Faculty Bibliography

Expanding epidemiologic and physiologic data suggest that urinary stone disease is best conceptualized as a chronic metabolic condition punctuated by symptomatic, preventable stone events. These acute events herald substantial future chronic morbidity, including decreased bone mineral density, cardiovascular disease, and CKD. Urinary stone disease imposes a large and growing public health burden. In the United States, 1 in 11 individuals will experience a urinary stone in their lifetime. Given this high incidence and prevalence, urinary stone disease is one of the most expensive urologic conditions, with health care charges exceeding $10 billion annually. Patient care focuses on management of symptomatic stones rather than prevention; after three decades of innovation, procedural interventions are almost exclusively minimally invasive or noninvasive, and mortality is rare. Despite these advances, the prevalence of stone disease has nearly doubled over the past 15 years, likely secondary to dietary and health trends. The NIDDK recently convened a symposium to assess knowledge and treatment gaps to inform future urinary stone disease research. Reducing the public health burden of urinary stone disease will require key advances in understanding environmental, genetic, and other individual disease determinants; improving secondary prevention; and optimal population health strategies in an increasingly cost-conscious care environment.

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

Kidney stones are a disease of worldwide prevalence with significant public health implications. About 60-80 % of stones are composed of calcium oxalate (CaOx). Hyperoxaluria is a major risk factor. Oxalobacter formigenes (OF), a member of the human colonic microbiota, plays a major role in net colonic oxalate absorption and secretion. We now report OF colonization rates in a young healthy population, the stability of colonization, the effects of antibiotic treatment, and OF colonization on urinary oxalate (Uox) excretion. We followed 64 healthy subjects tested for Helicobacter pylori (HP), who were treated with antibiotics (amoxicillin and clarithromycin for 2 weeks) for HP eradication. Using species-specific PCR, we tested for OF colonization at baseline and at follow-up. Urine samples 3 h after a low oxalate standard meal were analyzed for Uox, factored for urine creatinine (Cr). Of the 65 subjects (M/F: 23/42; mean age 25.2 +/- 5.7 years) tested for OF, 28 (43 %) were positive at baseline. Of 7 OF + subjects at baseline, subject to HP elimination, 6 became OF-negative at 12 wks, only 2 reverted to positive at week 24, and 4 patients remained negative at follow up (Mean 22.5 +/- 4.2 weeks). Of 18 untreated positive people with follow assessments, 16 (89 %) remained positive at follow up (Mean 23.0 +/- 4.2 week), but of 24 untreated negative subjects, only 3 (12 %) were positive at follow up (mean 20.2 +/- 6.8 weeks), significantly fewer than the untreated positives (p = 0.001 by Fisher exact test). We tested Uox/Cr in 137 samples from 46 subjects with no antibiotic exposure at different time points. We found that the presence of OF was associated with 14 % lower Uox/cr as compared with its absence (17.0 +/- 0.0 vs 19.4 +/- 0.1 mg/g, p = 0.04). We conclude that OF colonization status remains stable over a follow- up period of several months, with antibiotics suppressing colonization in the majority of people in the short term. The differences in urinary oxalate levels with respect to OF status is consistent with its protective effects for the prevention of calcium oxalate kidney stones

Diet, of course, influences urine chemistry. Yet only one randomized controlled trial has demonstrated that a change in diet led to reduction in stone recurrence. I will review some of the deficiencies in the current scientific dietary literature and suggest how these deficiencies could be addressed. Highlights will include comparisons of diet with pharmacologic therapy, how prescribing dietary patterns, rather than individual nutrients, might be a preferable way to address therapy, and the possible effect of the microbiome on how diet influences urinary chemistry

