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      Association of time‐updated plasma calcium and phosphate with graft and patient outcomes after kidney transplantation

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          Abstract

          Disturbances in calcium‐phosphate homeostasis are common after kidney transplantation. We aimed to assess the relationship between deregulations in plasma calcium and phosphate over time and mortality and death‐censored graft failure (DCGF). In this prospective cohort study, we included kidney transplant recipients with ≥2 plasma calcium and phosphate measurements. Data were analyzed using time‐updated Cox regression analyses adjusted for potential confounders including time‐updated kidney function. We included 2769 patients (mean age 47 ± 14 years, 42.3% female) with 138 496 plasma calcium and phosphate levels (median [IQR] 43 [31–61] measurements per patient). During follow‐up of 16.3 [8.7–25.2] years, 17.2% developed DCGF and 7.9% died. Posttransplant hypercalcemia was associated with an increased risk of mortality (1.63 [1.31–2.00], p < 0.0001), but not with DCGF. Hyperphosphatemia was associated with both DCGF (2.59 [2.05–3.27], p < .0001) and mortality (3.14 [2.58–3.82], p <  .0001). Only the association between hypercalcemia and mortality remained significant in sensitivity analyses censored by a simultaneous eGFR <45 mL/min/1.73 m 2. Hypocalcemia and hypophosphatemia were not consistently associated with either outcome. Posttransplant hypercalcemia, even in the presence of preserved kidney function, was associated with an increased mortality risk. Associations of hyperphosphatemia with DCGF and mortality may be driven by eGFR.

          Abstract

          This prospective cohort study shows that, in patients with preserved kidney function, hypercalcemia is associated with increased mortality risk.

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          A new equation to estimate glomerular filtration rate.

          Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. 8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES. GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%). The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. National Institute of Diabetes and Digestive and Kidney Diseases.
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            A Proportional Hazards Model for the Subdistribution of a Competing Risk

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              FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.

              We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism. The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes. To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals. An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h. FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.
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                Author and article information

                Contributors
                m.h.de.borst@umcg.nl
                Journal
                Am J Transplant
                Am J Transplant
                10.1111/(ISSN)1600-6143
                AJT
                American Journal of Transplantation
                John Wiley and Sons Inc. (Hoboken )
                1600-6135
                1600-6143
                12 January 2021
                July 2021
                : 21
                : 7 ( doiID: 10.1111/ajt.v21.7 )
                : 2437-2447
                Affiliations
                [ 1 ] Department of Surgery University of Groningen University Medical Center Groningen Groningen The Netherlands
                [ 2 ] Department of Internal Medicine Division of Nephrology University of Groningen University Medical Center Groningen Groningen The Netherlands
                [ 3 ] TransplantLines Biobank and Cohort Study Groningen The Netherlands
                Author notes
                [*] [* ] Correspondence

                Martin H. de Borst, Department of Internal Medicine Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

                Email: m.h.de.borst@ 123456umcg.nl

                Author information
                https://orcid.org/0000-0002-5758-2959
                https://orcid.org/0000-0003-2228-4676
                https://orcid.org/0000-0002-2236-5233
                https://orcid.org/0000-0002-5151-7320
                https://orcid.org/0000-0003-3356-6791
                https://orcid.org/0000-0002-4127-8733
                Article
                AJT16457
                10.1111/ajt.16457
                8359271
                33331113
                c1bd2068-51b4-46b9-840e-95f98dcd3a3f
                © 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 08 November 2020
                : 15 May 2020
                : 09 December 2020
                Page count
                Figures: 4, Tables: 3, Pages: 11, Words: 6713
                Categories
                Original Article
                ORIGINAL ARTICLES
                Clinical Science
                Custom metadata
                2.0
                July 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.5 mode:remove_FC converted:12.08.2021

                Transplantation
                clinical research/practice,health services and outcomes research,hyperparathyrodism,kidney (allograft) function/dysfunction,kidney transplantation/nephrology

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