Dual Blockade Of Renin-angiotensin System Research Articles

SEQUENTIAL NEPHRON BLOCKADE VERSUS DUAL RENIN-ANGIOTENSIN SYSTEM BLOCKADE IN TRUE RESISTANT HYPERTENSIVE PATIENTS: A SYSTEMATIC REVIEW

Objective: True resistant hypertension (RHTN) is a challenging medical condition in which the blood pressure remains uncontrolled despite the use of three different classes of antihypertensive agents at maximum tolerated dose. In order to reduce the sodium and volume overload in these patients and bring the blood pressure to acceptable levels, several pharmacologic agents that promote sequential nephron blockade (SNB) or dual renin- angiotensin system blockade (DRASB) can be used. Therefore, this review aims to evaluate the data presented in some clinical trials comparing the SNB to the DRASB. Design and method: A systematic search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was conducted in MEDLINE, Cochrane Library, EMBASE and LILACS, resulting in a total of 123 articles. One abstract and 4 randomized controlled trials were selected to be assessed in this review. Results: Both treatments decreased systolic blood pressure and diastolic blood pressure in ambulatory blood pressure monitoring. In one of the protocols, the decreases in the SNB group were significantly greater than in the DRASB group. A sub-analysis showed that the improvements in blood pressure were significant only in those with acceptable adherence to treatment. The two interventions reduced office blood pressure, with one study indicating that the reduction was superior in SNB. In markers of arterial stiffening and aging, there were no significant improvements. Pulse wave velocity and common carotid artery stiffness were similar in both groups and tended to decrease. One of the studies showed improvement in echocardiographic parameters for diastolic dysfunction. Conclusions: Despite the improvements in blood pressure in both groups, SNB therapy has a higher potential as a treatment for RHTN, especially when there is good adherence to the medication. Also, SNB tended to improve arterial stiffness and diastolic dysfunction. Nonetheless, there is a need for more studies for a better evaluation of these outcomes.

Effect of dual blockade of renin-angiotensin system on renal nephrin and vascular endothelial growth factor – A expression in diabetic-hypertensive rats

Objectives: The effects of early renin-angiotensin system (RAS) blockade using angiotensin-converting enzyme (ACE) inhibitor lisinopril and/or angiotensin receptor blocker valsartan on renal nephrin and vascular endothelial growth factor (VEGF)-A gene expression were investigated in diabetic-hypertensive rats. Materials and Methods: Diabetes and hypertension were induced in adult Wistar rats using streptozotocin (45 mg/kg, i.p.) and Nω-nitro-L-arginine methyl ester (60 mg/kg/12 h) for 4 consecutive days. Experimental animals were allocated into six groups (n = 6): normal control, diabetic control, diabetic-hypertensive control and lisinopril-, valsartan- and combination-treated diabetic-hypertensive groups (5 mg/kg/drug/day, p.o., for 21 days). Blood glucose, blood pressure, body weight, kidney weight to body weight ratio, serum albumin, creatinine, total protein and urea were measured and recorded every week. Nephrin and VEGF-A gene expression were measured using real-time polymerase chain reaction. Renal nephrin protein was measured using ELISA as well as nephrin immunostaining. Results: Blood pressure was significantly decreased by all treatments (P ≤ 0.05). All treatments normalised serum albumin and urea. Serum creatinine significantly decreased, while total protein significantly increased (P ≤ 0.05). Nephrin gene expression had a non-significant decrease in diabetic-hypertensive rats, yet it was statistically increased with individual treatments (P ≤ 0.05) and normalised with combined treatment. Renal nephrin protein significantly decreased in diabetic-hypertensive rats, normalised by lisinopril and significantly increased by valsartan and combined treatments (P ≤ 0.05). VEGF-A expression significantly increased in diabetic-hypertensive rats and significantly decreased with lisinopril and valsartan monotherapy and normalised with combined treatment (P ≤ 0.05). Immunostaining of nephrin also showed an obvious increase in the case of combined treatment. Conclusion: Early dual blockade of RAS in diabetic-hypertensive rats protected against renal damage and improved renal nephrin and VEGF-A gene expression as well as renal nephrin protein expression.

