Kidney Biopsy Teaching Case BK Virus Nephropathy in Heart Transplant Recipients Alin Joseph, MD, MS,1 Monika Pilichowska, MD, PhD,2 Helen Boucher, MD,3 Michael Kiernan, MD,4 David DeNofrio, MD,4 and Lesley A. Inker, MD, MS1 Polyomavirus-associated nephropathy (PVAN) has become an important cause of kidney failure in kidney transplant recipients. PVAN is reported to affect 1% to 7% of kidney transplant recipients, leading to premature transplant loss in approximately 30% to 50% of diagnosed cases. PVAN occurring in the native kidneys of solid-organ transplant recipients other than kidney only recently has been noted. We report 2 cases of PVAN in heart transplant recipients, which brings the total of reported cases to 7. We briefly review the literature on the hypothesized causes of PVAN in kidney transplant recipients and comment on whether these same mechanisms also may cause PVAN in other solid-organ transplant recipients. PVAN should be considered in the differential diagnosis when evaluating worsening kidney function. BK viremia surveillance studies of nonkidney solid-organ recipients should be conducted to provide data to assist the transplantation community in deciding whether regular monitoring of nonkidney transplant recipients for BK viremia is indicated. Am J Kidney Dis. -(-):---. ª 2015 by the National Kidney Foundation, Inc. INDEX WORDS: Polyomavirus-associated nephropathy (PVAN); BV virus nephropathy; cardiac transplantation; heart transplant recipient; native kidney; immunosuppression; viral reactivation; renal biopsy; tubular atrophy; interstitial fibrosis; kidney failure.
INTRODUCTION Polyomavirus-associated nephropathy (PVAN) is an important cause of kidney failure in kidney transplant recipients, reported to affect 1% to 7% of kidney transplant recipients and leading to premature transplant loss in approximately 30% to 50% of diagnosed cases. PVAN occurring in native kidneys of nonkidney transplant recipients only recently has been noted.1 We report on 2 cases of PVAN in heart transplant recipients.
CASE REPORT 1 Clinical History and Initial Laboratory Data A 63-year-old white man with a history of ischemic cardiomyopathy underwent cardiac transplantation in May 2009. Table 1 provides clinical and laboratory data at the time of transplantation and subsequent immunosuppressive regimen. His initial regimen included tacrolimus, mycophenolate mofetil (MMF), and prednisone. Shortly thereafter, prednisone therapy was stopped secondary to glaucoma, and MMF dosage was reduced secondary to leukopenia. In April 2010, he was noted to have moderate focal grade 1R rejection (1990 Grade 2) and was restarted on low-dose prednisone therapy, as well as an increased dose of MMF. Before transplantation, estimated glomerular filtration rate (eGFR) using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation2 had been 59 mL/min/ 1.73 m2. Postsurgery eGFRs were stable at w40 mL/min/1.73 m2 until spring 2012, when he was referred to nephrology for eGFR of 29 mL/min/1.73 m2. Serum BK viral load was quantified as 3,300,163 copies/mL (6.52 log10). Urine cytology revealed highly atypical urothelial cells with changes characteristic of polyomavirus. Positive results were obtained when a cytospin preparation was immunohistochemically stained using an antibody against SV40 (simian virus 40, a polyomavirus related closely enough to BK virus that anti-SV40 antibodies cross-react with BK virus antigens). MMF dosage subsequently was reduced to 250 mg twice daily and tacrolimus dosage was reduced to achieve a trough level of 4 to Am J Kidney Dis. 2015;-(-):---
6 ng/mL. Following these changes, no improvement in kidney function was noted and a kidney biopsy was performed.
Kidney Biopsy Morphologic examination of the kidney (Fig 1) revealed florid PVAN (stage B). There was prominent chronic inflammation seen predominantly in the medulla with patchy, mild cortical involvement. Long-term changes included focal global glomerulosclerosis, mild to moderate fibrosis and tubular atrophy, and mild vasculopathy.
Diagnosis Polyomavirus-associated nephropathy.
Clinical Follow-up Immunosuppression was reduced gradually to MMF, 250 mg, twice daily with a tacrolimus trough goal of 3 to 5 ng/mL. Given the persistence of BK viremia with no improvement in eGFR, the patient’s treatment regimen was converted from tacrolimus to sirolimus, and ciprofloxacin treatment was From the 1Division of Nephrology, 2Department of Pathology, and Divisions of 3Infectious Diseases and 4Cardiology, Tufts Medical Center, Boston, MA. Received June 9, 2014. Accepted in revised form December 12, 2014. Because the Editor-in-Chief and Deputy Editor recused themselves from consideration of this article, the peer-review and decision-making processes were handled entirely by the Pathology Editor (Helmut G. Rennke, MD) who served as Acting Editor-inChief. Details of the journal’s procedures for potential editor conflicts are given in the Information for Authors & Editorial Policies. Address correspondence to Lesley A. Inker, MD, MS, Division of Nephrology, 800 Washington St, Box #391, Tufts Medical Center, Boston, MA 02111. E-mail: [email protected] 2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2014.12.020 1
Joseph et al Table 1. Patient Characteristics Case 1
Case 2
Age & sex Cause of heart failure Initial immunosuppression Episodes of rejection or other increase in immunosuppression
60-y-old man Ischemic cardiomyopathy MMF/tacrolimus/prednisone taper Rejection 11 mo post-Tx: treated with pulse prednisone and increased MMF dose
CMV status of donor/recipient EBV status of donor/recipient Kidney function pre-Tx Baseline kidney function post-Tx Kidney function at time of biopsy CD4 count at PVAN diagnosis (3103/mL) Most recent CD4 count (3103/mL) Time post-Tx when PVAN diagnosed BK viremia titer at diagnosis (copies/mL) Treatment for PVAN
Positive/positive Positive/positive Scr, 1.32 mg/dL; eGFR, 59 mL/min/1.73 m2 Scr, 1.86 mg/dL; eGFR, 39 mL/min/1.73 m2 Scr, 2.82 mg/dL; eGFR, 23 mL/min/1.73 m2 560
43-y-old man GCM MMF/tacrolimus/prednisone 1. GCM pre-Tx: treated with muromonabCD3, high-dose prednisone 2. Recurrent GCM and grade 2A rejection 3 mo post-Tx: treated with thymoglobulin (7 doses over 12 d), increased MMF Negative/negative Positive/positive Scr, 2.41 mg/dL; eGFR, 32 mL/min/1.73 m2 Scr, 1.29 mg/dL; eGFR, 67 mL/min/1.73 m2 Scr, 2.36 mg/dL; eGFR, 32 mL/min/1.73 m2 84
248 3y 3,300,163
176 2y 810,700
Reduction in immunosuppression (MMF, 250 mg, 23/d; tacrolimus trough goal, 35 ng/mL); conversion from tacrolimus to sirolimus; ciprofloxacin; 8 doses of 100 mg/kg IVIG over 8 wk Started PD 2.3 y after diagnosis of PVAN
Reduction in immunosuppression (MMF, 250 mg, 23/d; tacrolimus trough goal, 5-7 ng/mL); ciprofloxacin
Status at last available follow-up
eGFR stable at 40 mL/min/1.73 m2
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; eGFR, estimated glomerular filtration rate; GCM, giant cell myocarditis; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; PD, peritoneal dialysis; PVAN, polyomavirus nephropathy; Scr, serum creatinine; Tx, transplantation.
