Targeting ferroptosis protects against experimental (multi)organ dysfunction and death.

The most common cause of death in the intensive care unit (ICU) is the development of multiorgan dysfunction syndrome (MODS). Besides life-supporting treatments, no cure exists, and its mechanisms are still poorly understood. Catalytic iron is associated with ICU mortality and is known to cause free radical-mediated cellular toxicity. It is thought to induce excessive lipid peroxidation, the main characteristic of an iron-dependent type of cell death conceptualized as ferroptosis. Here we show that the severity of multiorgan dysfunction and the probability of death are indeed associated with plasma catalytic iron and lipid peroxidation. Transgenic approaches underscore the role of ferroptosis in iron-induced multiorgan dysfunction. Blocking lipid peroxidation with our highly soluble ferrostatin-analogue protects mice from injury and death in experimental non-septic multiorgan dysfunction, but not in sepsis-induced multiorgan dysfunction. The limitations of the experimental mice models to mimic the complexity of clinical MODS warrant further preclinical testing. In conclusion, our data suggest ferroptosis targeting as possible treatment option for a stratifiable subset of MODS patients.

Use of lanthanum for water treatment A matter of concern?

Among several other eutrophication management tools, Phoslock®, a lanthanum modified bentonite (LMB) clay, is now frequently used. Concerns have been raised as to whether exposure to Phoslock®-treated water may lead to lanthanum accumulation/toxicity in both animals and humans. In the present experimental study, rats were administered lanthanum orally as either lanthanum carbonate, lanthanum chloride or Phoslock® at doses of either 0.5 or 17 mg/L during 10 weeks. Controls received vehicle. The gastrointestinal absorption and tissue distribution of lanthanum was investigated. Extremely strict measures were implemented to avoid cross-contamination between different tissues or animals. Results showed no differences in gastrointestinal absorption between the different compounds under study as reflected by the serum lanthanum levels and concentrations found in the brain, bone, heart, spleen, lung, kidney and testes. At sacrifice, significant but equally increased lanthanum concentrations versus vehicle were observed in the liver for the highest dose of each compound which however, remained several orders of magnitude below the liver lanthanum concentration previously measured after long-term therapeutic administration of lanthanum carbonate and for which no hepatotoxicity was noticed in humans. In conclusion, (i) the use of LMB does not pose a toxicity risk (ii) gastrointestinal absorption of lanthanum is minimal and independent on the type of the compound, (iii) with exception of the liver, no significant increase in lanthanum levels is observed in the various organs under study, (iv) based on previous studies, the slightly increased liver lanthanum levels observed in a worst case scenario do not hold any risk of hepatotoxicity.

[Blood lead levels and markers of renal dysfunction among mechanical workshop workers]. / Plomo y nefropatía: Biomarcadores urinarios en la detección de daño renal precoz.

UNLABELLED: The role of lead (Pb) as an environmental cause of nephropathy is difficult to ascertain due to the difficulty to determine clinically its exposure. AIM: To assess lead levels and renal function in a group of males working in mechanical workshops. MATERIAL AND METHODS: Blood and urine samples were obtained from 100 mechanical workshop workers aged 38 ± 16 years and 95 non-exposed office clerks aged 37 ± 17 years. Blood lead and creatinine levels were determined. In exposed workers, urinary excretion of intestinal alkaline phosphatases (IAP) and N-acetyl-glucosaminidase (NAG) were measured as early markers of renal failure. RESULTS: Blood lead levels were 66.4 ± 43 and 33.6 ± 18 µg/L among mechanical workshop workers and non-exposed controls, respectively, p < 0.01. The figures for serum creatinine were 0.9 ± 0.1 and 0.9 ± 0.1 respectively, p = NS. Among exposed workers urinary excretion of IAP was 0.47 ± 0.6 U/L and of NAG, 0.92 ± 1.1 U/L. There was a positive correlation between blood lead levels and NAG excretion (r = 0.284) and IAP excretion (r = 0.346). CONCLUSIONS: Exposed workers had higher blood lead levels and there was a weak positive association between these levels and the urinary excretion of NAG and IAP.