Antiproteinuric and Hyperkalemic Mechanisms Activated by Dual Versus Single Blockade of the RAS in Renovascular Hypertensive Rats.

This study aimed to investigate the antiproteinuric and hyperkalemic mechanisms activated by dual renin-angiotensin system (RAS) blockade in renovascular hypertensive rats (2-kidney 1-clip model [2K-1C]). Six weeks after clipping the left renal artery or sham operation (2K), rats were treated with losartan, enalapril, or both drugs for two weeks. We found that 2K-1C rats displayed higher tail-cuff blood pressure (BP), increased non-clipped kidney Ang II concentration, and more pronounced urinary albumin excretion than 2K. BP was decreased by the treatment with either enalapril or losartan, and the combination of both drugs promoted an additional antihypertensive effect in 2K-1C rats. Renal Ang II content and albuminuria were reduced by either enalapril or losartan in monotherapy and restored to control levels by dual RAS blockade. Albuminuria in 2K-1C rats was accompanied by downregulation of the glomerular slit protein podocin, reduction of the endocytic receptors megalin and cubilin, and a marked decrease in the expression of the ClC-5 chloride channel, compared to 2K animals. Treatment with losartan and enalapril in monotherapy or combination increased the expression of podocin, cubilin, and ClC-5. However, only the combined therapy normalized podocin, cubilin, and ClC-5 protein abundance in the non-clipped kidney of 2K-1C rats. Renovascular hypertensive 2K-1C rats had a lower concentration of plasma potassium compared to 2K rats. Single RAS blockade normalized potassium plasma concentration, whereas 2K-1C rats treated with dual RAS blockade exhibited hyperkalemia. Hypokalemia in 2K-1C rats was accompanied by an increase in the cleaved activated forms of α-ENaC and γ-ENaC and the expression of β-ENaC. Combined RAS blockade but not monotherapy significantly reduced the expression of these ENaC subunits in 2K-1C rats. Indeed, double RAS blockade reduced the abundance of cleaved-α-ENaC to levels lower than those of 2K rats. Collectively, these results demonstrate that the antiproteinuric effect of dual RAS blockade in 2K-1C rats is associated with the restored abundance of podocin and cubilin, and ClC-5. Moreover, double RAS blockade-induced hyperkalemia may be due, at least partially, to an exaggerated downregulation of cleaved α-ENaC in the non-clipped kidney of renovascular hypertensive rats.

ASIAN PACIFIC SOCIETY OF NEPHROLOGY CLINICAL PRACTICE GUIDELINE ON DIABETIC KIDNEY DISEASE - EXECUTIVE SUMMARY.

Introduction: COVID-19 is now a global pandemic affecting millions of people Patients on dialysis are at an increased risk to COVID-19 infection due to their exposure in the health care setting Strategies for infection control and prevention are also being implemented in the dialysis units because of the increased risk of virus transmission within the unit Objective: Describe the different measures and strategies done to mitigate the spread of COVID-19 outbreak in a hospital based dialysis centre Methods: Review of the epidemic course with contact tracing was done from March 14 to May 14, 2020 in the dialysis unit of a tertiary hospital Results: Of 167 haemodialysis patients, 20 were considered COVID-19 suspects Eight tested positive-2 were traced to be exposed with the first confirmed case, 2 were handled by a COVID-19 infected healthcare worker (HCW) who was asymptomatic at time of contact while 2 asymptomatic patients tested positive during mass screening Two of 67 HCWs tested positive were exposed to patients Key interventions during the course of the outbreak included: mass testing of patients and HCWs after identifying 6 patients and 2 HCWs infected with COVID-19 using nasopharyngeal/oropharyngeal swabs by RT-PCR;dialysis of COVID-19 confirmed and suspected cases in isolation rooms separate from the dialysis unit (instead of cohorting);provision of adequate protective personal equipment for HCWs and surgical masks for all patients, environmental disinfection especially in the waiting area with strict social distancing and screening for signs and symptoms at the entrance of the unit Conclusion: Infection control strategies are needed to manage the spread of COVID-19 in dialysis centres These infection prevention measures should be implemented at the first indication of transmission in the area and should be maintained for the duration of the pandemic and until the area show no more reports of transmission

Single versus dual blockade of the renin-angiotensin system in patients with IgA nephropathy

BackgroundInhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial.MethodsSTOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m2 and ESRD onset, were analyzed by logistic regression and linear mixed effects models.ResultsAmong the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies.ConclusionIn the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.

