Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

Подождите немного. Документ загружается.

Chapter 7 / Management of Oxaluria 113

promotion of other beneficial changes such as a reduction in calcium and uric acid

excretion and an increase in citrate excretion. Normal dietary calcium consumption is

important as reduced calcium intake is associated with an increase in oxalate excretion

(21). Supplementation of meals with calcium should also be considered, particularly in

those patients who do not like to, or cannot, consume dairy products.

Pyridoxine therapy is an option for those patients with poor response to dietary restric-

tions. The results with this therapy have been conflicting, however a trial of this agent

should be considered because there are no other known treatment options and the side

effects are minimal (113–118).

POTENTIAL FUTURE THERAPY

Probiotic Therapy

Campieri and colleagues reported that the urinary oxalate excretion decreased when

hyperoxaluric stone-formers were administered lactic acid bacteria (119). Although the

results need to be corroborated, this suggests that probiotic therapy may play a future

role in the management of this patient population. The utilization of O. formigenes for

this purpose has been undertaken. There are several reasons why this approach has been

proposed. This anaerobic bacterium is not pathogenic. A higher percentage of nonstone

formers have O. formigenes fecal colonization as compared to stone formers (120). An

inverse correlation between colonization and urinary oxalate excretion has been reported

(120). Some investigators have suggested that there is also an inverse correlation

between stone activity and fecal colonization with this organism (121). The administra-

tion of this bacterium to rats promoted a decrease in urinary oxalate excretion (121,122).

A pilot study suggested that the oral administration of this bacterium promoted a similar

response in humans (123). Although antegrade or retrograde (enema) colonization of

subjects lacking this bacterium in the colon may prove to be beneficial, the daily oral

administration of this organism with meals may allow for oxalate degradation in the

small bowel, an area where the majority of oxalate absorption is thought to occur.

Preliminary results have demonstrated that giving this bacterium to patients with PH1

may promote a reduction in oxalate excretion. This is hypothesized to be due to stimu-

lating oxalase secretion within the gut. An expanded ongoing study will hopefully define

the utility of this approach.

Enzymatic Therapy

Another approach for limiting oxalate absorption is the development of methods to

degrade this organic acid in the intestinal tract. Administering capsules containing

oxalate-degrading enzymes such as oxalate decarboxylase could possibly accomplish

this.

The control of oxalate and its effects at the renal level may be used to treat certain

calcium oxalate stone formers in the future. Brandle and colleagues have reported on the

development of an inhibitor of renal oxalate secretion (EO8) which is thought to have

an action on the oxalate/sulfate exchanger in the basolateral membrane of the proximal

tubule (124). EO8 significantly reduced oxalate clearance in rats without inducing an

increase in plasma oxalate. This indicates that EO8 might influence oxalate transport in

the gastrointestinal tract and liver where similar transporters exist.

114 Shah, Holmes, and Assimos

Phytotherapy/Complementary Medicine

Phytotherapy may prove to be beneficial for patients with hyperoxaluria. Investiga-

tors have found that banana stem extract significantly reduces oxalate excretion in rats

by unknown mechanisms (126).Some investigators have hypothesized that its high level

of oxalate oxidase could potentially degrade oxalate in the alimentary tract and therefore

decrease enteric oxalate absorption (127).We anticipate that other complementary agents

will surface in the future, but the actual benefit will need to be established in well-

controlled studies.

CONCLUSIONS

The therapy of hyperoxaluric patients should be directed by the underlying causes.

Future innovations should facilitate the management of individuals afflicted with

hyperoxaluric states.

REFERENCES

1. Assimos DG, Goodman HO, Holmes RP. Hyperoxaluria: Advances in medical therapy. Contemp

Urol. 1997; 47–60.

2. Senekjian HO, Weinman EJ. Oxalate transport by proximal tubule of the rabbit kidney. Am J

Physiol. 1982; 243(3): F271–275.

3. Greger R, Lang F, Oberleithner H, Deetjen P. Handling of oxalate by the rat kidney. Pflugers Arch.

1978; 374(3): 243–248.

4. Weinman EJ, Frankfurt SJ, Ince A, Sansom S. Renal tubular transport of organic acids. Studies

with oxalate and para- aminohippurate in the rat. J Clin Invest. 1978; 61(3): 801–806.

5. Williams HE, Johnson GA, Smith LH, Jr. The renal clearance of oxalate in normal subjects and

patients with primary hyperoxaluria. Clin Sci. 1971; 41(3): 213–218.

6. Karniski LP, Lotscher M, Fucentese M, Hilfiker H, Biber J, Murer H. Immunolocalization of sat-

1 sulfate/oxalate/bicarbonate anion exchanger in the rat kidney. Am J Physiol. 1998; 275(1 Pt 2):

F79–87.

7. Karniski LP, Aronson PS. Anion exchange pathways for Cl- transport in rabbit renal microvillus

membranes. Am J Physiol. 1987; 253(3 Pt 2): F513–521.

