Intestinal Phosphate Research Articles

New clinical trials with vitamin D and analogs in renal disease

Two new clinical trials highlight refinements in the use of vitamin D and its analogs in the treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD), and the treatment of proteinuria in diabetics. In patients with ESRD, alfacalcidol is as effective as paricalcitol in suppressing parathyroid hormone; the occurrence of hypercalcemia and hyperphosphatemia is infrequent and similar with the two analogs. Oral cholecalciferol reduces albuminuria and urinary transforming growth factor-β1 in patients with type 2 diabetes mellitus and proteinuria.

Hypophosphatemia Related to Paraneoplastic Cushing Syndrome in Prostate Cancer: Cure After Bilateral Adrenalectomy

We report the case of a 71-year-old man with progressive metastatic prostate cancer in whom simultaneous occurrence of paraneoplastic Cushing syndrome (CS) and tumor-induced osteomalacia (TIO) initially was suspected. However, the evolution of biochemical markers of phosphate metabolism during disease course and after bilateral adrenalectomy argued against the diagnosis of TIO. Despite the persistence of progressive prostate cancer, CS and hypophosphatemia resolved in parallel after bilateral adrenalectomy. Thus, these data suggest that paraneoplastic CS per se was involved in the pathogenesis of hypophosphatemia. Calcitriol and intact fibroblast growth factor 23 (FGF23) levels were within the reference range at onset, which is inappropriate in the setting of severe hypophosphatemia. All parameters of phosphate metabolism normalized after resolution of hypercortisolism. Based on the known suppressive effect of glucocorticoids (GCs) on bone remodeling and the inverse relationship between bone turnover rate and circulating FGF23 levels, we postulate that GCs interfere indirectly with phosphate homeostasis by inducing inappropriate FGF23 production and release. This mechanism could further aggravate the hypophosphatemia resulting from GC-induced inhibition of intestinal phosphate absorption. Studies directed at the identification of the molecular pathways in bone mediating the interference of GCs with phosphate metabolism are warranted.

Gut–Bone Interactions and Implications for the Child With Chronic Gastrointestinal Disease

Bone is not simply a framework on which to hang viscera and connective tissue; it is also a dynamic interactive organ system with roles in immunoregulation, adipogenesis, and vascular calcification, among others. Bone is intimately affected by chronic disease, including gastrointestinal disease. The mechanisms for bone loss in conditions such as inflammatory bowel disease, celiac disease, and cystic fibrosis are discussed with regard to the role of the inflammatory response. Furthermore, we raise the issue of effects of inflammation on both intestinal and renal calcium and phosphate transport, although the ways in which these actions affect bone are not explained and require further research. The stress response, a prominent feature following burn injury, is also elucidated and its relation to gastrointestinal disease is examined. We then discuss the importance of knowing the mechanism of bone loss to determine proper prevention and treatment for the bone loss in specific gastrointestinal conditions.

Liver X receptor-activating ligands modulate renal and intestinal sodium–phosphate transporters

Cholesterol is pumped out of the cells in different tissues, including the vasculature, intestine, liver, and kidney, by the ATP-binding cassette transporters. Ligands that activate the liver X receptor (LXR) modulate this efflux. Here we determined the effects of LXR agonists on the regulation of phosphate transporters. Phosphate homeostasis is regulated by the coordinated action of the intestinal and renal sodium-phosphate (NaPi) transporters, and the loss of this regulation causes hyperphosphatemia. Mice treated with DMHCA or TO901317, two LXR agonists that prevent atherosclerosis in ApoE or LDLR knockout mice, significantly decreased the activity of intestinal and kidney proximal tubular brush border membrane sodium gradient-dependent phosphate uptake, decreased serum phosphate, and increased urine phosphate excretion. The effects of DMHCA were due to a significant decrease in the abundance of the intestinal and renal NaPi transport proteins. The same effect was also found in opossum kidney cells in culture after treatment with either agonist. There was increased nuclear expression of the endogenous LXR receptor, a reduction in NaPi4 protein abundance (the main type II NaPi transporter in the opossum cells), and a reduction in NaPi co-transport activity. Thus, LXR agonists modulate intestinal and renal NaPi transporters and, in turn, serum phosphate levels.

