Angiotensin-converting Enzyme Inhibitor Therapy Research Articles

#530 Cardiorenal effects of dual blockade with ACE inhibitors and ARBs among people with CKD: emulation of a reference trial (ONTARGET) using CPRD

Abstract Background and Aims Cardiovascular disease (CVD) is a leading cause of death globally, and individuals with chronic kidney disease (CKD) are at increased risk. Results from the ONTARGET trial, in conjunction with the ALTITUDE and VA-Nephron-D studies, led to an end of recommendations for dual ACE inhibitor and ARB therapy due to an increase in acute kidney injury. However, these studies had low power to address long-term kidney outcomes and there remains uncertainty about whether dual therapy could be effective at reducing adverse cardiovascular and renal outcomes in patients with CKD. Observational data provides an opportunity to explore such hypotheses in subgroups underrepresented in trials and with power and follow-up enabling estimation of risk of rare outcomes. We aimed to use ONTARGET to perform a reference trial emulation analysis, before extending analysis to explore treatment effectiveness of dual ARB and ACEi use vs ACEi alone in preventing cardiovascular and renal outcomes among those with CKD. Method Using routinely-collected data from the UK Clinical Practice Research Datalink (CPRD) Aurum linked with Hospital Episode Statistics secondary care data, we applied the ONTARGET trial eligibility criteria to patients prescribed an ARB/ACE inhibitor between 1/1/2001-31/7/2019. As the number of patients receiving prescriptions for both medications on the same day was likely to be small in routine care, we used an operational definition to capture dual users. Outcomes included ONTARGET primary cardiovascular composite outcome of cardiovascular-related death, myocardial infarction, stroke, or hospitalisation for heart failure and a composite renal outcome of ≥50% reduction in GFR or end-stage kidney disease (ESKD). Within the trial-eligible cohort, outcomes of interest were compared between groups prescribed dual therapy vs ACE inhibitors alone using a propensity-score—weighted time-to-event analysis using a Cox proportional hazards model. Conditional on successfully benchmarking results against the ONTARGET trial, we explored treatment effect heterogeneity by chronic kidney disease (CKD) at baseline, with CKD defined as estimated glomerular rate (eGFR) < 60 ml/min/1.73 m2. Results 412,406 trial-eligible patients in CPRD were included in analysis. Among those with non-missing eGFR at baseline, 37% had CKD (Table 1). We found similar effectiveness of dual therapy and ACE inhibitors in reducing the risk of the primary composite cardiovascular outcome (HR 0.98 (95% CI: 0.93, 1.03), consistent with the ONTARGET trial results (HR 0.99 (95% CI: 0.92, 1.07), with no evidence of heterogeneity by CKD (P-value for interaction = 0.14). However, dual therapy use was associated with a greater risk for the composite renal outcome compared to ACE inhibitor, HR 1.24 (95% CI: 1.14, 1.35), with no evidence of heterogeneity by CKD (P = 0.93) (Fig. 1). Analysing components of the composite renal outcome separately gave consistent results (≥50% reduction in GFR: HR 1.22 (95% CI: 1.12, 1.33); ESKD: HR 1.34 (95% CI: 1.24, 1.57)), as did a post-hoc sensitivity analysis by proteinuria status (no proteinuria: HR 1.28 (95% CI: 1.03, 1.59); proteinuria: 1.27 (95% CI: 1.08, 1.49)). Conclusion We found evidence that dual therapy use was associated with increased risk of renal outcomes in both those with and without CKD at baseline. Applying a reference trial emulation approach and successfully benchmarking findings against ONTARGET, where confounding was not present due to randomisation, provides confidence in the validity of these results.

