AUA podium session on stone disease

Margaret Pearle and Dennis Venable moderated this very interesting session. (Abstract numbers follow the comments.)

J. Kyle Anderson and colleagues began by analyzing the “Effect of Calcium Carbonate Supplementation on Stone Forming Risk in Normal Subjects on a Liberal Oxalate Intake”. He reminded us that low calcium diets do not seem to prevent stones. Past studies in dietary supplementation with calcium implied that stone risk increased. They conducted a 2-phase randomized crossover study on a constant diet with calcium carbonate supplementation at 250 mg 4 times daily. Urine calcium did increase, oxalate did not change and citrate increased significantly. Overall, calcium oxalate saturation ratios did not change. Hence, such supplementation does not seem to increase stone risk. However, one attendee questioned the accuracy of the analysis of dietary oxalate performed and pointed out that bioavailability of oxalate from the diet may vary. #1036

M. R. Cooperberg and associates reviewed data on 339 patients with hyperparathyroidism who also received calcium supplementation. Of these, 21% had a history of stones. After their retrospective analysis, it appeared that such supplements actually lowered the risk of stone formation in these patients. However, on questioning, he noted that they did not have data on amounts or duration of calcium supplementation, and they could not predict when the effects became apparent. He summarized by stating “This is a hypothesis generating study.” #1037

David Kang with his co-workers discussed their findings after “Lemonade-based Dietary Manipulation in Patients with Hypocitraturic Nephrolithiasis”. He pointed out that taking prescription citrates can place a financial strain on the patient and may decrease compliance. So they retrospectively measured effects of lemonade supplementation that provided 5.9 gm citric acid from 2 liters of lemonade per 24 hours, and they documented a group of 12 patients followed for a minimum of 6 months. They compared this group with a matched group taking oral citrate tablets. In both groups, urinary citrate increased significantly, and in the lemonade group, rate of stone episodes and new stone formation decreased but did not reach significance. One could question whether some of the improvement came from increased urinary volume created by lemonade intake, but they stated that these volumes did not differ significantly between the groups. They recommend further prospective randomized studies on this subject. #1038

Effects of uricosuria on calcium oxalate stone formation remain controversial. Prior studies included patients on random diets. Pais et al tested whether 65 calcium oxalate stone formers showed hyperuricosuria while on 3 days of standardized formula diets with no uric acid content. They were compared to a similarly treated group of 61 age-matched non-stone formers by indexing urinary uric acid excretion to creatinine. Hyperuricosuria, under these conditions, was noted in 1-2% of stone formers and controls. Hence, it appears that previously noted differences were related to variable dietary intakes of uric acid precursors. #1039

Asplin and Coe reported their observations on urinary oxalate excretion in 132 patients who received some type of Bariatric Surgery in the recent years. In the past, jejuno-ileal bypass (JIB) was used, but it produced such great hyperoxaluria and calcium oxalate supersaturation that it was abandoned in 1979 or 1980. But they determined that even those treated by modern methods show levels of hyperoxaluria greater (83 mg/d) than that of stone formers (39 mg/d) or normals (34 mg/d). More importantly, their calcium oxalate supersaturation levels of 12.1 exceeded those of even JIB patients (8.9), stone formers (9.0) and, of course, normals (7.3). Hence, we must do prospective studies of stone formation in these patients. #1040

Williams, with others in the “Randall’s Plaque Study Group” presented their anatomic review of “Mapping the Precise Orientation of Attached Stones on the Renal Papilla”. They show that their studied calcium oxalate stones have attachment to the papilla via the calcium phosphate Randall’s Plaque, and that such plaques represent the initial nidus for formation of calcium oxalate stones. #1041

Sagi (presented by A. Haecker) and associates reported on their “New in vitro Model for cystinuria type I by RNAi transfection”. Their cell culture model should lead to further studies on possible gene therapy for cystinuria. #1042

 Koul and a number of co-workers presented their similar approach to “A Rational gene therapy for Primary Hyperoxaluria-1 (PH-1): Cloning, cellular transfection and sub cellular localization of AGT-GFP-fusion protein.” They were able to transfect AGT into hepatocyte cultures. They conclude by stating that “this is the first study to attempt recombinant AGT gene therapy for treatment of primary hyperoxaluria-1.” #1043

Once again, using cell cultures, Omekawa et al exposed confluent cultures of NRK52E cells to calcium oxalate monohydrate (COM) with or without pretreatment with diphenileneiodium chloride (DPI). They hypothesized that this latter agent would attenuate increased MCP1 (Monocyte chemotactic protein-1) production induced by COM. They also evaluated production of reactive oxygen species (ROS). Within this alphabet soup of abbreviations, they believe they showed that “generation of low concentration of ROS, possibly by NADPH oxidase, may represent a second messenger system for generation of COM induced MCP1 in the renal tubules.” #1044

Moving to animal models, Straub and his colleagues used micropuncture techniques in the rat model to investigate “The Role of Angiotensin 2 Receptor Subtypes in the Regulation of the Oxalate Transport in the Nephron”. They had already demonstrated that angiotensin 2 inhibited oxalate transport, resulting in higher urinary oxalate excretion. In this present experiment, they pretreated with AT1-receptor blocker Losartan® or the AT2 blocker PD123319. They measured luminal oxalate by micropuncture. Losartan® decreased transport but PD123319 increased transport. Hence, both receptor subtypes are involved in mediation of Angiotensin 2 renal oxalate transport. This knowledge may assist in future search for an “oxalate blocker”. One questioner expressed concern that treatment to decrease oxalate transport to urine would result in a deleterious increase in serum oxalate. Straub responded that perhaps this would be the result. #1045

S. Marengo and her associates again used a rat model to study “Continuous Infusion of Oxalate (Ox) Increases Intrarenal Concentrations of Calcium at Doses and in Regions Not Associated with Calcium Oxalate Nephrocalcinosis.” They used a mini-pump to infuse excessive potassium oxalate subcutaneously for 2 weeks. There was a complex relationship between doses of oxalate and resulting levels of nephrocalcinosis: 100% at 360 mM infusion per day, but only 28% at 300 mM/d and rarely at 240 mM/d. In addition, a second experiment showed increased amounts of intra-renal calcium in addition to increased amounts of oxalate.  They propose that “oxalate driven increases in calcium could play a role in the development of calcium oxalate nephrocalcinosis.” #1046

In the last paper of the session, Wen and his co-workers wished to determine if action of ketorolac resulted from inhibition of contractility or nociception. They used a pig ureter strip model to measure effects of various concentrations of ketorolac and compared its effect(s) to positive control indomethacin, and negative control DMSO. Ketorolac decreased ureteral contractility in a dose dependent fashion and was similar to indomethacin. DMSO resulted in minimal decreases in contractility. They suggest that local application of ketorolac might result in decreased stent pain, decreased edema and increased stone passage. #1047

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