Ramzia Abu Hamad

The effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipids, and inflammation in type 2 diabetes mellitus patients.

AIM This study evaluated the effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipid profile, oxidative stress, and high-sensitivity C-reactive protein (hsCRP) in type 2 diabetes mellitus patients. SUBJECTS AND METHODS Forty diabetes patients, inadequately controlled on metformin, were randomly assigned to either sitagliptin (100 mg/day) or glibenclamide (5 mg/day) for 3 months. Following a 1-month washout period, a crossover switch from glibenclamide to sitagliptin and vice versa was performed for an additional 3 months. Arterial stiffness, 24-h ambulatory blood pressure monitoring, lipids, hsCRP, glycated hemoglobin, fasting glucose, STAT-8-isoprostane (a measure of oxidative stress), body mass index (BMI), and waist circumference were measured at baseline and at 3 months with each of the study drugs. RESULTS Thirty-four patients completed the study. Glibenclamide had a better glucose-lowering effect than sitagliptin, but this was associated with more hypoglycemic events. BMI increased following glibenclamide treatment, whereas sitagliptin proved weight-neutral. Mean BMI gain was +0.5±1.0 kg/m(2) for glibenclamide versus -0.01±0.9 kg/m(2) for sitagliptin (P<0.001). Triglyceride levels significantly dropped following sitagliptin, although they remained unaltered after glibenclamide treatment. Mean triglyceride decrease was -18.4±45 mg/mL after sitagliptin but -0.2±57 mg/dL following glibenclamide treatment (P=0.018). There was no change in low-density lipoprotein, high-density lipoprotein, arterial stiffness, blood pressure monitoring, hsCRP, or STAT-8-isoprostane with each of the study drugs. CONCLUSIONS Sitagliptin, but not glibenclamide, demonstrated a significant beneficial effect on BMI and triglyceride levels. However, arterial stiffness, blood pressure, oxidative stress, and inflammatory status were not significantly affected by adding sitagliptin or glibenclamide to metformin-treated type 2 diabetes patients.

Effect of captopril treatment on recuperation from ischemia/reperfusion-induced acute renal injury

BACKGROUND Ischemia/reperfusion triggers acute kidney injury (AKI), mainly via aggravating hypoxia, oxidative stress, inflammation and renin-angiotensin system (RAS) activation. We investigated the role of angiotensin-converting enzyme (ACE) inhibition on the progression of AKI in a rat model of ischemia/reperfusion. METHODS Ninety-nine Sprague-Dawley rats were subjected to 1 h ischemia/reperfusion and/or left unilateral nephrectomy, with concurrent intraperitoneal implantation of Alzet pump. Via this pump, they were continuously infused with captopril 0.5 mg/kg/day, captopril 2 mg/kg/day or saline. The rats were sacrificed following 24, 48 or 168 h. Blood samples, 24-h urine collections and kidneys were allocated, to evaluate renal function, angiotensin-II, nitric oxide (NO), apoptosis, hypoxia, oxidative stress and inflammation. RESULTS Serum creatinine and cystatin-C significantly increased in ischemic rats, coinciding with histopathologic intrarenal damage, decreased NO, augmented angiotensin-II, interleukin (IL)-6, IL-10, transforming growth factor-beta. At the acute reperfusion stage, captopril prevented excessive angiotensin-II synthesis, ameliorated renal dysfunction, inhibited intrarenal inflammation and improved histopathologic findings. Most of the renoprotective effects of captopril were limited predominantly to acute reperfusion stage. Concurrently, captopril significantly decreased NO availability, exacerbated intrarenal hypoxia and augmented oxidative stress. CONCLUSIONS At the acute stage of renal ischemia/reperfusion-induced AKI, ACE inhibition substantially contributed to the amelioration of acute injury by improving renal function, inhibiting systemic and intrarenal angiotensin-II, attenuating intrarenal inflammation and preserving renal tissue structure. Later on, at the post-reperfusion stage, most of the beneficial effects of captopril administration on the recuperating post-ischemic kidney were no longer evident. Concurrently, ACE inhibition exacerbated intrarenal hypoxia and accelerated oxidative stress, indicating that renal adaptation to some consequences of ischemia does require bioavailability of RAS components.

Hyperglycaemia, inflammation, RAS activation: three culprits to blame for acute kidney injury emerging in healthy rats during general anaesthesia.

