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      Effect of Erythropoietin on Urinary Liver-Type Fatty-Acid-Binding Protein in Patients with Chronic Renal Failure and Anemia

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          Background/Aim: The urinary liver-type fatty-acid-binding protein (L-FABP) level reflects the clinical progression of chronic kidney disease. We conducted a study to determine whether administration of erythropoietin (EPO), which is produced in response to hypoxic stress, affects urinary protein excretion and L-FABP levels in patients with chronic renal failure (CRF) and anemia. Methods: The study was an interventional trial that included 20 anemic CRF patients (median serum creatinine level 2.0 mg/dl, range 1.3–2.9 mg/dl; median hemoglobin concentration 9.2 g/dl, range 8.2–9.8 g/dl; median estimated glomerular filtration rate 20.5 ml/min, range 15.0–28.0 ml/min; group A). Recombinant EPO (12,000 U twice/month) was given to these patients for 6 months. Urinary protein, L-FABP, 8-hydroxy-2′-deoxyguanosine, and hemoglobin levels were measured before and 3 and 6 months after treatment. Twenty nonanemic CRF patients were enrolled as controls (group B). Results: After 6 months, the hemoglobin level was increased as compared with the baseline level in group A treated with EPO (median 11.3 g/dl, range 9.3–13.8 g/dl, vs. median 9.2 g/dl, range 8.2–9.8 g/dl; p < 0.01) but not in the untreated group B (median 11.8 g/dl, range 10.2–13.0 g/dl, vs. median 12.1 g/dl, range 10.8–13.4 g/dl; not significant). The urinary protein excretion was decreased as compared with the baseline level in group A (median 1.2 g/day, range 0.6–1.9 g/day, vs. median 1.9 g/day, range 1.1–2.6 g/day; p < 0.01) but not in group B (median 1.4 g/day, range 0.7–2.2 g/day, vs. median 1.6 g/day, range 0.7–2.3 g/day; not significant). The urinary L-FABP level was also decreased as compared with the baseline level in group A (median 50.0 µg/g creatinine, range 7.5–90.0 µg/g creatinine, vs. median 115.0 µg/g creatinine, range 20.0–225.0 µg/g creatinine; p < 0.01) but not in group B (median 82.0 µg/g creatinine, range 15.5–158.0 µg/g creatinine, vs. median 76.0 µg/g creatinine, range 25.0–138.5 µg/g creatinine; not significant). The glomerular filtration rate changed little throughout the study period in either group. The urinary 8-hydroxy-2′-deoxyguanosine level was decreased as compared with the baseline level in group A (median 22.0 ng/mg creatinine, range 8.0–30.0 ng/mg creatinine, vs. median 38.5 ng/mg creatinine, range 14.0–68.0 ng/mg creatinine; p < 0.01) but not in group B (median 33.0 ng/mg creatinine, range 9.0–56.0 ng/mg creatinine, vs. median 30.0 ng/mg creatinine, range 10.0–54.0 ng/mg creatinine; not significant). Conclusion: EPO supplementation may ameliorate renal tubular damage, in part, due to a reduction of oxidative stress in CRF patients with anemia.

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          Most cited references 17

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          Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion.

          Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.
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            Erythropoietin protects against ischaemic acute renal injury.

