Endostatin, soluble tumour necrosis factor receptor 1 and soluble tumour necrosis factor receptor 2 cannot predict new onset of microalbuminuria in patients with type 2 diabetes.

AIMS: Inflammation and angiogenesis play an important role in the development of early diabetic kidney disease. We investigated the association of soluble Tumour Necrosis Factor Receptor 1 (sTNF-R1), sTNF-R2 and endostatin with new onset microalbuminuria in normoalbuminuric patients with diabetes mellitus type 2. METHODS: We conducted a case control study to assess serum levels of sTNF-R1, sTNF-R2 and endostatin in 169 patients with new onset microalbuminuria and in 188 matched normoalbuminuric, diabetic controls. Baseline serum samples from participants of the ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) and observational follow-up (ROADMAP-OFU) studies were used. RESULTS: Endostatin and sTNF-R1 but not sTNF-R2 were increased at baseline in patients with future microalbuminuria. In the multivariate analysis, each log2 increment in endostatin levels was associated with an increase of only 6% in the risk of development of microalbuminuria (adjusted HR (95% CI) 1.006 (1.001-1011). sTNF-R1 and sTNF-R2 levels were conversely associated with microalbuminuria, but the results did not reach statistical significance. The respective adjusted HRs (95% CI) were 1.305 (0.928-1.774) and 0.874 (0.711-1.074). CONCLUSIONS: sTNF-R1 and sTNF-R2 failed to predict the occurrence of microalbuminuria in normoalbuminuric patients with type 2 diabetes. Likewise, the utility of endostatin in predicting new onset proteinuria is limited.

2-Step-Scores with optional nephropathology for the prediction of adverse outcomes for brain-dead donor kidneys in Eurotransplant.

BACKGROUND AND HYPOTHESIS: The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. METHODS: The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. RESULTS: Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. CONCLUSION: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

Monitoring disease activity in antineutrophil antibody-associated vasculitis.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) comprises a group of multisystem disorders with alternating periods of relapse and remission. Beyond that, a smouldering progress during apparently clinically silent phases often develops. AAVs are subgrouped in microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and renal limited vasculitis (RLV). ANCA are hallmark of this disease entity, although they are not always present. Despite the simplification of treatment, fundamental aspects concerning assessment of its efficacy and its adaptation to encountered complications or to the relapsing/remitting/subclinical disease course remain still unknown. Through the advances in pathogenesis and pathophysiology of AAV a reliable biomarker-based monitoring and treatment algorithm has not been established and disease management follows not infrequently a "trial and error" approach. Here, we overviewed the most interesting biomarkers reported so far.

Performance of Scores Predicting Adverse Outcomes in Procurement Kidney Biopsies From Deceased Donors With Organs of Lower-Than-Average Quality.

Several scores have been devised for providing a prognosis of outcomes after kidney transplantation. This study is a comprehensive test of these scores in a cohort of deceased donors with kidneys of lower-than-average quality and procurement biopsies. In total, 15 scores were tested on a retrospective cohort consisting of 221 donors, 223 procurement biopsies, and 223 recipient records for performance on delayed graft function, graft function, or death-censored graft loss. The best-performing score for DGF was the purely clinical Chapal score (AUC 0.709), followed by the Irish score (AUC 0.684); for graft function, the Nyberg score; and for transplant loss, the Snoeijs score (AUC 0.630) and the Leuven scores (AUCs 0.637 and 0.620). The only score with an acceptable performance was the Chapal score. Its disadvantage is that knowledge of the cold ischemia time is required, which is not known at allocation. None of the other scores performed acceptably. The scores fared better in discarded kidneys than in transplanted kidneys. Our study shows an unmet need for practical prognostic scores useful at the time of a decision about discarding or accepting deceased donor kidneys of lower-than-average quality in the Eurotransplant consortium.

