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Vancomycin is a widely used glycopeptide antibiotic with the need for therapeutic drug monitoring to avoid renal toxicity. We report a case of severe vancomycin-associated anuric acute kidney injury managed with successful drug-removal by hemodialysis (HD) using different types of dialyzers. Medium cut-off (MCO) and high-flux dialyzers were effective in drug removal. Higher vancomycin elimination rate and lower plasma half-life were achieved with MCO dialyzer despite low-flow vascular access and intolerance to ultrafiltration. MCO dialyzers may be reasonable for drug removal in patients with intolerance of ultrafiltration, low-flow vascular access or impracticality of hemodiafiltration. Future studies should explore the use of MCO dialyzers in comparison with high-flux HD and hemodiafiltration in both the acute and chronic setting., Competing Interests: A.H.K. has received research funding, speaker fees and travel support, and has served on advisory boards for Baxter. M.K. has received travel support and speaker fees from Baxter., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Competing Interests: M.K. and A.R.R. received speaker fees from Baxter (Deerfield, IL, USA). A.H.K. has received speaker fees, travel support and research support and has served on advisory boards for Baxter. D.S. is co-inventor of patents in the field of blood volume and bioimpedance applications in hemodialysis and member of the American Renal Associates research board. J.A., N.G.O.S., N.G., M.S., R.R., P.P.R., T.N., K.E. and B.K. declare no conflict of interest.

In recent decades, insights into the molecular pathways involved in disease have revolutionized the treatment of autoimmune diseases. A plethora of targeted therapies have been identified and are at varying stages of clinical development in renal autoimmunity. Some of these agents, such as rituximab or avacopan, have been approved for the treatment of immune-mediated kidney disease, but kidney disease lags behind more common autoimmune disorders in new drug development. Evidence is accumulating as to the importance of adaptive immunity, including abnormalities in T-cell activation and signaling, and aberrant B-cell function. Furthermore, innate immunity, particularly the complement and myeloid systems, as well as pathologic responses in tissue repair and fibrosis, play a key role in disease. Collectively, these mechanistic studies in innate and adaptive immunity have provided new insights into mechanisms of glomerular injury in immune-mediated kidney diseases. In addition, inflammatory pathways common to several autoimmune conditions exist, suggesting that the repurposing of some existing drugs for the treatment of immune-mediated kidney diseases is a logical strategy. This new understanding challenges the clinical investigator to translate new knowledge into novel therapies leading to better disease outcomes. This review highlights promising immunomodulatory therapies tested for immune-mediated kidney diseases as a primary indication, details current clinical trials and discusses pathways that could be targeted in the future., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: We previously reported that modified-release nicotinamide (NAMR) was superior to placebo in reducing serum phosphate concentrations over 12 weeks in a large cohort of haemodialysis patients with hyperphosphataemia. Here we report outcomes after 52 weeks of treatment., Methods: NOPHOS was a phase 3, international, randomized, controlled, double-blind trial with a parallel group design. NAMR (250-1500 mg/day) was investigated in comparison to placebo as an add-on therapy to an individual therapy with approved phosphate binders., Results: In the intention-to-treat population (NAMR: n = 539; placebo: n = 183), serum phosphate was significantly lower in the NAMR group compared with the placebo group at week 24 (5.40 ± 1.55 versus 5.79 ± 1.37 mg/dl, P < .001) with a mean difference of -0.39 mg/dl [95% confidence interval (CI) -0.66 to -0.13], but was comparable between the groups at week 52 [mean difference -0.08 (95% CI -0.36-0.20)]. In the completer population (n = 358), statistical significance in favour of NAMR was reached at weeks 24 