Version May 2024
INTRODUCTION — Aluminum toxicity is a systemic disorder observed in patients on hemodialysis and occasionally in patients who have severe chronic kidney disease (CKD; ie, glomerular filtration rate [GFR] <30 mL/min/1.73 m2) but are not on dialysis. Aluminum toxicity primarily results from exposure to aluminum in dialysis fluid and from the ingestion of aluminum-containing phosphate binders among patients who cannot excrete it [1].
Aluminum toxicity is now uncommon because aluminum is removed from water used for dialysis and because nonaluminum-containing phosphate binders are widely available [2]. Aluminum toxicity is now thought to be limited to patients on hemodialysis in resource-limited countries where aluminum-based phosphate binders are occasionally used, patients in whom infrequent dialysate contamination occurs, and patients with unusual environmental exposures.
This topic reviews aluminum toxicity in patients with CKD, particularly in those on hemodialysis, in whom it is still occasionally observed. Other forms of bone disease commonly observed among patients with CKD are discussed elsewhere. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
Techniques that are utilized for the removal of aluminum from dialysis water are discussed elsewhere. (See "Assuring water quality for hemodialysis" and "Contaminants in water used for hemodialysis".)
Nonaluminum phosphate binders are discussed elsewhere. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Specific treatment'.)
EPIDEMIOLOGY — Aluminum toxicity used to be a fairly common problem among patients on hemodialysis worldwide. However, it is now uncommon in countries where the use of aluminum-based medications (eg, phosphate binders) has been abolished and strict dialysis water purification practices have been enforced [2-4]. Since 2003, 0.5 to 0.8 percent of patients on hemodialysis in the United States were found to have elevated serum aluminum levels [2,5,6]. Similarly, in one study of patients from Europe and the United States who underwent bone biopsies, aluminum staining was positive in only 0.6 percent of patients [7].
However, aluminum toxicity may still be a significant problem in certain other countries where limits on aluminum exposure among patients on dialysis are not strictly enforced [8-10]. As an example, in one study from Brazil, 38 percent of bone biopsies stained positive for aluminum [10].
Occasionally, there are cases of aluminum toxicity clustered among patients dialyzed at a facility. These are usually either due to an increase in the aluminum content in the municipal water that supplies the dialysis facility or due to malfunction of the water purification and/or distribution system within a dialysis unit [5,11,12]. (See 'Aluminum in dialysis fluid' below and "Contaminants in water used for hemodialysis", section on 'Aluminum'.)
Aluminum toxicity among patients with nondialysis chronic kidney disease (CKD) is exceedingly rare. Most reports of aluminum toxicity in this group are from patients who were ingesting aluminum-containing medications concurrently with citrate [13-15]. Citrate increases the intestinal absorption of aluminum [15]. (See 'Aluminum with citrate' below.)
SOURCES OF ALUMINUM — The major sources of aluminum exposure among patients on hemodialysis include the dialysis fluid and aluminum-containing phosphate binders and antacids [16-20]. Other medications may also contain small amounts of aluminum that can accumulate in patients with end-stage kidney disease (ESKD).
Aluminum utensils used for cooking may also be a potential source of aluminum accumulation. In one study of patients with ESKD, cooking with aluminum utensils was associated with chronic aluminum toxicity; serum aluminum levels were approximately eight-fold higher than that of controls [21]. In another study of patients with chronic kidney disease, replacement of aluminum utensils led to improvement in serum aluminum levels [22].
Aluminum in dialysis fluid — Municipal water supplies (which supply water to dialysis facilities) contain a relatively high concentration of aluminum. These concentrations are considered safe for the general population but are toxic for patients on hemodialysis. This is because patients on hemodialysis are exposed to very large volumes of dialysate water and have no means to excrete the aluminum that is in the fluid.
The toxicity of aluminum in dialysis water has been recognized since the 1970s [23-25]. This recognition led to the development of effective methods of water purification. In addition, after aluminum toxicity was recognized, stringent international and national guidelines were established that recommended the maximal allowable limit of aluminum in dialysate water. (See "Assuring water quality for hemodialysis" and "Contaminants in water used for hemodialysis", section on 'Aluminum'.)
