1. Introduction to Renal function and Renal Disease Farid Nakhoul M.D. Director Ambulatory Nephrology unit Rambam-Health Care Campus Faculty of Medicine Haifa Tel: 04-8542841 Fax: 048542946 Email:f_nakhoul@rambam.health.gov.il

3. Introduction Anatomy Physiology GFR Proteinuria ARF VS CRF Research

4. Tryggvason, K. et al. N Engl J Med 2006;354:1387-1401 Glomerular Filtration System

5. Structure of the Glomerulus(1) One of the central function of the kidney is to excrete low molecular weight water- soluble plasma waste products into the urine. Whereas macromolecules the size of albumin and larger are retained. The filtration of plasma occurs in specialized filtration units called Glomeruli.

6. Structure of the Glomerulus(2) The glomerular filtration barrier consists of the three layers of the capillary wall: 1. The innermost fenestrated vascular endothelium. 2. The GBM: the GBM is regarded as a primary size and charge-selective molecular sieve of the glomerulus. The GBM contains type IV collagen, laminin, nidogen, and proteoglycans as its main components. 3. Podocyte cell layer facing the urinary space.

11. Tryggvason, K. et al. N Engl J Med 2006;354:1387-1401 Components of the Slit-Diaphragm Protein Complex That Form a Porous Slit-Diaphragm Filter

12. Screening for Kidney Disease Urine Examination Urine Protein Urine Albumin Urine Sediment-Microscopy: Casts ! Hematuria: Microscopic or Macroscopic, Dysmorphic blood cells Leukocyturia

13. Proteinuria is the halmark of glomerular disease

14. Urinary Protein Excretion Measurment Negative Trace-between 15-30 mg/dl 1+ - between 30-100mg/dl 2+ - between 100-300 mg/dl 3+ - between 300- 1000mg/dl 4+ > 1000mg/dl

16. Protein-to-Creatinine Ratio Measurment of protein excretion in the urine can be performed by several different techniques. Previously, protein excretion was measured on a 24 hr urine collection (which remains the gold standard), with the normal value being less than 150 mg/day (10 mg albumin/day). Currently, the preferred methods is the total protein-to- creatinine ratio (mg/mg) or total albumin-to- creatinine ratio on a random urine specimen.

17. Urinary Protein/creatinine Ratio Creatinine excretion is 1mg/min>>1440mg/day (20-25 mg/kg) Women, Children, Elderly persons !!! Early morning urine sample 150-250 mg/day protein or Max. 30 mg Albumin per day or 20-25 mg/dl protein. Protein to Creatinine ratio greater than 3.0 or 3.5 or less than 0.2 mg/mg indicate protein excretion rates of greater than 3.0 or 3.5 gram/day or less than 0.2 gram/day respectively.

19. Stevens, L. A. et al. N Engl J Med 2006;354:2473-2483 Normal Values for GFR in Men and Women

21. Assessment of Kidney Function Plasma Creatinine BUN Uric Acid, Calcium-Phosphore,Albumin,Hb Plasma Creatinine/BUN Ratio CCT (GFR): Measured, Calculated

23. Stevens, L. A. et al. N Engl J Med 2006;354:2473-2483 Factors Affecting Creatinine Generation

28. Measuring GFR Exogenous substances –Inulin, Cr-EDTA, Iothalamate –Time consuming, expensive, radioactivity Endogenous substances –Creatinine (cystatin-C) –Over 40 GFR estimation equations based on serum creatinine

29. Cockcroft and Gault Developed in 1976 from 249 people (96% male) –Subsequently validated in at least 58 studies A measure of creatinine clearance Estimate urine creatinine based on age, weight and sex of patient. False elevation of serum creatinine assays (in 1976) gave lower results, serendipitously approximating the GFR Newer (better) creatinine assays give falsely elevated GFR estimates (approx 15%)

30. MDRD 1990s: Modification of Diet in Renal Disease study. Can progression of renal disease be slowed by dietary modification? Multiple ancillary studies to validate tools Devised and published the MDRD formulae for GFR estimation Used Beckman-Coulter CX3 assay at Cleveland Clinic Laboratory

31. MDRD - Opportunity MDRD formula adopted by the NKDEP National Kidney Disease Education Program Aim to highlight moderate to severe renal disease more simply than can be done from serum creatinine alone. Renal disease is bad for patients and health systems Earlier detection (pre-symptomatic) allows better chance for intervention

32. MDRD - Levy 1999 > +/- 30% scatter using results from one instrument

33. Stevens, L. A. et al. N Engl J Med 2006;354:2473-2483 Relationship of Serum Creatinine Level to Measured GFR in the Modification of Diet in Renal Disease Study

34. Stevens, L. A. et al. N Engl J Med 2006;354:2473-2483 Relation of Estimated GFR to Measured GFR in the Participants in the Modification of Diet in Renal Disease (MDRD) Study

37. Glomerular Disease Nephrotic Syndrome Sediment: Protein Nephritic Syndrome Sediment: Casts

38. Proteinuria Asymptomatic Non-nephrotic Proteinuria (<3.5 gr Protein/day). Nephrotic Syndrome: Pathognomonic of glomerular disease.

39. Nephrotic Syndrome Definition Urinary protein level exceeding 3.5 gr per 1.73m2 of body-surface area/day. Hypoalbuminemia. Sodium retention (Edema-State). Hyperlipoproteinemia. Hypercoagulability/Infections/Anemia

44. Renal Imaging: CT Scan\

45. Renal Imaging CT-Scan of abdomen with and without Contrast. Ultrasound( Parenchyma, Cortex/Medulla) Doppler of renal arteries Isotopes(DTPA, DMSA)

52. Introduction Diagnosis Kidney Needle Biopsy (KNB) (Closed, Laparoscopic)

58. Stevens, L. A. et al. N Engl J Med 2006;354:2473-2483 Normal Values for GFR in Men and Women