F. J. Bemelman

Meningococcal Sepsis Complicating Eculizumab Treatment Despite Prior Vaccination

Recently, the monoclonal antibody against complementfactor C5, eculizumab, was successfully applied in the treatment of recurrent atypical hemolytic-uremic syndrome (aHUS) in renal transplant recipients (RTR) (1). Guidelines for its use include meningococcal vaccination prior to treatment. Late complement–pathway– component deficiencies predispose to meningococcal infections by the absence of meningococcal lysis via classical and alternative pathways (2). Consequently, protection against meningococcal disease by antibody-mediated killing becomes essential. However, vaccination of patients using immunosuppressive drugs may be ineffective (3,4). Different immunosuppressive regimens vary in their effects on humoral responses after vaccination. Previously, we demonstrated that RTR treated with prednisolone and everolimus mount adequate humoral vaccination responses, measured by ELISA, against immunocyanin, tetanus-toxoid (TT) and pneumococcal polysaccharide (PPS). In contrast, treatment with mycophenolic mofetil (MMF) and prednisolone completely disturbed vaccination responses against these same antigens (3). Although immune responses after vaccination are generally used as markers of efficacy of vaccination, they are not synonymous with protection. Furthermore, in immunocompromised patients vaccination-induced responses may wane rapidly. Protection provided by vaccines after renal transplantation may be limited in quality and/or duration. This is illustrated by the following case.

Deep Sequencing of Antiviral T-Cell Responses to HCMV and EBV in Humans Reveals a Stable Repertoire That Is Maintained for Many Years

CD8+ T-cell responses against latent viruses can cover considerable portions of the CD8+ T-cell compartment for many decades, yet their initiation and maintenance remains poorly characterized in humans. A key question is whether the clonal repertoire that is raised during the initial antiviral response can be maintained over these long periods. To investigate this we combined next-generation sequencing of the T-cell receptor repertoire with tetramer-sorting to identify, quantify and longitudinally follow virus-specific clones within the CD8+ T-cell compartment. Using this approach we studied primary infections of human cytomegalovirus (hCMV) and Epstein Barr virus (EBV) in renal transplant recipients. For both viruses we found that nearly all virus-specific CD8+ T-cell clones that appeared during the early phase of infection were maintained at high frequencies during the 5-year follow-up and hardly any new anti-viral clones appeared. Both in transplant recipients and in healthy carriers the clones specific for these latent viruses were highly dominant within the CD8+ T-cell receptor Vβ repertoire. These findings suggest that the initial antiviral response in humans is maintained in a stable fashion without signs of contraction or changes of the clonal repertoire.

Donor feces infusion for eradication of Extended Spectrum beta-Lactamase producing Escherichia coli in a patient with end stage renal disease.

In an attempt to decolonise the patient from the ESBL producing E. coli, he underwent donor feces infusion in May 2013. Prior to this intervention, the presence of ESBL producing E. coli in the large intestine was again confirmed by a positive rectal culture. In addition his throat and perineum were also screened for the presence of ESBL producing Enterobacteriaceae, but both were negative. Culture of the urine was not possible because of the anuric condition of the patient. The donor feces infusion was performed according to the protocol as used in the FECAL trial [1]. In summary, donor feces were obtained from a young healthy Caucasian adult, who was periodically screened for various infectious and gastro-intestinal diseases. Feces from the donor were collected and processed within 6 h after production. First, the feces were diluted with sterile saline, and then poured through unfolded gauze in a funnel, in order to obtain a solution which was free of debris and solid particles. This solution was immediately infused in the patient through a nasoduodenal tube. Donor feces infusion was preceded by full colon lavage without prior use of antibiotics. Within the first 2 days after donor feces infusion the patient experienced mild diarrhoea and abdominal cramps, but no other adverse events occurred. Follow-up ESBL swab cultures of the rectum, perineum and throat were taken at week one, two, four, and twelve after the donor feces infusion. During these four follow-up time points the ESBL cultures of the

Effect of CYP3A4*22, CYP3A5*3, and CYP3A Combined Genotypes on Cyclosporine, Everolimus, and Tacrolimus Pharmacokinetics in Renal Transplantation

