Effects Of Renin-angiotensin System Blockade Research Articles

Cellular and metabolic effects of renin-angiotensin system blockade on glycogen storage disease type I nephropathy

Glycogen Storage Disease Type I (GSDI) is an inherited disease caused by glucose-6 phosphatase (G6Pase) deficiency, leading to a loss of endogenous glucose production and severe hypoglycemia. Moreover, most GSDI patients develop a chronic kidney disease (CKD) due to lipid accumulation in the kidney. Similar to diabetic CKD, activation of renin-angiotensin system (RAS) promotes renal fibrosis in GSDI. Here, we investigated the physiological and molecular effects of RAS blockers in GSDI patients and mice. A retrospective analysis of renal function was performed in 21 GSDI patients treated with RAS blockers. Cellular and metabolic impacts of RAS blockade were analyzed in K.G6pc−/− mice characterized by G6pc1 deletion in kidneys. GSDI patients started RAS blocker treatment at a median age of 21 years and long-term treatment reduced the progression of CKD in about 50% of patients. However, CKD progressed to kidney failure in 20% of treated patients, requiring renal transplantation. In K.G6pc−/− mice, CKD was associated with an impairment of autophagy and ER stress. RAS blockade resulted in a rescue of autophagy and decreased ER stress, concomitantly with decreased fibrosis and improved renal function, but without impact on glycogen and lipid contents. In conclusion, these data confirm the partial beneficial effect of RAS blockers in the prevention of CKD in GSDI. Mechanistically, we show that these effects are linked to a reduction of cell stress, without affecting metabolism.

Abstract P028: Activation Of The Renin-angiotensin System Drives Renal Metabolic Abnormalities In Diabetic Nephropathy

Activation of the renin-angiotensin system (RAS) is a major contributor to the pathogenesis of diabetic nephroathy (DN). However, the precise mechanisms of renoprotection associated with RAS blockade in DN are not entirely clear. The aim of this study is to examine whether metabolic effects of RAS blockade might contribute to renoprotection. We utilized a mouse model of DN combining severe type I diabetes (the Akita mutation) with a single-copy renin transgene (ReninTG) driven by the albumin promoter. Akita-ReninTG mice on a 129/Sv background (DN-susceptible mice) develop clinical features of human DN including high-grade albuminuria, renal interstitial inflammation and glomerulosclerosis, while Akita-ReninTG mice on a C57BL/6 background (DN-resistant mice) do not develop significant kidney disease. These two experimental groups were treated with the angiotensin receptor blocker (ARB) losartan 10 mg/kg/day for 12 weeks, and metabolic profiles in kidney tissues were examined using a targeted metabolomics assay. The DN-susceptible mice exhibited high-grade albuminuria that was significantly attenuated by ARB (Vehicle vs ARB: 1480±562 vs 193±42 μg/day, p =0.045), while DN-resistant mice had minimal albuminuria that was not affected by ARB (Vehicle vs ARB: 80±14 vs 75±14 μg/day, p =0.801). The metabolomics profiles of the DN-resistant mice were similar to C57BL/6 wild-type controls. By contrast, DN-susceptible mice exhibited broad reductions in even-chain acyl-carnitines and an abnormal profile of TCA cycle intermediates compared to 129/Sv wild-type controls, suggesting substantial impairments of renal mitochondrial fuel oxidation including altered fatty acid metabolism. RAS blockade had broad effects to correct this profile by increasing acetyl-carnitines generated from acetyl-CoA and concomitantly normalizing expression of genes associated with mitochondrial fatty acid metabolism including PPAR-α, PGC-1α, CPT1 and CPT2. ARB treatment restored TCA cycle activity to normal. These findings suggest that effects of RAS blockade re-establish normal fuel metabolism and mitochondrial fatty acid oxidation in kidney and may contribute to renoprotection.

Retrospective Analysis of Clinical Outcomes in Patients with Immunoglobulin A Nephropathy and Persistent Hematuria Following Renin-Angiotensin System Blockade.

