L. Frimat

Impact of Cyclosporine Reduction With MMF: A Randomized Trial in Chronic Allograft Dysfunction. The ‘Reference’ Study

Long‐term use of calcineurine inhibitors (CNIs) may contribute to the development of chronic allograft dysfunction (CAD). We investigate the impact of the introduction of MMF combined with cyclosporine (CsA) 50% dose reduction. An open, randomized, controlled, multicenter, prospective study was conducted in 103 patients, receiving a CsA‐based therapy with a serum creatinine between 1.7–3.4 mg/dL, more than 1 year after transplantation. They were randomized to receive MMF with half dose of CsA (MMF group) or to continue their maintenance CsA dose (control group). A total of 96 weeks after randomization, the evolution of renal function assessed by regression line analysis of 1/SeCr improved in the MMF group (positive slope) vs. the control group (negative slope), 4.2 × 10−4 vs. −3.0 × 10−4, respectively (p < 0.001). Concurrently, the absolute renal function improved significantly in the MMF group. No episode of biopsy‐proven acute rejection occurred. One patient in each group lost his graft because of biopsy‐proven chronic allograft nephropathy. There was a significant decrease of triglycerides level in the MMF group. Anemia and diarrhea were statistically more frequent in the MMF group.

Five-Year Metabolic, Functional, and Safety Results of Patients With Type 1 Diabetes Transplanted With Allogenic Islets Within the Swiss-French GRAGIL Network

OBJECTIVE To describe the 5-year outcomes of islet transplantation within the Swiss-French GRAGIL Network. RESEARCH DESIGN AND METHODS Retrospective analysis of all subjects enrolled in the GRAGIL-1c and GRAGIL-2 islet transplantation trials. Parameters related to metabolic control, graft function, and safety outcomes were studied. RESULTS Forty-four patients received islet transplantation (islet transplantation alone [ITA] 24 patients [54.5%], islet after kidney [IAK] transplantation 20 patients [45.5%]) between September 2003 and April 2010. Recipients received a total islet mass of 9,715.75 ± 3,444.40 IEQ/kg. Thirty-four patients completed a 5-year follow-up, and 10 patients completed a 4-year follow-up. At 1, 4, and 5 years after islet transplantation, respectively, 83%, 67%, and 58% of the ITA recipients and 80%, 70%, and 60% of the IAK transplant recipients reached HbA1c under 7% (53 mmol/mol) and were free of severe hypoglycemia, while none of the ITA recipients and only 10% of the IAK transplant recipients met this composite criterion at the preinfusion stage. Thirty-three of 44 patients (75%) experienced insulin independence during the entire follow-up period, with a median duration of insulin independence of 19.25 months (interquartile range 2–58). Twenty-nine of 44 recipients (66%) exhibited at least one adverse event; 18 of 55 adverse events (33%) were possibly related to immunosuppression; and complications related to the islet infusion (n = 84) occurred in 10 recipients (11.9%). CONCLUSIONS In a large cohort with a 5-year follow-up and in a multicenter network setting, islet transplantation was safe and efficient in restoring good and lasting glycemic control and preventing severe hypoglycemia in patients with type 1 diabetes.

ATG‐Induced Accelerated Immune Senescence: Clinical Implications in Renal Transplant Recipients

Persistent ATG‐induced CD4+ T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one‐year later in 97 incident RTR −62 patients receiving ATG and 35 receiving anti‐CD25 mAb (α‐CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34+ hematopoietic progenitor cells (CD34+HPC) and lymphoid (l‐HPC) and myeloid (m‐HPC) progenitor ratio; (iii) T cell phenotype; and (iv) measurement of T cell relative telomere length (RTL) and telomerase activity (RTA). Clinical correlates were analyzed with a 3 year follow‐up. Thymic output significantly decreased one‐year posttransplant in ATG‐treated patients. ATG was associated with a significant decrease in l‐HPC/m‐HPC ratio. Late stage differentiated CD57+/CD28− T cells increased in ATG‐treated patients. One‐year posttransplant T cell RTL and RTA were consequently lower in ATG‐treated patients. ATG is associated with accelerated immune senescence. Increased frequency of late differentiated CD4+ T cell frequency at transplantation tended to be predictive of a higher risk of subsequent opportunistic infections and of acute rejection only in ATG‐treated patients but this needs confirmation. Considering pretransplant immune profile may help to select those patients who may benefit from ATG to prevent severe infections and acute rejection.

Impact of the number of infusions on 2-year results of islet-after-kidney transplantation in the GRAGIL network.

