Post-transplant diabetes mellitus (PTDM) has been associated with an increased risk of cardiovascular disease (CVD) mortality following kidney transplantation, but the association between pre-diabetes (i.e. impaired fasting glucose and impaired glucose tolerance) and CVD mortality remains unclear. The aim of this study was to assess the association between abnormal glucose regulation and arterial stiffness at 3 and 15 months post-transplantation.This is a single-centre prospective cohort study of 83 non-diabetic kidney transplant recipients who received a kidney transplant between 2008 and 2011. All patients underwent an oral glucose tolerance test  and non-invasive measurements of arterial stiffness (aortic pulse wave velocity [PWV] and augmentation index [AIx]) 3 months post-transplantation. A sub-set of patients had repeat OGTT (n = 33) and arterial stiffness measurements (n = 28) at 15 months post-transplant.Of the 83 patients, 52% (n = 43) had normal glucose regulation, 31% (n = 26) had pre-diabetes and 17% (n = 14) developed PTDM. Compared with recipients with normal glucose regulation, recipients with PTDM  but not those with pre-diabetes  had significantly higher AIx 3 months after transplantation. No association was found between glucose regulation and PWV at 3 months after transplantation. There was no association between glucose regulation at 3 or 15 months and AIx and PWV at 15 months in a subset of recipients.Early onset PTDM is associated with increased systemic vascular stiffness (AIx) but not regional stiffness of large arteries (PWV) suggesting that small vessel dysfunction may be the earliest vascular change seen with PTDM. Thus, measurements of arterial stiffness after transplantation may assist in more accurately stratifying future CVD risk of kidney transplant recipients. Cardiovascular disease (CVD) remains one of the leading causes of death with functioning graft in kidney transplant recipients-3. The dNon-invasive measurements of arterial stiffness and wave reflection such as aortic augmentation index (AIx) and pulse wave velocity (PWV) are established surrogate markers of CVD mortality in the general population-15, patiThe aim of this prospective cohort study of non-diabetic kidney transplant recipients is to examine the associations between abnormal glucose regulation at 3 months after kidney transplantation and arterial stiffness and wave reflections at 3 and 15 months following transplantation.This single-centre, prospective cohort study included all incident non-diabetic live and deceased donor kidney transplant recipients (n = 83) at Sir Charles Gairdner Hospital  between January 2008 and January 2011. All recipients had normal fasting and random blood glucose levels prior to transplantation. The local institutional ethics committee approved the study and written informed consents were obtained from all patients.Patient characteristics , medical history  and kidney transplant-related characteristics  were extracted from medical records. Medications including immunosuppressive, anti-hypertensive and lipid-lowering agents at 3 months (baseline) and 15 months were recorded.All kidney transplant recipients received induction therapy with an anti-interleukin-2 receptor antibody  and were maintained on CNI (cyclosporin or tacrolimus), mycophenolic acid  and corticosteroids. The dose of CNI was adjusted to achieve target therapeutic levels as per local clinical practice. Recipients received two doses of intravenous methylprednisolone (day 0 and 1 post-transplant) and were then maintained on a tapering dose of prednisolone, reaching 10 mg daily by 3 months post-transplant. Indication and 3-month protocol biopsies were performed and management of acute rejection with intravenous methylprednisolone was according to standard local clinical practice (1 gram over 3 days).At 3 months after transplantation, height and weight , blood pressure (average of three readings), Modification Diet of Renal Disease (MDRD)-derived estimated glomerular filtration rate (eGFR), urine pAn oral glucose tolerance test (OGTT) was performed at 3 months in all kidney transplant recipients. This test was undertaken following an overnight 8-hour fast and venous blood samples for blood glucose  and fasting insulin were taken following administration of 75 g oral glucose load. Recipients were classified as having normal glucose regulation, pre-diabetes (IFG and/or IGT) or PTDM in accordance with the American Diabetes Association guidelines: IFG wasArterial stiffness and wave reflections were measured non-invasively following an overnight 8-hour fast by applanation tonometry at 3 months post-transplantation using SphygmoCor® . A single operator conducted the measurements with coefficient variation of <10%. Aortic PWV  was measured as the carotid-femoral PWV using the foot-to-foot method (average of two measurements). AIx adjIn a subset of kidney transplant recipients, a repeat OGTT (n = 33) and measurements of arterial stiffness and wave reflections (n = 28) were obtained at 15 months after transplantation. Clinical history (up to 15 months post-transplantation), BMI, blood pressure, MDRD-derived eGFR, uPCR, haematological and biochemical parameters were also obtained for this time-point.Characteristics of those kidney transplant recipients who were lost to follow-up at 15 months post-transplant were similar compared to those with 15-month data: There were no significant differences in recipient  and donor (age and donor type) characteristics, transplant  or vascular  outcomes.p-value of < 0.2 in the unadjusted models were included. To detect a 20% difference in AIx between kidney transplant recipients with normal glucose regulation and pre-diabetes, a sample size of 25 per group was required assuming an alpha of 5%, power of 80% and SD of 7%. Statistical evaluation was performed by SPSS version 10 statistical software program . A p-value of less than 0.05 was considered statistically significant.Results are presented as frequency (percentage) for categorical variables or as mean and standard deviation (SD) for continuous variables. Comparisons of baseline characteristics between the three groups  were made by chi-square test for categorical variables and one-way analysis of variance (ANOVA) for continuous variables. Associations between glucose regulation at 3 and 15-months and 3 and 15-months PWV and AIx were examined using unadjusted and adjusted linear regression. In the adjusted model, only covariates with 2 and -0.16 kg/m2, respectively) compared