Monitoring suPAR levels in post-kidney transplant focal segmental glomerulosclerosis treated with therapeutic plasma exchange and rituximab.

BACKGROUND: Therapeutic plasma exchange (TPE) is an important therapy for recurrent focal segmental glomerulosclerosis (rFSGS) post kidney transplant. suPAR has been causally implicated in rFSGS, and shown to be a unique biomarker for the occurrence and progression of chronic kidney disease. This study was targeted to evaluate the application of monitoring suPAR in TPE treated rFSGS. METHODS: A retrospective (n = 19) and a prospective (n = 15) cohort of post transplant FSGS patients treated with TPE and rituximab were enrolled. We measured serum suPAR levels before and after the combined therapies, and assessed the role of suPAR changes on proteinuria reduction and podocyte ß3- integrin activity. RESULTS: Treatment with TPE and rituximab resulted in significant decrease in proteinuria and suPAR levels. Among the variables including baseline suPAR, serum creatinine, proteinuria, eGFR, age at diagnosis, age at transplantation, transplantation numbers, time to recurrence, and TPE course numbers, only the reduction in suPAR levels and baseline proteinuria significantly correlated with the changes in proteinuria after treatment, with the former performed better in predicting proteinuria alteration. Additionally, the mean podocyte ß3 integrin activity significantly decreased after TPE and rituximab treatment (1.10 ± 0.08) as compared to before treatment (1.34 ± 0.08), p < 0.05. Only the reduction in suPAR predicted the response to therapies with an odds ratio of 1.43, 95% CI (1.02, 2.00), p < 0.05. CONCLUSIONS: Serum suPAR levels reduced significantly after TPE and rituximab treatment in post transplant FSGS patients. The reduction in suPAR levels may be utilized to assess the changes in proteinuria and monitor the response to the therapies. Larger, multi-centered prospective studies monitoring serum suPAR levels in TPE managed post transplant FSGS are warranted.

Quantitative characterization of T-cell repertoire and biomarkers in kidney transplant rejection.

BACKGROUND: T-cell-mediated rejection (TCMR) remains a major cause of kidney allograft failure. The characterization of T-cell repertoire in different immunological disorders has emerged recently as a novel tool with significant implications. We herein sought to characterize T-cell repertoire using next generation sequencing to diagnose TCMR. METHODS: In this prospective study, we analyzed samples from 50 kidney transplant recipients. We collected blood and kidney transplant biopsy samples at sequential time points before and post transplant. We used next generation sequencing to characterize T-cell receptor (TCR) repertoire by using illumina miSeq on cDNA synthesized from RNA extracted from six patients' samples. We also measured RNA expression levels of FOXP3, CD8, CD4, granzyme and perforin in blood samples from all 50 patients. RESULTS: Seven patients developed TCMR during the first three months of the study. Out of six patients who had complete sets of blood and biopsy samples two had TCMR. We found an expansion of the TCR repertoire in blood at time of rejection when compared to that at pre-transplant or one-month post transplant. Patients with TCMR (n = 7) had significantly higher RNA expression levels of FOXP3, Perforin, Granzyme, CD4 and CD8 in blood samples than those with no TCMR (n = 43) (P = 0.02, P = 0.003, P = 0.002, P = 0.017, and P = 0.01, respectively). CONCLUSIONS: Our study provides a potential utilization of TCR clone kinetics analysis in the diagnosis of TCMR. This approach may allow for the identification of the expanded T-cell clones associated with the rejection and lead to potential noninvasive diagnosis and targeted therapies of TCMR.

ACTH Gel in Resistant Focal Segmental Glomerulosclerosis After Kidney Transplantation.

BACKGROUND: Treatment of focal segmental glomerular sclerosis (FSGS) after kidney transplantation is challenging with unpredictable outcomes. The objective was to investigate the use of adrenocorticotropic hormone (ACTH) analogue gel in kidney transplant recipients with de novo or recurrent FSGS resistant to therapeutic plasma exchange (TPE) and/or rituximab. METHODS: We performed a retrospective review of cases of de novo or recurrent resistant FSGS at 2 large US transplant centers between April 2012 and December 2016. Proteinuria was measured by urine protein to creatinine ratio. RESULTS: We identified 20 cases of posttransplant recurrent and de novo FSGS resistant to conventional therapy with TPE and rituximab. Mean ± SD age was 49 ± 15.5 years, 14 (70%) were male, 13 (65%) were whites, and 8 (38%) had previous kidney transplants. Median (interquartile range) of recurrent and de novo FSGS was 3 (0.75-7.5) months posttransplant. The majority of patients, 15 (75%), received TPE as a treatment at the time of diagnosis and 10 (50%) received rituximab, which was started before the use of ACTH gel. There was a significant improvement of urine protein to creatinine ratio from a mean ± SD of 8.6 ± 7.6 g/g before ACTH gel to 3.3 ± 2.3 g/g after the use of ACTH gel (P = 0.004). Ten (50%) patients achieved complete or partial remission. CONCLUSIONS: Although, the response varied among the recipients, ACTH gel might be an effective therapy for posttransplant resistant FSGS cases that fail to respond to TPE and rituximab.

Rituximab and Therapeutic Plasma Exchange in Recurrent Focal Segmental Glomerulosclerosis Postkidney Transplantation.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease with a high rate of recurrence after kidney transplantation. Several factors, such as white race, rapid progression, and previous allograft failure due to recurrence, were found to be risks of recurrence. Data are limited on the benefits of rituximab and/or therapeutic plasma exchange (TPE) in preventing recurrence. In this study, we sought to assess the efficacy of rituximab and TPE for the prevention and treatment of recurrent FSGS after kidney transplantation. METHODS: We enrolled 66 patients with FSGS in this prospective observational study and followed their outcomes. Patients with high risk for recurrence received preventative therapy with TPE and/or rituximab. RESULTS: Twenty-three (62%) of the 37 patients who received preventative therapy developed recurrence compared with 14 (51%) recurrences of the 27 patients who did not receive any therapy (P = 0.21). There was a trend for less relapse when rituximab was used as a therapy for recurrent FSGS (6/22 vs 9/18, P = 0.066). We used a clinical score of 5 values to assess the prediction of FSGS recurrence. A score of 3 or more had a predictive receiver operating characteristic curve of 0.72. Treatment with TPE and/or rituximab resulted in better allograft survival than historical studies. Allograft failure because of recurrent FSGS occurred in only 6 (9%) patients. CONCLUSIONS: Preventative therapies do not decrease the recurrence rate of recurrent FSGS. However, prompt treatment of recurrence with these therapies may result in improved outcomes.