- Email: [email protected]
Lower hemoglobin concentrations and subsequent decline in kidney function in an apparently healthy population aged 60 year and older
Available online at www.sciencedirect.com
Clinica Chimica Acta 389 (2008) 25 – 30 www.elsevier.com/locate/clinchim
Lower hemoglobin concentrations and subsequent decline in kidney function in an apparently healthy population aged 60 year and older Ya-Ting Lee a,f , Herng-Chia Chiu b , Ho-Ming Su c , Jeng-Fu Yang d , Wen-Chol Voon c,e , Tsung-Hsien Lin c,e,⁎, Wen-Ter Lai c,e , Sheng-Hsiung Sheu c,e a
Division of Nephrology, Department of Pediatric, Kaohsiung Medical University Hospital, Taiwan, ROC Graduate Institute of Healthcare Administration, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Shi-Chuan 1st Road, Kaohsiung, 80708, Taiwan, ROC d Department of Preventive Medicine, Kaohsiung Medical University Hospital, Taiwan, ROC e Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, Taiwan, ROC f Department of Pediatric, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan, ROC b
c
Received 20 August 2007; received in revised form 19 November 2007; accepted 19 November 2007
Abstract Background: Anemia and decreased kidney function are recognized as risk factors for morbidity and mortality in the elderly. The role of hemoglobin in renal function changes among elderly patients is not fully understood. Methods: Of 1500 people screened, 121 normotensive non-diabetic elderly patients were recruited, and underwent biochemistry examinations at the baseline, second and fourth years of a 4-year longitudinal study. Serum creatinine and calculated renal parameters, including the Cockroft– Gault (CG) formula, Modification of Diet in Renal Disease (MDRD) Study and abbreviated MDRD (abMDRD) equations were used to evaluate renal function and progression of kidney disease. Chronic kidney disease (CKD) was defined as a glomerular filtration rate (GFR) of b 60 ml/min/ 1.73 m2. Multivariate regression analyses were used to explore predictors for decline in renal parameters. Results: Ages ranged from 60 to 81 year (mean: 71.8 ± 3.8). Baseline hemoglobin concentrations ranged from 11.9 to 17.3 g/dl (mean: 14.1 ± 1.1). Serum creatinine increased and CG creatinine clearance (CrCl), MDRD and abMDRD GFR decreased during follow-up (all p ≤ 0.001). The prevalence of CKD significantly increased only in those with baseline hemoglobin concentrations of b14 g/dl ( p ≤ 0.03, based on findings of both MDRD and abMDRD GFR). Baseline hemoglobin correlates with 4-year changes of MDRD and abMDRD GFR in univariate (both p b 0.001) and multivariate regression analyses (both p b 0.05). Conclusions: This longitudinal study revealed that the aging process was associated with decline of renal function in the elderly. Because hemoglobin concentrations are an independent predictor for subsequent decline in kidney function, it should be considered in the assessment of renal disease and GFR in the elderly. © 2007 Elsevier B.V. All rights reserved. Keywords: Renal function; Glomerular filtration rate; Hemoglobin; Chronic kidney disease; Aging
1. Introduction
Abbreviations: abMDRD, abbreviated Modification of Diet in Renal Disease; BMD, bone density; CG, Cockroft–Gault; CKD, chronic kidney disease; CrCl, creatinine clearance; DBP, diastolic blood pressure; MDRD, Modification of Diet in Renal Disease; SBP, systolic blood pressure. ⁎ Corresponding author. Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Shi-Chuan 1st Road, Kaohsiung, 80708, Taiwan, ROC. Tel.: +886 73121101x7738; fax: +886 73234845. E-mail address: [email protected] (T.-H. Lin). 0009-8981/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2007.11.012
Aging is associated with higher cardiovascular morbidity and mortality, partially caused by unfavorable changes in cardiovascular disease (CVD) risk factors [1]. Decreased kidney function is increasingly recognized as a risk factor for CVD mortality and all-cause mortality in the elderly [2]. Large epidemiological studies have shown that those with reduced renal function, defined as glomerular filtration rates (GFR) of b60 mL/min/1.73 m2, are at risk for the progression of kidney
26
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30
disease and development of end-stage renal disease (ESRD) [3]. The reason for this is not entirely clear, but is partly related to an excess prevalence of traditional cardiovascular risk factors, such as hypertension and diabetes, in patients with reduced GFR [4]. For elderly individuals without traditional risk factors, it is not known which factors make the subjects susceptible to reduced renal function. Therefore, it is necessary to seek risk factors which may predispose the elderly in renal function to decline. Anemia is an increasingly common medical disorder among elderly individuals, and its prevalence is known to increase with age, affecting approximately 12% of all people aged ≥ 60 year [5]. Studies have indicated that anemia in elderly individuals significantly increases the risk of mortality, and is associated with a number of comorbidities such as cardiovascular disease and chronic kidney disease (CKD), resulting in lower functional abilities and self-care deficits in the elderly [6–8]. Furthermore, lower hemoglobin concentrations are reported to have an impact on the progression of chronic kidney disease in type 2 diabetes, and in vitro and in vivo studies have found that anemia-induced renal hypoxia may be the cause [9,10]. To our knowledge, the influence of hemoglobin concentrations on renal function parameters and their decline in prospective elderly cohorts has not been reported. We have conducted a 4-year longitudinal study to investigate several physiological parameters in an elderly Chinese population living in Taiwan [11–13]. We tested the relationship between hemoglobin concentrations and the magnitude of decline of renal function in the elderly. 2. Materials and methods 2.1. Study population The participants were from a community-based longitudinal cohort study (Gerontology Research Laboratory: The Longitudinal Study of Aging), which was designed to investigate the changes of several physiological functions and structures associated with the aging process in healthy elderly persons. The details were described in a previous study [13]. Each participant recruited into the aging group needed to be free of disease at baseline. Baseline examinations were performed from October 1, 2000 to March 31, 2001, with 1500 potential candidates at the beginning. Fig. 1 indicates the number of participants at three stages of screening or examination. Inclusion criteria for healthy elderly subjects were: (1) age ≥60 year; (2) active, with no limitations in daily life; (3) no history of previously diagnosed diabetes, hypertension, ischemic heart disease or cerebrovascular accident, (4) not on any long-term medications. The Institutional Review Board, Kaohsiung Medical University l Hospital, approved this study, and all enrolled patients gave informed consent. Blood pressures were taken after resting comfortably for 10 min. A computerized automatic mercury-sphygmomanometer (CH-5000, Citizen, Tokyo, Japan) was used on the right arm while participants were in a seated position. The reading was repeated, and the mean of these 2 readings used. Body weight and height were measured and body mass index (BMI) was calculated. Subjects had blood drawn for the determination of hemoglobin, albumin, total cholesterol, sugar, blood urea nitrogen (BUN) and creatinine concentrations after an 8-h overnight fast. All measurements were repeated every 2 year, with examinations usually scheduled in the same month as the first visit to ensure the same interval of follow-up. For subjects enrolled in the present analysis, those who had baseline fasting glucose concentrations of ≤126 mg/dl and blood pressure reading of ≤ 140 mmHg in systole and ≤ 90 mmHg in diastole were finally included in the present analysis. One hundred and ninety-three subjects were enrolled initially and 144 participants completed 4 year of follow-up. Among the 144 subjects, 23 subjects were excluded because they had fasting glucose concentrations of N126 mg/dl,
Fig. 1. The percentage of chronic kidney disease (A). In all subjects (B). Based on the MDRD. (C). Based on abMDRD. NS, not significant; MDRD, modification of diet in renal disease; abMDRD, abbreviated MDRD. or blood pressure N140 mmHg in systole or N90 mmHg in diastole. A total of 121 subjects were finally included in the current study.
