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Genetic Hypercalciuria

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Genetic Hypercalciuria Disease of the Month Genetic Hypercalciuria Orson W. Moe and Olivier Bonny Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, and the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas Hypercalciuria is an important, identifiable, and reversible risk factor in stone formation. The foremost and most fundamental step in dissecting the genetics of hypercalciuria is understanding its pathophysiology. Hypercalciuria is a complex trait. This article outlines the various factors that compromise the attempt to dissect the genetics of hypercalciuria, summarizes the clinical and experimental monogenic causes of hypercalciuria, and outlines the initial results from attempts in studying polygenic hypercalciuria. Finally, the problem is set in perspective of the current database, technologic advances and limitations are highlighted, and prospects of further advances in the field are speculated upon. J Am Soc Nephrol 16: 729–745, 2005. doi: 10.1681/ASN.2004100888 he incidence and composition of kidney stones vary problem in perspective of our current database, highlight tech- considerably in different parts of the world, but neph- nologic advances and limitations, and speculate on prospects of T rolithiasis remains a formidable health problem world- further advances in the field. wide (1–4). It is important to emphasize that although nephro- lithiasis is accepted as a “diagnosis” in common clinical Pathophysiologic Considerations parlance, its presence confers little information about the un- Biomineralization: Crystallization of Calcium Salts as a derlying defect. The occurrence of a kidney stone can reflect a Physiologic Event diverse list of underlying diagnoses. From this standpoint, “Calcium stone formation” is mineral crystallization in body nephrolithiasis per se is not much more of a “diagnosis” than for tissue or fluid. The deposition of inorganic minerals, crystalline example high BP, ascites, or fever. Regional and etiologic vari- or noncrystalline, around biomolecules is universal in biology, ations not withstanding, calcium-containing stones consistently where inorganic crystals are harnessed to become an integral constitute the majority of nephrolithiasis in all parts of the part of organic tissue to provide hardness and strength. These world. Excessively high concentration of calcium in the urine is inorganic substances are capable of reversible interaction with one distinctly identifiable and correctable factor in stone for- biomolecules so that the crystalline structures can be remodeled mation, although the mechanisms that predispose to and/or for physiologic needs. Williams (9) discussed the unique ability result in precipitation and growth of calcium crystals in the of calcium to interact with biomolecules from the point of view urinary tract are still incompletely understood. of its concentration, binding strength, rate constants, and mo- This monograph aims to achieve several objectives. In the lecular structure. Calcium salts have highly adaptable coordi- first part of the article, we highlight the importance of under- nation geometry that greatly facilitates binding of calcium, in standing pathophysiology, accentuating specifically the com- its solid state or solution, to the irregular geometry of proteins. plexity and multiorgan nature of hypercalciuria. The intent is to The remarkable material properties of bones and teeth result underscore the critical importance of eliciting pathophysiology from the activities of proteins that function at the organic- when one attempts to dissect the genetics of a complex trait inorganic interface (10). Proteins have evolved domains that such as hypercalciuria. We then outline the various factors that specifically interact with calcium crystals. The aspartate-phos- compromise the attempt to dissect the genetics of hypercalci- phoserine-phosphoserine-glutamate-glutamate (DpSpSEE) mo- uria. In the second part, we summarize the clinical and exper- tif described in the saliva protein statherin is also found in other imental monogenic causes of hypercalciuria, not so much as a calcium crystal–interacting proteins, such as osteopontin mere reiteration of the numerous existing excellent reviews on (11,12). Unlike the EF hand that binds ionic calcium, this genetic causes of hypercalciuria (5–8) but rather to provide a DpSpSEE motif binds solid-phase calcium phosphate crystals framework to ponder about the formidable challenge that and is conserved down to invertebrates such as crustaceans. looms ahead—hypercalciuria as a complex trait. This final topic This motif is expressed in a protein at the foot pad that allows is the focus of the third