Urinary Phosphate Excretion Research Articles

Iron, aluminum, and lanthanum-based drugs for treatment of hyperphosphatemia

The control of the serum phosphorus (P) level in chronic kidney disease patients is important because elevated serum P levels are associated with progression of vascular calcification and increased mortality in these patients. In 2014, a novel phosphate binder, ferric citrate hydrate (Riona(®)), became available for the treatment of hyperphosphatemia in Japan, the first country to approve this medication. Ferric citrate hydrate, which relies upon the potent phosphate-binding capacity of ferric iron, inhibits P absorption by forming complexes between ferric iron and dietary phosphate in the gut. The active pharmaceutical ingredient in ferric citrate hydrate provides a larger specific surface area and higher water solubility; therefore, it is expected to have greater efficacy in terms of its phosphate-binding capacity. In clinical trials, ferric citrate hydrate significantly reduced the serum phosphate level and effectively maintained serum P concentrations throughout the duration of the trials. Moreover, in one clinical trial, ferric citrate hydrate significantly decreased levels of fibroblast growth factor-23 (FGF-23) in nondialysis patients. FGF-23 is an endocrine hormone that increases urinary phosphate excretion to maintain serum P at the proper level. A portion of the iron from ferric citrate hydrate is absorbed and transported throughout the body as transferrin-bound iron, where it is used for the synthesis of hemoglobin, enzymes, and others. Although safer and more effective phosphate binders are expected in the future, ferric citrate hydrate will become a new approach for the treatment of hyperphosphatemia.

Abstract P389: Effects of Dietary Patterns on Vitamin D and Other Markers of Bone-Mineral Metabolism: Results From the Dash Trial

Background: The relationship of CVD with vitamin D levels and other markers of bone-mineral metabolism is of substantial interest. The Dietary Approaches to Stop Hypertension (DASH) diet effectively lowers blood pressure and is now recommended to promote CV health. The effects of the DASH diet on vitamin D and other markers of bone-mineral metabolism is unknown. Objective: To determine the effect of dietary patterns on blood levels of vitamin D, PTH, and ionized calcium, and urinary excretion of calcium and phosphate. Methods: Data on study outcomes were available in 334 participants from the original DASH trial. Baseline levels were obtained from blood and urine collected at the end of the run-in while on the control diet. Participants were then randomized to control diet (37% kcal total fat); fruits & vegetable diet (also 37% kcal total fat); or the DASH diet (27% kcal total fat). Follow-up levels were obtained during the last week of the eight-week intervention period. Results: Mean (±SD) baseline blood levels of vitamin D, PTH , and ionized calcium were 15.1±3.7ng/ml, 46.1±18.5 ng/ml and 1.3±0.06 mmol/l, respectively. For urinary calcium and phosphate were 126.8±45.3mg/dl and 715.0±277.3 mg/dl, respectively. See table for within-diet changes. The DASH diet, net of control, reduced vitamin D by -1.29ng/ml (P= 0.005). In stratified analyses, the reduction in vitamin D appeared more prominent in blacks, but the p-value for interaction (race*diet) was non-significant (P=0.21). Otherwise, the DASH diet had no significant effect on the other markers, net of control. Compared to control, the fruit & vegetable diet reduced urinary calcium and phosphorus excretion. Conclusion: The DASH diet modestly reduced vitamin D levels among all participants, with potentially larger effects in blacks. The reduction in vitamin D levels might have resulted from the lower fat content of the DASH diet. Overall, during the eight-weeks of intervention, no major harm or benefit of the DASH diet was documented on biomarkers related to bone-mineral metabolism.

