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Table of Contents
CASE REPORT
Year : 2020  |  Volume : 14  |  Issue : 2  |  Page : 147-151

Coexistent BK-virus-associated nephropathy and ureteric stenosis in a patient with acute cellular rejection after renal transplantation: A case report and review of literature


1 Department of Nephrology, Virinchi Hospitals and Max Superspeciality Medical Centre, Hyderabad, Telangana, India
2 Department of Radiology, Niloufer Hospital, Hyderabad, Telangana, India
3 Department of Histopathology, Apollo Hospitals, Hyderabad, Telangana, India

Date of Submission17-Nov-2019
Date of Acceptance15-Mar-2020
Date of Web Publication06-Jul-2020

Correspondence Address:
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Virinchi Hospitals and Max Superspeciality Medical Centre, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_67_19

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  Abstract 


BK-virus-associated nephropathy (BKVN) is one of the most common causes of viral nephropathy in renal-transplant recipients. The intensity of immunosuppression is the most important risk factor for BKVN. Combined BKVN and rejection can occur rarely, which is difficult to diagnose and manage. Ureteritis, leading to ureteric stenosis, can result in secondary to both rejection and BK-virus (BKV) infection. We herein report a case of BKVN coexistent with the features of acute cellular rejection in a patient with ureteric stenosis probably induced by BKV infection, which was managed successfully with step-wise modification of immunosuppression along with double–J stenting, leading to stabilization of graft function.

Keywords: BK-virus-associated nephropathy, rejection, ureteric stenosis, ureteritis


How to cite this article:
Etta PK, Madhavi T, Gowrishankar S. Coexistent BK-virus-associated nephropathy and ureteric stenosis in a patient with acute cellular rejection after renal transplantation: A case report and review of literature. Indian J Transplant 2020;14:147-51

How to cite this URL:
Etta PK, Madhavi T, Gowrishankar S. Coexistent BK-virus-associated nephropathy and ureteric stenosis in a patient with acute cellular rejection after renal transplantation: A case report and review of literature. Indian J Transplant [serial online] 2020 [cited 2020 Aug 11];14:147-51. Available from: http://www.ijtonline.in/text.asp?2020/14/2/147/289052




  Introduction Top


BK-virus (BKV) is a ubiquitous polyomavirus; primary infection is usually acquired during childhood, leading to a seroprevalence of up to 80% in adults. Following primary infection, the virus establishes latency in the renal tubular and uroepithelial cells. Among renal transplantation recipients (RTRs), reactivation of latent infection or transmission of new infection via the donor kidney can lead to viruria, followed by viremia, followed by the development of BKV-associated nephropathy (BKVN). It is considered as the most common form of viral nephropathy in RTRs, with a prevalence of 5%–8%.[1] The degree of immunosuppression is the most important risk factor for BKVN, which is a form of tubulointerstitial nephritis. Asymptomatic slow progressive rise in the serum creatinine is the most common presentation of BKVN. The incidence of BKVN is highest in the first 2–6 months after RT. BKVN is rarely seen in nonkidney solid organ-transplant recipients. Although uncommon, ureteritis and ureteric stenosis secondary to BKV infection have been reported.[2],[3],[4],[5] Hemorrhagic cystitis due to BKV-associated hemorrhagic cystitis (BKHC) is commonly reported among hematopoietic stem cell-transplant (HSCT) recipients. The combined presence of BKVN and rejection has been described and is difficult to diagnose and manage.[6],[7] The coexistence of BKVN and ureteric stenosis in a patient with rejection has not been reported. We herein report a case of BKVN coexistent with the features of acute cellular rejection in a patient with ureteric stenosis probably induced by BKV infection, which was managed successfully with step-wise modification of immunosuppression along with double–J (DJ) stenting, leading to the stabilization of graft function.


