EDITORIAL COMMENT
1
factors in calcium oxalate stone disease. J. Urol.. 153: :wi. 199.5. 13. Zarembski, P. M. and Hodgkinson, A.: Some factors influencing 14. 15. 16. 17. 18. 19. 20 21 the urinary excretion of oxalic acid in man. Clin. Chim. Acts, 25: 1, 1969. Hesse, A., Siener, R., Heynck, H. and Jahnen, A,: The influence of dietary factors on the risk of urinary stone formation. Scan, Microsc., 7: 1119, 1993. Holmes, R. P., Goodman, H. O., Hart, L. J. and Assimos, D. G.: Relationship of protein intake to urinary oxalate and glycolate excretion. Kid. Int., 44: 366, 1993. Bella, D. L. and Stipanuk, M. H.: Effects of protein, methionine. or chloride on acid-base balance and on cysteine catabolism. her. J. Physiol., 269 E910, 1995. Pak, C. Y.: Citrate and renal calculi: an update. Min. Electr. Metab., 20: 371, 1994. Holmes, R. P., Goodman, H. 0. and Assimos, D. G.: Dietary oxalate and its intestinal absorption. Scan. Microsc., 9 1109, 1995. Scheid, C. R., Koul, H. K., Kennington, L., Hill, W. A,, Luber-Narod, J., Jonassen, J., Honeyman, T. and Menon, M.: Oxalate-induced damage to renal tubular cells. Scan. Microsc., 9: 1097, 1995. Robertson, W. G. and Hughes, H.: Importance of mild hyperox- aluria in the pathogenesis of urolithiasis-new evidence from studies in the Arabian peninsula. Scan. Microsc., 7: 391, 1993. Barditch-Crovo, P., Skowron, G., Lederman, M., Story, K., Webb, L. and Borum, P.: Human pharmacokinetic profile of oral Procysteine, L-2-oxothiazolidine-4-carboxylic acid. IXth Inter- national Conference on AIDS, Berlin, June 7-11, 1993. EDITORIAL COMMENT Urinary oxalate is considered by many to be an important risk factor in calcium oxalate stone formation. In a small subset of pa- tients with profound hyperoxaluria treatment options are limited. In most patients with primary hyperoxaluria only combined renal and liver transplantation offers a chance of controlling oxalosis, profound nephrolithiasis and ultimately renal failure. This phase 1 study offers a potential medical alternative for treatment of significant hyperoxaluria, and evaluates the safety and pharmacokinetics of a new medication, OTZ. After intravenous administration, this cys- teine precursor was shown to decrease significantly urinary oxalate excretion. Also noted was a decrease in urine pH and citrate excre- tion. While this medication may provide a useful alternative for the treatment of profound hyperoxaluria, there are some limitations of the current study design. As the authors acknowledge, the studies were not performed in a controlled environment, thereby allowing external variations in diet to impact the results. Furthermore, time variations during the urine collections can also lead to confusing results. Idc;illy. phiisr 2 s1udic.s should I)e pcvformed at a nwt:lt)olir resrarch unit, whcw dic>t;iry control and 24-hour urinr collcctitrns can be perfornird morc precisvly. Although this ncw mc.dication niay have a bencficial rolr in sig- nificantly dvcreasing urinary oxalate levels. :i secondary effect ap- pears to be increased acid production with :I suhsequent increase in urinary sulfate, and decrease in urine pH and citrate excretion. Unfortunately, increased urinary sulfate and hypocitraturia are known risk factors for recurrrnt calcium oxalate stones. A possible solution to be investigated further in phase 2 or 3 studies would he to administer an alkali preparation that can neutralize the acidotic effects of OTL. A combination of OTZ and neutral citratca might be a useful drug reblmen tn treat hyperoxaluric stone formers in the future. Glc,nn M. Premingcr Dirision of Urology Duke Unii~ersity Medical Center Durham, North Carolina REPLY BY AUTHORS We agree that OTZ has the potential to be a viable medical therapy for decreasing hepatic oxalate synthesis and the suggestion that it be administered with a neutral citrate salt for treating hyperoxaluria associated with calcium oxalate stone disease is good. We plan to investigate its efficacy for treating primary hyperoxaluria. The main question is whether the increase in hepatic cysteine will be sufficient to reduce the increased glyoxylate concentrations that presumably occur in these individuals. Hopefully lower oral doses than the in- travenous dose used in this study, which was the equivalent of 21 gm.170 kg. body weight daily. will be effective because of increased sensitivity due to higher glyoxylate concentrations. Two factors must be considered when administering OTZ for hy- peroxaluria in stone forming patients. 1) We recognize that the bulk of the oxalate excreted by hyperoxaluric stone forming patients has a dietary origin (unpublished data). consistent with the results we recently reported in normal individuals (mean dietary contribution 45%, range 10 to 72). More research is obviously needed to under- stand the relationship of dietary oxalate and other nutritional fac- tors to the intestinal absorption of oxalate, and determine what dietary recommendations or therapeutic strategies will decrease this absorption. 2) It must be determined whether large oral doses cause intestinal discomfort or other side effects, particularly if ingested with oral citrate, that will seriously interfere with patient compli- ance. 1. Holmes, R. P., Goodman, H. 0. and Assimos, D. G.: Metabolic effects of an oxylate-free formula diet. In: Urolithiasis 1996. Edited by C.Y.C. Pak, M. I. Resnick and G. M. Preminger. Dallas: Millet the Printer. DD. 167-168. 1996. ..
