Treatment of hyperphosphatemia: the dangers of high PTH levels.

The control of secondary hyperparathyroidism (SHPT) in pediatric chronic kidney disease is of utmost importance. Even though parathyroid hormone (PTH) is an important biomarker of mineral and bone disorders associated to CKD (CKD-MBD), calcium, phosphate, alkaline phosphatase, and vitamin D are also crucial and should be assessed together. In pediatric dialysis, high PTH levels have been associated with impaired longitudinal growth, bone disease, cardiovascular comorbidities, left ventricular hypertrophy, anemia, and even mortality (when PTH levels were above 500 pg/mL, i.e., 8.3-fold the upper normal limit (UNL)). As such, high PTH levels are for sure deleterious, but too low PTH levels have also been shown to impair growth and to promote vascular calcifications because of the underlying adynamic bone. This manuscript is part of a pros and cons debate for keeping PTH levels within the normal range in pediatric CKD, focusing on the pros. High bone turnover lesions can occur at lower PTH levels than "current" guidelines would suggest; thus, PTH alone is not a good predictor of the underlying osteodystrophy. PTH results can vary locally depending on the assay. Existing guidelines for PTH targets are conflicting and based on a very little evidence. However, the 120-180 pg/mL (2- to 3-fold the UNL) range is common to most of the guidelines; it seems to be a reasonable target in children undergoing dialysis, even though it does not correspond to "normal" PTH levels. As always, the philosophy of PTH levels in pediatric dialysis may be balanced, i.e., "not too low, not too high, and keep phosphate under control."

Effects of Highly Active Antiretroviral Therapy on Renal Function and Renal Phosphate Handling in African Adults with Advanced HIV and CKD.

BACKGROUND: Highly Active Antiretroviral Therapy (HAART) has been implicated in renal dysfunction with hypophosphataemia. OBJECTIVE: We prospectively evaluated renal phosphate excretion during HAART use. METHOD: Newly diagnosed human immunodeficiency virus (HIV)-infected individuals were treated with Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz (TDF/FTC/EFV), n=33; Zidovudine/Lamivudine/Nevirapine (ZDV/3TC/NVP), n=53; and Zidovudine/Lamivudine/Efavirenz (ZDV/3TC/EFV), n=16. Creatinine and phosphate were assayed in blood and urine simultaneously at baseline, 1, 3, 6 and 9 months. Glomerular filtration rate (eGFR), fractional phosphate excretion and reabsorption (FEPi % and TRP), and the ratio of tubular maximum reabsorption of phosphate (TmP) to GFR (TmP/GFR) were estimated. RESULTS: At baseline, eGFR showed moderate chronic kidney disease (mean: 35.50 ± 2.02, 33.14 ± 1.63, and 39.97±1.84 ml/min/1.73m2 in the 3 groups respectively); 54 (52.9%) patients had hyperphosphataemia (>1.4mmo/L); 43 (42.2%) had normophosphataemia (0.6-1.4mmol/L); 5 (4.9%) had hypophosphataemia (<0.6mmol/L). eGFR improved significantly from 1 month (≥60, 58.65 ± 1.11, and 51.76 ±1.59 ml/min/1.73m2; p=0.04, <0.001, 0.67 respectively), with a relapse at 9 months in TDFtreated subjects (50.10 ± 1.89 ml/min/1.73m2). TDF/FTC/EFV resulted in significantly greater reduction in plasma phosphate than ZDV/3TC/NVP (p=0.031), but not significantly different from ZDV/3TC/EFV (p=0.968). Similarly, ZDV/3TC/EFV resulted in significantly greater reduction in plasma phosphate than ZDV/3TC/NVP (p=0.036). FEP% progressively increased with HAART duration, more in TDF-treated and ZDV/3TC/EFV-treated groups than ZDV/3TC/NVP (p=0.014); TRP was elevated (>0.86), implying non-maximal phosphate reabsorption. TmP/GFR values were elevated, (>1.35mmol/l). CONCLUSION: HIV causes kidney dysfunction with reduced phosphate excretion resulting in hyperphosphataemia but HAART improves renal function. Prolonged use of TDF can cause renal toxicity with hypophosphataemia as fractional excretion progressively increased with duration of therapy unlike ZDV/3TC/NVP. The use of different third agents (either NVP or EFV) in zidovudine-based therapy results in significantly different plasma phosphate levels; ZDV/3TC/EFV, like TDF/FTC/EFV, resulted in significantly greater decline in plasma phosphate than ZDV/3TC/NVP. Thus, Evafirenz (EVF) may have similar or synergistic adverse effects with tenofovir disoproxil fumarate (TDF).

