Objectives. Hypertension, if uncontrolled, can lead to hypertensive crisis. We aim to determine the prevalence of hypertensive crisis, its management, and outcome in patients presenting to a tertiary care center in Karachi. Methods. This was a cross-sectional study conducted at the Aga Khan University, Karachi, Pakistan. Adult inpatients (>18 yrs) presenting to the ER who were known hypertensive and had uncontrolled hypertension were included. Results. Out of 1336 patients, 28.6% (387) had uncontrolled hypertension. The prevalence of hypertensive crisis among uncontrolled hypertensive was 56.3% (218). Per oral calcium channel blocker; 35.4% (137) and intravenous nitrate; 22.7% (88) were the most commonly administered medication in the ER. The mean (SD) drop in SBP in patients with hypertensive crisis on intravenous treatment was 53.1 (29) mm Hg and on per oral treatment was 43 (27) mm Hg. The maximum mean (SD) drop in blood pressure was seen by intravenous sodium nitroprusside; 80 (51) mm Hg in SBP. Acute renal failure was the most common complication with a prevalence of 11.5% (24). Conclusion. The prevalence of hypertensive crisis is high. Per oral calcium channel blocker and intravenous nitrate are the most commonly administered medications in our setup. Hypertension is a common chronic medical condition affecting people in Pakistan and the rest of the world . It is aHypertensive urgency” refers to severe hypertension without evidence of new or worsening end-organ injury while “Hypertensive emergency” refers to a severe hypertension that is associated with new or progressive end-organ damage [The prevalence of uncontrolled hypertension varies around the world, with the lowest prevalence in rural India (3.4% in men and 6.8% in women) and the highest prevalence in Poland (68.9% in men and 72.5% in women) [Hypertensive crises  represented more than one-fourth of all medical urgencies/emergencies. Hypertensive urgencies frequently present with headache (22%), epistaxis (17%), and psychomotor agitation 10%) and hypertensive emergencies frequently present with chest pain (27%), dyspnea (22%), and neurological deficit (21%) . The rea% and hypThis was a retrospective study conducted at the Aga Khan University, Karachi, Pakistan. The Aga Khan University Hospital (AKUH) has 563 beds in operation and provides services to over 50,000 hospitalized patients and to over 600,000 outpatients annually. Ethical approval from the ethics review committee of the Aga Khan University (1985-Med-ERC-11) was taken for conduct of the study.Adult inpatients (>18 yrs) presenting to the ER who were known hypertensive and had uncontrolled hypertension were included. Controlled blood pressure was defined as systolic blood pressure (SBP) <140 mm Hg or diastolic blood pressure (DBP) <90 mm Hg . UncontrData on demographics, comorbid conditions, clinical symptoms, blood pressure readings at subsequent time intervals, length of stay, and antihypertensive drug therapy was recorded by trained data collectors. Age and gender were recorded as mentioned at the time of admission. A history of physician-diagnosed diabetes mellitus (DM), chronic kidney disease (CKD), ischemic heart disease (IHD), and stroke was noted from the patient's medical record file. DM was defined as fasting plasma glucose ≥126 mg/dL at a prior visit . CKD was or a diastolic blood pressure >120 mm Hg [Blood pressure readings, at different time intervals, were recorded from vital sheets for nursing services. Blood pressure was measured using a mercury sphygmomanometer with the patient in sitting position. Hypertensive crisis was defined as a systolic blood pressure >180 mm Hg20 mm Hg . Managem2 saturation <90% on room air prior to treatment accompanied by severe respiratory distress, with crackles over the lungs and orthopnea [Outcome of patient was assessed in terms of length of stay and complications. Mean length of stay was recorded by calculating the time interval between the patient's admission date/time and discharge date/time from ER/ward. Various complications like myocardial infarction, stroke, aortic dissection, acute renal failure, and pulmonary edema developed during the hospital stay were recorded using the discharge summary notes filled by the primary consultant. Myocardial infarction was diagnosed when blood levels of sensitive and specific biomarkers such as cardiac troponin or CKMB are increased in the clinical setting of acute myocardial ischemia with electrocardiographic changes . Accordirthopnea . A minim t-test was used to compare quantitative variables.Data was analyzed using Statistical Package of Social Sciences (SPSS) version 19.1. Mean and standard deviation were used for qualitative variables and frequency and percentage for qualitative variables. Chi-square test was used to compare categorical variables and Student'sA total of 73,063 hypertensive patients presented to the ER between years 2005 and 2010 out of which a sample of 1336 (1.8%) patients was taken for this study. The prevalence (%) of uncontrolled hypertension was 28.9% (387). Prevalence of hypertensive crisis overall was 16.3% (218) and among those with uncontrolled hypertension is 56.3% (218). Mean age (SD) of patients presenting to the ER was 56.7 (14.7) and 175% (45.2) of patients were male. Overall, dyslipidemia was the most common comorbidity in patients presenting with uncontrolled hypertension to the ER with the prevalence of 43.2% (167) followed by diabetes mellitus, 36.9% (143), and ischemic heart disease, 21.4% (83), and 13.9% (54) of them were smokers. The baseline characteristics of patients overall, with hypertensive crisis and without hypertensive crisis, are given in P value = 0.002 and chest pain was present in 17.4% (38) versus 26.6% (45) P value = 0.02.Headache was the most common presenting symptom, 35.7% (138), followed by dyspnea, 32.6% (126), chest pain, 21.4% (83), dizziness, 21.2% (82), vomiting, 17.3% (67), epistaxis, 5.2% (20), and neurologic deficit, 3.6% (14). On comparison of patients with hypertensive crisis with those with no hypertensive crisis the clinical symptoms that were statistically significant were as follows: headache was present in 42.2% (92) versus 27.2% (46) Blood Pressure Trends of Patients with Hypertensive Crisis and without Hypertensive Crisis. The mean (SD) systolic blood pressure (SBP) recorded in patients with hypertensive crisis versus no hypertensive crisis in ER was 202 (17.971) and 158 (13.387) . The mean (SD) diastolic blood pressure in patients with hypertensive crisis versus no hypertensive crisis in ER was 108 (17.429) mm Hg and 87 (14.984) mm Hg, respectively, . The trend of blood pressure recorded in the ER is shown in Figures  was 202 7.971 andAntihypertensive Medications Used in Management of Patients with Hypertensive Crisis. Calcium channel blocker was the most widely used oral antihypertensive medication in the ER, 35.4% (137). Intravenous (IV) nitrate was the most commonly administered IV medication in ER, 22.7% (88). The mean (SD) drop in SBP in patients with hypertensive crisis who received intravenous medications versus oral medications was 53.1 (29) mm hg and 43 (27), respectively . The mean drop in DBP in patients with hypertensive crisis who received intravenous versus perioral medications was 25.8 (19) and mm hg and 17.8 (22) mm Hg, respectively . Comparison of blood pressure trends in patients with and without hypertensive crisis on intravenous or per oral medication is shown in The total length of stay (in days) for patients with hypertensive crisis was 2.46 (0.164) whereas the total length of stay (in days) for patients without hypertensive crisis was 2.20 (0.158).Overall prevalence (%) of complications was 47.7% (104) in patients with hypertensive crisis. Acute renal failure was the most common complication with the prevalence (%) of 41.3% (43) followed by myocardial infarction 28.8% (30) and pulmonary edema 18.26% (19). Stroke accounted for 6.5% (12) of complications. On comparison of patients with hypertensive crisis and patients without it, myocardial infarction occurred in 7.2% (15) versus 9% (15), stroke occurred in 2.4% (5) versus 4.2% (7), and acute kidney injury occurred in 11.5% (24) versus 11.4% (19) patients, respectively.On further categorization of patients with hypertensive crisis who received intravenous antihypertensive in ER versus not receiving intravenous medication, there was no significant difference in the complications in both groups.We have shown in this study on patients presenting to ER with hypertensive crisis that the prevalence of hypertensive crisis is high (56.3%). Headache was the most common symptom in patients presenting with this condition. The most potent intravenous medication for dropping blood pressure was sodium nitroprusside. Mean length of stay was longer in patients with hypertensive crisis and acute renal failure was the most common complication in these patients.Our study showed a prevalence of hypertensive crisis of 56%. The incidence of hypertensive crisis was 47.22% in a study conducted in Bosnia and 16% in a study conducted in Brazil . This inIn previous studies , 26, theThe most common intravenous medication used to control hypertensive crisis in this study was nitrates. Recommendation for use of intravenous nicardipine was reported by a study conducted in 2005  whereas The reduction in systolic and diastolic blood pressure reported in our study shows a smooth decline in order to avoid risks of potential side effects of a much rapid decline. It is recommended that the initial reduction in mean arterial pressure (MAP) in case of hypertensive emergency should not be more than 20%–25% below the pretreatment blood pressure or that MAP be reduced within the first 30–60 minutes to 110–115 mm Hg . This caThe strength of this study is that it is the first study from this region to report figures on prevalence of hypertensive crisis, as well as prevalence of complications as a result of hypertensive crisis among patients. Moreover, this study also reports management of these patients in terms of the treatment received in the ER and into the ward and their mean length of stay. However there are limitations in this study; firstly it has limited external validity as the sample is not representative for an entire population. It represents population visiting a single-tertiary care hospital and, hence, it is not representative of the entire population of Pakistan. Secondly, compliance issues with the medication regimen have not been taken into consideration; hence, the medications administered to the patients may be misjudged. Thirdly, some patients may also have gotten discharged against medical advice; hence, the optimal length of stay for these patients may not have been achieved. Fourth, this retrospective study cannot strongly give a cause and effect association and we have not reported the hypertensive urgencies and emergencies separately. We did not report data separately on hypertensive emergency and urgency and retinopathy could not be examined and reported in all patients.The prevalence of hypertensive crisis is high in our subjects. Per oral calcium channel blocker and intravenous nitrate are the most commonly administered medications in the ER and ward. Acute renal failure is the most common complication developed in hypertensive crisis.


