Kidney stone pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

Overview

It is understood that nephrolithiasis is the result of combination of different mechanism responsible for different types of stones. Calcium stones are the most common type of kidney stones. Approximately 80% of all calcium stones are calcium oxalate stones. The pathophysiology of calcium stones is complex and involves dietary concerns, hypercalciuria, hypocitaturia, hyperoxaluria, hyperuricosuria and biomineralization. The underlying pathophysiological mechanisms responsible for uric acid stones are low urine volume, hyperuricosuria and high acidic urine. Cystinuria is a rare hereditary gene disorder which causes impaired renal reabsorption of cationic amino acids and cystine. It is caused by mutations in either of the two subunits (rBAT(SLC3A2) and b0,+AT(SLC7A9)) forming cystine stones. Struvite stones are usually seen in patients which have infection with urease +ve organisms. Urine pH is usually alkaline (>7.2). Nephrolithiasis can be passed on to following generations due to rare causes of hypercalciuria such as hereditary distal renal tubular acidosis, dent disease, Bartter syndrome types III and IV, autosomal dominant hypocalcemic hypercalciuria and familial hypomagnesemia. Nephrolithiasis associated with Hyperparathyroidism, Gout, Hypocitaturia, Sarcoidosis, chronic urinary tract infections and Obesity.On gross pathology, the characteristic findings of nephrolithiasis include location = 80% unilateral, usually in calyces, pelvis or bladder. The size=variable, 2-3 mm usually. All stones contain an organic matrix of mucoprotein. The shape of struvite stone is staghorn shaped. On microscopic histopathological analysis, the characteristic findings of nephrolithiasis include different shapes of stones/crystals are such as cystine= hexagonal, struvite= coffin lid shape, calcium oxalate= pyramid shape to dumbbell shape and uric acid= rectangular/rhomboidal. Oxalate crystals are highlighted by polarized light. Also, foreign body giant cells and macrophages are seen with the stones.

Pathophysiology

Pathogenesis

• It is understood that nephrolithiasis is the result of combination of different mechanism responsible for different types of stones:

Calcium stones

• Calcium stones are the most common type of kidney stones.
• Approximately 80% of all calcium stones are calcium oxalate stones.
• The pathophysiology of calcium stones is complex and involves:
  • Dietary concerns
  • Hypercalciuria
  • Hypocitaturia
  • Hyperoxaluria
  • Hyperuricosuria
  • Biomineralization

Uric acid stones

• The underlying pathophysiological mechanisms responsible for uric acid stones are:
  • Low urine volume
  • Hyperuricosuria
  • High acidic urine.

Cystine stones

• Cystinuria is a rare hereditary gene disorder which causes impaired renal rabsorption of cationic amino acids and cystine.
• The cationic amino acids commonly involved are called as COLA amino acids that stands for:
  • C= cystine
  • O=ornithine
  • L=lysine
  • A=arginine
• It is caused by mutations in either of the two subunits (rBAT(SLC3A2) and b0,+AT(SLC7A9)) forming the apical transporter for cationic amino acids system b0,+; thus excretion of the dibasic COLA amino acids is increased.

Struvite/Ammonium magnesium sulfate stones

• These are usually seen in patients which have infection with urease +ve organisms.
• Urine pH is usually alkaline (>7.2)

The following table summarizes major mechanism of stone formation:

Type of stone/Mechanism		Cause	Pathophysiology	Stone composition	Labs
All stones	Low urine volume (raises production of solutes)	Reduced intake or increased loss of water	Renal water conservation	All stones	Urine volume <1 L per day Osmolarity >600 mOsm/kg
Calcium stones	Hypercalciuria (raises saturation of calcium salts)	Absorptive hypercalciuria	Increased absorption in gut	Calcium oxalate or phosphate	Urine calcium concentrations >6 mmol/L (240 mg) per day
		Hyperparathyroidism	Increased absorption in gut and bone release		High concentrations of parathyroid hormone
		Immobilization	Bone resorption		High concentrations of vitamin D
		Excess of sodium in the diet	Sodium-induced physiological renal calcium leak. Possible component of gut hyperabsorption		Urine sodium concentrations >200 mmol/L per day
		Excess of protein or acid in diet	Protein-induced bone loss and renal leak.		Urine ammonium iron concentrations high Urine sulfate concentrations high Urine pH low Urine citrate concentrations <1·7 mmol/L per day
		Range of monogenic disorders	Bone loss, gut hyperabsorption, and renal leak in various combinations
	Hypocitraturia (raises levels of ionised calcium and reduces inhibitor activity against calcium salts)	Renal tubular acidosis (distal type)	Renal defense of acid-base balance	Calcium phosphate	Urine citrate concentrations <1·7 mmol/L per day Urine pH high
		High acid load (absence of detectable acidemia)	Physiological hypocitraturia	Calcium oxalate or phosphate	Urine citrate concentrations <1·7 mmol/L per day Urine pH low
	Hyperoxaluria (raises saturation of calcium oxalate)	Excess of oxalate in diet	Increased delivery of luminal oxalate	Calcium oxalate	Urine oxalate concentrations >70·7 mmol/L per day
		Bowel pathology	Reduced formation of luminal calcium and calcium-oxalate complex
		Increased production of endogenous oxalate	Primary hyperoxaluria (type 1 and type 2)
	Hyperuricosuria (sodium urate precipitation causes crystallization of calcium salts)	High purine intake	Raised production and urinary excretion of sodium and urate		Urine uric acid concentrations >600 mg per day Hyperuricaemia
		Myeloproliferative diseases
		Enzymatic defects			Urine uric acid concentrations >600 mg per day
		Uricosuric drugs			Hypouricaemia
		Genetic primary renal leak	Increased excretion of uric acid
Uric acid stones	Low urine pH or hyperuricosuria	High acid load Metabolic syndrome	Titrates urate to poorly soluble uric acid	Uric acid	Urine pH <5·5
Cystine stones	Cystinuria	Congenital mutations of dibasic aminoacid transporter subunits rBAT and b0+AT	Renal leak of basic aminoacids	Cystine	Urine concentrations of cystine high (>150 μmol/mmol creatinine)
Infection stones	Urinary tract infection	Urea-splitting organisms	Production of ammonium and bicarbonate from urea	Magnesium ammonium phosphate Carbonate apatite	Urine pH high Pyuria Culture +ve for urease

Genetics

• Nephrolithiasis can be passed on to following generations due to rare causes of hypercalciuria:
  • Hereditary distal renal tubular acidosis
  • Dent disease
  • Bartter syndrome types III and IV
  • Autosomal dominant hypocalcemic hypercalciuria
  • Familial hypomagnesemia

Associated Conditions

• Hyperparathyroidism
• Gout
• Hypocitaturia
• Sarcoidosis
• Chronic urinary tract infections
• Obesity

Gross Pathology

• On gross pathology, the characteristic findings of nephrolithiasis are:
  • Location = 80% unilateral, usually in calyces, pelvis or bladder
  • Size=variable, 2-3 mm usually
  • All stones contain an organic matrix of mucoprotein
  • Shape:
    • Struvite stone= staghorn calculus

• 

  Nephrolithiasis, Source: Wikimedia commons

• 

  Staghorn shape of struvite stones, Source: Wikimedia commons

• 

  Renal calculi, different shapes and sizes, Source: Wikimedia commons

• 

  Kidney stone with a maximum dimension of 5mm, Source: Wikimedia commons

Microscopic Pathology

• On microscopic histopathological analysis, the characteristic findings of nephrolithiasis are:
  • Shapes of different stones/crystals are different:
    • Cysteine= hexagonal
    • Struvite= coffin lid shape
    • Calcium oxalate= pyramid shape
    • Calcium oxalate= dumbbell shape
    • Uric acid= rectangular/rhomboidal
  • Oxalate crystals are highlighted by polarized light
  • Foreign body giant cells and macrophages are seen with the stones

• 

  Type of stones. Light microscopy of urine crystals. (A) Hexagonal cystine crystal (200X); (B) coffin-lid shaped struvite crystals (200X); (C) pyramid-shaped calcium oxalate dehydrate crystals (200X); (D) dumbbell-shaped calcium oxalate monohydrate crystal (400X); (E) rectangular uric acid crystals (400X); and (F) rhomboidal uric acid crystals (400X).

• 

  Deposits of oxalate with variable size and form; they occupy mainly distal tubules. The asterisks indicate proximal tubules, which usually do not contain these crystals, H&E seen with polarized light, X200

• 

  Medullary interstitial urate crystal deposits in chronic nephropathy by urates as seen after Masson's trichome stain X400

• 

  Calcium oxalate dihydrate crystals under Scanning Electron Micrograph (SEM) taken at 30 KV. Source: Wikimedia commons

• 

  Density-dependent color scanning electron micrograph of kidney stone, Source: Wikimedia commons