Adrian Iaina

Nitric oxide in ischaemic acute renal failure of streptozotocin diabetic rats.

SummaryChanges in nitric oxide (NO) levels were determined in ischaemic acute renal failure in streptozotocin-induced diabetes mellitus rats. Two weeks after streptozotocin administration and immediately after right nephrectomy, the left renal artery was occluded for 60 min. Similar procedures were carried out in non-diabetic rats. The nitrite (NO2) + nitrate (NO3) levels were measured in plasma and urine. The effects of chronic oral supplementation with l-arginine and an NO synthase inhibitor (N-omega-nitro-l-arginine) were also studied in both diabetic and non-diabetic rats before and after renal artery clamping. The rats with diabetic acute renal failure had a much lower creatinine clearance (90±22 Μl · min−1 · 100 g body weight−1, p<0.005), and higher fractional excretion of sodium (FENa)% (10.90±4.2, p<0.001) and protein excretion (2078±69 Μg/ml creatinine clearance, p<0.001) compared with the respective values in the non-diabetic groups (163±30; 1.46±86; 453.3±31). The plasma and urine NO2 + NO3 levels were significantly higher in the untreated diabetic rats compared with the untreated normal rats before ischaemia (p<0.001). The ischaemic acute renal failure in non-diabetic rats increased the plasma and urinary NO2 + NO3 excretion after ischaemia. The urinary excretion of these metabolites decreased significantly and their plasma levels remained unchanged in the ischaemic diabetic rats. The l-arginine administration resulted in a small but significantly higher creatinine clearance after clamping in the non-diabetic rats. The NO synthase inhibitor caused deterioration in renal function in all ischaemic and non-ischaemic groups. In summary, the greater vulnerability to ischaemia of the diabetic kidney seems to be associated with both impaired response to and impaired production of NO.

Intravenous Iron in Heart Failure: Beyond Targeting Anemia

Iron deficiency is commonly seen in congestive heart failure (CHF) in both anemic and nonanemic patients. In six studies in which these iron-deficient patients with CHF were treated with intravenous (IV) iron, five found an improvement in the hemoglobin. In uncontrolled and controlled studies, the New York Heart Association (NYHA) class, quality of life, and exercise capacity were improved consistently with IV iron. In some studies, cardiac function also was improved. In one large, double-blind, placebo-controlled study of IV iron, the patient global assessment, quality of life, and NYHA class improved rapidly in both those who were anemic or not anemic. In contrast to these studies, another controlled study of anemia in CHF showed no effect of oral iron on hemoglobin or on any cardiac parameters over 1 year. These studies suggest that CHF in both anemic and nonanemic iron-deficient patients may benefit from a course of IV iron, but not oral iron.

Haptoglobin phenotype as a predictive factor of mortality in diabetic haemodialysis patients

Introduction: The mortality rate in diabetic dialysis patients (DDPs) is over 15% per year, with the cause of death most often attributed to cardiovascular disease (CVD) or bacterial infection (sepsis). Identification of genetic markers predictive of early mortality would be useful in the evaluation of therapies for the reduction of mortality rate in this population. Haptoglobin (Hp) is a polymorphic protein which appears to confer differential susceptibility to bacterial infection and CVD. We therefore proposed that Hp phenotype can predict mortality in DDPs. Methods: We tested this hypothesis prospectively in a longitudinal study of 392 dialysis patients from eight medical centres in Israel. Hp was determined by polyacrylamide gel electrophoresis. Patients were followed for all-cause mortality over a 3-year period. Results: We found that Hp phenotype was a significant predictor of mortality in DDPs stratified by age. In diabetic individuals over 60 years of age there was a decrease in mortality associated with the Hp 1-1 phenotype (P = 0.03). However, in younger DDPs the Hp 2-2 phenotype was associated with a decreased mortality rate (P = 0.003). Conclusion: Hp phenotype may be useful in the risk stratification algorithm and management of DDPs.

The importance of correction of anemia with erythropoietin and intravenous iron in severe resistant congestive heart failure

About one third to one half of patients with heart failure are anemic, in that they have a hemoglobin level of less than 12 g/dL. Anemia is more common and more severe as the clinical status of CHF worsens. In addition, anemia is associated with a higher mortality and higher rate of hospitalization, as well as with signs of malnutrition. In anemic CHF patients who are resistant to maximally tolerated CHF medications and who remain very symptomatic, both uncontrolled studies of a combination of subcutaneous erythropoietin (EPO) and IV ferric sucrose have reported a correction of the anemia. This correction has been associated with an improvement in NYHA functional status, left ventricular ejection fraction, and a marked reduction in the doses of diuretic needed and in the frequency and duration of hospitalizations. Renal function, which had been steadily falling before the correction of the anemia, was also stabilized. Other controlled studies have also found that anemia correction with EPO increased oxygen utilization during maximal exercise, exercise endurance and quality to life. The anemia is probably due mainly to a combination of renal failure and excessive cytokines, both of which interfere with EPO production and utilization. If confirmed by larger studies, correction of anemia with the EPO-IV iron combination may become a useful adjuvant to the treatment of CHF.