Little is known about the natural course of renal function and renal hemodynamics in heart failure patients with reduced ejection fraction (HFREF).125I-iothalamate/131I-hippuran clearances with a mean follow-up of 34.6 ± 4.4 months. Fifteen percent were female, with age 58 ± 12 years and left ventricular ejection fraction (LVEF) 29 ± 10 %. Baseline GFR was 81 ± 23 mL/min/1.73 m2 and declined 0.6 ± 4.7 mL/min/1.73 m2 per year. Baseline ERPF was 292 ± 83 mL/min/1.73 m2 and declined 4.3 ± 19 mL/min/1.73 m2 per year. Of the baseline variables, older age and high urinary kidney injury molecule-1 were the only variables associated with GFR decline (p < 0.05). Following stepwise backward analysis, only age (p < 0.001) remained significant. In addition, we found an association between change in GFR and changes in ERPF, N-terminal pro-brain natriuretic peptide and renovascular resistance. In the multivariable analysis, only the change in ERPF remained significantly associated with a change in GFR (p < 0.001).We prospectively studied effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in 73 HFREF patients with In this cohort of stable chronic HFREF patients, the average decline in GFR over time was small. The decline of GFR was associated with a higher age and a lower baseline GFR, and was strongly related to changes in renal perfusion.The online version of this article (doi:10.1007/s00392-015-0881-9) contains supplementary material, which is available to authorized users. Both chronic kidney disease (CKD) and worsening renal function are common in heart failure patients –3 and amN-terminal pro-brain natriuretic peptide (NT-proBNP), plasma renin activity, soluble vascular cell adhesion molecule-1 (sVCAM-1) levels and urinary albumin excretion (UAE) showed the strongest associations with renal blood flow  and RVR (0.01 ± 0.05 mmHg/mL/min) were modest. A decrease in ERPF and NT-proBNP and increase in RVR were associated with a decrease in GFR, while LVEF was not  blockers, which may decrease the filtration fraction by vasodilation of the efferent glomerular arteriole; however, this should cause a decrease in RVR. The high RVR, therefore, must reflect a different mechanism, possibly compromised kidney perfusion by increased venous pressure, sympathetic nerve activation or a decreased amount of functioning glomeruli.In our study, we found that the change in ERPF was the strongest determinant of the change in GFR. In contrast, in healthy individuals, GFR remains relatively stable with moderate changes in renal blood flow . It may This study has several limitations. First, not all patients were able to participate in the second measurement. The deceased patients had worse baseline renal function, lower blood pressure and higher NT-proBNP. Second, we only had two measurements; therefore, we cannot establish if there is a linear trend over time and cannot account for fluctuations. Furthermore, our study has a modest sample size. The measurements performed, however, are the gold standard for measuring renal function, with a day-to-day variation coefficient of less than 3 % for GFR and 5 % for ERPF. Patients were mostly stable on medication; however, some patients had minor changes in dose or type of medication. Finally, this was a relatively young cohort, with mostly male Caucasian patients.In these stable chronic HFREF patients, long-term changes in GFR were small, but strongly related to changes in ERPF. None of the investigated urinary biomarkers and hemodynamic parameters other than baseline GFR and age could predict changes in GFR. This underlines the need for the development of new renal risk markers and demonstrates that changes in GFR are mostly driven by changes in renal hemodynamics in chronic HFREF patients. Intervention trials should investigate whether targeting ERPF may improve GFR and reduce cardiac events and mortality.Supplementary material 1 (DOCX 16 kb)


Beneficial effects of omega-3 fatty acid (O3FA) supplementation in a wide range of disease condition have been well studied. However, there is limited information regarding the effects of O3FAs on chronic kidney disease (CKD), especially in diabetic nephropathy (DN) with hypertriglyceridemia. We investigate whether O3FA supplementation could help maintain renal function in patients with diabetes and hypertriglyceridemia. Total 344 type 2 diabetic patients with a history of O3FA supplementation for managing hypertriglyceridemia were included. Reduction in urine albumin to creatinine ratio (ACR) and glomerular filtrate rate (GFR) were examined. Subgroup analyses were stratified according to the daily O3FA doses. Serum total cholesterol, triglyceride, and urine ACR significantly reduced after O3FA supplementation. Overall, 172 (50.0%) patients did not experience renal function loss, and 125 (36.3%) patients had a GFR with a positive slope. The patients treated with O3FAs at 4g/day showed greater maintenance in renal function than those treated with lower dosages (p < 0.001). This dose dependent effect remains significant after adjustment for multiple variables. O3FA supplementation in diabetic patients with hypertriglyceridemia shows benefits of reducing albuminuria and maintaining renal function. The effects are dependent on the dose of daily O3FA supplementation. NeverthOmega-3 fatty acids (O3FAs) are polyunsaturated fatty acids (PUFAs) derived from fish oil; the three types are α-linoleic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These are essential fatty acids, and small amounts of dietary O3FAs enable normal growth. O3FAs also reduce blood triglyceride levels –9. AlthoNumerous studies have evaluated the potential beneficial effects of O3FAs on inflammatory, autoimmune, and renal diseases , 15. O3FHowever, there is limited information regarding the effects of O3FAs on CKD, especially in patients with DN. The role of O3FAs in DN has not been thoroughly investigated. Therefore, we performed a retrospective cohort study to examine whether O3FA supplementation could preserve renal function in diabetic subjects.In this retrospective study, subjects were identified by reviewing patient case notes using electronic medical records at Severance Hospital, a tertiary university hospital in Korea. We included 344 patients ≥ 20 years old with a history of O3FA (highly purified ethyl ester concentrate of EPA and DHA) supplementation for managing hypertriglyceridemia. Diabetes mellitus (DM) was defined according to the International Classification of Diseases 10th revision (ICD 10). Only new users who had not used O3FAs in a preceding year were enrolled. The mean supplement duration (‘after treatment’ period) was 1.9 ± 1.6 years (median 1.4 years). O3FA was used for at least 3 months. Subjects were excluded if they fulfilled any one of the following criteria: (1) kidney transplanted patient; (2) dialysis patient; (3) intrinsic renal disease (nephritis or nephrotic syndrome) patient; (4) acute renal failure due to septic shock, contrast agents, or drugs; and (5) postrenal disease patient. The patient records was anonymized and de-identified prior to analysis. The study protocol received ethical approval by the institutional review board at the Yonsei University College of Medicine (4-2014-0273).2).We evaluated the effects of O3FAs on DN and albuminuria. The dose-effect relationships between O3FAs and albuminuria, renal function were also analyzed. Baseline estimated glomerular filtration rates (GFRs), and spot urine ACRs were measured at the start of O3FA administration. Overnight 8-hours fasting random spot urine samples were collected, and urine ACR was measured with an immunoturbidimetric method. After O3FA treatment (median 1.4 years), we evaluated changes in these laboratory parameters and also examined clinical parameters, blood glucose, lipid profiles. GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation . Body maThe primary outcome was renal function changes during O3FAs supplementation, specifically in GFR and urine ACR. We compared the annual rates of GFR decline among three dose categories: 1 g/day, 2 g/day, and 4 g/day. Subgroup analyses were stratified according to daily O3FA doses; daily doses of 4 g O3FA were grouped into the high-dose group, and those <4 g were placed in the low-dose group. In addition, the proportion of subjects with preserved GFR was analyzed according to O3FA dosages.t-tests. Paired data measured at baseline and after O3FA supplementation were compared using paired t tests. Since urine ACR, total cholesterol, triglyceride, high density lipoprotein (HDL) cholesterol, and high sensitivity C-reactive protein (hsCRP) values were not normally distributed, analyses were performed using log- and back-transformed data. Chi-square tests were used to examine the relationships between multiple variables. The relative factor for GFR decline was obtained using univariate and multiple logistic regressions, and the risk is reported in the form of odds ratios (ORs) and 95% confidence intervals (CIs). All statistical analyses were performed using the SPSS statistical analysis program . For all tests, p < 0.05 was considered statistically significant.The data are reported as mean ± standard deviation (SD), and the real numbers of participants with the percentages follow in parentheses. Simple comparisons of continuous variables within or between sub-groups were made with Student’s 2 . GFR did not decrease in 172 (50.0%) patients and increased in 125 (36.3%) patients after O3FA supplementation. We also analyzed the baseline characteristics of study groups stratified by whether GFR was preserved . Univariate logistic regression analysis was performed to identify variables associated