fumarates and Kidney-Failure--Chronic

Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.. To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.. The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.. We included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.. Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.. We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect.  AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Cause of Death; Female; Fumarates; Heart Rate; Humans; Irbesartan; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Myocardial Infarction; Patient Dropouts; Ramipril; Randomized Controlled Trials as Topic; Renin

Non-diabetic glomerulonephritis is a frequent cause of end-stage renal disease. The use of renin-angiotensin-aldosterone system blockers is a fundamental therapeutic approach. However, converting enzyme inhibitors (ACE-is) and angiotensin receptor blockers do not always achieve the desired target of proteinuria. The induction of the prorenin and renin up-regulation is a possible explanation. Aliskiren is the first drug acting as direct inhibitor of plasmatic renin activity, also able to interfere with the prorenin and renin profibrotic escape. We aimed at reviewing the literature for the assessment of potential efficacy and safety of aliskiren in the treatment of non-diabetic glomerulonephritis. The data on this topic are limited; however, we concluded for a possible usefulness of aliskiren. The renal safety profile appears potentially acceptable in non-diabetic patients although extreme carefulness, particularly with respect to long-term renal and cardiovascular tolerability, is recommended.

Topics: Amides; Diabetes Mellitus; Fumarates; Glomerulonephritis; Humans; Kidney Failure, Chronic; Renin; Treatment Outcome

Inhibition of the RAAS (renin-angiotensin-aldosterone system) plays a pivotal role in the prevention and treatment of diabetic nephropathy and a spectrum of other proteinuric kidney diseases. Despite documented beneficial effects of RAAS inhibitors in diabetic patients with nephropathy, reversal of the progressive course of this disorder or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. Incomplete inhibition of the RAAS has been postulated as one of reasons for unsatisfactory therapeutic responses to RAAS inhibition in some patients. Inhibition of renin, a rate-limiting step in the RAAS activation cascade, could overcome at least some of the abovementioned problems associated with the treatment with traditional RAAS inhibitors. The present review focuses on experimental and clinical studies evaluating the two principal approaches to renin inhibition, namely direct renin inhibition with aliskiren and inhibition of the (pro)renin receptor. Moreover, the possibilities of renin inhibition and nephroprotection by interventions primarily aiming at non-RAAS targets, such as vitamin D, urocortins or inhibition of the succinate receptor GPR91 and cyclo-oxygenase-2, are also discussed.

Topics: Amides; Animals; Cyclooxygenase 2 Inhibitors; Diabetic Nephropathies; Fumarates; Humans; Kidney Failure, Chronic; Prorenin Receptor; Receptors, Calcitriol; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System; Urocortins; Vitamin D

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Disease Progression; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fumarates; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Kidney Function Tests; Phosphates; Predictive Value of Tests; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment

ACE inhibitors and angiotensin receptor blockers confer renal protection in proteinuric nephropaties, but recently worsening of renal outcomes has been reported in non-proteinuric patients treated with a combination of ramipril and telmisartan, compared to ramipril only. In view of these apparently contradictory data, the review wants to shed light on treatment modalities of patients with hypertension and chronic kidney disease.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diuretics; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Diseases; Kidney Failure, Chronic; Meta-Analysis as Topic; Natriuresis; Proteinuria; Randomized Controlled Trials as Topic; Water-Electrolyte Imbalance

Chronic kidney failure remains a major health problem worldwide. Although current treatment is focused on the renin-angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment.

Topics: Amides; Anticoagulants; Antihypertensive Agents; Bicarbonates; Chronic Disease; Enzyme Inhibitors; Fumarates; Glycosaminoglycans; Humans; Indoles; Iron Chelating Agents; Kidney Diseases; Kidney Failure, Chronic; Maleimides; Pentoxifylline; Phosphodiesterase Inhibitors; Protein Kinase C; Pyridones; Renin; Renin-Angiotensin System

