Genetic Hypercalciuria

Disease of the Month

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 nephrolithiasis 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 crystallization includes formation of exoskeleton, pearl, endoskeleton, and dentition, whereas pathophysiologic crystallization includes pyrophosphate arthropathy, pigmented gallstones, vas- cular calcification, and urolithiasis. Pathologic calcium crystallization 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 pathophysiology of calcium nephrolithiasis versus nephrocalcinosis is incompletely 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 versus 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 organs by predominantly endocrine mechanisms and fluxes through three target organs in concert effect calcium homeostasis. 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 pathophysiologic and genetic point of view, this is a very important classification. 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 primary 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 for the complete definition of pathophysiology and strive to uncover a slightly elevated parathyroid hormone, normal serum calcium, proximal (closer to the underlying lesion) phenotype. and normal filtered calcium; (3) persistent hypercalciuria is Figure 1, B and C, illustrates two additional scenarios with present even during fasting; and (4) increased bone resorption increased bone resorption and increased gut absorption as pri- markers and/or reduced bone mineral density. This battery of mary disturbances that cause hypercalciuria. Although the un- J Am Soc Nephrol 16: 729–745, 2005 Genetic Hypercalciuria 731 derlying causes are diverse and the physiologic profiles are completely different, all three situations culminate in hypercalciuria. Some have argued that because it is so difficult to separate and characterize the defects in these organs, one should forego that and simply aggregate everything into a pot of heterogeneous conditions. We submit the counter argument that unless one continuously strives to dissect and classify on the basis of pathophysiologic characteristics, it will be hopeless to advance our understanding.

Dissecting the Genetics of Hypercalciuria Approximately half of the patients who are labeled as having idiopathic hypercalciuria have a positive family history of kidney stones (21). Familial idiopathic hypercalciuria has been described as an autosomal dominant trait in the earlier litera- ture. This was a de facto conclusion based on the observation that it did not match a recessive pattern, and the male-to-male inheritance ruled out gender-linked transmission (22–26). This is clearly an oversimplification of the genetics of familial hypercalciuria. Not all genetic diseases can be dealt with with a Mendelian approach. Some unavoidable ambiguity in both genotyping and phenotyping notwithstanding, it is usually possible to discern whether one has clinical autosomal dominant polycystic kidney disease and whether one has mutations in polycystin-1 or -2. Such definitive assignments are not possible for hypercalciuria because of a number of immanent im- pediments. Hypercalciuria is a complex trait that cannot be slotted into classical Mendelian categories. The inherent diffi- culties of dissecting the genetics of hypercalciuria are schemat- ically summarized in Figure 2. As the central tenet to all genetic Figure 2. Hypercalciuria as a complex trait. Classical one gene– approaches involves some form of genotype-phenotype corre- one protein hence one mutation–one disease model. (A) The un- lation, phenotypic ambivalence can deliver a cataclysmic blow derlying mechanisms that account for this non-Mendelian inher- to the effort. Figure 2A depicts the breakdown of the classical itance pattern. (B) Complex traits create exceptions to this linear paradigm such as multiple mutations converging into one disease Mendelian perfectly co-segregating “one gene locus-one phe- (middle) or one mutation diverging into several diseases. notype” paradigm. Each of the following characteristics of hypercalciuria imparts equivocation in the genotype-phenotype correlation (Figure 2B). Although there is no good way of creating a sharp distinction when there is none, one can partially circumvent the problem by Continuous Variable analyzing relative supersaturation of calcium oxalate and phos- Whereas the presence or absence of a calcareous calculus in phate in addition to the amount of calcium in clinical samples. the urinary tract can theoretically and practically be classified as a “yes-no” event, the more proximal and more important Secondary and Compensatory Effects phenotype, hypercalciuria, cannot assume such binary status. As discussed above, hypercalciuria can be accompanied by Akin to parameters such as BP and body mass, urinary calcium an extensive panoply of effects that are downstream from or as excretion is a continuous variable. Although there is little dif- compensatory responses to the primary disturbance. This ren- ficulty in assigning disease status at the extreme ends of the ders the use of hypercalciuria singularly as a phenotypic vari- spectrum, there is really no sharp distinction of margins. “Dis- able very risky. As shown in Figure 1, three completely differ- ease” in this case refers to the bearing of increased statistical ent syndromes all share the feature of hypercalciuria. Unless risk of nephrolithiasis and/or nephrocalcinosis. Hypercalciuria one commits extra effort to dissect out and identify the primary is an example par excellence of a quantitative trait (Figure 2). versus secondary and compensatory changes, using one param- Further compounding the lack of discrete boundary is that the eter as “phenotype” will severely undermine the genotype- same amount of calcium in a 24-h urine sample can have phenotype correlation. completely different implications depending on the urine volume; pH; concentration of all of the calcium-interacting anions Phenocopy such as citrate, phosphate, and oxalate; and concentration of There are a host of nongenetic factors that can affect gut promoters and inhibitors of crystallization. Not to mention that calcium absorption, bone calcium release, and renal calcium each one of these other factors is also a continuous variable. handling. The cartoon in Figure 2A displays some dietary (rep- 732 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 729–745, 2005