The contribution of dialysis fluid to aluminum toxicity decreased markedly as a result of improved water purification [1]. The introduction of reverse osmosis for water purification has essentially eliminated the problem of water contamination with aluminum [26].
However, there are still occasional reports of high serum aluminum concentrations in patients on dialysis, despite water purification methods [5,11,12]. Such reports are all related to changes in the aluminum content of the municipal water supply or to defects in the water and dialysate purification and distribution systems within individual dialysis facilities [5,11,12]. As an example, in 2007, 10 patients with high serum aluminum concentrations were reported from a center in the United States [5]. The high aluminum concentrations resulted from contamination of dialysate acid concentrate by newly installed electric drum pumps [5]. In 2001, 27 patients dialyzed on the island of Curaçao, north of the Venezuelan coast, were exposed to toxic levels of aluminum resulting from the installation of a distribution pipe that supplied the dialysis facility with water; of these, 10 patients died from acute exposure [27]. (See "Contaminants in water used for hemodialysis" and 'Acute encephalopathy' below.)
In 2004 and 2005, several Canadian peritoneal dialysis centers noted increasing serum aluminum levels during yearly routine monitoring [28]. Investigation eventually documented high aluminum content in dialysates manufactured by Fresenius Canada. Serum aluminum was inversely correlated with kidney creatinine clearance. However, because the problem was detected rapidly, no clinical consequences were observed in the study cohort. The presence of residual kidney function was protective against aluminum accumulation.
Aluminum-containing phosphate binders and antacids — Aluminum-containing phosphate binders and antacids are a source of aluminum toxicity in patients with CKD. However, their use was restricted after reports of aluminum-related neurologic and bone disease.
Both the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines advise against long-term use of aluminum-containing binders [20,29]. Aluminum-containing phosphate binders are now infrequently prescribed across the world but are still being used in Australia and Russia, as well as some other countries. A study from Russia showed that aluminum-containing phosphate binders were used in 17.6 percent of their patients on hemodialysis [30].
The use of aluminum-containing phosphate binders has declined because nonaluminum-containing phosphate binders are now widely available. However, some patients may still be given aluminum-containing phosphate binders for a brief period of time (one to two weeks). Such patients include those with refractory hyperphosphatemia (which may respond better to aluminum-containing phosphate binders) and those with side effects to nonaluminum-containing phosphate binders (such as hypercalcemia). However, given that the amount of aluminum intake required to cause toxicity is not known, there is no "safe" dose of aluminum-containing phosphate binder [19].
There are still occasional reports of high aluminum concentrations that are presumed to be due to phosphate binders. As an example, in one report, among 136 patients on hemodialysis (many who reported use of aluminum-containing phosphate binders), 16 percent had serum aluminum levels greater than 30 mcg/L, and, in three cases, aluminum levels were higher than 60 mcg/L [31]. In another study from Taiwan, 44 of 473 patients on hemodialysis who underwent annual serum aluminum testing were found to have predialysis serum aluminum levels of ≥20 mcg/L [32]. Many of these patients were receiving aluminum-based phosphate binders.
Aluminum levels greater than 20 mcg/L are considered abnormal. The elevated aluminum concentrations were believed to be primarily due to the use of aluminum-containing binders because the dialysis water was shown to be within the maximum allowable limit for aluminum.
Aluminum with citrate — Citrate is a major factor in the toxicity of orally administrated aluminum [15,33]. Aluminum toxicity may occur in patients with CKD who are given aluminum-containing phosphate binders plus sodium citrate. Citrate markedly enhances intestinal aluminum absorption (figure 1) [15,33,34]. The mechanism by which this occurs is believed to be both by keeping aluminum soluble over the wider pH range (via the formation of aluminum citrate) and by chelating extracellular calcium leading to disruption of the integrity of intestinal epithelial cell tight junctions and opening the paracellular pathway for the absorption of soluble aluminum citrate [33-35].
The introduction of ferric citrate as a phosphate binder raised concern about enhanced aluminum absorption from drinking water, food, and drugs. However, one randomized control trial found no significant differences in serum aluminum levels between the ferric citrate-treated group and active control [36]. Among 185 participants in the ferric citrate group with available serum aluminum measurements, the median aluminum level was 6.0 (range, 5 to 24) mcg/L at baseline and 7.0 (5 to 23) mcg/L at the end of the 52-week active control period. These values were not significantly different from levels in the active control group [36]. Longer-term studies are needed to confirm these findings. Pending further data, regular monitoring for aluminum overload and toxicity has been suggested with long-term use of ferric citrate hydrate as a phosphate binder [37].