with kidney function loss , and total cholesterol decreased by 19% (p < 0.001). There were no significant changes in HDL cholesterol after O3FA treatment . HoweverThe major finding of this study is that O3FA supplementation may help with preserving renal function in type 2 diabetes patients with hypertriglyceridemia. O3FA influenced both urine ACR and GFR, indicating a protective effect for O3FA on DN. In addition, the effects were dependent on the dose of daily O3FA supplementation. Although GFR decline was observed in our study population, the mean annual rate of GFR decline was relatively slower than that reported in a previous study .y/Ta mice model, improved urine ACR and down regulated MCP-1 levels were observed [A possible association between O3FA supplementation and albuminuria reduction was first noticed after EPA was found to improve albuminuria in diabetic patients . After Eobserved . Mesangiobserved . Moreoveobserved . In our The dose-related effect of O3FAs on DN has not been studied, but it has been investigated in the context of heart disease. According to the American Heart Association guideline, consuming 2 servings (8 ounces) of food containing very long-chain O3FAs reduces the risks of sudden death and death from coronary artery disease . The mecStudies suggest that statin could reduce albuminuria and slow down kidney function loss –38. In sConversely, there are some reports that O3FA supplementation is not associated with reduced albuminuria or that this effect is not dose-dependent. A cohort study assessed both type 1 and 2 DM patients with microalbuminuria and reported that treatment with 4 g/day of O3FAs did not improve albuminuria . HoweverOur study had several limitations. Because it was a retrospective investigation, there were many critical confounders influencing albuminuria or nephropathy. First, ACE inhibitors and ARBs are known to ameliorate albuminuria in DN. More than half of patients (71.8%) were prescribed those medications. Although there were no differences in medication use between the GFR decline progression and no-progression groups, we analyzed ACE inhibitor or ARB use as a covariate factor. Second, medication compliance was not fully considered. As this was not a prospective study, we could not assess adherence with the prescribed O3FA. The study data were based on the proposition that all the prescribed medication was administrated to the subjects. Third, hyperglycemia was improved in the course of the study. Fasting and postprandial blood glucose levels were significantly decreased after O3FAs supplementation. There is a possibility that improved hyperglycemia may contribute to renal function maintain. However, the correlation analysis showed that improvement in serum triglyceride level is more closely associated with better GFR maintain after adjustment fasting blood glucose reduction . Fourth, most patients enrolled in this study were relatively early stage DN, as 77.9% of patients were treated with metformin (contraindicated for advanced kidney disease patients) and > 70% of patients were normo-, or microalbuminuria or CKD stage I or, II. In addition, we did not include a control group. However, it would be immoral practice to prescribe a placebo to patients with hypertriglyceridemia, especially to subjects with serum triglyceride more than 500 mg/dl, due to the risk of acute pancreatitis.Our study also had a major strength. We showed dose dependency in O3FAs effects on attenuating GFR loss. This is the first study reporting an association between O3FA supplementation dosages and DN. A novel finding is the identification of an effective O3FA dose in DN patients with hypertriglyceridemia. In addition, we enrolled compliant patients without other kidney diseases who were selected based on detailed reviews of their medical records.In conclusion, our findings demonstrate that O3FA supplementation in diabetic patients with hypertriglyceridemia ameliorated urine ACR and preserved GFR. This suggests that O3FA supplementation in diabetic patients with hypertriglyceridemia could ameliorate DN progression in a dose-dependent manner. However, further randomized trials are needed to quantify this beneficial effect compared to placebo and control groups. If there is clear dose-dependent effect of O3FAs on DN, high-dose O3FA administration will likely provide a therapeutic option for high-risk diabetic patients.S1 Dataset(XLSX)Click here for additional data file.S1 TableData are presented as N(%) or mean ± SD. DM, diabetes mellitus; O3FAs, omega-3 fatty acid; BMI, body mass index; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; SU, sulfonylurea; DPP4i, dipeptidyl peptidase-4 inhibitor; TZD, thiazolidinedione; Urine ACR, urine albumin to creatinine ratio; GFR, glomerular filtration rate; HbA1c, glycated hemoglobin; HDL cholesterol, high-density lipoprotein cholesterol; hsCRP, high sensitivity c-reactive protein.*Log transformed.(DOCX)Click here for additional data file.S2 TableData are presented as N(%) or mean ± SD. BMI, body mass index; HDL cholesterol, high density lipoprotein cholesterol; GFR, glomerular filtration rate; ACR, albumin to creatinine ratio; ACE inhibitor, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.*Log transformed.(DOCX)Click here for additional data file.S3 TableReference group = patients with O3FA 1g/day, Model 1: adjusted for age and sex, Model 2: adjusted for age, sex, diabetes duration, body mass index, systolic blood pressure, angiotensin-converting enzyme inhibitor/angiotensin II receptor, and statin use, Model 3: adjusted for age, sex, diabetes duration, body mass index, systolic blood pressure, angiotensin-converting enzyme inhibitor/angiotensin II receptor, statin, fenofibrate, fasting blood glucose, baseline GFR, triglycerides, and total cholesterol. GFR, glomerular filtration rate; O3FAs, omega-3 fatty acids; OR, odds ratio; 95% CI, 95% confidence interval.(DOCX)Click here for additional data file.


Biomarkers are useful tools for diagnosis and risk assessment of acute kidney injury and acute heart failure, particularly in ICU patients. Most biomarkers are produced or cleared by the kidney, so the presence of chronic kidney disease may affect their clinical reliability, particularly if the putative diagnosis of acute kidney injury or acute heart failure is based on a single measurement/single threshold approach. Better alternatives, such as establishing different diagnostic cutoff values per different chronic kidney disease strata or evaluating the diagnostic performance of a delta value (change from baseline levels) instead of a single threshold, should be carefully considered in critically ill patients with renal impairment and other co-morbidities.Chronic kidney disease (CKD) is highly prevalent in the ICU population and conveys a higher risk of developing both acute kidney injury (AKI) and acute heart failure (AHF). Early serum and urine biomarkers of AKI and AHF may improve diagnosis and risk stratification. Most biomarkers are affected by renal function impairment, however, so the presence of CKD may hamper their predictive capacity. Donadio investigated whether the presence of underlying CKD may affect the diagnostic performance of two of the most studied biomarkers of cardio-renal damage, namely neutrophil gelatinase-associated lipocalin (NGAL) and brain natriuretic peptide (BNP) . In thisNGAL is a kidney stress protein, the levels of which increase in plasma and urine of patients developing AKI, 2 to 8 hours after renal injuries of various nature . In CKD The effect of baseline renal function on the diagnostic performance of urinary NGAL was also evaluated recently by McIlroy and colleagues in a prospective observational study in 426 adults undergoing major cardiac surgery . In patiAs is well known, BNP is mostly useful for screening and prognosis of acute and chronic heart dysfunction. Although less than 5% of BNP is cleared by the renal route, accruing evidence indicates that the circulating levels of this biomarker are elevated in CKD patients despite an apparently conserved ventricular function ,7. In adFor biomarkers of AKI and AHF, we believe that, as a general rule, one size  cannot fit all. In other words, it is virtually impossible to consider univocal cutoff values able to stratify the risk of AKI or AHF in a miscellaneous population of critically ill patients as a whole. Considering different diagnostic thresholds for different CKD strata might help to improve the overall performance of NGAL and BNP but, predictably, this would not reduce the ground noise caused by other confounders. For instance, apart from renal damage, NGAL levels are known to be affected also by proteinuria, systemic inflammation, oxidative stress, iron balance, diabetes and existing cardiovascular disease , while BIn conclusion, the presence of CKD may actually impact upon the diagnostic performance and reliability of biomarkers of acute damage of kidney and heart. This holds true for biomarkers already used in daily clinical practice as well as for those emerging biomarkers whose promising, preliminary findings in homogeneous study cohorts still await an external validation. Since CKD is exceedingly prevalent in ICU patients, taking systematically into account the effect of residual renal function might enhance the diagnostic performance of biomarkers for the risk stratification of cardio-renal complications in critically ill patients.AHF: Acute heart failure; AKI: Acute kidney injury; BNP: Brain natriuretic peptide; CKD: Chronic kidney disease; GFR: Glomerular filtration rate; NGAL: Neutrophil gelatinase-associated lipocalin.The authors declare that they have no competing interests.


