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CXCL10 is a promising early noninvasive diagnostic marker for allograft rejection and predictive for long-term outcomes. However, its value when measured later in the posttransplant course has not yet been accurately analyzed.We investigated urinary CXCL10 in 141 patients from a prospective, observational renal transplant cohort with 182 clinically indicated allograft biopsies performed12 months posttransplant and corresponding urines. Urinary CXCL10 was retrospectively quantified on stored urines using the MSD V-Plex Chemokine Panel 1 sandwich immunoassay (Meso Scale Discovery). The primary outcome was a composite of allograft loss/renal function decline (30% estimated glomerular filtration rate [eGFR]-decrease between index biopsy and last follow-up).Seventy-two patients (51%) reached the primary outcome, and their urinary CXCL10 levels were significantly higher at the time of their biopsy compared with patients with stable allograft function (median 9.3 ng/mmol vs 3.3 ng/mmol, P.0001). Time-to-endpoint analyses according to high/low urinary CXCL10 demonstrated that low urinary CXCL10 (≤7.0 ng/mmol) was associated with 73% 5-year event-free graft survival compared with 48% with high urinary CXCL10 (7.0 ng/mmol; P = .0001). Even in histologically quiescent patients, high urinary CXCL10 was associated with inferior endpoint-free graft survival (P = .003), and it was an independent predictor of the primary outcome (P = .03).This study demonstrates that urinary CXCL10 has a promising diagnostic performance for detection of late allograft rejection and is an independent predictor of long-term renal allograft outcomes, even in histologically quiescent patients.

Background Cytomegalovirus (CMV) serostatus and CMV replication are considered as risk factors for inferior graft and patient survival after renal transplantation, but long-term outcome data are limited. The aim of this retrospective single-centre study was to investigate the impact of CMV serostatus and CMV replication/disease on long-term outcomes in a well-defined cohort managed by a standardized CMV prevention/treatment protocol. Methods We investigated 599 consecutive kidney transplantations having a CMV prevention protocol consisting of either prophylaxis (D+/R− and R+ with ATG induction) or screening/deferred therapy (R+ without ATG induction). Patients were grouped according to CMV serostatus [high risk (D+/R−): n = 122; intermediate risk (R+): n = 306; low risk (D−/R−): n = 171] and occurrence of CMV replication/disease (no CMV replication: n = 419; asymptomatic CMV replication: n = 110; CMV syndrome: n = 39; tissue-invasive CMV disease: n = 31). The median follow-up time was 6.5 years. Results Graft and patient survival were not different among the three CMV serostatus groups as well as the four CMV replication/disease groups (P ≥ 0.44). Eighty-seven patients died, 17 due to infections (21%), but none was attributable to CMV. The overall hospitalization incidence for CMV-related infection was 3% (17/599 patients). The incidence of clinical and (sub)clinical rejection was similar among the groups (P ≥ 0.17). In a multivariate Cox proportional hazard model, neither CMV serostatus, nor CMV replication, nor CMV disease were independent predictors for patient death or graft failure, respectively. Conclusions This retrospective single-centre study suggests that the negative impact of CMV infection on long-term patient and allograft survival as well as on allograft rejection can be largely eliminated with current diagnostic/therapeutic management.

Kidney Biopsies - the Basics and Recent Developments Abstract. Renal biopsies are taken to clarify the differential diagnosis of glomerular hematuria, proteinuria, and renal insufficiency. Nephropathology services are usually available at larger pathology units only because of the special equipment needed for light microscopy, immunohistology, and electron microscopy, the low number of biopsies processed compared to other fields, and the special expertise needed to read and sign out the cases. Biopsy diagnosis crucially contributes to the diagnostic workup and therapy of patients with kidney diseases. Increasingly, new immunohistochemical markers allow an etiological classification. We discuss paraprotein-associated kidney diseases in more detail because they are relatively common. Many of these patients do not fulfil the diagnostic criteria of plasma cell myeloma. Several years ago, the term «monoclonal gammopathy of renal significance» (MGRS) and a more aggressive therapeutic approach was introduced for these patients, with an improvement in mortality and morbidity. We also review the new group of complement C3-glomerulopathies. Although relatively rare, they have a very interesting pathophysiology and novel anti-complement therapies may provide new therapeutic approaches.

