Acute pyelonephritis in renal allografts: a new role for microRNAs?

Kidney transplantation, being an immunocompromised state, predisposes the recipient to a variety of bacterial, viral, and fungal infections. Urinary tract infections (UTIs) are common during the first several months posttransplantation, and these can predispose the patient to allograft pyelonephritis (1–8). The diagnosis of acute pyelonephritis (APN) in the native kidney is usually made based on the classic tetrad—fevers, costovertebral angle tenderness, history of lower urinary tract infection, and microbiological cultures of the urine. The native kidney is therefore rarely biopsied for APN. However, in the context of renal transplantation and immunosuppression, the classic clinical features of fever and pain are frequently subdued, and costovertebral angle tenderness is not an accompanying feature. Blood leukocyte counts can be altered by immunosuppressive medications. APN in the renal allograft is therefore often coincidentally discovered on allograft biopsy, and a definitive diagnosis can only be made if there is positive concomitant urine culture result. Allograft biopsy and urine culture are the best currently available tools to diagnose APN in the renal allograft, but both these methods have pitfalls. Interstitial inflammation with predominance of polymorphonuclear leukocytes (PMNs) and intratubular PMNs forming microabscesses are considered hallmark histologic features of APN. However, it is common to find PMNs in the inflammatory cell infiltrates of acute rejection (AR) as well. Also, the characteristic finding of neutrophilic tubulitis and tubular microabscesses in APN may not always be demonstrated in a biopsy because of the focal nature of these lesions and sampling issues. Thus, histologic features between APN and acute AR may overlap. Concomitant microbiological urine culture and colony counting by plating measured quantity of urine on culture plates is used to aid in the diagnosis. Colony count of 105 colony forming units per milliliter (CFU/mL) is considered to be diagnostic of true infection (as opposed to contamination by urogenital skin flora) (9). However, we have encountered cases with low colony counts despite biopsy features of APN in kidney transplant recipients. This can make the diagnosis of APN in renal allografts difficult. To further confound the diagnosis, rapid response to antibiotics may not always be achieved despite histologic findings of APN and positive urine culture results. The purpose of our study was twofold: 1. to retrospectively assess the degree of correlation between histologic features of APN on biopsy, and positive urine culture results in transplant patients; and 2. to explore the potential for intragraft microRNA profiling to distinguish between APN and AR. Intragraft miRNA profiling was performed on a subset of biopsies from our study cohort. MicroRNAs (miRNAs) are short noncoding RNAs that modulate physiological and pathological processes by inhibiting target gene expression by inducing mRNA degradation and blocking protein translation (10). MiRNAs potentially regulate the expression of thousands of proteins. The miRNA field is being extensively explored to discover new diagnostic biomarkers and potential treatments in cancer (11). MiRNA profiling is also being studied in native kidney disease and renal allografts (12–23, 26, 27, 33, 34).