Long‐term results of pancreas transplantation in patients older than 50 years

Aging of the population and improvements in diabetes therapy have led to an increased number of older pancreas transplant candidates. The aim of our retrospective study was to evaluate pancreas transplantation (PT) outcomes in patients ≥50 years, as limited data exist in these patients. We analyzed 398 consecutive pancreas transplant patients from June 1994 to June 2009 for different outcomes (patient/graft survival, rejection rate, and surgical complications) between the age groups ≥50 years (n = 69) and <50 years (n = 329). Donor and recipient characteristics were similar except for recipient age (54.0 vs. 38.8 years), BMI (24.6 vs. 22.9 kg/m²), and duration of diabetes mellitus (36.0 vs. 27.7 years). One‐, 5‐, and 10‐year patient and graft (kidney/pancreas) survival were not significantly different between the groups with patient survival rates reaching 84% and pancreas graft survival up to 67% after 10 years. Surgical complications such as relaparotomy rate (34% vs. 33%) or pancreas graft thrombosis (14% vs. 11%) as well as 1‐year rejection rates (35% vs. 31%) were not significantly different. PT in selected patients aged ≥50 years resulted in survival comparable with that of younger patients. In conclusion, advanced age should no longer be considered as an exclusion criterion for PT. However, good medical assessment and careful patient selection are necessary.     

Charcot neuroarthropathy after simultaneous pancreas–kidney transplantation: risk factors,prevalence, and outcome

We retrospectively analyzed outcome and risk factors of developing Charcot foot (CF) in 100 patients with type 1 diabetes mellitus who underwent a simultaneous pancreas–kidney (SPK) transplantation. Patients who developed CF after SPK transplantation had significantly higher mortality (56% vs. 18%) and more frequently graft failure (44% vs. 13%). Recipients with CF also experienced acute rejections more frequently (78% vs. 41%). They furthermore had higher pre‐transplant values of HbA_1c, received cyclosporine and azathioprine more often, and had significantly higher cumulative corticosteroid use. Patients transplanted in an earlier era (1992–1998) received cyclosporine and azathioprine more often and had a significantly higher cumulative corticosteroid use with the higher prevalence of CF. Conversely, patients with diabetes transplanted more recently (1999–2012) received lower doses of corticosteroids as part of their tacrolimus‐based immunosuppressive therapy, resulting in fewer CF attacks. In conclusion, development of CF after SPK is associated with poor patient and graft outcome. Poor pre‐transplant diabetic control and the use of high‐dose corticosteroids are risk factors for the development of CF. We recommend reduction in or even total avoidance of corticosteroids after SPK transplantation. Given the importance of the diagnosis of CF on outcome, a systematic examination of SPK patients' feet is recommended.     

Impact of graft implantation order on graft survival in simultaneous pancreas–kidney transplantation

The optimal order of revascularization for pancreas and kidney grafts in simultaneous pancreas–kidney transplantation has not been established. In this study, we investigate the influence of graft implantation order on graft survival in SPK. 12 700 transplantations from the Scientific Registry of Transplant Recipients were analyzed retrospectively. Graft implantation order was determined based on the reported ischemia times of pancreas and kidney grafts. Pancreas and kidney graft survivals were analyzed depending on graft implantation order at 3 months and 5 years using Kaplan–Meier plots. Significance was tested with log‐rank test and Cox regression model. In 8454 transplantations, the pancreas was implanted first (PBK), and in 4246 transplantations, the kidney was implanted first (KBP). The proportion of lost pancreas grafts at 3 months was significantly lower in PBK (9.4% vs. 10.8%, P = 0.011). Increasing time lag (>2 h) between kidney and pancreas graft implantation in KBP accentuated the detrimental impact on pancreas graft survival (12.5% graft loss at 3 months, P = 0.001). Technical failure rates were reduced in PBK (5.6 vs. 6.9%, P = 0.005). Graft implantation order had no impact on kidney graft survival. In summary, although observed differences are small, pancreas graft implantation first increases short‐term pancreas graft survival and reduces rates of technical failure.     