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 (

AIMS OF THE STUDY Non-adherence to immunosuppressive therapy in patients following solid organ transplantation is associated with an increased risk of transplant rejection and graft loss. A high pill burden can adversely affect patients’ implementation of their treatment regimens and may lead to omitting doses of medication. The aim of this study was to investigate medication implementation adherence in liver and kidney transplant recipients converted from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus. METHODS This multicentre, non-interventional, observational, 12-month study evaluated implementation adherence in routine practice at five hospitals in Switzerland. Patients attended four clinical visits: at baseline (pre-conversion), and then at week 2, month 6 and month 12 post-conversion. Implementation was defined as consistently taking medication at the correct time and at the correct dose in order to achieve target tacrolimus trough levels. Implementation adherence was evaluated in three ways: using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) interview questionnaire (at baseline and month 12), investigator-rated patient adherence (recorded at all visits), and tacrolimus trough levels (assessed throughout the study; sub-therapeutic levels were predefined by the investigator on an individual patient basis, over-therapeutic levels were defined as tacrolimus trough levels >15 ng/ml). The primary composite endpoint was non-adherence according to the BAASIS at month 12, any post-conversion investigator adherence rating of “poor”, or sub-therapeutic or over-therapeutic tacrolimus trough levels at month 6 or 12. Secondary endpoints included: individual components of the composite non-adherence primary endpoint, tacrolimus pill burden, patient satisfaction, and adverse drug reactions. RESULTS Seventy-five patients received prolonged-release tacrolimus; 68 patients (46 kidney and 22 liver transplant recipients) completed the study. Of these 68 patients, 24 had missing data for at least one component of the primary endpoint; therefore, data for the primary composite endpoint were evaluable for 44 patients. Most (81.8%; 36/44) patients were non-adherent for the composite endpoint. Sub-therapeutic tacrolimus trough levels outside of the predefined therapeutic range were the largest contributor to the composite endpoint, and were detected in 62.0% (31/50) of patients. Overall non-adherence according to the BAASIS was similar pre-conversion (30.7%) and at 12 months post-conversion (28.3%). Investigators rated adherence as “poor” for two patients. Prolonged-release tacrolimus decreased tacrolimus pill burden in 66.7% of patients. All patients were very satisfied / satisfied with prolonged-release tacrolimus; 75.0% found it easier to remember to take prolonged-release versus immediate-release tacrolimus. Twenty percent of patients reported adverse drug reactions, with infections being the most frequently reported (9.3%). CONCLUSION Overall, 1-year non-adherence rates were similar following conversion from immediate-release to prolonged-release tacrolimus; however, prolonged-release tacrolimus intake was more convenient. No new safety signals were detected.

Kidney Biopsies - the Basics and Recent Developments

Patient: Male, 56 Final Diagnosis: Hemorrhagic duodenitis Symptoms: Abdominal pain • melena Medication: — Clinical Procedure: CT scan • gastroscopy • colonoscopy • blood transfusion Specialty: General and Internal Medicine Objective: Challenging differential diagnosis Background: Hemorrhagic duodenitis is an exceptionally rare adverse event of sodium polystyrene sulfonate (SPS) treatment and is a common manifestation of cytomegalovirus (CMV) reactivation. SPS is known to cause marked inflammation in the lower gastrointestinal tract, including colonic necrosis, whereas involvement of the small bowel is uncommon. Although its effectiveness and safety has been disputed since its introduction, SPS remains widely used due to lack of alternatives. CMV infection and reactivation are well-known complications after solid-organ transplantation, particularly in seronegative recipients receiving organs from seropositive donors, and is associated with significant morbidity and mortality. The lower gastrointestinal tract is more commonly involved, but infections of all parts of the intestine are observed. Case Report: Here, we report the case of a 56-year-old man who presented with severe upper-gastrointestinal bleeding. Hemorrhagic duodenitis was initially attributed to the use of SPS, as abundant SPS crystals were detected in the duodenal mucosa but we found only 2 CMV-infected endothelial cells. Two weeks later, gastrointestinal bleeding recurred. However, this time, abundant CMV-infected cells were demonstrated in the duodenal biopsies. Conclusions: Our case report highlights an uncommon adverse event after SPS use with a simultaneous CMV reactivation. The main difficulty was to differentiate between CMV reactivation and CMV as an “innocent bystander”. This demonstrates the challenge of decision-making in patients with complex underlying diseases.

