Post-transplant Focal Segmental Glomerulosclerosis Recurrence Research Articles

Clinical Course of Nonresponders With Recurrent Focal Segmental Glomerulosclerosis After Pediatric Kidney Transplantation: A Retrospective Multicenter Study.

Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and is associated with poor graft survival. Patients who do not achieve remission (nonresponders) have an especially poor graft survival. However, the characteristics that may affect graft survival in nonresponders are unknown. This study aimed to determine the clinical characteristics associated with graft survival in nonresponders. We retrospectively collected the clinical records of patients with FSGS and an age at onset <16 years who experienced posttransplant recurrence of FSGS at six hospitals in Japan from 1993 to 2018. Eight nonresponders with recurrent FSGS were enrolled in this study. The median time to recurrence after kidney transplantation was 1 day (interquartile range, 1-2 days). All patients received therapeutic plasma exchange and methylprednisolone pulse therapy. Rituximab was used as an add-on therapy in three patients. Five patients lost their graft within 2 years after kidney transplantation (rapid group). In contrast, three patients had much longer graft survival (nonrapid group). We compared the clinical characteristics of the rapid and nonrapid groups. Proteinuria tended to be lower in the nonrapid group at the third and subsequent months of therapy. The rapid group had persistent nephrotic syndrome. The rate of reduction in proteinuria was lower in the rapid group than in the nonrapid group. Our study suggests that persistent nephrotic syndrome and a low rate of reduction in proteinuria may predict rapid progression to graft failure in nonresponders.

A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence

Possible roles of anti-nephrin antibodies in post-transplant recurrent focal segmental glomerulosclerosis (FSGS) have been reported recently. To confirm these preliminary results, we performed a multi-institutional study of 22 Japanese pediatric kidney transplant recipients with FSGS including eight genetic FSGS and 14 non-genetic (presumed primary) FSGS. Eleven of the 14 non-genetic FSGS patients had post-transplant recurrent FSGS. Median (interquartile range) plasma levels of anti-nephrin antibodies in post-transplant recurrent FSGS measured using ELISA were markedly high at 899 (831, 1292) U/mL (cut-off 231 U/mL) before transplantation or during recurrence. Graft biopsies during recurrence showed punctate IgG deposition co-localized with nephrin that had altered localization with increased nephrin tyrosine phosphorylation and Src homology and collagen homology A expressions. Graft biopsies after remission showed no signals for IgG and a normal expression pattern of nephrin. Anti-nephrin antibody levels decreased to 155 (53, 367) U/mL in five patients with samples available after remission. In patients with genetic FSGS as in those with non-genetic FSGS without recurrence, anti-nephrin antibody levels were comparable to those of 30 control individuals, and graft biopsies had no signals for IgG and a normal expression pattern of nephrin. Thus, our results suggest that circulating anti-nephrin antibodies are a possible candidate for circulating factors involved in the pathogenesis of post-transplant recurrent FSGS, and that this may be mediated by nephrin phosphorylation. Larger studies including other ethnicities are required to confirm this finding.