Serum Intestinal Fatty Acid Binding Protein and Phosphate Levels in the Diagnosis of Acute Intestinal Ischemia: An Experimental Study in Rabbits

BackgroundAcute intestinal ischemia is a serious clinical disorder with mesenteric infarction, which has high mortality. It is important to establish a biochemical marker for the early diagnosis of acute intestinal ischemia. ObjectivesThe aim of this experimental study was to assess the changes in the serum levels of intestinal fatty acid binding protein (IFABP) and phosphate by time using the acute intestinal ischemia model in rabbits. MethodsIn this study, 21 New Zealand rabbits were randomly divided into three groups. Blood samples were obtained at 0, 1, 3, and 6 h in the control group. Blood samples were obtained at 0, 1, 3, and 6 h in the sham group after simple laparotomy. Blood samples were obtained at the same hours in the ischemia group after simple laparotomy and ligation of the superior mesenteric artery. ResultsThere was no significant difference between the control, the sham, and the ischemia groups in terms of serum IFABP levels at any time (p > 0.05). Serum phosphate levels significantly increased in the ischemia group (p < 0.001). Studies on IFABP have begun emerging in the literature, and there is no standard approach for the technique to measure the IFABP level. No studies on IFABP were found in the literature on rabbits. ConclusionBased on our results, the role that IFABP levels play in the diagnosis of acute intestinal ischemia is unclear at this time. Serum phosphate levels continued to rise as the duration of ischemia was prolonged. These findings support the suggestion that serum phosphate levels are valuable for the diagnosis of acute intestinal ischemia.

The pathophysiology of early-stage chronic kidney disease–mineral bone disorder (CKD-MBD) and response to phosphate binders in the rat

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder that describes the complex bone and mineral abnormalities that occur in CKD. To understand the pathophysiology of CKD-MBD and determine whether the early use of phosphate binders would alter this physiology, we used a naturally occurring, slowly progressive model of CKD-MBD, the Cy/+ rat. Male Cy/+ rats were compared with their normal littermates at 20 weeks of age after 1 week of no phosphate binder, calcium carbonate, or sevelamer carbonate. The Cy/+ rat had renal function that was 50% of that of normal littermates, elevated parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), decreased 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels, but normal calcium and phosphorus levels. There was a significant positive correlation of blood FGF23 and phosphorus levels and blood FGF23 and urine phosphorus levels. There was an inverse correlation between FGF23 and calcium levels. mRNA from the kidney demonstrated 50% reduction in klotho and Npt2a expression but no difference in CYP27B1. In the intestine, CKD animals had reduced active phosphate absorption in the jejunum using modified Ussing chambers and a reduction in Npt2b expression throughout the small intestine compared with normal littermates. In bone, mRNA expression of FGF23 was reduced (driven by lowering with phosphate binders), and TRAP expression was increased in CKD. By histology, there was increased osteoclast activity and number, and there were reductions in some measures of femoral neck mechanical strength. One week of phosphate binders reduced intestinal phosphate flux, serum phosphorus levels, and urinary phosphate excretion. These results demonstrate marked abnormalities in kidney, intestine, and bone in early CKD-MBD. While phosphate binders were effective in lowering urine phosphorus, they had little effect on end organs after 1 week of administration.

Fibroblast growth factor 23 as a phosphotropic hormone and beyond

Fibroblast growth factor 23 (FGF23) is produced by bone and reduces serum phosphate by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption. Excess actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia while deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis. In addition, FGF23 has been shown to prevent the development of hyperphosphatemia during the progression of chronic kidney disease-mineral and bone disorder. Epidemiological studies have indicated that high FGF23 levels are associated with unfavorable events including higher mortality, cardiovascular events, progression of CKD and fracture; however, these associations are not observed unequivocally and it is not evident why they are present. While FGF23 has been shown to be a hormone that regulates phosphate metabolism, it remains to be established whether FGF23 has roles other than regulating mineral homeostasis.

