Urinary cytotoxic molecular markers for a noninvasive diagnosis in acute renal transplant rejection*

Abstract

Summary Perforin (P), Granzyme B (GB) and Fas‐Ligand (FAS‐L) are cytotoxic molecules involved in acute rejection (AR) after renal transplantation. A noninvasive diagnostic test to monitor AR and other complications could improve clinical management. We investigated the predictive and diagnostic interest of target mRNA measurements, with a quantitative PCR assay, in AR, as well as in other clinical complications recurrent in kidney transplantation. One hundred and sixty‐two urine specimens from 37 allograft recipients were investigated. Clinical settings were AR, urinary tract infection (UTI), cytomegalovirus infection (CMVi) or disease (CMVd), chronic allograft nephropathy (CAN), delayed graft function (DGF) and stable graft course (controls). In the case of AR, mRNA levels of all three molecules were significantly higher than in recipients not showing any clinically evident signs of complication. Indeed, it was observed that expression levels of P, GB and Fas‐L mRNA also increase in other clinical situations such as UTI, CMV and DGF. Finally, kinetic studies in three patients with AR revealed that increased P, GB and Fas‐L mRNA levels could precede or were concomitant with increased serum creatinin levels. P, GB and Fas‐L gene expression in urine specimens were upregulated in AR episodes but also in UTI, CMV infection and DGF. Therefore, this technique would appear to be of limited clinical value as a noninvasive method of diagnosing AR.

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

“…Numerous studies have reported elevated GrB levels in the plasma and inflammatory infiltrate of biopsies from patients experiencing acute rejection, suggesting GrB may be a useful biomarker for the prediction of acute rejection. [237][238][239][240][241][242][243][244][245] Although acute rejection constitutes a major challenge in the early postoperative period, the major impediment to longterm survival for solid organ transplant recipients is allograft vasculopathy (AV), which is an accelerated, immune-mediated form of occlusive arteriosclerotic vascular disease that affects vessels of solid organ allografts. 307,308 The pathogenesis of AV is complex and characterized by intimal accumulation of SMCs, T lymphocytes, and macrophages, as well as extensive medial thinning that is associated with increased SMC apoptosis.…”

Value of FOXP3 Expression in Peripheral Blood as Rejection Marker After Miniature Swine Lung Transplantation

“…In addition, our study suggested that FOXP3 may be superior to conventional rejection markers, such as perforin, Fas-L and IP-10, in terms of detecting early rejection. [44][45][46][47] The possibility of FOXP3 being a marker for an early phase of rejection was supported by our finding that a rescue immunosuppressive therapy, which was started when peak FOXP3 level was noted, significantly prolonged graft survival, but not in a therapy started when rejection was suspected by chest radiography. However, because the expression of FOXP3 was upregulated only early post-transplantation, a combination of FOXP3 and chest radiography may detect rejection more efficiently than FOXP3 alone or chest radiography alone.…”

Evaluation of Gene Panel mRNAs in Urine Samples of Kidney Transplant Recipients as a Non-invasive Tool of Graft Function

“…Recently Li et al (11) reported that mRNA levels of T cell-related cytotoxicity molecules perforin and granzyme B were enhanced in urine samples from AR patients. Other groups showed similar results (30)(31)(32). However, the role of the measurement of mRNA in urine samples as indicators of graft function at different times post-KT is less clear.…”