Renin-angiotensin-aldosterone Blockade Research Articles

Benefit of Renin Angiotensin Aldosterone Blockade in Kidney Transplant Recipients: Is the Verdict in or Still to Be Answered?

Benefit of Renin Angiotensin Aldosterone Blockade in Kidney Transplant Recipients: Is the Verdict in or Still to Be Answered?

Specifičnosti u lečenju hipertenzije kod bolesnika sa hroničnim bubrežnim oboljenjem

Today, it is believed that all over the world about 10% of the population has a kidney lesion, most often chronic kidney disease (CKD). Hypertension and diabetes mellitus are the most common causes of chronic kidney damage, and in everyday clinical practice, we often wonder whether hypertension is a consequence of a lesion of the kidney parenchyma and vasculature or is its cause. Patients with CKD have high cardiovascular (CV) morbidity and most often die from CV disease. The specificity of blood pressure treatment in patients with chronic kidney damage is that good control of hypertension not only leads to a reduction of CV risk but also to a slowing of the progression of chronic to terminal renal failure. There is no doubt that the first line of treatment for hypertension in patients with CKD is angiotensinconverting enzyme inhibitors (ACEi) and angiotensin-2 receptor blockers (ARB). They are recommended especially for those patients with diabetic nephropathy because, in addition to their antihypertensive effect, they reduce proteinuria, slow down the progression of chronic kidney failure, especially if given in the early stages of CKD, and reduce CV risk. However, for a long time, there have been controversial opinions about whether in the advanced stages of renal failure, when the glomerular filtration rate (GFR) is < 30 mL/min/1.73 m2, these drugs should be excluded. According to the latest KDIGO guidelines in 2021, renin-angiotensinaldosterone (RAAS) blockers are the first line in the treatment of proteinuric CKD patients, with and without diabetes mellitus, and in stage 4, with a note that these drugs should be continued in therapy unless there is marked hyperkalemia (potassium > 6 mmol/L), acute kidney damage or decrease in estimated glomerular filtration rate > 30%. The most important thing is to individualize the optimal therapy for each patient. In the guidelines for the treatment of hypertension in patients with CKD, there are no clear recommendations for the treatment of unregulated hypertension when target pressures cannot be achieved with RAAS blockade and when there are contraindications for the administration of this group of drugs. The addition of calcium channel blockers, diuretics, and beta blockers is based on expert opinion.

2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis

ObjectiveTo update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN).MethodsFollowing the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force...

CCR2 antagonism leads to marked reduction in proteinuria and glomerular injury in murine models of focal segmental glomerulosclerosis (FSGS).

Focal segmental glomerulosclerosis (FSGS) comprises a group of uncommon disorders that present with marked proteinuria, nephrotic syndrome, progressive renal failure and characteristic glomerular lesions on histopathology. The current standard of care for patients with FSGS include immunosuppressive drugs such as glucocorticoids followed by calcineurin inhibitors, if needed for intolerance or inadequate response to glucocorticoids. Renin-angiotensin-aldosterone (RAAS) blockers are also used to control proteinuria, an important signature of FSGS. Existing treatments, however, achieved only limited success. Despite best care, treatment failure is common and FSGS is causal in a significant proportion of end stage renal disease. Thus, an unmet need exists for novel disease modifying treatments for FSGS. We employed two widely-used murine models of FSGS to test the hypothesis that systemic inhibition of chemokine receptor CCR2 would have therapeutic benefit. Here we report that administration CCX872, a potent and selective small molecule antagonist of CCR2, achieved rapid and sustained attenuation of renal damage as determined by urine albumin excretion and improved histopathological outcome. Therapeutic benefit was present when CCX872 was used as a single therapy, and moreover, the combination of CCX872 and RAAS blockade was statistically more effective than RAAS blockade alone. In addition, the combination of CCR2 and RAAS blockade was equally as effective as endothelin receptor inhibition. We conclude that specific inhibition of CCR2 is effective in the Adriamycin-induced and 5/6 nephrectomy murine models of FSGS, and thus holds promise as a mechanistically distinct therapeutic addition to the treatment of human FSGS.

Renal Considerations in the Treatment of Hypertension.