Plomo y nefropatía: biomarcadores urinarios en la detección de daño renal precoz / Blood lead levels and markers of renal dysfunction among mechanical workshop workers

The role of lead (Pb) as an environmental cause of nephropathy is difficult to ascertain due to the difficulty to determine clinically its exposure. Aim: To assess lead levels and renal function in a group of males working in mechanical workshops. Material and Methods: Blood and urine samples were obtained from 100 mechanical workshop workers aged 38 ± 16 years and 95 non-exposed office clerks aged 37 ± 17 years. Blood lead and creatinine levels were determined. In exposed workers, urinary excretion of intestinal alkaline phosphatases (IAP) and N-acetyl-glucosaminidase (NAG) were measured as early markers of renal failure. Results: Blood lead levels were 66.4 ± 43 and 33.6 ± 18 µg/L among mechanical workshop workers and non-exposed controls, respectively, p < 0.01. The figures for serum creatinine were 0.9 ± 0.1 and 0.9 ± 0.1 respectively, p = NS. Among exposed workers urinary excretion of IAP was 0.47 ± 0.6 U/L and of NAG, 0.92 ± 1.1 U/L. There was a positive correlation between blood lead levels and NAG excretion (r = 0.284) and IAP excretion (r = 0.346). Conclusions: Exposed workers had higher blood lead levels and there was a weak positive association between these levels and the urinary excretion of NAG and IAP.

Selenium, lead, and cadmium levels in renal failure patients in China.

Whole blood and serum samples of Chinese stable chronic renal failure (CRF) patients (n = 81), hemodialysis patients (n = 135), posttransplant patients (n = 60), and subjects with normal renal function (NRF; N = 42) were collected, as well as water and dialysate samples from five dialysis centers. The concentration of selenium (Se), lead (Pb), and cadmium (Cd) was measured by atomic absorption spectrometry. The mean serum Se levels in patients with different degrees of renal failure were significantly lower than those of subjects with NRF (p < 0.01). Pb levels were not increased in renal failure patients, while the Cd levels in patients with various degrees of renal failure were higher than in subjects with NRF (p < 0.05). After correcting the results of Pb and Cd for hematocrit (Hct) however, Pb levels of dialysis patients were also increased. In the dialysis population under study, blood Pb and Cd levels were closely related to the time on dialysis, while contamination of the final dialysate may also contribute to the increased blood Cd and to a less extent Pb levels. Correction for Hct may be recommended to accurately compare blood Pb and Cd levels in dialysis patients and CRF patients with varying degrees of anemia to those of subjects with NRF.

Time-evolution and reversibility of strontium-induced osteomalacia in chronic renal failure rats.

BACKGROUND: Patients with impaired renal function can accumulate strontium in the bone, which has been associated with the development of osteomalacia. A causal role for strontium in the development of the disease was presented in chronic renal failure (CRF) rats. Strontium-ranelate has been put forward as a therapeutic agent in the treatment of osteoporosis. Since the target population for strontium treatment consists mainly in postmenopausal osteoporotic women, who may have a reduced renal function, the risk for osteomalacia should be considered. METHODS: To determine the time evolution and reversibility of the strontium-induced mineralization defect, CRF rats were loaded with strontium (2 g/L) (+/- 200 mg/kg/day) during 2, 6, and 12 weeks, followed by a washout period of 0, 2, 4, or 8 weeks. RESULTS: Histologic examination of the bone of the animals treated with strontium revealed signs of osteomalacia already after 2 weeks. Animals that received strontium during 6 and 12 weeks had a significantly higher osteoid perimeter, area and thickness as compared to CRF controls. After 12 weeks, the mineralization was significantly affected, as evidenced by a lower double-labeled surface, mineral apposition and bone formation rate in combination with an increased osteoid maturation time and mineralization lag time. The osteoblast perimeter was significantly lower in the strontium-treated animals. After the washout periods, these effects were reversed and the bone lesions evolved to the values of CRF controls. This went along with an 18% reduction of the bone strontium content. A significant rise in serum alkaline phosphatase (ALP) activity was apparent in the strontium-treated animals as compared to CRF controls. This was not only due to higher levels of the bone ALP but also to those of the liver and the intestinal isoenzymes. Serum parathyroid hormone (PTH) levels decreased during strontium treatment. After cessation of the treatment, the serum ALP activity and PTH concentration reversed to control levels. CONCLUSION: In this study evidence is provided for the rapid development of a mineralization defect in strontium-loaded CRF rats, accompanied by a reduced osteoblast number, reduced PTH synthesis or secretion, and increased serum ALP levels. These effects can be rapidly reversed after withdrawal of the compound.

