Renal function tests

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this is a series of notes on clinical pathology, useful for undergraduate and post graduate pathology students. Notes have been prepared from standard textbooks and are in a format easy to reproduce in exams.

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Renal function tests

  1. 1. 1 Renal Function Tests Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  2. 2. 2 Notes on Clinical Pathology Renal function tests By Dr. Ashish Jawarkar Consultant Pathologist Vadodara OVERVIEW 1. Indications 2. Classification a. Tests for glomerular function i. Clearance tests 1. Inulin clearance 2. creatinine clearance 3. cystatin c clearance 4. urea clearance ii. Blood biochemistry 1. BUN 2. Sr. Creatinine 3. BUN/Sr. Creatinine ratio 4. Urine proteins b. Tests for tubular function i. Tests for proximal tubular function 1. Glycosuria, aminoaciduria, LMW proteinuria 2. Urinary concentration of Na+ 3. Functional excretion of Na+ ii. Tests for distal tubular function 1. Specific gravity 2. Urine osmolality 3. Water deprivation test 4. Water loading – ADH suppression test 5. Ammonium chloride loading test 3. Each test in detail Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  3. 3. 3 * Indications for RFT 1. 2. 3. 4. 5. To identify early renal impairment in patients at risk, such as i. Diabetes mellitus ii. Hypertension iii. SLE iv. UTI v. UT obstruction vi. Older age To diagnose certain renal disorders to asses response to treatment in renal disorders to adjust dosage of chemotherapeutic drugs To plan renal replacement therapy in advanced renal diseases * Classification Tests for glomerular function 1. For GFR – clearance tests, indirect clearance 2. Blood biochemistry S. Creatinine, Bl Urea, BUN/S Creat ratio, Proteinuria (Albuminuria and microalbuminuria) Tests for tubular function For Proximal Tubules For distal tubules i. Glycosuria, i. Specific gravity and Phosphaturia, osmolality Uricosuria, ii. water deprivation test aminoaciduria, LMW iii. water loading test Proteinuria iv. Ammonium chloride ii. Urinary excretion of test sodium iii. fractional sodium excretion Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  4. 4. 4 *Tests to measure GFR GLOMERULAR FILTERATION RATE: Definition: Rate at which a substance is cleared from the plasma in unit time by the glomeruli (in ml/min) Rationale: i. ii. iii. iv. v. vi. vii. Best for assessing excretory renal function Varies according to age/sex/body surface area (BSA) Also depends on renal blood flow and pressure Normal GFR = 120ml/min/1.73m2 GFR declines with age after 40 @1ml/min/year due to progressive glomerular arteriosclerosis Fall in GFR leads to accumulation of waste products – GFR <15ml/min indicates uremia GFR <60ml/min/1.73m2 indicates >50% loss of renal function Classification of chronic kidney diseases based on GFR: Stage Stage I Stage II Stage III Stage IV Stage V Disease Kidney disease with Kidney disease with Kidney disease with Kidney disease with Renal Failure GFR Normal GFR Mild decreased GFR Moderate dec GFR Severe dec GFR Value (ml/min/1.73m2) >90 60-89 30-59 15-29 <15 TESTS TO MEASURE GFR: Direct assessment (Clearance Tests) Indirect assessment from Sr. Creatinine Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  5. 5. 5 (i) CLEARANCE TESTS: Volume of plasma that is completely cleared of that substance per minute C = UV/P C = clearance (ml/min), U=Concentration of substance in urine (mg/dl), V=Volume of urine per min (ml/min), P=concentration of substance in plasma (mg/dl) Ideal agent for clearance studies: No ideal agent has been found, however the agent used should fulfill most of the following criteria: i. Should not bind to plasma proteins ii. should be freely filtered across glomeruli iii. should not be reabsorbed iv. should not be metabolized by kidney v. should be excreted only through the kidney Agents used: Exogenous i. ii. iii. iv. Inulin radiolabelled EDTA Radiolabelled 125I thiocynate 99 Tc-DTPA i. ii. iii. Endogenous Creatinine Urea Cystatin C Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  6. 6. 6 (A) Inulin Clearance test: Rationale: 1. Gold Standard for measurement of GFR 2. Neither secreted nor absorbed and is completely filtered by glomeruli Method: 1. Bolus dose is administered followed by constant i.v. infusion for maintaining constant plasma levels 2. Timed urine samples are collected and blood samples are obtained at mid points of urine collection Disadvantage: Rarely used in practice because 1. Time consuming 2. Expensive 3. Need to maintain steady plasma levels Normal Values: Inulin clearance Males : 125 ml/min/1.73 m2 Females: 110 ml/min/1.73 m2 Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  7. 7. 