BackgroundRecent guidelines recommend that patients with immunoglobulin A nephropathy (IgAN) and proteinuria 0.5–1 g/d and >1 g/d be treated with long-term renin–angiotensin system blockade (RASB). This study investigated whether patients with IgAN and persistent hematuria, but without proteinuria, can benefit from RASB.Material/MethodsIgAN patients with persistent hematuria at four centers were recruited from January 2013 to December 2018. Patients were divided into those who did and did not receive long-term RASB. The primary outcome was the appearance of proteinuria, and the secondary outcomes were the decreased percentage of hematuria, rate of decline in estimated glomerular filtration rate (eGFR) and final blood pressure. The effects of RASB on these outcomes were assessed by multivariate Cox regression models and propensity score matching.ResultsOf the 110 eligible patients, 44 (40.0%) received RASB and 66 (60.0%) did not. Treated patients had higher diastolic pressure. The unadjusted primary outcome, the appearance of proteinuria, was significantly less frequent in individuals who were than who were not treated with RASB. Multivariate Cox regression showed that RASB reduced the risk of the primary outcome and the levels of hematuria. The rate of eGFR decline and final blood pressure did not differ in the two groups.ConclusionsRASB reduced the risk of proteinuria development and increased the remission of hematuria in patients with IgAN who presented with persistent hematuria alone. RASB, however, did not affect blood pressure in patients without hypertension and did not affect the rate of eGFR decline.

Effect of Renin-Angiotensin System Blockade on Mortality in Korean Hypertensive Patients with Proteinuria.

BackgroundAlthough renin-angiotensin system (RAS) blockade is recommended for hypertensive patients with proteinuria, the effect of RAS blockade on Korean hypertensive patients has not been investigated.MethodsAmong individuals who underwent a National Health Examination between 2002 and 2003 in Korea, hypertensive patients with proteinuria (defined as a dipstick test result ≥2+) were enrolled in this study. We investigated the outcomes of two groups stratified by RAS blockade prescription (with RAS blockade vs. without RAS blockade). Moreover, Cox proportional hazard regression and Kaplan-Meier analyses were performed to examine the effects of RAS blockade on mortality and end-stage renal disease (ESRD).ResultsA total of 8,460 patients were enrolled in this study, of whom 6,236 (73.7%) were prescribed with RAS blockade. The mean follow-up period was 129 months. A total of 1,003 (11.9%) patients died, of whom 273 (3.2%) died of cardiovascular (CV) events. The Kaplan-Meier curves for all-cause or CV mortality showed that the survival probability was significantly higher in the RAS blockade group than in the non-RAS blockade group. Multivariate Cox analysis also revealed RAS blockade significantly reduced the all-cause and CV mortality rates by 39.1% and 33.7%, respectively, compared with non-RAS blockade, even after adjusting for age, sex, and comorbid diseases; however, ESRD was not affected.ConclusionIn this study, we found that RAS blockade was significantly associated with a reduction in mortality but not in the incidence of ESRD. However, 26.3% of the enrolled patients did not use RAS blockade. Physicians need to consider the usefulness of RAS blockade in hypertensive patients with proteinuria.

TCT-688 Effect of renin-angiotensin system blockade in long term outcomes following transcatheter aortic valve implantation: Results from the retrospective cohort of the RASTAVI study

TCT-688 Effect of renin-angiotensin system blockade in long term outcomes following transcatheter aortic valve implantation: Results from the retrospective cohort of the RASTAVI study

Effect of renin-angiotensin system blockade in patients with severe renal insufficiency and heart failure