2.2. Laboratory methods Plasma glucose and serum albumin were detected by hexokinase, the glucose-6-phosphate dehydrogenase method and by bromcresol green method, respectively. BUN and creatinine were analyzed by urease-glutamate dehydrogenase and the Jaffe-kinetic method, respectively. Cholesterol and
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30 triglycerides were measured by enzymatic methods. Hemoglobin concentrations were determined by the sodium lauryl sulfate hemoglobin detection method. We used the same analysis methods in the same laboratory during the study.
27
predictors for decline in renal parameters, with adjustments for other covariates. All tests were 2-sided, and the concentration of significance was established as p b 0.05. The Statistical Package for the Social Sciences (SPSS) 11.0 for Windows (SPSS Inc, Chicago, IL) was used for statistical analysis.
2.3. Calculation of kidney function and definition of chronic kidney disease (CKD)
3. Results We estimated creatinine clearance (CrCl) from the serum creatinine using the most widely used equation, the Cockroft–Gault (CG) formula [14]. The CG estimate of renal function was calculated as [(140− age) × weight] / 72× (serum creatinine in mg/dl) × (0.85, if female). The estimated glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease (MDRD) Study equation [GFR= 170 × (serum creatinine in mg/dl)− 0.999 × (age)− 0.176 × (serum BUN in mg/dl)−0.170 × (serum albumin in g/dl)0.318 × (0.762, if the patient were female) [15]. We also calculated the abbreviated MDRD (abMDRD) estimate of renal function as 186.3 × (serum creatinine in mg/dl)− 1.154 × (age)− 0.203 × (0.742, if female) [16]. Chronic kidney disease (CKD) was defined as a GFR of less than 60 ml/min/ 1.73 m2. This range corresponds to stage ≥3 CKD, as defined by the National Kidney Foundation's classification scheme, and helps identify individuals with clinically significant CKD [3]. The follow-up every 2 year was chosen on the basis of a previous recommendation for an observation period of at least 2 year for valid determination of the rate of decline in GFR [17]. Accordingly, the frequency (%) of subjects with CKD was calculated at the baseline, second, and fourth year of study. Additionally, the 4-year change of serum creatinine concentrations as well as the GFR estimates by MDRD and abMDRD was also calculated. The 4-year change of a parameter is defined as the difference between values at baseline and at the end of 4 year.
2.4. Statistical analysis All data were expressed as mean ± SD. The paired t-test and McNemar test were used to evaluate the changes of continuous variables and differences of prevalence of CKD during the 4-year follow-up. Univariate correlation was analyzed using the Pearson and independent “t-tests”. Our independent covariates to correlate with changes of renal parameters included sex, age, height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), cholesterol, glucose, BUN, creatinine and hemoglobin concentrations at baseline. Subsequently, significantly correlated variables in the univariate analysis were further analyzed by multiple linear regression analysis to identify
Table 1 summarizes the general characteristics and kidney function parameters at baseline, second, and fourth year. The subjects included 94 men and 27 women (male 77.7%). Ages at the time of enrollment in the study ranged from 60 to 81 year (mean: 71.8 ± 3.8). There were no significant changes in systolic and diastolic blood pressure after 4 year in this population. Baseline hemoglobin ranged from 11.9 to 17.3 g/dl (mean: 14.1 ± 1.1). There was also no significant difference in hemoglobin concentrations between male and female subjects (14.0 ± 1.1 vs. 14.3 ± 1.1, p = 0.279). No significant change of hemoglobin concentrations was found during 4 year of follow-up. At baseline, the table also shows that the frequencies of subjects with CKD were 26% and 31%, based on estimates of GFR by MDRD and abMDRD, respectively. No significant change in these frequencies was observed during the study period. Serum creatinine was found to have gradually increased at both years 2 and 4. The decline of estimated renal function parameters between baseline and the follow-up periods also demonstrated the same pattern, with this decline being more pronounced in male subjects (all p ≦ 0.004). There was no significant change of BUN concentrations during the study period (Table 1). Fig. 1 (A,B,C) illustrates the prevalence of CKD at baseline and at the end of the 4-year study period. The prevalence of CKD at baseline was 26.4% (males 12.8%, females 74.1%) and 30.6% (males 18.1%, females 74.1%) as determined by MDRD and abMDRD, respectively (Fig. 1-A). No significant change in the
Table 1 Clinical characteristics and estimated renal parameters at different stages of study Baseline
Age (years) Height (cm) Weight (kg) SBP (mmHg) DBP (mmHg) Cholesterol (mg/dl) Glucose (mg/dl) Albumin (g/dl) BUN (mg/dl) Creatinine (mg/dl) Hemoglobin (g/dL) Estimated renal function Cockroft–Gault CrCl (ml/min) MDRD GFR (ml/min/1.73 m2) CKD based on MDRD (%) abMDRD GFR (ml/min/1.73 m2) CKD based on abMDRD (%)
The 2nd year
The 4th year
p value Year 2—baseline
Year 4—baseline
71.8 ± 3.8 162.4 ± 7.0 61.3 ± 8.9 123.6 ± 12.1 71.7 ± 8.0 192.5 ± 33.0 100.1 ± 7.9 4.14 ± 0.16 15.5 ± 3.4 1.09 ± 0.18 14.06 ± 1.10
73.8 ± 3.8 161.5 ± 7.3 60.2 ± 8.7 123.0 ± 12.9 72.1 ± 10.3 192.8 ± 29.8 99.2 ± 10.6 4.09 ± 0.14 15.4 ± 3.4 1.13 ± 0.18 14.01 ± 1.17
75.8 ± 3.8 161.0 ± 7.1 60.3 ± 8.9 126.9 ± 12.6 73.8 ± 12.0 189.5 ± 28.6 104.4 ± 13.2 3.98 ± 0.020 16.0 ± 4.0 1.15 ± 0.18 14.31 ± 1.39
– b0.001 b0.001 0.597 0.650 0.897 0.267 b0.001 0.681 b0.001 0.478
0.125 0.382 0.068 0.103 0.484 0.002 b0.001 0.349 0.015 0.151
52.6 ± 11.6 70.9 ± 15.0 26.4 69.0 ± 15.6 30.6
48.4 ± 11.3 67.5 ± 13.7 26,4 65.4 ± 14.2 37,2
46.3 ± 11.1 64.9 ± 11.2 33.1 63.4 ± 10.7 39.7
b0.001 b0.001 1.000 b0.001 0.350
b0.001 b0.001 0.302 0.001 0.169
Data are mean ± standard deviations; SBP, systolic blood pressure; DBP, diastolic blood pressure; BUN, blood urea nitrogen; CrCl, creatinine clearance; MDRD, modification of diet in renal disease; GFR, glomerular filtration rate; CKD, chronic kidney disease; abMDRD, abbreviated MDRD.
