Magnus Akerstrom

The relationship between cadmium in kidney and cadmium in urine and blood in an environmentally exposed population

INTRODUCTION Cadmium (Cd) is toxic to the kidney and a major part of the body burden occurs here. Cd in urine (U-Cd) and blood (B-Cd) are widely-used biomarkers for assessing Cd exposure or body burden. However, empirical general population data on the relationship between Cd in kidney (K-Cd), urine, and blood are scarce. Our objectives were to determine the relationship between cadmium in kidney, urine, and blood, and calculate the elimination half-time of Cd from the kidney. METHODS Kidney cortex biopsies, urine, and blood samples were collected from 109 living kidney donors. Cd concentrations were determined and the relationships between K-Cd, U-Cd, and B-Cd were investigated in regression models. The half-time of K-Cd was estimated from the elimination constant. RESULTS There was a strong association between K-Cd and U-Cd adjusted for creatinine (rp=0.70, p<0.001), while the association with B-Cd was weaker (rp=0.44, p<0.001). The relationship between K-Cd and U-Cd was nonlinear, with slower elimination of Cd at high K-Cd. Estimates of the K-Cd half-time varied between 18 and 44years. A K-Cd of 25μg/g corresponds to U-Cd of 0.42μg/g creatinine in overnight urine (U-Cd/K-Cd ratio: about 1:60). Multivariate models showed Cd in blood and urinary albumin as determinants for U-Cd excretion. DISCUSSION In healthy individuals with low-level Cd exposure, there was a strong correlation between Cd in kidney and urine, especially after adjustment for creatinine. Urinary Cd was also affected by Cd in blood and urinary albumin. Previous estimates of the U-Cd/K-Cd ratio may underestimate K-Cd at low U-Cd.

Associations between Urinary Excretion of Cadmium and Proteins in a Nonsmoking Population: Renal Toxicity or Normal Physiology?

Background: Associations between cadmium (Cd) and kidney function have been reported even at low levels of exposure in the general population. Recently, the causality of these associations has been questioned. Objectives: We examined associations between urinary Cd (U-Cd; a biomarker of exposure) and urinary proteins that are used as biomarkers of kidney effects, based on repeated short-term sampling in healthy subjects. Methods: Twenty-four hour urine samples were collected on 2 separate days at six fixed times from 30 healthy nonsmoking men and women (median age 39 years). We analyzed the samples (N = 354) for Cd (i.e., U-Cd) and two proteins used as kidney function biomarkers: urinary albumin (U-Alb) and alpha-1-microglobulin (U-A1M). Concentrations were adjusted for creatinine concentration or for specific gravity, and excretion rates (mass per hour) were calculated. Possible associations were assessed within each individual participant, and mean correlations and regressions were evaluated. Results: We found clear positive mean associations within individuals between the excretion of U-Cd [mean, 0.11 µg/g creatinine (range, 0.01–0.52 µg/g creatinine)] and both U-Alb and U-A1M. The associations were stronger for excretion rates and concentrations adjusted for specific gravity than for concentrations adjusted for creatinine. We also found significant positive associations of urinary flow with excretion of U-Cd, U-Alb, and U-A1M. Conclusions: Associations between short-term changes in U-Cd and markers of kidney function within individual nonsmoking study participants are unlikely to reflect effects of Cd toxicity. A more likely explanation is that these associations result from normal variation in renal function, including changes in urinary flow, that influence the urinary excretion of both Cd and proteins in the same direction. These effects of normal variability may result in overestimation of the adverse effects of Cd on kidney function at low-level Cd exposure.

Variability of urinary cadmium excretion in spot urine samples, first morning voids, and 24 h urine in a healthy non-smoking population: Implications for study design

When selecting the least biased exposure surrogate, for example, the concentration of a biomarker in a urine sample, information on variability must be taken into consideration. We used mixed-effects models to estimate the variability and determinants of urinary cadmium (U-Cd) excretion using spot urine samples collected at six fixed times during 2 days about 1 week apart, from 24 healthy non-smokers. The urine samples were analysed for U-Cd, the concentrations were adjusted for dilution, and the excretion rates were calculated. Between-individual variability dominated the total variability for most measures of U-Cd excretion, especially for 24 h urine and first morning samples. The U-Cd excretion showed a circadian rhythm during the day, and time point of sampling was a significant factor in the mixed-effects models, thus a standardised sampling time, such as first morning urine samples, needs to be applied. Gender, urinary flow rate, age, and urinary protein excretions were also significant determinants for U-Cd excretion. The choice of biomarker for U-Cd excretion was found to be more important in individually-based studies of exposure–response relationships than in studies of comparing Cd levels of groups. When planning a study, this variability of U-Cd in spot samples must be acknowledged.

