Renin-angiotensin-aldosterone System Blockers Research Articles

Intensity of hydration changes the role of renin-angiotensin-aldosterone system blockers in contrast-induced nephropathy risk after coronary catheterisation in patients with chronic kidney disease.

Objective:This study evaluated the potential effect of hydration intensity on the role of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on contrast-induced nephropathy in patients with renal insufficiency.Methods:All eligible patients were included and stratified according to hydration intensity defined as saline hydration volume to body weight tertiles: <10.21 mL/kg, 10.21 to <17.86 mL/kg, and ⩾17.86 mL/kg.Results:In total, 84 (6.7%) of 1254 patients developed contrast-induced nephropathy: 6.2% in the ACEI/ARB group versus 10.8% in the non-ACEI/ARB group (P=0.029), with an adjusted odds ratio (OR) of 0.89 (95% confidence interval (CI) 0.46–1.73, P=0.735). The incidence of contrast-induced nephropathy was lower in the ACEI/ARB group than in the non-ACEI/ARB group in the second tertile (P=0.031), while not significantly different in the first (P=0.701) and third (P=0.254) tertiles. ACEIs/ARBs were independently associated with a lower contrast-induced nephropathy risk (OR 0.26, 95% CI 0.09–0.74, P=0.012) and long-term all-cause death (hazard ratio 0.461, 95% CI 0.282–0.755, P=0.002) only in the second hydration volume to body weight tertile.Conclusion:The effects of ACEIs/ARBs on contrast-induced nephropathy risk vary according to saline hydration intensity in chronic kidney disease patients, and may further reduce contrast-induced nephropathy risk in patients administered moderate saline hydration.

Combination therapy with lercanidipine and enalapril in the management of the hypertensive patient: an update of the evidence.

Hypertension is an important risk factor for premature death as it increases the probability of stroke, myocardial infarction, and heart failure. Antihypertensive drugs can decrease cardiovascular (CV) morbidity and mortality. The majority of hypertensive patients need more than one antihypertensive agent to attain blood pressure (BP) targets. Monotherapy can effectively reduce BP only in 20%–40% of patients. Multiple mechanisms including increased peripheral vascular resistance, increased cardiac work, and hypervolemia are involved in the pathogenesis of hypertension. Targeting multiple pathways may more potently reduce BP. Increasing the dose of a single agent in many cases does not provide the expected BP-lowering effect because the underlying mechanism of the BP increase is either different or already corrected with the lower dose. Moreover, drugs acting on different pathways may have synergistic effects and thus better control hypertension. It is well known that diuretics enhance the actions of renin–angiotensin aldosterone system and activate it as a feedback to the reduced circulated blood volume. The addition of a renin–angiotensin aldosterone system blocker to a diuretic may more effectively reduce BP because the system is upregulated. Reducing the maximal dose of an agent may also reduce possible side effects if they are dose dependent. The increased prevalence of peripheral edema with higher doses of calcium channel blockers (CCBs) is reduced when renin–angiotensin aldosterone system blockers are added to CCBs through vein dilation. The effectiveness of the combination of enalapril with lercanidipine in reducing BP, the safety profile, and the use of the combination of angiotensin-converting enzyme inhibitors with CCBs in clinical trials with excellent CV hard end point outcomes make this combination a promising therapy in the treatment of hypertension.

