Treatment of acute aluminum toxicity due to alum bladder irrigation in a hemodialysis patient: a case report

Abstract Acute aluminum toxicity is encountered rarely in clinical practice but carries a high risk for morbidity and mortality. Despite this risk, our understanding of aluminum toxicity and its treatment is relatively limited. Due to decreased clearance, patients with renal failure have increased risk for significant aluminum-related central nervous system (CNS) toxicity. Medical advances have limited chronic aluminum exposure in these patients, but they are still at increased risk for acute toxicity from certain aluminum-based interventions such as alum bladder irrigation. We report a case of an 87-year-old man with end-stage renal disease on hemodialysis who developed acute aluminum toxicity from alum bladder irrigation. He was treated with daily deferoxamine infusions followed by dialysis with subsequent resolution of his encephalopathy. This case report uniquely documents trending of blood aluminum concentration (blood [Al]) during treatment providing insight into how aluminum blood concentrations shift during chelation therapy.


Introduction
Aluminum toxicity is an extremely rare, but potentially fatal clinical entity occurring almost exclusively in patients with renal insufficiency due to reduced clearance of the metal ion. Aluminum is a systemic toxin in humans but exerts its most potent effects in the CNS causing encephalopathy, seizures, and coma. Historically, toxicity has been primarily chronic due to accumulation of the metal through repeat exposures, but acute toxicity is also possible from certain iatrogenic sources. We report, in accordance with the CARE guidelines, a case of an 87-year-old man with end-stage renal disease on hemodialysis who developed acute aluminum toxicity from alum bladder irrigation.

Case report
An 87-year-old man with prostate cancer and end-stage renal disease (ESRD) on hemodialysis was admitted for radiation-induced hemorrhagic cystitis and pneumonia. He underwent bladder irrigation with a solution containing 30 g of alum (aluminum potassium sulfate) for his bleeding. Approximately 48 h later he appeared to be acutely encephalopathic. His vital signs and basic laboratory test results were unremarkable. A total whole blood aluminum concentration (blood [Al]) resulted four days later at 141 mcg/L (reference range: <60 mcg/L for dialysis patients).
Given the patient's acute mental status change and elevated blood [Al] he received intravenous deferoxamine (DFO) 10 mg/kg given over a two-hour period. His blood [Al] following the infusion was 537 mcg/L. Eight hours after the infusion was complete, he received four hours of hemodialysis. A blood [Al] obtained shortly after dialysis was 279 mcg/L. This regimen was repeated daily for a total of four infusions and four dialysis sessions. DFO infusions were all well tolerated without hypotension. Blood [Al]s during this treatment period were measured serially; they rose after each DFO infusion and improved after each dialysis session. (Figure 1). This is an open access article distributed under the terms of the creative commons attribution license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. KEYWORDS aluminum toxicity; bladder irrigation; hemodialysis; deferoxamine; case report On the sixth day after initiating chelation therapy and hemodialysis the patient's mental status was significantly improved despite having a persistently elevated blood [Al] of 249 mcg/L. Based on the patient's clinical improvement he began a schedule of weekly DFO infusions at a lower dose of 5 mg/kg weekly with his routine dialysis schedule. Nine days after beginning chelation therapy the patient was back to his baseline mental status. His blood [Al] at that time was 189 mcg/L.

Discussion
While aluminum toxicity is rare overall, alum bladder irrigation can cause acute toxicity in patients with renal insufficiency. This case uniquely documents serial pre-and post-DFO infusion blood [Al]s with intercurrent hemodialysis providing insight into how aluminum concentrations shift between physiologic compartments during chelation therapy. Each infusion of DFO appears to have mobilized aluminum into the blood from other compartments including the CNS. In the blood, chelated aluminum, or aluminoxamine, remains solubilized and physiologically inactive for a period while removal with hemodialysis can be performed. While this was evidenced clinically with resolution of the patient's encephalopathy and decreased blood concentrations following dialysis, we did not obtain dialysate levels of aluminum chelate which would have helped further elucidate the total amount and efficacy of aluminum removal per chelation-dialysis session.
While the patient's sensorium cleared with treatment, we found persistently and significantly elevated blood [Al]s likely due to aluminum equilibrating from other tissue stores. This pattern is suggestive of acute-on-chronic aluminum exposure whereby aluminum, accumulated in tissue over time, continued to equilibrate with blood but did not move into the CNS at toxic levels. Conversely, a single acute toxic exposure would be expected to resolve with a blood [Al] approaching zero during treatment. Potential sources of chronic aluminum exposure in a dialysis patient of this age include dialysis itself, which until the 1980s did not utilize reverse osmosis and deionization techniques leading to elevated aluminum levels in some dialysate fluids. Aluminum-containing phosphate binders were also in common use until their toxicity was recognized in the 1980s. Other iatrogenic sources of aluminum include some antidiarrheals, antacids, and buffered aspirins [1].
Aluminum has no role in human physiology, yet our exposure to the metal is nearly ubiquitous. Patients with kidney failure are at particular risk for toxicity because the aluminum ion is approximately 95% renally cleared [2]. However, routine hemodialysis alone is inefficient in removal. High levels of protein binding and organ accumulation give aluminum a very large volume of distribution causing it to be poorly dialyzable without chelation [3]. Aluminum in the blood is 90% bound to transferrin while the rest is bound to citrate and albumin. Uptake into cells may be through endocytosis of the aluminum-transferrin complex [1].
Given its potential for wide distribution in the human body, aluminum can cause multi-system toxicity. The pathophysiology of aluminum poisoning is complex and not fully described. However, as with many metals, it seems to exert its primary toxic effect directly through the generation of oxidant stress, free radicals, and lipid peroxidation. Intracellularly, aluminum appears to interfere with iron-sulfur complex and heme-dependent processes in the enzyme-laden mitochondria including progression of the tricarboxylic acid cycle [4]. This leads to inefficient energy generation as well as the generation of reactive oxygen species and high levels of lipid and protein peroxidation [5]. This pathophysiology is likely to occur in all energy producing cells but has more significant consequences in energy sensitive tissues such as the CNS.
In the brain, aluminum toxicity has been postulated to be related to, if not responsible for, the pathophysiologic effects behind the clinical entity known as "dialysis dementia". Significantly elevated grey-matter aluminum concentrations were first associated with a chronic, universally fatal syndrome called dialysis-associated encephalopathy in 1976. In post-mortem autopsies, those with the encephalopathy syndrome had statistically significantly elevated grey-matter aluminum burdens than both controls and dialysis patients without encephalopathy [6]. Aluminum entry into the CNS appears to be modulated by a transporter that effluxes aluminum from the CNS back into the blood [1]. It follows that neurotoxicity is unlikely to occur unless the total body load is chronically very high, or efflux mechanisms are acutely overwhelmed by a bolus of aluminum. This CNS handling may explain why our patient did not have recurrence of encephalopathy despite continued elevated blood [Al]s once his total body aluminum burden had been significantly reduced with treatment.
Most reported cases of alum-associated aluminum toxicity attribute the development of toxicity to a large absorptive surface area such as large tumor or diffusely friable bladder tissue from chemotherapy or radiation combined with renal dysfunction. Two similar cases from the literature involve patients with iatrogenic diffuse hemorrhagic cystitis and renal insufficiency [3,7]. Both developed acute encephalopathies following alum bladder irrigation and were found to have elevated blood [Al]s. Both patients received deferoxamine therapy, however, only one patient had concomitant initiation of hemodialysis. The patient whose renal insufficiency was not addressed prior to chelation had precipitous decline in mental status to the point of coma. It was postulated that this precipitous decline was likely due to mobilization of tissue aluminum without adequate clearance by her failing kidneys [3]. Once hemodialysis was initiated, both patients had rapid recovery of their mental status.
Treatment of aluminum toxicity in patients with renal dysfunction revolves around the use of deferoxamine as a chelator to form water-soluble aluminoxamine complexes in a one-to-one ratio. The first successful use of deferoxamine in this way was in a single patient with dialysis associated encephalopathy related to high aluminum content in the dialysis fluid. This use was modeled on the success of using deferoxamine to decrease the iron burden of another hemodialysis patient [8]. Since its initial use, the dose and timing of deferoxamine treatment for aluminum toxicity in the dialysis population has been refined based on its pharmacokinetics.
The appropriate duration of treatment in cases of acute aluminum toxicity remains uncertain. The risk of mobilizing tissue stores of aluminum and potentially causing CNS deposition is often cited as a concern for pursuing more aggressive chelation therapy. However, acute encephalopathy such as in our patient suggests an already toxic CNS burden. In these cases, diligent and efficient removal with dialysis after chelation avoids the potential risk of rebound neurotoxicity. A reasonable treatment endpoint would seem to be resolution of signs and symptoms of CNS toxicity.
While acute aluminum toxicity is quite rare overall, alum bladder irrigation has been implicated in cases involving patients with renal insufficiency. We report one such case, including detailed information regarding DFO administration, dialysis management, and blood aluminum concentrations trended throughout the treatment course.