Hyaluronan Inhibition as a Therapeutic Target for Diabetic Kidney Disease: What Is Next?

Diabetic kidney disease (DKD) is the leading cause of CKD and ESKD in the United States and worldwide. Pharmacotherapy and lifestyle modifications for glycemia, dyslipidemia, and BP control have shown success in slowing the progression of DKD. Traditional treatments, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and more recently the use of sodium-glucose cotransporter 2 inhibitors, nonsteroidal selective mineralocorticoid receptor antagonists, such as finerenone, and glucagon-like peptide 1 receptor agonists, have led to added benefits on various outcomes. However, significant residual risk for DKD progression remains despite the current standard-of-care approaches. Arteriolar hyalinosis (AH) is among the key findings seen on kidney biopsies of patients with DKD. It results from the excessive accumulation of hyaluronan (HA) in the arterioles. AH has not been targeted specifically by any of the therapeutic methods currently being used. We discuss in this manuscript the potential use of a selective therapy targeting AH and the increased total renal HA deposits using a HA synthesis inhibitor in DKD.

CMS ESRD quality incentive program has not improved patient dialysis vascular access.

PURPOSE: Over 468,000 patients in the United States use hemodialysis to manage End Stage Renal Disease (ESRD). The purpose of this study was to determine whether the dialysis access Clinical Performance Measures (CPMs) of Centers for Medicare & Medicaid Services (CMS) ESRD Quality Incentive Program (QIP) have increased arteriovenous fistula (AVF) rates and decreased long-term tunneled hemodialysis catheter (TDC) rates among hemodialysis patients in United States. METHODS: Retrospective observational study: evaluated reported AVF and long-term TDC rates of 4804 dialysis facilities which reported dialysis access data as part of the ESRD QIP from Payment Year (PY) 2014-2020. Facilities were also sorted by specific additional criteria to examine disparities in dialysis access. RESULTS: Mean AVF rates of included facilities increased from 63.7% in PY 2014 to 67.2% in PY 2016 (p < 0.05), did not change in PY 2017 (p > 0.05), and declined significantly in PY 2018-2020 to 64.1% in PY 2020, near AVF rates at the inception of program. Long-term TDC rates decreased from 10.4% in PY 2014 to 9.88% in PY 2015 (p < 0.05), then increased in PY 2015-PY 2020 to rates higher than at the inception of program, at 11.8% in PY 2020 (p < 0.05). Facilities serving majority Black ZIP Code Tabulation Areas (ZCTAs) or ZCTAs with median income <$45,000 achieved significantly lower AVF rates (p < 0.05) with no significant difference in long-term TDC rates (p > 0.05). AVF rates correlated positively and long-term TDC rates correlated negatively with star rating of facilities (p < 0.05). CONCLUSION: As one of the first financial QIPs in healthcare, the ESRD QIP has not achieved the stated goals of the CMS to increase AVF access rates above 68% and reduce long-term TDC clinical rates below 10%. Systemic disparities in race, geographic region, economic status, healthcare access, and education of providers and patients prevent successful attainment of goal metrics.

SHANK3 Genotype Mediates Speech and Language Phenotypes in a Nonclinical Population.

Mutations affecting the synaptic-scaffold gene SHANK3 represent the most common genetic causes of autism with intellectual disability, accounting for about 1-2% of cases. Rare variants of this gene have also been associated with schizophrenia, and its deletion results in the autistic condition known as Phelan-McDermid syndrome. Despite the importance of SHANK3 as a paradigmatic gene mediating neurodevelopmental disorders, its psychological effects in nonclinical populations have yet to be studied. We genotyped the nonsynonymous, functional SHANK3 SNP rs9616915 in a large population of typical individuals scored for autism spectrum traits (the Autism Quotient, AQ) and schizotypy spectrum traits (the Schizotypal Personality Questionnaire, SPQ-BR). Males, but not females, showed significant genotypic effects for the SPQ-BR subscale associated with speech and language: Odd Speech. These findings, in conjunction with animal model studies showing vocalization and auditory effects of SHANK3 mutations, and studies indicating severe language alterations and speech-associated white matter tract abnormalities in Phelan-McDermid syndrome, suggest that SHANK3 differentially affects the development and expression of human language and speech. Imaging genetic and speech-language studies of typical individuals carrying different genotypes of rs9616915 should provide novel insights into the neurological and psychological bases of speech and language alterations among individuals with SHANK3 mutations and Phelan-McDermid syndrome.

A Multicenter Randomized Clinical Trial of Hemodialysis Access Blood Flow Surveillance Compared to Standard of Care: The Hemodialysis Access Surveillance Evaluation (HASE) Study.

INTRODUCTION: Arteriovenous (AV) access thrombosis remains 1 of the most troubling AV access-related complications affecting hemodialysis patients. It necessitates an urgent and occasionally complicated thrombectomy procedure and increases the risk of AV access loss. AV access stenosis is found in the majority of thrombosed AV accesses. The routine use of AV access surveillance for the early detection and management of stenosis to reduce the thrombosis rate remains controversial. METHODS: We have conducted a multicenter, prospective, randomized clinical trial comparing the standard of care coupled with ultrasound dilution technique (UDT) flow measurement monthly surveillance with the standard of care alone. RESULTS: We prospectively randomized 436 patients with end-stage renal disease on hemodialysis with arteriovenous fistula (AVF) or arteriovenous graft (AVG) using cluster (shift) randomization to surveillance and control groups. There were no significant differences in the baseline demographic data between the 2 groups, except for ethnicity (P = 0.017). Patients were followed on average for 15.2 months. There were significantly less per-patient thrombotic events (Poisson rate) in the surveillance group (0.12/patient) compared with the control group (0.23/patient) (P = 0.012). There was no statistically significant difference in the total number of procedures between the 2 groups, irrespective of whether thrombectomy procedures were included or excluded, and no statistically significant differences in the rate of or time to the first thrombotic event or the number of catheters placed due to thrombosis. CONCLUSION: The use of UDT flow measurement monthly AV access surveillance in this multicenter randomized controlled trial reduced the per-patient thrombotic events without significantly increasing the total number of angiographic procedures. Even though there is a trend, surveillance did not reduce the first thrombotic event rate.

Early Last Interglacial ocean warming drove substantial ice mass loss from Antarctica.

The future response of the Antarctic ice sheet to rising temperatures remains highly uncertain. A useful period for assessing the sensitivity of Antarctica to warming is the Last Interglacial (LIG) (129 to 116 ky), which experienced warmer polar temperatures and higher global mean sea level (GMSL) (+6 to 9 m) relative to present day. LIG sea level cannot be fully explained by Greenland Ice Sheet melt (∼2 m), ocean thermal expansion, and melting mountain glaciers (∼1 m), suggesting substantial Antarctic mass loss was initiated by warming of Southern Ocean waters, resulting from a weakening Atlantic meridional overturning circulation in response to North Atlantic surface freshening. Here, we report a blue-ice record of ice sheet and environmental change from the Weddell Sea Embayment at the periphery of the marine-based West Antarctic Ice Sheet (WAIS), which is underlain by major methane hydrate reserves. Constrained by a widespread volcanic horizon and supported by ancient microbial DNA analyses, we provide evidence for substantial mass loss across the Weddell Sea Embayment during the LIG, most likely driven by ocean warming and associated with destabilization of subglacial hydrates. Ice sheet modeling supports this interpretation and suggests that millennial-scale warming of the Southern Ocean could have triggered a multimeter rise in global sea levels. Our data indicate that Antarctica is highly vulnerable to projected increases in ocean temperatures and may drive ice-climate feedbacks that further amplify warming.