Secondary Logo

Share this article on:

Improved Glucose Tolerance in a Kidney Transplant Recipient With Type 2 Diabetes Mellitus After Switching From Tacrolimus To Belatacept: A Case Report and Review of Potential Mechanisms

de Graav, Gretchen, N., MD, PhD1; van der Zwan, Marieke, MD1; Baan, Carla, C., MD, PhD1; Janssen, Joop, A.M.J.L., MD, PhD2; Hesselink, Dennis, A., MD, PhD1

doi: 10.1097/TXD.0000000000000767
Kidney Transplantation

The introduction of immunosuppressant belatacept, an inhibitor of the CD28-80/86 pathway, has improved 1-year outcomes in kidney transplant recipients with preexistent diabetes mellitus and has also reduced the risk of posttransplant diabetes mellitus. So far, no studies have compared a tacrolimus-based with a belatacept-based immunosuppressive regimen with regard to improving glucose tolerance after kidney transplantation. Here, we present the case of a 54-year-old man with type 2 diabetes mellitus who was converted from belatacept to tacrolimus 1 year after a successful kidney transplantation. Thereafter, he quickly developed severe hyperglycemia, and administration of insulin was needed to improve metabolic control. Six months after this episode, he was converted back to belatacept because of nausea, diarrhea, and hyperglycemia. After switching back to belatacept and within 4 days after stopping tacrolimus glucose tolerance improved and insulin therapy could be discontinued. Although belatacept is considered less diabetogenic than tacrolimus, the rapid improvement of glucose tolerance after switching to belatacept is remarkable. In this article, the potential mechanisms of this observation are discussed.

1 Division of Nephrology and Kidney Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

2 Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Published online 20 February, 2018.

Received 28 November 2017. Revision requested 29 December 2017.

Accepted 31 December 2017.

D.A.H. has received grant support from Bristol-Myers Squibb and Astellas Pharma and has received lecture and consulting fees from Astellas Pharma and Chiesi Pharmaceuticals. C.C.B. received a research grant from Bristol-Myers Squibb. G.N.d.G., M.v.d.Z., and J.A.M.J.L.J. declare no conflicts of interest.

No sources of funding were used in the preparation of this article.

G.N.d.G., M.v.d.Z., C.C.B., D.A.H. are part of the Rotterdam Transplant Group.

G.N.d.G., M.v.d.Z. contributed equally to the writing of this article.

Correspondence: Marieke van der Zwan, MD, Division of Nephrology and Kidney Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rm Na-523, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. (m.vanderzwan@erasmusmc.nl).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantationdirect.com).

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Kidney transplant recipients who have preexistent diabetes mellitus (DM) or who develop DM after transplantation (posttransplant DM [PTDM]) have a worse survival and suffer from more cardiovascular morbidity than those without.1-3 The calcineurin inhibitors (CNI), cyclosporine A (CsA) and tacrolimus, may decrease insulin secretion and increase insulin resistance.4 The latter is characterized by a decreased insulin sensitivity, that is, more insulin is needed to maintain serum glucose within the reference range.5

Belatacept, an inhibitor of the CD28-CD80/86 pathway,6 does not induce hyperglycemia nor PTDM. Despite the higher acute rejection risk observed in belatacept-treated patients,7-9 it improves 1-year allograft survival and renal function in kidney transplant recipients with preexistent DM compared with CsA-treated patients.3

In addition, belatacept-based therapy decreases the risk of developing PTDM. A meta-analysis which included 729 belatacept-treated and 320 CsA-treated patients showed a relative risk of 0.61 (95%-confidence interval, 0.40-0.93) to develop PTDM with belatacept compared to CsA.10 Tacrolimus is, nowadays, the most widely used CNI, and treatment with tacrolimus carries a higher risk of developing PTDM than CsA.11,12

Belatacept may be a therapeutic option for kidney transplant recipients that develop PTDM or for those with preexistent DM who develop worsening of metabolic control after starting a CNI-based regimen. Glucose metabolism has not been compared between belatacept- and tacrolimus-treated patients. In addition, no data on the safety and efficacy regarding insulin sensitivity of conversion from CNIs to belatacept after kidney transplantation have been reported.

