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Diagnosis: Post-Transplantation Recurrence of Focal Segmental Glomerulosclerosis

The risk of renal allograft loss due to recurrence of FSGS remains a worrisome and stark reality for some kidney transplant recipients (KTR). FSGS recurs in 14%–60% of first transplants and up to 80% of subsequent transplants. Forty to sixty percent of these recurrences result in graft loss, and recurrence of FSGS was the cause of 3.2% of all graft failures in a North American Pediatric Renal Trials and Collaborative Studies report (Harshman LA, et al. Focal segmental glomerulosclerosis: Risk for recurrence and interventions to optimize outcomes following recurrence. Pediatr Transplant. 2022;26(6):e14307. [PubMed link]).

The histologic findings of FSGS can be associated with a variety of causes. Although most cases are idiopathic, secondary causes include alterations in slit diaphragm proteins, hyperfiltration, severe obesity, and various drugs and toxins. Mutations in NPHS1, NPHS2, WT1, alph-actin-4, CD2AP TRPC6, and a number of other genes have been associated with FSGS (Harshman LA, et al. Focal segmental glomerulosclerosis: Risk for recurrence and interventions to optimize outcomes following recurrence. Pediatr Transplant. 2022;26(6):e14307. [PubMed link]).

Recurrence risk is related to the cause of FSGS, and screening for genetic mutations has become and should be a routine part of pretransplant evaluation in patients with FSGS. Unfortunately, the genotype–phenotype relationship for recurrence risk is not always clear, especially when identified variants are of unknown pathogenic significance. Pelletier et al. reported zero recurrences among 22 patients with genetic SRNS compared with 64 recurrences among 136 (47%) of those without an identified genetic cause (Pelletier JH, et al. Pediatr Nephrol. 2018;33(10):1773-1780. [PubMed link]). However, an identified genetic mutation does not guarantee a successful transplant. Ruf et al, reported posttransplant FSGS in two out of 24 patients with identified NPHS2 mutations (Ruf RG, et al. J Am Soc Nephrol. 2004;15(3):722-32 [PubMed link]). As new genetic associations with FSGS continue to be identified, reported risks of recurrence are expected to continue to evolve (Harshman LA, et al. Focal segmental glomerulosclerosis: Risk for recurrence and interventions to optimize outcomes following recurrence. Pediatr Transplant. 2022;26(6):e14307. [PubMed link]).

Two important things to highlight in our case, first: the presence of an established mutation in this patient, and despite this the disease recurred; it could be that there was another undiagnosed etiology (primary FSGS and not associated with the genetic alteration that was found?); or that there are genetically caused podocytopathies that may recur, as stated in the previous paragraph. The second: in the biopsy no focal and segmental sclerosing lesions were found and even so we diagnosed it as "recurrence of FSGS"; the biopsy showed diffuse podocyte damage, so it is a podocytopathy, and since we already knew from the pre-transplant study that the patient had FSGS, it is logical to think that the podocytopathy is a recurrence of the same native kidney disease: FSGS, only that due to the short post-transplant time the sclerosing lesions have not yet developed; this is the same thing that happens when a native kidney is biopsied for nephrotic syndrome and minimal change disease is found (diffuse podocytopathy without segmental hyaline or sclerosing lesions) and later, in a subsequent biopsy, these lesions are already evident, it is not that the disease has changed, it is the same disease from the beginning: FSGS, only that in the initial biopsy the segmental lesions were not evidenced.

See the chapter: Focal Segmental Glomerulosclerosis of our Tutorial

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