The three main causes of Chronic Kidney Diseases [CKD] are diabetes mellitus, chronic glomerulonephritis and hypertension. CKD is an increasing burden in the community as more patients fall prey to kidney failure. Both dialysis and renal transplantation are expensive modalities of treatment for end stage renal failure [ESRF]. Through the years many clinical trials have been performed to retard the progression of CKD to ESRF. Most of the trials focus on three main strategies which aim at renal retardation, namely, control of hypertension, treatment of proteinuria and control of hypercholesterolaemia. More recently, investigators have been exploring the role of high dose ARBs as well as the use of Aliskiren, a renin inhibitor. Early therapeutic intervention is necessary as it will contribute to better chances of minimising glomerular damage and in the case of some, even lead to the improvement of renal function with regression of glomerulosclerosis.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Combined Modality Therapy; Drug Therapy, Combination; Fumarates; Humans; Hypercholesterolemia; Hypertension; Kidney Failure, Chronic; Losartan; Proteinuria; Renal Replacement Therapy

Aliskiren represents the first member in a new class of antihypertensive drugs. Inhibiting the renin-angiotensin system at its rate-limiting step is an idea that has been pursued for >30 years; however, earlier compounds failed because of problems related to efficacy, bioavailability, and/or side effects. Aliskiren, a 610 Da nonpeptide molecule, has exceptional affinity for the human renin enzymatic site and a half-life of about 40 h, which make its 3% bioavailability clinically unimportant with continued administration. The drug is not metabolized by CYP P450 enzymes and is excreted >90% unchanged by the fecal route. No adjustments are necessary for renal function, liver function, age, ethnicity, or other prescribed drugs. Blood pressure reductions are similar to those provided by other monotherapies. Interestingly, aliskiren combined with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor therapy leads to a further blood pressure reduction as does combination with a diuretic or calcium channel blocker. The fact that plasma renin activity is reduced to low levels with aliskiren could provide a theoretical advantage over other treatments, while increases in total renin (prorenin) after the drug poses additional food for thought. Studies with primary cardiovascular and renal end points to address these possibilities are in progress.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Humans; Kidney Failure, Chronic; Renin-Angiotensin System

In 21 uraemic subjects not yet requiring dialysis, the serum values of citrate, fumarate, oxalacetate and malate were significantly increased, so that the sum of the concentrations of the TCA-cycle intermediates were increased threefold compared to that of 18 control subjects. The replenishment of TCA intermediates could, in theory, occur by several anaplerotic reactions, mainly those catalysed by pyruvate-carboxylase and malic enzyme. The overall pattern detected in uraemic patients is similar to that observed in rat skeletal muscle during exercise, in which increased acetyl CoA has been found.

Topics: Adult; Chromatography, High Pressure Liquid; Citrates; Citric Acid Cycle; Creatinine; Female; Fumarates; Humans; Kidney Failure, Chronic; Malates; Male; Middle Aged; Oxaloacetates

Extending kidney donor criteria, including donation after circulatory death (DCD), has resulted in increased rates of delayed graft function (DGF) and primary nonfunction. Here, we used Nuclear Magnetic Resonance (NMR) spectroscopy to analyze the urinary metabolome of DCD transplant recipients at multiple time points (days 10, 42, 180, and 360 after transplantation). The aim was to identify markers that predict prolonged duration of functional DGF (fDGF). Forty-seven metabolites were quantified and their levels were evaluated in relation to fDGF. Samples obtained at day 10 had a different profile than samples obtained at the other time points. Furthermore, at day 10 there was a statistically significant increase in eight metabolites and a decrease in six metabolites in the group with fDGF (N = 53) vis-à-vis the group without fDGF (N = 22). In those with prolonged fDGF (≥21 days) (N = 17) urine lactate was significantly higher and pyroglutamate lower than in those with limited fDGF (<21 days) (N = 36). In order to further distinguish prolonged fDGF from limited fDGF, the ratios of all metabolites were analyzed. In a logistic regression analysis, the sum of branched-chain amino acids (BCAAs) over pyroglutamate and lactate over fumarate, predicted prolonged fDGF with an AUC of 0.85. In conclusion, kidney transplant recipients with fDGF can be identified based on their altered urinary metabolome. Furthermore, two ratios of urinary metabolites, lactate/fumarate and BCAAs/pyroglutamate, adequately predict prolonged duration of fDGF.