Old known and possible new biomarkers of ANCA-associated vasculitis.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) comprises a group of multisystem disorders involving severe, systemic, small-vessel vasculitis with short- and long term serious and life-threating complications. Despite the simplification of treatment, fundamental aspects concerning assessment of its efficacy and its adaptation to encountered complications or to the relapsing/remitting/subclinical disease course remain still unknown. The pathogenesis of AAV is complex and unique, and despite the progress achieved in the last years, much has not to be learnt. Foremost, there is still no accurate marker enabling us to monitoring disease and guide therapy. Therefore, the disease management relays often on clinical judgment and follows a" trial and error approach". In the recent years, an increasing number of new molecules s have been explored and used for this purpose including genomics, B- and T-cell subpopulations, complement system factors, cytokines, metabolomics, biospectroscopy and components of our microbiome. The aim of this review is to discuss both the role of known historical and clinically established biomarkers of AAV, as well as to highlight potential new ones, which could be used for timely diagnosis and monitoring of this devastating disease, with the goal to improve the effectiveness and ameliorate the complications of its demanding therapy.

Monocyte chemoattractant protein-1 predicts the development of diabetic nephropathy.

AIM: Diabetic nephropathy (DN) is a devastating complication of diabetes mellitus (DM). Therefore, screening strategies in order to prevent its development and/or retard its progression are of paramount importance. We investigated if monocyte chemoattractant protein-1 (MCP-1) was associated with new onset microalbuminuria-the earliest sign of the albuminuric phenotype of DN- in patients with type 2 DM and normoalbuminuria. METHODS: We measured MCP-1 in serum and urine samples from patients of the Randomized Olmesartan And Diabetes Microalbuminuria Prevention (ROADMAP) study and its Observational Follow-up (OFU) cohort. A case control design was used with inclusion of 172 patients who developed microalbuminuria (MA) and of 188 well matched controls who remained normoalbuminuric. RESULTS: The median duration of follow-up for the ROADMAP cohorts was 6.5 years, whereas the mean time until occurrence of MA was 53.2 months. In the multivariate analysis, serum and urine MCP-1 remained significant predictors of new onset MA. The risk for MA increased continuously with increasing serum and urine MCP-1 levels but reached statistical significance only in the highest quartiles. The risk associations were stronger with serum MCP-1. CONCLUSIONS: MCP-1 is a marker and possibly a mediator of early diabetic nephropathy. Further prospective studies are necessary to test whether diabetic patients with elevated MCP-1 levels would benefit from specific therapeutic interventions.

Effect of creatinine metrics on outcome after transplantation of marginal donor kidneys.

INTRODUCTION: Predicting outcome after transplantation of marginal kidneys is a challenging task. Donor creatinine or estimated glomerular filtration rate (eGFR) are integral components of the respective risk scores. However, there is uncertainty on which of their values obtained successively during procurement is the most suitable. MATERIAL AND METHODS: This is a retrospective study of 221 adult brain death donors with marginal kidneys, transplanted in 223 recipients. We applied logistic regression analysis to investigate the association between initial (at hospital admission), nadir (lowest), zenith (highest) and terminal (at recovery) donor eGFR with primary non-function (PNF), delayed graft function (DGF), 3- and 12-month graft function and 1- and 3-year patient- and death-censored graft survival. RESULTS: In the multivariate analysis, admission, terminal, and the lowest donor eGFR could most accurately predict DGF. The respective ORs [95% CI] were: 0.875 [0.771-0.993], 0.818 [95% CI: 0.726-0.922] and 0.793 [0.689-0.900]. Although not being significant for DGF (OR 0.931 [95% CI: 0.817-1.106]), the highest eGFR was the best predictor of 3-month graft function (adjusted b coefficient 1.161 [95% CI: 0.355-1.968]). Analysis of primary nonfunction showed that determination of initial and the highest eGFR proved to be the best predictors. The respective ORs [95% CI] were: 0.804 [0.667-0.968] and 0.750 [0.611-0.919]. There were no differences in the risk associations of each of the four eGFR recordings with patient- and graft survival. CONCLUSION: The various eGFR recordings determined during the procurement process of marginal donors can predict PNF, DGF and 3- and 12-month graft function. Regarding short-term patient- and graft survival, there appears to be impacted by recipient factors rather than donor kidney function.

Clinical outcomes after ABO-incompatible renal transplantation: a systematic review and meta-analysis.

