Fixed low dose versus concentration-controlled initial tacrolimus dosing with reduced target levels in the course after kidney transplantation: results from a prospective randomized controlled non-inferiority trial (Slow & Low study).

Background: Optimal initial tacrolimus dosing and early exposure of tacrolimus after renal transplantation is not well studied. Methods: In this open-label, 6 months, multicenter, randomized controlled, non-inferiority study, we randomly assigned 432 renal allograft recipients to receive basiliximab induction, mycophenolate and steroids and either standard prolonged-release tacrolimus (trough levels: 7-9 ng/ml; Standard Care arm), or an initial 7-day fixed 5 mg/day dose of prolonged-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5-7 ng/ml; Slow & Low arm). The primary end point was the combined incidence rate of biopsy-proven acute rejections (BPAR; including borderline), graft failure, or death at 6 months with a non-inferiority margin of 12.5%. (EudraCT-Nr: 2013-001770-19. Findings: The combined primary endpoint in the Slow & Low arm was non-inferior compared to the Standard Care arm (22.1% versus 20.7%; difference: 1.4%, 90% CI -5.5% to 8.3%). The overall rate of BPAR including borderlines was similar (Slow & Low 17.4% versus Standard Care 16.6%). Safety parameters such as delayed graft function, kidney function, donor specific HLA-antibodies, infections, or post-transplantation diabetes mellitus did not differ. Interpretation: This is the first study to show that an initial fixed dose of 5 mg per day followed by lower tacrolimus exposure is non-inferior compared to standard tacrolimus therapy and equally efficient and safe within 6 months after renal transplantation. These data suggest that therapeutic drug monitoring for prolonged release tacrolimus can be abandoned until start of the second week after transplantation. Funding: Investigator-initiated trial, financial support by Astellas Pharma GmbH.

A paired-kidney allocation study found superior survival with HLA-DR compatible kidney transplants in the Eurotransplant Senior Program.

The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation.

Corrigendum: The Aquaporin 5 -1364A/C Promoter Polymorphism Is Associated With Cytomegalovirus Infection Risk in Kidney Transplant Recipients.

[This corrects the article DOI: 10.3389/fimmu.2019.02871.].

Study design and rationale of the pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R).

AIM: Due to improved therapy in childhood, many patients with congenital heart disease reach adulthood and are termed adults with congenital heart disease (ACHD). ACHD often develop heart failure (HF) as a consequence of initial palliative surgery or complex anatomy and subsequently require advanced HF therapy. ACHD are usually excluded from trials evaluating heart failure therapies, and in this context, more data about heart failure trajectories in ACHD are needed to guide the management of ACHD suffering from HF. METHODS AND RESULTS: The pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R) will collect data from ACHD evaluated or listed for heart or heart-combined organ transplantation from 16 countries in Europe and the Asia/Pacific region. We plan retrospective collection of data from 1989-2020 and will include patients prospectively. Additional organizations and hospitals in charge of transplantation of ACHD will be asked in the future to contribute data to the register. The primary outcome is the combined endpoint of delisting due to clinical worsening or death on the waiting list. The secondary outcome is delisting due to clinical improvement while on the waiting list. All-cause mortality following transplantation will also be assessed. The data will be entered into an electronic database with access to the investigators participating in the register. All variables of the register reflect key components important for listing of the patients or assessing current HF treatment. CONCLUSION: The ARTORIA-R will provide robust information on current management and outcomes of adults with congenital heart disease suffering from advanced heart failure.

[Pancreas transplantation-clinic, technique, and histological assessment]. / Pankreastransplantation ­ Klinik, Technik und histologische Beurteilung.