Prediction of renal impairment in elderly patients with congestive heart failure treated with captopril

SummaryThis study assessed the usefulness of the oral captopril test in the prediction of renal impairment among elderly patients with congestive heart failure (CHF). Fortyseven patients aged ≥65 years with CHF (EF <40%) participated in a prospective nonrandomized series. Blood samples for plasma renin activity (PRA) were drawn before and 60 minutes after 50 mg of oral captopril. Twenty-four hours later, captopril was administered (up to 75 mg/day over a 4 day period), and renal laboratory and clinical assessment were performed at baseline and for a 9 day period. In 7 of 47 patients (14.9%), deterioration of renal function was observed. During the captopril test, the PRA increased significantly after 1 hour in almost all patients and the mean blood pressure decreased from 99.2±14.6 mmHg to 92.2±13.7 mmHg (p<0.001). All patients whose baseline PRA level was <1.9 ng/ml/hr and whose stimulated PRA was <3.2 ng/ml/ hr maintained a stable renal function throughout the study period. Significant statistical correlation (p<0.05) was found between the initial PRA, the changes in PRA or mean blood pressure during the captopril test, and the change in plasma creatinine and creatinine clearance in the entire group, and was even more evident in a subgroup of patients with an ejection fraction ≥30%. All these correlations were not statistically significant in the patients with an ejection fraction <30%. It is thus concluded that measurement of pretreatment PRA levels might be a useful laboratory tool for predicting the renal safety of captopril use in patients with CHF whose EF ≥30%.

Tubular and Glomerular L-Arginine Transport (Uptake and Transporters) and the Nitric Oxide Synthases in Ischemic Acute Renal Failure (iARF) in Streptozotocin-Induced Diabetic Rats (STZ-DM)

Background. L-arginine or its metabolites may be important pathogenetic factors in ischemic acute renal failure (iARF) in rats. It was found that the L-arginine-nitric oxide synthase-nitric oxide system plays an important role in the renal hemodynamic alterations in the early stages of diabetes. The iARF in diabetic rats is much more severe than the normal rats exposed to a same ischemia time. The purpose of the present study was to evaluated L-arginine uptake and its transporters and nitric oxide synthase isoform expression in tubuli and glomeruli of STZ-induced diabetic rats with iARF. Methods. iARF was induced by right nephrectomy and left renal artery clamping for 60 min followed by a 60 min reflow period. iARF was induced in STZ diabetes rats two weeks after intraperitoneal streptozotocin (60 mg/kg body weight) and in normal control rats. L-arginine uptake, L-arginine transporters (CAT1 and CAT2) and nitric oxide synthases (iNOS, eNOS, and bNOS) were determined by RT-PCR) in both glomeruli and tubuli preparations. Results. The STZ diabetic rats compared with the non diabetic normal rats have a higher glomerular L-arginine uptake, higher iNOS mRNA, lower eNOS mRNA, and lower tubular CAT1 mRNA, eNOS mRNA, and bNOS mRNA. The diabetic iARF after one hour of reperfusion had lower glomerular L-arginine uptake, lower CAT1 mRNA, lower eNOS mRNA, lower bNOS, and higher tubular iNOS mRNA compared with iARF in normal rats. Conclusions. Our findings suggest a prolonged and more severe post-glomerular vasoconstriction very early after the reflow in the iARF of STZ diabetic rats compared with the iARF in the normal control rats. That may be a plausible explanation to the very significant decline in GFR and tubular necrosis that characterize the iARF in diabetic rats.

Effect of Chronic Cholesterol Loading in the Development of Acute Ischemic Renal Failure in Rats

The effect of chronic cholesterol loading and lovastatin administration in renal artery clamping acute renal failure in rats is not known. Acute renal failure was induced by 60-min left renal artery clamping immediately after right nephrectomy. The changes in renal function after renal artery clamping in the hyperlipidemic rats were unexpected. The acute renal failure in the cholesterol-loaded groups was less severe than in the nonhyperlipidemic rats. The lovastatin administration had some favorable effect on renal function after ischemia; however, this effect was not additive to the high dietary cholesterol administration. Our results seems to favor the concept that in this special form of experimental renal ischemic acute renal failure, serum cholesterol levels, elevated through diet, may have protective effects with respect to renal tubular lesions during or following the acute ischemic insult.

Metabolic alkalosis in skilled nursing patients

Renal failure is common among the long-term care (LTC) elderly. Little is known about the acid/base status of these patients. The aim of this study is to evaluate the relationship between the acid base status and renal function in a representative group of skilled nursing patients and relate it to their feeding status. LTC elderly patients, in stable clinical condition, 50 on naso-gastric tube (NGT) feeding, 40 orally fed (OF), were recruited to this study. As controls, we studied a group of 30 elderly independent, ambulatory patients admitted to the acute geriatric departments of the hospital for different causes which were not related to their acid-base status. Venous blood was taken for the routine tests and blood gases. In the LTC study groups a 24-h urine collection was examined for biochemical parameters and calculations of all clearances. Glomerular filtration rate (GFR) was estimated by the Cockroft and Goult and MDRD formulas. Renal function was similar in the two main study groups. Daily secretion of sodium and chloride were 50% lower in the NGT fed patients (p<0.001). The LTC elderly patients had significantly higher venous pH values, with no differences in pCO(2) or HCO(3). An alkalotic state (pH>7.45) was found in 13.6% of them (18% in the NGT and 6.5% in the OF) while none of the independent elderly had such values (p<0.05). Similarly, HCO(3)>34 was found in 12% of the LTC elderly versus none in the independents (p=0.06). Values of pO(2) and O(2) saturation were significantly higher in the nursing elderly and mainly those fed by NGT. Hemoglobin levels had a significantly negative correlation with the pH (r=-0.3, p<0.002). In conclusion, unexpected metabolic alkalosis was found in a group of skilled nursing patients, more prominent in those fed by NGT. This finding warrants the inclusion of routine pH determination in patients whenever pharmacokinetic considerations are essential.