There are renal implications when employing intensive blood pressure control strategies. While this approach provides cardiovascular benefit in patients with and without chronic kidney disease, the impact on renal disease progression differs according to the pattern of underlying renal injury. In the setting of proteinuria, stringent blood pressure control has generally conferred a protective effect on renal disease progression, but in the absence of proteinuria, this benefit tends to be much less impressive. Thiazide diuretics are frequently part of the regimen to achieve intensive blood pressure control. These drugs can cause hyponatremia and present with biochemical evidence mimicking the syndrome of inappropriate antidiuretic hormone secretion. Altered prostaglandin transport may explain the unique susceptibility to this complication observed in some patients. Hyperkalemia is also a complication of intensive blood pressure lowering particularly in the setting of renin-angiotensin-aldosterone blockade. There are strategies and new drugs now available that can allow use of these blockers and at the same time ensure a normal plasma potassium concentration.

Can SGLT2 Inhibitors Cause Acute Renal Failure? Plausible Role for Altered Glomerular Hemodynamics and Medullary Hypoxia.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide outstanding long-term cardiovascular and renal protection in high-risk patients with type 2 diabetes mellitus. Yet, despite encouraging renal safety outcomes reported in the EMPA-REG study, scattered reports suggest that there might be a risk for acute kidney injury (AKI), which may occasionally be fatal or might require renal replacement therapy. Reduced trans-glomerular pressure with a modest decline in kidney function, an inherent characteristic of SGLT2i therapy, conceivably forms the basis for the long-term renal protection, resembling agents that block the renin-angiotensin-aldosterone (RAAS) axis. Yet, a major decline in kidney function occasionally occurs, often associated with an acute illness or with specific co-administered medications. SGLT2i may lead to AKI by (a) effective volume depletion, due to excessive diuresis, particularly in hemodynamically unstable and volume-depleted patients; (b) excessive decline in trans-glomerular pressure, specifically in patients on RAAS blockade; and (c) induction of renal medullary hypoxic injury, related to enhanced distal tubular transport, especially with concomitant use of agents impairing medullary oxygenation, such as non-steroidal anti-inflammatory drugs and radiocontrast agents. The risk of developing renal impairment with SGLT2i and the role of these suggested mechanisms are yet to be defined, as there are conflicting data and inconsistent reporting with the various agents currently in use.

Diabetes Mellitus, Microalbuminuria, and Subclinical Cardiac Disease: Identification and Monitoring of Individuals at Risk of Heart Failure.

BackgroundPatients with type 2 diabetes mellitus and elevated urinary albumin:creatinine ratio (ACR) have increased risk of heart failure. We hypothesized this was because of cardiac tissue changes rather than silent coronary artery disease.Methods and ResultsIn a case‐controlled observational study 130 subjects including 50 ACR+ve diabetes mellitus patients with persistent microalbuminuria (ACR >2.5 mg/mol in males and >3.5 mg/mol in females, ≥2 measurements, no previous renin–angiotensin–aldosterone therapy, 50 ACR−ve diabetes mellitus patients and 30 controls underwent cardiovascular magnetic resonance for investigation of myocardial fibrosis, ischemia and infarction, and echocardiography. Thirty ACR+ve patients underwent further testing after 1‐year treatment with renin–angiotensin–aldosterone blockade. Cardiac extracellular volume fraction, a measure of diffuse fibrosis, was higher in diabetes mellitus patients than controls (26.1±3.4% and 23.3±3.0% P=0.0002) and in ACR+ve than ACR−ve diabetes mellitus patients (27.2±4.1% versus 25.1±2.9%, P=0.004). ACR+ve patients also had lower E′ measured by echocardiography (8.2±1.9 cm/s versus 8.9±1.9 cm/s, P=0.04) and elevated high‐sensitivity cardiac troponin T 18% versus 4% ≥14 ng/L (P=0.05). Rate of silent myocardial ischemia or infarction were not influenced by ACR status. Renin–angiotensin–aldosterone blockade was associated with increased left ventricular ejection fraction (59.3±7.8 to 61.5±8.7%, P=0.03) and decreased extracellular volume fraction (26.5±3.6 to 25.2±3.1, P=0.01) but no changes in diastolic function or high‐sensitivity cardiac troponin T levels.ConclusionsAsymptomatic diabetes mellitus patients with persistent microalbuminuria have markers of diffuse cardiac fibrosis including elevated extracellular volume fraction, high‐sensitivity cardiac troponin T, and diastolic dysfunction, which may in part be reversible by renin–angiotensin–aldosterone blockade. Increased risk in these patients may be mediated by subclinical changes in tissue structure and function.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01970319.

