Acute Renal Failure

Matthew L. Paden, MD Pediatric Critical Care Emory University Childrens Healthcare of Atlanta at Egleston

Structure and Function of the Kidney

Primary unit of the kidney is the nephron 1 million nephrons per kidney Composed of a glomerulus and a tubule Kidneys receive 20% of cardiac output
Renal Lecture Required Picture #1

Renal blood flow

Aorta Renal artery interlobar arteries interlobular arteries afferent arterioles glomerulus efferent arterioles In the cortex peritubular capillaries In the juxtamedullary region vasa recta Back to the heart through the interlobular intralobar renal veins

Glomerular Filtration Rate

Determined by the hydrostatic and oncotic pressure within the nephron Hydrostatic pressure in the glomerulus is higher than in the tubule, so you get a net outflow of filtrate into the tubule Oncotic pressure in the glomerulus is the result of non-filterable proteins

Greater oncotic pressure as you progress through the glomerulus

GFR = Kf (hydrostatic oncotic pressure)

Renal Lecture Required Picture #2

Glomerular Filtration Rate

The

capillary endothelium is surrounded by a basement membrane and podocytes Foot processes of the podocytes form filtration slits that :

Allow for ultrafiltrate passage Limit filtration of large negatively charged particles
Less than 5,000 daltons = freely filtered Large particles (albumin 69,000 daltons) not filtered

Tubular Function
Proximal

Most of reabsorption occurs here Fluid is isotonic with plasma 66-70% of sodium presented is reabsorbed Glucose and amino acids are completely reabsorbed

Tubule Function
Loop

of Henle

Urine concentration and dilution via changes in oncotic pressure in the vasa recta Descending tubule permeable to water, impermeable to sodium Ascending tubule actively reabsorbs sodium, impermeable to water

Tubular Function
Medullary

thick ascending limb critical for urinary dilution and most often damaged in ARF

ADH stimulates Na re-absorption in this area Most sensitive to ischemia

Low oxygen tension, high oxygen consumption

Lasix use here inhibits the Na-K-2Cl ATPase which in the face of ARF, may decrease oxygen consumption and ameliorate the severity of the ARF

Tubular Function
All

of those studies done in an in vitro model

In vivo, if you drop oxygen concentration even sub-atmospheric you do not get tubular damage even with increased tubular workload In vivo models exist where you do see that damage, but appears to need a second hit

Tubule Function
Distal

Tubule

Re-absorption of another ~12% of NaCl Proximal segment impermeable to water Distal segment is the cortical collecting duct and secretes K and HCO3

Tubular Function
Collecting

Duct

Aldosterone acts here to increase Na reuptake and K wasting ADH enhances water re-absorption Urea re-absorption to maintain the medullary interstitial concentration gradient

Acute Renal Failure - Definitions

Renal

failure is defined as the cessation of kidney function with or without changes in urine volume Anuria UOP < 0.5 cc/kg/hour Oliguria UOP more than 1 cc/kg/hour

Less than?

Acute Renal Failure - Definitions

70%

Non-oliguric , 30% Oliguric Non-oliguric associated with better prognosis and outcome Overall, the critical issue is maintenance of adequate urine output and prevention of further renal injury.

Are we converting non-oliguric to oliguric with our hemofilters?

Acute Renal Failure - Diagnosis

Pre-renal
Decrease in RBF constriction of afferent arteriole which serves to increase systemic blood pressure by reducing the shunt through the kidney, but does so at a cost of decreased RBF At the same time, efferent arteriole constricts to attempt to maintain GFR As GFR decreases, amount of filtrate decreases. Urea is reabsorbed in the distal tubule, leading to increased tubular urea concentration and thus greater re-absorption of urea into the blood.

Creatinine cannot be reabsorbed, thus leading to a BUN/Cr ratio of > 20

Pre-Renal vs. Renal Failure

Prerenal
BUN/Cr >20

Renal
<20

FENa
Renal Failure Index UNa Specific Gravity Uosm Uosm/Posm

<1%
<1% <20 mEq/L >1.020 >1.3

>2%
>1% >40 mEq/L <1.010 <1.3

>500 mOsm/L <350 mOsm/L

Renal Lecture Required Picture #3

Acute Renal Failure - Diagnosis

Diagnosis

Ultrasound
Structural anomalies polycystic, obstruction, etc. ATN

poor corticomedullary differentiation Increased Doppler resistive index (Systolic Peak Diastolic peak) / systolic peak

Nuclear medicine scans

DMSA Static - anatomy and scarring DTPA/MAG3 Dynamic renal function, urinary excretion, and upper tract outflow

Acute Renal Failure

Overall,

renal vasoconstriction is the major cause of the problems in ARF

Suggested ARF be replaced with vasomotor nephropathy

Insult

to tubular epithelium causes release of vasoactive agents which cause the constriction

Angiotensin II, endothelin, NO, adenosine, prostaglandins, etc.