#4635 CIRCULATING NEPHRIN AUTOANTIBODIES IN PATIENTS WITH POST-TRANSPLANT RECURRENCE OF PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Abstract Background and Aims Post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) is a major challenge in the field of nephrology and kidney transplantation. Primary FSGS is thought to be caused by circulating factors (CFs) that injure podocytes, but these factors remain unknown despite intensive efforts to identify them. Recently, one post-transplant recurrent FSGS patient with pretransplant nephrin autoantibodies was reported (Watts AJB et al, JASN 33:238, 2022). Furthermore, we reported very early post-transplant recurrence changes of podocytes and possible roles of circulating nephrin autoantibodies in a patient with FSGS recurrence (Hattori M et al, AJT 22:2478, 2022). To confirm these preliminary results, we examined the autoantibodies to nephrin and the punctate deposition of IgG colocalized with nephrin using stocked plasma samples and grafted kidney biopsy specimens of the patients with FSGS recurrence. Method This study was approved by the local Ethics Committee of Tokyo Women's Medical University (approval no. 2021-0184). The clinical and research activities reported here are consistent with the Principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism”. From 1989 to 2022, a total of 78 patients with FSGS underwent kidney transplantation in our institution, and 16 patients experienced post-transplant recurrence of FSGS. Since the stoked plasma samples were available in 14 out of 16 patients, these 14 patients were included in this study. All 14 patients showed immediate post-transplant recurrence and had no pathogenic variants in FSGS-related genes including NPHS1. Circulating anti-nephrin autoantibodies were measured using the ELISA methods based on the Watts's report with one modification, that is, recombinant extracellular domain of human nephrin was obtained commercially (R&amp;D systems, USA). To validate the ELISA system, circulating anti-nephrin autoantibodies were also measured in 9 genetic FSGS patients, 13 membranous nephropathy (MN) patients, 4 lupus nephritis (LN) patients, and 13 healthy controls. Dual immunofluorescence (IF) staining of nephrin and IgG and image acquisition using the two-dimensional structured illumination microscopy mode with a Nikon microscope were performed as previously reported (Hattori M et al, AJT 22:2478, 2022). Results The cut-off level of anti-nephrin antibody calculated from the results of a total 30 cases including 13 MN patients, 4 LN patients, and 13 healthy controls using Frey's formula (J Immunol Method, 1998) was 172.2 U/mL All 14 recurrent patients enrolled in this study had higher titter than the cut-off level and the mean ± SD of the anti-nephrin antibody level in these patients was 939.9 ± 261.8 U/mL. In contrast, the mean anti-nephrin antibody level in patients with genetic FSGS was 98.6 ± 77.3 U/mL, which was comparable with healthy controls. The IF staining of graft biopsy specimens showed punctate depositions of IgG colocalized with nephrin in all 14 recurrent patients. Conclusion The autoantibodies to nephrin in plasma samples and the punctate deposition of IgG colocalized with nephrin in grafted kidney biopsy specimens were observed in all 14 patients with post-transplant recurrent FSGS. Further studies in larger numbers of patients as well as in patients of other ethnicities are clearly required to confirm this surprising result; however, circulating nephrin autoantibodies could be a possible candidate for CFs in the pathogenesis of recurrent FSGS.

A Possible Role of Anti-Nephrin Autoantibody in Endocytosis of Nephrin in Patients With Post-Transplant Focal Segmental Glomerulosclerosis Recurrence and Minimal Change Disease

A Possible Role of Anti-Nephrin Autoantibody in Endocytosis of Nephrin in Patients With Post-Transplant Focal Segmental Glomerulosclerosis Recurrence and Minimal Change Disease

Amount and selectivity of proteinuria may predict the treatment response in post-transplant recurrence of focal segmental glomerulosclerosis: a single-center retrospective study.

Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and is associated with poor graft survival. To date, few studies have investigated predictive factors for treatment responses in recurrent FSGS. We retrospectively analyzed 16 patients who were < 16 years at the age of onset and had post-transplant recurrence of FSGS from 1993 to 2018. Patients who achieved complete remission or partial remission after initiating therapy for recurrent FSGS were defined as responders. We compared several clinical characteristics between responders and non-responders. Time to remission was also analyzed. Ten patients were responders, and six patients were non-responders. Univariate analysis showed that responders had a significantly lower amount of maximum proteinuria at the time of recurrence (P = 0.015) and more highly selective proteinuria (P = 0.013) than non-responders. The time to remission from initiation of therapy was 2 months (interquartile range 0.2-4.4). In all responders, except for one patient, remission was achieved within 6 months. Therapeutic responses may be predicted by examining the amount and selectivity of proteinuria at the time of recurrence. Further studies with larger numbers of patients are clearly required to validate these findings.