and 52. The treatment effect was reduced in patients with high baseline serum intact parathyroid hormone (iPTH) compared with patients with low baseline serum iPTH. Compliant patients in the NAMR group had a more pronounced and sustained reduction in serum phosphate than non-compliant patients. NAMR treatment was associated with a significantly increased risk of thrombocytopenia, pruritus, anaemia, and diarrhoea. Herpes zoster occurred exclusively in patients randomized to NAMR., Conclusions: NAMR combined with phosphate binders significantly reduced serum phosphate over the first 24 weeks of treatment, but the treatment effect was not maintained up to week 52. Non-compliance may have contributed to reduced long-term efficacy. Several newly identified safety signals warrant further evaluation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Hyperphosphatemia is associated with increased mortality and cardiovascular morbidity of end-stage kidney failure (ESKF) patients. Managing serum phosphate in ESKF patients is challenging and mostly based on limiting intestinal phosphate absorption with low phosphate diets and phosphate binders (PB). In a multi-centric, double-blinded, placebo-controlled study cohort of maintenance hemodialysis patients with hyperphosphatemia, we demonstrated the efficacy of nicotinamide modified release (NAMR) formulation treatment in addition to standard PB therapy in decreasing serum phosphate. Here we aimed to assess the relationship between phosphate, FGF23, inflammation and iron metabolism in this cohort., Methods: We measured the plasma concentrations of intact fibroblast growth factor 23 (iFGF23) and selected proinflammatory cytokines at baseline and Week 12 after initiating treatment., Results: We observed a strong correlation between iFGF23 and cFGF23 (C-terminal fragment plus iFGF23). We identified iFGF23 as a better predictor of changes in serum phosphate induced by NAMR and PB treatment compared with cFGF23. Recursive partitioning revealed at baseline and Week 12, that iFGF23 and cFGF23 together with T50 propensity were the most important predictors of serum phosphate, whereas intact parathyroid hormone (iPTH) played a minor role in this model. Furthermore, we found serum phosphate and iPTH as the best predictors of iFGF23 and cFGF23. Sex, age, body mass index, and markers of inflammation and iron metabolism had only a minor impact in predicting FGF23., Conclusion: Lowering serum phosphate in ESKF patients may depend highly on iFGF23 which is correlated to cFGF23 levels. Serum phosphate was the most important predictor of plasma FGF23 in this ESKF cohort., Competing Interests: The authors declare that they are not aware of any conflicts of interest and that the results presented in this paper have not been published previously in whole or part, except in abstract format. C.A.W. reports honoraria from Medice, Advicenne, Kyowa Kirin and Chugai. A.P. is an employee of Calciscon AG and reports holding stock in Calciscon AG, which commercializes the T50 test., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Hyperkalemia is a common complication in cardiorenal patients treated with agents interfering with renal potassium (K+) excretion. It frequently leads to discontinuation of potentially life-saving medication, which has increased the importance of K+ monitoring. Non-invasive means to detect hyperkalemia are currently unavailable, but would be of potential use for therapy guidance. The aim of the present study was to assess the analytical performance of genetically encoded potassium-ion indicators (GEPIIs) in measuring salivary [K+] ([K+]Saliva) and to determine whether changes of [K+]Saliva depict those of [K+]Plasma., Methods: We conducted this proof-of-concept study: saliva samples from 20 healthy volunteers as well as plasma and saliva from 29 patients on hemodialysis (HD) before and after three consecutive HD treatments were collected. We compared [K+]Saliva as assessed by the gold standard ion-selective electrode (ISE) with GEPII measurements., Results: The Bland-Altmann analysis showed a strong agreement (bias 0.71; 95% limits of agreement from -2.79 to 4.40) between GEPII and ISE. Before treatment, patients on HD showed significantly higher [K+]Saliva compared