The impact of withdrawing ACE inhibitors on erythropoietin responsiveness and left ventricular hypertrophy in haemodialysis patients

Ertürk, Şehsuvar; Nergızoğlu, Gökhan; Ateş, Kenan; Duman, Neval; Erbay, Bülent; Karatan, Oktay; Ertug, A. E.

doi:10.1093/ndt/14.8.1912

Cited by 40 publications

(20 citation statements)

References 29 publications

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“…The results were clear: restitution of angiotensin II elevated both systolic blood pressure and hematocrit to near normal levels. Although we have not eliminated the possibility that blood pressure itself played a role in erythrocyte formation, these studies compliment a host of clinical investigations suggesting a direct role of the RAS in erythropoiesis (16,19,33,55). It is well known that erythropoietin is dependent on the intracellular signaling of the Jak-STAT system for efficacy.…”

Section: Angiotensin II and Erythropoiesissupporting

confidence: 59%

New approaches to genetic manipulation of mice: tissue-specific expression of ACE

Cole

Xiao

Adams

et al. 2003

American Journal of Physiology-Renal Physiology

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. New approaches to genetic manipulation of mice: tissue-specific expression of ACE. Am J Physiol Renal Physiol 284: F599-F607, 2003; 10.1152/ajprenal.00308. 2002The renin-angiotensin system (RAS) plays a central role in body physiology, controlling blood pressure and blood electrolyte composition. ACE.1 (null) mice are null for all expression of angiotensin-converting enzyme (ACE). These mice have low blood pressure, the inability to concentrate urine, and a maldevelopment of the kidney. In contrast, ACE.2 (tissue null) mice produce one-third normal plasma ACE but no tissue ACE. They also have low blood pressure and cannot concentrate urine, but they have normal indices of renal function. These mice, while very informative, show that the null approach to creating knockout mice has intrinsic limitations given the many different physiological systems that no longer operate in an animal without a functioning RAS. To investigate the fine control of body physiology by the RAS, we developed a novel promoter swapping approach to generate a more selective tissue knockout of ACE expression. We used this to create ACE.3 (liver ACE) mice that selectively express ACE in the liver but lack all ACE within the vasculature. Evaluation of these mice shows that endothelial expression of ACE is not required for blood pressure control or normal renal function. Targeted homologous recombination has the power to create new strains of mice expressing the RAS in selected subsets of tissues. Not only will these new genetic models be useful for studying blood pressure regulation but also they show great promise for the investigation of the function of the RAS in complicated disease models.angiotensin-converting enzyme; blood pressure; angiotensin II; liver; renin-angiotensin system ROUGHLY ONE-HALF OF ALL AMERICANS die from cardiovascular disease. Put differently, more Americans die of cardiovascular disease than the next seven leading causes of death combined (1). To understand cardiovascular disease, one must understand how the body regulates blood pressure, a complex process governed by many different components, including multiple vasoconstrictors and vasodilators. Among these is the renin-angiotensin system (RAS), which produces the vasoconstrictor angiotensin II. The basic physiology by which angiotensinogen is degraded to angiotensin II has been known for many years, with the importance of this system underscored by the enormous clinical utility of pharmaceuticals that interrupt angiotensin II formation or action. So with all that is known about the RAS, what could conceivably be new? In fact, the use of targeted homologous recombination in mouse embryonic stem (ES) cells has produced a startling series of insights into the operation and functional importance of the RAS. This progress has been so rapid and dramatic as to implicate the RAS as easily the most important regulator of cardiovascular function as measured through blood pressure control.The use of homologous recombination to modify genes relies on the properties of cul...

