Persistent Hypophosphatemia Research Articles

CKD–Mineral and Bone Disorder Management in Kidney Transplant Recipients

Kidney transplantation, the most effective treatment for the metabolic abnormalities of chronic kidney disease (CKD), only partially corrects CKD-mineral and bone disorders. Posttransplantation bone disease, one of the major complications of kidney transplantation, is characterized by accelerated loss of bone mineral density and increased risk of fractures and osteonecrosis. The pathogenesis of posttransplantation bone disease is multifactorial and includes the persistent manifestations of pretransplantation CKD-mineral and bone disorder, peritransplantation changes in the fibroblast growth factor 23-parathyroid hormone-vitamin D axis, metabolic perturbations such as persistent hypophosphatemia and hypercalcemia, and the effects of immunosuppressive therapies. Posttransplantation fractures occur more commonly at peripheral than central sites. Although there is significant loss of bone density after transplantation, the evidence linking posttransplantation bone loss and subsequent fracture risk is circumstantial. Presently, there are no prospective clinical trials that define the optimal therapy for posttransplantation bone disease. Combined pharmacologic therapy that targets multiple components of the disordered pathways has been used. Although bisphosphonate or calcitriol therapy can preserve bone mineral density after transplantation, there is no evidence that these agents decrease fracture risk. Moreover, bisphosphonates pose potential risks for adynamic bone disease.

A case of severe osteomalacia secondary to phosphate diabetes in a renal transplant recipient

Transient hypophosphatemia is frequently observed during the first months after renal transplantation and is usually asymptomatic. Phosphate diabetes is defined as inadequate tubular phosphorus reabsorption leading to persistent renal phosphorus wasting, which is an important but overlooked cause of osteodystrophy in the post-renal transplantation population. We report the case of a 58-year-old male who presented with severe multiple osteoarticular pains within 3 months after successful first kidney transplantation. Bone disease was attributed initially to mild hyperparathyroidism secondary to vitamin D deficiency. Despite the correction of the hyperparathyroidism, the withdrawal of corticosteroids, and the reduction of immunosuppressive treatment to tacrolimus-based monotherapy, the osteoarticular pains persisted. Skeletal investigations at month 9 post-transplantation demonstrated a significant bone mineral density loss associated with osteomalacia and osteoporosis on the bone biopsy. Laboratory data showed persistent hypophosphatemia, and phosphate diabetes was then diagnosed explaining the post-transplant bone disease. A tacrolimus-induced renal tubular disorder was suspected to contribute to the excessive renal phosphorus wasting. The replacement of tacrolimus by sirolimus, in addition to oral phosphorus and vitamin D supplementations, led to the disappearance of pains, the normalization of urinary and plasma phosphate level, and a significant improvement of bone mineralization.

Nutritional Tips for Managing Electrolyte Imbalances in Post-Renal Transplant Patients

MOST PATIENTS LOOK forward to the nutrition and dietary freedoms after kidney transplant; however, electrolyte imbalances can still be of concern. Delayed graft function and side effects of immunosuppressive medications can typically lead to hyperkalemia and require a potassium restriction. Another common characteristic in post-renal transplant patients is persistent hypophosphatemia. One factor that can contribute to hypophosphatemia is persistent secondary hyperparathyroidism. Another factor identified by several studies is the phosphotonin fibroblast growth factor-23 as a key cause of hypophosphatemia after transplantation. In addition, glucocorticoidinduced gluconeogenesis in the renal proximal tubule contributes to phosphaturia. In some cases, increased intake of high-phosphorus foods may not be sufficient for repletion, and oral replacement may be needed. Educating patients on optimizing nutrition after kidney transplant is individualized. Laboratories must be monitored frequently, and nutrition recommendations can be made accordingly. Unfor-

Refractory tertiary hyperparathyroidism after calcimimetics and delayed parathyroidectomy in a kidney transplant recipient

