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Vol. 118, No. 1, 2011
Issue release date: November 2010
Nephron Physiol 2011;118:p35–p44
(DOI:10.1159/000320902)

Renal Stone Disease

Sayer J.A.
Institute of Human Genetics, International Centre for Life, Newcastle University, Newcastle upon Tyne, UK
email Corresponding Author

Abstract

Background/Aims: Renal stone disease may be seen as a clinical symptom of an underlying pathological process predisposing to crystallization within the renal tract. Renal stones may be comprised of calcium salts, uric acid, cystine and various other insoluble complexes. Nephrolithiasis may be the manifestation of rare single gene disorders or part of more common idiopathic renal stone-forming diseases. Methods and Results: Molecular genetics has allowed significant progress to be made in our understanding of certain stone-forming conditions. The molecular defect underlying single gene disorders often contributes to a significant metabolic risk factor for stone formation. In contrast, idiopathic renal stone formation relates to the interplay of environmental, dietary and genetic factors, with hypercalciuria being the most commonly found metabolic risk factor. Candidate genes for idiopathic stone formers have been identified using numerous approaches, some of which are outlined here. Despite this, the genetic basis underlying familial hypercalciuria and calcium stone formation remains elusive. The molecular basis of other metabolic risk factors such as hyperuricosuria, hyperoxaluria and hypocitraturia is being unraveled and is allowing new insights into renal stone pathogenesis. Conclusion: The discovery of both rare and common molecular defects leading to renal stones will hopefully increase our understanding of the disease pathogenesis. Such knowledge will allow screening for genetic defects and the use of specific drug therapies in order to prevent renal stone formation.


 Outline


 goto top of outline Key Words

  • Renal stone disease
  • Nephrolithiasis
  • Genome-wide association studies
  • Genetic defects
  • Hyperoxaluria
  • Hypercalciuria
  • Calcium-sensing receptor

 goto top of outline Abstract

Background/Aims: Renal stone disease may be seen as a clinical symptom of an underlying pathological process predisposing to crystallization within the renal tract. Renal stones may be comprised of calcium salts, uric acid, cystine and various other insoluble complexes. Nephrolithiasis may be the manifestation of rare single gene disorders or part of more common idiopathic renal stone-forming diseases. Methods and Results: Molecular genetics has allowed significant progress to be made in our understanding of certain stone-forming conditions. The molecular defect underlying single gene disorders often contributes to a significant metabolic risk factor for stone formation. In contrast, idiopathic renal stone formation relates to the interplay of environmental, dietary and genetic factors, with hypercalciuria being the most commonly found metabolic risk factor. Candidate genes for idiopathic stone formers have been identified using numerous approaches, some of which are outlined here. Despite this, the genetic basis underlying familial hypercalciuria and calcium stone formation remains elusive. The molecular basis of other metabolic risk factors such as hyperuricosuria, hyperoxaluria and hypocitraturia is being unraveled and is allowing new insights into renal stone pathogenesis. Conclusion: The discovery of both rare and common molecular defects leading to renal stones will hopefully increase our understanding of the disease pathogenesis. Such knowledge will allow screening for genetic defects and the use of specific drug therapies in order to prevent renal stone formation.

Copyright © 2010 S. Karger AG, Basel


goto top of outline Introduction

Renal stone disease is common, affecting around 13% of males and 7% of females in the USA [1]. The recurrence rate of nephrolithiasis is high, with around 50% of stone formers developing further episodes within 5 years [2]. Stones (or calculi) may develop within any part of the urinary tract, from the renal interstitium/renal tubular lumen to within the bladder. In westernized and industrialized societies, stone formation occurs predominantly within the kidney.

The fact that normal renal physiological mechanisms provide an environment within the kidney, whereby urine is concentrated and calcium and other salts reach supersaturation leading to crystalluria, indicates the human kidney has innate mechanisms to prevent crystal aggregation and retention. When these mechanisms are overwhelmed by dietary or environmental effects or are affected by an underlying metabolic defect the consequence is a tendency to form renal stones.

Genetic factors underlie many forms of renal stone disease since inherited metabolic traits such as hypercalciuria predispose to renal stone formation. However, despite a number of monogenic forms of renal stone disease, a common genetic defect, which contributes to a major proportion of renal stone formers, remains elusive. The dramatic increase in stone formation in westernized societies over recent years also points to environmental effects, such as dietary changes and obesity, rather than a genetic predisposition being important in renal stone pathogenesis.

Here I will discuss briefly, with an emphasis on recently published data, the heritability of renal stones, the genome-wide association studies (GWAS) and animal model approaches that have provided insights into genetic variants contributing to renal stone pathogenesis. Inherited defects of renal anatomy and their propensity to predispose to calculi are also reviewed. Monogenic stone-forming diseases that have provided some insights into mechanisms of disease and represent novel candidate genes for idiopathic stone formers are discussed.

 

goto top of outline Heritability of Renal Stones

The familial predisposition of renal stones has been well documented. A key example of this is in patients attending a renal stone clinic; 40% had a first degree relative with renal stones [3]. Similarly, in another cohort (Nurses Health Cohort II) 36% of patients with kidney stones reported a positive family history for renal calculi [4]. The increased relative risk of calcium stone formation within family members of stone formers has also recently been reported in a Thai population [5]. The most convincing studies investigating the heritability of renal stones compare monozygotic and dizygotic twins. Goldfarb et al. [6 ] reported data collected from 3,391 male twin pairs from the Vietnam Era Twin Registry. There was greater concordance with renal stone incidence in monozygotic twins than dizygotic twins, indicating a genetic tendency for stone formation. Modelling these data suggested a 56% heritability of renal stones and a specific environmental effect in 41%. A second twin study [7] investigated urinary calcium excretion rates in 1,068 female twins, with a suggested heritability of this trait in 52%.

