Chronic Kidney Disease (CKD)

Note: Davidson's Principles and Practice of Medicine is not available in the library. This account draws from Harrison's 22nd Edition, which provides the most current, authoritative coverage. Where relevant, classic Davidson's teaching points are noted from general medical knowledge.

1. DEFINITION

• The GFR and its trajectory over time
• The quantity of urinary albumin excretion (albuminuria)

2. EPIDEMIOLOGY

• At least 6% of the US adult population has CKD at stages 1 and 2
• An additional 4.5% has stages 3 and 4 CKD
• Globally, 5 clinical categories account for >90% of the CKD burden worldwide

3. ETIOLOGY

Five Most Common Causes (>90% of global CKD burden):

4. PATHOPHYSIOLOGY

A. Disease-Specific Initiating Mechanisms

• Genetic abnormalities, immune complex deposition, inflammation
• Metabolic injury (e.g., hyperglycemia), microvascular perturbation
• Toxin exposure affecting vascular, glomerular, or tubulointerstitial compartments

B. Non-Specific Adaptive/Maladaptive Mechanisms (Bricker's Intact Nephron Hypothesis)

• Surviving nephrons undergo hyperfiltration and hypertrophy to compensate for lost nephron mass
• Mediated by vasoactive hormones, cytokines, and growth factors
• Over time, these compensatory changes become maladaptive: increased intraglomerular pressure distorts glomerular architecture, impairs podocyte function, disrupts the filtration barrier
• Results in progressive glomerulosclerosis and nephron dropout
• Increased intrafrenal RAS activity and reduced tubuloglomerular feedback contribute to both initial hyperfiltration AND subsequent hypertrophy/sclerosis

Structural Changes

• Bilaterally small kidneys (<8 cm) on ultrasound indicate chronic atrophy with irreversibly low function
• Normal kidney length: 10-12 cm
• Thinning of the renal cortex is also a sign of chronicity
• Even atrophic kidneys may still produce renin (maintaining BP) and some erythropoietin

5. STAGING (KDIGO Classification)

eGFR Estimation:

• Estimated (not directly measured) using serum creatinine-based equations
• Valid only in steady state (creatinine neither rising nor falling)
• Race-free equations are now recommended (no longer adjusting for African ancestry)
• Cystatin-C can be used as an alternative, unaffected by muscle mass variables
• Normal GFR peaks at ~120 mL/min/1.73m² in the 3rd decade, then declines by ~1 mL/min/year

6. RISK FACTORS

7. CLINICAL FEATURES AND UREMIC SYNDROME

System-by-System Complications:

A. Fluid and Electrolyte Disturbances

• Salt and water retention → hypertension, edema, heart failure
• Hyperkalemia (especially with RAAS blockers or potassium-rich diet)
• Hyponatremia (dilutional, from impaired free water excretion)
• Metabolic acidosis - due to reduced ammoniagenesis and acid excretion; may worsen bone disease and accelerate muscle wasting

B. Cardiovascular (Most Common Cause of Death in Dialysis Patients)

• Hypertension - nearly universal; accelerates CKD progression
• Left ventricular hypertrophy (LVH) - from hypertension, anemia, and fluid overload
• Accelerated atherosclerosis - CKD is an independent cardiovascular risk factor
• Pericarditis - characteristic of advanced uremia; presents with chest pain with respiratory accentuation and pericardial friction rub; pericardial effusion and tamponade are complications
• Uremic pericarditis is an absolute indication for urgent initiation of dialysis

C. Hematological

• Normocytic, normochromic anemia appears as early as stage 3, almost universal by stage 4
• Primary cause: insufficient erythropoietin (EPO) production by diseased kidneys
• Additional factors: reduced red cell lifespan, iron deficiency, inflammation, blood loss during dialysis
• Consequences: decreased tissue O₂ delivery, increased cardiac output, ventricular dilation and hypertrophy, fatigue, decreased cognition, impaired immunity, growth restriction in children
• Treatment: Erythropoiesis-stimulating agents (ESAs; e.g., epoetin alfa, darbepoetin); target Hb ~10-11.5 g/dL (higher targets increase cardiovascular risk); iron supplementation (IV preferred in dialysis); newer agents - HIF prolyl hydroxylase inhibitors (e.g., roxadustat, daprodustat)

D. Bone and Mineral Metabolism - CKD-Mineral Bone Disorder (CKD-MBD)

• Low calcitriol (1,25(OH)₂D₃) - kidneys fail to activate vitamin D → hypocalcemia
• Hyperphosphatemia - impaired phosphate excretion
• Elevated FGF-23 - early marker; FGF-23 rises before phosphate to maintain phosphaturia
• Secondary hyperparathyroidism (2° HPT) - compensatory rise in PTH; very elevated PTH suggests CKD chronicity
  • A normal parathyroid gland (25 mg) is limited in how much PTH it can raise acutely; very high PTH = chronic process
• Renal osteodystrophy - bone disease from these derangements; includes osteitis fibrosa cystica (high turnover), adynamic bone disease, osteomalacia
• Vascular calcification - from hyperphosphatemia and elevated Ca×P product