Risk Factors of Recurrence of Diabetic Nephropathy in Renal Transplants

BackgroundRenal transplantation has been established as the treatment of choice for end-stage renal disease (ESRD) due to diabetic nephropathy. This study aimed to investigate the risk factors for recurrence of diabetic nephropathy (RDN) in renal allografts. MethodsWe studied 1,011 renal transplant patients from 1986 to 2003, of which 95 had ESRD due to diabetic nephropathy. We retrospectively analyzed the clinical characteristics and outcomes of RDN after renal transplantation. ResultsOf the 95 recipients with ESRD due to diabetic nephropathy, 41 developed RDN and 11 of those 41 underwent graft biopsy. The mean durations from transplantation to RDN and to renal replacement therapy was 81.58 months (range, 54–120 mo), and 109.66 months (range, 27–188.4 mo), respectively. At 5 years, treatment on statins and renin-angiotensin-aldosterone system (RAAS) blockers were associated with a higher survival free from RND (82.2% vs 63.2% [P = .070] and 100% vs 80% vs 0.6% [P = .013], respectively). Compared with cyclosporine, tacrolimus was associated with a higher risk for RND (odds ratio [OR], 4.27; 95% confidence interval [CI], 1.75–5.13; P = .047). High doses of prednisone (>0.06 mg/kg) were also associated with a higher risk of RDN (OR, 3.03; 95% CI, 1.19–8.30; P = .029). The combination of calcineurin inhibitor and mammalian target of rapamycin inhibitor (mTORi) demonstrated the highest risk of RDN (OR, 14.08; 95% CI, 3.72–53.29; P < .01). ConclusionsTreatment with tacrolimus and mTORi is the most diabetogenic immunosuppressive regimen. Treatment with tacrolimus entails a greater risk of RDN than with cyclosporine. The administration of statins or RAAS blockers could delay the progression of RDN.

Effects and Safety of Linagliptin as an Add-on Therapy in Advanced-Stage Diabetic Nephropathy Patients Taking Renin–Angiotensin–Aldosterone System Blockers

Abstract non disponibile

A high sodium intake reduces antiproteinuric response to renin–angiotensin–aldosterone system blockade in kidney transplant recipients

BackgroundPost-transplant proteinuria is associated with lower graft and patient survival. Renin–angiotensin–aldosterone system blockers are used to reduce proteinuria and improve renal outcome. Although it is known that a high salt intake blunts the antiproteinuric effect of ACEI and ARB drugs in non-transplant patients, this effect has not been studied in kidney transplant recipients. ObjectiveTo analyse the relationship between sodium intake and the antiproteinuric effect of ACEI/ARB drugs in kidney transplant recipients. MethodsWe selected 103 kidney transplant recipients receiving ACEI/ARB drugs for more than 6 months due to proteinuria >1g/day. Proteinuria was analysed at baseline and at 6 months after starting ACEI/ARB treatment. Salt intake was estimated by urinary sodium to creatinine ratio (uNa/Cr). ResultsProteinuria fell to less than 1g/day in 46 patients (44.7%). High uNa/Cr was associated with a smaller proteinuria decrease (r=−0.251, p=0.011). The percentage of proteinuria reduction was significantly lower in patients in the highest uNa/Cr tertile [63.9% (IQR 47.1%), 60.1% (IQR 55.4%), 38.9% (IQR 85.5%), p=0.047]. High uNa/Cr independently relates (OR 2.406 per 100mEq/g, 95% CI: 1.008–5.745, p=0.048) to an antiproteinuric response <50% after renin–angiotensin–aldosterone system blockade. ConclusionsA high salt intake results in a smaller proteinuria decrease in kidney transplant recipients with proteinuria treated with ACEI/ARB drugs.

SY 12-2 ACE INHIBITORS AND ARBS

Blockade of the renin-angiotensin-aldosterone system (RAAS) can be accomplished at the level of the angiotensin-generating enzymes renin and angiotensin-converting enzyme (ACE; using renin inhibitors or ACE inhibitors), the type 1 angiotensin II (AT1) receptor or mineralocorticoid receptor (MR; using angiotensin receptor blockers [ARBs] or MR blockers) and/or renin release (using beta-blockers). Several of these drugs are often combined-for example in heart failure-but such approaches may ultimately lead to RAAS annihilation with adverse consequences such as hypotension, renal dysfunction and hyperkalaemia. The biochemical consequences of each type of blockade are different. For instance, ACE inhibitors will lower angiotensin II, thus no longer allowing stimulation of both AT1 and type 2 angiotensin II (AT2) receptors, while ARBs raise angiotensin II, allowing selective stimulation of the unoccupied AT2 receptor. This might be of particular importance in women, in whom the protective AT2 receptor pathway is believed to be upregulated. Multiple clinical trials have compared the various types of RAAS blockers and/or their combination. This talk will summarize the current evidence with regard to similarities and differences between ACE inhibitors and ARBs, also considering their side-effect profile, dose and combination with other RAAS blockers.