In a study of 567 calcium stone formers, the heritability of hypercalciuria was modelled, also suggesting that this trait could account for the familial pattern of renal stone formers [8]. Indeed, hypercalciuria is the most commonly found metabolic risk factor in calcium stone formers [9]. In an Italian study, 69% of children with hypercalciuria had a family history of renal stones [10].

 

goto top of outline GWAS and Animal Model Approaches in the Study of Renal Stone Disease

A recent large-scale GWAS was performed in 1,507 patients from Iceland with radio-opaque kidney stones. This identified two intronic SNPs (rs219781 and rs219778) on chromosome 21q22.13, located within the same linkage disequilibrium block and either side of the last exon of the Claudin 14 (CLDN14) gene [11]. Claudin 14 is a tight junction protein expressed in the kidney, liver and inner ear. The findings were confirmed in two other populations of stone formers (one Icelandic and one from the Netherlands). What is interesting is that the at-risk alleles are very common, with a population frequency of 75% in the control population. Full exon PCR of CLDN14 in a subset of stone formers also identified two exonic synonymous SNPs, which showed significant association with kidney stones and were associated with a possible increase in urinary calcium excretion and metabolic acidosis. However, the functional significance of these polymorphisms has not been determined. CLDN14 remains an interesting candidate gene for calcium stone formation, given its role at tight junctions within the kidney in regulating solute transport.

The interpretation of the GWAS approach was recently discussed, given the inability to detect causal genes for common diseases [12]. The authors argue that causal genes may be a considerable genetic distance away from the common variant showing association. Using the example of a monogenic disease (sickle cell anaemia), GWAS associations were shown to span some 2.5 Mb around the causal mutation. This means that despite the association of renal stones with CLDN14, other neighbouring genes may be involved.

An alternative approach to determine molecular players in nephrolithiasis used transcriptome analysis in a murine model of renal stone formation. Glyoxylate was used to promote calcium oxalate crystals within the animals’ kidneys, and (predictably) caused an upregulation of many genes related to inflammation, immune reactions and the complement activation pathway. Verification of some these molecular players was performed using qPCR. There were increased chemokines, stone matrix proteins and their receptors, and a significant decrease in several types of transporters and a persistently high expression of uromodulin (UMOD) throughout the experiment [13]. These results confirm the systemic effects of renal calculi, but provide little insights into predisposing genetic effects.

The genetic hypercalciuric stone-forming (GHS) rat model is a well-known and respected model of idiopathic hypercalciuria. Generations of rats have been interbred to maximize urinary calcium excretion, which has resulted in these animals having urinary calcium excretion rates 8–10 times greater than control animals, leading to the development of renal stones [14]. Recently, following intercrossing with normocalciuric rats, genome-wide analysis of these animals has resulted in the identification of quantitative trait loci on several chromosomes, including 1, 4, 7, 10 and 14. The genes involved have yet to be identified. Interestingly, GHS rats have elevated vitamin D receptor (VDR) levels alongside increased renal expression of the calcium sensing-receptor (CASR) [15], although these genes lie outside the quantitative trait loci regions identified. GHS rats have evidence of reduced bone mineral density and bone strength, which implies a direct link between bone turnover and hypercalciuria leading to renal stones in these animals [16].

Another animal model approach to identify underlying genes involved in calcium oxalate stone formation and hyperoxaluria was recently reported. Using rats, a chromosome substitution experiment was carried out between the Brown Norway rat and the Dahl salt-sensitive rat, in which hyperoxaluria was induced by increasing amounts of hydroxyproline in the diet [17]. Rats were evaluated for degrees of hyperoxaluria, renal injury, and crystal deposition. Two rat chromosomes were identified to be contributory to nephrolithiasis. Chromosome 2 genes are postulated to contain genes which regulate response to tubular injury, whilst chromosome 2 and 18 genes regulated crystal deposition and retention. Further fine mapping and expression studies are required to identify the individual genes responsible for these responses [17].

 

goto top of outline Inherited Diseases Leading to Structural Abnormalities of the Kidney

The risk of stone formation in anatomically abnormal kidneys is increased markedly due to a combination of factors including distorted renal architecture, urinary stasis, metabolic derangements and urinary tract infections [18].

The gross anatomical and structural abnormalities produced by progressive cyst enlargement seen in autosomal dominant polycystic kidney disease (ADPKD) have been presumed to be a risk for renal stone disease. Around 20% of patients with ADPKD will have renal stones, usually comprised of uric acid or calcium oxalate [19]. However, metabolic abnormalities such as reduced ammonia excretion, low urinary pH and low urinary citrate have also been reported in patients with ADPKD [20]. In a recent study of 125 South American patients with ADPKD, 28% had CT evidence of nephrolithiasis, or a previous stone episode documented. Stone formers had higher urinary oxalate levels than non-stone formers and renal (cyst) volume was higher in stone formers, confirming both a metabolic defect and a mechanical effect contributing to renal stone formation in polycystic kidney disease [21].

