Short-term adverse effects of early subclinical allograft inflammation in kidney transplant recipients with a rapid steroid withdrawal protocol

Abstract

The impact of subclinical inflammation (SCI) noted on early kidney allograft biopsies remains unclear. This study evaluated the outcome of SCI noted on 3-month biopsy. A total of 273/363 (75%) kidney transplant recipients with a functioning kidney underwent allograft biopsies 3-months posttransplant. Among those with stable allograft function at 3 months, 200 biopsies that did not meet the Banff criteria for acute rejection were identified. These were Group I: No Inflammation (NI, n = 71) and Group II: Subclinical Inflammation (SCI, n = 129). We evaluated differences in kidney function at 24-months and allograft histology score at 12-month biopsy. SCI patients had a higher serum creatinine (1.6 ± 0.7 vs 1.38 ± 0.45; P = .02) at 24-months posttransplant, and at last follow-up at a mean of 42.5 months (1.69 ± 0.9 vs 1.46 ± 0.5 mg/dL; P = .027). The allograft chronicity score (ci + ct + cg + cv) at 12-months posttransplant was higher in the SCI group (2.4 ± 1.35 vs 1.9 ± 1.2; P = .02). The incidence of subsequent rejections within the first year in SCI and NI groups was 24% vs 10%, respectively (P = .015). De novo donor-specific antibody within 12 months was more prevalent in the SCI group (12/129 vs 1/71, P = .03). SCI is likely not a benign finding and may have long-term implications for kidney allograft function.

Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection

“…42,43 Increasingly TCMR recurrence or persistence has been reported in serial biopsy studies; however, definite risk factors have not been well elucidated. [12][13][14][15] In this study we found that the number of Banff Although tacrolimus trough level variation is not synonymous with inadequate tacrolimus exposure, it has been correlated with rejection, dnDSA development, and graft loss. [48][49][50] In our study mean CNI trough levels were no different in recipients with and without TCMR.…”

“…Mehta et al reported that i + t>0 biopsies (excluding Banff ≥ IA) had higher serum creatinine and Banff chronicity scores at 12 months compared to i + t = 0 biopsies; however, 21% of the i0t1 patients progressed to more severe forms of TCMR after the initial biopsy. 13 We found that in recipients where isolated mild tubulitis i0t1 was the most severe phenotype there was no association with dnDSA development or graft loss. Furthermore, traditional risk factors of alloimmunity did not correlate with the Banff i0t1 phenotype.…”

“…The key finding in this study is that in the absence of donor-specific memory (ie, no preformed DSA by solid phase single antigen bead assay) alloimmune risk assessment for TCMR can be more precisely Whereas some have argued that TCMR has limited relevance as a correlate of allograft loss, 9,21 others have shown a correlation between early clinical or subclinical TCMR and functional decline, interstitial fibrosis and tubular atrophy, and allograft loss. [12][13][22][23][24][25] Furthermore, multiple studies have reported that early TCMR correlates with later development of dnDSA, ABMR, and chronic glomerulopathy. [26][27][28][29][30][31][32] We found a significant correlation between those with Banff Borderline TCMR or Banff ≥ IA TCMR and death-censored allograft survival (Figure 1).…”

“…Precise risk factors for T cell-mediated rejection (TCMR) in the modern era are poorly defined resulting in one-size-fits-all prevention/treatment strategies for most patients and high recurrence rates reported in serial biopsy studies. [11][12][13][14][15] As the underlying driver of alloimmunity is the dissimilarity between donor and recipient at the molecular level, we hypothesized that the alloimmune risk categories developed using dnDSA free survival would also apply to TCMR. Indeed, we reported that the HLA-DR/DQ molecular mismatch score correlated with Banff ≥ IA TCMR in the first year posttransplant.…”

A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection

“…[5][6][7][8][9][10] The effect of milder subclinical inflammation, i.e., suspicious or borderline lesions, on allograft outcomes is even less characterized. 11 In current clinical practice, the diagnosis of either clinical or subclinical allograft rejection requires a biopsy, a procedure burdened by clinical risks and costs. To obviate these issues, prior studies have tested noninvasive profiling of urinary proteins 12,13 and blood transcriptomic signatures, [14][15][16] but results have been inconsistent so far.…”