Cyclosporine, everolimus, and tacrolimus are the cornerstone of immunosuppressive therapy in renal transplantation. These drugs are characterized by narrow therapeutic windows, highly variable pharmacokinetics (PK), and metabolism by CYP3A enzymes. Recently, the decreased activity allele, CYP3A4*22, was described as a potential predictive marker for CYP3A4 activity. This study investigated the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on cyclosporine, everolimus, and tacrolimus PK in renal transplant patients. CYP3A4*22 carriers showed a significant lower clearance for cyclosporine (−15%), and a trend was observed for everolimus (−7%) and tacrolimus (−16%). Patients carrying at least one CYP3A5*1 allele had 1.5‐fold higher tacrolimus clearance compared with noncarriers; however, CYP3A5*3 appeared to be nonpredictive for everolimus and cyclosporine. CYP3A combined genotype did not significantly improve prediction of clearance compared with CYP3A5*3 or CYP3A4*22 alone. These data suggest that dose individualization of cyclosporine, everolimus, or tacrolimus therapy based on CYP3A4*22 is not indicated.

Ureteral Reconstruction after Renal Transplantation: Clinical Outcome and Risk Factors

Introduction: The incidence of urological complications after renal transplantation ranges from 2.5 to 30%. Often surgical revision is necessary. The risk factors for surgical revision and which surgical techniques to apply are not elucidated. This study investigates the outcome and risk factors for surgical revision of the ureterocystostomy. Materials and Methods: Between January 1995 and March 2009, 1,157 consecutive kidney transplantations were performed. All patient charts and surgical reports were reviewed. Results: Urological complications occurred in 142 (12.3%) patients. In 60 patients (5.2%) surgical revision was necessary. Of these 60 patients, 43 (71.7%) received neoureterocystostomy, 10 (16.7%) ureteropyelostomy reconstruction and 7 (11.7%) other techniques. Independent risk factors for surgical revision were donor ureteral reconstruction (odds ratio (OR) 48.66, 95% confidence interval (CI) 5.01–472.97), recipient age <18 years (OR 4.85, 95% CI 1.50–15.72) and delayed graft function (OR 2.70, 95% CI 1.36–5.36). Ureteral stenting was a protective factor for surgical revision (OR 0.30, 95% CI 0.12–0.81). The urological complication rates after neoureterocystostomy, ureteropyelostomy reconstruction and other techniques were 16, 0 and 0%, respectively. The overall surgical success rate was 92%. Conclusions: Ureteral stenting, recipient age, delayed graft function and perioperative ureteral reconstruction are significant factors associated with surgical revision of the ureterocystostomy. Surgical revision of the ureterocystostomy is a successful therapy with a low recurrence rate.

Mumps: Not an Innocent Bystander in Solid Organ Transplantation

Recently two major outbreaks of mumps have occurred: in the UK more than 56,000 cases were notified between 2004 and 2005, and in the United States, 6,584 cases were reported in 2006. Most patients were young healthy adults, in whom mumps normally has a benign course. Little is known about mumps in the immunocompromised patient. Here, we report a case of a 56‐year renal transplant recipient who developed acute irreversible transplant failure due to interstitial nephritis caused by mumps. RNA of the mumps virus was detected in the urine as well as in a renal biopsy. In view of the ongoing presence of the mumps virus in the population, one should be aware of the possible occurrence of this infection in immunocompromised patients.

Virus-Specific CD8(+) T Cells Cross-Reactive to Donor-Alloantigen Are Transiently Present in the Circulation of Kidney Transplant Recipients Infected With CMV and/or EBV.

T cells play a dual role in transplantation: They mediate transplant rejection and are crucial for virus control. Memory T cells generated in response to pathogens can cross‐react to alloantigen, a phenomenon called heterologous immunity. Virus‐specific CD8+ T cells cross‐reacting to donor‐alloantigen might affect alloimmune responses and hamper tolerance induction following transplantation. Here, we longitudinally studied these cross‐reactive cells in peripheral blood of 25 kidney transplant recipients with a cytomegalovirus and/or Epstein‐Barr virus infection. Cross‐reactive T cells were identified by flow cytometry as virus‐specific T cells that proliferate in response to donor cells in a mixed‐lymphocyte reaction. In 13 of 25 patients, we found cross‐reactivity to donor cells for at least 1 viral epitope before (n = 7) and/or after transplantation (n = 8). Cross‐reactive T cells were transiently present in the circulation, and their precursor frequency did not increase following transplantation or viral infection. Cross‐reactive T cells expressed interferon‐γ and CD107a in response to both alloantigen and viral peptide and resembled virus‐specific T cells in phenotype and function. Their presence was not associated with impaired renal function, proteinuria, or rejection. In conclusion, virus‐specific T cells that cross‐react to donor‐alloantigen are transiently detectable in the circulation of kidney transplant recipients.

