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Research report
Nickel exposure and prevalent albuminuria and β2-microglobulinuria: evidence from a population-based study
  1. Gang Liu1,
  2. Qi Sun2,3,
  3. Mingjiang Zhu1,
  4. Liang Sun1,
  5. Zhenzhen Wang1,
  6. Huaixing Li1,
  7. Zi Li1,
  8. Yan Chen1,
  9. Huiyong Yin1,
  10. Xu Lin1
  1. 1From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Chinese Academy of Sciences, and University of Chinese Academy of Sciences, Shanghai, China
  2. 2Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  3. 3Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
  1. Correspondence to Professor Xu Lin, Institute for Nutritional Sciences, Chinese Academy of Sciences, 320 Yue-Yang Rd., Shanghai 200031, China; xlin{at}sibs.ac.cn Huiyong Yin, Institute for Nutritional Sciences, Chinese Academy of Sciences, 320 Yue-Yang Rd., Shanghai, 200031, China; hyyin@sibs.ac.cn.

Abstract

Background High exposure to nickel could induce renal dysfunction in rodents and occupational workers. However, little is known about the effects of non-occupational exposure to nickel on renal health in the general population. We aimed to examine the associations of urinary nickel concentrations with albuminuria and β2-microglobulinuria in Chinese adults.

Methods 2115 non-institutionalised Chinese men and women aged 55–76 years from Beijing and Shanghai were included. Urinary nickel concentrations were assessed by inductively coupled plasma mass spectroscopy. Plasma uric acid, urea nitrogen, C reactive protein and urinary albumin, β2–microglobulin and creatinine were measured. Albuminuria was defined as urinary albumin ≥30 mg/g creatinine, and β2-microglobulinuria was defined as urinary β2-microglobulin ≥200 µg/g creatinine.

Results Median concentration of urinary nickel was 3.95 μg/g creatinine (IQR: 2.57–6.71 μg/g creatinine), and prevalence of albuminuria, β2–microglobulinuria and both albuminuria and β2-microglobulinuria was 22.1%, 24.5% and 9.7%, respectively. Comparing the highest with the lowest quartile of urinary nickel, the ORs (95% CIs) were 1.99 (1.46 to 2.78) for albuminuria, 1.44 (1.07 to 1.95) for β2–microglobulinuria, and 2.95 (1.74 to 4.97) for both albuminuria and β2-microglobulinuria, after adjustment for demographic characteristics, lifestyle behaviours, body mass index, hypertension and diabetes. The association remained significant when further controlling for inflammatory markers or other heavy metals (all p trend <0.05).

Conclusions This study suggested that urinary nickel levels were positively associated with albuminuria and β2-microglobulinuria in Chinese men and women, who had relatively low background nickel exposure. More prospective studies are needed to confirm our findings.

  • EPIDEMIOLOGY
  • ENVIRONMENTAL HEALTH
  • RENAL

https://doi.org/10.1136/jech-2015-205994

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    Introduction

    Chronic kidney disease (CKD), a risk factor for cardiovascular disease, end-stage renal disease and other complications, has become one of the global disabling diseases that lead to tremendous loads on the society and economy.1–3 Currently, the prevalence of CKD accounted for 13.1% in adult Americans and 10.8% in adult Chinese.2 ,3 As expected, with rapidly increasing risk factors like type 2 diabetes and hypertension, CKD will threaten more people's health and bring an even greater economic burden in the foreseeable future.3 In order to facilitate disease prevention, it is critical to identify its risk factors. However, studies indicated that conventional risk factors could not fully explain the incidence of renal disease.4 ,5 Albuminuria or β2–microglobulinuria, reflecting a pathological condition when excess albumin or β2-microglobulin appears in the urine, is considered as an indicator of glomerular or tubular damage in the kidney.6 ,7 Recently, growing evidence suggested that exposure to heavy metals such as cadmium could result in albuminuria in the non-occupational population.8 ,9 It remains largely unknown about roles of other heavy metals in the pathogenesis of renal dysfunction.

