Objectives: To evaluate whether Banff 2018 classification of BK polyomavirus nephropathy better predicts graft outcomes compared with baseline graft function and viremia levels, we correlated clinicopathologic features and morphologic BK polyomavirus nephropathy classes with graft outcomes.
Materials and Methods: We retrospectively analyzed 23 cases of biopsy-proven BK polyomavirus nephropathy over 10 years (2014-2023). We stratified biopsy cases into polyoma virus nephropathy class 1, 2, or 3 per the Banff 2018 classification, based on intrarenal viral load (pvl score) and interstitial fibrosis (ci score). Outcomes included graft function (serum creatinine, estimated glomerular filtration rate) at 6 and 12 months and graft loss.
Results: Among classes, class 2 was the most common (60.86%), followed by class 1 (26.08%) and class 3 (13.04%). Baseline serum creatinine level, BK viremia, and acute inflammation scores did not differ significantly across classes. Cases classified as class 3 showed significantly worse renal function at 6 and 12 months than cases classified as class 1 and 2 (6-month serum creatinine level of 6.19 ± 3.72, 2.19 ± 0.54, and 2.15 ± 0.95 mg/dL for class 3, 1, and 2, respectively; P < .001). Graft loss occurred in 0 of 6 cases with polyoma virus nephropathy class 1, 1 of 14 cases with class 2, and 1 of 3 with class 3. Mortality was observed in 2 of 14 patients with class 2 (14.28%). Tubular atrophy (ct score) was significantly higher in class 2 and 3 cases versus class 1 cases (P = .046).
Conclusions: The Banff 2018 polyoma virus nephropathy classification is a robust predictor of graft outcomes. Class 3 was strongly associated with worse renal function and increased graft loss, largely driven by extent of interstitial fibrosis and tubular atrophy. Histopathological assessment is critical for prognostication as viral load alone does not predict outcomes and severity of BK virus nephropathy.

Key words : Allograft outcome, Banff classification, Interstitial fibrosis, Kidney transplantation

Introduction

The relative benefits of kidney transplant continue to increase, even for older and less healthy transplant recipients, validating efforts to expand access globally.¹ Despite advancements in immunosuppression and patient management, allograft survival remains susceptible to various insults, with BK polyomavirus-associated nephropathy (BKVN) recognized as a significant contributor to graft dysfunction and loss.² BK polyomavirus remains latent in the urinary tract of a large proportion of the general population and can reactivate and progress to BKVN in patients receiving potent immunosuppression. BK polyomavirus-associated nephropathy, characterized by viral replication within the renal tubular epithelium and interstitium, develops in up to 10% of allograft recipients and carries a substantial risk of irreversible graft injury and failure.^3,4
Current clinical strategies rely heavily on screening for BK polyomavirus viremia using quantitative nucleic acid amplification tests, followed by preemptive reduction of immunosuppression on detection of significant viral loads.^5,6 A commonly used threshold for intervention is a plasma viral load of >10,000 copies/mL. Renal allograft biopsy remains the gold standard for diagnosing definitive BKVN, allowing for histopathological assessment of viral cytopathic effects, inflammation, and chronicity.⁷ The Banff 2018 Working Group classification provides a standardized framework for grading BKVN severity (that is, PVN class), primarily based on percentage of tubules showing morphologic or immunohistochemical evidence of polyoma virus replication (pvl score) and extent of interstitial fibrosis (ci score), intended to guide therapeutic decisions and prognosis.^8,9
Despite marked advances in screening and diagnosis, predicting the clinical course and long-term outcomes of patients with BKVN remains challenging.¹⁰ The diverse outcomes after reduction in immunosuppression, ranging from viral clearance and stable graft function to severe interstitial fibrosis/tubular atrophy (IF/TA) and graft failure despite intervention, indicate that accurate risk stratification requires a more comprehensive assessment incorporating wider clinicopathologic features.^11,12
Earlier studies have proposed that factors such as the kinetics of viral load reduction, baseline allograft function, degree and type of inflammation, presence of concomitant rejection, and early markers of fibrosis might significantly influence outcomes beyond the established grading system.^13,14 Furthermore, understanding the interplay between these clinical variables and detailed pathologic findings is crucial for better risk stratification and personalized management strategies.
Therefore, this study aimed to comprehensively evaluate correlations between an integrated clinicopathologic profile, including demographic data, viral load, renal function, and histopathologic features encompassing Banff 2018 grading, and outcomes in a single-center cohort of kidney transplant recipients diagnosed with BKVN.