BackgroundRenin-angiotensin system blockade (RAB) is the cornerstone in the management of patients with heart failure. However, the benefit of RAB in patients with accompanying severe renal impairment is not clear. We aimed to examine the effect of RAB and the differential effect of RAB depending on renal replacement (RR) in patients with severe renal insufficiency and acute heart failure. Methods and ResultsAmong 5625 patients from the Korean Acute Heart Failure registry, 673 in-hospital survivors (70.9 ± 12.8 years, 376 men) who had left ventricular ejection fraction < 40% and estimated glomerular filtration rate < 30 mL/min/1.73 m2 during hospitalization were analyzed. The inverse probability of treatment weighting (IPTW)-adjusted survival analysis was used to compare the composite of all-cause mortality and rehospitalization between patients with and without pre-discharge RAB. A total of 334 (49.6%) adverse events were observed during the 1-year follow-up. The IPTW-adjusted Kaplan-Meier survival analysis showed that the 1-year event rate was 48.7% and 53.8% for patients with RAB and those without, respectively (log rank p = 0.048). RAB was significantly related to better prognosis in patients receiving RR therapy (hazard ratio [HR] = 0.436 [0.269–0.706], p = 0.001), but not in patients not receiving RR therapy (HR 0.956 [0.731–1.250], p = 0.742) in a weighted cohort (p for interaction = 0.005). ConclusionsEarly RAB treatment in patients with heart failure and severe renal insufficiency was related to better prognosis. The benefit of RAB was particularly prominent in patients receiving RR therapy.

Renin-angiotensin system blockade use and risks of cognitive decline and dementia: A meta-analysis

ObjectiveTo evaluate the effects of renin-angiotensin system blockade (RASB) and its classes on the incidences of cognitive decline and dementia. MethodsPubMed, the EMBASE database and Cochrane Library were searched through October 2015 for eligible studies. We included ten studies that analyzed the effects of RASB treatment on the incidence of cognitive decline or dementia. ResultsWe found that the use of RASB was associated with a reduced risk of dementia (RR, 0.84; 95% CI, 0.76–0.92), when randomized trials and observational trials were considered together. Meanwhile, regardless of the drug class, both the angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) were shown to effectively decrease the incidence rate of dementia (RR, 0.89; 95% CI, 0.82–0.96; RR, 0.79; 95% CI, 0.64–0.94, respectively). Furthermore, indirect comparison between ACEIs and ARBs revealed no correlation in incident dementia (RR, 0.89, 95% CI 0.72–1.09, p=0.26). However, centrally acting ACEIs (CACEIs) protected against the occurrence of dementia (RR, 0.94; 95% CI, 0.91–0.97); on the contrary, peripheral ACEIs (PACEIs) increased the risk of dementia (RR, 1.20; 95% CI, 1.00–1.43). In an analysis of cognitive decline, CACEIs use was shown to decrease the risk of cognitive decline (RR, 0.92; 95% CI, 0.83–1.00); however, ARBs use had no significant association with the risk of cognitive decline (RR, 0.98; 95% CI, 0.90–1.05). ConclusionsRASB antihypertensive drugs may be potential treatments for reducing the incidence of dementia, but ARBs use is likely to be analogous to ACEIs. The association of dementia with CACEIs and PACEIs may be opposite, with CACEIs being effective. Meanwhile, the benefit differing according to drug classes for cognitive decline, CACEIs use, rather than ARBs use, is likely to play protective role in cognitive decline.

The Metabolic Effects of Mineralocorticoid Receptor Antagonists in Heart Failure Patients

Heart failure (HF) remains a leading cause of cardiovascular morbidity and mortality worldwide. Mineralocorticod receptor (MR) antagonists (spironolactone and eplerenone) have been studied in HF patients and in patients with acute coronary syndrome or post-myocardial infarction and left ventricular (LV) dysfunction, as well as hypertensive subjects without HF symptoms. It has suggested that mineralocorticoid receptor antagonists provide cardiovascular protection beyond its diuretic and potassium-sparing capacities. Traditionally, progression of HF relates with not full blockade of renin-angiotensin system (RAS) activation and with so called “escape” phenomenon of neurohumoral activation from effects of angiotensin converting enzyme / angiotensin receptor blockers and beta-adrenoblockers. Circulating and local aldosteron over production is discussed a main cause of none adequate effect of RAS blockade contributed negative cardiovascular remodelling and worse survival. During the last decade, several studies have shown that completed control for RAS activation might be achieved through adding MR antagonists in contemporary treatment scheme. This approach raises survival and leads to a trend in declined mortality rate in patients with HF various etiologic causes. Therefore, there are increasing evidence that both MR antagonists spironolactone and eplerenone might have a different metabolic effect in HF patients and that this difference is required to pay attention in creating of optimal HF therapeutic program. The aim of the mini review is to evaluate clinically significance of metabolic effects of mineralocorticoid receptor antagonists in HF patients.

Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy.

Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear. This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8). Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well. Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.

The effect of renin-angiotensin system blockade on renal protection in chronic kidney disease patients with hyperkalemia.

The aim of this study was to determine the effects of renin-angiotensin system (RAS) blockade maintenance on renal protection in chronic kidney disease (CKD) patients with hyperkalemia occurring during treatment with RAS blockade. CKD III or IV patients, who were prescribed with RAS blockers and also had hyperkalemia, were included. The study population was divided into two groups based on maintenance or withdrawal of RAS blocker. Renal outcomes (doubling of creatinine or end-stage renal disease) and incidence of hyperkalemia were compared between the two groups. Out of 258 subjects who developed hyperkalemia during treatment with RAS blockers, 150 (58.1%) patients continued on RAS blockades, while RAS blockades were discontinued for more than 3 months in the remaining 108 patients. Renal event-free survival was significantly higher in the maintenance group compared with the withdrawal group. Cox proportional hazard ratio for renal outcomes was 1.35 (95% CI: 1.08-1.92, p=0.04) in the withdrawal group compared with the maintenance group. However, the incidence of hyperkalemia and hyperkalemia-related hospitalization or mortality did not differ between the two groups. This study demonstrated that the maintenance of RAS blockade is beneficial for the preservation of renal function and relatively tolerable in patients with CKD and hyperkalemia occurring during treatment with RAS blockade.

Effects of renin-angiotensin system blockade on mortality and hospitalization in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HF-PEF) is a well-recognized complication of long-standing hypertension. However, beyond the control of the traditional cardiovascular risk factors, there are few other recommendations for its management. To examine the potential benefit of renin-angiotensin system (RAS) inhibition in HF-PEF, we performed a systematic review of the published medical literature. MEDLINE, EMBASE, and COCHRANE databases were searched from 1966 to 2011 for longitudinal studies examining HF-PEF patients receiving treatment with RAS inhibitors, either ACE inhibitors (ACE-I) or angiotensin receptor blockers (ARB) in addition to their standard treatment compared to those receiving standard treatment alone. We examined the all-cause mortality, cardiovascular mortality, and hospitalizations for heart failure. A total of 12 studies with 11,259 participants were included in the analysis. Among the randomized clinical trials, with the use of RAS inhibitors over standard treatment, there was no improvement in all-cause mortality (RR: 0.99; 95% CI: 0.88-1.12; p = 0.88), while there was a trend toward lowered rates of hospitalization (RR: 0.93; 95% CI: 0.86-1.01; p = 0.08). There were no major differences in the outcomes between the ACE-I or ARB. However, among the observational studies with the use of RAS inhibitors, there was a significant benefit in all-cause mortality (RR: 0.76; 95% CI: 0.62-0.93; p = 0.009), with no significant impact on the hospitalization rates. RAS inhibition in HF-PEF was not associated with significant reduction in all-cause or cardiovascular mortality, but randomized control trials appear to demonstrate a trend toward reduction in the risk for subsequent hospitalization. Further prospective randomized trials are warranted to confirm the effects of RAS inhibition on mortality and hospitalization.

