A critical re-analysis of cases of post-transplantation recurrence in genetic nephrotic syndrome

Abstract

Background Genetic defects in podocyte proteins account for up to 30% of steroid-resistant nephrotic syndrome (SRNS) in the paediatric population. Most children with genetic SRNS are resistant to immunosuppression and at high risk of progression to stage 5 chronic kidney disease. Kidney transplantation is often the treatment of choice. The possibility of post-transplantation disease recurrence in genetic SRNS remains controversial, and poses fundamental questions about disease biology. Methods We critically evaluated the published cases of post-transplantation recurrence in genetic patients, particularly testing ‘mutations’ against the most recent population variant databases, in order to clarify the diagnoses, and compare the clinical courses and responses to therapy. Results Biallelic pathogenic variants in NPHS1 leading to a complete absence of nephrin were the most commonly reported and best understood instance of nephrotic syndrome occurring post-transplantation. This is an immune-mediated process driven by antibody production against the novel nephrin protein in the allograft. We also identified a number of plausible reported cases of post-transplantation recurrence involving pathogenic variants in NPHS2 (8 patients, biallelic), one in WT1 (monoallelic) and one in NUP93 (biallelic). However, the mechanism for recurrence in these cases remains unclear. Other instances of recurrence in genetic disease were difficult to interpret due to differing clinical criteria, inclusion of patients without true pathogenic variants or the influence of other factors on renal outcome. Conclusions Overall, post-transplantation recurrence remains very rare in patients with genetic SRNS. It appears to occur later after transplantation than in other patients and usually responds well to plasmapheresis with a good renal outcome.

Circulating Permeability Factors in Focal Segmental Glomerulosclerosis: In Vitro Detection

“… 22 Furthermore, finding a genetic cause of the NS will highly reduce the chance of a relapse after kidney transplantation. 23 Exclusion of a genetic cause is associated with a high chance of FSGS recurrence after transplantation, and until now no tests are available to determine the risk for recurrence. In the absence of such tests, preventive therapies and their potential benefits are difficult to evaluate, whereas preventive therapies for other plasma factors, for instance with ABO incompatible kidney transplantation, have proven to be beneficial.…”

“…Children with SRNS will generally be screened for genetic mutations, which assists in explaining the cause of the NS, and its management, as immunosuppressive drugs are generally avoided in genetic cases 22 . Furthermore, finding a genetic cause of the NS will highly reduce the chance of a relapse after kidney transplantation 23 . Exclusion of a genetic cause is associated with a high chance of FSGS recurrence after transplantation, and until now no tests are available to determine the risk for recurrence.…”

Treatment potential in APOL1-associated nephropathy

“…A series of reports support critical roles for kidney-synthesized APOL1 protein as a cause of nephropathy. Genetically mediated kidney diseases are typically cured by kidney transplants from donors who lack the causative mutation [17]. Because transplanted kidneys from deceased donors with African ancestry fail more rapidly than those from donors of other ancestries [18], APOL1 genotypes were assessed in African–American deceased donors for effects on outcomes after transplantation [19].…”

Steroidresistant nephrotic syndrome in a child associated with a mutation in the INF2 gene

“…Если у члена семьи будет выявлена мутация в гене INF2, это лишит его возможности быть донором почки для трансплантации. При отсутствии у донора явных признаков заболевания трансплантация почки может увеличить риск НС у реципиента и донора [10,20,21]. Возврат нефротического синдрома в почечный трансплантат встречается в 30-50 % случаев ФСГС после первой трансплантации и до 80 % при последующих трансплантациях [21].…”