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Introduction: From 2008 and following the withdrawal of rosiglitazone, obligatory cardiovascular outcomes trials are performed for glucose lowering drugs introduced to the market to ensure their cardiovascular (CV) safety. Paradoxically, these studies have demonstrated CV safety but also shown additional cardio-reno-vascular protection of some therapeutic agents. Additionally, nonsteroidal mineralocorticoid receptor antagonists (ns-MRA) have emerged as novel drugs for cardio – and renoprotection in type 2 diabetes (T2D) and chronic kidney disease (CKD). In addition to atherosclerotic CV disease, heart failure (HF) and CKD are important clinical problems in T2D leading to poor quality of life and premature death as such cardio-reno-vascular protection is an important clinical issue. Areas covered: We provide new insights into pharmacotherapeutic cardio-reno-vascular protection in T2D based on the new glucose lowering drugs and ns-MRA. PUB MED/CINAHL/Web of Science/Scopus were searched (May 2024). Expert opinion: The conventional glucose lowering approach alone which was implemented for decades is now replaced by the use of disease modifying drugs which lower the rates of CV events, HF decompensation, hospitalization due to HF, slow progression of CKD and all-cause mortality. Indeed, the choice of medications in T2D should be focused on underlying co-morbidities with cardio-reno-vascular protection rather than a gluco-centric approach. [ABSTRACT FROM AUTHOR]

Renal ischemia-reperfusion (I-R) injury is a complex pathophysiologic condition characterized by oxidative stress, inflammation and apoptosis. We investigated the potential renoprotective effect of nebivolol, a β1 adrenergic receptor blocker, against renal I-R injury. We focused on the role of nebivolol in activating p38 mitogen-activated protein kinase (MAPK) signaling, Akt (protein kinase B) and nuclear factor-κB (NFκB) transcription factors, which contribute to oxidative stress, inflammation and apoptosis during renal I-R. We divided 20 adult male Wistar albino rats into three experimental groups. Group 1 was a sham control in which only laparotomy was performed. Group 2 was the I-R group in which both kidneys were made ischemic for 45 min, then reperfused for 24 h. Group 3 was the I-R + nebivolol group in which 10 mg/kg nebivolol was administrated by gavage for 7 days before I-R. We measured Inflammation, oxidative stress and active caspase-3 as well as activation of p38 MAPK, Akt (protein kinase B) and NFκB transcription factor. Nebivolol significantly reduced oxidative stress and increased superoxide dismutase levels during renal I-R. We found that nebivolol significantly decreased interstitial inflammation, and TNF-α and interleukin-1β mRNA expression. Nebivolol significantly reduced active caspase-3 and kidney injury molecule-1 (KIM-1) expressions. Nebivolol also significantly decreased activation of p38 MAPK signaling and NFκB, and induced Akt activation during renal I-R. Our findings suggest that nebivolol may be useful for management of renal I-R injury. [ABSTRACT FROM AUTHOR]

The prevalence of chronic kidney disease (CKD) has increased markedly over past decades due to the aging of the worldwide population. Despite the progress in the prevention and treatment, the cardiovascular (CV) morbidity and mortality remain high among patients with CKD. Although CKD is a progressive and irreversible condition, it is possible to slow decreasing kidney function, as well as the development and progression of associated with kidney disease comorbidities. Diabetes mellitus has become major cause of CKD worldwide. It is estimated that the prevalence of diabetes will increase from 425 million worldwide in 2017 to 629 million by 2045, substantially the percentage of diabetic nephropathy among CKD patients is set to rise markedly. The results of multicenter trials concerning novel antidiabetic drugs suggest that efficacy in reducing CV risk is independent of the improvement in glycemic control. This review discusses underlying causes of high CV risk and strategies reducing individual burden among CKD patients. [ABSTRACT FROM AUTHOR]