Persistent hyperparathyroidism affects renal outcomes and mortality. After kidney transplantation, cinacalcet is not approved as treatment for hyperparathyroidism. Parathyroidectomy, on the other hand, reverses electrolytes and mineral bone metabolism in almost all cases. Early parathyroidectomy may increase the chance of resolving hyperparathyroidism. A 58–year-old man with ESRD status post deceased donor kidney transplantation 3 years prior presented with bone aches. He had persistent hypercalcemia and hypophosphatemia secondary to hyperparathyroidism. Serum calcium ranged 9.3–11.4 mg/dl and serum phosphorus was decreased with a lowest value of 2.1 mg/dl. Intact PTH level was elevated to 487 pg/ml and total 25–OH vitamin D was 20 ng/ml. Bone density studies indicated osteopenia. He refused parathyroidectomy and was treated with cinacalcet. Because of persistent hyperparathyroidism, he underwent subtotal parathyroidectomy. Postoperatively, he required high phosphorus diet, phosphate supplements, and cinacalcet to maintain normal serum phosphorus levels. Intact PTH was still elevated with the level of 188 pg/ml while he continued cinacalcet. Normally, parathyroidectomy is performed 1 year posttransplantion unless severe bone disease, refractory hypercalcemia, or difficulty controlling phosphate wasting occurs. Phosphate wasting from hyperparathyroidism in our patient indicated parathyroidectomy; however, the surgery was delayed for 3 years while cinacalcet had been used. Post parathyroidectomy, hyperparathyroidism still persisted. Both cinacalcet and parathyroidectomy are imperfect to reverse hyperparathyroidism. Timely parathyroidectomy may determine the reversal of electrolyte and metabolic bone diseases; however, a delayed procedure may not have the same benefit. Since hyperparathyroidism is associated with higher incidence of kidney allograft dysfunction and postoperative mortality, should there be a level where pretransplant parathyroidectomy is performed?

Iatrogenic Persistent Hypophosphatemia In A Simultaneous Liver-Kidney Transplant Recipient

Hypophosphatemia from renal phosphate wasting during the immediate postoperative kidney transplant period is common and improves with supplementation. We report a case of hypophosphatemia secondary to small bowel bypass surgery and over the counter antacid use in a patient with stage 4 chronic kidney disease (CKD) many years after simultaneous liver-kidney transplant (SLKT). A 43-year-old man with a history of alcoholic end-stage liver disease and hepatorenal syndrome status post SLKT 5 years prior presented with recurrent small bowel obstruction which persisted despite conservative treatment. Following exploratory laparotomy, he had a jejunal bypass surgery due to the intra-operative finding of jejunum adherent to a single mass. Due to the friability of the tissue, lysis of the adhesions was felt to be unsafe. Postoperatively, he developed hypophosphatemia and severe malnutrition due to short bowel syndrome. He required total parenteral nutrition which led to improvement in serum phosphorus. However, hypophosphatemia recurred and the lowest level of 1.1 mg/dl occurred during the transition from parenteral nutrition to partial enteral nutrition. On review of medication, he had been taking over the counter antacids for “indigestion”. Serum calcium was low normal and intact parathyroid hormone was within normal range. The patient also had vitamin D deficiency with a total 25-OH vitamin D of 23 ng/ml. The serum phosphorus improved after stopping antacids but remained persistently low normal despite oral supplementation, and he continues to require intermittent intravenous phosphate supplementation. Although hyperphosphatemia is common in CKD, hypophosphatemia can occur from overzealous dietary restrictions and use of phosphate binders. Aluminum hydroxide is a potent phosphate binder commonly found in over the counter antacids. Ongoing review of medications (both prescription and over the counter) is important to prevent hypophosphatemia. In addition, intestinal bypass, especially jejunal bypass, contributes to hypophosphatemia, and our case underscores the importance of the jejunum in phosphate absorption.