Here, a kidney transplant recipient with DM is described, who after conversion from belatacept to tacrolimus developed severe hyperglycemia. Glucose control was difficult and did not improve despite high doses of insulin. Within 4 days after stopping tacrolimus and reintroducing belatacept, a marked improvement of glucose tolerance was observed. The purpose of this case report is to discuss the possible pathophysiologic mechanisms explaining this observation and the role of immunosuppressive therapy therein.

Back to Top | Article Outline

CASE DESCRIPTION

A 54-year-old white man received a preemptive, living-unrelated donor kidney transplant in October 2013 because of hypertensive and diabetic nephropathy. His medical history included hypertension since 1992; type 2 DM since 2002; and since 2008, histologically confirmed diabetic and hypertensive nephropathies. The transplant was 2-2-1 mismatched (for HLA-A, HLA-B, and HLA-DR, respectively). Peak and actual panel reactive antibodies were 0%.

The patient was treated with belatacept according to the less-intensive regimen of the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression trials during the first posttransplantation year as part of a randomized-controlled trial.13,14 This trial compared belatacept with tacrolimus, and its main findings were described previously.14,15 In addition to belatacept, he also received induction therapy with 20 mg/kg basiliximab (days 0 and 4) and maintenance therapy with mycophenolate mofetil (targeted to predose concentrations of 1.5-3.0 mg/mL), and prednisolone, tapered to 5 mg/d by month 3 and maintained at 5 mg/d thereafter (Figure 1). The clinical course of the first posttransplant year was uneventful. Belatacept was not reimbursed by the health insurance companies in the Netherlands at the time the patient was 1 year after transplantation (October 2014). Belatacept was discontinued, and he was switched to tacrolimus (Advagraf; Astellas Pharma, Tokyo, Japan) targeted to predose concentrations of 5 to 7 ng/mL (Figure 1).

FIGURE 1

FIGURE 1

At the time of transplantation, his DM was well controlled: glycated hemoglobin (HbA1c) was 44 mmol/mol with 24 International Units (IU) of long-acting insulin-glargine (Lantus; Sanofi, Paris, France) daily. Before transplantation, he was taken care of by a nephrologist in a local hospital. Initially, his diabetes was managed with metformin only. When his renal function deteriorated, metformin was stopped, and he was started on long-acting insulin. After transplantation and in an attempt to take patient off insulin, he was started on metformin and glimepiride. Insulin-glargine was initially continued (mean dose, 28 IU/d). In addition, during the first month after transplantation, he received short-acting insulin-aspart (NovoRapid; Novo Nordisk, Bagsværd, Denmark, mean dose 18 IU/d). Four months after his transplantation and when prednisolone had been tapered to 5 mg daily, insulin could be discontinued completely. Figure 2 gives an overview of diabetes-related events, glucose and HbA1c concentrations, and glucose lowering medication. We believe that the combination of improved kidney function, possibly increased physical activity, the introduction of metformin and glimepiride and the tapering of prednisolone to 5 mg daily (Figure 2) allowed for the complete withdrawal of insulin therapy.

FIGURE 2

FIGURE 2

Within 14 days after conversion to tacrolimus, the patient developed severe hyperglycemic episodes (Figure 2). Glimepiride and metformin were increased to 6 mg and 3000 mg daily, respectively, without improvement of glucose control (Figure 2). Insulin therapy was restarted (Figure 2). The patient needed up to 50 IU of short- and long-acting insulin on a daily basis to improve metabolic control. Despite the high insulin dose, hyperglycemia persisted. During these hyperglycemic episodes, no infections or changes in bodyweight were observed.

