Summer Research Roundup July 21, 2017 by Kylie Karley Summer Research Roundup Summer is a great time to catch up on reading! If you’re sick of beach novels or historical biographies, consider catching up on science reading with our pick of recently published articles. We combed through the literature and found some interesting and relevant publications that may be relevant to Nephrotic Syndrome patients and families. The articles are listed in no particular order, and we do not endorse or prefer any of the research studies. Enjoy! A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease. Authors: Hayek SS, Koh KH, Grams ME, Wei C, Ko YA, Li J, Samelko B, Lee H, Dande RR, Lee HW, Hahm E, Peev V, Tracy M, Tardi NJ, Gupta V, Altintas MM, Garborcauskas G, Stojanovic N, Winkler CA, Lipkowitz MS, Tin A, Inker LA, Levey AS, Zeier M, Freedman BI, Kopp JB, Skorecki K, Coresh J, Quyyumi AA, Sever S, Reiser J. Dr. Reiser, a previous NKI grant recipient and Scientific Advisory Board Member, was a major contributor to this research Abstract: 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. Full article: Published in Nature Medicine and accessible here. Long-Term Outcomes in Children with Steroid-Resistant Nephrotic Syndrome Treated with Calcineurin Inhibitors Authors: Nathan T. Beins and Katherine M. Dell Abstract: Steroid-resistant nephrotic syndrome (SRNS) is an important cause of chronic kidney disease (CKD) in children that often progresses to end-stage renal disease (ESRD). Calcineurin inhibitors (CNIs) have been shown to be effective in inducing short-term remission in some patients with SRNS. However, there are little data examining their long-term impact on ESRD progression rates. We performed a retrospective chart review of all patients treated for SRNS with CNIs at our institution from 1995 to 2013. Data collected including demographics, initial response to medical therapy, number of relapses, progression to ESRD, and treatment complications. A total of 16 patients met inclusion criteria with a mean follow-up of 6.6 years (range 0.6–17.6 years). Histopathological diagnoses were focal segmental glomerulosclerosis (8), mesangial proliferative glomerulonephritis (4), IgM nephropathy (3), and minimal change disease (1). Three patients (18.8%) were unresponsive to CNIs while the remaining 13 (81.2%) achieved remission with CNI therapy. Six patients (37.5%) progressed to ESRD during the study period, three of whom did so after initially responding to CNI therapy. Renal survival rates were 87, 71, and 57% at 2, 5, and 10 years, respectively. Non-Caucasian ethnicity was associated with progression to ESRD. Finally, a higher number of acute kidney injury (AKI) episodes were associated with a lower final estimated glomerular filtration rate. Despite the majority of SRNS patients initially responding to CNI therapy, a significant percentage still progressed to ESRD despite achieving short-term remission. Recurrent episodes of AKI may be associated with progression of CKD in patients with SRNS. Full Article: Published in Frontiers in Pediatrics and available here Optimal management of primary focal segmental glomerulosclerosis in adults. Authors: Séverine Beaudreuil, Hans Kristian Lorenzo, Michele Elias, Erika Nnang Obada, Bernard Charpentier, and Antoine Durrbach Abstract: Focal segmental glomerulosclerosis (FSGS) is a frequent glomerular kidney disease that is revealed by proteinuria or even nephrotic syndrome. A diagnosis can be established from a kidney biopsy that shows focal and segmental glomerulosclerosis. This histopathological lesion may be caused by a primary podocyte injury (idiopathic FSGS) but is also associated with other pathologies (secondary FSGS). The first-line treatment for idiopathic FSGS with nephrotic syndrome is a prolonged course of corticosteroids. However, steroid resistance or steroid dependence is frequent, and despite intensified immunosuppressive treatment, FSGS can lead to end-stage renal failure. In addition, in some cases, FSGS can recur on a graft after kidney transplantation: an unidentified circulating factor may be implicated. Understanding of its physiopathology is unclear, and it remains an important challenge for the scientific community to identify a specific diagnostic biomarker and to develop specific therapeutics. This study reviews the treatment of primary FSGS and the recurrence of FSGS after kidney transplantation in adults. Full Article: Published