Diagnostic stain: congo red stain – dye that reacts with amyloid because of beta-
pleated sheet conformation
o Can also involve tubular basement membranes and vessels
o Polarize congo red stain: apple-green birefringence
o EM: amyloid = fibrils that obliterate GBM
o Glomerular architcture completely destroyed, leading to proteinuria and nephrotic
syndrome
o RA: precursor protein = SAA protein – acute phase reactant produced by liver
o All types of amyloid looks the same – can only differentiate by staining for
precursor protein
o Can include non-fibrillar protein (AP) – minor component
 Derived from normal circulating glycoprotein

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 • Dysproteinemias
o Primary AL – precursor proteins = light chains
o Multiple myeloma, B cell lymphomas, Waldenstrom’s macroglobulinemia, occult
plasma cell dyscrasia
• Longstanding inflammatory or infectious states
o Secondary AA – precursor proteins = SAA-protein
 Partially degraded by circulating monocytes
 Susceptibility to amyloidosis may depend on genetically determined
ability of monocytes to degrade SAA to intermediate sized peptides,
resistant to further enzyme degradation
o Usually inflammatory or infectious chronic diseases that have been going on for
years
o TB, leprosy, chronic heroin addiction, chronic osteomyelitis, paraplegia, chronic
bronchiectasis, cystic fibrosis, rheumatoid arthritis (5-10% of patients), familial
Mediterranean fever, psoriasis, IBD, ankylosing spondylitis
• End-stage kidneys normal sized despite loss of function
• Treatment
o Block production of abnormal protein – anti-TNF therapy for RA
o Reduction of proteinuria: ACEI
o Diuretic for edema

TONICITY

• Alterations in tonicity result in fluctuations in cell volume

o Interferes with cell function, especially in CNS
o Complications: impairment mentation to coma and death
• Tonicity is highly regulated

Objectives
• Serum sodium concentration is a function of water content
o Water is freely permeable through most cellular membranes
o NO osmotic gradients between fluid compartments (except in renal medulla)
o Osmotic pressure ~ serum [Na]
o Under most circumstances, normal [Na] reflects normal osmolality
o NOT function of salt content
• Hypo and hypernatremia reflect pathophysiology of water metabolism
o Hyponatremia – salt content may be high, low or normal but water content always
high
• Mechanisms regulating normal water metabolism mediate pathophysiology of hypo and
hypernatremia
o Tonicity: balance of free water input vs. free water output
o Only renal free water output is regulated
o Free water input = oral + IV
o Free water output = cutanous + respiratory insensible losses + renal
o Water intake and non-renal output highly variable

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  Thirst: stimulated by increased osmotic pressure but also by non-osmotic
stimuli (hypotension, plasma volume depletion – may stimulated despite
presence of hypo-osmolarity)
 Insensible loses increase with increased ambient temperature, fever or
extensive skin damage (burns)

• CHF case
o Serum Na concentration = 128 mEq/L = hyponatremia
o Why did this patient develop hyponatremia?

• 70 Kg subject
o Total body water = 42 L
 2/3 = intracellular (28 L)
 1/3 = extracellular (14 L) – contracted in diarrhea and expanded in CHF
• Volumes do NOT give any information about concentrations
• Can be hypo or hypernatremic in either case
• Volume determined by salt content
• Concentration determined by water balance
o Should NOT be in same paragraph!
• 2/3 interstitial (9 L)
• 1/3 intravascular (5L)

• Extracellular volume of normal subject

o Euvolemic – held constant
o Physiologic response to hypernatremia
o Mammals – response is NOT loss of Na, response = gain of water
 Stimulation of thirst and decreased excretion to dilute
 Water modulating mechanisms engaged by change in Na concentration

Tonicity and Serum [Na]

• Cell membranes are freely permeable to water
• No osmotic gradients exist between fluid compartments
• Tonicity of intravascular compartment reflects tonicity of all fluid compartments
• Calculated serum osmolality is given by
[Na] x 2 + [K] x 2 + [glucose]/2 + [BUN]/2.8
140 x 2 + 4 x2 + 90/18 + 12/2.8 = 297
Equation dominated by serum Na
• Diabetes: glucose can be very high
o DKA, hyperosmolar coma
o Osmolality will NOT just be determined by Na
o Hyperosmolar yet hyponatremic secondary to hyperglycemia
• Urea – passes through membranes: unless sudden change (dialysis), urea will not be
important osmotically
• Potassium compatible with life never varies enough to make a difference
• Hyperlipidemia – serum Na concentration measured in water; decreased amount of blood

40
 volume is aqueous = pseudohyponatremia

Free Water
• [Na] reflects balance of water relative to salt
• Water input and output must be assessed but again relative to salt input and output
• Concept of Free Water
o 1 L Half Normal Saline = ½ L Normal Saline + ½ L salt-free water
o Normal saline = isotonic to normal body concentration

Determinants of Tonicity
• Free water intake vs. free water excretion + free water losess
• Intake: oral, IV
• Losses: respiratory, cutaneous – increased by surgery, increased temperature, burns
• Excretion: regulated volume of urine
o Large volume of dilute urine or small volume of concentrated urine

Mechanisms of Free Water Handling: this is very important!

• Large volume of dilute urine: need normal filtration to deliver volume to collecting duct
o Distal Delivery
 Need GFR: creatinine increased with reduced GFR
 CHF: RAS activation – efferent arteriolar tone and FF increased: proximal
tubular reabsorption increased – less delivered distally: relative ability to
excrete large volumes of dilute urine reduced
• BUN:creatinine ratio – increased reflects increased FF etc.
 Na reabsorption in TALH but don’t get dilute urine until distal tubule
 This solute reabsorption in TALH establishes magnitude of medullary
concentration gradient = driving force of water reabsorption from
collecting duct
o Elaboration of dilute urine
 Cortical diluting segment: beginning of distal tubule
• Tonicity reduced to 1/3 of plasma levels
o Excretion of dilute urine
 Volume of hypotonic fluid reaching collecting duct ~ 25 L/day
 Also need impermeant collecting duct – prevent urine concentration
• Small volume of concentrated urine
o Concentrated medullary interstitium
 Need good ascending limb function
o Permeable collecting duct to resorb water
 If collecting duct fully permeable to water and medullary concentration
gradient undisturbed, water is maximally reabsorbs and small volume of
concentrated urine excreted (500 mls at 1200 mOsm/L)

Determinant of water handling at collecting duct = Vasopressin/ADH

• Synthesis in PVN and supraoptic nuclei and storage in neurohypophysis

41
 o ADH, through cAMP-mediated mechanism, inserts or unplugs small pores in
luminal membrane of cortical and medullary collecting duct, leading to increased
water absorption
• Regulated by osmoreceptor + baroreflex
o Release stimulated by hypotension, heart failure and intravascular volume
depletion
• Increasing plasma osmolality causes release of ADH
o No further decrease below set-point (level of osmolality) = “osmostat”
o As ADH levels rise, urine becomes more concentrated
o Tight, crisp control over water
o Vs. Change in Na intake – change in volume sensed which modulated Na
excretion mechanism
o Changes in tonicity not well tolerated

Hyponatremia (hypo-osmolar states)

• Hyponatremia is NOT hypo-osmolar state in these 2 examples:
o Marked hyperlipidemia: aqueous portion of volume of plasma reduced
 Pseudohyponatremia – Na appears low
o Hyperglycemia: serum Na concentration may be low but serum is hyperosmolar
because of elevated concentration of osmotically active glucose
 Dilutional hyponatremia with elevated plasma osmolarity
• Intake of free water > renal output + insensible losses
• Normally, kidney can excrete up to 20 L of free water/day
• Excessive intake: > 20 L/day = psychogenic polydipsia
• Failure to make large volume of dilute urine
o Failure to deliver to diluting segment
 Increased proximal tubule resorption
• Hypotension, extracellular volume depletion or edematous states
with arterial underfilling
• RAAS activation etc. to maintain blood volume
 Low GFR impairs delivery
• Oligoanuric acute renal failure or severe chronic renal failure
o Failure to dilute
 Salt must be resorbed and water left behind
 Hypothyroidism
• Decreased functioning Na pumps in medulla – decrease in salt
absorption from TALH
 Diuretics (thiazides)
• Poison salt absorption in cortical diluting segment
 Severe hypokalemia
• Decreased Na transport out of renal tubule cells
o Failure to suppress ADH – overwhelmingly, this is site of problem
 Tubule must remain impermeable to water after dilute urine formed
 Hyponatremia should have been sufficient to suppress ADH
 Volume stimuli (RAS activation) stimulate ADH secretion even in

42
 moderate congestive heart failure
• Skin tenting, dry mucous membranes, reduced axillary sweat
• Grossly edematous
 % Change in osmotic stimuli vs. pressure
• Levels of 5 pg/ml = maximal urine concentration
• Osmolality – straight line
• Plasma/volume – slope to begin, then more sleep
• Spectrum of curves between interaction of both stimuli
o Set-point and slope = separate parameters
o Arterial underfilling – set-point moves down and slope
becomes more steep
 Steepness of slope = tightness of range
 Set-point moving actually determines change in
values = decreased with decreasing extracellular
volume
 i.e. in a volume depleted person, same plasma
osmolality associated with greater ADH level
 Hypothyroidism and hypocortisolism
• Especially when due to hypopituitarism
• Cardiac output also depressed
• Patients can be euvolemic on exam – no pitting edema
 Chlorpropamide
• Increases ADH release and increases sensitivity of CD to ADH
 SIADH

Hyponatremia in CHF
• Free water intake > free water output
• Similar mechanism for extracellular volume depletion and cirrhosis
Why has kidney failed to make large volume of dilute urine?
• Thirst – AII: water intake increased
• Distal delivery impaired – AII, GFR down (creatinine elevated)
o RBF < GFR – increased FF
o Higher protein concentration in peritubular capillary = driving force for increased
fluid resorption by kidney
o Reduced fluid delivery to distal tubule
o There will also be increased reabsorption of urea and uric acid – increased BUN
and increased BUN: creatinine ratio
o Also expect to find evidence of salt retention with potential for mild GFR
decrease
• Dilution at distal tubule impaired – diuretics, hypokalemia
• ADH – volume stimulus to ADH: major cause despite presence of hyponatremia
o These patients require lower osmolality to turn off ADH secretion and have higher
ADH levels at osmolarites above set point
• Plot of plasma renin activity inversely proportional to Serum [Na]
• Initial insult: drop to lower position on Starling curve – salt content and ECF volume

43
 increases
o Increased LVEDP – shift to better position
o May suppress RAS and ADH – new phase of ADH secretion
o Second insult: no amount of volume retention able to de-activate baroreceptor
reflexes
 Tendency to hyponatremia if free water intake > free water output
 % survival based on [Na]
• If [Na] < 130 – poor survival: decompensating
• If [Na] > 130 – much better prognosis

Addison’s Disease
• Hypoaldosteronism – associated with hyponatremia because of extracellular volume
depletion secondary to reduced salt reabsorption in collecting duct
• High urinary salt excretion
• Glucocorticoid deficiency may also contribute

Diuretic-induced hyponatremia
• Extracellular volume depletion with activation of proximal and distal mechanisms for
decreased free water excretion
• Thiazide and loop diuretics: also poison salt reabsorption in diluting segment
o May produce hyponatremia even with normal extracellular volume
o Also cause potassium depletion, which decreases salt reabsorption in loop of
Henle with consequent decrease in dilution of urine
NSAIDS
• PGEs inhibit effect of ADH on collecting duct
• Therefore, NSAIDS increase sensitivity of collecting duct to ADH – this should not in
itself impair free water excretion
• PGEs also inhibit AII – FF increased etc. = decreased distal delivery

SIADH
• Patient with infusion of ADH - increase water intake
o Urinary osmolality abruptly rises and urine output abruptly falls
 Large volume of dilute urine to small volume of concentrated urine
o Retain water – input output imbalance:
 Sccumulation manifested by increase in weight
 More subtle: in context of total body water
 Small expansion of intravascular volume – 1/9 of all water retained
 Increase in volume will register at receptors: atrial stretch receptors,
aortic, carotid – suppress RAS: decreased Na reabsorption
• Urinary sodium increases over several days
• BUN will be lower than normal
• Plasma creatinine will be normal or lower – increased GFR
• Treatment: restrict H20 – high ADH = physiologic
o Natural to have high ADH with reduced intake
• Etiology

44
 o Ectopic ADH production from tumors
o Pulmonary disease
o CNS disease

Hypothyroidism
• High ADH levels (decreased CO)
• Thyroid hormone necessary to maintain Na pumps in kidney
• Less dilute urine formed because deficient Na pumping in TALH

Glucocorticoid deficiency
• Increased ADH release
• Non-volume stimulus still unknown

Approach to Hyponatremia
• Make sure hypo-osmolar hyponatremia
• Free water intake > free water output
o Increased intake
o Reduction in non-renal losses
• Eliminate severe renal failure – get creatinine in steady state
• Increased ADH despite decreased [Na]
o Normal urinary sodium – drugs, endocrinopathies, SIADH
 Euvolemic
 R/O drup related ADH release
 Thyroid function tests and cortisol level + physical exam
 SIADH = diagnosis of exclusion – CNS, pulmonary or neoplastic
• Urine osmolality elevated and urine Na also elevated
o Often decreased urinary sodium with increased urine osmolality
 ECF and intravascular compartments depleted (diarrhea)
 ECF expanded but intravascular compartment arterially underfilled (CHF)
• BUN/Cr – elevated

Hyperosmolar states
• Hypernatremia = increase in osmolality
o Normal or low sodium concentration can occur in hyperosmolar state
o Presence of another osmotically active species e.g glucose
• Deficit of free water
• Extent of insensible losses increases markedly with fever
• Failure to concentrate urine
o Loss of thirst
o Failure to maintain medullary concentration gradient
 Produced by dumping salt from TALH and urea from CD
 Renal failure – decreased delivery of salt = decreased concentrating
ability
 Tubulointerstitial disease – direct damage to tubules causing decreased
salt reabsorption (analgesic nephropathy, sickle cell disease)

45
 • Neither usually associated with significant hypernatremia
 Hypokalemia – decreases Na transport out of tubule cells
• Also impairs responsiveness to ADH
 Increased blood flow – makes medulla less concentrated
• Intravascular volume expansion and osmotic diuresis
• Wash-out of medullary gradient
 Osmotic diuretics
• Impair water reabsorption at collecting duct

Inadequate Secretion or Effectiveness of ADH

• Central diabetes insipidus: failure to release ADH
• Nephrogenic diabetes insipidus: lack of responsiveness of collecting duct
• Osmotic diuresis: excretion of large volume of osmotically active solute (glucose in
hyperglycemia) obligate water and thus increased water excretion even with urine
maximally concentrated
o Last two causes will not cause hyperosmolarity if thirst is intact

Approach to patient with hyperosmolar state

• Decreased intake/increased insensible loss
o Normally, obligate water loss = 500 ml – water vapor in inspired air and loss due
to sweating
o Fever can increase water loss
o Also, minimal water needed to keep urinary solutes in solution (500 ml)
o If daily water intake < obligate water loss, osmotic pressure of body fluids will
increase
o Protective mechanism = thirst
 Impaired if patient unable to drink freely or if hypothalamic thirst center
destroyed as result of trauma, hemorrhage, infection or tumor
• Diabetes insipidus
o Polyuria: excretion of large volume of dilute urine
 Problem is patient passes > 6-7 L of urine – interferes with sleep
 Dangerous if thirst depressed
 Repeated hyperosmolar episodes: irreversible brain damage
o Central – destruction of hypothalamus by tumor, head injury, hemorrage or
surgical trauma
o Nephrogenic –
 Congenital: massive dilation of pelvis, ureters and bladder
 Hypokalemia – inhibits effect of ADH via increased PG synthesis + thirst
 Hypercalemia – polyuria and ADH-resistant diabetes insipidus
 Lithium – severe polyuria
 Demeclocycline – tetracycline; used to treat SIADH
• Osmotic diuresis
o As blood concentration rises above capacity of kidney to resorb all of filtered
glucose, large urine volume due to glucosuria
o Solute obligates water that would be resorbed by maximal ADH

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 o Medullary blood flow increased – medullary wash-out
o Na reabsorption impaired – reduced Na concentration in filtrate due to higher
volume
 May also interfere with maintenance of medullary concentration gradient
o Increased urine flow predisposes to hypokalemia
 Independently impairs water reabsorption
o Plasma osmolality high but sodium concentration may be high, low or normal
o May also occur after relief of obstruction of urinary tract

INTRAVENOUS FLUIDS – a clinical approach

Objectives
• Volume of distribution
• IV fluid choices available
• Types of fluid depletion
• Specific clinical examples and treatment

