[Acute renal failure of the donor in encephalic death: A real contraindication to kidney transplantation?] / L'insuffisance rénale aiguë du donneur en mort encéphalique : une réelle contre-indication à la transplantation rénale ?

INTRODUCTION: The shortage of kidney transplants encourages the expansion of the limits of eligibility criteria for donation. Many donors who are brain dead display acute renal failure at the time of death; is this a real contraindication to harvesting? The aim of this study was to assess kidney graft survival from donors after brain death with confirmed acute renal failure, with or without anuria previous donation. MATERIALS AND METHODS: All of the transplants performed in two university hospitals between 2010 and 2017 were analyzed retrospectively. All patients who underwent single kidney transplant from a brain-dead donor with acute renal failure (ARF) were included in this study. ARI was defined here by a decrease over 50 % of glomerular filtration rate (GFR) to a threshold below 45mL/min/1.73 m2 at the time of kidney procurement. Kidney graft survival, incidence of delayed graft function (DGF) and the GFR at 12 months were analyzed. Analysis of kidney transplant survival based on pre-implantation biopsies was additionally done. RESULTS: One hundred and sixty four patients were transplanted with a kidney from donor with ARF during the selected period. At the admission in ICU the average GFR was 67,7±19mL/min/1,73m2. At the time of donation, the average age of donors was 56.4±17.7 years, the GFR was 33.7±8.0mL/min/1.73 m2 16 % of donors were anuric. Cold ischemia time (CIT) was 16.8±5.0hours. The average age of recipients was 55.6±14.1 years. 81 % of the cases were primary transplants. Graft function took place within 7.8±9.4 days after transplantation. There were two non-primary functions (PNF). One hundred and fifty two patients (93 %) had a functional graft at 12 months. The mean GFR at 12 months was 46.8±20.1mL/min/1.73 m2 and 122 patients (73 %) had a GFR greater than 30mL/min/1.73 m2. Seventy-one percent of preimplantation biopsies revealed acute tubular necrosis (ATU); no cortical necrosis was observed. Survival of theses grafts was 85 %, comparable to the total population of study (P=0,21) CONCLUSION: The acute renal failure of the brain-dead donor should not alone be systematically a contraindication to harvesting and kidney transplantation.

Management of vascular and nonvascular complications following pancreas transplantation with interventional radiology.

Pancreas transplantation exposes to high rates of complications, either vascular (thrombosis, stenosis, pseudoaneurysm, arteriovenous fistula) or nonvascular (fluid collection, graft rejection). With advances in percutaneous and endovascular techniques, interventional radiologists are increasingly involved in the management of these complications. In this article, we review the anatomical considerations relevant to pancreas transplantation, the techniques used for image-guided interventions for vascular and nonvascular complications, and the expected outcomes of these interventions.

Hypothermic pulsatile perfusion of human pancreas: Preliminary technical feasibility study based on histology.

BACKGROUND: There are currently two approaches to hypothermic preservation for most solid organs: static or dynamic. Cold storage is the main method used for static storage (SS), while hypothermic pulsatile perfusion (HPP) and other machine perfusion-based methods, such as normothermic machine perfusion and oxygen persufflation, are the methods used for dynamic preservation. HPP is currently approved for kidney transplantation. METHODS: We evaluated, for the first time, the feasibility of HPP on 11 human pancreases contraindicated for clinical transplantation because of advanced age and/or history of severe alcoholism and/or abnormal laboratory tests. Two pancreases were used as SS controls, pancreas splitting was performed on 2 other pancreases for SS and HPP and 7 pancreases were tested for HPP. HPP preservation lasted 24 h at 25 mmHg. Resistance index was continuously monitored and pancreas and duodenum histology was evaluated every 6 h. RESULTS: The main finding was the complete absence of edema of the pancreas and duodenum at all time-points during HPP. Insulin, glucagon and somatostatin staining was normal. Resistance index decreased during the first 12 h and remained stable thereafter. CONCLUSION: 24 h hypothermic pulsatile perfusion of marginal human pancreas-duodenum organs was feasible with no deleterious parenchymal effect. These observations encourage us to further develop this technique and evaluate the safety of HPP after clinical transplantation.

Liraglutide in whole-pancreas transplant patients with impaired glucose homoeostasis: A case series.

