Pediatric Nephrology

, Volume 34, Issue 4, pp 549–559 | Cite as

Renal phosphate handling and inherited disorders of phosphate reabsorption: an update

  • Carsten A. WagnerEmail author
  • Isabel Rubio-Aliaga
  • Nati Hernando


Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na+-dependent phosphate transporters located in the brush border membrane of the proximal tubule: NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Here we review new evidence for the role and relevance of these transporters in inherited disorders of renal phosphate handling. The importance of NaPi-IIa and NaPi-IIc for renal phosphate reabsorption and mineral homeostasis has been highlighted by the identification of mutations in these transporters in a subset of patients with infantile idiopathic hypercalcemia and patients with hereditary hypophosphatemic rickets with hypercalciuria. Both diseases are characterized by disturbed calcium homeostasis secondary to elevated 1,25-(OH)2 vitamin D3 as a consequence of hypophosphatemia. In vitro analysis of mutated NaPi-IIa or NaPi-IIc transporters suggests defective trafficking underlying disease in most cases. Monoallelic pathogenic mutations in both SLC34A1 and SLC34A3 appear to be very frequent in the general population and have been associated with kidney stones. Consistent with these findings, results from genome-wide association studies indicate that variants in SLC34A1 are associated with a higher risk to develop kidney stones and chronic kidney disease, but underlying mechanisms have not been addressed to date.


Proximal tubule Phosphate Nephrocalcinosis Nephrolithiasis FGF23 SLC34A1 SLC34A3 

Systemic phosphate balance depends on renal excretion

Phosphate is the third most abundant anion in the human body and accounts for about 1% of total body mass. Approximately 80–85% of total phosphate content is stored in bone in the form of apatite, contributing to bone stability, about 15% is distributed in soft tissues, and only 1% is contained in the rapidly exchangeable plasma pool.

Phosphate balance depends on dietary intake and intestinal absorption, distribution between organs, and renal filtration and reabsorption. As discussed below, it is mainly renal handling that is tightly regulated, thereby exerting ultimate control over whole body phosphate homeostasis. The recommended daily allowance (RDA) for phosphate is age-dependent, with infants recommended to receive daily about 100–275 mg and children and adolescents 460–1250 mg/day [1]. In growing children the phosphate balance should be positive to support building of bone and growth of soft tissues. In adults, intestinal net absorption and renal net excretion should ultimately remain zero to avoid phosphate overload or deficiency, respectively. However, in most industrialized countries the phosphate content of food exceeds the RDA [2, 3, 4].

The mechanisms underlying intestinal phosphate absorption are not fully elucidated. At present, experimental evidence from humans and animal models supports a bimodal pathway consisting of a transcellular, transporter-dependent pathway and a poorly defined paracellular route [5]. The transcellular route involves the sodium-driven phosphate transporter NaPi-IIb (Npt2b, SLC34A2), which is mostly expressed in the jejunum in humans [6, 7]. The expression of this transporter is regulated by dietary phosphate intake and 1,25 (OH)2 vitamin D3 [8, 9, 10]. However, its overall contribution to intestinal phosphate absorption may be low, at least under normal phosphate intake, as evident from mouse models deficient for NaPi-IIb/Slc34a2 and from humans with the rare inborn condition of pulmonary alveolar microlithiasis caused by loss-of-function mutations in SLC34A2/NaPi-IIb [8, 11, 12]. NaPi-IIb-depleted mice do not suffer from hypophosphatemia or any other obvious sign of systemic phosphate deficiency unless challenged with a low phosphate diet [8, 13, 14]. During low inorganic phosphate (Pi) availability, NaPi-IIb-deficient mice become highly hypercalciuric, at least in part due to increased osteoclast activity providing phosphate to the organism at the expense of bone density [14]. To date, no detailed analysis of phosphate balance has been reported in humans with SLC34A2 mutations. Two other phosphate transporters, PiT1 (SLC20A1) and PiT2 (SLC20A2), are also expressed in the small and large intestine at rather low levels, and their role and contribution to intestinal phosphate absorption are as yet unknown. Patients with mutations in SLC20A2 develop basal ganglia calcifications, but no other symptoms relating to systemic phosphate homeostasis have been reported [15].

Renal phosphate transporters

Renal phosphate excretion depends on the filtered load of phosphate and its subsequent reabsorption along the nephron. There is no evidence for active secretion of phosphate into urine. The bulk of tubular phosphate reabsorption occurs in the proximal tubule, with some evidence pointing also to a smaller component of active reabsorption in segments between the late proximal tubule and the connecting tubule [16].

In the proximal tubule, at least three different sodium-driven phosphate transporters mediate the initial step of phosphate reabsorption across the apical brush border membrane: NaPi-IIa (Npt2a, SLC34A1), NaPi-IIc (Npt2c, SLC34A3), and PiT2 (SLC20A2) (Fig. 1) [17, 18]. As discussed below, all evidence suggests that NaPi-IIa and NaPi-IIc play important roles in humans and rodent models, but possibly to different extent. The basolateral exit pathway for phosphate remains unknown but may involve a mechanism of anion exchange [19, 20]. Also, the molecular identity of potential phosphate transporter(s) in the more distal nephron segments has not been reported.
Fig. 1

Scheme of renal phosphate handling. a Renal phosphate reabsorption occurs mostly in the proximal segments of the nephron (orange). The segmental localization of all three known apical sodium-driven phosphate transporters is schematically shown in the nephron models. b Immunolocalization of NaPi-IIa (Npt2a, SLC34A1), NaPi-IIc (Npt2c, SLC34A3) and Pit-2 (SLC20A2) in rat kidney under phosphate-depleted conditions showing expression of NaPi-IIa in early and late segments of the proximal tubule, whereas NaPi-IIc and Pit-2 are localized only in the early proximal tubule. High magnification of early proximal tubules with NaPi-IIa, NaPi-IIc and Pit-2 stained in green, brush border membranes are marked in red, showing colocalization (yellow). Some NaPi-IIa molecules are also seen in intracellular compartments, presumably in the Golgi apparatus. c Model of a proximal tubule cell, with NaPi-IIa, NaPi-IIc, and Pit-2 localized in the brush border membrane, mediating sodium (Na+)-dependent reabsorption of phosphate. Phosphate reabsorption is mostly energized by the activity of basolateral Na+/K+-ATPases. The basolateral exit pathway for phosphate is not well defined

The three phosphate transporters expressed in the proximal tubule exhibit different transport modes, sensitivity to pH, and dynamics of regulation by dietary phosphate intake and phosphaturic hormones. Briefly, NaPi-IIa and NaPi-IIc transport divalent phosphate (HPO42−) whereas PiT2 prefers monovalent phosphate (H2PO4). Moreover, NaPi-IIa and PiT2 mediate the electrogenic transport of phosphate because of their coupling of the transport cycle to two or three sodium (Na+) ions, respectively, leading to the net translocation of one positive charge per phosphate ion. NaPi-IIc transports only two Na+ ions per phosphate and is therefore electroneutral (Fig. 1). Domains in NaPi-IIa and NaPi-IIc involved in sodium and phosphate binding have been identified [21].

Because of their different sensitivity to extracellular protons and preferred phosphate species (di- vs. monovalent phosphate), NaPi-IIa and NaPi-IIc operate most efficiently at a near neutral pH (~ pH 7.4–7.0), whereas PiT2 becomes more active at slightly more acidic conditions [18, 22].