Phosphate as a cardiovascular risk factor: effects on vascular and endothelial function

BackgroundHyperphosphataemia is a risk factor for accelerated cardiovascular disease in chronic kidney disease. The mechanism is poorly understood; it is unclear whether phosphate has direct effects or effects mediated via calcification or FGF23. We investigated direct effects of phosphate on endothelial function using myography to study rat and human blood vessels. In addition we assessed the effects of phosphate loading on endothelial function in a clinical study. MethodsResistance vessels from patients with (n=12) and without (n=13) chronic kidney disease were incubated in normal or high phosphate. Vasoconstrictor and vasorelaxation responses were measured. Concentration-response curves were constructed and comparisons made. Identical experiments were performed in rat mesenteric vessels with and without phosphodiesterase type 5 inhibitor. A cross-over study was done in 19 healthy volunteers receiving phosphate supplements or binders and endothelial function measured by flow mediated dilatation (FMD). Primary outcome was percent change in FMD from baseline. FindingsNine to 13 vessels were used in each group. Endothelium-dependent vasodilatation was impaired in high compared with normal phosphate in rat (mean maximum vasodilatation 64% [SE 9] vs 95 [1], p<0·001) and human vessels with (25·3 [11·1] vs 75·7 [13·6], p<0·001) and without chronic kidney disease (42·9 [12] vs 79·4 [8·2], p=0·003). In rat vessels, these effects were reversed by a phosphodiesterase type 5 inhibitor. In vivo in volunteers, endothelial function was reduced by phosphate loading (median maximum vasodilatation 3·38% [IQR 2·57–5·26] vs 8·4 [6·2–11·6], p<0·001); this effect was independent of serum phosphate concentration but associated with urinary phosphate excretion and serum FGF23 concentrations. InterpretationProlonged exposure to phosphate is associated with endothelial dysfunction, a direct effect of phosphate, which might contribute to cardiovascular risk in chronic kidney disease. In a high phosphate environment, endothelial and vascular dysfunction is evident in blood vessels and in man exposed to prolonged oral phosphate loading. These effects might be mediated by disruption of the NO pathway. FundingBritish Heart Foundation, Darlinda's Charity for Renal Research.

Phosphorus: a new cardiovascular risk factor?

Phosphorus is an essential mineral in the regulation of many metabolic processes. However, is known as alterations in serum phosphate levels, compared to the normal range, have clinical relevance: many studies about phosphorus and cardiovascular risk have shown that high serum phosphate levels are associated with clinical and subclinical cardiovascular disease, in CKD and non-CKD patients. In recent years, serum phosphate level within the upper limits of normal range is also identified as a "stealthier killer", and has emerged as a risk factor of cardiovascular mortality and progression of CKD. This mounting evidence suggests the possibility that lowering serum phosphate levels may be a future target of cardiovascular disease management, also through the use of early biomarkers of phosphate overload, such as FGF23, Klotho or the urinary fractional excretion of phosphate. The goal must be an early diagnosis and treatment of disordered phosphorus metabolism, before end-organ damage occurs. Since the western diet is rich in phosphate, a dietary restriction associated with the use of phosphate binders, as well as the use of intervention such as calcitriol supplementation, certainly will have a positive influence on the phosphate-regulatory axis.

Effect of a Toxic Dose of Acetaminophen on Electrolytes and Histopathological Changes in the Kidney.

Introduction: Acetaminophen in toxic doses can cause renal failure. The actual mechanism of acetaminopheninduced renal failure is still unknown. The aim of the current study is to investigate the effect of single toxic dose of acetaminophen on renal function and renal histopathological structure. Method: A single toxic dose of acetaminophen (500 mg/kg) was injected intraperitoneally into male Wistar rats. Serum acetaminophen, biochemical markers of renal and liver functions, serum and urine electrolytes were measured at 4, 12 and 24 h after drug injection. The histopathology of renal tissue was investigated. Results: Serum ALT, AST, BUN and creatinine were significantly deteriorated in the experiment group. Acetaminophen injection significantly caused serum sodium retention, hypokalemia and hyperosmolality. In the urine, there was significantly higher excretion of sodium, potassium and phosphate. Renal biopsy showed structural changes resembling acute tubular necrosis. The control group did not show any of the changes observed in the case group. Discussion: Acetaminophen in toxic doses can cause renal injury starting 12 to 24 h postinjection.The histopathological changes in kidney structure resemble acute tubular necrosis. Acetaminophen also alters the renal handling of electrolytes observed by sodium retention, an increase in serum osmolality, hypokalemia and an increase in the urinary excretion of sodium, potassium and phosphate.

