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'Assessing the impact of concomitant therapies on anemia in dialysis patients: case study of the anemic patient.

Goal

The goal of this CE offering is to provide the learner with information about varying types of anemia, as well as discuss the causative etiology of hyporesponse to Epoetin alfa in patients receiving replacement therapy.

Objectives

1. Discuss the factors contributing to hyporesponse to anemia therapy in ESRD patients.

2. Identify mechanisms of altered red cell production.

3. Describe nursing interventions to enhance anemia therapy.

Introduction

Optimizing anemia-related outcomes by maintaining patients in the target hemoglobin (Hb) range of 11 to 12 g/dL recommended by the National Kidney Foundation's Dialysis Outcomes Quality Initiative, (NKF-DOQI) has become a common quality indicator for many dialysis centers (Eknoyan & Levin, 1997). One of the primary challenges in achieving this therapeutic goal is determining the cause of hyporesponse--defined as a temporary or chronic Hb level below the target range--in an ESRD patient who is receiving Epoetin alfa (EPOGEN[R]).

A number of etiologies that can contribute to hyporesponse have been identified, including iron deficiency, blood loss, infection or inflammation, inadequate Epoetin alfa, dosage, protein malnutrition, aluminum toxicity,, and vitamin deficiency (Eknoyan & Levin, 1997). An additional etiology that is often overlooked is the potential effect of concomitant therapies on red blood cell production and the response to Epoetin alfa.

ESRD patients frequently receive treatment for comorbid conditions such as diabetes, hypertension, infection, inflammation, and cancer. Some of the medications prescribed for these conditions can affect red blood cell production or viability and precipitate hyporesponse to Epoetin alfa. As the day-to-day case managers for dialysis patients, nephrology nurses should know the medications their patients are taking. To assess the potential contribution of medications on anemia, nurses can perform initial (on admission) and monthly medication reviews, while counseling patients on the need to notify the nephrology team about any new medications or medication changes--including both those that are prescribed by primary care physicians, endocrinologists, or other specialists, and those OTC or herbal remedies that patients may be self-prescribing.

Drugs and other agents that contribute to anemia can be categorized on the basis of their effect on the erythropoietic process. Categories include ACE inhibitors, agents that cause aplastic anemia, agents that cause red cell aplasia, agents that cause vitamin [B.sub.12] folic acid, or iron deficiencies, agents that cause sideroblastic anemia, agents that cause hemolysis in G6PD-deficient patients, agents that cause hemolytic anemia, and other miscellaneous agents. By profiling the range of medications being taken and understanding how these preparations can contribute to anemia, nephrology nurses may be able to help prevent or minimize medication-related hyporesponsive episodes.

ACE Inhibitors and Anemia

There are conflicting reports on the potential effect of angiotensin converting enzyme (ACE) inhibitors on erythropoiesis in dialysis patients. Several studies have found that these drugs do not affect the action of Epoetin alfa, and that doses and Hb levels are similar among treated and control patients (Abu-Alfa, et al., 1997; Eknoyan & Levin, 1997). Other reports, where no other cause of Epoetin alfa hyporesponsiveness could be determined, concluded that ACE inhibitors decrease the effectiveness of Epoetin alfa therapy (Albitar, Genin, Fen-Chong, Servaeux, & Bourgeon, 1998; Matsumura, Nomura, Koni, & Mabuchi, 1997).

These latter reports suggest that the effect may be more prevalent with high-dose ACE inhibitors or with specific drugs (e.g., captopril). Although the potential mechanism of how ACE inhibitors affect erythropoiesis is not known, hypotheses include: (a) interference with native secretion of erythropoietin, and (b) direct inhibition of the bone marrow. The NKF-DOQI guidelines recommend monitoring patients who are receiving concomitant Epoetin alfa and ACE inhibitor therapies and adjusting the Epoetin alfa dose as necessary to sustain a stable Hb/Hct (Eknoyan & Levin, 1997). ACE inhibitors that may cause hyporesponse to Epoetin alfa therapy are outlined in Table 1.

