Introduction: There has been controversy about renin-angiotensin system (RAS) inhibition in IgAN patients with advanced (stage 4) chronic kidney disease (CKD). Therefore, we investigated the effect of RAS blockade in these patients.
Methods: Renal specimens of 50 IgAN patients who underwent renal biopsy during stage 4 CKD between 2010 and 2020, were stained using immunohistochemistry to detect the expression of RAS receptors (AT1R, AT2R, MasR, and MrgD). The primary endpoint was a composite of end-stage renal disease (ESRD) and death. Main baseline information and the administration of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) were collected.
Results: During a median follow-up time of 25.5 months, 21 (42.0%) patients reached ESRD and none died. Six patients had a baseline eGFR of 15-20 ml/min/1.73m2, and reached ESRD with a median renal survival time of 7.0 (range 6.0-23.0) months. Among patients with a baseline eGFR of 20-30 ml/min/1.73m2, the percentage of patients using ACEI/ARB in progressive group was much lower than that in stable group (33.3% vs. 62.1%, P = 0.045), together with a shorter renal survival time in progressive group (26.0 vs. 30.5 months, P = 0.033). Macroproteinuria (24 h - UP ≥ 2.5 g) was also associated with a shorter renal survival time, as well as a significant decline in eGFR of stable group (24.4 vs. 26.4 ml/min/1.73 m2, P = 0.026). Lower eGFR [hazards ratio (HR), 0.829, 95% confidence interval (CI), 0.724-0.950; P = 0.007] and use of ACEI/ARB (HR, 0.356, 95% CI, 0.133-0.953; P = 0.040) were predictive of time to ESRD in this stage. No differences were found in the expression of AT1R, AT2R, MasR, and MrgD of renal tissues at the time of biopsy between stable and progressive groups.
Conclusion: Contingent on monitoring serum creatinine and potassium levels, IgAN with macroproteinuria and a GFR of 20-30 ml/min/1.73m2 may still benefits from intrarenal RAS inhibition.
Background: Postcontrast acute kidney injury (PC-AKI) is an adverse reaction to iodinated contrast agents. In this study, we investigated the use of fibrinogen-to-albumin ratio (FAR) as a novel inflammatory marker to track the development and progression of PC-AKI in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) after the implantation of drug-eluting stents (DESs).
Methods: A total of 872 patients with NSTE-ACS were enrolled in this study. PC-AKI was identified when serum creatinine (SCr) levels increased >26.5 mol/L (0.3 mg/dL) or was 1.5 times the baseline level within 48-72 h of exposure to an iodinated contrast agent. The effects of different variables on PC-AKI were evaluated using univariate regression analysis. Multivariate logistic regression analysis was used to determine the independent predictors of PC-AKI. The predictive value of FAR was assessed by estimating the area under the receiver operating characteristic (ROC) curve.
Results: In total, 114 (13.1%) patients developed PC-AKI. The patients with PC-AKI had lower albumin levels (40.5 ± 3.4 vs. 39.0 ± 3.5, P < 0.001), higher fibrinogen levels (3.7 ± 0.6 vs. 4.1 ± 0.5, P < 0.001), and higher FAR levels (9.2 ± 1.7 vs. 10.5 ± 1.7, P < 0.001) than those with non-PC-AKI. There were no significant differences in the preoperative SCr levels between the two groups. After adjusting for confounding factors, FAR was found to be an independent predictor of PC-AKI (OR = 1.478, 95% CI = 1.298-1.684, P < 0.001). ROC analysis revealed that for PC-AKI prediction, the area under the curve for FAR was 0.702. The optimum cut-off value of FAR was 10.0, with a sensitivity of 64.9% and a specificity of 69.8%. Moreover, FAR had a higher predictive value for PC-AKI than the Mehran score (0.702 vs. 0.645).
Conclusion: Our study showed that elevated preoperative FAR was closely associated with the development of PC-AKI in patients with NSTE-ACS after implantation of DESs. Therefore, it may be worth monitoring FAR as a guide for using preventive measures to avoid the development of PC-AKI.
Despite the increase in assisted reproductive technologies, the high rates of infertility and pregnancy complications are a major concern to infertility specialists worldwide. Infertility may be attributed to pregnancy complications like thrombophilia, preeclampsia and fibrin-induced recurrent pregnancy loss (RPL). Renin-angiotensin-aldosterone system (RAAS) directly or indirectly causes preeclampsia and thrombophilia through the fibrinolytic pathway that ultimately leads to RPL or infertility. The underlying mechanisms of this interaction are still unclear. The present comprehensive review is intended to demonstrate the role and interaction of RAAS and fibrinolytic pathways in pregnancy complications. How this interaction can induce pregnancy complications, and ultimately infertility, is also discussed in the light of current evidence. This study also presents common markers that link RAAS and fibrinolytic processes in developing thrombophilia, preeclampsia and RPL. The common link in these pathways is ACE gene I/D polymorphism. Apart from ACE, PAI-1, VIIa, XIIa, AT1R, AT1AA, and TF are common molecules that can delineate the underlying causes of pregnancy complications and infertility.
