Faculty Bibliography

Each year approximately 13,000 Veterans transition to maintenance dialysis, mostly in the traditional form of thrice-weekly hemodialysis from the start. Among >6000 dialysis units nationwide, there are currently approximately 70 Veterans Affairs (VA) dialysis centers. Given this number of VA dialysis centers and their limited capacity, only 10% of all incident dialysis Veterans initiate treatment in a VA center. Evidence suggests that, among Veterans, the receipt of care within the VA system is associated with favorable outcomes, potentially because of the enhanced access to healthcare resources. Data from the United States Renal Data System Special Study Center "Transition-of-Care-in-CKD" suggest that Veterans who receive dialysis in a VA unit exhibit greater survival compared with the non-VA centers. Substantial financial expenditures arise from the high volume of outsourced care and higher dialysis reimbursement paid by the VA than by Medicare to outsourced providers. Given the exceedingly high mortality and abrupt decline in residual kidney function (RKF) in the first dialysis year, it is possible that incremental transition to dialysis through an initial twice-weekly hemodialysis regimen might preserve RKF, prolong vascular access longevity, improve patients' quality of life, and be a more patient-centered approach, more consistent with "personalized" dialysis. Broad implementation of incremental dialysis might also result in more Veterans receiving care within a VA dialysis unit. Controlled trials are needed to examine the safety and efficacy of incremental hemodialysis in Veterans and other populations; the administrative and health care as well as provider structure within the VA system would facilitate the performance of such trials.

PURPOSE: Kidney stone prevention relies on the 24-hour urine collection to diagnose metabolic abnormalities and direct dietary and pharmacologic therapy. While its use is guideline-supported for high risk and interested patients, evidence that the test can accurately predict recurrence or treatment response is limited. We sought to critically reassess the role of the 24-hour urine collection in stone prevention. MATERIALS AND METHODS: In addition to a MEDLINE(R) search to identify controlled studies of dietary and pharmacologic interventions, evidence supporting the AUA and EAU guidelines for metabolic stone prevention were evaluated. Additionally, placebo-arms of these studies were examined to assess the stone clinic effect: the impact of regular office visits without specific treatment on stone recurrence. RESULTS: The 24-hour urine test has several limitations including the complexity of interpretation, need for repeat collections, inability to predict stone recurrence with individual parameters and supersaturation values, unclear rationale of laboratory cutoff values, and difficulty with determining collection adequacy. Only one prospective trial has compared selective dietary recommendations based on 24-hour urine collection results versus general dietary instructions. While the trial supported the intervention arm, significant limitations to the study were found. Placebo arms of intervention trials have noted a 0-61% decrease in stone recurrence rate and a remission rate during the study of 20-86%. CONCLUSIONS: Whether all recurrent stone formers benefit from 24-hour urine collection has not been established. Additional comparative effectiveness trials are needed to determine which stone former benefits from selective therapy, as guided by the 24-hour urine collection.

Background/Purpose: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and European Union at 200 mg daily dose in combination with a xanthine oxidase inhibitor (XOI) for treatment of hyperuricemia associated with gout in patients unable to achieve target serum uric acid on XOI (allopurinol or febuxostat) alone. Approval of lesinurad was based on three pivotal, placebo-controlled, 12-month phase III (core) studies evaluating lesinurad 200 mg (LESU200) and 400 mg (LESU400) in combination with XOI. Patients completing core studies were eligible to enter extension studies, continuing LESU+XOI at the same dose or randomized from placebo to LESU200 or LESU400 plus XOI. Methods: Renal-related and kidney stone safety data were pooled from core studies to compare LESU200+XOI and LESU400+XOI with XOI alone and from core studies + extension studies to evaluate the impact on renal safety of extended LESU+XOI treatment. Renal-related treatment-emergent adverse events (TEAEs) were a customized list of 36 preferred terms selected from the Medical Dictionary for Regulatory Activities (MedRA) Renal and Urinary Disorders System Organ Class (SOC), the Investigations SOC and the Acute Renal Failure MedRA Standardized MedRA Query (SMQ). Descriptive statistics are provided for patients receiving >1 dose of study medication. To adjust for varying treatment duration, TEAEs are expressed as exposure-adjusted incidence rates (EAIRs; subjects with events per 100 person-years). Results: In the core studies, EAIRs for any renal-related TEAE, serious renal-related TEAEs, and renal-related TEAEs leading to discontinuation were similar with XOI alone and LESU200+XOI and lower than with LESU400 +XOI (Table 1). Similar results were found for kidney stone and serious kidney stone TEAEs. The most common renal-related TEAE was increased serum creatinine (sCr). EAIRs for sCr elevations >1.5x baseline were higher with LESU+XOI than XOI alone (Table 1). Overall, 75% and 84% of sCr elevations in the XOI alone and LESU+XOI groups, respectively, were resolved at last study assessment; 75% and 66% resolved without interruption of medication. Exposure to extended LESU+XOI treatment in core+extension studies did not show an increase from core studies in EAIRs for any renal-related or kidney stone adverse event category (Table 2). Conclusion: Lesinurad at the approved dose of 200 mg once-daily combined with XOI demonstrated comparable rate of adverse events to XOI alone. There was no clinically relevant increase in these adverse events with the extension of treatment beyond 1 year. (Table presented)

Nephrolithiasis is a complex disease of worldwide prevalence that is influenced by both genetic and environmental factors. About 75% of kidney stones are predominantly composed of calcium oxalate and urinary oxalate is considered a crucial risk factor. Microorganisms may have a role in the pathogenesis and prevention of kidney stones and the involvement of the intestinal microbiome in this renal disease has been a recent area of interest. Oxalobacter formigenes is a gram negative bacteria that degrades oxalate in the gut decreasing urinary oxalate excretion. In this review, we examine the data studying the role of Oxalobacter formigenes kidney stone disease in humans and animals, the effect of antibiotics on its colonization, and the potential role of probiotics and whole microbial communities as therapeutic interventions.

BACKGROUND: Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis, which are important also for clinical research. DESIGN: A steering committee identified 27 questions, which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these, 407 articles were deemed to provide useful scientific information. The Faculty, divided into working groups, analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved. RESULTS: Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during stone treatment in the management of these patients; on the identification of patients warranting preventive measures; on the role of fluid and nutritional measures and of drugs to prevent recurrent episodes of stones; and finally, on the cooperation between the urologist and nephrologist in the renal stone patients. CONCLUSIONS: This document has addressed idiopathic calcium nephrolithiasis from the perspective of a disease that can associate with systemic disorders, emphasizing the interplay needed between urologists and nephrologists. It is complementary to the American Urological Association and European Association of Urology guidelines. Future areas for research are identified.

l-Cystine bismorpholide (1a) and l-cystine bis(N'-methylpiperazide) (1b) were seven and twenty-four times more effective than l-cystine dimethyl ester (CDME) in increasing the metastable supersaturation range of l-cystine, respectively, effectively inhibiting l-cystine crystallization. This behavior can be attributed to inhibition of crystal growth at microscopic length scale, as revealed by atomic force microscopy. Both 1a and 1b are more stable than CDME, and 1b was effective in vivo in a knockout mouse model of cystinuria.

This symposium will review recent information regarding the relationship between diet and kidney stones. Information about diet and its effects on stone risk can be derived from 24 h urine collections. Recommendations regarding diet and beverage use will be surveyed. Proposals regarding randomized controlled trials, both past and future, will be presented