Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR–β3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.

Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.

In this analysis of prospectively collected data from a large series of ABO-incompatible living-donor kidney transplants performed at 101 centers, death-censored graft and patient survival rates were similar to those achieved in ABO-compatible control groups over the same period.

Background and objectives Patients receiving hemodialysis are at high risk for both SARS-CoV-2 infection and severe COVID-19 disease. A life-saving vaccine is available, but sensitivity to vaccines is generally lower in dialysis patients. Little is yet known about antibody responses after COVID-19 vaccination in this vulnerable group. Design, setting, participants, and measurements In this prospective single-center study, we included 22 dialysis patients and 46 healthy controls from Heidelberg University Hospital between December 2020 and February 2021. We measured anti-S1 IgG with a threshold index for detection >1, neutralizing antibodies with a threshold for viral neutralization of ≥30% and antibodies against different SARS-CoV-2 fragments 17-22 days after the first and 18-22 days after the second dose of the mRNA vaccine BNT162b2. Results After the first vaccine dose, 4/22 (18%) dialysis patients compared with 43/46 (93%) healthy controls developed positive anti-S1 IgG, with a median (IQR) anti-S1 IgG index of 0.2 (0.1-0.7) compared with 9 (4-16), respectively. SARS-CoV-2 neutralizing antibodies exceeded the threshold for neutralization in 4/22 (18%) dialysis patients compared with 43/46 (93%) in healthy controls, with a median (IQR) percent inhibition of 11 (3-24) compared with 65 (49-75), respectively. After the second dose, 14/17 (82%) of dialysis patients developed neutralizing antibodies exceeding the threshold for viral neutralization and antibodies against the receptor-binding S1-domain of the spike protein, compared to 46/46 (100%) of healthy controls, respectively. The median (IQR) percent inhibition was 51 (32-86) compared to 98 (97-98) in healthy controls. Conclusions Patients receiving long-term hemodialysis show a reduced antibody response to the first and second doses of the mRNA vaccine BNT162b2. The majority (82%) develop neutralizing antibodies after the second dose, but at lower levels than healthy controls.