Table 1. Monogenic diseases that lead to hypercalciuria: Intestine as the primary defect

Phenotype Disease OMIM Gene/Gene Product Renal Gastrointestinal Bone

Congenital lactase 223000 Unknown, autosomal Hypercalciuria, Hyperabsorption, deficiency recessive, locus linked nephrocalcinosis, diarrhea, poor to 2q21 hypercalcemia (33) weight gain Congenital sucrase- 222900 SI/sucrase-isomaltase Hypercalciuria. Hyperabsorption, isomaltase Nephrocalcinosis. chronic diarrhea, deficiency Hypercalcemia (34,35) failure to thrive Glucose/galactose 606824 SLC5A1/sodium-glucose Hypercalciuria, renal Severe diarrhea malabsorption co-transporter calculi, nephrocalcinosis hypercalcemia, glucosuria (36–38) Blue diaper 211000 Unknown, autosomal Hypercalciuria, Defect in intestinal syndrome recessive or X-linked, nephrocalcinosis, tryptophan possibly SLC16A10/T- hypercalcemia, transport type amino acid indicanuria (40) transporter (39) Hypophosphatemia 182309 NPT2/sodium-phosphate Phosphate wasting, Vitamin D– Osteoporosis (41) and absorptive co-transporter (41) hypercalciuria, renal mediated calcium hypercalciuria calculi (41) hyperabsorption (type 3) Hereditary 241530 Gene unknown, NPT2 Phosphate wasting, Vitamin D– Rickets/ hypophosphatemic locus excluded (42,43), hypercalciuria (44) mediated calcium osteomalacia rickets with autosomal recessive hyperabsorption hypercalciuria Williams-Beuren 194050 7q11.23 deletion, ELN/ Hypercalciuria (45–47) Calcium Rickets (45) syndrome (not elastin, LIMK1/LIM hyperabsorption monogenic) domain kinase 1, RFC2/replication factor C, subunit 2 Hyperabsorptive 607258 4q33-qter deletion Hypercalciuria, Calcium Facial and hypercalciuria nephrocalcinosis (48,49) hyperabsorption skeletal (not monogenic) abnormalities Down’s syndrome 190685 Trisomy 21 Hypercalciuria (50–56) Calcium Low bone (not monogenic) hyperabsorption mineral density (57,58)

resenting completely nongenetic) factors that can influence uri- guard against phenocopic artifacts is sound knowledge and nary calcium excretion (27). Other than a dietary history, which data in pathophysiology. is semiquantitative at best, it is very difficult to rule out increased dietary calcium intake as a cause for hypercalciuria. Polygenic Influence The cartoon also shows that high dietary protein (source of Adopting an exaggerated view for the sake of emphasizing a acid) and sodium can also cause “physiologic hypercalciuria” point, one can make the extreme statement that there is no such (27,28). In these instances, one can at least estimate from the condition as a pure monogenic disease. Consider some quint- ϩ 24-h urine sample the impact of salt (urinary Na ) and acid essential monogenic human diseases. Two different individuals ϩ 2Ϫ (urinary NH4 and SO4 ) on urinary calcium. As it is difficult may have the identical mutation in cystic fibrosis transmem- to collect and analyze 24-h urine under the luxury of dietary brane regulator (CFTR) and yet the clinical severity in cystic control in the setting of a clinical practice, metabolic studies in fibrosis can differ vastly (29). Similar can be said for the same the setting of a clinical research center are indispensable. In mutation in ␤-globin causing very mild or very severe sickle addition to dietary factors, there are multiple other nongenetic cell anemia (30). There is no doubt that modifier genes are at factors that affect intestinal calcium absorption and bone for- work. Consider the idealized situation in the laboratory, where mation/resorption (not covered in Figure 2A). The only safe- one specifically deletes one and only one gene in a murine J Am Soc Nephrol 16: 729–745, 2005 Genetic Hypercalciuria 733