Other medications — Other sources of aluminum include oral and injectable medications that are commonly administered to patients on dialysis [38-42]. Iron and calcium-containing medications have the highest aluminum levels, followed by calcitriol and vitamins B complex [38]. In one analysis, acetylsalicylic acid, calcitriol, clonidine, vitamins, iron sulfate, and calcium carbonate all contained between 85 and >200 mcg/g [38]. Most preparations tested in this study had much lower aluminum concentrations. Injectable drugs have much greater contamination than oral formulations. Among the medications investigated, injectables such as iron, erythropoietin, and insulin were found to be the most significant source of aluminum for patients on hemodialysis [42].
MONITORING — Routine monitoring of serum aluminum levels can identify excessive aluminum exposure in individual patients or detect accidental contamination of dialysate with aluminum [20].
However, given the low prevalence of aluminum toxicity among patients on hemodialysis patients, we do not routinely measure serum aluminum levels in all patients on hemodialysis. We believe that routine monitoring is not cost effective in most patients in the United States [3,4,43].
This practice differs from the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, which recommend serum aluminum testing at least annually in all patients on hemodialysis and every three months in those who receive aluminum-containing medications [20].
We suggest monitoring the following patients:
●Patients who receive hemodialysis in locations where water purification systems may be inadequate [12]. (See "Contaminants in water used for hemodialysis", section on 'Aluminum' and "Assuring water quality for hemodialysis".)
●Patients on dialysis and patients with nondialysis CKD who are receiving aluminum-based phosphate binders or who are on long-term treatment with ferric citrate.
●Patients (mostly those on hemodialysis) who are undergoing parathyroid surgery for CKD-related secondary hyperparathyroidism and who also have a history of aluminum exposure.
The optimal frequency and method of monitoring are not known. We monitor patients who are dialyzed in locations with inadequate water purification systems and those receiving aluminum-containing phosphate binders every four to six months [19]. We monitor for aluminum toxicity by measuring the unstimulated serum aluminum concentration (ie, the concentration in the absence of deferoxamine). Patients who are identified by monitoring to have serum aluminum concentration >20 mcg/L should be evaluated further for aluminum toxicity. (See 'Chronic toxicity' below.)
However, one report found that many serum aluminum concentrations in the toxic range were not confirmed after retesting [4]. In such cases, patients should be retested with another specimen before investigating sources of exposure or undergoing treatment.
Patients who are undergoing parathyroid surgery for CKD-related secondary hyperparathyroidism and who also have a history of aluminum exposure should be evaluated prior to surgery with an unstimulated serum aluminum concentration [44-46]. If the unstimulated concentration is <200 mcg/L, such patients should have further testing with a deferoxamine stimulation test (see 'Chronic toxicity' below). Evaluation of such patients is necessary because parathyroidectomy can worsen the clinical manifestations of aluminum toxicity among patients who have high aluminum concentrations. (See 'Osteomalacia' below and "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis".)
CLINICAL MANIFESTATIONS — The clinical manifestations of aluminum toxicity may be chronic or acute, depending on the rate and amount of aluminum accumulation.
Chronic toxicity — Manifestations of chronic aluminum toxicity result from exposure to low concentrations over a period of years. Chronic manifestations include bone and muscle pain, fracture, proximal muscle weakness, osteomalacia, iron-resistant microcytic anemia, hypercalcemia, and slowly progressive dementia [16,17].
Bone and muscle pain and muscle weakness — Patients with aluminum toxicity complain of generalized bone and joint pain and proximal muscle weakness.
The joint symptoms may reflect aluminum deposition within the joint. High aluminum concentrations have been observed in synovial fluid of patients taking aluminum-containing phosphate binders [47]. However, joint aspiration is generally not done for diagnosis. (See 'Diagnosis and evaluation' below.)
