There were 14 patients enrolled in the present study, including eight patients of SD/FR and six patients of SRNS. The demographic and clinical data of them are shown in Table 1.
All patients were over 15 years old with an average age of 31.1 ± 17.6 years. Before enrollment they had undergone the disease for 5 (2.0-11.0) years. Six patients with MCD received repeat kidney biopsy before rituximab administration, with three patients changed the diagnosis into primary FSGS and three patients remained the initial diagnoses. Thus, of the eight SD/FR patients, six patients were MCD and two patients were primary FSGS, with one of not otherwise specified (NOS) variant and one of tip variant. All the six SR patients were diagnosed as primary FSGS NOS variant.
All patients received previous steroids and immunosuppressive therapies, including the combination of steroids and tacrolimus in ten patients, cyclosporine in eight patients, cyclophosphamide in six patients, mycophenolate mofetil in eight patients, leflunomide in ten patients and azathioprine in three patients.
All the eight SD/FR patients underwent more than three times of relapse with the average of 9 (6-12) times. They all achieved complete remission by steroids and immunosuppressive drugs at the time of rituximab infusion, with six patients receiving prednisolone alone (32.5 ± 14.4 mg/d; range 15-55 mg/d), one patient receiving cyclosporin, and one patient receiving prednisolone combined with tacrolimus. Before rituximab treatment, they had received steroids for 10.5 (4.5-11.0) years with a cumulative dose of 49.1 ± 20.6 g.
All the six SR patients never responded to any regimens and presented with nephrotic syndrome at the time of rituximab infusion. By the time of enrollment, the average level of urinary protein was 15.7 ± 6.0 g/d, serum albumin was 17.8 ± 1.4 g/L, serum creatinine was 196.1 ± 86.4 μmol/L and eGFR was 45.8 ± 33.3 ml/min/1.73m2. The immunosuppressive drugs were stopped at least three months before rituximab administration, while prednisolone was continued (21.7 ± 15.1 mg/d; range 5-50 mg/day). Before rituximab treatment, they had received steroids of 2.0 (1.0-6.5) years and 25.3 ± 29.6 g.
All the 14 patients received B-cell-oriented rituximab administration, with each single dose of 375 mg/m2 adjusted according to eGFR. The amount of B cells was examined every one month. If it is over 5 cells/mm3, rituximab was prescribed with one single dose of 375 mg/m2. During the follow-up period of 15.0 (8.8-18.0) months, four patients received two infusions with the total dose of 975 ± 263 mg, two patients received three infusions with the total dose of 1600 ± 141 mg, seven patients received four infusions with the total dose of 2229 ± 605 mg, and one patient received five infusions with the total dose of 2900 mg. The total dose of rituximab was comparable between the SD/FR patients and the SR patients (1812.5 ± 780.9 vs. 1850.0 ± 828.9 mg, P=0.845). (Table 2).
All the eight SD/FR patients maintained complete remission. No relapse was observed in the follow-up period of 15.0 (8.8-18.0) months. Among them, six patients (5 MCD, 1 FSGS NOS) gradually withdrew and stopped steroid from 25.0 (11.3-36.3) mg/d in 10 (2.3-12.3) months. Four of them stopped both steroids and immunosuppressants treatments, one patient continued cyclosporin treatment and one patient continued tacrolimus treatment. The other two patients (1 MCD, 1 FSGS Tip) maintained steroid treatment, while the dose was decreased from 20 mg/d and 55 mg/d to 10 mg/d and 20 mg/d, respectively.
The six SR patients all showed no response to rituximab treatment and presented with severe nephrotic syndrome during the whole period of follow-up. Only one patient showed improvement of proteinuria, with the level of urinary protein decreased from 11.6 g/d to 6.1 g/d and the serum albumin increased from 17.6 g/L to 25.5 g/L, not achieving partial remission.
During the follow-up period of 15.0 (8.8-18.0) months, all the eight SD/FR patients remained stable kidney function with eGFR 107.4 ± 27.4 ml/min/1.73m2 at the time of rituximab treatment and eGFR 111.0 ± 31.5 ml/min/1.73m2 at the end of follow-up (P=0.600).
Of the six SR patients, one patient who got improvement of proteinuria also got improvement of kidney function, with the serum creatinine decreased from 212 μmol/L (eGFR 26.6 ml/min/1.73m2) to 123 μmol/L (eGFR 51.2 ml/min/1.73m2). The other five patients showed kidney function deterioration with the serum creatinine increased from 192.8 ± 96.1 μmol/L to 515.8 ± 303.1 μmol/L (P=0.047) and eGFR decreased from 49.6 ± 35.7 ml/min/1.73m2 to 15.9 ± 11.5 ml/min/1.73m2 (P=0.047). Three of them went into ESRD.
Rituximab was well tolerated and no adverse event was observed at the time of infusion. During follow-up, there was one SR patient once suffering from pneumonia and acute kidney injury at two months after the second dose of rituximab. At that time, the amounts of B cells and CD4+ T cells were 4.1/mm3 and 623.4/mm3, respectively. Her serum creatinine increased from 212 μmol/L to 390 μmol/L. All the etiological examinations were negative. The infection was successfully and empirically treated with moxifloxacin, sulperazone, oseltamivir, SMZCo and meropenem. Then the serum creatinine decreased to 123 μmol/L. No other severe adverse event was observed in other patients. No patient developed neutropenia, pneumocystis infection or cardiac arrhythm.