The Impact of Renin-Angiotensin-Aldosterone System Blockade on Heart Failure Outcomes and Mortality in Patients Identified to Have Aortic Regurgitation: A Large Population Cohort Study

The aim of this study was to investigate the effect of renin-angiotensin system blockade on outcomes in patients with aortic regurgitation (AR). Angiotensin-converting enzyme (ACE) inhibitors have the potential to reduce afterload, blunt left ventricular wall stress, and limit left ventricular dilation and hypertrophy. However, long-term studies have yielded inconsistent results, and very few have assessed clinical outcomes. The Health Informatics Centre dispensed prescription and morbidity and mortality database for the population of Tayside, Scotland, was linked through a unique patient identifier to the Tayside echocardiography database. Patients diagnosed with at least moderate AR from 1993 to 2008 were identified. Cox regression analysis was used to assess differences in all-cause mortality and cardiovascular (CV) and AR events (heart failure hospitalizations, heart failure deaths, or aortic valve replacement) between those treated with and without ACE inhibitors or angiotensin receptor blockers (ARBs). A total of 2,266 subjects with AR (median age 74 years; interquartile range: 64 to 81 years) were studied, with a mean follow-up period of 4.4 ± 3.7 years. Seven hundred and five patients (31%) received ACE inhibitor or ARB therapy. There were 582 all-cause deaths (25.7%). Patients treated with ACE inhibitors or ARBs had significantly lower all-cause mortality and fewer CV and AR events, with adjusted hazard ratios of 0.56 (95% confidence interval [CI]: 0.64 to 0.89; p < 0.01) for all-cause mortality, 0.77 (95% CI: 0.67 to 0.89; p < 0.01) for CV events, and 0.68 (95% CI: 0.54 to 0.87; p < 0.01) for AR events. This large retrospective study shows that the prescription of ACE inhibitors or ARBs in patients with moderate to severe AR was associated with significantly reduced all-cause mortality and CV and AR events. These data need to be confirmed by a prospective randomized controlled outcome trial.

World Kidney Day 2011: Protect Your Kidneys, Save Your Heart

March 10, 2011 will mark the celebration of the 6th World Kidney Day (WKD), an annual event jointly sponsored by the International Society of Nephrology and the International Federation of Kidney Foundations. Since its inception in 2006, WKD has grown dramatically to become the most widely celebrated event associated with kidney disease in the world and the most successful effort to raise awareness among both the general public and government health officials about the dangers of kidney disease, especially chronic kidney disease (CKD). In 2011, WKD will call attention to the large, and often unappreciated, role played by kidney dysfunction in increasing premature cardiovascular disease, the most common cause of morbidity and mortality worldwide [1]. Can a focus on early detection and prevention of kidney disease really improve long term cardiovascular health? In this editorial, we hope to convey the message that increased attention to the kidneys can indeed improve long-term health outcomes by reducing both kidney and cardiovascular disease and should therefore be a central component of any global health strategy intended to reduce the enormous and growing burden of chronic non-comunicable diseases (NCDs).

Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies

cardiovascular risk factors are associated with dementia and cognitive decline. We investigated the effects of renin-angiotensin system blockade on cognitive function in patients aged 55 years and older with established atherosclerotic cardiovascular disease or diabetes with end-organ damage in two clinical trials. in the main study, ONTARGET, a double-blind, double-dummy, randomised controlled trial, the effects on cardiovascular outcomes of standard doses of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), an angiotensin-receptor blocker (telmisartan), and a combination of the drugs were evaluated in 25 620 participants. In the parallel TRANSCEND trial, the effects of telmisartan were compared with those of placebo in 5926 participants intolerant to ACE inhibitors. Secondary outcomes included cognitive impairment (defined by investigator-reported diagnosis of dementia or significant cognitive dysfunction, or a score of ≤ 23 on the Mini-Mental State Examination [MMSE]) and cognitive decline (a decrease of ≤ 3 points on the MMSE from baseline during follow-up). Analyses were by intention to treat. We pooled data from these studies to identify baseline predictors of cognitive impairment and its frequency according to mean systolic blood pressure during follow-up. These studies were registered with ClinicalTrials.gov, number NCT00153101. During a median duration of 56 months (IQR 51-64) of follow-up in ONTARGET, cognitive impairment occurred in 652 (8%) of 7865 patients allocated ramipril, 584 (7%) of 7797 allocated telmisartan, and 618 (8%) of 7807 allocated combination treatment (combination vs ramipril, odds ratio [OR] 0·95, 95% CI 0·85-1·07, p= 0·39; telmisartan vs ramipril, OR 0·90, 0·80-1·01, p = 0·06). Corresponding figures for cognitive decline were 1314 (17%), 1279 (17%), and 1240 (17%) in each of the groups, respectively (telmisartan vs ramipril, OR 0·97, 0·89-1·06, p= 0·53; combination vs ramipril, OR 0·95, 0·88-1·04, p=0·28). In TRANSCEND, cognitive impairment occurred in 239 (9%) of 2694 participants allocated telmisartan compared with 245 (9%) of 2689 allocated placebo (OR 0·97, 0·81-1·17, p= 0·76). The corresponding figures for cognitive decline were 454 (17%) and 412 (16%; OR 1·10, 0·95-1·27, p= 0·22). In patients with cardiovascular disease or diabetes, different approaches to blocking of the renin-angiotensin system had no clear effects on cognitive outcomes. Although patients with the lowest systolic blood pressure had the greatest preservation of cognitive function, meta-regression analyses did not show any benefits of blood-pressure lowering on cognition over several years of treatment.

