Kidney transplantation remains the gold standard for managing end-stage kidney disease, providing superior survival and quality-of-life outcomes compared to dialysis. Despite the ongoing gap between organ availability and demand, it is inevitable that kidney transplantation will continue to grow. This is owed to broader organ sharing, increased comfort of transplant programs with marginal kidney utilization, and the expansion of paired exchange among living donor kidneys. The evolution of kidney transplantation could not have been possible without the availability of effective immunosuppressive regimens that prevent rejection and maintain graft function. Mycophenolic acid and calcineurin inhibitors continue to serve as the foundation of modern maintenance immunosuppression. While these agents have markedly reduced acute rejection rates, their long-term efficacy in graft survival remains suboptimal. Alternative immunosuppressive therapies, including belatacept and mammalian target of rapamycin inhibitors, have demonstrated potential benefits. However, concerns regarding an increased risk of rejection have limited their widespread adoption as primary treatment options. In addition to ongoing efforts to refine steroid- and calcineurin inhibitor-sparing strategies, the identification of practical and quantifiable biomarkers for predicting long-term graft survival remains a critical objective. This review evaluates contemporary immunosuppressive protocols, highlights existing challenges, and explores future directions for optimizing long-term transplant outcomes.

Viral infections influence every stage of the kidney transplantation continuum, shaping immunologic risk, graft outcomes, and long term patient survival. Pre transplant serologic assessments guide critical decisions, including vaccinations, the avoidance of lymphocyte depleting induction in Epstein-Barr virus (EBV) mismatched candidates and the selection of Cytomegalovirus (CMV) prophylaxis tailored to donor–recipient serostatus. Acceptance of hepatitis C viremic donor organs has significantly reduced wait times, while human immunodeficiency virus (HIV) positive donor organs remain restricted to HIV positive recipients. Post transplant, viral pathogens are major drivers of morbidity: CMV functions as an immunomodulator that increases susceptibility to rejection and opportunistic fungal infections, and routine surveillance for CMV and BK viremia is essential, especially following rejection therapies. BK virus nephropathy, adenovirus nephropathy, and JC virus nephropathy can lead to progressive allograft dysfunction. Additionally, COVID 19 and parvovirus infections have been associated with collapsing focal segmental glomerulosclerosis (FSGS) and severe graft injury. Persistent viral infections and virus associated glomerulopathies contribute to chronic graft loss, while EBV driven post transplant lymphoproliferative disorder (PTLD) remains a significant cause of cancer related mortality. Transplant recipients are also at increased risk for persistent human papillomavirus infection (HPV) and progression to anogenital and oropharyngeal malignancies. Finally, donor derived viral infections, including rabies, West Nile virus (WNV), and lymphocytic choriomeningitis virus (LCMV), though rare, are well described in the literature. Collectively, these viral complications substantially impact morbidity, graft survival, and overall mortality in kidney transplant recipients.