Managing Recurrent FSGS Post-Transplant: Risk Factors, Pathogenesis & Treatment Strategies

Abstract

FSGS is identified as one of the leading causes of nephrotic syndrome among children and adults, typically demonstrating a course to ESKD. It has been identified as a major risk for recurrence among patients undergoing kidney transplantation, leading to loss of the allograft as well as increased morbidity and mortality. Undeniably, universally accepted guidelines to identify patients at high risk for recurrence or standardized protocols for treating recurrent FSGS do not exist. It is in this context, based on recurrent FSGS that we have comprehensively reviewed 221 relevant studies out of an initial pool of 614 to develop consensus guidelines. Definition, epidemiology, risk factors, pathogenesis, and management strategies would form the crux of the discussion. Major risk factors associated with recurrence include genetic predisposition, age less than 20 years at onset of disease, and a history of recurrence after transplantation. Pathogenesis includes circulating permeability factors and immune dysregulation. Current management approaches include pretransplant risk assessments, plasmapheresis, rituximab, and experimental therapies. These guidelines lay the foundation for clinical decision-making, but further research is required to optimize treatment in recurrent FSGS and result in better outcomes for transplant recipients.

Introduction

FSGS, or focal segmental glomerular sclerosis is a serious disease of the kidneys, with scarring within the small filtering units called glomeruli. It features among the top causes of nephrotic syndrome in children and adults and may lead to ESKD. For patients suffering from kidney failure due to FSGS, the prognosis through kidney transplantation is almost its best shot. More feared, though, than such complications of a kidney transplant in FSGS patients is the recurrence of the disease in the transplanted kidney. Recurrent FSGS can significantly impair allograft survival, often leading to graft loss, increased morbidity, and mortality.

Although recurrent FSGS is an important condition, there are no universally accepted guidelines to identify the risk or recurrence and there have not been standardized protocols for its management. This has created uncertainty at both clinical and patient levels as to how recurrent FSGS should best be prevented and managed. To address this, a working group conducted a comprehensive review of relevant literature studying the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. After identifying 614 studies, 221 articles were selected for the development of consensus guidelines based on the strength of evidence obtained.

This article aims to provide an overview of recurrent FSGS in the context of kidney transplantation, its epidemiology, risk factors, mechanisms, and possible treatment strategies. In addition, we will outline areas requiring further research to improve patient outcomes and thus resolve the currently unsettled challenges in managing recurrent FSGS.

Understanding FSGS

Overview of FSGS

FSGS is one of the glomerular diseases in which all the glomeruli in the kidney are not scarred but only some of them. The disease may occur in several forms as primary or idiopathic and others are considered to be due to secondary causes associated with other disorders, including obesity, viral infections, and drug toxicity. The defining characteristic of FSGS is isolated proteinuria, often presenting as nephrotic-range values, and it can eventually progress to CKD or ESKD over time.

Underlying the pathophysiology of FSGS is the damage to the podocyte's highly specific cells constituting and thus crucial to the filtration barrier of the kidney. With damage to the podocytes, then there is a breach in their basement membrane and subsequent scarring known as glomerulosclerosis and leak of protein into the urine. The cause remains elusive, especially in the idiopathic form, even though the disease has seen better understanding with time.

The Impact of FSGS on Kidney Transplantation

Kidney transplantation is also regarded as the best treatment for patients with FSGS once reaching ESKD. Recurrence of FSGS in the transplanted kidney has been reported to occur approximately in 30-50% of these patients. The onset of recurrence is very rapid, which may present anywhere from days to weeks after transplantation, and carries a high risk of graft loss.

The recurrence of FSGS is quite challenging to control in patients who have received a kidney transplant, as the mechanisms of disease recurrence are not well understood. After the disease recurs, treatments are scarce and rarely successful in altering the course of the disease.

Risk Factors for Recurrence

Genetic Predisposition

One of the most known and commonly accepted predisposing factors to the recurrence of FSGS is genetic predisposition. Mutations in genes encoding functions related to podocytes are known to be responsible for familial as well as sporadic manifestations of FSGS. Genetic forms of FSGS may have less of a risk of recurrence because most of these cases represent an intrinsic defect in podocyte structure rather than a circulating factor causing damage to the podocyte.

