Potential Effects of 1,25-Dihydroxyvitamin D(3) in Renal Transplant Recipients

Potential Effects of 1,25-Dihydroxyvitamin D(3) in Renal Transplant Recipients S. Sezer, M. Uyar, Z. Arat, F.N. Özdemir, and M. Haberal

ABSTRACT Besides its effects on bone metabolism, calcitriol has an important immunomodulatory effect, which may be protective for a renal allograft. Therefore, we evaluated the effects of oral calcitriol administration in renal transplant recipients. One hundred ten renal transplant recipients (78 men, 32 women) of mean age 35.2 ⫾ 11.4 years and mean posttransplantation follow-up of 50.7 ⫾ 22.9 months were entered into the study. Patients in group 1 (n ⫽ 57) received calcitriol therapy and patients in group 2 (n ⫽ 53) did not. The mean start of calcitriol therapy was 22.4 ⫾ 19.1 months posttransplantation. We restrospectively collected pretransplantation and posttransplantation laboratory and clinical data as well as creatinine levels before and after the initiation of calcitriol therapy at 6-month intervals for 2 successive years. There were no significant differences in terms of age, gender, immunosuppression, bone mineral densitometry, and follow-up. Our results showed that patients in group 1 had lower pretransplantation and postransplantation body mass index (P ⬍ .03; P ⬍ .03, respectively), lower posttransplantation third year parathyroid hormone levels (P ⬍ .02), and lower requirements for pulse steroid doses (P ⬍ .04). Using Friedman repeated measures variance test to analyze the effect of calcitriol, the increase in creatinine levels was significantly lower in group 1 (P ⬍ .04). There was no significant difference between follow-up time and calcitriol dose (P ⬎ .05). In conclusion, calcitriol therapy may reduce the rate of loss of renal function among patients receiving renal transplants.

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STEOPOROSIS following renal transplantation is a major problem. Many conditions, including renal osteodystrophy, hyperparathyroidism, and immunosuppressive drugs, such as corticosteroids, affect renal transplant recipients, having a negative impact on bone metabolism.1 1,25-Dihydroxyvitamin D(3) (calcitriol) therapy has been used extensively for posttranslantation osteoporosis. Calcitriol increases calcium absorption, reduces osteoclastogenesis, and stimulates osteoblasts and bone formation.2 The discovery of vitamin-D receptor (VDR) in a wide variety of tissues previously regarded as unresponsive to vitamin D has yielded the realization that vitamin D functions beyond calcium-phosphorus homeostasis.3 The presence of VDR in most cell types of the immune system, in particular, in antigen-presenting cells such as macrophages and dendritic cells and in both CD4⫹ and CD8⫹ T cells, has led to the investigation of the immunomodulatory effects of calcitriol and its analogues.4,5 Calcitriol has been shown to inhibit cell proliferation, cytotoxic T-cell function, and MHC class II

expression on macrophages, and to decrease proliferation, immunoglobulin synthesis, and accumulation of cytokine transcripts, including interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor (TNF)-␣, TNF-␤, and interferon-␥.6 Several in vitro and experimental animal studies have investigated the immunomodulatory effects of calcitriol in different organ transplant settings.7,8 Numerous authors have analyzed vitamin D in human transplantation. However, most studies have focused on transplant-related bone disease. In the current study, we sought to determine whether vitamin D therapy had an additional protective effect against loss of allograft function among renal transplant recipients.