8. Brandle E, Bernt U, Hautmann RE. In situ characterization of oxalate transport across the

basolateral membrane of the proximal tubule. Pflugers Arch. 1998; 435(6): 840–849.

9. Lohi H, Kujala M, Makela S, et al. Functional characterization of three novel tissue-specific anion

exchangers SLC26A7, -A8, and -A9. J Biol Chem. 2002; 277(16): 14,246–14,254.

10. Danpure CJ. Primary hyperoxaluria. In: The Metabolic and Molecular Bases of Inherited Diseases,

(Scriver CR, Beaudet AL, Sly WS, et al., eds.). McGraw-Hill, New York, NY, 2001; pp. 3323–

3367.

11. Scheid CR, Koul H, Hill A, Lieske JC, Toback G, Menon M. Oxalate ion and calcium oxalate

crystal interactions with renal epithelial cells. In: Kidney Stones: Medical and Surgical Manage-

ment, (Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM, eds.). Lippincott-Raven, Philadel-

phia, PA, 1996; pp. 120–143.

12. Hautmann RE. The stomach: a new and powerful oxalate absorption site in man. J Urol. 1993;

149(6): 1401–1404.

13. Freel RW, Hatch M, Earnest DL, Goldner AM. Oxalate transport across the isolated rat colon. A

re-examination. Biochim Biophys Acta. 1980; 600(3): 838–843.

14. Hatch M, Freel RW, Goldner AM, Earnest DL. Oxalate and chloride absorption by the rabbit

colon: sensitivity to metabolic and anion transport inhibitors. Gut. 1984; 25(3): 232–237.

15. Hatch M, Freel RW, Vaziri ND. Characteristics of the transport of oxalate and other ions across

rabbit proximal colon. Pflugers Arch. 1993; 423(3–4): 206–212.

16. Hatch M, Freel RW, Vaziri ND. Mechanisms of oxalate absorption and secretion across the rabbit

distal colon. Pflugers Arch. 1994; 426(1–2): 101–109.

Chapter 7 / Management of Oxaluria 115

17. Hesse A, Schneeberger W, Engfeld S, Von Unruh GE, Sauerbruch T. Intestinal hyperabsorption

of oxalate in calcium oxalate stone formers: application of a new test with [13C2]oxalate. J Am

Soc Nephrol. 1999; 10 Suppl 14: S329–333.

18. Allison MJ, Dawson KA, Mayberry WR, Foss JG. Oxalobacter formigenes gen. nov., sp. nov.: oxalate-

degrading anaerobes that inhabit the gastrointestinal tract. Arch Microbiol. 1985; 141(1): 1–7.

19. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. Comparison of dietary calcium

with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in

women. Ann Intern Med. 1997; 126(7): 497–504.

20. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other

nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993; 328(12): 833–838.

21. Holmes RP, Goodman HO, Assimos DG. Contribution of dietary oxalate to urinary oxalate excre-

tion. Kidney Int. 2001; 59(1): 270–276.

22. Liebman M, Chai W. Effect of dietary calcium on urinary oxalate excretion after oxalate loads. Am

J Clin Nutr. 1997; 65(5): 1453–1459.

23. Bhandari A, Koul S, Sekhon A, et al. Effects of oxalate on HK-2 cells, a line of proximal tubular

epithelial cells from normal human kidney. J Urol. 2002; 168(1): 253–259.

24. Thamilselvan S, Khan SR. Oxalate and calcium oxalate crystals are injurious to renal epithelial

cells: results of in vivo and in vitro studies. J Nephrol. 1998; 11 Suppl 1: 66–69.

25. Thamilselvan S, Byer KJ, Hackett RL, Khan SR. Free radical scavengers, catalase and superoxide

dismutase provide protection from oxalate-associated injury to LLC-PK1 and MDCK cells. J Urol.

2000; 164(1): 224–229.

26. Scheid C, Koul H, Hill WA, et al. Oxalate toxicity in LLC-PK1 cells: role of free radicals. Kidney

Int. 1996; 49(2): 413–419.

27. Scheid C, Koul H, Hill WA, et al. Oxalate toxicity in LLC-PK1 cells, a line of renal epithelial cells.

J Urol. 1996; 155(3): 1112–1116.

28. Koul HK, Koul S, Fu S, Santosham V, Seikhon A, Menon M. Oxalate: from crystal formation to

crystal retention. J Am Soc Nephrol. 1999; 10 Suppl 14: S417–421.

29. Khan SR, Glenton PA. Increased urinary excretion of lipids by patients with kidney stones. Br J

Urol. 1996; 77(4): 506–511.

30. Khan SR, Maslamani SA, Atmani F, et al. Membranes and their constituents as promoters of

calcium oxalate crystal formation in human urine. Calcif Tissue Int. 2000; 66(2): 90–96.

