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In Reply to ‘Erythropoietin and Cancer: An Old Risk’
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ERYTHROPOIETIN AND CANCER: AN OLD RISK To the Editor: We read with interest the December 2008 In the Literature editorial by Crowther and Radwi1 regarding a JAMA article from Bennett et al.2 We believe it is high time to put an end to any doubts that erythropoietin-stimulating agents (ESAs) are tumor-stimulating factors. In the 1960s, Leaders et al3 and Thorling4 observed that erythropoietin (EPO) stimulated the development of some tumoral forms. EPO is argued to have a role in regenerative medicine in vitro and in vivo by stimulating angiogenesis, the persistent natural regenerative activity of humans.5 Certainly EPO receptors are present on endothelial cells, which, from an ontogenetic view point, have the same precursor as erythroblasts: hemangioblasts. The presence of EPO receptors in these cells has negative consequences in the context of cancer development, but is positive in other conditions because it can protect heart, brain, and kidney tissue.6 Bennett et al2 also emphasize that therapy with ESAs induces venous thromboembolic events, but neither they nor Crowther and Radwi1 discuss thrombopoiesis as a potential mechanistic explanation. It has been observed that recombinant human EPO radiolabeled with iodine125 binds to megakaryoblasts in bone marrow, thus confirming that specific EPO receptors are present in these cell types.7 Finally, we agree that it is of vital importance to determine the best possible approach for preventing negative effects of ESAs when administered to treat anemia in patients with cancer. We believe that transfusion therapy should be the first step in instituting therapy for anemia in patients with cancer. Only after a satisfactory hemoglobin value (⬃11 g/dL) has been achieved should “nephrological” doses of ESAs be administered for the maintenance phase (50 UI/kg of EPO alfa or beta or 50 g/kg of darbopoietin). Using this 1102
stepwise process for therapy perhaps will give us the best outcomes. Michele Buemi, MD Susanna Campo, MD Davide Bolignano, MD University of Messina Messina, Italy
ACKNOWLEDGEMENTS Financial Disclosure: None.
REFERENCES 1. Crowther M, Radwi G: Erythropoietin-stimulating agents: Ongoing concerns with safety. Am J Kidney Dis 52:1039-1041, 2008 2. Bennett CL, Silver SM, Djulbegovic B, et al: Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914-924, 2008 3. Leaders FE, Dixon RL, Osborne JW, Long JP: Erythropoietic stimulating factor (ESF) as a stimulant of tumor growth. Proc Soc Exp Biol Med 110:658-660, 1962 4. Thorling EB: On the effect of erythropoietin as an accelerant of tumour-growth. Acta Pathol Microbiol Scand 65:481-492, 1965 5. Ribatti D, Presta M, Vacca A, et al: Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 93:2627-2636, 1999 6. Brines M, Cerami A: Erythropoietin-mediated tissue protection: Reducing collateral damage from the primary injury response. J Intern Med 264:405-432, 2008 7. Fraser JK, Tan AS, Lin FK, Berridge MV: Expression of specific high-affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol 17:10-16, 1989 © 2009 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2009.03.006
IN REPLY TO ‘ERYTHROPOIETIN AND CANCER: AN OLD RISK’ We thank Drs Buemi, Campo, and Bolignano for their comments.1 We agree that research has suggested a variety of mechanisms for the adverse outcomes seen in patients with malignancies treated with erythropoietin-stimulating agents (ESAs); there is little doubt that these adverse effects are caused by effects remote from the activity of ESAs on bone marrow. As discussed by Buemi et al,1 these effects likely are mediated in part by specific cell-surface receptors and intracellular effectors for ESAs. Using ESAs for the treatment of patients with cancerassociated anemia should be undertaken only in compliance with the appropriate labeled indications for each individual
American Journal of Kidney Diseases, Vol 53, No 6 (June), 2009: pp 1102-1103
Correspondence
1103
product. Routine use in patients with cancer-associated anemia cannot be recommended and should not be endorsed because it may result in otherwise avoidable adverse outcomes, including death. Mark Crowther, MD, MSc McMaster University Ontario, Canada
ACKNOWLEDGEMENTS Financial Disclosure: None.
REFERENCE
Table 1. Salt Content of Turkish Breads and Estimated Daily Salt Intake From Bread Sodium chloride (g/100 g bread) Mean ⫾ SD 25th percentile 50th percentile 75th percentile Estimated daily intake from bread (g)*
1.82 ⫾ 0.41 1.58 1.76 2.05 7.28
Note: One hundred breads were studied from the 7 regions and 46 provinces of Turkey. The distribution of bread samples across regions and provinces was parallel to the populations of these regions and provinces. *Equal to mean sodium chloride multiplied by average bread consumption.