In addition, the patient developed tremors of the hands, nausea, and diarrhea that were all considered as side effects of tacrolimus. Clinically, no signs of tacrolimus-associated nephrotoxicity were observed. No (protocol) kidney biopsy was performed after conversion to tacrolimus. Because of these side effects, 6 months after conversion, belatacept (5 mg/kg bodyweight monthly) was restarted. Tacrolimus was discontinued overnight. Four days after discontinuing tacrolimus, the patient’s blood glucose concentrations improved tremendously, and insulin therapy could be stopped. During the 2-year follow-up period, the patient has remained in good clinical condition. No acute rejection occurred, and his eGFR has remained stable (55 mL/min per 1.73 m2; Figure S1, http://links.lww.com/TXD/A63). His current glucose-lowering treatment consists of metformin and glimepiride.

Back to Top | Article Outline

DISCUSSION

In this patient, a marked improvement in glucose tolerance was observed after switching from belatacept to tacrolimus. Improvement of glucose control occurred immediately after withdrawal of tacrolimus and exogenous insulin could be stopped within 4 days. The improvement in glucose was not related to changes in BMI (Figure S1, http://links.lww.com/TXD/A63). Although it is well known that belatacept is less diabetogenic than CNIs,10 the rapid improvement of glucose tolerance was remarkable and unexpected.

Tacrolimus may induce DM by several mechanisms. First, tacrolimus reduces insulin secretion by the pancreatic β cells via decreasing insulin mRNA expression through inhibition of 2 pathways (nuclear factor of activated T cells and cAMP response element-binding protein).16-19 Second, the insulin content of the β cell is diminished by tacrolimus.17 Third, the glucose-induced insulin release is inhibited by tacrolimus through reduced glucokinase activity.17,20 Fourth, tacrolimus directly induces β cell apoptosis and reduces islet cell proliferation.19,21 Altogether, these effects lead to a reduction of insulin secretion. Furthermore, CNIs may induce insulin resistance by stimulating endocytic removal of glucose transporter type 4 (Glut-4) from the cell membrane of adipocytes and muscle cells.22

The induction of hypomagnesemia is another mechanism by which tacrolimus may directly influence glucose tolerance.23 Tacrolimus can downregulate the magnesium absorbing channel transient receptor of potential melastatin (TRPM6) in the distal collecting tubule and thereby induce hypomagnesemia via renal magnesium wasting.24 Hypomagnesemia may contribute to insulin resistance by decreasing autophosphorylation of the β subunits of the insulin receptor.25 Besides, hypomagnesemia may reduce insulin secretion.25 Unfortunately, it is unknown if hypomagnesemia played a role in our case, because magnesium concentrations were not measured.

We think that the fast improvement of glucose control after switching to belatacept in our patient was mainly related to (1) the discontinuation of tacrolimus and/or (2) a direct effect on insulin resistance by CD80-86 blockade by belatacept. Several animal studies have described the effects of discontinuation of tacrolimus on glucose metabolism. Redmon et al17 observed reversibility of insulin secretion 72 hours after discontinuation of tacrolimus in hamster β-cells (HIT-T15). Another in vitro study using rat β cells found similar results.26 In an in vivo study, reversibility of rat β cells insulin gene expression, insulin content, and insulin secretion was observed 7 days after discontinuing tacrolimus.27 Another study in rats showed that the insulin resistance improved 5 days after the last dose of tacrolimus.28

All these studies show reversibility of impaired glucose tolerance after discontinuation of tacrolimus. However, these studies are limited by the short duration of tacrolimus treatment. Prolonged administration could possibly lead to a more severe reduction of functional β-cell mass and irreversibility of impaired glucose control. Furthermore, to the best of our knowledge, no studies in humans have analyzed directly the effects of insulin secretion and resistance after discontinuation of tacrolimus. Boots et al29 described the effect of tacrolimus dose reduction on insulin secretion. In 15 kidney transplant recipients without DM, a 33% reduction in the tacrolimus predose concentrations resulted in a 36% increase in β cell secretion capacity.29

