Aluminum Toxicity Following Administration of Aluminum-Based Phosphate Binders in 2 Dogs with Renal Failure

An 11-year-old, female spayed, Brittany Spaniel, weighing 22 kg, was referred to the Emergency Service of the Veterinary Medical Teaching Hospital (VMTH) at the University of California, Davis, and hospitalized for evaluation and treatment of acute kidney injury, following ingestion of an unknown amount of ethylene glycol, 3 days earlier. At presentation at the VMTH (day 1), the dog was ambulatory, but lethargic, and overhydrated. The remainder of the physical examination was unremarkable. A CBC revealed normocytic normochromic, nonregenerative anemia (Hct, 29%; reference range [RR], 40–55%). Serum chemistry abnormalities included azotemia (serum creatinine concentration, 8.1 mg/dL; RR, 0.5–1.6 mg/dL; blood urea nitrogen [BUN], 67 mg/dL; RR, 8–21 mg/dL), hyperphosphatemia (13.8 mg/dL; RR, 3.0–6.2 mg/dL), hypocalcemia (8.3 mg/dL; RR, 9.7–11.5 mg/dL), normokalemia (4.97 mmol/L; RR, 3.6–5.3 mmol/L), and metabolic acidosis (serum bicarbonate, 10 mmol/L; RR, 16–26 mmol/L). On urinalysis, specific gravity was 1.009, pH was 5, and occasional calcium oxalate crystals were observed. Urine culture for aerobic and anaerobic bacteria was negative. Abdominal ultrasound examination disclosed normal-sized kidneys with hyperechoic cortices bilaterally, consistent with ethylene glycol intoxication and focal hyperechoic appearance to the mesentery in the right cranial abdominal quadrant suggestive of pancreatitis. Owing to azotemia, clinical signs, and presumed ethylene glycol exposure, hemodialysis was initiated, using standard procedures as established for dogs.1,2 By day 11, clinical signs had resolved with the combination of hemodialysis and symptomatic treatment, and all caloric requirements and medications were provided via a gastrostomy tube placed during initial hospitalization. Renal function, however, did not improve, necessitating continued thrice weekly hemodialysis treatments on an outpatient basis. On the day of discharge (day 11), aluminum hydroxidea was added to the blended diet to provide 84 mg/kg/d in order to control the hyperphosphatemia. This dosage was increased to 126 mg/kg/d on day 22, because the serum phosphorus concentration exceeded the target range (<6 mg/dL). On day 36, erythropoietinb therapy was initiated at 100 U/kg thrice weekly, SC in combination with iron dextranc supplementation at 10 mg/kg IM every 3 weeks. The dog remained stable for the next 26 days on hemodialysis but no improvement in the kidney function was noticed. Mean serum creatinine and BUN concentrations before each dialysis treatment were 6.8 and 75 mg/dL, respectively. On day 62, lethargy and a decreased activity were noted by the owners. Both conditions worsened progressively to obtundation and complete recumbency by day 70. Neurologic examination revealed an inconsistent menace response, normal cranial reflexes, tetraparesis, reduced patellar reflexes in the hind limbs, and markedly reduced withdrawal reflexes in all 4 limbs. On the basis of these findings, the neurologic deficits were localized as diffuse cerebral and peripheral neuropathy or junctionopathy. Azotemia was unchanged from the time of discharge, and the remainder of the biochemistry results were unremarkable. A CBC revealed progressive microcytosis with a decrease in mean corpuscular volume (MCV) from 72 fL (RR 65–75) at discharge (day 11) to 57 fL on day 70 (Fig 1). On the basis of history, clinical signs and neurologic abnormalities, a tentative diagnosis of aluminum toxicity was made. Serum aluminum concentration measured on day 71 was markedly increased at 0.52 ppm (RR, 0.008–0.012),d confirming the diagnosis of aluminum toxicity. Progressive microcytosis following initiation of aluminum-based phosphate binders. Serial changes in mean corpuscular volume (MCV) over time in 2 dogs treated with aluminum-based phosphate binders from initiation of therapy (day 0) until diagnosis of aluminum toxicity. Each curve represents evaluation of a single dog. The shaded area represents the reference range for MCV. Aluminum hydroxide treatment was discontinued, and aluminum chelation therapy with deferoxaminee administered at 82 mg (3.7 mg/kg) in 250 mL of saline was delivered as a 3-hour infusion given IV 16 hours before the next hemodialysis treatment. The dog became substantially more alert, responsive, and ambulatory over the following 48 hours, but remained ataxic. Further improvement was