Agents That May Cause Aplastic Anemia

Aplastic anemia is a condition in which pancytopenia (including anemia, neutropenia, and thrombocytopenia) occurs after destruction or reduction of hematopoietic stem cells (the cells in the bone marrow that are responsible for producing red blood cells, white blood cells, and platelets). In its severest form, aplastic anemia is characterized by bone marrow that contains less than one-third of the normal amount of stem cells (Schrier, 2000a).

The most common therapies that may lead to aplastic anemia include ionizing radiation and myelosuppressive chemotherapy used to manage malignant or immunologic disorders. A listing of common agents used for this purpose is found in Table 2. Depending on the agent, the effect on red cell parameters may or may not be dose dependent (Schrier, 2000a).

Dialysis patients who receive chemotherapeutic agents may require higher doses of Epoetin alfa (150 to 300 Units/kg administered three times a week) to maintain Hb levels (Amgen Inc., 1999). While red blood cell levels typically return to normal when these agents are discontinued, interventions such as red blood cell transfusions or bone marrow or stem cell transplantation may be required, depending on the chemotherapy dose and the duration of the treatments.

Agents That May Cause Pure Red Cell Aplasia

Acquired pure red cell aplasia is a condition in which erythrocyte precursors in the bone marrow are virtually absent, while platelet and white cell levels are unaffected. It is thought that red cell aplasia is primarily caused by inhibition of immune mechanisms, which leads to suppression of erythroid progenitors. When this condition is identified as a cause of anemia, the offending drug should be discontinued and alternative therapies prescribed. Drugs commonly associated with pure red cell aplasia are listed in Table 3 (Schrier, 2000a).

Agents That Cause Folic Acid or Vitamin [B.sub.12] Deficiency

Vitamin [B.sub.12] and folio acid are necessary for DNA synthesis and the production of red blood cells. Neither folic acid nor vitamin [B.sub.12] are produced by humans, so both must be absorbed from the diet. Dialysis patients typically receive supplements of these vitamins, and deficiency secondary to nutritional imbalances is, therefore, rare. However, megaloblastic anemias can be caused by drugs that interfere with the absorption or metabolism of vitamin [B.sub.12] or folic acid (Schrier, 2000a).

Treatment of drug-induced vitamin deficiency typically focuses on discontinuing or reducing the dose of the offending agent and administering additional [B.sub.12] or folate supplements to achieve normal levels. Agents that can cause anemia by inducing vitamin [B.sub.12] or folic acid deficiency are listed in Tables 4 and 5.

Agents That Cause Sideroblastic Anemia

Sideroblastic anemias are a group of disorders that are characterized by ineffective erythropoiesis and anemia. The most typical cause is an abnormality in hemesynthesis that leads to impaired incorporation of iron into heme. Sideroblastic anemias are characterized by a high saturation of the serum iron-binding capacity (sometimes approaching 80%) and high iron levels in the presence of anemia. The most common therapies include antituberculosis drugs. Management involves stopping exposure to the offending agent and administering deferoxamine to absorb excess iron (Schrier, 2000a).

Agents That Cause Iron Deficiency

Iron deficiency in dialysis patients is often related to blood loss (especially in hemodialysis patients). However, certain medications can also contribute to iron deficiency. For example, salicylates (aspirin and its derivatives)--even in their buffered form--can cause gastrointestinal bleeding and occult blood loss. This risk could be accentuated in patients who ingest alcohol or receive oral anticoagulants or heparin. Combinations of these agents can lead to prolonged bleeding time or shortened erythrocyte survival time. Many of these agents can also irritate gastrointestinal mucosa, causing bleeding that often is not correlated with gastric distress. The amount of blood lost per day is usually insignificant, but prolonged use of these agents may result in peptic ulcers and iron deficiency anemia (Brittenham, 2000).