Fibroblast growth factor 23 and calcium phosphate homeostasis after pediatric renal transplantation

FGF23 is a circulating factor regulating TPR and is increased in CKD. After RT, it seems to induce phosphorus wasting in adults. Data on FGF23 after PRT are scarce. Parameters of bone metabolism including calcium, phosphate, 25-(OH) vitamin D, 1,25-(OH)(2) vitamin D, alkaline phosphatase, PTH, and FGF23 were analyzed in 57 children after PRT and 11 controls. Median time after PRT was 25.9 (range 2-135) months. eGFR after PRT ranged from 15 to 175 mL/min/1.73 qm. Mean (±s.e.) FGF23 and PTH levels were significantly elevated compared with controls (146 ± 30 vs. 43 ± 3 ng/L, p = 0.001 and 182 ± 42 vs. 74 ± 18 ng/L, p = 0.004, respectively). Highest FGF23 levels were found in children with an eGFR below 60 mL/min*1.73 sqm (280 ± 69 vs. 62 ± 5 ng/L, p = 0.001), but significantly elevated values were already present in CKD2T. In a multivariate analysis, eGFR, PTH, calcium, and phosphate were significantly associated with FGF23. In a subgroup of 17 patients (29.8%) with persistent hypophosphatemia, phosphate levels were significantly associated with FGF23 and not with PTH. FGF23 is increased in children after PRT, especially in patients with chronic allograft dysfunction, and seems to be a more sensitive marker of dysregulated calcium phosphate homeostasis than PTH.

Next‐generation Sequencing Facilitates the Diagnosis in a Child With Twinkle Mutations Causing Cholestatic Liver Failure

Next‐generation Sequencing Facilitates the Diagnosis in a Child With Twinkle Mutations Causing Cholestatic Liver Failure

Osteomalacia caused by tumors in facies cranii mimicking rheumatoid arthritis

Tumor-induced osteomalacia (TIO) is an extremely rare metabolic bone disease and the occult offending tumor arising in facies cranii is even more uncommon. In this report, we described 2 middle-aged females with TIO caused by the tumor in facies cranii, which had ever been misdiagnosed as rheumatoid arthritis. Case 1 was present with diffuse bone pain and muscle weakness for 4 years, as well as esotropia in the right eye for 1 month. Case 2 was present with progressive bone pain in low back and hip for 2 years. Biochemical studies both showed persistent hypophosphatemia and urinary over wasting phosphate. Radiological examinations revealed the infiltrative mass in right apex partis petrosae ossis temporalis in case 1, and the soft mass in left nasal cavity and ethmoid sinuses in case 2, respectively. The offending tumors were resected completely in case 2, however, incompletely in case 1. Pathology examination revealed mixed connective tissue variant phosphaturic mesenchymal tumors. In conclusion, TIO should be presumed in patients presenting with unexplained persistent hypophosphatemia osteomalacia, also a thorough detection for tumor in facies cranii should be performed.

Natural History of Mineral and Bone Disorders After Living‐Donor Kidney Transplantation: A One‐Year Prospective Observational Study

Mineral and bone disorders (MBD), including hypercalcemia and hypophosphatemia, are common complications after renal transplantation; however, the natural course of these disorders has not been well documented, and the pathogenesis of persistent post-transplant MBD still remains elusive. This study was carried out to show the natural history of mineral metabolism in recipients after living-donor kidney transplantation and also to clarify post-transplant risk factors of persistent hypercalcemia and/or hypophosphatemia at 12months after transplantation. Living-donor kidney transplant recipients (N=34) at Tokyo Women's Medical University were prospectively and consecutively recruited. Parameters of MBD, including intact parathyroid hormone and full-length fibroblast growth factor23, were followed. Serum calcium levels increased until the fourth week post-transplantation, after which it reached a plateau; and serum phosphate decreased substantially at one week post-kidney transplantation, but recovered to the reference level at two months. Fibroblast growth factor23 gradually decreased to comparable levels for renal function, while hyperparathyroidism persisted for 12months after transplantation. Multivariate linear regression analysis revealed that intact parathyroid hormone was the best correlating factor with both hypercalcemia and persistent hypophosphatemia at 12months. This study suggests the need for testing of other interventions used for treatment of hyperparathyroidism which may help to offer better management of MBD after kidney transplantation.