• Dietary phosphate restriction
• Oral phosphate binders (calcium-based: calcium carbonate, calcium acetate; non-calcium-based: sevelamer, lanthanum)
• Active vitamin D analogues (calcitriol, paricalcitol, doxercalciferol)
• Calcimimetics (cinacalcet) - sensitize parathyroid to calcium, reduce PTH secretion

E. Neurological

• Uremic encephalopathy - confusion, asterixis, myoclonus, seizures, coma
• Peripheral neuropathy - typically sensorimotor, stocking-glove distribution; "restless legs syndrome"
• Autonomic neuropathy

F. Gastrointestinal

• Anorexia, nausea, vomiting - common uremic symptoms
• Uremic fetor (urea converted to ammonia)
• GI bleeding (platelet dysfunction, uremic gastritis)
• Delayed gastric emptying

G. Dermatological

• Uremic pruritus - from calcium phosphate deposition in skin and uremic toxins
• Pallor (anemia)
• Uremic frost - rare; urea crystallizes on skin in very advanced disease
• Half-and-half nails (Lindsay's nails) - classic sign; proximal white, distal pink/brown

H. Endocrine/Metabolic

• Glucose intolerance (peripheral insulin resistance in uremia)
• Dyslipidemia - hypertriglyceridemia (reduced lipoprotein lipase), low HDL
• Hyperuricemia
• Malnutrition and protein-energy wasting (PEW)

I. Reproductive

• Menstrual irregularities and amenorrhea in women
• Impotence and reduced libido in men
• Reduced fertility in both sexes

8. MANAGEMENT

A. Slowing CKD Progression

• Target BP <130/80 mmHg (in proteinuric CKD, <125/75 mmHg is sometimes targeted)
• ACE inhibitors or ARBs are first-line in both diabetic and non-diabetic proteinuric CKD
  • Reduce intraglomerular pressure by dilating the efferent arteriole
  • Reduce proteinuria independently of BP effect
  • Combination ACE + ARB is NOT recommended (increased adverse effects without added benefit)
  • Caution: may worsen GFR acutely (acceptable up to 30% rise in creatinine), and cause hyperkalemia
• Very low BP targets may not be applicable to advanced CKD patients due to impaired renal autoregulation - sudden GFR decline with over-aggressive BP lowering should prompt therapy reduction

• Now a mainstay for both kidney protection and cardiovascular risk reduction in CKD
• Markedly ameliorate GFR decline in patients with and without diabetes
• Reduce cardiovascular events including heart failure, even in advanced stages (including stage 4)
• Examples: empagliflozin, dapagliflozin, canagliflozin

• HbA1c target ~7% (53 mmol/mol); avoid hypoglycemia in advanced CKD
• Metformin: hold at eGFR <30 (risk of lactic acidosis); use with caution 30-45
• SGLT2 inhibitors offer dual kidney and cardiac protection

• Low-protein diet (0.6-0.8 g/kg/day) - may slow progression, but monitor for malnutrition
• Sodium restriction (<2 g/day) - reduces BP and fluid overload
• Potassium restriction in hyperkalemia
• Phosphate restriction in advanced stages

• NSAIDs (reduce prostaglandin-mediated afferent dilation)
• Aminoglycosides, contrast agents, herbal nephrotoxins
• Judicious use of radiocontrast media (use lowest dose, ensure good hydration)

B. Treatment of Complications

C. Preparation for Renal Replacement Therapy (RRT)

• Referral to nephrologist when eGFR <30 (stage 4) for planning
• Options: Hemodialysis (HD), Peritoneal Dialysis (PD), or Kidney Transplantation
• Pre-emptive transplant listing when eGFR reaches 20
• Vascular access creation (AV fistula) ideally 6-12 months before anticipated start of HD
• Absolute indications to start dialysis: uremic pericarditis, uremic encephalopathy, refractory fluid overload, refractory hyperkalemia, refractory metabolic acidosis

9. ADDITIONAL SYSTEMIC CONSIDERATIONS

COVID-19 and CKD

• Up to 70% of ventilated COVID-19 patients developed multiorgan failure including AKI
• Post-COVID AKI may be a risk factor for subsequent CKD, though most patients recover baseline function
• SARS-CoV-2-associated nephropathy (especially in APOL1-variant carriers) has emerged as a new CKD etiology

CKD After AKI

• Clinically recovered AKI is now recognized as a risk factor for subsequent CKD
• Maladaptive tubular repair leading to fibrosis is the key mechanism

10. KEY DISTINGUISHING POINTS: CKD vs AKI

Summary

• Harrison's Principles of Internal Medicine, 22nd Edition (2025) - Chapter 322: Chronic Kidney Disease (Bargman JM, Skorecki KL), pp. 2429-2450
• Davidson's Principles and Practice of Medicine is not currently available in the library; the above account is based on Harrison's 22E. For Davidson's specific content (e.g., 24th edition Chapter on nephrology), the core framework is consistent as both texts are grounded in KDIGO guidelines.