Coordinate regulation of systemic and kidney tryptophan metabolism by the drug transporters OAT1 and OAT3.

How organs sense circulating metabolites is a key question. Here, we show that the multispecific organic anion transporters of drugs, OAT1 (SLC22A6 or NKT) and OAT3 (SLC22A8), play a role in organ sensing. Metabolomics analyses of the serum of Oat1 and Oat3 knockout mice revealed changes in tryptophan derivatives involved in metabolism and signaling. Several of these metabolites are derived from the gut microbiome and are implicated as uremic toxins in chronic kidney disease. Direct interaction with the transporters was supported with cell-based transport assays. To assess the impact of the loss of OAT1 or OAT3 function on the kidney, an organ where these uptake transporters are highly expressed, knockout transcriptomic data were mapped onto a "metabolic task"-based computational model that evaluates over 150 cellular functions. Despite the changes of tryptophan metabolites in both knockouts, only in the Oat1 knockout were multiple tryptophan-related cellular functions increased. Thus, deprived of the ability to take up kynurenine, kynurenate, anthranilate, and N-formylanthranilate through OAT1, the kidney responds by activating its own tryptophan-related biosynthetic pathways. The results support the Remote Sensing and Signaling Theory, which describes how "drug" transporters help optimize levels of metabolites and signaling molecules by facilitating organ cross talk. Since OAT1 and OAT3 are inhibited by many drugs, the data implies potential for drug-metabolite interactions. Indeed, treatment of humans with probenecid, an OAT-inhibitor used to treat gout, elevated circulating tryptophan metabolites. Furthermore, given that regulatory agencies have recommended drugs be tested for OAT1 and OAT3 binding or transport, it follows that these metabolites can be used as endogenous biomarkers to determine if drug candidates interact with OAT1 and/or OAT3.

The organic anion transporter (OAT) family: a systems biology perspective.

The organic anion transporter (OAT) subfamily, which constitutes roughly half of the SLC22 (solute carrier 22) transporter family, has received a great deal of attention because of its role in handling of common drugs (antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs), toxins (mercury, aristolochic acid), and nutrients (vitamins, flavonoids). Oats are expressed in many tissues, including kidney, liver, choroid plexus, olfactory mucosa, brain, retina, and placenta. Recent metabolomics and microarray data from Oat1 [Slc22a6, originally identified as NKT (novel kidney transporter)] and Oat3 (Slc22a8) knockouts, as well as systems biology studies, indicate that this pathway plays a central role in the metabolism and handling of gut microbiome metabolites as well as putative uremic toxins of kidney disease. Nuclear receptors and other transcription factors, such as Hnf4α and Hnf1α, appear to regulate the expression of certain Oats in conjunction with phase I and phase II drug metabolizing enzymes. Some Oats have a strong selectivity for particular signaling molecules, including cyclic nucleotides, conjugated sex steroids, odorants, uric acid, and prostaglandins and/or their metabolites. According to the "Remote Sensing and Signaling Hypothesis," which is elaborated in detail here, Oats may function in remote interorgan communication by regulating levels of signaling molecules and key metabolites in tissues and body fluids. Oats may also play a major role in interorganismal communication (via movement of small molecules across the intestine, placental barrier, into breast milk, and volatile odorants into the urine). The role of various Oat isoforms in systems physiology appears quite complex, and their ramifications are discussed in the context of remote sensing and signaling.

Unique metabolite preferences of the drug transporters OAT1 and OAT3 analyzed by machine learning.