To alleviate the effect of iron deficiency, nephrology nurses should closely monitor the dose of heparin and other agents known to increase bleeding and iron loss. In addition, patients should be routinely questioned on their use of OTC preparations, many of which contain salicylate derivatives or nonsteroidal anti-inflammatory agents. Other agents can temporarily or permanently bind iron, thereby decreasing overall iron levels. Medications commonly associated with iron deficiency through blood loss or iron binding are listed in Table 6.

Agents That Produce Hemolysis in G6PD-Deficient Patients

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common disorders in the world, "affecting about 10% of African-American men, large numbers of black Africans, and some people of Mediterranean origin. Some medications may cause hemolytic anemia in patients with G6PD deficiency. These medications may contribute to oxidative stress and consequential weakening of red blood cell membranes. However, these drugs may not affect patients universally. For example, chloramphenicol and quinine can cause hemolysis in patients with the Mediterranean variant of G6PD, but not in those with the A-variant typically found in black populations (Schrier, 2000b). It is important to screen patients for G6PD deficiency and avoid drugs that may produce hemolysis. A listing of implicated agents is found in Table 7.

Agents That May Cause Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemias are typically acute disorders that can lead to rapid hemolysis and a precipitous decline in Hb/Hct. Drugs can produce varying degrees of hemolysis, ranging from mild to severe. In sonic cases, drugs elicit an antibody response when the drug-antibody complex transiently binds to the erythrocyte surface, resulting in hemolysis. When assessed using a reagent against IgG, patients with autoimmune hemolytic anemia typically have a positive direct Coombs' test (Schrier, 2000b).

Switching to an alternative medication generally eliminates hemolysis because antibody reactions tend to be specific for a particular medication. Table 8 lists some of the agents known to cause this phenomenon. Drug-induced hemolysis can sometimes require blood transfusions.

Other Agents That May Contribute to Anemia

Drugs such as nitroglycerin, vitamin K analogues, dapsone, phenacetin, and sulfasalazine can insert themselves into the oxygen-binding cleft of hemoglobin, thereby generating oxidizing free radicals flint can damage red blood cell membranes and lead to anemia (Schrier, 2000b). A number of other miscellaneous agents (Table 9) that may be prescribed for dialysis patients have also been shown to cause varying degrees of anemia (Olin, 1999). Using nursing assessment skills to identify possible drug-related hyporesponse to Epoetin alfa is illustrated in the following case study.

Case Study

JT is a 64-year-old man who is new to hemodialysis. His iron levels are at the high end of the acceptable range, and his Hb level is 8 g/dL. Epoetin allot therapy is initiated at a dose of 5,500 Units three times a week, but after 9 weeks of therapy, his Hb has increased only to 9 g/dL.

Assessment revealed no history of acute bleeding, surgery, infection, intercurrent inflammatory disorder, or stool changes. The vascular access site was normal. Laboratory values were as follows (a) a white blood cell count of 5,200, (b) a reticulocyte count of 4%, (c) an increase in mean corpuscular volume from 82 to 87 [micro][m.sup.3], (d) a [B.sub.12] level of 93 pg/mL, and (e) a folic acid level of 4 ng/mL. His estimated protein intake was 0.9 gm/kg/day. The stool Guaiac test was positive. An assessment of the Epoetin alfa prescription revealed that the patient was only receiving 50 Units/kg/dose.

The patient was asked to bring in his medications, and the ones he brought in matched those prescribed. The patient could not remember taking any OTC preparations. A preliminary interview with his daughter revealed poor eating habits--he typically ate sweets and junk food when he was hungry. Alcoholism was suspected and queries indicated a high intake of alcohol and a history of alcoholism in the family.

Discussion

The positive Guaiac test, decreases in vitamin [B.sub.12] levels (below 150 pg/mL) and folic acid (below 5 ng/mL), and low protein intake led the nephrology team to suspect occult blood loss, vitamin deficiency, and protein malnutrition. Further probing revealed significant alcohol consumption.

