Treatment by immunoadsorption for recurrent focal segmental glomerulosclerosis after paediatric kidney transplantation: a multicentre French cohort

Treatment by immunoadsorption for recurrent focal segmental glomerulosclerosis after paediatric... ABSTRACT Background Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation (KTx) in children. This can lead to delayed graft loss. As the management of children with recurrent FSGS is not well established, apheresis strategies could be a cornerstone to control the disease. Immunoadsorption (IA) is a recent apheresis therapy. There have been few studies examining IA in this setting. We report the results of IA for management of recurrent FSGS after KTx in children in France. Methods We included all children treated with IA for early FSGS recurrence after KTx between January 2011 and June 2014 in France. We excluded genetic forms of FSGS. Patients’ characteristics and technical data on IA were retrospectively collected. Recurrence was defined as nephrotic proteinuria during the post-transplantation period. Partial and complete remissions were defined when urine protein:creatinine ratios were less than 0.2 and 0.05 g/mmol, respectively. Results Twelve patients, from six paediatric KTx units, presenting with FSGS recurrence between 0 and 21 days after KTx were treated with IA. Ten of 12 children were responders: 2 achieved partial remission and 8 complete remission. The decrease of proteinuria rapidly occurred within the first 10 sessions after initiating IA. After 3 months of IA, two patients maintained remission without IA and eight became IA dependent. No severe side effects were reported. Conclusions Our study reports on the efficacy of IA in the recurrence of FSGS after KTx in children. Further prospective controlled studies are required to confirm these results and to optimize the management of FSGS recurrence after paediatric KTx. focal segmental glomerulosclerosis, immunoadsorption, kidney transplantation, nephrotic syndrome INTRODUCTION Primary focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder in children, revealed by oedema and nephrotic proteinuria. Some children, despite steroids and immunosuppressive therapies, continue to have nephrotic proteinuria and progress to end-stage renal failure (ESRF). Approximately 30% of these patients experience a recurrence of FSGS within the first few days after kidney transplantation (KTx), leading to graft loss in half of these cases [1, 2]. The highest risk of disease recurrence is observed in patients who rapidly progressed to ESRF and in patients who lost their first graft due to FSGS recurrence [3, 4]. The management of patients with FSGS recurrence after KTx is challenging and is not well defined due to a lack of controlled studies. Most paediatric centres treat recurrent FSGS with intensification of immunosuppression such as pulse steroids, high-dose cyclosporine A (CsA), cyclophosphamide in combination with apheresis therapy and, more recently, rituximab [5–8]. Two reviews summarize these therapeutic options based on results from small series [4, 9, 10]. Both therapeutic plasma exchange (TPE) and immunoadsorption (IA) have been evaluated with FSGS because a circulating permeability factor has been suggested to play a role in the pathogenesis of this disease [3]. Studies have demonstrated a partial efficacy of TPE in children with FSGS [2, 6, 11]. In 2013, the American Society for Apheresis (ASFA) recommended TPE in combination with increased immunosuppression to treat recurrent FSGS [12]. However, TPE induces a loss of coagulation factors responsible for side effects such as postoperative bleeding. In contrast to TPE, IA is a selective apheretic procedure. Dantal et al. [13] demonstrated a beneficial effect of IA therapy in adults with relapse of FSGS after KTx. Reports on the use of IA in children with recurrent FSGS after KTx are scarce. Paediatric cases published as case reports or in adult series also reported the efficacy of IA in all cases [14–18]. However, no paediatric cohort has yet been published. IA therapy has been available in French paediatric nephrology units since 2011. This study reports the French experience of IA for the management of paediatric recurrent FSGS after KTx. MATERIALS AND METHODS Patients We conducted a retrospective review across all French paediatric KTx centres to select patients with recurrent FSGS post-transplantation treated with IA. All children (ages 1-15 years) presented were histologically confirmed with primary FSGS resulting in ESRF. They underwent KTx at a paediatric age, i.e. <18 years of age. They were treated with IA between January 2011 and June 2014 for recurrence in the post-transplantation period. We excluded secondary FSGS, including genetic forms. Data related to patients’ characteristics, biological tests and therapeutic strategies were retrospectively reviewed. Data on the technical characteristics of IA sessions were also collected, including dates of sessions, volume of plasma processed and percent reduction of immunoglobulin G (IgG). The ethics committees of all participant institutions approved the collection and publication of the data for all patients presented. Definitions Recurrence was defined as the occurrence of nephrotic-range proteinuria after KTx [urine protein:creatinine (UPCR) ratio >0.2 g/mmol]. The primary outcome was UPCR, used to assess IA response. Partial remission was arbitrarily defined as a UPCR between 0.2 and 0.05 g/mmol. Complete remission was defined as a UPCR <0.05 g/mmol. Sustained complete remission was defined as complete remission being maintained without relapse after stopping apheresis at the time of data collection. The delay between the first IA session and remission was expressed in days and in the number of IA sessions. IA was classified as a failure when proteinuria was still nephrotic after 20 sessions of IA. Apheresis dependence was considered when patients required TPE or IA therapy 3 months after post-transplantation relapse to maintain UPCR between 0.2 and 0.05 g/mmol. Graft failure was defined as returning to renal replacement therapy. Technical characteristics of IA sessions IA procedures were performed either with a protein A column (Immunosorba, Art/Adasorb, Fresenius Medical Care) or with an IgG column (Therasorb, Ig flex, Life18, Miltenyi Biotec), according to the availability of machines in the different centres. Previous studies showed that both protein A and IgG columns were strongly effective in retaining Ig and in reducing albuminuria in FSGS [13]. IA therapy started intensively and was gradually discontinued, according to medical experiences and the availability of machines. Patients received intravenous Ig supplementation after each IA session to replace depleted antibodies. Depending on the centre, adsorbers were replaced either every 10 sessions as recommended by the manufacturer or if the reduction of IgG was <80% or in case of a technical problem. Data on IgG circulating levels were immediately collected before and after the IA session. Physicians defined the plasma volume processed per each session. Data were presented as mean ± SD or median (range). RESULTS Patients’ characteristics and pre-transplantation data Twelve patients from six French paediatric KTx units were included in the study. Clinical features at presentation and treatments of the 12 patients are displayed in Table 1. The median age at diagnosis of nephrotic syndrome was 4.8 years. The sex ratio was 1. All patients received oral steroids except one due to late discovery of the disease at chronic kidney disease stage 4 (Patient 1; Table 1). One of the cases was steroid-sensitive FSGS at onset and became secondarily resistant to steroids. All other patients were initially steroid resistant. All patients but one were treated with calcineurin inhibitors (CNIs). Two patients were treated with ineffective TPE. None of the cases were treated with IA before KTx. Whatever immunosuppressive treatments were provided, the patients progressed quickly to ESRF [median time to ESRF 2.2 years (range 0.8–7.2 years)]. All of them required dialysis before KTx. Table 1 Clinical characteristics and therapeutic strategies of patients before KTx Patient Gender Age at onset of disease (years) Steroids Other IS drugs Apheresis Time to ESDRa (years) Length of dialysis (years) Bilateral nephrectomy 1 F 9.5 Y CsA, cycloph TPE 0.8 1.9 Y 2 M 13.7 N – – 1.7 0.2 N 3 F 4.0 Y MMF – 7.2 1.9 Y 4 M 4.3 Y CsA, FK TPE 2.2 0.8 Y 5 F 5.1 Y MMF, CsA – 2.0 2.0 N 6 F 5.9 Y CsA – 2.4 3.5 Y 7 M 5.6 Y CsA, RTX – 3.3 0.4 Y 8 M 4.6 Y MMF, CsA, FK, cycloph – 1.3 1.9 N 9 F 3.0 Y MMF, CsA, RTX – 2.8 1.0 Y 10 F 13.7 Y MMF, CsA, FK – 1.5 0.9 Y 11 M 2.9 Y CsA – 4.2 1.0 Y 12 M 2.7 Y MMF, CsA, FK – 2.1 1.3 Y Median (range) 4.9 (2.7–13.7) 2.2 (0.8–7.2) 1.2 (0.2–3.5) Patient Gender Age at onset of disease (years) Steroids Other IS drugs Apheresis Time to ESDRa (years) Length of dialysis (years) Bilateral nephrectomy 1 F 9.5 Y CsA, cycloph TPE 0.8 1.9 Y 2 M 13.7 N – – 1.7 0.2 N 3 F 4.0 Y MMF – 7.2 1.9 Y 4 M 4.3 Y CsA, FK TPE 2.2 0.8 Y 5 F 5.1 Y MMF, CsA – 2.0 2.0 N 6 F 5.9 Y CsA – 2.4 3.5 Y 7 M 5.6 Y CsA, RTX – 3.3 0.4 Y 8 M 4.6 Y MMF, CsA, FK, cycloph – 1.3 1.9 N 9 F 3.0 Y MMF, CsA, RTX – 2.8 1.0 Y 10 F 13.7 Y MMF, CsA, FK – 1.5 0.9 Y 11 M 2.9 Y CsA – 4.2 1.0 Y 12 M 2.7 Y MMF, CsA, FK – 2.1 1.3 Y Median (range) 4.9 (2.7–13.7) 2.2 (0.8–7.2) 1.2 (0.2–3.5) a Denotes the interval from the onset of proteinuria to end-stage renal disease. IS, immunosuppressive; FK, tacrolimus; RTX, rituximab; cycloph, cyclophosphamide; ESRD, end-stage renal disease. Table 1 Clinical characteristics and therapeutic strategies of patients before KTx Patient Gender Age at onset of disease (years) Steroids Other IS drugs Apheresis Time to ESDRa (years) Length of dialysis (years) Bilateral nephrectomy 1 F 9.5 Y CsA, cycloph TPE 0.8 1.9 Y 2 M 13.7 N – – 1.7 0.2 N 3 F 4.0 Y MMF – 7.2 1.9 Y 4 M 4.3 Y CsA, FK TPE 2.2 0.8 Y 5 F 5.1 Y MMF, CsA – 2.0 2.0 N 6 F 5.9 Y CsA – 2.4 3.5 Y 7 M 5.6 Y CsA, RTX – 3.3 0.4 Y 8 M 4.6 Y MMF, CsA, FK, cycloph – 1.3 1.9 N 9 F 3.0 Y MMF, CsA, RTX – 2.8 1.0 Y 10 F 13.7 Y MMF, CsA, FK – 1.5 0.9 Y 11 M 2.9 Y CsA – 4.2 1.0 Y 12 M 2.7 Y MMF, CsA, FK – 2.1 1.3 Y Median (range) 4.9 (2.7–13.7) 2.2 (0.8–7.2) 1.2 (0.2–3.5) Patient Gender Age at onset of disease (years) Steroids Other IS drugs Apheresis Time to ESDRa (years) Length of dialysis (years) Bilateral nephrectomy 1 F 9.5 Y CsA, cycloph TPE 0.8 1.9 Y 2 M 13.7 N – – 1.7 0.2 N 3 F 4.0 Y MMF – 7.2 1.9 Y 4 M 4.3 Y CsA, FK TPE 2.2 0.8 Y 5 F 5.1 Y MMF, CsA – 2.0 2.0 N 6 F 5.9 Y CsA – 2.4 3.5 Y 7 M 5.6 Y CsA, RTX – 3.3 0.4 Y 8 M 4.6 Y MMF, CsA, FK, cycloph – 1.3 1.9 N 9 F 3.0 Y MMF, CsA, RTX – 2.8 1.0 Y 10 F 13.7 Y MMF, CsA, FK – 1.5 0.9 Y 11 M 2.9 Y CsA – 4.2 1.0 Y 12 M 2.7 Y MMF, CsA, FK – 2.1 1.3 Y Median (range) 4.9 (2.7–13.7) 2.2 (0.8–7.2) 1.2 (0.2–3.5) a Denotes the interval from the onset of proteinuria to end-stage renal disease. IS, immunosuppressive; FK, tacrolimus; RTX, rituximab; cycloph, cyclophosphamide; ESRD, end-stage renal disease. KTx data KTx occurred at a median age of 10.5 (range 6.1–16.0) years. It was the first renal graft for all cases except one, who received a second renal graft. All patients received a cadaveric renal transplant. The median cold ischaemic time was 16.8 (range 10.0–30.0) h. Five of 10 patients had pre-transplantation anti-human leucocyte antigen (HLA) antibodies. The median HLA mismatch score was 3 (range 0–4). Induction immunosuppressive therapy included basiliximab (n = 9) or antithymocyte globulin (n = 3), intravenous CsA (n = 6) or oral tacrolimus (n = 6), mycophenolate mofetil (MMF) (n = 10) or azathioprin (n = 2; patients 11 and 12) and steroids (n = 12). Because of a significant risk of recurrence, one patient received rituximab before KTx (Patient 1) and two patients had preventive