    Nickel is a heavy metal widely distributed in the environment and extensively used in industrial processes, such as electroplating, and production of alloys, electronic equipment and nickel-cadmium batteries.10 ,11 Ordinary people may be exposed to nickel through the air, diet and water.12 Other sources include use of tobacco, stainless steel kitchen utensils, dental or orthopaedic implants, inexpensive jewellery and nickel-releasing coins.13 Nickel exposure is commonly evaluated by measuring its urinary concentration, since the majority of absorbed nickel is excreted in the urine with a half-life of 17–48 h in humans.14 ,15 Evidence from rodent models demonstrated that nickel exposure (100 mg/L and 223.5 mg/L nickel sulfate in drinking water) increased kidney weight and levels of blood urea nitrogen (UN) and urinary albumin.16 ,17 While data from studies in occupational workers (mean urinary nickel concentrations were 5.0 and 10.3 mg/g creatinine for men and women, respectively) suggested positive associations of urinary nickel with albuminuria and β2-microglobulinuria,18 ,19 it remains unclear whether non-occupational exposure to relatively lower levels of nickel is also associated with unfavourable renal function in general populations.

    In the current study, we aimed to investigate the associations of urinary nickel concentrations with prevalence of albuminuria and β2-microglobulinuria in middle-aged and elderly Chinese men and women who have not been occupationally exposed to nickel.

    Methods

    Study population

    This study is based on the Nutrition and Health of Aging Population in China (NHAPC) project, which is a population-based prospective study to determinate environmental and genetic factors in relation to chronic diseases. The baseline survey was conducted among 3289 community-dwelling residents aged 50–70 years recruited from Beijing and Shanghai in 2005 (the response rate was 95.6%).20 In 2011, all participants were contacted for the 6-year follow-up visit and a total of 2529 (76.9%) eligible participants were successfully followed up.21 Details of the baseline survey and the follow-up survey have been described elsewhere.20 ,21 Briefly, all of the study participants in 2005 were selected by using a multistage sampling method among residents living over 20 years in Beijing and Shanghai (2 urban districts and 1 rural district in each city), where an electroplating plant or alloy material factory was largely non-existent. This study was a cross-sectional analysis of the 2011 follow-up visit when urine samples were collected. After excluding the participants without urine samples (n=335), or those with missing data on covariates (n=79), 2115 individuals were included for the last analysis. All participants provided written informed consent. The study was approved by the Institutional Review Board of the Institute for Nutritional Sciences.

    Data collection

    Information on age, sex, residence (urban/rural), region (Beijing/Shanghai), education levels (0–6, 7–9, or ≥10 years), smoking (yes or no), alcohol use (yes or no), self-reported diabetes, hypertension and medication use was collected by trained medical professionals using a standardised questionnaire in 2011. The information of occupation (including farmer, factory worker, administrator, professionals, self-employed, housewife and soldier) was also included in the same questionnaire. Physical activity level was classified as low, moderate or high according to the International Physical Activity Questionnaire.20 Physical examination for measurement of weight, waist circumference, height and blood pressure was performed by trained health workers following a standardised protocol. Body mass index (BMI) was categorised as normal weight (<24.0 kg/m2), overweight (24.0–27.9 kg/m2) and obesity (≥28.0 kg/m2) for the Chinese population. Following at least 5 min of rest, blood pressures were measured three times on the right arm by utilising an electronic blood pressure monitor (Omron HEM-705CP, Vernon Hills, Illinois, USA), and mean values of the last two measurements were used in analysis. The time interval between each blood pressure measurement was 1 min. Hypertension was defined as systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mm Hg, or self-reported doctor-diagnosed hypertension or use of anti-hypertensive medications. Type 2 diabetes was defined as fasting plasma glucose concentration ≥7.0 mmol/L, taking antidiabetic drugs or self-reported doctor-diagnosed diabetes.