Aldosterone is associated with left ventricular hypertrophy in hemodialysis patients.

Patients with chronic kidney disease present a higher degree of left ventricular hypertrophy than expected for hypertension levels. In chronic kidney disease the plot between the quotient extracellular water/total body water and aldosterone is shifted up and to the right. There are few studies that verified the role of aldosterone in cardiac remodeling in this set of patients. The aim of this study was to evaluate the relationship between serum aldosterone and left ventricular mass index in patients with chronic kidney disease on hemodialysis. The patients were submitted to clinical and laboratory evaluation, bioelectrical impedance, echocardiography and ambulatory blood pressure monitoring. The 27 patients included were divided into two groups according to aldosterone level and compared with each other. The group of patients with higher aldosterone levels had higher left ventricular mass index. These groups were heterogeneous with regard to ambulatory systolic blood pressure, body mass index, and aldosterone levels and homogeneous with regard to the quotient extracellular water/total body water, renin-angiotensin-aldosterone system blockers, beta blocker use and other clinical characteristics. The association between aldosterone levels and left ventricular mass index was adjusted to confounding variables by a multiple linear regression analysis in which aldosterone was independently associated with left ventricular mass index. The data presented are consistent with a pathogenic role of aldosterone in left ventricular hypertrophy in patients with chronic kidney dialysis in dialysis patients. ClinicalTrials.gov identifier: NCT01128101.

Short- and long-term effects of the use of RAAS blockers immediately after renal transplantation

Background: The efficacy and safety of renin angiotensin aldosterone system blockers (RAASB’s) if introduced immediately after renal transplantation have not been extensively investigated.Methods: The medical charts of 142 kidney transplant recipients who received a RAASB in the early postoperative period and of 114 matched controls were analyzed. The RAASB was given primarily for blood pressure control.Results: 117 patients continued to receive and 50 controls remained continuously free of the RAASB in the first year. The RAASB was added on average at postoperative day 8 and the mean duration of follow-up was 5.4 years. Systolic, blood pressure at treatment initiation was increased in the RAASB group (150 ± 17 vs. 141 ± 16, p < 0.001). At discharge from hospital and during follow-up blood pressure was similar in both groups, without differences in GFR, potassium and proteinuria. The endpoints “graft failure” and “graft failure or death from any cause” were significantly better in patients treated with RAASB’s (p = 0.03 and p = 0.04, respectively). The treatment effects in the RAASB group persisted even after adjustment for demographic parameters, immunological risk factors, peritransplant risk factors, duration of dialysis prior to transplantation and medical comorbidities.Conclusions: Thus, RAASB’s can be used effectively and safely to treat hypertension in the early postoperative period after kidney transplantation and are renoprotective in the long term.

Effects and Safety of Linagliptin as an Add-on Therapy in Advanced-Stage Diabetic Nephropathy Patients Taking Renin-Angiotensin-Aldosterone System Blockers.