Hyperglycaemia may develop after whole-pancreas transplantation (PTX) in patients with type 1 diabetes mellitus (T1DM), but the efficacy and tolerability of GLP-1 receptor agonists have not been assessed in this population. This report is a 6-month prospective follow-up of six T1DM recipients of PTX (mean time after PTX: 68.8 ± 45.7 months), all of whom had an HbA1c>6.5% (48 mmol/mol) [mean: 7.1% (54 mmol/mol)] after initiation of liraglutide alone at 0.6 mg once daily titrated to 1.2mg once daily at week 1. Gastrointestinal disorders were reported in three of the six patients, with discontinuation of liraglutide in only one patient. HbA1c improved in the five remaining patients, with a median decrease of 0.8% (0.0-2.7%) at 6 months, and the median decrease in body weight was 2.0 kg. Immunosuppressive treatments remained unchanged with liraglutide. Thus, liraglutide appears to be an effective and well-tolerated option in PTX patients with impaired glucose homoeostasis, regardless of the cause.

Early corticosteroid avoidance in kidney transplant recipients receiving ATG-F induction: 5-year actual results of a prospective and randomized study.

One hundred ninety-seven patients received anti-T-lymphocyte globulins Fresenius, mycophenolate mofetil and delayed cyclosporine, and were randomized to ≥6-month corticosteroids (+CS; n=99) or no CS (-CS; n=98). One- and five-year actual graft survival (censored for death) was 93.2% and 86.4% in the +CS group versus 94.9% and 89.8% in the -CS group (5-year follow-up, p=0.487). Freedom from clinical rejection was 86.9% and 81.8% versus 74.5% and 74.5% (p=0.144), respectively, at 1 and 5 years; 5-year freedom from biopsy-proven rejection was 88.9% versus 83.7% (p=0.227). More late first rejections occurred in the +CS group. Significantly lower 5-year graft survival in patients experiencing rejection was observed for +CS (55.6% vs. 92.0%; p=0.005) with 8/18 versus 2/25 graft losses. Renal function at 5 years was stable and comparable (median serum creatinine, 159 vs. 145 µmol/L; creatinine clearance, 53.5 vs. 56.6 mL/min). More +CS patients developed diabetes, dyslipidemia and malignancies. Rejections in -CS patients occurred early after transplantation and did not impair long-term renal function. In patients receiving CS, rejections occurred later and with a higher risk for subsequent graft failure. A similar and not inferior 5-year efficacy profile and a reduced morbidity were observed in CS-free patients compared to patients who received CS for at least 6 months.

Early steroid withdrawal compared with steroid avoidance correlates with graft failure among kidney transplant recipients with an history of diabetes.

BACKGROUND: Steroid minimization strategies attempt to reduce morbidity in kidney transplantation. Concern still exists regarding long-term outcomes using either steroid withdrawal or steroid avoidance regimens. METHODS: During a 10-year period, 572 primary kidney transplant recipients were treated with basiliximab, calcineurin inhibitors, and mycophenolate mofetil: 417 (72.9%) underwent a steroid-taper regimen over 2-3 months (steroid withdrawal) and 155 (27.1%), complete steroid avoidance (steroid avoidance). RESULTS: Despite no significant difference during the first 3 months (hazard ratio [HR], 1.23; P = .5349), steroid withdrawal recipients showed an increased risk of late acute rejection episodes (HR, 4.06; P = .0585), independent of recipient age >55 years (HR, 1.84; P = .0272). The risk of any adverse event was not different among steroid regimen groups (HR, 0.98; P = .8458), independent of recipient age >55 years (HR, 1.69; P = .0002), delayed graft function (DGF) (HR, 1.54; P = .0001), and positive donor Epstein-Barr virus serology (HR, 0.68; P = .0471). Intention-to-treat analyses revealed a significantly greater risk of graft failure only in diabetic recipients in the steroid withdrawal group (HR, 8.18; P = .0065), independent of confounding risk factors such as recipient age >55 years (HR, 1.99; P = .0244), >4 human leukocyte antigen-A, -B, and -DR incompatibilities (HR, 1.64; P = .0475), and DGF occurrence (HR, 2.63; P < .0001). CONCLUSION: Although both steroid minimization strategies were comparable regarding long-term safety and efficacy, an increased rate of graft failure was observed among diabetics who underwent steroid withdrawal compared with steroid avoidance.

Posttransplant donor-specific anti-HLA antibodies negatively impact pancreas transplantation outcome.

