Sources: Harrison's Principles of Internal Medicine 22E (2025) | Comprehensive Clinical Nephrology 7E | Brenner & Rector's The Kidney | NKF Primer on Kidney Diseases 8E | KDIGO 2024 Guidelines

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1. DEFINITION

• eGFR < 60 mL/min/1.73 m² for >3 months, OR
• eGFR ≥ 60 mL/min/1.73 m² WITH evidence of kidney damage (proteinuria, hematuria, structural abnormality, biopsy-proven disease)

Exam pearl: The 3-month criterion distinguishes CKD from AKI. A single abnormal measurement is NOT sufficient for diagnosis.

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2. STAGING - KDIGO CGA CLASSIFICATION

Table 1: GFR Categories (G Stages)

Table 2: Albuminuria Categories (A Stages)

Table 3: KDIGO Heat Map - Risk of CKD Progression

Clinical/Exam Key: Risk = risk of CKD progression, cardiovascular events, and death. Green = low, Yellow = moderate, Orange = high, Red = very high.

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3. EPIDEMIOLOGY AND CAUSES

Table 4: Leading Etiologies of CKD (Harrison's 22E)

Exam pearl: Diabetes + hypertension together account for approximately 2/3 of CKD in adults. In children, CAKUT (congenital anomalies of kidney and urinary tract) accounts for ~2/3 of CKD cases.

Genetic Risk Factors

• APOL1 gene variants (G1/G2): High-risk genotypes drive FSGS, HIV-associated nephropathy, CKD with hypertension in populations of African ancestry
• IgA nephropathy genes: Identified genome-wide risk alleles
• ADPKD: PKD1/PKD2 mutations

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4. GFR ESTIMATION EQUATIONS

Table 5: GFR Estimating Equations

Clinical pearls:

• eGFR valid ONLY in steady state (SCr neither rising nor falling)
• In elderly: mild SCr elevation may hide severe GFR reduction
• Women have lower mean GFR than men; men at higher CKD risk
• Normal GFR decline with aging: ~1 mL/min/year after age 30
• Cystatin C not affected by muscle mass - use in extremes of body habitus, amputees

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5. CLINICAL PRESENTATION

Table 6: Symptoms and Signs by Stage

Physical Exam Clues Favoring Chronicity (vs AKI)

• Skin pigmentation (urochrome deposition)
• Scratch marks (pruritus)
• Left ventricular hypertrophy
• Hypertensive fundal changes
• Small kidneys on imaging
• Peripheral neuropathy
• Asterixis or pericardial friction rub = uremic syndrome present

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6. DIAGNOSIS AND WORKUP

Table 7: Initial Investigations in CKD

Exam pearl: Bilateral small echogenic kidneys on US = chronic, irreversible disease. Normal-sized or large kidneys in CKD suggest: diabetic nephropathy, amyloid, ADPKD, HIV nephropathy, myeloma.

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7. PATHOPHYSIOLOGY OF CKD PROGRESSION

1. Initial nephron loss (from any cause)
2. Remaining nephrons undergo compensatory hypertrophy and hyperfiltration
3. This generates increased intraglomerular pressure
4. Maladaptive: promotes further nephron loss even after original insult resolved
5. Self-perpetuating cycle of nephron loss

Key concept (Harrison's 22E): This is why RAAS blockade (ACEi/ARB) + SGLT2i are the cornerstone of CKD therapy - they reduce intraglomerular pressure via efferent and afferent arteriolar effects respectively.

Uremic Toxin Accumulation

1. Accumulation of excretory toxins (urea, creatinine, organic acids)
2. Loss of kidney metabolic/endocrine function (EPO, vitamin D, acid excretion)
3. Systemic inflammation - elevated CRP, low albumin and fetuin → malnutrition-inflammation-atherosclerosis syndrome

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8. FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS

Table 8: Electrolyte/Metabolic Complications

"Sick day" rule: Patients with CKD should be advised to temporarily withhold diuretics and antihypertensives during vomiting/diarrhea to avoid AKI.

