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PubMed2006

Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.

Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.

Aged↗

PubMed2006

Naïve and central memory T-cell lymphopenia in end-stage renal disease.

End-stage renal disease (ESRD) is associated with increased propensity to infections, diminished response to vaccination, impaired cell-mediated immunity, and reduced CD4+/CD8+ T-lymphocyte ratio. Four subsets of CD4+ and CD8+ T cells have been recently identified: naïve cells (as yet uncommitted), central memory (CM) cells (previously programmed), and CD45RA-positive and CD45RA-negative effector memory (EM) cells (programmed to perform specific effector functions). The effect of ESRD on subpopulations of T lymphocytes is unclear and was studied here. Twenty-one hemodialysis patients and 21 age-matched controls were studied. Pre- and post-dialysis blood samples were obtained and analyzed by three-color flow cytometry. CD4+/CD8+ ratio and the numbers of the naïve and CM CD4+ and CD8+ T cells were significantly reduced, whereas the numbers of EM CD4+ and CD8+ T cells were unchanged in the ESRD group. The reduction of the naïve and CM T-cell counts in the ESRD group was associated with increased apoptosis of these cells. Negative correlations were found between severity of azotemia, oxidative stress, and hyperphosphatemia with the number of naïve T cells. Comparison of diabetic with non-diabetic ESRD patients revealed higher numbers of total CD8+ cells and EM CD8+ T cells in the diabetic group. Dialysis did not significantly change the naïve and CM CD4+ or CD8+ cell counts, but significantly lowered CD8+ EM cell count. Thus, ESRD results in increased apoptosis and diminished populations of naïve and CM T lymphocytes. This phenomenon may, in part, contribute to the impaired immune response in this population.

CD4-Positive T-Lymphocytes↗

PubMed2006

Pathogenic mechanisms for parathyroid hyperplasia.

Parathyroid hyperplasia is the cause of parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced parathyroid expression of the potent growth promoter transforming growth factor alpha (TGFalpha) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFalpha-activated EGFR, completely prevented high P- and low Ca-induced parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced parathyroid growth in established secondary hyperparathyroidism, the latter characterized by marked TGFalpha and EGFR overexpression in the parathyroid glands. More importantly, the suppression of signals downstream from TGFalpha binding to EGFR with EGFR-TKI treatment also revealed that TGFalpha self-upregulation in the parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGFalpha activation of EGFR mediates the reduction in parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and parathyroid hormone-suppressive properties of calcitriol therapy.

Animals↗

PubMed2006

Vascular calcification: Hardening of the evidence.

In the past several years, basic-science studies have shown that vascular calcification is an active, cell-mediated process. It is increased in the uremic milieu and with hyperphosphatemia and therefore should be preventable. Additional advances in imaging techniques have facilitated the diagnosis of arterial calcification, a critical initial step in the translation of this knowledge to patient care.

Calcinosis↗

PubMed2006

Cognitive function in Stage 5 chronic kidney disease patients on hemodialysis: no adverse effects of lanthanum carbonate compared with standard phosphate-binder therapy.

Patients with Stage 5 chronic kidney disease who have hyperphosphatemia require treatment with phosphate binders to lower serum phosphorus levels. Existing binders are effective but may be associated with important safety disadvantages. Lanthanum carbonate is a phosphate binder with demonstrated efficacy, safety, and tolerability in clinical trials. Changes in cognitive function were evaluated over time using the Cognitive Drug Research computerized cognitive assessment system (Simple Reaction Time, Digit Vigilance Task, Choice Reaction Time, Numeric Working Memory, and Delayed Picture Recognition) in 360 hemodialysis patients who were enrolled in a 2-year, multicenter, comparative study of lanthanum carbonate versus standard therapy. A decline in cognitive function from baseline was observed in both groups. The deterioration in cognitive function was similar in both the lanthanum carbonate and standard therapy groups. One parameter - Numeric Working Memory - showed a statistically significant between-group difference in favor of lanthanum carbonate (P=0.02). Given the magnitude of the changes, however, and the differences that were observed at baseline between treatment groups, the clinical significance of this difference is doubtful. This study demonstrates that cognitive function deteriorates in hemodialysis patients over a 2-year time period. Use of lanthanum carbonate as a phosphate binder does not adversely affect cognitive function compared with standard therapy.