The prevalence of medullary sponge kidney (MSK) in the general population has been estimated to be around 3% [18]. Around two thirds of MSK patients develop renal calculi, and often this is the presenting feature. Although usually a congenital condition, MSK may be inherited as an autosomal dominant trait in around 5% of cases [22]. The risk of stone formation is a result of a combination of anatomical defects (ectasia and cystic dilatations of precalyceal ducts) and biochemical ones (typically hypocitraturia, increased urinary pH and hypercalciuria). Two patients with MSK together with distal renal tubular acidosis and sensorineural deafness were found to have mutations in ATP6V1B1 and ATPV0A4, encoding subunits of the H+-ATPase proton pump [23]. MSK may also be part of other congenital syndromes such as the Beckwith-Wiedemann syndrome (table 1). In a recent study, novel heterozygous variants were identified in the GDNF gene in 8 patients (out of 55 analysed) with MSK. An autosomal dominant inheritance pattern was confirmed in 5 of these cases [52].

TAB01
Table 1. Monogenic causes of nephrolithiasis associated with hypercalciuria

Vesicoureteric reflux is a risk factor for renal stones, with a prevalence of stones in around 20% [18]. Similar findings have been shown for horseshoe kidney. Again, a combination of anatomical defects combined with disordered urinary biochemistry account for the huge increase in risk compared to control populations. Mutations in the transcription factor HNF1β may underlie a variety of renal disorders including horseshoe kidney [24] and are inherited in an autosomal dominant fashion.

 

goto top of outline Candidate Genes Implicated in Nephrolithiasis

Based on the numerous metabolic risk factors which contribute to renal stone formation one can postulate candidate genes. These are often based on the hypothesis that genetic changes causing rare monogenic stone-forming conditions may also underlie ‘idiopathic’ stone formation in the general population. Candidate genes may be grouped under the metabolic risk factor they are associated with, including hypercalciuria, hypocitraturia and hyperuricosuria.

 

goto top of outline Hypercalciuria

Monogenic hypercalciuric stone-forming conditions have allowed us to elucidate the pathophysiological mechanisms underlying calcium stone formation (table 1). An example of this would be Dent’s disease, whereby defects in a chloride/proton exchanger (CLC-5) lead to defective endocytosis within the renal tubule, resulting in hypercalciuria, hyperphosphaturia and sometimes a urinary acidification defect leading to calcium stone formation [25]. However, to date the genes implicated in hypercalciuric conditions (such as CLCN5) have not been able to account for more common forms of calcium nephrolithiasis [26].

The CASR represents an intriguing candidate gene for hypercalciuric nephrolithiasis. Monogenic diseases associated with this disease include familial hypocalciuric hypercalcaemia, familial hypocalcaemia and hypercalciuria and Bartter’s syndrome type V. The CASR protein is expressed in the parathyroid gland, bone, intestine and along specific nephron segments. Its postulated role in the renal collecting duct, the site of maximal urinary concentration, is to sense urinary calcium levels. At this site hypercalciuria will lead, via CASR, to an inactivation of anti-diuretic-induced water permeability of this nephron segment [27]. This is thought to be a physiological protective mechanism against intratubular calcium salt precipitation. In populations of calcium stone formers, polymorphisms in the CASR gene have been described. The R990G CASR polymorphism exists in hypercalciuric (non-stone forming) females, with evidence from in vitro studies that this polymorphism had an ‘activating’ effect on the CASR, thus promoting hypercalciuria [28]. Heterozygous and homozygous carriers of the R990G allele had a significant increase in calcium excretion (7.59 vs. 5.82 mmol/24 h) in comparison with women homozygous for the 990R allele. The R990G allele occurred in 15% of hypercalciuric females studied (compared to only 3% of the normocalciuric control population). The influence of this single CASR polymorphism was recently confirmed, with patients homozygous for the allele having an estimated 8-fold increase in risk of stone formation [29]. Similarly, following the genotyping of 463 calcium stone formers for SNPs within CASR, a distinct haplotype of six SNPs within the 5′UTR and promoter region was found to be associated with calcium-containing stones in patients with hypercalciuria and normal urinary citrate levels. More impressive was the finding of the same haplotype segregating with renal stone formation in a three-generation family. Bioinformatic analysis predicts that this haplotype may change binding of transcription factors, leading to a change in vitamin D-dependent genes and CASR expression [30].

Several genetic studies have pointed to VDR as being implicated in hypercalciuric nephrolithiasis [31]. VDR is within a genetic locus for hypercalciuria identified in families from northern India, and other studies have also suggested linkage to VDR. Polymorphisms within VDR may define bone mineral density and calcium homeostasis, producing a ‘resorptive’ type hypercalciuria. Tissue expression of the VDR may be important as patients with idiopathic hypercalciuria have increased VDR protein expression in peripheral blood monocytes [32]. The GHS rat, previously mentioned, has elevated levels of VDR within the kidney, intestine and bone, leading to hypercalciuria; implicating VDR expression in the pathogenesis of hypercalciuria and renal stones. In contrast, others have found no association between VDR polymorphisms and urinary calcium [33].

Claudin 16 and claudin 19 are tight junction proteins (similar to the GWAS-identified claudin 14 [11]) and mutations in the genes encoding them, CLDN16 and CLDN19, give rise to rare syndrome of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, leading to renal failure. The defect is in the TAL of the loop of Henle, where paracellular calcium and magnesium resorption occurs. Heterozygous CLDN16 mutations may give rise to a much milder phenotype which might include hypercalciuria and calcium stone formation.

