Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients

Goßmann, Jan; Thürmann, Petra A.; Bachmann, Thomas; Weller, Stefan; Kachel, Hans-Georg; Schoeppe, W.; Scheuermann, Ernst-Heinrich

doi:10.1038/ki.1996.398

Cited by 76 publications

(44 citation statements)

References 28 publications

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“…However, there is still uncertainty about the exact relationship of ACE inhibition and erythropoietin levels in vivo. Some studies suggest that the administration of ACE inhibitors reduces plasma erythropoietin levels or induces resistance to this hormone (Walter, 1993;Gossmann et al, 1996;Albitar et al, 1998). Angiotensin II modulation of erythropoietin production is hypothesized to occur via activation of AT1 receptors and/or altered renal hemodynamics (Gossmann et al, 2001;Benohr et al, 2004).…”

Section: G Erythropoiesismentioning

confidence: 99%

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

et al. 2012

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Section: G Erythropoiesismentioning

confidence: 99%

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

et al. 2012

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“…These studies have disagreed as to the role of ACE inhibitors on erythropoietin production and effectiveness (4). Some groups suggest that ACE inhibitors reduce erythropoietin levels or induce resistance to erythropoietin (6,22,23,26). Other studies find no causative link between erythropoietin and the anemia induced by ACE inhibitors or AT 1 receptor antagonists (3,24,27,28).…”

Section: Figurementioning

confidence: 99%

“…Many more studies have examined the effect of ACE inhibitors and AT 1 receptor antagonists in renal dialysis and renal transplantation patients. In particular, a substantial number of clinical studies have commented that ACE inhibitors are often effective in reducing the erythrocytosis observed after renal transplantation (21)(22)(23)(24)(25). These studies have disagreed as to the role of ACE inhibitors on erythropoietin production and effectiveness (4).…”

Section: Figurementioning

confidence: 99%

Lack of angiotensin II–facilitated erythropoiesis causes anemia in angiotensin-converting enzyme–deficient mice

et al. 2000

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IntroductionThe renin-angiotensin system plays a critical role in blood pressure regulation and fluid hemodynamics. Pharmacologic inhibitors of this system are routinely used to treat hypertension and congestive heart failure. One of the most controversial effects of the reninangiotensin system has been the interplay of this system with erythrocyte production. A variety of clinical reports have noted an association between activation of the renin-angiotensin system and increased erythropoiesis (1-3). These studies have come from analyses of patients with a variety of chronic diseases including chronic obstructive pulmonary disease, heart failure, and renal transplantation. Other investigators have suggested a link between angiotensin-converting enzyme (ACE) inhibitors and worsened anemia, particularly in patients with chronic renal failure (4-6). While research has focused on the interplay of the renin-angiotensin system and erythropoietin, no mechanistic explanation for these observations has been generally accepted.Central to the renin-angiotensin system is ACE, a peptidase that converts angiotensin I to angiotensin II (7). In mammals, most ACE is bound to tissues such as endothelium, but enzymatic cleavage results in a circulating form within plasma. In vitro, ACE is capable of cleaving many small peptides besides angiotensin I. However, in vivo, with the exception of bradykinin, the significance of nonangiotensin peptides as ACE substrates is not well understood. ACE is a protein with two independent catalytic domains. While both catalytic sites hydrolyze angiotensin I with roughly equal efficiency, the amino-and carboxy-terminal catalytic domains differ in their rate constants for other peptides.Using targeted homologous recombination in embryonic stem (ES) cells, our laboratory created two lines of mice with modifications of the ACE gene (8, 9). These animals are termed ACE.1 and ACE.2. Mice homozygous for the ACE.1 allele (ACE.1 knockout mice) are null for all ACE production. They have a marked reduction of blood pressure, and a renal lesion characterized by hypoplasia of the renal medulla and papilla. In contrast to this null phenotype, animals homozygous for the ACE.2 allele (ACE.2 knockout mice) have a partial restoration of ACE activity. These animals express a truncated ACE protein containing only the amino-terminal catalytic domain. Since this shortened ACE protein lacks the carboxy-terminal domain that normally anchors ACE to cell membranes, the ACE.2 protein is exported from cells into blood and other extracellular fluids. Thus, while the plasma of ACE.2 mice converts angiotensin I to angiotensin II with about 34% of the activity of wild-type mouse plasma, tissues such as the lung and kidney completely lack ACE protein or activity. The systolic blood pressure of ACE.2 knockout mice averaged 75 mmHg, as low as that of the ACE.1 knockout animals.Here, we investigate an unexpected finding concerning the phenotypes of both the ACE.1 and ACE.2 mice. These animals are anemic. ACE.2 knockout mice are a p...

