Renal Targeted Therapies of Antihypertensive and Cardiovascular Drugs for Patients With Stages 3 Through 5d Kidney Disease.

The prevalence of chronic kidney disease (CKD) has risen remarkably over the past decades, and the number of patients with CKD is expected to continue to grow significantly in the next 10 years. The mean global prevalence of CKD was estimated to be 14.8% in the latest United States Renal Data System (USRDS) 2016 report, making CKD an important public health problem that has encompassed diabetes mellitus in prevalence. 45% of patients with CKD have Stage 3 disease, defined as an estimated glomerular filtration rate (eGFR) of 30-59 mL/min.

Resting heart rate is associated with renal disease outcomes in patients with vascular disease: results of the ONTARGET and TRANSCEND studies.

BACKGROUND: Resting heart rate (RHR) is associated with cardiovascular disease outcomes in high-risk patients. It is not known whether RHR is predictive of renal outcomes such as albuminuria, end-stage renal disease (ESRD) or doubling of creatinine. We evaluated whether RHR could predict renal endpoints in patients at a high risk of cardiovascular disease. We also tested the effects of RHR at different levels of systolic blood pressure (SBP). METHODS: We analysed data from 28 757 patients in the ONTARGET and TRANSCEND trials. RHR and SBP were available for a mean of 4.9 ± 0.4 visits (range 3-5) within the first 2 years of the studies. Albuminuria was determined at baseline, at 2 years and at study end. RESULTS: Mean RHR was predictive of incident micro-albuminuria [hazard ratio (HR) for RHR ≥80 vs. <60 beats min(-1) 1.49, 95% confidence interval (CI) 1.29-1.71, P < 0.0001], incident macro-albuminuria (HR 1.84, 95% CI 1.39-2.42, P < 0.0001), doubling of creatinine (HR 1.47, 95% CI 1.00-2.17, P = 0.050) and ESRD (HR 1.78, 95% CI 1.00-3.16, P = 0.050), and the combined renal end-point (HR 1.51, 95% CI 1.32-1.74, P < 0.0001). Associations were robust at SBPs from <120 to ≥150 mmHg, with the lowest risk at a SBP of 130-140 mmHg. CONCLUSION: Resting heart rate is a potent predictor of these renal outcomes, as well as their combination, in patients with cardiovascular disease. RHR at all SBP levels should be considered as a possible renal disease risk predictor and should be investigated as a treatment target with RHR-reducing agents.

Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease.

AIM: This study evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and within a subset of Stage 3 chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] ≥ 30 and <50 ml/min/1.73 m(2)). METHODS: In this 52-week, randomized, double-blind, placebo-controlled study, patients (N = 269; mean eGFR, 39.4 ml/min/1.73 m(2)) received canagliflozin 100 or 300 mg and placebo once daily. Efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and systolic blood pressure (BP); adverse events (AEs) were also recorded. RESULTS: At week 52, canagliflozin 100 and 300 mg reduced HbA1c compared with placebo (-0.19, -0.33 and 0.07%, respectively); placebo-subtracted differences (95% confidence interval) were -0.27% (-0.53, 0.001) and -0.41% (-0.68, -0.14). Canagliflozin also lowered FPG, body weight and BP versus placebo. Overall AE incidence was 85.6, 80.9, and 86.7% with canagliflozin 100 and 300 mg and placebo, respectively. Osmotic diuresis-related AEs were more common with both canagliflozin doses, and incidences of urinary tract infections and volume depletion-related AEs were higher with canagliflozin 300 mg versus placebo. Decreases in eGFR (-2.1, -4.0 and -1.6 ml/min/1.73 m(2)) were seen with canagliflozin 100 and 300 mg compared with placebo. Canagliflozin 100 and 300 mg provided median percent reductions in urine albumin to creatinine ratio versus placebo (-16.4, -28.0 and 19.7%). CONCLUSIONS: Canagliflozin improved glycaemic control and was generally well tolerated in patients with T2DM and within a subset of Stage 3 CKD over 52 weeks.

Sorafenib dose escalation is not uniformly associated with blood pressure elevations in normotensive patients with advanced malignancies.

Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects.

Antihypertensive efficacy of the angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril.

