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      Renal Parenchymal Hypoxia, Hypoxia Response and the Progression of Chronic Kidney Disease

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          Renal parenchymal hypoxia, documented under a variety of clinical conditions, conceivably contributes to the progression chronic kidney disease. In this review, normal physiologic medullary hypoxia and abnormal profiles of renal pO(2) in chronic kidney diseases are presented, and the mechanisms leading to anomalous renal tissue oxygenation are discussed. Direct measurements of pO(2) with oxygen electrodes, immunostaining with pimonidazole (which binds to regions with very low pO(2)), or the detection of hypoxia-inducible factor (HIF)-alpha (which accumulates in hypoxic regions, initiating hypoxia-adaptive responses), all serve to detect the distribution and extent of renal parenchymal hypoxia under experimental settings. The use of BOLD MRI as a noninvasive tool, detecting deoxygenated hemoglobin in hypoxic renal tissues, has evolved from experimental settings to human studies. All these modalities indicate that abnormal renal oxygenation develops under conditions such as chronic glomerular, tubulointerstitial or renovascular disease, in diabetes, hypertension, aging, renal hypertrophy, anemia or obstructive uropathy. Abnormal renal tissue hypoxia modifies the pattern of regional gene expression, evoking a host of adaptive and renoprotective pathways (such as HIF-mediated erythropoietin or heme-oxygenase-1), in parallel with the induction of potentially harmful mediators that participate in the progression of chronic kidney injury. Slowing the progression of chronic kidney disease may be achieved by a better understanding of these parallel processes and the accomplishment of a selective control of such protective and maladaptive responses. Copyright 2008 S. Karger AG, Basel.

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          Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure.

          Recent studies emphasize the role of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal failure. When advanced, tubulointerstitial damage is associated with the loss of peritubular capillaries. Associated interstitial fibrosis impairs oxygen diffusion and supply to tubular and interstitial cells. Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation. This in turn exacerbates fibrosis of the kidney and subsequent chronic hypoxia, setting in train a vicious cycle whose end point is ESRD. A number of mechanisms that induce tubulointerstitial hypoxia at an early stage have been identified. Glomerular injury and vasoconstriction of efferent arterioles as a result of imbalances in vasoactive substances decrease postglomerular peritubular capillary blood flow. Angiotensin II not only constricts efferent arterioles but, via its induction of oxidative stress, also hampers the efficient utilization of oxygen in tubular cells. Relative hypoxia in the kidney also results from increased metabolic demand in tubular cells. Furthermore, renal anemia hinders oxygen delivery. These factors can affect the kidney before the appearance of significant pathologic changes in the vasculature and predispose the kidney to tubulointerstitial injury. Therapeutic approaches that target the chronic hypoxia should prove effective against a broad range of renal diseases. Current modalities include the improvement of anemia with erythropoietin, the preservation of peritubular capillary blood flow by blockade of the renin-angiotensin system, and the use of antioxidants. Recent studies have elucidated the mechanism of hypoxia-induced transcription, namely that prolyl hydroxylase regulates hypoxia-inducible factor. This has given hope for the development of novel therapeutic approaches against this final common pathway.
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            Pathophysiology of progressive nephropathies.

             T Bertani,  G. Remuzzi (1998)
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              Hypoxia of the renal medulla--its implications for disease.


                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                October 2008
                18 July 2008
                : 28
                : 6
                : 998-1006
                aDepartments of Medicine, Hadassah Hospitals, Mt. Scopus and Ein Kerem and Hebrew University Medical School, Jerusalem, Israel; bDepartment of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass., USA; cNephrology and Medical Intensive Care, Charité University Clinic, Berlin, Germany
                146075 Am J Nephrol 2008;28:998–1006
                © 2008 S. Karger AG, Basel

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