Chronic kidney disease

Chronic kidney disease (CKD) is defined as an abnormality of the kidney structure or function for ≥ 3 months. The most common causes of CKD in the United States are diabetes mellitus, hypertension, and glomerulonephritis. Since the kidneys have exceptional compensatory mechanisms, most patients remain asymptomatic until kidney function is significantly impaired. Patients typically present with symptoms of fluid overload (e.g., peripheral edema) and uremia (e.g., fatigue, pruritus). Laboratory studies show hyperkalemia, hyperphosphatemia, hypocalcemia, and metabolic acidosis. Management focuses mainly on treating the underlying disease and preventing possible complications, e.g., treating hypertension, avoiding nephrotoxic substances, and maintaining adequate hydration. If chronic kidney disease progresses to end-stage renal disease (ESRD), renal replacement therapy (i.e., dialysis or kidney transplantation) becomes necessary.

• Chronic kidney disease is defined as an eGFR < 60 mL/min/1.73 m² and/or persistence ≥ 3 months findings indicating irreversible kidney damage, such as:
  • Albuminuria (ACR > 30 mg/g) or hematuria
  • Electrolyte imbalances
  • Retention of nitrogenous wastes
  • Acid-base imbalances
  • Reduced production of erythropoietin, 1,25-(OH)₂ vitamin D3 and/or renin
  • Imaging showing structural abnormalities (e.g., polycystic kidney disease)

• Prevalence ^[1]
  • An estimated 37 million individuals (15%) in the US have CKD.
  • 726,000 individuals have ESRD.
• Incidence: > 350 cases of ESRD per million individuals annually ^[1]
• Risk factors for CKD ^[1]
  • Diabetes
  • Hypertension
  • Obesity
  • Advanced age (> 60 years of age) ^[2]
  • Substance use (smoking, alcohol, recreational drugs)
  • Acute kidney injury
  • Family history of CKD
  • African American or Hispanic descent ^[3]

Epidemiological data refers to the US, unless otherwise specified.

1. Diabetic nephropathy (38%)
2. Hypertensive nephropathy (26%)
3. Glomerulonephritis (16%)
4. Other causes (15%, e.g., polycystic kidney disease; , analgesic misuse, amyloidosis)
5. Idiopathic (5%)

Reference: ^[1]

Pathophysiology depends on the underlying condition, any of which will eventually lead to progressive nephron loss, structural damage, and impaired kidney function.

Underlying conditions

• Diabetic nephropathy ^[4]
  • Hyperglycemia → nonenzymatic glycation of proteins → varying degrees of damage to all types of kidney cell.
  • Pathological changes include:
    • Hypertrophy and proliferation of mesangial cells, GBM thickening, and ECM protein accumulation → eosinophilic nodular glomerulosclerosis
    • Thickening and diffuse hyalinization of afferent and efferent arterioles/interlobular arteries
    • Interstitial fibrosis, TBM thickening, and tubular hypertrophy
• Hypertensive nephropathy: Due to protective autoregulatory vasoconstriction of preglomerular vessels, increases in systemic blood pressure do not normally affect renal microvessels. ^[5]
  • Increased systemic blood pressure (e.g., due to chronic hypertension) below the protective autoregulatory threshold → benign nephrosclerosis (sclerosis of afferent arterioles and small arteries) → ↓ perfusion → ischemic damage
  • In case BP exceeds threshold → acute injury → malignant nephrosclerosis (petechial subcapsular hemorrhages, visible infarction with necrosis of mesangial and endothelial cells, thrombosis of glomeruli capillaries, luminal thrombosis of arterioles, and red blood cell extravasation and fragmentation) → failure of autoregulatory mechanisms → ↑ damage
• Glomerulonephritis (GN)
  • Noninflammatory GN (e.g., minimal change GN, membranous nephropathy, focal segmental glomerulosclerosis)
  • Inflammatory GN (e.g., lupus nephritis, poststreptococcal GN, rapid progressive GN, hemolytic uremic syndrome)