In vitro properties of surface—modified solid lipid microspheres containing an antimalarial drug: halofantrine

Objective To formulate and evaluate in vitro, surface-modified solid lipid microspheres containing halofantrine using lipid matrix formed from goat fat and a phospholipid (P90H). Methods The model drug, halofantrine in an increasing concentration of 1%, 2%, 3%, 4% and 5% w/w was incorporated into surface-modified solid lipid microspheres formulated by hot homogenization. Effect of drug concentration on the encapsulation efficiency was studied. The dispersion was evaluated using particle size, particle morphology, pH and encapsulation efficiency. The drug formulation with highest encapsulation efficiency was selected and used for the release studies and compared with the release from a commercial dosage form (Halfan® 250 mg tablet, Glaxo-Smithkline, Mayenne France) using simulated gastric fluid (SGF pH 1.2), simulated intestinal fluid (SIF pH 7.2) and phosphate buffer (pH 6.8) as biorelevant media. Results were analyzed statistically and the level of significance was taken to be P < 0.05). Results Discrete and spherical solid lipid microspheres were produced. The particle size of the dispersion was low (32.48–33.87 μm) with minimal particle growth and high encapsulation efficiencies (86.8%–91.0%) after 3 months. The pH of the microspheres dispersion changed appreciably after 3 months. In vitro release result obtained revealed sustained and controlled drug release from the lipid microspheres compared with the tablet dosage form. Conclusions Formulation of halofantrine as solid lipid microspheres presents a better alternative to the conventional tablet formulation as the in vitro dissolution of the highly lipophilic halofantrine was highly improved.

Downregulation of NaPi-IIa and NaPi-IIb Na+-coupled Phosphate Transporters by Coexpression of Klotho

Klotho, a transmembrane protein, protease and hormone has been shown to exert a profound effect on phosphate metabolism. Klotho overexpression lowers and Klotho deficiency increases the plasma phosphate concentration, effects in part attributed to an inhibitory effect of Klotho on the formation of 1,25-dihydroxycholecalciferol (1,25(OH) ₂D₃), the active form of Vitamin D. Beyond that Klotho has been shown to decrease renal tubular phosphate transport more directly. The influence of Klotho on the plasma phosphate concentration contributes to the profound effect of Klotho on ageing and life span. The present study explored whether Klotho influences the major renal tubular (NaPi-IIa) and the major intestinal (NaPi-IIb) phosphate transporters. For functional analysis NaPi-IIa or NaPi-IIb were expressed in Xenopus oocytes both, without or with additional coexpression of Klotho and electrogenic phosphate transport was estimated from the phosphate-induced current (Ip). According to RT-PCR Klotho is expressed in the murine kidney and intestine. Coexpression of Klotho decreased Ip in both NaPi-IIa- and NaPi-IIb-expressing oocytes. Klotho decreased the maximal Ip without appreciably affecting the concentration required for halfmaximal Ip. Treatment of NaPi-IIa- or NaPi-IIb-expressing oocytes with Klotho protein similarly decreased Ip. In conclusion, Klotho down regulates both, renal (NaPi-IIa) and intestinal (NaPi-IIb) phosphate transporters.

The treatment of hyperphosphataemia in CKD: calcium-based or calcium-free phosphate binders?