Inherited forms of renal phosphate wasting

Renal phosphate wasting can occur as part of several systemic syndromes, generalized inherited or acquired dysfunction of the proximal tubule (e.g. Debre–DeToni–Fanconi syndrome), and in a number of inherited disorders specifically affecting renal and extrarenal phosphate homeostasis (for review see [23, 24]). Most inherited extrarenal disorders leading to changes in renal phosphate handling are caused by mutations in fibroblast growth factor 23 (FGF23) or factors controlling FGF23 levels or in the sensitivity of target cells. Thus, disorders such as X-linked hypophosphatemia (XLH; PHEX mutations), autosomal dominant hypophosphatemic rickets (ADHR; FGF23 mutations), familial tumoral calcinosis (FTC; GALNT3 or FGF23 mutations), fibrous dysplasia (McCune–Albright syndrome; GNAS mutations), osteoglophonic dysplasia [FGF-receptor 1 (FGFR1) mutations], osteosclerotic bone dysplasia (Raine syndrome; FAM20c mutations), or autosomal recessive hypophosphatemic rickets (ARHR; DMP1 or ENPP1 mutations), also known as autosomal recessive hypophosphatemia (ARHP), are primarily extrarenal disorders affecting renal phosphate handling [23, 24, 25, 26].

In contrast, mutations in NaPi-IIa, NaPi-IIc and maybe also in NHERF1 (Na/H exchanger factor 1) directly affect the renal capacity to reabsorb phosphate. The roles of two other proteins potentially involved in renal phosphate handling, PiT2 and XPR1, are currently unclear even though mutations in the genes of both proteins have been described in patients. .

Mutations in SLC34A1 and SLC34A3 cause nephrocalcinosis and kidney stones. The pathogenesis of nephrocalcinosis in the setting of various inherited and acquired kidney diseases has recently been reviewed in much detail [27, 28, 29, 30]. The pathophysiology underlying nephrocalcinosis in patients with mutations in SLC34A1 and SLC34A3 is thought to be caused by the primary loss of phosphate with urine and the consecutive stimulation of 1,25 (OH)2 vitamin D3 synthesis leading to enhanced intestinal calcium absorption and calcium overload. Renal excretion of calcium causes hypercalciuria, which together with elevated urinary phosphate levels can trigger the formation of calcium-phosphate containing crystals favoring the development of renal calcifications.

NaPi-IIa (SLC34A1)

SLC34A1 has been linked to phosphate homeostasis in humans by several lines of evidence. A genome-wide association study (GWAS) for determinants of serum phosphate levels identified SLC34A1 among other genes, including FGF23 and the calcium-sensing receptor CaSR [31]. Similarly, a GWAS for nephrolithiasis in a sample from the adult Japanese population linked a region near 5q35.3, implicating SLC34A1 (located at this site) in calcium phosphate kidney stone disease [32, 33, 34]. Also, the Icelandic genome analysis consortium identified SLC34A1 next to the CaSR and alkaline phosphatase as a risk gene for kidney stones and identified one specific marker within SLC34A1 as being associated with hypophosphatemia and low parathyroid hormone (PTH) levels [35].

Homozygous and (compound) heterozygous mutations or small insertions and deletions in SLC34A1 were independently identified by several laboratories when investigating adult patients with kidney stones and reduced bone density [36] or pediatric patients with either hypophosphatemia and hyperphosphaturia [37], infantile idiopathic hypercalciuria [38], or with nephrocalcinosis and kidney stones [35, 39, 40, 41, 42, 43, 44]. Larger deletions including the SLC34A1 gene can occur as part of Sotos syndrome, which is characterized by learning deficiencies, facial dysmorphia, overgrowth, hypercalcemia, and nephrocalcinosis [45].

To date, 29 distinct mutations have been identified in SLC34A1, most of which cause missense mutations, small in-frame deletions, frameshifts, or early stop codons, resulting in a truncated transporter [Fig. 2a; Electronic Supplementary Material (ESM) Table 1] [35, 36, 37, 39, 40, 41, 42, 44, 46]. Interestingly, most of these mutations appear to be located within regions predicted to be part of the transmembrane domains of the transporter. These regions are often highly conserved in transport proteins and are more sensitive to changes in their structure. Several of these mutated proteins were expressed and functionally analyzed in heterologous expression systems, such as Xenopus oocytes or the opossum kidney (OK) cell line resembling the proximal tubule. Collectively, these studies show reduced function of mutated transporters, mostly due to trafficking defects, with mutant proteins being retained intracellularly [37, 38, 41]. However, one mutation is of particular interest: a small in-frame deletion of seven amino acids at the N-terminus of NaPi-IIa (91del7) was identified in several patients as either one of two mutated alleles (compound heterozygous patients) or as homozygous mutation in at least one patient [38]. All of these patients showed symptoms similar to patients with other pathogenic mutations, suggesting that this mutation is deleterious. However, in vitro analysis in Xenopus oocytes showed no obvious transport defect [38, 47] whereas expression of the mutant protein in OK cells suggested reduced apical expression and partial retention, pointing to a possible trafficking defect [38]. Interestingly, inspection of public data bases like the ExAC revealed a high allele frequency of 0.018, suggesting that approximately 2% of the general population are heterozygous carriers of this mutation. The combined allele frequency of all proven pathogenic exonic mutations is 0.022, whereas the total allele frequency of all nucleotide changes leading to an altered amino acid sequence adds up to 0.07. The relevance of this finding is currently unclear but may link to an increased risk of developing calcium phosphate kidney stones in adulthood.
Fig. 2

Predicted models of NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) and localization of mutations identified in patients. For details on mutations and references see tables in the Electronic Supplementary Material

In pediatric patients, SLC34A1 mutations have been found to be mostly homozygous or compound heterozygous and the pattern of inheritance to be autosomal recessive. In one study no obvious pathology was detected in parents or other family members carrying only one affected allele. In contrast, three adult patients were described with only one allele mutated and presenting with calcium phosphate stones and reduced bone density [36]. However, no further genetic information was available and considering the relatively high frequency of stone disease and its association with reduced bone density in the adult population, it remains unclear whether the symptoms in these patients were caused by SLC34A1 mutations. Moreover, detailed functional analysis of the two reported gene variants yielded no obvious defect [48]. Also, in other families of affected homozygous patients, heterozygous carriers did not present with a high frequency of kidney stones, suggesting that heterozygosity per se may not cause a higher risk for kidney stones [37]. However, results from GWAS clearly support a role of SLC34A1 in stone disease [32, 33, 35]. NaPi-IIa interacts with itself by forming homodimers of two transporters [49]. Both subunits function independently in the healthy state [50]. It is unknown at which cellular level the interaction occurs (e.g., at the level of the endoplasmic reticulum, Golgi, or plasma membrane) and whether the interaction of a normal transporter with a mutant transporter may accelerate degradation or reduce membrane insertion. Interactions between a normal and mutant transporter could reduce overall NaPi-IIa expression by up to 75% and thereby help explain some of the clinical observations made in heterozygous carriers of NaPi-IIa mutations. Thus, it remains to be examined whether additional genetic or environmental factors together with the presence of one mutated allele may cause a higher risk for kidney stone disease.

Indeed, a mouse model of Slc34a1 deficiency presents calcium phosphate and calcium oxalate containing renal calcifications when challenged with high phosphate or oxalate diets [51, 52]. Slc34a1 knockout (KO) mice, similar to human patients with SLC34A1 mutations, are hypercalciuric [38, 53]. The renal loss of phosphate stimulates activation of 1,25(OH)2 vitamin D3 by the renal 1-alpha-hydroxylase (CYP27B1) and reduces inactivation by the 24-hydroxylase (CYP24A1). The elevated levels of 1,25(OH)2 vitamin D3 stimulate intestinal phosphate and calcium absorption. Calcium is excreted by the kidney, causing hypercalcuria and an increased risk of nephrolithiasis and nephrocalcinosis. Consistently, restricted 1,25(OH)2 vitamin D3 synthesis (or lower vitamin D3 supply) and enhanced phosphate supplementation reduces renal calcifications [54]. Thus, children with SLC34A1 mutations likely benefit from phosphate supplements and should not receive standard vitamin D3 supplements during the first years of life. Whether the mutation of one allele is sufficient to trigger a similar mechanism is currently unknown but may depend, among other factors, on dietary supply of vitamin D3, phosphate, and calcium.

