KDOQI (Kidney Disease Outcomes Quality Initiative)


NKF KDOQI GUIDELINES

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KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Children With Chronic Kidney Disease


Guideline 13. Treatment of Aluminum Toxicity

13.1 In all patients with baseline serum aluminum levels between 20-60 µg/L, a positive DFO test, or clinical symptoms consistent with aluminum toxicity (Guideline 12, Table 18) the source of aluminum should be identified and eliminated. (OPINION)

13.2 In symptomatic patients with serum aluminum levels >60 µg/L but <200 µg/L or increase in aluminum after DFO >50 µg/L, DFO should be given to treat the aluminum overload. (See Algorithm 8 and Algorithm 9.) (OPINION)

13.3 To avoid DFO-induced neurotoxicity in patients with serum aluminum >200 µg/L, DFO should not be given until the predialysis serum aluminum level has been reduced to <200 µg/L, which can be achieved by intensive dialysis with high-flux dialysis membrane and a dialysate aluminum level of <5 µg/L. (OPINION)

Background

When dialysis encephalopathy and dialysis-related bone disease were first recognized, most patients had progressive disease with profound morbidity and very high mortality. The early cases arose, in large part, due to aluminum-contaminated dialysate. However, most patients were also receiving aluminum gels to control hyperphosphatemia, as it was then believed that little or none of the aluminum was absorbed. The first successful reversal of symptoms of dialysis encephalopathy were observed with DFO given in doses of 20-40 mg/kg for treating patients with aluminum-related bone disease. There was clinical and histological improvement; however, immediate side-effects affecting vision and mental status appeared in isolated patients, and there was concern about the use of DFO. More ominous was the appearance of rapidly progressive and fatal mucormycosis in dialysis patients who had been receiving DFO treatment. At about the same time, there was the introduction of calcium-based phosphate binders as well as widespread purification of water used for dialysate, so the prevalence of severe aluminum toxicity seemed to diminish. However, some aluminum toxicity still occurs and there remains a question of when and how chelation therapy with DFO should be used.

Rationale

Beneficial Effect of DFO Treatment on Aluminum Bone Disease and Other Features of Aluminum Toxicity

Long-term DFO treatment reduces the surface-stainable aluminum on trabecular bone.460,480-483 This is associated with an increase of BFR,460,480-482 and symptoms of proximal muscle weakness and bone pain commonly improve.480,484,485 Isolated reports have shown improved neurological symptoms in patients with dialysis encephalopathy.486-490 In these reports, DFO doses have varied from 1-6 g460,484 or, expressed in relation to body weight, 30-40 mg/kg BW per treatment.481,482,491 The treatment was given once weekly in some trials,460,485 and with each dialysis (thrice weekly) in others.481,482,491 In one study,460 the reduction of stainable aluminum and improved BFRs were substantially less in patients with an earlier parathyroidectomy than in those with intact parathyroid glands. Treatment with DFO was associated with improvement of anemia in some, but not all, patients.483,491,492

Side-Effects of DFO Treatment

Two serious problems associated with DFO therapy are: (a) the precipitation of acute aluminum neurotoxicity; and (b) the development of mucormycosis, which is commonly fatal.

Precipitation of acute aluminum neurotoxicity

When DFO is given to patients with very high serum aluminum levels (>200 µg/L), acute and fatal aluminum neurotoxicity has been precipitated440,441; this presumably occurs because aluminum is rapidly mobilized from various tissue stores.

Fatal mucormycosis in dialysis patients receiving DFO

In experimental infections with Mucor species, DFO administration markedly augments the growth and pathogenicity of the mucormycosis.493,494 When DFO is given, it chelates iron to form feroxamine; the latter has a molecular weight of 714 Da and several dialysis treatments are needed to clear it from the circulation. Certain species of Mucor, with very low pathogenicity, exist widely in nature and are found on skin and mucous membranes; feroxamine enhances their growth and pathogenicity, thereby promoting the development of fatal disseminated or rhinocerebral mucormycosis in hemodialysis patients given DFO.465,495,496 Most afflicted patients had received DFO, 20-40 mg/kg BW, once or thrice weekly, with standard dialysis membranes (usually cuprophane) employed. The shortest reported duration of treatment before infection appeared was 3 weeks.465

Algorithm 8. DFO Treatment After P Al Rise between 50-300 µg/L

Methods to avoid serious side-effects

In patients exposed to high dialysate aluminum levels or with high serum aluminum levels (>60 µg/L), the following scheme is recommended to reduce the risk of acute neurotoxicity:

The very first dose of DFO is withheld until serum aluminum levels are substantially reduced after total withdrawal of aluminum exposure—both from dialysate and from ingesting aluminum-containing drugs. With serum aluminum levels >200 µg/L, daily hemodialysis should be done using high-flux membranes and dialysate aluminum concentration <5 µg/L. The first “low dose” DFO test (5 mg/kg) should be done only after 4-6 weeks of such treatment, with increment of serum aluminum determining the timing of subsequent DFO treatments. If the increment of aluminum is high (>300 µg/L), DFO treatments should be given via a peripheral vein, 5 hours before the next dialysis that uses a high-flux membrane; this allows for rapid removal of the DFO-aluminum complexes from the circulation and minimizes the duration of patient exposure to high concentrations of the DFO-aluminum chelate (aluminoxamine).

