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Quiz Page October 2010
QUIZ PAGE OCTOBER 2010 Anemia in a Patient Newly Transferred From Peritoneal Dialysis to Hemodialysis
CLINICAL PRESENTATION A 50-year-old man with end-stage renal failure from diabetic nephropathy on continuous ambulatory peritoneal dialysis therapy since 1999 was switched to high-flux hemodialysis therapy in March 2009 after an episode of Pseudomonas aeruginosa peritonitis. He was receiving erythropoietin beta at 2,000 U/wk with a hemoglobin level of approximately 10 g/dL (100 g/L). In April 2009, he developed progressive microcytic anemia as his hemoglobin level decreased to 5.6 g/dL (56 g/L), with a mean corpuscular volume of
75.9 fL, reticulocyte count of 1.8%, platelet count of 297 ⫻ 103/L (297 ⫻ 109/L), and white blood cell count of 14 ⫻ 103/L (14 ⫻ 109/L) without evidence of gastrointestinal bleeding. Concurrently, intra-abdominal abscesses caused by P aeruginosa were diagnosed, and he was treated with catheter drainage and intravenous ticarcillinclavulanic acid. Erythropoietin beta dosage was increased to 2,000 units twice weekly without response, and weekly blood transfusions were required. Severe iron overload devel-
oped with an iron level of 123 g/dL (22.0 mol/L), total ironbinding capacity of 140 g/dL (25.1 mol/L), transferrin saturation of 88%, and ferritin level of 1,468 ng/mL (1,468 g/L). In June, he developed recurrent seizures attributed to the antibiotics, and antibiotic and erythropoietin therapy were stopped. Bone marrow examination showed abnormal features (Fig 1A). He was initiated on treatment, with recovery of blood cell count and resolution of the abnormal feature a month later (Fig 1B).
What are the common causes of anemia unresponsive to erythropoiesis-stimulating agents in dialysis patients? What is the hematologic diagnosis, and what are common causes of this condition? What were the underlying contributing factors in this patient?
American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp xxxvii-xxxix
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Figure 1. Perls stain of bone marrow (A) before and (B) after treatment.
QUIZ PAGE OCTOBER 2010 ANSWERS DISCUSSION f What are the common causes of anemia unresponsive to erythropoiesis-stimulating agents in dialysis patients? Iron deficiency is by far the most common cause. Other causes include nutritional deficiencies due to poor intake or removal by dialysis therapy. Primary hematologic and bone marrow pathologic states also should be considered when other causes have been ruled out (Box 1). f What is the hematologic diagnosis, and what are common causes of this condition? The patient has features of sideroblastic anemia because bone marrow aspiration showed ring sideroblasts (Fig 1A) accounting for 42% of marrow erythroid cells. Sideroblastic anemia is diagnosed by the presence of ring sider-
oblasts (erythroblasts containing ⱖ5 iron-positive granules around one-third or more of the nuclear perimeter) and is characterized by decreased heme synthesis and mitochondrial iron overload.1 Erythrocytes are usually hypochromic and microcytic, but may be macrocytic in acquired forms other than pyridoxine deficiency. Common causes of sideroblastic anemia are pyridoxine deficiency, myelodysplastic syndrome (refractory anemia with ring sideroblasts), drugs that affect vitamin B6 metabolism (isoniazid, pyrazinamide, and cycloserine), alcoholism, copper deficiency, zinc overload, and Dpenicillamine use.1 The hereditary form, X-linked sideroblastic anemia, is caused by mutations in the ␦-aminolevulinic acid synthase 2 (ALAS2) gene, which encodes the erythroid-specific enzyme that catalyses the first step of the heme biosynthetic pathway.1 Most cases of X-linked sideroblastic anemia respond to pyridoxine therapy because pyridoxal
Box 1. Common Causes of Anemia Nonresponse to ESAs in Dialysis Patients ●