31. Bigelow MW, Wiessner JH, Kleinman JG, Mandel NS. Calcium oxalate-crystal membrane inter-

actions: dependence on membrane lipid composition. J Urol. 1996; 155(3): 1094–1098.

32. Khan SR, Shevock PN, Hackett RL. Presence of lipids in urinary stones: results of preliminary

studies. Calcif Tissue Int. 1988; 42(2): 91–96.

33. Asplin JR, Parks JH, Coe FL. Dependence of upper limit of metastability on supersaturation in

nephrolithiasis. Kidney Int. 1997; 52(6): 1602–1608.

34. Asplin JR, Parks JH, Chen MS, et al. Reduced crystallization inhibition by urine from men with

nephrolithiasis. Kidney Int. 1999; 56(4): 1505–1516.

35. Borghi L, Meschi T, Guerra A, Bergamaschi E, Mutti A, Novarini A. Effects of urinary macromol-

ecules on the nucleation of calcium oxalate in idiopathic stone formers and healthy controls. Clin

Chim Acta. 1995; 239(1): 1–11.

36. Borghi L, Guerra A, Meschi T, et al. Relationship between supersaturation and calcium oxalate

crystallization in normals and idiopathic calcium oxalate stone formers. Kidney Int. 1999; 55(3):

1041–1050.

37. Williams HE, Wandzilak TR. Oxalate synthesis, transport and the hyperoxaluric syndromes. J

Urol. 1989; 141(3 Pt 2): 742–749.

38. Nath R, Thind SK, Murthy MS, Talwar HS, Farooqui S. Molecular aspects of idiopathic urolithi-

asis. Mol Aspects Med. 1984; 7(1–2): 1–176.

39. Baker EM, Saari JC, Tolbert BM. Ascorbic acid metabolism in man. Am J Clin Nutr. 1966; 19(6):

371–378.

40. Wandzilak TR, D’Andre SD, Davis PA, Williams HE. Effect of high dose vitamin C on urinary

oxalate levels. J Urol. 1994; 151(4): 834–837.

41. Traxer O, Huet B, Pak CYC, Pearle MS. Stone forming risk of ascorbic acid. J Endourol. 2000;

14 (Suppl 1): A9.

116 Shah, Holmes, and Assimos

42. Goodman HO, Holmes RP, Assimos DG. Genetic factors in calcium oxalate stone disease. J Urol.

1995; 153(2): 301–307.

43. Nemeh MN, Weinman EJ, Kayne LH, Lee DBN. Absorption and excretion of urate, oxalate, and

amino acids. In: Kidney Stones: Medical and Surgical Management, (Coe FL, Favus MJ, Pak

CYC, Parks JH, Preminger GM, eds.). Lippincott-Raven, Philadelphia, PA, 1996; pp. 303–319.

44. Levy FL, Adams-Huet B, Pak CY. Ambulatory evaluation of nephrolithiasis: an update of a 1980

protocol. Am J Med. 1995; 98(1): 50–59.

45. Clayman RV, Buchwald H, Varco RL, DeWolf WC, Williams RD. Urolithiasis in patients with a

jejunoileal bypass. Surg Gynecol Obstet. 1978; 147(2): 225–230.

46. Gregory JG, Park KY, Schoenberg HW. Oxalate stone disease after intestinal resection. J Urol.

1977; 117(5): 631–634.

47. Earnest DL. Enteric hyperoxaluria. Adv Intern Med. 1979; 24: 407–427.

48. Earnest DL, Johnson G, Williams HE, Admirand WH. Hyperoxaluria in patients with ileal resec-

tion: an abnormality in dietary oxalate absorption. Gastroenterology. 1974; 66(6): 1114–1122.

49. Kaye MC, Streem SB, Hall PM. Enteric hyperoxaluria associated with external biliary drainage.

J Urol. 1994; 151(2): 396, 397.

50. Ogilvie D, McCollum JP, Packer S, et al. Urinary outputs of oxalate, calcium, and magnesium in

children with intestinal disorders. Potential cause of renal calculi. Arch Dis Child. 1976; 51(10):

790–795.

51. Dobbins JW, Binder HJ. Effect of bile salts and fatty acids on the colonic absorption of oxalate.

Gastroenterology. 1976; 70(6): 1096–1100.

52. Harvey JA, Zobitz MM, Pak CY. Calcium citrate: reduced propensity for the crystallization of

calcium oxalate in urine resulting from induced hypercalciuria of calcium supplementation. J Clin

Endocrinol Metab. 1985; 61(6): 1223–1225.

53. Rudman D, Dedonis JL, Fountain MT, et al. Hypocitraturia in patients with gastrointestinal mal-

absorption. N Engl J Med. 1980; 303(12): 657–661.

54. Hessov I, Hasselblad C, Fasth S, Hulten L. Magnesium deficiency after ileal resections for Crohn’s

disease. Scand J Gastroenterol. 1983; 18(5): 643–649.