Consequences

• Reduced GFR
  • ↓ Production of urine → ↑ extracellular fluid volume → total-body volume overload
  • ↓ Excretion of waste products (e.g., urea, drugs)
  • ↓ Excretion of phosphate → hyperphosphatemia
    • During the early stages of CKD, plasma phosphate levels will typically be normal due to the increased secretion of fibroblast growth factor 23 (FGF23). ^[6]
      • FGF23 is produced by osteoblasts in response to initial hyperphosphatemia and increased calcitriol.
      • Increased secretion of FGF23 leads to increased phosphate secretion and suppressed conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D.
      • In advanced CKD, the effects of FGF 23 subside (most likely due to development of resistance in target tissues). ^[6]
  • ↓ Maintenance of acid-base balance → metabolic acidosis
  • ↓ Maintenance of electrolyte concentrations → electrolyte imbalances (e.g., Na⁺ retention)
• Reduced endocrine activity
  • ↓ Hydroxylation of calcifediol → ↓ production of calcitriol → (in combination with ↓ excretion of phosphate) → ↓ serum Ca²⁺ → ↑ PTH
  • ↓ Erythropoietin → ↓ stimulation of erythropoiesis
• Reduced gluconeogenesis: ↑ risk of hypoglycemia

Patients are often asymptomatic until later stages due to the exceptional compensatory mechanisms of the kidneys.

Manifestations of Na⁺/H₂O retention

• Hypertension and heart failure
• Pulmonary and peripheral edema

Manifestations of uremia

• Definition: Uremia is defined as the accumulation of toxic substances due to decreased renal excretion. These toxic substances are mostly metabolites of proteins such as urea, creatinine, β₂ microglobulin, and parathyroid hormone.
• Constitutional symptoms
  • Fatigue
  • Weakness
  • Headaches
• Gastrointestinal symptoms
  • Nausea and vomiting
  • Loss of appetite
  • Uremic fetor: characteristic ammonia- or urine-like breath odor
• Dermatological manifestations
  • Pruritus
  • Skin color changes (e.g., hyperpigmentation, pallor due to anemia)
  • Uremic frost: uremia leads to high levels of urea secreted in the sweat, the evaporation of which may result in tiny crystallized yellow-white urea deposits on the skin.
• Serositis
  • Uremic pericarditis: a complication of chronic kidney disease that causes fibrinous pericarditis
    • Clinical features: chest pain worsened by inhalation
    • Physical examination findings
      • Friction rub on auscultation
      • ECG changes normally seen in nonuremic pericarditis (e.g., diffuse ST-segment elevation) are not usually seen.
  • Pleuritis
• Neurological symptoms
  • Asterixis
  • Signs of encephalopathy
    • Seizures
    • Somnolence
    • Coma
  • Peripheral neuropathy → paresthesias
• Hematologic symptoms
  • Anemia (caused by ↑ destruction of RBCs)
  • Leukocyte dysfunction → ↑ risk of infection
  • ↑ Bleeding tendency caused by abnormal platelet adhesion and aggregation ^[7]

Overview

• Chronic kidney disease is staged according to the CGA classification based on GFR and albuminuria categories.
• Higher categories are associated with poorer prognosis.
• There are two main categories: systemic causes and primary kidney disease
• Further differentiation based on location within the kidney (glomerular, tuberointerstitial, vascular, or cystic and congenital)

Categories and staging

Interpretation

• Not considered CKD (unless there is evidence of kidney damage, e.g., imaging showing PCKD)
  • G1A1
  • G2A1
• Mild CKD
  • G1A2
  • G2A2
  • G3aA1
• CKD
  • G1A3
  • G2A3
  • G3aA2
  • G3bA1
• End-stage kidney disease
  • G3aA3
  • G3bA2, G3bA3
  • G4A1, G4A2, G4A3
  • G5A1, G5A2, G5A3