Medications and other substances can dramatically affect the response to Epoetin alfa. Chronic ingestion of alcohol often results in iron, vitamin [B.sub.12], or folate deficiency; gastrointestinal bleeding; and the anemia of chronic disease. Alcohol can interfere with red cell production by precipitating a sharp decrease in folate and [B.sub.12] levels, thereby interfering with normal DNA synthesis. Further, alcoholism is often associated with a low protein intake. This patient's case was further complicated by a low dose of Epoetin alfa.

Treatment goals centered on correcting the underlying etiologies to reach a target Hb range of 11 to 12 g/dL. The Epoetin alfa dose was increased to 60 Units/kg TIW, and biweekly evaluations were performed to ensure that the patient's protein intake was maintained at 1.2 g/kg/day. Prescribed vitamin [B.sub.12] and folio acid supplements were administered during dialysis. Counseling was also initiated to eliminate alcohol consumption.

Conclusions

The severity, of drug-induced hyporesponse to Epoetin alfa therapy depends on the causative agent, the length of exposure, baseline anemia values, and other comorbid conditions that may be involved. Nurses are often in the best position to assess the use of prescribed and over-the-counter agents that can contribute to anemia. Through ongoing evaluation of each patient's medication profile, nephrology nurses can help detect and minimize exposure to these agents.

Assessing the Impact of Concomitant Therapies on Anemia in Dialysis Patients

By Nancy Gregory

Posttest Questions: 1.1 Contact Hours

(See posttest instructions on the answer form, next page)

The Nephrology Nursing Journal gratefully acknowledges Joan Hart-Nitz for writing the questions published in the CE posttest.

1. A hyporesponse to Epoetin alfa therapy is defined as

A. a temporary or chronic hemoglobin level below the target range of 11-12 g/dL.

B. a temporary or chronic hemoglobin level above the target range of 11-12 g/dL.

C. a chronic hemoglobin level at 15 g/dL.

D. a chronic hemoglobin level above 15 g/dL.

2. Dialysis patients receive many medications for comorbid conditions such as diabetes, hypertension, infection and cancer. Because of this

A. patients should be instructed not to worry about their medications.

B. patients should be instructed to self-prescribe with over-the-counter remedies.

C. nurses should find out what medications the patient is taking from all sources.

D. nurses should record only those medications ordered by the nephrologist.

3. There are conflicting reports on the potential effects of ACE inhibitors on erythropoiesis in dialysis patients. When patients are receiving both ACE inhibitors and Epoetin alfa therapy, the NKF-DOQI guidelines recommend

A. adjusting the EPO dosage upward by 10,000 units.

B. adjusting the EPO dosage downward by 4,00 units.

C. monitoring the patient's BP.

D. monitoring the Hgb and Hct as necessary to maintain target levels.

4. The most common causes of aplastic anemia are

A. ionizing radiation and myelosuppressive chemotherapy.

B. ionizing calcium and noninvasive chemotherapy.

C. stem cell transplants.

D. bone marrow transplants.

5. Pure red cell aplasia

A. is a condition in which platelet precursors are absent in the bone marrow.

B. is a condition in which erythrocyte precursors are absent in the bone marrow.

C. affects platelet and white cells.

D. affects platelets only.

6. Vitamin [B.sub.12] and folic acid are important in the production of red blood cells. When deficiencies of either of these substances occur

A. more Vitamin [B.sub.12] is produced in the liver.

B. more folic acid is released by the parathyroid gland.

C. supplements must be taken orally.

D. nutritional imbalances cannot be replaced.

7. Sideroblastic anemias are characterized by

A. high saturation of serum iron-binding capacity and high iron levels.

B. low saturation of serum iron-binding capacity and low iron levels.

C. high hematocrit and low iron levels.

D. high hematocrit and low white cell count.

8. The most common medications that may contribute to iron deficiency are

A. antacids.

B. antibiotics.

C. alcohol and salicylates.

D. anti-emetics and salt tablets.

9. Over-the-counter drugs responsible for causing iron deficiencies could be

A. Pepto Bismol[TM] and TUMS[TM].

B. ibuprofen and aspirin.

C. Metamucil[TM].

D. Colace[TM].

10. If a nurse suspects a patient is not responding to Epoetin alfa administration,

A. a glucose record should be kept for 1 week.

B. a blood pressure record should be kept for 1 week.

C. a complete physical should be done.

D. an evaluation of the patient's medication profile should be done.

ANSWER FORM ANNJ004

Assessing the Impact of Concomitant Therapies on Anemia in Dialysis Patients

By Nancy Gregory

Posttest Instructions

* Select the best answer and circle the appropriate letter on the answer grid below.