BACKGROUNDWe investigated the effects and safety of linagliptin as an add-on therapy in patients with advanced-stage diabetic nephropathy (DMN) taking renin–angiotensin–aldosterone system (RAAS) blockers.METHODTwenty advanced-stage DMN patients (estimated glomerular filtration rate (eGFR): 24.5 ± 13.4 mL/min/1.73 m2) taking RAAS blockers were administered 5 mg/day linagliptin for 52 weeks. Changes in glucose and lipid metabolism and renal function were evaluated.RESULTSLinagliptin decreased glycosylated hemoglobin levels (from 7.32 ± 0.77% to 6.85 ± 0.87%, P < 0.05) without changing fasting blood glucose levels, and significantly decreased total cholesterol levels (from 189.6 ± 49.0 to 170.2 ± 39.2 mg/dL, P < 0.05) and low-density lipoprotein cholesterol levels (from 107.1 ± 32.4 to 90.2 ± 31.0 mg/dL, P < 0.05) without changing high-density lipoprotein cholesterol and triglyceride levels. Urine protein/creatinine ratio and annual change in eGFR remained unchanged. No adverse effects were observed.CONCLUSIONLinagliptin as an add-on therapy had beneficial effects on glucose and lipid metabolism without impairment of renal function, and did not have any adverse effects in this population of patients with advanced-stage DMN taking RAAS blockers.

Early intensive treatment improves outcomes in patients with glomerular hyperfiltration and type 2 diabetes

Background and objectiveApproximately 24•40% of patients with type 2 diabetes mellitus (T2DM) develop kidney damage. Our objective was to evaluate the long-term evolution of renal function using isotopic determination of GFR and urinary albumin excretion (UAE) in patients with T2DM undergoing intensive treatment for renal and cardiovascular risk factors. Patients and methodsThis was a single-center, prospective study of 201 patients with T2DM and UAE who initiated intensive treatment. They were followed for 17.2±6.5 years. Patients were divided into three groups, according to renal function: 167(85.6%) had stable renal function, 16(8.2%) had creatinine levels that doubled and 12(6.2%) began renal replacement therapy (RRT). We performed periodic isotopic determinations of GFR using 125I-iothalamate. ResultsThere were significant differences between the three groups with respect to age, duration of T2DM at baseline, years of follow-up in the study and systolic blood pressure, serum creatinine, isotopic GFR, and UAE at baseline. Renal function evolution slopes were ∧1.55mL/min/1.73m2/year in patients with stable creatinine, ∧2.49mL/min/1.73m2/year in those with doubled creatinine, and ∧8.16mL/min/1.73m2/year in those requiring RRT. We also found that differences in renal events were determined by delayed initiation of intensive treatment. ConclusionPatients with glomerular hyperfiltration who were undergoing treatment with renin angiotensin aldosterone system blockers exhibited a better evolution in renal function, possibly because these patients initiated intensive treatment earlier. Although diabetic nephropathy is associated with classic risk factors, early initiation of intensive treatment should be a priority in order to prevent worsening renal function.

β遮断薬およびrenin–angiotensin–aldosterone系拮抗薬によってsteroid療法から離脱し得たFontan手術後タンパク漏出性腸症の2自験例

Fontan循環における肺循環へ血液を拍出する心室を欠く特殊性による中心静脈圧（CVP）の上昇，心拍出量低下はタンパク漏出性腸症（PLE）の発症要因と考えられている．我々は開窓部閉塞を契機にPLEを発症し，prednisolone（PSL）による寛解後，直ちに血行動態を評価し血管拡張療法を強化したところ，寛解を維持したままPSLを中止し得た2症例を経験したので報告する．2症例ともPLE寛解直後のカテーテル検査で心係数（CI）と右室駆出率（RVEF）の低下，体血管抵抗（SVR）と右室の拡張能を表すと考えられる右室拡張末期圧（RVEDP）/CIの上昇が認められた．右室拡張障害の改善を主目的としてβ遮断薬（BB），アンギオテンシン変換酵素阻害薬（ACEi），アンギオテンシンII受容体拮抗薬（ARB），spironolactone（SPL）の併用療法を強化したところ，PSL中止時にはSVR, RVEDP/CIは低下しCI, RVEFは改善していた．PLE発症には心拍出量低下への反応であるSVR上昇と，それによる体循環心室機能低下が関与するものと推測された．また，交感神経系抑制薬とrenin–angiotensin–aldosterone（RAA）系抑制薬の併用療法は，Fontan手術後に発症するPLE治療の一選択肢と考えられた．

