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1. RENAL FUNCTION TESTS DEPT. OF BIOCHEMISTRY

2. FUNCTIONS OF KIDNEY Formation of urine. Excretion of nonprotein nitrogenous (NPN) substances. Regulation of water, electrolyte and acid-base balance Production of hormones, e.g. Erythropoietin, renin and calcitriol . Activation of vitamin D. Regulation of blood glucose.

3. Component parts of the nephron of the kidney

4. Urine formation Filtration. Reabsorption. Secretion .

5. Classification of renal function test 1. Urine analysis Physical examination Chemical examination Microscopic examination 2.Tests for assessment of glomerular function Renal clearance test Blood analysis of urea and creatinine Proteinuria Haematuria . 3.Tests to measure renal plasma flow(RPF) Para- aminohippurate test

6. 4.Tests for assessment of tubular function Urine concentration test ( Water deprivation test) Urine dilution test (Excess fluid intake test ) Glycosuria Amino aciduria Acid load test (Ammonium chloride loading test) Phenosulfonpthalein test (PSP) 5.In addition, renal biopsy is performed to confirm the diagnosis and renal disease .

7. URINE ANALYSIS It may reveal the disease anywhere in the urinary tract. The standard urine analysis include: Physical examination Chemical examination and Microscopic examination of urine. Physical Examination Includes: The 24 hours urinary output (volume) Appearance Colour Odour. pH Specific gravity and osmolality

8. VOLUME The daily ouput of urine in adult is 1000 to 2000ml with an average of 1,500ml/day. The quantity normally depends on the Water intake External Temperature Diet Mental and Physical State Cardiovascular Function Renal Function

9. POLYURIA Volume more than 2,500 ml/day occur in Diabetes mellitus – 5-6 L/day Diabetes insipidus – 10-20 L/day Later stages of chronic glomerulonephritis – 2-3 L/day OLIGURIA Volume 500 ml/day due to Fever Diarrhoea Acute nephritis Early stages of glomerulonephritis Cardiac failure

10. ANURIA Volume less than 100 ml/day of urine occur in: Acute tubular necrosis Bilateral renal stones Surgical shock COLOUR Normal urine is of pale yellow or amber colour . Variation in colour may be physiological and pathological. Darkening of urine color indicates more concentrated urine or presence of urochrome pigment . Haemoglobin and myoglobin in urine produce a brownish coloration . Turbidity in a fresh sample may indicate infection but also may be due to fat particles in an individual with nephrotic syndrome . Reddish coloration in haematuria is due to renal stones, cancer, some injury or disease of kidneys or urinary tract .

11. ODOUR Fresh urine normally has Ammoniacal odour. Foul smell indicates bacterial infection. pH The urine is normally acidic in nature with a pH about 6.0 ( range 5 to 7 ) Alkaline urine is found in urinary tract infection .

12. SPECIFIC GRAVITY It indicates the concentrating ability of the kidney . It normally varies from 1.016 to 1.024 It can vary widely depending on diet, fluid intake and renal function. Measured by Urinometer .

13. OSM0LALITY The urine osmolality of normal individuals varies widely, depending on the state of hydration After excessive intake of fluids, the osmotic conc may fall as low as 50 mosm /kg Restricted fluid intake – 1,200 mosm /kg On average fluid intakes 300 to 900 mosm /kg.

14. CHEMICAL EXAMINATION It includes detection of the followings: Glucose, Protein and Blood. Glucose Normal urine contains small amounts of glucose which cannot be detected by routine tests Excretion of detectable amounts of reducing sugar in urine is called glycosuria

15. Protein Increased amount of protein in urine, i.e. Proteinuria can be caused by, Increased glomerular permeability or Reduced tubular reabsorption Overflow Proteinuria . Most common type of proteinuria is due to albumin. Blood Presence of blood in urine is called haematuria and is commonly seen due to some injury or disease of kidneys or urinary tract. It may found in renal stones, cancer, tuberculosis, trauma of kidney or acute glomerulonephritis

16. BLOOD ANALYSIS Clearance determination may be most helpful in the early stages of progressive renal disease while blood analysis may be more sensitive when renal failure is advanced . Impairment of renal function results in elevation of blood urea (normal range 20-40 mg/dl) and creatinine (normal range 0.5 to 1.5 mg/dl). An increase of these end products in the blood is called Azotaemia . Plasma urea is less reliable than creatinine because it is affected by dietary protein intake and liver function.

