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The Significance of Oxalate in Renal Failure
AMERICAN
~ The Official Journal
of
. . - The National Kidney Foundation
JOURNAL
OF
KIDNEY DISEASES
VOL IV, NO 2, SEPTEMBER 1984
EDITORIAL
The Significance of Oxalate in Renal Failure
O
XALIC ACID is a dicarboxylic acid derived from the metabolism of amino acids and ascorbic acid. In humans it is a metabolic end product whose sole route of excretion is the kidney. I It is not surprising, therefore, that in patients with renal insufficiency, oxalate accumulates in the body. Until recently, however, the kinetics of oxalate metabolism as well as the clinical significance of the accumulation of oxalate has attracted only limited attention. As evidenced by the two reports in this issue of the American Journal of Kidney Diseases, there appears to be a growing appreciation of the consequences of sustained hyperoxalemia in renal failure. 2.3 The pool size of oxalate in the body represents the balance between the absorption of oxalate by the gut, endogenous biosynthesis, and renal excretion. Dietary contribution of oxalate is highly variable and dependent upon the ingestion of certain foods such as spinach, rhubarb, and parsley, which are concentrated sources of oxalate. In the gut, oxalate complexed as the sodium salt is more readily absorbed than calcium oxalate. I The presence of certain fatty acids and bile salts in the colon enhances the absorption of oxalate. 4 Under normal conditions only about 10% of the dietary intake of oxalate is absorbed. 5 Endogenous oxalate production is the result of two separate pathways: (1) oxidation of glyoxylic acid and (2) metabolism of ascorbic acid. Glyoxylic acid is a versatile intermediate whose precursors include glycine, glycolic acid, and a-keto-'¥hydroxyglutarate. Although the oxidation of glyoxylic acid to oxalate is irreversible, glyoxylic acid readily reconverts to its three major precursors . 1 The controlling factors in these reactions are not well understood. Ascorbic acid is an es-
tablished oxalate precursor and may account for 30 % to 50 % of daily urinary oxalate excretion. 1 Nevertheless, most studies indicate that urinary oxalate excretion increases only when the dose of ascorbic acid is massive (8 to 10 g/d).6 Oxalate is excreted exclusively by the kidney. It is freely filtered by the glomerulus. The ratio of the clearance of oxalate to the clearance of inulin exceeds unity, indicating net tubular secretion. 7 Micropuncture studies in the rat have indicated that oxalate is actively secreted in the early portions of the proximal tubule by an organic anion secretory mechanism. 8 Calcium oxalate is the highly insoluble salt of oxalic acid. The term oxalosis describes the deposition of calcium oxalate in tissue. 9 Primary oxalosis is a genetically transmitted condition characterized by increased biosynthesis of oxalate as a result of at least two possible enzymatic defects in oxalate metabolism. 1 The primary disease conditions are characterized by the presence ofhyperoxaluria, calcium oxalate nephrolithiasis, nephrocalcinosis, and renal failure at a young age. 10 Oxalosis may also occur as a secondary consequence of other clinical conditions. Excessive dietary ingestion of oxalate or oxalate precursors such as ethylene glycol may exceed the ability of the kidney to excrete oxalate and result in hyperoxalemia. 9 Augmented absorption of oxalate from the gastrointestinal tract has been documented as a complication of various intestinal dis-
From the Division of Nephrology. University of Texas Medi· cal School at Houston. Address reprint requests to Catherine S. Thompson, MD, Division of Nephrology. PO Box 20708, Houston, TX 77025.