Topics: Adult; Aged; Amino Acids, Branched-Chain; Area Under Curve; Biomarkers; Delayed Graft Function; Female; Fumarates; Glomerular Filtration Rate; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Lactic Acid; Magnetic Resonance Spectroscopy; Male; Middle Aged; Pyrrolidonecarboxylic Acid; ROC Curve; Time Factors

The primary results of the ALTITUDE trial showed no benefit of aliskiren on renal outcomes (doubling of serum creatinine and end-stage renal disease) when used as an adjunct to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease. We did a prespecified analysis of the ALTITUDE trial to analyse the effects of aliskiren on surrogate renal outcomes in all patients and on primary renal outcomes in subgroups of patients.. In the double-blind, randomised, controlled ALTITUDE trial, 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease were randomly assigned (1:1) to receive aliskiren 300 mg per day or placebo as an adjunct to ACE inhibitors or ARBs. Randomisation was stratified on the basis of baseline urinary albumin-to-creatinine ratio and presence of cardiovascular disease history, and treatment assignments were masked to all patients and study staff. Patients were followed up for a median of 2·6 years (IQR 2·0-3·2). In our secondary analysis, we investigated prespecified intermediate renal outcomes of transitions in albuminuria stages (ie, transitions between normoalbuminuria, microalbuminuria, and macroalbuminuria) and rate of change of estimated glomerular filtration rate (eGFR). We investigated all outcomes in the intention-to-treat population. The primary composite renal outcome of ALTITUDE was defined as a sustained doubling of serum creatinine, end-stage renal disease, or renal death. The ALTITUDE trial is registered with ClinicalTrials.gov, number NCT00549757.. Aliskiren significantly decreased progression (hazard ratio [HR] 0·83, 95% CI 0·75-0·93) and increased regression (HR 1·29, 95% CI 1·19-1·39) of transitions in albuminuria classes. The annual rate of change of eGFR was -3·1 mL/min/1·73 m(2) per year (95% CI -2·9 to -3·3) in the aliskiren group and -3·0 mL/min/1·73 m(2) per year (-2·8 to -3·2) in the placebo group (p=0·52). eGFR change during the first 6 months was significantly larger with aliskiren than with placebo (-2·5 mL/min/1·73 m(2), 95% CI -2·9 to -2·2 vs -1·4 mL/min/1·73 m(2), 95% CI -1·7 to -1·0; p<0·0001). Subsequent eGFR change did not differ significantly between groups (-2·8 mL/min/1·73 m(2) per year, 95% CI -3·0 to -2·6 with aliskiren vs -3·1 mL/min/1·73 m(2) per year, 95% CI -3·3 to -2·8 with placebo; p=0·068). The absence of a benefit of aliskiren on the primary composite renal endpoint in the overall population was also seen in various subgroups.. Aliskiren showed no beneficial effect on hard renal outcomes in the overall population or in various subgroups, but delayed progression to microalbuminuria and macroalbuminuria, and improved regression to microalbuminuria and normoalbuminuria. Whether the chosen intermediates are poor surrogates for clinical outcomes or whether off-target effects disrupt the association between the surrogate and clinical outcomes requires further study.. Novartis.

Topics: Aged; Albuminuria; Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Netherlands; Prevalence; Prognosis; Survival Rate

In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity.. We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria.. Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients.. DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen.

Topics: Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Prospective Studies; Renin; Renin-Angiotensin System; Treatment Outcome

Combination therapy of aliskiren and an angiotensin II receptor blocker (ARB) has been reported to be effective for reducing the level of proteinuria. However, it remains unclear whether this combination therapy contributes to suppression of kidney disease progression. The aim of this study was to investigate the effect of aliskiren on hard renal endpoints, when added to an ARB, in patients with advanced chronic kidney disease (CKD).. The study design was a prospective, randomized open-label design. 83 CKD patients (52 men and 31 women) were enrolled and assigned randomly to an aliskiren add-on group (n = 42) or control group (n = 41). Entry criteria included elevated serum creatinine ≥ 1.5 mg/dl, urine protein excretion (≥ 1+ on urine dipstick test), and hypertension. All participants were treated with an ARB. The follow-up period was 12 months. 12 participants were withdrawn during the study period and the study was terminated in January 2012 as a consequence of the results of the interim analysis of the ALTITUDE study.. Nine patients in the aliskiren group and seven patients in the control group started dialysis. Doubling of the serum creatinine level occurred in one patient in the control group. A Cox proportional hazards test showed that dual blockade of the renin-angiotensin-aldosterone system with aliskiren and ARB was not associated with improvement in hard renal endpoints.. We conclude that aliskiren add-on therapy to an ARB may not give any benefit and, therefore, should not be recommended in CKD patients.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Female; Fumarates; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renin; Treatment Outcome