The relative role of fibroblast growth factor 23 and parathyroid hormone in predicting future hypophosphatemia and hypercalcemia after living donor kidney transplantation: a 1-year prospective observational study

Kidney transplantation (KTx) restores many of the disorders accompanying end-stage renal failure. However, hypercalcemia and hypophosphatemia are both common complications after renal transplantation. Prospective observation of these complications has not been well described and pre-transplant predictors also remain unknown. This prospective observational cohort study was carried out to clarify pre-transplant risk factors of persistent hypophosphatemia and/or hypercalcemia at 12 months after transplantation. Consecutive living donor KTx recipients (n = 39) at Tokyo Women's Medical University were prospectively recruited. Parameters of bone and mineral metabolism including intact parathyroid hormone (iPTH) and full-length fibroblast growth factor (FGF) 23 were followed. FGF23 decreased to comparable levels for renal function while hyperparathyroidism persisted at 12 months after transplantation. Multivariate linear regression analysis revealed that pre-transplant iPTH correlated with hypercalcemia at 12 months and pre-transplant FGF23 was the best pre-transplant predictor of persistent hypophosphatemia at 12 months. It is intriguing that although FGF23 is not a causal factor for hypophosphatemia at 12 months post-transplantation, it is a significant predictor of this common complication.

Elevated Fibroblast Growth Factor 23 in a Patient With Metastatic Prostate Cancer and Hypophosphatemia

Elevated Fibroblast Growth Factor 23 in a Patient With Metastatic Prostate Cancer and Hypophosphatemia

FGF23 Concentrations Vary With Disease Status in Autosomal Dominant Hypophosphatemic Rickets

We measured FGF23 concentrations in subjects with ADHR. FGF23 and serum phosphate correlated positively in controls and negatively in subjects with ADHR. Elevated FGF23 concentrations were associated with lower phosphate values. The variable phenotype in ADHR may be caused by fluctuations in FGF23. Autosomal dominant hypophosphatemic rickets (ADHR) is a rare disorder of phosphaturia, hypophosphatemia, inappropriately low/normal calcitriol, and rickets/osteomalacia. ADHR is caused by mutations in a circulating peptide, fibroblast growth factor 23 (FGF23). We present the first report of FGF23 concentrations in subjects with ADHR. The aim was to test the hypotheses that subjects with ADHR have elevated FGF23 concentrations and that FGF23 concentrations are associated with disease severity. This was an observational study at a tertiary referral center. Subjects were from three kindreds with FGF23 mutations causing ADHR (n = 42). Controls were participants from these families without mutations (n = 55). Fasting blood and urine samples were obtained. Biochemistries were determined, and FGF23 concentrations were measured using two ELISAs. Three cases are presented illustrating activity of disease and FGF23 concentrations. One case shows persistent hypophosphatemia and elevation of FGF23 concentrations, whereas another shows remission of hypophosphatemia corresponding to a decrease in previously elevated FGF23 concentrations. Overall cross-sectional group differences were nonsignificant for serum phosphate and FGF23 concentrations. C-terminal FGF23 concentration in controls was 61.0 +/- 28.6 (SD) RU/ml (median, 52.5 RU/ml), and in subjects with mutations was 148.8 +/- 374.5 RU/ml (median, 63.1 RU/ml). Mean intact FGF23 concentration in controls was 44.7 +/- 14.9 pg/ml (median, 40.4 pg/ml), and in subjects with mutations was 83.2 +/- 233.0 pg/ml (median, 39.0 pg/ml). C-terminal FGF23 concentrations were at least +2 SD in 10/42(24%), and intact FGF23 concentrations were at least +2 SD in 3/34(9%). Phosphate correlated positively with C-terminal and intact FGF23 in both controls and in subjects with mutations with phosphate >2.5 mg/dl but correlated significantly negatively with C-terminal and intact FGF23 in ADHR subjects with phosphate < or =2.5 mg/dl. Elevated FGF23 concentrations are associated with hypophosphatemia in ADHR, and remission of the phenotype is associated with lower FGF23 concentrations. FGF23 has an opposite relationship with phosphate in ADHR compared with controls. We conclude that ADHR symptoms and disease severity likely fluctuate with FGF23 concentrations.