Despite the increasing prevalence of chronic kidney disease (CKD) in sub-Saharan Africa, few community-based screenings have been conducted in Uganda. Opportunities to improve the management of CKD in sub-Saharan Africa are limited by low awareness, inadequate access, poor recognition, and delayed presentation for clinical care. Therefore, the Uganda Kidney Foundation engaged key stakeholders in performing a screening event on World Kidney Day.We conducted a cross-sectional pilot study in March 2013 from a convenience sample of adult, urban residents in Kampala, Uganda. We advertised the event using radio and television announcements, newspapers, billboards, and notice boards at public places, such as places of worship. Subsequently, we screened for proteinuria, hypertension, fasting glucose impairment, and obesity in a central and easily-accessible location.We enrolled 141 adults most of whom were female (57 %), young , and had a professional occupation (52 %). The prevalence of proteinuria , hypertension , and impaired fasting glucose  were high in this study population. Proteinuria was most prevalent among young (18–39 years) adults  and among those who reported a history of alcohol intake .The prevalence of proteinuria was high among a convenience sample of urban residents in a sub-Saharan African setting. These results represent an important effort by the Ugandan Kidney Foundation to increase awareness and recognition of CKD, and they will help formulate additional epidemiological studies on NCDs in Uganda which are urgently needed and now feasible. Chronic kidney disease (CKD) is a growing health burden globally, with many known and unknown etiologies . In sub-Opportunities to improve the management of CKD in SSA are limited by low awareness, inadequate access, poor recognition, and delayed presentation for clinical care . As suchGiven the limited understanding of kidney disease in Uganda, the Uganda Kidney Foundation was founded on March 13th 2013 to advocate, increase awareness, and improve care for kidney disease in Uganda. To achieve this mission, demonstrating the feasibility of screening studies that can describe the epidemiology of kidney disease are urgently needed. Therefore, as part of the International Society of Nephrology World Kidney Day Campaign on March 13th 2013 in Kampala, we performed a community-based pilot study to raise awareness by assessing kidney function through proteinuria measurements.Ethical approval for this study was granted by the Mulago Hospital Ethical Review Board. Informed consent was obtained from all participants prior to their enrollment.We conducted a cross-sectional pilot study in March 2013 from a convenience sample of adult (≥18 years old) urban residents in Kampala, Uganda. Kampala is the largest city in Uganda with a population of more than 1.5 million people . Most rePrior to the study, we advertised using radio and television announcements, newspapers, billboards, and noticeboards at public places, such as places of worship. The advertisements were designed to produce a study catchment area that included all the five divisions of Kampala . To be eWe collected socio-demographic characteristics from interviewer-administered surveys, as well as anthropometric and blood pressure measurements, random blood glucose (RBG) using a finger-prick glucose assay, and a mid-stream clean-catch urine for urine protein. Individuals who screened positive for disease were provided appropriate referral to Mulago Hospital for further clinical care.2). Overweight was defined as BMI between 25 and 30 kg/m2; obesity was defined as BMI ≥30 kg/m2.For the anthropometric measurements, weight was measured in kilograms (kg) using a pre-calibrated weighing scale . Height was measured in centimeters (cm) using a standardized stadiometer. Body mass index (BMI) was calculated from the weight and height measurements for respondents as follows: BMI =  ≥140 mmHg, and diastolic hypertension was defined as an average diastolic blood pressure (DBP) ≥90 mmHg. Hypertension was defined as the presence of systolic or diastolic hypertension, or on-going use of blood pressure lowering medicines among those with self-reported history of hypertension.Finger-prick blood samples were obtained to measure random blood glucose using the Accu-Chek Active glucometer , which was calibrated according to the manufacturer’s recommendation. Fasting glucose impairment was defined as RBG >126 mg/dl, or on-going use of anti-diabetic medicines among those who reported having diabetes. Respondents also provided a clean-catch midstream urine specimen in sterile containers for a dipstick urinalysis . Proteinuria was defined as a urine protein of ≥1+ on dipstick in the absence of hematuria and leukocyturia.Data were manually entered into a Microsoft Excel spreadsheet. All entries were double-checked for accuracy by two independent study personnel, and then exported to STATA v.13 software  for analyses. Continuous variables were summarized by their median and inter-quartile range (IQR) and categorical variables as crude counts and percentages. We estimated the crude, unweighted prevalence of proteinuria and other CKD co-morbidities with 95 % confidence intervals (CI). We used generalized linear models with a log link to report prevalence ratios (PR) and explore associations between proteinuria, hypertension, obesity, impaired fasting glucose, and socio demographic and lifestyle characteristics. A p value of <0.05 was considered statistically significant.A secondary interest of the study was to identify high risk groups in the community. We estimated the potential benefit of screening among these high risk groups as the number needed to screen (NNS) in order to identify one case of proteinuria, which was defined as the reciprocal of the absolute risk reduction . Using BWe enrolled 141 adults, most of whom were female , 18–39 years of age , and had a professional occupation . Fewer than half reported a history of alcohol intake , and only two (1 %) reported a history of smoking. Few respondents had a self-reported medical history of hypertension n = 21; 15 %), diabetes , or heart disease  . More than half of respondents were overweight  and many  were obese. The median SBP was 128 (IQR 120–138) mmHg, and median DBP was 78 (IQR 71–85) mmHg. The prevalence of hypertension was 38 % (95 % CI 31–47 %). Among participants with hypertension (n = 54), systolic hypertension was more prevalent  than diastolic hypertension . The median random blood glucose for participants was 91 (IQR 80–105) mg/dl, and 19  participants had impaired fasting glucose. Eighteen participants  had proteinuria, of whom 16 had proteinuria of 1+ (89 %) and 2 (11 %) had proteinuria ≥2+  were unaware of having hypertension, and of the 10 participants with impaired fasting glucose, most  were unaware.Proteinuria was most prevalent among young (18–39 years) adults , and it was more prominent in those who reported a history of alcohol intake . It was also most prevalent among adults with impaired fasting glucose , those who reported a history of diabetes , those with systolic hypertension , and those occupied as wage earner   and younger age (18–39 years old)  were significantly associated with proteinuria. There was no significant association between proteinuria and impaired fasting glucose, hypertension, overweight, obesity, smoking, gender, or occupation  adults, six among young (18–39 years old) adults who were occupied as professionals, and four among young (18–39 years old) adults who had hypertension. Among adults who report a history of alcohol intake, the number needed to screen to identify one case of proteinuria was eight across all age groups, and four among young (18–39 years) adults.Our pilot study is one of the first to assess kidney function, fasting glucose impairment, hypertension, and obesity in a community setting in Uganda. The prevalence of proteinuria was high in this study population, and it was most prevalent among younger participants. Concurrent with this high prevalence was low disease awareness for hypertension and impaired fasting glucose.Although non-communicable diseases (NCDs) such as diabetes and hypertension account for most cases of CKD in high-income countries , many reIn LMICs, CKD affects younger portions of the population which reflects the different population demographics observed in these countries , 7, 8. OIn response to the need for increasing awareness and screening for NCDs such as CKD, the Uganda Kidney Foundation has used various platforms and strategies to engage key stakeholders, such as physicians, nurses, medical officers, and public health officials in the Ministry of Health. The Uganda Kidney Foundation also partnered with professional societies including the International Society of Nephrology (ISN) to organize the first international kidney conference in Kampala in 2012 to increase awareness and care for kidney disease among clinicians . BecauseOur study has many strengths. The screening activity was carried out by internal medicine residents at MakCHS, who obtained relevant medical history from respondents during the screening to exclude data from respondents with proteinuria secondary to other medical conditions, such as urinary tract infections (UTIs). Additionally, with limited resources, we were able to screen for proteinuria, hypertension, impaired fasting glucose, and obesity using standard definitions and diagnostic tests.Despite these strengths, we noted several limitations. Because urine dipstick measurements for proteinuria can be non-specific, we could not exclude orthostatic or transient proteinuria, or evaluate for possible glomerulonephritis, and we did not repeat the proteinuria assessment. Additionally, we did not assess kidney function using serum creatinine and estimated glomerular filtration rate, and the cross-sectional design prevents any causal assumptions about etiologies. For example, the association between alcohol intake and proteinuria that we observed could be due to unmeasured confounding effects. Because we obtained a convenience sample of people who attended the World Kidney Day celebrations in Kampala, our prevalence estimates are not generalizable to the Kampala urban population. As such, our confidence intervals are intended to measure the variance of the observed sample, and not the underlying Kampala general population. Selection bias was also a concern. Health-conscious individuals were more likely to participate in screening activities than the general population. Nonetheless, our pilot findings highlight the urgent need for and feasibility of future epidemiological studies pertaining to CKD and other NCDs in Uganda.We observed a high prevalence of proteinuria in a convenience sample of urban residents in a sub-Saharan African setting. These results are among the first to be reported for a community-based sample in Uganda, and they represent an important effort by the Uganda Kidney Foundation to increase awareness and recognition of CKD. These estimates will help formulate additional epidemiological studies on NCDs in Uganda which are urgently needed.


