Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Association of Estimated Glomerular Filtration Rate with Hemoglobin Level in Korean Adults: The 2010–2012 Korea National Health and Nutrition Examination Survey

  • Sang Youb Han,

    Affiliation Department of Internal Medicine, Inje University Ilsan-Paik Hospital, Goyang, Korea

  • Se Won Oh,

    Affiliation Department of Internal Medicine, Inje University Ilsan-Paik Hospital, Goyang, Korea

  • Jae Won Hong,

    Affiliation Department of Internal Medicine, Inje University Ilsan-Paik Hospital, Goyang, Korea

  • Seong Yoon Yi,

    Affiliation Department of Internal Medicine, Inje University Ilsan-Paik Hospital, Goyang, Korea

  • Jung Hyun Noh,

    Affiliation Department of Internal Medicine, Inje University Ilsan-Paik Hospital, Goyang, Korea

  • Hye Ran Lee,

    Affiliation Department of Internal Medicine, Inje University Ilsan-Paik Hospital, Goyang, Korea

  • Dong-Jun Kim

    djkim@paik.ac.kr

    Affiliation Department of Internal Medicine, Inje University Ilsan-Paik Hospital, Goyang, Korea

Association of Estimated Glomerular Filtration Rate with Hemoglobin Level in Korean Adults: The 2010–2012 Korea National Health and Nutrition Examination Survey

  • Sang Youb Han, 
  • Se Won Oh, 
  • Jae Won Hong, 
  • Seong Yoon Yi, 
  • Jung Hyun Noh, 
  • Hye Ran Lee, 
  • Dong-Jun Kim
PLOS
x

Abstract

Purpose

Little is known about anemia in patients with early renal dysfunction. We aimed to investigate the association of hemoglobin level and anemia prevalence with estimated glomerular filtration rate (eGFR) decline using a nation-wide representative sample of the adult Korean population.

Methods

In total, 17,373 participants (7,296 men; weighted n = 18,330,187; mean age, 44.2±0.3 years; 9,886 women, weighted n = 18,317,454; mean age, 46.9±0.3 years) were included. eGFR was divided into 5 groups: Group 1, ≥105; Group 2, 90–104; 75–89; Group 4, 60–74; and Group 5, <60 mL/min/1.73m2.

Results

The weighted anemia prevalence rates were 2.6% in men and 12.8% in women. In men, the weighted hemoglobin level increased with a decrease in eGFR; this value peaked at an eGFR of 60–89 mL/min/1.73m2 and decreased thereafter at an eGFR of <60 mL/min/1.73m2 (15.19±0.03, 15.35±0.03, 15.53±0.03, 15.52±0.06, and 14.90±0.12 g/dL from Groups 1 to 5) after adjustment for age, college graduation, cancer history, current smoking, waist circumference, serum cholesterol level, serum triglyceride level, and diastolic blood pressure. In women, the weighted hemoglobin level increased with a decrease in eGFR; this value peaked with an eGFR of 75–89 mL/min/1.73m2 and decreased thereafter (12.90±0.03, 13.08±0.02, 13.20±0.04, 13.14±0.05, and 12.47±0.11 g/dL from Groups 1 to 5) after adjustment for menstruation, pregnancy, estrogen replacement, and the above-mentioned variables. In both sexes, the weighted prevalence of anemia with an eGFR of 60–104 mL/min/1.73m2 was significantly lower than that with an eGFR of ≥105 mL/min/1.73m2 (men, 3.2±0.4%, 1.9±0.3%, 1.8±0.3%, 2.0±0.9%, and 18.1±3.1%; women, 14.0±0.8%, 11.2±0.7%, 10.5±1.0%, 13.2±1.6%, and 32.3±3.2% from Groups 1 to 5).

Conclusions

We noted a compensatory increase in the hemoglobin level with a minor decline in kidney function (in the range of eGFR ≥60 mL/min/1.73m2) prior to a marked decrease in hemoglobin level with severe renal dysfunction.

