Abstract
Introduction:
Roux-en-Y gastric bypass (RYGB) is a bariatric surgical procedure that is associated with higher risk of kidney stones after surgery. We examined urine composition in 18 men and women before and after RYGB to examine differences in kidney stone risk.
Methods:
Three 24-hour urine collections were performed before and 1 year after RYGB. We analyzed mean urinary values for pre- and post-RYGB collections and compared men and women.
Results:
Seven men and eleven women completed pre- and post-RYGB urine collections. Pre-RYGB, men had higher calcium oxalate supersaturation (7.0 vs. 5.0, p=0.04) compared with women. Post-RYGB, women had higher urine calcium oxalate supersaturation (13.1 vs. 4.6, p=0.002), calcium phosphate supersaturation (1.04 vs. 0.59, p=0.05), and lower urine volumes (1.7 vs. 2.7L, p<0.001) compared with men.
Discussion/Conclusion:
There are important differences in urine composition by sex that may contribute to higher kidney stone risk in women after RYGB compared with men.
Keywords: calcium oxalate, nephrolithiasis
Introduction
Roux-en-Y gastric bypass (RYGB) is a bariatric surgical procedure that is highly effective in the management of morbid obesity, with significant weight loss and improvement in metabolic syndrome and cardiovascular outcomes.1,2 However, RYGB is also associated with higher risk of kidney stone formation after surgery with a multivariate hazards ratio of 2.13 compared to obese controls.3 The mechanisms for increased stone risk in RYGB patients are not completely understood. Most stones formed after bariatric surgery are calcium oxalate (CaOx) and RYGB patients who form kidney stones have higher urine CaOx supersaturation (CaOx SS) eight months post-operatively compared to those who do not form kidney stones.3 This is important because the risk of being a kidney stone former increases with higher levels of urine CaOx SS in men and women.4
Explanations for the higher CaOx SS and kidney stone risk after RYGB have focused on urine oxalate, which is often elevated in these patients.3,5,6 However, in a recent study comparing the same patients before and one year after RYGB there was no difference in mean urine oxalate levels in pre- versus post-RYGB patients.7 Levels of urine oxalate were high both before and after surgery, although only after surgery was urine oxalate correlated with steatorrhea. Stone risk was not assessed in this paper.
In order to determine if other stone risk factors are altered post-RYGB, we reviewed primary 24-hour urine data collected in the study described above, before and after surgery in 18 participants.7 We completed an analysis of the data focusing on differences in kidney stone risk after RYGB. We hypothesized that independent from urine oxalate there are other established urine stone risk factors,8,9 such as urine volume and citrate, that differ from pre- to post-RYGB and predict kidney stone risk.
Methods
Patient recruitment and data collection for this study have been previously described.7 In brief, patients were recruited from a bariatric surgery clinic prior to scheduled laparoscopic long-limb RYGB. Participants were started on daily vitamins, including 200mg of elemental calcium and 120mg of ascorbic acid and admitted to the clinical research center where they were continued on the supplements and provided meals similar to their home diet. Diet during the study was not controlled and participants were able to eat ad lib. Three consecutive 24-hour urine and stool collections were performed in the clinical research center. The same protocol was repeated 1 year after surgery. Urine collections were sent to Litholink (Chicago, IL) for measurement of urine chemistries. Our study is a secondary analysis of the pre- and post-RYGB 24-hour urine samples.
Statistics
We performed Wilcoxon rank-sum tests and to compare mean urinary values in the men for pre- to post-RYGB collections, in the women for pre- to post-RYGB collections, and to compare men and women in the post-RYGB collections. We used linear regression to evaluate predictors of calcium oxalate and calcium phosphate supersaturations. All statistical analyses were done using R (R Core Team 2019).
Results
Pre-RYGB
There were 7 men and 11 women who completed pre- and post-RYGB urine collections. Pre-RYGB, there were no differences by sex in age (52.6 vs. 50.4 years, p=0.58) or body mass index (BMI) (54.9 vs. 55.1 kg/m2, p=0.57). Men had higher caloric intake (4384 vs. 3845 Kcal/d, p=0.04). Men also had higher CaOx SS (7.0 vs. 5.0, p=0.04) and uric acid (UA) SS (1.1 vs 0.83, p < 0.009) compared with women pre-RYGB, translating into higher stone risk in men. There were no differences in urine volume or calcium excretion between men and women, but urine pH and citrate excretion were higher in women (Table 1)
Table 1.