Effects of dual blockade in heart failure and renal dysfunction: Systematic review and meta-analysis.

Objective:The effect of dual renin–angiotensin system (RAS) inhibition in heart failure (HF) is still controversial. Systematic reviews have shown that dual RAS blockade may reduce mortality and hospitalizations, yet it has been associated with the increased risk of renal dysfunction (RD). Surprisingly, although RD in patients with HF is frequent, the effect of combining RAS inhibitors in HF patients with RD has never been studied in a meta-analysis.Methods:A systematic review and meta-analysis of randomized clinical trials involving HF patients with RD who received dual blockade analyzing death, cardiovascular (CV) death or HF hospitalization, and adverse events.Results:Out of 2258 screened articles, 12 studies were included (34,131 patients). Compared with monotherapy, dual RAS inhibition reduced hazard ratio of death to 0.94 (p=0.07) and significantly reduced CV death or HF hospitalization to 0.89 (p=0.0006) in all individuals, and to 0.86 (p=0.005) in patients with RD and to 0.91 (p=0.04) without RD. Nevertheless, dual RAS blockade significantly increased the risk of renal impairment (40%), hyperkalemia (44%), and hypotension (42%), although discontinuation of treatment occurs only in 3.68% versus 2.19% (p=0.00001).Conclusions:Dual RAS inhibition therapy reduces the risk of CV death or HF hospitalization. However, cautions monitoring for specific adverse events may be warranted.

SUN-021 DUAL BLOCKADE OF THE RENIN-ANGIOTENSIN SYSTEM IN PATIENTS WITH IGA NEPHROPATHY - INSIGHTS FROM THE STOP-IGAN TRIAL

Inhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). In the randomized STOP-IgAN trial we observed that the addition of immunosuppressive therapy to optimized supportive care did not significantly improve renal outcomes over the 3-year study phase as compared to supportive measures alone. Here we analyzed the effects of single versus dual RAS blockade during the 6-month run-in phase that preceded the randomized study phase on renal endpoints.

Combined use of drugs inhibiting the renin-angiotensin system: prescribing patterns and risk of acute kidney injury in German nursing home residents.

Background/aimsIn 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.MethodsBased 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.ResultsOf 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).ConclusionsPrescribing 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.

The Effect of Dual Renin-angiotensin System Blockade Compared to Conventional Antihypertensive Combination on Blood Pressure and Renal Function After Heart Transplantation: A Randomized Controlled Trial

Altered cardiovascular regulation and use of immunosuppressive drugs after heart transplantation (HTx) are associated with development of arterial hypertension (AHT) and nephrotoxicity. HTx-related AHT can be difficult to control and combination of antihypertensives is often necessary. We compared the effect of the standard antihypertensive medication (aHTM) with dual blockade of the renin-angiotensin system (dual RAS combination) on blood pressure control and renal functions.

Angiotensin receptor blockers are associated with lower mortality than ACE inhibitors in predialytic stage 5 chronic kidney disease: A nationwide study of therapy with renin-angiotensin system blockade.

Dual renin angiotensin system (RAS) blockade using angiotensin-receptor blockers (ARBs) in combination with angiotensin converting enzyme inhibitors (ACEIs) is reported to improve proteinuria in both diabetic and non-diabetic patients. However, its renoprotective effect and safety remain uncertain in patients with advanced chronic kidney disease (CKD). From January 1, 2000 through June 30, 2009, we enrolled 14,117 pre-dialytic stage 5 CKD patients with serum creatinine >6mg/dL and hematocrit <28% under the treatment with erythropoiesis stimulating agents and RAS blockade. We used Cox proportional hazards regression models to estimate the hazard ratios (HRs) against the commencement of long-term dialysis and all-cause mortality for ACEI/ARB users. Over a median follow-up of 7 months, 9,867 patients (69.9%) required long-term dialysis and 2,805 (19.9%) died before progression to end-stage renal disease requiring dialysis. In comparison with the ARB-only users, dual blockade with ACEIs and ARBs was associated with a significantly higher risk of (1) death in all CKD patients (HR = 1.49, [95%CI, 1.30–1.71]; P = 0.02) and in diabetic subgroup (HR = 1.58, [95%CI, 1.34–1.86]; P = 0.02); (2) composite endpoint of long-term dialysis or death in diabetic subgroup (HR = 1.10, [95%CI, 1.01–1.20]; P = 0.04); (3) hyperkalemia-associated hospitalization in non-diabetic subgroup (HR, 2.74, [95%CI, 1.05–7.15]; P = 0.04). However, ACEIs users were associated with higher mortality than ARBs users in all CKD patients (HR = 1.17, [95%CI, 1.07–1.27]; P = 0.03) and in diabetic subgroup (HR = 1.32, [95%CI, 1.18–1.48]; P = 0.03). Monotherapy of RAS blockade, especially ARB, is more effective and safer than dual RAS blockade in pre-dialytic stage 5 CKD patients.

