distal renal tubular acidosis (dRTA)

It is known that subtle forms of dRTA can occur only with hy- percalciuria and recurrent calcium nephrolithiasis. Thus, it is possible that the same molecular defects responsible for the full range dRTA are also causative of cases of familial and spo­radic forms of PH and ICN. As yet, both the ss1 subunit of the vacuolar H+-ATPase (ATP6B1) and the carbonic anhydrase II genes have not been investigated in sporadic and familial forms of ICN. On the contrary the possible existence of a link­age between the Anione Exchanger (A E1) locus and familial ICN was the working hypothesis of a previous study of Gam- baro et al. They formerly described the association of an anom­alous erythrocyte oxalate self-exchange with ICN, dependent on an abnormal phosphorylation of the AE1-band 3 exchanger. Physiological and clinical studies showed the rele­vance of this defect on ICN, and interestingly subclinical acidifi­cation defects were disclosed in stone patients with the ery­throcyte anomaly. In a family study, the abnormal erythro- cyte oxalate self-exchange appeared to be genetically deter­mined, segregating as a Mendelian autosomal dominant trait, although polygenic inheritance could not be excluded. However, a linkage analysis between the 17q21-qter loci, con­taining the AE1 gene and the abnormal oxalate self-exchange, in 2 of three-generation families with renal stones was negative. Thus, the suggested hypothesis is that the erythrocyte ox- alate self-exchange is an intermediate phenotype, possibly with a polygenic determination. Canadian Drugstore 


As discussed, the frequencies of dominant and recessive re­nal-stone-related conditions are uncommon to rare, reflecting the rarity of mutated genes producing them. In these disorders the inheritance of one or a couple of defective alleles is neces­sary and sufficient to induce the disease in the absence of any particular environmental factors. In polygenic diseases the indi­vidual genes by per se are not capable to cause the disease; but individual environmental factors are also incapable to de­termine the disease. However, individual genes and environ­mental factors, in various combinations, account for common types of calcium nephrolithiasis. We have already discussed that mutations of genes involved in monogenic disorders were not found in sporadic idiopathic stone formers. However, a pos­sible explanation is that some of candidate, and still unknown genes, have to be analyzed in this regard; alternatively, only a small subset of PH and ICN patients has a Mendelian disorder. Similar considerations suggest the possibility that mutations in the AE1 gene or in the ATP6B1 gene which have been de­scribed in recessive forms of dRTA are responsible for spo­radic PH and ICN. Subtle defects in renal acidification, and hypocitraturia, in some cases markers of mild form of dRTA, are too much frequently observed in idiopathic patients. On the contrary, familial dRTA, particularly the recessive forms, are extremely rare conditions.

An autosomal dominant inheritance has also been suggested in families with PH (both the absorp­tive and renal types) and calcium renal stone forming subjects.              However, since in as high as 55-60% of index cases (probands) no other case can be recognized in the family, un­der the hypothesis that hypercalciuria is an autosomal disorder it is very unlikely that a mutation occurs in 50% of hypercalci- uric subjects. That possibility would require a new mutation rate greater than observed in humans. On the other hand, by excluding probands from the analysis of these observations, the proportion of hypercalciuric siblings decreases to value as low as 10%, a proportion very far from expected in a case of an autosomal dominant inheritance. A polygenic model of in­heritance of renal stones was proposed by Resnick et al based on the observation that there is a higher proportion of af­fected younger siblings in which one of two oldest siblings is af­fected than when both are unaffected. Several Authors have al­ready noted that some of the quantitative traits encountered in idiopathic calcium stone formers have a normal distribution with no evidence for bimodal distribution; as observed for the renal phosphate threshold and hypophosphatemia and for cal- ciuria.

These findings suggest that the biochemical phenotypes encountered in PH and ICN are complex traits controlled by multiple factors (social, cultural, environmental, dietary, etc.), and multiple genes. The complexity of this apparently simple and clear statement is huge and generated by difficulties in dis­secting non-hereditary from hereditary factors. This is the real gamble in grasping complex diseases. The genetic component of complex, polygenic diseases as PH and ICN may become evident only through a careful control of non-hereditary factors. Dietary habits of stone formers compared with nonstone form­ers are very similar, indirectly suggesting that part of the variability in stone-related traits is genetically raised; moreover, investigation of a cohort of 101 normal subjects under self-se­lected, controlled and formula diets provided the development of a computer model showing that with only three genes a pat­tern of inheritance is generated, simulating the observed inheri­tance in ICN in the population and among relatives of stone for­mers. This certainly is an oversimplification, but it is a clear demonstration that the idiopathic renal stone disease is a poly- genic disorder. Indeed, we have no idea about the number of genes predisposing to hypercalciuria and calcium stone forma­tion. Furthermore, we do know neither whether among several genes one or few genes play a major role, nor whether differ­ent degrees of risk are associated with each locus. Larger population studies have to be performed, and environ­mental factors, particularly nutrients, have to be accurately evaluated together with complex genotyping in order to esta­blish their importance in masking/unmasking functional variants correlated to specific genetic background and to create more effective preventive strategies for PH and ICN. Accurate stan­dardized phenotype definitions are needed to add a more pow­erful statistical value to family-base studies. Comparative ge­netics will add informations on potentially interesting genes in humans once quantitative traits in animal models are identified. Great results are expected from development of new DNA mi- croarray and bioinformatic technologies not only for gene vari­ants detection, but also for “proteomic and metabolomic” as­pects of the pathogenesis of PH and ICN, providing new oppor­tunities to identify individuals at risk for these disorders and to develop new tailored therapies by newly designed clinical trial involving less genetically unselected individuals, creating also the opportunity of avoiding/reducing severe side effects.