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1.3:1 for childhood presentation and 1:2 for adult presentation. Complement Factor I and Membrane Cofactor Protein mutations were more common in patients with initial presentation as adults and children, respectively. Initial presentation in childhood significantly predicted ESRD risk (adjusted hazard ratio 0.55 [95% confidence interval 0.41-0.73], whereas sex, race, family history of aHUS, and time from initial presentation to diagnosis, did not. Patients with a Complement Factor H mutation had reduced ESRD-free survival, whereas Membrane Cofactor Protein mutation was associated with longer ESRD-free survival. Additionally extrarenal organ manifestations occur in 19%-38% of patients within six months of initial disease presentation (dependent on organ). Thus, our real-world results provide novel insights regarding phenotypic variables and genotypes on the clinical manifestation and progression of aHUS.

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.

Renal dysfunction in the setting of cholestatic liver disease is multifactorial but most often due to decreased kidney perfusion from intravascular volume depletion, acute tubular injury/necrosis, and hepatorenal syndrome. Drug-induced hepatotoxicity may be associated with a cholestatic injury pattern. We report a case of a 56-year-old man with a diagnosis of bile cast nephropathy, as a complication of drug-induced severe hyperbilirubinemia due to the abuse of intramuscular anabolic steroids bought on the internet to increase muscular mass for bodybuilding training. Kidney biopsy showed the histological pattern of diffuse potentially reversible tubular damage with intratubular bile casts obstructing the renal tubules. The patient developed acute kidney injury and needed dialysis treatment for 4 weeks until renal function recovered. The severity of the kidney injury and the requirement of hemodialysis observed in our patient are unique and have not been previously described. As full recovery of renal function is suspected with decreasing bilirubin levels, early recognition and treatment of the underlying disease is essential.

Delayed graft function (DGF) and pretransplant donor-specific HLA-antibodies (DSA) are both regarded as risk factors for rejection and lower graft survival. However, the combined impact of DGF and DSA has not been studied in detail.We investigated 375 deceased donor kidney transplantations, which had DSA assignment by single-antigen bead technology and which had surveillance biopsies at 3 of 6 months. Median follow-up time was 6.1 years.DGF occurred in 137 of 375 patients (37%), and DSA were present in 85 of 375 patients (23%). The incidence of DGF was similar in DSA-positive (DSApos)-patients and DSA-negative (DSAneg)-patients (40% versus 36%; P = 0.45). In DSAneg-patients, 5-year graft survival was not different with/without DGF (81% versus 83%; P = 0.48). By contrast, in DSApos-patients, 5-year graft survival was significantly lower with DGF (64% versus 79%; P = 0.01). Moreover, DSApos-patients with DGF had a higher 1-year incidence of subclinical rejection, which were mostly antibody-mediated or mixed rejection phenotypes. Graft loss due to rejection was significantly more frequent in DSApos-patients with DGF (5/34; 15%) compared to DSApos-patients without DGF (2/51; 4%), and DSAneg-patients with/without DGF (3/103; 3% and 4/187; 2%, respectively) (P = 0.005). In a multivariate Cox model, DSA with DGF was an independent predictor for graft (hazard ratio = 2.84 [95% confidence interval, 1.54-5.06]; P = 0.001) and death-censored graft loss (hazard ratio = 4.65 [95% confidence interval, 1.83-11.51]; P = 0.002).DGF has a much more detrimental impact in DSApos-patients than in DSAneg-patients, which is likely related to a higher incidence of antibody-mediated rejection. If possible, the combined risks of DGF and DSA should be avoided.

