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Objective: To determine whether serum urate reduction with allopurinol lowers blood pressure (BP) in young adults and the mechanisms mediating this hypothesized effect. Methods: We conducted a single‐center, randomized, double‐blind, crossover clinical trial. Adults ages 18–40 years with baseline systolic BP ≥120 and <160 mm Hg or diastolic BP ≥80 and <100 mm Hg, and serum urate ≥5.0 mg/dl for men or ≥4.0 mg/dl for women were enrolled. Main exclusion criteria included chronic kidney disease, gout, or past use of urate‐lowering therapies. Participants received oral allopurinol (300 mg daily) or placebo for 1 month followed by a 2–4 week washout and then were crossed over. Study outcome measures were change in systolic BP from baseline, endothelial function estimated as flow‐mediated dilation (FMD), and high‐sensitivity C‐reactive protein (hsCRP) levels. Adverse events were assessed. Results: Ninety‐nine participants were randomized, and 82 completed all visits. The mean ± SD age was 28.0 ± 7.0 years, 62.6% were men, and 40.4% were African American. In the primary intent‐to‐treat analysis, systolic BP did not change during the allopurinol treatment phase (mean ± SEM −1.39 ± 1.16 mm Hg) or placebo treatment phase (−1.06 ± 1.08 mm Hg). FMD increased during allopurinol treatment periods compared to placebo treatment periods (mean ± SEM 2.5 ± 0.55% versus −0.1 ± 0.42%; P < 0.001). There were no changes in hsCRP level and no serious adverse events. Conclusion: Our findings indicate that urate‐lowering therapy with allopurinol does not lower systolic BP or hsCRP level in young adults when compared with placebo, despite improvements in FMD. These findings do not support urate lowering as a treatment for hypertension in young adults. [ABSTRACT FROM AUTHOR]

Uric acid has been suspected to be a risk factor for hypertension since the 1870s. Numerous epidemiological studies demonstrate an association between uric acid and both incident and prevalent hypertension in diverse populations. Studies in elderly patients have had more variable results, raising the possibility that uric acid may be more significant to hypertension in the young. Animal models support a two-phase mechanism for the development of hyperuricemic hypertension. Initially, uric acid induces vasoconstriction by activation of the renin-angiotensin system and reduction of circulating nitric oxide, which can be reversed by lowering uric acid. Over time, uric acid uptake into vascular smooth muscle cells causes cellular proliferation and secondary arteriolosclerosis that impairs pressure natriuresis, causing sodium-sensitive hypertension. Consistent with the animal model data, small clinical trials performed in adolescents with newly diagnosed essential hypertension demonstrate that at least in certain young patients, reduction of serum uric acid can mitigate blood pressure elevation. While more research is clearly necessary, the available data suggest that uric acid is likely causative in some cases of early-onset hypertension. [ABSTRACT FROM AUTHOR]

Recent studies in both humans and experimental animals have led to renewed interest in uric acid and its association with hypertension, cardiovascular events and renal disease progression. This has also refuelled a longstanding debate regarding the precise role of this ubiquitous breakdown product of purine metabolism in these disease processes. Various lines of evidence suggest that uric acid may have a direct role in the pathogenesis of hypertension and vascular disease. Regardless of this possibility, it is apparent that serum uric acid levels serve as a powerful‘biomarker’ or independent predictor of prognosis and outcome in certain renal, cardiovascular and cerebrovascular diseases. Whether these outcomes can be improved by specifically treating asymptomatic hyperuricaemia remains inadequately resolved at this stage. Data from various animal studies suggests that lowering uric acid levels may be of benefit, but the crucial human studies are still lacking. This review will examine some of the recent evidence supporting a causal and contributory role for uric acid in cardiovascular and renal disease. How clarification of the role of uric acid may guide future treatment strategies will also be discussed. [ABSTRACT FROM AUTHOR]

Background: Optimal management of immunosuppression in kidney transplantation requires a delicate balance of efficacy and toxicity. Tacrolimus (TAC) dose requirements are significantly impacted by genetic variation in CYP3A5 polymorphisms, however the impact that genotype has on clinical outcomes in the pediatric kidney transplant population remains unclear. Methods: We evaluated a retrospective cohort of 98 pediatric kidney transplant recipients. The primary exposure was CYP3A5 genotype, which classified each recipient into the expresser (at least one CYP3A5*1 allele) or non‐expresser group (only CYP3A5*3 alleles). The primary outcome was time to achieve a steady therapeutic TAC concentration. Secondary outcomes include incidence of early allograft rejection and calcineurin inhibitor (CNI) nephrotoxicity during the first year post‐transplant. Results: The study cohort included 55 (56%) expressers and 43 (44%) non‐expressers of the CYP3A5*1 allele. Expressers had a significantly longer time to achieve a steady therapeutic TAC concentration than non‐expressers (log rank, P = 0.03). Expressers had a trend for higher incidence of early allograft rejection (29.1% vs 16.3%, log rank, P = 0.16). Early biopsy‐proven CNI nephrotoxicity was seen in 60% of recipients, with no differences in the rate between expressers and non‐expressers. Conclusions: Pediatric kidney transplant recipients with the CYP3A5*1 allele (expressers) take a longer time to achieve therapeutic TAC levels than those with the CYP3A5*3 allele (non‐expressers). However, we observed no significant differences in acute rejection or CNI nephrotoxicity based on CYP3A5 genotype. Thus CYP3A5 genotype was not observed to have an immediate impact on early transplant outcomes. [ABSTRACT FROM AUTHOR]