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Fish Oil Supplementation and Urinary Oxalate Excretion in Normal Subjects on a Low-oxalate Diet
Endourology and Stones Fish Oil Supplementation and Urinary Oxalate Excretion in Normal Subjects on a Low-oxalate Diet Jessica N. Lange, Patrick W. Mufarrij, Linda Easter, John Knight, Ross P. Holmes, and Dean G. Assimos OBJECTIVE MATERIALS AND METHODS
RESULTS
CONCLUSION
To determine if fish oil supplementation reduces endogenous oxalate synthesis in healthy subjects. Fifteen healthy nonestone-forming adults participated in this study. Subjects first abstained from using vitamins, medications, or foods enriched in omega-3 fatty acids for 30 days. Next, they collected two 24-hour urine specimens while consuming a self-selected diet. Subjects consumed an extremely low-oxalate and normal-calcium diet for 5 days and collected 24-hour urine specimens on the last 3 days of this diet. Next, the subjects took 2 fish oil capsules containing 650-mg eicosapentaenoic acid and 450-mg docosahexaenoic acid twice daily for 30 days. They consumed a self-selected diet on days 1-25 and the controlled diet on days 26-30. Twenty-four-hour urine samples were collected on days 28-30. Excretion levels of urinary analytes including oxalate and glycolate were analyzed. Although there was a significant reduction in urinary oxalate, magnesium, and potassium excretions and an increase in uric acid excretion during the controlled dietary phases compared with the self-selected diet, there were no significant differences in their excretion during controlled diet phases with and without fish oil supplementation. These results suggest that fish oil supplementation does not reduce endogenous oxalate synthesis or urinary oxalate excretion in normal adults during periods of extremely low oxalate intake. However, these results do not challenge the previously described reduction in urinary oxalate excretion demonstrated in normal subjects consuming a moderate amount of oxalate in conjunction with fish oil. UROLOGY 84: 779e782, 2014. 2014 Elsevier Inc.
C
alcium oxalate is the most common type of kidney stones.1 Increased urinary oxalate excretion is a risk factor for calcium oxalate kidney stone formation,2-4 and small increases in urinary oxalate excretion are associated with significant increases in stone risk.5 Urinary oxalate is derived from both dietary sources and endogenous synthesis.6 It has been demonstrated that the administration of fish oil, a rich source of omega-3 fatty acids, reduces urinary oxalate excretion.7-9 Siener et al9 attribute this to an altered fatty acid pattern of membrane phospholipids and
Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This study was supported by National Institutes of Health grants DK62284 (D.G. Assimos) and DK73732 (R.P. Holmes). From the Department of Urology, Wake Forest Baptist Health, Winston-Salem, NC; the Department of Urology, George Washington University Medical Center, Washington, DC; and the Department of Urology, University of Alabama-Birmingham Medical Center, Birmingham, AL Reprint requests: Jessica N. Lange, M.D., Department of Urology, Wake Forest Baptist Health, Medical Center Blvd., Winston-Salem, NC 27157. E-mail: jelange@ wakehealth.edu Submitted: February 7, 2014, accepted (with revisions): April 26, 2014
ª 2014 Elsevier Inc. All Rights Reserved
changes in oxalate transporter activity. This can result in altered gastrointestinal and/or renal oxalate handling and promote reduced urinary oxalate excretion. Another possibility is that fish oil supplementation promotes a reduction in endogenous oxalate synthesis. Fish oil has known anti-inflammatory properties, and the latter may be associated with a reduction in oxidative stress. Oxidative stress has been proposed to increase endogenous oxalate synthesis because of the conversion of the reactive dialdehyde, glyoxal, to glyoxylate, the immediate precursor of oxalate.10 Herein, we report a study to assess whether fish oil supplementation reduces endogenous oxalate synthesis.
MATERIALS AND METHODS After study approval by the Wake Forest School of Medicine Institutional Review Board, 15 healthy nonestone-forming adults (average age, 25.3 2.7 years; body mass index <30 kg/m2; 8 men; and 7 women) were recruited to participate in this study. Potential subjects abstained from utilization of any supplements including vitamins, medications, or foods http://dx.doi.org/10.1016/j.urology.2014.04.052 0090-4295/14
779
Table 1. Components of controlled diet Nutrient Oxalate Calcium Sodium Magnesium Phosphorus Potassium Vitamin C Fluids
Daily Content 50 mg 1000 mg 3500 mg 300 mg 1500 mg 3000 mg 125 mg 2.5 L
enriched in omega-3 fatty acids and consumed a self-selected diet for 30 days and then collected two 24-hour urine specimens. These were analyzed for volume, creatinine, sodium, potassium, magnesium, calcium, oxalate, uric acid, phosphate, citrate, urea nitrogen, and Tiselius index for calcium oxalate. Urinary analytes other than oxalate were measured on a Beckman C5E analyzer (Beckman Coulter, Inc, Brea, CA). Oxalate was measured using a kit provided by Trinity Biotech (St. Louis, MO). The subjects then consumed a controlled low-oxalate normal-calcium diet for 5 days. Dietary components are listed in Table 1. This diet was intended to dramatically limit the contribution of dietary oxalate to the urinary oxalate pool. The meals were prepared in the metabolic kitchen of the Wake Forest Clinical Research Unit and were tailored to each subject’s daily caloric needs. The participants collected 24-hour urine specimens on days 3-5 of the initial controlled diet phase. Next, the subjects began taking 2 fish oil supplement capsules containing 650mg eicosapentaenoic acid (EPA) and 450-mg docosahexaenoic acid (DHA; Nordic Naturals, Watsonville, CA) twice daily for 30 days while consuming a self-selected diet. On days 25-30 of the supplement period, the subjects again consumed the same controlled low-oxalate diet for 5 days and collected 24-hour urine specimens on days 3-5. The same urinary parameters were measured. Statistical analyses included repeated-measures analysis of variance and the Student t test.
RESULTS A comparison of the self-selected dietary phase, controlled dietary phase without fish oil supplementation, and controlled dietary phase with fish oil supplementation revealed no significant differences in urinary volume, creatinine, sodium, citrate, urea nitrogen, phosphate, or calcium excretions, nor was a significant difference found in the Tiselius index for calcium oxalate. Analyses of variance of daily oxalate, potassium, magnesium, and uric acid excretions were significant (P <.05). There was a significant decrease in oxalate, magnesium, and potassium excretions between the selfselected diet and both controlled diet phases (P <.05) but no significant difference between the controlled diet phases before and after fish oil supplementation (Table 2). Uric acid excretion was significantly higher on the controlled diets compared with the self-selected diet (<0.05); however, there were no differences between the controlled diet phases with and without fish 780
oil supplementation. Table 2 lists the mean analyte excretion during each study phase.
COMMENT A number of investigators have reported that the administration of fish oil supplements promotes a reduction in urinary oxalate excretion. Buck et al8 treated 12 recurrent hypercalciuric stone formers with 1800-mg EPA and 1200-mg DHA daily for 8 weeks. Urinary calcium and oxalate excretions significantly decreased after administration of fish oil supplements, but the diets were not controlled in this study. Baggio et al7 noted that urinary calcium and oxalate excretions declined in a study in which 24 recurrent calcium oxalate stone formers ingested 850 mg of omega-3 fatty acid ethyl esters 3 times daily for 30 days. Again, dietary components were not strictly controlled in this study. Siener et al9 studied 15 healthy subjects who consumed a standardized diet for 5 days, a self-selected diet for 20 days, and a standardized diet again for 5 days. Each participant took 900-mg EPA and 600-mg DHA daily for the last 25 days of the study. The average standardized diet consisted of 2237 kilocalories, 68-g protein, 297-g carbohydrate, 83-g fat, 35-g fiber, 3502mg potassium, 982-mg calcium, 359-mg magnesium, 2085-mg sodium, 1220-mg phosphorus, 197-mg oxalate, and 3734-mL fluid daily. Results revealed significantly decreased oxalate excretion (13%) and urinary calcium oxalate supersaturation. Similar to the findings of our study, calcium excretion was not significantly affected. Our results suggest that fish oil supplementation does not have a profound effect on the contribution of endogenous oxalate synthesis to the urinary oxalate pool in healthy individuals with normal baseline urinary oxalate excretion. It could be that the mechanisms proposed by Siener et al, alterations in renal secretion of oxalate or a reduction in net gastrointestinal oxalate absorption, are valid.9 Perhaps, the responses would be different in a diseased cohort. Our subjects may have had low levels of oxidative stress. Their urinary analyte profile while on a self-selected diet is reflective of healthy eating habits as indicated by higher urinary potassium and magnesium excretion. The response may have been different in calcium oxalate stone formers, especially those with increased oxalate excretion or increased oxidative stress. Therefore, similar studies should be considered in such subjects. We recognize that our study has certain limitations. Our cohort size was relatively small, but the number is comparable to that of Siener et al.9 In addition, we measured neither the plasma levels of fatty acids in red blood cell membranes to assess compliance with the fish oil supplement regimen nor the markers of oxidative stress.