Low-dose adefovir dipivoxil may induce Fanconi syndrome: clinical characteristics and long-term follow-up for Chinese patients.

Adefovir dipivoxil (ADV) nephrotoxicity is well known at a dose of 60 mg day(-1) or 120 mg day(-1). However, renal toxicity at a low-dose of 10 mg ADV for HBV-infected patients is not fully described. Our objective was to analyse the clinical features and outcomes of ADV-related Fanconi's syndrome in the Chinese population. This was a retrospective study. A total of 35 patients with ADV-related Fanconi's syndrome were studied. Clinical manifestations and biochemical parameters were analysed. 19 patients were from Peking Union Medical College Hospital (PUMCH) included from August 2010 to December 2012. A total of 16 patients were eligible from case reports in the Chinese population retrieved in PUBMED, WANFANG and CNKI database. Bone mineral density and biochemical parameters including serum phosphate, calcium, creatinine, alkaline phosphatase (ALP) were measured before and after ADV cessation and during the follow-up. All recruited patients had hypophosphataemia, increased urinary phosphate excretion and elevated alkaline phosphatase. Serum phosphate levels rapidly increased especially within the 4 weeks after ADV cessation. Serum creatinine remained high or at the upper limit of normal range even after ADV cessation for 1 year. ALP increased in the first three months of ADV cessation and decreased at the 24th week. Bone mineral density was significantly improved after 6 months cessation of ADV. ADV can be nephrotoxic at prolonged low doses of 10 mg. For those who take ADV long term, regular monitoring of serum phosphate, creatinine levels and urine routine tests are required.

Effects of renal Na+/Ca2+ exchanger 1 inhibitor (SEA0400) treatment on electrolytes, renal function and hemodynamics in rats.

Na(+)/Ca(2+) exchanger 1 (NCX1) controls intracellular Ca(2+) concentration in various cell types. In the kidney, NCX1 is expressed mainly in the distal tubular basolateral membrane as well as in vascular smooth muscle. Tubular NCX1 is involved in Ca(2+) reabsorption, and NCX1 in renal arterioles may control intraglomerular pressure. However, the functions of renal NCX1 have not been studied in vivo. Therefore, this study examined the effects of renal NCX1 blockade on water and solute metabolism, renal function and blood pressure in rats. Wistar-Kyoto rats were uninephrectomized, and an osmotic mini pump was implanted to infuse the remnant kidney cortex with a specific NCX1 inhibitor, SEA0400 (SEA), or vehicle for 7 days. Serum Ca(2+) concentration and urinary Ca(2+) excretion were similar between the vehicle- and SEA-treated groups. However, serum phosphate was significantly decreased by 8 % in the SEA group, with similar urinary phosphate excretion between the two groups. Systolic blood pressure was higher in the SEA group (117 ± 3 vs. 126 ± 1 mmHg, n = 9-11), with a 1.6-fold increase in plasma aldosterone concentration. However, SEA significantly reduced urinary protein excretion and the glomerular sectional area by 16 and 8 %, respectively. Similar experiment in spontaneously hypertensive rats produced different results. Renal SEA treatment reduced serum phosphate concentration, urinary protein and glomerular size with higher systemic blood pressure compared to control Wistar-Kyoto rats. Further study on renal NCX1 may be beneficial in delineating the pathophysiology of glomerular pressure control and calcium/phosphate regulations.

AMELIORATIVE ANTIUROLITHIATIC EFFECT OF A POLYHERBAL SUSPENSION

A polyherbal suspension was prepared for use in urolithiasis. Three drugs namely Cyperus rotundus roots, Azadirachta indica leaves and Bryophyllum pinnatum leaves were used in the formulation. Antiurolithiatic activity was studied in the ethylene glycol induced urolithiasis model at a dose of 100, 200 and 300mg/kg polyherbal suspension in wistar rats. Cystone was used as the standard drug. All the doses were found to be effective in a dose related manner. There was an increase in the urinary excretion of calcium, oxalate, phosphate, urea, uric acid and creatinine significantly in the suspension treated group. P&lt;0.001was obtained when compared to control. The results show that the polyherbal suspension has prevented or decreased the supersaturation of urine leading to prevention of stone formation and agglomeration. The excretion of these ions was much lesser when compared to the negative control group. The dose of 300mg/kg of polyherbal suspension had activity quite similar to that of the standard drug cystone. Thus we conclude that the formulated polyherbal suspension has potential antiurolithiatic activity.Keywords: Antiurolithiatic activity, Cyperus rotundus, Azadirachta indica, Bryophyllum pinnatum, Polyherbal suspension.