Post-renal transplantation hypophosphatemia: a review and novel insights

This review intends to elucidate the pathophysiologic mechanism of renal phosphorus loss in the post-renal transplantation population. This review will provide new insight in to the pathophysiologic mechanism(s) responsible for the development of this phenomenon and will also explore the pathogenetic role of persistent phosphorus wasting in the development of post-renal transplantation osteodystrophy. Recently, the phosphaturic hormone, fibroblast growth factor-23, has been ascertain to be increased in the sera of patients with chronic kidney and end-stage renal disease. There is new evidence that a non-PTH humoral factor is persistently present in post-renal transplantation patients that is likely responsible for the observed persistent renal phosphorus loss. We offer that fibroblast growth factor-23 (and/or other phosphatonins) is the culprit factor responsible for the phenomenon of persistent hypophosphatemia in post-renal transplantation patients. Moreover, we believe that the phenomenon of persistent renal phosphorus wasting is an important but overlooked cause of osteodystrophy and increased fracture risk in this patient population. The pathophysiology of post-renal transplantation phosphorus wasting is complex and to date is still not fully recognized. Further studies of the regulatory mechanism of fibroblast growth factor-23 and its metabolism may offer additional insights into phosphorus homeostasis and its clinical application in the post-renal transplantation population.

Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter.

Epidemiologic studies suggest that genetic factors confer a predisposition to the formation of renal calcium stones or bone demineralization. Low serum phosphate concentrations due to a decrease in renal phosphate reabsorption have been reported in some patients with these conditions, suggesting that genetic factors leading to a decrease in renal phosphate reabsorption may contribute to them. We hypothesized that mutations in the gene coding for the main renal sodium-phosphate cotransporter (NPT2a) may be present in patients with these disorders. We studied 20 patients with urolithiasis or bone demineralization and persistent idiopathic hypophosphatemia associated with a decrease in maximal renal phosphate reabsorption. The coding region of the gene for NPT2a was sequenced in all patients. The functional consequences of the mutations identified were analyzed by expressing the mutated RNA in Xenopus laevis oocytes. Two patients, one with recurrent urolithiasis and one with bone demineralization, were heterozygous for two distinct mutations. One mutation resulted in the substitution of phenylalanine for alanine at position 48, and the other in a substitution of methionine for valine at position 147. Phosphate-induced current and sodium-dependent phosphate uptake were impaired in oocytes expressing the mutant NPT2a. Coinjection of oocytes with wild-type and mutant RNA indicated that the mutant protein had altered function. Heterozygous mutations in the NPT2a gene may be responsible for hypophosphatemia and urinary phosphate loss in persons with urolithiasis or bone demineralization.

Consequences of the correction of post-transplantation hypophosphatemia on mineral metabolism

To study the effect of the correction of post-transplantation Hypophosphatemia on mineral metabolism. 15 patients with renal transplants for 3 to 12 months, Serum Creatinine "177 micmol/1, were treated with oral phosphorus (P) for persistent hypophosphatemia. 3 periods of blood and urine collection at intervals of 3 weeks. T1 under basal treatment with oral P, T2 after 3 weeks off medication with P, Ca, or P binders. T3 3 weeks after going back on oral P supplements. Serum P dropped from T1 to T2 (1.03 +/- 0.03 mmol/L to 0.83 +/- 0.03 mmol/L, p "0.0001), rising again in T3 to 1.06 +/- 0.03 mmol/L. From T1 to T2, PTHi decreased from 95.4 +/- 8.7 to 66.8 8.9pg/ml), osteocalcin rose from 3.8 +/- 1.2 to 16.6 +/- 2.3ng/ml (p<0.001) and 25-Vit D rose from 16.7 +/- 1.9 to 21.4 +/- 2.1 ng/l (p<0.001), with the reversal of these changes from T2 to T3 when serum P increased once again. There was a significant correlation between serum P and PTHi and serum P and 25-Vit D. There were no significant variations of the serum Ca, Alk. Phosph., ICTP and CaFE values in the three periods. 1-Serum P never dropped below 0.55 mmol/L, which had no clinical consequences, 2- When the P dropped, PTHi also dropped and osteocalcin and 25-Vit D rose, without any major variation in bone catabolism, 3- Correction of hypophosphatemia may delay recovery from secondary hyperparathyroidism.

