Acute kidney injury (AKI) is common in critically ill patients and is associated with increased morbidity and mortality. Dysfunction of other organs is an important cause of poor outcomes from AKI. Ample clinical and epidemiologic data show that AKI is associated with distant organ dysfunction in lung, heart, brain, and liver. Recent advancements in basic and clinical research have demonstrated physiologic and molecular mechanisms of distant organ interactions in AKI, including leukocyte activation and infiltration, generation of soluble factors such as inflammatory cytokines/chemokines, and endothelial injury. Oxidative stress and production of reactive oxygen species, as well as dysregulation of cell death in distant organs, are also important mechanism of AKI-induced distant organ dysfunction. This review updates recent clinical and experimental findings on organ crosstalk in AKI and highlights potential molecular mechanisms and therapeutic targets to improve clinical outcomes during AKI.

Acute kidney injury (AKI) is a significant problem in both native and transplant kidneys. There have been significant advances in understanding the role of immune cells in the early injury and repair from AKI. In this brief review, we aim to update information on the pathophysiologic impact of various immune cells in AKI, with special emphasis on repair. An improved understanding of the AKI immunopathology will lead to new therapies that prevent AKI, accelerate repair, and prevent the progression of AKI to chronic kidney disease.

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Background: Cancer patients suffer from worse coronavirus disease-2019 (COVID-19) outcomes. Whether active oncologic treatment is an additional risk factor in this population remains unclear. Therefore, here we have conducted a systematic review and meta-analysis to summarize the existing evidence for the effect of active oncologic treatment on COVID-19 outcomes. Methods: Systematic search of databases (PubMed, Embase) was conducted for studies published from inception to July 1, 2020, with a subsequent search update conducted on 10 October 2020. In addition, abstracts and presentations from major conference proceedings (ASCO, ESMO, AACR) as well as pre-print databases (medxriv, bioxriv) were searched. Retrospective and prospective studies reporting clinical outcomes in cancer patients with laboratory confirmation or clinical diagnosis of COVID-19 and details of active or recent oncologic treatment were selected. Random-effects model was applied throughout meta-analyses. Summary outcome measure was the pooled odds ratio (OR) of death for active cancer therapy versus no active cancer therapy for each of the following modalities: recent surgery, chemotherapy, targeted therapy, immunotherapy, or chemoimmunotherapy. Results: Sixteen retrospective and prospective studies (3558 patients) were included in the meta-analysis. Active chemotherapy was associated with higher risk of death compared to no active chemotherapy (OR, 1.60, 95% CI, 1.14-2.23). No significant association with risk of death was identified for active targeted therapy, immunotherapy, chemoimmunotherapy, or recent surgery. Meta-analysis of multivariate adjusted OR of death for active chemotherapy was consistently associated with higher risk of death compared to no active chemotherapy (OR, 1.42, 95% CI, 1.01-2.01). Conclusions: Active chemotherapy appears to be associated with higher risk of death in cancer patients with COVID-19. Further research is necessary to characterize the complex interactions between active cancer treatment and COVID-19.

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Background CD4 2 CD8 2 double-negative (DN) ab T cells with innate-like properties represent a significant component of T cells in human and mouse kidneys. They spontaneously proliferate in the steady state and protect against ischemic AKI. However, the mechanisms regulating DN T cell homeostasis and responses to external danger signals from "sterile" inflammation remain poorly understood.Methods We used knockout mice, functional assays, and an established ischemic AKI model to investigate the role of various MHC class I and II molecules in regulating kidney DN T cells. We also studied human nephrectomy samples.Results Deficiency of b2m-dependent MHC class I (but not MHC class II) molecules led to significant reduction in frequency or absolute numbers of kidney DN T cells due to impaired activation, proliferation, increased apoptosis, and loss of an NK1.1 + subset of DN T cells. The remaining DN T cells in b2m knockout mice mainly comprised a programmed cell death protein-1 receptor (PD-1 + ) subset that depends on IL-2 provided by conventional T cells for optimal homeostasis. However, this PD-1 + subset remained highly responsive to changes in milieu, demonstrated by responses to infused lymphocytes. It was also the major responder to ischemic AKI; the NK1.1 + subset and CD8 + T cells had minimal responses. We found both DN T cell subsets in normal and cancerous human kidneys, indicating possible clinical relevance.Conclusions DN T cells, a unique population of kidney T cells, depend on nonclassical b2m molecules for homeostasis and use MHC-independent mechanisms to respond to external stimuli. These results have important implications for understanding the role these cells play during AKI and other immune cell-mediated kidney diseases.

Acute kidney injury (AKI) due to cisplatin is a significant problem that limits its use as an effective chemotherapeutic agent. T cell receptor+CD4−CD8− double negative (DN) T cells constitute the major T cell population in the human and mouse kidney, express programmed cell death protein (PD)-1, and protect from ischemic AKI. However, the pathophysiological roles of DN T cells in cisplatin-induced AKI is unknown. In this study, wild-type mice were treated with cisplatin (30 mg/kg) or vehicle, and the effects on kidney DN T cell numbers and function were measured. In vitro experiments evaluated effects of kidney DN T cells on cisplatin-induced apoptosis and PD ligand 1 (PD-L1) in renal epithelial cells. Adoptive transfer experiments assessed the therapeutic potential of DN T cells during cisplatin-induced AKI. Our results show that kidney DN T cell population increased at 24 h and declined by 72 h after cisplatin treatment. Cisplatin treatment increased kidney DN T cell proliferation, apoptosis, CD69, and IL-10 expression, whereas CD62L, CD44, IL-17A, interferon-γ, and TNF-α were downregulated. Cisplatin treatment decreased both PD-1 and natural killer 1.1 subsets of kidney DN T cells with a pronounced effect on the PD-1 subset. In vitro kidney DN T cell coculture decreased cisplatin-induced apoptosis in kidney proximal tubular epithelial cells, increased Bcl-2, and decreased cleaved caspase 3 expression. Cisplatin-induced expression of PD ligand 1 was reduced in proximal tubular epithelial cells cocultured with DN T cells. Adoptive transfer of DN T cells attenuated kidney dysfunction and structural damage from cisplatin-induced AKI. These results demonstrate that kidney DN T cells respond rapidly and play a protective role during cisplatin-induced AKI.

Low serum TA-iPTH is a useful clinical marker of both overall mortality and MACCEs in patients undergoing incident dialysis, mediated by vascular calcification.