    Laboratory measurement

    Fasting blood samples were collected by tubes with EDTA and centrifuged at 3000 rpm for 15 min, and then stored at −80°C until analysis. Plasma glucose, UN and uric acid (UA) were measured with reagents from Wako Pure Chemical Industries (Osaka, Japan). Urinary albumin and β2-microglobulin concentrations were determined using immunoturbidimetric assays and urinary creatinine was measured by using an alkaline-picrate acid method (Roche Diagnostics, Mannheim, Germany). All of the aforementioned assays were conducted by an automatic analyser (Hitachi 7080, Tokyo, Japan). Plasma high-sensitive C reactive protein (CRP) was evaluated by a particle-enhanced immunoturbidimetric assay (Ultrasensitive CRP kit; Orion Diagnostica, Espoo, Finland). The intra-assay and inter-assay coefficients of variation ranged from 1% (UN) to 6% (β2-microglobulin), and 1% (UA) to 10% (albumin), respectively. Plasma creatinine was measured by using an enzymatic method with intra-assay and inter-assay CVs <3%. The estimated glomerular filtration rate (eGFR) was calculated on the basis of the Modification of Diet in Renal Disease (MDRD) Study Equation for Chinese with minor modifications.22 In sensitivity analysis, eGFR was also calculated using the Cockcroft-Gault formula.

    Urinary nickel determination

    Morning urine samples were collected in clean containers and stored at −80 until analysis. 1 mL of the urine samples was mixed with 1 mL 2% HNO3, and then centrifuged at 4000 rpm for 10 min. Supernatants were detected by the Agilent 7700 inductively coupled plasma mass spectroscopy system (ICP-MS, Agilent Technologies, Tokyo, Japan). The interassay and intra-assay coefficients of variation were 10% and 8%, respectively. To account for urine dilution, urinary nickel concentrations were adjusted for urinary creatinine concentrations.

    Assessment of albuminuria and β2-microglobulinuria

    Albuminuria was defined as urinary albumin concentration ≥30 mg/g creatinine,6 ,9 and β2-microglobulinuria was defined as urinary β2–microglobulin concentration ≥200 μg/g creatinine.6 ,23

    Statistical analysis

    Comparisons between participants with and without albuminuria (or β2–microglobulinuria) were tested by using Student's t test for normally distributed variables, Wilcoxon rank-sum test was used for skewed variables, and χ2 test was employed for categorical variables. Logistic regression models were applied to estimate the ORs and 95% CIs for albuminuria, β2–microglobulinuria, and both of them, comparing the highest to the lowest urinary nickel quartile with adjustment for age, sex, region, residence, education, smoking, alcohol use, physical activity, BMI, hypertension and diabetes. We further controlled for CRP to examine the influence of inflammatory status on the association. A restricted cubic spline regression model with three knots at the 5th, 50th and 95th centiles of log10-transformed nickel distribution was used to detect log-linear dose–response relationships.24 In secondary analysis, the associations of urinary nickel with albuminuria or β2–microglobulinuria were also estimated in fully adjusted models stratified by age (<65, ≥65), sex, residence, region, BMI category (<24, 24–27.9, ≥28.0 kg/m2), current smoking status, hypertension, diabetes and tertiles of arsenic and cadmium. A likelihood ratio test was used to detect interactions.

    Several sensitivity analyses were also carried out. First, considering potential bias when adjusting for creatinine to account for urine dilution, additional analyses were conducted without any adjustment for creatinine. Second, urinary arsenic and cadmium were additionally adjusted in the models to evaluate the influence of these elements on the associations of urinary nickel with albuminuria and β2–microglobulinuria.8 ,9 Third, in order to minimise unawareness of occupational nickel exposure during earlier years, previous factory workers were excluded in further analyses. In another sensitivity analysis, urinary β2-microglobulin ≥300 μg/g creatinine was used to define renal tubular damage.25 All analyses were performed with SAS (V.9.3; SAS Institute Inc, Cary, North Carolina, USA). Two-sided p values <0.05 were considered statistically significant.

    Results

    Median concentration of urinary nickel was 3.95 μg/g creatinine (IQR: 2.57, 6.71 μg/g creatinine) in our study. Prevalence was 22.1% for albuminuria (≥30 mg/g creatinine), 24.5% for β2–microglobulinuria (≥200 μg/g creatinine), and 9.7% for having both outcomes. As shown in table 1, participants with albuminuria were older and more likely to be female, rural and Shanghai residents. They also had lower levels of eGFR, educational attainment and physical activity and higher prevalence of hypertension and diabetes, as well as higher levels of BMI, β2–microglobulin, CRP and urinary nickel than persons without albuminuria. Similar characteristics were also detected in those participants with β2–microglobulinuria. Correlations of nickel, arsenic, cadmium, eGFR and CRP are presented in online supplementary table S1. Spearman correlation coefficient was 0.34 for nickel and arsenic, and 0.38 for nickel and cadmium, respectively.