The fast improvement of glucose tolerance in this case may also have been caused by the introduction of belatacept (rather than the withdrawal of tacrolimus). One study has suggested that CD86 may play a role in insulin resistance via interaction with the adiponectin axis.30

Interestingly, a case report of a patient with rheumatoid arthritis reported an improvement of insulin resistance 4 weeks after treatment with abatacept, which is considered a lower-affinity version of belatacept.31 In another study, improved insulin sensitivity was observed in 15 patients 6 months after the start of abatacept treatment.32

In contrast to the findings of the studies described above, Zhong et al33 found in mice and humans that a higher CD80/86 expression was negatively correlated with insulin resistance. No effect of adiponectin on CD80/86 expression was noted on human macrophages in another study.34

The main limitation of this case report is that the mechanistic evidence of the effect of belatacept and tacrolimus on glucose tolerance is lacking. We did not examine endogenous insulin secretion and insulin resistance.

In conclusion, a kidney transplant recipient with preexisting type 2 DM is described who showed a rapid improvement of glucose tolerance after switching from tacrolimus to belatacept. Such a strategy may be beneficial in comparable cases although high-quality evidence of the safety of this intervention in terms of rejection is currently lacking.

Back to Top | Article Outline

REFERENCES

1. Cosio FG, Hickson LJ, Griffin MD, et al. Patient survival and cardiovascular risk after kidney transplantation: the challenge of diabetes. Am J Transplant. 2008;8:593–599.
2. Revanur VK, Jardine AG, Kingsmore DB, et al. Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation. Clin Transplant. 2001;15:89–94.
3. Rostaing L, Neumayer HH, Reyes-Acevedo R, et al. Belatacept-versus cyclosporine-based immunosuppression in renal transplant recipients with pre-existing diabetes. Clin J Am Soc Nephrol. 2011;6:2696–2704.
4. Bamgbola O. Metabolic consequences of modern immunosuppressive agents in solid organ transplantation. Ther Adv Endocrinol Metab. 2016;7:110–127.
5. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2017;40(Suppl 1):S1–S135.
6. de Graav GN, Bergan S, Baan CC, et al. Therapeutic drug monitoring of belatacept in kidney transplantation. Ther Drug Monit. 2015;37:560–567.
7. Grinyo JM, Del Carmen Rial M, Alberu J, et al. Safety and efficacy outcomes 3 years after switching to belatacept from a calcineurin inhibitor in kidney transplant recipients: results from a phase 2 randomized trial. Am J Kidney Dis. 2017;69:587–594.
8. Cohen JB, Eddinger KC, Forde KA, et al. Belatacept compared with tacrolimus for kidney transplantation: a propensity score matched cohort study. Transplantation. 2017;101:2582–2589.
9. Keith DS, Vranic G, Nishio-Lucar A. Graft function and intermediate-term outcomes of kidney transplants improved in the last decade: analysis of the United States Kidney Transplant Database. Transplant Direct. 2017;3:e166.
10. Masson P, Henderson L, Chapman JR, et al. Belatacept for kidney transplant recipients. Cochrane Database Syst Rev. 201411:CD010699.
11. Luan FL, Steffick DE, Ojo AO. New-onset diabetes mellitus in kidney transplant recipients discharged on steroid-free immunosuppression. Transplantation. 2011;91:334–341.
12. Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant. 2007;7:1506–1514.
13. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010;10:535–546.
14. de Graav GN, Baan CC, Clahsen-van Groningen MC, et al. A randomized controlled clinical trial comparing belatacept with tacrolimus after de novo kidney transplantation. Transplantation. 2017;101:2571–2581.