Table 2. Monogenic diseases that lead to hypercalciuria: Bone as the primary defect

Phenotype Disease OMIM Gene/Gene Product Renal Gastrointestinal Bone

Osteogenesis 166200 COL1A1 and Hypercalciuria (59–61) Fractures imperfecta type 1 COL1A2/ collagen type 1, ␣1 and 2 MEN1 syndrome 131100 MEN1/Menin Hyperparathyroidism, Increased bone with with hypercalciuria, turnover hyperparathyroidism nephrocalcinosis, renal stones (62) Neonatal self- 239199 Gene unknown; Hypercalciuria, Increased bone limited primary autosomal nephrocalcinosis, turnover hyperparathyroidism recessive (63) renal tubular acidosis (63) Metaphyseal 156400 PTHR/parathyroid Hypercalciuria, High bone resorption chondrodysplasia hormone hyperphosphaturia, with metaphyseal Jansen type receptor-1 high urinary cAMP deformities (64,65) Infantile 241500 ALPL/alkaline Hypercalcemia, Rickets, hypophosphatasia phosphatase hypercalciuria, craniosynostosis nephrocalcinosis (66) McCune-Albright 174800 GNAS1/guanine Hypercalciuria, Fibrous dysplasia, syndrome nucleotide nephrocalcinosis, rickets, craniofacial binding protein hyperphosphaturia hyperostosis, (G protein), a- (67–69) deformity of femur stimulating activity polypeptide 1

model with a completely homogeneous (as far as one can tell) tion, then inheriting all five predisposing alleles can theoreti- genetic background. This is probably the closest example that cally raise urinary calcium by 2.5 mmol/d (100 mg). one can fathom of a pure monogenic disorder. It is already well known that the same gene knockout in the background of Loci Heterogeneity different strains can have completely different effects. As the Similar reasoning along the lines of polygenic influence is investigator delights with the emergence of the good news that loci heterogeneity. Different underlying genetic lesions can 80% of the null mice survives and hence can be studied, one start the pathophysiologic cascade in vastly different manners, should wonder about the effect of the gene deletion on the 20% but by the time the lesion reaches the whole organism (clinical) of the mortal ones. Penetrance of a singular gene may be small level, they may have converged on an end organ in a very or even negligible, but multiple genes in concert can have a restricted manner. Renal cysts in humans can result from mu- significant impact on the phenotype. Envision five hypothetical tations in ADPKD1, ADPKD2, or ARPKD (31). In animals, there genes that have an impact on urinary calcium excretion. Each of is an enormous collection of monogenic mutations that con- these genes is polymorphic in Homo sapiens with multiple fully verge into a final common phenotype of renal cyst formation functional alleles that have small quantitative differences in (32). As depicted in Figure 2B, two individuals with identical function. For instance, gene product 1 influences intestinal phenotypes may actually have no overlap whatsoever in their calcium absorption, gene product 2 modifies the ability of underlying disease-causing genetic loci. Thus, launching a ge- dietary acid to release calcium from bone, gene product 3 netic search from hypercalciuria as a starting point may lead an controls paracellular calcium permeability in the thick ascend- investigator to multiple and confusing destinations. However, ing limb, gene product 4 influences calcium absorption in the these different loci will likely have a different pathogenic path- distal convoluted tubule, and gene product 5 alters the sensi- way en route to hypercalciuria and will manifest with different tivity of the renal calcium sensing receptor to plasma calcium proximal phenotypes. concentration. If each of these gene products contributes to a The complex nature of hypercalciuria is addressed in more trivial 0.5 mmol/d (20 mg) increase in urinary calcium excre- detail below. Before one embarks on this formidable exercise, 734 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 729–745, 2005

Table 3. Monogenic diseases that lead to hypercalciuria: Kidney as the primary defect