Materials and Methods

A total of 2075 renal transplants were performed at our center from January 2014 through December 2023. Within this period, 1235 indication graft biopsies were performed and evaluated; of these, 23 cases of BKVN were identified. None of the biopsies were performed at predetermined intervals, as our center does not perform protocol biopsies. The study received ethical approval from the Ethics Committee of our institute (approval letter No. EC/07/25/2740).

Biopsy evaluation
The renal allograft biopsies were stained with hematoxylin and eosin, periodic acid Schiff, and periodic acid silver methanamine for light microscopic assessment. The biopsies were evaluated according to the 2022 Banff update on renal allograft pathology. Immunohistochemistry for BK virus was assessed using a mouse monoclonal anti-SV40 large T-cell antibody (Clone MRQ-4, Cell Marque) to detect characteristic nuclear staining. BK polyoma intrarenal load (PVL score) was determined with immunohistochemistry for SV40 large T-cell antibody and/or characteristic intranuclear inclusions in renal tubular epithelial cells, both within the cortex and medulla, by morphologic assessment as per Banff 2018 working group classification of BKVN. Interstitial fibrosis was assessed and scored (ci score). Both PVL score and ci score were used to determine PVN classes as defined in Banff 2018 working classification of BKVN as follows: class 1 had PVL score 1 and ci score 0-1; class 2 had PVL score 1 and ci score 2-3, PVL score 2 and ci score 0-3, or PVL score 3 and ci score 0-1; and class 3 had PVL score 3 and ci score 2-3.⁸ Immunohistochemistry for C4d (C4d polyclonal ready-to-use antibody, BioGenex) was also performed on renal graft biopsies. The Leica Bond-Max platform was used for immunostaining. Other histopathological parameters, including acute inflammatory scores (i, t, ptc, g, v) and chronicity parameters (ct, cv, cg), were also assessed. All biopsies were reviewed by a single experienced renal pathologist (P.G.) to ensure consistency in scoring. A formal interobserver variability analysis was not performed as part of this retrospective study.
For demographic and laboratory parameters, we collected demographic details, biochemical records, and BK viremia (serum BK virus polymerase chain reaction) results from hospital records. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation.

Statistical analyses
We used IBM SPSS software version 25 to perform statistical analyses. We reported continuous variables as mean ± SD and categorical variables as percentages. We used the χ² test to calculate significance for categorical variables and analysis of variance to calculate significance for continuous variables among the 3 BKVN classes (class 1, class 2, and class 3). P < .05 was considered as statistically significant.

Results

Of the 1235 indication biopsies performed during the study period for kidney transplant recipients, 23 (1.1%) were identified as BKVN. Among the 23 patients, mean age was 46.56 ± 15.35 years (range, 14-67 y), 19 were male patients, and 4 were female patients. Basic disease before transplant was autosomal dominant polycystic kidney disease in 2 patients, biopsy-proven focal segmental glomerulosclerosis in 2 patients, immune complex-mediated membranoproliferative glomerulonephritis in 1 patient, and presumed to be chronic glomerulonephritis in the remaining patients (no native kidney biopsy was done for these patients). All 23 patients had living related or spousal donors (emotionally related); no donors were unrelated or deceased in our cohort. There were 20 ABO-compatible and 3 ABO-incompatible donors. Mean duration between transplant and detection of biopsy-proven BKVN was 24 ± 32.91 months (range, 1-163 months) (Table 1).
All patients were on triple immunosuppression. Twenty-two of 23 patients were on triple immunosuppressive therapy with tacrolimus, mycophenolate mofetil, and steroids, and 1 patient received sirolimus, mycophenolate mofetil, and steroids. Induction therapy was used in 20 patients; 13 patients received antithymocyte globulin, 5 received Grafalon (anti-T lymphocyte globulin), and 2 received basiliximab.

