Renin-angiotensin System Blockade Research Articles

Real-world effectiveness of sodium-glucose cotransporter-2 inhibitors on the progression of chronic kidney disease in patients without diabetes, with and without albuminuria.

To examine the renal effects of sodium-glucose cotransporter-2 (SGLT2) inhibition among non-diabetic individuals with chronic kidney disease (CKD) in a real-world setting. We collected de-identified data on adults without diabetes and with an estimated glomerular filtration rate (eGFR) of 25-60 mL/min/1.73 m2, who initiated the SGLT2 inhibitors dapagliflozin or empagliflozin between September 2020 and November 2022 at Maccabi Healthcare Services, an Israeli health maintenance organization. We assessed the effects of SGLT2 inhibitors on renal function (changes in eGFR slope/time). Index date was defined as the date of the first dispensing of SGLT2 inhibitors. Annual baseline slope was calculated using all eGFR measurements during the 2 years prior to index date (median = 7 measurements), while annual follow-up slope was calculated from all evaluations during 90-900 days post index date, along with baseline measurement at index date (median = 6 measurements). Paired t tests were used to compare differences between baseline and follow-up annual slopes. Of a total of 354 participants with CKD, without diabetes, who received SGLT2 inhibitors and were followed for a median of 527 days, the mean age was 72.8 ± 11.8 years, 26% were female, and 91% used renin-angiotensin system blockade. The mean eGFR was 45.4 ± 9.5 mL/min/1.73 m2. The mean body mass index was 29.1 ± 5.4 kg/m2. During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) <30 mg/g, 81 (23%) had a UACR of 30-300 mg/g, 74 (21%) had a UACR >300 mg/g, and 53 (15%) had no UACR evaluation. The mean eGFR slope over time was -5.6 ± 7.7 mL/min/1.73 m2 per year at baseline, which improved to -1.7 ± 6.8 mL/min/1.73 m2 per year after SGLT2 inhibitor administration (p <0.001). This effect was independent of UACR. In a real-world study of primarily older non-diabetic adults with CKD, SGLT2 inhibition was associated with a slower rate of kidney function decline, regardless of baseline UACR level.

Dihydropyridine Calcium Channel Blockers and Kidney Outcomes.

Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria. We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade modified these associations. We conducted a target trial emulation study using a new user, active comparator design and electronic health record data from Geisinger Health. We included patients without severe albuminuria or KFRT who were initiated on a DCCB or thiazide (active comparator) between January 1, 2004, and December 31, 2019. Using inverse probability of treatment weighting, we performed doubly robust Cox proportional hazards regression to estimate the association of DCCB initiation with incident severe albuminuria (urine albumin to creatinine ratio > 300 mg/g) and KFRT, overall and stratified by RAS blocker use. There were 11,747and 26,758 eligible patients initiating a DCCB and thiazide, respectively, with a weighted baseline mean age of 60 years, systolic blood pressure of 143 mm Hg, and eGFR of 86 mL/min/1.73 m2, and with a mean follow-up of 8 years. Compared with thiazides, DCCBs were significantly associated with the development of severe albuminuria (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.16-1.43), with attenuation of risk in the presence of RAS blockade (P for interaction < 0.001). The risk of KFRT was increased among patients without RAS blockade (HR, 1.66; 95% CI, 1.19-2.31), but not with RAS blockade (P for interaction = 0.005). DCCBs were associated with increased risk of albuminuria and, in the absence of RAS blockade, KFRT. These findings suggest coupling DCCB therapy with RAS blockade may mitigate adverse kidney outcomes.

Non-steroidal anti-inflammatory drugs, renin-angiotensin system blockade or diuretics and risk of acute kidney injury: A case-crossover study

