Chronic renal failure

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Chronic Renal Failure (Chronic Kidney Disease — CKD)

Definition

Chronic kidney disease (CKD) is defined as kidney damage or decreased kidney function persisting for 3 months or longer, based on:

Glomerular filtration rate (GFR) < 60 mL/min/1.73 m²
Albuminuria > 30 mg/day
Pathological, blood, urine, or imaging abnormalities

— Goldman-Cecil Medicine, p. 1342

Staging (KDIGO Classification)

Stage	Description	GFR (mL/min/1.73 m²)
G1	Kidney damage, normal GFR	≥ 90
G2	Mild decrease	60–89
G3a	Mild-to-moderate decrease	45–59
G3b	Moderate-to-severe decrease	30–44
G4	Severe decrease	15–29
G5	Kidney failure (ESRD)	< 15

Albuminuria is staged separately: A1 (<30 mg/g), A2 (30–300 mg/g), A3 (>300 mg/g). Risk of progression and complications scales with both the GFR category and albuminuria category.

— Textbook of Family Medicine, p. 1191; Goldman-Cecil Medicine

Causes / Etiology

The most common causes worldwide:

Diabetic nephropathy (leading cause; ~40% of ESRD)
Hypertensive nephrosclerosis
Glomerulonephritis (IgA nephropathy, FSGS, membranous, etc.)
Polycystic kidney disease (ADPKD, ARPKD)
Obstructive uropathy / chronic pyelonephritis
Lupus nephritis / vasculitis
Drug-induced nephrotoxicity (NSAIDs, analgesics, aminoglycosides, contrast)
Ischemic nephropathy / renovascular disease

Non-diabetic causes should be considered even in diabetic patients if GFR declines rapidly, hypertension is refractory, active urine sediment is present, or systemic disease is suspected. — Brenner & Rector's The Kidney

Pathophysiology

Nephron Loss & Hyperfiltration

Progressive nephron loss triggers compensatory hyperfiltration in surviving nephrons (increased single-nephron GFR). This initially maintains total GFR but causes glomerular hypertension → proteinuria → further glomerulosclerosis → a self-perpetuating cycle of nephron loss. GFR is therefore a poor early indicator of disease burden; significant parenchymal loss occurs before GFR drops. — Brenner & Rector's The Kidney

Key Pathways

Renin-angiotensin-aldosterone system (RAAS) activation → hypertension, proteinuria, fibrosis
TGF-β → tubulointerstitial fibrosis
Oxidative stress & inflammation → endothelial injury, cardiovascular disease
Impaired erythropoietin production → anemia
Phosphate retention → secondary hyperparathyroidism → renal osteodystrophy

Cardiorenal-Anemia Syndrome in CKD: bidirectional relationships between CKD, heart failure, and anemia

Clinical Manifestations

CKD is usually asymptomatic in early stages (G1–G2). Manifestations emerge progressively:

Stages G1–G2

New/worsening hypertension
Proteinuria (may cause edema in nephrotic range)
Incidental electrolyte or urinalysis abnormalities

Stages G3–G4

Anemia (fatigue, weakness, exertional dyspnea) — due to ↓ erythropoietin
Renal osteodystrophy — pathologic fractures, soft-tissue/vascular calcification
Hyperphosphatemia → elevated Ca×P product → calciphylaxis, vascular calcification → LV hypertrophy, heart failure
Metabolic acidosis — normal anion gap at G3b; high anion gap (retained phosphate/sulfate) at G4–G5
Hyperkalemia — especially with RAAS blockade; mild (5.0–5.5 mEq/L) to severe (>6.5 mEq/L) at advanced stages
Malnutrition / muscle and fat wasting
Sexual dysfunction — amenorrhea, impotence, oligospermia

Stage G5 — Uremic Syndrome (GFR <15 mL/min/1.73 m²)

Fluid overload / hypertension
Peripheral neuropathy
Pruritus (uremic)
Pericarditis (uremic)
GI symptoms — nausea, vomiting, anorexia
Encephalopathy — altered mental status, seizures
Increased infection risk

— Goldman-Cecil Medicine, pp. 1342–1343

Diagnosis

Systematic evaluation includes:

Serum creatinine + eGFR (CKD-EPI equation preferred; MDRD also used)
Urine albumin-to-creatinine ratio (ACR)
Complete urinalysis (casts, hematuria, proteinuria)
Renal ultrasound (size, echogenicity, obstruction, cysts)
Serum electrolytes, bicarbonate, CBC, PTH, phosphate, calcium
HbA1c if diabetic etiology suspected
Complement, ANA, ANCA if glomerulonephritis suspected
Kidney biopsy — when etiology is uncertain and affects management

Key point: Serum creatinine alone is inadequate — a "normal" creatinine may correspond to substantially reduced GFR in older patients, women, or those with low muscle mass. — Textbook of Family Medicine, p. 1192

