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COVID-19 morbidity and mortality are increased via unknown mechanisms in patients with diabetes and kidney disease. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Because ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of kidney biopsies from healthy living donors and patients with diabetic kidney disease revealed ACE2 expression primarily in proximal tubular epithelial cells. This cellspecific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin-angiotensin-aldosterone system inhibitors in diabetic kidney disease. Bayesian integrative analysis of a large compendium of public-omics datasets identified molecular network modules induced in ACE2-expressing proximal tubular epithelial cells in diabetic kidney disease (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The diabetic kidney disease ACE2-positive proximal tubular epithelial cell module overlapped with expression patterns seen in SARS-CoV-2-infected cells. Similar cellular programs were seen in ACE2-positive proximal tubular epithelial cells obtained from urine samples of 13 hospitalized patients with COVID-19, suggesting a consistent ACE2-coregulated proximal tubular epithelial cell expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19-related kidney damage.

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Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods1. Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.

Coffee drinking may be associated with reduced risk of endometrial cancer; however, prospective data are limited. Further, it is not clear whether any association between coffee and endometrial cancer differs according to coffee caffeine content. The association of coffee drinking with incidence of endometrial cancer was evaluated among 226,732 women, aged 50–71, enrolled in the NIH-AARP Diet and Health Study who completed a baseline epidemiologic questionnaire. Following a mean 9.3 years of follow-up, data were available for 1,486 incident endometrial cancer cases. Cox proportional hazards models were used to estimate associations of coffee with endometrial cancer incidence. Sub-group analyses were performed according to smoking status, hormone therapy use (HT) and body habitus. Coffee drinking was inversely related to incidence of endometrial cancer (Hazard Ratio [HR] comparing drinking of >3 cups/day versus no cups=0.64, 95%CI, 0.51–0.80; Ptrend= 0.0004). The association of coffee with endometrial cancer risk was apparent for consumption of both regular (HR per cup= 0.90, 95%CI, 0.86–0.95) and decaffeinated coffee (HR per cup=0.93, 95%CI, 0.87–0.99). The relation of coffee with endometrial cancer incidence varied significantly by HT use (Pinteraction=0.03) with an association only apparent among HT-never users (HR comparing drinking >3 cups/day versus no cups= 0.54, 95%CI, 0.41–0.72; Ptrend=0.0005). Endometrial cancer incidence appears to be reduced among women that habitually drink coffee, an association that does not differ according to caffeine content.

Structured Abstract Objectives To determine if Amino-terminal Pro B-type Natriuretic Peptide (NT-proBNP) has different diagnostic and prognostic utility in patients with renal dysfunction. Background Patients with renal dysfunction have higher NT-proBNP, which may complicate interpretation for diagnosis of acute decompensated heart failure (ADHF) or prognosis. Methods We searched MEDLINE and EMBASE through August 2014 for studies with a subgroup analysis by renal function of the diagnostic or prognostic ability of NT-proBNP. Results For diagnosis, nine studies were included with 4,287 patients and 1,325 ADHF events. Patients were mostly divided into sub-groups with and without renal dysfunction by an estimated glomerular filtration rate of 60 ml/min/1.73m2. In patients with renal dysfunction, the area under the curve (AUC) for NT-proBNP ranged from 0.66 to 0.89 with a median cut-point of 1980 pg/ml, while the AUC ranged from 0.72 to 0.95 with a cut-point of 450 pg/ml in patients with preserved renal function. For prognosis, 30 studies with 32,203 patients were included, and mortality in patients with renal dysfunction (25.4%) was twice that of patients with preserved renal function (12.2%). The unadjusted pooled risk ratio (RR) for NT-proBNP and mortality was 3.01 (95% CI, 2.53-3.58) in patients with preserved renal function and was similar in patients with renal dysfunction (3.25 [CI, 2.45-4.30]). Upon meta-regression, heterogeneity was partially explained if patients with heart failure or coronary artery disease were enrolled. Conclusions NT-proBNP retains utility for diagnosis of ADHF in patients with renal dysfunction with higher cut-points. Elevated NT-proBNP confers a worse prognosis regardless of renal function.

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