#2954 A comparative view of IgA nephropathy care across four global regions

Abstract Background and Aims IgA nephropathy (IgAN) is a chronic, rare, and slow progressing glomerular disease. IgAN treatment currently consists of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), sodium-glucose co-transporter 2 (SGLT2) inhibitors, corticosteroids, and recently approved Nefecon and sparsentan in select markets. This research compares approaches to IgAN treatment in four regions of the world. Method Data was collected in partnership with 730 nephrologists submitting chart data from 1,570 of their most recently seen IgAN patients to create a representative sample across the US, EU5 (UK, Germany, Italy, France, and Spain), Japan, and China via parallel online surveys in 2023. Results Regardless of their geographic location, audited patient charts revealed that hypertension, hyperlipidemia, obesity, and diabetes were the leading comorbid conditions among IgAN patients. Across the four regions evaluated, Japanese patients were the healthiest (44% have no comorbid conditions vs. 28% EU5, 25% China, 18% US) and Japanese nephrologists perceived 79% of their IgAN patients to be in “excellent” overall health. Comparatively, patients in the US had the highest calculated body mass index (28.2) and the most comorbid conditions reported. Audited records also revealed that patients in Japan and China were referred to nephrology care earlier in their CKD progression as measured by eGFR levels, with over 50% of patients referred to their current nephrologist in CKD Stages 1 or 2, compared to approximately 35% of patients in the US and EU5. Chinese nephrologists (59%) and those in the US (53%) were most likely to agree that it is easy to identify IgAN patients who are likely to have rapid progression (vs. 43% EU5 and 40% Japan). When treating their IgAN patients, Japanese nephrologists ordered labs on a more frequent basis compared to those in the US, EU5, and China and on average, Japanese patients had blood work and urinalysis labs conducted six times within the past twelve months (versus four in the other countries.) Most audited patients had a calculated annual eGFR decline of 1 ml/year or more. Chinese patients (77%) were most notable for their IgAN progression, while those in Japan were least likely to be progressing in their disease (41%). Due to its chronic nature, most IgAN patients will eventually need dialysis, and while still representative of the majority of their audited patients, US nephrologists projected the lowest percentage of IgAN patients to eventually progress to end stage renal disease (66% vs. 73% Japan, 75% EU5, and 85% China). Most participating nephrologists reported that they closely adhere to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines when treating their IgAN patients. Nearly all audited IgAN patients were on baseline therapy of ACE inhibitors or ARBs, while the uptake of SGLT2 inhibitors has been notable in China (44%), the US (43%), and EU5 (43%), with Japan (33%) trailing in current treatment rates. Meanwhile, the use of corticosteroid was also higher in patients in Japan (65%) and China (59%) compared to those in the EU5 (51%) and US (43%). Of note, tonsillectomies are frequently used as a treatment approach for IgAN patients in Japan, with 45% of patients having received the procedure, whereas this approach is used much less often in the other regions. Following a tonsillectomy, nearly all Japanese patients received a pulse of steroids, leading to higher overall corticosteroid use compared to other regions. At the time of fielding, Nefecon was available to prescribe in the US and Germany with 9% and 7% of patients currently on treatment, respectfully; however, sparsentan had not been approved in any regions. Conclusion The comparison of patient chart data across various regions reveals differences in perspectives and IgAN treatment approaches among nephrologists. Prognostic and predictive tools are available and utilized globally, but the reliability and correlation between results, lab values, and disease progression calls for better education and alignment of global treatment guidelines.

Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease.

Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease.

Mathematical modelling of the influence of ACE I/D polymorphism on blood pressure and antihypertensive therapy

The angiotensin-converting enzyme (ACE) gene (ACE) insertion/deletion (I/D) polymorphism raises the possibility of personalising ACE inhibitor therapy to optimise its efficiency and reduce side effects in genetically distinct subgroups. However, the extent of its influence among these subgroups is unknown. Therefore, we extended our computational model of blood pressure regulation to investigate the effect of the ACE I/D polymorphism on haemodynamic parameters in humans undergoing antihypertensive therapy. The model showed that the dependence of blood pressure on serum ACE activity is a function of saturation and therefore, the lack of association between ACE I/D and blood pressure levels may be due to high ACE activity in specific populations. Additionally, in an extended model simulating the effects of different classes of antihypertensive drugs, we explored the relationship between ACE I/D and the efficacy of inhibitors of the renin–angiotensin–aldosterone system. The model predicted that the response of cardiovascular and renal parameters to treatment directly depends on ACE activity. However, significant differences in parameter changes were observed only between groups with high and low ACE levels, while different ACE I/D genotypes within the same group had similar changes in absolute values. We conclude that a single genetic variant is responsible for only a small fraction of heredity in treatment success and its predictive value is limited.

The Potential Role of Angiotensin-Converting Enzyme Inhibitors and Beta-Blockers in Reducing Pneumonia Severity in Older Adults.

Background Understanding the impact of pharmacological therapy on pneumonia severity is crucial for effective clinical management. The impact of angiotensin-converting enzyme inhibitors (ACEis) and beta-blockers (BBs) on pneumonia severity remains unknown, warranting further investigation. Methodology This retrospective study examined the hospital records of inpatients (≥75 years) admitted with community-acquired pneumonia in 2021. Pneumonia severity associated with the use of pre-established ACEi and BB therapy was documented using CURB-65 (confusion, uraemia, respiratory rate, blood pressure, age ≥65 years) and pneumonia severity index (PSI) scores. Descriptive statistics and multivariable linear regression were used to analyse differences across BB therapy, ACEi therapy, their combination, or neither (control group). Results A total of 803 patient records were examined, of whom 382 (47.6%) were male and 421 (52.4%) were female. Sample sizes for each group were as follows: control (n = 492), BB only (n = 185), ACEi only (n = 68), and BB + ACEi (n = 58). Distribution of aspiration pneumonia (AP) versus non-AP for each group, respectively, was control (21.1% vs. 78.9%), BB only (9.7% vs. 90.3%), ACEi only (7.3% vs. 92.7%), and ACEi + BB (12.1% vs. 87.9%). No significant differences in PSI and CURB-65 scores were found between intervention groups even after controlling for patient characteristics and irrespective of AP or non-AP aetiology. Patients with AP had significantly higher CURB-65 (p = 0.026) and PSI scores (p = 0.044) compared to those with non-AP. Conclusions Pre-prescribed ACEi or BB therapy did not appear to be associated with differences in pneumonia severity. There were no differences in pneumonia severity scores with ACEi and BB monotherapy or combined ACEi and BB therapy.

Isolated Laryngeal Angioedema in a Patient with Long-term ACE Inhibitor Use: A Case Report.

