Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease.

People of recent sub-Saharan African ancestry develop kidney failure much more frequently than other groups. A large fraction of this disparity is due to two coding sequence variants in the APOL1 gene. Inheriting two copies of these APOL1 risk variants, known as G1 and G2, causes high rates of focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy and hypertension-associated end-stage kidney disease. Disease risk follows a recessive mode of inheritance, which is puzzling given the considerable data that G1 and G2 are toxic gain-of-function variants. We developed coisogenic bacterial artificial chromosome (BAC) transgenic mice harboring either the wild-type (G0), G1 or G2 forms of human APOL1. Expression of interferon gamma (IFN-γ) via plasmid tail vein injection results in upregulation of APOL1 protein levels together with robust induction of heavy proteinuria and glomerulosclerosis in G1/G1 and G2/G2 but not G0/G0 mice. The disease phenotype was greater in G2/G2 mice. Neither heterozygous (G1/G0 or G2/G0) risk variant mice nor hemizygous (G1/-, G2/-) mice had significant kidney injury in response to IFN-γ, although the heterozygous mice had a greater proteinuric response than the hemizygous mice, suggesting that the lack of significant disease in humans heterozygous for G1 or G2 is not due to G0 rescue of G1 or G2 toxicity. Studies using additional mice (multicopy G2 and a non-isogenic G0 mouse) supported the notion that disease is largely a function of the level of risk variant APOL1 expression. Together, these findings shed light on the recessive nature of APOL1-nephropathy and present an important model for future studies.

More Specialties, Less Problems: Using collaborative competency between Infectious Disease, Podiatry, and Pathology to improve the care of patients with diabetic foot osteomyelitis.

BACKGROUND: Diabetic Foot Osteomyelitis (DFO) is a common infection where treatment involves multiple services including Infectious Disease (ID), Podiatry, and Pathology. Despite its ubiquity in the hospital, consensus on much of its management is lacking. METHODS: Representatives from ID, Podiatry, and Pathology interested in quality improvement (QI) developed multidisciplinary institutional recommendations culminating in an educational intervention describing optimal diagnostic and therapeutic approaches to DFO. Knowledge acquisition was assessed by pre- and post-intervention surveys. Inpatients with forefoot DFO were retrospectively reviewed pre- and post- intervention to assess frequency of recommended diagnostic and therapeutic maneuvers, including appropriate definition of surgical bone margins, definitive histopathology reports, and unnecessary intravenous antibiotics or prolonged antibiotic courses. RESULTS: A post-intervention survey revealed significant improvements in knowledge of antibiotic treatment duration and the role of oral antibiotics in managing DFO. There were 104 consecutive patients in the pre-intervention cohort (4/1/2018-4/1/2019) and 32 patients in the post-intervention cohort (11/5/2019-03/01/2020), the latter truncated by changes in hospital practice during the COVID-19 pandemic. Non-categorizable or equivocal pathology reports decreased from pre-intervention to post-intervention (27.0% vs 3.3%, respectively, P=0.006). We observed non-significant improvement in correct bone margin definition (74.0% vs 87.5%, p=0.11), unnecessary PICC line placement (18.3% vs 9.4%, p=0.23), and unnecessary prolonged antibiotics (21.9% vs 5.0%, p=0.10). Additionally, by working as an interdisciplinary group, many solvable misunderstandings were identified, and processes were adjusted to improve the quality of care provided to these patients. CONCLUSIONS: This QI initiative regarding management of DFO led to improved provider knowledge and collaborative competency between these three departments, improvements in definitive pathology reports, and non-significant improvement in several other clinical endpoints. Creating collaborative competency may be an effective local strategy to improve knowledge of diabetic foot infection and may generalize to other common multidisciplinary conditions.