- Email: [email protected]
Aluminum and Phosphate: The Double Bind
Aluminum and Phosphate: The Double Bind Michael Kaye, MD, and Raymonde Gagnon, MD INDEX WORDS: Aluminum; aluminum accumulation; phosphate binders; dialysis; hemodialysis; dialysis prescription.
T
HE recognition that aluminum contaminated dialyzate was responsible for dementia and osteomalacic bone disease led to the expectation that with suitable water treatment, aluminum storage, and, on occasion, intoxication, would be eliminated. I -5 Instead the epidemiology has changed so that sporadic cases are occurring rather than the clusters seen previously. 5-8 This represents an indication of the more gradual, insidious exposure to aluminum by the oral rather than by the dialyzate route. In areas such as our own where dialyzate has always been essentially aluminum free, 26 out of 47 patients or 55 % on dialysis for at least one year have stainable bone aluminum. All except three had taken oral aluminum compounds and these had negative staining. The prescription of oral aluminum salts, usually the hydroxide (AI(OHh), has been widely employed once it was shown that hyperphosphatemia was pivotal in the progression of the secondary hyperparathyroidism of end-stage renal disease (ESRD). It is necessary then to examine the major determinants of serum phosphorus in patients on renal replacement therapy. These would include residual renal function, bone resorption, dietary phosphorus, dialysis prescription, and, finally, dose of Al(OHh. Residual renal function, urine volume, and, hence, solute excretion are generally insignificant in patients on dialysis. The few with creatinine clearances of 4 to 6 mLimin will see these decline following the initiation of dialysis. The subjects own excretory function for phosphate (although not necessarily for water and other solutes) can therefore usually be ignored. Increased rates for bone resorption are characteristic of secondary hyperparathyroidism and would lead to increased flux of calcium and phosphate into extracellular fluid. Hypercalcemia, while it does occur, is uncommon and because calcium and phosphorus are found in a fixed ratio in apatite, hyperphosphatemia also would be infrequent. The reason for this anomaly is the coupling of formation to resorption so that although more
bone is removed more is also formed at roughly equal rates. A further consideration is that if hyperphosphatemia is in fact responsible for secondary hyperparathyroidism then the finding of high serum phosphate levels are not necessarily the result of the parathyroid hyperactivity leading to augmented bone turnover but rather the cause. This is probably the reason for the previous report of higher serum phosphorus levels in patients with overt hyperparathyroidism when compared to those without, although several in the former group were hypercalcemic. 9 In our data, 39 patients were divided on the basis of their bone histology into either absent or minimal hyperparathyroidism (17 patients) or active disease (22 patients). Predialysis serum phosphorus was 6.2 ± 0.3 in both groups. Agreement with these propositions means that dietary phosphorus intake and the dialysis prescription for most patients are the only important parameters determining the predialysis serum phosphorus levels, in addition to oral AI(OHh intake. Any attempt to decrease AI(OH)3 intake will necessitate changes in either dietary phosphorus and/ or the amount of phosphorus removed by dialysis. Dietary phosphorus intake in the usual European and North American diet is quite high and the decreased incidence of renal osteodystrophy in Israel was reported to be associated with lower protein and phosphorus intakes and lower serum phosphorus values. lo In the National Cooperative Dialysis Study (NCDS) mean dietary phosphorus during the control phase for the 162 subjects was 879 mg/d with a standard deviation of 248 mg. II This indicates that a proportion of these selected compliant patients were ingesting more than 1,000 From the Division of Nephrology. Montreal General Hospital. Montreal . Quebec. Address reprint requests to Dr Michael Kaye, Division of Nephrology, Montreal General Hospital, 1650 Cedar Ave , Montreal, Quebec, H3G lA4. © 1985 by The National Kidney Foundation, Inc. 0272-6386/85/0605-0018$03.00/0
American Journal of Kidney Diseases, Vol VI, No 5, November 1985
365
366
KAYE AND GAGNON Table 1.