Renin–angiotensin–aldosterone system blockers for heart failure with reduced ejection fraction or left ventricular dysfunction: Network meta-analysis

BackgroundRenin–angiotensin–aldosterone system (RAAS) blockers are effective therapies for heart failure and reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVD). We aimed to assess the efficacy and safety of RAAS blockers in these patients. MethodsWe searched MEDLINE, EMBASE, and Cochrane Library in May 2015. Twenty-one double-blind randomized controlled trials (RCTs) with 69,229 patients were included this network meta-analysis. ResultsCompared with placebo, an angiotensin receptor–neprilysin inhibitor (ARNI) had the highest probability of reducing all-cause mortality (odds ratio [OR]=0.67, 95% credible interval [CrI]: 0.48–0.86), followed by an aldosterone receptor antagonist (ARA, OR=0.74, 95% CrI: 0.62–0.88) and an angiotensin-converting enzyme inhibitor (ACEI, OR=0.80, 95% CrI: 0.71–0.89). The most efficacious therapy for preventing heart failure hospitalization was ARNI (OR=0.55, 95% CrI: 0.40–0.71), followed by combination therapy with an angiotensin II receptor blocker (ARB) plus an ACEI (OR=0.61, 95% CrI: 0.49–0.75), then an ACEI alone (OR=0.69, 95% CrI: 0.61–0.77). Sensitivity analysis restricted to nine RCTs with a high background use of ACEI and/or ARB (>80%) indicated that adding an ARA to current standard therapy significantly reduced mortality (OR=0.73, 95% CrI: 0.51–0.95) and hospitalization risk (OR=0.67, 95% CrI: 0.47–0.87), but did not significantly increase the discontinuation risk (OR=1.29, 95% CrI: 0.83–2.31). ConclusionsARNI has the highest probability of being the most efficacious therapy for HFrEF in reducing death and hospitalization for heart failure. ARA has the most favorable benefit–risk profile as an adjunct to background ACEI and/or ARB therapy.

The clinical profile of women with stable ischemic heart disease in Spain. More effort is needed in secondary prevention. SIRENA study

ObjectivesCardiovascular diseases are the leading cause of death for women, especially ischemic heart disease, which is still considered a man's disease. In Spain, there are various registries on ischemic heart disease, although none are exclusively for women. The objectives of the SIRENA study were to describe the clinical profile of women with ischemic heart disease treated in cardiology consultations, to estimate its prevalence of cardiovascular risk factors and understand its clinical management. Patients and methodsA multicentre observational study was conducted with a sample of 631 women with stable ischemic heart disease, consecutively included during cardiology consultations. Forty-one researchers from all over Spain participated in the study. ResultsThe mean age was 68.5 years. The clinical presentation was in the form of acute coronary syndrome in up to 67.2% of the patients. The prevalence of cardiovascular risk factors was high (77.7% of the patients had hypertension, 40.7% had diabetes and 68% had dyslipidaemia), with 30.7% having uncontrolled hypertension, 78.4% having LDL-cholesterol levels higher than 70mg/dL and 49.2% having HbA1c levels greater than 7%. The considerable majority of the patients underwent optimal medical treatment with antiplatelet agents, beta-blockers, renin–angiotensin–aldosterone system blockers and hypolipidaemic agents. Coronary angiography was performed for 88.3% of the patients, and 63.4% underwent percutaneous coronary intervention. ConclusionsWomen with stable ischemic heart disease in Spain initially present some form of acute coronary syndrome and a high prevalence of inadequately controlled cardiovascular risk factors, despite undergoing optimal medical therapy. A high percentage of these women undergo coronary revascularisation. Increased efforts are required for secondary prevention in women with stable ischemic heart disease.

Renin-Angiotensin-Aldosterone System Blockers in Elderly Adults with Chronic Kidney Disease without Diabetes Mellitus or Proteinuria.

