Objectives: Nephropathy from BK virus is an increasing problem in renal transplant recipients and has been correlated with newer immuno­suppressive agents and the decline in acute rejection rates. We aimed to evaluate the effect of BK virus-positive kidney donors on the outcome of kidney transplant recipients after mean follow-up 21 months.

Materials and Methods: Among 18 kidney donors with BK virus in blood and urine, 5 donors were fit for donation. Clinical information was reviewed for the 5 kidney transplant recipients who received kidney allografts from these donors (mean donor age, 35 ± 3 y).

Results: All recipients except 1 were women (mean age, 49.4 ± 4.2 y; body weight, 68.2 ± 4 kg, follow-up, 21.6 ± 4 mo). All patients except 1 received antithymocyte globulin induction, and all 5 patients received steroids, tacrolimus, and mycophenolate mofetil as maintenance therapy. Ureter stenting was a routine procedure in each case. Human leukocyte antigen Cw7 was detected in 4 of 5 recipients, and the fifth case, the antigen was detected in the donor. At last follow-up, all patients were enjoying functioning grafts without recurrence of BK virus infection.

Conclusions: Polyoma BK virus-positive people can be accepted safely for kidney donation, especially with a possible protective role of human leukocyte antigen Cw7.

Key words : BK virus, End-stage renal disease, Immuno­suppression, Outcome, Virology

Introduction

Polyoma BK viruses are widespread, double-stranded, nonencapsulated DNA viruses comprising BK and JC strains that are pathogenic in humans.^1,2 Approximately 60% to 90% adult people worldwide are seropositive for BK virus. Primary infections usually occur early in childhood by oral and/or respiratory exposure.^3,4 These infections usually are asymptomatic, but they have tropism for renal tubular and transitional cells and remain latent within the genitourinary tract.^5-8 These viruses need immune modulation and host cell activation for replication with an impaired immune system, and this is prevalent in renal transplant patients (10%-60%).⁹ In more recent reports, reactivation occurs soon after transplant and is identified in the urine of 30% to 50% patients at 3 months after transplant.^1,2

Progression from viruria to viremia and nephro­pathy is accepted as a stepwise transition.^1,3,4 Such activation is determined by the detection of free viral particles in the urine by polymerase chain reaction (PCR), intranuclear viral-inclusion-bearing cells, decoy cells in urine cytology samples, and viremia by plasma PCR.^10,11 Only 1% to 10% affected patients change from reactivated infection to histologically confirmed BK virus nephropathy, usually at mean 10 to 13 months after transplant (range, 6 days to 5 years).^9,12-17 In other reports, it has been concluded that the median time to detect BK virus nephropathy after kidney transplant is 9.5 months, but the duration until graft failure is only 4 months after incidence of BK virus nephropathy.¹⁶

Diagnosis of BK virus nephropathy is based on histologic appearance characterized by lymphocytic interstitial infiltrates, nuclear reaction to the anti-SV-40T antibody as evidence of viral replication, and positive PCR for BK virus DNA. It is difficult to make a clear differential diagnosis between BK virus nephropathy and acute cellular rejection. Moreover, it is well known that these diseases may coexist in the same patient, and the relation between their cause and effect remain controversial. We lack specific and effective antiviral treatment. Therefore, a decrease or discontinuation of immunosuppressive agents is essential as initial treatment for BK virus nephropathy.¹²

Potent immunosuppression is believed to be the cause of the resurgence of BK virus in kidney transplant patients. Factors that may be associated with the risk of BK virus nephropathy include older age, male sex, white ethnicity, diabetes, renal tissue injury from ischemia, presence of cytomegalovirus, acute rejection, and treatment with high-dose steroid pulses.^12,15

The BK virus nephropathy is 1 of the major causes of allograft dysfunction or graft loss in patients in an overly immunosuppressed state. It has been showed that 45% patients with BK virus nephropathy progressed to irreversible graft failure with tubular atrophy and interstitial fibrosis.¹⁸ Although immunosuppressive agents are essential for therapy after organ transplant, these agents increase the incidence and deteriorate the severity of BK virus infection. Calcineurin inhibitors and mycophenolate mofetil are important in reactivation of latent BK virus infection.

