fumarates and Renal-Insufficiency--Chronic

The Renin-Angiotensin-Aldosterone System (RAAS) is profoundly involved in the pathogenesis of renal and cardiovascular organ damage, and has been the preferred therapeutic target for renal protection for over 30 years. Monotherapy with either an Angiotensin Converting Enzime Inhibitor (ACE-I) or an Angiotensin Receptor Blocker (ARB), together with optimal blood pressure control, remains the mainstay treatment for retarding the progression toward end-stage renal disease. Combining ACE-Is and ARBs, or either one with an Aldosterone Receptor Antagonist (ARA), has been shown to provide greater albuminuria reduction, and to possibly improve renal outcome, but at an increased risk of potentially severe side effects. Moreover, combination therapy has failed to provide additional cardiovascular protection, and large prospective trials on hard renal endpoints are lacking. Therefore this treatment should, at present, be limited to selected patients with residual proteinuria and high renal risk. Future studies with novel agents, which directly act on the RAAS at multiple levels or have a more favourable side effect profile, are greatly needed to further explore and define the potential for and the limitations of profound pharmacologic RAAS inhibition.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Fumarates; Humans; Hypertension, Renal; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Renin-Angiotensin System

Soon after the emergence of the renin-angiotensin-aldosterone system (RAAS) blocking treatment as the cornerstone of renoprotective treatment in the prevention and treatment of diabetic and nondiabetic CKD, it was investigated if a higher degree of achievable RAAS blockade by combining more than one compound is feasible and advantageous. Regardless of the benefits from using monotherapy for diabetic kidney disease, there is still much improvement to wish for in terms of kidney prognosis in these populations. A great deal of research has gone into evaluating combinations of the RAAS blocking treatments in different populations and with different drugs and doses. Studies have mostly been short-term and use surrogate endpoints such as albuminuria. Side effects have been well known and expected in terms of increasing potassium levels and hypotension, but to an acceptable extent. With recent disappointing results from major hard endpoint trials using dual RAAS blockade the concept is now under scrutiny. In this review we will discuss the pros and cons of dual RAAS blockade, with facts and findings from smaller studies, endpoint trials, and meta-analyses.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Humans; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Risk Assessment; Treatment Outcome

Activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the progression of chronic kidney disease (CKD). RAAS inhibitors, such as angiotensin converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs), decrease the rate of progression of diabetic and non-diabetic nephropathies and are first-line therapies for CKD. Although these agents are highly effective, current therapeutic strategies are unable to sufficiently suppress the RAAS and stop CKD progression. Aliskiren, the first in a new class of RAAS-inhibiting agents (direct renin inhibitors) has been approved to treat hypertension. Aliskiren exerts renoprotective, cardioprotective, and anti-atherosclerotic effects in animal models that appear to be independent of its blood pressure lowering activity. Early clinical studies using urinary protein excretion as a marker of renal involvement suggest a possibly novel role for aliskiren in treating CKD. This review discusses the antiproteinuric efficacy and safety of aliskiren and considers the evidence for its potential renoprotection.

Topics: Amides; Animals; Fumarates; Humans; Kidney; Proteinuria; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of progression of arterial hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD). Previous studies suggested that a direct renin inhibitor, aliskiren, may be effective for blood pressure lowering, renoprotection and cardiovascular protection. This review focuses on the effects of aliskiren for arterial hypertension, CKD and CVD.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renal Insufficiency, Chronic; Renin

For approximately 6 years, the only commercially available direct renin inhibitor, aliskiren, which inhibits the renin-angiotensin-aldosterone system at the initial rate limiting step, has been marketed for the treatment of hypertension. Concurrently, much attention has been given to the possibility that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need for improved treatment and prognosis in these patients. Several short term studies have been performed in diabetic nephropathy, showing a consistent effect on the surrogate endpoint lowering of albuminuria, both as monotherapy and in combination with other blockers of the renin-angiotensin-aldosterone system. In addition, combination treatment also seemed safe and effective in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but was terminated early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic kidney disease by reporting the studies published so far as well as a perspective on the future possibilities.