1. Buemi M, Campo S, Bolignano D: Erythropoietin and cancer: An old risk. Am J Kidney Dis 53:1102, 2009 (ltr) © 2009 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2009.03.007
HYPERTENSION, SALT, AND BREAD To the Editor: Hypertension is the major risk factor for development and progression in patients with chronic kidney disease (CKD) and has become the most important intervention in the management of all forms of CKD.1 The message of World Kidney Day 2009 is “Keep the pressure down.” Similarly, the theme for World Hypertension Day 2009 is “Salt and high blood pressure: two silent killers.” Reduction in dietary salt intake is one of the effective measures to prevent hypertension.2 Average salt intake is 9 to 12 g/d in the Western world; however, the daily recommended amount is no more than 6 g.2 The Relationship between Hypertension and Salt Intake in Turkish Population Study (SALTURK) showed that daily salt intake was about 18 g/person in Turkey.3 Bread is one of the major sources of calories/energy in Turkey, and average bread consumption is about 400 g/d/person. Based on these data, we suspected that bread may be a major source of salt intake in Turkey and therefore investigated the salt content of breads by using the titrimetric method. Results, as well as an estimate of daily salt intake from bread in the Turkish diet, are listed in Table 1. The estimated intake (7.28 g/d) is more than the upper limit of daily recommended amount. We suggest that local patient education programs focused on specific foods (such as the case of bread in Turkey) will decrease salt intake and be useful in
the global prevention and treatment of hypertension, CKD, and related problems. Tekin Akpolat, MD Ragıp Kadı, MD Ondokuz Mayıs University School of Medicine Samsun, Turkey Cengiz Utas¸, MD Erciyes University School of Medicine Kayseri, Turkey
ACKNOWLEDGEMENTS We thank Hasan Yetim and Safa Karaman (Erciyes University) for performing salt content measurements. Support: The study was supported by the Turkish Society of Nephrology, Kayseri Branch. Financial Disclosure: None.
REFERENCES 1. Bakris GL, Ritz E: World Kidney Day 2009: Hypertension and kidney disease is a marriage that should be prevented. Am J Kidney Dis 53:373-376, 2009 2. Chobanian AV, Bakris GL, Black HR, et al: Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42:1206-1252, 2003 3. Erdem Y, Arici M, Altun B, et al: The SALTURK (The Relationship between Hypertension and Salt Intake in Turkish Population) study. Available at: http://www.turkhipertansiyon. org/UserFiles/File/salt.pdf. Accessed February 1, 2009 © 2009 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2009.03.005
ERYTHROPOIETIN AND CANCER: AN OLD RISK To the Editor: We read with interest the December 2008 In the Literature editorial by Crowther and Radwi1 regarding a JAMA article from Bennett et al.2 We believe it is high time to put an end to any doubts that erythropoietin-stimulating agents (ESAs) are tumor-stimulating factors. In the 1960s, Leaders et al3 and Thorling4 observed that erythropoietin (EPO) stimulated the development of some tumoral forms. EPO is argued to have a role in regenerative medicine in vitro and in vivo by stimulating angiogenesis, the persistent natural regenerative activity of humans.5 Certainly EPO receptors are present on endothelial cells, which, from an ontogenetic view point, have the same precursor as erythroblasts: hemangioblasts. The presence of EPO receptors in these cells has negative consequences in the context of cancer development, but is positive in other conditions because it can protect heart, brain, and kidney tissue.6 Bennett et al2 also emphasize that therapy with ESAs induces venous thromboembolic events, but neither they nor Crowther and Radwi1 discuss thrombopoiesis as a potential mechanistic explanation. It has been observed that recombinant human EPO radiolabeled with iodine125 binds to megakaryoblasts in bone marrow, thus confirming that specific EPO receptors are present in these cell types.7 Finally, we agree that it is of vital importance to determine the best possible approach for preventing negative effects of ESAs when administered to treat anemia in patients with cancer. We believe that transfusion therapy should be the first step in instituting therapy for anemia in patients with cancer. Only after a satisfactory hemoglobin value (⬃11 g/dL) has been achieved should “nephrological” doses of ESAs be administered for the maintenance phase (50 UI/kg of EPO alfa or beta or 50 g/kg of darbopoietin). Using this 1102
stepwise process for therapy perhaps will give us the best outcomes. Michele Buemi, MD Susanna Campo, MD Davide Bolignano, MD University of Messina Messina, Italy
ACKNOWLEDGEMENTS Financial Disclosure: None.