Ubiquitin COOH-terminal hydrolase L1 deletion is associated with urinary α-klotho deficiency and perturbed phosphate homeostasis.

Loss of ubiquitin COOH-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme required for neuronal function, led to hyperphosphatemia accompanied by phosphaturia in mice, while calcium homeostasis remained intact. We therefore investigated the mechanisms underlying the phosphate imbalance in Uchl1-/- mice. Interestingly, phosphaturia was not a result of lower renal brush border membrane sodium-phosphate cotransporter expression as sodium-phosphate cotransporter 2a and 2c expression levels was similar to wild-type levels. Plasma parathyroid hormone and fibroblast growth factor 23 levels were not different; however, fibroblast growth factor 23 mRNA levels were significantly increased in femur homogenates from Uchl1-/- mice. Full-length and soluble α-klotho levels were comparable in kidneys from wild-type and Uchl1-/- mice; however, soluble α-klotho was reduced in Uchl1-/- mice urine. Consistent with unchanged components of 1,25(OH)2D3 metabolism (i.e., CYP27B1 and CYP24A1), sodium-phosphate cotransporter 2b protein levels were not different in ileum brush borders from Uchl1-/- mice, suggesting that the intestine is not the source of hyperphosphatemia. Nonetheless, when Uchl1-/- mice were fed a low-phosphate diet, plasma phosphate, urinary phosphate, and fractional excretion of phosphate were significantly attenuated and comparable to levels of low-phosphate diet-fed wild-type mice. Our findings demonstrate that Uchl1-deleted mice exhibit perturbed phosphate homeostasis, likely consequent to decreased urinary soluble α-klotho, which can be rescued with a low-phosphate diet. Uchl1-/- mice may provide a useful mouse model to study mild perturbations in phosphate homeostasis.

Continuous Subcutaneous Recombinant Parathyroid Hormone (1-34) Infusion in the Management of Childhood Hypoparathyroidism Associated with Malabsorption.

BACKGROUND/AIMS: Hypoparathyroidism associated with malabsorption can be particularly challenging to manage due to limited and erratic intestinal absorption of calcium and vitamin D analogues, resulting in episodes of hypo- or hypercalcaemia. We evaluated the role of continuous subcutaneous recombinant parathyroid hormone (rhPTH 1-34) infusion (CSPI) in children with hypoparathyroidism associated with intestinal malabsorption resistant to conventional therapy. METHOD: Four patients (8-13 years of age), with symptomatic hypocalcaemia resistant to conventional therapy, were started on CSPI (follow-up 3-8 years) in two paediatric endocrinology units in Europe. RESULTS: Serum calcium normalized within 48 h of commencing treatment in all 4 patients. An average rhPTH 1-34 dose of 0.4 µg/kg/day resulted in a substantial reduction in symptomatic hypocalcaemia and hypo-/hypercalcaemia-related hospital admissions. An increased alkaline phosphatase activity was noted in the first 6 months on CSPI, indicating an increase in bone turnover. In 2 patients with elevated urinary calcium excretion before CSPI, this normalized in the first year on treatment. No significant side effects were noticed in the short or long term, with patient-reported preference of CSPI over conventional treatment. CONCLUSION: CSPI is a promising and effective treatment option for managing hypocalcaemia and hyperphosphataemia in children with hypoparathyroidism associated with intestinal malabsorption.

Habitual dietary phosphorus intake and urinary excretion in chronic kidney disease patients: a 3-day observational study.

Hyperphosphatemia in chronic kidney disease (CKD) is associated with vascular calcification, cardiovascular morbidity and mortality. The aim of this study was to estimate the daily dietary phosphorus intake compared with recommendations in CKD patients and to evaluate the reproducibility of the 24-h urinary phosphorus excretion. Twenty CKD patients stage 3-4 from the outpatient clinic, collected 24-h urine and kept dietary records for 3 consecutive days. The mean daily phosphorus intake was 1367±499, 1642±815 and 1426±706 mg/day, respectively (P=0.57). The mean urinary phosphorus excretion was 914±465, 954±414 and 994±479 mg/day, respectively (P=0.21). In this population of CKD patients stage 3-4 the daily phosphorus intake was above the recommended. Twenty-four-hour urinary phosphorus excretion was reproducible and the data indicate that a single 24-h urine collection is sufficient to estimate the individual phosphorus excretion.

Bixalomer, a novel phosphate binder with a small swelling index, improves hyperphosphatemia in chronic kidney disease rat.

