Interpretation of renal biochemistry

1. Interpretation of renal biochemistry Doc. Dr. Mine KUCUR

2. Overview • Renal function tests • Tests for GFR • Urinalysis • Tests for Renal Tubular Acidosis • Tests of Kidney Concentrating Ability • Summary

3. Renal function tests • Detect renal damage • Monitor functional damage • Help determine etiology

4. glomerular filtration rate (GFR) plasma creatinine plasma urea urine volume urine urea minerals in urine urine protein urine glucose hematuria osmolality Laboratory tests of renal function

5. glomerular filtration rate=GFR plasma creatinine= Pcr plasma urea-Purea urine volume= V urine urea- Uurea cystatin C in plasma? urine protein urine glucose hematuria osmolality Tests of renal function

6. Tests of Glomerular FiltrationRate • Urea • Creatinine • Creatinine Clearance • eGFR • Cystatin C

7. Glomerular Filtration Rate (GFR) • Volume of blood filtered across glomerulus per unit time • Best single measure of kidney function

8. GFR • Normally 100-130 ml/min • Determined by: • Net filtration pressure across glomerular basement membrane • Permeability and surface area of glomerular basement membrane

9. GFR • Patient’s remain asymptomatic until there has been a significant decline in GFR • Can be very accurately measured using “goldstandard” technique

10. GFR • Ideal Marker • Produced normally by the body • Produced at a constant rate • Filtered across glomerular membrane • Removed from the body only by the kidney filtered only, not reabsorbed or secreted

11. Candidate markers for GFR Inulin +Filtered only – Not made by body; must be injected Creatinine +An endogenous product of muscle metabolism; near-constant production – Filtered, but a bit secreted Urea +An endogenous product of protein intake – Filtered and absorbed; synthesis varies with diet0

12. Urea • Used historically as marker of GFR • Freely filtered but both re-absorbed and excreted into the urine • Re-absorption into blood increased with volume depletion; therefore GFR underestimated • Diet, drugs, disease all significantly effect Urea production

13. Urea • Product of protein catabolism • Filtered • Reabsorbed in proximal tubule • If sodium is avidly reabsorbed, so is urea • Serum urea concentration measured as “Blood Urea Nitrogen (BUN)”

14. Urea • Increase • Volume depletion • Dietary protein • Corticosteroids • Tetracyclines • Blood in G-I tract • Decrease • Volume Expansion • Liver disease • Severe malnutrition

15. Why does BUN increase?  GFR, but also: Increased renal reabsorption: • ECV depletion Increased hepatic urea synthesis • High protein feeding • Corticosteroid treatment (Prednisone, etc.) • GI blood absorption

16. BUN: Uses • Imperfect marker of  GFR • Marker for adequacy of protein intake • Marker for presence of uremic toxins in chronic renal failure • BUN:Cr ratio reflects ECV volume status: • 10:1 = normal • >20:1 if ECV contracted. Why???  Proximal tubule Na and urea reabsorption!

17. Creatinine • Product of muscle metabolism • Some creatinine is of dietary origin • Freely filtered, but also actively secreted into urine • Secretion is affected by several drugs

18. Serum Creatinine • Increase • Male • Meat in diet • Muscular body type • Cimetidine & some other medications • Decrease • Age • Female • Malnutrition • Muscle wasting • Amputation

19. Serum Creatinine Concentration • Normally 0.7-1.4 mg/dl, depending on muscle mass • Inversely proportional to GFR • Good way to follow changes in GFR • BUT also elevated by  muscle mass,  tubular secretion

20. Creatinine Clearance • Measure serum and urine creatinine levels and urine volume and calculate serum volume cleared of creatinine • Same issues as with serum creatinine, except muscle mass • Requirements for 24 hour urine collection adds variability and inconvenience

21. Creatinine Clearance • Therefore, it represents the volume of serum completely cleared of creatinine per unit time • Since virtually all creatinine is cleared via glomerular filtration, it closely approximates the GFR

22. Creatinine Clearance EXAMPLE: UCr = 72 mg/dl SCr = 2.0 mg/dl V = 2 liters time = 24 hours

23. Limitations of Creatinine Clearance • Only valid at steady state—[Cr]serum must be stable • Trimethoprim, cimetidine lower tubular Cr secretion and lower CrCl without changing GFR: • Becomes more inaccurate at low GFR

24. Another Problem with Creatinine Clearance • Must be done on a properly collected, timed urine sample--patient error • How can we check accuracy of any timed urine collection?