American Journal of Kidney Diseases, Vol IV, No 2, September 1984
97
98
eases including extensive resection of the small bowel and jejunoileal bypass. 5.11 Deficiencies of pyridoxine, an essential cofactor in glyoxalate metabolism , may lead to overproduction of glyoxylate with shunting into the oxalate pathway.12 Finally, oxalate may accumulate in patients with renal failure as a consequence of a diminished rate of urinary excretion. 13 The secondary oxalosis of renal failure has been recognized for more than 20 years, but the details of its prevalence and clinical features have been addressed only recently. Autopsy studies of patients who died with renal failure have suggested that the incidence and extent of calcium oxalate crystal deposition is correlated closely with the duration of renal failure. 14.15 Sustained hyperoxalemia has been postulated to be the major factor, although local alterations in tissue environment have not been rigorously excluded as a contributing feature. Calcium oxalate is recognized on hematoxylineosin stain by the presence of golden-brown diamond or rosette-shaped crystals. Typical birefringence is noted under a polarizing microscope. Histochemical confirmation of calcium oxalate, xray diffraction, electron microprobe, and chromatography have been used to verify the composition of these deposits.9 The most frequently involved sites of calcium oxalate deposition include the kidney, myocardium, and thyroid gland, although deposits have also been noted in bone, synovium , spleen, pancreas, lung, and blood vessels. 14.15 This extensive tissue accumulation is often asymptomatic and recognized only at autopsy. Recent reports, however, suggest that patients with renal failure may develop clinically apparent disease related to organ deposition of calcium oxalate crystalS. 16-18 In patients with advanced renal insufficiency, extensive precipitation of calcium oxalate is often found in the myocardial interstitium and within muscle fibers . Chronic inflammatory reaction and fibrosis surrounding the deposits are common. Congestive cardiac failure has been reported, and crystal deposition in the bundle branches may lead to conduction disturbances . 16.19 In the kidney, calcium oxalate crystals are commonly seen within renal tubules and less frequently in the interstitium. 14 Clinically evident calcium oxalate nephrolithiasis has been noted in patients on peritoneal dialysis who were not stone formers prior to dialy-
THOMPSON AND WEINMAN
sis.20 Precipitation of oxalate in the synovial space has been identified in the hemodialysis population in association with inflammatory arthritis and chondrocalcinosis.1 9 The secondary oxalosis of renal failure is believed to be the result of chronic elevation of the plasma concentration of oxalate. Although hyperoxalemia is well documented both in patients with renal insufficiency and those on maintenance dialysis, it is not known with certainty if there is a critical plasma concentration at which precipitation and tissue deposition occurs. The role of plasma or local inhibitors of crystallization in these patients has not been explored. Part of the difficulty in understanding the factors that determine precipitation is the uncertainty of the measurement of the plasma concentration of oxalate. Depending on the technique employed, the "normal" value for plasma oxalate may vary by a factor of 30. 2 It is generally agreed that direct assay of the plasma concentration of oxalate overestimates the plasma concentration as calculated from simultaneous measurement of urine concentrations of oxalate and the isotopic renal clearance of oxalate. 2 Despite the lack of a uniform standard for determining the plasma concentration of oxalate, clinical studies comparing groups of patients are valid. In this issue, Boer and colleagues employ an enzymatic method to measure plasma oxalate and clearly demonstrate a close correlation between the plasma concentrations of oxalate and creatinine in patients with chronic renal failure of diverse etiologies . 2 As anticipated, patients with primary hyperoxaluria had extreme elevations of the plasma concentration of oxalate, a point that separated these individuals from those with secondary hyperoxalemia of renal failure . The secondary oxalosis of chronic renal failure is currently an untreatable condition. Oxalate production continues unabated in renal failure , and although evidence exists that significant oxalate removal occurs with hemodialysis, plasma levels remain elevated over control values. 2.7 .2 1.22 Ramsay and Reed , in this issue, report on the effect of a single hemodialysis treatment on the plasma concentration of oxalate. 3 Employing a chromatographic technique to assay plasma oxalate, they found a significant reduction in the plasma concentration of oxalate after hemodialysis. Nonetheless, plasma concentrations of oxalate remained three to
99
SIGNIFICANCE OF OXALATE IN RENAL FAILURE
four times that of control, nonuremic patients. These authors assumed that the clearance of oxalate during hemodialysis approximated the clearance of phosphate, a similarly sized divalent species, and estimated the clearance of oxalate to be 80 to 100 mLimin. 3 Clearance studies have not been reported in peritoneal dialysis except in a single patient with primary hyperoxaluria where oxalate removal averaged only 5 to 6 mLimin.23 Additional studies comparing hemodialysis with peritoneal dialysis need to be performed, particularly in view of the suggestion that calcium oxalate nephrolithiasis occurs more comnionly in patients on continuous ambulatory peritoneal dialysis. 20 If, indeed, hemodialysis is more efficient at oxalate removal and these differences are clinically significant, the relative merits of one modality versus the other would require reexamination. Other methods of reducing the oxalate burden in chronic renal failure have been suggested but as yet have not been subjected to rigorous clinical trials. Balcke and colleagues studied the use of vitamin B6 (pyridoxine) in hyperoxalemic hemodialysis patients and found a significant reduction in the plasma concentration of oxalate after several week of therapy.24 Others have cautioned against the routine use of ascorbic acid supplements in uremic patients on the theory that it may add to the oxalate burden. 25 Although oxalate kinetics have not been studied in patients with renal failure given exogenous doses of ascorbic acid, this may be a reasonable suggestion.