Introduction

Anemia is a common complication of chronic kidney disease (CKD), and is associated with an increased risk of cardiovascular disease (CVD) and mortality, particularly in high-risk populations [1,2]. The National Health and Nutrition Examinational Survey (NHANES) III in the USA reported that the prevalence of anemia is increased in subjects with a glomerular filtration rate (GFR) of <60 mL/min/1.73m2[3]. Anemia associated with decreased renal function is attributed to the reduced production of erythropoietin. However, as renal function deteriorates, anemia may be attributed to other factors such as iron deficiency, blood loss, and inflammation [4,5].

Although it is well known that the prevalence of anemia is higher among cases with an eGFR of <60 mL/min/1.73m2, information on this association during early renal dysfunction is scarce, and only few studies have reported on this issue. Furthermore, the findings of most studies are not applicable to the general population, and most studies did not consider the factors that may affect the hemoglobin level [6]. In the present study, we aimed to investigate the association of hemoglobin level and prevalence of anemia with the decline in eGFR using a nation-wide representative sample of the adult Korean population.

Subjects and Methods

Study population and data collection

This study is based on data from the 2010–2012 Korea National Health and Nutrition Examination Survey (KNHANES), which is a cross-sectional and nationally representative survey conducted by the Korean Center for Disease Control and Prevention. The following information is reproduced from our previous work [7]. The KNHANES has been conducted periodically since 1998 to assess the health and nutritional status of the civilian non-institutionalized population of Korea. A representative population was recruited using population-allocation-systematic sampling with multistage stratification. The study was approved by the Institutional Review Board of Ilsan-Paik Hospital (IB-1412-056). The KNHANES dataset was made available at the request of the investigator after approval. Since the dataset did not include any personal information and the participants in KNHANES had already consented, our study was exempted by the board from the necessity to obtain participant consent.

Laboratory tests

Hemoglobin (Hb) was measured by XE-2100D (Sysmex, Kobe, Japan) in Neodin. The serum creatinine concentrations of a random sample were measured using a colourimetric method (Hitachi Automatic Analyser, Hitachi, Japan). Serum iron and Unsaturated iron binding capacity levels were measured by using the direct bathophenanthroline method (Hitachi Automatic Analyzer 7600, Hitachi, Japan), whereas serum ferritin levels were measured by using an immunoradiometric assay (1470 WIZARD gamma-counter, PerkinElmer, Finland).

The eGFR was determined using the Chronic Kidney Disease Epidemiology Collaboration formula: eGFR (ml/min/1.73 m2) = 141 × min(SCr/k,1)a × max(SCr/k,1)-1.209 × 0.993Age [1.018 if Female] × [1.159 if Black] (SCr: serum creatinine [mg/dL], k: 0.7 for females and 0.9 for males, a: -0.329 for females and -0.411 for males, min: minimum of SCr/k or 1, and max: maximum of SCr/k or 1) [8]. The results of the detailed health interviews, physical examinations, and other laboratory procedures have been published elsewhere [9].

Anemia was defined as a hemoglobin level of less than 13 g/dL in men and less than 12 g/dL in women according to the criteria of the World Health Organization [10]. Iron deficiency anemia (IDA) was defined as a transferrin saturation of less than 10% or ferritin levels of less than 15 ug/L. Obesity was defined as a BMI of ≥25 kg/m2[11]. The eGFR was classified into 5 groups: Group 1, ≥105; Group 2, 90–104; Group 3, 75–89; Group 4, 60–74; Group 5, <60 mL/min/1.73m2.

Statistical analyses

The following information is reproduced from our previous work [7]. The KNHANES participants were not randomly sampled. The survey was designed using a complex, stratified, multistage probability sampling model; thus, individual participants were not equally representative of the Korean population. To obtain representative prevalence rates from the dataset, it was necessary to consider the power of each participant (sample weight) as representative of the Korean population. After approval was obtained from the Korea Centers for Disease Control and Prevention, we received a survey dataset that included information about the survey location; strata by age, sex, and various other factors; and the sample weight for each participant. The survey sample weights, calculated while considering the sampling rate, response rate, and age/sex proportions of the reference population (2005 Korean National Census Registry), were used in all analyses to provide representative estimates of the non-institutionalized Korean civilian population.