NaPi-IIc (SLC34A3)

Mutations in SLC34A3 are the cause of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) [55, 56, 57]. In contrast to patients with mutations in SLC34A1, rickets is a common feature together with hypophosphatemia, hyperphosphaturia, hypercalciuria, and elevated 1,25(OH)2 vitamin D3. Consequently, many patients develop kidney stones or nephrocalcinosis. It appears that the problems experienced by patients with mutations in SLC34A3 persist into adulthood, whereas the clinical symptoms in patients with SLC34A1 mutations may improve with reaching adulthood. This difference suggests that NaPi-IIa may play a more prominent role in earlier phases of life and that NaPi-IIc may be the more important transporter in the adult kidney (in contrast to rodents where NaPiIIc appears to be mostly expressed during growth). However, this hypothesis is based only on few observations, and longer follow-ups are required in patients with the different mutations for any definitive conclusion to be reached.

To date, 32 different mutations in SLC34A3 have been reported [55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70], including mostly missense mutations, mutations affecting potential splice sites, and smaller and larger deletions causing premature stop codons with expression of a truncated transporter (Fig. 2b; ESM Table 2). Some of these mutations have been further characterized using in vitro expression systems and found to cause mostly retention of NaPi-IIc in the endoplasmic reticulum, but also to reduce its stability in the plasma membrane or to decrease its transport activity [57, 58, 62], similar to findings for SLC34A1 mutations. Proven pathogenic SLC34A3 mutations (allele frequency 0.002) are less frequent in the general population than are those for SLC34A1. However, when suspected mutations are considered (e.g., without clear genetic or experimental proof), total allele frequency increases to 1.5, but mostly due to two very frequent allele variants with nearly 0.4 and 0.8 allele frequency, respectively. At this point in time, the relevance of NaPi-IIc activity is unclear, and better genetic and experimental evidence is needed to provide insights into whether these alleles may contribute to an increased risk to develop kidney stones as discussed above for SLC34A1.

Different mouse models of NaPi-IIc deficiency have been created to further examine the role of the transporter and to gain better insights into the pathology of HHRH. A constitutive Slc34a3 KO mouse model showed normal growth and no evidence for renal phosphate losses, was normophosphatemic, and had normal bone growth and morphology [71]. However, NaPi-IIc KO mice had hypercalcemia, hypercalciuria, and high levels of 1,25(OH)2 vitamin D3, whereas the FGF23 level was reduced [71]. A second mouse model with an inducible deletion of renal NaPi-IIc was generated to examine whether acute or chronic compensatory mechanisms may mask some of the expected pathology in the constitutive KO mouse. Surprisingly, inducible NaPi-IIc KO mice showed no biochemical abnormalities and had similar levels of calcium in the plasma and urine as well as normal levels of 1,25(OH)2 vitamin D3 and FGF23. No evidence for compensation by other renal phosphate transporters, i.e., NaPi-IIa or PiT2, was found [72].


NHERF1, also known as PDZK3 or binding protein 50 (EBP50), is encoded by the SLC9A3R1 gene and acts as a scaffold protein for brush border membrane-associated proteins in the proximal tubule. Among its binding partners are NaPi-IIa, the PTH receptor 1, and phospholipase C [73, 74, 75, 76, 77, 78]. NHERF1 stabilizes these proteins at the brush border membrane and creates a platform for PTH signaling to NaPi-IIa [73, 74, 78, 79, 80]. Prie and colleagues reported that eight patients with hyperphosphaturia and kidney stone disease carried heterozygous gene variants in NHERF1 [81, 82]. Expression of the L110 V, R153Q, and E225K gene variants in cell culture models was found to increase PTH-responsive downregulation of NaPi-IIa [81]. The E68A variant was reported to disrupt the interaction with NaPi-IIa, possibly leading to destabilization of the transporter at the brush border membrane [82]. Of note, all patients were only heterozygous carriers of the reported variants and, as noted by others, the same gene variants are found at high frequency in public databases, raising the question of whether the observed gene variants are causative for disease [83]. Also, mice lacking only one copy of NHERF1 show no major abnormalities [78, 80].

Other renal phosphate transporters

The kidney expresses at least two additional proteins that may also participate in renal phosphate transport: PiT2 (SLC20A2) and XPR1 (xenotropic and polytropic retrovirus receptor 1).


The expression and localization of PiT2 has been described in some detail in the rodent kidney. PiT2 localizes to the brush border membrane of the proximal tubule, colocalizing with NaPi-IIa and NaPi-IIc [84, 85]. More recently, a subset of patients with familial idiopathic basal ganglia calcification, a specific form of primary brain calcifications, was shown to harbor mutations in SLC20A2 [15, 86]. However, while other defects have been observed, no renal phenotype or disorders related to phosphate homeostasis have been reported to date. Thus, the role of SLC20A2 in renal phosphate handling and inherited disorders of mineral balance remains to be examined.


XPR1 has been linked to phosphate transport based on its homology to plant and yeast phosphate transporters, on harboring an SPX domain found in various plants, yeast, and bacterial proteins involved in cellular phosphate homeostasis, and on the modulation of phosphate efflux from plant and mammalian cells with XPR1 deficiency or overexpression [87, 88]. It has been suggested that XPR1 may be part of the long-sought basolateral efflux pathway in epithelial cells of the kidney and small intestine and/or may participate in cellular phosphate sensing [89]. Indeed, XPR1 mRNA expression is high in the kidney and small intestine of rodents. However, definite proof is lacking regarding the basolateral expression of XPR1 in the kidney and intestinal epithelia, as well as its implication in the actual transport pathway and/or cellular phosphate sensing in mammalian cells. The data presented to date clearly support a role in cellular phosphate homeostasis, but the conclusions drawn are mostly based on experiments from plant cells, yeast, or prokaryotic systems. Interestingly, mutations in XPR1 are also found in some patients with familial idiopathic basal ganglia calcification [90, 91]. However a renal involvement has not been reported to date. A recent study with an inducible kidney-specific Xpr1 KO mouse demonstrated a very severe disease with symptoms of a generalized proximal tubular defect, mild hypophosphatemia, and bone disease [92]. However, the study did not provide definite answers to the question of whether XPR1 is part of the basolateral phosphate efflux pathway.


Patients from two consanguineous families were reported that presented with hypophosphatemic rickets and renal phosphate wasting in the one family and with a generalized proximal tubulopathy, including hypercalciuria and only mildly increased urinary phosphate excretion, in the second family [93]. Genetic analysis revealed two novel homozygous mutations, IVS4-2A > G and R124S, in the SLC2A2 gene encoding the GLUT2 glucose transporter. GLUT2 is localized at the basolateral side of proximal tubule cells and serves as the main exit pathway for glucose. Mutations in SLC2A2 are the cause of Fanconi–Bickel syndrome, which includes a generalized dysfunction of proximal tubule cells with urinary loss of low molecular weight proteins, bicarbonate, glucose, and phosphate [94, 95]. Of interest, mice lacking Glut2 in the kidney showed greatly reduced expression levels of NaPiIIa and NaPiIIc, which explains, at least in part, the urinary phosphate loss [93]. Thus, mutations of genes such as those that affect the general function of the proximal tubule may also cause renal phosphate losses, as in Dent’s disease, due to mutations in chloride voltage-gated channel 5 (CLCN5) or ORCL (Oculocerebrorenal Syndrome of Lowe) [96, 97].

