International comparison and time trends of first kidney transplant recipient characteristics across Europe: an ERA Registry study.

BACKGROUND: The aim of this study was to provide an overview of age, sex and primary renal disease (PRD) distribution among first kidney transplant recipients across Europe. METHOD: The European Renal Association (ERA) Registry database was used to obtain data on patients aged 20 years or older receiving their first kidney transplant between 2010 and 2019 from 12 European countries. The numbers and percentages of recipients in each age, sex and PRD group were calculated by country, donor type and year. RESULTS: In total, 99 543 adults received a first kidney transplant. Overall, 23% of the recipients were 65 years or older, 36% were female, and 21% had glomerulonephritis and 15% diabetes mellitus as PRD. Compared with deceased donor kidney transplant recipients, living donor kidney transplant recipients were less often 65 years or older (13% versus 26%), more often had glomerulonephritis (25% versus 20%) and less often diabetes mellitus (8% versus 17%) as PRD. We found large international differences, which were most prominent for age and PRD and less prominent for sex. Over time, the largest change in recipient characteristics was observed for the percentage of recipients aged 65 years or older, increasing from 18% in 2010 to 28% in 2019 for all countries combined with a similar trend in most countries. CONCLUSION: We observed large differences for age and PRD distribution between recipients of living and deceased donor kidneys and between European countries. Over time, the percentage of older first kidney transplant recipients increased.

Time trends in preemptive kidney transplantation in Europe: an era registry study.

BACKGROUND: Preemptive kidney transplantation has better outcomes when compared to transplantation after dialysis. We aimed to examine trends in preemptive kidney transplantation between 2000 and 2019 in Europe and to provide an overview of associated policies, barriers and initiatives. METHODS: Adult patients from 12 European countries who received a preemptive kidney transplant were included. The representatives of the registries providing these data were questioned on the policies, barriers and initiatives around preemptive kidney transplantation. RESULTS: Between 2000 and 2019, 20 251 adults underwent preemptive kidney transplantation (11 169 from living donors, 8937 from deceased donors). The proportion of first kidney transplantations that were preemptive more than doubled from 7% in 2000 to 18% in 2019, reflecting a similar relative increase for living donor kidney recipients (from 21% to 43%) and deceased donor kidney recipients (from 4% to 11%). Large international differences were found. The increase in preemptive kidney transplantation was observed across all age, sex and primary renal disease groups. Countries had similar criteria for preemptive waitlisting. Barriers mentioned included donor shortage, late referral to the transplant center and long donor or recipient work-up. Suggested initiatives included raising awareness on the possibility of preemptive kidney transplantation, earlier start and shorter work-up time for recipient and living donor. CONCLUSIONS: Over the last two decades the proportion of patients receiving a first kidney transplant preemptively has more than doubled, reflecting a similar relative increase for living and deceased donor kidney recipients.

Changes in the epidemiology of kidney replacement therapy across Europe in 2020 - the first year of the COVID-19 pandemic: an ERA Registry study.

BACKGROUND: In 2020, the COVID-19 pandemic caused disruptions in kidney replacement therapy (KRT) services worldwide. The aim of this study was to assess the effect of the COVID-19 pandemic in 2020 on the incidence of KRT, kidney transplantation activity, mortality and prevalence of KRT across Europe. METHODS: Patients receiving KRT were included from 17 countries providing data to the European Renal Association Registry. The epidemiology of KRT in 2020 was compared with average data from the period 2017-2019. Also changes occurring during the first and second wave of the pandemic were explored. RESULTS: The incidence of KRT was 6.2% lower in 2020 compared with 2017-2019, with the lowest point (-22.7%) during the first wave in April. The decrease varied across countries, was smaller in males (-5.2%) than in females (-8.2%), and was moderate for peritoneal dialysis (-3.7%) and haemodialysis (-5.4%), but substantial for pre-emptive kidney transplantation (-23.6%). The kidney transplantation rate decreased by 22.5%, reaching a nadir of -80.1% during the first wave, and most for living donor kidney transplants (-30.5%). While in most countries the kidney transplantation rate decreased, in the Nordic/Baltic countries and Greece there was no clear decline. In dialysis patients, mortality increased by 11.4%, and was highest in those aged 65-74 years (16.1%), in those with diabetes as primary renal disease (15.1%), and in those on haemodialysis (12.4%). In transplant recipients, the mortality was 25.8% higher, but there were no subgroups that stood out. In contrast to the rising prevalence of KRT observed over the past decades across Europe, the prevalence at the end of 2020 (N=317787) resembled that of 2019 (N=317077). CONCLUSION: The COVID-19 pandemic has had a substantial impact on the incidence of KRT, kidney transplant activity, mortality of KRT, and prevalence of KRT in Europe with variations across countries.

