Osteodystrophy in the millennium

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

Cuprammonium membranes stimulate interleukin 1 release and arachidonic acid metabolism in monocytes in the absence of complement

Contact of blood with foreign surfaces, specifically dialysis membranes, causes cell activation which has widely been assumed to be mediated by complement (C). To explore the possibility of C-independent activation, we examined different cell types: PMN, human monocytes and the cell lines U937 or HL60, washed human platelets and rat glomerular epithelial cell (primary) cultures (GEC), under serum-free conditions and after addition of anti-C3 F(ab)2, respectively. The monitored biological effects were release of PGE2, TXB2 or interleukin 1 and generation of O2− radicals. To further explore the mechanisms involved, phospholipid metabolism was studied by measuring IP3 and DG (14C-arachidonic or oleic acid prelabeled U937 and HL60 cells); changes of cytosolic Ca++ (Quin2 technique) were also determined. The results show that in absence of C, brief (2 min) contact with cuprammonium (CU) stimulated: (a) PGE2 release in U937 and human monocytes or GEC; (b) TXB2 release in washed platelets; (c) slow interleukin 1 release by monocytes; and (d) generation of O2− radicals in PMN. Artifacts due to endotoxin were excluded by appropriate polymyxin control experiments and by comparison of effects with those of bacterial LPS. Potential synthesis of C3 by U937 was excluded by addition of anti-C3 F(ab)2. C-independent cell activation was accompanied by increase of DG, but not IP3 (suggesting involvement of protein C kinase dependent mechanisms) and by increased cytosolic Ca++. To further explore the initial signal involved, incubations were carried out with covalently modified CU members (DEAE cellulose) and in the presence of mM concentrations of monosaccharides. Cationic modification of CU membranes reduced C-independent cell activation. Activation of arachidonic acid metabolism and increase in cytosolic calcium by unmodified CU membranes were stereospecifically inhibited by L-fucose, pointing to involvement of carbohydrates in the recognition signal

Predictors and consequences of altered mineral metabolism: The Dialysis Outcomes and Practice Patterns Study

Predictors and consequences of altered mineral metabolism: The Dialysis Outcomes and Practice Patterns Study.BackgroundAltered mineral metabolism contributes to bone disease, cardiovascular disease, and other clinical problems in patients with end-stage renal disease.MethodsThis study describes the recent status, significant predictors, and potential consequences of abnormal mineral metabolism in representative groups of hemodialysis facilities (N = 307) and patients (N = 17,236) participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) in the United States, Europe, and Japan from 1996 to 2001.ResultsMany patients fell out of the recommended guideline range for serum concentrations of phosphorus (8% of patients below lower target range, 52% of patients above upper target range), albumin-corrected calcium (9% below, 50% above), calcium-phosphorus product (44% above), and intact PTH (51% below, 27% above). All-cause mortality was significantly and independently associated with serum concentrations of phosphorus (RR 1.04 per 1 mg/dL, P = 0.0003), calcium (RR 1.10 per 1 mg/dL, P < 0.0001), calcium-phosphorus product (RR 1.02 per 5 mg2/dL2, P = 0.0001), PTH (1.01 per 100 pg/dL, P = 0.04), and dialysate calcium (RR 1.13 per 1 mEq/L, P = 0.01). Cardiovascular mortality was significantly associated with the serum concentrations of phosphorus (RR 1.09, P < 0.0001), calcium (RR 1.14, P < 0.0001), calcium-phosphorus product (RR 1.05, P < 0.0001), and PTH (RR 1.02, P = 0.03). The adjusted rate of parathyroidectomy varied 4-fold across the DOPPS countries, and was significantly associated with baseline concentrations of phosphorus (RR 1.17, P < 0.0001), calcium (RR 1.58, P < 0.0001), calcium-phosphorus product (RR 1.11, P < 0.0001), PTH (RR 1.07, P < 0.0001), and dialysate calcium concentration (RR 0.57, P = 0.03). Overall, 52% of patients received some form of vitamin D therapy, with parenteral forms almost exclusively restricted to the United States. Vitamin D was potentially underused in up to 34% of patients with high PTH, and overused in up to 46% of patients with low PTH. Phosphorus binders (mostly calcium salts during the study period) were used by 81% of patients, with potential overuse in up to 77% patients with low serum phosphorus concentration, and potential underuse in up to 18% of patients with a high serum phosphorus concentration.ConclusionThis study expands our understanding of the relationship between altered mineral metabolism and outcomes and identifies several potential opportunities for improved practice in this area