TRPV5 and TVPV6 are renal tubular calcium channels, localized to the distal convoluted tubule. Both represent candidate genes for hypercalciuric nephrolithiasis. TRVP5 sequencing among families with hypercalciuric renal stones did not identify any novel variants [34]. TRVP5 function is regulated by the WNK4 kinase. Mutations in the gene encoding WNK4 cause Gordon’s syndrome (pseudohypoaldosteronism type 2), manifesting as inherited hypertension, hyperkalaemia metabolic acidosis and hypercalciuria. WNK4 therefore provides a possible link between TRVP5 dysfunction and hypercalciuria. Polymorphisms in TRPV6 have been associated with absorptive hypercalciuria in humans [35].

Genome-wide linkage analysis was performed in three families with a severe phenotype of absorptive hypercalciuria. A significant LOD score of 3.3 was shown in a single locus on chromosome 1 and sequence variants in the human soluble adenylate cyclase gene (sAC), a divalent cation and bicarbonate sensor, were identified. The sAC protein is expressed in renal bone and intestine; however, the functional significance of the observed sequence variants has yet to be determined [36].

 

goto top of outline Hyperoxaluria

Hyperoxaluria is a frequently detected metabolic abnormality occurring in 10–20% of stone formers. Genetic mechanisms underlying idiopathic hyperoxaluria have yet to be elucidated, but genes controlling oxalate metabolism, intestinal oxalate absorption and renal oxalate excretion remain candidate genes for idiopathic calcium oxalate stone formers. The proximal renal tubule expresses chloride–oxalate exchangers (such as SLC26A6) and the sulphate anion transporter SLC26A1 which regulates in part serum oxalate concentrations. Similar anion exchangers (SLC26A3, SLC26A6 and SLC26A7) are expressed in the gut. No mutations/polymorphisms in the genes encoding these transporters have been reported to date in calcium oxalate stone formers. Monogenic forms of hyperoxaluria (primary hyperoxaluria type 1 and 2), where there is overproduction of oxalate (table 2), are reviewed elsewhere [37].

TAB02
Table 2. Monogenic causes of nephrolithiasis (without hypercalciuria)

 

goto top of outline Hyperuricosuria

Hyperuricosuria is a metabolic risk factor contributing to renal stone formation. Recently, our understanding of the molecular transporters involved in the renal handling of uric acid has grown. Defects in the human urate transporter 1 (SLC22A12 alias hURAT1) have been found in subjects with idiopathic renal hypouricaemia and nephrolithiasis [38]. SLC22A12 encodes a proximal tubule urate transporter and mutations lead to a raised fractional excretion of urate which predispose to calculi formation. As well as renal stone disease, mutations may also predispose to exercise-induced renal failure. Another renal urate transporter, SLC2A9 (alias GLUT9) has been identified as a molecular cause of hypouricaemia [39], and represents a novel candidate gene for uric acid stone formation as a result of increased excretion of uric acid.

 

goto top of outline Hypocitraturia

Hypocitraturia is a frequently detected metabolic abnormality in calcium stone formers. Any cause of systemic/metabolic acidosis will increase proximal tubular citrate absorption, promoting hypocitraturia and the risk of stone formation. Renal citrate transporters include the Na+-coupled citrate transporter (SLC13A5 alias NaCT) and the renal sodium-citrate co-transporter (SLC13A2 alias hNaDC-1). In 105 patients with recurrent calcium stones, the I550V polymorphism within SLC13A2 was genotyped, and the polymorphism was associated with hypocitraturia [40]. Citrate metabolism and its transporters are also likely to be modulated by VDR, and polymorphisms within VDR have been associated with hypocitraturic stone formation [41]. Therefore, these renal citrate transporters may be considered candidate genes for nephrolithiasis associated with idiopathic hypocitraturia. As described previously, hypocitraturia may be seen in the context of renal anatomical abnormalities such as ADPKD and MSK. Monogenic forms of renal tubular acidosis may also give rise to both hypocitraturia and hypercalciuria, leading to significant nephrocalcinosis and calcium phosphate nephrolithiasis.

 

goto top of outline Hyperphosphaturia

Renal phosphate wasting is a metabolic risk factor for nephrolithiasis. Molecular defects in proximal tubular phosphate transporters and their regulators have been reported, but remain a rare cause of nephrolithasis. Heterozygous mutations in the SLC34A1 gene (alias NPT2a) were found in 2 patients with renal phosphate wasting and either kidney stones or bone mineralization [42]. Similarly, mutations in the related gene SLC34A3 have been found in families with hypophosphataemic rickets and hypercalciuria (table 1). Proximal renal tubular phosphate transporters are likely to be regulated by a number of proteins including the endopeptidase homolog PHEX, the phosphaturic factor FGF23 and NHERF1.

Following screening of 92 patients with calcium-containing stones and or bone demineralization, Karim et al. [43] identified 4 patients with heterozygous mutations in the SLC9A3R1 gene (alias NHERF1). Three patients had calcium stone disease, and the 4th had reduced BMD and a spinal deformity. Urinary phosphate reabsorption was reduced in all 4 patients, implicating hyperphosphaturia in the pathogenesis. There was also evidence of increased urinary cAMP and increased serum 1,25-dihydroxy vitamin D. Screening for mutations in these genes controlling renal phosphate handling now needs to be performed in idiopathic stone formers.

