Abstract

Key words : FSGS recurrence, Kidney transplantation, Pediatric patients, Plasma exchange, Rituximab

Introduction

Focal segmental glomerulosclerosis (FSGS) is a histological injury involving podocytes and causing complex damage to glomerular capillaries.^1,2 Primary FSGS is rare and has a high incidence of progression to end-stage renal disease (ESRD) and higher risk of recurrence after renal transplant than secondary forms.³ Primary FSGS recurs in 15% to 52% of first transplants and up to 85% of retransplants.^4-10 Recurrence rate is 30% to 60% in children.^6,11 These patients are at risk of delayed graft function and graft loss, approaching 30% to 50% at 5 years posttransplant.^12,13 Risk of recurrence has been associated with younger age at diagnosis of FSGS and renal transplant, rapid progression to ESRD in the native kidneys, and previous graft loss due to FSGS.^5,10 Other reported risk factors are white ethnicity, graft from a living donor, and native kidney nephrectomy, but these are still debatable. Duration of dialysis and immunosuppressive treatment do not seem to affect risk of recurrence.^4,6

The rapid recurrence of proteinuria after transplant supports the view that causative factors responsible for inducing podocyte injury and glomerular permeability are present in the circulation, including soluble urokinase plasminogen activator receptors and/or antibodies binding the CD40 molecule.^14-16 Based on this, therapeutic plasma exchange (PE) or immunoadsorption is used for treatment of recurrence to remove these factors from the circulation. Although several therapies have been described, most centers use therapeutic PE or immunoadsorption, alone or in combination with rituximab. Other treatment options are not routinely used, and there is no consensus on optimal treatment of FSGS recurrence.^4,11,17 Here, we investigated the recurrence rates, recurrence risk factors, management strategies, and long-term graft function in pediatric renal transplant recipients at our center with FSGS as primary disease.

Materials and Methods

We retrospectively evaluated the medical records of 34 pediatric renal transplant recipients (male-to-female ratio of 19:15) who had been diagnosed with FSGS by biopsy of native kidney and who had undergone renal transplant between January 2004 and December 2019 at our center. Patients with familial or secondary FSGS were excluded. All patients had a minimum follow-up time of 1 year posttransplant. Demographic data, donor type, immunosuppressive medications, laboratory findings, rejection episodes, recurrence, graft loss, and survival data were analyzed from patient medical records.

Recurrence of FSGS after renal transplant was defined as the presence of hypoalbuminemia (albumin <2.5 g/dL) and edema with nephrotic proteinuria. Nephrotic proteinuria was defined according to the criteria of the International Study for Kidney Disease in Children as 40 mg/m² per hour, measured by 24-hour urine collection or urinary protein-to-creatinine ratio (UPCR) >2.¹⁸ Recurrence of FSGS was confirmed with graft biopsy. At the time of recurrence, graft biopsies were used to rule out acute tubular necrosis, acute rejection, toxicity, and infection. After transplant, urine protein excretion was measured daily for the first 2 weeks, weekly for the next month, every 2 weeks for 1 month more, monthly until 1 year had passed, and thereafter every 3 months. Delayed graft function was defined as dialysis requirement within 1 week after transplant.¹⁹

All patients received an anti-CD25 monoclonal antibody (basiliximab) as induction immunosuppression, as well as 30 mg/kg methylprednisolone to a maximum dose of 1 g as induction therapy. Maintenance immunosuppression consisted of a calcineurin inhibitor, mycophenolate mofetil/mycophenolate sodium, and prednisolone with a gradually tapering maintenance dose. All patients received trimethoprim and sulfamethoxazole prophylaxis against Pneumocystis carinii pneumonia for 6 months and valganciclovir prophylaxis against cytomegalovirus for 3 months.

In accordance with our center’s prophylactic PE protocol, all recipients of living donor allografts underwent PE for 3 consecutive days in the preoperative period. Recipients of deceased donor allografts underwent 1 session of prophylactic PE immediately before transplant. After transplant, patients received 3 daily sessions of PE. Plasma exchange was discontinued when albumin reached <0.5 g/24 hours. At follow-up, when a patient was diagnosed with recurrence, we started therapeutic PE as soon as possible. Plasma exchange was applied for 3 consecutive days followed by 3 sessions per week for the next 3 weeks; treatment was then individualized based on patient response. Rituximab was added for patients who did not respond to PE.