BackgroundControversy exists regarding the renoprotective effect of erythropoiesis-stimulating agent (ESA) in progressive chronic kidney disease (CKD) with renal anemia. In this study, we examined whether ESA therapy has a renoprotective effect in progressive CKD.MethodsThe subjects in this retrospective observational study were 68 non-dialysis dependent CKD patients with renal anemia. We compared the progression rate (PR), defined by the slope of the linear regression line of estimated glomerular filtration rate, measured during 6 months just before and after the start of ESA therapy. We also investigated the factors affecting renoprotective efficacy of ESA therapy against the progression of CKD.ResultsMedian (interquartile range) PR decreased significantly from 6.2 (3.7–12.7) to 4.0 (−0.3 to 7.3) mL/min/1.73 m2/year after the start of ESA therapy. Blood pressure levels and rate of medication with renin-angiotensin system inhibitors were comparable between the two periods. Next, we investigated the factors affecting renoprotective efficacy of ESA therapy against the progression of CKD. Thirty patients were good renal responders, defined as those with the ratio of post-/pre-PR of <0.5 and the difference of pre- minus post-PR >5.0 mL/min/1.73 m2/year, and 38 patients were poor renal responders who did not meet the definition of good renal responders. Multivariable logistic regression analysis showed that weekly ESA dose, but not increase in hemoglobin level, was a significant and independent determinant of the renoprotective effect of ESA.ConclusionESA therapy slows the progression of CKD and part of the effect might be attributed to the direct renoprotective action of ESA. [ABSTRACT FROM AUTHOR]

We investigated the renoprotective effects of imidapril hydrochloride ((-)-(4 S)-3-[(2 S)-2-[[(1 S)-1-ethoxycarbonyl-3-phenylpropyl] amino] propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril), an angiotensin-converting enzyme inhibitor, in a diabetic animal model. We used BKS.Cg-+ Leprdb/+ Leprdb (db/db) mice, a genetic animal model of obese type 2 diabetes. Diabetic db/db mice suffered from glomerular hyperfiltration, albuminuria and hypoalbuminemia. Oral administration of 5 mg/kg/day of imidapril for 3 weeks suppressed renal hyperfiltration, reduced albuminuria and normalized hypoalbuminemia. Imidapril did not influence body weights, blood pressure or blood glucose concentrations in db/db mice. Urinary excretion of heparan sulfate (HS) in non-treated 11-week-old db/db mice was significantly lower than that in age-matched non-diabetic db/+m mice. HS is a component of HS proteoglycans, which are present in glomerular basement membranes and glycocalyx of cell surfaces. Reduced urinary HS excretion indicated glomerular HS loss in db/db mice. Imidapril increased urinary excretion of HS to concentrations observed in db/+m mice, indicating that imidapril prevented the loss of renal HS. These results suggest that imidapril ameliorates renal hyperfiltration and loss of renal contents of HS. Improvement of filtration function and maintenance of HS, which is an important structural component of glomeruli, may contribute to renoprotective effects of imidapril. [ABSTRACT FROM AUTHOR]

The aim of this study was the long-term retrospective analysis of chronic kidney disease (CKD) progression in children, especially with regard to the presence of hypertension (HTN). The average rate of progression of CKD was higher in patients with HTN than without HTN. Hypertension treatment requires multidrug schemes which need to be intensified with extended time of CKD duration. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To evaluate and compare the relative contribution of different therapeutic agents for renoprotection against complete unilateral ureteric obstruction (UUO), using a rabbit model sampled at different times. Materials and methods: Eighty-four male New Zealand White rabbits were divided into seven groups of 12 rabbits; a sham group, a control (left UUO+no medication) or left UUO and treated with either enalapril, losartan, verapamil, l-arginine or antioxidant (vitamin E and selenium mixture). Rabbits in the control and treated groups were subjected to 3, 10 and 21 days of complete ureteric ligation and then killed humanely. The control and treated groups were evaluated at baseline and at the end of the experiment, by measuring split effective renal plasma flow (ERPF) using diuretic renography, and the split glomerular filtration rate (GFR) using selective creatinine clearance. Renal histopathology was evaluated using a tubulo-interstitial damage score. Results: In the sham group there was no significant effect on any of the evaluated variables. For split ERPF, losartan showed the highest renoprotective effect, saving 44% and 77% of ERPF at 3 and 21 days after UUO, respectively. Losartan was also the best renoprotective agent for GFR. For renal histopathology, enalapril showed the earliest and greatest improvement as assessed by the damage score, reaching 60% at 21 days after UUO. l-Arginine was the next best effect to blockade the renin-angiotensin system for renoprotection. Conclusion: We suggest that blockade of the renin-angiotensin system provides the best renoprotection against the effects of complete UUO. [Copyright &y& Elsevier]

