|Year : 2022 | Volume
| Issue : 1 | Page : 61-66
Clinicopathologic features of polyomavirus nephropathy: Our experience - A retrospective observational study
Ramya Veduruvada1, Nishika Madireddy1, Soundarya Samskruthi Koyya1, Swarnalatha Guditi2, Gangadhar Taduri2, Sree Bhushan Raju2, Megha Shantveer Uppin1
1 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
|Date of Submission||05-Sep-2020|
|Date of Acceptance||08-May-2021|
|Date of Web Publication||31-Mar-2022|
Dr. Megha Shantveer Uppin
Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
Introduction: Polyomavirus nephropathy (PVN) is now being frequently encountered in renal transplant recipients receiving highly potent immunosuppressive drugs and has emerged as an important cause of allograft loss. In this study, we tried to study the clinical and morphological features while incorporating the latest Banff 2018 classification of PVN and correlating it with graft outcomes. Materials and Methods: This was a retrospective study including ten patients with biopsy-proven PVN. The risk factors, clinical, histomorphological, and immunohistochemical features of all the patients were studied. We scored the intrarenal polyomavirus load and Banff interstitial fibrosis as described by Banff 2018 working group. Results: There were 6 male and 4 female patients and the mean age at the time of biopsy was 42.5 ± 10.8 years. All patients were on triple immunosuppression and the mean transplant duration to the time of diagnosis was 6.98 ± 4 months. The mean serum creatinine at the time of biopsy was 2.73 ± 1.12 mg/dl. A prior history of antibody-mediated rejection was present in two patients. All ten biopsies showed tubular epithelial basophilic, intranuclear inclusions suggestive of BK virus which was confirmed by positivity for SV40 antigen on immunohistochemistry (IHC). As per the Banff 2018 classification, seven biopsies were categorized as Class 2 and three were class 3. On follow-up, three patients went into graft loss, five patients had persistent graft dysfunction, and two expired. Conclusion: PVN is an important cause of renal dysfunction and premature allograft loss. Light microscopy for viral cytopathic changes aided by IHC with SV40 is essential for the diagnosis of PVN. The Banff scheme of classification is helpful in predicting the prognosis. It is important to diagnose PVN and differentiate it from rejection for appropriate management.
Keywords: Banff 2018 classification, polyomavirus nephropathy, prognosis, rejection, renal allograft
|How to cite this article:|
Veduruvada R, Madireddy N, Koyya SS, Guditi S, Taduri G, Raju SB, Uppin MS. Clinicopathologic features of polyomavirus nephropathy: Our experience - A retrospective observational study. Indian J Transplant 2022;16:61-6
|How to cite this URL:|
Veduruvada R, Madireddy N, Koyya SS, Guditi S, Taduri G, Raju SB, Uppin MS. Clinicopathologic features of polyomavirus nephropathy: Our experience - A retrospective observational study. Indian J Transplant [serial online] 2022 [cited 2022 Dec 8];16:61-6. Available from: https://www.ijtonline.in/text.asp?2022/16/1/61/342424
| Introduction|| |
Renal transplantation has for long been the preferred choice of treatment in patients with end-stage renal disease. The advent of highly efficacious immunosuppressive drugs has on one hand appreciably improved the short-term outcome of the renal allografts, but on the other hand, these drugs have predisposed the renal allografts to numerous opportunistic infections. Polyomavirus nephropathy (PVN) is one such entity that has a deleterious effect on the renal allografts leading to renal dysfunction and premature allograft loss. PVN first described in 1995 is caused by BK virus (BKV), a double-stranded DNA virus, belonging to polyomaviridae family. Rarely, JC virus and SV40 belonging to the same family may also be involved.,, PVN shows no specific clinical symptoms except for acute renal failure reflected by elevated serum creatinine levels and is often detected on biopsies performed to evaluate the cause of renal failure.,, Prognosis and progression of PVN can also be predicted by morphology.,,,, Banff working group proposed three morphological classes by combining intrarenal polyomavirus load (pvl) scores and Banff interstitial fibrosis [ci] scores and deciphered that Class 1 showed a favorable prognosis, whereas the graft loss rate was as high as 50% in Class 3. Early diagnosis and subsequent modification of immunosuppressive therapy can successfully prevent allograft failure.,, In the present study, we have attempted to evaluate the clinical and histomorphological features of PVN. We have also applied the latest Banff 2018 classification and tried to correlate it with the graft outcomes.
| Materials and Methods|| |
This was a retrospective evaluation of all biopsy-proven cases of PVN in renal allografts over 2 ½ years from January 2018 to May 2020. Informed consent was obtained from patients before biopsy.
