Chapter 18. Anemia & Chronic Kidney Disease

• Anemia is a comorbidity of progressive chronic kidney disease (CKD).
• Anemia of CKD results from the inability of the kidney to produce significant quantities of erythropoietin.
• Decreased red blood cell survival and iron deficiency are cofactors.

Since the initial observations by Richard Bright in 1836 on the relationship of anemia to renal inefficiency, anemia has remained as an ever-present comorbidity of progressive chronic kidney disease (CKD). The Kidney Disease Outcomes Quality Initiatives (K/DOQI) clinical practice guidelines for chronic kidney disease first published in 2002 helped focus attention on chronic kidney disease and its comorbidities, specifically anemia.

Recent data support the direct relationship of anemia to cardiovascular disease and to patient mortality in end-stage renal disease (ESRD). Anemia of CKD is generally caused by the inability of the kidneys to produce significant quantities of erythropoietin, but other factors are frequently involved including decreased red blood cell survival and iron deficiency. Despite the clinical introduction of recombinant human erythropoietin (rHuEPO) in 1989, there is still an estimated 1.5 million individuals with anemia in the United States. Additionally, anemia (hemoglobin <12 mg/dL) is present in greater than 75% of dialysis patients.

The availability of rHuEPO revolutionized our understanding of uremia and quickly became a major tool in the armamentarium of nephrologists to improve symptoms previously thought to be due to the “uremic syndrome.” Correction of anemia in these patients resulted in an improved sense of well being, improved energy levels, a significant improvement in sleep disturbances, improved cognitive function, and an improvement in the ability to perform tasks of daily living. More significantly, improved hemoglobin levels in CKD patients have been correlated with decreased left ventricular hypertrophy (LVH) and improved cardiovascular outcomes.

Although debate continues on the proper “target” hemoglobin, the days of accepting hemoglobins less than the K/DOQI guideline recommended of 11–12 g have passed. Clinical research identifying cardiovascular events as a leading cause of mortality in CKD, ESRD, and transplant patients has made a critical understanding of the management of anemia essential to the practice of nephrology.

Under normal homeostatic conditions, the kidney very precisely regulates plasma volume through the reabsorption or excretion of salt and water. Hemoglobin levels are maintained in response to the production of erythropoietin to tissue hypoxia.

Erythropoietin is known to be a multifunctional tropic factor with effects on not only the bone marrow but on the central nervous system where studies have shown both neurotrophic and neuroprotective functions. Its primary target although is the pluripotent hematopoietic stem cells of the bone marrow. This cell line is capable of forming erythrocytes, leukocytes, and megakaryocytes. Erythropoietin is produced by specialized fibroblasts in the interstitium of the kidney in response to hypoxia (Figure 18–1).

As renal function declines, anemia becomes more common. The majority of patients with a GFR less than 60 mL/minute/1.73 m2 (K/DOQI stage 3) have insufficient erythropoietin production to maintain hemoglobin >12 g/dL. This results in the typical normochromatic normocytic anemia present in CKD and ESRD. However, anemia of CKD often has etiologies other than insufficient erythropoietin levels.

Historical Perspective

Prior to the clinical introduction of cloned erythropoietin (rHuEPO) in 1989, the world of nephrology was very different. There was no focus on CKD, little focus on treating anemia, but considerable focus on improving the adequacy of dialysis (delivered amount of dialysis). The continued evolution of dialysis equipment including volumetric dialysis machines and dialyzer membrane biocompatibility with improvement of uremic symptoms was of paramount importance. Our ability to more accurately measure the amount of delivered dialysis added to these endeavors.

Anemia was managed in two ways: Severe anemia with hemoglobins less than 8 g/dL was treated with blood transfusions. Less critical management of anemia, viewed as “maintenance management,” involved the use of anabolic steroids. Iron deficiency was rarely a problem; indeed, iron overload from frequent blood transfusions was a much greater problem occasionally resulting in secondary hemachromatosis.

The introduction of erythropoietin and the correction of anemia resulted in the elimination of many symptoms previously thought to be due to uremia. The avid production of new red blood cells consumed the additional iron stores and secondary hemachromatosis soon became a historical footnote along with the use of steroids and their inherent side effects.

Cardiovascular Disease and Anemia

See Chapter 19, on cardiovascular disease.

Current Management of Anemia of CKD

Although anemia of CKD has a direct impact on cardiovascular mortality and the availability of recumbent erythropoietin, only approximately 30% of patients with CKD are treated with erythropoietin. The mean hematocrit of this treated population remains below K/DOQI guidelines at 30.2% (recommended 33–36%). Although there is great debate about why so many patients remain untreated (barriers by insurers, fragmentation of care, late referrals, etc.), studies looking at the logistics of management of anemia in nephrology offices suggest that a lack of an organized methodology to treat anemia is still missing in most nephrology clinical settings.

