Identification and local delivery of vasodilators for the reduction of ureteral contractions.

Kidney stones and ureteral stents can cause ureteral colic and pain. By decreasing contractions in the ureter, clinically prescribed oral vasodilators may improve spontaneous stone passage rates and reduce the pain caused by ureteral stenting. We hypothesized that ureteral relaxation can be improved via the local administration of vasodilators and other smooth muscle relaxants. Here, by examining 18 candidate small molecules in an automated screening assay to determine the extent of ureteral relaxation, we show that the calcium channel blocker nifedipine and the Rho-kinase inhibitor ROCKi significantly relax human ureteral smooth muscle cells. We also show, by using ex vivo porcine ureter segments and sedated pigs that, with respect to the administration of a placebo, the local delivery of a clinically deployable formulation of the two drugs reduced ureteral contraction amplitude and frequency by 90% and 50%, respectively. Finally, we show that standard oral vasodilator therapy reduced contraction amplitude by only 50% and had a minimal effect on contraction frequency. Locally delivered ureteral relaxants therefore may improve ureter-related conditions.

Impact of calcium intake and intestinal calcium absorption on kidney stones in older women: the study of osteoporotic fractures.

PURPOSE: Intestinal calcium absorption is thought to have a critical role in nephrolithiasis. However, to our knowledge no study has directly assessed this association. Therefore, we explored the relationship among intestinal fractional calcium absorption, calcium intake and nephrolithiasis. MATERIALS AND METHODS: The Study of Osteoporotic Fractures is a prospective cohort of 9,704 postmenopausal women recruited from population based listings in 1986 and followed for more than 20 years. Secondary analyses were performed of 7,982 women who reported their history of nephrolithiasis, of which 5,452 (68%) underwent an oral radioactive calcium assay (45Ca). The impact of dietary and supplemental calcium on intestinal fractional calcium absorption was evaluated, and factors independently associated with nephrolithiasis were determined. RESULTS: Fractional calcium absorption decreased with increased calcium intake, with no difference between dietary and supplemental calcium. Fractional calcium absorption was higher in women with a nephrolithiasis history among all calcium intake groups. Increased dietary calcium intake reduced the likelihood of nephrolithiasis by 45% to 54% (p=0.03). Women with a history of nephrolithiasis were less likely to supplement calcium (p<0.001). In adjusted analyses women who supplemented calcium were 21% to 38% less likely to have a nephrolithiasis history (p=0.007) and there was a 24% increased risk of kidney stones for each 10% increase in fractional calcium absorption (p=0.008). CONCLUSIONS: Fractional calcium absorption is higher in women with a history of nephrolithiasis. Higher intestinal fractional calcium absorption is associated with a greater risk of historical nephrolithiasis. Dietary and supplemental calcium decrease fractional calcium absorption, and may protect against nephrolithiasis.

Dietary therapy for patients with hypocitraturic nephrolithiasis.

Citrate is an inhibitor of urinary stone formation. Clinical and in vitro data suggest that increasing urine citrate levels will decrease the precipitation of calcium stones. Historically, low urinary citrate has been treated with oral potassium citrate or sodium citrate supplementation, but recent studies have shown the potential of dietary interventions to raise urine citrate levels. Dietary therapy with commercial or homemade beverages is attractive to patients who would prefer nonpharmacological intervention. To date, several drinks have shown promise but no single beverage has been found to consistently raise urine citrate levels in a reproducible fashion. Further research is necessary to develop the ideal dietary therapy for hypocitraturic calcium nephrolithiasis.

Citrate, malate and alkali content in commonly consumed diet sodas: implications for nephrolithiasis treatment.

PURPOSE: Citrate is a known inhibitor of calcium stone formation. Dietary citrate and alkali intake may have an effect on citraturia. Increasing alkali intake also increases urine pH, which can help prevent uric acid stones. We determined citrate, malate and total alkali concentrations in commonly consumed diet sodas to help direct dietary recommendations in patients with hypocitraturic calcium or uric acid nephrolithiasis. MATERIALS AND METHODS: Citrate and malate were measured in a lemonade beverage commonly used to treat hypocitraturic calcium nephrolithiasis and in 15 diet sodas. Anions were measured by ion chromatography. The pH of each beverage was measured to allow calculation of the unprotonated anion concentration using the known pK of citric and malic acid. Total alkali equivalents were calculated for each beverage. Statistical analysis was done using Pearson's correlation coefficient. RESULTS: Several sodas contained an amount of citrate equal to or greater than that of alkali and total alkali as a lemonade beverage commonly used to treat hypocitraturic calcium nephrolithiasis (6.30 mEq/l citrate as alkali and 6.30 as total alkali). These sodas were Diet Sunkist Orange, Diet 7Up, Sprite Zero, Diet Canada Dry Ginger Ale, Sierra Mist Free, Diet Orange Crush, Fresca and Diet Mountain Dew. Colas, including Caffeine Free Diet Coke, Coke Zero, Caffeine Free Diet Pepsi and Diet Coke with Lime, had the lowest total alkali (less than 1.0 mEq/l). There was no significant correlation between beverage pH and total alkali content. CONCLUSIONS: Several commonly consumed diet sodas contain moderate amounts of citrate as alkali and total alkali. This information is helpful for dietary recommendations in patients with calcium nephrolithiasis, specifically those with hypocitraturia. It may also be useful in patients with low urine pH and uric acid stones. Beverage malate content is also important since malate ingestion increases the total alkali delivered, which in turn augments citraturia and increases urine pH.

