Pathophysiology/Complications ORIGINAL ARTICLE Kidney Function After Islet Transplant Alone in Type 1 Diabetes Impact of immunosuppressive therapy on progression of diabetic nephropathy 1 2 PAOLA MAFFI, MD, PHD ANDREA CAUMO, PHD he Diabetes Control and Complica- 1 1 FEDERICO BERTUZZI, MD PAOLO POZZI, MD tions Trial has shown that in pa- 1 3 FRANCESCA DE TADDEO, MD CARLO SOCCI, MD 1 4 tients with type 1 diabetes, intensive AOLA AGISTRETTI PHD ASSIMO ENTURINI MD T P M , M V , 1 4 diabetes treatment reduces incidence and RITA NANO, MD ALESSANDRO DEL MASCHIO, MD 1 1 delays progression of long-term compli- PAOLO FIORINA, MD, PHD ANTONIO SECCHI, MD cations (1). The Epidemiology of Diabetes Intervention and Complications (EDIC) study, a follow-up of the original Diabetes OBJECTIVE — Islet transplantation alone is an alternative for the replacement of pancreatic Control and Complications Trial cohort, endocrine function in patients with type 1 diabetes. The aim of our study was to assess the impact of the Edmonton immunosuppressive protocol (tacrolimus-sirolimus association) on kidney function. has shown a sustained effect of intensive diabetes treatment on the development RESEARCH DESIGN AND METHODS — Nineteen patients with type 1 diabetes and and progression of nephropathy and ma- metabolic instability received islet transplantation alone and immunosuppressive therapy ac- crovascular disease (2). Furthermore, the cording to the Edmonton protocol. Serum creatinine (sCr), creatinine clearance (CrCl), and 24-h EDIC study has shown that patients with urinary protein excretion (UPE) were assessed at baseline and during a follow-up of 339 patient- type 1 diabetes with some endogenous C- months. peptide reserve have a lower risk of pro- gression of retinopathy and neuropathy RESULTS — After islet transplantation we observed 1) sCr within the normal range in all but two patients in whom sCr increased immediately after islet transplantation, and despite with- (2). However, the benefits of intensive di- drawal of immunosuppression, patients progressed to end-stage renal disease (ESRD); 2) CrCl abetes treatment come with the price of remained within the normal range for those patients who had normal baseline values and severe hypoglycemia and increased body decreased, progressing to ESRD in two patients with a decreased baseline CrCl; and 3) 24-h UPE weight (1). worsened (Ͼ300 mg/24 h) in four patients. In the two patients who progressed to ESRD, the Several studies have reported a high worsening of 24-h UPE occurred immediately after islet transplantation. In one patient 24-h UPE rate of insulin independence and normal- worsening occurred at 18 months, and, after withdrawal of immunosuppression, it returned to ization of blood glucose and A1C levels the normal range. In another patient 24-h UPE increased at 24 months and remained stable while after either pancreas or islet transplanta- immunosuppression was continued. tion (3–7). In patients with type 1 diabe- CONCLUSIONS — In type 1 diabetic patients receiving islet transplantation alone, the tes, pancreas or islet transplantation has association of tacrolimus and sirolimus should be used only in patients with normal kidney improved kidney graft survival (8,9), function. Alternative options for immunosuppressive treatment should be considered for pa- whereas the positive impact of pancreas tients with even a mild decrease of kidney function. transplantation on the native kidney has been counterbalanced by the nephrotox- Diabetes Care 30:1150–155, 2007 icity of immunosuppressants, namely cal- cineurin inhibitors (10,11). Since the advent of the Edmonton protocol, islet transplantation alone, i.e., regardless of the need for kidney trans- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● plantation, has been proposed for pa- From the 1Department of Medicine, Transplant Unit, San Raffaele Scientific Institute, Milan, Italy; the tients with type 1 diabetes who have an 2Metabolism and Nutrition Unit, San Raffaele Scientific Institute, Milan, Italy; the 3Department of Surgery, increased risk of acute or chronic compli- San Raffaele Scientific Institute, Milan, Italy; and the 4Department of Radiology, San Raffaele Scientific cations (3). However, few data have been Institute, Milan, Italy. reported on kidney function after islet Address correspondence and reprint requests to Paola Maffi, MD, PhD, Department of Medicine, Trans- plant Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy. E-mail: paola.maffi@hsr.it. transplantation alone (12,13), despite im- Received for publication 24 August 2006 and accepted in revised form 19 January 2007. munosuppression according to the Edm- Published ahead of print at http://care.diabetesjournals.org on 26 January 2007. DOI: 10.2337/dc06- onton protocol, which is the association 1794. of two potentially nephrotoxic drugs, Abbreviations: CrCl, creatinine clearance; EDIC, Epidemiology of Diabetes Intervention and Complica- tions; ESRD, end-stage renal disease; MMF, mycophenolate mofetil; sCr, serum creatinine; UPE, urinary namely tacrolimus and sirolimus (14– protein excretion. 16). The aim of our study was to assess the A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion impact of the Edmonton immunosup- factors for many substances. pressive protocol on kidney function after © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby islet transplantation alone in patients with marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. type 1 diabetes. 1150 DIABETES CARE, VOLUME 30, NUMBER 5, MAY 2007 Maffi and Associates RESEARCH DESIGN AND Other medications Follow-up METHODS — For the purpose of this Short-term antibiotic prophylaxis was ad- Nineteen patients had 3 months of fol- study, we analyzed data on 19 patients ministered immediately before and after low-up, 18 patients had 6 months, 17 pa- who received islet transplantation at the islet infusion (intravenous cephtazidime, tients had 12 months, 13 patients had 18 San Raffaele Scientific Institute between 1 g t.i.d. for 1 day). For 3 months after months, and 8 patients had 24 months. February 2001 and March 2005. Patients islet infusion, patients were treated with Total follow-up was 339 patient-months; with type 1 diabetes were eligible for islet trimethoprim (800 mg/day once a day), median follow-up was 18 patient-months transplantation alone if they met the fol- sulfamethoxazole (160 mg/day once a (range 3–24). Two patients dropped out lowing criteria: 1) diabetes duration Ͼ5 day), and acyclovir (200 mg t.i.d.) to pre- of the study at 8 and 12 months, respec- years, 2) decreased awareness of hypogly- vent Pneumocystis carinii and cytomegalo- tively, when immunosuppression was cemia, 3) metabolic instability, or 4) pro- virus infection. In six patients, acyclovir withdrawn because of deterioration of gressive chronic complications despite an was stopped because of gastric intoler- kidney function. One patient elected to intensive insulin regimen (i.e., Ն4 insulin ance. Fifteen patients were treated with withdraw from the study at 4 months be- cause of intolerance to immunosuppres- injections/day or continuous subcutane- statins because of hypercholesterolemia sion; in one patient immunosuppression ous insulin infusion). Patients with severe and four patients with ACE inhibitors be- was withdrawn after 21 months because cardiovascular disease, evidence of pro- cause of macroproteinuria (n ϭ 1) or hy- of graft failure. gressive nephropathy (urinary protein pertension (n ϭ 3). During the first 3 days Ͼ The following variables were mea- excretion 500 mg/24 h or serum creat- after islet infusion, insulin was adminis- Ͼ ␮ sured at baseline and every 3 months after inine 135 mol/l), a history of chronic tered intravenously using an infusion infectious disease (viral hepatitis or tuber- the first islet infusion: A1C (percent), fast- pump and then was administered subcu- ing C-peptide (nanomoles per liter), ex- culosis), or malignancy were not eligible. taneously until withdrawal. Patients were 10 men and 9 women, ogenous insulin requirement, episodes of with mean Ϯ SD age of 37.2 Ϯ 9.0 years severe hypoglycemia, serum creatinine (sCr) (micromoles per liter), creatinine (range 2–61) and duration of diabetes of Islet transplantation Ϯ clearance (CrCl) (milliliters per second) 23.3 9.0 years (11–37). All patients had Islets were isolated from pancreata ob- decreased hypoglycemia awareness, 11 estimated using the Cockcroft-Gault tained from heart-beating cadaveric mul- equation (20), and 24-h urinary protein patients had retinopathy, 12 patients tiorgan donors, using an automated excretion (UPE) (grams per 24 h). had peripheral neuropathy, and 1 patient method, modified as described previ- had gastroparesis. Four patients had hy- ously (17). Purification was performed by Statistical analysis pertension and were treated with ACE the centrifugation on discontinuous Fi- Statistical analysis was performed using inhibitors. Two patients had mild nephrop- coll gradients (Sigma Chemical, St. Louis, SPSS for Windows (version 10.1; SPSS, athy: one patient had macroproteinuria MO) and was assayed by a computerized Chicago, IL). Data are presented as for 2 years before islet transplantation and morphometric method (Leica Imaging means Ϯ SD. A two-sided paired Stu- the other had a serum creatinine level