Holger Dressel

Cadmium or cadmium compounds and chronic kidney disease in workers and the general population: a systematic review

Abstract Background: Cadmium (Cd) is abundantly documented as a metal mainly affecting tubular function both in workers and in the general population indirectly exposed via the environment. Results from epidemiological studies linking Cd exposure and risk of progression to chronic kidney disease (CKD) are, however, conflicting. Objectives: To perform a systematic review of the association between Cd exposure and CKD. Methods: A systematic appraisal of publications found in MEDLINE (1946–2014), EMBASE (1974–2012) and an in-house database (1986–2013) was conducted. Additional studies were searched for by contacting experts and checking reference lists. Search terms used key and text words. No language restriction was applied. Cohort, case–control and case-series with follow-up including individual and objective assessment of occupational or environmental exposure were eligible. Studies were selected and data extracted by two independent reviewers using predefined forms. Study characteristics and results were extracted to structured tables. Synthesis was qualitative and results appraised with causality criteria. Results: Thirty-four exposed groups, totaling more than 3000 participants, were eligible. Overall, results disclosed no convincing evidence supporting a risk of progression to CKD in populations exposed to Cd. Lack of information about methods, risk of bias and heterogeneity were identified as limitations and precluded conducting a meta-analysis. Publication bias did not appear as a major problem. Conclusions: This qualitative systematic review does not support the contention that human exposure to Cd leads to progressive CKD.

Intra-session and inter-session variability of nitric oxide pulmonary diffusing capacity in adults with cystic fibrosis.

We evaluated the intra-session and inter-session variability of the diffusing capacity of nitric oxide (DLNO), carbon monoxide (DLCO), alveolar-capillary membrane diffusing capacity for carbon monoxide (DMCO) and pulmonary capillary blood volume (Vc) in patients with cystic fibrosis (CF). Patients performed single-breath diffusing capacity measurements during all of 3 consecutive study visits. Precision of gas diffusing parameters was quantified by within-subject standard deviation (SDws) and coefficient of variation (CV). Intra-session and inter-session reproducibility was determined by SDws*2.77. 15 clinically stable patients were included. The intra-session precision of gas diffusing parameters improved over the study visits. The inter-session SDws for DLNO, DLCO, DMCO, and Vc was 4.8, 1.3, 2.4, and 4.3, respectively. Reproducibility was 13.3, 3.8, 6.7 and 12.0mLmin-1mmHg-1; CV was 4.4, 4.7, 4.4 and 5.8%, respectively. The intra-session variability of DLNO, DLCO, DMCO and Vc improves with breath-hold maneuver training in test-naïve patients with CF, indicating a learning effect. Inter-session reproducibility data are lower than those previously reported in healthy subjects.

Predicted Mercury Soil Concentrations from a Kriging Approach for Improved Human Health Risk Assessment

Health-risks from contaminated soils are assessed all over the world. An aspect that many risk assessments share is the heterogeneity in the distribution of contaminants. In a preceding study, we assessed potential health-risks for mothers and children living on mercury-contaminated soils in Switzerland using human biomonitoring-values (HBM) and soil samples. We assessed 64 mothers and 107 children who had resided in a defined area for at least 3 months. HBM-concentrations for mercury in urine and hair were measured, a detailed questionnaire was administered for each individual, and more than 4000 individual mercury soil values were obtained in 2015. In this study, we aimed at investigating possible associations of mercury soil- and HBM-values by re-analyzing our data, using predictions of the mercury concentrations at the exact location of the participant’s homes with a kriging approach. Although kriging proved to be a useful method to predict mercury soil concentrations, we did not detect an association between mercury soil- and HBM-values, in agreement with earlier findings. Benefits of geostatistical methods seem to be limited in the context of our study. Conclusions made in our preceding study about potential health risks for the residential population are robust and not altered by the current study.

Human-biomonitoring and individual soil measurements for children and mothers in an area with recently detected mercury-contaminations and public health concerns: a cross-sectional study

ABSTRACT In this study, we assessed intracorporal mercury concentrations in subjects living on partially mercury-contaminated soils in a defined area in Switzerland. We assessed 64 mothers and 107 children who resided in a defined area for at least 3 months. Mercury in biological samples (urine and hair) was measured, a detailed questionnaire was administered for each individual, and individual mercury soil values were obtained. Human biomonitoring results were compared with health-related and reference values. Mothers and children in our study had geometric means (GMs) of 0.22 µg Hg/g creatinine in urine (95th percentile (P95) = 0.85 µg Hg/g) and 0.16 µg Hg/g (P95 = 0.56 µg Hg/g), respectively. In hair, mothers and children had GMs of 0.21 µg Hg/g (P95 = 0.94 µg/g) and 0.18 µg/g (P95 = 0.60 µg/g), respectively. We found no evidence for an association between mercury values in soil and those in human specimens nor for a health threat in residential mothers and children.

