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Eplets are functional units of structural epitopes on donor HLA, potentially recognized by complementarity-determining regions of the paratope of the recipients' B-cell receptors or antibodies (Ab). Their individual immunogenicity is poorly described, yet this feature would be of clinical importance for pretransplant risk assessment. The aim of this study was to determine the relative immunogenicity of HLA class I eplets in the pregnancy setting, where mismatched eplets are present on paternal HLA antigens of the unborn child. One hundred fifty-nine predominantly Caucasian mothers giving birth at the University Hospital Basel and their first newborns were HLA-typed at high-resolution by next-generation sequencing (NGS) (NGSgo Workflow and NGSengine from GenDx; sequencing with a Miseq from Illumina) and eplets were determined using HLAMatchmaker. HLA class I specific IgG Ab was assessed in maternal sera drawn immediately after full-term delivery, by OneLambda LABScreen single antigen ibeads. The Ab profile was subsequently evaluated for eplet-associated patterns. All 72 currently Ab-verified HLA class I eplets were examined for their immunogenicity according to the frequency of child-specific HLA Ab (CSA) directed against their structures. Four hundred twelve of 477 (86.4%) paternal HLA-A, -B or -C alleles were mismatched. CSA were present in 46 mothers (28.9%), directed against 80 (19.4%) of these mismatches. The 10 most immunogenic eplets were 62GK, 145KHA, 144TKH, 62GE, 107W, 80I, 82LR, 41T, 127K, 45KE with immunogenicity rates between 45.8% and 27.3%. This pregnancy study also identified five non-reactive eplets: 62RR, 76ESN, 80TLR, 156DA, 163RW. Based on our results, immunogenic hot and cold spots on the surface of HLA class I molecules were localized and visualized on 3D models. This study strengthens the presumption that different eplets represent different immunogenic potentials. Validation of these results in the clinical transplant setting is an essential next step in identifying those eplets representing a particularly high-risk potential.

BackgroundPatients returning to dialysis after graft loss have high early morbidity and mortality.MethodsWe used data from the Swiss Transplant Cohort Study to describe the current practice and outcomes in Switzerland. All patients who received a renal allograft between May 2008 and December 2014 were included. The patients with graft loss were divided into two groups depending on whether the graft loss occurred within 1 year after transplantation (early graft loss group) or later (late graft loss group). Patients with primary non-function who never gained graft function were excluded.ResultsSeventy-seven out of 1502 patients lost their graft during follow-up, 40 within 1 year after transplantation. Eleven patients died within 30 days after allograft loss. Patient survival was 86, 81 and 74% at 30, 90 and 365 days after graft loss, respectively. About 92% started haemodialysis, 62% with definitive vascular access, which was associated with decreased mortality (hazard ratio = 0.28). At the time of graft loss, most patients were on triple immunosuppressive therapy with significant reduction after nephrectomy. One year after graft loss, 77.5% (31 of 40) of patients in the early and 43.2% (16 out of 37) in the late-loss group had undergone nephrectomy. Three years after graft loss, 36% of the patients with early and 12% with late graft loss received another allograft.ConclusionIn summary, our data illustrate high mortality, and a high number of allograft nephrectomies and re-transplantations. Patients commencing haemodialysis with a catheter had significantly higher mortality than patients with definitive access. The role of immunosuppression reduction and allograft nephrectomy as interdependent factors for mortality and re-transplantation needs further evaluation.

The aim of this retrospective single-center study was to investigate the short- and long-term impact of neutropenia occurring within the first year after kidney transplantation, with a special emphasis on different neutropenia grades. In this unselected cohort, 225/721 patients (31%) developed 357 neutropenic episodes within the first year post-transplant. Based on the nadir neutrophil count, patients were grouped as neutropenia grade 2 (

Few data on husband-to-wife transplantations with mutual children (H2W) exist in the current era. We investigated the outcome of H2W transplantations (n = 25) treated with T cell-depleting induction compared to women with prior pregnancies also receiving their first HLA-mismatched kidney transplant, but from a different donor source: (i) other living donor (n = 52) and (ii) deceased donor (n = 120). Seventy-four percent of the women had ≥2 pregnancies; median follow-up time was 5 years. Death-censored allograft survival was significantly lower in the H2W group compared to the other two groups (p = 0.03). Three of four graft losses in the H2W group were due to rejection. 5-year patient survival in the H2W group was high and similar compared to the other living donor group (100 vs. 98%; p = 0.28). The incidence of (sub)clinical antibody-mediated rejection was higher in the H2W group (36 vs. 20 vs. 18%) (p = 0.10). The frequency of infections was similar among the three groups. No immunological parameter was predictive for rejection or graft loss in H2W transplantations. In conclusion, H2W transplantation is a valuable option, but associated with a higher risk for allograft loss due to rejection despite T cell-depleting induction. Further research is required for better risk prediction on an individual patient level.

Background: Data on individualized immunosuppressive protocols for the pediatric heart recipients are missing in Europe. To contribute to this very small but specialized field, we describe the use of induction therapy (IT) in pediatric heart transplant patients in Switzerland and the retrospective outcomes. Method: This is a retrospective national database analysis of children

Previous studies have indicated an association between coronavirus disease 2019 (COVID-19) and acute kidney injury (AKI) but lacked a control group. The prospective observational COronaVIrus-surviVAl (COVIVA) study performed at the University Hospital, Basel, Switzerland consecutively enrolled patients with symptoms suggestive of COVID-19. We compared patients who tested positive for SARS-CoV-2 with patients who tested negative but with an adjudicated diagnosis of a respiratory tract infection, including pneumonia. The primary outcome measure was death at 30 days, and the secondary outcomes were AKI incidence and a composite endpoint of death, intensive care treatment or rehospitalization at 30 days. Five hundred and seven patients were diagnosed with respiratory tract infections, and of those, 183 (36%) had a positive PCR swab test for SARS-CoV-2. The incidence of AKI was higher in patients with COVID-19 (30% versus 12%, p &lt, 0.001), more severe (KDIGO stage 3, 22% versus 13%, p = 0.009) and more often required renal replacement therapy (4.4% versus 0.93%, p = 0.03). The risk of 30-day mortality and a composite endpoint was higher in patients with COVID-19-associated AKI (adjusted hazard ratio (aHR) mortality 3.98, 95% confidence interval (CI) 1.10–14.46, p = 0.036, composite endpoint aHR 1.84, 95% CI 1.02–3.31, p = 0.042). The mortality risk was attenuated when adjusting for disease severity (aHR 3.60, 95% CI 0.93–13.96, p = 0.062). AKI occurs more frequently and with a higher severity in patients with COVID-19 and is associated with worse outcomes.