There have been 10 cases in which the absence of human leukocyte antigen- (HLA-) C7 allele (a genetic trait) was observed in donors and recipients with sustained BK viremia.¹⁹ The precise role of the HLA-C7 gene is unknown, but its absence may increase the risk that infection will advance to sustained viremia, a preceding factor in BK virus nephropathy. Active BK virus infection has been detected in 35.4% renal transplant recipients.²⁰ After studying pretransplant donor and recipient samples for BK virus antibody titer and HLA alleles, it was concluded that the data supported donor origin for early BK virus infection in kidney transplant recipients, and it was suggested that a specific HLA-C locus may be associated with failure to control BK virus infection.²⁰

Many (27%) kidney donors have positive PCR for BK virus.21 Based on preliminary results analyzing the molecular fingerprints of donor and recipient pairs, the donor may be the source of BK infection in some cases.²¹ The purpose of this study was to evaluate the effect of BK virus-positive kidney donors on the outcome of kidney transplant recipients after mean follow-up 21 months.

Materials and Methods

Patients
In 45 kidney donors screened for BK virus, 18 (40%) had positive BK virus in blood and urine (both qualitative and quantitative PCR), and only 5 donors (mean age, 35 ± 3 y) were fit for donation. We reviewed data about the 5 kidney transplant recipients who received kidney allografts from 2008 to 2009 at Hamed Al-Essa Organ Transplant Center in Kuwait. The management was approved by the local institutional ethical and scientific committees and is compliant with the principles laid down in the Helsinki’s declaration.

Induction and immunosuppression protocol
Immunologically low-risk patients were treated with 2 doses of basiliximab (first dose, 20 mg) on day 0 and second dose on day 4, but patients who had high risk received 5 doses of antithymocyte globulin as induction immunosuppression in addition to methylprednisolone (1000 mg intravenous) before transplant. Subsequently, tacrolimus was started (initial dose, 0.15 mg/kg; then twice daily to achieve plasma level 8-10 ng/mL during the first month and 5-8 ng/mL during the second and later months). Mycophenolate mofetil was prescribed (500 mg twice daily; increased to 750 mg twice daily in the first month). Methylprednisolone was given (500 mg intravenous 12 hours postoperative; then 250 mg for 3 successive days; then oral prednisolone in tapering doses aimed at 5 mg daily at the end of the sixth posttransplant month).

Quantitative polymerase chain reaction
Quantitative BK virus DNA was measured in serum at 2, 4, 6, 12, and 20 months after transplant date. This was performed by the National Virus Reference Laboratory using a qualitative assay (LightCycler, Roche, Basel, Switzerland) and a quantitative real-time assay (TaqMan, Roche). Low viral load was defined as < 5000 viral copies/mL; intermediate viral load 5000-10 000 copies/mL, and high viral load > 10 000 copies/mL. Data collected included demographics, type of transplant, HLA match, type and dose of immunosuppression, use of indwelling ureter stents, history of delayed graft function, acute rejection episodes, pretransplant diabetes mellitus, and cold ischemia time. The serum creatinine level at baseline (2 weeks posttransplant) and at the most recent follow-up or October 2011 was evaluated.

Results

All recipients except 1 were female (mean age, 49.4 ± 4.2 y; body weight, 68.2 ± 4 kg; follow-up, 21.6 ± 4 mo) (Table 1). The original kidney disease was diagnosed in 1 patient each as autosomal dominant polycystic kidney disease, chronic interstitial nephritis, focal segmental glomerulosclerosis, diabetic nephropathy, and idiopathic. All patients except 1 receive antithymocyte globulin induction, and all patients were maintained on steroids, tacrolimus, and mycophenolate mofetil (Table 1).