Cardiovascular protection: a breakthrough for high-risk patients?

Angiotensin II has diverse effects on cardiovascular structure and function, and hence drugs that inhibit the formation or activity of this peptide have attained a central position in the prevention of morbidity and mortality from cardiovascular causes. The recent ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) has shown that, in patients with vascular disease or patients with diabetes who were at high risk of cardiovascular events, the angiotensin II receptor blocker telmisartan is noninferior to the angiotensin-converting enzyme inhibitor ramipril in preventing such events, despite the ONTARGET patients receiving better background preventive therapy than those enrolled in the earlier Heart Outcomes Prevention Evaluation (HOPE) study. In addition, telmisartan offers superior tolerability to that of ramipril. Moreover, the finding in this study that combination therapy with telmisartan and ramipril produced no further reduction in cardiovascular events than either drug alone, despite producing greater reductions in blood pressure, highlights the potential importance of endothelial effects of renin-angiotensin system blockade in cardiovascular protection.

Tissue Factor Modulation by Angiotensin II: A Clue to a Better Understanding of the Cardiovascular Effects of Renin-Angiotensin System Blockade?

Systemic hypertension, a pathological process to which the renin-angiotensin system contributes importantly, is characterized by a thrombophilic diathesis and an increased risk for acute ischemic coronary events. That apparently contradictory profile might, to some extent, relate to the modulating properties of Angiotensin II, the effector arm of the renin angiotensin system, on tissue factor expression, the physiologic initiator of blood coagulation and a basic mechanism in the pathogenesis of acute thrombosis. In fact, monocytes and macrophages within the atherosclerotic plaque as well as inflamed vascular endothelial cells may locally synthesize Angiotensin II. In turn, the peptide, by binding to its specific membrane receptors, activates a series of intracellular signals eventually converging upon NF-kappaB, a transcription factor that upregulates tissue factor expression. Drugs interfering with the renin-angiotensin system, either by inhibiting conversion of Angiotensin I to Angiotensin II or by blocking its receptors, have the potential to inhibit tissue factor expression and to modulate its procoagulant effect. This property may contribute to the protection exerted by renin-angiotensin blockers from acute ischemic events in patients with hypertension and other cardiovascular diseases.

Acute effects of renin-angiotensin system blockade on arterial function in hypertensive patients