Volume of Distribution
• Males: 60% of weight is water
• Females: 50% of weight is water
• Water compartment: 2/3 intracellular and 1/3 extracellular
o Water diffuses freely
o Na restricted to extracellular compartment
• EC compartments
o Interstitial – ¾
o Intravascular- ¼
o Salt and water equally accessible to both compartments
• “Third Space”
o Acute sequestration of (usually isotonic) fluid in body compartment that is not in
equilibrium with ECF – filling of potential space
o Fluid derived from extracellular fluid
o IV replacement frequently necessary to prevent/treat extracellular volume
depletion
o Examples
 Intestinal obstruction
 Severe pancreatitis – leakage of plasma into retroperitoneal area
 Peritonitis – blockage in SVC: seepage of fluid into arms and face
 Major venous obstruction
 Capillary leak syndrome – sepsis; fluid exits intravascular compartment
• Aggressively hydrate to restore intravascular volume

Fluid Balance – Maintenance fluid requirements

• Drink: 1-1.5 L/day
• Insensible loses: increases in febrile etc. – 500 ml normal loss
o Fever: losses increase by 100-150 mg/degree centigrade

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 o Sweating (hypotonic) – e.g. marathon running – ¼ or ½ NS
o NG suction (hypotonic): ¼ or ½ NS (significant K losses)
o Osmotic diuresis (hypotonic) – e.g. uncontrolled diabetes
 ¼ or ½ normal saline
o Third spacing (isotonic) e.g. ileus – NS
o Bleeding (isotonic): normal saline
• Stool: 500 ml/day
o Diarrhea (hypotonic): ½ NS
• Metabolism generates 300 ml/day
• Total urine output: usually 1-1.5 L
• Need 1-1.5 L/day to maintain normal afebrile adult
o If IV fluids = sole source, ½ or ¼ normal saline should be used
o Dextrose may be added to provide some nutrition
 1 L of D51/2NS = 200 calories/L

Math on Volume Distribution

• Total body water: 60% body weight = 0.6 x 70 kg = 42 liters
• ECF = 1/3 = 13 L
o Blood = ¼ ECF = 3.3 L
• ICF = 2/3 = 25 L

Principles of Treatment
• How much volume? Need to estimate fluid deficit
• Which fluid?
o Which fluid compartment is predominantly affected?
o Need evaluation of other acid/base/electrolyte/nutrition issues

IV Fluid Supermarket
• Crystalloids
o Dextrose in water – 5 W, 10W and 15 W
 Dextrose metabolized – way of providing free water
 Giving high concentrations of dextrose to a diabetic without insulin may
cause osmotic diuresis and worsen extracellular volume depletion
o Saline – doesn’t diffuse through all compartments since cell membrane is
impermeable to sodium: disperses throughout extracellular space
 Isotonic (normal – 0.9%)
 Hypotonic
• ½ normal saline (0.45%) = ½ free water and ½ saline
• Giving hypotonic solutions to patient with extracellular volume
depletion (e.g. post-surgical) may cause symptomatic hyponatremia
 Hypertonic
o Combination
o Ringer’s lactate “physiologic” (K, HCO3, Mg, Ca)
 Will cause hyperkalemia in patient with renal failure

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 • Colloids
o Albumin – 5% in NS or 25% (salt poor)
o Stays in intravascular space
• Blood

1 Liter of Normal Saline (0.9%)

• Saline stays in extracellular compartment
• ¼ stays inside vessels (250 mls)
• ¾ stays in interstitial space (750 mls)
• Shock with fluid depletion: 1 L of intravascular saline = 4 L total saline may be required
to restore hemodynamics

1 Liter of 5% dextrose
• 1 L of water diffuses easily through compartments
• 1 L of D5W in 70 Kg male
o Intravascular – 60 mls
o Interstitial fluid – 240 mls
o Intracellular – 700 mls
• DON’T give dextrose if someone is in shock

1 Liter of 5% Albumin
• Capillary membrane not normally permeable to albumin
• Capillary leak syndrome: albumin will leak out into interstitial space over hours
o In patients who are hypoalbuminemic (cirrhosis, nephrotic syndrome)
• In normal person, plasma expander – most efficient way to treat shock
• Comparison of albumin and saline for fluid resuscitation in intensive care unit
o Virtually identical mortality, though may get blood pressure up more quickly with
albumin because need to give more saline to get same intravascular volume
o Only reason to give albumin: correct volume deficits with hypoalbuminemia

Volume Deficit – Clinical Types

• Total body water: water loss (diabetes insipidus, osmotic diarrhea, osmotic diuresis)
o Dehydration depletes all compartments equally
o Leads to hypernatremic dehydration
o Followed by intense thirst and rapid restoration of fluid deficit
o If access to free water restricted (demented or ventilated patients), can’t correct
• Extracellular
o Salt and water (isotonic) loss (secretory diarrhea, ascites, edema, burns)
o Third spacing
o Diuretic therapy
• Intravascular
o Acute hemorrhage – GI bleed

Clinical Examination – only way to diagnose which compartment at risk

• Intravascular depletion

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 o Mean arterial pressure = CO x SVR
o Hemodynamic effects
 BP: orthostatic then frank hypotension
 HR increased
 JVP low
 Cool extremities – sympathetic vasoconstriction
 Reduced sweating
 Dry mucus membranes
• ECF depletion
o Skin turgor (tenting), sunken eyeballs
o Decrease in weight
o Hemodynamic effects
• Water depletion
o Hypernatremia
o Body weight will be lowered
o Thirst may be only manifestation in physical exam

GI Bleed
• 25 y.o. man presents with massive hematemesis x 1 hour
• History of peptic ulcer disease
• Exam:
o Diaphoretic, normal skin tugor
o Supine BP: 120/70 HR 100
o Sitting BP: 90/50 HR 140
• Serum Na = 140
• What is nature of fluid deficit? Intravascular volume
• What IV fluid resuscitation would you prescribe? Blood or Albumin or massive Saline
• Hematocrit at time of presentation? No time yet for interstitial fluid to come back
o Usually normal in first hour or two
o After, ingress of interstitial fluid – will dilute down hemoglobin

Consequences of Shock
• Organ dysfunction (definition) with drop in BP
• May be associated with parenchymal damage if prolonged and severe
• Acute tubular necrosis
• Watershed CNS infarction
• “Shock” liver
• Ischemic colitis
• If don’t rescue patient before irreversible phase, they will die

Diarrhea and Vomiting

• 18 y.o. previously healthy medical student – tan and severe diarrhea and vomiting for 48
hours
• Sunken eyeballs, poor skin turgor and dry mucus membranes
• BP 80/70 and HR 130 supine

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 • Labs: Na 130 (low) K = 2.8 HCO3 = 12
• ABG: 7.26/26/100
• What is nature of fluid deficit? Extracellular compartment reduced
• What fluid will you prescribe?
o Patient needs potassium and bicarbonate to combat acidosis
o (WHY is there acidosis?)
o Calculate amount of bicarbonate need to get back to 20 mEq/L
o Saline + K + bicarbonate
• What would happen if D5W were to be used?
o Would take 67% more than would need with NS
o Serum sodium already low – ADH level high with volume depletion
o Serum Na will decrease further – D5W is contraindicated; can lead to seizures

Hyperosmolar state
• 85 y.o. nursing home resident with dementia and known diabetes admitted with confusion
• Exam: disoriented
• BP: 110/70 supine, BP 90/70 sitting. Decreased skin turgor
• Labs: Na – 150 mEq/L, weight = 50 kg
• BUN/Cr = 50/1.8
• Blood sugar = 1200 mg/dl
• Hb = 45
• What is pathogenesis of fluid and electrolyte disorder?
o Dementia – dependent on external fluid intake
o Elevated glucose – osmotic diuresis – loss of free water
o Kidneys stop working because BP drops
o Massive volume depletion state – more free water lost than salt
• Treatment
o Need to address extracellular volume deficit
 NaCl (NS) to restore intravascular and interstitial volume
o Need to address free water deficit
 Hypotonic saline – 2.6 L of half normal saline

Calculation of Water Deficit

• Osm (Na) x volume = constant
• Normal plasma Na = 140 mEq/L
• Present plasma Na = 150 mEq/L
• Volume at time of present = ½ of body weight
• Need to calculate volume when patient was healthy
• NBW = 26.8 L
o Water deficit = NBW – CBE = 26.8 – 2.5 = 1.8 liters

Cirrhotic
• 40 y.o. patient with known alcoholic cirrhosis, portal tension and ascites admitted with
rising creatinine

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 • Exam: BP 100/70 (no orthostasis), JVP = 5 cm, +++ ascites, no peripheral edema, +
asterixis
• BUN = 12 mg/dl, Creatinine = 2mg/dl, Albumin = 2.0 g/dl
• Urine lytes: Na = 6 mEq/L, FeNa = 0.5%
• Urine volume = 200 cc/24 hours
• Patients tend to lose fluid progressively
• Very difficult to tell if volume depleted or not

• Renal failure due to hepatorenal syndrome

• Demonstrated if intravascular depleted: if give albumin and doesn’t respond, NOT
intravascular volume depletion

Post-op Abdominal Distension

• 60 male with pancreatic carcinoma has undergone total pancreaticoduodenectomy and
gastrojejunal bypass
• On post-op day 3, he develops abdominal distension – BP 110/60 and HR increases from
100 to 130 on sitting. Bowel sounds absent
• AXR reveals multiple fluid levels in abdomen. NG suction tube initiated
• Intraluminal fluid not in equilibrium with intravascular space – fluid deficit will expand
to include entire extracellular compartment
• Treatment: NS
o Also loss of K, Bicarb, Mg and Ca + a little sugar
o Ringer’s lactate

Nutritional Dilemma
• D4W-NS at 100 mls/hour (5% dextrose in 0.9% saline)
• Total volume = 100 mls x 24 hours = 2400 mls
• Total dextrose (5 g/100 ml) = 120 g/day
• Total calories = 120 g/day x 4 kcals/g = 480 kcals – NOT ENOUGH NUTRITION
o Use D10W-NS instead or provide standardized solution of nutrition

Conclusions
• crystalloids generally adequate for most situations needing fluid management
• Composition of solution and rate of administration are important when addressing a
specific situation
• Colloids may be indicated when more rapid hemodynamic equilibration required
(inadequate data)

ACID BASE

Task of kidney in acid-base balance: excretion of daily acid load

• Oxidation of amino acids, fats, carbohydrates often lead to acid production
o On an average American diet, we produce about 1 H+ mEq/kg/day
 Organic carbon oxidized to carbonic acid (H2CO3)
 Sulfur to sulfuric acid (H2SO4)

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  Acid load must be excreted
 Role of kidney = regeneration of titrated HCO3-
• Paradigm Chemical Equations
o A0 to B- and H+
o B- to A0 and OH-
o C+ to A0 and H+
o Glucose to CO2 and H2O – no hydrogen ions: 99%
o Glucose0 via partial oxidation to Lactate- and H+ = lactic acidosis – 1%
o Partial oxidation of glycerol to beta-hydroxybutyric acid
o Lactate- to CO2 and OH- to HCO3-
• Buffering of Acid load
o Ability of fluid to prevent change in [H+]
o Proteins – slow turnover; cannot be used for regulation
o Buffering of produced acid consumes HCO3 and is lost from body as CO2
o HCO3- + H+ to H2CO3 (carbonic acid) to CO2 and H2O
 Decreased HCO3 and CO2 breathed off
o CO2 + H2O to H2CO3
o CO2 to OH- to HCO3-
o OH- and H+ to H2O
o Henderson Hasselbalch Equation
o pH = pK + log [HCO3]
alpha pCO2
 pK = 6.1 at 37 C and 0.15 M salt
 alpha = 0.03
• HCO3- resorption by H+ secretion
o H2O split to H+ and OH-
o H+ pumped into lumen: combined with HCO3 by CA IV to CO2 and H2O
o OH- combined with CO2 by CA II to HCO3-, which is pumped out of cell
o CA = carbonic anhydrase
o Every day kidney must produce 1 mEq bicarbonate/mEq/day or more to match the
acid production of the body
o Large capacity to produce bicarbonate
o 25 mEq/L of bicarbonate filtered per day
o This needs to be absorbed + need to produce more
• Proximal tubule
o Secretion of H+ by:
 Proton translocating ATPase
 Protein that exchanges Na for H+
o Bicarbonate added to body fluids – transporter only present on lateral and basal
surface
• Collecting tubule
o Principal cell: Na+ absorption (ENaC), water absorption (aquaporin 2) and K+
secretion (ROMK)
o Intercalated cell: H+ translocating ATPase
 Cl: HCO3- exchanger
 H+ secretion depends on creating gradient

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  After HCO3- reabsorbed, pH in lumen falls and filtered HPO4= and NH3
are protonated
 In steady state, HCO3- generated through the excretion of H2PO4- and
NH4+ matches the nonvolatile acid load
• Regulation of H+ Transport
o pCO2 – lung can change pCO2 of body fluids
 CO2 stimulates exocytosis of H+ ATPase vesicles by decreasing cell pH
 Increased H+ secretion
 E.g. Hyperventilation – pCO2 low
• Respiratory alkalosis: H+ concentration galls because blowing
off CO2
• Decreased delivery due to hypoxemia, hypotension, severe anemia
or CO poisoning activating chemoreceptors in aortic and carotid
bodies, stimulating CNS respiratory center
• Pulmonary states such as pneumonia, pulmonary edema or
pulmonary emboli stimulating the respiratory center via irritant
receptors and vagal afferents
• Medullary respiratory center stimulated directly by hepatic failure,
Gram-negative sepsis, pain and salicylate ingestion
• Acute: cellular buffering
o HCO3- moves into cells in exchange for chloride and H+
pumped extracellularly to titrate HCO3-
o Protons derived from proteins, phosphate, hemoglobin
o Not very effective – pCO2 falls from 40-20 mmHg, HCO3
acutely decrease from 24 to 20 mEq/L
o Also - initially plasma bicarbonate goes down because CO2
needed to generate bicarbonate
• Chronic: renal compensation
o Decrease in pCO2 inhibits acid secretion by kidney via
reduction in number of proton pumps in luminal membrane
of cortical CD epithelial cells
o By reducing H+ secretion, also reduce HCO3- absorption
o New bicarbonate production also reduced because of
decreased NH4+ excretion – NH3 needs to be acidified to
be secreted
o Over next 2-3 days, plasma bicarbonate keeps going down
o Kidney compensates for respiratory alkalosis
o Over time, alkalosis becomes less severe but never fully
back to normal: to pH 7.47 (instead of pH 7.70)
 E.g. Hypoventilation – high pCO2: Respiratory Acidosis
• Small amount of bicarbonate instantly produced
• Over days, bicarbonate goes up to compensate –I ncreased H+
secretion into urine
• Acute respiratory acidosis – no renal compensation
• Chronic respiratory acidosis – renal compensation has occurred

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 • NO compensating organ ever compensates perfectly i.e.
bringing the pH to a normal level for a primary acid-base
abnormality
o Stimulus for progressive compensation will be turned off as
HCO3/CO2 ratio approaches normal
o Compensatory changes require normal function of
compensating organs
o Aldosterone
 At every pH and membrane potential, aldosterone increases number of
proton pumps in cell membrane
 Also important regulator of Na absorption
 Increased Na – membrane becomes hyperpolarized
• H+ ion pump accelerates secretion of H+ ions
• Also increases K+ secretion
o Acid-base status, K, NH3
o pH gradient of urine – the lower the pH of urine, the less H+ secretion there is
 pH of 4.4 – shuts off H+ pump
 No one can have urine pH < 4.4
o Membrane potential – also important in regulating H+ transport

Net Acid Excretion

• Net acid production about 60 mEq
• 1L of urine at pH 5.0 = 10 mEq H+
• Hence, acid excretion must occur by means other than “naked” protns
• Net acid excretion = NH4 + Titratable acid – HCO3-
• NH3 + H+ to NH4+ - not reabsorbable - excreted
• HPO4= + H+ to H2PO4-
• Hydrogen ions secreted in urine “hidden” in other chemical substances
• We excreted 100 mEq of acid buffers

Gluconeogenesis – in kidney and liver

• Glutamine to glutamate produces NH3
• Glutamate to alpha-keto-glutarate produces NH3
• To PEP to intermediates to glucose
• NH3 diffuses out and combines with H+

Ammonia Production
• Highly regulated process that responds to acid production
• 40 mEq/day produced ~ daily acid load
• Acid ingestion increases ammonia synthesis and excretion by saturable mechanism
• From 40-240 mEq can be produced – each nephron can increase acid production by 5 fold
• Only will become acidotic if < 1/5 of nephrons functioning – late manifestation
• Provided that model of renal disease = removal of nephrons
• All glomerular disease – glomerular fibrosis = as if nephron dead because no filtration
o Do not develop acidosis until creatinine is 4-5

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 • If creatinine is 2 and become acidotic, either excess acid production, excess bicarbonate
loss or kidney cannot make ammonia = tubulointerstitial diseases
o Disease primarily in interstitium to prevent ammonia from being made

Approach to Acid Base Abnormalities

• Measure arterial pH, HCO3 and pCO2
• You need all three measurements!
• If pH < 7.4 = acidosis
• If pH > 7.4 = alkalosis

