phosphorus-radioisotopes and Kidney-Failure--Chronic

Studies were conducted to compare the phosphate-binding efficacy of lanthanum carbonate directly with other clinically used phosphate binders and to evaluate any potential adverse pharmacology. To examine the phosphate-binding efficacy, rats with normal renal function and chronic renal failure received lanthanum carbonate, aluminum hydroxide, calcium carbonate, or sevelamer hydrochloride in several experimental models. Lanthanum carbonate and aluminum hydroxide markedly increased excretion of [(32)P]-phosphate in feces and reduced excretion in urine in rats with normal renal function (p < 0.05), indicating good dietary phosphate-binding efficacy. In rats with chronic renal failure, lanthanum carbonate and aluminum hydroxide reduced urinary phosphate excretion to a greater degree and more rapidly than calcium carbonate, which in turn was more effective than sevelamer hydrochloride. The potential to induce adverse pharmacological effects was assessed systematically in mice, rats, and dogs with normal renal function using standard in vivo models. There was no evidence of any adverse secondary pharmacological effects of lanthanum carbonate on the central nervous, cardiovascular, respiratory, or gastrointestinal systems. These studies indicate that lanthanum carbonate is the more potent of the currently available dietary phosphate binders. No adverse secondary pharmacological actions were observed in vivo in a systematic evaluation at high doses.

Topics: Aluminum Hydroxide; Animals; Calcium; Calcium Carbonate; Chelating Agents; Dogs; Drug Evaluation, Preclinical; Feces; Hyperphosphatemia; Kidney Failure, Chronic; Lanthanum; Male; Mice; Phosphates; Phosphorus Radioisotopes; Polyamines; Rats; Rats, Sprague-Dawley; Sevelamer

Cardiovascular disease is commonly observed in patients with chronic renal failure and this is a leading cause of death in patients with end-stage renal disease undergoing maintenance dialysis. Myocardial energy production is a very crucial aspect of cardiac function. Therefore, to evaluate energy metabolism of myocardial muscle in peritoneal dialysis (PD) patients, we carried out the following study using Magnetic resonance spectroscopy (MRS). Fourteen chronic renal failure patients and eight healthy volunteers were enrolled. The ratio of the phosphocreatine peak to the beta-phosphate to ATP peak (PCr/beta-ATP) was calculated from their MR spectra obtained by 31P-MR spectroscopy (Gyroscan S15, Philips). To determine the correlation between cardiac function and energy status, the left atrial diameter, the left ventricular (LV) end-diastolic diameter, the ejection fraction, the fraction of shortening and the LV mass index were measured by echocardiography. Peripheral blood sampling was also performed for creatinine, blood urea nitrogen, hematocrit, hemoglobin, beta2-microglobuline, intact parathyroid hormone. PCr/beta-ATP was significantly lower in PD (1.03 +/- 0.15 vs. 1.40 +/- 0.18: p = 0.0002), although all patients showed normal systolic function. No correlation was found between PCr/beta-ATP and cardiac function or hematological or biochemical markers. A negative correlation was present between PCr/beta-ATP and dialysis duration (r = 0.57, p < 0.05). Altered energy status of the myocardium in PD should be considered even if the patients did not show any systolic dysfunction. 31P-MRS is a useful tool to evaluate the energy status of the myocardium.

Topics: Adenosine Triphosphate; Adult; Echocardiography; Female; Heart; Humans; Kidney Failure, Chronic; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardium; Peritoneal Dialysis; Phosphorus Radioisotopes; Time Factors

Patients undergoing successful kidney transplantation often manifest overt hypophosphatemia associated with exaggerated phosphaturia during the early post-transplant period (2 weeks to 3 months). The mechanism for this phenomenon has not been fully elucidated. We tested the hypothesis that a circulating serum factor [non-parathyroid hormone (non-PTH)], which operates during chronic renal failure (CRF) to maintain phosphate (Pi) homeostasis, can increase fractional excretion of Pi (FE(PO4)) in normal functioning kidney grafts during the early post-transplant period, thereby causing phosphaturia and hypophosphatemia.. Five groups of patients were studied: control subjects (group 1, N = 16), "early" (2 weeks to 1 month) post-transplant patients (group 2, N = 22), "late" (9 to 12 months) post-transplant patients (group 3, N = 14), patients with advanced CRF (glomerular filtration rate = 30 to 40 mL/min; group 4, N = 8), and patients who suffered from end-stage renal failure and were treated by chronic hemodialysis (group 5, N = 14). Group 2 manifested significant hypophosphatemia and phosphaturia when compared with groups 1 and 3 (Pi = 0.9 +/- 0.003 mg/dL, FE(PO4) = 68+/- 5%, P < 0.0005 vs. groups 1 and 3). Sera were taken from each of the five subject groups and applied to the proximal tubular opossum kidney (OK) cells. The activity of Na/Pi-type 4 (that is, OK-specific type II transporter) was evaluated by measuring Na(+)-dependent (32)Pi flux. The expression of Na/Pi type II mRNA and the abundance of Na/Pi protein were determined by Northern and Western blot assays, respectively.. When compared with sera from groups 1 and 3, 10% sera taken from groups 2, 4, and 5 (incubated overnight with OK cells) inhibited (32)Pi flux by 25 to 30% (P < 0.0003). Both Na/Pi mRNA and the expression of Na/Pi protein were markedly augmented under the same conditions (P < 0.05 groups 2, 4, and 5 vs. groups 1 and 3). Time-course analysis revealed that the up-regulation of Na/Pi protein by sera from groups 2, 4, and 5 was observed as early as four hours of incubation, whereas augmented abundance of Na/Pi mRNA was only seen after eight hours of incubation. The addition of PTH (1-34) to sera from groups 2, 4, and 5 abolished the augmented expression of NaPi protein. We labeled OK cell surface membrane proteins with N-hydroxysuccinimide bound to biotin (NHS-SS-biotin). Biotinylated transporters incubated with the different sera were precipitated by strepavidin and identified by Western blot analysis. Cells incubated in sera from group 2 showed increased membrane bound transporter when compared with control sera, whereas the intracellular pool of the transporter was comparable between the two groups.. A non-PTH circulating serum factor (possibly phosphatonin) that increases FE(PO4) during CRF is also responsible for phosphaturia and hypophosphatemia in the early period following successful kidney transplantation. The putative factor inactivates Na/Pi activity along with inhibition of the transporter trafficking from the cell membrane into the cytosol.