Drug therapy often fails to control hypertension. Azilsartan medoxomil (AZL-M) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability. This double-blind, controlled, randomised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril (RAM) in patients with clinic systolic blood pressure (SBP) 150-180 mm Hg. Patients were randomised (n=884) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks, then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks. The primary endpoint was change in trough, seated, clinic SBP. Mean patient age was 57±11 years, 52.4% were male, 99.5% were Caucasian. Mean baseline BP was 161.1±7.9/94.9±9.0 mm Hg. Clinic SBP decreased by 20.6±0.95 and 21.2±0.95 mm Hg with AZL-M 40 and 80 mg vs12.2±0.95 mm Hg with RAM (P<0.001 for both AZL-M doses). Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg (2.4% and 3.1%, respectively) than with RAM (4.8%). These data demonstrated that treatment of stage 1-2 hypertension with AZL-M was more effective than RAM and better tolerated.

Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease.

AIMS: Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m(2)]. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated. RESULTS: Both canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (-0.33, -0.44 and -0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin. CONCLUSION: Canagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD.

Effects of combining simvastatin with rosiglitazone on inflammation, oxidant stress and ambulatory blood pressure in patients with the metabolic syndrome: the SIROCO study.

AIM: Individually, statins and thiazolidinediones (TZDs) show positive effects on atherosclerosis progression in cellular and animal models as well as patients with diabetes; however, their combined effects have not been studied. This study examines the effects of simvastatin combined with rosiglitazone on vascular inflammation, oxidant stress, ambulatory blood pressure (BP) and other atherosclerotic factors in patients with the metabolic syndrome. METHODS: This is a randomized, double blind, placebo-controlled study in 53 subjects with the metabolic syndrome. Participants were randomized to simvastatin 40 mg/day plus placebo vs. simvastatin 40 mg/day plus rosiglitazone 4 mg/day for 6 months. The primary endpoint was the between-group difference in high-sensitivity C-reactive protein (hs-CRP) and secondary variables including urinary isoprostanes, serum malondialdehyde (MDA), ambulatory BP, adiponectin, and lipid and glycaemic profiles. RESULTS: At study end, the group randomized to the simvastatin/rosiglitazone combination had a greater reduction in hs-CRP of 1.33 mg/dl, (p = 0.029) and showed a trend for a greater reduction in urinary isoprostane (-39%), (p = 0.056) compared to simvastatin/placebo group. Changes in MDA levels did not differed between groups (p = 0.81). 24-h systolic blood pressure (SBP) also showed a 4.5 mmHg reduction at 6 months (p = 0.06). Adiponectin levels increased by 3.91 µg/ml in the combination group over placebo, (p = 0.03) and blood glucose decreased in combination group vs. placebo. CONCLUSION: Our data show that patients with the metabolic syndrome given a statin/TZD combination manifest greater reductions in markers of vascular inflammation and oxidant stress, 24-h ambulatory BP and increases in adiponectin as well as improved glycaemic indices.

Limitations of metformin use in patients with kidney disease: are they warranted?

AIM: To show that metformin, one of the most widely used agents, is contraindicated in patients with diabetes having chronic kidney disease (CKD) (i.e. serum creatinine >1.5 mg/dl) secondary to fear of lactic acidosis. The overall incidence of lactic acidosis is estimated at an upper limit of eight cases per 100 000 patient-years. We evaluated metformin use in two cohorts, one from the University of Chicago Diabetes Center and the other from National Health and Nutrition Examination Survey (NHANES) 1999-2006. METHODS: Estimated glomerular filtration rate (eGFR) was calculated using the re-expressed Modification of Diet in Renal Disease (MDRD) Study equation and compared to serum creatinine. We hypothesized that metformin is used in patients with undetected advanced CKD (i.e. serum creatinine is ≥1.5 mg/dl). A chi-squared test was used to compare per cent differences of metformin use across demographic variables and eGFR in the NHANES cohort. RESULTS: At the University of Chicago Diabetes Center, 36 of 234 (15.3%) patients with an eGFR of <60 ml/min/1.73 m(2) were receiving metformin. Data from NHANES, age >18 years and eGFR <60 ml/min/1.73 m(2) showed that Blacks with advanced nephropathy were three times more likely to receive metformin. CONCLUSIONS: We conclude that metformin utilization occurs with a higher frequency than predicted by serum creatinine in people with eGFR <60 ml/min/1.73 m(2) . Given the very low incidence of lactic acidosis, the recommendation should be changed to reflect eGFR cut-off values rather than serum creatinine.

