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Chronic Kidney Disease

Chapter 322 | Part 9: Disorders of the Kidney and Urinary Tract · Part 9 – Renal & Urinary Tract Disorders · Chapter 322

Key Clinical Points

  1. CKD is defined by a progressive decline in GFR and/or albuminuria, categorized using KDIGO criteria.
  2. Staging (G1-G5) based on eGFR and risk stratification via albuminuria (A1-A3).
  3. eGFR estimation (CKD-EPI, MDRD) is preferred over timed collections; race-free equations are standard.
  4. Primary causes include diabetic nephropathy, glomerulonephritis, hypertension-associated CKD, ADPKD, and other cystic/tubulointerstitial diseases.
  5. Uremic syndrome involves toxin accumulation, loss of homeostatic control (fluid, electrolytes, hormones), and systemic inflammation.
  6. Metabolic acidosis is common; treat with oral sodium bicarbonate if serum bicarbonate <20-23 mmol/L.
  7. Hyperkalemia management requires caution with RAS inhibitors and potassium-sparing diuretics; gliflozins help maintain potassium balance.
  8. Anemia in CKD results from reduced EPO, decreased RBC survival, iron deficiency, and chronic inflammation.
  9. Dialysis is indicated for intractable hyperkalemia, volume overload, or uremic symptoms (Stage 5 CKD).
  10. Gliflozins reduce intraglomerular hypertension by restoring tubuloglomerular feedback (TGF).

DEFINITION & CLASSIFICATION

• Definition (Harrison's 22e): Chronic kidney disease (CKD) encompasses a spectrum of pathophysiologic processes associated with abnormal kidney function, often with a progressive decline in glomerular filtration rate (GFR). • End-Stage Renal Disease: Now referred to as Stage 5 CKD; characterized by accumulation of toxins, fluid, and electrolytes requiring renal replacement therapy. • Staging Criteria: Based on two primary metrics: ◦ GFR: Estimated (eGFR) using serum creatinine, age, sex, and other factors. ◦ Albuminuria: Used for risk stratification of mortality and progression (KDIGO classification). • Pathophysiology Mechanisms: ◦ Specific: Initiated by underlying etiology (genetics, immune complexes, inflammation, etc.). ◦ Non-specific: Resulting from reduced nephron mass → hyperfiltration and hypertrophy of remaining nephrons. ◦ Maladaptive Transition: Initial compensation via increased pressure/flow leads to glomerular architecture distortion, podocyte dysfunction, and fibrosis.

Staging of CKD

• eGFR Validity: Valid only if serum creatinine is in a steady state (not rising or falling over days). • Age-Related Decline: Normal mean decline ≈ 1 mL/min per year after age 30; significant reduction in elderly may be masked by 'normal' serum creatinine. • Equation Selection: Use of race-free eGFR equations is standard; adjustments for muscle mass or limb loss may be made if specific clinical decisions require it. Refer to Table 322-3 for specific formulas (CKD-EPI and MDRD).

EPIDEMIOLOGY

• Prevalence: ≥6% of US adults have Stage 1-2; 4.5% have Stage 3-4. • Primary Cause: Diabetic nephropathy (most often from Type 2 DM). • Risk Factors (Table 322-1): ◦ Noncommunicable: Diabetes, high BMI, autoinflammatory disease, nephrotoxic exposure, hypertension. ◦ Communicable: Streptococcal/Mycobacterial infections, HIV, SARS-CoV-2, HBV, HCV. ◦ Demographic/Genetic: Age, male sex, population ancestry, family history, and monogenic/polygenic risks (e.g., APOL1). ◦ Other: Prior AKI, Preeclampsia, premature/SGA birth.

ETIOLOGY & PATHOPHYYSOLOGY

• Primary Clinical Categories (Table 322-4): 1. Diabetic nephropathy. 2. Glomerulonephritis. 3. Hypertension-associated CKD (includes vascular/ischemic and primary glomerular disease). 4. Autosomal dominant polycystic kidney disease (ADPKD). 5. Other cystic and tubulointerstitial nephropathy. • Uremic Syndrome: ◦ Not just urea/creatinine; involves accumulation of various solutes, loss of metabolic/endocrine functions (anemia, mineral metabolism), and systemic inflammation. ◦ Inflammation component: Linked to the 'malnutrition-inflammation-atherosclerosis/calcification' syndrome.

Genetic Risk Factors

• Monogenic Risks (Table 322-2): ◦ ADPKD (ADPKD1, ADPKD2). ◦ Type IV collagen-associated nephropathy (COL4A3, COL4A4, COL4A5). ◦ Tubulointerstitial disease (UMOD, MUC1, HNF1B). ◦ Nephronophthisis (NPHP genes). ◦ APOL1: Associated with higher frequency of non-diabetic CKD in African/Hispanic populations.

