Post-transplant Focal Segmental Glomerulosclerosis Research Articles

Multiple-target Therapy for Posttransplant Focal Segmental Glomerulosclerosis.

There is no consensus on the ideal strategy to treat posttransplant focal segmental glomerulosclerosis. The multiple-target therapy, which consisted of high-dose intravenous cyclosporine, prednisone, and plasmapheresis, showed favorable results. This single-center, prospective study sought to evaluate the multiple-target therapy in an independent cohort of patients. Thirteen patients with posttransplant focal segmental glomerulosclerosis received multiple-target therapy. Complete remission was achieved in 2 patients (15.4%), and partial remission in another 2 patients (15.4%). Four patients (30.7%) did not show remission, and 5 patients (38%) lost the graft because of posttransplant focal segmental glomerulosclerosis during the 12-mo follow-up. Premature discontinuation of treatment occurred in 10 patients (77%), all associated with infectious adverse events. Cytomegalovirus was the most common complication, and preemptive therapy was used instead of prophylaxis. In this cohort of patients, the efficacy of the multiple-target therapy was poor and limited by the high incidence of infectious adverse events.

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.

An 8-Year Retrospective Review of Human Albumin Solution (HAS) Use August 2015 to March 2023; Guy's and St Thomas' NHS Foundation Trust (GSTFT)

Abstract Background: HAS is widely used in clinical practice for a variety of haematological, renal, neurological, respiratory and metabolic conditions. A United Kingdom shortage in 2015 prompted a demand management guideline incorporating the American Society for Apheresis (ASFA) indications 1 and GSTFT criteria 2 for other indications. Objectives:The objective of this study was to evaluate the indications for HAS usage following the introduction of the GSTFT demand management guideline. Methods: We audited HAS usage from August 2015 to March 2023 at GSTFT. Data was entered in SPSS version 20, with categorical variables described as frequencies and percentages. Results: 4816 patients received HAS during the study period, totaling 21,231 infusions. We recorded 16,772 (79%) infusions for 20% HAS in 4,145 patients. The indications for 20% HAS included; volume resuscitation for hypovolaemia 5237 (31%), severe sepsis/septic shock 3528 (21%), acute lung injury and severe respiratory failure 2987 (18%), paracentesis 2402 (14%), hepatorenal syndrome 1710 (10%), childhood nephrotic syndrome 685 (4.1%) and spontaneous bacterial peritonitis 223 (1.3%) (Table 1). According to GSTFT criteria infusions were recorded in the following indication categories: Red 7099 (42.3%), Blue 4436 (26.4%) and Grey 5237 (31.2%). A total of 4459 (21%) infusions were recorded for 4.5 and 5% HAS. A total of 3628 (81%) infusions were used for plasma exchange (PEX) in 305 patients; 2817(76.99%) ASFA category I, 445(12.03%) category II, 290(7.97%) category III and 92 (2.5%) for indications not specified according to ASFA; 826 infusions (18.5%) were for volume resuscitation for hypovolaemia (Grey indication) in 389 patients, the remaining 5 infusions (0.1%) were in 3 patients for burns and thermal injuries (Table 1). Major indications for PEX included post-transplant focal segmental glomerulosclerosis 911 infusions (20%) in 9 patients, familial hypercholesterolaemia 738 infusions (16%) in 5 patients, antibody mediated rejection 439 infusions (10%) in 71 patients (Table 2). Conclusions: This report provides a rare long term retrospective review of total albumin usage in a large UK tertiary referral center. The majority (97.5%) of PEX HAS indications were within ASFA guidelines. Aside from apheresis the main indication for HAS was volume resuscitation, a grey indication, where evidence is weak. REFERENCES (1) Padmanabhan A, Connelly-Smith L, Aqui N, Balogun RA, Klingel R, Meyer E, Pham HP, Schneiderman J, Witt V, Wu Y, Zantek ND, Dunbar NM, Schwartz GEJ. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34(3):171-354. doi: 10.1002/jca.21705. PMID: 31180581 (2) Yazdani MS, Retter A, Maggs T, Li P, Robson MG, Reid C, Holmes P, Garood T, Robinson SE. Where does the Albumin go? Human Albumin Solution usage following the implementation of a demand management programme. Transfus Med. 2017 Jun;27(3):192-199. doi: 10.1111/tme.12406. Epub 2017 Apr 3. PMID: 28370709.

