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Evaluating hyporesponsiveness to ESA therapy in patients with chronic kidney disease.

Q: We have several patients with chronic kidney disease (CKD) currently coming to the outpatient department on a monthly basis to get the same dose of an erythropoietin stimulating agent (ESA), and yet, their hemoglobin remains at 9.0 g/dL. Should we be making some adjustments in the treatment plan, like increasing the dose?

A: Evaluating the patient's response (or lack thereof) to ESA therapy is best accomplished by assessing the patient's clinical status and pertinent laboratory data. Keep in mind the physiological changes that take place as the glomerular filtration rate (GFR) decreases and uremia increases in this patient population. Hyporesponse to ESA therapy has been associated with decreased survival and increased hospitalization rates (Johnson, Pollack, & MacDougall, 2007).

Recent changes in the recommended target hemoglobin level have been adopted due to studies that indicate improved patient outcomes at lower hemoglobin levels. The goal for hemoglobin levels has been narrowed by this newest research and should not exceed 12 g/dL (Demiljian & Nurko, 2008). Reimbursement for ESA medication is highly regulated and linked to hemoglobin levels.

The literature describes hyporesponsiveness to ESA therapy as failure to achieve a target hemoglobin in the presence of adequate iron stores at an ESA subcutaneous dose of 300 units/kg/week of recombinant human erythropoietin or 1.5 ug/kg (100 ug/week) of darbepoefin alfa or failure to maintain a target hemoglobin at that dose within 4 to 6 months (Kwack & Balakrishnan, 2006).

It has been reported that 50/0 to 10% of patients with CKD treated with ESA therapy demonstrate some degree of resistance, so diligence in tracking and trending over time is warranted (Johnson et al., 2007).

Questions and Situations Used to Evaluate Hyporesponse to ESA Therapy

Does the Patient Have the Correct Amount Of Necessary Components to Make Red Blood Cells?

There are certain conditions that should be ruled out prior to starting ESA therapy. These include deficiencies of vitamin [B.sub.12], folic acid, and/or iron, all key ingredients to develop healthy red blood cells (RBCs). These RBCs grow to maturity and survive approximately l20 days in subjects without renal disease (Coyer & Lash, 2008).

If these are not in adequate supply, they must be replaced prior to or simultaneously with the use of ESA therapy. Patients may receive a vitamin B12 injection, if deficient, at the same time they receive an ESA. Review those test results, if available, and/or order them when evaluating patients who are not responding as anticipated.

Does the Patient's Laboratory Data Indicate An Increase in the Formation of RBCs?

If not done prior to the initiation of therapy as recommended, then an absolute reticulocyte count could help explain why there is hyporesponse to the ESAs. A reticulocyte count is an indirect measurement of recent erythropoietic activity and provides information about the rate at which the bone marrow is producing these cells. In ESA therapy, the reticulocyte count should be increased, demonstrating a positive bone marrow response to the medication. If the reticulocyte count is not increasing, and other reasons for hyporesponse (such as bleeding, infection, and inflammation) have been ruled out, then a hematology consult may be warranted (National Anemia Action Council, 2002).

What Do the Iron Studies Indicate?

Absolute iron deficiency and iron restricted erythropoiesis are the most common reasons for the lack of consistent ability to reach and maintain the target range. Most patients receiving ESAs on a regular basis will eventually deplete iron stores and require IV iron replacement in order to reach or maintain the target hemoglobin goal. The serum iron, total iron binding capacity (TIBC), transferritin saturation (TSAT), and serum ferritin should be monitored every three months. If the TSAT is less than 20%, IV iron may be indicated (National Kidney Foundation, 2000). If serum iron or ferritin is inadequate, the hemoglobin will drift downward. This may suggest a need for an increase in the ESA dose or frequency adding inappropriately to the already high cost of this therapy.


Intravenous iron therapy is an integral part of anemia management. Newer preparations of IV iron are easily administered in an outpatient setting. Using our protocol, we administer 1,000 mg of iron sucrose (Venofer[R]) in 5, 200 mg divided doses over 14 days with each bolus administered in 3 to 5 minutes with good outcomes and very few side effects. While patient results may vary, the majority experience a new sense of energy and zest for life upon completion of the iron repletion course.