To compare the effect of renin-angiotensin-aldosterone system (RAAS) blockers with that of other antihypertensive agents on outcomes in a cohort of elderly veterans with incident chronic kidney disease (CKD) without diabetes mellitus or proteinuria. Retrospective cohort study. Veterans Affairs (VA) Upstate New York Healthcare System. All participants were seen in primary care clinic in Veterans Integrated Service Network 2, which comprises five VA medical centers and 29 community-based outpatient clinics, from April 2001 to April 2008. Veterans with incident CKD who were taking antihypertensive medications and did not have proteinuria or diabetes mellitus on the date of onset of CKD were selected from this population. The outcome variables studied were progression of kidney disease (doubling of serum creatinine level or Stage 5 CKD (estimated glomerular filtration rate <15mL/min per 1.73m2 )), all-cause mortality, and combined outcome. Analysis included 2,474 participants, 47.9% of whom were taking RAAS blockers at baseline and the rest other antihypertensives. Time-varying Cox proportional hazards analyses did not reveal a statistically significant difference in primary combined outcome in participants taking RAAS blockers and those taking other antihypertensives (hazard ratio=1.09, 95% confidence interval=0.93-1.27). There was also no significant effect on individual outcomes (death or progression of kidney disease). Use of RAAS blockers was not associated with less hazard of combined and individual outcomes (doubling of serum creatinine, Stage 5 CKD, death) in elderly veterans with incident CKD without diabetes mellitus or proteinuria.

Динамика показателей структурно-функционального состояния сердца, сосудов, почек и содержания в крови ренина и альдостерона при лечении блокаторами ренин-ангиотензин-альдостероновой системы больных гипертонической болезнью с сопутствующим хроническим пиел

SUMMARY. The dynamics of indicators of structural and functional state of the heart, blood vessels, kidneys and neurohumoral status in patients with essential hypertension (EH) 1 degree with concomitant chronic pyelonephritis (CRD) and chronic heart failure (CHF) II functional class (FC) with preserved left ventricular ejection fraction (LVEF) of the heart was studied. It is proved that the treatment of hypertensive patients with chronic renal failure 1 degree and CHF FC II by renin-angiotensin-aldosterone system (RAAS) blockers – angiotensin-converting enzyme (ACE) inhibitors spirapril a daily dose of 3 mg, candesartan in a daily dose of 16-24 mg, combination ACE inhibitors spirapril a daily dose of 3 mg and direct renin inhibitor aliskiren in a daily dose of 150 mg – leads to reliable comparable increases in distance of the 6-minute walk test, LVEF, endothelium-dependent vasodilation (EDVD), glomerular filtration rate (GFR) and reliable reducing the size of the left atrium, end-diastolic diameter (EDD) and end-systolic diameter (ESD), the mean pulmonary artery pressure (PASP), aldosterone and daily albuminuria. The efficacy of antihypertensive therapy in patients with EH 1 degree with chronic CKD and heart failure class II combination of ACE inhibitors spirapril and direct renin inhibitor aliskiren during 14 weeks exceeds the effects of monotherapy with ACE inhibitors and is accompanied by a significantly greater reduction in the EDD, myocardial mass index, plasma aldosterone blood significantly greater increases in GFR, EDVD and decreased plasma renin activity with an increase in the latter during treatment with ACE inhibitors. KEY WORDS: RAAS blockers, spirapril, hypertension, chronic pyelonephritis, chronic heart failure.

