Exploring Net Immunosuppressive Status with Torque Teno Virus Viral Load in Kidney Transplant Recipients with High Molecular Injury

<b>Background/Objectives</b>: New monitoring methods are being developed to improve the kidney transplant outcome. Among them, the measurement of Torque Teno virus load (TTV load) has been associated with the overall immunosuppressive status and the percentage of donor-derived circulating free DNA (dd-cfDNA) with molecular graft injury, mainly related to antibody-mediated rejection (AbMR). Both methods provide complementary information, but they have not been previously used together for the monitoring of kidney transplant recipients (KTx). <b>Methods</b>: A prospective study including 42 KTx performed in our centre was conducted, in which we monitored dd-cfDNA using a targeted NGS assay (AlloSeq cfDNA) in the first month and the TTV load with in-house PCR in the first and third months. <b>Results</b>: Eleven KTx with high molecular injury defined by dd-cfDNA ≥ 1.0% were selected. The TTV load showed a non-significant trend of being lower in AbMR patients (2.91, IQR 4.18 vs. 3.48, IQR 1.47 log10 copies/mL, <i>p</i> = 0.788). No overimmunosuppressed patient developed AbMR, whereas 40% of non-overimmunosuppressed patients showed AbMR (<i>p</i> = 0.428). The TTV load increased more in the AbMR-treated KTx (0.00, IQR 4.71 vs. +6.58, IQR 4.04 log10 copies/mL, <i>p</i> = 0.042) from months one to three, with all AbMR-treated KTx becoming overimmunosuppressed. KTx with opportunistic infections showed higher TTV loads in the third month (5.18, IQR 5.92 vs. 11.53, IQR 3.54 log10 copies/mL, <i>p</i> = 0.024). <b>Conclusions</b>: KTx with molecular injury secondary to rejection tended to be less immunosuppressed, as indicated by a low TTV load. After AbMR therapy, all KTx became overimmunosuppressed and suffered a higher risk of opportunistic infections. Dual monitoring provides useful complementary information for the follow-up of kidney transplant recipients.