Clinical presentation
Most patients presented with a gradual rise in serum creatinine and underwent an indication renal graft biopsy because of graft dysfunction (rise in serum creatinine levels 15% to 20% above baseline levels). One patient had indication because of decreased urine output. At time of biopsy, mean serum creatinine level was 2.45 ± 0.56 mg/dL and proteinuria was observed in 11 patients, with mean of 0.68 g (24-hour urine protein range, 0.1-4.16 g). The serum BK viremia levels performed within 14 days after confirmation of BK polyoma virus nephropathy on biopsy ranged from 0.63 × 10⁴ to 2.4 × 10⁶ copies/mL (Table 2).

Histopathological findings in different PVN classes
Renal biopsy slides were evaluated as per Banff 2018 working group criteria for evaluation of BKVN and were classified into PVN classes based on the extent of intrarenal BK virus replication in tubules (pvl score) and associated interstitial fibrosis (ci score). At our center, we routinely perform immunohistochemistry for SV40 large T-cell antigen staining in all patients undergoing indication biopsies for graft dysfunction. Both cortex and medulla were included in 14 biopsies; the remaining 9 biopsies had only cortex included. Primarily, PVN was diagnosed in renal biopsy by performing immunohistochemistry for anti-SV40 large T-cell antigen, which showed characteristic intranuclear positivity in all 23 patients. On morphology, tubular epithelial cell inclusions were positive in 20 patients (87%), and 3 patients had no obvious inclusions (13%). Seventeen patients had type 1 inclusions, with 4 of these also accompanied by type 3 inclusions; 1 patient had accompanying both type 3 and type 4 inclusions; 3 patients had type 2 inclusions, 1 of which also had type 4 inclusions; and 2 patients also showed glomerular parietal epithelial cell inclusions. Most patients (15/23) had mild chronicity with a ci score of 1, whereas 4 patients had a ci score of 2, and 4 patients had no interstitial fibrosis (ci score of 0).
Overall, PVN class 2 was the most commonly seen (in 60.86% of patients), PVN class 1 was seen in 26.08% of patients, and PVN class 3 was seen in 13.04% of patients. No significant differences were shown in mean serum creatinine at time of biopsy according to PVN classes (2.43 ± 0.43, 2.42 ± 0.54, and 2.68 ± 0.99 mg/dL for class 1, 2, and 3, respectively) or in eGFR (33.66 ± 7.78, 32.35 ± 10.24, and 31 ± 12.12 mL/min for class 1, 2, and 3, respectively) (Table 2).
Acute tubular injury was a common finding seen in 61% patients (14/23) without any significant difference in the 3 classes (P = .815). Tubulitis was a common finding and was present in 74% patients (17/23), with t1 in 15 patients and t2 in 2 patients. Similarly, interstitial inflammation was commonly found in 82% patients (19/23), with i1 in 10 patients and i2 in 9 patients. However, no significant differences were shown among classes concerning tubulitis (t score) (P = .856) or interstitial inflammation (i score) (P = .575). Tubular atrophy (ct score) was significantly more common in PVN class 2 (100%) and PVN class 3 (66%) compared with PVN class 1 (50%) (P = .046) (Table 2). Two patients had concomitant acute cellular rejection with moderate interstitial inflammation (i2) and moderate tubulitis (t2). None of the cases had any evidence of arteritis (Banff score v>0). Diagnosis of BKVN with coexisting Banff category 3 suspicious/borderline acute T-cell-mediated rejection could not be reliably excluded, and there are no reliable criteria to distinguish them. C4d was negative in all cases except in cases of 3 ABO-incompatible transplants. No patients had evidence of microvascular inflammation (Banff score g >0 or ptc >0). Only 1 patient had significant proteinuria (24-h urine protein of 4.16 g). On biopsy, this patient, apart from having PVN class 2 BKVN, also had evidence of recurrent immune complex-mediated membranoproliferative glomerulonephritis with crescent.

