Chronic Kidney Disease (CKD)

Definition

• Textbook of Family Medicine 9e, p. 1191
• Harrison's Principles of Internal Medicine 22e, p. 2438

Epidemiology

• Approximately 20 million persons in the United States have CKD
• Leading cause of end-stage kidney disease (ESKD) in the US: diabetes mellitus (~45%), followed by hypertension (~30%)
• Other prevalent causes: glomerulonephritis, polycystic kidney disease, obstructive uropathy
• ESKD is disproportionately higher in African Americans, partly due to APOL1 high-risk gene alleles
• Over 800,000 patients in the US have treated ESKD (requiring dialysis or transplantation)
• Harrison's Principles of Internal Medicine 22e, p. 2437

Staging (KDIGO Classification)

Fig. 50.7 - Proteinuria reduction correlates strongly with slower progression to ESKD. Reducing proteinuria by ≥50% (purple line, right panel) markedly lowers kidney event risk. (NKF Primer on Kidney Diseases, 8e)

• Textbook of Family Medicine 9e, p. 1191
• NKF Primer on Kidney Diseases, 8e, p. 528

Common Causes / Etiologies

1. Diabetic nephropathy - most common cause in developed countries
2. Hypertensive nephrosclerosis - second most common
3. Glomerulonephritis - (IgA nephropathy, FSGS, membranous, lupus nephritis)
4. Polycystic kidney disease (PKD) - hereditary
5. Tubulointerstitial nephritis - drug-induced, reflux, chronic infection
6. Obstructive uropathy - BPH, stones, strictures
7. Hereditary/genetic - Alport syndrome, Fabry disease, cystinosis, APOL1-related nephropathy

• Harrison's Principles of Internal Medicine 22e, p. 2437

Pathophysiology

Common Pathways of Progression

1. Glomerular hyperfiltration - When nephrons are lost, surviving nephrons compensate by increasing single-nephron GFR. This hyperfiltration causes intraglomerular hypertension, podocyte injury, and eventual sclerosis - a self-perpetuating cycle of nephron loss.
2. Proteinuria and tubular toxicity - Filtered proteins are toxic to tubular cells, triggering inflammation, tubular atrophy, and interstitial fibrosis.
3. RAAS activation - Angiotensin II causes efferent arteriolar constriction (worsening glomerular hypertension), promotes fibrosis via TGF-β, and drives sodium retention and systemic hypertension.
4. Chronic inflammation and fibrosis - Progressive interstitial fibrosis via TGF-β, cytokines (TNF-α, IL-1, IL-6), and myofibroblast activation is the final common pathway to ESKD.
5. Metabolic acidosis - As GFR falls, the kidney loses ability to handle the daily dietary acid load. Acidosis accelerates bone disease, sarcopenia, and CKD progression itself.
6. AKI-on-CKD - Episodes of acute kidney injury accelerate progression and may account for a sizable fraction of ESKD cases. Iatrogenic AKI (hypotension, nephrotoxins, contrast) should be actively avoided.

• NKF Primer on Kidney Diseases, 8e, pp. 528-530

Clinical Presentation

• Early/moderate CKD: usually asymptomatic; found incidentally on labs or urinalysis
• Hypertension - both a cause and consequence of CKD
• Edema - sodium and water retention
• Fatigue, pallor - from anemia of chronic kidney disease
• Sensory polyneuropathy - peripheral numbness/tingling
• Late/uremic CKD: nausea, anorexia, weight loss, hiccups, pruritus, muscle cramps, restless legs, asterixis ("flap"), pericardial friction rub

• Harrison's Principles of Internal Medicine 22e, p. 2437

Workup / Diagnosis

Laboratory

• Serum creatinine + eGFR (calculated by CKD-EPI or MDRD equation)
• Urine albumin-to-creatinine ratio (uACR) or 24-h urine protein
• Serum electrolytes - look for hyperkalemia, metabolic acidosis (low bicarb)
• Calcium, phosphorus, PTH - evaluate CKD-mineral bone disorder
• CBC - hemoglobin for anemia; iron, B12, folate
• Urinalysis + microscopy - hematuria, casts, proteinuria
• Serum and urine protein electrophoresis (SPEP/UPEP) in patients >35 with unexplained CKD to rule out multiple myeloma
• Autoimmune panel (ANA, anti-dsDNA) and hepatitis B/C, HIV if hematuria or proteinuria

Imaging

• Renal ultrasound (first-line): checks kidney size/symmetry, excludes obstruction and masses
  • Bilaterally small kidneys = long-standing CKD
  • Large kidneys: diabetic nephropathy (early), amyloidosis, HIV nephropathy, or PKD

Predicting Progression

• Harrison's Principles of Internal Medicine 22e, p. 2438
• NKF Primer on Kidney Diseases, 8e, p. 529

Complications of CKD

1. Cardiovascular Disease

2. Anemia

• Caused primarily by decreased erythropoietin (EPO) production from damaged peritubular cells
• Iron deficiency frequently coexists
• Managed with iron repletion and erythropoiesis-stimulating agents (ESAs) (e.g., epoetin alfa, darbepoetin)
• Target Hb generally 10-11.5 g/dL (avoid >13 g/dL due to cardiovascular risk)