Topics: Amides; Angiotensin Receptor Antagonists; Animals; Clinical Trials as Topic; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Humans; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Treatment Outcome

Topics: Amides; Blood Pressure; Fumarates; Humans; Kidney; Renal Insufficiency, Chronic; Renin

The self-administered Michigan Neuropathy Screening Instrument (MNSI) is used to diagnose diabetic peripheral neuropathy. We examined whether the MNSI might also provide information on risk of death and cardiovascular outcomes.. In this post hoc analysis of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, we divided 8463 participants with type 2 diabetes and chronic kidney disease (CKD) and/or cardiovascular disease (CVD) into independent training (n = 3252) and validation (n = 5211) sets. In the training set, we identified specific questions that were independently associated with a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction/stroke, heart failure hospitalisation). We then evaluated the performance of these questions in the validation set.. In the training set, three questions ('Are your legs numb?', 'Have you ever had an open sore on your foot?' and 'Do your legs hurt when you walk?') were significantly associated with the cardiovascular composite outcome. In the validation set, after multivariable adjustment for key covariates, one or more positive responses (n = 3079, 59.1%) was associated with a higher risk of the cardiovascular composite outcome (HR 1.54 [95% CI 1.28, 1.85], p < 0.001), heart failure hospitalisation (HR 1.74 [95% CI 1.29, 2.35], p < 0.001), myocardial infarction (HR 1.81 [95% CI 1.23, 2.69], p = 0.003), stroke (HR 1.75 [95% CI 1.20, 2.56], p = 0.003) and three-point major adverse cardiovascular events (MACE) (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) (HR 1.49 [95% CI 1.20, 1.85], p < 0.001) relative to no positive responses to all questions. Associations were stronger if participants answered positively to all three questions (n = 552, 11%). The addition of the total number of affirmative responses to existing models significantly improved Harrell's C statistic for the cardiovascular composite outcome (0.70 vs 0.71, p = 0.010), continuous net reclassification improvement (+22% [+10%, +31%], p = 0.027) and integrated discrimination improvement (+0.9% [+0.4%, +2.1%], p = 0.007).. We identified three questions from the MNSI that provide additional prognostic information for individuals with type 2 diabetes and CKD and/or CVD. If externally validated, these questions may be integrated into the clinical history to augment prediction of CV events in high-risk individuals with type 2 diabetes.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fumarates; Humans; Male; Prognosis; Renal Insufficiency, Chronic; Surveys and Questionnaires

The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

Topics: Aged; Aldosterone; Amides; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Kidney; Kidney Function Tests; Male; Middle Aged; Receptors, Cell Surface; Renal Insufficiency, Chronic; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases; Vascular Stiffness

To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit.. In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression.. The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints).. The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm.

Topics: Aged; Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Male; Middle Aged; Practice Guidelines as Topic; Renal Insufficiency, Chronic; Renin; Risk Factors

This is a report of a clinical trial on the therapeutic efficacy and safety of combined aliskiren and losartan (an angiotensin II receptor blocker (ARB)) versus aliskiren alone and ARB alone in non-diabetic chronic kidney disease (CKD) over a 3-year period.. This was a randomised trial in 155 patients with non-diabetic CKD comparing aliskiren (150 mg/day) (n=52) versus losartan (100 mg/day) (n=52) and the third group aliskiren (150 mg/day) combined with losartan (100 mg/day) (n=51). The trial utilised primary renal end points of eGFR <15 ml/min or end-stage renal failure.. All three groups had significant reduction of proteinuria (p<0.001 for all). The changes in eGFR, total urinary protein from baseline to each year were not significantly different between the three therapeutic groups.. This study in non-diabetic CKD patients showed that combination therapy with aliskiren and ARB was as efficacious as aliskiren alone and ARB alone. There was one patient who developed a non-fatal stroke in the combined aliskiren and ARB group while the other two groups had none.