apheresis therapy hours before KTx (IA: Patient 1; PE: Patient 4). All patients received sulfamethoxazole–trimethoprim as prophylaxis against Pneumocystis carinii. For cytomegalovirus or Epstein–Barr virus mismatch risk, the medical attitude was not homogeneous among centres: some patients received valganciclovir during 6 months, while the others had no prophylaxis but an intensive follow-up of viral loads. Recurrence of FSGS All patients experienced early FSGS recurrence, with a median time of 4.5 (range 0–21) days after KTx. The median peak UPCR before starting IA therapy was 1.2 (range 0.2–4.2) g/mmol and the median serum albumin was 28 (range 20–37) g/L. Renal graft biopsies, performed in four patients the day after the recurrence, were normal in two cases and showed borderline rejection in two cases. Management of recurrence of FSGS For all patients, the management of FSGS included increased immunosuppressive therapy, apheresis and the addition of anti-proteinuric drugs such as angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). The timing and management of recurrent FSGS are displayed in Table 2. Table 2 Timing and management of FSGS recurrence after KTx Patient Graft range Age at KTx (years) Recurrencea (days) UPCR at recurrence (g/mmol) CNIs RTX Other therapies before (b), during (d) and after (a) IA TPE before IA Delay between recurrence to first TPE (days) Delay between last TPE and first IA (days) Delay between recurrence and first IA (days) 1 First 12.2 0 1.83 FK Nb N 0 2 First 15.6 7 0.87 FK N N 0 3 First 13.2 21 1.34 FK Y N 1 4 First 7.3 18 0.56 IV CsA Y (b) bortezomib, saquinavir, etanercept, galactose; (a) galactose Y 1 1257 1644 5 Second 14.9 9 0.33 IV CsA Y (d) abatacept N 2 6 First 11.8 8 0.45 FK Y (d) levamisole, galactose; (a) abatacept N 4 7 First 9.3 8 1.08 IV CsA Y (a) saquinavir Y 2 4 342 8 First 7.8 2 1.61 IV CsA Y Y 2 4 226 9 First 6.8 2 1.31 IV CsA Y Y 10 7 399 10 First 16.0 2 0.20 IV CsA Y (d) cycloph Y 1 4 15 11 First 8.2 1 0.58 IV CsA Y Y 6 28 69 12 First 6.1 2 4.20 IV CsA Y N 1 Median (range) 10.6 (6.1–16.0) 5 (0–21) 0.98 (0.20–4.20) 10 (0–1644) Patient Graft range Age at KTx (years) Recurrencea (days) UPCR at recurrence (g/mmol) CNIs RTX Other therapies before (b), during (d) and after (a) IA TPE before IA Delay between recurrence to first TPE (days) Delay between last TPE and first IA (days) Delay between recurrence and first IA (days) 1 First 12.2 0 1.83 FK Nb N 0 2 First 15.6 7 0.87 FK N N 0 3 First 13.2 21 1.34 FK Y N 1 4 First 7.3 18 0.56 IV CsA Y (b) bortezomib, saquinavir, etanercept, galactose; (a) galactose Y 1 1257 1644 5 Second 14.9 9 0.33 IV CsA Y (d) abatacept N 2 6 First 11.8 8 0.45 FK Y (d) levamisole, galactose; (a) abatacept N 4 7 First 9.3 8 1.08 IV CsA Y (a) saquinavir Y 2 4 342 8 First 7.8 2 1.61 IV CsA Y Y 2 4 226 9 First 6.8 2 1.31 IV CsA Y Y 10 7 399 10 First 16.0 2 0.20 IV CsA Y (d) cycloph Y 1 4 15 11 First 8.2 1 0.58 IV CsA Y Y 6 28 69 12 First 6.1 2 4.20 IV CsA Y N 1 Median (range) 10.6 (6.1–16.0) 5 (0–21) 0.98 (0.20–4.20) 10 (0–1644) a Day of FSGS recurrence after KTx. b Patient 1 received RTX 1 month before KTx. IV, intravenous; FK, tacrolimus; RTX, rituximab; cycloph, cyclophosphamide. Table 2 Timing and management of FSGS recurrence after KTx Patient Graft range Age at KTx (years) Recurrencea (days) UPCR at recurrence (g/mmol) CNIs RTX Other therapies before (b), during (d) and after (a) IA TPE before IA Delay between recurrence to first TPE (days) Delay between last TPE and first IA (days) Delay between recurrence and first IA (days) 1 First 12.2 0 1.83 FK Nb N 0 2 First 15.6 7 0.87 FK N N 0 3 First 13.2 21 1.34 FK Y N 1 4 First 7.3 18 0.56 IV CsA Y (b) bortezomib, saquinavir, etanercept, galactose; (a) galactose Y 1 1257 1644 5 Second 14.9 9 0.33 IV CsA Y (d) abatacept N 2 6 First 11.8 8 0.45 FK Y (d) levamisole, galactose; (a) abatacept N 4 7 First 9.3 8 1.08 IV CsA Y (a) saquinavir Y 2 4 342 8 First 7.8 2 1.61 IV CsA Y Y 2 4 226 9 First 6.8 2 1.31 IV CsA Y Y 10 7 399 10 First 16.0 2 0.20 IV CsA Y (d) cycloph Y 1 4 15 11 First 8.2 1 0.58 IV CsA Y Y 6 28 69 12 First 6.1 2 4.20 IV CsA Y N 1 Median (range) 10.6 (6.1–16.0) 5 (0–21) 0.98 (0.20–4.20) 10 (0–1644) Patient Graft range Age at KTx (years) Recurrencea (days) UPCR at recurrence (g/mmol) CNIs RTX Other therapies before (b), during (d) and after (a) IA TPE before IA Delay between recurrence to first TPE (days) Delay between last TPE and first IA (days) Delay between recurrence and first IA (days) 1 First 12.2 0 1.83 FK Nb N 0 2 First 15.6 7 0.87 FK N N 0 3 First 13.2 21 1.34 FK Y N 1 4 First 7.3 18 0.56 IV CsA Y (b) bortezomib, saquinavir, etanercept, galactose; (a) galactose Y 1 1257 1644 5 Second 14.9 9 0.33 IV CsA Y (d) abatacept N 2 6 First 11.8 8 0.45 FK Y (d) levamisole, galactose; (a) abatacept N 4 7 First 9.3 8 1.08 IV CsA Y (a) saquinavir Y 2 4 342 8 First 7.8 2 1.61 IV CsA Y Y 2 4 226 9 First 6.8 2 1.31 IV CsA Y Y 10 7 399 10 First 16.0 2 0.20 IV CsA Y (d) cycloph Y 1 4 15 11 First 8.2 1 0.58 IV CsA Y Y 6 28 69 12 First 6.1 2 4.20 IV CsA Y N 1 Median (range) 10.6 (6.1–16.0) 5 (0–21) 0.98 (0.20–4.20) 10 (0–1644) a Day of FSGS recurrence after KTx. b Patient 1 received RTX 1 month before KTx. IV, intravenous; FK, tacrolimus; RTX, rituximab; cycloph, cyclophosphamide. Immunosuppressive drugs All patients had already received steroids as induction immunosuppressive therapy either as a pulse of methylprednisolone or as a high dose of oral prednisone. The scheme of CNI therapy was changed in three cases: from tacrolimus to intravenous CsA (n = 2) and from CsA to tacrolimus (n = 1). For five patients, target levels of CNI were increased immediately after recurrence (T0 tacrolimus ∼15 ng/mL; T0 CsA 300 ng/mL and T2 CsA 1000 ng/mL) and the dose of CNI was adjusted accordingly. Borderline rejections were also treated with increasing immunosuppression. In summary, eight patients were treated with intravenous CsA prior to apheresis. In addition to Patient 1 treated before KTx with rituximab, 10 patients received rituximab (375 mg/m2 body surface area, median number of doses 2). Among them, seven received rituximab during the IA period; the other three had received rituximab at the time of TPE (Patients 7, 8 and 11). Other therapies used before IA, during IA and after IA are described in Table 2. Apheresis Data concerning the management of FSGS recurrence are presented in Table 2; results of IA are summarized in Tables 3 and 4. Table 3 Management and results of IA Patient Number of plasma volumes processed Mean reduction of IgG (%) IVIG dose supplementation (g/kg) Number of sessions before UPCR <0.2 g/mmol Number of sessions before UPCR <0.05 g/mmol Number of IA sessions Time of IA therapy (months) 1 6.2 65 NA 9 11 14 3 2 2.3 71 NA 2 6 10 1 3 3.0 76 0.35 3 3 111 16 4 3.2 63 0.40 1 4 30 3 5* 3.9 84 0.20 1 1 51 15 6 3.3 67 NA 6 8 40 4 7* 2.3 69 0.33 1 3 32 4 8 2.7 NA 0.50 1 4 38 4 9 NA 66 NA 3 NR 45 7 10* 1.7 54 0.40 7 NR 49 6 11 2.8 NA 0 NR NR 10 1 12 4.0 78 0.5–0.75 NR NR 71 4 Median (range) 3.0 (1.7–6.2) 68 (54–84) 3 (1–9) 4 (1–11) 39 (10–111) 4 (1–16) Patient Number of plasma volumes processed Mean reduction of IgG (%) IVIG dose supplementation (g/kg) Number of sessions before UPCR <0.2 g/mmol Number of sessions before UPCR <0.05 g/mmol Number of IA sessions Time of IA therapy (months) 1 6.2 65 NA 9 11 14 3 2 2.3 71 NA 2 6 10 1 3 3.0 76 0.35 3 3 111 16 4 3.2 63 0.40 1 4 30 3 5* 3.9 84 0.20 1 1 51 15 6 3.3 67 NA 6 8 40 4 7* 2.3 69 0.33 1 3 32 4 8 2.7 NA 0.50 1 4 38 4 9 NA 66 NA 3 NR 45 7 10* 1.7 54 0.40 7 NR 49 6 11 2.8 NA 0 NR NR 10 1 12 4.0 78 0.5–0.75 NR NR 71 4 Median (range) 3.0 (1.7–6.2) 68 (54–84) 3 (1–9) 4 (1–11) 39 (10–111) 4 (1–16) * patients treated by protein A column. IVIG, intravenous immunoglobulin; NA, not available; NR, non-responder. Table 3 Management and results of IA Patient Number of plasma volumes processed Mean reduction of IgG (%) IVIG dose supplementation (g/kg) Number of sessions before UPCR <0.2 g/mmol Number of sessions before UPCR <0.05 g/mmol Number of IA sessions Time of IA therapy (months) 1 6.2 65 NA 9 11 14 3 2 2.3 71 NA 2 6 10 1 3 3.0 76 0.35 3 3 111 16 4 3.2 63 0.40 1 4 30 3 5* 3.9 84 0.20 1 1 51 15 6 3.3 67 NA 6 8 40 4 7* 2.3 69 0.33 1 3 32 4 8 2.7 NA 0.50 1 4 38 4 9 NA 66 NA 3 NR 45 7 10* 1.7 54 0.40 7 NR 49 6 11 2.8 NA 0 NR NR 10 1 12 4.0 78 0.5–0.75 NR NR 71 4 Median (range) 3.0 (1.7–6.2) 68 (54–84) 3 (1–9) 4 (1–11) 39 (10–111) 4 (1–16) Patient Number of plasma volumes processed Mean reduction of IgG (%) IVIG dose supplementation (g/kg) Number of sessions before UPCR <0.2 g/mmol Number of sessions before UPCR <0.05 g/mmol Number of IA sessions Time of IA therapy (months) 1 6.2 65 NA 9 11 14 3 2 2.3 71 NA 2 6 10 1 3 3.0 76 0.35 3 3 111 16 4 3.2 63 0.40 1 4 30 3 5* 3.9 84 0.20 1 1 51 15 6 3.3 67 NA 6 8 40 4 7* 2.3 69 0.33 1 3 32 4 8 2.7 NA 0.50 1 4 38 4 9 NA 66 NA 3 NR 45 7 10* 1.7 54 0.40 7 NR 49 6 11 2.8 NA 0 NR NR 10 1 12 4.0 78 0.5–0.75 NR NR 71 4 Median (range) 3.0 (1.7–6.2) 68 (54–84) 3 (1–9) 4 (1–11) 39 (10–111) 4 (1–16) * patients treated by protein A column. IVIG, intravenous immunoglobulin; NA, not available; NR, non-responder. Table 4 Results of IA according to the delay of initiation after FSGS recurrence Response to TPE Response to IA Patient Initial Continuation Initial Follow-up Continuation Reason of stopping IA Current UPCR (g/mmol) Current SCr (µmol/L) Follow-up time since first IA (months) Early initiation of IA (0–69 days) (n = 8) 1 — — CR Sustained CR N Sustained CR 0.01 97 30 2 — — CR Sustained CR N Sustained CR 0.01 118 16 3 — — CR IA dependance Y 0.63 139 16 5 — — CR IA dependance Y 0.01 52 15 6 — — CR IA dependance Y Switch to TPE available in the centre of follow-up 0.38 35 10 12 — — NR No effect of IA N Failure 0.80 72 8 10 PR Y PR IA dependance Y 0.57 121 6 11 NR Y NR No effect of IA N Failure 0.26 58 12 Later initiation of IA (226–1644 days) (n = 4) 4 PR N CR IA dependance N Poor quality of life 0.19 52 6 7 CR Y CR IA dependance N Switch to TPE because of the cost of the technique 0.03 53 24 8 PR Y CR IA dependance N Poor quality of life 1.51 74 15 9 NR Y PR IA dependance N Poor quality of life 0.65 53 10 Response to TPE Response to IA Patient Initial Continuation Initial Follow-up Continuation Reason of stopping IA Current UPCR (g/mmol) Current SCr (µmol/L) Follow-up time since first IA (months) Early initiation of IA (0–69 days) (n = 8) 1 — — CR Sustained CR N Sustained CR 0.01 97 30 2 — — CR Sustained CR N Sustained CR 0.01 118 16 3 — — CR IA dependance Y 0.63 139 16 5 — — CR IA dependance Y 0.01 52 15 6 — — CR IA dependance Y Switch to TPE available in the centre of follow-up 0.38 35 10 12 — — NR No effect of IA N Failure 0.80 72 8 10 PR Y PR IA dependance Y 0.57 121 6 11 NR Y NR No effect of IA N Failure 0.26 58 12 Later initiation of IA (226–1644 days) (n = 4) 4 PR N CR IA dependance N Poor quality of life 0.19 52 6 7 CR Y CR IA dependance N Switch to TPE because of the cost of the technique 0.03 53 24 8 PR Y CR IA dependance N Poor quality of life 1.51 74 15 9 NR Y PR IA dependance N Poor quality of life 0.65 53 10 IA dependence was defined as dependence to the technique to maintain complete or partial remission at 3 months of follow-up. SCr, serum creatinine; NA, not available; CR, complete remission (UPCR <0.05 g/mmol); PR, partial remission (UPCR 0.05–0.20 g/mmol); NR, non-responder [—: no TPE before IA]. Table 4 Results of IA according to the delay of initiation after FSGS recurrence Response to TPE Response to IA Patient Initial Continuation Initial Follow-up Continuation Reason of stopping IA Current UPCR (g/mmol) Current SCr (µmol/L) Follow-up time since first IA (months) Early initiation of IA (0–69 days) (n = 8) 1 — — CR Sustained CR N Sustained CR 0.01 97 30 2 — — CR Sustained CR N Sustained CR 0.01 118 16 3 — — CR IA dependance Y 0.63 139 16 5 — — CR IA dependance Y 0.01 52 15 6 — — CR IA dependance Y Switch to TPE available in the centre of follow-up 0.38 35 10 12 — — NR No effect of IA N Failure 0.80 72 8 10 PR Y PR IA dependance Y 0.57 121 6 11 NR Y NR No effect of IA N Failure 0.26 58 12 Later initiation of IA (226–1644 days) (n = 4) 4 PR N CR IA dependance N Poor quality of life 0.19 52 6 7 CR Y CR IA dependance N Switch to TPE because of the cost of the technique 0.03 53 24 8 PR Y CR IA dependance N Poor quality of life 1.51 74 15 9 NR Y PR IA dependance N Poor quality of life 0.65 53 10 Response to TPE Response to IA Patient Initial Continuation Initial Follow-up Continuation Reason of stopping IA Current UPCR (g/mmol) Current SCr (µmol/L) Follow-up time since first IA (months) Early initiation of IA (0–69 days) (n = 8) 1 — — CR Sustained CR N Sustained CR 0.01 97 30 2 — — CR Sustained CR N Sustained CR 0.01 118 16 3 — — CR IA dependance Y 0.63 139 16 5 — — CR IA dependance Y 0.01 52 15 6 — — CR IA dependance Y Switch to TPE available in the centre of follow-up 0.38 35 10 12 — — NR No effect of IA N Failure 0.80 72 8 10 PR Y PR IA dependance Y 0.57 121 6 11 NR Y NR No effect of IA N Failure 0.26 58 12 Later initiation of IA (226–1644 days) (n = 4) 4 PR N CR IA dependance N Poor quality of life 0.19 52 6 7 CR Y CR IA dependance N Switch to TPE because of the cost of the technique 0.03 53 24 8 PR Y CR IA dependance N Poor quality of life 1.51 74 15 9 NR Y PR IA dependance N Poor quality of life 0.65 53 10 IA dependence was defined as dependence to the technique to maintain complete or partial remission at 3 months of follow-up. SCr, serum creatinine; NA, not available; CR, complete remission (UPCR <0.05 g/mmol); PR, partial remission (UPCR 0.05–0.20 g/mmol); NR, non-responder [—: no TPE before IA]. Six patients initially received TPE before IA. The TPE procedures were started between 1 and 10 days after recurrence. Four patients achieved remission (partial response: Patients 4, 8 and 10; complete response: Patient 7), while two patients were non-responders to TPE (Patients 9 and 11). Six patients were treated with IA only; in these cases IAs were begun immediately after FSGS recurrence, namely between 0 and 4 days after recurrence. In Table 4 we present the two categories of patients: eight with an early initiation of IA (without TPE or in rescue of TPE failure) and four with a long delay between recurrence of the disease and initiation of IA (226–1644 days). Results of IA A total of 501 IA sessions were performed. Three patients (Patients 5, 7 and 10) were treated with a protein A column and nine with an IgG column. The median patient age at the first IA session was 11.8 (range 6.1–16.1) years and median body weight was 32.5 (range 21–67) kg. They had a median of 4.2 sessions during the first week after the first IA and 2.5 sessions during the second week. Sessions lasted a median of 129 (range 85–240) min. The median plasma volume processed per session was 128 mL/kg (3.2 plasma volumes processed per session; n = 11). The only reported side effect was an anaphylactoid reaction in Patient 5: in this specific case, the columns had been conserved for a long time at −4°C (1 month) without using them, corresponding to a therapeutic window of IA. During this period, IAs were withdrawn to evaluate a potential response to abatacept. The anaphylactoid reaction occurred when IA sessions were restarted. An exhaustive allergic investigation did not find a real allergic reaction and no other side effects were reported after the replacement of columns. All children had nephrotic proteinuria before starting IA, except one patient (Patient 7) who was successfully treated with TPE. Eight patients achieved complete remission, two achieved partial remission and two had no remission after IA (Table 3). For the group with early initiation of IA, two patients (Patients 10 and 11) received IA in rescue of inefficient TPE, and we noticed that the efficacy of IA was not superior to TPE. Two patients had a complete sustained remission after stopping IA (Patients 1 and 2). In patients with IA dependence, the level of UPR was variable (from 0.01 to 0.6 g/mmol). Patient 6 was switched to TPE due to a problem of availability of IA in the medical centre. For the second group (i.e. delayed IA), IA seems to be superior to TPE in Patients 8 and 9, nevertheless IA was also stopped because the treatment was considered too constraining. Patient 4 was initially partially treated with TPE after recurrence, then by other therapies without efficacy. Fifty-four months after KTx he was successfully treated with IA. This therapy was stopped because he had good graft function 5 years after KTx and because of the bad quality of life of the treatment. Physicians considered IA as rescue therapy for him in the event his graft function deteriorated. Finally, Patient 7 received IA with the hope of decreasing in the number of apheresis sessions, but the results were equal with IA and he was switched to TPE because of the cost of the technique. The median follow-up time was 16 months after KTx and 13 months after the first IA session. At the end of the follow-up, IA was continued in three patients and TPE was continued in two patients. IA removed Igs from plasma, resulting in a mean decrease in their circulating levels of 72 ± 8.7% for IgG (n = 10), 51 ± 10.6% for IgA (n = 9) and 45 ± 11.4% for IgM (n = 9). The mean percent reduction of IgG, IgA and IgM was 70 ± 8.8%, 32 ± 6.4% and 44 ± 4%, respectively, with a protein A column (n = 3) and 72 ± 6.7% for IgG (n = 7), 61 ± 11% for IgA (n = 7) and 46 ± 11.5% for IgM (n = 7) with an IgG column. Figure 1 illustrates the evolution of IgG levels during IA therapy per patient. FIGURE 1 View largeDownload slide Evolution of IgG level during IA session per patient. Values were expressed as mean ± SD. Data were not available for Patients 8 and 11. Total number of measurements of IgG is indicated for each patient. FIGURE 1 View largeDownload slide Evolution of IgG level during IA session per patient. Values were expressed as mean ± SD. Data were not available for Patients 8 and 11. Total number of measurements of IgG is indicated for each patient. Graft outcomes None of the patients experienced graft rejection during the follow-up, however, two patients had borderline rejection on initial biopsy. Systematic graft biopsies performed 3 months after KTx in 11 patients showed normal renal tissue, no segmental glomerular sclerosis, no signs of rejection, all Banff items equal to zero with negative C4d. Four patients had other biopsies. Two biopsies performed at 6 months showed mesangial hypercellularity (Patients 3 and 4). One patient (Patient 3) experienced concurrently a severe BK virus nephropathy 6 months after KTx, documented by increased viraemia, histologic lesions and elevation of serum creatinine. Immunosuppressive therapies were decreased to control this graft complication (monotherapy with T0 tacrolimus 5 ng/mL). Two biopsies performed at 1 year after transplantation were normal (Patients 1 and 2). At the end of the follow-up, all patients had functioning grafts. DISCUSSION The management of recurrent FSGS in both adults and children is still a matter of debate. Several therapeutic options have been attempted, including apheresis procedures. Only six paediatric cases of IA have been reported but no paediatric cohort has been published. This study aims at reporting the effects of IA on proteinuria in a cohort of paediatric renal recipients with recurrent FSGS. Despite great heterogeneity in our cohort concerning the delay of initiation of IA, results of our series of 12 children were encouraging and confirmed the safety and benefit of IA. In 1994, Dantal et al. [14] reported the first paediatric case of recurrent FSGS successfully treated with IA. Since this influential publication, five other cases have been published individually [15–18], summarized in Table 5. Our study demonstrated a beneficial effect of IA in 10 of 12 patients (83%). Previously published results reported a higher success rate of IA. However, the initial response as a complete remission defined by a UPCR <0.05 g/mmol was reached in our cohort in 8 of 10 patients (versus 2 of 6 in previously published cases). Two patients in our cohort maintained complete remission after a short series of IA, confirming what had previously been reported in both children and adults [14, 18]. Among responder patients, the response occurred rapidly after initiating IA therapy. The UPCR decreased below the nephrotic range before the 10th session and was <0.05 g/mmol before the 12th session in patients with complete remission. Dantal et al. [14] reported a similar rapid effect of IA. Unfortunately, for eight children in our series, the effect of IA was limited in time and patients needed chronic IA—between one and three sessions per week—to maintain remission. In our cohort we defined two types of clinical profiles that are differentiated by the level of IA dependence. Some children were slightly dependent and others were highly dependent on IA. In highly dependent patients, the frequency of sessions impacts their quality of life. Although effective, IA could be stopped if their quality of life is unacceptable. Table 5 Review of FSGS recurrence after KTx and IA [14–18] Age at diagnosis (years)/ gender Time to ESRD (years) UP at recurrence (g/24 h) PTD of recurrence (days) TPE before IA Delay between recurrence to first IA (months) Efficacy of IA Renal function Dantal et al. [14] 10/F 2 11 10 3 Partial response (UP 1.2 g/day) Good graft function Relapse after cessation of IA Franke et al. [15] 5.9/M 3 ND 1 Y 27 Partial response eGFR 57 mL.min.1.73m2 IA dependence Belson et al. [16] ND/F ND 10.7 7 Y 8 Partial response (UP 1–2 g/day) eGFR 60 mL.min.1.73m2 IA and TPE dependence Fencl et al. [17] 12/F 3 19 1 Y 7 Partial response SCr 80 μmol/L IA dependence (UP 3 g/day) 9/F 3 14 2 Y 16 Complete response SCr 120 μmol/L IA dependence (UP 0.4 g/day) Paglialonga et al. [18] ND/ND ND ND ND ND Sustained remission after cessation IA ND Age at diagnosis (years)/ gender Time to ESRD (years) UP at recurrence (g/24 h) PTD of recurrence (days) TPE before IA Delay between recurrence to first IA (months) Efficacy of IA Renal function Dantal et al. [14] 10/F 2 11 10 3 Partial response (UP 1.2 g/day) Good graft function Relapse after cessation of IA Franke et al. [15] 5.9/M 3 ND 1 Y 27 Partial response eGFR 57 mL.min.1.73m2 IA dependence Belson et al. [16] ND/F ND 10.7 7 Y 8 Partial response (UP 1–2 g/day) eGFR 60 mL.min.1.73m2 IA and TPE dependence Fencl et al. [17] 12/F 3 19 1 Y 7 Partial response SCr 80 μmol/L IA dependence (UP 3 g/day) 9/F 3 14 2 Y 16 Complete response SCr 120 μmol/L IA dependence (UP 0.4 g/day) Paglialonga et al. [18] ND/ND ND ND ND ND Sustained remission after cessation IA ND ND, not done; PTD, post-transplant day; SCr, serum creatinine; UP, urine protein. Table 5 Review of FSGS recurrence after KTx and IA [14–18] Age at diagnosis (years)/ gender Time to ESRD (years) UP at recurrence (g/24 h) PTD of recurrence (days) TPE before IA Delay between recurrence to first IA (months) Efficacy of IA Renal function Dantal et al. [14] 10/F 2 11 10 3 Partial response (UP 1.2 g/day) Good graft function Relapse after cessation of IA Franke et al. [15] 5.9/M 3 ND 1 Y 27 Partial response eGFR 57 mL.min.1.73m2 IA dependence Belson et al. [16] ND/F ND 10.7 7 Y 8 Partial response (UP 1–2 g/day) eGFR 60 mL.min.1.73m2 IA and TPE dependence Fencl et al. [17] 12/F 3 19 1 Y 7 Partial response SCr 80 μmol/L IA dependence (UP 3 g/day) 9/F 3 14 2 Y 16 Complete response SCr 120 μmol/L IA dependence (UP 0.4 g/day) Paglialonga et al. [18] ND/ND ND ND ND ND Sustained remission after cessation IA ND Age at diagnosis (years)/ gender Time to ESRD (years) UP at recurrence (g/24 h) PTD of recurrence (days) TPE before IA Delay between recurrence to first IA (months) Efficacy