Algorithm 9. Subsequent DFO Treatment after P Al Rise ≥300 µg/L

If the increment of serum aluminum after the first DFO test is <300 µg/L and no neurological or ophthalmological symptoms appear, the DFO can be given over the last hour of dialysis, with the next dialysis done using a high-flux dialyzer, 44 hours later. The dose of DFO should be 5 mg/kg, with an expanded interval between treatments of 3-4 dialysis procedures using a high-flux hemodialysis membrane; this allows for more complete clearance of feroxamine from the circulation, reducing the risk of mucormycosis. Intravenous iron should be avoided while DFO is being given to limit the formation of feroxamine.465,493

Management of aluminum overload without symptoms

The proper management of aluminum overload in the absence of symptoms is not established. There have been “consensus” viewpoints that aluminum overload be treated with DFO497; however, there are no data to support this recommendation. When CKD Stage 5 patients with aluminum overload and high serum aluminum levels have aluminum gels withdrawn and they undergo dialysis with aluminum-free dialysate (<5 µg/L), serum aluminum levels fall substantially and progressively.166,244,472 Small numbers of patients with histomorphometric features of aluminum bone disease but without any musculoskeletal symptoms were treated as above; after 1 year, repeat bone biopsies showed a reduction of surface stainable aluminum and a rise in BFR consistent with reversal of aluminum bone disease.498,499 The exception was two patients who had previously undergone parathyroidectomy; in these patients, there was a modest reduction of surface-stainable aluminum but BFR did not improve to normal.499 These data suggest that DFO therapy may not be needed for the treatment of such patients.

Strength of Evidence

Beneficial Effects of DFO Therapy

Several trials with DFO therapy showed a reduction of surface aluminum staining,460,481-484 and an increase in BFR,460,481,482,484 after treatment periods of 8-12 months. Meta-analysis of four trials that provided data on aluminum staining and three trials with BFR are shown in Figure 8 and Figure 9, respectively. The doses used were variable, ranging from 20-40 mg/kg; there are no data to indicate a benefit of thrice-weekly treatment compared to once-weekly. All these trials utilized standard dialysis membranes (probably cuprophane). The data on improvement of neurological features of dialysis encephalopathy involve many reports of small numbers of patients who received such treatment.486-490,500-502

Fig 8. Individual Study and Summary Effect Sizes for the Effect of DFO Therapy on Bone Formation Rate

Fig 9. Individual Study and Summary Effect Sizes for the Effect of DFO Therapy on Bone Surface Aluminum Stain

Data on the most efficient means to clear DFO-bound aluminum from the circulation include dialysis using a high-flux membrane503 or hemoperfusion with a charcoal filter504; these methods remove aluminum more rapidly than standard dialysis using cuprophane membranes. A crossover study compared: a) the combination of charcoal perfusion combined with standard dialysis; b) dialysis using a high-flux membrane; and c) standard dialysis. The hemoperfusion/hemodialysis combination had a small advantage over the high-flux dialyzer,505 and standard dialysis was inferior to both. In this study, the removal of feroxamine (the DFO-iron complex) was far greater with either the high-flux dialyzer or the hemoperfusion/hemodialysis combination than with the standard cuprophane dialyzer. Other studies showed that either intraperitoneal or intramuscular administration of DFO was effective in augmenting aluminum removal in patients undergoing peritoneal dialysis.506,507 The intramuscular administration of DFO, as it is sometimes given in hematological disorders, may provide a convenient method 4-5 hours before dialysis when an intravenous route is not available.507

Experience with the “safe” long-term treatment with DFO is derived from an outbreak of marked aluminum loading due to aluminum contamination of water used to prepare the dialysate solution. A 6-month course of “low-dose” DFO treatment was used in 42 patients exposed to high dialysate aluminum.508 After neurological symptoms first appeared, but before the diagnosis of aluminum intoxication was made, 11 patients had died. Forty-two other patients were followed. All aluminum gels were stopped, a new reverse-osmosis system was installed, and an alternate water source was used (dialysate Al <2 µg/L). The initial basal aluminum levels were 506 ± 253 µg/L [mean ± SD; range, 104-1,257 µg/L]; hemodialysis was done for 4 hours, 6 days per week; charcoal hemoperfusion was combined with the dialysis weekly. (High-flux dialysis membranes, which had similar clearance of DFO-stimulated aluminum as hemoperfusion, were not available.) After 4 weeks, the frequency of dialysis was reduced to thrice weekly with hemoperfusion once weekly.