IntroductionSubclinical inflammation is an important predictor of death-censored graft loss, and its treatment has been shown to improve graft outcomes. Urine CXCL10 outperforms standard post-transplant surveillance in observational studies, by detecting subclinical rejection and early clinical rejection before graft functional decline in kidney transplant recipients.Methods and analysisThis is a phase ii/iii multicentre, international randomised controlled parallel group trial to determine if the early treatment of rejection, as detected by urine CXCL10, will improve kidney allograft outcomes. Incident adult kidney transplant patients (n~420) will be enrolled to undergo routine urine CXCL10 monitoring postkidney transplant. Patients at high risk of rejection, defined as confirmed elevated urine CXCL10 level, will be randomised 1:1 stratified by centre (n=250). The intervention arm (n=125) will undergo a study biopsy to check for subclinical rejection and biopsy-proven rejection will be treated per protocol. The control arm (n=125) will undergo routine post-transplant monitoring. The primary outcome at 12 months is a composite of death-censored graft loss, clinical biopsy-proven acute rejection, de novo donor-specific antibody, inflammation in areas of interstitial fibrosis and tubular atrophy (Banff i-IFTA, chronic active T-cell mediated rejection) and subclinical tubulitis on 12-month surveillance biopsy. The secondary outcomes include decline of graft function, microvascular inflammation at 12 months, development of IFTA at 12 months, days from transplantation to clinical biopsy-proven rejection, albuminuria, EuroQol five-dimension five-level instrument, cost-effectiveness analysis of the urine CXCL10 monitoring strategy and the urine CXCL10 kinetics in response to rejection therapy.Ethics and disseminationThe study has been approved by the University of Manitoba Health Research Ethics Board (HS20861, B2017:076) and the local research ethics boards of participating centres. Recruitment commenced in March 2018 and results are expected to be published in 2023. De-identified data may be shared with other researchers according to international guidelines (International Committee of Medical Journal Editors [ICJME]).Trial registration numberNCT03206801; Pre-results.

Introduction Recurrence of atypical hemolytic uremic syndrome (aHUS) in renal allografts is common, leading to dialysis and graft failure. Pretransplant versus posttransplant initiation of eculizumab treatment in patients with aHUS has not been rigorously investigated. We hypothesized eculizumab pretransplant would reduce dialysis incidence posttransplant. Methods Of patients enrolled in the Global aHUS Registry (n = 1549), 344 had ≥1 kidney transplant. Of these, 188 had received eculizumab. Eighty-eight patients (47%) were diagnosed with aHUS and received eculizumab before, and during, their most recent transplant (group 1). A total of 100 patients (53%; group 2) initiated eculizumab posttransplantation. This second group was subdivided into those diagnosed with aHUS before (n = 52; group 2a) or after (n = 48; group 2b) their most recent transplant. Results Within 5 years of transplantation, 47 patients required dialysis; the risk of dialysis after transplantation was significantly increased in group 2b (hazard ratio [HR] 4.6; confidence interval [CI] 1.7–12.4) but not 2a (HR 2.3; CI 0.9–6.2). Graft function within 6 months of transplantation was significantly better in group 1 (median estimated glomerular filtration rate of 60.6 ml/min per 1.73 m2) compared with 31.5 and 9.6 ml/min per 1.73 m2 in groups 2a (P = 0.004) and 2b (P = 0.0001), respectively. One meningococcal infection (resolved with treatment) and 3 deaths (deemed unrelated to eculizumab) were reported. Conclusions Outcomes for transplant patients with aHUS treated with eculizumab were improved compared with previous reports of patients with aHUS not treated with eculizumab. Our findings suggest delayed aHUS diagnosis and therefore treatment is associated with an increased risk of dialysis posttransplantation and reduced allograft function., Graphical abstract

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

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.

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.

