Chronic Kidney Disease: Progression Modifying Therapies Chapter 46 Pharmacotherapy: A Pathophysiologic Approach The McGraw-Hill Companies
Key Concepts • Chronic Kidney Disease (CKD) US Prevalence • ~19 million • The Kidney Disease Outcomes Quality Initiative (K/DOQI) • CKD risk factor categories • susceptibility factors • initiation factors • progression factors
Key Concepts • Mechanisms of CKD progression • reduction in kidney mass • glomerular hypertension • intratubular proteinuria • 5 CKD stages based on • structural damage • renal function
Key Concepts • Serum creatinine (SCr): • unreliable marker of kidney function in select patients • elderly • malnourished • children • estimate GFR • used to evaluate rate of disease progression
Key Concepts • Stage 5 CKD symptoms: • asterixis • pruritus • dysgeusia • nausea, vomiting • anorexia, weight loss • susceptibility to bleeding • Signs/symptoms of uremia foundational to decision to implement kidney replacement therapy
Key Concepts • Titrate ACEI/ARB to maximal suppression of urinary albumin excretion for DM patients with persistent microalbuminuria despite intensive insulin therapy • even without HTN • ACEIs/ARBs: key pharmacologic treatments • hemodynamic & BP reduction effects limit kidney disease progression
Key Concepts • Supportive therapies may slow CKD progression • dietary protein restriction • lipid-lowering medications • smoking cessation • anemia management • Limit progression with hyperglycemia & HTN treatment
Epidemiology • Worldwide public health problem: “silent epidemic “ • CKD affects ~5% of adult US population • CKD defined as SCr > 1.2 to 1.5 mg/dL • The Third National Health And Nutritional Examination Survey (NHANES III) • nationally representative sample of US adult population • > 10.9 million people have SCr> 1.5 mg/dL • CKD prevalence ~10.9% of US population age > 20 yrs (19 million) if microalbuminuria & proteinuria included Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann Intern Med 2003;139:137–147. Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levels in the U.S. population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 1998;32:992–999.
Etiology • Susceptibility factors: • advanced age • low income or education • racial/ethnic minority status • reduced kidney mass • low birth weight • family history • Useful for identifying populations at high risk for CKD
Etiology • Initiation factors: • result in direct kidney damage • modifiable by pharmacologic therapy • DM, HTN, autoimmune diseases, polycystic kidney disease, systemic infections, urinary tract infections, urinary stones, lower urinary tract obstructions, drug toxicity • Most common causes of CKD in the US: • diabetes mellitus • HTN • glomerular diseases
Etiology • Progression factors: • associated with further kidney damage • evident as increased decline in kidney function in patients who already have kidney damage • proteinuria, elevated BP, smoking • Predictors of progressive CKD: • persistence of underlying initiation factors • DM • HTN • glomerulonephritis • polycystic kidney disease
The Kidney • 2 million nephrons • filter • reabsorb • excrete solutes • excrete water • Primary regulator • Na+ & H2O balance • acid–base homeostasis • Hormone production necessary for RBC synthesis & Ca2+ homeostasis
Pathophysiology • Heterogeneous causes • diabetic nephropathy: glomerularmesangial expansion • hypertensive nephrosclerosis: kidney's arterioles have arteriolar hyalinosis; renal cysts present in polycystic kidney disease • initial structural damage may depend on the 1˚ disease • Progressive nephropathies result in irreversible renal parenchymal damage & ESRD • Key pathway elements • loss of nephron mass • glomerular capillary hypertension • proteinuria
Pathophysiology • Initiation factor exposure • remaining nephrons hypertrophy to compensate for loss of nephron mass and renal function • compensatory hypertrophy may be adaptive • hypertrophy may lead to intraglomerular hypertension • possibly mediated by angiotensin II
Kidney Disease/Injury • acute renal failure: • rapid loss of kidney function • hours to weeks • 50% increase in SCr (> 0.5 g/dL) • chronic kidney disease: • also called chronic renal insufficiency, progressive kidney disease • progressive loss of function • months to years • gradual replacement of normal kidney architecture with interstitial fibrosis