After 6 weeks of such “intensive hemodialysis/hemoperfusion,” the basal serum aluminum fell from 506 ± 253 µg/L to 121 ± 46 µg/L (mean ± SD). The first DFO infusion test (5 mg/kg) was given during the last hour of dialysis; the increment of serum aluminum was 300 µg/L in 11 patients, seven of whom developed neurological symptoms (headache, hallucinations, or myoclonic jerks) and two developed ophthalmological symptoms (transiently blurred vision) after the DFO test; 30 patients had increments of serum aluminum <300 µg/L, only three of whom had developed neurological symptoms. These three symptomatic patients and the 11 patients with a post-DFO aluminum increment <300 µg/L received DFO treatment given via a peripheral vein 5 hours before starting a hemodialysis/hemoperfusion session (Group 1). The other 27 patients (Group 2) received DFO (5 mg/kg) during the last hour of dialysis with a hemodialysis/hemoperfusion session done 44 hours later. The DFO treatments were given weekly in all patients. After 4 months, DFO was stopped for a 4-week “washout,” and the DFO test was repeated. If the basal serum aluminum was <60 µg/L and the increment after DFO was <50 µg/L, the DFO treatment was stopped (2/14 of Group I and 8/27 of Group 2). If the basal serum aluminum level or the increment exceeded these limits, DFO treatment was continued weekly for an additional 2 months. There have been no comparisons of different doses of DFO, although cross-over studies with single infusions and small short-term studies suggest that doses lower than 5 mg/kg may be useful.

Throughout this 6 months of DFO treatment, no neurological or ophthalmological symptoms appeared and the baseline serum aluminum gradually fell, as did the increment after DFO. There were significant increments in the mean cell volume (MCV) of RBCs and a modest rise in serum PTH levels in both groups.509

Mucormycosis and DFO Treatment

Numerous case reports have described fulminant, fatal cases of systemic or rhinocerebral mucormycosis in dialysis patients being treated with DFO for aluminum toxicity,465,495,496,510,511 while reports of mucormycosis among dialysis patients not receiving DFO are unusual.420 An international registry collected 59 cases of mucormycosis among dialysis patients465; among these, 78% had been treated with DFO for aluminum or iron overload. In this report, the mortality was 91%, the disorder was the disseminated or rhinocerebral variety in 75% of the cases, and a diagnosis of mucormycosis was made only at autopsy in 61%. Experimental infections with mucormycosis in animals demonstrated that DFO, and in particular feroxamine, augmented the pathogenicity of certain species of Mucor and prevented effective treatment with amphotericin B.493,494,512 Increased susceptibility to mucormycosis was found to occur because of persistence of significant concentrations of feroxamine, the iron chelate with DFO, in CKD patients given DFO. Such feroxamine is rapidly excreted by the kidneys of hematology patients treated with the drug, and mucormycosis has been very rare among DFO-treated hematology patients with normal kidney function.420 The clearance of feroxamine by a standard dialyzer is quite low, and three to four dialysis treatments may be required to clear this substance from the blood.505

With proper water purification and reduction in the intake of aluminum gels, the incidence of aluminum bone disease and other features of aluminum toxicity has decreased substantially. Over the same period, there have been trials utilizing much lower doses of DFO to treat aluminum toxicity. Also, there appeared to be fewer cases of mucormycosis in 1986-1989 as the DFO usage decreased. For a recent review of mucormycosis, an attempt was made to locate cases that had occurred over the last 10 years; in communications with various individuals in Belgium, Spain, Portugal, and the U.S. with interest in aluminum toxicity and use of DFO, no recent cases of mucormycosis associated with DFO therapy could be identified.513

Attention has been given to methods that utilize DFO in a manner that reduces its risk. By reducing the time between the administration of DFO and the next dialysis, and by doing the dialysis with a highly permeable membrane, both feroxamine and the aluminum chelate, aluminoxamine, are removed more effectively.503 Hemoperfusion with a sorbent cartridge has also been very effective505; however, such cartridges are not presently available in the U.S. In addition, there has been a reduction of the DFO dose from 20-40 mg/kg to 5-10 mg/kg, with the DFO dose given 4-6 hours before the next dialysis, along with the use of a high-flux or highly permeable dialysis membrane and/or the use of a sorbent system.508 Also, DFO should only be given every 7-10 days,508 with three to four dialysis procedures between each dose of DFO.508 With attention to prevention of aluminum toxicity by curtailing the administration of aluminum-containing drugs and attention to proper water purification, the incidence of aluminum toxicity is now much lower than it was 10-15 years ago. It has not been possible to identify patients who have developed mucormycosis when these newer protocols have been followed.