Abstract P430: Soluble Epoxide Hydrolase Inhibition Augments Ras Blockade Renoprotection in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats With Chronic Kidney Disease

Rationale and Objective: We showed recently that increasing kidney tissue epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH) and thereby blocking EETs degradation to inactive dihydroxyeicosatrienoic acids (DHETEs) substantially attenuated the progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) subjected to 5/6 renal mass reduction (5/6 NX). In this study we examined if in this model addition of sEH inhibition to the complex (dual) renin-angiotensin system (RAS) blockade would bring additional renoprotective effects in already established CKD. Methods: TGR aged 9 weeks underwent 5/6 NX and then were left untreated for 6 weeks to develop CKD. Then dual RAS blockade : ACE inhibition (trandolapril) + angiotensin AT 1 receptor blockade (losartan) was instituted, alone or combined with sEH inhibition (c-AUCB, 3 mg/l in drinking water). During the 60 weeks’ follow-up period albuminuria and urinary creatinine excretion was repeatedly determined. The following experimental groups were investigated: ; 1) sham-operated TGR; 2) Untreated 5/6 NX TGR; 3) 5/6 NX TGR + RAS blockade ; 4) 5/6 NX TGR + RAS + sEH blockade. Sham-operated transgene-negative normotensive Hannover-Sprague Dawley (HanSD) rats served as basic controls. In separate groups renal glomerular and tubulointerstitial injury was assessed, and effects of two weeks’ treatments on systolic blood pressure (SBP, measured by telemetry) and on kidney ANG II, ANG 1-7, EETs and DHETEs levels were determined. Results: All untreated TGR died by week 14 after 5/6 NX. RAS blockade increased the final survival rate to 23%, normalized SBP (116 ± 3 vs. 198 ± 3 mmHg, p&lt;0.0015), reduced albuminuria (46 ± 5 vs. 102 ± 12 mg/24 h, p&lt;0.001) and intrarenal ANG II (27 ± 8 vs. 189 ± 14 fmol/g p&lt;0.0015) and did not alter kidney EETs/DHETEs ratio. After addition of sEH blockade kidney EETs/DHETEs ratio increased to 2.89 ± 0.42 (p&lt;0.001 vs. 5/6 NX TGR treated with RAS blockade), the final survival rate increased to 42% and indices of renal glomerular and tubulointerstial injury improved. Conclusion: Addition of sEH blockade to the RAS blockade brings additional renoprotective effects on the CKD progression in 5/6 NX TGR, even when applied in the advanced phase of the disease.

Patterns of progression of chronic kidney disease at later stages.