All biopsy-proven cases of PVN were included in the study.
Allograft biopsies with features other than PVN were excluded from the study.
The demographic and clinical details including age, gender, clinical presentation, type and duration of transplant, serum creatinine, follow-up, and immunosuppressive regimens of all the cases were obtained from the patients' files.
The biopsies were evaluated by light microscopy with the help of hematoxylin and eosin, periodic acid–Schiff, Masson trichrome, and Jones methenamine silver. Immunohistochemistry (IHC) using SV40 (BIOSB) and C4d antibody (cat no. AR 572-5R, Biogenex) was also performed. All the biopsies were examined for viral cytopathic features in the tubules and the intrarenal pvl was semi-quantitatively assessed as described by the Banff 2018 working group by evaluating the percentage of tubules showing morphologically evident intranuclear inclusions or SV40 positivity as follows: pvl 1: <1%, pvl 2: 1-10%, and pvl 3: >10%. In addition, the degree of interstitial inflammation and fibrosis, glomerular, and vascular features were also examined and scored according to the Banff criteria. Immunofluorescence using fluorescein isothiocyanate-tagged antibodies to immunoglobulins IgM, IgA, and IgG, C3, C19, and kappa and lambda chains was also performed on all biopsies. Subsequently, all the biopsies were put into three morphological classes according to the definitions given by Banff 2018 classification scheme [Table 1]. In our institute, allograft biopsies are usually indicated biopsies performed during an episode of graft dysfunction, and protocol biopsies are not routinely performed.
All ten patients received standard triple immunosuppression. While 7/10 patients received prednisolone, mycophenolate mofetil (MMF), and tacrolimus, two patients received sirolimus instead of tacrolimus and one patient received rituximab instead of MMF. Four patients had received induction with basiliximab.
Graft loss was defined as complete graft dysfunction, significantly elevated serum creatinine levels, or dialysis dependence. Patients with uremic symptoms or a baseline serum creatinine >1.5 mg/dl were categorized as persistent graft dysfunction, and normal graft function was defined as absence for uremic symptoms and serum creatinine levels <1.5 mg/dl.
The study is an observational retrospective type. The clinical and laboratory findings of the patients are tabulated. Statistical analysis was not used for comparison.
The patient consent has been obtained for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.
The study was a retrospective analysis of findings on renal allograft biopsies for diagnosis of graft dysfunction. Archival tissue material was used for analysis and their was no actual patient participation.
| Results|| |
A total of 207 allograft biopsies were performed during the study period of which 10 biopsies were diagnosed as PVN.
Demographics and clinical data
Ten patients included six males and four females with a mean age at the time of biopsy of 42.5 ± 10.8 years. Four patients had live-related grafts and six received cadaveric transplant. Of the ten patients, nine underwent an allograft biopsy to assess the cause of renal failure, while one underwent a protocol biopsy for tacrolimus conversion. The mean transplant duration to the time of diagnosis was 6.98 ± 4 months and the mean serum creatinine at the time of biopsy was 2.73 ± 1.12 mg/dl. A prior history of antibody-mediated rejection was present in two patients. The detailed demographics and clinical data of the patients are depicted in [Table 2].
Histomorphological and immunohistochemistry features
All ten biopsies showed tubular epithelial intranuclear inclusions of which 8/10 showed amorphous, basophilic ground-glass inclusion bodies (type 1) and 2/10 showed eosinophilic granular inclusions surrounded by an incomplete halo (type 2). Accompanying lymphocytic tubulitis was observed in six biopsies. All the biopsies showed infiltrate of lymphocytes and plasma cells and interstitial fibrosis was seen in five biopsies. All the ten biopsies showed a strong positivity for SV40 antigen on immunohistochemisry. According to the Banff 2018 classification scheme of PVN, seven biopsies were categorized as Class 2 and the other three as Class 3. One biopsy showed additional features of combined acute cellular (Banff Grade Ib) and antibody-mediated rejection and this biopsy showed concurrent positivity for C4d in the peritubular capillaries. The relevant biopsy and IHC features are depicted in [Figure 1].
|Figure 1: (a) The allograft biopsy showing dense plasma cell infiltrates. H and E ×100. (b) The tubular epithelial cells showing viral cytopathic effects in the form of enlarged nuclei showing ground glass appearance and prominent nucleoli. H and E ×1000. (c) The immunostain with SV40 positive in the viral inclusions in the tubular epithelial cells. SV40 horse radish peroxidase (HRP) Polymer ×100. (d) The viral inclusions seen as bright positivity in the nuclei of the epithelial cells. SV40, HRP polymer ×400|
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Treatment and follow-up
The intensity of immunosuppression was reduced by 25% in 9/10 patients, while one patient was lost to follow-up. In addition, leflunomide and intravenous immunoglobulins were introduced in seven patients. None of the patients received any antivirals. On follow-up, 3/10 patients went into graft loss, 5/10 patients had persistent graft dysfunction, and two patients, both, belonging to Class 3 expired.