Statistical analyses were performed using SPSS software (ver. 21.0 for Windows; SPSS, Chicago, IL, USA). To compare the weighted prevalence of anemia according to age and sex, the chi-square test was performed. We compared age- and sex-adjusted clinical characteristics according to the presence of anemia for each sex using a general linear model (GLM). Weighted and adjusted hemoglobin level, weighted and adjusted prevalence of anemia, and weighted and adjusted prevalence of IDA and non-IDA were compared among the 5 eGFR groups using the GLM. All tests were two-sided, and P-values of < .05 were considered to indicate statistical significance.

Results

Demographics and clinical characteristics of the study population

A total of 25,534 people participated in the KNHANES V-2, 2010–2012. Of those, 19,599 participants were aged 19 years and older. Among them, a total of 17,373 participants (weighted number, 36,647,641) who completed the laboratory examination were finally included in the analysis. The overall mean age was 45.0±0.2 years (95% confidence interval [CI], 44.7–46.5). The weighted mean age of the men (unweighted n = 7,296/weighted n = 18,330,187) and women (unweighted n = 9,886/weighted n = 18,317,454) were 44.2±0.3 and 46.9±0.3 years, respectively. The demographics and clinical characteristics of the study population are presented in Table 1.

Prevalence of anemia according to age and sex

The weighted prevalence of anemia was 2.6% (95% CI, 2.2–3.1) in men and 12.8% (95% CI, 12.0–13.6) in women (Table 2). In men, the weighted prevalence of anemia significantly increased with increasing age (0.9% [95% CI, 0.5–1.6] in younger adults, 2.6% [95% CI, 1.9–3.4] in middle-aged adults, and 11.1% [95% CI, 9.4–13.1] in older adults). In women, the weighted prevalence of anemia was the lowest in middle-aged adults (14.1% [95% CI, 12.8–15.4] in younger adults, 9.7% [95% CI, 8.6–10.9] in middle-aged adults, and 15.7% [95% CI, 13.9–17.8] in older adults)

thumbnail
Table 2. Estimated prevalence of anemia in the Korean adults by age and sex.

https://doi.org/10.1371/journal.pone.0150029.t002

The weighted prevalence of IDA differed between the sexes. IDA was more common among women (men: 0.7% [95% CI, 0.5–0.9] vs. women: 8.0% [95% CI, 7.3–8.7]). In men, the weighted prevalence of IDA significantly increased with increasing age (0.4% [95% CI, 0.2–0.8] in younger adults, 0.8% [95% CI, 0.5–1.2] in middle-aged adults, and 1.9% [95% CI, 1.2–2.9] in older adults). However, in women, the prevalence of IDA decreased with increasing age (10.9% [95% CI, 9.8–12.1] in younger adults, 6.2% [95% CI, 5.3–7.3] in middle-aged adults, and 2.8 [95% CI, 2.0–3.7] in older adults).

Demographic and clinical characteristics according to the presence of anemia

In weighted and age-adjusted comparisons, we noted that although anemic individuals were more likely to have a history of cancer, they were less likely to be heavy alcohol drinkers, current smokers, obese, and college graduates, and were also less likely to have lower diastolic blood pressure, serum total cholesterol levels, and serum triglyceride levels (Table 3).

thumbnail
Table 3. Weighted age and age-adjusted demographic and clinical characteristics of Korean men and women by the presence of anemia.

https://doi.org/10.1371/journal.pone.0150029.t003

Moreover, we found that anemic women were likely to have higher a rate of menstruation and pregnancy, and were more likely to be college graduates. However, they were less likely to be heavy alcohol drinkers, current smokers, and obese, and were also less likely to have lower systolic and diastolic BP, serum total cholesterol levels, and serum triglyceride levels.

Hemoglobin level according to eGFR

In men, the weighted hemoglobin level increased with a decrease in eGFR (at an eGFR of ≥90 mL/min/1.73m2); the weighted hemoglobin level then peaked at an eGFR of 60–89 mL/min/1.73m2, and decreased thereafter (at an eGFR of <60 mL/min/1.73m2) (15.19±0.03 in Group 1, 15.35±0.03 in Group 2, 15.53±0.03 in Group 3, 15.52±0.06 in Group 4, and 14.90±0.12 g/dl in Group 5) after adjustment for age, college graduation, cancer history, current smoking, waist circumference, serum cholesterol level, serum triglyceride level, and diastolic BP (Table 4, Fig 1).

thumbnail
Fig 1. Adjusted hemoglobin levels according to estimated glomerular filtration rate (eGFR).