28
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30
percentage of CKD was observed at the end of the 4-year study. However, when the frequency of CKD was investigated according to hemoglobin (Hb) concentrations, subjects with initial Hb b 14.0 g/dl (n = 58, males 81%, mean age 71.9 + 4.1 year) had
Table 2 Independent predictors for magnitude of renal functional decline in the fourth year as determined by multiple regression analysis Coefficient
t
p value
− 5.029 − 1.183 0.481
b0.001 0.239 b0.001
Cockroft–Gault CrCl (Intercept = −93.03, R2 = 0.525) Sex 6.482 2.510 Baseline age 0.923 3.238 Baseline hemoglobin 1.890 1.172 Baseline creatinine 13.731 4.588 Baseline weight −0.878 − 6.983
0.013 0.002 0.084 b0.001 b0.001
MDRD GFR (Intercept = −112.564, R2 = 0.623) Sex 11.791 Baseline hemoglobin 2.184 Baseline creatinine 67.101
4.783 2.144 10.853
b0.001 0.034 b0.001
abMDRD GFR (Intercept = − 115.523, R2 = 0.655) Sex 12.426 Baseline hemoglobin 2.027 Baseline creatinine 72.031
5.107 2.016 11.803
b0.001 0.046 b0.001
2
Creatinine (Intercept = 1.397, R = 0.642) Sex − 0.181 Baseline hemoglobin − 0.018 Baseline creatinine 0.001
CrCl, creatinine clearance; MDRD, modification of diet in renal disease GFR, glomerular filtration rate; abMDRD, Abbreviated MDRD.
significant increase of CKD prevalence at the end of the 4-year study as compared to subjects with Hb concentrations N14 g/dl. Fig. 1-B and C represent the prevalence of CKD in the two groups of subjects based on MDRD and on abMDRD GFR estimates, respectively. Baseline hemoglobin is correlated with 4-year changes of creatinine (r = −0.368, p b 0.001), MDRD (r = 0.417, p b 0.001) and abMDRD (r = 0.415, p b 0.001) but has only a borderline association with 4-year changes of CG CrCl (r = 0.174, p = 0.056) (Fig. 2). Table 2 illustrates the correlation between kidney function parameters and other variables using multivariate linear regression analysis. The table shows that male gender ( p b 0.001), initial hemoglobin ( p = 0.034) and creatinine concentrations at baseline ( p b 0.001) to be significant predictors of 4-year changes of MDRD. The percentage of 4-year MDRD change variance explained by these variables was 62.3%. It has also been shown that male gender ( p b 0.001), and initial hemoglobin ( p = 0.046) and creatinine concentrations at baseline ( p b 0.001) are significant predictors of 4-year changes of abMDRD. The percentage of 4-year abMDRD change variance explained by these variables was 65.5%. There is a clearly observable trend for initial hemoglobin concentrations to serve as a predictor of 4-year changes of CG CrCl ( p = 0.084), but not for 4-year changes of creatinine. 4. Discussion Fig. 2. Regression plot showing correlation between change of estimated renal parameters and baseline hemoglobin (A) Creatine (mg/dl) (B) Cockroft–Gault creatinine clearance; (ml/min) (C) MDRD GFR and abMDRD GFR (ml/min/ 1.73 cm2). CrCl, creatinine clearance; GFR, glomerular filtration rate; MDRD, modification of diet in renal disease; abMDRD, abbreviated MDRD.
In this 4-year longitudinal study we found that, (1) the aging process was associated with the decline of renal functional parameters among the elderly. (2) We further demonstrated that baseline hemoglobin and creatinine concentrations are
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30
associated with the decline of renal functional parameters among the elderly. Those subjects among the elderly population with lower hemoglobin concentrations had a higher decline of renal functional parameters. (3) Subjects with initial hemoglobin concentrations b 14 g/dl had a significant increase of CKD prevalence after a 4 y follow-up. Aging is associated with a decreasing number of nephrons and tubular cells, as well as reduced renal blood flow [18–21]. The participation of cellular and molecular factors and subsequent accumulation of extracellular matrix components with the development of kidney fibrosis are closely related to the progression of kidney disease [22,23]. After the loss of a certain number of nephrons, the remaining nephrons undergo compensatory functional and structural adaptations. Thereafter, renal function progressively deteriorates. As noted in many of the references, there are limitations to some longitudinal and crosssectional studies of the elderly population. Elderly individuals represent survivors who may not be completely representative of the initial cohort. The cross-sectional study is also more subject to ascertainment bias than prospective studies. Our longitudinal study enrolled subjects who had accomplished 4 years of follow-up and were completely representative of the initial cohort. Furthermore, we also used the MDRD Study equation, which showed greater similarity to GFR than the CG formula in the elderly population [24]. Therefore, our data provided more reliable evidence in evaluating the effect of aging on renal function. We found that the aging process was associated with decline of renal functional parameters in the elderly. Furthermore, we also found that baseline creatinine concentrations, possibly reflecting the renal functional reserve, serve as an independent predictor for renal functional parameters in the fourth year. We think that baseline creatinine concentrations, still reflecting a continuum of risk even within the normal range, should be considered as a risk factor for declining renal function. Changes of renal function have been shown to follow the spontaneous or induced dynamicity of the pathological process in some kidney diseases. Furthermore, physiological characteristics may change with time to influence the changes of renal parameters. Several factors have been demonstrated to cause the worsening of renal function. For example, hypertension, diabetes and medications have been reported as risk factors [25,26]. None of the subjects in our study had hypertension, diabetes or long-term medications which could have influenced renal function. Therefore, something else must be contributing to these renal parameter changes. Hypoxia plays a significant role in the pathogenesis and progression of chronic renal damage [27], and lower hemoglobin concentrations are also reported to impact on the progression of kidney disease in type 2 diabetics, although the mechanisms are unclear [9]. Anemia is associated with inadequate oxygen delivery to renal tubular cells, capillary hypoperfusion, and impairment of energy generation. Furthermore, hypoxia can activate hypoxia inducing factor-1 (HIF-1) and transform growth factor-β (TGF-β) expression, which contributes to the accumulation of mesangial/tubular cell extracellular matrix with the development of kidney fibrosis [28,29]. Although the accumulation of extracellular matrix components
29
with the development of kidney fibrosis is closely related with aging to the progression of kidney disease, hypoxia may aggravate this process [22,23]. Altogether, these findings may partially explain why lower hemoglobin concentrations are an important factor in the progression of kidney disease among our elderly. Anemia is also frequently associated with chronic kidney disease (CKD). Although inadequate production of erythropoietin, leading to decreased stimulation of the bone marrow in producing red blood cells, is usually considered the cause of anemia, erythropoietin concentrations rose significantly among the normotensive non-diabetic aging subjects in a previous longitudinal study [30]. Therefore, we think that lower hemoglobin concentrations might be the cause, instead of the result, of CKD in our healthy elderly. When classifying our elderly subjects by their original readings, those with initial hemoglobin concentrations b 14 g/dl had an increase of CKD prevalence after 4 year but not those individuals with baseline hemoglobin concentrations the ≥ 14 g/dl group. This result is consistent with previous reports that hypoxia and lower hemoglobin concentrations can accelerate the progression of renal damage [9,27]. Because CKD is increasingly recognized as a risk factor for cardiovascular disease, our data supports that elderly subjects with higher hemoglobin concentrations maybe less subject to renal function deterioration and development of CKD, which might possibly reduce cardiovascular and all-cause mortality in the elderly. Anemia in older individuals is also associated with a very wide range of complications, including increased risk for mortality, cardiovascular disease, cognitive dysfunction, and longer hospitalization for elective procedures [31]. In older subjects, mildly low and low-normal hemoglobin concentrations were independently associated with increased frailty [32]. The probability of elderly patients recovering daily living activity was greater at higher hemoglobin concentrations among the hospitalized patients [33]. Because lower hemoglobin concentrations are a potentially modifiable risk factor for older adults, it appears that the strategy to maintain adequate hemoglobin concentrations may be beneficial not only for the prevention of anemia-related complications, but also for reduction of CKD risk. Future research on hemoglobin concentrations in the elderly should focus on the age-related physiological changes underlying this condition, and whether correction of anemia can reduce anemia-associated risks and improve quality of life. A previous report found that urinary creatinine excretion significantly decreased with aging, and this decline is more pronounced among males [34]. In a community-based, prospective observational study of 20-year duration, the adjusted hazard ratio of normotensive women developing CKD was higher than for normotensive men [35]. Both of the above findings have also been noted in our study. Gender differences in the progression of CKD are still controversial. Although it is not as yet fully elucidated, sex hormones may play a role in CKD by mediating alterations in the renin–angiotensin system, reduction in mesangial collagen synthesis, modification of collagen degradation, and up-regulation of nitric oxide (NO) synthesis [36].
30
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30
There were 2 limitations to this study. First, although our findings are intriguing, the results need to be replicated for confirmation in view of the small sample size. We believe we have been able to detect a difference in the decline of renal parameters, despite our small sample size, because our patient groups were well-defined at baseline and because we investigated elderly subjects who may be more predisposed to renal function alteration. Our findings of higher declines in renal function in subjects with lower hemoglobin concentrations are consistent with the published literature. Second, we did not measure erythropoietin concentrations, which may have further clarified the relationship between hemoglobin concentrations and the aging process. In conclusion, this longitudinal study revealed an association between the hemoglobin concentrations and the magnitude of renal parameters decline in an elderly Chinese cohort. Those subjects in our study population with lower hemoglobin concentrations had more rapid declines in calculated GFR. This provides further knowledge essential in the assessment of renal disease and determination of renal function in older subjects. Acknowledgments This work was supported by a National Health Research Institutes Grant (NHRI-EX93-8903PL) from the Department of Health, Executive Yuan, Taiwan, ROC. The authors are grateful for the secretarial assistance of Shin-Fang Wu and Ting-In Lin. None of the authors have any conflicts of interest to declare. References [1] Rhoades DA, Welty TK, Wang W, et al. Aging and the prevalence of cardiovascular disease risk factors in older American Indians: the strong heart study. J Am Geriatr Soc 2007;55:87–94. [2] Manjunath G, Tighiouart H, Coresh J, et al. Concentration of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 2003;63:1121–9. [3] National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1):S1–S266. [4] Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis 2000;35(4 Suppl 1):S117–31. [5] Salive ME, Cornoni-Huntley J, Guralnik JM, et al. Anemia and hemoglobin concentrations in older persons: relationship with age, gender, and health status. J Am Geriatr Soc 1992;40:489–96. [6] Ania BJ, Suman VJ, Fairbanks VF, Rademacher DM, Melton III LJ. Incidence of anemia in older people: an epidemiologic study in a well defined population. J Am Geriatr Soc 1997;45:825–31. [7] Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. JAMA 1999 12;281:1714–7. [8] Metivier F, Marchais SJ, Guerin AP, Pannier B, London GM. Pathophysiology of anaemia: focus on the heart and blood vessels. Nephrol Dial Transplant 2000;15(Suppl 3):14–8. [9] Babazono T, Hanai K, Suzuki K, et al. Lower haemoglobin concentration and subsequent decline in kidney function in type 2 diabetic adults without clinical albuminuria. Diabetologia 2006;49:1387–93. [10] Norman JT, Clark IM, Garcia PL. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int 2000;58:2351–66. [11] Lin TH, Chiu HC, Su HM, et al. The D-allele of ACE polymorphism is associated with increased magnitude of QT dispersion prolongation in elderly Chinese—4-year follow-up study. Circ J 2007;71:39–45.
[12] Lin TH, Chiu HC, Su HM, et al. Association between fasting plasma glucose and left ventricular mass/hypertrophy over 4 years in a healthy population aged 60 and older. J Am Geriatr Soc 2007;55:717–24. [13] Lin TH, Chiu HC, Lee YT, et al. The C-allele of tissue inhibitor of metalloproteinases 2 is associated with increased magnitude of QT dispersion prolongation in elderly Chinese—4-years follow-up study. Clin Chim Acta 2007;386:87–93. [14] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. [15] Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–70. [16] Levey AS, Greene T, Kusek JW. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:A0828. [17] Levey AS, Gassman JJ, Hall PM, Walker WG. Assessing the progression of renal disease in clinical studies: effects of duration of follow-up and regression to the mean. Modification of Diet in Renal Disease (MDRD) Study Group. J Am Soc Nephrol 1991;1:1087–94. [18] Epstein M. Aging and the kidney. J Am Soc Nephrol 1996;7:1106–22. [19] Meyer BR. Renal function in aging. J Am Geriatr Soc 1989;37:791–800. [20] Goyal VK. Changes with age in the human kidney. Exp Gerontol 1982;17:321–31. [21] Hollenberg NK, Adams DF, Solomon HS, Rashid A, Abrams HL, Merrill JP. Senescence and the renal vasculature in normal man. Circ Res 1974;34:309–16. [22] Remuzzi G, Ruggenenti P, Benigni A. Understanding the nature of renal disease progression. Kidney Int 1997;51:2–15. [23] Floege J, Burns MW, Alpers CE, et al. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int 1992;41:297–309. [24] Wasen E, Isoaho R, Mattila K, Vahlberg T, Kivela SL, Irjala K. Estimation of glomerular filtration rate in the elderly: a comparison of creatinine-based formulae with serum cystatin C. J Intern Med 2004;256:70–8. [25] Jacobsen P, Rossing K, Tarnow L, et al. Progression of diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int Suppl 1999;71:S101–5. [26] Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med 1994;330:877–84. [27] Eckardt KU, Bernhardt WM, Weidemann A, et al. Role of hypoxia in the pathogenesis of renal disease. Kidney Int Suppl 2005;99:S46–51. [28] Norman JT, Clark IM, Garcia PL. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int 2000;58:2351–66. [29] Sahai A, Mei C, Schrier RW, Tannen RL. Mechanisms of chronic hypoxiainduced renal cell growth. Kidney Int 1999;56:1277–81. [30] Ershler WB, Sheng S, McKelvey J, et al. Serum erythropoietin and aging: a longitudinal analysis. J Am Geriatr Soc 2005;53:1360–5. [31] Penninx BW, Pahor M, Woodman RC, Guralnik JM. Anemia in old age is associated with increased mortality and hospitalization. J Gerontol A Biol Sci Med Sci 2006;61:474–9. [32] Chaves PH, Semba RD, Leng SX, et al. Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women's Health and Aging Studies I and II. J Gerontol A Biol Sci Med Sci 2005;60:729–35. [33] Maraldi C, Volpato S, Cesari M, et al. Anemia and recovery from disability in activities of daily living in hospitalized older persons. J Am Geriatr Soc 2006;54:632–6. [34] Hosoya T, Toshima R, Icida K, Tabe A, Sakai O. Changes in renal function with aging among Japanese. Intern Med 1995;34:520–7. [35] Haroun MK, Jaar BG, Hoffman SC, Comstock GW, Klag MJ, Coresh J. Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland. J Am Soc Nephrol 2003;14: 2934–41. [36] Seliger SL, Davis C, Stehman-Breen C. Gender and the progression of renal disease. Curr Opin Nephrol Hypertens 2001;10:219–25.