Cardiovascular risk modification in participants with coronary disease screened by the Kidney Early Evaluation Program.

BACKGROUND: Coronary artery disease (CAD) identifies the need for intensive treatment of risk factors among individuals with chronic kidney disease (CKD), a high-risk, complex cardiovascular risk state. METHODS: An estimated glomerular filtration rate<60 mL/min/1.73 m2 or a urine albumin:creatinine ratio (ACR)≥30 mg/g (3.4 mg/mmol) defined CKD. RESULTS: Of 70,454 volunteers screened the mean age was 53.5±15.7 years and 68.3% were female. A total of 5410 (7.7%) had a self-reported history of CAD; 1295 (1.8%) had a history of prior percutaneous coronary intervention (PCI); and 1124 (1.6%) had a prior history of coronary artery bypass surgery (CABG). Multivariate analysis for the outcome of suboptimal CAD risk management (composite of systolic blood pressure≥130 mmHg, glucose≥125 mg/dL (6.9 mmol/L) for diabetics, total cholesterol≥200 mg/dL (5.2 mmol/L), or current smoking; n=38,746/53,403, 72.5%) revealed older age (per year) (odds ratio (OR)=1.04, 95% confidence interval (CI) 1.03-1.04, P<0.0001), male gender (OR=1.40, 95% CI 1.34-1.47, P<0.0001), ACR≥30 mg/g (3.4 mg/mmol) (OR=1.66, 95% CI 1.55-1.79, P<0.0001), body mass index (per kg/m2) (OR=1.06, 95% CI 1.06-1.06, P<0.0001), CAD without a history of revascularization (OR=1.14, 95% CI 1.02-1.28, P=0.02) and care received by a nephrologist (OR=1.49, 95% CI 1.22-1.83, P<0.0001) were associated with worse risk factor control. Prior coronary revascularization and being under the care of a cardiologist were not associated with either improved or suboptimal risk factor control. CONCLUSIONS: Chronic kidney disease is associated with overall poor rates of CAD risk factor control.

The message for World Kidney Day 2009: hypertension and kidney disease--a marriage that should be prevented.

The prevalence of chronic kidney disease (CKD) continues to increase worldwide as does end stage renal disease. The most common, but not the only, causes of CKD are hypertension and diabetes. CKD is associated with a significant increase in cardiovascular (CV) risk as most patients with CKD die of a CV cause. Moreover, CV risk increases proportionally as eGFR falls below 60 ml min(-1). CV causes of death in CKD are more prevalent than those from cancer are; as a result, the identification and reduction of CKD is a public health priority. High blood pressure is a key pathogenic factor that contributes to the deterioration of kidney function. The presence of kidney disease is a common and underappreciated pre-existing medical cause of resistant hypertension. Therefore, treatment of hypertension has become the most important intervention in the management of all forms of CKD. For this reason, the forthcoming World Kidney Day on 12 March 2009 will emphasize the role of hypertension.

Comparison of carvedilol and metoprolol on serum lipid concentration in diabetic hypertensive patients.