Beneficial long-term effect of aldosterone antagonist added to a traditional blockade of the renin–angiotensin–aldosterone system among patients with obesity and proteinuria

IntroductionOver the past decade, obesity has become a risk factor for developing chronic kidney disease. Proteinuria is known to be an independent determinant of the progression of chronic kidney disease, and adipose tissue is a recognized source of components of the renin–angiotensin–aldosterone system (RAAS). Recent studies have shown that plasma aldosterone levels are disproportionately higher in patients with obesity. Drugs that block the RAAS are unable to inhibit aldosterone in the long term. The aim of our study was to analyze the renoprotective effect of an aldosterone antagonist in combination with RAAS blockers in patients with obesity and proteinuric nephropathy. Material and methodsThis study is a substudy of previously published study on the renoprotective effect of mineralocorticoid receptor blockers in patients with proteinuric nephropathies. Patients with proteinuria levels >1g/24h who were taking spironolactone and were being treated with other RAAS blockers were divided according to body mass index (BMI) into an obesity group (BMI ≥30kg/m2) and a control group. ResultsSeventy-one patients were included in the study, with a mean age of 56.7±15.1 years. More than 50% of the patients in both groups had diabetes. Thirty-two patients were included in the obesity group and 39 were included in the control group. There were no significant differences in renal function, proteinuria, blood pressure, serum potassium levels and the percentage of RAAS blockers in both groups. After a follow-up of 28.9 (14–84) months, there was a 59.4% reduction in proteinuria in the obesity group (2.8±2.1 vs. 1.3±1.6g/24h, p<.05). The reduction in proteinuria was greater than 50% in 22 (68.8%) cases, and the mean blood pressure showed a significant decrease (from 100.6±9 to 92.1±7.4mm Hg, p<.05). The control group showed a 69.6% reduction in proteinuria (1.9±1.4 to 0.8±0.5, p<0.05). The reduction of proteinuria was higher than 50% in 22 (68.8%) cases in obese patients and in 33 (84.6%) cases in non-obese group. Renal function remained stable in both groups during the follow-up. Nine patients (28.1%) in the obesity group experienced gynecomastia. The incidence of hyperkalemia was similar for the 2 groups (6.3%). ConclusionAldosterone antagonist treatment in obese patients with proteinuric nephropathies induces a drastic and sustained reduction in proteinuria but not more than the non-obese group. There was a trend toward slowing progression of renal failure with few adverse events.

Beneficial long-term effect of aldosterone antagonist added to a traditional blockade of the renin–angiotensin–aldosterone system among patients with obesity and proteinuria

IntroductionOver the past decade, obesity has become a risk factor for developing chronic kidney disease. Proteinuria is known to be an independent determinant of the progression of chronic kidney disease, and adipose tissue is a recognized source of components of the renin–angiotensin–aldosterone system (RAAS). Recent studies have shown that plasma aldosterone levels are disproportionately higher in patients with obesity. Drugs that block the RAAS are unable to inhibit aldosterone in the long term. The aim of our study was to analyze the renoprotective effect of an aldosterone antagonist in combination with RAAS blockers in patients with obesity and proteinuric nephropathy. Material and methodsThis study is a substudy of previously published study on the renoprotective effect of mineralocorticoid receptor blockers in patients with proteinuric nephropathies. Patients with proteinuria levels >1g/24h who were taking spironolactone and were being treated with other RAAS blockers were divided according to body mass index (BMI) into an obesity group (BMI ≥30kg/m2) and a control group. ResultsSeventy-one patients were included in the study, with a mean age of 56.7±15.1 years. More than 50% of the patients in both groups had diabetes. Thirty-two patients were included in the obesity group and 39 were included in the control group. There were no significant differences in renal function, proteinuria, blood pressure, serum potassium levels and the percentage of RAAS blockers in both groups. After a follow-up of 28.9 (14–84) months, there was a 59.4% reduction in proteinuria in the obesity group (2.8±2.1 vs. 1.3±1.6g/24h, p<.05). The reduction in proteinuria was greater than 50% in 22 (68.8%) cases, and the mean blood pressure showed a significant decrease (from 100.6±9 to 92.1±7.4mm Hg, p<.05). The control group showed a 69.6% reduction in proteinuria (1.9±1.4 to 0.8±0.5, p<0.05). The reduction of proteinuria was higher than 50% in 22 (68.8%) cases in obese patients and in 33 (84.6%) cases in non-obese group. Renal function remained stable in both groups during the follow-up. Nine patients (28.1%) in the obesity group experienced gynecomastia. The incidence of hyperkalemia was similar for the 2 groups (6.3%). ConclusionAldosterone antagonist treatment in obese patients with proteinuric nephropathies induces a drastic and sustained reduction in proteinuria but not more than the non-obese group. There was a trend toward slowing progression of renal failure with few adverse events.