55. Gerlach K, Morowitz DA, Kirsner JB. Symptomatic hypomagnesemia complicating regional

enteritis. Gastroenterology. 1970; 59(4): 567–574.

56. Galland L. Magnesium and inflammatory bowel disease. Magnesium. 1988; 7(2): 78–83.

57. Caspary WF, Tonissen J, Lankisch PG. ‘Enteral’ hyperoxaluria. Effect of cholestyramine, cal-

cium, neomycin, and bile acids on intestinal oxalate absorption in man. Acta Hepatogastroenterol

(Stuttg). 1977; 24(3): 193–200.

58. Smith LH, Fromm H, Hofmann AF. Acquired hyperoxaluria, nephrolithiasis, and intestinal dis-

ease. Description of a syndrome. N Engl J Med. 1972; 286(26): 1371–1375.

59. Pak CY, Fuller C, Sakhaee K, Preminger GM, Britton F. Long-term treatment of calcium neph-

rolithiasis with potassium citrate. J Urol. 1985; 134(1): 11–19.

60. Barcelo P, Wuhl O, Servitge E, Rousaud A, Pak CY. Randomized double-blind study of potas-

sium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol. 1993; 150(6): 1761–

1764.

61. Danpure CJ, Jennings PR, Watts RW. Enzymological diagnosis of primary hyperoxaluria type 1

by measurement of hepatic alanine: glyoxylate aminotransferase activity. Lancet. 1987; 1(8528):

289–291.

62. Danpure CJ, Jennings PR, Fryer P, Purdue PE, Allsop J. Primary hyperoxaluria type 1: genotypic

and phenotypic heterogeneity. J Inherit Metab Dis. 1994; 17(4): 487–499.

63. Purdue PE, Lumb MJ, Fox M, et al. Characterization and chromosomal mapping of a genomic

clone encoding human alanine:glyoxylate aminotransferase. Genomics. 1991; 10(1): 34–42.

64. Takada Y, Kaneko N, Esumi H, Purdue PE, Danpure CJ. Human peroxisomal L-alanine: glyoxylate

aminotransferase. Evolutionary loss of a mitochondrial targeting signal by point mutation of the

initiation codon. Biochem J. 1990; 268(2): 517–520.

65. Cochat P. Primary hyperoxaluria type 1. Kidney Int 1999; 55(6): 2533–2547.

66. Lumb MJ, Danpure CJ. Functional synergism between the most common polymorphism in human

alanine:glyoxylate aminotransferase and four of the most common disease- causing mutations. J

Biol Chem. 2000; 275(46): 36,415–36,422.

Chapter 7 / Management of Oxaluria 117

67. Milliner DS, Eickholt JT, Bergstralh EJ, Wilson DM, Smith LH. Results of long-term treatment

with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med. 1994;

331(23): 1553–1558.

68. Rumsby G. Experience in prenatal diagnosis of primary hyperoxaluria type 1. J Nephrol. 1998; 11

Suppl 1: 13–14.

69. Neuhaus TJ, Belzer T, Blau N, Hoppe B, Sidhu H, Leumann E. Urinary oxalate excretion in

urolithiasis and nephrocalcinosis. Arch Dis Child. 2000; 82(4): 322–326.

70. Daudon M, Estepa L, Lacour B, Jungers P. Unusual morphology of calcium oxalate calculi in

primary hyperoxaluria. J Nephrol. 1998; 11 Suppl 1: 51–55.

71. Kopp N, Leumann E. Changing pattern of primary hyperoxaluria in Switzerland. Nephrol Dial

Transplant. 1995; 10(12): 2224–2227.

72. Cochat P, Deloraine A, Rotily M, Olive F, Liponski I, Deries N. Epidemiology of primary

hyperoxaluria type 1. Societe de Nephrologie and the Societe de Nephrologie Pediatrique. Nephrol

Dial Transplant. 1995; 10(Suppl 8): 3–7.

73. Hoppe B, Kemper MJ, Bokenkamp A, Langman CB. Plasma calcium-oxalate saturation in chil-

dren with renal insufficiency and in children with primary hyperoxaluria. Kidney Int. 1998; 54(3):

921–925.

74. Schnitzler CM, Kok JA, Jacobs DW, et al. Skeletal manifestations of primary oxalosis. Pediatr

Nephrol. 1991; 5(2): 193–199.

75. Toussaint C, De Pauw L, Vienne A, et al. Radiological and histological improvement of oxalate

osteopathy after combined liver-kidney transplantation in primary hyperoxaluria type 1. Am J

Kidney Dis. 1993; 21(1): 54–63.

76. Leumann E, Hoppe B. The primary hyperoxalurias. J Am Soc Nephrol. 2001; 12(9): 1986–1993.

77. Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr. 1990; 149(8): 518–522.

78. Marangella M, Petrarulo M, Vitale C, et al. Serum calcium oxalate saturation in patients on

maintenance haemodialysis for primary hyperoxaluria or oxalosis-unrelated renal diseases. Clin

Sci (Lond). 1991; 81(4): 483–490.

