| Abstract|| |
Body iron stores should be assessed regularly and accurately during erythropoietin(r-HuEPO) replacement therapy. To evaluate the accuracy of the current tests, transferrin saturation (TSAT) and serum ferritin levels, in assessing and monitoring body iron stores, we studied 24 regular hemodialysis patients (19 males, mean age 47±18 years, and mean duration on hemodialysis 15±13 months) on regular erythropoietin therapy over a 12 month period. Patients were classified as having normal, deficient, indeterminate, or overload status depending on the values of TSAT and serum ferritin. Using TSAT and serum ferritin, iron status could be determined in 16 (67%) patients only; 12 (50%) had adequate (or normal) iron status, 3 (12.5%) had iron deficiency, and one (4.2%) had iron overload. In the remaining 8 patients, iron status was indeterminate; six patients had high serum ferritin with low TSAT(functional iron deficiency), and two patients had high TSAT values and low serum ferritin. Serum ferritin alone had very low specificity in diagnosing iron overload. In conclusion, when used together, TSAT and serum ferritin have a low sensitivity for diagnosing the iron status of CKD patients on HD. When TSAT and serum ferritin values diverge, they become unreliable in guiding iron therapy, and this set of findings generally indicates functional iron deficiency. There is a clear need to use the newer indices, like reticulocyte hemoglobin concentration and percentage of hypochromic red cells, which are more sensitive. This is likely to make the diagnosis of iron status more accurate and may reduce the requirements and frequency of iron and r-HuEPO administration.
Keywords: Iron, Chronic renal Disease, Ferritin, Transferrin saturation
|How to cite this article:|
Rafi A, Karkar A, Abdelrahman M. Monitoring Iron status in End-Stage Renal Disease Patients on Hemodialysis. Saudi J Kidney Dis Transpl 2007;18:73-8
|How to cite this URL:|
Rafi A, Karkar A, Abdelrahman M. Monitoring Iron status in End-Stage Renal Disease Patients on Hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2020 Aug 13];18:73-8. Available from: http://www.sjkdt.org/text.asp?2007/18/1/73/31849
| Introduction|| |
Anemia is a major factor that limits the quality of life in chronic kidney failure (CKD) patients and may affect their morbidity and mortality. Insufficient production of erythropoietin from the failed kidneys is the major cause of anemia in this population. Several other factors, which include deficiencies of iron, folic acid, and vitamin B12, blood loss, and short half-life of red blood cells, may complicate the management of anemia.,,,
Recent advances in molecular biology have largely contributed to cloning and production of different forms of recombinant human erythropoietin (r-HuEPO), which is now regularly used, with great success, for the correction of anemia in CKD patients. However, a suboptimal response to r-HuEPO in some patients is attributed to multiple causes. These include low body stores of iron, infection, chronic inflammation, hyperparathyroidism, and aluminum intoxication. ,,
Iron deficiency is considered the most common cause of inadequate response to rHuEPO. Body iron stores should be assessed regularly and accurately. Body stores of iron are usually assessed by transferrin saturation (TSAT) levels (normal: 20%-30%) and serum ferritin levels (normal >150ng/ml). TSAT and serum ferritin are extensively used in clinical practice in monitoring iron status of patients with CKD on r-HuEPO treatment. ,,
The aim of our study is to evaluate the accuracy of the current tests, TSAT and serum ferritin, in assessing and monitoring body iron stores, which can influence iron management and r-HuEPO treatment in patients with CKD.
| Methods and patients|| |
This study included patients undergoing regular hemodialysis over a 12 month period. We studied 24 patients (19 males, mean age 47±18 years, and mean duration on hemodialysis 15±13 months). The underlying diseases were diabetes mellitus and hypertension in 14 patients, chronic glomerulonephritis in seven, and other causes in three: lupus nephritis in one patient and neurogenic bladder in two. The vascular access was arterio-venous fistula (AVF) in 13 patients and permanent catheter in 11. All patients were HbsAg and HCV negative. There was no evidence of infection or inflammation, such as fever, leukocytosis, vascular access-related sepsis, or other acute or chronic infection in the patients at the time of study. Iron status investigations were obtained within two weeks of the last dose of iron. Iron status was assessed by measuring serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT), and serum ferritin. All patients were on r-HuEPO treatment.
Patients were classified as having normal, deficient, indeterminate, or overload status depending on the values of TSAT and serum ferritin. Iron deficiency was defined as serum ferritin <150 ng/ml and TSAT <20%, while iron overload as serum ferritin >500ng/ml and TSAT >50%. Patients who had values between these limits were labeled as normal status, while those not conforming to any of these groups were classified as indeterminate. The sensitivity of these two indices to correctly diagnose iron status was calculated by dividing the number of patients correctly diagnosed for their iron status by the total number of patients and was expressed as a percentage.
| Results|| |
The mean hemoglobin and hematocrit (Hct) values of the studied patients were 93.9 ± 1.4 gm/L and 27.08 ± 4.88 %, respectively [Table - 1]. The iron indices of these patients showed the following values: serum iron 79.79 ± 53.68 ng/ml, total iron binding capacity (TIBC) 236 ± 56 ng/ml, serum ferritin 344 ± 197 ng/ml, and transferring saturation (TSAT) 33.63 ± 22.57 % [Table - 2]. The mean dose of erythropoietin (EPO) used by each patient was 8900 ± 3800 iu/week.
Using TSAT and serum ferritin, iron status could be determined in 16 (67%) patients only; 12 (50%) had adequate (or normal) iron status, 3 (12.5%) had iron deficiency, and one (4.2%) had iron overload [Table - 2]. In the remaining 8 patients, iron status was indeterminate; six patients had high serum ferritin with low TSAT (functional iron deficiency), and two patients had high TSAT values and low serum ferritin.
Seven patients had serum ferritin > 500 ng/ml; six patients had indeterminate iron status, and one had true iron overload. If we had used serum ferritin alone for monitoring the iron status of these CKD patients, 40% of these patients would have been wrongly diagnosed as having iron overload (i.e. very low specificity).
| Discussion|| |
The assessment of iron status is easy if the TSAT and serum ferritin are both low or high in the evaluated patients. However, if these two values diverge, such as if the TSAT is low while the serum ferritin is high, the diagnosis of iron status becomes difficult, and this limits the sensitivity of these parameters in diagnosing iron status. This is evidently shown in our study, where iron status could be determined in only 67% of the patients on hemodialysis using TSAT and serum ferritin, while 30% of the patients demonstrated high serum ferritin and low TSAT.
The first step in the management of iron deficiency in ESRD is to differentiate between absolute and functional iron deficiency (FID). [ 5] Absolute deficiency is due to low iron stores, while FID reflects impaired iron mobilization from stores to bone marrow as in different settings of infections and inflammation. FID may also be due to over utilization of iron from circulation by intense erythropoiesis induced by r-HuEPO therapy; in this instance, iron stores will be normal or low. In fact, FID is an important cause of widening of the gap between TSAT and serum ferritin values in CKD patients, and this reduces the diagnostic value of these two indices for iron status.  Thus, FID may be associated with high, normal, or low iron stores.
Serum ferritin is an acute phase reactant and thus may be elevated in a number of conditions, ,  including infections, inflammation, malignancy, and liver disease. Many of these conditions are common in CKD patients. This is reflected in high serum ferritin in 7 of our patients, only one of whom had iron overload, whereas the rest had indeterminate status.
Similarly, low TSAT may reflect either iron deficiency or intense erythropoiesis, causing a disequilibrium between iron stores, the circulation, and the bone marrow. In addition, TSAT is calculated as the ratio of serum iron and TIBC, and TIBC is known to fall during infections and inflammation, both of which are common in dialysis patients. If TIBC falls acutely, TSAT values may be falsely high. This may explain the high TSAT values in two of our patients in this study where serum ferritin was comparatively low, though this may also represent a laboratory error.
