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Phosphate imbalance: a culprit or victim in renal failure?
Hong Kong Journal of Nephrology 2002;4(1):1-2.
E d i t o r i a l
Phosphate imbalance: a culprit or victim in renal failure? Hyperphosphatemia is a common problem in patients with end-stage renal disease. In this issue, Goodman (1) gives an extensive review on the novel management of renal bone disease, the result of secondary hyperparathryoidism, and associated hyperphosphatemia. On the contrary, hypophosphatemia is not an uncommon disorder in post-renal-transplant patients. More than 50% of post-renal-transplant patients in a major renal unit in Hong Kong have hypophosphatemia (2). Phosphate supplements may be needed during the early posttransplant period to correct hypophosphatemia (2). The kidneys have an important role in the maintenance of phosphate balance. About 80% to 85% of the phosphate filtered at the glomeruli is reabsorbed. Glomerular filtration rate (GFR) declines with renal failure. With the initial fall in GFR, filtered phosphate load as well as excretion are diminished. The net effect will be phosphate retention and a small increase in the plasma phosphate concentration. This small increase in phosphate will combine with ionized calcium. The lowered ionized calcium level stimulates secretion of parathyroid hormone (PTH) and results in secondary hyperparathyroidism, as proposed in the “trade-off” hypothesis (3,4). However, the initial minor increase in phosphate may not be sufficient to cause a significant hypocalcemia to enhance hypersecretion of PTH (5). Recent studies have demonstrated that phosphate may directly enhance PTH secretion (6). In early chronic renal failure, phosphate retention suppresses 1α-hydroxylase activity, thus the renal synthesis of 1,25-dihydroxyvitamin D3 that has inhibitory effect on the parathyroid gland. Dietary phosphate restriction may restore vitamin D3 levels and diminish PTH secretion (7,8). The initial hypersecretion of PTH is appropriate in the sense that it inhibits phosphate reabsorption in proximal tubules and lowers the plasma phosphate concentration towards normal. However, in the long run, the hyperparathyroidism is maladaptive. Chronic exposure to high levels of PTH can lead to potentially serious bone disease. In addition, PTH fails to increase phosphate excretion when GFR declines to less than 20 mL/min. At this point, decreased phosphate excretion and increased phosphate release from bone by PTH would result in persistent hyperphosphatemia, if phosphate intake is not diminished.
A vicious cycle is developed as hyperphosphatemia stimulates further PTH release directly (9). Following successful renal transplantation, hypophosphatemia may develop secondary to urinary phosphate wasting. Although this complication may be due to hyperparathyroidism-dependent or -independent mechanisms (10), pretransplant serum phosphate level is significantly higher in hypophosphatemic than the normophosphatemic group (2). Oral phosphate supplementation is the common treatment. Unfortunately, administration of oral phosphate may exacerbate hyperparathyroidism due to its complexion with calcium and lowering intestinal calcium absorption. To break the viscous cycle of hyperphosphatemiahyperparathyroidism, maintaining normal plasma phosphate is the mainstay of therapy in chronic renal failure. The review by Goodman (1) in this issue outlines all the possible ways to control hyperphosphatemia. The use of newer and potentially safer phosphate binder (sevelamer), calcimimectic agents, as well as nocturnal hemodialysis has been proposed and proven effective in lowering hyperphosphatemia and thus hyperparathyroidism. However, these treatments are associated with increased cost and they are usually instituted after hyperphosphatemia and secondary hyperparathyroidism are established. In advanced chronic renal failure with creatinine clearance below 15 to 20 mL/min, patients are referred to nephrologists. They are then started on a combination of low protein, low phosphate diet and phosphate binders. These measures may help to lower serum PTH levels, but patients have to comply with a rather monotonous diet. Milk, cheese, eggs, meat, fish, peas, beans, soya products, and cereals have to be reduced or restricted. Compliance to this diet is doubtful and benefit is questionable at this stage. Coburn et al (11) suggested that the optimal benefits of preventing secondary hyperparathyroidism are best achieved when creatinine clearance is still within the 25to-60 mL/min range. Lower phosphate level may also slow down the progression of renal failure (12). Longterm survivors with non-progressive chronic renal failure have unusually low plasma phosphate. This supports the 1
Hong Kong J Nephrol 2002;4(1):1-2.