Background. Insulin independence after islet transplantation is generally achieved after multiple infusions. However, single infusion would increase the number of recipients. Our aim was to evaluate the results of islet-after-kidney transplantation according to the number of infusions. Methods. Islets were isolated at the Geneva University, shipped, and transplanted into French patients from the Swiss-French GRAGIL network, on the “Edmonton” immunosuppression protocol between 2004 and 2010. Results. Nineteen patients were transplanted with 33 preparations. Fifteen patients reached 24 months follow-up; eight subjects were single-graft recipients and seven were double-graft recipients. Finally, single-graft recipients received a median of 5312 islet equivalents/kg (5186–6388) vs. 10,564 (10,054–11,375) for double-graft recipients (P=0.0003) with similar islet mass at first infusion. Insulin independence was achieved in five of eight single-graft subjects (62.5%) versus five of seven in double-graft subjects (71.4%), not significant. Median insulin independence duration was 4.7 (3.1–15.2) months after one infusion vs. 19 (9.6–20.8) months after two infusions (not significant). At 24 months posttransplant, comparing single- with double-graft patients, insulin doses were 0.23 (0.11–0.34) U/kg vs. 0.02 (0.0–0.23) U/kg, P=0.11; HbA1c was 6.5% (5.9%–6.8%) vs. 6.2% (5.9%–6.3%), P=0.16; and basal C-peptide was 302 (143–480) pmol/L vs. 599 (393–806) pmol/L, P=0.05. Only 37.5% of single-graft patients had a &bgr;-score ≥4 compared with 100% of double-graft patients (P=0.03). Two recipients experienced postinfusion bleeding, and two patients (13%) showed renal dysfunction in the absence of biopsy-proven rejection. Conclusions. One infusion achieves good glycemic control and sometimes insulin independence. However, double-graft patients remain insulin-free longer, tend to have lower HbA1c, and show better graft function 24 months after transplant.

Impact of pre‐transplant dialysis modality on post‐transplant diabetes mellitus after kidney transplantation

Courivaud C, Ladrière M, Toupance O, Caillard S, de Ligny BH, Ryckelynck J‐P, Moulin B, Rieu P, Frimat L, Chalopin J‐M, Chauvé S, Kazory A, Ducloux D. Impact of pre‐transplant dialysis modality on post‐transplant diabetes mellitus after kidney transplantation.
Clin Transplant 2011: 25: 794–799.

Pre-transplant end-stage renal disease-related immune risk profile in kidney transplant recipients predicts post-transplant infections

End‐stage renal disease (ESRD) is associated with premature aging of the T‐cell system. Nevertheless, the clinical significance of pre‐transplant ESRD‐related immune senescence is unknown.

Is Thyroid Cancer Recurrence Risk Increased After Transplantation

CONTEXT An increased cancer mortality is reported in transplanted patients. OBJECTIVE This multicentric study aimed to investigate the rate of thyroid cancer recurrence after transplantation. RESULTS Sixty-eight patients (35 male/33 female) with a history of both thyroid cancer and organ transplantation were recruited via two nationwide French networks. Histological analysis identified 58 papillary (88%), 5 follicular (7.5%), and 3 poorly differentiated cancer cases (4.5 %). Thirty-one patients (52%) presented high recurrence risk tumors. In the 36 patients with thyroid cancer diagnosed after transplantation, the 5-year disease-free survival (DFS) was 74.7% (SE: 7.3%). One patient died after progression of a poorly differentiated cancer. Persistent disease was observed in six high-risk patients. One of them underwent a second transplantation and disease remained stable after 5 years of follow-up. Thyroid cancer had been diagnosed before transplantation in 32 patients. One patient with cystic fibrosis and thyroid lung metastases at the time of lung transplantation underwent a 4-year remission. For the 31 patients in remission at the time of transplantation, the 5-year DFS was 93.1% (SE: 4.8%). Two patients with local recurrence presented subsequent remission. For the entire study population, the 5-year and 9-year DFS were 81.9% (SE: 5.5%) and 75.6% (SE: 7.9%), respectively. Recurrence or persistent disease occurred in patients with high-risk tumors. CONCLUSIONS The prognosis of thyroid cancer does not seem to be altered by transplantation. This suggests that a history of thyroid cancer should not be considered a contraindication.

Pretransplant thymic function predicts acute rejection in antithymocyte globulin–treated renal transplant recipients