Clinicopathological differences in focal segmental glomerulosclerosis depending on the accompanying pathophysiological conditions in renal allografts

Primary focal segmental glomerulosclerosis (FSGS) is thought to be caused by circulating factors leading to podocytopathy, whereas segmental sclerotic lesions (FSGS lesions) have several causes. We studied the clinicopathological differences of FSGS-lesions in 258 cases of FSGS in renal allografts, depending on the following accompanying pathophysiology: recurrence of primary FSGS, calcineurin inhibitor (CNI)-induced arteriolopathy, antibody-mediated rejection (ABMR), and other conditions. All cases were categorized with the Columbia classification. Recurrent FSGS developed the earliest after transplantation and showed the highest percentage of the collapsing (COL) variant in which collapse of the glomerular capillaries with epithelial hypertrophy was apparent. FSGS accompanying CNI-induced arteriolopathy predominantly developed the not otherwise specified (NOS) variant, showing severe ultrastructural endothelial injury. On the contrary, approximately 7% of the cases showed the COL variant, presenting glomerular endothelial damage such as double contours of glomerular basement membrane and endothelial cell swelling as well as epithelial cell proliferation. FSGS with ABMR had the highest creatinine levels and cellular variant percentage, with marked inflammation and ultrastructural endothelial injury. Approximately two-thirds of the cases without ABMR, CNI-induced arteriopathy, or recurrent FSGS had other coexisting conditions such as glomerulonephritis, T cell-mediated rejection, and reflux nephropathy with progressive tubulointerstitial fibrosis. Most of these cases were of the NOS variant. The clinicopathologic features of post-transplant FSGS differed depending on the associated conditions, and endothelial injury was apparent especially in cases of CNI-induced arteriolopathy and ABMR. Precise observation of FSGS lesions may facilitate the diagnosis and clinical management of FSGS during renal transplantation.

#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&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

Circulating nephrin autoantibodies and posttransplant recurrence of primary focal segmental glomerulosclerosis

To the Editor: Posttransplant recurrence of primary focal segmental glomerulosclerosis (FSGS) is a major challenge in the field of kidney transplantation. Primary FSGS is thought to be caused by circulating factors (CFs) that injure podocytes,1 but these factors remain unknown despite intensive efforts to identify them.2 Recently, one posttransplant recurrent FSGS patient with pretransplant nephrin autoantibodies was reported; however, the involvement of nephrin autoantibodies in the pathogenesis of recurrence has not been clarified.3 Here, we present very early posttransplant recurrence changes of podocytes and possible roles of circulating nephrin autoantibodies in FSGS recurrence. This study was approved by the local Ethics Committee of Tokyo Women’s Medical University (approval no. 2021–0184). We analyzed plasma samples and kidney tissue specimens of preperfusion (0 h) and postperfusion (1 h) in one patient (patient 1) with and one (patient 2) without FSGS recurrence after first kidney transplantation. Patient 1 had no pathogenic variants in FSGS-related genes including NPHS1. Patient 2 was shown to carry compound heterozygous LAMB2 variants after his kidney transplantation. Plasma samples were obtained before any prophylactic therapies were administered for their kidney transplantation. Patient clinical data are presented in Table S1 and methods are provided in the Supplementary Methods. We identified autoantibodies to nephrin in plasma of the patient showing recurrence (patient 1), but not in plasma of the patient without recurrence (patient 2) (Figure 1A). We further observed that punctate IgG was present and specifically colocalized with nephrin in the 1 h biopsy from the FSGS recurrent patient (Figure 1B and Figure S1), which is in line with the findings of Watts et al. for a subset of minimal change disease biopsies.3 In a previous in vitro experiment, a monoclonal anti-nephrin antibody induced nephrin tyrosine phosphorylation.4 Moreover, Src homology and collagen homology A (ShcA) protein was found to be expressed at low levels in podocytes and to bind tyrosine-phosphorylated nephrin as an adaptor protein.5 Here, dual immunofluorescence (IF) staining for IgG and phosphorylated (p)-nephrinY1176 revealed induced nephrin tyrosine phosphorylation colocalizing with IgG in the 1 h biopsy from the recurrent patient (Figure 1C and Figure S2). We further observed increased expression of ShcA in the 1 h biopsy from the recurrent patient and observed it to colocalize with nephrin (Figure 1D and Figure S3). These findings indicate that nephrin tyrosine phosphorylation was induced very early after exposure of circulating nephrin autoantibodies. Nephrin tyrosine phosphorylation is known to influence signal transduction pathways which control several podocyte functions including nephrin trafficking and cytoskeletal organization.5 In this study, IF staining for nephrin showed linear expression along the glomerular capillary in the 0 h biopsy from the recurrent patient, but nephrin expression took on a granular pattern in the 1 h biopsy (Figure 1E). Moreover, glomeruli appeared normal under light microscopy in the 1 h biopsy (Figure 1F), but podocyte foot process effacement (FPE) was segmentally observed under electron microscopy in the 1 h biopsy from the recurrent patient (Figure 1G and Figure S4). Further studies are clearly needed to confirm our preliminary results; however, our current findings indicate that circulating nephrin autoantibodies detected in plasma from a recurrent patient induce nephrin tyrosine phosphorylation that leads to increased ShcA expression, altered nephrin distribution, and podocyte FPE very early after kidney transplantation. Furthermore, circulating nephrin autoantibodies could be a possible candidate for CFs in the pathogenesis of recurrent FSGS. We thank the affected individuals, their families, and their physicians who contributed to this study. In this research work, we used instruments in the Medical Research Institute, Tokyo Women’s Medical University. This work was supported in part by Grants-in-Aid Scientific Research (C) (JP18K07857 [MH], JP21K07829 [KM], and JP21K07857 [NK]) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Efficacy of intravenous combined immunosuppression with plasmapheresis in adult patients with refractory primary focal segmental glomerulosclerosis