Topics: Amides; Blood Pressure; Comorbidity; Demography; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Humans; Hyperkalemia; Losartan; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Systole

Pharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) may have a beneficial impact on proteinuria and chronic kidney diseases (CKD) progression. Despite recent progress by means of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), there is still no optimal therapy which can stop progression of the nephropathy. Recently introduced aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. The purpose was to evaluate the extent of oxidative stress and tubular injury after the direct renin inhibitor, aliskiren compared with placebo and perindopril in patients with non-diabetic chronic kidney disease (NDCKD).. A randomized, double-blind, cross-over trial was performed in 14 patients receiving 300mg aliskiren, 10mg perindopril and placebo in random order. The end point was a change in the urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and α1-microglobulin (α1m) and 15-F(2α)-isoprostane.. Aliskiren reduced excretion of 15-F(2α)-isoprostane (p=0.03) and α1m (p=0.01) as compared to placebo. There were no differences between aliskiren and perindopril in this regard. NAG urine excretion did not change after aliskiren and perindopril.. Aliskiren attenuates oxidative stress and may improve functional status of tubules in patients with NDCKD.

Topics: Adult; Amides; Antihypertensive Agents; Cohort Studies; Cross-Over Studies; Double-Blind Method; Female; Fumarates; Humans; Kidney Tubules; Male; Oxidative Stress; Renal Insufficiency, Chronic; Renin

The combination therapy of aliskiren and renin-angiotensin-aldosterone system (RAAS) blocker in chronic kidney disease (CKD) is controversial. Whether such dual blockade can effectively apply to patients with CKD irrespective of stage and amount of proteinuria remains uncertain.. We added aliskiren at a dosage of 150 mg/day for six months in 103 Chinese CKD patients who had been treated with angiotensin converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) and still had significant proteinuria or uncontrolled hypertension. Blood pressure, serum creatinine, estimated glomerular filtration rate (eGFR), potassium, and spot urine protein-to-creatinine ratio (UPCR) were measured at three and six months after aliskiren add-on therapy and compared with baseline.. The combination of aliskiren and ACEi or ARB significantly reduced UPCR by 23% (p=0.001) and mean arterial pressure by 7.9 ± 13.8 mmHg (p<0.001) at six months. Twenty-five percent of subjects had a greater than 50% reduction in UPCR. No significant changes in eGFR and serum potassium level were noted at six months.. Adding aliskiren on ACEi or ARB in CKD patients, both in diabetes and non-diabetes, has a favorable effect on reducing residual proteinuria and inadequately controlled blood pressure.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Creatinine; Demography; Female; Fumarates; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome

An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18) or the benazepril add-on group (n = 18). Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI) was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.

Topics: Aged; Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Cardio-Renal Syndrome; Female; Fumarates; Heart Function Tests; Heart Rate; Humans; Hypertrophy, Left Ventricular; Kidney Function Tests; Male; Oxidative Stress; Renal Insufficiency, Chronic

We aimed to assess the effect of aliskiren treatment on blood pressure, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label study of 67 patients with CKD who were already being treated with other antihypertensives. Inclusion criteria were blood pressure (BP) ≥130/80 mmHg, albuminuria ≥30 mg/g, and estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2). Subjects were treated with 150 mg/day aliskiren, which was increased to 300 mg/day for the 24-week study period. Aliskiren effectively reduced both systolic and diastolic BP, plasma renin activity (PRA), serum aldosterone concentration, albuminuria, urinary N-acetyl-glucosaminidase, and urinary β2-microglobulin levels. Although eGFR was significantly decreased after 4 weeks of aliskiren treatment, it recovered to a pretreatment level within 12 weeks of treatment initiation. There were no significant differences in the percent reduction of albuminuria or changes of eGFR levels when the subjects were divided into three groups on the basis of baseline eGFR (stages 1/2, 3, and 4) and the presence or absence of diabetes mellitus (DM group and non-DM group). Furthermore, in patients not treated with renin-angiotensin-aldosterone-system (RAAS) inhibitors, including angiotensin receptor blockers or angiotensin-converting enzyme inhibitors at baseline, changes in eGFR were significantly increased compared with those already treated with RAAS inhibitors at baseline. Aliskiren administration reduced BP, PRA, serum aldosterone levels, and albuminuria, while maintaining eGFR, regardless of the presence or absence of DM or the degree of eGFR.