Hot tub lung: an occupational hazard

To the Editor: Hot tub baths have become increasingly common in residences as well as hotels and spa facilities. Recently, such baths have been associated with an emerging disorder known as hot tub lung (HTL). HTL is a diffuse granulomatous lung disease caused by inhalation of water aerosol containing non-tuberculous mycobacteria (NTM), in most cases belonging to the Mycobacterium avium complex [1]. Here, we report a cluster of confirmed, probable and possible HTL with occupational associations. To our knowledge, case 1 is the first confirmed case of occupational HTL in the literature. A 30-yr-old hotel technician (case 1, table 1) developed episodes of cough, dyspnoea, fever and joint pain. His condition progressed with fatigue, weight loss and increasing dyspnoea. He was hospitalised at his third emergency visit. His oxygen tension was moderately reduced (8.9 kPa). His C-reactive protein level was 16 mg·L−1. A chest radiograph was normal but computed tomography showed ground-glass opacities without signs of embolism. He was dismissed after spontaneous remission 3 days later. He continued having some fatigue and dyspnoea on exertion. Fever, accentuated dyspnoea and cough relapsed twice after returning to work. Chest radiography showed diffuse interstitial infiltration and his diffusion capacity was reduced. Lymphocytosis was found in his bronchoalveolar lavage (BAL) fluid, and transbronchial biopsies showed interstitial inflammation and granuloma. HTL was diagnosed when growth of M. avium was found in BAL fluid and it became clear that he had cleaned the hotel’s hot tub facility (facility 1) and its nylon filters with a pressure washer twice weekly. View this table: Table 1. Characterisation of a cluster of confirmed, probable and possible cases of hot tub lung related to maintenance work on hot tubs Two colleagues who had substituted for the first hotel technician at servicing the bath facility during his sick leave also fell ill with similar symptoms (cases 2 and 3, table 1). They were eventually diagnosed with probable HTL but the work-up was insufficient …

Physiologically-based Toxicokinetic Model for Cadmium Using Markov-Chain Monte Carlo Analysis of Concentrations in Blood, Urine, and Kidney Cortex from Living Kidney Donors

The health effects of low-level chronic exposure to cadmium are increasingly recognized. To improve the risk assessment, it is essential to know the relation between cadmium intake, body burden, and biomarker levels of cadmium. We combined a physiologically-based toxicokinetic (PBTK) model for cadmium with a data set from healthy kidney donors to re-estimate the model parameters and to test the effects of gender and serum ferritin on systemic uptake. Cadmium levels in whole blood, blood plasma, kidney cortex, and urinary excretion from 82 men and women were used to calculate posterior distributions for model parameters using Markov-chain Monte Carlo analysis. For never- and ever-smokers combined, the daily systemic uptake was estimated at 0.0063 μg cadmium/kg body weight in men, with 35% increased uptake in women and a daily uptake of 1.2 μg for each pack-year per calendar year of smoking. The rate of urinary excretion from cadmium accumulated in the kidney was estimated at 0.000042 day(-1), corresponding to a half-life of 45 years in the kidneys. We have provided an improved model of cadmium kinetics. As the new parameter estimates derive from a single study with measurements in several compartments in each individual, these new estimates are likely to be more accurate than the previous ones where the data used originated from unrelated data sets. The estimated urinary excretion of cadmium accumulated in the kidneys was much lower than previous estimates, neglecting this finding may result in a marked under-prediction of the true kidney burden.

Relationship between mercury in kidney, blood, and urine in environmentally exposed individuals, and implications for biomonitoring

