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Nephrology 19, Suppl. 3 (2014) 11–16
Mini Review
Current problems in screening, diagnosis and treatment of polyomavirus BK nephropathy KOSUKE MASUTANI Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
KEY WORDS: acute tubular injury, decoy cells, inflammation, polymerase chain reaction, staging system. Correspondence: Dr Kosuke Masutani, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University. Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Email: [email protected] Accepted for publication 27 February 2014. doi:10.1111/nep.12254 Conflicts of interest: The author has no conflicts of interest to declare.
ABSTRACT: Polyomavirus BK nephropathy (BKVN) is an important infectious complication in kidney transplantation. Since graft survival in patients with BKVN is poor, current clinical practice focuses on screening for viral replication, and pre-emptive reduction of immunosuppression in viraemic patients. Urinary cytology, nucleic acid testing of urine and/or plasma, and viralspecific staining of biopsy specimens are necessary for diagnosis. Infected tubular cells show intranuclear inclusions, lysis or necrosis, and shedding into the tubular lumen. But such light microscopy findings are quite focally observed in many cases, and varying degrees of tubulointerstitial inflammation mimicking T-cell-mediated acute rejection make accurate diagnosis difficult. There is a histological classification of BKVN originally reported by the University of Maryland in 2001, and modified by American Society of Transplantation Infectious Disease Community of Practice, which focuses on interstitial inflammation and fibrosis. Another classification was proposed by the Banff Working Group in 2009 (Banff Working Proposal), which focuses on acute tubular injury instead of interstitial inflammation. The usefulness of the Banff Working Proposal is now under consideration with a multicenter study being conducted, but it has not yet reached a clear conclusion. In this review, the current screening strategies for the replication of BK virus, difficulties with diagnosis, histopathological classifications, treatments, and prognostic factors of BKVN are discussed.
Polyomavirus BK (BKV) is an important pathogen in organ transplant patients. BKV was first isolated from urine and ureteral epithelial cells of a kidney transplant patient,1 and is known to cause ureteral stenosis and hemorrhagic cystitis in kidney and hematopoietic stem cell transplant patients. The first case of tissue destructive nephropathy, called polyomavirus BK nephropathy (BKVN), in a kidney allograft was reported in 1995,2 and numerous studies on various aspects of the causative virus and the disease have been published. BKV is ubiquitously present in the general population, and 90% or more of tested individuals may be seropositive.3,4 It is demonstrated that BKV is transmitted to the patient through the donor kidney with a latent infection,5 and is reactivated with immunosuppressive treatment. Urinary shedding of the virus, called viruria, is the first step of viral reactivation, followed by viraemia, and nephropathy after the 6–12-week window period.6 © 2014 Asian Pacific Society of Nephrology
Progression of BKVN is associated with interstitial fibrosis, and subsequent acute rejection followed by the reduction of immunosuppression also induces allograft injury. Since graft survival in patients with BKVN is much poorer than those without the disease,7 current clinical practice focuses on the early detection of viral replication and pre-emptive reduction of immunosuppression.8–10 The management of BKV infection appeared in Kidney Disease Improving Global Outcome (KDIGO) guidelines in 2009,8 and the American Society of Transplantation (AST) Infectious Disease Community of Practice also published guidelines.9,10 There are also different histological classifications of BKVN: the schema recommended by AST,9,10 modified after the schema reported by the University of Maryland,11 and the staging system proposed by the Banff Working Group in 2009, which is under consideration.12,13 In this review, current problems in screening, diagnosis, histological classifications, treatments and prognostic factors are discussed. 11
K Masutani
CURRENT SCREENING STRATEGY FOR BKV REPLICATION AND PRE-EMPTIVE REDUCTION OF IMMUNOSUPPRESSION As the initial presentation of BKVN is insidious, it is strongly recommended that kidney transplant patients are screened regularly for the early detection of viral replication. Both KDIGO and AST guidelines suggest screening for BKV with nuclear acid testing of plasma.8–10 Unfortunately, the costs associated with screening all patients using quantitative PCR are high. Most Japanese and many American transplant centres perform urinary cytology tests initially, and then test plasma by PCR if they find urinary decoy cells consistently. AST also suggests urinary cytology for decoy cells, electron microscopy in search of viral aggregation, quantitative PCR of urine for >7 log10 copies/mL of BKV DNA10 followed by PCR of plasma. They also emphasize the advantages of testing urine, these being: a high negative predictive value, a longer window period (6–12 weeks) before viraemia and BKVN, and lower cost, especially for cytology tests. However, physicians should also consider the disadvantages, such as: a low positive predictive value, and