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Divisions of *Nephrology and Biostatistics, University of California, San Francisco, San Francisco, California; and Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
Correspondence to Dr. Chi-yuan Hsu, Division of Nephrology, University of California, San Francisco, Room 672 HSE, Box 0532, 513 Parnassus Avenue, San Francisco, CA 94143-0532. Phone: 415-353-2379; Fax: 415-476-3381; E-mail: hsuchi{at}medicine.ucsf.edu
Abstract
ABSTRACT. Much has been written on the important contribution of iron deficiency toward anemia and epoetin resistance among end-stage renal disease (ESRD) patients, but there are few studies of iron status among chronic renal insufficiency (CRI) subjects not yet requiring dialysis. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) Practice Guidelines recommend maintaining ferritin 
100 ng/ml and transferrin saturation (TSAT) 20% to ensure adequate iron supply for erythropoiesis among patients with chronic kidney disease, whether or not they are dialysis-dependent. Analysis of the nationally representative data from the Third National Health and Nutrition Examination Survey (NHANES III 1988–1994) revealed that only a minority of anemic CRI subjects in the United States met these K/DOQI targets. For example, in the range of creatinine clearance (CrCl) 30 to 50 ml/min, less than one third of men with hemoglobin <12 g/dl and women with hemoglobin <11 g/dl had ferritin 100 ng/ml and TSAT 20%. In addition, TSAT levels above 20% were independently associated with higher hemoglobin levels. Such data raise the question whether the K/DOQI targets should be reevaluated. It is concluded that ferritin and TSAT targets derived from ESRD studies may not be applicable to subjects with CRI. Further studies are needed to guide optimization of iron status and hemoglobin level in the much larger CRI population.
Availability of iron is key for optimal erythropoiesis. Much has been written on the important contribution of iron deficiency toward anemia and epoetin resistance among end-stage renal disease (ESRD) patients. The very high cost of epoetin therapy renders optimizing iron status particularly important. Hemodialysis patients are at especially high risk for iron deficiency because of blood loss associated with the dialysis procedure.
In contrast to the abundant ESRD literature, there are few studies of iron status among chronic renal insufficiency (CRI) subjects, defined here as those with decreased GFR but not requiring dialysis or transplantation (1). Recent studies, however, show that the CRI population is much larger than the ESRD population and that a substantial number of individuals with CRI are anemic (2–6).
The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) Practice Guidelines recommend maintaining ferritin 100 ng/ml and transferrin saturation (TSAT) 20% to ensure adequate iron supply for erythropoiesis (7). Although these targets are recommended for both dialysis-dependent ESRD patients and nondialysis CRI patients, the data supporting these targets are derived from studies of ESRD patients (7).
What proportion of anemic CRI subjects have ferritin 100 ng/ml and TSAT 20%? Are these targets in fact appropriate for the CRI population (8,9)? The answer to these questions have substantial public health and policy implications, given the large number of anemic CRI subjects and the enormous cost that would result from widespread and aggressive use of epoetin (or darbepoetin) in this population.
Materials and Methods
This is a follow-up study of our previous report of anemia associated with CRI analyzing data from the Third National Health and Nutrition Examination Survey (NHANES III 1988–1994) (2). NHANES III was a complex, stratified random sample of the US population designed to provide national estimates of the health and nutritional status of the civilian noninstitutionalized population (10). There were 15,837 NHANES III examinees aged >18 yr with complete measurements of hemoglobin, serum creatinine, ferritin, and TSAT (2). In the current study, we first analyzed the subset of 378 female and 191 male examinees with anemia (regardless of renal function; results presented in Table 1). Following the NKF-D/DOQI Guidelines, anemia was defined here as hemoglobin <12 g/dl in men and <11 g/dl in women. We then analyzed the subset of 3063 female and 2042 male examinees with Cockcroft-Gault creatinine clearance (CrCl) 
70 ml/min (regardless of hemoglobin level; results in Tables 2 and 3).
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Data management and statistical analyses were conducted using SAS version 8 (SAS Institute, Cary, NC) (PROC SURVEYREG and PROC SURVEYMEANS). All models of the relationship between iron indexes and hemoglobin were stratified by gender and adjusted for age, race-ethnicity, and Cockcroft-Gault CrCl (as ordinal variable) (2,13).
Results
Only a minority of anemic CRI subjects in the United States met the NKF-K/DOQI Guidelines recommended ferritin 100 ng/ml and TSAT 20% (Table 1). For example, among anemic subjects with CrCl 30 to 50 ml/min, less than one third of men or women had ferritin 100 ng/ml and TSAT 20%.
Among subjects with CrCl 70 ml/min, meeting the NKF-K/DOQI targets was associated with higher hemoglobin, independent of renal function and demographic features. For example, compared with those with ferritin 100 ng/ml and TSAT 20%, men and women with ferritin 100 ng/ml but TSAT <20% had mean hemoglobin that was lower by 0.4 and 0.3 g/dl, respectively (P = 0.004 and 0.001, respectively; Table 2). Serum ferritin levels below 25 ng/ml were associated with lower hemoglobin concentration. Levels above 100 ng/ml were not consistently associated with higher hemoglobin concentration (Table 3). In addition, there appeared to be no threshold effect at TSAT of 20%, because TSAT levels above 20% were associated with stepwise increases in hemoglobin. For example, compared with those with TSAT 20 to 30%, men with TSAT <16% had mean hemoglobin that was lower by 0.3 g/dl and those with TSAT 40% had mean hemoglobin higher by 0.6 g/dl (Table 3).
Serum ferritin or TSAT were not significantly associated with total dietary iron intake as assessed by the NHANES III 24-h dietary recall (data not shown).