The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largely-redundant roles. However, whereas examination of metabolomics data from Oat-knockout mice (Oat1 and Oat3KO) revealed considerable overlap, over a hundred metabolites were increased in the plasma of one or the other of these knockout mice. Many of these relatively unique metabolites are components of distinct biochemical and signaling pathways, including those involving amino acids, lipids, bile acids, and uremic toxins. Cheminformatics, together with a "logical" statistical and machine learning-based approach, identified a number of molecular features distinguishing these unique endogenous substrates. Compared with OAT1, OAT3 tends to interact with more complex substrates possessing more rings and chiral centers. An independent "brute force" approach, analyzing all possible combinations of molecular features, supported the logical approach. Together, the results suggest the potential molecular basis by which OAT1 and OAT3 modulate distinct metabolic and signaling pathways in vivo As suggested by the Remote Sensing and Signaling Theory, the analysis provides a potential mechanism by which "multispecific" kidney proximal tubule transporters exert distinct physiological effects. Furthermore, a strong metabolite-based machine-learning classifier was able to successfully predict unique OAT1 versus OAT3 drugs; this suggests the feasibility of drug design based on knockout metabolomics of drug transporters. The approach can be applied to other SLC and ATP-binding cassette drug transporters to define their nonredundant physiological roles and for analyzing the potential impact of drug-metabolite interactions.

The systems biology of uric acid transporters: the role of remote sensing and signaling.

PURPOSE OF REVIEW: Uric acid homeostasis in the body is mediated by a number of SLC and ABC transporters in the kidney and intestine, including several multispecific 'drug' transporters (e.g., OAT1, OAT3, and ABCG2). Optimization of uric acid levels can be viewed as a 'systems biology' problem. Here, we consider uric acid transporters from a systems physiology perspective using the framework of the 'Remote Sensing and Signaling Hypothesis.' This hypothesis explains how SLC and ABC 'drug' and other transporters mediate interorgan and interorganismal communication (e.g., gut microbiome and host) via small molecules (e.g., metabolites, antioxidants signaling molecules) through transporters expressed in tissues lining body fluid compartments (e.g., blood, urine, cerebrospinal fluid). RECENT FINDINGS: The list of uric acid transporters includes: SLC2A9, ABCG2, URAT1 (SLC22A12), OAT1 (SLC22A6), OAT3 (SLC22A8), OAT4 (SLC22A11), OAT10 (SLC22A13), NPT1 (SLC17A1), NPT4 (SLC17A3), MRP2 (ABCC2), MRP4 (ABCC4). Normally, SLC2A9, - along with URAT1, OAT1 and OAT3, - appear to be the main transporters regulating renal urate handling, while ABCG2 appears to regulate intestinal transport. In chronic kidney disease (CKD), intestinal ABCG2 becomes much more important, suggesting remote organ communication between the injured kidney and the intestine. SUMMARY: The remote sensing and signaling hypothesis provides a useful systems-level framework for understanding the complex interplay of uric acid transporters expressed in different tissues involved in optimizing uric acid levels under normal and diseased (e.g., CKD, gut microflora dysbiosis) conditions.

An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network.

There has been a recent interest in the broader physiological importance of multispecific "drug" transporters of the SLC and ABC transporter families. Here, a novel multi-tiered systems biology approach was used to predict metabolites and signaling molecules potentially affected by the in vivo deletion of organic anion transporter 1 (Oat1, Slc22a6, originally NKT), a major kidney-expressed drug transporter. Validation of some predictions in wet-lab assays, together with re-evaluation of existing transport and knock-out metabolomics data, generated an experimentally validated, confidence ranked set of OAT1-interacting endogenous compounds enabling construction of an "OAT1-centered metabolic interaction network." Pathway and enrichment analysis indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins. The partly validated reconstructed network is also consistent with a major role for OAT1 in modulating metabolic and signaling pathways involving uric acid, gut microbiome products, and so-called uremic toxins accumulating in chronic kidney disease. Together, the findings are compatible with the hypothesized role of drug transporters in remote inter-organ and inter-organismal communication: The Remote Sensing and Signaling Hypothesis (Nigam, S. K. (2015) Nat. Rev. Drug Disc. 14, 29). The fact that OAT1 can affect many systemic biological pathways suggests that drug-metabolite interactions need to be considered beyond simple competition for the drug transporter itself and may explain aspects of drug-induced metabolic syndrome. Our approach should provide novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes, and chronic kidney disease.

Association of the ADRB2 (rs2053044) polymorphism and angiotensin-converting enzyme-inhibitor blood pressure response in the African American Study of Kidney Disease and Hypertension.