A 12-Week, Double-Blind, Placebo-Controlled Trial of Ferric Citrate for the Treatment of Iron Deficiency Anemia and Reduction of Serum Phosphate in Patients With CKD Stages 3-5

Iron deficiency anemia and serum phosphate levels > 4.0mg/dL are relatively common in chronic kidney disease stages 3 to 5 and are associated with higher risks of progressive loss of kidney function, cardiovascular events, and mortality. Double-blind, placebo-controlled, randomized trial. 149 patients with estimated glomerular filtration rates < 60 mL/min/1.73 m(2), iron deficiency anemia (hemoglobin, 9.0-12.0 g/dL; transferrin saturation [TSAT]≤ 30%, serum ferritin ≤ 300 ng/mL), and serum phosphate levels ≥ 4.0 to 6.0mg/dL. Use of intravenous iron or erythropoiesis-stimulating agents was prohibited. Randomization to treatment for 12 weeks with ferric citrate coordination complex (ferric citrate) or placebo. Coprimary end points were change in TSAT and serum phosphate level from baseline to end of study. Secondary outcomes included change from baseline to end of treatment in values for ferritin, hemoglobin, intact fibroblast growth factor 23 (FGF-23), urinary phosphate excretion, and estimated glomerular filtration rate. Ferric citrate treatment increased mean TSAT from 22% ± 7% (SD) to 32% ± 14% and reduced serum phosphate levels from 4.5 ± 0.6 to 3.9 ± 0.6 mg/dL, while placebo exerted no effect on TSAT (21% ± 8% to 20% ± 8%) and less effect on serum phosphate level (4.7 ± 0.6 to 4.4 ± 0.8 mg/dL; between-group P<0.001 for each). Ferric citrate increased hemoglobin levels (from 10.5 ± 0.8 to 11.0 ± 1.0 g/dL; P<0.001 vs placebo), reduced urinary phosphate excretion 39% (P<0.001 vs placebo), and reduced serum intact FGF-23 levels from a median of 159 (IQR, 102-289) to 105 (IQR, 65-187) pg/mL (P=0.02 vs placebo). The incidence and severity of adverse effects were similar between treatment arms. The study is limited by relatively small sample size and short duration and by having biochemical rather than clinical outcomes. Short-term use of ferric citrate repletes iron stores, increases hemoglobin levels, and reduces levels of serum phosphate, urinary phosphate excretion, and FGF-23 in patients with chronic kidney disease stages 3 to 5.

Efficacy and acceptability of the new oral phosphate binder Lenziaren(®) in healthy cats fed a renal diet.

The efficacy and acceptability of the new oral phosphate binder Lenziaren(®) (SBR759) were evaluated in healthy cats fed with a commercial diet containing low amounts of phosphate ('renal diet'). Lenziaren(®) at 0.125, 0.25, 0.5 and 1 g/day was compared to a reference product Lantharenol(®) (3.0 g/day) and a placebo in a masked, randomized, parallel-group design study in 36 cats (n = 6 per group). All products were mixed with the ration which was fed once daily for 28 days. Lenziaren(®) produced significant dose-related reductions in serum and urine phosphate concentrations, faecal apparent phosphorus digestibility and fractional urinary phosphate excretion. Cats administered Lenziaren(®) consumed significantly less food than the placebo group, but this had no negative impact on body weight or acceptability assessments. When compared to the positive control, Lantharenol(®) , Lenziaren(®) was significantly more acceptable (0.125, 0.5 and 1.0 g/day doses), was associated with higher food consumption (0.125, 0.5 and 1.0 g/day doses) and had greater efficacy in reducing serum phosphate (0.5 and 1.0 g/day) and urine phosphate concentrations (1.0 g/day). In conclusion, Lenziaren(®) was an effective oral phosphate binder in healthy cats fed with a renal diet. Lenziaren(®) was well accepted and tolerated. Dosages of 0.25-1.0 g/cat per day are recommended for clinical testing.

