Therapeutic Advances in Diabetic Nephropathy

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD) in the United States. Risk factor modification, such as tight control of blood glucose, management of hypertension and hyperlipidemia, and the use of renin–angiotensin–aldosterone system (RAAS) blockade have been proven to help delay the progression of DKD. In recent years, new therapeutics including sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), have provided additional treatment options for patients with DKD. This review discusses the various treatment options available to treat patients with diabetic kidney disease.

Synergic Renoprotective Effects Of Combined ASC Therapy With RAAS Blockade In Experimental Advanced CKD

ABSTRACTGlobal prevalence of chronic kidney disease (CKD) has increased considerably in the recent decades. Overactivity of the renin-angiotensin-aldosterone system (RAAS), associated to renal inflammation and fibrosis contribute to its evolution. The treatments currently employed to control CKD progression are limited and mainly based on the pharmacological inhibition of RAAS, associated with diuretics and immunosuppressive drugs. However, this conservative management promotes only partial deceleration of CKD evolution, and does not completely avoid the progression of the disease and the loss of renal function, which motivates the medical and scientific community to investigate new therapeutic approaches to detain renal inflammation / fibrosis and CKD progression. Recent studies have shown the application of mesenchymal stem cells (mSC) to exert beneficial effects on the renal tissue of animals submitted to experimental models of CKD. In this context, the aim of the present study was to evaluate the effects of subcapsular application of adipose tissue-derived mSC (ASC) in rats submitted to the 5/6 renal ablation model, 15 days after the establishment of CKD, when the nephropathy was already severe. We also verify whether ASC associated to Losartan, would promote greater renoprotection when compared to the respective monotherapies. Animals were followed until 30 days of CKD, when body weight, systolic blood pressure, biochemical, histological, immunohistochemical and gene expression analysis were performed. The combination of ASC and Losartan was more effective than Losartan monotherapy in reducing systolic blood pressure and glomerulosclerosis, and also promoted the complete normalization of proteinuria and albuminuria, a significant reduction in renal interstitial macrophage infiltration and downregulation of renal IL-6 gene expression. The beneficial effects of ACS are possibly due to the immunomodulatory and anti-inflammatory role of factors secreted by these cells, modulating the local immune response. Although studies are still required, our results demonstrated that a subcapsular inoculation of ASC, associated with the administration of Losartan, exerted additional renoprotective effect in rats submitted to a severe model of established CKD, when compared to Losartan monotherapy, thus suggesting ASC may be a potential adjuvant to RAAS-blockade therapy currently employed in the conservative management of CKD.

Association of renin–angiotensin system blockers with COVID-19 diagnosis and prognosis in patients with hypertension: a population-based study

Background The effect of renin-angiotensin(RAS) blockade either by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARBs) on coronavirus disease 2019(COVID-19) susceptibility, mortality and severity is inadequately described. We examined the association between renin-angiotensin system (RAS) blockade and COVID-19 diagnosis and prognosis in a large population-based cohort of patients with hypertension. Methods This is a cohort study using regional health records. We identified all individuals aged 18-95 years from 87 health care reference areas of the main health provider in Catalonia(Spain), with a history of hypertension from primary care records. Data were linked to COVID-19 test results, hospital, pharmacy and mortality records from 1 March 2020 to 14 August 2020. We defined exposure to RAS blockers as the dispensation of ACEi/ARBs during the three months before COVID-19 diagnosis or 1 March 2020. Primary outcomes were: COVID-19 infection, and severe progression in hospitalized patients with COVID-19(the composite of need for invasive respiratory support or death). For both outcomes and for each exposure of interest (RAAS blockade, ACEi or ARB) we estimated associations in age-sex-area-propensity matched samples. Results From a cohort of 1,365,215 inhabitants we identified 305,972 patients with hypertension history. Recent use of ACEi/ARBs in patients with hypertension was associated with a lower 6 month-cumulative incidence of COVID-19 diagnosis (3.78% [95% CI: 3.69% - 3.86%] vs 4.53% [95% CI: 4.40% - 4.65%]; p < 0.001). In the 12,344 patients with COVID-19 infection, the use of ACEi/ARBs was not associated with a higher risk of hospitalization with need for invasive respiratory support or death (OR = 0.91 (0.71 – 1.15); p = 0.426). Conclusion RAS blockade in patients with hypertension is not associated with higher risk of COVID-19 infection or with a worse progression of the disease.