Regulation of Renal Blood Flow

In

adults auto-regulated over a range of MAPs 80-160 Developmental changes

Doubling of RBF in first 2 weeks of life Triples by 1 year Approaches adult levels by preschool

Renal

blood flow regulation is complex

No one system accounts for everything..

Renin-Angiotensin Axis

For the one millionth time. Hypovolemia leads to decreased afferent arteriolar pressure which leads to decreased NaCl re-absorption which leads to decreased Cl presentation to the macula densa which increases the amount of renin secreted from the JGA which increases conversion angiotensinogen to AGI to AGII which increases Aldosterone secretion from the adrenal cortex and ADH which leads to increased sodium and thus water re-absorption from the tubule which increases your blood pressurewhew

Renin Angiotensin Axis

Renal Lecture Required Picture #4

Renin Angiotensin Axis

Renins

role in pathogenesis of ARF

Hyperplasia of JGA with increased renin granules seen in patients and experimental models of ARF Increased plasma renin activity in ARF patients Changing intra-renal renin content modifies degree of damage
Feed animals high salt diet (suppress renin production) renal injury less renal injury than those fed a low sodium diet

Renin Angiotensin Axis

Not

the only thing going on though

You can also ameliorate renal injury by induction of solute diuresis with mannitol or loop diuretics (neither affect the RAS) No change in renal injury in animals given ACE inhibitors, competitive antagonist to angiotensin II

Overall,

role of RAS in ARF is uncertain

Prostaglandins
PGE

2 and PGI

Very important for renal vasodilation, especially in the injured kidney Act as a buffer against uncontrolled A2 mediated constriction
If you constrict the afferent arteriole, you will decrease GFR

The

RAS and Prostaglandin pathways account for ~60% of RBF autoregulation

Adenosine
Potent

renal vasoconstrictor

Peripheral vasodilator

Infusion

of methylxanthines (adenosine receptor blockers) inhibits the decrease in GFR that is seen with tubular damage Some animal models show that infusion of methylxanthines lessen renal injury in ARF

Adenosine
But.

Likely not a major factor in ARF

Methylxanthines have lots of other actions besides adenosine blockade Adenosine is rapidly degraded after production Intra-renal adenosine levels diminish very rapidly after reperfusion, but the vasocontriction remains for a longer period Finally, if you block ADA, creating higher tissue adenosine levels, and then create ischemia you actually get an enhancement of renal recovery

Endothelin

21 amino acid peptide that is one of the most potent vasoconstrictors in the body

Can be used as a pressor

Its role in unclear in normal state In ARF, overproduction by cells (both in and outside of the kidney) leads to decreased afferent flow and thus decreased RBF and GFR

Endothelin increases mesangial cell contraction which reduces glomerular ultrafiltration

Stimulates ANP release at low doses and can increase UOP Anti-endothelin antibodies or endothelin receptor antagonists decrease ARF in experimental models

Nitric Oxide
Produced

by multiple iso-enzymes of NOS In addition to its role in vasodilation, likely has a role in sodium re-absorption

Give a NOS blocker and you get naturesis

Important

in the overall homeostasis of

RBF Exact mechanisms not worked out completelyat least when Rogers was written.

Obligatory Incomprehensible Pathway for Jim #1

Nitric Oxide
Confusing

results

Ischemic rat kidney model inducing NOS causes increasing injury Hypoxic tubular cell culture model inducing NOS causes increasing injury But if you block NOS production, you get worsening of renal function and severe vasoconstriction

Nitric Oxide
So

stimulation of NO in the renal vasculature will modulate vasoconstriction and lead to lesser injurybut That same induction of NO in the tubular cells will cause increased cytotoxic effects

Dopamine
Dopamine

receptors in the afferent

arteriole Dilation of renal vasculature at low doses, constriction at higher doses Also causes naturesis (? Reason for increased UOP after starting) Renal dose dopamine controversy.

Renal Hemodynamics and ARF

Conclusions.

Renal vasoconstriction is a well documented cause of ARF Renal vasodilation does not consistently reduce ARF once established
Although renal hemodynamic factors play a large role in initiating ARF, they are not the dominant determinants of cell damage

ARF - Pathophysiology
Damage

is caused mostly by renal perfusion problems and tubular dysfunction Usual causes

Hypo-perfusion and ischemia Toxin mediated Inflammation

ARF Pathophysiology
Hypo-perfusion

Well perfused kidney 90% of blood to cortex Ischemia increased blood flow to medulla Outcome may be able to be influenced by restoration of energy/supply demands
Lasix example

Leads to tubular damage

ARF - Pathophysiology
Oxidative

damage

Especially during reperfusion injuries Main players

Super-oxide anion, hydroxyl radical highly ionizing Hydrogen peroxide, hypochlorous acid not as reactive, but because of that have a longer half life and can travel farther and cause injury distal to the site of production

ARF - Pathophysiology
Ischemia

Damage to mitochondrial membrane and change of xanthine dehydrogenase (NAD carrier) to xanthine oxidase (produces O2 radicals) Profound utilization of ATP 5-10 minutes of ischemia you use ~90% of your ATP
Make lots of adenosine, inosine, hypoxanthine

