Several studies in patients with type 1 diabetes have examined the impact of islet transplantation (ITx) on renal function (1–3). Our group and others (1,4) have reported the beneficial effect of ITx. Equally relevant, however, is the assessment of renal function in patients with graft failure (GF) who are exposed to the well-known potential toxicity from immunosuppressive drugs and risk of development or progression of diabetic nephropathy related to unstable glycemic control (5). In this study, we examined the renal function of 12 recipients of allogeneic ITx who developed GF (stimulated C-peptide <0.3 ng/mL) but had at least 1 year (range 1.0–5.1) of graft function. Maintenance immunosuppression consisted of sirolimus and tacrolimus, which were discontinued after GF. Patients were enrolled in the ongoing Long Term Surveillance of Islet Transplant Recipients Following Complete Graft Loss study at the University of Miami, 6.0 ± 1.8 years (range 2.9–8.8) after GF. In this interim report, we provide data on renal function for a mean of 10.7 years after islet GF (Fig. 1A). The estimated glomerular filtration rate (eGFR) at the end of follow-up was comparable to eGFR at time of GF (86.0 ± 21.1 vs. 88.3 ± 21.8 mL/min/1.73 m2; P = 0.95 after comparison of all study time points) (Fig. 1B). The rate of eGFR decline, variable among individuals, was not significantly different after immunosuppression discontinuation (0.5 ± 0.9 and 0.1 ± 1.0 mL/min/1.73 m2/year after ITx and GF, respectively; P = 0.35) (Fig. 1C). By contrast, microalbuminuria (urine albumin–creatinine ratio 30–299 mg/g Cr) was observed in 2/12 (16.6%) subjects at ITx, 3/12 (25%) at half-graft survival, 5/12 (41.7%) at GF, and 1/11 (9.0%) at the last follow-up visit (Fig. 1D). None had macroalbuminuria. Four of the five subjects with microalbuminuria at GF had resolution after discontinuation of immunosuppression (P = 0.0007). One subject continued to have microalbuminuria, but this initially appeared at GF. Two subjects with preexisting microalbuminuria and resolution after immunosuppression discontinuation were switched from tacrolimus to mycophenolate mofetil while having graft function because of tacrolimus toxicity. HbA1c improved following ITx and worsened after GF, despite reintroduction of insulin therapy, but was not significantly different throughout follow-up. Overall, we did not observe any association between proteinuria and renal function at time of ITx, blood pressure, use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (3/5 subjects with microalbuminuria), or immunosuppression drug levels. We recognize that limitations of this study include the small sample size, a selection bias because inclusion criteria for ITx required an eGFR >60 mL/min/1.73 m2 (in one case the eGFR was 55), and lack of a control group to better address the association between immunosuppression and albuminuria. Nevertheless, in this patient population, the eGFR was not compromised during the 10-year follow-up after occurrence of islet GF and microalbuminuria regressed after discontinuation of immunosuppression in four out of five subjects. The careful selection of islet recipients, improvement of metabolic control during graft function, management of risk factors, and withdrawal of calcineurin inhibitor therapy may be responsible for stabilization of kidney function.
Acknowledgments. The authors appreciate the continued support from the staff of the Clinical Cell Transplant Program at the Diabetes Research Institute.
Funding. This work was supported by U.S. National Institutes of Health grants MO1RR16587, 1RO1-DK55347, IU42 RR016603, and 1UL1TR000460; the Miami Clinical and Translational Science Institute; the National Center for Advancing Translational Sciences; the National Institute on Minority Health and Health Disparities; and JDRF grant 4-200-946. A.F. is supported by U.S. National Institutes of Health grant DK82636, by the Forest County Potawatomi Community Foundation, and by the Max and Yetta Karasik Family Foundation.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. E.P. researched and analyzed data, reviewed/edited the manuscript, contributed to discussion, and wrote the manuscript. F.V. analyzed data, reviewed/edited the manuscript, contributed to discussion, and wrote the manuscript. A.Ar. N.P., and D.B., and A.Al. researched data, reviewed/edited the manuscript, and contributed to discussion. V.D. researched data. A.F. reviewed/edited the manuscript and contributed to discussion. C.R. and R.A. contributed to the discussion and reviewed/edited the manuscript. R.A. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
E.P. and F.V. contributed equally to this work.