Background and Aims Previous studies have indicated a coherency between coronavirus disease 2019 (COVID-19) and acute kidney injury (AKI), indicating poor outcomes. However, most studies only included patients with COVID-19 and lacked a control group. Therefore, the aim of this study was to investigate the prevalence and prognostic impact of AKI in patients with COVID-19 in comparison with other respiratory tract infections. Method The prospective single-center observational case-control COronaVIrus surviVAl (COVIVA, clinicaltrials.gov NCT04366765) study performed at the University Hospital Basel Switzerland consecutively enrolled patients presenting to the emergency department with symptoms suggestive of COVID-19 between March 23 and May 31, 2020. The final diagnosis that led to the inclusion in the study was adjudicated by physicians after reviewing all available medical data including laboratory test results 30 days after discharge. For this analysis, we compared patients tested positive for SARS-CoV-2 with patients tested negative but with an adjudicated diagnosis of upper or lower respiratory tract infection including pneumonia. Primary outcome measure was death at 30 days, secondary outcomes were AKI incidence, renal recovery and need for renal replacement therapy. AKI was defined according to the serum creatinine criteria of the 2012 KDIGO clinical practice guideline. Results Of the 1086 patients included, 507 had a final adjudicated diagnosis of respiratory tract infection and were eligible for this analysis. Of those, 183 (36%) had a positive PCR swab test for SARS-CoV-2. Baseline characteristics were comparable between patients with and without COVID-19. AKI occurred in 95 patients (19%) with a higher incidence (30%, 95%CI 24-37 versus 12%, 95%CI 9-17, p Conclusion AKI occurs more frequently and more severely in patients with COVID-19 compared to other respiratory tract infections. It is associated with an increased risk for death, with the highest risk observed in COVID-19 patients. This underlines the augmented burden of AKI during the COVID-19 pandemic.

Introduction: To date, 23 lung transplant recipients have been described with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections worldwide Eight had severe coronavirus disease 2019 (COVID-19), but none were placed on extracorporeal membrane oxygenation (ECMO) support We aimed to describe our experience Methods: Lung transplant recipients who were admitted to our hospital with SARS-CoV-2 infections from the beginning of the pandemia until May 25th, 2020 were included Clinical charts were retrospectively retrieved and data analysed Results: Four patients (3 males, 75%) with a median age of 58 5 years (47-66) were admitted for SARS-CoV-2 infections in our center Three patients had double-lung transplantation for chronic thromboembolic pulmonary hypertension, idiopathic pulmonary fibrosis and cystic fibrosis One patient had singlelung transplantation for non-specific interstitial pneumonia SARS-CoV-2 infections were diagnosed by nasopharyngeal swabs in all patients within one month post-transplant (n=2), or after 13 months (n=1) and 15 years (n=1) Dyspnea was present in all patients Worsening of symptoms occurred in three patients after a median of 8 days (1 to 8) after diagnosis Imaging showed a highly variable degree of infiltrations Mechanical ventilation was required in three patients They all underwent prone positioning Veno-venous ECMO was required in two patients In all patients, immunosuppression consisted of prednisone and tacrolimus, while mycophenolate mofetil was stopped Treatment with hydroxychloroquine was attempted in the first three patients At last follow-up, one patient was discharged home and one was weaned from mechanical ventilation Both ECMO supported patients died from multiple organ failure, despite ECMO could be weaned in one patient Conclusion: A highly variable course of COVID-19 disease was observed in four patients after lung transplantation More data is needed to better understand prognostic factors and management of this patient cohort

Purpose: PD-(L)1–blocking antibodies have clinical activity in metastatic non–small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. Experimental Design: Peripheral blood mononuclear cells were collected from 35 patients with NSCLC receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and nonresponders to treatment. Findings were confirmed in additional cohorts of patients with NSCLC receiving immune checkpoint blockade. Results: We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR, 1.72; 95% confidence interval, 1.10–2.68; P = 0.017). No relationship was seen in cohorts of patients with NSCLC who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be due to NK-cell dysfunction. Conclusions: We identified an association of the KIR3DS1 allelic variant with response to PD-1–targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. Although the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive markers for response to PD-1–targeted immunotherapy.

Kidney transplantation from older and marginal donors is effective to confront organ shortage. However, limitations after transplantation of kidneys from very marginal kidney donors remain unclear. We compared patient and graft outcome, achieved allograft function and quality of life of renal transplantations from Very Senior Donors (VSD, defined as donors aged 70 years and older) with Senior Donors (SD, aged 60-70 years) and Regular Donors (RD, aged younger than 60 years) in Switzerland. We evaluated the outcome of 1554 adult recipients of deceased donor kidney transplantations from 05/2008 to 12/2019; median follow-up was 4.7 years. Failure-free survival (freedom from graft loss or death), glomerular filtration rate (eGFR), and quality of life at 12 months were analyzed for RD (reference group, n = 940), SD (n = 404), and VSD (n = 210). Failure-free survival decreased with increasing donor age, mainly attributable to premature graft loss. Still, overall 5-year failure-free survival reached 83.1%, 81.0%, and 64.0% in the RD, SD, and VSD subgroups, respectively. eGFR 12 months post-transplantation was significantly higher in RD compared with SD and VSD. The acceptance rate of donor candidates for kidney TPL was 78% for the entire cohort (87% for RD, 79% for SD, and 56% for VSD). Deceased donor kidney transplantation from donors aged 70 years or older is associated with an inferior, yet acceptable failure-free outcome, with sustained quality of life.

Screening for de novo donor-specific HLA antibodies (DSA) after kidney transplantation is widely recommended. The aim of this single-center, cross-sectional study was to investigate the frequency of therapeutic interventions triggered by de novo DSA screening. We included 464 patients screened for de novo DSA at annual visits after a median of 5 years post-transplant (range 1 to 19 years). Overall, de novo DSA were detected in 55/464 patients (11.9%) with a stepwise increase of the prevalence from 4.9% at one-year post-transplant to 18.9% at >10 years post-transplant. Subsequent allograft biopsies were performed in 24/55 patients (44%). The main reasons to omit biopsies were good/stable allograft function and anticipated lack of clinical consequences (e.g. relevant comorbidities). Rejection processes were detected in 16/24 biopsies (67%). Therapeutic interventions were made in 18/464 screened patients (3.9%) with a significantly higher rate in the youngest quartile of patients (≤48 years; 7.9%) compared to the middle 50% (49-67 years; 3%) and the oldest quartile (≥68 years; 1.7%) (p=0.03). Our study suggests that the frequency of therapeutic interventions triggered by de novo DSA screening after kidney transplantation is overall low, but significantly higher in younger patients, arguing for a personalized, age-adapted de novo DSA screening strategy.

We report the effectiveness of daratumumab, a human IgGκ monoclonal antibody targeting CD38 on plasma cells, for therapy-refractory antibody-mediated rejection (AMR) due to blood group antibodies in a 59-year-old man who received a living ABO-incompatible kidney transplantation. Standard treatment options for AMR due to blood group antibodies including immunoadsorption, lymphocyte depletion with anti-human T-lymphocyte globulins, intravenous methylprednisolone pulses and eculizumab limited tissue injury, however failed to sufficiently suppress blood group antibody production. After administration of daratumumab as a rescue therapy, blood group antibody titers decreased and remained at low levels without further immunoadsorption and allowed kidney graft function to recover.