The hemoglobin value was adjusted for age, college graduation, cancer history, current smoking, waist circumference, serum cholesterol level, serum triglyceride level, and diastolic blood pressure in men, and additionally for menstruation, pregnancy, and estrogen replacement in women. Group 1, eGFR of ≥105; Group 2, eGFR of 90–104; Group 3, eGFR of 75–89; Group 4, eGFR of 60–74; Group 5, eGFR of <59 mL/min/1.73m2. * P < .01, ** P < .05.

https://doi.org/10.1371/journal.pone.0150029.g001

In women, the weighted hemoglobin level increased with a decrease in eGFR (at an eGFR of ≥90 mL/min/1.73m2); the weighted hemoglobin level then peaked at an eGFR of 75–89 mL/min/1.73m2 (Group 3), and decreased thereafter (at an eGFR of <75 mL/min/1.73m2) (12.90±0.03 in Group 1, 13.08±0.02 in Group 2, 13.20±0.04 in Group 3, 13.14±0.05 in Group 4, and 12.47±0.11 g/dl in Group 5) after adjustment for menstruation, pregnancy, estrogen replacement, and the above-mentioned variables (Table 4, Fig 1).

Prevalence of anemia, IDA, and non-IDA according to eGFR

In both sexes, the weighted and adjusted prevalence of anemia at an eGFR of 60–104 mL/min/1.73m2 was significantly lower than that at an eGFR of ≥105 mL/min/1.73m2, whereas the weighted prevalence of anemia at an eGFR of <60 mL/min/1.73m2 was markedly higher than that at an eGFR of 60–104 mL/min/1.73m2 (men, 3.2±0.4% in Group 1, 1.9±0.3% in Group 2, 1.8±0.3% in Group 3, 2.0±0.9% in Group 4, and 18.1±3.1% in Group 5; women, 14.0±0.8% in Group 1, 11.2±0.7% in Group 2, 10.5±1.0% in Group 3, 13.2±1.6% in Group 4, and 32.3±3.2% in Group 5).

The weighted prevalence of IDA did not differ according to the eGFR in men but was likely to decrease with a decline in eGFR in women (Table 5, Fig 2).

thumbnail
Fig 2. Weighted prevalence of anemia according to estimated glomerular filtration rate (eGFR).

The weighted prevalence of anemia was adjusted for age, college graduation, cancer history, current smoking, waist circumference, serum cholesterol level, serum triglyceride level, and diastolic blood pressure in men, and additionally for menstruation, pregnancy, and estrogen replacement in women. Group 1, eGFR of ≥105; Group 2, eGFR of 90–104; Group 3, eGFR of 75–89; Group 4, eGFR of 60–74; Group 5, eGFR of <59 mL/min/1.73m2. * P < .01, ** P < .05.

https://doi.org/10.1371/journal.pone.0150029.g002

thumbnail
Table 5. Weighted and adjusted prevalence of anemia, iron deficiency anemia, and non-iron deficiency anemia in each sex.

https://doi.org/10.1371/journal.pone.0150029.t005

Discussion

In this nation-wide representative population-based analysis, the prevalence of anemia was 2.6% (IDA: 0.7%) in men and 12.8% (IDA: 8.0%) in women. The study showed that the estimated hemoglobin level increased with a decrease in the eGFR; this value then peaked at an eGFR of 60–89 mL/min/1.73m2 and decreased thereafter, following the adjustment for several factors; the estimated prevalence of anemia at an eGFR of 60–104 mL/min/1.73m2 was significantly lower than that at an eGFR of ≥105 mL/min/1.73m2; and the weighted prevalence of anemia at an eGFR of <60 mL/min/1.73 m2 was markedly higher than that at an eGFR of 60–104 mL/min/1.73m2.