BACKGROUND: ABO-incompatible renal transplantation (ABOi-rTx) is increasingly used to overcome organ shortage. Evidence about its non-inferiority in comparison with ABO-compatible renal transplantation (ABOc-rTx) needs to be analysed at early and late timepoints. We aimed to investigate differences in outcome after ABOi-rTX and ABOc-rTX. METHODS: We did a systematic review and meta-analysis of observational studies published up until Dec 31, 2017, that reported outcome data (≥1 year of follow-up) after ABOi-rTx and included an ABO-compatible control group, by searching the Cochrane Central Register of Controlled Trials (CENTRAL), Embase Ovid, MEDLINE Ovid, and PubMed. Trials on recipients of ABOi-rTx were assessed, if an ABO-compatible control group was included and if outcome data on at least graft or recipient survival with 1 year or more of follow-up were available. Exclusion criteria included case reports, editorials, reviews and letters, animal studies, meeting papers, studies unable to extract data, non-renal solid organ and bone-marrow transplant studies, and deceased donor ABOc-rTx. Data were extracted from published reports. Primary endpoints were all-cause mortality and graft survival at 1, 3, 5, and more than 8 years after transplantation. In the meta-analysis, we used a fixed-effects model if the I2 value was 0, and both a fixed-effects and random-effects model if I2 was more than 0. This study is registered with PROSPERO, number CRD42018094550. FINDINGS: 1264 studies were screened and 40 studies including 49 patient groups were identified. 65 063 patients were eligible for analysis, 7098 of whom had undergone ABOi-rTx. Compared with ABOc-rTx, ABOi-rTx was associated with significantly higher 1-year mortality (odds ratio [OR] 2·17 [95% CI 1·63-2·90], p<0·0001; I2=37%), 3 years (OR 1·89 [1·46-2·45], p<0·0001; I2=29%), and 5 years (OR 1·47 [1·08-2·00], p=0·010; I2=68%) following transplantation. Death-censored graft survival was lower with ABOi-rTx than with ABOc-rTx at 1 year (OR 2·52 [1·80-3·54], p<0·0001; I2=61%) and 3 years (OR 1·59 [1·15-2·18], p=0·0040; I2=58%) only. Graft losses were equivalent to that of ABOc-rTx after 5 years and patient survival after 8 years. No publication bias was detected and the results were robust to trial sequential analysis until 5 years after transplantation; thereafter, data became futile or inconclusive. INTERPRETATION: Despite progress in desensitisation protocols and optimisation of ABOi-rTx procedures, excess mortality and loss of kidney grafts was found compared with ABOc-rTx within the first 3 years after transplantation. Only long-term outcomes after 5 years yielded equivalent survival rates and organ function. Awareness of the increased risks of infection, organ rejection, and bleeding could improve care of patients and promote efforts towards paired kidney exchange programmes. FUNDING: None.

Influence of pre-treatment blood pressure levels on antihypertensive drug benefits in diabetics: the roadmap experience.

Purpose: Most guidelines for treatment of hypertension in the setting of diabetes recommend a blood pressure (BP) target of <130/80 mmHg. However, uncertainty exists about the extent, effectiveness and safety of lowering BP in diabetics. To expand the evidence on this issue, we analysed data from the Randomised Olmesartan and Diabetes MicroAlbuminuria Prevention (ROADMAP) study population.Material: Substudy with blood pressure readings.Methods: The response after initiation of therapy and adequacy of BP control across patients with different BP levels at baseline were analysed.Results: BP at randomisation was 136.2(15.3)/80.6(9.5) [mean (SD)] mmHg with a range of 87-213/37-123 mmHg. At 1 year, mean BP was 127 (11.9)/75 (8.1) mmHg and the overall control rate (<130/80 mmHg) exceeded 61% in this population. The mean reductions in systolic [-9.4 (15.4) mmHg] and diastolic BP [-5.4 (9.5) mmHg] were highly dependent on the BP stage at Visit 1. At 1 year, treatment decreased the prevalence of patients with baseline BP levels of >160/100 from 9 to 2%[[mean BP change -31 (15.7)/ -14 (9.8) mmHg]] and of 140-159/90-99 mmHg from 32 to 11% [[mean BP change -16(12.7)/ -8.9 (8.7) mmHg]], with corresponding increases in the prevalence of patients with baseline BP levels of 120-139/80-99 from 48 to 65% [[mean BP change -4.1 (10.6)/ -3.1 (7.8) mmHg]]and of <120/80 from 11 to 22% [[mean BP change +5.9 (11.8)/+2.5 (8.6) mmHg]]. These effects did not change significantly thereafter and were maintained throughout follow-up.Conclusion: Blood pressure control is feasible in patients with diabetes without nephropathy, independent of baseline BP values. Asymmetric BP-lowering in the first year after starting therapy represents a true antihypertensive effect with sustainable shifts in BP severity.

