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Kovesdy C.P.,Salem Medical Center | Kovesdy C.P.,University of Virginia | Kuchmak O.,Carilion Clinic | Lu J.L.,Salem Research Institute | Kalantar-Zadeh K.,University of California at Los Angeles
American Journal of Kidney Diseases

Background Phosphorus binders are used to treat hyperphosphatemia in maintenance dialysis patients, in whom the use of these medications has been associated with lower mortality in some observational studies. It is not clear whether similar benefits can be seen in patients with nondialysis-dependent chronic kidney disease (CKD). Study Design Historical cohort. Setting & Participants 1,188 men with moderate and advanced nondialysis-dependent CKD at a single medical center. Predictor Administration of any phosphorus binder. Outcomes & Measurements We examined associations of any phosphorus-binder administration with all-cause mortality and the slopes of estimated glomerular filtration rate using time-varying Cox models and mixed-effects models. Associations also were examined in intention-to-treat analyses and in 133 patient-pairs matched according to propensity scores. Results 344 patients were treated with a phosphorus binder; 658 patients died (mortality rate, 141 deaths/1,000 patient-years; 95% CI, 131-153) during a median follow-up of 3.1 years. Treatment with phosphorus binders was associated with significantly lower mortality (adjusted HR, 0.61; 95% CI, 0.45-0.81; P < 0.001). Results were similar when exposure was modeled in intention-to-treat analyses and examining propensity-matched patients. Phosphorus-binder use was not associated with significant changes in kidney function loss. Limitations Results may not apply to all patients with nondialysis-dependent CKD. Conclusions Administration of phosphorus binders is associated with lower mortality in men with moderate and advanced nondialysis-dependent CKD. Clinical trials are needed to determine the risks and benefits of phosphorus-binder use in this patient population. © 2010 National Kidney Foundation, Inc. Source

Ricks J.,University of California at Los Angeles | Molnar M.Z.,University of California at Los Angeles | Molnar M.Z.,Semmelweis University | Kovesdy C.P.,Salem Medical Center | And 6 more authors.

Previous observational studies using differing methodologies have yielded inconsistent results regarding the association between glycemic control and outcomes in diabetic patients receiving maintenance hemodialysis (MHD). We examined mortality predictability of A1C and random serum glucose over time in a contemporary cohort of 54,757 diabetic MHD patients (age 63 ± 13 years, 51% men, 30% African Americans, 19% Hispanics). Adjusted all-cause death hazard ratio (HR) for baseline A1C increments of 8.0-8.9, 9.0-9.9, and ≥10%, compared with 7.0-7.9% (reference), was 1.06 (95% CI 1.01-1.12), 1.05 (0.99-1.12), and 1.19 (1.12-1.28), respectively, and for time-averaged A1C was 1.11 (1.05-1.16), 1.36 (1.27-1.45), and 1.59 (1.46-1.72). A symmetric increase in mortality also occurred with time-averaged A1C levels in the low range (6.0-6.9%, HR 1.05 [95% CI 1.01-1.08]; 5.0-5.9%, 1.08 [1.04-1.11], and ≤5%, 1.35 [1.29-1.42]) compared with 7.0-7.9% in fully adjusted models. Adjusted all-cause death HR for time-averaged blood glucose 175-199, 200-249, 250-299, and ≥300 mg/dL, compared with 150-175 mg/dL (reference), was 1.03 (95% CI 0.99-1.07), 1.14 (1.10-1.19), 1.30 (1.23-1.37), and 1.66 (1.56-1.76), respectively. Hence, poor glycemic control (A1C ≥8% or serum glucose ≥200 mg/dL) appears to be associated with high all-cause and cardiovascular death in MHD patients. Very low glycemic levels are also associated with high mortality risk. © 2012 by the American Diabetes Association. Source

Kovesdy C.P.,Salem Medical Center | Kovesdy C.P.,University of Virginia
Clinical Journal of the American Society of Nephrology

