Advanced Glycation End Products Evolution after Pancreas-Kidney Transplantation: Plasmatic and Cutaneous Assessments.

Diabetes mellitus leads to increased Advanced Glycation End Products (AGE) production, which has been associated with secondary diabetic complications. Type 1 diabetic patients undergoing pancreas-kidney transplantation (SPKT) can restore normoglycemia and renal function, eventually decreasing AGE accumulation. We aimed to prospectively study AGE evolution after SPKT. Circulating AGE were assessed in 20 patients, at time 0 (T0), 3 months (T3), 6 months (T6), and 12 months (T12) after successful SPKT. Global AGE and carboxymethyllysine (CML) were analyzed, as well as advanced oxidation protein products (AOPP). Skin biopsies were obtained at T0 and T12. Immunohistochemistry with anti-AGE antibody evaluated skin AGE deposition. AGE mean values were 16.8 ± 6.4 µg/mL at T0; 17.1 ± 3.8 µg/mL at T3; 17.5 ± 5.6 µg/mL at T6; and 16.0 ± 5.2 µg/mL at T12. CML mean values were 0.94 ± 0.36 ng/mL at T0; 1.11 ± 0.48 ng/mL at T3; 0.99 ± 0.42 ng/mL at T6; and 0.78 ± 0.38 ng/mL at T12. AOPP mean values were 130.1 ± 76.8 µMol/L at T0; 137.3 ± 110.6 µMol/L at T3; 116.4 ± 51.2 µMol/L at T6; and 106.4 ± 57.9 µMol/L at T12. CML variation was significant (P = 0.022); AOPP variation was nearly significant (P = 0.076). Skin biopsies evolved mostly from a cytoplasmic diffuse to a peripheral interkeratinocytic immunoreaction pattern; in 7 cases, a reduction in AGE immunoreaction intensity was evident at T12. In conclusion, glycoxidation markers decrease, plasmatic and on tissues, may start early after SPKT. Studies with prolonged follow-up may confirm these data.

Pancreas-Kidney transplantation: Impact of dialysis modality on the outcome.

It remains controversial whether dialysis modality prior to SPKT (simultaneous pancreas-kidney transplantation) affects the outcome. We analyzed outcomes in type 1 diabetic patients undergoing SPKT, comparing peritoneal dialysis (PD) and hemodialysis (HD) groups: 119 had been on HD; 39 on PD. They were comparable except regarding dialysis time, higher in HD patients (30 ± 23 vs. 21 ± 15 months, P = 0.003). Thrombosis-driven relaparotomy was more frequent in PD patients (12.8% vs. 1.7%, P = 0.014). Pancreas loss due to infection was higher in PD patients (12.8% vs. 3.4%, P = 0.042). Thrombosis-related kidney loss was more frequent in PD patients (5.1%, vs. 0% in HD patients, P = 0.058). Thirteen deaths occurred, more within the PD group (17.9% vs. 5%; P = 0.011), being infection the leading cause (13.5%, vs. 1.7% in HD patients, P = 0.010). Patient survival was inferior in PD patients. Besides PD, cardiovascular disease and graft failure were independent predictors of patient death. In conclusion, PD patients more frequently complicated with intra-abominal infection leading to pancreatic loss and with renal thrombosis, with adverse impact on survival. As a PD first strategy in end-stage renal disease patients is generally associated with good outcomes, these gloomier results after SPKT urge for careful adjustment of infection and thrombosis prophylactic protocols in PD patients.

Health-related quality of life may improve after transplantation in pancreas-kidney recipients.

Pancreas-kidney transplantation (PKT) may significantly improve quality of life (HRQOL) in patients with type 1 diabetes. We have assessed the changes felt by PKT patients, using the Gastrointestinal Quality of Life Index (GIQLI) and EuroQol-5D questionnaires. Patients were asked to compare how their HRQOL had changed from pre-transplantation to the last visit. The 60 men and 66 women enrolled had a mean follow-up of five yr; 84.1% with both grafts, 15.9% with one graft functioning. In all domains of EuroQol-5D scores improved after PKT, as well as the visual analogue scale health state (from 38% to 84%, p < 0.001; effect size 3.34). In GIQLI, physical function was felt better after PKT than before (14.83 ± 3.86 vs. 7.86 ± 4.43, p < 0.001; effect size 1.68); the same was observed for psychological status, social function, and GI complaints. Concerning the burden of medical treatment, the score significantly improved (from 1.31 to 3.63, p < 0.001, effect size 2.02). The rate of unemployed patients decreased after PKT (from 50.8% to 36.5%, p < 0.001). Multivariate analysis showed that having only one functioning graft was associated with worse HRQOL scores (B = -5.157, p = 0.015). In conclusion, for all assessed domains, patients reported a significant improvement in HRQOL after PKT. Maintenance of the two grafts functioning predicted higher improvement of HRQOL scores.

Pancreatic autoantibodies after pancreas-kidney transplantation - do they matter?

