Kidney Transplantation For Focal Segmental Glomerulosclerosis: Can We Prevent Ⅱ Its Recurrence? Personal Experience And Literature Review

4. Discussion

The rate of recurrence of primary FSGS on a renal graft was 20 to 40% for a first graft, but reached 80 to 100% recurrence on subsequent grafts if there was recurrence on the first graft [5,18]. In our case series, the rate of recurrence of primary FSGS on the kidney transplant was 47%. Kalliopi Vallianou et al. [19] also found 54% recurrence of primary FSGS (25 patients) among 46 kidney-transplant recipients; in addition, recurrence developed very soon after transplantation; i.e., the median recurrence time was 0.5 months (0.1–1). The main risk factors for FSGS recurrence were recurrence on a previous transplant, rapid progression to stage 5 CKD on native kidneys, and young age at the time of initial diagnosis [5,20–22]. An albuminemia level of <25 g/L at the time of diagnosis was also considered to be a risk factor for recurrence on the renal transplant [23]. In contrast, the type of donor (living vs. deceased) did not influence the risk of FSGS recurrence [19].

In our study, all patients who relapsed with a first graft also relapsed with subsequent grafts. The time to progression to stage 5 CKD and young age at diagnosis of FSGS were lower in the relapsers (group 1) compared to the non-relapsers (group 2); i.e., 5 (min: 1; max: 26) vs. 2 (min: 1; max: 26) years, and 16 (min: 4; max: 55) vs. 34 (min: 6; max: 48) years, respectively. Two of our patients received transplants from living donors. 

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Despite rituximab and apheresis prophylaxis, group 1 patients had FSGS recurrence after a median of 3 (min: 1; max: 4745) days, and two subsequently lost their allograft. In general, renal transplantation from a living donor allowed better graft survival compared to transplantation from a deceased donor. However, in view of the significant risk of recurrence of primary FSGS, it was not advisable to propose a kidney transplant from a living donor in the event of primary FSGS, especially if there had been recurrence on a previous graft because, to date, there is still no effective prophylaxis that can prevent FSGS recurrence [24,25].

In group 2, no patient had FSGS recurrence in the kidney transplant. The mean age in this group at FSGS diagnosis was 34 (min: 6; max: 48) years. The genetic study was not carried out in these patients. We did not find any secondary causes of FSGS, but we therefore could not rule out a genetic cause explaining the absence of FSGS recurrence. Morello et al. [26], in a study published on 101 kidney transplant patients for steroid-resistant nephrotic syndrome (SRNS), after a median follow-up of 58.5 months, found a SRNS recurrence in the first renal transplant in 53.3% of patients with a nongenetic cause, and in none in those who had a genetic SRNS. They concluded that the absence of a causative mutation represented the major risk factor for post-transplant recurrence in children with SRNS.

In our series, prophylaxis with rituximab and apheresis did not appear to reduce the risk of recurrence of primary FSGS. In fact, the combination of plasmapheresis and rituximab immediately before kidney transplantation in 87.5% of these patients did not prevent recurrence. However, after an average follow-up of 7 ± 3 years, this association of treatments seemed to be effective when recurrence occurred at post-transplantation; i.e., remission was induced in 50% of cases. 

Prophylaxis is based on the assumption of the existence of a soluble permeability factor [4,5]. This factor has been suggested by several observations, including the development of proteinuria in rats after injection of proteins eluted from an immunoadsorption (IA) column used by FSGS-treated patients [27]. This was also suggested by: (i) the disappearance of nephrotic syndrome after transplantation of a kidney from an FSGS patient into a non-FSGS kidney recipient [7,28,29]; (ii) the occurrence of a nephrotic syndrome in a newborn of an FSGS mother [30]; and (iii) the control of nephrotic syndrome with apheresis [31]. 

Several factors have been mentioned, such as suPAR, cardiotrophin-like cytokine-1 (CLCF-1), apolipoprotein A1, anti-tyrosine phosphatase antibody of the O receptor, CAsK, and sCD40L [4,8–14], with different mechanisms of action. It seems obvious that the pathophysiology of FSGS is multifactorial. To prevent the recurrence of FSGS on the kidney transplant, rituximab and apheresis (IA and plasma exchange (PLEX)) are the most frequent treatments used. Apheresis would make it possible to eliminate the soluble hyperpermeability factor, whereas rituximab (anti-CD20 monoclonal antibody) would have two mechanisms of action: (i) depletion of B lymphocytes and facilitating the production of regulatory T cells, thereby influencing the production of circulating factor; and (ii) inhibition of the degradation of actin in podocytes [32,33] by regulating the activity of acid sphingomyelinase using SMPDL-3B (sphingomyelin phosphodiesterase acid-like 3b).

None of the preventive intervention measures showed any benefits in the recurrence of primary FSGS after kidney transplantation. However, Kalliopi Vallianou et al. [19] found that 90% of patients without recurrence had received prophylaxis by plasmapheresis, versus 62% of recurrent patients (p = 0.029). In contrast, Alasfar et al. [24] carried out a retrospective study that included 37 kidney-transplant recipients at high risk of recurrence for FSGS and that had received preventive treatment with PLEX and/or rituximab. A total of 23 (62%) of the 37 patients who received preventive treatment developed recurrence, compared to 14 (51%) recurrences in the 27 patients who received no treatment (p = 0.21). Likewise, Verghese et al. [25] retrospectively reviewed pediatric patients with FSGS (n = 57) and who had received a kidney transplant. They compared two groups (group 1: kidney transplant recipients after 2006 and who had received a PLEX before transplantation (n = 31); and group 2: kidney-transplant patients who received a transplant before 2006 and had not received a PLEX (n = 26)). They found no significant difference in the incidence (27 vs. 26%, p = 1.0) or the time until FSGS recurrence (p = 0.22) between the two groups.

Table 3 summarizes the main studies published for adults and children regarding the prevention of FSGS recurrence after kidney transplantation by apheresis and/or rituximab. These were mainly retrospective studies. We found no prospective randomized studies. The preventive protocol varied from one study to the other. However, apart from the case reports, we noticed that prophylaxis by apheresis and/or rituximab did not prevent FSGS recurrence. Finally, genetic studies were also missing in most of the studies.

Plasmapheresis allowed complete or partial remission in 70% of children and 63% of adults when commenced soon after a recurrence [6]. Indeed, Trachtman et al. [46], in a literature review, reported that rituximab was associated with remission of nephrotic syndrome in ~75% of patients after FSGS recurrence on a kidney allograft. Likewise, Kashgary et al. [47] published a meta-analysis that included 413 renal-transplant recipients who had relapsing primary FSGS. After a median follow-up of 19 months, they found complete or partial remission in 71% (95% CI 66–75%) of patients after treatment with plasma exchange. Patients treated within 2 weeks of recurrence showed a trend towards a greater likelihood of remission (OR 2.16; 95% CI 0.93–5.01). In a study conducted by Kalliopi Vallianou et al. [19], patients with FSGS recurrence on a kidney allograft were treated by plasmapheresis and/or rituximab: this resulted in complete remission in 27% of cases and partial remission in 42.3% after an average therapy duration of 3 ± 1.79 and 4.4 ± 2.25 months, respectively. 

In addition to plasmapheresis, semispecific IA is effective at causing remission. Lionaki et al. [48] reported on 12 adult renal-transplant patients with re-current FSGS that were treated with IA ± rituximab: after a mean follow-up of 48.3 months, there was complete remission in 58.3% of cases and partial remission in 41.7%. Likewise, Allard et al. [49] reported complete remission in 67% and partial remission in 33% of 12 children who had undergone renal transplantation and had FSGS recurrence treated with IA sessions. After 3 months of IA treatment, two patients maintained remission without IA, and eight became IA-dependent [49]. 