BACKGROUND: In Germany pancreas transplants are performed in only a few selected and specialized centres, usually combined with a kidney transplant. Knowlegde of the indications for and techniques of transplantation as well as of the histopathological assessment for rejection in pancreas and duodenal biopsies is not very widespread. AIM: To give an overview of the development and status quo in pancreas-kidney-transplantation in Germany summarizing the experience of the largest German pancreas transplant centre and to give a résumé of the results of histological diagnoses of biopsy specimens submitted between 06/2017 and 12/2020. Moreover, a detailed description and illustration of histological findings is included. MATERIAL AND METHODS: A thorough literature search for aspects of the history, technique and indication for pancreas transplantation was performed and discussed in the context of the local experience and technical particularities specific for the transplant centre in Bochum. The occurrence of complications was compared with international reports. Results of pancreas and duodenal biopsies submitted to Erlangen between 06/2017 and 12/2020 for histological evaluation, which were evaluated according to the Banff classification, were summarized. For a better understanding key histological findings of pancreas rejection and differential diagnoses were illustrated and discussed. RESULTS: A total of 93 pancreas transplant specimens and 3 duodenal biopsies were included. 34.4% of pancreas specimens did not contain representative material for a diagnosis. In the remaining 61 biopsies 24.6% showed no rejection, 62.3% were diagnosed with acute T-cell mediated rejection (TCMR) and 8.2% with signs suspicious of antibody-mediated rejection (ABMR). Acute acinary epithelial injury was seen in 59%, pancreatitis in 8.2% and allograft fibrosis was reported in as many as 54.1%. Calcineurin-inhibitor toxicity was discussed in only 4.9%. CONCLUSION: Pancreas-kidney-transplantation and standardized histological assessment of the transplanted pancreas or rarely duodenum with reporting according to the updated Banff classification of pancreas transplants or previous reports of duodenal rejection are important mainstays in the management of patients with diabetes.

Challenges Associated with Pancreas and Kidney Retransplantation-A Retrospective Analysis.

Simultaneous pancreas and kidney transplantation (SPK) is an accepted treatment for diabetic patients with renal failure, and is associated with increased survival and quality of life for recipients. There are only a few publications on the outcomes of simultaneous pancreas-kidney retransplantation (Re-SPK) after previous SPK and the loss of function of both grafts. A total of 55 patients with type 1 diabetes mellitus underwent pancreas retransplantation at our center between January 1994 and March 2021. Twenty-four of these patients underwent Re-SPK after a previous SPK. All 24 operations were technically feasible. Patient survival rate after 3 months, 1 year, and 5 years was 79.2%, 75%, and 66.7%, respectively. The causes of death were septic arterial hemorrhage (n = 3), septic multiorgan failure (n = 2), and was unknown in one patient. Pancreas and kidney graft function after 3 months, 1 year, and 5 years were 70.8% and 66.7%, 66.7% and 62.5%, and 45.8% and 54.2%, respectively. Relaparotomy was performed in 13 out of 24 (54.2%) patients. The results of our study show that Re-SPK, after previously performed SPK, is a technical and immunological challenge, associated with a significantly increased mortality and complication rate; therefore, the indication for Re-SPK should be very strict. Careful preoperative diagnosis is indispensable.

Detection of pre-existing SARS-CoV-2-reactive T cells in unexposed renal transplant patients.