Phenotype Disease OMIM Gene/Gene Product Renal Gastrointestinal Bone

Dent’s disease (X- 300009 CLC5/chloride Hypercalciuria, Rickets linked recessive channel 5 hyperphosphaturia, nephrolithiasis, tubular proteinuria, X-linked Fanconi syndrome, hypophosphatemic nephrocalcinosis, renal rickets, low calculi (70,71) molecular weight proteinuria) Lowe 309000 OCRL/inositol Hypercalciuria, Vitamin D–resistant oculocerebrorenal polyphosphate 5 aminoaciduria, rickets syndrome phosphatase phosphaturia, Fanconi syndrome, nephrocalcinosis, renal calculi (72,73) Bilateral macular 248190 Unknown probably Hypercalciuria (74) coloboma with autosomal recessive hypercalciuria Wilson’s disease 277900 ATP7B/copper- Hypercalciuria, renal calculi, Liver disease Osteoporosis (82) transporting hyperphosphaturia, partial ATP-ase Fanconi syndrome, proteinuria, distal tubular acidosis (75–81) Tyrosinemia type 1 276700 FAH/fumarylaceto- Hypercalciuria, Fanconi Hepatomegaly, Rickets acetase syndrome, liver disease nephrocalcinosis, renal calculi (83) Glycogen storage 232200 G6PC/glucose-6- Hypercalciuria, Fanconi Hepatomegaly, Osteopenia, fracture disease type 1a phosphatase syndrome, hypocitraturia, poor growth, (86) nephrocalcinosis, hypoglycemia proteinuria (84,85) Familial 248250 PCLN-1/paracellin-1 Hypercalciuria, magnesium hypomagnesemia or claudin 16 (87) wasting, nephrocalcinosis with hypercalciuria (88–90); heterozygotes and nephrocalcinosis more prone to renal calculi (91) Bartter syndrome type 1 601678 NKCC2/sodium- Hypercalciuria, Osteopenia (98) potassium-chloride nephrocalcinosis, co-transporter metabolic alkalosis (92) type 2 241200 ROMK/renal outer- Hypercalciuria, Osteopenia medullary nephrocalcinosis, potassium channel metabolic alkalosis (93) type 3 607364 CLC-Ka-b chloride Less severe hypercalciuria, channels no nephrocalcinosis (94) type 4 602522 Barttin Congenital deafness (95) type 5 601199 CaSR/calcium-sensing Overlap between autosomal receptor dominant hypocalcemia and Bartter syndrome (96,97) J Am Soc Nephrol 16: 729–745, 2005 Genetic Hypercalciuria 735

Table 3. Continued

Phenotype Disease OMIM Gene/Gene Product Renal Gastrointestinal Bone

Autosomal dominant 601198 CaSR/calcium-sensing Hypercalciuria (99,100) hypocalcemia receptor (activating mutations) Familial isolated 146200 CaSR/calcium-sensing Hypercalciuria hypoparathyroidism receptor (activating mutations) (101) PTH/parathyroid hormone (102–104) GCMB/glial cells missing B (105) Familial hypertensive 145260 WNK4/protein kinase Hypercalciuria, mild hyperkalemia or lysine deficient 4 metabolic acidosis pseudohypoaldosteronism (106) Normocalciuria (107) type 2 WNK1/protein kinase, lysine deficient 1 Renal tubular acidosis distal AR, with 267300 ATP6V1B1/V-ATP- Nephrocalcinosis, Hyperabsorption Acidosis-related deafness ase, ␤ subunit (108) hypercalciuria bone resorption distal AR, normal 602722 ATP6V0A4/V-ATP- Nephrocalcinosis, hearing ase, ␣ subunit (109) hypercalciuria distal AD 179800 SLC4A1/anion Nephrocalcinosis, renal exchanger (110,111) stones (110) mixed RTA 259730 CAII/carbonic Nephrocalcinosis, Osteopetrosis, anhydrase II (112) urolithiasis (112–114) brain calcifications Liddle’s syndrome 177200 SCNN1B and Hypercalciuria and SCNN1G/epithelial nephrocalcinosis in two sodium channel, ␤ cases (115) and ␥ subunits