Adult↗

PubMed2006

Novel insights into vascular calcification.

Vascular calcification is not just a hallmark of uremic arterio- and atherosclerosis, but also a significant cardiovascular risk factor in patients with chronic kidney disease. In contrast to the previous assumption that vascular calcification predominantly occurs by passive precipitation of calcium and phosphate ions, recent research led to the insight that extraosseous calcification is a highly regulated process. High serum phosphate and calcium levels may induce a process of osteogenic 'bone-like' differentiation of vascular smooth muscle cells, while deficiencies of calcification inhibitors or a disturbed balance towards calcification inducers may have a relevant pathophysiological influence on the initiation and progression of calcified lesions. This overview summarizes some of the best explored novel risk factors for disturbances of calcium and phosphate homeostasis and points to the integral role of hyperphosphatemia as a modifiable key trigger in calcification processes.

Atherosclerosis↗

PubMed2006

Cost of applying the K/DOQI guidelines for bone metabolism and disease to a cohort of chronic hemodialysis patients.

Hyperphosphatemia is a common feature of advanced chronic kidney disease (CKD) and is treated routinely with oral calcium-based phosphate binders. In 2003, the National Kidney Foundation Kidney Disease Outcomes and Quality Initiative (K/DOQI) published Clinical Practice Guidelines (CPGs) for the treatment of Bone Metabolism and Disease in CKD. These advocate broad usage of expensive non-calcium-based phosphate binders such as sevelamer. This study was designed to determine the cost of implementation of the K/DOQI CPGs as they pertain to phosphate binding in a large Canadian hemodialysis (HD) unit. Laboratory and medication data for all chronic HD patients at the Ottawa Hospital were reviewed (n=416). Patients meeting each of the relevant K/DOQI guidelines were identified. Where guidelines would recommend a switch to non-calcium binders, equivalent sevelamer doses were estimated. The cost of implementing each guideline was then calculated individually and an estimate total cost of implementing all the guidelines was derived. Overall, 53% (222) patients fulfilled at least one criterion for sevelamer use. The yearly cost of implementation of the K/DOQI guidelines at this center was estimated at 500,605 dollars (American dollars). Given the significant cost, widespread adoption of the K/DOQI CPGs for Bone Metabolism and Disease should await the publication of compelling data demonstrating significant improved outcomes in patients treated with sevelamer.

Aged↗

PubMed2006

The therapeutic application of lanthanides.

The biological properties of the lanthanides, based on their similarity to calcium, have stimulated research into their therapeutic application. Historical medical uses of the lanthanides and recent advances and successes will be described in the context of the biological chemistry of lanthanides, including a new metal-based drug, lanthanum carbonate, which has recently been approved as a phosphate binder for the treatment of hyperphosphatemia. This tutorial review will be of interest to those working on metal-based drugs, including inorganic chemists, and biological scientists.

Humans↗

PubMed2003

Management of secondary hyperparathyroidism of dialysis patients.

Hyperphosphatemia, vitamin D deficiency, and resulted hypocalcemia have been regarded as classical pathogeneses of secondary hyperparathyroidism. These factors have been treated by the administration of phosphorus binder and vitamin D derivatives. However, these therapies have not brought about a successful result for the prevention and treatment of secondary hyperparathyroidism. The reason could be mainly attributed to the hypercalcemia that results from the administration of calcium salts as a phosphorus binder and the calcemic action of vitamin D. To prevent hypercalcemia, non-calcium containing phosphorus binder (sevelamer hydrochloride) and vitamin D analogues, which suppress PTH secretion with minimum calcemic action, have been developed. These new vitamin D analogues include 19-nor-1-alpha, 25-dihydroxyvitamin D2 (paricalcitol), 1-alpha-hydroxyvitamin D2 (doxercalciferol), 22oxa-calcitriol (maxacalcitol) and F6-calcitriol (falecalcitriol). Furthermore, calcimimetics that stimulate calcium-sensing receptor of parathyroid cells as calcium and suppress PTH secretion are now under clinical trial. Percutaneous direct injection therapy of vitamin D, vitamin D analogue or calcimimetics into parathyroid gland has also been reported. The combination of these new strategies is expected to effectively and safely suppresses secondary hyperparathyroidism that has been resistant to conventional medical treatments.