Discontinuation of Renine Angiotensine Aldosterone Blockade System did not reduced Post Coronary Surgery Renal Failure

Discontinuation of Renine Angiotensine Aldosterone Blockade System did not reduced Post Coronary Surgery Renal Failure Objective: To evaluate if preoperative discontinuation reninangiotensin- aldosterone blockade system (RAABS) reduces postoperative acute renal failure incidence in patients undergoing on or off pump coronary artery bypass grafting. Design: Prospective, double blind, randomized study. Setting: Single center study made in a tertiary cardiovascular care facility. Participants: Patients with at least one month of renin-angiotensinaldosterone blockade system treatment, scheduled for coronary artery bypass surgery were included. Patients with cardiogenic shock, acute or end stage chronic renal disease, acute coronary syndrome, hypertension development due to treatment suspension, acute heart failure or increased functional class of chronic heart failure within last 30 days were excluded. Interventions: Patients were randomized in two groups: a) 72 hours RAABS suspension and b) RAABS administration until surgery. Measurements and main results: post-operative acute renal failure was assumed by RIFLE criteria: whether as an increase of 0.5 mg/ dl and/or decrease of creatinine clearance of 75% and/or triplicated the serum creatinine value 48 hours after surgery. 118 patients were included, 83 male. Overall incidence of end point was 13.3%. The incidence was 6.8 vs. 14.3% p=0.38 (0.524 IC 95% 0.15 to 1.83) between discontinuation and continuation respectively. Conclusion: Discontinuation of RAABS system before coronary surgery did not reduce the incidence of post-operative acute renal failure.

Renin–angiotensin–aldosterone–blockade is associated with decreased use of antidepressant therapy in patients with type 1 diabetes and diabetic nephropathy

Hypertension and depression are frequent comorbidities of diabetes. Studies suggest that antihypertensive medication affecting the renin-angiotensin-aldosterone system (RAAS) might also relieve depression. Whether this is also seen in patients with type 1 diabetes is not known. We therefore studied whether use of RAAS-modifying medication is associated with reduced antidepressant use in type 1 diabetes. In all, 1,705 participants in the FinnDiane Study were included (57% men, mean age 46±11years). Data on medications were obtained from the Drug Prescription Register. Based on their albumin excretion rate (AER), the patients were classified as having normal AER, microalbuminuria, or macroalbuminuria. Diabetic nephropathy was defined as macroalbuminuria or end-stage renal disease (dialysis or renal transplant). A total of 8.4 and 10.9% of patients with and without RAAS-modifying medication, respectively, had antidepressant medication purchases (NS). In logistic regression analysis, after adjusting for potential confounding factors, use of RAAS-modifying medication was not associated with antidepressant purchases. However, when patients with and without diabetic nephropathy were analyzed separately, RAAS-modifying medication was associated with lower frequency of antidepressant purchases among patients with established diabetic nephropathy. In conclusion, use of RAAS-modifying medication may improve mood in patients with type 1 diabetes and established diabetic nephropathy.

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012

Diuretic use, RAAS blockade and morbidity in elderly patients presenting to the Emergency Department with non-specific complaints

Up to 20% of elderly patients present to the emergency department (ED) with non-specific complaints (NSC), such as "generalised weakness", the majority suffering from serious conditions requiring timely intervention. Little is known about the use and influence of diuretics and renin-angiotensin-aldosterone (RAAS) blockade on morbidity in those patients. Thehypothesis was tested that the use of diuretics and RAAS blockade could be associated with an increased incidence of serious conditions in those patients. During a 23-month period, all adult non-trauma patients with an Emergency Severity Index (ESI) of 2 or 3 were prospectively enrolled. Serious conditions were defined as potentially life-threatening conditions or conditions requiring early intervention to prevent further morbidity and mortality. Study population consisted of 633 patients with median age 82 years, median Charlson comorbidity index 2. 59% of all subjects suffered from a serious condition. 299 subjects (47.2%) used diuretics, of which 65.6% suffered from a serious condition. Combination therapy of RAAS blockade and diuretics was found in 158 subjects (24.9%), 70.3% of which suffered from a serious condition. The intake of two or more diuretics, loop diuretics and a combination therapy with diuretics and RAAS blockade were associated with an increased risk for serious condition (p = 0.036; p = 0.021; p = 0.004). Treatment with two or more diuretics, loop diuretics, or a combination therapy with RAAS blockade and diuretics are independently associated with serious condition and therefore should be recognized as "red flags" in elderly patients presenting to the ED with NSC.

