Long‐term outcome of belatacept therapy in de novo kidney transplant recipients – a case‐match analysis

While belatacept has shown favorable short‐ and midterm results in kidney transplant recipients, only projections exist regarding its potential impact on long‐term outcome. Therefore, we performed a retrospective case‐match analysis of the 14 belatacept patients originally enrolled in the phase II multicenter trial at our center. Fifty six cyclosporine (CyA)‐treated patients were matched according to age at transplantation, first/retransplant, and donor type. Ten years after kidney transplantation, kidney function remained superior in belatacept‐treated patients compared with the CyA control group. Moreover, none of the belatacept‐treated patients had donor‐specific antibodies ≥10 years post‐transplantation compared with 38.5% of tested CyA‐treated subject (0/10 vs. 5/13; P = 0.045). Notably, however, patient and graft survival was virtually identical in both groups (71.4% vs. 71.3%; P = 0.976). In the present single‐center study population, patients treated with belatacept demonstrated a patient and graft survival at 10 years post‐transplant which was comparable to that of similarly selected CNI‐treated patients. Larger studies with sufficient statistical power are necessary to definitively determine long‐term graft survival with belatacept.     

Long‐term outcome of pediatric renal transplantation: a single center experience

Abe T, Ichimaru N, Kakuta Y, Okumi M, Imamura R, Isaka Y, Takahara S, Kokado Y, Okuyama A. Long‐term outcome of pediatric renal transplantation: a single center experience.
Clin Transplant 2011: 25: 388–394. © 2010 John Wiley & Sons A/S. Abstract: Renal transplantation is the optimal treatment for pediatric end‐stage renal disease. We examined 51 children <20 yr old who underwent a total of 52 living‐donor renal transplantations at Osaka University Hospital between 1972 and 2004. The mean age at transplantation was 13.7 (3–19 yr). The mean duration of follow‐up was 16.5 yr. The five‐, 10‐, and 20‐yr patient survival rates following renal transplantation were 94%, 90%, and 87%, respectively. The five‐, 10‐, and 20‐yr graft survival rates were 76%, 65%, and 48%, respectively. A double‐drug regimen was used before 1987; this was replaced by a triple‐drug regimen including a calcineurin inhibitor in 1988. The five‐, 10‐, and 20‐yr graft survival rates after 1988 (89%, 80%, and 60%, respectively) were higher than those before 1987. Growth was examined among patients <15 yr old at the time of surgery, and height standard deviation (SD) scores (Z‐scores) were analyzed in 14 patients who displayed favorable renal function after transplantation. At the time of transplantation, mean SD score (SDS) was ?2.39, and mean final adult SDS was ?1.79. Rates of patient and graft survival after renal transplantation were mostly favorable. Future goals must include overcoming chronic rejection and establishing a steroid discontinuation protocol to improve growth.     

Long‐term dosing patterns of enteric‐coated mycophenolate sodium or mycophenolate mofetil with tacrolimus after renal transplantation

MORE was a four‐yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric‐coated mycophenolate sodium (EC‐MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC‐MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy‐proven acute rejection, graft loss or death to be similar for EC‐MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC‐MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC‐MPS and MMF cohorts during follow‐up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC‐MPS vs. MMF, without an increase in adverse events.     

Long‐term outcomes of donation after cardiac death liver allografts from a single center

Abstract: Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non‐heart‐beating or donation after cardiac death (DCD) are encouraging. However, long‐term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow‐up >4.5 years. During 1998–2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart‐beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non‐function and biliary complications as compared with SCD and ECD. The overall one‐, two‐, and five‐yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long‐term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.     

