Overview of the causes and treatment of hyperphosphatemia
- Jason R Stubbs, MD
Jason R Stubbs, MD
- Associate Professor of Medicine
- Division of Nephrology & Hypertension
- University of Kansas Medical Center
- Alan S L Yu, MB, BChir
Alan S L Yu, MB, BChir
- Harry Statland and Solon Summerfield Professor of Medicine
- University of Kansas Medical Center
Phosphate is an inorganic molecule consisting of a central phosphorus atom and four oxygen atoms. In the steady state, the serum phosphate concentration is primarily determined by the ability of the kidneys to excrete dietary phosphate. The diagnostic approach to hyperphosphatemia involves elucidating why phosphate entry into the extracellular fluid exceeds the degree to which it can be excreted in order to maintain normal plasma levels.
A broad overview of the causes and treatment of hyperphosphatemia is presented in this topic. Detailed discussions of renal osteodystrophy and the treatment of hyperphosphatemia in patients with chronic kidney disease (CKD) are found elsewhere. (See "Overview of chronic kidney disease-mineral bone disease (CKD-MBD)" and "Treatment of hyperphosphatemia in chronic kidney disease" and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients".)
OVERVIEW OF THE CAUSES OF HYPERPHOSPHATEMIA
Renal excretion is so efficient in normal subjects that balance can be maintained with only a minimal rise in serum phosphate concentration even if phosphorus intake is increased to as much as 4000 mg/day (130 mmol/day). Phosphorus intake above 4000 mg/day (130 mmol/day) causes only small elevations in serum phosphate concentrations as long as the intake is distributed over the course of the day. If, however, an acute phosphate load is given over several hours, transient hyperphosphatemia will ensue.
The diagnostic approach to hyperphosphatemia involves elucidating why phosphate entry into the extracellular fluid exceeds the degree to which it can be excreted or why the renal threshold for phosphate excretion is increased above normal. There are four general circumstances in which this occurs (table 1):
●Acute phosphate load
- Tsokos GC, Balow JE, Spiegel RJ, Magrath IT. Renal and metabolic complications of undifferentiated and lymphoblastic lymphomas. Medicine (Baltimore) 1981; 60:218.
- Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin's lymphoma. Am J Med 1993; 94:133.
- Arrambide K, Toto RD. Tumor lysis syndrome. Semin Nephrol 1993; 13:273.
- Grossman RA, Hamilton RW, Morse BM, et al. Nontraumatic rhabdomyolysis and acute renal failure. N Engl J Med 1974; 291:807.
- Llach F, Felsenfeld AJ, Haussler MR. The pathophysiology of altered calcium metabolism in rhabdomyolysis-induced acute renal failure. Interactions of parathyroid hormone, 25-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol. N Engl J Med 1981; 305:117.
- Fine A, Patterson J. Severe hyperphosphatemia following phosphate administration for bowel preparation in patients with renal failure: two cases and a review of the literature. Am J Kidney Dis 1997; 29:103.
- Fass R, Do S, Hixson LJ. Fatal hyperphosphatemia following Fleet Phospo-Soda in a patient with colonic ileus. Am J Gastroenterol 1993; 88:929.
- Beloosesky Y, Grinblat J, Weiss A, et al. Electrolyte disorders following oral sodium phosphate administration for bowel cleansing in elderly patients. Arch Intern Med 2003; 163:803.
- Curran MP, Plosker GL. Oral sodium phosphate solution: a review of its use as a colorectal cleanser. Drugs 2004; 64:1697.
- McBryde KD, Wilcox J, Kher KK. Hyperphosphatemia due to fosphenytoin in a pediatric ESRD patient. Pediatr Nephrol 2005; 20:1182.
- Desmeules S, Bergeron MJ, Isenring P. Acute phosphate nephropathy and renal failure. N Engl J Med 2003; 349:1006.
- Markowitz GS, Nasr SH, Klein P, et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004; 35:675.
- Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005; 16:3389.
- Gonlusen G, Akgun H, Ertan A, et al. Renal failure and nephrocalcinosis associated with oral sodium phosphate bowel cleansing: clinical patterns and renal biopsy findings. Arch Pathol Lab Med 2006; 130:101.
- O'Connor LR, Klein KL, Bethune JE. Hyperphosphatemia in lactic acidosis. N Engl J Med 1977; 297:707.
- Sternbach GL, Varon J. Severe hyperphosphatemia associated with hemorrhagic shock. Am J Emerg Med 1992; 10:331.