Primary focal segmental glomerulosclerosis (FSGS) treatment is based on immunosuppressive therapies. Since refractory disease is common, alternative methods are emerging. One of these methods is plasmapheresis with intravenous cyclosporine and corticosteroids, and it could be an option in post-transplant recurrent FSGS. We retrospectively investigated the efficacy of this combined treatment in adult patients with refractory primary FSGS. Seven refractory primary FSGS patients were included. Demographics, estimated glomerular filtration rates, serum albumin levels, urine protein/creatinine ratios, and previous treatments were evaluated. Also, complications and remission rates were assessed. Median patient age was 23 years. Median duration of diagnosis was 2 years. Median number of plasmapheresis sessions was 14. Five of seven patients (71.4%, one complete, four partial remissions) were responders after the protocol. Changes in serum albumin levels and proteinuria after protocol were statistically significant (P= 0.018 and P= 0.018, respectively). eGFR levels did not change statistically (P= 0.753). Median follow-up duration after the treatment was 17 months. However, two patients experienced disease relapse (28.5%). End-stage kidney disease was developed in two patients. Sustained remission rate was 42.8% during follow-up (One complete and two partial remissions). Also, 42.8% of patients experienced catheter infections. Catheter-associated thrombosis that required surgery was observed in a patient. Plasmapheresis combined with intravenous cyclosporine and corticosteroids could be an option in refractory primary FSGS. High response rates after this protocol were encouraging. However, the relapsing disease was observed after the cessation of apheresis. Also, complications of the protocol could limit the applicability.

Benefit of B7-1 staining and abatacept for treatment-resistant post-transplant focal segmental glomerulosclerosis in a predominantly pediatric cohort: time for a reappraisal

BackgroundPrimary FSGS manifests with nephrotic syndrome and may recur following KT. Failure to respond to conventional therapy after recurrence results in poor outcomes. Evaluation of podocyte B7-1 expression and treatment with abatacept (a B7-1 antagonist) has shown promise but remains controversial.MethodsFrom 2012 to 2020, twelve patients developed post-KT FSGS with nephrotic range proteinuria, failed conventional therapy, and were treated with abatacept. Nine/twelve (< 21 years old) experienced recurrent FSGS; three adults developed de novo FSGS, occurring from immediately, up to 8 years after KT. KT biopsies were stained for B7-1.ResultsNine KTRs (75%) responded to abatacept. Seven of nine KTRs were B7-1 positive and responded with improvement/resolution of proteinuria. Two patients with rFSGS without biopsies resolved proteinuria after abatacept. Pre-treatment UPCR was 27.0 ± 20.4 (median 13, range 8–56); follow-up UPCR was 0.8 ± 1.3 (median 0.2, range 0.07–3.9, p < 0.004). Two patients who were B7-1 negative on multiple KT biopsies did not respond to abatacept and lost graft function. One patient developed proteinuria while receiving belatacept, stained B7-1 positive, but did not respond to abatacept.ConclusionsPodocyte B7-1 staining in biopsies of KTRs with post-transplant FSGS identifies a subset of patients who may benefit from abatacept.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Recurrent Glomerular Disease after Kidney Transplantation: Diagnostic and Management Dilemmas.