17. PROTEINURIA (Marker of Glomerular Permeability) Protein in urine is an indicator of leaky glomeruli and is the first sign of glomerular injury before a decrease in GFR . The glomerular basement membrane does not usually, allow a passage of albumin and large proteins . A small amount of protein usually less than 30 mg/24 hour , is found in urine . Excretion of albumin more than 300 mg/day is indicative of significant damage to the glomerular membrane . Excretion of albumin in the range 30-300 mg/day is termed Microalbuminuria Microalbuminuria is the earliest sign of renal damage due to diabetes mellitus and hypertension.

18. HAEMATURIA Intact glomerulus does not allow passage of RBC. But with severe glomerular damage, RBC leakage occurs . Thus detection of microscopic haematuria or RBC casts confirm glomerular damage and is an earliest sign before the decrease in GFR.

19. MICROSCOPIC EXAMINATION Microscopic examination of the centrifuged urinary sediment is done to detect: Cells e.g. RBC, WBC, pus cells Crystals, e.g. Calcium phosphate, calcium oxalate, amorphos phosphate, etc Casts, e.g. Hyaline casts, granular casts, red blood casts, etc Presence of crystals in the urine may be a clue to the diagnosis of a specific type of renal calculus. It is completed by screening for bacteria.

20. TESTS OF GLOMERULAR FUNCTION RENAL CLEARANCE TEST A renal clearance test is employed to assess the rate of glomerular filtration and renal blood flow. The renal clearance of a substance is defined as the volume of plasma from which the substance is completely cleared by the kidneys per minute . This depends on the plasma conc of the substance and its excretory rate, which in turn, depends on the GFR and renal plasma flow. GFR can be measured by determining the excretion rate of a substance which is filtered through the glomerulus but subsequently, is neither absorbed nor secreted by tubules.

21. The GFR is usually equal to clearance of that substance and is calculated by the following equation: C = U × V / P where, C is the clearance of the substance in ml/min U is the concentration of the substance in urine P is the concentration of substance in plasma V is the volume of urine passed per minute. Lower than normal GFR measurements indicate: Acute tubular necrosis Glomerulonephritis Shock Acute and Chronic renal failure.

22. In order to determine GFR, the substance should be selected in such a way that which is, Freely filtered by glomerulus Should not be secreted or reabsorbed Should not be metabolized by the kidney Should not be toxic Should not be affected by dietary intake. The substances which are used for clearence tests include: Endogenous Creatinine and Urea . Exogenous Inulin

23. UREA CLEARANCE TEST Urea clearance is defined as the quantity of blood or plasma completely cleared of urea per unit time and is expressed in ml/min. Urea clearence = U×V/P Where U=mg of urea/ml of urine P= mg of urea/ml of plasma V=ml of urine excreted per min This is called as MAXIMUM URINE CLEARENCE. STANDARD UREA CLEARENCE=UX √V /P Standard urea clearance is used when the volume of urine is less than 2ml/min

24. Urea clearance may also used as a measure of the GFR. The normal value of urea clearance is 75ml/min . The sensitivity of the urea clearance test is much less than the creatinine clearance because : Plasma concentration of urea is affected by number of factors, e.g. Dietary protein, fluid intake, infection, surgery, etc. And Approximately 40% of the filtered urea is normally reabsorbed by the tubules.

25. Normal serum urea level is 10 to 40 mg/dl BUN = urea/2.14 PRERENAL causes of increased blood urea levels are Dehydration, vomiting intestinal obstruction, severe diarrhea , diabetic coma, burns etc. RENAL causes are Acute glomerular nephritis, end stage renal disease, malignant Hypertension POST RENAL causes are stones in the urinary tract, stricture of urethra, enlarged prostate, tumours of the bladder Medications like ACE inhibitors, Acetaminophen, Aminoglycosides , Amphotericin B, Diuretics, NSAIDs.

26. CREATININE CLEARANCE TESTS Creatinine clearance is defined as the quantity of blood or plasma completely cleared of creatinine per unit time and is expressed in ml/min. This test is the renal function test based on the rate of excretion by the kidneys of metabolically produced creatinine . Creatinine is freely filtered at the glomerulus and is not reabsorbed by the tubules. A small amount of creatinine is secreted by tubules. Because of these properties the creatinine clearance can be used to estimate GFR.