AIM/OBJECTIVES/BACKGROUND: Hypertension is a risk factor for cardiovascular and kidney disease and is most prevalent in African-American adults. The renin-angiotensin-aldosterone system is integral in blood pressure regulation; angiotensin-converting enzyme inhibitors such as ramipril are first-line treatment options. As decreases in angiotensin result in catecholamine release, ß-adrenergic receptor (ADRB) polymorphisms may influence blood pressure response to ramipril. METHODS: Associations between ADRB polymorphisms and blood pressure response to ramipril were analyzed in the African American Study of Kidney Disease and Hypertension, a randomized clinical trial. A total of 336 participants were included in this analysis. Six polymorphisms were analyzed here: (a) ADRB1 rs1801252 (Ser49Gly) and rs1801253 (Gly389Arg); and (b) ADRB2 rs2053044, rs1042711, rs1042713 (Arg16Gly), and rs1042714 (Gln27Glu). Time to reach a mean arterial pressure (MAP) of 107 mmHg within the first 60 days after randomization was studied using Kaplan-Meier and Cox proportional hazards modeling for univariate and adjusted analyses. RESULTS: Genotypes at rs2053044, upstream from the ADRB2 5' untranslated region, were associated with time to reach target MAP among those randomized to the usual treatment group. Participants with the GG genotype achieved target MAP on average 12.2 days (38.1%) later than in comparison with those with the A allele (P=0.01). After adjusting for covariates, those with the AA/AG genotype had 2.09 greater odds of reaching MAP of 107 mmHg or less within 60 days of treatment in comparison with those with a GG genotype (hazard ratio=2.09, 95% confidence interval=1.21-3.60). CONCLUSION: Results suggest that ADRB2 rs2053044 genotypes may be a determinant of blood pressure response to ramipril. Additional studies are needed to clarify the effect of rs2053044 and other 5' untranslated region polymorphisms on gene expression and blood pressure response to angiotensin-converting enzyme inhibitors.

Association of phosphodiesterase 4 polymorphism (rs702553) with blood pressure in the African American Study of Kidney Disease and Hypertension Genomics Study.

Hypertension is a risk factor for diseases such as stroke, heart and kidney disease. Phosphodiesterase (PDE) enzymes play a significant role in regulating inflammation and there is some association between increased inflammatory cell mediators and development of hypertension. Previous research has shown the single nucleotide polymorphism (rs702553) on the PDE4D gene to be associated with stroke and carotid atherosclerosis. This research analyzed the association of rs702553 with baseline mean arterial blood pressure (MAP) in a subset of the African American Study of Kidney Disease and Hypertension Cohort. Data analysis identified baseline diuretic use as an interaction term in the association between this polymorphism and MAP. Compared with participants with AA/AT genotypes, those with a TT genotype at rs702553 had significantly lower baseline MAP among study participants on a diuretic (P=0.02). To our knowledge, the influence of rs702553 on final PDE4D gene expression has not yet been studied. Additional clinical and in-vitro studies are needed to better understand the biological mechanisms from gene expression to enzyme translation that affect blood pressure.

Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC).

BACKGROUND: Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. METHODS: We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over ∼4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over ∼4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. RESULTS: In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. CONCLUSION: We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association.

Challenges and Solutions in Automated Tongue Diagnosis Techniques: A Review.

Tongue diagnosis is used in various traditional medicine cultures as a non-invasive method for assessing an individual's health. Tongue image analysis has the potential for assessing the metabolism and functionality of the internal organs, making it a quick method of diagnosis. As automated systems give quantitative and objective results thereby effective in facilitating diagnosis, a review was conducted to evaluate literature on current methods of tongue diagnosis. Different methods of tongue diagnosis in the literature were identified and compared. Information on automated tongue diagnosis system, such as image acquisition, color correction, segmentation, feature extraction and classification, particularly in traditional medicine were reviewed. The aim of the review was to identify effective image processing techniques to be compatible with automated system for tongue diagnosis using some easily available to all imaging device rather than a dedicated state of art acquisition systems, which may not be easily accessible to general public. All methods identified were either being researched or developed and no specific system was identified that is currently available for routine use in clinics or home monitoring for patients. The healthcare sector could benefit from access to validated and automated tongue diagnosis systems. The feasibility of a mobile enabled platform to intelligently make use of this traditional method of diagnosis should be explored. In order to provide cheap and quick preliminary diagnosis for clinical practice automation of this noninvasive traditional technique can prove to be a boon for health care sector.