Duodenal graft complications requiring duodenectomy after pancreas and pancreas–kidney transplantation

Duodenal graft complications are poorly reported complications of pancreas transplantation that can result in graft loss. Excluding patients with early graft failure, after a median follow‐up period of 126 months (range 23‐198) duodenectomy was required in 14 of 312 pancreas transplants (4.5%). All patients were insulin‐independent at the time of diagnosis. Reasons for duodenectomy included delayed duodenal graft perforation (n = 10, 71.5%) and refractory duodenal graft bleeding (n = 4, 28.5%). In patients with duodenal graft bleeding, a total duodenectomy was performed. In patients with duodenal graft perforation, preservation of a duodenal segment was possible in five patients but completion duodenectomy was necessary in one patient. After total duodenectomy, immediate enteric duct drainage was feasible in seven patients. In two patients, a pancreaticocutaneous fistula was created that was subsequently converted to enteric drainage in one patient. In the other patient, enteric fistulization occurred as a consequence of silent pressure perforation of the draining catheter on the ascending colon. After a mean follow‐up period of 52 months (21‐125), all patients were alive, well, and insulin‐independent. An aggressive and timely surgical approach may permit graft rescue in patients with severe duodenal graft complications occurring after pancreas transplantation. Generalization of these results remains to be established.     

Cytomegalovirus prophylaxis with valganciclovir in kidney, pancreas-kidney, and pancreas transplantation

Cytomegalovirus, seen in more than 50% of solid organ transplant recipients, is responsible for numerous direct and indirect consequences, including infection with opportunistic pathogens and allograft rejection. Prophylaxis with intravenous ganciclovir has been the gold standard for prevention; however, intravenous treatment is expensive and carries risks of its own. Oral ganciclovir, to be effective, must be given in large, divided doses. Valganciclovir, the valine ester of ganciclovir, at 900 mg/day, provides oral bioavailability equivalent to that of intravenous ganciclovir and superior to that of oral ganciclovir. This retrospective study assessed the efficacy of 3 months prophylaxis with valganciclovir in kidney, simultaneous pancreas-kidney, and pancreas transplantation. Of 161 patients, all of whom received potent immunosuppressive regimens and were followed for a mean of 440 days, only one developed cytomegalovirus infection, at 120 days post-transplantation. Two patients died, and two others lost their grafts. There were seven incidents of acute rejection. Only seven patients discontinued treatment early, five because of leukopenia. These results suggest that prophylaxis with 900 mg/day of valganciclovir for at least 3 months safely and effectively prevents cytomegalovirus infection in kidney, simultaneous pancreas-kidney and pancreas transplant recipients on highly potent immunosuppression.     

The impact of functioning pancreas–kidney transplantation and pancreas alone transplantation on the lipid metabolism of statin‐naïve diabetic patients

Abstract: Objective: To compare the lipid profile (total cholesterol – TC, triglycerides – TG, high density lipoprotein cholesterol – HDL‐c, low density lipoprotein cholesterol – LDL‐c and non‐HDL cholesterol – NHDL‐c) of patients with functioning pancreas–kidney transplantation (PKT) or pancreas transplantation alone (PTA) after one (T1) and two yr (T2) following their pre‐transplantation data (T0). Methods: Fifty‐three type 1 diabetic patients underwent pancreas transplantation (42 PKT and 11 PTA) remaining euglycemic after transplantation were evaluated before and one and two yr after the procedures. They were using predominantly tacrolimus‐mycophenolate mofetil‐based immunosuppression and low glucocorticoid dose with systemic venous drainage of the pancreatic graft. None of them used hypolipidemic agents for economical reasons. Lipids were reported as means ± standard error of the mean. Data obtained in T0 were compared with T1 and T2 using ANOVA followed by Student’s t‐test. Results: TC, LDL‐c, NHDL‐c and TG were lower in T1 and T2 when compared with T0 (p < 0.05) in PKT, while no change was observed for HDL‐c (p > 0.05). PTA group showed no significant changes in lipids. Conclusion: In spite of the known side effects of tacrolimus‐based immunosuppression to lipids, our study with a statin‐naïve sample showed improvements (PKT) or stabilization (PTA) in the serum lipid profile after pancreas transplantation.     