Need For Long-Term Care in Children is Increasingly Caused by Disorders of Psychological Development. Changes in the Care Causing Diagnoses According to German Social Code (SGB XI) Between 2009–2014

AIM OF THE STUDY There is an ongoing discussion on the increasing number of children with mental and developmental disorders, with some even needing long-term care according to the German Social Code XI. This study was performed to identify the main diagnoses justifying such care in children and to analyse their prevalence over time. METHODS The diagnoses justifying long-term care were evaluated using care assessments of Bavarian children and adolescents between 2009 to 2014 by the medical service of statutory health insurance. RESULTS Over the years investigated, the percentage of assessments due to a mental and behavioural disorder rose significantly from 36.2 to 42.2%. Since 2012, the most common diagnose changed from Downs syndrome to pervasive developmental disorders with marked increase of also mixed specific developmental disorders. In new applications for nursing insurance services the proportion of pervasive developmental disorders rose gradually from 151 in 2010 to 254 in 2014. During the whole period of time, the overall care dependency in children seemed to be stable. CONCLUSIONS These observations might rather be influenced by altered awareness of health and illness, increasing readiness to seek help with psychological or developmental impairments as well as changed diagnostic criteria than by a steady increase in affected individuals.

Can serum cytokine profile discriminate irritant-induced and allergen-induced symptoms? A cross-sectional study in workers mostly exposed to laboratory animals

Background In workers exposed mostly to laboratory animals (LA), symptoms may be due to irritants or allergens. Correct aetiological diagnosis is important for health surveillance. Objectives This study aims to test whether work-related (WR) allergen-induced symptoms are associated with a cytokine profile distinct from that due to irritants. Methods In a cross-sectional study (n=114), WR respiratory and/or skin symptoms were assessed through a standardised clinical examination and sensitisation to rat and/or mouse allergen determined by serum immunoglobulin E. Serum cytokine concentrations were measured by multiplex assays. The predefined cytokine profiles ‘sensitiser’ (interleukin (IL)-4, IL-5, IL-13, eotaxin-1) and ‘irritation’ (IL-8, IL-17A, IL-17F, IL-22) were considered positive, when ≥3 concentrations exceeded the 95th percentile of the asymptomatic non-sensitised group. Results were examined by hierarchical clustering analyses (HCA) and multiple linear regression. Explorative analyses were carried out for nine additional cytokines. Exposure to allergens and endotoxin was assessed in a subpopulation. Results The prevalence of the profile ‘irritation’ was comparable in 28 symptomatic non-sensitised workers and 71 asymptomatic non-sensitised workers. HCA showed that nearly all symptomatic non-sensitised workers were gathered in two subclusters, characterised by high IL-17A levels, but different IL-8 levels. Multiple linear regression identified drug consumption and current complaints as confounders. Sensitised subjects were too few (n=14) for testing the profile ‘sensitiser’. Conclusions In this unselected population of LA workers, the profile ‘irritation’ did not prove to be a valuable health surveillance tool. Low power precluded assessment of the profile ‘sensitiser’. The increased IL-17A concentration may originate from irritative constituents of organic dust.

Effects of growth and aging on the reference values of pulmonary nitric oxide dynamics in healthy subjects

The lung just like all other organs is affected by age. The lung matures by the age of 20 and age-related changes start around middle age, at 40-50 years. Exhaled nitric oxide (FENO) has been shown to be age, height and gender dependent. We hypothesize that the nitric oxide (NO) parameters alveolar NO (CANO), airway flux (JawNO), airway diffusing capacity (DawNO) and airway wall content (CawNO) will also demonstrate this dependence. Data from healthy subjects were gathered by the current authors from their earlier publications in which healthy individuals were included as control subjects. Healthy subjects (n = 433) ranged in age from 7 to 78 years. Age-stratified reference values of the NO parameters were significantly different. Gender differences were only observed in the 20-49 age group. The results from the multiple regression models in subjects older than 20 years revealed that age, height and gender interaction together explained 6% of variation in FENO at 50 ml s-1 (FENO50), 4% in JawNO, 16% in CawNO, 8% in DawNO and 12% in CANO. In conclusion, in this study we have generated reference values for NO parameters from an extended NO analysis of healthy subjects. This is important in order to be able to use these parameters in clinical practice.