Ten‐year observational follow‐up of a randomized trial comparing cyclosporine and tacrolimus therapy combined with steroid withdrawal in living‐donor renal transplantation

Although various strategies for steroid withdrawal after transplantation have been attempted, there are few reports of the long‐term results of steroid withdrawal regimens in kidney transplantation. Earlier, we reported on a 5‐year prospective, randomized, single‐center trial comparing the safety and efficacy of cyclosporine (CsA) plus mycophenolate mofetil (MMF) with that of tacrolimus (TAC) plus MMF, when steroids were withdrawn 6 months after kidney transplantation in low‐risk patients. We now report the 10‐year observational data on the study population. We collected data from the database of the Organ Transplantation Center, Samsung Medical Center for 5 years after completion of the original study (TAC group n = 62; CsA group n = 55). The 10‐year patient survival, death‐censored graft survival, and acute rejection‐free survival did not differ between groups (98% vs 96%; P = 0.49, 78% vs 85%; P = 0.75 and 84% vs 76%; P = 0.14 in the TAC group vs CsA group, respectively). In low‐risk patients, there was no difference in long‐term patient and graft survival between TAC‐ and CsA‐based late steroid withdrawal regimens that included MMF treatment. More long‐term randomized clinical trials are needed to clarify the benefits of late steroid withdrawal in kidney transplantation.     

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10‐year postrandomization follow‐up study

Long‐term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post‐transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients’ survival was 100%, 94.2%, and 95.8% (P = 0.25), and death‐censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m², respectively (P = 0.16). The incidence of biopsy‐proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus‐associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody‐mediated rejection (n = 6). De novo donor‐specific antibodies were detected in 13% of AZA‐, 21% of MMF‐, and 14% of CsA‐treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well‐selected renal transplant recipient ( ClinicalTrials.gov number: 980654).     

Progressive improvement in short‐, medium‐ and long‐term graft survival in kidney transplantation patients in Ireland – a retrospective study

It is often quoted that while short‐term graft survival in kidney transplantation has improved in recent years, it has not translated into a commensurate improvement in long‐term graft survival. We considered whether this was true of the entire experience of the national kidney transplant program in Ireland. A retrospective analysis of the National Kidney Transplant Service (NKTS) database was undertaken to investigate patient and graft survival for all adult first deceased donor kidney transplant recipients in Ireland, 1971–2015. Three thousand two hundred and sixty recipients were included in this study. Kaplan–Meier methods were used to estimate survival at each time period post transplant for the various eras of transplantation. Uncensored graft survival has improved over the course of the program in Ireland at various time points despite risk factors for graft failure progressively increasing over successive eras. For example the graft survival at 15 years post transplant has increased from 10% in 1971–1975 to 45% by 1996–2000. Ireland has experienced a progressive improvement in long‐term graft survival following kidney transplantation. Whether these trends are attributable to biological or nonbiological factors is unclear but likely involves a combination of both.     

Long‐term graft function with tacrolimus and cyclosporine in renal transplantation: Paired kidney analysis

Aim: The first prospective, randomized trial with paired kidney analysis was conducted to compare the efficacy and safety of tacrolimus with cyclosporine‐based immunosuppressive therapy in renal transplant recipients. This paper reports the long‐term follow‐up results of the authors' previously published study, with the main focus on graft survival and renal function. Methods: Chinese patients transplanted in our centre between June 1998 and June 2005 with their first deceased renal transplant were included. Patients were included if both kidneys were received by the authors' centre, thus allowing a paired analysis. Patients were randomized to receive triple immunosuppressive therapy with either tacrolimus or Neoral cyclosporine, concomitantly with prednisolone and azathioprine therapy. Results: Seventy‐six patients received cadaveric kidneys from 38 donors. Each pair of kidneys was randomly assigned to a separate group (38 subjects/group). The mean follow‐up duration was 6.1 ± 1.8 years. The mean calculated creatinine clearance was significantly higher in patients receiving tacrolimus‐based therapy. The rate of biopsy‐proven acute rejection was lower in the tacrolimus group (18.4% vs 42.1%, P = 0.03). The patient and graft survival were comparable in both treatment arms. Significantly fewer patients on tacrolimus‐based therapy developed hypercholesterolaemia (P = 0.05). However, there was no significant difference in the development of post‐transplant diabetes mellitus, hypertension, opportunistic infection and malignancy between both groups. Conclusion: Using the immunosuppressive regimen, tacrolimus‐based therapy provided adequate immunosuppression with better renal function and less acute rejection, as compared with cyclosporine‐based therapy.     