  Case Report Top


A 42-year-old man presented at 15 months of RT, with progressive rise in the serum creatinine level from 3 weeks' duration. His native kidney disease was unknown. He received a live-unrelated (6/6 human leukocyte antigen [HLA] mismatch) RT, with low-dose rabbit antithymocyte globulin (rATG) (1 mg/kg) as induction. He was on triple-immunosuppressive therapy with prednisolone, mycophenolate mofetil (MMF), and tacrolimus (TAC) and had normal graft function (baseline creatinine of 1.3 mg/dl). At presentation to us, he had pallor, pulse rate was 84/min, and his blood pressure was 130/90 mmHg. Rest of the examination was unremarkable. The laboratory findings revealed hemoglobin of 10.4 g/dL, total leukocyte count of 8.0 × 103/μL, platelet count of 258 × 103/μL, blood urea of 42 mg/dl, serum creatinine of 2.6 mg/dl, total protein of 7.0 g/dl, and albumin of 4.2 g/dl. His urine examination showed 1 + albumin, 8–10 red blood cell/hpf, and 6–8 pus cells/hpf. Spot urine protein-to-creatinine ratio was 1.1. Urine culture was sterile. Serology for human immunodeficiency virus and hepatitis B and C was negative. Whole-blood TAC trough level was optimal. Ultrasound (USG) and Doppler showed mild graft hydroureteronephrosis (HDUN) with a raised resistive index (0.9). Voiding cystourethrogram showed no evidence of reflux. As HDUN was not significant, allograft biopsy was performed.

Light microscopy showed combined features of BKVN and acute T-cell-mediated rejection, Banff, Type 1a, with mild chronicity. The interstitial inflammation and tubulitis were extended beyond the areas of viral cytopathic changes, indicating concurrent rejection. There was no vascular involvement due to rejection. Immunohistochemistry (IHC) was positive after using cross-reacting antibody for simian virus 40 large T-antigen (SV-40T), and C4d staining was negative [Figure 1] and [Figure 2]. SV-40 staining was negative in the remote areas of inflammation beyond viral cytopathic changes. Electron microscopic (EM) study was not done. Follow-up USG scan after 1 week showed worsening of HDUN; diuretic renography with 99 mTc-ethylenedicysteine scan showed moderate hydronephrotic graft kidney with significantly delayed drainage. Plasma BKV quantitative nucleic acid testing (NAT) assay showed a viral load of 3.2 × 108 copies/mL. In view of combined rejection and BKVN, he was treated cautiously with pulse steroids. His regimen included two doses 500 mg of intravenous (IV) methyl prednisolone and single dose of IV immunoglobulin (IVIG, 400 mg/kg), and his maintenance immunosuppression was reduced with 50% dose reduction of MMF after 2 weeks following partial graft functional recovery. TAC dose was reduced to attain and maintain the target trough level of 3–4 ng/ml. In view of late-onset significant HDUN on background of BKVN with very high viral load level, ureteric stenosis was thought to be secondary to BKV-induced ureteritis. As there was no vascular involvement by rejection, it might have not played a role in ureteritis. Urine examination for acid-fast bacilli and urine polymerase chain reaction (PCR) for Mycobacterium were negative.
Figure 1: Panel a showing moderate interstitial inflammation and some of the tubular lining cells appear large with smudged nuclei (H and E, ×100). Panel b showing cytopathic changes in the tubular lining cells (PAS, ×400). Panel c showing moderate tubulitis (H and E, ×400). Panel d showing nuclear positivity for simian virus 40 large T-antigen (IHC, ×200)

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Figure 2: Significant interstitial lymphocytic infiltration, tubulitis, and tubular injury in areas away from the viral cytopathic changes (H and E, left panel ×20, right panel ×40)

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Due to unsuccessful retrograde stenting, he was treated with percutaneous nephrostomy under USG guidance followed by antegrade insertion of DJ stent. With this therapy, his creatinine settled to 1.9 mg/dl at the end of 12 weeks and DJ stent was removed. At the end of 6 months, his creatinine was reduced to 1.6 mg/dl, mild residual HDUN was persisting on USG, and repeat plasma BKV-NAT assay showed a viral load of 2.1 × 103 copies/ml. In view of history of concurrent rejection and significant graft functional recovery, we have not reduced his immunosuppression further. He is under close follow-up and is asymptomatic.


  Discussion Top


BKVN is the most common form of viral nephropathy in RTRs. Although BKV infection usually occurs within 6 months of RT, it can occur at any time depending on intensity of immunosuppression, especially in RTRs with a history of treated rejection episodes; however, our patient has not had any past rejection episodes. The identification of viruria–viremia–nephritis sequence has provided the tools for screening RTRs and the possibility of earlier intervention with improved outcomes. Kidney Disease: Improving Global Outcome (KDIGO) suggests screening all RTRs for BKV with quantitative plasma NAT at least monthly for the first 3–6 months after transplantation, then every 3 months until the end of the 1st posttransplant year; whenever there is an unexplained rise in serum creatinine and after treatment for acute rejection.[8] Recently published American Society of Transplantation-Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommend screening all RTRs for BKV-DNAemia monthly until 9 months and then every 3 months until 2 years posttransplant; extended screening after 2 years may be considered in pediatric RT.[9] However, the optimal screening strategy, thresholds for reducing immunosuppression, and obtaining a renal allograft biopsy have not been determined, and approaches vary among centers.[10],[11] Recent AST-IDCOP guidelines do not recommend allograft biopsy for treating BKV-DNAemic patients with baseline renal function.[9]