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Deficiency states 〫 Iron deficiency from chronic blood loss, reduced intake, failure of iron absorption, and functional iron deficiency 〫 Increased loss and reduced intake: folate, L-carnitine, pyridoxine, and ascorbic acid Chronic infection and inflammation Inadequate dialysis Severe secondary hyperparathyroidism Aluminum toxicity Pure red cell aplasia from antierythropoietin antibody Unrelated to ESRD or dialysis: coexisting primary bone marrow disorders or hematologic diseases, such as thalassemia or hemolytic anemia
Abbreviations: ESA, erythropoiesis-stimulating agent; ESRD, end-stage renal disease. xxxviii
5=-phosphate is a key cofactor for ALAS.1 f What were the underlying contributing factors in this patient? Pyridoxine is a water-soluble vitamin and is dialyzable through hemodialysis and peritoneal dialysis, and pyridoxine-responsive sideroblastic anemia has been reported in hemodialysis patients.2 Other water-soluble substances, including ascorbic acid, folate, and L-carnitine, also are cleared by dialysis and can lead to anemia. Pyridoxine deficiency caused by hemodialysis may uncover occult inherited enzyme deficiencies in heme biosynthesis, such as X-linked sideroblastic anemia.3 Pyridoxine clearance is much higher in hemodialysis than continuous ambulatory peritoneal dialysis. High-flux hemodialysis further increases the clearance by almost 50%.4 According to Kasama et al,4 pyridoxine clearance with a high-flux cellulose acetate hemodialyzer was 173 mL/min, equivalent to approximately 100 L/wk, whereas according to Mydlik et al,5 its clearance was 0.91 mL/ min with 1.5% glucose peritoneal dialysate over 6 hours, equivalent to only 9 L/wk. Our patient was a nondrinker and had not been given vitamin supplementation. Coupled with poor intake from concurrent sepsis, the conversion to high-flux hemodialysis predisposed our patient to pyridoxine deficiency. Pyridoxine therapy was initi-
American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp xxxvii-xxxix
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Figure 2. Trends in the patient’s hemoglobin (Hb) and mean corpuscular volume (MCV) values after the start of pyridoxine treatment (thick arrow).
ated at 100 mg/d, with a prompt improvement in anemia. One month later, his hemoglobin level increased to 8.9 g/dL (89 g/L), with mean corpuscular volume of 93 fL and reticulocyte count of 3.3% (Fig 2). Repeated bone marrow examination showed complete disappearance of ring sideroblasts (Fig 1B). Plasma pyridoxal 5=-phosphate level 3 months after replacement was 9.4 ng/mL (reference range, 4.9-49.4 ng/mL). Although the baseline pyridoxine level was not checked, pyridoxine deficiency was evidenced by the complete reversal of sideroblastic anemia with pyridoxine therapy; in addition, sequencing of the ALAS2 gene showed no known mutations.
FINAL DIAGNOSIS Sideroblatic anemia from pyridoxine deficiency precipitated by conversion to high-flux hemodialysis therapy.
ACKNOWLEDGEMENTS We thank Dr Sing-Leung Lui for his contribution to this article.
REFERENCES 1. Sheftel AD, Richardson DR, Prchal J, Ponka P. Mitochondrial iron metabolism and sideroblastic anemia. Acta Haematol. 2009;122(2-3): 120-133. 2. Nankivell BJ. Vitamin B6 deficiency on hemodialysis causing sideroblastic anemia. Nephron. 1991; 59(4):674-675.
3. Furuyama K, Harigae H, Kinoshita C, et al. Late-onset X-linked sideroblastic anemia following hemodialysis. Blood. 2003;101(11):4623-4624. 4. Kasama R, Koch T, CanalsNavas C, Pitone JM. Vitamin B6 and hemodialysis: the impact of high-flux/ high-efficiency dialysis and review of the literature. Am J Kidney Dis. 1996;27(5):680-686. 5. Mydlík M, Derzsiová K, Svác J, Dlhopolcek P, Zemberová E. Peritoneal clearance and peritoneal transfer of oxalic acid, vitamin C, and vitamin B6 during continuous ambulatory peritoneal dialysis. Artif Organs. 1998;22(9):784-788. CASE PROVIDED AND AUTHORED BY Harinder Gill, MRCP(UK),1 Terence Yip, FHKCP,2 Chi-Chiu So, FRCPath,3 and Wai-Kei Lo, FRCP,2 1 Department of Medicine, Queen Mary Hospital; 2Department of Medicine, Tung Wah Hospital; and 3 Department of Pathology, Queen Mary Hospital, Hong Kong. Address correspondence to Wai-Kei Lo, FRCP, Department of Medicine, Tung Wah Hospital, 12 Po Yan St, Hong Kong. E-mail: [email protected] © 2010 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2010.03.015 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
