Perivascular compartments surrounding the penetrating arteries in the brain are part of a physiologic system, which facilitates fluids exchange and clearance of solutes from the brain. The perivascular compartments become visible on MRI when enlarged and are commonly referred to as perivascular spaces (ePVS). Previous studies on the association between ePVS and dementia have been inconsistent due to varying methods of measuring ePVS. As a frame of reference for future MRI studies on ePVS, we systematically review the literature on ePVS as a marker of vascular brain injury related to dementia from population-based as well as hospital-based settings. We identified three longitudinal and ten cross-sectional studies involving 7,581 persons. Potential outcomes were all-cause dementia, Alzheimer's disease, and vascular dementia. There was considerable heterogeneity in ePVS assessment: with studies using either visual inspection or segmentation, examining different brain locations and implementing different grading scales. Moreover, out of the total of 13 studies, all five studies on vascular dementia reported an association with presence of basal ganglia ePVS after adjustment for age, gender, and white matter hyperintensities. For seven studies on Alzheimer's disease and all-cause dementia, the results were ambiguous. This review did not identify an independent association of ePVS with prevalent or incident dementia. Harmonized methods for ePVS assessment, tested across different populations, may benefit future MRI studies on ePVS and dementia.

Purpose of reviewTo summarize new clinical findings of endothelin receptor antagonists (ERA) in various etiologies of kidney disease targeted in clinical trials. Recent findingsEndothelin-1 is a multifunctional peptide with potential relevance to glomerular and tubulointerstitial kidney diseases. The phase 3 SONAR trial demonstrated a significant reduction in clinically relevant kidney outcomes for patients with diabetic kidney disease (DKD) after long-term treatment with the ERA, atrasentan, in addition to blockade of the renin-angiotensin-aldosterone system. Promising preclinical disease models and small clinical trials in non-DKD resulted in the initiation of phase 3 trials investigating the effects of long-term treatment with ERA in patients with immunoglobulin A (IgA) nephropathy and focal segmental glomeruloscelerosis (FSGS). The mechanisms by which ERA protects the kidneys have been extensively studied with evidence for the protection of tubule cells, podocytes, mesangial cells, the endothelial glycocalyx, and a reduction in glomerular perfusion pressure. The occurrence of fluid retention during ERA treatment, particularly in susceptible populations, necessitates strategies to support safe and effective treatment.

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Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25-75 mL/min/1.73 m 2 , and a urine albumin-to-creatinine ratio of 300-5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin-1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasmaconcentration time curve from zero to infinity (AUC 0−inf ) 41.3 ng•h/mL) or slow (atrasentan AUC 0−inf 49.7 ng•h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45-0.81) and 1.35 (95% CI: 0.84-2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95-4.03, P-interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37-12.7, P-interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant betweenpatient variability in atrasentan plasma exposure and long-term efficacy and safety.