Cardiac Surgery-Associated Acute Kidney Injury.

AKI is a common and serious complication of cardiac surgery that has a significant impact on patient morbidity and mortality. The Kidney Disease Improving Global Outcomes definition of AKI is widely used to classify and identify AKI associated with cardiac surgery (cardiac surgery-associated AKI [CSA-AKI]) on the basis of changes in serum creatinine and/or urine output. There are various preoperative, intraoperative, and postoperative risk factors for the development of CSA-AKI which should be recognized and addressed as early as possible to expedite its diagnosis, reduce its occurrence, and prevent or ameliorate its devastating complications. Crucial issues are the inaccuracy of serum creatinine as a surrogate parameter of kidney function in the perioperative setting of cardiothoracic surgery and the necessity to discover more representative markers of the pathophysiology of AKI. However, except for the tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 ratio, other diagnostic biomarkers with an acceptable sensitivity and specificity are still lacking. This article provides a comprehensive review of various aspects of CSA-AKI, including pathogenesis, risk factors, diagnosis, biomarkers, classification, prevention, and treatment management.

Short-, Mid-, and Long-term Outcomes after Deceased Donor Kidney Transplantation in Patients with Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is a common complication in hospitalized patients and may occur in potential kidney donors. Observational studies have suggested that kidney transplantation in patients with AKI is feasible and safe, but no systematic evaluation has been performed. METHODS: We performed a systematic review and meta-analysis to evaluate the outcomes of kidney transplantation in patients with AKI. We searched MEDLINE, EMBASE, Cochrane, Google Scholar, and other databases for studies reporting outcomes of donor kidneys with AKI. We included single-center, multicenter, and registry-based studies and analyzed them according to the definition and severity of AKI. Endpoints were primary and delayed graft function (PNF, DGF), length of hospital stay, rejection, graft function, patient and graft survival at one, three, five, and eight to ten years after transplantation. This study was registered in PROSPERO, number CRD42021260088. RESULTS: We identified 33 single-center, 4 multicenter, and 7 registry studies with more than 100,000 patients published between 2005 and 2022. Recipients from donors with AKI had a higher risk of delayed graft function (RR 1.51, 95% CI 1.35-1.68). Graft function at discharge was worse in the AKI group (MDCrea (95%CI): 0.96 mg/dl (0.36-1.56 I2=96%), MDGFR (95%CI): -8.88 ml/min1.73 m2 (-15.32 - -2.44 I2=93%)), but improved thereafter and was similar in both groups at 3 months after transplantation (MDCrea (95%CI): -0.05 mg/dl (-0.18-0.07 I2=0%), MDGFR (95%CI): -1.83 ml/min1.73 m2 (-5.29 - 1.63 I2=91%)). PNF and patient and graft survival were simila at one, three, five, and eight to ten years after transplantation. There were no differences in rejections regardless of AKI definition and severity. CONCLUSION: Transplantation of kidneys with AKI is associated with satisfactory short- and long-term outcomes and should be pursued to increase the donor pool.

Association of metabolic syndrome and chronic kidney disease.