Clinica Chimica Acta 389 (2008) 25 – 30 www.elsevier.com/locate/clinchim
Lower hemoglobin concentrations and subsequent decline in kidney function in an apparently healthy population aged 60 year and older Ya-Ting Lee a,f , Herng-Chia Chiu b , Ho-Ming Su c , Jeng-Fu Yang d , Wen-Chol Voon c,e , Tsung-Hsien Lin c,e,⁎, Wen-Ter Lai c,e , Sheng-Hsiung Sheu c,e a
Division of Nephrology, Department of Pediatric, Kaohsiung Medical University Hospital, Taiwan, ROC Graduate Institute of Healthcare Administration, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Shi-Chuan 1st Road, Kaohsiung, 80708, Taiwan, ROC d Department of Preventive Medicine, Kaohsiung Medical University Hospital, Taiwan, ROC e Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, Taiwan, ROC f Department of Pediatric, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan, ROC b
c
Received 20 August 2007; received in revised form 19 November 2007; accepted 19 November 2007
Abstract Background: Anemia and decreased kidney function are recognized as risk factors for morbidity and mortality in the elderly. The role of hemoglobin in renal function changes among elderly patients is not fully understood. Methods: Of 1500 people screened, 121 normotensive non-diabetic elderly patients were recruited, and underwent biochemistry examinations at the baseline, second and fourth years of a 4-year longitudinal study. Serum creatinine and calculated renal parameters, including the Cockroft– Gault (CG) formula, Modification of Diet in Renal Disease (MDRD) Study and abbreviated MDRD (abMDRD) equations were used to evaluate renal function and progression of kidney disease. Chronic kidney disease (CKD) was defined as a glomerular filtration rate (GFR) of b 60 ml/min/ 1.73 m2. Multivariate regression analyses were used to explore predictors for decline in renal parameters. Results: Ages ranged from 60 to 81 year (mean: 71.8 ± 3.8). Baseline hemoglobin concentrations ranged from 11.9 to 17.3 g/dl (mean: 14.1 ± 1.1). Serum creatinine increased and CG creatinine clearance (CrCl), MDRD and abMDRD GFR decreased during follow-up (all p ≤ 0.001). The prevalence of CKD significantly increased only in those with baseline hemoglobin concentrations of b14 g/dl ( p ≤ 0.03, based on findings of both MDRD and abMDRD GFR). Baseline hemoglobin correlates with 4-year changes of MDRD and abMDRD GFR in univariate (both p b 0.001) and multivariate regression analyses (both p b 0.05). Conclusions: This longitudinal study revealed that the aging process was associated with decline of renal function in the elderly. Because hemoglobin concentrations are an independent predictor for subsequent decline in kidney function, it should be considered in the assessment of renal disease and GFR in the elderly. © 2007 Elsevier B.V. All rights reserved. Keywords: Renal function; Glomerular filtration rate; Hemoglobin; Chronic kidney disease; Aging
1. Introduction
Abbreviations: abMDRD, abbreviated Modification of Diet in Renal Disease; BMD, bone density; CG, Cockroft–Gault; CKD, chronic kidney disease; CrCl, creatinine clearance; DBP, diastolic blood pressure; MDRD, Modification of Diet in Renal Disease; SBP, systolic blood pressure. ⁎ Corresponding author. Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Shi-Chuan 1st Road, Kaohsiung, 80708, Taiwan, ROC. Tel.: +886 73121101x7738; fax: +886 73234845. E-mail address: [email protected] (T.-H. Lin). 0009-8981/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2007.11.012
Aging is associated with higher cardiovascular morbidity and mortality, partially caused by unfavorable changes in cardiovascular disease (CVD) risk factors [1]. Decreased kidney function is increasingly recognized as a risk factor for CVD mortality and all-cause mortality in the elderly [2]. Large epidemiological studies have shown that those with reduced renal function, defined as glomerular filtration rates (GFR) of b60 mL/min/1.73 m2, are at risk for the progression of kidney
26
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30
disease and development of end-stage renal disease (ESRD) [3]. The reason for this is not entirely clear, but is partly related to an excess prevalence of traditional cardiovascular risk factors, such as hypertension and diabetes, in patients with reduced GFR [4]. For elderly individuals without traditional risk factors, it is not known which factors make the subjects susceptible to reduced renal function. Therefore, it is necessary to seek risk factors which may predispose the elderly in renal function to decline. Anemia is an increasingly common medical disorder among elderly individuals, and its prevalence is known to increase with age, affecting approximately 12% of all people aged ≥ 60 year [5]. Studies have indicated that anemia in elderly individuals significantly increases the risk of mortality, and is associated with a number of comorbidities such as cardiovascular disease and chronic kidney disease (CKD), resulting in lower functional abilities and self-care deficits in the elderly [6–8]. Furthermore, lower hemoglobin concentrations are reported to have an impact on the progression of chronic kidney disease in type 2 diabetes, and in vitro and in vivo studies have found that anemia-induced renal hypoxia may be the cause [9,10]. To our knowledge, the influence of hemoglobin concentrations on renal function parameters and their decline in prospective elderly cohorts has not been reported. We have conducted a 4-year longitudinal study to investigate several physiological parameters in an elderly Chinese population living in Taiwan [11–13]. We tested the relationship between hemoglobin concentrations and the magnitude of decline of renal function in the elderly. 2. Materials and methods 2.1. Study population The participants were from a community-based longitudinal cohort study (Gerontology Research Laboratory: The Longitudinal Study of Aging), which was designed to investigate the changes of several physiological functions and structures associated with the aging process in healthy elderly persons. The details were described in a previous study [13]. Each participant recruited into the aging group needed to be free of disease at baseline. Baseline examinations were performed from October 1, 2000 to March 31, 2001, with 1500 potential candidates at the beginning. Fig. 1 indicates the number of participants at three stages of screening or examination. Inclusion criteria for healthy elderly subjects were: (1) age ≥60 year; (2) active, with no limitations in daily life; (3) no history of previously diagnosed diabetes, hypertension, ischemic heart disease or cerebrovascular accident, (4) not on any long-term medications. The Institutional Review Board, Kaohsiung Medical University l Hospital, approved this study, and all enrolled patients gave informed consent. Blood pressures were taken after resting comfortably for 10 min. A computerized automatic mercury-sphygmomanometer (CH-5000, Citizen, Tokyo, Japan) was used on the right arm while participants were in a seated position. The reading was repeated, and the mean of these 2 readings used. Body weight and height were measured and body mass index (BMI) was calculated. Subjects had blood drawn for the determination of hemoglobin, albumin, total cholesterol, sugar, blood urea nitrogen (BUN) and creatinine concentrations after an 8-h overnight fast. All measurements were repeated every 2 year, with examinations usually scheduled in the same month as the first visit to ensure the same interval of follow-up. For subjects enrolled in the present analysis, those who had baseline fasting glucose concentrations of ≤126 mg/dl and blood pressure reading of ≤ 140 mmHg in systole and ≤ 90 mmHg in diastole were finally included in the present analysis. One hundred and ninety-three subjects were enrolled initially and 144 participants completed 4 year of follow-up. Among the 144 subjects, 23 subjects were excluded because they had fasting glucose concentrations of N126 mg/dl,
Fig. 1. The percentage of chronic kidney disease (A). In all subjects (B). Based on the MDRD. (C). Based on abMDRD. NS, not significant; MDRD, modification of diet in renal disease; abMDRD, abbreviated MDRD. or blood pressure N140 mmHg in systole or N90 mmHg in diastole. A total of 121 subjects were finally included in the current study.