Lack of clear identification of patients at high risk of acute rejection hampers the ability to individualize immunosuppressive therapy. Here we studied whether thymic function may predict acute rejection in antithymocyte globulin (ATG)-treated renal transplant recipients in 482 patients prospectively studied during the first year post-transplant of which 86 patients experienced acute rejection. Only CD45RA(+)CD31(+)CD4(+) T cell (recent thymic emigrant [RTE]) frequency (RTE%) was marginally associated with acute rejection in the whole population. This T-cell subset accounts for 26% of CD4(+) T cells. Pretransplant RTE% was significantly associated with acute rejection in ATG-treated patients (hazard ratio, 1.04; 95% confidence interval, 1.01-1.08) for each increased percent in RTE/CD4(+) T cells), but not in anti-CD25 monoclonal (αCD25 mAb)-treated patients. Acute rejection was significantly more frequent in ATG-treated patients with high pretransplant RTE% (31.2% vs. 16.4%) or absolute number of RTE/mm(3) (31.7 vs. 16.1). This difference was not found in αCD25 monclonal antibody-treated patients. Highest values of both RTE% (>31%, hazard ratio, 2.50; 95% confidence interval, 1.09-5.74) and RTE/mm(3) (>200/mm(3), hazard ratio, 3.71; 95% confidence interval, 1.59-8.70) were predictive of acute rejection in ATG-treated patients but not in patients having received αCD25 monoclonal antibody). Results were confirmed in a retrospective cohort using T-cell receptor excision circle levels as a marker of thymic function. Thus, pretransplant thymic function predicts acute rejection in ATG-treated patients.

Incidence de l’insuffisance rénale chronique en population générale, étude EPIRAN

AIMS To assess incidence of chronic kidney disease in general population and to describe baseline characteristics of incident patients. METHODS Between 1st/01/04 and 30/06/06 all incident cases of chronic kidney disease in the Nancy district were prospectively identified. New cases were identified from all medical laboratories in this area and determined by a persistently increased serum creatinine level (> or = 150micromol/l, or paediatric levels) for 3 months after the 1st/01/04, and by living in Nancy area. RESULTS The annual incidence rate of detected chronic kidney disease was 1 per thousand inhabitants (1,3 per thousand for men and 0,7 per thousand for women). Incidents patients were old (mean age: 77 years) and with numerous comorbidities (diabetes: 34 %, cardiac failure: 23 %). More than 30% of incident patients were diagnosed at sever stage of chronic kidney disease (<30ml/min/1,73m(2)). CONCLUSIONS The annual incidence of diagnosed chronic kidney disease is common: 10 times more than end-stage renal disease in France. Most of these patients are diagnosed in a severe stage of chronic kidney disease whereas they could be detected earlier and benefit from adequate, appropriate and multidisciplinary take care.

Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial

BACKGROUND Islet transplantation is indicated for patients with type 1 diabetes with severe hypoglycaemia or after kidney transplantation. We did a randomised trial to assess the efficacy and safety of islet transplantation compared with insulin therapy in these patients. METHODS In this multicentre, open-label, randomised controlled trial, we randomly assigned (1:1) patients with type 1 diabetes at 15 university hospitals to receive immediate islet transplantation or intensive insulin therapy (followed by delayed islet transplantation). Eligible patients were aged 18-65 years and had severe hypoglycaemia or hypoglycaemia unawareness, or kidney grafts with poor glycaemic control. We used computer-generated randomisation, stratified by centre and type of patient. Islet recipients were scheduled to receive 11 000 islet equivalents per kg bodyweight in one to three infusions. The primary outcome was proportion of patients with a modified β-score (in which an overall score of 0 was not allocated when stimulated C-peptide was negative) of 6 or higher at 6 months after first islet infusion in the immediate transplantation group or 6 months after randomisation in the insulin group. The primary analysis included all patients who received the allocated intervention; safety was assessed in all patients who received islet infusions. This trial is registered with ClinicalTrials.gov, number NCT01148680, and is completed. FINDINGS Between July 8, 2010, and July 29, 2013, 50 patients were randomly assigned to immediate islet transplantation (n=26) or insulin treatment (n=24), of whom three (one in the immediate islet transplantation group and two in the insulin therapy group) did not receive the allocated intervention. Median follow-up was 184 days (IQR 181-186) in the immediate transplantation group and 185 days (172-201) in the insulin therapy group. At 6 months, 16 (64% [95% CI 43-82]) of 25 patients in the immediate islet transplantation group had a modified β-score of 6 or higher versus none (0% [0-15]) of the 22 patients in the insulin group (p<0·0001). At 12 months after first infusion, bleeding complications had occurred in four (7% [2-18]) of 55 infusions, and a decrease in median glomerular filtration rate from 90·5 mL/min (IQR 76·6-94·0) to 71·8 mL/min (59·0-89·0) was observed in islet recipients who had not previously received a kidney graft and from 63·0 mL/min (55·0-71·0) to 57·0 mL/min (45·5-65·1) in islet recipients who had previously received a kidney graft. INTERPRETATION For the indications assessed in this study, islet transplantation effectively improves metabolic outcomes. Although studies with longer-term follow-up are needed, islet transplantation seems to be a valid option for patients with severe, unstable type 1 diabetes who are not responding to intensive medical treatments. However, immunosuppression can affect kidney function, necessitating careful selection of patients. FUNDING Programme Hospitalier de Recherche Clinique grant from the French Government.