Renal Genetics Clinic: 3-Year Experience in the Cleveland Clinic.

Rationale & Objective: There has been an increasing demand for the expertise provided by a renal genetics clinic. Such programs are limited in the United States and typically operate in a genomics research setting. Here we report a 3-year, real-world, single-center renal genetics clinic experience. Study Design: Retrospective cohort. Setting & Participants: Outpatient cases referred to the renal genetics clinic of the Cleveland Clinic between January 2019 and March 2022 were reviewed. Analytical Approach: Clinical and laboratory characteristics were analyzed. All genetic testing was performed in clinical labs. Results: 309 new patients referred from 15 specialties were evaluated, including 118 males and 191 females aged 35.1 ± 20.3 years. Glomerular diseases were the leading presentation followed by cystic kidney diseases, electrolyte disorders, congenital anomalies of kidneys and urinary tract, nephrolithiasis, and tubulointerstitial kidney diseases. Dysmorphic features were noted in 27 (8.7%) patients. Genetic testing was recommended in 292 (94.5%) patients including chromosomal microarray (8.9%), single-gene tests (19.5%), multigene panels (77.3%), and exome sequencing (17.5%). 80.5% of patients received insurance coverage for genetic testing. 45% (115/256) of patients had positive results, 25% (64/256) had variants of unknown significance, and 22.3% (57/256) had negative results. 43 distinct monogenic disorders were diagnosed. Family history of kidney disease was present in 52.8% of patients and associated with positive genetic findings (OR, 2.28; 95% CI, 1.40-3.74). 69% of patients with positive results received a new diagnosis and/or a change in the diagnosis. Among these, 39.7% (31/78) of patients received a significant change in disease management. Limitations: Retrospective and single-center study. Conclusions: The renal genetics clinic plays important roles in the diagnosis and management of patients with genetic kidney diseases. Multigene panels are the most frequently used testing modality with a high diagnostic yield. Family history of kidney disease is a strong indication for renal genetics clinic referral.

A quality improvement project to increase compliance with diabetes measures in an academic outpatient setting.

BACKGROUND: American Diabetes Association (ADA) sets annual guidelines on preventative measures that aim to delay the onset of severe diabetes mellitus complications. Compared to private internal medicine clinics, resident clinics provide suboptimal diabetic preventative care as evidenced by decreased compliance with ADA guidelines. The purpose of our study is to improve diabetic care in resident clinics through quality improvement (QI) projects, with A1C value as primary outcome and other ADA guidelines as secondary outcomes. METHODS: Our resident clinic at Beaumont Hospital, Royal Oak consists of 76 residents divided in 8 teams. In November 2016, baseline data on ADA guideline measures was obtained on 538 patients with diabetes mellitus. A root cause analysis was conducted. 5 teams developed a QI intervention plan to improve their diabetes care and 3 teams served as comparisons without intervention plans. In November 2017, post-intervention data was collected. RESULTS: Baseline characteristics demonstrate mean age of intervention groups at 60.9 years and of comparison groups at 58.9 years. The change in A1C value from baseline to post-intervention was + 0.09 vs. + 0.322 in the intervention and comparison groups respectively (p = 0.174). As a group, the changes in secondary outcome measures were as follows: eye examinations (+ 5% in intervention vs. -7% in comparison, p < 0.01), foot examinations (+ 13% vs. + 5%, p = 0.09), lipid panel testing (+ 7% vs. -5%, p < 0.01), micro-albumin/creatinine ratio testing (+ 4% vs. + 1%, p = 0.03), and A1C testing (+8% vs. + 5%, p = 0.24). CONCLUSIONS: While the QI project did not improve A1C value, it did have significant improvement in several secondary outcomes within intervention groups. One resident team implemented an intervention involving protected half-day blocks to identify overdue examinations and consequently had the largest improvements, thus serving as a potential intervention to further study. Given our study results, we believe that QI interventions improve preventative care for patients with diabetes in resident clinics.

Targeting botulinum neurotoxin persistence by the ubiquitin-proteasome system.

Botulinum neurotoxins (BoNTs) are the most potent natural toxins known. The effects of BoNT serotype A (BoNT/A) can last several months, whereas the effects of BoNT serotype E (BoNT/E), which shares the same synaptic target, synaptosomal-associated protein 25 (SNAP25), last only several weeks. The long-lasting effects or persistence of BoNT/A, although desirable for therapeutic applications, presents a challenge for medical treatment of BoNT intoxication. Although the mechanisms for BoNT toxicity are well known, little is known about the mechanisms that govern the persistence of the toxins. We show that the recombinant catalytic light chain (LC) of BoNT/E is ubiquitylated and rapidly degraded in cells. In contrast, BoNT/A LC is considerably more stable. Differential susceptibility of the catalytic LCs to ubiquitin-dependent proteolysis therefore might explain the differential persistence of BoNT serotypes. In this regard we show that TRAF2, a RING finger protein implicated in ubiquitylation, selectively associates with BoNT/E LC and promotes its proteasomal degradation. Given these data, we asked whether BoNT/A LC could be targeted for rapid proteasomal degradation by redirecting it to characterized ubiquitin ligase domains. We describe chimeric SNAP25-based ubiquitin ligases that target BoNT/A LC for degradation, reducing its duration in a cellular model for toxin persistence.