BackgroundTwo coding renal risk variants (RRVs) of the APOL1 gene (G1 and G2) are associated with large increases in CKD rates among populations of recent African descent, but the underlying molecular mechanisms are unknown. Mammalian cell culture models are widely used to study cytotoxicity of RRVs, but results have been contradictory. It remains unclear whether cytotoxicity is RRV-dependent or driven solely by variant-independent overexpression. It is also unknown whether expression of the reference APOL1 allele, the wild-type G0, could prevent cytotoxicity of RRVs.MethodsWe generated tetracycline-inducible APOL1 expression in human embryonic kidney HEK293 cells and examined the effects of increased expression of APOL1 (G0, G1, G2, G0G0, G0G1, or G0G2) on known cytotoxicity phenotypes, including reduced viability, increased swelling, potassium loss, aberrant protein phosphorylation, and dysregulated energy metabolism. Furthermore, whole-genome transcriptome analysis examined deregulated canonical pathways.ResultsAt moderate expression, RRVs but not G0 caused cytotoxicity in a dose-dependent manner that coexpression of G0 did not reduce. RRVs also have dominant effects on canonical pathways relevant for the cellular stress response.ConclusionsIn HEK293 cells, RRVs exhibit a dominant toxic gain-of-function phenotype that worsens with increasing expression. These observations suggest that high steady-state levels of RRVs may underlie cellular injury in APOL1 nephropathy, and that interventions that reduce RRV expression in kidney compartments may mitigate APOL1 nephropathy.

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Obstetric fistula is a severe maternal morbidity which can have devastating consequences for a woman's life and is generally associated with poor obstetric services leading to prolonged obstructed labour. The predisposing factors and consequences of obstetric fistula differ from country to country and from community to community. The World Health Organization estimated that more than 2 million women in sub-Saharan Africa, Asia, the Arab region, Latin America, and the Caribbean are living with the fistula, and some 50,000 to 100,000 new cases develop annually with 30,000–90,000 new cases developing each year in Africa alone. This study aimed at describing and exploring the experiences of women living with obstetric fistulas following corrective surgery in Benadir and Mudug regions, Somalia. Women living with obstetric fistula who had surgical repairs at Daynile and GMC fistula centers and key informants were identified purposively. Twenty-one individual in-depth interviews among women with obstetric fistula and eight key informant interviews were conducted. Thematic analyses were used. Codes were identified, and those codes with similar connections were organized together as to form themes. Detailed reading and rereading of the transcribed interviews were employed in order to achieve and identify themes and categories. Themes, categories, and subcategories illustrating the experiences of women living with obstetric fistula emerged from the thematic analysis of individual in-depth and key informant interviews. These were challenges of living with OBF which include “wounds around genitalia, bad odour, incontinences of urine and feces, stigma, isolation, divorce, powerlessness, dependency, financial constraints, and loss of healthy years” and coping mechanisms which include “withdrawal from the community and improved personal hygiene.” Women with obstetric fistula experience serious health and social consequences which prevents them fulfill social, family, and personal responsibilities. We recommend expansion of BEmONC services to underserved areas, capacity building for local OBF surgeons, and improved media campaign and birth preparedness at community levels.