Is the Patient Experiencing Gastrointestinal Bleeding?

As the GFR decreases and uremic toxin levels rise, patients with progressing CKD are more prone to gastrointestinal bleeding. The loss of blood is another common reason why the hemoglobin may not respond to the ESA therapy. Assessment questions focusing on changes in bowel pattern, color, consistency, history of gastrointestinal surgeries, last colonoscopy/esophagogastroduodenscopy, reflux disease, and abdominal or rectal pain are important to review periodically with this patient group (Johnson et al., 2007).

In some cases, as the hemoglobin is plotted on a graph (see Figure 1), it becomes obvious that there may have been a major blood loss. The patient's hemoglobin will change from a steady level and decrease by perhaps 2 or 3 grams. The visual graph allows for more prompt identification and immediate intervention, including transfusions, hospital admissions, and much needed gastrointestinal evaluations.

In some instances, there is not a rapid decrease but a slower loss of blood, as in the case of diagnosed angiodysplasia of the gastrointestinal (GI) tract. This patient group is slowly losing blood in the GI track and therefore, has a steady state of RBC loss. This type of blood loss can be compared to the patient undergoing chronic hemodialysis where RBCs are lost with each treatment (Johnson et al., 2007).

Careful review of the history, physical examination, and attention to trending will reveal a sub-optimal hemoglobin with iron stores that remain low despite intravenous replacement. Creative solutions to this patient scenario may include a monthly low maintenance dose of IV iron, along with the ESA therapy, in order to obtain optimum hemoglobin results.

Is an Infection or Inflammatory Process Present?

It is important to note the effects of the uremic toxins on the immune system for this patient population. Patients with renal disease are more susceptible to bacterial, fungal, and viral infections than those without this condition (Choudhury & Luna-Salazar, 2008).

Careful assessment for rashes, open areas of non-intact skin, inflamed joints, gout, cellilitis, and non-healing foot ulcers for patients with diabetes mellitus are physical signs that can be observed. Complaints of congestion, sinus drainage, seasonal allergies, coughing, and flu-like symptoms may also be elicited during the visit, as well as recent medical procedures or surgeries (such as vascular access placement or intervention). Recommendation of routine vaccinations and screenings is an important part of nursing care for this patient population in an effort to maximize protection.

When infection or inflammation is suspected as the cause of hyporesponse to ESA therapy, a C-reactive protein level (CRP), an acute phase reactant, may be a useful evaluation tool. An elevated serum ferritin may suggest inflammation or infection because it is also an acute phase reactant that becomes elevated during infection or inflammation. There is ongoing research to determine if other laboratory data can help evaluate inflammation in this patient population when there are no obvious signs. An increased white blood cell count and a decreased serum albumin were recently linked to adverse events similar to that of an increased CRP (Weiner et al., 2008).

In some cases, this type of investigation can help reveal undiagnosed cancer, flares of gout in need of ongoing medication, and appropriate referrals to specialists for diagnosis so treatment can be initiated. Interventions deemed at locating and treating the infection and/or inflammations are indicated. As the problem is successfully treated, the patient may again respond to the ESA medication.

Is the Patient Eating?

Low serum albumin levels have been associated with all-cause and cardiovascular mortality in patients on dialysis (Kaysen, 2001). As CKD progresses, patients may experience altered taste, dislike to certain foods, and a loss in body weight. In the older adult patient population, this can be even more pronounced because ill-fitting dentures may further affect chewing food, and relocation to different settings necessitates altered meal offerings.

Whether protein-reduced diets can retard the progression of CKD remains a topic of debate. It is clear that dietary protein intake must be balanced with dietary energy intake to optimize the nutritional status in the patient population with CKD (Kent, 2005).

Assessing appetite and monitoring weights, fluid status, and serum albumin and pre-albumin levels are important practice parameters to keep in mind if the patient is not achieving the hemoglobin goal. Interventions may include linking patients who are at risk with renal dietitians.

What Is the Parathyroid Hormone Level (PTH)?

Secondary hyperparathyroidism that can accompany CKD has also been implicated as a factor affecting ESA therapy resistance. While not completely understood, increased levels of PTH and decreased levels of calcitrol have been linked to reduced erythropoiesis and RBC survival (Drueke & Eckardt, 2002). While playing a more minor role, the literature does note that patient response to ESA was better following parathyroidectomy procedures (Kwack & Balakrishnan, 2006).

