Renal Insufficiency

The use of blood viscosity may be able to provide mechanistic insights into cardiovascular disease (CVD) complications in renal insufficiency, especially for patients who are treated for anemia. Erythropoiesis-stimulating agents (ESA) are routinely used for anemia correction in chronic and end-stage renal disease, and new classes of anemia therapies as well as biosimilar ESA's are in development. Recombinant human erythropoietin offers an effective treatment for many forms of anemia and has long been considered a major advance in the management of patients with the severe anemia that accompanies end-stage renal disease [1]. In chronic kidney disease (CKD), anemia is recognized as a risk factor for stroke, myocardial infarction (MI) and left ventricular hypertrophy [2,3].

While the anemia of kidney disease has been routinely treated with ESA’s, all of the randomized controlled clinical trials designed to demonstrate improved cardiovascular prognoses through the administration of ESA’s in both end-stage and chronic kidney disease, including the Normal Hematocrit Study [4,5], the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) [6], and the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) [7], failed to show the expected beneficial cardiovascular effects. These studies showed poorer cardiovascular outcomes when treating patients with renal insufficiency to higher hemoglobin targets.

The adverse effects of supplemental erythropoietin were demonstrated in a meta-analysis of anemic patients with chronic renal disease [8]. In erythropoietin treated patients, those with higher hematocrits had higher all-cause mortality, increased arteriovenous access thrombosis, and poorly-controlled blood pressure, all of which can reasonably be attributed to elevated blood viscosity. Blood viscosity is sensitive to hemoglobin and hematocrit levels: a 10% increase in Hct has been reported to increase high-shear blood viscosity levels by as much as 20% [9]. In hemodialysis patients, erythropoietin administration increases blood viscosity [10], and CKD patients have been shown to have higher blood viscosity relative to healthy controls [11]. Using older, single-point measurement techniques for blood viscosity, a number of outcome studies have demonstrated the risk of major CVD events, including death and MI, increased with blood viscosity [12,13]. Using one such technique, a rotating cone-and-plate viscometer, blood viscosity levels adjusted for age and sex were shown to be higher in subjects that experienced CVD events than those who did not, and with further adjustment for conventional CVD risk factors, the association with blood viscosity remained significant only for stroke [14]. Stroke patients were previously shown to have chronically elevated blood viscosity relative to healthy controls [15]. Separately, a higher risk of stroke and vascular mortality has been associated with ESA administration [16,17].

These studies support the concept that hyperviscosity is an important risk marker for cerebral ischemia and CVD events in ESA-treated patients with renal insufficiency. Elevated blood viscosity increases risk of CVD events including stroke. Correction of anemia will increase blood viscosity and, potentially, reduce cerebral perfusion and increase the risk of stroke and cardiovascular death. As anemia impairs quality of life in CKD patients, and correction of anemia mitigates these symptoms, it is essential to define the risks and benefits of ESA administration with higher clarity through the use of a new generation of biomarkers. Additional diagnostic insights may be available through monitoring of fluid dynamic markers like blood viscosity that have not been understood through measurements of Hb or Hct alone. We propose that viscosity measurements may provide clinically relevant insights into the balance between efficacy and safety of ESA’s. Patients who are the most resistant to erythropoietin therapy may be those with the lowest hematocrit-to-viscosity ratio and the ones at highest risk for complications of therapy. Clinical investigations are needed to determine whether or not blood viscosity monitoring can be used to stratify patients based on the effect of ESA on blood viscosity to determine if viscosity surges following ESA administration are predictive of CVD events.

  1. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med 1989;111:992-1000.
  2. Abramson JL, Jurkovitz CT, Vaccarino V, et al. Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study. Kidney Int 2003;64:610-615.
  3. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis 1999;34:125-134.
  4. Besarab A, Bolton WK, Browne JK, et al. 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 1998;339:584-590.
  5. Besarab A, Goodkin DA, Nissenson AR. The normal hematocrit study--follow-up. N Engl J Med 2008;358:433-434.
  6. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071-2084.
  7. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-2098.
  8. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treat with erythropoietin: a meta-analysis. Phrommintikul A, Haas SJ, Elsik M, Krum H. The Lancet 2007; 369 (9559): 381-388
  9. Brun JF, Bouchahda C, Chaze D, et al. The paradox of hematocrit in exercise physiology: which is the "normal" range from an hemorheologist's viewpoint? Clin Hemorheol Microcirc 2000;22:287-303.
  10. Shand BI, Buttimore AL, Lynn KL, Bailey RR, Robson RA. Effect of hemodialysis and recombinant human erythropoietin on determinants of blood viscosity. Ren Fail 1994;16:407-413.
  11. Brimble KS, McFarlane A, Winegard N, et al. Effect of chronic kidney disease on red blood cell rheology. Clin Hemorheol Microcirc 2006;34:411-420.
  12. Ciuffetti G, Schillaci G, Lombardini, et al. Prognostic impact of low-shear whole blood viscosity in hypertensive men. Eur J Clin Invest 2005;35:93-98.
  13. Danesh J, Collins R, Peto R, Lowe GD. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J 2000;21:515-520.
  14. Lowe GD, Lee AJ, Rumley A, Price JF, Fowkes FG. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997;96:168-173.
  15. Coull BM, Beamer N, de Garmo P, et al. Chronic blood hyperviscosity in subjects with acute stroke, transient ischemic attack, and risk factors for stroke. Stroke 1991;22:162-168.
  16. Pfeffer MA, Burdmann EA, Chen C-Y, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019-2032.
  17. Ehrenreich H, Weissenborn K, Prange H, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 2009;40:e647-56.