MetroHealth Drive R415, Cleveland, OH 44109-1998. E-mail address: john.sedor@case.edu (J.R. Sedor). 0095-4543/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2008.01.008 primarycare.theclinics.com Prim Care Clin Office Pract 35 (2008) 329–344 a concomitant serum creatinine concentration, a more practical approach in the office is to estimate GFR (estimated GFR or eGFR) from the serum creatinine concentration, using either the Cockcroft-Gault or the Modification of Diet in Renal Disease (MDRD) Study estimating equations. Web-based tools are available for both estimating equations (MDRD eGFR: http:// www.nkdep.nih.gov/professionals/gfr_calculators/index.htm; CockcroftGault eGFR: http://www.mdcalc.com/cockcroftgault). Both complications and likelihood of progression to end-stage renal disease requiring renal replacement therapy are more likely to occur in patients with severe CKD. In addition, early intervention will more commonly reduce serious CKD sequelae and slow CKD progression. To facilitate assessment of CKD severity, the National Kidney Foundation developed criteria as part of its Kidney Disease Outcomes Quality Initiative (NKF K/DOQI) to stratify CKD patients [4]: Stage 1: normal eGFR R 90 mL/min per 1.73 m2 and persistent albuminuria Stage 2: eGFR between 60 to 89 mL/min per 1.73 m2 Stage 3: eGFR between 30 to 59 mL/min per 1.73 m2 Stage 4: eGFR between 15 to 29 mL/min per 1.73 m2 Stage 5: eGFR ! 15 mL/min per 1.73 m2 or end-stage renal disease The prevalence of these stages of CKD in the US population is as follows: 1.8% for stage 1, 3.2% for stage 2, 7.7% for stage 3, and 0.35 % for stages 4 and 5. Patients with stage 3 or 4 disease progress to end-stage renal disease or stage 5 at a rate of 1.5% per year. Stage 1 or 2 CKD patients progress to more advanced stages at approximately 0.5% per year [5]. In addition, the NKF K/DOQI provides evidence-based, clinical practice guidelines for all stages of chronic kidney disease to optimize management of related complications. Twelve sets of guidelines have been published and are available on the NKF Web site (http://www.kidney.org/professionals/KDOQI/). Each of the complications discussed in this article is addressed by the NKF K/DOQI guidelines. Chronic kidney disease–associated anemia Anemia is defined as a reduction in one or more of the major red blood cell measurements: hemoglobin concentration, hematocrit, or red blood cell count. The World Health Organization defines anemia as a hemoglobin level less than 13 g/dL in men and postmenopausal women, and less than 12 g/dL in premenopausal women [6]. The NKF defines anemia as a hemoglobin of less than 13.5 g/dL in men and less than 12.0 g/dL in women [2]. A normochromic, normocytic anemia usually accompanies progressive CKD [7], and the overall prevalence of CKD-associated anemia is approximately 50% [8]. Although anemia may be diagnosed in patients at any stage of CKD, there is a strong correlation between the prevalence of anemia and 330 THOMAS et al the severity of CKD. One quarter of stage 1 CKD patients; half of those stratified to CKD stages 2, 3, and 4; and three quarters of CKD patients starting dialysis suffer from anemia [8]. Therefore, primary care providers play an important role in diagnosing and managing anemia in CKD patients. While anemia in CKD can result from multiple mechanisms (iron, folate, or vitamin B12 deficiency; gastrointestinal bleeding; severe hyperparathyroidism; systemic inflammation; and shortened red blood cell survival), decreased erythropoietin synthesis is the most important and specific etiology causing CKD-associated anemia. Erythropoietin is a glycoprotein secreted by the kidney interstitial fibroblasts [9] and is essential for the growth and differentiation of red blood cells in the bone marrow. In CKD, tubular atrophy generates tubulointerstitial fibrosis, which compromises renal erythropoietin synthetic capacity and results in anemia. The anemia of CKD increases morbidity and mortality from cardiovascular complications (angina, left ventricular hypertrophy [LVH], and worsening heart failure) [7], which may lead to further deterioration of renal function and the establishment of a vicious cycle termed the ‘‘cardiorenal anemia syndrome.’’ The presence of LVH is associated with decreased survival of patients on dialysis. In fact, end-stage renal disease patients with LVH have a 30% lower 5-year survival rate than individuals lacking LVH [10]. In addition, anemia is an independent predictor of death in stable coronary artery disease patients with CKD [11]. The anemia of CKD is treated via recombinant human erythropoietin (epo). This intervention has replaced transfusions as the mainstay of treatment and improved the survival of anemic CKD patients [12]. The target level of Hgb in patients with CKD has changed as more studies have been reported. Normalization of hemoglobin levels is no longer considered the goal of therapy since these target levels have been associated with higher mortality [13]. The Correction of Hemoglobin and Outcomes In Renal Insufficiency (CHOIR) trial studied the outcomes of anemia treatment in over 1400 CKD patients (MDRD eGFR between 15 to 50 mL/min per 1.73