From the Departments of Nephrology and General Surgery, Bas¸kent University Faculty of Medicine, Ankara, Turkey. Address reprint requests to Murathan Uyar, MD, Fevzi Cakmak Cad. 10. sok. No: 45 Bahcelievler Ankara 06490, Turkey. E-mail: [email protected]

© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.07.026

Transplantation Proceedings, 37, 3109 –3111 (2005)

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MATERIALS AND METHODS This study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the University Research Ethics Commitee. We included 78 men and 32 women (mean age of 35.2 ⫾ 11.4 years) who had undergone deceased donor and living-related renal transplantation between 1995 and 2001 at our institution with a mean posttransplantation follow-up time of 50.7 ⫾ 18.9 months and duration of graft functioning longer than 12 months. All recipients had been followed for a minimum of 18 months posttransplantation. The exclusion criteria were recurrence of original disease, age younger than 18 years, and noncompliance with medical therapy. The renal transplant recipient population was administered calcitriol because of osteoporosis (group 1, n ⫽ 57) and was compared with other patients (group 2, n ⫽ 53) without osteoporosis who did not receive calcitriol. Patients were matched for age, gender, donor source, transplantation duration, acute rejection episodes, and immunosuppressives received at the first and second years of the posttransplantation period. Mean time to start calcitriol therapy was 22.4 ⫾ 6.8 months posttransplantation; the indication for calcitriol therapy was osteoporosis. Although clinical and biochemical parameters were similar in group 2, the patients did not receive calcitriol because they did not have osteoporosis according to bone mineral densitometry measurement at the beginning of the calcitriol therapy. The pretransplantation and posttransplantation dataset included age, gender, age at transplantation, pretransplantation hemodialysis duration, follow-up time, body mass index (BMI), and annually recorded serum albumin, calcium, phosphorus, intact parathyroid hormone (iPTH), and C-reactive protein (CRP) levels, as well as number of acute rejection episodes, immunosuppression, presence of chronic rejection, and graft survival. Additionally, creatinine, Ca, P, PTH, and CRP levels before and after the initiation of calcitriol therapy were recorded at 6-month intervals for 2 successive years in both groups. BMI was calculated at 6-month intervals during the first year posttransplantation and yearly thereafter. Clinical and laboratory parameters were recorded at the initiation of calcitriol therapy in group 1, at the mean of 24 months (range, 18 –26 months) in group 2, and thereafter for a period of 2 years. All patients received prednisone, azathioprine (AZA), and cyclosporine (CsA) for maintenance immunosuppression. Treatment was started at 48 hours before transplantation. The initial immunosuppressive therapy consisted of CsA, azathioprine, and prednisolone. Cyclosporine was initiated at 8 –10 mg/kg/d postoperative in 2 divided doses and then adjusted to maintain whole-blood trough levels between 100 and 200 ng/mL using a modular ISE 900 machine with a homogenous enzyme immunoassay system (CEDIA Cyclosporine Assay, Roche Diagnostic Corp, Indianapolis, Ind, United States). Prednisolone was initiated at 1–2 mg/kg/d postoperative and then tapered over 6 months to a maintenance dosage of 10 mg/d. Acute rejection (AR) episodes suspected on clinical grounds were always confirmed using kidney biopsy. These episodes were treated with methylprednisolone pulses (10 mg/kg/d for 3 days). Steroid-resistant cases were treated with OKT3 monoclonal antibody. Chronic rejection was diagnosed if the patient met at least 1 of the following criteria: progressive deterioration of renal allograft function, or histologically documented features of chronic rejection.9 Renal biopsy was not performed in the patients who had normal, stable renal function according to the laboratory results from the time of transplantation to the time of the study analysis.

SEZER, UYAR, ARAT ET AL These patients were considered practically free of chronic allograft nephropathy.

Statistical Analyses All calculations were performed with SPSS software (Statistical Package for the Social Sciences, version 10.0, SSPS Inc, Chicago, III, United States). Catetogorical variables were analyzed using chi-square or Fisher exact probability test, as appropriate. Differences between groups were tested with the Student t or MannWhitney U test. Friedman repeated measures variance test was performed to analyze the effect of calcitriol on creatinine levels. Data are expressed as mean values ⫾ SD, and P ⬍ .05 was considered statistically significant.

