MicroRNAs in Diabetic Nephropathy: From Biomarkers to Therapy

Recent estimates suggest that 1 in 12 of the global population suffers from diabetes mellitus. Approximately 40 % of those affected will go on to develop diabetes-related chronic kidney disease or diabetic nephropathy (DN). DN is a major cause of disability and premature death. Existing tests for prognostic purposes are limited and can be invasive, and interventions to delay progression are challenging. MicroRNAs (miRNAs) are a recently described class of molecular regulators found ubiquitously in human tissues and bodily fluids, where they are highly stable. Alterations in miRNA expression profiles have been observed in numerous diseases. Blood and tissue miRNAs are already established cancer biomarkers, and cardiovascular, metabolic and immune disease miRNA biomarkers are under development. Urinary miRNAs represent a potential novel source of non-invasive biomarkers for kidney diseases, including DN. In addition, recent data suggest that miRNAs may have therapeutic applications. Here, we review the utility of miRNAs as biomarkers for the early detection and progression of DN, assess emerging data on miRNAs implicated in DN pathology and discuss how the data from both fields may contribute to the development of novel therapeutic agents

Lymphotoxin expression in human and murine renal allografts

The kidney is the most frequently transplanted solid organ. Recruitment of inflammatory cells, ranging from diffuse to nodular accumulations with defined microarchitecture, is a hallmark of acute and chronic renal allograft injury. Lymphotoxins (LTs) mediate the communication of lymphocytes and stromal cells and play a pivotal role in chronic inflammation and formation of lymphoid tissue. The aim of this study was to assess the expression of members of the LT system in acute rejection (AR) and chronic renal allograft injury such as transplant glomerulopathy (TG) and interstitial fibrosis/tubular atrophy (IFTA). We investigated differentially regulated components in transcriptomes of human renal allograft biopsies. By microarray analysis, we found the upregulation of LT beta, LIGHT, HVEM and TNF receptors 1 and 2 in AR and IFTA in human renal allograft biopsies. In addition, there was clear evidence for the activation of the NF kappa B pathway, most likely a consequence of LT beta receptor stimulation. In human renal allograft biopsies with transplant glomerulopathy (TG) two distinct transcriptional patterns of LT activation were revealed. By quantitative RT-PCR robust upregulation of LTa, LT beta and LIGHT was shown in biopsies with borderline lesions and AR. Immunohistochemistry revealed expression of LT beta in tubular epithelial cells and inflammatory infiltrates in transplant biopsies with AR and IFTA. Finally, activation of LT signaling was reproduced in a murine model of renal transplantation with AR. In summary, our results indicate a potential role of the LT system in acute renal allograft rejection and chronic transplant injury. Activation of the LT system in allograft rejection in rodents indicates a species independent mechanism. The functional role of the LT system in acute renal allograft rejection and chronic injury remains to be determined

Elektrisch evozierte Summenaktionspotenziale: Vergleich von intra- und postoperativer Messung

Hintergrund: Die Messung der elektrisch evozierten Summenaktionspotenziale (ECAP) gehört zum Standard während der Insertion eines Cochlea-Implantats (CI). Die Funktionsfähigkeit des CIs und Lage des Elektrodenträgers lassen sich so einschätzen. Auch in den nachfolgenden Anpassungen des Sprachprozessors liefert die ECAP-Messung Hinweise für die Einstellung gerade bei nicht-kooperativen Patienten, z.B. kleinen Kindern.Wir sind der Frage nachgegangen, wie sich die ECAP-Schwellen während der CI-Einheilung verändern und ob ein Zusammenhang zum erreichten Sprachverstehen besteht.Material und Methoden: Es wurden ECAPs bei 32 Patienten mit Implantaten der Firma Cochlear (25 CI522, 3 CI532, 2 CI512, 1 CI622, 1 CI422) während der Implantation (IntraOp) und einen Monat nach der ersten Einstellung (PostOp) gemessen. Die IntraOp-Messungen wurden im automatischen Modus der Mess-Software (Custom Sound EP, Cochlear) durchgeführt und die PostOp-Messung mit nach Berger modifizierten Parametern (Pulsweite 50 µs, Interphase Gap 24 µs). Es wurden der Abstand und die Korrelation zwischen der IntraOp- und der PostOp-Messung berechnet, nach denen die Probanden in eine Hälfte mit guter (rho>0,87, Median) und schlechter Korrelation eingeteilt wurden. Das Sprachverstehen der Gruppen wurde 1 Monat, 3 Monate und 6 Monate nach der Implantation mit einer zweifaktoriellen Varianzanalyse mit Messwiederholung (Faktoren Zeitpunkt und Korrelation) ausgewertet.Ergebnisse: Im Mittel lagen die Differenzen der ECAP-Schwellen zwischen den Messungen bei 47±7 CL (current level). Die Varianzanalyse zeigte bezüglich der Korrelation keine signifikanten Effekte. Die Mittelwerte des Sprachverstehens lagen bei 43±27%, 53±23% und 60±22% nach 1, 3 und 6 Monaten in der Gruppe mit hoher Korrelation und bei 50±32%, 67±25% und 72±22% in der Gruppe mit schlechter Korrelation.Diskussion: Die Unterschiede in den ECAP-Schwellen lassen sich nur zum Teil mit den modifizierten Parametern mit 30 CL erklären. Dies bedeutet, dass 17 CL auf andere Effekte zurückzuführen sind, eine Möglichkeit wäre hier die Einheilung des Elektrodenträgers. Das Sprachverstehen scheint in der Gruppe mit einer niedrigeren Korrelation zwischen intra- und postoperativer ECAP-Schwelle tendenziell besser zu sein. Ein Zusammenhang zur Veränderung der ECAP-Schwelle ist nicht nachweisbar und wird eventuell durch hier nicht berücksichtigte Effekte überdeckt

Clazakizumab in late antibody-mediated rejection: study protocol of a randomized controlled pilot trial

Abstract Background Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials (RCT) have failed to demonstrate the efficacy of widely used therapies, such as rituximab plus intravenous immunoglobulin or proteasome inhibition (bortezomib), reinforcing a great need for new therapeutic concepts. One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity. Methods This investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR ≥ 365 days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charité University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25 mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4–12), all patients will receive clazakizumab at 25 mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival. Discussion Currently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection. Trial registration ClinicalTrials.gov, NCT03444103. Registered on 23 February 2018 (retrospective registration)