Adding salt to food at table as an indicator of gastric cancer risk among adults: a prospective study.

BACKGROUND: While dietary salt intake has been linked with gastric cancer risk in Asian studies, findings from Western populations are sparse and limited to case-control studies. Our aim was to evaluate the frequency of adding salt to food at table in relation to gastric cancer risk among UK adults. METHODS: We evaluated associations between the frequency of adding salt to food and the risk of gastric cancer in the UK Biobank (N = 471,144) using multivariable Cox regression. Frequency of adding salt to food was obtained from a touchscreen questionnaire completed at baseline (2006-2010). 24-h urinary sodium excretion was estimated using INTERSALT formulae. Cancer incidence was obtained by linkage to national cancer registries. RESULTS: During a median follow-up period of 10.9 years, 640 gastric cancer cases were recorded. In multivariable models, the gastric cancer risk among participants reporting adding salt to food at table "always" compared to those who responded "never/rarely" was HR = 1.41 (95% CI: 1.04, 1.90). There was a positive linear association between estimated 24-h urinary sodium levels and the frequency of adding salt to food (p-trend <0 .001). However, no significant association between estimated 24-h urinary sodium with gastric cancer was observed (HR = 1.19 (95% CI: 0.87, 1.61)). CONCLUSIONS: "Always adding salt to food" at table was associated with a higher gastric cancer risk in a large sample of UK adults. High frequency of adding salt to food at table can potentially serve as a useful indicator of salt intake for surveillance purposes and a basis for devising easy-to-understand public health messages.

Pregnancy in Complement-Mediated Thrombotic Microangiopathy: Maternal and Neonatal Outcomes.

Rationale & Objective: Pregnancy, delivery, and neonatal outcomes in women with complement-mediated thrombotic microangiopathy (cTMA) have not been well described. A better understanding of these outcomes is necessary to provide women with competent pregnancy counseling. Study Design: Cohort study. Setting and Participants: Women with a history of cTMA and pregnancies enrolled into the Vienna thrombotic microangiopathy cohort. Exposure: New onset or relapses of cTMA. Outcomes: Pregnancy, delivery, and neonatal outcomes of pregnancies in women (a) before cTMA manifestation, (b) complicated by pregnancy-associated cTMA (P-cTMA), and (c) after first manifestation of cTMA or P-cTMA. Analytical Approach: Mixed models were used to adjust the comparison of pregnancy, delivery, and neonatal outcomes between conditions (before, with, and after cTMA) for repeated pregnancies using the mother's ID as random factor. In addition, the fixed factors, mother's age and neonate's sex, were used for adjustment. For (sex-adjusted and age-adjusted) centile outcomes, only the mother's age was used. Adjusted odds ratios were derived from a generalized linear mixed model with live birth as the outcome. Least squares means and pairwise differences between them were derived from the linear mixed models for the remaining outcomes. Results: 28 women reported 74 pregnancies. Despite higher rates of fetal loss before the diagnosis of P-cTMA and preterm births with P-cTMA, most of the women were able to conceive successfully. Neonatal development in all 3 conditions of pregnancies was excellent. Pregnancy and neonatal outcomes were better in women with a pregnancy after the diagnosis of cTMA. Limitations: Although our data set comprises a considerable number of 74 pregnancies, the effective sample size is lower because only 28 mothers with multiple pregnancies were observed. The statistical power for detecting clinically relevant effects was probably low. A recall bias for miscarriages cannot be ruled out. Conclusions: Prepregnancy counseling of women with a history of cTMA can be supportive of their desire to become pregnant.

Complement-Mediated Thrombotic Microangiopathy Related to COVID-19 or SARS-CoV-2 Vaccination.

Introduction: Infectious diseases and vaccinations are trigger factors for thrombotic microangiopathy. Consequently, the COVID-19 pandemic could have an effect on disease manifestation or relapse in patients with atypical hemolytic syndrome/complement-mediated thrombotic microangiopathy (aHUS/cTMA). Methods: We employed the Vienna TMA cohort database to examine the incidence of COVID-19 related and of SARS-CoV-2 vaccination-related relapse of aHUS/cTMA among patients previously diagnosed with aHUS/cTMA during the first 2.5 years of the COVID-19 pandemic. We calculated incidence rates, including respective confidence intervals (CIs) and used Cox proportional hazard models for comparison of aHUS/cTMA episodes following infection or vaccination. Results: Among 27 patients with aHUS/cTMA, 13 infections triggered 3 (23%) TMA episodes, whereas 70 vaccinations triggered 1 TMA episode (1%; odds ratio 0.04; 95% CI 0.003-0.37, P = 0.01). In total, the incidence of TMA after COVID-19 or SARS-CoV-2 vaccination was 6 cases per 100 patient years (95% CI 0.017-0.164) (4.5/100 patient years for COVID-19 and 1.5/100 patient years for SARS-CoV-2 vaccination). The mean follow-up time was 2.31 ± 0.26 years (total amount: 22,118 days; 62.5 years) to either the end of the follow-up or TMA relapse (outcome). Between 2012 and 2022 we did not find a significant increase in the incidence of aHUS/cTMA. Conclusion: COVID-19 is associated with a higher risk for aHUS/cTMA recurrence when compared to SARS-CoV-2 vaccination. Overall, the incidence of aHUS/cTMA after COVID-19 infection or SARS-CoV-2 vaccination is low and comparable to that described in the literature.

Remdesivir for COVID-19 and acute kidney injury: disproportionality analysis of data from the U.S. Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Evidence about remdesivir-associated acute kidney injury (AKI) among patients with novel coronavirus disease 2019 (COVID-19) was controversial. AIM: To investigate the signal of disproportionate reporting of remdesivir-related AKI in COVID-19 patients over time with data from US Food and Drug Administration Adverse Event Reporting System. METHOD: Adverse events in COVID-19 patients reported between April 2020 and September 2022 were included. Reporting odds ratios (RORs) of AKI and renal disorders (a more sensitive definition for AKI) were estimated to compare remdesivir with other medications prescribed in comparable situations of COVID-19. RESULTS: During the entire study period, significant signals were identified for remdesivir-related AKI (ROR 2.00, 95% CI: 1.83-2.18) and renal disorder (ROR 2.35, 95% CI: 2.17-2.54) when compared to all comparable drugs. However, in the third quarter of 2022 (the most recent quarter) signals disappeared as the ROR of AKI was 1.50 (95% CI 0.91-2.45) and ROR of renal disorder was 1.69 (95% CI 1.06-2.70). Number of signals in sensitivity analyses and the proportion of AKI in remdesivir-associated events decreased over time. CONCLUSION: In COVID-19 patients, we observed diminishing signals of remdesivir-associated AKI over time and no significant signal in the most recent quarter, suggesting remdesivir might not be nephrotoxic.

SARS-CoV-2 IgG spike protein antibody response in mRNA-1273 Moderna® vaccinated patients on maintenance immunoapheresis - a cohort study.

Background: The SARS-CoV-2 pandemic increased mortality and morbidity among immunocompromised populations. Vaccination is the most important preventive measure, however, its effectiveness among patients depending on maintenance immunoglobulin G (IgG) apheresis to control autoimmune disease activity is unknown. We aimed to examine the humoral immune response after mRNA-1273 Moderna® vaccination in immunoapheresis patients. Methods: We prospectively monitored SARS-CoV-2 IgG spike (S) protein antibody levels before and after each IgG (exposure) or lipid (LDL) apheresis (controls) over 12 weeks and once after 24 weeks. Primary outcome was the difference of change of SARS-CoV-2 IgG S antibody levels from vaccination until week 12, secondary outcome was the difference of change of SARS-CoV-2 IgG S antibody levels by apheresis treatments across groups. Results: We included 6 IgG and 18 LDL apheresis patients. After 12 weeks the median SARS-CoV-2 IgG S antibody level was 115 (IQR: 0.74, 258) in the IgG and 1216 (IQR: 788, 2178) in the LDL group (p=0.03). Median SARS-CoV-2 IgG S antibody reduction by apheresis was 76.4 vs. 23.7% in the IgG and LDL group (p=0.04). The average post- vs. pre-treatment SARS-CoV-2 IgG S antibody rebound in the IgG group vs. the LDL group was 46.1 and 6.44%/week from prior until week 12 visit. Conclusions: IgG apheresis patients had lower SARS-CoV-2 IgG S antibody levels compared to LDL apheresis patients, but recovered appropriately between treatment sessions. We believe that IgG apheresis itself probably has less effect on maintaining the immune response compared to concomitant immunosuppressive drugs. Immunization is recommended independent of apheresis treatment.

Eculizumab use in a tertiary care nephrology center: data from the Vienna TMA cohort.

BACKGROUND: Practice patterns of eculizumab use are not well described. We examined indications for, and outcomes of, eculizumab therapy in a tertiary care nephrology center. METHODS: We used the "Vienna TMA cohort" and the hospital pharmacy database at the Medical University of Vienna to identify patients that received eculizumab treatment between 2012 and 2019. We describe clinical characteristics, details of eculizumab use, and outcomes of patients with complement gene-variant mediated TMA (cTMA), secondary TMA (sTMA) and C3 glomerulopathy (C3G). RESULTS: As of December 2019, 23 patients received complement blockade at the Division of Nephrology and Dialysis: 15 patients were diagnosed with cTMA, 6 patients with sTMA and 2 patients with C3G. Causes of sTMA were bone marrow transplantation (n = 2), malignant hypertension, malignant tumor, systemic lupus erythematosus, antiphospholipid syndrome and lung transplantation (each n = 1). Across all indications, patients had a median age of 31 and were predominantly female (78%) and the median duration of treatment was 227 days. Hematological recovery was seen in most patients, while renal response was best in patients with cTMA. Adverse events were recorded in 26%. CONCLUSIONS: In summary, eculizumab is the treatment of choice for cTMA patients that do not respond to plasma therapy. In patients with sTMA and C3G, the response rates to therapy are much lower and therefore, the decision to start therapy needs to be considered carefully.

Antibody Response and Safety After mRNA-1273 SARS-CoV-2 Vaccination in Peritoneal Dialysis Patients - the Vienna Cohort.

Background: Dialysis patients are at high risk for a severe clinical course after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Safety and early immune responses after mRNA-based vaccination have been reported mostly in patients on hemodialysis (HD), whereas reports of peritoneal dialysis (PD) patients remain rare. Methods: In this retrospective observational study, 39 PD patients had received two doses of the mRNA-1273 Moderna® vaccine. We analyzed SARS-CoV-2 Spike (S) antibody titers 4 weeks after each dose of mRNA-1273 and report local and systemic side effects in PD patients that occurred within one week after each mRNA-1273 dose. Using a quantile regression model we examined factors that might influence SARS-CoV-2 S antibody levels in PD patients. Results: Four weeks after the first dose of mRNA-1273 vaccine 33 of 39 (84.6%) PD patients seroconverted and presented with 6.62 U/mL (median; IQR 1.57-22.5) anti-SARS-CoV-2 S antibody titers. After the second dose, 38 of 39 (97.4%) PD patients developed anti-SARS-CoV-2 S antibodies and titers increased significantly (median 968 U/mL; IQR 422.5-2500). Pain at the injection site was the most common local adverse event (AE) (71%). Systemic AEs occurring after the first dose were mostly fatigue (33%) and headache (20%). No severe systemic AEs were reported after the first injection. After the second dose the incidence and the severity of the systemic AEs increased. The most common systemic AEs were: fatigue (40.5%), headache (22.5%), joint pain (20%), myalgia (17.5%) and fever (13%). Lower Davies Comorbidity Score (p=0.04) and shorter dialysis vintage (p=0.017) were associated with higher antibody titers after the first dose. Patients with higher antibody titers after the first dose tended to have higher antibody titers after the second dose (p=1.53x10-05). Conclusions: Peritoneal dialysis patients in this cohort had a high seroconversion rate of 97.4%, showed high antibody titers after full vaccination and tolerated the anti-SARS-CoV-2 mRNA-1273 vaccine well without serious adverse events.

Effect of Oral Sodium Bicarbonate Treatment on 24-Hour Ambulatory Blood Pressure Measurements in Patients With Chronic Kidney Disease and Metabolic Acidosis.

Background: Sodium bicarbonate supplementation is a mainstay in the treatment of metabolic acidosis in patients with chronic kidney disease (CKD). Recent studies showed reduction of progression of CKD and reduced all-cause mortality. However, additional sodium loading could worsen arterial hypertension, a well-known contributor to progression of CKD. This patient-relevant and economically negative side effect is under-studied in prospective studies up until now. Objective: The aim of this study was to analyze the effect of sodium bicarbonate treatment on arterial blood pressure at baseline and after 8 weeks. Methods: The SoBic study is an ongoing randomized controlled trial, in which patients with CKD receive either a high dose of oral sodium bicarbonate or a rescue treatment, if necessary. We used standardized office blood pressure and 24-hour ambulatory blood pressure monitoring (24h-ABPM). Regression models were adjusted for estimated glomerular filtration rate and change of antihypertensives. Results: 47 subjects were enrolled and the mean age was 57 (±14.6) years and 18 (38%) were female. In 43 randomized subjects with sufficiently performed 24h-ABPM neither systolic 24h-ABPM (2.522; 95%CI: -2.364, 7.408; mmHg) nor diastolic 24h-ABPM (0.868; 95%CI: -2.411, 4.147; mmHg) was affected by study group allocation. When looking at the effect of individual sodium bicarbonate dose on 24h-ABPM, the fully adjusted model suggested an increase of 0.047 (95%CI: -0.026, 0.119) mmHg by each mg/kg per day increase of sodium bicarbonate dose. Conclusion: Sodium bicarbonate supplementation over 8 weeks did not significantly increase blood pressure measured by 24h-ABPM in CKD patients. Trial Registration: EUDRACT Number: 2012-001824-36; 12/07/2012 (https://www.clinicaltrialsregister.eu).

FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy.

Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.

COVID-19 serology in nephrology healthcare workers.

BACKGROUND: Chronic kidney disease patients show a high mortality in cases of a severe acute respiratory syndrome coronavirus-2 (SARS-CoV­2) infection. Thus, information on the sero-status of nephrology personnel might be crucial for patient protection; however, limited information exists about the presence of SARS-CoV­2 antibodies in asymptomatic individuals. METHODS: We examined the seroprevalence of SARS-CoV­2 IgG and IgM antibodies among healthcare workers of a tertiary care kidney center during the the first peak phase of the corona virus disease 2019 (COVID-19) crisis in Austria using an orthogonal test strategy and a total of 12 commercial nucleocapsid protein or spike glycoprotein-based assays as well as Western blotting and a neutralization assay. RESULTS: At baseline 60 of 235 study participants (25.5%, 95% confidence interval, CI 20.4-31.5%) were judged to be borderline positive or positive for IgM or IgG using a high sensitivity/low specificity threshold in one test system. Follow-up analysis after about 2 weeks revealed IgG positivity in 12 (5.1%, 95% CI: 2.9-8.8%) and IgM positivity in 6 (2.6%, 95% CI: 1.1-5.6) in at least one assay. Of the healthcare workers 2.1% (95% CI: 0.8-5.0%) showed IgG nucleocapsid antibodies in at least 2 assays. By contrast, positive controls with proven COVID-19 showed antibody positivity among almost all test systems. Moreover, serum samples obtained from healthcare workers did not show SARS-CoV­2 neutralizing capacity, in contrast to positive controls. CONCLUSION: Using a broad spectrum of antibody tests the present study revealed inconsistent results for SARS-CoV­2 seroprevalence among asymptomatic individuals, while this was not the case among COVID-19 patients. TRIAL REGISTRATION NUMBER: CONEC, ClinicalTrials.gov number NCT04347694.

Pregnancies in kidney transplant recipients with complement gene variant-mediated thrombotic microangiopathy.

BACKGROUND: Pregnancies in patients with complement gene variant-mediated thrombotic microangiopathy (cTMA) are challenging, and pregnancies in such patients after kidney transplantation (KTX) are even more so. METHODS: We identified nine pregnancies following KTX of three genetically high-risk cTMA patients enrolled in the Vienna thrombotic microangiopathy cohort. Preventive plasma therapy was used in three pregnancies, and one patient had ongoing eculizumab (ECU) therapy during two pregnancies. RESULTS: Seven out of nine pregnancies (78%) resulted in the delivery of healthy children. The other two included one early abortion at gestational Week 12 during ongoing ECU therapy and one late foetal death at gestational Week 33 + 3, most likely not related to complement dysregulation. Kidney transplant function after delivery remained stable in all but one pregnancy. In the aforementioned case, a severe cTMA flare occurred after delivery despite use of preventive plasma infusions. Kidney graft function could be rescued in this patient by ECU. As such, successful pregnancies can be accomplished in kidney transplant recipients (KTRs) with a history of cTMA. We used preemptive plasma therapy or ongoing ECU treatment in selected cases. CONCLUSIONS: Thus, becoming pregnant can be encouraged in KTRs with native kidney cTMA. Extensive preconception counselling, however, is mandatory in such cases.

The comparative risk of acute kidney injury of vancomycin relative to other common antibiotics.

The glycopeptide antibiotic vancomycin is a mainstay in the treatment of Gram-positive infection. While its association with acute kidney injury (AKI) has waxed and waned, recent data suggest nephrotoxicity, even as mono-therapy. Our study aimed to evaluate the 2-week risk of AKI after at least 3 days of intravenous vancomycin mono-therapy initiated within 5 days of hospitalization compared to other intravenous antibiotics used for similar indications. We used a new user-active comparator study design and identified patients with a first hospitalization during which they received vancomycin or comparator, from commercial claims based in the United States. We estimated incidence rates, hazard ratios using adjusted cox-regression models, and standardized mortality/morbidity ratio weighted cox-regression models. In the 32,997 patients vancomycin was used in 17% of patients and 129 cases of AKI were observed. Overall incidence of AKI was 9.3 (95% CI 0.78-1.22) per 100 person-years. The adjusted hazard ratio for vancomycin versus all other comparators was 0.74 (95% CI 0.45-1.21). Separate models for respective comparators resulted in hazard ratios below the null, except for vancomycin vs. cefazolin. Intravenous vancomycin mono-therapy does not increase the risk of AKI compared to other intravenous antibiotics used for similar indication in this cohort of hospitalized patients.

Successful Pregnancies During Ongoing Eculizumab Therapy in Two Patients With Complement-Mediated Thrombotic Microangiopathy.

In patients with pregnancy-associated complement gene variant-mediated thrombotic microangiopathy (cTMA), terminal complement blockade is used for treatment of cTMA flares during pregnancy or following delivery. We report pregnancy and delivery outcomes of 2 genetically high-risk patients with cTMA, including 1 kidney transplant recipient, during ongoing eculizumab therapy. In both patients, the first manifestation of cTMA occurred independent from pregnancy. One patient has a history of 2 uneventful pregnancies with prophylactic plasma infusions, and the other has a history of early abortion during long-term eculizumab therapy following kidney transplantation. Overall, pregnancy and delivery outcomes under ongoing eculizumab therapy in our 2 patients with preserved kidney function were excellent as compared with other patients reported in the literature. Eculizumab plasma concentrations were maintained in the therapeutic range during pregnancy and were also detectable in cord blood. Results of cord blood analysis showed deficient complement activity, with low factor and regulator levels, most likely reflecting the age of the neonates and presence of eculizumab in cord blood. In conclusion, pregnancy during ongoing eculizumab treatment appeared to be safe in 2 women with a history of high-risk genetic cTMA and excellent kidney function, even following kidney transplantation.

Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis.

BACKGROUND: A novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers. METHODS: A total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated. RESULTS: High levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2-which is not reliable because of the small number of cases-strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3-4 had worse renal survival than patients in Clusters 1-2. CONCLUSIONS: Our results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.

Sex Differences in Clinical Presentation and Outcomes among Patients with Complement-Gene-Variant-Mediated Thrombotic Microangiopathy.

Sex differences among patients with complement-gene-variant-mediated thrombotic microangiopathy (cTMA) are not well established. We examined demographic and clinical data from female and male patients with a history of cTMA enrolled in the Vienna thrombotic microangiopathy (TMA) cohort. Follow-up was three years after first presentation with cTMA. In this single-center study, we identified 51 patients with a first manifestation of cTMA between 1981 and 2019; 63% were female (p = 0.09). The median age at diagnosis did not differ between females and males. There was also no disparity between the sexes with regard to renal function or the need for renal replacement therapy at presentation. Furthermore, we observed similar use of plasma or eculizumab therapy and a comparable evolution of renal function of female and male patients. More females showed risk haplotypes of complement factor H (CFH) and CD46 (97% vs. 68%, p = 0.01), but there was no difference in the prevalence of rare pathogenic variants in complement-associated genes with regard to sex. In conclusion, the majority of cTMA patients enrolled in the Vienna TMA cohort were female. Clinical presentation and renal function did not differ between the sexes, but females more frequently presented with cTMA risk haplotypes.

Preemptive plasma therapy prevents atypical hemolytic uremic syndrome relapse in kidney transplant recipients.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) frequently leads to renal failure, and kidney transplantation bears a high risk of disease recurrence and graft loss. METHODS: Patients who received a kidney graft in our center were retrospectively identified using our Vienna Thrombotic Microangiopathy Cohort. Since 2005, the majority of aHUS patients received perioperative plasma exchange (PE) followed by plasma infusions (PI). Patients were switched to eculizumab in case of plasma intolerance or failure. Those with no preemptive therapy served as controls. We used proportional Cox regression and logistic regression to examine predictors of graft survival. RESULTS: 19 aHUS patients received 32 grafts and had a follow-up > 1 year. Eight patients received preventive plasma therapy for eight transplants and 13 patients (including 2 patients who received plasma therapy for their last transplant) had no preventive therapy for 24 grafts. The median graft survival was 2.372 days in patients, that received preemptive therapy and 411 days in patients, that did not receive preemptive treatment (hazard ratio: 0.11; p= 0.03). Four patients were switched to eculizumab because of plasma intolerance or failure. Additionally, one patient, that was not transplanted according to the above-mentioned protocol, received eculizumab for aHUS relapse. Additionally, relapse of aHUS (p = 0.01) and year of transplantation (p<0.01) had an effect on graft failure. CONCLUSIONS: This study shows that preemptive plasma therapy and eculizumab rescue in selected cases improve graft survival among kidney transplant recipients with aHUS.

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy.

BACKGROUND: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. RESULTS: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF. CONCLUSIONS: In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.

An updated classification of thrombotic microangiopathies and treatment of complement gene variant-mediated thrombotic microangiopathy.

Conditions presenting with signs of thrombotic microangiopathies (TMAs) comprise a wide spectrum of different diseases. While pathological hallmarks are thrombosis of arterioles and capillaries, clinical signs are mechanical haemolysis, thrombocytopenia and acute renal injury or neurological manifestations. The current classification of various syndromes of TMA is heterogeneous and often does not take the underlying pathophysiology into consideration. Therefore we propose a simplified classification based on the aetiology of different syndromes leading to TMA. We propose to categorize different TMA syndromes in hereditary and acquired forms and classify them based on the genetic background or underlying conditions. Of course, this classification is not always distinctly applicable in each case and from time to time reassessment of the established diagnosis is strongly recommended. The recommended treatment of TMA in the past was plasma exchange (PE). However, recently, the terminal complement inhibitor eculizumab became commercially available and has shown promising results in different open-label studies and case series. In our centre, first-line therapy is PE; however, patients are instantly switched to complement inhibitory therapy in case of treatment failure or intolerance.

Oral Sodium Bicarbonate Supplementation Does Not Affect Serum Calcification Propensity in Patients with Chronic Kidney Disease and Chronic Metabolic Acidosis.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD) and metabolic acidosis might accelerate vascular calcification. The T50 calcification inhibition test (T50-test) is a global functional test analyzing the overall propensity of calcification in serum, and low T50-time is associated with progressive aortic stiffening and with all-cause mortality in non-dialysis CKD, dialysis, and transplant patients. Low serum bicarbonate is associated with a short T50-time and alkali supplementation could be a simple modifier of calcification propensity. The aim of this study was to investigate the short-term effect of oral sodium bicarbonate supplementation on T50-time in CKD patients. MATERIAL AND METHODS: The SoBic-study is an ongoing randomized-controlled trial in CKD-G3 and G4 patients with chronic metabolic acidosis (serum HCO3- ≤21 mmol/L), in which patients are randomized to either achieve serum HCO3- levels of 24 ± 1 mmol/L (intervention group) or 20 ± 1 mmol/L (rescue group). The effect of bicarbonate treatment on T50-time was assessed. RESULTS: The study cohort consisted of 35 (14 female) patients aged 57 (±15) years, and 18 were randomized to the intervention group. The mean T50-time was 275 (± 64) min. After 4 weeks, the mean change of T50-time was 4 (±69) min in the intervention group and 18 min (±56) in the rescue group (ß = -25; 95% CI: -71 to 22; p = 0.298). Moreover, change of serum bicarbonate in individual patients was not associated with change in T50-time, analyzed by regression analysis. Change of serum phosphate had a significant impact on change of T50-time (ß = -145; 95% CI: -237 to -52). CONCLUSION: Oral sodium bicarbonate supplementation showed no effect on T50-time in acidotic CKD patients.