Prevalence of cervical human papillomavirus in kidney transplant recipients: A systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aims to investigate the prevalence of cervical high-risk human papillomavirus (hrHPV) among kidney transplant recipients (KTRs) and, furthermore to compare it to that in immunocompetent controls. METHODS: A systematic literature search was conducted in PubMed, EMBASE, and Cochrane Library databases from January 2000 to February 2023, to identify studies investigating the prevalence of cervical hrHPV in KTRs. Pooled cervical hrHPV prevalences, odds ratios (ORs) comparing KTRs to controls and corresponding confidence intervals (CIs) were estimated using random effects logistic regression models. Heterogeneity between studies was assessed through the I2 statistic, and the significance was evaluated by the Cochrane's Q test. RESULTS: Altogether, 16 studies covering >1200 KTRs were included. The prevalence of cervical hrHPV in KTRs was 27.7% (95% CI 21.3-35.1) with substantial interstudy heterogeneity. Stratification indicated a higher prevalence in recent years (2019-2023) and in Asia (39% (95% CI 11.2-61.4)). The prevalence of HPV16 and HPV18 in KTRs was 8.0% (95% CI 3.9-15.9) and 1.7% (95% CI 0.8-3.7), respectively. Comparing hrHPV prevalence in KTRs and controls based on six studies including >500 KTRs and 1000 controls, the OR for hrHPV was 2.0 (95% CI 1.1-3.6). CONCLUSIONS: This meta-analysis establishes an increased cervical hrHPV prevalence in KTRs compared to controls. The increased risk may be associated with immunosuppressive therapy post-transplantation. Further research is needed to explore the potential benefits of HPV vaccination, including potential revaccination strategies in KTRs.

Lattice dynamics and heat transport in zeolitic imidazolate framework glasses.

The glassy state of zeolitic imidazolate frameworks (ZIFs) has shown great potential for energy-related applications, including solid electrolytes. However, their thermal conductivity (κ), an essential parameter influencing thermal dissipation, remains largely unexplored. In this work, using a combination of experiments, atomistic simulations, and lattice dynamics calculations, we investigate κ and the underlying heat conduction mechanism in ZIF glasses with varying ratios of imidazolate (Im) to benzimidazolate (bIm) linkers. The substitution of bIm for Im tunes the node-linker couplings but exhibits only a minor impact on the average diffusivity of low-frequency lattice modes. On the other hand, the linker substitution induces significant volume expansion, which, in turn, suppresses the contributions from lattice vibrations to κ, leading to decreased total heat conduction. Furthermore, spatial localization of internal high-frequency linker vibrations is promoted upon substitution, reducing their mode diffusivities. This is ascribed to structural deformations of the bIm units in the glasses. Our work unveils the detailed influences of linker substitution on the dual heat conduction characteristics of ZIF glasses and guides the κ regulation of related hybrid materials in practical applications.

Water as a Modifier in a Hybrid Coordination Network Glass.

Chemical diversification of hybrid organic-inorganic glasses remains limited, especially compared to traditional oxide glasses, for which property tuning is possible through addition of weakly bonded modifier cations. In this work, it is shown that water can depolymerize polyhedra with labile metal-ligand bonds in a cobalt-based coordination network, yielding a series of nonstoichiometric glasses. Calorimetric, spectroscopic, and simulation studies demonstrate that the added water molecules promote the breakage of network bonds and coordination number changes, leading to lower melting and glass transition temperatures. These structural changes modify the physical and chemical properties of the melt-quenched glass, with strong parallels to the "modifier" concept in oxides. It is shown that this approach also applies to other transition metal-based coordination networks, and it will thus enable diversification of hybrid glass chemistry, including nonstoichiometric glass compositions, tuning of properties, and a significant rise in the number of glass-forming hybrid systems by allowing them to melt before thermal decomposition.

Early- and late-onset posttransplant lymphoproliferative disorders among adult kidney and liver transplant recipients.