Angiotensin converting enzyme (ACE) inhibitor-associated angioedema is the most common cause of angioedema seen in the emergency department (ED) and can be associated with a high morbidity. Most cases occur within months of initiation of an ACE inhibitor and are associated with facial and/or oropharyngeal swelling. We present a case of isolated laryngeal edema requiring intubation following 10years of ACE inhibitor therapy. An 82-year-old female, who was on lisinopril therapy for 10years, presented to the ED with shortness of breath and a sensation that her throat was swelling. She appeared to be in mild respiratory distress and could only speak in one-word sentences. On the physical exam, there was no swelling in the tongue, lips, or face, and the uvula was midline. There was mild posterior pharyngeal edema and swelling noted, but the airway was not visibly obstructed. She was tachypneic and stridor was present. After no improvement with medications, anesthesia successfully intubated her in the operating room. It was deemed a difficult airway secondary to posterior pharyngeal erythema and edema. She was diagnosed with ACE inhibitor-associated angioedema and was extubated four days later. Her lisinopril was discontinued, and she has not had a recurrence of angioedema. ACE inhibitor-induced angioedema commonly presents with facial and oropharyngeal swelling. Its recognition, even years after starting an ACE inhibitor, is necessary to ensure swift and appropriate treatment of potentially life-threatening posterior pharyngeal edema.

Get reliable laboratory findings- how to recognize the deceptive effects of angiotensin-converting enzyme inhibitor therapy in the laboratory diagnostics of sarcoidosis?

Serum angiotensin-converting enzyme (ACE) is the only biomarker routinely used in the laboratory diagnostics of sarcoidosis, and ACE inhibitor (ACEi) drugs are among the most prescribed drugs worldwide. Taking ACEi can mislead medical teams by lowering ACE activity, delaying diagnosis and giving a false impression of disease activity of sarcoidosis. We aimed to develop a simple method to detect the presence of ACEi drugs in samples, to investigate the ACEi medication-caused interference and consequences in a retrospective study. ACE activity and the level of ACE inhibition were determined for 1823 patients with suspected sarcoidosis. These values were compared with the therapeutic information at the first and follow-up visits. A total of 302 patients had biochemical evidence of an ACEi drug effect during diagnostic ACE activity testing. In their case, ACE activity was significantly lower (median(IQR): 4.41 U/L(2.93-6.72)) than in patients not taking ACEi (11.32 U/L(8.79-13.92), p<0.01). In 62 sarcoidosis patients, the ACEi reduced ACE activity to the reference range or below. Only in 40 % of the cases was the medication list recorded in the outpatient chart and only in 3 cases was low ACE activity associated with ACEi use. 67 % of the repeated ACE activity measurements were also performed during ACEi therapy. Our study revealed that the use of ACEi is common in patients with suspected sarcoidosis. The ACE activity lowering effect of ACEi drugs may escape the attention of medical teams which can lead to diagnostic errors and unnecessary tests. Nevertheless, these pitfalls can be avoided by using a method suggested by our team.

The role of angiotensin converting enzyme (insertion)/(deletion) and angiotensin II type 1 receptor (A1166C) gene polymorphisms in antiproteinuric effect of ACE inhibitors in type 2 diabetic Iraqi patients

The angiotensin converting enzyme (ACE) I\D gene polymorphism influences the blood ACE enzyme activity. Renoprotective effect of ACE inhibitors (ACEIs) varies among patients due to genetic variation, particularly in Renin-Angiotensin-Aldosterone System genes. This study investigates the genetic variations of ACE I\D and AGT1RA1166C gene polymorphisms in the antiproteinuric effect of ACEI therapy in type 2 diabetes mellitus (T2DM) patients. This is a cross-sectional study that included 76 T2DM patients who are ACEI users, divided into two groups: T2DM without diabetic kidney disease (DKD) included 31 patients, and T2DM with DKD included 45 patients. Urine samples were taken for measurement of urine albumin and creatinine, then calculation of albumin-creatinine ratio (ACR). Blood samples were taken for the measurement of serum parameters and also for the extraction of DNA for genetic evaluation of ACEI/D and AGT1RA1166C gene polymorphisms. The results reveal that T2DM patients carrying the ID genotype have significantly lower ACE1 levels compared to DD and II carriers (p = 0.012). When grouping patients according to the ACR, serum ACE1 and angiotensin-converting enzyme 2 (ACE2) levels were higher in DKD compared to normalbuminuric patients, with the only significant difference for ACE2. After subdividing according to ACE I\D genotypes, the ACE2 differences were only significant in DD genotype carriers (p = 0.049) between DKD and normalbuminuric groups. While for AGT1RA1166C polymorphisms, the AC genotype shows non-significantly lower levels for ACE1 and ACE2. After subdividing according to AGT1RA1166C genotypes, ACE2 levels were significantly higher in DKD patients carrying the AA genotype (p = 0.015). Binary logistic regression analysis revealed that both ACE (I\D) and AGT1RA1166C genes are significant predictors of ACE1 levels after controlling age, gender, and DKD state. This study concluded that both genes are predictors of ACE1 levels; in addition, ID genotype carriers and AC genotype carriers had lower ACE1 and ACE2 levels with lower ACR and higher glomerular filtration rate, identifying better ACEIs responses in ID and AC carriers.