CONCLUSION It appears that fish oil supplementation does not reduce endogenous oxalate synthesis in healthy nonestoneforming subjects. UROLOGY 84 (4), 2014
Table 2. Mean urinary analyte excretion Parameter
Self-selected Diet (Mean St Dev)
Volume (mL/d) Creatinine (mg/d) Sodium (mg/d) Potassium (mg/d) Calcium (mg/d) Magnesium (mg/d) Citrate (mg/d) Uric acid (mg/d) Urea nitrogen (mg/d) Phosphate (mg/d) Oxalate (mg/d) Tiselius index for CaOx
2268 1534 3167 2980 143 89 447 548 10,849 892 33 0.84
826 468 1054 1288* 58 31* 320 154* 3230 312 10* 0.45
Controlled Diet 1 (Mean St Dev) 2012 1759 2785 2312 119 71 406 621 10,842 924 26 0.63
397 435 740 599 44 18 169 173 2199 336 6 0.33
Controlled Diet 2 (Mean St Dev) 2103 1682 2834 2135 141 74 333 675 11,548 984 26 0.72
307 475 857 580 51 20 131 162 2456 248 5 0.28
P Value .41 .21 .30 <.01 .16 .04 .18 .02 .32 .28 <.01 .06
St Dev, standard deviation. * Statistically significant difference from controlled dietary phases.
References 1. Coe FL, Parks JH, Asplin JR. The pathogenesis and treatment of kidney stones. N Engl J Med. 1992;327:1141-1152. 2. Curhan GC, Willett WC, Knight EL, et al. Dietary factors and the risk of incident kidney stones in younger women: Nurses’ Health Study II. Arch Intern Med. 2004;164:885-891. 3. Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of followup. J Am Soc Nephrol. 2004;15:3225-3232. 4. Curhan GC, Willett WC, Speizer FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997; 126:497-504. 5. Curhan GC, Taylor EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 2008;73:489-496. 6. Holmes RP, Goodman HO, Assimos DG. Contribution of dietary oxalate to urinary oxalate excretion. Kidney Int. 2001;59:270-276. 7. Baggio B, Gambaro G, Zambon S, et al. Anomalous phospholipid n-6 polyunsaturated fatty acid composition in idiopathic calcium nephrolithiasis. J Am Soc Nephrol. 1996;7:613-620. 8. Buck AC, Davies RL, Harrison T. The protective role of eicosapentaenoic acid [EPA] in the pathogenesis of nephrolithiasis. J Urol. 1991;146:188-194. 9. Siener R, Jansen B, Watzer B, et al. Effect of n-3 fatty acid supplementation on urinary risk factors for calcium oxalate stone formation. J Urol. 2011;185:719-724. 10. Knight J, Assimos DG, Easter L, et al. Metabolism of fructose to oxalate and glycolate. Horm Metab Res. 2010;42:868-873.
EDITORIAL COMMENT Urinary stone diseases include a number of different and distinct phenotypes,1 so that understanding the etiologies of “stone disease” is an ongoing and complex research program.2 However, a great many stone formers can benefit from simple changes to diet that reduce the levels of urine supersaturation for the mineral(s) that they deposit in their stones.3 In 2011, Siener et al showed that the addition of n-3 fatty acids (which are characteristically high in fish oil) to the diet of healthy subjects led to a reduction in the urinary excretion of oxalate, with a concomitant lowering of the supersaturation level of oxalate in the urine.4 They proposed that this change might have been caused by the increased incorporation of n-3 fatty acids into plasma membranes of epithelial cells, so that oxalate transport is altered in the intestine and kidney. UROLOGY 84 (4), 2014
This hypothesis—that alteration of the fatty acid composition of membranes will itself alter oxalate handling in the body—is also supported by the work of Baggio et al, who reported an apparent anomaly in the fatty acid composition of membranes from calcium stone formers.5,6 They proposed that this abnormal composition of plasma membranes leads to alteration in the transport of oxalate (and of calcium) so that such persons are prone to the formation of calcium oxalate stones.7 Thus, in the study by Siener et al, they supported this general concept by showing in a carefully controlled study that dietary alterations in fatty acids can alter oxalate excretion. However, oxalate excretion is not the product solely of diet and epithelial transport; an important proportion of oxalate in the urine comes from metabolism of other substances.8 This means that the effect of n-3 fatty acids on oxalate excretion could be due to an alteration of oxalate synthesis in the body, rather than an effect on oxalate transport in the intestine and kidney. In the present study, the effects of fish oil supplementation on endogenous oxalate synthesis were studied in subjects on a very low-oxalate diet. They showed no alterations in oxalate excretion with n-3 fatty acid supplementation, suggesting that changing dietary fatty acid does not alter endogenous oxalate metabolism. Thus, the changes reported by earlier studies may well be due to some relationship between fatty acid composition of membranes and oxalate transport. Little work has been done to identify the type of stone former that might benefit from fish oil supplementation, but dietary fatty acids have shown no correlation with stone formation in large cohort studies.9 Thus, if fish oil can help stone formers, it is likely to be the people whose disease is related to dietary oxalate. Some evidence suggests that the hard dark form of calcium oxalate monohydrate is almost always associated with some form of hyperoxaluria.10 About 30% of all stone formers make some or all of their stones with this kind of calcium oxalate.11 Could it be that such stone formers would benefit from taking fish oil supplements? Future work remains to be done. James C. Williams, Jr., Ph.D., Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN
References 1. Coe FL, Evan AP, Lingeman JE, Worcester EM. Plaque and deposits in nine human stone diseases. Urol Res. 2010;38:239-247.