Dose-dependent effects of strontium on bone of chronic renal failure rats.

BACKGROUND: We previously reported on increased bone strontium (Sr) levels in dialysis patients with osteomalacia versus those presenting other types of renal osteodystrophy. A causal role of strontium in the development of osteomalacia was established in a chronic renal failure (CRF) rat model. METHODS: In the present study we investigated whether the effect of Sr on bone was related to dosage. Four groups of CRF rats were studied: a control group (control-CFR; N=6) not receiving strontium and three groups of animals loaded orally with Sr during 18 weeks by adding the element as the SrCl2. H20 compound to the drinking water at concentrations of 0.03 g/100mL (Sr-30; N=6), 0.075 g/100mL (Sr-75; N=6), or 0.15 g/100mL (Sr-150; N=6) respectively. A fifth group consisting of seven animals with intact renal function (control-NRF), not receiving Sr served as controls for the effect of CRF on bone histology. RESULTS: As compared to the control-NRF and control-CRF groups, Sr administration resulted in a dose-dependent increase in bone and serum Sr levels. No difference in body weight and biochemical serum and urinary parameters [i.e., calcium (Ca), phosphorus (P), and creatinine] was noted between the various CRF groups. At sacrifice, intact parathyroid hormone (iPTH) levels of CRF groups were significantly (P < 0.05) higher than the values measured in the control-NRF group indicating the development of hyperparathyroidism secondary to the installation of the CRF. This is further supported by the differences in bone histomorphometry between the control-CRF and control-NRF animals, which, respectively, showed an increased amount of osteoid (mean +/- SEM 3.4 +/- 1.2% vs. 0.37 +/- 0.14%, P < 0.05) in combination with a distinct osteoblastic activity (35 +/- 11% vs. <2%, P < 0.05) and an increased bone formation rate [(BFR), 677 +/- 177 microm 2/mm2/day vs. 130 +/- 50 microm 2/mm2/day, P < 0.05]. Bone surface area and erodic perimeter did not differ between the various study groups. In the Sr-30 group, Sr loading went along with a dramatic reduction of the BFR as indicated by the total absence of double tetracyclin labels and osteoblastic activity, which in the presence of a low to normal amount of osteoid (2.7 +/- 1.9%) points to the development of the adynamic type of renal osteodystrophy. Interestingly, compared to the control-CRF group, histodynamic and histologic parameters of the Sr-75 group did not differ significantly and a substantial osteoblastic activity (7.6 +/- 4.0%) was seen also. In the Sr-150 group, the various osteoid parameters were significantly (P < 0.05) increased vs. all other groups and were accompanied by a reduced BFR and mineral apposition rate (MAR) and an increased mineralization lag time (MLT), indicating a mineralization defect and the development of osteomalacia. CONCLUSIONS: Our findings indicate that the role of Sr in the development of bone lesions in renal failure is complex and that, depending on the dose, the element may act via multiple pathways.