Urinary matrix calculi consisting of microfibrillar protein in patients on maintenance hemodialysis

Urinary matrix calculi consisting of microfibrillar protein in patients on maintenance hemodialysis. In seven patients on maintenance hemodialysis,de novo recurrent renal stone formation was observed. In all patients, the underlying disease was glomerulonephritis, with or without the nephrotic syndrome. All patients had considerable persistent proteinuria. The stones consisted predominantly of protein, as revealed by amino acid analysis, and had a negligible carbohydrate and lipid content. Only in some specimens, X-ray diffraction and scanning electron microscopy revealed the presence of small amounts of whewellit (calcium oxalate monohydrate) and/or uric acid. In semithin sections, the stones had a laminated texture and exhibited structural anisotropy under polarized light. With transmission electron microscopy, they were found to consist of peculiar microfibrils. The proteinaceous material differed from fibrin or Tamm-Horsfall-protein, as indicated by ultrastructure, carbohydrate analysis, and amino acid analysis. Symptomaticde novo matrix stone formation constitutes another complication of dialyzed patients which has not been reported so far.Calculs urinaires constitués de protéines microfibrillaires chez des malades en hémodialyse chronique. Chez sept malades en hémodialyse chronique, la formation récidivante de calculs urinaires a été observée. Chez tous les malades, la maladie initiale était une glomérulonéphrite avec ou sans syndrome néphrotique. Tous les malades avaient une protéinurie importante. Les calculs étaient essentiellement constitués de protéine, comme l'indiquait l'analyse des acides aminés, et avaient un contenu négligeable en hydrates de carbone et lipides. Dans quelques échantillons seulement la diffraction X et la microscopie électronique à balayage ont révélé la présence de faibles quantités d'oxalate de calcium monohydrate et/ou d'acide urique. Sur les coupes semifines les calculs avaient un aspect laminé et étaient anisotropiés en lumière polarisée. En microscopie électronique à transmission il a été observé des microfibrilles particulières. La substance protéique diffère de la fibrine ou de la protéine de Tamm-Horsfall d'après l'étude ultrastructurale, l'analyse des hydrates de carbone, et l'analyse des acides aminés. La formation de novo de calculs, accompagnée de syndromes de lithiase, constitue une complication non encore rapportée à ce jour au cours de la dialyse chronique

Pharmacokinetics of Sulfobutylether-Beta-Cyclodextrin and Voriconazole in Patients with End-Stage Renal Failure during Treatment with Two Hemodialysis Systems and Hemodiafiltration▿

Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. At the start of renal replacement therapy, the patients received a single 2-h infusion of voriconazole (4 mg per kg of body weight) solubilized with SBECD. SBECD, voriconazole, and voriconazole-N-oxide concentrations were quantified in plasma and dialysate samples by high-performance liquid chromatography (HPLC) and by HPLC coupled to tandem mass spectrometry (LC-MS-MS) and analyzed by noncompartmental methods. Nonparametric repeated-measures analysis of variance (ANOVA) was used to analyze differences between treatment phases. SBECD and voriconazole recoveries in dialysate samples were 67% and 10% of the administered doses. SBECD concentrations declined with a half-life ranging from 2.6 ± 0.6 h (Genius dialysis) to 2.4 ± 0.9 h (hemodialysis) and 2.0 ± 0.6 h (hemodiafiltration) (P < 0.01 for Genius dialysis versus hemodiafiltration). Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased