Showing papers by "Tilman B. Drüeke published in 2007"

Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): Rationale and Design Overview

Abstract: Background and Objectives: The dramatically high rates of mortality and cardiovascular morbidity observed among dialysis patients highlights the importance of identifying and implementing strategies to lower cardiovascular risk in this population. Results from clinical trials undertaken thus far, including trials on lipid reduction, normalization of hematocrit, and increased dialysis dosage, have been unsuccessful. Available data indicate that abnormalities in calcium and phosphorus metabolism, as a result of either secondary hyperparathyroidism alone or the therapeutic measures used to manage secondary hyperparathyroidism, are associated with an increased risk for death and cardiovascular events. However, no prospective trials have evaluated whether interventions that modify these laboratory parameters result in a reduction in adverse cardiovascular outcomes. Design, Setting, Participants, & Measurements: Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events is a global, phase 3, double-blind, randomized, placebo-controlled trial evaluating the effects of cinacalcet on mortality and cardiovascular events in hemodialysis patients with secondary hyperparathyroidism. Approximately 3800 patients from 22 countries will be randomly assigned to cinacalcet or placebo. Flexible use of traditional therapies will be permitted. The primary end point is the composite of time to all-cause mortality or first nonfatal cardiovascular event (myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular disease, including lower extremity revascularization and nontraumatic amputation). Results: The study will be event driven (terminated at 1882 events) with an anticipated duration of approximately 4 yr. Conclusions: Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events will determine whether management of secondary hyperparathyroidism with cinacalcet reduces the risk for mortality and cardiovascular events in hemodialysis patients.

Effect of oral calcium carbonate on aortic calcification in apolipoprotein E-deficient (apoE−/−) mice with chronic renal failure

Abstract: Background. In chronic kidney disease (CKD) patients, the intake of calcium-based phosphate binders is associated with a marked progression of coronary artery and aortic calcification, in contrast to patients receiving calcium-free phosphate binders. The aim of this study was to reexamine the role of calcium carbonate in vascular calcification and to analyse its effect on aortic calcification-related gene expression in chronic renal failure (CRF). Methods. Mice deficient in apolipoprotein E underwent either sham operation or subtotal nephrectomy to create CRF. They were then randomly assigned to one of the three following groups: a control non-CRF group and a CRF group fed on standard diet, and a CRF group fed on calcium carbonate enriched diet, for a period of 8 weeks. Aortic atherosclerotic plaque and calcification were evaluated using quantitative morphologic image processing. Aortic gene and protein expression was examined using immunohistochemistry and Q-PCR methods. Results. Calcium carbonate supplementation was effective in decreasing serum phosphorus but was associated with a higher serum calcium concentration. Compared with standard diet, calcium carbonate enriched diet unexpectedly induced a significant decrease of both plaque (p < 0.05) and non-plaque-associated calcification surface (p < 0.05) in CRF mice. It also increased osteopontin (OPN) protein expression in atherosclerotic lesion areas of aortic root. There was also a numerical increase in OPN and osteoprotegerin gene expression in total thoracic aorta but the difference did not reach the level of significance. Finally, calcium carbonate did not change the severity of atherosclerotic lesions.

Inconsistency of reported uremic toxin concentrations.

Abstract: Discrepancies in reported uremic toxin concentrations were evaluated for 78 retention solutes. For this analysis, 378 publications were screened. Up to eight publications per toxin were retained. The highest and the lowest reported concentrations, as well as the median reported concentration were registered. The ratio between the highest and the lowest (H/L) concentrations and, for some solutes, also the ratio between the highest and the median (H/M) concentrations were calculated. The compounds were arbitrarily subdivided into three groups based on their H/L ratio: group A, H/L 8.5 (n = 25). Solutes of groups A and B showed a low to intermediate scatter, suggesting a homogeneity of reported data. Group C showed a more substantial scatter. For at least 10 compounds of group C, extremely divergent concentrations were registered (H/M > 5.5) using scatter plot analysis. For all solutes of groups A and B, the highest reported concentration could be used as a reference. For some solutes of group C and for the compounds showing a divergent scatter analysis, however, more refined directives should be followed.