An organized methodology of identification, evaluation, treatment, and maintenance of anemia has now become a critical requirement in all nephrology practices. Although this will vary from practice to practice, algorithms (Figure 18–2) help define the minimum steps necessary to identify the majority of patients with anemia and guide them toward treatment solutions.

Providing all patients upon introduction to the CKD clinic with information on anemia and the fact that they may become anemic is critical. Checking their hemoglobin at each visit will ensure a focus on one of the major comorbidities of their disease.

Iron Supplementation

The K/DOQI guidelines recommend baseline iron studies prior to initiation of erythropoietin therapy (serum iron, transferrin, and ferritin levels).

Although some controversy exists as to the best methods of continually accessing adequate iron stores and iron delivered to the bone marrow, the most universally available test remains transferrin saturation and serum ferritin. If iron deficiency is identified, an appropriate workup including evaluation for gastrointestinal sources of blood loss (gastritis or malignancy) must be initiated.

The USRDS Dialysis Morbidity and Mortality (UDMM) Study showed that up to 50% of patients receiving epoetin were iron deficient, making this the most common cause of “erythropoietin resistance.” Although multiple normograms exist for the replacement of iron, two important points need to be made concerning oral iron. First, oral iron can rarely be given in doses high enough to compensate for iron requirements in patients receiving erythropoietin therapy. Second, oral iron is rarely well tolerated and can cause gastric upset, which can easily be misidentified as uremic symptoms. The use of oral iron with gastrointestinal upset may further demoralize patients and dissuade them from compliance with other medications important to their care, which they may believe to be the cause of their gastric upset. Therefore in the United States the standard route for iron replacement remains the intravenous route.

Most protocols established for iron repletion are predicated on the iron requirements of ESRD patients. The goals, however, remain the same, achieving a TSAT of greater than 20% and a ferritin >100 ng/mL. Approximately 1 g of iron is required to increase the hematocrit 10% over a 3-month period. Currently available commercial iron products are listed in Table 18–1. It should be noted that intravenous iron dextrin (INFeD) has been associated with fatal anaphylactic reactions and must be preceded by a test dose. Newer preparations such as iron gluconate (Ferrlecit) and iron sucrose (Venofer) have substantially lower rates of anaphylactic reactions and do not require test dosing. Recently Venofer has been approved by the U.S. Food and Drug Administration (FDA) for use in CKD patients. Rapid administration of high doses of iron (>500 mg) has recently been made possible by the introduction of ferumoxytol. As compared to currently available iron formulations, this product is isotonic and has very low free iron levels which may account for its very low incidence of anaphylactoid reactions.

During active administration of erythropoietin most protocols recommend reevaluating iron stores every three months as patients vary in their ability to utilize iron.

Erythropoietin Therapy

There are currently two commercially available erythropoietic agents to treat anemia: Epoetin-alfa and darbepoetin-alfa. Epoetin-alfa is manufactured and sold under two brand names, Epogen (Amgen, Inc.) and Procrit (Ortho-Biotech, Johnson & Johnson). Both these products are biologically and structurally identical.

Epoetin-alfa is immunologically and biologically indistinguishable from endogenous erythropoietin. Darbepoetin-alfa (AraNESP) structurally differs from endogenous erythropoietin by having additional oligosaccharide chains and a rearranged amino acid sequence. It has a higher molecular weight then epoetin-alfa resulting in a longer half-life, estimated to be approximately three times that of epoetin-alfa (8 hours versus 25 hours).

Although there have been no randomized controlled studies comparing the efficacy of each of these products to the other, they have both been shown to effectively treat anemia of chronic kidney disease. Drug selection is predicated upon the comfort level of the clinical nephrologist and cost. Although darbepoetin-alfa has a prolonged half-life and its labeling allows for dosing every 2 weeks, evidence has accumulated that both darbepoetin-alfa as well as epoetin-alfa can be dosed as infrequently as once every 4 weeks. Initial dosing of epoetin-alfa is generally 10,000 units per week subcutaneously. Depending on the protocol used, once the desired hemoglobin range is achieved (11–12 g/dL) most physicians will double the administered dose and double the administrative time (10,000 units once a week becomes 20,000 units every 2 weeks and then 40,000 units every 4 weeks). Once a convenient time interval is reached for the patient, ie, once-a-month dosing, titration of the dose up or down is used to maintain the target hemoglobin.

As mentioned, darbepoetin-alfa has a significantly longer half life and is typically started at 0.45–0.60 μg/kg/week subcutaneously. It too can be titrated by increasing the dose and increasing the time interval to reach an administrative schedule convenient for the patient.