with healthy controls [median 37.7 (30.85; 48.46) vs 23.8 (21.63; 25.23) mmol/L; P < .05]. [K+]Plasma in HD patients decreased significantly after dialysis. This was paralleled by a significant decrease in [K+]Saliva, and both parameters increased until the subsequent HD session. Despite similar kinetics, we found weak or no correlation between [K+]Plasma and [K+]Saliva., Conclusion: GEPIIs have shown an excellent performance in determining [K+]Saliva. [K+]Plasma and [K+]Saliva exhibited similar kinetics. To determine whether saliva could be a suitable sample type to monitor [K+]Plasma, further testing in future studies are required., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Historically the treatment of lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was 'one size fits all'; however, with the emergence of precision medicine initiatives, the field is moving towards more personalized treatment approaches. The recent development of a more accurate and reproducible histopathological classification system for LN could lead to better disease categorization and therefore more targeted therapies. A better understanding of the pathophysiology of LN has provided evidence that not only T but also B cells play an important role, opening new opportunities for individualized treatment approaches. Recent trials have shown calcineurin inhibitors and the anti-CD20 antibodies rituximab and ofatumumab to be effective in the treatment of LN, adding new treatment options. State-of-the-art targeted therapy in ANCA-associated vasculitis (AAV) takes interindividual heterogeneity in disease severity, type of ANCA antibody [myeloperoxidase versus proteinase 3 (PR3)] and the risk for side effects of therapy into consideration. In addition, within an individual, induction therapy differs from maintenance therapy, the same holding true in incident and relapsing disease. Rituximab is now widely used in AAV and it has become clear that prolonged B cell depletion, as in LN, must be achieved to obtain a long-lasting clinical response, especially in anti-PR3-associated disease. Still, despite these advances, molecular and genetic markers are rarely incorporated into diagnostic and treatment algorithms and true precision medicine remains an aspiration that hopefully can be achieved., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Kidney transplant recipients exhibit a dramatically increased cardiovascular (CV) risk. In 2007, Austrian centres implemented a consensus of comprehensive CV screening programme prior to kidney transplantation (KT). The consensus placed a particular emphasis on screening for coronary artery disease (CAD) with cardiac computed tomography (CT) or coronary angiography (CAG) in patients with diabetes mellitus, known CAD or those having multiple conventional CV risk factors. Here, we investigate if this affected risk stratification and post-transplant CV outcomes., Methods: In a retrospective chart review, we evaluated 551 KTs performed from 2003 to 2015 in our centre. Patients were categorized into three groups: KT before (2003-07), directly after (2008-11) and 5 years after (2012-15) implementation of the consensus. We analysed clinical characteristics, the rate of cardiac CTs and CAGs prior to KT as well as major adverse cardiac events (MACEs) during a 2-year follow-up after KT., Results: The three study groups showed a homogeneous distribution of comorbidities and age. Significantly more cardiac CTs (13.6% versus 10.2% versus 44.8%; P = 0.002) and CAGs (39.6% versus 43.9% versus 56.2%; P = 0.003) were performed after the consensus. Coronary interventions were performed during 42 out of 260 CAGs (16.2%), the cumulative 2-year MACE incidence was 8.7%. Regarding MACE occurrence, no significant difference between the three groups was found., Conclusion: CV risk stratification has become more rigorous and invasive after the implementation of the consensus; however, this was not associated with an improvement in CV outcome., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: The kinetics of β2-microglobulin during hemodialysis and hemodiafiltration is well described by a two-compartment model where clearance by the dialyzer is from a central compartment volume that approximates plasma