Long‐term patient survival and kidney allograft survival in post‐transplant diabetes mellitus: a single‐center retrospective study

A decade ago, observations suggested that post‐transplant diabetes mellitus (PTDM) was linked to allograft loss and shorter patient survival. Increasing awareness, improvements in care, and changes in the immunosuppressive regimen may have modified this association. Single‐center analysis of 1990 (age>18; transplantation date 1996–2012) primary kidney recipients (KTR). Patients with <12 months follow‐up were excluded. Diabetes was diagnosed according to ADA criteria and characterized as follows: No diabetes, PTDM in the first post‐transplant year not treated with glucose‐lowering medications (GLM) at 12 months, PTDM in the first post‐transplant year treated with GLM at 12 months, and pretransplant diabetes. Cox proportional hazards models were used to examine the relationship of PTDM with allograft and patient survival. Mean follow‐up time was 6.8 years for allograft survival and 7.4 years for patient survival. PTDM treated with medication at year one was not associated with allograft survival (HR 1.28, 95% CI 0.97–1.69), but was significantly associated with overall mortality and death with functioning graft (DWFG) (HR overall: 1.81, 95% CI 1.36–2.39; HR DWFG: 1.59 95% CI 1.05–2.38). In this cohort, KTR with PTDM being treated with glucose‐lowering medication at 12 months experienced significantly shorter overall survival and survival with functioning graft.     

Randomized trial of cyclosporine and tacrolimus therapy with steroid withdrawal in living‐donor renal transplantation: 5‐year follow‐up

The aim of this study was to compare the long‐term safety and efficacy of immunosuppressive regimens consisting of cyclosporine (CsA) plus mycophenolate mofetil (MMF) or tacrolimus (TAC) plus MMF after steroid withdrawal 6 months after kidney transplantation in low‐risk patients. One hundred and thirty‐one patients were randomized to receive either CsA (n = 63) or TAC (n = 68). Of these, 117 patients satisfied the criteria for steroid withdrawal (no biopsy‐proven rejection episode and serum creatinine level <2.0 mg/dl 6 months after transplantation). Fifty‐five recipients were of the CsA group, and 62 were of the TAC group. The 5‐year graft survival rate did not differ between groups (90.5% vs. 93.3% respectively; P = 0.55). The cumulative incidence of acute rejection 5 years after transplantation was 16.4% and 8.1% for the CsA and TAC groups respectively (P = 0.15). Post‐transplantation diabetes mellitus was more frequent in the TAC group than in the CsA group (P = 0.05), but the incidence of other side‐effects did not differ between groups. In conclusion, CsA‐ and TAC‐based regimens in conjunction with MMF have similar patient‐ and graft survival rates in low‐risk patients who underwent steroid withdrawal 6 months after kidney transplantation.     

Four-year follow-up of a prospective randomized trial of mycophenolate mofetil with cyclosporine microemulsion or tacrolimus following liver transplantation

