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      Severe secondary hyperparathyroidism in patients on haemodialysis is associated with a high initial serum parathyroid hormone and beta-CrossLaps level: Results from an incident cohort

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          Abstract

          Background

          Secondary hyperparathyroidism (SHPT) is a frequent complication of renal disease and most commonly occurs in patients on haemodialysis (HD) with metabolic, vascular, endocrine, and bone complications. The aim of this study was to analyze the evolution of mineral metabolism parameters during the first 36 months of HD treatment and identify the initial factors associated with severe SHPT.

          Methods

          Serum parathyroid hormone (PTH), calcium and phosphate levels were measured monthly; bone-specific alkaline phosphatase (b-ALP) and beta-CrossLaps (CTX) were measured biannually. Severe SHPT was defined as the need for cinacalcet treatment. Patients with less than 24 months of follow-up were excluded.

          Results

          One hundred thirty-three incident HD patients were included. Baseline mean PTH was 275 ± 210 pg/mL. After an initial drop at the third month (172 ± 133 pg/mL), the serum PTH level progressively increased to the maximum at 36 months (367 ± 254 pg/mL). This initial drop was associated with the initial correction of both hypocalcaemia and hyperphosphataemia. Serum CTX and b-ALP revealed no significant changes over time. Severe SHPT was observed in 18% of patients and was associated with higher mean calcaemia and phosphataemia. In logistic regression, the initial factors associated with the risk of severe SHPT were: female sex, higher baseline PTH and CTX values. A receiver operation characteristic curve analysis identified a cut-off value of >374 pg/mL for baseline PTH and >1.2 μg/L for CTX for increased risk of developing severe SHPT. The relative risk of developing severe SHPT was 3.7 (1.8–7.5, p = 0.002) for high baseline CTX, 4.9 (2.4–9.7, p = 0.001) for high baseline PTH, and 7.7 (3.6–16, p< 0.0001) when both criteria were present.

          Conclusion

          After an initial drop, a progressive increase in the serum PTH level during the first 3 years of HD treatment was observed despite aggressive therapy. High baseline levels of PTH and CTX increased the risk of developing severe SHPT.

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          Most cited references28

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

          Altered mineral metabolism contributes to bone disease, cardiovascular disease, and other clinical problems in patients with end-stage renal disease. This 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. Many 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 mg(2)/dL(2), 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. This study expands our understanding of the relationship between altered mineral metabolism and outcomes and identifies several potential opportunities for improved practice in this area.
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            Timing of onset of CKD-related metabolic complications.

            Chronic kidney disease (CKD) guidelines recommend evaluating patients with GFR <60 ml/min per 1.73 m(2) for complications, but little evidence supports the use of a single GFR threshold for all metabolic disorders. We used data from the NephroTest cohort, including 1038 adult patients who had stages 2 through 5 CKD and were not on dialysis, to study the occurrence of metabolic complications. GFR was measured using renal clearance of (51)Cr-EDTA (mGFR) and estimated using two equations derived from the Modification of Diet in Renal Disease study. As mGFR decreased from 60 to 90 to <20 ml/min per 1.73 m(2), the prevalence of hyperparathyroidism increased from 17 to 85%, anemia from 8 to 41%, hyperphosphatemia from 1 to 30%, metabolic acidosis from 2 to 39%, and hyperkalemia from 2 to 42%. Factors most strongly associated with metabolic complications, independent of mGFR, were younger age for acidosis and hyperphosphatemia, presence of diabetes for acidosis, diabetic kidney disease for anemia, and both male gender and the use of inhibitors of the renin-angiotensin system for hyperkalemia. mGFR thresholds for detecting complications with 90% sensitivity were 50, 44, 40, 39, and 37 ml/min per 1.73 m(2) for hyperparathyroidism, anemia, acidosis, hyperkalemia, and hyperphosphatemia, respectively. Analysis using estimated GFR produced similar results. In summary, this study describes the onset of CKD-related complications at different levels of GFR; anemia and hyperparathyroidism occur earlier than acidosis, hyperkalemia, and hyperphosphatemia.
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              Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials.

