Aluminium toxicity in people on dialysis

Aluminium toxicity in people on dialysis is the accumulation of aluminium in the body of patients with advanced kidney failure treated by haemodialysis or peritoneal dialysis, producing bone disease, anaemia and encephalopathy.透析人群中的铝毒性指接受血液透析或腹膜透析的晚期肾衰竭患者体内铝蓄积，可导致骨病、贫血与脑病。

It became a recognised clinical problem in the 1970s, when dialysis units reported clusters of dementia, fractures and erythropoietin-resistant anaemia that were traced to aluminium in the water used to prepare dialysate.该问题在二十世纪七十年代被确认为临床疾病，当时多个透析中心报告痴呆、骨折与促红细胞生成素抵抗性贫血的聚集，并被追溯至配制透析液用水中的铝。

Terminology and classification

• The condition is also called aluminium intoxication, aluminium overload or dialysis-associated aluminium toxicity, and older texts use the term dialysis dementia for its neurological form.该病又称铝中毒、铝负荷过重或透析相关铝毒性，早期文献以透析性痴呆指称其神经型。
• Three organ systems dominate the clinical picture, namely aluminium-induced bone disease, a microcytic hypochromic anaemia and a neurological syndrome that ranges from subtle speech disorder to frank encephalopathy.临床表现集中于三个系统，即铝所致骨病、小细胞低色素性贫血，以及从轻微言语障碍到明显脑病的神经综合征。
• Aluminium bone disease is classified within renal osteodystrophy, and the aluminium-related pattern is usually osteomalacia with low bone turnover rather than the high-turnover osteitis fibrosa of severe hyperparathyroidism.铝性骨病归入肾性骨营养不良，其铝相关类型通常为骨软化伴低骨转换，而非严重甲状旁腺功能亢进所致的高转换性纤维囊性骨炎。
• Dialysis encephalopathy syndrome was the historical name for the neurological form, described by Alfrey and colleagues in 1976 as a progressive and often fatal disorder of speech, movement and cognition.透析脑病综合征是该神经型的历史名称，由 Alfrey 及其同事于 1976 年描述为一种进行性且常致命的言语、运动与认知障碍。^[1]
• The entity is distinct from contact allergy to aluminium salts and from the macrophage myofasciitis attributed to aluminium adjuvants, both of which are immune phenomena rather than systemic metal accumulation.该疾病不同于铝盐接触过敏与归因于铝佐剂的巨噬细胞性肌筋膜炎，后两者属于免疫现象而非全身性金属蓄积。
• In the International Classification of Diseases tenth revision the toxic effect of aluminium is coded under T56.8 for other metals, and the encephalopathic and bone manifestations are usually indexed under their own symptom or renal osteodystrophy codes.在国际疾病分类第十版中，铝的毒性效应归于其他金属项下的 T56.8，而脑病与骨病变通常另按症状编码或肾性骨营养不良编码。

History

• Aluminium was rarely considered a toxin before the dialysis era, because healthy kidneys excrete absorbed metal efficiently and gastrointestinal absorption is low.在透析时代之前铝很少被视为毒物，因为健康肾脏能有效排出吸收的金属，且胃肠道吸收率低。
• Outbreaks in the 1970s were linked to high aluminium concentrations in municipal water and to the use of aluminium sulphate as a flocculant in water treatment plants.二十世纪七十年代的暴发与市政供水铝浓度过高以及水厂以硫酸铝作絮凝剂有关。^[2]
• Alfrey's 1978 review consolidated the syndrome and established aluminium as a cause of dialysis-associated dementia and osteomalacia, a view that was initially contested by nephrologists who favoured uraemic toxins.Alfrey 1978 年的综述整合了该综合征，并确立铝为透析相关痴呆与骨软化的病因，这一观点最初受到倾向尿毒症毒素学说的肾脏病学家质疑。^[3]
• Alfrey, LeGendre and Kaehny reported in the New England Journal of Medicine in 1976 that brain aluminium was elevated in patients dying with dialysis encephalopathy, and proposed aluminium intoxication as the cause.Alfrey、LeGendre 与 Kaehny 于 1976 年在《新英格兰医学杂志》报告，死于透析脑病的患者脑铝升高，并提出铝中毒为病因。^[1]
• The introduction of reverse osmosis, deionisation and distillation for dialysate preparation, together with limits on aluminium-based phosphate binders, caused the syndrome to become rare in units with modern water treatment.透析液制备引入反渗透、去离子与蒸馏，并限制含铝磷结合剂后，该综合征在现代水处理的透析中心变得罕见。
• The 2005 Kidney Disease Outcomes Quality Initiative guideline on bone metabolism in children with chronic kidney disease recommended a pre-dialysis serum aluminium below 20 micrograms per litre and dialysate aluminium below 0.01 milligrams per litre.2005 年慢性肾病儿童骨代谢的肾脏疾病结局质量倡议指南建议透析前血铝低于 20 微克每升、透析液铝低于 0.01 毫克每升。
• Deferoxamine, an iron chelator that also binds aluminium, was introduced in 1980 and remains the only established pharmacological treatment for aluminium overload.去铁胺是一种同时结合铝的铁螯合剂，于 1980 年引入，至今仍是铝负荷过重唯一成熟的药物治疗。
• Cases continue to be reported in the reverse osmosis era, usually in patients with long dialysis vintage, aluminium-containing binders or incomplete water treatment, so the diagnosis must still be considered.反渗透时代仍有病例报告，多见于透析年限长、使用含铝结合剂或水处理不彻底的患者，因此仍须考虑该诊断。^[4]

Epidemiology

• Population-level incidence is no longer measurable in countries with regulated dialysis water, and a 2018 review noted that current estimates come from unit audits and case series rather than from registries.在透析用水受监管的国家已无法测量人群发病率，2018 年的一篇综述指出，现有估计来自透析中心审计与病例系列而非登记系统。^[5]
• A Taiwanese cross-sectional study published in 2022 found blood aluminium above the reference range in about 2.2 per cent of haemodialysis and peritoneal dialysis patients.2022 年发表的一项台湾横断面研究发现，约 2.2% 的血液透析与腹膜透析患者血铝高于参考范围。^[6]
• Before water treatment was standardised, encephalopathy outbreaks affected a substantial minority of patients in the involved units, and mortality within a year was high.在水处理标准化之前，脑病暴发累及相关中心相当比例的患者，一年内死亡率很高。
• Risk is highest with long cumulative dialysis exposure, use of aluminium hydroxide as a phosphate binder, aluminium-contaminated dialysate, parenteral nutrition and probably childhood because of growing bone.累积透析暴露时间长、以氢氧化铝作磷结合剂、透析液铝污染、肠外营养以及生长期儿童（因骨生长活跃）风险最高。
• Geographical variation reflects water aluminium content and local prescribing habits, and resource-limited centres without reverse osmosis still carry a measurable burden.地理差异反映供水铝含量与当地处方习惯，没有反渗透设备的资源有限中心仍承受可测量的负担。
• Because serum aluminium is not measured routinely in many programmes, asymptomatic overload is probably under-recognised and the true prevalence is unknown.由于许多透析项目不常规检测血铝，无症状负荷过重很可能被低估，真实患病率不明。

Pathophysiology

• Aluminium enters through the dialysate, because the dialyser does not remove aluminium efficiently and can transfer it from contaminated water into the blood, and through the gut when aluminium binders or antacids are taken.铝经透析液进入体内，因为透析器不能有效清除铝，反而可将污染水中的铝转入血液；口服含铝结合剂或抗酸剂时铝也经肠道吸收。
• More than 80 per cent of circulating aluminium is bound to transferrin, so diffusive clearance during dialysis is small and tissue stores accumulate over years.循环中八成以上的铝与转铁蛋白结合，因此透析时弥散清除量很小，组织储存逐年累积。^[5]
• In bone, aluminium deposits at the mineralisation front, inhibits hydroxyapatite formation and impairs osteoblast function, producing osteomalacia and a low-turnover adynamic pattern.在骨内铝沉积于矿化前沿，抑制羟基磷灰石形成并损害成骨细胞功能，造成骨软化与低转换的无力型骨。
• In erythroid precursors aluminium interferes with haem synthesis, so anaemia is microcytic and hypochromic and responds poorly to erythropoietin and iron.在红系前体细胞中铝干扰血红素合成，故贫血呈小细胞低色素性，对促红细胞生成素与铁剂反应差。
• In the brain aluminium accumulates in cortical and subcortical grey matter, where it is thought to disturb neurotransmitter release and neuronal calcium handling, although no specific histological lesion is pathognomonic.在脑内铝蓄积于皮质与皮质下灰质，据认为可扰乱神经递质释放与神经元钙稳态，但无特异性的病理组织学病灶。
• Aluminium also suppresses parathyroid hormone secretion and action, which contributes to the adynamic bone disease and blunts the usual biochemical response to low calcium.铝还抑制甲状旁腺激素的分泌与作用，促成无力型骨病，并削弱对低钙的常规生化反应。
• Deferoxamine mobilises aluminium from bone and brain stores into plasma, which explains both its therapeutic effect and the transient worsening of encephalopathy seen at the start of treatment.去铁胺将铝从骨与脑的储存中动员入血浆，这既解释其治疗作用，也解释治疗初期可见的脑病暂时加重。

Clinical features

• Early toxicity is non-specific, with anorexia, malaise, weight loss, bone pain and proximal muscle weakness that are easily attributed to uraemia or dialysis inadequacy.早期中毒表现非特异，包括食欲减退、乏力、体重下降、骨痛与近端肌无力，易被归因于尿毒症或透析不充分。
• The speech disorder is characteristic, beginning as stuttering or hesitancy and progressing to dysarthria, mutism and inability to communicate.言语障碍具有特征性，起初为口吃或迟疑，继而发展为构音障碍、缄默与无法交流。
• Myoclonus, asterixis, generalised seizures, personality change and progressive dementia complete the encephalopathic picture, and the course may be stepwise rather than smoothly progressive.肌阵挛、扑翼样震颤、全面性癫痫、人格改变与进行性痴呆构成脑病全貌，病程可呈阶梯式而非平稳进展。
• Bone involvement causes deep bone pain, tenderness over the ribs and pelvis, recurrent fractures and, in children, growth retardation and rickets-like deformities.骨受累引起深部骨痛、肋骨与骨盆压痛、反复骨折，儿童则出现生长迟缓与佝偻病样畸形。
• Anaemia is typically mild to moderate, microcytic and hypochromic, with low mean corpuscular volume and a poor reticulocyte response despite adequate iron stores.贫血通常轻至中度、呈小细胞低色素性，平均红细胞体积降低，即使铁储备充足网织红细胞反应仍差。
• Many patients have biochemical overload without symptoms, and the finding is then made only because serum aluminium or bone histology is examined.许多患者存在生化性负荷过重而无症状，仅在检测血铝或行骨组织学检查时才被发现。
• Encephalopathy and bone disease often coexist, and the combination of speech disorder, myoclonus and fractures in a long-term dialysis patient should prompt immediate aluminium testing.脑病与骨病常同时存在，长期透析患者若出现言语障碍、肌阵挛与骨折组合，应立即检测铝。

Diagnosis

• Serum aluminium is the first-line test, interpreted against the reference values of below 6 micrograms per litre in normal renal function and below 20 micrograms per litre in dialysis patients.血铝是首选检查，应参照肾功能正常者低于 6 微克每升、透析患者低于 20 微克每升的参考值判读。^[7]
• A concentration above 100 micrograms per litre is generally regarded as toxic, whereas values of 50 to 60 micrograms per litre suggest increased body burden and warrant assessment for chelation.浓度高于 100 微克每升通常视为中毒，而 50 至 60 微克每升提示体内负荷增加，应评估是否需螯合治疗。^[7]
• The deferoxamine challenge test measures serum aluminium before and after a 5 milligram per kilogram infusion, and a substantial rise indicates mobilisable tissue stores.去铁胺激发试验在 5 毫克每千克输注前后测定血铝，显著升高提示存在可动员的组织储存。
• Bone biopsy with aurin tricarboxylic acid staining remains the reference standard and shows aluminium at the mineralisation front, but it is invasive and rarely necessary when biochemistry is typical.骨活检配合金精三羧酸染色仍是参考标准，可显示矿化前沿的铝沉积，但属侵入性检查，生化表现典型时很少必需。
• Iron deficiency, vitamin D deficiency, hyperparathyroidism and beta-2 microglobulin amyloidosis are the main differential diagnoses and must be excluded by appropriate tests.缺铁、维生素 D 缺乏、甲状旁腺功能亢进与 β2 微球蛋白淀粉样变为主要鉴别诊断，须以相应检查排除。
• Dialysate and feed water should be tested against the Association for the Advancement of Medical Instrumentation limit of 0.01 milligrams per litre, because unit-level contamination explains clusters.透析液与供水应按医疗器械促进协会 0.01 毫克每升的限值检测，因为中心层面的污染可解释病例聚集。
• Neuroimaging and electroencephalography are non-specific but help to exclude stroke, infection, uraemic encephalopathy and non-convulsive status epilepticus.神经影像与脑电图无特异性，但有助于排除卒中、感染、尿毒症脑病与非惊厥性癫痫持续状态。