7 (B) Creatinine Clearance Test Rationale: 1. Most commonly used for measuring GFR 2. Produced constantly from creatine in muscles 3. completely filtered by glomeruli, not reabsorbed, but is secreted in a small amount – there is overestimation of GFR by 10% 4. Can help in finding out the number of nephrons damaged by disease process Method: 1. 24 hour urine sample is preferred 2. First voided sample is discarded 3. Subsequently all urine passed is collected in containers 4. Next morning voided sample is collected and all containers are sent to laboratory 5. A blood sample is obtained at midpoint of urine collection 6. Cimetidine which blocks renal secretionocan be used to prevent overestimation 7. Final calculation is by the formula UV/P, with adjustment of 10% for secretion As we can see from the graph, as the creatinine clearance decreases, the remaining nephrons in the kidney decrease Also the dotted line shows that the serum creatinine begins to rise only after 50% of the nephrons are damaged, i.e. serum creatinine though useful is a less sensitive indicator of renal function. Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  8. 8. 8 Disadvantages: 1. small amounts of creatinine secreted by renal tubules can increase even further in advanced renal failure 2. Creatinine level is affected by intake of meat and muscle mass 3. collection of urine is incomplete often 4. Creatinine levels are affected by drugs such as cimetidine, probenecid and trimethoprim that block tubular secretion Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  9. 9. 9 (C) Cystatin – C clearance test Rationale: 1. It is a protease produced by all nucleated cells of the body at a constant rate 2. It is not bound to proteins, freely filtered by glomeruli and not absorbed Advantages over Creatinine: 1. More sensitive and specific 2. Not affected by sex/diet/muscle mass Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  10. 10. 10 (D) Urea clearance test Rationale: 1. Urea is freely filtered by the glomeruli but about 40% is reabsorbed 2. Thus it underestimates GFR and is not a sensitive marker Importance of clearance tests: As we saw in creatinine clearance graph, BUN and Sr. creatinine are not sensitive indicators of early renal impairment For serum creatinine to rise from 0.5mg/dl (normal) to 1.0 mg/dl, nearly 50% of the renal mass should have been damaged Clearance tests are more helpful in this scenario of detection of early renal impairment Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  11. 11. 11 (II) Indirect estimation of clearance from serum creatinine value Creatinine clearance = (140 – age in years) x Body weight in kg ( 72 x serum creatinine in mg/dl) Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  12. 12. 12 *Blood Biochemisty (a) Blood Urea Nitrogen (BUN) Earlier methods measured only nitrogen content of blood urea. 28 gms nitrogen is present in a gram mole of urea and molecular weight of urea is 60 . So urea: nitrogen = 60:28. ie BUN can be converted to urea by multiplying by 2.14 Newer methods directly measure blood urea. Production of Urea: Proteins Amino acids Synthesis of tissue proteins Energy Ammonia Urea Cycle Urea Excretion in urine Rationale: 1. Completely filtered by glomeruli and 30-40 % is reabsorbed 2. State of hydration affects estimation 3. Affected by non renal factors such as - high protein diet - upper g.i. hemorrhage 4. Less sensitive – considerable destruction of renal parenchyma has to occur before urea is elevated Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  13. 13. 13 Methods: 1. Direct method (Di acetyl monoxamine method) Urea + DAM Yellow diazine derivative High temp, strong acid, oxidizing agent Intesity of color is measured 2. Indirect method (Urease Bertholet reaction) 37 C Urea Alkaline hypochlorite Ammonia Urease Iodophenol Phenol Intensity of color is measured Normal levels: Normal Adults – 7-18 mg/dl Adults > 60 years – 8-21 mg/dl Causes of increased BUN: Azotemia – increase in level of BUN/urea Uremia – clinical syndrome resulting from azotemia 1. 2. 3. 4. Pre renal shock CHF dehydration high protein diet, trauma, burns, g.i. hemorrhage Renal Impairment of renal function Post renal Obstruction of urinary tract Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  14. 14. 14 (b) Serum Creatinine Production of Creatinine: Creatinine is a nitrogenous waste product formed in muscle from creatine phosphate. Rationale: 1. Creatinine is produced from muscles at a constant rate 2. Production is proportional to muscle mass and body weight 3. Its not reabsorbed, secreted in a small amount 4. It is not sensitive (see graph) The dotted line shows that the serum creatinine begins to rise only after 50% of the nephrons are damaged, i.e. serum creatinine though useful is a less sensitive indicator of renal function. Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  15. 15. 15 Methods: 1. Jaffe’s method Creatinine + Picric acid Alkaline reagent Colored product Spectrophotometer Picric acid also reacts with glucose, protein and fructose, hence actual level is 0.2 to 0.4 mg /dl lower 2. Enzymetic method Creatinine H2O2 + phenol + dye Colored product enzymes spectrophotometer Normal Range: Serum Creatinine Males 0.7 to 1.3 mg/dl Females 0.6 to 1.1 mg/dl Causes of: Increased serum creatinine 1. Azotemia 2. dietary meat 3. Acromegaly, gigantism Decreased serum creatinine 1. Pregnancy (hemodilution) 2. Old age (decreased muscle mass) Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  16. 16. 16 (c) BUN/Serum creatinine ratio Normal: BUN:Sr. Creatinine 12:1 to 20:1 Causes of Ratio >20:1 INCREASED BUN WITH NORMAL CREATININE 1. 2. 3. 4. High protein diet Increased protein catabolism G.I. Hemorrhage Dehydration – decreased renal perfusion (Pre renal azotemia) In these conditions there is increased protein break down – increased BUN Muscle creatine is not broken down – hence no increase in serum creatinine INCREASED BUN AND INCREASED CREATININE BUT INCREASE IN BUN IS MORE 1. Post renal azotemia (obstruction) Ratio <12:1 INCREASED CREATININE WITH NORMAL BUN 1. Starvation 2. Low protein diet 3. severe liver disease In these three conditions, there is increased creatine breakdown in muscles to synthesize proteins – increased creatinine BUN is normal INCREASED BUN AND CREATININE BUT INCREASE IN CREATININE IS MORE 1. Acute tubular necrosis In this condition there is obstruction to urine flow which pushes urea back into circulation - increase in BUN is more than that of creatinine Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  17. 17. 17 (iv) Proteinuria Rationale: 1. Normally a very small amount of albumin is excreted in urine. 2. Earlest evidence of glomerumlar damage in diabetes mellitus is occurrence of microalbuminuria (albuminuria in range of 30 to 300 mg/24 hrs) 3. Albuminuria >300mg/24 hour is termed clinical or overt proteinuria and indicates significant glomerular damage. For details see notes on urine analysis – Protein in urine Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  18. 18. 18 *Tests to assess proximal tubular function: (i) Glycosuria, aminoaciduria, LMW proteinuria Rationale: 1. Proximal tubules reabsorb 99% of glomerular filterate. 2. Substances such as glucose, aminoacids and LMW proteins are reabsorbed by PCT. 3. Hence measurine these substances in urine gives us an idea about the function of PCT, if PCT are non functioning (or these substances are in excess) they will appear in urine. 1. Glycosuria – i. ii. in renal glycosuria, glucose is excreted in urine when blood levels are normal due to lesion in tubules Glycosuria can also occur in Fanconi syndrome 2. Generalised aminoaciduria i. many aminoacids are excreted in urine due to proximal tubular dysfunction 3. Tubular proteinuria (Low molecular weight proteinuria) i. substances such as beta 2 microglobulin, retinol binding protein, lysozyme and alpha 1 microglobulin are completely reabsorbed by tubules ii. Detected by urine protein electrophoresis. Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  19. 19. 19 (ii) Urinary concentration of sodium: Rationale: 1. Used to differentiate between pre renal azotemia and acute tubular necrosis 2. In pre renal azotemia, tubular function is preserved, i.e. reabsorption of sodium is preserved 3. In acute tubular necrosis, tubular function is not preserved, ie. Sodium is not reabsorbed. Values: 1. Pre renal azotemia: Urinary Na+ < 20 mEq/L 2. Acute tubular necrosis: Urinary Na+ > 20 mEq/L Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  20. 20. 20 + + (iii) Functional excretion of Na (FNa ) Rationale: Measurement of urinary sodium is affected by urine volume (mEq/L) Hence to avoid this we can measure the exact quantity of Na+ reabsorbed as a fraction of amount of Na+ filtered to amount excreted As with above test, this test is used to differentiate between pre and renal azotemia Method: F Na+ = Urine Na+ x Plasma Creatinine Plasma Na+ x Urine Creatinine x 100 Values: 1. Pre renal azotemia - <1% 2. ATN - >3% Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  21. 21. 