Aim:  Major surgery under general anaesthesia might evoke acute kidney injury (AKI), sometimes culminating in end stage renal disease. We investigated the roles of hyperglycaemia, inflammation and renin‐angiotensin system (RAS) activation in induction of AKI following anaesthesia by different anaesthetic drugs and/or regimens.

Renoprotective Effects of DNAse-I Treatment in a Rat Model of Ischemia/Reperfusion-Induced Acute Kidney Injury

Background: Massive DNA destruction/accumulation of cell-free DNA debris is a sensitive biomarker of progressive organ/tissue damage. Deleterious consequences of DNA debris accumulation are evident in cardiac ischemia, thrombosis, auto-inflammatory diseases, SLE-induced lupus nephritis and cystic fibrosis. In case of renal pathologies, degradation and elimination of DNA debris are suppressed, due to downregulated DNAse-I activity within the diseased kidneys. The aim of the current study was to evaluate whether exogenous DNAse-I administration might exert renoprotective effects in the setting of acute kidney injury (AKI or acute renal failure). Methods: Sprague-Dawley rats underwent unilateral nephrectomy, with simultaneous clamping of contralateral kidney artery. The treated group received DNAse-I injection before discontinuing anesthesia. Positive (ischemic) controls received saline injection. Negative (non-ischemic) controls were either non-operated or subjected to surgery of similar duress and duration without ischemia. Renal perfusion was evaluated using the Laser-Doppler technique. Blood was procured for evaluating DNAse-I activity, renal functioning, renal perfusion. The kidneys were allocated for histopathologic examinations and for the evaluation of renal hypoxia, intra-renal apoptosis and proliferation. Results: Contrary to the situation in untreated ischemic rats, renal perfusion was significantly improved in DNAse-treated animals, concomitantly with significant amelioration of damage to renal functioning and tissue integrity. Treatment with DNAse-I significantly decreased the ischemia-induced renal hypoxia and apoptosis, simultaneously stimulating renal cell proliferation. Exogenous DNAse-I administration accelerated the clearance of intra-renal apoptotic DNA debris. Conclusion: Functional/histologic hallmarks of renal injury were ameliorated, renal functioning improved, intra-renal hypoxia decreased and intra-renal regeneration processes were activated. Thus, DNAse-I treatment protected the kidney from deleterious consequences of ischemia-induced AKI.

Mesangial cells are responsible for orchestrating the renal podocytes injury in the context of malignant hypertension.

Two populations of renal cells fully possess functional contractile cell apparatus: mesangial cells and podocytes. Previous studies demonstrated that in the context of malignant hypertension overproduction of Angiotensin‐II by the contracting mesangial cells aggravated hypercellularity and apoptosis of adjacent cell populations. The role of podocytes in pathogenesis of malignant hypertension is unclear. We investigated responsiveness of normal vs. hyperglycaemic podocytes to pressure in a model of malignant hypertension.

Hyperglycaemia emerging during general anaesthesia induces rat acute kidney injury via impaired microcirculation, augmented apoptosis and inhibited cell proliferation

Aim:  Major surgery under general anaesthesia frequently triggers acute kidney injury by yet unknown mechanisms. We investigated the role of anaesthesia‐triggered systemic hyperglycaemia in impairment of renal functioning, renal tissue injury, intra‐renal Angiotensin‐II synthesis and endogenous insulin production in anaesthetized rats.

Response of Renal Podocytes to Excessive Hydrostatic Pressure: a Pathophysiologic Cascade in a Malignant Hypertension Model