Three‐month pancreas graft function significantly influences survival following simultaneous pancreas‐kidney transplantation in type 2 diabetes patients

Successful simultaneous pancreas‐kidney transplantation (SPK) improves quality‐of‐life and prolongs kidney allograft and patient survival in type‐1 diabetic (T1DM) patients. However, the use of SPK in type‐2 diabetic (T2DM) patients remains limited. We examined a national transplant registry for 35 849 T2DM kidney disease patients who received transplant between 2000 and 2016 and survived the first 3 months with a functioning kidney, and categorized as: deceased‐donor kidney transplant alone (DD‐KA, 68%), living‐donor kidney transplant alone (LD‐KA, 30%), or SPK (2%). Among SPK recipients, 6% had pancreas allograft failure within 3 months (SPK,P‐) and 94% had a functional pancreas (SPK,P+). Associations of transplant type with kidney allograft failure and death (multivariable‐adjusted hazard ratio, _95%LCLaHR_95%UCL), over follow‐up through December 2018, were quantified by multivariable inverse probability of treatment weighted survival analyses. SPK recipients had better kidney graft and patient survival than LD‐KA or DD‐KA recipients. Compared to SPK,P+, DD‐KA, or LD‐KA recipients had significantly higher risk of kidney allograft failure (DD‐KA: aHR _1.532.20_3.17; LD‐KA: aHR _1.291.87_2.71) and death (DD‐KA: aHR _2.123.25_5.00; LD‐KA: aHR _1.542.35_3.59). SPK,P‐ recipients had significantly higher risk of death (aHR _1.683.30_6.50). Similar to T1DM, T2DM patients with SPK have a survival benefit compared to those with kidney transplant alone, but this benefit depends upon successful early pancreas function.     

BK virus nephropathy after simultaneous pancreas–kidney transplantation

Akpinar E, Ciancio G, Sageshima J, Chen L, Guerra G, Kupin W, Roth D, Ruiz P, Burke G. BK virus nephropathy after simultaneous pancreas–kidney transplantation.
Clin Transplant 2010: 24: 801–806. © 2010 John Wiley & Sons A/S. Abstract: Background: BK virus nephropathy (BKVN) was reported in up to 7.5% of patients after simultaneous pancreas–kidney transplantation (SPK). Its management by reduction in immunosuppression might pre‐dispose to pancreatic graft loss. Methods: A retrospective analysis of 178 SPK recipients was performed. All patients received thymoglobulin, daclizumab and a maintenance of low‐dose steroids, tacrolimus, and either sirolimus or mycophenolate. Results: Two (1.1%) patients were identified with BKVN. Time of diagnosis was 22 and 45 months after transplant. Both patients had superimposed calcineurin toxicity in their graft biopsies. Immunosuppression was reduced in both patients, and leflunomide (LEF) was used in one patient. Concurrent kidney rejection episodes were treated with steroid pulses in both patients. One kidney graft improved with a last estimated glomerular filtration rate (GFR) of 43 mL/min, and another kidney graft showed limited improvement with a last GFR of 30 mL/min. Pancreatic graft function remained excellent in both patients as assessed by serum c‐peptide, glycosylated hemoglobin, amylase‐lipase, and urine amylase levels. Conclusion: Low incidence of BKVN was observed in our SPK series. Reduction in immunosuppression and sometimes LEF can be effective. The underlying mechanism of stable pancreatic allograft function despite ongoing kidney rejection warrants further investigation.     

Diminished impact of cytomegalovirus infection on graft vasculopathy development in the antiviral prophylaxis era – a retrospective study