Increased risk of acute kidney injury in coronavirus disease patients with renin–angiotensin–aldosterone-system blockade use: a systematic review and meta-analysis

Acute kidney injury (AKI) is a severe complication of coronavirus disease (COVID-19) that negatively affects its outcome. Concern had been raised about the potential effect of renin–angiotensin–aldosterone system (RAAS) blockades on renal outcomes in COVID-19 patients. However, the association between RAAS blockade use and incident AKI in COVID-19 patients has not been fully understood. We investigated the association between RAAS blockade exposure and COVID-19-related AKI in hospitalized patients through meta-analysis. Electronic databases were searched up to 24th December 2020. Summary estimates of pooled odds ratio (OR) of COVID-19-related AKI depending on RAAS blockade exposure were obtained through random-effects model. The random-effect meta-analysis on fourteen studies (17,876 patients) showed that RAAS blockade use was significantly associated with increased risk of incident AKI in hospitalized COVID-19 patients (OR 1.68; 95% confidence interval 1.19–2.36). Additional analysis showed that the association of RAAS blockade use on COVID-19-related AKI remains significant even after stratification by drug class and AKI severity. RAAS blockade use is significantly associated with the incident AKI in hospitalized COVID-19 patients. Therefore, careful monitoring of renal complications is recommended for COVID-19 patients with recent RAAS blockade use due to the potential risk of AKI.

MO421THE EFFECT OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM BLOCKADE MEDICATIONS ON CONTRAST-INDUCED NEPHROPATHY IN PATIENTS UNDERGOING CORONARY ANGIOGRAPHY

Background and Aims Contrast-induced nephropathy (CIN) is the main complication of contrast media administration in patients undergoing coronary angiography (CAG). This complication may be accelerated by concurrent renin-angiotensin-aldosterone system (RAAS) blockers . Current literature is inconclusive. We investigated the impact of RAAS blockade on the occurrence of CIN in patients undergoing CAG. Method We prospectively enrolled 158 patients who underwent CAG with or without percutaneous coronary intervention from December 2017 to February 2018 at a cardiology department . CIN was defined as an increase in serum creatinine level >25% or 0.5 mg/dL after 48 hours postcardiac catheterization. Results Of 158 patients (females=36.1%, mean age 60.0 ± 11 years) who underwent CAG , 15 (9,5%) developed CIN . Eighty one patients (51,2%) were chronic RAAS blockade users. There was no significant difference between the two groups, RAAS blockade 'used' versus 'not-used', in the incidence of postprocedural CIN (7,5% vs 11,5%, p=0,38). However , the pre-contrast use of RASS blockers decrease the risk of CIN in patients with chronic renal failure (12,5% vs 66,6% , p=0,042) . Conclusion RAAS blockade isn’t associated with a significantly higher incidence of CIN, whereas it has the potential to mitigate the incidence of CIN in patients with chronic renal failure. This low cost intervention could be considered when referring a patient for cardiac catheterization.

MO306IGA NEPHROPATHY: A 20 YEAR RETROSPECTIVE SINGLE CENTRE EXPERIENCE

Background and Aims IgA nephropathy is the most common glomerulonephritis worldwide. The clinical course is heterogeneous and not always easy to predict. As such, determining which patients to treat with immunosuppression has been the cause of much debate. Over recent years there has been a focus on risk prediction to help with treatment decisions (such as the widely validated International IgA Risk Prediction Tool). Here, we present a 20 year retrospective study from a single centre with the following aims: to describe the epidemiology of our cohort, to assess outcomes (such as progression to ESKD requiring RRT, mortality), and to determine if treatment choices have changed over time. Method We collected all cases of IgA nephropathy from our biopsy database between January 2020 and December 2019. This totalled 525 biopsies. Of these, a number were excluded from analysis, including transplant biopsies and repeat biopsies in the same patient. After exclusion, the original 525 biopsies were narrowed down to 452 patients for analysis. We collected demographic data for each patient, along with creatinine and proteinuria values over time, MEST-C scores, progression to ESKD, mortality, use of RAAS blockade and immunosuppressants. Initial analysis was performed using Excel. We plan to perform further multivariate Cox regression analysis to determine if there are associations with progression to ESKD such as degree of proteinuria, MEST-C scores and immunosuppression treatment. Results We identified 452 patients with biopsy confirmed IgA nephropathy at our centre between January 2000 and December 2019. 138 (30.5%) were female and 314 (69.4%) were male. The average age at time of biopsy was 45.7 years. Mortality over this period was 19.2% (87 patients). 126 (27.9%) progressed to ESKD requiring RRT, 6 (1.3%) required temporary dialysis whilst 313 (69.2%) did not require RRT. With regards to treatment, 329 (72.8%) were treated with RAAS blockade in comparison to 85 (18.8%) who were not (in 38 patients this was unclear). No immunosuppression was used in 349 (77.2%), whilst a combination of prednisolone; IV cyclophosphamide and prednisolone; and MMF and prednisolone was used in 97 (21.5%). Conclusion We present here a large single centre dataset of IgA nephropathy patients over a 20 year period. We show that there remains a significant risk of progression to ESKD over time. It is important to identify those patients most at risk of progression early on in their disease course so that optimal treatment can be initiated. Further analysis of this dataset will allow us to assess whether treatment strategies in recent years has had a beneficial effect on outcomes, and also to assess the correlation between MEST-C scores and treatment decisions.

The Role of the Renin-Angiotensin-Aldosterone System in Cardiovascular Disease: Pathogenetic Insights and Clinical Implications

Increased attention has been placed on the activation of the renin-angiotensin-aldosterone system (RAAS) and pathogenetic mechanisms in cardiovascular disease. Multiple studies have presented data to suggest that cardiac and arterial stiffness leading to adverse remodeling of both the heart and vasculature leads to the various pathological changes seen in coronary artery disease, heart failure (with preserved and reduced ejection fractions), hypertension and renal disease. Over-activation of the RAAS is felt to contribute to these structural and endocrinological changes through its control of the Na+/K+ balance, fluid volume, and hemodynamic stability. Subsequently, along these lines, multiple large investigations have shown that RAAS blockade contributes to prevention of both cardiovascular and renal disease. We aim to highlight the known role of the activated RAAS and provide an updated description of the mechanisms by which activation of RAAS promotes and leads to the pathogenesis of cardiovascular disease.

Coronary Vasculature and Myocardial Structure in HIV: Physiologic Insights from the Renin-Angiotensin-Aldosterone System

The landscape of HIV medicine dramatically changed with the advent of contemporary antiretroviral therapies (ART) which has allowed persons with HIV (PWH) to achieve good virologic control, essentially eliminating HIV-related complications and increasing life expectancy. As PWH are living longer, non-communicable diseases, such as cardiovascular disease (CVD), have become a leading cause of morbidity and mortality in PWH with rates that are 50-100% higher than in well-matched persons without HIV. In this review, we focus on disease of the coronary microvasculature and myocardium in HIV. We highlight a key hormonal system important to cardiovascular endocrinology, the renin-angiotensin-aldosterone system (RAAS), as a potential mediator of inflammatory driven-vascular and myocardial injury and consider RAAS blockade as a physiologically-targeted strategy to reduce CVD in HIV.

Clinical effects of angiotensin-converting-enzyme inhibitors on lung computed tomography findings in patients with COVID-19 pneumonia: Is it useful?

Aim: Angiotensin-converting enzyme 2 (ACE2) has a significant physiological role in the renin – angiotensin – aldosterone system (RAAS) pathway. The ACE2 receptor acts as a virus receptor in the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease. In this study, we aimed to investigate the effects of ACEIs use on radiological imaging and clinical course in COVID-19. Methods: In this study, patients who had been using medications for the diagnosis of hypertension and who were hospitalized in Haydarpasa Numune Training and Research Hospital due to COVID-19 pneumonia were retrospectively evaluated. Results: The mean age of 107 patients included in this study was 68,49±11,95, and 50.5% (n = 54) of them were male. The patients were divided into two separate study groups as ACEIs users and non-users. In the first of these groups, 55 patients were using ACEIs due to hypertension. In the second group, 52 patients were using calcium channel blockers (CCBs), β-blockers, alpha-2 blockers, or diuretics, alone or in combination. When the lung computed tomography images were examined, multilobar findings were less common in the ACEIs group, which was remarkable (p <0.001). When the clinical endpoint was evaluated, the findings showed that the mortality rates were different in the groups ACEIs users and non-users (12.7% vs. 32.7%, respectively, p=0.013). Conclusion: Although the role of RAAS blockade in COVID-19 is still not fully elucidated, we have shown that COVID-19 progresses with less damage in the lungs with patients who have been using ACEIs.