delayed or lack of clearance after treatment, which can cause overly reduced immunosuppression and subsequent acute rejection. Another issue with screening for BKV is how often and how long patients should be screened. KDIGO guidelines suggest monthly screening for the first 3–6 months, then every 3 months until the end of the first year post-transplant; and adding tests when the patient shows an unexplained rise in serum creatinine and after anti-rejection treatment.8 AST guidelines differ, recommending screening at least once every 3 months during the first 2 years, and then annually until the fifth year.9,10 The author reviewed 71 cases of biopsy-proven BKVN at the University of Pittsburgh Medical Center and found that the median time of diagnosis was 355 days post-transplant (range: 74–2856 days),14 which is similar to results reported by Vasudev et al. (median: 318 days; range: 48–1356 days).15 These findings indicate that BKVN is a relatively later complication, and screening at least every 3 months during the first 2 year period seems appropriate to cover more than 80% of BKVN cases. Several studies have reported on protocols for the reduction of immunosuppression.16–18 Currently, two strategies are recommended by AST, these being: (1) dose reduction of calcineurin inhibitor by 25–50% in one or two steps, followed by reducing the antiproliferative drug by 50%, followed by discontinuing the latter; and (2) reduction of the antiproliferative drug by 50%, followed by reducing calcineurin inhibitors by 25–50%, followed by discontinuing the antiproliferative drug.10 Although there is no controlled study, a high incidence of viral clearance in plasma was obtained. However, the time at which to start reducing immunosuppression after the recognition of BKV reactivation remains an unresolved problem. KDIGO and AST guidelines define a BK viral load of ≥4 log10 copies/mL (10 000 12
copies/mL) as ‘presumptive’ BKVN and recommend reduction of immunosuppression. But they make no mention of inter-laboratory variation or target genes of the PCR assay. Recent studies have demonstrated different sensitivities among target genes, such as the large T antigen and VP1 genes, and suggest that a cut-off point of ≥4 log10 copies/mL shows high specificity but low sensitivity in the diagnosis of BKVN in the assay targeting the large T antigen gene.19 Standardization of PCR assays and the establishment of values that reliably correlate with BKVN are essential for accurate diagnosis.
DIFFICULTIES IN THE PATHOLOGICAL DIAGNOSIS OF BKVN Although screening strategies and several non-invasive tests have been developed, the gold standard for confirming diagnosis of BKVN is allograft biopsy. Typical BKVN shows virally infected tubular cells with intranuclear inclusions (Fig. 1A), lysis or necrosis, shedding into the tubular lumen (Fig. 1B), and viral-specific staining using commercially available antisimian virus (SV) 40 large T antigen antibody (Fig. 1C), or in situ hybridization of BKV DNA. Tubulointerstitial inflammation is also observed in many cases (Fig. 1D). However, diagnosis of BKVN is sometimes difficult, even for experienced pathologists, because of some difficulties in the pathology. The first difficulty is that typical cytopathic changes in tubular cells are quite focally observed and might cause misdiagnosis through sampling error, especially in the early stages of the disease. The focal nature might also cause falsenegative viral staining. To avoid false-negative biopsy, AST guidelines recommend that at least two biopsy cores be taken, preferentially containing medullary tissue.9 The second difficulty is that SV40 large T antigen staining might not detect all infected cells. Seemayer et al. investigated the expression of viral protein and cell-cycle proteins using frozen sections from BKVN biopsies20 and hypothesized that during the life-cycle of viral infection the expression of large T antigen increases for the first 10 h with the expression of p53 and increasing nuclear size, and then decreases with up-regulation of VP1 protein and viral DNA replication. Wiesend et al. focused on the expression of p53 in infected cells, and demonstrated that there were three patterns of virally infected cells: (1) an initial early phase with SV40 staining only (16.7%); (2) an early phase with both SV40 and p53 staining (38.9%); and (3) a late phase with p53 staining only (44.4%) before tubular cell lysis.21 These findings suggest that we need to take into account the possibility of false-negatives with any biopsy, and take enough samples, carefully observe serial sections, and re-cut sections or perform re-biopsy in cases clinically suspicious for BKVN with positive BK viraemia. The third difficulty is that many BKVN cases show tubulointerstitial inflammation mimicking T-cell mediated acute rejection, which is another cause of misdiagnosis. © 2014 Asian Pacific Society of Nephrology
Problems in polyomavirus BK nephropathy
A
B
C
D
Fig. 1 (A) Viral infected tubular cells showing intranuclear inclusions (arrow) (haematoxylin and eosin (H&E) stain, magnification ×400). (B) Severe tubular cell shedding into the lumen and overt denudation of tubular basement membrane (H&E stain, magnification ×400). (C) Interstitial inflammation with plasma cells (H&E stain, magnification ×400). (D) Viral infected tubular cells showing positive SV40 large T antigen staining (magnification ×400).
Interpretation of the inflammation is still under debate; concurrent acute rejection, or inflammation as an anti-viral immune response. The relationship between viral infection and rejection is known to be bi-directional: viral infection can trigger rejection or vice versa. Recent studies suggest that putative episodes of acute rejection develop at the same time or after the onset of viruria.22,23 In the setting of sustained BK viruria, biopsies with rejection-like episodes that satisfy Banff criteria for diagnosis do not always respond to steroids,23 suggesting the inflammatory response is induced by BKV. In addition, with regard to biopsy samples of BKVN, Menter et al. reported that tissue obtained in the decreasing phase of the plasma BK viral load showed more severe interstitial infiltrates and tubulitis,24 suggesting that the immune response that facilitates the clearance of the virus from tissues might cause self-limiting tubulointerstitial nephritis. It is currently thought that inflammation from viral or allograft antigens cannot be reliably distinguished by light microscopy. Although several molecules have been reported to be markers for distinguishing BKVN and rejection,25–27 they are not yet in clinical application. Further study is required to identify molecular markers in biopsy tissues, urine or blood samples that distinguish the cause of inflammation easily in routine practice.
HISTOLOGIC STAGING SYSTEMS AND PROGNOSTIC FACTOR OF BKVN The ability to predict the clinical outcome in individual patients is important in BKVN. Clinical factors reported to be © 2014 Asian Pacific Society of Nephrology
associated with a poor prognosis include deceased donor, female recipient, high serum creatinine, serum creatinine increase from baseline, late diagnosis and plasma viral load.14,28–30 As BKVN is ultimately a pathological diagnosis, there has been much interest in exploring the effects of histologic variables on the course of the disease. The percentage of tubular cross-sections showing infection and degree of interstitial fibrosis and tubular atrophy was identified as important in an early study.30 A composite system to stage the disease based on viral cytopathic effect, extent of inflammation and severity of fibrosis was first proposed by Drachenberg et al. (University of Maryland schema),11 and AST has published variations of this schema (AST schema).9,10 The Banff Working Group also proposed a staging system in 2009, which places emphasis on the extent of virus-induced tubular epithelial injury as measured by necrosis, cell lysis, shedding into the tubular lumen, and denudation of tubular basement membranes (Banff Working Proposal).12,13 The three staging systems are summarized in the Table 1. A point of difference between the Banff Working Group proposal and the two other schemas is in the definition of pattern/stage A and B. The University of Maryland schema and AST schema focus on the presence or absence of interstitial inflammation as well as tubular atrophy and the extent of viral cytopathic changes, whereas the Banff Working Proposal emphasizes acute tubular injury (tubular cell necrosis, shedding into the tubular lumen, and denudation of tubular basement membrane), and the degree of inflammation is not taken into account in the staging. 13
K Masutani
Table 1 Salient features of histologic grading systems of BKVN
Patten/Stage A
Pattern/Stage B
Pattern/Stage C
University of Maryland
American Society of Transplantation†
Banff Working Proposal‡
Variable number of virus-infected cells with ANY degree of tubular injury but NO or NEGLIGIBLE INFLAMMATION. Variable number of virus-infected cells with ANY degree of tubular injury AND SIGNIFICANT INFLAMMATION affecting less than 25% (pattern B1), 25–50% (pattern B2) or >50% (pattern B3) of the core biopsy. Variable number of infected cells with ANY degree of tubular injury AND tubular ATROPHY/FIBROSIS affecting >50% of core biopsy.
