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Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, my

Julio Pascual,1 Titte R Srinivas,2 Steven Chadban,3 Franco Citterio,4 Federico Oppenheimer,5 Helio Tedesco,6 Mitchell L Henry,7 Christophe Legendre,8 Yoshihiko Watarai,9 Claudia Sommerer,10 Po-Chang Lee,11 J Mark Hexham,12 Gaohong Dong,12 Peter Bernhardt,13 Flavio Vincenti14 1Nephrology Department, Hospital del Mar, Barcelona, Spain; 2Division of Nephrology, Medical University of South Carolina, Mt Pleasant, SC, USA; 3Department of Transplantation, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; 4Centro Trapianti d'Organo Istituto di Clinica Chirurgica, Università Cattolica del Sacro Cuore, Policlinico Universitario A Gemelli, Rome, Italy; 5Renal Transplant Unit, Hospital Clínic de Barcelona, Barcelona, Spain; 6Nephrology Division, Hospital do Rim, UNIFESP, São Paulo, Brazil; 7The Comprehensive Transplant Center, The Ohio State University, Wexner Medical Center, Columbus, OH, USA; 8Service de Transplantation Adultes, Université Paris Descartes and Hôpital Necker, Paris, France; 9Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya City, Aich, Japan; 10Medizinische Klinik, Sektion Nephrologie, Universitätsklinikum Heidelberg, Heidelberg, Germany; 11Medical College, National Cheng Kung University, Tainan City, Taiwan; 12Biometrics and Statistical Science, Novartis Pharmaceuticals, East Hanover, NJ, USA; 13Research and Development, Novartis Pharma AG, Basel, Switzerland; 14Kidney Transplant Service, University of California San Francisco, San Francisco, CA, USA Abstract: Two well defined, modifiable risk factors for kidney allograft failure are acute rejection and poor graft function at one year post-transplant. Regulatory bodies and expert panels in the USA and Europe have recognized that both acute rejection and one-year graft function should be assessed when evaluating immunosuppressive regimens. TRANSFORM (Clinicaltrials.gov NCT01950819) is one of the first trials to adopt this approach and the first that applies a novel combined clinically meaningful endpoint to take the first step towards changing the paradigm for immunosuppression in kidney transplant patients. Everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy is a strategy designed to reduce the risk of chronic nephrotoxicity and other dose-dependent complications associated with CNI therapy. In TRANSFORM, de novo kidney transplant patients are randomized to everolimus with reduced-exposure CNI, or mycophenolic acid with standard-exposure CNI, both with induction therapy and maintenance steroids. The primary endpoint is a composite of treated biopsy-proven acute rejection or estimated glomerular filtration rate ,50 mL/min/1.73 m2 at month 12 post-transplant, which is expected to be sensitive both to the effects of acute and chronic allograft rejection and nephrotoxic side effects of immunosuppressive therapies. The construct of this endpoint allows the integration of a continuous outcome (graft function) with a logistic outcome (rejection). The trial uses a randomized, multicenter, open-label, two-arm design. After completion of a 2-year core study, patients enter a further 3-year prospective observational study. By capturing follow-up to 5 years, TRANSFORM will provide substantial data on the incidence of graft loss, graft dysfunction, cancer, cardiovascular events, and other patient-relevant outcomes. TRANSFORM will determine whether de novo CNI reduction with an everolimus-based regimen achieves short-term outcomes compared with standard CNI. As the largest clinical trial undertaken to date in kidney transplantation, recruiting more than 2,000 patients, and with extended follow-up to 5 years, TRANSFORM will provide critical data required to help maximize long-term outcomes. Keywords: mTOR inhibitor, calcineurin inhibitor, reduced exposure

As the whole world is epidemically aging, the burden of periodontitis and tooth loss is becoming a major health concern. Growing meta-epidemiological data implicate chronic systemic inflammation/infection due to periodontitis as an independent risk factor for aging-related diseases and mortality. However, because people age differently, chronological age is not a reliable marker of an individual's functional status. Recent advances in geroscience have shown that various biomarker signatures of biological aging are longitudinally associated with declined physical function, morbidity, and mortality due to major age-related diseases, including periodontitis. Here, we emphasize novel research developments bidirectionally linking periodontitis to accelerated biological aging. Using a composite biomarker age estimator, a striking increase in periodontitis and tooth loss was observed in subjects whose biological age at baseline was higher than their chronological age. Moreover, significantly shortened telomeres were encountered in populations affected by severe periodontitis. Second, we elucidate the cellular and molecular pillars of the aging process at the periodontal level. Accumulating evidence suggests that cellular senescence, stem cell exhaustion, and immunoaging are hallmarks of biological aging implicated in the impairment of periodontal homeostasis and the pathophysiology of periodontitis. Indeed, persistent bacteria-derived lipopolysaccharide stimulation influences cellular senescence in osteocytes, driving alveolar bone resorption. Moreover, inflammaging status induced by chronic hyperglycemia elevates the burden of senescent cells in gingival tissues, impairing their barrier function. Lastly, we reviewed a recent breakthrough in senotherapy to directly target the mechanisms of aging at the periodontal level. Physical exercise and intermittent fasting, together with natural compounds, senolytic drugs, and cell therapy, are increasingly being evaluated to rejuvenate the oral cavity. Following these innovations in geroscience, further advancements could provide oral clinicians the chance to intercept biological aging when still "subclinical" and set interventions for halting or delaying the trajectory toward aging-related diseases while patients are still chronologically young. [ABSTRACT FROM AUTHOR]