OBJECTIVES: Posttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients has a high mortality and may present early (<2 years) or late (≥2 years) posttransplantation. We investigated the clinical characteristics of early and late PTLD among kidney and liver transplant recipients. METHODS: Recipients, transplanted at Rigshospitalet, with PTLD development as adults from January 2010 to August 2020, were included. Clinical characteristics, laboratory parameters, and pathology of early and late PTLD were compared. RESULTS: Thirty-one PTLD cases were detected where 10 (32%) were early and 21 (68%) were late PTLD. EBV DNA in plasma was detected in 78% versus 28% in early and late PTLD (p = .037). None of the recipients with early PTLD and nine recipients with late PTLD (47%) had Ann Arbor stage IV at the time of their diagnosis (p = .006). Cyclophosphamid-Hydroxyrubicin-Oncovin-Prednisolon was used for treatment in 10 (48%) recipients with late PTLD (p = 0.032) only. There was no difference in mortality between the two groups. CONCLUSIONS: Recipients with late PTLD had a lower prevalence of detectable EBV DNA in plasma, were diagnosed with more advanced disease, and were more frequently treated with chemotherapy compared to recipients with early PTLD.

Risk of Anal High-grade Squamous Intraepithelial Lesions Among Renal Transplant Recipients Compared With Immunocompetent Controls.

BACKGROUND: Renal transplant recipients (RTRs) have increased risk of human papillomavirus (HPV)-related cancers, including anal cancer. We investigated the prevalence of anal high-grade intraepithelial lesions (HSILs) in RTRs compared with immunocompetent controls and risk factors for anal HSIL in RTRs. METHODS: We included 247 RTRs and 248 controls in this cross-sectional study. We obtained anal samples for HPV testing with INNO-LiPA and performed high-resolution anoscopy on all participants. The participants completed a questionnaire on lifestyle and sexual habits. We used logistic regression to estimate odds ratios (ORs) of histologically confirmed anal HSIL in RTRs vs controls and risk factors for anal HSIL in RTRs, stratified by sex and anal high-risk (hr) HPV status, adjusting for age, smoking, lifetime sexual partners, and receptive anal sex. RESULTS: RTRs had higher anal HSIL prevalence than controls, both among men (6.5% vs 0.8%; adjusted OR [aOR], 11.21 [95% confidence interval {CI}, 1.46-291.17]) and women (15.4% vs 4.0%; aOR, 6.41 [95% CI, 2.14-24.10]). Among those with anal hrHPV, RTRs had higher anal HSIL prevalence than controls (33.8% vs 9.5%; aOR, 6.06 [95% CI, 2.16-20.27]). Having had receptive anal sex (aOR, 6.23 [95% CI, 2.23-19.08]) or genital warts (aOR, 4.21 [95% CI, 1.53-11.48]) were risk factors for anal HSIL in RTRs. All HSIL cases occurred in individuals with anal hrHPV. CONCLUSIONS: RTRs had increased risk of anal HSIL compared with immunocompetent controls, with particularly high prevalence in female RTRs. Receptive anal sex, previous genital warts, and anal hrHPV infection were risk factors for anal HSIL in RTRs. Screening for anal HSIL in RTRs should be considered. CLINICAL TRIALS REGISTRATION: NCT03018927.

The HLA-DR4-DQ8 phenotype of the recipient is associated with increased mortality after kidney transplantation.

The importance of the human leukocyte antigen (HLA) system in kidney transplantation is well-known, but it remains unexplored if patient HLA antigens constitute independent risk factors in complications after transplantation. We hypothesized that specific HLA class II phenotypes associated with immune-mediated disease (HLA-IMD) predispose to immunological activity and/or complications after kidney transplantation. Based on the literature we defined HLA-DR2-DQ6; -DR3-DQ2 and -DR4-DQ8 as HLA-IMD phenotypes. We investigated associations between HLA-IMD phenotypes in patients, biomarkers of systemic chronic inflammation at the time of transplantation, and the outcome after kidney transplantation in a retrospective cohort study of 611 kidney transplanted patients. The HLA-IMD phenotypes were associated with higher levels of biomarkers of systemic inflammation. The HLA-DR4-DQ8 phenotype was associated with mortality after transplantation in Cox analyses with adjustments for confounders. Data support the hypothesis that specific HLA class II phenotypes affects immunological pathways that determine the midterm clinical outcome of kidney transplantation.