We evaluated the anti-hypertensive and anti-albuminuric effect of the angiotensin receptor blocker telmisartan alone and in combination with torasemide and amlodipine. Patients were hypertensive, both diabetics and non-diabetics with persistent microalbuminuria. Our primary endpoint was a change in microalbuminuria levels, while the secondary endpoints were changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), serum creatinine levels, and glomerular filtration rate.After the 16-week treatment period, the patients significantly reduced microalbuminuria levels (76.4 ± 52.4 μg/min; p < 0.001), SBP (16.4 ± 8.7 mmHg; p < 0.001) and DBP (17.7 ± 5.9 mmHg; p < 0.001). Both diabetics and non-diabetics showed an identical pattern of significance with respect to the whole population. Systolic blood pressure, DBP, and microalbuminuria were significantly reduced as a consequence of therapy, both in diabetics and non-diabetics. [ABSTRACT FROM AUTHOR]

Context: Cisplatin-induced nephrotoxicity has been accepted as an important obstacle for efficient cisplatin-based chemotherapy. Silymarin from seeds of milk thistle [ Silybum marianum L. (Asteraceae)] has been shown to possess various potential pharmacological properties; however, whether or not this agent selectively protects renal cells from cisplatin-induced cell death with no interfering effect on cancer cells is not clear. Objective: Potential of silymarin in protection of cisplatin-induced renal cell death without compromising effect on anticancer activity of cisplatin was demonstrated in this study. Materials and methods: Cisplatin-induced cell death was evaluated in human proximal tubular HK-2, lung carcinoma H460, and melanoma G361 cells using MTT, Hoechst 33342, and propidium iodide assays. Results: Cisplatin induced both apoptosis and necrosis in HK-2 cells and caused a decrease in cell viability by ~40% and 60% at the doses of 25 and 100 µM, respectively. Pretreatment with 25-200 µM of silymarin significantly protected against cisplatin-induced cell death in a dose-dependent manner. In contrast, pretreatment of silymarin (25-100 µM) caused no significant change on cisplatin-induced cell death in H460 cells but significantly potentiated cisplatin-induced apoptosis in G361 cells. Discussion and conclusion: These findings reveal the selectivity of silymarin in protection of renal cells from cisplatin-induced cell death and could be beneficial for the development of this considerately safe compound as a renoprotective agent. [ABSTRACT FROM AUTHOR]

Objectives: Small dense low-density lipoprotein (LDL) plays an important role in glomerular injury through conversion to an oxidatively modified form of LDL. However, few studies have evaluated the effects of antilipidemic agents on the LDL particle size and renal function in hyperlipidemic patients with nondiabetic nephropathy. Methods: This study was a randomized crossover trial comparing the effects of atorvastatin (10 mg/day) and probucol (500 mg/day) administered for 24 weeks in 31 patients (urinary albumin excretion 0.3–2.0 g/day and creatinine clearance >30 mL/min/1.73 m2). Lipid parameters, mean LDL particle diameter, creatinine clearance, and urinary albumin to creatinine excretion ratio were measured before and during treatment periods. Main findings: Atorvastatin and probucol significantly reduced the serum total cholesterol and LDL cholesterol concentrations. When stratified by mean baseline LDL particle size at 25.5 nm, atorvastatin increased ( p < 0.05) LDL particle size from 24.6 ± 0.5 to 25.2 ± 0.9 nm only in the <25.5 nm (pattern B) group, whereas probucol decreased ( p < 0.05) LDL size from 24.8 ± 0.9 to 24.2 ± 0.9 nm in the pattern B group and from 25.9 ± 0.5 to 24.6 ± 0.8 nm in the ≥25.5 nm (pattern A) group. No significant differences in urinary albumin/creatinine excretion ratio and creatinine clearance were observed in both groups during treatment. Conclusions: Only atorvastatin improved the LDL-subtype distribution in hyperlipidemic patients with nondiabetic nephropathy, although both agents exhibited no renoprotective action, suggesting that the effects on LDL-subtype distribution do not directly lead to renoprotection. [ABSTRACT FROM AUTHOR]