Changes in urinary stone risk factors in hypocitraturic calcium oxalate stone formers treated with dietary sodium supplementation.

PURPOSE: We investigated the effects of supplemental dietary sodium on risk factors for urinary stone disease in stone forming patients with hypocitraturia. MATERIALS AND METHODS: Ten patients diagnosed with recurrent isolated hypocitraturic calcium urolithiasis were identified. Baseline 24-hour urinalysis was performed with patients on their regular diet, including citrate replacement with 20 mEq potassium citrate 3 times per day. Strict daily dietary logs were kept for a 7-day period, during which patients had normal oral intake and potassium citrate replacement. Patients then received supplemental sodium chloride for 1 week (1 gm orally 3 times per day), in addition to their regular diets and potassium citrate supplementation. Dietary logs were continued and 24-hour urinalysis was performed at the end of 1 week of supplemental sodium. Risk factors for urinary stone disease were compared using the Student t test and ANOVA. RESULTS: Two patients were unable to comply with sodium supplementation based on 24-hour urinalysis and, therefore, they were excluded from study. The remaining 8 patients were analyzed. Patients on supplemental dietary sodium demonstrated significantly increased mean urinary voided volume (933 ml per day above baseline, p <0.05) and mean urinary sodium excretion (66 mEq per day above baseline, p <0.05). There was no statistically significant change in urinary calcium, oxalate or uric acid. The urinary supersaturation relative risk ratio decreased for calcium oxalate stones (0.93 vs 0.63, p <0.05), while those of brushite, struvite and uric acid were not different before vs after supplemental sodium. CONCLUSIONS: Dietary sodium supplementation resulted in an increased voided urine volume and decreased the relative risk supersaturation ratio for calcium oxalate stones in patients with a history of hypocitraturic calcium oxalate nephrolithiasis. Urinary calcium excretion as well as other urine parameters that are risk factors for nephrolithiasis was not changed. Sodium restriction may be inappropriate in patients with hypocitraturia and recurrent urinary stones. Sodium supplementation may be beneficial in these patients because it results in voluntary increased fluid intake.

Protecting the ureter during radiofrequency ablation of renal cell cancer: a pilot study of retrograde pyeloperfusion with cooled dextrose 5% in water.

PURPOSE: To describe early experience with cooled dextrose 5% in water (D5W) solution retrograde pyeloperfusion during radiofrequency (RF) ablation of renal cell carcinoma (RCC) within 1.5 cm of the ureter with respect to feasibility, safety, and incidence of residual/recurrent tumor in proximity to the cooled collecting system. MATERIALS AND METHODS: Between November 2004 and April 2007, 17 patients underwent 19 RF ablation sessions of RCCs within 1.5 cm of the ureter during cooled D5W pyeloperfusion (nine men, eight women; mean tumor size, 3.5 cm; mean age, 73 y; mean distance to ureter, 7 mm). RF ablation was performed with pulsed impedance control current. The records and imaging studies of patients treated with this technique were reviewed for demographics, indication, technique, complications, and tumor recurrence. RESULTS: All 19 RF ablation and ureteral catheter placement procedures were technically successful. No patient developed a ureteral stricture or hydronephrosis during a mean of 14 months of follow-up (range, 4-32 months). Three patients had residual tumor on the first follow-up imaging study, but all three tumors were completely ablated after a second RF ablation session. No complications or deaths occurred. No recurrent tumor was seen anywhere in the treated tumors, and there was complete ablation of the tumor margin in proximity to the collecting system. CONCLUSIONS: RF ablation of RCC within 1.5 cm of the ureter is feasible with cooled D5W retrograde pyeloperfusion and is not associated with reduced efficacy, ureteral injury, or early recurrence.