Recurrence of glomerulonephritis after kidney transplant

INTRODUCTION

Glomerulonephritis (GN) is the third most common cause of end-stage kidney disease (ESKD). The definition and classification of GN depend on kidney histology, with attention to the pattern of injury and when possible, the relevant clinical history and underlying etiology since both inform management of the disease [1]. The risk of GN recurrence in the kidney allograft is based on the type of GN and is the second or third most common cause of death-censored graft loss [2] (Figure 1). Therefore, recognizing and managing this risk with the patient before and after kidney transplant is critical to long-term outcomes.

APPROACH TO DIAGNOSIS AND RISK ASSESSMENT

Patients with recurrent GN can present with hypertension, new-onset or worsening proteinuria, and active urinary sediment with or without worsening kidney function. A kidney allograft biopsy is recommended whenever GN is suspected and full evaluation should include immunofluorescence (IF) and electron microscopy (EM). Native kidney biopsy should be reviewed if available since histology serves not only to establish the diagnosis and characterize severity, but may also help determine the recurrence risk. However, many patients do not have a native biopsy, especially if they present with advanced kidney disease. Some of the ‘de novo’ GN posttransplant might actually reflect a recurrence of undiagnosed disease pretransplant.

Many GN patients were exposed to immunosuppression before transplant, so they are at cumulatively higher risk of infection and malignancy than most kidney transplant recipients.

SPECIFIC GNS

Recognizing the limitations in the current classification of GN, we provide a brief overview of various GNs pre- and posttransplant. In general, supportive therapy involving renin-aldosterone-angiotensin system (RAAS) blockade for glomerular protection, sodium restriction and blood pressure control should be instituted.

IgA nephropathy

IgA nephropathy (IgAN) is the most common GN worldwide and is comprised of a heterogeneous group of pathways resulting in glomerular deposition of galactose-deficient IgA1-based immune complexes. IgAN tends to recur early with a histological recurrence rate of 50–60% and a clinically significant recurrence rate of 7–30%, yet graft loss is uncommon [3]. Risk factors include younger age, living-related donor, steroid-free regimen, non-thymocyte globulin induction and crescentic lesions in native kidneys [4]. Treatment is not well established but includes anti-proteinuric therapy in addition to steroids or more intensive immunosuppression.

Focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) encompasses a wide array of underlying mechanisms including primary, secondary and genetic. It is important, although difficult, to delineate the etiology since it is a major determinant of recurrence risk. Genetic FSGS should be suspected in those with childhood onset, family history or resistance to steroids. Common forms of genetic FSGS, such as nephrin (NPHS2), podocin (NPHS1), etc., are less likely to recur, but some rare recurrences have been reported [5]. APOL1 risk variants are associated with FSGS, with a low likelihood of no evidence of recurrence [6]. Secondary FSGS should not recur if the underlying etiology is no longer present. Primary (or idiopathic) FSGS has a relatively high risk of recurrence in the allograft, ∼30% (17–55%) [7], and can lead to allograft loss. Recurrence that usually occurs early is thought to be mediated by unidentified circulating factors causing podocyte injury and clinically manifests with proteinuria or nephrotic syndrome. Risk factors for recurrence include aggressive native disease with nephrotic syndrome and a history of prior recurrence. Careful assessment of living-related kidney donors is required in the setting of a family history of FSGS, including those with APOL1 risk variants, and genetic testing should be considered [8]. Prior recurrence greatly increases the risk of subsequent recurrence, but does not preclude repeat transplant, and decisions should be individualized [7]. Therefore, close monitoring of proteinuria is important in the immediate posttransplant period. Preventive plasmapheresis or rituximab has a variable success rate. Treatment options include plasmapheresis and rituximab, but lack of mechanistic understanding often limits control of the disease.

Membranous nephropathy

Membranous nephropathy (MN) is classified into primary or secondary. In primary MN, circulating antibody to phospholipase A2 receptor (PLA2R) is positive in the majority (∼70%), making it an invaluable biomarker to monitor disease activity. It is desirable to have a suppressed level of PLA2R pretransplant, although not absolutely required. Rising antibody titers are associated with a higher risk of recurrence and should prompt intervention. Multiple other antibodies have been described and are advancing our understanding of this disease. Primary MN recurrence risk is 10–50% [9]. Rituximab is recommended to treat MN recurrence [9], while other approaches are similar to treating native disease. For secondary MN, control of underlying etiology should prevent recurrence.

Membranoproliferative GN

Membranoproliferative GN (MPGN) is a histologic pattern of injury associated with multiple disease processes. Overall, it has a high risk of recurrence and graft loss [2]. MPGN can be classified into two subtypes: immune complex MPGN and C3G. Immune complex GN can be idiopathic or associated with systemic processes such as autoimmunity, infection or monoclonal gammopathy. Idiopathic immune-complex MPGN recurs in 19–48% [2] and treatment includes steroids, higher dose mycophenolate or calcineurin inhibitor, while control of secondary MPGN requires treatment of involved systemic processes. Monoclonal immunoglobulin-associated MPGN recurs frequently (up to 60%) with a high risk of graft loss even if monoclonal protein remains undetectable [3]. Therapy against antibody production is recommended. C3G-associated MPGN has a significant recurrence risk (>50%) [10]. The specific complement-based abnormality should inform treatment, with target-based therapy, plus augmented mycophenolate-based immunosuppression.

Other GNs

Other secondary GNs, including anti-neutrophilic cytoplasmic autoantibody (ANCA) vasculitis, anti-glomerular basement membrane disease and lupus nephritis, are at low risk of recurrence if the disease is controlled before transplant. However, it is important to monitor patients and it is desirable to have disease quiescence and suppressed titers for 6–12 months before transplant. Treatment of recurrence is similar to that used in the native kidney [9].

CONCLUSION AND FUTURE CONSIDERATIONS

GN is a common etiology of ESKD and posttransplant recurrence remains a significant cause of allograft loss. Management of recurrent GN relies on understanding the pathophysiology and timely application of diagnostic and therapeutic tools. Kidney biopsy remains the gold standard for diagnosis of recurrent GN and should include IF and EM evaluation. Accurate pretransplant diagnosis, including native kidney biopsy whenever possible, greatly improves transplant care planning and outcomes. Patients should be monitored closely and educated about the recurrence risk, treatment options and limitations. Financial considerations are important since many therapies are costly. Finally, more studies including registries and randomized controlled trials are needed to further understand each disease in the native and transplant kidney.

CONFLICT OF INTEREST STATEMENT

None declared.

REFERENCES