Transfusions are the mainstay of supportive therapy in patients with aplastic anemia (AA) and may lead to anti- HLA alloimmunization, thereby also increasing the risk for donor-specific antibodies in the setting of HLA-mismatched transplantation. Historically, AA patients were thought to be at particularly high risk for HLA alloimmunization. In past decades, blood product manufacturing (leukoreduction) and HLA antibody testing have improved significantly by single antigen bead (SAB) technology. It is currently unknown how those developments have impacted HLA alloimmunization and treatment outcome in patients with AA. We retrospectively investigated 54 AA patients treated by immunosuppressive therapy or allogeneic hematopoietic cell transplantation after the introduction of the SAB assay at our center. We compared the HLA antibody results to a historical AA cohort (n = 26), treated before introduction of leukoreduced blood products from 1975 to 1995. HLA alloimmunization was detected in 43 of 54 (80%) recently treated patients. Past pregnancy, female gender, disease severity, age, and a history of other transfusions were significantly associated with a larger number or higher intensity (mean fluorescence intensity) of HLA antibodies. Treatment outcome including bleeding episodes, response to treatment, engraftment, graft-versus-host disease, and overall survival was not associated with HLA alloimmunization. In the historical cohort a significantly higher number of HLA antibodies (P < .01) with a higher mean fluorescent intensity (P < .01) was observed. HLA alloimmunization remains frequent in AA tested by current techniques, but it has significantly decreased since prior decades and does not affect treatment outcome. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

AIMS The aim of this study was to analyse the demographics, risk factors and in-hospital mortality rates of patients admitted with coronavirus disease 2019 (COVID-19) to a tertiary care hospital in Switzerland. METHODS In this single-centre retrospective cohort study at the University Hospital Basel, we included all patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection hospitalised from 27 February 2020 to 10 May 2021. Patients’ characteristics were extracted from the electronic medical record system. The primary outcome of this study was temporal trends of COVID-19-related in-hospital mortality. Secondary outcomes were COVID-19-related mortality in patients hospitalised on the intensive care unit (ICU), admission to ICU, renal replacement therapy and length of hospital stay, as well as a descriptive analysis of risk factors for in-hospital mortality. RESULTS During the study period we included 943 hospitalisations of 930 patients. The median age was 65 years (interquartile range [IQR] 53–76) and 63% were men. The numbers of elderly patients, patients with multiple comorbidities and need for renal replacement therapy decreased from the first and second to the third wave. The median length of stay and need for ICU admission were similar in all waves. Throughout the study period 88 patients (9.3%) died during the hospital stay. Crude in-hospital mortality was similar over the course of the first two waves (9.5% and 10.2%, respectively), whereas it decreased in the third wave (5.4%). Overall mortality in patients without comorbidities was low at 1.6%, but it increased in patients with any comorbidity to 12.6%. Predictors of all-cause mortality over the whole period were age (adjusted odds ratio [aOR] per 10-year increase 1.81, 95% confidence interval [CI] 1.45–2.26; p

BACKGROUND Alloimmunization against human platelet antigens (HPAs) during pregnancy is rare but can lead to severe bleeding disorders, such as fetal and neonatal alloimmune thrombocytopenia. STUDY DESIGN AND METHODS In a cohort of 241 uncomplicated pregnancies, we investigated the immunogenicity of HPA mismatches and correlated HLA sensitization with HPA antibody formation. HPA antibodies were measured with a Luminex-based multiplex assay. RESULTS HPA mismatches were observed in 109 of 241 pregnancies (45%), but child-specific HPA antibodies were only found in two of 109 cases (2%), indicating a low immunogenicity. Only nine of 241 women (4%) had detectable HPA antibodies. HLA sensitization was identified as a strong and independent predictor for HPA antibody formation (hazard ratio, 10.2; 95% confidence interval, 1.8-193; p = 0.006), whereas the number of pregnancies was not. CONCLUSION Our observational data indicated a low immunogenicity of HPA and suggest that a broader immune response—inferred by HLA sensitization—is probably associated with HPA antibody induction.

BACKGROUND Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene that obliterate or markedly reduce α-galactosidase A activity. This results in the systemic accumulation of its glycosphingolipid substrates in body fluids and organs, including the kidney. Fabry nephropathy can lead to end-stage renal disease requiring kidney transplantation. Little is known about its long-term outcomes and the overall patient survival after kidney transplantation. METHODS Here, we report 17 Fabry patients (15 male and 2 female subjects) who received kidney transplants and their long-term treatment and follow-up at 4 specialized Fabry centers. RESULTS The posttransplant follow-up ranged to 25 years, with a median of 11.5 (range, 0.8-25.5] years. Graft survival was similar, and death-censored graft survival was superior to matched controls. Fabry patients died with functioning kidneys, mostly from cardiac causes. In 2 male subjects 14 and 23 years posttransplant, the grafts had a few typical FD lamellar inclusions, presumably originating from invading host macrophages and vascular endothelial cells. CONCLUSIONS We conclude that kidney transplantation has an excellent long-term outcome in FD.

BACKGROUND Data about patients in Europe with corona virus disease-2019 (COVID-19) and acute kidney injury (AKI) are scarce. We examined characteristics, presentation and risk factors of AKI in patients hospitalised with COVID-19 in a tertiary hospital in Switzerland. METHODS We reviewed health records of patients hospitalised with a positive nasopharyngeal polymerase chain reaction test for SARS-CoV2 between 1 February and 30 June 2020, at the University Hospital of Basel. The nadir creatinine of the hospitalisation was used as baseline. AKI was defined according the KDIGO guidelines as a 1.5× increase of baseline creatinine and in-hospital renal recovery as a discharge creatinine

Background Reducing immunosuppression is the mainstay of treating BK polyomavirus (BKPyV) viraemia after kidney transplantation, but the best approach, efficacy and impact are undefined. We established a standard operating procedure (SOP) treating BKPyV viraemia based on first reducing calcineurin inhibitor (‘CNI first’). The aim of this study was to investigate long-term outcomes in 644 consecutive transplantations using this SOP. Methods Patients were monitored for active BKPyV infection by urinary decoy cells and, if positive, by BKPyV viraemia. In case of sustained BKPyV viraemia >1000 copies/mL, immunosuppression was reduced stepwise according to the SOP. Patients were classified as ‘no decoy cells’ [n = 432 (66%)], ‘decoy cells/no viraemia’ [n = 107 (17%)] and ‘viraemia’ [n = 105 (17%)]. Results At 6-years post-transplant, graft survival was ∼84%, the clinical rejection rate was ∼25% and they were not different among the three groups (P = 0.14; P = 0.91). The median estimated glomerular filtration rate at the last follow-up was similar (range 49–53 mL/min, P = 0.08). Of 105 viraemic patients, 101 (96%) cleared BKPyV viraemia. In 39% of patients, viraemia clearance followed a tacrolimus reduction. A reduction of mycophenolic acid was required in 43% and discontinuation in 3%. No short-term graft loss was directly attributable to BKPyV-associated nephropathy. After a median follow-up of 5 years after clearance of BKPyV viraemia, 11/101 patients (11%) developed clinical rejection: 7 (7%) T-cell-mediated rejection and 4 (4%) antibody-mediated rejection (ABMR). Conclusions Immunosuppression reduction based on ‘CNI first’ leads to similar long-term outcomes in patients with/without BKPyV viraemia and is associated with a low risk for ABMR after clearance of BKPyV viraemia. Randomized trials are needed to compare the risks and benefits of immunosuppression reduction strategies in kidney transplant patients with BKPyV viraemia.

