Effect of Being Overweight on Urinary Metabolic Risk Factors for Kidney Stone Formation

Linda Shavit; Pietro Manuel Ferraro; Nikhil Johri; William Robertson; Steven B. Walsh; Shabbir Moochhala; Robert Unwin

Disclosures

Nephrol Dial Transplant. 2015;30(4):607-613. 

In This Article

Discussion

The present study analysed a large data set of stone formers attending a metabolic stone clinic over almost two decades. OW was highly prevalent and actually represents the largest subgroup of this population. Not unexpectedly, gradual and significant increases in prevalence of diabetes, hypertension and gout were detected in OW and obese patients. Our study demonstrated multiple alterations in metabolic urinary profiles in OW KSF that are associated with increased overall risk of stone formation. These main risk factors appear to be due to raised urinary excretion of uric acid and sodium, higher prevalence of hypercalciuria and more acidic urine. Moreover, urinary volume, citrate and magnesium excretion were not influenced by higher BMI, leading to an imbalance between promoters and inhibitors of lithogenesis in the urine of even modestly obese KSF. Notably, our study demonstrated a significantly increased proportion of uric acid, but not calcium oxalate stones in the OW KSF. In addition, we established that OW KSF present with urinary metabolic parameters that are similar to those detected in overtly obese patients, while the prevalence and severity of biochemical alterations positively correlate with increasing BMI. Therefore, the same factors affect urinary lithogenic potential in OW KSF, putting these patients at considerable risk for recurrent stone formation.

Several previous studies have addressed the effect of obesity on urinary stone risk factors. Powell et al.[11] found higher excretion rates of calcium, oxalate and uric acid, and lower urine pH in obese KSF, along with higher urinary citrate excretion and urine volume. However, in this large study, obesity was defined as weight >120 kg in males and >100 kg in females. Therefore, the effect of modest overweight on urinary parameters cannot be determined. Subsequently, Taylor and Curhan[2] performed 24-h urine studies on subsets of three large cohort studies (NHS I and II and HPFS), including subjects with and without a history of kidney stone disease. In this study, each cohort was divided into quintiles of BMI. Similar to our findings, higher BMI positively correlated with higher urinary excretion rates of oxalate, sodium, uric acid and phosphorus, as well as a lower urine pH. Gender-related differences in urinary lithogenic parameters have been shown in several studies that investigated obese KSF. A study by Siener et al.[12] revealed a significant positive relationship between BMI and urinary uric acid, sodium, ammonium and phosphate excretion, and an inverse correlation between BMI and urinary pH in both men and women; whereas BMI was associated with urinary oxalate excretion only among women and with urinary calcium excretion only among men. Eisner et al.[13] reported increasing urine sodium and decreasing pH in men and increasing urine uric acid, sodium, and decreasing urine citrate in women.

Moreover, the contribution of dietary factors to the risk of kidney stone formation has been demonstrated by several studies. For example, consumption of a DASH-style diet rich in fruits and vegetables, moderate in low-fat dairy products, and low in animal protein, has been reported to be associated with a marked decrease in the risk of incident kidney stones.[14] This positive effect appears to be mainly due to increasing urinary citrate excretion and urine volume.[15] In addition, the higher DASH scores are also associated with higher 24-h urinary excretions of potassium, magnesium, sulfate and phosphate, and higher urinary pH values due to the higher levels of alkali, potassium, magnesium and phosphorus that are consumed in fruits, vegetables and nuts. Furthermore, consumption of different beverages has been associated with a different incidence of kidney stones. Intake of sugar-sweetened soda and punch is associated with a higher risk of stone formation, whereas coffee, tea, beer, wine and orange juice are associated with a lower risk.[16] Despite these findings, our study failed to demonstrate any statistically significant associations between urine parameters and stone composition with the dietary covariates of intake of fluid, calcium, magnesium, oxalate, animal protein and sodium.

Although we could not demonstrate a significant association between dietary intakes and urinary metabolic abnormalities, higher excretion of urinary oxalate in OW patients has been detected by univariate analysis. While diet has been suggested to play a major role in idiopathic hyperoxaluria, studies have provided evidence that intestinal hyperabsorption of dietary oxalate, rather than the quantity of the ingested oxalate, is a major risk factor for hyperoxaluria.[17,18] A significant relationship has been demonstrated between dietary intake of ascorbic acid, a precursor of oxalate, and urinary oxalate excretion in stone formers.[19,20] However, controversy remains about whether the increased urinary oxalate is attributable to increased intestinal absorption of oxalate or to endogenous metabolism of absorbed ascorbate, or whether a high ascorbate intake is a marker for a high consumption of oxalate-rich fruits and vegetables. Moreover, an insufficient supply of calcium seems to play an important role. Obesity has been shown to be associated with an increased oxalate excretion, although the exact mechanism is still unclear.[11] Obesity-related alterations in the gut microbiome leading to decreased or lack of intestinal colonization by oxalate-degrading Oxalobacter formigenes can represent a possible pathological pathway resulting in increased intestinal oxalate absorption in OW KSF.[21,22] However, there are no current studies specifically addressing this issue. In the present study, the link between nutritional status, as reflected by BMI, and hyperoxaluria was confirmed by univariate, but not multivariate analysis.