Only a few reports have described the association between hemoglobin concentration and a minor decline in eGFR in patients with CKD stage 1 and 2. In the Kidney Early Evaluation Program (KEEP) study, the serum hemoglobin levels were reported to be 13.5, 13.7, and 13.5 g/dL in CKD Stages 1,2, and 3, respectively [1]. NHANES III showed a slight elevation in the hemoglobin level at an eGFR of 60–89 mL/min/1.73m2, through a graph of hemoglobin percentile versus eGFR [3]. The Atherosclerosis Risk in Communities (ARIC) study showed a subtle increase in hemoglobin concentration and decrease in anemia prevalence at an eGFR of 75–89 mL/min/1.73m2 (hemoglobin concentration of 13.1±1.3 at an eGFR of ≥90, 13.3±1.2 at an eGFR of 75–89, 13.1±1.4 at an eGFR of 60–74, and 12.6±1.4 g/dL at an eGFR of 30–59 mL/min/1.73m2; anemia prevalence of 22.1% at an eGFR of ≥90, 16.5% at an eGFR of 75–89, 23.9% at an eGFR of 60–74, and 37.5% at an eGFR of 30–59 mL/min/1.73m2)[12]. Recently, in an analysis of 145,865 adults who visited a health promotion center in Korea, Oh et al reported that a higher hemoglobin level was associated with a subtle decline in renal function at an early CKD stage [6]. Their study indicated a peak hemoglobin level at an eGFR of 50–69 mL/min/1.73m2 (women: mean [95% CI], 12.91 [12.88–12.96] at an eGFR of ≥100, 12.98 [12.96–13.01] at an eGFR of 90–99, 12.98 [12.99–13.03] at an eGFR of 80–89, 13.16 [13.15–13.18] at an eGFR of 70–79, 13.32 [13.28–13.31] at an eGFR of 60–69, and 13.41 [13.31–13.38] g/dL at an eGFR of 50–59 mL/min/1.73m2; men: mean [95% CI], 15.12 [15.09–15.16] at an eGFR of ≥100, 15.25 [15.22–15.27] at an eGFR of 90–99, 15.34 [15.32–15.35] at an eGFR of 80–89, 15.46 [15.45–15.47] at an eGFR of 70–79, 15.59 [15.58–15.61] at an eGFR of 60–69, and 15.62 [15.58–15.65] g/dL at an eGFR of 50–59 mL/min/1.73m2) [6]. All these findings were comparable with our results.

However, the above-mentioned studies have certain limitations that preclude the drawing of conclusions regarding this issue. First, the main purpose of the analyses was not the investigation of the association between hemoglobin concentration and minor decline in eGFR in population with eGFR greater than 60 mL/min/1.73m2, except for the study of Oh et al. For example, the main aim of the ARIC study was to investigate the association of kidney function and hemoglobin level with left ventricular morphology. Second, the KEEP, ARIC, and Oh et al studies were not representative of the general population. As the KEEP and ARIC studies involved a screening program that targeted the high-risk population, the prevalence of obesity, diabetes, hypertension, and cardiovascular risk factors would be much higher in the samples of these studies than in the general population. Moreover, the study of Oh et al analyzed participants who visited a health promotion center for a general check-up. Third, to examine the changes in hemoglobin level according to the decline of renal function alone, we need to adjust for several variables that could potentially affect the hemoglobin level. The adjustment of several parameters (age, college graduation, smoking history, cancer history, degree of obesity, serum lipid level, blood pressure, and menstruation history of women) in the present study facilitated the observation of a more direct association between the hemoglobin level and mild decline in renal function, with minimal concerns regarding confounding effects. Furthermore, as the prevalence of anemia is markedly higher in women than in men, it would be desirable to perform analyses after stratification according to sex. A major salient feature of this study is that it is the first report regarding the association of hemoglobin concentration and anemia prevalence with a minor decline in eGFR at earlier CKD stages from a nation-wide representative population after stratification according to sex and adjustment for several confounding factors.

The main causes of anemia in advanced CKD may be multifactorial, and include erythropoietin deficiency, uremia-induced inhibition of erythropoiesis, shorter red blood cell survival, and iron metabolism disorders [1315]. Although the pathogenesis of anemia during early CKD is unclear, angiotensin II is suggested as a possible cause of tissue hypoxia during early CKD. Initial hypoxia in a remnant kidney model is dependent on the activation of the renin-angiotensin system and hemodynamic alterations after nephron loss [16]. The activated renin-angiotensin system induces tubular sodium reabsorption and vasoconstriction of the afferent arteriole, resulting in higher oxygen consumption and relative tubular hypoxia [1719]. Peritubular cells sense low oxygen tension, produce hypoxia-inducible factor and erythropoietin, thus increasing hemoglobin synthesis [2022]. However, it is conflicting whether serum erythropoietin level is increased or not in patients with eGFR greater than 60 mL/min/1.73m2 [23,24]. In the present study, the prevalence of IDA did not differ according to eGFR in men, and but decreased according to eGFR in women. Therefore, the influence of certain causes of anemia, other than IDA, should be clarified in patients with early CKD.