Introduction: Serum uric acid (SUA) is considered a marker for natural progression of chronic heart failure (CHF) mediated cardiovascular remodelling. CHF associates with declining of circulating mononuclear progenitor cells (MPCs). The objective of this study was to evaluate the interrelationship between SUA concentrations and proangiogenic MPCs in ischemic CHF patients.Methods:  The study population was structured retrospectively after determining the coronary artery disease (CAD) by contrast-enhanced spiral computed tomography angiography in 126 subjects with symptomatic ischemic mild-to-severe CHF and 128 CAD subjects without CHF. Baseline biomarkers were measured in all patients. Cox proportional multivariate hazard ratio was calculated for predictors of MPCs declining in both CHF and non-CHF patient population predictors of MPCs declining in CHF subjects were examined in stepwise logistic regression. C-statistics, integrated discrimination indices (IDI) and net-reclassification improvement were utilized for prediction performance analyses.Results: Cox proportional adjusted hazard ratio analyses for CD14+CD309+ and CD14+CD309+Tie2+ MPCs by SUA has shown that the higher quartiles (Q3 and Q4) of SUA compared to the lower quartiles (Q1 and Q2) are associated with increased risks of depletion of both CD14+CD309+ and CD14+CD309+Tie2+ MPCs. The addition of Q4 SUA to the ABC model improved the relative IDI by 13.8% for depletion of CD14+CD309+ MPCs and by 14.5% for depletion of CD14+CD309+Tie2+ MPCs.Conclusion:  Circulating levels of proangiogenic MPCs are declined progressively depending on the levels of SUA in the HF subjects with CHF. We suggest that even mild elevations of SUA might be used to predict of relative depletion of proangiogenic MPCs among chronic HF patients. Therefore, CD34+ MPC count is not associated with cardiovascular remodelling or clinical outcome in CHF patients.13Less is known about the association between SUA levels and circulating mononuclear progenitor cells (MPCs). These cells possess angiopoetic function and are crucial in tissue repair.+CD309+ and CD14+CD309+Tie+2 MPCs is decreased in patients with compensated CHF, however, a linear relation between the number of these cells and SUA level has yet to be investigated.14 the objective of this study was to evaluate such a relationship between SUA and the number of proangiogenic population of MPCs in the peripheral blood of the patients with ischemic CHF.Recent evidence suggests that the number of circulating proangiogenic CD1415 All patients consented to voluntary participation in the study. Patients were excluded if they had a recent (within 3 months prior to study enrolment) myocardial infarction (MI) with or without Q-wave. Additional exclusion criteria included severe kidney disease with serum creatinine >440 μmol/L or estimated glomerular filtration rate  <35 ml/min/m2 ;liver diseases that may affect clinical outcomes; malignancy; brain injury within 3 months prior to study enrolment; pulmonary edema; tachyarrhythmias; valvular heart disease; thyrotoxicosis; ischemic stroke; intracranial haemorrhage; acute infections; surgery; trauma; inflammation within a previous month; neoplasm; pregnancy; implanted pacemaker, and patient’s refusal to participate in the study.The study population was structured retrospectively after determining the coronary artery disease (CAD) by contrast-enhanced spiral computed tomography angiography in 126 subjects with symptomatic ischemic mild-to-severe CHF and 128 CAD subjects without HF. CHF was diagnosed according to the current clinical guidelines.® scanner  with two detector rows.17 After preliminary native scanning, non-ionic contrast Omnipak  was administered for the optimal image of the coronary arteries. To reconstruct the image, 0.6-mm-width axial tomographic slices were used.Multiplex spiral computed tomographic angiography was carried out to verify the ischemic origin of CHF for all patients prior to their inclusion in the study. When atherosclerotic lesions of the coronary arteries were verified, patients were subjected to conventional angiographic examination provided indications for revascularization were available. Diagnosis of CAD was made only by angiographic exams carried out within 6 months of the study. The coronary artery wall structure was measured while patients were holding their respiration. All measurements were obtained by means of contrast spiral computed tomographic angiography on Somatom Volum Zoom®  system with a 5 МHz transducer. Routine B-mode images and Doppler measurements were obtained both at the bedside and by post processing. Left ventricular end-diastolic and end-systolic volumes were measured by modified Simpson’s method. Left ventricular ejection fraction (LVEF) was assessed in compliance with the requirements of American Society of Echocardiography.18 Tissue Doppler echocardiography was carried out in 4-, 3- and 2-chamber projections in each of 16 segments of the left ventricle and in 4 spots of the mitral annulus: at the base of posterior septal, lateral, inferior, and anterior left ventricular walls.18 Peak systolic (Sm), early diastolic (Em), and late diastolic (Аm) myocardial velocities were measured in the mitral annulus area, followed by calculating velocity of early diastolic left ventricular filling (E) to Аm (Е/Аm) ratio and to Em (Е/Em) ratio.19A two-dimensional transthoracic echocardiography was performed for all patients using AcusonºС until they were analysed. Samples were processed according to the recommendations of the manufacturer of the analytical technique. SUA level was measured by enzymatic methods using a chemical analyzer Beckman . Analytical range average for SUA was 0.5-82 mmol/L. N-terminal pro-brain natriuretic peptide (NT-pro-BNP) was measured by immune-electro-chemiluminescence method using sets by R&D Systems  on Elecsys 1010 analyzer . Calibration of the assay was performed according to the manufacturer’s recommendations and values were normalized to a standard curve. Concentrations of total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol were determined with Dimension Clinical Chemistry System® . Low-density lipoprotein (LDL) cholesterol was calculated using Friedewald formula.20Fasting venous blood samples were collected into silicone test tubes. They were centrifuged upon cooling at 6,000 rpm 430 g for 3 minutes. Then, plasma was refrigerated immediately and stored at a temperature no higher than -35 21 Accordingly, the cells in question were labeled on the basis of their forward scatter characteristic (FSC) and side scatter characteristic (SSC) profiles. The cells were directly stained and analysed for the phenotypic expression of surface proteins using anti-human monoclonal antibodies, including anti-CD45 FITC , anti-CD34 FITC , anti-VEGFR-2 known as anti-CD309 FITC , anti-Tie2  and anti-CD14  . The fluorescence minus one technique was used to provide negative controls and establish positive stain boundaries. After lysis of erythrocytes with Utilize® wash solution, the samples were centrifuged at 200 g for 15 min; then they were washed twice with phosphate buffer solution and fixed immediately. Double- or triple-positive events were determined using Boolean principles . Circulating endothelial progenitor cells (EPCs) are defined as CD34/VEGFR2 positive cells in lack of CD45 expression. 500,000 events were analyzed from each tube. For CD14+ populations, co-expression with Tie-2- and/or VEGFR-2- was determined using quadrant analysis. Standardized cell counts were presented as a percentage of total white blood cells count, which were identified as the total number of all CD45+ cells.High-Definition Fluorescence Activated Cell Sorter (HD-FACS) was used to detect circulating cells subsets depending on the expression of CD45, CD34, CD14, Tie-2, and VEGFR2, as previously described.2 ) and Fisher’s exact test were used. The circulating NT-pro-BNP and SUA level in the blood failed to have a normal distribution, while distribution of the TG (triglycerides) and cholesterol fractions had a normal character (estimated by means of Kolmogorov-Smirnov test) and was not subjected to any mathematical transformation. Kruskal–Wallis test was used for difference in medians across quartiles of SUA. For further analysis concentrations of SUA in CHF patients were distributed by quartiles: QI (less 22.33 mmol/L), QII (23.2 to 31/10 mmol/L), QIII (32.0 to 39.0 mmol/L), QIV (40.00 to 49.60 mmol/L). QI=20.11 (19.0622.33) mmol/L; QII=27.53  mmol/L; QIII=35.80  mmol/L; and QIV=44.9  mmol/L. The factors, which could be associated potentially with MPCs declining, were determined by univariate and then multivariate regression analysis. Cox proportional multivariate odds ratio (OR) and 95% CI were calculated for predictors of MPCs declining in CHF and non-CHF patient population. Receiver operating characteristic (ROC) curves was configured to establish cut-off points of SUA level that optimally predicted decreased MPCs. Predictors of MPCs declining were examined in stepwise logistic regression with subjects with complications at the time of enrollment excluded from analyses. C-statistics, integrated discrimination indices (IDI) and net-reclassification improvement (NRI) were utilized for prediction performance analyses in CHF patients. A calculated probability of less than 0.05 was considered significant.Statistical analysis of the results obtained was carried out in SPSS system for Windows, Version 20 . The data were presented as mean and the standard errors of means or 95% confidence interval (CI); median and interquartile range (IQR). To compare categorical variables between groups, Chi squaretest (χth quartile of SUA when compared to other quartiles (P<0.05). No significant difference was found in anatomic distribution of the stenotic coronary arteries and related atheromatous lesions among the SUA quartiles.There was no difference in gender, age and body habitus distribution among SUA quartiles of patients with CHF. However, in patients with no evidence of CHF, SUA concentrations were significantly higher in men  than those in women . The prevalence of comorbidities; cardiovascular risk, hemodynamic parameters NT-pro-BNP and the NYHA functional class; serum creatinine concentrations and eGFR values; fasting blood glucose concentrations and HbA1c percentages were similar among different quartiles of SUA. The prevalence of premature CAD was higher in 4Baseline angiographic and treatment characteristics of study patient population are presented in +MPCs in the peripheral blood. Subjects with higher SUA quartile had significantly lower MPCs counts when compared with patient with low quartiles. CD45+CD34+ cell count was positively correlated to the LVEF , negatively correlated to the Е/Аm ratio , the Е/Еm ratio . CD45+CD34+ cell count was also correlated negatively to eGFR , SUA , and the NT-pro-BNP concentrations .+ cell count in the peripheral blood was negatively associated with T2DM , SUA , hypertension , the NT-pro-BNP level , eGFR , active smoking . A positive association was found between the CD45-CD34+ cell count and LVEF , the Е/Аm ratio  and the Е/Еm ratio . The CD14+CD309+ subpopulation count was associated positively with LVEF , the Е/Еm ratio , the Е/Аm ratio ; and it was associated negatively with the NYHA class , T2DM , SUA , NT-pro-BNP level , hypertension , the total cholesterol level , adherence to smoking  and patient’s age . The CD14+CD309+Tie2+ subpopulation count showed a positive association with LVEF , the Е/Еm ratio , eGFR ; and a negative association with the NYHA class , SUA , T2DM , the NT-pro-BNP level , the serum concentrations of low-density lipoproteins , the TG level , adherence to smoking , the body mass index .On the other hand, CD45-CD34+CD34+ MPCs ; CD45-CD34+ MPCs ; CD14+CD309+ MPCs ; CD14+CD309+Tie2+ MPCs . Multivariable linear regression analyses were performed for CD34+phenotypes of MPCs, adjusted for eGFR, BMI, LVEF, NYHA, diuretics, and T2DM. SUA level independently impacted the count of CD14+CD309+ cells  and CD14+CD309+Tie2+ cells , while it had no impact on the number of CD45+CD34+ cells  and CD45-CD34+ cells . The higher quartiles (Q3 and Q4) compared to the lower quartiles (Q1 and Q2) were associated with increased risk of cell depletion of both CD14+CD309+ and CD14+CD309+Tie2+ MPCs among CHF patients, while such a drop was not observed in non-CHF subjects ; T2DM , NT-pro-BNP , diuretics , body mass index , hyperlipidemia , age , male gender , and inversely correlated with eGFR , LVEF , CD45subjects .+CD309+ and CD14+CD309+Tie2+in the patients with CHF was performed using ROC-analysis, the results of which are presented in +CD309+ and CD14+CD309+Tie2+)in CHF patients. The estimated areas under the curves (AUC) were 0.631  for CD14+CD309+ cells and 0.687  for CD14+CD309+Tie2+ cell population. The cut-off value for the SUA level that predicted the cell loss best in both models was 31.5 mmol/L. Of all the variables  included in our multivariate model, SUA was the strongest predictor of proangiogenic MPCs depletion. However, the addition of SUA over cut-off point to the ABC model improved the relative IDI by 13.8% for depletion of CD14+CD309+ MPCs and by 14.5% for depletion of CD14+CD309+Tie2+MPCs  and mortality.24 Arguing against a pure protective role of SUA in cardiovascular disease25 , we found that levels of SUA remained independently associated with depletion of proangiogenic MPCs after adjusting for parameters with known effects. These cells play critical role in tissue repair and neovascularization due to their angiogenic property. Elevated levels of SUA in CHF patient population were associated with progressively declining proangiogenic MPC.Previous reports have been predominantly elucidated a relationship between cardiovascular outcomes and documented hyperuricemia in patients with acute and CHF.26 Amin et al reported that even mild elevation of SUA is associated with impaired clinical and hemodynamic profile in patients with systolic CHF and suggested that SUA might be used as a non-invasive indicator of elevated left ventricular filling pressures.27 Misra et al demonstrated a reverse impact of CHF status (compensation or decompensation) on SUA levels among men with high cardiovascular risk profile.28 These investigators found that mild elevated SUA associated with increased risk of CHF decompensation .These findings add to the existing controversy on the role of SUA in the evolution of CHF and its related outcomes. Elevated levels of SUA have been linked to the body habitus, diuretic use, declining eGFR, as wells as both biochemical (NT-pro-BNP) and hemodynamic (E/Ea and LVEF) markers of CHF by several investigators.Although hyperuricemia predominantly affects men, our findings failed to show differences in SUA between men and women diagnosed with CHF. According to our findings, there was no documented case of hyperuricemia (defined as SUA ≥6 mg/dL for women [35.6 mmol/L] and ≥8 mg/dL for men [47.6 mmol/L]). Moreover, none of our patients was treated for symptomatic hyperuricemia. However, the interpretation of SUA levels for individuals with CHF may be confusing, as even a small increase in SUA levels is probably viewed as a marker of endothelial dysfunction and an indicator of tissue repair in symptomatic CHF patients. Current evidence suggests that SUA could be a marker of oxidative damage in several settings associated with CHF, such as overweight, obesity, diuretic use. Although we described a modest linear association between SUA and body habitus and between SUA and diuretic use as we failed to show any correlation between these variables and the number of circulating MPCs.29It has predisposed that SUA may realize their antioxidative capacity. Therefore, it is not clear whether this increase in SUA levels may be an epiphenomenon, a counter-regulatory process or a detrimental factor that is contributing to the underlying pathophysiology. Since uric acid is a byproduct of purine catabolism and its serum levels increase as the enzymatic activity of xanthine oxidase surges in tissue hypoxia and subsequent apoptosis in CHF settings.31 This finding suggests that hyperuricemia may predict poor outcomes when it primarily increased due to enhanced oxidative activity rather than the conditions where its renal excretion is impaired.30 Conversely Filippatos et al have found no association between SUA and BMI, as it is the case with our report.29 Diuretics, mainly the hydrochlorothiazides, are widely used to treat CHF, meanwhile elevating serum concentrations of uric acid by increasing the reabsorption of sodium and urate in the proximal tubule. Although we reported an association between SUA and diuretics administration, the direct effect of diuretics in depletion of MPCs in patient study population was not determined.The association between hyperuricemia and poor outcomes of CHF is more noticeable in patients without renal dysfunction than those with CKD.+phenotypes of MPCs demonstrated that even following an adjustment for eGFR, LVEF, NYHA functional class, diuretics, and T2DM, SUA had an independent impact of on the cell count of CD14+CD309+ MPCs and CD14+CD309+Tie2+ MPCs. We speculate that tissue ischemia results in enhanced oxidative activity of xanthine oxidase and subsequent production of uric acid. The observed suppression in recruitment, mobbing, differentiation and functional status of MPCs are mediated through Akt/STAT/MAP-kinase mechanisms as a reflection of chronic oxidative stress and probably, enhanced catabolic state in CHF.34 It is possible to address to new investigations whether relationships between SUA and proangiogenic MPCs are multidimensional, or if they can be associated with clinical outcomes.SUA may associate with CAD through its effect on coronary risk factors, such as obesity, hypertension, hypertriglyceridemia, dyslipidaemia and T2DM. Multivariate linear regression model that was constructed for CD34Circulating level of proangiogenic MPCs declines progressively depended on quartiles of SUA level in CHF subjects. We suggest that mild elevation of SUA (>31.5 mmol/L) might be considered a predictor of decline in the number of proangiogenic MPCs in patients diagnosed with CHF.This study has some restrictions. The authors believe that a greater cohort is to be desirable to improve the power of the study. There is a variation in the definition of EPCs, the number of existing cardiovascular risk factors in various patients, and in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets. The authors suppose that these restrictions might have no significant impact on the study data interpretation.We thank all patients for their participation in the investigation, staff of the Regional Zaporozhye Hospital (Ukraine) and the doctors, nurses, and administrative staff in City hospital # 6 , general practices, and site-managed organizations that assisted with the study.The study was approved by an institutional review committee. The investigators followed strictly all the requirements to clinical trials in conformity with the World Medical Association Declaration of Helsinki, 1964, 2008, good clinical practice provided by International Conference on Harmonization (GCP-ICH), Council of Europe Convention for the Protection of Human Rights and Dignity of the Human Being in view of using achievements in biology and medicine, convention on Human Rights and Biomedicine, including Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research, and legislation of Ukraine.This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The Authors declare that they have no competing interests.


Using a novel method called near-infrared transillumination backscattering sounding (NIR-T/BSS) that allows for the non-invasive measurement of pial artery pulsation (cc-TQ) and subarachnoid width (sas-TQ) in humans, we assessed the influence of sympathetic activation on the cardiac and respiratory contribution to blood pressure (BP) cc-TQ oscillations in healthy subjects.2 (EtCO2) and end-tidal O2 (EtO2) were measured using a metabolic and spirometry module of the medical monitoring system. Wavelet transform analysis was used to assess the relationship between BP and cc-TQ oscillations.The pial artery and subarachnoid width response to handgrip (HGT) and cold test (CT) were studied in 20 healthy subjects. The cc-TQ and sas-TQ were measured using NIR-T/BSS; cerebral blood flow velocity (CBFV) was measured using Doppler ultrasound of the left internal carotid artery; heart rate (HR) and beat-to-beat mean BP were recorded using a continuous finger-pulse photoplethysmography; respiratory rate (RR), minute ventilation (MV), end-tidal CO2  EtO2  RR  and MV , while sas-TQ was diminished , and a clear trend toward cc-TQ decline was observed . CBFV  and EtCO2  did not change during HGT. CT evoked an increase in BP , sas-TQ  and SaO2. HR , CBFV , EtO2  and EtCO2  remained unchanged. A trend toward decreased cc-TQ was observed . The sas-TQ response was biphasic with elevation during the first 40 seconds  and subsequent decline . No change with respect to wavelet coherence and wavelet phase coherence was found between the BP and cc-TQ oscillations.HGT evoked an increase in BP , HR , SaOShort sympathetic activation does not affect the cardiac and respiratory contribution to the relationship between BP—cc-TQ oscillations. HGT and CT display divergent effects on the width of the subarachnoid space, an indirect marker of changes in intracranial pressure. The cardiovascular system consists of the heart and blood vessels. The heart can be described as a pump that drives the blood through the closed circuit of elastic vessels. The respiratory activity generates a pressure that assists in the return of blood to the heart. The flow of blood largely depends on the resistance of the vessels, which is controlled by adjustment of their diameter. Consequently, the power of cardiac oscillations dominates the aortic flow and is significantly decreased in blood flow through the capillaries. The cardiac and respiratory oscillations have frequencies of around 1 Hz and 0.3 Hz, respectively, which originate centrally and are propagated through the system . Current0) and its harmonics  [Non-invasive assessment of pial artery pulsation became possible due to a recently developed method based on infrared radiation (IR) called near-infrared transillumination/backscattering sounding (NIR-T/BSS). In contrast to near-infrared spectroscopy (NIRS), which relies on the absorption of IR by haemoglobin , NIR-T/B f2, f3) . As show f2, f3) ,14.Dynamic cardiovascular responses arise from different autonomic pathways, depending upon the stimuli. A voluntary muscle contraction during the handgrip test (HGT) elicits heart rate (HR) increases through the integration of autonomic regulatory networks with sensory and motor components of the cortex, cerebellum and basal ganglia . ExposurIt has previously been shown that breath-hold apnoea diminishes the cardiac contribution to BP cc-TQ oscillations . However2); none of them were smokers. All subjects received detailed information about the study objectives and any