Blockade of Organic Anion Transport in Humans After Treatment With the Drug Probenecid Leads to Major Metabolic Alterations in Plasma and Urine.

Probenecid is used to treat gout and hyperuricemia as well as increase plasma levels of antiviral drugs and antibiotics. In vivo, probenecid mainly inhibits the renal SLC22 organic anion transporters OAT1 (SLC22A6), OAT3 (SLC22A8), and URAT1 (SLC22A12). To understand the endogenous role of these transporters in humans, we administered probenecid to 20 healthy participants and metabolically profiled the plasma and urine before and after dosage. Hundreds of metabolites were significantly altered, indicating numerous drug-metabolite interactions. We focused on potential OAT1 substrates by identifying 97 metabolites that were significantly elevated in the plasma and decreased in the urine, indicating OAT-mediated clearance. These included signaling molecules, antioxidants, and gut microbiome products. In contrast, urate was the only metabolite significantly decreased in the plasma and elevated in the urine, consistent with an effect on renal reuptake by URAT1. Additional support comes from metabolomics analyses of our Oat1 and Oat3 knockout mice, where over 50% of the metabolites that were likely OAT substrates in humans were elevated in the serum of the mice. Fifteen of these compounds were elevated in both knockout mice, whereas six were exclusive to the Oat1 knockout and 4 to the Oat3 knockout. These may be endogenous biomarkers of OAT function. We also propose a probenecid stress test to evaluate kidney proximal tubule organic anion transport function in kidney disease. Consistent with the Remote Sensing and Signaling Theory, the profound changes in metabolite levels following probenecid treatment support the view that SLC22 transporters are hubs in the regulation of systemic human metabolism.

Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease.

In patients with liver or kidney disease, it is especially important to consider the routes of metabolism and elimination of small-molecule pharmaceuticals. Once in the blood, numerous drugs are taken up by the liver for metabolism and/or biliary elimination, or by the kidney for renal elimination. Many common drugs are organic anions. The major liver uptake transporters for organic anion drugs are organic anion transporter polypeptides (OATP1B1 or SLCO1B1; OATP1B3 or SLCO1B3), whereas in the kidney they are organic anion transporters (OAT1 or SLC22A6; OAT3 or SLC22A8). Since these particular OATPs are overwhelmingly found in the liver but not the kidney, and these OATs are overwhelmingly found in the kidney but not liver, it is possible to use chemoinformatics, machine learning (ML) and deep learning to analyze liver OATP-transported drugs versus kidney OAT-transported drugs. Our analysis of >30 quantitative physicochemical properties of OATP- and OAT-interacting drugs revealed eight properties that in combination, indicate a high propensity for interaction with "liver" transporters versus "kidney" ones based on machine learning (e.g., random forest, k-nearest neighbors) and deep-learning classification algorithms. Liver OATPs preferred drugs with greater hydrophobicity, higher complexity, and more ringed structures whereas kidney OATs preferred more polar drugs with more carboxyl groups. The results provide a strong molecular basis for tissue-specific targeting strategies, understanding drug-drug interactions as well as drug-metabolite interactions, and suggest a strategy for how drugs with comparable efficacy might be chosen in chronic liver or kidney disease (CKD) to minimize toxicity.

CYP3A4 and CYP3A5 polymorphisms and blood pressure response to amlodipine among African-American men and women with early hypertensive renal disease.

