Changes in Urinary Microbiome Populations Correlate in Kidney Transplants With Interstitial Fibrosis and Tubular Atrophy Documented in Early Surveillance Biopsies

Abstract

An unbalanced microbiome may lead to disease by creating aberrant immune responses. A recent association of cellular rejection with the development of interstitial fibrosis and tubular atrophy (IFTA) suggests the role of immune-mediated tissue injury. We hypothesized that developing IFTA correlates with altered urinary tract microbiomes (UMBs). UMBs at two serial time points, 1 and 6-8 months post-transplant, were assessed by 16S microbial ribosomal gene sequencing in 25 patients developing biopsy-proven IFTA compared to 23 transplant patients with normal biopsies and excellent function (TX) and 20 healthy non-transplant controls (HC). Streptococcus, the dominant genera in HC males, was lower in IFTA and TX males at 1 month compared to HCs. At 6-8 months, Streptococcus was further decreased in IFTA males, but normalized in TX. IFTA males and females had increases in number of genera per sample at 6-8 months. UMB composition varied substantially between individuals in all groups. Despite the wide variation in UMBs between individuals, IFTA associated with a loss in dominant resident urinary microbes in males, and a parallel increase in non-resident, pathogenic bacteria in males and females. UMB changes may contribute to IFTA development by alteration of the host immune response.

Urinary microbiome associated with chronic allograft dysfunction in kidney transplant recipients

“…Lee et al investigated kidney transplant recipients found to have AR but the authors examined the gut microbiome rather than urine. The work of Modena et al studied the urinary microbiome as a marker for kidney allograft dysfunction, but all of these patients had already developed the irreversible changes of IFTA (scored moderate to severe by 2007 Banff criteria). Based on index biopsy data, the prevalence of moderate to severe IFTA in our cohort was less than in Salomon's cohort (see Table ); greater than 80% of our allograft biopsies (cases as well as controls) were scored at 0 or 1 by Banff criteria for interstitial fibrosis.…”

“…Several Corynebacterium species are known skin and mucosal commensals, and others are known to cause urinary tract infections, but the significant incidence increase in cases suggests their presence is due to more than simple contamination. All patients were instructed by study coordinators on proper clean‐catch technique for urine sampling, and this would have minimized skin flora contamination as in other urine microbiome studies with similar outlined protocols . Our study initially set out to identify both bacterial and fungal signatures in the cohort.…”

“…All patients were instructed by study coordinators on proper clean-catch technique for urine sampling, and this would have minimized skin flora contamination as in other urine microbiome studies with similar outlined protocols. 16 Our study initially set out to identify both bacterial and fungal signatures in the cohort. However, the fungal results were not revealing, due in part to low numbers of OTUs aligning with existing mycobiome libraries, but further study with ongoing development of a more robust ITS1/2 database may shine light onto this F I G U R E 5 Cladogram of LEfSe analysis results comparing male vs female cases.…”

“…Alterations in the urinary microbiome have been explored in a variety of lower urinary tract disorders such as urinary incontinence, interstitial cystitis, urologic cancers, and chronic prostatitis, but little is yet known about urinary microbiome alterations in renal allograft dysfunction. Quantification of the urinary microbiome in renal allograft recipients has been performed in small cohorts, and dysregulation of the microbiome has been associated with interstitial fibrosis and tubular atrophy (IFTA) . However, to our knowledge, the urinary microbiome has not been studied in CAD prior to IFTA development.…”

“…Quantification of the urinary microbiome in renal allograft recipients has been performed in small cohorts, 14,15 and dysregulation of the microbiome has been associated with interstitial fibrosis and tubular atrophy (IFTA). 16 However, to our knowledge, the urinary microbiome has not been studied in CAD prior to IFTA development. We hypothesized that CAD is associated with alterations in the urinary microbiome in renal transplant recipients.…”