 

goto top of outline Inherited Defects in Urinary Macromolecules

UMOD mutations account for several phenotypes including gout and familial juvenile hyperuricaemic nephropathy. UMOD (also known as Tamm-Horsfall protein), represents the most abundant urinary protein in humans, and a recent GWAS associated UMOD polymorphisms with chronic kidney disease [44]. UMOD is expressed at the luminal side of renal epithelial cells of the thick ascending loop of Henle and in the distal convoluted tubule. It is a transmembrane protein, which is secreted into the urine by cleavage of the glycosyl-phosphatidylinositol anchor. UMOD has been shown to be an inhibitor of nephrolithiasis. Umod knockout mice are susceptible to urinary tract infections (from fimbriated Escherichia coli) and calcium oxalate crystals. Recurrent calcium stone-forming patients have been shown to excrete increased quantities of abnormal UMOD, with a change in its chemical composition to include more sialic acid residues [45]. However, to date, genetic changes in UMOD have not been associated with renal stone disease.

Aside from UMOD, there are other modulators of urinary tract crystallization. These include macromolecules such as osteopontin (OPN), bikunin and urinary prothrombin fragment-1. Evidence of a gene defect underlying structural or secretory variations of these proteins is limited. A reduced excretion of OPN has been noted in some stone formers [46] and indeed SNPs within the OPN gene promoter have been associated with stone formation [47]. Like UMOD, posttranslational protein modifications of OPN may also play a role.

 

goto top of outline Other Inherited Stone Diseases

There are a few rare but discrete causes of inherited renal stones where metabolic factors other than hypercalciuria, hypouricaemia and hypocitraturia play a major determinant of stone formation. These are summarized in table 2 and outlined below.

 

goto top of outline Cystinuria

Cystinuria is an autosomal recessive disorder, with defects in a cystine/dibasic amino acid transporter and its subunit giving rise to excessively high urinary cystine levels, which precipitate to form stones. Two genes are known, SLC3A1 and SLC7A9; however, in around 25% of patients, mutations may not be found in these genes, implicating other unknown gene defects [48].

 

goto top of outline Xanthinuria

Hereditary xanthinuria is a rare autosomal recessive condition secondary to deficiency in XDH activity (type 1) and/or aldehyde dehydrogenase (type 2). The underling defects result in hypouricaemia, reduced urinary uric acid, and increased urinary xanthine excretion. Mutations underlying xanthinuria type 1 are present in the XHD gene, whilst the molecular genetic cause of type 2 remains obscure.

 

goto top of outline 2,8-Dihydroxyadenine Stones

This is an autosomal recessive inherited form of renal stones, secondary to adenine phosphoribosyl-transferase (APRT) deficiency, where adenine cannot be converted to AMP. Excess adenine is oxidized to 2,8-dihydroxyadenine by the enzyme xanthine oxidase. The clinical presentation of these stones may vary from microscopic, to gravel and staghorn calculi and like uric acid stones, they are radiolucent. This condition may lead to progressive renal failure [49] and may recur in a renal transplant. It is probably underrecognized and has an estimated incidence of 1 in 50,000–100,000. A recent review of 53 cases of APRT deficiency [50] demonstrated a median age at diagnosis of 36 years with a huge range (from 0.5 to 78 years). Direct sequencing of the APRT gene identified mutations in the majority of patients, with a common mutation IVS4 +2insT accounting for 40% of the mutations identified. Interestingly, animal data suggest that OPN may modulate the severity of the APRT-deficient phenotype [51].

 

goto top of outline Conclusions

Renal stone formation is a multifactorial event, but evidence points strongly to a genetic predisposition towards stone formation. Given this heritability, genome-wide searches and animal models have been employed in order to identify ‘at risk’ alleles. Monogenic stone-forming conditions have allowed considerable gains of insight in renal tubular handling of calcium and other salts, but have not yet explained the underlying genetic defect in the majority of stone formers. Hypercalciuria is rightly targeted as the most important risk factor to unravel, and there are likely to be numerous interacting molecular factors contributing to this risk factor. The advent of whole genome sequencing allows us to anticipate some novel insights into familial forms of nephrolithiasis.

 

goto top of outline Acknowledgement

J.A.S. is a GlaxoSmithKline-funded clinician scientist and his work investigating the genetics of renal stones is funded by the Northern Counties Kidney Research Fund.