The acute effects of the renin-angiotensin system (RAS) blockers may be important in some clinical settings. To assess the acute impact of such drugs on arterial function, we studied the effects of captopril 25 mg, quinapril 20 mg and telmisartan 80 mg on 100 hypertensive patients, according to a randomized, double-blind, placebo-controlled study. Central (aortic) blood pressure (BP) and augmentation index (AIx, a measure of wave reflections), as well as flow-mediated dilatation (FMD) of the brachial artery and forearm blood flow (FBF) (measures of conduit and resistance artery endothelial function, respectively), were evaluated before and 2 h after oral drug administration. Compared to placebo, captopril and quinapril decreased central systolic (by 7.5 mm Hg, P<0.05 and by 12.3 mm Hg, P<0.001) and diastolic BP (by 4.9 mm Hg, P<0.01 and by 8.4 mm Hg, P<0.001), whereas telmisartan had no significant effect (P=NS). Additionally, AIx was reduced after quinapril (absolute decrease of 7.2%, P<0.01) and marginally after captopril (decrease of 4.7%, P=0.07). Only quinapril led to a beneficial change of FMD (absolute increase of 2.7%, P<0.001). No treatment was related to significant changes of peak hyperaemic or 3-min hyperaemic FBF. In adjusted analyses, all the favourable alterations induced by quinapril were independent of potential confounding haemodynamic factors. Our data show that acute RAS inhibition with quinapril (20 mg) may be more beneficial in terms of arterial function and central haemodynamics compared to captopril (25 mg) or telmisartan (80 mg). Further studies are needed to investigate whether these acute arterial effects of quinapril are clinically significant.

Antihypertensive and Renal Protective Effects of Renin-Angiotensin System Blockade in Uremic Rats Treated With Erythropoietin

Correcting anemia with recombinant human erythropoietin (rhEPO) in chronic renal failure has been associated with an increased blood pressure (BP), which may accelerate the decline in renal function. This has been attributed, in part, to the activation of the renin-angiotensin system. The present study was designed to investigate the protective effect of the angiotensin II-receptor blocker losartan compared with the angiotensin-converting enzyme inhibitor captopril and conventional triple therapy (TRx) in uremic rats receiving rhEPO therapy. Renal failure was induced by renal mass ablation followed by a 3-week stabilization period. Uremic rats were then divided into five groups with similar systolic BP: vehicle; rhEPO (100 U/kg, subcutaneously, three times per week); rhEPO + losartan (20 mg/kg/d); rhEPO + captopril (20 mg/kg/d); and rhEPO + TRx (reserpine 5 mg/L, hydralazine 80 mg/L, hydrochlorothiazide 20 mg/L). Systolic BP as well as blood and renal parameters were assessed before and after a 3-week treatment period. Renal histology was evaluated at the end of the study. The uremic rats developed hypertension, anemia, proteinuria, and increased urinary endothelin-1 (ET-1) excretion. The rhEPO corrected the anemia but aggravated the hypertension (P < .01), glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Treatment with losartan, captopril, and the TRx prevented the rhEPO-induced increased in systolic BP. The TRx was less effective in preventing histologic injuries despite similar systolic BP reduction. Blockade of the renin-angiotensin system is highly effective in preventing both hypertension and renal histologic damage in rhEPO-treated uremic rats and this benefit seems to extend beyond the antihypertensive effect.

Renoprotection by blocking the RAAS in diabetic nephropathy—fact or fiction?