Virus infection and cytopathic effect in
Nephrology 19, Suppl. 3 (2014) 11–16
Mini Review
Current problems in screening, diagnosis and treatment of polyomavirus BK nephropathy KOSUKE MASUTANI Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
KEY WORDS: acute tubular injury, decoy cells, inflammation, polymerase chain reaction, staging system. Correspondence: Dr Kosuke Masutani, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University. Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Email: [email protected] Accepted for publication 27 February 2014. doi:10.1111/nep.12254 Conflicts of interest: The author has no conflicts of interest to declare.
ABSTRACT: Polyomavirus BK nephropathy (BKVN) is an important infectious complication in kidney transplantation. Since graft survival in patients with BKVN is poor, current clinical practice focuses on screening for viral replication, and pre-emptive reduction of immunosuppression in viraemic patients. Urinary cytology, nucleic acid testing of urine and/or plasma, and viralspecific staining of biopsy specimens are necessary for diagnosis. Infected tubular cells show intranuclear inclusions, lysis or necrosis, and shedding into the tubular lumen. But such light microscopy findings are quite focally observed in many cases, and varying degrees of tubulointerstitial inflammation mimicking T-cell-mediated acute rejection make accurate diagnosis difficult. There is a histological classification of BKVN originally reported by the University of Maryland in 2001, and modified by American Society of Transplantation Infectious Disease Community of Practice, which focuses on interstitial inflammation and fibrosis. Another classification was proposed by the Banff Working Group in 2009 (Banff Working Proposal), which focuses on acute tubular injury instead of interstitial inflammation. The usefulness of the Banff Working Proposal is now under consideration with a multicenter study being conducted, but it has not yet reached a clear conclusion. In this review, the current screening strategies for the replication of BK virus, difficulties with diagnosis, histopathological classifications, treatments, and prognostic factors of BKVN are discussed.
Polyomavirus BK (BKV) is an important pathogen in organ transplant patients. BKV was first isolated from urine and ureteral epithelial cells of a kidney transplant patient,1 and is known to cause ureteral stenosis and hemorrhagic cystitis in kidney and hematopoietic stem cell transplant patients. The first case of tissue destructive nephropathy, called polyomavirus BK nephropathy (BKVN), in a kidney allograft was reported in 1995,2 and numerous studies on various aspects of the causative virus and the disease have been published. BKV is ubiquitously present in the general population, and 90% or more of tested individuals may be seropositive.3,4 It is demonstrated that BKV is transmitted to the patient through the donor kidney with a latent infection,5 and is reactivated with immunosuppressive treatment. Urinary shedding of the virus, called viruria, is the first step of viral reactivation, followed by viraemia, and nephropathy after the 6–12-week window period.6 © 2014 Asian Pacific Society of Nephrology
Progression of BKVN is associated with interstitial fibrosis, and subsequent acute rejection followed by the reduction of immunosuppression also induces allograft injury. Since graft survival in patients with BKVN is much poorer than those without the disease,7 current clinical practice focuses on the early detection of viral replication and pre-emptive reduction of immunosuppression.8–10 The management of BKV infection appeared in Kidney Disease Improving Global Outcome (KDIGO) guidelines in 2009,8 and the American Society of Transplantation (AST) Infectious Disease Community of Practice also published guidelines.9,10 There are also different histological classifications of BKVN: the schema recommended by AST,9,10 modified after the schema reported by the University of Maryland,11 and the staging system proposed by the Banff Working Group in 2009, which is under consideration.12,13 In this review, current problems in screening, diagnosis, histological classifications, treatments and prognostic factors are discussed. 11
K Masutani
CURRENT SCREENING STRATEGY FOR BKV REPLICATION AND PRE-EMPTIVE REDUCTION OF IMMUNOSUPPRESSION As the initial presentation of BKVN is insidious, it is strongly recommended that kidney transplant patients are screened regularly for the early detection of viral replication. Both KDIGO and AST guidelines suggest screening for BKV with nuclear acid testing of plasma.8–10 Unfortunately, the costs associated with screening all patients using quantitative PCR are high. Most Japanese and many American transplant centres perform urinary cytology tests initially, and then test plasma by PCR if they find urinary decoy cells consistently. AST also suggests urinary cytology for decoy cells, electron microscopy in search of viral aggregation, quantitative PCR of urine for >7 log10 copies/mL of BKV DNA10 followed by PCR of plasma. They also emphasize the advantages of testing urine, these being: a high negative predictive value, a longer window period (6–12 weeks) before viraemia and BKVN, and lower cost, especially for cytology tests. However, physicians should also consider the disadvantages, such as: a low positive predictive value, and delayed