Hypercholesterolemia in Renal Failure
Elevated levels of LDL cholesterol (LDLc) constitute an established risk factor for cardiovascular disease in patients with chronic kidney disease (CKD). Although statins indisputably reduce plasma cholesterol levels, not all patients with renal disease benefit from them, making cardiovascular disease the leading cause of CKD-related mortality. This paradox has prompted a search for novel mechanisms for dyslipidemia in kidney disease. CKD induces hyperelongation of hepatic heparan sulfate chains from heparan sulfate proteoglycans (HSPG), thereby increasing the HSPG–proprotein convertase subtilisin kexin type-9 (PCSK9) interaction. These changes associate with elevated LDLc levels without affecting LDL-receptor expression. Using rat models, Shrestha et al. provide evidence for a novel mechanism behind hypercholesterolemia in CKD. These findings suggest that the HSPG-PCSK9 interaction is a potential drug target, and heparin-related glycomimetics targeting interruption of HSPG-PCSK9 binding might benefit CKD patients. See Shrestha et al., pages 1371–1388.
ADAM10 and Antibody-Mediated Podocyte Injury
Interdigitating podocytes form the renal blood filter through a modified adherens junction, the slit diaphragm. Altered adhesion and podocyte loss are common features of podocyte injury, which could be mediated by the cleavage of podocyte cell adhesion molecules through the action of cell surface?expressed proteases, such as the sheddase A disintegrin and metalloproteinase 10 (ADAM10), a protease known to mediate ectodomain shedding of adhesion molecules, among others. ADAM10 is highly abundant at the podocyte foot processes. The authors evaluated the involvement of ADAM10 in the process of antibody-induced podocyte injury, finding that podocyte-expressed ADAM10 is not required for renal filter development, but it is upregulated in humans and mice after antibody-mediated injury. The protein cleaves cell-adhesion molecules at the slit diaphragm, leading to Wnt/β-catenin signaling and podocyte loss. The authors propose that ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury. See Sachs et al., pages 1389–1408.
Effects of COVID-19 in ESKD Patients
Although reports from around the world have indicated the case fatality rate of novel coronavirus disease 2019 (COVID-19) among patients with end-stage kidney disease (ESKD) is between 20% and 30%, COVID-19’s population-level effect is uncertain. In a retrospective analysis of data from the Centers for Medicare & Medicaid Services, the authors found that adjusted relative rates of death during epidemiologic weeks 13–27 of 2020 were 17% higher among patients undergoing dialysis and 30% higher among patients with a kidney transplant relative to corresponding weeks in 2017 to 2019. Non-Hispanic Black race and Hispanic ethnicity associated with higher higher COVID-19 hospitalization rates, whereas peritoneal dialysis was associated with lower rates. Excess mortality was higher among non-Hispanic Black, Hispanic, and Asian patients. The severe effects of COVID-19 on patients with ESKD should be considered in prioritizing these patients for COVID-19 vaccination. See Weinhandlet et al., pages 1444–1453.
Advance Care Planning for Patients with CKD
Although advance care planning (ACP) is critical to patient-centered care, older patients with advanced chronic kidney disease (CKD), who are at high risk for serious complications and death, seldom discuss ACP with their kidney clinicians. Ladin et al. performed a qualitative analysis of data from interviews with 68 patients, care partners, and clinicians in the United States. They found very discordant views about who is responsible for broaching ACP and the scope of ACP. Many nephrologists did not view ACP as their responsibility, leaving ACP insufficiently discussed in nephrology clinics—shifting responsibility to patients and primary care providers and often leading patients to address ACP concerns outside of the medical sphere, if at all. The authors conclude that training of nephrologists should emphasize their role in ACP as critical to increasing equitable access for older patients. See Ladin et al., pages 1527–1535. Also see related editorial by Schell, pages 1273–1274.