some consideration will be given to monogenic causes of hy- allow investigators to plant two pillars on solid grounds and percalciuria both in human diseases and in animal models. work out the elusive black boxes in between. A number of monogenic causes of hypercalciuria have been Hypercalciuria as a Monogenic Trait identified, and there is no simple classification. Tables 1 Monogenic diseases often conjure up a sense of disinterest through 5 present a summary of these diseases in terms of their (disgust to some) in many practitioners because of their exotic effects on the three principle organs of calcium homeostasis. nature and commonly perceived detachment from the every- We took the liberty to include experimental monogenic dis- day reality of medical practice. This is a misconception but a eases (Table 5) because these man-made monogenic disease perfectly understandable one. As one peruses a typical cata- models are rapidly becoming more common than naturally logue of this nature (e.g., tables in this article), one notices that occurring monogenic diseases. Tables 1 through 4 classify these half of the names of diseases are not recognizable and the other disorders into whether the primary lesion primarily ails the half are not pronounceable, all of which will probably never gastrointestinal tract, kidneys, bone, or other organs. Regard- show up in our clinic. With such pretext, how does one justify less of the site of the primary lesion, multiple organs are always devoting the majority of his or her time and effort on such a involved. minority of medical illnesses? The answer lies in the relatively Detailed discussion of each of these conditions is beyond the “clean” nature of the primary lesion. These diseases allow one objective of this review. Some highlights are presented. Gastro- to build upon two irrefutable facts: The mutation of a single intestinal monogenic diseases associated with hypercalciuria gene and an unmistakable phenotype well known and charac- are uncommon (Table 1) (33–58). There is a group of monogenic terized by clinicians as a delineated syndrome. These two facts diseases in which intestinal calcium hyperabsorption has been 736 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 729–745, 2005 described (Table 1) but the mechanism is undetermined (33– tions, patients with WNK4Q596E mutation have hypercalciuria 40). A second group of monogenic diseases have vitamin and low bone mineral density (107), while patients who carry D–mediated intestinal hyperabsorption including primary re- the WNK1 intronic deletion are not reported to have hypercal- nal diseases such as renal phosphate wasting (41–44). Finally, ciuria. The way by which WNK kinase mutations lead to hy- there is a group of chromosomal deletion syndromes (not mo- percalciuria is not yet clear. The renal tubular acidoses (108– nogenic) in which intestinal hyperabsorption has been de- 112) present a complex picture of the multiorgan origin of scribed but the mechanisms are unknown (45–58). Monogenic hypercalciuria. In addition to gut and bone compensation, aci- diseases that affect primarily the bone leads to hypercalciuria demia per se can increase bone resorption. Finally, a group of largely via increased calcium release into the circulating pool hypercalciuric diseases (116–121) with a wealth of mechanisms (Table 2) (59–69). These can be due to conditions related to are awaiting to be explored (Table 4). structural defects in bone such as osteogenesis imperfecta (59– Animal models of monogenic diseases are valuable. The 61), part of a hyperparathyroid state (62–65), or ricketic-like genetically altered animals listed in Table 5 have hypercalciuria bone lesion (66–69). from targeted deletion of known disease-causing genes (122– Primary renal monogenic lesions are summarized in Table 3. 127) and genes coding for important calcium homeostatic pro- Several treatises of a similar nature have been published (5–8), teins (20,128–134), and some have hypercalciuria of serendipity and we do not delve into this topic any further except to (135,136). Animal models using ClC5 knockdown (122) or highlight a few notions. There is a large group of monogenic knockout (123,124) have captured some but not all of the salient proximal tubulopathies with variable features of the Fanconi features of Dent’s disease. This most likely reflects polygenic syndrome that, when full-blown, represent general proximal modifiers in action. Even in a classical monogenic disorder, tubule dysfunction (70–86). The mechanism of hypercalciuria there may be some loci heterogeneity as evident by the fact that is not understood in these diseases, but this is an excellent some patients with classic features of Dent’s do not harbor example of loci heterogeneity. We elected to classify primary mutations in ClC5 (137). The variable phenotype of calbindin- renal phosphate wasting from mutations of the Na-phosphate 28K deletion is another testimony of polygenic modifiers (130– co-transporter NaPi-IIa in Table 1 because of the compensatory 133). An intact animal with a known deliberate gene deletion increase in vitamin D. Thick ascending limb tubulopathies in- and a phenotype that bears resemblance to human disease is volve reduced paracellular calcium permeability (87–91), re- highly useful for working out the intermediate steps in the duction of driving force (92–98), and the erroneous resetting of pathogenesis. physiologic control for calcium absorption (99–105). The distal tubulopathies also represent a heterogeneous group of primary Hypercalciuria as a Complex Trait hypercalcurias (106–113). Despite the near identical effects on Calcium nephrolithiasis is a very distal (many steps down- ϩ ϩ ϩ Na ,K , and H homeostasis by WNK1 and WNK4 muta- stream from the primary lesion) phenotype that can result from