PURPOSE: To explore the association between CYP3A4 and CYP3A5 gene polymorphisms and blood pressure response to amlodipine among participants from the African-American Study of Kidney Disease and Hypertension Trial randomized to amlodipine (n = 164). METHODS: Cox proportional hazards models were used to determine the risk of reaching a target mean arterial pressure (MAP) of < or =107 mm Hg by CYP3A4 (A-392G and T16090C) and CYP3A5 (A6986G) gene polymorphisms, stratified by MAP randomization group (low or usual) and controlling for other predictors for blood pressure response. RESULTS: Women randomized to a usual MAP goal with an A allele at CYP3A4 A-392G were more likely to reach a target MAP of 107 mm Hg. The adjusted hazard ratio (AA/AG compared to GG) with 95% confidence interval was 3.41 (1.20-9.64; p = 0.020). Among participants randomized to a lower MAP goal, those with the C allele at CYP3A4 T16090C were more likely to reach target MAP: The adjusted hazard ratio was 2.04 (1.17-3.56; p = 0.010). After adjustment for multiple testing using a threshold significance level of p = 0.016, only the CYP3A4 T16090C SNP remained significant. CYP3A5 A6986G was not associated with blood pressure response. CONCLUSIONS: Our findings suggest that blood pressure response to amlodipine among high-risk African-Americans appears to be determined by CYP3A4 genotypes, and sex specificity may be an important consideration. Clinical applications of CYP3A4 genotype testing for individualized treatment regimens warrant further study.

Common charge-shift mutation Glu65Lys in K+ channel ß1-Subunit KCNMB1: pleiotropic consequences for glomerular filtration rate and progressive renal disease.

BACKGROUND: Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca(2+) influx, which is controlled by the regulatory ß1-subunit (KCNMB1) of large-conductance heteromeric K+ ('BK') channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline. METHODS: We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance). RESULTS: The 65Lys variant was relatively common, occurring on ∼5-10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019). CONCLUSIONS: Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.

Progression of chronic kidney disease: Adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis.

BACKGROUND: African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease. METHODS: We used the African-American Study of Kidney Disease to probe whether beta2-adrenergic receptor (ADRB2) predicts glomerular filtration rate (GFR) decline rate. A total of 580 participants were included. Baseline GFR was 51.2 +/- 0.5 ml/min/1.73 m2. Subjects were randomized in a 2 x 3 block design: to intensively lowered (MAP < or = 92 mm Hg) versus 'usual' (MAP = 102-107 mm Hg) blood pressure goal groups, and also divided by three randomized antihypertensive drugs (ramipril, metoprolol, or amlodipine). We scored 4 SNPs at the ADRB2 locus. RESULTS: Haplotypes at ADRB2 predicted chronic GFR decline rate, GFR declined more slowly in individuals with haplotype-1 (-804G-->173T-->16Gly-->27GIn), and faster in those who carried haplotype-3 (-804G-->173T-->16Arg-->27Gln). ADRB2 genotype interacted with antihypertensive drug class to influence GFR slope (p = 0.001-0.037). We extended our findings to an independent case/control sample of Black hypertensive ESRD, in which we found that variant Gly16Arg that tagged the GFR slope-determining ADRB2 haplotype also conferred risk for the ESRD trait in Blacks. CONCLUSIONS: The GFR decline/progression rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway.

Naturally occurring genetic variants in human chromogranin A (CHGA) associated with hypertension as well as hypertensive renal disease.

Chromogranin A (CHGA) plays a fundamental role in the biogenesis of catecholamine secretory granules. Changes in storage and release of CHGA in clinical and experimental hypertension prompted us to study whether genetic variation at the CHGA locus might contribute to alterations in autonomic function, and hence hypertension and its target organ consequences such as hypertensive renal disease (nephrosclerosis). Systematic polymorphism discovery across the human CHGA locus revealed both common and unusual variants in both the open reading frame and such regulatory regions as the proximal promoter and 30-UTR. In chromaffin cell-transfected CHGA 30-UTR and promoter/luciferase reporter plasmids, the functional consequences of the regulatory/non-coding allelic variants were documented. Variants in both the proximal promoter and the 30-UTR displayed statistical associations with hypertension. Genetic variation in the proximal CHGA promoter predicted glomerular filtration rate in healthy twins. However, for hypertensive renal damage, both end-stage renal disease and rate of progression of earlier disease were best predicted by variants in the 30-UTR. Finally, mechanistic studies were undertaken initiated by the clue that CHGA promoter variation predicted circulating endothelin-1. In cultured endothelial cells, CHGA triggered co-release of not only the vasoconstrictor and pro-fibrotic endothelin-1, but also the pro-coagulant von Willebrand Factor and the pro-angiogenic angiopoietin-2. These findings, coupled with stimulation of endothelin-1 release from glomerular capillary endothelial cells by CHGA, suggest a plausible mechanism whereby genetic variation at the CHGA locus eventuates in alterations in human renal function. These results document the consequences of genetic variation at the CHGA locus for cardiorenal disease and suggest mechanisms whereby such variation achieves functional effects.

Active surveillance compared with initial treatment for men with low-risk prostate cancer: a decision analysis.

CONTEXT: In the United States, 192,000 men were diagnosed as having prostate cancer in 2009, the majority with low-risk, clinically localized disease. Treatment of these cancers is associated with substantial morbidity. Active surveillance is an alternative to initial treatment, but long-term outcomes and effect on quality of life have not been well characterized. OBJECTIVE: To examine the quality-of-life benefits and risks of active surveillance compared with initial treatment for men with low-risk, clinically localized prostate cancer. DESIGN AND SETTING: Decision analysis using a simulation model was performed: men were treated at diagnosis with brachytherapy, intensity-modulated radiation therapy (IMRT), or radical prostatectomy or followed up by active surveillance (a strategy of close monitoring of newly diagnosed patients with serial prostate-specific antigen measurements, digital rectal examinations, and biopsies, with treatment at disease progression or patient choice). Probabilities and utilities were derived from previous studies and literature review. In the base case, the relative risk of prostate cancer-specific death for initial treatment vs active surveillance was assumed to be 0.83. Men incurred short- and long-term adverse effects of treatment. PATIENTS: Hypothetical cohorts of 65-year-old men newly diagnosed as having clinically localized, low-risk prostate cancer (prostate-specific antigen level <10 ng/mL, stage ≤T2a disease, and Gleason score ≤6). MAIN OUTCOME MEASURE: Quality-adjusted life expectancy (QALE). RESULTS: Active surveillance was associated with the greatest QALE (11.07 quality-adjusted life-years [QALYs]), followed by brachytherapy (10.57 QALYs), IMRT (10.51 QALYs), and radical prostatectomy (10.23 QALYs). Active surveillance remained associated with the highest QALE even if the relative risk of prostate cancer-specific death for initial treatment vs active surveillance was as low as 0.6. However, the QALE gains and the optimal strategy were highly dependent on individual preferences for living under active surveillance and for having been treated. CONCLUSIONS: Under a wide range of assumptions, for a 65-year-old man, active surveillance is a reasonable approach to low-risk prostate cancer based on QALE compared with initial treatment. However, individual preferences play a central role in the decision whether to treat or to pursue active surveillance.

Clinic Use at the Departments of Defense and Veterans Affairs Following Combat Related Amputations.