Temporal trends in the quality of deceased donor kidneys and kidney transplant outcomes in Europe: an analysis by the ERA-EDTA Registry.

BACKGROUND: We investigated 10-year trends in deceased donor kidney quality expressed as the kidney donor risk index (KDRI) and subsequent effects on survival outcomes in a European transplant population. METHODS: Time trends in the crude and standardized KDRI between 2005 and 2015 by recipient age, sex, diabetic status and country were examined in 24 177 adult kidney transplant recipients in seven European countries. We determined 5-year patient and graft survival probabilities and the risk of death and graft loss by transplant cohort (Cohort 1: 2005-06, Cohort 2: 2007-08, Cohort 3: 2009-10) and KDRI quintile. RESULTS: The median crude KDRI increased by 1.3% annually, from 1.31 [interquartile range (IQR) 1.08-1.63] in 2005 to 1.47 (IQR 1.16-1.90) in 2015. This increase, i.e. lower kidney quality, was driven predominantly by increases in donor age, hypertension and donation after circulatory death. With time, the gap between the median standardized KDRI in the youngest (18-44 years) and oldest (>65 years) recipients widened. There was no difference in the median standardized KDRI by recipient sex. The median standardized KDRI was highest in Austria, the Netherlands and the Basque Country (Spain). Within each transplant cohort, the 5-year patient and graft survival probability were higher for the lowest KDRIs. There was no difference in the patient and graft survival outcomes across transplant cohorts, however, over time the survival probabilities for the highest KDRIs improved. CONCLUSIONS: The overall quality of deceased donor kidneys transplanted between 2005 and 2015 has decreased and varies between age groups and countries. Overall patient and graft outcomes remain unchanged.

Interatomic potential parameterization using particle swarm optimization: Case study of glassy silica.

Classical molecular dynamics simulations of glassy materials rely on the availability of accurate yet computationally efficient interatomic force fields. The parameterization of new potentials remains challenging due to the non-convex nature of the accompanying optimization problem, which renders the traditional optimization methods inefficient or subject to bias. In this study, we present a new parameterization method based on particle swarm optimization (PSO), which is a stochastic population-based optimization method. Using glassy silica as a case study, we introduce two interatomic potentials using PSO, which are parameterized so as to match structural features obtained from ab initio simulations and experimental neutron diffraction data. We find that the PSO algorithm is highly efficient at searching for and identifying viable potential parameters that reproduce the structural features used as the target in the parameterization. The presented approach is very general and can be easily applied to other interatomic potential parameterization schemes.

Human papillomavirus-related anogenital premalignancies and cancer in renal transplant recipients: A Danish nationwide, registry-based cohort study.

In this registry-based cohort study, we estimated the risk of human papillomavirus (HPV)-related anogenital premalignancies and cancer in renal transplant recipients (RTRs) compared to a nontransplanted comparison cohort. We identified all first-time RTRs in Denmark during 1990-2015 in a nationwide nephrology register. For each RTR, we randomly selected 50 age- and sex-matched non-RTRs from the background population. The study population was followed for diagnoses of cervical, vaginal, vulvar, penile and anal intraepithelial neoplasia grades 2-3 (IN2/3) and cancer for up to 27 years. We estimated hazard ratios (HRs) of anogenital IN2/3 and cancer in RTRs vs. non-RTRs by Cox regression separately for men and women using age as underlying timescale, adjusting for income, education, HPV vaccination and immunocompromising conditions. We included 4,261 RTRs and 213,673 non-RTRs. RTRs had increased hazard of cervical (HR = 2.1, 95% CI: 1.7-2.8), vaginal (HR = 35.0, 95% CI: 13.9-87.7), vulvar (HR = 16.4, 95% CI: 10.4-25.8), penile (HR = 21.9, 95% CI: 11.1-43.5) and anal (women: HR = 51.1, 95% CI: 28.0-93.1; men: HR = 39.0, 95% CI: 16.7-91.1) IN2/3. The HRs of anogenital cancers were also increased at most sites. The HR of anogenital IN2/3 in female RTRs tended to be higher during graft function than during dialysis. In female RTRs aged <40 years at transplantation, 10-15% had cervical IN2/3 and 5-12% had vaginal/vulvar/anal IN2/3 within 20 years after transplantation, compared to 4-8 and 0.2-0.4%, respectively, of female non-RTRs. In conclusion, RTRs had substantially higher risk of HPV-related anogenital premalignancies and cancer than non-RTRs.