21 *Tests that assess distal tubular function (i) Specific Gravity Rationale: 1. It is the ratio of density of substance to density of fresh water at 4˚C (39˚F) 2. At this temperature density of water is greatest and equals 1gm/dl 3. It means that a substance with specific gravity >1(@4˚C) will sink and <1(@4˚C) will float. Factors affecting specific gravity: 1. State of hydration 2. Tubule concentrating ability 3. Number and nature of dissolved particles – HMW solutes like proteins and glucose affect specific gravity Methods: See notes on urine examination Causes: Increased specific gravity Decreased specific gravity 1. Proteinuria 2. Glycosuria (diabetes mellitus) 3. Nephrotic syndrome 4. urinary tract obstruction with preserved concentrating ability 5. decreased renal perfusion with preserved concentrating ability 1. Diabetes insipedus 2. CRF with decreased concentrating ability 3. increased water intake Fixed specific gravity (@1.010) Chronic renal failure Normal Value: Specific gravity 1.003 to 1.030 Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  22. 22. 22 (ii) Urine Osmolality Rationale: 1. Osmolality measures the number of dissolved particles in a solution. 2. It is most sensitive and most commonly employed method to find out urinary concentrating ability Method: When solute dissolves in a solvent it leads to 1. Lowering of freezing point 2. increase in boiling point 3. decrease in vapour pressure 4. increase in oncotic pressure These properties are used while measuring osmolality by a osmometer Method: 0.1 M sucrose Semipermeable Membrane Final level indicates osmolality as water enters The tube, its level rises Water Simple osmometer Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  23. 23. 23 Factors affecting osmolality: 1. depends only on number of dissolved particles 2. it doesnot depend on nature or molecular weight of dissolved particles like specific gravity does Normal: Urine osmolality (24 hour) 500 - 800 mOsm/kg of water With restricted fluid intake - >800 mOsm/kg of water Application: (Urine : plasma osmolality ratio is calculated, used to differentiate pre renal and renal azotemia) Decreased urine:plasma osmolality ratio (either urine osmolality is decreased or plasma osmolality is increased) Seen in Acute tubular necrosis (decreased concentrating ability) Increased urine:plasma osmolality ratio (either urine osmolality is increased or plasma osmolality is decreased) Pre renal azotemia – preserved concentrating ability Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  24. 24. 24 (iii) Water deprivation test for urine osmolality and specific gravity Rationale: Measures concentrating ability of kidney with fluid restriction Method: Measurement of urine osmolality and specific gravity Restriction of water intake for a specified period of time Measurement of urine osmolality and specific gravity and comparison with earlier values Rise in specific gravity and urine osmolality (>800 mOsm/kg of water, >1.025) No rise in specific gravity and osmolality Urinary concentrating ability maintained Or false positive result* Administer desmopressin Rise in sp. Gravity Central DI (diabetes insipedus) No rise Nephrogenic DI * false positive result is obtained in case of low salt, low protein diet or major electrolyte disturbances Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  25. 25. 25 (iv) Water loading – ADH suppression test Rationale: Measures ability of kidney to dilute urine after water loading Method: Over night fast Drink 20 ml/kg of water in 15-20 min Collect urine at hourly interval for next 4 hours 1. 2. 3. 4. Measure Specific gravity urine volume osmolality (serum and urine) plasma levels of ADH Scenario 1 1. >90% of fluid load excreted in 4 hours 2. specific gravity <1.003 after 4 hours 3. Urine osmolality <100 mOsm/kg after 4 hrs 4. ADH level decreased with decreased osmolality Normal diluting ability of kidney Scenario 2 1. <80% excreted 2. >1.003 3. >100 mOsm/kg 4. ADH fails to decrease Renal function impairment OR False negative* * False negative seen in 1. dehydration 2. cirrhosis 3. Malabsorption 4. adrenocortical insufficiency 5. congestive heart failure Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes
  26. 26. 26 (v) Ammonium chloride loading test Rationale: After all the causes of metabolic acidosis have been ruled out Renal tubular acidosis is the most likely diagnosis This test is done to confirm or rule out renal tubular acidosis After overnight fast, urine pH should be <5.4 If results are inconclusive , we administer ammonium chloride which increases urinary pH and remeasure Method: Measure baseline urinary pH and plasma HCO3- levels Overnight fast and collect urine for next 6-8 hours Scenario 1 1. Urine pH <5.4 2. plasma HCO3- Normal /high Scenario 2 1. Urine pH > 5.4 2. Plasma HCO3- low Scenario 3 Inconclusive results Normal renal Acidifying ability Type I renal tubular acidosis Give NH4Cl orally Collect urine samples Over next 6-8 hrs If pH <5.4, acidifying Ability maintained Notes on renal function tests… By Dr. Ashish Jawarkar Contact: pathologybasics@gmail.com Website: pathologybasics.wix.com/notes

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