Topics: Adult; Aged; Animals; Biological Transport; Blood; Carrier Proteins; Cell Line; Female; Humans; Hypophosphatemia; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Opossums; Phosphorus Radioisotopes; Postoperative Complications; RNA, Messenger; Sodium-Phosphate Cotransporter Proteins; Sodium-Phosphate Cotransporter Proteins, Type II; Symporters; Thymic Factor, Circulating

Assessment of left ventricular metabolism and function is important in patients on maintenance dialysis because congestive heart failure occurs quite frequently and has a poor prognosis. The purpose of this study was to evaluate the changes of myocardial high energy metabolism in dialysis patients by using phosphorus-31 (31P) magnetic resonance (MR) spectroscopy.. Phosphorus-31 spectra were obtained from anteroseptal wall of the heart in six normal subjects (mean age, 24 +/- 1 years) and 14 dialysis patients (mean age, 52 +/- 11 years), using a 1.5-tesla clinical MR system. Four patients had previous history of heart failure. Echocardiography was performed in all patients to evaluate left ventricular (LV) hypertrophy and LV function.. The averaged ratio of phosphocreatine (PCr)/beta-adenosine triphosphate (beta-ATP) in dialysis patients (1.15 +/- 0.25 mean +/- standard deviation), was significantly lower than that in healthy subjects (1.63 +/- 0.21; P < 0.01). There was no significant difference in PCr/beta-ATP ratios between the non-LV hypertrophy group (1.21 +/- 0.24; n = 7) and the LV hypertrophy group (1.09 +/- 0.24; n = 7). The averaged PCr/beta-ATP ratio in four patients with history of heart failure (0.96 +/- 0.18) was significantly lower than that of the 10 patients without history of heart failure (1.22 +/- 0.23; P < 0.05).. These results indicate that patients on maintenance dialysis have decreased PCr/beta-ATP ratio and 31P MR spectroscopy can provide noninvasive assessment of altered high energy phosphate metabolism.

Topics: Adenosine Triphosphate; Adult; Aged; Female; Heart Failure; Heart Ventricles; Humans; Kidney Failure, Chronic; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardium; Phosphocreatine; Phosphorus; Phosphorus Radioisotopes; Renal Dialysis

A modified double-isotope method was used to determine the absorption of calcium and phosphate in patients with chronic renal failure. Eight hemodialysis patients and six healthy control subjects received an intravenous dose of 45calcium and 32phosphate and an oral tracer dose of 45Ca and 32P was administered two weeks later. Timed plasma samples were obtained on each occasion to determine fractional absorption rates and cumulative absorption of either tracer from both tracer sets with deconvolution analysis. Stool collections were analyzed. Calcium absorption in normal subjects peaked at 12% over fifteen minutes at one hour and declined rapidly thereafter. Absorption was essentially complete at four hours and cumulative absorption at this time was 72 +/- 6%. The pattern of phosphate absorption was similar and cumulative absorption at 4 hours was 80 +/- 3%. Calcium absorption in dialysis patients was significantly impaired with a flattened profile, a maximal 15-min absorption rate of 2% and cumulative 4-h absorption of 20 +/- 2%. Phosphate absorption in dialysis patients was also impaired to a comparable degree with a maximal rate of 3.6% and a more delayed cumulative total of 35 +/- 5%. Stool data showed good agreement with deconvolution analysis in volunteers but always overestimated absorption in patients. Sequential double isotope analysis provided a simple and convenient method for the concurrent estimation of calcium and phosphate absorption in humans.

Topics: Aged; Calcium; Calcium Radioisotopes; Female; Humans; Intestinal Absorption; Kidney Failure, Chronic; Malabsorption Syndromes; Male; Middle Aged; Phosphates; Phosphorus Radioisotopes; Renal Dialysis

1. Intestinal phosphate absorption was measured in normal subjects, in patients with chronic renal failure, and in post-transplant patients, by a double isotope technique involving oral administration of 32P and simultaneous intravenous injection of 33P with subsequent deconvolution analysis. 2. By this technique intestinal phosphate absorption has been shown to have two components: an initial rapid phase, which is completed by 3 h, and a slower more prolonged phase, which continues beyond 7 1/2 h. 3. Phosphate malabsorption has been demonstrated in chronic renal failure and transplant patients, which is accounted for by impairment of the initial rapid phase of absorption. 4. Results obtained by deconvolution analysis have been compared with other estimates of phosphate absorption obtained from analysis of 32P radioactivity curves alone. 5. The fractional hourly rate of absorption and the plasma 32P radioactivity at 60 min corrected for extracellular fluid volume provided the best approximations to the result obtained by deconvolution analysis, with respect to both the maximal rate of phosphate absorption and cumulative percentage phosphate absorption.

Topics: Administration, Oral; Humans; Injections, Intravenous; Intestinal Absorption; Kidney Failure, Chronic; Methods; Phosphates; Phosphorus Radioisotopes