2.2. Laboratory methods Plasma glucose and serum albumin were detected by hexokinase, the glucose-6-phosphate dehydrogenase method and by bromcresol green method, respectively. BUN and creatinine were analyzed by urease-glutamate dehydrogenase and the Jaffe-kinetic method, respectively. Cholesterol and
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30 triglycerides were measured by enzymatic methods. Hemoglobin concentrations were determined by the sodium lauryl sulfate hemoglobin detection method. We used the same analysis methods in the same laboratory during the study.
27
predictors for decline in renal parameters, with adjustments for other covariates. All tests were 2-sided, and the concentration of significance was established as p b 0.05. The Statistical Package for the Social Sciences (SPSS) 11.0 for Windows (SPSS Inc, Chicago, IL) was used for statistical analysis.
2.3. Calculation of kidney function and definition of chronic kidney disease (CKD)
3. Results We estimated creatinine clearance (CrCl) from the serum creatinine using the most widely used equation, the Cockroft–Gault (CG) formula [14]. The CG estimate of renal function was calculated as [(140− age) × weight] / 72× (serum creatinine in mg/dl) × (0.85, if female). The estimated glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease (MDRD) Study equation [GFR= 170 × (serum creatinine in mg/dl)− 0.999 × (age)− 0.176 × (serum BUN in mg/dl)−0.170 × (serum albumin in g/dl)0.318 × (0.762, if the patient were female) [15]. We also calculated the abbreviated MDRD (abMDRD) estimate of renal function as 186.3 × (serum creatinine in mg/dl)− 1.154 × (age)− 0.203 × (0.742, if female) [16]. Chronic kidney disease (CKD) was defined as a GFR of less than 60 ml/min/ 1.73 m2. This range corresponds to stage ≥3 CKD, as defined by the National Kidney Foundation's classification scheme, and helps identify individuals with clinically significant CKD [3]. The follow-up every 2 year was chosen on the basis of a previous recommendation for an observation period of at least 2 year for valid determination of the rate of decline in GFR [17]. Accordingly, the frequency (%) of subjects with CKD was calculated at the baseline, second, and fourth year of study. Additionally, the 4-year change of serum creatinine concentrations as well as the GFR estimates by MDRD and abMDRD was also calculated. The 4-year change of a parameter is defined as the difference between values at baseline and at the end of 4 year.
2.4. Statistical analysis All data were expressed as mean ± SD. The paired t-test and McNemar test were used to evaluate the changes of continuous variables and differences of prevalence of CKD during the 4-year follow-up. Univariate correlation was analyzed using the Pearson and independent “t-tests”. Our independent covariates to correlate with changes of renal parameters included sex, age, height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), cholesterol, glucose, BUN, creatinine and hemoglobin concentrations at baseline. Subsequently, significantly correlated variables in the univariate analysis were further analyzed by multiple linear regression analysis to identify
Table 1 summarizes the general characteristics and kidney function parameters at baseline, second, and fourth year. The subjects included 94 men and 27 women (male 77.7%). Ages at the time of enrollment in the study ranged from 60 to 81 year (mean: 71.8 ± 3.8). There were no significant changes in systolic and diastolic blood pressure after 4 year in this population. Baseline hemoglobin ranged from 11.9 to 17.3 g/dl (mean: 14.1 ± 1.1). There was also no significant difference in hemoglobin concentrations between male and female subjects (14.0 ± 1.1 vs. 14.3 ± 1.1, p = 0.279). No significant change of hemoglobin concentrations was found during 4 year of follow-up. At baseline, the table also shows that the frequencies of subjects with CKD were 26% and 31%, based on estimates of GFR by MDRD and abMDRD, respectively. No significant change in these frequencies was observed during the study period. Serum creatinine was found to have gradually increased at both years 2 and 4. The decline of estimated renal function parameters between baseline and the follow-up periods also demonstrated the same pattern, with this decline being more pronounced in male subjects (all p ≦ 0.004). There was no significant change of BUN concentrations during the study period (Table 1). Fig. 1 (A,B,C) illustrates the prevalence of CKD at baseline and at the end of the 4-year study period. The prevalence of CKD at baseline was 26.4% (males 12.8%, females 74.1%) and 30.6% (males 18.1%, females 74.1%) as determined by MDRD and abMDRD, respectively (Fig. 1-A). No significant change in the
Table 1 Clinical characteristics and estimated renal parameters at different stages of study Baseline
Age (years) Height (cm) Weight (kg) SBP (mmHg) DBP (mmHg) Cholesterol (mg/dl) Glucose (mg/dl) Albumin (g/dl) BUN (mg/dl) Creatinine (mg/dl) Hemoglobin (g/dL) Estimated renal function Cockroft–Gault CrCl (ml/min) MDRD GFR (ml/min/1.73 m2) CKD based on MDRD (%) abMDRD GFR (ml/min/1.73 m2) CKD based on abMDRD (%)
The 2nd year
The 4th year
p value Year 2—baseline
Year 4—baseline
71.8 ± 3.8 162.4 ± 7.0 61.3 ± 8.9 123.6 ± 12.1 71.7 ± 8.0 192.5 ± 33.0 100.1 ± 7.9 4.14 ± 0.16 15.5 ± 3.4 1.09 ± 0.18 14.06 ± 1.10
73.8 ± 3.8 161.5 ± 7.3 60.2 ± 8.7 123.0 ± 12.9 72.1 ± 10.3 192.8 ± 29.8 99.2 ± 10.6 4.09 ± 0.14 15.4 ± 3.4 1.13 ± 0.18 14.01 ± 1.17
75.8 ± 3.8 161.0 ± 7.1 60.3 ± 8.9 126.9 ± 12.6 73.8 ± 12.0 189.5 ± 28.6 104.4 ± 13.2 3.98 ± 0.020 16.0 ± 4.0 1.15 ± 0.18 14.31 ± 1.39
– b0.001 b0.001 0.597 0.650 0.897 0.267 b0.001 0.681 b0.001 0.478
0.125 0.382 0.068 0.103 0.484 0.002 b0.001 0.349 0.015 0.151
52.6 ± 11.6 70.9 ± 15.0 26.4 69.0 ± 15.6 30.6
48.4 ± 11.3 67.5 ± 13.7 26,4 65.4 ± 14.2 37,2
46.3 ± 11.1 64.9 ± 11.2 33.1 63.4 ± 10.7 39.7
b0.001 b0.001 1.000 b0.001 0.350
b0.001 b0.001 0.302 0.001 0.169
Data are mean ± standard deviations; SBP, systolic blood pressure; DBP, diastolic blood pressure; BUN, blood urea nitrogen; CrCl, creatinine clearance; MDRD, modification of diet in renal disease; GFR, glomerular filtration rate; CKD, chronic kidney disease; abMDRD, abbreviated MDRD.
