Long-term efficacy and safety of SARS-CoV-2 vaccination in patients with chronic kidney disease, on dialysis or after kidney transplantation: a national prospective observational cohort study.

BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients.

BACKGROUND: In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. METHODS: This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is 'successful transplantation', defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. CONCLUSIONS: The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03797196 , registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

DCD donor hemodynamics as predictor of outcome after kidney transplantation.

Insufficient hemodynamics during agonal phase-ie, the period between withdrawal of life-sustaining treatment and circulatory arrest-in Maastricht category III circulatory-death donors (DCD) potentially exacerbate ischemia/reperfusion injury. We included 409 Dutch adult recipients of DCD donor kidneys transplanted between 2006 and 2014. Peripheral oxygen saturation (SpO2-with pulse oximetry at the fingertip) and systolic blood pressure (SBP-with arterial catheter) were measured during agonal phase, and were dichotomized into minutes of SpO2 > 60% or SpO2 < 60%, and minutes of SBP > 80 mmHg or SBP < 80 mmHg. Outcome measures were and primary non-function (PNF), delayed graft function (DGF), and three-year graft survival. Primary non-function (PNF) rate was 6.6%, delayed graft function (DGF) rate was 67%, and graft survival at three years was 76%. Longer periods of agonal phase (median 16 min [IQR 11-23]) contributed significantly to an increased risk of DGF (P = .012), but not to PNF (P = .071) and graft failure (P = .528). Multiple logistic regression analysis showed that an increase from 7 to 20 minutes in period of SBP < 80 mmHg was associated with 2.19 times the odds (95% CI 1.08-4.46, P = .030) for DGF. In conclusion, duration of agonal phase is associated with early transplant outcome. SBP < 80 mmHg during agonal phase shows a better discrimination for transplant outcome than SpO2 < 60% does.

Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant.

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.

Reversal of threatening blindness after initiation of eculizumab in Purtscher-like retinopathy secondary to atypical hemolytic uremic syndrome.

Purtscher-like retinopathy, a rare manifestation of systemic thrombotic microangiopathy, is a potentially visually debilitating condition with no effective proven treatment. Distinct pathogenic pathways have been proposed as etiological factors. We revisit the etiology of Purtscher-like retinopathy based on the rapid response and profound visual improvement after initiation of systemic intravenous eculizumab, an inhibitor of the complement cascade, in a patient with Purtscher-like retinopathy secondary to familial atypical hemolytic uremic syndrome (aHUS) due to a mutation in complement factor H. We hypothesize that the efficacy of eculizumab in this patient provides evidence for pathogenic events in the retina similar to those encountered in the renal microvasculature of aHUS patients, namely complement-mediated thromboembolization as a result of activation of the complement cascade in endothelial cells with release of tissue factor and development and amplification of a procoagulant state. To the best of our knowledge, this is the first report in the literature of eculizumab as an effective therapeutic strategy in Purtscher-like retinopathy.

Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial.

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.

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.

Incidence, risk factors, and the impact of allograft pyelonephritis on renal allograft function.

BACKGROUND: The impact of allograft pyelonephritis (AGPN) on renal allograft function is controversial. In this study, we evaluated the incidence, risk factors, and the impact of AGPN on renal allograft function. METHODS: Retrospective cohort study in adult renal allograft recipients with 1-year follow-up after transplantation (Tx). Renal allograft function was evaluated by estimated glomerular filtration rate (eGFR) (by Modification of Diet in Renal Disease formula) and 24-h urine protein excretion. RESULTS: A total of 431 renal allograft recipients were analyzed; 57 (13.2%) developed AGPN within 1 year after Tx. Median time between Tx and AGPN was 50 days. Risk factors for AGPN were the presence of a urological catheter (odds ratio [OR] = 18.93, 95% confidence interval [CI] = 8.00-44.81, P < 0.001) and preceding asymptomatic bacteriuria (ASB) (OR = 2.16, 95% CI = 1.20-3.90, P = 0.009). In 72.7%, the causative microorganism of ASB was identical to that of the succeeding AGPN episode. Multivariable linear regression analysis showed that experiencing AGPN did not decrease the eGFR (P = 0.61) nor did increased proteinuria (P = 0.29) 1 year after Tx. For the eGFR, an interaction was found between AGPN/bacteriuria (BU) and acute rejection (AR): the group experiencing BU preceding AR had significantly (P < 0.001) lower eGFR compared with the group that experienced only AR (21 mL/min/1.73 m2 vs. 48 mL/min/1.73 m2 ), as a result of increased prevalence of combined rejections within the BU group. CONCLUSION: Indwelling urological catheters and preceding ASB are associated with developing AGPN. An incident of AGPN itself does not impair renal allograft function 1 year after Tx. However, a relevant interaction occurs between BU and AR, in which the sequence of occurrence of these 2 events synergistically impairs the eGFR.