15. de Graav GN, Hesselink DA, Dieterich M, et al. An acute cellular rejection with detrimental outcome occurring under belatacept-based immunosuppressive therapy: an immunological analysis. Transplantation. 2016;100:1111–1119.
16. Ozbay LA, Smidt K, Mortensen DM, et al. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells. Br J Pharmacol. 2011;162:136–146.
17. Redmon JB, Olson LK, Armstrong MB, et al. Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells. J Clin Invest. 1996;98:2786–2793.
18. Kruger M, Schwaninger M, Blume R, et al. Inhibition of CREB- and cAMP response element-mediated gene transcription by the immunosuppressive drugs cyclosporin A and FK506 in T cells. Naunyn Schmiedebergs Arch Pharmacol. 1997;356:433–440.
19. Heit JJ, Apelqvist AA, Gu X, et al. Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. Nature. 2006;443:345–349.
20. Radu RG, Fujimoto S, Mukai E, et al. Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity. Am J Physiol Endocrinol Metab. 2005;288:E365–E371.
21. Drachenberg CB, Klassen DK, Weir MR, et al. Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation. 1999;68:396–402.
22. Pereira MJ, Palming J, Rizell M, et al. Cyclosporine A and tacrolimus reduce the amount of GLUT4 at the cell surface in human adipocytes: increased endocytosis as a potential mechanism for the diabetogenic effects of immunosuppressive agents. J Clin Endocrinol Metab. 2014;99:E1885–E1894.
23. Augusto JF, Subra JF, Duveau A, et al. Relation between pretransplant magnesemia and the risk of new onset diabetes after transplantation within the first year of kidney transplantation. Transplantation. 2014;97:1155–1160.
24. Nijenhuis T, Hoenderop JG, Bindels RJ. Downregulation of Ca(2+) and Mg(2+) transport proteins in the kidney explains tacrolimus (FK506)-induced hypercalciuria and hypomagnesemia. J Am Soc Nephrol. 2004;15:549–557.
25. Gommers LM, Hoenderop JG, Bindels RJ, et al. Hypomagnesemia in type 2 diabetes: a vicious circle? Diabetes. 2016;65:3–13.
26. Uchizono Y, Iwase M, Nakamura U, et al. Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling. Endocrinology. 2004;145:2264–2272.
27. Hernandez-Fisac I, Pizarro-Delgado J, Calle C, et al. Tacrolimus-induced diabetes in rats courses with suppressed insulin gene expression in pancreatic islets. Am J Transplant. 2007;7:2455–2462.
28. Rodriguez-Rodriguez AE, Trinanes J, Velazquez-Garcia S, et al. The higher diabetogenic risk of tacrolimus depends on pre-existing insulin resistance. A study in obese and lean Zucker rats. Am J Transplant. 2013;13:1665–1675.
29. Boots JM, van Duijnhoven EM, Christiaans MH, et al. Glucose metabolism in renal transplant recipients on tacrolimus: the effect of steroid withdrawal and tacrolimus trough level reduction. J Am Soc Nephrol. 2002;13:221–227.
30. Pang TT, Chimen M, Goble E, et al. Inhibition of islet immunoreactivity by adiponectin is attenuated in human type 1 diabetes. J Clin Endocrinol Metab. 2013;98:E418–E428.
31. Fedele AL, Alivernini S, Gremese E, et al. CTLA-4 Ig as an effective treatment in a patient with type I diabetes mellitus and seropositive rheumatoid arthritis. Clin Exp Rheumatol. 2016;34:315–317.
32. Ursini F, Russo E, Letizia Hribal M, et al. Abatacept improves whole-body insulin sensitivity in rheumatoid arthritis: an observational study. Medicine (Baltimore). 2015;94:e888.
33. Zhong J, Rao X, Braunstein Z, et al. T-cell costimulation protects obesity-induced adipose inflammation and insulin resistance. Diabetes. 2014;63:1289–1302.
34. Wolf AM, Wolf D, Rumpold H, et al. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun. 2004;323:630–635.

Supplemental Digital Content

Back to Top | Article Outline
© 2018 The Authors. Published by Wolters Kluwer Health, Inc.