Humoral immunity in renal transplantation: clinical significance and therapeutic approach

Abstract:  Donor‐specific antibodies (DSA) form a significant barrier in solid organ transplantation of highly pre‐sensitized candidates. Although avoiding transplantation over a positive cross‐match test can largely prevent the occurrence of hyperacute antibody‐mediated rejection, transplantation of highly pre‐sensitized candidates is often complicated by the occurrence of acute and chronic antibody‐mediated graft rejection leading to diminished graft function and survival. The pre‐existent HLA and/or non‐HLA‐specific antibodies are without any doubt important contributing factors underlying humoral‐mediated graft injury. Furthermore, increasing evidence underlines the association of newly formed de novo DSA after transplantation with poor graft function and survival. There is still a need to further develop desensitizing therapies not only to make transplantation of highly pre‐sensitized candidates feasible, but also to reduce the new formation of allo‐antibodies. Here, we summarize current views on desensitization therapies and the impact of the presence of DSA on the fate of the kidney graft.

Treatment of acute kidney allograft rejection with a non-mitogenic CD3 antibody.

T3/4.A is a non‐mitogenic murine IgA mAb to human CD3 that was selected for clinical studies to provide an alternative for the mitogenic, T cell‐activating, therapeutic mAb OKT3. Previously, we reported that T3/4.A is better tolerated in humans than the IgG2a‐CD3 mAb T3/4.2a. Here we report the results of a phase II clinical trial to assess the immunosuppressive potential of T3/4.A. Eighteen first kidney transplant recipients with a first rejection episode were included. Baseline immunosuppression consisted of cyclosporin and prednisolone. Rejection treatment consisted of 5 mg mAb per day during 10 days. Fourteen patients responded, of whom four experienced a second rejection within 2 weeks, one experienced chronic rejection after 2·5 years, whereas the others remained rejection‐free after treatment (median duration of follow‐up 42 months). Four patients did not respond and eventually lost their graft. These results are similar to treatment results with OKT3, as reported in the literature. Following the first dose of T3/4.A, side effects were limited, and reduced compared to OKT3‐treated controls. On the second day, 15 patients developed transient vomiting and/or diarrhoea, which coincided with elevated serum levels of proinflammatory cytokines. Minimal or even no side effects occurred during the remaining days, which is in sharp contrast to that seen generally during OKT3 treatment. Both T cell numbers and TCR expression were reduced during the therapy. We conclude that T3/4.A is a good alternative for OKT3 to treat rejection episodes in renal transplant recipients.

The PROCARE consortium: Toward an improved allocation strategy for kidney allografts

Kidney transplantation is the best treatment option for patients with end-stage renal failure. At present, approximately 800 Dutch patients are registered on the active waiting list of Eurotransplant. The waiting time in the Netherlands for a kidney from a deceased donor is on average between 3 and 4 years. During this period, patients are fully dependent on dialysis, which replaces only partly the renal function, whereas the quality of life is limited. Mortality among patients on the waiting list is high. In order to increase the number of kidney donors, several initiatives have been undertaken by the Dutch Kidney Foundation including national calls for donor registration and providing information on organ donation and kidney transplantation. The aim of the national PROCARE consortium is to develop improved matching algorithms that will lead to a prolonged survival of transplanted donor kidneys and a reduced HLA immunization. The latter will positively affect the waiting time for a retransplantation. The present algorithm for allocation is among others based on matching for HLA antigens, which were originally defined by antibodies using serological typing techniques. However, several studies suggest that this algorithm needs adaptation and that other immune parameters which are currently not included may assist in improving graft survival rates. We will employ a multicenter-based evaluation on 5429 patients transplanted between 1995 and 2005 in the Netherlands. The association between key clinical endpoints and selected laboratory defined parameters will be examined, including Luminex-defined HLA antibody specificities, T and B cell epitopes recognized on the mismatched HLA antigens, non-HLA antibodies, and also polymorphisms in complement and Fc receptors functionally associated with effector functions of anti-graft antibodies. From these data, key parameters determining the success of kidney transplantation will be identified which will lead to the identification of additional parameters to be included in future matching algorithms aiming to extend survival of transplanted kidneys and to diminish HLA immunization. Computer simulation studies will reveal the number of patients having a direct benefit from improved matching, the effect on shortening of the waiting list, and the decrease in waiting time.