volume and a total distribution volume that approximates extracellular fluid volume. The kinetics of middle molecules with molecular weights larger than β2-microglobulin have not been extensively studied., Methods: Intradialytic plasma concentrations and overall dialyzer clearances of β2-microglobulin (11.8 kD), myoglobin (16.7 kD) and complement factor D (24.4 kD) were used to estimate three kinetic parameters from a two-compartment model, namely intercompartmental clearance, central compartment volume and total distribution volume, in hemodialysis patients; these data were collected during two clinical trials of medium cut-off dialyzers (with extended middle molecule removal) during hemodialysis and high-flux dialyzers during hemodialysis and hemodiafiltration. In the current exploratory analyses, the kinetic parameters from all dialyzers were combined. Overall dialyzer clearance was evaluated by total mass removed in the dialysate., Results: In total, 345 sets of kinetic parameters from 35 patients were determined. Intercompartmental clearance and central compartment volume for myoglobin and complement factor D were smaller (P < 0.001) than those for β2-microglobulin. Independent of middle molecule, intercompartmental clearance and central compartment volume were associated with overall dialyzer clearance (P < 0.001), but total distribution volume was not (P = 0.083)., Conclusions: A two-compartment kinetic model can only describe intradialytic kinetics of middle molecules with molecular weights larger than β2-microglobulin if the central compartment is small and dependent on overall dialyzer clearance., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Compared to high-flux dialysis membranes, novel medium cut-off (MCO) membranes show greater permeability for larger middle molecules., Methods: In two prospective, open-label, controlled, randomized, crossover pilot studies, 39 prevalent hemodialysis (HD) patients were studied in four dialysis treatments as follows: study 1, three MCO prototype dialyzers (AA, BB and CC with increasing permeability) and one high-flux dialyzer in HD; and study 2, two MCO prototype dialyzers (AA and BB) in HD and high-flux dialyzers in HD and hemodiafiltration (HDF). Primary outcome was lambda free light chain (λFLC) overall clearance. Secondary outcomes included overall clearances and pre-to-post-reduction ratios of middle and small molecules, and safety of MCO HD treatments., Results: MCO HD provided greater λFLC overall clearance [least square mean (standard error)] as follows: study 1: MCO AA 8.5 (0.54), MCO BB 11.3 (0.51), MCO CC 15.0 (0.53) versus high-flux HD 3.6 (0.51) mL/min; study 2: MCO AA 10.0 (0.58), MCO BB 12.5 (0.57) versus high-flux HD 4.4 (0.57) and HDF 6.2 (0.58) mL/min. Differences between MCO and high-flux dialyzers were consistently significant in mixed model analysis (each P < 0.001). Reduction ratios of λFLC were greater for MCO. Clearances of α1-microglobulin, complement factor D, kappa FLC (κFLC) and myoglobin were generally greater with MCO than with high-flux HD and similar to or greater than clearances with HDF. Albumin loss was moderate with MCO, but greater than with high-flux HD and HDF., Conclusions: MCO HD removes a wide range of middle molecules more effectively than high-flux HD and even exceeds the performance of high-volume HDF for large solutes, particularly λFLC., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: End-stage renal disease (ESRD) is strongly associated with arterial calcification of the tunica media, decreased vascular compliance and sudden cardiac death. Here, we analysed the distribution pattern of uraemic media calcification and concomitant inflammation in mice and men., Methods: Uraemia was induced in DBA/2 mice with high-phosphate diet. Subsequently, we analysed arterial medial calcification using histology, mass spectrometry, and wire myography. Gene expression was quantified using a whole transcriptome array and quantitative PCR. In a cohort of 36 consecutive patients with CKD stage 4-5, we measured the calcium score of the coronary arteries, the ascending thoracic aorta and the infrarenal abdominal aorta using computed tomography scans., Results: Uraemic DBA/2 mice showed only minor calcifications in thoracic aortas, whereas there was overt media calcification in abdominal aortas. The transcriptional profile and immunohistochemistry revealed induction of Vcam1 expression by vascular smooth muscle cells in uraemic abdominal aortas. Macrophages infiltrated the tunica media of the abdominal aorta. Anti-inflammatory treatment did not improve uraemic media calcification in our animal model. Arterial calcifications in ESRD patients showed a similar distribution pattern in computed tomography scans, with higher calcium scores of the abdominal aorta when compared with the thoracic aorta., Conclusion: Taken together, there was a similar heterogeneous pattern of calcification in both mice and humans, where the abdominal aorta was more prone to media calcification when compared with the thoracic aorta. In uraemia, smooth muscle cells of the abdominal aorta showed a phenotypic switch to an inflammatory and osteoblastic phenotype., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in Austria, accounting for a high burden of morbidity and mortality. In this nationwide study, we aimed to evaluate the incidence and fate of patients with DKD-ESRD over time., Methods: Data (collected annually) from the Austrian Dialysis- and Transplant Registry were analysed for the development of ESRD due to DKD from 1965 to 2013., Results: Over 48 years, 8322 and 22 975 patients with ESRD due to diabetes and non-diabetes, respectively, entered dialysis. While DKD-ESRD-patients were not dialysed until 1974, in 1975 seven type 1- and one type 2-diabetics started dialysis (1.06 per million population-PMP). In the mid-eighties, DKD-ESRD-patients increasingly were accepted for dialysis (1986: 14.53 PMP, 1996: 31.16 PMP). After a peak incidence of 415 diabetic ESRD-patients in 2006 (50.19 PMP), numbers decreased continuously thereafter (2013: 299 patients, 35.73 PMP). Mean age at start of dialysis increased over time and was lower in type 1- and higher in type 2- compared with non-diabetic patients. Five-year-survival-probability in two diabetic ESRD-cohorts, starting in 2007/08 and 10 years earlier was calculated. Five-year-survival was 28% in 1997/98 and 37.5% in 2007/08. Adjusted relative risk reduction was 33% (HR 0.67, CI 95% 0.57-0.78; P < 0.001)., Conclusion: Despite a growing prevalence of diabetes, the incidence of diabetic ESRD has decreased after 2006. Five-year-survival-probability has improved over 10 years. Multifactorial therapeutic interventions may have resulted in this improvement., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Due to its reported antimicrobial effects, hypertonic citrate (46.7%) is a widely used catheter lock solution, but following instillation, citrate inevitably spills into the systemic circulation. This process is mainly driven by hydraulic effects during instillation and density differences between blood and lock solution. Hence, in haemodialysis catheters, intra-luminal citrate concentration ranges from 0% (at the tip in catheters with side holes), 3% (between the side holes and the highest point of the catheter) to 46.7% (at the Luer end) with possible differences in antimicrobial effects. We investigated in vitro the antimicrobial effect of pure citrate 46.7%, citrate 46.7% diluted with saline and blood to a net concentration of 3% (=citrate 3%), and of citrate-free blood, simulating in vivo conditions in different catheter sections., Methods: Time-kill studies measuring the antimicrobial effect of citrate 46.7%, citrate 3% and citrate-free blood were performed with overnight cultures of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus)., Results: Citrate 46.7% reduced the number of E. coli by 2 log units but after 24 h, 10(6) CFU/mL were still present. Citrate 3% and citrate-free blood had no antimicrobial effect on E. coli. Citrate 46.7%, citrate 3% and citrate-free blood had scarce antimicrobial effect on S. aureus within 24 h., Conclusions: Spillage of catheter lock solution leading to reduced intra-luminal citrate concentrations considerably reduces the antimicrobial effect of citrate 46.7% on E. coli. As none of the solutions tested had relevant antimicrobial effect on S. aureus, the antimicrobial effect of 46.7% citrate lock solution in vivo has to be seriously questioned.