QUIZ PAGE
CLINICAL PRESENTATION A 50-year-old man with end-stage renal failure from diabetic nephropathy on continuous ambulatory peritoneal dialysis therapy since 1999 was switched to high-flux hemodialysis therapy in March 2009 after an episode of Pseudomonas aeruginosa peritonitis. He was receiving erythropoietin beta at 2,000 U/wk with a hemoglobin level of approximately 10 g/dL (100 g/L). In April 2009, he developed progressive microcytic anemia as his hemoglobin level decreased to 5.6 g/dL (56 g/L), with a mean corpuscular volume of
75.9 fL, reticulocyte count of 1.8%, platelet count of 297 ⫻ 103/L (297 ⫻ 109/L), and white blood cell count of 14 ⫻ 103/L (14 ⫻ 109/L) without evidence of gastrointestinal bleeding. Concurrently, intra-abdominal abscesses caused by P aeruginosa were diagnosed, and he was treated with catheter drainage and intravenous ticarcillinclavulanic acid. Erythropoietin beta dosage was increased to 2,000 units twice weekly without response, and weekly blood transfusions were required. Severe iron overload devel-
oped with an iron level of 123 g/dL (22.0 mol/L), total ironbinding capacity of 140 g/dL (25.1 mol/L), transferrin saturation of 88%, and ferritin level of 1,468 ng/mL (1,468 g/L). In June, he developed recurrent seizures attributed to the antibiotics, and antibiotic and erythropoietin therapy were stopped. Bone marrow examination showed abnormal features (Fig 1A). He was initiated on treatment, with recovery of blood cell count and resolution of the abnormal feature a month later (Fig 1B).
What are the common causes of anemia unresponsive to erythropoiesis-stimulating agents in dialysis patients? What is the hematologic diagnosis, and what are common causes of this condition? What were the underlying contributing factors in this patient?
American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp xxxvii-xxxix
xxxvii
QUIZ PAGE
Figure 1. Perls stain of bone marrow (A) before and (B) after treatment.
QUIZ PAGE OCTOBER 2010 ANSWERS DISCUSSION f What are the common causes of anemia unresponsive to erythropoiesis-stimulating agents in dialysis patients? Iron deficiency is by far the most common cause. Other causes include nutritional deficiencies due to poor intake or removal by dialysis therapy. Primary hematologic and bone marrow pathologic states also should be considered when other causes have been ruled out (Box 1). f What is the hematologic diagnosis, and what are common causes of this condition? The patient has features of sideroblastic anemia because bone marrow aspiration showed ring sideroblasts (Fig 1A) accounting for 42% of marrow erythroid cells. Sideroblastic anemia is diagnosed by the presence of ring sider-
oblasts (erythroblasts containing ⱖ5 iron-positive granules around one-third or more of the nuclear perimeter) and is characterized by decreased heme synthesis and mitochondrial iron overload.1 Erythrocytes are usually hypochromic and microcytic, but may be macrocytic in acquired forms other than pyridoxine deficiency. Common causes of sideroblastic anemia are pyridoxine deficiency, myelodysplastic syndrome (refractory anemia with ring sideroblasts), drugs that affect vitamin B6 metabolism (isoniazid, pyrazinamide, and cycloserine), alcoholism, copper deficiency, zinc overload, and Dpenicillamine use.1 The hereditary form, X-linked sideroblastic anemia, is caused by mutations in the ␦-aminolevulinic acid synthase 2 (ALAS2) gene, which encodes the erythroid-specific enzyme that catalyses the first step of the heme biosynthetic pathway.1 Most cases of X-linked sideroblastic anemia respond to pyridoxine therapy because pyridoxal
Box 1. Common Causes of Anemia Nonresponse to ESAs in Dialysis Patients ●
● ● ● ● ●
QUIZ PAGE
●
Deficiency states 〫 Iron deficiency from chronic blood loss, reduced intake, failure of iron absorption, and functional iron deficiency 〫 Increased loss and reduced intake: folate, L-carnitine, pyridoxine, and ascorbic acid Chronic infection and inflammation Inadequate dialysis Severe secondary hyperparathyroidism Aluminum toxicity Pure red cell aplasia from antierythropoietin antibody Unrelated to ESRD or dialysis: coexisting primary bone marrow disorders or hematologic diseases, such as thalassemia or hemolytic anemia