Metabolic Acidosis: low pH, low HCO3, low pCO2

• Increased metabolic acid production = lactic or ketoacidosis
o Complete oxidation of glucose reduces
 Anerobic glycolysis continues – excess lactate production
o Ketoacidosis: increased FA oxidation producing beta-hydroxybutyrate and
acetoacetic acid
• HCO3 loss
o Renal – RTA (renal tubular acidosis)
o Non-renal: mostly GI – colon and ileum secrete bicarbonate
 Diarrhea fluid has high bicarbonate concentration – loss of bicarbonate
 Most common cause of metabolic acidosis
• Renal failure – severe: don’t have enough nephrons to produce normal amount of
bicarbonate or ammonia
• Acid ingestion
o Hyperalimentation – increased acid load

• Brain senses low pH and increases respiration = hyperventilation

o Helps to normalize pH – but can never achieve complete compensation because
signal will go away

“Anion Gap” = Na – (Cl + HCO3-)

• Normal: 10-15
• Unmeasured anions – mostly albumin and other proteins
• Lactic or ketoacidosis: anions also unmeasured
o When a nonvolatile acid added to body fluids, HCO3- is titrated + replaced by A-
o Na and Cl remain unchanged = anion gap
o Note: absence of anion gap does not exclude increased HA load
o If acidosis continues for some time, anion accompanying acid may be lost in urine
• Vs. diarrhea – decreased bicarbonate but no change in measured anions
• No anion gap if A- = Cl-
o Cl- increases as HCO3- decreases

Acidosis + Unmeasured Anion

• Lactic acidosis – Diagnosis: measure plasma lactate
o Lactic acid = end product of anaerobic glucose metabolism

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 o Derived from pyruvate: pyruvic acid + NADH = lactic acid + NAD
o Intracellular hypoxia results in a shift in redox potential with accumulation of
NADH, which drives the equilibrium to the right and produces lactic acid
o Lactic acid titrates HCO3-, causing a high anion gap acidosis
o The liver normally converts lactate back to glucose or oxidize it to CO2 and H2O,
consuming H+ in the process and generating bicarbonate
o Problem: rate of production > rate of metabolism
o Most common cause: severe circulatory failure and shock
o May preced major decrease in blood pressure, indicating tissue hypoxia, increased
anaerobic metabolism and insufficient hepatic utilization of lactate
o May also occur in settings of seizures, severe hypoxemia (pO2 < 40) and leukemia
• Diabetic ketoacidosis – beta-hydroxybutyrate, acetoacetate and lactate
o Diabetic, alcoholic, starvation
o Starvation
 Increased formation of ketoacids – mild metabolic acidosis because
ketoacids promote insulin secretion: responds to hydration and feeding
o Alcoholic
 Chronic alcoholics – heavy ethanol consumption associated with anorexia,
N/V and followed by reduced food and alcohol intake over several days
 Associated with high anion gap (25 mEq/L) due to accumulation beta-
hydroxybutyric acid and acetoacetic acid
 Insulin suppression due to fasting and alcohol inhibition of
gluconeogenesis
 Increase in NADH:NAD ratio in mitochondria due to oxidation of ethanol
with overproduction and decreased peripheral utilization of ketoacids
 Diminished urinary excretion of ketoacids as a result of extracellular
volume depletion
o Osmotic diuresis in diabetes – severe intravascular volume depletion
o Hypotension and lactic acidosis may accompany DKA
 If lactic acidosis, NADH elevated – beta-hydroxybutyrate predominates
(product of acetoacetic acid + NADH)
 During treatment as NADH levels fall with improved tissue perfusion,
ketonemia may appear to worsen as beta-hydroxybutyrate is converted to
acetoacetate
o Excessive bicarbonate replacement can result in metabolic alkalosis during
recovery phase – correction of blood pH decreases drive for hyperventilation and
leads to rise in blood pCO2
o Diagnosis: serum glucose and ketones
• Renal failure
o Acute and severe chronic – phosphate, sulfate and other organic anions
• Toxins
o Salicylate – lactate, salicylate
 Acetylsalicylic acid, salicylamide or methyl salicylate
 Most common poisoning
 Hypernea, respiratory alkalosis
 Produce high anion gap metabolic acidosis with accumulation of keto,

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 lactic and other organic acids
 Clinical history, symptoms of salicylism (tinnitus, nausea and vomiting)
and combination of respiratory alkalosis and high anion gap metabolic
acidosis
o Methanol – formate
 12-48 hours after ingestion – oxidation of methanol to formaldehyde and
formic acid
 CNS depression with coma and convulsions, profound and resistant
acidosis and retinal edema and blindness
o Ethylene glycol – oxalate
 E.g. ingestion of antifreeze
 Accumulation of metabolic products of toxin, inhibition of oxidative
phosphorylation and altered glucose metabolism
 CNS dysfunction, cardiopulmonary failure with pulmonary congestion,
rhabdomyolysis and acute oliguric renal failure
o Paraldehyde - ?

Normal Anion Gap Metabolic Acidosis – hyperchloremic

• Non-renal HCO3 loss
• Renal HCO3 wasting

Non-renal HCO3 Loss

Diarrhea
• GI loss of HCO3-
• Most common cause of metabolic acidosis with normal anion gap
• Loss of highly alkaline secretions from biliary drainage and small bowel or pancreatic
secretions will also cause hyperchloremic metabolic acidosis

Ureterosigmoidostomy and Ileal Conduit

• Hyperchloremic acidosis
• Slow passage of urine over sigmoid mucosa results in bicarbonate-chloride exchange
• Reflex nephropathy and infection may lead to renal tubulo-interstitial damage and type IV
form of renal tubular acidosis

Renal HCO3 Wasting

Renal losses of HCO3 with Carbonic Anhydrase Inhibitors
• Decrease secretion of H+ and thus decrease reabsorption of filtered HCO3-
• Loss of HCO3- results in hyperchloremic metabolic acidosis

Renal Tubular Acidosis

• Syndrome of disordered renal acidification associated with only a mild reduction in renal
function

• Proximal tubule defect: can’t absorb bicarbonate = Type II

o Excrete massive amounts of bicarbonate (over 15% of filtered load)
o Proximal tubule normally able to resorb large amounts of bicarbonate

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 o Type II associated with partial failure of proximal tubule to secrete H+
o Associated with other proximal tubular defects: aminoaciduria, phosphaturia,
uricosuria and glycosuria (Fanconi’s syndrome)
o Eventually, as plasma bicarbonate goes down, amount of bicarbonate filtered also
goes down until equal to capacity of diseased proximal tubule
o At this point, bicarbonaturia will cease and urine pH will fall to normal levels
o Amyloidosis, multiple myeloma, renal transplantation, medullary cystic kidney
disease, drug ingestion and cadmium and lead poisoning
o Patient is acidotic – may also have loss of K and phosphate
o If given bicarbonate, will rapidly excrete bicarbonate and alkalize urine
• Distal (collecting) tubule defect: can’t secrete H+ = Type I
o Urine has abnormally high pH
o When given bicarbonate, little increased in urinary HCO3 losses or urine pH,
indicating adequate proximal tubular function in resorbing HCO3-
o Can never acidify urine to minimum urine pH (4.4)
o Segment of kidney that reduces pH to 5 and below is collecting duct
o Epithelium can be leaky to protons or not enough H+ pumps: can’t generate or
maintain 1000:1 H+ gradient between distal tubular cells and tubular lumen
o Etiology: autosomal dominant defect in children, drug ingestion (amphotericin B,
aminoglycosides, lithium), autoimmune disorders, diseases associated with
nephrocalcinosis, UT obstruction and renal transplantation
• Type IV RTA: lack of ammonia production
o Seen in patients with hyporeninemic hypoaldosteronism (diabetics, chronic
interstitial nephritis) or primary adrenal failure
o Hyperkalemia inhibits ammoniagenesis and prevents adequate NH+ excretion
o Urine pH acidic: decreased buffering capacity decreases magnitude of H+
secretion and HCO3- generation – daily nonvolatile acid load not matched and
acidosis ensues

Infusion and ingestion of chloride-containing acids

• Hydrochloric acid, lysine HCl or arginine HCl
• Hyperalimentation fluid which ontains dibasic amino acids in form of hydrochloride salts
can also produce this acid-base abnormality
• NH4Cl ingestion: NH4+ converted to urea in liver with release of H+

Renal Failure
• Both acute and chronic renal failure cause metabolic acidosis through failure to excrete 1
mEq/kg of nonvolatile acid generated daily
• Acute renal failure
o GFR and urine output often profoundly reduced, diminishing opportunity for H+
to be added to urine
o Anions (sulfates, phosphates, organic acids) not filtered – contribute to anion gap
• Chronic renal failure
o Nephron population progressively reduced
o Acidosis stimulates ammoniagenesis by kidney, resulting in increase in acid
excretion per nephron

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 o Each nephron able to increase NH3 production by 4-5 fold
o Only when GFR < ¼-1/5 normal will renal NH3 production be reduced
o Retained anions with low GFR will cause high anion gap
• Moderate chronic renal failure – normal anion gap
o Should NOT cause metabolic acidosis

• Clinical features and compensation for metabolic acidosis

o As much acid generated in minutes of hypotension-induced lactic acidosis as in
weeks of renal tubular acidosis
o Clinical course depends on anion (if not chloride) accompanying proton
o Both lungs and kidney respond to acidosis

Metabolic Alkalosis: high pH, high HCO3-, high pCO2

• With high blood pH, respiration suppressed (pCO2 > 40)
o Respiration can’t be very suppressed – hypoxia is primary drive for respiration
o Respiratory compensation
• Development of metabolic alkalosis
o Generation of excess HCO3
 HCO3 ingestion or acid loss
 Capacity of kidney to excrete HCO3 is very high
• Need H+ secretion to reabsorb HCO3
 Stomach secretes acid – absorbed in intestine: no net change
 Vomiting or aspiration of gastric contents – acid loss
• These also produce volume depletion and hypoaldosteronism
 HCO3 generation
• Lactate (back to HCO3- and lactic acid), citrate, beta-OH butyrate,
HCO3- administration for treatment of metabolic acidosis
o Maintenance of excess HCO3 ***
 Metabolic alkalosis most often seen in context of volume depletion such
as that which occurs during gastric suction and diuretic treatment or
primary hyperaldosteronism
 Increased renal H+ secretion
• Decreased filtration rate – may maintain alkalemia that was
independently generated
• Volume depletion – increased absorption of everything (both
proximally and distally)
o High FF
o AII stimulates Na:H exchanger
• Hyperaldosteronism: increases collecting duct H+ secretion and
HCO3 generation – 99.9% of patients with metabolic alkalosis
have maintained bicarbonate excess by hyperaldosteronism
• Explains “paradoxical” acidic urine observed in metabolic
alkalosis with volume depletion
• Hypokalemia also increases proximal HCO3 reabsorption
o More H+ in cells – intracellular acidosis facilitates H+

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 luminal transport and HCO3- reabsorption
• Isolated volume depletion does not cause significant alkalosis despite elevated serum
aldosterone level
o Increased proximal resorption of Na reduces distal delivery of Na and reduces the
lumen-negative membrane potential generated by electrogenic Na reabsorption
o Electrogenic H+ secretion is impaired by diminution of lumin-negative driving
force
• Two high aldosterone states associated with metabolic alkalosis
o Volume depletion due to thiazide or loop diuretics
 Most frequent cause of metabolic alkalosis
 Aldosterone (elevated in volume depletion) stimulates H+ ATPase
 Na delivery to distal neprhon maintained by more proximally acting
diuretic and aldosterone stimulates distal reabsorption of Na
 Proton secretion at cortical CD both hormonally and electrically stimulated
– metabolic alkalosis generated and maintained
 Also associated with hypokalemia, which increases proximal reabsorption
of HCO3-
o Primary hyperaldosteronism
 Much less common
 Distal reabsorption of Na by aldosterone expands intravascular volume,
which decreases filtration fraction and increases distal delivery of Na
 Increasing distal delivery of Na overwhelms even aldosterone-stimulated
Na reabsorption and urine Na rises until input matches output
 H+ pump stimulatied by aldosterone: Na delivery and reabsorption
generate membrane potential facilitates H+ secretion
 Also results in hypokalemia, which contributes to maintenance of alkalosis
 Same mechanism in Cushing’s syndrome
• Clinical findings of metabolic alkalosis
o NG suction: poor skin turgor, decreased axillary sweat, postural hypotension or
tachycardia
o Primary hyperaldosteronism: hypertensive
o Prediposes to tetany

• Sudden correction of primary acid-base abnormality may lead to appearance of new acid-
base abnormality
o Results from compensatory process
o E.g. Chronic respiratory acidosis with pCO2 suddenly corrected
o Situation = metabolic alkalosis
o Similar results for chronic respiratory alkalosis
• Extracellular pH not always completely informative
o Metabolic acidosis due to drainage of bicarbonate-containing biliary fluid result in
extracellular HCO3- loss and the cell pH declines after the fall in extracellular pH
o Lactic acidosis: cells generate acid themselves and are acidic before any change in
extracellular pH
o As extracellular pH declines, intracellular buffers get titrated slowly downward
• Measurement of buffering capacity

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 o Diabetic with mild acute ketoacidosis – HCO3- 18 mEq/L
 Only extracellular buffers have been titrated
o Chronic renal failure with same HCO3-
 Significant H+ retention through titration of bone buffers, which
equilibrate slowly
 This patient would need 100s of mEqs more of bicarbonate than the first to
bring the same blood HCO3- to normal
 Intracellular buffers have all been titrated

POTASSIUM REGULATION
• Intracellular
o [K] = 110 mEq/L
o [Na] = 10 mEq/L
o Total body K = 4400 mEq
• Extracellular
o [K] = 4 mEq/L
o [Na] = 140 mEq/L
o Extracellular = 50 mEq
• Can’t talk about K depletion or excess by examining plasma
• Can talk about hypo and hyperkalemia
o Derangement of extracellular [K+] correlates with important neuromuscular and
cardiovascular signs and symptoms

How is K regulated in body fluid?

• Kidney regulates extracellular [K+] by altering excreton to match variable dietary intake
• So much of K+ is intracellular that small shift of K+ can result in large fluctuations of
plasma [K+]
o Increased or decreased plasma [K+] must be assessed in terms of intake, output
and cellular shifts of K+
o K+ intake: typically 100-300 mmoles/day – K is a major component of all cells
 May be low in starvation or not adding K to IV
o K output:
 Non-renal: GI, cutaneous – diarrhea, sweat
 Renal: 90% of daily K loss
• Disposal of ingested K load occurs by re-distribution (between cells and extracellular
space) and by urinary excretion
o Filtered K+ is completely absorbed proximally and then secreted distally
o Secretion of K+ into lumen involves transport of cellular K+ down concentration
gradient
 Change in luminal [K+]
 Change in transport processes
 Change in cellular [K+]
• Distribution of K and Excretion heavily regulated by pH
o Acidosis/diabetes/beta blockers:
 After ingesting K, bigger increase in K and slower decline
 Diabetic often hyperkalemic

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 o Alkalosis/insulin/epinephrine: smaller increase and faster decline
 Severe hyperkalemia – treated with glucose/insulin
• Hypokalemia or hyperkalemia may not reflect body K stores
o Patient with 1 week of diarrhea and new hyperkalemia in setting of sudden severe
acidosis due to hypotension – low total body K content
o Treatment: directed at reversing acidosis with HCO3 rather than trying to lower
K+ with K+ exchange resin

Potassium Excretion
• K is freely filtered
• > 95% of filtered K is reabsorbed in proximal tubule and TALH
• What appears in urine is secreted by distal tubule and collecting duct!
• K+ secretion in collecting duct
o Principal cell: secretes K and absorbs Na
o Luminal membrane: Na channel (lets Na in) and K channel (lets K out)
o Concentrations in cell (low Na, high K) maintained by Na-K ATPase
o Concentration difference = driving force of K+ secretion
 Aldosterone controls degree of opening of K+ channel
 The more aldosterone, the more channel is opened
 Aldosterone regulated by AII and potassium (stimulated by high K)
 Also increases Na-K ATPase – increased intracellular [K+]
o Transepithelial membrane potential generated by Na absorption also important
for K secretion
 More Na absorption = more luminal negativity = more K secretion
 Aldosterone also increases Na absorption
 Increased Na: larger electrogenic gradient and increased substrate for Na-
K ATPase
o Most important: Tubule Flow Rate
 The more urine flowing in (very low K tubular fluid), the more K secreted
 Increases concentration gradient
 However, secretion still dependent on open or closed state of channel
 If low K diet, effect is blunted
o Acid-base balance
 Alkalosis: increased K inside cell – more secretion because bigger gradient
 Acidosis: decreased K inside cell – less secretion
• Many patients with acidosis have hyperkalemia

Approach to Patient with Hypo or Hyperkalemia

• Redistribution – acid/base status, insulin, catecholamines
• Intake – dietary, IV
o No such thing as zero K diet
• Renal excretion
o Aldosterone
o Urine flow rate
o Acid/base status

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 o Renal failure
o Interstitial disease
• Non-renal loss
o GI
o Sweat