Approach ^[9]

Diagnosing CKD requires the integration of information from clinical presentation, laboratory tests, imaging, and, if necessary, pathology. The following steps should be included in the process:

1. Thorough review of patient medical records for information suggesting CKD and potential underlying conditions
2. Physical examination with fluid status, thorough abdominal status, exploration of signs of common comorbidities, and clues of underlying conditions
3. Laboratory tests (see below) to assess kidney function
4. Imaging (see “Doppler ultrasound” below) to assess kidney structure
5. If necessary, kidney biopsy

Laboratory tests

Blood work

• Complete blood count: normochromic, normocytic anemia
• Basic metabolic panel
  • ↑ Creatinine and BUN
  • Hyperkalemia
  • Hyperphosphatemia and hypocalcemia
• Coagulation screen
  • Normal PT, PTT, and platelet count
  • ↑ Bleeding time
• Lipid panel: dyslipidemia (↑ triglycerides are common)
• Blood pH: metabolic acidosis ^[10]
• Hormones: ↑ PTH
• Vitamins: ↓ calcitriol
• Parameters of renal function
  • ↓ eGFR
  • ↑ Serum cystatin C
  • See “Renal function tests.”
• Serology: may be necessary to identify underlying condition (e.g., ↑ complement levels, ↑ ANA)

Urinalysis

• Urine dipstick
  • Proteinuria
  • Hematuria
• Spot urine microalbumin: ↑ albumin-to-creatinine ratio
• Urine microscopy: : abnormal urine sediment, e.g., presence of waxy casts

Doppler ultrasound ^[11]

Doppler ultrasound is the first-line imaging technique for the assessment of kidney structure.

• Pathological findings
  • ↓ Length and ↓ cortical thickness of kidneys
  • Cysts
  • Calcifications
  • ↓ Perfusion and ↓ vascularity

Pathology

• Renal biopsy: indicated when diagnosis by other means remains inconclusive regarding the underlying condition

Kidney OUTAGES: hyperKalemia, renal Osteodystrophy, Uremia, Triglyceridemia, Acidosis (metabolic), Growth delay, Erythropoietin deficiency (anemia), Sodium/water retention (consequences of chronic kidney disease)

In chronic renal disease, close surveillance of serum potassium, calcium, and phosphate levels is essential.

General measures

Diet

• Fluid intake: monitor appropriate fluid intake
• Protein and energy consumption ^[12]
  • Mediterranean diet, ↑ fruit and vegetable intake
  • Protein restriction to 0.55–0.6 g/kg/day
• Electrolytes ^[13]
  • Sodium restriction
  • Potassium intake adjustment (e.g., avoidance of high-potassium foods) to reduce the risk of hyperkalemia (see “Hyperkalemia”)
  • Phosphorus restriction
• Micronutrients: vitamin D supplementation with cholecalciferol/ergocalciferol ^[13]

Avoidance of nephrotoxic substances

• NSAIDs
• Antifungals (e.g., amphotericin B)
• Antibiotics
  • Aminoglycosides
  • Vancomycin
  • Cephalosporins
  • Colistin
  • Sulfonamides
  • Streptomycin
• Antivirals
  • Acyclovir
  • Foscarnet
  • Cidofovir
• Antimetabolites
  • Methotrexate
  • Cladribine
• Platinum-based chemotherapeutic agents (e.g., cisplatin, carboplatin)
• Immunosuppressants (e.g., cyclosporine)
• Inhalational anesthetics

Vaccination ^[14]

• Recommended immunizations: influenza, Pneumococcus, and varicella zoster
• MMR and varicella for individuals who were vaccinated as infants or currently do not have immunity

Pharmacological treatment

Blood pressure

• General: Well-controlled blood pressure is essential to prevent progression of CKD and complications resulting from cardiovascular disease (CVD).
• Goal: < 130/80 mmHg ^[15]
• First-line treatment: inhibitors of the renin-angiotensin-aldosterone system
  • Nephroprotective
  • Reduce proteinuria
  • May cause hyperkalemia
• Second-line treatment
  • Diuretics
  • Calcium channel blockers
  • β-blockers
  • α-blockers
  • See also “Antihypertensive therapy.”