ATP ADP AMP

Adenylosuccinate

Adenosine

IMP

Hypoxanthine
H20 O2 Xanthine H2O2

Inosine

H20 O2
Uric Acid H20 O2

H2O2

CO2

Allantoin

ARF - Pathophysiology

Once you get reperfusion, the hypoxanthine gets metabolized to xanthine and uric acid each creating one H2O2 and one super-oxide radical intermediate Reactive oxygen species oxidize cellular proteins resulting in:

Change in function/inactivation/activation Loss of structural integrity Lipid peroxidation (leads to more radical formation) Direct DNA damage

ARF Pathophysiology
Amount

of damage depends on ability to replete ATP stores

Continued low ATP leads to disruption of cell cytoskeleton, increased intracellular Ca, activation of phospholipases and subsequently the apoptotic pathways

Obligatory Incomprehensible Pathway for Jim #2

ARF Pathophysiology
Amount

of damage depends on ability to replete ATP stores

Continued low ATP leads to disruption of cell cytoskeleton, increased intracellular Ca, activation of phospholipases and subsequently the apoptotic pathways

This

endothelial cell injury sparks an immune response.that cant be good.

ARF - Prevention
Maintenance

of blood flow

Cardiac output, isovolemia, etc

Avoidance

of toxins

Aminoglycosides, amphoteracin, NSAIDs

Easy

on paper.difficult in practice

ARF - Prevention
Lasix

May have uses early in ARF

May work by
Increasing flow through tubules, preventing obstruction Osmotic action, decreasing endothelial swelling Decreased blood viscosity with increased renal perfusion (???) Free radical scavenging

Mannitol

ARF - Prevention
Renal

dose dopamine. Endothelin antibodies

No human trials More rapid improvement of renal function in animals Increased uptake of ADP to form ATP or cell membrane stabilization as a possible cause

Thyroxine

ARF - Prevention

ANP

Improve renal function and decrease renal insufficiency ? Nesiritide role

Adenosine antagonist prevents reduction in GFR. After ischemic insult, infusion of IGF-I, Epidermal GF, Hepatocyte GF improved GFR, diminished morphologic injury, diminished mortality

Theophyline

Growth Factors

None of these things are well tested..

ARF Prevention in Specific Cases

Hemoglobinuria/Myoglobinuria

Mechanism of toxicity
Disassociation to ferrihemate, a tubular toxin, in acidic urine Tubular obstruction Inhibition of glomerular flow by PGE inhibition or increased renin activation

Treatments (?)
Aggressive hydration to increase UOP Alkalinization of urine Mannitol/Furosemide to increase UOP ?Early Hemofiltration

ARF Prevention in Specific Cases

Uric

Acid Nephropathy

A thing of the past thanks to Rasburicase? Treatments

Aggressive hydration to drive UOP Alkalinization of the urine Xanthine oxidase inhibitors

ARF - Management
Electrolyte

management

Sodium
Hyponatremia fluid restriction first, 3% NaCl if AMS or seizing

Potassium
Calcium/Bicarb/Glucose/Insulin/Kayexalate Hemodialysis

ARF - Management
Nutrition

management

Initially very catabolic Goals:

Adequate calories Low protein Low K and Phos Decreased fluid intake

Renal Replacement Therapy

Peritoneal

Dialysis Acute Intermittent Hemodialysis Continuous Hemofiltration

CAVH SCUF CVVH, CVVHD And others.

Peritoneal dialysis
Advantages

Disadvantages

Simple to set up & perform Easy to use in infants Hemodynamic stability No anti-coagulation Bedside peritoneal access Treat severe hypothermia or hyperthermia

Unreliable ultrafiltration Slow fluid & solute removal Drainage failure & leakage Catheter obstruction Respiratory compromise Hyperglycemia Peritonitis Not good for hyperammonemia or intoxication with dialyzable poisons

Intermittent Hemodialysis
Advantages

Disadvantages

Maximum solute clearance of 3 modalities Best therapy for severe hyperkalemia Limited anti-coagulation time Bedside vascular access can be used

Hemodynamic instability Hypoxemia Rapid fluid and electrolyte shifts Complex equipment Specialized personnel Difficult in small infants

Continuous Hemofiltration
Advantages

Disadvantages

Easy to use in PICU Rapid electrolyte correction Excellent solute clearances Rapid acid/base correction Controllable fluid balance Tolerated by unstable pts. Early use of TPN Bedside vascular access routine

Systemic anticoagulation (except citrate) Frequent filter clotting Vascular access in infants

Indications for RRT

Still evolving.Generally accepted

Oliguria/Anuria Hyperammonemia Hyperkalemia Severe acidemia Severe azotemia Pulmonary Edema Uremic complications Severe electrolyte abnormalities Drug overdose with a filterable toxin Anasarca Rhabdomyolysis