Semantic Data Platform for Healthcare Lead beneficiary: MUG D3.1 Sketch of system Date: 31/03/2014 architecture specification Nature: Report WP3 – Architecture and Dissemination level: PU D3.1 – Sketch of system architecture specification WP3: Architecture and Requirements Dissemination level: Public Authors: Philipp Daumke, Carla Haid, Luke Mertens (Averbis),
Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type2 diabetesRole of elevated serum uric acid levels at theonset of overt nephropathy in the risk for renalfunction decline in patients with type 2diabetesKentaro Tanaka1, Shigeko Hara1, Masakazu Hattori2, Ken Sakai3, Yukiko Onishi1, Yoko Yoshida1, Shoji Kawazu1,Akifumi Kushiyama1*1Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, 3Department of Nephrology, School of Medicine, Faculty of Medicine, TohoUniversity, Tokyo, and 2Division of Diabetes, Clinical Research Center for Endocrinology and Metabolic Diseases, National Hospital Organization, Kyoto Medical Center, Kyoto, Japan Risk factors, Type 2 diabetic Aims/Introduction: Despite the use of intensive therapies, declining renal function is nephropathy, Uric acid often observed during the overt nephropathy stage of type 2 diabetes. We aimed atinvestigating the role of serum uric acid (SUA) levels at the onset of overt nephropathy in the risk of renal function decline in type 2 diabetes patients.
Akifumi Kushiyama Materials and Methods: The present cohort study included 290 type 2 diabetes Tel.: +81-3-3639-5501 patients who were followed from the onset of overt nephropathy. The relationship Fax: +81-3-3639-5520 between SUA and declining renal function was assessed using Cox regression models E-mail address: [email protected] after adjusting for known risk factors.
Results: Over a median 4.8-year follow-up period, 85 patients (4.9/100 person-years) J Diabetes Invest 2014 showed serum creatinine (Cr) doubling with a total cumulative incidence of 71.9% at20 years of follow up. The highest SUA tertile resulted in significantly a higher incidence doi: 10.1111/jdi.12243 (7.7/100 person-years) and cumulative incidence at 20 years (85.7%) than the middle (3.9/100 person-years, 54.2%) and lowest (3.0/100 person-years, 55.5%) tertiles. The univariateCox hazard model resulted in significant risks for Cr doubling related to female sex, shortdiabetes duration, smoking and elevated levels of low-density lipoprotein cholesterol (LDL-c), glycated hemoglobin and SUA tertiles. SUA tertiles remained statistically significant inthe multivariate model (highest vs lowest hazard ratio 2.68, 95% confidence interval 1.48-5.00, P = 0.0009).
Conclusions: Elevated SUA levels within the normal range (men >6.3 mg/dL, women>5.1) at the onset of overt nephropathy resulted in an increased risk for declining renalfunction in type 2 diabetes patients.
arterial blood pressure, albuminuria, glycemic control and lipid Nephropathy related to type 2 diabetes is one of the leading control, play a role in the progression of diabetic nephropathy2.
causes of end-stage renal disease (ESRD), and is also associated In the early microalbuminuria stage, intensive multifactorial with an increased risk of cardiovascular morbidity and mortal- therapy that includes glycemic, lipid and blood pressure control, ity. Over the past 15 years, it has emerged as the primary rea- in addition to smoking cessation, has induced remission and son for initiating dialysis in Japan1. Modiﬁable factors, such as improved renal function3,4. There is little evidence of the contri-bution of these factors in the prevention of the progressive lossof renal function in advanced diabetic nephropathy5. The evi- Received 13 November 2013; revised 11 March 2014; accepted 7 April 2014 dence is limited to the effect of hypertension management and ª 2014 The Authors. Journal of Diabetes Investigation published by Asian Association of the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd J Diabetes Invest Vol. No. 2014 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution andreproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
a low-protein diet6. Despite the use of these intensive therapies, Cr from the baseline values: the Cr doubling group (doubling the loss of renal function progresses, after the onset of overt of serum Cr) and the non-doubling group.
nephropathy, to ESRD in the majority of cases. One studyreported that various early biomarkers are associated with the Clinical Measurements development of diabetic nephropathy7.