Background. The urine C-X-C motif chemokine 10 (CXCL10) is a promising screening biomarker for renal allograft rejection. The aim of the study was to investigate important technical and biological aspects as well as potential confounders when measuring urine CXCL10. Methods. We analyzed 595 urine samples from 117 patients, who participated in a randomized controlled trial investigating the clinical utility of urine CXCL10 monitoring for posttransplant management. Urine CXCL10 was measured by an immunoassay using electrochemiluminescence. Results. Intraassay coefficient of variation was 2.5%, and interassay coefficient of variation was 10%. Urine CXCL10 remained stable (ie

Introduction In immunosuppressed hosts, rapid identification of microorganisms of bloodstream infections is crucial to ensuring effective antimicrobial therapy. Conventional culture requires up to 72 h from sample collection to pathogen identification. Methods We used the SepsiTyper Kit and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Microflex, Bruker) directly from positive blood culture (BacT/ALERT 3D, FN/FA vials; bioMerieux) in comparison to standard culture methodology (VITEK 2; bioMerieux) for species identification. Results A total of 62 consecutive positive blood cultures from immunosuppressed patients (solid organ or hematopoietic transplant recipients, or with febrile neutropenia) were analyzed. Culture yielded gram-negative bacteria (GNB) in 27/62 (43.5%) and gram-positive (GPB) in 35/62 (56.5%) vials. For GNB, the predominant species identified by MALDI-TOF and confirmed by VITEK were Escherichia coli (16/16 correctly identified) and Enterobacter cloacae (4/4), with a sensitivity and specificity of 92.6% and 100%, respectively. For GPB, predominant species were Staphylococcus aureus (3/3), coagulase-negative staphylococci (12/24), and Enterococcus faecium (6/6) with a sensitivity of 100%, 60%, and 100%, respectively. The median time from blood collection to species identification was 27.4 h with MALDI-TOF identification and 46.6 h with conventional methodology. Conclusion Using MALDI-TOF directly from positive blood cultures allowed a shorter time to identification with high sensitivity and specificity in immunosuppressed patients.

Background: Renal transplant recipients (RTRs) have an increased risk of developing nonmelanoma skin cancer, mainly cutaneous squamous cell carcinoma (cSCC). Two genes (TMC6/EVER1 and TMC8/EVER2), mutated in epidermodysplasia verruciformis (EV) patients with an increased risk of cSCC development, contain numerous single-nucleotide polymorphisms (SNPs). Aim: To evaluate the effect of SNPs in both TMC/EVER genes on the different susceptibilities of RTRs to cSCC. Method: We determined the occurrence of cSCC in 105 RTRs who were transplanted at least 7 years previously and investigated the frequency of 26 SNPs within both TMC/EVER genes in severely affected (n = 16) as well as in nonaffected RTRs (n = 25). Results: Our data did not indicate a significant association between any SNP genotype and risk of cSCC development in RTRs. Conclusion: To clarify the correlation between SNPs in both TMC genes and cSCC development in RTRs, integrated investigations of large cohorts including both RTRs and immunocompetent individuals with consideration of cSCC status, SNP genotype and human papillomavirus status might be necessary.

Background Urinary CXC chemokine ligand 10 (CXCL10) is a promising biomarker for subclinical tubulointerstitial inflammation, but limited data exist regarding its correlation with (micro)vascular inflammation. Furthermore, no study has evaluated whether concomitant serum CXCL10 improves the discrimination for (micro)vascular inflammation. Methods We investigated whether serum/urinary CXCL10 reflect subclinical inflammation within different renal compartments. Patients (n = 107) with 107 surveillance biopsies were classified as: normal histology (n = 47), normal histology with polyomavirus BK (BKV) or cytomegalovirus (CMV) viremia (n = 17), moderate-severe tubulointerstitial inflammation (tubulitis ≥2, n = 18), pure microvascular inflammation (n = 15), and isolated v lesions (n = 10). Serum and urinary CXCL10 Enzyme-linked Immunosorbent Assay was performed. An independent validation set was evaluated for urine CXCL10: normal histology (n = 14), normal histology with BKV or CMV viremia (n = 19), tubulitis ≥2 (n = 15), pure microvascular inflammation (n = 41), and isolated v lesions (n = 14). Results Elevated urinary CXCL10 reflected inflammation within the tubulointerstitial (urinary CXCL10/creatinine, 1.23 ng/mmol vs 0.46 ng/mmol; P = 0.02; area under the curve, 0.69; P = 0.001) and microvascular compartments (urinary CXCL10/creatinine, 1.72 ng/mmol vs 0.46 ng/mmol; P = 0.03; area under the curve, 0.69; P = 0.02) compared to normal histology. Intriguingly, urinary CXCL10 was predominantly elevated with peritubular capillaritis, but not glomerulitis (P = 0.04). Furthermore, urinary CXCL10 corresponded with BKV, but not CMV viremia (P = 0.02). These urine CXCL10 findings were confirmed in the independent validation set. Finally, serum CXCL10 was elevated with BKV and CMV viremia but was not associated with microvascular or vascular inflammation (P ≥ 0.19). Conclusions Urinary CXCL10 reflects subclinical inflammation within the tubulointerstitial and peritubular capillary spaces, but not the vascular/systemic compartments; this was consistent with BKV (tubulointerstitial) and CMV viremia (systemic). Serum CXCL10 was not a useful marker for (micro)vascular inflammation.

BACKGROUND Right-sided retroperitoneoscopic living donor nephrectomy (LDN) has been shown to be safe for the donor but it is unknown whether the short renal vein is associated with complications or an impaired long-term outcome in the recipient. METHODS In this retrospective cohort study, consecutive transplant recipients after retroperitoneoscopic LDN were enrolled. Complications occurring within 1 year were classified according to the Clavien-Dindo Classification for Surgical Complications and analysed using multivariable logistic regression. Predictors of 1-year creatinine clearance were analysed with multivariable linear regression. Cox proportional hazard models were used to analyse graft survival. RESULTS Of the 251 recipients, 193 (77%) received a left kidney and 58 (23%) a right kidney. Surgical complications of Clavien-Dindo grade 3 or higher were comparable in recipients of right and left kidneys (33% vs 29%, odds ratio 0.98, 95% confidence interval [CI] 0.50, 1.94). The occurrence of a surgical complication had a significant impact on creatinine clearance at 1 year (decrease of 6 ml/min/m2, p = 0.016). Vascular complications in right kidneys were more common but were all corrected without impact on graft survival. One-year graft-survival was similar in recipients of right (98.3%) and left (96.9%) kidneys, as was creatinine clearance one year after transplantation (mean difference 3.3 ml/min/m2, 95% CI -1.5, 8.1; p = 0.175). After a median follow-up of 5 years, neither the side (hazard ratio 1.56, 95% CI 0.67, 3.63) nor surgical complications (hazard ratio 1.44, 95% CI 0.65, 3.19) were associated with graft failure. CONCLUSION Right retroperitoneoscopic LDN does not compromise the outcome of transplantation. Surgical complications, long-term graft function and graft survival were comparable in right and left kidneys.

Complement factor H (CFH) mutation is one of the causes of atypical haemolytic uraemic syndrome (aHUS). Patients with CFH mutation-associated aHUS progress often to end-stage renal disease despite plasma exchange therapy. When such patients are transplanted, aHUS recurs almost invariably and causes graft failure making the rationale of single kidney allograft transplantation questionable. Since CFH is synthesized mostly by the liver, combined liver-kidney transplantation has been recommended. However, fatal outcomes have been reported using this strategy. We report a case of successful single kidney allograft transplantation in a patient with a CFH gene mutation (R1210C), who had end-stage renal failure after three flares of aHUS treated with plasma exchange. He received peri- and postoperative infusions of fresh frozen plasma, which to date has prevented recurrence of the disease. He has preserved renal function 1-year post-transplant.

