The Calcineurin Inhibitor-Sparing (CIS) Trial - individualised calcineurin-inhibitor treatment by immunomonitoring in renal allograft recipients: protocol for a randomised controlled trial

Background: Adequate monitoring tools are required to optimise the immunosuppressive therapy of an individual patient. Particularly, in calcineurin inhibitors, as critical dose drugs with a narrow therapeutic range, the optimal monitoring strategies are discussed in terms of safety and efficacy. Nevertheless, no pharmacokinetic monitoring markers reflect the biological activity of the drug. A new quantitative analysis of gene expression was employed to directly measure the functional effects of calcineurin inhibition: the transcriptional activities of the nuclear factor of activated T-cell (NFAT)-regulated genes in the peripheral blood. Methods/Design: The CIS study is a randomised prospective controlled trial, comparing a ciclosporin A (CsA)-based immunosuppressive regimen monitored by CsA trough levels to a CsA-based immunosuppressive regimen monitored by residual NFAT-regulated gene expression. Pulse wave velocity as an accepted surrogate marker of the cardiovascular risk is assessed in both study groups. Our hypothesis is that an individualised CsA therapy monitored by residual NFAT-regulated gene expression results in a significantly lower cardiovascular risk compared to CsA therapy monitored by CsA trough levels. Discussion: There is a lack of evidence in individualising standard immunosuppression in renal allograft recipients. The CIS study will consider the feasibility of individualised ciclosporin A immunosuppression by pharmacodynamic monitoring and evaluate the opportunity to reduce cardiovascular risk while maintaining sufficient immunosuppression. Trial registration: EudraCT identifier 2011-003547-21, registration date 18 July 201

Hepatic and Renal Failure after Anterior Myocardial Infarction Induced Apical Ventricular Septal Defect

We report the case of a 68-year-old man suffering from incremental hepatic and renal failure one month after anterior myocardial infarction. Cardiac MRI showed a pronounced apical post-AMI aneurysm, a moderate to severe mitral and tricuspid regurgitation as well as a hemodynamically highly significant 12 mm apical ventricular septal defect with a left-to-right ventricular shunt of almost 63% as the underlying cause. Heart X-ray revealed a severe LAD in-stent restenosis. CAPD catheter drainage of hydroperitoneum due to congestive liver and renal failure was provided in combination with intensified CAPD hemodialysis. Heart surgery was performed where the apical aneurysm was excised, the mitral valve was reconstructed, the IVSD was closed and the subtotally in-stent occluded LAD was bypassed. Post-surgery, the ascites were significantly reduced, and CAPD hemodialysis therapy could be terminated since the renal function gradually improved (MDRD = 25 mL/min). To our knowledge, for the first time we report successful CAPD catheter drainage of hydroperitoneum in combination with CAPD hemodialysis

Association of low serum TGF-β level in hantavirus infected patients with severe disease

Background: Hantaviruses are emerging zoonotic pathogens which cause hemorrhagic fever with renal syndrome, an immune-mediated pathogenesis is discussed. The aim of the present study was to investigate the role of TGF-β expression in acute hantavirus infection. Results: We retrospectively studied 77 patients hospitalised with acute Puumala infection during a hantavirus epidemic in Germany in 2012. Hantavirus infection was confirmed by positive anti-Puumala hantavirus IgG and IgM. Plasma levels of transforming growth factor (TGF)-β1 and TGF-β2 were analysed. Based on glomerular filtration rate on admission, patients were divided in mild and severe course of disease. Puumala virus RNA was detected by PCR amplification of the viral L segment gene. Out of 77 Puumala virus infected patients, 52 (68%) were male. A seasonal distribution was detected in our cohort with a peak in summer 2012, the highest incidence was observed in the age group of 30–39 years. Puumala virus RNA was detectable in 4/77 cases. Patients with severe disease had a significant longer hospital stay than patients with mild disease (6.2 vs 3.6 days). Thrombocyte count (186 vs 225 per nl), serum TGF-β1 (74 vs 118 ng/l) and TGF-β2 (479 vs 586 pg/l) were significantly lower in severe compared to mild disease. However, C-reactive protein (CRP) was significantly higher in patients with severe disease (62 vs 40 mg/l). TGF-β1/Cr was the most sensitive and specific marker associated with renal dysfunction. Conclusion: High serum CRP and low serum TGF-β in the early phase of hantavirus infection is associated with a severe course of disease. Our results support the hypothesis of an immune-mediated pathogenesis in hantavirus infection