The recent publication of the novel KDIGO chronic kidney disease (CKD) guidelines in 2009 [1] clearly underlined the importance of bone and vascular health for patients with CKD. Our understanding is rapidly increasing of how closely disturbances in mineral metabolism are linked to bone and vascular disease (the so-called bone–vascular axis). A decade ago, the first published studies on this deleterious interplay focused upon dialysis patients [2,3]. However, it has recently become evident that patients in the early stages of CKD also exhibit profound pathological changes in the bone–vascular axis, termed CKD–mineral bone disorder (CKD–MBD) [4]. CKD–MBD is a descriptive term that encompasses serum biochemistry changes such as hyperphosphataemia or hyperparathyroidism, renal osteodystrophy, and the problem of vascular calcification [5]. Our current understanding of these disorders has switched the focus of interest towards patients with earlier forms of CKD, as prevention of occurrence (primary prevention) might be easier than prevention of progression. In the light of overall rather disappointing results of interventional trials in patients with end-stage renal disease (ESRD), the idea that primary prophylaxis may be promising is fascinating. This concept is supported by the data from lipid modification trials indicating that statin therapy in ESRD is not effective and probably starts too late [6]. In contrast, statin therapy in patients with moderate CKD lowers cardiovascular risk comparable to patients with normal renal function. The data from the Pravastatin Pooling Project (PPP) demonstrated that pravastatin significantly reduced the incidence of cardiovascular events in people with or at risk for coronary disease and concomitant moderate CKD [7]. In this respect, we are awaiting the SHARP trial results. In line with these data, in patients with moderately reduced kidney function, ‘subclinical’ or modestly elevated serum phosphorus levels may pose an appreciable threat to patients [8,9]. In a recent issue of theNewEngland Journal of Medicine, we found of interest the review article by Tonelli et al. [10] on the use of oral phosphate binders in CKD patients undergoing dialysis. The revision of the literature in the field appears to be complete. However, we would like to discuss critically the authors' conclusions on considering calcium-based phosphate binders to be the first-line therapy for dialysis patients. In contrast to the strict focus on available evidence-based medicine data as chosen by Tonelli et al., we suggest a more integrative and translational approach to this crucial question. In our opinion, several issues have not been sufficiently appreciated by Tonelli et al. [10]: for example, the data regarding occurrence of hypercalcaemic episodes, the development of vascular calcifications as a surrogate for cardiovascular disease [11], and the deleterious interaction of inflammation, dyslipidaemia and vascular disease. Although prolonged hypercalcaemia is not a common event in dialysis patients [12], any serum calcium levels below overt hypercalcaemia do not necessarily mean a well-balanced calcium metabolism given the poor reflection of serum spot measurements with overall total body calcium and with direction of calcium flux. In our opinion, several issues have not been sufficiently appreciated by Tonelli et al. [10]: for example, the data regarding occurrence of hypercalcaemic episodes, the development of vascular calcifications as a surrogate for cardiovascular disease [11], and the interaction of inflammation, dyslipidaemia and vascular disease. Serum phosphate levels in uraemic patients can be controlled by the reduction of oral phosphate intake, an adequate dialysis schedule and the use of intestinal phosphate binders. During homeostasis, ~60% of the ingested phosphate is absorbed via the gut. This amount is increased by (active) vitamin D. Strict dietary counselling may reduce daily oral intake of phosphate. However, following daily dietary protein recommendations of 1000–1200 g/kg/body weight, CKD patients ingest a consistent amount of at least 900–1000 mg phosphate per day [13]. It is a common observation that rigid dietary phosphorus restriction is rarely followed by most patients in the long term. Moreover, the

Reciprocal Control of 1,25-Dihydroxyvitamin D and FGF23 Formation Involving the FGF23/Klotho System

Fibroblast growth factor 23 (FGF23) is a circulating hormone that is synthesized by osteocytes and osteoblasts. This glycosylated peptide controls phosphate balance by modulating urinary phosphate excretion and indirectly intestinal phosphate absorption by reducing expression of the renal and intestinal sodium phosphate transporters. In a feedback loop, 1,25-dihydroxyvitamin D and phosphate intake control FGF23 production. FGF23 is inactivated by cleavage by a still unidentified enzyme. FGF23 cleavage occurs within cells and probably in the circulation. Klotho, a protein expressed at the cell surface of few organs, forms complexes with FGF receptors, which increases their affinity for FGF23. Klotho is also released into the plasma and urine by an enzymatic cleavage. FGF23 plays a central role in vitamin D metabolism: It inhibits calcitriol synthesis in the kidney and stimulates the catabolism of active vitamin D sterols. In turn, calcitriol stimulates FGF23 and Klotho expression. In chronic kidney diseases, FGF23 concentration increases as GFR declines, whereas Klotho tissue expression decreases. The modifications of FGF23 and Klotho expression are probably involved in the genesis of hyperparathyroidism and the resistance to vitamin D receptor (VDR) activation in chronic kidney disease. Low vitamin D, high FGF23 concentrations, and defects in VDR activation are associated with similar risks, which evoke the possibility that potential FGF23 toxicity might be partly mediated by FGF23-induced decrease in calcitriol or 25-hydroxyvitamin D. Conversely, VDR activators could be used to modulate Klotho or FGF23 expression.