Patient
S K C A
R B H Mean ± SEM
Phosphorus (P) Recovered From Total Dialyzate Volume of a Single Dialysis· Diet P (mg/d)
Dialysis Duration (H)
Predialysis (P mg/dL)
Postdialysis (P mg/dL)
800 650 800 1120 850 1250 1600 1010.0 ± 122.5
3.5 4.0 4.0 4.0 3.75 5.0 4.0 4.04 ± 0.176
7.6 4.8 5.2 6.4 8.3 16.2 9.2 8.24 ± 1.46
3.3 2.7 3.7 3.3 9.4 4.48 ± 1.24
P Recovered (mg)
Removed/d (mg)
632 520 740 882 818 2461 1139 1027 ± 250
271 223 211 378 234 1055 488 409 ± 114
P
·Blood flow 200 mL/min, Gambro 120M dialyzer. All patients dialyzed three times a week except for C and R.
mg/d of phosphorus. This is probably an underestimate as shown by the discrepancies between the reported protein intakes and the calculated protein catabolic rates. II The patients in the study were considered representative of those in the rest of the United States and had similar plasma phosphate levels predialysis. 12 Reduction in diet phosphorus to 1 g daily or less would be expected to decrease the requirement for Al(OHh, although data to prove this is unavailable in the literature. In one of the few studies on this point, Clarkson et al were unable to show any relationship between dietary phosphorus and the fall in serum phosphorus induced by Al(OHh.13 However these patients with residual renal function were not yet on dialysis and therefore were not comparable to patients on dialysis with much smaller amounts of urinary phosphorus excretion. In the NCDS study the two groups with low morbidity, mortality, and low blood urea nitrogens (BUN) had stable intakes of Al(OHh throughout the 48 weeks of the study. The two high BUN groups required Al(OHh from 3.5 to 4.7 and 3.6 to 4.9 g/d, respectively, to keep the plasma phosphorus from rising. 14 Turning to phosphorus losses on dialysis, the data of Bishop et al in five patients treated with Kiil dialyzers for 10 hours thrice weekly, the loss for each dialysis was about 1 g with an averaged daily mean of 403 mg. 15 Assuming a dietary intake as in the NCDS study of 879 mg/d , the dialyzer loss is approximately one half of this. If only 70 % of dietary phosphorus is actually absorbed then this would be 615 mg/d. 16 Data for a hollow fiber dialyzer (Gambro 120M, Gambro, Missassauga, Ontario) of surface area 1.2 m2 is shown in Table 1. It can be seen that a mean of 788 ± 87.8 mg of phosphorus was lost in the dialyzate during one dialysis, which over a week gives an estimated
value equal to 300.8 ± 44.9 mg/d. (Patient B who was not taking any binders was excluded from the calculation.) With a mean daily absorption of 615 mg the dialyzer loss is 49 % of the absorbed phosphorus. These figures, although crude, clearly show that a major determinant of phosphorus balance is loss through the dialyzer. Reducing dialysis time and/or dialyzer efficiency will decrease the phosphorus loss, lead to more hyperphosphatemia, and require extra Al(OHh to be prescribed. Several studies have suggested that aluminum accumulation is related to total daily oral dose of aluminum salts. 6.17·19 We would argue therefore that prevention of aluminum storage can be equated with either the use of other methods of phosphate binding or increasing dialysis time/efficiency. Dialysis efficiency has to be increased either by using large surface area dialyzers and/or increasing blood flow. Use of calcium carbonate, magnesium salts, cationic charged polymers, and seaweed derivatives have all been tried or await further testing. In the meantime reduction or abolition of aluminum ingestion is possible by attention to diet and adjustment of dialysis prescription. While much attention has focused on urea removal by dialysis , this solute represents a highly permeable substance. Phosphate with a clearance for most hollow fiber dialyzers of only 57 % of urea is more slowly removed and judgment of adequacy of dialysis by urea levels as in the NCDS study and common clinical practice will result in postdialysis serum phosphorus levels in the 3 to 5 mg/dL range. Instead, determining time and/or efficiency of dialysis by the goal of phosphate removal would permit postdialysis levels in the 2 to 3 mg/dL range. For some, phosphate binders would be obviated, for others weak binders such as calcium carbonate would suffice, leaving a residual group
367
ALUMINUM AND PHOSPHATE
who would need AI(OHh but in reduced dosage. The ease, safety, and simplicity of this approach does not explain why it is not used. Presumably physician and patient acceptance, scheduling, and the general desire to minimize restrictions are all factors of importance. It is suggested that aluminum storage from oral ingestion has to be taken seriously and that until
such time as alternate safe binders are available, consideration should be given to diet control and increased dialysis time and/or efficiency.