Is the alpha-galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review.

The identification of pathogenic GLA variants plays a central role in the establishment of a definite Fabry disease (FD) diagnosis. We aimed to review and interpret the published data on the p.Asp313Tyr (p.D313Y) variant pathogenicity and clinical relevance. We performed a systematic review of peer-reviewed publications and case-reports on individuals and populations harbouring the p.Asp313Tyr variant. Overall, 35 studies were included in this review. We collected data regarding the clinical manifestations, alpha-galactosidase A enzyme activity, levels of the biomarkers globotriaosylceramide (Gb3 ) and sphingosine-globotriaosylceramide (lyso-Gb3 ) and histological findings of p.Asp313Tyr carriers. The prevalence of p.Asp313Tyr in populations at risk for FD (kidney, heart, neurologic disorders, or symptomatic populations) was calculated. We found high residual enzyme activity, low frequency of clinical features specific for FD, non-elevated lysoGb3 /Gb3 concentrations and lack of intracellular Gb3 accumulation in biopsies in the p.Asp313Tyr carriers. The prevalence of the variant in populations at risk for FD was comparable to the reported frequency in the general population. A possible higher frequency was only observed in neurologic disorders. p.Asp313Tyr can be classified as neutral or variant of unknown significance. Further investigations will be helpful to clarify a possible association between the variant and manifestations in the brain vessels.

Relative and absolute cancer risks among Nordic kidney transplant recipients-a population-based study.

Kidney transplant recipients (KTRs) have an increased cancer risk compared to the general population, but absolute risks that better reflect the clinical impact of cancer are seldom estimated. All KTRs in Sweden, Norway, Denmark, and Finland, with a first transplantation between 1995 and 2011, were identified through national registries. Post-transplantation cancer occurrence was assessed through linkage with cancer registries. We estimated standardized incidence ratios (SIR), absolute excess risks (AER), and cumulative incidence of cancer in the presence of competing risks. Overall, 12 984 KTRs developed 2215 cancers. The incidence rate of cancer overall was threefold increased (SIR 3.3, 95% confidence interval [CI]: 3.2-3.4). The AER of any cancer was 1560 cases (95% CI: 1468-1656) per 100 000 person-years. The highest AERs were observed for nonmelanoma skin cancer (838, 95% CI: 778-901), non-Hodgkin lymphoma (145, 95% CI: 119-174), lung cancer (126, 95% CI: 98.2-149), and kidney cancer (122, 95% CI: 98.0-149). The five- and ten-year cumulative incidence of any cancer was 8.1% (95% CI: 7.6-8.6%) and 16.8% (95% CI: 16.0-17.6%), respectively. Excess cancer risks were observed among Nordic KTRs for a wide range of cancers. Overall, 1 in 6 patients developed cancer within ten years, supporting extensive post-transplantation cancer vigilance.

Evaluation of an electronic, patient-focused management system aimed at preventing cytomegalovirus disease following solid organ transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is common among solid organ transplant (SOT) recipients and may cause CMV disease. To optimize the implementation of existing prevention strategies, the Management of Post-transplant Infections in Collaborating Hospitals (MATCH) program was developed. Two key performances of MATCH (diagnosing CMV infection at low viral load (VL) and before the onset of CMV disease) were assessed prior to, during and after the implementation of MATCH. METHODS: The MATCH program included a personalized surveillance plan, prophylaxis and preemptive therapy determined by the recipient's risk of CMV infection. The plan was composed through predefined algorithms and implemented through harvesting of real-time data from medical records. Risk of CMV disease was compared for recipients transplanted during and after vs prior to the implementation of MATCH. Lung and non-lung transplants were analyzed separately. RESULTS: A total of 593, 349, 520, and 360 SOT recipients were transplanted before (2007-2010), during (2011-2012), early after (2013-2015), and late after (2016-2017) implementation of MATCH with an observed reduction of diagnostic VL (P < .001) over time. Risk of CMV disease was reduced among non-lung transplant recipients transplanted during (adjusted hazard ratios [95% CI] 0.15 [0.04-0.54], P = .003), early after (aHR 0.27 [0.11-0.63], P = .003), and late after (aHR 0.17 [0.06-0.52], P = .002) compared with prior to MATCH. No significant change was observed among lung transplants. CONCLUSION: Implementation of CMV preventive strategies through MATCH was associated with a reduced risk of CMV disease among non-lung transplant recipients. Furthermore, the limitations of VL as a sole indicator for CMV disease in lung transplants were emphasized.