Hypokalemia
• Redistribution: alkalosis, glucose/insulin, catecholamines
o Often observed in treatment of diabetic hyperglycemia – insulin actions
o May be observed in use of beta-agonists for bronchospasm
• Deficient intake: rare but may happen in starvation or if K not included in IV
o Minimal K secretion – never combination of low urinary flow rates and
aldosterone levels
 Volume depletion: low urinary flow rate but high aldosterone
 Volume expansion: low aldosterone but high urinary flow rate
• Increased excretion
o Hyperaldosteronism
 Primary (adrenal adenoma or hyperplasia) or secondary (reininoma)
 Hypercortisolism
 Hypomagnesemia
o Increased urine flow rate – diuretics (loop and osmotic)
 Also cause hyperaldosteronism through volume depletion and alkalosis
through aldosterone-stimulated H+ secretion
 Additional stimulation from electrogenic gradient from increased Na
absorption – cause of hypokalemic in distal and proximal RTA
o Alkalosis – increases K+ excretion and predisposes to hypokalemia
o Drugs – amphotericin B, barium poisoning
• Extra-renal loss: sweating, diarrhea, vomiting

Hyperkalemia
• Resdistribution: metabolic acidosis, diabetes, beta-blockers
o Decrease in Na-K ATPase: shift of K+ out of cells
o Rhabdomyolysis – release of K from damage muscle cells
o Hemolysis or cell death following chemotherapy
• Increased intake: oral or IV (with renal failure)
o Rare that increased intake alone would lead to hyperkalemia
o Usually stimulation of aldosterone and increased K secretion
o Greater risk with IV supplementation of K+ - change in aldosterone occurs over
days
• Decreased output
o Low aldosterone
 Primary adrenal insufficiency
 Hyporeninemic hypoaldosteronism (type IV RTA)
o Decreased flow rate (oliguria)
 Acute renal failure – get hyperkalemia because of severe flow
impairment

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  Chronic renal failure – don’t get hyperkalemia because not oliguric
 Oliguria due to extracellular volume depletion, CHF and cirrhosis –
maintain normal plasma [K] because aldosterone elevated
o Acidosis – drives K out of tubular cells
o Drugs
 NSAIDS can inhibit renin release
 K-sparing diuretics
• Spironolactone – antagonism of aldosterone
• Amiloride, triamterine – inhibition of electrogenic Na reabsorption

Clinical Manifestations of Hypokalemia

• Muscle weakness – eventually paralysis, occasionally rhabdomyolysis
o Membrane potential dependent on intracellular/extracellular K
• Cardiac arrhythmias and heart block

Clinical Manifestations of Hyperkalemia

• Cardiac arrhythmia to ventricular fibrillation
• Peaked T waves characteristic

GLOMERULONEPHRITIS

Glomerulonephritis
• Broad category of glomerular disease manifesting cellular proliferation and inflammation
of glomeruli
• NOT glomerulopathy: non-proliferative disease of glomerulus
• Primary Glomerulonephritis
o Acute post-streptococcal glomerulonephritis
o IgA nephropathy (Berger’s disease)
o Goodpasture’s (anti-GBM) disease
o Membranoproliferative glomerulonephritis
• Glomerulonephritis in systemic diseases
o Lupus nephritis
o Microscopic polyangiitis
o Wegener’s granulomatosis
o Cryoglobulinemic glomerulonephritis

Approach to Glomerular Diseases: clinical presentation

• Glomerular injury
o Impaired renal function (azotemia)
o Reduced urine output (oliguria or anuria)
o Fluid overload (edema)
o Hypertension
o Hematuria (often with RBC casts)
o Leukocyturia

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 o Proteinuria
• Nephrotic syndrome
o Heavy proteinura (over 3.5 g/day)
o Low serum albumin
o Edema
o Hyperlipidemia
o Lipiduria
o Causes: minimal change disease, FSGS, membranous glomerulopathy, diabetic
nephropathy and renal amyloidosis
• Acute nephritic syndrome: actively inflamed kidney
o Acute onset of renal insufficiency
o Hypertension
o Hematuria (gross or microscopic)
o Classical presentation of post-streptococcal GN
• Rapidly progressive renal failure
o All features from nephritic syndrome with more accelerated course, often leading
to renal failure in weeks
o Urine output: oliguric or anuric – leading to volume overload
o Crescents on biopsy
o Crescentic glomerulonephritis – immunofluorescence findings
 Linear staining (Goodpasture’s/anti-GBM disease)
 Granular staining (due to immune complec mediated glomerulonephritis
such as post-infectious GN, lupus nephritis, IgA nephropathy etc)
 No immune staining (pauci-immune crescenteric glomerulonephritis, such
as microscopic polyangiitis or Wegener’s granulomatosis)
• Chronic renal failure
o Common end-stage of many glomerular diseases of diverse etiologies in which
widespread glomerulosclerosis, tubular atrophy and interstitial fibrosis occur
o Azotemia, acidosis, hypocalcemia, hyperphosphatemia and hyperkalemia
o Salt retention and volume overload, leading to edema and hypertension
o Elevated levels of nitrogenous wastes may cause GI symptoms of ulceration and
hemorrhae
o Neurologic changes: encephalopathy and peripheral neuropathy, osteodystrophy
due to altered Ca-P metabolic, pericarditis and hematopoietic effects such as
anemia and altered platelet function
o Increased blood volume can cause CHF and pulmonary edema
• Asymptomatic hematuria and/or proteinuria
o Hereditary nephropathies and IgG nephropathy

Reduced Serum Complement

• Acute post-infectious glomerulonephritis
• Lupus nephritis
• Membranoproliferative glomerulonephritis
• Cryoglobuinemic glomerulonephritis

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Urine Analysis in Nephritis
• Urinary RBCs, sometimes deformed
o “Mickey-mouse ears” – dysmorphic red cells in urine after being squeezed
through glomerular basement membrane
• RBC casts – RBC embedded in matrix
• Large amounts of albumin (> 3 g/day)

Vulnerability of Glomerulus to IC Injury

• Majority of glomerular diseases are immunologically mediated
Prone to injury because of:
• 20-25% of cardiac output
• High glomerular capillary pressure
• Fenestrated endothelium – maximize contact with glomerular capillary wall
• Concentration (sieving effect) – within glomerular capillaries

Mechanisms of Immunologic Injury to Glomerulus

• Glomerular deposition of circulating Ab-Ag complexes
o Glomerulus = innocent bystander
o Complexes have no specificity for glomerulus – trapped within glomerular tuft
during normal glomerular filtration
o Granular by IF
o Antigens responsible may be exogenous or endogenous
o Injury mediated by complement activation, release of complement-derived
anaphylatoxins and chemotactic substances, attraction of circulating leukocytes
and release of cytokines, lysosomal enzymes and toxic oxygen radicals, thereby
causing damage to glomerular capillary wall
o Reactions:
 Endothelial cells: activated, swell, degenerate or proliferate
 Mesangial cells: secrete cytokines, proliferate and synthesize increased
matrix
 Podocytes: swell, develop fusion of foot processes or detach from GBM
 Parietal epithelial cells: proliferate to form crescents (extracapillary
proliferation)
 Gaps can form in GBM
 Inflammation, capillary thrombosis and necrosis present to varying degrees
 If injury is severe or protracted, it may lead to glomerular sclerosis and
atrophy of dependent tubules with accompanying interstitial fibrosi
• Binding of circulating Ab to fixed glomerular Ag (e.g. anti-GBM Ab)
o Linear by IF – antigen regularly distributed in glomerular capillary wall
o Globular, noncollagenous (NC1) domain of alpha 3 chain of collagen IV = target
of immunologic attack
o Normally the epitope reactive with anti-GBM antibody is sequestered inside
hexameric structure of globular domain of collagen IV
 Infections/toxins (hydrocarbons) may expose otherwise inaccessible Ag,
initiating Ab production in predisposed individuals
• In-situ immune complex formation

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 o Membranous nephropathy
o Antigens “planted” in glomerular capillary wall because of local production, size,
charge or other factors
o Antigens bind to specific Ab, forming immune complexes in situ
• Vasculitis (pauci-immune)
o Anti-neutrophil cytoplasmic antibody

Deposits within mesangial matrix = mesangial immune deposits

Subendothelial – between glomerular endothelium and GBM
Subepithelial/epimembranous – between podocyte (visceral epithelium) and GBM
• What governs where complexes locate?
o Size, charge, avidity and affinity
o Lupus – can be in all areas

Once immune complexes form within glomerular capillary walll, incite cascade of immune
events
• Activation of complement on heavy chain of Ig
• Release of chemotactins (C3a and C5a)
• Attract leukocytes into glomerulo-capillary lumen: inflammatory component
• Can release toxic oxygen radicals and proteases – damage to GBM
• Damage to endothelium – clotting cascade, leading to intravascular coagulation
• PDF can stimulate proliferation and increased matrix production from mesangial cells

Glomerular Proliferation – within glomerular tuft

• Mesangial - confined only to mesangium – IgA nephropathy
• Endocapillary – predominantly mesangial, endothelial cells and infiltrating leukocytes
o Causes narrowing or occlusion of glomerular capillary lumens
• Extracapillary (crescentic) – proliferation of parietal epithelial cells within Bowman’s
space i.e. outside glomerular capillaries
o Most closely matched to rapidly progressive glomerulonephritis

GBM Thickening
• Thickening of GBM proper (diabetic glomerulosclerosis)
• Thickening of glomerular capillary walls by immune deposits
o May be subendothelial, subepithelial or with GBM

Hyalinization
• Presence of amorphous eosinophilic material within glomerular tuft
• “Plasmatic insudation”
• Accumulation of circulating plasma proteins (albumin, IgM) in areas of thickened
basement membranes
• Commonly seen in diabetic glomerulosclerosis and FSGS

Glomerulosclerosis
• Obliteration of glomerulus by large amounts of basement membrane collagen, leading to

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 glomerular obsolescence
• Commonly seen in any chronic glomerulonephritis in which glomeruli irreversibly
injured
• Sclerosed glomeruli appear histologically as rounded acellular balls of eosinophilic
basement membrane material with complete obliteration of glomerular architecture
• Glomeruli are functionally dead – evental atrophy of dependent portion of nephron
(tubular atrophy, interstitial fibrosis and arteriosclerosis)
Patterns of Glomerular Disease
• Focal vs. Diffuse – number of glomeruli
• Segmental vs. Global – portion of individual glomerulus

Approach to Glomerular Disease: Etiology

• History
• Physical Exam
• Laboratory, radiological tests
• Two Groups
o Primary glomerular disease – localized to kidney e.g. minimal change disease,
IgA nephropathy
o Secondary (systemic) disease – e.g. lupus

Case 1. Post-streptococcal glomerulonephritis

• 7 y.o. child
o Children 5-10 years of age most commonly affected
• Several days of sore throat and low grade fever
• Given acetominophen – recovers
• 2 weeks later: develops dark colored urine (due to hematuria) and less volume
o Onset of renal disease usually occurs 11-14 days following pharyngeal or skin
infection by GAS
• Exam: pedal edema and elevated blood pressure
• Labs
o Urine: RBCs, RBC cats and 2+ protein (proteinuria)
o Creatinine 2.4 mg/dl (very high for child) – renal insufficiency
o Would also be hypocomplementemia and elevated titers of ASO
• Acute Nephritic Syndrome
o Decreased GFR – renal failure
o Oliguria
o Edema
o Hypertension
o Active urine sediment: hematuria, proteinuria
• Kidney Biopsy
o Diffuse and global endocapillary proliferation occluding capillary lumen
o Three types: endothelial, mesangial and leukocytes
o Creatinine clearance is inversely proportional to glomerular capillary
obliteration
o Why are cells proliferating?

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  Glomerular deposits located on outside of glomerular capillary wall =
subepithelial location (same location as membranous
glomerulonephropathy but not separated by spikes)
 Hump-shaped deposits – large, electron dense
 Antigen not known
 Complement activation on inside of lumen
 Typical granular pattern of IgG and complement staining (C3)
• Granule = hump-shaped deposit
o Leukocytes release proteases and oxygen radicals in capillary wall
 Gaps form in GBM
 Formed blood elements – RBCs – can escape into urinary space
 Also leukocyturia
 Increased permeability to plasma proteins - proteinuria
 Form “cast” of tubule – can know that hematuria is of renal origin (vs.
bladder, urethra) = RBC casts
• Now, with dialysis, can tide patient over for period of 1 month+ while normal renal
recovery takes place
o Classic “flea-bitten” appearance of kidney when children used to die of infection
o RBC casts seen through surface of kidney, which is large and swollen
• Experimental model: acute 1-shot serum sickness
o Injection of foreign antigen into rabbits
o Glomerulonephritis produced: cellular proliferation and leukocytic infiltration
o Takes 1 week for primary immune response to occur
o Ab-Ag complexes in serum
o At critical level, activation of complement and deposition of immune complexes
in heart, joints and kidney – glomerulonephritis and vasculitis
o Decreased level of serum complement due to activation and fixation of
complement by circulating complexes
o As antigen consumed, glomerulonephritis resolves
o ASO titers can remains elevated for many weeks after infection
• Similarities between animals and humans
o % of animals that develop disease
 Only 10-20% develop nephritis
 If animal mounts profound immune response, large immune complexes
readily cleared
 If not good Ab formed, not enough to initiate disease
 Develop disease if produce intermediate-sized complexes in moderate Ag
excess
o Lag period between exposure to antigen and development of nephritis
 10-14 days after development of pharyngitis
o Self-limited nature of immune response
 95% resolve within 6 weeks
• Resolution phase
o Humps disappear – proliferation and leukocyte accumulation cease
o Chronic latent glomerulonephritis – if kidney stressed, can develop recurrent
episodes of hematuria and proteinura

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  Mesangial proliferation can persist and develop chronic
glomerulonephritis and glomerulosclerosis (scarring of matrix)
 If persists for 2+ years, high probability that will progress to chronic renal
failure
 Tubules receive post-glomerular circulation: efferent arterioles will have
reduced supply + no filtrate – functionally dead
 Kidneys contracted, small and granular surface
• Granularity due to nephron atrophy (depression) and compensatory
hypertrophy of remaining nephrons (elevation)
• < 2% have more severe crescentic pattern: extracapillary proliferation in addition to
endocapillary proliferation
o Rapidly progressive glomerulonephritis
o Cortex becomes atrophied – 5 mm
o Likely to progress to end-stage renal failure and least likely to resolve
• Post-infectious glomerulonephritis can be seen in other settings
o Impetigo (skin infection)
o Endocarditis – used to be called focal embolic glomerulonephritis, but can also be
seen in right-sided endocarditis: same mechanism as above
o Staph infection
o Viral or protozoal infections
• Etiology: post-streptococcal GN
o Following infection with certain “nephritogenic” streptococcal strains
(pharyngitic, dermal etc)
o Children more common than adults
o Time lag from infection to onset of GN: 7-10 days
o Nephrotic picture common
o Low complement and C3
o Positive serologic tests for recent strep infection
o Prognosis: excellent in children (95+%), good in adults (85%)
• Serum complement levels of glomerulonephritis
o Low Levels
 Acute post-infectious GN
 Lupus nephritis
 Idiopathtic MPGN
 Cryoglobulinemic GN
o Normal Levels
 IgA nephropathy
 ANCA-RPGN/Wegner’s/Microscopic PAN
 Anti-GBM disease
 Minimal change, FSGS, Membranous, Diabetes, Amyloid etc.