INTRODUCTION: Little population-based research has described the transition from Department of Defense (DoD) to Department of Veterans Affairs (VA) healthcare following combat related amputations. The objectives were to describe (1) to what extent patients used either DoD only facilities, both DoD and VA facilities, or VA only facilities during the first 5 years postinjury, (2) which specific clinics were used and (3) clinic use among patients with different levels of amputation (upper versus lower), and among patients with early or late amputation. MATERIALS AND METHODS: This was a retrospective analysis of health data extracted from the expeditionary medical encounter database (EMED) and national DoD and VA databases. Patients were 649 US service members who sustained a single major limb amputation following injuries in the Iraq and Afghanistan conflicts, 2001-2008. We compared yearly DoD and VA clinic use by patient groups with different levels of amputation (upper limb: above versus below elbow or lower limb: above versus below knee), different timing of amputation (early: within 90 days postinjury versus late: more than 90 days postinjury), military component (Active Duty versus National Guard/Reserve) and race (White versus Black). For all groups, we calculated the percentage of patients using: (1) DoD only, (2) both DoD and VA or 3) VA only clinics during each of postinjury years 1 through 5. We also calculated the percentage of patients who used specific clinics (e.g., social work, prosthetics, mental health) during each postinjury year. RESULTS: During postinjury year 1, over 98% of patients used DoD only or both DoD and VA clinics. Most individuals (70% to 78%) used both DoD and VA clinics during postinjury year 1. Use of VA only clinics increased gradually between postinjury year 2 (15% to 30% of patient groups) and year 5 (75% to 88%). This gradual transition to use of VA only clinics was seen consistently across patient groups with different anatomical levels or timing of amputation, military component or race. Patients with lower levels of amputation (versus higher levels) and individuals with early amputations (versus late) transitioned earlier to VA only care. Overall, clinic use was high as 91% to 100% of all patient groups used one or more clinics (DoD or VA) during each of the first 5 years. For specific clinics, most patients used DoD facilities related to rehabilitation (physical therapy, prosthetics) or transitional care (social work) particularly during postinjury year 1. Use of most VA clinics studied (social work, primary care, prosthetics, mental health) showed a modest increase primarily after postinjury year 1 and remained stable through postinjury year 5. The results indicated apparent underuse of psychiatric/mental health and prosthetics between postinjury year 1 and 2. CONCLUSIONS: The present study indicated a gradual transition from DoD to VA only healthcare which extended across 5 years following combat related amputations. Patients with lower levels of amputation or early amputation generally transitioned earlier to VA only healthcare. These results can inform medical planning to support a timely and clinically effective transition from DoD to VA healthcare.

Outpatient Pharmacy Prescriptions During the First Year Following Serious Combat Injury: A Retrospective Analysis.

INTRODUCTION: Limited research has analyzed the full range of outpatient medication prescription activity following serious combat injury. The objectives of this study were to describe (1) outpatient medication prescriptions and refills during the first 12 months after serious combat injury, (2) longitudinal changes in medication prescriptions during the first-year postinjury, and (3) patient characteristics associated with outpatient prescriptions. MATERIALS AND METHODS: This was a retrospective analysis of existing health and pharmacy data for a random sample of U.S. service members who sustained serious combat injuries in the Iraq and Afghanistan conflicts, 2010-2013 (n = 381). Serious injury was defined by an Injury Severity Score (ISS) of 9 or greater. These patients typically participate in military rehabilitation programs (eg, amputation care) where prescription medications are essential. Data sources were the Expeditionary Medical Encounter Database for injury-specific data, the Pharmacy Data Transaction Service for outpatient medication prescriptions and refills, and the Military Health System Data Repository for diagnostic codes of pain and psychological disorders. Military trauma nurses reviewed casualty records to identify types of injuries. Using the American Hospital Formulary Service Pharmacologic-Therapeutic Classification system, clinicians identified 13 categories of prescription medications (eg, opioid, psychotherapeutic, immunologic) for analysis. Multivariable negative binomial and logistic regression analyses evaluated significant associations between independent variables (eg, blast injury, traumatic brain injury [TBI], ISS, limb amputation, diagnoses of chronic pain, or psychological disorders) and prescription measures (ie, number or category of medication prescriptions). We also describe longitudinal changes in prescription activity postinjury across consecutive quarterly intervals (91 days) during the first-year postinjury. RESULTS: During the first-year postinjury, patients averaged 61 outpatient prescriptions, including all initial prescriptions and refills. They averaged eight different categories of medications, primarily opioid, immunologic, gastrointestinal/genitourinary, central nervous system (CNS), nonopioid analgesic, and psychotherapeutic medications (representing 82% of prescriptions) during the first year. Prescription activity generally declined across quarters. There was still substantial prescription activity during the fourth quarter, as 79% of patients had at least one prescription. From 39 to 49% of patients had fourth-quarter prescriptions for opioid, CNS, or psychotherapeutic medications. Longitudinally, we found that 24-34% of patients had an opioid, CNS, or psychotherapeutic prescription during each of the final three quarters. In multivariable analysis, ISS, limb amputation (particularly bilateral amputation), and diagnoses of chronic pain and post-traumatic stress disorder (PTSD) were associated with significantly higher counts of individual and multiple medication prescriptions. TBI was associated with significantly lower numbers of prescriptions for certain medications. CONCLUSIONS: This is one of the first studies to provide a systematic analysis of outpatient medication prescriptions following serious combat injury. The results indicate substantial prescription activity from multiple medication categories throughout the first-year postinjury. Diagnoses of chronic pain, PTSD, and limb amputation and ISS were associated with significantly higher counts of prescriptions overall and more prescription medication categories. This study provides initial evidence to better understand medication prescription activity following serious combat injury. The results inform future research on medication prescription practices and planning for rehabilitation.