Osteomalacia — Aluminum toxicity used to be the most common cause of osteomalacia in patients with CKD but, as noted above, is now uncommon. The incidence of aluminum-induced osteomalacia is not known, since few bone biopsies are performed.
Osteomalacia is characterized by a very low rate of bone turnover, low number of bone-forming and bone-resorbing cells, a mineralization defect, and marked accumulation of unmineralized osteoid (bone matrix) [16,17]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Abnormalities in bone turnover, mineralization, volume linear growth, or strength'.)
Aluminum overload causes defective mineralization, increased matrix synthesis by osteoblasts, inhibition of osteoblast differentiation, and the inhibition of osteoclast function [48].
Hyperparathyroidism, which is common among CKD patients, appears to protect against aluminum-induced osteomalacia, perhaps by increasing bone turnover [17]. This relationship becomes clinically important when therapeutic parathyroidectomy is being considered. Aluminum-induced osteomalacia must be excluded in such patients since lowering parathyroid hormone (PTH) levels by parathyroidectomy can lead to worsening of aluminum-induced osteomalacia [17] (see 'Monitoring' above and "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis"). Lowering PTH levels medically by the administration of calcitriol also may accelerate aluminum bone disease, although this is less common [49,50].
The risk of aluminum-induced osteomalacia is greater in diabetic patients compared with nondiabetic patients [51,52]. The increased risk may be related to a lower than normal bone formation rate [51,53] and lower serum levels of PTH in patients with diabetes [53-55]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Abnormalities in bone turnover, mineralization, volume linear growth, or strength'.)
Iron-resistant microcytic anemia — Accumulation of aluminum in bone marrow causes a reversible microcytic anemia that is unaccompanied by evidence of iron deficiency. The anemia in such patients is resistant to iron supplementation [20,56]. The exact mechanism by which aluminum causes anemia is unclear but may involve displacing iron from transferrin [57].
Hypercalcemia — Hypercalcemia may be observed among patients with aluminum-induced osteomalacia. Hypercalcemia is caused by aluminum deposition on the mineralization front, which blocks calcium uptake into bone. Aluminum toxicity should be suspected among CKD patients who have hypercalcemia without marked elevations in serum intact PTH (eg, <500 pg/mL) and are not taking vitamin D or calcium supplements [20].
Dementia — A slowly progressive dementia (formerly called dialysis dementia) results from prolonged aluminum toxicity. Aluminum-related dementia is characterized by dysarthria, myoclonus, mental changes, hallucinations, and seizures [58]. Symptoms are intermittent and may transiently worsen immediately following dialysis [20]. Increased aluminum has been described in the brain tissue of affected patients [59].
Epidemic forms of dialysis dementia have been reported in areas where the municipal water supply was heavily contaminated with aluminum [1,20]. Epidemic dialysis dementia has largely disappeared with the introduction of improved methods of water purification [20].
Acute toxicity — Manifestations of acute aluminum toxicity result from exposure to very high concentrations of aluminum in the dialysate (ie, >200 mcg/L). The major clinical manifestation is acute encephalopathy, which can be fatal [27].
Acute encephalopathy — Acute aluminum-induced encephalopathy is characterized by altered consciousness, seizures, and coma [20,27]. The mortality of patients with acute aluminum-induced encephalopathy is high [20,27]. Aluminum-induced acute encephalopathy may occur in the following patients:
●Patients on hemodialysis who are exposed to very high levels of aluminum in the dialysate (ie, >200 mcg/L; the maximum allowable limit is 10 mcg/L). In this setting, most patients in the same dialysis center become ill simultaneously.
●Patients with nondialysis CKD with estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2 who are given aluminum-containing phosphate binders plus sodium citrate (ie, Bicitra or Shohl’s solution). Citrate markedly enhances intestinal aluminum absorption (figure 1) both by keeping aluminum soluble (via the formation of aluminum citrate) and by complexing with calcium in the intestinal lumen [33,34]. (See 'Aluminum with citrate' above.)
●Patients who have large body stores of aluminum and are treated with high doses of deferoxamine (ie, 20 to 40 mg/kg).
DIAGNOSIS AND EVALUATION — The diagnostic approach to aluminum toxicity depends upon whether toxicity is chronic or acute.
Chronic toxicity — The diagnosis of chronic aluminum toxicity should be suspected in patients on hemodialysis who have the constellation of signs and symptoms including bone and muscle pain, weakness, iron-resistant anemia, and neurologic changes, especially if in the setting of known aluminum exposure (such as aluminum-containing phosphate binders).
While a definitive diagnosis is made by the demonstration of aluminum deposition on bone biopsy, in practice, bone biopsies are rarely done since the expertise to perform and interpret the biopsy is frequently not available. Bone biopsy shows increased aluminum staining of the bone surface (>15 to 25 percent) and often adynamic bone or osteomalacia [20]. (See "Evaluation of renal osteodystrophy".)
In the absence of a bone biopsy, the diagnosis is based upon the baseline (ie, unstimulated) serum aluminum concentration, followed by, in selected patients, the deferoxamine-stimulated serum aluminum level.
The deferoxamine stimulation test measures the rise in serum aluminum concentration after an intravenous infusion of deferoxamine. The test is considered positive if there is an increase in serum aluminum of ≥50 mcg/L after administration of deferoxamine. Among patients with mildly elevated (ie, 20 to 60 mcg/L) serum aluminum concentrations, the deferoxamine stimulation test provides a more accurate measure of tissue aluminum concentration than is provided by the unstimulated serum concentration, which may just reflect a recent, limited exposure to aluminum [60-63]. In addition to providing a more accurate diagnosis among patients with mildly elevated unstimulated serum aluminum concentrations, the deferoxamine stimulation test is also used to guide treatment in patients. (See 'Treatment' below.)
The optimal deferoxamine dose and regimen for testing are not clear. We suggest that, for patients who require testing, deferoxamine at a dose of 5 mg/kg be administered one hour prior to the end of the dialysis session. There does not appear to be any benefit to using higher doses of deferoxamine. Two studies have shown comparable diagnostic sensitivity when 5 and 10 mg/kg test doses are used [44,64]. High doses of deferoxamine (40 mg/kg) have been associated with toxic side effects including irreversible ophthalmologic damage and mucormycosis [65]. (See 'Adverse effects of deferoxamine' below.)
The serum aluminum should be measured prior to and two days after the deferoxamine infusion (before the next dialysis session). The test is considered positive if there is an increase in serum aluminum of ≥50 mcg/L.
We select patients for deferoxamine-stimulated serum aluminum levels based upon the serum aluminum level and the presence or absence of typical symptoms (algorithm 1) [20]:
●Unstimulated serum aluminum levels <20 mcg/L – Aluminum toxicity is unlikely in patients with baseline unstimulated serum aluminum concentrations <20 mcg/L [20]. Such patients do not require further testing with the deferoxamine stimulation.
●Asymptomatic, unstimulated aluminum levels 20 to 60 mcg/L – Among patients who have no symptoms of toxicity and are found to have unstimulated serum aluminum concentration of 20 to 60 mcg/L on routine screening, we suggest not performing a deferoxamine stimulation test. Among such patients, the risk of deferoxamine toxicity (either for diagnostic testing or treatment) outweighs any known benefit. Such patients should have a comprehensive review of medications to exclude aluminum-containing medications. Serum aluminum concentrations should be repeated in one month. (See "Assuring water quality for hemodialysis".)
●Symptomatic, unstimulated serum aluminum levels 20 to 60 mcg/L – Among patients who have an unstimulated serum aluminum concentration between 20 and 60 mcg/L who have symptoms of aluminum toxicity, we suggest deferoxamine stimulation testing to confirm diagnosis and to guide treatment if the deferoxamine stimulation test is positive. Patients who have a negative deferoxamine stimulation test should have the unstimulated aluminum concentration rechecked after one month since the initial level may have reflected a recent, limited exposure to aluminum. (See 'Symptomatic patients' below.)
●Unstimulated serum aluminum levels 60 to 200 mcg/L – Among all patients who have unstimulated serum aluminum concentration between 60 and 200 mcg/L, we suggest deferoxamine stimulation testing, whether or not symptoms of toxicity are present. Unstimulated serum aluminum concentrations >60 strongly support the diagnosis of aluminum toxicity. In such patients, the deferoxamine stimulation test is used to guide the treatment approach. (See 'Treatment' below.)