During a 9-year follow-up, 167 consecutive pancreas transplant recipients (152 simultaneous pancreas-kidney [SPK]) were followed for the detection of posttransplant anti-HLA antibodies. Forty patients (24%) developed anti-HLA antibodies, 26 (65%) had donor-specific antibodies (DSA; 61% anticlass 2) and 14 (35%) non-DSA (78.6% anticlass 1). More rejection episodes were observed in patients with positive anti-HLA antibodies than in patients without antibodies (42.5% vs. 11%; p = 0.001), with the highest incidence observed in DSA patients (53.8%). More severe rejections (according to rescue therapy) were observed in DSA patients compared to non-DSA (p < 0.05) or to negative patients (p < 0.001). Contrasting with the kidney, pancreas graft survival did not differ between patients with or without anti-HLA antibodies. On the contrary, pancreas and kidney survivals were significantly lower in DSA positive patients (75% for both organs) as compared to non-DSA positive patients (100% for pancreas and 92% for kidney) or to HLA-negative patients (91% for pancreas and 89% for kidney). Nontechnical pancreas and kidney graft failures were significantly higher in positive than in negative anti-HLA patients (32.5% vs. 11%; p < 0.01). Occurrence of posttransplant DSA was an independent risk factor for both pancreas and kidney survival (HR 3.2; p = 0.039) in diabetic transplant recipients.

Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.

Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel.

Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi-disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell-mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better- or worse-graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody-mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined. The availability of a simple, reproducible, clinically relevant and internationally accepted schema for grading rejection should improve the level of diagnostic accuracy and facilitate communication between all parties involved in the care of pancreas transplant recipients.

[Dialysis-associated spondyloarthropathy. Case report and literature review]. / La spondylarthropathie érosive du dialysé rénal. A propos d'un cas, revue de la littérature.

Hemodialysis has considerably prolonged the life of patients suffering from terminal renal failure. However, long-term hemodialysis leads to new bone complications and spinal disorders such as destructive spondyloarthropathy (DSA). At the present time DSA is reported in 8% to 18% of the dialysed patients. Diagnosis is based on severe narrowing of the intervertebral disk, erosions and geodes of the adjacent vertebral plates simulating infectious spondylitis. Lesions progressively involve posterior joints and may lead to severe destruction of the spine. The pathogenesis of this syndrome is still unknown. Several factors have been implicated, including microcrystal deposition, amyloidosis, inflammatory and foreign body reactions and suggest that the pathogenesis of erosive spondyloarthropathies of hemodialysed patients is multifactorial. Spinal instability inducing myelopathy and radiculopathy were observed in 8% of the cases. Treatment must be accorded to the natural disease course and to the quality of the bone. We report the case of a chronic dialysed patient with destructive spondyloarthropathy involving the cervical and thoracic spine. Pathogenesis, radiological datas and therapeutic approach are discussed.

Prevention of acute rejection with antithymocyte globulin, avoiding corticosteroids, and delaying cyclosporin after renal transplantation.

BACKGROUND: Despite their well-known side-effects, corticosteroids (Cs) are currently used after kidney transplantation. Avoidance of Cs may improve patient quality of life and eventual long-term survival. We report on a regimen using antithymocyte globulin (ATG) and mycophenolate mofetil (MMF) for induction, and cyclosporin (CsA) plus MMF for maintenance treatment of recipients of primary kidney transplantation. METHODS: We studied 11 consecutive, non-sensitized renal transplant patients (nine cadaver and two living donors). Initial immunosuppression consisted of ATG (1.5 mg/kg/day, i.v.) given for 10 days and MMF (1.0 g/b.i.d.). CsA (8 mg/kg, in two divided doses) was started on post-operative day 11. Cs were only allowed in the case of MMF discontinuation, for the treatment of acute rejection, and in the event of recurrence of the primary glomerulonephritis. RESULTS: All patients completed the entire 10-day ATG course. Main side-effects included fever (>38 degrees C) and serum sickness, observed in 73 and 27% of the patients respectively. The incidence of acute rejection was 27% (three of 11 patients). In two patients with acute rejection, serum sickness was concomitantly diagnosed and renal histology was partially compatible with immune-complex disease. The remaining patient had two episodes of low-grade rejection. All rejection episodes were rapidly reversed. Two patients (18%) were treated with ganciclovir for cytomegalovirus (CMV) infection. Two patients (18%) are currently receiving Cs for recurrence of the native glomerulonephritis and two rejection episodes respectively. All patients are currently alive with functioning kidneys (average follow-up of 8.4 months; average creatinine level of 128 micromol/l). CONCLUSION: This pilot study suggests that ATG induction in combination with MMF and delayed introduction of CsA, in the absence of Cs, is not well tolerated in recipients of kidney transplants. An earlier introduction of calcineurin inhibitors and/or a shorter course of ATG may reduce the incidence of fever and serum sickness secondary to ATG.