Applying a direct renin inhibitor (DRI) to advanced stage chronic kidney disease (CKD) patients is a matter of controversy. The purpose of this study was to evaluate the effect of the DRI, aliskiren, in patients with therapy-resistant hypertension undergoing hemodialysis (HD).. The study was a prospective, randomized multicenter trial exploring the antihypertensive effect of aliskiren in comparison with amlodipine, a calcium channel blocker, in patients undergoing HD. A total of 83 participants whose blood pressure (BP) had previously been treated with more than one antihypertensive agent and not having achieved the BP goal of <140/90 mmHg were randomly assigned to either aliskiren 150 mg or amlodipine 5 mg as an add-on therapy.. A significant decrease in pre-dialysis clinic BP and home BP was found only in the amlodipine group and not in the aliskiren group. In contrast, there was a significant decrease in atrial natriuretic peptide (ANP) in the aliskiren group but not in the amlodipine group. N-terminal pro-B-type natriuretic hormone remained unchanged in both groups. Aliskiren significantly reduced angiotensin I and II, plasma renin activity, and increased plasma renin content. However, such changes were not observed in the amlodipine group.. Amlodipine, not aliskiren, effectively reduces BP in CKD patients with refractory hypertension undergoing HD. Aliskiren suppresses the renin-angiotensin system and reduces ANP. Whether the DRI is beneficial in improving cardiovascular events in patients undergoing HD remains to be elucidated in future studies.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Female; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

The renin-angiotensin-aldosterone system is not necessarily suppressed in end-stage renal disease patients undergoing dialysis. Of all the inhibitors of this system, the clinical efficacy of the renin inhibitor, aliskiren, has not been well demonstrated in dialysis patients. We evaluated the antihypertensive effect of aliskiren, administered as a single daily dose of 150 mg for 24 weeks, in 23 chronic hemodialysis patients (age 65 ± 12 years, 15 men and eight women) with blood pressure ≥140/90 mm Hg, and assessed the factors relating to blood pressure reduction. At 4 weeks, the average systolic blood pressure before the dialysis session was insignificantly reduced from 163 ± 10 mm Hg to 160 ± 15 mm Hg, while it was significantly lowered at 12 (154 ± 13 mm Hg) and 24 weeks (155 ± 10 mm Hg), although the pulse rate was not significantly altered. Serum K increased at 24 weeks from 4.9 ± 0.6 mEq/L to 5.2 ± 0.8 mEq/L. Only 10 out of 23 patients showed systolic blood pressure reduction by ≥10 mm Hg. Naturally, plasma renin immunoreactivity increased, while plasma renin activity, along with angiotensin II and aldosterone levels decreased. Basal levels of the components of the renin-angiotensin-aldosterone system were not significantly different in patients showing systolic blood pressure reduction by ≥10 mm Hg (n = 10) vs. those with <10 mm Hg changes (n = 13). The reduction in systolic blood pressure in all 23 patients taken as a whole correlated with changes in plasma renin activity (r = -0.432, P < 0.05) and angiotensin II (r = 0.467, P < 0.05). In chronic hemodialysis patients, aliskiren modestly lowers blood pressure over the long term, although the antihypertensive effect seems dependent on the changes, but not on the basal levels of plasma renin activity and angiotensin II.

Topics: Aged; Amides; Angiotensin II; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

Tubular injury is more important than glomerulopathy for renal prognosis in chronic kidney disease (CKD) patients. Numerous studies have demonstrated the active participation of the renin-angiotensin system (RAS) in CKD. However, whether addition of aliskiren, a direct renin inhibitor, to olmesartan improves renal tubular injury in CKD patients is unknown.. This study compared the effects of aliskiren (300 mg daily), olmesartan (40 mg daily), and its combination therapy on urinary L-fatty acid binding protein (L-FABP), a marker of tubular injury in stage I or II CKD patients. It also examined which clinical variables were independently correlated with tubular damage.. Olmesartan or aliskiren monotherapy for 6 months comparably decreased blood pressure (BP) and proteinuria. BP and proteinuria levels were reduced more by combination therapy than by either monotherapy. Olmesartan or aliskiren decreased urinary L-FABP level, and combination therapy produced more incremental reduction in L-FABP level relative to each monotherapy. Multiple stepwise regression analysis revealed that BMI, low-density lipoprotein (LDL)-cholesterol and proteinuria were independently related to urinary L-FABP level.. The present study demonstrated that addition of aliskiren to olmesartan decreased urinary L-FABP level partly via reduction of proteinuria in stage I or II CKD patients.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fatty Acid-Binding Proteins; Female; Fumarates; Humans; Imidazoles; Kidney Failure, Chronic; Kidney Tubules; Male; Proteinuria; Regression Analysis; Tetrazoles