BackgroundAging-related physiological changes, such as decline in renal function, not only exacerbates pre-existing comorbidities but also escalate the susceptibility to adverse events. Previous studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI), and the concomitant use of renin-angiotensin system blockade or diuretics may further potentiate the risk. However, studies evaluating the risk of AKI associated with NSAIDs (including routes, concomitant use of different NSAIDs, categories (traditional NSAIDs or COX-2 inhibitors), and cumulative doses of NSAIDs) are limited, particularly the risk of AKI associated with the dual or triple combination of NSAIDs with renin-angiotensin system blockade (RAS blockades) and/or diuretics. MethodsA case-crossover study utilized two sets of longitudinal data from Taiwan's National Health Insurance Research Database (NHIRD). Newly admitted patients with a primary AKI diagnosis were included, with the index date defined as the first admission date. The 1–7 days and 181–187 days prior to the index date served as the case and control periods. Exposure to NSAIDs and co-exposures of RAS blockade and/or diuretics were assessed in both periods. Multivariable conditional logistic regression models, adjusting for potential confounders, estimated adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) for AKI associated with NSAIDs, dual, or triple combinations. Sensitivity analyses explored result robustness by varying case and control period lengths. ResultsThe study included 1,284 newly diagnosed AKI patients. NSAIDs showed a 3.55-fold increased risk of AKI (aOR: 3.55; 95 % CI 2.70–4.65), with similar risks for traditional NSAIDs and COX-2 inhibitors. Use of multiple NSAIDs, parenteral dosage forms, and higher cumulative doses increased AKI risk. Dual combination with either RAS blockade or diuretics resulted in a 2.90-fold (aOR: 2.90; 95 %CI 1.47–5.70) and 12.68-fold (aOR: 12.68; 95 %CI 6.15–26.12) risk, respectively. The highest risk occurred with triple combination (aOR: 29.22; 95 %CI 12.82–66.64). ConclusionsNSAIDs, including both non-selective NSAIDs and COX2 inhibitors, elevate the risk of AKI. Increased AKI risk is linked to using multiple NSAIDs, the parenteral dosage form, and higher cumulative doses. Dual combination of RAS blockade with NSAIDs or diuretics with NSAIDs, as well as triple therapy, heightens the risk, with the latter associated with the highest risk of AKI.

Four-week inhibition of the renin-angiotensin system in spontaneously hypertensive rats results in persistently lower blood pressure with reduced kidney renin and changes in expression of relevant gene networks.

Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown. In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme (ACE) inhibitor, perindopril (with controls for non-specific effects of lowering BP) on differential RNA expression, DNA methylation and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a 6-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 x 10-6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4), the miRNA miR-145-3p and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS and the kidneys. Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks.

Unveiling the pathogenesis and therapeutic approaches for diabetic nephropathy: insights from panvascular diseases.

Diabetic nephropathy (DN) represents a significant microvascular complication in diabetes, entailing intricate molecular pathways and mechanisms associated with cardiorenal vascular diseases. Prolonged hyperglycemia induces renal endothelial dysfunction and damage via metabolic abnormalities, inflammation, and oxidative stress, thereby compromising hemodynamics. Concurrently, fibrotic and sclerotic alterations exacerbate glomerular and tubular injuries. At a macro level, reciprocal communication between the renal microvasculature and systemic circulation establishes a pernicious cycle propelling disease progression. The current management approach emphasizes rigorous control of glycemic levels and blood pressure, with renin-angiotensin system blockade conferring renoprotection. Novel antidiabetic agents exhibit renoprotective effects, potentially mediated through endothelial modulation. Nonetheless, emerging therapies present novel avenues for enhancing patient outcomes and alleviating the disease burden. A precision-based approach, coupled with a comprehensive strategy addressing global vascular risk, will be pivotal in mitigating the cardiorenal burden associated with diabetes.

Influence of renin-angiotensin system blockades on vascular access survival in patients on maintenance hemodialysis.

Results on the association between the use of renin-angiotensin system blockades (RASBs) and vascular access-related outcomes are inconsistent. We aimed to compare vascular access-related outcomes according to the use of RASBs in hemodialysis patients. This study used data from a national hemodialysis quality assessment program of the Republic of Korea (n = 54,903). Group 1 was not prescribed any blood pressure-lowering drugs (n = 28,521). Group 2 was prescribed other blood pressure-lowering agents except for RASBs (n = 9571). Group 3 was prescribed RASBs (n = 16,811). Vascular access-related outcomes were classified into intervention-free survival (IFS), thrombosis-free survival (TFS), and vascular access survival (VAS). No significant difference in the three access survival rates was identified among the three groups. The multivariate Cox regression analyses indicated that Group 3 had better outcomes in IFS and TFS than Group 1. The numbers of angioplasties performed were significantly greater in Group 1 than in the other two groups. The numbers of thrombectomies performed were significantly the lowest in Group 3 among all the groups. Our study revealed different results according to types of access survival in univariate or multivariate analyses. The association of RASBs with favorable outcomes in vascular access remains unclear.