3. CKD-Mineral Bone Disorder (CKD-MBD)

• Hyperphosphatemia - impaired phosphate excretion → elevated FGF-23 → reduced calcitriol synthesis
• Hypocalcemia - due to low calcitriol + hyperphosphatemia
• Secondary hyperparathyroidism (SHPT) - PTH rises to correct calcium; causes high-turnover bone disease (osteitis fibrosa cystica)
• Treatment: dietary phosphate restriction → phosphate binders (calcium-based or non-calcium) → active vitamin D (calcitriol, paricalcitol) → calcimimetics (cinacalcet) for severe SHPT

4. Metabolic Acidosis

• Low bicarb from impaired tubular ammoniagenesis and reduced acid excretion
• Leads to bone dissolution (carbonate buffers H⁺), sarcopenia, and faster CKD progression
• Treated with oral sodium bicarbonate supplementation
• Multiple RCTs and a recent meta-analysis suggest treating acidosis may slow CKD progression

5. Hyperkalemia

• Impaired potassium excretion (high risk with RAAS inhibitors)
• Most serious electrolyte complication - can cause fatal arrhythmias
• Managed with dietary potassium restriction, diuretics, patiromer, or sodium zirconium cyclosilicate (SZC)
• NKF Primer on Kidney Diseases 8e; Harrison's 22e; Miller's Anesthesia 10e

6. Volume Overload and Hypertension

• Sodium/water retention worsens hypertension and cardiac preload
• Loop diuretics are key (thiazides lose efficacy at GFR <30)

7. Uremia (End-Stage)

• Accumulation of uremic toxins: encephalopathy, pericarditis, coagulopathy, immune dysfunction
• Indication for renal replacement therapy

Management

Disease-Modifying Therapies (Slow Progression)

1. RAAS Blockade - First Line

• ACE inhibitors or ARBs reduce intraglomerular pressure, proteinuria, and fibrosis
• Established benefit in diabetic and non-diabetic CKD with proteinuria (>300 mg/day)
• Do NOT combine ACEi + ARB (no added benefit, increased harm)
• NKF Primer; Brenner & Rector's The Kidney

2. SGLT2 Inhibitors - Major Advance

• Empagliflozin, dapagliflozin, canagliflozin - originally anti-diabetic, now proven renoprotective in diabetic AND non-diabetic CKD
• Reduce glomerular hyperfiltration, proteinuria, inflammation, and fibrosis
• Dapagliflozin (DAPA-CKD trial): reduced CKD progression and cardiovascular events even in non-diabetic CKD
• Now considered standard of care alongside RAAS blockade
• Harrison's Principles of Internal Medicine 22e; NKF Primer 8e

3. Finerenone (Non-steroidal MRA)

• Novel mineralocorticoid receptor antagonist (not spironolactone)
• FIDELIO and FIGARO trials (>13,000 patients): 18% relative risk reduction in CKD endpoint + 13% reduction in major adverse cardiovascular events in patients with diabetes and CKD
• NKF Primer on Kidney Diseases, 8e, p. 530

4. GLP-1 Receptor Agonists

• Semaglutide and liraglutide show additional cardiorenal benefit in diabetes + CKD
• Reduce albuminuria and slow GFR decline

Blood Pressure Control

• Target: <130/80 mmHg (KDIGO 2021) for most CKD patients with albuminuria
• Usually requires 2-4 antihypertensive agents (RAAS blocker + diuretic as backbone)
• A "J-curve" effect exists: very low systolic BP (<120 mmHg) may increase risk (ACCORD trial data)
• NKF Primer on Kidney Diseases, 8e, pp. 535-538

Glycemic Control

• HbA1c target ~7% in most diabetic CKD patients
• SGLT2 inhibitors preferred for dual glycemic + renal benefit

Dietary Management

• Protein restriction (0.6-0.8 g/kg/day) may reduce hyperfiltration and proteinuria
• Low phosphate, low potassium diet in stages 4-5
• Low sodium (<2 g/day) to control BP and volume
• Avoid nephrotoxins: NSAIDs, contrast where possible

Management by Stage

Renal Replacement Therapy (ESKD)

• Uremic symptoms (encephalopathy, pericarditis, bleeding)
• Hyperkalemia unresponsive to conservative measures
• Persistent volume overload despite diuretics
• Refractory metabolic acidosis
• eGFR <10 mL/min/1.73m² (not an absolute trigger - symptoms matter)

• Hemodialysis (HD): 3x/week, 3-4h sessions; most common in developed world
• Peritoneal dialysis (PD): home-based, daily; comparable outcomes but less used
• Kidney transplantation: best outcomes - superior survival compared to dialysis; pre-emptive transplant (before dialysis) is ideal

• Harrison's Principles of Internal Medicine 22e, pp. 2437-2440

Key Points Summary

• NKF Primer on Kidney Diseases, 8e (pp. 528-560)
• Harrison's Principles of Internal Medicine 22e (pp. 2437-2445)
• Brenner and Rector's The Kidney, 2-Volume Set
• Textbook of Family Medicine 9e (pp. 1191-1192)
• Comprehensive Clinical Nephrology, 7th Edition