Enalapril Is Superior to Lisinopril in Improving Endothelial Function without a Difference in Blood-Pressure-Lowering Effects in Newly Diagnosed Hypertensives.

Here, we tested if lipophilicity affects the efficacy of ACE inhibitory drugs when used as the first therapy in newly identified hypertensives in a prospective study. We tested the differences in the cardiovascular efficacy of the hydrophilic lisinopril (8.3 ± 3.0 mg/day) and the lipophilic enalapril (5.5 ± 2.3 mg/day) (n = 59 patients). The cardiovascular parameters were determined using sonography (flow-mediated dilation (FMD) in the brachial artery, intima-media thickness of the carotid artery), 24 h ambulatory blood pressure monitoring (peripheral arterial blood pressure), and arteriography (aortic blood pressure, augmentation index, and pulse wave velocity) before and after the initiation of ACE inhibitor therapy. Both enalapril and lisinopril decreased blood pressure. However, lisinopril failed to improve arterial endothelial function (lack of effects on FMD) when compared to enalapril. Enalapril-mediated improved arterial endothelial function (FMD) positively correlated with its blood-pressure-lowering effect. In contrast, there was no correlation between the decrease in systolic blood pressure and FMD in the case of lisinopril treatment. The blood-pressure-lowering effects of ACE inhibitor drugs are independent of their lipophilicity. In contrast, the effects of ACE inhibition on arterial endothelial function are associated with lipophilicity: the hydrophilic lisinopril was unable to improve, while the lipophilic enalapril significantly improved endothelial function. Moreover, the effects on blood pressure and endothelial function did not correlate in lisinopril-treated patients, suggesting divergent mechanisms in the regulation of blood pressure and endothelial function upon ACE inhibitory treatment.

Effect of vitamin D receptor genetic polymorphism on the clinical response to angiotensin converting enzyme inhibitors therapy among breast cancer patients with chemotherapy induced cardiomyopathy

Abstract Background Blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone treatment of chemotherapy induced cardiomyopathy (CIC) yet, variability in response to angiotensin converting enzyme inhibitors (ACEIs) acting on the RAAS is well-documented. Vitamin D was found to play a role in regulating RAAS. Previous studies revealed an inverse relationship between levels of vitamin D in serum and RAAS activation. Purpose The current study is primarily to evaluate the association between genetic variants in the vitamin D receptor (VDR) and clinical response to ACEIs among breast cancer patients receiving chemotherapy with CIC. Methods A total of 60 breast cancer patients with CIC (mean ejection fraction 30%) on β-blocker therapy were started on a ACEIs and followed for 6 months. Post-ACEIs-treatment changes in ejection fraction (EF) and serum potassium (K) were evaluated. We genotyped VDR gene polymorphisms including; ApaI (rs7975232), TaqI (rs731236), BsmI (rs1544410) and FokI (rs2228570) variants using TaqMan technique. Stepwise linear regression was performed to identify genetic and clinical factors associated with variability in ACEIs response, with adjustment for all potential confounding covariates. Results BsmI (rs1544410) (CT) heterozygous and TaqI (rs731236) (GA) genotypes had a significant increase in EF (12.8% and 10.8 %, respectively) and serum K (1.1 mEq/L and 0.91 mEq/L respectively); adjusted-p = 0.0001 and 0.004 for ∆EF and adjusted-p = 0.005 and 0.002 for ∆K. In contrast, (AA) homozygous carriers of the ApaI SNP (rs7975232) had a smaller increase in EF (∆EF = 1.2%) and K (∆K = 0.1 mEq/L) compared to (CA) (∆EF = 6.5%, ∆K = 0.73mEq/L) and (CC) (∆EF = 9%, ∆K = 0.9mEq/L) carriers; adjusted-p = 0.003 for ∆EF, adjusted-p = 0.004 for ∆K. Finally, for the FokI SNP (rs2228570), there was no significant change in EF and serum K level. Conclusion The results from this study highlight that BsmI (rs1544410) and TaqI (rs731236) are strong predictors of response to ACEIs therapy in chemotherapy-induced cardiomyopathy (CIC).

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial.

Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Response and survival of dogs with proteinuria (UPC > 2.0) treated with angiotensin converting enzyme inhibitors.