79. Hoppe B, Graf D, Offner G, et al. Oxalate elimination via hemodialysis or peritoneal dialysis in

children with chronic renal failure. Pediatr Nephrol. 1996; 10(4): 488–492.

80. Watts RW, Veall N, Purkiss P. Oxalate dynamics and removal rates during haemodialysis and

peritoneal dialysis in patients with primary hyperoxaluria and severe renal failure. Clin Sci (Lond).

1984; 66(5): 591–597.

81. Gibbs DA, Watts RW. The action of pyridoxine in primary hyperoxaluria. Clin Sci. 1970; 38(2):

277–286.

82. Marangella M. Transplantation strategies in type 1 primary hyperoxaluria: the issue of pyridoxine

responsiveness. Nephrol Dial Transplant. 1999; 14(2): 301–303.

83. Leumann E, Matasovic A, Niederwieser A. Pyridoxine in primary hyperoxaluria type I. Lancet.

1986; 2(8508): 699.

84. Smith LH, Jr., Williams HE. Treatment of primary hyperoxaluria. Mod Treat. 1967; 4(3): 522–530.

85. Watts RW, Veall N, Purkiss P, Mansell MA, Haywood EF. The effect of pyridoxine on oxalate

dynamics in three cases of primary hyperoxaluria (with glycollic aciduria). Clin Sci (Lond). 1985;

69(1): 87–90.

86. Alinei P, Guignard JP, Jaeger P. Pyridoxine treatment of type 1 hyperoxaluria. N Engl J Med 1984;

311(12): 798, 799.

87. Leumann E, Hoppe B. What is new in primary hyperoxaluria? Nephrol Dial. Transplant 1999;

14(11): 2556–2558.

88. Coe FL, Parks JH. New insights into the pathophysiology and treatment of nephrolithiasis: new

research venues. J Bone Miner Res. 1997; 12(4): 522–533.

89. Leumann E, Hoppe B, Neuhaus T. Management of primary hyperoxaluria: efficacy of oral citrate

administration. Pediatr Nephrol. 1993; 7(2): 207–211.

90. Leumann E, Hoppe B, Neuhaus T, Blau N. Efficacy of oral citrate administration in primary

hyperoxaluria. Nephrol Dial Transplant. 1995; 10(Suppl 8): 14–16.

91. Broyer M, Brunner FP, Brynger H, et al. Kidney transplantation in primary oxalosis: data from the

EDTA Registry. Nephrol Dial Transplant. 1990; 5(5): 332–336.

118 Shah, Holmes, and Assimos

92. Saborio P, Scheinman JI. Transplantation for primary hyperoxaluria in the United States. Kidney

Int. 1999; 56(3): 1094–1100.

93. Watts RW, Calne RY, Rolles K, et al. Successful treatment of primary hyperoxaluria type I by

combined hepatic and renal transplantation. Lancet. 1987; 2(8557): 474, 475.

94. Cochat P, Gaulier JM, Koch Nogueira PC, et al. Combined liver-kidney transplantation in primary

hyperoxaluria type 1. Eur J Pediatr. 1999; 158 Suppl 2: S75–80.

95. Jamieson NV. The European Primary Hyperoxaluria Type 1 Transplant Registry report on the

results of combined liver/kidney transplantation for primary hyperoxaluria 1984–1994. European

PH1 Transplantation Study Group. Nephrol Dial Transplant. 1995; 10(Suppl 8): 33–37.

96. Jamieson NV. The results of combined liver/kidney transplantation for primary hyperoxaluria

(PH1) 1984-1997. The European PH1 transplant registry report. European PH1 Transplantation

Study Group. J Nephrol. 1998; 11 Suppl 1: 36–41.

97. Nolkemper D, Kemper MJ, Burdelski M, et al. Long-term results of pre-emptive liver transplan-

tation in primary hyperoxaluria type 1. Pediatr Transplant. 2000; 4(3): 177–181.

98. Holmes RP, Assimos DG, Leaf CD, Whalen JJ. The effects of (L)-2-oxothiazolidine-4-carboxy-

late on urinary oxalate excretion. J Urol. 1997; 158(1): 34–37.

99. Holmes RP, Assimos DG, Wilson DM, Milliner DS. (L)-2-oxothiazolidine-4-carboxylate in the

treatment of primary hyperoxaluria type 1. BJU Int. 2001; 88(9): 858–862.

100. Grossman M, Wilson JM. Retroviruses: delivery vehicle to the liver. Curr Opin Genet Dev. 1993;

3(1): 110–114.

101. Ledley FD. Hepatic gene therapy: present and future. Hepatology. 1993; 18(5): 1263–1273.

102. Raper SE, Wilson JM. Cell transplantation in liver-directed gene therapy. Cell Transplant. 1993;

2(5): 381–400; discussion 407–410.

