Faculty Bibliography

Careful phenotyping of patients to classify those with kidney stones has a long and important history in revealing the chemical basis for stone formation. Advances in our genetic understanding of kidney stones will lead to incredible insights regarding the pathophysiology of this common disorder. At this time, both evaluation of urine chemistry and genotyping of patients are extremely useful in the setting of a university and research-based kidney stone clinic. For much of the world, in a more clinically focused setting, these techniques are neither available nor absolutely necessary. Careful implementation of an empiric prescription based on stone composition would have an important effect to reduce stone recurrence in the world's many stone formers. Increased fluid intake, generic dietary manipulations, and prescription of potassium citrate and thiazides are all appropriate empiric therapies for people with calcium and uric acid kidney stones.

Objective/UNASSIGNED:Lesinurad (LESU) is a selective urate reabsorption inhibitor approved at 200 mg daily for use with a xanthine oxidase inhibitor (XOI) to treat hyperuricaemia in gout patients failing to achieve target serum urate on XOI. The aim of the study was to investigate the long-term safety of LESU + XOI therapy. Methods/UNASSIGNED:Safety data were pooled from three 12-month phase III (core) trials evaluating LESU 200 and 400 mg/day combined with an XOI (LESU200+XOI and LESU400+XOI), and two 12-month extension studies using descriptive statistics. To adjust for treatment duration, treatment-emergent adverse events (TEAEs) were expressed as exposure-adjusted incidence rates (patients with events per 100 person-years). Results/UNASSIGNED:In the core studies, exposure-adjusted incidence rates for total and total renal-related TEAEs were comparable for XOI alone and LESU200+XOI but higher with LESU400+XOI. Exposure-adjusted incidence rates for serum creatinine (sCr) elevations ⩾1.5×baseline were 2.9, 7.3 and 18.7, respectively. Resolution (sCr ⩽1.2×baseline) occurred in 75-90% of all events, with 66-75% occurring without any study medication interruption. Major adverse cardiovascular events were 3, 4 and 9 with XOI, LESU200+XOI and LESU400+XOI, respectively. Longer exposure in core+extension studies did not increase rates for any safety signals. Conclusion/UNASSIGNED:At the approved dose of 200 mg once-daily combined with an XOI, LESU did not increase renal, cardiovascular or other adverse events compared with XOI alone, except for sCr elevations. With extended exposure in the core+extension studies, the safety profile was consistent with that observed in the core studies, and no new safety concerns were identified.

Protein-energy wasting (PEW) is a major diet-related complication in hemodialysis (HD) patients. Nutrient-based dietary guidelines emphasize animal-based protein foods for preventing and managing PEW in HD patients. Although dietary protein intake is important for protein anabolism, other dietary factors contribute to PEW. In this article, we examine the diet-related etiologies of PEW in HD patients, and discuss how they may be affected differently by animal- and plant-based protein foods. In general, animal foods are superior sources of protein, but may contribute more to metabolic derangements that cause PEW. Given the potential mixed effects of animal-based protein foods on PEW, human research studies are needed to determine the impact of liberalizing the diet to allow plant-based protein foods on protein status.

Introduction: This study examines the use of dialysis services by end-stage renal disease (ESRD) patients following the Superstorm Sandy-related, months-long closure of the New York campus of the US Department of Veterans Affairs (VA) New York Harbor VA Healthcare System (NYHHS, Manhattan VAMC). Methods: Outpatient visits, dialysis care, emergency department visits, and hospitalizations at VA and non-VA facilities for 47 Manhattan VAMC ESRD patients were examined 12 months pre- and post-Sandy using VA administrative and clinical data. Results: The Brooklyn campus of NYHHS, which is within ten miles of Manhattan VAMC, experienced the largest increase in the number of dialysis encounters after the closure. Dialysis encounters for VA patients also increased at non-VA facilities, rising on average, to 106 per month. For the James J Peters Bronx VAMC, the number of total dialysis encounters for Manhattan VAMC patients fluctuated between 39 and 43 per month, dropping to less than 30 after the Manhattan VAMC dialysis unit reopened. Conclusion: Manhattan VAMC ESRD patients used nearby alternate VA sites and non-VA clinics for their care during the closure of the Manhattan VAMC dialysis unit. The VA electronic health records played an important role in ensuring continuity of care for patients who exclusively used VAMC facilities post-Sandy because patient information was immediately accessible at other VA facilities. The events related to Superstorm Sandy highlight the need for dialysis providers to have a comprehensive disaster plan, including nearby alternate care sites that can increase service capacity when a dialysis facility is closed because of a disaster.