Despite modern immunosuppression, renal allograft rejection remains a major contributor to graft loss. Novel biomarkers may help improve posttransplant outcomes through the early detection and treatment of rejection. Our objective is to provide an overview of proteomics, review recent discovery-based rejection studies, and explore innovative approaches in biomarker development.Urine MMP7 was identified as a biomarker of subclinical and clinical rejection using two-dimensional liquid chromatography tandem-mass spectrometry (LC-MS/MS) and improved the overall diagnostic discrimination of urine CXCL10 : Cr alone for renal allograft inflammation. A novel peptide signature to classify stable allografts from acute rejection, chronic allograft injury, and polyoma virus (BKV) nephropathy was identified using isobaric tag for relative and absolute quantitation (TRAQ) and label-free MS, with independent validation by selected reaction monitoring mass spectrometry (SRM-MS). Finally, an in-depth exploration of peripheral blood mononuclear cells identified differential proteoform expression in healthy transplants versus rejection.There is still much in the human proteome that remains to be explored, and further integration of renal, urinary, and exosomal data may offer deeper insight into the pathophysiology of rejection. Functional proteomics may be more biologically relevant than protein/peptide quantity alone, such as assessment of proteoforms or activity-based protein profiling. Discovery-based studies have identified potential biomarker candidates, but external validation studies are required.

Background Besides ‘definitive rejection’, the Banff classification includes categories for ‘suspicious for rejection’ phenotypes. The aim of this study was to determine the frequency and phenotypes of rejection episodes in 316 consecutive renal transplants from 2009 to 2014 grouped into patients without/with pretransplant HLA-DSA (ptDSAneg, n = 251; ptDSApos, n = 65). Methods All adequate indication (n = 125) and surveillance biopsies (n = 538) performed within the first year posttransplant were classified according to the current Banff criteria. Results ‘Suspicious for rejection’ phenotypes were 3 times more common than ‘definitive rejection’ phenotypes in biopsies from ptDSAneg patients (35% vs 11%) and equally common in biopsies from ptDSApos patients (25% vs 27%). In both groups, ‘suspicious for rejection’ phenotypes were more frequent in surveillance than in indication biopsies (28% vs 16% in ptDSAneg patients, and 37% vs 29% in ptDSApos patients). ‘Borderline changes: ‘Suspicious' for acute T-cell mediated rejection’ (91%) were the dominant ‘suspicious for rejection’ phenotype in ptDSAneg patients, whereas ‘borderline changes’ (58%) and ‘suspicious for acute/active antibody-mediated rejection’ (42%) were equally frequent in biopsies from ptDSApos patients. Inclusion of ‘suspicious for rejection’ phenotypes increased the 1-year incidence of clinical (ptDSAneg patients: 18% vs 8%, P = 0.0005; ptDSApos patients: 24% vs 18%, P = 0.31) and (sub)clinical rejection (ptDSAneg patients: 59% vs 22%, P < 0.0001; ptDSApos patients: 68% vs 40%, P = 0.004). Conclusions ‘Suspicious for rejection’ phenotypes are very common in the current era and outnumber the frequency of ‘definitive rejection’ within the first year posttransplant.

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.

Der Nachweis einer Proteinurie ist ein häufiger Zufallsbefund im Urinteststreifen. Die klinische Bedeutung reicht von einer harmlosen Ursache bis zum Ausdruck einer schweren Nierenerkrankung. Deshalb ist bei Nachweis einer Proteinurie mittels Testreifenuntersuchung eine weiterführende Abklärung notwendig. Dabei empfiehlt sich ein systematisches Vorgehen mit Quantifizierung der Proteinurie mittels Albumin/Kreatinin-Quotienten im Spoturin. Zudem lassen sich mit einer systematischen Untersuchung verschiedene Formen der Proteinurie abgrenzen (glomerulär vs tubulär vs „Überlastung“). Im Kontext mit der Klinik sind eine Beurteilung des Urinsedimentes, die Bestimmung der Nierenfunktion und eine Sonographie der Nieren und ableitenden Harnwege sinnvoll. Patienten mit ungeklärter persistierender Proteinurie und Patienten mit einer ausgeprägten Proteinurie (≥ 1 g pro Tag) müssen einem Nephrologen zugewiesen werden.