Decreased concentration of 1,25-dihydroxyvitamin D 3 receptors in peripheral mononuclear cells of patients with X-linked hypophosphatemic rickets: effect of phosphate supplementation

Abnormal renal tubular phosphate transport is considered to be the primary defect in X-linked hypophosphatemic rickets (XLH). However, the resistance to vitamin D treatment in XLH cannot be explained by hypophosphatemia alone. Since most of the actions of vitamin D are mediated by its receptors (VDR), abnormalities of VDR have been postulated in XLH. In order to investigate this possibility, we measured the concentration of VDR in PHA-activated peripheral mononuclear cells from 10 XLH patients. Patients without phosphate supplementation showed significantly lower concentration (21.7 ± 5.1 fmol/mg protein, mean ± SEM) compared to the normal controls (60.7 ± 4.0). On the contrary, there was no significant difference between the phosphate-supplemented patients (58.3 ± 2.7) and controls. There was a significant positive correlation between VDR concentration and serum phosphate ( P < 0.05). In two patients, VDR was increased after daily phosphate supplementation was started. These results indicate that a decreased concentration of VDR secondary to persistent hypophosphatemia is one of the causes of vitamin D resistance in XLH.

Rickets and Metabolic Disorders

In Reply.— We have reviewed the letter from Drs Ozsoylu and Besim and have reviewed the metabolic data from our patient with tyrosinosis to determine if there was evidence of rickets in our patient. At the time that the published x-rays were obtained, the patient had normal serum calcium and phosphorus. However, a month earlier, when the x-rays appeared normal apart from probable osteopenia, the patient did have persistent hypophosphatemia, 1.5 to 1.8 mg/dL (normal 4.0 to 6.0 mg/dL), and elevated alkaline phosphatase, 956 IU/L (normal 50 to 380 IU/L).

Differences between the effects of phosphate deficiency and vitamin D deficiency on bone metabolism

It has been widely believed that phosphate deficiency causes osteomalacia. Based on this belief, the rickets of familial hypophosphatemia has been attributed to phosphate deficiency associated with the hypophosphatemia. The present studies on rats have, however, demonstrated significant differences between the effects of phosphate deficiency on bone metabolism and the characteristic features of rickets. Weanling rats, maintained on a mildly phosphate deficient diet, had hypercalcemia and hypophosphatemia, and impairment of body growth, bone growth, and bone mineralization. The maximum effect was observed at 5 wk; between 5 and 20 wk the rats improved despite persistent hypophosphatemia. Histologically, at 5 wk the bone showed thick unmineralized osteoid seams covering most bone surfaces, but the epiphyseal cartilage was normal. In addition, the excess osteoid readily incorporated tetracycline indicating normal mineralization and, based on a new sequential pulse labeling technique, the linear bone apposition rate (LBA) was significantly ( p < 0.001) increased above control values. This increase was observed within the initial 4 days of phosphate (P) deficiency and persisted up to 15 wk. This effect of P deficiency on LBA was dependent on vitamin D activity. At 4 wk, the mean LBA was 0.106 ± 0.003 (1 SE) in control rats, 0.149 ± 0.008 μm/hr in P deficient rats, 0.083 ± 0.004 μm/hr in vitamin D deficient rats and 0.086 ± 0.006 μm/hr in rats deficient in both P and vitamin D. We have reported a similar increase in LBA with parathyroid hormone activity. With vitamin D deficiency, phosphate deficient rats showed all the characteristic features of rickets; disorganization of epiphyseal cartilage, excessive unmineralized osteoid, and reduced mineralization based on the incorporation of tetracycline. We conclude that the effects of phosphate deficiency on bone metabolism more closely resembles the effects of PTH activity than the characteristic effects of osteomalacia and rickets.

