Crimson Publishers Publish With Us Reprints e-Books Video articles

Full Text

Experimental Techniques in Urology & Nephrology

Vitamin D Pleiotropy after Renal Transplantation

Jean J Filipov*

Department of Nephrology and Transplantation, University Hospital “Alexandrovska", Bulgaria

*Corresponding author: Jean J Filipov, Department of Nephrology and Transplantation, University Hospital 'Alexandrovska”, Sofia, Bulgaria Clinical Center of Nephrology, Medical University-Sofia, Bulgaria

Submission: January 22, 2018;Published: January 31, 2018

DOI: 10.31031/ETUN.2018.01.000516

ISSN: 2578-0395
Volume1 Issue4

Abbreviations

Abbreviations: KT: Kidney Transplantation; KTRs: Kidney Transplant Recipients; CKD: Chronic Kidney Disease; UTI: Urinary Tract Infections; DM: Diabetes Mellitus; NODAT: New Onset DM After Transplantation; RCTs: Randomized Controlled Trials; CVD: Cardio Vascular Disease

Introduction

Vitamin D (VD) insufficiency is widely spread worldwide. It is even more often detected after kidney transplantation (KT). Graft and patient survival are limited after KT due to neoplasia, cardiovascular mortality and infection. In addition, VD has increasing importance, spanning beyond calcium-phosphorus metabolism. It is associated with renal protection, anti-neoplastic properties, diabetes control, and immune modulation. Therefore, vitamin D is being evaluated as a treatment option for improvement patients' outcomes after KT.

Prevalence and Causes for Vitamin D Insufficiency after Kidney Transplantation

It could be expected, that after successful KT a rapid improvement in VD status occurs. However, the suboptimal VD levels are highly prevalent in kidney transplant recipients (KTRs). Our studies demonstrate VD sufficiency rate below 20% in the summer-autumn period, dropping further to 2.59% in the winter fall [1,2]. Similar findings were detected in other centers [3]. Several factors explain these results. Firstly, there is a high prevalence of chronic kidney disease (CKD) stage 3 and over after KT-up to 70%. Secondly, transplant-specific factors play an important role: reduced sun exposure and use of sun-protecting cosmetics in order to reduce the risk for skin carcinomas; posttransplant proteinuria, diabetes and obesity (due to increased urine loss, reduced intestinal reabsorption and lower bioavailability). Immunosuppressive agents also have detrimental effect on VD status-e.g. steroids (increased VD catabolism) and calcineurin inhibitors (suppressed hepatic synthesis). Similar to the general population, 25-hydroxyvitamin D (25VD) is used to evaluate the vitamin D status after renal transplantation.

Vitamin D, Proteinuria and Renal Function after Kidney Transplantation

Several post-transplant studies indicated, that lower 25VD levels are associated with poorer graft function, faster decline of graft GFR, and worse kidney function in the long run [4,5]. Our findings also demonstrate that poorer VD status in KTRs is associated with higher proteinuria [6]. Possible explanations for the findings are RAAS suppression, nuclear factor kB inactivation, Wnt/β- catenin pathway suppression, and up regulation of slit- diaphragm proteins. In addition, paricalcitol treatment ameliorated proteinuria after KT [7]. Contrary to these findings, cholecalciferol supplementation did not significantly affect proteinuria and tubular atrophy/interstitial fibrosis after KT. The single-center study VITA-D also failed to demonstrate significant renoprotection from cholecalciferol treatment [8,9].

Vitamin D and Infection after Kidney Transplantation

KTRs are at increased risk for infection, especially during the early post-transplant period. However, infection is a leading cause for patient and graft loss after KT. Several studies showed lower infection risk in patients with higher VD levels in the general population [10]. There are conflicting reports considering the association between infection risk and post-transplant VD status. Lower VD was associated with higher incidence of opportunistic pulmonary infections in KTRs [11,12]. However, VD supplementation did not reduce infection rate after KT, according to the VITA-D study [9]. VD status had no influence on the prevalence of urinary tract infections (UTI) in our transplant center; However, Kwon et al. [13] demonstrated that VD is an independent risk factor for post-transplant UTI [12,13].

Vitamin D and Diabetes Mellitus

Despite the studies in the general population, indicating inverse correlation between 25VD and diabetes mellitus (DM) incidence, the data in KTRs are scarce. After KT, the development of post-transplant diabetes mellitus is usually linked to steroid and calcineurin inhibitors use. Our experience did not demonstrate better VD status in KTRs with better-controlled DM [14]. In addition, currently there are no results from interventional studies in this cohort of patients. However, an interventional trial is currently underway, evaluating the effect of cholecalciferol supplementation on the incidence of new onset DM after transplantation (NODAT)[15] .