Background: The locking anticoagulant plays a decisive role in the patency of central venous catheters (CVCs) used for haemodialysis. During injection, the hydraulic effects inevitably cause lock solution to spill into the systemic circulation. Density differences between whole blood (WB) and the lock solution cause further gravity-induced seepage of lock solution. This is followed by an influx of WB into the catheter, also described for trisodium citrate, which is a common agent for serum protein precipitation. Embolic complications from haemodialysis catheters locked with hypertonic trisodium citrate have been reported. We aimed to investigate protein precipitation in trisodium citrate locked catheters as a possible cause of pulmonary embolisms., Methods: In vitro, WB and trisodium citrate (concentrations ranging from 4.7 to 46.7%) mixtures in a ratio of 1:4 were used to assess protein precipitation. Additionally, WB/trisodium citrate mixture was pumped through a 20-μm mesh filter, simulating pulmonary vessels, and filtrate pressure was measured. In vivo, listed filling volumes of haemodialysis catheters locked with trisodium citrate 4% (n=10), 10% (n=10), 20% (n=10) or 46.7% (n=10) were aspirated and then analysed for protein precipitation., Results: In vitro, protein precipitation capable of causing filter occlusion was observed in test solutions containing trisodium citrate above a concentration of 12%. In vivo, protein precipitation was detected in all samples from the CVCs filled with trisodium citrate 46.7% (n=10) and 20% (n=10). In contrast, there were no signs of precipitation in samples from the catheters filled with trisodium citrate 4% (n=10) or 10% (n=10)., Conclusions: Our in vitro results demonstrate that protein precipitates inside haemodialysis catheters when trisodium citrate is used above the concentrations of 12%. Precipitated protein may have contributed to the pathophysiology of reported embolisms from haemodialysis catheters filled with hypertonic trisodium citrate. Based on our findings, we suggest that trisodium citrate lock solution up to the concentration of 10% can be used safely.

Background: Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) generates inorganic pyrophosphate, a solute that serves as an essential physiological inhibitor of calcification. Inactivating mutations of ENPP1 are associated with generalized arterial calcification of infancy. We hypothesized the ENPP1 K121Q variant to be associated with increased vascular calcification in patients with end-stage renal failure., Subjects and Methods: We recruited 79 patients with end-stage renal failure undergoing dialysis treatment and genotyped them for the ENPP1 K121Q polymorphism. Next, we matched to each patient with ENPP1 121KQ genotype (n=15) a respective control with ENPP1 121KK genotype by gender, age, diabetes and duration of dialysis treatment. The matching ratio was 1:1. Severity of coronary calcification was quantified by computed tomography, and aortic stiffness was measured by pulse-wave analysis., Results: Patients with ENPP1 121KQ genotype had a significantly higher coronary calcium score (1385 vs 94; n=30; P=0.033), and also a higher aortic pulse-wave velocity when compared to matched controls with ENPP1 121KK genotype (13.69 m/s vs 9.37 m/s; P=0.003)., Conclusions: Taken together, our study suggests a potential role of the ENPP1 K121Q polymorphism in arterial calcification of patients with end-stage renal failure. Patients heterozygous for the ENPP1 K121Q polymorphism have higher coronary calcification scores and increased aortic stiffness, and may benefit from more intense treatment in order to prevent progression of arterial calcification.

Background: Haemodialysis (HD) with bioincompatible cellulosic membranes like Cuprophan (CU) is considered to influence negatively the clinical outcome of acute and chronic renal failure. In this effect, apart from the disturbance of phagocytosis or oxygen species production by leukocytes, increased apoptosis also has been implicated recently. The objective of this study was to study the effect of HD membranes on apoptosis induction in polymorphonuclear neutrophils (PMN)., Methods: PMN from healthy donors and uraemic patients were isolated and apoptosis was induced by co-incubation with CU, Hemophan or polyamide hollow fibres in the presence of serum from healthy or uraemic humans. Apoptosis was quantified by flow cytometry using Annexin V-FITC and propidium iodide staining and was confirmed by the detection of DNA fragmentation on gel electrophoresis. The deposition of immunoglobulins (Ig) and complement factors on hollow fibres was detected by direct immunofluorescence., Results: Heat inactivation or the depletion of complement components or Ig significantly reduced apoptosis, indicating its dependence on classical complement activation. The detection of IgG on hollow CU fibres and the restored acceleration of apoptosis by the appropriate replenishment of Ig-deficient sera additionally confirmed these findings. Inhibition experiments revealed that caspases were necessary mainly, but not exclusively, for apoptosis to occur after complement activation. Uraemia led to increased PMN apoptosis in the presence of bioincompatible, but not biocompatible, membranes., Conclusions: Our results suggest that the acceleration of PMN apoptosis in the presence of CU is mediated via an antibody-dependent activation of the classical complement pathway mobilizing both caspase-dependent and -independent pathways.