The prevalence of kidney disease is increasing rapidly worldwide, reflecting rising rates of obesity, diabetes, and associated metabolic syndrome (MetS). Chronic kidney disease and related comorbidities such as obesity, diabetes, and hypertension place a significant financial burden on healthcare systems. Despite the widespread use of RAAS inhibitors, intensive blood pressure and glycemic control, and newer therapeutic options consisting of sodium/glucose cotransporter-2 (SGLT-2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists, a significant risk of progression to end-stage renal disease remains in the high-risk obese and diabetic population. The MetS is a cluster of cardiovascular risk factors that adversely affect the development and progression of chronic kidney failure. According to the criteria of the World Health Organization, it is defined by visceral adiposity, impaired glucose tolerance or insulin resistance, atherogenic dyslipidemia, raised blood pressure, and microalbuminuria with a albumin-to-creatinine ratio ≥30 mg/g. At molecular level MetS is marked by a proinflammatory state and increased oxidative stress leading to various pathophysiological changes causing endothelial dysfunction and a hypercoagulable state. Because the kidney is a highly vascularized organ, it is especially susceptible for those microvascular changes. Therefore, the MetS and its individual components are associated with the premature development, acceleration, and progression of chronic kidney disease. Therefore, it is becoming increasingly important to elucidate the underlying mechanisms of MetS-associated chronic kidney disease in order to develop new strategies for preventing and slowing the progression of renal disease. In this review, we will elucidate (i) the renal structural, hemodynamic, and metabolic changes that occur in obesity and obesity-related kidney injury; (ii) the clinicopathological characteristics of obesity-related kidney injury, primarily focusing on obesity-associated glomerulopathy; (iii) the potential additional factors or predisposing factors that may turn patients more susceptible to renal structural or functional compensatory failure and subsequent injury.

Clinical and histopathological characteristics of acute kidney injury in a cohort of brain death donors with procurement biopsies.

BACKGROUND: Kidney biopsies are routinely used for diagnostic and prognostic purposes but their utility in the intensive care unit (ICU) setting is limited. We investigated the associations of clinical and histopathological risk factors with ICU-acute kidney injury (AKI) in donors with brain death (DBD) with kidneys of lower quality and procurement biopsies. METHODS: Overall, 221 donors with brain death, 239 biopsies and 197 recipients were included. The biopsies were reread and scored according to the Banff recommendations. Clinical and histopathological data were compared between donors with and without AKI defined by serum creatinine and by urine output. Logistic regression analysis was applied to identify independent clinical and histopathological risk factors for both phenotypes. Lastly, the impact of each AKI phenotype on outcome was explored. AKI was diagnosed based on the RIFLE (Risk, Injury, Failure, Loss of function, End-stage kidney disease) AKIN (Acute Kidney Injury Network) or KDIGO (Kidney Disease Improving Global Outcomes) criteria. RESULTS: Acute kidney injury occurred in 65% of donors based both upon serum creatinine and by urine output. Serum creatinine was able to better discriminate AKI. Multiorgan failure and severe AKI were captured by serum creatinine, and hemodynamic instability by urine output. Donors with serum creatinine-AKI showed lower chronic macrovascular scores, while donors with urine output-AKI had higher chronic microvascular and tubulointerstitial scores. Tubular injury was similar between the subgroups. Except for delayed graft function and one-year death-censored graft survival, the other short-term recipient outcomes were similar for both AKI phenotypes. CONCLUSION: Serum creatinine is more suitable than urine output for defining AKI in donors with brain death. There are distinct clinical risk factors for each AKI-ICU phenotype. Donor AKI phenotype does not predict the recipient´s prognosis. Kidney biopsies do not seem to confer any tangible benefit in defining AKI in donors with brain death.

Telemedical Monitoring of Plantar Temperature in Diabetic Patients at Risk of Foot Ulcers.

BACKGROUND: The worldwide prevalence of diabetic foot ulcers (DFUs) among persons with diabetes is estimated at 6.3%, with an annual incidence of 9.1 to 26.1 million persons. The early detection of asymmetrical plantar temperature elevation, followed by reduction of weight-bearing on the affected foot, may be an effective mode of prevention. METHODS: Patients with diabetes and peripheral neuropathy (DFU risk groups 2/3) were monitored for plantar abnormalities with a telemedical system consisting of sole inserts with temperature sensors and photographic documentation. An open, prospective, randomized controlled trial was performed to determine whether this system prevented DFUs. The intervention and control groups were also trained in ulcer prevention and observed in follow-up at 6-month intervals for 24 months. RESULTS: 283 patients were recruited. In 85 137 observation days, DFUs arose in five patients in the control group (n = 143) and in no patient in the intervention group (n = 140). The primary outcome measure was the hazard ratio, which was calculated to be 0.015 (95% confidence interval [0; 19,717]; p = 0.25) after adjustment for age, sex, severity of neuropathy, and risk class. There were 239 alarms and 75 instructions to reduce weight-bearing on the foot. The subjects carried out the telemedical application on about 70% of the days of observation. Quality of life improved in both groups. CONCLUSION: The tele-health system used in this trial is practical and enables the early detection of morbidity. Likely explanations for the unexpectedly low ulceration rate in this trial (and, in turn, for the lack of statistical significance) include the availability of a training program and regular follow-up examinations to patients in both arms of the trial, along with lower mobility levels due to the COVID pandemic.

