ABSTRACT
OBJECTIVE: The aim of our study was to investigate whether current eGFR equations in clinical use might systematically over-estimate the kidney function, and thus misclassify CKD status, of Black Americans with HIV. Specifically, we evaluated the impact of removing the race coefficient from the MDRD and CKD-EPI equations on comparisons between Black and White HIV-infected veterans related to: 1) the prevalence of reduced eGFR; 2) the distribution of eGFR values; and 3) the relationship between eGFR and all-cause mortality. DESIGN: Retrospective cohort study. SETTING: The Department of Veterans Affairs (VA) HIV Clinical Case Registry (CCR), which actively monitors all HIV-infected persons receiving care in the VA nationally. PATIENT/PARTICIPANTS: 21,905 treatment-naïve HIV-infected veterans. MAIN OUTCOME MEASURES: Estimated glomerular filtration rate (eGFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) formula with and without (MDRD-RCR) the race coefficient and all-cause mortality. RESULTS: Persons with eGFR <45 mL/min/1.73m(2) had a higher risk of death compared with those with eGFR >80 mL/min/1.73m(2) among both Blacks (HR=2.8, 95%CI: 2.4-3.3) and Whites (HR=1.9, 95%CI: 1.4-2.6), but the association appeared to be stronger in Blacks (P=.038, test for interaction). Blacks with eGFR 45-60 mL/min/1.73m(2) also had a higher risk of death (HR=1.7, 95%CI: 1.4-2.1) but Whites did not (HR=.86, 95%CI: .67-1.10; test for interaction: P<.0001). Racial differences were substantially attenuated when eGFR was re-calculated without the race coefficient. CONCLUSIONS: Our findings suggest that clinicians may want to consider estimating glomerular filtration rate without the race coefficient in Blacks with HIV.
Subject(s)
Creatinine/metabolism , Glomerular Filtration Rate , HIV Infections/ethnology , Kidney Failure, Chronic/ethnology , Adult , Aged , Female , HIV Infections/complications , Humans , Kidney Failure, Chronic/complications , Male , Middle Aged , Prevalence , Registries , Retrospective Studies , Veterans , White PeopleABSTRACT
The SAR of the lead compound 3, a novel ligand for the alpha(2)delta subunit of voltage-gated calcium channels, was rapidly explored. Utilizing a parallel solution-phase Sn2Ar coupling approach, a focused library was obtained. The library was evaluated in vitro and afforded a series of analogues with improved potencies. The SAR trends of the library are also described.
Subject(s)
Calcium Channels/metabolism , Combinatorial Chemistry Techniques/methods , Ion Channel Gating , Protein Subunits/metabolism , Calcium Channels/chemistry , Calcium Channels/drug effects , Humans , Ligands , Protein Subunits/chemistry , Solutions/chemistry , Structure-Activity RelationshipABSTRACT
A novel class of 6-aryl-6H-pyrrolo[3,4-d]pyridazine ligands for the alpha2delta subunit of voltage-gated calcium channels has been described. Substitutions in the aryl ring of the molecule were generally not tolerated, and resulted in diminished binding to the alpha2delta subunit. Modifications to the pyridazine ring revealed numerous permissive substitutions, and detailed SAR studies were carried out in this portion of the molecule. Replacement of the pyridazine ring methyl group with an aminomethyl functionality provided greatly improved potency over the initial lead. The initial lead compound displayed good rat pharmacokinetic properties, and was shown to be efficacious in the Chung model for neuropathic pain in rats.
