Faculty Bibliography

OBJECTIVE: Hyperuricemia of gout can arise due to either overproduction or underexcretion of uric acid. Not all available urate-lowering therapies are equally effective and safe for use in patients with renal disease. The objective of this post-hoc analysis was to determine the effectiveness of the xanthine oxidase inhibitor febuxostat in reducing serum urate (sUA) levels in gouty patients who were either overproducers or underexcretors. METHODS: Gouty subjects 18 to 85 years of age with sUA >/= 8.0 mg/dl at baseline were enrolled in a Phase 2, 28-day, multicenter, randomized, double-blind, placebo-controlled trial and randomized to receive febuxostat 40 mg, 80 mg, or 120 mg daily, or placebo. The primary efficacy endpoint was the proportion of subjects with sUA < 6.0 mg/dl at Day 28. Secondary efficacy endpoints included percentage reductions in sUA and urinary uric acid (uUA) from baseline to Day 28. RESULTS: Of the 153 subjects, 118 (77%) were underexcretors (uUA </= 800 mg/24 h) and 32 (21%) were overproducers (uUA > 800 mg/24 h); baseline uUA data were missing for 3 subjects. Treatment with febuxostat led to the majority of subjects achieving sUA < 6.0 mg/dl at Day 28. Treatment with any dose of febuxostat led to significantly greater percentage reductions in uUA than that observed in the placebo group, for both underexcretors and overproducers. CONCLUSION: Febuxostat is a highly efficacious urate-lowering therapy in patients with gout regardless of overproduction or underexcretion status

Nephrolithiasis is a common disease across the world that is becoming more prevalent. Although the underlying cause for most stones is not known, a body of literature suggests a role of heat and climate as significant risk factors for lithogenesis. Recently, estimates from computer models predicted up to a 10% increase in the prevalence rate in the next half century secondary to the effects of global warming, with a coinciding 25% increase in health-care expenditures. Our aim here is to critically review the medical literature relating stones to ambient temperature. We have categorized the body of evidence by methodology, consisting of comparisons between geographic regions, comparisons over time, and comparisons between people in specialized environments. Although most studies are confounded by other factors like sunlight exposure and regional variation in diet that share some contribution, it appears that heat does play a role in pathogenesis in certain populations. Notably, the role of heat is much greater in men than in women. We also hypothesize that the role of a significant human migration (from rural areas to warmer, urban locales beginning in the last century and projected to continue) may have a greater impact than global warming on the observed worldwide increasing prevalence rate of nephrolithiasis. At this time the limited data available cannot substantiate this proposed mechanism but further studies to investigate this effect are warranted.Kidney International advance online publication, 30 March 2011; doi:10.1038/ki.2011.76

Several well-documented outbreaks of melamine poisoning have occurred in both animals and humans during the past 7 years, which led to the identification of melamine and cyanuric acid as nephrotoxins. This Review provides an overview of the known experimental and observational data (including toxicology, epidemiology, and pathology) concerning melamine contamination of foodstuffs, both alone and in combination with cyanuric acid. The various renal effects of ingestion of these compounds in both animals and humans are described, and a hypothesis on the mechanism of formation of melamine-based kidney stones is presented. Finally, the public health measures taken in the wake of the melamine contamination events are discussed

During the past 25 years, numerous changes have taken place in the use of hemodialysis as a therapeutic modality. Advances in technologies and a progression in our collective understanding of the pharmacokinetics of certain xenobiotics have resulted in alterations in the indications, effectiveness, and safety of hemodialysis. However, these changes have not necessarily been reflected in the current published data regarding treatment of intoxications. Reported clearance rates often reflect what was achievable in the 1970s and 1980s, and more recent reports are frequently lacking. Our goal in this review is to summarize the changes in hemodialysis and in other extracorporeal removal technologies and highlight the effects of these changes on the current indications for hemodialysis of the poisoned patient. Changes in dialysis performance that are reviewed in this article include the use of high-efficiency and high-flux dialysis membranes, improved hemodynamic stability because of ultrafiltration control, and the use of bicarbonate as a source of base. We review the indications for hemodialysis for removal of specific toxins, including vancomycin, methotrexate, carbamazepine, and valproic acid