Angiotensin-converting enzyme inhibitors (ACEi) are a recommended treatment for glomerular proteinuria. Frequency of response to ACEi and the association of achieving proposed urine protein-to-creatinine ratio (UPC) targets on survival is unknown. To determine response rates to ACEi therapy and whether a positive response is associated with improved survival. Eighty-five dogs with proteinuria (UPC > 2.0). Retrospective study including dogs (UPC > 2.0) prescribed an ACEi for treatment of proteinuria. Baseline creatinine, albumin, cholesterol, UPC, and systolic blood pressure were recorded, and cases reviewed to track UPC. Treatment response was defined as achieving a UPC of <0.5 or reduction of ≥50% from baseline within 3 months. Outcome data were collected to determine overall and 12-month survival. Thirty-five (41%) dogs responded to ACEi treatment. Treatment response was statistically associated with both median survival time (664 days [95% confidence interval (CI): 459-869] for responders compared to 177 [95% CI: 131-223] for non-responders) and 12-month survival (79% responders alive compared to 28% non-responders). Baseline azotemia or hypoalbuminemia were also associated with a worse prognosis, with odds ratios of death at 12 months of 5.34 (CI: 1.85-17.32) and 4.51 (CI: 1.66-13.14), respectively. In the 25 dogs with normal baseline creatinine and albumin, response to treatment was associated with 12-month survival (92% responders alive compared to 54% non-responders, P = .04). When the UPC is >2.0, achieving recommended UPC targets within 3 months appears to be associated with a significant survival benefit. Response to treatment is still associated with survival benefit in dogs with less severe disease (no azotemia or hypoalbuminemia).

IgA nephropathy in children with minimal proteinuria: to biopsy or not to biopsy?

Tubulointerstitial lesions and glomerular inflammation severity have been shown to correlate with proteinuria in children with IgA nephropathy (cIgAN). However, there is a lack of data regarding severity of histopathologic findings in cIgAN in patients with minimal to absent proteinuria since kidney biopsy indications are not well defined in these cases. Twenty-eight cIgAN patients with kidney biopsy from 4 different centers in Paris (France) and Montreal (Canada) with a urine protein/creatinine ratio (UPCr) ≤ 0.03g/mmol and a normal estimated glomerular filtration rate (eGFR > 90ml/min/1.73 m2) on the day of kidney biopsy prior to treatment were included. Median age was 11.82 (9.32-13.45) years, and median follow-up was 4years (2.87-6.53). At time of biopsy, median eGFR was 116 (102.3-139.7) ml/min/1.73 m2, and median UPCr was 0.02 (0.011-0.03) g/mmol. Microscopic or macroscopic hematuria was present in 35.7% and 64.3% of cases, respectively. Kidney biopsy microscopy analysis showed mesangial (M1), endocapillary (E1), or extracapillary (C1) hypercellularity in 53.5%, 32.1%, and 7.1% of patients, respectively. Chronic histological lesions were also present: glomerulosclerosis (S1) in 42.8% and tubular atrophy/interstitial fibrosis in 7.1%. Podocytopathic features were detected in 21.4%. An ACE inhibitor or immunosuppressive therapy (IS) was prescribed in 42.8% and 21.4% of these patients respectively. One-third (35.7%) received no treatment. At last follow-up, median eGFR was 111.9 (90.47-136.1) ml/min/1.73 m2, and median UPCr was 0.028 (0.01-0.03) g/mmol. cIgAN with minimal proteinuria at time of biopsy might be linked with acute and chronic glomerular lesions.

Sex Differences in Glomerular Lesions, in Atherosclerosis Progression, and in the Response to Angiotensin-Converting Enzyme Inhibitors in the ApoE-/- Mice Model.

This study analyzes sex-based differences in renal structure and the response to the Angiotensin-Converting Enzyme (ACE) inhibitor enalapril in a mouse model of atherosclerosis. Eight weeks old ApoE-/- mice received enalapril (5 mg/kg/day, subcutaneous) or PBS (control) for an additional 14 weeks. Each group consisted of six males and six females. Females exhibited elevated LDL-cholesterol levels, while males presented higher creatinine levels and proteinuria. Enalapril effectively reduced blood pressure in both groups, but proteinuria decreased significantly only in females. Plaque size analysis and assessment of kidney inflammation revealed no significant sex-based differences. However, males displayed more severe glomerular injury, with increased mesangial expansion, mesangiolysis, glomerular foam cells, and activated parietal epithelial cells (PECs). Enalapril mitigated mesangial expansion, glomerular inflammation (particularly in the female group), and hypertrophy of the PECs in males. This study demonstrates sex-based differences in the response to enalapril in a mouse model of atherosclerosis. Males exhibited more severe glomerular injury, while enalapril provided renal protection, particularly in females. These findings suggest potential sex-specific considerations for ACE inhibitor therapy in chronic kidney disease and atherosclerosis cardiovascular disease. Further research is needed to elucidate the underlying mechanism behind these observations.

Trends in Medical and Device Therapies Following Incident Heart Failure in Denmark during 1996-2019: A Nationwide Register-Based Follow-Up Study.

Introduction: Data on temporal trends in guideline-based medical and device therapies in real-world chronic heart failure (HF) patients are lacking. Methods: Register-based nationwide follow-ups of temporal trends in characteristics, guideline-recommended therapies, one-year all-cause mortality, and HF rehospitalizations in incident HF patients in Denmark during 1996-2019. Results: Among 291,720 incident HF patients, the age at the onset of HF was stable over time. While initially fairly equal, the sex distribution markedly changed over time with more incidents occurring in men overall. Hypertension and diabetes increased significantly over time, while other comorbidities remained stable. Between 1996 and 2019, significant increases in angiotensin-converting enzyme inhibitor and angiotensin II-receptor blocker (ACEi/ARB) therapy (38.2% to 69.9%), beta-blocker therapy (15.5% to 70.6%), and mineralocorticoid receptor antagonist (MRA) therapy (11.8% to 34.5%) were seen. Angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) were introduced in the middle of the past decade, with minor increases but overall low uses: ARNI (2015: 0.1% vs. 2019: 3.9%) and SGLT2i (2012: <0.1% vs. 2019: 3.9%). Between 1999 and 2019, implantable cardioverter-defibrillator (ICD) use increased significantly: 0.1% to 3-4%. Cardiac resynchronization therapy (CRT) use similarly increased between 2000 and 2019: 0.2% to 2.3%. Between 1996 and 2019, one-year all-cause mortality decreased significantly: 34.6% to 20.9%, as did HF rehospitalizations (6% to 1.3%). Conclusions: Among 291,720 incident HF patients in Denmark during 1996-2019, significant increases in the use of ACEi/ARB, beta-blockers, MRAs, and devices were seen, with concurrent significant decreases in the one-year all-cause mortality and HF rehospitalization rates. The use of CRT, ARNI, and SGLT2i remained low, and MRAs were relatively underutilized, thereby representing future targets to potentially further improve HF prognoses.

ФАКТОРЫ РИСКА НЕБЛАГОПРИЯТНОГО НЕФРОЛОГИЧЕСКОГО ПРОГНОЗА У МАЛЬЧИКОВ С Х-СЦЕПЛЕННЫМ СИНДРОМОМ АЛЬПОРТА: ОДНОЦЕНТРОВОЕ КОГОРТНОЕ ИССЛЕДОВАНИЕ

Males with X-linked Alport syndrome (XLAS) have a poor prognosis with a risk of developing kidney failure at a young age. Renal survival in glomerulopathies is determined by genetic and non-genetic risk factors with the role of the latter in Alport syndrome not being studied enough as yet. The purpose of this research was to determine the risk factors for poor nephrological prognosis in boys with XLAS. Materials and methods used: 89 boys aged 3 to 14 y/o with XLAS were included in a single-center cohort retrospective study. Blood pressure (BP), proteinuria (Pr, mg/m2/day), estimated glomerular filtration rate according to Bedside Schwartz Formula (eGFR, ml/min/1.73 m2 with norm≥90 ml/min/1.73 m2) and the data on therapy with angiotensin-converting enzyme inhibitors (ACEI) were monitored one time per 6 to 12 months for 4 [3; 6] years. BP≥90% was defined as uncontrolled (UHBP); proteinuria criterion Pr&gt;100 mg/m2/day; the research endpoint was the time to reach eGFR&lt;60 ml/min/1.73 m2. Results: 69 children had eGFR≥60 ml/min/1.73 m2 in dynamics (Group 1), 20 had reached the endpoint (Group 2). Age at inclusion, incidence of non-missense COL4A5 variants, birth weight, incidence of low body weight for gestational age, gross hematuria and age at onset of hematuria were not statistically significantly different between groups; UHBP (0.2 for G1 vs. 0.65 for G2; p&lt;0.001), Pr (0.61 vs. 0.95, respectively; p=0.004), decrease in eGFR (0.06 vs. 0.45; p&lt;0.001) were statistically significantly more common in G2. Boys from G2 were less likely to receive ACEI therapy (0.97 vs. 0.65; p=0.012); age of onset and doses of ACEI for ramipril were not statistically significantly different between the groups. Non-missense variants of COL4A5 (p=0.007), NBP (p&lt;0.001), persistence of Pr&gt;250 mg/m2/day (p&lt;0.001), no ACEI therapy (p&lt;0.001) and its onset at the stage of proteinuria (p&lt;0.001) were the risk factors for reaching the endpoint. Persistence of Pr, UHBP, initiation of ACEI therapy at the proteinuria stage independently affected the progression of the disease. Conclusion: UHBP, proteinuria, lack of therapy/appointment of ACEI at the proteinuria stage of the disease are the risk factors for further poor nephrological prognosis in boys with XLAS.

ЭФФЕКТИВНОСТЬ ТЕРАПИИ ИНГИБИТОРАМИ АНГИОТЕНЗИН- ПРЕВРАЩАЮЩЕГО ФЕРМЕНТА В ПРОФИЛАКТИКЕ РАЗВИТИЯ ПРОТЕИНУРИИ У МАЛЬЧИКОВ С Х-СЦЕПЛЕННЫМ СИНДРОМОМ АЛЬПОРТА: ДАННЫЕ ОДНОЦЕНТРОВОГО КОГОРТНОГО НЕРАНДОМИЗИРОВАННОГО ИССЛЕДОВАНИЯ

Patients with a hemizygous mutation in the COL4A5 gene have a high risk of developing renal failure at a young age. Proteinuria reflects the progression of glomerulopathy in Alport syndrome (AS). In order to improve renal survival in AS patients with proteinuria are prescribed with angiotensin system inhibitors. There is a limited, insufficient number of studies demonstrating the effectiveness of angiotensin-converting enzyme inhibitors (ACEI) in children with AS; the therapeutic effect initiated prior to the development of proteinuria has not been studied as yet. The purpose of the research was to determine the effectiveness of ACEI therapy in the form of enalapril in the prevention of proteinuria in boys with X-linked AS (XLAS). Materials and methods used: boys aged 2 to 15 y/o with genetically confirmed XLAS were included in a single-center prospective cohort study. Enalapril was prescribed at doses of 1 to 3 mg/m2/day. Urinary protein excretion (Pr) and estimated glomerular filtration rate (eGFR) were studied at the time of inclusion and with a frequency of one time per six months for the three-year period or longer. The primary endpoint was the time of onset of proteinuria. Results: 72 boys in total, incl. 29 without proteinuria, who received enalapril therapy (Group 1, age 6.2±1.9 y/o, Pr 67±20 mg/m2/day, eGFR 118±15.2 ml /min/1.73 m2) and 43 children without therapy (Group 2, age 6.8±1.9 y/o, Pr 87±23 mg/m2/day, eGFR 119±17.3 ml/min/1.73 m2). The incidence of proteinuria (0.45 in G1 vs. 0.98 in G2, p&lt;0.001), incl. up to the age of 10 y/o (0.42 vs 0.91, respectively, p&lt;0.001) was statistically significantly lower in G1. Proteinuria developed later in the treatment group (10.2±2.9 vs. 4.9±1.4 years, p=0.300). Non-missense mutations in the COL4A5 gene, episodes of macrohematuria in records and lack of therapy were the risk factors for proteinuria; the lack of enalapril therapy was a predictor for proteinuria. The risk of proteinuria during therapy was reduced by 50% (RR=0.46 (95% CI 0.31; 0.68); ARR=0.53; NNT=1.9). Conclusion: initiation of enalapril therapy at the pre-proteinuria stage of nephropathy in boys with XLAS reduces the risk of proteinuria preventing its occurrence in every 50$ of cases when receiving treatment. Early initiation of therapy may be effective in preventing the progression of kidney disease in boys with XLAS.

Acute angioedema in Cape Town emergency centres and a suggested algorithm to simplify and improve management.

Angioedema is the most common acute allergic presentation to emergency centres (EC), with hospitalisation rates increasing in high-income countries. Angioedema can complicate with life-threatening laryngeal obstruction. There are no local data; therefore, we aimed to characterise acute angioedema cases presenting to ECs and develop a simple management algorithm. To characterise the clinical presentation, management and outcomes of acute angioedema cases presenting to ECs. Based on these findings, we developed a management algorithm for acute angioedema to improve the care of acute angioedema in South Africa (SA). We conducted a retrospective folder review of all patients admitted to Groote Schuur Hospital (tertiary) and Mitchells Plain District Hospital (secondary) ECs from 1 June 2018 to 31 June 2020. Using ICD-10 coding, folders of adults ≥18 years with possible angioedema presenting to the ECs were screened. An allergist extracted demographics, medical history, management and outcome data for each angioedema event. A total of 142acute angioedema episodes were included, with a median (interquartile range) age of 42 (28- 58) years, and 62% of patients were female. The majority (124/142, 87%) of acute angioedema EC presentations involved swelling above the shoulders, with airway involvement in 20(14%) patients, with two patients requiring intubation. Nineteen (13%) patients required admission, with five (26%) admitted to high care/intensive care. Drug-induced angioedema was the most common cause, with 64/142 (45%) linked to a known offending drug, 42/64 (65.6%) being angiotensin-converting enzyme inhibitor (ACE-I). Critical information to guide angioedema management, including past personal/family allergy history, and duration of angioedema prior to EC visit, was not recorded in 64.7% and 37.8% of EC records, respectively. Unnecessary treatment with corticosteroids or antihistamines occurred in 19/53 (36%) and 16/53 (30%) cases with bradykinin-mediated angioedema ACE-I angioedema and hereditary angioedema). Overall, only 36/142 (25%) of angioedema patients were connected to allergy care. Angioedema is the most common allergy presentation to two ECs in Cape Town, SA. Bradykinin-mediated angioedema secondary to ACE-I therapy is the single most common offender, and was not appropriately managed in more than a third of cases. Based on these findings, we have developed a management algorithm that easily stratifies patients into bradykinin or mast cell-mediated angioedema with a step-by-step management approach that is applicable to the SA context. Ongoing awareness and education on allergy emergencies are required to ensure accurate diagnosis of less common causes of angioedema (particularly bradykinin-mediated angioedema) and linkage to allergy specialist care.

#4057 SUPERIOR PROTEINURIA REDUCTION WITH SPARSENTAN IN IMMUNOGLOBULIN A NEPHROPATHY (IGAN): A PROTECT STUDY INTERIM ANALYSIS

Abstract Background and Aims IgAN is the most common glomerular disease worldwide. Despite optimized standard of care, most patients with IgAN progress to kidney failure within 10-15 years, consequently seriously affecting their quality of life and mortality. Treatments that reduce proteinuria and risk of kidney disease progression are urgently needed for IgAN. Sparsentan is a novel, oral, non-immunosuppressive, single molecule that is a dual endothelin and angiotensin receptor antagonist being investigated for IgAN and focal segmental glomerulosclerosis. The Phase 3 PROTECT study is examining the long-term antiproteinuric and nephroprotective potential and safety of sparsentan compared with an active control, angiotensin receptor blocker (ARB) irbesartan, in adults with IgAN. Reported here are the PROTECT pre-specified interim primary efficacy endpoint and safety outcomes. Method PROTECT is an ongoing, global, Phase 3, multicenter, randomized, double-blind, active controlled study designed to evaluate the efficacy and safety of sparsentan versus the active control irbesartan in adults with IgAN with overt proteinuria despite receiving maximized treatment with an angiotensin converting enzyme inhibitor (ACEi) and/or ARB. The study duration is 270 weeks; the double-blind period is 114 weeks (110 treatment and 4 follow-up) with an open-label extension period up to 156 weeks. Adult patients with biopsy-proven IgAN (excluding IgAN secondary to another condition or IgA vasculitis), urine protein excretion value ≥1.0 g/day, eGFR ≥30 mL/min/1.73m2, systolic/diastolic blood pressure ≤150/≤100 mmHg, and on a stable dose of ACEi and/or ARB therapy for at least 12 weeks prior to screening that is both the patient's maximum tolerated dose and at least one-half of the maximum labeled dose were eligible for inclusion. Patients took their last ACEi and/or ARB dose the day before randomization. Patients were randomized 1:1 to sparsentan or irbesartan (target dose 400 and 300 mg/day, respectively), stratified by screening eGFR and urine protein excretion values. The pre-specified interim primary efficacy endpoint of change from baseline in urine protein/creatinine ratio (UP/C, based on a 24-hour urine sample) at Week 36 was analyzed using a mixed model repeated measures analysis. The safety evaluation included assessment of treatment emergent adverse events. Results A total of 671 patients were screened; 406 patients from clinical sites in 18 countries, including sites in North America, Europe, and Asia Pacific, met eligibility criteria and were enrolled and randomized into PROTECT. Two randomized patients withdrew from the study prior to initiating study treatment. The 404 randomized patients who received study drug were included in the primary analysis population. The mean reduction in UP/C from baseline at 36 weeks was significantly greater in the patients who received sparsentan (-49.8%) versus irbesartan (-15.1%, P&amp;lt;0.0001). Proteinuria reduction consistency across baseline demographic and clinical characteristics and rates of complete and partial remission are reported, as well as sustained proteinuria reduction over time. Safety outcomes related to edema and liver function tests are reported. Overall, sparsentan was generally well-tolerated and comparable to irbesartan. Conclusion The interim results of the PROTECT study show that in adult patients with IgAN and persistent proteinuria above 1 g/day despite being treated with ACEis and/or ARBs, once-daily treatment with sparsentan compared head-to-head with maximum labelled or tolerated irbesartan produced a robust and clinically meaningful reduction in proteinuria. The safety of sparsentan was consistent with previous studies in FSGS and comparable to irbesartan.

#4881 NEPHROPROTECTION IN BOYS WITH X-LINKED ALPORT SYNDROME: THE SOONER THE BETTER

Abstract Background and Aims Proteinuria (Pr) is a marker of glomerular diseases progression. The aim of study was to define the efficiency of angiotensin-converting enzyme inhibitors (ACEi) treatment in prevention of Pr development in boys with X-linked Alport's syndrome (XLAS). Method Single center observation study included boys with confirmed XLAS (n = 87). Twenty nine pts (1gr) started ACEi (enalapril 4.2±1.4 mg/m2/day) in non-proteinuric stage of disease (Pr≤100 mg/m2/day); mean age 6.2±3.9 yrs, eGFR Schwartz 118±15.2 ml/min/1.73 m2, Pr 67±23 mg/m2/day. Fifty eight pts (2gr) without preemptive ACEi treatment were observed from mean age 6.8±4.9 yrs, eGFR 119±17.3 ml/min/1.73 m2, Pr 87±43 mg/m2/day. Follow up was 6.2±3.9 yrs, mean age at the last observation was 11.7±3.9 yrs vs 14.2±4.6 yrs (p = 0.67) in 1gr and 2gr, respectively. The occurrence of Pr (Pr&amp;gt;100 mg/m2/day) was defined as primary end point of the study. Results The pts of 1gr had lower rate (0.48 vs 0.94, p&amp;lt;0.001) and higher age (10.2±3.9 vs 4.9±3.4 yrs, p = 0.3) of Pr occurrence than in 2gr. ACEi treatment reduced risk of Pr onset (OR = 0.05(95%CI 0.013-0.2)) with absolute risk reduction of Pr by 47% (RD = 0.47) and number of treated pts to prevent Pr development (NNT) 2.14. No difference was revealed between 1gr pts with and without Pr development in age of therapy start (7.1±3.3 vs 6.3±2.8 yrs), ACEi dose (2.3±0.8 vs 2.1±0.6 mg/m2/day) and COL4A5 gene mutation type (missense variants 0.72 vs 0.86). Arterial hypertension was a risk factor of Pr occurrence in 1gr (χ2 = 4,42, p = 0.04); children with Pr development was older at the last observation: 13.5±3.2 vs 9.9±3.8 yrs, p = 0.47. No side effects of treatment were observed. Conclusion The early ACEi therapy halves the risk of Pr development in boys with XLAS and may prevent the disease progression in these patients.