Cold shock Y-box protein-1 proteolysis autoregulates its transcriptional activities.

BACKGROUND: The Y-box protein-1 (YB-1) fulfills pleiotropic functions relating to gene transcription, mRNA processing, and translation. It remains elusive how YB-1 shuttling into the nuclear and cytoplasmic compartments is regulated and whether limited proteolysis by the 20S proteasome releases fragments with distinct function(s) and subcellular distribution(s). RESULTS: To address these questions, mapping of domains responsible for subcellular targeting was performed. Three nuclear localization signals (NLS) were identified. NLS-1 (aa 149-156) and NLS-2 (aa 185-194) correspond to residues with unknown function(s), whereas NLS-3 (aa 276-292) matches with a designated multimerization domain. Nuclear export signal(s) were not identified. Endoproteolytic processing by the 20S proteasome before glycine 220 releases a carboxy-terminal fragment (CTF), which localized to the nucleus, indicating that NLS-3 is operative. Genotoxic stress induced proteolytic cleavage and nuclear translocation of the CTF. Co-expression of the CTF and full-length YB-1 resulted in an abrogated transcriptional activation of the MMP-2 promoter, indicating an autoregulatory inhibitory loop, whereas it fulfilled similar trans-repressive effects on the collagen type I promoter. CONCLUSION: Compartmentalization of YB-1 protein derivatives is controlled by distinct NLS, one of which targets a proteolytic cleavage product to the nucleus. We propose a model for an autoregulatory negative feedback loop that halts unlimited transcriptional activation.

Low levels of complement factor C3 at diagnosis can predict outcome in antineutrophil antibody associated vasculitis.

INTRODUCTION: Experimental data support the involvement of complement in the pathogenesis of antineutrophil antibody associated vasculitis, and clinical studies describe a more severe disease phenotype in patients with antineutrophil antibody associated vasculitis and complement activation. In the present study, we looked for an association between circulating serum complement factor 3 levels at diagnosis and outcomes. METHODS: One hundred sixty-four patients with antineutrophil antibody associated vasculitis who underwent kidney biopsy at our center during the last 15 years were retrospectively reviewed. Patients were categorized according to their serum complement factor 3 level at diagnosis. Patient and renal survival were compared between those above and below the median serum complement factor 3 at diagnosis. RESULTS: During the first year, 6 patients died and 53 reached end-stage renal disease. Death or end-stage renal disease at one-year were significantly more common in the low serum complement factor 3 group (44 vs. 29%, p = 0.037). In the multivariable analysis, serum complement factor 3 was the strongest negative outcome predictor (HR, 95%CI 0.118, (0.021-0.670)). The lower the serum complement factor 3 level at baseline, the higher the risk of dialysis and death. The risk was particularly high for both endpoints if the serum complement factor 3 concentration was below 0.9 g/l at baseline. CONCLUSION: Complement activation at diagnosis may identify a distinct subgroup of patients with antineutrophil antibody associated vasculitis and higher risk for poor outcomes. However, it remains to be proven whether inhibition of serum complement factor 3 is beneficial and safe in the clinical setting.

Factors Affecting Performance of DNA Methylation as a Potential Biomarker in Ascites for Peritonitis and Peritoneal Carcinomatosis.