Limitations

The trials showing beneficial effects of DFO treatment on bone biopsies and symptoms of aluminum bone disease were done several years ago when symptomatic aluminum bone disease was common, and most used DFO in doses of 20-40 mg/kg BW. Despite this, the numbers of patients in prospective trials were relatively small; also, because of the severity of the disorder and poor prognosis in untreated patients, there were no controlled trials. In a small trial of asymptomatic patients found to have biopsy evidence of aluminum bone disease, there was reduced surface staining of aluminum and increased bone formation when all exposure to aluminum was eliminated.499 There is evidence in one trial that the use of DFO in a dose of 5 mg/kg is effective in lowering basal serum aluminum. The largest trial represented acute marked aluminum loading, and neurological rather than skeletal disease was the major risk. Fourteen patients who were not treated died, and there was only one death (due to hyperkalemia) among 42 patients who followed the recommended protocol.434 Small studies suggest that doses of DFO as low as 1 mg/kg and 0.5 mg/kg can raise the ultrafilterable aluminum in serum, so such aluminum can be removed by dialysis, but there are no long-term data documenting the effectiveness of such low doses.

With regard to the safety of using low doses of DFO, the reduced frequency of its administration to once weekly, and use of high-flux dialyzers to minimize the increased susceptibility to mucormycosis, the evidence is only indirect. It has not been possible to find any cases of mucormycosis with this schema. If no new cases of fatal mucormycosis appear, this will be presumptive evidence of the effectiveness of the preventive measures.

The management of dialysis patients with “asymptomatic aluminum loading” has not been carefully evaluated, and the recommendation of treating such patients with DFO497 has not been critically evaluated. There was a small number of dialysis patients with elevated serum aluminum levels and histological features of aluminum bone disease, who had repeat biopsies approximately 12 months after all aluminum was withdrawn.498,499 The close association between the reduction of surface stainable aluminum and the improvement of bone formation and mineralization rate499 is consistent with a “cause and effect” relationship. Whether such patients would have had greater improvement after receiving DFO treatment is uncertain. The lack of improvement of bone formation in the patients with earlier parathyroidectomy499 is consistent with failure of bone histomorphometry to improve in DFO-treated patients with symptomatic aluminum bone disease.460

Clinical Applications

The proper and early identification and treatment of aluminum toxicity, even that occurring accidentally via unusual contamination of dialysate or water, is now possible and safe using the low doses of DFO that are recommended. Although prevention of aluminum toxicity is greatly preferred, the early recognition and initiation of aggressive treatment might reduce the very high mortality associated with acute aluminum neurotoxicity when patients are seen in the early phases and treated with daily, high-efficiency dialysis until it is safe to begin DFO treatment. A clinician's fear of using DFO, based entirely on problems that occurred with use of DFO in doses of 20-40 mg/kg, should give way to the timely use of DFO when it is needed using a “safe” dose of 5 mg/kg, followed by dialysis using a high-efficiency dialysis membrane. These precautions are designed to minimize any risk of side-effects of the DFO treatment.

Recommendations for Research

With the great reduction of incidences of aluminum toxicity, large clinical trials to evaluate its treatment are not likely to occur or to be possible. Some nephrologists still believe that certain “low doses” of aluminum gels are indeed both safe and effective to control serum phosphorus levels. It would be well to establish long-term, prospective trials in such patients to assess the safety of the treatment in comparison to other nonaluminum-based phosphate binders. There is little doubt that aluminum-based phosphate binders are more potent and effective in binding dietary phosphate, in comparison to similar doses of other phosphate-binding agents.174

Very small and uncontrolled trials indicate that it is possible to give aluminum-based binders combined with very small doses of DFO (<1 mg/kg), and the investigators reported a slow, gradual reduction of serum aluminum levels during such treatment.468 Others have shown that DFO in doses of 0.5-1.0 mg/kg increases the ultrafilterable (and hence the dialyzable) level of serum aluminum in dialysis patients with elevated serum aluminum levels.467 These data provide the background for a potential prospective trial that could test the safety and effectiveness of aluminum gels combined with repeated, very low doses of DFO in comparison to other nonaluminum-based phosphate binders.

Investigators with interest in aluminum toxicity and its treatment need to collect additional series and cases where the DFO is given in “low” doses of 5 mg/kg BW or even less. Recognizing whether cases of mucormycosis will be seen with such doses and use of high-efficiency dialyzers is also needed.

In a population with substantial numbers of patients with aluminum overload and minimal symptoms, controlled trials comparing total aluminum withdrawal with DFO treatment would be worthwhile to prove the advantage of DFO treatment over total withdrawal of exposure to aluminum.