Evidence concerning an association between cytomegalovirus (CMV) infection and accelerated cardiac allograft vasculopathy (CAV) is inconclusive. Data were analyzed retrospectively from 297 consecutive heart transplants between 1.1.2002 and 31.12.2012. Patients ≤18 years of age, survival, and follow‐up ≤1‐year post‐transplant and patients with early CAV were excluded. CMV‐infection was diagnosed and monitored closely in the first year. CAV was diagnosed by coronary angiography via left heart catheterization, and results were categorized according to the International Society of Heart and Lung Transplantation (ISHLT) scoring system. Risk factors for CAV were tested in a multivariable model. Median follow‐up was 7.5 years (IQR: 5.6–10.3). CMV infection in the first year after transplantation occurred in 26% of patients (n = 78), CMV disease in 5% (n = 15). CAV ≥1 ISHLT was detected in 36% (n = 108). Incidence of CAV >1 ISHLT and severity of CAV increased over time. No statistically significant association between CMV infection and disease within the first year and risk of CAV after 1‐year post‐HTx was detected in the univariate (P = 0.16) and multivariable [hazard ratio (HR), 1.36; confidence interval (CI), 0.89–2.07; P = 0.16] Cox regression. In the multivariable Cox regression, donor age (HR, 1.04; 95% CI, 1.02–1.06; P < 0.01) and acute cellular rejection (ACR) ≥2R in the first year after HTx (HR, 1.77; 95% CI, 1.06–2.95; P = 0.03) were independent risk factors for CAV development. In our cohort, CMV infection and disease in the first year after transplantation did not significantly influence the risk of CAV in the long‐term follow‐up.     

Long-term outcome of cytomegalovirus infection in simultaneous pancreas–kidney transplant recipients without ganciclovir prophylaxis

As cytomegalovirus (CMV) infection frequently occurs in simultaneous pancreas kidney transplantation (SPKT), most centers use general ganciclovir prophylaxis. The aim of the study was to analyze the impact of CMV in a patient cohort with preemptive therapy only. Incidence, course and risk factors of CMV infection were retrospectively analyzed in 94 adult SPK recipients without prophylaxis. Patients with asymptomatic pp65-antigenemia were treated preemptively with intravenous ganciclovir for 14 days. Survival rates after 1, 3, and 5 years were 98%, 97%, and 94% for patients, 96%, 94%, and 88% for renal grafts and 88%, 85%, and 82% for pancreas grafts. CMV infections occurred in 51% of patients and CMV syndrome in 16%. No tissue-invasive disease was observed. Thirty-eight per cent of patients with CMV infection developed a recurrence. Risk factors for CMV in multivariate analysis were the D+/R- constellation, acute rejections, anti-rejection therapy and coronary heart disease. CMV had no impact on patient or graft survival, occurrence of acute or chronic rejection and bacterial infections. Preemptive therapy seems to be safe and effective in SPK recipients, but as the present study was retrospective, prospective randomized studies are needed to confirm our results.     

Impact of antiviral prophylaxis in adults Epstein–Barr Virus‐seronegative kidney recipients on early and late post‐transplantation lymphoproliferative disorder onset: a retrospective cohort study

Post‐transplantation lymphoproliferative disorder (PTLD ) pathogenesis is related to EBV infection. Mismatch with the donor (EBV D+/R?) is the main risk factor for both early PTLD (<1 year post‐transplantation) and late (>1 year). In these at‐risk patients, the role of antiviral prophylaxis for preventing PTLD remains controversial. We analyzed the impact of antiviral drugs given to prevent CMV disease in a monocentric retrospective cohort of 73 adult kidney or kidney–pancreas EBV ‐seronegative recipients, transplanted between 01/01/2000 and 01/01/2016. Thirty‐seven (50.7%, prophylaxis group) received (val‐)aciclovir or (val‐)ganciclovir for 3–6 months and 36 (49.3%, no‐prophylaxis group) received no‐prophylaxis. Mean follow‐up was 69 ± 7.2 months in the prophylaxis group and 91 ± 10.3 months in the no‐prophylaxis group. Monitoring of EBV PCR revealed that prophylaxis delayed primary infection at 100 days (43% vs. 84%, P = 0.02). Early PTLD incidence was not different between groups (4/37 vs. 4/36, P = 0.99). Concerning late events, EBV ‐related neoplasia incidence was significantly lower in treated patients among whom no cases were observed, while in the no‐prophylaxis group 6 cases were reported (P = 0.02). Despite a weak level of evidence our study suggests that antiviral prophylaxis could prevent late onset PTLD .     