initiated with some initial improvement in BK viral load (to 10,120 copies/mL [4.01 log10]) and eGFR (from 19 to 25 mL/ min/1.73 m2). A subsequent rejection episode noted on a screening endomyocardial biopsy was treated with pulse steroids and an increase in MMF dosage to 500 mg twice a day; this resulted in an increase in viral load to 236,704 copies/mL (5.37 log10). The patient began treatment with intravenous immunoglobulin therapy (100 mg/kg) and received 8 doses over a period of 8 weeks. eGFR gradually worsened and he started peritoneal dialysis therapy 2.3 years after the initial presentation with PVAN.
CASE REPORT 2 Clinical History and Initial Laboratory Data A 45-year-old man with a history of giant cell myocarditis (GCM) underwent orthotopic heart transplantation in summer 2010. Prior to the procedure, he received 10 doses of muromonab-C3, high-dose steroids, and cyclosporine (trough of 100-150 ng/mL) for treatment of GCM. Initial immunosuppression after transplantation included tacrolimus, prednisone, and MMF. He was found to have recurrent GCM on his first posttransplantation biopsy and began treatment with pulse dose steroids, a 12-day course of thymoglobulin, and increased MMF dosage (from 1,500 mg to 2,000 mg twice daily). MMF dosage subsequently was decreased to 500 mg twice daily due to leukopenia. Prior to receiving the heart transplant, the patient’s eGFR had been 22 mL/min/1.73 m2. After surgery, there was an improvement in eGFR, which reached 54 mL/min/1.73 m2. In summer 2012, he was noted to have a decline in eGFR to 33 mL/min/1.73 m2. Serum BK virus levels were quantified at 2
810,700 copies/mL (5.91 log10). Urine sediment evaluation revealed decoy cells.
Kidney Biopsy Morphologic examination of the kidney revealed advanced florid PVAN (stage B evolving to C) involving both medulla and cortex (Fig 2). Long-term changes were pronounced and included moderate tubular atrophy and moderate interstitial fibrosis in both medullary and cortical areas.
Diagnosis Polyomavirus-associated nephropathy.
Clinical Follow-up The patient was treated for PVAN with a reduction in immunosuppression: target tacrolimus trough levels were 5 to 7 ng/mL, MMF dosage was 250 mg twice daily, and prednisone dosage was 2.5 mg daily. He also was initiated on ciprofloxacin therapy. Following these changes, his kidney function improved, with the most recent eGFR of 40 mL/min/1.73 m2 and BK viral load of 181,970 copies/mL (5.26 log10).
DISCUSSION In kidney transplant recipients, PVAN is an important cause of kidney failure following transplantation, but this has not been described extensively in nonkidney solid-organ transplant recipients. BK virus is a human polyomavirus of the Papoviradae family. It is a small, nonenveloped, doublestranded DNA virus with a seroprevalence of 60% Am J Kidney Dis. 2015;-(-):---
BK Nephropathy in Heart Transplant Recipients
Figure 1. Kidney biopsy specimen of BK nephropathy case 1. (A) There is marked interstitial lymphocytic infiltrate with patchy destructive tubular lesions. Some tubular epithelial cells show nuclear enlargement and hyperchromasia (arrows) suggestive of polyomavirus (BK virus) infection (periodic acid–Schiff stain; original magnification, 3200). (B) There is significant tubular atrophy and interstitial fibrosis. A segment of the represented glomerulus appears relatively unremarkable. (Trichrome stain; original magnification, 3200). (C) Immunoperoxidase-based stain with a monoclonal antibody to polyomavirus confirms the presence of polyomavirus in numerous nuclei (eg, as indicated by arrow; original magnification, 3200).
