1. Pathophysiology of Disease: Chapter 16 (394-398) RENAL DISEASE: CHRONIC RENAL FAILURE Pathophysiology of Disease: Chapter 16 (394-398) Jack DeRuiter, PhD Department of Pharmacal Sciences April, 2000

2. ETIOLOGY (page 394) Diabetes mellitus (28%) Hypertension (25%) Glomerulonephritis (21%) Polycystic Kidney Diease (4%) Other (23%): Obstruction, infection, etc.

3. Pathology and Pathogenesis (page 395) Chronic vs Acute renal failure pathogenesis: –Acute: tubular cell death and regeneration (reversible) –Chronic: Irreversible nephron loss Glomerular Hyperfiltration: –Compensatory mechanism with increased nephron GFR: –Pre-disposition to glomerular sclerosis Azotemia at 30-35% GFR Uremia: <20% normal excretory capacity

4. Pathogenesis of Uremia Retention of nitrogenous wastes Increased intracellular Na and water Decreased intracellular K Increased levels of bioactive substances normally cleared renally (hormones) Decreased levels of hormones and other mediators produced by the kidney Decreased basal body temperature Diminished lipoprotein lipase activity

5. CHRONIC RENAL FAILURE: CLINICAL MANIFESTATIONS (pages 395-398) Sodium and water retention Hyperkalemia Metabolic Acidosis Mineral and Bone metabolism Cardiovascular and Pulmonary Disorders Hematologic Abnormalities Neuromuscular Abnormalities Gastrointestinal Abnormalities Endocrine Abnormalities Dermatologic Abnormalities

6. CHRONIC RENAL FAILURE: Sodium and Volume Balance (page 395) Sodium and water retention: –CHF, Hypertension, ascites, edema Enhanced sensitivity to extra-renal sodium and water loss –vomiting, diarrhea, fever, sweating –Symptoms: dry mouth, dizziness, tachycardia, etc. Recommendations –Avoid excess salt and water intake –Diuretics or dialysis

7. CHRONIC RENAL FAILURE: Potassium Balance (pages 395-396) Hyperkalemia (GFR below 5 mL/min) –GFRs >5 mL/min: compensatory aldosterone- mediated K transport in the DCT –K-sparing diuretics, ACEis, beta-blockers impair Aldosterone-mediated actions –Exacerbation of hyperkalenia: Exogenous factors: K-rich diet, etc. Endogenous factors: infection, trauma, etc.

8. CHRONIC RENAL FAILURE: Potassium Balance and Diabetes (page 396) Diabetics (major cause of CRF): –Hyporeninemic hypoaldosteronism –Lack of renin - decreased angiotensin II - impaired aldosterone secretion - loss of compensation for low GFr

9. CHRONIC RENAL FAILURE: Metabolic Acidosis (page 396) Decreased acid excretion and ability to maintain physiologic buffering capacity: GFR > 20 mL/min: transient moderate acidosis Treat with oral sodium bicarbonate Increased susceptibility to acidosis

10. CHRONIC RENAL FAILURE: Mineral and Bone (page 396-397) Bone disease (Figure 16-6) from: Decreased Ca absorption from the gut Over-production of PTH Altered Vitamin D metabolism Chronic metabolic acidosis

11. CHRONIC RENAL FAILURE: Cardiovascular and Pulmonary Abnormalities (page 397) Volume and salt overload –CHF and pulmonary edema –Hypertension Hyperreninemia: Hypertension Pericarditis: Remic toxin accumulation Accelerated atherosclerosis: linked to factors above and metabolic abnormalities (Ca alterations, hyperlipidemia)

12. CHRONIC RENAL FAILURE: Hematological Abnormalities (page 397) Anemia: lack of erythropoietin production Bone marrow suppression: –uremic poisons: leukocyte suppression - infection –bone marrow fibrosis: elevated PTH an aluminum toxicity from dialysis Increased bruising, blood loss (surgery) and hemorrhage Lab Abnormalities: Prolonged bleeding time, abnormal platelet aggregation

13. CHRONIC RENAL FAILURE: Neuromuscular Abnormalites (page 397) CNS Abnormalities: –Mild-Moderate: Sleep disorders, impaired concentration and memory, irritability –Severe: Asterixis, myoclonus, stupor, seizures and coma Peripheral neuropathies: –“restless legs” syndrome Hemodialysis-related neuropathies

14. CHRONIC RENAL FAILURE: Gastrointestinal Abnormalities (page 397) Peptic Ulcer disease: Secondary hyperparathyrodism? Uremic gastroenteritis: mucosal alterations Uremic Fetor: bad breath (ammonia) Non-Specific abnormalities: –anorexia, nausea, vomiting, diverticulosis, hiccoughs

15. CHRONIC RENAL FAILURE: Endocrine Abnormalities (page 398) Insulin: Prolonged half-life due to reduced clearance (metabolism) Amenorrhea and pregnancy failure: low estrogen levels Impotence, oligospermia and geminal cell dysplasia: Low testosterone levels

16. CHRONIC RENAL FAILURE: Dermatologic Abnormalities (page 398) Pallor: anemia Skin color changes: accumulation of pigments Ecchymoses and hematomas: clotting abnormalities Pruritus and Excoriations: Ca deposits from secondary hyperparathyroidism