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9. COMPLICATIONS OF CKD

9A. CARDIOVASCULAR DISEASE ⭐ (Leading cause of death in CKD)

• CKD patients have 10-200x higher CV risk than age-matched general population
• Most CKD patients die of CV disease BEFORE reaching stage 5
• 30-45% of those reaching stage 5 have advanced CV complications

Traditional Risk Factors (in CKD):

CKD-Specific Risk Factors:

Cardiac Manifestations:

• Left ventricular hypertrophy (LVH) - most common; driven by hypertension + ECFV overload
• Dilated cardiomyopathy - strong risk factor for mortality
• Heart failure (preserved EF - diastolic, or reduced EF - systolic)
• "Bat-wing" pulmonary edema - uremic increased alveolar permeability; responds to dialysis
• Pericarditis - uremic or dialysis-related
• Elevated troponin without acute ischemia - serial measurements required; trend more informative than single value

Exam pearl: Troponin is chronically elevated in CKD due to LVH and myocardial stress - do NOT interpret a single elevated troponin as ACS in CKD. Look for rising trend (delta troponin).

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9B. ANEMIA OF CKD ⭐

Pathophysiology:

• Decreased erythropoietin (EPO) production by peritubular fibroblasts (primary mechanism)
• Reduced RBC survival (uremic toxin hemolysis)
• Iron deficiency (blood loss via dialysis, reduced absorption)
• Functional iron deficiency (inflammatory block - hepcidin)
• Folate/B12 deficiency (dialysis losses)

Diagnosis:

• Normochromic normocytic anemia
• Low reticulocyte count
• Low serum EPO (relative to degree of anemia)
• Iron studies: serum ferritin, transferrin saturation (TSAT)

Table 9: Iron Status Targets in CKD Anemia (KDIGO)

Treatment of Anemia:

1. Correct iron first - IV iron preferred in dialysis patients (oral iron poorly absorbed + GI side effects)
2. Erythropoiesis-stimulating agents (ESA): Epoetin alfa/beta, darbepoetin alfa
   • Start when Hb < 10 g/dL
   • Target Hb: 10-11.5 g/dL - higher targets (>13 g/dL) associated with increased CV events and stroke
   • ESA hyporesponsiveness: look for iron deficiency, infection, inflammation, hyperparathyroidism, malignancy
3. HIF-PHI (HIF prolyl hydroxylase inhibitors): Roxadustat, daprodustat - new oral agents; increase endogenous EPO; approved in many countries
4. Blood transfusion - avoid if possible (sensitization risk pre-transplant); use only for acute symptomatic severe anemia

⭐ HIGH-YIELD EXAM POINT: Target Hb 10-11.5 g/dL for ESA. Aiming for normal Hb (>13) causes HARM (TREAT trial). The NORMAL trial showed increased CV events with high-dose ESA targeting near-normal Hb.

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9C. CKD-MINERAL AND BONE DISORDER (CKD-MBD) ⭐

Pathophysiology Cascade (Know this sequence):

↓ GFR → ↑ FGF-23 (earliest marker) → ↓ 1,25(OH)2D (calcitriol)
    → ↓ calcium absorption → hypocalcemia
    → ↑ PTH (secondary hyperparathyroidism)
    → ↑ phosphate retention (due to ↓ GFR)
    → hyperphosphatemia + hypocalcemia → further ↑ PTH
    → osteitis fibrosa cystica (high-turnover bone disease)
    → vascular/soft tissue calcification

Table 10: Types of Renal Osteodystrophy

Exam pearl: PTH target in CKD stage 5/dialysis = 2-9x upper limit of normal. Very LOW PTH = adynamic bone disease risk (fractures, vascular calcification).

Table 11: Management of CKD-MBD

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9D. DIABETIC NEPHROPATHY (DIABETIC KIDNEY DISEASE) ⭐

Natural History / Stages (Classic Mogensen Stages for Type 1 DM):

Note: Type 2 DM frequently presents at stage III or IV; may have CKD without preceding microalbuminuria in some.

Pathology:

• Glomerular hypertrophy
• Glomerular basement membrane (GBM) thickening
• Diffuse mesangial expansion (most common)
• Kimmelstiel-Wilson (KW) nodules (pathognomonic - focal nodular glomerulosclerosis)
• Afferent AND efferent arteriolar hyalinosis (efferent involvement distinguishes from hypertensive nephropathy)
• Tubular atrophy and interstitial fibrosis (late)

Exam pearl: KW nodules = nodular glomerulosclerosis = PATHOGNOMONIC of diabetic nephropathy. Formed by laminated accumulation of collagen IV and fibronectin in mesangium.

Management of Diabetic Kidney Disease:

Table 12: Stepwise Treatment of Diabetic CKD (Evidence-Based, 2024-2026)

⭐ 2024-2026 KEY UPDATE (KDIGO 2024): SGLT2 inhibitors are now first-line alongside RAAS blockade for CKD (both diabetic AND non-diabetic) with eGFR ≥20 and uACR ≥200 mg/g. The EMPA-KIDNEY and DAPA-CKD trials extended benefit to non-diabetic CKD.