documented with a gradual resolution of all neuromuscular deficits over the next 10 days. The dog remained asymptomatic for the next 2 weeks, but then (day 97) became lethargic and manifested facial swelling. Laboratory assessment disclosed leukocytosis (33,810 cells/μL) with neutrophilia (32,253 cells/μL), and blood culture grew Escherichia coli. A catheter-related infection and thrombosis were suspected. Serum aluminum concentration was within the RR (0.012 ppm). Despite antibiotic therapy with ampicillinf at 20 mg/kg IV q8h and enrofloxacing at 10 mg/kg slow IV q24h no clinically relevant improvement was noticed and on day 100 the dog suffered cardiopulmonary arrest and died. Necropsy examination indicated severe multifocal tubular necrosis of the kidneys, disseminated intratubular oxalate crystal deposition, lymphocytic interstitial nephritis, nephron atrophy, and fibrosis. Other findings included locally extensive myocardial degeneration with necrosis and thrombus formation in the right atrium, emphysematous and perivascular lymphocytic cystitis, and multiple thrombi in the gallbladder. A 12-year-old Labrador Retriever dog weighing 33 kg was presented to the VMTH with a complaint of lethargy, anorexia, and intermittent vomiting of 1-week duration. The dog was diagnosed with urinary incontinence and early nonproteinuric, normotensive IRIS stage III chronic kidney disease (CKD), 3 years earlier. During this period, multiple episodes of urinary tract infection were diagnosed, and the dog was treated intermittently with antibiotics. At presentation to the VMTH (day 1) the dog was quiet, alert, and responsive. Physical examination was unremarkable. A CBC revealed mild normocytic normochromic, nonregenerative anemia (Hct = 34%), and serum biochemistry results included severe azotemia (serum creatinine concentration 16.6 mg/dL, BUN concentration 120 mg/dL), hyperphosphatemia (14.0 mg/dL), and normokalemia (4.7 mmol/L). Ultrasound examination demonstrated bilaterally small kidneys with irregular cortical margins, hyperechoic cortices, decreased corticomedullary definition, and small cysts within the renal cortices bilaterally. On urinalysis, microscopic hematuria and pyuria were observed, and urine culture was negative for bacterial growth. A tentative diagnosis of acute on CKD was made. The dog was hospitalized and placed on IV fluids (lactated Ringer's solution, 3.7 mL/kg/h), but became overhydrated during the next 48 hours. Because of the severity of azotemia and overhydration, hemodialysis was initiated on day 4 of hospitalization. The dog was discharged on day 7 after an esophagostomy feeding tube was placed, and hemodialysis was continued thrice weekly on an outpatient basis. On day 10, aluminum hydroxidea was prescribed at a dosage of 45 mg/kg/d as an intestinal phosphate-binding agent (provided with blended food via the feeding tube) to control the hyperphosphatemia. Additional medical management included darbepoetinh at 0.46 μg/kg weekly SQ and iron dextranc at 10 mg/kg IM every 3 weeks. The aluminum hydroxide dosage was increased to 87 mg/kg/d on day 17 and further increased to 145 mg/kg/d on day 28 due to persistent hyperphosphatemia (7.4 mg/dL). On day 35, hemodialysis was discontinued because of improvement in kidney function and partial resolution of the azotemia as reflected by stabilized serum creatinine concentration of 7.0 mg/dL. On day 50, the dog was stable on medical management but the serum phosphorus concentration was 8.7 mg/dL, and the aluminum hydroxide dosage was increased to 200 mg/kg/d in the blended food. On day 65, the dog was presented again to the VMTH for signs of weakness and ataxia that progressed to recumbency over a 3-day period. Neurologic examination revealed decreased menace response, tetraparesis, absent patellar reflexes bilaterally, and decreased pelvic limb withdrawal reflexes. The signs were ascribed to diffuse cerebral and peripheral neuropathy or junctionopathy. A CBC revealed mild microcytic, normochromic anemia (Hct, 34.6%; MCV, 62 fL) but was otherwise unremarkable. Serum biochemistry revealed stable azotemia (serum creatinine concentration, 7.0 mg/dL; BUN concentration, 108 mg/dL) and hyperphosphatemia (8.7 mg/dL). Serum iron concentration and total iron-binding capacity (TIBC) were markedly increased (772 μg/dL; RR, 33–147 μg/dL and 989 μg/dL; RR, 282–386 μg/dL, respectively) due to iron therapy. Serum aluminum concentration on day 65 was markedly increased (0.318 ppm).d On the basis of the