Batya Kristal

The polymorphonuclear leukocyte--a new target for erythropoietin.

A previous study from our laboratory has shown that erythropoietin (EPO), beside its traditional role in erythropoiesis, acts as an alleviator of oxidative stress and inflammation in chronic hemodialysis (HD) patients, conferred in part by activated polymorphonuclear leukocytes (PMNLs). To substantiate this phenomenon, the existence of EPO receptors (EPO-Rs) on PMNL membrane was examined at the transcriptional and translational levels. mRNA for EPO-R was detected in PMNLs using specific primers directed towards the extracellular region of human EPO-R cDNA. The predicted 300-bp fragment was amplified by reverse transcriptase-polymerase chain reaction. Subcloning and sequence analysis revealed 100% homology of this fragment with human EPO-R. The receptor protein was detected on the surface of intact PMNLs using 125I-EPO. The protein was further demonstrated by flow cytometric analysis using a fluorescent monoclonal anti-EPO-R. The percentage of PMNLs expressing EPO-R showed a strong correlation with the level of EPO in the serum, suggesting an upregulation of the receptor by the hormone. Taken together with our recent findings that EPO attenuates the oxidative stress and inflammation contributed by PMNLs in HD patients, the detection of functional EPO-R expression in PMNLs places these cells among the nonerythroid, EPO-responsive target populations.

HEPARIN INDUCES APOPTOSIS IN HUMAN PERIPHERAL BLOOD NEUTROPHILS

Programmed cell death, by apoptosis, has been shown to play an important role in the regulation of haemopoiesis. Using trypan blue exclusion for distinguishing intact membranes, flow cytometry for detection of sub G1 peak and in situ terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL), this study shows that heparin induces apoptosis in vitro in human peripheral blood neutrophils. The known anti‐proliferative effect of heparin in several in vitro cell systems has therefore to be interpreted in the light of apoptosis. In addition, apoptosis may help explain the anti‐inflammatory effects resulting from the interaction between vessel wall heparan sulphate and chemoattracted peripheral blood neutrophils.

Renal Ischemia – Reperfusion Injury: Contribution of Nitric Oxide and Renal Blood Flow

The contributions of nitric oxide (NO) and renal blood flow (RBF) were examined in ischemia-reperfusion injury in the rat kidney. The function of both kidneys was assessed by glomerular filtration rate (GFR), and fractional excretion of sodium (FENa), calculated before, during unilateral renal artery clamping (45 min), and following reperfusion (90 min). RBF was measured in the same model by ultrasonic flowmetry. Intrarenal NO levels were modulated by administration of S-nitroso-N-acetylpenicillamine (SNAP), L-arginine, acetylcholine, and the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). SNAP increased GFR from 0.20 ± 0.04 ml/min in control ischemic kidney to 0.38 ± 0.06 ml/min and reduced FENa from 19.3 ± 3.4 to 9.5 ± 1.8%. Similar results were observed when L-arginine was administered. Acetylcholine had no effect on GFR or FENa. RBF was fully restored within 60 min following reperfusion, with no change in the rate of recovery by L-arginine. L-NAME aggravated the ischemia-reperfusion injury, preventing full restoration of RBF, further reducing GFR and worsening FENa. In conclusion, ischemia-reperfusion injury ends in low intrarenal levels of NO. We propose that this low NO level results from damage to the endothelial receptor signal transduction process and is not due to impaired NO synthase activity or to changes in RBF.

Is Anemia at Hospital Admission Associated with In-Hospital Acute Kidney Injury Occurrence?

Background: The effect of acute kidney injury (AKI) on anemia has been well-documented. However, the effect of ‘preexisting’ anemia on AKI has been less addressed. The aims of the present study were to investigate (1) the association between anemia at hospital admission and AKI occurrence, and (2) the effect of ‘preexisting’ anemia on the clinical outcomes of AKI. Methods: A retrospective cohort study was undertaken among patients aged ≧17 years who were admitted to our hospital during the year 2006 (n = 34,802). Anemia at hospital admission and AKI occurrences were determined using the WHO definition and the RIFLE criteria, respectively. A subgroup of patients with an estimated glomerular filtration rate ≧60 ml/min/1.73 m2 was analyzed separately to control for the effect of chronic kidney disease on anemia. Results: The cumulative incidence of AKI was 11.2% in anemic patients at hospital admission, compared to 5.5% in nonanemic subjects. The association between anemia at admission and AKI occurrence remained statistically significant after controlling for potential confounders (odds ratio 1.5, 95% CI 1.4–1.6). In addition, an association between anemia at hospital admission and clinical outcomes of AKI was observed. Conclusion: Anemia at hospital admission should be recognized as a potential risk factor for in-hospital AKI occurrence.

Effect of Erythropoietin Therapy on Red Cells Filterability and Left Ventricular Mass in Predialysis Patients

Background. Cardiovascular complications are the leading cause of mortality in patients with end-stage renal disease. Left ventricular hypertrophy (LVH) is recognized as an independent risk factor for cardiovascular morbidity and mortality. At the onset of dialysis, more than 70% of the patients with chronic kidney disease have echocardiographic evidence of LVH. Anemia, increased red cells filterability time (RCFT), and blood viscosity are known to induce LVH. Aim. To evaluate, prospectively, the effects of erythropoietin (EPO) therapy for 20 weeks on RCFT and left ventricular mass (LVM). Patients and Methods. Twenty uremic and anemic predialysis patients with creatinine clearance test below 35 mL/min were studied. RCFT test and three-dimensional echocardiography were performed at 0, 10, and 20 weeks. Results. EPO therapy for 20 weeks did not adversely affect renal function and did not significantly change the mean blood pressure. It significantly increased the hemoglobin and fibrinogen levels, and decreased RCFT and LVM (p < .01). Conclusion. Although correction of anemia can contribute to regression of LVM, we speculate that an increasing number of cells with normalized viscoelastic properties and a direct effect of EPO on erythrocytes and myocardiocytes, through specific receptors, may also play an important role.

Electrophysiological Abnormalities in Upper Extremities After Brachiocephalic A‐V Fistulas Construction in Predialysis Patients

Background: Peripheral neuropathy is considered a common complication in patients suffering from advanced chronic kidney disease (CKD). Superimposed peripheral multiple neuropathies may complicate arteriovenous (A‐V) fistulas construction. Aim: To evaluate, prospectively, the influence of brachiocephalic A‐V fistulas construction on the peripheral nerves of the same extremity and to characterize the patients at risk for developing ischemic and neurological complications. Patients and Methods: Twenty patients suffering from advanced CKD were enrolled in the study: 10 diabetic and 10 non‐diabetic patients. All patients underwent electrophysiological evaluation one week before, 3 weeks and 3 months after surgery. Median, ulnar and radial nerves were studied. Results: In non‐diabetic patients MNCV was normal before and after surgery, but were significantly lower and reduced progressively and significantly after surgery in diabetic patients (p ≤ 0.02). In both non‐diabetic and diabetic patients SNCV was reduced, but were significantly lower in diabetic patients before and after surgery (p ≤ 0.03). In diabetic patients it reduced progressively and significantly after surgery (p < 0.01). Thirty percent of patients developed local edema and significant decrease of CMAP of median nerve three weeks after surgery (p = 0.02) with complete resolution at three months. Conclusion: Diabetic uremic patients are at increased risk to develop disabling neurological complications after the construction of A‐V fistulas. Diabetes was the only predictive risk factor for developing these complications. Prevention requires careful preoperative electrophysiological evaluation and postoperative follow‐up.