Immunization after renal transplantation: current clinical practice.

BACKGROUND: The use of potent immunosuppressive drugs and increased travel by renal transplant recipients (RTR) has augmented the risk for infectious complications. Immunizations and changes in lifestyle are protective. The Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group has developed guidelines on vaccination following solid organ transplantation. The degree of adherence to these guidelines is unknown, as is which barriers must be overcome to improve adherence. METHODS: We performed a cross-sectional national survey among Dutch nephrologists to assess vaccination policy and adherence to the KDIGO guidelines. In addition, to investigate awareness and attitude of RTR regarding their risk of infection, we performed a cross-sectional survey of RTR in our outpatient clinic. RESULTS: A total of 132 (63%) nephrologists completed the survey. Reported immunization rates were 90.8% for influenza and 27.3% for hepatitis B. However, pneumococcal, tetanus toxoid, and meningococcal immunization rates were low. Twenty-seven percent of respondents were familiar with the guideline contents. The most frequent perceived barrier to guideline adherence was expectation of low effectiveness. A total of 403 RTR (62%) completed the survey. Sixty-eight percent perceived more risk for complicated infection. A significant correlation was found between education level and variables concerning awareness and attitude toward risk of infection. CONCLUSIONS: Our results show that nephrologists' knowledge of and adherence to the recommendations regarding immunization after renal transplantation is suboptimal. Most Dutch RTR are aware of their increased risk and the possible seriousness of infectious complications. However, their behavior does not match their awareness. This disparity points to an important role for nephrologists in providing adequate counseling.

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 Vß 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.

Abdominal wall phlebitis due to Prevotella bivia following renal transplantation in a patient with an occluded inferior vena cava.

Pre-existing occlusion of the inferior vena cava may complicate renal transplantation. Suppurative abdominal wall phlebitis following renal transplantation was diagnosed in a patient with pre-existing thrombosis of the inferior vena cava of unknown cause. The phlebitis developed in the subcutaneous collateral veins of the abdominal wall contra-laterally to the renal transplant. Cultures from abdominal wall micro-abscesses yielded Prevotella bivia as the causative agent. This complication has not been described before in the context of renal transplantation. The pathogenesis and management of this serious complication are discussed in this paper.

Eculizumab Rescue Therapy in Patients With Recurrent Atypical Hemolytic Uremic Syndrome After Kidney Transplantation.

Introduction: Since 2016, kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) in the Netherlands is performed without eculizumab prophylaxis. Eculizumab is given in case of posttransplant aHUS recurrence. Eculizumab therapy is monitored in the CUREiHUS study. Methods: All participating kidney transplant patients who received eculizumab therapy for a suspected posttransplant aHUS recurrence were evaluated. Overall recurrence rate was monitored prospectively at Radboud University Medical Center. Results: In the period from January 2016 until October 2020, we included 15 (12 females, 3 males; median age 42 years, range 24-66 years) patients with suspected aHUS recurrence after kidney transplantation in this study. The time interval to recurrence showed a bimodal distribution. Seven patients presented early after transplantation (median 3 months, range 0.3-8.8 months), with typical aHUS features: rapid loss of estimated glomerular filtration rate (eGFR) and laboratory signs of thrombotic microangiopathy (TMA). Eight patients presented late (median 46 months, range 18-69 months) after transplantation. Of these, only 3 patients had systemic TMA, whereas 5 patients presented with slowly deteriorating eGFR without systemic TMA. Treatment with eculizumab resulted in improvement or stabilization of eGFR in 14 patients. Eculizumab discontinuation was tried in 7 patients; however, it was successful only in 3. At the end of the follow-up (median 29 months, range 3-54 months after start of eculizumab), 6 patients had eGFR <30 ml/min per 1.73 m2. Graft loss had occurred in 3 of them. Overall, aHUS recurrence rate without eculizumab prophylaxis was 23%. Conclusions: Rescue treatment of posttransplant aHUS recurrence is effective; however, some patients suffer from irreversible loss of kidney function, likely caused by delayed diagnosis and treatment and/or too aggressive discontinuation of eculizumab. Physicians should be aware that recurrence of aHUS can present without evidence of systemic TMA.

The natural history of clinical operational tolerance after kidney transplantation through twenty-seven cases.

We report here on a European cohort of 27 kidney transplant recipients displaying operational tolerance, compared to two cohorts of matched kidney transplant recipients under immunosuppression and patients who stopped immunosuppressive drugs and presented with rejection. We report that a lower proportion of operationally tolerant patients received induction therapy (52% without induction therapy vs. 78.3%[p = 0.0455] and 96.7%[p = 0.0001], respectively), a difference likely due to the higher proportion (18.5%) of HLA matched recipients in the tolerant cohort. These patients were also significantly older at the time of transplantation (p = 0.0211) and immunosuppression withdrawal (p = 0.0002) than recipients who rejected their graft after weaning. Finally, these patients were at lower risk of infectious disease. Among the 27 patients defined as operationally tolerant at the time of inclusion, 19 still display stable graft function (mean 9 ± 4 years after transplantation) whereas 30% presented slow deterioration of graft function. Six of these patients tested positive for pre-graft anti-HLA antibodies. Biopsy histology studies revealed an active immunologically driven mechanism for half of them, associated with DSA in the absence of C4d. This study suggests that operational tolerance can persist as a robust phenomenon, although eventual graft loss does occur in some patients, particularly in the setting of donor-specific alloantibody.

