Focal segmental glomerulosclerosis is a common cause of end-stage renal disease in children. Focal segmental glomerulosclerosis recurrence in renal transplants is a challenging disease, and can cause graft dysfunction and loss. Different therapies exist with varying responses, from complete remission to resistance to all modes of treatment. Abatacept was recently introduced as a treatment for primary focal segmental glomerulosclerosis in native kidneys and in recurrent disease after transplant. We present a pediatric case with immunosuppression-resistant primary NPHS2-negative focal segmental glomerulosclerosis recur-rence after renal transplant. The standard therapy for recurrent focal segmental glomerulosclerosis (rituximab, plasmapheresis, high-dose cyclosporine, and corticosteroids) was tried but failed to induce remission. Abatacept (10 mg/kg) was given at 0, 2, and 4 weeks (total, 3 doses) with no good response. We conclude that abatacept may work in patients with B7-1-positive focal segmental glomerulosclerosis recurrence and its efficacy is uncertain in disease with B7-1-negative or unknown staining status.
Key words : End-stage renal disease, Immunosuppression, Pediatric, Renal transplant
Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disease that leads to end-stage renal disease in adults and children in the United States of America.1 Despite the advances of immunosuppressive therapy in the treatment of glomerular diseases, some FSGS patients are resistant to single or combination immunosuppressive therapy that may include glucocorticoids, cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil (MMF), and/or rituximab.1,2
The primary form of FSGS, observed in most pediatric FSGS patients, can recur after kidney transplant in 30% cases and is the main cause of graft failure in these patients.3 The risk of FSGS recurrence increases to 50% to 80% in subsequent transplants.3,4 There previously has been no single treatment that can prevent or cure FSGS recurrence in all patients. Different centers use different protocols that include 1 drug or a combination of corticosteroids, high-dose calcineurin inhibitors, plasmapheresis, and/or rituximab in addition to antiproteinuric agents such as angiotensin converting enzyme inhibitors (ACE-Is) or angiotensin II receptor blockers (ARBs).5-7
Abatacept cytotoxic T-lymphocyte-associated protein 4 immunoglobulin [CTLA-4-Ig] is a drug that has been used to treat autoimmune diseases, most commonly rheumatoid arthritis.8,9 It is an inhibitor of the T-cell costimulatory molecule B7-1 (CD80).10 The B7-1 staining was observed in renal biopsy specimens of native kidneys in patients with primary FSGS and in FSGS recurrence after kidney transplant.11 A previous study showed that abatacept successfully induced partial or complete remission in 4 patients with rituximab-resistant recurrent FSGS after transplant and 1 patient with glucocorticoid-resistant primary FSGS.11
We present a case of pediatric primary FSGS that recurred after kidney transplant, in which treatment with abatacept failed to induce remission.
An 11-year-old girl presented with nephrotic syndrome in July 2011. She was resistant to glucocorticoid treatment and underwent a kidney biopsy that showed 2 of 16 glomeruli with focal tuft scarring. The immunoperoxidase staining tests for C3 and immunoglobulin A, G, and M were negative. She was tested for podocin (NPHS2) gene mutation, which was negative. Different immunosuppressive therapies were attempted (tacrolimus, cyclosporine, MMF, and rituximab) but failed to induce partial or complete remission. She was treated with an ACE-I and intravenous albumin infusion. Her kidney function gradually deteriorated and hemodialysis was initiated in June 2013. During pretransplant evaluation, she had heavy proteinuria despite a reduction of her urine output, and bilateral native nephrectomies were performed before transplant.
According to the protocol in our center, she received 2 plasma exchange treatments (3 and 2 days before transplant) and 1 dose of rituximab (375 mg/m2) on the day of transplant as prophylaxis against FSGS recurrence. She received a living-related kidney transplant (from her father) in November 2013 (day 0). The intraoperative course was uncomplicated. She received standard immunosuppressive therapy that included basiliximab, corticosteroids, MMF, and cyclosporine. The lowest creatinine level was observed on posttransplant day 5 (67 μmol/L) (Figure 1).
On posttransplant day 2, the urine dipstick started to show proteinuria. On day 6, her 24-hour proteinuria was 8.9 g, with normal serum albumin and cholesterol. A diagnosis of FSGS recurrence was made and she was started on daily plasmapheresis (1.5 × plasma volume exchange, 30% albumin, and 70% plasma) on days 6 to 8. A sudden marked rise in serum creatinine was noted on days 7 to 9 with no obvious reason; she had no hypotension, no high cyclosporine level, and negative urine culture. She underwent kidney biopsy (day 9) that was complicated by kidney bleeding; surgical exploration showed a spurting artery on the lower pole, and the artery was sutured and the bleeding controlled. She received 3 methylprednisone pulses (10 mg/kg) and plasma exchange was held. Her creatinine peak was 451 μmol/L (day 13), and she required 1 session of hemodialysis, primarily to treat fluid overload. Graft Doppler ultrasonography was unremarkable. Nuclear renal scan was suggestive of acute tubular necrosis. Graft biopsy revealed evidence of acute tubular necrosis and mild interstitial fibrosis < 10%. There was no evidence of T-cell or antibody-mediated rejection or FSGS recurrence on light microscopy examination, and electron microscopy was not performed. Her proteinuria dropped markedly with kidney function impairment (minimum, 2 g/d on day 14) (Figure 1). The second dose of rituximab (375 mg/m2) was given on day 10 and an intensive treatment course of almost-daily plasma exchange was resumed (11 sessions in 12 days [day 14-25], followed by 3 sessions/wk for 2 wk). Her B-cell suppression following rituximab was confirmed with CD19 level 0 cells/μL.