Quantitative plasma BKV-DNA by NAT (PCR) is the preferred and commonly used screening test at most centers. Evidence suggests that the presence of BK viremia/DNAemia precedes BKVN with a median of 8 weeks. The persistently elevated plasma BKV viral load level of > 104 copies/mL (or BKV urine load of > 107/mL) usually correlates with biopsy-proven BKVN (presumptive BKVN). Other useful laboratory tests include quantitative urinary NAT for BKV-DNA and cytologic examination of the urine to identify decoy cells, and the gold standard method is renal allograft biopsy. In Papanicolaou-stained cytology smears, decoy cells are comet-shaped cells with large basophilic, amorphous, homogenous, ground-glass-like intranuclear inclusion bodies and a condensed rim of chromatin. Renal biopsy showing characteristic cytopathic changes and positive IHC for SV-40T antigen is diagnostic. Because of the focal nature of early disease, at least two biopsy cores, preferably including medulla (BKV has tropism for medullary tubules), should be examined. The viral cytopathic changes are characterized by the presence of basophilic intranuclear inclusions; four varieties of them have been described: ground-glass type surrounded by chromatin (most common), inclusions surrounded by a halo (Cytomegalovirus [CMV]-like), multinucleated (finely irregular nuclear alterations), and vesicular type (with clumped chromatin and nucleoli).[12] Other histological features include anisonucleosis, hyperchromasia, chromatin clumping of infected cells, interstitial mononuclear or polymorphonuclear cell infiltrates, and tubular injury. Tubulitis and peritubular inflammation can also be seen in BKVN, which can be difficult to differentiate from rejection. Coexistent BKVN and acute rejection can occur rarely; however, more commonly rejection is precipitated following a reduction in immunosuppression to treat BKV viremia or BKVN. The presence of extensive tubulitis/interstitial inflammation in areas remote from the viral cytopathic changes, endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries, and tubular HLA-DR expression may suggest concurrent rejection.[13] Li et al. tried to differentiate BKVN and rejection by identifying the inflammatory cellular constituents, their immunophenotyping, and tubule cells expression of HLA-DR. They suggested that the number of CD20 cells and the percentages of CD3, CD4, CD8, and CD20 cells in renal biopsies may help in distinction between BKVN and rejection.[14] EM in BKVN reveals intranuclear viral inclusions with a diameter of 30–50 nm. In 2018, the Banff Working Group on Polyomavirus Nephropathy proposed a classification system that defined three histologic classes of BKVN on the basis of two morphologic variables: intrarenal BKV load levels and Banff interstitial fibrosis ci scores.[15] It describes Class 1 as an early BKVN stage with favorable outcome and Classes 2 and 3 as having more pronounced impact on function with graft failure rates reaching 50% in Class 3. Negative staining EM of the urine of the patients with BKVN often reveals the presence of cast-like, BKV aggregates, termed as Haufen bodies. In a study, the detection of Haufen in the urine had a sensitivity, specificity, negative predictive value, and positive predictive value for biopsy-proven BKVN of > 95%.[16]