* Complete the evaluation.

* Send only the answer form to the ANNA National Office; East Holly Avenue Box 56; Pitman, NJ 08071-0056.

* Enclose a check or money order payable to ANNA

ANNA Member--$15

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Expiration Date-- (from membership card)

* Posttests must be postmarked by June 20, 2002. If you receive a passing score of 70% or better, a certificate for 1.1 contact hours will be awarded by ANNA.

* Please allow 6-8 weeks for processing. You may submit multiple answer forms in one mailing, however, because of various processing procedures for each answer form, you may not receive all of your certificates returned in one mailing.

* This article qualifies for credit toward the 30 contact hours of fundamental nephrology nursing education required to take the CNN examination effective January 1, 2000. For further explanation, see ANNA link (www.annanurse.org).
Complete the Following

Name:--

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ANNA Member --Yes   --No   CNN   --Yes   --No

Source of Article:   [] Journal   [] ANNA Web site (ANNAlink)

Note: If you wish to keep the journal intact, you may photocopy the
answer sheet

Posttest Answer Grid

Please circle your answer choice:

1.  a   b   c   d

2.  a   b   c   d

3.  a   b   c   d

4.  a   b   c   d

5.  a   b   c   d

6.  a   b   c   d

7.  a   b   c   d

8.  a   b   c   d

9.  a   b   c   d

10. a   b   c   d


Goal

The goal of this CE offering is to provide the learner with information about varying types of anemia, as well as discuss the causative etiology of hyporesponse to Epoetin alfa in patients receiving replacement therapy.
                                                Strongly   Strongly
Evaluation                                      disagree      agree

1. The objectives were related to the goal.
   a. Discuss the factors contributing to
      hyporesponse to anemia therapy in
      ESRD
      patients.                                1    2    3     4     5
   b. Identify mechanisms of altered red
      cell production.                         1    2    3     4     5
   c. Describe nursing interventions to
      enhance anemia therapy.                  1    2    3     4     5
2. The teaching/learning resources were
   effective to complete this activity.        1    2    3     4     5
3. A self-study format was effective for
   the content.                                1    2    3     4     5
4. The On-Line format was effective. (if
   downloaded)                                 1    2    3     4     5
5. Minutes required to complete self-study,
   including the posttest:                    50   75   100   125   150

Comments--

Table 1: ACE Inhibitors That May Cause Anemia in Dialysis Patients

* Benazepril    * Lisinopril   * Captopril
* Perindopril   * Cilazapril   * Ramipril
* Enalapril     * Temocapril   * Imidapril


Table 2: Agents/Treatments That May Cause Aplastic Anemia

* Irradiation

* Alklyating agents (melphalan, cyclophosphamide, chlorambucil, busulfan)

* Antimetabolites (azathioprine, 6-mercaptopurine, hydroxyurea, methotrexate)

* Other antitumor agents (dounorubicin, doxorubicin, carmustine, lomustine, amsacrine)

* Agents that occasionally cause myelosuppression (chloramphenicol, gold compounds, arsenic, sulfonamides, mephenytoin, trimethodione, phenylbutazone, quinacrine, indomethacin, diclofenac, felbamate)

Table 3: Agents That May Cause Red Cell Aplasia

* Phenytoin

* Chlorpropamide

* Zidovudine

* Trimethoprim-sulfamethoxazole

* Isoniazid
Table 4: Agents That May Cause Vitamin [B.sub.12] Deficiency

* Neomycin              * Biguanides
* Colchicine            * Ethanol
* Aminosalicylic acid   * Omeprazole