BACKGROUND: Recent data demonstrate potentially protective pre-existing T cells reactive against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in samples of healthy blood donors, collected before the SARS-CoV-2 pandemic. Whether pre-existing immunity is also detectable in immunosuppressed patients is currently not known. METHODS: Fifty-seven patients were included in this case-control study. We compared the frequency of SARS-CoV-2-reactive T cells in the samples of 20 renal transplant (RTx) patients to 20 age/gender matched non-immunosuppressed/immune competent healthy individuals collected before the onset of the SARS-CoV-2 pandemic. Seventeen coronavirus disease 2019 (COVID-19) patients were used as positive controls. T cell reactivity against Spike-, Nucleocapsid-, and Membrane- SARS-CoV-2 proteins were analyzed by multi-parameter flow cytometry. Antibodies were analyzed by neutralization assay. RESULTS: Pre-existing SARS-CoV-2-reactive T cells were detected in the majority of unexposed patients and healthy individuals. In RTx patients, 13/20 showed CD4+ T cells reactive against at least one SARS-CoV-2 protein. CD8+ T cells reactive against at least one SARS-CoV-2 protein were demonstrated in 12/20 of RTx patients. The frequency and Th1 cytokine expression pattern of pre-formed SARS-CoV-2 reactive T cells did not differ between RTx and non-immunosuppressed healthy individuals. CONCLUSIONS: This study shows that the magnitude and functionality of pre-existing SARS-CoV-2 reactive T cell in transplant patients is non-inferior compared to the immune competent cohort. Although several pro-inflammatory cytokines were produced by the detected T cells, further studies are required to prove their antiviral protection.

Impact of Histidine-Tryptophan-Ketoglutarate Versus University of Wisconsin Solution on the Outcome of Pancreas Transplant With Cold Ischemic Time ≥12 Hours: A Retrospective Study.

OBJECTIVES: Histidine-tryptophan-ketoglutarate and University of Wisconsin solutions are currently used for pancreas graft preservation. Our hypothesis was whether the use of histidine-tryptophan-ketoglutarate solution is associated with worse pancreas graft survival than University of Wisconsin solution, in general and after prolonged cold ischemic time of ≥12 hours. MATERIALS AND METHODS: This retrospective study investigated the impact of static cold storage in histidine-tryptophan-ketoglutarate (n = 133) versus University of Wisconsin (n = 107) solution on outcomes of 240 pancreas transplant procedures. Patient and graft survival rates were compared after 1, 3, and 5 years in both groups. Serum lipase, amylase, and C-reactive protein levels and incidence of surgical complications were evaluated at postoperative week 1. A subgroup analysis of 96 grafts (52 with histidine-tryptophanketoglutarate/44 with University of Wisconsin) with pancreas graft cold ischemic time ≥12 hours was also performed. RESULTS: At mean follow-up of 75.2 ± 9.9 months, both groups demonstrated comparable short- and long-term patient survival. Overall, pancreas graft survival was slightly better in the histidine-tryptophan-ketoglutarate group (Kaplan-Meier analysis, log-rank P = .013). However, the subgroup analysis of grafts with cold ischemic time ≥12 hours showed slightly better pancreatic graft survival in the University of Wisconsin group, although not significantly (log-rank P = .95). Serum lipase and C-reactive protein levels at postoperative week 1 were higher in the histidinetryptophan-ketoglutarate group. Surgical complications were comparable. Multivariable Cox regression analysis identified neither solution as a risk factor affecting patient and graft survival. CONCLUSIONS: Although a direct comparison between histidine-tryptophan-ketoglutarate and University of Wisconsin showed better pancreas graft survival with histidine-tryptophan-ketoglutarate, the multivariable analysis showed that the perfusion solution does not significantly influence patient and graft survival. However, in the analysis of transplants with cold ischemic time ≥12 hours, pancreas graft survival was slightly better in the University of Wisconsin group, although not significantly.

The Magnitude and Functionality of SARS-CoV-2 Reactive Cellular and Humoral Immunity in Transplant Population Is Similar to the General Population Despite Immunosuppression.