Recurrent glomerular disease after kidney transplant remains an important cause of allograft failure. Many of the different entities post-transplant still suffer from incomplete knowledge on pathophysiology, and therefore lack targeted and effective therapies. In this review, we focus on specific clinical dilemmas encountered by physicians in managing recurrent glomerular disease by highlighting new insights into the understanding and treatment of post-transplant focal segmental glomerulosclerosis, membranous nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, amyloid light-chain (AL) amyloidosis, and IgA nephropathy.

Combination of High-Dose Intravenous Cyclosporine and Plasma Exchange Treatment Is Effective in Post-Transplant Recurrent Focal Segmental Glomerulosclerosis: Results of Case Series

BackgroundIdiopathic focal segmental glomerulosclerosis (FSGS) commonly recurs in the early post-transplant period. The treatment protocols and results are conflictive in recurrent FSGS. We aimed to present the results of our treatment protocol and basic approach to the disease recurrences. MethodsThis prospective, single-center study was conducted between the years 2015 and 2018. Twelve patients who fit completely the diagnosis of idiopathic FSGS by clinical, laboratory, and biopsy findings were included. A specific treatment protocol which consists of plasma exchange and high dose intravenous cyclosporine was delivered to the patients independently of induction protocols. Twenty-four months of outcomes of graft functions were evaluated. ResultsNine patients completed the treatment protocol and were documented for evaluation. All patients achieved a complete or partial remission in an average 24 months of follow-up period. ConclusionIdiopathic FSGS is more commonly recurrent than thought to be. The early detection of proteinuria is crucial because the administration of a plasma exchange–based treatment protocol can reverse proteinuria. We think our treatment protocol is a well-established, efficient, and safe choice for post-transplant recurrent FSGS in adults.

LDL-apheresis-induced remission of focal segmental glomerulosclerosis recurrence in pediatric renal transplant recipients.

Focal segmental glomerulosclerosis (FSGS) in pediatric patients is typically difficult to treat and will progress to end-stage renal disease (ESRD) in about 10% of cases. Following kidney transplantation, FSGS can recur in up to 56% of renal allografts-with a near 100% recurrence in subsequent transplants. Four different pediatric centers across the USA and the UK employed a protocol using LDL-apheresis (LDL-A) and pulse solumedrol to treat recurrent FSGS after transplantation in seven patients. All the patients included in this series demonstrated immediate, or early, recurrence of FSGS, which clinically presented as nephrotic-range proteinuria within hours to days after implantation of the kidney. All patients experienced reductions in urinary protein to creatinine ratios resulting in partial or complete remission. All patients demonstrated improvements in their estimated GFRs at their most recent follow-up since LDL-A discontinuation. This case series describes the successful treatment, across four different pediatric centers, of seven pediatric patients with recurrent post-transplant FSGS using the Liposorber® LA-15 in combination with pulse solumedrol.

Successful management of post-transplant focal segmental glomerulosclerosis with therapeutic plasma exchange and rituximab.

Post-transplant focal segmental glomerulosclerosis (FSGS) is associated with renal allograft loss. Currently, optimal treatment remains controversial. The aim of our study was to examine the efficacy and safety of therapeutic plasma exchange (TPE), and rituximab (RTX), in the management of post-transplant FSGS. The treatment protocol consisted of RTX and monthly cycles of 5 plasma exchanges for 6 months. We treated 10 transplant recipients with biopsy-proven post-transplant FSGS. Lastly, we compared the studied group to a historic control group of nine patients with post-transplant FSGS. 9 out of 10 patients achieved remission after the conclusion of treatment (4 complete and 5 partial), while 1 patient did not respond to treatment. During the follow-up period, there was one graft loss and one patient died while in remission from unrelated complications. There was a significant reduction in mean uPCR between diagnosis (517.4 ± 524.2mg/mmol) and last follow-up (87 ± 121.6mg/mmol) in the patients with sustained remission (p = 0.026). There was no significant decline in eGFR in the eight relapse-free responders at the end of follow-up. (54.4 ± 16.7 from 49.8 ± 20.4ml/min) (p = 0.6) An increased response rate to the combined TPE and RTX treatment was demonstrated, when compared to a historic control group of nine patients with post-transplant FSGS, as only five out of nine patients achieved remission (two complete and three partial) in that group. In this study, treatment with TPE and RTX appears to be safe, well tolerated and effective in the management of patients with post-transplant FSGS.