Effect of dietary phosphate intake on the circadian rhythm of serum phosphate concentrations in chronic kidney disease: a crossover study

Previous trials of binders in chronic kidney disease (CKD) stages 3-5 have shown only modest changes in serum phosphate but evaluated morning phosphate. It is unknown whether a circadian pattern of phosphate concentrations exists in CKD and is modifiable by dietary manipulation. We determined the circadian pattern of serum phosphate concentrations in CKD and whether it was modifiable by altering absorbable phosphate. This was a crossover feeding study in 11 CKD participants (estimated glomerular filtration rate: 30-45 mL · min(-1) · 1.73 m(-2)) and 4 healthy control subjects. All subjects received high-phosphate (2500 mg/d), normal-phosphate (1500 mg/d), and low-phosphate (1000 mg/d plus 1000 mg lanthanum carbonate 3 times/d) diets for 5 d followed by a 10-d washout. After each 5-d feed, phosphate and other measurements were made every 4 h over 1 day. In CKD participants who consumed the high-phosphate diet, there were circadian changes in phosphate with lowest concentrations (± SDs) at 0800 (4.2 ± 0.5 mg/dL) and 2 peaks at 1600 and 0400 (4.5 ± 0.8 and 4.4 ± 0.6 mg/dL, respectively), which were similar to those in healthy controls. Results with the normal-phosphate diet were similar. The low-phosphate diet altered the circadian rhythm (P = 0.02) such that 0400 and 1600 peaks were absent. Differences in phosphate for lowest- compared with highest-phosphate diets were smallest at 0800 and largest at 1600 (0.5 compared with 1.0 mg/dL) in CKD. Circadian changes in phosphate were not explained by urine phosphate excretion, parathyroid hormone, or fibroblast growth factor-23. A circadian pattern of serum phosphate is observed in CKD with lowest concentrations at 0800 and highest at 1600 and 0400. This circadian pattern is modifiable by phosphate intake and most evident at 1600. Future intervention studies targeting intestinal phosphate absorption should consider afternoon phosphate measurements.

Impact of westernization on fibroblast growth factor 23 levels among individuals of African ancestry.

The Western diet is associated with high consumption of processed foods preserved with phosphate. Higher dietary phosphate consumption stimulates production of fibroblast growth factor 23 (FGF23), which heightens risk for cardiovascular disease and mortality. We hypothesized that adults living in a more westernized society have higher levels of FGF23 due to increased phosphate consumption as measured by urinary phosphate excretion. We measured plasma C-terminal FGF23 levels and urinary phosphate and creatinine levels in timed urine collections among 100 African adults living in the rural area of Igbo-Ora, Nigeria (52 women, 48 men), and 100 African Americans (32 women, 68 men) living in Maywood, IL, an urban suburb of Chicago, IL, USA. Among these 200 participants, urine collections were adequate in 76 and 68 of the Maywood and Igbo-Ora participants, respectively. In the total group, the mean age and body mass index, respectively, were 34.6 ± 8.2 years and 22.1 ± 3.9 kg/m(2) in Igbo-Ora, and 42.8 ± 7.2 years and 25.8 ± 6.5 kg/m(2) in Maywood. Demographic characteristics for each site were very similar after excluding participants without adequate urine collections. Among all 200 participants, the median (interquartile range) FGF23 levels were significantly higher in Maywood versus Igbo-Ora [63.8 (45.0-89.9) versus 12.5 RU/mL (8.5-18.5); P < 0.0001] and these differences did not change substantially after excluding nine women from Maywood with FGF23 levels >400 RU/mL or after excluding participants with inadequate urine collections. Among participants with adequate urine collections, the mean 24-h urinary phosphate excretion was significantly higher in Maywood versus Igbo-Ora (810.6 ± 309.0 versus 347.5 ± 153.1 mg; P < 0.001) and FGF23 levels correlated significantly with total urinary phosphate excretion (r = 0.62; P < 0.001) and urinary phosphate-to-creatinine ratios (r = 0.50; P < 0.001). Living in a more westernized society may be associated with greater net phosphate absorption, as reflected by higher urinary phosphate excretion, and higher FGF23 levels.