28
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30
percentage of CKD was observed at the end of the 4-year study. However, when the frequency of CKD was investigated according to hemoglobin (Hb) concentrations, subjects with initial Hb b 14.0 g/dl (n = 58, males 81%, mean age 71.9 + 4.1 year) had
Table 2 Independent predictors for magnitude of renal functional decline in the fourth year as determined by multiple regression analysis Coefficient
t
p value
− 5.029 − 1.183 0.481
b0.001 0.239 b0.001
Cockroft–Gault CrCl (Intercept = −93.03, R2 = 0.525) Sex 6.482 2.510 Baseline age 0.923 3.238 Baseline hemoglobin 1.890 1.172 Baseline creatinine 13.731 4.588 Baseline weight −0.878 − 6.983
0.013 0.002 0.084 b0.001 b0.001
MDRD GFR (Intercept = −112.564, R2 = 0.623) Sex 11.791 Baseline hemoglobin 2.184 Baseline creatinine 67.101
4.783 2.144 10.853
b0.001 0.034 b0.001
abMDRD GFR (Intercept = − 115.523, R2 = 0.655) Sex 12.426 Baseline hemoglobin 2.027 Baseline creatinine 72.031
5.107 2.016 11.803
b0.001 0.046 b0.001
2
Creatinine (Intercept = 1.397, R = 0.642) Sex − 0.181 Baseline hemoglobin − 0.018 Baseline creatinine 0.001
CrCl, creatinine clearance; MDRD, modification of diet in renal disease GFR, glomerular filtration rate; abMDRD, Abbreviated MDRD.
significant increase of CKD prevalence at the end of the 4-year study as compared to subjects with Hb concentrations N14 g/dl. Fig. 1-B and C represent the prevalence of CKD in the two groups of subjects based on MDRD and on abMDRD GFR estimates, respectively. Baseline hemoglobin is correlated with 4-year changes of creatinine (r = −0.368, p b 0.001), MDRD (r = 0.417, p b 0.001) and abMDRD (r = 0.415, p b 0.001) but has only a borderline association with 4-year changes of CG CrCl (r = 0.174, p = 0.056) (Fig. 2). Table 2 illustrates the correlation between kidney function parameters and other variables using multivariate linear regression analysis. The table shows that male gender ( p b 0.001), initial hemoglobin ( p = 0.034) and creatinine concentrations at baseline ( p b 0.001) to be significant predictors of 4-year changes of MDRD. The percentage of 4-year MDRD change variance explained by these variables was 62.3%. It has also been shown that male gender ( p b 0.001), and initial hemoglobin ( p = 0.046) and creatinine concentrations at baseline ( p b 0.001) are significant predictors of 4-year changes of abMDRD. The percentage of 4-year abMDRD change variance explained by these variables was 65.5%. There is a clearly observable trend for initial hemoglobin concentrations to serve as a predictor of 4-year changes of CG CrCl ( p = 0.084), but not for 4-year changes of creatinine. 4. Discussion Fig. 2. Regression plot showing correlation between change of estimated renal parameters and baseline hemoglobin (A) Creatine (mg/dl) (B) Cockroft–Gault creatinine clearance; (ml/min) (C) MDRD GFR and abMDRD GFR (ml/min/ 1.73 cm2). CrCl, creatinine clearance; GFR, glomerular filtration rate; MDRD, modification of diet in renal disease; abMDRD, abbreviated MDRD.
In this 4-year longitudinal study we found that, (1) the aging process was associated with the decline of renal functional parameters among the elderly. (2) We further demonstrated that baseline hemoglobin and creatinine concentrations are
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30
associated with the decline of renal functional parameters among the elderly. Those subjects among the elderly population with lower hemoglobin concentrations had a higher decline of renal functional parameters. (3) Subjects with initial hemoglobin concentrations b 14 g/dl had a significant increase of CKD prevalence after a 4 y follow-up. Aging is associated with a decreasing number of nephrons and tubular cells, as well as reduced renal blood flow [18–21]. The participation of cellular and molecular factors and subsequent accumulation of extracellular matrix components with the development of kidney fibrosis are closely related to the progression of kidney disease [22,23]. After the loss of a certain number of nephrons, the remaining nephrons undergo compensatory functional and structural adaptations. Thereafter, renal function progressively deteriorates. As noted in many of the references, there are limitations to some longitudinal and crosssectional studies of the elderly population. Elderly individuals represent survivors who may not be completely representative of the initial cohort. The cross-sectional study is also more subject to ascertainment bias than prospective studies. Our longitudinal study enrolled subjects who had accomplished 4 years of follow-up and were completely representative of the initial cohort. Furthermore, we also used the MDRD Study equation, which showed greater similarity to GFR than the CG formula in the elderly population [24]. Therefore, our data provided more reliable evidence in evaluating the effect of aging on renal function. We found that the aging process was associated with decline of renal functional parameters in the elderly. Furthermore, we also found that baseline creatinine concentrations, possibly reflecting the renal functional reserve, serve as an independent predictor for renal functional parameters in the fourth year. We think that baseline creatinine concentrations, still reflecting a continuum of risk even within the normal range, should be considered as a risk factor for declining renal function. Changes of renal function have been shown to follow the spontaneous or induced dynamicity of the pathological process in some kidney diseases. Furthermore, physiological characteristics may change with time to influence the changes of renal parameters. Several factors have been demonstrated to cause the worsening of renal function. For example, hypertension, diabetes and medications have been reported as risk factors [25,26]. None of the subjects in our study had hypertension, diabetes or long-term medications which could have influenced renal function. Therefore, something else must be contributing to these renal parameter changes. Hypoxia plays a significant role in the pathogenesis and progression of chronic renal damage [27], and lower hemoglobin concentrations are also reported to impact on the progression of kidney disease in type 2 diabetics, although the mechanisms are unclear [9]. Anemia is associated with inadequate oxygen delivery to renal tubular cells, capillary hypoperfusion, and impairment of energy generation. Furthermore, hypoxia can activate hypoxia inducing factor-1 (HIF-1) and transform growth factor-β (TGF-β) expression, which contributes to the accumulation of mesangial/tubular cell extracellular matrix with the development of kidney fibrosis [28,29]. Although the accumulation of extracellular matrix components
29
with the development of kidney fibrosis is closely related with aging to the progression of kidney disease, hypoxia may aggravate this process [22,23]. Altogether, these findings may partially explain why lower hemoglobin concentrations are an important factor in the progression of kidney disease among our elderly. Anemia is also frequently associated with chronic kidney disease (CKD). Although inadequate production of erythropoietin, leading to decreased stimulation of the bone marrow in producing red blood cells, is usually considered the cause of anemia, erythropoietin concentrations rose significantly among the normotensive non-diabetic aging subjects in a previous longitudinal study [30]. Therefore, we think that lower hemoglobin concentrations might be the cause, instead of the result, of CKD in our healthy elderly. When classifying our elderly subjects by their original readings, those with initial hemoglobin concentrations b 14 g/dl had an increase of CKD prevalence after 4 year but not those individuals with baseline hemoglobin concentrations the ≥ 14 g/dl group. This result is consistent with previous reports that hypoxia and lower hemoglobin concentrations can accelerate the progression of renal damage [9,27]. Because CKD is increasingly recognized as a risk factor for cardiovascular disease, our data supports that elderly subjects with higher hemoglobin concentrations maybe less subject to renal function deterioration and development of CKD, which might possibly reduce cardiovascular and all-cause mortality in the elderly. Anemia in older individuals is also associated with a very wide range of complications, including increased risk for mortality, cardiovascular disease, cognitive dysfunction, and longer hospitalization for elective procedures [31]. In older subjects, mildly low and low-normal hemoglobin concentrations were independently associated with increased frailty [32]. The probability of elderly patients recovering daily living activity was greater at higher hemoglobin concentrations among the hospitalized patients [33]. Because lower hemoglobin concentrations are a potentially modifiable risk factor for older adults, it appears that the strategy to maintain adequate hemoglobin concentrations may be beneficial not only for the prevention of anemia-related complications, but also for reduction of CKD risk. Future research on hemoglobin concentrations in the elderly should focus on the age-related physiological changes underlying this condition, and whether correction of anemia can reduce anemia-associated risks and improve quality of life. A previous report found that urinary creatinine excretion significantly decreased with aging, and this decline is more pronounced among males [34]. In a community-based, prospective observational study of 20-year duration, the adjusted hazard ratio of normotensive women developing CKD was higher than for normotensive men [35]. Both of the above findings have also been noted in our study. Gender differences in the progression of CKD are still controversial. Although it is not as yet fully elucidated, sex hormones may play a role in CKD by mediating alterations in the renin–angiotensin system, reduction in mesangial collagen synthesis, modification of collagen degradation, and up-regulation of nitric oxide (NO) synthesis [36].
