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Profiling of mRNA of interstitial fibrosis and tubular atrophy with subclinical inflammation in recipients after kidney transplantation.

ABSTRACT: Interstitial fibrosis and tubular atrophy (IFTA) with inflammation (IFTA-I) is strongly correlated with kidney allograft failure. Diagnosis of IFTA-I accurately and early is critical to prevent graft failure and improve graft survival. In the current study, through analyzing the renal allograft biopsy in patients with stable function after kidney transplantation (STA), IFTA and IFTA-I group with semi-supervised principal components methods, we found that CD2, IL7R, CCL5 based signature could not only distinguish STA and IFTA-I well, but predict IFTA-I with a high degree of accuracy with an area under the curve (AUC) of 0.91 (P = 0.00023). Additionally, IRF8 demonstrated significant differences among STA, IFTA and IFTA-I groups, suggesting that IRF8 had the capacity to discriminate the different classifications of graft biopsies well. Also, with Kaplan-Meier and log-rank methods, we found that IRF8 could serve as the prognostic marker for renal graft failure in those biopsies without rejection (AUC = 0.75) and the recipients expressing high had a higher risk for renal graft loss (P < 0.0001). This research may provide new targets for therapeutic prevention and intervention for post-transplantation IFTA with or with inflammation.

SUBMITTER: Fu Q

PROVIDER: S-EPMC6682514 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Profiling of mRNA of interstitial fibrosis and tubular atrophy with subclinical inflammation in recipients after kidney transplantation.

Fu Qiang Q Liao Minxue M Feng Cheng C Tang Jichao J Liao Rui R Wei Liang L Yang Hongji H Markmann James F JF Chen Kai K Deng Shaoping S

Aging 20190701 14

Interstitial fibrosis and tubular atrophy (IFTA) with inflammation (IFTA-I) is strongly correlated with kidney allograft failure. Diagnosis of IFTA-I accurately and early is critical to prevent graft failure and improve graft survival. In the current study, through analyzing the renal allograft biopsy in patients with stable function after kidney transplantation (STA), IFTA and IFTA-I group with semi-supervised principal components methods, we found that CD2, IL7R, CCL5 based signature could not ...[more]

PMID: 31343413

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Project description:This study examines the effect of interstitial inflammation and interstitial fibrosis and tubular atrophy on renal survival in lupus nephritis.Baseline characteristics, initial (n = 301) and repeat biopsies (n = 94) and clinical outcomes for patients with biopsy-proven lupus nephritis from 1998 to 2014 were retrospectively collected from the medical record. Clinical and morphologic variables were evaluated using a Cox proportional hazards model and multiple imputation to address missing data. Renal survival was defined as the time from initial biopsy to end-stage renal disease [estimated glomerular filtration rate (eGFR) <15?mL/min/1.73 m2], dialysis or transplant.A total of 218 patients had follow-up and Class IV had worse renal survival, especially in patients with active and chronic glomerular lesions {relative to non-IV; Class IV-A: hazard ratio [HR] 0.92 [95% confidence interval (CI) 0.41-2.04], Class IV-AC: HR 5.02 [95% CI 2.70-9.36]}. Interstitial inflammation grade [relative to interstitial inflammation <5%; interstitial inflammation 5-25%: HR 2.36 (95% CI 1.13-4.91), interstitial inflammation 25-50%: HR 3.84 (95% CI 1.53-9.62), interstitial inflammation >50%: HR 7.67 (95% CI 3.75-15.67)] and increased interstitial fibrosis and tubular atrophy (IFTA) category [relative to IFTA <5%; IFTA 5-25%: HR 3.93 (95% CI 1.58-9.75), IFTA 25-50%: HR 4.01 (95% CI 1.37-11.70), IFTA >50%: HR 13.99 (95% CI 4.91-39.83)] predicted worse renal survival among all patients and those with Class IV on initial and repeat biopsy (n = 94) in a dose-dependent manner. Interstitial inflammation grade and IFTA category were significant predictors of renal survival in a multivariable model adjusted for age, gender, race, ethnicity and serum creatinine.Interstitial inflammation and IFTA independently affect renal survival and grading these lesions stratifies risk within the International Society of Nephrology and Renal Pathology Society classification of lupus nephritis.

Project description:Background and Objectives: Inflammatory interstitial fibrosis and tubular atrophy (i-IFTA) is an inflammation in the area of tubular atrophy and fibrosis. i-IFTA is poorly associated with graft outcome and associated with infiltration of inflammatory mononuclear cells. A cytotoxic T cell is a granzyme B+CD8+CD3+ T cell, mainly secret granzyme B. Granzyme B is a serine protease that may mediate allograft injury and inflammatory interstitial fibrosis and tubular atrophy (i-IFTA). However, there is no report identifying the association of granzyme B with i-IFTA after a long post-transplant interval. Material and Methods: In this study, we have measured the cytotoxic T-cell frequency with flow cytometry, serum and PBMCs culture supernatants granzyme-B levels with ELISA and intragraft granzyme-B mRNA transcript expression with the RT-PCR in RTRs in 30 patients with biopsy-proven i-IFTA and 10 patients with stable graft function. Result: The frequency of cytotoxic T cells (CD3+CD8+ granzyme B+) in SGF vs. i-IFTA was (27.96 ± 4.86 vs. 23.19 ± 3.85%, p = 0.011), the serum granzyme-B level was (100.82 ± 22.41 vs. 130.32 ± 46.60, p = 0.038 pg/mL) and the intragraft granzyme-B mRNA transcript expression was (1.01 ± 0.048 vs. 2.10 ± 1.02, p < 0.001 fold). The frequency of CD3+ T cells in SGF vs. i-IFTA was (66.08 ± 6.8 vs. 65.18 ± 9.35%; p = 0.68) and that of CD3+CD8+ T cells was (37.29 ± 4.11 vs. 34.68 ± 5.43%; p = 0.28), which were similar between the 2 groups. CTLc frequency was negatively correlated with urine proteinuria (r = -0.51, p < 0.001), serum creatinine (r = -0.28, p = 0.007) and eGFR (r = -0.28, p = 0.037). Similarly, the PBMC culture supernatants granzyme-B level was negatively correlated with urine proteinuria (r = -0.37, p < 0.001) and serum creatinine (r = -0.31, p = 0.002), while the serum granzyme-B level (r = 0.343, p = 0.001) and intragraft granzyme-B mRNA transcript expression (r = 0.38, p < 0.001) were positively correlated with proteinuria. Conclusions: A decrease in the CTLc frequency in circulation and an increased serum granzyme-B level and intragraft granzyme-B mRNA expression shows that cytotoxic T cells may mediate the allograft injury in RTRs with i-IFTA by releasing granzyme B in serum and intragraft tissue.

Dataset Information

Profiling of mRNA of interstitial fibrosis and tubular atrophy with subclinical inflammation in recipients after kidney transplantation.

Publications

Profiling of mRNA of interstitial fibrosis and tubular atrophy with subclinical inflammation in recipients after kidney transplantation.

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