Efficacy, acceptability and tolerability of the new oral phosphate binder Lenziaren® in healthy cats fed a standard diet

BackgroundThe efficacy, acceptability and tolerability of the new oral phosphate binder Lenziaren® (SBR759) were evaluated in a randomized parallel-group design study in 36 healthy cats (n = 6 per group). Five groups were fed once daily with a commercial diet containing 0.2% phosphorus (“standard diet”) into which was mixed Lenziaren® at 0.25, 0.5, 1.0 or 2.0 g/day or no treatment (control group) daily for 30 days. A sixth group was fed a commercial diet containing lower amounts (0.12%) of phosphorus (“renal diet”) and no treatment.ResultsWhen compared to the control group, Lenziaren® produced significant dose-related reductions in urine phosphate concentrations, urine phosphate excretion and fractional urinary phosphate excretion. Significant effects versus the control group were observed at the 0.5, 1.0 and 2.0 g/day dosages. Lenziaren® was well tolerated and was associated with higher food consumption and serum iron concentrations versus the control.When compared to the control group, the renal diet was associated with significantly lower urine phosphate concentrations and loss of body weight. Lenziaren® had similar effects on urine phosphate concentrations compared to the renal diet, but was not associated with loss of body weight.ConclusionsLenziaren® was effective as an oral phosphate binder in cats fed with a standard diet containing 0.2% phosphorus. The acceptability and tolerability were good. Dosages of 0.5-1.0 g/cat per day are recommended for clinical testing in cats fed with a standard diet.

Ethnic differences in urinary calcium and phosphate excretion between Gambian and British older adults.

SummaryEthnic differences in renal calcium and phosphate excretion exist, which may depend on differences in their dietary intakes and regulatory factors. We report highly significant differences in urinary calcium and phosphate excretion between white British and Gambian adults after statistical adjustment for mineral intakes, indicating an independent effect of ethnicity.IntroductionPopulations vary in their risk of age-related osteoporosis. There are racial or ethnic differences in the metabolism of the bone-forming minerals calcium (Ca) and phosphate (P), with a lower renal Ca and P excretion in African-Americans compared to white counterparts, even at similar intakes and rates of absorption. Also, Africans in The Gambia have a lower Ca excretion compared to white British subjects, groups known to differ in their dietary Ca intake. Here, we report on differences in urinary Ca and P excretion between Gambian and white British adults while allowing for known predictors, including dietary intakes.MethodsParticipants were healthy white British (n = 60) and Gambian (n = 61) men and women aged 60–75 years. Fasting blood and 2-h urine samples were collected. Markers of Ca and P metabolism were analysed. Dietary intake was assessed with country-specific methods.ResultsWhite British older adults had higher creatinine-corrected urinary Ca and P excretion (uCa/uCr, uP/uCr) and lower tubular maximum of Ca and P compared to Gambian counterparts. The predictors of urinary Ca and P differed between groups. Multiple regression analysis showed that dietary Ca and Ca/P were predictors of uCa/uCr and uP/uCr, respectively. Ethnicity remained a significant predictor of uCa/uCr and uP/uCr after adjustment for diet and other factors.ConclusionsGambian older adults have higher renal Ca conservation than British counterparts. Dietary mineral intakes were predictors of the differences in urinary Ca and P excretion, but ethnicity remained a highly significant predictor after statistical adjustment. This suggests that ethnicity has an independent effect on renal Ca and P handling.

Alpha Klotho and phosphate homeostasis.

