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      A Retrospective Evaluation of 1,25-Dihydroxyvitamin D 3 and Its Potential Effects on Renal Allograft Function


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          Background/Aims: 1,25-Dihydroxyvitamin D<sub>3</sub> (1,25-(OH)<sub>2</sub>D<sub>3</sub>) plays an important role in regulating immunologic responsiveness in addition to its effects on bone metabolism. This is potentially beneficial in the transplant setting. Animal studies have demonstrated the utility of 1,25-(OH)<sub>2</sub>D<sub>3</sub> in prolonging allograft survival. Therefore, we evaluated the effects of 1,25-(OH)<sub>2</sub>D<sub>3</sub> (oral calcitriol) in human renal transplant recipients. Methods: A case-control study was undertaken assessing the effects of calcitriol on transplant function. The effect of calcitriol on renal function was analyzed using general linear mixed modeling of the change in slope of serum creatinine (Scr) prior to and following the start of calcitriol therapy. Results: There was a significant increase in baseline Scr (p < 0.001) prior to starting calcitriol. Following initiation of calcitriol, there was a deceleration in the rate of loss of graft function (p = 0.031 at day 300 of therapy). Graft survival was also prolonged in calcitriol-treated patients compared to a control population with evidence of chronic allograft nephropathy but no calcitriol therapy (p < 0.03). Overall, there were no adverse or harmful effects related to calcitriol therapy. 1,25-(OH)<sub>2</sub>D<sub>3</sub> therapy was associated with (1) a deceleration in the rate of loss of renal function in transplant recipients with more than one year of allograft function, and (2) no significant change in allograft function early after transplantation. Conclusion: These data suggest that short- and long-term prospective trials evaluating 1,25-(OH)<sub>2</sub>D<sub>3</sub> or 1,25-(OH)<sub>2</sub>D<sub>3</sub> analogs in human kidney transplantation are warranted. Such trials may help us elucidate mechanism and duration of action, as well as safety issues related to these novel immunomodulatory agents.

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          Immunomodulatory actions of 1,25-dihydroxyvitamin D3.

          The sterol, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has immunosuppressive activity. The hormone inhibits the production of lymphokines (IL-2, IFN-gamma) and monocyte-derived cytokine (IL-12) leading to inhibition of helper T cell subset type 1 (Th1). When given in vivo, the hormone prevents the development of spontaneous and induced models of autoimmunity. Analogs of 1,25(OH)2D3, with reduced hypercalcemic effects, display an enhanced activity in autoimmunity compared to the sterol and prolong graft survival in experimental transplantation. This paper reviews our understanding of the cellular actions of the hormone and the therapeutic application of 1,25(OH)2D3 and analogs in autoimmunity and transplantation.
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            Immunomodulatory effects of vitamin D analog KH1060 on an experimental skin transplantation model

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              1,25–Dihydroxyvitamin D 3 Stimulates Transforming Growth Factor–β1 Synthesis by Mouse Renal Proximal Tubular Cells

              1,25–Dihydroxyvitamin D 3 [1,25–(OH) 2 D 3 ] is a secosteroid hormone with effects on cell growth, differentiation and immunoregulatory functions in a number of tissues not primarily involved in mineral metabolism. We recently demonstrated growth–regulating effects of 1,25–(OH) 2 D 3 on human mesangial cells and proximal tubular cells. To investigate whether 1,25–(OH) 2 D 3 might also affect the synthesis of cytokines and growth factors in proximal tubular cells, we assessed in the present study the expression and secretion of transforming growth factor–β1 (TGF–β1) in a mouse proximal tubular cell line (MCT) in vitro. TGF–β1 synthesis was measured by a monospecific ELISA in culture supernatant. The secreted TGF–β1 was proven to be biologically active by means of a bioassay system (CCL–64 mink lung epithelial cell proliferation assay). TGF–β1 gene expression was assessed by RT–PCR. To analyze whether TGF–β1 expression mediates the 1,25–(OH) 2 D 3 –induced antiproliferative actions in MCT, proliferation studies in the absence or presence of a blocking monoclonal anti TGF–β1–3 antibody were performed. 1,25–(OH) 2 D 3 (10 –11 to 10 –7 M) specifically increased the TGF–β1 protein secretion in MCT with a maximum at 10 –8 M. No detectable effect was found with 25 D 3 at 10 times higher concentrations. A synthetic 20–epi analogue, MC 1288, increased TGF–β1 secretion up to similar amounts at equimolar concentrations as the natural hormone 1,25–(OH) 2 D 3 . Steady–state TGF–β1 mRNA concentration in MCT was transiently increased by 1,25–(OH) 2 D 3 between 12 and 24 h, returning to control values at 48 h. Blocking TGF–β1 did not reduce or abrogate the antiproliferative effect of 1,25–(OH) 2 D 3 . In conclusion, 1,25–(OH) 2 D 3 stimulates TGF–β1 expression in renal proximal tubular cells, a growth factor with anti–inflammatory and profibrotic actions which plays an important role in the development and progression of nephrosclerosis.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                December 2002
                07 October 2002
                : 22
                : 5-6
                : 515-520
                aDivision of Transplantation, Department of Surgery, and bDivision of Nephrology, Department of Medicine, University of Wisconsin, and Department of Veterans Affairs Medical Center, Madison, Wisc., USA
                65289 Am J Nephrol 2002;22:515–520
                © 2002 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                : 09 October 2001
                : 11 June 2002
                Page count
                Figures: 1, Tables: 2, References: 24, Pages: 6
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/65289
                Self URI (text/html): https://www.karger.com/Article/FullText/65289
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Clinical Study

                Cardiovascular Medicine,Nephrology
                Vitamin D,Kidney transplantation,1,25-Dihydroxyvitamin D3 ,Chronic allograft nephropathy,Calcitriol


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