part of this article. We poise the the mussel to attach to calcareous substratum (13). More than 200 yr ago, Hunter (14) articulated about the similarity between stone formation and calcification. He Published online ahead of print. Publication date available at www.jasn.org. pointed out the equivalence of enamel, eggshell, gallstones, and Address correspondence to: Dr. Orson W. Moe, Charles and Jane Pak Center of kidney stones. Thus, mineralization can be arbitrarily divided Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8855. Phone: into physiologic and pathologic. The partition is not always 214-648-7993; Fax: 214-645-9993; E-mail: [email protected] distinct but can be distinguished on the basis of favorable versus Copyright © 2005 by the American Society of Nephrology ISSN: 1046-6673/1603-0729 730 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 729–745, 2005 undesired consequences to the organism. Physiologic crystalli- zation includes formation of exoskeleton, pearl, endoskeleton, and dentition, whereas pathophysiologic crystallization in- cludes pyrophosphate arthropathy, pigmented gallstones, vas- cular calcification, and urolithiasis. Pathologic calcium crystal- lization is a physiologic process in the wrong place and the wrong time. Multiorgan Approach to Hypercalciuria Because isolated hypercalciuria per se is not detrimental, a clinician’s interest in hypercalciuria concerns the complications that include mainly nephrolithiasis and nephrocalcinosis and perhaps also less morbid conditions such as hematuria (15) and possibly polyuric enuresis in children (16). The pathophysiol- ogy of calcium nephrolithiasis versus nephrocalcinosis is incom- pletely understood, but the reader is referred to a recent review by Sayer et al. (17). It is not the purpose of this review to tackle the debate about the relative importance of hypercalciuria ver- sus hyperoxaluria in calcium oxalate stones, but a recent study clearly demonstrates that urinary calcium and oxalate are equally important for stone formation (18). A majority of patients with this condition have been catego- rized as “idiopathic hypercalciuria.” The term is decades old and seemed to have secured an indelible place in medical idiom. Although linguistically correct without doubt, it carries an implicit presumption that this is a single condition that is inevitably incorrect and furthermore takes on certain overtones of futility in unraveling the underlying cause. Although the use of this term is convenient in common clinical lingo, one must caution the absolute and unquestioned acceptance of this term as a “diagnosis.” Calcium homeostasis involves multiple or- gans by predominantly endocrine mechanisms and fluxes through three target organs in concert effect calcium homeosta- sis. Any analysis of hypercalciuria should at least take the three organs into consideration. Pak et al. pioneered this attempt back in 1975 by introducing a tripartite classification of absorptive, resorptive, and renal hypercalciuria (19). From a pathophysio- logic and genetic point of view, this is a very important classi- fication. Figure 1. Pathophysiology of hypercalciuria. Hypercalciuric Figure 1 depicts three scenarios in which in each, a primary syndromes all are multisystemic diseases and are arbitrarily disturbance occurs in one of the three calcium homeostatic divided into three overlapping categories according to the pri- mary or predominant disturbance. In each instance, secondary organs. Figure 1A shows an example of pure renal leak. Al- compensatory changes involve multiple hormones such as though a lot of causes of hypercalciuria such as acid load– parathyroid hormone (PTH) and 1,25-dihydroxy-vitamin D3 induced hypercalciuria has a component of renal leak, multiple [1,25-(OH)2vit D]. (A) Renal leak with secondary gut hyperab- mechanisms often come into play. Pure renal hypercalciuria sorption and increased bone release. (B) Imbalance between can be seen in mice with deletion of the TRPV5 calcium channel bone formation and resorption. (C) Intestinal hyperabsorption. gene (20). Compensatory intestinal hyperabsorption and bone The three primary disturbances can occur simultaneously. resorption maintains serum calcium at normal levels (20). It is understandable how the usual battery of clinical tests at the outpatient setting may not recognize the hypercalciuria as a information may not be feasible in clinical practice with the renal leak. One has to possess some or all of the following data: time, infrastructure, and financial constraints. However, it is (1) Serum parathyroid hormone and 1,25-(OH)2 vitamin D are absolutely imperative that one not abandon the quest for a higher than expected; (2) hypercalciuria is inappropriate
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