Prevalence, type distribution and risk factors for oral HPV in Danish renal transplant recipients.

OBJECTIVE: To assess the prevalence and type distribution of oral human papillomavirus (HPV) among renal transplant recipients (RTRs) and healthy controls and to examine risk factors for oral HPV among RTRs. MATERIALS AND METHODS: During 2016-2017 we recruited 250 RTRs and 250 controls. Oral samples were tested for HPV DNA with INNO-LiPA HPV Genotyping Extra II. All participants answered a questionnaire on lifestyle and sexual behaviour, and characteristics of RTRs were obtained from medical files. We assessed prevalence and type distribution of oral HPV. Using logistic regression, the risk of oral HPV and risk factors for oral HPV among RTRs were estimated as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Overall, 30 RTRs (12.1%) and 26 controls (10.4%) were oral HPV positive (OR = 1.14; 95% CI: 0.64-2.05). Female RTRs tended to have a higher oral HPV prevalence than controls (OR = 1.73; 95% CI: 0.63-4.77), while no difference was observed among men. HPV51 was the commonest genotype. Sexual behaviour tended to be associated with oral HPV among RTRs. CONCLUSIONS: There was no overall difference in oral HPV prevalence between RTRs and controls, but female RTRs tended to have a higher prevalence of oral HPV than controls.

Pre-existing malignancies in renal transplant candidates-time to reconsider waiting times.

Current proposals for waiting times for a renal transplant after malignant disease may not be appropriate. New data on malignancies in end-stage renal disease and recent diagnostic and therapeutic options should lead us to reconsider our current practice.

Age-related renal function decline in Fabry disease patients on enzyme replacement therapy: a longitudinal cohort study.

BACKGROUND: Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age. METHODS: This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included. RESULTS: In all, 52 patients with consecutive mGFR values (n = 841) over median 7 years (range 1-13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of -0.8 ± 0.2 with an annual slope of -0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin-creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender. CONCLUSIONS: ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data.

IL-10-specific autoantibodies predict major adverse cardiovascular events in kidney transplanted patients - a retrospective cohort study.

End-stage renal failure is associated with persistent systemic inflammation. The aim of this study was to investigate if systemic inflammation at the time of kidney transplantation is linked to poor graft survival, major adverse cardiovascular events (MACE), and increased mortality, and if these processes are modulated by naturally occurring cytokine-specific autoantibodies (c-aAbs), which have been shown to regulate cytokine activity in vitro. Serum levels of cytokines, high-sensitivity C-reactive protein (hsCRP) and c-aAbs specific for interleukin (IL)-1α, tumor necrosis factor (TNF)-α, IL-6, and IL-10 were measured at the time of transplantation in a retrospective cohort study of 619 kidney transplanted patients with a median follow-up of 4.9 years (range 1.2-8.2 years). Systemic inflammation was associated with all-cause mortality in simple and multiple Cox regression analyses. IL-10-specific c-aAbs were associated with MACE after transplantation, suggesting that IL-10 may be a protective factor. Similarly, patients with a history of MACE before transplantation had lower levels of TNF-α-specific c-aAbs, hence we hypothesized that TNF may be a risk factor of MACE. These findings support that pro-inflammatory activity before transplantation is a pathological driver of MACE and all-cause mortality after transplantation. This information adds to pretransplantation risk estimation in renal transplant candidates.

Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.

BACKGROUND: IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035. FINDINGS: Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24·4% (SEM 7·7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0·74; 95% CI 0·59-0·94; p=0·0066). At 9 months, mean UPCR had decreased by 27·3% in 48 patients who received 16 mg/day (0·71; 0·53-0·94; p=0·0092) and 21·5% in the 51 patients who received 8 mg/day (0·76; 0·58-1·01; p=0·0290); 50 patients who received placebo had an increase in mean UPCR of 2·7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later). INTERPRETATION: TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation. FUNDING: Pharmalink AB.