to 100% in the general population; however, it causes clinical disease only among immunocompromised hosts.1,3 BK virus infection is thought to occur through the respiratory route in childhood; the virus then can establish latent infection in uroepithelial cells. Under conditions of immunocompromise, viral shedding and occasionally interstitial nephritis and kidney damage may occur.1,4 In kidney transplantation, viral shedding has been reported to occur in 30% of transplant recipients; the prevalence of documented PVAN is substantially lower at 5%.5
There are only a few previously reported cases of PVAN in cardiac transplant recipients.6-10 The prevalence of PVAN in this population is not known, in part because it is not commonly tested for. The prevalence of eGFR , 30 mL/min/1.73 m2 at 5 years after heart transplantation has been estimated to be 10.9%,7,8 but the cause of the kidney disease often is attributed to diabetes, hypertension, chronic toxicity from calcineurin inhibitors, or hemodynamic changes, and biopsies are not commonly performed. In one small study of solid-organ transplant recipients, BK
Figure 2. Kidney biopsy specimen of BK nephropathy case 2. (A) Glomeruli show mild expansion of the mesangial matrix and no other significant pathology (hematoxylin and eosin [H&E]; original magnification, 3200). (B) Some tubular epithelial cells show markedly enlarged and hyperchromatic nuclei (arrows). A sprinkling of interstitial lymphocytes and tubular atrophy also are present (H&E; original magnification, 3200). (C) Immunoperoxidase-based stain with a monoclonal antibody to polyomavirus highlights the affected nuclei (eg, arrows; original magnification, 3200). Am J Kidney Dis. 2015;-(-):---
3
4
Table 2. Comparison of Prior Published Case Reports of PVAN in Cardiac Transplant Recipients Age, Sex, and HF Cause
Kidney Function
Viral Load
History of Rejection Episodes
Immunosuppression
PVAN Treatment & Outcome
Barber6,a (2006)
25-y-old man with DCM
Pre-BKV: Scr 5 1.07, eGFR 5 96; post-BKV: Scr 5 1.95; eGFR 5 46
Plasma BKV titer 5 494,000 copies/mL; urine cytology positive for decoy cells
Schmid26 (2005)
57-y-old man with DCM
Pre-BKV: Scr 5 1.6, eGFR 5 47; post-BKV: Scr 5 3.4, eGFR 5 19b
Plasma BKV Induction with titer 5 1-5 3 106 cyclosporine, copies/mL; urine azathioprine, steroids; after rejection episode positive for BKV & JCV, numerous switched to tacrolimus, decoy cells on sirolimus, prednisone urine cytology NA NA
Repeated rejection episodes
NA
Outcome: died (postmortem diagnosis)
NA
NA
Immunosuppression reduced to prednisolone, 5 mg, and sirolimus, 4 mg, daily; then treated with low doses of cidofovir after pt’s urine continued to be BKV positive by PCR Treated with IVIG, 0.5 g/kg, cidofovir at 0.5 mg/kg/dose; subsequently, weekly doses of cidofovir given at 0.25 mg/kg for 5 additional wk; pt was not tolerating cidofovir, so decreasing immunosuppression also attempted; received maintenance HD while awaiting kidney Tx; outcome: died
Limaye29 (2005)
Menahem27
59-y-old man with severe ischemic cardiomyopathy (2005) 59-y-old woman with DCM, biopsy revealed GCM
Sahney28 (2009)
7-y-old boy with idiopathic cardiomyopathy
Pre-BKV: Scr 5 1.6, eGFR 5 46; post-BKV: Scr 5 4.5, eGFR 5 13 Pre-BKV: Scr 5 0.45, eGFR 5 124; post-BKV: Scr 5 3.17, eGFR 5 20
Pre-BKV: Scr 5 0.4, eGFR 5 187; post-BKV: Scr 5 0.9, eGFR 5 134
Initial: tacrolimus, MMF, prednisone; sirolimus added 4 mo later due to multiple rejection episodes
Developed recurrent (33) rejection, so immunosuppression increased (prednisolone, tacrolimus, MMF, sirolimus)
Multiple bouts requiring pulse steroids
(Continued)
Joseph et al
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NA BKV PCR of urine: Recurrent (38) rejection 2 3 109 copies/mL episodes; all episodes treated with IV methylprednisolone; had second heart Tx, received induction therapy with antithymocyte globulin and methylprednisolone with maintenance of tacrolimus and sirolimus; immunosuppression: tacrolimus, MMF
Discontinued tacrolimus, increased prednisone to 5 mg/d, decreased MMF to 1 g 23/d; started on low-dose cidofovir (0.5 mg/kg) with infusions every 2 wk for 6 doses (due to continued increase in BKV load, last 2 doses were 1 mg/kg); MMF stopped due to leukopenia Immunosuppressive therapy reduced stepwise; antiviral treatment (cidofovir, 1 mg/kg) initiated; outcome: started maintenance HD
Age, Sex, and HF Cause
Kidney Function
Viral Load
Immunosuppression
Lorica30 (2013)
15-y-old male adolescent with tetralogy of Fallot
1 wk post-Tx, urine output decreased; pre-BKV: Scr 5 0.4; post-BKV: Scr 5 2.3
Plasma BKV titer 5 7.6 3 106 copies/mL; decoy cells on urine cytology
Immunosuppression: azathioprine, prednisone, tacrolimus; 3 y later changed to tacrolimus only; had abdominal pain and found to have PTLD
Ali31,a (2010)
10-y-old boy with DCM secondary to prior doxorubicin chemotherapy
5 mo post-Tx, pre-BKV: Scr 5 0.5; post-BKV: Scr 5 1
Plasma BKV titer 5 3.1 3 106 copies/mL
Immunosuppression with tacrolimus, MMF, basiliximab; chemotherapy: ifosfamide, doxorubicin
History of Rejection Episodes
PVAN Treatment & Outcome
Noted to have grade 1R Kidney biopsy revealed 9 glomeruli acute rejection and was (2 globally sclerosed, 1 with segmental sclerotic lesion), a pulsed with steroids; tacrolimus was few tubules had enlarged maintained at 4-6 mg/mL epithelial cells with chromatin migration and intranuclear inclusions consistent with viral cytopathic changes, IHC positive for SV40; course: ciprofloxacin was added, had grade 1B rejection, clinically deteriorated; Scr peaked at 3 mg/dL and pt initiated HD; serum BKV titer decreased to 1.5 3 106 copies/ mL; cidofovir given; outcome: family withdrew support, pt had multiorgan failure Kidney biopsy 21 mo post-Tx Complicated by grade 3A diagnosed PVAN; course: 4 wkly rejection (given doses of 0.3 mg/kg cidofovir, methylprednisolone and starting 23 mo after Tx; kidney increased doses of failure developed; now has tacrolimus) and CMV functioning kidney transplant colitis; developed recurrent rejection postreduction in immunosuppression (steroid/increased MMF)
Abbreviations and definitions: CMV, cytomegalovirus; DCM, dilated cardiomyopathy; eGFR, estimated glomerular filtration rate (given in mL/min/1.73 m2); GCM, giant cell myocarditis; HD, hemodialysis; HF, heart failure; IHC, immunohistochemistry; IV, intravenous; IVIG, intravenous immunoglobulin; JCV, John Cunningham virus; MMF, mycophenolate mofetil; NA, not available; PCR, polymerase chain reaction; post-BKV, following development of PVAN; pre-BKV, preceding development of PVAN; pt, patient; PTLD, posttransplant lymphoproliferative disorder; PVAN, polyomavirus-associated nephropathy; Scr, serum creatinine (given in mg/dL); SV40, simian virus 40; Tx, transplant(ation). a Follow-up information was obtained by personal communication with the authors. b Kidney biopsy occurred 29 mo after heart Tx.