| Discussion|| |
The development of highly potent immunosuppressive regimens has helped mitigate transplant rejection and improve the short-term survival of the renal allografts. However, the major drawback of these immunosuppressive agents is that they have led to a widespread increase in the incidence of opportunistic infections triggering a premature graft loss., Viral infections caused by cytomegalovirus (CMV) and BKV are well-established complications of intensive immunosuppression. BKV, the primary virus involved in the pathogenesis of PVN, is known to be ubiquitous with a seroprevalence rate of 80%–90% in the adults., PVN in transplanted kidney develops either due to reactivation of latent infection in the recipient's urinary tract or as a result of primary infection of the transplanted kidney. While well-defined protocols for prevention and treatment of CMV infection have obtained impressive results, satisfactory management of PVN is yet to evolve and the prognosis remains suboptimal.,
In this study, we evaluated a series of 10 patients with histologically proven PVN of which 6 were male and 4 were female patients. The mean age of these ten patients at the time of biopsy was 42.5 ± 10.8 years which was close to the mean ages, 40 ± 12 years, and 45.8 years observed in the retrospective analysis conducted by Kim et al. and Wen et al..
PVN is typically encountered within 1 year after transplantation; however, approximately 25% may occur later.,,,,,In our study, the mean time to the diagnosis of PVN was 6.98 ± 4 months. This observation was comparable to the observations of Binet et al. and Kim et al. wherein the mean time to the development of PVN was 9 ± 2 and 7.8 months, respectively. However, Costa et al. in their 10-year retrospective analysis established a diagnosis of PVN in patients with chronic allograft dysfunction at 17.8 ± 33.3 months posttransplantation.
It is now perceived that the pathogenesis of PVN is multifactorial, involving the interplay of immunosuppression, donor and recipient characteristics, and the type of virus; however, a clear understanding of the impact of these factors is yet to be achieved., Several risk factors including older age, male sex, diabetes, HLA mismatch, deceased donor, prior episode of rejection, and negative serostatus of the recipient have been suggested; however, there is a high degree of discordance among various studies.,,,,,,,,, In our study, a prior history of antibody-mediated rejection was seen in 2/10 patients.
Currently, rigorous immunosuppression is the principal risk factor for the development of PVN.,,, Both Mengel et al. and Brennan et al. individually concluded that there was a particularly increased risk of developing PVN in patients who received a combination of tacrolimus and MMF. However, it has been documented that patients receiving sirolimus or cyclosporine also developed PVN. Thus, the intensity rather than the agent of suppression may be responsible for PVN. In our study, while 7/10 patients had received a combination of tacrolimus, prednisolone, and MMF, two patients received sirolimus instead of tacrolimus and one patient received rituximab instead of MMF. This observation in our study perhaps favors the inference that the degree of immunosuppression rather than the type of immunosuppression is involved in the development of PVN.
The clinical presentation of PVN is nonspecific with the majority of the patients presenting with acute renal failure reflected by an increase in the baseline creatinine level.,, Very rarely, ureteric obstruction, cystitis, or hydronephrosis may be encountered., Most biopsies are performed to evaluate the cause of acute renal failure as was the case in our study wherein 9/10 patients underwent a biopsy to evaluate the cause of renal failure, while one patient with stable graft function underwent a protocol biopsy for tacrolimus conversion.
Drachenberg et al. evaluated the factors affecting the graft outcome in 90 patients with PVN and inferred that graft loss was more frequently seen with a mean serum creatinine levels of 3 mg/dl at the time of biopsy. On the other hand, Vasudev et al. encountered a high risk of graft loss even with a serum creatinine level of 2.2 mg/dl. In our study, the mean serum creatinine level at the time of biopsy was 2.71 ± 1.18 mg/dl and was associated with adverse graft outcomes.