Comparison of clinical profiles among PVN classes
Mean serum creatinine levels at 6 months of follow-up after diagnosis of PVN for class 1, class 2, and class 3 were 2.19 ± 0.54, 2.15 ± 0.95, and 6.19 ± 3.72 mg/dL, respectively, and significantly different (class 1 vs class 3: P = .002; class 2 vs class 3: P < .001), suggesting worsening of renal function with class progression being worst in PVN class 3. Mean serum creatinine levels at 1 year of follow-up in class 1, class 2, and class 3 were 2.56 ± 1.01, 2.53 ± 1.79, and 5.69 ± 2.48 mg/dL, respectively, and significantly different (class 1 vs class 3: P = .057; class 2 vs Class 3: P = .031) among the 3 classes, suggesting worsening of renal function with class progression being worst in PVN class 3. We also noted significant differences in eGFR at 6-month follow-up (class 1 vs class 3: P = .046; class 2 vs class 3: P = .019) and at 1-year follow-up (class 2 vs class 3: P = .043) (Figure 1). No significant differences were shown among the 3 PVN classes concerning level of BK viremia within 14 days of biopsy (131383.5 ± 176186.01, 469267.57 ± 686969.74, and 376500 ± 314325.99 copies/mL for class 1, 2, and 3, respectively; P = .490) or at 1-year follow-up 1 year after biopsy diagnosis (40434 ± 80317.89, 33544.93 ± 105994.40, and 35340 ± 36984.89 copies/mL for class 1, 2, and 3, respectively; P = 0.991) (Figure 2).

Management of patients with BK virus nephropathy
After the diagnosis of BKVN on graft biopsy, serum BK virus load estimation was performed within 14 days of index biopsy, and values were taken as baseline viral load. Depending on immunological risk and evidence of rejection in graft biopsy, patients with BK polyomavirus DNAemia loads persisting >1000 copies/mL or exceeding 10000 copies/mL (or equivalent) had initial dose of immunosuppression reduced as first-line therapy.¹⁵ First, mycophenolate mofetil dose was reduced by 50% or stopped if indicated by the persistence of viremia. Second, calcineurin inhibitor dose was reduced by 25% to 50% to keep the trough levels to 50 to 75 μg/L for cyclosporine and <4 μg/L for tacrolimus. Viremia was checked at regular intervals of 2 to 4 weeks. If there was no decrease in viremia by 8 weeks, then tacrolimus was switched to cyclosporine, cyclosporine to everolimus or sirolimus, and mycophenolate to leflunomide, in line with established management strategies aimed at reducing overall immunosuppressive load while maintaining antirejection efficacy.^16,17 Leflunomide was given at 100 mg daily for 5 days, followed by 40 mg daily to attain blood levels of 50 to 100 μg/L. If viremia persisted, then intravenous immunoglobulin was used at a dose of 100 mg/kg weekly for 10 weeks (total dose of 1 g/kg), which was also used for patients who showed evidence of rejection with BKVN. Treatment was continued until resolution of BK polyomavirus viremia or stabilization of graft functions.
Treatment for BKVN at our institute is performed according to guidelines from the Transplantation Society International BK Polyomavirus Consensus Group, which has shown benefits of reducing immunosuppression and other adjuvant therapies in stabilizing graft functions.¹⁵ After viral clearance is sustained, immunosuppression was increased modestly to prevent any rejection, and regular monitoring of BK polyomavirus viremia was done. There was no difference in the immunosuppression protocol before index biopsy, nor was there a difference in the management of the 3 classes of PVN after index biopsy. In our study, median follow-up duration after index biopsy was 13 months (range, 7-44 months). Patients with recorded serum creatinine levels >7 mg/dL or those returning to dialysis were considered as graft failure.
Graft loss occurred in 7.14% (1/14) and 33.33% (1/3) of patients in PVN class 2 and PVN class 3, respectively, with none in PVN class 1, whereas 2 patients (14.28%) with PVN class 2 BKVN died during follow-up, but none in PVN class 1 or class 3. On follow-up, 1 patient developed high-grade urothelial carcinoma of the bladder 3 years after diagnosis of BKVN. Immunohistochemistry for SV40 large T-cell antigen was found to be positive in the tumor cells, and BK viremia was 340 copies/mL at the time of diagnosis of bladder carcinoma.