Response to letter to the editor from Elinder and Nordberg concerning Byber et al. 2016. Cadmium or cadmium compounds and chronic kidney disease in workers and the general population: a systematic review, Crit Rev Toxicol. 46(3):191-240. DOI: 0.3109/10408444.2015.1076375.

We are grateful for the opportunity to answer the letter by C.G. Elinder and G.F. Nordberg (2017) that raises interesting points. To meet the requested format of this response, we included here below the reference to the pages of the published paper rather than reproducing extracts. It is quite right that the criteria for classifying chronic kidney disease (CKD) into categories as defined nowadays [categories G1 to G5 and A1 to A3] were not in use when the first publications about cadmium-induced kidney disease were published. However, these current categories should not be confused with the definition of the disease characteristics or markers currently considered robust for diagnosing CKD (hematuria and hypertension, markers of glomerular filtration, proteinuria or albuminuria, histopathology) (Byber et al. 2016, p. 192–194). In other words, the literature search has not been restricted to publications applying the current CKD categorizing criteria, but used disease characteristics or markers currently considered robust for diagnosing CKD (Byber et al. 2016, p. 195). This was indispensable to avoid the problem of “chronic renal confusion” resulting from using different CKD definitions and a disturbing plethora of laboratory markers with ambiguous or unknown clinical significance (Byber et al. 2016, p. 192–193). The objective of our review was not to assess whether authors used the best criteria at the time their study was conducted, but to assess whether the evidence of a link with CKD (defined with criteria considered as robust and sound) and Cd exposure is currently available. These clinical characteristics and laboratory markers of disease (urea, creatinine, proteinuria) were well-known in the oldest studies (Byber et al. 2016, p. 212–213 and 223) and we indicated for each study whether changes in proteinuria and/ or GFR had occurred regardless of the current categorizing criteria (Table 1). The problem that could not be solved was a re-interpretation of pooled laboratory findings in the light of the current categorizing criteria. Indeed, a meta-analysis was impossible (Byber et al. 2016, p. 227–228). However, the changes concerning proteinuria and/or markers of GFR in each individual study between baseline and last examination did not indicate a consistent increase (Byber et al. 2016, p. 220, Tables S1–S34). To summarize, the current categories of the CKD classification were neither a search term nor an inclusion criterion and the disease characteristics currently considered sound for diagnosing CKD were already in use at the time of the oldest publications. Regarding the Swedish studies (J€arup et al. 1993, 1995), Elinder and Nordberg do not mention that the measurements they report did not show clear evidence of a decrease in measured GFR. The decrease was very small (<2.5ml/min/ 1.73m) and of doubtful clinical significance at best. This “decrease” was not confirmed by the three GFR estimates used in this study and not confirmed at the longest followup. Furthermore, a presentation bias may have been an issue (Byber et al. 2016, p. 209, 221 and 224). Finally, according to the outcome selected in our study (Byber et al. 2016, p. 195), the crucial point was GFR measurement, because it is considered the best overall index of kidney function (Byber et al. 2016, p. 193). It was measured with a reliable method (CrEDTA clearance) and the association with the “degree of tubular damage” was non-relevant for the purpose of our study. Lastly, in our opinion, kidney stones are not a typical form of CKD, and this information was, therefore, not discussed in depth (as in all other studies reporting kidney stones). The results summarized by Piscator (1984) had a fairly high risk of bias requiring very cautious interpretation (Byber et al. 2016, p. 209–210 and 223–224). As explicitly stated, ecological studies were not included in the systematic review (Byber et al. 2016, p. 194–195). A change in the inclusion criteria is imaginable but cannot be restricted to the study by Hellstr€ om et al. (2001) only. The other ecological studies would have to be considered as well for being able to assess the whole evidence (Byber et al. 2016, p. 218–219). Moreover, it cannot be ignored that the confidence interval in the publication by Hellstr€ om et al. (2001) was extremely wide and even compatible with a protective effect of cadmium exposure (Byber et al. 2016, p. 211). Furthermore, the exposure indicator was not reliable, which was reported by the same authors in a second publication (Hellstr€ om et al. 2004; Byber et al. 2016, p. 211 and 227). The occupational mortality studies mentioned by Elinder and Nordberg were discussed (Byber et al. 2016, p. 211). Of note, publications pertaining to the same population cannot be cited as independent studies and the evidence from the most recent and/or most detailed studies should be presented. With respect to publications by Nishijo et al. (2017) cited by Elinder and Nordberg, the inclusion criteria are again the decisive point. Studies were either excluded because they did not fulfill the inclusion criteria or were included. However, in