BACKGROUND: Patients with gout have comorbidities, but the impact of these comorbidities on treatment has not been studied. METHODS: A total of 575 patients with gout were stratified according to certainty of diagnosis according to International Classification of Diseases, 9th Revision, Clinical Modification code alone (cohort I), American College of Radiology criteria (cohort II), and crystal diagnosis (cohort III). Comorbid conditions were defined according to International Classification of Diseases, 9th Revision, Clinical Modification codes, and stratified as either moderate or severe. Drug contraindications were defined as moderate or strong, based on Food and Drug Administration criteria and severity of disease. RESULTS: The most common comorbidity was hypertension (prevalence 0.89). The presence of comorbidities resulted in a high frequency of contraindications to approved gout medications. More than 90% of patients had at least 1 contraindication to nonsteroidal anti-inflammatory drugs. Many patients demonstrated multiple contraindications to 1 or more gout medications. Frequently, patients were prescribed medications to which they harbored contraindications. The prevalence of patients prescribed colchicine despite having at least 1 strong contraindication was 30% (cohort I), 37% (cohort II), and 39.6% (cohort III). CONCLUSION: Patients with gout typically harbor multiple comorbidities that result in contraindications to many of the medications available to treat gout. Frequently, despite contraindications to gout therapies, patients are frequently prescribed these medications

We examined the effect of a controlled diet and two probiotic preparations on urinary oxalate excretion, a risk factor for calcium oxalate kidney stone formation, in patients with mild hyperoxaluria. Patients were randomized to a placebo, a probiotic, or a synbiotic preparation. This tested whether these probiotic preparations can increase oxalate metabolism in the intestine and/or decrease oxalate absorption from the gut. Patients were maintained on a controlled diet to remove the confounding variable of differing oxalate intake from food. Urinary oxalate excretion and calcium oxalate supersaturation on the controlled diet were significantly lower compared with baseline on a free-choice diet. Neither study preparation reduced urinary oxalate excretion nor calcium oxalate supersaturation. Fecal lactobacilli colony counts increased on both preparations, whereas enterococcal and yeast colony counts were increased on the synbiotic. Total urine volume and the excretion of oxalate and calcium were all strong independent determinants of urinary calcium oxalate supersaturation. Hence, dietary oxalate restriction reduced urinary oxalate excretion, but the tested probiotics did not influence urinary oxalate levels in patients on a restricted oxalate diet. However, this study suggests that dietary oxalate restriction is useful for kidney stone prevention

Crystallization of L-cystine is a critical step in the pathogenesis of cystine kidney stones. Treatments for this disease are somewhat effective but often lead to adverse side effects. Real-time in situ atomic force microscopy (AFM) reveals that L-cystine dimethylester (L-CDME) and L-cystine methylester (L-CME) dramatically reduce the growth velocity of the six symmetry-equivalent {100} steps because of specific binding at the crystal surface, which frustrates the attachment of L-cystine molecules. L-CDME and L-CME produce l-cystine crystals with different habits that reveal distinct binding modes at the crystal surfaces. The AFM observations are mirrored by reduced crystal yield and crystal size in the presence of L-CDME and L-CME, collectively suggesting a new pathway to the prevention of L-cystine stones by rational design of crystal growth inhibitors

Mammalian urine contains a range of macromolecule proteins that play critical roles in renal stone formation, among which Tamm-Horsfall protein (THP) is by far the most abundant. While THP is a potent inhibitor of crystal aggregation in vitro and its ablation in vivo predisposes one of the two existing mouse models to spontaneous intrarenal calcium crystallization, key controversies remain regarding the role of THP in nephrolithiasis. By carrying out a long-range follow-up of more than 250 THP-null mice and their wild-type controls, we demonstrate here that renal calcification is a highly consistent phenotype of the THP-null mice that is age and partially gene dosage dependent, but is gender and genetic background independent. Renal calcification in THP-null mice is progressive, and by 15 mo over 85% of all the THP-null mice develop spontaneous intrarenal crystals. The crystals consist primarily of calcium phosphate in the form of hydroxyapatite, are located more frequently in the interstitial space of the renal papillae than intratubularly, particularly in older animals, and lack accompanying inflammatory cell infiltration. The interstitial deposits of hydroxyapatite observed in THP-null mice bear strong resemblances to the renal crystals found in human kidneys bearing idiopathic calcium oxalate stones. Compared with 24-h urine from the wild-type mice, that of THP-null mice is supersaturated with brushite (calcium phosphate), a stone precursor, and has reduced urinary excretion of citrate, a stone inhibitor. While less frequent than renal calcinosis, renal pelvic and ureteral stones and hydronephrosis occur in the aged THP-null mice. These results provide direct in vivo evidence indicating that normal THP plays an important role in defending the urinary system against calcification and suggest that reduced expression and/or decreased function of THP could contribute to nephrolithiasis