The discovery of fingolimod (FTY720/Gilenya; Novartis), an orally active immunomodulatory drug, has opened up new approaches to the treatment of multiple sclerosis, the most common inflammatory disorder of the central nervous system. Elucidation of the effects of fingolimod--mediated by the modulation of sphingosine 1-phosphate (S1P) receptors--has indicated that its therapeutic activity could be due to regulation of the migration of selected lymphocyte subsets into the central nervous system and direct effects on neural cells, particularly astrocytes. An improved understanding of the biology of S1P receptors has also been gained. This article describes the discovery and development of fingolimod, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.

Delayed graft function (DGF) may be associated with diminished kidney allograft survival. We studied the risk factors that lead to nonimmediate function of a renal allograft and the consequences of DGF on short- and long-term renal transplant survival. Data from the U.S. Renal Data System were used to measure the relationships among cold ischemia time, delayed graft function, acute rejection, and graft survival in 37,216 primary cadaveric renal transplants (1985-1992). These relationships were investigated using the unconditional logistic and Cox multivariate regression methods. Cold ischemia time was strongly associated with DGF, with a 23% increase in the risk of DGF for every 6 hr of cold ischemia (P<0.001). Acute transplant rejection occurred more frequently in grafts with delayed function (37% vs. 20%; odds ratio=2.25, P=0.001). DGF was independently predictive of 5-year graft loss (relative risk=1.53, P<0.001). The presence of both early acute rejection and DGF portended a dismal 5-year graft survival rate of 35%. Zero-HLA mismatch conferred a 10-15% improvement in 1- and 5-year graft survival regardless of early functional status of the allograft. However, the 5-year graft survival rate in HLA-mismatched kidneys without DGF was significantly higher than that of zero-mismatched kidneys with DGF (63% vs. 51%; P<0.001). DGF independently portends a significant reduction in short- and long-term graft survival. Delayed function and early rejection episodes exerted an additive adverse effect on allograft survival. The deleterious impact of delayed function is comparatively more severe than that of poor HLA matching.

There is a paucity of biomarkers that reliably detect nephrotoxicity. The Predictive Safety Testing Consortium (PSTC) faced several challenges in identifying novel safety biomarkers in the renal setting.The kidney is a major site of organ damage caused by drug toxicity. This frequently manifests during drug development and/or in standard clinical care. Nephrotoxicity resulting from drug exposure has been estimated to contribute to 19-25% of all cases of acute kidney injury (AKI, the currently preferred term for the clinical disorder formerly called acute renal failure) in critically ill patients 1 . Given the societal cost of nephrotoxicity and the insensitivity of current methods to detect it, sensitive methods for prediction of toxicity in preclinical studies and identification of injury in humans are extremely important for patient safety in clinical practice and in all stages of the drug-development process. It is in the interest of patients, physicians, the drug industry and health regulatory bodies to prevent new nephrotoxic drugs from entering the market or, when the medical need dictates use of such an agent, to be able to identify early and best manage nephrotoxicity.This article discusses the purview of the first effort of the PSTC-a collaboration of the biotech and pharmaceutical industry, the US Food and Drug Administration (FDA; Rockville, MD), the European Medicines Agency (EMEA; London, UK) and academia-to facilitate the qualification of renal biomarkers for safety in drug development. It brings together expertise from a variety of disciplines to organize and/or create evidentiary datasets to present to the regulatory agencies for qualification decision-making. Although this first

The loss of a primary renal allograft was associated with significant mortality, especially in recipients with type I DM. Repeat transplantation was associated with a substantial improvement in 5-year patient survival. Recipients with type I DM achieved the greatest proportional benefit from repeat transplantation.