The following data were collected: age (years), body mass index Recent studies have documented that elevated serum uric (BMI; kg/m2), diabetes duration (years), systolic and diastolic blood pressure (mmHg), glycated hemoglobin (HbA1c; %), development of type 2 diabetes itself8. SUA is also associated high-density lipoprotein-cholesterol (HDL-C; mg/dL), low-den- with known risk factors for kidney disease progression9, sity lipoprotein-cholesterol (LDL-C; mg/dL), triglycerides (mg/ including hypertension10, cardiovascular disease11–13 and ath- dL), SUA (mg/dL), Cr (mg/dL), estimated glomerular ﬁltration erosclerosis12. SUA has not been investigated as a risk factor rate (eGFR; mL/[min1.73 m2]), hemoglobin (g/dL), smoking for declining renal function in patients with type 2 diabetes status (yes/no) and medication usage. HbA1c values were con- who are at the onset of overt nephropathy, although SUA verted as previously described16,17. A turbidimetric immunoas- was previously reported in the early stage of diabetic say (Code 468-34691; Wako Pure Chemical Industries, Ltd, Osaka, Japan) was used for the measurement of urinary albu- The present study aimed to determine the role of SUA levels min. The eGFR was calculated using the estimation formula at the onset of overt nephropathy in the risk of renal function advocated by the Japanese Society of Nephrology18: eGFR (mL/ decline in patients with type 2 diabetes.
[min1.73 m2]) = 194 9 Cr-1.094 9 age-0.287 female patients). In the case of serum creatinine concentration being measured by Jaffe assay, the enzymatic value was esti- Study Design and Participants The present study was a retrospective, observational cohort enzyme = 0.977 9 serum creatinine Jaffe - 0.199 (given in study of patients with type 2 diabetes attending the Institute for mg/dL)19. Proteinuria was examined by dipstick analysis, semi- Adult Diseases, Asahi Life Foundation, Tokyo, Japan. The pro- quantitatively deﬁned as ‘1+', which indicated approximately tocol was approved by the Committee of Ethics in this institu- 30 mg/dL, approximately 0.3 g/day urinary protein excretion; tion. Patients gave informed consent.
‘2+' 100 mg/dL, approximately 1 g/day; and ‘3+' ≥300 mg/dL, The inclusion criteria included the following: (i) aged approximately 3 g/day, respectively20. All laboratory data were ≥18 years; (ii) attending the hospital outpatient clinic for treat- measured under the right conditions (without gout and change ment of type 2 diabetes; (iii) diagnosis of diabetic nephropathy of prescription).
between January 1969 and December 2008.
Diabetic nephropathy was clinically diagnosed using the fol- lowing criteria15: (i) diabetes duration >10 years; (ii) diabetic Decline in renal function was deﬁned as the doubling of serum retinopathy before the onset of overt proteinuria; and (iii) Cr. Hypertension was deﬁned as a systolic blood pressure persistent albuminuria with no evidence of other kidney or uro- ≥130 mmHg and/or a diastolic blood pressure ≥80 mmHg logical disease. The onset of overt nephropathy was deﬁned as and/or the current use of antihypertensive medication. Dyslipi- the data of ﬁrst urinary albumin/creatinine ratio ≥300 mg/g demia was deﬁned as a LDL-C level ≥120 mg/dL, HDL-C level creatinine (Cr) or positive proteinuria by dipstick analysis <40 mg/dL and/or the current use of lipid-lowering medication.
examination. The albuminuria or proteinuria was conﬁrmed by Hyperuricemia was deﬁned as a SUA level ≥7.0 mg/dL for repeated testing on a different day, and the follow-up period men or ≥6.0 mg/dL for women and/or the current use of anti- started. Diabetic retinopathy was diagnosed as retinal bleeding and was conﬁrmed by an ophthalmologist. From these criteria, Coronary heart disease (CHD) was deﬁned as myocardial 313 patients were included.
infarction, and angina pectoris was conﬁrmed by coronary The exclusion criteria included the following: (i) undeﬁned intervention. Stroke was deﬁned as bleeding, and ischemic history of nephropathy onset; (ii) patients with other kidney or stroke included lacunae infarctions with symptoms conﬁrmed urological disease; and (iii) patients with another cause of pro- by brain computed tomography (CT) or magnetic resonance teinuria, such as acute infectious disease and heart failure.
imaging (MRI). Arteriosclerosis obliterans (ASO) was diagnosed Patients with hypertension were not excluded if there was no using angiography with enhanced CT or MRI and/or an ankle- evidence of a causal role of hypertension in proteinuria.
brachial pressure index (ABI) <0.9. Aortic calciﬁcation was con- We excluded 23 patients with an undeﬁned history of ﬁrmed by chest radiography.
nephropathy onset. The remaining 290 patients (231 men and59 women, age 35-94 years, median follow-up period Statistical Analysis 4.8 years) comprised the sample for the present study, and The data are expressed as mean – standard deviation (SD).
were followed from the onset of nephropathy until October The differences between the two groups were assessed 2009. The patients were grouped according to changes in serum using unpaired Student's t-tests for continuous variables and J Diabetes Invest Vol. No. 2014 ª 2014 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd Role of uric acid in T2DN chi-squared tests for categorical variables. The relationship Figure 1 shows the results of the Kaplan–Meier survival between SUA levels and residual renal function (eGFR) was ana- analysis for the incidence of Cr doubling. A total of 85 lyzed using Spearman's correlation analysis. SUA levels were strat- (29.3%) of the 290 patients showed Cr doubling during the iﬁed into tertiles, which were calculated separately for men (lower follow-up period (median 4.8 years, range 0-22 years), result- tertile: <310 lmol/L [5.2 mg/dL]; middle: 310-380 lmol/L [5.2- ing in an incidence of 4.9 out of 100 person-years and a total 6.3 mg/dL]; upper: >380 lmol/L [6.3 mg/dL]) and women cumulative incidence of 71.9% at 20 years of follow up. Analy- (lower tertile: <244 lmol/L [4.1 mg/dL]; middle: 244-303 lmol/ sis according to the baseline SUA tertiles resulted in an inci- L [4.1-5.1 mg/dL]; upper: >303 lmol/L [5.1 mg/dL], respec- dence and cumulative incidence of Cr doubling at 20 years of tively), because SUA levels in women tend to be lower than those 3.0 out of 100 person-years and 55.5% in the lowest tertile, 3.9 out of 100 person-years and 54.2% in the middle tertile, and Decline in renal function (doubling of serum Cr) was ana- 7.7 out of 100 person-years and 85.7% in the highest tertile.
lyzed using the Kaplan–Meier method, and the signiﬁcance was Patients in the highest tertile had a signiﬁcantly higher risk of calculated using the log–rank test. Cox proportional hazards Cr doubling than those in the lower two tertiles (log–rank test, regression modeling was used to assess the independent risk P = 0.0008).
factors for Cr doubling. The multivariate model accounted for The results from the univariate Cox regression analyses are baseline values of age (years), sex (men vs women), diabetes shown in Table 2. Cr doubling was signiﬁcantly associated with duration (years), smoking status (yes/no), BMI (kg/m2), HbA1c sex (women HR 2.28, 95% CI 1.42-3.57, P = 0.0009), diabetes (%), systolic blood pressure (mmHg), LDL-C (mg/dL), use of duration (HR 0.95, 95% CI 0.93-0.98, P = 0.004), LDL-C (HR medical agents (antiplatelet, antihyperuricemic, antihypertensive 1.00, 95% CI 1.00-1.01, P = 0.03), smoking status (yes HR or lipid lowering medication), eGFR (mL/[min1.73 m2]), 2.17, 95% CI 1.40-3.43, P = 0.0005), HbA1c levels (HR 1.32, proteinuria (1+, 2+, 3+) and SUA. These results are presented 95% CI 1.19-1.46, P < 0.0001), eGFR (HR 1.01, 95% CI 1.00- as hazard ratios (HR) with 95% conﬁdence intervals (95% CI).