Relevance of SLC34A1 for chronic kidney disease

Genome-wide association studies have linked SLC34A1 to the risk for developing chronic kidney disease (CKD) [98, 99]. This association has been replicated in large cohorts with different ethnic background and shows a very high significance [100, 101]. Progression of kidney disease has been shown to associate with reduced SLC34A1 mRNA and protein expression in human kidney biopsies [102]. However, whether the reduced SLC34A1 is the cause or consequence of kidney disease remains unclear. Detailed functional analysis of the genetic loci linking SLC34A1 to CKD risk and development in suitable animal models may be needed to unravel the nature of this association. Also, the frequency of single nucleotide polymorphisms in the general population and in patients with CKD has to be examined to determine the relevance of SLC34A1 for CKD. Nevertheless, the fact that rare pathogenic mutations in SLC34A1 cause nephrocalcinosis and progressive loss of renal function, at least in some patients, may suggest that less severe alterations in SLC34A1 function may contribute to a slower loss of kidney function in adults.

Summary and outlook

The kidney is the gate-keeper of systemic phosphate homeostasis, and the severe alterations in mineral homeostasis found in patients with mutations in key players of renal phosphate handling underline this notion. Biallelic mutations in the coding regions of the renal phosphate transporter genes SLC34A1 (NaPi-IIa) and SLC34A3 (NaPi-IIc) cause massive renal phosphate loss leading to secondary elevation of 1,25(OH)2 vitamin D3 and hypercalciuria, driving the development of nephrolithiasis or nephrocalcinosis predisposing to progressive loss of renal function. Surprisingly, monoallelic pathogenic mutations in SLC34A1 and SLC34A3 are relatively frequent in the general population. Whether carriers of these mutations may have a higher risk for developing kidney stones remains to be fully established. Moreover, SLC34A1 is associated with the risk for developing CKD in the general population, but the mechanisms and its relevance to overall CKD risk remain to be examined.



This work has been supported by the ERA-Net E-Rare Research Programme for Rare Diseases (IIH-ECC) and by the Swiss National Science Foundation supported National Center for Competence in Research NCCR Kidney.CH to C.A.W.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

467_2017_3873_MOESM1_ESM.pdf (199 kb)
ESM 1 (PDF 199 kb)