The difficulties in the interpretation of the above results demonstrate the need of applying more sensitive tests, such as the percentage of circulating hypochromic red cells (HRC) and reticulocyte hemoglobin concentration (CHr).,, The HRC represents the percentage of RBCs containing low hemoglobin. This can be measured by using special analyzers introduced by Green. ,,, The HRC reflects only the availability of iron, not the iron stores. An HRC of <2.5% is normal, 2.5-10% reflects indeterminate measurement, and >10% indicates definite FID. The HRC should be measured in fresh samples (< 4 hours). One limitation of HRC is the lack of availability of special analyzers.
On the other hand, reticulocyte hemoglobin concentration (CHr) is derived from simultaneous measurement of volume and hemoglobin concentration in reticulocytes. It shows diurnal and intrapatient variation., An inverse relation has been shown between CHr and r-HuEPO dose. ,  CHr measurement also requires special analyzers. A CHr of less then 26 pg indicates FID. In situations where the TSAT is low while serum ferritin is high, CHr can help in deciding about iron therapy.
Studies have shown that none of the traditional iron indices, such as TSAT and serum ferritin, have a high level of utility i.e. sensitivity and specificity of >80%.,,, Newer indices like CHr and HRC have been compared with traditional indices in monitoring iron status in CKD patients. ,  The CHr was superior to TSAT in monitoring iron status., However, Bovey et al observed that the HRC reflected integrated effects of iron stores, inflammation, and erythropoietic stimulation on iron availability in CKD patients on hemodialysis (HD).  In a randomized study of HD patients, CHr was associated with use of lower doses of intravenous iron compared to the combined use of TSAT and ferritin. However, comparisons between the HRC and CHr have been rather inconclusive. 
In conclusion, when used together, TSAT and serum ferritin have a low sensitivity for diagnosing the iron status of CKD patients on HD. When TSAT and serum ferritin values diverge, they become unreliable in guiding iron therapy, and this set of findings generally indicates FID. There is a clear need to use the newer indices like CHr and HRC, which are more sensitive. This is likely to make the diagnosis of iron status more accurate and may reduce the requirements and frequency of iron and EPO administration.
| References|| |
|1.||Schmidt RJ, Janet L, Smith RN, Jeanine R, et al. Use of the reticulocyte hemoglobin content parameter increases the efficacy of anemia management in hemodialysis patients. Dial Transplant2005; 34(4): 216-22. |
|2.||Horl WH, Cavill I, Mac Dougall IC, Schaefer RM, Sunder-Plassmann G. How to diagnose and correct iron deficiency during rHuEpo therapy: a consensus report. Nephrol Dial Transplant 1996; 11:246-50. |
|3.||National Kidney Foundation. K/DOQI Clinical practice guide lines for the treatment of anemia of chronic renal failure. Am J Kidney Dis 1997; 30(3): S192-S240. |
|4.||Macdougall IC. Monitoring of iron status and iron supplementation in patients treated with erythropoietin. Curr Opin Nephrol Hypertens 1994; 3: 620-5. [PUBMED] |
|5.||Jacobs et al. Medical management of the dialysis patient. In Davison AM et al(ed). Oxford Textbook Of Clinical Nephrology, third edition, Oxford Univ Press.2005.????? |
|6.||Macdougall IC, Cavill I, Hulme B, et al. Detection of functional iron deficiency during erythropoietin treat-ment: a new approach. BMJ 1992; 304: 225-6. [PUBMED] |