The role of plasma exchange in treating post-transplant focal segmental glomerulosclerosis: A systematic review and meta-analysis of 77 case-reports and case-series.

BackgroundEvidence on the role of plasma exchange for treating recurrent post-transplant focal segmental glomerulosclerosis (FSGS) comes largely from individual cases and uncontrolled series. We conducted a systematic review and meta-analysis to estimate the remission rate after treatment with plasma exchange, and to determine if remission varied with patient or treatment characteristics.MethodsWe searched MEDLINE, EMBASE, Science Citation Index Expanded, and the Conference Proceedings Citation Index (Science and BIOSIS) for studies of patients with post-transplant recurrent FSGS who were treated with plasma exchange after recurrence (1950–2012). Of 678 studies screened, 77 met our inclusion criteria: 34 case reports (45 patients) and 43 case series (378 patients). We extracted patient-level data from each study and used random-effects models to calculate remission, defined as proteinuria <3.5 g/day (partial) or <0.5 g/day (complete).ResultsThe overall remission rate in 423 patients with outcome data was 71 % (95 % CI: 66 % to 75 %). In 235 patients with data on age, remission was similar for adults and children: 69.1 % (95 % CI: 59.6 % to 77.2 %) and 70.2 % (95 % CI: 61.1 % to 77.9 %). Males were more likely to achieve remission (OR = 2.85; 95 % CI: 1.44 to 5.62) and patients treated within 2 weeks of recurrence showed a trend towards higher likelihood of remission (OR = 2.16; 95 % CI: 0.93 to 5.01). Proteinuria >7 g/day at recurrence was inversely associated with remission (OR = 0.43; 95 % CI: 0.19 to 0.97). Age and type of kidney transplant (living vs. deceased) did not associate with remission.ConclusionIn this systematic review of patients with recurrent post-transplant FSGS, 71 % of patients achieved full or partial remission after treatment with plasma exchange; however, extensive missing data and lack of a control group limit any conclusions on causality.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0322-7) contains supplementary material, which is available to authorized users.

Alemtuzumab Induction and Post-Transplant Glomerulonephritis in Kidney Transplantation.

Background: The incidence and nature of Post-Transplant Glomerulonephritis (PTGN) in patients receiving Alemtuzumab induction has been rarely reported. In this study we investigate the incidence of PTGN and its effect on outcomes in kidney transplant recipients receiving a steroid sparing immunosuppressive regime with Alemtuzumab induction. Methods: We retrospectively reviewed the medical records of 848 (544 male, mean age 48.4 +/- 13.3 years) kidney transplant recipients in our centre between November 2005 and June 2013 for the occurrence of PTGN. All the patients received a steroid sparing immunosuppressive regime with Alemtuzumab induction and tacrolimus monotherapy. Steroids and MMF were only introduced to treat rejection. Results: 66 out of 848 patients (7.8%) developed biopsy proven PTGN. A male predominance was found in the PTGN group (9.56% male vs 4.8% female, p=0.01), while PTGN was found not to be related to ethnicity (p=0.404), or donor type (p=0.167). Mean follow up of PTGN patients was 40.3 (+24.5) months and mean time from transplantation to diagnosis was 20.4 (+20.2) months. Out of 66 PTGN patients, 16(1.9%) were diagnosed with Focal Segmental Glomerulosclerosis (FSGS), 37(4.4%) IgA Nephropathy (IGAN), 2(0.2%) Lupus nephritis(LN), 3(0.4%) Membranous Nephropathy (MN) and 8(0.9%) with other PTGN's.Table: No Caption available.There was no difference in patient survival between the PTGN and the non-PTGN groups at 1 (98.4 vs 97.8%) and 3 years (96.7% vs 94.3%) post transplantation. (p=0.2) Censored allograft survival did not differ between the 2 groups (95.6% and 91.1% in the PTGN vs. 100% and 88.3% in the non-PTGN group at 1 and 3 years; p=0.11). When stratified according to diagnosis, censored allograft survival was found to be lower in the patients diagnosed with FSGS (100% and 67.3% at 1 and 5 years) when compared to the non-PTGN group (95.6% and 87.1%% at 1 and 5 years). (p=0.02) Conclusion: Although these are medium term data, the incidence of PTGN in patients receiving Alemtuzumab induction appears similar to other induction agents. Post-transplant FSGS is associated with a poor prognosis and we are developing new strategies to deal with this problem.

Pretransplant Anti-Angiotensin Type 1 Receptor Antibodies (Anti-AT1R) Can Predict Patients at High Risk of Post-Transplant Focal Segmental Glomerulosclerosis (FSGS) Recurrence.