Anemia is a well-known risk factor for cardiovascular morbidity and all-cause mortality in patients with CKD [25,26]. Anemia is also important in patients with an eGFR of >60 mL/min/1.73m2. In particular, among non-CKD patients with heart failure, a hemoglobin level of <13.0 g/dL is an independent risk factor of death [27]. However, patients with a hemoglobin level of <14 g/dL also show a higher mortality rate as compared to those with hemoglobin levels of 14–14.9 or >15 g/dL [28]. These results indicate that survival could be affected by subtle changes in the hemoglobin concentration, or even at a normal hemoglobin level, in patients with CKD stage 1 or 2.

This study has several limitations. The main limitation is that it is performed on a limited cross-section of the population. To clarify the causal relationship between early renal dysfunction and hemoglobin level, a longitudinal prospective study is needed. Second, we used the change in GFR based on serum creatinine level as a marker of renal dysfunction. However, the use of creatinine to estimate GFR has certain limitations in terms of tubular secretion of creatinine and the variability in creatinine generation between individuals and for the same individual [29]. Although serum cystatin C or 51Cr-EDTA GFR can be used to validate an eGFR, these tools are not available in our study. Third, the history of specific drug use, which might affect the hemoglobin level or eGFR, was not available. Fourth, no information on iron supplementation was available.

In conclusion, the estimated prevalence of anemia in Korean adults was approximately 2.6% in men and 12.8% in women. The data indicate a compensatory increase in hemoglobin level with a minor decline in kidney function, prior to a marked decrease in hemoglobin level with severe renal dysfunction (eGFR < 60 mL/min/1.73m2). However, the lower prevalence of anemia with an eGFR of 60–104 mL/min/1.73m2 could not be explained by the difference in IDA prevalence. Nevertheless, larger prospective studies of the association between hemoglobin level and early renal dysfunction, as well as re-analysis of the datasets of previous cohort studies, are required.

Author Contributions

Conceived and designed the experiments: SYH DJK. Performed the experiments: SYH DJK. Analyzed the data: DJK. Contributed reagents/materials/analysis tools: SWO JWH SYY JHN HRL. Wrote the paper: SYH DJK.