Although higher initial doses of erythropoietic agents may result in a more rapid increase in hemoglobin, this is rarely necessary (rapid correction) and should be avoided as higher costs and potential target hemoglobin overshoots will result.

Recent studies, CHOIR and CREATE, have suggested that targeting higher hemoglobin levels (generally >12.5 g/dL) may result in higher cardiovascular events. Reanalysis of the CHOIR data though, has linked these adverse events to patients receiving higher doses of epoetin-alfa and not reaching their target hemoglobins. Those patients achieving higher target hemoglobins did not show increased risk of cardiovascular events.

Until the debate on appropriate hemoglobin targets is settled; NKF KDOQI guidelines recommend a target range of 11-12 g/dL and avoidance of targets >13 g/dL.

Adverse Effects Associated with Epoetin-Alfa

The common side effects from the use of epoetin-alfa and darbepoetin-alfa are generally mild and transient. Approximately 5% of patients will experience flu-like symptoms and 12–15% will experience headaches. The relationship between administration of epoetin-alfa and hypertension has been well documented and occurs in approximately 23% of patients. Therefore, increases in blood pressure should be closely monitored following initiation of therapy. This hypertension appears to be related to an imbalance between endothelin and proendothelin resulting in increased responsiveness to the vasoconstricting actions of norepinephrine and decreased responsiveness to the vasodilatory affects of nitric oxide. This affect (hypertension) is seen most frequently when the route of administration is intravenous.

Recently approximately 100 cases of pure red blood cell aplasia have been reported in Europe. This has been linked to the European formulation of epoetin-alfa (Eprex), with patients producing neutralizing antiepoetin antibodies. This appears to be linked to a different immunogenicity of Eprex. No cases of red cell aplasia have been reported to date in patients using darbepoetin-alfa.

Resistance to Epoetin

Resistance to epoetin-alfa is seen primarily in patients with ESRD receiving dialysis, but is now being observed in CKD patients. Resistance is defined as the need for >150 units/kg of epoetin-alfa three times per week or the development of refractiveness to a previous stable dose allowing the hemoglobin level to fall below the targeted hemoglobin range. Although reports vary, approximately 5–10% of all patients with ESRD can be categorized as resistant. It is not known how many patients with CKD fall into this category. However, the numbers may be higher due to the persistent chronic “inflammatory” state in which these patients exist.

Resistance to Erythropoietin

Iron Deficiency

Iron deficiency is the most common cause of resistance as previously mentioned. Serum iron saturation, ferritin, and transferrin should be checked frequently to avoid this condition. Ensuring adequate iron stores also allows epoetin-alfa to be administered in a cost-effective manner.

Infection and Inflammation

Infection and inflammation are the second most common conditions resulting in hyporesponsiveness to epoetin-alfa. Mediators of inflammation [tumor necrosis factor (TNF) and interleukin-1 (IL-1] directly cause hyporesponsiveness to epoetin. Patients should be carefully scrutinized for conditions that result in chronic inflammatory processes.

Hyperparathyroidism

Although a much less common cause of resistance in the era of multiple vitamin D analogs and cinacalcet (Sensipar) availability, severe untreated hyperparathyroidism can result in fibrosis of the bone marrow. Unfortunately, the relationship between serum PTH levels does not directly correlate with the required epoetin dose and resistance.

Hemoglobinopathies

Sickle cell disease accounts for the majority of patients with resistance who have a hemoglobinopathy. High-dose epoetin-alfa therapy has mixed results with this disorder, often not reaching target hemoglobin goals.

Thalassemia

Thalassemia accounts for the remainder of resistant hemoglobinopathies and does respond to high-dose epoetin-alfa therapy.

Cofactor Deficiency and Malnutrition

Cofactor deficiency and malnutrition should cause close scrutiny on the part of the physician, who should then consider the initiation of dialytic therapy, particularly in the elderly who may downplay their uremic symptoms. Anorexia is an early, subtle, symptom of uremia. Falling serum albumin levels and/or the development of folate or vitamin B12 deficiencies necessitate close observation and treatment (dialysis) as they are directly related to dialytic mortality.

As expectations of care continue to evolve on both the payer and patient side, closer scrutiny will be made of those disorders whose treatment results in improved outcomes. The more actionable a treatment parameter, the more likely physicians will be held accountable for its identification and management. There is considerable literature concerning the relationship of anemia to CKD, the growing population of patients with CKD and anemia, and the relationship of anemia to cardiovascular mortality. This knowledge, coupled with the availability of highly effective erythropoietic-stimulating factors and dosing strategies, makes the identification and treatment of anemia in CKD of paramount importance in the management of this at-risk population.