Antibody‐mediated rejection (AMR) after pancreas and pancreas–kidney transplantation

Antibody‐mediated rejection (AMR) requires specific diagnostic tools and treatment and is associated with lower graft survival. We prospectively screened C4d in pancreas (n = 35, in 27 patients) and kidney (n = 33, in 21 patients) for cause biopsies. Serum amylase and lipase, amylasuria, fasting blood glucose (FBG) and 2‐h capillary glucose (CG) were also analysed. We found that 27.3% of kidney biopsies and 43% of pancreatic biopsies showed C4d staining (66.7% and 53.3% diffuse in peritubular and interacinar capillaries respectively). Isolated exocrine dysfunction was the main indication for pancreas biopsy (54.3%) and was followed by both exocrine and endocrine dysfunctions (37.1%) and isolated endocrine dysfunction (8.6%). Laboratorial parameters were comparable between T‐cell mediated rejection and AMR: amylase 151.5 vs. 149 U/l (P = 0.075), lipase 1120 vs. 1288.5 U/l (P = 0.83), amylasuria variation 46.5 vs. 61% (P = 0.97), FBG 69 vs. 97 mg/dl (P = 0.20) and 2‐h CG maximum 149.5 vs. 197.5 mg/dl (P = 0.49) respectively. Amylasuria values after treatment correlated with pancreas allograft loss (P = 0.015). These data suggest that C4d staining should be routinely investigated when pancreas allograft dysfunction is present because of its high detection rate in cases of rejection.     

Use of tacrolimus and mycophenolate mofetil as induction and maintenance in simultaneous pancreas‐kidney transplantation

Abstract Clinical trials using quadruple immunosuppression that include the combination of tacrolimus and mycophenolate mofetil have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas‐kidney (SPK) transplantation. In an attempt to obtain a low rejection rate without antibody induction therapy, we undertook a prospective study of combined tacrolimus and mycophenolate mofetil and steroids as primary immunosuppression for SPK transplantation. In this study, we analyzed 17 patients who received low‐dose intravenous tacrolimus as induction therapy. This was combined with oral tacrolimus, mycophenolate mofetil, and steroids as the primary immunosuppression regimen. There was a significant reduction of empirically and biopsy‐proven rejection with an incidence of 23 % (4 patients). Leukopenia, gastroparesis, and gastrointestinal side‐effects were the cause of discontinuation of mycophenolate mofetil, or low tacrolimus trough level in those patients who developed rejection. All rejection episodes were easy to treat, and none of them required antibody therapy. The combination of tacrolimus with mycophenolate mofetil without antibody induction therapy is effective in preventing early acute rejection. This combination is safe and effective as an alternative immunosuppressive regimen after SPK transplantation.     

Performances of creatinine‐based glomerular filtration rate estimating equations in simultaneous pancreas‐kidney transplant recipients: a single center cohort study

Estimating glomerular filtration rate (GFR) is important for clinical management and research studies in simultaneous pancreas‐kidney transplantation (SPK) recipients. No study has specifically investigated the reliability of recent creatinine–based GFR estimating equations in this singular population. We assessed the performances of CKD‐EPI, MDRD, Schwartz‐2009, Schwartz‐Lyon, Lund‐Malmo and Full Age Spectrum equations for estimating GFR after SPK. 126 patients were included. GFR was measured by a reference method (mGFR) one year after SPK and estimated with the different equations from a standardized measure of serum creatinine. Relative bias, precisions, 10% and 30% accuracies (P30) were used to determine equations reliability. Ages ranged from 29 to 58. Mean mGFR was 56.3 ± 13.3 [23.6–92.5] ml/min/1.73 m². In the whole population, P30 of the CKD‐EPI and MDRD equations were 42% (38.0; 46.0) and 65% (61.5; 69) respectively. As compared to the other equations, the Schwartz‐Lyon equation was significantly more accurate (P30 = 86.0% [83.5–88.0], P < 0.01) and less biased (1.13 [1.06–1.19], P < 0.01). Conclusions were similar whatever the age class (<40 or ≥40) and mGFR level (<60 or ≥60 ml/min/1.73 m²). This study suggests that the CKD‐EPI and MDRD equations have poor performances in SPK recipients and that the Schwartz‐Lyon equation is a reliable alternative.