EXPERIMENTAL AND CLINICAL TRANSPLANTATION

BK virus infection accompanied with plasma cell-rich infiltrates is a dilemma in renal transplant recipients. One young female patient diagnosed as BK virus-associated nephropathy with plasma cell-rich infiltrates at 16 months after renal transplant was treated with bortezomib and a sequential immuno-suppressive protocol of tacrolimus combined with leflunomide. After a short period of reduction, her serum creatinine increased slowly with stable BK viruria. The patient underwent repeat biopsy. The histologic changes showed a decrease in plasma cells and CD20⁺ cells in the allograft, but the other mononuclear cells showed no difference from the first biopsy. The immunosuppressive protocol was converted to tacrolimus combined with enteric-coated mycophenolate sodium. Her serum creatinine decreased gradually during 6 months of follow-up. We speculate that bortezomib can be used in BK virus-associated nephropathy accompanied with plasma cell-rich infiltrates, and this effect might be mediated through a decrease of plasma cells and CD20+ cells in the allograft. The dosage and time of therapy need to be explored in the future; additional studies of large samples are needed.

Key words : BK virus, Bortezomib, Plasma cell, Polyomavirus-associated nephropathy, Renal transplant

BK virus-associated nephropathy (BKVN) can affect the outcome of renal allotransplant significantly and has been on the increase over the past 10 years. Although some selective therapies have been reported during that time, the disease outcome was poor, especially in some BKVN cases accompanied with intensive inflammatory cell infiltrates. There have been some reports revealing that infiltration of CD20+ cells and plasma cells is a predictor of poor outcome in certain conditions after renal transplant, such as rejection.^1,2 So, BKVN with plasma cell-rich infiltrates is also a major challenge for the transplant physician.

Bortezomib is a proteasome inhibitor approved for the treatment of multiple myeloma (a plasma cell neoplasm),³ and it induces plasma cell apoptosis. It has shown promise for desensitization and treatment of antibody-mediated rejection in transplant recipients,⁴ and does not increase the risk of infection because of the different mechanism of this drug. Therefore, we speculate that bortezomib can be used for diseases with plasma cell-rich infiltration, especially when complicated with infectious diseases. We report a case of BKVN with plasma cell-rich infiltrates treated with a bortezomib-based regimen. Serum creatinine (SCr) decreased and renal allograft function remained stable during the follow-up period.

A 29-year-old Chinese woman with graft dysfunction for 3 months after renal transplant was admitted to Jinling Hospital in November 2011. She received an ABO-compatible, living-related donor renal transplant with a kidney donated from her elder sister, who was 34 years old and had no kidney disease, in July 2010 at another hospital. The initial immunosuppressive protocol was tacrolimus combined with mycophenolate mofetil (MMF) and prednisone, and renal allograft function recovered quickly and SCr was 70.72 μmol/L 1 week after the operation. Two months after transplant she experienced pneumonia, so MMF was changed to mizoribine, and SCr was stable during that period. Mizoribine was converted to MMF again 3 months later. One year after the operation, her SCr increased to 109.62 μmol/L and she received pulsed intravenous methylprednisolone (500 mg/day × 3). In September 2011, tacrolimus was converted to sirolimus because of increasing SCr.

In November 2011, she underwent the first renal allograft biopsy in our hospital because SCr had increased to 212.16 μmol/L, and she was diagnosed as BKVN with plasma cell-rich infiltrates (Figure 1 A1-G1). She received pulsed intravenous methylprednisolone (500 mg/day × 3) and then the immunosuppressive protocol of tacrolimus combined with leflunomide (60 mg/d), and prednisone. Then, she received intravenous bortezomib (1.3 mg/m² × 4) from 9 to 20 December 2011. No obvious adverse effects were observed during the therapy.

After decreasing for a short time, SCr increased slowly and reached 380.12 μmol/L in June 2012. A repeat biopsy was performed, which showed that BKVN and mononuclear cell infiltration were still present (Figure 1 A2-G2). But the types of infiltrating cells were different on repeat biopsy. The CD20⁺ cells and CD138⁺ cells (plasma cells) decreased clearly in contrast to the first biopsy (Figure 2). Renal allograft tubular HLA-DR expression also was decreased from 56% to 10% on the second biopsy (Figure 1 G1-G2), and C4d was still negative. However, the other types of monocytes remained similar to the first biopsy (Figure 2).

BK virus copies in the urine also were detected by polymerase chain reaction (the lower limit of sensitivity was set at 10⁶ copies/mL) between the 2 biopsies, and there was no major change (about 7.0 × 10⁸ copies/mL). The panel-reactive antibody levels were in the normal range of the 2 biopsies. The immunosuppressive protocol was converted to tacrolimus combined with enteric-coated mycophenolate sodium (EC-MPS) (540 mg/d), and prednisone after the repeat renal allograft biopsy. During the follow-up, SCr decreased gradually 6 months after the conversion and the renal allograft function remained stable (Figure 3).

