Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease

Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors

Early surgery for severe aortic regurgitation.

One hundred and fourteen consecutive patients who underwent aortic valve replacement (AVR) for isolated aortic regurgitation (AR) from 1965 to 1981 are presented. Sixty eight (60%) were preoperatively in NYHA class I-II and 46 (40%) were in NYHA class III-IV. Eighty-two patients had left and right heart catheterization prior to the operation and the severity of regurgitation was assessed angiographically in 93% of those in functional class (FC) I-II. Left ventricular (LV) end-diastolic volume index and end-systolic volume index were elevated even in the mildly symptomatic patients (156.1 and 61.0 ml/m2 respectively). The ratio of LV end-systolic pressure to LV end systolic volume index was diminished in the FC I-II patients. Two patients in FC III died in hospital (operative mortality: 1.7%) and there were 21 late deaths with a 5-year survival of 82.7%. Late survival differed significantly between patients who were preoperatively in FC I and II or III and IV (P less than 0.03). These data suggest that severe AR with altered LV function is an indication for early operation regardless of the presence of absence of symptoms

Viability of long-term cryopreserved human saphenous veins.

The feasibility of maintaining long-term viability of human venous allografts by cryopreservation has been investigated. Segments of vein were obtained from 85 patients undergoing a stripping operation for varicose veins. The venous segments were immersed in a dimethylsulfoxide 15% solution, deep frozen at -196 degrees C in liquid nitrogen and preserved for a duration of 1 week to 24 months. Light microscopy (n = 126) failed to demonstrate striking differences between control veins and any of the cryopreserved veins. The types of damage observed at scanning electron microscopy included endothelial cell separation, endothelial cell loss, exposed basement membrane and exposed fibrillar collagen, which were graded on a scale. The score for short term (less than 3 weeks) stored veins was 8.1 +/- 0.9 (mean +/- SEM) and did not differ from the long-term (greater than 10 weeks) stored veins score (6.3 +/- 1.0, p NS). The tissue enzymes LDH, GOT, GPT, CPK were measured in the frozen vein groups (n = 115) after thawing to room temperature. Cryopreservation did not alter any of the tissue enzymes measured when compared to controls. Endothelial fibrinolytic activity (FA) of 58 venous segments cryopreserved for a mean duration of 20 months was 6136.4 +/- 292.1 Tissue Activator Units (TAU) and did not differ from FA of 11 controls (5989.1 +/- 696.8 TAU). Synthesis of 6-Keto-PGF1-alpha-2, a stable breakdown product of PGI2, measured in 10 venous segments cryopreserved for 10 months, was significantly higher than in 13 veins stored in saline for 12 hours at 4 degrees C (2.8 +/- 0.4 vs 0.4 +/- 0.1 PG ml-1mg-1min-1, respectively; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS

Clinical Evaluation of Duraflo(r) II Heparin treated Extracorporeal Circulation Circuits (2nd version)- The European Working Group on Heparin Coated Extracorporeal Circulation Circuits

OBJECTIVES: To evaluate whether the application of heparin treated circuits for elective coronary artery surgery improves postoperative recovery, a European multicenter randomised clinical trial was carried out. METHODS: In 11 European heart centers, 805 low-risk patients underwent cardiopulmonary bypass (CPB) with either an untreated circuit (n = 407) or an identical but heparin treated circuit (n = 398, Duraflo II). RESULTS: Significant differences were found among participating centers with respect to patient characteristics, blood handling procedures and postoperative care. The use of heparin treated circuits revealed no overall changes in blood loss, blood use, time on ventilator, occurrence of adverse events, morbidity, mortality, and intensive care stay. These results did not change after adjustment for centers and (other) prognostic factors as analysed with logistic regression. In both groups no clinical or technical (patient or device related) side effects were reported. Because female gender and aortic cross clamp time appeared as prognostic factors in the logistic regression analysis, a subgroup analysis with these variables was performed. In a subpopulation of females (n = 99), those receiving heparin treated circuits needed less blood products, had a lower incidence of rhythm disturbances and were extubated earlier than controls. In another subgroup of patients with aortic cross clamp time exceeding 60 min (n = 197), the amount of patients requiring prolonged intensive care treatment (> 24 h) was significantly lower when they received heparin treated circuits versus controls. CONCLUSION: These findings suggest that improved recovery can be expected with heparin treated circuits in specific higher risk patient populations (e.g. females) and when prolonged aortic cross clamp time is anticipated. Further investigations are recommended to analyses the clinical benefit of heparin treated circuits in studies with patients in different well defined risk categories and under better standardised circumstances