Sex Differences of Kidney Stone Urine Risk Factors after Roux-en-Y Gastric Bypass

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) 8 months postoperatively 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 1 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 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-h 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.

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 200 mg of elemental calcium and 120 mg 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-h 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-h urine samples.

We performed Wilcoxon rank-sum tests 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 CaOx and calcium phosphate supersaturations (CaP SS). All statistical analyses were done using R (R Core Team 2019).

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 BMI (54.9 vs. 55.1 kg/m², p = 0.57). Men had higher caloric intake (4,384 vs. 3,845 kcal/d, p = 0.04). Men also had higher CaOx SS (7.0 vs. 5.0, p = 0.04) and uric acid 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)

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 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. 2.7 L, 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.

Urine volume was most strongly associated with post-RYGB urine CaOx SS (−6.4 [−8.7 to −4.0] CaOx SS per 1 L 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.

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).

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 women [10], 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 2 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.

Last, urine calcium and oxalate were not statistically associated with CaOx SS in our study but they are 2 primary contributors to CaOx SS [13] 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.

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.

We would like to acknowledge Dr. Fred Coe for his overall support and guidance with data interpretation.

The authors have no conflicts of interest to disclose.

NIH 5KL2TR002387-04, NIH DKP0156788.

M.P. completed data analysis and interpretation, initial manuscript preparation, and manuscript review. J.A. contributed data interpretation support and manuscript review. A.C. contributed data interpretation support and manuscript review. E.W. contributed to data interpretation and manuscript review and editing.