It has been widely accepted that early diagnosis of PVN and subsequent modification of immunosuppressive therapy can successfully prevent allograft failure; however, lack of specific symptoms makes it difficult to identify PVN in the early stages.,,, PVN is almost always preceded by viruria and viremia and despite a negative biopsy, a diagnosis of presumptive PVN is recommended when viruria and viremia last longer than 3 weeks,,,,,,,[37 Brennan et al. studied the impact of preemptive reduction of immunosuppression and postulated that preemptive reduction of immunosuppression in the presence of viremia can prevent the progression to PVN. Hence, screening for viral replication using assays such as quantification of viral DNA in urine and plasma and urine cytology for decoy cells facilitates early identification and preemptive intervention.,,,, A screening for BKV every 3 months for 2 years after transplantation and annually thereafter up to 5 years has been recommended., Although the sensitivity of these surrogate markers is good, the positive predictive values are low, thus warranting a biopsy for a definite diagnosis,
PVN shows a multifocal and patchy distribution involving both cortex and medulla; thus, inadequate sampling can result in the diagnosis being missed on almost 25%–37% of the biopsies.,,, Nonetheless, identification of characteristic basophilic, intranuclear inclusions in the tubular epithelial cells accompanied by nucleomegaly and varying degrees of tubulointerstitial inflammation on histopathology remains the gold standard for the diagnosis of PVN.,,, Morphological parameters such as the degree of tubular injury, fibrosis, and extent of inflammation have been identified as predictors of allograft outcome and various histological gradings have been proposed in an attempt to correlate these parameters with prognosis.,,,, Recently, the Banff 2018 working group identified that intrarenal pvl and interstitial fibrosis accounted for the greatest variation in allograft function and presented a classification scheme reflecting three clinical parameters including presentation at the time diagnosis, renal function following index biopsy, and graft failure. In our study, the serum creatinine at the time of biopsy was >2.5 mg/dl in all three patients categorized as Class 3 PVN and while all patients belonging to Class 2 were diagnosed within 1 year of transplantation, one patient categorized as Class 3 was diagnosed 13 months after transplantation. On follow–up, 2/3 patients belonging to Class 3 PVN expired and one progressed to graft loss. 5/7 patients belonging to Class 2 had persistent graft dysfunction and 2/7 went into graft loss.
Owing to the presence of tubulitis and interstitial inflammation PVN is often confused with acute rejection.,, The absence of characteristic endotheliitis, glomerulitis, fibrinoid necrosis, and C4d capillary deposits readily distinguishes acute rejection from PVN.,, However, acute rejection and PVN can coexist.,, Drachenberg et al. recorded concomitant acute rejection in 21.2% of their patients and correlated it with a greater risk of graft loss. The only patient diagnosed with PVN with concomitant combined acute cellular and antibody-mediated rejection in our study expired.
At times, the cytopathic features of other viral infections such as adenovirus, herpes simplex virus, and CMV can be indistinguishable from that of PVN. Thus, IHC for the identification of SV40 antigens is necessary for a definite diagnosis., In our study, we had two biopsies with ambiguous cytopathic features; however, on IHC, a strong positivity for SV40 antigen and negativity for CMV antibody ruled out CMV infection.
Reactive atypia seen in acute tubular necrosis can mimic PVN due to marked nuclear enlargement; however, these two processes can be differentiated with the help of IHC., All the ten biopsies in our study showed a strong diffuse positivity for SV40, thus proving that the cytopathic changes and nucleomegaly were indeed due to BKV infection.
Currently, modulation of immunosuppression either by reduction or switching of immunosuppressive drugs is the only reliable mode of intervention.,,,, The most commonly followed approach includes cessation of MMF or azathioprine and reducing the immunosuppression by 25%–50%., Despite reducing immunosuppression, the prognosis of PVN continues to remain dismal with almost 30%–60% of the patients progressing to graft failure.,, Ramos et al. studied the clinical course of PVN in 67 patients and observed that once the patients present with renal failure, there was no difference in the allograft outcome irrespective of whether the immunosuppression was reduced or maintained. On the other hand, Vasudev et al. postulated that a reduction in calcineurin inhibitors may improve graft function. Williams et al. studied the efficacy of leflunomide on 17 patients with PVN and observed that 15/17 patients receiving a combination of MMF, tacrolimus, and steroids showed improved graft function when MMF was switched with leflunomide. However, a meta-analysis by Johnston et al. saw no benefit with either leflunomide or cidofovir. In our study, while immunosuppression was reduced by 25% in 9/10 patients, five patients each received leflunomide and immunoglobulins alongside a reduction in immunosuppression and one patient received no treatment; however, we did not observe any difference in the graft outcomes.
Despite accumulating knowledge about BKV which has led to its early identification, the prognosis continues to be dismal. Meticulous risk stratification of the patients before transplantation as well as individualizing immunosuppression during the posttransplant period is the need of the hour.
| Conclusion|| |
Light microscopy for viral cytopathic changes and IHC with SV40 are essential for the diagnosis of PVN. The Banff scheme of classification is helpful in predicting the prognosis. It is important to diagnose PVN and differentiate it from rejection for appropriate management.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]