of IA Renal function Dantal et al. [14] 10/F 2 11 10 3 Partial response (UP 1.2 g/day) Good graft function Relapse after cessation of IA Franke et al. [15] 5.9/M 3 ND 1 Y 27 Partial response eGFR 57 mL.min.1.73m2 IA dependence Belson et al. [16] ND/F ND 10.7 7 Y 8 Partial response (UP 1–2 g/day) eGFR 60 mL.min.1.73m2 IA and TPE dependence Fencl et al. [17] 12/F 3 19 1 Y 7 Partial response SCr 80 μmol/L IA dependence (UP 3 g/day) 9/F 3 14 2 Y 16 Complete response SCr 120 μmol/L IA dependence (UP 0.4 g/day) Paglialonga et al. [18] ND/ND ND ND ND ND Sustained remission after cessation IA ND ND, not done; PTD, post-transplant day; SCr, serum creatinine; UP, urine protein. No comparison trial between TPE and IA in recurrent FSGS in children has been conducted. Half of children in our cohort received TPE before IA, with TPE being effective in four cases (67%), similar to previously published results [5, 8]. In patients treated with early IA, we did not notice a clear benefit of IA compared with TPE (Patients 10 and 11). We could only highlight that no side effect, particularly bleeding, was observed in patients undergoing IA in a context of recent surgery. In patients treated with IA with a long delay from recurrence, IA seemed to be better than TPE only in Patients 8 and 9, switched from chronic treatment with TPE to IA; nevertheless, the quality of life with a high dependence on IA was not acceptable and the technique was stopped. In Patient 4, tested 54 months after the recurrence, no conclusion could be drawn, recognizing that the FSGS response to different therapies can evolve over time. Because our patients received several concomitant immunosuppressive therapies, we cannot affirm that the decrease in proteinuria was only due to IA. Combined use of IA and other therapies may increase the efficacy of both treatments. Because of the limited number of patients and the heterogeneity of the cohort, we failed to show a difference between the responder and the non-responder patients. However, we tried to identify factors influencing IA response. We initially focused on the two patients who did not respond to IA. Patient 11 received only 10 sessions, which was probably an insufficient number to conclude the failure of IA. Indeed, even though the response occurred rapidly in the main responder patients (median number of sessions to achieve a negative proteinuria was 4), one patient needed 9 and 11 sessions to obtain partial and complete remission, respectively. We therefore suggest that a minimum of 15 or 18 sessions (3 sessions per week for 5–6 weeks) should be performed before concluding the absence of efficacy of the IA technique. Despite some physicians suggesting that high levels of IgG supplementation is beneficial to avoid circulating factor production and to improve the clearance of circulating immune complexes, we note that Patient 12 failed to decrease his proteinuria with IA despite higher doses of IgG supplementation than the other patients. We could also hypothesize that in this technique, high-dose Ig could saturate adsorbers, limiting extraction of the circulating factor responsible for FSGS. However, at this stage a consensual dose of intravenous Ig cannot be established, because of the lack of bibliography and comparative/prospective studies. Moreover, due to the retrospective design of this study, we did not seek to determine the superiority of the protein A or IgG column used for the IA technique. The efficacy of anti-proteinuric renin—angiotensin—aldosterone system treatment was not studied in this cohort because of the heterogeneity and the dose variations of medication over time, depending on circulating creatinine and electrolytes. However, we cannot rule out that anti-proteinuric therapies could have influenced the evolution of UPCR, especially in patients receiving delayed IA. The immunosuppressive maintenance therapy could also influence remission. All patients received steroids, anti metabolites and CNI. The two non-responder patients received azathioprine as an antimetabolite. Since MMF had benefits in cortico-dependent nephrotic syndrome, we might wonder if MMF is involved in inducing remission of recurrent FSGS. Almost all patients received rituximab, but we noted that one of the two patients with complete and sustained remission received it before transplantation; nevertheless, because of the data disparities, it was not possible to determine the efficacy of rituximab in post-transplant recurrence of FSGS. Concerning preventive treatment, some recent reports have suggested that prophylactic TPE before transplantation could have a preventive role against recurrence [19, 20]. However, Gonzalez et al. [21] reported that TPE did not decrease the rate of FSGS recurrence but might be beneficial in treating high-risk patients, e.g. previous graft secondary to recurrence. Similar experiences have been reported with IA in an adult cohort [22]. In our series, two patients had preventive apheresis hours before KTx. Interestingly, the only child who had preventive IA presented complete and sustained remission after IA. Finally, we have to keep in mind that rare spontaneous remissions of FSGS have been described in the literature [23–25]. Our study had several limitations, including the retrospective design, the use of several treatment protocols and the absence of a control group, due to the scarcity of pathologic cases. There was no control group because there is no gold standard treatment for recurrent FSGS after KTx. Nevertheless, we reported the results of the first paediatric cohort, well-defined inclusion criteria and long-term and detailed follow-up. To date, there is no guideline on management of IA in recurrent primary FSGS after KTx, and it would be interesting to have a standardized practice. In 2010, Vinai et al. [4] proposed a management algorithm for children with recurrent FSGS after KTx. Today, following recent published results, it appears justified that IA is now proposed alongside TPE as soon as recurrence is diagnosed. Based on the literature review and our experience, we propose the algorithm illustrated in Figure 2. FIGURE 2 View largeDownload slide Suggested algorithm for a method of surveillance and treatment of recurrent FSGS after KTx in children. *Intensive means at least 3 IA sessions per week for 6 weeks (i.e. at least 18 sessions) and at least 5 daily consecutive TPE sessions (repeated once if necessary). **With the limits of our study, we suggest at least a substitution dose of IVIG (0.2–0.4 g/kg) after each IA session; higher doses should be evaluated in further studies. ESRD, end-stage renal disease; IVIG, intravenous immunoglobulin. FIGURE 2 View largeDownload slide Suggested algorithm for a method of surveillance and treatment of recurrent FSGS after KTx in children. *Intensive means at least 3 IA sessions per week for 6 weeks (i.e. at least 18 sessions) and at least 5 daily consecutive TPE sessions (repeated once if necessary). **With the limits of our study, we suggest at least a substitution dose of IVIG (0.2–0.4 g/kg) after each IA session; higher doses should be evaluated in further studies. ESRD, end-stage renal disease; IVIG, intravenous immunoglobulin. In conclusion, we reported the efficacy and safety of IA in 10 of 12 children treated for recurrent FSGS after KTx. IA can be considered as a therapeutic options in the recurrence of FSGS after KTx and is an alternative therapy to TPE due to its more selective performance. Additional follow-up will be required to determine the long-term prognosis for these patients. ACKNOWLEDGEMENTS This French cohort was exhaustive thanks to the collaboration of French paediatric nephrologists. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 D’Agati VD , Kaskel FJ , Falk RJ. Focal segmental glomerulosclerosis . N Engl J Med 2011 ; 365 : 2398 – 2411 Google Scholar CrossRef Search ADS PubMed 2 Straatmann C , Kallash M , Killackey M et al. . Success with plasmapheresis treatment for recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients . Pediatr Transplant 2014 ; 18 : 29 – 34 Google Scholar CrossRef Search ADS PubMed 3 McCarthy ET , Sharma M , Savin VJ. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis . Clin J Am Soc Nephrol 2010 ; 5 : 2115 – 2121 Google Scholar CrossRef Search ADS PubMed 4 Vinai M , Waber P , Seikaly MG. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review . Pediatr Transplant 2010 ; 14 : 314 – 325 Google Scholar CrossRef Search ADS PubMed 5 Salomon R , Gagnadoux MF , Niaudet P. Intravenous cyclosporine therapy in recurrent nephrotic syndrome after renal transplantation in children . Transplantation 2003 ; 75 : 810 – 814 Google Scholar CrossRef Search ADS PubMed 6 Cochat P , Kassir A , Colon S et al. . Recurrent nephrotic syndrome after transplantation: early treatment with plasmapheresis and cyclophosphamide . Pediatr Nephrol 1993 ; 7 : 50 – 54 Google Scholar CrossRef Search ADS PubMed 7 Sellier-Leclerc AL , Macher MA , Loirat C et al. . Rituximab efficiency in children with steroid-dependent nephrotic syndrome . Pediatr Nephrol 2010 ; 25 : 1109 – 1115 Google Scholar CrossRef Search ADS PubMed 8 Raafat RH , Kalia A , Travis LB et al. . High-dose cyclosporine therapy for recurrent focal segmental glomerulosclerosis in children . Am J Kidney Dis 2004 ; 44 : 50 – 56 Google Scholar CrossRef Search ADS PubMed 9 Cravedi P , Kopp JB , Remuzzi G. Recent progress in the physiopathology and treatment of FSGS recurrence . Am J Transplant 2013 ; 13 : 266 – 274 Google Scholar CrossRef Search ADS PubMed 10 Bacchetta J , Cochat P. Primary disease recurrence-effects on paediatric renal transplantation outcomes . Nat Rev Nephrol 2015 ; 11 : 371 – 384 Google Scholar CrossRef Search ADS PubMed 11 Ponticelli C. Recurrence of focal segmental glomerular sclerosis (FSGS) after renal transplantation . Nephrol Dial Transplant 2010 ; 25 : 25 – 31 Google Scholar CrossRef Search ADS PubMed 12 Schwartz J , Winters JL , Padmanabhan A et al. . Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue . J Clin Apheresis 2013 ; 28 : 145 – 284 Google Scholar CrossRef Search ADS PubMed 13 Dantal J , Godfrin Y , Koll R et al. . Antihuman immunoglobulin affinity immunoadsorption strongly decreases proteinuria in patients with relapsing nephrotic syndrome . J Am Soc Nephrol 1998 ; 9 : 1709 – 1015 Google Scholar PubMed 14 Dantal J , Bigot E , Bogers W et al. . Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome . N Engl J Med 1994 ; 330 : 7 – 14 Google Scholar CrossRef Search ADS PubMed 15 Franke D , Zimmering M , Wolfish N et al. . Treatment of FSGS with plasma exchange and immunoadsorption . Pediatr Nephrol 2000 ; 14 : 965 – 969 Google Scholar CrossRef Search ADS PubMed 16 Belson A , Yorgin PD , Al-Uzri AY et al. . Long-term plasmapheresis and protein A column treatment of recurrent FSGS . Pediatr Nephrol 2001 ; 16 : 985 – 989 Google Scholar CrossRef Search ADS PubMed 17 Fencl F , Simková E , Vondrák K et al. . Recurrence of nephrotic proteinuria in children with focal segmental glomerulosclerosis after renal transplantation treated with plasmapheresis and immunoadsorption: case reports. Transplant Proc 2007 ; 39 : 3488 – 3490 18 Paglialonga F , Schmitt CP , Shroff R et al. . Indications, technique, and outcome of therapeutic apheresis in European pediatric nephrology units . Pediatr Nephrol 2015 ; 30 : 103 – 111 Google Scholar CrossRef Search ADS PubMed 19 Ohta T , Kawaguchi H , Hattori M et al. . Effect of pre- and postoperative plasmapheresis on posttransplant recurrence of focal segmental glomerulosclerosis in children . Transplantation 2001 ; 71 : 628 – 633 Google Scholar CrossRef Search ADS PubMed 20 Gohh RY , Yango AF , Morrissey PE et al. . Preemptive plasmapheresis and recurrence of FSGS in high-risk renal transplant recipients . Am J Transplant 2005 ; 5 : 2907 – 2912 Google Scholar CrossRef Search ADS PubMed 21 Gonzalez E , Ettenger R , Rianthavorn P et al. . Preemptive plasmapheresis and recurrence of focal segmental glomerulosclerosis in pediatric renal transplantation . Pediatr Transplant 2011 ; 15 : 495 – 501 Google Scholar CrossRef Search ADS PubMed 22 Lionaki S , Vlachopanos G , Georgalis A et al. . Individualized scheme of immunoadsorption for the recurrence of idiopathic focal segmental glomerulosclerosis in the graft: a single center experience . Renal Fail 2015 ; 26 : 1 – 7 23 Striegel JE , Sibley RK , Fryd DS et al. . Recurrence of focal segmental sclerosis in children following renal transplantation . Kidney Int Suppl 1986 ; 19 : S44 – S50 Google Scholar PubMed 24 Habib R , Antignac C , Hinglais N et al. . Glomerular lesions in the transplanted kidney in children . Am J Kidney Dis 1987 ; 10 : 198 – 207 Google Scholar CrossRef Search ADS PubMed 25 Saeed B , Mazloum H , Askar M. Spontaneous remission of post-transplant recurrent focal and segmental glomerulosclerosis . Saudi J Kidney Dis Transpl 2011 ; 22 : 1219 – 1222 Google Scholar PubMed © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Treatment by immunoadsorption for recurrent focal segmental glomerulosclerosis after paediatric kidney transplantation: a multicentre French cohort

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Oxford University Press
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0931-0509
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Abstract

ABSTRACT Background Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation (KTx) in children. This can lead to delayed graft loss. As the management of children with recurrent FSGS is not well established, apheresis strategies could be a cornerstone to control the disease. Immunoadsorption (IA) is a recent apheresis therapy. There have been few studies examining IA in this setting. We report the results of IA for management of recurrent FSGS after KTx in children in France. Methods We included all children treated with IA for early FSGS recurrence after KTx between January 2011 and June 2014 in France. We excluded genetic forms of FSGS. Patients’ characteristics and technical data on IA were retrospectively collected. Recurrence was defined as nephrotic proteinuria during the post-transplantation period. Partial and complete remissions were defined when urine protein:creatinine ratios were less than 0.2 and 0.05 g/mmol, respectively. Results Twelve patients, from six paediatric KTx units, presenting with FSGS recurrence between 0 and 21 days after KTx were treated with IA. Ten of 12 children were responders: 2 achieved partial remission and 8 complete remission. The decrease of proteinuria rapidly occurred within the first 10 sessions after initiating IA. After 3 months of IA, two patients maintained remission without IA and eight became IA dependent. No severe side effects were reported. Conclusions Our study reports on the efficacy of IA in the recurrence of FSGS after KTx in children. Further prospective controlled studies are required to confirm these results and to optimize the management of FSGS recurrence after paediatric KTx. focal segmental glomerulosclerosis, immunoadsorption, kidney transplantation, nephrotic syndrome INTRODUCTION Primary focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder in children, revealed by oedema and nephrotic proteinuria. Some children, despite steroids and immunosuppressive therapies, continue to have nephrotic proteinuria and progress to end-stage renal failure (ESRF). Approximately 30% of these patients experience a recurrence of FSGS within the first few days after kidney transplantation (KTx), leading to graft loss in half of these cases [1, 2]. The highest risk of disease recurrence is observed in patients who rapidly progressed to ESRF and in patients who lost their first graft due to FSGS recurrence [3, 4]. The management of patients with FSGS recurrence after KTx is challenging and is not well defined due to a lack of controlled studies. Most paediatric centres treat recurrent FSGS with intensification of immunosuppression such as pulse steroids, high-dose cyclosporine A (CsA), cyclophosphamide in combination with apheresis therapy and, more recently, rituximab [5–8]. Two reviews summarize these therapeutic options based on results from small series [4, 9, 10]. Both therapeutic plasma exchange (TPE) and immunoadsorption (IA) have been evaluated with FSGS because a circulating permeability factor has been suggested to play a role in the pathogenesis of this disease [3]. Studies have demonstrated a partial efficacy of TPE in children with FSGS [2, 6, 11]. In 2013, the American Society for Apheresis (ASFA) recommended TPE in combination with increased immunosuppression to treat recurrent FSGS [12]. However, TPE induces a loss of coagulation factors responsible for side effects such as postoperative bleeding. In contrast to TPE, IA is a selective apheretic procedure. Dantal et al. [13] demonstrated a beneficial effect of IA therapy in adults with relapse of FSGS after KTx. Reports on the use of IA in children with recurrent FSGS after KTx are scarce. Paediatric cases published as case reports or in adult series also reported the efficacy of IA in all cases [14–18]. However, no paediatric cohort has yet been published. IA therapy has been available in French paediatric nephrology units since 2011. This study reports the French experience of IA for the management of paediatric recurrent FSGS after KTx. MATERIALS AND METHODS Patients We conducted a retrospective review across all French paediatric KTx centres to select patients with recurrent FSGS post-transplantation treated with IA. All children (ages 1-15 years) presented were histologically confirmed with primary FSGS resulting in ESRF. They underwent KTx at a paediatric age, i.e. <18 years of age. They were treated with IA between January 2011 and June 2014 for recurrence in the post-transplantation period. We excluded secondary FSGS, including genetic forms. Data related to patients’ characteristics, biological tests and therapeutic strategies were retrospectively reviewed. Data on the technical characteristics of IA sessions were also collected, including dates of sessions, volume of plasma processed and percent reduction of immunoglobulin G (IgG). The ethics committees of all participant institutions approved the collection and publication of the data for all patients presented. Definitions Recurrence was defined as the occurrence of nephrotic-range proteinuria after KTx [urine protein:creatinine (UPCR) ratio >0.2 g/mmol]. The primary outcome was UPCR, used to assess IA response. Partial remission was arbitrarily defined as a UPCR between 0.2 and 0.05 g/mmol. Complete remission was defined as a UPCR <0.05 g/mmol. Sustained complete remission was defined as complete remission being maintained without relapse after stopping apheresis at the time of data collection. The delay between the first IA session and remission was expressed in days and in the number of IA sessions. IA was classified as a failure when proteinuria was still nephrotic after 20 sessions of IA. Apheresis dependence was considered when patients required TPE or IA therapy 3 months after post-transplantation relapse to maintain UPCR between 0.2 and 0.05 g/mmol. Graft failure was defined as returning to renal replacement therapy. Technical characteristics of IA sessions IA procedures were performed either with a protein A column (Immunosorba, Art/Adasorb, Fresenius Medical Care) or with an IgG column (Therasorb, Ig flex, Life18, Miltenyi Biotec), according to the availability of machines in the different centres. Previous studies showed that both protein A and IgG columns were strongly effective in retaining Ig and in reducing albuminuria in FSGS [13]. IA therapy started intensively and was gradually discontinued, according to medical experiences and the availability of machines. Patients received intravenous Ig supplementation after each IA session to replace depleted antibodies. Depending on the centre, adsorbers were replaced either every 10 sessions as recommended by the manufacturer or if the reduction of IgG was <80% or in case of a technical problem. Data on IgG circulating levels were immediately collected before and after the IA session. Physicians defined the plasma volume processed per each session. Data were presented as mean ± SD or median (range). RESULTS Patients’ characteristics and pre-transplantation data Twelve patients from six French paediatric KTx units were included in the study. Clinical features at presentation and treatments of the 12 patients are displayed in Table 1. The median age at diagnosis of nephrotic syndrome was 4.8 years. The sex ratio was 1. All patients received oral steroids except one due to late discovery of the disease at chronic kidney disease stage 4 (Patient 1; Table 1). One of the cases was steroid-sensitive FSGS at onset and became secondarily resistant to steroids. All other patients were initially steroid resistant. All patients but one were treated with calcineurin inhibitors (CNIs). Two patients were treated with ineffective TPE. None of the cases were treated with IA before KTx. Whatever immunosuppressive treatments were provided, the patients progressed quickly to ESRF [median time to ESRF 2.2 years (range 0.8–7.2 years)]. All of them required dialysis before KTx. Table 1 Clinical characteristics and therapeutic strategies of patients before KTx Patient Gender Age at onset of disease (years) Steroids Other IS drugs Apheresis Time to ESDRa (years) Length of dialysis (years) Bilateral nephrectomy 1 F 9.5 Y CsA, cycloph TPE 0.8 1.9 Y 2 M 13.7 N – – 1.7 0.2 N 3 F 4.0 Y MMF – 7.2 1.9 Y 4 M 4.3 Y CsA, FK TPE 2.2 0.8 Y 5 F 5.1 Y MMF, CsA – 2.0 2.0 N 6 F 5.9 Y CsA – 2.4 3.5 Y 7 M 5.6 Y CsA, RTX – 3.3 0.4 Y 8 M 4.6 Y MMF, CsA, FK, cycloph – 1.3 1.9 N 9 F 3.0 Y MMF, CsA, RTX – 2.8 1.0 Y 10 F 13.7 Y MMF, CsA, FK – 1.5 0.9 Y 11 M 2.9 Y CsA – 4.2 1.0 Y 12 M 2.7 Y MMF, CsA, FK – 2.1 1.3 Y Median (range) 4.9 (2.7–13.7) 2.2 (0.8–7.2) 1.2 (0.2–3.5) Patient Gender Age at onset of disease (years) Steroids Other IS drugs Apheresis Time to ESDRa (years) Length of dialysis (years) Bilateral nephrectomy 1 F 9.5 Y CsA, cycloph TPE 0.8 1.9 Y 2 M 13.7 N – – 1.7 0.2 N 3 F 4.0 Y MMF – 7.2 1.9 Y 4 M 4.3 Y CsA, FK TPE 2.2 0.8 Y 5 F 5.1 Y MMF, CsA – 2.0 2.0 N 6 F 5.9 Y CsA – 2.4 3.5 Y 7 M 5.6 Y CsA, RTX – 3.3 0.4 Y 8 M 4.6 Y MMF, CsA, FK, cycloph – 1.3 1.9 N 9 F 3.0 Y MMF, CsA, RTX – 2.8 1.0 Y 10 F 13.7 Y MMF, CsA, FK – 1.5 0.9 Y 11 M 2.9 Y CsA – 4.2 1.0 Y 12 M 2.7 Y MMF, CsA, FK – 2.1 1.3 Y Median (range) 4.9 (2.7–13.7) 2.2 (0.8–7.2) 1.2 (0.2–3.5) a Denotes the interval from the onset of proteinuria to end-stage renal disease. IS, immunosuppressive; FK, tacrolimus; RTX, rituximab; cycloph, cyclophosphamide; ESRD, end-stage renal disease. Table 1 Clinical characteristics and therapeutic strategies of patients before KTx Patient Gender Age at onset of disease (years) Steroids Other IS drugs Apheresis Time to ESDRa (years) Length of dialysis (years) Bilateral nephrectomy 1 F 9.5 Y CsA, cycloph TPE 0.8 1.9 Y 2 M 13.7 N – – 1.7 0.2 N 3 F 4.0 Y MMF – 7.2 1.9 Y 4 M 4.3 Y CsA, FK TPE 2.2 0.8 Y 5 F 5.1 Y MMF, CsA – 2.0 2.0 N 6 F 5.9 Y CsA – 2.4 3.5 Y 7 M 5.6 Y CsA, RTX – 3.3 0.4 Y 8 M 4.6 Y MMF, CsA, FK, cycloph – 1.3 1.9 N 9 F 3.0 Y MMF, CsA, RTX – 2.8 1.0 Y 10 F 13.7 Y MMF, CsA, FK – 1.5 0.9 Y 11 M 2.9 Y CsA – 4.2 1.0 Y 12 M 2.7 Y MMF, CsA, FK – 2.1 1.3 Y Median (range) 4.9 (2.7–13.7) 2.2 (0.8–7.2) 1.2 (0.2–3.5) Patient Gender Age at onset of disease (years) Steroids Other IS drugs Apheresis Time to ESDRa (years) Length of dialysis (years) Bilateral nephrectomy 1 F 9.5 Y CsA, cycloph TPE 0.8 1.9 Y 2 M 13.7 N – – 1.7 0.2 N 3 F 4.0 Y MMF – 7.2 1.9 Y 4 M 4.3 Y CsA, FK TPE 2.2 0.8 Y 5 F 5.1 Y MMF, CsA – 2.0 2.0 N 6 F 5.9 Y CsA – 2.4 3.5 Y 7 M 5.6 Y CsA, RTX – 3.3 0.4 Y 8 M 4.6 Y MMF, CsA, FK, cycloph – 1.3 1.9 N 9 F 3.0 Y MMF, CsA, RTX – 2.8 1.0 Y 10 F 13.7 Y MMF, CsA, FK – 1.5 0.9 Y 11 M 2.9 Y CsA – 4.2 1.0 Y 12 M 2.7 Y MMF, CsA, FK – 2.1 1.3 Y Median (range) 4.9 (2.7–13.7) 2.2 (0.8–7.2) 1.2 (0.2–3.5) a Denotes the interval from the onset of proteinuria to end-stage renal disease. IS, immunosuppressive; FK, tacrolimus; RTX, rituximab; cycloph, cyclophosphamide; ESRD, end-stage renal disease. KTx data KTx occurred at a median age of 10.5 (range 6.1–16.0) years. It was the first renal graft for all cases except one, who received a second renal graft. All patients received a cadaveric renal transplant. The median cold ischaemic time was 16.8 (range 10.0–30.0) h. Five of 10 patients had pre-transplantation anti-human leucocyte antigen (HLA) antibodies. The median HLA mismatch score was 3 (range 0–4). Induction immunosuppressive therapy included basiliximab (n = 9) or antithymocyte globulin (n = 3), intravenous CsA (n = 6) or oral tacrolimus (n = 6), mycophenolate mofetil (MMF) (n = 10) or azathioprin (n = 2; patients 11 and 12) and steroids (n = 12). Because of a significant risk of recurrence, one patient received rituximab before KTx (Patient 1) and two patients had preventive apheresis therapy hours before KTx (IA: Patient 1; PE: Patient 4). All patients received sulfamethoxazole–trimethoprim as prophylaxis against Pneumocystis carinii. For cytomegalovirus or Epstein–Barr virus mismatch risk, the medical attitude was not homogeneous among centres: some patients received valganciclovir during 6 months, while the others had no prophylaxis but an intensive follow-up of viral loads. Recurrence of FSGS All patients experienced early FSGS recurrence, with a median time of 4.5 (range 0–21) days after KTx. The median peak UPCR before starting IA therapy was 1.2 (range 0.2–4.2) g/mmol and the median serum albumin was 28 (range 20–37) g/L. Renal graft biopsies, performed in four patients the day after the recurrence, were normal in two cases and showed borderline rejection in two cases. Management of recurrence of FSGS For all patients, the management of FSGS included increased immunosuppressive therapy, apheresis and the addition of anti-proteinuric drugs such as angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). The timing and management of recurrent FSGS are displayed in Table 2. Table 2 Timing and management of FSGS recurrence after KTx Patient Graft range Age at KTx (years) Recurrencea (days) UPCR at recurrence (g/mmol) CNIs RTX Other therapies before (b), during (d) and after (a) IA TPE before IA Delay between recurrence to first TPE (days) Delay between last TPE and first IA (days) Delay between recurrence and first IA (days) 1 First 12.2 0 1.83 FK Nb N 0 2 First 15.6 7 0.87 FK N N 0 3 First 13.2 21 1.34 FK Y N 1 4 First 7.3 18 0.56 IV CsA Y (b) bortezomib, saquinavir, etanercept, galactose; (a) galactose Y 1 1257 1644 5 Second 14.9 9 0.33 IV CsA Y (d) abatacept N 2 6 First 11.8 8 0.45 FK Y (d) levamisole, galactose; (a) abatacept N 4 7 First 9.3 8 1.08 IV CsA Y (a) saquinavir Y 2 4 342 8 First 7.8 2 1.61 IV CsA Y Y 2 4 226 9 First 6.8 2 1.31 IV CsA Y Y 10 7 399 10 First 16.0 2 0.20 IV CsA Y (d) cycloph Y 1 4 15 11 First 8.2 1 0.58 IV CsA Y Y 6 28 69 12 First 6.1 2 4.20 IV CsA Y N 1 Median (range) 10.6 (6.1–16.0) 5 (0–21) 0.98 (0.20–4.20) 10 (0–1644) Patient Graft range Age at KTx (years) Recurrencea (days) UPCR at recurrence (g/mmol) CNIs RTX Other therapies before (b), during (d) and after (a) IA TPE before IA Delay between recurrence to first TPE (days) Delay between last TPE and first IA (days) Delay between recurrence and first IA (days) 1 First 12.2 0 1.83 FK Nb N 0 2 First 15.6 7 0.87 FK N N 0 3 First 13.2 21 1.34 FK Y N 1 4 First 7.3 18 0.56 IV CsA Y (b) bortezomib, saquinavir, etanercept, galactose; (a) galactose Y 1 1257 1644 5 Second 14.9 9 0.33 IV CsA Y (d) abatacept N 2 6 First 11.8 8 0.45 FK Y (d) levamisole, galactose; (a) abatacept N 4 7 First 9.3 8 1.08 IV CsA Y (a) saquinavir Y 2 4 342 8 First 7.8 2 1.61 IV CsA Y Y 2 4 226 9 First 6.8 2 1.31 IV CsA Y Y 10 7 399 10 First 16.0 2 0.20 IV CsA Y (d) cycloph Y 1 4 15 11 First 8.2 1 0.58 IV CsA Y Y 6 28 69 12 First 6.1 2 4.20 IV CsA Y N 1 Median (range) 10.6 (6.1–16.0) 5 (0–21) 0.98 (0.20–4.20) 10 (0–1644) a Day of FSGS recurrence after KTx. b Patient 1 received RTX 1 month before KTx. IV, intravenous; FK, tacrolimus; RTX, rituximab; cycloph, cyclophosphamide. Table 2 Timing and management of FSGS recurrence after KTx Patient Graft range Age at KTx (years) Recurrencea (days) UPCR at recurrence (g/mmol) CNIs RTX Other therapies before (b), during (d) and after (a) IA TPE before IA Delay between recurrence to first TPE (days) Delay between last TPE and first IA (days) Delay between recurrence and first IA (days) 1 First 12.2 0 1.83 FK Nb N 0 2 First 15.6 7 0.87 FK N N 0 3 First 13.2 21 1.34 FK Y N 1 4 First 7.3 18 0.56 IV CsA Y (b) bortezomib, saquinavir, etanercept, galactose; (a) galactose Y 1 1257 1644 5 Second 14.9 9 0.33 IV CsA Y (d) abatacept N 2 6 First 11.8 8 0.45 FK Y (d) levamisole, galactose; (a) abatacept N 4 7 First 9.3 8 1.08 IV CsA Y (a) saquinavir Y 2 4 342 8 First 7.8 2 1.61 IV CsA Y Y 2 4 226 9 First 6.8 2 1.31 IV CsA Y Y 10 7 399 10 First 16.0 2 0.20 IV CsA Y (d) cycloph Y 1 4 15 11 First 8.2 1 0.58 IV CsA Y Y 6 28 69 12 First 6.1 2 4.20 IV CsA Y N 1 Median (range) 10.6 (6.1–16.0) 5 (0–21) 0.98 (0.20–4.20) 10 (0–1644) Patient Graft range Age at KTx (years) Recurrencea (days) UPCR at recurrence (g/mmol) CNIs RTX Other therapies before (b), during (d) and after (a) IA TPE before IA Delay between recurrence to first TPE (days) Delay between last TPE and first IA (days) Delay between recurrence and first IA (days) 1 First 12.2 0 1.83 FK Nb N 0 2 First 15.6 7 0.87 FK N N 0 3 First 13.2 21 1.34 FK Y N 1 4 First 7.3 18 0.56 IV CsA Y (b) bortezomib, saquinavir, etanercept, galactose; (a) galactose Y 1 1257 1644 5 Second 14.9 9 0.33 IV CsA Y (d) abatacept N 2 6 First 11.8 8 0.45 FK Y (d) levamisole, galactose; (a) abatacept N 4 7 First 9.3 8 1.08 IV CsA Y (a) saquinavir Y 2 4 342 8 First 7.8 2 1.61 IV CsA Y Y 2 4 226 9 First 6.8 2 1.31 IV CsA Y Y 10 7 399 10 First 16.0 2 0.20 IV CsA Y (d) cycloph Y 1 4 15 11 First 8.2 1 0.58 IV CsA Y Y 6 28 69 12 First 6.1 2 4.20 IV CsA Y N 1 Median (range) 10.6 (6.1–16.0) 5 (0–21) 0.98 (0.20–4.20) 10 (0–1644) a Day of FSGS recurrence after KTx. b Patient 1 received RTX 1 month before KTx. IV, intravenous; FK, tacrolimus; RTX, rituximab; cycloph, cyclophosphamide. Immunosuppressive drugs All patients had already received steroids as induction immunosuppressive therapy either as a pulse of methylprednisolone or as a high dose of oral prednisone. The scheme of CNI therapy was changed in three cases: from tacrolimus to intravenous CsA (n = 2) and from CsA to tacrolimus (n = 1). For five patients, target levels of CNI were increased immediately after recurrence (T0 tacrolimus ∼15 ng/mL; T0 CsA 300 ng/mL and T2 CsA 1000 ng/mL) and the dose of CNI was adjusted accordingly. Borderline rejections were also treated with increasing immunosuppression. In summary, eight patients were treated with intravenous CsA prior to apheresis. In addition to Patient 1 treated before KTx with rituximab, 10 patients received rituximab (375 mg/m2 body surface area, median number of doses 2). Among them, seven received rituximab during the IA period; the other three had received rituximab at the time of TPE (Patients 7, 8 and 11). Other therapies used before IA, during IA and after IA are described in Table 2. Apheresis Data concerning the management of FSGS recurrence are presented in Table 2; results of IA are summarized in Tables 3 and 4. Table 3 Management and results of IA Patient Number of plasma volumes processed Mean reduction of IgG (%) IVIG dose supplementation (g/kg) Number of sessions before UPCR <0.2 g/mmol Number of sessions before UPCR <0.05 g/mmol Number of IA sessions Time of IA therapy (months) 1 6.2 65 NA 9 11 14 3 2 2.3 71 NA 2 6 10 1 3 3.0 76 0.35 3 3 111 16 4 3.2 63 0.40 1 4 30 3 5* 3.9 84 0.20 1 1 51 15 6 3.3 67 NA 6 8 40 4 7* 2.3 69 0.33 1 3 32 4 8 2.7 NA 0.50 1 4 38 4 9 NA 66 NA 3 NR 45 7 10* 1.7 54 0.40 7 NR 49 6 11 2.8 NA 0 NR NR 10 1 12 4.0 78 0.5–0.75 NR NR 71 4 Median (range) 3.0 (1.7–6.2) 68 (54–84) 3 (1–9) 4 (1–11) 39 (10–111) 4 (1–16) Patient Number of plasma volumes processed Mean reduction of IgG (%) IVIG dose supplementation (g/kg) Number of sessions before UPCR <0.2 g/mmol Number of sessions before UPCR <0.05 g/mmol Number of IA sessions Time of IA therapy (months) 1 6.2 65 NA 9 11 14 3 2 2.3 71 NA 2 6 10 1 3 3.0 76 0.35 3 3 111 16 4 3.2 63 0.40 1 4 30 3 5* 3.9 84 0.20 1 1 51 15 6 3.3 67 NA 6 8 40 4 7* 2.3 69 0.33 1 3 32 4 8 2.7 NA 0.50 1 4 38 4 9 NA 66 NA 3 NR 45 7 10* 1.7 54 0.40 7 NR 49 6 11 2.8 NA 0 NR NR 10 1 12 4.0 78 0.5–0.75 NR NR 71 4 Median (range) 3.0 (1.7–6.2) 68 (54–84) 3 (1–9) 4 (1–11) 39 (10–111) 4 (1–16) * patients treated by protein A column. IVIG, intravenous immunoglobulin; NA, not available; NR, non-responder. Table 3 Management and results of IA Patient Number of plasma volumes processed Mean reduction of IgG (%) IVIG dose supplementation (g/kg) Number of sessions before UPCR <0.2 g/mmol Number of sessions before UPCR <0.05 g/mmol Number of IA sessions Time of IA therapy (months) 1 6.2 65 NA 9 11 14 3 2 2.3 71 NA 2 6 10 1 3 3.0 76 0.35 3 3 111 16 4 3.2 63 0.40 1 4 30 3 5* 3.9 84 0.20 1 1 51 15 6 3.3 67 NA 6 8 40 4 7* 2.3 69 0.33 1 3 32 4 8 2.7 NA 0.50 1 4 38 4 9 NA 66 NA 3 NR 45 7 10* 1.7 54 0.40 7 NR 49 6 11 2.8 NA 0 NR NR 10 1 12 4.0 78 0.5–0.75 NR NR 71 4 Median (range) 3.0 (1.7–6.2) 68 (54–84) 3 (1–9) 4 (1–11) 39 (10–111) 4 (1–16) Patient Number of plasma volumes processed Mean reduction of IgG (%) IVIG dose supplementation (g/kg) Number of sessions before UPCR <0.2 g/mmol Number of sessions before UPCR <0.05 g/mmol Number of IA sessions Time of IA therapy (months) 1 6.2 65 NA 9 11 14 3 2 2.3 71 NA 2 6 10 1 3 3.0 76 0.35 3 3 111 16 4 3.2 63 0.40 1 4 30 3 5* 3.9 84 0.20 1 1 51 15 6 3.3 67 NA 6 8 40 4 7* 2.3 69 0.33 1 3 32 4 8 2.7 NA 0.50 1 4 38 4 9 NA 66 NA 3 NR 45 7 10* 1.7 54 0.40 7 NR 49 6 11 2.8 NA 0 NR NR 10 1 12 4.0 78 0.5–0.75 NR NR 71 4 Median (range) 3.0 (1.7–6.2) 68 (54–84) 3 (1–9) 4 (1–11) 39 (10–111) 4 (1–16) * patients treated by protein A column. IVIG, intravenous immunoglobulin; NA, not available; NR, non-responder. Table 4 Results of IA according to the delay of initiation after FSGS recurrence Response to TPE Response to IA Patient Initial Continuation Initial Follow-up Continuation Reason of stopping IA Current UPCR (g/mmol) Current SCr (µmol/L) Follow-up time since first IA (months) Early initiation of IA (0–69 days) (n = 8) 1 — — CR Sustained CR N Sustained CR 0.01 97 30 2 — — CR Sustained CR N Sustained CR 0.01 118 16 3 — — CR IA dependance Y 0.63 139 16 5 — — CR IA dependance Y 0.01 52 15 6 — — CR IA dependance Y Switch to TPE available in the centre of follow-up 0.38 35 10 12 — — NR No effect of IA N Failure 0.80 72 8 10 PR Y PR IA dependance Y 0.57 121 6 11 NR Y NR No effect of IA N Failure 0.26 58 12 Later initiation of IA (226–1644 days) (n = 4) 4 PR N CR IA dependance N Poor quality of life 0.19 52 6 7 CR Y CR IA dependance N Switch to TPE because of the cost of the technique 0.03 53 24 8 PR Y CR IA dependance N Poor quality of life 1.51 74 15 9 NR Y PR IA dependance N Poor quality of life 0.65 53 10 Response to TPE Response to IA Patient Initial Continuation Initial Follow-up Continuation Reason of stopping IA Current UPCR (g/mmol) Current SCr (µmol/L) Follow-up time since first IA (months) Early initiation of IA (0–69 days) (n = 8) 1 — — CR Sustained CR N Sustained CR 0.01 97 30 2 — — CR Sustained CR N Sustained CR 0.01 118 16 3 — — CR IA dependance Y 0.63 139 16 5 — — CR IA dependance Y 0.01 52 15 6 — — CR IA dependance Y Switch to TPE available in the centre of follow-up 0.38 