Table 4. Monogenic diseases that lead to hypercalciuria: Unknown mechanisms

Phenotype Disease OMIM Gene/Gene Product Renal Gastrointestinal Bone

Cystic fibrosis 219700 CFTR/cystic fibrosis Microscopic Calcium transmembrane nephrocalcinosis absorption conductance (116); hypercalciuria not defined regulator (117) ␤-Thalassemia 141900 HBB/␤-globin Hypercalciuria, Calcium Decreased bone proximal tubulopathy absorption mineral density, (118) not defined osteomalacia (119) Beckwith- 130650 p57(KIP2)/cyclin- Hypercalciuria, Calcium Wiedemann dependent kinase nephrocalcinosis absorption syndrome inhibitor 1C (120) not defined NSD1/nuclear receptor binding SET domain protein 1 H19/H19 gene Phenylketonuria 261600 PKU1/phenylalanine Hypercalciuria (121) Calcium Osteopenia (121) hydroxylase absorption not defined J Am Soc Nephrol 16: 729–745, 2005 Genetic Hypercalciuria 737

Table 5. Animal models of monogenic hypercalciuria

Phenotype Gene Animal Model Renal Gastrointestinal Bone

CLC5 Ribosomal knockdown Hypercalciuria Not described (122) Mouse knockout (123) Normocalciuria, Not described hyperphosphaturia Mouse knockout (124) Hypercalciuria, Spinal deformities hyperphosphaturia, proteinuria NPT2 Mouse knockout (125) Hypercalciuria, Higher alkaline hyperphosphaturia, phosphatase, renal calcifications retarded secondary ossification NHERF-1 Mouse knockout (128) Male: Normal overall Female: Bone fracture, renal function, 25–30% reduced bone hypercalciuria, mineral density, 40% hyperphosphaturia, reduced bone mineral hypermagnesuria content, low serum alkaline phosphatase TRPV5 Mouse knockout (20) Hypercalciuria, Increased Reduced trabecular and hyperphosphaturia intestinal cortical thickness of calcium bones absorption VDR Mouse knockout (128,129) Hypercalciuria on high- Rickets calcium, high-lactose diet Calbindin- Mouse knockout Normocalciuria, D28k normocalcemia (130) Hypercalciuria (131,132) Normocalciuria (132) Calbindin- Mouse double knockout Hypercalciuria, Reduced food Severe rickets D28k and (134) hyperphosphaturia intake by VDR reduced body weight NKCC2 Mouse knockout (126) Hypercalciuria, Growth polyuria, retardation hydronephrosis, proteinuria Caveolin-1 Mouse knockout (135) Hypercalciuria in male, bladder stone AKr1b1 Mouse knockout (136) Hypercalciuria, (aldose hypercalcemia, reductase) hypermagnesemia, increased urine volume and decreased urine osmolarity CaSR Not knockout; isopropyl Ectopic calcifications, Ectopic methane sulfonate no hypercalciuria by calcifications mutagenesis, CaSR calcium/creatinine activating mutation ratio (127) 738 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 729–745, 2005 a variety of causes. Even if one takes a step more proximal from calcium stones to hypercalciuria, one is still confronted with a phenotype governed by multiple organs with numerous genetic and environmental determinants. There is no doubt that hypercalciuria is a complex trait. After the display of the diffi- culties in studying a trait as complex as hypercalciuria, one wonders whether there is any hope in ever unraveling the genetics in this conditions. The approaches outlined by the classic review by Lander and Schork (138) a decade ago are still in active use today, and the reader is referred there for an excellent detailed discussion. A more recent update can be found in the review by Risch and Merikangas (139). One can fathom ways to bypass or counteract the complexity Figure 3. The commonly encountered association study. Cases and enable some degree of informative genotype-phenotype and controls are defined by phenotypic criteria selected by the correlation. One can confine the phenotype to the most severe investigator. The frequency of a polymorphic candidate gene end of the calciuria continuum, restrict it to a subgroup of with two or more alleles is determined in the two populations. fasting hypercalciuria or hypercalciuria accompanied by A typical positive result is shown with allele A1 more common in affected cases (70%) versus controls (30%). This statistical heightened intestinal absorption and reduced bone density, or finding can be due to several possible reasons. (1)GeneAisa include only hypercalciuric patients with a strong family his- disease locus and allele A1 is a mutation that causes hypercal- tory. All of these efforts are directed