Case 2. IgA Nephropathy (Berger’s Disease)

• 16 y.o. high school junior notices dark brown urine after playing basketball
• Labs
o Creatinine 1.1 mg/dl
o Urinary sediment has RBCs and RBC casts (hematuria)

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 o Creatinine clearance 128 cc/min
o 660 mg proteinuria/day
o Serologic tests are normal or negative
• Kidney biopsy
o Increased number of cell confined to mesangium
o Patent capillaries
o Diffuse and global distribution
o Mesangial areas light up on IF for IgA: matrix infiltrated by electron dense
immune deposits – usually also C3
o Forms beneath GBM reflection over mesangial areas
• Demographics of IgA Nephropathy
o Most common in 2nd and 3rd decades of life, but occurs in all age groups
o Rare in blacks
o M/F = 2/1
o Incidence: 5-10% of all glomerulonephritis in US, 20-40% in Europe, Australia
and Asia
o After 20 years, 20-50% have progressed to chronic renal failure
• Related entity: Henoch -Schonlein Purpura
o Arthralgias
o Skin purpura – IgA deposition in extremities
o GI pain and bleeding – vasculitis in gut
o IgA dominant glomerulonephropathy
o Systemic disease vs. IgA nephropathy = renal limited end of spectrum
• Classification
o Primary: IgA nephropathy or HSP
o Secondary
 Liver cirrhosis – esp. alcoholic
 IBD
• Pathogenesis
o Defective hepatic clearance of IgA: liver cirrhosis
 Polymeric IgA absorbed by hepatocytes and transported and secreted into
bile
o Increased IgA production
 Association with elevated serum IgA
 Onset may follow URI (NO lag period) or gastroenteritis
o Defect of antigen exclusion at mucosal surface – mucosal inflammation
 Reflux of IgA bound to antigen into serum, then gets stuck in kidney
 URI
 Gastroenteritis
 Celiac disease
• IgA
o IgA 1 – bone marrow and mucosa: complexed into polymers
 J chain
 Type of IgA seen deposited in kidney
 Secretory piece – some from mucosa

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 o IgA 2 – from mucosa
• Etiology: IgA nephropathy
o Most common idiopathtic GN worldwide
o Defined by IgA deposition in mesangium
o Clinical presentation
 Young – gross hematuria
 Adults – proteinuria and hematuria: insidious onset
o Not “benign” hematuria (Berger’s Disease)
 20-30% progress ESRD over 20 years
 Poor prognosis
• Heavy proteinuria
• Impaired creatinine clearance
• Hypertension
• Offer treatment if any of these present
o Treatment options
 ACE Inhibitors/ARBs – especially if hypertensive
 Steroids
 Fish oil
 Mycophenolate – cytotoxics

Case 3. Nephritis in SLE

• 29 y.o. saleswoman develops arthritis of multiple joints and fever
• Exam: lymphadenopathy and malar rash (butterfly rash)
o Clinical renal disease develops in 70% of patients at some time but 100% may
actually have morphologic evidence of immune complex deposition in glomeruli
o 50% progress to chronic renal failure
• Labs:
o Urinalysis 3+ protein, 18-20 RBCs
o Creatinine 1.2 mg/dl
o 24 hour protein 1.8
o Complement 18% (normal 50-150%)
o ANA (anti-nuclear antibodies) positive, anti-DNA strongly positive
• Kidney Biopsy
o Antigen endogenous –autoimmune disease with decreased tolerance to self
antigens, including to dsDNA
o Kidney injury – chronic immune complex injury
o Diffuse proliferative glomerulonephritis – most severe form
o Endocapillary proliferation: increased endothelial and mesangial cells as well as
leukocytes
o Wire-loop immune deposits – pink material in glomeruli
 Massive thickening of GBM due to immune deposits
 Inflammatory cells reacting to immune deposits
 Full House – stain for IgG, IgM, IgA, complement
 Deposition in mesangium and peripheral capillary walls
o Subendothelial formation of immune deposits

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  Smooth contour (NOT granular) – presence of outer delimiting
membrane
o Presence of hematoxyphil bodies – pathognomonic
 Correspond to nuclei after being acted on by anti-nuclear antibody
o Circulating immune complexes with low levels of serum complement
 Mild: mesangial proliferative GN
• Mesangial deposits (not involving capillaries)
• Hypercellularity and proliferation of mesangium
• Intact foot processes – minimal proteinuria, mild hematuria,
normal GFR
• Sparing peripheral capillary walls
• Glomerular capillary lumens still patent
• Mild hematuria and/or proteinuria but renal function normal
 Focal endocapillary proliferative GN
• Mesangial & subendothelial – but limited to particular segments of
glomerulus with corresponding proliferative
• Diffuse – when involves more than 50%
 Membranous GN
• Mesangial
• Subendothelial – spike formation
• Pesent with severe proteinuria nephrotic syndrome
• Better prognosis than diffuse proliferative GN
 Can progress advanced sclerosing LN
 Renal biopsy is critical to management
• Treatment approach to SLE nephritis
o Mesangial (minimal and proliferative) LN: treat extrarenal lupus
o Focal LN: steroids, cytotoxics
 Prednisone is insufficient: need cyclophosphamide
 Side effects: major infections, osteoporosis, premature menopause
o Diffuse LN: steroids, cytotoxics
o Membranous LN: steroids, cytotoxics (in high risk patients)
 Indolent course: manifests as nephrotic syndrome rather than progressive
renal failure
o Advanced sclerotic LN: prepare for renal replacement
• Strategies for alternative therapies
o Sequential cytotoxic therapy
 Cyclophosphamide followed by mycophenolate/Imuran
 Mycophenolate
o Immunomodulation
 IvIg
 Anti-CD40-ligan
o Immunoablation

Case 4. Wegner’s Granulomatosis

• 58 y.o. insurance salesman develops sinusitis, weight loss, malaise and dry cough over 3

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 weeks
• Sinus films show opacification of left maxially sinus and found to have cavitary lesion on
chest x-ray
o Upper and lower respiratory as well as renal involvement
• Labs
o Urinalysis: RBCs, WBCs and RBC casts
o Creatinine 2.7 mg/dl
o Serum complement NORMAL
o Anti-GBM antibodies absent
o ANCA positive: anti-neutrophil cytoplasmic antibodies
• Kidney biopsy
o Characteristic morphologic finding: focal segmental necrotizing and crescentic
glomerulonephritis
o Wegner’s granulomatosis, PAN or renal limited
o Proliferative in extracapillary region = urinary space = crescents
 Between glomerular tuft and Bowman’s capsule
o Broad ruptures of capillary wall due to necrosis – goes with crescents
o IF: fibrin in distribution of crescents – necrosis and activation of coagulation
cascade in glomerular capillaries and fibrin passage into urinary space: growth
factor for parietal epithelial cells, forming crescents
o Rapidly progressive renal failure
o Absence of immune deposits = pauci-immune
 No electron dense deposits – not immune complex mediated
glomerulonephritis
o Inflammation of glomeruli & vessels = vasculitis
 Vasculitis of glomerular capillaries
o Lung involvement
 Necrotizing capillaritis: inflammation of alveolar capillary bed
• Can cause massive pulmonary hemorrhage
 Granuloma formation in Wegner’s
o Sinusitis
 Granulomatous inflammation with destruction of bone and cartilage in
upper airways
• Etiology of ANCA-associated disease
o No immune deposits
o ANCA
 Cytoplasmic staining: proteinase 3 – Wegener’s granulomatosis
 Perinuclear staining: myeloperoxidase (normally cytoplasmic distribution,
due to alcohol fixation) – microscopic polyangiitis
 Both antigens located in lysosomes of neutrophils
• How does ANCA cause disease?
o Neutrophils have to be primed
o URI may precede infection
o Priming – PMNs exposed to cytokines
o ANCA antigen, normally sequestered in lysosomes, resdistributed to surface of
cell

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 o Once expressed on surface, free to interact with ANCA-Ab
o Once Ab-Ag occurs, PMN can be stimulated to undergo respiratory burst: release
of oxygen radicals and cytokines onto endothelial surfaces
• Pulmonary-renal vasculitic syndrome
o Pauci-immune (usually ANCA associated)
 Wegner’s granulomatosis
 Microscopic polyangiitis
o Immune Complex Deposits (granular)
 SLE
 Cryoglobuinemic vasculitis
o Anti-GBM Ab deposists (linear)
 Goodpasture’s syndrome – when lung also involved

Anti-GBM Nephritis
• Rare disease – mostly occurs in 2nd and 3rd decade of life in males, another peak in elderly
females
• Renal involvement with pulmonary hemorrhage = Goodpasture’s disease
• Renal biopsy: crescent glomerulonephritis
o Quickly proceeded to anuria: rapidly progressive renal failure – poor prognosis
o Trichrome: extracapillary distribution of proliferation and fibrin
o IF: linear staining for IgG – pathognomonic (in kidney and lung)
 Target antigen = normal structural component of GBM (alpha 3 subunit of
collagen IV; regularly distributed within lamina densa)
• The same collagen is present in lung
• Damage to lung (influenza, hydrocarbons): exposure of normally
sequestered antigen – can be production of autoantibody to portion
of collagen IV
• Cross reacts with alveolar and glomerular basement membrane
 Local activation of complement (but NOT low serum complement)
 Chemotaxis of leukocytes – release of elastase, oxygen radicals etc.
 Endothelial injury exposes underlying GBM, allowing Hagemann factor
and fibrin deposition
 Fibrin and other growth factors pass into Bowman’s space, stimulating
parietal epithelial cells to proliferate, forming crescents
 Crescents obliterate urinary space – olguria or anuria
 Gaps in GBM where rupture has occurred
• Appearance of kidney
o Typical “flea bitten” appearance – massive RBC casts seen through surface of
kidney: kidney enlarged and hemorrhagic
• Rapidly progressive glomerulonephritis
o Rapidly progressive renal failure (weeks)
o RPGN = crescenteric GN
o Pathogenesis
 Anti-GBM disease
 Pauci-immune GN – ANCA associated
 Immune complex GN – SLE, IgA nephropathy: very rare

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 o Treatment and course depends on etiology and stage
• ANCA-associated
o Sinusitis and developing lung infiltrates
o Huge dose of steroids and cytotoxics
o Plasma exchange to reduce ANCA antibodies with severe disease – approaching
renal failure or hemoptysis
• Anti-GBM
o Steroid, cytotoxics, PTE
• Immune complex associated
o Rare – often missed
o Same treatment

Membranoproliferative Glomerulonephritis
• Thickening of GBM with proliferation of cells within glomerulus
• Most common in children and young adults - idiopathic
• Acute nephritic and/or nephrotic syndrome
• Severe and prolonged hypocomplementemia, especially C3
• Few remissions occur
• Slowly progressive course – 50% have chronic renal failure in 20 years
• In adults, may occur secondary to infection (hepatitis B or C) or cryoglobulinemia
• Cryoglobulins = immunoglobulins that precipitate in cold
o Associated with hepatitis, EBV, lymphoproliferative disease or collagen vascular
disease
o Hypocomplementemia
o Vasculitis of skin (purpuric rash) and arthritis
• Glomeruli enlarged and display diffuse, global endocapillary proliferation with resultant
accentiation of glomerular lobules
o Proliferation of mesangial cells, which frequently extend outward along peripheral
capillary wall between glomerular endothelial cells and GBM (mesangial
interposition or circumferential extension)
o Thickening of glomerular basement membrane walls
• IF: deposits of IgG, IgM and C3 usually found in subendothelial position

Chronic Glomerulonephritis
• Final common pathway of many forms of glomerulonephritis that develop advanced and
irreversible glomerular scarring
• Kidneys markedly reduced in size with finely granular cortical surface
• Disease in all four compartments: glomeruli, tubules, interstitium and vessels
• Chronic glomerulonephritis only if evidence of glomerular proliferation
• Otherwise, called “end-stage kidney”
• Patients usually have severe renal insufficiency and hypertension progressing to
syndrome of chronic renal failure
• If glomerulosclerosis not too advanced, hematuria and proteinuria may be present

CHRONIC RENAL FAILURE

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Chronic renal failure and end-stage renal disease
• 1999, 11 million patients with creatinine > 1.5 mg/dl
• End-stage renal disease: 500,000 on dialysis
• Reduced glomerular filtration rate that is inadequate to sustain life
• Renal failure is irreversible because of extensive kidney damage and fibrosis
• Although may occur after acute ilnness, majority have months-years of chronic renal
insufficiency characterized by moderately reduced glomerular filtration and few
symptoms
• Chronic renal insufficiency is almost progressive and irreversibl: GFR declines
inexorably until symptoms of uremic syndrome appear = end-stage kidney

Chronic vs. Acute Renal Failure

• Chronic: sufficient time for kidney to adapt to loss of functional renal parenchyma
o Most patients with significant chronic renal insufficienct able to maintain fluid
and electrolyte balane until this glomerular filtration rate has fallen greatly
o Finite but reduced rate of glomerular filtration
o Irreversible
• Acute: unable to cope with normal dietary water and electrolytes
o Often no GFR during acute episode
o Often reversible

Pathogenesis of Chronic Renal Failure

• Primary disease = initial damage to renal parenchyma
• Represents common response to kidney damage rather than the result of primary renal
disease
o Renal function continues to worsen after termination of primary disease
o Fall in GFR indepent of activity of primary disease
o Can be induced in normal kidneys by excising 1 ½ kidneys – reduction in renal
mass itself eventually leads to irreversible damage

Most Common Causes of Chronic Renal Failure

• Diabetes
• Hypertension
• Glomerulonephritis
• Polycystic kidney disease
o Even if the renal diseases are progressive, progressive and irreversible damage to
parenchyma is also result of secondary injury

Secondary Injury to Kidney

Glomerular hypertrophy and hyperfiltration

• Response to reduction in functional renal mass
• Increase in single nephron glomerular filtration rate and hypertrophy of surviving
nephrons

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 o Hypertrophy is driven both by hormones and by changes in renal blood flow
o Hyperfiltration is driven by an increase in renal plasma flow and an elevated
glomerular hydrostatic pressure
o Increased ANP
• Hyperfunctioning of intact nephrons initially mitigates decline in GFR that results from
loss of intact renal parenchyma
• However the mechanisms that cause hypertrophy and hyperfiltration eventually cause
irreversible harm to kidney
o Preventing these compensatory changes in animal models (reducing dietary
protein, blockade of AII or Ca channel blockers) slows progression to renal failure
o May lead to glomerulosclerosis and proteinuria
• Treatment
o Protein restriction, ACE I or ARB, glucose control

Phosphate retention and elevated PTH

• Universal complications of chronic renal disease
• Phosphate retention + elevated PTH = deleterious effects on renal parenchyma
• PTH – reduces permeability of GBM
• Phosphate retention – deposition of calcium and phosphate until renal parenchyma and
subsequent destruction of functional renal mass
• Vicious cycle: parenchymal damage causes phosphate retention and PTH elevation,
which causes further parenchymal damage

Systemic Hypertension
• Common complication
• Increase in systemic blood pressure accelerates decline in renal function

Hyperlipidemia
• May be result of chronic renal dise4ase
• Contributes to worsening renal insufficiency and destruction of renal parenchyma

Clinical Spectra and Chronic Renal Disease

• Decreased number of functioning nephrons
• Remaining nephrons filter supranormally – more than 40% must be lost before capacity
for compensatory hypertrophy exceeded and GFR falls
• Range of ability to excrete electrolytes and water is limited
o Diminished ability both to handle excess water/salt or conserve water/salt

Sodium Excretion
• GFR = 200 L/day
o Excretion = 1 L/day by 2 million nephrons
o Each nephron normally excretes 0.5 microliters
o Tubules normally poised for avid salt reabsorption
• GFR = 20 L/day
o Excretion = 1 L/day by 1/10 of nephrons

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 o Each nephron excretes 5 microliters
o It is as if water and solute intake were increased 10 fold over normal kidney
o Represents necessary salt wasting
• Proposed mechanisms
o Volume expansion with inhibition of RAAS
o As nephrons are lost, GFR of remaining nephrons increases, increasing the single
nephron filtered load of Na
 If Na reabsorption not increased, Na excretion per nephron will decrease
o Elevated ANP as a result of volume expansion
 Enhanced afferent vasodilation – used as diuretic
 Enhanced RBF – oncotic pressure does not rise as quickly for any given
spot in glomerulus (will not reach filtration reversal point)
 Also increases hydrostatic pressure in glomerular capillary
 GFR will increase because increased hydrostatic pressure and decreased
oncotic pressure
 Also activation of ANP receptos (gc-A) in collecting ducts reduces Na
recovery
• Range of response to dietary changes is limited
o Sudden increase in dietary Na – Na retention and volume overload results
 Clinical: hypertension and edema (also pulmonary)
o Sudden decrease in dietary Na – negative Na balance and pre-renal azotemia
 Acute decrease in GFR may initially be pre-renal and reversible with
volume replacement but may progress to ATN (less likely to resolve and
more likely to be severe in patient with chronic renal failure)
 Chronic renal failure secondary to tubulointerstitial disease is sometimes
associated with excessive salt wasting that can cause symptomatic volume
depletion
• Treatment
o Anti-hypertensive medication
o Diuretics
o Fixed salt intake

Water Excretion
• Dilution – maintained until late in progression of chronic renal failure
o Ability to generate solute free filtrate by TALK and DCT remain intact
o Reduction in GFR limits amount of free water (in excess of solute) that can be
excreted – lower volume of dilute urine
o 12 mL free water/100 mL GFR – fixed by function of TALH and distal
convoluted tubule
o If GFR = 200 L/day, then 24 L of free water is maximal generation (12% of GFR)
 600 mOsm/30 mOsm/L = 20 L dilute urine
o If GFR = 20 L/day, maximal free water that can be excreted is 2.4 L
 Large water load, which would be excreted by normal kidneys, will cause
hyponatremia in chronic renal failure
 Maximal dilution of urine is not achieved
 600 mOsm/160 mOsm/L = 3.8 L dilute urine

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 • Concentrated
o Lost early by anatomical disturbance of renal medulla
o Degree of separation between tubule and peritubular capillaries by fibrosis
correlates with failure to concentrate urine
o Sickle cell anemia, analgesic nephropathy, cystic diseases, obstruction and
nephrocalcinosis distorts relationship
o To concentrate urine, need:
 Undisturbed medullary osmotic gradient
• Problem: medullary blood flow increases as number of functioning
nephrons decreases – medullary wash-out of gradient
 Propr regulation of water permeability at collecting duct to ADH
• Problem: uremia impairs effect of ADH on collecting duct
o Nocturia will result
 600 mOsm/1200 mOsm/L = 0.51 L
 600 mOsm/400 mOsm/L = 1.51 L
• Treatment of inflexible handling of water
o Water restriction