in International Journal of Nephrology and Renovascular Diseases and available here Recent Treatment Advances and New Trials in Adult Nephrotic Syndrome Authors: Eva Königshausen and Lorenz Sellin Abstract: The etiology of nephrotic syndrome is complex and ranges from primary glomerulonephritis to secondary forms. Patients with nephrotic syndrome often need immunosuppressive treatment with its side effects and may progress to end stage renal disease. This review focuses on recent advances in the treatment of primary causes of nephrotic syndrome (idiopathic membranous nephropathy (iMN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS)) since the publication of the KDIGO guidelines in 2012. Current treatment recommendations are mostly based on randomized controlled trials (RCTs) in children, small RCTs, or case series in adults. Recently, only a few new RCTs have been published, such as the Gemritux trial evaluating rituximab treatment versus supportive antiproteinuric and antihypertensive therapy in iMN. Many RCTs are ongoing for iMN, MCD, and FSGS that will provide further information on the effectiveness of different treatment options for the causative disease. In addition to reviewing recent clinical studies, we provide insight into potential new targets for the treatment of nephrotic syndrome from recent basic science publications. Full Article: Published in BioMed Research International and available here Autoimmune Thyroiditis and Glomerulopathies Authors: Santoro D, Vadalà C, Siligato R, Buemi M, Benvenga S. Abstract: Autoimmune thyroiditis (AIT) is generally associated with hypothyroidism. It affects ~2% of the female population and 0.2% of the male population. The evidence of thyroid function- and thyroid autoantibody-unrelated microproteinuria in almost half of patients with AIT and sometimes heavy proteinuria as in the nephrotic syndrome point to a link of AIT with renal disease. The most common renal diseases observed in AIT are membranous nephropathy, membranoproliferative glomerulonephritis, minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis, antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, and amyloidosis. Different hypotheses have been put forward regarding the relationship between AIT and glomerulopathies, and several potential mechanisms for this association have been considered. Glomerular deposition of immunocomplexes of thyroglobulin and autoantibodies as well as the impaired immune tolerance for megalin (a thyrotropin-regulated glycoprotein expressed on thyroid cells) are the most probable mechanisms. Cross-reactivity between antigens in the setting of genetic predisposition has been considered as a potential mechanism that links the described association between ANCA vasculitis and AIT. Full Article: Published in Frontiers in Endocrinology and available here New insights into the pathogenesis of IgA nephropathy Authors: Yeo SC, Cheung CK, Barratt J Abstract: IgA nephropathy is the most common form of glomerulonephritis in many parts of the world and remains an important cause of end-stage renal disease. Current evidence suggests that IgA nephropathy is not due to a single pathogenic insult, but rather the result of multiple sequential pathogenic “hits”. An abnormally increased level of circulating poorly O-galactosylated IgA1 and the production of O-glycan-specific antibodies leads to the formation of IgA1-containing immune complexes, and their subsequent mesangial deposition results in inflammation and glomerular injury. While this general framework has formed the foundation of our current understanding of the pathogenesis of IgA nephropathy, much work is ongoing to try to precisely define the genetic, epigenetic, immunological, and molecular basis of IgA nephropathy. In particular, the precise origin of poorly O-galactosylated IgA1 and the inciting factors for the production of O-glycan-specific antibodies continue to be intensely evaluated. The mechanisms responsible for mesangial IgA1 deposition and subsequent renal injury also remain incompletely understood. In this review, we summarize the current understanding of the key steps involved in the pathogenesis of IgA nephropathy. It is hoped that further advances in our understanding of this common glomerulonephritis will lead to novel diagnostic and prognostic biomarkers, and targeted therapies to ameliorate disease progression. Full Article: Published in Pediatric Nephrology and available here.