CLINICAL FEATURES

• Stage 1-2: Typically asymptomatic; often identified via routine lab work. • Stage 3-4: Prominent complications include: ◦ Anemia (fatigability). ◦ Malnutrition (decreased appetite). ◦ Mineral/Bone issues: Abnormal Ca, P, PTH, 1,25(OH)D, and FGF-23. ◦ Fluid/Electrolyte/Acid-Base disturbances. • Stage 5: Full uremic syndrome; significant impact on daily living and safety.

Fluid, Electrolyte, and Acid-Base Disorders

• Sodium & Water: ◦ Retention → ECFV expansion → Hypertension. ◦ Management: Loop diuretics (furosemide, bumetanide, torsemide) or combination with metolazone. ◦ Resistance to loop diuretics may indicate a need for dialysis. ◦ 'Sick Day' Rule: Hold diuretics/antihypertensives during periods of vomiting/diarrhea to avoid pre-renal state. • Potassium: ◦ Hyperkalemia risk factors: High intake, hemolysis, transfusion, metabolic acidosis. ◦ Medication risks: RAS inhibitors, spironolactone, amiloride, eplerenone, triamterene. ◦ Gliflozins: Maintain potassium balance even in advanced CKD. • Metabolic Acidosis: ◦ Common in CKD; often hyperkalemic and hyperchloremic. ◦ Treatment: Oral sodium bicarbonate if serum bicarbonate <20-23 mmol/L.

DIFFERENTIAL DIAGNOSIS

• CKD vs. AKI: ◦ CKD: Progressive decline in GFR/albuminuria. ◦ AKI: Abrupt decrease in GFR (e.g., ≥0.3 mg/dL increase in creatinine within 48 hours). • Prerenal Azotemia: Generally has a better prognosis than intrinsic AKI; however, survivors of dialysis-requiring AKI have high risk for progression to CKD. • Risk Stratification: Measurement of albuminuria after an AKI episode is a key tool to predict future progression.

DIAGNOSTIC APPROACH

  1. Initial Assessment: Evaluate GFR and albuminuria to determine stage and risk (Figure 2).
  2. Etiology Identification: Categorize into the five main groups (Table 322-4) to guide specific management.
  3. Anemia Workup: Assess for multiple causes including EPO deficiency, iron deficiency, and inflammation (Table 322-5).
  4. Monitoring: For stable Stage 2/3 patients without proteinuria or uncontrolled hypertension, interval testing is sufficient; otherwise, refer to nephrology.

MANAGEMENT & TREATMENT

  1. Pharmacologic Management: • Hypertension/Volume: Use loop diuretics (furosemide, bumetanide, torsemide) for sodium management; use higher doses in CKD. • Renoprotection: RAS inhibitors used cautiously with monitoring of potassium. • SGLT2 Inhibitors (Gliflozins): Used to reduce intraglomerular pressure by restoring tubuloglomerular feedback (Figure 6). • Acid-Base: Oral sodium bicarbonate for serum bicarbonate <20-23 mmol/L.
  2. Dialysis and Renal Replacement: • Indications:
  3. Intractable hyperkalemia.
  4. Volume overload (refractory to diuretics).
  5. Uremic symptoms in Stage 5 CKD.

COMPLICATIONS & PROGNOSIS

• Anemia: Resulting from multiple factors: ◦ Reduced EPO production. ◦ Diminished RBC survival. ◦ Iron deficiency (poor absorption/GI loss). ◦ Chronic inflammation. ◦ Other: Hyperparathyroidism, folate deficiency, hemoglobinopathy. • Vascular Calcification: Associated with hyperphosphatemia and low PTH; independent risk factor for mortality. • Calciphylaxis: Serious complication of ESRD involving skin necrosis (Figure 5). • Tumoral Calcinosis: Soft tissue calcification due to severe hyperphosphatemia (Figure 4).

SPECIAL POPULATIONS

• Genetic Risk: ◦ APOL1 variants in African/Hispanic ancestry increase risk of non-diabetic CKD. ◦ Monogenic forms like ADPKD (Table 322-2) require specific management pathways.

KEY PEARLS & HIGH-YIELD POINTS

• SGLT2 Inhibitors: Work by restoring tubuloglomerular feedback (TGF), reducing intraglomerular pressure (Figure 6). • Hyperfiltration: A short-term adaptation to nephron loss that becomes maladaptive, leading to glomerular damage (Figure 3). • Uremia: A complex syndrome of toxin accumulation, metabolic/endocrine failure, and systemic inflammation. • Potassium Management: Gliflozins are unique in their ability to maintain potassium balance in advanced CKD.