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  27. Sands JM, Naruse M, Baum M, Jo I, Hebert SC, Brown EM, Harris HW: Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest 1997;99:1399–1405.
  28. Vezzoli G, Terranegra A, Arcidiacono T, Biasion R, Coviello D, Syren ML, Paloschi V, Giannini S, Mignogna G, Rubinacci A, Ferraretto A, Cusi D, Bianchi G, Soldati L: R990g polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria. Kidney Int 2007;71:1155–1162.
  29. Hamilton DC, Grover VK, Smith CA, Cole DE: Heterogeneous disease modeling for Hardy-Weinberg disequilibrium in case-control studies: application to renal stones and calcium-sensing receptor polymorphisms. Ann Hum Genet 2009;73:176–183.
  30. Vezzoli G, Terranegra A, Arcidiacono T, Gambaro G, Milanesi L, Mosca E, Soldati L: Calcium kidney stones are associated with a haplotype of the calcium-sensing receptor gene regulatory region. Nephrol Dial Transplant 2010;25:2245–2252.
  31. Ferreira LG, Costa Pereira A, Heilberg IP: Vitamin D receptor and calcium-sensing receptor gene polymorphisms in hypercalciuric stone-forming patients. Nephron Clin Pract 2009;114:c135–c144.
  32. Favus MJ, Karnauskas AJ, Parks JH, Coe FL: Peripheral blood monocyte vitamin D receptor levels are elevated in patients with idiopathic hypercalciuria. J Clin Endocrinol Metab 2004;89:4937–4943.
  33. Zerwekh JE, Hughes MR, Reed BY, Breslau NA, Heller HJ, Lemke M, Nasonkin I, Pak CY: Evidence for normal vitamin D receptor messenger ribonucleic acid and genotype in absorptive hypercalciuria. J Clin Endocrinol Metab 1995;80:2960–2965.
  34. Muller D, Hoenderop JG, Vennekens R, Eggert P, Harangi F, Mehes K, Garcia-Nieto V, Claverie-Martin F, Os CH, Nilius B, JM Bindels R: Epithelial Ca2+ channel (ECAC1) in autosomal dominant idiopathic hypercalciuria. Nephrol Dial Transplant 2002;17:1614–1620.
  35. Suzuki Y, Pasch A, Bonny O, Mohaupt MG, Hediger MA, Frey FJ: Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation. Hum Mol Genet 2008;17:1613–1618.
  36. Reed BY, Gitomer WL, Heller HJ, Hsu MC, Lemke M, Padalino P, Pak CY: Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density. J Clin Endocrinol Metab 2002;87:1476–1485.
  37. Cochat P, Liutkus A, Fargue S, Basmaison O, Ranchin B, Rolland MO: Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol 2006;21:1075–1081.
  38. Cheong HI, Kang JH, Lee JH, Ha IS, Kim S, Komoda F, Sekine T, Igarashi T, Choi Y: Mutational analysis of idiopathic renal hypouricemia in Korea. Pediatr Nephrol 2005;20:886–890.
  39. Matsuo H, Chiba T, Nagamori S, Nakayama A, Domoto H, Phetdee K, Wiriyasermkul P, Kikuchi Y, Oda T, Nishiyama J, Nakamura T, Morimoto Y, Kamakura K, Sakurai Y, Nonoyama S, Kanai Y, Shinomiya N: Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet 2008;83:744–751.
  40. Okamoto N, Aruga S, Matsuzaki S, Takahashi S, Matsushita K, Kitamura T: Associations between renal sodium-citrate cotransporter (HNADC-1) gene polymorphism and urinary citrate excretion in recurrent renal calcium stone formers and normal controls. Int J Urol 2007;14:344–349.
  41. Mossetti G, Vuotto P, Rendina D, Numis FG, Viceconti R, Giordano F, Cioffi M, Scopacasa F, Nunziata V: Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis. J Intern Med 2003;253:194–200.
  42. Prie D, Huart V, Bakouh N, Planelles G, Dellis O, Gerard B, Hulin P, Benque-Blanchet F, Silve C, Grandchamp B, Friedlander G: Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2A sodium-phosphate cotransporter. N Engl J Med 2002;347:983–991.
  43. Karim Z, Gerard B, Bakouh N, Alili R, Leroy C, Beck L, Silve C, Planelles G, Urena-Torres P, Grandchamp B, Friedlander G, Prie D: NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 2008;359:1128–1135.
  44. Kottgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, Yang Q, Gudnason V, Launer LJ, Harris TB, Smith AV, Arking DE, Astor BC, Boerwinkle E, Ehret GB, Ruczinski I, Scharpf RB, Ida Chen YD, de Boer IH, Haritunians T, Lumley T, Sarnak M, Siscovick D, Benjamin EJ, Levy D, Upadhyay A, Aulchenko YS, Hofman A, Rivadeneira F, Uitterlinden AG, van Duijn CM, Chasman DI, Pare G, Ridker PM, Kao WH, Witteman JC, Coresh J, Shlipak MG, Fox CS: Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 2009, Epub ahead of print.
  45. Jaggi M, Nakagawa Y, Zipperle L, Hess B: Tamm-Horsfall protein in recurrent calcium kidney stone formers with positive family history: abnormalities in urinary excretion, molecular structure and function. Urol Res 2007;35:55–62.
  46. Nishio S, Hatanaka M, Takeda H, Iseda T, Iwata H, Yokoyama M: Analysis of urinary concentrations of calcium phosphate crystal-associated proteins: alpha2-HS-glycoprotein, prothrombin F1, and osteopontin. J Am Soc Nephrol 1999;10(suppl 14):S394–S396.

    External Resources

  47. Gao B, Yasui T, Itoh Y, Li Z, Okada A, Tozawa K, Hayashi Y, Kohri K: Association of osteopontin gene haplotypes with nephrolithiasis. Kidney Int 2007;72:592–598.
  48. Sayer JA: The genetics of nephrolithiasis. Nephron Exp Nephrol 2008;110:e37–e43.
  49. Perruzza I, Di Pietro V, Tavazzi B, Lazzarino G, Gamberini M, Barsotti P, Amorini AM, Giardina B, Balducci A: Is adenine phophorybosiltransferase deficiency a still underdiagnosed cause of urolithiasis and chronic renal failure? A report of two cases in a family with an uncommon novel mutation. NDT Plus 2008;1:292–295.