The proteinuria started to worsen as the renal function improved, and it reached a plateau at 3 to 3.5 g/d. A decision was made to attempt abatacept. She was given 2 doses of abatacept (10 mg/kg), 2 weeks apart (day 24 and 38), and plasma exchange treatment was held on day 38 after the second dose of abatacept. Within several days of the second abatacept dose and holding plasmapheresis, the proteinuria started to rise (5.1 g/d on day 41 and 6.9 g/d on day 48). Another course of intensive plasma exchange (12 sessions in 14 days) was started on day 54, followed with twice-weekly maintenance treatment. A third dose of abatacept was given on day 66, which was 4 weeks after the second dose. Her proteinuria remained at 6.2 to 7.4 g/d. The ACE-I or ARB treatment could not be added because of refractory hyperkalemia.
Patients with primary genetic-negative FSGS are at risk of recurrence after transplant.4 Different therapies have been tried and variable results have been reported to date. Recently, a promising drug (abatacept) was shown to be effective in treating FSGS recurrence in 4 kidney transplant recipients with only 1 or 2 doses.11 The present patient was an NPHS2-negative FSGS patient of unknown B7-1 staining status who had recurrence after kidney transplant and failed to show a short-term positive response to different FSGS treatments including abatacept.
In a previous study, 2 of 4 patients were children, were female, and received grafts from living-related donors.11 The immunosuppressive agents for all patients were daclizumab and/or antithymocyte globulin, tacrolimus, MMF, and glucocorticoids. All patients received 1 dose of rituximab (375 mg/m2) and plasmapheresis before abatacept treatment. In that study, 2 patients received a single abatacept dose and 2 patients each received 2 doses. All patients had proteinuria < 0.51 g/g (range, 0.05-0.5 g/g) at long-term follow-up (10-48 mo).11 Therefore, our patient was not markedly different than some of the previously reported patients in age, sex, immuno-suppressive therapy, and FSGS treatment except that the B7-1 status was unknown.11
In another study, Benigni and colleagues showed no B7-1 signal in recurrent FSGS patients and positive B7-1 staining in membranous nephropathy patients.12 In addition, Alachkar and colleagues reported 5 recurrent FSGS patients with positive B7-1 staining but negative response to B7-1 blockers.13 However, the authors of the primary abatacept paper stated that Benigni and colleagues did not have a positive control to compare to their B7-1-negative staining in recurrent FSGS patients.14 In addition, they refuted the conclusion of Alachkar and colleagues with several criticisms.14 First, B7-1 staining in the absence of a control was ambiguous. Second, the first 3 patients seemed to have secondary FSGS. Third, the underlying diagnoses for native kidneys were unknown in patient 1 and lupus nephritis in patient 2. Fourth, patients 2 and 3 had nonnephrotic-range proteinuria at the time of diagnosis. Finally, and most importantly, patients 2 through 5 received belatacept, which has a different treatment protocol and marked affinity to B7-2.14
Although we initially believed that primary FSGS could be treated easily with the new treatment abatacept, our result was disappointing. A possible explanation for this negative result is that not all patients with primary FSGS may have positive B7-1 staining. Although all 5 patients in the study by Yu and coworkers had positive B7-1 staining the study had few patients, and larger cohorts are required to confirm this finding.11 We did not test our patient for B7-1 staining. Further cases and studies are needed to approve or disapprove the use of abatacept in treating FSGS recurrence and to determine whether the effectiveness of abatacept is only applicable to B7-1-positive immunostaining patients.
Volume : 14
Issue : 4
Pages : 456 - 459
DOI : 10.6002/ect.2014.0154
From the 1Division of Pediatric Nephrology, Mubarak Al-Kabeer
Hospital; and the 2Division of Nephrology, Hamid Al-Essa Organ
Transplant Center, Sabah Health Region, Shuwaikh, Kuwait
Acknowledgements: The authors have no conflicts of interest to disclose. We thank our patient and her parents for consent for publication of this case report and Glenda MacFarlane for proofreading the manuscript.
Corresponding author: Omar Alkandari, Mubarak Al-Kabeer Hospital, Division of Pediatric Nephrology, Ward 6, Al-Jabriya, Block 4, Street 103, Kuwait
Phone: +965 2531 2700 (ext 2618)
Fax: +965 2532 0319
Figure 1. Serum Creatinine Level, Proteinuria, and Treatment of Focal Segmental Glomerulosclerosis After Renal Transplant