Chronic Kidney Disease ? Major world-wide health concern ? In US number of patients requiring dialysis or transplant is projected to increase from 340,000 in 1999 to 651,000 in 2010 ? National Kidney Foundation-attempts to standardize definition, stages and laboratory tests to assess kidney function Am J Kidney Dis. (2000) 366 suppl 2:S1–S279 S-M Huang et al. Clinical Pharmacology & Therapeutics (2009) 86 5, 475–479 Chronic Kidney Disease – Definition.
“Kidney damage for three months or more, with or without decreased GFR, manifested by pathologic abnormalities or markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging tests” GFR < 60 mL per minute per 1. 73 m2 for three months or more, with or without kidney damage National Kidney Foundation, 2004 Renal Drug Clearance • Glomerular Filtration • Tubular Secretion • Tubular Re-absorption – 20-25% Cardiac output or 1.
1L/min goes to kidneys – 10% of it is filtered at glomerulus – Normal GFR is 120 ml/min for a 70kg, 20 year old man Verbeeck RK, et al. Eur J Clin Pharmacol (2009) 65:757–773 Effect of Renal Dysfunction on PK processes • Absorption – increased tmax for certain drugs in severe renal dysfunction – Changes pre-systemic elimination • Distribution – Plasma protein binding of many acidic drugs decrease in renal impairment – 1-Acid glycoprotein levels may show an increase – Changes in volume of distribution.
• Metabolism – Renal dysfunction may alter even non-renal elimination – Accumulation of active metabolites • Elimination – Transporters – Renal failure may affect multiple organ systems Dose adjustments! Estimation of Renal Function ? GFR as overall measure of renal function ? Exogenous markers like inulin – not widely used clinically ? Most popular- Creatinine clearance from serum creatinine (Cockcroft-Gault equation) ? eGFR from Modification of Diet in Renal Disease (MDRD) study S-M Huang et al.
Clinical Pharmacology & Therapeutics (2009) 86 5, 475–479 Normal values for GFR in Men and Women Wesson LG. Physiology of the Human Kidney1969: 96-108 Xiao S. Clinical pharmacology Advisory Committee, 2008, CDER/FDA Ideal Markers for GFR • • • • • Freely filterable at the glomerulus Neither secreted nor reabsorbed by the tubules Steady state concentrations in blood No extra-renal route of excretion Easily and accurately measured Exogenous Markers Inulin • Gold standard • Constant infusion and bladder catheterization for good reproducibility • Significant blood sample volume.
• Assay is difficult • Expensive and time consuming • Limited to investigational research Endogenous markers Creatinine • Filtered by the glomerulus • No protein binding • Generation determined by muscle mass and dietary intake • Need 24-hour urine collection and blood sampling during the collection period • Cumbersome for timed urinary collection • Susceptible to error National Kidney Foundation Defines Five Stages of CKD Stage 1 2 3 4 5 GFR (ml/min/1. 73m2) ? 90 60-89 30-59 15-29.