Two previous studies (<10 patients each) have demonstrated that alkali therapy may reduce urine calcium excretion in patients with calcium oxalate nephrolithiasis. The hypothesized mechanisms are (1) a decrease in bone turnover due to systemic alkalinization by the medications; (2) binding of calcium by citrate in the gastrointestinal tract; (3) direct effects on TRPV5 activity in the distal tubule. We performed a retrospective review of patients on potassium citrate therapy to evaluate the effects of this medication on urinary calcium excretion. A retrospective review was performed of a metabolic stone database at a tertiary care academic hospital. Patients were identified with a history of calcium oxalate nephrolithiasis and hypocitraturia who were on potassium citrate therapy for a minimum of 3 months. 24-h urine composition was assessed prior to the initiation of potassium citrate therapy and after 3 months of therapy. Patients received 30-60 mEq potassium citrate by mouth daily. Inclusion criterion was a change in urine potassium of 20 mEq/day or greater, which suggests compliance with potassium citrate therapy. Paired t test was used to compare therapeutic effect. Twenty-two patients were evaluated. Mean age was 58.8 years (SD 14.0), mean BMI was 29.6 kg/m2 (SD 5.9), and gender prevalence was 36.4 % female:63.6 % male. Mean pre-treatment 24-h urine values were as follows: citrate 280.0 mg/day, potassium 58.7 mEq/day, calcium 216.0 mg/day, pH 5.87. Potassium citrate therapy was associated with statistically significant changes in each of these parameters-citrate increased to 548.4 mg/day (p < 0.0001), potassium increased to 94.1 mEq/day (p < 0.0001), calcium decreased to 156.5 mg/day (p = 0.04), pH increased to 6.47 (p = 0.001). Urine sodium excretion was not different pre- and post-therapy (175 mEq/day pre-therapy versus 201 mEq/day post-therapy, p = NS). Urinary calcium excretion decreased by a mean of 60 mg/day on potassium citrate therapy-a nearly 30 % decrease in urine calcium excretion. These data lend support to the hypothesis that alkali therapy reduces urine calcium excretion.

Hyperoxaluria is a frequent complication of inflammatory bowel diseases, ileal resection and Roux-en-Y gastric bypass and is well-known to cause nephrolithiasis and nephrocalcinosis. The associated prevalence of chronic kidney disease and end-stage kidney disease (ESKD) is less clear but may be more consequential than recognized. In this review, we highlight three cases of ESKD due to enteric hyperoxaluria following small bowel resections. We review current information on the pathophysiology, complications and treatment of this complex disease.

The exposome is the assembly and measure of all the exposures of an individual in a lifetime. An individual's exposures begin before birth and include insults from environmental and occupational sources. The associated field is called exposomics, which relies on the application of internal and external exposure assessment methods. Exposomics has not yet been thoroughly applied to the study of kidney stones although much is known about how diet and fluid intake affect nephrolithiasis. Some other novel exposures that may contribute to kidney stones are discussed including use of antibiotics, urbanization and migration to urban heat islands, and occupation. People whose school and jobs limit their access to fluids and adequate bathroom facilities may have higher prevalence of stones. Examples include athletes, teachers, heathcare workers, and cab drivers. Occupational kidney stones have received scant attention and may represent a neglected, and preventable, type of stone. An exposomic-oriented history would include a careful delineation of occupation and activities.

Oxalobacter formigenes, a member of the human colonic microbiota that plays a major role in net colonic oxalate transport and secretion, is protective against formation of calcium oxalate kidney stones. We now describe the prevalence, relative abundance and stability of O. formigenes in healthy young adults in the United States, as revealed by Human Microbiome Project (HMP) data from fecal samples from 242 healthy young adults who had 1-3 study visits. Samples underwent whole-genomic shotgun (WGS) sequencing, and/or 16S rRNA sequencing. Three datasets available from the processed sequence data were studied: WGS metagenomic analysis by alignment to reference genomes (HMSCP) or using MetaPhlAn, or QIIME analysis of the V1-3 or V3-5 16S sequences. O. formigenes was detected in fecal samples using both the WGS and 16S rRNA data. Analysis of the WGS dataset, using HMSCP, showed that 29 (31%) of 94 subjects were O. formigenes-positive while the V1-3 and V3-5 analyses were less sensitive for O. formigenes detection. When present, O. formigenes relative abundance varied over 3 log10, and was normally distributed. For 66 samples studied by all three methods, all assays agreed in 58 (88%). Of 14 subjects who were O. formigenes-positive at baseline, 13 (93%) were positive on follow-up visit, indicating the stability of colonization. O. formigenes appears to be stably present in fewer than half of healthy young USA adults and is most sensitively detected by WGS.

The prevalence of kidney stones is increasing worldwide. Various etiologies may in part explain this observation including increased prevalence of diabetes, obesity and the metabolic syndrome, increased dietary protein and salt content, and decreased dietary dairy products. We hypothesize an additional and novel potential contributor to increasing kidney stone prevalence: migration to urban settings, or urbanization, and resultant exposure of the population to the higher temperatures of urban heat islands (UHIs). Both urbanization and exposure to UHIs are worldwide, continuous trends. Because the difference in temperature between rural and urban settings is greater than the increase in temperature caused by global warming, the potential effect of urbanization on stone prevalence may be of greater magnitude. However, demonstration of a convincing link between urbanization and kidney stones is confounded by many variables simultaneously affected by migration to cities, such as changes in occupation, income, and diet. No data have yet been published supporting this proposed association. We explore the plausibility and limitations of this possible etiology of increasing kidney stone prevalence.