Finerenone (NOT the older spironolactone/eplerenone) is preferred MRA in CKD due to less hyperkalemia and greater selectivity.

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9E. UREMIC NEUROPATHY ⭐

1. Peripheral Neuropathy (Most Common)

• Distal symmetric sensorimotor polyneuropathy
• Begins in lower limbs; stocking-glove distribution
• Loss of vibration sense earliest
• Burning, numbness, "restless legs syndrome"
• Caused by uremic toxin accumulation (e.g., medium-molecular-weight molecules)
• Treatment: Dialysis improves; transplant best treatment

2. Autonomic Neuropathy

• Postural hypotension
• Impaired heart rate variability
• GI dysmotility
• Erectile dysfunction
• Impaired sweating

Note: "Uremic neuropathy" vs "diabetic neuropathy" - distinguish clinically: Uremic neuropathy improves with dialysis/transplant; diabetic neuropathy is largely irreversible and related to hyperglycemia duration.

3. Uremic Encephalopathy (Severe/Late)

• Confusion, asterixis (metabolic flap), myoclonus, seizures
• Pericardial rub = uremic pericarditis (EMERGENCY - initiate dialysis)
• Asterixis + pericardial rub = initiate dialysis urgently

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9F. COAGULOPATHY AND BLEEDING IN CKD ⭐

Uremic Bleeding Tendency:

• Platelet dysfunction (qualitative, not quantitative) = primary defect
  • Impaired platelet adhesion (decreased GPIb-vWF interaction)
  • Decreased platelet aggregation
  • Reduced platelet TXA2 production
  • Uremic toxins impair platelet membranes
• Normal or elevated PT/aPTT (coagulation cascade usually intact)
• Elevated von Willebrand factor (paradox)

Clinical Manifestations:

• Prolonged bleeding time
• GI bleeding (most common serious bleed)
• Epistaxis, ecchymoses
• Subdural hematoma
• Retroperitoneal hemorrhage

Management:

⭐ Exam pearl: CKD coagulopathy = PLATELET DYSFUNCTION (prolonged bleeding time) not clotting factor deficiency. Bleeding time prolonged; PT/aPTT normal. DDAVP is the rapid treatment.

Anticoagulation in CKD: Warfarin associated with calciphylaxis in CKD - use with extreme caution. Direct oral anticoagulants (DOACs) require dose adjustment based on GFR; dabigatran CONTRAINDICATED in advanced CKD (eGFR <30).

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9G. OTHER IMPORTANT COMPLICATIONS

Table 13: Summary of CKD Complications by System

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10. SLOWING CKD PROGRESSION - TREATMENT PILLARS ⭐

Table 14: Evidence-Based Interventions to Slow CKD Progression

⭐ SGLT2i mechanism in CKD: Afferent arteriolar VASOCONSTRICTION (via tubuloglomerular feedback - macula densa perceives sodium as now delivered due to SGLT2 block in PCT) → reduces intraglomerular pressure. Complementary to ACEi/ARB (efferent dilation). COMBINATION ACEi+SGLT2i = synergistic renoprotection.

Combo therapy avoided: ACEi + ARB together (dual RAAS blockade) - more AKI + hyperkalemia + adverse cardiac events. ONTARGET trial confirms harm.

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11. HYPERTENSION IN CKD

BP Targets:

• Standard: <130/80 mmHg (KDIGO 2021/2024, SPRINT data)
• Elderly/frail: individualize (higher targets acceptable to avoid falls)
• Consider home/ambulatory monitoring - up to 30% "white coat" effect in CKD

Antihypertensive Therapy Sequence:

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12. INDICATIONS TO REFER TO NEPHROLOGY ⭐

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13. END-STAGE RENAL DISEASE (ESKD) AND KIDNEY REPLACEMENT THERAPY ⭐

When to Initiate Dialysis (KDIGO):

• Symptoms of serositis (uremic pericarditis, pleuritis)
• Acid-base or electrolyte abnormalities not manageable medically
• Inability to control volume/blood pressure
• Progressive nutritional deterioration refractory to dietary intervention
• Cognitive impairment attributable to uremia
• Typically occurs at eGFR <15 mL/min/1.73 m² but timing is based on symptoms, not number alone

Important: Planned early dialysis (eGFR 10-14 vs. <7) does NOT improve outcomes. Start when indicated, not prophylactically.