Aliskiren represents a novel class of orally active renin inhibitors. This study analyses the pharmacokinetics, tolerability and safety of single-dose aliskiren inpatients with end-stage renal disease (ESRD) undergoing haemodialysis.. Six ESRD patients and six matched healthy volunteers were enrolled in an open-label, parallel-group, single-sequence study. The ESRD patients underwent two treatment periods where 300 mg of aliskiren was administered 48 or 1 h before a standardized haemodialysis session (4 h, 1.4 m(2) high-flux filter, blood flow 300 mL/min, dialysate flow 500 mL/min). Washout was >10 days between both periods. Blood and dialysis samples were taken for up to 96 h postdose to determine aliskiren concentrations.. Compared with the healthy subjects (1681 ± 1034 ng·h/mL), the area under the plasma concentration-time curve (AUC) from time zero to infinity was 61% (haemodialysis at 48 h) and 41% (haemodialysis at 1 h) higher in ESRD patients receiving single-dose aliskiren 300 mg. The maximum (peak) plasma drug concentration (481 ± 497 ng/mL in healthy subjects) was 17% higher (haemodialysis at 48 h) and 16% lower (haemodialysis at 1 h). In both treatment periods, dialysis clearance was below 2% of oral clearance and the mean fraction eliminated from circulation was 10 and 12% in period 1 and 2, respectively. Drug AUCs were similar in ESRD patients receiving aliskiren 1 or 48 h before dialysis. No severe adverse events occurred.. The exposure of aliskiren is moderately higher in ESRD patients. Only a minor portion is removed by a typical haemodialysis session. Aliskiren exposure is not significantly affected by intermittent haemodialysis, suggesting that no dose adjustment is necessary in this population.

Topics: Administration, Oral; Adult; Amides; Blood Pressure; Drug Administration Schedule; Fumarates; Humans; Hypertension; Hypoglycemic Agents; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin

The renin-angiotensin-aldosterone system (RAAS) has pivotal roles in the pathogenesis of hypertension in hemodialysis-dependent chronic kidney disease (HDD-CKD) patients. Activated RAAS also increases inflammatory mediators by directly increasing proinflammatory gene expression and by putting oxidative stress on the vascular endothelium. Both hypertension and inflammation are major risk factors for cardiovascular disease (CVD) in HDD-CKD patients. In this study, we assessed the efficacy of a direct renin inhibitor, aliskiren, on blood pressure (BP) and CVD predictive biomarkers, such as brain natriuretic peptide (BNP), high-sensitivity C-reactive protein (hs-CRP) and diacron-reactive oxygen metabolite (d-ROM). A total of 30 hypertensive HDD-CKD patients were assigned to receive aliskiren (150 mg) orally once daily with their existing antihypertensives. After 8 weeks, aliskiren treatments reduced systolic blood pressure (SBP) from 169.0±20.1 to 153.7±19.6 mmHg (P<0.001) and diastolic blood pressure (DBP) from 78.1±12.0 to 73.0±13.6 mmHg (P=0.048). RAAS was suppressed by aliskiren treatment as follows: PRA (from 3.6±4.0 to 1.0±1.5 ngml(-1)h(-1) (P=0.004)), angiotensin I (from 1704.0±2580.9 to 233.7±181.0 pgml(-1) (P=0.009)), angiotensin II (from 70.2±121.5 to 12.4±11.5 pgml(-1) (P=0.022)) and aldosterone (from 107.9±148.0 to 73.1±34.6 pgml(-1) (NS)). The biomarkers for CVD were inhibited by aliskiren: BNP (from 362.5±262.1 to 300.0±232.0 pgml(-1) (P=0.043)), hS-CRP (from 6.2±8.1 to 3.5±3.7 mgl(-1) (P=0.022)) and d-ROM (from 367.0±89.8 to 328.3±70.9 U.CARR (P=0.022)). The inhibition levels of biomarkers for CVD by aliskiren did not correlate with the decreased levels of SBP and DBP. These results suggested that aliskiren was effective for BP control and may have cardiovascular protective effects in hypertensive HDD-CKD patients.