Renal brush border membrane adaptation to phosphorus deprivation in the Hyp/Y mouse.

Human X-linked hypophosphataemia (XLH)1 involves a partial loss in net renal reabsorption of phosphate anion (Pi). The mutant male hemizygote has about half the normal renal transport activity2 and this is quite insensitive to circulating parathyroid hormone (PTH)2,3. The renal defect is sufficient to explain persistent hypophosphataemia in XLH. The hypophosphataemic mouse (Hyp)4 also has an X-linked defect in renal reabsorption of Pi (refs 4–7). The mutant male hemizygote (Hyp/Y) has about half the normal renal reabsorption activity and this abnormality persists after parathyroidectomy7. Conservation of the X chromosome during mammalian evolution and evidence for functional homology between species for specific X-linked genes8 have encouraged us to use the Hyp mouse as a model for the renal defect in XLH. We have studied Pi transport in purified renal brush border membrane vesicles (BBMV) prepared from Hyp/Y mice5,9. A selective loss involving almost half the Na+-dependent Pi co-transport activity is present in Hyp/Y membranes. These findings, genetic studies in man2,10 and recent physiological evidence11 suggest that Pi transport in the mammalian nephron occurs by at least two processes: one under the control of an X-linked gene that is more sensitive to PTH inhibition and another process, controlled by an autosomal locus, that is less sensitive to the hormone. We report here on the ability of the Hyp/Y mouse to adapt to phosphorus deprivation; the response is observed both in vivo in net reabsorption of Pi and in vitro in BBMV transport of Pi.

Renal adaptation to phosphate deprivation in the Hyp mouse with X-linked hypophosphatemia.

The mechanism of renal adaptation to variation in dietary inorganic phosphate (Pi) was investigated in intact Hyp/+ (heterozygous) mice and +/+ (normal homozygous) female siblings. Hyp/+ mice were selected for expression of the X-linked Hyp allele, when fed the control diet (0.6% P), by evidence of persistent postweaning hypophosphatemia (1.78 ± 0.08 mM, mean ± SE, versus 2.68 ± 0.19 mM in +/+ siblings (p &lt; 0.01)). Hyp/+ mice had an elevated fractional excretion index for Pi (FEIPi) (0.570 ± 0.024, mean ± SE) on this diet versus +/+ siblings (0.352 ± 0.025, p &lt; 0.001). Renal cortex content of Pi (~46 nmol/mg protein) and net radioisotopic uptake of Pi by slices were similar in Hyp/+ and +/+ mice. Purified brush border membrane vesicles (BBMV) from Hyp/+ kidney cortex transported labelled Pi (100 μM) by a Na+-dependent mode at about one-half the rate (p &lt; 0.001) observed in +/+ mice. Hyp/+ and +/+ mice fed a low P diet (0.03%) maintained their phenotypic differences in vivo and in vitro. Both adapted to chronic (&gt; 2 week) Pi deprivation with a striking reduction (40- to 50-fold) of FEIPi (p &lt; 0.001) and a fall in plasma [Pi] (p &lt; 0.001). Neither the renal Pi content nor uptake of Pi by slices changed in deprived Hyp/+ and +/+ mice. On the other hand, BBMV uptake by Na+-dependent cotransport increased 200% (p &lt; 0.001) during Pi deprivation in both the Hyp/+ and +/+ mouse. D-glucose transport did not increase. We conclude that renal adaptation to phosphate deprivation is achieved by modulation of a component of Na+-dependent cotransport in brush border membrane that is not controlled by the X-linked gene.