●Unstimulated serum aluminum levels >200 mcg/L – Patients with serum aluminum levels >200 mcg/L are very likely to have aluminum toxicity. However, the deferoxamine test should not be performed in such patients. This is because the administration of deferoxamine causes severe, and occasionally fatal, neurotoxicity when it is administered to patients with very high serum aluminum concentrations [66,67]. This is presumed to be related to deferoxamine-induced mobilization of aluminum that has been deposited in tissues, resulting in transiently increased aluminum concentrations in the cerebrospinal fluid [68]. (See 'Adverse effects of deferoxamine' below.)
Acute toxicity — Acute aluminum neurotoxicity is diagnosed when consistent clinical features (ie, encephalopathy) are associated with increased serum aluminum levels of 400 to 1000 mcg/L [20]. Deferoxamine testing is not done among such patients.
TREATMENT
Our approach — Treatment for aluminum toxicity includes all or some of the following interventions:
●Identification and removal of all sources of aluminum
●Intensive (six days per week) dialysis with high-flux dialysis
●Administration of deferoxamine
The optimal approach is not known. Our approach is generally consistent with the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines [20] and is based on the severity of stimulated or unstimulated aluminum concentrations along with the presence or absence of characteristic symptoms.
All patients with increased unstimulated serum aluminum (ie, >20 mcg/L) should be assessed for sources of aluminum exposure. Drugs, including over-the-counter preparations, should be reviewed for potential aluminum content. Agents that are obvious sources of aluminum (such as aluminum-containing phosphate binders) should be discontinued, if at all possible. All medications that are not absolutely necessary and that may contain small amounts of aluminum should be discontinued. (See 'Other medications' above.)
Our approach for symptomatic patients and for patients with increased aluminum concentrations detected by routine screening is described below (algorithm 2 and algorithm 3).
Symptomatic patients
Serum concentration 20 to 200 mcg/L — All symptomatic patients with unstimulated serum aluminum 20 to 200 mcg/L should undergo deferoxamine stimulation testing to determine the optimal treatment. Our approach is as follows (algorithm 2):
●Deferoxamine-stimulated aluminum concentration increase of 50 to 299 mcg/L – We give deferoxamine 5 mg/kg weekly for eight doses. Deferoxamine removes aluminum that has been deposited in tissue [69-73]. There are no good randomized trials that have examined the efficacy of deferoxamine for aluminum toxicity. However, in small clinical series and in case reports, deferoxamine has been shown to decrease the symptoms of bone pain [60,71,74], proximal muscle weakness [60,71,74], neurologic symptoms [75-79], and anemia [56,80,81].
Deferoxamine is generally given intravenously over the last hour of hemodialysis. However, if there are side effects to deferoxamine administration (such as nausea, pruritus, myalgias, hypotension, anaphylaxis, or neurologic changes), deferoxamine should be given five hours prior to the performance of high-efficiency hemodialysis (see "Dialysis modality and patient outcome", section on 'High-flux and high-efficiency hemodialysis'). This strategy should maximize removal of the deferoxamine-aluminum complex, which is presumed to cause the toxic effects [82].
We repeat the deferoxamine stimulation test one month after completion of the eight-week course. If there is an increase in deferoxamine-stimulated aluminum concentration of 50 to 299 mcg/L, we give eight more weekly doses of 5 mg/kg and repeat the stimulation test after an additional month.
If, after eight weeks of treatment, the deferoxamine-stimulated aluminum increases by <50 mcg/L, then no further deferoxamine is given. The stimulation test should be repeated at one month and again at four months.
●Deferoxamine-stimulated aluminum concentration increase of ≥300 mcg/L – We give deferoxamine 5 mg/kg weekly for 16 doses (four months). Deferoxamine is given over one hour, five hours prior to the performance of high-efficiency hemodialysis (see "Dialysis modality and patient outcome", section on 'High-flux and high-efficiency hemodialysis'). This strategy should maximize removal of the deferoxamine-aluminum complex and minimize side effects [82].
We repeat the deferoxamine stimulation test one month after the 16-week course. If there is an increase in deferoxamine-stimulated aluminum concentration >300 mcg/L, we give an additional 16 weekly doses of deferoxamine 5 mg/kg.