Abbreviations: ESA, erythropoiesis-stimulating agent; ESRD, end-stage renal disease. xxxviii
5=-phosphate is a key cofactor for ALAS.1 f What were the underlying contributing factors in this patient? Pyridoxine is a water-soluble vitamin and is dialyzable through hemodialysis and peritoneal dialysis, and pyridoxine-responsive sideroblastic anemia has been reported in hemodialysis patients.2 Other water-soluble substances, including ascorbic acid, folate, and L-carnitine, also are cleared by dialysis and can lead to anemia. Pyridoxine deficiency caused by hemodialysis may uncover occult inherited enzyme deficiencies in heme biosynthesis, such as X-linked sideroblastic anemia.3 Pyridoxine clearance is much higher in hemodialysis than continuous ambulatory peritoneal dialysis. High-flux hemodialysis further increases the clearance by almost 50%.4 According to Kasama et al,4 pyridoxine clearance with a high-flux cellulose acetate hemodialyzer was 173 mL/min, equivalent to approximately 100 L/wk, whereas according to Mydlik et al,5 its clearance was 0.91 mL/ min with 1.5% glucose peritoneal dialysate over 6 hours, equivalent to only 9 L/wk. Our patient was a nondrinker and had not been given vitamin supplementation. Coupled with poor intake from concurrent sepsis, the conversion to high-flux hemodialysis predisposed our patient to pyridoxine deficiency. Pyridoxine therapy was initi-
American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp xxxvii-xxxix
xxxix
Figure 2. Trends in the patient’s hemoglobin (Hb) and mean corpuscular volume (MCV) values after the start of pyridoxine treatment (thick arrow).
ated at 100 mg/d, with a prompt improvement in anemia. One month later, his hemoglobin level increased to 8.9 g/dL (89 g/L), with mean corpuscular volume of 93 fL and reticulocyte count of 3.3% (Fig 2). Repeated bone marrow examination showed complete disappearance of ring sideroblasts (Fig 1B). Plasma pyridoxal 5=-phosphate level 3 months after replacement was 9.4 ng/mL (reference range, 4.9-49.4 ng/mL). Although the baseline pyridoxine level was not checked, pyridoxine deficiency was evidenced by the complete reversal of sideroblastic anemia with pyridoxine therapy; in addition, sequencing of the ALAS2 gene showed no known mutations.
FINAL DIAGNOSIS Sideroblatic anemia from pyridoxine deficiency precipitated by conversion to high-flux hemodialysis therapy.
ACKNOWLEDGEMENTS We thank Dr Sing-Leung Lui for his contribution to this article.
REFERENCES 1. Sheftel AD, Richardson DR, Prchal J, Ponka P. Mitochondrial iron metabolism and sideroblastic anemia. Acta Haematol. 2009;122(2-3): 120-133. 2. Nankivell BJ. Vitamin B6 deficiency on hemodialysis causing sideroblastic anemia. Nephron. 1991; 59(4):674-675.
3. Furuyama K, Harigae H, Kinoshita C, et al. Late-onset X-linked sideroblastic anemia following hemodialysis. Blood. 2003;101(11):4623-4624. 4. Kasama R, Koch T, CanalsNavas C, Pitone JM. Vitamin B6 and hemodialysis: the impact of high-flux/ high-efficiency dialysis and review of the literature. Am J Kidney Dis. 1996;27(5):680-686. 5. Mydlík M, Derzsiová K, Svác J, Dlhopolcek P, Zemberová E. Peritoneal clearance and peritoneal transfer of oxalic acid, vitamin C, and vitamin B6 during continuous ambulatory peritoneal dialysis. Artif Organs. 1998;22(9):784-788. CASE PROVIDED AND AUTHORED BY Harinder Gill, MRCP(UK),1 Terence Yip, FHKCP,2 Chi-Chiu So, FRCPath,3 and Wai-Kei Lo, FRCP,2 1 Department of Medicine, Queen Mary Hospital; 2Department of Medicine, Tung Wah Hospital; and 3 Department of Pathology, Queen Mary Hospital, Hong Kong. Address correspondence to Wai-Kei Lo, FRCP, Department of Medicine, Tung Wah Hospital, 12 Po Yan St, Hong Kong. E-mail: [email protected] © 2010 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2010.03.015 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests.
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