Background and objectivesActionable genetic findings have implications for care of patients with kidney disease, and genetic testing is an emerging tool in nephrology practice. However, there are scarce data regarding best practices for return of results and clinical application of actionable genetic findings for kidney patients.Design, setting, participants, & measurementsWe developed a return of results workflow in collaborations with clinicians for the retrospective recontact of adult nephrology patients who had been recruited into a biobank research study for exome sequencing and were identified to have medically actionable genetic findings.ResultsUsing this workflow, we attempted to recontact a diverse pilot cohort of 104 nephrology research participants with actionable genetic findings, encompassing 34 different monogenic etiologies of nephropathy and five single-gene disorders recommended by the American College of Medical Genetics and Genomics for return as medically actionable secondary findings. We successfully recontacted 64 (62%) participants and returned results to 41 (39%) individuals. In each case, the genetic diagnosis had meaningful implications for the patients’ nephrology care. Through implementation efforts and qualitative interviews with providers, we identified over 20 key challenges associated with returning results to study participants, and found that physician knowledge gaps in genomics was a recurrent theme. We iteratively addressed these challenges to yield an optimized workflow, which included standardized consultation notes with tailored management recommendations, monthly educational conferences on core topics in genomics, and a curated list of expert clinicians for patients requiring extranephrologic referrals.ConclusionsDeveloping the infrastructure to support return of genetic results in nephrology was resource-intensive, but presented potential opportunities for improving patient care.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_16_12481019.mp3

Cocaine has long been known to produce an initial “high” followed by an aversive/anxiogenic “crash”. While much is known about the neurobiology of cocaine’s positive/rewarding effects, the mechanisms that give rise to the drug’s negative/anxiogenic actions remain unclear. Recent research has implicated the lateral habenula (LHb) in the encoding of aversive events including the anxiogenic response to cocaine. Of particular interest in this regard are the reciprocal connections between the LHb and the ventral tegmental area (VTA). VTA-DA neurons innervate different subsets of LHb cells that in turn feedback upon and modulate VTA neuronal activity. Here we examined the impact of D2 receptor activation and inhibition on the anxiogenic response to cocaine using a runway model of self-administration that is sensitive to the dual and opposing effects of the drug. Male rats ran a straight alley for IV cocaine (1.0 mg/kg) following bilateral intra-LHb infusions of the D2 receptor antagonist, cis-flupenthixol (0, 7.5 or 15μg/side) or the D2 agonist, sumanirole (0, 5 or 10μg/side). Vehicle-pretreated controls developed approach-avoidance conflict behaviors about goal-box entry reflective of the dual positive and negative effects of cocaine. These behaviors were significantly diminished during LHb-D2 receptor antagonism and increased by the LHb D2 receptor agonist. These results demonstrate that activity at the D2 receptor in the lateral habenula serves to modulate the anxiogenic response to cocaine.

Studies have shown that 1 in 10 adults with chronic kidney disease has a genetic component to their disease. However, genetic services in adult nephrology are limited. An adult Kidney Genetics Clinic was established within the nephrology division at a large urban academic medical center to increase access to genetic services and testing in adults with kidney disease. Between June 2019 through December 2021, a total of 363 patients were referred to the adult Kidney Genetics Clinic. Of those who completed genetic testing, a positive, diagnostic finding was identified in 27.14% and a candidate diagnostic finding was identified in 6.67% of patients, while a non-diagnostic positive finding was identified in an additional 8.57% of patients, resulting in an overall yield of 42.38% for clinically relevant genetic findings in tested patients. A genetic diagnosis had implications for medical management, family member testing, and eligibility for clinical trials. With the utilization of telemedicine, genetic services reached a diverse geographic and patient population. Genetic education efforts were integral to the clinic's success, as they increased visibility and helped providers identify appropriate referrals. Ongoing access to genomic services will remain a fundamental component of patient care in adults with kidney disease.

Narcolepsy, characterized by excessive daytime sleepiness, is associated with dysfunction of the hypothalamic hypocretin/orexin (Hcrt) system, either due to extensive loss of Hcrt cells (Type 1, NT1) or hypothesized Hcrt signaling impairment (Type 2, NT2). Accordingly, efforts to recapitulate narcolepsy-like symptoms in mice have involved ablating these cells or interrupting Hcrt signaling. Here, we describe orexin/Arch mice, in which a modified archaerhodopsin-3 gene was inserted downstream of the prepro-orexin promoter, resulting in expression of the yellow light-sensitive Arch-3 proton pump specifically within Hcrt neurons. Histological examination along with ex vivo and in vivo electrophysiological recordings of male and female orexin/Arch mice demonstrated silencing of Hcrt neurons when these cells were photoilluminated. However, high expression of the Arch transgene affected cellular and physiological parameters independent of photoillumination. The excitability of Hcrt neurons was reduced, and both circadian and metabolic parameters were perturbed in a subset of orexin/Arch mice that exhibited high levels of Arch expression. Orexin/Arch mice also had increased REM sleep under baseline conditions but did not exhibit cataplexy, a sudden loss of muscle tone during wakefulness characteristic of NT1. These aberrations resembled some aspects of mouse models with Hcrt neuron ablation, yet the number of Hcrt neurons in orexin/Arch mice was not reduced. Thus, orexin/Arch mice may be useful to investigate Hcrt system dysfunction when these neurons are intact, as is thought to occur in narcolepsy without cataplexy (NT2). These results also demonstrate the utility of extended phenotypic screening of transgenic models when specific neural circuits have been manipulated.