Topics: Aged; Albuminuria; Aldosterone; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Japan; Kidney; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

Blockade of the renin-angiotensin-aldosterone system is a therapeutic mainstay in patients with chronic kidney disease (CKD). However, the renoprotective effect of the novel direct renin inhibitor aliskiren is unknown.. We performed a prospective study in 10 CKD patients. All 10 patients with persistent proteinuria (urinary protein-to-creatinin ratio 0.3-3.5 g/g), despite good blood pressure control (<130/80 mmHg) with olmesartan, were started on 150 mg/day aliskiren. Clinical parameters were examined before and after 4, 8, 12, and 16 weeks of treatment.. Urinary protein-to-creatinine ratio significantly decreased by about 40% at 16 weeks from baseline (P = 0.0002), although estimated glomerular filtration rate and blood pressure did not change throughout the study period. Plasma renin activity also decreased significantly from baseline (P = 0.019), although plasma aldosterone concentration did not change.. Aliskiren combined with olmesartan reduces proteinuria in CKD patients.

Topics: Adult; Aldosterone; Amides; Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Creatinine; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Humans; Imidazoles; Male; Middle Aged; Olmesartan Medoxomil; Proteinuria; Renal Insufficiency, Chronic; Renin; Tetrazoles; Young Adult

Pharmacological inhibition of renin-angiotensin-aldosteron system (RAAS) may reduce proteinuria and the rate of chronic kidney disease progression. The aim was to compare the effects on albuminuria of the therapy with either: (i) telmisartan 80 mg and aliskiren 300 mg, (ii) telmisartan 80 mg and eplerenone 50 mg, (iii) telmisartan 160 mg as monotherapy.. Randomized, double-center, double-blind, cross-over, three treatments-three periods of 8 weeks each study. 18 patients with non-diabetic proteinuric CKD stage 1-3 completed the protocol.. There was significant difference in albuminuria between studied therapies (ANOVA; p<0.01). The combination therapy with telmisartan plus aliskiren decreased albuminuria more effectively than the treatment with telmisartan plus eplerenone and monotherapy with telmisartan 160 mg OD [376 mg/g creatinine (286-686) vs. 707 (502-1204) vs. 525 (318-763); post-hoc p<0.01 and p<0.05, respectively].. The study demonstrated that the combination therapy with angiotensin receptor blocker (ARB) and renin inhibitor was more effective in albuminuria lowering than the concomitant usage of ARB and mineralocorticoid receptor antagonist as well as than ARB in doses two-fold higher than usually used in treatment of hypertension in patients with non-diabetic CKD and that this higher antiproteinuric efficacy was independent on changes in blood pressure.

Topics: Adult; Albuminuria; Amides; Angiotensin Receptor Antagonists; Benzimidazoles; Benzoates; Comorbidity; Cross-Over Studies; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Eplerenone; Female; Fumarates; Humans; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Severity of Illness Index; Spironolactone; Telmisartan; Treatment Outcome

To evaluate the proteinuria-lowering effect of a renin inhibitor (aliskiren), compared to placebo and to an angiotensin-converting enzyme inhibitor (perindopril), in patients with non-diabetic chronic kidney disease.. A randomised, double-blind, crossover trial was performed in 14 patients with nondiabetic chronic kidney disease with 24-h mean proteinuria of 2.01 g (95% CI, 1.36–2.66) and estimated creatinine clearance of 93±6.8 ml/min. The study consisted of five treatment periods. The patients were randomly assigned to receive aliskiren (150 mg), aliskiren (300 mg), perindopril (5 mg), perindopril (10 mg) or placebo.. Aliskiren and perindopril reduced proteinuria. These effects were dose-dependent. Furthermore, 24-h proteinuria was reduced by 23% (mean 95% CI; 2–44) by treatment with aliskiren (150 mg), by 36% (95% CI, 17–55; P<0.001) with aliskiren (300 mg), by 7.1% (95% CI, 11–26) with perindopril (5 mg) and by 25% (95% CI, 11–39; P<0.05) with perindopril (10 mg), compared to placebo. No significant difference was found between the effects of aliskiren and perindopril.. Aliskiren significantly reduced proteinuria. The antiproteinuric effect is probably similar to that of perindopril, for equivalent hypotensive dosages. The renin inhibitor provides a promising alternative approach for the treatment of patients with chronic proteinuric non-diabetic kidney disease.