Discussion

BK virus nephropathy remains a formidable challenge in kidney transplant and can substantially affect long-term allograft survival. This study aimed to correlate a comprehensive clinicopathologic profile, including Banff 2018 BKVN grading, with outcomes in a cohort of 23 patients with biopsy-proven BKVN. We observed that biopsies with higher Banff PVN (classes 2 and 3) were significantly associated with worse graft function (serum creatinine/eGFR at 6 and 12 months) and higher risk of graft loss, independent of initial viral load, acute inflammatory scores (i score, t score) at diagnosis, or therapeutic intervention. Furthermore, we observed a strong correlation between PVN classes and the degree of IF/TA, as indicated by ci scores and ct scores.
Our study showed a mean time to biopsy diagnosis of BKVN after transplant of 24 months without any significant difference among the PVN classes; however, this time was just 24 weeks in the study by Nickeleit and colleagues, who also found a significant earlier detection for PVN class I cases at 16.9 weeks.¹⁸ Another study reported a median time from transplant to BKVN diagnosis on biopsy of 10.3 months.¹⁹ The time differences in the presentation of BKVN may be due to differences in the approach for performing protocol/indication biopsy followed in different studies. No significant difference in baseline allograft function was observed among the PVN classes, and similar observations were reported by earlier studies.^18-20
The Banff 2018 working group classification for BKVN,⁸ based on the extent of viral replication (PVL score) and associated chronic injury (ci scores), showed significant differences in clinical presentation, graft function, and outcomes with class progression, as reinforced by our present study. Patients with PVN class 3, characterized by advanced (ci score 2-3) and high viral load (PVL score 3), showed significantly poor renal function at follow-up and a 33.33% graft loss compared with 7.14% for class 2 and none for class 1. This finding aligns with previous reports highlighting that considerable, often irreversible, parenchyma damage occurs with BKVN progression to PVN class 3, limiting the efficacy of immunosuppression reduction.^15,16 The mean serum creatinine and eGFR in our PVN class 3 patients at 6 months (6.19 ± 3.72 mg/dL and 15.33 ± 12.85 mL/min) was sharply distinct from the more stable function at 6 months for PVN class 1 (2.19 ± 0.54 mg/dL and 39.16 ± 9.32 mL/min) and PVN class 2 (2.15 ± 0.95 mg/dL and 40.0 ± 13.78 mL/min), which was also demonstrated at 1 year after biopsy for PVN class 3 (5.69 ± 2.48 mg/dL and 14.33 ± 9.29 mL/min) versus PVN class 1 (2.56 ± 1.01 mg/dL and 34.33 ± 10.68 mL/min) and PVN class 2 (2.53 ± 1.79 mg/dL and 36.57 ± 14.29 mL/min), emphasizing the severity of this PVN class and its effect on graft function. In contrast, findings from Bouatou and colleagues found no significant difference in graft function or subsequent graft loss on follow-up among the 3 PVN classes, although graft function was worst in PVN class 3.²⁰ The discrepancy between their findings and ours could be due to differences in cohort size, duration of follow-up, or patient demographics, which can influence the statistical power to detect differences in outcomes.
Interestingly, although patients with PVN class 1 and 2 showed no significant difference in serum creatinine at time of biopsy and follow-up in our cohort, having PVN class 2 was associated with significantly higher tubular atrophy (ct score) and higher ci score compared with class 1. This finding suggested that, on reducing immunosuppression to stabilize kidney function in many PVN class 2 patients, preexisting chronic damage may still predispose patients to subsequent deterioration and subsequent graft loss as 7.14% of patients with PVN class 2 developed graft loss on follow-up. This risk could be exacerbated by factors not apparent from a single biopsy or by the limited duration of follow-up. Furthermore, the variable and, in some cases, limited duration of follow-up may not be sufficient to capture late graft loss events, potentially underestimating the long-term risk in this intermediate group.^11,21 The graft loss (7.14%) and mortality (14.28%) observed in our patients with PVN class 2, although based on small numbers, warrant attention to this intermediate-risk group. Recipients with PVN class 3 showed maximum graft loss (33.3%) on follow-up. These findings correlated with previous studies.^18,19 We found viral inclusions in the tubular epithelial cells in 87% of cases, whereas an earlier study found that polyoma viral inclusion was seen in only 57% of biopsies, and immunohistochemistry for SV40 large T-cell antigen is a necessary diagnostic for BKVN.¹⁸
A notable observation from our study was the lack of significant correlation between BK viremia levels at the time of biopsy and either the PVN class or subsequent graft function at 1 year. We found no correlation between BK viremia at the time of biopsy or at 1-year follow-up among the 3 PVN classes of BKVN, as also observed by Wang and colleagues. In Wang and colleagues, no correlation was shown between the BK viremia in urine and serum and pvl score or PVN class,¹⁹ although Nickeleit and colleagues found a significant difference in BK viremia among the PVN classes, with the highest being in PVN class 3.¹⁸
Although quantitative BK polyomavirus DNAemia has been reported as crucial for screening and initiating diagnostic biopsy,²² our data suggested that, once BKVN is histologically established, the degree of parenchymal injury (reflected by PVN class and IF/TA) becomes a more potent predictor of outcome than the concurrent viral load. This finding is consistent with other studies indicating that viral load dynamics after reduction of immunosuppression, rather than a single viral load at diagnosis, might be more informative; however, histological features often dictate the ceiling of potential recovery.^23,24 Similarly, acute inflammation scores (i score and t score) did not significantly differ across PVN classes in predicting outcomes. This may indicate that IF/TA, which is central to PVN classification, dominates the prognostic effect of acute inflammation seen at a single biopsy or that reduction of immunosuppression effectively mitigates IF/TA across classes with variable success, depending on underlying chronicity.^25,26 This is in contrast to a previous study, which found more decline in the eGFR trajectory on follow-up in patients with i2 score compared with i1 score in index biopsy.²⁰
The overall incidence of biopsy-proven BKVN in our transplant cohort over the 10 years was 1.1% (23 of 2075), which is at the lower end of the 1% to 10% range reported in the literature.^2,8,18 It would be interesting to investigate in future larger studies why, despite performing SV40 large T cell antigen staining in all our indication graft biopsies (although routine surveillance for urine/serum BK viremia is not performed at our center), the incidence was low in our cohort. Another interesting and notable finding in our study was the development of SV40-positive urothelial carcinoma in a patient at 3 years after BKVN diagnosis; this finding is an important reminder of the oncogenic potential of BK polyomavirus, particularly in the setting of long-term immunosuppression, a rare but increasingly recognized complication.²⁷
Our study, although a single-center and smaller in scale design, serves as an important real-world validation of the Banff 2018 classification in a cohort from the Indian subcontinent. Unlike the large multicenter study by Nickeleit and colleagues, which established the classification's broad applicability, our findings provide granular, longitudinal data from a single institution with consistent management protocols, minimizing variability from intercenter practices. Although Bouatou and colleagues did not find a significant difference in graft loss among PVN classes in their cohort, our data are aligned more closely with Nickeleit and colleagues in demonstrating a clear prognostic gradient, especially for poor outcomes in PVN class 3. This finding reinforces the classification's robustness across different health care settings and patient populations.^18,20
Strengths of this study include the systematic application of the Banff 2018 working group classification of BKVN by an experienced pathologist, detailed histopathological analysis, and correlation with longitudinal graft function data.