Reference Tables

TABLE 322-2 Monogenic Risk Loci for Chronic Kidney Disease (CKD) Copy Number Variants Causative of Congenital Renal…

Harrison's 22e, p.2388

  • Noncommunicable Diseases
    Diabetes
    Increased BMI
    Autoinflammatory disease (e.g., lupus, vasculitis, cancer immunotherapy)
    Nephrotoxic exposure (including many antineoplastic therapies)
    Hypertension (risk, cause, or consequence)
    Communicable Diseases
    Streptococcal infection
    Mycobacterial infection
    HIV infection (HIVAN)
    SARS-CoV-2
    HBV, HCV
    Demographic, Anthropomorphic, Ancestry, Geographic
    Age
    Male sex
    Population ancestry
    Region-specific CKD risk of uncertain etiology (e.g., Central America,
    Sri Lanka, and indigenous peoples of Australia and New Zealand)
    Family history of kidney disease
    Genetic
    Monogenic inheritance with (1) high penetrance or (2) low to medium
    penetrance
    Polygenic risk factors
    Childhood-Related Risk Factors
    Premature and SGA birth
    Persistent asymptomatic microscopic hematuria
    Childhood kidney disease (even resolved)
    Treated childhood cancer
    Lifestyle
    Tobacco use
    Sedentary lifestyle
    Other
    Prior acute kidney injury
    Preeclampsia
    Kidney donation (or other acquired nephrectomy)

TABLE 322-2 Monogenic Risk Loci for Chronic Kidney Disease (CKD)

  • Copy Number Variants Causative of Congenital Renal Anomalies
    1q21
    4p16.1-p16.3
    16p11.2
    16p13.11
    17q12
    22q11.2
    Five Most Predominant Causes of CKD with Mendelian Inheritance
    Genes for autosomal dominant polycystic kidney disease
    ADPKD1
    ADPKD2
    IFT140
    GANAB
    DNAJB2
    ALG9
    Genes for type IV collagen-associated nephropathy
    COL4A3
    COL4A4
    COL4A5
    Genes for autosomal dominant tubulointerstitial kidney disease
    UMOD
    MUC1
    HNF1B
    Genes for nephronophthisis
    NPHP genes
    Other
    Genes with known common variants that confer increased risk with odds ratio
    exceeding 2 with non-Mendelian inheritance patterns
    APOL1

Harrison's 22e, p.2388

    1. Equation from the Modification of Diet in Renal Disease Study
  • Estimated GFR (mL/min per 1.73 m2) = 1.86 × (S )−1.154 × (age)−0.203
    Cr
    Multiply by 0.742 for women
    Multiply by 1.21 for African ancestry (currently under review)
    1. CKD-EPI Equation
  • GFR = 141 × min(S /kappa, 1)α × max(S /kappa, 1)–1.209 × 0.993Age
    Cr Cr
    Multiply by 1.018 for women
    Multiply by 1.159 for African ancestry (currently under review)
    where S is serum creatinine in mg/dL, kappa is 0.7 for females and 0.9 for
    Cr
    males, α is –0.329 for females and –0.411 for males, min indicates the minimum of
    S /kappa or 1, and max indicates the maximum of S /kappa or 1.
    Cr Cr

TABLE 322-4 Leading Categories of Etiologies of Chronic Kidney Disease (CKD) a • Diabetic nephropathy •…

Harrison's 22e, p.2389

  • • Diabetic nephropathy
    • Glomerulonephritis
    • Hypertension-associated CKD (includes vascular and ischemic kidney disease
    and primary glomerular disease with associated hypertension)
    • Autosomal dominant polycystic kidney disease
    • Other cystic and tubulointerstitial nephropathy

TABLE 322-5 Causes of Anemia in Chronic Kidney Disease Relative deficiency of erythropoietin Diminished red blood cell…

Harrison's 22e, p.2393

  • Relative deficiency of erythropoietin
  • Diminished red blood cell survival
  • Bleeding diathesis
  • Iron deficiency due to poor dietary absorption and gastrointestinal blood loss
  • Hyperparathyroidism/bone marrow fibrosis
  • Chronic inflammation
  • Folate or vitamin B deficiency
    12
  • Hemoglobinopathy
  • Comorbid conditions: hypo-/hyperthyroidism, pregnancy, HIV-associated
    disease, autoimmune disease, immunosuppressive drugs