Oxidative stress due to abnormal production of reactive oxygen molecules (ROM) is believed to be involved in the etiology of toxicities of many xenobiotics. Evidence suggested that ROM is involved in the nephrotoxicity of a widely used synthetic anticancer drug cisplatin. The nephroprotective effects of ethanol extract of Aulosira fertilisima Ghose (EEA) was evaluated using cisplatin (5 mg/kg−1 i.p.)-induced renal damage in rats. EEA showed higher significant effect on DPPH radical scavenging activity as compared with methanol extract of A. fertilisima (MEA) and water extract of A. fertilisima (WEA). Thus, EEA was selected for further in vivo studies. The serum urea and creatinine levels in the cisplatin alone-treated group were significantly elevated with respect to normal group of animals. The levels were reduced in the EEA (100 mg/kg, p.o) plus cisplatin-treated groups. Renal oxidative stress was determined by renal TBARS, CD and reduced glutathione levels, and by enzymatic activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione transferase (GST). A single dose of cisplatin-produced marked renal oxidative and nitrosative stress and significantly deranged renal functions. Chronic EEA treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation, and enhanced reduced glutathione levels, superoxide dismutase, and catalase activities. The results of the study indicated that A. fertilisima significantly and dose-dependently protected the nephrotoxicity induced by cisplatin. This protection is mediated either by preventing the cisplatin-induced decline of renal antioxidant defense system or by their direct free radical scavenging activity. [ABSTRACT FROM AUTHOR]

Aim. To investigate antiproteinuric effect of spironolactone in patients with chronic kidney disease (CKD) treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1 receptor blockers (ARBs). Methods. This study was performed in 33 CKD patients with proteinuria. 24 h urinary protein excretion and biochemical parameters were obtained before the therapy. Then, spironolactone (25 mg/d) was added to the therapy. The antiproteinuric effect of spironolactone was examined for eight weeks. Results. At eight weeks, there was a significant decrease in proteinuria ( p < 0.001, 47.9% decrease). Systolic and diastolic blood pressures were significantly decreased ( p < 0.004, p < 0.001, respectively). However, no correlation was detected between the reductions in systolic and diastolic BP and the reduction in proteinuria ( p = 0.464, p = 0.239, respectively). Serum potassium level increased significantly ( p < 0.001). Conclusions. Our study suggests that spironolactone significantly reduces urinary protein excretion. This strategy may be useful to slow the progression of CKD. However, hyperkalemia is the most important side effect of treatment, and it is necessary to monitor potassium level. Further studies are needed to determine the efficacy of spironolactone on proteinuria. [ABSTRACT FROM AUTHOR]

Hypertension is an important risk factor for cardiovascular disease (CVD), particularly in patients with comorbid obesity, diabetes, metabolic disease, or end-organ damage. An integrated CV risk management approach is being adopted: aggressive blood pressure (BP) control is important in patients with high CVD risk, and well-tolerated antihypertensive agents with protective benefits beyond BP lowering are advantageous. The renin-angiotensin system is integral to blood pressure control and is well established in the pathophysiology of CVD. Angiotensin II receptor blockers (ARBs) are highly efficacious, persistent, well-tolerated antihypertensive agents, with additional benefits in comorbid hypertension, CV pathologies, end-organ damage, and, in diabetes, diabetic nephropathy or metabolic syndrome. ARBs decrease overall risk of CV and end-organ disease, CVD-related mortality, and cerebrovascular events in patients with hypertension. [ABSTRACT FROM AUTHOR]