Limitations
Our study had several limitation, First was the retrospective nature of the study and the relatively small sample size (n = 23), which was particularly pronounced for the PVN class 3 subgroup (n = 3). This small number restricted the statistical power for subgroup analyses and precluded definitive conclusions about this high-risk group; thus the findings for class should be interpreted with caution. As a single-center study, inherent biases related to local immunosuppression or management protocols may exist.
Clinically, our findings underscored the vital importance of renal allograft biopsy in patients with suspected BKVN. Histological classification, especially the assessment of IF/TA, provides critical prognostic information beyond viral load alone and helps stratify patients for appropriate management and counseling.⁷ Early detection and intervention, ideally before the establishment of significant IF/TA characterizing higher PVN classes, remain crucial for preserving graft function.
Future research should also continue to explore noninvasive biomarkers that can accurately reflect histological severity. Markers such as donor-derived cell-free DNA and specific urinary chemokines (eg, CXCL10) have shown promise in monitoring allograft injury and could potentially aid in the early detection of BKVN or in tracking response to therapy, complementing traditional biopsy findings and refining risk stratification.²⁸

Conclusions

This study confirmed that the Banff PVN classification is a robust predictor of long-term graft outcomes in kidney transplant recipients with BKVN. Higher PVN classes, especially class 3, were associated with significantly worse renal function and an increased risk of graft loss, largely driven by the extent of underlying interstitial fibrosis and tubular atrophy. Although BK viremia is an essential screening tool, histopathological assessment remains indispensable for prognostication and guiding the management of established BKVN.

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