We have found an association between sugar-sweetened sodas and albuminuria, which is a marker of early kidney damage. To our knowledge, this is the first report of such an association. In the United States, sugary sodas are predominantly sweetened with high fructose corn syrup 
. Over the past 30 years, both the availability of HFCS 
and sugary soft drink consumption 
have risen markedly. The prevalences of obesity, diabetes, and ESRD have all followed these trends; shows the temporal correlation of ESRD due to diabetes with calories due to high fructose corn syrup and soda consumption 
. While ESRD rates prior to 1992 may have risen due to better recognition and expanding treatment by renal replacement therapy, more recent trends likely reflect genuine increases in kidney failure 
. Because there are many unobserved characteristics that also change over time, inferring causation from correlated trends is problematic. Nevertheless, the finding of an individual-level association between sugary soda consumption and albuminuria are consistent with the hypothesis that HFCS is contributing to the kidney disease epidemic 
. We note that neither diet soda nor moderate intake of one serving of sugary soda was associated with albuminuria in this study.
U.S. trends in total sugar availability, High Fructose Corn Syrup (HFCS) availability, soft drink consumption, and incident diabetic end-stage renal disease (ESRD) over time.
The strongest associations were seen among those with lower body weight and females. It is not clear why females should be more susceptible to sugary soft drinks than males. Women were much less likely to consume 2 or more sugary drinks per day, eliminating residual confounding as an explanation. Women are also more likely to under-report (and men more likely to over-report) their energy intake according to perceived social norms 
. Such misclassification may differentially bias results toward the null, because the absolute degree of under- or over-reporting differs by gender. Biological differences, such as lower energy intake need among women, might also account for the interaction of consumption and gender. However, this interaction was not an artifact of using gender-specific albuminuria cutpoints, because when we used log urinary albumin as the dependent variable, we still found significant interaction between gender and sugary soda consumption.
Optimal body weight may increase susceptibility because obesity is a competing mechanism by which sugar consumption could cause kidney damage 
. If subjects are already obese, and their albuminuria is due to obesity, then any additional effects of sugary sodas would be attenuated. Alternatively, differential reporting may account for the apparent lack of association among the overweight and obese, as food intake is more likely to be underreported as BMI increases and body image satisfaction decreases 
. Nevertheless, underreporting by BMI is not supported by these data, as evidenced by the lack of a significant association between BMI categories and sugary soda consumption within quartiles of energy intake ().
Our results suggest that fructose may be nephrotoxic via pathways other than diabetes, long-term blood glucose level, hypertension, or obesity, because adjusting for these potential mediators did not eliminate the association. We caution that mediator-adjusted models are not causal models, and they rarely meet the conditions necessary to accurately identify independent effects of the main exposure 
. Nevertheless, were these factors to truly explain our findings, we should have seen greater attenuation of the odds ratio than we did. It may be that fructose causes both kidney damage and obesity in parallel. Although fructose has not been directly linked to kidney disease, Johnson and Nielson have speculated that it may be directly pathogenic to human kidneys 
. The results are consistent with laboratory studies implicating fructose in rat models of kidney disease 
. Johnson hypothesized that fructose – kidney associations may be explained by uric acid 
. However, adjustment for uricemia did not attenuate this association in our study. Identification of pathways leading from albuminuria to kidney damage would strengthen the case for the observed association being a causal one.