Transcript of EDITORIAL COMMENT
factors in calcium oxalate stone disease. J. Urol.. 153: :wi. 199.5.
13. Zarembski, P. M. and Hodgkinson, A.: Some factors influencing
14.
15.
16.
17.
18.
19.
20
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the urinary excretion of oxalic acid in man. Clin. Chim. Acts, 25: 1, 1969.
Hesse, A., Siener, R., Heynck, H. and Jahnen, A,: The influence of dietary factors on the risk of urinary stone formation. Scan, Microsc., 7: 1119, 1993.
Holmes, R. P., Goodman, H. O., Hart , L. J. and Assimos, D. G.: Relationship of protein intake to urinary oxalate and glycolate excretion. Kid. Int., 44: 366, 1993.
Bella, D. L. and Stipanuk, M. H.: Effects of protein, methionine. or chloride on acid-base balance and on cysteine catabolism. h e r . J. Physiol., 269 E910, 1995.
Pak, C. Y.: Citrate and renal calculi: an update. Min. Electr. Metab., 20: 371, 1994.
Holmes, R. P., Goodman, H. 0. and Assimos, D. G.: Dietary oxalate and its intestinal absorption. Scan. Microsc., 9 1109, 1995.
Scheid, C. R., Koul, H. K., Kennington, L., Hill, W. A,, Luber-Narod, J., Jonassen, J., Honeyman, T. and Menon, M.: Oxalate-induced damage to renal tubular cells. Scan. Microsc., 9: 1097, 1995.
Robertson, W. G. and Hughes, H.: Importance of mild hyperox- aluria in the pathogenesis of urolithiasis-new evidence from studies in the Arabian peninsula. Scan. Microsc., 7: 391, 1993.
Barditch-Crovo, P., Skowron, G., Lederman, M., Story, K., Webb, L. and Borum, P.: Human pharmacokinetic profile of oral Procysteine, L-2-oxothiazolidine-4-carboxylic acid. IXth Inter- national Conference on AIDS, Berlin, June 7-11, 1993.
EDITORIAL COMMENT
Urinary oxalate is considered by many to be an important risk factor in calcium oxalate stone formation. In a small subset of pa- tients with profound hyperoxaluria treatment options are limited. In most patients with primary hyperoxaluria only combined renal and liver transplantation offers a chance of controlling oxalosis, profound nephrolithiasis and ultimately renal failure. This phase 1 study offers a potential medical alternative for treatment of significant hyperoxaluria, and evaluates the safety and pharmacokinetics of a new medication, OTZ. After intravenous administration, this cys- teine precursor was shown to decrease significantly urinary oxalate excretion. Also noted was a decrease in urine pH and citrate excre- tion.
While this medication may provide a useful alternative for the treatment of profound hyperoxaluria, there are some limitations of the current study design. As the authors acknowledge, the studies were not performed in a controlled environment, thereby allowing external variations in diet to impact the results. Furthermore, time variations during the urine collections can also lead to confusing
results. Idc;illy. phiisr 2 s1udic.s should I)e pcvformed at a nwt:lt)olir resrarch unit, w h c w dic>t;iry control and 24-hour urinr collcctitrns can be perfornird morc precisvly.
Although this ncw mc.dication niay have a bencficial rolr in sig- nificantly dvcreasing urinary oxalate levels. :i secondary effect ap- pears to be increased acid production with :I suhsequent increase in urinary sulfate, and decrease in urine pH and citrate excretion. Unfortunately, increased urinary sulfate and hypocitraturia are known risk factors for recurrrnt calcium oxalate stones. A possible solution to be investigated further in phase 2 or 3 studies would he to administer an alkali preparation that can neutralize the acidotic effects of OTL. A combination of OTZ and neutral citratca might be a useful drug reblmen tn treat hyperoxaluric stone formers in the future.
Glc,nn M . Premingcr Dirision of Urology Duke Unii~ersity Medical Center Durham, North Carolina
REPLY BY AUTHORS
We agree tha t OTZ has the potential to be a viable medical therapy for decreasing hepatic oxalate synthesis and the suggestion tha t it be administered with a neutral citrate salt for treating hyperoxaluria associated with calcium oxalate stone disease is good. We plan to investigate its efficacy for treating primary hyperoxaluria. The main question is whether the increase in hepatic cysteine will be sufficient to reduce the increased glyoxylate concentrations tha t presumably occur in these individuals. Hopefully lower oral doses than the in- travenous dose used in this study, which was the equivalent of 21 gm.170 kg. body weight daily. will be effective because of increased sensitivity due to higher glyoxylate concentrations.
Two factors must be considered when administering OTZ for hy- peroxaluria in stone forming patients. 1) We recognize tha t the bulk of the oxalate excreted by hyperoxaluric stone forming patients has a dietary origin (unpublished data). consistent with the results we recently reported in normal individuals (mean dietary contribution 45%, range 10 to 72). More research is obviously needed to under- stand the relationship of dietary oxalate and other nutritional fac- tors to the intestinal absorption of oxalate, and determine what dietary recommendations or therapeutic strategies will decrease this absorption. 2 ) It must be determined whether large oral doses cause intestinal discomfort or other side effects, particularly if ingested with oral citrate, that will seriously interfere with patient compli- ance.
1. Holmes, R. P., Goodman, H. 0. and Assimos, D. G.: Metabolic effects of an oxylate-free formula diet. In: Urolithiasis 1996. Edited by C.Y.C. Pak, M. I. Resnick and G. M. Preminger. Dallas: Millet the Printer. DD. 167-168. 1996. ..