clinical signs and high serum aluminum concentration, a diagnosis of aluminum intoxication was made. Chelation therapy with deferoxaminee (5 mg/kg infused IV over 1 hour), followed by hemodialysis treatment 12 hours later was performed on the next 2 consecutive days. Forty-eight hours after the second chelation-hemodialysis treatment, the dog was normally ambulatory and neurologic examination was unremarkable. The dog's neurologic status was normal for the next 3 weeks but kidney function worsened and the dog was euthanized on day 96. CKD is common in dogs.3 Hyperphosphatemia is an expected feature of CKD and may promote secondary hyperparathyroidism, progression of CKD, and increased mortality in human patients and dogs with CKD.4,5 Therapeutic control and normalization of serum phosphorus concentration is a mainstay in the management of CKD. Recommended therapeutic approaches include feeding phosphate-restricted diets and use of intestinal phosphate-binding agents to minimize intestinal absorption of phosphate. Aluminum-based intestinal phosphate-binding agents are used commonly in veterinary medicine because they are effective, inexpensive, and are associated with relatively few reported adverse effects. Long-term use of aluminum-based phosphate-binding agents in human patients with CKD however has been documented to cause high serum aluminum concentrations and accumulation of aluminum in a variety of tissues including the brain.6 These findings have prompted discontinuation of aluminum-based phosphate-binding agents in human patients with CKD, although the exact pathophysiology of aluminum intoxication is not completely understood. Clinical manifestations of aluminum toxicity in human patients include encephalopathy, microcytic anemia, and osteomalacia.7–10 Aluminum accumulation also is associated with the development of Alzheimer's disease.11,12 Currently, human CKD patients managed with aluminum-based phosphate-binding agents are considered at risk for aluminum toxicity and are screened routinely for potential toxicity. To date, there is no documentation of aluminum toxicity associated with administration of phosphate-binding agents in dogs with naturally occurring kidney disease. van Toor et al13 reported a case of aluminum toxicity in a dog after ingestion of an aluminum foreign object. Clinical signs included convulsions and muscle twitching, which resolved gradually after removal of the foreign object. Dogs with advanced renal dysfunction that are supplemented with aluminum-based phosphate binders may accumulate excessive amounts of aluminum in their tissues, because aluminum is eliminated primary by the kidneys, as has been recognized in human patients with CKD.6 The lack of recognition of aluminum toxicity in uremic dogs may be related partially to clinicians' lack of awareness of this intoxication. In human patients, early clinical manifestations of aluminum toxicity include speech disturbances and variable degrees of dementia.14,15 Such subtle clinical signs in human patients may not be recognized in dogs. Moreover, clinicians may attribute neurologic abnormalities to the kidney disease itself (eg, uremia, hypertension) and overlook the potential for aluminum accumulation and toxicity. The apparent decreased risk of aluminum toxicity in dogs compared with human patients maintained on aluminum-based phosphate-binding agents also may be related to the difficulty of managing animal patients with advanced CKD long enough for signs of toxicity to develop. Alternatively, conventional dosage recommendations for aluminum-containing salts may not be sufficient to promote aluminum toxicity. These conventional dosages however may be insufficient to adequately control hyperphosphatemia in some patients. Therefore, administered aluminum salts may be less likely to result in serum aluminum concentrations sufficiently high to cause overt clinical manifestations in animals with short life spans or in those given subtherapeutic dosages of phosphate binders. Nevertheless, animals with advanced renal disease now are maintained for longer period of times, and guidelines for control of serum phosphorus concentration in dogs with CKD have become more stringent, making patients with advanced disease that are managed with aluminum-based phosphate binders at risk for aluminum toxicity. The dogs reported here developed severe neuromuscular abnormalities consistent with aluminum toxicity. The likelihood these signs were attributable to aluminum accumulation