Lowering low-density lipoprotein cholesterol has been shown to clearly reduce the risk of atherosclerotic vascular disease in CKD [40]

Lowering low-density lipoprotein cholesterol has been shown to clearly reduce the risk of atherosclerotic vascular disease in CKD [40]. measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in TSPAN2 eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. Results Dantrolene sodium Hemiheptahydrate Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. Conclusions UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD. (%)Number entering run-in566= 414)(%), mean SD or median (interquartile range). CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; LDL, low-density lipoprotein. DISCUSSION The UK HARP-III trial has recruited 414 participants with CKD and will provide information on the short-term effects of sacubitril/valsartan on the change in kidney function (using mGFR) and the tolerability and safety of the drug compared with irbesartan in people with CKD. The trial will also provide information on the effects of sacubitril/valsartan on albuminuria, blood pressure and other biomarkers of both kidney and cardiac function. These results are important because sacubitril/valsartan has now entered routine clinical practice as a treatment for heart failure with reduced ejection fraction (HFrEF) [30], and many of these patients also have CKD. Moreover, NEPi has the potential to be a useful treatment for CKD itself. Large randomized trials of interventions to slow the progression of CKD are required since currently available treatments do not prevent ESRD in all patients with CKD. Although ACEis and ARBs reduce the risk of progression of proteinuric diabetic and non-diabetic kidney disease, their effect (like most medical treatments) is moderate. For example, in Dantrolene sodium Hemiheptahydrate proteinuric diabetic kidney disease, irbesartan reduced the risk of ESRD, doubling of creatinine or death from any cause by 20% compared with placebo hazard ratio [HR] 0.80 [95% confidence interval (CI) 0.66C0.97]; P = 0.02, but this composite outcome still occurred in nearly one-third of those allocated irbesartan (and 14% reached ESRD) during the mean 2.6 years of follow-up [6]. Other strategies to reduce the risk of renal progression have either been ineffective, hazardous or both [31C33]. Neprilysin inhibition appears to be effective in rat models of CKD [15, 16, Dantrolene sodium Hemiheptahydrate 34], but these are poorly predictive of efficacy in humans [35, 36]. In addition, sacubitril/valsartan has been shown to increase albuminuria in trials among patients with heart failure (who typically have very low baseline albuminuria) [18, 20]. NPs (particularly atrial NP) cause afferent arteriolar vasodilatation [37, 38] that may lead to improved intraglomerular pressure and hyperfiltration, which would be detrimental to the kidney. However, NEPi also disturbs degradation of additional vasoactive peptides, so the net effect of NEPi on glomerular haemodynamics is definitely uncertain, and in rat Dantrolene sodium Hemiheptahydrate models at least, it appears to be favourable [15, 16, 34]. NPs may alter glomerular permeability and/or tubular reabsorption of protein, which may lead to albuminuria without hyperfiltration, the consequences of which are uncertain. UK HARP-III is the 1st trial of NEPi in humans with CKD and the measurements of GFR, albuminuria and additional markers of kidney function and damage will help to deal with these uncertainties. Most individuals with CKD do not progress to ESRD [39], but are at high risk of CVD [4]. Decreasing low-density lipoprotein cholesterol offers been shown to clearly reduce the risk of atherosclerotic vascular disease in CKD [40]. However, as renal function declines, the pattern of CVD changes from atherosclerotic disease (i.e. myocardial infarction, ischaemic stroke) to non-atherosclerotic disease (characterized by arteriosclerosis and structural heart disease, which manifests clinically similarly to heart failure, with a high incidence of sudden cardiac death) [4, 41C43], but effective treatments.