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.

Cystinuria, a genetic disorder of cystine transport, is characterized by excessive excretion of cystine in the urine and recurrent cystine stones in the kidneys and, to a lesser extent, in the bladder. Males generally are more severely affected than females. The disorder may lead to chronic kidney disease in many patients. The cystine transporter (b^0,+) is a heterodimer consisting of the rBAT (encoded by SLC3A1) and b^0,+AT (encoded by SLC7A9) subunits joined by a disulfide bridge. The molecular basis of cystinuria is known in great detail, and this information is now being used to define genotype-phenotype correlations. Current treatments for cystinuria include increased fluid intake to increase cystine solubility and the administration of thiol drugs for more severe cases. These drugs, however, have poor patient compliance due to adverse effects. Thus, there is a need to reduce or eliminate the risks associated with therapy for cystinuria. Four mouse models for cystinuria have been described and these models provide a resource for evaluating the safety and efficacy of new therapies for cystinuria. We are evaluating a new approach for the treatment of cystine stones based on the inhibition of cystine crystal growth by cystine analogs. Our ongoing studies indicate that cystine diamides are effective in preventing cystine stone formation in the Slc3a1 knockout mouse model for cystinuria. In addition to crystal growth, crystal aggregation is required for stone formation. Male and female mice with cystinuria have comparable levels of crystalluria, but very few female mice form stones. The identification of factors that inhibit cystine crystal aggregation in female mice may provide insight into the gender difference in disease severity in patients with cystinuria.

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.

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.

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.

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

Background: Kidney stones commonly affect US adults. In recent years, there has been increasing interest in the human anaerobic colonic bacterium Oxalobacter formigenes because of its ability to metabolize oxalate, and its potential to protect against calcium oxalate kidney stones. Currently, there are two known groups of O. formigenes (Group 1 and Group 2) with only a few isolates from each group characterized. In our experiments, we aimed to isolate O. formigenes from subjects with primary hyperoxaluria (PH), enteric hyperoxaluria (EH) and healthy controls (HC) to compare their metabolic activities. Understanding these differences will help expand our knowledge about this important organism and its effect on oxalate homeostasis in humans.
Method(s): We collected fecal samples from 37 patients via clinical trials at New York University Langone Medical Center and Mayo Clinic with PH, EH and HC. We cultured fecal samples in 25mM oxalate-rich selective media, then isolated O. formigenes by picking characteristic colonies from calcium oxalate agar. We identified and grouped isolates using PCR and Sanger sequencing of the oxc gene. We then tested their oxalate consumption via Oxalate Degradation Assay to compute mean oxalate degradation rates (ODR) for each group of isolates.
Result(s): We isolated 25 O. formigenes colonies from 14 subjects, with all isolates belonging to either HC (n=11) or PH (n= 14) patients, and none from EH patients. Based on oxc sequences, we identified Group 1 (n=17) and Group 2 (n=5) strains, and potentially a new taxonomic group Group 3 (n=3). We were able to regrow 13 (76%) of 17, 1 (20%) of 5, and 1 (33%) of 3 Group 1, 2, and 3 strains, respectively. All 14 PH patient colonies were identified as Group 1, while HC had a mix of all three groups. Mean ODR was significantly higher in Group 1 vs Group 2 isolates (8.5 +/- 3.3 vs 2.8 +/- 1.9 micromole/ hour, p=0.02). Group 3 isolates had intermediate ODR (5.7 +/- 3.1) values. As expected, the ODRs of our Group 1 isolates were similar to the control group 1 strain OXCC13 (11.1 +/- 1.2). Mean ODR between PH, EH and HC did not differ significantly.
Conclusion(s): We were able to isolate and characterize 25 colonies of O. formigenes, including a potential new group of O. formigenes. Group 1 strains appear to be most metabolically active in vitro, and were exclusively present in PH patients

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