Topics: Adult; Amides; Blood Pressure; Cross-Over Studies; Double-Blind Method; Female; Fumarates; Humans; Male; Proteinuria; Renal Insufficiency, Chronic; Renin

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Female; Fumarates; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System

Chronic kidney disease (CKD) involves significant metabolic abnormalities and has a high mortality rate. Because the levels of serum metabolites in patients with CKD might provide insight into subclinical disease states and risk for future mortality, we determined which serum metabolites reproducibly associate with mortality in CKD using a discovery and replication design. Metabolite levels were quantified via untargeted liquid chromatography and mass spectroscopy from serum samples of 299 patients with CKD in the Modification of Diet in Renal Disease (MDRD) study as a discovery cohort. Six among 622 metabolites were significantly associated with mortality over a median follow-up of 17 years after adjustment for demographic and clinical covariates, including urine protein and measured glomerular filtration rate. We then replicated associations with mortality in 963 patients with CKD from the African American Study of Kidney Disease and Hypertension (AASK) cohort over a median follow-up of ten years. Three of the six metabolites identified in the MDRD cohort replicated in the AASK cohort: fumarate, allantoin, and ribonate, belonging to energy, nucleotide, and carbohydrate pathways, respectively. Point estimates were similar in both studies and in meta-analysis (adjusted hazard ratios 1.63, 1.59, and 1.61, respectively, per doubling of the metabolite). Thus, selected serum metabolites were reproducibly associated with long-term mortality in CKD beyond markers of kidney function in two well characterized cohorts, providing targets for investigation.

Topics: Adult; Aged; Allantoin; Biomarkers; Cause of Death; Cohort Studies; Female; Follow-Up Studies; Fumarates; Humans; Kidney; Male; Metabolomics; Middle Aged; Renal Insufficiency, Chronic

In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade.. Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities.. Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15).. Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Case-Control Studies; Cohort Studies; Diabetes Mellitus; Drug Prescriptions; Drug Therapy, Combination; Female; Fumarates; Germany; Humans; Male; Nursing Homes; Renal Insufficiency, Chronic; Renin-Angiotensin System; Risk Factors

Metabolites in the tricarboxylic acid (TCA) cycle are not only involved in energy metabolism but also play important roles in non-energy production activities.. To study whether baseline urine key TCA cycle metabolites (lactate, pyruvate, citrate, α-ketoglutaric acid, succinate, fumarate, and malate) independently predict risk of chronic kidney disease (CKD) progression [fast estimated glomerular filtration rate (eGFR) decline] in individuals with type 2 diabetes mellitus (T2DM).. One discovery and one validation nested case-control studies in two independent T2DM cohorts.. Subjects with T2DM were recruited and followed in a regional hospital and at a primary care facility.. eGFR trajectory (slope) was estimated by linear regression. Progressive CKD was defined as eGFR decline of ≥5 mL/min/1.73 m2 per year.. As compared with those with stable renal function (n = 271), participants who experienced progressive CKD (n = 116) had a lower level of urine citrate but significantly higher levels of lactate, fumarate, and malate levels at baseline. Both fumarate and malate predicted progressive CKD independent of traditional cardio-renal risk factors, including eGFR and albuminuria. Fumarate interacted with sex (P for interaction = 0.03) and independently predicted progressive CKD in male but not female participants. All these findings were reproducible in a validation study (case n = 96, control n = 402). Exploratory analysis suggested that fumarate might partially mediate the effect of oxidative stress on CKD progression.. Key TCA cycle metabolites, especially fumarate, may be involved in the pathophysiologic pathway independent of traditional cardio-renal risk factors, leading to CKD progression in patients with T2DM.