Ethanol↗

PubMed1999

22-oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure.

BACKGROUND: Calcitriol therapy suppresses serum levels of parathyroid hormone (PTH) in patients with renal failure but has several drawbacks, including hypercalcemia and/or marked suppression of bone turnover, which may lead to adynamic bone disease. A new vitamin D analogue, 22-oxacalcitriol (OCT), has been shown to have promising characteristics. This study was undertaken to determine the effects of OCT on serum PTH levels and bone turnover in states of normal or impaired renal function. METHODS: Sixty dogs were either nephrectomized (Nx, N = 38) or sham-operated (Sham, N = 22). The animals received supplemental phosphate to enhance PTH secretion. Fourteen weeks after the start of phosphate supplementation, half of the Nx and Sham dogs received doses of OCT (three times per week); the other half were given vehicle for 60 weeks. Thereafter, the treatment modalities for a subset of animals were crossed over for an additional eight months. Biochemical and hormonal indices of calcium and bone metabolism were measured throughout the study, and bone biopsies were done at baseline, 60 weeks after OCT or vehicle treatment, and at the end of the crossover period. RESULTS: In Nx dogs, OCT significantly decreased serum PTH levels soon after the induction of renal insufficiency. In long-standing secondary hyperparathyroidism, OCT (0.03 microg/kg) stabilized serum PTH levels during the first months. Serum PTH levels rose thereafter, but the rise was less pronounced compared with baseline than the rise seen in Nx control. These effects were accompanied by episodes of hypercalcemia and hyperphosphatemia. In animals with normal renal function, OCT induced a transient decrease in serum PTH levels at a dose of 0.1 microg/kg, which was not sustained with lowering of the doses. In Nx dogs, OCT reversed abnormal bone formation, such as woven osteoid and fibrosis, but did not significantly alter the level of bone turnover. In addition, OCT improved mineralization lag time, (that is, the rate at which osteoid mineralizes) in both Nx and Sham dogs. CONCLUSIONS: These results indicate that even though OCT does not completely prevent the occurrence of hypercalcemia in experimental dogs with renal insufficiency, it may be of use in the management of secondary hyperparathyroidism because it does not induce low bone turnover and, therefore, does not increase the risk of adynamic bone disease.

Animals↗

PubMed1999

New analogs of vitamin D3.

Calcitriol, the most active metabolite of vitamin D, controls parathyroid gland growth and suppresses the synthesis and secretion of parathyroid hormone (PTH). However, because of its potent effects on intestinal calcium absorption and bone mobilization, calcitriol treatment can induce hypercalcemia, often precluding its use at therapeutic doses. Hyperphosphatemia is also a persistent problem among patients undergoing chronic hemodialysis and can be aggravated by therapeutic doses of calcitriol. Several pharmaceutical companies were able to modify the side-chain of the 1,25(OH)2D3, allowing some of these new analogs to retain the action on the parathyroid glands while decreasing their hypercalcemic and hyperphosphatemic effects. The structure-activity relationship for ligand-mediated transcriptional regulation has been studied in detail. In some analogs the serum binding protein (DBP) plays a key role in determining the pharmacokinetics of the vitamin D compound. The affinity to DBP for 22-oxacalcitriol (OCT), an analog of calcitriol for the treatment of secondary hyperparathryoidism, is approximately 300-400 times lower than that of calcitriol and the analog is rapidly cleared from the circulation. The mechanisms for the selectivity of 19-nor-1,25(OH)2D2 (paricalcitol) (Zemplar) another analog of calcitriol, is clearly different from OCT. Although the mechanisms of action is not completely known, it does appear that paricalcitol down-regulates the VDR in the intestine. It is likely that the unique biological profiles of vitamin D analogs in vivo are due to multiple mechanisms. Understanding the molecular basis of the analog selectivity will not only provide an explanation for their unique actions but allow intelligent design of more effective analogs in the future.

Animals↗

PubMed1999

Predialysis management of divalent ion metabolism.