potential adverse reactions, and they provided written informed consent to participate in the study. The experimental protocol and the study were approved by the Ethics Committee of the Medical University of Gdansk. Although none of the participants suffered from known disorders or were taking any medication, a general and neurological examination was performed before the experiment. Nicotine, coffee, tea, cocoa and methylxanthine-containing food and beverages were not permitted for 8 hours before the tests. Additionally, prior to each test, the volunteers were asked to rest comfortably for 30 minutes in the supine position.Experiments were performed on a group of 20 healthy volunteers  at 30% of maximum. After practice, subjects were allowed to return to a baseline state. The CT consisted of 10 minutes at baseline, 2 minutes' hand immersion to approximately wrist height in cold water  and 10 minutes' recovery. One investigator lifted the hand into and out of the water at the appropriate times.2) was measured continuously  with a finger-clip sensor. Expired air was analysed with a spirometry module of the medical monitoring system  for respiratory rate (RR) and minute ventilation (MV). Gas samples from the mouthpiece were constantly analysed using the side-stream technique for end-tidal CO2 (EtCO2) and end-tidal O2 (EtO2) with the metabolic module of the same medical monitoring system . Doppler ultrasound of the internal carotid artery was performed  to assess the mean cerebral blood flow velocity (CBFV). Changes in the amplitude of pial artery pulsation and in the width of the SAS with NIR-T/BSS were recorded with a head-mounted SAS 100 Monitor . The theoretical and practical foundations of the NIR-T/BSS method have been published previously [ECG was recorded using a standard electrocardiograph. Mean BP was measured using continuous finger-pulse photoplethysmography . Finger blood pressure was calibrated against brachial arterial pressure. Oxyhaemoglobin saturation  is the wavelet coefficient, g(u) is the time series, and φ is the Morlet mother wavelet, scaled by factor s and translated in time by t. The Morlet mother wavelet is defined by the equation:The wavelet transform is a method that transforms a time signal from the time domain to the time-frequency domain. The definition of the wavelet transform is:an shape ,21. The http://www.mathworks.com/help/wavelet/examples/wavelet-coherence.html. In all calculations, we estimated the normalised value of WCO:1 ) is the wavelet coefficient for the first (the second) signal and * indicates the complex conjugate. We observed stronger coherence when the WCO value increased. The value of WPCO is between 0 and 1. When two oscillations are unrelated, their phase difference continuously changes with time, thus their WPCO approaches zero. If the WPCO is around 1, the two oscillations are related and significant coherence is observed.Wavelet coherence (WCO) and wavelet phase coherence (WPCO) were estimated using the Matlab function ‘wcoher.m’ with ‘morl’ (Morelet function) as a mother wavelet, and a scale from 1 to 500, which corresponds to the frequency interval from 0.097 to 56.7 Hz. A detailed description with clear examples can be found at: 2, EtCO2, EtO2, respiratory rate and MV in response to HGT and CT.Wilcoxon signed-rank test was used to compare the changes in WCO, WPCO, cc-TQ, BP, HR, CBFV, SaO2, EtO2, respiratory rate and MV, while sas-TQ diminished, and a clear trend toward cc-TQ decline was observed, although the cc-TQ change was not statistically significant. CBFV and EtCO2 did not change during HGT  and subsequent decline to +4.1% versus baseline  short sympathetic activation does not affect the cardiac and respiratory contribution to the relationship between BP—pial artery pulsation oscillations, 2) HGT and CT display divergent effects on the width of the subarachnoid space, an indirect marker of changes in intracranial pressure.The role of SNS in CBF regulation remains a matter of controversy –24. NeveAlternatively, we are tempted to consider that SNS mediated CBF control mechanism is biphasic. Pial artery time to response to BP fluctuations is limited to seconds ,28,31 anWe decided to examine the whole duration of HGT and CT 120 s). These periods were compared to the 120 s at baseline (Figs 0 s. ThesIt has been shown by our team and others that HGT increases cerebral blood volume and decreases the subarachnoid width, suggesting an increase in intracranial pressure ,42. In cThe high within- and between-subject reproducibility and repeatability of NIR-T/BSS measurements were demonstrated previously . NIR-T/BNIR-T/BSS offers unique possibility to measure non-invasively direction of changes in ICP in diseases like stroke, traumatic brain injury or obstructive sleep apnoea. The “standard of care” monitoring of ICP is highly invasive and therefore restricted to critically ill patients or post neurosurgery procedures. Non-invasive, even if indirect, monitoring of ICP opens completely new fields in cardiovascular and neurological research. Exposure to pulsatile pressure and augmented flow, which exists in the carotid artery may lead to vascular damage  and/or pTo conclude, we have shown that SNS activation does not affect the cardiac and respiratory contribution to the relationship between the BP and pial artery pulsation oscillations in healthy subjects. In fact, it seems that a high sympathetic drive tends to stabilise the relationship between the analysed signals. The current study establishes the reference for future research in subjects with autonomic imbalances, for instance, in subjects suffering from obstructive sleep apnoea. Furthermore, we have demonstrated that HGT and CT exert opposite effects on the subarachnoid width, an indirect marker of intracranial pressure. We postulate that the SNS influence on cerebral blood volume and regulation of intracranial pressure may vary depending on the involvement of particular central SNS circuits.


Inhaled corticosteroids (ICS) are the cornerstone of asthma therapy. The ICS-to-total-asthma-medication ratios, calculated from claims data, indicate potentially risky disease management in asthma. Our aim was to assess the utility of ICS-to-total-asthma-medication ratios from primary care electronic medical records (EMRs) in detecting patients at risk of asthma exacerbation, as approached by prescription of oral corticosteroids and/or antibiotics.Retrospective cohort studies were identified, using the Health Improvement Network general practice database  and the Cegedim Longitudinal Patient Data (France). We selected asthma patients aged 16–40 years, with ≥ 4 prescriptions for asthma medications in 2007 and ≥ 1 prescription in 2008. For each country, three groups were defined according to ratio value in 2008: 0% (non-ICS users), <50% (low-ICS-ratio group) and ≥50% (high-ICS-ratio group). Outcomes were marker of asthma exacerbations: systemic corticosteroids and antibiotics. They were compared between groups in each country.Among 38,637 British and 4,587 French patients, higher numbers of prescriptions per patient of systemic corticosteroids, antibiotics and total asthma medications were observed in the low-ICS-ratio groups compared to other groups (p < 0.0001 for each outcome in both countries). Likewise, low-ICS-ratio patients had more medical contacts (p < 0.0001 in both countries), suggesting poorly controlled asthma. ICS-treated patients had lower risks of receiving systemic corticosteroids in 2008 in the high-ICS-ratio group, compared to the low-ICS-ratio group: RR = 0.54, 95%CI = [0.50-0.57] and RR = 0.78, 95%CI = [0.67-0.91] in the UK and France, respectively.Patients with high ICS-to-total-asthma-medication ratios presented fewer asthma-related outcomes. The low ICS-to-total-asthma-medication ratio calculated with EMRs data reflects insufficient prescribing of ICS relative to all asthma medications, which may lead to deteriorated asthma control. The controller-to-total-asthma-medication ratio has been used to assess the quality of asthma care using the United States claims data -3. Patie. This system rewards general practices that achieve targets set over a wide range of clinical indicators. For instance, physicians are encouraged to perform annual disease reviews for their asthma patients, which include an assessment of disease control [Prescribing data reflect health care professional’s (HCP) diagnoses and decisions and, therefore, provide information that is complementary to claims data, which result from both HCP’s prescribing and patients’ compliance with prescription orders. Hence, using prescribing data, it is possible to assess if high-ICS-ratio patients present fewer asthma exacerbations than those with lower ratio values. Further, as prescribing may be affected by the local organization of health care, e.g. national prescribing guidelines, it was of interest to explore the relationship between ratios and medical resource utilisation in countries with two different health care systems, i.e. France and the United Kingdom (UK). In the United Kingdom, GPs are employed by the NHS or by general practices whereas most French primary care physicians have a liberal status, and their incomes primarily depend on the volume of their activity. In contrast, the quality of care impacts British physicians’ salary due to the presence of a pay for performance scheme control .Our objective was to determine whether ICS-to-total-asthma-medication ratios, computed in primary care prescribing data, could be used to detect patients at risk of asthma exacerbation, by comparing prescriptions and medical contacts between non-ICS users, low- and high-ICS-ratio groups.We conducted a database study using primary care electronic medical records data from the UK and France . The data between 1st January 2007 and 31th December 2008 were extracted for all patients with at least one prescription in 2007 of respiratory drug ATC: R03. Extractions included patients’ age, gender, and information on general practitioner visits and medication prescribing in 2007 and 2008.THIN collects anonymized longitudinal primary care patient records including demographic, medical and prescription information at an individual patient level from participating general practices in the UK that routinely record these data. The data collection was approved by the NHS South-East Multi-centre Research Ethics Committee in 2003. The THIN data were shown to be generalizable to the UK population ,10.To derive data for the French patients, the LPD database was used. The database includes anonymous data on patient consultations and prescribed medications. General practitioners belonging to the LPD Network are representative of the French GP population based on age, gender and geographical region. LPD holds an ethical approval from the French National Data Protection Authority (CNIL) for data collection since 2002. As our study utilized anonymized patients data only, no additional ethical approval was needed.We received extractions of patients with at least one prescribed asthma drug (ATC Classification: R03) in 2007, from THIN (United-Kingdom) and the LPD database (France). From these data, we selected patients aged between 16 and 40 years who received at least 4 prescriptions for asthma medications in 2007  and at lRespiratory medications included short-acting beta-2-adrenoreceptor agonists (SABA), anticholinergics, SABA/anticholinergic fixed combinations, long-acting beta-2-adrenoreceptor agonists (LABA), inhaled corticosteroids (ICS), LABA/ICS fixed combinations, leukotriene receptor