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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 5  |  Page : 1073-1081
Elimination of BK viremia in renal transplant recipients by optimization of immunosuppressive medications without precipitating acute rejection


1 Department of Nephrology, Royal Hospital, Muscat, Oman
2 Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia

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Date of Submission12-Mar-2018
Date of Acceptance13-Mar-2018
Date of Web Publication26-Oct-2018
 

   Abstract 

BK Polyomavirus-associated nephropathy (BKVAN) has been recognized as an increasing threat in renal transplant patients (RTP) for more than a decade. Reduction in immunosuppression is the mainstay of treatment through various options of treatment has been suggested. Published reports on these protocols have shown mixed results, and no randomized controlled trials have compared one strategy with another. In this context, we hypothesize that the appearance of BKV in the blood compels one to optimize the immunosuppression with possible long-term beneficial effects. We conducted a retrospective study among the RTP being followed up by the Renal Medicine Department at Royal Hospital who tested positive for BKV-polymerase chain reaction and whose immunosuppression was altered with a final aim to get rid of BK viremia, yet avoiding acute rejection. Results were analyzed by the clinical and statistical approach. Extensive literature review was carried out to look into the prevalence, prognosis, and treatment of BKVAN. In all the patients in whom BKV was detected alteration in immunosuppression resulted in eliminating the virus without precipitating acute rejection. The study shows that in the exercise of eliminating BKV by alteration of immunosuppression, we have “tailored” the immunosuppression in each particular RTPs, without precipitating acute rejection.

How to cite this article:
Jha A, Ahmed W, Pakkyara A, Shaheen F, Al Salmi I. Elimination of BK viremia in renal transplant recipients by optimization of immunosuppressive medications without precipitating acute rejection. Saudi J Kidney Dis Transpl 2018;29:1073-81

How to cite this URL:
Jha A, Ahmed W, Pakkyara A, Shaheen F, Al Salmi I. Elimination of BK viremia in renal transplant recipients by optimization of immunosuppressive medications without precipitating acute rejection. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2018 Dec 15];29:1073-81. Available from: http://www.sjkdt.org/text.asp?2018/29/5/1073/243976

   Introduction Top


Advances in immunosuppressive therapy have vastly improved short-term kidney transplant outcomes. There has been a substantial decrease in acute rejection rates, and in most centers, one-year graft survival has now exceeded 95%. In contrast, recent years have seen only minimal gains in long-term transplant outcomes.[1],[2],[3] Death-censored graft survival has only marginally increased, and life expectancy of the renal transplant patients (RTP) remains markedly lower than that of the general population.[2],[3],[4],[5] This is mainly due to various complications associated with lifelong immunosuppression.

BK Polyomavirus-associated nephropathy (BKVAN) has been increasingly detected for the past 10–15 years.[6] Studies have shown reduction in BKV replication following immunosuppression minimization, which remains the cornerstone of treatment.[6],[7],[8] Published reports on these protocols have yielded mixed results, and no randomized controlled trials have compared one strategy with another.[9]

This article is based on the analysis of the data obtained in a retrospective study we have conducted among the RTP who were tested positive for BKV-polymerase chain reaction (PCR) being followed up by the Renal Medicine Department at Royal Hospital, Muscat. According to this study, we possibly would be able to determine the optimum immunosuppression that a particular RTP needs to get rid of this opportunistic infection without precipitating acute rejection.


   Objectives Top


We hypothesize that the appearance of BKV in the blood compels one to optimize with possible long-term beneficial effects. While achieving this, we will be able to determine the optimum immunosuppression that a particular RTP needs at which he or she can get rid of opportunistic infections without being susceptible to rejection.

In the absence of any markers that can tell as to what the optimum immunosuppression in a particular patient is, this exercise can perhaps be a guide for us to that goal. This may have possible long-term benefits by avoiding effects of over immunosuppression.


   Materials and Methods Top


Study design

This is a retrospective descriptive epidemiological study with a clinical insight and the target population was the renal transplant recipients who were tested positive for BKV-PCR. No exclusion criteria were set as all those tested positive for BKV and had PCR tests were included. No pilot or feasibility study was done to estimate the number but utilized the main researchers’ experience of cases in the department. Limitation of the study is that it is a retrospective and noninterventional study and hence no major concerns about ethical consideration.

Sample design

The RTPs followed up in a unit of renal transplant clinic at Royal Hospital from 2012 to 2016 who were tested positive for BKV-PCR were studied as the target population.

Data collected included the type of renal transplantation, the induction immunosuppression, maintenance immunosuppression, and treatment instituted for acute rejection, the time of appearance of BKV, what reduction or alteration in immunosuppression was done to eliminate BKV, how long did it take and how have the patients fared after that in terms of their graft kidney function.

Data collection measurements and tools

The Royal Hospital has an excellent medical records and Information Technology system where everything is computerized through elaborate software called Al-Shifa system which had received a well-recognized international certificate of excellence for its achievement. Relevant list of all RTPs followed up at Royal Hospital for the last three years are collected. A list of all patients that been diagnosed with BKV infection and their laboratory reports were obtained through the Al-Shifa system. A list of drugs used for treating BKV also obtained from the Pharmacy department. Two clinicians entered the data and rechecked by other two team members. Statistical analysis was performed using STATA software, (StataCorp LLC, Texas, USA).


   Results Top


One hundred and fifty-two RTPs were seen in the transplant clinic of a particular unit at the Royal Hospital, Muscat, Oman from 2012 to 2016. Of these 152 cases, 12 patients were found to have Polyoma BKV viremia [Table 1]. Among these 12 transplant recipients, nine were male and three were female. Eleven patients had live unrelated renal transplant, whereas one patient had live-related renal transplant. The age of renal transplant recipients ranged from 22 to 80 years. Nine patients received basiliximab as an induction therapy, while one patient received antithymocyte globulin (ATG) whereas in two patients with commercial renal transplantation, no documentation of induction could be ascertained. Four patients with BKV viremia had a single episode of acute rejection prior to the detection of BKV and were managed successfully. Out of these four patients with rejection, three patients had acute cellular rejection (ACR) (2 had Banff II and 1 Banff I) and one patient had mixed acute cellular and antibody mediated rejection. One patient with ACR (Banff I) was treated successfully with injection methylprednisolone, whereas two patients with acute T-cell-mediated rejection (Banff II) were treated with ATG. The patient with mixed ACR and antibody-mediated rejection was treated with ATG along with plasma exchanges and intravenous immunoglobulin [Table 1].
Table 1: Baseline demographic and other data.

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All renal transplant recipients were on triple immunosuppressant therapy, that comprised tacrolimus in eight patients, cyclosporine in four patients while mycophenolate mofetil (MMF) or myfortic and prednisolone was being received by all 12 renal transplant recipients. At the time of the first appearance of polyoma BKV viremia, four patients were found to have high cyclosporine or tacrolimus levels. The interval from the date of renal transplant to the appearance of BKV viremia ranged from 35 to 454 days. The BKV viral load at the time of first detection ranged from 2000 to 20300 copies/mL (via PCR method) [Table 2]. All of the 12 transplant patients were on valganciclovir for cytomegalovirus (CMV) prophylaxis for the initial six months posttransplant period and none of them was found to be CMV PCR positive at the times of BKV PCR detection [Table 2].
Table 2: Patients' data on BKV and CMV.

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[Table 3] shows the drug level at the time of BKV detection. It also shows the reduction in medications at the time of BKV infection. [Table 4] shows the various management strategies at time and post-BKV detection with various management reduction and or changes of medications.
Table 3: Reduction/change in immunosuppressant after BKV first detected.

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Table 4: Various management strategies before and during BKV infection and outcomes after immunosuppression adjustments.

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[Table 5] shows the number of months from the time of detection of BKV to its level become undetected by PCR technique. This period various from four weeks to 25 weeks. [Table 6] shows the estimated glomerular filtration rate (mL/min) after complete disappearance of BKV, which shows a good improvement in almost all cases. It also shows the duration for the complete disappearance of BKV which varies from four months to 26 months duration.
Table 5: Time taken for BKV to be below detection.

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Table 6: Impact on renal function and acute rejection if any.

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   Discussion Top


BKV infection in immune-compromised possibly cannot be predicted. The assessment and evaluation of risk before citizens or residents being immune-compromised is sub-optimal. The methodology of assessment immunocompromised state needs to be improved and steps must be implemented to reduce the risk of acquiring BKV infection.

Viruses are among the most common causes of opportunistic infection after transplantation. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used and other host factors governing susceptibility. Although CMV is the most common opportunistic pathogen seen in transplant recipients but pre- and post-transplant screening and prophylactic anti-CMV therapy limits the impact of infections. Thus, the mandatory prophylactic regimen does prevent CMV infection but also masks the effects of over immunosuppression.[10]

BKVAN was essentially an unknown entity in the era of cyclosporine-based immunosuppression, with increasing identification of BKVAN coinciding with the inclusion of tacrolimus and MMF in immunosuppressive regimens.[6] This has led to the suggestion that these agents may be specifically responsible. In the present studies, 60% of patients were on tacrolimus and 40% were on cyclosporin as shown in [Table 3] and [Table 4]. Furthermore, in support of this, multiple retrospective and observational studies have demonstrated a substantial increase in the risk of BKV replication in the context of tacrolimus and MMF use.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13] In the past 10–15 years, improved immunosuppression drugs have decreased the rates of acute rejection in kidney transplantation but have also led to the emergence of BKVAN.[14],[15]

Immunosuppression is the most significant and the only widely accepted risk factor for posttransplant BKV replication. This is largely because BKV associated disease is seen only in immunosuppressed populations, and because multiple studies have shown reductions in BKV replication following immunosuppression minimization.[6] Consequently, reduction of immunosuppression remains the mainstay of treatment, despite the increased risk of immunological allograft damage associated with this approach. As shown in [Table 4], multiple strategies are currently utilized, including reducing or ceasing antimetabolite therapy, lowering calcineurin inhibitor target concentrations, switching from tacrolimus to cyclosporine, and conversion from calcineurin inhibitor to sirolimus.[7],[8] In the present study, all these strategies were employed with good response. However, as outlined in a recent systematic review,[9] published reports on these protocols have yielded mixed results, and no randomized controlled trials have compared one strategy with another. Thus, as shown in the present studies and illustrated in [Table 4], reduction/adjustment in immunosuppression remains the cornerstone for the treatment or prevention of BKVAN.[7],[15],[16],[17] While urinary “decoy cells” have excellent sensitivity for the detection of overt BKVAN, PCR is four times more sensitive than urine cytology for monitoring asymptomatic viruria.[18] Of note, in more recent times, many centers, such as in the present study, have instituted routine screening of urine or blood for BKV DNA. Such programs have reported significant improvements in graft outcomes, possibly due to early detection of viral presence and reduction of immunosuppression before the onset of graft damage.[16],[19],[20],[21]


   Conclusions Top


BKV infection in immune-compromised patients cannot be predicted due to lack of modalities to recognize this risk. However once BKV infection is established it indicates that the individual is over immunosuppressed. In patients with organ transplants, this may lead to graft dysfunction or failure resulting in lack of well-being and high economical cause.

There are no markers available for the optimization of the immunosuppression in a particular patient. Although inducing “tolerance” remains the Holy Grail, the next best alternative is to optimize or ‘tailor’ the immunosuppression for the solid organ recipient. However, this remains mostly elusive in trying to achieve the fine balance of not only preventing rejection but also opportunistic infections, particularly in the early posttransplant period.

Our findings may help to draw relevant conclusions to determine the optimum immunosuppression that a particular patient needs to get rid of the BKV viremia without being susceptible to rejection. However, more elaborate studies have to be conducted before application of our findings to a wider range of RTPs.

Conflict of interest: None declared.

 
   References Top

1.
Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4:378-83.  Back to cited text no. 1
    
2.
Chang SH, Russ GR, Chadban SJ, Campbell SB, McDonald SP. Trends in kidney transplantation in Australia and New Zealand, 1993-2004. Transplantation 2007;84:611-8.  Back to cited text no. 2
    
3.
US Renal Data System. USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, USA: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2006.  Back to cited text no. 3
    
4.
Hariharan S, Stablein DE. Improvements in long-term renal transplant graft survival. Am J Transplant 2005;5:630-1.  Back to cited text no. 4
    
5.
Ashton-Chess J, Giral M, Soulillou JP, Brouard S. Can immune monitoring help to minimize immunosuppression in kidney transplantation? Transpl Int 2009;22:110-9.  Back to cited text no. 5
    
6.
Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis 2003;3:611-23.  Back to cited text no. 6
    
7.
Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: Interdisciplinary analyses and recommendations. Transplantation 2005; 79:1277-86.  Back to cited text no. 7
    
8.
Hirsch HH, Randhawa P; AST Infectious Diseases Community of Practice. BK virus in solid organ transplant recipients. Am J Transplant 2009;9 Suppl 4:S136-46.  Back to cited text no. 8
    
9.
Johnston O, Jaswal D, Gill JS, et al. Treatment of polyomavirus infection in kidney transplant recipients: A systematic review. Transplantation 2010;89:1057-70.  Back to cited text no. 9
    
10.
Cukuranovic J, Ugrenovic S, Jovanovic I, Visnjic M, Stefanovic V. Viral infection in renal transplant recipients. Scientific World Journal 2012;2012:820621.  Back to cited text no. 10
    
11.
Binet I, Nickeleit V, Hirsch HH, et al. Polyomavirus disease under new immunosuppressive drugs: A cause of renal graft dysfunction and graft loss. Transplantation 1999;67:918-22.  Back to cited text no. 11
    
12.
Barri YM, Ahmad I, Ketel BL, et al. Polyoma viral infection in renal transplantation: The role of immunosuppressive therapy. Clin Transplant 2001;15:240-6.  Back to cited text no. 12
    
13.
Nickeleit V, Hirsch HH, Binet IF, et al. Polyomavirus infection of renal allograft recipients: From latent infection to manifest disease. J Am Soc Nephrol 1999;10:1080-9.  Back to cited text no. 13
    
14.
Ramos E, Drachenberg CB, Wali R, Hirsch HH. The decade of polyomavirus BK-associated nephropathy: State of affairs. Transplantation 2009;87:621-30.  Back to cited text no. 14
    
15.
Randhawa P, Ramos E. BK viral nephropathy: An overview. Transplantat Rev 2007;21:77-85.  Back to cited text no. 15
    
16.
Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 2002;347:488-96.  Back to cited text no. 16
    
17.
Jiang M, Abend JR, Johnson SF, Imperiale MJ. The role of polyomaviruses in human disease. Virology 2009;384:266-73.  Back to cited text no. 17
    
18.
Randhawa P, Vats A, Shapiro R. Monitoring for polyomavirus BK and JC in urine: Comparison of quantitative polymerase chain reaction with urine cytology. Transplantation 2005;79:984-6.  Back to cited text no. 18
    
19.
Trofe J, Cavallo T, First MR, et al. Polyomavirus in kidney and kidney-pancreas transplantation: A defined protocol for immunosuppression reduction and histologic monitoring. Transplant Proc 2002;34:1788-9.  Back to cited text no. 19
    
20.
Randhawa PS, Vats A, Zygmunt D, et al. Quantitation of viral DNA in renal allograft tissue from patients with BK virus nephropathy. Transplantation 2002;74:485-8.  Back to cited text no. 20
    
21.
Ramos E, Drachenberg CB, Papadimitriou JC, et al. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 2002;13:2145-51.  Back to cited text no. 21
    

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Correspondence Address:
Dr. Issa Al Salmi
Department of Nephrology, Royal Hospital, P. O. Box 1331,P. C. 111, Muscat
Oman
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DOI: 10.4103/1319-2442.243976

PMID: 30381503

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