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Section: Angiotensin II and Erythropoiesissupporting

confidence: 59%

New approaches to genetic manipulation of mice: tissue-specific expression of ACE

Cole

Xiao

Adams

et al. 2003

American Journal of Physiology-Renal Physiology

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“…ACE inhibitors even affect hematocrit in hemodialysis patients, who require recombinant Epo substitution because of impaired endogenous Epo production (as discussed in more detail above). This occurs because treatment with ACE inhibitors is associated with higher recombinant human Epo (rhEpo) requirements (whereas withdrawal of ACE inhibitors decreases rhEpo doses), reflecting the direct effect of angiotensin II on erythropoiegenesis (89). Exceptions to the link of renin-angiotensin system activation and increased hematocrit are often cases in which increment of red blood cells mass are masked by volume expansion (i.e., in patients with severe heart failure) (90).…”

Section: Interplay Of Renin-angiotensin and Epo Systemsmentioning

confidence: 99%

Physiology of the Renal Interstitium

Zeisberg

Kalluri

2015

Clinical Journal of the American Society of Nephrology

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Long overlooked as the virtual compartment and then strictly characterized through descriptive morphologic analysis, the renal interstitium has finally been associated with function. With identification of interstitial reninand erythropoietin-producing cells, the most prominent endocrine functions of the kidney have now been attributed to the renal interstitium. This article reviews the functional role of renal interstitium.

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“…The connection between RAS and erythropoiesis has been observed in animal studies 12 and has been confirmed in clinical studies involving patients on hemodialysis 11,21 and in renal transplant recipients. 20,21 These adverse hematopoietic effects of ACEIs/ARBs have been utilized successfully in the treatment of post kidney transplant erythrocytosis that is partly caused by the release of EPO from the native/transplanted kidneys and partly due to the increased expression of AT 1 receptors.…”

Section: Clinical Studiesmentioning

confidence: 74%

“…20,21 These adverse hematopoietic effects of ACEIs/ARBs have been utilized successfully in the treatment of post kidney transplant erythrocytosis that is partly caused by the release of EPO from the native/transplanted kidneys and partly due to the increased expression of AT 1 receptors. 20,22,23 Studies in patients undergoing dialysis have shown that the withdrawal of ACEIs caused a rebound increase in Hct to the extent of alleviating the need for EPO in several patients.…”

Section: Clinical Studiesmentioning

confidence: 99%

“…20,22,23 Studies in patients undergoing dialysis have shown that the withdrawal of ACEIs caused a rebound increase in Hct to the extent of alleviating the need for EPO in several patients. 21 Two case reports have shown that ARBs have reduced hematocrit in individual patients with polycythemia vera, secondary erythrocytosis of chronic obstructive pulmonary disease 24,25 and post renal transplant erythrocytosis. Researchers have disagreed as to whether ACEIs/ARBs decrease or increase EPO levels and whether they cause EPO resistance.…”

Section: Clinical Studiesmentioning

confidence: 99%

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Anemia in heart failure-A concise review

2005

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Summary: Heart failure affects 5 million persons in the United States, with 400,000 new cases occurring every year. Paradoxically, although advances in coronary angioplasty and effective drugs have increased survival post infarction, the myocardial damage and subsequent neurohormonal activation-induced remodeling causes significant morbidity years later in the form of heart failure. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) together with beta blockers modify the neurohormonal activation associated with heart failure and are key treatments for improving cardiac function and survival. Anemia is a significant risk factor predicting morbidity and mortality in heart failure. This article describes the various etiologies of anemia in heart failure. Of particular importance is the fact that recent stem cell studies have shown that the drugs acting on the renin-angiotensin system inhibit erythropoiesis in vivo and may cause anemia in patients with both normal renal function and end-stage renal disease (ESRD). The role of angiotensin-II as an erythropoietic growth factor and ACE in facilitating erythropoiesis is described in this article. Anemia has been shown to be a modifiable risk factor and its treatment correlates with improvement in clinical outcomes. Thus, anemia, its etiology (especially the contribution of ACEIs and ARBs), physiologic and prognostic impact, and treatment in the setting of heart failure are critical areas for investigation.

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The impact of withdrawing ACE inhibitors on erythropoietin responsiveness and left ventricular hypertrophy in haemodialysis patients

Cited by 40 publications

References 29 publications

New approaches to genetic manipulation of mice: tissue-specific expression of ACE

New approaches to genetic manipulation of mice: tissue-specific expression of ACE

Physiology of the Renal Interstitium

Anemia in heart failure-A concise review

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