REFERENCES 1. Crowther M, Radwi G: Erythropoietin-stimulating agents: Ongoing concerns with safety. Am J Kidney Dis 52:1039-1041, 2008 2. Bennett CL, Silver SM, Djulbegovic B, et al: Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914-924, 2008 3. Leaders FE, Dixon RL, Osborne JW, Long JP: Erythropoietic stimulating factor (ESF) as a stimulant of tumor growth. Proc Soc Exp Biol Med 110:658-660, 1962 4. Thorling EB: On the effect of erythropoietin as an accelerant of tumour-growth. Acta Pathol Microbiol Scand 65:481-492, 1965 5. Ribatti D, Presta M, Vacca A, et al: Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 93:2627-2636, 1999 6. Brines M, Cerami A: Erythropoietin-mediated tissue protection: Reducing collateral damage from the primary injury response. J Intern Med 264:405-432, 2008 7. Fraser JK, Tan AS, Lin FK, Berridge MV: Expression of specific high-affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol 17:10-16, 1989 © 2009 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2009.03.006
IN REPLY TO ‘ERYTHROPOIETIN AND CANCER: AN OLD RISK’ We thank Drs Buemi, Campo, and Bolignano for their comments.1 We agree that research has suggested a variety of mechanisms for the adverse outcomes seen in patients with malignancies treated with erythropoietin-stimulating agents (ESAs); there is little doubt that these adverse effects are caused by effects remote from the activity of ESAs on bone marrow. As discussed by Buemi et al,1 these effects likely are mediated in part by specific cell-surface receptors and intracellular effectors for ESAs. Using ESAs for the treatment of patients with cancerassociated anemia should be undertaken only in compliance with the appropriate labeled indications for each individual
American Journal of Kidney Diseases, Vol 53, No 6 (June), 2009: pp 1102-1103
Correspondence
1103
product. Routine use in patients with cancer-associated anemia cannot be recommended and should not be endorsed because it may result in otherwise avoidable adverse outcomes, including death. Mark Crowther, MD, MSc McMaster University Ontario, Canada
ACKNOWLEDGEMENTS Financial Disclosure: None.
REFERENCE
Table 1. Salt Content of Turkish Breads and Estimated Daily Salt Intake From Bread Sodium chloride (g/100 g bread) Mean ⫾ SD 25th percentile 50th percentile 75th percentile Estimated daily intake from bread (g)*
1.82 ⫾ 0.41 1.58 1.76 2.05 7.28
Note: One hundred breads were studied from the 7 regions and 46 provinces of Turkey. The distribution of bread samples across regions and provinces was parallel to the populations of these regions and provinces. *Equal to mean sodium chloride multiplied by average bread consumption.
1. Buemi M, Campo S, Bolignano D: Erythropoietin and cancer: An old risk. Am J Kidney Dis 53:1102, 2009 (ltr) © 2009 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2009.03.007
HYPERTENSION, SALT, AND BREAD To the Editor: Hypertension is the major risk factor for development and progression in patients with chronic kidney disease (CKD) and has become the most important intervention in the management of all forms of CKD.1 The message of World Kidney Day 2009 is “Keep the pressure down.” Similarly, the theme for World Hypertension Day 2009 is “Salt and high blood pressure: two silent killers.” Reduction in dietary salt intake is one of the effective measures to prevent hypertension.2 Average salt intake is 9 to 12 g/d in the Western world; however, the daily recommended amount is no more than 6 g.2 The Relationship between Hypertension and Salt Intake in Turkish Population Study (SALTURK) showed that daily salt intake was about 18 g/person in Turkey.3 Bread is one of the major sources of calories/energy in Turkey, and average bread consumption is about 400 g/d/person. Based on these data, we suspected that bread may be a major source of salt intake in Turkey and therefore investigated the salt content of breads by using the titrimetric method. Results, as well as an estimate of daily salt intake from bread in the Turkish diet, are listed in Table 1. The estimated intake (7.28 g/d) is more than the upper limit of daily recommended amount. We suggest that local patient education programs focused on specific foods (such as the case of bread in Turkey) will decrease salt intake and be useful in
the global prevention and treatment of hypertension, CKD, and related problems. Tekin Akpolat, MD Ragıp Kadı, MD Ondokuz Mayıs University School of Medicine Samsun, Turkey Cengiz Utas¸, MD Erciyes University School of Medicine Kayseri, Turkey
ACKNOWLEDGEMENTS We thank Hasan Yetim and Safa Karaman (Erciyes University) for performing salt content measurements. Support: The study was supported by the Turkish Society of Nephrology, Kayseri Branch. Financial Disclosure: None.
REFERENCES 1. Bakris GL, Ritz E: World Kidney Day 2009: Hypertension and kidney disease is a marriage that should be prevented. Am J Kidney Dis 53:373-376, 2009 2. Chobanian AV, Bakris GL, Black HR, et al: Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42:1206-1252, 2003 3. Erdem Y, Arici M, Altun B, et al: The SALTURK (The Relationship between Hypertension and Salt Intake in Turkish Population) study. Available at: http://www.turkhipertansiyon. org/UserFiles/File/salt.pdf. Accessed February 1, 2009 © 2009 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2009.03.005