|7.||Schaefer RM, Schaefer L. The hypochromic red cell: a new parameter for monitoring of iron supplementation during rhEPO therapy. J Perinat Med 1995;23:83-8. [PUBMED] |
|8.||Braun J, Lindner K, Schreiber M, Heidler RA, Horl WH. Percentage of hypochromic red cells as predictor of erythropoietic and iron response after i.v. iron supplementation in maintenance haemodialysis patients. Nephrol Dial Transplant 1997;12: 1173-81. |
|9.||Green R. Quantitative red cell analysis: iron metabolism. In: Cavill I ed. Proceedings of the red blood cell revisited Symposium. London;1992: 22-5. |
|10.||Olmer M, Fossat C, Bouchouareb D, Purgus R. Hypochromic red cells in uremic dialysed patients receiving rHuEPO treatment. J Am Soc Nephrol 1997; 8: 206A. |
|11.||Macdougall IC. What is the most appropriate strategy to monitor functional iron deficiency in the dialyzed patient on rhEPO therapy? Merits of percentage hypochromic red cells as a marker of functional iron deficiency. Nephrol Dial Transplant 1998;13: 847-9. |
|12.||Horl WH. What is the most appropriate strategy to monitor functional iron deficiency in the dialyzed patient on rhEPO therapy? Measurement of hypochromic red cells is not the first line procedure to identify the patient with iron deficiency. Nephrol Dial Transplant 1998;13: 850-1. |
|13.||Ponchio L, Farina G, Pedrotti C, Rostei V, Bergamaschi G, Cazzola M. Recombinant human erythropoietin in hematological malignancies. In:Bauer C, Koch KM, Sciagalla P, Wieczorek L, eds. Erythropoietin: Molecular physiology and clinical applications. Marcell Dekker, Inc.,New York; 1993: 311-23. |
|14.||Fishbane S, Shapiro W, Dutka P, Valenzuela OF, Faubert J. A randomized trial of iron deficiency testing strategies in haemodialysis patients. Kidney Int 2001; 60: 2406-11. [PUBMED] [FULLTEXT]|
|15.||Cullen P, Soffker J, Hopfl M, et al. Hypochromic red cells and reticulocyte haemoglobin content as markers of irondeficient erythropoiesis in patients undergoing chronic haemodialysis. Nephrol Dial Transplant 1999;14: 659-65. [PUBMED] [FULLTEXT]|
|16.||Besarb A, Amin N, Ahsan M, et al. Optimization of epoietin therapy with intravenous therapy in hemodialysis patients. J Am Soc Nephrol 2000; 11: 530-8. |
|17.||Hasegava M, Kawamura N, Koide S, et al. Evaluation of reticulocyte hemoglobin content, percentage of hypochromic red blood cells and ratio of serum transferrin receptor level/serum iron level as markers of iron-deficiency erythropoiesis in patients undergoing haemodialysis [Japanese]. Nippon Jinzo Gakkai Shi 2000; 44: 453-63. |
|18.||Hulthen L, Lindstedt G, Lunberg PA, Hallberg L. Effect of mild infection on serum ferritin concentration: clinical and epidemiological implications. Eur J Clin Nutr 1998; 52: 376-9. |
|19.||Cavill I, Iron status as measured by serum ferritin: the marker and its limitations. Am J Kidney Dis 1999; 34: S12-7. |
|20.||Tessitore N,Solero GP, Lippe G, et al. The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant 2001, 16: 1416-23. |
|21.||Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in haemodialysis patients. J Am So Nephrol 1996; 7: 2654-7. [PUBMED] |
|22.||Mittman N, Sreedhara R, Mushnik R, et al. Reticulocyte hemoglobin predicts functional iron deficiency in haemodialysis patients receiving rHuEPO. Am J Kidney Dis 1997; 30: 912-22. |
|23.||Bovy C, Tsobo C, Crapanzano L, et al. Factors determining the percentage of hypochromic red cells in haemodialysis patients. Kidney Int 1999; 56: 1113-9. [PUBMED] [FULLTEXT]|
|24.||Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102:783-8. [PUBMED] [FULLTEXT]|
Dammam Medical Complex, PO Box 8061, Dammam-31482
[Table - 1], [Table - 2]