- Kebler R, McDonald FD, Cadnapaphornchai P. Dynamic changes in serum phosphorus levels in diabetic ketoacidosis. Am J Med 1985; 79:571.
- Murer H. Homer Smith Award. Cellular mechanisms in proximal tubular Pi reabsorption: some answers and more questions. J Am Soc Nephrol 1992; 2:1649.
- Murer H, Lötscher M, Kaissling B, et al. Renal brush border membrane Na/Pi-cotransport: molecular aspects in PTH-dependent and dietary regulation. Kidney Int 1996; 49:1769.
- Quigley R, Baum M. Effects of growth hormone and insulin-like growth factor I on rabbit proximal convoluted tubule transport. J Clin Invest 1991; 88:368.
- Walton RJ, Russell RG, Smith R. Changes in the renal and extrarenal handling of phosphate induced by disodium etidronate (EHDP) in man. Clin Sci Mol Med 1975; 49:45.
- Challa A, Noorwali AA, Bevington A, Russell RG. Cellular phosphate metabolism in patients receiving bisphosphonate therapy. Bone 1986; 7:255.
- Mitnick PD, Goldfarb S, Slatopolsky E, et al. Calcium and phosphate metabolism in tumoral calcinosis. Ann Intern Med 1980; 92:482.
- Topaz O, Shurman DL, Bergman R, et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 2004; 36:579.
- Frishberg Y, Ito N, Rinat C, et al. Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J Bone Miner Res 2007; 22:235.
- Chefetz I, Heller R, Galli-Tsinopoulou A, et al. A novel homozygous missense mutation in FGF23 causes Familial Tumoral Calcinosis associated with disseminated visceral calcification. Hum Genet 2005; 118:261.
- Araya K, Fukumoto S, Backenroth R, et al. A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab 2005; 90:5523.
- Ichikawa S, Imel EA, Kreiter ML, et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 2007; 117:2684.
- Yancovitch A, Hershkovitz D, Indelman M, et al. Novel mutations in GALNT3 causing hyperphosphatemic familial tumoral calcinosis. J Bone Miner Metab 2011; 29:621.
- Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281:6120.
- Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770.
- Slavin RE, Wen J, Kumar D, Evans EB. Familial tumoral calcinosis. A clinical, histopathologic, and ultrastructural study with an analysis of its calcifying process and pathogenesis. Am J Surg Pathol 1993; 17:788.
- Mozaffarian G, Lafferty FW, Pearson OH. Treatment of tumoral calcinosis with phosphorus deprivation. Ann Intern Med 1972; 77:741.
- Yamaguchi T, Sugimoto T, Imai Y, et al. Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide. Bone 1995; 16:247S.
- Larner AJ. Pseudohyperphosphatemia. Clin Biochem 1995; 28:391.
- Adler SG, Laidlaw SA, Lubran MM, Kopple JD. Hyperglobulinemia may spuriously elevate measured serum inorganic phosphate levels. Am J Kidney Dis 1988; 11:260.
- Leehey DJ, Daugirdas JT, Ing TS, Reid RW. Spurious hyperphosphatemia due to hyperlipidemia. Arch Intern Med 1985; 145:743.
- Randall AG, Garcia-Webb P, Beilby JP. Interference by haemolysis, icterus and lipaemia in assays on the Beckman Synchron CX5 and methods for correction. Ann Clin Biochem 1990; 27 ( Pt 4):345.
- Lane JW, Rehak NN, Hortin GL, et al. Pseudohyperphosphatemia associated with high-dose liposomal amphotericin B therapy. Clin Chim Acta 2008; 387:145.
- Schiller B, Virk B, Blair M, et al. Spurious hyperphosphatemia in patients on hemodialysis with catheters. Am J Kidney Dis 2008; 52:617.
- Ball CL, Tobler K, Ross BC, et al. Spurious hyperphosphatemia due to sample contamination with heparinized saline from an indwelling catheter. Clin Chem Lab Med 2004; 42:107.
- OVERVIEW OF THE CAUSES OF HYPERPHOSPHATEMIA
- Acute phosphate load
- - Tumor lysis syndrome
- - Rhabdomyolysis
- - Exogenous phosphate
- Acute phosphate nephropathy
- Acute extracellular shift of phosphate
- Acute or chronic kidney disease
- Increased tubular reabsorption of phosphate
- - Hypoparathyroidism
- - Acromegaly
- - Bisphosphonates
- - Vitamin D toxicity
- - Familial tumoral calcinosis
- TREATMENT OF HYPERPHOSPHATEMIA
- Chronic hyperphosphatemia
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS