The 2018 Banff Working Group classification of definitive polyomavirus nephropathy: A multicenter validation study in the modern era

Abstract

Polyomavirus nephropathy (PVN) remained inadequately classified until 2018 when the Banff Working Group published a new 3-tier morphologic classification scheme derived from in-depth statistical analysis of a large multinational patient cohort. Here we report a multicenter "modern-era" validation study that included 99 patients with definitive PVN transplanted post January 1, 2009 and followed the original 2018 study design. Results validate the PVN classification, that is, the 3 PVN disease classes predicted clinical presentation, allograft function, and outcome independent of therapeutic intervention. PVN class 1 compared to classes 2 and 3 was diagnosed earlier (16.9 weeks posttransplant [median], P = .004), and showed significantly better function at 24 months postindex biopsy (serum creatinine 1.75 mg/dl, geometric mean, vs class 2: P = .037, vs class 3: P = .013). Class 1 presented during long-term follow-up with a low graft failure rate: 5% class 1, vs 30% class 2, vs 50% class 3 (P = .009). Persistent PVN was associated with an increased risk for graft failure (and functional decline in class 2 at 24 months postdiagnosis; serum creatinine with persistence: 2.48 mg/dL vs 1.65 with clearance, geometric means, P = .018). In conclusion, we validate the 2018 Banff Working Group PVN classification that provides significant clinical information and enhances comparative data analysis.

Keywords: classification systems: Banff classification; clinical research/practice; complication: infectious; infection and infectious agents - viral: BK/JC/polyoma; infectious disease; kidney disease; kidney transplantation/nephrology; pathology/histopathology; translational research/science.

FIGURE 1

Histology of polyomavirus nephropathy (PVN) disease classes. PVN Class 1 (A/D): Renal cortex lacking significant changes including diagnostic intra nuclear viral inclusion bodies in a hematoxylin and eosin (H&E) stained section (A). Immunohistochemistry (IHC; SV40‐T) shows evidence of PV replication (intranuclear staining pattern) in several tubular cross sections (arrows in D). The overall biopsy findings were scored as pvl: 1, ci: 0; 10× original magnification. PVN Class 2 (B/E): Tubules with few intra nuclear viral inclusion bodies in an H&E stained section (arrows in B). IHC (SV40‐T) shows evidence of PV replication (intra nuclear staining pattern) in many tubular cross sections (E). Note: only minimal inflammation is present. The overall biopsy findings were scored as pvl: 3, ci: 1; 20× original magnification. PVN Class 3 (C/F): Renal cortex with diffuse fibrosis and tubular atrophy; diagnostic intra nuclear viral inclusion bodies are not present (C; Masson Trichrome stain). IHC (SV40‐T) shows evidence of PV replication (intranuclear staining pattern) in many tubular cross sections (F). The overall biopsy findings were scored as pvl: 3, ci: 3; 10× original magnification. LS, least squares; pvl, polyomavirus load level; SV40‐T, simian virus 40 large‐T antigen

FIGURE 2

Polyomavirus nephropathy (PVN) disease classes and serum creatinine levels during follow‐up. Geometric least squares mean serum creatinine (y axis) is plotted by visit month (x axis) for PVN classes 1‐3 (total N = 99 patients). Significant differences in serum creatinine (S‐Cr) levels are seen, highlighted here at 12 and 24 months, when comparing PVN disease classes, especially class 1 vs classes 2 and 3 (linear mixed‐effects model for repeated measures [MMRM] on the log‐transformed S‐Cr, controlling for baseline S‐Cr and study center). Baseline mean S‐Cr values were determined from the exponential of the raw means of the log‐transformed S‐Cr readings; follow‐up mean S‐Cr values were calculated from the exponential of the MMRM least squares means of the log‐transformed data

FIGURE 3

Polyomavirus nephropathy (PVN) disease classes and estimated glomerular filtration rate (eGFR) during follow‐up. Geometric least squares mean estimated glomerular filtration rate (y axis) is plotted by visit month (x axis) for PVN classes 1‐3 (total N = 99 patients). Significant differences in eGFR are seen, highlighted here at 12 and 24 mo, when comparing PVN disease classes, especially class 1 vs classes 2 and 3 (linear mixed‐effects model for repeated measures [MMRM] on the log‐transformed eGFR, controlling for baseline eGFR and study center). Baseline mean eGFR values were determined from the exponential of the raw means of the log‐transformed eGFR readings; follow‐up mean eGFR values were calculated from the exponential of the MMRM least squares means of the log‐transformed data. LS, least squares

FIGURE 4

The impact of polyomavirus nephropathy (PVN) clearance or persistence on allograft function. This is a subanalysis (N = 64) examining the impact of PVN clearance on allograft function over time. Included are patients who either cleared PVN (defined by all negative repeat biopsies or, if no follow‐up biopsies were performed, BK‐viremia reading below threshold within 3‐mo postindex biopsy) or who presented with persistent PVN during 24‐month follow‐up (defined as all repeat biopsies positive or, in the absence of follow‐up biopsies, all reported polymerase chain reaction (PCR) reads above threshold over 24‐mo follow‐up). Significant differences are seen in class 2. A mixed‐effects model for repeated measures [MMRM] on the log‐transformed serum creatinine (S‐Cr), controlling for baseline S‐Cr and study center revealed overall significantly better S‐Cr in patients who cleared PVN (P = .002). Differences to patients in class 2 with persistent disease are highlighted at 12 mo (P = .048) and 24 mo (P = .018). PVN clearance did not significantly alter allograft function during follow‐up for class 1 patients. There were insufficient data for class 3 patients to make a determination. LS, least squares