Faculty Bibliography

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: 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

Diet is a key determinant of several common and serious disease complications in hemodialysis (HD) patients. The recommended balance and variety of foods in the HD diet is designed to limit high potassium and phosphorus foods while maintaining protein adequacy. In this report, we examine the potassium, phosphorus, and protein content of foods, and identify critical challenges, and potential pitfalls when translating nutrient prescriptions into dietary guidelines. Our findings highlight the importance of individualized counseling based on a comprehensive dietary assessment by trained diet professionals, namely renal dietitians, for managing diet-related complications in HD patients.

Medullary sponge kidney (MSK) is a cause of nephrocalcinosis, associated with hematuria, renal colic, pyelonephritis. There are rare and atypical MSK cases characterized by chronic severe pain (CP), whose features are unknown, in particular the relationship with the stone disease activity. This study analyzes a cohort of MSK-CP patients belonging to three North-America self-support Facebook groups. Patients had to self-administer an on-line questionnaire (on intensity, progression and MSK-associated conditions, stone-related disease, pain features, drug use), the Brief Pain Inventory, the Fatigue Severity Score, and Wisconsin Quality of Life (WQL) in stone formers questionnaires. Ninety-two patients with a diagnosis of MSK joined our survey. Stone rate was very high (3.1 stones per patient-year, < 15% of patients had ≤ 1 stone per year). Most patients had repeated hospitalizations for stones symptoms (p < 0.001) or pain (p < 0.005). 71% of participants referred a daily pain that interfered strongly with everyday life and quality of life (WQL mean value 29.4). 69% used pain medications daily (70% opioids). In most cases, pain was associated with stone passage, while 15% referred a sine materia pain. We showed how MSK-CP symptoms affect very negatively on the quality of life of these patients. They also have a definite risk of progressing to end-stage kidney disease. Generally, CP seems to be associated with an exceptionally high lithogenic activity, suggesting that a better and earlier metabolic treatment for stone prevention should be the first approach in these patients before mini-invasive treatments to prevent pain.

IMPORTANCE:The World Trade Center (WTC) attacks on September 11, 2001, created an unprecedented environmental exposure to known and suspected carcinogens suggested to increase the risk of multiple myeloma. Multiple myeloma is consistently preceded by the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS, detectable in peripheral blood. OBJECTIVE:To characterize WTC-exposed firefighters with a diagnosis of multiple myeloma and to conduct a screening study for MGUS and light-chain MGUS. DESIGN, SETTING, AND PARTICIPANTS:Case series of multiple myeloma in firefighters diagnosed between September 11, 2001, and July 1, 2017, together with a seroprevalence study of MGUS in serum samples collected from Fire Department of the City of New York (FDNY) firefighters between December 2013 and October 2015. Participants included all WTC-exposed FDNY white, male firefighters with a confirmed physician diagnosis of multiple myeloma (n = 16) and WTC-exposed FDNY white male firefighters older than 50 years with available serum samples (n = 781). EXPOSURES:WTC exposure defined as rescue and/or recovery work at the WTC site between September 11, 2001, and July 25, 2002. MAIN OUTCOMES AND MEASURES:Multiple myeloma case information, and age-adjusted and age-specific prevalence rates for overall MGUS (ie, MGUS and light-chain MGUS), MGUS, and light-chain MGUS. RESULTS:Sixteen WTC-exposed white male firefighters received a diagnosis of multiple myeloma after September 11, 2001; median age at diagnosis was 57 years (interquartile range, 50-68 years). Serum/urine monoclonal protein isotype/free light-chain data were available for 14 cases; 7 (50%) had light-chain multiple myeloma. In a subset of 7 patients, myeloma cells were assessed for CD20 expression; 5 (71%) were CD20 positive. In the screening study, we assayed peripheral blood from 781 WTC-exposed firefighters. The age-standardized prevalence rate of MGUS and light-chain MGUS combined was 7.63 per 100 persons (95% CI, 5.45-9.81), 1.8-fold higher than rates from the Olmsted County, Minnesota, white male reference population (relative rate, 1.76; 95% CI, 1.34-2.29). The age-standardized prevalence rate of light-chain MGUS was more than 3-fold higher than in the same reference population (relative rate, 3.13; 95% CI, 1.99-4.93). CONCLUSIONS AND RELEVANCE:Environmental exposure to the WTC disaster site is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype.

Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidneys' thick ascending limb (TAL) of loop of Henle. Despite the unique location and recent association of THP gene mutations with hereditary uromodulin-associated kidney disease and THP single nucleotide polymorphisms with chronic kidney disease and hypertension, the physiological function(s) of THP and its pathological involvement remain incompletely understood. By studying age-dependent changes of THP knockout (KO) mice, we show here that young KO mice had significant salt and water wasting but were partially responsive to furosemide, due to decreased luminal translocation of Na-K-Cl cotransporter 2 (NKCC2) in the TAL. Aged THP KO mice were, however, markedly oliguric and unresponsive to furosemide, and their NKCC2 was localized primarily in the cytoplasm as evidenced by lipid raft floatation assay, cell fractionation, confocal and immunoelectron microscopy. These aged KO mice responded to metolazone and acetazolamide, known to target distal and proximal tubules, respectively. They also had marked upregulation of renin in juxtaglomerular apparatus and serum, and they were hypertensive. Finally, the aged THP KO mice had significant upregulation of Na-coupled urate transporters Slc5a8 and Slc22a12 as well as sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule and elevated serum uric acid and allantoin. Collectively, our results suggest that THP deficiency can cause progressive disturbances in renal functions via initially NKCC2 dysfunction and later compensatory responses resulting in prolonged activation of the renin-angiotensin-aldosterone axis and hyperuricema.

Background Although intestinal and urinary microbiome perturbations are associated with nephrolithiasis, whether antibiotics are a risk factor for this condition remains unknown.Methods We determined the association between 12 classes of oral antibiotics and nephrolithiasis in a population-based, case-control study nested within 641 general practices providing electronic health record data for >13 million children and adults from 1994 to 2015 in the United Kingdom. We used incidence density sampling to match 25,981 patients with nephrolithiasis to 259,797 controls by age, sex, and practice at date of diagnosis (index date). Conditional logistic regression models were adjusted for the rate of health care encounters, comorbidities, urinary tract infections, and use of thiazide and loop diuretics, proton-pump inhibitors, and statins.Results Exposure to any of five different antibiotic classes 3-12 months before index date was associated with nephrolithiasis. The adjusted odds ratio (95% confidence interval) was 2.33 (2.19 to 2.48) for sulfas, 1.88 (1.75 to 2.01) for cephalosporins, 1.67 (1.54 to 1.81) for fluoroquinolones, 1.70 (1.55 to 1.88) for nitrofurantoin/methenamine, and 1.27 (1.18 to 1.36) for broad-spectrum penicillins. In exploratory analyses, the magnitude of associations was greatest for exposure at younger ages (P<0.001) and 3-6 months before index date (P<0.001), with all but broad-spectrum penicillins remaining statistically significant 3-5 years from exposure.Conclusions Oral antibiotics associated with increased odds of nephrolithiasis, with the greatest odds for recent exposure and exposure at younger age. These results have implications for disease pathogenesis and the rising incidence of nephrolithiasis, particularly among children.

Temperature and relative humidity have opposing effects on evaporative water loss, the likely mediator of the temperature-dependence of nephrolithiasis. However, prior studies considered only dry-bulb temperatures when estimating the temperature-dependence of nephrolithiasis. We used distributed lag non-linear models and repeated 10-fold cross-validation to determine the daily temperature metric and corresponding adjustment for relative humidity that most accurately predicted kidney stone presentations during hot and cold periods in South Carolina from 1997 to 2015. We examined three metrics for wet-bulb temperatures and heat index, both of which measure the combination of temperature and humidity, and for dry-bulb temperatures: (1) daytime mean temperature; (2) 24-h mean temperature; and (3) most extreme 24-h temperature. For models using dry-bulb temperatures, we considered four treatments of relative humidity. Among 188,531 patients who presented with kidney stones, 24-h wet bulb temperature best predicted kidney stone presentation during summer. Mean cross-validated residuals were generally lower in summer for wet-bulb temperatures and heat index than the corresponding dry-bulb temperature metric, regardless of type of adjustment for relative humidity. Those dry-bulb models that additionally adjusted for relative humidity had higher mean residuals than other temperature metrics. The relative risk of kidney stone presentations at the 99th percentile of each temperature metric compared to the respective median temperature in summer months differed by temperature metric and relative humidity adjustment, and ranged from an excess risk of 8-14%. All metrics performed similarly in winter. The combination of temperature and relative humidity determine the risk of kidney stone presentations, particularly during periods of high heat and humidity. These results suggest that metrics that measure moist heat stress should be used to estimate the temperature-dependence of kidney stone presentations, but that the particular metric is relatively unimportant.