Aluminum Overload: An Easily-Ignored Problem in Dialysis Patients with Hyperparathyroidism

Wei-Chih Kan1,2, Chih-Chiang Chien1,2, Yi-Hua Lu1, Jyh-Chang Hwang1, Shih-Bin Su3,4 and Hsien-Yi Wang1,5 1Department of Nephrology, Chi-Mei Medical Center, Tainan 2Chung Hwa University of Medical Technology, Tainan 3Department of Family Medicine, Chi-Mei Medical Center, Tainan 4Department of Biotechnology, Southern Taiwan University, Tainan 5Chia Nan University of Pharmacy and Science, Tainan Taiwan, R.O.C.


Introduction
Dialysis patients are at high risk for aluminum overload, especially patients with hyperparathyroidism, who may occasionally take aluminum-containing phosphate binders. Dialysis patients with aluminum overload may have various symptoms, such as general bone or muscle pain, iron-resistant anemia, hypercalcemia, and neurologic abnormalities, which are sometimes difficult to differentiate from clinical manifestations of hyperparathyroidism. Because of the different therapeutic strategies between aluminum overload and hyperparathyroidism, an overview of aluminum overload in dialysis patients with hyperparathyroidism is presented in the following sections.

Aluminum overload in dialysis patients
Dialysis patients are at high risk for aluminum overload (Jaffe, J.A. et al., 2005) because of long-term use of aluminum-containing phosphate binders (Humpfner, A. et al., 1993;Salusky, I.B., 2006), poor renal excretion of aluminum, and contact with aluminumcontaining dialysate. Aluminum can be eliminated from dialysate by using reverse osmosis and deionization techniques. The dialysate concentration of aluminum is suggested to be maintained at <10 µg/L (Fernández-Martin, J.L. et al., 1998;National Kidney Foundation [NKF], 2003). Therefore, aluminum-containing phosphate binders had been documented as the predominant source of aluminum exposure in dialysis patients (Savory, J. et al., 1989;Slatopolsky, E., 1987). Because of multiple systemic aluminum-related complications, reducing the exposure of dialysis patients to aluminum by substituting calcium-and other non-aluminum-based phosphate binders is a well-known concept. However, some patients with refractory hyperphosphatemia or calcium-induced hypercalcemia still require aluminum therapy (NKF, 2003). While aluminum-based phosphate binders used as shortterm therapy are suggested by the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, these medications are prohibited in some countries (Koiwa, F., & Sato, Y., 2009). Non-calcium and non-aluminum phosphate binders (such as sevelamer hydrochloride and lanthanum carbonate) are suggested as substitutes. However, these newly developed medications have not become popular in many countries because of their high cost (Koiwa, F. & Sato, Y., 2009). In addition, the source of aluminum may contribute to extra aluminum intake from other medications (Bohrer, D. et al., 2009). Therefore, aluminum overload is still a potential problem in the dialysis population.

Frequency of aluminum overload
The declining exposure of aluminum-containing dialysate and medications with commonly use of high flux dialyzers has resulted in a low incidence of abnormal aluminum levels in current dialysis patients (Cannata-Andía, J.B. & Fernández-Martín, J.L., 2002). In one retrospective study on more than 43,000 dialysis patients, 2.5% of the patients had elevated serum aluminum levels (>50 g/L) that significantly declined year by year (Jaffe, J.A. et al., 2005). However, the prevalence of aluminum overload might be higher in countries that still commonly used aluminum-containing phosphate binders (Kan, W.C. et al., 2010).

Dialysis encephalopathy
Dialysis encephalopathy is usually a slowly progressive disorder with symptoms appearing after a patient has undergone dialysis for 1 year or even longer. Increased aluminum is found in the brain tissue of affected patients (Alfrey, A.C. et al., 1976). It is characterized by myoclonic jerks, mental changes, speech disturbances, visual or auditory hallucinations, paranoid behaviors, and even seizures. These neurologic abnormalities maybe fluctuate and often worsen temporarily after hemodialysis. The typical electroencephalographic (EEG) findings differ from the generalized slow wave with other causes of metabolic encephalopathy (Hughes, J.R. & Schreeder, M.T., 1980). However, due to its insidious progression, diagnosing these neurological disorders depends on clinical observation and suspicion, the finding of elevated plasma aluminum levels, and associated EEG features. New cases of dialysis encephalopathy disappeared after the initiation of water purification in 1979, and no more new cases have been reported in the developed countries since then (NKF, 2003).

Aluminum-induced bone disease
Aluminum can affect normal bone formation via several mechanisms. First, it interferes with mineralization of the matrix by forming crystals to compete for the site of calcium deposition, and it inhibits the activity of osteoblasts, both of which impair bone-building (Jeffery, E.H. et al., 1996). Second, it binds in the parathyroid gland, which inhibits the normal secretion of parathyroid hormone (PTH) (Cannata, J.B. et al., 1988), and it impairs PTH synthesis at the transcriptional level (Díaz-Corte, C. et al., 2001). Because of abnormal bone formation, osteomalacia is the most frequently seen aluminum-induced bone disease, but its prevalence is reported to have markedly decreased after reduced exposure to aluminum (NKF, 2003). Osteomalacia is characterized by a low rate of bone turnover, a decreased number of bone-forming and bone-resorbing cells, and an increased volume of unmineralized bone (Delmez, J.A. & Slatopolsky, E., 1992;Slatopolsky, E., 1987). In addition, because of its potential to excessively suppress PTH, aluminum overload may cause adynamic bone disease in a minority of cases.