Kidney Disease Classification • National Kidney Foundation's (NKF) Kidney Dialysis Outcomes & Quality Initiative (K/DOQI) CKD classification system (stages 1 to 5) • Categories based on structural kidney damage &/or functional changes in GFR for > 3 months • stage 1: mild structural changes evidenced by microalbuminuria with "normal" kidney function • stage 5: analogous to end stage renal disease: dialysis or kidney transplantation may be necessary • increasing number: more advanced stage of disease • SCr: inaccurate index of GFR
Kidney Disease • Normal adult kidney function • GFR ~120 mL/min/1.73 m2 • Can diagnose CKD when GFR > 90 mL/min/1.73 m2 based on: • proteinuria • hematuria • evidence of structural damage from kidney biopsy
CKD Stages a Glomerular filtration rate (mL/min/1.73 m2) b CKD can be present with normal/near normal GFR if other markers of kidney disease are present c Based on elevated albumin to creatinine ratio dincludes patients on dialysis DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com
Presentation/Diagnosis • Development & progression may be insidious • CKD diagnosis • measure SCr, estimate GFR • assess urine for protein &/or albumin • CKD stages 3, 4, 5 require additional workup • anemia • CV disease • metabolic bone disease • malnutrition • fluid & electrolyte disorders
CKD Risk Factors DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com
Diabetes • Not all individuals with diabetic nephropathy progress to stage 5 CKD; however, high lifetime risk • Multiple Risk Factor Intervention Trial (MRFIT) • prospective study • > 300,000 individuals screened • ~3% of DM patients develop stage 5 CKD • DM subjects: 12-fold greater RR of stage 5 CKD • increased risk of nondiabetic CKD causes • suggests underlying genetic susceptibility Brancati FL, Whelton PK, Randall BL, Neaton JD, Stamler J, Klag MJ. Risk of end-stage renal disease in diabetes mellitus: A prospective cohort study of men screened for MRFIT. Multiple Risk Factor Intervention Trial. JAMA 1997;278:2069–2074.
Diabetes & CKD • Type 1 DM patients: 40% lifetime risk of developing CKD • Type 2 DM patients: 50% lifetime riskof developing CKD • Greater prevalence of type 2 DM compared to type 1 • 10:1 ratio in most countries • majority of CKD due to DM among type 2 DM patients Hasslacher C, Ritz E, Wahl P, Michael C. Similar risks of nephropathy in patients with type I or type II diabetes mellitus. Nephrol Dial Transplant 1989;4:859–863.
Hypertension • Increases CKD risk • Exact role as cause/consequence debated • Kidney has a role in HTN development/modulation • Generally develops concomitantly with progressive kidney disease • Early HTN treatment to aggressive goals slows CKD progression
Hypertension • Multiple Risk Factor Intervention Trial • 1˚ prevention • evaluated effect of an intervention on CHD mortality • 16 year follow-up • lifetime risk of stage 5 CKD for patients with HTN: 5.6% • risk varied dramatically by BP • 0.33% SBP 140 to 150 mm Hg &/or DBP 90 to 100 mm Hg • 4.5% for SBP > 180 mm Hg or DBP > 110 mm Hg Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334:13–18.
Hypertension • Elevated BP increases risk for developing CKD • Prospective study (n=316,675) managed care patients • increased stage 5 CKD risk in patients with elevated baseline BP • odds ratio for CKD development: • 2.0 (95% confidence interval [CI] 1.6 to 2.5) for SBP 120 to 129 mm Hg & DBP 80 to 84 mm Hg diastolic • 4.3 (95% CI 2.6 to 6.9) for SBP > 210 mm Hg or DBP >120 mm Hg compared to BP SBP < 120 and DBP < 80 mm Hg Perneger TV, Nieto FJ, Whelton PK, Klag MJ, Comstock GW, Szklo M. A prospective study of blood pressure and serum creatinine. Results from the "Clue" Study and the ARIC Study. JAMA 1993;269:488–493. Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med 2005;165:923–928.
Glomerulonephritis • Glomerular diseases: initiation factors with variable epidemiology, pathophysiology • Goodpasture's disease or Wegener's granulomatosus may progress rapidly to stage 5; cause ARF • Immunoglobulin (Ig) A nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, lupus nephritis, & others more indolent cause of CKD • chronic glomerular diseases progress at variable rates • loss of GFR 1.4 to 9.5 mL/min/year
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