Disordered divalent ion metabolism has its origins in the earliest stages of renal impairment. Early intervention is essential to minimize its effects, especially in the light of recent reports demonstrating an association between serum phosphate and relative risk of mortality in dialysis patients. As the age and comorbidity of patients accepted for renal replacement therapy increases, the complexity of their management also increases. A dedicated "predialysis" enables a multidisciplinary team to intervene in an orderly and appropriate fashion to delay progression, modify comorbidity, prevent uraemic complications and prepare the patient mentally and physically for dialysis and renal transplantation. Part of this process involves the identification of patients at high risk of the skeletal and biochemical complications of renal osteodystrophy. Correction of hypocalcemia, acidosis, hyperphosphatemia and rising PTH levels should be achieved quickly. Oral calcitriol therapy is frequently necessary, and requires careful monitoring and supervision.

Calcitriol↗

PubMed1999

Phosphate binders on iron basis: a new perspective?

Uremic patients on maintenance hemodialysis are in positive phosphate balance. This is mainly the result of the complex elimination kinetics of phosphate during dialysis. Removal of phosphate is less than net dietary intake. Classical phosphate binders such as calcium carbonate, calcium acetate, and aluminum-based compounds are limited by side effects (hypercalcemia) and outright toxicity (aluminium). There have been numerous recent attempts to develop alternative phosphate binders, e.g., polyallylamine-hydrochloride (Renagel), lanthanum carbonate, and trivalent iron-containing compounds. The latter is based on old observations that iron salts may cause hyperphosphatemia and rickets in experimental animals and in patients. This idea has recently been taken up again, and effective inhibition of net intestinal phosphate uptake in non-uremic and uremic rats has been shown using simple iron salts (citrate, chloride, ammonium citrate) and complex compounds (cross-linked dextran and stabilized polynuclear iron hydroxide). In uremic rats, the latter compound reduces urinary phosphate excretion as an indicator of reduced intestinal phosphate uptake and has also been shown to be effective in subjects with preterminal renal failure. So far, no side effects or short-term toxicity has been observed. The compound appears promising and deserves further evaluation.

Animals↗

PubMed1999

Osteodystrophy in the millennium.

Despite three decades of intensive research on the derangements of calcium phosphate metabolism of renal failure, several unresolved issues are still with us at the turn of the millennium: poor control of hyperphosphatemia, relative inefficacy of active vitamin D to prevent progressive parathyroid hyperplasia, and persistence of bone disease despite lowering of parathyroid hormone (PTH) and administration of active vitamin D. Although predictions are problematic, it is not unreasonable to hope that, barring unforeseen side effects, calcimimetics will prove to be valuable for suppressing or even preventing hyperparathyroidism, thus potentially replacing, at least in part, active vitamin D. There is also reason to hope that more effective phosphate binders with fewer side effects will become available and that controlled studies will provide a rationale for the administration of estrogens to dialyzed women. As regards understanding the pathological mechanisms, one can anticipate that the disturbances leading to autonomous growth of parathyroid cells will be elucidated and the signals involved in osteoclast/osteoblast differentiation pathways and osteoclast/osteoblast coupling will be clarified, with obvious impact on patient management.

Animals↗

PubMed2000

Chronic metabolic acidosis in azotemic rats on a high-phosphate diet halts the progression of renal disease.

BACKGROUND: Hyperphosphatemia and metabolic acidosis are general features of advanced chronic renal failure (RF), and each may affect mineral metabolism. The goal of the present study was to evaluate the effect of chronic metabolic acidosis on the development of hyperparathyroidism and bone disease in normal and azotemic rats on a high-phosphate diet. Our assumption that the two groups of azotemic rats (acid-loaded vs. non-acid-loaded) would have the same degree of renal failure at the end of the study proved to be incorrect. METHODS: Four groups of rats receiving a high-phosphate (1.2%), normal-calcium (0.6%) diet for 30 days were studied: (1) normal (N); (2) normal + acid (N + Ac) in which 1.5% ammonium chloride (NH4Cl) was added to the drinking water to induce acidosis; (3) RF, 5/6 nephrectomized rats; and (4) RF + acid (RF + Ac) in which 0.75% NH4Cl was added to the drinking water of 5/6 nephrectomized rats to induce acidosis. RESULTS: At sacrifice, the arterial pH and serum bicarbonate were lowest in the RF + Ac group and were intermediate in the N + Ac group. Serum creatinine (0.76 +/- 0.08 vs. 1.15 +/- 0.08 mg/dL), blood urea nitrogen (52 +/- 8 vs. 86 +/- 13 mg/dL), parathyroid hormone (PTH; 180 +/- 50 vs. 484 +/- 51 pg/mL), and serum phosphate (7.46 +/- 0.60 vs. 12.87 +/- 1.4 mg/dL) values were less (P < 0.05), and serum calcium (9.00 +/- 0.28 vs. 7.75 +/- 0.28 mg/dL) values were greater (P < 0.05) in the RF + Ac group than in the RF group. The fractional excretion of phosphate (FEP) was greater (P < 0.05) in the two azotemic groups than in the two nonazotemic groups. In the azotemic groups, the FEP was similar even though PTH and serum phosphate values were less in the RF + Ac than in the RF group. NH4Cl-induced acidosis produced hypercalciuria in the N + Ac and RF + Ac groups. When acid-loaded (N + Ac and RF + Ac) and non-acid-loaded (N and RF) rats were combined as separate groups, serum phosphate and PTH values were less for a similarly elevated serum creatinine value in acid-loaded than in non-acid-loaded rats. Finally, the osteoblast surface was less in the N + Ac group than in the other groups. However, in the acid-loaded azotemic group (RF + Ac), the osteoblast surface was not reduced. CONCLUSIONS: The presence of chronic metabolic acidosis in 5/6 nephrectomized rats on a high-phosphate diet (1) protected against the progression of RF, (2) enhanced the renal clearance of phosphate, (3) resulted in a lesser degree of hyperparathyroidism, and (4) did not reduce the osteoblast surface. The combination of metabolic acidosis and phosphate loading may protect against the progression of RF and possibly bone disease because the harmful effects of acidosis and phosphate loading may be counterbalanced.

Acidosis↗

PubMed2000

Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. Durham Renal Osteodystrophy Study Group.

UNLABELLED: Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. BACKGROUND: In the management of patients with mild secondary hyperparathyroidism, it is not known whether calcium supplementation alone is sufficient to correct abnormalities in bone and mineral metabolism or if calcitriol is needed in either physiologic oral or intravenous pharmacologic doses. METHODS: This was a 40-week prospective nonmasked trial of 52 patients [parathyroid hormone (PTH) 150 to 600 pg/mL] who were randomized to receive escalating doses of either calcium carbonate (CaCO3) alone (calcium group, N = 11), daily oral calcitriol (oral group, N = 20), or intermittent intravenous calcitriol (IV group, N = 21). The groups were compared with regard to changes in serum intact PTH, serum bone-specific alkaline phosphatase (BAP), incidence of hypercalcemia (>10.5 mg/dL), and hyperphosphatemia (>6.5 mg/dL). RESULTS: PTH levels decreased in all groups (P < 0.01, paired t-test). In the calcium group, PTH (mean +/- SEM) decreased from 325 +/- 46.2 to 160 +/- 44.5 pg/mL. In the oral group, it decreased from 265 +/- 26.4 to 125 +/- 23.7 pg/mL, and in the IV group, it decreased from 240 +/- 27.7 to 65 +/- 10.0 pg/mL. Upon analysis of covariance, controlling for the initial PTH level, we found no differences in the PTH response between the groups (P > 0.10). In contrast, the BAP concentration increased from 20.7 +/- 7.6 to 27.5 +/- 7.0 microg/L in the calcium group (P = 0.17), decreased from 20. 6 +/- 3.9 to 17.8 +/- 4.5 microg/L in the oral group (P = 0.26), and from 19.1 +/- 2.6 to 10.6 +/- 1.1 microg/L in the IV group (P = 0. 007). Serum calcium increased significantly in all groups from 8.4 +/- 0.25 to 9.0 +/- 0.28, 8.5 +/- 0.16 to 9.2 +/- 0.27, and 8.7 +/- 0.16 to 9.4 +/- 0.18 mg/dL in the calcium, oral, and IV groups, respectively (P = NS difference between groups). Serum phosphorus was significantly lower in the calcium group throughout the study (P = 0.02). Hypercalcemic episodes were 2.0 +/- 0.8, 3.0 +/- 0.6, and 3. 4 +/- 0.6 per patient-year (P > 0.10), and hyperphosphatemic episodes were 0.9 +/- 0.56, 4.2 +/- 0.79 and 4.9 +/- 0.84 in the calcium, oral, and IV groups, respectively (P < 0.01). CONCLUSION: In mild secondary hyperparathyroidism, all three strategies are effective. High-dose CaCO3 alone may be sufficient to control PTH with a favorable side-effect profile, but calcitriol appears to have additional suppressive effects on bone that are greater following the intravenous route of administration and may increase the risk of adynamic bone disease.

