Background Critically ill coronavirus disease 2019 (COVID-19) patients have a high risk of acute kidney injury (AKI) that requires renal replacement therapy (RRT). A state of hypercoagulability reduces circuit life spans. To maintain circuit patency and therapeutic efficiency, an optimized anticoagulation strategy is needed. This study investigates whether alternative anticoagulation strategies for RRT during COVID-19 are superior to administration of unfractionated heparin (UFH). Methods Retrospective cohort study on 71 critically ill COVID-19 patients (≥18 years), admitted to intensive care units at a tertiary health care facility in the southwestern part of Germany between February 26 and May 21, 2020. We collected data on the disease course, AKI, RRT, and thromboembolic events. Four different anticoagulatory regimens were administered. Anticoagulation during continuous veno-venous hemodialysis (CVVHD) was performed with UFH or citrate. Anticoagulation during sustained low-efficiency daily dialysis (SLEDD) was performed with UFH, argatroban, or low molecular weight heparin (LMWH). Primary outcome is the effect of the anticoagulation regimen on mean treatment times of RRT. Results In patients receiving CVVHD, mean treatment time in the UFH group was 21.3 h (SEM: ±5.6 h), in the citrate group 45.6 h (SEM: ±2.7 h). Citrate anticoagulation significantly prolonged treatment times by 24.4 h (P = .001). In patients receiving SLEDD, mean treatment time with UFH was 8.1 h (SEM: ±1.3 h), with argatroban 8.0 h (SEM: ±0.9 h), and with LMWH 11.8 h (SEM: ±0.5 h). LMWH significantly prolonged treatment times by 3.7 h (P = .008) and 3.8 h (P = .002), respectively. Conclusions UFH fails to prevent early clotting events in the dialysis circuit during COVID-19. For patients, who do not require effective systemic anticoagulation, regional citrate dialysis is the most effective strategy. For patients, who require effective systemic anticoagulation, the usage of LMWH results in the longest circuit life spans. The proposed anticoagulatory strategies are safe, can easily be monitored, and allow an individualized treatment. Graphical abstract
Genome editing tools such as CRISPR/Cas9 enable the rapid and precise manipulation of genomes. CRISPR-based genome editing has greatly simplified the study of gene function in cell lines, but its widespread use has also highlighted challenges of reproducibility. Phenotypic variability among different knockout clones of the same gene is a common problem confounding the establishment of robust genotype–phenotype correlations. Optimized genome editing protocols to enhance reproducibility include measures to reduce off-target effects. However, even if current state-of-the-art protocols are applied phenotypic variability is frequently observed. Here we identify heterogeneity of wild-type cells as an important and often neglected confounding factor in genome-editing experiments. We demonstrate that isolation of individual wild-type clones from an apparently homogenous stable cell line uncovers significant phenotypic differences between clones. Strikingly, we observe hundreds of differentially regulated transcripts (477 up- and 306 downregulated) when comparing two populations of wild-type cells. Furthermore, we show a variety of cellular and biochemical alterations in different wild-type clones in a range that is commonly interpreted as biologically relevant in genome-edited cells. Heterogeneity of wild-type cells thus contributes to variability in genome-edited cells when these are generated through isolation of clones. We show that the generation of monoclonal isogenic wild-type cells prior to genomic manipulation reduces phenotypic variability. We therefore propose to generate matched isogenic control cells prior to genome editing to increase reproducibility.
BACKGROUNDOne of the common late sequela in patients with end-stage renal disease (ESRD) is the calcium phosphate disorder leading to chronic hypercalcemia and hyperphosphatemia causing the precipitation of calcium salt in soft tissues. Tumoral calcinosis is an extremely rare clinical manifestation of cyst-like soft tissue deposits in different periarticular regions in patients with ESRD and is characterized by extensive calcium salt containing space-consuming painful lesions. The treatment of ESRD patients with tumoral calcinosis manifestation involves an increase in or switching of renal replacement therapy regimes and the adjustment of oral medication with the goal of improved hypercalcemia and hyperphosphatemia.CASE SUMMARYWe describe a 40-year-old woman with ESRD secondary to IgA-nephritis and severe bilateral manifestation of tumoral calcinosis associated with hypercalcemia, hyperphosphatemia and tertiary hyperparathyroidism. The patient was on continuous ambulatory peritoneal dialysis and treatment with vitamin D analogues. After switching her to a daily hemodialysis schedule and adjusting the medical treatment, the patient experienced a significant dissolution of her soft tissue calcifications within a couple of weeks. Complete remission was achieved 11 mo after the initial diagnosis.CONCLUSIONReduced patient compliance and subsequent insufficiency of dialysis regime quality contribute to the aggravation of calcium phosphate disorder in a patient with ESRD leading to the manifestation of tumoral calcinosis. However, the improvement of the treatment strategy and reinforcement of patient compliance enabled complete remission of this rare disease entity.
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