BackgroundAt later stages of chronic kidney disease (CKD), a pattern of linear and irreversible renal function decline is thought to be the most common. The objective of this study was to describe the characteristics of the different patterns of CKD progression, and to investigate potentially modifiable factors associated with the rate of decline of renal function.MethodsThis was a retrospective, observational study in a cohort of adult patients with CKD Stage 4 or 5 not on dialysis. Decline in renal function was estimated as the slope of the individual linear regression line of estimated glomerular filtration rate (eGFR) over time. The following patterns of CKD progression were considered: unidentifiable, linear, nonlinear (curvilinear) and positive (improvement of renal function).ResultsThe study group consisted of 915 patients (mean ±SD age 65 ± 14 years, 48% females, median follow-up time 16 months). A linear pattern was observed in 38%, unidentifiable in 23%, nonlinear in 24% and positive in 15% of the study patients. The mean eGFR slope was: −3.35 ± 4.45 mL/min/year. Linear and unidentifiable patterns were associated with more rapid loss of renal function. By multiple linear and logistic regression analysis, the magnitude of proteinuria, the systolic blood pressure and the treatment with dual renin–angiotensin system blockade were associated with more rapid CKD progression. On the contrary, older age and discontinuation of commonly prescribed medication with potential influence on renal function or eGFR measurements were associated with slower CKD progression.ConclusionsA majority of patients with advanced CKD show patterns of renal function decline different from linear, and several of the main determinants of CKD progression are potentially modifiable.

Effect of dual compared to no or single renin-angiotensin system blockade on risk of renal replacement therapy or death in predialysis patients: PREPARE-2 study

Current guidelines on hypertension treatment in chronic kidney disease (CKD) patients discourage combined angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II receptor blocker (ARB) use due to the risk of an increased kidney function decline. However, dual compared to single renin-angiotensin system (RAS) blockade may have more efficacy with regard to hypertension and proteinuria. Among incident predialysis patients (CKD 4-5), we compared dual with no or single RAS blockade regarding kidney function decline and risk of renal replacement therapy (RRT) or death. In a multicenter cohort study, 495 incident predialysis patients (>18 years) were included between 2004 and 2011 and followed until RRT, death, or October 2016. At baseline, patients were divided into four categories: nonuser, single or dual user of ACEi and/or ARB. Cox models were used to estimate the hazard ratio for the combined end point RRT or death. Differences in decline of kidney function among the four drug groups were compared with a linear mixed model. A total of 119 patients were nonusers, 164 ACEi users, 133 ARB users, and 79 dual RAS users. Compared to nonusers, the multivariable adjusted hazard ratio (95% confidence interval) for the combined end point was 0.75 (0.65 to 0.86) for ACEi users, 0.87 (0.76 to 1.00) for ARB users, and 0.79 (0.67 to 0.94) for dual RAS users. The average annual decline in kidney function did not differ among the four groups. We observed in predialysis patients that compared to no RAS blockade, both dual RAS blockade and single ACEi use were associated with about 20%-25% lower risk of RRT or death, without difference in kidney function decline.

The dilemma of dual renin-angiotensin system blockade in chronic kidney disease: why beneficial in animal experiments but not in the clinic?

Drugs interfering with the renin-angiotensin-aldosterone system (RAAS) improved the prognosis in patients with hypertension, heart failure, diabetes and chronic kidney disease. However, combining different drugs brought no further benefit while increasing the risk of hyperkalemia, hypotension and acute renal failure. This was so with combining angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptors type 1 antagonists (ARB). Dissimilarly, in animal disease models this dual therapy proved clearly superior to single drug treatment and became the optimal standard regime for comparison with other treatments. This review analyzes the causes of the discrepancy of effects of the dual therapy between animal experiments versus clinical studies, and is focused on the outcomes in chronic kidney disease. Discussed is the role of species differences in RAAS, of the variability of the disease features in humans versus relative stability in animals, of the genetic uniformity in the animals but not in humans, and of the biased publication habits of experimental versus clinical studies. We attempt to understand the causes and reconcile the discordant findings and suggest to what extent dual RAAS inhibition should be continued in animal experiments and why its application in the clinics should be limited to strictly selected groups of patients.

Dual renin–angiotensin system blockade for nephroprotection

In experimental diabetic and nondiabetic chronic kidney disease, angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blockers (ARB) combination therapy reduce proteinuria and prevent structural lesions more effectively than either drug alone. Consistently, in humans, a multidrug individually tailored antiproteinuric treatment based on combination therapy with maximum tolerated doses of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (“Remission Clinic”) reduced proteinuria and prevented end-stage renal disease more effectively than angiotensin-converting enzyme/angiotensin receptor blockers monotherapy, in particular in subjects with nondiabetic chronic kidney disease. Fixed doses of an angiotensin-converting enzyme inhibitor or renin inhibitor added-on losartan failed to exert any additional renoprotective effect as compared with losartan monotherapy in patients with type 2 diabetes and overt nephropathy. However, the VA NEPHRON D study found that losartan and lisinopril combination therapy reduced by 34 % the risk of pre-defined reductions in estimated glomerular filtration rate, end-stage renal disease or death as compared to losartan in 1448 type 2 diabetes patients with overt nephropathy. Unfortunately, treatment effect failed to achieve the nominal significance (P=0.07) because of premature trial interruption. Thus, the Remission Clinic protocol is the most powerful tool to prevent progression to end-stage renal disease in nondiabetic proteinuric chronic kidney disease. Results of the ongoing VALID trial will show whether this approach can be safely extended to type 2 diabetes patients.