Evaluation and Pharmacologic Approach to Patients with Resistant Hypertension

Patients are diagnosed as having resistant hypertension when they have blood pressure readings that remain above goal despite the concomitant use of 3 optimally dosed antihypertensive agents from different classes, with 1 of the agents being a diuretic. Prior to diagnosing a patient as having resistant hypertension, it is important to document adherence and exclude white–coat hypertension, inaccurate measurement of blood pressure, and secondary causes of hypertension (eg, aldosterone excess). After determining resistance, optimization of the medication regimen is essential. Combination strategies, which might include dual renin–angiotensin–aldosterone blockade with spironolactone as 1 agent, have been proven successful. This article focuses on the safety and efficacy of spironolactone when added to an optimized 3–drug regimen. Additionally, the use of spironolactone in chronic kidney disease and obstructive sleep apnea complicated by resistant hypertension is discussed. These 2 clinical entities are frequently accompanied by resistant hypertension and are indications for the use of spironolactone as well.

Body Mass Index and the Risk of Progression of Chronic Kidney Disease

To examine the independent relationship between obesity, as estimated by body mass index (BMI), and progression of chronic kidney disease. We hypothesized that BMI would be associated with decline in estimated glomerular filtration rate (eGFR), independent of diabetes mellitus, hypertension, and other risk factors for progression of chronic kidney disease. A retrospective cohort study was carried out. The study was carried out at Nephrology ambulatory clinics of the London Health Sciences Centre, Canada. The study included incident and prevalent patients with eGFR <60 mL/min/1.73 m(2). Eligible patients were observed between the calendar years 2005 and 2007. Subjects were excluded on the basis of <12 months of follow-up, age <18 years, or past kidney transplantation. Least-squares regression was used to estimate change of eGFR over time. Baseline clinical and demographic factors, including BMI and diabetes, were examined in univariate and multivariate analyses. Change in eGFR over time was assessed in this study. A total of 214 subjects were observed for a mean of 4.48 ± 1.84 years. In univariate analysis, BMI was not statistically associated with eGFR change as either a continuous or a categorical variable. Using a BMI cut-off of 30 kg/m(2), no statistical difference in slope of eGFR was found, with a decline of 2.2 mL/min/1.73 m(2) per year in the nonobese group, and 2.69 mL/min/1.73 m(2) per year in the obese group (P = .13). Multivariate analysis demonstrated high baseline eGFR, proteinuria, and diabetic nephropathy to be associated with a faster decline in eGFR. Use of renin-angiotensin-aldosterone blockade was associated with an improved slope of eGFR over time. Our results do not support the hypothesis that obesity is independently associated with a decline in kidney function.

Does concurrent renin‐angiotensin‐aldosterone blockade in (older) chronic kidney disease patients play a role in the acute renal failure epidemic in US hospitalized patients?—Three cases of severe acute renal failure encountered in a northwestern Wisconsin Nephrology practice

Following the publication of several large multicenter randomized placebo-controlled trials showing reno-protection with renin-angiotensin-aldosterone (RAAS) blockade, the last 2 decades have witnessed an escalating use of the angiotensin-converting enzyme inhibitors and the angiotensin receptor blockers. Simultaneously, we continue to experience an increasing epidemic of acute renal failure (ARF) both in community-based and in hospital-based studies. Even though other factors would be contributing to this ARF epidemic, recent published data have raised concerns of a plausible connection between increased use of the RAAS blocking agents and this ARF epidemic. In our 4-nephrologist northwestern practice, we have, in recent years, anecdotally encountered an increasing number and severity of ARF, often with hyperkalemia, sometimes requiring dialysis intervention, in patients concurrently on these agents. Over the 3-day Christmas weekend in 2007, we treated 3 cases of severe ARF (peak serum creatinine of 7.0 (3.3-9.2) mg/dL), all on RAAS blockade. Renin-angiotensin-aldosterone blockade was promptly discontinued. All patients received intravenous fluid repletion. Kidney function rapidly normalized in 2 within 1 week. One patient required hemodialysis for 14 days before his serum creatinine returned to normal after 5 weeks. All 3 patients have continued to maintain baseline serum creatinine several months later, still off RAAS blockade. The mean baseline eGFR for the 3 patients was 46 (41-51) mL/min/1.73 m(2) body surface area. This phenomenon of ARF exacerbation, which may have implications for chronic kidney disease progression to ESRD especially in the elderly, merits further study. We support the recommendation that (older, >65 years old) chronic kidney disease patients on RAAS blocking agents should have the medications temporarily suspended during any acute illness, before major surgical procedures, and before iodinated contrast or oral phosphate sodium administration.

AT1 receptor antagonists—beyond blood pressure control: possible place in heart failure treatment

The renin-angiotensin system (RAS) plays an important role in heart failure, and renin angiotensin aldosterone blockade has been shown to be of benefit in its treatment. The effectiveness of angiotensin...