AWY YU
view that hyperphosphatemia has an independent deleterious effect. To prevent the progression of renal failure and its complications, more research on the effect of phosphate on renal failure and PTH secretion should be carried out at the early stage of renal failure when the creatinine clearance is still above 50%.
the "trade-off hypothesis". Kidney Int 1985;28:932-5. 6. Kates DM, Sherrard DJ, Andress DL. Evidence that serum phosphate is independently associated with serum PTH in patients with chronic renal failure. Am J Kidney Dis 1997;30:809-13. 7. Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab 1985;61:601-6. 8. Portale AA, Booth BE, Halloran BP, Morris RC Jr. Effect of dietary
Alex Wai-Yin Yu Editor-in-Chief
phosphorus on circulating concentrations on 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 1984;73:1580-9.
REFERENCES 1. Goodman WG. Evolving concepts in the management of renal osteodystrophy. Hong Kong J Nephrol 2002;4:22-8. 2. Tong GMW, Mak SK, Lo KY, Wong PN, Wong AKM. Comparison of clinical course and outcome of hypophosphatemia with and without
Fernandez Cruz L, Campistol JM, Torres A, Rodriguez M. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 1998;9:1845-52.
oral phosphate supplementation in the first year after renal
10. Mucsi I, Hercz G, Uldall R, Ouwendyk M, Francoeur R, Pierratos A.
transplantation: a single center retrospective study. Hong Kong J
Control of serum phosphate without any phosphate binders in
Nephrol 2002;4:43-50.
patients treated with nocturnal hemodialysis. Kidney Int 1998;53:
3. Slatopolsky E, Bricker NS. The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 1973;4:141-5. 4. Herbert LA, Lemann J Jr, Peterson JR, Lennon EJ. Studies of the mechanism by which phosphate infusion lowers serum calcium concentration. J Clin Invest 1966;45:1886. 5. Adler AJ, Ferran N, Berlyne GM. Effects of inorganic phosphate on serum ionized calcium concentration in vitro : A reassessment of
2
9. Almaden Y, Hernandez A, Torregrosa V, Canalejo A, Sabate L,
1399-404. 11. Coburn JW, Elangovan L. Prevention of metabolic bone disease in the pre-end-stage renal disease setting. J Am Soc Nephrol 1998;9 (Suppl 12):S71-7. 12. Lau K. Phosphate excess and progressive renal failure: The precipitation-calcification hypothesis. Kidney Int 1989;36:918-37. 13. Plante GE. Urinary phosphate excretion determines the progression of renal disease. Kidney Int 1989;36(Suppl 27):S128-32.
E d i t o r i a l
Phosphate imbalance: a culprit or victim in renal failure? Hyperphosphatemia is a common problem in patients with end-stage renal disease. In this issue, Goodman (1) gives an extensive review on the novel management of renal bone disease, the result of secondary hyperparathryoidism, and associated hyperphosphatemia. On the contrary, hypophosphatemia is not an uncommon disorder in post-renal-transplant patients. More than 50% of post-renal-transplant patients in a major renal unit in Hong Kong have hypophosphatemia (2). Phosphate supplements may be needed during the early posttransplant period to correct hypophosphatemia (2). The kidneys have an important role in the maintenance of phosphate balance. About 80% to 85% of the phosphate filtered at the glomeruli is reabsorbed. Glomerular filtration rate (GFR) declines with renal failure. With the initial fall in GFR, filtered phosphate load as well as excretion are diminished. The net effect will be phosphate retention and a small increase in the plasma phosphate concentration. This small increase in phosphate will combine with ionized calcium. The lowered ionized calcium level stimulates secretion of parathyroid hormone (PTH) and results in secondary hyperparathyroidism, as proposed in the “trade-off” hypothesis (3,4). However, the initial minor increase in phosphate may not be sufficient to cause a significant hypocalcemia to enhance hypersecretion of PTH (5). Recent studies have demonstrated that phosphate may directly enhance PTH secretion (6). In early chronic renal failure, phosphate retention suppresses 1α-hydroxylase activity, thus the renal synthesis of 1,25-dihydroxyvitamin D3 that has inhibitory effect on the parathyroid gland. Dietary phosphate restriction may restore vitamin D3 levels and diminish PTH secretion (7,8). The initial hypersecretion of PTH is appropriate in the sense that it inhibits phosphate reabsorption in proximal tubules and lowers the plasma phosphate concentration towards normal. However, in the long run, the hyperparathyroidism is maladaptive. Chronic exposure to high levels of PTH can lead to potentially serious bone disease. In addition, PTH fails to increase phosphate excretion when GFR declines to less than 20 mL/min. At this point, decreased phosphate excretion and increased phosphate release from bone by PTH would result in persistent hyperphosphatemia, if phosphate intake is not diminished.