References

  1. 1. McFarlane SI, Chen SC, Whaley-Connell AT, Sowers JR, Vassalotti JA et al. (2008) Prevalence and associations of anemia of CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999–2004. Am J Kidney Dis 51:S46–S55. pmid:18359408
  2. 2. Hayashi T, Suzuki A, Shoji T, Togawa M, Okada N et al. (2000) Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure. Am J Kidney Dis 35:250–256. pmid:10676724
  3. 3. National Kidney Foundation. (2002) K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease. Am J Kidney Dis 39:S111–S169.
  4. 4. National Kidney Foundation. (2006) KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 47:S11–S145. pmid:16678659
  5. 5. Nurko S. (2006) Anemia in chronic kidney disease: Causes, diagnosis, treatment. Cleve Clin J Med 3:289–297.
  6. 6. Oh SW, Baek SH, Kim YC, Goo HS, Chin HJ et al. (2012) Higher hemoglobin level is associated with subtle declines in renal function and presence of cardiorenal risk factors in early CKD stages. Nephrol Dial Transplant 27:267–275. pmid:21669882
  7. 7. Won JC, Lee YJ, Kim JM, Han SY, Noh JH, et al. (2012) Prevalence of and Factors Associated with Albuminuria in the Korean Adult Population: The 2011 Korea National health and Nutrition Examination Survey. PLoS ONE 8:e83273.
  8. 8. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd et al. (2009) A new equation to estimate glomerular filtration rate. Ann Int Med 150 (9): 604–612. pmid:19414839
  9. 9. Korea Centers for Disease Control and Prevention (KCDC). (2013) Korea National Health and Nutrition Examination Survey. Available from http://knhanes.cdc.go.kr/accessed 27 June 2013.
  10. 10. Report of a WHO scientific group (1968) Nutritional anaemias. World Health Organ Tech Rep Ser. 405:1–40
  11. 11. WHO/IASO/IOTF (2000) The Asia-Pacific Perspective: Redefining Obesity and Its Treatment. Health Communications Australia Melbourne, Australia.
  12. 12. Astor BC, Arnett DK, Brown A, Coresh J et al. (2004) Association of kidney function and hemoglobin with left ventricular morphology among African Americans: the Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis 43: 836–845 pmid:15112174
  13. 13. Eschbach JW Jr, Funk D, Adamson J, Kuhn I, Scribner BH, Finch CA et al. (1967) Erythropoiesis in patients with renal failure undergoing chronic dialysis. N Engl J Med 276: 653–658. pmid:6018456
  14. 14. Vos FE, Schollum JB, Coulter CV, Doyle TC, Duffull SB, Walker RJ et al. (2011) Red blood cell survival in long-term dialysis patients. Am J Kidney Dis 58: 591–598. pmid:21715072
  15. 15. Babitt JL, Lin HY: Molecular mechanisms of hepcidin regulation: Implications for the anemia of CKD. Am J Kidney Dis. 2010;55: 726–741 pmid:20189278
  16. 16. Manotham K1, Tanaka T, Matsumoto M, Ohse T, Miyata T, Inagi R et al.(2004) Evidence of tubular hypoxia in the early phase in the remnant kidney model. J Am Soc nephrol. 15(5):1277–1288. pmid:15100368
  17. 17. Peti-Peterdi J, Harris RC. (2010) Macula densa sensing and signaling mechanisms of renin release. J Am Soc Nephrol. 21:1093–1096. pmid:20360309
  18. 18. Dunn A, Lo V, Donnelly S. (2007) The role of the kidney in blood volume regulation: the kidney as a regulator of the hematocrit. Am J Med Sci.334:65–71. pmid:17630596
  19. 19. Vlahakos DV, Marathias KP, Madias NE. (2010) The role of the renin-angiotensin system in the regulation of erythropoiesis. Am J Kidney Dis. 56:558–565. pmid:20400218
  20. 20. Maxwell P. (2003) HIF-1: an oxygen response system with special relevance to the kidney. J Am Soc Nephrol. 14: 2712–2722 pmid:14569080
  21. 21. Gunaratnam L, Bonventre JV. (2009) HIF in kidney disease and development. J Am Soc Nephrol. 20: 1877–1887. pmid:19118148
  22. 22. Donnelly S. (2003) Why is erythropoietin made in the kidney? The kidney functions as a 'critmeter' to regulate the hematocrit. Adv Exp Med Biol. 543:73–87 pmid:14713115
  23. 23. Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM. (1979) Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood. 54(4):877–84. pmid:476305
  24. 24. Mercadal L, Metzger M, Casadevall N, Haymann JP, Karras A, Boffa JJ, et al. (2012) Timing and determinants of erythropoietin deficiency in chronic kidney disease. Clin J Am Soc Nephrol.;7(1):35–42 pmid:22096037
  25. 25. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group (2012) KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int. suppl 2: 279–335
  26. 26. Vlagopoulos PT, Tighiouart H, Weiner DE, Griffith J, Pettitt D, Salem DN et al. (2005) Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease. J Am Soc Nephrol. 16(11):3403–3410. pmid:16162813
  27. 27. Go AS, Yang J, Ackerson LM, Lepper K, Robbins S, Massie BM et al. (2006) Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study. Circulation.13;113(23):2713–2723. pmid:16754803
  28. 28. Kim YC, Koo HS, Ahn SY, Oh SW, Kim S, Na KY et al. (2012) The low number of red blood cells is an important risk factor for all-cause mortality in the general population. Tohoku J Exp Med 227:149–159. pmid:22729150
  29. 29. Ferguson MA, Waikar SS. (2012) Established and emerging markers of kidney function. Clin Chem. 58:680–689. pmid:22311920