              Vitamin D deficiency is highly prevalent among patients with chronic kidney disease (CKD). The benefits and harms of vitamin D supplementation (ergocalciferol or cholecalciferol) were assessed in patients with nondialysis-dependent CKD, dialysis-dependent CKD, and renal transplant recipients. MEDLINE (1966 to September 2009), SCOPUS (September 2009), and nephrology conference proceedings were searched for relevant observational and randomized controlled trials (RCTs). Treatment effects were summarized as mean differences (MDs) with 95% confidence intervals (CIs) using a random effects model. Separate analyses were conducted for observational studies and RCTs. Twenty-two studies (17 observational and 5 RCTs) were included. There was a significant improvement in 25-hydroxyvitamin D (MD 24.1 ng/ml, 95% CI 19.6 to 28.6) and an associated decline in parathyroid hormone (PTH) levels (MD -41.7 pg/ml, 95% CI -55.8 to -27.7) among observational studies. PTH reduction was higher in dialysis patients. Among RCTs, there was a significant improvement in 25-hydroxyvitamin D (MD 14 ng/ml, 95% CI 5.6 to 22.4) and an associated decline in PTH levels (MD -31.5 pg/ml, 95% CI -57 to -6.1). A low incidence of hypercalcemia and hyperphosphatemia was reported with vitamin D supplementation. Cardiovascular and skeletal effects of vitamin D supplementation have not been studied. Included studies were mostly of low to moderate quality. Available evidence from low-to-moderate quality observational studies and fewer RCTs suggests that vitamin D supplementation improves biochemical endpoints. However, whether such improvements translate into clinically significant outcomes is yet to be determined.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: Writing – original draft
                Role: MethodologyRole: ValidationRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: Formal analysisRole: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Formal analysisRole: Project administrationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 June 2018
                2018
                : 13
                : 6
                : e0199140
                Affiliations
                [1 ] NEPHROCARE Tassin-Charcot, Haemodialysis, Sainte Foy-les-Lyon,France
                [2 ] Institut National de la Sante et de la Recherche Medical (INSERM) 890, CHU, Saint-Etienne, France
                [3 ] Université Paris Descartes, Inserm U845, and Hôpital Necker, Service d’explorations fonctionnelles, Paris,France
                [4 ] CERBALLIANCE, Laboratoire de biologie médicale du Grand Vallon, Sainte Foy-les-Lyon, France
                [5 ] F CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
                The University of Tokyo, JAPAN
                Author notes

                Competing Interests: The authors have the following interests: Guillaume JEAN, Patrik DELEAVAL, Christie LORRIAUX, Jean-Marc HUROT, Brice MAYOR, Manolie MEHDI and Charles CHAZOT are employed by NEPHROCARE and Sylvain LECHEVALLIER by CERBALLIANCE. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Author information
                http://orcid.org/0000-0003-4757-9956
                Article
                PONE-D-17-22685
                10.1371/journal.pone.0199140
                6005469
                29912988
                194c6eed-36fe-49fe-8079-44a061cf819d
                © 2018 Jean et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 July 2017
                : 1 June 2018
                Page count
                Figures: 6, Tables: 3, Pages: 15
                Funding
                NEPHROCARE (Fresenius Medical Care France) and CERBALLIANCE provided support in the form of salaries for authors GJ, PD, CL, JMH, BM, MM, CC and SL but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Nephrology
                Medical Dialysis
                Biology and Life Sciences
                Biochemistry
                Hormones
                Parathyroid Hormone
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Physical Sciences
                Chemistry
                Chemical Compounds
                Phosphates
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Endocrinology
                Endocrine Disorders
                Diabetes Mellitus
                Medicine and Health Sciences
                Metabolic Disorders
                Diabetes Mellitus
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Bone and Mineral Metabolism
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Phosphatases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Phosphatases
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized
                Uncategorized

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