27. Procedure: Give 500ml of water to the patient, to promote good urine flow. After about 30 minutes, ask to empty the bladder and discard the urine. Exactly after one hour, again void the bladder and collect the urine, and note the volume. Take one blood sample. Creatinine level in blood and urine are tested and calculated : Uncorrected Creatinine clearance = U×V/P Where, U is Urinary creatinine P is Plasma creatinine V is volume of urine (ml/min) The obtained Clearance to be corrected with body surface area and expressed as ml/min/1.73Sq m so that it would be comparable between males, females and children.

28. Clinical interpretation The normal range for creatinine clearance is 100 to 120 ml/min. A decreased creatinine clearance is a very sensitive indicator of a decreased glomerular filtration rate. The reduced filtration rate may be caused by acute or chronic damage to the glomerulus or any of its components. Reduced blood flow to the glomeruli may also produce a decreased cretinine clearance.

29. Advantages Extrarenal factors will rarely interfere. Conversion of creatine phosphate to creatinine is spontaneous, non enzymatic. As the production is continuous, the blood level will not fluctuate. Blood may be collected at any time. It is not affected by diet or exercise.

30. Disadvantages Creatinine is filtered by glomeruli and actively secreted by the tubules. Of the total excretion, about 10% is by tubular component. The creatinine clearance is said to overestimate GFR by about 10-20 ml/min. Very early stages of decrease in GFR may not be identified by creatinine clearance( Creatinine blind area). Prerenal , renal and post renal causes will influence the creatinine clearance.

31. Estimated GFR ( eGFR ) It’s a simpler technique of estimating creatinine clearance and thereby GFR by using serum creatinine level. This would eliminate the need for timed urine collections. A commonly used formula is Cockcroft- Gault equation. Creat Cl =(140-Age in years) X Weight in Kg /72 X S Cr Creat Cl =(140-Age in years) X Weight in Kg(.85 in F)/ 72 X S Cr A more recent equation used in the MDRD study is more accurate. This equation directly estimates GFR. 186 X ( Creatinine /88.4) – 1.154 X (Age) – 0.203 [x0.742 if female]

32. Creatinine Co-efficient It is the urinary creatinine expressed in mg/kg body weight. The value is elevated in muscular dystrophy. Normal range Males : 20 - 28 mg/kg Females : 15 – 21 mg / kg.

33. Cystatin C Cystatin C is a 13 KD non glycosylated protein. Normal blood level of cystatin is 0.8 to 1.2 mg/L. Cystatin C is produced at a constant rate and is freely filtered by kidney glomeruli . It is completely reabsorbed; but degraded in the tubules; thus making it an excellent GFR marker. It is sensitive to changes in the so called creatinine blind area of GFR (40-70 ml/min/1.73metre square). Since there is no tubular secretion of Cystatin C, it is extemely sensitive to minor changes in GFR in the earliest stages of chronic kidney disease.

34. INULIN CLEARANCE TEST Inulin clearance is the method of choice when accurate deteremination of GFR is required. Inulin is a polysaccharide of fructose, which is filtered by the glomerulus, but not reabsorbed, secreted or metabolically altered by the renal tubule. About 100ml of 10% sterile solution of inulin is given intravenously over a period of 2 hours. Urine sample during this period is collected. Blood sample is taken in the middle of the test. Urine and blood level of inulin is estimated.

35. INULIN CLEARANCE TEST The normal value of inulin clearance is 125 ml/min. Inulin Clearance=GFR The main disadvantages in the measurement of inulin clearance are: The need for its intravenous administration. The technical difficulty of the analysis.

36. TESTS FOR TUBULAR FUNCTION Assessment of the concentrating and diluting ability of the kidney can provide the most sensitive means of detecting early impairment in renal function since the ability to concentrate or dilute urine is dependent upon: Adequate GFR Renal plasma flow Tubular mass Healthy tubular cells Presence of antidiuretic hormone (ADH). The urinary specific gravity and osmolality are used to measure the concentrating and diluting ability of the tubules.