Acid-Base Balance
• Daily load of nonvolatile acid = 1 mEq/kg/d – MUST be excreted to maintain acid-base
balance
• Protons pumped into lumen of CD titrate NH3 secreted by duct
• Excretion of NH4+ accounts of 80% of required acid excretion
• Surviving nephrons have only 4-5 fold ability to increase ammonia secretion
• If further decline in GFR, metabolic acidosis results
• High anion gap due to accumulation of organic anions, sulfate and phosphate
• Acidosis seen at lower creatinine in patients with tubulointerstitial disease
o Diabetes – type IV RTA: hyporeninemic hypoaldosteronism
o Elevated plasma K+ suppresses ammoniogenesis
o Deficiency in urinary buiffer limits H+ secretion and excretion
• Metabolic acidosis due to chronic renal failure is usually not very severe
o Massive base defect but occurs over long period
o Buffers, particularly in bone, maintain blood [HCO3] above 15 mEq/l until very
late in disease
o Titration of bone buffers is responsible for bone disease in chronic renal failure

Potassium excretion
• Secreted by distal nephron – relatively independent of GFR
• Secretion function of urine flow rate, aldosterone secretion and acid0base status
• Plasma K+ maintained in normal range until very lare in chornic renal failure
o Single nephron K+ increases due to progressive increase in single nephron
distal flow rate
o Also increased basolateral membrane (Na-K ATPase) perhaps due to aldosterone,
stimulated by hyperkalemia
o Increased urine flow rate and structural changes > acidosis (hyperkalemia)

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 • Acute renal failure: oliguria – hyperkalemia very common
• Subset of patients with tubulointerstitial disease develops hyperkalemia with Cr 2-4
o Hyporeninism with subsequent hypoaldosteronism
o AII trophic for zona glomerulosa – basal secretion of AII may be necessary for
aldosterone secretion in response to increased [K+]

Calcium and phosphorous metabolism

• Normal plasma phosphate – 3-5 mg/100 ml
o As GFR decreases, unless tubular resorption decreases, excretion of phosphate
declines - hyperphosphatemia
• Normal plasma concentrations: activity product of Ca and PO4 sufficiently near
saturation that crystallization is prevented only by presence of circulating inhibitors
o Significant increase in concentration of phosphate tends to result in precipitation
of calcium phosphate, especially in areas of body with higher pH
o Kidney – calcinosis accelerates renal failure
o Stomach, skin, lung and cornea
o High calcium content of uremic skin – uremic itching
o Metastatic calcification leads to a decrease in free calcium, increasing PTH
• Elevation in PTH during progression to chronic renal failure is also due to effects of
phosphate retention on vitamin D metabolism
o High phosphate and acidosis both suppress 1,25 OH2 D formation
o Reduced 1,25 OH2 D further stimulates PTH
• PTH reduces phosphate absorption by renal tubule
o Early phase: phosphate excretion increase and plasma phosphate normal
• All patients in chronic renal failure have elevated PTH
o Resorbs bone and releases calcium hydroxylate into blood (base – helps with acid
base balance)
o PTH bone disease: osteitis fibrosa cystica
o May also have role in peripheral neuropathy and be toxic to kidney
• Problem: 1,25 OH2 D synthesized in kidney – not made in renal failure
o Decreased calcium absorption from gut
o Osteomalacia in adults and rickets in children
• Treatment
o Limit phosphate intake
 Alumin hydroxide, oral calcium or ion exchange resins that bind ingested
phosphate
o Give 1, 25 OH2 D after phosphate corrected if hypocalcemic
o Bicarbonate to mitigate acidosis
o Supply calcium
o PTH antagonism or removal

Chronic Renal Failure

• Irreversible loss of GFR after injury
• Residual function (Cr > normal)
• Residual function can be compatible with life but characterized by series of defects in

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 handling of Na/water/H and also Ca/PO4. In addition, there is usually severe anemia.
These defects are unremitting.
• Residual function progressively lost over period of year, eventually resulting in end-stage
renal failure.
• Progressive loss of GFR is not related to primary injury but due to slowly acting
secondary changes in kidney, such as scarring.
• These secondary changes are stimulated by:
o Systemic and glomerular hypertension
o Deranged Ca/PO4 metabolism
o Anemia
o Hyperlipidemia
o Hyperglycemia
o Proteinuria – chronic proteinuria is toxic to nephron

End Stage Renal Disease

• Minimal or no residual function that produces unremitting defects in handling of
Na/water/H and also Ca/PO4 which are incompatible with more than few days-weeks of
life. Compensatory mechanisms no longer adequate.
• Uremia occurs in end stage.
o Severe derangement in fluids and electrolytes
o Deposition of Ca/PO4
o Severe anemia and bleeding
o Changes in mental state – drowsiness
o Cerebellar activity – asterixis
o Neuromuscular activity – clonus
o Change in lining of membranes surrounding heart and lung – changes in heart
sounds (rub); dangerous and must be treated

• Course of chronic renal failure is long – may take decades

• Even when ESRD occurs, can keep patients alive – dialysis and renal transplant

• Normally, huge ability to conserve or excrete salt and water

• Kidney protects body from environmental perturbations
• Chronic renal failure:
o Can only excrete a few liters of water a day (vs. 20 L)
o Obligate loss of 1 L
o Only 200-50 mEq of NaCl excretion
o Severe limited range and lack of flexibility
o Mostly, this is asymptomatic – if we can limit environmental perturbations, match
kidney’s capacity to excrete
o If there is diarrhea or febrile illness, may get volume depletion and
hyperosmolarity because kidney can’t conserve salt or water
o Most common presentation: volume overloaded and hypo-osmolar – unable to
excrete excess salt and water
o Excesses are cumulative

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 o As kidney fails, range of function becomes more limited

Glomerular disease – capacity for compensation because not diffuse

Tubulointerstitial disease – reduced capacity for compensation because all nephrons affected

Loss of renal function = linear disease

• If fall off line, must be due to another cause

Exacerbation of Loss of GFR

• HTN and glomerular HTN
• Metabolic stress (protein load, DM, pregnancy)
• Derangements in Ca and PO3
• Hyperlipidemia

Organ System Dysfunction

• Renal osteodystrophy: combination of hyperparathyroidism, vitamin D3 deficiency and
chronic metabolic acidosis
o May be subclinical or patient may present with bone pain
o Increased risk of fracture
• Anemia
o Erythropoietin derived from kidney – deficiency with loss of renal mass
o Hemolysis increased by unknown mechanism
o Uremic gastritis predisposes to bleeding
o Clinical: SOB, fatigue, decreased cognitive function
• Uremia – indication for dialysis
o Accumulation of “uremic toxins”
o Disturbed mental function: lethargy or confusion
o Seizures, asterixis
o Uremic serositis: pericarditis or pleuritis
o Uremic gastris
o Edema

GFR vs. Creatinine

• When glomerular filtration rate declines, serum creatinine will increase exponentially
• GFR = UcV/Pc
• Deceptive small increase in serum creatinine
o Increase of 1 mg % when creatinine is low = significantly greater loss of GFR
than same 1 mg% when creatinine is high
o Ask how many-fold creatinine is changed over initial, normal value

Observing Renal Parenchymal Damage

• Reserve: ability to increase single-nephron glomerular filtration rate x 2
o Removal of kidney from donor
 Immediately, GFR falls to 50%
 Over time, compensation so GFR of remaining kidney x2

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 • If filtration rate is normal, even with significant loss of renal parenchyma, there will be no
change in serum creatinine

Progression of Renal Failure

• Once irreversible damage with loss of 50% of GFR has occurred, slow progression to
complete renal failure usually observed
• Loss of GFR:
o Hyperphosphatemia – deposition of calcium salts damage kidney
o Hypocalcemia causes secondary hyperparathyroidism – toxic to glomerulus
o Hypertension accelerates nephron loss
o Survivors hypertrophy and hyperfilter – process is deleterious: glomerulosclerosis
with further loss of nephrons results
o Excessive dietary protein exacerbates problem

RENAL REPLACEMENT THERAPY

Treatment Options for Chronic Renal Failure

• Anti-hypertensives
• Diuretics
• Diabetic control
• Phosphate binders/calcium/vitamin D3
• Erythropoietin, iron
• Sodium bicarbonate
• ACE Inhibitor, ARB
• Dietary restrictions: potassium, sodium, water, protein etc.

End-stage Renal Disease

• Irreversible reduction in intrinsic renal function below that which can be compensated for
by any adjustments in diet or medications, such that there is continuing accumulation of
nitrogenous waste products etc.

Indications for Renal Replacement Therapy

• Intractable volume overload
• Hyperkalemia
• Anorexia, nausea, vomiting, gastritis
• Lethargy, seizures, com
• Pericarditis
• Bleeding due to platelet dysfunction

Causes of End-stage Renal Disease

• Diabetes – 40%
• Hypertension – 27%
• Glomerulonephritis – 12%
• Cystic diseases – 3%

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 • Interstitial nephritis – 3%
• Collagen vascular diseases – 2%
• Obstructive uropathy – 2%

• Many diseases that used to kill people are better treated – more people end up in ESRD

End-Stage Renal Disease: treatment options

Dialysis
• Hemodialysis – 2/3 of patients
o Hollow-fiber artifical kidney
o 400 mls/min
o Tissue blood equilibrium
o Rapid correct of metabolic, fluid imbalance
 See-saw of electrolytes – affects patient well-being
o Cardiovascular instability
o Angio-access required
o Three times weekly
o Better clearance of small molecules
• Peritoneal Dialysis – 5%
o Dialysis fluid goes into patient’s peritoneal cavity
o Exchange takes place across peritoneal membrane
o Bigger gaps between mesothelial cells vs. hemodialysis cartridge – larger particles
filtered better
o Not as efficient – needs longer time
o Gradual correction of metabolic, fluid imbalance
 Blood chemistries ~ steady state
o Respiratory embarrassment – pushes up diaphragm
o Peritoneal access – potential source of infection
o Daily treatments: how much fluid goes into belly, how long it stays there and
glucose concentration
 Can’t leave fluid in too long – dwell time
o Loss of albumin
o Better clearance of “middle molecules” – advantageous in treating uremia and
more liberal dietary restrictions
• Factors determining clearance of substances by dialysis
o Molecular size
 BUN – small molecule: cleared proportionally to blood flow
 Larger molecules – increased blood flow does not increase clearance
o Protein binding
o Relative concentration (tissue vs. blood vs. dialysate)
o Membrane characteristics (pore size)
o Blood flow
o Diasylate flow
• Dialysate solution

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 o High concentration of sugar to pull Na and water in
o Low K
o Bicarbonate higher
o Calcium higher
o No phosphorous, creatinine or urea
o All concentrations can be adjusted for individual patients
• Mortality of dialysis remain high
o Population is generally sick
o Accelerated cardiovascular disease
• “High intensity” hemodialysis: more dialysis = better outcome
o Increased duration: same frequency, longer treatments
o Increased frequency: daily short treatments
o Increased frequency and duration: daily (nocturnal), longer treatments

Basic Principles
• Convection
o Movement of solutes across a semi-permeable membrane carried in bulk
movement of water (hydrostatic pressure, “ultrafiltration”)
• Diffusion
o Movement of solutes across a semi-permeable membrane down their
concentration gradient

Renal transplanation – 1/3 of patients: 16,000/year

• Cadaver donor – 55%
• Living donor – 45%
o Living related donors
o Living unrelated donors (spouses, friends)
• Living donor kidneys have better survival than cadaveric kidneys
• Waiting list: 60,000

• Single kidney from donor implanted into iliac fossa of recipient

• Renal artery and vein anastamosed to external iliac artery and vein. Ureter implanted into
bladder.
• Recipients native kidneys are not removed
• Major barrier to success is immunologic

Advantages vs. Dialysis

• Better renal function
• No further need for dialysis
• Complete corretion of fluid and electrolytes abnormalities
• Improved quality of life
• Improved longevity (for comparable patients)
Disadvantages
• Lifelong immunosuppression
• Possible rejection (likely eventual allograft failure)

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Allograft Immunogenicity
• MHC – HLA
• 2 HLA-A, 2 HLA-B and 2 HLA-DR examined, one paternal and one maternal
o Mismatch at HLA-DR locus have greater impact on outcome
• Antibody or T cell mediated rejection
• Main target of cellular rejection = renal tubular cells (rarely glomeruli)
• Main target of antibodies = glomerular and vascular

Immunosuppression
• Corticosteroids
o Inhibit APCs and T cells
• Lymphocyte proliferation/purine synthesis inhibitors – mycophenolate mofetil
• Calcineurin inhibitors – cyclosporine, tacrolimus
o Crucial for activation of T cells and production of Il-2
• mTOR inhibitors – rapamycin (sirolimus)
o Protein kinase cascade when T cells activated in response to Il-2
• Anti-lymphocytes antibodies – polyclonal or monoclonal
• Often combination therapy: calcineurin inhibitor + purine synthesis inhibitor +/-
corticosteroids

Matching donors and recipients

• Essential: if either is negative, can get hyperacute rejection!
o ABO compatibility
o Negative cross-match
 Ab reactive with donor HLA
 Donor lymphocytes + recipient serum + complement - ? cytolytic Ab
 Transfusion, pregnancy, failure of previous transplant
• Desirable: HLA compatibility

Challenges to long-term success

• Donor shortage
• Chronic allograft nephropathy – long-term progressive deterioration in renal function
• Patient death
o Cardiovascular disease
o Complications of long-term immunosuppresion
 Malignancy
 Infection

Chronic allograft nephropathy

• Immunologic
o HLA mismatch
o Acute rejection episodes
o Prior sensitization (anti-HLA antibodies)
o Inadequate immunosuppression

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 • Non-immunologic
o Donor organ quality
 Number of nephrons
 Delayed graft function/ischemia-rejection
o Nephrotoxicity of immunosuppressive drugs
o Hypertension
o Hyperlipidemia
o Hyperfiltration

VASCULAR DISEASE

Case 1.
• 28 y.o. black male presents with acute low back pain following weekend basketball game
• History of HTN
• BP: 148/90 – persistent
• HTN in both parents
• BUN 13 mg/dl, creatinine 0.9 mg/dl
• Fasting glucose: 96 mg/dl
• Lifestyle modifications alone may be sufficient – few other cardiovascular risks
o Weight reduction
o DASH diet – high vegetable, high fruit diets
o Sodium reduction
o Physical activity
o Moderate alcohol consumption
o These will not only lower BP numbers but also reduce incidence of CV events –
strokes and MI
• If lifestyle modifications does not achieve BP in 3-6 months, use medication

• 1/3 of population over 18 y.o. have HTN

• Increased prevalence in older population
• 2nd most common cause of ESRD (after diabetes)
• Every diabetic patient who reaches dialysis or transplantation = hypertensive

Pathology of Hypertensive Arterionephrosclerosis

• Renal disease cause hypertension
• Hypertension can cause renal disease – hardening of artery
• Most patients are asymptomatic
• Kidneys: bilateral, small kidneys with granular appearance and uniform thinning of cortex
• Granularity – patchy scarring of kidney
o Hyalinosis and sclerosis of arterioles
 Damage to blood vessel wall, leading to insudation of plasma proteins and
degenerating medical myocytes
o Compensatory glomerulomegaly
o Perihilar segmental or globular glomerulosclerosis – seen in patients with HTN
and proteinuria

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 o Patchy distribution of tubular atrophy and interstitial fibrosis

Case 2.
• 60 y.o. with severe hypertension presents to ER with severe headaches over last few
weeks and chest pain and SOB of 2 hours duration
• BP 190/130, P 84, R 18/min, blurring of disc margins on eye exam – early papilloedema
from malignant hypertension
• S4G, rales at both bases and no edema
• Labs: BUN 38, Cr 2.4, U/A 2+ protein, 2+ heme 10-15 RBC no cases
o Some proteinuria in urine – but not in nephrotic range
• CXray cardiomegaly
• EKG shows LVH+ evidence of acute inferior MI
• Given IV labetalol, ASA and plavix and bare-metal cardiac stent placed in his R coronary
artery
• BP controlled with beta blocker, ACE I and diuretic
• Feels much improved but BUN and Cr only change slightly
• USG shows 10 cm echogenic kidney – small; echogenic = scarred

• What are the consequences of severe (accelerated, malignant) HTN?

o End-organ damage
o Papilledema of eye discs
o MI
o Renal damage: proteinuria, elevated BUN and Cr

• What is likely to happen to kidney function if stops BP medications after discharge?

o Likely to have progressive renal failure
• What will happen to kidney if he stays on BP medications?
• How many BP medications will it take to control his HTN?
o More than 1: it takes multiple medications to get BP under control
o Events lowest with blockers of RAS
• If this patient died from MI, what would kidneys look like on autopsy?