Review on uraemic solutes II—Variability in reported concentrations: causes and consequences

Abstract: The aim of this manuscript is to initiate a constructive discussion about deviations in measured concentrations of uraemic solutes; these deviations, if not perceived or handled appropriately, may lead to incorrect interpretations of the pathophysiological role of uraemic solutes and/or to erroneous therapeutic decisions. To come to an objective approach towards this problem, variability analysis of reported concentrations may be of help. Striking outliers should either be discarded or considered together with other values which are more consistent with the majority of reported data.

Lanthanum carbonate as a first-line phosphate binder: the "cons".

Abstract: Controlling serum phosphorus levels in patients with renal failure is critical The use of oral phosphate-binding agents is universal for patients with end-stage kidney disease to reduce phosphate absorption The therapeutic goal is to reduce serum phosphorus levels without disturbing calcium homeostasis or promoting accumulation of potentially toxic elements from the medication Aluminum hydroxide effectively reduces serum phosphorus, but has largely been abandoned as a first-line phosphate binder because of hazards associated with metal absorption and tissue accumulation Traditional calcium-based phosphate binders tend to promote hypercalcemia and calcium overloading, and are linked to accelerated cardiovascular calcification Interest in aluminum-free, calcium-free phosphate-binding agents continues to grow Sevelamer hydrochloride, a metal-free, calcium-free hydrogel, is not absorbed, has been proven safe and efficacious in controlling serum phosphorus, and is associated with attenuated progression of cardiovascular calcification Lanthanum carbonate is a newer aluminum-free, calcium-free phosphate-binding agent Lanthanum is a rare-earth trace metal with industrial and agricultural applications As a therapeutic, this metal-based binder appears effective in reducing serum phosphorus, yet concerns remain about lanthanum accumulation in tissues during long-term oral administration Similar to the metal aluminum, lanthanum is absorbed in the intestine and accumulates in body tissues, especially in the liver, bone, muscle, kidney, and brain Moreover, the rate of intestinal absorption of lanthanum is enhanced in chronic renal failure Our experience with aluminum hydroxide suggests caution regarding the long-term use of another metal-based agent that displays enhanced absorption in the uremic state and progressive tissue accumulation

Klotho spins the thread of life—what does Klotho do to the receptors of fibroblast growth factor-23 (FGF23)?

Abstract: Klotho is one of the three goddesses of the Moirae, who in Greek mythology control the life and destiny of everyone. She is the goddess who helps life to unfold, in contrast to the (apoptotic) goddess Atropos, who cuts the thread of life. Prolonging lifespan is probably the most important role of the ageing-suppressor gene Klotho, named after the Greek goddess. Klotho was identified 10 years ago, by the Japanese group of Kuro-o et al. [1]. They reported that a defect in Klotho gene expression in the mouse resulted in a syndrome that resembled human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. The gene encoded a membrane protein that shared sequence similarity with the beta-glucosidase enzymes. This led them to conclude that the protein might function as part of a signalling pathway involved in the regulation of ageing and related diseases. One year later, the same group isolated the human homologue of the Klotho gene and determined its structure [2].

Animal models--what they can tell us about vascular calcification in CKD

Abstract: The development of cardiovascular calcifications in chronic kidney disease (CKD) patients involves multiple risk factors with additive effects. However, a number of questions concerning cardiovascular calcifications in CKD patients remain unanswered at present due to lack of clinical data or due to the impossibility of conducting clinical trials to investigate these issues. In this review, we discuss how animal models could help us understand better the pathophysiology and management of calcifying cardiovascular complications associated with CKD.