Effect of galactose on glomerular permeability and proteinuria in steroid-resistant nephrotic syndrome

Idiopathic steroid-resistant nephrotic syndrome (SRNS) has been associated with the presence of a circulating focal sclerosis permeability factor (FSPF) thought to damage the glomerular barrier and increase permeability to albumin. Galactose binds and inactivates FSPF in vitro, but its effect in vivo is uncertain. A prospective clinical trial was conducted to investigate the effect of oral galactose on FSPF and proteinuria in children with SRNS. Seven pediatric subjects with idiopathic SRNS and positive FSPF activity (>0.5) were treated with oral galactose (0.2gm/kg/dose twice daily) for 16weeks. Post-treatment FSPF and proteinuria were measured. Focal sclerosis permeability factor activity of the seven subjects decreased from 0.69 ± 0.11 to 0.35 ± 0.21 (p = 0.009) in response to galactose. The two subjects with post-transplant recurrence of focal segmental glomerulosclerosis (FSGS) demonstrated the most significant improvement in FSPF (p = 0.006). Despite this decrease in FSPF, the pre- and post-treatment urine protein:creatinine ratio remained unchanged and no subject achieved remission. Galactose decreases FSPF in children with SRNS, with the most significant improvement in those with post-transplant FSGS recurrence, but it fails to improve proteinuria. At the present time there is no evidence to support the use of galactose in children with FSGS, either pre- or post-transplant. Future studies to investigate the role of galactose as preemptive therapy to decrease the risk of post-transplant FSGS recurrence may be useful.

Outcome of Primary Glomerular Disease in Pediatric Renal Transplantation: A Single-Center Experience

Introduction The recurrence of primary disease in transplantation is a well-known problem. We report our single-center experience to assess the frequency of the recurrence of primary glomerulonephritis in children after renal transplantation. Patients and methods Medical reports of 14 children with primary glomerular disease were evaluated. Among the 14 grafts were 10 from living related and four from cadaveric donors. Ten were diagnosed as focal segmental glomerulosclerosis (FSGS), two membranoproliferative glomerulonephritis (MPGN), and two polyarteritis nodosa (PAN). The original diagnosis was biopsy-proven in every case. All patients were treated with calcineurin-based immunosuppressive therapy. Results The mean age was 15.5 ± 5.4 years. The median transplantation duration was 47 months; however, one of the FSGS patient had hyperacute rejection. Five years later she received a second graft with a serum creatinine of 0.7 mg/dL at 7 years after transplantation. Posttransplant recurrence of FSGS was confirmed in two patients (20%), who were treated with plasmapheresis with no improvement of proteinuria, two FSGS patients had thromboses after transplantation. One had a cardiac thrombosis with heterozygote MTHFR mutation and one, a renal artery thrombosis and loss of graft with prothrombin 20210A mutation. They all have functioning grafts except these two. We did not observe recurrence of PAN or MPGN in patients. Conclusion Although the number of patients is quite small, our recurrence rate was compatible with the previous reports. Additionally, we strongly recommend evaluation of all risk factors for thrombosis and give appropriate anticoagulation.

Direct effect of plasma permeability factors from patients with idiopatic FSGS on nephrin and podocin expression in human podocytes

The presence of circulating plasma factors (PF) altering renal permeability to proteins has been previously described in patients with focal segmental glomerulosclerosis (FSGS). Since these patients show reduced nephrin and podocin expression at renal biopsy, we evaluated the effect of serum and PF from patients with FSGS on nephrin and podocin expression in human podocytes. We studied 7 sera from patients with steroid-resistant FSGS, 3 from patients with nephrotic syndrome caused by non-immune disease, and 6 from healthy subjects. PF was prepared from plasmapheresis eluates of 2 patients with post-transplant recurrence of FSGS. Purification procedure was based on protein A Sepharose chromatography and differential precipitation in ammonium sulphate. Nephrin and podocin expression was semi-quantitatively evaluated by immunofluorescence. We found that serum and PF from FSGS patients rapidly induced redistribution and loss of nephrin in podocytes. This effect was associated with cytoskeleton redistribution and inhibited by cytochalasin B and sodium azide. On the contrary, podocin expression was unchanged after incubation with serum and PF from FSGS patients for short periods, but markedly reduced at 24 h. Our results demonstrate that serum and PF from FSGS patients may directly affect nephrin and podocin in human podocytes, thus providing new insights into the mechanisms causing proteinuria in FSGS.

