A Crossover Trial Using High‐Fidelity Cardiovascular Phenotyping

Background Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization‐activated cyclic nucleotide–gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. Methods and Results We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading. Conclusions HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation

Rationale and design of the RIACT–study: a multi-center placebo controlled double blind study to test the efficacy of RItuximab in Acute Cellular tubulointerstitial rejection with B-cell infiltrates in renal Transplant patients: study protocol for a randomized controlled trial

BACKGROUND: Acute kidney allograft rejection is a major cause for declining graft function and has a negative impact on the long-term graft survival. The majority (90%) of acute rejections are T-cell mediated and, therefore, the anti-rejection therapy targets T-cell-mediated mechanisms of the rejection process. However, there is increasing evidence that intragraft B-cells are also important in the T-cell-mediated rejections. First, a significant proportion of patients with acute T-cell-mediated rejection have B-cells present in the infiltrates. Second, the outcome of these patients is inferior, which has been related to an inferior response to the conventional anti-rejection therapy. Third, treatment of these patients with an anti-CD20 antibody (rituximab) improves the allograft outcome as reported in single case observations and in one small study. Despite the promise of these observations, solid evidence is required before incorporating this treatment option into a general treatment recommendation. METHODS/DESIGN: The RIACT study is designed as a randomized, double-blind, placebo-controlled, parallel group multicenter Phase III study. The study examines whether rituximab, in addition to the standard treatment with steroid-boli, leads to an improved one-year kidney allograft function, compared to the standard treatment alone in patients with acute T-cell mediated tubulointerstitial rejection and significant B-cell infiltrates in their biopsies. A total of 180 patients will be recruited. DISCUSSION: It is important to clarify the relevance of anti-B cell targeting in T-cell mediated rejection and answer the question whether this novel concept should be incorporated in the conventional anti-rejection therapy. TRIAL REGISTRATION: Clinical trials gov. number: NCT0111766

Cholemic nephropathy causes acute kidney injury and is accompanied by loss of aquaporin 2 in collecting ducts

Impairment of renal function often occurs in patients with liver disease. Hepatorenal syndrome is a significant cause of acute kidney injury (AKI) in cirrhotic patients (HRS-AKI, type 1). Causes of non-HRS AKI include cholemic nephropathy (CN), a disease that is characterized by intratubular bile casts and tubular injury. As data on patients with CN is mostly obtained from case reports or autopsy studies, we aimed to investigate the frequency and clinical course of CN. We identified 149 patients who underwent kidney biopsy between 2000 to 2016 at the Department of Gastroenterology, Hepatology and Endocrinology. Of these, 79 had a history of liver disease and deterioration of renal function. When applying recent EASL criteria 45 of the 79 patients (57%) presented with AKI, whereas 34 patients (43%) had chronic kidney disease (CKD) (43%). Renal biopsy revealed the diagnosis of CN in 8 of the 45 patients with AKI (17.8%), whereas none of the patients with CKD was diagnosed with CN. Univariate analysis identified serum bilirubin, alkaline phosphatase and urinary bilirubin and urobilinogen as predictive factors for the diagnosis of CN. Histological analysis of AKI patients with normal bilirubin, elevated bilirubin and the diagnosis of CN revealed loss aquaporin 2 (AQP2) expression in collecting ducts in patients with elevated bilirubin and CN. Biopsy related complications requiring medical intervention occurred in four of 79 patients (5.1%). In conclusion, CN is a common finding in patients with liver disease, AKI and highly elevated bilirubin. Loss of AQP2 in AKI patients with elevated bilirubin and CN might be the result of toxic effects of cholestasis and be in part responsible for the impairment of renal function

RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies

BACKGROUND: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. METHODS AND FINDINGS: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75-1.42] and 1.11 [0.81-1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (&gt;22,000 cases, &gt;60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years). CONCLUSIONS: High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies

RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies

Background: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±

Manual therapy applied by general practitioners for nonspecific low back pain: results of the ManRück pilot-study