Use of ACE inhibition and blood pressure management in deferring dialysis initiation.

Elevated blood pressure is one of the most significant risk factor for the development of chronic kidney disease (CKD); its treatment is a milestone in CKD management. While it is accepted that a stricter blood pressure control is indicated in patients with proteinuria or microalbuminuria, the exact degree of blood pressure reduction to be obtained in CKD patients is still under debate. Following more recent interpretation of old trials, a BP target for <140/90 mmHg is suggested for non-proteinuric CKD patients. In those with microalbuminuria/proteinuria, the ideal blood pressure target should be ≤130/80 mmHg. Recently, the SPRINT trial put new emphasis on a stricter blood pressure control, mainly from the cardiovascular point of view. The blockers of the renin-angiotensin system (RAS) are recommended as first line treatment in all CKD hypertensive patients with micro or macroalbuminuria either diabetics or not. However, their nephroprotective efficacy is less relevant in non-proteinuric patients. The dual RAS blockade was proposed as an additional option. Despite a greater antiproteinuric effect, some large trials in patients at high cardiovascular risk did not demonstrate significant advantage on hard endpoint. Its use is now contraindicated in diabetic CKD patients. Given that RAS blockers can cause acute derangements in kidney function and hyperkalemia, caution is needed with their use, especially in frail and old patients with cardiovascular disease or in the presence of advanced CKD.

Incidence, Severity, and Outcomes of AKI Associated with Dual Renin-Angiotensin System Blockade.

The benefit of dual blockade of the renin-angiotensin system is limited by adverse effects. We performed a secondary analysis of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Study to describe the effect of increased intensity of renin-angiotensin system blockade on the incidence, risk factors, and outcomes of AKI. In the VA NEPHRON-D Study, we randomized 1148 veterans receiving outpatient care with type 2 diabetes mellitus, eGFR of between 30 and 89.9 ml/min per 1.73 m2, and urinary albumin excretion of at least 300 μg/mg creatinine (or a urinary total protein of at least 0.5 mg/mg creatinine) to either combination therapy with losartan and lisinopril or monotherapy with losartan. We identified hospitalized AKI events and their outcomes during a median follow-up of 2.2 years through systematic reporting of serious adverse events. The incidence of AKI was 12.2 (95% confidence interval, 10.5 to 14.0) versus 6.7 (95% confidence interval, 5.6 to 8.2) per 100 patient-years in the combination arm versus monotherapy arms (P<0.001). Individuals with AKI were more likely to develop the primary study end point of death, ESRD, or decline in kidney function (hazard ratio, 1.78; 95% confidence interval, 1.34 to 2.26; P<0.001). Patients with AKI in the combination arm had greater recovery of kidney function (75.9% versus 66.3%; P=0.04), lower 30-day mortality (4.7% versus 15.0%; P<0.01), and lower hazard for development of the primary study end point (hazard ratio, 0.60; 95% confidence interval, 0.37 to 0.98). Dual renin-angiotensin system blockade was associated with an increased risk of AKI compared with monotherapy, but AKI in the setting of monotherapy was associated with lower rates of recovery of kidney function, higher mortality, and higher risk of progression of kidney disease.

Overexpression of angiotensinogen downregulates aquaporin 1 expression via modulation of Nrf2-HO-1 pathway in renal proximal tubular cells of transgenic mice.