Complete remission was defined as reduction of proteinuria, with UPCR <0.2 or <0.5. Partial remission was defined as UPCR of 0.2 to 2 or need for PE to maintain UPCR <0.2. A failure was defined as persistent UPCR >2 in spot urine or 40 mg/m2 per hour in 24-hour urine collection. Patients with partial remission received a prolonged course of PE during the postoperative period. Treatment was individualized on the basis of each patient’s response and outcome. Patients with graft failure also received rituximab once per week for a maximum of 4 courses, with doses of 375 mg/m² each. When combined with PE, rituximab was administered after a session and 24 to 48 hours before the next one, in order to minimize drug removal during the exchange. No additional doses were necessary.

Statistical analyses
Statistical analysis was performed with SPSS for Windows 22.0 (IBM). Categorical variables are expressed as frequencies (percents), and numerical data for normally distributed data are expressed as means ± standard deviation; abnormally distributed data are shown as medians (interquartile range [IQR]). Differences were analyzed using chi-square and the Fisher exact tests. We used t tests for normally distributed data and Mann-Whitney U tests for abnormally distributed data. P < .05 was considered statistically significant.

Results

Thirty-four patients with primary FSGS who had undergone renal transplant at our center from 2004 to 2019 were included in our analyses. The male-to-female ratio was 19:15. Mean age at transplant was 12.72 ± 5.46 years. Mean duration of dialysis before transplant was 2.29 ± 1.35 years. In our patient group, 29 received living-related donor allografts (85.3%) and 5 received allografts from deceased donors (14.7%). Mean follow-up after transplant was 8.87 ± 4.08 years. Fourteen recipients (41.2%) had proteinuria (UPCR >0.2) after transplant, and 5 recipients (14.7%) had UPCR >2, with FSGS recurrence confirmed with graft biopsy. All recurrences were observed early, in the first 3 months, with median time to recurrence of 25 days (range, 3-62 days) (Table 1).

When patients with and without recurrence were compared in terms of age, sex, and donor type, there were no significant differences between groups. Time from FSGS diagnosis to ESRD and duration of dialysis were shorter in the recurrence group than in the nonrecurrence group (48.4 months [IQR, 2-90 mo] vs 65.1 months [IQR, 8-123 mo] and 1.41 ± 0.82 vs 3.18 ± 1.88 years, respectively; P < .05). All patients were first transplant recipients, and there was no delayed graft function in the recurrence group. At year 3, glomerular filtration rate was lower in the recurrence group (61.65 ± 15.47 vs 105.60 ± 45.19 mL/min/1.73m2, P < .05). Graft failure was observed in 1 patient (20%) due to FSGS recurrence in the recurrence group; in the nonrecurrence group, graft failure was observed in 1 patient (3.4%) due to acute rejection (P < .05, Table 2).

Table 3 shows the treatment and outcomes of patients with recurrence. All 5 patients in this group were treated with an additional course of PE. Four patients were in partial remission and had addition of rituximab. One of these responded with partial remission (25%), and 3 had complete remission (75%). The patient whose proteinuria decreased with PE did not receive rituximab, but recurrence and graft loss developed after 3 months (20%). The patient who had graft loss received a second allograft from a living donor after 3 years. He received prophylactic and therapeutic PE with rituximab, and now has no proteinuria and a functional graft. All patients tolerated the PE treatment without complications. We also did not observe any complications related to rituximab treatment.

Discussion

In pediatric and/or adult patients, the reported incidence of FSGS recurrence ranges from 25% to 56%.^4,6-8,20 The incidence of FSGS recurrence in pediatric renal transplant recipients has been reported to be similar to that shown in adults, although at a slightly higher frequency of 45% to 60%.^6,21,22 In our study of pediatric renal transplant recipients with primary FSGS, the rate of FSGS recurrence was 14.7%. However, data compiled by the United Network for Organ Sharing over the same period showed an increase in cases of recurrent FSGS of 5.8% per year.²³ In our study, our rate of recurrence was lower; although this may be due to the small number of patients in our study, it may also be related to our use of prophylactic PE.