Mechanism of Intestinal Phosphate Transport

Mechanism of Intestinal Phosphate Transport

Phosphate homeostasis and the renal-gastrointestinal axis

Transport of phosphate across intestinal and renal epithelia is essential for normal phosphate balance, yet we know less about the mechanisms and regulation of intestinal phosphate absorption than we do about phosphate handling by the kidney. Recent studies have provided strong evidence that the sodium-phosphate cotransporter NaPi-IIb is responsible for sodium-dependent phosphate absorption by the small intestine, and it might be that this protein can link changes in dietary phosphate to altered renal phosphate excretion to maintain phosphate balance. Evidence is also emerging that specific regions of the small intestine adapt differently to acute or chronic changes in dietary phosphate load and that phosphatonins inhibit both renal and intestinal phosphate transport. This review summarizes our current understanding of the mechanisms and control of intestinal phosphate absorption and how it may be related to renal phosphate reabsorption; it also considers the ways in which the gut could be targeted to prevent, or limit, hyperphosphatemia in chronic and end-stage renal failure.

Rapamycin-induced phosphaturia

The mammalian target of rapamycin (mTOR) is known to stimulate a variety of transport mechanisms including the intestinal phosphate transporter NaPi-IIb. The present study was performed to elucidate whether mTOR similarly regulates the major renal tubular phosphate transporter NaPi-IIa. To this end, NaPi-IIa was expressed in Xenopus oocytes with or without mTOR and phosphate transport estimated from phosphate-induced (1 mM) current (I(pi)). As a result, I(pi) was observed in NaPi-IIa-expressing but not in H(2)O-injected Xenopus oocytes. Co-expression of mTOR significantly enhanced I(pi) in NaPi-IIa-expressing Xenopus oocytes, an effect abrogated by treatment with rapamycin (50 nM for the last 24 h of incubation). In a second series of experiments, the effect of rapamycin was analysed in mice. The in vivo administration of rapamycin (3 microg/g body weight/day) for 3 days resulted in phosphaturia in mice despite a tendency of plasma phosphate concentration to decrease. mTOR contributes to the regulation of renal phosphate transport, and rapamycin thus influences phosphate balance.

The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the “Fountain of Youth” to mediate healthful aging

The nuclear vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D 3 (1,25D), its high affinity renal endocrine ligand, to signal intestinal calcium and phosphate absorption plus bone remodeling, generating a mineralized skeleton free of rickets/osteomalacia with a reduced risk of osteoporotic fractures. 1,25D/VDR signaling regulates the expression of TRPV6, BGP, SPP1, LRP5, RANKL and OPG, while achieving feedback control of mineral ions to prevent age-related ectopic calcification by governing CYP24A1, PTH, FGF23, PHEX, and klotho transcription. Vitamin D also elicits numerous intracrine actions when circulating 25-hydroxyvitamin D 3, the metabolite reflecting vitamin D status, is converted to 1,25D locally by extrarenal CYP27B1, and binds VDR to promote immunoregulation, antimicrobial defense, xenobiotic detoxification, anti-inflammatory/anticancer actions and cardiovascular benefits. VDR also affects Wnt signaling through direct interaction with β-catenin, ligand-dependently blunting β-catenin mediated transcription in colon cancer cells to attenuate growth, while potentiating β-catenin signaling via VDR ligand-independent mechanisms in osteoblasts and keratinocytes to function osteogenically and as a pro-hair cycling receptor, respectively. Finally, VDR also drives the mammalian hair cycle in conjunction with the hairless corepressor by repressing SOSTDC1, S100A8/S100A9, and PTHrP. Hair provides a shield against UV-induced skin damage and cancer in terrestrial mammals, illuminating another function of VDR that facilitates healthful aging.