Alkaline Phosphatase↗

PubMed2001

Risk factors and mortality associated with calciphylaxis in end-stage renal disease.

BACKGROUND: We conducted a case control study to determine risk factors and mortality associated with calciphylaxis in end-stage renal disease. METHODS: Cases of calciphylaxis diagnosed between December 1989 and January 2000 were identified. Three controls were identified for each hemodialysis patient, with calciphylaxis matched to the date of initiation of hemodialysis. Laboratory data and medication doses were recorded during the 12 months prior to the date of diagnosis and at the time of diagnosis of calciphylaxis. Conditional logistic regression was used to identify risk factors for calciphylaxis. Cox proportional hazards models were used to estimate the risk of death associated with calciphylaxis. RESULTS: Nineteen cases and 54 controls were identified. Eighteen patients were hemodialysis patients, and one had a functioning renal allograft. Diagnosis was confirmed by skin biopsy in 16 cases. Women were at a sixfold higher risk of developing calciphylaxis (OR = 6.04, 95% CI 1.62 to 22.6, P = 0.007). There was a 21% lower risk of calciphylaxis associated with each 0.1 g/dL increase in the mean serum albumin during the year prior to diagnosis and at the time of diagnosis of calciphylaxis (OR = 0.79, 95% CI, 0.64 to 0.99, P = 0.037, and OR = 0.80, 95% CI, 0.67 to 0.96, P = 0.019, respectively). There was a 3.51-fold increase in the risk of calciphylaxis associated with each mg/dL increase in the mean serum phosphate during the year prior to diagnosis (95% CI, 0.99 to 12.5, P = 0.052). At the time of diagnosis of calciphylaxis, for each 10 IU/L increment in alkaline phosphatase, the risk of calciphylaxis increased by 19% (OR = 1.19, 95% CI, 1.00 to 1.40, P = 0.045). Body mass index, diabetes, blood pressure, aluminum, and higher dosage of erythropoietin and iron dextran were not independent predictors of calciphylaxis. Calciphylaxis independently increased the risk of death by eightfold (OR = 8.58, 95% CI, 3.26 to 22.6, P < 0.001). CONCLUSIONS: Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are risk factors for calciphylaxis. Calciphylaxis is associated with a very high mortality.

Alkaline Phosphatase↗

PubMed2002

Phosphate kinetics during hemodialysis: Evidence for biphasic regulation.

BACKGROUND: Hyperphosphatemia in the hemodialysis population is ubiquitous, but phosphate kinetics during hemodialysis is poorly understood. METHODS: Twenty-nine hemodialysis patients each received one long and one short dialysis, equivalent in terms of urea clearance. Phosphate concentrations were measured during each treatment and for one hour thereafter. A new model of phosphate kinetics was developed and implemented in VisSim. This model characterized additional processes involved in phosphate kinetics explaining the departure of the measured data from a standard two-pool model. RESULTS: Pre-dialysis phosphate concentrations were similar in long and short dialysis groups. Post-dialysis phosphate concentrations in long dialysis were higher than in short dialysis (P < 0.02) despite removal of a greater mass of phosphate (P < 0.001). In both long and short dialysis serum phosphate concentrations initially fell in accordance with two-pool kinetics, but thereafter plateaued or increased despite continuing phosphate removal. Implementation of an additional regulatory mechanism such that a third pool liberates phosphate to maintain an intrinsic target concentration (1.18 +/- 0.06 mmol/L; 95% confidence intervals, CI) explained the data in 24% of treatments. The further addition of a fourth pool hysteresis element triggered by critically low phosphate levels (0.80 +/- 0.07 mmol/L, CI) yielded an excellent correlation with the observed data in the remaining 76% of treatments (cumulative standard deviation 0.027 +/- 0.004 mmol/L, CI). The critically low concentration correlated with pre-dialysis phosphate levels (r=0.67, P < 0.0001). CONCLUSION: Modeling of phosphate kinetics during hemodialysis implies regulation involving up to four phosphate pools. The accuracy of this model suggests that the proposed mechanisms have physiological validity.

Adult↗