or lack of clearance after treatment, which can cause overly reduced immunosuppression and subsequent acute rejection. Another issue with screening for BKV is how often and how long patients should be screened. KDIGO guidelines suggest monthly screening for the first 3–6 months, then every 3 months until the end of the first year post-transplant; and adding tests when the patient shows an unexplained rise in serum creatinine and after anti-rejection treatment.8 AST guidelines differ, recommending screening at least once every 3 months during the first 2 years, and then annually until the fifth year.9,10 The author reviewed 71 cases of biopsy-proven BKVN at the University of Pittsburgh Medical Center and found that the median time of diagnosis was 355 days post-transplant (range: 74–2856 days),14 which is similar to results reported by Vasudev et al. (median: 318 days; range: 48–1356 days).15 These findings indicate that BKVN is a relatively later complication, and screening at least every 3 months during the first 2 year period seems appropriate to cover more than 80% of BKVN cases. Several studies have reported on protocols for the reduction of immunosuppression.16–18 Currently, two strategies are recommended by AST, these being: (1) dose reduction of calcineurin inhibitor by 25–50% in one or two steps, followed by reducing the antiproliferative drug by 50%, followed by discontinuing the latter; and (2) reduction of the antiproliferative drug by 50%, followed by reducing calcineurin inhibitors by 25–50%, followed by discontinuing the antiproliferative drug.10 Although there is no controlled study, a high incidence of viral clearance in plasma was obtained. However, the time at which to start reducing immunosuppression after the recognition of BKV reactivation remains an unresolved problem. KDIGO and AST guidelines define a BK viral load of ≥4 log10 copies/mL (10 000 12
copies/mL) as ‘presumptive’ BKVN and recommend reduction of immunosuppression. But they make no mention of inter-laboratory variation or target genes of the PCR assay. Recent studies have demonstrated different sensitivities among target genes, such as the large T antigen and VP1 genes, and suggest that a cut-off point of ≥4 log10 copies/mL shows high specificity but low sensitivity in the diagnosis of BKVN in the assay targeting the large T antigen gene.19 Standardization of PCR assays and the establishment of values that reliably correlate with BKVN are essential for accurate diagnosis.
DIFFICULTIES IN THE PATHOLOGICAL DIAGNOSIS OF BKVN Although screening strategies and several non-invasive tests have been developed, the gold standard for confirming diagnosis of BKVN is allograft biopsy. Typical BKVN shows virally infected tubular cells with intranuclear inclusions (Fig. 1A), lysis or necrosis, shedding into the tubular lumen (Fig. 1B), and viral-specific staining using commercially available antisimian virus (SV) 40 large T antigen antibody (Fig. 1C), or in situ hybridization of BKV DNA. Tubulointerstitial inflammation is also observed in many cases (Fig. 1D). However, diagnosis of BKVN is sometimes difficult, even for experienced pathologists, because of some difficulties in the pathology. The first difficulty is that typical cytopathic changes in tubular cells are quite focally observed and might cause misdiagnosis through sampling error, especially in the early stages of the disease. The focal nature might also cause falsenegative viral staining. To avoid false-negative biopsy, AST guidelines recommend that at least two biopsy cores be taken, preferentially containing medullary tissue.9 The second difficulty is that SV40 large T antigen staining might not detect all infected cells. Seemayer et al. investigated the expression of viral protein and cell-cycle proteins using frozen sections from BKVN biopsies20 and hypothesized that during the life-cycle of viral infection the expression of large T antigen increases for the first 10 h with the expression of p53 and increasing nuclear size, and then decreases with up-regulation of VP1 protein and viral DNA replication. Wiesend et al. focused on the expression of p53 in infected cells, and demonstrated that there were three patterns of virally infected cells: (1) an initial early phase with SV40 staining only (16.7%); (2) an early phase with both SV40 and p53 staining (38.9%); and (3) a late phase with p53 staining only (44.4%) before tubular cell lysis.21 These findings suggest that we need to take into account the possibility of false-negatives with any biopsy, and take enough samples, carefully observe serial sections, and re-cut sections or perform re-biopsy in cases clinically suspicious for BKVN with positive BK viraemia. The third difficulty is that many BKVN cases show tubulointerstitial inflammation mimicking T-cell mediated acute rejection, which is another cause of misdiagnosis. © 2014 Asian Pacific Society of Nephrology
Problems in polyomavirus BK nephropathy
A
B
C
D
Fig. 1 (A) Viral infected tubular cells showing intranuclear inclusions (arrow) (haematoxylin and eosin (H&E) stain, magnification ×400). (B) Severe tubular cell shedding into the lumen and overt denudation of tubular basement membrane (H&E stain, magnification ×400). (C) Interstitial inflammation with plasma cells (H&E stain, magnification ×400). (D) Viral infected tubular cells showing positive SV40 large T antigen staining (magnification ×400).
