Neutralizing Antibody-Mediated Response and Risk of BK Virus-Associated Nephropathy

Abstract

BK virus-associated nephropathy (BKVAN) causes renal allograft dysfunction. The current management of BKVAN relies on pre-emptive adaptation of immunosuppression according to viral load monitoring. However, this empiric strategy is not always successful. Therefore, pretransplant predictive markers are needed. In a prospective longitudinal study, we enrolled 168 kidney transplant recipients and 69 matched donors. To assess the value of BKV genotype-specific neutralizing antibody (NAb) titers as a predictive marker for BKV replication, we measured BKV DNA load and NAb titers at transplant and followed patients for 24 months. After transplant, 52 (31%) patients displayed BKV replication: 24 (46%) patients were viruric and 28 (54%) patients were viremic, including 13 with biopsy-confirmed BKVAN. At any time, patients with high NAb titers against the replicating strain had a lower risk of developing BKV viremia (hazard ratio [HR], 0.44; 95% confidence interval [95% CI], 0.26 to 0.73; P=0.002). Each log₁₀ increase in NAb titer decreased the risk of developing viremia by 56%. Replicating strains were consistent with donor transmission in 95% of cases of early BKV replication. Genotype mismatch between recipients' neutralization profiles before transplant and their subsequently replicating strain significantly increased the risk of developing viremia (HR, 2.27; 95% CI, 1.06 to 4.88; P=0.04). A NAb titer against the donor's strain <4 log₁₀ before transplant significantly associated with BKV replication after transplant (HR, 1.88; 95% CI, 1.06 to 3.45; P=0.03). BKV genotype-specific NAb titers may be a meaningful predictive marker that allows patient stratification by BKV disease risk before and after transplant.

Keywords: Predictive marker; Viral infection; immunology; kidney transplantation; transplant outcomes.

Graphical abstract

Figure 1.

Monitoring of BK virus (BKV) replication. Kaplan–Meier estimates of BKV viruria, viremia, and BKVAN in 168 kidney transplant recipients followed-up for 24 months post-transplant. BKVAN was diagnosed on the basis of histologic findings in allograft biopsy specimens. (A) Cumulative incidence values at month 24 are indicated. (B) Virologic characteristics of viruric, viremic, and BKVAN groups are shown. NA, not applicable.

Figure 2.

BK virus (BKV) genotype–specific seroconversion after transplantation. Genotype specificity was determined for each patient on the basis of NAb titers. Percentages of patients who were (A) BKV DNA–negative and (B) BKV DNA–positive displaying NAbs against genotype I, II, IV, or multiple genotypes at the time of transplantation and 24 months post-transplantation are shown. (C) NAb titers against the replicative strain and the other genotypes are depicted at month 24 for patients who were BKV DNA–positive.

Figure 3.

A delayed and weak NAb response is associated with severe BK virus (BKV) infection outcome. (A) The evolution of NAb titers directed against the replicating strain in patients who were viruric, viremic, and those with BKVAN. NAb titer distribution is depicted in colored bars and mean NAb titer values (log₁₀ IC₅₀) for each group are represented by colored squares. (B) The detailed evolution of three representative patients of viruric, viremic, and BKVAN groups. Dotted and solid lines represent urine and blood viral loads, respectively. NAb titers are depicted by gray areas. (C) The association of NAb titers, donor/recipient genotype mismatch, and urine BKV DNA loads with the risk of transition from viruria to viremia state. Continuous or joint models were used. HR (95% CI) and P values were calculated using two-fold crossvalidation after section of the optimal cutoff at 4 log₁₀ IC₅₀ NAb titer. (D) Spearman’s rank correlation between NAb titers and mycophenolic acid (MMF) area under the concentration time curve (AUC), alone or associated to cyclosporine or tacrolimus. Spearman’s coefficient and associated P value are indicated.

Figure 4.

Neutralizing titers before transplantation predict the development and outcome of BK virus (BKV) infection after transplantation. Kaplan–Meier curves represent (A) BKV viruria and (B) viremia cumulative incidence according to NAb titer (log₁₀ IC₅₀) at the time of transplantation (day 0 NAbs). Black curves indicate NAb titers ≤4log₁₀ IC₅₀ and green curves indicate NAb titers >4log₁₀ IC_50. Numbers at risk are indicated at each timepoint. Cumulative incidence values at month 24 are indicated.