  1. 1.
    Standing Committee on the Scientific Evaluation of Dietary Reference Intakes FaNB, Institute of Medicine (1997) Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. National Academies Press (US), Washington DCGoogle Scholar
  2. 2.
    Calvo MS, Uribarri J (2013) Public health impact of dietary phosphorus excess on bone and cardiovascular health in the general population. Am J Clin Nutr 98:6–15PubMedGoogle Scholar
  3. 3.
    Dhingra R, Sullivan LM, Fox CS, Wang TJ, D’Agostino RB Sr, Gaziano JM, Vasan RS (2007) Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 167:879–885PubMedGoogle Scholar
  4. 4.
    Chang AR, Lazo M, Appel LJ, Gutierrez OM, Grams ME (2014) High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III. Am J Clin Nutr 99:320–327PubMedGoogle Scholar
  5. 5.
    Christakos S, Lieben L, Masuyama R, Carmeliet G (2014) Vitamin D endocrine system and the intestine. Bonekey Rep 3:496PubMedPubMedCentralGoogle Scholar
  6. 6.
    Walton J, Gray TK (1979) Absorption of inorganic phosphate in the human small intestine. Clin Sci (Lond) 56:407–412Google Scholar
  7. 7.
    Nishimura M, Naito S (2008) Tissue-specific mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab Pharmacokinet 23:22–44PubMedGoogle Scholar
  8. 8.
    Hernando N, Myakala K, Simona F, Knopfel T, Thomas L, Murer H, Wagner CA, Biber J (2015) Intestinal depletion of NaPi-IIb/Slc34a2 in mice: renal and hormonal adaptation. J Bone Miner Res 30:1925–1937PubMedGoogle Scholar
  9. 9.
    Radanovic T, Wagner CA, Murer H, Biber J (2005) Regulation of intestinal phosphate transport. I. Segmental expression and adaptation to low-P(i) diet of the type IIb Na(+)-P(i) cotransporter in mouse small intestine. Am J Physiol Gastrointest Liver Physiol 288:G496–G500PubMedGoogle Scholar
  10. 10.
    Capuano P, Radanovic T, Wagner CA, Bacic D, Kato S, Uchiyama Y, St-Arnoud R, Murer H, Biber J (2005) Intestinal and renal adaptation to a low-pi diet of type II NaPi cotransporters in vitamin D receptor- and 1alphaOHase-deficient mice. Am J Physiol Cell Physiol 288:C429–C434PubMedGoogle Scholar
  11. 11.
    Ferreira Francisco FA, Pereira e Silva JL, Hochhegger B, Zanetti G, Marchiori E (2013) Pulmonary alveolar microlithiasis. State-of-the-art review. Respir Med 107:1–9PubMedGoogle Scholar
  12. 12.
    Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U, Calisir H, Yildirim Z, Gocmen A, Tolun A (2006) Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet 79:650–656PubMedPubMedCentralGoogle Scholar
  13. 13.
    Sabbagh Y, O’Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, Schiavi SC (2009) Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol 20:2348–2358PubMedPubMedCentralGoogle Scholar
  14. 14.
    Knopfel T, Pastor-Arroyo EM, Schnitzbauer U, Kratschmar DV, Odermatt A, Pellegrini G, Hernando N, Wagner CA (2017) The intestinal phosphate transporter NaPi-IIb (Slc34a2) is required to protect bone during dietary phosphate restriction. Sci Rep 7:11018PubMedPubMedCentralGoogle Scholar
  15. 15.
    Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, de Oliveira JR, Sobrido MJ, Quintans B, Baquero M, Cui X, Zhang XY, Wang L, Xu H, Wang J, Yao J, Dai X, Liu J, Zhang L, Ma H, Gao Y, Ma X, Feng S, Liu M, Wang QK, Forster IC, Zhang X, Liu JY (2012) Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 44:254–256PubMedGoogle Scholar
  16. 16.
    Blaine J, Chonchol M, Levi M (2015) Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol 10:1257–1272PubMedGoogle Scholar
  17. 17.
    Biber J, Hernando N, Forster I (2013) Phosphate transporters and their function. Annu Rev Physiol 75:535–550PubMedGoogle Scholar
  18. 18.
    Wagner CA, Hernando N, Forster IC, Biber J (2014) The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch 466:139–153PubMedGoogle Scholar
  19. 19.
    Reshkin SJ, Forgo J, Biber J, Murer H (1991) Functional asymmetry of phosphate transport and its regulation in opossum kidney cells: phosphate "adaptation". Pflugers Arch 419:256–262PubMedGoogle Scholar
  20. 20.
    Reshkin SJ, Forgo J, Murer H (1990) Functional asymmetry of phosphate transport and its regulation in opossum kidney cells: phosphate transport. Pflugers Arch 416:554–560PubMedGoogle Scholar
  21. 21.
    Fenollar-Ferrer C, Patti M, Knöpfel T, Werner A, Forster IC, Forrest LR (2014) Structural fold and binding sites of the human Na+−phosphate cotransporter NaPi-II. Biophys J 106:1268–1279PubMedPubMedCentralGoogle Scholar
  22. 22.
    Forster IC, Hernando N, Biber J, Murer H (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol Asp Med 34:386–395Google Scholar
  23. 23.
    Wagner CA, Rubio-Aliaga I, Biber J, Hernando N (2014) Genetic diseases of renal phosphate handling. Nephrol Dial Transplant 29[Suppl 4]:iv45–iv54PubMedGoogle Scholar
  24. 24.
    Bergwitz C, Juppner H (2012) FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol 728:41–64PubMedPubMedCentralGoogle Scholar
  25. 25.
    Bergwitz C, Juppner H (2009) Disorders of phosphate homeostasis and tissue mineralisation. Endocr Dev 16:133–156PubMedGoogle Scholar
  26. 26.
    Clinkenbeard EL, White KE (2017) Heritable and acquired disorders of phosphate metabolism: etiologies involving FGF23 and current therapeutics. Bone 102:31–39PubMedPubMedCentralGoogle Scholar
  27. 27.
    Shavit L, Jaeger P, Unwin RJ (2015) What is nephrocalcinosis? Kidney Int 88:35–43PubMedGoogle Scholar
  28. 28.
    Coe FL, Worcester EM, Evan AP (2016) Idiopathic hypercalciuria and formation of calcium renal stones. Nat Rev Nephrol 12:519–533PubMedPubMedCentralGoogle Scholar
  29. 29.
    Mulay SR, Anders HJ (2016) Crystallopathies. N Engl J Med 374:2465–2476PubMedGoogle Scholar
  30. 30.
    Oliveira B, Kleta R, Bockenhauer D, Walsh SB (2016) Genetic, pathophysiological, and clinical aspects of nephrocalcinosis. Am J Physiol Renal Physiol 311:F1243–F1252PubMedGoogle Scholar
  31. 31.
    Kestenbaum B, Glazer NL, Kottgen A, Felix JF, Hwang SJ, Liu Y, Lohman K, Kritchevsky SB, Hausman DB, Petersen AK, Gieger C, Ried JS, Meitinger T, Strom TM, Wichmann HE, Campbell H, Hayward C, Rudan I, de Boer IH, Psaty BM, Rice KM, Chen YD, Li M, Arking DE, Boerwinkle E, Coresh J, Yang Q, Levy D, van Rooij FJ, Dehghan A, Rivadeneira F, Uitterlinden AG, Hofman A, van Duijn CM, Shlipak MG, Kao WH, Witteman JC, Siscovick DS, Fox CS (2010) Common genetic variants associate with serum phosphorus concentration. J Am Soc Nephrol 21:1223–1232PubMedPubMedCentralGoogle Scholar
  32. 32.
    Yasui T, Okada A, Urabe Y, Usami M, Mizuno K, Kubota Y, Tozawa K, Sasaki S, Higashi Y, Sato Y, Kubo M, Nakamura Y, Matsuda K, Kohri K (2013) A replication study for three nephrolithiasis loci at 5q35.3, 7p14.3 and 13q14.1 in the Japanese population. J Hum Genet 58:588–593PubMedGoogle Scholar
  33. 33.
    Urabe Y, Tanikawa C, Takahashi A, Okada Y, Morizono T, Tsunoda T, Kamatani N, Kohri K, Chayama K, Kubo M, Nakamura Y, Matsuda K (2012) A genome-wide association study of nephrolithiasis in the Japanese population identifies novel susceptible loci at 5q35.3, 7p14.3, and 13q14.1. PLoS Genet 8:e1002541PubMedPubMedCentralGoogle Scholar
  34. 34.
    Monico CG, Milliner DS (2012) Genetic determinants of urolithiasis. Nat Rev Nephrol 8:151–162Google Scholar
  35. 35.
    Oddsson A, Sulem P, Helgason H, Edvardsson VO, Thorleifsson G, Sveinbjornsson G, Haraldsdottir E, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Masson G, Holm H, Gudbjartsson DF, Thorsteinsdottir U, Indridason OS, Palsson R, Stefansson K (2015) Common and rare variants associated with kidney stones and biochemical traits. Nat Commun 6:7975PubMedPubMedCentralGoogle Scholar
