Primary focal segmental glomerulosclerosis recurrence occurs in 10% to 50% of recipients after kidney transplant and may affect both children and adults. Treatment after recurrence with plasma exchange and immunosuppression is quite variable and challenging, and those who do not respond usually progress to allograft failure. Podocyte injury and B7-1 expression and subsequently its blockade (abatacept) have been reported to be associated with complete remission of proteinuria in 4 patients with focal segmental glomerulosclerosis recurrence after kidney trans-plantation and in 1 patient with focal segmental glomerulosclerosis in native kidney. Here, we report our experience of successfully treating 3 consecutive patients with focal segmental glomerulosclerosis recurrence after kidney transplant with abatacept, which induced proteinuria remission.
Key words : End-stage renal disease, Plasma exchange, Renal transplantation
Patients with primary focal segmental glomerulo-sclerosis (FSGS) frequently present with nephrotic-range proteinuria, which portends a poor prognosis; approximately 50% progress to end-stage renal disease (ESRD) over 3 to 8 years.1 After kidney transplant, the recurrence rate is high, with up to 10% to 50% of patients presenting with primary FSGS.2-4 Recurrence of FSGS negatively impacts allograft survival; graft survival is around 50% in patients with FSGS recurrence and is significantly worse than in patients without recurrence.2,3
The pathogenesis of FSGS is not well understood and is thought to be due to the existence of 1 or more circulating factors that target podocytes.5 Despite advancements in science and improved therapies, treatment of primary FSGS and recurrent FSGS after kidney transplant with plasma exchange (PE), calcineurin inhibitor, and rituximab is often unsuccessful.3,4,6 Yu and associates7 used abatacept (CTLA-4-Ig), an inhibitor of the T-cell costimulatory molecule B7-1 (CD80), in 4 patients with recurrent FSGS after kidney transplant who were resistant to rituximab treatment and in 1 patient with steroid-resistant primary FSGS in the native kidney. All 5 patients achieved either complete or nearly complete remission with abatacept treatment. Here, we present 3 consecutive cases of FSGS recurrence after kidney transplant who were successfully treated with abatacept (Table 1).
A 48-year-old female patient developed ESRD secondary to collapsing FSGS 6 years after donating a kidney to her sister. She underwent nonrelated living-donor kidney transplant in Egypt, which failed immediately due to severe antibody-mediated rejection. She received a second living-donor kidney transplant from her son with 4/8 mismatches and negative flow cytometry crossmatch. She was induced with 3 doses of thymoglobulin at 1.5 mg/kg. Day one after kidney transplant, she underwent a biopsy as she became anuric; biopsy showed diffuse foot process effacement on electron microscopy. She was commenced on hemodialysis and PE, and tacrolimus was switched to cyclosporine. On day 12, she received 500 mg of rituximab infusion. After 10 sessions of PE, at 3 weeks after FSGS recurrence, she remained dialysis dependent.
The patient was then treated with abatacept (10 mg/kg body weight), with 2 doses 2 weeks apart. Her urine output gradually improved, and she came off hemodialysis 1 week after receiving a first dose of abatacept. Plasma exchange sessions were gradually tapered and then stopped completely after a total of 40 sessions once she had achieved complete remission (24 h urine protein < 300 mg/d). Her latest serum creatinine at 8 months posttransplant was 122 μmol/L.
A 22-year-old male patient was diagnosed with primary FSGS on kidney biopsy. He eventually reached ESRD 2 years later despite treatment with steroids and tacrolimus. He was commenced on hemodialysis; 3 years later, he received a full-match but ABO-incompatible (B to A) kidney transplant. He received 1 dose of 500 mg rituximab and 3 sessions of PE prior to kidney transplant. He was induced with 3 doses of thymoglobulin at 1.5 mg/kg. Graft function was successful for the first 2 days; however, his urine output then dropped significantly with a decline in graft function and development of nephrotic-range proteinuria. His ABO isotiter levels remained suppressed below 1:8 for immunoglobulin G and immunoglobulin M. A biopsy was performed, which showed diffuse foot process effacement on electron microscopy. He was started on hemodialysis and PE on day 4 posttransplant.
He was given abatacept 10 mg/kg body weight on day 10 posttransplant and a second dose 2 weeks later. Hemodialysis was discontinued 2 weeks after the patient received the first dose of abatacept. He continued PE until he achieved complete remission of proteinuria. In total, he received 34 sessions of PE. His 12-month follow-up showed serum creatinine and urine albumin-creatinine ratio (UACR) of 110 μmol/L and 2.3 mg/mmol, respectively.
A 51-year-old female patient reached ESRD secondary to primary FSGS 25 years after development of subnephrotic-range proteinuria during her pregnancy. She underwent living-donor kidney transplant as a part of a paired kidney donation, receiving a kidney with 3/8 mismatches, no donor-specific antibodies, and a negative flow cytometry crossmatch. She was induced with thymoglobulin. Her postoperative course was uncomplicated, achieving serum creatinine level of 93 μmol/L. Three months posttransplant, her serum creatinine went up to 170 μmol/L, and she develo-ped nephrotic-range proteinuria of 12 g/day. Allograft biopsy was performed, which showed diffuse foot process effacement on electron microscopy. She was commenced on PE, and, after 7 sessions of PE, she developed severe pancytopenia that persisted for several weeks. Bone marrow biopsy was performed, which showed slightly hypocellular marrow but was otherwise normal. Parvovirus, IgM, cytomegalovirus, and Epstein-Barr virus polymerase chain reaction results were negative. Her pancytopenia improved gradually, and serum creatinine decreased to 151 μmol/L and UACR to 70 mg/mmol. One month later, the patient was readmitted with rising proteinuria (UACR of 398.4 μmol/L).
She was treated with 2 doses of abatacept 10 mg/kg body weight 2 weeks apart. She did not receive rituximab during any stage after recurrence of FSGS. Her condition started to improve along with allograft function and reduction of proteinuria. At 9-month follow-up, serum creatinine and UACR levels in the patient were 142 μmol/L and 4.4 mg/mmol, respectively.
In this case series, we observed that abatacept treatment was effective at treating FSGS recurrence after kidney transplant, achieving complete remission. Two patients developed FSGS recurrence within the first 3 days and 1 after 2 months posttransplant. The rational of using abatacept in these patients was based on almost complete remission of FSGS recurrence in a previous study.7
Standard treatment, including use of high-dose cyclosporine, PE, and rituximab, is based on small case series with variable responses.4,8 Patients who respond poorly to the treatment often progress to graft failure. All of our patients were started immediately on PE after FSGS recurrence and received on average 27 sessions (range, 7-40). One patient received rituximab after recurrence, the second received it before kidney transplant as a part of ABO-incompatible desensitization, hence treatment was not repeated after recurrence, and the third did not receive it as she had severe pancytopenia. Two patients were switched from tacrolimus to cyclosporine as they developed recurrence in the first 3 days; for the third patient, who developed recurrence 2 month post-transplant, we decided to continue with tacrolimus. Plasma exchange was stopped once the patient achieved complete remission of proteinuria.
Podocyte injury is the hallmark association in patients with nephrotic syndrome, and B7-1 expression has been found to be induced in certain proteinuric kidney diseases, including primary FSGS.7 B7-1 immunostaining of podocytes has been shown to be negative in most patients with secondary FSGS and in allograft specimens of all other patients. This indicates that inhibition of B7-1 (abatacept) would lead to reversal of podocyte injury and improvement in proteinuria. Because of early posttransplant recurrence of FSGS in 2 of our patients, suggesting the aggressive nature of the condition, we decided to institute abatacept early in the course of the treatment paradigm.
In contrast, Delville and associates9 did not find B7-1 expression in his series of patients with recurrent FSGS after kidney transplant. In addition, B7-1 blockade did not induce proteinuria remission.9 B7-1 podocyte staining was not performed in our patients’ biopsy specimens; therefore, it is unknown whether the complete response to treatment in our patients was mainly due to abatacept therapy.
Data on abatacept use are based on small case series; therefore, additional confirmation in a prospective trial to study the role of B7-1 in FSGS is required.
Volume : 17
Issue : 1
Pages : 178 - 180
DOI : 10.6002/ect.MESOT2018.P53
From the Department of Adult Kidney and Pancreas Transplantation, King Faisal
Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Yaser Shah, Department of Adult Kidney and Pancreas Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, PO Box: 3354, Saudi Arabia
Phone: +966 11 4647272
Table 1. Study Patients With Recurrent Focal Segmental Glomerulosclerosis After Kidney Transplant