103. Chlebeck PT, Milliner DS, Smith LH. Long-term prognosis in primary hyperoxaluria type II (L-

glyceric aciduria). Am J Kidney Dis. 1994; 23(2): 255–259.

104. Chalmers RA, Tracey BM, Mistry J, Griffiths KD, Green A, Winterborn MH. L-Glyceric aciduria

(primary hyperoxaluria type 2) in siblings in two unrelated families. J Inherit Metab Dis. 1984;

7(Suppl 2): 133, 134.

105. Seargeant LE, deGroot GW, Dilling LA, Mallory CJ, Haworth JC. Primary oxaluria type 2 (L-

glyceric aciduria): a rare cause of nephrolithiasis in children. J Pediatr. 1991; 118(6): 912–914.

106. Williams HE, Smith LH, Jr. L-glyceric aciduria. A new genetic variant of primary hyperoxaluria.

N Engl J Med. 1968; 278(5): 233–238.

107. Cramer SD, Ferree PM, Lin K, Milliner DS, Holmes RP. The gene encoding hydroxypyruvate

reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II. Hum Mol Genet.

1999; 8(11): 2063–2069.

108. Webster KE, Ferree PM, Holmes RP, Cramer SD. Identification of missense, nonsense, and

deletion mutations in the GRHPR gene in patients with primary hyperoxaluria type II (PH2).

Hum Genet. 2000; 107(2): 176–185.

109. Milliner DS, Wilson DM, Smith LH. Phenotypic expression of primary hyperoxaluria: compara-

tive features of types I and II. Kidney Int. 2001; 59(1): 31–36.

110. Monico CG, Persson M, Ford GC, Rumsby G, Milliner DS. Potential mechanisms of marked

hyperoxaluria not due to primary hyperoxaluria I or II. Kidney Int. 2002; 62(2): 392–400.

111. Breslau NA, Brinkley L, Hill KD, Pak CY. Relationship of animal protein-rich diet to kidney stone

formation and calcium metabolism. J Clin Endocrinol Metab. 1988; 66(1): 140–146.

112. Nguyen QV, Kalin A, Drouve U, Casez JP, Jaeger P. Sensitivity to meat protein intake and

hyperoxaluria in idiopathic calcium stone formers. Kidney Int. 2001; 59(6): 2273–2281.

113. Edwards P, Nemat S, Rose GA. Effects of oral pyridoxine upon plasma and 24-hour urinary

oxalate levels in normal subjects and stone formers with idiopathic hypercalciuria. Urol Res. 1990;

18(6): 393–396.

114. Balcke P, Schmidt P, Zazgornik J, Kopsa H, Minar E. Pyridoxine therapy in patients with renal

calcium oxalate calculi. Proc Eur Dial Transplant Assoc. 1983; 20: 417–421.

115. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of the intake of vitamins

C and B6, and the risk of kidney stones in men. J Urol. 1996; 155(6): 1847–1851.

Chapter 7 / Management of Oxaluria 119

116. Mitwalli A, Ayiomamitis A, Grass L, Oreopoulos DG. Control of hyperoxaluria with large doses

of pyridoxine in patients with kidney stones. Int Urol Nephrol. 1988; 20(4): 353–359.

117. Prien EL, Sr., Gershoff SF. Magnesium oxide-pyridoxine therapy for recurrent calcium oxalate

calculi. J Urol. 1974; 112(4): 509–512.

118. Rattan V, Sidhu H, Vaidyanathan S, Thind SK, Nath R. Effect of combined supplementation of

magnesium oxide and pyridoxine in calcium-oxalate stone formers. Urol Res. 1994; 22(3): 161–

165.

119. Campieri C, Campieri M, Bertuzzi V, et al. Reduction of oxaluria after an oral course of lactic acid

bacteria at high concentration. Kidney Int. 2001; 60(3): 1097–1105.

120. Kumar R, Mukherjee M, Bhandari M, Kumar A, Sidhu H, Mittal RD. Role of Oxalobacter

formigenes in calcium oxalate stone disease: a study from north India. Eur Urol. 2002; 41(3): 318–

322.

121. Sidhu H, Schmidt ME, Cornelius JG, et al. Direct correlation between hyperoxaluria/oxalate stone

disease and the absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes:

possible prevention by gut recolonization or enzyme replacement therapy. J Am Soc Nephrol.

1999; 10 Suppl 14: S334–S340.

122. Sidhu H, Allison MJ, Chow JM, Clark A, Peck AB. Rapid reversal of hyperoxaluria in a rat model

after probiotic administration of Oxalobacter formigenes. J Urol. 2001; 166(4): 1487–1491.

123. Duncan SH, Richardson AJ, Kaul P, Holmes RP, Allison MJ, Stewart CS. Oxalobacter formigenes

and its potential role in human health. Appl Environ Microbiol. 2002; 68(8): 3841–3847.