37. Urine concentration test In the fluid deprivation test, fluid intake is withheld for about 15 hours. The patient is allowed to have no food or water after a meal at 6pm. The next day at 7am the bladder is emptied and specimen is discarded. A second sample is collected at 8am and specific gravity is measured. If it exceeds osmolality 850 mosmol /kg or specific gravity of 1.025, the renal concentrating ability is considered normal. Dehydration maximally stimulates ADH secretion. If kidney is normal, water is selectively reabsorbed resulting in excretion of urine of high solute concentration and urine osmolality should be atleast three times that of plasma (286 mosmol /kg)

38. Clinical interpretation In case the urine does not have specific gravity 1.025 or osmolality 850 mosmol /kg, it would suggest that renal concentrating ability is impaired either due to: Tubular defect or Decreased secretion of ADH (diabetes insipidus ) So ADH test must be carried out . If the tubules and collecting ducts are working efficiently, and if ADH is present they will be able to reabsorb water .

39. In polyuria of diabetes insipidus , where the hormone ADH is lacking or in nephrogenic diabetes insipidus (lack of response to ADH), the osmolality will remain constant even after fluid deprivation. In practice, the fluid deprivation test is extremely unpleasant for the patient. It is potentially dangerous if there is severe inability to retain water. Clinically, the loss of concentrating ability is manifested by nocturia (passage of urine at night) and polyuria .

40. Urine dilution test In dilution test, after emptying the bladder, 1200 ml of water is given over next 30 minutes to the patient. Urine specimens are then collected every hour for next 4 hours . Volume, Specific gravity and osmolality of each sample are measured. Clinical Interpretation If the functioning of renal tubule is normal, the urinary specific gravity should fall to 1.005 or less or an osmolality of less than 100 mosm /kg. If the renal tubules are diseased, the concentration of solutes in the urine will remain constant irrespective of excess fluid intake.

41. Acid load test or tubular acidosis test or ammonium chloride loading test or urine acidification test The acid load test is occasionally used for the diagnosis of renal tubular acidosis in which metabolic acidosis arises. Renal tubular acidosis may be due to either of the following reason: Defective H+ ion secretion in the distal tubules which may be inherited or acquired. Reduced capacity to reabsorb bicarbonate in the proximal tubule.

42. Acid load test or tubular acidosis test or ammonium chloride loading test or urine acidification test Ammonium chloride is admininstered orally in gelatin capsule (100mg/kg body weight) to cause metabolic acidosis and the capacity of kidneys is assessed for the production of acidic urine Urine acidification is a function of the distal tubules which can secrete H+ ions. Urine is collected hourly for 8 hours after ingestion. The pH and acid excretion of each sample is noted. Atleast one sample should have a pH of 5.3 or less. In RTA, pH of 5.3 is not achieved. Liver disease is a contraindication to perform this test.

43. Phenolsulfonphthalein (PSP) test or phenol red test Dyes are widely used for excretion tests. PSP dye is nontoxic and exclusively excreted by kidney and hence, is the dye of choice for excretory function of kidney. The test is conducted by measuring the rate of excretion of the dye following intramuscular or intravenous administration. The intravenous test is more valid, since it eliminates the uncertainties of absorption which exist in intramuscular test. After interavenous injection of 6mg of PSP in 1 ml of saline. Urine specimen may be collected at 15, 30, 60 and 120 min.

44. CLINICAL INTERPRETATION If the 15 min urine contains 25% or more of the injected PSP, the test is normal. 40 to 60% of the dye is normally excreted in the first hour and 20 to 25% in the second hour. Excretion of less than 23% of the dye during the 15 min urine indicates impaired renal excretory function even though t wo hour excretion may be normal. The test is contraindicated in azotemia and in patients with urinary retention.

45. Specific proteinuria or tubular proteinuria β 2 - microglobulin and α 1 -macroglobulin are small proteins which are filtered at the glomeruli and are reabsorbed by the tubular cells The presence of these proteins in urine is a sensitive indicator of renal tubular cell damage because after filtration, it is normally totally reabsorbed β 2 and α 1 -microglobulin are detected by electrophoresis, which are not normally seen in plasma electrophoresis.

46. Amino aciduria Normally amino acids in the glomerular filtrate are reabsorbed in the proximal tubules They may be present in urine in excessive amount because: The plasma concentration of amino acids exceeds the renal threshold or More commonly because of acquired renal tubular damage or There is specific failure of normal tubular reabsorptive mechanisms, e.g. In the inherited metabolic disorder cystinuria

47. glycosuria The presence of glucose in urine when blood glucose is normal usually reflects the inability of the tubules to reabsorb glucose because of specific tubular lesion This is called renal glycosuria and is a benign condition.

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