BACKGROUND: The ability of transplant (Tx) patients to generate a protective antiviral response under immunosuppression is pivotal in COVID-19 infection. However, analysis of immunity against SARS-CoV-2 is currently lacking. METHODS: Here, we analyzed T cell immunity directed against SARS-CoV-2 spike-, membrane-, and nucleocapsid-protein by flow cytometry and spike-specific neutralizing antibodies in 10 Tx in comparison to 26 nonimmunosuppressed (non-Tx) COVID-19 patients. RESULTS: Tx patients (7 renal, 1 lung, and 2 combined pancreas-kidney Txs) were recruited in this study during the acute phase of COVID-19 with a median time after SARS-CoV-2-positivity of 3 and 4 d for non-Tx and Tx patients, respectively. Despite immunosuppression, we detected antiviral CD4+ T cell-response in 90% of Tx patients. SARS-CoV-2-reactive CD4+ T cells produced multiple proinflammatory cytokines, indicating their potential protective capacity. Neutralizing antibody titers did not differ between groups. SARS-CoV-2-reactive CD8+ T cells targeting membrane- and spike-protein were lower in Tx patients, albeit without statistical significance. However, frequencies of anti-nucleocapsid-protein-reactive, and anti-SARS-CoV-2 polyfunctional CD8+ T cells, were similar between patient cohorts. Tx patients showed features of a prematurely aged adaptive immune system, but equal frequencies of SARS-CoV-2-reactive memory T cells. CONCLUSIONS: In conclusion, a polyfunctional T cell immunity directed against SARS-CoV-2 proteins as well as neutralizing antibodies can be generated in Tx patients despite immunosuppression. In comparison to nonimmunosuppressed patients, no differences in humoral and cellular antiviral-immunity were found. Our data presenting the ability to generate SARS-CoV-2-specific immunity in immunosuppressed patients have implications for the handling of SARS-CoV-2-infected Tx patients and raise hopes for effective vaccination in this cohort.

Biopsy findings after detection of de novo donor-specific antibodies in renal transplant recipients: a single center experience.

BACKGROUND: De novo donor-specific antibodies (DSA) are associated with an increased risk of antibody-mediated rejection and a substantial reduction of allograft survival. We hypothesized that detection of DSA should prompt a biopsy even in the absence of proteinuria and loss of estimated glomerular filtration rate (eGFR). However, data on a population without proteinuria or loss of kidney function is scant, and this is the main novelty of our study design. METHODS: Single center retrospective analysis on biopsy findings after detection of de novo DSA. One-hundred-thirty-two kidney and pancreas-kidney transplant recipients were included. Eighty-four of these patients (63.6%) underwent allograft biopsy. At the time of biopsy n = 50 (59.5%) had a protein/creatinine ratio (PCR) > 300 mg/g creatinine and/or a loss of eGFR ≥ 10 ml/min in the previous 12 months, whereas 40.5% did not. Diagnosis of rejection was performed according to Banff criteria. RESULTS: Seventy-seven (91.7%) of the biopsies had signs of rejection (47.6% antibody mediated rejection (ABMR), 13.1% cellular, 20.2% combined, 10.7% borderline). Among subjects without proteinuria or loss of eGFR ≥ 10 ml/min/a (n = 34), 29 patients (85.3%) showed signs of rejection (44.1% antibody mediated (ABMR), 14.7% cellular, 11.8% combined, 14.7% borderline). CONCLUSION: The majority of subjects with de novo DSA have histological signs of rejection, even in the absence of proteinuria and deterioration of graft function. Thus, it appears reasonable to routinely perform an allograft biopsy after the detection of de novo DSA.

The NFKB1 Promoter Polymorphism (-94ins/delATTG) Is Associated with Susceptibility to Cytomegalovirus Infection after Kidney Transplantation and Should Have Implications on CMV Prophylaxis Regimens.