124. Brandle E, Bernt U, Kleinschmidt K. EO8: a specific inhibitor of the renal tubular oxalate secretion

- a new concept in the medical treatment of calcium oxalate stones. In: Urolithiasis 2000 Book of

Proceedings. Vol. 2., (Rodgers AL, Hibbert BE, Hess B, Khan SR, Preminger GM, eds.). Univer-

sity of Cape Town, Cape Town, 2000; p. 480.

125. Kothari S, Verma N, Barjatiya MK. Antioxidants have adjuvant therapeutic value in the man-

agement of hyperoxaluria. In: Urolithiasis 2000 Book of Proceedings. Vol. 2., (Rodgers AL,

Hibbert BE, Hess B, Khan SR, Preminger GM, eds.). University of Cape Town, Cape Town,

Africa, 2000; p. 482.

126. Poonguzhali PK, Chegu H. The influence of banana stem extract on urinary risk factors for stones

in normal and hyperoxaluric rats. Br J Urol. 1994; 74(1): 23–25.

127. Ramakrishnan V, Lathika KM, D’Souza SJ, Singh BB, Raghavan KG. Investigation with chitosan-

oxalate oxidase-catalase conjugate for degrading oxalate from hyperoxaluric rat chyme. Indian J

Biochem Biophys. 1997; 34(4): 373–378.

128. Buck AC, Lote CJ, Sampson WF. The influence of renal prostaglandins on urinary calcium excre-

tion in idiopathic urolithiasis. J Urol. 1983; 129(2): 421–426.

129. Naya Y, Ito H, Masai M, Yamaguchi K. Association of dietary fatty acids with urinary oxalate

excretion in calcium oxalate stone-formers in their fourth decade. BJU Int. 2002; 89(9): 842–846.

130. Buck AC, Davies RL, Harrison T. The protective role of eicosapentaenoic acid [EPA] in the

pathogenesis of nephrolithiasis. J Urol. 1991; 146(1): 188–194.

131. Baggio B, Budakovic A, Nassuato MA, et al. Plasma phospholipid arachidonic acid content and

calcium metabolism in idiopathic calcium nephrolithiasis. Kidney Int. 2000; 58(3): 1278–1284.

Chapter 8 / Renal Acid–Base Balance 121

121

From: Current Clinical Urology, Urinary Stone Disease:

A Practical Guide to Medical and Surgical Management

Edited by: M. L. Stoller and M. V. Meng © Humana Press Inc., Totowa, NJ

Renal Acid–Base Balance

and Renal Tubular Acidosis

Andrew I. Chin, MD

CONTENTS

INTRODUCTION

ACID–BASE CHEMISTRY

ENDOGENOUS ACID PRODUCTION

PULMONARY AND OTHER NONRENAL ACID–BASE REGULATION

RENAL ACID–BASE REGULATION

URINARY PH AND ASSESSMENT OF ACID EXCRETION

RENAL TUBULAR ACIDOSIS

REFERENCES

Key Words: Nephrolithiasis; pH; renal physiology.

INTRODUCTION

Renal stone disease is frequently associated with abnormal urinary acid–base bal-

ance. Renal tubular defects may influence urinary pH and alter urinary excretion of

various substances, predisposing to stone formation. This chapter provides a back-

ground for the understanding of acid–base disorders, mainly from a renal perspective.

Most of the concepts of pulmonary and renal acid–base regulation are well established.

The concepts of renal tubular acidosis, however, are still being refined. In the past

several years, the developments of microbiological and genetic research have added

new insights to the pathophysiology of renal tubular disorders. The topics in this section

will touch on basic renal and nonrenal acid–base regulation, systemic and urinary buff-

ering, and focus on regulation of urinary pH, and renal tubular acidosis.

ACID–BASE CHEMISTRY

A substance that donates a free hydrogen ion or proton (H

) in solution is termed an

acid, whereas a substance that binds a free proton in solution is termed a base. The

122 Chin

concentration of free protons in a heterogeneous solution of various acids and bases can

be measured. By convention, the resulting number of free protons is stated as a pH value,

simply the negative logarithm of the concentration of free hydrogen ion: pH = –log [H

]

(where the concentration of H

is in units of moles per liter). Normal physiologic arterial

serum pH of 7.40 ± 0.02 indicates a free proton concentration around 40 nanomol per L

(4  10

–8

mol/L). Values of pH greater than 7.42 indicate an alkalemia and values less

than 7.38 indicate an acidemia.

Buffering

Despite the constant bombardment of acid and alkali, the body maintains a remark-

ably stable pH. Both the serum and the urine contain buffers to minimize the degree of

shift in pH when acid or alkali is added to the solution. A buffer is essentially a weak acid

and its conjugate base:

HA ↔ H

+ A

–

(1)

The rates of association and dissociation in Eq. 1 depend on the particular type of

buffer, as well as the temperature of the solution. The rate of dissociation is given as the

ionization constant, Ka, for a particular acid–base pair. The negative logarithm of this

constant is termed pKa. For all weak acids, the law of mass action relates pH to the

concentrations of the acid and conjugate base:

pH = pKa + log {[A

–

]/[HA]} (2)

When the solution pH is less than the pKa, more protons are bound. When the solution

pH is greater than the pKa, more of the acid will be dissociated yielding more free

protons.