Clinical relevance of direct quantification of pp65 antigenemia using flow cytometry in solid organ and stem cell transplant recipients.

A total of 1,305 blood samples from 85 solid organ transplant (SOT) recipients and 25 stem cell transplant (SCT) recipients at risk for cytomegalovirus (CMV) infection were prospectively collected and tested using the shell vial assay (SVA) and a leukocytic qualitative PCR (q-PCR). Of these, 462 specimens were further tested by direct quantification of CMV antigenemia by flow cytometry (FC-Ag), 125 were tested with a quantitative competitive PCR, and 200 were tested for pp65 antigenemia using the slide method (S-Ag). Laboratory data were statistically analyzed according to the presence of CMV-related symptoms. In SOT and SCT recipients, active CMV infection occurred in 63.5 and 36%, respectively, and CMV disease occurred in 53 and 24%, respectively. FC-Ag results correlated better with q-PCR and S-Ag than with SVA. The first test found to be positive during follow-up was FC-Ag in 73% of cases. In SOT recipients, FC-Ag showed the highest sensitivity and negative predictive value for the diagnosis of any grade of CMV disease. For FC-Ag, the threshold beyond which CMV disease was highly probable seemed to lie at 0.20% positive polymorphonuclear leukocytes. FC-Ag appears to be a useful test for the early detection of CMV infection and the prediction of CMV disease.

Evaluation of clinical guidelines for the management of end-stage renal disease in europe: the EU BIOMED 1 study.

BACKGROUND: There are wide national and international variations in the management of patients with end-stage renal disease (ESRD). The aim of this study was to develop, harmonize, implement, and evaluate consensus-based clinical guidelines for the management of renal anaemia and renal bone disease in patients with ESRD, and for the prevention and management of cytomegalovirus disease in renal transplant recipients across six renal centres in Europe. METHODS: The trial was a prospective, multicentre, randomized balanced incomplete block design. Nephrologists from the six European renal units were randomized to develop and implement guidelines for two out of the three conditions and to act as a control for the third condition. Data were collected pre- (1 year) and post- (9 months) intervention on aspects of patient monitoring, management, and outcome. RESULTS: Eight hundred and twenty-nine dialysis patients from the six European dialysis centres were included in the study. Multivariate analysis (adjusting for case-mix and secular trends) showed a significant increase in the number of monitoring events in the guideline group compared with control group (6%, 95% CI, 1-11%). There was no concomitant increase in either appropriate management or the number of favourable patient outcomes. CONCLUSIONS: In the first European collaboration on renal guidelines, the introduction of the guidelines improved the monitoring of the patients, but did not improve patient management or outcome. This study suggests the potential for creating clinical guidelines with the aim of standardizing treatment protocols across international boundaries, and improving the quality of the medical care provided.

Low incidence of kidney rejection after simultaneous kidney-pancreas transplantation after antithymocyte globulin induction and in the absence of corticosteroids: results of a prospective pilot study in 28 consecutive cases.

BACKGROUND: Recipients of simultaneous kidney-pancreas transplantation receive a combination of polyclonal antithymocyte globulin (ATG), cyclosporin or tacrolimus, mycophenolate mofetil (MMF) and corticosteroids (Cs). To avoid the side effects and adverse events associated with Cs, we investigated a new immunosuppressive regimen without Cs after simultaneous kidney-pancreas transplantation. METHODS: A total of 28 consecutive patients who underwent simultaneous kidney-pancreas transplantation were included in this study. All patients received ATG, cyclosporin, and MMF. RESULTS: All patients but one tolerated the ATG course well. MMF was definitively discontinued in three patients because of leukopenia. Cytomegalovirus infection was diagnosed in eight patients (28.5%). Only two patients (7%) required an antirejection treatment. Patient, kidney, and pancreas survival is currently 96.4, 96.4, and 75%, respectively. CONCLUSIONS: The combination of ATG, cyclosporin, and MMF, without Cs, was well tolerated. The unexpectedly low (7%) incidence of acute kidney rejection observed suggests that Cs may partially interfere with the immunosuppressive effect of ATG.

Use of reverse transcription polymerase chain reaction with colorimetric plate hybridization to detect a cytomegalovirus late spliced mRNA in polymorphonuclear leukocytes from renal transplant patients.

Human cytomegalovirus replication was evaluated in polymorphonuclear leukocytes from ten renal transplant recipients. Three new reverse transcription polymerase chain reactions with plate hybridization suitable for automation were developed for the detection of immediate-early spliced UL123 mRNA, early-late pp65 mRNA, and late spliced UL22 mRNA. The presence of UL22mRNA was found to be significantly associated with the occurrence of cytomegalovirus (CMV) disease.

