Background Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell-targeted therapies in some patients, together with the known proteinuric effect of antinephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. Methods We evaluated sera from patients with minimal change disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence Results In two independent patient cohorts, we identified in a subset of patients with minimal change disease circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end-stage kidney disease; she developed a massive posttransplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. Conclusions Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as framework for instigation of precision therapeutics for these patients.

Although people with HIV infection (PLWH) are at higher risk of polypharmacy and substance use, there is limited knowledge about potential harms associated with polypharmacy such as falls and fractures in this population. The study objective was to determine whether polypharmacy, as measured by the number and type of medication, is associated with falls and fractures among PLWH and DSM-IV substance dependence in the past year or ever injection drug use (IDU). We identified the number of medications by electronic medical record review in the following categories: (i) systemically active, (ii) non-antiretroviral (non-ARV), (iii) sedating, (iv) non-sedating as well as any opioid medication and any non-opioid sedating medication. Outcomes were self-reported (1) fall/accident requiring medical attention and (2) fracture in the previous year. Separate logistic regression models were fitted for medications in each category and each outcome. Among 250 participants, the odds of a fall requiring medical attention were higher with each additional medication overall (odds ratio [OR] 1.12, 95% Confidence Interval [CI] = 1.05, 1.18), each additional non-ARV medication (OR 1.13, 95%CI = 1.06, 1.20), each additional sedating medication (OR 1.36, 95%CI = 1.14, 1.62), and a non-opioid sedating medication (OR 2.89, 95%CI = 1.06, 7.85) but not with an additional non-sedating medication or opioid medication. In receiver operating characteristic (ROC) curve analyses, optimal cutoffs for predicting falls were: ≥8 overall and ≥2 sedating medications. Odds ratios for fracture in the previous year were OR 1.05, 95%CI = 0.97, 1.13 for each additional medication overall and OR 1.11, 95%CI = 0.89, 1.38 for each additional sedating medication. In PLWH and substance dependence or ever IDU, a higher number of medications was associated with greater odds of having a fall requiring medical attention. The association appeared to be driven largely by sedating medications. Future studies should determine if reducing such polypharmacy, particularly sedating medications, lowers the risk of falls.

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