Effect of Iron(III) Chitosan Intake on the Reduction of Serum Phosphorus in Rats

Because of the widespread use of aluminium- and calcium-containing phosphate binders for the control of hyperphosphataemia in patients with end-stage renal failure, an iron(III) chitosan complex was synthesised and fed to rats to measure its effect on serum phosphorus and calcium, intestinal phosphate binding and phosphate absorption. Thirty-six Wistar rats were randomly selected and distributed into a baseline group (n = 6), a control group (n = 8 (days 0-15), n = 8 (days 16-30)) and a treatment group (n = 8 (days 0-15), n = 8 (days 16-30)). The control groups ingested AIN-76 diet mix with a 1% w/w fibre content; however, the treatment groups had the fibre content completely substituted with iron(III) chitosan. The mean weights of the treated rats were slightly lower from 15 days (not significant); but overall, rat growth was not stunted in the treatment groups. The serum phosphorus levels of the treated group (n = 8) were significantly reduced after 15 days (P = 0.004; control: 5.7+/-0.9 mg dL(-1); treatment: 4.4+/-0.5 mg dL(-1); 95% CI of difference: 0.5-2.2) and 30 days (P = 0.002; control: 5.5+/-0.9 mg dL(-1); treatment = 4.1+/-06 mg dL(-1); 95% CI of difference: 0.6-2.3) as compared with the respective control group. The serum calcium-phosphorus product was 62.0+/-12.1 mg2 dL(-2) for the control and 45.1+/-6.6 mg2 dL(-2) for the treatment group after 30 days (P = 0.004). The serum iron concentration of the treatment group did not differ from the baseline value after 15 and 30 days, but the treatment group was significantly higher than the control group (P<0.05) after 30 days. The faeces phosphorus levels (mg day(-1)) were higher (P<0.01) and its iron content was much higher (P<0.01) for the treated group. The urine phosphorus (mg kg(-1)) was not significantly reduced for the treated group, but the mean was consistently less. The kidney and liver weights of both groups were similar, but the phosphorus content of the kidney (mg (g kidney)(-1)) was higher for the treated group after 30 days (P = 0.041; control, 4.2+/-1.2 mg g(-1) vs treatment, 5.6+/-1.4 mg g(-1). Because iron(III) chitosan had a high phosphorus-binding capacity of 308 (mg P) per gram of Fe3+ for both the in-vitro (pH 7.5) and in-vivo studies, which is greater than nearly all commonly used phosphate binders, and a small net phosphorus absorption difference of 3.7 mg day(-1), it is an efficient phosphate binder for lowering serum phosphate levels without increasing serum calcium levels.

Chitosan Iron(III) Reduces Phosphorus Levels in Alloxan Diabetes-Induced Rats with Signs of Renal Failure Development

This study evaluates the effect of complex cross-linked chitosan iron-(III) (CH-FeCL) polymer as phosphate binder in renal failure induced by alloxan (150 mg/kg, i.p.) in rats. The animals (male and female) were divided into four groups and received the treatment once a day for 15 days: (i) control group, which received a single injection of saline (3 ml/kg, i.p.) and normal diet; (ii) alloxan group, which received only a dose of alloxan and normal diet; (iii) phosphate (PO4) group, which received diet supplemented with phosphate 1.2%; and (iv) CH-FeCL group, which received diet supplemented with phosphate 1.2% + CH-FeCL 0.5% (0.054% Fe elemental). It was observed that the CH-FeCL treatment did not alter body-weight, relative weight of the organs and haematological parameters in the treated and control groups for both sexes. However, a decrease in serum phosphorus level of the CH-FeCL group was observed after 15 days, compared with the phosphate group in both sexes. The serum iron concentration of the CH-FeCL group did not differ from the control group in either sex. CH-FeCL polymer decreases intestinal phosphate absorption in rats with renal failure and is promising for the treatment of phosphate retention in patients with renal failure.

