COMMENTARIES

Atherosclerosis May Change an Angel to a Devil Lessons from Anemia Treatment in Chronic Kidney Disease

Tetsuo Shoji, M.D., Ph.D., Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Abenoku, Asahimachi, Osaka 545-8585, Japan, Tel: (+81) 6-6645-3806, Fax: (+81) 6-6645-3808, Email: t-shoji@med.osaka-cu.ac.jp

Patients with chronic kidney disease (CKD) are at an elevated risk of death from cardiovascular disease (CVD) [1]. The relative risk of death from coronary heart disease is as high as 10 to 100 in patients with CKD stage 5 hemodialysis patients. The raised risk for CVD can be attributable to changes in the heart, blood vessels, blood, and others. Patients with advanced CKD often suffer from cardiac hypertrophy, cardiac dilatation, and cardiac failure. These are due partly to coronary artery disease as a part of advanced systemic atherosclerosis, and also to salt retention and volume overload associated with impaired kidney function. Renal anemia, caused by erythropoietin depletion, is believed to contribute to the increased CVD risk by inducing ischemia of tissues, especially of myocardium and brain, and also by promoting left ventricular hypertrophy in response to increased cardiac output due to reduced hemoglobin levels. Thus, since the cardiovascular system is closely linked to the kidney and anemia, treatment of anemia with erythropoietic stimulating agents (ESA) was expected to improve survival of renal patients. However, randomized controlled trials (RCTs) revealed that normalization, as compared to partial correction, of hemoglobin/hematocrit levels with ESA did not improve but rather worsened cardiovascular outcomes in hemodialysis patients [2,3] and predialysis patients with advanced CKD [4,5]. What is the mechanism that underlies the unexpected but consistent results?

         What happens if experimental animals are exposed to a higher level of hemoglobin induced by ESA? According to the experiments by Ruschitzka et al. [6], transgenic mice overexpressing the human erythropoietin gene have an increased hematocrit of 79%, as compared to 39% of the wild-type counterparts. But the polycythemic transgenic mice showed no increase in mortality rate. Histological examinations revealed that blood vessels were dilated in response to higher hematocrit levels. Upregulation of eNOS was also evident. Interestingly, the transgenic mice died within a few days following inhibition of the NOS system by intraperitoneal administration of L-NAME, whereas the same treatment did not shorten the lives of wild-type mice. This experiment tells us that a higher hematocrit will harm if endothelial function is impaired.

         Endothelial function is impaired in patients with CVD, and it correlates with carotid atherosclerosis expressed as increased carotid artery intima-media thickness (CA-IMT). Maekawa et al. [7] tested a hypothesis that the hematocrit-mortality relationship may differ between hemodialysis patients with and without atherosclerotic vascular complications in an observational cohort of 505 hemodialysis patients. Among them, 153 had clinical history of CVD at baseline while the remaining did not. During the 10-year follow-up, 268 patients died. In the group without CVD, a higher hematocrit level was associated with a better survival. In contrast, the group with CVD at baseline did not show such a beneficial association between a higher hematocrit and a reduced mortality risk. Similar observations were made when the subjects were divided based on CA-IMT instead of the presence of CVD.

         We should learn at least two lessons from these studies. The first is that a good thing for someone may not be good or rather bad for others. It depends on the condition of the host. We know it well, but we forget it easily. Exercising is good for your health, but it should be avoided when you are sick. Fruits and vegetables may be good for your health, but they should be avoided when you have kidney failure. Going back to the above studies, status of endothelial function appears to be a key.

         The second lesson is the importance of differential analyses in distinct strata of the total subjects. If the effect of a factor completely differs among subgroups, it may not be appropriately “adjusted” by simply applying multivariate analysis. We may have overlooked important facts by careless use of multivariate models.

         Subanalyses of the above RCTs with ESA will provide further information. Also, normalization of hemoglobin levels may improve survival of CKD patients and concomitant treatment for endothelial dysfunction should be considered, using statins, inhibitors of renin-angiotensin system, or eicosapentaenoic acid, for example.

References

1.    Foley RN, Parfrey PS, Sarnak MJ. 1998. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32: S112-19.
2.    Besarab A, Bolton WK, Browne JK, et al. 1998. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339: 584-90.
3.    Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D. 2005. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 16: 2180-89.
4.    Drueke TB, Locatelli F, Clyne N, et al. 2006. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355: 2071-84.
5.    Singh AK. 2006. The target hemoglobin in patients with chronic kidney disease. Nephrol News Issues 20: 29-30.
6.    Ruschitzka FT, Wenger RH, Stallmach T, et al. 2000. Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proc Natl Acad Sci U S A 97: 11609-13.
7.    Maekawa K, Shoji T, Emoto M, et al. 2008. Influence of atherosclerosis on the relationship between anaemia and mortality risk in haemodialysis patients. Nephrol Dial Transplant 23: 2329-36. [Epub ahead of print] doi: 10.1093/ndt/gfm929.