Recurrent focal segmental glomerulosclerosis (FSGS) after renal transplantation is difficult to treat. Recently a series of four patients unresponsive to plasma exchange (PE) and rituximab, who were successfully treated with abatacept, has been reported. We present a 26-year-old Caucasian patient who suffered from juvenile rheumatoid arthritis and developed severe proteinuria eleven days after transplantation. An allograft biopsy was suggestive of recurrent focal segmental glomerulosclerosis. He did not respond to PE therapy. A first dose of abatacept produced partial remission. Four weeks later proteinuria again increased and a second biopsy showed progression of disease. After another ineffective course of PE he was given a second dose of abatacept, which was followed by rapid, complete, and sustained resolution of proteinuria. This treatment caused a significant increase in BK and JC viremia. Whether abatacept ameliorated proteinuria via an effect on podocytes or on the patient’s primary disease remains speculative.
Primary focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome and leads to end-stage renal disease in approximately 40% of cases. Recurrence after kidney transplantation occurs in 20% to 50% of patients and has been associated with decreased allograft survival [
SuPAR probably causes podocyte damage and proteinuria by inducing podocyte B7-1 (CD80) expression, which leads to podocyte migration through inactivation of
A 26-year-old Caucasian man with end-stage renal disease received kidney transplantation from a deceased donor in October 2013 after having performed chronic peritoneal dialysis and hemodialysis for seven years. He had suffered from juvenile rheumatoid arthritis since early childhood. Because the patient had initially been admitted with end-stage renal disease, his primary renal diagnosis was unknown, but secondary amyloidosis due to rheumatic disease was suspected.
The patient received induction therapy with basiliximab followed by an immunosuppressive regimen consisting of tacrolimus, mycophenolate mofetil (MMF), and prednisolone. Because of CMV mismatch he also received valganciclovir prophylaxis. He was discharged ten days after transplantation with serum creatinine of 83
Light microscopy of the second biopsy shows mild mesangial matrix expansion and increase in mesangial cell number with focal accentuation (PAS, 200x).
Electron microscopy revealed dystrophic podocytes with flattened foot processes (Figure
Electron microscopy of the renal biopsy reveals partial effacement and flattening of podocyte foot processes. The glomerular basement membrane is normal. No immune complex deposits are detected (4000x).
The patient was treated with further eight PEs, which reduced proteinuria to around 3.0 g/g creatinine with a tendency to increase. We therefore decided to give a second dose of abatacept. This was followed by a rapid decline in proteinuria to 1.0 g/g and a further decline to 0.15 g/g in the following months. The time course of treatment with PE and abatacept, serum creatinine, and proteinuria is shown in Figure
Time course of serum creatinine and proteinuria in relation to therapeutic interventions.
Two weeks after the second dose of abatacept BK viremia was detected. BK viremia increased to 200.000 copies/mL and JC viremia (6800 copies/mL) was also detected. We discontinued MMF and reduced the tacrolimus dose, aiming for trough levels between 3 and 5 ng/mL, and prednisolone to 5 mg daily. JC viremia subsided after five months, whereas mild BK viremia (10.000 copies/mL) persisted. As the patient had negative EBV serology, regular EBV DNA monitoring was performed, which remained negative throughout the disease course. Over the next year, the patient remained in complete remission without proteinuria and with serum creatinine stable at 125
Recurrence of primary FSGS after transplantation poses a serious threat to allograft function. Current therapeutic strategies such as high-dose cyclosporine A, cyclophosphamide, PE, and rituximab will induce a remission in only up to 60% of patients [
The enthusiasm elicited by the first report was rapidly dampened by a letter describing treatment failure of belatacept in five patients with recurrent FSGS [
Our case includes several interesting aspects. First, the primary renal disease was unknown and the diagnosis of FSGS recurrence came as a surprise. It is possible that there is a link between our patient’s renal disease and juvenile rheumatoid arthritis, although such an association has not been described. Abatacept is effective in and approved for the treatment of juvenile rheumatoid arthritis [
It is difficult to know why some patients seem to respond to abatacept while the majority of patients do not. The pathophysiological mechanisms underlying FSGS may be different from case to case, ranging from nonspecific podocyte injury to abnormal immune response (probably in our patient) with production of CLCF-1 or anti-CD40 antibodies and suPAR and up to podocyte expression of molecules including B7-1, B7-2, and CD40.
Following unsuccessful PE therapy, our next choice would have been rituximab.
Our patient’s very low serum immunoglobulin levels made us reluctant to prescribe a therapy that might further impair the humoral immune response. We also excluded other treatment options such as high-dose cyclosporine A and steroids or cyclophosphamide because of their potential to cause severe side effects.
Although abatacept’s package insert clearly excludes an increased risk for lymphoma in rheumatoid arthritis patients, the situation may be different when it is used in combination with calcineurin inhibitors and MMF. Treatment with belatacept is associated with an increased risk for lymphoma in EBV-negative renal allograft recipients [
In contrast to previous reports, we found BK virus and JC virus reactivation in our patient following abatacept therapy. To avoid overimmunosuppression we had already halved the MMF dose at initiation of abatacept. Only few data are available on virus replication and virus infection in patients receiving CTLA-4-immunoglobulins. A single-center study compared the incidence of BK virus and JC virus infection in 62 de novo kidney transplant patients, who were enrolled in the BENEFIT studies and received either belatacept or cyclosporine [
The authors declare that they have no competing interests.