Background: A novel collagen called type XXVIII collagen (COL28) is involved in cancer and lung fibrosis. Preliminary data showed that renal tubular epithelial cells could proliferate, migrate, and undergo an epithelial-mesenchymal transition (EMT) when COL28 was overexpressed; however, it is still unknown how this occurs and what the underlying mechanism is.
Methods: We analyzed the differential expression of genes (DEGs) in the stable COL28 overexpression HK-2 cell lines by RNA-sequencing analysis, before which Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genomes (KEGG) analyses were performed. Genes related to COL28 promoting HK-2 cell proliferation and EMT were screened and verified. By using western blot and immunofluorescence, the effects of COL28 on the expression of α-SMA, E-cadherin, Snail, HKDC1, and SREBP1 were detected. The effect of COL28 overexpression on renal fibrosis in unilateral ureteral obstruction (UUO) mice was detected by H&E and Masson staining. HKDC1 interference agent was synthesized and transfected into the HK-2 cell line stably overexpressing COL28. In HK-2 cells, the effects of HKDC1 interference on the expression of α-SMA, E-cadherin, and Snail were detected.
Results: We screened and verified that HKDC1 was related to COL28 and promoted HK-2 cell proliferation and EMT. WB showed that in HK-2 cells, COL28 overexpression increased α-SMA, Snail, HKDC1, and SREBP1 expressions and decreased E-cadherin expression. Overexpression of COL28 aggravated renal interstitial fibrosis in UUO mice; upregulated α-SMA, Snail, HKDC1, and SREBP1 expressions; and decreased the E-cadherin protein expression in UUO mice. Interference of HKDC1 expression promoted the E-cadherin protein expression while inhibiting α-SMA, Snail, HKDC1, and SREBP1 protein expressions.
Conclusion: Overexpression of COL28 can aggravate renal interstitial fibrosis by encouraging renal tubular epithelial cells to undergo EMT, and interference with HKDC1 expression can alleviate fibrosis by reversing EMT induced by COL28 overexpression.
Background: The efficacy of sacubitril/valsartan, a newly introduced combination drug for heart failure with reduced ejection fraction (HFrEF), was demonstrated in the PARADIGM-HF trial conducted in Western countries. However, these findings need to be verified in the Middle Eastern context, where patients may exhibit a different response due to different environmental and racial factors.
Objectives: The goal of this study was to evaluate the efficacy of submaximal sacubitril/valsartan doses in terms of improving the disease symptoms, as measured by the New York Heart Association (NYHA) classification and left ventricular ejection fraction (LVEF) percentage, as well as establish long-term morbidity and mortality associated with HFrEF among Palestinian patients administered target doses of an angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs). Material and Methods. This study involved a retrospective review of charts related to patients with HFrEF maintained on sacubitril/valsartan and was conducted in a referral cardiology clinic in Palestine. The inclusion criteria were age 18+, HFrEF diagnosis, sacubitril/valsartan usage for at least six months during the period between January 1, 2016, and June 30, 2019, and LVEF < 40%. The exclusion criteria included LVEF ≥ 40% and drug administration duration < 6 months. The collected data included NYHA class, as well as LVEF, serum sodium (Na), potassium (K), serum creatinine (Cr), and blood urea nitrogen (BUN) levels and the mortality rate before and after the minimum treatment duration. IBM SPSS STATISTICS for Windows, version 20.0, Armonk, NY: IBM Corp. IBM Corp., released 2012, was used for data analysis, whereby T score was calculated for comparisons between numerical groups, and p < 0.05 was considered statistically significant.
Results: The initial study sample comprised of 205 consecutive patients with HFrEF maintained on sacubitril/valsartan for at least six months from January 1, 2016, to June 30, 2019. Three patients were excluded due to attrition, along with further 12 patients with LVEF ≥ 40% (based on the PARADIGM-HF trial criteria). Throughout the treatment period, most patients showed escalating improvement in terms of the LVEF and NYHA classification, as LVEF = 29.8% and NYHA = 3 were obtained on average before initiating sacubitril/valsartan, compared to 41% and 1.7, respectively, after 6-month treatment (p = 0.0003 and 0.046, respectively). These improvements in LVEF and NYHA class were noted across all sacubitril/valsartan doses (50-400 mg). However, 23 patients (12%) died while undergoing sacubitril/valsartan treatment.
Conclusion: A significant long-term reduction in the mortality and morbidity rates was observed in Palestinian patients with HFrEF maintained on submaximal doses of sacubitril/valsartan.
Colorectal cancer (CRC) is one of the globally prevalent and virulent types of cancer with a distinct alteration in chromosomes. Often, any alterations in the adenomatosis polyposis coli (APC), a tumor suppressor gene, and methylenetetrahydrofolate reductase (MTHFR) gene are related to surmise colorectal cancer significantly. In this study, we have investigated chromosomal and gene variants to discern a new-fangled gene and its expression in the southern populations of India by primarily spotting the screened APC and MTHFR variants in CRC patients. An equal number of CRC patients and healthy control subjects (n = 65) were evaluated to observe a chromosomal alteration in the concerted and singular manner for APC and MTHFR genotypes using standard protocols. The increasing prognosis was observed in persons with higher alcoholism and smoking (P < 0.05) with frequent alterations in chromosomes 1, 5, 12, 13, 15, 17, 18, 21, and 22. The APC Asp 1822Val and MTHFR C677T genotypes provided significant results, while the variant alleles of this polymorphism were linked with an elevated risk of CRC. Chromosomal alterations can be the major cause in inducing carcinogenic outcomes in CRCs and can drive to extreme pathological states.
The RAS (renin-angiotensin system) is the part of the endocrine system that plays a prime role in the control of essential hypertension. Since the discovery of brain RAS in the seventies, continuous efforts have been put by the scientific committee to explore it more. The brain has shown the presence of various components of brain RAS such as angiotensinogen (AGT), converting enzymes, angiotensin (Ang), and specific receptors (ATR). AGT acts as the precursor molecule for Ang peptides-I, II, III, and IV-while the enzymes such as prorenin, ACE, and aminopeptidases A and N synthesize it. AT1, AT2, AT4, and mitochondrial assembly receptor (MasR) are found to be plentiful in the brain. The brain RAS system exhibits pleiotropic properties such as neuroprotection and cognition along with regulation of blood pressure, CVS homeostasis, thirst and salt appetite, stress, depression, alcohol addiction, and pain modulation. The molecules acting through RAS predominantly ARBs and ACEI are found to be effective in various ongoing and completed clinical trials related to cognition, memory, Alzheimer's disease (AD), and pain. The review summarizes the recent advances in the brain RAS system highlighting its significance in pathophysiology and treatment of the central nervous system-related disorders.
Coronavirus disease 2019 (COVID-19) can occur due to contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has no confined treatment and, consequently, has high hospitalization and mortality rates. Moreover, people who contract COVID-19 present systemic inflammatory spillover. It is now known that COVID-19 pathogenesis is linked to the renin-angiotensin system (RAS). COVID-19 invades host cells via the angiotensin-converting enzyme 2 (ACE2) receptor-as such, an individual's susceptibility to COVID-19 increases alongside the upregulation of this receptor. COVID-19 has also been associated with interstitial pulmonary fibrosis, which leads to acute respiratory distress, cardiomyopathy, and shock. These outcomes are thought to result from imbalances in angiotensin (Ang) II and Ang-(1-7)/alamandine activity. ACE2, Ang-(1-7), and alamandine have potent anti-inflammatory properties, and some SARS-CoV-2 patients exhibit high levels of ACE2 and Ang-(1-7). This phenomenon could indicate a failing physiological response to prevent or reduce the severity of inflammation-mediated pulmonary injuries. Alamandine, which is another protective component of the RAS, has several health benefits owing to its antithrombogenic, anti-inflammatory, and antifibrotic characteristics. Alamandine alleviates pulmonary fibrosis via the Mas-related G protein-coupled receptor D (MrgD). Thus, a better understanding of this pathway could uncover novel pharmacological strategies for altering proinflammatory environments within the body. Following such strategies could inhibit fibrosis after SARS-CoV-2 infection and, consequently, prevent COVID-19.
Objective: Angiotensin-III (Ang-III) is the downstream product of angiotensin-II (Ang-II) metabolized by aminopeptidase A (APA). At present, the research of Ang-III mainly concentrates on hypertension and the central renin-angiotensin system (RAS). However, few studies have focused on the relationship between Ang-III and coronary atherosclerosis (CAS).
Methods and results: Plasma Ang-III and APA levels were measured by the enzyme-linked immunosorbent assay (ELISA) in 44 normal subjects and 84 patients confirmed as having CAS by coronary angiography. Circulating Ang-III levels were significantly lower in patients with CAS than in normal controls (P = 0.013). APA levels were slightly lower in the CAS group (P = 0.324). According to the severity of atherosclerosis, CAS patients were divided into two groups. Compared with the controls, the APA and Ang-III levels were lower in the high scoring group and APA decreased significantly.
Conclusions: Circulating Ang-III levels were reduced in patients with CAS, and the possible reason may be related to the decrease in the APA level.
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