Panel-reactive antibodies are widely regarded as an important immunological risk factor for rejection and graft loss. The broadness of sensitization against HLA is most appropriately measured by the "calculated population-reactive antibodies" (cPRA) value. In this study, we investigated whether cPRA represent an immunological risk in times of sensitive and accurate determination of pretransplantation donor-specific HLA antibodies (DSA). Five hundred twenty-seven consecutive transplantations were divided into four groups: cPRA 0% (n = 250), cPRA 1-50% (n = 129), cPRA 51-100% (n = 43), and DSA (n = 105). Patients without DSA were considered as normal risk and received standard immunosuppression without T cell-depleting induction. Patients with DSA received an enhanced induction therapy and maintenance immunosuppression. Surveillance biopsies were performed at 3 and 6 months. Median follow-up was 5.7 years. Among the three cPRA groups, there were no differences regarding the 1-year incidence of ABMR (p = 0.16) and TCMR (p = 0.75). The 5-year allograft survival rates were similar and around 87% (p = 0.28). The estimated glomerular filtration rate at last follow-up was 50-53 mL/min (p = 0.45). On multivariable Cox proportional hazard analysis, the strongest independent predictor for ABMR and (death-censored) graft survival was pretransplantation DSA. cPRA were not predictive for ABMR, TCMR, or (death-censored) graft survival. We conclude that with current DSA assignment, the broadness of sensitization measured by cPRA does not imply an immunological risk.

Progressive interstitial fibrosis and tubular atrophy (IF/TA) is a leading cause of chronic allograft dysfunction. Increased extracellular matrix remodeling regulated by matrix metalloproteases (MMPs) and their inhibitors (TIMPs) has been implicated in the development of IF/TA. The aim of this study was to investigate whether urinary/serum MMPs/TIMPs correlate with subclinical IF/TA detected in surveillance biopsies within the first 6months post-transplant. We measured eight different MMPs/TIMPs simultaneously in urine and serum samples from patients classified as normal histology (n=15), IF/TA 1 (n=15) and IF/TA 2-3 (n=10). There was no difference in urinary MMPs/TIMPs among the three groups, and only 1/8 serum MMPs/TIMPs (i.e. MMP-1) was significantly elevated in biopsies with IF/TA 2-3 (p=0.01). In addition, urinary/serum MMPs/TIMPs were not different between surveillance biopsies demonstrating an early development of IF/TA (i.e. delta IF/TA≥1 compared to a previous biopsy obtained three months before; n=11) and stable grade of IF/TA (i.e. delta IF/TA=0; n=20). Next, we investigated whether urinary/serum MMP/TIMP levels are elevated during acute subclinical tubulitis in surveillance biopsies obtained within the first 6months post-transplant (n=25). Compared to biopsies with normal histology, serum MMPs/TIMPs were not different; however, all urinary MMP/TIMP levels were numerically higher during subclinical tubulitis (MMP-1, MMP-7, TIMP-1 with p≤0.04). We conclude that urinary/serum MMPs/TIMPs do hardly correlate with existing or early developing IF/TA in surveillance biopsies obtained within the first 6months post-transplant. This could be explained by the dynamic process of extracellular matrix remodeling, which seems to be active during acute tubulo-interstitial injury/inflammation, but not in quiescent IF/TA.

Inherited paternal HLA antigens from the semi-allogeneic fetus may trigger maternal immune responses during pregnancy, leading to the production of child-specific HLA antibodies. The prevalence of these HLA antibodies increases with the number of successful pregnancies. In the present study, we investigated the effect of a single prior miscarriage on HLA antibody formation during a subsequent successful pregnancy. Women with a successful pregnancy with one or more prior miscarriages (n = 229) and women with a successful pregnancy without a prior miscarriage (n = 58), and their children were HLA typed. HLA antibody analyses were performed in these women to identify whether HLA antibodies were formed against mismatched HLA class-I antigens of the last child. The percentage of immunogenic antigens was significantly lower after a single successful pregnancy that was preceded by a single miscarriage (n = 18 women) compared to a successful pregnancy that was preceded by a first successful pregnancy (n = 62 women). Thus, our data suggest that a previous miscarriage has a different impact on child-specific HLA antibody formation during a subsequent successful pregnancy than a previous successful pregnancy. The lower immunogenicity in these women cannot be explained by reduced numbers of immunogenic B-cell and T-cell epitopes. In conclusion, our observations indicate that increasing gravidity is not related to an increased prevalence of HLA antibodies in a single successful pregnancy that was preceded by a single prior miscarriage.

Background Induction treatment with rabbit polyclonal antithymocyte globulins (ATGs) is frequent used in kidney transplant recipients with donorspecific HLA antibodies and shows acceptable outcomes. The two commonly used ATGs, Thymoglobulin and ATG-F have slightly different antigen profile and antibody concentrations. The two compounds have never been directly compared in a prospective trial in immunological high-risk recipients. Therefore we performed a prospective randomized controlled study comparing the two compounds in immunological high-risk kidney recipients in terms of safety and efficacy. Methods Immunological high-risk kidney recipients, defined as the presence of HLA DSA but negative CDC-B and T-cell crossmatches were randomized 1:1 to receive ATG-F or Thymoglobulin. Maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and steroids. Results The per-protocol analysis included 35 patients. There was no immediate infusion reaction observed with both compounds. No PTLD or malignancy occurred during the follow-up in both groups. The incidence of viral and bacterial infections was similar in both groups (p = 0.62). The cumulative incidence of clinical and subclinical antibody mediated allograft rejection as well as T-cell mediated allograft rejection during the first year between ATG-F and Thymoglobulin was similar (35% versus 19%; p = 0.30 and 11% versus 18%; 0.54 respectively). The two-year graft function was similar with a median eGFR of 56 ml/min/1.73m2 (range 21–128) (ATG-F-group) and 51 ml/min/1.73m2 (range 22–132) (Thymo-group) (p = 0.69). Conclusion We found no significant differences between the compared study drugs for induction treatment in immunological high-risk patients regarding safety and efficacy during follow-up with good allograft function at 2 years after transplantation.

One of the major tasks of human leukocyte antigen (HLA) laboratories is the pretransplant determination of unacceptable HLA antigen mismatches (UAM) in organ transplant recipients. HLA antigen specificities are determined against which the patient has circulating alloantibodies that are expected to harm the transplanted organ. Using the information on UAM, negative crossmatch (XM) prediction or 'virtual XM' is possible when a potential donor's complete HLA typing is available. Before the introduction of solid-phase antibody detection assays, UAM were determined using the complement-dependent cytotoxicity methodology. After the introduction of the single antigen bead technique, however, various UAM determination algorithms have emerged. In this report, six different laboratories worldwide present how they determine UAM in their collective of kidney transplant recipients in the pretransplant phase and proceed thereafter to transplantation.

Soluble CD30 (sCD30) has been proposed as a promising noninvasive biomarker for clinical renal allograft rejection, but its diagnostic characteristics regarding detection of subclinical rejection have not been assessed. We investigated sCD30 in 146 consecutive kidney allograft recipients under tacrolimus-mycophenolate-based immunosuppression having 250 surveillance biopsies at 3 and 6 months as well as 52 indication biopsies within the first year post-transplant. Allograft histology results were classified as (i) acute Banff score zero or interstitial infiltrates only, (ii) tubulitis t1, (iii) tubulitis t2-3 and (iv) isolated vascular compartment inflammation. sCD30 correlated well with the extent of clinical (P < 0.0001), but not subclinical tubulointerstitial rejection (P = 0.06). To determine diagnostic characteristics of sCD30, histological groups were assigned to two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (tubulitis t1-3 and isolated vascular compartment inflammation). For clinical allograft inflammation, AUC was 0.87 (sensitivity 89%, specificity 79%; P = 0.0006); however, for subclinical inflammation, AUC was only 0.59 (sensitivity 50%, specificity 69%; P = 0.47). In conclusion, sCD30 correlated with clinical, but not subclinical renal allograft rejection limiting its clinical utility as a noninvasive rejection screening biomarker in patients with stable allograft function receiving tacrolimus-mycophenolate-based immunosuppression.