    External Resources

  50. Bollee G, Dollinger C, Boutaud L, Guillemot D, Bensman A, Harambat J, Deteix P, Daudon M, Knebelmann B, Ceballos-Picot I: Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency. J Am Soc Nephrol 2010;21:679–688.
  51. Vernon HJ, Osborne C, Tzortzaki EG, Yang M, Chen J, Rittling SR, Denhardt DT, Buyske S, Bledsoe SB, Evan AP, Fairbanks L, Simmonds HA, Tischfield JA, Sahota A: Aprt/Opn double knockout mice: osteopontin is a modifier of kidney stone disease severity. Kidney Int 2005;68:938–947.
  52. Torregrossa R, Anglani F, Fabris A, Gozzini A, Tanini A, Del Prete D, Cristofaro R, Artifoni L, Abaterusso C, Marchionna N, Lupo A, D’Angelo A, Gambaro G: Identification of GDNF gene sequence variations in patients with medullary sponge kidney disease. Clin J Am Soc Nephrol 2010;5:1205–1210.

 goto top of outline Author Contacts

John A. Sayer
Institute of Human Genetics, International Centre for Life
Newcastle University, Central Parkway
Newcastle upon Tyne NE1 3BZ (UK)
Tel. +44 191 2418 608, Fax +44 191 2418 666, E-Mail j.a.sayer@ncl.ac.uk


 goto top of outline Article Information

Published online: November 11, 2010
Number of Print Pages : 10
Number of Figures : 0, Number of Tables : 2, Number of References : 52


 goto top of outline Publication Details

Nephron Physiology

Vol. 118, No. 1, Year 2011 (Cover Date: November 2010)

Journal Editor: Kleta R. (London)
ISSN: 1660-2137 (Print), eISSN: 1660-2137 (Online)

For additional information: http://www.karger.com/NEP


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background/Aims: Renal stone disease may be seen as a clinical symptom of an underlying pathological process predisposing to crystallization within the renal tract. Renal stones may be comprised of calcium salts, uric acid, cystine and various other insoluble complexes. Nephrolithiasis may be the manifestation of rare single gene disorders or part of more common idiopathic renal stone-forming diseases. Methods and Results: Molecular genetics has allowed significant progress to be made in our understanding of certain stone-forming conditions. The molecular defect underlying single gene disorders often contributes to a significant metabolic risk factor for stone formation. In contrast, idiopathic renal stone formation relates to the interplay of environmental, dietary and genetic factors, with hypercalciuria being the most commonly found metabolic risk factor. Candidate genes for idiopathic stone formers have been identified using numerous approaches, some of which are outlined here. Despite this, the genetic basis underlying familial hypercalciuria and calcium stone formation remains elusive. The molecular basis of other metabolic risk factors such as hyperuricosuria, hyperoxaluria and hypocitraturia is being unraveled and is allowing new insights into renal stone pathogenesis. Conclusion: The discovery of both rare and common molecular defects leading to renal stones will hopefully increase our understanding of the disease pathogenesis. Such knowledge will allow screening for genetic defects and the use of specific drug therapies in order to prevent renal stone formation.



 goto top of outline Author Contacts

John A. Sayer
Institute of Human Genetics, International Centre for Life
Newcastle University, Central Parkway
Newcastle upon Tyne NE1 3BZ (UK)
Tel. +44 191 2418 608, Fax +44 191 2418 666, E-Mail j.a.sayer@ncl.ac.uk


 goto top of outline Article Information

Published online: November 11, 2010
Number of Print Pages : 10
Number of Figures : 0, Number of Tables : 2, Number of References : 52


 goto top of outline Publication Details

Nephron Physiology

Vol. 118, No. 1, Year 2011 (Cover Date: November 2010)

Journal Editor: Kleta R. (London)
ISSN: 1660-2137 (Print), eISSN: 1660-2137 (Online)