            Erythropoietin (EPO) has recently been shown to exert important cytoprotective and anti-apoptotic effects in experimental brain injury and cisplatin-induced nephrotoxicity. The aim of the present study was to determine whether EPO administration is also renoprotective in both in vitro and in vivo models of ischaemic acute renal failure. Primary cultures of human proximal tubule cells (PTCs) were exposed to either vehicle or EPO (6.25-400 IU/ml) in the presence of hypoxia (1% O(2)), normoxia (21% O(2)) or hypoxia followed by normoxia for up to 24 h. The end-points evaluated included cell apoptosis (morphology and in situ end labelling [ISEL], viability [lactate dehydrogenase (LDH release)], cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA synthesis (thymidine incorporation). The effects of EPO pre-treatment (5000 U/kg) on renal morphology and function were also studied in rat models of unilateral and bilateral ischaemia-reperfusion (IR) injury. In the in vitro model, hypoxia (1% O(2)) induced a significant degree of PTC apoptosis, which was substantially reduced by co-incubation with EPO at 24 h (vehicle 2.5+/-0.5% vs 25 IU/ml EPO 1.8+/-0.4% vs 200 IU/ml EPO 0.9+/-0.2%, n = 9, P<0.05). At high concentrations (400 IU/ml), EPO also stimulated thymidine incorporation in cells exposed to hypoxia with or without subsequent normoxia. LDH release was not significantly affected. In the unilateral IR model, EPO pre-treatment significantly attenuated outer medullary thick ascending limb (TAL) apoptosis (EPO 2.2+/-1.0% of cells vs vehicle 6.5+/-2.2%, P<0.05, n = 5) and potentiated mitosis (EPO 1.1+/-0.3% vs vehicle 0.5+/-0.3%, respectively, P<0.05) within 24 h. EPO-treated rats exhibited enhanced PCNA staining within the proximal straight tubule (6.9+/-0.7% vs vehicle 2.4+/-0.5% vs sham 0.3+/-0.2%, P<0.05), proximal convoluted tubule (2.3+/-0.6% vs vehicle 1.1+/-0.3% vs sham 1.2+/-0.3%, P<0.05) and TAL (4.7+/-0.9% vs vehicle 0.6+/-0.3% vs sham 0.3+/-0.2%, P<0.05). The frequency of tubular profiles with luminal cast material was also reduced (32.0+/-1.6 vs vehicle 37.0+/-1.3%, P = 0.05). EPO-treated rats subjected to bilateral IR injury exhibited similar histological improvements to the unilateral IR injury model, as well as significantly lower peak plasma creatinine concentrations than their vehicle-treated controls (0.04+/-0.01 vs 0.21+/-0.08 mmol/l, respectively, P<0.05). EPO had no effect on renal function in sham-operated controls. The results suggest that, in addition to its well-known erythropoietic effects, EPO inhibits apoptotic cell death, enhances tubular epithelial regeneration and promotes renal functional recovery in hypoxic or ischaemic acute renal injury.
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              Evidence of tubular hypoxia in the early phase in the remnant kidney model.

              The remnant kidney model is a mainstay in the study of progressive renal disease. The earliest changes in this model result from glomerular hemodynamic alterations. Given that progressive renal disease is the result of subsequent interstitial damage initiated by undetermined pathogenic factors, the authors investigated the role of hypoxia as a pathogenic factor in tubulointerstitial damage after renal ablation in rats. Cortical tissue hypoxia in the early phase (4 and 7 d) in remnant kidney rats, sham-operated rats, and animals treated with the angiotensin II receptor blocker (ARB) olmesartan (10 mg/kg per d) was assessed by uptake of a hypoxic probe, pimonidazole, expression of HIF-1alpha, and by increased transcription of hypoxia-responsive genes. Physiologic perfusion status of the postglomerular peritubular capillary network was evaluated by lectin perfusion and Hoechst 33342 diffusion techniques. Results showed that the number of hypoxic tubules was markedly increased 4 and 7 d after nephron loss. These findings antedated any histologic evidence of tubulointerstitial damage. The hypoxic state persisted until interstitial damage developed. These results were confirmed using HIF-1alpha immunoprecipitation and increase of hypoxia-responsive genes. Pathologic studies of the vasculature demonstrated significant functional changes that generated a hypoxic milieu. ARB treatment prevented vascular changes and ameliorated tubular hypoxia. These results suggest that the initial tubulointerstitial hypoxia in remnant kidney model plays a pathogenic role in the subsequent development of tubulointerstitial injury. The initial hypoxia in this model was dependent on activation of the renin-angiotensin system and hemodynamic alterations after nephron loss.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                July 2006
                19 July 2006
                : 26
                : 3
                : 276-280
                aDepartment of Internal Medicine, Shinmatsudo Central General Hospital, Chiba, bResearch Unit for Organ Regeneration, Riken Kobe Institute, Kobe, cDepartment of Pathology, Koshigaya Hospital, Dokkyo University School of Medicine, Tochigi, and dDepartment of Internal Medicine, Koto Hospital, Tokyo, Japan
                93934 Am J Nephrol 2006;26:276–280
                © 2006 S. Karger AG, Basel

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                Page count
                Tables: 2, References: 21, Pages: 5
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                Original Report: Laboratory Investigation


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