A reference tissue atlas for the human kidney.

Kidney Precision Medicine Project (KPMP) is building a spatially specified human kidney tissue atlas in health and disease with single-cell resolution. Here, we describe the construction of an integrated reference map of cells, pathways, and genes using unaffected regions of nephrectomy tissues and undiseased human biopsies from 56 adult subjects. We use single-cell/nucleus transcriptomics, subsegmental laser microdissection transcriptomics and proteomics, near-single-cell proteomics, 3D and CODEX imaging, and spatial metabolomics to hierarchically identify genes, pathways, and cells. Integrated data from these different technologies coherently identify cell types/subtypes within different nephron segments and the interstitium. These profiles describe cell-level functional organization of the kidney following its physiological functions and link cell subtypes to genes, proteins, metabolites, and pathways. They further show that messenger RNA levels along the nephron are congruent with the subsegmental physiological activity. This reference atlas provides a framework for the classification of kidney disease when multiple molecular mechanisms underlie convergent clinical phenotypes.

Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning with fibrosis in severe cases, and high prevalence in obesity. We aimed at defining NASH signature in morbid obesity by mass spectrometry-based lipidomic analysis. METHODS: We analyzed systemic blood before and 12 months after bariatric surgery, along with portal blood and adipose tissue lipid efflux collected from obese women at the time of surgery (9 structural classes, 150 species). RESULTS: Increased concentrations of several glycerophosphocholines (PC), glycerophosphoethanolamines (PE), glycerophosphoinositols (PI), glycerophosphoglycerols (PG), lyso-glycerophosphocholines (LPC), and ceramides (Cer) were detected in systemic circulation of NASH subjects. Post-surgery weight loss (12 months) improved the levels of liver enzymes, as well as several lipids, but most PG and Cer species remained elevated. Analysis of lipids from hepatic portal system at the time of surgery revealed limited lipid alterations compared to systemic circulation, but PG and PE classes were found significantly increased in NASH subjects. We evaluated the contribution of visceral adipose tissue to lipid alterations in portal circulation by measuring adipose tissue lipid efflux ex vivo, and observed only minor alterations in NASH subjects. Interestingly, integration of clinical and lipidomic data (portal and systemic) led us to define a NASH signature in which lipids and clinical parameters are equal contributors. CONCLUSIONS: Circulatory (portal and systemic) phospholipid profiling and clinical data defines NASH signature in morbid obesity. We report weak contribution of visceral adipose tissue to NASH-related portal lipid alterations, suggesting possible contribution from other organs draining into hepatic portal system.