  36. 36.
    Prie D, Huart V, Bakouh N, Planelles G, Dellis O, Gerard B, Hulin P, Benque-Blanchet F, Silve C, Grandchamp B, Friedlander G (2002) Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med 347:983–991PubMedGoogle Scholar
  37. 37.
    Rajagopal A, Debora B, James TL, Soledad K, Florencia C, Hamilton C, David L, Jose Miguel L, Graciela V, Ignacio B, Richard G, Campeau P, Lee B (2014) Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis. J Clin Endocrinol Metab 99(11):E2451–E2456PubMedPubMedCentralGoogle Scholar
  38. 38.
    Schlingmann KP, Ruminska J, Kaufmann M, Dursun I, Patti M, Kranz B, Pronicka E, Ciara E, Akcay T, Bulus D, Cornelissen EA, Gawlik A, Sikora P, Patzer L, Galiano M, Boyadzhiev V, Dumic M, Vivante A, Kleta R, Dekel B, Levtchenko E, Bindels RJ, Rust S, Forster IC, Hernando N, Jones G, Wagner CA, Konrad M (2016) Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate Cotransporter 2A cause idiopathic infantile Hypercalcemia. J Am Soc Nephrol 27:604–614PubMedGoogle Scholar
  39. 39.
    Braun DA, Lawson JA, Gee HY, Halbritter J, Shril S, Tan W, Stein D, Wassner AJ, Ferguson MA, Gucev Z, Fisher B, Spaneas L, Varner J, Sayer JA, Milosevic D, Baum M, Tasic V, Hildebrandt F (2016) Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. Clin J Am Soc Nephrol 11:664–672PubMedPubMedCentralGoogle Scholar
  40. 40.
    Halbritter J, Baum M, Hynes AM, Rice SJ, Thwaites DT, Gucev ZS, Fisher B, Spaneas L, Porath JD, Braun DA, Wassner AJ, Nelson CP, Tasic V, Sayer JA, Hildebrandt F (2015) Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol 26:543–551PubMedGoogle Scholar
  41. 41.
    Dinour D, Davidovits M, Ganon L, Ruminska J, Forster IC, Hernando N, Eyal E, Holtzman EJ, Wagner CA (2016) Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency. Pediatr Nephrol 31:2289–2297PubMedGoogle Scholar
  42. 42.
    Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, Selig S, Lapointe JY, Zelikovic I, Skorecki K (2010) A loss-of-function mutation in NaPi-IIa and renal Fanconi’s syndrome. N Engl J Med 362:1102–1109PubMedGoogle Scholar
  43. 43.
    Demir K, Yildiz M, Bahat H, Goldman M, Hassan N, Tzur S, Ofir A, Magen D (2017) Clinical heterogeneity and phenotypic expansion of NaPi-IIa-associated disease. J Clin Endocrinol Metab 102:4604–4614PubMedGoogle Scholar
  44. 44.
    Daga A, Majmundar AJ, Braun DA, Gee HY, Lawson JA, Shril S, Jobst-Schwan T, Vivante A, Schapiro D, Tan W, Warejko JK, Widmeier E, Nelson CP, Fathy HM, Gucev Z, Soliman NA, Hashmi S, Halbritter J, Halty M, Kari JA, El-Desoky S, Ferguson MA, Somers MJG, Traum AZ, Stein DR, Daouk GH, Rodig NM, Katz A, Hanna C, Schwaderer AL, Sayer JA, Wassner AJ, Mane S, Lifton RP, Milosevic D, Tasic V, Baum MA, Hildebrandt F (2017) Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney Int.
  45. 45.
    Kenny J, Lees MM, Drury S, Barnicoat A, Van’t Hoff W, Palmer R, Morrogh D, Waters JJ, Lench NJ, Bockenhauer D (2011) Sotos syndrome, infantile hypercalcemia, and nephrocalcinosis: a contiguous gene syndrome. Pediatr Nephrol 26:1331–1334PubMedGoogle Scholar
  46. 46.
    Pronicka E, Ciara E, Halat P, Janiec A, Wojcik M, Rowinska E, Rokicki D, Pludowski P, Wojciechowska E, Wierzbicka A, Ksiazyk JB, Jacoszek A, Konrad M, Schlingmann KP, Litwin M (2017) Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases. J Appl Genet 58:349–353PubMedPubMedCentralGoogle Scholar
  47. 47.
    Lapointe J-Y, Tessier J, Paquette Y, Wallendorff B, Coady M, Pichette V, Bonnardeaux A (2006) NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int 69:2261–2267PubMedGoogle Scholar
  48. 48.
    Virkki LV, Forster IC, Hernando N, Biber J, Murer H (2003) Functional characterization of two naturally occurring mutations in the human sodium-phosphate cotransporter type IIa. J Bone Miner Res 18:2135–2141PubMedGoogle Scholar
  49. 49.
    Gisler SM, Kittanakom S, Fuster D, Wong V, Bertic M, Radanovic T, Hall RA, Murer H, Biber J, Markovich D, Moe OW, Stagljar I (2008) Monitoring protein-protein interactions between the mammalian integral membrane transporters and PDZ-interacting partners using a modified split-ubiquitin membrane yeast two-hybrid system. Mol Cell Proteomics 7:1362–1377PubMedPubMedCentralGoogle Scholar
  50. 50.
    Köhler K, Forster IC, Lambert G, Biber J, Murer H (2000) The functional unit of the renal type IIa Na+/Pi cotransporter is a monomer. J Biol Chem 275:26113–26120PubMedGoogle Scholar
  51. 51.
    Khan SR, Glenton PA (2008) Calcium oxalate crystal deposition in kidneys of hypercalciuric mice with disrupted type IIa sodium-phosphate cotransporter. Am J Physiol Renal Physiol 294:F1109–F1115PubMedPubMedCentralGoogle Scholar
  52. 52.
    Chau H, El-Maadawy S, McKee MD, Tenenhouse HS (2003) Renal calcification in mice homozygous for the disrupted type IIa Na/pi cotransporter gene Npt2. J Bone Miner Res 18:644–657PubMedGoogle Scholar
  53. 53.
    Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS (1998) Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci USA 95:5372–5377PubMedGoogle Scholar
  54. 54.
    Tenenhouse HS, Gauthier C, Chau H, St-Arnaud R (2004) 1alpha-Hydroxylase gene ablation and pi supplementation inhibit renal calcification in mice homozygous for the disrupted Npt2a gene. Am J Physiol Renal Physiol 286:F675–F681PubMedGoogle Scholar
  55. 55.
    Dasgupta D, Wee MJ, Reyes M, Li Y, Simm PJ, Sharma A, Schlingmann KP, Janner M, Biggin A, Lazier J, Gessner M, Chrysis D, Tuchman S, Baluarte HJ, Levine MA, Tiosano D, Insogna K, Hanley DA, Carpenter TO, Ichikawa S, Hoppe B, Konrad M, Savendahl L, Munns CF, Lee H, Juppner H, Bergwitz C (2014) Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. J Am Soc Nephrol 25:2366–2375PubMedPubMedCentralGoogle Scholar
  56. 56.
    Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, Gershoni-Baruch R, Albers N, Lichtner P, Schnabel D, Hochberg Z, Strom TM (2006) Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet 78:193–201PubMedGoogle Scholar
  57. 57.
    Bergwitz C, Roslin, N M, Tieder, M, Loredo-Osti, J C, Bastepe, M, Abu-Zahra, H, Frappier, D, Burkett, K, Carpenter, T. O, Anderson, D, Garabedian, M, Sermet, I, Fujiwara, T M, Morgan, K, Tenenhouse, H S, Juppner, H (2006) SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaP(i)-IIc in maintaining phosphate homeostasis. Am J Hum Genet 78:179-192Google Scholar
  58. 58.
    Jaureguiberry G, Carpenter TO, Forman S, Juppner H, Bergwitz C (2008) A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc. Am J Physiol Renal Physiol 295:F371–F379PubMedPubMedCentralGoogle Scholar
  59. 59.
    Page K, Bergwitz C, Jaureguiberry G, Harinarayan CV, Insogna K (2008) A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3. Endocr Pract 14:869–874PubMedPubMedCentralGoogle Scholar
  60. 60.
    Abe Y, Nagasaki K, Watanabe T, Abe T, Fukami M (2014) Association between compound heterozygous mutations of SLC34A3 and hypercalciuria. Horm Res Paediatr 82:65–71PubMedGoogle Scholar
  61. 61.
    Mejia-Gaviria N, Gil-Pena H, Coto E, Perez-Menendez TM, Santos F (2010) Genetic and clinical peculiarities in a new family with hereditary hypophosphatemic rickets with hypercalciuria: a case report. Orphanet J Rare Dis 5:1PubMedPubMedCentralGoogle Scholar
  62. 62.
