Peritubular and Tubulointerstitial Inflammation as Predictors of Impaired Viral Clearance in Polyomavirus Nephropathy

Abstract

Introduction: Polyomavirus-associated nephropathy (BKPyVAN) is a common complication in kidney transplant recipients. The histological changes in the context of BKPyVAN and their association with the viral load and outcomes are still being investigated. Methods: This retrospective study involved 100 adult patients transplanted between 2000 and 2021, with available archived biopsy slides, aiming to analyze associations between viral load clearance in the blood (reduction in BKPyVAN-DNAemia below detection level) and histological features in biopsy-proven BKPyVAN. A kidney pathologist blinded to the clinical data reassessed the BANFF 2019 lesion scores in the BKPyVAN index biopsy. The primary endpoint was viral clearance three months after the diagnosis. Results: The presence of tubulointerstitial inflammation, peritubular capillaritis, and higher PVN Class at the diagnosis was linked to a reduced likelihood of viral clearance three months later (interstitial inflammation OR = 0.2, 95% CI [0.07-0.55], tubulitis OR = 0.39, 95% CI [0.21-0.73], peritubular capillaritis OR = 0.25, 95% CI [0.08-0.82], PVN Score OR = 0.1, 95% CI [0.03-0.4]), independently of other covariates. Combining the four lesions using the ROC analysis enhanced their capability to predict persistent BK viremia after 3 months with an AUC of 0.94. Conclusions: The presence of interstitial inflammation, tubulitis, and peritubular capillaritis, as well as the higher PVN Score, was associated with an up to 90% lower likelihood of viral load clearance three months post-diagnosis. These findings underscore the importance of histological evaluation as a surrogate of subsequent viral clearance and offer valuable insights for the management of BKPyVAN.

Keywords: PVN; inflammation; kidney transplantation; peritubular capillaritis; polyomavirus.

Figure 1

Aligned dot plot for the viral load before and after the Biopsy. Values displayed as Median/IQR. Zero values are not plotted due to the logarithmic axis. The medians for variables with a low number of cases (<10) were not plotted.

Figure 2

Stacked column graphs showing the distribution of BANFF lesion scores in the index biopsy. Panel design was used for easier visualization; g: glomerulitis, ah: arteriolar hyalinosis, t: tubulitis, v: intimal arteritis, cg: double contours, ci: interstitial fibrosis, ct: tubular atrophy, cv: intimal thickening, i: interstitial inflammation, ptc: peritubular capillaritis, PVN: PVN Class, pvl: intrarenal polyomavirus load levels.

Figure 3

(A) Viral load at the BKPyVAN biopsy according to different peritubular capillaritis grades; p = 0.37, (B) viral load according to the interstitial inflammation grade; p = 0.87, (C) viral load according to the tubulitis; p = 0.58, (D) viral load according to the PVN Class; p = 0.001 (*). Values are displayed as median and IQR.

Figure 4

Forest plot displaying Odds ratios for viral load clearance in BKPyVAN three months after the diagnosis using a binary logistic regression model: (A) Unadjusted model; (B) model adjusted for viral load at the diagnosis (copies/mL); presence of any concomitant rejection and use of ATG induction therapy; (C) Multivariable analysis of histological lesions/PVN Classification for viral clearance after 3 months; i: interstitial inflammation, g: glomerulitis, t: tubulitis, ci: interstitial fibrosis, ct: tubular atrophy, cv: intimal thickening, ah: arteriolar hyalinosis, ati: acute tubulus injury, ptc: peritubular capillaritis, PVN: Polyoma viral load Class; pvl: intrarenal polyomavirus load levels. Values displayed as Odds Ratio for viral clearance three months after diagnosis of BKPyVAN (95% CI).

Figure 5

Receiver Operating Characteristic (ROC) analyses for assessment of the diagnostic accuracy of four crucial histological parameters for viral load persistence at month 3—interstitial inflammation (i), PVN-Class, peritubular capillaritis (ptc), and tubulitis (t): (A) Interstitial inflammation: AUC = 0.76, PVN-Class: AUC = 0.75, Peritubular capillaritis: AUC = 0.69 Tubulitis: AUC = 0.70; (B); AUC results for combinations of each histologic parameters; (C) AUC for integrated analysis = 0.94.