We observed that glomerular filtration rate was lower at the third year in patients in the recurrence group, with graft failure observed in 1 patient (20%) due to FSGS recurrence. Other reports have shown that 30% to 50% of recipients with recurrent FSGS lose their graft within 5 to 7 years.^5,7,10,13,24 Although there was no statistically significant difference in transplant age in our study, we observed that patients with recurrence were younger at the time of transplant. Patients with recurrence had more rapid progression to ESRD after FSGS diagnosis. It has been reported that younger age at transplant recipient and shorter course from primary disease diagnosis to ESRD were associated with increased rate of FSGS recurrence.^4-6,20,23,25 Although increased incidence of recurrence in female patients has been reported,²¹ we did not find any difference in terms of sex.

Another risk factor that has been described is living donors,^14,26 although some recent studies have shown that donor type is not important in terms of recurrence risk.^20,23 Similarly, we did not observe any differences in donor type between patients with and without recurrence. The other important risk factor is loss of previous grafts due to FSGS and delayed graft function.^5-7,24 Graft failure from recurrent FSGS was reported to be more common among pediatric renal transplant recipients with delayed graft function.⁶ In our study, all patients were recipients of first transplants, and there was no delayed graft function in the recurrence group; thus, the 2 groups could not be compared in this respect. One of the patients who had graft failure 3 months after his first transplant received a second allograft from a living donor 3 years after graft loss and now has a functional graft.

Management of patients with recurrent FSGS is difficult and controversial, and the absence of formal, standardized guidelines on the treatment of recurrent FSGS has led to continued research. Plasma exchange appears to be moderately effective as prophylaxis for FSGS recurrence before renal transplant and as treatment of recurrence after renal transplant, with a response rate of approximately 60%.^21,25 In a study that reported the use of prophylactic exchange in children with primary FSGS, favorable results were observed, with 33% recurrence in patients who had received prophylaxis versus 67% in those who had not received prophylaxis.²⁷ However, several studies have not found favorable results with prophylactic PE.^28,29 We applied prophylactic PE as per our center’s protocol, and FSGS recurrence was 14.7%, with PE then used as the main treatment for FSGS recurrence. Only 1 patient (20%) among those with recurrence in our study had graft failure; this patient did not receive additional immunosuppressive drugs due to his decreased proteinuria after PE. The need for administration of additional treatment modalities to achieve remission or to significantly decrease proteinuria is apparent. Rituximab is the most frequently used immunosuppressive agent in addition to PE. Bayrakci and colleagues reported a case with recurrent FSGS early after kidney transplant who had no response to PE and then was successfully treated with rituximab.³⁰

Various studies have assessed the efficacy of rituximab for recurrent FSGS. Reports have shown that the response rate with rituximab can range from 58% to 79%.^28,31,32 Other treatment options, such as abatacept or adrenocorticotropic hormone, have also been used, but their effects on remission are not clear.^20,33-35 In our study, 4 of 5 patients with recurrent FSGS also received rituximab. The patient who did not receive rituximab had graft failure during follow-up. Of the 4 patients who received rituximab, 1 had a partial response and 3 had complete remission. However, studies have reported failed responses to rituximab.^36-39 In a multicenter international cohort study, PE with or without rituximab was associated with complete remission in 21%, partial remission in 36%, and no response in 43%. Recently, a single-center study on PE with rituximab reported complete remission in 27%, partial remission in 42%, and no response in 31% of patients.²⁰ Of note, we had a small number of patients with recurrence who received PE and rituximab; however, our results were better than previous studies, with 75% having complete remission and 25% having partial remission. An additional concern with the use of rituximab is its side effects. We did not observe any complications related to rituximab treatment.

Our study has limitations. It had a retrospective design and sample small size. Plasma exchange and rituximab administration levels were not standard, randomized, adjusted for each patient, or individualized according to patient response. Therefore, it is difficult to evaluate treatment efficacy. However, as the number of reported cases increases and with the conduct of larger multicenter prospective studies, treatment protocols can be established for recurrent FSGS.

Conclusions

Prophylactic PE and the use of a combined PE-rituximab regimen for FSGS recurrence treatment resulted in low recurrence and good remission rates. Although studies have recommended concomitant use of PE and rituximab at varying doses and times, there is no official standardized guideline for recurrent FSGS. Moreover, new therapies are being tested. Larger multicenter prospective studies are required to determine recurrence risk factors and to evaluate the outcomes of treatment.

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