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2. Williams JC Jr, McAteer JA. Retention and growth of urinary stones—insights from imaging. J Nephrol. 2013;26:25-31. 3. Penniston KL, Nakada SY. Diet and alternative therapies in the management of stone disease. Urol Clin North Am. 2013;40:31-46. 4. Siener R, Jansen B, Watzer B, Hesse A. Effect of n-3 fatty acid supplementation on urinary risk factors for calcium oxalate stone formation. J Urol. 2011;185:719-724. 5. Baggio B, Budakovic A, Nassuato MA, et al. Plasma phospholipid arachidonic acid content and calcium metabolism in idiopathic calcium nephrolithiasis. Kidney Int. 2000;58:1278-1284. 6. Baggio B, Gambaro G, Zambon S, et al. Anomalous phospholipid n-6 polyunsaturated fatty acid composition in idiopathic calcium nephrolithiasis. J Am Soc Nephrol. 1996;7:613-620. 7. Baggio B, Gambaro G. Abnormal arachidonic acid content of membrane phospholipids—the unifying hypothesis for the genesis of hypercalciuria and hyperoxaluria in idiopathic calcium nephrolithiasis. Nephrol Dial Transplant. 1999;14:553-555. 8. Holmes RP, Goodman HO, Assimos DG. Contribution of dietary oxalate to urinary oxalate excretion. Kidney Int. 2001;59:270-276. 9. Taylor EN, Stampfer MJ, Curhan GC. Fatty acid intake and incident nephrolithiasis. Am J Kidney Dis. 2005;45:267-274. 10. Daudon M, Jungers P. Clinical value of crystalluria and quantitative morphoconstitutional analysis of urinary calculi. Nephron Physiol. 2004;98:31-36. 11. Daudon M. Analyse et classification des calculs: contribution a l’etiologie de la maladie lithiasique [Analysis and classification of calculi: contribution to the etiology of calculous disease]. Rev Med Suisse Romande. 2004;124:445-453.
alteration of cell membranes and thus oxalate transport. The mechanism of this response is not completely understood. Our study attempted to further refine our knowledge of this relationship by investigating the effect of omega-3 fatty acids specifically on endogenous oxalate production. Our results revealed that omega-3 fatty acid supplementation does not appear to decrease this production. Thus, we agree that future research may be best focused on the relationship of fatty acids to dietary oxalate intake and patients with hyperoxaluria. Determining the predominant type of calcium oxalate crystal in stones in an effort to guide dietary therapy is of interest but may prove difficult to validate. Jessica N. Lange, M.D., Wake Forest Baptist Health, Winston-Salem, NC Patrick W. Mufarrij, M.D., George Washington University Medical Center, Washington, DC Linda Easter, R.D., Wake Forest Baptist Health, WinstonSalem, NC John Knight, Ph.D., Ross P. Holmes, Ph.D., and Dean G. Assimos, M.D., University of Alabama-Birmingham Medical Center, Birmingham, AL
http://dx.doi.org/10.1016/j.urology.2014.04.053 UROLOGY 84: 781e782, 2014. 2014 Elsevier Inc.
REPLY We agree that the work of Siener et al1 and Baggio et al2 has laid the foundation of our knowledge regarding fish oil supplementation and oxalate excretion. Our study attempted to build on their results, which showed that omega-3 fatty acid supplementation reduces urinary oxalate excretion likely through
782
References 1. Siener R, Jansen B, Watzer B, et al. Effect of n-3 fatty acid supplementation on urinary risk factors for calcium oxalate stone formation. J Urol. 2011;185:719. 2. Baggio B, Gambaro G, Zambon S, et al. Anomalous phospholipid n-6 polyunsaturated fatty acid composition in idiopathic calcium nephrolithiasis. J Am Soc Nephrol. 1996;7:613.
http://dx.doi.org/10.1016/j.urology.2014.04.054 UROLOGY 84: 782, 2014. 2014 Elsevier Inc.
