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  • Review Article
  • Published:

Genetic determinants of urolithiasis

Nature Reviews Nephrology volume 8, pages 151–162 (2012)Cite this article

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Abstract

Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made in identifying the metabolic risk factors that predispose to this complex trait, among which hypercalciuria predominates. The specific genetic and epigenetic factors involved in urolithiasis have remained less clear, partly owing to the candidate gene and linkage methods that have been available until now, being inherently low in their power of resolution and in assessing modest effects in complex traits. However, together with investigations of rare, Mendelian forms of urolithiasis associated with various metabolic risk factors, these methods have afforded insights into biological pathways that seem to underlie the development of stones in the urinary tract. Monogenic diseases account for a greater proportion of stone formers in children and adolescents than in adults. Early diagnosis of monogenic forms of urolithiasis is of importance owing to associated renal injury and other potentially treatable disease manifestations, but diagnosis is often delayed because of a lack of familiarity with these rare disorders. In this Review, we will discuss advances in the understanding of the genetics underlying polygenic and monogenic forms of urolithiasis.

Key Points

  • Calcium oxalate urolithiasis most often presents as a complex trait, which arises from the interaction of multiple genes and their interplay with dietary and environmental factors

  • The search for genetic factors underlying the most common idiopathic form of urolithiasis has yielded a number of promising candidate genes

  • Urolithiasis is also a manifestation of rare, single-gene disorders, many of which present in childhood or adolescence

  • Early diagnosis of monogenic causes of urolithiasis is necessary to prevent renal injury or other disease manifestations; however, diagnosis is often delayed owing to unfamiliarity with these rare, single-gene disorders

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Figure 1: Transporter, channel and receptor proteins of the renal tubule that are implicated in urolithiasis.
Figure 2: Kidney biopsy tissue showing 2,8-DHA crystal nephropathy in a patient with APRT deficiency.
Figure 3: Photomicrograph of 2,8-dihydroxyadenine crystals in the urine of a patient with adenine phosphoribosyltransferase deficiency (magnification ×400).
Figure 4: Kidney biopsy tissue from a patient with primary hyperoxaluria.
Figure 5: Photomicrograph of a cystine crystal in the urine of a patient with cystinuria.

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Authors and Affiliations

  1. Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic Hyperoxaluria Center, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Carla G. Monico & Dawn S. Milliner

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  1. Carla G. Monico
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  2. Dawn S. Milliner
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C. G. Monico researched data to include in the article and wrote the manuscript. Both authors contributed equally to the discussion of content for the article and the reviewing and editing of the manuscript before submission.

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Correspondence to Dawn S. Milliner.

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The authors declare no competing financial interests.

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Monico, C., Milliner, D. Genetic determinants of urolithiasis. Nat Rev Nephrol 8, 151–162 (2012). https://doi.org/10.1038/nrneph.2011.211

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