Renal transplantation may offer the best solution to the problems of secondary oxalate deposition in renal failure for some patients. Little is known about the excretion of oxalate after transplantation, but in theory, transient hyperoxaluria might result from mobilization of tissue stores of oxalate. In patients with primary hyperoxaluria and renal failure, recurrent hyperoxaluria posttransplantation has been identified as a major reason for allograft failure. Recent evidence, however, suggests that with careful adherence to a protocol of aggressive pretransplant hemodialysis coupled with postoperative administration of oral pyridoxine, neutral phosphate, and magnesium, long-term allograft function in patients with primary hyperoxaluria is possible. 26 Concern for the long-term sequelae of calcium oxalate accumulation in patients with chronic renal failure is warranted. Although the precise factors that modulate oxalate biosynthesis and precipitation in tissue are unknown, there is renewed interest in these issues. It remains possible that oxalate deposition in patients with end-stage renal disease is an important contributing factor to morbidity and mortality. Clearly, additional investigation into the clinical significance of hyperoxalemia and methods of preventing or reducing tissue deposition is needed. Catherine S. Thompson, MD Edward J. Weinman, MD University of Texas Medical School at Houston Division of Nephrology
REFERENCES 1. Williams HE, Smith LH: Primary hyperoxaluria, in Stanbury JB. Wyngaarden JB (eds): The Metabolic Basis of Inherited Disease. New York. McGraw-Hill. 1983, pp 204-224. 2. Boer P, van Leersum L, Hene RJ, et al: Plasma oxalate concentration in chronic renal disease. Am J Kidney Dis 4:118-122,1984 3. Ramsey AG, Reed RG: Oxalate removal by hemodialysis in end-stage renal disease. Am J Kidney Dis 4: 123-127, 1984 4. Dobbins JW, Binder HG: The effect of bile salts and fatty acids on the colon absorption of oxalate. Gastroenterology 70:1096-1100,1976 5. Chadwick YS, Modha K, Dowling RH: Mechanism for hyperoxaluria in patients with ileal dysfunction. N Engl J Med 289:172-176,1973 6. Schmidt KH, Hagmaier V, Hornig DH, et al: Urinary oxalate excretion after large intakes of ascorbic acid in man. Am J Clin Nutr 34:305-311 7. Constable AR, Joekes AM, Kasidas Gp, et al: Plasma level and renal clearance of oxalate in normal subjects and in
patients with primary hyperoxaluria or chronic renal failure or both. Clin Sci 56:299-304, 1979 8. Weinman EJ, Frankfurt SJ, Ince A, et al: Renal tubular transport of organic acids. J Clin Invest 61:801-806, 1978 9. Chaplin AJ: Histopathological occurrence and characterization of calcium oxalate: A review. J Clin Pathol 30:800811,1977 10. Hockaday TDR, Clayton JE, Frederick EW, et al: Primary hyperoxaluria. Medicine 43:315-345, 1964 11. Drenick EJ, Stanley TM, Border WA, et al: Renal damage with intestinal bypass. Ann Intern Med 89:594-599, 1978 12. Faber SR, Feitler WW, Bleiler RE, et al: The effects of an induced pyridoxine and pantothenic acid deficiency on excretions of oxalic and xanthurenic acids in the urine. Am J Clin Nutr 12:406-412, 1963 13. Zarembski PM, Hodgkinson A, Parsons FM: Elevation of the concentration of plasma oxalic acid in renal failure. Nature 212:511-512,1966
100 14. Salyer WR, Keren D: Oxalosis as a complication of chronic renal failure. Kidney Int 4:61-66, 1973 15. Fayemi AO, Ali M, Braun EV: Oxalosis in hemodialysis patients. Arch Pathol Lab Med 103:58-62, 1979 16. Salyer WR, Hutchins G: Cardiac lesions in secondary oxalosis. Arch Intern Med 134:250-252, 1974 17. O'Callaghan JW, Arbuckle SM, Craswel pw, et al : Rapid progression of oxalosis induced cardiomyopathy despite adequate hemodialysis. Mineral and Electrolyte Metabolism 10:48-51 , 1984 18. Hoffman GS, Schumacher HR, Paul H, et al: Calcium oxalate microcrystalline associated arthritis in end stage renal disease. Ann Intern Med 97:36-42, 1982 19. Lewis RD, Lowenstam HA, Rossman GR: Oxalate nephrosis and crystalline myocarditis. Arch Pathol 98: 149155, 1974 20. Oren A. Husda H, Cheng P, et al: Calcium oxalate kidney stones in patients on continuous ambulatory peritoneal dialysis. Kidney Int 25:534-538, 1984