BACKGROUND AND AIMS: Despite limited sensitivity, the gold standard for the diagnosis of malignant cells in ascites is still cytology. The aim of this prospective proof-of-principle study was to evaluate DNA methylation as a molecular tool for the differential diagnosis of benign and malignant ascites. METHODS: A cohort of 79 patients with malignant and non-malignant ascites was prospectively enrolled. Ascites was assessed by cytopathological and laboratory examination. Cell pellets obtained by centrifugation were analyzed for differences in DNA methylation of of long interspersed nuclear element-1 (LINE-1) and microRNA-137. Quantitative determination of methylation in bisulfite-converted DNA was performed by pyrosequencing. In a subsequent stage, we compared our data to previously published data in the field following systematic review of the literature. RESULTS: Methylation status of studied LINE-1 and microRNA-137 could be reliably detected in all samples. Systematic evaluation revealed reliable reproducibility with satisfactory short- and long-term stability against degradation. Ascites from patients with a malignancy had a significantly higher methylation level of microRNA-137 compared with patients without tumor disease, whereas patients with peritonitis had significantly decreased methylation of microRNA-137. In contrast, differences in the measurement of the methylation status of LINE-1 could only be detected between patients with portal hypertension and a combination of malignant and infectious ascites. Inflammatory cells reflecting peritonitis correlated to DNA methylation changes. CONCLUSIONS: Analysis of DNA methylation in ascites is technically feasible, well reproducible and may lead to identification of potential biomarkers for peritoneal carcinomatosis and other conditions. Inflammatory cells due to peritonitis may also be associated with DNA methylation changes and need to be considered in future studies. Profiling studied under standardized conditions will be needed to identify the appropriate biomarkers for differential diagnosis of ascites.

Short-term outcomes after transplantation of deceased donor kidneys with acute kidney injury: a retrospective analysis of a multicenter cohort of marginal donor kidneys with post-explantation biopsies.

BACKGROUND: Deceased donor kidneys with acute kidney injury (AKI) are often discarded because of concerns about inferior transplant outcomes. A means of grading the quality of such kidneys is the performance of procurement biopsies. METHODS: This is a retrospective study of 221 brain death donors with marginal kidneys transplanted in 223 recipients in Germany. Marginal kidneys were defined as kidneys with procurement biopsies done exceptionally to assess suitability for transplantation in otherwise potentially discarded organs. The impact of deceased donor AKI on patient survival and death-censored graft survival at 1, 3 and 5 years and graft function at 1 and 3 years after transplantation was investigated. RESULTS: Recipients of kidneys with stage 3 AKI had a greater incidence of delayed graft function [DGF; ORStage 1: 1.435 (95% CI 0.438-0.702), ORStage 2: 2.463 (95% CI 0.656-9.245), ORStage 3: 4.784 (95% CI 1.421-16.101)] but a similar graft and patient survival compared to recipients of donors without AKI and with AKI stage 1 and 2 as well. The coexistence of recipient DGF and donor AKI was associated with the lowest graft survival and function rates. CONCLUSION: The transplantation of deceased donor marginal kidneys with AKI confers a higher risk for DGF but is associated with acceptable graft and patient outcomes, which do not differ in comparison with marginal donor kidneys without AKI. Graft prognosis is especially poor if donor AKI and recipient DGF concur. Donor AKI was a risk factor independent of the histological lesions of procurement biopsies.

Histological and clinical evaluation of discarded kidneys in a European cohort of deceased brain death donor kidneys of marginal quality.

BACKGROUND: Despite organ shortages, the discard rate of deceased donor kidneys is high. Risk factors for this trend warrant further study. METHODS: We investigated reasons for discard in a cohort of brain death donors with marginal kidneys and procurement biopsies. Paraffin embedded procurement biopsies were systematically reevaluated and graded for the purpose of the study. Assessment included percentage of global glomerulosclerosis, Banff Lesion scores and tubular epithelial damage. Donor-, transplant process-, perfusion quality-, histopathology-, and recipient-related parameters were compared between discarded and transplanted organs. RESULTS: Although most clinical characteristics were similar between donors whose kidneys were transplanted and those whose kidneys were procured but discarded, discarded kidneys were more likely to be from donors with hepatitis C, to have undergone wedge biopsies, to show changes of acute and chronic injury and to be deemed poor quality. Except for obvious anatomic abnormalities, kidneys were often discarded due to the findings of procurement biopsies. Donors of kidneys discarded for histologic reasons more often had hypertension, coronary artery disease, stroke, and increased serum creatinine. The reason for discard was unknown in 20% of cases. Discarded kidneys came from donors who appeared to be clinically similar to donors whose kidneys were utilized for transplant. CONCLUSION: A considerable proportion of discarded kidneys were of acceptable quality. The analysis of the outcome of every recovered organ could help to overcome this problem. Procurement biopsies more often lead to discard than to transplantation of recovered organs. Proper handling during allocation has to be determined.