DISCUSSION
In this retrospective cross-sectional study, we analyzed the renal
transplantation recipients with allograft biopsy-proven BKVN followed-up
in 30 transplantation centers all over our country and presented the
BKVN data with the largest patient sample in the literature.
BKV infection is a significant complication of renal transplantation.
First described and isolated in a renal transplant recipient in 1971,
BKV is recognized as a cause of allograft failure in renal transplant
recipients[1]. BKV is
classified into at least four major genotypes (I, II, III, and IV) and
several subgroups (including Ia, Ib1, Ib2, Ic, IVa1, IVa2, IVb1, IVb2,
IVc1, and IVc2) based on deoxyribonucleic acid sequence
variations[5]. BKV
genotype I is the most common subtype worldwide, followed by genotype
IV[6].
The incidence of BKV infection after renal transplantation varies
between 30-and 60% in the first four
weeks[7]. In the
following four weeks, the frequency of viremia is 12-13%. The incidence
of viremia in the first three months is around 50%. BKVN develops in
the following 4-8 weeks. BKVN occurs in 95% of viremic patients within
the first two years after
transplantation[7] . The
incidence of BKVN varies between 1-and 10% in different
studies[8]. In our
study, approximately 14 thousand patients were screened, and BKVN was
detected in 248 patients (1.7%) after an average of 15.8±22.2 (1-156)
months after transplantation, and our results are consistent with the
literature.
BKV replication usually occurs immediately after transplantation and
after rejection therapy, in which cellular immunity is most
suppressed[9]. Induction
with T-cell depleting agents and polyclonal antibodies is associated
with the development of BKV infection after
transplantation[9]. Some
studies have shown that exposure to triple immunosuppression with Tac,
MMF/MFA, and steroids is associated with a higher risk of BKV infection.
In our study, 144 (69%) of the patients had induction IS treatment with
ATLG, and 164 (79%) of the patients with BKVN were receiving
prednisolone/MMF-MFA/tacrolimus maintenance treatment after
transplantation. Acute rejection was detected in 49 patients in the
first six months, pulse steroid treatment was given to all patients, and
ATLG was given to 46 patients. Both the triple maintenance IS protocol
and the acute rejection treatment with ATLG may have facilitated the
development of BKVN in these patients.
BKVN can have an insidious course after renal transplantation. The most
common findings in patients were elevated serum creatinine and the
development of proteinuria. The mean creatinine of our patients at the
time of diagnosis was 1.8±0.7 mg/dl, eGFR was 45.8±19.6 ml/min, and the
amount of proteinuria at the time of diagnosis was 0.6±1.6 g. The
earlier the diagnosis is made in these patients, the less allograft
dysfunction occurs. The American Society of Transplantation Infectious
Diseases Community of Practice guideline (AST-IDCOP) suggests screening
for BK viremia by quantitative testing (RT-PCR) monthly until month 9,
then every three months until two years
post-transplant[10]. On
the other hand, the Kidney Disease Improving Global Outcomes (KDIGO)
guideline suggests that quantitative testing should be performed every
month for the first 3–6 months after transplantation and then every
three months until the end of the first post-transplant
year[11]. In addition,
it was emphasized that the BKV DNA levels of the patients should be
checked if the serum creatinine rises and cannot be explained otherwise
and after each acute rejection treatment. Screening can be done via
sampling serum and urine for BKV DNA or examining the urine
cytology[12]. The
presence of BKV-infected cells (DECOY) in the urine sample is the clue
for BKV infection. The positive predictive value is 20% with high
sensitivity, and the negative predictive value is 100% (12). The
positive predictive value of urine BKV DNA follow-up is 40%, and its
negative predictive value is 100%. If urine BKV DNA is
>107 copies/mL, it is interpreted as a
positive result[13].
There is no need to look for BKV DNA in the blood of patients with
negative BKV DNA in the urine. The positive predictive value of BKV DNA
follow-up in serum is 60%, and its negative predictive value is
high[12,13]. A result of
BKV DNA is >104 copies/mL in plasma
sampling is considered positive. In our sample, plasma BKV-DNA was
screened monthly for the first nine months after transplantation and
then every three months in 110 patients, and urine BKV-DNA was screened
in 25 patients. Although our study is retrospective, currently, we think
that plasma BKV DNA monitoring after transplantation is higher in our
centers.
Allograft biopsy is the gold standard in the diagnosis of BKVN. The
diagnosis is made by detecting typical basophilic nuclear bodies,
inflammatory infiltration, and fibrosis in epithelial
cells[14]. In addition,
three patterns are seen in histopathology: Model A; cytopathic changes,
normal renal parenchyma, interstitial fibrosis, and inflammatory
infiltration are observed, and tubular atrophy is absent. Model B;
cytopathic changes include focal, multifocal areas with tubular atrophy,
interstitial fibrosis, and inflammation. Model C; may include diffuse
renal tissue involvement and extensive tubular atrophy, with cytopathic
change, ischemic glomerulopathy, transplant glomerulopathy, crescentic
appearance, plasma cell infiltration, interstitial fibrosis, and
inflammation[14,
15]. In our study, BKVN was proven by biopsy in all patients. The
main findings in biopsies were the fibrosis with typical basophilic
nuclear bodies [SV40 (+)] and varying degrees of inflammatory
infiltration in epithelial cells. However, the staging was not performed
in our biopsies, so we cannot give information about the pathological
stage of the patients. The most important differential diagnosis is
acute rejection. In the presence of diffuse tubulitis in areas far from
viral cytopathic changes, acute cellular rejection with BKVN should also
be considered[16].
Co-occurrence of endarteritis, fibrinoid vascular necrosis,
glomerulitis, and C4d accumulation in peritubular capillaries is
evidence of humoral
rejection[16].
There were BK virus nephropathy + cellular rejection in 21 study
patients and BK virus nephropathy + humoral rejection findings in 4
patients. Although the association of BKVN and rejection has been
reported at rates of up to 50% in the literature
[16], this rate was
12% in our study. The main question is the choice of treatment in the
presence of rejection because steroid or ATLG treatment may exacerbate
BKVN and contribute to the risk of allograft loss. Steroid plus IVIG
treatment is considered a more innocent modality and is recommended. In
our study, ten patients received pulse steroid treatment, ten received
steroid + IVIG treatment, and five were not treated with additional IS
therapy. While allograft loss developed in 12 patients (48%) with
concomitant rejection, this rate was 10% in patients without rejection.
Therefore, concomitant rejection in these patients negatively affects
allograft survival.
The leading cause of the development of BKVN is excess
immunosuppression. Therefore, the first intervention in patients with
BKVN should be evaluation and reduction of the current IS therapy. The
interventions to be considered are discontinuation of the
antimetabolites, dose reduction of the CNIs, or switching the CNI to a
mTORi[17].
Therefore, it is recommended to keep tacrolimus level < 6
ng/ml, daily MMF dose ≤ 1 g/day, and blood CSA around 100-150
mg/ml[17]. It takes
4-10 weeks for the viremia to start decreasing and 7-20 weeks for the
viremia to disappear. If there is no decrease in viral load within four
weeks, the dose of IS drugs should be reduced or discontinued, or
antiviral treatment should be planned. In our study, the antimetabolite
dose alone was reduced in 18 patients, antimetabolite treatment alone
was discontinued in 45 patients, the antimetabolite was discontinued
plus the CNI dose was reduced in 47 patients, the antimetabolite was
switched to AZA in 30 patients, antimetabolites were switched to AZA
plus CNI dose was reduced to 50% in 11 patients, and CNI was switched
to mTORi in 56 patients. In the literature review, it is seen that the
IS intervention approaches of different centers are pretty similar to
our centers.
Although some agents have been suggested to be effective in treating
BKVN, there are no randomized controlled studies in the literature to
make a recommendation. Cidofovir, leflunomide, quinolones, and IVIG are
the most preferred agents worldwide. There is no randomized prospective
controlled studies of cidofovir. Since the doses of the IS drugs are
also reduced in reported cases where the viral load is decreased, there
is no definite evidence of its independent effect. Cidofovir is an
expensive drug applied at 0.25-1 mg/kg doses for 1-3 weeks. Anterior
uveitis has been reported in 12-35% of
cases[18]. In the
cidofovir study with the largest number of patients, it was observed
that while GFR was stable in the short term follow-up in 75 patients,
GFR decreased in the long term observations. In our study, graft loss
developed in 7 (38%) of 18 patients who received cidofovir. Leflunomide
is developed for the treatment of rheumatoid arthritis and psoriatic
arthritis. It was found to be effective against CMV and polyomavirus in
vitro. In BKVN, leflunomide dose is 20-40 mg/day. A series of 26
patients followed up for 15 months; Tac was maintained within serum
levels of 4-6 ng/ml, MMF discontinued, leflunomide initiated as 50-100
mg/ml, and 9 of the patients were also given cidofovir. Stable kidney
function was achieved in 23 of 26 patients, and leflunomide was
suggested to be an effective
option[19]. There
was no graft loss in our study in 11 patients receiving leflunomide and
12 patients receiving leflunomide + IVIG. Thus leflunomide seems to be
the most effective treatment compared to other treatments. There is
limited information about the efficacy of IVIG in BKVN. In a series of 8
patients, IS medications were reduced by 50%, and IVIG 2g/kg was given
for 2-5 days. The follow-up period was 15 months, and graft function was
preserved in 7 patients
(88%)[20]. In our
study, graft loss occurred in only 2 of 15 patients given IVIG, and IVIG
can also be considered an effective treatment. Quinolones may be
effective against BKV. There is a limited number of studies examining
its effectiveness in BKVN treatment. A meta-analysis showed that
fluoroquinolones did not prevent the development of BKVN after
transplantation[21].
Fluoroquinolones may reduce the rate of the BK virus to some extent but
may not have sufficient clinical
effects[22]. In our
study, graft loss developed in only 1 (5%) of 17 patients treated with
quinolones, and quinolones were both cost and clinically effective.
There are also reports about patients who underwent retransplantation
after allograft loss due to BKVN. In a series of 126 patients, graft
survival at 1 and 3 years after retransplantation was 99% and 94%, and
BKVN recurred in
17.5%[22]. In our
study, five patients were retransplanted, and none developed BKVN in the
follow-up.
Our study has the largest number of patients in the literature so far.
However, there are some limitations, such as its retrospective design.
On the other hand, it is a multicenter study, and the centers’ IS
reduction or discontinuation policies are different. However, there is a
lack of information about the rationale for the treatment choices for
patients.
In conclusion, BKVN is still an important and unclarified problem in
renal transplantation. There are no randomized controlled studies, so
the optimal treatment is not standardized. Therefore, randomized
controlled studies and studies with larger samples are needed.
Acknowledgments: Organ transplant is teamwork. Therefore, we
would like to thank transplant surgeons, pathologists, microbiologists,
and interventional radiologists for their efforts in diagnosing and
treating the patients we included in the study.
Disclosure: All the authors have declared no competing
interest.