Mutation analysis and serum FGF23 level in a patient with pulmonary alveolar microlithiasis

Pulmonary alveolar microlithiasis (PAM) is a rare, hereditary disorder characterized by ectopic formation of calcium-phosphate microliths in the alveolar space. PAM has been reported to arise from inactivating mutations in SLC34A2, encoding a sodium-dependent phosphate co-transporter essential for phosphate transport in the lungs and small intestine. Serum levels of the phosphaturic hormone fibroblast growth factor-23 (FGF23) in PAM have not been determined. Our objectives were to investigate the genetic etiology and circulating level of FGF23 in a 50-year-old male with clinical characteristics of PAM and extra-pulmonary calcifications. The SLC34A2 and FGF23 genes were sequenced for mutations and serum FGF23 analyzed by ELISA. We found no disease-causing mutations or single nucleotide polymorphisms in the genes investigated. Importantly, repeated measurements revealed undetectable or markedly low serum FGF23 (<3-11 RU/ml). Surprisingly, in the face of low serum FGF23, 1,25-dihydroxy vitamin D₃ level was low-normal and parathyroid hormone mildly elevated. Total 24-h urinary excretion of phosphate and calcium were low, as was fractional urinary excretion of calcium. In contrast, fractional excretion of phosphate was above normal, likely due to elevated PTH. Collectively, PAM may be a polygenic disorder that arises from mutations other than in SLC34A2. The low FGF23 level in our PAM patient supports an intestinal-bone axis, leading to decreased FGF23 expression when intestinal phosphate absorption is compromised.

Dietary Fructose Inhibits Intestinal Calcium Absorption and Induces Vitamin D Insufficiency in CKD

Renal disease leads to perturbations in calcium and phosphate homeostasis and vitamin D metabolism. Dietary fructose aggravates chronic kidney disease (CKD), but whether it also worsens CKD-induced derangements in calcium and phosphate homeostasis is unknown. Here, we fed rats diets containing 60% glucose or fructose for 1 mo beginning 6 wk after 5/6 nephrectomy or sham operation. Nephrectomized rats had markedly greater kidney weight, blood urea nitrogen, and serum levels of creatinine, phosphate, and calcium-phosphate product; dietary fructose significantly exacerbated all of these outcomes. Expression and activity of intestinal phosphate transporter, which did not change after nephrectomy or dietary fructose, did not correlate with hyperphosphatemia in 5/6-nephrectomized rats. Intestinal transport of calcium, however, decreased with dietary fructose, probably because of fructose-mediated downregulation of calbindin 9k. Serum calcium levels, however, were unaffected by nephrectomy and diet. Finally, only 5/6-nephrectomized rats that received dietary fructose demonstrated marked reductions in 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) levels, despite upregulation of 1alpha-hydroxylase. In summary, excess dietary fructose inhibits intestinal calcium absorption, induces marked vitamin D insufficiency in CKD, and exacerbates other classical symptoms of the disease. Future studies should evaluate the relevance of monitoring fructose consumption in patients with CKD.

Treatment options for hyperphosphatemia in feline CKD: what's out there?

Phosphorus is retained in chronic kidney disease (CKD), promoting renal secondary hyperparathyroidism and eventually resulting in hyperphosphatemia. Most agree that phosphate retention is a major contributor to the progression of CKD in many species and it is well known that hyperphosphatemia is associated with a significant mortality risk in humans with end-stage renal disease. Chronic kidney disease is a common ailment of geriatric cats. There is evidence in cats suggesting that the use of a phosphate-restricted diet in IRIS stage 2-3 disease has a beneficial effect on clinical outcome. However, despite the fact that intestinal phosphate binders are commonly used in veterinary practice for patients with CKD, there have been few published reports focusing on the safety and efficacy of these products in veterinary medicine. No phosphorus binders are licensed as medications for dogs or cats. This article draws on data from clinical trials in humans and studies in cats to discuss treatment goals and options for phosphate retention and hyperphosphatemia in feline CKD. With careful monitoring of serum phosphate and parathyroid hormone, and implementation of phosphate-restricted dietary management and intestinal phosphate binders, progression of CKD and the degree of hyperparathyroidism in cats may be reduced. Companion animal and feline practitioners are at the forefront in the management of CKD in cats.