Early intensive treatment improves outcomes in patients with glomerular hyperfiltration and type 2 diabetes

Background and objectiveApproximately 24–40% of patients with type 2 diabetes mellitus (T2DM) develop kidney damage. Our objective was to evaluate the long-term evolution of renal function using isotopic determination of GFR and urinary albumin excretion (UAE) in patients with T2DM undergoing intensive treatment for renal and cardiovascular risk factors. Patients and methodsThis was a single-center, prospective study of 201 patients with T2DM and UAE who initiated intensive treatment. They were followed for 17.2±6.5 years. Patients were divided into three groups, according to renal function: 167(85.6%) had stable renal function, 16(8.2%) had creatinine levels that doubled and 12(6.2%) began renal replacement therapy (RRT). We performed periodic isotopic determinations of GFR using 125I-iothalamate. ResultsThere were significant differences between the three groups with respect to age, duration of T2DM at baseline, years of follow-up in the study and systolic blood pressure, serum creatinine, isotopic GFR, and UAE at baseline. Renal function evolution slopes were −1.55mL/min/1.73m2/year in patients with stable creatinine, −2.49mL/min/1.73m2/year in those with doubled creatinine, and −8.16mL/min/1.73m2/year in those requiring RRT. We also found that differences in renal events were determined by delayed initiation of intensive treatment. ConclusionPatients with glomerular hyperfiltration who were undergoing treatment with renin angiotensin aldosterone system blockers exhibited a better evolution in renal function, possibly because these patients initiated intensive treatment earlier. Although diabetic nephropathy is associated with classic risk factors, early initiation of intensive treatment should be a priority in order to prevent worsening renal function.

Renin angiotensin system blockers-associated angioedema in the Thai population: analysis from Thai National Pharmacovigilance Database

Renin-angiotensin-aldosterone system (RAS) blockers are commonly used for cardiovascular diseases. Currently, little information exists for the Asian population on angioedema, a rare yet serious adverse event. This study aimed to describe characteristics of RAS blockers-associated angioedema (RASBA) in Thai patients. A retrospective study using the national pharmacovigilance database of Thailand was undertaken. Cases indicating the presence of angioedema with RAS blockers uses from 1984-2011 were identified. Patient demographics, co-morbidities, concomitant drugs, information for the RAS blockers and angioedema were obtained as well as causality assessment and quality of reports. A total of 895 cases were identified. Mean age was 59.9+12.8 years and 66.5% being female. Most angioedema events (48.6%) occurred during the first week of treatment. Angiotensin converting enzyme inhibitors (87.7%) were the most commonly implicated agents followed by angiotensin receptor blockers (10.5%), aldosterone antagonist (2.1%) and direct renin inhibitor (0.2%). Out of the 895 cases incorporated in this study, 165 (18.4%) were classified as serious events and resulted in hospitalization. The overall case fatality rate was 0.4%. Respiratory disturbance occurred in 46 cases (5.1%). Patients with respiratory complications tended to be younger (53.4+13.9 vs 60.3+12.7 years old; p=0.002) and with higher frequency of allergy history (26.1% vs 14.7%; p=0.032) compared to those without respiratory complications. Based on multivariate logistic regression, the adjusted OR for history of allergy was 2.23 (95%CI: 1.04 - 4.78, p = 0.041). RASBA in Thai population occurred mostly in elderly female patients and often led to hospitalization. Since large number of patients is regularly exposed to RAS-blockers, a nationwide attempt to raise awareness of clinicians when prescribing RAS-blockers is prudent.

Hypertension

Blockers of the renin-angiotensin-aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension.