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Multiple Myeloma and Its Precursor Disease Among Firefighters Exposed to the World Trade Center Disaster

Landgren, Ola; Zeig-Owens, Rachel; Giricz, Orsolya; Goldfarb, David; Murata, Kaznouri; Thoren, Katie; Ramanathan, Lakshmi; Hultcrantz, Malin; Dogan, Ahmet; Nwankwo, George; Steidl, Ulrich; Pradhan, Kith; Hall, Charles B; Cohen, Hillel W; Jaber, Nadia; Schwartz, Theresa; Crowley, Laura; Crane, Michael; Irby, Shani; Webber, Mayris P; Verma, Amit; Prezant, David J
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.
PMID: 29710195
ISSN: 2374-2445
CID: 5863792

Tamm-Horsfall Protein/Uromodulin Deficiency Elicits Tubular Compensatory Responses Leading to Hypertension and Hyperuricemia

Liu, Yan; Goldfarb, David; El-Achkar, Tarek M; Lieske, John C; Wu, Xue-Ru
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.
PMCID:6032075
PMID: 29357410
ISSN: 1522-1466
CID: 2929382

Oral Antibiotic Exposure and Kidney Stone Disease

Tasian, Gregory E; Jemielita, Thomas; Goldfarb, David S; Copelovitch, Lawrence; Gerber, Jeffrey S; Wu, Qufei; Denburg, Michelle R
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.
PMCID:6054354
PMID: 29748329
ISSN: 1533-3450
CID: 3101652

Assessment of the combination of temperature and relative humidity on kidney stone presentations

Ross, Michelle E; Vicedo-Cabrera, Ana M; Kopp, Robert E; Song, Lihai; Goldfarb, David S; Pulido, Jose; Warner, Steven; Furth, Susan L; Tasian, Gregory E
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.
PMCID:5811384
PMID: 29289860
ISSN: 1096-0953
CID: 2899692

Personalized Intervention in Monogenic Stone Formers

Policastro, Lucas J; Saggi, Subodh J; Goldfarb, David S; Weiss, Jeffrey P
PURPOSE/OBJECTIVE:Treatment of a first-time renal stone consists of acute management followed by medical efforts to prevent stone recurrence. Although nephrolithiasis is roughly 50% heritable, the presence of a family history usually does not affect treatment since most stone disease is regarded as polygenic, ie not attributable to a single gene. Recent evidence has suggested that single mutations could be responsible for a larger proportion of renal stones than previously thought. This intriguing possibility holds the potential to change the management paradigm in stone prevention from metabolically directed therapy to more specific approaches informed by genetic screening and testing. This review synthesizes new findings concerning monogenic kidney stone disease, and provides a concise and clinically useful reference for monogenic causes. It is expected that increased awareness of these etiologies will lead to increased use of genetic testing in recurrent stone formers and further research into the prevalence of monogenic stone disease. MATERIALS AND METHODS/METHODS:We assembled a complete list of genes known to cause or influence nephrolithiasis based on recent reviews and commentaries. We then comprehensively searched PubMed® and Google Scholar™ for all research on each gene having a pertinent role in nephrolithiasis. We determined which genes could be considered monogenic causes of nephrolithiasis. One gene, ALPL, was excluded since nephrolithiasis is a relatively minor aspect of the disorder associated with the gene (hypophosphatasia). We summarized selected studies and assembled clinically relevant details. RESULTS:A total of 27 genes were reviewed in terms of recent findings, mode of inheritance of stone disease, known or supposed prevalence of mutations in the general population of stone patients and specific therapies or considerations. CONCLUSIONS:There is a distinct opportunity for increased use of genetic testing to improve the lives of pediatric and adult stone patients. Several genes first reported in association with rare disease may be loci for novel mutations, heterozygous disease and forme frustes as causes of stones in the broader population. Cases of idiopathic nephrolithiasis should be considered as potentially having a monogenic basis.
PMCID:5910290
PMID: 29061541
ISSN: 1527-3792
CID: 3150212

Comparison of the effect of allopurinol and febuxostat on urinary 2,8-dihydroxyadenine excretion in patients with APRT deficiency: A clinical trial