due to the administration of aluminum-based phosphate binders was high based on the temporal association of these signs with progressively higher dosages of aluminum-based phosphate binders, the extremely high serum aluminum concentrations, and the resolution of signs with chelation therapy. The possibility that the dialysate solution contained aluminum and was a contributing factor in the reported patients is unlikely because both the product water and the final dialysate solution were monitored routinely and aluminum was consistently undetectable. The reported patients did not overlap temporally precluding the possibility of inadvertent contamination, and water and dialysate quality assurance assessments were carried out during this time, precluding the likelihood of chronic contamination. To eliminate the possibility of inadvertent acute contamination, water quality was independently evaluated during one of the episodes and it contained no detectible aluminum. Nevertheless, in patients treated chronically with hemodialysis this possibility should be considered. On the basis of the reported observations, aluminum toxicity should be suspected in dogs with CKD that are presented with diffuse cerebral deficits or generalized neuromuscular disease if they have been treated concurrently with aluminum-based phosphate binders. Moreover, aluminum accumulation should be considered in the differential diagnosis in dogs at any stage of CKD if they have been managed with aluminum-based phosphate binders, even if only subtle signs of weakness and obtundation are present. Progressive microcytosis consistently was associated with development of neuromuscular signs and aluminum toxicity in the dogs of this report, and these signs are well documented in human patients.9,10 Thus, microcytosis possibly could be used as an early indicator of aluminum accumulation in CKD patients treated with aluminum-based phosphate binders. Progressive microcytosis may initially be difficult to distinguish from iron deficiency associated with erythropoietin therapy in uremic animals,16 as was the case in the patients described here that were treated with erythropoietin and became overtly symptomatic before serum iron concentration and TIBC results were available. Nevertheless, in the reported cases, the routine use of iron dextran along in conjunction with erythropoietin, and the high serum iron and TIBC concentrations, measured in one of the dogs, make iron deficiency less likely as a cause of progressive microcytosis. The elimination of aluminum from uremic animals that are symptomatic for aluminum toxicity remains problematic. Deferoxamine has been used successfully as an aluminum chelating agent in both human patients and laboratory animals.17,18 The coupling of deferoxamine chelation with hemodialysis is likely to be more effective, because the kidney is the primary route for elimination of chelated aluminum, and its clearance will be impaired in patients with poor renal function.18 In the dogs reported here, neurological signs improved substantially within 48 hours of the treatment with deferoxamine, suggesting that aluminum toxicity was the cause for the clinical signs and that deferoxamine treatment in combination with hemodialysis is an effective treatment for aluminum overload in dogs with CKD. In conclusion, these cases demonstrate that aluminum toxicity can occur in dogs with CKD that are supplemented with aluminum-based phosphate binders at dosage required to normalize serum phosphorus concentration. Progressive decreases in MCV and microcytosis are early indicators of aluminum overdose and toxicity, and should be monitored in dogs treated with aluminum-based phosphate binders. Similarly, aluminum toxicity should be considered in animals manifesting neurologic or neuromuscular signs under these circumstances. Treatment with deferoxamine followed by hemodialysis should be considered for the management of patients with severe neuromuscular complications of aluminum intoxication. aAluminum hydroxide gel, amphogel, Rugby, Duluth, GA bErythropoetin, Epogen, Amgen, Thousand Oaks, CA cIron dextran, inj, Vedco, Phoenix Scientific Inc, St Joseph, MO dUtah Veterinary Diagnostic Laboratory, Logan, UT eDeferoxamine, 500 mg/Vial Inj, Desferal, Novartis, Schaffhauserstrasse, Switzerland fAmpicillin injection, Sandoz Inc, Broomfield, CO gEnrofloxacin, Baytril, 2.27% Inj, Bayer, Shawnee, KS hDarbepoetin, Aranesp, Amgen

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