UROLOGY 84 (4), 2014
RESULTS
CONCLUSION
To determine if fish oil supplementation reduces endogenous oxalate synthesis in healthy subjects. Fifteen healthy nonestone-forming adults participated in this study. Subjects first abstained from using vitamins, medications, or foods enriched in omega-3 fatty acids for 30 days. Next, they collected two 24-hour urine specimens while consuming a self-selected diet. Subjects consumed an extremely low-oxalate and normal-calcium diet for 5 days and collected 24-hour urine specimens on the last 3 days of this diet. Next, the subjects took 2 fish oil capsules containing 650-mg eicosapentaenoic acid and 450-mg docosahexaenoic acid twice daily for 30 days. They consumed a self-selected diet on days 1-25 and the controlled diet on days 26-30. Twenty-four-hour urine samples were collected on days 28-30. Excretion levels of urinary analytes including oxalate and glycolate were analyzed. Although there was a significant reduction in urinary oxalate, magnesium, and potassium excretions and an increase in uric acid excretion during the controlled dietary phases compared with the self-selected diet, there were no significant differences in their excretion during controlled diet phases with and without fish oil supplementation. These results suggest that fish oil supplementation does not reduce endogenous oxalate synthesis or urinary oxalate excretion in normal adults during periods of extremely low oxalate intake. However, these results do not challenge the previously described reduction in urinary oxalate excretion demonstrated in normal subjects consuming a moderate amount of oxalate in conjunction with fish oil. UROLOGY 84: 779e782, 2014. 2014 Elsevier Inc.
C
alcium oxalate is the most common type of kidney stones.1 Increased urinary oxalate excretion is a risk factor for calcium oxalate kidney stone formation,2-4 and small increases in urinary oxalate excretion are associated with significant increases in stone risk.5 Urinary oxalate is derived from both dietary sources and endogenous synthesis.6 It has been demonstrated that the administration of fish oil, a rich source of omega-3 fatty acids, reduces urinary oxalate excretion.7-9 Siener et al9 attribute this to an altered fatty acid pattern of membrane phospholipids and
Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This study was supported by National Institutes of Health grants DK62284 (D.G. Assimos) and DK73732 (R.P. Holmes). From the Department of Urology, Wake Forest Baptist Health, Winston-Salem, NC; the Department of Urology, George Washington University Medical Center, Washington, DC; and the Department of Urology, University of Alabama-Birmingham Medical Center, Birmingham, AL Reprint requests: Jessica N. Lange, M.D., Department of Urology, Wake Forest Baptist Health, Medical Center Blvd., Winston-Salem, NC 27157. E-mail: jelange@ wakehealth.edu Submitted: February 7, 2014, accepted (with revisions): April 26, 2014
ª 2014 Elsevier Inc. All Rights Reserved
changes in oxalate transporter activity. This can result in altered gastrointestinal and/or renal oxalate handling and promote reduced urinary oxalate excretion. Another possibility is that fish oil supplementation promotes a reduction in endogenous oxalate synthesis. Fish oil has known anti-inflammatory properties, and the latter may be associated with a reduction in oxidative stress. Oxidative stress has been proposed to increase endogenous oxalate synthesis because of the conversion of the reactive dialdehyde, glyoxal, to glyoxylate, the immediate precursor of oxalate.10 Herein, we report a study to assess whether fish oil supplementation reduces endogenous oxalate synthesis.