BK Nephropathy in Heart Transplant Recipients
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Table 2 (Cont’d). Comparison of Prior Published Case Reports of PVAN in Cardiac Transplant Recipients
5
Joseph et al
viremia was observed in 7% of heart transplant recipients compared to 12.2% of kidney transplant recipients.11 When PVAN has been diagnosed in cardiac transplant recipients, outcomes generally have been poor, most likely secondary to late diagnosis as well as ineffective treatment options (Table 2).6-10 Decreased cellular immunity, which appears to be a key factor in the pathogenesis, is related to aggressive immunosuppressive regimens, and recurrent episodes of rejection and its treatment are associated with PVAN in kidney transplant recipients.1 It is possible that intensified immunosuppression for treatment of rejection also may contribute to PVAN in nonkidney solid-organ transplant recipients. However, not all patients develop PVAN even with high doses of immunosuppression, and therefore host factors presumably play a role as well. Documented risk factors include increasing age, male sex, greater HLA donor/ recipient mismatch, more rejection episodes, and use of corticosteroids.9,10,12 Humoral immunity against the virus also appears to be relevant to the development of PVAN in kidney transplant recipients because patients who have been exposed previously to BK virus appear to be less likely to develop PVAN even in the presence of high viral levels.10 The possible role of humoral immunity in other solidorgan transplant recipients is not clear because the virus is not known to be present in other organs. The most important aspect of the therapy for PVAN is to reduce the immunosuppression.13,14 Target levels of calcineurin inhibitors should be individualized; general recommendations regarding the degree of immunosuppressant minimization are difficult to make without patient-specific details, including prior rejection history and baseline dosing/ trough goals. Second-line therapy is less clear. Cidofovir, the only antiviral agent known to have activity against BK virus, is nephrotoxic, making it challenging to use.15-18 Some reports suggest that transition from a calcineurin inhibitor to an mTOR inhibitor–based regimen may minimize further calcineurin nephrotoxicity, as well as potentially reducing BK viral replication.19 Other strategies include use of agents that reactivate the immune system, such as intravenous immunoglobulin, or that have antiviral activity, such as leuflonomide.9,14,20,21-23 Recent reports suggest that quinolones are not effective in preventing or treating PVAN.24,25 In conclusion, reactivation of polyomavirus may occur in the native kidneys of recipients of other solid-organ transplants and can cause substantial decreases in kidney function. PVAN should be considered in the differential diagnosis when evaluating worsening kidney function. Large surveillance studies for BK viremia should be conducted in nonkidney solid-organ recipients to provide data that would 6
assist the transplantation community in deciding whether regular monitoring of nonkidney transplant recipients for BK viremia is indicated. The advantages of any screening program need to be weighed against the costs and the false-positive rate associated with high BK levels that do not result in nephropathy.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Fishman JA. BK virus nephropathy—polyomavirus adding insult to injury. N Engl J Med. 2002;347(7):527-530. 2. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9): 604-612. 3. Buehrig CK, Lager DJ, Stegall MD, et al. Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus-associated nephropathy. Kidney Int. 2003;64(2): 665-673. 4. Mylonakis E, Goes N, Rubin RH, Cosimi AB, Colvin RB, Fishman JA. BK virus in solid organ transplant recipients: an emerging syndrome. Transplantation. 2001;72(10):1587-1592. 5. Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation. 2009;87(7): 1019-1026. 6. Barber CE, Hewlett TJ, Geldenhuys L, Kiberd BA, Acott PD, Hatchette TF. BK virus nephropathy in a heart transplant recipient: case report and review of the literature. Transpl Infect Dis. 2006;8(2):113-121. 7. Bloom RD, Reese PP. Chronic kidney disease after nonrenal solid-organ transplantation. J Am Soc Nephrol. 2007;18(12):30313041. 8. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349(10): 931-940. 9. Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirusassociated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005;79(10):12771286. 10. Dall A, Hariharan S. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol. 2008;3(suppl 2):S68-S75. 11. Munoz P, Fogeda M, Bouza E, Verde E, Palomo J, Banares R. Prevalence of BK virus replication among recipients of solid organ transplants. Clin Infect Dis. 2005;41(12):1720-1725. 12. Randhawa P, Brennan DC. BK virus infection in transplant recipients: an overview and update. Am J Transplant. 2006;6(9): 2000-2005. 13. Hirsch HH, Randhawa P. BK virus in solid organ transplant recipients. Am J Transplant. 2009;9(suppl 4):S136-S146. 14. Trofe J, Hirsch HH, Ramos E. Polyomavirus-associated nephropathy: update of clinical management in kidney transplant patients. Transpl Infect Dis. 2006;8(2):76-85. 15. Keller LS, Peh CA, Nolan J, Bannister KM, Clarkson AR, Faull RJ. BK transplant nephropathy successfully treated with cidofovir. Nephrol Dial Transplant. 2003;18(5):1013-1014. 16. Andrei G, Snoeck R, Vandeputte M, De Clercq E. Activities of various compounds against murine and primate polyomaviruses. Antimicrob Agents Chemother. 1997;41(3): 587-593. Am J Kidney Dis. 2015;-(-):---
BK Nephropathy in Heart Transplant Recipients 17. Tong CY, Hilton R, MacMahon EM, et al. Monitoring the progress of BK virus associated nephropathy in renal transplant recipients. Nephrol Dial Transplant. 2004;19(10): 2598-2605. 18. Celik B, Shapiro R, Vats A, Randhawa PS. Polyomavirus allograft nephropathy: sequential assessment of histologic viral load, tubulitis, and graft function following changes in immunosuppression. Am J Transplant. 2003;3(11): 1378-1382. 19. Wali RK, Drachenberg C, Hirsch HH, et al. BK virusassociated nephropathy in renal allograft recipients: rescue therapy by sirolimus-based immunosuppression. Transplantation. 2004;78(7):1069-1073. 20. Sharma BN, Li R, Bernhoff E, Gutteberg TJ, Rinaldo CH. Fluoroquinolones inhibit human polyomavirus BK (BKV) replication in primary human kidney cells. Antiviral Res. 2011;92(1): 115-123. 21. Williams JW, Javaid B, Kadambi PV, et al. Leflunomide for polyomavirus type BK nephropathy. N Engl J Med. 2005;352(11):1157-1158. 22. Leung AY, Chan MT, Yuen KY, et al. Ciprofloxacin decreased polyoma BK virus load in patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2005;40(4):528-537. 23. Sener A, House AA, Jevnikar AM, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation. 2006;81(1):117-120.
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24. Knoll GA, Humar A, Fergusson D, et al. Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial. JAMA. 2014;312(20):2106-2114. 25. Lee BT, Gabardi S, Grafals M, et al. Efficacy of levofloxacin in the treatment of BK viremia: a multicenter, doubleblinded, randomized, placebo-controlled trial. Clin J Am Soc Nephrol. 2014;9(3):583-589. 26. Schmid H, Burg M, Kretzler M, Banas B, Grone HJ, Kliem V. BK virus associated nephropathy in native kidneys of a heart allograft recipient. Am J Transplant. 2005;5(6):1562-1568. 27. Menahem SA, McDougall KM, Thomson NM, Dowling JP. Native kidney BK nephropathy post cardiac transplantation. Transplantation. 2005;79(2):259-260. 28. Sahney S, Yorgin P, Zuppan C, Cutler D, Kambham N, Chinnock R. BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient. Pediatr Transplant. 2010;14(3): E11-E15. 29. Limaye AP, Smith KD, Cook L, et al. Polyomavirus nephropathy in native kidneys of non-renal transplant recipients. Am J Transplant. 2005;5(3):614-620. 30. Lorica C, Bueno TG, Garcia-Buitrago MT, Rusconi P, Gonzalez IA. BK virus nephropathy in a pediatric heart transplant recipient with post-transplant lymphoproliferative disorder: a case report and review of literature. Pediatr Transplant. 2013;17(2): E55-E61. 31. Ali FN, Meehan SM, Pahl E, Cohn RA. Native BK viral nephropathy in a pediatric heart transplant recipient. Pediatr Transplant. 2010;14(4):E38-E41.
7
INTRODUCTION Polyomavirus-associated nephropathy (PVAN) is an important cause of kidney failure in kidney transplant recipients, reported to affect 1% to 7% of kidney transplant recipients and leading to premature transplant loss in approximately 30% to 50% of diagnosed cases. PVAN occurring in native kidneys of nonkidney transplant recipients only recently has been noted.1 We report on 2 cases of PVAN in heart transplant recipients.
CASE REPORT 1 Clinical History and Initial Laboratory Data A 63-year-old white man with a history of ischemic cardiomyopathy underwent cardiac transplantation in May 2009. Table 1 provides clinical and laboratory data at the time of transplantation and subsequent immunosuppressive regimen. His initial regimen included tacrolimus, mycophenolate mofetil (MMF), and prednisone. Shortly thereafter, prednisone therapy was stopped secondary to glaucoma, and MMF dosage was reduced secondary to leukopenia. In April 2010, he was noted to have moderate focal grade 1R rejection (1990 Grade 2) and was restarted on low-dose prednisone therapy, as well as an increased dose of MMF. Before transplantation, estimated glomerular filtration rate (eGFR) using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation2 had been 59 mL/min/ 1.73 m2. Postsurgery eGFRs were stable at w40 mL/min/1.73 m2 until spring 2012, when he was referred to nephrology for eGFR of 29 mL/min/1.73 m2. Serum BK viral load was quantified as 3,300,163 copies/mL (6.52 log10). Urine cytology revealed highly atypical urothelial cells with changes characteristic of polyomavirus. Positive results were obtained when a cytospin preparation was immunohistochemically stained using an antibody against SV40 (simian virus 40, a polyomavirus related closely enough to BK virus that anti-SV40 antibodies cross-react with BK virus antigens). MMF dosage subsequently was reduced to 250 mg twice daily and tacrolimus dosage was reduced to achieve a trough level of 4 to Am J Kidney Dis. 2015;-(-):---
6 ng/mL. Following these changes, no improvement in kidney function was noted and a kidney biopsy was performed.
Kidney Biopsy Morphologic examination of the kidney (Fig 1) revealed florid PVAN (stage B). There was prominent chronic inflammation seen predominantly in the medulla with patchy, mild cortical involvement. Long-term changes included focal global glomerulosclerosis, mild to moderate fibrosis and tubular atrophy, and mild vasculopathy.
Diagnosis Polyomavirus-associated nephropathy.
Clinical Follow-up Immunosuppression was reduced gradually to MMF, 250 mg, twice daily with a tacrolimus trough goal of 3 to 5 ng/mL. Given the persistence of BK viremia with no improvement in eGFR, the patient’s treatment regimen was converted from tacrolimus to sirolimus, and ciprofloxacin treatment was From the 1Division of Nephrology, 2Department of Pathology, and Divisions of 3Infectious Diseases and 4Cardiology, Tufts Medical Center, Boston, MA. Received June 9, 2014. Accepted in revised form December 12, 2014. Because the Editor-in-Chief and Deputy Editor recused themselves from consideration of this article, the peer-review and decision-making processes were handled entirely by the Pathology Editor (Helmut G. Rennke, MD) who served as Acting Editor-inChief. Details of the journal’s procedures for potential editor conflicts are given in the Information for Authors & Editorial Policies. Address correspondence to Lesley A. Inker, MD, MS, Division of Nephrology, 800 Washington St, Box #391, Tufts Medical Center, Boston, MA 02111. E-mail: [email protected] 2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2014.12.020 1
Joseph et al Table 1. Patient Characteristics Case 1
Case 2
Age & sex Cause of heart failure Initial immunosuppression Episodes of rejection or other increase in immunosuppression
60-y-old man Ischemic cardiomyopathy MMF/tacrolimus/prednisone taper Rejection 11 mo post-Tx: treated with pulse prednisone and increased MMF dose
CMV status of donor/recipient EBV status of donor/recipient Kidney function pre-Tx Baseline kidney function post-Tx Kidney function at time of biopsy CD4 count at PVAN diagnosis (3103/mL) Most recent CD4 count (3103/mL) Time post-Tx when PVAN diagnosed BK viremia titer at diagnosis (copies/mL) Treatment for PVAN
Positive/positive Positive/positive Scr, 1.32 mg/dL; eGFR, 59 mL/min/1.73 m2 Scr, 1.86 mg/dL; eGFR, 39 mL/min/1.73 m2 Scr, 2.82 mg/dL; eGFR, 23 mL/min/1.73 m2 560
43-y-old man GCM MMF/tacrolimus/prednisone 1. GCM pre-Tx: treated with muromonabCD3, high-dose prednisone 2. Recurrent GCM and grade 2A rejection 3 mo post-Tx: treated with thymoglobulin (7 doses over 12 d), increased MMF Negative/negative Positive/positive Scr, 2.41 mg/dL; eGFR, 32 mL/min/1.73 m2 Scr, 1.29 mg/dL; eGFR, 67 mL/min/1.73 m2 Scr, 2.36 mg/dL; eGFR, 32 mL/min/1.73 m2 84
248 3y 3,300,163
176 2y 810,700
Reduction in immunosuppression (MMF, 250 mg, 23/d; tacrolimus trough goal, 35 ng/mL); conversion from tacrolimus to sirolimus; ciprofloxacin; 8 doses of 100 mg/kg IVIG over 8 wk Started PD 2.3 y after diagnosis of PVAN
Reduction in immunosuppression (MMF, 250 mg, 23/d; tacrolimus trough goal, 5-7 ng/mL); ciprofloxacin
Status at last available follow-up
eGFR stable at 40 mL/min/1.73 m2
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; eGFR, estimated glomerular filtration rate; GCM, giant cell myocarditis; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; PD, peritoneal dialysis; PVAN, polyomavirus nephropathy; Scr, serum creatinine; Tx, transplantation.
initiated with some initial improvement in BK viral load (to 10,120 copies/mL [4.01 log10]) and eGFR (from 19 to 25 mL/ min/1.73 m2). A subsequent rejection episode noted on a screening endomyocardial biopsy was treated with pulse steroids and an increase in MMF dosage to 500 mg twice a day; this resulted in an increase in viral load to 236,704 copies/mL (5.37 log10). The patient began treatment with intravenous immunoglobulin therapy (100 mg/kg) and received 8 doses over a period of 8 weeks. eGFR gradually worsened and he started peritoneal dialysis therapy 2.3 years after the initial presentation with PVAN.
CASE REPORT 2 Clinical History and Initial Laboratory Data A 45-year-old man with a history of giant cell myocarditis (GCM) underwent orthotopic heart transplantation in summer 2010. Prior to the procedure, he received 10 doses of muromonab-C3, high-dose steroids, and cyclosporine (trough of 100-150 ng/mL) for treatment of GCM. Initial immunosuppression after transplantation included tacrolimus, prednisone, and MMF. He was found to have recurrent GCM on his first posttransplantation biopsy and began treatment with pulse dose steroids, a 12-day course of thymoglobulin, and increased MMF dosage (from 1,500 mg to 2,000 mg twice daily). MMF dosage subsequently was decreased to 500 mg twice daily due to leukopenia. Prior to receiving the heart transplant, the patient’s eGFR had been 22 mL/min/1.73 m2. After surgery, there was an improvement in eGFR, which reached 54 mL/min/1.73 m2. In summer 2012, he was noted to have a decline in eGFR to 33 mL/min/1.73 m2. Serum BK virus levels were quantified at 2
810,700 copies/mL (5.91 log10). Urine sediment evaluation revealed decoy cells.
Kidney Biopsy Morphologic examination of the kidney revealed advanced florid PVAN (stage B evolving to C) involving both medulla and cortex (Fig 2). Long-term changes were pronounced and included moderate tubular atrophy and moderate interstitial fibrosis in both medullary and cortical areas.
Diagnosis Polyomavirus-associated nephropathy.
Clinical Follow-up The patient was treated for PVAN with a reduction in immunosuppression: target tacrolimus trough levels were 5 to 7 ng/mL, MMF dosage was 250 mg twice daily, and prednisone dosage was 2.5 mg daily. He also was initiated on ciprofloxacin therapy. Following these changes, his kidney function improved, with the most recent eGFR of 40 mL/min/1.73 m2 and BK viral load of 181,970 copies/mL (5.26 log10).
DISCUSSION In kidney transplant recipients, PVAN is an important cause of kidney failure following transplantation, but this has not been described extensively in nonkidney solid-organ transplant recipients. BK virus is a human polyomavirus of the Papoviradae family. It is a small, nonenveloped, doublestranded DNA virus with a seroprevalence of 60% Am J Kidney Dis. 2015;-(-):---
BK Nephropathy in Heart Transplant Recipients
Figure 1. Kidney biopsy specimen of BK nephropathy case 1. (A) There is marked interstitial lymphocytic infiltrate with patchy destructive tubular lesions. Some tubular epithelial cells show nuclear enlargement and hyperchromasia (arrows) suggestive of polyomavirus (BK virus) infection (periodic acid–Schiff stain; original magnification, 3200). (B) There is significant tubular atrophy and interstitial fibrosis. A segment of the represented glomerulus appears relatively unremarkable. (Trichrome stain; original magnification, 3200). (C) Immunoperoxidase-based stain with a monoclonal antibody to polyomavirus confirms the presence of polyomavirus in numerous nuclei (eg, as indicated by arrow; original magnification, 3200).
to 100% in the general population; however, it causes clinical disease only among immunocompromised hosts.1,3 BK virus infection is thought to occur through the respiratory route in childhood; the virus then can establish latent infection in uroepithelial cells. Under conditions of immunocompromise, viral shedding and occasionally interstitial nephritis and kidney damage may occur.1,4 In kidney transplantation, viral shedding has been reported to occur in 30% of transplant recipients; the prevalence of documented PVAN is substantially lower at 5%.5
There are only a few previously reported cases of PVAN in cardiac transplant recipients.6-10 The prevalence of PVAN in this population is not known, in part because it is not commonly tested for. The prevalence of eGFR , 30 mL/min/1.73 m2 at 5 years after heart transplantation has been estimated to be 10.9%,7,8 but the cause of the kidney disease often is attributed to diabetes, hypertension, chronic toxicity from calcineurin inhibitors, or hemodynamic changes, and biopsies are not commonly performed. In one small study of solid-organ transplant recipients, BK
Figure 2. Kidney biopsy specimen of BK nephropathy case 2. (A) Glomeruli show mild expansion of the mesangial matrix and no other significant pathology (hematoxylin and eosin [H&E]; original magnification, 3200). (B) Some tubular epithelial cells show markedly enlarged and hyperchromatic nuclei (arrows). A sprinkling of interstitial lymphocytes and tubular atrophy also are present (H&E; original magnification, 3200). (C) Immunoperoxidase-based stain with a monoclonal antibody to polyomavirus highlights the affected nuclei (eg, arrows; original magnification, 3200). Am J Kidney Dis. 2015;-(-):---
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Table 2. Comparison of Prior Published Case Reports of PVAN in Cardiac Transplant Recipients Age, Sex, and HF Cause
Kidney Function
Viral Load
History of Rejection Episodes
Immunosuppression
PVAN Treatment & Outcome
Barber6,a (2006)
25-y-old man with DCM
Pre-BKV: Scr 5 1.07, eGFR 5 96; post-BKV: Scr 5 1.95; eGFR 5 46
Plasma BKV titer 5 494,000 copies/mL; urine cytology positive for decoy cells
Schmid26 (2005)
57-y-old man with DCM
Pre-BKV: Scr 5 1.6, eGFR 5 47; post-BKV: Scr 5 3.4, eGFR 5 19b
Plasma BKV Induction with titer 5 1-5 3 106 cyclosporine, copies/mL; urine azathioprine, steroids; after rejection episode positive for BKV & JCV, numerous switched to tacrolimus, decoy cells on sirolimus, prednisone urine cytology NA NA
Repeated rejection episodes
NA
Outcome: died (postmortem diagnosis)
NA
NA
Immunosuppression reduced to prednisolone, 5 mg, and sirolimus, 4 mg, daily; then treated with low doses of cidofovir after pt’s urine continued to be BKV positive by PCR Treated with IVIG, 0.5 g/kg, cidofovir at 0.5 mg/kg/dose; subsequently, weekly doses of cidofovir given at 0.25 mg/kg for 5 additional wk; pt was not tolerating cidofovir, so decreasing immunosuppression also attempted; received maintenance HD while awaiting kidney Tx; outcome: died
Limaye29 (2005)
Menahem27
59-y-old man with severe ischemic cardiomyopathy (2005) 59-y-old woman with DCM, biopsy revealed GCM
Sahney28 (2009)
7-y-old boy with idiopathic cardiomyopathy
Pre-BKV: Scr 5 1.6, eGFR 5 46; post-BKV: Scr 5 4.5, eGFR 5 13 Pre-BKV: Scr 5 0.45, eGFR 5 124; post-BKV: Scr 5 3.17, eGFR 5 20
Pre-BKV: Scr 5 0.4, eGFR 5 187; post-BKV: Scr 5 0.9, eGFR 5 134
Initial: tacrolimus, MMF, prednisone; sirolimus added 4 mo later due to multiple rejection episodes
Developed recurrent (33) rejection, so immunosuppression increased (prednisolone, tacrolimus, MMF, sirolimus)
Multiple bouts requiring pulse steroids
(Continued)
Joseph et al
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NA BKV PCR of urine: Recurrent (38) rejection 2 3 109 copies/mL episodes; all episodes treated with IV methylprednisolone; had second heart Tx, received induction therapy with antithymocyte globulin and methylprednisolone with maintenance of tacrolimus and sirolimus; immunosuppression: tacrolimus, MMF
Discontinued tacrolimus, increased prednisone to 5 mg/d, decreased MMF to 1 g 23/d; started on low-dose cidofovir (0.5 mg/kg) with infusions every 2 wk for 6 doses (due to continued increase in BKV load, last 2 doses were 1 mg/kg); MMF stopped due to leukopenia Immunosuppressive therapy reduced stepwise; antiviral treatment (cidofovir, 1 mg/kg) initiated; outcome: started maintenance HD
Age, Sex, and HF Cause
Kidney Function
Viral Load
Immunosuppression
Lorica30 (2013)
15-y-old male adolescent with tetralogy of Fallot
1 wk post-Tx, urine output decreased; pre-BKV: Scr 5 0.4; post-BKV: Scr 5 2.3
Plasma BKV titer 5 7.6 3 106 copies/mL; decoy cells on urine cytology
Immunosuppression: azathioprine, prednisone, tacrolimus; 3 y later changed to tacrolimus only; had abdominal pain and found to have PTLD
Ali31,a (2010)
10-y-old boy with DCM secondary to prior doxorubicin chemotherapy
5 mo post-Tx, pre-BKV: Scr 5 0.5; post-BKV: Scr 5 1
Plasma BKV titer 5 3.1 3 106 copies/mL
Immunosuppression with tacrolimus, MMF, basiliximab; chemotherapy: ifosfamide, doxorubicin
History of Rejection Episodes
PVAN Treatment & Outcome
Noted to have grade 1R Kidney biopsy revealed 9 glomeruli acute rejection and was (2 globally sclerosed, 1 with segmental sclerotic lesion), a pulsed with steroids; tacrolimus was few tubules had enlarged maintained at 4-6 mg/mL epithelial cells with chromatin migration and intranuclear inclusions consistent with viral cytopathic changes, IHC positive for SV40; course: ciprofloxacin was added, had grade 1B rejection, clinically deteriorated; Scr peaked at 3 mg/dL and pt initiated HD; serum BKV titer decreased to 1.5 3 106 copies/ mL; cidofovir given; outcome: family withdrew support, pt had multiorgan failure Kidney biopsy 21 mo post-Tx Complicated by grade 3A diagnosed PVAN; course: 4 wkly rejection (given doses of 0.3 mg/kg cidofovir, methylprednisolone and starting 23 mo after Tx; kidney increased doses of failure developed; now has tacrolimus) and CMV functioning kidney transplant colitis; developed recurrent rejection postreduction in immunosuppression (steroid/increased MMF)
Abbreviations and definitions: CMV, cytomegalovirus; DCM, dilated cardiomyopathy; eGFR, estimated glomerular filtration rate (given in mL/min/1.73 m2); GCM, giant cell myocarditis; HD, hemodialysis; HF, heart failure; IHC, immunohistochemistry; IV, intravenous; IVIG, intravenous immunoglobulin; JCV, John Cunningham virus; MMF, mycophenolate mofetil; NA, not available; PCR, polymerase chain reaction; post-BKV, following development of PVAN; pre-BKV, preceding development of PVAN; pt, patient; PTLD, posttransplant lymphoproliferative disorder; PVAN, polyomavirus-associated nephropathy; Scr, serum creatinine (given in mg/dL); SV40, simian virus 40; Tx, transplant(ation). a Follow-up information was obtained by personal communication with the authors. b Kidney biopsy occurred 29 mo after heart Tx.
BK Nephropathy in Heart Transplant Recipients
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Table 2 (Cont’d). Comparison of Prior Published Case Reports of PVAN in Cardiac Transplant Recipients
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Joseph et al
viremia was observed in 7% of heart transplant recipients compared to 12.2% of kidney transplant recipients.11 When PVAN has been diagnosed in cardiac transplant recipients, outcomes generally have been poor, most likely secondary to late diagnosis as well as ineffective treatment options (Table 2).6-10 Decreased cellular immunity, which appears to be a key factor in the pathogenesis, is related to aggressive immunosuppressive regimens, and recurrent episodes of rejection and its treatment are associated with PVAN in kidney transplant recipients.1 It is possible that intensified immunosuppression for treatment of rejection also may contribute to PVAN in nonkidney solid-organ transplant recipients. However, not all patients develop PVAN even with high doses of immunosuppression, and therefore host factors presumably play a role as well. Documented risk factors include increasing age, male sex, greater HLA donor/ recipient mismatch, more rejection episodes, and use of corticosteroids.9,10,12 Humoral immunity against the virus also appears to be relevant to the development of PVAN in kidney transplant recipients because patients who have been exposed previously to BK virus appear to be less likely to develop PVAN even in the presence of high viral levels.10 The possible role of humoral immunity in other solidorgan transplant recipients is not clear because the virus is not known to be present in other organs. The most important aspect of the therapy for PVAN is to reduce the immunosuppression.13,14 Target levels of calcineurin inhibitors should be individualized; general recommendations regarding the degree of immunosuppressant minimization are difficult to make without patient-specific details, including prior rejection history and baseline dosing/ trough goals. Second-line therapy is less clear. Cidofovir, the only antiviral agent known to have activity against BK virus, is nephrotoxic, making it challenging to use.15-18 Some reports suggest that transition from a calcineurin inhibitor to an mTOR inhibitor–based regimen may minimize further calcineurin nephrotoxicity, as well as potentially reducing BK viral replication.19 Other strategies include use of agents that reactivate the immune system, such as intravenous immunoglobulin, or that have antiviral activity, such as leuflonomide.9,14,20,21-23 Recent reports suggest that quinolones are not effective in preventing or treating PVAN.24,25 In conclusion, reactivation of polyomavirus may occur in the native kidneys of recipients of other solid-organ transplants and can cause substantial decreases in kidney function. PVAN should be considered in the differential diagnosis when evaluating worsening kidney function. Large surveillance studies for BK viremia should be conducted in nonkidney solid-organ recipients to provide data that would 6
assist the transplantation community in deciding whether regular monitoring of nonkidney transplant recipients for BK viremia is indicated. The advantages of any screening program need to be weighed against the costs and the false-positive rate associated with high BK levels that do not result in nephropathy.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
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