Introduction to Renal function and Renal Disease Farid Nakhoul M.D. Director Ambulatory Nephrology unit Rambam-Health Care Campus Faculty of Medicine Haifa Tel: Fax:

Introduction Anatomy Physiology GFR Proteinuria ARF VS CRF Research

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

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.

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.

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

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

Proteinuria is the halmark of glomerular disease

Urinary Protein Excretion Measurment Negative Trace-between mg/dl 1+ - between mg/dl 2+ - between mg/dl 3+ - between mg/dl 4+ > 1000mg/dl

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.

Urinary Protein/creatinine Ratio Creatinine excretion is 1mg/min>>1440mg/day (20-25 mg/kg) Women, Children, Elderly persons !!! Early morning urine sample mg/day protein or Max. 30 mg Albumin per day or 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.

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

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

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

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

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%)

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

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

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

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

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

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

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

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

Renal Imaging: CT Scan\

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

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

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