Edvardsson, Vidar O; Runolfsdottir, Hrafnhildur L; Thorsteinsdottir, Unnur A; Sch Agustsdottir, Inger M; Oddsdottir, G Steinunn; Eiriksson, Finnur; Goldfarb, David S; Thorsteinsdottir, Margret; Palsson, Runolfur
INTRODUCTION/BACKGROUND:Adenine phosphoribosyltransferase (APRT) deficiency is a rare, but significant, cause of kidney stones and progressive chronic kidney disease. The optimal treatment has not been established. The purpose of this pilot study was to compare the effect of the xanthine oxidoreductase inhibitors allopurinol and febuxostat on urinary 2,8-dihydroxyadenine (DHA) excretion in APRT deficiency patients. MATERIALS AND METHODS/METHODS:Patients listed in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, currently receiving allopurinol therapy, were invited to participate. The trial endpoint was the 24-h urinary DHA excretion following treatment with allopurinol (400mg/day) and febuxostat (80mg/day). Urinary DHA was measured using a novel ultra-performance liquid chromatography - electrospray tandem mass spectrometry assay. RESULTS:Eight of the 10 patients invited completed the study. The median (range) 24-h urinary DHA excretion was 116 (75-289) mg at baseline, and 45 (13-112) mg after 14days of allopurinol therapy (P=0.036). At the end of the febuxostat treatment period, 4 patients had urinary DHA below detectable limits (<20ng/mL) compared with none of the participants following allopurinol treatment (P=0.036). The other 4 participants had a median 24-h urinary DHA excretion of 13.2 (10.0-13.4) mg at the completion of febuxostat therapy (P=0.036). CONCLUSION/CONCLUSIONS:Urinary DHA excretion in APRT deficiency patients decreased with conventional doses of both allopurinol and febuxostat. Febuxostat was, however, significantly more efficacious than allopurinol in reducing DHA excretion in the prescribed doses. This finding, which may translate into improved outcomes of patients with APRT deficiency, should be confirmed in a larger sample.
PMCID:5817015
PMID: 29241594
ISSN: 1879-0828
CID: 2843942

Falsely elevated salicylate concentration in a patient with hypertriglyceridemia

Biary, Rana; Kremer, Arye; Goldfarb, David S; Hoffman, Robert S
Because salicylism is a clinical diagnosis, the serum concentration should be interpreted in conjunction with the clinical presentation. A 26-year-old man presented to the Emergency Department with abdominal painand had extremely elevated serum triglycerides (>7000 mg/dL). Ethanol, acetaminophen, and salicylate concentrations were checked because of concern of self-injurious behavior, which returned at 13.1 mg/dL, undetectable, and >100 mg/dL, respectively. His basic metabolic panel revealed a bicarbonate of 23 mEq/L and an anion gap of 11. An arterial blood gas showed a pH 7.39 and a PCO2 of 36.6 mmHg. On physical examination, he was awake and alert, and had a respiratory rate of 12–14/min. The possible effect of hyperlipidemia to falsely elevate the salicylate concentration was recognized. He was treated for severe hypertriglyceridemia and as his triglyceride level dropped, his repeat salicylate concentration was <1 mg/dL. Since dfferent sized lipoproteins contribute variably to serum sample turbiditythey have the potential to interfere with the absorption of light thereby producing erroneous laboratory results . Clinicians need to be aware of the implications of severe hyperlipidemia and interference to prevent clinical errors based on false positive laboratory results
ORIGINAL:0012414
ISSN: 2473-4306
CID: 2898312

The Healthy Hearts and Kidneys (HHK) study: Design of a 2x2 RCT of technology-supported self-monitoring and social cognitive theory-based counseling to engage overweight people with diabetes and chronic kidney disease in multiple lifestyle changes

Sevick, Mary Ann; Woolf, Kathleen; Mattoo, Aditya; Katz, Stuart D; Li, Huilin; St-Jules, David E; Jagannathan, Ram; Hu, Lu; Pompeii, Mary Lou; Ganguzza, Lisa; Li, Zhi; Sierra, Alex; Williams, Stephen K; Goldfarb, David S
Patients with complex chronic diseases usually must make multiple lifestyle changes to limit and manage their conditions. Numerous studies have shown that education alone is insufficient for engaging people in lifestyle behavior change, and that theory-based behavioral approaches also are necessary. However, even the most motivated individual may have difficulty with making lifestyle changes because of the information complexity associated with multiple behavior changes. The goal of the current Healthy Hearts and Kidneys study was to evaluate, different mobile health (mHealth)-delivered intervention approaches for engaging individuals with type 2 diabetes (T2D) and concurrent chronic kidney disease (CKD) in behavior changes. Participants were randomized to 1 of 4 groups, receiving: (1) a behavioral counseling, (2) technology-based self-monitoring to reduce information complexity, (3) combined behavioral counseling and technology-based self-monitoring, or (4) baseline advice. We will determine the impact of randomization assignment on weight loss success and 24-hour urinary excretion of sodium and phosphorus. With this report we describe the study design, methods, and approaches used to assure information security for this ongoing clinical trial. Clinical Trials.gov Identifier: NCT02276742.
PMCID:6007843
PMID: 28867396
ISSN: 1559-2030
CID: 2688792

Comparison of three technology-supported behavioral interventions for phosphorus management in hemodialysis patients [Meeting Abstract]

St-Jules, D E; Goldfarb, D S; Pompeii, M L; Sevick, M A
Background: Behavioral methods enhance the effectiveness of lifestyle interventions, but are often resource intensive. Although mobile health (mHealth) technology can help create lower input interventions, their feasibility, acceptability and efficacy have not been adequately evaluated in hemodialysis (HD) patients.
Method(s): Maintenance HD patients with persistent hyperphosphatemia (n=40) were randomized to receive: (1) educational (Edu) videos (EDU), (2) Edu + mobile selfmonitoring (SM) with MyNetDiary (MON), or (3) Edu + SM + social cognitive theory (SCT)-based behavioral counseling videos (SCT) over a 12-week period with videos for each group delivered using iPads. Serum phosphorus concentrations (sPO4) were measured at baseline, 12 and 24 weeks, and a 5-point Likert scale survey on the mHealth technology was completed at 24-weeks. Two participants in the EDU group with no follow-up sPO4 measurements were excluded; missing sPO4 measurements at 12-and 24-weeks were imputed by carrying forward the most recent sPO4 values.
Result(s): At the end of the intervention phase (12-weeks), there was a non-significant trend towards greater decreases in sPO4 in the MON (-0.5+/-1.6 mg/dL, p=0.32) and SCT (-0.3+/-2.1 mg/dL, p=0.56) groups compared to the EDU group (+0.2+/-1.4 mg/dL), but these differences had mostly disappeared by the end of the monitoring phase (24-weeks) (EDU +0.1+/-1.2 mg/dL, MON -0.1+/-1.9 mg/dL, SCT -0.1+/-2.1 mg/dL). Most participants agreed or strongly agreed that the iPads were convenient (64%), and SM helped them stay motivated (68%), take binders (61%), and limit phosphorus intake (68%). Relatively few participants reported that they agreed or strongly agreed that they sometimes "got lost" maneuvering the iPad programs (24%), felt that SM wasn't worthwhile (16%), or would have preferred face-to-face meetings offsite (4%).
Conclusion(s): Many HD patients are willing, able and report benefits of engaging in technology-supported behavioral interventions involving SM and SCT. Although these programs are easy to disseminate with limited resources once developed, any benefits for phosphorus management in HD patients may last only as long as the intervention is active
EMBASE:633733211
ISSN: 1533-3450
CID: 4755482

Analysis of gut microbiome alterations in hyperoxaluric patients [Meeting Abstract]

Nazzal, L; Liu, M; Seide, B M; Mcintosh, M; Granja, I; Asplin, J R; Ho, M; Milliner, D S; Goldfarb, D S; Blaser, M J
Background: About 60-80% of kidney stones are composed of calcium oxalate (CaOx); idiopathic CaOx kidney stones (CaOPx), primary hyperoxaluria (PH) and enteric hyperoxaluria (EH) are diseases predisposing to stones. Oxalobacter formigenes (Oxf) is a human gut commensal that depends on oxalate for its carbon and energy, and may be protective against CaOx stones. We hypothesize that the microbiome community structure differs between patients with CaOx, PH, EH and normal subjects (NS). We also expect that Oxf isolates from PH patients will result in further reduction in urinary oxalate when compared to Oxf reference strain CC13, in a germ-free (GF) mouse model.
Method(s): We collected fecal specimens from 34 subjects (mean age: 39.1 +/- 11.9 years) with PH (n=6), CaOPx (n=10), EH (n= 5) and NS (n=13) in a cross-sectional observational study, and tested fecal samples from the groups by: 1)16S rRNA sequencing to determine the microbiome community structure, 2)PCR and qPCR for Oxf colonization and, 3) culturing in high oxalate selective media for indication of Oxf presence and subsequent isolation. We isolated Oxf from 4 PH (Oxf PH) subjects. We gavaged a growing culture of PH Oxf (n=6), Oxf reference strain CC13 (Oxf CC13) (n=5), and sham (n=6) into adult C5B6 GF mice, observing them for 4 weeks. We collected urine from mice for 48 hours before sacrifice to be tested for oxalate and creatinine (Uox/cr).
Result(s): Oxf was detected in 6 (46%) of 13 NS, 1 (10%) of 10 CaOPx, 0 (0%)of 4 EH, and 5 (83%) of 6 PH. Microbiome analysis revealed that the 4 groups differed in beta diversity, based on Bray-Curtis dissimilarity (p=0.08). Alpha diversity analysis trended toward lower Shannon and phylogenetic diversity index in the CaOPx and EH subjects compared to PH and NS. Introducing the PH Oxf to GF mice led to lower Uox/cr than in uninoculated controls (0.68 +/- 0.14, and 2.26 +/-0.49, respectively, p=0.04 by Mann-Whitney U test), but not significantly different from the Oxf CC13-innoculated mice (0.68 +/- 0.14, and 0.91 +/-0.24, respectively, p=0.26 by Mann-Whitney U test).
Conclusion(s): These studies provide evidence of differences in Oxf colonization rates and in microbiome composition in patients with CaOx stones and show the functional capacity of a PH Oxf strain to ameliorate hyperoxaluria. Studies to expand these patient groups are on-going
EMBASE:633735254
ISSN: 1533-3450
CID: 4755782