In the present study, we evaluated the in vitro characteristics of bixalomer for phosphate binding and swelling and assessed the urinary phosphorus excretion and plasma phosphorus level-lowering effect of bixalomer. The maximum phosphate binding capacity was 6.49 mmol/g and was maximized at pH 6.09. In rats, consuming a high-phosphorus diet resulted in elevated urinary phosphorus excretion, while consuming a diet of bixalomer (0.3-9%) or sevelamer hydrochloride (sevelamer HCl; 3-9%) mixed with a high-phosphorus diet resulted in a dose-dependent reduction in urinary phosphorus excretion. Rats with adenine sulfate-induced chronic kidney disease (CKD) had plasma phosphorus levels of 14.9-18.8 mg/dl, while CKD rats administered a 3% bixalomer or 3% sevelamer HCl diet for 4 weeks had relatively decreased plasma phosphorus levels (6.86 ± 1.42 or 5.32 ± 0.27 mg/dl, respectively). Bixalomer elevated the lowered blood pH in acidemic CKD rats, while sevelamer HCl administration only exacerbated the acidemia. The swelling index, which represents water adsorption capacity, of bixalomer was measured by subtracting the dry weight from the hydrated wet weight of the polymer. The swelling index of bixalomer was four times lower than that of sevelamer HCl. Bixalomer was found to reduce the plasma phosphorus level in CKD rats by binding phosphate in the small intestine and reducing phosphate absorption. Bixalomer showed favorable characteristics of a smaller swelling index than sevelamer HCl and amelioration of metabolic acidosis. These findings suggest that bixalomer may be useful in treating hyperphosphatemia, with fewer gastrointestinal side effects and amelioration of metabolic acidosis than sevelamer HCl.

Hyperphosphatemia, hypocalcemia and increased serum potassium concentration as distinctive features of early hypomagnesemia in magnesium-deprived mice.

Magnesium-deficient patients show dysfunctional calcium (Ca(2+)) metabolism due to defective parathyroid hormone (PTH) secretion. In mice and rats, long-term magnesium (Mg(2+)) deprivation causes hyperphosphaturia and increases fibroblast growth factor 23 (FGF23) secretion, despite normal serum phosphate (Pi) and Ca(2+). Electrolyte disturbances during early hypomagnesemia may explain the response of mice to long-term Mg(2+) deprivation, but our knowledge of electrolyte homeostasis during this stage is limited. This study compares the effect of both short- and long-term Mg(2+) restriction on the electrolyte balance in mice. Mice were fed control or Mg(2+)-deficient diets for one to three days, one week, or three weeks. Prior to killing the mice, urine was collected over 24 h using metabolic cages. Within 24 h of Mg(2+) deprivation, hypomagnesemia, hypocalcemia and hyperphosphatemia developed, and after three days of Mg(2+) deprivation, serum potassium (K(+)) was increased. These changes were accompanied by a reduction in urinary volume, hyperphosphaturia, hypocalciuria and decreased Mg(2+), sodium (Na(+)) and K(+) excretion. Surprisingly, after one week of Mg(2+) deprivation, serum K(+), Pi and Ca(2+) had normalized, showing that mineral homeostasis is most affected during early hypomagnesemia. Serum Pi and K(+) are known to stimulate secretion of FGF23 and aldosterone, which are usually elevated during Mg(2+) deficiency. Thus, the hyperphosphatemia and increased serum K(+) concentration observed during short-term Mg(2+) deprivation may help our understanding of adaptation to chronic Mg(2+) deficiency.

Use of a standard urine assay for measuring the phosphate content of beverages.

Hyperphosphatemia is strongly associated with cardiovascular morbidity and mortality in patients with chronic kidney disease. Phosphate in beverages is readily absorbed and could have a significant impact on serum phosphate levels. Patients are routinely warned about the phosphoric acid in colas, but information on the phosphate content of other beverages is difficult to find. We have shown that the phosphomolybdate method, which is used in the vast majority of hospital laboratories for measuring phosphate in urine, can give an accurate measurement of the phosphate content of beer, cider, wine, and soft drinks. No change to the standard assay protocol is required. There was considerable variation between different types of wine and beer, probably due to the methods of production. The information the assay provides could enable staff providing dietary advice to compare locally available beverages and help patients to avoid or limit their intake of those with high phosphate content.

Estimation of 24-hour urine phosphate excretion from spot urine collection: development of a predictive equation.

