Alport syndrome and autosomal dominant tubulointerstitial kidney disease frequently underlie end-stage renal disease of unknown origin-a single-center analysis.

BACKGROUND: The prevalence of end-stage renal disease of unknown etiology in adult patients is globally high and accounts for almost 20% of all dialysis patients. Recent studies have suggested that the percentage of adult patients with a causal genetic variant has been underestimated so far. Despite severe prognostic and therapeutic implications, awareness about prevalence and manifestations of genetic kidney diseases in adult renal patients is still limited. METHODS: We recruited 58 individuals from 39 families at our transplantation center, fulfilling at least one of the following criteria: (i) unclear etiology of kidney disease, (ii) clinically suspected genetic kidney disease and (iii) positive family history for nephropathies. The cohort consisted of patients waitlisted for kidney transplantation and patients in the follow-up after transplantation. Detailed documentation of family history and phenotype was obtained before initiating gene panel sequencing of 479 nephropathy-associated genes. RESULTS: With this study design, a molecular genetic diagnosis was established in one-third of all patients. Mutations in the collagen COL4A genes, and mutations in MUC1 and UMOD were the most frequent among all detected causal variants. Overall, rare genetic variants were detected in more than half of all cases. CONCLUSION: The combination of detailed phenotyping prior to next-generation sequencing diagnostics was highly efficient. Elucidating the underlying genetic causes in a cohort of adult renal patients has considerable clinical impact on medical management.

Hydroxymethylglutaryl coenzyme A reductase inhibition reduces Chlamydia pneumoniae-induced cell interaction and activation.

BACKGROUND: Chlamydia pneumoniae stimulates chronic inflammation in vascular cells. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) may have an ameliorating effect. We investigated possible mechanisms. METHODS AND RESULTS: We infected human macrophages that in coculture spread infection to vascular smooth muscle cells (VSMCs). Cerivastatin (250 nmol/L) reduced VSMC infection by 33%. Western blotting made it apparent that VSMC infection resulted in increased cell membrane-associated RhoA and Rac1, implying increased prenylation of these proteins. This effect was blocked by statin but circumvented by mevalonate. Cytochrome C assays showed that infected VSMCs produced increased reactive oxygen species that was blocked by statin. Infection increased nuclear transcription factor-kappaB expression in VSMCs that was dose-dependently suppressed by statin. Infected VSMCs produced and released RANTES and MCP-1. Statin dose-dependently blocked this production both at the mRNA and protein levels. Mevalonate and M geranylgeranylpyrophosphate circumvented these effects. CONCLUSIONS: C pneumoniae can be transmitted from macrophages to VSMCs. VSMCs showed an activation profile typical of atherosclerosis, namely Rac1 and RhoA prenylation, nuclear transcription factor-kappaB activation, reactive oxygen species production, and chemokine production. Statin reduces macrophage-mediated C pneumoniae-induced signaling and transmission.

Severe QTc prolongation under mild hypothermia treatment and incidence of arrhythmias after cardiac arrest--a prospective study in 34 survivors with continuous Holter ECG.

BACKGROUND: Mild hypothermia treatment (32-34°C) in survivors after cardiac arrest (CA) is clearly recommended by the current guidelines. The effects of cooling procedure towards QT interval have not been evaluated so far outside of case series. In a prospective study 34 consecutive survivors after cardiac arrest were continuously monitored with Holter ECG over the first 48 h. PATIENTS AND METHODS: A total of 34 patients were analysed and received mild therapeutic hypothermia treatment (MTH) according to the current guidelines and irrespective of the initial rhythm. At admission to hospital and in the field in case of OHCA, a 12-lead ECG was performed in all patients. RESULTS: During cooling the incidence of ventricular tachycardia was low (8.8%) and in none of the patients Torsade de pointes occurred. The QTc interval was within normal range at first patient contact with EMS in the field (440.00 ms; IQR 424.25-476.75; n=17) but during hypothermia treatment the QTc interval was significantly prolonged at 33°C after 24h of cooling (564.47 ms; IQR 512.41-590.00; p=0.0001; n=34) and decreased after end of hypothermia to baseline levels (476.74 ms; 448.71-494.97; p=0.15). CONCLUSION: The QTc interval was found to be significantly prolonged during MTH treatment, and some severe prolongations >670 ms were observed, without a higher incidence of life-threatening arrhythmias, especially no Torsade des pointes were detected. However, routine and frequent ECG recording with respect to the QTc interval should become part of any hypothermia standard operation protocol and should be recommended by official guidelines.

Mild therapeutic hypothermia after cardiac arrest and the risk of bleeding in patients with acute myocardial infarction.

BACKGROUND: The aim of the study was to report the impact of our hypothermia protocol on survival and neurological outcome. Furthermore, we were interested in the risk of bleeding complications in patients with acute myocardial infarction (AMI) being treated with percutaneous coronary revascularisation (PCI) and therapeutic hypothermia. METHODS AND RESULTS: In a prospective observational study we identified 31 comatose patients (25 male, age 65+/-13 years) admitted to our intensive care unit with out-of-hospital cardiac arrest due to AMI who were treated with hypothermia. They were compared to 31 historical age- and gender-matched controls (25 male, age 65+/-12 years) admitted after out-of-hospital cardiac arrest due to AMI in the era prior to hypothermia treatment. Peak creatinine kinase-MB was 118 U/L (94-248) in the hypothermia group and 131 U/L (98-257) in controls (p=0.51). In the hypothermia group, 19 patients were discharged with a favourable neurological outcome, whereas in controls, such outcome was observed in only six patients (p=0.002). In both groups, haemoglobin values and platelet counts declined during the first 48 h (all p<0.001). No differences regarding bleeding complications (p=1.0), transfusion requirements (p=1.0), and the number of transfusions (p=0.9) were observed between the groups. CONCLUSIONS: A major improvement in neurological outcome was observed in patients treated with hypothermia. Our results indicate that the combination of reperfusion strategies and the application of hypothermia do not carry an excessive risk of bleeding complications. Patients with AMI and out-of-hospital cardiac arrest should receive the optimal therapy for both conditions, that is, either thrombolysis or PCI and therapeutic hypothermia.

Combination of bortezomib-based chemotherapy and extracorporeal free light chain removal for treating cast nephropathy in multiple myeloma.

Besides amyloidosis and light chain deposition disease, the most common histological type of renal lesion is cast nephropathy in 30% of patients with multiple myeloma [2]. In contrast to amyloidosis, cast nephropathy is believed to be potentially reversible when circulating light chains are rapidly reduced. We report on three patients with multiple myeloma and cast nephropathy treated with a bortezomib-based chemotherapy in addition to a newly developed high-cutoff polyflux® haemofilter. Reduction in serum free light chain levels was achieved within 10-12 days, with all three patients improving their renal function.