To assess the benefit of adding rituximab to plasmapheresis to treat an FSGS relapse after kidney transplantation, Linares et al. [50] identified 148 adult FSGS patients who received a renal transplant between 2004 and 2018; of these, 109 received plasmapheresis (G1) and 39 received combined plasmapheresis with rituximab (G2). In the G1 group, rituximab was introduced only after failure of plasma-exchange therapy (n = 31); i.e., after an average of 28 days. Complete remission was achieved in 46.6% of patients, and partial remission was achieved in 33.1%. Analysis of the propensity score showed no difference in the rates of complete remission and partial remission between G1 (82.6%) and G2 (71.8%) (p = 0.08). Following the addition of rituximab, 26.3% of patients had complete remission, and 31.6% had partial remission. The incidence of severe infection was similar between patients treated with or without rituximab. In multivariate analysis, infectious episodes were associated with hypogammaglobulinemia < 5 g/L.

Our study had some limitations, including its relatively small sample size, retrospective nature, heterogeneity of treatments given, and absence of genetic testing. Indeed, only one of our patients underwent genetic exploration. 

5. Conclusions 

We concluded that pretransplant prophylaxis with plasmapheresis and rituximab did not appear to reduce the risk of recurrence of primary FSGS on the graft, but potentially could allow remission in the event of recurrence, to be confirmed by randomized studies. Because recurrence can occur several years after transplantation, this justifies rigorous monitoring of patients with FSGS, more so than for other kidney transplant recipients. 

References 

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2. Haas, M.; Spargo, B.H.; Coventry, S. Increasing incidence of focal-segmental glomerulosclerosis among adult nephropathies: A 20-year renal biopsy study. Am. J. Kidney Dis. 1995, 26, 740–750. [CrossRef]

3. Korbet, S.M. Treatment of primary FSGS in adults. J. Am. Soc. Nephrol. 2012, 23, 1769–7176. [CrossRef] [PubMed] 

4. Ponticelli, C.; Glassock, R.J. Posttransplant Recurrence of Primary Glomerulonephritis. Clin. J. Am. Soc. Nephrol. 2010, 5, 2363–2372. [CrossRef]

5. D'Agati, V.D.; Kaskel, F.J.; Falk, R.J. Focal segmental glomerulosclerosis. N. Engl. J. Med. 2011, 365, 2398–2411. [CrossRef] [PubMed]

6. Canaud, G.; Martinez, F.; Noël, L.H.; Mamzer, M.F.; Niaudet, P.; Legendre, C. Therapeutic approach to focal and segmental glomerulosclerosis recurrence in kidney transplant recipients. Transplant. Rev. 2010, 24, 21–128. [CrossRef] [PubMed]

7. Königshausen, E.; Sellin, L. Circulating Permeability Factors in Primary Focal Segmental Glomerulosclerosis: A Review of Proposed Candidates. BioMed Res. Int. 2016, 2016, 3765608. [CrossRef]

8. McCarthy, E.T.; Sharma, M.; Savin, V.J. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 2010, 5, 2115–2121. [CrossRef] 

9. Wei, C.; El Hindi, S.; Li, J.; Fornoni, A.; Goes, N.; Sageshima, J.; Maiguel, D.; Karumanchi, S.A.; Yap, H.K.; Saleem, M.; et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 2011, 17, 952–960. [CrossRef] 10. Wei, C.; Möller, C.C.; Altintas, M.; Li, J.; Schwarz, K.; Zacchigna, S.; Xie, L.; Henger, A.; Schmid, H.; Rastaldi, M.P.; et al. Modification of kidney barrier function by the urokinase receptor. Nat. Med. 2008, 14, 55–63. [CrossRef] 11. Bock, M.E.; Price, H.E.; Gallon, L.; Langman, C.B. Serum soluble urokinase-type plasminogen activator receptor levels and idiopathic FSGS in children: A single-center report. Clin. J. Am. Soc. Nephrol. 2013, 8, 1304–1311. [CrossRef] 12. Charba, D.S.; Wiggins, R.C.; Goyal, M.; Wharram, B.L.; Wiggins, J.E.; McCarthy, E.T.; Sharma, R.; Sharma, M.; Savin, V.J. Antibodies to protein tyrosine phosphatase receptor type O (PTPro) increase glomerular albumin permeability (P(alb)). Am. J. Physiol. Ren. Physiol. 2009, 297, F138–F144. [CrossRef] 

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