to capture a more proximal ciuria. (2) Gene A is closely situated to gene B and therefore phenotype and hopefully more homogeneous genetics. This recombines rarely (linkage disequilibrium). In the two study underscores once again the critical importance of good meta- populations, allele A1 is co-segregating with the disease gene B, bolic evaluation of patients and that hypercalciuria per se is not so A1 seems to occur with higher frequency in the cases. (3) an adequate phenotype for genetic studies. Another approach Neither gene A nor any other gene in the region is contributing is to use single large kindreds. The reason is that the degree of to hypercalciuria. Allele A1 is occurring with higher frequency polygenic influence and loci heterogeneity in the general pop- in the affect versus unaffected individuals because the two ulation is much reduced in a single pedigree as long as the populations are not comparable. number of individuals offers adequate power for the analysis. Allele-sharing method between sibling pairs is founded on the rationale that even though a trait is polygenic, the inheritance of than a dozen clinical conditions, we are hardly closer to the a given gene (albeit amid numerous modifiers) is Mendelian truth. Having stated the caveats and limitations with this tech- (138–140). In this section, we highlight a few issues and review nique, there is no doubt that association studies are readily and some existing data that are germane to hypercalciuria. easily performed. The wealth of information derived from monogenic human Association diseases and rodents with single gene deletions provides a The easiest method that has been widely used in a lot of valuable database for candidate genes to be screened in hu- complex traits is a population-based association study (Figure mans. Genes along the vitamin D axis were examined. Small 3). This is a case-control design that examines the frequency of studies have shown association of restriction site polymor- a particular allele in affected versus unaffected individuals. phisms with one form of phenotypic parameter or another Unfortunately, this is also the weakest design in terms of gen- (141–143). However, several other studies have found no dif- erating definitive information. The ambiguity of affected versus ference in the phenotype of vitamin D receptor expression, unaffected has already been discussed. The polygenic nature induction, allelic frequencies, coding region sequence between and loci heterogeneity further worsens the problem. In addi- controls, and well characterized hyperabsorptive hypercalci- tion, the phenomenon of population admixture renders this uric stone formers (144,145). The closest positive outcome has method ridden with artifacts (138). It is highly likely that two been the identification of potential susceptibility locus in the populations differ in aspects other than the disease of interest; vicinity of the vitamin D receptor gene in 47 French-Canadian hence, any given allele will have a good chance of having kindreds using sib-pair analysis (146). One must exercise ut- different frequency in two different populations (Figure 3). most caution and rigor before accepting such data as proof of Positive studies are common with the association approach, the hypothesis. and the caveats are summarized in Figure 3. If the different Other candidate genes were also pursued. Apart from its alleles of the gene of interest have defined differences in func- known implication in Bartter syndrome and autosomal domi- tion and that difference can account for some phenotypic dif- nant hypocalcemia, the calcium sensing receptor (CaSR) is a ferences, then an association will carry more meaning. If the candidate gene for multigenic hypercalciuria and bone resorp- alleles are simply polymorphisms, the one has to be extra tion. One study showed associative correlation between a sin- cautious in interpreting the outcome. After more than a decade gle amino acid change (unknown whether it is a polymorphism of copious positive case-control studies of angiotensinogen and or a mutation) and the phenotype (147); there were no point angiotensin-converting enzyme gene polymorphisms in more mutations in seven families with idiopathic hypercalciuria J Am Soc Nephrol 16: 729–745, 2005 Genetic Hypercalciuria 739