1.02, P = 0.01) and SUA tertiles (main effect P = 0.001; highest HRs for continuous variables are described against a 1-SD vs middle HR 1.87, 95% CI 1.12-3.23, P = 0.01; middle vs low- change. Furthermore, P-values <0.05 were considered to be sta- est HR 1.35, 95% CI 0.71-2.59, P = 0.34; highest vs lowest HR tistically signiﬁcant. Analyses were carried out using JMP soft- 2.54, 95% CI 1.50-4.50, P = 0.0004). Of note, the highest tertile ware (version 9.0; SAS Institute, Cary, NC, USA).
for SUA was a strong risk factor for declining renal function,even though 86.2% of the patients in the highest SUA tertile Power Calculation had borderline normal levels (6.3-7.0 mg/dL in men and 5.1- We are planning a study with 96 experimental participants, 96 7.0 mg/dL in women). Age, BMI, systolic blood pressure, use control participants, an accrual interval of 0 years, and addi- of antiplatelet agents, use of antihypertensive agents, use of sta- tional follow up of a median of 4.8 years. In a previous study22, tin, degree of proteinuria and a previous history of coronary the median survival time on the control treatment was 5 years.
heart diseases were not signiﬁcant risk factors. Furthermore, a If the true hazard ratio of control participants relative to experi- previous history of stroke and ASO, and aortic calciﬁcation mental participants is 2, we will be able to reject the null were not signiﬁcant (data not shown).
hypothesis that the experimental and control survival curves In the multivariate Cox regression analysis, model 1 includes are equal with probability (power) 0.871. The type I error prob- parameters only signiﬁcant in the univariate model and ability associated with this test of the null hypothesis is 0.05.
model 2 includes all. In model 1, the risks for Cr doublingincluded sex, smoking status, HbA1c levels and SUA tertiles (main effect: P = 0.008; highest vs lowest HR 2.37, 95% CI The demographic and clinical characteristics of the 290 patients 1.35-4.30, P = 0.002; highest vs middle HR 1.70, 95% CI at baseline are shown in Table 1. The mean age of study par- 0.88-3.31, P = 0.11; middle vs lowest HR 1.39, 95% CI 0.81- ticipants was 61.9 – 9.8 years, the mean diabetes duration was 2.46, P = 0.23) remained signiﬁcant. In model 2, the risks for 18.0 – 8.5 years and the mean duration of study follow up was Cr doubling included smoking status (yes HR 1.74, 95% CI 5.8 – 4.1 years. The baseline biochemical and clinical character- 1.07-2.87, P = 0.02), HbA1c levels (HR 1.25, 95% CI 1.09- istics of the patients in their respective groups (Cr doubling or 1.42, P = 0.0009) and SUA tertiles (main effect P = 0.003; non-doubling) are also shown in Table 1. A total of 135 highest vs lowest HR 2.68, 95% CI 1.48-5.00, P = 0.0009; patients were treated with insulin, and 144 patients were treated highest vs middle HR 1.70, 95% CI 0.88-2.86, P = 0.12; mid- with diet therapy and oral hypoglycemic drugs at the baseline.
dle vs lowest HR 1.57, 95% CI 0.86-3.40, P = 0.12). The high- As compared with the non-doubling group, the Cr doubling est SUA remained signiﬁcant after adjustment for confounding group was signiﬁcantly younger, with a signiﬁcantly shorter duration of diabetes; however, the Cr doubling group showed a In the non-doubling group, there was a signiﬁcant (r = 0.35, signiﬁcantly more severe pathological state (higher HbA1c lev- P < 0.0001) correlation between eGFR and SUA, but the same els, more overt proteinuria, major angiopathy and higher SUA relationship was not signiﬁcant (r = 0.20, P = 0.062) in the doubling group (Figure 2a,b).
ª 2014 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd J Diabetes Invest Vol. No. 2014 Table 1 Demographics and clinical characteristics of participants at the start of follow up Total sample (n = 290) Cr doubling group (n = 85) Non-doubling group (n = 205) Diabetes duration (years) Body mass index (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) Triglycerides (mg/dL) Uric acid (mg/dL) Creatinine (mg/dL) eGFR (mL/[min1.73 m2]) Hemoglobin (g/dL) Proteinuria (1+, 2+, 3+) (%) Smoking status, % (n) Hypertension, % (n) Dyslipidemia, % (n) Hyperuricemia, % (n) Antiplatelet agent use, % (n) Antihypertensive agent use, % (n) Renin–angiotensin system inhibitors, % (n) Statin use, % (n) Antihyperuricemia agent use, % (n) Aortic calcification, % (n) ASO, arteriosclerosis obliterans; BP, blood pressure; CHD, coronary heart disease; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemo-globin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. aThe statistical significance was estimated using inde-pendent Student's t-tests for continuous variables and chi-squared tests for categorical variables (P < 0.05). Comparisons were made between thecreatinine (Cr) doubling group and the non-doubling group. Values are reported as mean – standard deviation or as % (n), where indicated.