Interpretation of the inflammation is still under debate; concurrent acute rejection, or inflammation as an anti-viral immune response. The relationship between viral infection and rejection is known to be bi-directional: viral infection can trigger rejection or vice versa. Recent studies suggest that putative episodes of acute rejection develop at the same time or after the onset of viruria.22,23 In the setting of sustained BK viruria, biopsies with rejection-like episodes that satisfy Banff criteria for diagnosis do not always respond to steroids,23 suggesting the inflammatory response is induced by BKV. In addition, with regard to biopsy samples of BKVN, Menter et al. reported that tissue obtained in the decreasing phase of the plasma BK viral load showed more severe interstitial infiltrates and tubulitis,24 suggesting that the immune response that facilitates the clearance of the virus from tissues might cause self-limiting tubulointerstitial nephritis. It is currently thought that inflammation from viral or allograft antigens cannot be reliably distinguished by light microscopy. Although several molecules have been reported to be markers for distinguishing BKVN and rejection,25–27 they are not yet in clinical application. Further study is required to identify molecular markers in biopsy tissues, urine or blood samples that distinguish the cause of inflammation easily in routine practice.
HISTOLOGIC STAGING SYSTEMS AND PROGNOSTIC FACTOR OF BKVN The ability to predict the clinical outcome in individual patients is important in BKVN. Clinical factors reported to be © 2014 Asian Pacific Society of Nephrology
associated with a poor prognosis include deceased donor, female recipient, high serum creatinine, serum creatinine increase from baseline, late diagnosis and plasma viral load.14,28–30 As BKVN is ultimately a pathological diagnosis, there has been much interest in exploring the effects of histologic variables on the course of the disease. The percentage of tubular cross-sections showing infection and degree of interstitial fibrosis and tubular atrophy was identified as important in an early study.30 A composite system to stage the disease based on viral cytopathic effect, extent of inflammation and severity of fibrosis was first proposed by Drachenberg et al. (University of Maryland schema),11 and AST has published variations of this schema (AST schema).9,10 The Banff Working Group also proposed a staging system in 2009, which places emphasis on the extent of virus-induced tubular epithelial injury as measured by necrosis, cell lysis, shedding into the tubular lumen, and denudation of tubular basement membranes (Banff Working Proposal).12,13 The three staging systems are summarized in the Table 1. A point of difference between the Banff Working Group proposal and the two other schemas is in the definition of pattern/stage A and B. The University of Maryland schema and AST schema focus on the presence or absence of interstitial inflammation as well as tubular atrophy and the extent of viral cytopathic changes, whereas the Banff Working Proposal emphasizes acute tubular injury (tubular cell necrosis, shedding into the tubular lumen, and denudation of tubular basement membrane), and the degree of inflammation is not taken into account in the staging. 13
K Masutani
Table 1 Salient features of histologic grading systems of BKVN
Patten/Stage A
Pattern/Stage B
Pattern/Stage C
University of Maryland
American Society of Transplantation†
Banff Working Proposal‡
Variable number of virus-infected cells with ANY degree of tubular injury but NO or NEGLIGIBLE INFLAMMATION. Variable number of virus-infected cells with ANY degree of tubular injury AND SIGNIFICANT INFLAMMATION affecting less than 25% (pattern B1), 25–50% (pattern B2) or >50% (pattern B3) of the core biopsy. Variable number of infected cells with ANY degree of tubular injury AND tubular ATROPHY/FIBROSIS affecting >50% of core biopsy.
Virus infection and cytopathic effect in
