Acute Pyelonephritis in Renal Allografts–A New Role for MicroRNAs?

Abstract

Background Acute pyelonephritis (APN) versus acute rejection (AR) is a frequently encountered diagnostic and therapeutic dilemma in kidney transplants. Variable culture results, overlapping histologic features, and persistent graft dysfunction despite antibiotics are frequently encountered. Therefore, we explored the utility of intragraft microRNA profiles to distinguish between allograft APN and AR. Materials and Methods Between 2003 and 2011, we identified 49 patients with biopsy features of APN, within the first 2 years posttransplant. MicroRNA profiling was performed on 20 biopsies (normal kidney, n=4; unequivocal AR, n=5; features of APN, n=11). Results Only 32% (16/49) of the patients had concomitant positive urine cultures at biopsy, and in 8 of 16 patients, colony count was less than 105 CFU/mL. In 14 of 49 patients, positive urine culture did not coincide with the biopsy, and in 19 of 49 patients, urine cultures were negative. On microRNA profiling, good clustering was seen among the normal kidneys and among AR biopsies. Among the 11 biopsies with features of APN, 4 biopsies showed good clustering with a pattern distinct from AR; (these patients recovered graft function with antibiotics); 7 of 11 biopsies showed heterogeneity in microRNA profiles and variable outcomes with antibiotic treatment. We identified a panel of 25 microRNAs showing statistical difference in expression between AR and APN. MiR-99b, miR-23b let-7b-5p, miR-30a, and miR-145 were validated using qPCR. Conclusion Allograft pyelonephritis can be a diagnostic and therapeutic challenge. A gestalt approach is required. In addition to histology and cultures, differential intragraft microRNA expression may prove helpful to distinguish APN from AR in renal allograft biopsies.

Differential gene expression pattern in biopsies with renal allograft pyelonephritis and allograft rejection

“…in which they report that only 23.5% of their patients had positive urine cultures. In our previous study of 49 kidney transplant recipients with APN in first two years post‐transplant, we showed that only 32% (16/49) had concomitant positive urine cultures at biopsy, and in 8 of these 16 patients, colony count was less than 10 5 CFU/mL. In 14 of 49 patients, positive urine culture did not coincide with the biopsy (had positive culture beyond 10 days before or after biopsy), and in 19 of 49 patients, urine cultures were negative.…”

“…This is a retrospective study using biopsy tissue remaining in the paraffin blocks after routine pathology workup. We previously published a case series describing biopsy findings and urine culture results in 49 renal allograft recipients with APN . The histologic criteria that were used for biopsy diagnosis of APN include—interstitial inflammation with predominance of neutrophils, tubular infiltration with neutrophils, and formation of tubular microabscesses .…”

Applying genomics in heart transplantation

“…Comparing biomarker signatures across different solid organ allograft studies is also an area of major value as while there are clearly organ‐specific signals in post‐transplant outcomes, there is also biological overlap in a number of processes related to rejection and other post‐transplant complications across all solid organ transplants. Levels of miR‐21 were observed to be associated with AR, fibrosis, and CAV in heart recipients but were also associated with ischemia–reperfusion injury, fibrosis AbMR, and other complications in kidney and with graft dysfunction in lung allografts . Furthermore, downstream miRNAs derived from miR‐142 (miR‐142‐5p and miR‐142‐3p) are associated with AR, chronic rejection, and/or fibrosis across all four major solid organ transplantations .…”

Gram-negative sepsis following biopsy of a transplant recipient with asymptomatic allograft pyelonephritis

“…Treatment of AGPN is primarily antibiotics and reduction in immunosuppression, whereas ACR is generally treated with increased corticosteroids and often an increase in other immunosuppressive therapy, which may potentially further potentiate the risk of infection. Given the importance of determination of new methods to differentiate between AGPN and ACR, investigators have researched the potential use of microRNAs to differentiate AGPN from ACR on biopsy samples, but studies to date are small in number and results will require extensive validation and optimization before these techniques are clinically established [9].…”