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.

BACKGROUND Early prognostic markers that identify high-risk patients could lead to increased surveillance, personalized immunosuppression, and improved long-term outcomes. The goal of this study was to validate 6-month urinary chemokine ligand 2 (CCL2) as a noninvasive predictor of long-term outcomes and compare it with 6-month urinary CXCL10. METHODS A prospective, observational renal transplant cohort (n = 185; minimum, 5-year follow-up) was evaluated. The primary composite outcome included 1 or more: allograft loss, renal function decline (>20% decrease estimated glomerular filtration rate between 6 months and last follow-up), and biopsy-proven rejection after 6 months. CCL2/CXCL10 are reported in relation to urine creatinine (ng/mmol). RESULTS Fifty-two patients (52/185, 28%) reached the primary outcome at a median 6.0 years, and their urinary CCL2:Cr was significantly higher compared with patients with stable allograft function (median [interquartile range], 38.6 ng/mmol [19.7-72.5] vs 25.9 ng/mmol [16.1-45.8], P = 0.009). Low urinary CCL2:Cr (≤70.0 ng/mmol) was associated with 88% 5-year event-free survival compared with 50% with high urinary CCL2:Cr (P < 0.0001). In a multivariate Cox-regression model, the only independent predictors of the primary outcome were high CCL2:Cr (hazard ratio [HR], 2.86; 95% confidence interval [95% CI], 1.33-5.73) and CXCL10:Cr (HR, 2.35; 95% CI, 1.23-4.88; both P = 0.009). Urinary CCL2:Cr/CXCL10:Cr area under the curves were 0.62 (P = 0.001)/0.63 (P = 0.03), respectively. Time-to-endpoint analysis according to combined high or low urinary chemokines demonstrates that endpoint-free survival depends on the overall early chemokine burden. CONCLUSIONS This study confirms that urinary CCL2:Cr is an independent predictor of long-term allograft outcomes. Urinary CCL2:Cr/CXCL10:Cr alone have similar prognostic performance, but when both are elevated, this suggests a worse prognosis. Therefore, urinary chemokines may be a useful tool for timely identification of high-risk patients.

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.

Delayed graft function (DGF) is considered as a risk factor for renal allograft rejection, but this association might be confounded by diagnostic biases (e.g., higher biopsy frequency in patients with DGF, inclusion of clinically diagnosed rejection episodes, and limited details on the rejection phenotype). This retrospective study including 329 deceased donor transplantations aimed to clarify a causal relationship between DGF and rejection. DGF occurred in 93/329 recipients (28%), whereas immediate graft function (IGF) in 236/329 recipients (72%). The percentage of patients with ≥1 allograft biopsy within the first year post-transplant was similar between the DGF and IGF group (96% vs. 94%; p = 0.60). The cumulative one-yr incidence of biopsy-proven clinical (35% vs. 34%; p = 0.62) and combined (sub)clinical rejection (58% vs. 60%; p = 0.79) was not different between the two groups. Furthermore, there were no differences regarding rejection phenotypes/severities and time frame of occurrence. By multivariable Cox regression analysis, donor-specific HLA antibodies, younger recipient age, and immunosuppressive regimens were independent predictors for clinical rejection, while DGF was not. These results in an intermediate sized, but thoroughly investigated patient population challenge the concept that DGF is a risk factor for rejection and highlights the need for additional studies in this regard.

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.