CONTEXT: Vasoconstricting beta-blocker use is associated with a reduction in HDL cholesterol, higher triglyceride, total cholesterol and LDL cholesterol levels, whereas carvedilol, a vasodilating beta-blocker, has not been associated with these effects. OBJECTIVE: To compare in a randomized, double-blind study, the effects of the beta 1-blocker metoprolol tartrate with the combined alpha 1, beta-blocker carvedilol on serum lipid concentrations. METHODS: A prospective randomized, double-blind, parallel-group trial compared the effects of carvedilol and metoprolol on total cholesterol, triglycerides, calculated LDL, HDL and non-HDL cholesterol levels at baseline and after 5 months of therapy as a secondary objective in the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensive (GEMINI) study. In this study, 1235 participants with type 2 diabetes and hypertension who were receiving renin-angiotensin system blockers were randomized either to carvedilol, receiving 6.25-25 mg twice daily, or to metoprolol tartrate, receiving 50-200 mg twice daily. If needed, hydrochlorothiazide and a dihydropyridine calcium channel blocker were added to achieve blood pressure goals. RESULTS: In the metoprolol tartrate group, triglycerides and non-HDL cholesterol increased and both the LDL and the HDL cholesterol levels decreased. In the carvedilol group, total LDL and HDL cholesterol decreased, non-HDL cholesterol was unchanged and triglycerides increased. Comparing the carvedilol and metoprolol tartrate groups, there was no statistically significant difference in LDL and HDL cholesterol levels, but there was a significantly greater decreases with carvedilol in total cholesterol [-2.9%, 95% confidence interval (CI) -4.60 to -1.15, p < 0.001], triglycerides (-9.8%, 95% CI -13.7, -5.75%, p < 0.001) and non-HDL cholesterol (-4.03%, 95% CI -6.3 to -1.8, p < 0.0006). At the end of the study, significantly more participants in the metoprolol tartrate group had had initiation of statin therapy or the statin dose increased than those in the carvedilol group (11 vs. 32%, p = 0.04). CONCLUSIONS: In patients with type 2 diabetes currently receiving a renin-angiotensin blocker, compared with metoprolol tartrate, the addition of carvedilol for blood pressure control resulted in a significant decrease in triglyceride, total cholesterol and non-HDL cholesterol levels. The use of metoprolol resulted in a significantly greater rate of initiation of statin therapy or an increase in the dose of existing statin therapy when compared with carvedilol utilization.

Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study.

Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes. Dihydropyridine calcium channel blockers, however, may lower blood pressure but not albuminuria in these patients. Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics. We conducted a double blind randomized controlled trial on 332 hypertensive, albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year. The trial employed a non-inferiority design. Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort. The percentage of patients progressing to overt proteinuria was similar for both groups. When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria. We conclude that initial treatment using benzaepril with a diuretic resulted in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker. In contrast, blood pressure reduction, particularly the diastolic component, favored the combination with amilodipine. The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure.

Calcium antagonists: Do they equally protect against kidney injury?

Calcium antagonists are a heterogeneous group of drugs that affect not only different channels but different parts of the same channel. These differences translate into different renal hemodynamic effects. This Commentary discusses the implications of these differences for surrogate markers of outcome.

N-terminal prohormone brain natriuretic peptide as a predictor of cardiovascular disease and mortality in blacks with hypertensive kidney disease: the African American Study of Kidney Disease and Hypertension (AASK).

BACKGROUND: Higher levels of N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) predict cardiovascular disease (CVD) in several disease states, but few data are available in patients with chronic kidney disease or in blacks. METHODS AND RESULTS: The African American Study of Kidney Disease and Hypertension trial enrolled hypertensive blacks with a glomerular filtration rate of 20 to 65 mL x min(-1) x 1.73 m(-2) and no other identified cause of kidney disease. NT-proBNP was measured with a sandwich chemiluminescence immunoassay (coefficient of variation 2.9%) in 994 African American Study of Kidney Disease and Hypertension participants. NT-proBNP was categorized as undetectable, low, moderate, or high. Proteinuria was defined as 24-hour urinary protein-creatinine ratio >0.22. A total of 134 first CVD events (CVD death or hospitalization for coronary artery disease, heart failure, or stroke) occurred over a median of 4.3 years. Participants with high NT-proBNP were much more likely to have a CVD event than participants with undetectable NT-proBNP after adjustment (relative hazard 4.0 [95% confidence interval [CI] 2.1 to 7.6]). A doubling of NT-proBNP was associated with a relative hazard of 1.3 (95% CI 1.0 to 1.6) for coronary artery disease, 1.7 (95% CI 1.4 to 2.2) for heart failure, 1.1 (95% CI 0.9 to 1.4) for stroke, and 1.8 (95% CI 1.4 to 2.4) for CVD death. The association of NT-proBNP with CVD events was significantly stronger (P(interaction)=0.05) in participants with than in those without proteinuria. Higher NT-proBNP was not associated with renal disease progression. CONCLUSIONS: These results suggest that elevated NT-proBNP levels are associated with higher CVD risk among blacks with hypertensive kidney disease. This association may be stronger in individuals with significant proteinuria.