Laparoscopic donor nephrectomy was a routine procedure in our center with average warm ischemia time 5 to 6 minutes and cold ischemia time 30 to 40 minutes, and ureter stenting was performed in all cases. There were 3 patients who had biopsied and acute tubular necrosis was the primary finding in all biopsies. Successful treatment in 1 patient was with plasma exchange for an episode of acute antibody mediated rejection (Table 1).

The mean creatinine level at baseline (2 weeks after transplant) was 108.8 μmol/L and at most recent follow-up was 116.4 μmol/L. At most recent follow-up, all patients had functioning grafts without evidence of recurrent BK virus infection.

Discussion

Nephropathy from BK virus is 1 of the major causes of allograft dysfunction or graft loss in patients with an overly immunosuppressed state. It has been reported that the median time to detect BK virus nephropathy after kidney transplant is 9.5 months with shorter time to graft failure.¹⁶ It was shown that 45% patients with BK virus nephropathy progressed to irreversible graft failure with tubular atrophy and interstitial fibrosis.²¹ Although immunosuppressive agents are essential for therapy after organ transplant, these agents increase the incidence and deteriorate the severity of infection. Calcineurin inhibitors and mycophenolate mofetil are important in reactivation of latent BK virus infection. Potent immunosuppression is believed to be responsible for BK virus in kidney transplant patients, especially in the presence of risk factors. The role of HLA-C7 allele is unknown, but its absence may increase the risk that infection will advance to sustained viremia, a preceding factor in BK virus nephropathy.^12,15

In our series, we found that many risk factors were observed (3 males and 3 elderly in 5 patients) and all these patients received antithymocyte globulin induction and maintenance immuno­suppression based on tacrolimus and mycophenolate mofetil. All were diabetics with ureter stenting. Moreover, all patients received their grafts from BK virus-positive kidney donors. The donor origin for early BK virus infection was noted in data about kidney transplant recipients,²⁰ and similar data were reported by others.²¹ Despite these risk factors, none of our patients developed BK viremia or viruria (confirmed by qualitative and quantitative PCR) after follow-up > 12 months, an observation that could be explained by the presence of the protective HLA-Cw7 observed in 4 patients and in the donor of the remaining fifth case. These HLA antigens are a well-known group of genes that produce interferon. It also has been suggested that a specific HLA-C locus may be associated with failure to control BK virus infection.²¹

Since natural killer (NK) cells are involved in the protection from viral infection, a reduced size of a ligand-specific NK subset in individuals homo­zygous for some HLA-B/C haplotypes may help explain their increased susceptibility to virus-induced diseases.²² In the same direction, others suggested a link between the product of a gene in the HLA-A1-Cw7-B8-DR3 haplotype and disease related to human immunodeficiency virus 1 (HIV-1).²³

It is worthwhile to mention that cytotoxic T lymphocytes (CTLs) constitute a major immune defence mechanism for sustained recovery from viral infections. A previous study supported the role of the HLA-C locus in generating CTL responses and constituted the first report of an HLA-Cw7-restricted HIV-1 envelope-specific CTL response in HIV-positive patients, which may be important in the control of HIV replication in vivo.²⁴ Moreover, another study concluded that, in Croatian patients with chronic hepatitis C, HLA-Cw7 was the predictor of sustained virologic response to interferon α therapy.²⁵ It is possible that this HLA allele may be involved in presenting a BK virus antigen and initiating a CTL-mediated immune response, as shown for Hantavirus.²⁶ The HLA-C alleles may play a role as determinants of the level of NK cell activity. This effect has been postulated to relate to the finding that HLA-C molecules are ligands for inhibitory and activating receptors for NK cell activity, especially with viral infections.²⁷ In a previous study, sustained viremia occurred in only 1 recipient with HLA-C7, and it developed late (at 9 months), approximately 1 month after an increase in immunosuppression; they suggested that the protective effect of HLA-C7 can be overcome by excess immunosuppression.²⁰

In conclusion, Polyoma BK virus-positive people can be accepted safely for kidney donation especially with the possible protective role of HLA-Cw7. Further long-term and larger randomized studies are required to evaluate this issue.

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