Introduction:We aimed to examine the regulation of aquaporin 1 expression in an angiotensinogen transgenic mouse model, focusing on underlying mechanisms.Methods:Male transgenic mice overexpressing rat angiotensinogen in their renal proximal tubular cells (RPTCs) and rat immortalised RPTCs stably transfected with rat angiotensinogen cDNA were used.Results:Angiotensinogen-transgenic mice developed hypertension and nephropathy, changes that were either partially or completely attenuated by treatment with losartan or dual renin–angiotensin system blockade (losartan and perindopril), respectively, while hydralazine prevented hypertension but not nephropathy. Decreased expression of aquaporin 1 and heme oxygenase-1 and increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and sodium–hydrogen exchanger 3 were observed in RPTCs of angiotensinogen-transgenic mice and in angiotensinogen-transfected immortalised RPTCs. These parameters were normalised by dual renin–angiotensin system blockade. Both in vivo and in vitro studies identified a novel mechanism in which angiotensinogen overexpression in RPTCs enhances the cytosolic accumulation of Nrf2 via the phosphorylation of pGSK3β Y216. Consequently, lower intranuclear Nrf2 levels are less efficient to trigger heme oxygenase-1 expression as a defence mechanism, which subsequently diminishes aquaporin 1 expression in RPTCs.Conclusions:Angiotensinogen-mediated downregulation of aquaporin 1 and Nrf2 signalling may play an important role in intrarenal renin–angiotensin system-induced hypertension and kidney injury.

Disputes in the Treatment of Diabetic Nephropathy: The Dual Blockade of Renin-Angiotensin System.

The prevention and the treatment with drugs interacting with the renin-angiotensin system (RAAS) are one of the greatest successes of the pharmacological research in the last years. Many trials demonstrated the efficacy of ARBs and ACEi in preventing or reducing the progression of albuminuria, the loss of kidney function and the mortality in diabetic population.The rationale for applying a dual RAAS blockade is based on data showing that ACEi mono-therapy produces an incomplete RAAS blockade with angiotensin I and renin accumulation and the subsequent angiotensin II 'escape' production by non-ACE pathways. The use of ARBs and ACEi in combination could lead to a stronger RAAS block and consequently to a more effective nephroprotection. Years ago, some studies performed in small groups of patients with diabetic nephropathy confirmed the effectiveness of this pharmacological approach.In contrast recent important trials, like ONTARGET, ALTITUDE and VA NEPHRON-D failed to demonstrate the effectiveness of this therapeutic strategy, suggesting that probably not all the diabetic patients with nephropathy should be considered equal as regard the response to this therapy. These 3 long-term studies showed that the dual blockade of RAAS may bring cardiovascular and renal adverse events, even in presence of a reduction of albuminuria. Dual blockade of RAAS is not currently feasible in patients with diabetic nephropathy, but we consider that the effort to try to apply a complete RAAS blockade should be pursued and that probably through an accurate selection of patients in the future we could reconsider this kind of therapy.

Effect of single and dual renin-angiotensin blockade on stroke in patients with and without diabetes in VALIANT.

Concern has been raised about a possible increase in risk of stroke in patients with diabetes treated with the combination of the renin-inhibitor aliskiren and an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. We compared the rate of stroke in patients with and without diabetes treated with single or dual renin-angiotensin system blockade after acute myocardial infarction. We performed a post hoc analysis of the Valsartan in Acute Myocardial Infarction trial in which 14,703 patients with heart failure, left ventricular systolic dysfunction or both, were randomised to captopril (C), valsartan (V) or both (C + V) after 0.5-10 days after acute myocardial infarction and followed for a median of 2.1 years. We used Cox proportional-hazard regression to estimate the hazard ratios [HR (95% CI)] of stroke in each treatment group. Among patients with diabetes, 60/1303 (4.6%) receiving captopril, 60/1337 (4.5%) valsartan and 41/1340 (3.1%) valsartan plus captopril suffered a stroke: V + C versus V or C HR 0.68 (0.47-0.96), p = 0.03. The corresponding numbers in patients without diabetes were 106/3606 (2.9%), 97/3572 (2.7%) and 99/3545 (2.8%): V + C versus V or C HR 0.99 (0.78-1.26), p = 0.92 (interaction p = 0.08). The risk of stroke after myocardial infarction in patients with diabetes was lower in patients treated with both an angiotensin converting enzyme inhibitor and angiotensin receptor blocker than in patients receiving either monotherapy.