ACKNOWLEDGMENT We wish to thank Miss Karen Murray, renal dietitian, for her adv Ice, and Mrs Hermania Esposito for secretarial help.
REFERENCES 1. Alfrey AC , LeGendre GR, Kaehny WD: The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 294:184-188,1976 2. Platts MM , Goode GC, Hislop JS: Composition of the domestic water supply and the incidence of fractures and encephalopathy in patients on home dialysis. Br Med J 2:657660, 1977 3. Elliott HL, Dryburgh F, Fell GS , et al: Aluminum toxicity during regular haemodialysis. Br Med J I: 1101-1103 , 1978 4. Alfrey AC, Hegg A, Craswell P: Metabolism and toxicity of aluminum in renal failure. Am J Clin Nutr 33: 1509- 1516, 1980 5. Report from the Registration Committee of the European Dialysis and Transplant Association: Dialysis dementia in Europe. Lancet 2:190-192 , 1980 6. Alfrey AC: Aluminum intoxication. N Engl J Med 310:1113-1115 , 1984 7. Buge A, Poisson M, Masson S, et al: Encephalopathie reversible des dialyses apres arret de l'apport d'aluminum. Nouv Presse Med 8:2729-2733 , 1979 8. Kaye M: Oral aluminum toxicity in a non-dialysed patient with renal failure. Clin Nephrol 20:208-211, 1983 9. Massry SG. Coburn Jw, Popovtzer M, et al: Secondary hyperparathyroidism in chronic renal failure. The clinical spectrum in uremia. during hemodialysis and after renal transplantation. Arch Intern Med 124:431-441. 1969 10. Berlyne GM, Ben-Ari J, Epstein N, et al : Rarity of renal osteodystrophy in Israel due to low phosphorus intake. Nephron 10:141-156,1973 II. Schoenfeld PY, Henry RR, Laird NM, et al : Assessment
of nutritional status of the National Cooperative Dialysis Study popUlation. Kidney Int 23:S80-S88 , 1983 12. Parker TF, Reed RB, Lowrie EG: Description of the participating centers and the patient population in the National Cooperative Dialysis StUdy. Kidney Int 23:S37-S41, 1983 13. Clarkson EM , Luck VA, Hynson WV, et al: The effect of aluminum hydroxide on calcium, phosphorus and aluminum balances, the serum parathyroid hormone concentration and the aluminum content of bone in patients with chronic renal failure . Clin Sci 43:519-531 , 1972 14. Harter HR, Laird NM, Teehan BP: Effects of dialysis prescription 0- bone and mineral metabolism: The National Cooperative Dialysis StUdy. Kidney Int 23:S73-S79, 1983 15 . Bishop MC , Ledingham JGG, Oliver DO: Phosphate deficiency in haemodialysed patients. Proc Eur Dial Transplant Assoc 8: 106-114, 1971 16. Coburn Jw, Llach F: Renal osteodystrophy and maintenance dialysis, in Drukker W. Parsons FM, Maher JF (eds): Replacement of Renal Function by Dialysis. Boston, Kluwer Academic , 1983 , p 690 17 . Winney RJ, Cowie JF, Cumming AD, et al: Epidemiology of aluminum toxicity in a 'low incidence' area. Contrib Nephrol 38:47-58 , 1984 18. Heaf JG, Nielsen LP: Serum aluminum in haemodialysis patients: Relation to osteodystrophy, encephalopathy and aluminum hydroxide consumption . Miner Electrolyte Metab 10:345-350, 1984 19. Boukari M, Rottembourg J, Jaudon M-C , et al : Influence de la prise prolongee de gels d'alumine sur les taux seriques d' aluminium chez les patients atteints d' insu ffisance renale chronique. Nouv Presse Med 7:85-88, 1978
T