Topics: Aged; Case-Control Studies; Citrates; Citric Acid Cycle; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Kidney; Lactates; Malates; Male; Middle Aged; Prognosis; Renal Insufficiency, Chronic; Risk Factors

Topics: Amides; Captopril; Female; Fumarates; Humans; Kidney; Magnetic Resonance Imaging; Male; Oxygen; Renal Insufficiency, Chronic; Renin-Angiotensin System

Imaging of the kidney using blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) presents a major opportunity to examine differences in tissue oxygenation within the cortex and medulla applicable to human disease. The aim of this study was to evaluate BOLD signals before and after treatment with RAS inhibitors in hypertensive chronic kidney disease (CKD) patients. Ten patients with stable CKD and 5 healthy volunteers were included. Five CKD patients were subjected to BOLD MRI scan before and after chronic treatment with 300 mg/day aliskiren for at least 6 weeks. Five other CKD patients received BOLD MRI before and 1 hour after acute treatment with 50 mg captopril. A group of healthy volunteers (n=5) was scanned before and 1 hour after acute treatment with 50 mg captopril. The 10 patients had a mean age of 61±17 years; eGFR of 30±11 mL/min per 1.73 m(2) . Office systolic and diastolic blood pressures when on a RAS inhibito, were 130±10 and 86±5 mmHg in CKD patients. Control subjects had normal kidney function and were not on any medication. In untreated condition, systolic and diastolic arterial blood pressure elevated, 145±6 and 95±4 mmHg, respectively. After chronic treatment with aliskiren, arterial blood pressure decreased in all patients in this group, 127±3 mmHg and 77±3 mmHg. After acute treatment with captopril arterial blood pressure reduced to 125±4 and 71±8 mmHg. Tissue intensity signal (T2*) was increased in medulla after chronic treatment from 29±6 to 34±6 and after acute treatment with captopril from 34±9 to 38±11 in CKD patients. In addition, T2* ratio between cortex and medulla decreased in CKD patients after chronic treatment and acute treatment. This ratio remained stable in healthy volunteers before and after treatment with captopril 1.62±0.1 and 1.65±0.1, respectively. This study shows for the first time that RAS inhibitors change BOLD signal in CKD patients. Importantly, in healthy volunteers, a RAS inhibitor had no such effect. Further investigation is required.

Topics: Adult; Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Case-Control Studies; Comorbidity; Feasibility Studies; Female; Fumarates; Humans; Hypertension; Kidney; Magnetic Resonance Imaging; Male; Middle Aged; Oxygen; Pilot Projects; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Treatment Outcome

Most hypertensive dialysis patients are currently treated with angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Aliskiren, the direct renin inhibitor, has not been specifically studied in peritoneal dialysis patients. The aim of the study was to compare hypotensive effects of aliskiren and ramipril and their influence on serum potassium and inflammatory parameters in hypertensive peritoneal dialysis patients. Eighteen hypertensive patients on chronic peritoneal dialysis were enrolled in an open-label comparative fixed-order study. The patients had been off RAAS blocking drugs for ≥4 weeks prior to an inclusion. At each of 3 study visits (baseline and after each of the treatment periods) blood pressure, serum lipids, potassium, renin, aldosterone, C-reactive protein (CRP) and monocyte chemotactic protein-1 (MCP-1) were measured. After the baseline visit aliskiren was started (150 mg/d) and after 12 weeks replaced with ramipril (5 mg/d) for the next 12 weeks. Blood pressure was 142/88±15/11 mmHg at baseline, 137/84±10/8 mmHg after aliskiren (ns) and 126/81±11/7 mmHg after ramipril (p<0.05 vs baseline and aliskiren). No incidents of hyperkalemia were observed. Plasma renin concentration increased significantly during aliskiren treatment compared to ramipril (227,6±844 vs. 58,3±765 pg/mL). CRP was similar after both therapies (8,8±34 vs. 8,4±32 µg/mL) but MCP-1 concentration was significantly lower after aliskiren than after ramipril (294,0±172,6 vs. 358,9±183,3 pg/mL). Aliskiren 150 mg/day decreases blood pressure less effectively than ramipril 5 mg/day in peritoneal dialysis patients. It does not influence serum potassium. The decrease of MCP-1 concentration after aliskiren treatment may provide an indirect evidence for its blood pressure independent cardioprotective and anti-inflammatory effects.