The virtual crossmatch (virtual-XM) has been proposed for accurate identification of donor-specific HLA-antibodies, but large prospective studies assessing its value for pretransplant risk stratification are lacking. A total of 233 consecutive renal allograft recipients were prospectively stratified according to the virtual-XM. In patients with a negative virtual-XM (n=190, 82%), prospective cytotoxicity crossmatches (CDC-XM) were omitted, and they received standard immunosuppression. Virtual-XM positive patients were only transplanted if CDC-XM were negative. They received additional induction with anti-T-lymphocyte-globulin and intravenous immunoglobulins (n=43, 18%). The cumulative incidence of clinical/subclinical antibody-mediated rejection (AMR) at 1 year was lower in the negative virtual-XM than in the positive virtual-XM group [15/190 (8%) vs. 18/43 (42%); P>0.0001]. After a median follow-up of 2.6 years, allograft loss because of AMR occurred less often in the negative virtual-XM group (1% vs. 7%; P=0.04) and death-censored allograft survival at 2 years was higher (98% vs. 91%; P=0.02). Serum creatinine was not different at the last follow-up (129 ?m vs. 130 ?m; P=0.58). We conclude that a negative virtual-XM defines patients at low risk for AMR and early allograft loss, while a positive virtual-XM represents a significant risk for AMR despite enhanced induction therapy. This supports the utility of the virtual-XM for risk stratification and treatment allocation.

Steroid withdrawal following renal transplantation is challenging and widely debated. This retrospective study aimed at investigating the frequency and determinants of successful steroid withdrawal guided by surveillance biopsies. We analyzed 156 pretransplant DSA-negative renal transplants receiving basiliximab induction and maintenance immunosuppression with tacrolimus-mycophenolate-steroids. The absence of rejection in surveillance biopsies at 3 or 6 months post-transplant initiated steroid withdrawal, which was monitored by subsequent indication and/or surveillance biopsies. The primary outcome was the frequency of successful (i.e., rejection-free) steroid withdrawal at 1 year post-transplant. In the whole study population, successful steroid withdrawal was achieved in 73 of 156 patients (47%). Steroid withdrawal was initiated in 98 of 156 patients (63%) and successful in 73 of 98 patients (74%). Subsequent clinical rejection occurred in only one of 98 patients (1%), whereas 24 of 98 patients (24%) experienced subclinical rejection. Steroid withdrawal was not initiated in 58 of 156 patients (37%) mainly due to current or prior severe (Banff TCMR ≥IA) subclinical rejection. Prediction of successful steroid withdrawal by pretransplant or early post-transplant parameters was poor. In conclusion, (sub)clinical rejection-free steroid withdrawal can be expected in about half of pretransplant DSA-negative patients. As successful steroid withdrawal cannot be well predicted by pre- and early post-transplant parameters, guidance by surveillance biopsies is an attractive strategy.

Summary QUESTIONS UNDER STUDY: The aim of this study was to evaluate risk factors and outcome of expanded-criteria donor (ECD) kidney transplants in patients with low immunological risk. METHODS: We evaluated graft survival and graft function in 265 recipients with low immunological risk defined as the absence of pretransplant donor-specific HLA antibodies. RESULTS: A total of 112 (42%) kidneys derived from ECD and 153 (58%) from standard-criteria donors (SCDs). Overall, in a multivariate Cox regression, ECD status was the only significant risk factor for graft failure (hazard ratio [HR] 2.31, 95% confidence interval [CI] 1.22–4.37; p = 0.01). In the SCD group there was an increased risk for graft failure with increasing recipient age (HR 1.06 per year, CI 1.01–1.10; p = 0.02) and in the ECD group a trend for risk reduction for recipients treated with tacrolimus (Tac) (HR 0.46, CI 0.20‒1.06; p = 0.07). One, three and five-year graft survival of ECD kidneys was significantly better when recipients were treated with Tac (95%, 88% and 72%, respectively) than when they were treated without Tac (73%, 65% and 50%, respectively) (p = 0.008). At three years, ECD kidneys had a lower median estimated creatinine clearance (eCrCl) than SCD kidneys (37 vs 58 ml/min, p