If there is an increase 50 to 299 mcg/L, we give an additional eight weekly doses of deferoxamine 5 mg/kg. The stimulation test is repeated one month after completion of the eight-week course.
Serum concentration >200 mcg/L — Patients with unstimulated serum aluminum >200 mcg/L should not undergo a deferoxamine stimulation test (see 'Chronic toxicity' above). We also do not treat such patients with deferoxamine. The administration of deferoxamine causes severe and occasionally fatal neurotoxicity when it is administered to patients with very high serum aluminum concentrations [66,67]. This is thought to be related to deferoxamine-induced mobilization of aluminum that has been deposited in tissues, which causes transient increases in aluminum concentrations in the cerebrospinal fluid [68].
Such patients should be treated with intensive hemodialysis (six times per week) for four to six weeks or as long as is required for the serum aluminum concentration to decrease to <200 mcg/L. A high-flux dialysis membrane should be used to provide the maximum clearance of aluminum [82] (see "Dialysis modality and patient outcome", section on 'High-flux and high-efficiency hemodialysis'). The dialysis fluid aluminum concentration should be ≤5 mcg/L, which is approximately half the maximum concentration for aluminum allowed by international standards (table 1) [83]. (See "Contaminants in water used for hemodialysis", section on 'Aluminum'.)
These measures are continued for at least four to six weeks and until serum aluminum levels are <200 mcg/L. If the baseline serum aluminum is reduced to <200 mcg/L after intensive hemodialysis, a low-dose deferoxamine test is performed, with subsequent treatment based upon the results of the stimulation test. (See 'Serum concentration 20 to 200 mcg/L' above.)
Asymptomatic patients (increased aluminum detected on routine screening)
Serum concentration 20 to 60 mcg/L — As noted above, we do not perform deferoxamine stimulation testing on patients who have aluminum concentrations 20 to 60 mcg/L and have no symptoms of toxicity. We also do not treat such patients with deferoxamine, since the risk of deferoxamine toxicity outweighs any known benefit. Such patients are assessed for sources of aluminum exposure, including prescription and nonprescription medications. All medications that are not absolutely necessary and which may contain small amounts of aluminum should be discontinued (algorithm 3).
Serum concentration >60 mcg/L — Patients who have serum aluminum concentrations of >60 mcg/L should be treated the same as patients with similar aluminum concentrations who have symptoms of toxicity (algorithm 3). (See 'Symptomatic patients' above.)
ADVERSE EFFECTS OF DEFEROXAMINE — Major side effects with deferoxamine therapy include neurotoxicity [66,67] and increased risk of mucormycosis [65]. Neurotoxicity may result from transiently increased concentrations of aluminum in the cerebrospinal fluid [68]. The risk of mucormycosis increases because deferoxamine chelation of iron enhances the growth and pathogenicity of Rhizopus species [84,85]. (See "Mucormycosis (zygomycosis)", section on 'Deferoxamine and iron overload'.)
Deferoxamine can also cause nausea, pruritus, myalgias, hypotension, and anaphylaxis [66,86].
There is an increased risk of adverse effects among patients who have high serum aluminum concentrations or are treated with high doses of deferoxamine.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Aluminum toxicity is a complication observed in hemodialysis patients that results from exposure to aluminum in dialysis fluid and in aluminum-containing phosphate binders. Aluminum toxicity is uncommon in developed countries with improved purification techniques for dialysis fluid and with availability of nonaluminum-containing phosphate binders. (See 'Introduction' above and 'Epidemiology' above.)
●The major sources of aluminum exposure for hemodialysis patients include the dialysis fluid and aluminum-containing phosphate binders and antacids. The ingestion of both aluminum and citrate-containing medications (such as Bicitra or Shohl’s solution and possibly ferric citrate) increases the risk of aluminum toxicity for chronic kidney disease (CKD) patients since citrate enhances the absorption of aluminum. Other medications also contain small amounts of aluminum that may accumulate in end-stage kidney disease (ESKD) patients. (See 'Sources of aluminum' above.)
●We selectively monitor at-risk patients with serum aluminum levels:
•In locations where water purification systems may be inadequate or aluminum-based phosphate binders are still prescribed, we suggest measuring serum aluminum every four to six months. Patients who have serum aluminum concentration >20 mcg/L should be evaluated further for aluminum toxicity. (See 'Monitoring' above.)