The aim was to investigate changes in kidney allograft donor/recipient characteristics and outcomes at our centre.We retrospectively reviewed all 2222 kidney transplantations performed between 1967 and 2015. The population was divided into four eras on the basis of time intervals corresponding to major changes in immunosuppression and pretransplant risk stratification: (i.) 1967-1980 (n = 231), (ii.) 1981-1997 (n = 883), (iii.) 1998-2004 (n = 437), (iv.) 2005-2015 (n = 671).In deceased donor transplants, we observed a continuous increase of the median recipient (45, 51, 56 and 58 years; p0.0001) and donor (26, 36, 49 and 54 years; p0.0001) age. Notably, the frequency of expanded criteria donors increased dramatically (1%, 10%, 28%, 40%, p0.0001). Graft survival at 1 year (63%, 82%, 89%, 95%), 5 years (46%, 66%, 72%, 78%) and 10 years (27%, 46%, 48%, 61%) significantly improved (p0.0001). Patient survival also significantly improved and remained stable at a high level within the last three eras (1 year: 97%; 5 years: 87%; 10 years: 71%). Similar trends along with slightly better outcomes were noticed in living donor transplantations. In the most recent era, graft losses in elderly patients were in 81% of cases related to the patient's death, whereas in young patients 83% of graft losses were caused by transplant failure (mainly rejection). Allograft function at the time of patients' deaths would have allowed for calculated 10 additional years with an estimated glomerular filtration rate15 ml/min.Despite increasing donor and recipient age, outcomes improved, illustrating ongoing progress in kidney transplantation. A major new challenge is to match the functional capacity of the donor organ with the anticipated lifespan of the recipient.

Urinary CXCL10 is a promising noninvasive biomarker for tubulo-interstitial allograft inflammation, but its diagnostic characteristics have not been assessed in a real-life setting. We investigated urinary CXCL10 in 213 consecutive renal allograft recipients having 362 surveillance biopsies at 3/6 months and 80 indication biopsies within the first year posttransplant. Allograft histology results were classified as (i) acute Banff score zero, (ii) interstitial infiltrates only, (iii) tubulitis t1, (iv) tubulitis t2-3 and (v) isolated vascular compartment inflammation. For clinical and subclinical pathologies, urinary CXCL10 correlated well with the extent of tubulo-interstitial inflammation. To determine diagnostic characteristics of urinary CXCL10, histological groups were separated into two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (i.e. tubulitis t1-3 and isolated vascular compartment inflammation). For subclinical pathologies, AUC was 0.69 (sensitivity 61%, specificity 72%); for clinical pathologies, AUC was 0.74 (sensitivity 63%, specificity 80%). A urinary CXCL10-guided biopsy strategy would have reduced performance of surveillance and indication biopsies by 61% and 64%, respectively. Missed (sub)clinical pathologies were mostly tubulitis t1 and isolated vascular compartment lesions. In real life, urinary CXCL10 had clinically useful diagnostic properties making it a candidate biomarker to guide allograft biopsies.

Human cytomegalovirus (HCMV) can cause life-threatening disease in infected hosts. Immunization with human leukocyte antigen (HLA)-restricted immunodominant synthetic peptides and adoptive transfer of epitope-specific T cells have been envisaged to generate or boost HCMV-specific cellular immunity, thereby preventing HCMV infection or reactivation. However, induction or expansion of T cells effective against HCMV are limited by the need of utilizing peptides with defined HLA restrictions. We took advantage of a combination of seven predictive algorithms to identify immunogenic peptides of potential use in the prevention or treatment of HCMV infection or reactivation. Here we describe a pp65-derived peptide (pp65(340-355), RQYDPVAALFFFDIDL: RQY16-mer), characterized by peculiar features. First, RQY-16mer is able to stimulate HCMV pp65 specific responses in both CD4(+) and CD8(+) T cells, restricted by a wide range of HLA class I and II determinants. Second, RQY-16mer is able to induce an unusually wide range of effector functions in CD4(+) T cells, including proliferation, killing of autologous HCMV-infected target cells and cytokine production. Third, and most importantly, the RQY-16mer is able to stimulate CD4(+) and CD8(+) T-cell responses in pharmacologically immunosuppressed patients. These data suggest that a single reagent might qualify as synthetic immunogen for potentially large populations exposed to HCMV infection or reactivation.

Viral infection is a common complication after kidney transplantation. The role of natural killer cells (NK cells) in this setting remains unknown. NK cells express activating and inhibitory killer cell immunoglobulin-like receptors (KIR). We analyzed whether activating KIR genes carried by kidney transplant-recipients influence the rate of viral infection during the first year after transplantation. In patients with a KIR A/A genotype (n = 40, KIR2DS4 only activating KIR) the rate of cytomegalovirus (CMV) infection and reactivation was 36%, as compared to 20% in transplant recipients with more than one activating KIR gene (KIR B/X genotype, n = 82, p = 0.04). Adjusting for other risk factors in Cox regression, the relative risk of B versus A genotype patients was 0.34 (95% CI 0.15-0.76, p = 0.009). The degree of protection increased with the number of activating KIR genes. Symptomatic CMV disease was only observed in four individuals, all carrying a KIR A/A genotype. As for viral infections other than CMV, and for bacterial infections, no KIR-linked protective effect could be detected. Also, graft function and the rate-rejection episodes were similar in KIR A/A and KIR B/X genotype individuals. This study supports a role for activating KIR in the control of CMV infection after kidney transplantation.

The purpose of this pictorial essay is to describe the role of intraoperative color duplex ultrasound in detecting vascular complications during renal transplantation. Intraoperative color duplex scanning during renal transplantation detects vascular complications noninvasively. Reasons for disturbed perfusion can be malposition or external compression, intravascular thrombi, vessel wall dissection and vasospasm. Color duplex ultrasound is a useful procedure in selected conditions with an intraoperatively suspected perfusion problem during renal transplantation.

In renal transplant recipients Parvovirus B19 (PB19) infection can lead to severe anaemia, due to lytical replication within erythroid progenitor cells. Clearance of PB19-infection and protective immunity is assumed to be provided by specific PB19-IgG-antibodies [1]. In fact, passive transfer of PB19-IgG-antibodies by means of intravenous immunoglobulin (IvIg) preparations is successfully used to treat PB19-related anaemia [1,2]; however, several reports have shown that PB19related anaemia can recur despite treatment with IvIg [2–11]. In this report we describe in detail a renal transplant patient who experienced relapsing severe PB19-related anaemia and we reviewed the current literature regarding factors associated with relapsing disease. Our data suggest that primary PB19-infection after kidney transplantation and polyclonal T-cell depleting therapies are risk factors for relapsing PB19-related anaemia. In addition, they support the concept that a PB19specific cellular immune response is critical to control PB19-infection and establish protective immunity.