Topics: Adult; Aged; Amides; Anti-Inflammatory Agents; Antihypertensive Agents; Blood Pressure; C-Reactive Protein; Chemokine CCL2; Combined Modality Therapy; Comorbidity; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Peritoneal Dialysis; Pilot Projects; Potassium; Ramipril; Renal Insufficiency, Chronic; Renin; Treatment Outcome

The role of the renin-angiotensin system in chronic kidney disease involves multiple peptides and receptors. Exerting antipodal pathophysiological mechanisms, renin inhibition and AT(1) antagonism ameliorate renal damage. However, it is unclear which mechanism exerts better nephroprotection. We compared the renin inhibitor aliskiren with the AT(1) antagonist losartan in mice with chronic kidney disease due to renal ablation. Doses were adjusted to equipotent inhibition of the renin-angiotensin system, determined via a dose-response quantifying plasma and renal renin expression. Six-week treatment with either 500 mg/l drinking water losartan or 50 mg·kg(-1)·day(-1) aliskiren significantly decreased albuminuria, glomerular damage, and transcription rates of renal injury markers to a similar extent. An array analysis comparing renal gene expression of losartan- and aliskiren-treated mice evaluating >34,000 transcripts demonstrated regulation for 14 genes only, with small differences. No superior nephroprotection was found by combining losartan and aliskiren. Compared with plasma concentrations, aliskiren accumulated ∼7- to 29-fold in the heart, liver, lung, and spleen and ∼156-fold in the kidney. After withdrawal, plasma concentrations dropped to zero within 24 h, whereas renal tissue concentrations declined slowly over days. Withdrawal of aliskiren in mice with chronic kidney disease revealed a significantly delayed re-increase in albuminuria compared with withdrawal of losartan. This study demonstrates equieffective nephroprotection of renin inhibition and AT(1) antagonism in mice with chronic kidney disease without additional benefit of combination therapy. These observations underscore the pivotal role of targeting ANG II to reduce renal injury.

Topics: Albuminuria; Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Dose-Response Relationship, Drug; Fumarates; Gene Expression; Kidney; Losartan; Male; Mice; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Treatment Outcome

The renin-angiotensin-aldosterone system (RAAS) plays an important role in the progression of chronic kidney disease (CKD). Although dual RAAS inhibition results in worse renal outcomes than monotherapy in high risk type 2 diabetes patients, the effect of dual RAAS inhibition in patients with non-DM CKD is unclear. The aim of this study was to evaluate the potential renoprotective effect of add-on direct renin inhibitor in non-DM CKD patients.. We retrospectively enrolled 189 non-DM CKD patients who had been taking angiotensin II receptor blockers (ARBs) for more than six months. Patients were divided into an add-on aliskiren group and an ARB monotherapy group. The primary outcomes were a decline in glomerular filtration rate (GFR) and a reduction in urinary protein-to-creatinine ratio at six months.. The baseline characteristics of the two groups were similar. Aliskiren 150 mg daily reduced the urinary protein-to-creatinine ratio by 26% (95% confidence interval, 15 to 37%; p < 0.001). The decline in GFR was smaller in the add-on aliskiren group (-2.1 vs. -4.0 ml/min, p = 0.038). Add-on aliskiren had a neutral effect on serum potassium in the non-DM CKD patients. In subgroup analysis, the proteinuria-reducing effect of aliskiren was more prominent in patients with a GFR less than 60 ml/min, and in patients with a urinary protein-to-creatinine ratio greater than 1.8. The effect of aliskiren in retarding the decline in GFR was more prominent in patients with hypertensive nephropathy than in those with glomerulonephritis.. Add-on direct renin inhibitor aliskiren (150 mg daily) safely reduced proteinuria and attenuated the decline in GFR in the non-DM CKD patients who were receiving ARBs.