Whole or fragmentary information on parathyroid hormone

Abstract: More than a decade ago, Brossard et al. (1) drew attention to the fact that the so-called “intact,” second-generation parathyroid hormone (PTH) assays measured not only the PTH-(1-84) molecule but also large PTH fragments in patients with chronic kidney disease (CKD). One of the major problems is that the proportion of PTH-(1-84) and its fragments in the circulation changes in response to the serum level of ionized calcium; therefore, in presence of hypercalcemia, the parathyroid gland releases less PTH-(1-84) but more PTH fragments. The reverse is true in the presence of hypocalcemia, where more active PTH-(1-84) is needed. The difference is particularly striking in patients with CKD. When considering the potential biologic relevance of this finding, it is even more disturbing that at least one of the fragments, namely PTH-(7-84), has been shown to act as a partial antagonist of PTH-(1-84), with opposite biologic activities (2–4). Progressive awareness of these methodologic problems and the underlying biologic complexity went along with the development of third-generation PTH assays that recognize only PTH-(1-84), also called “whole,” “bio-intact,” or “biologically active” PTH (5). Theoretically, the assessment of second- and third-generation PTH assays combined should reflect parathyroid activity more adequately than second-generation assays alone, reflecting the sum of potentially opposing effects of PTH-(1-84) and its fragments. …

Renal function and bisphosphonate safety.

Abstract: The recent report by Jamal et al. should further raise awareness that some women with osteoporosis have chronic kidney disease (CKD). However, their manuscript has misinterpreted the Kidney Diseases Outcome Quality Initiative (K/DOQI) classification. In their paper, they state that “severe” disease is defined as an estimated glomerular filtration rate (eGFR) of <45 ml/min (estimated with a method using bone densitometric measurements of lean body weight, without a reference given about validation of this technique). This could cause misunderstanding in the care of patients with osteoporosis and CKD, because the term was intended for use only in CKD stages 4 and 5. As kidney function and muscle mass decrease with aging, a “normal” serum creatinine frequently is found in elderly patients with stages 3 and 4 CKD [The K/DOQI of the National Kidney Foundation has proposed a classification of CKDs that is gaining international acceptance. This important initiative has improved communication about the stages of kidney diseases between physicians, investigators, and patients. The details of the scheme can be found on the Kidney Foundation website (http://www.kidney.org/ professionals/KDOQI/guidelines_ckd/toc.htm). The stages are based on the eGFR, derived from the modification of diet in renal disease (MDRD) formula as follows: stage 1 eGFR > 90 ml/min/1.73 m but with other manifestations of kidney disease such as proteinuria; stage 2 eGFR between 60 and 89 ml/min/1.73 m; stage 3 eGFR between 30 and 59 ml/min/1.73 m; stage 4 eGFR between 15 and 29 ml/min/1.73 m; stage 5 eGFR < 15 ml/min/1.73 m. The term “severe” can be used for stages 4 and 5.] Thus, many patients with postmenopausal osteoporosis also have early stages of CKD. It is essential that physicians recognize that kidney disease may complicate some of the bone disease in their patients. In the FIT trial, the upper limit of serum creatinine was 144 M; about one half of the women had stage 2 CKD, ∼45% had stage 3 CKD, but <20 women had stage 4 CKD. Furthermore, women were excluded from the osteoporosis trial if they had evidence of increased serum PTH levels or alkaline phosphatase activity, which are frequently manifestations of the bone disease seen in stage 4 CKD. Therefore, the results of their study do not show that alendronate is safe or effective in “severe” kidney disease. Rather, the study was not able to detect any decrease in effectiveness or safety in women with stage 3 CKD who had an eGFR < 45 ml/min. The effectiveness or safety of chronic bisphosphonate therapy in stages 4 or 5 CKD is currently unknown. Miller et al. analyzed the use of risedronate in clinical osteoporosis trials, which included a group of women with eGFR < 30 ml/min, in whom risedronate reduced vertebral fracture rate but did not increase femoral neck BMD. In this group, the median eGFR was 27 ml/min (although the formula for eGFR determination differed from that used in the K/DOQI classification system), and none had elevations of PTH, so the findings may not apply to all patients with stage 4 CKD. A recent abstract presented by Amerling et al. found that there was a 100% incidence of low turnover bone disease with absent tetracycline uptake in patients with stages 2–5 CKD who were taking oral alendronate. Lu et al. reported increased PTH levels with pamidronate use in dialysis patients. Further research into methods of treating bone disease in patients with CKD stages 4 and 5 is clearly needed.

[Influence of microinflammation and oxidative stress on atherosclerosis progression and calcifications in cardiovascular system of hemodialyzed patients during two years follow-up].

Abstract: Atherosclerosis and calcifications in the cardio-vascular system are the most frequent causes of increased morbidity and mortality in patients with end-stage renal disease treated with hemodialyses. The aim of this study was to estimate the atherosclerosis progression and presence of calcifications in the circulatory system in patients treated with hemodialyses using, non-invasive imaging diagnostic techniques and to search for the relationships between these changes and microinflammation and oxidative stress during two years. The study was performed in 73 patients (36 female and 37 male), aged 25 to 75 years (mean -49.5), treated with hemodialyses, 3 times/week for 12 to 275 months (mean -73.8). In each patient before starting hemodialysis levels of: ox-LDL, Lp (a), procalcitonin, IL-1beta, IL-6, CRP, TGFbeta, TNFalpha, PDGF, AOPP and MPO were determined. Presence of artery calcifications was detected by Multi-Row Spiral Computed Tomography (MSCT) and expressed as coronary artery calcification score (CACS). Ultrasonography was used to evaluate CCA-IMT. During the study CACS increased significantly after 12 and 24 months (p < 0.00001) as compare with baseline. After 12 months, CACS increase significantly correlated with procalcitonin level (r = 0.30 p = 0.01) and after 24 months with CRP (r = 0.46; p = 0.0002) and IL-6 (r = 0.36; p = 0.005). Independent factor of coronary artery calcification progression after 24 months of observation was only CRP (beta = 0.569). CCA-IMT increased during the study and this increase was statistically significant (p < 0.00001). CCA-IMT increase correlated with CACS growth after 12 (r = 0.36; p = 0.003) and 24 months (r = 0.39; p = 0.002). After 12 months significant relationship was noted with procalcitonin (r = 0.29; p = 0.022). After 24 months CCA-IMT correlated with AOPP (r = -0.30; p = 0.017). The independent factor of CCA-IMT progression after 24 months of observation was only CACS (delta CACS beta = 0.49). From the performed study, we can conclude that exacerbation of atherosclerosis and calcification in the circulatory system of patients treated with maintenance hemodialyses depends on microinflammation and oxidative stress. Reasonable tools for diagnostic algorithm estimation of atherosclerosis advancement in this group of patients are non-invasive, visual diagnostic techniques such as MSCT and ultrasonography.

Optimal dialysate calcium and vascular calcification

Abstract: Sir, Yamada et al. [1] report that the rate of progression of aortic calcification is related to the increase of serum calcium during the haemodialysis session ( Ca), using a stepwise multivariate regression analysis. The only other serum parameter that exhibited an association with the progression of aortic calcification was CRP. The authors hypothesized that the excess calcium transferred into patients on intermittent haemodialysis treatment when using a dialysate calcium concentration of 3.0mEq/l was responsible for this association. We would like to ask why the authors did not correct for post-dialysis haemoconcentration, when calculating Ca? They could have proceeded to this correction easily, since they measured serum albumin and presumably also blood haemoglobin, although this is not indicated in the article. We respectfully question the hypothesis that the perdialytic Ca is the major culprit. An alternative hypothesis is that higher serum calcium levels simply reflect higher haemoconcentration at the end of the dialysis session, and that this in turn is the expression of a greater removal of sodium and water in patients with larger interdialytic body weight gain. Although the authors failed to observe a correlation between Ca and ultrafiltration rate in univariate analysis (Table 2), there was a correlation between these two parameters in step-wise multivariate regression analysis (Table 3). Our hypothesis is supported by the latter positive association and also by the negative association of Ca with the serum calcium concentration before the dialysis session. We therefore believe, in disagreement with the 2003 K/ DOQI guidelines [2], that the dialysate calcium concentration should generally not be lowered to <3.0mEq/l, unless patients are receiving high doses of active vitamin D derivatives and/or calcium-containing phosphate binders. Low calcium concentrations in the dialysis fluid may be hazardous in chronic haemodialysis patients with cardiovascular disease, who are hypotension-prone [3] and in those who are receiving calcimimetics. The latter have the capacity to lower serum calcium [4] and to delay the progression of vascular calcification [5,6].