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Background: Kidney stone disease has traditionally been considered an isolated and benign condition. Recent adult literature has suggested an association between urolithiasis and cardio-vascular disease. These disease processes may share common pathways/risk factors that have not been fully identified. We assessed (1) the differences in the function of urinary proteins between children with kidney stones and hypercalciuria (Cal), hypocitraturia (Cit), normal metabolic work-up (NM), and healthy controls (HC), (2) the association of these proteins with cardiovascular disease, and (3) the common pathways shared by the proteins found in both kidney stone and cardiovascular disease .
Methods: We have performed a quantitative proteomic comparison of pooled urine between Cal, Cit and NM, and their age and gender matched HC (N=10), using liquid chromatography-mass spectrometry (LC-MS/MS). Relative protein abundance was estimated using spectral counting. Proteins of interest were selected based on patient/control abundance ratios of >5 or <0.2, and compared against the Genetic Association Database (GAD) via the DAVID online bioinformatics resource.
Results: Demographic characteristics of the patients are presented in Table 1. Of the 1816 proteins, 214 proteins were unique to Cal, 246 to Cit and 53 to NM. GAD/David analysis revealed a significant association with cardiovascular disease in Cal and Cit groups (Table 2). The majority of these proteins were involved in lipid metabolism and atherosclerosis (Apolipoprotein C-III, Apolipoprotein A-IV, Fatty acid-binding protein, adipocyte, Fatty acid-binding protein, liver), inflammation (fibrinogen and complement H), adhesion (vascular cell adhesion molecule), renin-angiotensin system (angiotensinogen), and oxidative stress (catalase and myeloperoxidase). Acute inflammatory response, classical and alternative complement activation, and immune response were significantly more represented in normal metabolic group.

	Hypercalciuria N=10	Hypocitraturia N=10	Normal Metabolic N=10
Gender (Male/Female)	4/6	2/8	2/8
Mean age ± SD (years) (Range)	11.64 ± 4.46 (5-17.4)	14.83 ± 2.61 (10.5-18.1)	12.37 ± 4.4 (5.8-17.7)
Race/Ethnicity Caucasian African-American Other	N=7 N=2 N=1	N=6 N=2 N=2	N=6 N=1 N=3
Urinary calcium (mg/kg/day) Mean± SD(range)	5.37 ± 1.57 (4.04-8.62)	2.41 ± 0.86 (0.7-3.86)	2.26 ± 0.83 (0.72-3.76)
Urinary citrate (mg/gr creatinine) Mean± SD(range)	865.98 ± 370.6 (361-1589)	263.6 ± 46.5 (170.6-384.7)	680.5 ± 113.2 (513-830.2)

Groups	GAD term	Number of Hits	P-Value
Cal	CARDIOVASCULAR*	19	0.0230
Cit	CARDIOVASCULAR**	18	0.0024

* Cardiomyopathy, Hypertension
** Myocardial infarction, Aneurysm
Conclusions: There are major differences in the function of urinary proteins isolated from each group, indicating a different mechanism for stone formation. There is proteomic evidence that hypercalciuric and hypocitraturic kidney stone is associated with cardiovascular disease. Further understanding of the pathophysiological link between urolithiasis and cardiovascular disease is necessary for developing new therapeutic targets.