BACKGROUND: This is a 4-yr follow-up of a trial using mycophenolate mofetil (MMF) induction in orthotopic liver transplantation (OLT). The goal of this study was to evaluate a multidrug approach that would reduce both early and long-term morbidity related to immunosuppression while maintaining an acceptable freedom from rejection. METHODS: This was a prospective, randomized, intent to treat study designed to compare the primary endpoints of rejection and infection, and secondary endpoints of liver function, renal function, bone marrow function, cardiovascular risk factors, and the recurrence of hepatitis C. Ninety-nine consecutive patients with end stage liver disease who underwent OLT were randomized to receive either cyclosporine microemulsion (N) (50 patients) or tacrolimus (FK) (49 patients) starting on postoperative day 2, with MMF and an identical steroid taper begun preoperatively. RESULTS: Ninety of 99 patients (N 46, FK 44) completed the 4-yr follow-up. The overall 4-yr patient and graft survivals were 93 and 89%, respectively. There was no significant difference in 4-yr patient (N 96% vs. FK 90%, p = ns) or graft (N, 90% vs. FK, 88%, p = ns) survival between groups. The 4-yr rejection rate was not significantly different in either arm (N = 34%, FK = 24%; p = 0.28). There were no differences in infection rates in either arm. The patients with hepatitis C had no differences in the viral titers or Knodell biopsy scores between groups. However, in the hepatitis C subgroup (37 patients), the FK patients had a significantly lower rejection rate (p = 0.0097) and a significantly lower clinically recurrent hepatitis C rate (p = 0.05) than the N patients. No difference was seen in the percent of patients weaned off of steroids after 4 yr (N 51%, FK 49%). There were no differences in the incidences of diabetes mellitus and hypertension. When renal dysfunction was analyzed, a significant difference in the number of patients whose creatinine had increased twofold since transplant was seen (N 63%, FK 38%, p = 0.04). CONCLUSIONS: Use of MMF induction and maintenance following OLT in conjunction with either N or FK and an identical steroid taper, resulted in an acceptable long-term incidence of rejection and infection, without an increase in long-term graft or patient morbidity.     

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.     

Steroid withdrawal at 3 months after kidney transplantation: a comparison of two tacrolimus-based regimens

The 6 month prospective, randomized study compared the steroid-sparing potential of two tacrolimus-based regimens after renal transplantation. A total of 489 patients were randomized (1:1) to receive tacrolimus/mycophenolate mofetil (MMF)/steroids (n = 243; group Tac/MMF/S) or tacrolimus/azathioprine/steroids (n = 246; group Tac/Aza/S). At 3 months, steroids were tapered off in 267 (54.6%) patients free from steroid-resistant acute rejection and with serum creatinine concentrations <160 micromol/l. The incidence of biopsy-confirmed acute rejection at month 3 was lower in group Tac/MMF/S compared with group Tac/Aza/S (18.1% vs. 26.0%,P = 0.035). Moreover, more patients in the Tac/MMF/S group met the criteria for steroid withdrawal than in the Tac/Aza/S group (60.5% vs. 48.8%; P < 0.01). The incidence of acute rejection during months 4-6 was low in all groups, both for patients on steroid-free dual therapy (Tac/MMF: 2.7%, Tac/Aza: 0.8%) and for patients who continued steroid maintenance therapy (Tac/MMF/S: 3.5%, Tac/Aza/S: 7.1%). Moreover, kidney function was well preserved in steroid-free patients with month 6 median serum creatinine levels of 119.5 micromol/l (Tac/MMF), and 115.1 micromol/l (Tac/Aza). For patients who continued to receive steroids, month 6 median creatinine levels were 130.5 micromol/l (Tac/MMF/S) and 132.8 micromol/l (Tac/Aza/S). The criteria for the selection of patients to discontinue steroids were adequate. Both tacrolimus-based regimens allowed the safe discontinuation of steroids in low-risk patients at month 3. The Tac/MMF combination was superior in the prevention of acute rejections and more patients met the chosen criteria for steroid withdrawal.     