Infections with cytomegalovirus (CMV) are one of the most frequent opportunistic infections in kidney transplant recipients. Current risk-adapted CMV chemoprophylaxis regimens are based almost solely on the donor and recipient CMV serostatus. Of note, the NFKB1 -94ins/delATTG promoter polymorphism was recently associated with a higher risk of CMV infection. Since single genetic association studies suffer from poor reliability for drawing therapeutic implications, we performed this confirmatory study and included 256 kidney transplant recipients from 2007 to 2014 in this retrospective study. Patients were genotyped for the -94ins/delATTG NFKB1 promoter polymorphism and followed up for 12 months. The incidence of CMV infection within 12 months after kidney transplantation was 37.5% (33/88) for the ins/ins, 21.5% (28/130) for the ins/del, and 23.7% (9/38) for the del/del genotypes (p = 0.023). Moreover, we evaluated the time of CMV infection onset. Ins/ins carriers had primarily late-onset CMV infection (median 194 days; interquartile range (IQR) 117-267 days) compared with heterozygous (ins/del; median 158 days; IQR 82-195 days) and homozygous deletion allele carriers (del/del; median 95 days; 84-123 days). Multivariate-restricted Cox regression model confirmed the ins/ins genotype to be an independent risk factor for the development of late-onset CMV infections. These findings should have an impact on post-kidney transplantation CMV chemoprophylaxis regimens.

STABIL-study: The Course of Therapy, Safety and Pharmacokinetic Parameters of Conversion of Prograf® to Tacrolimus HEXAL®/Crilomus® in Renal Transplant Recipients - an Observational Study in Germany.

BACKGROUND/OBJECTIVE: Tacrolimus HEXAL®/Crilomus® is an approved generic immunosuppressant for the prevention and treatment of rejection following renal transplantation. For safe and socioeconomically efficient conversion of the innovator into a generic formulation, high- -quality data are necessary, in view of the different and country-specific comorbidities and pharmacokinetics in kidney transplant recipients. PATIENTS AND METHODS: From 2014 to 2017, we enrolled 32 kidney transplant recipients, receiving newly prescribed Tacrolimus HEXAL®/Crilomus® in 5 German centers. Efficacy and safety data were collected over 6-8 months and retrospectively compared to the period prior to conversion. RESULTS: The mean tacrolimus trough level was 4.91 ng/mL Standard Deviation (SD) (SD ±1.7) before and 5.06 ng/mL (SD ±1.97) after conversion. Mean tacrolimus trough concentration-dose-ratio (+/- SD) was 187.1 ng/mL/mg/kg/day (SD 99.2) for the reference and 205.1 ng/mL/mg/kg/day (SD 133) for the generic product, resulting in a non-significant difference of 18.0 ng/mL/mg/kg/day (SD 71.8) (p=0.84, Wilcoxon V=180). Overall, dosing had to be changed in 4 (14.8%) patients. Graft function remained stable and no rejections occurred. CONCLUSION: In conclusion, conversion to the generic tacrolimus formulation can be considered safe and feasible in long-term kidney transplant recipients in Germany. As suggested by guidelines, vigilant therapeutic drug monitoring is recommended to account for possible tacrolimus concentration variability on the individual patient level.

Renal Function and Patient-Reported Outcomes in Stable Kidney Transplant Patients Following Conversion From Twice-Daily Immediate-Release Tacrolimus to Once-Daily Prolonged-Release Tacrolimus: A 12-Month Observational Study in Routine Clinical Practice in Germany (ADAGIO).

INTRODUCTION: This 12-month, noninterventional study on routine clinical practice in Germany evaluated renal function in stable kidney transplant recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). METHODS: Renal function was assessed in 183 patients by estimated glomerular filtration rate using the modification of diet in renal disease-4 formula. Self-reported gastrointestinal health-related quality of life, adherence, satisfaction with PR-T, suspected rejection episodes, and safety were also assessed at conversion and at 3, 6, and 12 months. RESULTS: Conversion from IR-T to PR-T resulted in stable kidney function over 12 months, with a difference in estimated glomerular filtration rate between the first and final visits of 0.1 mL/min/1.73 m2 (95% confidence interval, -1.6, 1.8). Eight patients experienced an acute rejection episode (4.4%). At each assessment, gastrointestinal health-related quality of life was low and adherence was high. Most patients reported that they were very satisfied (69.8%) or satisfied (28.1%) with PR-T at the final visit. Among patients reporting a preference, 78.4% preferred PR-T, 2.2% preferred IR-T, and 19.4% reported no preference. The safety profile of PR-T was consistent with that previously described. CONCLUSION: Conversion of stable kidney transplant recipients from IR-T to PR-T provided stable kidney and graft function over 12 months (Verband Forschender Arzneimittelhersteller--registered study: NIS ADV-02).