Vitamin D and Rejection

The vitamin D receptor is detected in all immune cells. In vitro studies demonstrated that calcitriol suppressed T and B-lymphocyte proliferation, inhibited dendritic cells and macrophages, suppressed interleukin and immunoglobulin G production, and down regulated major histo compatibility complex class II expression. Unfortunately, the trials in KTRs have controversial findings. Bienaime et al. [16] demonstrated lower acute rejection incidence in better VD status [16] . Yet, the initial results from the VITA-D study do not reveal any positive effects from cholecalciferol supplementation on rejection prevalence [9]. The present controversy indicates the need for more multicenter randomized controlled trials (RCTs), evaluating the association between rejection and VD status after KT.

Vitamin D and Neoplasia after Renal Transplantation

Neoplasia is a major cause for patient and graft loss after KT. VD suppresses cellular proliferation and angiogenesis, stimulates cell differentiation and reduces the metastatic potential. Several human studies in the general population indicate lower cancer incidence (colorectal, breast and pancreatic cancer) in VD sufficient subjects [17] . The studies in KTRs are controversial. Poorer pre-transplant VD status was related to higher post-transplant cancer incidence [18] . In addition, supplementation with active VD also reduced the malignancy risk in KTRs for certain types of neoplasia-breast, colon and ovary [19]. Other studies do not demonstrate positive effect from calcitriol prevention in KTRs [20]. Therefore, the antineoplastic properties of VD after renal transplantation need further assessment.

Vitamin D and Cardiovascular Disease (CVD) after Renal Transplantation

CVD is a major contributor to mortality after successful KT, due to the persistent CKD-associated vascular and cardiac abnormalities. Several reports associated low VD with increased vascular calcifications after KT, probably by influencing endothelial dysfunction or suppressing cardiomyocyte proliferation via the VD receptor [21,22]. However, Zitterman et al. [22] demonstrated that high post-transplant 25VD levels were also linked to increased calcification risk [22]. A more recent study also did not establish significant protective role of 25VD levels in CVD incidence in KTRs [19] .

Vitamin D and Mortality after Kidney Transplantation

Higher overall mortality in KTRs is observed, compared to the general population, due to CKD-related mineral bone disease, infection, CVD, and neoplasia. Several reports indicate better survival in subjects with higher 25VD, both in the general population and CKD cohorts. Similar findings were established after renal transplantation-poorer VD status was associated with poorer post-transplant patient survival [4]. Unfortunately, prospective interventional RCTs are still lacking.

Conclusion

Despite the numerous results from in vivo and animal studies, or in the general population, the results for VD pleiotropy in KTRs are still controversial. This is due to the small, single center, usually observational trials. Currently, two large prospective, interventional RCTs (VITALE, CANDLE-KIT) are being performed, evaluating the effect of cholecalciferol supplementation on different end-points: post-transplant mineral bone disease, graft function, proteinuria, blood pressure, incidence of rejection, NODAT, cancer, CVD, and allcause mortality. In addition, we can speculate, that a target 25VD level is needed for VD pleiotropy to occur, similarly to the effect of 25VD on calcium-phosphorus metabolism. Another issue to consider in the future is the type of supplementation to achieve the needed pleiotropic effect-native VD or calcitriol/VD-analogue.