THOMPSON AND WEINMAN
21. Maggiore Q, Poggi A, Pariongo A, et al: Oxalate removal by dialysis and hemoperfusion. Proc Eur Dial Transplant Assoc 16:717-718, 1979 22 . Balcke P, Schmidt P, Zazgornik J, et al: Secondary oxalosis in chronic renal insufficiency. N Engl J Med 303:944, 1980 23. Zarembski PM , Rosen SM, Hodgkinson A: Dialysis in the treatment of primary hyperoxaluria. Br J Urol41 :530-533, 1%9 24. Balcke P, Schmidt P, Zazgornik J, et al : Effect of vitamin B6 administration on elevated plasma oxalic acid levels in hemodialyzed patients. Eur J Clin Invest 12:481-483, 1982 25. Friedman A, Chesney RW, Gilbert EF, et al: Secondary oxalsis as a complication of parenteral alimentation in acute renal failure. Am J Nephrol 3:248-252, 1983 26. Scheinman 11, Najarian JS, Mauer SM: Successful strategies for renal transplantation in primary oxalosis. Kidney Int 25 :804-811, 1984
~ The Official Journal
of
. . - The National Kidney Foundation
JOURNAL
OF
KIDNEY DISEASES
VOL IV, NO 2, SEPTEMBER 1984
EDITORIAL
The Significance of Oxalate in Renal Failure
O
XALIC ACID is a dicarboxylic acid derived from the metabolism of amino acids and ascorbic acid. In humans it is a metabolic end product whose sole route of excretion is the kidney. I It is not surprising, therefore, that in patients with renal insufficiency, oxalate accumulates in the body. Until recently, however, the kinetics of oxalate metabolism as well as the clinical significance of the accumulation of oxalate has attracted only limited attention. As evidenced by the two reports in this issue of the American Journal of Kidney Diseases, there appears to be a growing appreciation of the consequences of sustained hyperoxalemia in renal failure. 2.3 The pool size of oxalate in the body represents the balance between the absorption of oxalate by the gut, endogenous biosynthesis, and renal excretion. Dietary contribution of oxalate is highly variable and dependent upon the ingestion of certain foods such as spinach, rhubarb, and parsley, which are concentrated sources of oxalate. In the gut, oxalate complexed as the sodium salt is more readily absorbed than calcium oxalate. I The presence of certain fatty acids and bile salts in the colon enhances the absorption of oxalate. 4 Under normal conditions only about 10% of the dietary intake of oxalate is absorbed. 5 Endogenous oxalate production is the result of two separate pathways: (1) oxidation of glyoxylic acid and (2) metabolism of ascorbic acid. Glyoxylic acid is a versatile intermediate whose precursors include glycine, glycolic acid, and a-keto-'¥hydroxyglutarate. Although the oxidation of glyoxylic acid to oxalate is irreversible, glyoxylic acid readily reconverts to its three major precursors . 1 The controlling factors in these reactions are not well understood. Ascorbic acid is an es-
tablished oxalate precursor and may account for 30 % to 50 % of daily urinary oxalate excretion. 1 Nevertheless, most studies indicate that urinary oxalate excretion increases only when the dose of ascorbic acid is massive (8 to 10 g/d).6 Oxalate is excreted exclusively by the kidney. It is freely filtered by the glomerulus. The ratio of the clearance of oxalate to the clearance of inulin exceeds unity, indicating net tubular secretion. 7 Micropuncture studies in the rat have indicated that oxalate is actively secreted in the early portions of the proximal tubule by an organic anion secretory mechanism. 8 Calcium oxalate is the highly insoluble salt of oxalic acid. The term oxalosis describes the deposition of calcium oxalate in tissue. 9 Primary oxalosis is a genetically transmitted condition characterized by increased biosynthesis of oxalate as a result of at least two possible enzymatic defects in oxalate metabolism. 1 The primary disease conditions are characterized by the presence ofhyperoxaluria, calcium oxalate nephrolithiasis, nephrocalcinosis, and renal failure at a young age. 10 Oxalosis may also occur as a secondary consequence of other clinical conditions. Excessive dietary ingestion of oxalate or oxalate precursors such as ethylene glycol may exceed the ability of the kidney to excrete oxalate and result in hyperoxalemia. 9 Augmented absorption of oxalate from the gastrointestinal tract has been documented as a complication of various intestinal dis-