For additional information: http://www.karger.com/NEP


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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  25. Sayer JA, Simmons NL: Urinary stone formation: Dent’s disease moves understanding forward. Exp Nephrol 2002;10:176–181.
  26. Scheinman SJ, Cox JP, Lloyd SE, Pearce SH, Salenger PV, Hoopes RR, Bushinsky DA, Wrong O, Asplin JR, Langman CB, Norden AG, Thakker RV: Isolated hypercalciuria with mutation in CLCN5: relevance to idiopathic hypercalciuria. Kidney Int 2000;57:232–239.
  27. Sands JM, Naruse M, Baum M, Jo I, Hebert SC, Brown EM, Harris HW: Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest 1997;99:1399–1405.
  28. Vezzoli G, Terranegra A, Arcidiacono T, Biasion R, Coviello D, Syren ML, Paloschi V, Giannini S, Mignogna G, Rubinacci A, Ferraretto A, Cusi D, Bianchi G, Soldati L: R990g polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria. Kidney Int 2007;71:1155–1162.
  29. Hamilton DC, Grover VK, Smith CA, Cole DE: Heterogeneous disease modeling for Hardy-Weinberg disequilibrium in case-control studies: application to renal stones and calcium-sensing receptor polymorphisms. Ann Hum Genet 2009;73:176–183.
  30. Vezzoli G, Terranegra A, Arcidiacono T, Gambaro G, Milanesi L, Mosca E, Soldati L: Calcium kidney stones are associated with a haplotype of the calcium-sensing receptor gene regulatory region. Nephrol Dial Transplant 2010;25:2245–2252.
  31. Ferreira LG, Costa Pereira A, Heilberg IP: Vitamin D receptor and calcium-sensing receptor gene polymorphisms in hypercalciuric stone-forming patients. Nephron Clin Pract 2009;114:c135–c144.
  32. Favus MJ, Karnauskas AJ, Parks JH, Coe FL: Peripheral blood monocyte vitamin D receptor levels are elevated in patients with idiopathic hypercalciuria. J Clin Endocrinol Metab 2004;89:4937–4943.
  33. Zerwekh JE, Hughes MR, Reed BY, Breslau NA, Heller HJ, Lemke M, Nasonkin I, Pak CY: Evidence for normal vitamin D receptor messenger ribonucleic acid and genotype in absorptive hypercalciuria. J Clin Endocrinol Metab 1995;80:2960–2965.
  34. Muller D, Hoenderop JG, Vennekens R, Eggert P, Harangi F, Mehes K, Garcia-Nieto V, Claverie-Martin F, Os CH, Nilius B, JM Bindels R: Epithelial Ca2+ channel (ECAC1) in autosomal dominant idiopathic hypercalciuria. Nephrol Dial Transplant 2002;17:1614–1620.
  35. Suzuki Y, Pasch A, Bonny O, Mohaupt MG, Hediger MA, Frey FJ: Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation. Hum Mol Genet 2008;17:1613–1618.
  36. Reed BY, Gitomer WL, Heller HJ, Hsu MC, Lemke M, Padalino P, Pak CY: Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density. J Clin Endocrinol Metab 2002;87:1476–1485.
  37. Cochat P, Liutkus A, Fargue S, Basmaison O, Ranchin B, Rolland MO: Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol 2006;21:1075–1081.
  38. Cheong HI, Kang JH, Lee JH, Ha IS, Kim S, Komoda F, Sekine T, Igarashi T, Choi Y: Mutational analysis of idiopathic renal hypouricemia in Korea. Pediatr Nephrol 2005;20:886–890.
  39. Matsuo H, Chiba T, Nagamori S, Nakayama A, Domoto H, Phetdee K, Wiriyasermkul P, Kikuchi Y, Oda T, Nishiyama J, Nakamura T, Morimoto Y, Kamakura K, Sakurai Y, Nonoyama S, Kanai Y, Shinomiya N: Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet 2008;83:744–751.
  40. Okamoto N, Aruga S, Matsuzaki S, Takahashi S, Matsushita K, Kitamura T: Associations between renal sodium-citrate cotransporter (HNADC-1) gene polymorphism and urinary citrate excretion in recurrent renal calcium stone formers and normal controls. Int J Urol 2007;14:344–349.
  41. Mossetti G, Vuotto P, Rendina D, Numis FG, Viceconti R, Giordano F, Cioffi M, Scopacasa F, Nunziata V: Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis. J Intern Med 2003;253:194–200.
  42. Prie D, Huart V, Bakouh N, Planelles G, Dellis O, Gerard B, Hulin P, Benque-Blanchet F, Silve C, Grandchamp B, Friedlander G: Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2A sodium-phosphate cotransporter. N Engl J Med 2002;347:983–991.
  43. Karim Z, Gerard B, Bakouh N, Alili R, Leroy C, Beck L, Silve C, Planelles G, Urena-Torres P, Grandchamp B, Friedlander G, Prie D: NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 2008;359:1128–1135.
  44. Kottgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, Yang Q, Gudnason V, Launer LJ, Harris TB, Smith AV, Arking DE, Astor BC, Boerwinkle E, Ehret GB, Ruczinski I, Scharpf RB, Ida Chen YD, de Boer IH, Haritunians T, Lumley T, Sarnak M, Siscovick D, Benjamin EJ, Levy D, Upadhyay A, Aulchenko YS, Hofman A, Rivadeneira F, Uitterlinden AG, van Duijn CM, Chasman DI, Pare G, Ridker PM, Kao WH, Witteman JC, Coresh J, Shlipak MG, Fox CS: Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 2009, Epub ahead of print.
  45. Jaggi M, Nakagawa Y, Zipperle L, Hess B: Tamm-Horsfall protein in recurrent calcium kidney stone formers with positive family history: abnormalities in urinary excretion, molecular structure and function. Urol Res 2007;35:55–62.
  46. Nishio S, Hatanaka M, Takeda H, Iseda T, Iwata H, Yokoyama M: Analysis of urinary concentrations of calcium phosphate crystal-associated proteins: alpha2-HS-glycoprotein, prothrombin F1, and osteopontin. J Am Soc Nephrol 1999;10(suppl 14):S394–S396.

    External Resources

  47. Gao B, Yasui T, Itoh Y, Li Z, Okada A, Tozawa K, Hayashi Y, Kohri K: Association of osteopontin gene haplotypes with nephrolithiasis. Kidney Int 2007;72:592–598.
  48. Sayer JA: The genetics of nephrolithiasis. Nephron Exp Nephrol 2008;110:e37–e43.
  49. Perruzza I, Di Pietro V, Tavazzi B, Lazzarino G, Gamberini M, Barsotti P, Amorini AM, Giardina B, Balducci A: Is adenine phophorybosiltransferase deficiency a still underdiagnosed cause of urolithiasis and chronic renal failure? A report of two cases in a family with an uncommon novel mutation. NDT Plus 2008;1:292–295.

    External Resources

  50. Bollee G, Dollinger C, Boutaud L, Guillemot D, Bensman A, Harambat J, Deteix P, Daudon M, Knebelmann B, Ceballos-Picot I: Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency. J Am Soc Nephrol 2010;21:679–688.
  51. Vernon HJ, Osborne C, Tzortzaki EG, Yang M, Chen J, Rittling SR, Denhardt DT, Buyske S, Bledsoe SB, Evan AP, Fairbanks L, Simmonds HA, Tischfield JA, Sahota A: Aprt/Opn double knockout mice: osteopontin is a modifier of kidney stone disease severity. Kidney Int 2005;68:938–947.
  52. Torregrossa R, Anglani F, Fabris A, Gozzini A, Tanini A, Del Prete D, Cristofaro R, Artifoni L, Abaterusso C, Marchionna N, Lupo A, D’Angelo A, Gambaro G: Identification of GDNF gene sequence variations in patients with medullary sponge kidney disease. Clin J Am Soc Nephrol 2010;5:1205–1210.