Overview

Prevalence

• 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

Risk factors for CKD

• Diabetes

• Hypertension

• Obesity

• Advanced age (> 60 years of age)

• Substance use (smoking, alcohol, recreational drugs)

• Acute kidney injury

• Family history of CKD

• African American or Hispanic descent

Diabetic nephropathy (38%)

Hypertensive nephropathy (26%)

Glomerulonephritis (16%)

Other causes (15%, e.g., polycystic kidney disease, analgesic misuse, amyloidosis)

Idiopathic (5%)

Diabetic nephropathy [6]

• 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. [7]

• 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)

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). [8]

    • 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). [8]

• ↓ 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