    View this table:
    Table 1

    Characteristics of participants (N=2115) by albuminuria and β2-microglobulinuria status, Nutrition and Health of Aging Population in China Study, 2011*

    Elevated urinary nickel levels were associated with higher odds of albuminuria and β2-microglobulinuria after adjustment for age, sex, residence and region (table 2). Further, controlling for education, alcohol use, smoking, physical activity, BMI, hypertension, diabetes and CRP did not materially change the association (all p trend <0.05). In the participants with albuminuria, fully adjusted ORs (95% CIs) across urinary nickel quartiles were 1.00 (reference), 1.49 (1.05 to 2.10), 1.93 (1.38 to 2.70) and 2.04 (1.46 to 2.85), respectively, (p trend <0.001). In the participants with β2–microglobulinuria, fully adjusted ORs (95% CIs) across urinary nickel quartiles were 1.00 (reference), 1.27 (0.93 to 1.72), 1.26 (0.93 to 1.72) and 1.48 (1.09 to 2.00), respectively, (p trend=0.02). In the participants with albuminuria and β2-microglobulinuria, fully adjusted ORs (95% CIs) across urinary nickel quartiles were 1.00 (reference), 2.70 (1.58 to 4.60), 2.37 (1.39 to 4.05) and 3.04 (1.80 to 5.15), respectively (p trend <0.001). Positive log-linear dose–response relationships were evidenced between urinary nickel and risk of albuminuria and β2-microglobulinuria (figure 1, p<0.05 for linearity), although the significant relationship remained only for albuminuria without adjustment for creatinine.

    View this table:
    Table 2

    Association between urinary nickel concentrations and prevalent albuminuria and β2-microglobulinuria (N=2115), Nutrition and Health of Aging Population in China Study, 2011

    Figure 1
    Figure 1

    OR of Albuminuria and β2-Microglobulinuria by Urinary Nickel Concentrations (N=2115), Nutrition and Health of Aging Population in China Study, 2011. Lines represent ORs (95% CI) based on restricted cubic splines for log-transformed nickel concentrations with knots at 5th, 50th and 95th centiles. The reference was set at the 10th percentile of urinary nickel distribution. ORs were estimated using a logistic regression model after adjustment for age (continuous), sex, region (Beijing/Shanghai), residence (urban/rural), BMI (continuous), educational attainment (≤6, 7–9, or ≥10 years), alcohol drinking (yes, no), smoking status (yes, no), physical activity (high, moderate, low), hypertension (yes, no), diabetes (yes, no) and C reactive protein (continuous). Both p for linear <0.05. Bars represent the numbers of participants; 6 equally sized bins were selected from the 5th to the 95th centiles of log-transformed nickel distribution. BMI, body mass index.

    In stratified analyses, the associations of urinary nickel with albuminuria or β2–microglobulinuria remained positive across most of the subgroups defined by age, sex, region, residence, BMI, smoking, hypertension, diabetes and tertiles of arsenic and cadmium, although some of the associations lacked statistical significance because of reduced power (table 3). In sensitivity analyses, a similar result was obtained when creatinine was not adjusted for. Among the participants with albuminuria (≥30 mg/L, cases=448), fully adjusted ORs (95% CIs) across urinary nickel quartiles were 1.00 (reference), 1.20 (0.85 to 1.68), 1.79 (1.30 to 2.48) and 2.04 (1.47 to 2.82), respectively (p trend <0.001). Among the participants with β2–microglobulinuria (≥200 μg/L, cases=513), fully adjusted ORs (95% CIs) across urinary nickel quartiles were 1.00 (reference), 1.18 (0.87 to 1.60), 1.65 (1.23 to 2.22) and 1.25 (0.93 to 1.70), respectively (p trend=0.04). Moreover, when further adjustment for arsenic and cadmium (as continuous variables) on the basis of model 3, the results did not materially change (OR, 1.98, 95% CI 1.41 to 2.77 for albuminuria; OR, 1.42, 95% CI 1.05 to 1.92 for β2-microglobulinuria, both p trend <0.05). In addition, similar results were observed when excluding all of the previous factory workers in further analyses (data not shown). Finally, when renal tubular damage was defined as urinary β2-microglobulin concentration ≥300 μg/g creatinine,25 the associations remained significant (see online supplementary table S2).