From the Division of Nephrology. University of Texas Medi· cal School at Houston. Address reprint requests to Catherine S. Thompson, MD, Division of Nephrology. PO Box 20708, Houston, TX 77025.
American Journal of Kidney Diseases, Vol IV, No 2, September 1984
97
98
eases including extensive resection of the small bowel and jejunoileal bypass. 5.11 Deficiencies of pyridoxine, an essential cofactor in glyoxalate metabolism , may lead to overproduction of glyoxylate with shunting into the oxalate pathway.12 Finally, oxalate may accumulate in patients with renal failure as a consequence of a diminished rate of urinary excretion. 13 The secondary oxalosis of renal failure has been recognized for more than 20 years, but the details of its prevalence and clinical features have been addressed only recently. Autopsy studies of patients who died with renal failure have suggested that the incidence and extent of calcium oxalate crystal deposition is correlated closely with the duration of renal failure. 14.15 Sustained hyperoxalemia has been postulated to be the major factor, although local alterations in tissue environment have not been rigorously excluded as a contributing feature. Calcium oxalate is recognized on hematoxylineosin stain by the presence of golden-brown diamond or rosette-shaped crystals. Typical birefringence is noted under a polarizing microscope. Histochemical confirmation of calcium oxalate, xray diffraction, electron microprobe, and chromatography have been used to verify the composition of these deposits.9 The most frequently involved sites of calcium oxalate deposition include the kidney, myocardium, and thyroid gland, although deposits have also been noted in bone, synovium , spleen, pancreas, lung, and blood vessels. 14.15 This extensive tissue accumulation is often asymptomatic and recognized only at autopsy. Recent reports, however, suggest that patients with renal failure may develop clinically apparent disease related to organ deposition of calcium oxalate crystalS. 16-18 In patients with advanced renal insufficiency, extensive precipitation of calcium oxalate is often found in the myocardial interstitium and within muscle fibers . Chronic inflammatory reaction and fibrosis surrounding the deposits are common. Congestive cardiac failure has been reported, and crystal deposition in the bundle branches may lead to conduction disturbances . 16.19 In the kidney, calcium oxalate crystals are commonly seen within renal tubules and less frequently in the interstitium. 14 Clinically evident calcium oxalate nephrolithiasis has been noted in patients on peritoneal dialysis who were not stone formers prior to dialy-
THOMPSON AND WEINMAN
sis.20 Precipitation of oxalate in the synovial space has been identified in the hemodialysis population in association with inflammatory arthritis and chondrocalcinosis.1 9 The secondary oxalosis of renal failure is believed to be the result of chronic elevation of the plasma concentration of oxalate. Although hyperoxalemia is well documented both in patients with renal insufficiency and those on maintenance dialysis, it is not known with certainty if there is a critical plasma concentration at which precipitation and tissue deposition occurs. The role of plasma or local inhibitors of crystallization in these patients has not been explored. Part of the difficulty in understanding the factors that determine precipitation is the uncertainty of the measurement of the plasma concentration of oxalate. Depending on the technique employed, the "normal" value for plasma oxalate may vary by a factor of 30. 