Aluminum overload in the reverse osmosis dialysis era: does it exist?

BACKGROUND: Aluminum accumulation is a well-described complication in dialysis patients. Improvements in hemodialysis technology have possibly eliminated the occurrence of aluminum overload. Limited evidence suggests that aluminum overload may decline in the era of aluminum removal from dialysis fluids, even with the use of aluminum binders. METHODS: We examined the data from January 2014 to June 1, 2020, identified through our electronic records, to evaluate the desferrioxamine (DFO) test results for aluminum overload. The presentation and treatment of aluminum overload were recorded. RESULTS: Ninety-nine dialysis patients were enrolled for the DFO test. Forty-seven patients (47.5%) were identified as DFO test positive for aluminum overload, of which 14 (14/47) patients had symptoms, including one patient with an unexplained fracture, eight patients with unexplained anemia despite high-dose erythropoiesis-stimulating agents, and five patients with hypercalcemia (serum calcium >11 mg dL-1). None of the patients with aluminum overload developed encephalopathy. Only four of the 47 patients had microcytic anemia. Patients requiring longer treatments (>10 months versus <10 months) had similar basal serum aluminum (p = 0.219) but had an increase in serum aluminum after DFO (p = 0.041). Furthermore, the treatments decreased erythropoietin doses in the aluminum overload group, with serum total alkaline phosphatase levels <60 U L-1 (p = 0.028). CONCLUSION: We concluded that aluminum overload existed in the reverse osmosis dialysis era. In light of non-obvious symptoms, such as anemia and bone turnover change, serum aluminum in dialysis patients should be monitored in countries using aluminum-based phosphate binders, despite reverse osmosis dialysis.

CysLTR1 Blockage Ameliorates Liver Injury Caused by Aluminum-Overload via PI3K/AKT/mTOR-Mediated Autophagy Activation in Vivo and in Vitro.

Aluminum (Al) is a trivalent cation that can accumulate in animal organs, especially in the liver. We previously demonstrated that Al-overload could induce liver morphologic aberrations and dysfunction. However, the molecular mechanism underlying liver injury caused by Al-overload still remains unknown. In the present study, we investigated the relationship between leukotrienes receptors and the PI3K/AKT/mTOR pathway in Al-induced liver injury in vivo and in vitro. We demonstrated that Al-overload significantly increased the protein expression levels of CysLTR1, PI3K, AKT, mTOR, and p62, while significantly decreasing the LC3BII protein levels in rat liver; thus, suggesting that the autophagy process was inhibited in Al-overloaded rat liver. In addition, MK-571, an inhibitor of CysLTR1, effectively protected the human hepatocyte L02 cells against injury caused by Al exposure. Moreover, CysLTR1 blockage could significantly down-regulate the PI3K/AKT/mTOR pathway and activate autophagy. The effect of MK-571 on cell viability was abolished by the treatment with the autophagy inhibitor (wortmannin) but not with the autophagy agonist (rapamycin). Taken together, our results indicated that the blockage of the leukotriene receptor of CysLTR1 promotes autophagy and further reduces hepatocyte death through the PI3K/AKT/mTOR pathway inhibition. CysLTR1 thus could represent a potential target for the new drug development for chronic noninfective liver injury.

Effect of PGE2-EPs pathway on primary cultured rat neuron injury caused by aluminum.

To observe the characteristic changes of PGE2-EPs pathway and divergent functions of PGE2 receptor subtypes on neuronal injury. The primary cultured rat hippocampus neuron injury model was established via aluminum maltolate (100 µM). The aluminum-overload neurons were treated with the agonists of EP1 (17-phenyl trinor Prostaglandin E2 ethyl amide), EP2 (Butaprost), EP3 (Sulprostone) and EP4 (CAY10598) and antagonists of EP1 (SC-19220), EP2 (AH6809) and EP4 (L-161982) at different concentrations, respectively. The neuronal viability, lactate dehydrogenase leakage rate and PGE2 content were detected by MTT assay, lactate dehydrogenase assay kit and enzyme-linked immunosorbent assay, respectively. The mRNA and protein expressions of mPGES-1 and EPs were determined by RT-PCR and western blot, respectively. The pathomorphology was identified by hematoxylin-eosin staining. In the model group, neuronal viability significantly decreased, while lactate dehydrogenase leakage rate and PGE2 content increased. The mPGES-1, EP1, EP2 and EP4 mRNA expression, and the mPGES-1, EP1 and EP2 protein expression increased, while EP3 level decreased. EP3 agonist exerted protective function in neuronal viability and lactate dehydrogenase leakage rate, while EP1 agonist, EP2 and EP4 antagonist exerted an opposite effect. In conclusion, aluminum-overload caused an imbalance of PGE2-EP1-4 pathway and activation of EP receptor may provide a viable therapeutic target in neuronal injury.

Effects of DP2 intervention on primary cultured rat hippocampal neuron treated with aluminum overload / 中国药理学通报

Aim To establish primary cultured rat hip-pocampal neuron damage model induced by aluminum maltolate and study the effect of intervention for DP2 on primary cultured rat hippocampal neuron treated with aluminum overload. Methods The hippocampus was dissected out from fetal rat ( embryonic 18 d ) . After being cultured for 7 d, the hippocampal neuron was treated with Al( malt) 3 to establish the model of prima-ry cultured rat hippocampal neuron damage and mean-while treated with DP2 agonist DK-PGD2 and DP2 an-tagonist CAY10471, respectively. After treatment for 24 h, the cell viability was measured by MTT and LDH, Ca2+ fluorescence intensity. Neuronal pathomor-phology was observed by HE staining. Results The purity of hippocampal neuron was more than 95%. Compared with the control group, the number of hipp-ocampal neurons was reduced and neurons became chromatic agglutination and karyopyknosis in aluminum overload group. Treatment of aluminum caused a sig-nificant decrease in MTT value ( P<0. 01 ) and an in-crease in the LDH leakage rate (P<0. 01). The Ca2+fluorescence intensity significantly increased ( P <0. 01 ) in aluminum overload group. Compared with that of the aluminum overload group, treatment of DK-PGD2 , a selective DP2 agonist, significantly aggravated the primary cultured rat hippocampal neuron injury caused by aluminum overload accompanied with the significant decrease of MTT value ( P <0. 01 , P <0. 05 ) and an increase of the LDH leakage rate ( P<0. 01), significant increase of Ca2+ fluorescence inten-sity of neuron. Treatment of CAY10471, a selective DP2 antagonist, had opposite effects of DK-PGD2 . Conclusion The activation of DP2 can increase hipp-ocampal neural susceptibility to aluminum overload.

Effects of beraprost sodium on cerebral cortical neuron injury induced by chronic aluminum-overload in rats / 中国药理学通报

