Bone marrow amyloidosis with erythropoietin-resistant anemia in a patient undergoing chronic hemodialysis treatment. (Case Report).

Abstract: The resistance to erythropoietin, which is used to treat normochromic, normocytic anemia in chronic renal failure, can develop in patients with conditions such as iron deficiency, aluminum toxicity, hyperparathyroidism, chronic inflammatory diseases, and primary hematological disorders. We found amyloidosis in the bone marrow of a woman without any other etiology for erythropoietin resistance who was undergoing chronic hemodialysis. Her anemia did not improve, despite 6 months of erythropoietin therapy. Bone marrow amyloidosis was found to be the reason for erythropoietin-resistant anemia in our patient with chronic renal failure and renal anemia. We present the case of bone marrow amyloidosis because it is a very rare cause of erythropoietin resistance.

Key Words: bone marrow amyloidosis, chronic renal failure, erythropoietin resistance

**********

Key Points

* The primary cause of anemia in patients with chronic renal failure is insufficient production of erythropoietin by the diseased kidneys.

* Principal treatment of renal anemia consists of effective dialysis, restoration of missing components (especially iron), control of renal osteodystrophy, as well as erythropoietin therapy.

* If anemia is not corrected in a patient, despite appropriate dosage and duration of therapy with erythropoietin, then the etiology should be investigated; in our patient, we thought erythropoietin resistance could be due to bone marrow amyloidosis.

Normocytic, normochromic anemia is present in the majority of patients with chronic renal failure (CRF). The primary cause of anemia in patients with CRF is insufficient production of erythropoietin (EPO) by the diseased kidneys. In CRF, the development of anemia is due to not only EPO deficiency but also to factors such as iron deficiency, acute and chronic blood loss, severe hyperparathyroidism, acute and chronic inflammatory conditions, aluminum toxicity, folate and vitamin [B.sub.12] deficiency, malnutrition, inadequate hemodialysis, shortened erythrocyte survival time, hypothyroidism, underlying hemoglobinopathies, multiple myeloma, and hemolysis. (1-4) Principal treatment of renal anemia consists of effective dialysis, restoration of missing components (especially iron), and control of renal osteodystrophy, as well as the appropriate dosage and duration of treatment with EPO. Recombinant human EPO has been used in the treatment of the anemia of CRF since 1986. (5) EPO resistance in patients can be due t o infections, chronic blood loss, osteitis fibrosa, aluminum toxicity, primary hematological diseases, folic acid or vitamin [B.sub.12] deficiency, multiple myeloma, malnutrition, or iron deficiency. EPO resistance due to angiotensin-converting enzyme inhibitors has been suggested. If anemia is not corrected in a patient, despite appropriate dosage and duration of therapy, then the reasons for this should be explored. (5,6) We present a case of amyloidosis of the bone marrow in a patient without any other etiology for erythropoietin resistance whose anemia has not improved, despite 6 months of EPO therapy.

Discussion

Patients with CRF have benefited greatly and their need for blood transfusions has decreased remarkably since EPO has been included in their therapy. Some patients, though, have not achieved the expected response. Inadequate response to EPO therapy is defined as failure to achieve target hematocrit/hemoglobin levels within 4 to 6 months in the presence of adequate iron stores at an EPO dose of 450 U/kg/wk intravenously or 300 U/kg/wk subcutaneously, or failure to subsequently maintain target hematocrit/hemoglobin levels at that dose. Since there is wide variability in dose response to EPO, however, an individual patient may respond to as little as 75 U/kg/wk intravenously (or 50 U/kg/wk subcutaneously). (5,6)

Iron, folic acid, and [B.sub.12] vitamin deficiencies, chronic infection, primary hematological diseases (eg, multiple myeloma, hemoglobinopathy), hyperparathyroidism, chronic blood losses, aluminum intoxication, malnutrition, and ineffective dialysis should be investigated as potential causes in patients with EPO resistance. (5-7)

These causes should be eliminated by clinical and laboratory means, and patients with positive test results should be treated. Iron stores are depleted especially easily in patients who are using EPO due to the increased demand. Hypochromic, microcytic anemia appears. Due the increased use, as well as the loss during hemodialysis, folic acid and vitamin [B.sub.12] deficiencies may occur, causing macrocytic anemia. Chronic infection and rheumatologic diseases cause EPO-resistant normochromic, normocytic anemia. Use of aluminum-containing drugs or improperly treated water for dialysis often causes microcytic anemia. Hyperparathyroidism due to poor control of renal osteodystrophy is also an important cause of EPO resistance. (4-7) In our case, all of these causes were researched thoroughly. There were no deficiencies of iron, folic acid, or vitamin [B.sub.12], hyperparathyroidism, chronic infection, or primary hematological disease identified. Because the anemia was normocytic and normochromic, no aluminum-conta ining drugs were used, and standard procedures with regular water standard controls were used to treat the dialysis water-there was no suggestion of aluminum toxicity. The patient had no chronic blood loss from the gastrointestinal system or any other system. After all the other causes have been eliminated, bone marrow biopsy is advised in patients with EPO-resistant anemia. (8) We thought EPO resistance in our patient could be due to bone marrow amyloidosis; amyloidosis was diagnosed on the bone marrow biopsy. In our search through the published studies, we did not find any report of bone marrow amyloidosis as the cause of EPO resistance.