A vicious cycle is developed as hyperphosphatemia stimulates further PTH release directly (9). Following successful renal transplantation, hypophosphatemia may develop secondary to urinary phosphate wasting. Although this complication may be due to hyperparathyroidism-dependent or -independent mechanisms (10), pretransplant serum phosphate level is significantly higher in hypophosphatemic than the normophosphatemic group (2). Oral phosphate supplementation is the common treatment. Unfortunately, administration of oral phosphate may exacerbate hyperparathyroidism due to its complexion with calcium and lowering intestinal calcium absorption. To break the viscous cycle of hyperphosphatemiahyperparathyroidism, maintaining normal plasma phosphate is the mainstay of therapy in chronic renal failure. The review by Goodman (1) in this issue outlines all the possible ways to control hyperphosphatemia. The use of newer and potentially safer phosphate binder (sevelamer), calcimimectic agents, as well as nocturnal hemodialysis has been proposed and proven effective in lowering hyperphosphatemia and thus hyperparathyroidism. However, these treatments are associated with increased cost and they are usually instituted after hyperphosphatemia and secondary hyperparathyroidism are established. In advanced chronic renal failure with creatinine clearance below 15 to 20 mL/min, patients are referred to nephrologists. They are then started on a combination of low protein, low phosphate diet and phosphate binders. These measures may help to lower serum PTH levels, but patients have to comply with a rather monotonous diet. Milk, cheese, eggs, meat, fish, peas, beans, soya products, and cereals have to be reduced or restricted. Compliance to this diet is doubtful and benefit is questionable at this stage. Coburn et al (11) suggested that the optimal benefits of preventing secondary hyperparathyroidism are best achieved when creatinine clearance is still within the 25to-60 mL/min range. Lower phosphate level may also slow down the progression of renal failure (12). Longterm survivors with non-progressive chronic renal failure have unusually low plasma phosphate. This supports the 1
Hong Kong J Nephrol 2002;4(1):1-2.
AWY YU
view that hyperphosphatemia has an independent deleterious effect. To prevent the progression of renal failure and its complications, more research on the effect of phosphate on renal failure and PTH secretion should be carried out at the early stage of renal failure when the creatinine clearance is still above 50%.
the "trade-off hypothesis". Kidney Int 1985;28:932-5. 6. Kates DM, Sherrard DJ, Andress DL. Evidence that serum phosphate is independently associated with serum PTH in patients with chronic renal failure. Am J Kidney Dis 1997;30:809-13. 7. Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab 1985;61:601-6. 8. Portale AA, Booth BE, Halloran BP, Morris RC Jr. Effect of dietary
Alex Wai-Yin Yu Editor-in-Chief
phosphorus on circulating concentrations on 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 1984;73:1580-9.
REFERENCES 1. Goodman WG. Evolving concepts in the management of renal osteodystrophy. Hong Kong J Nephrol 2002;4:22-8. 2. Tong GMW, Mak SK, Lo KY, Wong PN, Wong AKM. Comparison of clinical course and outcome of hypophosphatemia with and without
Fernandez Cruz L, Campistol JM, Torres A, Rodriguez M. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 1998;9:1845-52.
oral phosphate supplementation in the first year after renal
10. Mucsi I, Hercz G, Uldall R, Ouwendyk M, Francoeur R, Pierratos A.
transplantation: a single center retrospective study. Hong Kong J
Control of serum phosphate without any phosphate binders in
Nephrol 2002;4:43-50.
patients treated with nocturnal hemodialysis. Kidney Int 1998;53:
3. Slatopolsky E, Bricker NS. The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 1973;4:141-5. 4. Herbert LA, Lemann J Jr, Peterson JR, Lennon EJ. Studies of the mechanism by which phosphate infusion lowers serum calcium concentration. J Clin Invest 1966;45:1886. 5. Adler AJ, Ferran N, Berlyne GM. Effects of inorganic phosphate on serum ionized calcium concentration in vitro : A reassessment of
2
9. Almaden Y, Hernandez A, Torregrosa V, Canalejo A, Sabate L,
1399-404. 11. Coburn JW, Elangovan L. Prevention of metabolic bone disease in the pre-end-stage renal disease setting. J Am Soc Nephrol 1998;9 (Suppl 12):S71-7. 12. Lau K. Phosphate excess and progressive renal failure: The precipitation-calcification hypothesis. Kidney Int 1989;36:918-37. 13. Plante GE. Urinary phosphate excretion determines the progression of renal disease. Kidney Int 1989;36(Suppl 27):S128-32.