The introduction of calcitriol followed by several of its analogs in the 1990s made vitamin D receptor activators (VDRA) the cornerstone of therapy for secondary hyperparathyroidism. The 2003 publication of the first major epidemiologic study describing the association of VDRAs with survival in ESRD has raised the awareness of the nephrology community about the potential impact of these agents on morbidity and mortality. This study was followed by numerous other epidemiologic studies which attempted to address the inherent shortcomings of observational studies by using sophisticated statistical methods. The complex nature of the statistical designs applied by some of these studies has led to some confusion about how to interpret the results, and how to use the results in a way that offers the most help for patients, but does not impede future scientific research. This report presents a discussion of relevant studies examining the association between VDRA and survival, with the goal to examine shortcomings that still exist in the knowledge on this subject. Special emphasis is placed on the discussion of studies with discrepant results to highlight remaining controversies and to emphasize areas in need of further research. Not withstanding all of the limitations of epidemiologic studies, the preponderance of evidence favors a survival benefit for ESRD patients treated with VDRA. This should provide a powerful impetus to investigate in clinical trials the risks and benefits of VDRA administration as a means to prolong survival. Copyright © 2010 by the American Society of Nephrology. Source

Molnar M.Z.,University of California at Los Angeles | Ojo A.O.,University of Michigan | Bunnapradist S.,University of California at Los Angeles | Kovesdy C.P.,Salem Medical Center | Kalantar-Zadeh K.,University of California at Los Angeles
Nature Reviews Nephrology

Over the past two decades, most guidelines have advocated early initiation of dialysis on the basis of studies showing improved survival in patients starting dialysis early. These recommendations led to an increase in the proportion of patients initiating dialysis with an estimated glomerular filtration rate (eGFR) >10 ml/min/1.73 m 2, from 20% in 1996 to 52% in 2008. During this period, the percentage of patients starting dialysis with an eGFR ≥15 ml/min/1.73 m 2 increased from 4% to 17%. However, recent studies have failed to substantiate a benefit of early dialysis initiation and some data have suggested worse outcomes for patients starting dialysis with a higher eGFR. Several reasons for this seemingly paradoxical observation have been suggested, including the fact that patients requiring early dialysis are likely to have more severe symptoms and comorbidities, leading to confounding by indication, as well as biological mechanisms that causally relate early dialysis therapy to adverse outcomes. Patients with a failing renal allograft who reinitiate dialysis encounter similar problems. However, unique factors associated with a failed allograft means that the optimal timing of dialysis initiation in failed transplant patients might differ from that in transplant-naive patients with chronic kidney disease. In this Review, we discuss studies of dialysis initiation and compare risks and benefits of early versus late initiation and reinitiation of dialysis therapy. © 2012 Macmillan Publishers Limited. All rights reserved. Source

Linhart K.,University of Heidelberg | Bartsch H.,Salem Medical Center | Seitz H.K.,German Cancer Research Center
Redox Biology

Exocyclic etheno-DNA adducts are mutagenic and carcinogenic and are formed by the reaction of lipidperoxidation (LPO) products such as 4-hydoxynonenal or malondialdehyde with DNA bases. LPO products are generated either via inflammation driven oxidative stress or via the induction of cytochrome P-450 2E1 (CYP2E1). In the liver CYP2E1 is induced by various compounds including free fatty acids, acetone and ethanol. Increased levels of CYP2E1 and thus, oxidative stress are observed in the liver of patients with non-alcoholic steatohepatitis (NASH) as well as in the chronic alcoholic. In addition, chronic ethanol ingestion also increases CYP2E1 in the mucosa of the oesophagus and colon. In all these tissues CYP2E1 correlates significantly with the levels of carcinogenic etheno-DNA adducts. In contrast, in patients with non-alcoholic steatohepatitis (NASH) hepatic etheno-DNA adducts do not correlate with CYP2E1 indicating that in NASH etheno-DNA adducts formation is predominately driven by inflammation rather than by CYP2E1 induction. Since etheno-DNA adducts are strong mutagens producing various types of base pair substitution mutations as well as other types of genetic damage, it is strongly believed that they are involved in ethanol mediated carcinogenesis primarily driven by the induction of CYP2E1. © 2014 The Authors. Source

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