35 10 12 — — NR No effect of IA N Failure 0.80 72 8 10 PR Y PR IA dependance Y 0.57 121 6 11 NR Y NR No effect of IA N Failure 0.26 58 12 Later initiation of IA (226–1644 days) (n = 4) 4 PR N CR IA dependance N Poor quality of life 0.19 52 6 7 CR Y CR IA dependance N Switch to TPE because of the cost of the technique 0.03 53 24 8 PR Y CR IA dependance N Poor quality of life 1.51 74 15 9 NR Y PR IA dependance N Poor quality of life 0.65 53 10 IA dependence was defined as dependence to the technique to maintain complete or partial remission at 3 months of follow-up. SCr, serum creatinine; NA, not available; CR, complete remission (UPCR <0.05 g/mmol); PR, partial remission (UPCR 0.05–0.20 g/mmol); NR, non-responder [—: no TPE before IA]. Table 4 Results of IA according to the delay of initiation after FSGS recurrence Response to TPE Response to IA Patient Initial Continuation Initial Follow-up Continuation Reason of stopping IA Current UPCR (g/mmol) Current SCr (µmol/L) Follow-up time since first IA (months) Early initiation of IA (0–69 days) (n = 8) 1 — — CR Sustained CR N Sustained CR 0.01 97 30 2 — — CR Sustained CR N Sustained CR 0.01 118 16 3 — — CR IA dependance Y 0.63 139 16 5 — — CR IA dependance Y 0.01 52 15 6 — — CR IA dependance Y Switch to TPE available in the centre of follow-up 0.38 35 10 12 — — NR No effect of IA N Failure 0.80 72 8 10 PR Y PR IA dependance Y 0.57 121 6 11 NR Y NR No effect of IA N Failure 0.26 58 12 Later initiation of IA (226–1644 days) (n = 4) 4 PR N CR IA dependance N Poor quality of life 0.19 52 6 7 CR Y CR IA dependance N Switch to TPE because of the cost of the technique 0.03 53 24 8 PR Y CR IA dependance N Poor quality of life 1.51 74 15 9 NR Y PR IA dependance N Poor quality of life 0.65 53 10 Response to TPE Response to IA Patient Initial Continuation Initial Follow-up Continuation Reason of stopping IA Current UPCR (g/mmol) Current SCr (µmol/L) Follow-up time since first IA (months) Early initiation of IA (0–69 days) (n = 8) 1 — — CR Sustained CR N Sustained CR 0.01 97 30 2 — — CR Sustained CR N Sustained CR 0.01 118 16 3 — — CR IA dependance Y 0.63 139 16 5 — — CR IA dependance Y 0.01 52 15 6 — — CR IA dependance Y Switch to TPE available in the centre of follow-up 0.38 35 10 12 — — NR No effect of IA N Failure 0.80 72 8 10 PR Y PR IA dependance Y 0.57 121 6 11 NR Y NR No effect of IA N Failure 0.26 58 12 Later initiation of IA (226–1644 days) (n = 4) 4 PR N CR IA dependance N Poor quality of life 0.19 52 6 7 CR Y CR IA dependance N Switch to TPE because of the cost of the technique 0.03 53 24 8 PR Y CR IA dependance N Poor quality of life 1.51 74 15 9 NR Y PR IA dependance N Poor quality of life 0.65 53 10 IA dependence was defined as dependence to the technique to maintain complete or partial remission at 3 months of follow-up. SCr, serum creatinine; NA, not available; CR, complete remission (UPCR <0.05 g/mmol); PR, partial remission (UPCR 0.05–0.20 g/mmol); NR, non-responder [—: no TPE before IA]. Six patients initially received TPE before IA. The TPE procedures were started between 1 and 10 days after recurrence. Four patients achieved remission (partial response: Patients 4, 8 and 10; complete response: Patient 7), while two patients were non-responders to TPE (Patients 9 and 11). Six patients were treated with IA only; in these cases IAs were begun immediately after FSGS recurrence, namely between 0 and 4 days after recurrence. In Table 4 we present the two categories of patients: eight with an early initiation of IA (without TPE or in rescue of TPE failure) and four with a long delay between recurrence of the disease and initiation of IA (226–1644 days). Results of IA A total of 501 IA sessions were performed. Three patients (Patients 5, 7 and 10) were treated with a protein A column and nine with an IgG column. The median patient age at the first IA session was 11.8 (range 6.1–16.1) years and median body weight was 32.5 (range 21–67) kg. They had a median of 4.2 sessions during the first week after the first IA and 2.5 sessions during the second week. Sessions lasted a median of 129 (range 85–240) min. The median plasma volume processed per session was 128 mL/kg (3.2 plasma volumes processed per session; n = 11). The only reported side effect was an anaphylactoid reaction in Patient 5: in this specific case, the columns had been conserved for a long time at −4°C (1 month) without using them, corresponding to a therapeutic window of IA. During this period, IAs were withdrawn to evaluate a potential response to abatacept. The anaphylactoid reaction occurred when IA sessions were restarted. An exhaustive allergic investigation did not find a real allergic reaction and no other side effects were reported after the replacement of columns. All children had nephrotic proteinuria before starting IA, except one patient (Patient 7) who was successfully treated with TPE. Eight patients achieved complete remission, two achieved partial remission and two had no remission after IA (Table 3). For the group with early initiation of IA, two patients (Patients 10 and 11) received IA in rescue of inefficient TPE, and we noticed that the efficacy of IA was not superior to TPE. Two patients had a complete sustained remission after stopping IA (Patients 1 and 2). In patients with IA dependence, the level of UPR was variable (from 0.01 to 0.6 g/mmol). Patient 6 was switched to TPE due to a problem of availability of IA in the medical centre. For the second group (i.e. delayed IA), IA seems to be superior to TPE in Patients 8 and 9, nevertheless IA was also stopped because the treatment was considered too constraining. Patient 4 was initially partially treated with TPE after recurrence, then by other therapies without efficacy. Fifty-four months after KTx he was successfully treated with IA. This therapy was stopped because he had good graft function 5 years after KTx and because of the bad quality of life of the treatment. Physicians considered IA as rescue therapy for him in the event his graft function deteriorated. Finally, Patient 7 received IA with the hope of decreasing in the number of apheresis sessions, but the results were equal with IA and he was switched to TPE because of the cost of the technique. The median follow-up time was 16 months after KTx and 13 months after the first IA session. At the end of the follow-up, IA was continued in three patients and TPE was continued in two patients. IA removed Igs from plasma, resulting in a mean decrease in their circulating levels of 72 ± 8.7% for IgG (n = 10), 51 ± 10.6% for IgA (n = 9) and 45 ± 11.4% for IgM (n = 9). The mean percent reduction of IgG, IgA and IgM was 70 ± 8.8%, 32 ± 6.4% and 44 ± 4%, respectively, with a protein A column (n = 3) and 72 ± 6.7% for IgG (n = 7), 61 ± 11% for IgA (n = 7) and 46 ± 11.5% for IgM (n = 7) with an IgG column. Figure 1 illustrates the evolution of IgG levels during IA therapy per patient. FIGURE 1 View largeDownload slide Evolution of IgG level during IA session per patient. Values were expressed as mean ± SD. Data were not available for Patients 8 and 11. Total number of measurements of IgG is indicated for each patient. FIGURE 1 View largeDownload slide Evolution of IgG level during IA session per patient. Values were expressed as mean ± SD. Data were not available for Patients 8 and 11. Total number of measurements of IgG is indicated for each patient. Graft outcomes None of the patients experienced graft rejection during the follow-up, however, two patients had borderline rejection on initial biopsy. Systematic graft biopsies performed 3 months after KTx in 11 patients showed normal renal tissue, no segmental glomerular sclerosis, no signs of rejection, all Banff items equal to zero with negative C4d. Four patients had other biopsies. Two biopsies performed at 6 months showed mesangial hypercellularity (Patients 3 and 4). One patient (Patient 3) experienced concurrently a severe BK virus nephropathy 6 months after KTx, documented by increased viraemia, histologic lesions and elevation of serum creatinine. Immunosuppressive therapies were decreased to control this graft complication (monotherapy with T0 tacrolimus 5 ng/mL). Two biopsies performed at 1 year after transplantation were normal (Patients 1 and 2). At the end of the follow-up, all patients had functioning grafts. DISCUSSION The management of recurrent FSGS in both adults and children is still a matter of debate. Several therapeutic options have been attempted, including apheresis procedures. Only six paediatric cases of IA have been reported but no paediatric cohort has been published. This study aims at reporting the effects of IA on proteinuria in a cohort of paediatric renal recipients with recurrent FSGS. Despite great heterogeneity in our cohort concerning the delay of initiation of IA, results of our series of 12 children were encouraging and confirmed the safety and benefit of IA. In 1994, Dantal et al. [14] reported the first paediatric case of recurrent FSGS successfully treated with IA. Since this influential publication, five other cases have been published individually [15–18], summarized in Table 5. Our study demonstrated a beneficial effect of IA in 10 of 12 patients (83%). Previously published results reported a higher success rate of IA. However, the initial response as a complete remission defined by a UPCR <0.05 g/mmol was reached in our cohort in 8 of 10 patients (versus 2 of 6 in previously published cases). Two patients in our cohort maintained complete remission after a short series of IA, confirming what had previously been reported in both children and adults [14, 18]. Among responder patients, the response occurred rapidly after initiating IA therapy. The UPCR decreased below the nephrotic range before the 10th session and was <0.05 g/mmol before the 12th session in patients with complete remission. Dantal et al. [14] reported a similar rapid effect of IA. Unfortunately, for eight children in our series, the effect of IA was limited in time and patients needed chronic IA—between one and three sessions per week—to maintain remission. In our cohort we defined two types of clinical profiles that are differentiated by the level of IA dependence. Some children were slightly dependent and others were highly dependent on IA. In highly dependent patients, the frequency of sessions impacts their quality of life. Although effective, IA could be stopped if their quality of life is unacceptable. Table 5 Review of FSGS recurrence after KTx and IA [14–18] Age at diagnosis (years)/ gender Time to ESRD (years) UP at recurrence (g/24 h) PTD of recurrence (days) TPE before IA Delay between recurrence to first IA (months) Efficacy of IA Renal function Dantal et al. [14] 10/F 2 11 10 3 Partial response (UP 1.2 g/day) Good graft function Relapse after cessation of IA Franke et al. [15] 5.9/M 3 ND 1 Y 27 Partial response eGFR 57 mL.min.1.73m2 IA dependence Belson et al. [16] ND/F ND 10.7 7 Y 8 Partial response (UP 1–2 g/day) eGFR 60 mL.min.1.73m2 IA and TPE dependence Fencl et al. [17] 12/F 3 19 1 Y 7 Partial response SCr 80 μmol/L IA dependence (UP 3 g/day) 9/F 3 14 2 Y 16 Complete response SCr 120 μmol/L IA dependence (UP 0.4 g/day) Paglialonga et al. [18] ND/ND ND ND ND ND Sustained remission after cessation IA ND Age at diagnosis (years)/ gender Time to ESRD (years) UP at recurrence (g/24 h) PTD of recurrence (days) TPE before IA Delay between recurrence to first IA (months) Efficacy of IA Renal function Dantal et al. [14] 10/F 2 11 10 3 Partial response (UP 1.2 g/day) Good graft function Relapse after cessation of IA Franke et al. [15] 5.9/M 3 ND 1 Y 27 Partial response eGFR 57 mL.min.1.73m2 IA dependence Belson et al. [16] ND/F ND 10.7 7 Y 8 Partial response (UP 1–2 g/day) eGFR 60 mL.min.1.73m2 IA and TPE dependence Fencl et al. [17] 12/F 3 19 1 Y 7 Partial response SCr 80 μmol/L IA dependence (UP 3 g/day) 9/F 3 14 2 Y 16 Complete response SCr 120 μmol/L IA dependence (UP 0.4 g/day) Paglialonga et al. [18] ND/ND ND ND ND ND Sustained remission after cessation IA ND ND, not done; PTD, post-transplant day; SCr, serum creatinine; UP, urine protein. Table 5 Review of FSGS recurrence after KTx and IA [14–18] Age at diagnosis (years)/ gender Time to ESRD (years) UP at recurrence (g/24 h) PTD of recurrence (days) TPE before IA Delay between recurrence to first IA (months) Efficacy of IA Renal function Dantal et al. [14] 10/F 2 11 10 3 Partial response (UP 1.2 g/day) Good graft function Relapse after cessation of IA Franke et al. [15] 5.9/M 3 ND 1 Y 27 Partial response eGFR 57 mL.min.1.73m2 IA dependence Belson et al. [16] ND/F ND 10.7 7 Y 8 Partial response (UP 1–2 g/day) eGFR 60 mL.min.1.73m2 IA and TPE dependence Fencl et al. [17] 12/F 3 19 1 Y 7 Partial response SCr 80 μmol/L IA dependence (UP 3 g/day) 9/F 3 14 2 Y 16 Complete response SCr 120 μmol/L IA dependence (UP 0.4 g/day) Paglialonga et al. [18] ND/ND ND ND ND ND Sustained remission after cessation IA ND Age at diagnosis (years)/ gender Time to ESRD (years) UP at recurrence (g/24 h) PTD of recurrence (days) TPE before IA Delay between recurrence to first IA (months) Efficacy of IA Renal function Dantal et al. [14] 10/F 2 11 10 3 Partial response (UP 1.2 g/day) Good graft function Relapse after cessation of IA Franke et al. [15] 5.9/M 3 ND 1 Y 27 Partial response eGFR 57 mL.min.1.73m2 IA dependence Belson et al. [16] ND/F ND 10.7 7 Y 8 Partial response (UP 1–2 g/day) eGFR 60 mL.min.1.73m2 IA and TPE dependence Fencl et al. [17] 12/F 3 19 1 Y 7 Partial response SCr 80 μmol/L IA dependence (UP 3 g/day) 9/F 3 14 2 Y 16 Complete response SCr 120 μmol/L IA dependence (UP 0.4 g/day) Paglialonga et al. [18] ND/ND ND ND ND ND Sustained remission after cessation IA ND ND, not done; PTD, post-transplant day; SCr, serum creatinine; UP, urine protein. No comparison trial between TPE and IA in recurrent FSGS in children has been conducted. Half of children in our cohort received TPE before IA, with TPE being effective in four cases (67%), similar to previously published results [5, 8]. In patients treated with early IA, we did not notice a clear benefit of IA compared with TPE (Patients 10 and 11). We could only highlight that no side effect, particularly bleeding, was observed in patients undergoing IA in a context of recent surgery. In patients treated with IA with a long delay from recurrence, IA seemed to be better than TPE only in Patients 8 and 9, switched from chronic treatment with TPE to IA; nevertheless, the quality of life with a high dependence on IA was not acceptable and the technique was stopped. In Patient 4, tested 54 months after the recurrence, no conclusion could be drawn, recognizing that the FSGS response to different therapies can evolve over time. Because our patients received several concomitant immunosuppressive therapies, we cannot affirm that the decrease in proteinuria was only due to IA. Combined use of IA and other therapies may increase the efficacy of both treatments. Because of the limited number of patients and the heterogeneity of the cohort, we failed to show a difference between the responder and the non-responder patients. However, we tried to identify factors influencing IA response. We initially focused on the two patients who did not respond to IA. Patient 11 received only 10 sessions, which was probably an insufficient number to conclude the failure of IA. Indeed, even though the response occurred rapidly in the main responder patients (median number of sessions to achieve a negative proteinuria was 4), one patient needed 9 and 11 sessions to obtain partial and complete remission, respectively. We therefore suggest that a minimum of 15 or 18 sessions (3 sessions per week for 5–6 weeks) should be performed before concluding the absence of efficacy of the IA technique. Despite some physicians suggesting that high levels of IgG supplementation is beneficial to avoid circulating factor production and to improve the clearance of circulating immune complexes, we note that Patient 12 failed to decrease his proteinuria with IA despite higher doses of IgG supplementation than the other patients. We could also hypothesize that in this technique, high-dose Ig could saturate adsorbers, limiting extraction of the circulating factor responsible for FSGS. However, at this stage a consensual dose of intravenous Ig cannot be established, because of the lack of bibliography and comparative/prospective studies. Moreover, due to the retrospective design of this study, we did not seek to determine the superiority of the protein A or IgG column used for the IA technique. The efficacy of anti-proteinuric renin—angiotensin—aldosterone system treatment was not studied in this cohort because of the heterogeneity and the dose variations of medication over time, depending on circulating creatinine and electrolytes. However, we cannot rule out that anti-proteinuric therapies could have influenced the evolution of UPCR, especially in patients receiving delayed IA. The immunosuppressive maintenance therapy could also influence remission. All patients received steroids, anti metabolites and CNI. The two non-responder patients received azathioprine as an antimetabolite. Since MMF had benefits in cortico-dependent nephrotic syndrome, we might wonder if MMF is involved in inducing remission of recurrent FSGS. Almost all patients received rituximab, but we noted that one of the two patients with complete and sustained remission received it before transplantation; nevertheless, because of the data disparities, it was not possible to determine the efficacy of rituximab in post-transplant recurrence of FSGS. Concerning preventive treatment, some recent reports have suggested that prophylactic TPE before transplantation could have a preventive role against recurrence [19, 20]. However, Gonzalez et al. [21] reported that TPE did not decrease the rate of FSGS recurrence but might be beneficial in treating high-risk patients, e.g. previous graft secondary to recurrence. Similar experiences have been reported with IA in an adult cohort [22]. In our series, two patients had preventive apheresis hours before KTx. Interestingly, the only child who had preventive IA presented complete and sustained remission after IA. Finally, we have to keep in mind that rare spontaneous remissions of FSGS have been described in the literature [23–25]. Our study had several limitations, including the retrospective design, the use of several treatment protocols and the absence of a control group, due to the scarcity of pathologic cases. There was no control group because there is no gold standard treatment for recurrent FSGS after KTx. Nevertheless, we reported the results of the first paediatric cohort, well-defined inclusion criteria and long-term and detailed follow-up. To date, there is no guideline on management of IA in recurrent primary FSGS after KTx, and it would be interesting to have a standardized practice. In 2010, Vinai et al. [4] proposed a management algorithm for children with recurrent FSGS after KTx. Today, following recent published results, it appears justified that IA is now proposed alongside TPE as soon as recurrence is diagnosed. Based on the literature review and our experience, we propose the algorithm illustrated in Figure 2. FIGURE 2 View largeDownload slide Suggested algorithm for a method of surveillance and treatment of recurrent FSGS after KTx in children. *Intensive means at least 3 IA sessions per week for 6 weeks (i.e. at least 18 sessions) and at least 5 daily consecutive TPE sessions (repeated once if necessary). **With the limits of our study, we suggest at least a substitution dose of IVIG (0.2–0.4 g/kg) after each IA session; higher doses should be evaluated in further studies. ESRD, end-stage renal disease; IVIG, intravenous immunoglobulin. FIGURE 2 View largeDownload slide Suggested algorithm for a method of surveillance and treatment of recurrent FSGS after KTx in children. *Intensive means at least 3 IA sessions per week for 6 weeks (i.e. at least 18 sessions) and at least 5 daily consecutive TPE sessions (repeated once if necessary). **With the limits of our study, we suggest at least a substitution dose of IVIG (0.2–0.4 g/kg) after each IA session; higher doses should be evaluated in further studies. ESRD, end-stage renal disease; IVIG, intravenous immunoglobulin. In conclusion, we reported the efficacy and safety of IA in 10 of 12 children treated for recurrent FSGS after KTx. IA can be considered as a therapeutic options in the recurrence of FSGS after KTx and is an alternative therapy to TPE due to its more selective performance. Additional follow-up will be required to determine the long-term prognosis for these patients. ACKNOWLEDGEMENTS This French cohort was exhaustive thanks to the collaboration of French paediatric nephrologists. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 D’Agati VD , Kaskel FJ , Falk RJ. Focal segmental glomerulosclerosis . N Engl J Med 2011 ; 365 : 2398 – 2411 Google Scholar CrossRef Search ADS PubMed 2 Straatmann C , Kallash M , Killackey M et al. . Success with plasmapheresis treatment for recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients . Pediatr Transplant 2014 ; 18 : 29 – 34 Google Scholar CrossRef Search ADS PubMed 3 McCarthy ET , Sharma M , Savin VJ. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis . Clin J Am Soc Nephrol 2010 ; 5 : 2115 – 2121 Google Scholar CrossRef Search ADS PubMed 4 Vinai M , Waber P , Seikaly MG. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review . 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Recurrence of nephrotic proteinuria in children with focal segmental glomerulosclerosis after renal transplantation treated with plasmapheresis and immunoadsorption: case reports. Transplant Proc 2007 ; 39 : 3488 – 3490 18 Paglialonga F , Schmitt CP , Shroff R et al. . Indications, technique, and outcome of therapeutic apheresis in European pediatric nephrology units . Pediatr Nephrol 2015 ; 30 : 103 – 111 Google Scholar CrossRef Search ADS PubMed 19 Ohta T , Kawaguchi H , Hattori M et al. . Effect of pre- and postoperative plasmapheresis on posttransplant recurrence of focal segmental glomerulosclerosis in children . Transplantation 2001 ; 71 : 628 – 633 Google Scholar CrossRef Search ADS PubMed 20 Gohh RY , Yango AF , Morrissey PE et al. . Preemptive plasmapheresis and recurrence of FSGS in high-risk renal transplant recipients . Am J Transplant 2005 ; 5 : 2907 – 2912 Google Scholar CrossRef Search ADS PubMed 21 Gonzalez E , Ettenger R , Rianthavorn P et al. . Preemptive plasmapheresis and recurrence of focal segmental glomerulosclerosis in pediatric renal transplantation . Pediatr Transplant 2011 ; 15 : 495 – 501 Google Scholar CrossRef Search ADS PubMed 22 Lionaki S , Vlachopanos G , Georgalis A et al. . Individualized scheme of immunoadsorption for the recurrence of idiopathic focal segmental glomerulosclerosis in the graft: a single center experience . Renal Fail 2015 ; 26 : 1 – 7 23 Striegel JE , Sibley RK , Fryd DS et al. . Recurrence of focal segmental sclerosis in children following renal transplantation . Kidney Int Suppl 1986 ; 19 : S44 – S50 Google Scholar PubMed 24 Habib R , Antignac C , Hinglais N et al. . Glomerular lesions in the transplanted kidney in children . Am J Kidney Dis 1987 ; 10 : 198 – 207 Google Scholar CrossRef Search ADS PubMed 25 Saeed B , Mazloum H , Askar M. Spontaneous remission of post-transplant recurrent focal and segmental glomerulosclerosis . Saudi J Kidney Dis Transpl 2011 ; 22 : 1219 – 1222 Google Scholar PubMed © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Nephrology Dialysis TransplantationOxford University Press

Published: Jul 28, 2017

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