(148). In 55 French-Canadian pedigrees, no association was complex pathophysiology lends credence to the polygenic de- found between CaSR locus and idiopathic hypercalciuria and terminants of calcium excretion. Although the physiology dif- calcium nephrolithiasis (149). Direct sequencing of the ClC-5 fers somewhat from those described in humans, the GHS rat chloride channel was negative in a case-control study (150). definitely shows multiorgan pathophysiology with intestinal Thus far, association studies with candidate genes have not hyperabsorption, increased bone calcium mobilization, and pri- been particularly informative in genetic hypercalciuria. mary renal leak, a “full house” coverage of Figure 1. The well-characterized pathophysiology has been summarized in Linkage several recent reviews (6,162,163). Linkage is a powerful alternative and complement to associ- There are two reasons that the study of these animals is more ation studies. As opposed to association, linkage detects geno- utilitarian than humans in studying complex traits. In addition type-phenotype co-segregation within families and has been to a valuable source of pathophysiology, a major reason for the workhorse for disease-locus discovery in monogenic dis- having such strains is identification of disease susceptibility loci eases (151,152). The Hoˆpital Maisonneuve-Rosemont group using breeding experiments. A region of the chromosome (per- from Montreal has used nonparametric (i.e., a model-free test to haps containing one gene) that determines the magnitude of a avoid a priori assumption of a particular inheritance pattern) continuous trait is called a quantitative trait locus (QTL). With linkage analysis in large numbers of French-Canadian concor- the a priori assumption that the trait is genetic, one crosses two dant affected sib-pairs on a large number of candidate genes inbred strains (hypercalciuric and normocalciuric) to produce including the vitamin D receptor (146); 1-␣-hydroxylase (153); recombinant strains followed by backcrosses with one of the the CaSR (148); and crystallization modifiers such as osteopon- original strains until one can link the genetic loci (QTL) being tin, Tamm-Horsefall protein, and osteocalcin-related gene delivered, to the phenotypic trait (hypercalciuria). One works (154). on the implicit hypothesis that the QTL confers the hypercal- Instead of candidate genes, Reed et al. (155) performed a ciuria. The loci identification will be followed by mapping of linkage analysis of three large kindreds with absorptive hyper- the genes. Hoopes et al. (164) reported on several QTL that are calciuria using nonparametric testing. This was the first suc- linked to the hypercalciuria in the GHS rats. Although none of cessful genome-wide search in this complex trait. One large the QTL are in regions that harbor the usual set of suspect kindred contributed to the particularly high logarithm of odds candidate genes, these are indeed encouraging results, and the score of Ͼ12 for the region in 1q23.4 to 24, which contains hurdle to surmount now is to proceed from locus to gene. several known genes and a number of putative genes. After Although traditional QTL approaches are powerful, a recent several known genes were sequenced and no sequence differ- advance in this field that may revolutionize the dissection of ences were found in affected versus unaffected individuals, a rodent polygenic traits is the development of chromosome hypothetical protein with adenylyl cyclase motifs that spans substitution strains (165,166). In classical QTL studies, one 104.5 kB with 33 exons (Gen Bank AL035122) was identified crosses two inbred strains with differing phenotypes to create (156). During the course of the work, a homologous rat gene hybrids that then are intercrossed and/or backcrossed eventu- coding for a soluble adenylyl cyclase (sAC) was cloned by Buck ally to generate recombinant inbred or cogenic strains that et al. (157). The human ortholog of sAC is polymorphic with 18 carry portions of the genome of the original parental disease- base substitutions (156). When this gene was examined outside carrying strain in the genetic background of the nonaffected the original kindreds, five sequence variations occurred with parental strain (Figure 4). Because these strains are hypercalci- increased frequency in the hypercalciuria population compared uric, linkage can be performed to identify loci that segregate with normal volunteers, and the number of base substitutions with the QTL of interest. With knowledge of the loci, finer seems to correlate with lower spinal bone density and intestinal structural mapping can be performed to eventually hone in on calcium absorption (156,158), two cardinal features of the ab- the genes. In the chromosomal substitution approach, instead sorptive calciuria syndrome. The pathophysiologic relationship of pieces of DNA randomly scattered through the genome, a between the human ortholog of sAC and intestinal calcium panel in which entire chromosomes from one strain are reabsorption remains to be determined. The efforts on human placed with the corresponding chromosome from another is familial hypercalciuric nephrolithiasis has yielded some en- created (165,166) (Figure 4) in defined and uniform genetic couraging but far-from-groundbreaking information. background. The latter approach is more challenging because the panel of strains has to be generated and is limited by large Animal Models DNA regions (entire chromosome versus the typical 20 cM of A large number of rodent models of complex traits have been QTL). However, no crosses (usually a colossal number for QTL) generated in the past several decades (159,160), and they are need to be performed and genotyping is not required because catalogued at the Rat Genome Database (http://www.rgd.mcw. the segregation of the genome is known from the way the panel edu). These models are instrumental for both geneticists and is generated. physiologists. The best animal model of polygenic hypercalci- Genetic manipulations in rodents are usually performed to uria to date is the genetic hypercalciuria stone-forming rats examine the whole organism phenotype of the disruption of a (GHS rats) created by Bushinsky et al. (161) more than one and gene product or to create a model of known monogenic dis- a half decades ago. That one can breed the physiologic extreme eases for detailed invasive phenotypic characterization that is end of calciuria in “normal” rats to a hypercalciuric state with not possible in humans. With the ever-expanding list of artifi- 740 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 729–745, 2005

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