Background: Individuals without occupational exposure are exposed to mercury (Hg) from diet and dental amalgam. The kidney is a critical organ, but there is limited information regarding the relationship between Hg in kidney (K‐Hg), urine (U‐Hg), blood (B‐Hg), and plasma (P‐Hg). Objectives: The aim was to determine the relationship between K‐Hg, U‐Hg, B‐Hg, and P‐Hg among environmentally exposed individuals, estimate the biological half‐time of K‐Hg, and provide information useful for biomonitoring of Hg. Methods: Kidney cortex biopsies and urine and blood samples were collected from 109 living kidney donors. Total Hg concentrations were determined and the relationships between K‐Hg, U‐Hg, P‐Hg, and B‐Hg were investigated in regression models. The half‐time of K‐Hg was estimated from the elimination constant. Results: There were strong associations between K‐Hg and all measures of U‐Hg and P‐Hg (rp = 0.65–0.84, p < 0.001), while the association with B‐Hg was weaker (rp = 0.29, p = 0.002). Mean ratios between K‐Hg (in &mgr;g/g) and U‐Hg/24h (in &mgr;g) and B‐Hg (in &mgr;g/L) were 0.22 and 0.19 respectively. Estimates of the biological half‐time varied between 30 and 92 days, with significantly slower elimination in women. Adjusting overnight urine samples for dilution using urinary creatinine resulted in less bias in relation to K‐Hg or U‐Hg/24h, compared with other adjustment techniques. Conclusions: The relationship between K‐Hg and U‐Hg is approximately linear. K‐Hg can be estimated using U‐Hg and gender. Women have longer half‐time of Hg in kidney compared to men. Adjusting overnight urine samples for creatinine concentration resulted in less bias. HIGHLIGHTSThe first study of the relation between Hg in kidney, blood and urine at low U‐HgSimultaneous samples were collected from healthy kidney donors.There was a linear relationship between mercury in kidney and urine.Kidney Hg can be estimated using U‐Hg and gender.Women have longer half‐time of Hg in kidney compared to men.

Effect of molybdenum oxide interference on urinary cadmium analyses

We would like to stress the need for the correction of molybdenum (Mo)-based interference on urinary cadmium analysis. Mo is an essential element for humans and the main source of Mo is from the diet (Nordberg et al. 2007). The primary route of excretion is through urine and the excretion is directly related to recent dietary intake. On average, excretions of Mo between 49 lg/day and 71 lg/ day have been reported (Nordberg et al. 2007). During metal analysis, using inductively coupled plasma mass spectrometry (ICP-MS), Mo present in the urine may be oxidised to molybdenum oxide (MoO) during analysis. The formed molecular interferences MoO and MoO will interfere with cadmium (Cd) isotopes Cd and Cd used for the determination of Cd (Jarrett et al. 2008; Suzuki et al. 2008). At low urinary Cd (U-Cd) excretion, typically in biomonitoring of environmentally exposed subjects, the interference of MoO has been shown to substantially affect the analysis of U-Cd, thus the correction of Mo-based interference is needed (Jarrett et al. 2008; Suzuki et al. 2008). In the large NHANES biobank, a substantial reduction (41 %) in U-Cd was seen when the interference from MoO was removed (Jarrett et al. 2008). In the same study, blood cadmium was not affected by the Mo-based interference because of the low levels of Mo in blood (Jarrett et al. 2008). The performance when external quality control samples are used may well be satisfactory since these samples often have higher Cd concentrations, making the interference from MoO less important (Jarrett et al. 2008). In 2012, we reanalysed urine samples [24-h urine (U24), N = 131, and overnight urine (UON), N = 146, samples] from a study of 152 healthy kidney donors collected between 1999 and 2005, published in this journal (Akerstrom et al. 2012). This was done since it had become clear that only two of the four analytical rounds had been corrected for Mo-based interference in the initial analysis. The samples had been frozen (-20 C) since the collection. Repeated measurement (N = 20) of specific gravity showed good agreement with the measurements taken on fresh urine, indicating that no dehydration of the samples had occurred (data not shown). The samples were reanalysed using ICP-MS (ICP-MS; Thermo X7, Thermo Elemental, Winsford, UK) in samples diluted ten times with an alkaline solution according to (Barany et al. 1997). U-Cd samples were now corrected for MoO interference. Mo (500 lg/L) was added to blank urine several times in each analytical run, and the formation of MoO was evaluated. Mo was determined in all urine samples, and thus correction for the MoO interference could be performed. A separate experiment where Mo was added to urine at seven different concentrations in the range 25–500 lg/L (N = 21) showed that there is a linear relationship between the formation of MoO and the Mo concentrations in urine (MoO = 0.0016 9 Mo-0.0004; r = 0.999) within each series of analysis. Oxidation levels could however vary from day to day, resulting in different slopes. The results of the reanalysis of U-Cd, corrected for Mo-based interference, showed substantially lower U-Cd M. Akerstrom (&) L. Barregard G. Sallsten Department of Occupational and Environmental Medicine, Sahlgrenska University Hospital and Academy, University of Gothenburg, PO Box 414, SE-405 30 Gothenburg, Sweden e-mail: magnus.akerstrom@amm.gu.se

Quantitative analyses of mycobacteria in water: adapting methods in clinical laboratories.

An outbreak of occupational hot tub lung necessitated quantitative analysis of mycobacteria in water samples. We combined procedures for cultivation of mycobacteria in urine and quantitative analyses of dialysis water. Whirlpool spa water samples were analyzed showing promising results. In conclusion, quantitative mycobacterial culture of water is possible by adapting methods routinely used in clinical laboratories.