Previous Transplantation History

Patients who have experienced a recurrence of FSGS in a prior kidney transplant are at significantly increased risk for recurrence in subsequent transplants. This creates the impression that some patients have a recurrent phenotype rendering them likely to eventually develop FSGS even when receiving a new kidney.

Age at Disease Onset

Several studies have shown that younger age at the onset of FSGS, particularly in pediatric patients, is associated with a higher risk of recurrence post-transplant. The reasons for this age-related risk remain unclear, but it may be related to differences in immune system regulation or circulating factors in younger individuals.

Other Factors

Additional risk factors for recurrence include the presence of heavy proteinuria at the time of transplantation, the rapid progression of the original disease, and certain histological subtypes of FSGS, such as collapsing variant FSGS, which appears to carry a particularly poor prognosis.

Pathogenesis of Recurrent FSGS

The Role of Circulating Factors

One of the leading hypotheses regarding the pathogenesis of recurrent FSGS is the involvement of circulating permeability factors that target podocytes. These factors, which are thought to be produced by the immune system, may cause direct injury to the transplanted kidney, leading to podocyte dysfunction and eventual glomerulosclerosis. The identity of these factors remains elusive, but potential candidates include soluble urokinase-type plasminogen activator receptor (suPAR) and other immune mediators.

Immune Dysregulation

Immune system dysregulation is believed to play a key role in the recurrence of FSGS. Some studies suggest that abnormal T-cell and B-cell activity may contribute to the production of circulating factors that damage the podocytes. This is supported by the observation that therapies targeting the immune system, such as rituximab (an anti-CD20 antibody), have shown some efficacy in preventing or treating recurrent FSGS.

Management Strategies for Recurrent FSGS

Pre-Transplantation Risk Assessment

Given the significant risk of recurrence in some patients, pre-transplantation risk assessment is crucial. Genetic testing for podocyte-related mutations can help identify patients at lower risk for recurrence. Additionally, assessing proteinuria levels and other clinical markers of disease activity before transplantation can provide valuable information regarding recurrence risk.

Post-Transplant Monitoring

Close monitoring for proteinuria in the early post-transplant period is essential for the early detection of recurrence. Patients at high risk for recurrence should undergo frequent urine protein testing, as recurrent FSGS often presents with a sudden increase in proteinuria.

Therapeutic Interventions

Plasmapheresis: This therapy has been used in some cases of recurrent FSGS to remove circulating factors thought to contribute to the disease. While plasmapheresis may offer short-term benefits, its long-term efficacy remains controversial.

Rituximab: As an immune-targeting therapy, rituximab has been employed to prevent or treat recurrent FSGS, particularly in patients suspected of having immune-related recurrence. However, its effectiveness is inconsistent, and more research is needed to determine which patients are most likely to benefit from this therapy.

Calcineurin Inhibitors: Drugs such as cyclosporine and tacrolimus have shown some success in reducing proteinuria and delaying disease progression in recurrent FSGS. These medications may work by stabilizing podocyte structure and function.

Experimental Therapies

Several emerging therapies are being investigated for the treatment of recurrent FSGS. These include targeted biologics, such as abatacept, and novel approaches aimed at inhibiting suPAR and other circulating factors implicated in disease recurrence.

Future Directions and Conclusion

While a better understanding of predisposing factors and mechanisms for recurrent FSGS has been achieved, much is still to be conquered. The development of universally accepted guidelines for predicting recurrence and managing recurrent cases would remain an issue for further investigation. The most critical point, however, is the discovery of circulating factors that cause podocyte damage and the availability of neutralizing targeted therapies against these factors.

In conclusion, recurrent FSGS is a significant barrier to the success of kidney transplantation in these patients. A better understanding of the disease's pathogenesis and management strategy will offer hope for better outcomes in the future. The extant literature achievement of consensus guidelines is an important step in this direction, but further studies are warranted to strengthen these recommendations and provide clearer pathways for clinicians managing this challenging condition.

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