MATERIALS AND METHODS After study approval by the Wake Forest School of Medicine Institutional Review Board, 15 healthy nonestone-forming adults (average age, 25.3 2.7 years; body mass index <30 kg/m2; 8 men; and 7 women) were recruited to participate in this study. Potential subjects abstained from utilization of any supplements including vitamins, medications, or foods http://dx.doi.org/10.1016/j.urology.2014.04.052 0090-4295/14
779
Table 1. Components of controlled diet Nutrient Oxalate Calcium Sodium Magnesium Phosphorus Potassium Vitamin C Fluids
Daily Content 50 mg 1000 mg 3500 mg 300 mg 1500 mg 3000 mg 125 mg 2.5 L
enriched in omega-3 fatty acids and consumed a self-selected diet for 30 days and then collected two 24-hour urine specimens. These were analyzed for volume, creatinine, sodium, potassium, magnesium, calcium, oxalate, uric acid, phosphate, citrate, urea nitrogen, and Tiselius index for calcium oxalate. Urinary analytes other than oxalate were measured on a Beckman C5E analyzer (Beckman Coulter, Inc, Brea, CA). Oxalate was measured using a kit provided by Trinity Biotech (St. Louis, MO). The subjects then consumed a controlled low-oxalate normal-calcium diet for 5 days. Dietary components are listed in Table 1. This diet was intended to dramatically limit the contribution of dietary oxalate to the urinary oxalate pool. The meals were prepared in the metabolic kitchen of the Wake Forest Clinical Research Unit and were tailored to each subject’s daily caloric needs. The participants collected 24-hour urine specimens on days 3-5 of the initial controlled diet phase. Next, the subjects began taking 2 fish oil supplement capsules containing 650mg eicosapentaenoic acid (EPA) and 450-mg docosahexaenoic acid (DHA; Nordic Naturals, Watsonville, CA) twice daily for 30 days while consuming a self-selected diet. On days 25-30 of the supplement period, the subjects again consumed the same controlled low-oxalate diet for 5 days and collected 24-hour urine specimens on days 3-5. The same urinary parameters were measured. Statistical analyses included repeated-measures analysis of variance and the Student t test.
RESULTS A comparison of the self-selected dietary phase, controlled dietary phase without fish oil supplementation, and controlled dietary phase with fish oil supplementation revealed no significant differences in urinary volume, creatinine, sodium, citrate, urea nitrogen, phosphate, or calcium excretions, nor was a significant difference found in the Tiselius index for calcium oxalate. Analyses of variance of daily oxalate, potassium, magnesium, and uric acid excretions were significant (P <.05). There was a significant decrease in oxalate, magnesium, and potassium excretions between the selfselected diet and both controlled diet phases (P <.05) but no significant difference between the controlled diet phases before and after fish oil supplementation (Table 2). Uric acid excretion was significantly higher on the controlled diets compared with the self-selected diet (<0.05); however, there were no differences between the controlled diet phases with and without fish 780
oil supplementation. Table 2 lists the mean analyte excretion during each study phase.
COMMENT A number of investigators have reported that the administration of fish oil supplements promotes a reduction in urinary oxalate excretion. Buck et al8 treated 12 recurrent hypercalciuric stone formers with 1800-mg EPA and 1200-mg DHA daily for 8 weeks. Urinary calcium and oxalate excretions significantly decreased after administration of fish oil supplements, but the diets were not controlled in this study. Baggio et al7 noted that urinary calcium and oxalate excretions declined in a study in which 24 recurrent calcium oxalate stone formers ingested 850 mg of omega-3 fatty acid ethyl esters 3 times daily for 30 days. Again, dietary components were not strictly controlled in this study. Siener et al9 studied 15 healthy subjects who consumed a standardized diet for 5 days, a self-selected diet for 20 days, and a standardized diet again for 5 days. Each participant took 900-mg EPA and 600-mg DHA daily for the last 25 days of the study. The average standardized diet consisted of 2237 kilocalories, 68-g protein, 297-g carbohydrate, 83-g fat, 35-g fiber, 3502mg potassium, 982-mg calcium, 359-mg magnesium, 2085-mg sodium, 1220-mg phosphorus, 197-mg oxalate, and 3734-mL fluid daily. Results revealed significantly decreased oxalate excretion (13%) and urinary calcium oxalate supersaturation. Similar to the findings of our study, calcium excretion was not significantly affected. Our results suggest that fish oil supplementation does not have a profound effect on the contribution of endogenous oxalate synthesis to the urinary oxalate pool in healthy individuals with normal baseline urinary oxalate excretion. It could be that the mechanisms proposed by Siener et al, alterations in renal secretion of oxalate or a reduction in net gastrointestinal oxalate absorption, are valid.9 Perhaps, the responses would be different in a diseased cohort. Our subjects may have had low levels of oxidative stress. Their urinary analyte profile while on a self-selected diet is reflective of healthy eating habits as indicated by higher urinary potassium and magnesium excretion. The response may have been different in calcium oxalate stone formers, especially those with increased oxalate excretion or increased oxidative stress. Therefore, similar studies should be considered in such subjects. We recognize that our study has certain limitations. Our cohort size was relatively small, but the number is comparable to that of Siener et al.9 In addition, we measured neither the plasma levels of fatty acids in red blood cell membranes to assess compliance with the fish oil supplement regimen nor the markers of oxidative stress.
CONCLUSION It appears that fish oil supplementation does not reduce endogenous oxalate synthesis in healthy nonestoneforming subjects. UROLOGY 84 (4), 2014
Table 2. Mean urinary analyte excretion Parameter
Self-selected Diet (Mean St Dev)
Volume (mL/d) Creatinine (mg/d) Sodium (mg/d) Potassium (mg/d) Calcium (mg/d) Magnesium (mg/d) Citrate (mg/d) Uric acid (mg/d) Urea nitrogen (mg/d) Phosphate (mg/d) Oxalate (mg/d) Tiselius index for CaOx
2268 1534 3167 2980 143 89 447 548 10,849 892 33 0.84
826 468 1054 1288* 58 31* 320 154* 3230 312 10* 0.45
Controlled Diet 1 (Mean St Dev) 2012 1759 2785 2312 119 71 406 621 10,842 924 26 0.63
397 435 740 599 44 18 169 173 2199 336 6 0.33
Controlled Diet 2 (Mean St Dev) 2103 1682 2834 2135 141 74 333 675 11,548 984 26 0.72
307 475 857 580 51 20 131 162 2456 248 5 0.28
P Value .41 .21 .30 <.01 .16 .04 .18 .02 .32 .28 <.01 .06
St Dev, standard deviation. * Statistically significant difference from controlled dietary phases.
References 1. Coe FL, Parks JH, Asplin JR. The pathogenesis and treatment of kidney stones. N Engl J Med. 1992;327:1141-1152. 2. Curhan GC, Willett WC, Knight EL, et al. Dietary factors and the risk of incident kidney stones in younger women: Nurses’ Health Study II. Arch Intern Med. 2004;164:885-891. 3. Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of followup. J Am Soc Nephrol. 2004;15:3225-3232. 4. Curhan GC, Willett WC, Speizer FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997; 126:497-504. 5. Curhan GC, Taylor EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 2008;73:489-496. 6. Holmes RP, Goodman HO, Assimos DG. Contribution of dietary oxalate to urinary oxalate excretion. Kidney Int. 2001;59:270-276. 7. Baggio B, Gambaro G, Zambon S, et al. Anomalous phospholipid n-6 polyunsaturated fatty acid composition in idiopathic calcium nephrolithiasis. J Am Soc Nephrol. 1996;7:613-620. 8. Buck AC, Davies RL, Harrison T. The protective role of eicosapentaenoic acid [EPA] in the pathogenesis of nephrolithiasis. J Urol. 1991;146:188-194. 9. Siener R, Jansen B, Watzer B, et al. Effect of n-3 fatty acid supplementation on urinary risk factors for calcium oxalate stone formation. J Urol. 2011;185:719-724. 10. Knight J, Assimos DG, Easter L, et al. Metabolism of fructose to oxalate and glycolate. Horm Metab Res. 2010;42:868-873.
EDITORIAL COMMENT Urinary stone diseases include a number of different and distinct phenotypes,1 so that understanding the etiologies of “stone disease” is an ongoing and complex research program.2 However, a great many stone formers can benefit from simple changes to diet that reduce the levels of urine supersaturation for the mineral(s) that they deposit in their stones.3 In 2011, Siener et al showed that the addition of n-3 fatty acids (which are characteristically high in fish oil) to the diet of healthy subjects led to a reduction in the urinary excretion of oxalate, with a concomitant lowering of the supersaturation level of oxalate in the urine.4 They proposed that this change might have been caused by the increased incorporation of n-3 fatty acids into plasma membranes of epithelial cells, so that oxalate transport is altered in the intestine and kidney. UROLOGY 84 (4), 2014
This hypothesis—that alteration of the fatty acid composition of membranes will itself alter oxalate handling in the body—is also supported by the work of Baggio et al, who reported an apparent anomaly in the fatty acid composition of membranes from calcium stone formers.5,6 They proposed that this abnormal composition of plasma membranes leads to alteration in the transport of oxalate (and of calcium) so that such persons are prone to the formation of calcium oxalate stones.7 Thus, in the study by Siener et al, they supported this general concept by showing in a carefully controlled study that dietary alterations in fatty acids can alter oxalate excretion. However, oxalate excretion is not the product solely of diet and epithelial transport; an important proportion of oxalate in the urine comes from metabolism of other substances.8 This means that the effect of n-3 fatty acids on oxalate excretion could be due to an alteration of oxalate synthesis in the body, rather than an effect on oxalate transport in the intestine and kidney. In the present study, the effects of fish oil supplementation on endogenous oxalate synthesis were studied in subjects on a very low-oxalate diet. They showed no alterations in oxalate excretion with n-3 fatty acid supplementation, suggesting that changing dietary fatty acid does not alter endogenous oxalate metabolism. Thus, the changes reported by earlier studies may well be due to some relationship between fatty acid composition of membranes and oxalate transport. Little work has been done to identify the type of stone former that might benefit from fish oil supplementation, but dietary fatty acids have shown no correlation with stone formation in large cohort studies.9 Thus, if fish oil can help stone formers, it is likely to be the people whose disease is related to dietary oxalate. Some evidence suggests that the hard dark form of calcium oxalate monohydrate is almost always associated with some form of hyperoxaluria.10 About 30% of all stone formers make some or all of their stones with this kind of calcium oxalate.11 Could it be that such stone formers would benefit from taking fish oil supplements? Future work remains to be done. James C. Williams, Jr., Ph.D., Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN
References 1. Coe FL, Evan AP, Lingeman JE, Worcester EM. Plaque and deposits in nine human stone diseases. Urol Res. 2010;38:239-247.