Many patients in US are not at JNC-recommended BP goals

• 4-32% not at diastolic goal
o Also very important for mortality
• Many more not getting to systolic goal – this is killer; more related to CHD events
o Direct relationship between loss of kidney function and systolic BP

Acclerated Hypertension
• Gross: depends on time course
o Long history: shrunken and granular
o Short history: normal in size, smooth but multiple petechial hemorrhages
• Glomerulus underperfused
• Fibrinoid necrosis of vessel wall – proliferation of endothelial cells and occlusion of
lumen

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 o Fibrin deposition and entrapped RBCs
o Damaged RBCs = schistocytes in peripheral blood smear
o Microangiopathic hemolysis – loss of RBCs with formation of schistocytes
• Thrombotic microangiopathy
o Acute renal failure
o Microangiopathtic anemia
o Thrombocytopenia
o Result: dysfunction of vital organs
• Endothelial injury = cell event in thrombosis in thrombotic microangiopathy
o Tips balance toward procoagulation and thrombin formation

Anti-phospholipid antibody syndrome

• Producing anti-cardiolipin that is reacting with endothelium: + ANA
o Don’t develop lupus
• Family of antibodies (IgG, IgM, IgA) against negatively charged phospholipids
• Hypercoagulable secondary to damage to endothelium
• False + VDRL
• Prolonged PTT – looks like anti-coagulant
• Hypertension
• Active urine sediment – hematuria, proteinuria
• Three conditions
o SLE
o Lupus-like syndrome
o Primary anti-phospholipid antibody syndrome
• Recurrent arterial and venous thromboses
• Placental thromboses and spontaneous abortions
• Livedo reticularis – skin change: dilated network of veins
• CNS complications – strokes, seizures
• Pulmonary hypertension
• If anticoagulate them, improve renal function and better outcome

Pathology
• Glomeruli show ischemic changes (global wrinkling of GBM, tuft retraction and cystic
dilation of Bowman’s space)
• Glomeruli show segmental intracapillary fibrin – distinctive for TMA
• Arteries show widespread luminal narrowing with extensive subendothelial hyalinosis,
endothelial swelling, focal myocyte dropout
• Focal mucoid intimal fibroplasias – trapped RBC and fibrin within damaged vessels
• IF usually negative; can see fibrin staining
• EM: subendothelial fibrin with widening of subendothelial space – not electron dense

Hemolytic Uremic syndrome

• Diarrhea and ARF

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 • Petechial rash on lower extremities
• Anemic, thrombocytopenic
• Proteinuria, hematuria, + RBC casts
• BUN 45, Cr 3.1
• Renal disease progressive – Cr goes up to 6

• Shiga toxin associated

• Peak < 5 y.o.
• Onset GI sx, cramps, diarrhea, n/v, fever
• 70% bloody diarrhea w/I 2 days
• E.coli 0157 – toxin can be found in sstool
• Hemorrhagic colitis +/- HUS
• Usually beef contaminated at slaughter, also raw milk, vegetables and fruit juice

Pathology
• Fibrin thrombi in TMA – predominantly glomerular capillaries
• Can get cortical necrosis – likely to develop ESRD
• Vessels spared
• May also get hemorrhagic necrosis of colon – correlates with bloody diarrhea
• STX binds to receptor on endothelial cells and GI tract
o Subunit binds 60S ribosomes, inhibit protein synthesis
o 5 B subunits binds to glycolipid receptors (gp3) on surface of colonic epithelium,
endothelium and WBCs
• Higher risk for HUS
o Antibiotics
o Bloody diarrhea
o Fever, vomiting
o Leukocytosis
o < 5 y.o.
o Females
• Outcome
o 50% dialysis during treatment
o 25% have neurological signs – CVA, seizures, coma
o 3-5% die in acute phase
o Long term renal dysfunction common
o 3-18% ESRD
o Duration of anuria predicts dysfunction

DISEASES OF TUBULES AND INTERSTITIUM

• Ischemic/toxic
o Acute Tubular Necrosis
• Inflammatory
o Tubulointerstitial nephritis
 Infection, allergic/drug-induced, systemic disease

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Case 1.
• ETOH abuse but normal function function 2 months ago
• Unarousable – drinking binge
• BP 100/60, temp 101
• Extremities – swelling and tenderness of both legs
• BUN 48, Cr 6.2
• CBC – 15,000 with increased polys
• U/A 4+ heme, no rbc or wbc
• Chest x-ray: pulmonary infiltrate
• Given gentamicin and ampicillin
• Hypotensive and swollen tender muscles – heme+ but no RBCs = rhabdomyolysis
• Hypotension – dehydration and volume depletion causes rhabdomyolysis-induced renal
failure
• ATN muddy brown casts

Biopsy
• Finding in tubules – marked damage to tubular epithelium, sloughing of epithelium with
“naked” interspaces
• Loss of brush border
• Mitochondria swollen
• Areas where tubular epithelium lost attachment to basement membrane
• Dark brown casts – rhabdomyolysis; also tips of papillae have discoloration

Predisposition of tubular epithelial cell

• High metabolic activity/O2 requirements – ischemic ATN
o Decreased renal blood flow
o Trauma, severe blood loss, CHF, septic shock
o Gross: P & S (pale and swollen)
• Role in concentrating and reabsorbing filtrate

Three Phases of Ischemic ATN

• Initiation
o First 36 hours, dominated by initial event
• Maintenance
o Up to 3 weeks, oliguric, dialysis required
• Recovery – “diuretic phase”
o Increasing urine output
o Often substantial because hasn’t reconstituted brush border

Nephrotoxic ATN
• Many toxins: gentamicin, amphotericin B, cisplatin, zolerdronate, ethylene glycol,
mannitol, hemoglobin, myoglobin
• Similar pathology to ischemic ATN
• Additional, toxin-specific findings

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 o Ethylene glycol – calcium oxalate crystals and ballooning vacuolization
o Osmotic agents/radiocontrast – osmotic nephrosis
o Abnormally high levels of normal physiologic substances: e.g. multiple myeloma
 Massive amounts of light chain
 Crystals and casts within lumen with giant cell reaction

Case 2.
• 65 y.o. retired ob-gyn referred for presumed RPGN (rapidly progressive
glomerulonephritis – crescenteric)
• HBP x 40 years controlled on meds; arrhythmias – verapamil, hypothyroidism
• Urinary urgency – urologic check-up: urinalysis negative
• Urticarial rash on legs
• 1 week PTA – donated blood then gave blood
• BUN 94, Cr. 4.4, K 6.7, Hct slightly reduced, platelet count normal
• U/A – RBC but no casts
• BP 170/90, fine maculo-papular rash on chest and upper arms
• BUN 96, 2+ hematuria

Pathology
Acute Interstitial Nephritis
• Pathogenesis: cell-mediated hypersensitivity reaction
• Interstitial inflammation and edema
• Inflammatory cells extending over tubular basement membranes to cause tubulitis
• Eosinophils – drug induced/allergic
• +/- granulomas
• Clinical features: rash, fever, eosinophilia; hypersensitivity triad = 30%
o Rash – maculopapular mobiliform rash
• Classic drugs: penicillins and beta-lactams
o Other antibiotics – quinolones: ciprofloxacin
o Proton pump inhibitors
o Diuretics
o NSAIDs
• May be non-oliguric renal failure
• Urinary findings:
o Mild proteinuria
o Hematuria – may be gross
o Sertile pyuria
o Eosinophiluria – strongly suggestive of acute interstitial nephritis

Case 3.
• 64 y.o. black female with diabetes and mild HBP for 6 years
• BS has been poorly controlled – polyuria and nocturia
• Recently, dysuria and frequency
• Develops fever, chills and left flank pain which increases over 24 hours

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 • BP 110/72, pulse 100, temp 102
• Marked L CVA tenderness
• BUN 35, Cr 1.4 – may be twice normal
• WBC – 16,500, Hct 39% - not anemic
• 3+ glucosuria, +++WBCs and WBC casts, + heme
• Urinary sodium: 42, FeNa = 1.8
• Stone in left kidney – no dilatation or blockage
• Treated with hydration, ampicillin, gentamicin
• Over next 24 hours, BP increases to 145/82, urine output remains copious
• BUN decrease to 14 and Cr down to 0.7

Pathology
Acute pyelonephritis
• Diffuse interstitial inflammation
• NO eosinophils
• Neutrophils plugging tubular lumen
• WBC casts with many PMNs
• Generally unilateral – her renal insufficiency more likely due to sepsis
• Clinica: back pain, fever, pyuria +/- Renal insufficiency
• Routes of infection
o Ascending > hematogenous
o More common in women
• 85% gram negative bacilli – E. coli
• Hematogenous – more likely Gm +
• Gross: kidneys normal size +/- coalescent abscesses
• Micro: severe inflammation, PMNs
o Microabscesses
o PMN cats and tubules

Increased Risk
• Obstruction: prostate, pregnancy, tumors, neurogenic bladder (DM)
• Instrumentation
• Vesicoureteral reflux
o 50% of UTIs in 1st year of life
o Congenital anomaly: intravesical portion of ureter lacks normal oblique course
that prevents reflux
o Voiding cystourethrogram – radiocontrast in bladder; goes back into collecting
system if VUR

Chronic Pyelonephritis
• Defintion: chronic renal disorder with scarring, inflammation and deformity of
calyces/pelvis (ascending)
• Gross: shrunken
o Irregular, asymmetric broad/flat (U-shaped) scars

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 o Papillary blunting
• Micro: tubulointerstitial inflammation
o Dilated flattened epithelium – thyroid type tubular atrophy
• Clinical: insidious onset of renal insufficiency
• +/- HTN, mild proteinuria, decreased urinary concentration, culture negative
• Rarely followed “usual” acute pyelo
• More common with persistent obstruction or VUR
• +/- awareness of acute episodes
• Rx: relieve obstruction

Case 4.
• 52 y.o. female with rheumatoid arthritis – aspirin, tyelonal and NSAIDS daily
• Develops R flank pain, no fever, no chills, no dysuria
• No edema
• Labs: trace proteinura, few RBCs, many WBCs
• Urine culture = no growth
• Abnormalities in parts of collecting system

Papillary necrosis
• Green-black necrosis at tips of papillae
• Analgesic nephropathy
o Abusers and users: headaches and arthritis
o Female: male = 6:1
o Large amounts over prolonged time periods
o Renal abnormalities
 Sterile pyuria
 Only mild proteinuria and hyeprperfusion
 Decreased concentration ability
 Decreased net acid excretion
 Salt wasting
 Papillary necrosis
o Patients can recover function if stop analgesic use
• Causes of papillary necrosis
o Obstructive pyelonephritis
o Sickle cell anemia – medulla leads to sickling, which causes medullary ischemia
o Analgesic abuse (phenacetin)
 Increased risk with combinations
 Direct toxicity and ASA-induced PG deficiency
o Diabetes mellitus
• NSAIDs
o Multiple patterns of renal disease
 Acute interstitial nephritis
 Acute tubular necrosis: loss of PG vasodilation/ precipitates ATN in
setting of volume depletion
 Minimal change disease/membranous glomerulopathy

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  Papillary necrosis
 Same nephrotoxicity for COX-2 inhibitors

MICROSCOPIC

• Membranous glomerulopathy
o Subepithelial immune deposits
o Thickening of GBM
• Membranoproliferative glomerulonephritis
o Proliferative (increased cellularity) and thickening of basement membrane
o Mesangial interposition – migrate into capillary wall
o Commonest cause in adults: hepatitis C, B cell neoplasia (positive only for kappa
or for lambda light chain), endocarditis – subacute
 Chronic circulating immune complexes leading to glomerular deposits
 Complement activation
o Lobulated tufts
o Silver stain – tram tracks
o Type I
 Subendothelial immune deposits
 IF: IgG and C3
o Type II: same on light microscopy
 EM: dense deposit disease
 Intramembranous dense deposits
 Entire GBM darker than usual

Diabetic glomerulosclerosis
• Diabetes, HTN
• Early stages: glomerulomegaly linked to hyperglycemia – microalbuminuria
• Progression: thickening of basement membrane – sclerosis (not proliferative)
• Mesangial sclerosis – increased mesangial maxtrix and arteriosclerosis (severe
thickening and hyalinosis ~ exaggerated hypertensive kidney changes)
• Progression: nodular mesangial sclerosis and microaneurysms of glomerular
capillaries
• Large lesions: Kimmelsteil-Wilson lesions = severe nodular mesangial sclerosis
o Nodules of acellular matrix material

End-stage Kidney
• Sclerotic glomeruli
• Arterio-arteriolosclerosis
• Tubular atrophy
• Interstitial fibrosis

HYPERTENSION

• Life insurance data: inverse relationship between life expectancy and blood pressure

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 • No sharp cut-off in terms of risk that defines “hypertensive”
• Framingham study: 2/5 of population have > 160/95, incidence increases with age

Mechanisms of Hypertension
• BP ~ CO x vascular resistance
• Vasoconstrictors:
o NE – pheochromocytoma: excessive vasoconstriction
o AII – overactivity of Renin-Angiotensin System: HLT due to high ECFV
 E.g. Renal artery stenosis – kidney secretes renin in response to decrease
in perfusion pressure secondary to atherosclerotic plaque/disease of
vascular smooth muscle
 AII = direct vasoconstrictive effect – acute effect
 AII also increases aldosterone that increases CDTR as well as efferent
constriction, increased FF and PTR – causes volume expansion
 Even if deactivate RAS secondary to volume expansion, new steady state
reached at higher plasma volume – steady increase in MAP
• Volume expansion increases cardiac output? Mechanism not
known
• If Na depleted animal e.g. via diuretic, renin will increase again
and HTN is now due to AII and sensitive to its inhibition
 Excess aldosterone due to adrenal tumor
• Expands extracellular fluid volume – HTN
• Onset: CDTR increased and decreased Na excretion
• Result: ECV expanded = increasing weight
• Overtime, expansion will occur until return to new steady state (Na
excretion = Na intake) when all other mechanisms of ECFV
antagonize effects of aldosterone (e.g. decreased AII and increased
ANP)
• However, as long as subject in given MC, extra Na and water will
be retained, ECFV will be expanded and HTN will be present
 Excess aldosterone due to genetic mutation: glucocorticoid-sensitive
• Chimeric enzyme: controlled by ACTH but produces aldosterone
• If administered glucocorticoids, shut down ACTH
 Kidney with hyperactive Na+ channel in collecting duct
• Channel under control of aldosterone
• Normally, if eat excess Na, Na channel inactivated
• Lyddle’s syndrome – truncated mutation of regulatory subunit
o Channel always open = gain of function
o Plasma renin activity and aldosterone undetectable
o ANP very high
 Loss of kidney excretory function: renal failure
• BP drops immediately following dialysis treatment – acute
decrease in body weight due to decrease in ECFV
 High Na intake with no clear abnormality
• Can induce volume expanded HTN

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  Why does high ECFV cause HPT?
• Not known
• Increased cardiac return – increased CO?
• Problem: no detectable increase in CO
• May be due to increased vasoconstriction
• Ouabain = vasoconstrictor: inhibits Na-K ATPase
o If intracellular Na increases, increases intracellular Ca
o Endogenous ouabain is secreted during volume expansion
and inhibitos of Na-Ca exchanger lower BP
 Effect of Na on BP dependent on K
• Evolution: low Na and high K
• If diet 1:1 in Na:K – closer to normal
• If more Na than K, HTN
o ADH
o Others
• Vasodilators:
o NO
o Atrial natriuretic peptide
o CGRP
o Adenosine
o Others

Consequences of HTN
• Hypertrophy of blood vessels and heart
• Thrombosis of major vessels leading to infarcts
• Potentiation of atherosclerosis
• Not know why HTN leads to all these diseases
o If vascular muscle cells grown under strain, will grow under effect of PDGF
• Lowering BP by treatment has dramatic effect on survival
o Dramatic reduction in CVA

TREATMENT OF HYPERTENSION

• Prevelance of BP > 140/90

o 50-59: 38%
o 60-69: 51%
o 70-79: 66%
o 80+: 72%

BP Classification
• Normal < 120/80
• Prehypertension: 120-139/80-89
• Stage 1 HTN: 140-159/90-99
• Stage 2 HTN > 160/100

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Why treat hypertension?
Decreases:
• CVA – 35-40%
• Coronary events – 20-25%
• Heart failure – 50%
• Progression to renal disease
• Progression to severe HTN
• All cause mortality

BP Measurement Techniques
• In office: 2 readings, 5 minutes apart, sitting in chair. Confirm elevated reading in
contralateral arm.
• Ambulatory BP monitoring: Indicated for evaluation of “white-coat” HTN
o Absence of 10-20% BP decrease during sleep may indicate increased CVD risk
• Self-measurement
o Provides information on response to therapy
o May help improve adherence to therapy and evaluate “white-coat” HTN

BP Treatment
• Lifestyle changes
• Co-existent disease
• Drugs themselves
• Cost
• Side effects

No “average” patient
• 45 AA male with BP 170/100
• Smokes 1 ppd, 50 y.o. broth who died of MI

Factors to consider in treating HTN

• Repeat readings
• R/O secondary causes – 10%
• Estimate CV risk status
• Co-morbid conditions – e.g. diabetes
• Lifestyle changes
• Drugs

Secondary HTN
• Difficult to control
• Sudden onset of HTN
• Well controlled becomes difficult to control
• Severe HTN
• History/physical/labs
o Big difference in BP in upper vs. lower limbs: coarctation of aorta

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 o Hypokalemia: hyperaldosteronism

Initial Work-up of Secondary HTN

• Renal parenchymal disease
o UA, spot urine protein/creatinine, serum creatinine, USG
• Renovascular
o Captopril scan – if KO RAS, will be sharp drop in GFR in stenosed site
• Coarctation – lower extremity BP
• Primary aldosteronism
o Serum and urinary K
o Plasma renin and aldosterone ratio
• Pheochromocytoma
o Spot urine for metanephrine/creatinine

