The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.

The US Food and Drug Administration (FDA) is currently developing a guidance for industry to replace a previous guidance, "Pharmacokinetics in Patients With Impaired Renal Function--Study Design, Data Analysis, and Impact on Dosing and Labeling" (renal guidance) issued in May 1998. The impact of the 1998 renal guidance was assessed following a survey of 94 new drug applications (NDAs) for small-molecule new molecular entities (NMEs) approved over the past 5 years (2003-2007). The survey results indicate that 57% of these NDAs included renal impairment study data, that 44% of those with renal data included evaluation in patients on hemodialysis, and that 41% of those with renal data resulted in recommendation of dose adjustment in renal impairment. In addition, the survey results provided evidence that renal impairment can affect the pharmacokinetics of drugs that are predominantly eliminated by nonrenal processes such as metabolism and/or active transport. The latter finding supports our updated recommendation to evaluate pharmacokinetic/pharmacodynamic alterations in renal impairment for those drugs that are mainly eliminated by nonrenal processes, in addition to those that are mainly excreted unchanged by the kidney.

To optimize drug therapy for individuals, it is critical to understand how various intrinsic (e.g., age, gender, race, genetics, organ impairment) and extrinsic factors (e.g., diet, smoking, concomitantly administered drugs) affect drug exposure and response.(1) Up to now, it has been far easier to discover effects on exposure caused by these factors, and the US Food and Drug Administration (FDA) has published several guidance documents with recommendations on how to evaluate these factors during drug development.

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Hypertension in end-stage renal disease (ESRD) may involve lack of endothelial nitric oxide (NO), as suggested by reduced total NO synthase (NOS) in dialysis patients. One reason might be due to substrate deficiency. To test the hypothesis that uremia is a state of intracellular L-arginine deficiency, uremic plasma was obtained from dialysis patients, and its effect was tested on arginine transport in cultured vascular endothelial cells. L-arginine transport (P < 0.01) was reduced in human dermal microvascular endothelial cells (HDMEC) incubated for 6 h with 20% uremic plasma from peritoneal dialysis and hemodialysis patients obtained immediately predialysis. Similar transport inhibition was seen with ESRD plasma in human glomerular capillary and bovine aortic endothelial cells. Hemodialysis partially reversed inhibition of L-arginine transport. HDMECs incubated for 6 h with synthetic media containing high (uremic) urea concentrations showed inhibition of L-arginine transport, but this was not competitive because acute exposure to urea had no impact on L-arginine transport. Over a 6-h period, urea-induced inhibition of L-arginine transport was not sufficient to inhibit NOS activity, but after 7 days NOS activity was reduced. These cellular findings suggest that substrate delivery may be lowered, thus reducing endothelial NOS activity and contributing to hypertension in ESRD patients.

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Abstract-Reduced nitric oxide synthesis by glomerular endothelial cells and increased proliferation of glomerular mesangial cells is associated with glomerular remodeling that leads to accelerated glomerulosclerosis. Estradiol induces nitric oxide synthesis and slows the progression of renal disease. Because the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol are more potent than estradiol in inhibiting growth of vascular smooth muscle cells, which are phenotypically similar to mesangial cells, we compared the effects of estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol on growth of glomerular mesangial cells and on basal nitric oxide synthesis by glomerular endothelial cells. In human glomerular mesangial cells, estradiol and its metabolites concentration-dependently (1 nmol/L to 10 mol/L) inhibited serum (2.5%)-induced DNA synthesis, cell proliferation, and collagen synthesis with the order of potency being 2-methoxyestradiol Ͼ 2-hydroxyestradiol Ͼ estradiol. ICI182780 (100 mol/L, an estrogen receptor antagonist) blocked the growth inhibitory effects of estradiol but not 2-hydroxyestradiol or 2-methoxyestradiol. Treatment with estradiol, but not 2-hydroxyestradiol and 2-methoxyestradiol, induced nitric oxide synthesis (PϽ0.05, assayed by the formation of 3 H-L-citrulline from 3 H-L-arginine) in human glomerular endothelial cells, and these effects were blocked by ICI182780 and L-NMA (a nitric oxide synthesis inhibitor). In conclusion, estradiol may attenuate glomerulosclerosis by inducing nitric oxide synthesis via an estrogen receptor-dependent mechanism and by conversion to 2-hydroxyestradiol and 2-methoxyestradiol, which inhibit glomerular mesangial cell proliferation independent of estrogen receptors.

High plasma levels of ADMA in CRD patients are independent of reduced renal clearance, suggesting an alteration in ADMA synthesis and/or degradation. High ADMA is a marker and is partly responsible for the inhibition of eNOS activity in cultured cells and may also result in reduced eNOS activity in vivo, with consequent hypertension.