2 It is generally agreed that direct assay of the plasma concentration of oxalate overestimates the plasma concentration as calculated from simultaneous measurement of urine concentrations of oxalate and the isotopic renal clearance of oxalate. 2 Despite the lack of a uniform standard for determining the plasma concentration of oxalate, clinical studies comparing groups of patients are valid. In this issue, Boer and colleagues employ an enzymatic method to measure plasma oxalate and clearly demonstrate a close correlation between the plasma concentrations of oxalate and creatinine in patients with chronic renal failure of diverse etiologies . 2 As anticipated, patients with primary hyperoxaluria had extreme elevations of the plasma concentration of oxalate, a point that separated these individuals from those with secondary hyperoxalemia of renal failure . The secondary oxalosis of chronic renal failure is currently an untreatable condition. Oxalate production continues unabated in renal failure , and although evidence exists that significant oxalate removal occurs with hemodialysis, plasma levels remain elevated over control values. 2.7 .2 1.22 Ramsay and Reed , in this issue, report on the effect of a single hemodialysis treatment on the plasma concentration of oxalate. 3 Employing a chromatographic technique to assay plasma oxalate, they found a significant reduction in the plasma concentration of oxalate after hemodialysis. Nonetheless, plasma concentrations of oxalate remained three to
99
SIGNIFICANCE OF OXALATE IN RENAL FAILURE
four times that of control, nonuremic patients. These authors assumed that the clearance of oxalate during hemodialysis approximated the clearance of phosphate, a similarly sized divalent species, and estimated the clearance of oxalate to be 80 to 100 mLimin. 3 Clearance studies have not been reported in peritoneal dialysis except in a single patient with primary hyperoxaluria where oxalate removal averaged only 5 to 6 mLimin.23 Additional studies comparing hemodialysis with peritoneal dialysis need to be performed, particularly in view of the suggestion that calcium oxalate nephrolithiasis occurs more comnionly in patients on continuous ambulatory peritoneal dialysis. 20 If, indeed, hemodialysis is more efficient at oxalate removal and these differences are clinically significant, the relative merits of one modality versus the other would require reexamination. Other methods of reducing the oxalate burden in chronic renal failure have been suggested but as yet have not been subjected to rigorous clinical trials. Balcke and colleagues studied the use of vitamin B6 (pyridoxine) in hyperoxalemic hemodialysis patients and found a significant reduction in the plasma concentration of oxalate after several week of therapy.24 Others have cautioned against the routine use of ascorbic acid supplements in uremic patients on the theory that it may add to the oxalate burden. 25 Although oxalate kinetics have not been studied in patients with renal failure given exogenous doses of ascorbic acid, this may be a reasonable suggestion.
Renal transplantation may offer the best solution to the problems of secondary oxalate deposition in renal failure for some patients. Little is known about the excretion of oxalate after transplantation, but in theory, transient hyperoxaluria might result from mobilization of tissue stores of oxalate. In patients with primary hyperoxaluria and renal failure, recurrent hyperoxaluria posttransplantation has been identified as a major reason for allograft failure. Recent evidence, however, suggests that with careful adherence to a protocol of aggressive pretransplant hemodialysis coupled with postoperative administration of oral pyridoxine, neutral phosphate, and magnesium, long-term allograft function in patients with primary hyperoxaluria is possible. 26 Concern for the long-term sequelae of calcium oxalate accumulation in patients with chronic renal failure is warranted. Although the precise factors that modulate oxalate biosynthesis and precipitation in tissue are unknown, there is renewed interest in these issues. It remains possible that oxalate deposition in patients with end-stage renal disease is an important contributing factor to morbidity and mortality. Clearly, additional investigation into the clinical significance of hyperoxalemia and methods of preventing or reducing tissue deposition is needed. Catherine S. Thompson, MD Edward J. Weinman, MD University of Texas Medical School at Houston Division of Nephrology