Aim To investigate the protective effects of beraprost sodium on cerebral cortical neuron injury in chronic aluminum-overload rats and its effects on PGIS-IP signaling pathway. Methods 75 SD rats were randomized into five groups: normal control group, chronic aluminum-overload group ( model group) and beraprost sodium groups-low dose (6 μg· kg-1 ), medium dose ( 12 μg · kg-1 ) and high dose (24 μg·kg-1). Aluminum gluconate (Al3+ 200 mg ·kg-1 d-1, once a day, 5d a week, for 20 weeks, p. o. ) was administered to rats of cerebral damage model. The rats of experimental groups were concomi-tantly treated with beraprost sodium ( p. o. ) daily for 20 weeks. After the model was built successfully, the spatial learning and memory( SLM) function was done by Morris water maze. The cortical neurons damage was detected by HE staining, SOD activities and MDA contents. The 6-k-PGF1α levels in cortex were meas-ured by ELISA. The expressions of PGIS, IP mRNA and IP protein were also studied. Results Compared with the rats of normal control group, the SLM function was significantly impaired ( P<0. 01 ) and considera-ble karyopycnosis was observed in model group rats. The SOD activities were weakened ( P <0. 01 ), the MDA contents increased ( P<0. 05 ) and the levels of 6-k-PGF1α raised significantly ( P <0. 01). The ex-pressions of PGIS and IP mRNA in the rats cortex obvi-ously increased ( P<0. 01 ), so did the expression of IP protein(P<0. 05). Compared with the rats of mod-el group, the SLM function of rats in experimental groups decreased significantly ( P<0. 01 ) and damage of cortical neurons reduced remarkably. The SOD ac-tivities increased ( P <0. 01 ) and the MDA contents decreased ( P <0. 01). Besides, the content of 6-k-PGF1α, the expressions of PGIS mRNA and IP protein in the rats cortex decreased significantly ( P<0. 05 ) as well as IP mRNA ( P<0. 01). Conclusion Our re-sults demonstrate that in cerebral cortical neuron of chronic aluminum-overload rats, beraprost sodium has notably protective effects and the mechanism might be related to PGIS-IP signaling pathway.

Protective effect of caffeic acid on damage induced by aluminum-overload in primary cultured rat hippocampal neuron / 中国药理学通报

Aim In order to study the protective effect of caffeic acid on damage induced by aluminum-overload in primary cultured rat hippocampal neuron.Methods Primary cell cultures were obtained from the cerebral hippocampus of Newly born SD rats within 24 h.On the d 7 of neuronal culture, the immunohistory of NSE was used to identify the purity of neuron.There were 5 experimental groups,NaCl(200 μmol·L~(-1))-treated group, AlCl_3-treated group(200 μmol·L~(-1)),and aluminum+caffeic acid(10~(-6) mol·L~(-1),10~(-7) mol·L~(-1) and 10~(-8) mol·L~(-1))-treated groups. HE staining was used to observe the change of neuronal pathomorphology. The cell viability was measured by MTT assay. SOD activity, LDH leakage and MDA contents were also detected.Results The purity of neurons was more than 95%. Aluminum administration induced loss of neurons and damage to dendrite and axon.Compared with that of the control group,the decreased viability of neurons,increased leakage of LDH, decreased activity of SOD and increased contents of MDA were observed in aluminum-treated groups.Compared with that of the model group, the administration of Caffeic acid could significantly blunt the death of the primary cultured hippocampal neurons, and blunt the decrease of neuronal viability and SOD activity and the increase of LDH leakage and MDA contents.Conclusions These results suggest that caffeic acid has an obvious protective effect against neuronal damage induced by aluminum overload in primary cultured neurons. The mechanism of protection might involve the anti-inflammation and anti-oxidative effects of caffeic acid.

Neurotoxicity of chronic aluminum overload and protective effects of nimodipine in rats / 第三军医大学学报

Objective To study the neurotoxicity of chronic aluminum overload and the protective effects of nimodipine in rats.Methods The brain damage models of rats were established via intragastric administration of aluminum gluconate(element aluminum 400 mg/kg)once a day,5 d/week for 12 weeks.The step-down test and programmed Morris water maze test were used to evaluate the changes of learning and memory functions of rats.Pathomorphological changes of hippocampi of rats were observed.The activities of SOD,ChAT,AchE,MAO-B and the contents of MDA of brain tissue in rats were also measured.Nimodipine(80 mg/kg)were intragastrically administered 4 h after aluminum administration every time for 12 weeks.Results Chronic aluminum administration induced the impairment of avoidance learning and memory ability and spatial oriental ability.Consistent with the behavioral changes,neuronal death in the hippocampi,decreased activities of SOD and ChAT,increased content of MDA,and increased activity of MAO-B and AchE were detected in the aluminum-overload mice.The administration of nimodipine could significantly protect rats from the brain damage,and behavioral and biochemical changes above caused by aluminum overload were in a dose-dependent manner.Conclusion These results suggest that changes of cellular calcium overload and oxide stress and MAO-B activities are involved in pathophysiological mechanisms of brain injury induced by chronic aluminum overload.Nimodipine has a protective effect on neurotoxicity of chronic aluminum overload.

Effects of caffeic acid on brain damage induced by chronic aluminum overload in rats / 中国药理学通报

Aim To study the protective effect of caffeic acid on brain damage induced by chronic aluminum overload in rats.Methods The brain injury model of rats was established via intragastric administration of aluminum gluconate(element aluminum 200 mg?kg-1) once a day,5 d a week for 20 weeks.The 5-LO inhibitor caffeic acid(30 mg?kg-1,10 mg?kg-1) was intragastrically administered 1 h after aluminum administration.Pathomorphological changes of hippocampal neuron and the spatial learning and memory function were observed.The MAO-B,AChE and SOD activities,and the MDA contents of brain tissue in rats were measured.Results Chronic aluminum overload could markedly induce spatial learning and memory function impairment,and hippocampal neuronal injury in rats.The MAO-B and AChE activities,and the MDA content significantly increased,while SOD activities significantly decreased in chronic aluminum overload rats.The administration of the caffeic acid can significantly prevent rats from learning and memory function impairments and hippocampal neuronal death,and blunted the decrease of SOD activities and increased MDA contents induced by chronic aluminum overload in rats.Caffeic acid also obviously decreased the MAO-B activities and AChE activities of chronic aluminum overload rats.Conclusion Administration of caffeic acid can prevent the rat brain from damage induced by chronic aluminum overload.

Correlation between aluminum overload-induced brain neurodegeneration and monoamine oxidase B in mouse brain / 重庆医科大学学报

Objective:To adopt the brain lesion model of mouse induced by overload aluminum to study the relationship between monoamine oxidase B disorder and neurodegeneration induced by overload aluminum(Al).Method:Aluminum overload models were established by injection of 3?l AlCl3 into lateral ventricle of miceeach day for 5d.The AlCl3 solutions injected in different modelswere with different concentrations and they were 0.125%,0.25%,0.5%.On d10,d20,and d30 after the final administration of AlCl3 solution,the learning and memory function of mice,pathomorphology of hippocampi,and MAO-B activity were determined.Results:Aluminum overload elevated MAO-B activity,caused karyopyknosis and loss of neurons in CA1 area of hippocampi,in dose-and time-dependent manners.Conclusion:The results indicate that neurodegeneration induced by Al toxicity may be related to the monoamine oxidase B homeostasis interfered by Al overload.

Study of the relationship between aluminum overload-induced neurodegeneration and systems of oxidative stress and anti-oxidative stress in mice / 重庆医科大学学报

Objective: To study the roles of the oxidative stress system and the anti-oxidative stress system in neurodegenerative processes induced by aluminum overload in mice.Methods: The neurodegenerative model of mice was established via intragastric administration of AlCl3 solution(element aluminum 400 mg/kg)once a day,with 6 days of week for 3 months.The light-dark test and morris-water-maze were used to evaluate the learning and memory functions.The activities of SOD and SOD2 as well as the contents of MDA in both cortices and hippocampi were measured.Pathomorphological changes of hippocampi were observed.Results: Aluminum overload significantly decreased capacity of passive avoidance learning and memory and spatial recognition,caused the pyknosis and neuron loss of hippocampi,and parallelly increased SOD and SOD2 activities as well as MDA content in cortex and hippocampi,with a tendency of raising first and then gradually decreasing.Conclusions: Aluminum overload markedly causes neurodegeneration and damages learning and memory function in mice,the mechanism of which may be related to the imbalance between oxidative stress and anti-oxidative stress systems in brain induced by aluminum overload.