RESULTS

The patients in groups 1 and 2 had similar ages at transplantation, follow-up times, pretransplantation hemodialysis duration, and creatinine levels at the initiation of calcitriol therapy (P ⬎ .05). Patients in group 1 had lower pretransplantation and postransplantation BMIs (P ⬍ .03). They also had lower posttransplantation third year PTH levels (P ⬍ .02) (Table 1). There was a slight increase in calcium levels in group 1, but it had no clinical or statistical significance. Although there was no significant difference in the number of acute rejection episodes between the groups, patients who had been given calcitriol needed fewer pulse steroid doses (P ⬍ .04). When a Friedman repeated measures variance test was performed to analyze the effect of calcitriol on creatinine levels, group 1 showed a significantly reduced increase in creatinine levels (P ⬍ .04). There was no significant difference among other parameters tested.

Table 1. Comparison of Calcitriol-Treated and Control Patients Group 1 (n ⫽ 57)

Group 2 (n ⫽ 53)

19.9 ⫾ 2.6 21.0 ⫾ 2.5 Pretrans BMI (kg/m2) Calcium before calcitriol therapy (mg/dL) 9.4 ⫾ 0.6 9.4 ⫾ 0.7 Phosphorus before calcitriol therapy (mg/dL) 3.4 ⫾ 0.8 3.3 ⫾ 0.6 PTH before calcitriol therapy (pg/mL) 96.9 ⫾ 77.1 56.6 ⫾ 27.9 Creatinine level before calcitriol therapy (mg/dL) 1.6 ⫾ 0.7 1.3 ⫾ 0.3 Calcium* (mg/dL) 9.6 ⫾ 0.6 9.3 ⫾ 0.6 Phosphorus* (mg/dL) 3.3 ⫾ 0.5 3.5 ⫾ 0.8 PTH* (pg/mL) 112.7 ⫾ 67.0 173.4 ⫾ 267.2 Creatinine* (mg/dL) 1.6 ⫾ 0.6 2.5 ⫾ 2.2 Calcium† (mg/dL) 9.5 ⫾ 0.6 9.5 ⫾ 0.5 Phosphorus† (mg/dL) 3.4 ⫾ 0.9 3.4 ⫾ 1.0 PTH† (pg/mL) 166.4 ⫾ 218.4 517.5 ⫾ 793.3 Creatinine† (mg/dL) 1.7 ⫾ 1.4 2.7 ⫾ 2.5 BMI† (kg/m2) 22.0 ⫾ 3.1 23.2 ⫾ 2.4 Pulse steroid dose† (mg) 3507.3 ⫾ 1997.4 4553 ⫾ 2323.6 Abbreviation: NS, not significant. *After the first year of calcitriol administration. † After the second year of calcitriol administration.

P

.03 NS NS NS NS .03 NS NS .01 NS NS .04 .02 .02 .04

1,25-DIHYDROXYVITAMIN D(3)

DISCUSSION

Calcitriol and its analogues have been used extensively in transplant recipients who develop osteoporosis. As has been shown in various experimental and clinical studies, calcitriol and vitamin D analogues have remarkable effects on the immune system.10 We, therefore, hypothesized that they might serve as a useful immunosuppressive agent in a transplant setting. In clinical renal transplantation, various limited studies have shown a deceleration in the loss of renal allograft function, and even a slight improvement in function with the administration of calcitriol.11 Our study retrospectively evaluated the effects of calcitriol on graft function among renal transplant recipients. Subjects selected among renal transplant recipients based on calcitriol treatment because of osteoporosis were compared with a group matched by laboratory and clinical parameters who did not receive calcitriol therapy. The clinical and laboratory data of the groups were collected retrospectively for 2 years posttransplantation. In this study, we showed significantly less increase in creatinine levels among patients who were administered calcitriol, suggesting a deceleration in the loss rate of allograft function during follow-up. The effect of calcitriol on creatinine levels was prominent even after the first year of calcitriol adminitration (1.6 ⫾ 0.6 vs 2.5 ⫾ 2.2 mg/dL, group 1 and group 2, respectively). This benefit of calcitriol suggests that it might have a role in the prevention of chronic allograft nephropathy. The positive effect of calcitriol on graft function may occur because of a series of interactions between calcitriol and the immune system. One of the important issues is the interplay between calcitriol and transforming growth factor-␤ (TGF-␤) pathways. Calcitriol has been found to modify TGF-␤ expression and related pathways; consequently it may limit scarring in allografts. In addition, calcitriol altered peripheral blood mononuclear cell proliferation, differentiation, and activity using in vitro and in vivo studies.6 It also modified T-cell, B-cell, monocyte, and macrophage responsiveness through VDR down-regulating cytokine production.5,6 All of these immunomodulatory properties are beneficial in the transplant setting. Although no significant difference was found regarding the number of acute rejection episodes, patients in group 1 needed lower pulse steroid doses during acute rejection episodes. The immunomodulatory properties of calcitriol may act complementary to steroids, ultimately lowering the dose to suppress an acute rejection attack. Moreover, some of the calcitriol effect may have occurred as a result of partially normalizing a state of hyperparathyroidism. However, there is no strong evidence to suggest that calcitriol administration significantly limits progressive kidney disease through PTH suppression. Therefore, this is