Laboratory Tests in Uncomplicated HTN

• ECG: LVH
• Urine analysis: incipient renal disease
• Blood glucose, hematocrit
• Basic metabolic panel
• Lipid profile after 9-12 hour fast
• Urine microalbumin
• Looking for co-morbid conditions and effect of HTN

Estimate Risk Status

• HTN
• Smoking
• Obesity (BMI > 30)
• Dyslipidemia
• Diabetes
• Microalbuminemia or GFR < 60 ml/min
• Age > 55 for men, 65 for women
• Family history of CVD
• Metabolic syndrome = in bold – more aggressive treatment

Target Organ Damage

• Heart Disease
o CAD, LVH, heart failure
• Stroke/TIA
• Chronic kidney disease
• Peripheral arterial disease
• Retinopathy

Goals of Therapy
• BP < 140/90 mmHg

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 • BP < 130/80 mmHg in patients with diabetes or chronic kidney disease
• Achieve SBP goal especially in persons > 50 years of age – closely correlated with risk
of stroke

Lifestyle Modifications – prehypertensive or HTN

• Weight reduction: 5-20 mmHg/10 kg weight loss
• Adopt DASH diet: 8-14 mmHg
• Dietary sodium reduction: 2-8 mmHg
• Physical activity: 4-9 mmHg
• Moderation of alcohol consumption: 2-4 mmHg
o If more alcohol = most common cause of reversible HTN

Drugs for Hypertension

• Diuretics: thiazide, loop diuretics, aldosterone antagonists, K-sparing
• Adrenergic inhibitors
o Peripheral agents
o Central (alpha-agonists)
o Alpha-blockers – not given monotherapy
o Beta-blockers
o Alpha + beta blockers
• Direct vasodilators – not given monotherapy
• Calcium channel blockers
• ACE inhibitors
• ARBs

Current recommendations: low doses of two+ medications

• Balance of therapeutic effects and side effects
• Low dose, titrate upwards
• Once-daily dosing with 24 hour efficacy
o Long acting agents
 Better compliance
 May cost less
 HTN control persistent and smooth
 Protection against sudden death/MI/CVA associated with abrupt increase
in BP after arising from overnight sleep
• Consider low dose combinations
• Demographics
o African-americans and elderly more responsive to calcium-channel blockers and
diuretics than ACE inhibitors or beta-blockers
 More likely to have sodium-sensitive HTN
o Younger Caucasian patients: more likely to be sympathetic nervous system
dysfunction
• Drug interactions
o Diltiazem reduces dose of cyclosporine
o NSAIDS blunt action of diuretics

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 • Side effects
o Reserpine – depression
o Hydralazine and minoxidil (direct acting smooth muscle vasodilators) –
sympathetic activation and fluid retention
o Nifedipine – has precipitated ischemic events and have been reported to increase
mortality in patients with MI

Algorithm for treatment of HTN

• Always start with lifestyle modifications
• If not at goal BP – start with drugs
• Initial drug choises
o Compelling indications
 Heart failure: Don’t use CCB!
 Post-MI: beta blockers, ACE I and Aldosterone antagonists
 High CAD risk: similar to post MI
 Diabetes: drug of choice = ACE I/ARBs
 Chronic kidney disease: drug of choice = ACE I/ARBs
 Recurrent stroke prevention: diuretic and ACE I
o No compelling indications
 Stage 1: thiazides, ACE I, ARBs, CCB, BB or combination
 Stage 2: 2-drug combination – thiazide + other drug
 If not at goal BP: keep adding or changing
• If doesn’t work, refer to BP specialist

55 y.o. man with history of COPD and HTN

• HTN well controlled with nifedipine
• Comes in with evolving anterior wall MI
• Nifedipine NO good as sole agent with MI – reves up sympathetic nervous system;
can increase mortality
• Good: beta-blocker, ACE I or aldosterone antagonist
• COPD: may be exacerbated by beta-blocker
o May start off with short-acting metoprolol
• Short acting agents preferred in acute setting

HTN with CAD

• Beta blockers - cardioprotective (reinfarction, arrhythmias, sudden death)
• ACE inhibitors – especially useful with MI with systolic dysfunction – heart failure and
mortality improved

30 with IDDM referred with difficult to control HTN on diltiazem and clonidine
• Exam: BP 190/100, 3+ edema
• Proteinuria, worsening kidney function

HTN with Renal Insufficiency

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Goal: BP < 130/80
• ACE Inhibitors/ARBs should be used if no C/I
o Initial transient drop in GFR expected
o If persistently elevated, bilateral renal artery stenosis should be suspected
• Most patients have volume overload (edema):
o Diuretics should be included
o Thiazides ineffective if serum creatinine > 2.5

40 y.o. brought to ER with 3 days of progressive SOB and blurred vision in both eyes
BP 240/140
• Retinal ischemia and hemorrhage
• Bilateral crackles – pulmonary edema
• Soft S4
• Hyperkalemia and renal impairment
• 10-15 RBC, 2+ albumin

Suggests: Hypertensive encephalopathy/malignant HTN

• Severe endothelial cell damage
• Failure of autoregulation
• Direct transmission of high pressure to organs
• True emergency that requires immediate BP decrease to 160 systolic
• DON’T use nifedipine!

HTN Emergencies
• Hypertensive encephalopathy
• Acute pulmonary edema
• Aortic dissection
• Cardiac ischemia
• Pheochromocytoma
• Eclampsia
• Require immediate blood pressure reduction

Parenteral Drugs for Treatment of Hypertensive Emergencies

• Vasodilators
o Nitroprusside – very quick on and off
o Fenoldopam – dopamine agonist: doesn’t cause renal ischemia because renal
vasodilator
o Nitroglycerine – venodilator
o Enalaprilat – ACE Inhibitor: onset in ½ hour but slow offset
o Nicardipine: cause reflex tachycardia: used in setting of subarachnoid
hemorrhage
o Hydralazine: no teratogenic effect – used in pregnancy
• Adrenergic inhibitors
o Labetolol
o Esmolol– used for patients with pheochromocytoma

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 o Phentolamine

24 y.o. primiparous woman seen in obstetric clinic at 30 months gestation

* BP 160/100
Drug of choice: methyldopa
Not in early pregnancy: beta blockers – can accelerate fetal loss
Hydralazine = parenteral drug of choice
Most agents if used prior to pregnancy may be continued
• Don’t use ACEI/ARBs because renin important for maintaining blood flow to
placenta

Resistent Hypertension
• Improper BP measurement – white coat HTN
• Compliance
• Excess sodium intake
• Inadequate diuretic therapy
• Medication
o Inadequate doses
o Drug actions and interactions (e.g. NSAIDs, illicit drugs, sympathomimetics, oral
contraceptives)
o OTC (decongestants) and herbal supplements (ephedra)
• Excess alcohol status
• Identifiable causes of HTN – hyperaldo state, pheochromocytoma

Older patients often respond to salt reduction and weight loss

• Starting doses should be ½ of younger patients
• Diuretics and calcium channel blockers better than beta-blockers and ACE inhibitors

Key Messages
• For persons > 50, SBP is more important than DBP as CVD risk factor
• Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg
throughout BP range
• Those with SBP 120-139 mmHg or DBP 80-89 mmHg should be considered
prehypertensive who require health-promoting lifestyle modifications to prevent CVD
• Thiazide diuretics should be initial drug therapy for most, either alone or combined with
other drugs
• Certain high-risk condition are compelling indications for other drug classes
• Most patients will require two or more antihypertensive drugs

PATHOLOGY REVIEW

• Conditions associated with nephrotic syndrome

o Glomerulus usually has normal number of cells
o Minimal change disease: normal appearing glomerulus with fusion of foot
processes on EM

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  Most common cause of nephrotic syndrome in children
 Good response to steroid therapy
o FSGS: some glomeruli and only portion of glomerulus
 GBM wrinkled and scarred, hyaline entrapement
 Matrix synthesis increased
 Distinct pattern: collapsing FSGS – HIV nephropathy
• Glomerular capillary loops have shrunken
• Visceral epithelium proliferation
o Membranous glomerulopathy
 Marked GBM thickening
 Spikes (GBM) with granular IgG deposits = subepithelial
 IgG staining
o Diabetic glomerulosclerosis
 Mesangial nodules – capillary microaneurysms
 GBM thickening
 Hyaline and lipid entrapment (insudation)
 EM: GBM thickening and increase in mesangial matrix
o Amyloidosis
 Uneven distribution in glomerulus
 Glassy, amorphous look
 Matrix expansion not proliferative process
 Congo red staining and apple-green birefringence
 EM: randomly oriented fibrils – 10 nm in diameter

• Conditions associated with nephritic syndrome

o Glomerulus has too many cells
o Membranoproliferative glomerulonephritis (MPGN)
 Nephritic and nephrotic: proteinuria, hematuria
 Hypercellular, enlarged, lobulated glomeruli
 Tram-tracks of GBM – mesangial cells between layers with mesangial
matrix
 Subendothelial smooth deposits: staining for C3
 Low complement
o Post-infectious glomerulonephritis
 Diffuse proliferative
 PMNs
 Low complement – deposits stain for C3
 EM: subepithelial deposits = hump-shaped
o IgA Nephropathy
 Increased mesangial proliferation – seen in IgA and lupus
 IF: stains only for IgA (not IgG)
o SLE nephropathy
 Increased mesangial proliferation
 Deposits clustered in central mesangial regions – stain for IgG
 4 Basic Patterns:
• Mesangial

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 • Segmental endocapillary proliferation
• Diffuse endocapillary proliferation
o Deposits may form balls that occlude capillary loops =
hyaline thrombi
o May get huge subendothelial deposits = wire-loop
• Membranous proliferation – very common
o Crescentic GN
 Severe enough damage to rupture GBM – inflammatory cells and fibrin in
urinary space cause proliferation of parietal epithelium
 80% positive for ANCA
 Immunofluorescence
• Granular: IgA, SLE, post-infectious
• Linear: anti-GBM disease (Goodpasture’s disease)
• Pauci-immune: IF negative

Vascular Disease
• Renal Artery Stenosis
o E.g. atherosclerosis
o Ischemic nephropathy in one kidney and hypersecretes renin
o Raises BP – other kidney is granular and has hypertensive changes
• Atheroembolization
o Vascular cause of acute renal failure
• Benign HTN
o GN and HTN both produce granular kidneys
• Malignant HTN
o Kidneys swollen with hemorrhagic, flea-bitten look
• HUS
o Fibrin thrombi filling capillary loops

Tubulointerstitial Disease
• ATN
o Sloughing of cells into tubules
o Maintenance phase: slowly reconstituting kidney
o Recovery phase: not enough reabsorption because no brush border – diuretic
phase
o Giant cell with crystals: myeloma-cast nephropathy
• Chronic pyelonephritis
o U-shaped scars
o Chronic inflammation with sparing of glomeruli
o Thyroidization
• Papillary necrosis - green-black necrotic debris at tips of papillae
o Pyelonephritis
o Analgesic nephropathy
o Diabetic nephropathy
o Sickle cell anemia

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 • Acute allergic interstitial nephritis
o Interstitial inflammation
o Tubulitis – inflammation in tubules
o Eosinophils
o Beta-lactam antibiotics (NOT gentamicin – causes ATN)
• Polycystic kidney disease
o Autosomal dominant: ADPKD
o Cysts fill kidney and liver; 5% have berry aneurysms of circle of Willis

PATHOPHYSIOLOGY REVIEW

Type of Lesions

Proliferative
1. Mesangial – IgA nephropathy, mild lupus nephritis
2. Endocapillary – APIGN, severe lupus nephritis, MPGN
3. Extracapillary (crescenteric) – anti-GBM nephritis, pauci-immune (ANCA – no
deposits), severe immune complex-GN (any type)

GBM Thickening
1. Deposits – subepithelial (APIGN – humps, MG – spikes and domes: granular staining)
vs. subendothelial (severe proliferative LN – wire loops, MPGN: linear staining) vs.
mesangial (IgA nephropathy – stalks, not loops, also seen in lupus)
2. Spikes – MGN: subepithelial
3. BM material – diabetic GS
4. Amyloid

Sclerosis
1. FSGS
2. Diabetic nephropathy
3. Chronic (scarred) GN

Hyalinosis
1. FSGS
2. Diabetic nephropathy

Membranoproliferative Glomerulonephritis
• Endocapillary proliferative pattern with accentuated lobularity
• Glomerular basement membrane thickened and duplicated = tram-track in silver stain
• Deposits laids down in subendothelial region – mesangial cells go in to eat up deposits
and produce matrix material in peripheral of tuft in GBM
• Confluent, granular-semi-linear deposits on IF
• In children, most MPGN = idiopathtic after URI with abrupt onset of nephrotic +/-
nephritic syndrome – low complement; progress to renal failure
• In adults, association with underlying conditions: hepatitis C infection and
crytoglobulinemia (immunoglobulins that reversibly precipitate in cold – IgG-IgM)

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 o Cryoglobulins are anti-HCV antibodies in many patients

Minimal change disease

• 5-10% of adults with NS, > 85% of children
• Usually sudden onset, heavy proteinuria and edema
• In adults: HBP 30%, microheme 30% +/- low GFR (volume depletion)
• Course: respond to steroids, relapse, no renal failure
• NO renal biopsy – vast majority of children will have one pattern; if treat and don’t
respond, then biopsy
• EM: fusion of podocyte foot processes; no findings on light microscopy/IF
• Patent capillaries, no endo or extracapillary hypercellularity

FSGS
• Heavy non-selective proteinuria, hypoalbuminemia, elevated cholesterol, normal
creatinine
• Related to minimal change; because it is focal, may be missed in 1 biopsy
• Doesn’t respond to steroids
• Increased frequency > 20% NS – most common nephrotic syndrome in African-
Americans
• In adults, onset 2/3 NS, 1/3 proteinuria
• HBP > 30%, microhematuria > 30%, renal dysfunction 50%
• Predictors of ESRD: heavy proteinura, AA, high creatinine, on BX – interstitial fibrosis
and collapse
• Steroids > 50% respond, cytotoxan, cyclosporine, MMF
• Normal clearance, GFR = 100 cc/min
• Cr 2.4, GFR ~ 35 cc/min
• Recurrence after transplant – 30%
• No electron dense deposits – IF can be negative if glomeruli not sclerotic; IF can be
positive for IgM and C3 in areas of sclerosis
• Similar changes seen in HIV – subset of FSGS
• Associated with heroin nephropathy, obesity, SS disease

Membranous glomerulopathy
• Proteinuria without hematuria and nephrotic syndrome
• HBP, microhematuria not rare
• Thromboses – renal vein thrombosis
• Most common nephrotic syndrome in white Caucasian male
• Dipstick
o Trace to 4+ semiquantitative
o Reflects concentration of protein not total thus affected by dilution
o Insensitive to globulins – Bence Jones protein
o Transit proteinuria also occurs commonly with CHF, seizures, pneumonia,
infection, COPD, fever
o Good to repeat 5 days later – if still elevated, do 24 hour urine and ultrasound

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 • 24 hour protein
o Collection problems
o Heavy excretion (over 3 g/day)
o Usually glomerular disease
o Heavy excretion can be due to Bence Jones proteins
• LM: thickening of basement membrane in clear loops
• Silver stain: shows spike and dome subepithelial deposits
• IF stain: granular, ruffled
• EM: spike and dome – electron dense deposits – in situ immune complex formation
• Pathogenesis:
• Significant percentage respond to therapy (steroids, immunosuppressive agents)
• Odds of ESRD in 10 years: ¼ spontaneously remit, 20% in renal failure 20 years later
• Pattern associated: HBV, lupus, secondary syphilis, carcinoma, and gold salt therapy
for RA, captopril
• Lithium associated with minimal change disease

• Nephrotic patient can lie flat in bed – periorbital edema

o CHF, ascites – can’t lie flat
• Nephrotic patient: foamy urine – due to high levels of albumin
o Maltese crosses – fat bodies: hyperlipidemia and lipiduria secondary to nephrotic
syndrome
• ATN: muddy brown casts, tubular cells in cast
• Eosinophils: acute interstitial nephritis
• WBC casts: acute pyelonephritis

SLE
• Low grade rash, arthralgias, lymphadenopathy
• Hypocomplementemia, ANA+, anti-DNA antibody very elevated
• Urinalysis: active glomerulonephritis = RBC casts
• Renal biopsy: many different patterns
o Mesangial proliferative
o Endocapillary proliferative – focal or diffuse – may even have crescents
o Membranous glomerulopathy
• Can recur in transplant but rare – high doses of immunosuppression
• SLE patients almost never have normal kidney biopsy even if normal clinically

Diabetic glomerulosclerosis
• Eye exam: retinopathy almost always concurrent with renal disease
• Sclerosing process – NOT proliferative: matrix mesangial increase, GBM thickened
but smooth – hyalinosis
• Glomerular capillary microaneurysm – analogous to retinal changes
• 1# cause for patients going onto dialysis
• EM: thickening of basement membrane

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• To slow the course of progression to ESRD:
o Control glomerular capillary hypertension (ACEI/ARB)
o Role of glycemic control
o Role of blood pressure control: goal = 130/80
o Role of lipid control: cholesterol < 200, LDL < 100

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