The predominant serum buffer system is represented by carbonic acid (H

) and

its conjugate base, bicarbonate (HCO

–

+ HCO

–

↔ H

(3)

Most individuals accumulate acid in the course of a day through regular metabolic

activities, developing a net acid load (see next section) of 50–100 mmol. Without a

buffering system, the addition of this daily acid load to an average-sized individual

would drop the pH to around 3.0. This does not occur, as the produced H

is buffered by

binding to HCO

–, forming the weak acid H

and maintaining the [H

] close to

physiologic levels. The H

does not accumulate to any large extent because of the

action of carbonic anhydrase (CA) to produce water and carbon dioxide:

↔ H

O + CO

(4)

The constant removal of CO

by the pulmonary system is the other crucial step in

maintaining a pH of 7.40 during this buffering process, discussed in a later section.

Equations 3 and 4 can be combined to give the familiar expression:

+ HCO

–

↔ H

O + CO

(5)

If we use (Eq. 2) in the above relationship, and knowing the pKa

of carbonic acid to

be about 6.10 (at 37°C), we get the following:

pH = 6.10 + log {[HCO

–

]/[CO

]} (6)

The dissolved concentration of CO

is very low and is related to the partial pressure

of CO

(pCO

) by a factor of 0.03 to give the Henderson–Hasselbalch equation:

pH = 6.10 + log {[HCO

–

]/(0.03  pCO

)} (7)

Chapter 8 / Renal Acid–Base Balance 123

Now, not only can the pH be calculated by knowing the serum HCO

–

and the serum

pCO

, but also any single unknown in this relationship can be calculated when the other

two variables are known. This formula is the basis for most of the clinical charts and

tables relating pCO

, pH, and HCO

–

found in almost all acid–base texts and handbooks.

Other important serum buffers include phosphates and sulfates, derived from phos-

phoproteins and sulfur-containing amino acids, respectively. These buffers are found at

much lower concentrations than bicarbonate but play an important role as urinary buff-

ers. Anionic serum proteins, such as albumin, also buffer H

to a limited extent. Another

major serum buffer is the skeletal system (1). Phosphates in mineralized bone can take

up free protons in exchange for other bone cations such as sodium and calcium. Chronic

acidosis can lead to decreased bone mineral content (2,3).

ENDOGENOUS ACID PRODUCTION

Inorganic Acids

For the most part, normal physiologic activities result in acid production. Daily endo-

genous noncarbonic acid production or the “acid load” is derived from dietary protein

metabolism, predominantly those containing the amino acids cystine, methionine and

arginine. Cystine and methionine result in the production of sulfuric acid, and arginine

(also lysine and histinine) produces hydrochloric acid. The resulting acids (sulfuric and

hydrochloric) are termed “fixed” or “inorganic” acids. As these are relatively strong

acids with low pKa, they are mostly found in dissociated form at physiologic conditions.

This implies that the dissociated H

will bind to the serum buffer HCO

–

, consuming one

molecule of bicarbonate for each molecule of inorganic acid formed. The carbonic acid

) created by the reaction is broken down to H

O and CO

. The lungs normally

exhale the CO

. The average Western diet, which is quite high in protein, contributes

about 50–100 mmol of H

(approx 1 mmol/kg of body weight) to the endogenous daily

acid load.

Organic Acid and Carbonic Acid

Organic acids, including ketoacids, acetoacids, lactic acid, and uric acid, accumulate

from normal metabolic activities and from the diet. The organic acids (or organic anions)

differ from the inorganic acids, in that many organic anions can be further metabolized

to a neutral end product plus HCO

–

. Organic anions, therefore, represent a potential

bicarbonate source, if the appropriate metabolic pathways are intact. When these path-

ways are disrupted, the organic anions may accumulate and result in an anion gap

metabolic acidosis. On the other hand, if organic anions are lost, for example through

abnormal renal proximal tubular handling, a mild nonanion gap metabolic acidosis may

result from the loss of a potential bicarbonate source. Some investigators believe that

organic ion metabolism may actually account for an important fraction of the bicarbon-

ate regenerated in maintaining homeostasis (4).

The metabolism of carbohydrates and fats produces upwards of 15,000 mmol of CO

which has the potential to form carbonic acid (H

) when combined with H

(Eq. 4). The constant removal of CO

via the pulmonary system prevents H

from

accumulating, and the actual serum concentration of H

is insignificant. H

often termed a “volatile” acid and does not contribute to the usual daily endogenous acid

load in a healthy individual. With impaired ventilation, a respiratory acidosis will occur

with build up of CO

and subsequently H

. By measuring arterial pCO

and serum