The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology.

Quantitative systems pharmacology (QSP) has emerged as a transformative science in drug discovery and development. It is now time to fully rethink the biological functions of drug metabolizing enzymes (DMEs) and transporters within the framework of QSP models. The large set of DME and transporter genes are generally considered from the perspective of the absorption, distribution, metabolism, and excretion (ADME) of drugs. However, there is a growing amount of data on the endogenous physiology of DMEs and transporters. Recent studies-including systems biology analyses of "omics" data as well as metabolomics studies-indicate that these enzymes and transporters, which are often among the most highly expressed genes in tissues like liver, kidney, and intestine, have coordinated roles in fundamental biological processes. Multispecific DMEs and transporters work together with oligospecific and monospecific ADME proteins in a large multiorgan remote sensing and signaling network. We use the Remote Sensing and Signaling Theory (RSST) to examine the roles of DMEs and transporters in intratissue, interorgan, and interorganismal communication via metabolites and signaling molecules. This RSST-based view is applicable to bile acids, uric acid, eicosanoids, fatty acids, uremic toxins, and gut microbiome products, among other small organic molecules of physiological interest. Rooting this broader perspective of DMEs and transporters within QSP may facilitate an improved understanding of fundamental biology, physiologically based pharmacokinetics, and the prediction of drug toxicities based upon the interplay of these ADME proteins with key pathways in metabolism and signaling. The RSST-based view should also enable more tailored pharmacotherapy in the setting of kidney disease, liver disease, metabolic syndrome, and diabetes. We further discuss the pharmaceutical and regulatory implications of this revised view through the lens of systems physiology.

Association of Race and Major Adverse Cardiac Events (MACE): The Atherosclerosis Risk in Communities (ARIC) Cohort.

BACKGROUND AND AIMS: To evaluate the association of self-reported race with major adverse cardiac events (MACE) and modification of this association by paraoxonase gene (PON1, PON2, and PON3) single nucleotide polymorphisms (SNPs). METHODS: Included in this longitudinal study were 12,770 black or white participants from the Atherosclerosis Risk in Communities (ARIC) cohort who completed a baseline visit (1987-1989) with PON genotyping. Demographic, behavioral, and health information was obtained at baseline. MACE was defined as first occurrence of myocardial infarction, stroke, or CHD-related death through 2004. Cox proportional hazards regression was used to evaluate the association between race and MACE after adjustment for age, gender, and other demographic and cardiovascular risk factors such as diabetes and hypertension. Modification of the association between PON SNPs and MACE was also assessed. RESULTS: Blacks comprised 24.6% of the ARIC cohort; overall, 14.0% of participants developed MACE. Compared with whites, blacks had 1.24 times greater hazard of MACE (OR = 1.24,95%CI = 1.10,1.39) than whites after adjusting for age, gender, BMI, cigarette and alcohol use, educational and marital status, and aspirin use. This association became nonsignificant after further adjustment for high cholesterol, diabetes, and hypertension. None of the evaluated SNPs met the significance level (p < 0.001) after Bonferroni correction for multiple comparisons. CONCLUSIONS: No association between race and MACE was identified after adjusting for high cholesterol, diabetes, and hypertension, suggesting that comorbidities are major determinants of MACE; medical intervention with focus on lifestyle and health management could ameliorate the development of MACE. Further studies are needed to confirm this observation.