Psychological Responses to the Coronavirus Disease 2019 Pandemic in Renal Transplant Recipients.

BACKGROUND: Renal transplant recipients are at increased risk for an adverse course of coronavirus disease 2019 (COVID-19), most likely due to immunosuppression and the high level of cardiovascular comorbidity. Many transplant recipients are aware of these facts. The psychological effects of this knowledge, however, remain elusive. METHODS: Cross-sectional study on 62 renal transplant recipients. Fifty cardiovascular outpatients without immunosuppression and 55 healthy subjects served as control. We performed a focused psychological assessment during the pandemic (April 2020) and compared the data with a time 6 months before. Additionally, an intergroup analysis was performed for the data during the pandemic. The analysis was performed by means of a questionnaire derived from KPD-38. We extracted 5 questions focusing on the parameters "life satisfaction" and perceived "action competence." Life satisfaction score ranged from 2 to 8, and the score for action competence from 5 to 20. RESULTS: Both life satisfaction and perceived action competence were significantly lower during the pandemic than 6 months before in all the 3 groups (P < .005 each). During the pandemic median levels of life satisfaction did not significantly differ between the 3 groups (transplant recipients 6, interquartile range [IQR] 4-7; cardiovascular patients 5, IQR: 4-6; healthy controls 6, IQR 5-7; Kruskal-Wallis P > .05). In contrast, the perceived action competence was higher in healthy subjects (15, IQR 12-17) than in both renal transplant recipients (13, IQR 10-15) and cardiovascular patients (13, IQR 8-14, Kruskal-Wallis P = .0003). CONCLUSION: The COVID-19 pandemic has negative effects on life satisfaction and perceived action competence in renal transplant recipients, cardiovascular patients without immunosuppression, and healthy subjects. The effects on life satisfaction in transplant recipients did not differ from nonimmunocompromised patients or healthy controls. In contrast, the feeling of reduced action competence exceeded healthy controls, most likely due to a subjective need for stricter social distancing to avoid infection.

Lessons for the clinical nephrologist: recurrence of nephrotic syndrome induced by SARS-CoV-2.

SARS-CoV-2 is characterized by a multiorgan tropism including the kidneys. Recent autopsy series indicated that SARS-CoV-2 can infect both tubular and glomerular cells. Whereas tubular cell infiltration may contribute to acute kidney injury, data on a potential clinical correlative to glomerular affection is rare. We describe the first case of nephrotic syndrome in the context of COVID-19 in a renal transplant recipient. A 35 year old male patient received a kidney allograft for primary focal segmental glomerulosclerosis (FSGS). Three months posttransplant a recurrence of podocytopathy was successfully managed by plasma exchange, ivIG, and a conversion from tacrolimus to belatacept (initial proteinuria > 6 g/l decreased to 169 mg/l). Six weeks later he was tested positive for SARS-CoV-2 and developed a second increase of proteinuria (5.6 g/l). Renal allograft biopsy revealed diffuse podocyte effacement and was positive for SARS-CoV-2 in RNA in-situ hybridation indicating a SARS-CoV-2 associated recurrence of podocytopathy. Noteworthy, nephrotic proteinuria resolved spontaneously after recovering from COVID-19. The present case expands the spectrum of renal involvement in COVID-19 from acute tubular injury to podocytopathy in renal transplant recipients. Thus, it may be wise to test for SARS-CoV-2 prior to initiation of immunosuppression in new onset glomerulopathy during the pandemic.

Immune monitoring facilitates the clinical decision in multifocal COVID-19 of a pancreas-kidney transplant patient.