Bone marrow involvement and its diagnostic value in patients with secondary AA amyloidosis due to familial Mediterranean fever have been discussed in another report, (9) which found that 79% of the cases had bone marrow amyloidosis. This result shows that, especially in patients with CRF due to amyloidosis, bone marrow amyloidosis is an important entity.

Conclusion

When all other possible causes have been eliminated in patients with amyloidosis in their etiology of their CRF, performing a bone marrow biopsy should be a priority. In addition to amyloidosis, biopsy can identify other bone marrow pathologies that can cause EPO resistance, such as fibrosis.

Accepted December 10, 2001.

References

(1.) Eschbach JW, Adamson JW. Anemia of end-stage renal disease (ESRD). Kidney Int 1985;28:1-5.

(2.) Rao DS, Shih MS, Mohini R. Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 1993;328:171-175.

(3.) Grutzmacher P, Ehmer B, Limbach J, Messinger D, Kulbe KD, Scigalla P. Treatment with recombinant human erythropoietin in patients with aluminum overload and hyperparathyroidism. Blood Purif 1990;8:279-284.

(4.) Steffen HM, Brunner R, Muller R, Degenhardt S, Pollok M, Lang R, et al. Peripheral hemodynamics, blood viscosity, and the renin-angiotensin system in hemodialysis patients under therapy with recombinant human erythropoietin. Contrib Nephrol 1989;76:292-298.

(5.) Rosenlof K, Fyhrquist F, Tenhunen R. Erythropoietin, aluminium, and anaemia in patients on haemodialysis. Lancet 1990;335:247-249.

(6.) Muirhead N, Hodsman AB, Hollomby DJ, Cordy PE. The role of aluminium and parathyroid hormone in erythropoietin resistance in haemodialysis patients. Nephrol Dial Transplant 1991;6:342-345.

(7.) Grutzmacher P, Ehmer B, Messinger D, Kulbe KD, Scigalla P. Effect of aluminum overload on the bone marrow response to recombinant human erythropoietin. Contrib Nephrol 1989;76:315-323.

(8.) Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease: Results of a Phase III multicenter clinical trial. Ann Intern Med 1989;111:992-1000.

(9.) Sungur C, Sungur A, Ruacan S, Arik N, Yasavul U, Turgan C, et al. Diagnostic value of bone marrow biopsy in patients with renal disease secondary to familial Mediterranean fever. Kidney Int 1993;44:834-836.

RELATED ARTICLE: Case Report

In March 1999, a 31-year-old woman diagnosed with end-stage renal failure was undergoing chronic hemodialysis 3 times per week for 4 hours, using 1.2 to 1.4 [m.sup.2] low-flux membranes and bicarbonate solutions, with blood flow rate 300 ml/min and dialysate flow rate 500 ml/min. She had a diagnosis of nephrotic syndrome, and the reason for her renal failure was diagnosed with rectal biopsy in March 1999 as AA amyloidosis. She had experienced abdominal and joint pain every 3 weeks during a 10-year period, and there was a family history of fever. She had been diagnosed with amyloidosis due to familial Mediterranean fever.

She had a 6-month history of normocytic, normo-chromic anemia resistant to EPO (at a dose of 50 to 100 U/kg), which was administered subcutaneously after each dialysis session. Physical examination revealed pale skin and mucous membranes; painless, smooth splenomegaly in the left midclavicular line, 8 cm below the costal arcus; and painless hepatomegaly in the right mid-clavicular line, 5 cm below the costal arcus. Laboratory tests showed the following values: hemoglobin, 6.4 g/dl; hematocrit, 19%; erythrocyte count, 1.98 X [10.sup.12]/L, leukocyte count, 10.1 X [10.sup.9]/L; platelet count, 266 X [10.sup.9]/L; median erythrocyte cell volume, 91.4 fl; median hemoglobin concentration, 29.9 pg; median erythrocyte hemoglobin concentration, 32.7 g/dl; serum iron, 65 [micro]g/dl (normal, 50-175 [micro]g/dl); serum ferritin, 475 [micro]g/dl (normal, 4.9-233 [micro]g/d1); serum folic acid, 16 ng/mL (normal, 3-17 ng/ml); serum [B.sub.12], 16 ug/ml (normal, 3-17 ng/ml); and intact parathormone, 29.8 pg/ml (normal, 12- 72 pg/ml). Kt/V average value was 1.3.

Seven units of erythrocyte suspension were given to the patient during a 6-month period. Oral iron and folic acid and parenteral vitamin [B.sub.12] were administered, along with EPO. All possible causes of EPO resistance were researched thoroughly, and no reason was found. Bone marrow biopsy was performed to search for the suspected amyloidosis, and pathologic examination was positive for capillary amyloid deposition. The amyloid proved to be sensitive to potassium permanganate, characterizing it as AA amyloidosis (Fig. 1).

From the Departments of Nephrology, Pathology, and Hematology, Medical Faculty, University of Ataturk, Erzumm, Turkey.

Reprint requests to Ramazan Cetinkaya, MD, Terminal Cad. Polat sitesi A-Blok, Kat: 5, Daire:9, 25040 Erzurum, Turkey. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9605-0491