OW KSFs in our study showed increased prevalence of features of the 'metabolic syndrome': in addition to obesity, they present with a proportionally higher predominance of diabetes, hypertension and dyslipidaemia. Recent evidence suggests that the metabolic syndrome is associated with a significantly higher frequency of nephrolithiasis. Potential pathogenic links between the two conditions include metabolic factors that promote insulin resistance, as well as stone formation in urine, environmental factors such as diet, oxidative stress and inflammation and molecular changes affecting the transport of some analytes in urine.[23] Our study demonstrates that being even modestly overweight is associated with the metabolic syndrome and increased excretion of urinary lithogenic factors, and it supports the evidence that metabolic syndrome-related nephrolithiasis can be considered to be a multifactorial systemic disorder needing a multidisciplinary approach for its prevention and management.

While higher BMI is a surrogate marker of body fat mass, the role of body composition (lean mass and fat mass) on the urine metabolic profile is of some interest. Studies have provided evidence that lean mass seems to significantly influence urine composition, both in terms of lithogenesis promoters and inhibitors, while fat mass does not.[24] Moreover, both muscularity and adiposity (measured by BMI) seem to have a modest, but significant impact on urinary pH in young adults; however, fat mass did not affect urinary pH in the elderly.[25] In addition, the significance and magnitude of the 24-h urine chemistry abnormalities appear to differ by age and gender, a finding that also points towards the possibility that body composition, rather than just BMI, contributes to these alterations.[26]

In our study, a large proportion of patients had biochemical stone analyses that clearly demonstrated that OW KSF, similar to obese patients, have a significantly higher prevalence of uric acid stones and a lower prevalence of calcium phosphate stones, a finding that is in keeping with patients having a more acid urine. Consistent with this are the Psf values calculated for the whole cohort that showed an increased risk for uric acid stone formation, along with a lesser risk for calcium phosphate stones. Generally, Psf represents an overall measure of the risk of forming five different types of stones, ranging from pure uric acid to calcium phosphate, including mixtures with urate and oxalate, and it calculates the risk of stone formation on a probability scale from 0 (improbable) to 1 (highly probable).[9,10] The technique combines small 'abnormalities' in urine biochemistry that by themselves are not outside the normal range, and so may not seem significant as an individual risk factor, although their particular combination can make the Psf value high because of the additive effect of small differences in measured parameters. In the recurrent KSFs, the higher the value of Psf, the greater is the severity of the disorder when defined by the average number of stone episodes experienced by a given patient per year over a long period of observation. Our study clearly demonstrated an association between OW and higher Psf for uric acid and calcium oxalate, which is consistent with the urinary metabolic abnormalities and stone composition (higher prevalence of hypercalciuria, hyperuricosuria and uric acid stones).

Our study has some limitations. First, it was based on observational data and we cannot rule out all known or unknown confounding factors to explain our results. Second, we evaluated only KSF without a control non-KSF group. Third, sources of potential error include over-collection or under-collection of 24-h urine specimens; although there is little reason to believe that participants with larger body size are more likely to provide inaccurate 24-h urine collections. Moreover, the observed relation between BMI and urinary creatinine excretion was as expected. However, our study does have the advantage that it investigated a large data set of UK stone formers with a high prevalence of overweight and obesity. We were also able to record dietary intake in a large subset of patients with biochemical stone analyses and calculated Psf values, and we could evaluate the relation between body size and urine composition.

In conclusion, our study focused on overweight (OW) KSF and demonstrated that even a slight increase in BMI is associated with multiple and marked differences in urine composition, and that these differences are similar to those found previously in obese patients. Our finding is of some importance, because of the increasing prevalence of OW and kidney stones in developed and developing countries, and that renal stone disease is emerging as a risk factor for both cardiovascular disease (CVD) and chronic kidney disease (CKD).[27,28] Therefore, appropriate evaluation and follow-up is warranted in OW and modestly obese patients, especially those with a history of KSF, due to their increased risk of forming kidney stones. Recommendation and adherence to a DASH-style diet may have a positive effect on urinary composition, as well as reducing CVD risk, and potentially CKD. However, whether modest weight loss in OW KSF will have a favourable impact on their metabolic urinary profiles and diminish their risk of further stone formation needs to be tested.

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