The optimal management in transplant recipients with coronavirus disease 2019 (COVID-19) remains uncertain. The main concern is the ability of immunosuppressed patients to generate sufficient immunity for antiviral protection. Here, we report on immune monitoring facilitating a successful outcome of severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated pneumonia, meningoencephalitis, gastroenteritis, and acute kidney and pancreas graft failure in a pancreas-kidney transplant recipient. Despite the very low numbers of circulating B, NK, and T cells identified in follow-up, a strong SARS-CoV-2 reactive T cell response was observed. Importantly, we detected T cells reactive to Spike, Membrane, and Nucleocapsid proteins of SARS-CoV-2 with majority of T cells showing polyfunctional proinflammatory Th1 phenotype at all analyzed time points. Antibodies against Spike protein were also detected with increasing titers in follow-up. Neutralization tests confirmed their antiviral protection. A correlation between cellular and humoral immunity was observed underscoring the specificity of demonstrated data. We conclude that analyzing the kinetics of nonspecific and SARS-CoV-2-reactive cellular and humoral immunity can facilitate the clinical decision on immunosuppression adjustment and allow successful outcome as demonstrated in the current clinical case. Although the antiviral protection of the detected SARS-CoV-2-reactive T cells requires further evaluation, our data prove an ability mounting a strong SARS-CoV-2-reactive T cell response with functional capacity in immunosuppressed patients.

Clinical characteristics and outcomes of patients with adult congenital heart disease listed for heart and heart‒lung transplantation in the Eurotransplant region.

BACKGROUND: The therapeutic success in patients with congenital heart disease (CHD) leads to a growing number of adults with CHD (adult CHD [ACHD]) who develop end-stage heart failure. We aimed to determine patient characteristics and outcomes of ACHD listed for heart transplantation. METHODS: Using data from all the patients with ACHD in 20 transplant centers in the Eurotransplant region from 1999 to 2015, we analyzed patient characteristics, waiting list, and post-transplantation outcomes. RESULTS: A total of 204 patients with ACHD were listed during the study period. The median age was 38 years, and 62.3% of the patients were listed in high urgency (HU), and 37.7% of the patients were in transplantable (T)-listing status. A total of 23.5% of the patients died or were delisted owing to clinical worsening, and 75% of the patients underwent transplantation. Median waiting time for patients with HU-listing status was 4.18 months and with T-listing status 9.07 months. There was no difference in crude mortality or delisting between patients who were HU status listed and T status listed (p = 0.65). In multivariable regression analysis, markers for respiratory failure (mechanical ventilation, hazard ratio [HR]: 1.41, 95% CI: 1.11-1.81, p = 0.006) and arrhythmias (anti-arrhythmic medication, HR: 1.42, 95% CI: 1.01-2.01, p = 0.044) were associated with a higher risk of death or delisting. In the overall cohort, post-transplantation mortality was 26.8% after 1 year and 33.4% after 5 years. CONCLUSIONS: Listed patients are at high risk of death without differences in the urgency of listing. Respiratory failure requiring invasive ventilation and possibly arrhythmias requiring anti-arrhythmic medication indicate worse outcomes on waiting list.

Vaccination Against Urinary Tract Infection After Renal Transplantation.

BACKGROUND: Recurrent urinary tract infections (UTIs) increase mortality and reduce graft survival after renal transplantation. Because current prophylactic strategies such as methionine, cranberry juice, and antibiotics fail to sufficiently prevent recurrent infections in a substantial number of patients, there is a clinical need for alternative approaches. The present work describes first experiences with an immunization strategy against bacterial strains after kidney transplantation. METHODS: We performed a retrospective single-center analysis of an immunization approach against 10 strains of inactivated bacteria (StroVac). A total of 14 renal transplant recipients with 3 or more UTI episodes/year underwent immunization with 3 subcutaneous injections of inactivated bacteria (follow-up 12 months before to 12 months after immunization). These patients were compared to 14 renal transplant patients without immunization who were matched for number of UTIs and time after transplantation (24 months follow-up). We compared the UTI incidence and potential side effects, including development of de novo donor-specific antibodies (DSA). RESULTS: The immunization significantly decreased the incidence of UTIs from 3.4 ± 1.3 to 0.9 ± 1.0 by 74.9%. The incidence did not change from year 1 to year 2 of the observation period in the control group. Immunization was tolerated well, without any clinical complaints. There were no de novo DSAs in the first year after immunization. CONCLUSIONS: Immunization against inactivated bacterial strains substantially reduced the incidence of UTIs without eliciting any safety concerns in this small cohort of renal transplant recipients. This strategy may be a helpful expansion of our preventive measures in patients with recurrent UTIs.

Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) preferentially affects epithelia of the upper and lower respiratory tract. Thus, impairment of kidney function has been primarily attributed until now to secondary effects such as cytokine release or fluid balance disturbances. We provide evidence that SARS-CoV-2 can directly infiltrate a kidney allograft. A 69-year-old male, who underwent pancreas-kidney transplantation 13 years previously, presented to our hospital with coronavirus disease 2019 (COVID-19) pneumonia and impaired pancreas and kidney allograft function. Kidney biopsy was performed showing tubular damage and an interstitial mononuclear cell infiltrate. Reverse transcriptase polymerase chain reaction from the biopsy specimen was positive for SARS-CoV-2. In-situ hybridization revealed SARS-CoV-2 RNA in tubular cells and the interstitium. Subsequently, he had 2 convulsive seizures. Magnetic resonance tomography suggested meningoencephalitis, which was confirmed by SARS-CoV-2 RNA transcripts in the cerebrospinal fluid. The patient had COVID-19 pneumonia, meningoencephalitis, and nephritis. SARS-CoV-2 binds to its target cells through angiotensin-converting enzyme 2, which is expressed in a broad variety of tissues including the lung, brain, and kidney. SARS-CoV-2 thereby shares features with other human coronaviruses including SARS-CoV that were identified as pathogens beyond the respiratory tract as well. The present case should provide awareness that extrapulmonary symptoms in COVID-19 may be attributable to viral infiltration of diverse organs.

The Aquaporin3 Promoter Polymorphism -1431 A/G is Associated with Acute Graft Rejection and Cytomegalovirus Infection in Kidney Recipients Due to Altered Immune Cell Migration.

Major complications after kidney transplantation are graft rejection and cytomegalovirus (CMV) infection, which are related to T-cell function, which depends on aquaporin3 (AQP3) expression. The impact of the AQP3 A(-1431)G promoter polymorphism in kidney transplant recipients was unelucidated and we explored the effect of AQP3 polymorphism on immune cell function and its association with graft rejection and CMV infection in 237 adult patients within 12 months after transplantation. AQP3 promoter polymorphism was molecular and functional characterized. Kaplan-Meier plots evaluated the relationship between genotypes and the incidence of CMV infection and graft rejection. AQP3 A(-1431)G A-allele was associated with enhanced immune cell migration and AQP3 expression in T-cells. The incidences of rejection were 45.4% for the A-allele and 27.1% for G-allele carriers (p = 0.005) and the A-allele was a strong risk factor (hazard ratio (HR): 1.95; 95%CI: 1.216 to 3.127; p = 0.006). The incidences for CMV infection were 21% for A-allele and 35% for G-allele carriers (p = 0.013) and G-allele was an independent risk factor (p = 0.023), with a doubled risk for CMV infection (HR: 1.9; 95%CI: 1.154 to 3.128; p = 0.012). Hence, A-allele confers more resistance against CMV infection, but susceptibility to graft rejection mediated by T-cells. Thus, AQP3-genotype adapted management of immunosuppression and antiviral prophylaxis after kidney transplantation seems prudent.