Table 5: Agents That May Cause Folic Acid Deficiency

* Methotrexate             * Trimethoprim
* Primethamine             * Sulfasalazine
* Phenytoin                * Ethanol
* Antituberculosis drugs   * Oral contraceptives


Table 6: Agents That May Cause Iron Deficiency

* Alcohol

* Salicylates

* Steroids

* Nonsteroidol anti-inflammatory drugs

* Deferoxamine

Table 7: Agents That May Cause Hemolysis in G6PD-Deficient Patients

* Antimalarials (primaquine, chloroquine)

* Sulfonamides (sulfamethoxazole, sulfapyridine)

* Solfones (dapsone)

* Analgesics (acetanilid, phenacetin, acetylsalicylic acid)

* Nitrofurans (nitrofurantoin, furazolidone)

* Water-soluble vitamin K derivatives (menadiol)

* Quinine

* Chloramphenicol
Table 8: Agents That May Cause Autoimmune Hemolytic Anemia

* Stibophen             * Phenacetin
* Aminosalicylic acid   * Isoniazid
* Rifampin              * Sulfanamides and solfonylureas
* Quinidine, quinine    * Chlorpropamide
* Immunosuppressants

Table 9: Other Agents That May Cause Anemia

* H2 blockers/proton pump inhibitors   * Phosphate binders
* Tetracyclines                        * Penicillins
* Cephalosporins                       * Hydralazine
* Phenacetin                           * Nitroglycerin
* Vitamin K analogues                  * Sulfasalazine
* Dapsone                              * Ribavirin
* Alpha interferons


Note: This article is supported by a financial grant from Amgen Inc. The manuscript has undergone an anonymous peer review. The information does not necessarily reflect the opinions of ANNA or the sponsor.

References

Abu-Alfa, A., Cruz, D., Mahnensmith, R., Perazella, M., Simon, D., & Bia, M.J. (1997). ACE-inhibitors do not induce EPOGEN[R] resistance in hemodialysis patients: A prospective crossover study. Journal of the American Society of Nephrology, 9, 225A.

Albitar, S., Genin, R., Fen-Chong, M., Servaeux, M.O., & Bourgeon, B. (1998). High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients. Nephrelogy Dialysis Transplantation, 13, 1206-1210.

Amgen Inc. (1999). EPOGEN[R] (Epoetin alfa) Package Insert. Thousand Oaks, CA: Amgen, Inc.

Brittenham, G.M. (2000). Red blood cell function and disorders of iron metabolism. In: Dale, D.C., & Federman, D.D., eds. Scientific American Medicine, New York, NY. Scientific American Medicine, Section 5, 1-13.

Eknoyan, G., & Levin, N. (1997). National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) Clinical Practice Guidelines for the Treatment of the Anemia of Chronic Renal Failure. American Journal of Kidney Diseases, 30(44), S192-S237.

Matsumura, M., Nomura, H., Koni, I., & Mabuchi, H. (1997). Angiotensin-converting enzyme inhibitors are associated with the need for increased recombinant human erythropoietin maintenance doses in hemodialysis patients. Nephron, 77, 164-168.

Olin, B.R. (ed.). (1999). Facts and Comparisons, St. Louis, MO: Facts and Comparisons.

Schrier, S.L. (2000a). Anemia: production defects. In: Dale, D.C., & Federman, D.D., eds. Scientific American Medicine, New York, NY. Scientific American Medicine, Section 5-3, 1-13.

Schrier, S.L. (2000b).Anemia: hemolysis. In: Dale, D.C., & Federman, D.D., eds. Scientific American Medicine, New York, NY Scientific American Medicine, Section 5-4, 1-33.

Nancy Gregory, RN, CNN, is the Clinical Manager a Gambro Health Care, Richmond/MCV, Richmond, VA USA
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Title Annotation:Educational Supplement
Author:Gregory, Nancy
Publication:Nephrology Nursing Journal
Date:Jun 1, 2000
Words:3636
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