Pretransplant Anti-Angiotensin Type 1 Receptor Antibodies (Anti-AT1R) Can Predict Patients at High Risk of Post-Transplant Focal Segmental Glomerulosclerosis (FSGS) Recurrence.

Response: galactose treatment in focal and segmental glomerulosclerosis

Dear Editors, We would like to thank the authors of this “letter to the editor” for their interest in our study and for sharing their perspective [1]. We are in agreement with many of the points noted in the letter and have discussed them in our manuscript. The in vitro studies of Savin et al. [1], as well as the case reports by Kopac [2] and De Smet [3], were the catalyst for undertaking this investigation, and are reviewed in our manuscript [4]. The authors state that the lack of response to galactose in our study may be due to preexisting permanent irreversible glomerular damage; we agree with this, and have delineated this as a possible explanation in our discussion section. We have also discussed in our manuscript the possibility that a higher dose of galactose or longer duration of therapy could have yielded different results. We fully agree that there may be subgroups of patients that would benefit from galactose; we therefore proposed further investigation of galactose as a preemptive therapy for prevention of post-transplant focal segmental glomerulosclerosis (FSGS) recurrence, as our permeability activity results suggest a greater chance of response in this subgroup. This does not exclude the possibility that other subgroups of patients may respond to galactose, however at the present time there is no evidence to support this, based on our data. As our study is the first published prospective trial of galactose therapy in steroid-resistant nephrotic syndrome (SRNS), our conclusion stating that galactose is presently of uncertain clinical benefit is based on our results. While galactose is safe and non-toxic, it is also a very expensive therapy and merits further proof of its benefit. We look forward to learning about any new data, including the authors’ unpublished observations, that will yield further insight as to if, when, how, and in which subgroup of children with SRNS, this novel therapy can be utilized to achieve partial or complete remission of disease.

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.

Successful treatment of recurrent focal segmental glomerulosclerosis combined with calcineurin inhibitor nephrotoxicity four yr after kidney transplantation

A 31-yr-old Japanese man with end-stage kidney disease caused by primary focal segmental glomerulosclerosis (FSGS) underwent living related kidney transplantation at the age of 26 yr. The allograft functioned well immediately after surgery, and we did not observe histological findings of rejection and recurrent FSGS in protocol biopsies at two months and one yr after transplantation. Four years after transplantation, the urine protein excretion reached 11 g/d, and the serum creatinine increased over 2.5 mg/dL. We diagnosed nephrotic syndrome due to recurrent FSGS with graft dysfunction and confirmed FSGS lesions with severe endothelial injury with an allograft biopsy, associated with calcineurin inhibitor (CNI) nephrotoxicity. Thereafter, we performed plasmapheresis and steroid therapy with subsequent low-density lipoprotein adsorption, combined with the reduction of tacrolimus. The nephrotic syndrome improved dramatically with the multiple therapeutic approaches. Primary FSGS recurs frequently in patients immediately after kidney transplantation. Post-transplant FSGS has various causes, such as recurrent primary disease, obesity, hyperfiltration, donor-related nephrosclerosis, and CNI-induced arteriolopathy. In the case of nephrotic syndrome after kidney transplantation, we should consider not only recurrent FSGS, but also CNI-induced nephrotoxicity to determine the optimal treatment.

Protocol biopsies for focal segmental glomerulosclerosis treated with plasma exchange and rituximab in a renal transplant patient

We discuss a renal transplant patient with focal segmental glomerulosclerosis (FSGS) treated with plasma exchange and rituximab. A 45-yr-old woman underwent cadaveric renal transplantation in May 2008. She had started hemodialysis support in 1991. Immediately after transplantation, massive proteinuria (1-5 g/d) appeared. Graft biopsy at one h showed minor glomerular abnormalities with partial foot process effacement on electric microscopy. Protocol biopsy at three months after transplantation for persistent proteinuria showed obvious FSGS under light microscopy. Plasma exchange and rituximab administration were subsequently initiated in August 2008, and proteinuria disappeared within a month after starting these treatments. Protocol graft biopsy one yr after transplantation (2009) showed increased global sclerosis and a decrease in segmental sclerosis. In addition, foot process effacement had recovered by one yr after transplantation. Plasma exchange and subsequent rituximab administration led to clinical remission of post-transplant FSGS with improvement in podocyte structure. Rituximab should be considered soon after several sessions of plasmapheresis in transplant patients with recurrent FSGS.