Type 1 diabetes recurrence has been documented in simultaneous pancreas-kidney transplants (SPKT), but this diagnosis may be underestimated. Antibody monitoring is the most simple, noninvasive, screening test for pancreas autoimmune activity. However, the impact of the positive autoimmune markers on pancreas graft function remains controversial. In our cohort of 105 SPKT, we studied the cases with positive pancreatic autoantibodies. They were immunosuppressed with antithymocyte globulin, tacrolimus, mycophenolate, and steroids. The persistence or reappearance of these autoantibodies after SPKT and factors associated with their evolution and with graft outcome were analyzed. Pancreatic autoantibodies were prospectively monitored. Serum samples were collected before transplantation and at least once per year thereafter. At the end of the follow-up (maximum 138 months), 43.8% of patients were positive (from pre-transplant or after recurrence) for at least one autoantibody - the positive group. Antiglutamic acid decarboxylase was the most prevalent (31.4%), followed by anti-insulin (8.6%) and anti-islet cell autoantibodies (3.8%). Bivariate analysis showed that the positive group had higher fasting glucose, higher glycated hemoglobin (HbA1c), lower C-peptide levels, and a higher number of HLA-matches. Analyzing the sample divided into four groups according to pre-/post-transplant autoantibodies profile, the negative/positive group tended to present the higher HbA1c values. Multivariate analysis confirmed the significant association between pancreas autoimmunity and HbA1c and C-peptide levels. Positivity for these autoantibodies pre-transplantation did not influence pancreas survival. The unfavorable glycemic profile observed in the autoantibody-positive SPKT is a matter of concern, which deserves further attention.

Pulmonary alveolar proteinosis: a rare pulmonary toxicity of sirolimus.

The aim of our paper is to describe an unusual pulmonary toxicity of sirolimus (SRL) in a kidney transplant recipient. We present a 34-year-old woman with a second renal transplantation, complicated with steroid-resistant acute rejection and chronic allograft dysfunction. Two years after initiating SRL, she presented complaints of progressive dyspnoea, nonproductive cough, chest pain and low-grade fever of 1 month duration. She had chronic allograft nephropathy and slight elevation of lactic dehydrogenase levels. After exclusion of common reasons of this condition, a computed tomography (CT) of the thorax and bronchoscopy was performed, revealing ground-glass opacification with polygonal shapes on CT and an opaque appearance with numerous macrophages on bronchoalveolar lavage. The alveolar macrophages stained positive by Periodic acid-Schiff. Diagnosis of pulmonary alveolar proteinosis (PAP) was made and drug-induced toxicity was suspected. SRL was withdrawn with marked improvement in the patients' clinical and radiological status. PAP resolved within 3 months without further therapy. PAP is a very rare complication of SRL therapy with only a few cases described. Withdrawal of SRL with conversion to another immunosuppressant seems to be an appropriate procedure in this condition.

Early cyclosporine a withdrawal in kidney-transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions.

BACKGROUND: Nephrotoxicity of calcineurin inhibitors (CNIs) is partially responsible for the development of chronic allograft nephropathy (CAN). Sirolimus has demonstrated its potential to substitute for CNIs because it lacks significant nephrotoxicity and shows a short-term immunosuppressive capacity comparable with that of cyclosporine. This results in the maintenance of better renal function when cyclosporine is eliminated, but it has not been demonstrated whether this benefit is associated with an improvement in the pathologic substrate and a reduction in CAN. METHODS: We analyzed pretransplant and 1-year renal-allograft biopsies from 64 patients enrolled in a multicenter trial. Patients received cyclosporine and sirolimus during the first 3 months after transplant and were then randomly assigned to continue with cyclosporine or have it withdrawn. Histologic chronic allograft lesions were compared between groups. RESULTS: The percentage of patients in whom chronic pathologic lesions progressed was lower in the group of cyclosporine elimination. Significant differences were observed in chronic interstitial and tubular lesions (70% vs. 40.9% [P<0.05] and 70% vs. 47.8% [P<0.05], respectively), whereas no differences were observed in acute lesions (subclinical rejection). Prevalence of CAN at 1 year was lower in this group, as was the severity and incidence of new cases (P<0.05). CONCLUSIONS: Early cyclosporine withdrawal associated with sirolimus administration is followed by an improvement in renal function, a reduction in the progression of chronic pathologic allograft lesions, and a lower incidence of new cases and severity of CAN during the first year after transplantation. This benefit may result in better long-term graft outcome.

Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study.

INTRODUCTION: The purpose of this study was to evaluate early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen. METHODS: Within 48 hr after transplantation, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of SRL (troughs >5 ng/mL; immunoassay), CsA, and ST. Those eligible (430) were randomly assigned (1:1) at 3 months +/- 2 weeks to remain on triple-drug therapy (SRL-CsA-ST group) or to have CsA withdrawn and SRL trough concentrations targeted to 20 to 30 ng/mL (SRL-ST group) until month 12, and 15 to 25 ng/mL thereafter. RESULTS: At 24 months, there were no statistically significant differences in patient survival (94.0% vs. 95.3%), graft survival (91.2% vs. 93.5%), acute rejection after randomization (5.1% vs. 9.8%) or discontinuations (34% vs. 33%) for SRL-CsA-ST versus SRL-ST, respectively. Serum creatinine level was significantly better in patients who had CsA withdrawn (167 vs. 128 micromol/L, P<0.001), as was the slope of 1/creatinine. Similarly, systolic blood pressure was lower in patients who had CsA withdrawn (141 vs. 134 mm Hg, P<0.001). High-density lipoprotein cholesterol was significantly higher in the SRL-ST group, whereas total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were not significantly different. Hypertension, creatinine increase, abnormal kidney function, toxic nephropathy, edema, hyperuricemia, cataracts, Herpes zoster, and malignancy were reported significantly more often in patients continuing CsA. Thrombocytopenia, hypokalemia, abnormal liver function tests, abnormal wound healing, ileus, and pneumonia were reported significantly more frequently with SRL-ST. CONCLUSION: Data at 2 years confirm that early CsA withdrawal followed by an SRL-ST maintenance regimen results in long-term improvement in both renal function and blood pressure, without increased risk of graft loss or late acute rejection.