Dyslipidemia ^[16]

• General: Individuals with CKD often have dyslipidemia (e.g., ↑ LDL, ↓ HDL) due to alterations in lipoprotein metabolism.
• Preferred substances: statins

Renal replacement therapy

• Indications
  • Volume overload/hypertension
  • Metabolic acidosis
  • Hyperkalemia
  • Uremic pericarditis
  • Other uremic symptoms (e.g., signs of encephalopathy)
• Nonoperative
  • Dialysis (hemodialysis or peritoneal dialysis)
  • Hemofiltration
  • Hemodiafiltration
• Operative: kidney transplantation

Chronic kidney disease-mineral and bone disorder (CKD-MBD)

• Definition: abnormalities of the mineral or bone metabolism in the setting of chronic kidney disease
• Pathophysiology
  • Chronic kidney disease results in hypocalcemia via different mechanisms
    • ↓ Renal excretion of phosphate → hyperphosphatemia → calcium-phosphate precipitation in tissues → ↓ Ca²⁺
    • ↓ Renal hydroxylation of vitamin D → ↓ 1,25-(OH)₂ vitamin D3 → ↓ intestinal Ca²⁺ absorption → ↓ Ca²⁺
  • Chronically decreased calcium levels can cause secondary hyperparathyroidism (which can progress to tertiary hyperparathyroidism)
• Classification
  • Metabolic bone disease: hyperparathyroid (high turnover) bone disease (osteitis fibrosa cystica)
  • Mixed (high turnover with mineralization defect) bone disease
  • Osteomalacia
  • Adynamic bone disease (ABD)
  • Amyloid bone disease
  • Aluminum bone disease
• Clinical features
  • Subperiosteal bone thinning
  • Fractures
  • Bone pain
  • Avascular necrosis
• Diagnostics: x-ray may show rugger-jersey spine
• Treatment: See “Treatment” above and “Management of hyperparathyroidism.”

Patients develop secondary hyperparathyroidism and subsequent renal osteodystrophy due to hyperphosphatemia, hypocalcemia, and the insufficient production of vitamin D.

Secondary hyperparathyroidism

• Can be treated surgically (e.g., parathyroidectomy) or with calcimimetics (e.g., cinacalcet)
• See “Management of hyperparathyroidism.”

Anemia of chronic kidney disease

• Pathophysiology: ↓ synthesis of erythropoietin → ↓ stimulation of RBC production → normocytic, normochromic anemia
• Laboratory findings: ↓ hemoglobin, but normal MCV
• Goal: target hemoglobin concentration should be > 10.0 g/dl ^[17]
• Treatment: synthetic EPO
  • Potentially in conjunction with iron replacement ^[18]
  • Adverse effects include increased risk of thrombosis, an increase in blood pressure, and headache.

End-stage renal disease (ESRD)

• Definition: irreversible kidney dysfunction requiring renal replacement therapy
• Treatment
  • Renal replacement therapy
  • Until a kidney transplant is available, affected individuals require either dialysis (hemodialysis or peritoneal dialysis), hemofiltration, or hemodiafiltration.

Growth delay and developmental delay in children

• Contributing factors include:
  • Malnutrition (protein and calorie deficit)
  • Metabolic acidosis
  • Growth hormone resistance
  • Anemia
  • Renal osteodystrophy

Cardiovascular-associated CKD-complications

• Increased risk of coronary artery disease ^[19]
• Increased risk of stroke ^[20]

We list the most important complications. The selection is not exhaustive.

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