Topics: Aged; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Renal Dialysis; Renin; Renin-Angiotensin System; Treatment Outcome

This case represents an individual with accelerating hypertension and declining kidney function associated with atherosclerotic renal artery stenosis. Key features include loss of GFR (reaching stage V CKD) during intensified antihypertensive drug therapy including agents that block the renin-angiotensin system and failure to appreciate the extent to which moderate renal artery stenosis was affecting his better kidney. Interpretation of duplex ultrasound studies was complicated by a discrepancy between near-normal peak systolic velocities and markedly abnormal segmental arterial waveforms. It was essential to recognize that both kidneys were abnormal and focus on recovery of perfusion to the better of these kidneys. Successful revascularization of one kidney allowed major improvement in GFR and BP control.

Topics: Aged; Amides; Antihypertensive Agents; Atherosclerosis; Atrophy; Blood Pressure; Carbazoles; Carvedilol; Disease Progression; Drug Therapy, Combination; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Propanolamines; Renal Artery Obstruction; Stents; Teaching Rounds

Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, P<0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, P<0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.

Topics: Amides; Animals; Antihypertensive Agents; Caspase 3; Collagen Type I; Disease Models, Animal; Female; Fibrosis; Fumarates; Glucuronidase; Ischemia; Kidney; Kidney Failure, Chronic; Klotho Proteins; Mice; Mice, Inbred Strains; Renal Artery; Renin; Surgical Instruments

We report a case of acute kidney injury (AKI) caused by a novel direct renin inhibitor, aliskiren. A 43-year-old Japanese man with dilated cardiomyopathy on cardiac resynchronization therapy with defibrillator and chronic kidney disease (CKD) was started on aliskiren in addition to enalapril, carvedilol, furosemide, and spironolactone for worsening cardiac function suggested by the elevation of serum brain natriuretic peptide. After 1 month, he noticed general malaise, loss of appetite and his serum creatinine level increased from 2.0 to 7.24 mg/dL. He had no evidence of exacerbation of hemodynamic instability (heart failure or hypotension) or post-renal cause of AKI. Although a cessation of aliskiren did not ameliorate AKI, renal function returned to baseline after withholding enalapril. Careful monitoring is necessary when aliskiren is used in patients with CKD and/or significant systolic dysfunction since it can cause normotensive ischemic AKI, especially when there is a concomitant use of other renin-angiotensin-aldosterone system inhibitors.

Topics: Acute Kidney Injury; Adult; Amides; Antihypertensive Agents; Cardiomyopathy, Dilated; Fumarates; Humans; Kidney Failure, Chronic; Male; Natriuretic Peptide, Brain

Topics: Amides; Animals; Female; Fumarates; Ischemia; Kidney; Kidney Failure, Chronic; Renin

Aliskiren, a novel direct renin inhibitor, is hypothesized to inhibit the renin-angiotensin- system. This study attempted to provide insight into this mechanism by examining the antihypertensive and renoprotective effects of aliskiren in hypertensive chronic kidney disease (CKD) patients.. After recruitment, 43 hypertensive CKD patients (mean age, 53.7 years) began treatment of aliskiren. The patients were classified into high (over 30 mL/min/1.73 m(2)) estimated glomerular filtration rate (eGFR) group or low (under 30 mL/min/1.73 m(2)) eGFR group for comparison of measurements of various parameters over the 6-month observation period.. Systolic blood pressure/diastolic blood pressure of 150 mg/day group decreased to an average of 126.8 ± 21.6 mmHg/69.3 ± 15.1 mmHg (average decrease: -7.4/-8.3 mmHg) over the 6-month observation period, while that of 300 mg/day group significantly decreased to an average of 133.5 ± 14.0 mmHg/71.5 ± 11.7 mmHg (average decrease: -21.1/-14.6 mmHg). Urinary protein of all patients decreased slightly and insignificantly to 1.1 ± 1.7 g/gCr from 1.4 ± 2.5 g/gCr. The serum creatinine (Cr) level of all patients decreased from 1.81 ± 1.10 mg/dL to 1.78 ± 0.82 mg/dL. Although the serum Cr level of the high eGFR group decreased from 1.28 ± 0.45 mg/dL to 1.27 ± 0.57 mg/dL, that of the low eGFR group slightly but insignificantly increased from 2.49 ± 0.64 mg/dL to 2.69 ± 1.11 mg/dL.. Administration of aliskiren exerts an antihypertensive effect on hypertensive CKD patients that may lead to a decrease in urinary protein and an improvement in renal functioning.