During the last 10 years, polyoma BK-virus associated nephropathy (PVAN) has emerged as a serious complication in renal transplant recipients [1]. Due to the establishment of an accurate non-invasive screening procedure measuring polyomavirus BK-viraemia, BK-viruria and decoy cells in urine, PVAN can be diagnosed at early stages [2]. This allows for timely therapeutic intervention, which has significantly reduced the incidence of severe PVAN courses including graft loss [3,4]. Management of PVAN is mainly based on a reduction of the immunosuppressive drugs, while the impact of anti-viral therapy is not yet clear [5]. This strategy bears the inherent risk that allograft rejection may arise, which is difficult to differentiate from an immune response to the BK-virus, because both entities can present as morphologically and molecularly indistinguishable, with interstitial infiltrates and tubulitis [1,5–7]. Therefore, more data regarding the natural course of PVAN under reduced immunosuppression might be helpful to illuminate the scope of post-intervention responses.

BACKGROUND Tubulointerstitial injury due to rejection leads to tubular atrophy (TA)/interstitial fibrosis (IF) followed by deterioration of allograft function. This study investigated whether urinary tubular injury biomarkers can detect subclinical tubulitis found in protocol biopsies allowing for a noninvasive screening procedure. METHODS Four rigidly defined groups (stable transplants with normal tubular histology [n=24], stable transplants with subclinical tubulitis [n=38], patients with clinical tubulitis Ia/Ib [n=18], and patients with other clinical tubular pathologies [n=20]) were compared for differences in urinary intact/cleaved beta2-microglobulin (i/cbeta2m), retinol-binding protein (RBP), neutrophil-gelatinase-associated lipocalin (NGAL), and alpha1-microglobulin (alpha1m). RESULTS Tubular proteinuria was present in 38% (RBP) to 79% (alpha1m) of patients in the stable transplant with normal tubular histology group. The stable transplant with subclinical tubulitis group had slightly higher levels of i/cbeta2m (P=0.11), RBP (P=0.17), alpha1m (P=0.09), and NGAL (P=0.06) than the stable transplant with normal tubular histology group with a substantial overlap. The clinical tubulitis Ia/Ib and the other clinical tubular pathology groups had significantly higher levels of RBP, NGAL, and alpha1m than stable transplants with normal tubular histology or stable transplants with subclinical tubulitis (P

BACKGROUND The ABO blood group is a major determinant in living donor kidney transplantation since AB antigens are expressed on renal tissue. Little attention has been directed to the ABH-secretor status of the donor kidney. As renal tissue is capable of secreting soluble ABH antigens in secretors, we examined the influence of the ABH-secretor status of kidney donors on outcome in ABO-mismatched living donor kidney transplantation. STUDY DESIGN AND METHODS We retrospectively analyzed all patients who underwent ABO-mismatched kidney transplantation at the University Hospital Basel from September 2005 to October 2013. The ABH-secretor status was determined in all donors by molecular genetic analysis. RESULTS Of all 55 patients who received transplants, we excluded all patients with donor-specific antibodies (n = 4). Forty-one donors were secretors (78%) and 11 were nonsecretors (22%). Recipients of ABH-secretor donor organs showed a significantly higher glomerular filtration rate throughout the first 6 months posttransplant, whereas no significant influence on posttransplant anti-A/B titers was found. Regression analysis revealed a significant impact on humoral rejection, whereas not on vascular or interstitial rejection in protocol kidney biopsies. CONCLUSION The donor ABH-secretor status may have an influence on early posttransplant renal function in patients undergoing ABO-mismatched living donor kidney transplantation. Further prospective studies with long-term follow-up are needed to elucidate involved pathomechanisms.

There are conflicting data on the role of the lectin pathway of complement activation and its recognition molecules in acute rejection and outcome after transplantation. To help resolve this we analyzed polymorphisms and serum levels of lectin pathway components in 710 consecutive kidney transplant recipients enrolled in the nationwide Swiss Transplant Cohort Study, together with all biopsy-proven rejection episodes and 1-year graft and patient survival. Functional mannose-binding lectin (MBL) levels were determined in serum samples, and previously described MBL2, ficolin 2, and MBL-associated serine protease 2 polymorphisms were genotyped. Low MBL serum levels and deficient MBL2 diplotypes were associated with a higher incidence of acute cellular rejection during the first year, in particular in recipients of deceased-donor kidneys. This association remained significant (hazard ratio 1.75, 95% confidence interval 1.18-2.60) in a Cox regression model after adjustment for relevant covariates. In contrast, there was no significant association with rates of antibody-mediated rejection, patient death, early graft dysfunction or loss. Thus, results in a prospective multicenter contemporary cohort suggest that MBL2 polymorphisms result in low MBL serum levels and are associated with acute cellular rejection after kidney transplantation. Since MBL deficiency is a relatively frequent trait in the normal population, our findings may lead to individual risk stratification and customized immunosuppression.

This literature review summarizes the evidence on the prevalence, determinants, clinical and economic consequences of nonadherence with immunosuppressive drugs in renal transplant patients. A literature search yielded 38 articles measuring nonadherence by self-report, collateral report, assay, refill prescriptions or electronic monitoring. The weighted mean prevalence of self-reported nonadherence was 28%. Nonadherence is associated with poor clinical outcomes, contributing to 20% of late acute rejection episodes and 16% of the graft losses (weighted means). In addition, nonadherence results in lower lifetime costs because of shorter survival, yet also in a lower number of quality adjusted life years. Consistent determinants of nonadherence were younger age, social isolation, and cognitions (e.g. low self-efficacy, certain health beliefs). Determinants concerning the health care system/team seem to be under-investigated. Because the evidence summarized in this review is based on older immunosuppressive regimens, further research should focus on prevalence, determinants and consequences of nonadherence with newer immunosuppressive regimens.

Our aim is to develop noninvasive tests to monitor the renal allograft posttransplant. Previously we have reported that an unbiased proteomic based approach can detect urine protein peaks associated with acute tubulointerstitial renal allograft rejection. Identification of these proteins peaks by mass spectrometry demonstrated that they all derive from nontryptic cleaved forms of beta2 microglobulin. In vitro experiments showed that cleavage of intact beta2 microglobulin requires a urine pH < 6 and the presence of aspartic proteases. Patients with acute tubulointerstitial rejection had lower urine pH than stable transplants and healthy individuals. In addition they had higher amounts of aspartic proteases and intact beta2 microglobulin in urine. These factors ultimately lead to increased amounts of cleaved urinary beta2 microglobulin. Cleaved beta2 microglobulin as an indicator of acute tubular injury may become a useful tool for noninvasive monitoring of renal allografts.

Aim Inherited paternal HLA antigens from the semi-allogeneic fetus may trigger maternal immune responses during pregnancy, leading to the production of child-specific HLA antibodies. The prevalence of these HLA antibodies increases with the number of successful pregnancies. In the present study we investigated the effect of a single prior miscarriage on HLA antibody formation during a subsequent successful pregnancy. Methods Women with a successful pregnancy with one or more prior miscarriages (n = 58) and women with a successful pregnancy without a prior miscarriage (n = 229) and their children were HLA typed. HLA-antibody analyses were performed in these women to identify whether HLA antibodies were formed against mismatched HLA class-I antigens of the last child. Results The percentage of immunogenic antigens was significantly lower after a single successful pregnancy that was preceded by a single miscarriage (n = 18 women) compared to a successful pregnancy that was preceded by a first successful pregnancy (n = 62 women). Conclusions Our data suggest that a previous miscarriage has a different impact on child-specific HLA antibody formation during a subsequent successful pregnancy than a previous successful pregnancy. The lower immunogenicity in these women cannot be explained by reduced numbers of immunogenic B-cell and T-cell epitopes. Our observations indicate that increasing gravidity is not related to an increased prevalence of HLA antibodies in a single successful pregnancy that was preceded by a single prior miscarriage.