    View this table:
    Table 3

    Stratified analyses of the associations (OR and 95% CI) between urinary nickel concentrations and prevalent albuminuria and β2-microglobulinuria by characteristics of participants (N=2115), Nutrition and Health of Aging Population in China Study, 2011

    Discussion

    To the best of our knowledge, this is the first community-based population study suggesting that non-occupational exposure to nickel, indicated by its urinary levels, was positively associated with albuminuria and β2-microglobulinuria, independent of established risk factors of renal dysfunction, including lifestyle, BMI, hypertension, diabetes and inflammatory markers in middle-aged and elderly Chinese men and women.

    In contrast to its wide environmental distribution in air, drinking water and various foods like dark chocolate, spinach, dry legumes, and oatmeal,12 the association of nickel and human health has not been well studied in people without occupational exposure. Previously, elevated urinary nickel was reported by Vyskocil et al18 to be significantly correlated with increased urinary β2-microglobulin, N-acetyl-β-D-glucosaminidase and retinal binding protein in 12 female workers who were exposed to highly soluble nickel compounds. A transient increasing urinary albumin was also observed by Sunderman et al19 in three electroplating workers who accidentally drank water contaminated with nickel sulfate and chloride (1.63 g/L). The role of nickel exposure on impaired renal function was also investigated in few experimental animal studies.16 ,17 Treating rats with 100 mg/L of nickel sulfate in drinking water for 6 months significantly increased kidney weight and urinary excretion of albumin.16 Significantly elevated circulating UN and declined urine volume were also documented after male rats received 223.5 mg/L nickel sulfate in drinking water for 13 weeks.17 In this study, we found a positive association, as well as a positive log-linear dose–response relationship of urinary nickel with either albuminuria or β2-microglobulinuria. It was noticed that the risk of albuminuria was more profound in participants aged ≥65 years (p for interaction=0.04) than those people aged <65 years. Indeed, existing evidence showed that advancing age could accelerate deteriorating renal function.26 On the other hand, a significant association between urinary arsenic levels and albuminuria was only found in American Indians aged 45–55 years but not in participants aged 55–74 years.9 Nonetheless, when waiting for more convincing evidence, special attention should be paid to elderly people who might be more susceptible to environmental hazards including nickel exposure. In addition, it is unclear whether relatively higher nickel exposure in certain countries like Finland was also linked with elevated risk of renal dysfunction or CKD. On the other hand, there are no national representative data regarding the prevalence of renal dysfunction/CKD in Finland to date, though a relatively higher prevalence of end-stage kidney disease (Finland:∼0.08% vs China:∼0.01%) was reported by Jha.27 Notably, there are no any international standardised measurement and cut-off criteria for assessment of nickel exposure at the present time. Therefore, it is difficult to compare nickel exposure levels across populations, since different methods were used in sample pretreatment (microwave dissolution or not) and detection (ICP-MS vs electrothermal atomic absorption spectrometry) among studies. Nevertheless, the finding from our study at least provides an important clue about the potential adverse effect of environmental nickel exposure on renal function in the general public.

    Little is known about underlying mechanisms linking environmental nickel exposure to impaired renal function. A previous study in rats showed a dose-response relationship for lipid peroxidation in kidneys following administration of different doses of nickel chloride.28 Moreover, treating rats with Ni(II) also induced renal DNA damage, protein degradation or DNA-protein crosslinks.29 ,30 Thus, whether the results from animal models are relevant for humans need to be investigated in future studies.