HE recognition that aluminum contaminated dialyzate was responsible for dementia and osteomalacic bone disease led to the expectation that with suitable water treatment, aluminum storage, and, on occasion, intoxication, would be eliminated. I -5 Instead the epidemiology has changed so that sporadic cases are occurring rather than the clusters seen previously. 5-8 This represents an indication of the more gradual, insidious exposure to aluminum by the oral rather than by the dialyzate route. In areas such as our own where dialyzate has always been essentially aluminum free, 26 out of 47 patients or 55 % on dialysis for at least one year have stainable bone aluminum. All except three had taken oral aluminum compounds and these had negative staining. The prescription of oral aluminum salts, usually the hydroxide (AI(OHh), has been widely employed once it was shown that hyperphosphatemia was pivotal in the progression of the secondary hyperparathyroidism of end-stage renal disease (ESRD). It is necessary then to examine the major determinants of serum phosphorus in patients on renal replacement therapy. These would include residual renal function, bone resorption, dietary phosphorus, dialysis prescription, and, finally, dose of Al(OHh. Residual renal function, urine volume, and, hence, solute excretion are generally insignificant in patients on dialysis. The few with creatinine clearances of 4 to 6 mLimin will see these decline following the initiation of dialysis. The subjects own excretory function for phosphate (although not necessarily for water and other solutes) can therefore usually be ignored. Increased rates for bone resorption are characteristic of secondary hyperparathyroidism and would lead to increased flux of calcium and phosphate into extracellular fluid. Hypercalcemia, while it does occur, is uncommon and because calcium and phosphorus are found in a fixed ratio in apatite, hyperphosphatemia also would be infrequent. The reason for this anomaly is the coupling of formation to resorption so that although more
bone is removed more is also formed at roughly equal rates. A further consideration is that if hyperphosphatemia is in fact responsible for secondary hyperparathyroidism then the finding of high serum phosphate levels are not necessarily the result of the parathyroid hyperactivity leading to augmented bone turnover but rather the cause. This is probably the reason for the previous report of higher serum phosphorus levels in patients with overt hyperparathyroidism when compared to those without, although several in the former group were hypercalcemic. 9 In our data, 39 patients were divided on the basis of their bone histology into either absent or minimal hyperparathyroidism (17 patients) or active disease (22 patients). Predialysis serum phosphorus was 6.2 ± 0.3 in both groups. Agreement with these propositions means that dietary phosphorus intake and the dialysis prescription for most patients are the only important parameters determining the predialysis serum phosphorus levels, in addition to oral AI(OHh intake. Any attempt to decrease AI(OH)3 intake will necessitate changes in either dietary phosphorus and/ or the amount of phosphorus removed by dialysis. Dietary phosphorus intake in the usual European and North American diet is quite high and the decreased incidence of renal osteodystrophy in Israel was reported to be associated with lower protein and phosphorus intakes and lower serum phosphorus values. lo In the National Cooperative Dialysis Study (NCDS) mean dietary phosphorus during the control phase for the 162 subjects was 879 mg/d with a standard deviation of 248 mg. II This indicates that a proportion of these selected compliant patients were ingesting more than 1,000 From the Division of Nephrology. Montreal General Hospital. Montreal . Quebec. Address reprint requests to Dr Michael Kaye, Division of Nephrology, Montreal General Hospital, 1650 Cedar Ave , Montreal, Quebec, H3G lA4. © 1985 by The National Kidney Foundation, Inc. 0272-6386/85/0605-0018$03.00/0
American Journal of Kidney Diseases, Vol VI, No 5, November 1985
365
366
KAYE AND GAGNON Table 1.