    Haito-Sugino S, Ito M, Ohi A, Shiozaki Y, Kangawa N, Nishiyama T, Aranami F, Sasaki S, Mori A, Kido S, Tatsumi S, Segawa H, Miyamoto K (2012) Processing and stability of type IIc sodium-dependent phosphate cotransporter mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria. Am J Physiol Cell Physiol 302:C1316–C1330PubMedGoogle Scholar
  63. 63.
    Phulwani P, Bergwitz C, Jaureguiberry G, Rasoulpour M, Estrada E (2011) Hereditary hypophosphatemic rickets with hypercalciuria and nephrolithiasis-identification of a novel SLC34A3/NaPi-IIc mutation. Am J Med Genet A 155A:626–633PubMedGoogle Scholar
  64. 64.
    Braithwaite V, Pettifor JM, Prentice A (2013) Novel SLC34A3 mutation causing hereditary hypophosphataemic rickets with hypercalciuria in a Gambian family. Bone 53:216–220PubMedPubMedCentralGoogle Scholar
  65. 65.
    Tencza AL, Ichikawa S, Dang A, Kenagy D, McCarthy E, Econs MJ, Levine MA (2009) Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis. J Clin Endocrinol Metab 94:4433–4438PubMedPubMedCentralGoogle Scholar
  66. 66.
    Yu Y, Sanderson SR, Reyes M, Sharma A, Dunbar N, Srivastava T, Juppner H, Bergwitz C (2012) Novel NaPi-IIc mutations causing HHRH and idiopathic hypercalciuria in several unrelated families: long-term follow-up in one kindred. Bone 50:1100–1106PubMedPubMedCentralGoogle Scholar
  67. 67.
    Chi Y, Zhao Z, He X, Sun Y, Jiang Y, Li M, Wang O, Xing X, Sun AY, Zhou X, Meng X, Xia W (2014) A compound heterozygous mutation in SLC34A3 causes hereditary hypophosphatemic rickets with hypercalciuria in a Chinese patient. Bone 59:114–121PubMedGoogle Scholar
  68. 68.
    Rafaelsen S, Johansson S, Raeder H, Bjerknes R (2016) Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 174:125–136PubMedGoogle Scholar
  69. 69.
    Ichikawa S, Sorenson AH, Imel EA, Friedman NE, Gertner JM, Econs MJ (2006) Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab 91:4022–4027PubMedGoogle Scholar
  70. 70.
    Ichikawa S, Tuchman S, Padgett LR, Gray AK, Baluarte HJ, Econs MJ (2014) Intronic deletions in the SLC34A3 gene: a cautionary tale for mutation analysis of hereditary hypophosphatemic rickets with hypercalciuria. Bone 59:53–56PubMedGoogle Scholar
  71. 71.
    Segawa H, Onitsuka A, Kuwahata M, Hanabusa E, Furutani J, Kaneko I, Tomoe Y, Aranami F, Matsumoto N, Ito M, Matsumoto M, Li M, Amizuka N, Miyamoto K (2009) Type IIc sodium-dependent phosphate transporter regulates calcium metabolism. J Am Soc Nephrol 20:104–113PubMedPubMedCentralGoogle Scholar
  72. 72.
    Myakala K, Motta S, Murer H, Wagner CA, Koesters R, Biber J, Hernando N (2014) Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice. Am J Physiol Renal Physiol 306:F833–F843PubMedGoogle Scholar
  73. 73.
    Mahon MJ, Donowitz M, Yun CC, Segre GV (2002) Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature 417:858–861PubMedGoogle Scholar
  74. 74.
    Capuano P, Bacic D, Roos M, Gisler SM, Stange G, Biber J, Kaissling B, Weinman EJ, Shenolikar S, Wagner CA, Murer H (2007) Defective coupling of apical PTH receptors to phospholipase C prevents internalization of the Na+−phosphate cotransporter NaPi-IIa in Nherf1-deficient mice. Am J Physiol Cell Physiol 292:C927–C934PubMedGoogle Scholar
  75. 75.
    Gisler SM, Stagljar I, Traebert M, Bacic D, Biber J, Murer H (2001) Interaction of the type IIa Na/Pi cotransporter with PDZ proteins. J Biol Chem 276:9206–9213PubMedGoogle Scholar
  76. 76.
    Hernando N, Deliot N, Gisler SM, Lederer E, Weinman EJ, Biber J, Murer H (2002) PDZ-domain interactions and apical expression of type IIa Na/P(i) cotransporters. Proc Natl Acad Sci USA 99:11957–11962PubMedGoogle Scholar
  77. 77.
    Lederer ED, Khundmiri SJ, Weinman EJ (2003) Role of NHERF-1 in regulation of the activity of Na-K ATPase and sodium-phosphate co-transport in epithelial cells. J Am Soc Nephrol 14:1711–1719PubMedGoogle Scholar
  78. 78.
    Shenolikar S, Voltz JW, Minkoff CM, Wade JB, Weinman EJ (2002) Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci USA 99:11470–11475PubMedGoogle Scholar
  79. 79.
    Mahon MJ, Cole JA, Lederer ED, Segre GV (2003) Na+/H+ exchanger-regulatory factor 1 mediates inhibition of phosphate transport by parathyroid hormone and second messengers by acting at multiple sites in opossum kidney cells. Mol Endocrinol 17:2355–2364PubMedGoogle Scholar
  80. 80.
    Weinman EJ, Cunningham R, Wade JB, Shenolikar S (2005) The role of NHERF-1 in the regulation of renal proximal tubule sodium-hydrogen exchanger 3 and sodium-dependent phosphate cotransporter 2a. J Physiol 567:27–32PubMedPubMedCentralGoogle Scholar
  81. 81.
    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 (2008) NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 359:1128–1135PubMedGoogle Scholar
  82. 82.
    Courbebaisse M, Leroy C, Bakouh N, Salaun C, Beck L, Grandchamp B, Planelles G, Hall RA, Friedlander G, Prie D (2012) A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism. PLoS One 7:e34764PubMedPubMedCentralGoogle Scholar
  83. 83.
    Bergwitz C, Bastepe M (2008) NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 359:2615–2616. author reply 2616–2617PubMedGoogle Scholar
  84. 84.
    Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, Biber J, Forster IC (2009) The Na+-pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary pi. Am J Physiol Renal Physiol 296:F691–F699PubMedGoogle Scholar
  85. 85.
    Picard N, Capuano P, Stange G, Mihailova M, Kaissling B, Murer H, Biber J, Wagner CA (2010) Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters. Pflugers Arch 460:677–687PubMedGoogle Scholar
  86. 86.
    Hsu SC, Sears RL, Lemos RR, Quintans B, Huang A, Spiteri E, Nevarez L, Mamah C, Zatz M, Pierce KD, Fullerton JM, Adair JC, Berner JE, Bower M, Brodaty H, Carmona O, Dobricic V, Fogel BL, Garcia-Estevez D, Goldman J, Goudreau JL, Hopfer S, Jankovic M, Jauma S, Jen JC, Kirdlarp S, Klepper J, Kostic V, Lang AE, Linglart A, Maisenbacher MK, Manyam BV, Mazzoni P, Miedzybrodzka Z, Mitarnun W, Mitchell PB, Mueller J, Novakovic I, Paucar M, Paulson H, Simpson SA, Svenningsson P, Tuite P, Vitek J, Wetchaphanphesat S, Williams C, Yang M, Schofield PR, de Oliveira JR, Sobrido MJ, Geschwind DH, Coppola G (2013) Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. Neurogenetics 14:11–22PubMedPubMedCentralGoogle Scholar
  87. 87.
    Giovannini D, Touhami J, Charnet P, Sitbon M, Battini JL (2013) Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans. Cell Rep 3:1866–1873PubMedGoogle Scholar
  88. 88.
    Wege S, Poirier Y (2014) Expression of the mammalian xenotropic polytropic virus receptor 1 (XPR1) in tobacco leaves leads to phosphate export. FEBS Lett 588:482–489PubMedGoogle Scholar
  89. 89.
    Wild R, Gerasimaite R, Jung JY, Truffault V, Pavlovic I, Schmidt A, Saiardi A, Jessen HJ, Poirier Y, Hothorn M, Mayer A (2016) Control of eukaryotic phosphate homeostasis by inositol polyphosphate sensor domains. Science 352:986–990PubMedGoogle Scholar
  90. 90.
    Legati A, Giovannini D, Nicolas G, Lopez-Sanchez U, Quintans B, Oliveira JR, Sears RL, Ramos EM, Spiteri E, Sobrido MJ, Carracedo A, Castro-Fernandez C, Cubizolle S, Fogel BL, Goizet C, Jen JC, Kirdlarp S, Lang AE, Miedzybrodzka Z, Mitarnun W, Paucar M, Paulson H, Pariente J, Richard AC, Salins NS, Simpson SA, Striano P, Svenningsson P, Tison F, Unni VK, Vanakker O, Wessels MW, Wetchaphanphesat S, Yang M, Boller F, Campion D, Hannequin D, Sitbon M, Geschwind DH, Battini JL, Coppola G (2015) Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet 47:579–581PubMedPubMedCentralGoogle Scholar
