Per Bjellerup

Tubular and glomerular kidney effects in Swedish women with low environmental cadmium exposure

Cadmium is a well-known nephrotoxic agent in food and tobacco, but the exposure level that is critical for kidney effects in the general population is not defined. Within a population-based women’s health survey in southern Sweden (Women’s Health in the Lund Area, WHILA), we investigated cadmium exposure in relation to tubular and glomerular function, from 1999 through early 2000 in 820 women (71% participation rate) 53–64 years of age. Multiple linear regression showed cadmium in blood (median, 0.38 μg/L) and urine (0.52 μg/L; density adjusted = 0.67 μg/g creatinine) to be significantly associated with effects on renal tubules (as indicated by increased levels of human complex-forming protein and N-acetyl-β-d-glucosaminidase in urine), after adjusting for age, body mass index, blood lead, diabetes, hypertension, and regular use of nephrotoxic drugs. The associations remained significant even at the low exposure in women who had never smoked. We also found associations with markers of glomerular effects: glomerular filtration rate and creatinine clearance. Significant effects were seen already at a mean urinary cadmium level of 0.6 μg/L (0.8 μg/g creatinine). Cadmium potentiated diabetes-induced effects on kidney. In conclusion, tubular renal effects occurred at lower cadmium levels than previously demonstrated, and more important, glomerular effects were also observed. Although the effects were small, they may represent early signs of adverse effects, affecting large segments of the population. Subjects with diabetes seem to be at increased risk.

Cadmium-induced effects on bone in a population-based study of women

High cadmium exposure is known to cause bone damage, but the association between low-level cadmium exposure and osteoporosis remains to be clarified. Using a population-based women’s health survey in southern Sweden [Women’s Health in the Lund Area (WHILA)] with no known historical cadmium contamination, we investigated cadmium-related effects on bone in 820 women (53–64 years of age). We measured cadmium in blood and urine and lead in blood, an array of markers of bone metabolism, and forearm bone mineral density (BMD). Associations were evaluated in multiple linear regression analysis including information on the possible confounders or effect modifiers: weight, menopausal status, use of hormone replacement therapy, age at menarche, alcohol consumption, smoking history, and physical activity. Median urinary cadmium was 0.52 μg/L adjusted to density (0.67 μg/g creatinine). After multivariate adjustment, BMD, parathyroid hormone, and urinary deoxypyridinoline (U-DPD) were adversely associated with concentrations of urinary cadmium (p < 0.05) in all subjects. These associations persisted in the group of never-smokers, which had the lowest cadmium exposure (mainly dietary). For U-DPD, there was a significant interaction between cadmium and menopause (p = 0.022). Our results suggest negative effects of low-level cadmium exposure on bone, possibly exerted via increased bone resorption, which seemed to be intensified after menopause. Based on the prevalence of osteoporosis and the low level of exposure, the observed effects, although slight, should be considered as early signals of potentially more adverse health effects.

Cadmium Exposure in Pregnancy and Lactation in Relation to Iron Status

OBJECTIVES The purpose of this study was to determine the impact of iron status on cadmium dose among pregnant women. METHODS Iron status and cadmium concentration in blood, urine, and placenta were determined among women followed for 2 years from early pregnancy. RESULTS Blood cadmium and urinary cadmium were correlated with iron status throughout the study period. Urinary cadmium increased longitudinally among women with exhausted iron stores during their pregnancy. The increase in urinary cadmium with age was more pronounced in multiparous than in nulliparous women. CONCLUSIONS Iron deficiency during pregnancy leads to increased cadmium absorption and body burden. Multiparous women exhibit additional increases with increasing age.

Metal-bone interactions.

Recent studies indicate that lead and cadmium may exert both direct and indirect actions on bone turnover, indirectly via kidney dysfunction, and directly on osteoblast and osteoclast function. Increased blood lead concentrations, most likely as a result of an increased bone turnover, have been detected in pregnant, lactating, and menopausal women. Lead exposure has also been negatively associated with childrens growth in stature. Both lead and cadmium are nephrotoxic and can disturb vitamin D metabolism. Cadmium has been shown to induce kidney damage and osteoporosis/osteomalacia at long-term high-level exposure. A negative association between cadmium dose and bone mass has recently been detected in both occupationally and environmentally exposed people at relatively low cadmium exposure.

Evaluation of kits for measurement of the soluble transferrin receptor.

Three commercially available kits for determination of the soluble serum transferrin receptor (sTfR), R&D Systems, UK, Ramco Laboratories, USA and Orion, Finland were compared with respect to practicability, comparability and ability to discriminate between iron deficient and non-iron deficient subjects. Serum samples representing different concentrations of sTfR were tested. The three kits involved virtually the same laboratory procedures except for a predilution step for Ramco. Both the absolute amounts and the units (mg/L and nmol/L) differed among the kits, emphasizing the need for internationally accepted reference material and comparable units. The correlation coefficients were 0.974 (Ramco and R&D), 0.769 (R&D and Orion) and 0.759 (Ramco and Orion), indicating a lower comparability for Orion compared to the other two kits. The differences between the kits may be attributed to uncertainties in the reference intervals and to variations in kit format. This may have implications for studies of the usefulness of sTfR as a marker of iron deficiency.

Soluble transferrin receptor: longitudinal assessment from pregnancy to postlactation.

OBJECTIVE To assess the impact of pregnancy and lactation on iron status and erythropoiesis as measured by the soluble transferrin receptor (sTfR). METHODS We recruited women in early pregnancy to be followed for 2 years. We determined sTfR and sTfR/serum ferritin (sTfR/Fer) during puerperium (n = 77), lactation (n = 111), and postlactation (n = 57), with comparison to data obtained during pregnancy (n = 224). Data were evaluated using analysis of variance for repeated measures as the women continuing the study were found to be representative of those entering the study. RESULTS We found that sTfR and sTfR/Fer were significantly higher at all sampling occasions compared with early pregnancy (P < .001). Iron status markers did not regain first‐trimester levels postpartum. Postlactation, 20% of the women had depleted iron stores (sTfR/Fer greater than 500), and 10% had tissue iron deficiency (sTfR greater than 8.3 mg/L). Iron status worsened with increasing parity and was significantly correlated to blood loss at delivery. In a subgroup of women with persistent adequate iron stores, first‐trimester sTfR was similar to that in the puerperium but significantly lower than that postlactation. Cord sTfR (n = 32) was twice maternal sTfR and not correlated to maternal serum ferritin, gestational age, or other birth variables. CONCLUSION Our data show decreased erythropoiesis in early gestation and during the first week of the puerperium. To prevent a negative effect of childbearing on iron status, postpartum iron supplementation should be considered in women who bleed excessively at parturition and in those who choose to take a low dose of iron or none at all during pregnancy.

Bone turnover from early pregnancy to postweaning

Background.  To elucidate the sequences of changes in bone metabolism and bone density during pregnancy, lactation and postweaning.

Retinol May Counteract the Negative Effect of Cadmium on Bone

Cadmium and high vitamin A intake are both proposed risk factors for low bone mineral density (BMD), but potential interactions have not been studied. Within the Womens Health in the Lund Area, a population-based study in southern Sweden, we measured retinol in serum among 606 women aged 54-64 y. Data on BMD were measured by DXA at the distal forearm. Parathyroid hormone (PTH), bone alkaline phosphatase (bALP), and osteocalcin in serum and deoxypyridinoline (DPD) and cadmium in urine were available. Associations were evaluated using multivariable-adjusted linear regression analysis. Serum retinol concentrations (median, 1.9; range, 0.97-4.3 μmol/L) were inversely associated with the bone formation markers bALP and osteocalcin (P ≤ 0.04) and with PTH (P = 0.07) and tended to be positively associated with BMD (P = 0.08) but not with the bone resorption marker DPD, indicating different effects on bone compared to urinary cadmium (median, 0.66; range, 0.12-3.6 nmol/mmol creatinine). Women with serum retinol less than the median and cadmium greater than the median had lower BMD than those with retinol greater than the median and cadmium less than the median (P = 0.016 among all women and P = 0.010 among never-smokers). Our findings suggest that adequate vitamin A status may counteract the adverse association between cadmium and BMD.

Cadmium exposure in pregnancy and lactation in relation to iron status

Evidence is mounting that dietary cadmium may lead to renal tubular damage and progress to end-stage kidney disease. Because more cadmium is absorbed when iron stores are depleted and iron absorption is elevated in late pregnancy, this prospective study estimated blood and urinary cadmium concentrations and related them to iron status in 254 women 20 to 45 years of age who were followed from early in their pregnancies; 15% were current smokers. In addition, estimates were made in 106 placental and 32 cord blood samples collected at the time of delivery. Cadmium levels were determined by atomic absorption spectrophotometry. Nonsmoking women had a medium cadmium level of 0.16 μg/liter. Smokers, with levels 4 to 5 times higher, were excluded from further analyses. Both blood and urinary cadmium levels correlated negatively with the serum ferritin level and positively with the level of soluble transferrin receptor as well as the receptor/serum ferritin ratio. Age was not a confounding factor. More than half the women had exhausted their iron stores by late gestation, and 15% of them had tissue iron deficiency. The latter women had blood and urinary cadmium levels 40% to 50% higher than those without tissue iron deficiency during the period of lactation. The blood cadmium level increased approximately 20% from early gestation to lactation and the postlactation period. Only iron-depleted women had increased urine levels at the time of lactation, and they exhibited a further increase after lactation. Urinary cadmium increased with both advancing age and parity, which themselves interacted. Total placental cadmium content (but not concentration) correlated with the soluble transferrin receptor/serum ferritin ratio in late gestation and with the receptor concentration in cord blood serum. These findings suggest that the increased cadmium burden in women compared with men is a result of pregnancy and low iron status. Those with low iron stores, particularly women having multiple pregnancies, may be at increased risk for developing osteoporosis. Cereals and vegetables, which frequently are recommended for health-related reasons, are the major dietary sources of cadmium.