Proteinuria is a common incidental finding in primary care. A systematic approach is necessary to differentiate benign causes of proteinuria from severe kidney diseases. Glomerular proteinuria is the predominant pathophysiologic mechanism of the three types of proteinuria (i. e. glomerular, tubular and "overflow") and usually corresponds to urinary protein excretion1 g per day. When urine dipstick analysis is positive a quantitative measurement of urinary protein excretion is necessary. Therefore, quantification by albumin/creatinine ratio measurement in a random urine specimen is an important and reliable next step. Patients with persistent proteinuria, in whom the underlying aetiology remains unclear, besides extensive analysis or with a proteinuria ≥ 1 g per day should be referred to a nephrologist for further diagnosis and timely therapeutic interventions.Der Nachweis einer Proteinurie ist ein häufiger Zufallsbefund im Urinteststreifen. Die klinische Bedeutung reicht von einer harmlosen Ursache bis zum Ausdruck einer schweren Nierenerkrankung. Deshalb ist bei Nachweis einer Proteinurie mittels Testreifenuntersuchung eine weiterführende Abklärung notwendig. Dabei empfiehlt sich ein systematisches Vorgehen mit Quantifizierung der Proteinurie mittels Albumin/Kreatinin-Quotienten im Spoturin. Zudem lassen sich mit einer systematischen Untersuchung verschiedene Formen der Proteinurie abgrenzen (glomerulär vs tubulär vs „Überlastung“). Im Kontext mit der Klinik sind eine Beurteilung des Urinsedimentes, die Bestimmung der Nierenfunktion und eine Sonographie der Nieren und ableitenden Harnwege sinnvoll. Patienten mit ungeklärter persistierender Proteinurie und Patienten mit einer ausgeprägten Proteinurie (≥ 1 g pro Tag) müssen einem Nephrologen zugewiesen werden.

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 (P0.0001), 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.

Cryoglobulinemia induces an immune complex-mediated glomerulonephritis that is characterized by the presence of large immune deposits, including complement C3 and C5b-9, marked macrophage influx and mesangial cell proliferation. The precise role of complement in cryoglobulin-induced glomerulonephritis in humans remains unclear, whereas in mice there has been evidence that complement activation might be a central factor favoring glomerular inflammation, particularly by the recruitment of neutrophils. We report on an exceptional case of cryoglobulin-induced glomerulonephritis in a patient with mixed essential cryoglobulinemia type II. The clinical features included relapsing proteinuria and renal function impairment that were controlled by plasmapheresis. Complement was low in plasma and two renal biopsies at 1-year interval showed prominent immunoglobulin and complement deposits, with unusual high numbers of neutrophils. In a 1-patient clinical trial, we tested whether the monoclonal anti-C5 antibody eculizumab would be sufficient to control renal function at the time of a relapse. Although during the initial weeks renal function was stabilized, slow increase in creatinine could not be controlled by this treatment, so that plasmapheresis was reinstituted. This result suggests that despite evidence for a role of complement in enhancing renal damage in this patient, other inflammatory processes dominated.

The virtual crossmatch (virtual-XM) has been proposed for accurate identification of donor-specific HLA-antibodies, but large prospective studies assessing its value for pretransplant risk stratification are lacking. A total of 233 consecutive renal allograft recipients were prospectively stratified according to the virtual-XM. In patients with a negative virtual-XM (n=190, 82%), prospective cytotoxicity crossmatches (CDC-XM) were omitted, and they received standard immunosuppression. Virtual-XM positive patients were only transplanted if CDC-XM were negative. They received additional induction with anti-T-lymphocyte-globulin and intravenous immunoglobulins (n=43, 18%). The cumulative incidence of clinical/subclinical antibody-mediated rejection (AMR) at 1 year was lower in the negative virtual-XM than in the positive virtual-XM group [15/190 (8%) vs. 18/43 (42%); P0.0001]. After a median follow-up of 2.6 years, allograft loss because of AMR occurred less often in the negative virtual-XM group (1% vs. 7%; P=0.04) and death-censored allograft survival at 2 years was higher (98% vs. 91%; P=0.02). Serum creatinine was not different at the last follow-up (129 μm vs. 130 μm; P=0.58). We conclude that a negative virtual-XM defines patients at low risk for AMR and early allograft loss, while a positive virtual-XM represents a significant risk for AMR despite enhanced induction therapy. This supports the utility of the virtual-XM for risk stratification and treatment allocation.