BK virus-associated neuropathy has increased in recent decades, especially in patients received tacrolimus combined with MMF and prednisone.⁵ The pathogenic mechanism of BKVN remains unknown, although over-immunosuppression may be the cause. Previously, the prognosis was poor because of the lack of special effective therapy. Some studies showed that leflunomide and sirolimus were partially effective in these patients.^6,7 Anti-BK virus drugs such as cidofovir also have been used in some patients, but the efficacy was not satisfactory because of many adverse effects.⁸ Therefore, the mechanism and effect of BKVN should be explored in the future.There are sporadic reports of BKVN with plasma cell-rich infiltrates. Plasma cell-rich infiltrates occur in about 50% of cases of BKVN,⁹ and even in BKVN with decreasing viremia, the rate is still more than 30%.¹⁰ However, the mechanism of plasma cell infiltration in BKVN is complex, because it is difficult to distinguish infiltrates of BK virus-specific cells from acute cellular rejection. As mentioned, interstitial infiltration of plasma cells in the graft is a predictor of poor outcome after renal transplant, so we think that treatment by reducing plasma cell-rich infiltrates in BKVN may improve its prognosis.

Bortezomib was initially used in multiple mye-loma.³ Bortezomib can induce plasma cell apoptosis and decrease antibody production; therefore, it has been used in humoral rejection, lupus nephritis, and some other antibody-mediated diseases.^4,11-13 However, there are no reports showing that bortezomib can be used to alleviate inflammatory infiltrates of plasma cells in some special infectious diseases. Bortezomib differs from other immuno-suppressant because it does not increase the strength of immunosuppression and the risk of infection. We speculate that bortezomib should be beneficial in plasma cell-rich infiltrates by inducing apoptosis of plasma cells, and better for BKVN than other drugs such as methylprednisolone, antithymocyte globulin (ATG), and anti-CD20 monoclonal antibody because it does not increase immunosuppression. That is also the reason for the increase of SCr after a short period of reduction after the application of bortezomib.

Bortezomib therapy for this type of case has not been reported before, and we would like to establish the mechanism of action of this drug for BKVN with plasma cell-rich infiltrates. The repeat biopsy showed that the infiltrating type of mononuclear cells had changed. The density of CD20⁺ cells and plasma cells in the repeat biopsy had clearly decreased compared with the first biopsy. The over-expression of HLA-DR in the renal tubules of the allograft has been suggested as a marker of acute cellular rejection.¹⁴ However, tubular HLA-DR expression also is common in BKVN, and even 40% of the resolving cases of BKVN show tubular HLA-DR expression, because it is induced by proinflammatory cytokines (such as interferon-γ) released by infiltrating lymphocytes.^10,15

In the present case, HLA-DR expression on the renal tubules of the allograft also decreased in the repeat biopsy, which showed that the condition of BKVN had improved since the first biopsy. Therefore, we speculate that bortezomib can decrease B-cell (CD20⁺ and plasma cells) infiltrates, which should have a beneficial effect on the outcome of this type of BKVN. However, infiltration of CD3⁺, CD4⁺, CD8⁺ and CD68⁺ cells did not differ significantly between the 2 biopsies, which indicated that bortezomib was primarily focused on the B cells (unlike ATG) and the reduction of B cells is induced by bortezomib instead of the recovery of BKVN. BK virus-associated neuropathy immunochemistry and BK virus replication remained stable during the 2 biopsy periods, which demonstrated that bortezomib did not activate BK virus.

The immunosuppressive regimen of tacrolimus combined with leflunomide is used in most cases of BKVN. The sustained immunosuppressive protocol in the present case was different from the routine protocol in patients with pure BKVN without plasma cell-rich infiltrates. So far, it is still difficult to distinguish BKVN from acute cellular rejection, so it is reasonable to presume that BKVN may coexist with latent acute rejection if increasing SCr accompanies decreasing or stable BK viruria. The combination of tacrolimus and leflunomide was not suitable for the control of latent rejection. Therefore, SCr in the present case increased gradually after conversion to tacrolimus combined with leflunomide, and decreased after conversion from leflunomide to EC-MPS (low dosage). We think that leflunomide is unsuitable for acute rejection because of its poor immunosuppressive effect. Therefore, the immunosuppressive protocol should be specific to cases diagnosed as BKVN concurrent with latent acute rejection.

Therapy of BKVN with plasma cell-rich infiltrates is a dilemma. Bortezomib can be used in these special cases, and its mechanism might be related to the clearance of plasma cells and CD20⁺ cells. However, the dosage and time of therapy need to be explored in the future, additional studies of large samples are needed. The sustaining immunosuppressive protocol should be stronger than that used in pure BKVN, tacrolimus combined with low-dose EC-MPS may be a better choice for these cases with increasing SCr concurrent with decreasing or stable BK viruria.

Volume: 13 Issue: 6 December 2015

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