An Introduction to Kidney Disorders Aims of this session To briefly revise kidney function To revisit means of assessing kidney function Gain an understanding of common kidney disorders Understand pre-renal, intra-renal and post-renal concepts Learn how to investigate and manage renal disease Apply knowledge to clinical scenarios (cases) Important points to remember Renal disease is rarely straight-forward this session will not teach you everything you need to know but were afraid to ask about renal disease Use the references cited to expand your knowledge Use Textbooks (Tietz, Marshall etc)
Make a friend of the kidney and its role in health and disease Although sometimes (!) complicated, the kidneys role is crucial to understanding many disease processes Use a multi-disciplinary approach to clinical problems
THE KIDNEY A REFRESHER KIDNEY FUNCTIONS Maintains water and electrolyte homeostasis Controls volume and composition of ECF
Removes water-soluble waste products and toxins Nitrogenous compounds Maintains acid-base balance (excretion of H + )
Produces (and responds to) chemical messengers Role in Vitamin D metabolism Role in haemoglobin synthesis When renal function is impaired, for WHATEVER reason, it will hinder the kidneys ability to perform these functions KIDNEY FUNCTIONS Maintains water and electrolyte homeostasis Sodium, glucose, bicarbonate reabsorption Potassium, phosphate, acid (H+) excretion Water control Electroneutrality
In order to function, the kidney needs Adequate perfusion (blood supply) Positive pressure differential at the glomerulus Viable, semi-permeable glomerular membrane Intact, functioning tubular endothelium Channels Transporters Gradients (electrochemical, concentration) Clear passage for filtrate to travel Appropriate hormonal activity (and ability to respond) Energy! ASSESSING RENAL FUNCTION Which function to measure.?
Ability to maintain water and electrolyte balance?
Ability to select what is allowed to enter the tubule?
Ability to remove waste products?
Ability to produce (and respond to) chemical mediators?
ASSESSING RENAL FUNCTION Broadly divided into:
Assessment of glomerular filtration Ability to remove waste products Assessment of glomerular integrity Ability to select what is allowed to enter the tubule Assessment of tubular cell function Ability to reabsorb or secrete compounds Ability to respond to stimulation
AT THE MACROSCOPIC LEVEL Imaging studies are used to indicate anatomical changes Radiography Ultrasonography CT, MRI Angiography Urinalysis is a simple way to indicate renal pathology Appearance (cloudy? Bloody? Strange colour? Smell?) Specific gravity and osmolality pH Protein Sediment Other substances AT THE MICROSCOPIC LEVEL Immunological analysis Auto-antibodies against renal components Immuno-histochemical analysis
Biochemical analysis is the mainstay of renal investigations ASSESSING GLOMERULAR FILTRATION As Biochemists, our frontline test measures the ability of the kidneys to excrete nitrogenous (azotemic) waste products. Creatinine Urea Borne from the (uneasy) relationship between serum creatinine concentration and glomerular filtration rate. Urea used as a side-kick. Although beyond the scope of this lecture to discuss the advantages and disadvantages of estimating glomerular filtration rate (eGFR) as a function of serum creatinine concentration (and other confounding variables), it would be prudent to read the following: Assessing Kidney Function Measured and Estimated Glomerular Filtration Rate L. Stevens et al., New England Journal of Medicine (2006), 354 2473-83
Creatinine and glomerular filtration rate: evolution of an accommodation C. Diskin, Annals of Clinical Biochemistry (2007), 44 1619 Creatinine clearance is not and has never been synonymous with GFR, and no regression analysis will make it so, because the serum creatinine depends upon many other factors than filtration. ASSESSING GLOMERULAR INTEGRITY Detection of compounds not normally present in the urine due to the selectivity of the glomerular basement membrane Albumin is the predominant plasma protein responsible for many physiological functions (solute transport, oncotic pressure etc). Normally not filtered at the glomerulus due to Size (~66 kDa) Charge (net negative charge)
Its presence in urine signals loss of glomerular integrity Microalbuminuria Used to monitor CKD
ASSESSING TUBULAR FUNCTION The most common tests of tubular function assess: Ability to excrete an acid load (Urine pH e.g. RTA) Ability to concentrate urine (Urine osmo. e.g. SIADH, DI) Ability to respond to hormones (plasma and urine electrolytes e.g. Addisons) Ability to reabsorb solutes (urine glucose e.g. DM) NB. Many re-absorption mechanisms are saturable. The presence of small molecular weight solutes in the urine that arent normally there may reflect over-production rather than under-reabsorption e.g. Glucose in Diabetes Mellitus Amino acids in some inborn errors of metabolism RENAL DISORDERS Acute Renal Failure (ARF) More recently referred to as Acute Kidney Injury (AKI) Describes a clinical scenario of kidney failure that develops over hours or days (as opposed to weeks or months) May be superimposed on established, chronic renal failure (CRF) and is then referred to as acute on chronic RF
Traditionally separated into three major groups Pre-renal (insult occurs before the kidneys) Renal (intrinsic, tubular dysfunction) Post-renal (blockage of the flow of urine to the ureters/bladder) Acute Kidney Injury J. Kellum. Crit Care Med (2008), 36 [Supplement] S141S145 Reminder: in order to function, the kidney needs Adequate blood/fluid supply Positive pressure differential at the glomerulus Viable, semi-permeable glomerular membrane Intact, functioning tubular endothelium Clear passage for filtrate to travel Appropriate hormonal activity (and ability to respond) Energy In Pre-Renal Conditions Adequate blood and fluid supply? Positive pressure differential at the glomerulus? Pre-renal ARF implies some form of hypoperfusion which may be a result of: Dehydration Haemorrhage or thrombosis Renal artery stenosis Acute cardiac failure Sepsis Pre-renal ARF can be considered an appropriate response to hypovolaemia, conserving water and sodium at the expense of GFR NOT AVAI L AB L E I N P R I MAR Y CAR E ( NOT AL WAY S ACCU R AT E I N S E CONDAR Y CAR E ! ! ) FLUID BALANCE CHARTS! INTRINSIC RENAL FAILURE Due to their high metabolic rate, the kidneys are extremely vulnerable to ischaemia prolonged episodes may cause renal damage that persists after the underlying cause has been resolved - termed Acute Tubular Necrosis Causes of intrinsic renal failure Glomerulonephritis Goodpastures disease Systemic Lupus Eryths (SLE) Cryoglobulinaemia
Not exactly common Pre-renal causes of ATN Drugs Tubular nephritis Sarcoidosis Poisoning Rhabdomyolysis Etc
A lot more common POST-RENAL FAILURE Obstruction is the most common cause of post- renal failure. The main culprits are: Renal calculi Retroperitoneal fibrosis Invasive bladder carcinoma Benign or malignant prostatic disease (males) A very un-holy trinity!! SOME FEATURES OF ARF Metabolic Feature Clinical Feature Retention of nitrogenous waste products Nausea, vomiting, disturbance of consciousness, coma Retention of sodium and water (usually with hyponatraemia) Peripheral and pulmonary oedema, ascites, pleural effusion Hyperkalaemia ECG changes (peaked or tented T waves, flat P waves, QRS depression), muscle weakness, paralysis Retention of acid (metabolic acidosis) Kussmaul breathing, hypotension INVESTIGATING ARF/AKI Urine dipstick testing for blood and protein suggest glomerular disease What if no urine is available? Guidelines suggest serum creatinine and urine output are the best biomarkers of AKI UK Renal Association Guidelines issued in March 2011 MULTI-DISCIPLINARY APPROACH Clinical PMH Medications
Biochemistry Urinalysis protein and blood U&E, Calcium, phosphate, CRP, CK, LFT Arterial blood gases
Haematology Red cell casts Full blood count
Microbiology Cultures and serology
Immunology Auto-antibody screens (ANCA, Anti-GBM etc.) Cryoglobulin MANAGEMENT OF ARF/AKI Establish whether acute, chronic or acute-on- chronic Identify whether pre-renal and resuscitate with fluids Discontinue nephrotoxic drugs Treat metabolic complications Exclude urinary tract obstruction Investigate for intrinsic disease Involve Nephrologists! Prognosis can be very poor. Acute Renal Failure R. Hilton. BMJ (2006), 333 p 7572 CHRONIC RENAL FAILURE (CRF) CHRONIC RENAL FAILURE Unlike ARF/AKI, the onset of CRF is much more gradual, presenting over months and years Usually asymptomatic (initially, at least) Only presents when renal functional threshold is crossed Usually secondary to other pathologies Natural decline of GFR with age In many cases, progresses to End-Stage Renal Failure (ESRF)
Although there are many causes of CRF, the clinical features tend to be similar as the condition reflects the decline in the number of functioning nephrons Causes of CRF There are many, classified into 4 groups: Vascular disease Renal artery stenosis Glomerular disease (primary or secondary) Primary - Membranoproliferative glomerulonephritis Secondary DM, SLE, BJP, Auto-immune etc Tubulointerstitial disease Drugs (allopurinol), infections, sarcoidosis, heavy metals Urinary tract obstruction Stones, tumours, fibrosis
Effects of CRF CRF Acid-base disturbances Calcium, phosphate, magnesium Endocrinopathies (thyroid, gonadal) Carbohydrate and lipid metabolism Retention of nitrogenous waste products Sodium and water disturbances Potassium metabolism Management of CRF/CKD Control the underlying co-morbidity Slow progression of kidney disease Anti-hypertensives etc Prevent complications (CV, anaemia etc) Strict diet, supplementation Prepare for renal replacement therapy (dialysis, transplant) www.kidney.org CLINICAL CASES Remember!! Always consider (pre-)analytical causes Patient demographics Past medical history Presenting symptoms Where the patient has come from? Medications Multi-disciplinary approach Multi-condition appreciation! A wise old Biochemist once said: When you hear hooves, think horses not zebras! i.e. common things happen often, rare things happen rarely Case 1 KB, 50 years old, female. Sample received from Cardiology Outpatients Clinical details: HF, fluid retention Medications not stated Assumptions? Biochemistry Date Sodium (135-145 mmol/L) Potassium (3.5-5.5 mmol/L) Urea
Creatinine 19/08/11 144 4.3 28.4 181 21/09/11 142 4.2 27.1 199 11/10/11 142 4.8 28.6 214 What else do we need? Are there any Biochemistry tests wed like to add on? Are there any haematology or immunology tests wed like to do? Whats the diagnosis? How do we manage patients with this condition? Case 2 CC, 34 years old, female. Patient location: Ward 6 Clinical details: HD Medications not stated Biochemistry Analyte Range 15/09/11 06/10/11 06/10/11 Sodium 135 -145 mmol/L 138 139 139 Potassium 3.5 - 5.5 mmol/L 4.0 6.4 3.7 Urea 2.5 - 7.0 mmol/L 2.9 25.5 2.2 Creatinine 50 - 130 mol/L 146 735 127 Phosphate 0.70 - 1.40 mmol/L N/A 1.04 N/A Calcium 2.20 - 2.60 mmol/L N/A 2.53 N/A Hb 11.8 16.7 d/dL 11.2 10.9 N/A 25 (OH) Vit D >50 nmol/L N/A 60 N/A Diagnosis and Management What is going on in this patient? How are these patients managed? Dialysis Management (continued) As mentioned earlier: Dietary interventions Reduced potassium, phosphate, sodium, protein etc Controlling blood pressure ACEIs/ARBs Reduce CV risk Statins, lipid-lowering agents, anti-coagulation therapy Control renal bone disease Monitoring markers of turnover Vitamin D Monitoring other complications Anaemia Case 3 RD, 55 years old, male. Patient location: Ward 2B Clinical details: None supplied Medications not stated Biochemistry & Haematology Analyte Range 17/10/09 10/10/11 Sodium 135 -145 mmol/L 133 127 Potassium 3.5 - 5.5 mmol/L 3.8 4.7 Urea 2.5 - 7.0 mmol/L 9.8 17.9 Creatinine 50 - 130 mol/L 156 244 Phosphate 0.70 - 1.40 mmol/L 1.01 1.22 Calcium 2.20 - 2.60 mmol/L 2.14 2.45 Hb 11.8 16.7 d/dL 10.1 9.6 hsTrop T <14 ng/L N/A 561 Diagnosis and Management Acute-on-chronic renal failure Presents a double whammy to the kidneys Management revolves around treating the acute insult while protecting the remaining renal function Prognosis is poor Case 4 JT, 38 years old, male. Patient location: Ward 5Y Clinical details: Ca GI, post-chemo Medications not stated Biochemistry Analyte Range 07/10/11 11/10/11 12/10/11 Sodium 135 -145 mmol/L 125 116 114 Potassium 3.5 - 5.5 mmol/L 4.2 4.5 3.9 Urea 2.5 - 7.0 mmol/L 3.3 23.2 22.5 Creatinine 50 - 130 mol/L 45 338 241 Phosphate 0.70 - 1.40 mmol/L 0.51 1.92 1.46 Calcium 2.20 - 2.60 mmol/L 2.17 1.72 1.86 Bilirubin 2 - 17 mol/L 179 205 206 Summary - Learning points Look at the whole picture (and just the facts!) Gain an appreciation for homeostatic mechanisms and what can go wrong Many medications are nephrotoxic (very rare that clinicians tell us what a patient is taking) Knowing what each wards speciality is can help Familiarising with Consultants names also. Think multi-disciplinary! Renal impairment affects many organ systems