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not likely to be the primary benefit, but it could be a contributing factor to the salutary effects of calcitriol on posttransplantation renal allograft function. Lower PTH level can also be related to relatively normalized Ca-P metabolism, because of better allograft function in the calcitriol group. Further controlled prospective studies are needed to identify whether the PTH level is a cause or a result of better allograft function. These data reinforce in vitro and experimental data suggesting that calcitriol is effective in renal transplantation. It is a natural substance with a lower adverse effect profile. Absence of significant hypercalcemia and the additive potential of calcitriol and other vitamin D analogues with classical immunosuppressive drugs may produce a dose reduction in nephrotoxic immunosuppressants without a loss of efficacy. In conclusion, calcitriol therapy, in addition to its therapeutic and protective effects on posttransplantation osteoporosis, may be used safely, leading to a deceleration in the rate of loss of renal function among renal transplant recipients.

REFERENCES 1. Wolpaw T, Deal CL, Fleming-Brooks S, et al: Factors influencing vertebral bone density after renal transplantation. Transplantation 58:1186, 1994 2. Nielsen HK, Brixen K, Kassem M, et al: Acute effect of 1,25-dihydroxyvitamin D3, prednisone, and 1,25-dihydroxyvitamin D3 plus prednisone on serum osteocalcin in normal individuals. J Bone Miner Res 6:435, 1991 3. Veldman CM, Cantorna MT, DeLuca HF: Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 374:334, 2000 4. Boonstra A, Barrat FJ, Crain C, et al: 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(⫹) T cells to enhance the development of Th2 cells. J Immunol 167:4974, 2001 5. Tokuda N, Kano M, Meiri H, et al: Calcitriol therapy modulates the cellular immune responses in hemodialysis patients. Am J Nephrol 20:129, 2000 6. Mathieu C, Adorini L: The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med 8:174, 2002 7. Hullett DA, Cantorna MT, Redaelli C, et al: Prolongation of allograft survival by 1,25-dihydroxyvitamin D3. Transplantation 66:824, 1998 8. Bertolini DL, Araujo PR, Silva RN, et al: Immunomodulatory effects of vitamin D analog KH1060 on an experimental skin transplantation model. Transplant Proc 31: 2998, 1999 9. Kreis HA, Ponticelli C: Causes of late renal allograft loss: chronic allograft dysfunction, death, and other factors. Transplantation 71:SS5, 2001 10. Johnsson C, Tufveson G: MC 1288-a vitamin D analogue with immunosuppressive effects on heart and small bowel grafts. Transpl Int 7:392, 1994 11. O’Herrin JK, Hullett DA, Heisey DM, et al: A retrospective evaluation of 1,25-dihydroxyvitamin D(3) and its potential effects on renal allograft function. Am J Nephrol 22:515, 2002