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Nearly one-third of patients with calcium stones have hyperuricosuria. In vitro studies and clinical trials have investigated the relationship between uric acid and calcium stones, but the association between hyperuricosuria and calcium stone formation in patients is still being debated. Uric acid appears to cause salting out of calcium oxalate in human urine. However, the importance of this in vitro phenomenon to the proposed association is not supported in cross-sectional observational studies. A small placebo-controlled randomized clinical trial showed that allopurinol decreased the rate of recurrent calcium oxalate calculi in patients with hyperuricosuria and normocalciuria. An assessment of the effect of combination therapy of allopurinol with indapamide showed no additive effect. Allopurinol may have antioxidant effects that are responsible for its reducing calcium stone formation, which are independent of xanthine oxidase inhibition. In addition, a newer xanthine oxidoreductase inhibitor, febuxostat, may also be effective in the prevention of calcium stones, as it reduces urinary uric acid excretion.

INTRODUCTION: and Objectives: To examine kidney stone disease as a potential risk factor for chronic kidney disease (CKD), end-stage kidney disease and treatment with dialysis (ESKD). METHODS: The National Health and Nutrition Examination Survey (NHANES 2007-2010) database was interrogated for patients with a history of kidney stones. Demographics and comorbid conditions including age, sex, body mass index (BMI), diabetes, hemoglobin A1c, hypertension, gout and smoking were also assessed. Multivariate analysis adjusting for patient demographics and comorbidities was performed to assess differences in the prevalence of CKD and treatment with dialysis between the two groups. History of nephrolithiasis was assessed by the question "Have you ever had kidney stones?" CKD was defined as patients with either an eGFR of < 60 mL/min/1.73 m2 or a urinary albumin to creatinine ratio >30 mg/g or both. Statistical calculations were performed using Stata software (StataCorp LP, Texas) with determinations of p-values and 95% confidence intervals where appropriate. RESULTS: The study included an analysis of 5,971 NHANES participants for whom data on CKD and kidney stones was available, of whom 521 reported a history of kidney stones. On multivariate analysis, a history of kidney stones was associated with CKD and treatment with dialysis (OR 1.50 (1.10-2.04) p= 0.013, and 2.37 (1.13- 4.96) p=0.025). This difference appeared to be driven by women, where a history of kidney stones was associated with a higher prevalence of CKD (OR 1.76 (1.13-2.763) p=0.016) and treatment with dialysis (OR 3.26 (1.48-7.16) p=0.004). There was not a significant association between kidney stone history and CKD or treatment with dialysis in men. CONCLUSIONS: Kidney stone history is associated with an increased risk of CKD and treatment with dialysis among women even after adjusting for co-morbid conditions. Large-scale prospective studies are needed to further characterize the relationship between nephrolithiasis and CKD.

OBJECTIVE: To assess the effectiveness of l-cystine dimethyl ester (CDME), an inhibitor of cystine crystal growth, for the treatment of cystine urolithiasis in an Slc3a1 knockout mouse model of cystinuria. MATERIALS AND METHODS: CDME (200 mug per mouse) or water was delivered by gavage daily for 4 weeks. Higher doses by gavage or in the water supply were administered to assess organ toxicity. Urinary amino acids and cystine stones were analyzed to assess drug efficacy using several analytical methods. RESULTS: Treatment with CDME led to a significant decrease in stone size compared with that of the water group (P = .0002), but the number of stones was greater (P = .005). The change in stone size distribution between the 2 groups was evident by micro computed tomography. Overall, cystine excretion in urine was the same between the 2 groups (P = .23), indicating that CDME did not interfere with cystine metabolism. Scanning electron microscopy analysis of cystine stones from the CDME group demonstrated a change in crystal habit, with numerous small crystals. l-cysteine methyl ester was detected by ultra-performance liquid chromatography-mass spectrometer in stones from the CDME group only, indicating that a CDME metabolite was incorporated into the crystal structure. No pathologic changes were observed at the doses tested. CONCLUSION: These data demonstrate that CDME promotes formation of small stones but does not prevent stone formation, consistent with the hypothesis that CDME inhibits cystine crystal growth. Combined with the lack of observed adverse effects, our findings support the use of CDME as a viable treatment for cystine urolithiasis.

Introduction: We assessed (1) the differences in the function of urinary proteins between children with cystinuria and kidney stones (CYS), and healthy controls (HC), and (2) the presence of diagnostic biomarkers for CYS. Material and methods: We compared urinary proteomes of 2 children with CYS and 2 age- and gender-matchedHC, using liquid chromatography-mass spectrometry (LC-MS/MS). Relative protein abundance was estimated using spectral counting. Proteins of interest were selected using the following criteria: 1) >5 spectral counts; 2) >2-fold difference in spectral counts; and 3) <0.05 p-value for the Fisher's Exact Test. Protein function was analyzed using the DAVID online bioinformatics resource, and Cytoscape was used to investigate the key nodes of unique proteins. Results: Of the 623 proteins identified by proteomic analysis, 180 exhibited at least 2-fold difference between CYS and HC. Of those, 94 proteins were up-regulated in CYS, 26 of which were involved in response to wounding, 21 in inflammatory response, 18 in immune response, and 4 in cellular response to oxidative stress. 86 proteins were down-regulated in CYS, 26 of which were involved in cell adhesion. 140 proteins were found only in children with CYS, 33 of which met the selection criteria. Proteinprotein interaction modeling of CYS unique proteins identified actin, vimentin, heat shock 70 kDa protein (HSP70), inter-alpha-trypsin-inhibitor heavy chain (ITIH), and matrix metalloproteinase-9 (MMP-9) as the key nodes, proteins associated with fibrosis pathways. Conclusions: We provide proteomic evidence of oxidative injury, inflammation, wound healing and fibrosis in children with cystinuria and kidney stones. We speculate that oxidative stress and inflammation may cause remodeling via actin and vimentin pathways, leading to fibrosis. Additionally, we identified ITIH and MMP-9 as potential diagnostic biomarkers and novel therapeutic targets in CYS. These unique proteins merit further investigation