References

  1. Filipov JJ, Zlatkov B, Dimitrov E, Svinarov D (2015) Relationship between vitamin D status and immunosuppressive therapy in kidney transplant recipients. Biotechnol Biotechnol Equip 29(2): 331-335.
  2. Filipov JJ, Zlatkov B, Dimitrov E, Svinarov D (2014) Seasonal variations of 25-hydroxyvitamin D in Bulgarian kidney transplant recipients. Medical Review 50(3): 37-41.
  3. Marcen R, Ponte B, Rodri'guez-MN, Fernandez-RA, Galeano C, et al. (2009) Vitamin D deficiency in kidney transplant recipients: risk factors and effects of vitamin D3 supplements. Transplant Proc 41(6): 23882390.
  4. Keyzer CA, Riphagen IJ, Joosten MM, Navis G, Muller KAC, et al. (2015) NIGRAM consortium. Associations of 25(OH) and 1, 25(OH)2 vitamin D with long-term outcomes in stable renal transplant recipients. J Clin Endocrinol Metab 100(1): 81-89.
  5. Bienaime F, Girard D, Anglicheau D, Canaud G, Souberbielle JC, et al. (2013) Vitamin D status and outcomes after renal transplantation. J Am Soc Nephrol 24(5): 831-841.
  6. Filipov JJ, Zlatkov B, Dimitrov E, Svinarov D (2016) Higher 25-Hydroxyvitamin D Levels Are Associated With Lower Proteinuria in Kidney Transplant Recipients. Exp Clin Transplant 14(6): 629-633.
  7. Trillini M, Cortinovis M, Ruggenenti P, Reyes LJ, Courville K, et al. (2015) Paricalcitol for secondary hyperparathyroidism in renal transplantation. J Am Soc Nephrol 26(5): 1205-1214.
  8. Courbebaisse M, Xu-Dubois YC, Thervet E, Prie D, Zuber J, et al. (2011) Cholecalciferol supplementation does not protect against renal allograft structural and functional deterioration: a retrospective study Transplantation 91(2): 207-212.
  9. Thiem U, Heinze G, Segel R, Perkmann T, Kainberger F, et al. (2015) VITA-D study: outcome of a 1-year randomized controlled trial to evaluate vitamin D3 supplementation in vitamin D deficient renal transplant patients. European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 52nd Congress: Abstract LBA-3564, London, UK, p. 28-31.
  10. Khoo AL, Chai L, Koenen H, Joosten I, Netea M, et al. (2012) Translating the role of Vitamin D3 in infectious diseases. Crit Rev Microbiol 38(2): 122-135.
  11. Rech MA, Fleming JN, Moore CL (2014) 25-hydroxyvitamin D deficiency and opportunistic viral infections after kidney transplant. Exp Clin Transplant 12(2): 95-100.
  12. Filipov JJ, Zlatkov B, Dimitrov E, Svinarov D (2014) Vitamin D status has no influence on the incidence of recurrent urinary tract infections after kidney transplantation. BANTAO Journal 12(2): 114-118.
  13. Kwon YE, Kim H, Oh HJ, Park JT, Han SH, et al. (2015) Vitamin D Deficiency >Is an Independent Risk Factor for Urinary Tract Infections after Renal Transplants. Medicine (Baltimore) 94(9): e594.
  14. Filipov J, Zlatkov B, Dimitrov EP, Houbanov N, Svinarov D (2013) Association of 25-hydroxyvitamin D with diabetes and glycemic control after kidney transplantation. Nefrologia, Dializa, Transplantacia 19(4): 41-46.
  15. Courbebaisse M, Alberti C, Colas S, Prie D, Souberbielle JC, et al. (2014) VITamin D supplementation in renal transplant recipients (VITALE): a prospective, multicentre, double-blind, randomized trial of vitamin D estimating the benefit and safety of vitamin D3 treatment at a dose of 100,000 UI compared with a dose of 12,000 UI in renal transplant recipients: study protocol for a doubleblind, randomized, controlled trial. Trials 15: 430.
  16. Bienaime F, Girard D, Anglicheau D, Canaud G, Souberbielle JC, et al. (2013) Vitamin D status and outcomes after renal transplantation. J Am Soc Nephrol 24(5): 831-841.
  17. Stolzenberg-SRZ, Jacobs EJ, Arslan AA, Qi D, Patel AV, et al. (2010) Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol 172(1): 81-93.
  18. Ducloux D, Courivaud C, Bamoulid J, Kazory A, Dumoulin G, et al. (2008) Pretransplant serum vitamin D levels and risk of cancer after renal transplantation. Transplantation 85(12): 1755-1759.
  19. Marcen R, Jimenez S, Fernandez-RA, Galeano C, Villafruela JJ, et al. (2012) Are low levels of 25-hydroxyvitamin D a risk factor for cardiovascular diseases or malignancies in renal transplantation? Nephrol Dial Transplant 27(Suppl 4): iv47-52.
  20. Obi Y, Ichimaru N, Hamano T, Tomida K, Matsui I, et al. (2012) Orally active vitamin D for potential chemoprevention of posttransplant malignancy. Cancer Prev Res (Phila) 5(10): 1229-1235.
  21. Moe SM, O'Neill KD, Reslerova M, Fineberg N, Persohn S, et al. (2004) Natural history of vascular calcification in dialysis and transplant patients. Nephrol Dial Transplant 19(9): 2387-2393.
  22. Zittermann A, Schleithoff SS, Koerfer R (2007) Vitamin D and vascular calcification. Curr Opin Lipidol 18(1): 41-46.

© 2018 Jean J Filipov. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and build upon your work non-commercially.



About Crimson

We at Crimson Publishing are a group of people with a combined passion for science and research, who wants to bring to the world a unified platform where all scientific know-how is available read more...

Leave a comment

Contact Info

  • Crimson Publishers, LLC
  • 555 Madison Avenue, 5th floor
  •     New York, NY 10022, USA
  • +1 (929) 600-8049
  • +1 (929) 447-1137
  • info@crimsonpublishers.com
  • www.crimsonpublishers.com