Lesson for the clinical nephrologist: immune monitoring of human JC-polyomavirus in kidney transplantation

Abstract

The case We report the case of a 53-year-old woman who underwent kidney transplantation (KT) for IgA nephropathy in 2012, from a 59-year-old deceased donor. After induction with anti-thymocyte globulin (ATG, 100 mg/day for 5 days), the immunosuppressive regimen included mycophenolate mofetil (MMF) 2 g/day, tacrolimus (trough levels 8–10 ng/ mL) and corticosteroids (10 mg/day). Cytomegalovirus (CMV) serology was negative in the recipient and donor, Epstein-Barr Virus serology was positive for both. On day-38, she developed Posterior Reversible Encephalopathy Syndrome (PRES). After excluding other etiologies of PRES, tacrolimus was discontinued and replaced by belatacept. Following the switch, neurological symptoms rapidly receded, and hospital discharge occurred on day-74. Several cerebral Magnetic Resonance Imaging (MRI) were performed until total regression of PRES lesions. After KT, she developed three herpes zoster recurrences, Bowen’s disease and Norovirus gastroenteritis, requiring a decrease in MMF dosage to 500 mg/day. In August 2017, she complained of vertigo. A cerebral MRI found abnormalities evocative of Progressive Multifocal leukoencephalopathy (PML) (Fig. 1a), which was confirmed by the detection of JCV RNA in the cerebrospinal fluid. Belatacept and MMF were then withdrawn (latest injection end-September) and corticosteroids were maintained at 10 mg/day. Concomitantly, total lymphocyte count was 0.160 G/L. To assess the restoration of T-cell immunity to JCV after immunosuppressive treatment discontinuation, we used an IFNɣ ELISpot assay (supplementary data 1). The first IFNɣ ELISpot was done in December 2017 (month-2 after PML diagnosis and immunosuppressive drug withdrawal). Low but significant numbers of JCV-specific T cells reactive to 2/5 antigens were identified (83 specific T cells/106 CD3 + T cells) despite severe lymphopenia (0.245 G/L with CD3 + T lymphocytes = 0.036 G/L) (Fig. 2). At month-6, CD3 + T cell count slightly improved (0.201 G/L) and the IFNɣ ELISpot assay identified an increased response to JCV, both in its magnitude (3.6-fold) and diversity (4/5 positive antigens) (Table 1). This immunological restoration was associated with an improvement in neurological and radiological examinations. Thereafter, despite persistent lymphopenia < 0.300 G/L, IFNɣ ELISpot showed constant enrichment in JCV-specific T cells up to month-10 (11.7-fold compared to baseline). Based on these results and stable CD3 + T cell counts around 0.200 G/L, 1 mg/day sirolimus was introduced. However, at month-12, worsening of lymphopenia (CD3 + T cells = 0.060 G/L) prompted its * Tristan de Nattes [email protected]