Patient
S K C A
R B H Mean ± SEM
Phosphorus (P) Recovered From Total Dialyzate Volume of a Single Dialysis· Diet P (mg/d)
Dialysis Duration (H)
Predialysis (P mg/dL)
Postdialysis (P mg/dL)
800 650 800 1120 850 1250 1600 1010.0 ± 122.5
3.5 4.0 4.0 4.0 3.75 5.0 4.0 4.04 ± 0.176
7.6 4.8 5.2 6.4 8.3 16.2 9.2 8.24 ± 1.46
3.3 2.7 3.7 3.3 9.4 4.48 ± 1.24
P Recovered (mg)
Removed/d (mg)
632 520 740 882 818 2461 1139 1027 ± 250
271 223 211 378 234 1055 488 409 ± 114
P
·Blood flow 200 mL/min, Gambro 120M dialyzer. All patients dialyzed three times a week except for C and R.
mg/d of phosphorus. This is probably an underestimate as shown by the discrepancies between the reported protein intakes and the calculated protein catabolic rates. II The patients in the study were considered representative of those in the rest of the United States and had similar plasma phosphate levels predialysis. 12 Reduction in diet phosphorus to 1 g daily or less would be expected to decrease the requirement for Al(OHh, although data to prove this is unavailable in the literature. In one of the few studies on this point, Clarkson et al were unable to show any relationship between dietary phosphorus and the fall in serum phosphorus induced by Al(OHh.13 However these patients with residual renal function were not yet on dialysis and therefore were not comparable to patients on dialysis with much smaller amounts of urinary phosphorus excretion. In the NCDS study the two groups with low morbidity, mortality, and low blood urea nitrogens (BUN) had stable intakes of Al(OHh throughout the 48 weeks of the study. The two high BUN groups required Al(OHh from 3.5 to 4.7 and 3.6 to 4.9 g/d, respectively, to keep the plasma phosphorus from rising. 14 Turning to phosphorus losses on dialysis, the data of Bishop et al in five patients treated with Kiil dialyzers for 10 hours thrice weekly, the loss for each dialysis was about 1 g with an averaged daily mean of 403 mg. 15 Assuming a dietary intake as in the NCDS study of 879 mg/d , the dialyzer loss is approximately one half of this. If only 70 % of dietary phosphorus is actually absorbed then this would be 615 mg/d. 16 Data for a hollow fiber dialyzer (Gambro 120M, Gambro, Missassauga, Ontario) of surface area 1.2 m2 is shown in Table 1. It can be seen that a mean of 788 ± 87.8 mg of phosphorus was lost in the dialyzate during one dialysis, which over a week gives an estimated
value equal to 300.8 ± 44.9 mg/d. (Patient B who was not taking any binders was excluded from the calculation.) With a mean daily absorption of 615 mg the dialyzer loss is 49 % of the absorbed phosphorus. These figures, although crude, clearly show that a major determinant of phosphorus balance is loss through the dialyzer. Reducing dialysis time and/or dialyzer efficiency will decrease the phosphorus loss, lead to more hyperphosphatemia, and require extra Al(OHh to be prescribed. Several studies have suggested that aluminum accumulation is related to total daily oral dose of aluminum salts. 6.17·19 We would argue therefore that prevention of aluminum storage can be equated with either the use of other methods of phosphate binding or increasing dialysis time/efficiency. Dialysis efficiency has to be increased either by using large surface area dialyzers and/or increasing blood flow. Use of calcium carbonate, magnesium salts, cationic charged polymers, and seaweed derivatives have all been tried or await further testing. In the meantime reduction or abolition of aluminum ingestion is possible by attention to diet and adjustment of dialysis prescription. While much attention has focused on urea removal by dialysis , this solute represents a highly permeable substance. Phosphate with a clearance for most hollow fiber dialyzers of only 57 % of urea is more slowly removed and judgment of adequacy of dialysis by urea levels as in the NCDS study and common clinical practice will result in postdialysis serum phosphorus levels in the 3 to 5 mg/dL range. Instead, determining time and/or efficiency of dialysis by the goal of phosphate removal would permit postdialysis levels in the 2 to 3 mg/dL range. For some, phosphate binders would be obviated, for others weak binders such as calcium carbonate would suffice, leaving a residual group
367
ALUMINUM AND PHOSPHATE
who would need AI(OHh but in reduced dosage. The ease, safety, and simplicity of this approach does not explain why it is not used. Presumably physician and patient acceptance, scheduling, and the general desire to minimize restrictions are all factors of importance. It is suggested that aluminum storage from oral ingestion has to be taken seriously and that until
such time as alternate safe binders are available, consideration should be given to diet control and increased dialysis time and/or efficiency.