antagonists (LTRA), xanthines and cromones.The ICS-to-total-asthma-medication ratio constituted the proportion of prescribed units of ICS out of the overall number of respiratory medication units  prescribThe outcomes were prescriptions for systemic corticosteroids and respiratory antibiotics . All outcomes were assessed from 1 January 2008 to 31 December 2008.Distribution of ratios and definition of groupsThe distribution of the ICS-to-total-asthma-medication ratios was first examined. The patients were then assigned into the ratio groups .b.Univariate analyses2 test and ANOVA were used for univariate analyses.Then, the different groups of patients were compared according to patients’ age and gender, number of GP visits, and the total number of prescribed asthma medications in 2008 (marker of asthma severity), and the systemic corticosteroids and antibiotics prescribing levels (outcomes). Chic.Multivariate analysesMultivariate logistic regression models were then conducted among ICS-treated patients only (low and high-ICS ratio groups) to determine the adjusted risk of receiving systemic corticosteroids (respiratory antibiotics) according to ratio value (high vs. low). Adjustments were made for age, gender, use of a fixed LABA-ICS combinations in 2008, and the number of respiratory medications prescribed in 2008 . For all models, the low-ICS-users group was used as the reference.d.Sensitivity analysesSensitivity analyses on prescriptions for systemic corticosteroids and antibiotics in patients receiving ≥ 6 prescribed units of respiratory medications (≥6 prescriptions in the UK) were also performed in univariate analyses, as some ratios may be high as a consequence of low prescribing levels of respiratory medications . Furthermore, in case of clearly distinguishable subgroups within the low, or within the high-ICS-ratio group in the main analysis, complementary comparisons between the different subgroups were performed in the given group according to patient number of medical contacts, studied outcomes and prescribed asthma medications in 2008.We analysed the data from the UK and France according to the same statistical analysis plan, in four successive steps.All analyses were performed using SAS statistical software, version 9.2 . All reported p-values are 2-tailed, with significance level set at 5%.The extractions of patients under respiratory therapy in 2007 included 343,156 patients in the UK and 119,265 in France. After applying inclusion criteria, we identified in the extractions 38,637 patients (11.2%) in the UK THIN data  and 4,587 patients (3.8%) in the French LPD data . The ratio distributions for the UK and France are presented in Figure The shape of the observed ICS-to-total-medication ratios distribution was similar in both countries; however there were differences in the proportion of non ICS users (26% in France vs. 18% in the UK). In the low-ICS-ratio groups, the distributions presented a Gaussian-like pattern in both countries, with a maximal frequency in the 30–39.9% interval.More than 40% of British and French patients belonged to the high-ICS-ratio group  and three distinct sub-groups were identified within this group in both countries. We observed a clear distribution peak right after the 50% threshold, in the 50–59.9% interval. These patients accounted for 65% of the high-ICS-ratio group in the UK and 38% in France. Another sub-population could be identified for the highest ratio values, the 90% and greater, notably in France (33% of the high-ICS-ratio group), and to a lesser extent, in the UK (12% of this group).The medical resource utilization data for the three groups are presented in Table We were able to identify three subgroups in the high-ICS-ratio groups . These subgroups were compared in terms of number of GP visits and prescribed therapy. In both countries, patients with the highest ratio values (≥90%) were prescribed fewer systemic corticosteroids and antibiotics as well as asthma medications, more markedly in the UK, where these patients also visited their GPs less frequently. The differences between the 50–59.9% and 60–89.9% subgroups, however, were less pronounced for systemic corticosteroids. We did not observe any apparent uniform downward trend in number of systemic corticosteroids and antibiotic prescriptions in the three subgroups as the ratio increased Table .In the multivariate main analyses performed on the UK data, the high-ICS-ratio group had a significantly lower risk of receiving a prescription for systemic corticosteroids or antibiotics than the low-ICS-ratio group. The conclusions for French patients were similar, suggesting that there was an association between the high-ICS-to-total-asthma-medication ratio and lower number of systemic corticosteroids prescriptions, while decreased risks of receiving antibiotics were also observed. It approached significance in France Table .Table 1In this database study utilizing primary care data we calculated ICS-to-total-asthma-medication ratios and assessed asthma related outcomes in more than 40,000 patients from the UK and France. Although not identical, the distributions of therapeutic ratios presented similarities in both countries, with a Gaussian-like pattern in the low-ICS-ratio groups. Patients untreated by ICs were more numerous in France. In both countries, patients in the low-ICS-ratio group (<50%) were prescribed more systemic corticosteroids, antibiotics and asthma medications than patients from other groups. These patients also visited their GPs more frequently than the high-ICS-ratio group.Our findings are consistent with prior research on the controller-to-total-asthma-medication ratios performed in claims data using asthma-related hospital contact as outcome ,3. A lowThe interpretation of ratio values computed from primary care prescribing data differs from that of claims data. A high ratio in prescribing data may not reflect patients’ actual exposure to ICS, as prescriptions not dispensed by community-pharmacies are included in analyses. Conversely, unlike claims databases, a low ICS-to-total-asthma-medication ratio in primary care data is fully attributable to insufficient prescribing of ICS by physicians, irrespective of patients’ behaviour, except in case of fragmented care.Our findings suggest that some GPs insufficiently prescribe ICS and that such prescribing patterns may facilitate asthma exacerbations . UtilisiThe guidelines ,16 recomIn patients receiving ICS, we selected the 50% ratio value as a cut-off to classify the patients into the low-ICS-ratio and the high-ICS-ratio group. Altogether, more than one third of all patients were in the low-ICS-to-total-asthma-medication group. Patients from this group were prescribed more asthma medications, systemic corticosteroids, and they visited their GP more frequently. Our multivariate models suggested that, compared to these patients, the high-ICS-ratio group presented lower risks of both receiving systemic corticosteroids and antibiotics Table . It cannThe low-ICS-ratio patients also tended to be prescribed fewer fixed LABA-ICS fixed combinations, particularly in France. Patients prescribed fixed LABA-ICS combinations may require less SABA and non-combined LABA which in turn decreases the ratio denominator. This higher use of fixed combinations in the high ICS ratio group has been observed previously .Upon examining the distribution within the high-ICS-ratio group we identified three subgroups . In France the three subgroups did not differ significantly from one another in terms of systemic corticosteroids, antibiotics prescribing and medical visits. In the UK, however, the ≥90% subgroup patients received fewer systemic corticosteroids and antibiotics, while they visited their GPs less frequently. Also, the number of prescriptions for all respiratory medications was lower in patients in this subgroup with the highest ratios (≥90%), both in the UK and in France, which could suggest a milder asthma or less regular prescribing. The 90% threshold, however, is not clinically meaningful in assessing the quality of care as only a marginal proportion of patients with a milder disease can be identified. Therefore, our data supports the choice of the 50% threshold value, as the outcomes in the three high-ICS-ratio subgroups showed no steady trend towards improvement in asthma control with increasing ICS-to-total-asthma-medication ratio. A possible direction for further research will be to bring together primary care prescribing data, medication dispensation data and patient-reported data to determine the best cut-off values for ICS-to-total-asthma-medication ratio threshold.We were not able to use an identical ratio definition in both countries due to differences in the data on prescribed medications. The UK data did not contain information allowing counting the number of prescribed packages for oral therapy. We therefore calculated the ratios for the UK patients using the number of ICS prescriptions in the numerator and the number of all respiratory medication prescriptions in the denominator. However, this potential bias should not have affected the validity of this definition as both the numerator and denominator were similarly approximated. Despite these discordant definitions, consistent results were obtained between the two countries. Our definitions of ratio did not take into account the dosing of ICS canisters nor the potency of the molecule, hence can be considered ‘unweighted’. In comparison with a more elaborate alternative , this tuOur study has some limitations. As we wanted to include patients receiving regular prescribing for asthma, our study population corresponded to a minority of selected persistent asthmatics with a close supervision in primary care. Thus, these patients were not representative of the overall population of asthmatics. Prescriptions from physicians not affiliated to the study networks were not available in the database. Henceforth, the number of prescriptions might have been underestimated if fragmented care or partial supervision by specialists did occur. Nevertheless, we believe that this bias may not affect our conclusions. Firstly, analyses were conducted in patients with at least four annual prescriptions of asthma medications during baseline period 2007). Then, the underestimation of prescriptions should be similar in both numerator and denominator of therapeutic ratios. As another limitation, major outcomes such as hospital admissions or emergency room visits were not available in these databases. We used proxies, such as systemic corticosteroids and antibiotics prescriptions, to identify asthma exacerbations. Unlike systemic corticosteroids, antibiotics however are not listed as outcomes for asthma 07. Then,, though Based on these findings, it should be of interest to verify whether patients of the low ratio group are more likely to be supervised by specific profiles of GPs. In such case, the reasons that lead these physicians to prescribe a limited amount of ICS compared to other anti-asthma drugs needs to be better understood. Then, targeted educational campaigns should be carried out in primary care to improve the quality of prescribing in asthma, specifically among low prescribers of ICS.In conclusion, our findings suggest that insufficient prescribing of ICS in primary care may lead to asthma exacerbations and, consequently, increased medical resource utilization. Quality of care could improve if the ICS-to-total-asthma-medications ratios were used to screen irregular use of ICS in asthma before potential occurrence of adverse outcomes.