Article inclusion definitions not described. 

Not mentioned.

Recruitment:  Methods for article inclusion not described.

Design:  Narrative Review.

Blinding used (if applicable):  not applicable.

Intervention (if applicable):  not applicable.

Statistical Analysis:  statistical analysis not performed.

Timing of Measurements:  not applicable

Dependent Variables:  not applicable

Independent Variables:  not applicable

Control Variables:  not applicable

Initial N: 110 references included

Attrition (final N): 110

Age:  not mentioned

Ethnicity:  not mentioned

Other relevant demographics:

Anthropometrics: 

Location:  Worldwide studies

Other findings:

Benefits of Anemia Treatment

• Several studies have shown that correction of anemia with rHuEPO in those with CKD is associated with significant improvements in health-related quality of life, overall well-being, energy level, work capacity, aerobic capacity, cognitive function, sexual function, and immune function.
• There is also evidence of improvement in left ventricular hypertrophy (LVH) and decreased complications of CVD.

CVD is the Major Cause of Morbidity and Mortality Among Patients with CRI

• CVD is the leading cause of death in patients with CKD, accounting for ~50% of deaths.

CVD is Common in CKD

• Complications of CVD are prevalent at the time of initiation of chronic dialysis and echocardiographic evidence of LVH has been documented in 63% to 75% at initiation of dialysis.

CVD Develops Early in CKD

Anemia is a Risk Factor for CVD

• Hemodynamic changes induced by anemia can precipitate high output CHF and ischemic cardiac events.
• Recent studies have shown anemia is an independent risk factor for LVH among patients with CRI
  446 patients with CrCl of 20-75 ml/min were followed prospectively with serial echocardiograms. After 12 months, Hgb and systolic blood pressure were the only variables that differed significantly between patients with and without an increase in Left Ventricular Mass Index (LVMI). Hgb decreased by a mean of 0.75 g/dL in patients with an increase in LVMI, compared with 0.1 g/dL among patients with no increase in LVMI (P<0.001).
• Canadian Multicenter Study in Early Renal Disease

Correction of Anemia Results in Regression of LVH

• Evidence has emerged that partial correction of anemia with rHuEPO in dialysis patients results in partial regression of LVH, independent of hypertension control.
• Hayashi et al, demonstrated the effect of normalizing Hct with rHuEPO in 9 patients with CKD, whose mean pretreatment serum creatinine was 6.2+/- 0.7 mg/dL.

Support for Early Treatment of Anemia in CKD

• Early correction of anemia with rHuEPO during the Renal Anemia Management Period would appear to result in improved long-term clinical outcomes.
• Although there is a lack of controlled clinical studies amount patients with CKD, two lines of indirect evidence exist to support the hypothesis that correction of the anemia of CKD with rHuEPO could result in reduced CVD morbidity and mortality.
  • First, treatments that reduce LVH have been shown to reduce mortality among patients with essential hypertension.
  • Second, studies in those with ESRD have shown an association between increased Hgb and a decreased risk for mortality and hospitalization.
• Non-cardiac benefits of treating anemia in CRI:
  • Revicki et al, found that patients in the group targeted to achieve Hct >36% (achieved by 79% of subjects) had significantly improved quality of life compared with untreated controls with Hct of 26%.
  • US Recombinant Human Erythropoietin Predialysis Study documented improved quality of life as Hct increased to >30%.
  • Further studies are needed to confirm the noncardiac benefits of early treatment of anemia in CKD.

“Optimal” Hct/Hgb

• Optimal target Hct and Hgb levels for CRI patients remain unclear
• NKF-DOQI guidelines for dialysis and nondialysis recommend a target Hct for rHuEPO therapy between 33% (Hgb, 11 g/dL) and 36% (Hgb, 12 g/dL).
• Trials of the impact of normalizing Hct levels on clinical outcomes among anemic patients with CRI are unavailable
• Collins, et al. described an inverse relationship among mortality, hospitalization rates and Hct levels in the first few months of dialysis among incident dialysis patients in the US. Patients with Hct of 33% to 36% had the lowest risk of death and hospitalization compared with those with lower Hct.

Current Practices of Anemia Management

• The importance of developing guidelines for the management of anemia is highlighted by recent studies suggesting a lack of attention to this complication of uremia.
• Obrador et al, evaluated Hct levels and rHuEPO use before initiation of chronic dialysis between 1995 and 1997 in the US. 51% had Hct <28% and 67% had Hct <30%.
  • Overall, only 23% had received rHuEPO before initiation of dialysis and among patients with Hct <28%, only 20% had received rHuEPO.
• These studies suggest that inadequate use of rHuEPO and iron is likely contributing to the high prevalence of severe anemia among patients starting renal replacement therapy.
• The early identification and treatment of the anemia of CRI may be of critical importance in reducing the incidence of and consequences associated with CVD among patients with kidney disease.

Treatment Strategies for Anemia of CKD Goals of Therapy

• NKF-DOQI recommends a target Hct of 33% to 36% for predialysis patients.
• Numerous studies in CKD suggest that this range can be safely achieved with no increase in the rate of progression of CKD.
• Hct and Hgb should be monitored every 1-2 wks at the beginning of rHuEPO therapy or after a major change in dose and thereafter every 4 to 12 wks or when indicated clinically.
• Patients should reach target Hct/Hgb levels within 2 to 4 months of treatment.
•  Because treatment of anemia with rHuEPO may be associated with an increase in blood pressure, an essential goal of therapy is to control hypertension or prevent its development.