Discussion
To our knowledge, this is the largest study using nationally representative data to determine the iron status of CRI subjects with anemia. We found that the majority of anemic CRI subjects in the United States would be considered iron deficient according to the current NKF-K/DOQI targets, because only a minority of men with hemoglobin <12 g/dl and women with hemoglobin <11 g/dl had ferritin 100 ng/ml and TSAT 20%. Furthermore, in this cross-sectional study, there was no threshold effect at the NKF-K/DOQI target of TSAT of 20%. Using TSAT 20% to 30% as the reference, the increase in hemoglobin associated with TSAT 40% was similar in magnitude to the decrease in hemoglobin associated with TSAT <16% (a indicator of "absolute iron deficiency").
These results bring into question whether the current K/DOQI ferritin and TSAT targets, derived from studies of ESRD patients, are applicable to CRI subjects. In this context, the ESRD population differs from the CRI (and healthy) population in several important ways. First, for those on hemodialysis, there is obligatory blood loss several times a week. Second, it is generally agreed that ESRD patients suffer from generalized inflammation, which has been ascribed to clinically apparent infection, occult vascular access infection, less-than-sterile dialysate, dialysate back leak, and nonbiocompatible membranes (14). Inflammation leads to blockage in iron utilization and "anemia of chronic disease." Ferritin levels are elevated and TIBC levels are depressed in the presence of inflammation; therefore, the diagnostic properties of these parameters may be altered in ESRD (14).
If ferritin and TSAT targets developed for the ESRD population might not be applicable to evaluating iron status in CRI subjects, what parameters should clinicians use? For those with only mild CRI, do the conventional cutoffs of ferritin 12 ng/ml and TSAT 16% apply? Following this line of reasoning, is there a level of CrCl at which clinicians should transition from the normal renal function cutoffs to the ESRD cutoffs?
Answers to these questions and development of treatment guidelines to optimize iron status and hemoglobin level in this population can only come from studies conducted specifically among CRI patients. So far, there have been few of these. Silverberg et al. (8,9) showed that intravenous (IV) iron alone increased hemoglobin concentration, even among CRI subjects who reach K/DOQI ferritin and TSAT targets. This is consistent with our observation that there is no threshold effect at TSAT 20%. However, advocating widespread use of IV iron in the CRI population is premature; the much higher alternative ferritin and TSAT targets proposed by Silverberg et al. (500 ng/ml and 40%, respectively) (15) cannot be accepted without further study. The risks and costs resulting from an aggressive IV iron strategy in the large CRI population have not been clearly defined. Potential risks include those of adverse drug reactions, iron overload, increased oxidative stress, and infection. Cost considerations must include the logistic problems of IV medication delivery in this population. It may turn out in CRI patients that parameters other than ferritin or TSAT are diagnostically superior. Ferritin and TSAT are known to have limited sensitivity and specificity in predicting bone marrow iron stores (7). A recent study by Lorenz et al. (16) of kidney transplant recipients (mean CrCl, 53 ml/min) showed that percentage of hypochromic red blood cells (HRBC) was more strongly associated with risk of anemia than either ferritin or TSAT. Ideal markers for iron deficiency should not only correlate well with degree of anemia but also predict response to iron repletion.
To conclude, using a nationally representative survey, we demonstrated that the majority of anemic CRI patients in the United States do not meet the current NKF-K/DOQI ferritin target of 100 ng/ml and TSAT target of 20%. Furthermore, TSAT levels above the current target of 20% are associated with higher hemoglobin levels, raising the question whether these targets should be reevaluated. Given the enormous cost anticipated from widespread and aggressive use of epoetin (or darbepoetin), more studies are needed to guide optimization of iron status and hemoglobin level in the large CRI population.
Acknowledgments
Drs. Hsu, McCulloch, and Curhan are supported by the National Institutes of Health (DK61520, DK58411, and DK52866).
References
This article has been cited by other articles:
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  B. S. Spinowitz, A. T. Kausz, J. Baptista, S. D. Noble, R. Sothinathan, M. V. Bernardo, L. Brenner, and B. J. G. Pereira Ferumoxytol for Treating Iron Deficiency Anemia in CKD J. Am. Soc. Nephrol., August 1, 2008; 19(8): 1599 - 1605. [Abstract] [Full Text] [PDF]
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 L. De Nicola, G. Conte, P. Chiodini, B. Cianciaruso, A. Pota, V. Bellizzi, G. Tirino, D. Avino, F. Catapano, and R. Minutolo Stability of Target Hemoglobin Levels during the First Year of Epoetin Treatment in Patients with Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., September 1, 2007; 2(5): 938 - 946. [Abstract] [Full Text] [PDF]
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W. H. Horl Clinical Aspects of Iron Use in the Anemia of Kidney Disease J. Am. Soc. Nephrol., February 1, 2007; 18(2): 382 - 393. [Full Text] [PDF]
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 M. M. Nascimento, M. E. Suliman, A. Bruchfeld, S. Y. Hayashi, R. C. Manfro, A. R. Qureshi, R. Pecoits-Filho, M. A. Pachaly, L. Renner, P. Stenvinkel, et al. The influence of hepatitis C and iron replacement therapy on plasma pentosidine levels in haemodialysis patients Nephrol. Dial. Transplant., December 1, 2004; 19(12): 3112 - 3116. [Abstract] [Full Text] [PDF]
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D. B. Van Wyck, B. G. Danielson, and G. R. Aronoff Making Sense: A Scientific Approach to Intravenous Iron Therapy J. Am. Soc. Nephrol., December 1, 2004; 15(suppl_2): S91 - S92. [Full Text] [PDF]
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