Noting calcium, phosphorus, and intact parathyroid hormone levels that are out of range can reveal a reason for ESA resistance. If the serum phosphorus level is elevated, it is never too early to begin patient education on the impact of CKD on bone health. Lesson plans should include dietary phosphorus restrictions, taking prescribed medications (including the use of phosphorous binders), and reviewing the blood tests with the patient as warranted.

Implications for Practice

A variety of reasons exists why patients may not be responding to a regularly scheduled dose of ESA medications. It is critical to understand that it is not enough to just administer this medication; it needs to be managed. Tracking and trending over time helps with this management. Figure 1 is an example of a tool currently used in our clinic. It serves several purposes:

* It provides a visual tool for management of the patient's anemia over time.

* It serves as our medication administration record.

* It is used as a communication tool to the physician initiating the referral to the clinic.

The graph section of the tool paints a picture of the patient's progress toward the hemoglobin goal, making it easy to see the climb or the descent when interventions are most readily needed. The current goal for our clinic is a hemoglobin level of 11.0 to 11.9 g/dL. We expect no reimbursement for a hemoglobin level at or above 12.0 g/dL and are not starting the ESA therapy until the hemoglobin is less that 10.0 g/dL. For patient convenience, we strive for monthly dosing as warranted by patient condition and response to the ESA therapy.

Nurses who are responsible for administering ESAs have a great opportunity to assist patients with CKD to feel well while having an impact on the cost associated with this therapy. This is best accomplished by investigating resistance and evaluating hyporesponse before raising the dose of these agents. Several reasons for hyporesponsiveness have been addressed here. There is ongoing research into other reasons for a lack of response to ESA therapy in patients with CKD, necessitating diligent attention to the literature.


Choudhury, D., & Luna-Salazar, C. (2008). Preventive health care in chronic kidney disease and end-stage renal disease. Nature Clinical Practice Nephrology, 4(4). 194-206.

Coyer, S.M., & Lash, A.A. (2008). Pathophysiology of anemia and nursing implications. MEDSURG Nursing, 17(2). 77-84.

Demirjian, S.G., & Nurko, S. (2008) Anemia of chronic kidney disease: When normalcy becomes undesirable. Cleveland Clinic Journal of Medicine, 75(5). 353-356.

Drueke, T.B. & Eckardt, K. (2002). Role of secondary hyper-parathyroidism in erythropoietin resistance of chronic renal failure patients. Nephrology Dialysis Transplantation, 17(Suppl. 5), 28-31.

Johnson, D.W., Pollack, C.A., & MacDougall, I.C. (2007). Erythropoiesis-stimulating agent hyporesponsiveness. Nephrology, 12. 321-330.

Kaysen, G.A., (2001). The microinflammatory state in uremia: Causes and potential consequences. Journal of the American Society of Nephrology, 12. 1549-1557.

Kent, P.S. (2005). Integrating clinical nutrition practice guidelines in chronic kidney disease. Nutrition in Clinical Practice, 20(2). 213-217.

Kwack, C., & Balakrishnan, V.S. (2006). Managing erythropoietin hyporesponsiveness. Seminars in Dialysis, 19(2), 146-151.

National Anemia Action Council (NAAC). (2002). Anemia monograph: A hidden epidemic. Retrieved on July 25, 2008, from

National Kidney Foundation. (2000). K/DOQI clinical practice guidelines for anemia of chronic kidney disease, 2000. American Journal of Kidney Diseases, 37, S182-S238.

Weiner, D.E., Tighiouart, H., Elsayed, E.F., Griffith, J.L., Salem, D.N., Levey, A.S., & Sarnak, M.J. (2008). Inflammation and cardiovascular events in individuals with and without chronic kidney disease. Kidney International, 73. 1406-1412.

Mary T. Sinnen, APRN, BC, ANP, is Director of Nephrology Services, Wheaton Franciscan Healthcare, and a Member of ANNA's Wisconsin Chapter.
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Title Annotation:Clinical Consult
Author:Sinnen, Mary T.
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:Sep 1, 2008
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