Recent reports have shown that fructose consumption in the form of soft drinks increases the risk of kidney stones and gout 
, which suggest a link between soda consumption, high fructose corn syrup, and chronic kidney disease. Diet sodas have also been associated with the development of metabolic syndrome 
, which is itself a risk factor for CKD, although we did not find an association. We know of just one prior study directly examining soda consumption and kidney disease. Saldana and colleagues conducted a case-control study of 465 newly diagnosed chronic kidney disease patients in North Carolina, comparing their carbonated beverage consumption to 467 community controls 
. They found an association between sugar-sweetened and diet colas with CKD, but not non-cola carbonated beverages. Our study differs from theirs in several respects. First, we used albuminuria as the outcome variable rather than diagnosed CKD. Albuminuria is a subclinical condition that may appear years before diagnosed CKD, and CKD may follow pathophysiological pathways that do not involve albuminuria. Second, the focus of Saldana's analysis was on carbonated beverages and cola consumption, not sugary soft drinks. They found similar odds ratios of sugar-sweetened and diet colas with CKD, while we found an association only with sugar-sweetened sodas, but not diet colas or other diet sodas. Third, they asked subjects to recall average adult beverage consumption prior to 1980, while NHANES was a cross sectional study that employed a 24-hour recall instrument. Studies relying on retrospective recall may yield biased results 
, although Saldana and colleagues discount the possibility of differential recall because data were collected before researchers suspected cola consumption might be linked to kidney disease. Another potential reason for the differences in findings is that carbonated beverages were overwhelmingly sweetened with sucrose in the early 1980s 
, perhaps accounting for Saldana's finding of similar associations between sugar-sweetened and diet cola beverages; in contrast, HFCS was in wide use when our study was conducted (see ) 
. Finally, our study used nationally representative data, while theirs was confined to hospital patients and community controls in North Carolina.
Several limitations must be noted. First, this study was cross-sectional, precluding us from observing longitudinal associations. In particular, we could not determine if the complex interaction between BMI, soda consumption, and albuminuria was confounded by processes such as wasting associated with chronic disease 
. Second, the NHANES surveys employ a 24 hour dietary recall and did not have measurement of diet over time, which may have led to underreporting of intake by obesity status. However, 24 hour recall provides valid estimates of group-average dietary intake 
. Third, we did not have a direct measurement of intake of HFCS, which is ubiquitous in the American diet. If HFCS is the salient exposure, and non-consumers of sugary sodas have significant intake of HFCS from other sources, then we may have misclassified people by using soda consumption, underestimating the true effect. Fourth, albuminuria was assessed using a single specimen. In a random population-based sample (including non-diabetics), microalbuminuria persist in only 61% of participants with a single positive result 
. Nevertheless, albuminuria persistence should be non-differential with respect to soda consumption, making the results reported here underestimates. Finally, tastes serve as markers of social class 
, suggesting that soda consumption is linked to myriad lifestyle factors that have not been fully captured here. This leaves open the possibility that these results are due to residual confounding, a problem generic to nutritional epidemiology studies. Understanding why sugary soda drinkers consume these beverages, while others do not, would improve both control of confounding, and potentially lead to more successful interventions.
In spite of these limitations, several strengths deserve mention. First, we used nationally representative data drawn from the NHANES surveys, yielding population-based measures of association that are generalizable to the general population, including racial and ethnic minorities. Second, because we had over 9,000 subjects and over 1,000 cases, we could explore effect measure modification (interactions) and estimate associations within subgroups of participants. Third, the richness of the NHANES dataset allowed us to adjust for a host of potential confounders and mediators, and associations with sugary soda consumption remained elevated even after adjusting for these factors. We conducted several sensitivity analyses, including modeling the log of albumin excretion, use of energy intake to define soda consumption, and adjustment for overall energy intake and basal metabolic rate. The associations were robust to different definitions of exposure, outcome, and adjustment factors. Finally, we found that the association of sugary soda consumption with eGFR below <45 ml/min/1.73 m2
was stronger than the association with albuminuria, which may reflect an association with more advanced chronic kidney disease 
In conclusion, we have found that sugary soft drink consumption is associated with albuminuria. While these results are consistent with prior knowledge, they can only suggest that HFCS plays a causal role in kidney disease. Longitudinal studies, with measures of HFCS and other sugar consumption, are needed to formally test this hypothesis. At this point in time, policy recommendations regarding soda consumption or HFCS would be premature. Our findings should be seen in the context of disparate associations with CKD and metabolic syndrome that have recently been found for colas (but not sugary non-colas) and diet sodas 
. Additional study is needed before we may determine whether these findings are due to unmeasured lifestyle factors, other residual confounders, or truly causal associations.