function in the univariate analysis, and we hypothesize that the To our knowledge, this is the ﬁrst report to show SUA levels at eGFR would continue to increase in the high-risk group, if the the onset of overt nephropathy as a risk factor for declining follow up continued.
renal function in patients with type 2 diabetes. An elevated Elevated SUA levels have previously been associated with SUA level within the normal range (>380 lmol/L [6.4 mg/dL] eGFR, albeit with decreased eGFR28. SUA levels are determined in men, >303 lmol/L [5.1 mg/dL] in women) emerged as a by UA production and excretion, and UA is produced by xan- strong and independent risk factor for renal function decline.
thine oxidoreductase. Oxidoreductase activity also contributes These ﬁndings complement those reported previously in type 1 to macrophage foam cell formation and inﬂammation29, and diabetes regarding the signiﬁcant predictive abilities of UA for macrophage activation is thought to be involved in the patho- the development of diabetic nephropathy23,24.
genesis of overt nephropathy30. Therefore, UA production Renal condition at baseline, measured as the eGFR, is might be assessed using SUA and eGFR, which could be a another important predictor of the decline in renal function.
diagnostic and monitoring marker for renal injury.
Generally, low eGFR is considered a risk factor for the progres- The target SUA value for therapeutic intervention has not sion of renal dysfunction25. However, in patients with type 2 been clariﬁed to prevent renal function decline or arteriosclero- diabetes, glomerular hyperﬁltration and the accompanying sis. It is speculated from the present results and previous small increase in eGFR, which is observed in 0–40% of patients with size, short-term intervention studies including non-diabetic type 2 diabetes26, contributes to loss of renal function patients that UA-lowering treatment has a renoprotective effect, and nephropathy27. Similarly, in the current study, increased and inhibits oxidative stress, atherogenesis, hypertension and eGFR at baseline was a signiﬁcant risk factor for impaired renal vascular endothelial damage31–33. The use of UA-lowering J Diabetes Invest Vol. No. 2014 ª 2014 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd Role of uric acid in T2DN The recommended multifactorial management of type 2 dia- betic nephropathy is to stop smoking35 and to maintain the fol- P = 0.0008 lowing: blood pressure <130/85 mmHg, HbA1c <7.0% and LDL-C < 100 mg/dL36. Of these, poor glycemic control, ele- vated LDL-C and smoking, but not high blood pressure, were signiﬁcant risk factors for renal dysfunction in the currentstudy. In addition to these known factors, SUA also probably increased the risk of declining renal function. Further evidence for the use of UA-lowering treatment for renoprotection is The present study had several limitations. First, this was a retrospective observational study carried out in a single institution. A large-scale intervention is required to verify the effectiveness of UA-lowering therapy for renoprotection.
Second, the artiﬁcial conversion between serum creatinine Figure 1 Kaplan–Meier curves for the doubling of serum creatinine values obtained in different periods was a limitation.
(Cr) in 290 patients with type 2 diabetes and overt nephropathy Furthermore, we did not evaluate the available types of anti- stratified by sex-specific tertiles (T1, T2, T3) of serum uric acid (SUA) hypertensive agents, which might affect SUA levels. The levels. Tertiles of SUA levels: T1 (n = 99): SUA <5.2 mg/dL (men), existence of nephrosclerosis was not fully denied in the <4.1 mg/dL (women). T2 (n = 98): SUA 5.2-6.3 mg/dL (men), 4.1- present study, because not all patients underwent kidney 5.1 mg/dL (women). T3 (n = 93): SUA >6.3 mg/dL (men), >5.1 mg/dL Despite these limitations, the long-term follow up in the cur- rent study provides a certain level of conﬁdence in using the treatment for renoprotection has not been incorporated into results to reﬁne the therapeutic approaches for overt nephropa- existing guidelines; instead, elevated SUA has historically been thy with the aim of preventing the progression to ESRD. Inter- addressed only as a means to prevent gout attacks34.
ventions to address elevated SUA levels, even within the Table 2 Risk factors of creatinine doubling as assessed by Cox proportional hazards models Multivariate model 1 Multivariate model 2 Highest (T3) vs middle (T2) 1.87 (1.12–3.23) 1.70 (0.88–3.31) 1.70 (0.86–3.40) Middle (T2) vs lowest (T1) 1.35 (0.71–2.59) 1.39 (0.81–2.46) 1.57 (0.88–2.87) Highest (T3) vs lowest (T1) 2.54 (1.50–4.50) 2.37 (1.35–4.30) 2.68 (1.48–5.00) 0.97 (0.95–1.00) 1.01 (0.97–1.05) 2.28 (1.42–3.57) 1.65 (0.98–2.71) 1.64 (0.92–2.86) Diabetes duration (years) 0.95 (0.93–0.98) 0.97 (0.94–1.00) 0.96 (0.93–1.00) 2.17 (1.40–3.43) 1.76 (1.12–2.84) 1.74 (1.07–2.87) Body mass index (kg/m2) 0.98 (0.90–1.06) 0.92 (0.84–1.00) 1.32 (1.19–1.46) 1.21 (1.08–1.36) 1.25 (1.09–1.43) Systolic blood pressure (mmHg) 0.99 (0.98–1.00) 1.00 (0.98–1.01) 1.00 (1.00–1.01) 1.00 (0.99–1.00) 1.00 (0.99–1.01) Antiplatelet agents 0.76 (0.42–1.28) 0.76 (0.40–1.37) Antihyperuricemic agents 0.97 (0.45–1.84) 1.54 (0.69–3.04) Antihypertensive agents 0.80 (0.52–1.24) 1.09 (0.65–1.84) 0.80 (0.45–1.34) 0.91 (0.50–1.58) eGFR (mL/min/1.73 m2) 1.01 (1.00–1.02) 1.00 (0.99–1.01) 1.01 (1.00–1.02) 1.09 (0.75–1.57) 0.87 (0.59–1.27) 1.24 (0.77–1.96) 0.98 (0.59–1.55) Results are expressed as hazard ratios (95% confidence intervals [CI]). The hazard ratio (HR) for continuous variables was computed for 1 standarddeviation change. Cohort size, n = 290 (male : female, 231:59). CHD, coronary heart disease; CI, confidence interval; eGFR, estimated glomerular fil-tration rate; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol; SUA, serum uric acid. T1, first tertile; T2, second tertile; T3, thirdtertile.
ª 2014 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd J Diabetes Invest Vol. No. 2014 4. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366: 1849–1861.
5. Pistrosch F, Passauer J, Herbrig K, et al. Effect of thiazolidinedione treatment on proteinuria and renalhemodynamic in type 2 diabetic patients with overt nephropathy. Horm Metab Res 2012; 44: 914–918.
6. Hansen HP, Tauber-Lassen E, Jensen BR, et al. Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int 2002; 62: 220–228.
7. Wu J, Ding Y, Zhu C, et al. Urinary TNF-alpha and NGAL are correlated with the progression of nephropathy in patients with type 2 diabetes. Exp Ther Med 2013; 6: 1482–1488.
eGFR (mL/[min-1.73m2]) 8. Kodama S, Saito K, Yachi Y, et al. Association between serum uric acid and development of type 2 diabetes.
Diabetes Care 2009; 32: 1737–1742.
9. Merjanian R, Budoff M, Adler S, et al. Coronary artery, aortic P < 0.0001 wall, and valvular calcification in nondialyzed individualswith type 2 diabetes and renal disease. Kidney Int 2003; 64: 10. Krishnan E, Kwoh CK, Schumacher HR, et al. Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension 2007; 49: 298–303.
11. Zoppini G, Targher G, Negri C, et al. Elevated serum uric acid concentrations independently predict cardiovascularmortality in type 2 diabetic patients. Diabetes Care 2009; 32: eGFR (mL/[min-1.73m2]) 12. Tavil Y, Kaya MG, Oktar SO, et al. Uric acid level and its association with carotid intima-media thickness in patients Figure 2 Correlation between estimated glomerular filtration rate with hypertension. Atherosclerosis 2008; 197: 159–163.
(eGFR) and serum uric acid (SUA) levels in the (a) serum creatinine 13. Tanaka K, Hara S, Kushiyama A, et al. Risk of macrovascular doubling group and (b) serum creatinine non-doubling group.
disease stratified by stage of chronic kidney disease in type2 diabetic patients: critical level of the estimated glomerularfiltration rate and the significance of hyperuricemia. Clin Exp normal range, in patients with type 2 diabetes might include Nephrol 2011; 15: 391–397.
appropriate renoprotective therapy.
14. Miao Y, Ottenbros SA, Laverman GD, et al. Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of The authors thank Mineko Okayasu for her programming endpoints in non-insulin-dependent diabetes mellitus with efforts. The authors declare no conﬂict of interest.
the Angiotensin II Antagonist Losartan Trial. Hypertension2011; 58: 2–7.
15. Floege J, Johnson RJ, Feehally J. Comprehensive Clinical 1. Wakai K, Nakai S, Kikuchi K, et al. Trends in incidence of Nephrology, 4th edn. Section 5 diabetic neprology 2010, end-stage renal disease in Japan, 1983–2000: age-adjusted Mosby, Missouri, 359–376.
and age-specific rates by gender and cause. Nephrol Dial 16. Kushiyama A, Yoshida Y, Kikuchi T, et al. Twenty-year trend Transplant 2004; 19: 2044–2052.
of increasing obesity in young patients with poorly 2. Hovind P, Rossing P, Tarnow L, et al. Progression of diabetic controlled type 2 diabetes at first diagnosis in urban Japan.
nephropathy. Kidney Int 2001; 59: 702–709.
J Diabetes Invest 2011; 4: 540–545.
3. Intensive blood-glucose control with sulphonylureas or 17. Kashiwagi A, Kasuga M, Araki E, et al. International clinical insulin compared with conventional treatment and risk of harmonization of glycated hemoglobin in Japan: from complications in patients with type 2 diabetes (UKPDS 33).
Japan Diabetes Society to National Glycohemoglobin UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; Standardization Program values. J Diabetes Invest 2012; 3: 352: 837–853.
J Diabetes Invest Vol. No. 2014 ª 2014 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd Role of uric acid in T2DN 18. Matsuo S, Imai E, Horio M, et al. Revised equations for 28. Chonchol M, Shlipak MG, Katz R, et al. Relationship of uric estimated GFR from serum creatinine in Japan. Am J Kidney acid with progression of kidney disease. Am J Kidney Dis Dis 2009; 53: 982–992.
2007; 50: 239–247.
19. Horio M, Orita Y. Comparison of Jaffe rate assay and 29. Kushiyama A, Okubo H, Sakoda H, et al. Xanthine enzymatic method for the measurement of creatinine oxidoreductase is involved in macrophage foam cell clearance. Nihon Jinzo Gakkai Shi 1996; 38: 296–299.
formation and atherosclerosis development. Arterioscler 20. Meyer NL, Mercer BM, Friedman SA, et al. Urinary dipstick Thromb Vasc Biol 2012; 32: 291–298.
protein: a poor predictor of absent or severe proteinuria.
30. Lan HY, Bacher M, Yang N, et al. The pathogenic role of Am J Obstet Gynecol 1994; 170: 137–141.
macrophage migration inhibitory factor in immunologically 21. Akizuki S. Serum uric acid levels among thirty-four thousand induced kidney disease in the rat. J Exp Med 1997; 185: people in Japan. Ann Rheum Dis 1982; 41: 272–274.
22. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective 31. Sezai A, Soma M, Nakata K, et al. Comparison of febuxostat effect of the angiotensin-receptor antagonist irbesartan in and allopurinol for hyperuricemia in cardiac surgery patients with nephropathy due to type 2 diabetes. N Engl J patients (NU-FLASH Trial). Circ J 2013; 77: 2043–2049.
Med 2001; 345: 851–860.
32. Siu YP, Leung KT, Tong MK, et al. Use of allopurinol in 23. Hovind P, Rossing P, Tarnow L, et al. Serum uric acid as a slowing the progression of renal disease through its ability predictor for development of diabetic nephropathy in type to lower serum uric acid level. Am J Kidney Dis 2006; 47: 1 diabetes: an inception cohort study. Diabetes 2009; 58: 33. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of 24. Ficociello LH, Rosolowsky ET, Niewczas MA, et al. High- allopurinol in chronic kidney disease progression normal serum uric acid increases risk of early progressive and cardiovascular risk. Clin J Am Soc Nephrol 2010; 5: renal function loss in type 1 diabetes: results of a 6-year follow-up. Diabetes Care 2010; 33: 1337–1343.
34. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American 25. Chang TI, Li S, Chen SC, et al. Risk factors for ESRD in College of Rheumatology guidelines for management of individuals with preserved estimated GFR with and without gout. Part 1: systematic nonpharmacologic and albuminuria: results from the Kidney Early Evaluation pharmacologic therapeutic approaches to hyperuricemia.
Program (KEEP). Am J Kidney Dis 2013; 61: S4–S11.
Arthritis Care Res (Hoboken) 2012; 64: 1431–1446.
26. Jerums G, Premaratne E, Panagiotopoulos S, et al. The 35. Gambaro G, Bax G, Fusaro M, et al. Cigarette smoking is a clinical significance of hyperfiltration in diabetes.
risk factor for nephropathy and its progression in type 2 Diabetologia 2010; 53: 2093–2104.
diabetes mellitus. Diabetes Nutr Metab 2001; 14: 337–342.
27. Ruggenenti P, Porrini EL, Gaspari F, et al. Glomerular 36. Seaquist ER, Ibrahim HN. Approach to the patient with type hyperfiltration and renal disease progression in type 2 2 diabetes and progressive kidney disease. J Clin Endocrinol diabetes. Diabetes Care 2012; 35: 2061–2068.
Metab 2010; 95: 3103–3110.
ª 2014 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd J Diabetes Invest Vol. No. 2014
Ethics of memory dampening using propranolol as a treatment for post traumatic stress disorder in the field of emergency medicine
Ethics of Memory Dampening Using Propranolol as a Treatment for Post Traumatic Stress Disorder in the Field of Emergency Medicine Rachel FischellDuke University ABSTRACTImagine a world in which one could selectively recall memories - the undesirable memories would not be retrievable, leaving us with only pleasant remains to be remembered. In this world, an emergency medical technician (EMT) forced to witness a violent mutilation following a severe car accident could forget every detail of what they'd observed and avoid the emotional aftermath. In many emergency situations worldwide, emergency medical personnel, such as first responders, EMT-B's, or paramedics are relied on to provide critical pre-hospital care. While this pre-hospital care is often necessary to save citizens' lives, those providing the care are consistently exposed to cognitively corrosive events. The nature of the field of emergency medicine causes the incidence of mental disorders to be incredibly high in this profession compared to other healthcare professions. Post-Traumatic Stress Disorder (PTSD) is particularly common amongst emergency medical personnel. This mental disorder, often characterized by reiterations of the trauma through intrusive and distressing recollections of the event, flashbacks or nightmares, affects approximately 20 percent of those employed in emergency medicine (Slaymaker 1999). In part, this has caused the average career of an emergency medical professional to last only 4-7 years. One potential solution to the high prevalence of PTSD and the elevated personnel turnover rate involves neurocognitive enhancement, one of the fundamental issues raised in neuroethics. Administration of propranolol prior to or immediately following traumatic situations to prevent emotional memory consolidation may ensure that no traumatic experience becomes embedded in the amygdala as a non-conscious emotional memory. Pre-hospital workers could take advantage of this effect and use propranolol, a sympatholytic non-selective beta-blocker, as a preventative measure. Specifically, propranolol administration could help emergency personnel to avoid the chronic hyperactive fear response triggered by certain stimuli that is the basis of PTSD (Glannon 2006). For example, the EMT from earlier would be administered propranolol either before or immediately after treating the victims of the violent car accident to help prevent emotional memory consolidation. Without the emotional component of the memory, the EMT would be far less likely to develop symptoms of PTSD. However, this must be weighed against the potential negative consequences. Because propranolol works to prevent aspects of memory consolidation via reduction of emotion, moral judgments that might arise during such traumatic situations could be affected, thus compromising the quality of patient care. In this paper, I will examine the ethical implications