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“…Some authors have suggested distinguishing early from late PTA, with the cutoff between the two periods being the 6-mo posttransplantation time point (10,(15)(16)(17)(18). Several risk factors have been associated with PTA, including chronic allograft dysfunction, antiproliferative immunosuppression (e.g., mycophenolate mofetil [MMF], sirolimus), chronic iron deficiency, and renin-angiotensin system blocking therapies (angiotensin-converting enzyme inhibitors [ACEI] and angiotensin II type 1 receptor blockers [ARB]) (10,13,18,19). PTA has been associated with an increased risk for congestive heart failure and left ventricular hypertrophy in kidney recipients (20 -22).…”

mentioning

confidence: 99%

Posttransplantation Anemia at 12 Months in Kidney Recipients Treated with Mycophenolate Mofetil

Imoagene-Oyedeji¹,

Rosas²,

Doyle³

et al. 2006

Journal of the American Society of Nephrology

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Although posttransplantation anemia (PTA) is common in the mycophenolate mofetil era, its impact on patient survival is unknown. This retrospective cohort study characterized factors that are associated with PTA 12 mo after transplantation in mycophenolate mofetil-treated kidney recipients and explored whether 12-mo PTA affects outcomes. The records of 626 kidney recipients were examined for presence of anemia (hemoglobin <12 g/dl). Multivariate regression models, fit with covariates that had unadjusted relationships, investigated both risk factors for 12-mo PTA and whether 12-mo PTA contributes to mortality. Anemia prevalence was 72, 40, and 20.3% at 1, 3, and 12 mo, respectively. By multivariate logistic regression, anemia at 3 mo (odds ratio [OR] 10.0; 95% confidence interval [CI] 5.3 to 17.1; P ‫؍‬ 0.0001), donor age (OR 1.0; 95% CI 1.1 to 1.3; P ‫؍‬ 0.005), and 3-mo creatinine (OR 2.0; 95% CI 1.2 to 3.3; P ‫؍‬ 0.044) were associated with 12-mo PTA. The PTA cohort had inferior patient survival (P ‫؍‬ 0.02, log rank) and a higher proportion of cardiovascular deaths (6.3 versus 2.2%; P ‫؍‬ 0.017) than nonanemic patients. By Cox regression, 12-mo PTA (hazard ratio [HR] 3.0; 95% CI 1.3 to 6.7; P ‫؍‬ 0.009), 12-mo creatinine (HR 1.3; 95% CI 1.1 to 1.4; P ‫؍‬ 0.008), age at transplantation (HR 1.1; 95% CI 1.1 to 1.2; P ‫؍‬ 0.004), and hepatitis C seropositivity (HR 2.8; 95% CI 1.1 to 7.0; P ‫؍‬ 0.03) were associated with mortality. There was no interaction between 12-mo PTA and serum creatinine. In conclusion, 12-mo PTA is associated with an increased risk for patient death. The presence of anemia 3 mo after kidney transplantation is a major determinant of 12-mo PTA. PTA in kidney recipients therefore should be defined by its persistence or occurrence beyond the third posttransplantation month.

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Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients

Cited by 76 publications

References 28 publications

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

Lack of angiotensin II–facilitated erythropoiesis causes anemia in angiotensin-converting enzyme–deficient mice

Posttransplantation Anemia at 12 Months in Kidney Recipients Treated with Mycophenolate Mofetil

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