Management

Principles

Management is cause-specific + stage-based, cumulative across stages. — Goldman-Cecil Medicine, p. 1341

Lifestyle & Diet

Sodium restriction (<2 g/day) for hypertension
Protein intake: 0.6–0.8 g/kg/day at G3–G5 (slows solute retention, may slow progression)
Total calories: 25–35 kcal/kg/day (prevent protein-calorie malnutrition)
Mediterranean/DASH diet; tobacco cessation; physical activity
Registered dietitian involvement is essential

Blood Pressure Control

Target SBP <130 mmHg (some guidelines recommend <120 mmHg)
ACE inhibitor or ARB — first-line for albuminuria with or without diabetes; reduces albuminuria and slows GFR decline
Add diuretics or calcium-channel blockers as needed
Finerenone (non-steroidal mineralocorticoid receptor antagonist) — effective in diabetic CKD with albuminuria (20 mg/day if eGFR >60; 10 mg/day if eGFR 25–59)

SGLT2 Inhibitors & GLP-1 Agonists

SGLT2 inhibitors (canagliflozin 100 mg, dapagliflozin 5 mg, empagliflozin 10 mg daily) reduce albuminuria, slow GFR decline, and reduce risk of kidney failure and cardiovascular events — in both diabetic and non-diabetic CKD with albuminuria. GLP-1 agonists also reduce albuminuria in type 2 diabetes. — Goldman-Cecil Medicine, p. 1343

Glycemic Control

HbA1c target similar to non-CKD diabetes; may be less strict in elderly/comorbid patients

Lipid-Lowering Therapy

Statins recommended (cardiovascular benefit); however, no direct benefit on CKD progression

Management of Specific Complications

Complication	Target	Treatment
Anemia	Hb 90–110 g/L	Treat iron deficiency first; then erythropoiesis-stimulating agents (ESA, e.g., darbepoetin alpha 0.45 μg/kg q4 weeks) when Hb <9 g/dL; HIF-stabilizers (non-US approved for pre-dialysis)
Metabolic acidosis	Bicarbonate >22 mmol/L	Sodium bicarbonate 650 mg BD, titrate to target
Metabolic bone disease / Secondary HPT	Ca 2.2–2.35, PO₄ <1.8 mmol/L	Phosphate binders; active vitamin D (calcitriol 0.25–0.5 μg/day); calcimimetics (cinacalcet 30 mg/day) on dialysis; parathyroidectomy if refractory
Hyperkalemia >5.5 mEq/L	K <5.5 mEq/L	Dietary restriction (<2 g/day K); potassium-binding agents; loop diuretics; insulin/glucose for acute elevations; dialysis if severe
Malnutrition	Adequate intake	Dietitian support; 25–35 kcal/kg/day
Edema (nephrotic)	—	Diuretics ± albumin infusion if refractory

— Comprehensive Clinical Nephrology 7th Ed., p. 1123; Goldman-Cecil Medicine, pp. 1343–1345

Referral to Nephrology

Refer when:

eGFR < 30 mL/min/1.73 m² (stage G4–G5)
ACR ≥ 300 mg/g (A3)
Rapid progression (sustained GFR drop >5 mL/min/1.73 m²/year or change of GFR category)
Unexplained hematuria, resistant hypertension, persistent K abnormalities, hereditary kidney disease

— Comprehensive Clinical Nephrology 7th Ed., Box 82.1

Kidney Replacement Therapy (Stage G5)

When conservative care no longer controls uremic symptoms:

Hemodialysis — most common; thrice-weekly; high risk of cardiovascular complications
Peritoneal dialysis — home-based; continuous or intermittent
Kidney transplantation — preferred; extends life and quality of life over dialysis

Shared decision-making and advance care planning should begin well before uremia develops. — Goldman-Cecil Medicine, p. 1345

Prevention

Primary: Treat hypertension, diabetes, obesity; avoid nephrotoxic drugs; healthy lifestyle
Secondary: Early detection via ACR + eGFR screening in at-risk patients (diabetics, hypertensives, family history of CKD); RAAS blockade and SGLT2 inhibition to slow progression
Tertiary: Prevent cardiovascular complications (leading cause of death in CKD)

Key Points to Remember

CKD is defined by persistence >3 months — acute kidney injury can mimic CKD until chronicity is established.
Serum creatinine is unreliable alone — eGFR and ACR together define risk.
Cardiovascular disease is the #1 cause of death in CKD, not kidney failure.
SGLT2 inhibitors are now established as kidney-protective in both diabetic and non-diabetic CKD with albuminuria.
ESAs should target Hb 10–11 g/dL only — higher targets worsen cardiovascular outcomes.
Avoid NSAIDs, iodinated contrast, gadolinium, and other nephrotoxins.

Sources: Goldman-Cecil Medicine (22nd Ed.); Comprehensive Clinical Nephrology (7th Ed.); Brenner & Rector's The Kidney; Textbook of Family Medicine (9th Ed.)

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