Ureteral stenosis affects 3.1%–10.2% of patients after RT.[17],[18] Ureteric stenosis can be early onset (<3 months) or late onset (>3 months); ureteral devascularization leading to ischemia and stricture formation is the most common cause. The first association of BKV with ureteral stenosis was in the seminal paper published in 1971 reporting isolation of a new virus, BK, named after the initials of the first patient who presented 3 months after transplant with obstructive uropathy.[19] Early-onset stenosis can be due to surgical errors during ureteroneocystostomy, extrinsic compression (due to hematoma, lymphocele, urinoma), kinking of a redundant ureter, collecting system hematoma, calculus, and anastomotic edema. Late-onset stenosis can result from ureteral ischemia, vasculitis secondary to acute rejection, lymphocele, fibrosis from immunosuppressive medications, neoplastic disease, tuberculosis, and ureterolithiasis. The risk factors for ureteric stenosis include excessive dissection in the “golden triangle” area (the site confined by ureter, kidney, and renal vessels), unilateral dual transplantation, old age donor, pediatric recipient, deceased donor, presence of inferior polar artery, diabetes mellitus, BKVN and CMV infection in recipient, prolonged cold ischemic time, and delayed graft function.[20] In our case, both rejection and BKV may cause ureteritis; however, in the absence of vascular involvement due to rejection in biopsy and with the presence of very high level of BKV-DNAemia, we ascribed ureteric stenosis to be due to BKV alone. Since the stenosis developed more than 1 year of RT, it is less likely to be due to surgical factors. BKV-associated stenosis usually affects distal part of the ureter, especially around the site of anastomosis at the ureterovesical junction. The identification of BKV-induced histologic changes in the ureteric biopsy is diagnostic, but it is difficult to perform.[21] It remains unknown whether BKV is the primary cause of ureteric stenosis or whether BKV infects previously injured ureter (from ischemia or trauma after stenting) as a secondary insult.[22],[23] Few reports have noted ureteric stenosis secondary to BKV-induced cystitis (BKHC), especially in cases of HSCT recipients.[4],[24]

The cornerstone of management of BKVN is to decrease immunosuppression. The KDIGO suggests reducing immunosuppressive medications when BKV plasma NAT is persistently > 104 copies/mL. Recently published AST-IDCOP guidelines recommend step-wise immunosuppression reduction for RTRs patients with plasma BKV-DNAemia of > 1000 copies/mL sustained for 3 weeks or increasing to > 10,000 copies/mL reflecting “probable” and “presumptive” BKVN, respectively.[9] This approach applies to both for the prevention of BKVN in patients with BKV viremia detected by routine screening and for the treatment of patients with biopsy-proven (”definitive”) BKVN. The optimal approach to reducing immunosuppression has not been defined, but the goal is to restore immunity against the virus without triggering rejection. Published reports on these reduction protocols have shown mixed results, and no randomized controlled trials (RCTs) have compared one strategy with another. An RCT reported that viruria was the highest with TAC + MMF (46%) and the lowest with cyclosporine-A (CsA) + MMF (13%) combination; withdrawal of the antimetabolite resulted in the clearance of viremia without progression to BKVN. It concluded that monitoring and preemptive withdrawal of immunosuppression were associated with the resolution of viremia and the absence of BKVN without acute rejection or graft loss.[25] A common practice of immunosuppressive dose reduction is the withdrawal of antimetabolite (azathioprine or MMF) and reduction in calcineurin inhibitor dosage by 50%. In refractory cases, other agents such as IVIG, leflunomide, or cidofovir may be tried; however, the efficacy of these agents has not been established. Appropriate RCTs are lacking to generally recommend treatment by switching from TAC to CsA, from MMF to mammalian target of rapamycin inhibitors or leflunomide, or by the adjunct use of IVIG, leflunomide, or cidofovir.[26] As per the AST-IDCOP, fluoroquinolones are not recommended for prophylaxis or therapy.[9]

There is no evidence to guide the optimal management of patients with coexistent BKVN and acute rejection; the management of these patients is complicated by the conflicting ideals of decreasing immunosuppression to treat the former and increasing immunosuppression to treat the latter. A retrospective study compared prognosis of BKVN patients with and without rejection. It concluded that the prognosis of combined BKVN and acute rejection after antirejection therapy followed by antiviral therapy was similar to that of BKVN alone after antiviral therapy.[27] Another retrospective study also concluded that transient bolus steroid administration to patients with coexistent acute rejection and BK viremia or nephropathy does not preclude subsequent viral clearance, as long as subsequent reduction of immunosuppression is carried out, with or without antiviral therapy.[28] The AST-IDCOP suggests that in cases with sustained BKV-DNAemia and biopsy-proven acute rejection (with or without evidence of concurrent BKVN), antirejection treatment has priority, and in case of clinical and laboratory response, it should be followed by reducing immunosuppression as a second step (e.g., after 2 weeks).[9] Retransplantation in patients with graft failure due to BKVN can be successful if BKV-DNAemia is definitively cleared, independent of failed allograft nephrectomy.

In conclusion, BKVN can coexist with acute rejection; extreme caution and delicate management are required while modifying immunosuppressive regimen. Most of the published literature suggests initial antirejection therapy followed by reducing immunosuppression as a second step. Ureteric stenosis can result from both vasculitis due to rejection and BKV infection, and it may require urologic intervention and stenting. Timely management can help in restoring the graft function and better long-term graft outcome.

Declaration of patient consent

The authors certify that patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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