Modalities of Kidney Replacement Therapy:

Table 15: Comparison of KRT Modalities

Vascular Access (for HD) - Hierarchy (BEST to WORST):

1. Arteriovenous fistula (AVF) - gold standard; requires 8-12 weeks to mature; plan early
2. Arteriovenous graft (AVG) - synthetic; ready in 2-3 weeks
3. Tunneled cuffed central venous catheter - immediate use but highest complication rate

⭐ Create AVF early when eGFR <20-25 mL/min - takes 8-12 weeks to mature. Do NOT use central veins for IV lines in patients likely to need HD (damages veins).

Hemodialysis Adequacy:

• Target Kt/V ≥ 1.4 per session (urea clearance measure)
• OR urea reduction ratio (URR) >65%

Peritoneal Dialysis:

• CAPD: 4 exchanges/day, 2L each, manual
• CCPD/APD: Automated overnight cycling
• Target Kt/V ≥1.7/week
• Peritonitis = most dangerous complication; Gram-positive staph most common; empiric intraperitoneal vancomycin + gentamicin

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14. KIDNEY TRANSPLANTATION ⭐

Timing:

• Pre-emptive transplantation (before dialysis) preferred if possible - best outcomes
• Consider when eGFR <20 mL/min/1.73 m²
• Living donor > deceased donor (better outcomes)

Contraindications:

• Active malignancy (wait 2-5 years post-treatment depending on type)
• Active infection
• Severe cardiac/pulmonary disease precluding surgery
• Non-compliance (relative contraindication)

Immunosuppression Regimen (typical):

• Induction: Anti-thymocyte globulin or basiliximab
• Maintenance: Tacrolimus + mycophenolate mofetil + low-dose prednisolone

Post-Transplant Complications:

• Early: Delayed graft function, acute rejection, surgical complications
• Late: Chronic rejection, post-transplant CKD, cardiovascular disease
• Infection: CMV, BK virus nephropathy (monitor BK PCR), PCP, fungal infections
• Malignancy: Skin cancers (HPV-related), PTLD (EBV-related lymphoma)
• Post-transplant diabetes (PTDM): Especially with tacrolimus + steroids

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15. CONSERVATIVE (NON-DIALYTIC) MANAGEMENT OF ESKD

• Recognition that dialysis may not improve quality of life in all patients
• Patients choosing conservative management may have similar hospital-free days as those on HD
• Multidisciplinary approach: nephrology + palliative care
• Symptom control: pain, dyspnea, pruritus, nausea
• Advance care planning

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16. VACCINATION AND INFECTION PREVENTION IN CKD

Table 16: Recommended Vaccines in CKD

Vaccinate early at higher GFR levels - immune response is better. CKD patients are immunosuppressed (impaired T and B cell function).

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17. DRUG PRESCRIBING IN CKD

Table 17: Key Drug Dose Adjustments / Contraindications

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18. MONITORING SCHEDULE IN CKD (KDIGO 2024)

Table 18: Frequency of Monitoring by Stage

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19. HIGH-YIELD EXAM SUMMARY TABLE ⭐

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20. RECENT UPDATES (2024-2026) - CLINICAL PRACTICE ALERTS ⭐

1. KDIGO 2024 CKD Guideline (published Ann Intern Med 2025): SGLT2i now first-line for CKD with eGFR ≥20 and uACR ≥200, regardless of diabetes status.
2. EMPA-KIDNEY trial (2023): Empagliflozin reduced kidney disease progression and CV death by 28% in CKD patients (including non-diabetic).
3. DAPA-CKD trial: Dapagliflozin benefit in non-diabetic CKD confirmed (IgA nephropathy, focal segmental glomerulosclerosis).
4. Finerenone (non-steroidal MRA): FIDELIO-DKD + FIGARO-DKD trials - superior to placebo on cardiorenal outcomes in T2DM + CKD; less hyperkalemia than spironolactone.
5. FLOW trial (semaglutide): GLP-1 RA reduces risk of kidney failure in T2DM + CKD.
6. Inaxaplin: Specific APOL1 channel inhibitor - reduces proteinuria in APOL1 high-risk genotype FSGS (early access).
7. KDIGO 2025 ADPKD guideline (PMID 39848746): Updated tolvaptan use criteria.
8. Race-free eGFR equations: CKD-EPI 2021 (without race variable) now universally recommended.
9. HIF-PHI agents (roxadustat, daprodustat): Oral alternatives to EPO for anemia in CKD - approved in many countries.
10. CKD-MBD KDIGO Controversies 2025 (PMID 39864017): Reassessment of phosphate targets and calcimimetic use.

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