Rapid T cell repopulation after rabbit anti-thymocyte globulin (rATG) treatment is driven mainly by cytomegalovirus.

Rabbit anti-thymocyte globulin (rATG) induces a long-lasting lymphocytopenia. CD4(+) T cells remain depleted for up to 2 years, whereas the CD8(+) T cell compartment is refilled rapidly by highly differentiated CD27(-) CD45RA(+) CD57(+) effector-type cells. Because the presence of these highly differentiated CD8(+) T cells has been associated with cytomegalovirus (CMV) infection, we questioned to what extent restoration of CMV T cell immunity contributes to the re-emergence of T cells following rATG treatment. We compared T cell repopulation in six CMV-seropositive patients with CMV reactivation (reactivating CMV(+) ) to that in three CMV(+) patients without reactivation (non-reactivating CMV(+) ), and to that in three CMV-seronegative recipients receiving a kidney from a CMV-seronegative donor (CMV(-/-) ). All patients received rATG because of acute allograft rejection. Total CD4 and CD8 counts, frequency and phenotype of virus-specific CD8(+) T cells were determined. In reactivating CMV(+) patients, total CD8(+) T cells reappeared rapidly, whereas in non-reactivating CMV(+) patients they lagged behind. In CMV(-/-) patients, CD8(+) T cell counts had not yet reached pretransplant levels after 2 years. CMV reactivation was indeed followed by a progressive accumulation of CMV-specific CD8(+) T cells. During lymphocytopenia following rATG treatment, serum interleukin (IL)-7 levels were elevated. Although this was most prominent in the CMV-seronegative patients, it did not result in an advantage in T cell repopulation in these patients. Repopulated CD8(+) T cells showed increased skewing in their Vß repertoire in both CMV(-/-) and reactivating CMV-seropositive patients. We conclude that rapid T cell repopulation following rATG treatment is driven mainly by CMV.

Characteristics of alloreactive T cells measured before renal transplantation.

Several assays to measure pre-existing allospecific T cell immunity in renal transplant candidates have been developed in the past years. In 46 patients, we used flow cytometry-based mixed lymphocyte culture to measure the precursor frequency and phenotype of alloreactive T cells before renal transplantation, using donor-specific or third-party cells for allostimulation. Allostimulation induced up-regulation of co-stimulatory molecules, chemokine receptors relevant for migration of T cells into the graft and effector proteins. Recipients prone for acute rejection had a higher precursor frequency of alloreactive CD8(+) T cells and a lower percentage of interleukin (IL)-7Rα expressing alloreactive CD8(+) T cells than non-rejectors. These data point to quantitative and qualitative differences between T cells of patients who will experience acute cellular rejection episodes from those who will not.

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.

The pyrimidin analogue cyclopentenyl cytosine induces alloantigen-specific non-responsiveness of human T lymphocytes.

Cyclopentenyl cytosine (CPEC) has been shown to induce apoptosis in human T lymphoblastic cell lines and T cells from leukaemia patients. In this study we have addressed the question of whether CPEC is able to decrease proliferation and effector functions of human alloresponsive T lymphocytes and induce T cell anergy. The proliferative capacity of human peripheral blood mononuclear cells in response to allogeneic stimulation was measured by 5,6-carboxy-succinimidyl-diacetate-fluorescein-ester staining. Flow cytometric analysis was performed using surface CD4, CD8, CD25, CD103 and intracellular perforin, granzyme A, granzyme B, caspase-3 and forkhead box P3 (FoxP3) markers. The in vivo immunosuppressive capacity was tested in a murine skin graft model. Addition of CPEC at a concentration of 20 nM strongly decreased the expansion and cytotoxicity of alloreactive T cells. Specific restimulation in the absence of CPEC showed that the cells became anergic. The drug induced caspase-dependent apoptosis of alloreactive T lymphocytes. Finally, CPEC increased the percentage of CD25(high) FoxP3+ CD4+ and CD103+ CD8+ T cells, and potentiated the effect of rapamycin in increasing the numbers of alloreactive regulatory T cells. Treatment with CPEC of CBA/CA mice transplanted with B10/Br skin grafts significantly prolonged graft survival. We conclude that CPEC inhibits proliferation and cytotoxicity of human alloreactive T cells and induces alloantigen non-responsiveness in vitro.