Case description
A 23-year-old female with primary focal segmental glomerulosclerosis (FSGS), diagnosed at the age of 16, underwent a living-related kidney transplantation (KT). She was on hemodialysis for 2 years before transplant but still had residual urine output of 500 mL/day with a random urine protein-to-creatinine ratio (UPCR) of 1.5 g/gCr. On post-operative day 4, UPCR was noted as 14 g/gCr. A kidney allograft biopsy demonstrated diffuse effacement of podocyte foot processes with no evidence of acute rejection.
What are the risk factors and mechanisms of recurrent primary FSGS posttransplant? What treatment options (pre- and posttransplant) might benefit this patient?
Introduction
Primary FSGS is rare; however, it is the most common histopathologic pattern of glomerular injury in adult nephrotic syndrome. The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases proposed eliminating the term idiopathic from the FSGS lexicon and only using primary FSGS (1). Recurrent FSGS refers to the development of primary podocytopathy in KT recipients with a history of primary FSGS as the cause of end stage kidney disease. Recurrence may occur in more than 32% of cases (2) but is rare in patients with genetic FSGS (e.g., podocin mutations) and those without nephrotic syndrome at the initial presentation (3).
Risk factors
Several factors are associated with a higher risk of recurrence: younger age of disease onset, rapid progression of initial disease, living-related KT, history of recurrence in a previous kidney allograft, and native kidney nephrectomies (2).
A family history of FSGS, histologic subtype in the native kidney, and choice of transplantation immunosuppressive therapy have not been shown to alter the risk of recurrence.
Pathogenesis
Mechanisms of recurrent FSGS are not entirely understood.
Mechanisms of recurrent FSGS are not entirely understood. In addition to genetic and immunological modifiers, circulating factor(s) have been suggested, which may cause injury to the podocytes and/or glomerular capillary wall. Case reports demonstrated that re-transplantation of a kidney allograft removed from a KT recipient who developed biopsy-proven recurrent FSGS (4) resulted in complete resolution of proteinuria and reversal of histologic lesions, supporting the presence of circulating permeability factor(s) indirectly.
Several molecules (including soluble urokinase-type plasminogen activator receptor, cardiotrophin-like cytokine factor 1, apolipoprotein A1, anti-CD40 antibody, and anti-nephrin (5)) have been proposed as potential circulating factors. Nevertheless, none has been validated as a biomarker in clinical practice (6, 7).
Clinical manifestation and diagnosis
Patients with recurrent primary FSGS typically present with rapid nephrotic-range proteinuria with a median time to recurrence of 1.5 months (2). For the patients with nephrotic-range proteinuria after 3 months’ posttransplantation, an evaluation for causes of secondary FSGS should also be performed (e.g., maladaptive response to hyperfiltration, viruses, drugs, and toxins).
Proteinuria from native kidneys decreases significantly within 1 month of transplantation; thus, proteinuria detected more than 1 month after KT is most likely derived from the allograft and should trigger further investigation (8).
A kidney allograft biopsy is critical to diagnose recurrent primary FSGS. As a spectrum of primary podocytopathy, early recurrence of primary FSGS may lack sclerotic lesions by light microscopy, and it may only involve diffuse podocyte foot process effacement by electron microscopy. Podocyte foot process effacement tends to be segmental in secondary forms (9).
Therapeutic options
For patients with recurrent primary FSGS, plasmapheresis is suggested to remove the hypothesized circulating permeability factor, with or without rituximab in combination (10). However, there is a lack of clear evidence of benefit with use of the rituximab in this setting (11).
Several additional treatment options for patients with recurrent FSGS who do not respond to initial therapy of plasmapheresis, with or without rituximab, have been explored, including adrenocorticotropic hormone (12), galactose (13), lipid apheresis (14), and abatacept (15). The clear benefit of these therapies should be tested in the future, and there are multiple ongoing clinical trials for primary FSGS, which may be effective for recurrent FSGS (16).
Consideration for re-transplantation
Patients who developed recurrent FSGS in the first KT are at very high risk (up to 75%) for recurrence in subsequent kidney allografts. Some clinicians have suggested that if a first graft is lost due to recurrent disease, then a second KT should be delayed for 1−2 years or avoided (17). This delay may result in the disappearance of the circulating factors responsible for the glomerular injury. However, the efficacy of this approach is not proven. A third KT in patients with two previous transplant losses due to recurrent FSGS should generally be avoided. Prophylactic plasmapheresis and rituximab do not appear to decrease the rate of recurrence after transplantation (18).
Perspectives from patients living with FSGS
Living with primary FSGS sets challenges for a patient's daily life. According to the patient forum organized by the National Kidney Foundation, the patients and their care partners shared that they experience not only physical symptom burden (e.g., fatigue and edema) but also psychosocial burden (e.g., fear and anxiety of FSGS recurrence after transplant). Participants reported that social isolation was frequently caused by the “invisible” nature of their disease, which made it difficult for others to understand possible complications in the lives of people with FSGS. This sometimes caused irreconcilable strains on friendships and workplace relationships. The lack of perceived importance of mental health relative to physical symptoms was pointed out (19).
Conclusions
Recurrence of primary FSGS after KT is immensely challenging. The understanding of pathogenesis, development of diagnostic biomarkers, and effective therapeutics are urgently needed. Future clinical trials that include a tight partnership with patients and their care partners are awaited.
References
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