BACKGROUND: The management of hyperphosphatemia in patients with moderate to severe chronic kidney disease (CKD) includes dietary phosphate restriction and/or prescription of phosphate binders. Measuring phosphate intake in CKD is important for monitoring dietary adherence and for the effectiveness of therapeutic interventions. The 24-hour urine collection is the gold standard method for determining phosphate intake; however, timed urine collections are cumbersome and prone to error. We investigated the precision and accuracy of spot urine phosphate measurements, compared to 24-hour urine phosphate (24hUrP) collection. STUDY DESIGN, SETTING, AND PARTICIPANTS: We evaluated simultaneous spot and 24hUrP measurements, collected on multiple occasions, from 143 participants in the Phosphate Normalization Trial, a randomized trial of phosphate binders versus placebo among persons with an estimated glomerular filtration rate between 20-45 mL/minute per 1.73 m2. We used residual analyses and graphical methods to model the functional relationship of spot urine phosphate and creatinine measurements with 24hUrP. We used multiple linear regression to test whether additional covariates improved model prediction, including treatment assignment, age, sex, height, weight, urine collection time, and last meal time. We internally validated results using leave-one-out cross-validation, and externally validated in an independent replication cohort. RESULTS: A log-log relation between the spot urine phosphate-to-creatinine ratio and 24hUrP excretion yielded the best model fit. In addition to spot urine phosphate and creatinine concentrations, inclusion of age, sex, and weight significantly improved prediction of 24hUrP. Compared with a spot urine phosphate-to-creatinine ratio alone (r2 = 0.12, P < .001), the new equation more accurately predicted 24hUrP (leave-one-out validation r2 = 0.43, P < .001, independent validation r2 = 0.39, P < .001). CONCLUSION: We describe a novel equation to predict 24hUrP excretion using spot urine phosphate and creatinine, age, sex, and weight. The equation is more accurate and precise than the urine phosphate-to-creatinine ratio alone, and it provides a simple method for estimating 24hUrP excretion in patients with nondialysis-requiring CKD.

Hyperphosphatemia is associated with overt proteinuria in non-diabetic patients with late-stage chronic kidney disease: a cross-sectional study.

PURPOSE: Proteinuria plays an important role in the progression of chronic kidney disease (CKD), as well as a powerful predictor of cardiovascular morbidity and mortality. The aim of our study was to investigate the potential determinants associated with overt proteinuria in non-diabetic patients with late-stage CKD. METHODS: Between January 2006 and September 2011, a total of 418 non-diabetic patients with CKD stage 3-5 were enrolled from the outpatient department of nephrology. Urinary protein-to-creatinine ratio and serum phosphorus were determined. Other laboratory parameters, associated comorbidities, medication use, body mass index, and blood pressure were also assessed. RESULTS: The mean age of the patients was 66.7 ± 14.0 years. In multiple logistic regression analysis and adjusting for established risk factors, the odds ratios for overt proteinuria were 3.96 (95 % confidence interval, 1.80-8.76; p = 0.001) for higher serum phosphorus level (≥4.3 mg/dl) and 3.56 (95 % confidence interval, 1.47-8.63; p = 0.005) for hypercholesterolemia (≥217 mg/dl), compared to subjects with serum phosphorus <3.3 mg/dl and cholesterol level 158-184 mg/dl. The similar significant findings remained robust in individuals not receiving phosphate binder. CONCLUSIONS: Hyperphosphatemia and high serum cholesterol are associated with overt proteinuria in non-diabetic patients with late-stage CKD. Further studies should clarify whether this relation is causal and whether serum phosphorus level should be a new therapeutic target for proteinuria reduction.

Lanthanum carbonate reduces urine phosphorus excretion: evidence of high-capacity phosphate binding.

The effectiveness of phosphate binders can be assessed by evaluating urinary phosphorus excretion in healthy volunteers, which indicates the ability of the phosphate binder to reduce gastrointestinal phosphate absorption. Healthy volunteers were enrolled into one of five separate randomized trials; four were open label and one double blind. Following a screening period of ≤28 days, participants received differing tablets containing lanthanum carbonate [LC, 3000 mg/day of elemental lanthanum (in one study other doses were also used)]. Participants received a standardized phosphate diet and remained in the relevant study center throughout the duration of each treatment period. The end point in all studies was the reduction in urinary phosphorus excretion. Reductions in mean 24-h urinary phosphorus excretion in volunteers receiving a lanthanum dose of 3000 mg/day were between 236 and 468 mg/day over the five separate studies. These data in healthy volunteers can be used to estimate the amount of reduction of dietary phosphate absorption by LC. The reduction in 24-h urinary phosphorus excretion per tablet was compared with published data on other phosphate binders. Although there are limitations, evidence suggests that LC is a very effective phosphate binder in terms of binding per tablet.

Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.

Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.