ACKNOWLEDGMENT We wish to thank Miss Karen Murray, renal dietitian, for her adv Ice, and Mrs Hermania Esposito for secretarial help.
REFERENCES 1. Alfrey AC , LeGendre GR, Kaehny WD: The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 294:184-188,1976 2. Platts MM , Goode GC, Hislop JS: Composition of the domestic water supply and the incidence of fractures and encephalopathy in patients on home dialysis. Br Med J 2:657660, 1977 3. Elliott HL, Dryburgh F, Fell GS , et al: Aluminum toxicity during regular haemodialysis. Br Med J I: 1101-1103 , 1978 4. Alfrey AC, Hegg A, Craswell P: Metabolism and toxicity of aluminum in renal failure. Am J Clin Nutr 33: 1509- 1516, 1980 5. Report from the Registration Committee of the European Dialysis and Transplant Association: Dialysis dementia in Europe. Lancet 2:190-192 , 1980 6. Alfrey AC: Aluminum intoxication. N Engl J Med 310:1113-1115 , 1984 7. Buge A, Poisson M, Masson S, et al: Encephalopathie reversible des dialyses apres arret de l'apport d'aluminum. Nouv Presse Med 8:2729-2733 , 1979 8. Kaye M: Oral aluminum toxicity in a non-dialysed patient with renal failure. Clin Nephrol 20:208-211, 1983 9. Massry SG. Coburn Jw, Popovtzer M, et al: Secondary hyperparathyroidism in chronic renal failure. The clinical spectrum in uremia. during hemodialysis and after renal transplantation. Arch Intern Med 124:431-441. 1969 10. Berlyne GM, Ben-Ari J, Epstein N, et al : Rarity of renal osteodystrophy in Israel due to low phosphorus intake. Nephron 10:141-156,1973 II. Schoenfeld PY, Henry RR, Laird NM, et al : Assessment
of nutritional status of the National Cooperative Dialysis Study popUlation. Kidney Int 23:S80-S88 , 1983 12. Parker TF, Reed RB, Lowrie EG: Description of the participating centers and the patient population in the National Cooperative Dialysis StUdy. Kidney Int 23:S37-S41, 1983 13. Clarkson EM , Luck VA, Hynson WV, et al: The effect of aluminum hydroxide on calcium, phosphorus and aluminum balances, the serum parathyroid hormone concentration and the aluminum content of bone in patients with chronic renal failure . Clin Sci 43:519-531 , 1972 14. Harter HR, Laird NM, Teehan BP: Effects of dialysis prescription 0- bone and mineral metabolism: The National Cooperative Dialysis StUdy. Kidney Int 23:S73-S79, 1983 15 . Bishop MC , Ledingham JGG, Oliver DO: Phosphate deficiency in haemodialysed patients. Proc Eur Dial Transplant Assoc 8: 106-114, 1971 16. Coburn Jw, Llach F: Renal osteodystrophy and maintenance dialysis, in Drukker W. Parsons FM, Maher JF (eds): Replacement of Renal Function by Dialysis. Boston, Kluwer Academic , 1983 , p 690 17 . Winney RJ, Cowie JF, Cumming AD, et al: Epidemiology of aluminum toxicity in a 'low incidence' area. Contrib Nephrol 38:47-58 , 1984 18. Heaf JG, Nielsen LP: Serum aluminum in haemodialysis patients: Relation to osteodystrophy, encephalopathy and aluminum hydroxide consumption . Miner Electrolyte Metab 10:345-350, 1984 19. Boukari M, Rottembourg J, Jaudon M-C , et al : Influence de la prise prolongee de gels d'alumine sur les taux seriques d' aluminium chez les patients atteints d' insu ffisance renale chronique. Nouv Presse Med 7:85-88, 1978