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  Disease summary:

  
  
  
  
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    Nephrolithiasis is the pathologic process of stone (calculus) formation within the renal tract. The resulting renal calculi are composed of calcium salts, uric acid, cystine, and other insoluble complexes.

  
  
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  Hereditary basis:

  
  
  
  
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    Nephrolithiasis may occur either as part of the phenotype of rare single gene disorders or as an “idiopathic” renal stone-forming disease with a polygenic inheritance.

    
    
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    The genetic basis of single gene disorders includes autosomal recessive, autosomal dominant, and X-linked disorders. Each of these single gene disorders usually leads to a significant metabolic risk factor for nephrolithiasis.

    
    
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    Idiopathic renal stone formation is caused by an interplay of environmental, dietary, and genetic factors. Twin studies demonstrate a significant contribution of genetic factors in stone formation, whilst the recent rise in stone formation in Westernized societies is likely to be secondary to nongenetic factors such as diet and obesity.

    
    
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    Hypercalciuria is the most commonly found metabolic risk factor in “idiopathic” stone formers. There are many candidate genes for “idiopathic” hypercalciuric stone formers but the genetic basis remains elusive since hypercalciuria is a quantitative trait and may be polygenic.

    
    
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    The genetic basis of other metabolic risk factors such as hyperuricosuria, hyperoxaluria, and hypocitraturia is beginning to be understood as molecular transporters of various solutes are cloned and characterized.

  
  
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  Differential diagnosis:

  
  
  
  
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    Nephrolithiasis may be part of a more generalized calcification of the kidney termed nephrocalcinosis. It may be part of multisystem disorders and congenital abnormalities of the kidney or urinary tract (CAKUT). Nephrolithiasis may be a complicating feature of autosomal dominant polycystic kidney disease and medullary sponge kidney due to architectural and metabolic abnormalities associated with these conditions.

    
    
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    It is useful to distinguish between calcium-containing and noncalcium-containing stones (eg, urate, cystine), as this will determine the best imaging modality for diagnosis and follow-up.

Diagnostic Criteria

Nephrolithiasis is derived from the Greek words nephros and lithos meaning kidney stone. Urolithiasis is defined as a condition giving rise to a stone within the urinary tract (including kidneys, ureters, and bladder). Nephrocalcinosis is calcification of the kidney which can be microscopic or macroscopic.

The diagnosis of nephrolithiasis is made clinically by presenting features that may include loin pain, spasms of pain radiating to the groin (renal colic), hematuria (visible and nonvisible), urinary frequency, urgency, and dysuria. The diagnosis is confirmed using imaging of the stone (radiologic or ultrasound studies), serum and urine biochemistry, and, once the stone is passed or removed, by physical and chemical examination of the stone morphology and composition.

Urinary tract infection may present concurrently with a renal stone. Stones may be a complication of other anatomic abnormalities of the kidneys, including autosomal dominant polycystic kidney disease. Nephrolithiasis, strictly speaking, is a symptom rather than a diagnosis and an underlying cause must be sought in all cases.

Clinical Characteristics

Stones may vary in size from microscopic crystals forming within the urine and within renal tissues to huge “staghorn” calculi that completed fill or replace the renal pelvis. The majority of renal stones are composed of calcium oxalate (60%) or calcium phosphate (20%) and are therefore radio-opaque. Uric acid (~10%), struvite (~8%), and cystine (~2%) are rarer but can all give rise to Staghorn calculi. Stones may present acutely as an episode of renal colic or an obstructed urinary system, necessitating urgent decompression. Nephrocalcinosis and some forms of renal stone disease (eg, 2,8-dihydroxyadenine [DHA] stones) are more insidious and may present with chronic kidney disease or end-stage renal failure rather than renal colic. It is important to note that hypercalciuria or crystalluria per se may be a cause of invisible (microscopic) hematuria.

Screening

A diagnostic algorithm approach to all patients with nephrolithiasis will aid the identification of a metabolic diagnosis in idiopathic stone formers. Establishing such a diagnosis allows both metabolic and molecular screening of family members at risk of inherited renal stone disorders. No clear evidence of benefit from screening of family members exists for idiopathic stone diseases whilst monogenic disorders may be screened according to the specific diagnosis.

Counseling

For known monogenic diseases, genetic counseling and advice should be given, according to the Mendelian pattern of the disease. Examples of X-linked forms of nephrolithiasis include Dent disease. Autosomal dominant forms of nephrolithiasis include forms of distal renal tubular acidosis and an example of an autosomal recessive disorder would be primary hyperoxaluria.

Family clustering is common with idiopathic hypercalciuric renal stones, with around half of patients with this diagnosis having a family history of kidney stones. The inheritance pattern is likely to be polygenic, given that hypercalciuria is a phenotype which is a continuous variable and the fact that the molecular genetic identification of monogenic causes of hypercalciuria has not proven to be the sole cause of many idiopathic hypercalciuric stone formers (Tables 145-1 and 145-2).