Timing of Therapy

• NKF-DOQI:  patients with CRI should be monitored regularly for dexlining Hct.
  • Thorough investigation for nonrenal causes of anemia if Hct declines to 80% of the mean level for the gender- and age-matched population.
• The more aggressive approach of investigation and treatment of anemia as soon as the Hct decreases below the normal range would appear to be the ideal strategy, however, third-party payers in the US do not begin to cover the cost of rHuEPO until the Hct has fallen <30%.

Erythropoietin Mechanism of Action

• RHuEPO stimulates erythropoiesis by binding to specific receptors on erythroid precursors that have already differentiated from pluripotential stem cells.
• Beneficial Effects
  • Several US and European clinical trials have shown unequivocally that rHuEPO is effective in correcting anemia in CRI and ESRD patients.
  • US rHuEPO Predialysis Study, 117 patients with serum creatinine 3-10 mg/dL were randomized to receive IV rHuEPO or placebo for 8 wk or until the anemia was correctedCorrectionofanemia(Hct40%males;35%corrected. Correction of anemia (Hct, 40%, males; 35%, females) occurred in 87% of those patients receiving 150 U/kg, 64% of those receiving 100 U/kg and 46% of those receiving 50 U/kg.
  • Austrian Multicenter Study Group, 123 patients with a mean serum creatinine level of 6.2+0.2 mg/dL received 10,000 U rHuEPO once/wk via subcutaneous administration. The mean Hct level increased from 26% to 34%.
• Side Effects
  • Hypertension occurs in 17% to 65% of patients who receive rHuEPO.
  • Attributed to increase in both peripheral vascular resistance following relief of hypoic vasodilatation and an increase in whole blood viscosity.
  • Serious complications from hypertension now much less frequently observed, probably because reversal of anemia is achieved more slowly and blood pressure control has improved.
  • Several studies in humans have shown no significant acceleration of progression of kidney disease by correction of anemia with rHuEPO, provided that blood pressure control is adequate.
• Dose and route of administration of rHuEPO
  • should be based on the severity of anemia
  • starting doses of 50-150 U/kg studied.
    • higher doses more effective for those with Hct less than 30%
    • individualize maintenance dose
  • Subcutaneous should be principal method for CRI patients.

Iron

• Iron deficiency is the most frequent cause of failure to respond adequately to rHuEPO.
• Iron stores are rapidly depleted in response to rHuEPO therapy.
• For those with moderate renal insufficiency, oral or parenteral iron therapy may be sufficient initially to raise/maintain Hct/Hgb.
• Intravenous iron may be necessary in more severe anemia.
• Side effects
  • Early studies with iron dextran in doses ranging from less than 100 mg to greater than 1,000 mg showed 26% of patients had immediate or delayed reactions, including life-threatening anaphylactoid reactions (0.6%).
  • These observations led to recommendation that parenteral iron dextran be reserved for patients who do not respond to oral iron.
  • Most recent studies of iron dextran and other iron preparations in patients with CRI have not described serious adverse consequences.
  • The potential long-term consequence of increased atherosclerotic risk has not been studied.
• Dosage and Administration
  • NKF-DOQI recommends transferrin saturation >20% and ferritin >100 ng/mL.
  • Oral iron may be sufficient in early phases of CRI.
  • Parenteral dosing may become necessary with advancing CRI, esp. if resistant to rHuEPO.
  • Safe dosing in CRI: 
    • 200-mg infusions monthly for 5 months
    • total dose infusions up to 1,600 mg.

Other Causes of Anemia

• Important to search for nutritional deficiencies among elderly
  • iron, B12, folate
• L-carnitine appears to decrease rHuEPO requirements in CRI patients
• Deficiencies in B6, B12, folate unlikely in predialysis patients
• Inflammatory conditions, chronic infections may result in rHuEPO resistance
• ACE inhibitors causes anemia- may need more rHuEPO
• Aluminum bone toxicity from aluminum-containing antacids

Economic Implicaitons of Improved Anemia Treatment in CKD

• There are few studies of the cost implications of treatment of anemia with rHuEPO in CKD (non-dialysis) and no cost benefit analysis.
•  A study from France estimated that the incremental cost of treating 1,000 to 1,250 patients with CKD with rHuEPO 50 to 150 U/kg/wk was between 2.2 and 6.5 million Swiss francs/year or between 50,000 and 140,000 Swiss francs/million population.
• From a study in Canada, the cost of rHuEPO was ~$600 Canadian/month compared to $3,300/month for dialysis.
• The cost to treat in U.S. would be high
  • Reduced CVD burden, deferred cost of dialysis may offset the high cost of rHuEPO

• The introduction of rHuEPO more than a decade ago provided the first effective treatment for anemia of CKD. The use of rHuEPO in the treatment of anemia has been associated with a partial regression of LVH among both dialysis and nondialysis patients, and has been shown to reduce the frequency of cardiac complications such as CHF and number of days of hospitalization among dialysis patients. Despite this evidence, the anemia of CKD remains prevalent, under recognized and under treated. A number of considerations arise regarding the management of anemia among patients with CKD.
• Data are currently insufficient to provide a firm Hct target in the management of anemia of CKD. However, several studies of the use of rHuEPO does not increase the rate of progression of kidney disease as long as hypertension (which can be exacerbated by treatment) is controlled.
• Studies suggest that inadequate use of rHuEPO and iron is likely contributing to the reduced prevalence of severe anemia among patients starting renal replacement therapy.
• The early identification & treatment of the anemia of CKD may be of critical importance in reducing the incidence of and consequence associated with CVD in CKD.
• Further studies are needed to investigate the impat of earlier treatment of anemia on clinicl outcomes, such as rate of progression of kidney disease, morbidity and mortality, and quality of life, and to determine the cost-benefit and societal impact of improved anemia management in patients with CRI.