Topics: Aged; Amides; Blood Pressure; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Japan; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Renin; Renin-Angiotensin System; Treatment Outcome

Hypertensive chronic kidney disease (CKD) patients often have sympathetic hyperactivity. In this pilot study, we evaluated the effect of 6 weeks treatment with aliskiren on sympathetic activity in hypertensive Stages 2-4 CKD patients.. In 10 CKD patients (8 males, aged 44 ± 11 years, estimated glomerular filtration rate ( 57 ± 22 mL/min/1.73 m(2)), blood pressure and sympathetic activity [quantified by assessment of muscle sympathetic nerve activity (MSNA)] were assessed, while taken off renin-angiotensin blocker, and during the 6 weeks of treatment with aliskiren 300 mg/day. Ten other CKD patients served as control and were studied twice with an interval of 6 weeks without any change in medication, to quantify within subject reproducibility.. In the aliskiren study group, MSNA was reduced from 36 ± 8 to 26 ± 8 bursts/min (P = 0.01). Aliskiren lowered supine systolic and diastolic blood pressure from 147 ± 10 to 120 ± 8 and from 96 ± 7 to 83 ± 7 mmHg, respectively (both P < 0.05). MSNA changed in patients treated with aliskiren [-9.6 bursts/min with 95% confidence interval (CI) -4.0 to -15.0; P-value = 0.003] but not in controls (-0.7 bursts/min with 95% CI -2.2 to 4.0; P-value = 0.6). The mean difference in change between aliskiren group and the control group was -8.9 with 95% CI of -15 to -3; P = 0.005.. In hypertensive CKD patients, 6 weeks aliskiren treatment lowers blood pressure and MSNA (Clinical trial government identifier number: NCT00719316).

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Case-Control Studies; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Prognosis; Survival Rate; Sympathetic Nervous System

Hypertensive chronic kidney disease (CKD) patients often have sympathetic hyperactivity, which appears to contribute to the pathogenesis of hypertension and cardiovascular organ damage. Experimental studies and some clinical studies have shown that statin therapy can reduce central sympathetic activity. Blockade of the renin-angiotensin system (RAS), which is standard treatment for CKD, is known to lower sympathetic activity. We hypothesized that adding a statin for 6 weeks to RAS blockade would further lower sympathetic activity in hypertensive stage 2-4 CKD patients.. In 10 stable CKD patients (eight men, aged 45 ± 11 years, estimated glomerular filtration rate 56 ± 22 ml/min per 1.73 m2), who were on chronic treatment with aliskiren 300 mg, blood pressure and sympathetic activity (quantified by assessment of muscle sympathetic nerve activity, MSNA) were assessed at baseline and 6 weeks after atorvastatin 20 mg/day was added. Ten other CKD patients served as time control and were studied twice with an interval of 6 weeks without any change in medication, to quantify within participant reproducibility.. Mean arterial blood pressure remained stable throughout the study (93 ± 5 versus 94 ± 5 mmHg). MSNA was reduced from 28 ± 8 to 20 ± 6 bursts/min (P = 0.01), while heart rate remained stable during the study. In the control CKD group, MSNA did not change: 26 ± 5 to 25 ± 6 bursts/min. Atorvastatin reduced total and low-density lipoprotein cholesterol.. Atorvastatin has a further sympatholytic effect in CKD patients, who are on chronic aliskiren, which is independent of blood pressure and heart rate.

Topics: Adult; Amides; Arteries; Atorvastatin; Blood Pressure; Case-Control Studies; Female; Fumarates; Glomerular Filtration Rate; Heart Rate; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Failure, Chronic; Male; Middle Aged; Pyrroles; Sympathetic Nervous System; Sympatholytics; Time Factors

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Myocardial Infarction; Patient Readmission; Renin; Renin-Angiotensin System; Treatment Outcome

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Renin-Angiotensin System