25. Creatinine Excretion • The amount of creatinine excreted per day is stable for a given patient • It is function of muscle mass: generally higher in men vs. women, youth vs. elderly • expressed per kg lean body mass as the creatinine index

26. Quick formulae for estimating GFRInclude some combination of sex, weight, serum creatinine, race, and age. Use only at steady state (stable SCr) Useful screens for decreased GFR, esp. in elderly and small people, where errors in drug dosing may be major

27. Creatinine Test Summary

28. Cystatin C • Cystatin C is a 13 KD protein produced by all cells at a constant rate • Freely filtered • Re-absorbed and catabolized by the kidney and does not appear in the urine

29. eGFR • Increasing requirements for dialysis and transplant (8 – 10% per year) • Shortage of transplantable kidneys • Large number at risk

30. eGFR

31. eGFR

32. Problem • Need an easy test to screen for early decreases in GFR that you can apply to a large, at-risk population • Can serum creatinine be made more sensitive by adding more information?

33. eGFR by MDRD Formula • Mathematically modified serum creatinine with additional information from patients age, sex and ethnicity • eGFR = 30849.2 x (serum creatinine)-1.154 x (age)-0.203 (if female x (0.742))

34. eGFR • eGFR calculation has been recommended by National Kidney Foundation whenever a serum creatinine is performed in adults

35. Screen High Risk Groups • eGFR • Urinalysis • Albumin / Creatinine Ratio

36. Tests that predict kidney disease • eGFR • Albumin Creatinine Ratio (aka ACR or Microalbumin)

37. Proteinuria • In health: • High molecular weight proteins are retained in the circulation by the glomerular filter (Albumin, Immunoglobulins) • Low molecular weight proteins are filtered then reabsorbed by renal tubular cells

38. Proteinuria • Glomerular: • Mostly albumin, because of its high concentration and therefore high filtered load • Tubular: • Low molecular weight proteins not reabsorbed by tubular cells (e.g. alpha-1 microglobulin) • Overflow: • Excessive filtration of one protein exceeds reabsorbtive capacity (Bence-Jones, myoglobin)

39. Albumin Creatinine Ratio (Microalbumin) • Normal albumin molecule • In health, there is very little or no albumin in the urine • Most dip sticks report albumin at greater than 150 mg/L

40. Urinary Albumin • Detection of low levels of albumin (even if below dipstick cut-off) is predictive of future kidney disease with diabetes • Very significant biologic variation usually requires repeat collections • Treatment usually based on timed urine albumin collections

41. Follow-up based on Screen Results • Kidney Ultrasound • Specialist Referral • Cardiovascular Risk Assessment • Diabetes Control • Smoking cessation • Hepatitis / Influenza Management

42. Creatinine Standardization inBritish Columbia • Based on Isotope dilution /mass spectrometry measurements of creatinine standards • Permits estimation and correction of creatinine and eGFR bias at the laboratory level

43. Importance of Standardization • Low bias creatinine: • Causes inappropriately increased eGFR • Patients will not receive the benefits of more intensive investigation of treatment • High bias creatinine: • Causes inappropriately decreased eGFR • Patients receive investigations and treatment which is not required. Wastes time, resources and increases anxiety.

44. Poor Creatinine Precision • Incorrect categorization of patients with both “normal” and decreased eGFR.

45. Total Error • TE = % bias + 1.96 CV • Goal is <10% (requires bias ≤ 4% and CV ≤ 3%)

46. Kidney Functions • Selectively secretes into or re-absorbs from the filtrate to maintain • Water Balance • Tests: specific gravity, osmolarity, water deprivation testing, Antidiuretic hormone • Retention of nutrients • Tests: proteins, sugar, amino acids, phosphate • Secretes waste products • Tests: urate, oxalate, bile salts

47. Kidney Functions • Selectively secretes into or re-absorbs from the filtrate to maintain • Salt Balance • Tests: Na+, Cl-, K+ Aldosterone, Renin • Acid Base Balance • Tests: pH, HCO3-, NH4+ Acid loading, Urinary Anion Gap

48. Kidney Functions • Target organ • Parathyroid hormone (Ca++, Mg++) • Aldosterone (salt balance) • ADH (water balance) • Production • Erythropoietin • 1, 25 dihydroxycholecalciferol

49. Urinalysis • Dipstick • Protein • Useful screening test • Dipstick more sensitive to albumin than other proteins • Large biologic variation

50. Urinalysis • Dipstick – cont’d • Hemoglobin • Glomerular, tubular or post-renal source • Reasonably sensitive • Positive dipstick and negative microscopy with lysed red cells