Topics: Adult; Aged; Aged, 80 and over; Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Renin; Retrospective Studies; Treatment Outcome

The complex pathophysiological interactions between heart and kidney diseases are collectively known as cardiorenal syndrome. The renin-angiotensin system (RAS) may have a pivotal role in the development of cardiorenal syndrome. The aim of this study was to elucidate the RAS activity responsible for adverse post-infarction remodeling and prognosis in mice with renal failure. To establish the type IV cardiorenal syndrome model, 5/6 nephrectomy (NTX) was performed in a surgical procedure, followed by the induction of myocardial ischemia (MI) by a coronary artery ligation 4 weeks later. NTX and MI resulted in deteriorated left ventricular remodeling and RAS activation, which was improved by an aliskiren that appeared to be independent of renal function and blood pressure (BP). Moreover, MI induced in renin and angiotensinogen double-transgenic (Tg) mice showed comparable effects to MI plus NTX mice, including advanced ventricular remodeling and enhancement of RAS, oxidative stress, and monocytes chemoattractant protein (MCP)-1. Aliskiren suppressed these changes in the MI-induced Tg mice. In in vitro study, Nox2 expression was elevated by the stimulation of plasma from NTX mice in isolated neonatal cardiomyocytes. However, Nox2 upregulation was negated when we administered plasma from aliskiren-treated-NTX mice or isolated cardiomyocytes from AT1-deficient mice. Primary mononuclear cells also showed an upregulation in the expression of Nox2 and MCP-1 by stimulation with plasma from NTX mice. Our data suggest that renal disorder results in ventricular dysfunction and deteriorates remodeling after MI through excessive RAS activation. Moreover, renin inhibition improved the changes caused by cardiorenal syndrome.

Topics: Amides; Analysis of Variance; Animals; Atrial Natriuretic Factor; Chemokine CCL2; Disease Models, Animal; Fumarates; Humans; Hypertension; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocardium; Nephrectomy; Oxidative Stress; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Ventricular Remodeling

The hyperactivation of renin-angiotensin-aldosterone system (RAAS) underlies the development and the progression of arterial hypertension and chronic kidney diseases. Aldosterone is the main unit of RAAS and self-sufficient predictor of the development of cardiovascular events. In this study, the angiotensin receptor blocker valsartan, ACE inhibitor enalapril, and direct renin inhibitor aliskiren were used for the correction of blood pressure and aldosterone levels in patients with hypertension and chronic kidney diseases. The data obtained suggest that the proposed complex therapy provides the most complete blood pressure reduction and aldosterone level correction (as evidence of RAAS activity recovery), greatly improves the prognoses, and ensures maximum nephroprotection in the patients with arterial hypertension and chronic kidney diseases.

Topics: Aged; Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Drug Therapy, Combination; Enalapril; Female; Fumarates; Humans; Hypertension; Indapamide; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Scleroderma renal crisis (SRC) is an important complication of scleroderma associated with significant morbidity and mortality. Current treatment of patients with SRC focuses on renin-angiotensin-aldosterone system (RAAS) blockade, ideally using angiotensin-converting enzyme inhibitors. We present a case of SRC in a patient established on maximal tolerable RAAS-blocking treatment. Introduction of a selective endothelin-A receptor antagonist followed by a direct renin inhibitor provided excellent blood pressure control and complete abrogation of heavy proteinuria. This was associated with a decrease in kidney function, with serum creatinine level increasing by approximately 30%. This increase is considered acceptable after the introduction of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, is regarded as an indicator of drug efficacy, and confers longer term renal protection. Both endothelin receptor antagonism and direct renin inhibition offer alternate novel therapies for patients with SRC. Their ability to preserve or improve kidney function is unclear.

Topics: Amides; Antihypertensive Agents; Atrophy; Biomarkers; Biopsy; Endothelin Receptor Antagonists; Female; Fibrosis; Fumarates; Humans; Hypertension, Renal; Isoxazoles; Kidney; Middle Aged; Proteinuria; Pulmonary Fibrosis; Renal Insufficiency, Chronic; Renin; Scleroderma, Systemic; Thiophenes; Treatment Outcome