Combining renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibition in experimental diabetes results in synergistic beneficial effects.

Sodium-glucose cotransporter-2 (SGLT2) inhibition exerts cardioprotective and renoprotective effects, often on top of renin-angiotensin system (RAS) blockade. We investigated this in diabetic hypertensive (mREN2)27 rats. Rats were made diabetic with streptozotocin and treated with vehicle, the angiotensin receptor blocker valsartan, the SGLT2 inhibitor empagliflozin, or their combination. Blood pressure (BP) was measured by telemetry. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis, without a change in glomerular filtration rate. Empagliflozin did not lower BP, while valsartan did, and when combined the BP drop was largest. Only dual blockade reduced cardiac hypertrophy and prevented left ventricular dilatation. Valsartan, but not empagliflozin, increased renin, and the largest renin rise occurred during dual blockade, resulting in plasma angiotensin II [but not angiotensin-(1-7)] upregulation. In contrast, in the kidney, valsartan lowered angiotensin II and angiotensin-(1-7), and empagliflozin did not alter this. Although both valsartan and empagliflozin alone tended to diminish albuminuria, the reduction was significant only when both drugs were combined. This was accompanied by reduced glomerulosclerosis, no change in glomerular filtration rate, and a favorable expression pattern of fibrosis and inflammatory markers (including SGLT2) in the kidney. RAS blockade and SGLT2 inhibition display synergistic beneficial effects on BP, kidney injury and cardiac hypertrophy in a rat with hypertension and diabetes. The synergy does not involve upregulation of angiotensin-(1-7), but may relate to direct RAS-independent effects of empagliflozin in the heart and kidney.

Understanding patient needs and predicting outcomes in IgA nephropathy using data analytics and artificial intelligence: a narrative review.

This narrative review explores two case scenarios related to immunoglobulin A nephropathy (IgAN) and the application of predictive monitoring, big data analysis and artificial intelligence (AI) in improving treatment outcomes. The first scenario discusses how online service providers accurately understand consumer preferences and needs through the use of AI-powered big data analysis. The author, a clinical nephrologist, contemplates the potential application of similar methodologies, including AI, in his medical practice to better understand and meet patient needs. The second scenario presents a case study of a 20-year-old man with IgAN. The patient exhibited recurring symptoms, including gross haematuria and tonsillitis, over a 2-year period. Through histological examination and treatment with renin-angiotensin system blockade and corticosteroids, the patient experienced significant improvement in kidney function and reduced proteinuria over 15years of follow-up. The case highlights the importance of individualized treatment strategies and the use of predictive tools, such as AI-based predictive models, in assessing treatment response and predicting long-term outcomes in IgAN patients. The article further discusses the collection and analysis of real-world big data, including electronic health records, for studying disease natural history, predicting treatment responses and identifying prognostic biomarkers. Challenges in integrating data from various sources and issues such as missing data and data processing limitations are also addressed. Mathematical models, including logistic regression and Cox regression analysis, are discussed for predicting clinical outcomes and analysing changes in variables over time. Additionally, the application of machine learning algorithms, including AI techniques, in analysing big data and predicting outcomes in IgAN is explored. In conclusion, the article highlights the potential benefits of leveraging AI-powered big data analysis, predictive monitoring and machine learning algorithms to enhance patient care and improve treatment outcomes in IgAN.

Systemic and targeted steroids for the treatment of IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is a common glomerulonephritis partially correlated with mucosal immune system dysfunction. Progressive renal failure occurs in many patients, with about 30-50% of the patients with IgAN developing end-stage kidney disease (ESKD). Many treatments have been used for decades, despite uncertainty about their effectiveness and the ideal dose. Randomised controlled trials reported that systemic glucocorticoids can be an effective treatment for patients with persistent and significant proteinuria despite renin-angiotensin system inhibitors use possibly causing systemic side effects. The primary focus of IgAN management should be based on optimised supportive care, including renin-angiotensin system (RAS) blockade and now SGLT2 inhibitors. The novel targeted-release formulation (TRF) of budesonide has been tested to reduce the adverse events of systemic steroids by delivering the drug to the distal ileum. The local efficacy of TRF-budesonide may represent a novel and promising approach to treating IgAN. Two clinical trials showed that TRF-budesonide could significantly reduce proteinuria and haematuria and possibly preserve renal function while significantly reducing the side effects. However, the limited number of treated patients and the relatively short follow-up suggest caution before considering budesonide superior to the current six-months steroid pulses scheme. Long-term data on the efficacy and safety of TRF budesonide are awaited, together with the design of trials with a head-to-head comparison with systemic steroids before considering TRF-budesonide as the standard of care treatment for IgAN nephropathy.

Randomized Trial of SGLT2 Inhibitor Identifies Target Proteins in Diabetic Kidney Disease

IntroductionSodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as novel therapeutics to treat diabetic kidney disease (DKD). Albeit the beneficial effects of SGLT2i have been demonstrated, their target mechanisms on kidney function are unknown. The current study aimed to elucidate these mechanisms by studying SGLT2i-induced changes in the urinary proteome of persons with type 2 diabetes (T2D) and DKD. Methods40 T2D participants were enrolled in a double blind randomized cross-over trial at the Steno Diabetes Center Copenhagen, Denmark. They were treated with 10 mg of dapagliflozin for 12 weeks. 32 participants with complete urinary proteomics measures before and after the trial were included. All participants received RAS blockade and had albuminuria, (UACR ≥ 30 mg/g). A type 1 diabetes cohort consisting healthy controls and persons with DKD was included for validation. Urinary proteome changes were analyzed using Wilcoxon signed-rank test. Functional enrichment analysis was conducted to discover affected biological processes. ResultsDapagliflozin treatment significantly (Padjusted < 0.05) affected 36 urinary peptide fragments derived from 19 proteins. 18 proteins were correspondingly reflected in the validation cohort. A multi-fold change in peptide abundance was observed in many proteins (A1BG, ALB, CALD1, COLCRNN, HSP90AB1, IGLL5, PI16, PTGDS, SERPINA1). These also included urinary biomarkers of kidney fibrosis and function (type I & III collagens and albumin). Biological processes relating inflammation, wound healing, and kidney fibrosis were enriched. ConclusionThe current study discovers the urinary proteome impacted by the SGLT2i providing new potential target sites and pathways especially relating to wound healing and inflammation.

Renal safety and survival among acutely ill hospitalized patients treated by blockers of the Renin-Angiotensin axis or loop diuretics: a single-center retrospective analysis

Background Concern exists regarding the renal safety of blocking the renin-angiotensin system (RAS) during acute illness, especially in the presence of volume depletion and hemodynamic instability. Methods We explored the impact of loop diuretics and RAS blockers on the likelihood of developing acute kidney injury (AKI) or acute kidney functional recovery (AKR) among inpatients. Adjusted odds ratio for AKI, AKR and mortality was calculated, using logistic regression models, with subgroup analysis for patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2, corrected for blood pressure measurements. Results 53,289 patients were included. RAS blockade was associated with reduced adjusted odds ratio for both AKI (0.76, CI 0.70–0.83) AKR (0.55, 0.52–0.58), and mortality within 30 days (0.44, 0.41–0.48), whereas loop diuretics were associated with increased risk of AKI (3.75, 3.42–4.12) and mortality (1.71, 1.58–1.85) and reduced AKR (0.71, 0.66–0.75). Comparable impact of RAS blockers and loop diuretics on renal outcomes and death was found among 6,069 patients with eGFR < 30 ml/min/1.73m2. RAS inhibition and diuretics tended to increase the adjusted odds ratios for AKI and to reduce the likelihood of AKR in hypotensive patients. Conclusions Reduced blood pressure, RAS blockers and diuretics affect the odds of developing AKI or AKR among inpatients, suggesting possible disruption in renal functional reserve (RFR). As long as blood pressure is maintained, RAS inhibition seems to be safe and renoprotective in this population, irrespective of kidney function upon admission, and is associated with reduced mortality.

Abstract 16652: Cardiovascular Outcomes of Renin-Angiotensin System Inhibition Amongst Non-Proteinuric Chronic Kidney Disease Patients in the Chronic Renal Insufficiency Cohort

Introduction: Chronic kidney disease is a leading cause of CVD morbidity and mortality. The majority of CKD patients do not have proteinuria. Current therapies, including renin-angiotensin system (RAS) blockers, are only known to be beneficial in proteinuric CKD. Our goal was to evaluate the association of RAS blockade with long-term CVD outcomes and survival among those with non-proteinuric CKD. Methods: The cohort included subjects in the prospective Chronic Renal Insufficiency Cohort Study without proteinuria at study entry. Non-proteinuric CKD was defined as urine protein &lt;0.5g/day. We excluded subjects with heart failure or not on hypertension treatment. We used Cox proportional hazards regression to evaluate the association of RAS blockade vs. other antihypertensive therapy with CVD outcomes and death. The primary outcome was a composite of physician-adjudicated CVD events, including MI, stroke, heart failure hospitalization and death. Baseline covariates were adjusted through inverse probability of treatment weighting including: age, sex, race, education, smoking, BMI, diabetes, blood pressure, eGFR, and statin use. Results: A total of 2,825 of subjects met inclusion criteria. There were 2,068 subjects using vs 757 not using (73% vs 27%) RAS blockade at entry. Users had a similar age (61 vs 62 years) and eGFR (50 vs 51ml/min/1.73m 2 ) to non-users. Users were more likely to be male (66% vs 46%), to have diabetes (59% vs 30%), and to be on a statin (61% vs 50%). No significant association was found between RAS blockade and CVD events (adjusted HR 0.90, 95% CI 0.76-1.07) or mortality (adjusted HR 0.84, 95% CI 0.68-1.04) compared to other antihypertensive therapy. Conclusions: Among adults with non-proteinuric CKD, baseline use of RAS blockade was not associated with a lower risk of long-term events or mortality. Further studies are needed to determine if RAS blockade may play a role in high-risk patients with non-proteinuric CKD.

Renin Trajectories and Outcome in Stable Heart Failure with Reduced Ejection Fraction (HFrEF) on Contemporary Therapy: A Monocentric Study from an Austrian Tertiary Hospital Outpatient Clinic

Introduction. The renin-angiotensin system (RAS) is the main target of neurohumoral therapy in heart failure with reduced ejection fraction (HFrEF) effectively reducing mortality. Reasonably, renin might serve as a biomarker for risk prediction and therapy response. Renin indeed bears some additional value to clinical risk models, albeit the effect is not pronounced. Whether assessing renin trajectories can overcome the weaknesses of single renin measurements has not been reported. Methods. A total of 505 patients with stable HFrEF were enrolled prospectively and followed through routine clinical visits. Active plasma renin concentration was documented up to 5 years. Changes in renin were analyzed throughout the disease course, and survival was compared for different renin trajectories within the first year. Results. Baseline renin levels were not related to all-cause mortality (crude HR for an increase of 100 μiE/ml: 1.01 (95% CI: 0.99–1.02), p = 0.414 ) but associated with unplanned HF hospitalizations (crude HR: 1.01 (95% CI: 1.00-1.02), p = 0.015 ). Renin increased during the disease course from baseline to 1-year and 2-year FUP (122.7 vs. 185.6 μIU/ml, p = 0.039 , and 122.7 vs. 258.5 μIU/ml, p = 0.001 ). Both survival and unplanned HF hospitalization rates were comparable for different renin trajectories at 1-year FUP ( p = 0.546 , p = 0.357 ). Conclusions. Intriguingly, renin is not a good biomarker to indicate prognosis in HF, while renin trajectories over a 1-year period do not have an additional value. Rapid physiologic plasma renin variations, but also opposing effects of angiotensinogen-derived metabolites under presence of RAS blockade, might obscure the predictive ability of renin.

Should we enlarge the indication for kidney biopsy in diabetics? The con part.

Diabetes is the most common cause of chronic kidney disease (CKD), a condition found in 850 million persons and projected to become the fifth global cause of death by 2040. Research is needed that examines kidney tissue to characterize distinct phenotypes in patients with diabetes mellitus (DM) and CKD so as to identify non-invasive biomarker signatures and develop targeted therapeutic approaches. However, from a routine care point of view, kidney biopsy is likely overused in patients with CKD and DM, as most biopsy results are not expected to be associated with a therapeutic approach that differs from standard kidney protection with triple or quadruple therapy (renin-angiotensin system blockade, sodium-glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists and glucagon-like peptide-1 receptor agonists). Moreover, expanding the kidney biopsy criteria will increase the absolute number of complications from kidney biopsies, which may reach 27000 to 108000 deaths of persons that would derive little benefit from kidney biopsy if all people with DM and severe CKD were biopsied globally. Finally, limited resources should be optimally allocated. The cost of one kidney biopsy can fund 7000 semiquantitative urinary albumin:creatinine ratio assessments that could identify earlier stages of the disease and allow treatment that prevents progression to a stage at which kidney biopsy may be considered.

Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy for CKD but are underused, in part because they are frequently withheld and not restarted due to hyperkalemia, AKI, or hospitalization. Consequently, ensuring persistent use of ACE inhibitors and ARBs in CKD has long been a major clinical priority. In this joint analysis of the CREDENCE and DAPA-CKD trials, the relative risk of discontinuation of ACE inhibitors and ARBs was reduced by 15% in patients randomized to sodium-glucose cotransporter 2 (SGLT2) inhibitors. This effect was more pronounced in patients with urine albumin:creatinine ratio ≥1000 mg/g, for whom the absolute benefits of these medications are the greatest. These findings indicate that SGLT2 inhibitors may enable better use of ACE inhibitors and ARBs in patients with CKD. Strategies to enable persistent use of renin-angiotensin system (RAS) blockade to improve outcomes in CKD have long been sought. The effect of SGLT2 inhibitors on discontinuation of RAS blockade has yet to be evaluated. We conducted a joint analysis of canagliflozin and renal events in diabetes with established nephropathy clinical evaluation (CREDENCE) and dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD), two randomized, double-blind, placebo-controlled, event-driven trials of SGLT2 inhibitors in patients with albuminuric CKD. The main outcome was time to incident temporary or permanent discontinuation of RAS blockade, defined as interruption of an ACE inhibitor or ARB for at least 4 weeks or complete cessation during the double-blind on-treatment period. Cox regression analyses were used to estimate the treatment effects from each trial. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled with fixed effects meta-analysis to obtain summary treatment effects, overall and across key subgroups. During median follow-up of 2.2 years across both trials, 740 of 8483 (8.7%) patients discontinued RAS blockade. The relative risk for discontinuation of RAS blockade was 15% lower in patients randomized to receiving SGLT2 inhibitors (HR, 0.85; 95% CI, 0.74 to 0.99), with consistent effects across trials ( P -heterogeneity = 0.92). The relative effect on RAS blockade discontinuation was more pronounced among patients with baseline urinary albumin:creatinine ratio ≥1000 mg/g (pooled HR, 0.77; 95% CI, 0.63 to 0.94; P -heterogeneity = 0.009). In patients with albuminuric CKD with and without type 2 diabetes, SGLT2 inhibitors facilitate the use of RAS blockade. ClinicalTrials.gov, NCT02065791 and NCT03036150 . This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_11_21_JASN0000000000000248.mp3.

Targeting Angiotensinogen With N-Acetylgalactosamine-Conjugated Small Interfering RNA to Reduce Blood Pressure.

Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent N-acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.

Renin Inhibition and the Long-Term Renal Function in Patients With Hypertensive Emergency: A Retrospective Cohort Study.

The rehospitalization rate in a hypertensive emergency is high, indicating the necessity for optimizing its long-term management. The role of the renin-angiotensin system (RAS) blockade in this disorder remains uncertain. We conducted a retrospective analysis involving 20 admitted patients who received aliskiren, a direct renin inhibitor (DRI), for the management of hypertensive emergency associated with elevated plasma renin activity (PRA). We analyzed the changes in blood pressure (BP), kidney function, and RAS activity in the subacute and chronic phases. The use of DRI was associated with a marked reduction in PRA (median, from 25.0 to 1.2 ng/ml/h) and serum aldosterone levels (from 404 to 130 pg/ml) during the index admission. BP also decreased from 226/143 to 142/80 mm Hg. A comparison of clinical characteristics according to the renal function indicated that dialysis-dependent patients had higher aldosterone levels than non-dialysis-dependent patients at admission, despite comparable BP levels. After a median follow-up of 567 days in non-dialysis-dependent patients with DRI, eGFR levels were significantly increased from 14.3 to 23.1 ml/min/1.73 m2. PRA levels were consistently suppressed at 0.8 ng/ml/h. We found a significant correlation between the degree of PRA suppression and changes in eGFR (r = -0.58), indicating that the effective blockade of RAS is associated with the preservation of eGFR in the study subjects. DRI can successfully suppress PRA in patients with high-renin hypertensive emergency in both subacute and chronic phases. An efficient RAS blockade is associated with preserved renal function in these patients.

Paradoxically Effects of Renin-Angiotensin System Suppression

Abstract Is any specific organ protection by blocking the renin-angiotensin system? What is the role of the renin-angiotensin system (RAS) in progressive renal disease? The renoprotective effect of ACE-inhibitors and angiotensin II (Ang II) receptor blockers is not only mediated via their renal hemodynamic effects, but also through non-hemodynamic mechanisms? What is the clinical evidence for the importance of local renin-angiotensin system (RAS)? These are several questions of a medical reality: that pharmacological blockade of reninangiotensin system (RAS) is paradoxically effective although circulating plasma renin activity (PRA) is low. An overview of the normal function of the system, as well as ramifications of its dysfunction (overactivity) and potentials for therapeutic blockade, is provided below.

Cardiorenal Outcomes with Finerenone in Asian Patients with Chronic Kidney Disease and Type 2 Diabetes: A FIDELIO-DKD post hoc Analysis

Introduction: In FIDELIO-DKD, finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease and type 2 diabetes (T2D). This post hoc analysis explores finerenone in patients from the Asian region. Methods: In FIDELIO-DKD, 5,674 patients with T2D and urine albumin-to-creatinine ratio (UACR) ≥30–<300 mg/g and estimated glomerular filtration rate (eGFR) ≥25–<60 mL/min/1.73 m² or UACR ≥300–≤5,000 mg/g and eGFR ≥25–<75 mL/min/1.73 m², treated with optimized renin-angiotensin system blockade, were randomized 1:1 to finerenone or placebo. Efficacy outcomes included a primary kidney composite (time to kidney failure, sustained decrease of ≥40% in eGFR from baseline, and death from renal causes) and secondary cardiovascular (CV) (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and kidney (time to kidney failure, sustained decrease of ≥57% in eGFR from baseline, and death from renal causes) composites. Results: Of 1,327 patients in the Asian subgroup, 665 received finerenone. Finerenone reduced the ≥40% and ≥57% eGFR kidney and CV composite outcomes versus placebo in the Asian subgroup (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.56–0.87, HR: 0.73; 95% CI: 0.55–0.97, and HR: 0.85; 95% CI: 0.59–1.21, respectively), with no apparent differences versus patients from the rest of the world (HR: 0.88; 95% CI: 0.77–1.02; p interaction 0.09, HR: 0.78; 95% CI: 0.64–0.95; p interaction 0.71, and HR: 0.86; 95% CI: 0.74–1.00; p interaction 0.95, respectively). The safety profile of finerenone was similar across subgroups. Conclusion: Finerenone produces similar cardiorenal benefits in Asian and non-Asian patients.

Abstract P220: Angiotensin II Dependent And Independent Pressor Effect Of Ang-(1-12)

Background: Ang-(1-12) serves as a functional substrate for the formation of Ang II in the blood and tissues. It remains unknown whether the hypertensive effect of Ang-(1-12) is solely caused by Ang II formation or whether the peptide itself exerts a pressor effect by binding to the AT1-receptor or a yet-to-be-identified receptor subtype. Here we examined the possibility of Ang II independent pressor effects of Ang-(1-12). Methods: Anesthetized male c57bl6 mice were injected with Ang II or Ang-(1-12) (0.2 μg/g BW) and the systolic blood pressure (SBP) was measured continuously for 15 minutes. To evaluate whether Ang-(1–12) vasoconstrictor activity is due to its processing into Ang II, mice were preinjected with Telmisartan or Lisinopril before Ang-(1-12) injection. We further assessed the effect of recombinant (r) ACE2 as a way to augment Ang II metabolism and therefore unravel Ang II independent pressor effects of Ang-(1-12). Results: Ang-(1-12) infusion led to a peak increase in SBP almost as high as Ang II (145 ±24 mmHg vs. 160±26 mmHg, respectively). The pressor effect of Ang-(1-12) was completely abolished by either Telmisartan or Lisinopril (103±11 mmHg and 98±12 mmHg, respectively). rACE2 prevented the sustained rise in SBP induced by Ang II (Fig. 1), but it did not affect the pressor effect of Ang-(1-12) (Fig. 1). Conclusions: Ang-(1–12) hypertensive effect is blocked by RAS blockade consistent with an action dependent on Ang II formation and coupling to AT-1 receptors. In contrast, Ang-(1–12) pressor activity is not modified when Ang II is rapidly metabolized by rACE2. These data suggest a vasoactive action of Ang-(1–12) that is, in part, independent of its conversion into Ang II.