Abstract Background Nonspecific acute low back pain (LBP) is a common reason for accessing primary care. German guidelines recommend non-steroidal anti-inflammatory drugs and physical activity as evidence-based treatments. Manual Therapy (MT) remains controversial. To increase evidence-based treatment options for general practitioners (GPs), a Pilot-Study was set up to gather information about the required conditions and setting for an RCT. Methods The open pilot-study assesses recruitment methods for GPs and patients, timelines, data collection and outcomes of treatment immediately (T0) and 1, 6 and 12 weeks after consultation (T1, T2, T3). Inclusion criteria for GPs were: no experience of MT; for patients: adults between 18 and 50 suffering from LBP for less than 14 days. Study process: Patients’ control-group (CG) was consecutively recruited first and received standard care. After GPs received a single training session in MT lasting two and a half hours, they consecutively recruited patients with LBP to the intervention group (IG). These patients received add-on MT. Primary outcomes: (A): timelines and recruitment success, (B): assessment tools and sample size evaluation, (C) clinical findings: pain intensity change from baseline to day 3 and time till (a) analgesic use stopped and (b) 2-point pain reduction on an 11-point scale occurred. Secondary outcomes: functional capacity, referral rate, use of other therapies, sick leave, patient satisfaction. Results 14 GPs participated, recruiting 42 patients for the CG and 45 for the IG; 49% (56%) of patients were women. Average baseline pain was 5.98 points, SD: ±2.3 (5.98, SD ±1.8). For an RCT an extended timeline and enhanced recruitment procedures are required. The assessment tools seem appropriate and provided relevant findings: additional MT led to faster pain reduction. IG showed reduced analgesic use and reduced pain at T1 and improved functional capacity by T2. Conclusions Before verifying the encouraging findings that additional MT may lead to faster pain reduction and reduced analgesic use via an RCT, the setting, patients’ structure, and inclusion criteria should be considered more closely. Trial registration Number: DRKS00003240 Registry: German Clinical Trials Registry (DRKS) URL: https://www.drks.de/drks_web/. Registration date: 14.11.2011. First patient: March 2012. Funding: the Rut and Klaus Bahlsen Stiftung, Hannover

Critical appraisal of arguments for the delayed-start design proposed as alternative to the parallel-group randomized clinical trial design in the field of rare disease

Abstract Background A number of papers have proposed or evaluated the delayed-start design as an alternative to the standard two-arm parallel group randomized clinical trial (RCT) design in the field of rare disease. However the discussion is felt to lack a sufficient degree of consideration devoted to the true virtues of the delayed start design and the implications either in terms of required sample-size, overall information, or interpretation of the estimate in the context of small populations. Objectives To evaluate whether there are real advantages of the delayed-start design particularly in terms of overall efficacy and sample size requirements as a proposed alternative to the standard parallel group RCT in the field of rare disease. Methods We used a real-life example to compare the delayed-start design with the standard RCT in terms of sample size requirements. Then, based on three scenarios regarding the development of the treatment effect over time, the advantages, limitations and potential costs of the delayed-start design are discussed. Results We clarify that delayed-start design is not suitable for drugs that establish an immediate treatment effect, but for drugs with effects developing over time, instead. In addition, the sample size will always increase as an implication for a reduced time on placebo resulting in a decreased treatment effect. Conclusions A number of papers have repeated well-known arguments to justify the delayed-start design as appropriate alternative to the standard parallel group RCT in the field of rare disease and do not discuss the specific needs of research methodology in this field. The main point is that a limited time on placebo will result in an underestimated treatment effect and, in consequence, in larger sample size requirements compared to those expected under a standard parallel-group design. This also impacts on benefit-risk assessment

A multicenter, randomized, open-labeled study to steer immunosuppressive and antiviral therapy by measurement of virus (CMV, ADV, HSV)-specific T cells in addition to determination of trough levels of immunosuppressants in pediatric kidney allograft recipients (IVIST01-trial): study protocol for a randomized controlled trial

Background: After kidney transplantation, immunosuppressive therapy causes impaired cellular immune defense leading to an increased risk of viral complications. Trough level monitoring of immunosuppressants is insufficient to estimate the individual intensity of immunosuppression. We have already shown that virus-specific T cells (Tvis) correlate with control of virus replication as well as with the intensity of immunosuppression. The multicentre IVIST01-trial should prove that additional steering of immunosuppressive and antiviral therapy by Tvis levels leads to better graft function by avoidance of over-immunosuppression (for example, viral infections) and drug toxicity (for example, nephrotoxicity). Methods/design: The IVIST-trial starts 4 weeks after transplantation. Sixty-four pediatric kidney recipients are randomized either to a non-intervention group that is only treated conservatively or to an intervention group with additional monitoring by Tvis. The randomization is stratified by centre and cytomegalovirus (CMV) prophylaxis. In both groups the immunosuppressive medication (cyclosporine A and everolimus) is adopted in the same target range of trough levels. In the non-intervention group the immunosuppressive therapy (cyclosporine A and everolimus) is only steered by classical trough level monitoring and the antiviral therapy of a CMV infection is performed according to a standard protocol. In contrast, in the intervention group the dose of immunosuppressants is individually adopted according to Tvis levels as a direct measure of the intensity of immunosuppression in addition to classical trough level monitoring. In case of CMV infection or reactivation the antiviral management is based on the individual CMV-specific immune defense assessed by the CMV-Tvis level. Primary endpoint of the study is the glomerular filtration rate 2 years after transplantation; secondary endpoints are the number and severity of viral infections and the incidence of side effects of immunosuppressive and antiviral drugs. Discussion: This IVIST01-trial will answer the question whether the new concept of steering immunosuppressive and antiviral therapy by Tvis levels leads to better future graft function. In terms of an effect-related drug monitoring, the study design aims to realize a personalization of immunosuppressive and antiviral management after transplantation. Based on the IVIST01-trial, immunomonitoring by Tvis might be incorporated into routine care after kidney transplantation