Pancreas and kidney transplantation: long‐term endocrine function

Mora M, Ricart MJ, Casamitjana R, Astudillo E, López I, Jiménez A, Fernández‐Cruz L, Esmatjes E. Pancreas and kidney transplantation: long‐term endocrine function.
Clin Transplant 2010: 24: E236–E240. © 2010 John Wiley & Sons A/S. Abstract: Objective: To describe the characteristics of metabolic control and beta‐cell function in the long‐term follow‐up of patients with type‐1 diabetes (T1D) who have undergone pancreas and kidney transplantation (PKTx). Patients and methods: Twelve patients (eight males/four females) with normal pancreas and kidney graft function for more than 15 yr were included. Patient age at the time of transplantation was 35.8 ± 6.9, with a duration of diabetes of 19.0 ± 4.6 yr and time on dialysis of 18.7 ± 12.4 months. In all the cases, bladder derivation was performed to drain exocrine secretion, with subsequent conversion to the intestinal tract in 42% of the patients. The functional evaluation was made at one, five, 10, and 15 yr after PKTx determining: glycosylated hemoglobin (HbA1c), oral glucose tolerance test (OGTT), measuring insulinemia, and anti‐GAD antibody. Results: Comparing the results between one and 15 yr after transplantation: (i) no differences were observed in either HbA1c (4.68% vs. 4.76%) or basal glycemia (71 vs. 79 mg/dL), but an increase was seen in the area under the curve (AUC) of glucose (11 983 vs. 15 875 mg/dL/120′, p = 0.02); (ii) a trend to a reduction in basal insulinemia (24 vs. 15 mU/L, p = 0.11) and a trend to a reduction in the AUC of insulinemia (8446 vs. 7057 mU/L/120′, p = 0.22) were observed. The OGTT was normal in six patients, intolerant in two and diabetic in four patients. No variations were seen in insulin resistance (FIRI, QUICKI). Anti‐GAD antibody became positive in one case. Conclusions: The results of this study demonstrate that pancreas transplantation has long‐term functional viability, being an essential strategy for the treatment of patients with T1D with end‐stage renal failure. Nevertheless, lesser response to OGTT can be expected suggesting certain deterioration in the functional capability of the pancreas graft during follow‐up.     

Tacrolimus plus mycophenolate mofetil vs. cyclosporine plus everolimus in deceased donor kidney transplant recipients: three‐yr results of a single‐center prospective clinical trial

We compared in kidney transplantation two immunosuppressive regimens: tacrolimus plus mycophenolate mofetil (MMF) (TAC) and everolimus plus low‐dose cyclosporine (EVE). Sixty consecutive patients received TAC (30 patients) or EVE (30 patients) as immunosuppressive regimen; all subjects also received induction with basiliximab and corticosteroids. After three‐yr follow‐up, no difference was found in patient and graft survival (PTS: TAC: 97% vs. EVE: 100%; GS: TAC: 93% vs. EVE: 93%). The incidence of acute rejection was higher in the EVE group but the difference was not statistically significant (17% vs. 23%, p = ns). Patients in EVE showed higher serum cholesterol (205 ± 41 vs. 235 ± 41 mg/dL, p = 0.0012) and lower hemoglobin concentration (13.6 ± 1.4 vs. 12.4 ± 1.9, p = 0.01). Renal function was not significantly different in the two groups (3 Y creatinine: TAC 1.4 ± 0.8 vs. EVE 1.6 ± 0.8 mg/dL, p = ns). Treatment discontinuation was higher in the EVE group (TAC 17 vs. EVE 36%, p = ns). Our data show that in the middle‐term follow‐up, an immunosuppressive regimen with tacrolimus plus MMF has a similar efficacy and safety profile in comparison with the combination of low‐exposure cyclosporine plus everolimus. Further follow up could evidence the benefits related to the anti‐proliferative effects of everolimus.     

Long‐term survival after kidney transplantation in an HIV‐positive patient

Abstract: Only a decade ago, human immunodeficiency virus (HIV)‐seropositivity was considered an absolute contraindication for organ transplantation. With the currently available experience, it is no longer justified to deny HIV‐positive patients access to transplantation. To the best of our knowledge, we here present the longest surviving HIV‐positive patient after renal transplantation. The follow‐up period after renal transplantation in this HIV‐positive female is now 13 yr and she is in good general condition with excellent renal function. Throughout her post‐transplant follow‐up, we encountered a number of problems that are illustrative of the HIV‐positive patient.