Complete remission of post-transplant FSGS recurrence by long-term plasmapheresis

Focal segmental glomerulosclerosis (FSGS) is known to recur in approximately 30% of renal allografts with graft loss in about half of these cases. The exact etiology remains unclear, though a putative circulating permeability factor or loss of inhibitory substances is being discussed. Different therapeutic approaches have been used. We report on a 10-year-old Arabian boy with a recurrence of FSGS immediately after transplantation. In addition to intensifying immunosuppressive therapy with high-dose cyclosporin A and cyclophosphamide, plasmapheresis was initiated and remission was achieved after 8 months. Three weeks after cessation of plasmapheresis a relapse occurred. Plasmapheresis was resumed and remission was achieved again after four additional sessions. The interval between plasmapheresis treatments was then gradually increased and fourteen months after transplantation plasmapheresis was stopped again. Since then (1.5 years after cessation of treatment) the patient has been in complete remission without any further episode of proteinuria. In conclusion, complete and sustained remission with stable renal function was achieved in our patient by long-term plasmapheresis in combination with intensified immunosuppression. Therefore, continuation of plasmapheresis treatment should be considered even in the situation of initial non-response.

Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin

Background:Posttransplant recurrence of focal segmental glomerulosclerosis (FSGS) occurs in a relevant proportion of FSGS patients and represents an important clinical emergency. It is taken as a proof of the existence of circulating permeability plasma factor(s) that are also putative effectors of original proteinuria in these patients. Familial forms of FSGS do not recur, but the discovery of numerous patients with sporadic FSGS and mutations of podocin (NPHS2, that is actually an inherited disease) who received a renal graft require a re-evaluation of the problem. Methods:To evaluate the incidence of posttransplant recurrence of FSGS in patients with NPHS2, the authors screened for podocin mutations in 53 patients with the clinical and pathologic stigmata of FSGS who had renal failure and who had undergone renal transplantation. Results.Twelve children were found to carry a homozygous (n9) or a heterozygous (n4) mutation of podocin and were classified, according to current criteria, as patients with inherited FSGS. In 5 patients of this group (38%), proteinuria recurred after renal graft and in 2, renal biopsy results showed recurrence of FSGS. Prerecurrence serum of 3 patients of this cohort was tested for antipodocin antibodies with indirect immuno-Western utilizing human podocyte extracts and were found negative. The rate of FSGS recurrence was comparable in non-NPHS2-FSGS children (12 of 27) and adults (3 of 13). Also clinical outcome of recurrence and response to plasmapheresis and immunosuppressors were comparable, suggesting a common mechanism. Conclusion:These data show a high rate of FSGS recurrence in patients with NPHS2 mutations that is comparable with idiopathic FSGS and describe the successful therapeutic approach. Recurrence of an apparently inherited disease should stimulate a critical review of the mechanisms of recurrence and of original proteinuria in these cases.

Recurrent focal segmental glomerulosclerosis following renal transplantation in Korean pediatric patients.

The recurrence of focal segmental glomerulosclerosis (FSGS) in transplants is a well-known problem in pediatric renal transplantation (Tx). Recently, the race of the recipient was recognized as a major variable associated with disease recurrence. In view of this finding, we report on our single-center experience of FSGS recurrence in Korean children, an ethnically homogeneous Far East Asian population. Clinical records and renal biopsy specimens, both native and graft, were reviewed for all pediatric renal Txs (recipient age < or = 18 yr) performed at Seoul National University Hospital from 1984 to 1999. Twenty-two children with primary FSGS received 22 allografts for renal replacement. The mean age of disease onset in these patients was 5.9 yr. The grafts were from 12 living-related, six living-unrelated, and four cadaveric donors, and all recipients were immunosuppressed with cyclosporin A (CsA)-based regimens. Post-transplant recurrence of FSGS was confirmed in nine patients (41%). Long-term graft survival in recurrent and non-recurrent groups was not significantly different. Risk factor analysis showed that patients with a disease duration shorter than 48 months (odds ratio 11.7, 95% CI 1.53-89.1) and a glomerulosclerosis percentage of < 55% by renal biopsy (odds ratio 16.0, 95% CI 1.45-176) were at greater risk of disease recurrence. These results suggest that Korean children are similar to non-African-American youngsters in the USA and Europe with respect to post-transplant recurrence of FSGS. The same may be true of other Far Eastern Asian children.