Characteristics presented by sex and pre- and post- RYGB
| Urine Variable | Men (N=7) Pre-RYGB | Men (N=7) Post-RYGB | Women (N=11) Pre-RYGB | Women (N=11) Post-RYGB | p-value men vs. women pre-RYGB | p-value men vs. women post-RYGB |
|---|---|---|---|---|---|---|
| Creatinine (mg/d) | 2472 (397) | 2011 (480)† | 1751 (338) | 1244 (257) ‡ | <0.001 | <0.001 |
| SS CaOx | 7.0 (4) | 4.6 (2)$ | 5.0 (5.0) | 13.1 (14)‡ | 0.04 | 0.002 |
| SS CaP | 1.0 (1.0) | 0.59 (0.7) | 0.55 (0.59) | 1.04 (1.0)$ | 0.39 | 0.02 |
| SS UA | 1.1 (0.6) | 0.53 (0.6)† | 0.83 (1.1) | 0.57 (0.5) | 0.009 | 0.51 |
| Volume (L/d) | 2.1 (0.8) | 2.7 (1.0)$ | 2.5 (1.0) | 1.7 (0.8)‡ | 0.15 | <0.001 |
| Calcium (mg/d) | 175 (113) | 113 (83) | 131 (91) | 130 (65) | 0.32 | 0.45 |
| Oxalate (mg/d) | 67 (13) | 99 (61) | 65 (38) | 71 (79) | 0.02 | 0.16 |
| Citrate (mg/d) | 697 (665) | 694 (431) | 1031 (378) | 650 (335)‡ | 0.004 | 0.69 |
| pH | 5.8 (0.5) | 6.1 (0.5)$ | 6.1 (0.5) | 6.3 (0.5) | 0.04 | 0.36 |
| Sodium (mmol/d) | 232 (106) | 245 (78) | 282 (76) | 176 (57)‡ | 0.14 | 0.001 |
| Potassium (mmol/d) | 75 (26) | 70 (19) | 66 (15) | 35 (16)‡ | 0.05 | <0.001 |
| Magnesium (mg/d) | 142 (53) | 162 (45) | 107 (50) | 105 (42) | 0.01 | <0.001 |
| Phosphorus (g/d) | 1.51 (0.4) | 1.19 (0.4)$ | 1.05 (0.2) | 0.62 (0.2)‡ | <0.001 | <0.001 |
| Ammonium (mmol/d) | 52 (18) | 38 (11.1)† | 37 (14) | 31 (12)$ | 0.003 | 0.06 |
| Chloride (mmol/d) | 208 (95) | 223 (69) | 251 (63) | 153 (54)‡ | 0.13 | <0.001 |
| Sulfate (meq/d) | 63 (17) | 44 (11)‡ | 50 (10) | 27 (11)‡ | <0.001 | <0.001 |
| UUN | 18 (5) | 13 (7)‡ | 13 (2) | 8 (2)‡ | <0.001 | <0.001 |
| PCR | 0.78 (0.1) | 0.83 (0.2) | 0.75 (0.1) | 0.72 (0.2) | 0.39 | 0.04 |
| Uric Acid | 0.72 (0.2) | 0.59 (0.2) | 0.75 (0.2) | 0.47 (0.1)‡ | 0.47 | 0.01 |
| GI alkali absorption (meq/d) | 33 (32) | 42 (15) | 51 (25) | 36 (23)$ | 0.09 | 0.27 |
| Titratable Acid (meq/d) | 32.3 (9.5) | 21.6 (10)‡ | 19.8 (7.0) | 10.8 (6.0) ‡ | <0.001 | <0.001 |
Variables are presented in mean (standard deviation).
SS CaOx, calcium oxalate supersaturation; SS CaP, calcium phosphate supersaturation; SS UA, uric acid supersaturation; UUN, urea nitrogen; PCR, protein catabolic rate
, p<= 0.05 Comparing pre- vs. post-RYGB in men and women;
, p<= 0.01 Comparing pre- vs. post-RYGB in men and women;
, p<= 0.001 Comparing pre- vs. post-RYGB in men and women
Post-RYGB
Post-RYGB there were no differences by sex in BMI (36.4 vs. 36.8 kg/m2, p=0.58). Women had significantly higher urine CaOx SS (13.1 vs. 4.6, p=0.002) and calcium phosphate supersaturation (CaP SS) (1.04 vs. 0.59, p=0.05) after surgery than men (Table 1). Urine volumes were significantly lower in women (1.7 vs. 2.7L, p<0.001) compared with men post-RYGB, and there was a significant drop in urine volume after surgery in women but not men. Urine calcium, oxalate and citrate excretions did not differ between the sexes, but urine citrate fell markedly in women after surgery.