Aim Pregnancy can prime maternal immune responses against inherited paternal HLA of the fetus, leading to the production of child-specific HLA antibodies. We previously demonstrated that donor-specific HLA antibody formation after kidney transplantation is associated with donor-derived HLA epitopes presented by recipient HLA class-II (PIRCHE-II). In the present study we evaluated the role of PIRCHE-II in the child-specific HLA antibody formation during pregnancy. Methods A total of 229 mother–child pairs were HLA-typed. For all mismatched HLA class-I molecules of the child (inherited paternal antigens (IPA), we subsequently predicted the number of HLA epitopes that can be presented by maternal HLA class-II molecules. Child-specific antigens were classified as either immunogenic HLA or non-immunogenic HLA based upon the presence of specific antibodies and correlated to PIRCHE-II numbers. Results Immunogenic HLA contained higher numbers of PIRCHE-II than non-immunogenic HLA (median increases 1.3-fold). Moreover, the probability of IPA-specific antibody production during pregnancy increased with the number of PIRCHE-II. Conclusions In conclusion, our data suggest that the number of PIRCHE-II is related to the formation of child-specific HLA antibodies during pregnancy. The present confirmation of the role of PIRCHE-II in antibody formation outside the transplantation setting suggests that the PIRCHE-II concept is a universal principle.

Galactose-deficient IgA1 (Gd-IgA1) and IgA-IgG complexes are known to play an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed therefore to determine the impact of immunosuppression on the serum levels of Gd-IgA1, total IgA1 and IgA-IgG complexes in IgAN patients. In a retrospective study, serum samples from IgAN patients collected before transplantation (t0) and at 3- and 6-month posttransplant (t3 & t6) were used to measure the levels of Gd-IgA1, total IgA1 and IgA-IgG complexes. The area under the curves (AUC) of immunosuppressants was calculated by the plot of plasma trough level or dosage of each immunosuppressant versus time and was interpreted as the extent of drug exposure. Thirty-six out of 64 IgAN patients, who underwent kidney transplantation between 2005 and 2012, were enrolled. From t0 to t3, serum Gd-IgA1 and total IgA1 decreased significantly (24.7 AU (18.6-36.1) to 17.2 (13.1-29.5) (p

Summary Non-HLA antibodies against the angiotensin II type 1 receptor (AT1R) and the C-terminal fragment of perlecan (i.e., LG3) are associated with the development of renal allograft rejection. It is currently unknown how humans develop anti-AT1R or anti-LG3 antibodies. The aim of this study was to investigate whether pregnancy—as a model of sensitization to polymorphic proteins—induces anti-AT1R and/or anti-LG3 antibodies. We included 104 samples from women obtained after physiologic full-term pregnancy and 80 samples from healthy nonsensitized controls (40 women and 40 men). Both anti-AT1R and anti-LG3 antibody levels were lower in pregnancy samples than in controls (both P

Control of polyomavirus BK (BKV) is achieved by reducing immunosuppression allowing an effective BKV-specific T-cell response. The morphology of resolving BKV-associated nephropathy (PyVAN) has not been systematically investigated. Ninety-nine surveillance biopsies of 35 patients with BKV viremia treated exclusively by immunosuppression reduction were scored according to Banff criteria and grouped relative to BKV viremia as pre-, increasing, decreasing and post-BKV viremia. Thirty-four of 35 patients (97%) cleared BKV viremia after a median of 9 months posttransplantation. The tubulitis score, extent of tubules with intraepithelial lymphocytes, and interstitial inflammation significantly increased from the time of increasing to decreasing viremia. Tubulointerstitial inflammation, to a lower extent, persisted after clearance. The number of SV40+ tubules correlated with the BKV load in plasma, but SV40 immunohistochemistry was frequently negative (60%). During decreasing viremia, 31% of PyVAN cases were plasma cell-rich and 40% showed tubular HLA-DR expression. Compared to baseline 1 month posttransplantation, allograft function remained stable or improved in 29/35 patients (83%) after a median follow-up of 48 months. Within 1 year after clearance of BKV viremia, clinical rejection occurred in 2/35 patients (6%). Our data suggest that resolving PyVAN is typically characterized by a self-limiting acute interstitial nephritis, morphologically indistinguishable from interstitial rejection.

Background Kidneys from pediatric donors weighing 15 kg can be safely transplanted as single kidneys. However, single kidney transplantation from donors weighing 10–14 kg is controversial and has not been well investigated. Methods We analyzed the outcome of 15 recipients of single kidneys from donors weighing 10–14 kg (study group) with 40 recipients receiving an allograft from ideal deceased donors (control group). Results After a follow-up of three yr, death-censored graft survival was 100% in both groups. The calculated creatinine clearance was lower in the study group at six months (53 vs. 71 mL/min; p = 0.01) and similar at 12 months (68 vs. 68 mL/min; p = 0.48), 24 months (81 vs. 70 mL/min; p = 0.58), and 36 months (74 vs. 69 mL/min; p = 0.59). Urinary albumin/creatinine ratios were comparable between the two groups up to two yr. At three yr, urinary albumin/creatinine ratios were higher in the study group than the control group (10.5 vs. 0.9 mg/mmol; p = 0.007). Surveillance biopsies at three and six months post-transplant revealed no evidence for focal segmental glomerulosclerosis in the study group. Conclusions Transplantation of single pediatric kidneys from donors weighing 10–14 kg into adult recipients provides excellent intermediate-term outcomes. Low-grade albuminuria, three yr post-transplant, might indicate late-onset hyperfiltration injury.

The aim of this study was to define the frequency and determinants of pregnancy-induced child-specific sensitization shortly after full-term delivery using sensitive single HLA-antigen beads (SAB) and high resolution HLA-typing of the mothers and their children (n = 301). A positive SAB result was defined by a background normalized ratio >1 or a mean fluorescence intensity (MFI) >300, >500 and >1000, respectively. The overall frequency of pregnancy-induced sensitization determined by SAB shortly after full-term delivery was between 45% (MFI > 1000 cut-off) and 76% (ratio cut-off). The rate of child-specific sensitization at the HLA-A/B/C/DRB1 loci was between 28% (MFI > 1000 cut-off) and 38% (ratio cut-off). The number of live birth was associated with a higher frequency of sensitization, which was driven by child-specific, but not third party HLA-antibodies. There was a clear hierarchy of sensitization among the investigated loci (B-locus: 31%; A-locus: 26%; DRB1-locus: 20%; C-locus: 15%; p < 0.0001). Some mismatched paternal HLA-antigens led to a significantly higher rate of sensitization than the average (e.g. HLA-A2, HLA-B49, HLA-B51, HLA-C*15). Furthermore, the mother's own HLA-phenotype--especially HLA-A/B homozygosity--was associated with a higher rate and broadness of sensitization. The number of mismatched HLA-A/B/C eplets strongly correlated with the rate of child-specific class I sensitization.