•Patients who are undergoing parathyroid surgery for CKD-related secondary hyperparathyroidism and who have a history of aluminum exposure should undergo screening with an unstimulated serum aluminum concentration. If the unstimulated concentration is <200 mcg/L, such patients should have further testing with a deferoxamine stimulation test. (See 'Monitoring' above.)
●Manifestations of chronic aluminum toxicity include bone and muscle pain, weakness, osteomalacia, iron-resistant microcytic anemia, hypercalcemia, and slowly progressive dementia. This can occur in the setting of aluminum levels that are 20 mcg/L or greater.
The major clinical manifestation of acute aluminum toxicity is encephalopathy, which can be fatal. Increased serum levels of aluminum of 400 to 1000 mcg/L are typically observed. (See 'Clinical manifestations' above.)
●The diagnosis of aluminum toxicity is based upon the baseline (ie, unstimulated) serum aluminum concentration and followed by, in selected patients, a deferoxamine-stimulated serum aluminum level (algorithm 1). To test with deferoxamine, we administer deferoxamine at a dose of 5 mg/kg one hour prior to the end of the dialysis session. The serum aluminum is measured prior to and two days after the deferoxamine infusion (before the next dialysis session). The test is considered positive if there is an increase in serum aluminum of ≥50 mcg/L.
Patients with serum aluminum levels >200 mcg/L should not undergo a deferoxamine stimulation test, because the administration of deferoxamine may cause severe, and occasionally fatal, neurotoxicity when it is administered to patients with very high unstimulated serum aluminum concentrations. (See 'Chronic toxicity' above.)
●Our approach to treatment is consistent with the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines and is summarized in the algorithms (algorithm 2 and algorithm 3).
All patients with consistently increased serum aluminum (ie, >20 mcg/L) should be assessed for sources of aluminum exposure. Aluminum-containing phosphate binders and all other medications that may contain even small amounts of aluminum should be discontinued, if possible. (See 'Our approach' above.)
All symptomatic patients who have unstimulated serum aluminum 20 to 200 mcg/L should undergo deferoxamine stimulation testing to determine the optimal treatment.
•For patients with a deferoxamine-stimulated aluminum concentration increase of 50 to 299 mcg/L, we suggest deferoxamine (Grade 2C). (See 'Serum concentration 20 to 200 mcg/L' above.)
•For patients with deferoxamine-stimulated aluminum concentration increase of ≥300 mcg/L, we suggest deferoxamine (Grade 2C). (See 'Serum concentration 20 to 200 mcg/L' above.)
•For patients with unstimulated serum aluminum >200 mcg/L, we suggest intensive hemodialysis (six times per week) for at least four weeks and as long as is required for the serum aluminum concentration to decrease to <200 mcg/L. (See 'Serum concentration >200 mcg/L' above.)
●The treatment of asymptomatic patients who have increased serum aluminum detected on routine screening is based upon the unstimulated aluminum concentration and, in selected patients, the deferoxamine-stimulated concentration.
•For patients with unstimulated aluminum concentrations 20 to 60 mcg/L, we suggest NOT treating with deferoxamine (Grade 1C) (see 'Serum concentration 20 to 60 mcg/L' above). The risk of deferoxamine toxicity outweighs any known benefit. Such patients are assessed for sources of aluminum exposure, including prescription and nonprescription medications. All medications that are not absolutely necessary and that may contain small amounts of aluminum should be discontinued.
•Patients who have asymptomatic serum aluminum concentrations of >60 mcg/L should be treated the same as patients with similar aluminum concentrations who have symptoms of toxicity. (See 'Serum concentration >60 mcg/L' above.)
●Major side effects with deferoxamine therapy include neurotoxicity and increased risk of mucormycosis. Deferoxamine can also cause nausea, pruritus, myalgias, hypotension, and anaphylaxis. There is an increased risk of adverse effects among patients who have high serum aluminum concentrations or are treated with high doses of deferoxamine. (See 'Adverse effects of deferoxamine' above.)
ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Robert E Cronin, MD, and William L Henrich, MD, MACP, who contributed to an earlier version of this topic review.
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