Anemia
Aluminum can also affect normal hemopoietic processes via several mechanisms. First, it impairs intestinal absorption, serum transport, and cellular uptake of iron, because aluminum and iron share a common absorption pathway and, in the serum, they are transported on the same carriers in humans (Kausz, A.T. et al., 1999). These carriers include large proteins (such as transferrin and albumin) and small molecules (such as citrate and phosphate). In several animal and human studies, a significant negative correlation was found between aluminum load and iron transferrin saturation (Cannata, J.B. et al., 1991), and additional reductions in the use of aluminum-containing medications led to significant increases in hemoglobin and reductions in the need for intravenous iron supplementation in hemodialysis patients (Cannata, J.B. et al., 1983a). Second, aluminum may induce resistance to the hematopoietic effects of recombinant human erythropoietin (rHuEPO) in both rats and dialysis patients (Drüeke, T.B., 1990;Losekann, A. et al., 1990). Therefore, dialysis patients with an obvious aluminum overload may need larger doses of rHuEPO to overcome this resistance, which significantly increases the cost of patient care.

Hypercalcemia
Aluminum-related bone disease may cause hypercalcemia (Norris, K.C. et al., 1985). In a rat study, aluminum changed the relationships between serum PTH, calcium, and phosphorus (Felsenfeld, A.J. et al., 1993). In a study of 25 patients on continuous ambulatory peritoneal dialysis (Cannata, J.B. et al., 1983b) who had accidentally been exposed to high level of aluminum in the dialysate for a month, serum calcium levels significantly increased from 2.27 to 2.44 mmol/L, while serum PTH levels declined from 744 to 580 ng/L. In another study of hemodialysis patients (Cannata, J.B. et al., 1983c), a high serum aluminum level was strongly associated with hypercalcemia and low serum PTH level. Therefore, the suspicion of aluminum overload should be kept in mind in the patient who does not have obvious elevations in serum intact PTH (e.g., less than 500 pg/mL) or who is not taking vitamin D therapy (NKF, 2003).

Screening and diagnosis for aluminum overload
A histological examination of bone biopsy specimens is still considered the gold standard for diagnosing dialysis patients with an aluminum overload. Biopsies, however, are invasive and expensive. Therefore, several studies have reported their efforts to develop less invasive diagnostic methods of diagnosing aluminum overload (Milliner, D.S. et al., 1984). Serum aluminum measurements are of limited value due to its high tissue accumulation. However, aluminum overload is unlikely in dialysis patients with baseline serum aluminum concentrations (without desferrioxamine (DFO) "stimulation") less than 20 µg/L (NKF, 2003). In one study, 50 dialysis patients undergoing bone biopsy seemed distinguishable, after a DFO www.intechopen.com

Managing aluminum overload in dialysis patients with hyperparathyroidism
In patients with hyperparathyroidism, calcium-based phosphate binders are always unsuitable because of the frequently associated symptoms of hypercalcemia. Therefore, aluminum-based binders were used, which created a high risk of aluminum overload. Because PTH can protect against aluminum deposition at the mineralization front, perhaps by increasing bone turnover (Slatopolsky, E., 1987), the symptoms of aluminum-related bone diseases may be "masked" in dialysis patients with hyperparathyroidism. However, this "protection" will disappear in patients who have undergone a parathyroidectomy (PTX), because lowered PTH levels will accelerate bone aluminum deposition (Slatopolsky, E., 1987). Therefore, it is generally suggested that aluminum bone disease be excluded before PTX. Similarly, medical treatment of hyperparathyroidism with active Vitamin D3 (calcitriol) also may accelerate aluminum bone disease. In addition, the risk of aluminum bone disease is greater in diabetics (Andress, D.L. et al., 1987;Pei, Y. et al., 1993), which may be related to a lower bone turnover rate, which has been reported in type 1 diabetics before the onset of clinical renal disease (Andress, D.L. et al., 1987;Vincenti, F. et al., 1984). Therefore, because of the sometimes similar clinical manifestations of hyperparathyroidism and aluminum overload, physicians treating dialysis patients with hyperparathyroidism should consider the possibility of concurrent aluminum problems, especially in high-risk diabetic patients.
The side effects of DFO are dose-dependent and potentially life-threatening. Although the standard dose for aluminum overload is 5 mg/kg/week for a total of 8 weeks, there are still reports of fatal mucormycosis on such a regimen (Petrikkos, G. & Drogari-Apiranthitou, M., 2011). A lower dose of DFO, if it offers good efficacy with fewer side effects, may be promising for managing such complicated patients (Kan, W.C. et al., 2010).

Conclusion
Although the prevalence of aluminum overload in dialysis patients is decreasing, it is still an insidious problem worldwide, especially in these dialysis patients still often exposed to aluminum-containing medications. In these patients with hyperparathyroidism, calciumand aluminum-based binders are not suitable for long-term use (particularly for patients on concurrent vitamin D therapy). Therefore, in these particular patients, especially those with a history of aluminum-containing medications or water exposure, possible concurrent aluminum overload should be kept in mind before medical or surgical intervention. Otherwise, aluminum-related bone disease will be aggravated after treatments. Therefore, several non-calcium, non-aluminum phosphate binders (such as sevelamer hydrochloride and lanthanum carbonate) are suggested despite the high cost and consequent unpopularity of these newly developed medications.

Acknowledgment
Sincerely thankful to Miss Hui-Li Hsiao, the Matron of the Dialysis Center in Chi-Mei Medical Center, and all the staff nurses, whose full support and encouragement enabled us to complete the related studies.