  91. 91.
    Anheim M, Lopez-Sanchez U, Giovannini D, Richard AC, Touhami J, N’Guyen L, Rudolf G, Thibault-Stoll A, Frebourg T, Hannequin D, Campion D, Battini JL, Sitbon M, Nicolas G (2016) XPR1 mutations are a rare cause of primary familial brain calcification. J Neurol 263:1559–1564PubMedGoogle Scholar
  92. 92.
    Ansermet C, Moor MB, Centeno G, Auberson M, Hu DZ, Baron R, Nikolaeva S, Haenzi B, Katanaeva N, Gautschi I, Katanaev V, Rotman S, Koesters R, Schild L, Pradervand S, Bonny O, Firsov D (2017) Renal Fanconi syndrome and hypophosphatemic rickets in the absence of xenotropic and polytropic retroviral receptor in the nephron. J Am Soc Nephrol 28:1073–1078PubMedGoogle Scholar
  93. 93.
    Mannstadt M, Magen D, Segawa H, Stanley T, Sharma A, Sasaki S, Bergwitz C, Mounien L, Boepple P, Thorens B, Zelikovic I, Juppner H (2012) Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations. J Clin Endocrinol Metab 97:E1978–E1986PubMedPubMedCentralGoogle Scholar
  94. 94.
    Mihout F, Devuyst O, Bensman A, Brocheriou I, Ridel C, Wagner CA, Mohebbi N, Boffa JJ, Plaisier E, Ronco P (2014) Acute metabolic acidosis in a GLUT2-deficient patient with Fanconi-Bickel syndrome: new pathophysiology insights. Nephrol Dial Transplant 29[Suppl 4]:iv113–iv116PubMedGoogle Scholar
  95. 95.
    Santer R, Schneppenheim R, Dombrowski A, Gotze H, Steinmann B, Schaub J (1997) Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet 17:324–326PubMedGoogle Scholar
  96. 96.
    Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV (1996) A common molecular basis for three inherited kidney stone diseases. Nature 379:445–449PubMedGoogle Scholar
  97. 97.
    Devuyst O, Thakker RV (2010) Dent’s disease. Orphanet J Rare Dis 5:28PubMedPubMedCentralGoogle Scholar
  98. 98.
    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, 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 (2009) Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 41:712–717PubMedPubMedCentralGoogle Scholar
  99. 99.
    Kottgen A, Pattaro C, Boger CA, Fuchsberger C, Olden M, Glazer NL, Parsa A, Gao X, Yang Q, Smith AV, O’Connell JR, Li M, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson AD, Dehghan A, Teumer A, Pare G, Atkinson EJ, Zeller T, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tonjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Boerwinkle E, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer IH, Haritunians T, Lumley T, Siscovick D, Psaty BM, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turner ST, Schillert A, Ziegler A, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Illig T, Klopp N, Meisinger C, Wichmann HE, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Schreiber S, Aulchenko YS, Felix JF, Rivadeneira F, Uitterlinden AG, Hofman A, Imboden M, Nitsch D, Brandstatter A, Kollerits B, Kedenko L, Magi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Volzke H, Kroemer HK, Nauck M, Volker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Blankenberg S, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Gudnason V, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, van Duijn CM, Borecki I, Kramer BK, Rudan I, Gyllensten U, Wilson JF, Witteman JC, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS (2010) New loci associated with kidney function and chronic kidney disease. Nat Genet 42:376–384PubMedPubMedCentralGoogle Scholar
  100. 100.
    Mahajan A, Rodan AR, Le TH, Gaulton KJ, Haessler J, Stilp AM, Kamatani Y, Zhu G, Sofer T, Puri S, Schellinger JN, Chu PL, Cechova S, van Zuydam N, Arnlov J, Flessner MF, Giedraitis V, Heath AC, Kubo M, Larsson A, Lindgren CM, Madden PA, Montgomery GW, Papanicolaou GJ, Reiner AP, Sundstrom J, Thornton TA, Lind L, Ingelsson E, Cai J, Martin NG, Kooperberg C, Matsuda K, Whitfield JB, Okada Y, Laurie CC, Morris AP, Franceschini N (2016) Trans-ethnic fine mapping highlights kidney-function genes linked to salt sensitivity. Am J Hum Genet 99:636–646PubMedPubMedCentralGoogle Scholar
  101. 101.
    Pattaro C, Teumer A, Gorski M, Chu AY, Li M, Mijatovic V, Garnaas M, Tin A, Sorice R, Li Y, Taliun D, Olden M, Foster M, Yang Q, Chen MH, Pers TH, Johnson AD, Ko YA, Fuchsberger C, Tayo B, Nalls M, Feitosa MF, Isaacs A, Dehghan A, d’Adamo P, Adeyemo A, Dieffenbach AK, Zonderman AB, Nolte IM, van der Most PJ, Wright AF, Shuldiner AR, Morrison AC, Hofman A, Smith AV, Dreisbach AW, Franke A, Uitterlinden AG, Metspalu A, Tonjes A, Lupo A, Robino A, Johansson A, Demirkan A, Kollerits B, Freedman BI, Ponte B, Oostra BA, Paulweber B, Kramer BK, Mitchell BD, Buckley BM, Peralta CA, Hayward C, Helmer C, Rotimi CN, Shaffer CM, Muller C, Sala C, van Duijn CM, Saint-Pierre A, Ackermann D, Shriner D, Ruggiero D, Toniolo D, Lu Y, Cusi D, Czamara D, Ellinghaus D, Siscovick DS, Ruderfer D, Gieger C, Grallert H, Rochtchina E, Atkinson EJ, Holliday EG, Boerwinkle E, Salvi E, Bottinger EP, Murgia F, Rivadeneira F, Ernst F, Kronenberg F, Hu FB, Navis GJ, Curhan GC, Ehret GB, Homuth G, Coassin S, Thun GA, Pistis G, Gambaro G, Malerba G, Montgomery GW, Eiriksdottir G, Jacobs G, Li G, Wichmann HE, Campbell H, Schmidt H, Wallaschofski H, Volzke H, Brenner H, Kroemer HK, Kramer H, Lin H, Leach IM, Ford I, Guessous I, Rudan I, Prokopenko I, Borecki I, Heid IM, Kolcic I, Persico I, Jukema JW, Wilson JF, Felix JF, Divers J, Lambert JC, Stafford JM, Gaspoz JM, Smith JA, Faul JD, Wang JJ, Ding J, Hirschhorn JN, Attia J, Whitfield JB, Chalmers J, Viikari J, Coresh J, Denny JC, Karjalainen J, Fernandes JK, Endlich K, Butterbach K, Keene KL, Lohman K, Portas L, Launer LJ, Lyytikainen LP, Yengo L, Franke L, Ferrucci L, Rose LM, Kedenko L, Rao M, Struchalin M, Kleber ME, Cavalieri M, Haun M, Cornelis MC, Ciullo M, Pirastu M, de Andrade M, McEvoy MA, Woodward M, Adam M, Cocca M, Nauck M, Imboden M, Waldenberger M, Pruijm M, Metzger M, Stumvoll M, Evans MK, Sale MM, Kahonen M, Boban M, Bochud M, Rheinberger M, Verweij N, Bouatia-Naji N, Martin NG, Hastie N, Probst-Hensch N, Soranzo N, Devuyst O, Raitakari O, Gottesman O, Franco OH, Polasek O, Gasparini P, Munroe PB, Ridker PM, Mitchell P, Muntner P, Meisinger C, Smit JH, Kovacs P, Wild PS, Froguel P, Rettig R, Magi R, Biffar R, Schmidt R, Middelberg RP, Carroll RJ, Penninx BW, Scott RJ, Katz R, Sedaghat S, Wild SH, Kardia SL, Ulivi S, Hwang SJ, Enroth S, Kloiber S, Trompet S, Stengel B, Hancock SJ, Turner ST, Rosas SE, Stracke S, Harris TB, Zeller T, Zemunik T, Lehtimaki T, Illig T, Aspelund T, Nikopensius T, Esko T, Tanaka T, Gyllensten U, Volker U, Emilsson V, Vitart V, Aalto V, Gudnason V, Chouraki V, Chen WM, Igl W, Marz W, Koenig W, Lieb W, Loos RJ, Liu Y, Snieder H, Pramstaller PP, Parsa A, O’Connell JR, Susztak K, Hamet P, Tremblay J, de Boer IH, Boger CA, Goessling W, Chasman DI, Kottgen A, Kao WH, Fox CS (2016) Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat Commun 7:10023PubMedPubMedCentralGoogle Scholar
  102. 102.
    Ledo N, Ko YA, Park AS, Kang HM, Han SY, Choi P, Susztak K (2015) Functional genomic annotation of genetic risk loci highlights inflammation and epithelial biology networks in CKD. J Am Soc Nephrol 26:692–714PubMedGoogle Scholar

Copyright information

© IPNA 2017

Authors and Affiliations

  1. 1. Institute of PhysiologyUniversity of ZurichZurichSwitzerland
  2. 2.National Center for Competence in Research (NCCR) Kidney.CHZurichSwitzerland

Personalised recommendations