Gender disparity in health-related quality of life and fatigue after living renal donation

Background: The clinical outcome and health-related quality of life (HRQoL) of living kidney donors is mostly not detrimental, but some donors experience impairment after donation. Gender-specific effects of living kidney donors was evaluated. Methods: Clinical outcome was assessed in living kidney donors and HRQoL was obtained by self-reporting validated test systems as the Multidimensional Fatigue Inventory (MFI-20), the Short Form 36 (SF-36), and the Patient Health Questionnaire (PHQ-9). Results: Two hundred and eleven (211) living renal donors were evaluated (female 62.2%). Response rate was 80.8%. In both genders, a decrease of renal function of 26% was observed after donation. De novo antihypertensives were introduced in 28.3% of women and 36.5% of men. HRQoL was comparable in female and male donors, except for mental HRQoL, which was lower in 51- to 60-year-old female donors, compared to age-matched male donors and to the female general population. Female donors aged 40–59 years demonstrated more fatigue than the age-matched general population. A low mental HRQoL (MCS; SF-36) was associated with higher values for fatigue (General Fatigue Score; MFI-20) in both genders. Multiple regression analysis detected the General Fatigue score of the MFI-20 questionnaire and depression identified by the PHQ-9 score as independent variables predicting MCS of the SF-36 in both genders. Lower age at time of donation contributed to a lower MCS in female donors. Conclusions: Overall, HRQoL in living kidney donors exceeds that of the general population. Inferior mental health status and fatigue seem to be a problem, especially in middle-aged female donors, but not in all female donors. Psychological evaluation pre donation and psychological support post donation are required

Motility of human renal cells is disturbed by infection with pathogenic hantaviruses

Background: Hemorrhagic fever with renal syndrome (HFRS) caused by pathogenic hantaviruses in Europe and Asia is often characterized by acute kidney injury (AKI) with massive proteinuria. Renal filtration depends on the integrity of epithelial and endothelial monolayers in the tubular and glomerular apparatus. Tubular and glomerular cells represent target cells of hantavirus infection. However, the detailed mechanisms of renal impairment induced by hantaviruses are not well understood. Methods: We analyzed the cellular consequences of hantavirus infection by measuring adhesion and migration capacity of human renal cells infected with Puumala (PUUV) or Hantaan (HTNV) virus. The impact of hantaviral nucleocapsid proteins (N proteins) on motility was examined by transfection of podocytes. Results: Infection of kidney cells with hantavirus species PUUV and HTNV causes a significant reduction of migration capacity. The impaired motility depends on viral replication and transfection of podocytes with N protein of PUUV or HTNV reveals that the expression of N protein alone is sufficient to deteriorate podocyte function. The cellular effects are more pronounced for the more pathogenic HTNV than for PUUV that causes a milder form of HFRS. Conclusions: The direct impairment of migration capacity of renal cells by hantaviral N proteins may contribute substantially to proteinuria observed in the clinical picture of hantavirus infection

Clinical Relevance of HLA Antibodies in Kidney Transplantation: Recent Data from the Heidelberg Transplant Center and the Collaborative Transplant Study

Herein, we summarize our recent findings from the international Collaborative Transplant Study (CTS) and Heidelberg Transplant Center regarding the role of HLA antibodies in kidney transplantation and their application into the clinical routine. Based on the antibody findings from the CTS serum study, an algorithm was developed in 2006 for the transplantation of high-risk sensitized patients at the Heidelberg Transplant Center which includes seven different pre-and posttransplant measures. Using this algorithm, the number of transplantations could be increased in high-risk presensitized patients and the previously existing impact of antibodies on graft survival could greatly be diminished but not totally eliminated. More recent findings led to the hypothesis that T cell help from a preactivated immune system supports the harmful effects of pretransplant donor-specific HLA antibodies that otherwise disappear in many cases after transplantation without any consequence

Procalcitonin as marker of infection in patients with Goodpasture's syndrome is misleading

Abstract Background. Procalcitonin (PCT) is routinely measured to differentiate autoimmune disorders from infection. There are reports, however, where PCT is high in the absence of infection, i.e. in vasculitis. To investigate the value of PCT in Goodpasture's syndrome, we reviewed the charts of patients with Goodpasture's syndrome who were treated from 1996 to 2006. Methods. PCT (normal range <0.5 ng/ml) was measured with an immunoluminometric assay, C-reactive protein (CRP; normal range <5 mg/l) with nephelometry. Anti-glomerular basement membrane antibodies (normal range <1:10) were measured with ELISA