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Gipson Debbie S.; Wang Chia-shi; Salmon Eloise; Gbadegesin Rasheed; Naik Abhijit; Sanna-Cherchi Simone; Fornoni Alessia; Kretzler Matthias; Merscher Sandra; Hoover Paul;  Kidwell Kelley; Saleem Moin; Riella Leonardo;  Holzman Lawrence; Annette Jackson; Opeyemi Olabisi; Paolo Cravedi; Benjamin Solomon Freedman; Himmelfarb Jonathan; Vivarelli Marina; Harder Jennifer; Klein Jon; Burke George; Rheault Michelle; Spino Cathie;  Desmond Hailey E.; Trachtman Howard: FSGS Recurrence Collaboration: Report of a Symposium. Glomerular Diseases DOI 10.1159/000535138

The “primary” form of the focal segmental glomerulosclerosis (FSGS) lesion (commonly associated with the presence of circulating permeability-promoting factors, notably anti-nephrin auto-antibody, among others) frequently (25–40% or higher) recurs in kidney allografts, most commonly early post-transplantation (even immediately upon returning blood circulation to the graft). Such recurrences curtail graft survival. This vexing problem represents a major obstacle to the use of kidney transplantation to restore health to the patients with primary FSGS who develop end-stage kidney disease (ESKD).

Gipson and many expert colleagues report on a virtual Symposium devoted to this topic held on December 14–15, 2021. The intent of the gathering was to summarize the state-of-the-art of this topic with respect to pathogenesis, detection and management in children and adults as well as to suggest a future research agenda that might close some knowledge gaps. Not surprisingly, considerable attention was devoted to the native FSGS disease.

Clinical and pathological risk factors for the development of recurrent FSGS have been described, most notably rapid progression to ESKD of the native kidney disease, co-existent mesangial hypercellularity, the late development of steroid resistance following a period of steroid sensitivity for the native FSGS, and performance of second kidney transplant after the loss of an initial kidney allograft from a recurrence of FSGS. The presence of pre-transplant anti-nephrin auto-antibodies in the recipient seems to predict recurrence of FSGS. The recurrence rate of FSGS can be as high as 90% with the presence of some of these risk factors. Monogenetic forms of FSGS do not recur in the kidney allograft, with a few exceptions. HLA polymorphisms may act to increase or decrease the risk of recurrent FSGS, but this needs more study. APOL1 high-risk alleles (in donor or recipient) are associated with higher risk of graft loss, but do not seem to influence recurrent disease. De novo FSGS, including collapsing nephropathy, is more common in donor kidneys having high-risk APOL1 alleles. The APOLLO study is examining this aspect of FSGS in donors and recipients more carefully.

Circulating “permeability factors” seem to be involved in recurrence, but their precise identification has so far been elusive. Anti-nephrin auto-antibodies are emerging as an important cause of recurrent FSGS, and this phenomenon is under intense study.

Management of recurrent FSGS by combinations of plasma exchange (PLEX) or lipid apheresis and rituximab (or other anti-CD20 monoclonal antibodies) and steroids seems to be effective in about 50% of cases, but PLEX dependence can be observed. Major gaps in treatment of recurrent FSGS currently exist. Anecdotes suggest that ACTH gel or high-dose calcineurin inhibitors can be effective in some cases. Early diagnosis is critical, as any delay in therapy is associated with a poor outcome. Failure of therapy to reduce proteinuria predicts a risk of graft loss.

This niche area of clinical medicine has many knowledge gaps, identified in this summary. A better understanding of the mechanisms involved in the native disease is required to help avoid its development and to successfully treat recurrent FSGS in kidney allografts.

Quoted Karger Article

FSGS Recurrence Collaboration: Report of a Symposium

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