Randomized comparison of triple therapy and antithymocyte globulin induction treatment after simultaneous pancreas-kidney transplantation.

BACKGROUND: The incidence of acute rejection is considered to be higher after simultaneous pancreas-kidney (SPK) transplantation as compared to renal transplant alone. Therefore, the majority of SPK transplant recipients commonly receive a combination of cyclosporine (CsA) or tracolimus, and azathioprine or mycophenolic mofetyl, corticosteroids and/or antilymphocyte preparations. This study was designed to compare two immunosuppressive protocols for the prevention of acute rejection in patients undergoing SPK transplantation. The primary end-point was the incidence of acute rejection during the first 12 months after transplantation METHODS: Fifty patients with type-I insulin-dependent diabetes and chronic renal failure were randomized to receive a triple drug immunosuppressive regimen including CsA, azathioprine and corticosteroids (N = 25), or the quadruple sequential combination of rabbit antithymocyte globulin (ATG) given for 10 days, azathioprine, corticosteroids and delayed CsA (N = 25). Maintenance immunosuppression (CsA and azathioprine, without corticosteroids) was similar in both arms. RESULTS: The average follow-up was 36 months in both groups (range 9 to 60 months). No patient was excluded from the study. Although the percentage of patients with adverse events was higher in the ATG group (80 vs. 40%, P < 0.01), none of them resulted in premature discontinuation of the drug. Patients receiving ATG experienced a lower incidence (36% vs. 76%, P < 0.01) and number (13 vs. 29, P < 0.05) of acute renal rejection episodes. However, no difference was observed in patient, pancreas and kidney survival rates between groups. No case of isolated pancreas rejection was observed. CONCLUSIONS: The quadruple sequential combination ATG, azathioprine, corticosteroid and CsA significantly reduced the one year incidence of acute renal rejection after SPK transplantation, compared to a triple immunosuppressive regimen.

Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys.

BACKGROUND: We reviewed 843 first cadaver kidney transplants carried out consecutively at our center to examine the effect on long-term graft survival of the duration of delayed graft function (DGF), defined as the time taken for the kidney to attain the threshold of a Cockcroft calculated creatinine clearance (cCCr) > or = 10 ml/min. METHODS: Using a multivariate Cox survival analysis we evaluated the consequences of DGF on allograft survival, and then by regression analysis identified the factors contributing to the occurrence of DGF. Finally, using a Kaplan Meier analysis we compared the profiles of graft failure according to the duration of DGF. RESULTS: Defining DGF in terms of cCCr rather than necessity for dialysis after transplantation allowed better prediction of long-term graft loss. Indeed, patients with a Cockcroft-based DGF > six days who did not require dialysis (12%) had a significantly poorer long-term graft outcome than those with a DGF < or = six days. Furthermore, we showed that a DGF of six days could be taken as a cut-off point that marked a significant difference in the long-term graft survival rate (P < 0.0001). Surprisingly, further extension of the duration of DGF > six days was not associated with further worsening of graft survival (except in DGF > 30 days). CONCLUSION: Our results suggest a threshold effect in the lesions that ultimately results in long-term functional deficiency. In addition, we show that the need for dialysis is not an adequate criterium for DGF in terms of long-term outcome prediction.

Efficacy Endpoints Conference on Acute Rejection in Kidney Transplantation: review of the conference questionnaire.

Basic differences in the diagnosis and management of acute rejection in renal transplant can be found between centers. A questionnaire was developed to ascertain the profile of these variables. Sixteen fundamental questions were presented to the program directors of 17 transplant groups from around the world. The questions were brief and designed to identify clinical practice and behaviors related to the definition of acute and steroid-resistant rejection, successful response to therapy, use of histological diagnosis, estimated frequency of rejection, and frequency of mild, moderate, or severe acute rejections. Clinicians were presented with case studies and asked to respond to specific questions regarding the rejection management described in these cases to determine similarities in management practices. Results indicated that clinicians relied on clinical symptoms only rarely. Biopsy findings were used by 53% of clinicians, and 94% of clinicians indicated that rejection was suspected if creatinine increased. Successful response was defined as a return to prerejection creatinine level by 77% of clinicians and that steroid-resistant rejection is evident by 5 days. Biopsy was used by 80% of centers to diagnose first acute rejection episode, and only 18% of rejection episodes are expected to be severe. This report was then used to develop a more detailed questionnaire to be used in profiling acute rejection in consecutive transplant recipients.