Predictors of supersaturation post-RYGB
Urine volume was most strongly associated with post-RYGB urine CaOx SS (−6.4 (−8.7 to −4.0) CaOx SS per 1 liter of urine volume excretion). Citrate was also associated with CaOx SS (−1 (−1.6 to −0.2) CaOx SS per 100 mg of citrate). Calcium and oxalate were not significantly associated with CaOx SS. For CaP SS, higher urine calcium and pH were associated with higher CaP SS (0.5 (0.4 to 0.6) CaP SS per 50 mg calcium and 1.3 (0.8 to 1.7) CaP SS per level of pH). Higher urine volume was associated with lower CaP SS (−0.4 (−0.6 to −0.10) CaP SS per 1 L urine volume), and citrate was not significant.
Serum Creatinine and Bicarbonate
There were 7 men and 9 women who completed pre- and post-RYGB blood collections. Serum creatinine decreased from pre-RYGB to post-RYGB for both men (0.99 vs 0.92 mg/dL, p=0.01) and women (0.90 vs. 0.74 mg/dL, p<0.001). Serum bicarbonate increased from pre-RYGB to post-RYGB in both men (25.8 vs. 27.8 mmol/L) and women (26.7 vs. 28.6 mmol/L, p=0.001).
Discussion
Women had higher CaOx and CaP SS post-RYGB (but not pre-RYGB) compared with men and this was largely driven by post-RYGB changes in urine volume and citrate. To our knowledge, this is the first study that has noted that differences in urinary risk factors for kidney stones after RYGB may differ by sex. Bariatric surgery is much more common in women10 and thus, any sex differences may not have been previously appreciated. Differences in diet or gut absorption between men and women, or a combination of the two, may have contributed to our observations of the urine volume and citrate changes, this suggests a need for additional studies in which the behaviors of men and women after RYGB are individually observed and could be compared.
Some of these differences we observed could have been due to diet. The patients were not on prescribed diets, but followed their usual dietary patterns during the study. Differences in urine volume and citrate could reflect deliberate diet choices that differ between the sexes. Both men and women had a reduction in body size and caloric intake from pre- to post-RYGB. This matter cannot be resolved within the present set of data and would require new research.
The lower urine volume and citrate may also be due to differences in gut absorption after RYGB. Salt and water are typically highly absorbed in the gut,11 however, there may be differences after a malabsorptive procedure, such as RYGB. In addition to citrate, GI alkali absorption overall fell in women, but not in men, suggesting the possibility of a change in gut alkali handling in women. There were no documented differences in surgical technique between men and women that would indicate potential risk of differences in absorption and the combined limb length was similar between the two sexes. Additionally, fecal fat, a marker of global malabsorption,12 increased in men and women post-RYGB but was higher in men compared with women in this study. It seems likely that both alterations in gut function and in diet are contributing to the observed differences in urine chemistry post-RYGB by sex.
Lastly, urine calcium and oxalate were not statistically associated with CaOx SS in our study but they are two primary contributors to CaOx SS13 and are independently associated with being a kidney stone former.9 Our analysis of this association may have been limited due to our small participant numbers. However, this also highlights that urine volume and citrate are important contributors to kidney stone risk after surgery. The patients in this study had not formed stones, and it is likely that only a subset of similar patients will go on to do so. However, this study makes clear that several factors that increase risk for stones, in addition to hyperoxaluria, are common after RYGB surgery, and these changes may be more common among women. Additional understanding of mechanisms for why these factors change after RYGB is crucial to understanding risk of kidney stones for these patients.
Our study has limitations. This was a small post-hoc analysis of data collected for a previous study. The participants were not on a controlled diet and thus, some differences may be a result of a systematic difference in diet between men and women post-RYGB. Due to our small sample size we were unable to do multivariate modeling.
Conclusion
Lower post-RYGB urine volume and citrate are important contributors to higher CaOx SS in women compared with men. These differences may contribute to differences in kidney stone risk after surgery. Additional study is needed to better understand mechanisms for why these differences exist.
Acknowledgements:
We would like to acknowledge Dr. Fred Coe for his overall support and guidance with data interpretation.
Funding: NIH 5KL2TR002387-04, NIH DKP0156788
Footnotes
Conflict of interest: No known conflicts of interest to disclose.
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