REFERENCES 1. Williams HE, Smith LH: Primary hyperoxaluria, in Stanbury JB. Wyngaarden JB (eds): The Metabolic Basis of Inherited Disease. New York. McGraw-Hill. 1983, pp 204-224. 2. Boer P, van Leersum L, Hene RJ, et al: Plasma oxalate concentration in chronic renal disease. Am J Kidney Dis 4:118-122,1984 3. Ramsey AG, Reed RG: Oxalate removal by hemodialysis in end-stage renal disease. Am J Kidney Dis 4: 123-127, 1984 4. Dobbins JW, Binder HG: The effect of bile salts and fatty acids on the colon absorption of oxalate. Gastroenterology 70:1096-1100,1976 5. Chadwick YS, Modha K, Dowling RH: Mechanism for hyperoxaluria in patients with ileal dysfunction. N Engl J Med 289:172-176,1973 6. Schmidt KH, Hagmaier V, Hornig DH, et al: Urinary oxalate excretion after large intakes of ascorbic acid in man. Am J Clin Nutr 34:305-311 7. Constable AR, Joekes AM, Kasidas Gp, et al: Plasma level and renal clearance of oxalate in normal subjects and in
patients with primary hyperoxaluria or chronic renal failure or both. Clin Sci 56:299-304, 1979 8. Weinman EJ, Frankfurt SJ, Ince A, et al: Renal tubular transport of organic acids. J Clin Invest 61:801-806, 1978 9. Chaplin AJ: Histopathological occurrence and characterization of calcium oxalate: A review. J Clin Pathol 30:800811,1977 10. Hockaday TDR, Clayton JE, Frederick EW, et al: Primary hyperoxaluria. Medicine 43:315-345, 1964 11. Drenick EJ, Stanley TM, Border WA, et al: Renal damage with intestinal bypass. Ann Intern Med 89:594-599, 1978 12. Faber SR, Feitler WW, Bleiler RE, et al: The effects of an induced pyridoxine and pantothenic acid deficiency on excretions of oxalic and xanthurenic acids in the urine. Am J Clin Nutr 12:406-412, 1963 13. Zarembski PM, Hodgkinson A, Parsons FM: Elevation of the concentration of plasma oxalic acid in renal failure. Nature 212:511-512,1966
100 14. Salyer WR, Keren D: Oxalosis as a complication of chronic renal failure. Kidney Int 4:61-66, 1973 15. Fayemi AO, Ali M, Braun EV: Oxalosis in hemodialysis patients. Arch Pathol Lab Med 103:58-62, 1979 16. Salyer WR, Hutchins G: Cardiac lesions in secondary oxalosis. Arch Intern Med 134:250-252, 1974 17. O'Callaghan JW, Arbuckle SM, Craswel pw, et al : Rapid progression of oxalosis induced cardiomyopathy despite adequate hemodialysis. Mineral and Electrolyte Metabolism 10:48-51 , 1984 18. Hoffman GS, Schumacher HR, Paul H, et al: Calcium oxalate microcrystalline associated arthritis in end stage renal disease. Ann Intern Med 97:36-42, 1982 19. Lewis RD, Lowenstam HA, Rossman GR: Oxalate nephrosis and crystalline myocarditis. Arch Pathol 98: 149155, 1974 20. Oren A. Husda H, Cheng P, et al: Calcium oxalate kidney stones in patients on continuous ambulatory peritoneal dialysis. Kidney Int 25:534-538, 1984
THOMPSON AND WEINMAN
21. Maggiore Q, Poggi A, Pariongo A, et al: Oxalate removal by dialysis and hemoperfusion. Proc Eur Dial Transplant Assoc 16:717-718, 1979 22 . Balcke P, Schmidt P, Zazgornik J, et al: Secondary oxalosis in chronic renal insufficiency. N Engl J Med 303:944, 1980 23. Zarembski PM , Rosen SM, Hodgkinson A: Dialysis in the treatment of primary hyperoxaluria. Br J Urol41 :530-533, 1%9 24. Balcke P, Schmidt P, Zazgornik J, et al : Effect of vitamin B6 administration on elevated plasma oxalic acid levels in hemodialyzed patients. Eur J Clin Invest 12:481-483, 1982 25. Friedman A, Chesney RW, Gilbert EF, et al: Secondary oxalsis as a complication of parenteral alimentation in acute renal failure. Am J Nephrol 3:248-252, 1983 26. Scheinman 11, Najarian JS, Mauer SM: Successful strategies for renal transplantation in primary oxalosis. Kidney Int 25 :804-811, 1984