Background: Cystinuria is a disease of impaired absorption of cystine and dibasic amino acids (DAA) from the intestine and renal tubule leading to formation of cystine kidney stones. However, the metabolic impact of reduced amino acid absorption and excessive loss in the urine is poorly understood. We measured endogenous, gut microbial, and xenobiotic metabolites, providing insight into consequences of the disease and its treatment.
Method(s): Urinary biochemicals were assayed using LC-MS in 293 urine specimens from patients with cystinuria or control urinary phenotypes. Multivariate statistical analyses were conducted to reveal statistically significant biochemical signatures of the disease and products of cysteine-binding thiol drugs (CBTDs). 16s rRNA gene sequencing was performed on fecal samples from 12 wildtype (WT) and 12 cystinuric (Slc3a1 knockout; KO) mice to evaluate their gut microbial composition.
Result(s): Cystinuric urine samples had elevated levels of cysteine-gamma-glutamyl cystine disulfide (glutathione precursor), indole-3-acetic acid (microbial tryptophan metabolism), and novel conjugated forms of putrescine (microbial DAA decomposition). Conversely, taurine (sulfur metabolism), indole-3-acetic acid-glucuronide, and novel urinary metabolite N-methyl pipecolic acid (lysine metabolism) were reduced in cystinuric urine. Where cysteine-bound CBTDs were observed, substantial amounts of "wasted" drug were also detected as CBTD homodimers, non-cysteine disulfides, and mixed drug disulfides. The differentiation of gut microbially-derived metabolites led us to evaluate the gut microbiome diversity and composition in a mouse model of cystinuria revealing clear beta diversity and taxa differentiation between WT and KO mice.
Conclusion(s): Cystinuria is associated with unique urinary metabolic profiles beyond hyperexcretion of cystine and DAA, indicating perturbed metabolic processes and potential gut microbial effects. Study of the gut microbiome of WT and KO mice provides the first evidence for them having distinct taxa, perhaps due to poorly absorbed DAA present in the intestinal lumen. Urinary profiles allow us to characterize the excretion profiles of CBTDs, providing insight which may be helpful to tailor treatment

Background: We have shown previously that PH has better HRQoL compared to cystine stone formers and the US Standard Population. Now we show the first crosssectional HRQoL profiles of PH patients.
Method(s): PH participants were enrolled from the Rare Kidney Stone Consortium (RKSC) registry. The group of PH participants consist of PH 1, 2, 3, and PH-NMD (no mutation detected). PH-NMD met clinical criteria for PH. HRQoL was measured with the generic non-disease specific instrument (SF-36v2). Results were calculated as norm-based scores (NBS) based on US Standard Population (mean domain score = 50). We created three stone event groups (<= 30 days, 31-365 days, >=366 days). We compared HRQoL by last stone event for PH participants without a liver and/or kidney transplant. Group means < 47 indicate the presence of impaired functioning in associated dimensions.
Result(s): We used 184 surveys of adults with PH at different time points, adjusted for the last stone event, and compared SF-36 domain profiles. 56 participants were included with multiple surveys (PH1 26, PH2 8, PH3 13, PH-NMD 9; 30 males, 26 females; 42 years old, males 42 years, females 41 years). Lowest domain results were found in participants that experienced a stone event <= 30 days before the survey. Participants with no stone event within a year had the best HRQoL with domain scores above the US Standard Population. PH-NMD compared to PH1, PH2 and PH3 had the highest stone event rate within one year of the survey (58.1 vs 35 vs 3 vs 29.5%). All PH patients with a stone event within 30 days of the survey trended towards higher urine oxalate excretion and lower eGFR (underpowered, not significant). Figure 1 shows that time since the last stone significantly affected HRQoL.
Conclusion(s): PH participants as a group are not homogeneous and experience different HRQoL based on proximity to stone event. PH type is a covariate. Overall PH2 has fewer stone events compared to other PH participants, with an expected direct impact on HRQoL

Background: Potassium citrate is a mainstay of treatment to prevent calcium stones. However, it can increase urine pH and calcium phosphate (CaP) supersaturation (SS). HCA, extracted from garcinia cambogia, is a potent inhibitor of calcium oxalate (CaOx) crystal growth in vitro and may not yield HCO3. It is "generally regarded as safe" and available over the counter. We studied how HCA supplementation affects urine chemistry.
Method(s): We enrolled 2 groups: calcium stone formers (SF) and non-stone forming (NSF) controls. Thiazides and potassium citrate were held for 2 weeks prior to study. Participants recorded a self-selected diet for 2 days and performed 24-hour urine collection on day 2. HCA 300 mg 3 times daily was taken orally for 7 days, and 24-hour urine collected on day 7 while the patient replicated the initial, self-selected diet.
Result(s): 13 people, aged 26-76 years, participated. There were 6 SF and 7 NSF, combined into 1 group of 13. Patients replicated their diets well, as urine Na, volume, and creatinine were similar (data not shown). Results presented in Table. HCA increased urine K and citrate (P < 0.001 and 0.013 respectively). Mean urine pH was unchanged (6.25 to 6.47, P=0.14), while urinary NH4 fell (P = 0.017). 24h excretion of Ca and Ox did not change. SS of CaOx and CaP did not change. Serum values did not change: baseline HCO3 and K were 23.5 +/- 2.5 and 4.0 +/- 0.2 meq/L and 23.7 +/- 1.8 and 4.4 +/- 0.6 meq/L after HCA.
Conclusion(s): Urine K excretion rose by 29 meq/day compared with an expected increase based on the label of 14 meq, suggesting the label was not accurate. Increased citrate and lower NH4 suggest some K is in the form of alkali salts or that some HCA is metabolized to bicarbonate. There was no change in CaP or CaOx SS. The lack of effect on SS may not reflect the potential ability of HCA to inhibit calcium crystallization, as it inhibits Ca crystal growth in vitro in supersaturated media