Diabetic nephropathy is characterized by proteinuria, blood pressure elevation, a relentless decline in renal function and a high risk of cardiovascular disease. In 1992, based on clinical studies, it was suggested that angiotensin-converting enzyme inhibitors (ACEIs) offer renoprotection in diabetic nephropathy—i.e. an effect protecting the kidney function above and beyond what was offered by similar blood pressure reduction with other antihypertensive agents [1]. This study was conducted in type 1 diabetic patients with moderately impaired renal function. The finding was confirmed and extended by the Collaborative Study Group [2] in a study with a median follow-up, 3 years; range, 1.8–4.8, demonstrating that in type 1 diabetic patients, ACEIs were associated with a 50% [95% confidence intervals (CI) 18–70] reduced risk of dialysis/transplantation or death. Subsequently blockade of the renin–angiotensin system (RAS) was investigated in type 2 diabetic patients using angiotensin II receptor blockers (ARB), and a renoprotective effect was again demonstrated, compared with placebo (standard antihypertensive therapy) in hypertensive microalbuminuric type 2 diabetic patients in the IRMA 2 trial lasting 2 years, where a 70% reduction in the progression to overt nephropathy was observed in patients receiving the maximal dose of irbesartan 300 mg daily [3]. Again, this effect was shown to be present beyond the bloodpressure-lowering effect of ARB-intervention. This was further substantiated in a substudy, in which it was documented that there was no difference in 24-h blood pressure in patients treated with ARB or standard antihypertensive therapy [4]. In patients with type 2 diabetes and overt diabetic nephropathy, the IDNT study with a mean follow-up time of 2.6 years demonstrated a significant 20% reduction in the development of the combined endpoint doubling of S-creatinine, end-stage renal disease (ESRD) or death in the patients treated with irbesartan compared with placebo (standard antihypertensive therapy), and 23% risk reduction compared with the calcium channel blocker amlodipine [5]. It should be stressed that, particularly in comparison with the amlodipine arm, the systemic blood pressure was completely identical. The RENAAL study with a mean follow-up time of 3.4 years (range, 2.3–4.6) similarly demonstrated that ARB losartan could significantly reduce the development of doubling of creatinine, ESRD and death by 16% compared with standard antihypertensive therapy [6]. Following these studies, FDA and EMEA approved irbesartan and losartan for renoprotection in diabetic patients (beyond blood pressure). Clinical guidelines recommended the use of inhibition of the RAS for prevention of diabetic nephropathy and ESRD. Despite all this evidence, the renoprotective effects of RAS blockade in diabetic nephropathy have recently been questioned on several occasions. In this article, we critically assess three recent publications that have challenged the specific renoprotective role of ACEI/ARBs in proteinuric diabetic patients suffering from diabetic kidney disease. We will not discuss the role of ACE inhibition or ARB in non-proteinuric kidney diseases in diabetic patients.

Impact of renin angiotensin system blockade on night to day blood pressure ratio in diabetic nephropathy

Sir, Elevated systemic blood pressure is a risk factor for progression of diabetic nephropathy. Ambulatory blood pressure measurements offer additional risk stratification compared to office blood pressure in patients with hypertension [1]. In addition, an abnormal diurnal blood pressure pattern characterized by an elevated night to day ratio is found more commonly in diabetic patients and, as reviewed by Miller et al. [2], is associated with poor renal outcome. The renin angiotensin system (RAS) is involved in both initiation and progression of diabetic nephropathy and blocking this system with ACE-inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARBs) improves kidney survival and prognosis. Miller et al. [2] reported that treatment with enalapril (0.1 mg/kg BID) corrects the abnormally high night to day blood pressure ratio found in 10 uncomplicated adolescents, and this could contribute to the beneficial renoprotective effects of RAS blockade. In this letter, we further investigate whether RAS blockade corrects an abnormal 24 h blood pressure pattern by presenting data on the short-term effects of single and dual blockade of the RAS on a 24 h blood pressure profile and a night to day blood pressure ratio in type 1 diabetic patients with diabetic nephropathy. Our data are a post-hoc analysis of three earlier studies [3–5]. As described previously [3], we performed a randomized, double blind, cross-over trial, in which 18 patients received 8 weeks of placebo, benazepril 20 mg once daily, valsartan 80 mg once daily and a combination of benazepril 20 mg and valsartan 80 mg once daily in random order [3]. The main findings were: (1) mono-therapy with ACE-I or ARBs treatment was equally effective with regard to antialbuminuric and antihypertensive effects; (2) dual blockade of the RAS caused a further reduction in albuminuria of 43% and 7/6 mmHg in 24 h blood pressure compared with both mono-therapies; (3) night to day ratio of 24 h blood pressure on each treatment is shown in Table 1. A post-hoc power calculation estimated a power in each study of � 0.80 to detect a difference of 0.05 in night to day ratio with a significance level of 0.05. In agreement, when looking at the fraction of patients with night to day blood pressure ratio above the median on placebo treatment (>0.91), we found no changes in the night to day ratio on RAS blockade. Furthermore, in two other studies demonstrating that dual blockade of the RAS