Background/Aims: Renal injuries induced by increased intra-glomerular pressure coincide with podocyte detachment from the glomerular basement membrane (GBM). In previous studies, it was demonstrated that mesangial cells have a crucial role in the pathogenesis of malignant hypertension. However, the exact pathophysiological cascade responsible for podocyte detachment and its relationship with mesangial cells has not been fully elucidated yet and this was the aim of the current study. Methods: Rat renal mesangial or podocytes were exposed to high hydrostatic pressure in an in-vitro model of malignant hypertension. The resulted effects on podocyte detachment, apoptosis and expression of podocin and integrinβ1 in addition to Angiotensin-II and TGF-β1 generation were evaluated. To simulate the paracrine effect podocytes were placed in mesangial cell media pre-exposed to pressure, or in media enriched with Angiotensin-II, TGF-β1 or receptor blockers. Results: High pressure resulted in increased Angiotensin-II levels in mesangial and podocyte cells. Angiotensin-II via the AT1 receptors reduced podocin expression and integrinβ1, culminating in detachment of both viable and apoptotic podocytes. Mesangial cells exposed to pressure had a greater increase in Angiotensin-II than pressure-exposed podocytes. The massively increased concentration of Angiotensin-II by mesangial cells, together with increased TGF-β1 production, resulted in increased apoptosis and detachment of non-viable apoptotic podocytes. Unlike the direct effect of pressure on podocytes, the mesangial mediated effects were not related to changes in adhesion proteins expression. Conclusions: Hypertension induces podocyte detachment by autocrine and paracrine effects. In a direct response to pressure, podocytes increase Angiotensin-II levels. This leads, via AT1 receptors, to structural changes in adhesion proteins, culminating in viable podocyte detachment. Paracrine effects of hypertension, mediated by mesangial cells, lead to higher levels of both Angiotensin-II and TGF-β1, culminating in apoptosis and detachment of non-viable podocytes.

Effect of N-Acetylcysteine on Residual Renal Function in Chronic Haemodialysis Patients Treated with High-Flux Synthetic Dialysis Membranes: A Pilot Study

Background. Preservation of residual renal function in chronic dialysis patients has proven to be a major predictor of survival. The aim of the present study was to investigate an ability of the combined use of N-acetylcysteine and high-flux biocompatible haemodialysis membranes to improve residual renal function in haemodialysis patients. Patients and Methods. Chronic haemodialysis patients with a residual urine output of at least 100 mL/24 h were administered oral an N-acetylcysteine 1200 mg twice daily for 2 weeks. Treatment group included patients treated with dialysers using high-flux synthetic biocompatible membranes. Control group included patients treated with dialysers using low-flux semisyntetic triacetate haemodialysis membranes. Results. Eighteen patients participated in the study. The residual glomerular filtration rate showed a nonsignificant trend for increase in both groups. The magnitude of GFR improvement after N-acetylcysteine administration was less pronounced in the group treated with high-flux biocompatible membranes: +0.17 ± 0.56 mL/min/1.73 m2 in treatment group and +0.65 ± 0.53 mL/min/1.73 m2 in control group (P < 0.05). Conclusion. In this study of favorable effect of N-acetylcysteine on residual renal function in chronic haemodialysis patients may be less pronounced when using high-flux biocompatible, rather than low-flux semisyntetic, HD membranes.

Abdominal obesity in normal weight versus overweight and obese hemodialysis patients: associations with nutrition, inflammation, muscle strength and quality of life

OBJECTIVE The biological basis of abdominal obesity leading to more severe outcomes in patients with normal body mass index (BMI) on maintenance hemodialysis (MHD) is unclear. The aim of this study was to compare the properties of abdominal obesity in different BMI categories of patients on MHD. METHODS We performed a cross-sectional study of 188 MHD patients (52.7% women; mean age, 69.4 ± 11.5 y) with abdominal obesity in different BMI groups using criteria from the World Health Organization. Appetite and dietary intake, body composition, handgrip strength, malnutrition inflammation score (MIS), inflammatory biomarkers, adipokines, and health-related quality-of-life (QoL) questionnaires were studied. RESULTS According to multivariable analyses, abdominally obese patients with normal BMIs consumed less protein per day (P = 0.04); had lower measurements of surrogates of lean (P < 0.001) and fat mass (P < 0.001); and had higher total cholesterol, tumor necrosis factor-α (P < 0.05), and ratios of adiponectin to leptin (P = 0.003) than overweight and obese patients with abdominal obesity. Multivariable analyses showed no differences in handgrip strength among the study groups.The abdominally obese study participants with normal weight had significantly lower scores in role physical (P = 0.003) and pain (P = 0.04) scales after multivariable adjustments. CONCLUSIONS Normal-weight MHD patients with abdominal obesity exhibited a more proatherogenic profile in terms of inflammatory markers and adipokine expression, lower body composition reserves, and lower physical ability than patients with abdominal obesity with overweight and obesity. This at least partially explains the abdominal obesity paradox in the MHD population in which worse clinical outcomes are seen in abdominally obese patients with normal BMIs, as opposed to overweight and obese patients who are also abdominally obese.