    In recent years, the role of chronic low-grade inflammation in the pathogenesis of renal dysfunction has been attracting increasing attention.31 ,32 Studies in vitro suggested that environmental chemicals such as arsenic could increase expression of interleukin-6, tumour necrosis factor, and NF-κB in cell culture.33 ,34 However, this study did not find a significant correlation between levels of urinary nickel and plasma CRP, and also the association of nickel exposure with albuminuria or β2–microglobulinuria was not attenuated by adjusting for CRP. Meanwhile, the modifying effect in our study was only observed for β2–microglobulinuria, which might be subject to chance. A stronger association of nickel exposure with β2–microglobulinuria was found in those individuals with diabetes than their non-diabetic counterparts (p for interaction =0.02). Previously, we also discovered a positive association between urinary nickel and type 2 diabetes in the same study population.35 Although it is unclear how nickel interacted with the diabetic condition, some studies suggested that kidney damage induced by environmental chemicals such as arsenic might be attributable to the influence of diabetes.9 In fact, data from animal studies and epidemiological studies demonstrated that arsenic aggravated nephrotoxicity in the presence of diabetes.36 ,37 Collectively, it is possible that coexisting enviromental nickel exposure and diabetic condition might exacerbate renal dysfunction, which is also one of the major complications in patients with diabetes.

    The strength of this first large-scale population-based study included that all participants were recruited from the north (Beijing) and the south (Shanghai) and urban and rural areas in China, reflecting environmental nickel exposure levels across different geographic locations. Moreover, established risk factors of renal dysfunction were carefully adjusted in the analyses to control for confounding. Our study also has certain limitations and should be interpreted with caution. First, owing to the cross-sectional nature, a causal relationship of nickel exposure with kidney dysfunction cannot be established, and a reverse causality is also possible that elevated urinary nickel might be as a consequence of renal dysfunction. Future prospective studies are needed to establish causality. Second, owing to the short half-life of nickel in urine, repeated measurements of urinary nickel are needed in future studies, though a single urine measure was considered as an acceptable method by Wilhelm et al38 if continuously consumed nickel-rich foods were consistent with urinary nickel concentration. Third, we only collected first morning urine samples and used urinary creatinine levels to account for urine dilution. However, the associations remained materially unchanged when creatinine was not adjusted in the sensitivity analyses. Although controlling for specific gravity was considered as an alternative method to account for urine dilution, it might not be very useful in our study because of the high prevalence of albuminuria.39 In addition, since how to appropriately evaluate joint effects across multiple metals remains controversial,40 developing a new approach for handling multiexposures is important. Meanwhile, well-designed prospective studies are warranted to estimate the joint effect between nickel and other heavy metals on renal dysfunction in the future. Finally, effects of residual confounding could not be fully eliminated. More studies are needed to clarify the main source of nickel exposure in the general population, which is critical to control residual confounding and perform bias estimation.

    In conclusion, our study suggested that increased non-occupational exposure to nickel could be a risk factor for renal dysfunction in middle-aged and elderly Chinese men and women. These findings need to be confirmed prospectively in more future studies among different populations.

    What is already known on this subject

    • High exposure to nickel could induce renal dysfunction in rodents and occupational workers. Little is known about effects of non-occupational exposure to nickel on renal health in the general population.

    What this study adds

    • This is the first community-based study revealing that non-occupational exposure to nickel is positively associated with albuminuria and β2-microglobulinuria in Chinese men and women.

    • This study has provided a novel and important clue that environmental nickel exposure might be linked with potential renal hazard in a general population.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Contributors GL, MZ and ZL contributed to data collection and analysis. GL, QS, LS, ZW, HL, YC, HY and XL interpreted the data and drafted the article. All authors contributed to the study design, critically revised the article and approved the final version for submission.

    • Funding The study was supported by the Ministry of Science and Technology of China (2013BAI04B03 to ZW and 2012BAK01B00), the National Natural Science Foundation of China (30930081, 81321062, 81202272, 81390353, and 31170809), the Chinese Academy of Sciences (KSCX2-EW-R-08 and KSCX2-EW-R-10), the International Postdoctoral Exchange Fellowship Program 2015, the Knowledge Innovation Program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (2013KIP107), the SA-SIBS Scholarship Program, and Hundred Talents Program from CAS (2012OHTP07, HY).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval The study was approved by the Institutional Review Board of the Institute for Nutritional Sciences.

    • Provenance and peer review Not commissioned; externally peer reviewed.