Management

• The first step is to remove the source, which means aluminium-free dialysate produced by reverse osmosis or deionisation and substitution of aluminium hydroxide with calcium carbonate, sevelamer or other non-aluminium binders.第一步是去除来源，即使用反渗透或去离子制备的无铝透析液，并以碳酸钙、司维拉姆或其他非铝结合剂替代氢氧化铝。
• Deferoxamine is given intravenously at about 5 milligrams per kilogram after dialysis once weekly, with dose adjustment and close monitoring because the margin between benefit and toxicity is narrow.去铁胺通常在透析后静脉给药，约每周一次、每次 5 毫克每千克，因获益与毒性之间界限狭窄，须调整剂量并密切监测。
• Chelation lowers serum aluminium, improves anaemia and bone pain and can reverse early encephalopathy, but established neurological damage may not recover.螯合治疗可降低血铝、改善贫血与骨痛，并可逆转早期脑病，但已形成的神经损害未必恢复。
• Deferoxamine can cause hypotension, visual and auditory toxicity, and an increased risk of mucormycosis, especially with prolonged high-dose use.去铁胺可引起低血压、视觉与听觉毒性，并增加毛霉病风险，长期大剂量使用时尤为明显。
• Seizures require anticonvulsant therapy, and severe encephalopathy needs supportive care, nutritional support and, in some cases, intensification of dialysis.癫痫需抗癫痫药物治疗，严重脑病需支持治疗、营养支持，部分病例需加强透析。
• Anaemia management combines iron repletion, erythropoiesis-stimulating agents and chelation, and haemoglobin should be monitored after aluminium burden falls.贫血处理结合补铁、红细胞生成刺激剂与螯合治疗，铝负荷下降后应监测血红蛋白变化。
• Prevention is the mainstay, and every dialysis programme should monitor water aluminium, avoid aluminium-containing binders and measure serum aluminium in patients at risk.预防是根本，每个透析项目都应监测供水铝含量、避免含铝结合剂，并对高危患者检测血铝。

Research and controversies

• Residual aluminium overload in the reverse osmosis era is still reported, and surveys suggest that water quality monitoring is uneven between centres and countries.反渗透时代仍有残余铝负荷过重的报告，调查提示各中心与国家之间的水质监测并不均衡。^[4]
• The optimal deferoxamine dose, schedule and duration have never been tested in large randomised trials, and practice is based on small series and expert opinion.去铁胺的最佳剂量、方案与疗程从未在大规模随机试验中检验，实践依据来自小样本系列与专家意见。
• Non-invasive biomarkers of tissue aluminium burden are lacking, so bone biopsy remains necessary in atypical cases and research into serum or imaging markers continues.组织铝负荷的非侵入性生物标志物尚缺，非典型病例仍需骨活检，血标志物与影像标志物的研究仍在继续。
• The relationship between low-level aluminium exposure and progression of chronic kidney disease, neurocognitive decline and cardiovascular risk remains uncertain and is an active area of epidemiological research.低水平铝暴露与慢性肾病进展、神经认知衰退及心血管风险的关系仍不确定，是流行病学研究的热点。
• Public health attention has shifted to ensuring safe dialysis water in low-resource settings, where the cost of reverse osmosis and routine aluminium testing remains the principal barrier.公共卫生关注已转向确保资源匮乏地区透析用水安全，反渗透设备与常规铝检测的成本仍是主要障碍。