30
Y.-T. Lee et al. / Clinica Chimica Acta 389 (2008) 25–30
There were 2 limitations to this study. First, although our findings are intriguing, the results need to be replicated for confirmation in view of the small sample size. We believe we have been able to detect a difference in the decline of renal parameters, despite our small sample size, because our patient groups were well-defined at baseline and because we investigated elderly subjects who may be more predisposed to renal function alteration. Our findings of higher declines in renal function in subjects with lower hemoglobin concentrations are consistent with the published literature. Second, we did not measure erythropoietin concentrations, which may have further clarified the relationship between hemoglobin concentrations and the aging process. In conclusion, this longitudinal study revealed an association between the hemoglobin concentrations and the magnitude of renal parameters decline in an elderly Chinese cohort. Those subjects in our study population with lower hemoglobin concentrations had more rapid declines in calculated GFR. This provides further knowledge essential in the assessment of renal disease and determination of renal function in older subjects. Acknowledgments This work was supported by a National Health Research Institutes Grant (NHRI-EX93-8903PL) from the Department of Health, Executive Yuan, Taiwan, ROC. The authors are grateful for the secretarial assistance of Shin-Fang Wu and Ting-In Lin. None of the authors have any conflicts of interest to declare. References [1] Rhoades DA, Welty TK, Wang W, et al. Aging and the prevalence of cardiovascular disease risk factors in older American Indians: the strong heart study. J Am Geriatr Soc 2007;55:87–94. [2] Manjunath G, Tighiouart H, Coresh J, et al. Concentration of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 2003;63:1121–9. [3] National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1):S1–S266. [4] Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis 2000;35(4 Suppl 1):S117–31. [5] Salive ME, Cornoni-Huntley J, Guralnik JM, et al. Anemia and hemoglobin concentrations in older persons: relationship with age, gender, and health status. J Am Geriatr Soc 1992;40:489–96. [6] Ania BJ, Suman VJ, Fairbanks VF, Rademacher DM, Melton III LJ. Incidence of anemia in older people: an epidemiologic study in a well defined population. J Am Geriatr Soc 1997;45:825–31. [7] Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. JAMA 1999 12;281:1714–7. [8] Metivier F, Marchais SJ, Guerin AP, Pannier B, London GM. Pathophysiology of anaemia: focus on the heart and blood vessels. Nephrol Dial Transplant 2000;15(Suppl 3):14–8. [9] Babazono T, Hanai K, Suzuki K, et al. Lower haemoglobin concentration and subsequent decline in kidney function in type 2 diabetic adults without clinical albuminuria. Diabetologia 2006;49:1387–93. [10] Norman JT, Clark IM, Garcia PL. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int 2000;58:2351–66. [11] Lin TH, Chiu HC, Su HM, et al. The D-allele of ACE polymorphism is associated with increased magnitude of QT dispersion prolongation in elderly Chinese—4-year follow-up study. Circ J 2007;71:39–45.
[12] Lin TH, Chiu HC, Su HM, et al. Association between fasting plasma glucose and left ventricular mass/hypertrophy over 4 years in a healthy population aged 60 and older. J Am Geriatr Soc 2007;55:717–24. [13] Lin TH, Chiu HC, Lee YT, et al. The C-allele of tissue inhibitor of metalloproteinases 2 is associated with increased magnitude of QT dispersion prolongation in elderly Chinese—4-years follow-up study. Clin Chim Acta 2007;386:87–93. [14] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. [15] Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–70. [16] Levey AS, Greene T, Kusek JW. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:A0828. [17] Levey AS, Gassman JJ, Hall PM, Walker WG. Assessing the progression of renal disease in clinical studies: effects of duration of follow-up and regression to the mean. Modification of Diet in Renal Disease (MDRD) Study Group. J Am Soc Nephrol 1991;1:1087–94. [18] Epstein M. Aging and the kidney. J Am Soc Nephrol 1996;7:1106–22. [19] Meyer BR. Renal function in aging. J Am Geriatr Soc 1989;37:791–800. [20] Goyal VK. Changes with age in the human kidney. Exp Gerontol 1982;17:321–31. [21] Hollenberg NK, Adams DF, Solomon HS, Rashid A, Abrams HL, Merrill JP. Senescence and the renal vasculature in normal man. Circ Res 1974;34:309–16. [22] Remuzzi G, Ruggenenti P, Benigni A. Understanding the nature of renal disease progression. Kidney Int 1997;51:2–15. [23] Floege J, Burns MW, Alpers CE, et al. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int 1992;41:297–309. [24] Wasen E, Isoaho R, Mattila K, Vahlberg T, Kivela SL, Irjala K. Estimation of glomerular filtration rate in the elderly: a comparison of creatinine-based formulae with serum cystatin C. J Intern Med 2004;256:70–8. [25] Jacobsen P, Rossing K, Tarnow L, et al. Progression of diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int Suppl 1999;71:S101–5. [26] Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med 1994;330:877–84. [27] Eckardt KU, Bernhardt WM, Weidemann A, et al. Role of hypoxia in the pathogenesis of renal disease. Kidney Int Suppl 2005;99:S46–51. [28] Norman JT, Clark IM, Garcia PL. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int 2000;58:2351–66. [29] Sahai A, Mei C, Schrier RW, Tannen RL. Mechanisms of chronic hypoxiainduced renal cell growth. Kidney Int 1999;56:1277–81. [30] Ershler WB, Sheng S, McKelvey J, et al. Serum erythropoietin and aging: a longitudinal analysis. J Am Geriatr Soc 2005;53:1360–5. [31] Penninx BW, Pahor M, Woodman RC, Guralnik JM. Anemia in old age is associated with increased mortality and hospitalization. J Gerontol A Biol Sci Med Sci 2006;61:474–9. [32] Chaves PH, Semba RD, Leng SX, et al. Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women's Health and Aging Studies I and II. J Gerontol A Biol Sci Med Sci 2005;60:729–35. [33] Maraldi C, Volpato S, Cesari M, et al. Anemia and recovery from disability in activities of daily living in hospitalized older persons. J Am Geriatr Soc 2006;54:632–6. [34] Hosoya T, Toshima R, Icida K, Tabe A, Sakai O. Changes in renal function with aging among Japanese. Intern Med 1995;34:520–7. [35] Haroun MK, Jaar BG, Hoffman SC, Comstock GW, Klag MJ, Coresh J. Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland. J Am Soc Nephrol 2003;14: 2934–41. [36] Seliger SL, Davis C, Stehman-Breen C. Gender and the progression of renal disease. Curr Opin Nephrol Hypertens 2001;10:219–25.