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2. Williams JC Jr, McAteer JA. Retention and growth of urinary stones—insights from imaging. J Nephrol. 2013;26:25-31. 3. Penniston KL, Nakada SY. Diet and alternative therapies in the management of stone disease. Urol Clin North Am. 2013;40:31-46. 4. Siener R, Jansen B, Watzer B, Hesse A. Effect of n-3 fatty acid supplementation on urinary risk factors for calcium oxalate stone formation. J Urol. 2011;185:719-724. 5. Baggio B, Budakovic A, Nassuato MA, et al. Plasma phospholipid arachidonic acid content and calcium metabolism in idiopathic calcium nephrolithiasis. Kidney Int. 2000;58:1278-1284. 6. Baggio B, Gambaro G, Zambon S, et al. Anomalous phospholipid n-6 polyunsaturated fatty acid composition in idiopathic calcium nephrolithiasis. J Am Soc Nephrol. 1996;7:613-620. 7. Baggio B, Gambaro G. Abnormal arachidonic acid content of membrane phospholipids—the unifying hypothesis for the genesis of hypercalciuria and hyperoxaluria in idiopathic calcium nephrolithiasis. Nephrol Dial Transplant. 1999;14:553-555. 8. Holmes RP, Goodman HO, Assimos DG. Contribution of dietary oxalate to urinary oxalate excretion. Kidney Int. 2001;59:270-276. 9. Taylor EN, Stampfer MJ, Curhan GC. Fatty acid intake and incident nephrolithiasis. Am J Kidney Dis. 2005;45:267-274. 10. Daudon M, Jungers P. Clinical value of crystalluria and quantitative morphoconstitutional analysis of urinary calculi. Nephron Physiol. 2004;98:31-36. 11. Daudon M. Analyse et classification des calculs: contribution a l’etiologie de la maladie lithiasique [Analysis and classification of calculi: contribution to the etiology of calculous disease]. Rev Med Suisse Romande. 2004;124:445-453.
alteration of cell membranes and thus oxalate transport. The mechanism of this response is not completely understood. Our study attempted to further refine our knowledge of this relationship by investigating the effect of omega-3 fatty acids specifically on endogenous oxalate production. Our results revealed that omega-3 fatty acid supplementation does not appear to decrease this production. Thus, we agree that future research may be best focused on the relationship of fatty acids to dietary oxalate intake and patients with hyperoxaluria. Determining the predominant type of calcium oxalate crystal in stones in an effort to guide dietary therapy is of interest but may prove difficult to validate. Jessica N. Lange, M.D., Wake Forest Baptist Health, Winston-Salem, NC Patrick W. Mufarrij, M.D., George Washington University Medical Center, Washington, DC Linda Easter, R.D., Wake Forest Baptist Health, WinstonSalem, NC John Knight, Ph.D., Ross P. Holmes, Ph.D., and Dean G. Assimos, M.D., University of Alabama-Birmingham Medical Center, Birmingham, AL
http://dx.doi.org/10.1016/j.urology.2014.04.053 UROLOGY 84: 781e782, 2014. 2014 Elsevier Inc.
REPLY We agree that the work of Siener et al1 and Baggio et al2 has laid the foundation of our knowledge regarding fish oil supplementation and oxalate excretion. Our study attempted to build on their results, which showed that omega-3 fatty acid supplementation reduces urinary oxalate excretion likely through
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References 1. Siener R, Jansen B, Watzer B, et al. Effect of n-3 fatty acid supplementation on urinary risk factors for calcium oxalate stone formation. J Urol. 2011;185:719. 2. Baggio B, Gambaro G, Zambon S, et al. Anomalous phospholipid n-6 polyunsaturated fatty acid composition in idiopathic calcium nephrolithiasis. J Am Soc Nephrol. 1996;7:613.
http://dx.doi.org/10.1016/j.urology.2014.04.054 UROLOGY 84: 782, 2014. 2014 Elsevier Inc.
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