The Klotho family consists of three single-pass transmembrane proteins—αKlotho, βKlotho and γKlotho. Each of them combines with fibroblast growth factor (FGF) receptors (FGFRs) to form receptor complexes for various FGF’s. αKlotho is a co-receptor for physiological FGF23 signaling and appears essential for FGF23-mediated regulation of mineral metabolism. αKlotho protein also plays a FGF23-independent role in phosphate homeostasis. Animal experimental studies and clinical observations have demonstrated that αKlotho deficiency leads to severe hyperphosphatemia; moderate elevation of αKlotho reduces serum phosphate and extremely high αKlotho induces hypophosphatemia and high-FGF23. αKlotho maintains circulating phosphate in a narrow range by modulating intestinal phosphate absorption, urinary phosphate excretion by the kidney, and phosphate distribution into bone rather than soft tissue in concerted interaction with other calciophosphotropic hormones such as PTH, FGF23, and 1,25-(OH)2 vitamin D. The role of αKlotho in maintenance of phosphate homeostasis is mediated by direct suppression of Na-dependent phosphate cotransporters in target organs. Therefore, αKlotho manipulation may be a novel strategy for genetic and acquired phosphate disorders and for medical conditions with αKlotho deficiency such as chronic kidney disease in future.

Efficacy and safety of lanthanum carbonate in pre-dialysis CKD patients with hyperphosphatemia: a randomized trial.

Lanthanum carbonate (LC), an effective non-calcium phosphate binder is widely used to manage hyperphosphatemia in patients with chronic kidney disease (CKD) on dialysis. Recently, the additional indication for control of hyperphosphatemia in CKD patients not on dialysis has been approved. A multicenter, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of LC in Japanese hyperphosphatemic stage 4 - 5 CKD patients not on dialysis. After a 4-week run-in period, 143 eligible subjects with serum phosphate levels of 5.6 - 11.0 mg/dL were randomized (2 : 1) to receive LC or placebo (88 vs. 55) for 8 weeks; 119 subjects completed the study (76 vs. 43). The starting LC dose was 750 mg/day, which was then up-titrated to 2,250 mg/day as needed while tolerated. Primary efficacy analysis was performed on the intent-to-treat (ITT) population of 141 patients (86 vs. 55). LC produced a significantly greater reduction in serum phosphate level compared with placebo after 8 weeks of treatment (difference, 0.97 (95% CI: 0.58, 1.37) mg/ dL; p < 0.0001). The cumulative proportion of subjects with controlled phosphate levels ≤ 4.6 mg/dL was higher in the LC group than the placebo group (59.56% vs. 10.46%). LC caused significantly greater reductions in serum Ca × P product and urinary phosphate excretion compared with placebo. The safety profile of LC was similar to that of placebo. This study demonstrated the effectiveness of LC to control hyperphosphatemia in pre-dialysis CKD patients.

Urinary excretion of calcium, magnesium, phosphate, citrate, oxalate, and uric acid by healthy schoolchildren using a 12-h collection protocol.

Although we do not have reliable data for the true prevalence of urolithiasis during childhood, the number of patients seen in outpatient clinics and admitted for stone-related problems is steadily increasing worldwide. As for most pediatric patients a metabolic disease is the reason for stone development, because a high number of patients have severely recurrent urolithiasis, early and proper diagnostic evaluation is necessary to begin adequate and preventive treatment. However, diagnostic evaluation, especially in infants and younger children, is not always easy, and frequently a diagnosis is made late. Diagnostic evaluation should start with repeated urine analysis; but how and which urine should be collected and analyzed? What is the best and most accurate method for urine collection? In a paper published in a recent issue of Pediatric Nephrology, Torres and colleagues describe a more simplified method of urine collection. They propose analysis of late-afternoon spot-urine samples as well as an overnight collection of urine as the most appropriate to evaluate patient-specific urinary risk factors. Is this truly the case?

Serum fibroblast growth factor-23 is associated with incident kidney disease.

Fibroblast growth factor-23 is a bone-derived hormone that increases urinary phosphate excretion and inhibits hydroxylation of 25-hydroxyvitamin D. Recent studies suggest that fibroblast growth factor-23 may be an early biomarker of CKD progression. However, its role in kidney function decline in the general population is unknown. We assessed the relationship between baseline (1990-1992) serum levels of intact fibroblast growth factor-23 and incident ESRD in 13,448 Atherosclerosis Risk in Communities study participants (56.1% women, 74.7% white) followed until December 31, 2010. At baseline, the mean age of participants was 56.9 years and the mean eGFR was 97 ml/min per 1.73 m(2). During a median follow-up of 19 years, 267 participants (2.0%) developed ESRD. After adjustment for demographic characteristics, baseline eGFR, traditional CKD risk factors, and markers of mineral metabolism, the highest fibroblast growth factor-23 quintile (>54.6 pg/ml) compared with the lowest quintile (<32.0 pg/ml) was associated with risk of developing ESRD (hazard ratio, 2.10; 95% confidence interval, 1.31 to 3.36; trend P<0.001). In a large, community-based study comprising a broad range of kidney function, higher baseline fibroblast growth factor-23 levels were associated with increased risk of incident ESRD independent of the baseline level of kidney function and a number of other risk factors.

Sodium-phosphate cotransporter mediates reabsorption of lithium in rat kidney

Lithium, used for the treatment of bipolar disorders, is reabsorbed via sodium-transport system in the proximal tubule. This step causes intra-/inter-individual difference of lithium disposition, and it has not been unclear which transporter contributes. In this study, we examined effect of foscarnet and parathyroid hormone (PTH), inactivators for sodium-phosphate cotransporter, and phlorizin, a typical inhibitor for sodium-glucose cotransporter, on the disposition of lithium in rats. Their intravenous administration stimulated urinary excretion of phosphate or glucose. After the intravenous injection of lithium chloride as a bolus, plasma concentration of lithium decreased time-dependently. The renal clearance of lithium was calculated to be 0.740ml/min/kg in control rats, and this was 26.7% of creatinine clearance. Foscarnet and PTH significantly increased the renal clearance of lithium and its ratio to creatinine clearance, suggesting that they prevented the reabsorption of lithium. No effect of phlorizin on the renal handling of lithium was recognized. In control rats, the renal clearance of lithium showed a strong correlation with the renal excretion rate of phosphate, compared with creatinine clearance. These findings suggest that sodium-phosphate cotransporter reabsorbs lithium in the rat kidney. Furthermore, its contribution was estimated to be more than 65.9% in the lithium reabsorption. And, this study raised the possibility that therapeutic outcome of lithium is related with the functional expression of sodium-phosphate cotransporter in the kidney.

Spontaneous acromegaly: A retrospective case control study in German shepherd dogs

Acromegaly results from the overproduction of growth hormone in adulthood and is characterised by overgrowth of soft tissue and/or bone as well as insulin resistance. There are few data indicating the risk factors associated with this disease in dogs or its clinicopathological features and sequelae. The objective of this retrospective study was to catalogue and assess these aspects of the disease in German shepherd dogs (GSDs) which were found to be over-represented among acromegalic dogs attending two veterinary referral clinics over a period of 7 years. Each acromegalic dog (AD) was compared with two breed/age/sex matched controls.Clinical signs of acromegaly included panting, polyuria/polydipsia, widened interdental spaces, weakness, inspiratory stridor, macroglossia, weight gain, redundant skin folds, thick coat, exophthalmos and mammary masses. Serum alkaline phosphatase, creatine-kinase, glucose, triglyceride, phosphate ion, and ‘calcium per phosphate product’ concentrations were significantly higher in acromegalic animals while haemoglobin concentration, blood urea nitrogen, sodium and chloride ion concentrations, and urinary specific gravity, osmolality and fractional excretion of phosphate were significantly lower. Although, in the majority of cases clinicopathological abnormalities resolved following ovariohysterectomy, in one dog, acromegalic signs abated and insulin-like growth factor-1 concentrations normalised only following the surgical excision of mammary tumours carried out 2 months after ovariohysterectomy. The findings of this study indicate that GSDs are predisposed to the development of acromegaly with a suspected inherited susceptibility.