to those with normal glucose regulation . The proportion of live-donor kidney transplants was similar . There was no significant difference in the proportion of recipients maintained on tacrolimus or cyclosporin or CNI drug levels.Of the 83 kidney transplant recipients, 43 (52%) had normal glucose regulation, 26 31%) had pre-diabetes and 14 (17%) developed PTDM at 3 months after transplantation. Table % had pre2 p = 0.55). There was no significant difference in tacrolimus and cyclosporin drug levels and CNI type in those with and without rejection. Similarly, mean eGFR and uPCR were not statistically different between groups  occurred beyond 3 months post-transplant, at least 1 month after the 3-month OGTT. The proportion of recipients who experienced biopsy-proven acute rejection was not significantly different between groups . Mean ± SD HOMA-IR scores were similar between groups . Serum calcium and phosphate levels were comparable between the three glucose regulation groups.There were no significant differences in cholesterol or triglyceride levels although more recipients with PTDM were prescribed a statin . PWV, systolic and diastolic blood pressures were similar across the three groups. The number and type of anti-hypertensive medications including the use of beta-blockers, calcium channel blockers, angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors were comparable between the three groups.At 3 months post-transplant, recipients with PTDM had significantly higher mean ± SD AIx (26.4 ± 6.7%) compared with those with pre-diabetes (22.9 ± 6.8%) and normal glucose regulation  and adjusted linear regression models . In contrast, recipients with pre-diabetes had similar AIx compared to recipients with normal glucose regulation . There was no association between glucose regulation and PWV in both the unadjusted and adjusted models (Table p > 0.2).Compared with recipients with normal glucose regulation, recipients with PTDM had significantly higher AIx in both the unadjusted  and adjusted models . There was no association between glucose regulation at 15 months and AIx and PWV at 15 months in both the unadjusted and adjusted models.In a subset of 28 kidney transplant recipients, mean ± SD AIx and PWV at 15 months were not significantly different between groups  and the proportion of recipients maintained on tacrolimus (70% to 58%). The change in CNI type was directed by each patient’s physician and specific reasons were not collected. As per standard local practice, therapeutic levels of CNI were lower at 15 months compared to 3 months post-transplant.This study has shown that early development of PTDM but not pre-diabetes at 3 months following kidney transplantation is associated with increased AIx as compared to those with normal glucose regulation, independent of traditional CVD risk factors such as age, eGFR and gender. However, there was no association between glucose regulation and aortic PWV. In a sub-study, we have also shown that glucose regulation post-transplantation is a dynamic process with over 10% of recipients normalizing their abnormal glucose regulation between 3 and 15 months post-transplant, predominantly in those with pre-diabetes at 3 months post-transplant.p < 0.01)[This is the first prospective study that has evaluated the association between early development of abnormal glucose regulation after kidney transplantation and arterial stiffness and wave reflections. A study of 79 kidney transplant recipients maintained on CNI, MPA and corticosteroids demonstrated that recipients with PTDM (n = 11) had significantly higher brachial-ankle PWV (1.59 ± 0.34 m/s) compared to recipients without PTDM . Unlike  < 0.01).p = 0.003) and 49% (p < 0.001) increased risk of non-fatal and fatal CVD events respectively, independent of other CVD risk factors. The inclusion of PWV and central augmentation pressure to the European SCORE system, the equivalent of the Framingham Risk Score for CVD mortality, significantly improved CVD risk reclassification by almost 16%[Non-invasive measurements of arterial stiffness and wave reflections are established surrogate markers of CVD and all-cause mortality. Carotid-femoral (aortic) PWV is a reliable measurement of central arterial stiffness; whereas AIx is a measurement of systemic arterial stiffness, which reflects both elastic and muscular arterial stiffness and wave reflections,27. Elevmost 16%.Our study has shown that early development of PTDM at 3 months post-transplantation was associated with higher systemic (AIx) but not central arterial stiffness (aortic PWV), suggesting that small vessel dysfunction may be the earliest detectable vascular damage in those with early PTDM. Longer follow-up of recipients with PTDM may be required to detect changes in large vessel arterial stiffness (PWV). Two general population-based cohorts totaling 5685 individuals demonstrated that arterial stiffness increases and arterial compliance decreases significantly with increasing severity of abnormal glucose regulation, with patients with PTDM and pre-diabetes having a 17%/10% and 10%/5% respectively higher brachial-ankle PWV/lower total systemic arterial compliance compared to those with normal glucose regulation-32. UnliGlucose regulation after kidney transplantation appears to be a dynamic process. In our study, up to 30% of kidney transplant recipients with pre-diabetes at 3 months normalized their abnormal glucose regulation at 15-months post-transplant, likely related to overall reduction in immunosuppression such as corticosteroids and CNI, agents known to induce insulin resistance and/or beta cell dysfunction. SimilarThe strength of this study is the completeness of data in our cohort and the availability of longer-term data in a subset of kidney transplant recipients. Our study is limited by the lack of pre-transplant measurements of arterial stiffness and wave reflections  and the relatively small numbers (type II error) which may explain the absence of an association between arterial stiffness and abnormal glucose regulation in our sub-study analysis. As with any single-centre study, the generalizability of our findings to other population groups may be limited. Even though all kidney transplant recipients had normal fasting and random blood glucose levels prior to transplantation, the unavailability of pre-transplant OGTT may potentially have led to inclusion of recipients with unrecognized pre-transplant diabetes or pre-diabetes.At three months following kidney transplantation, PTDM is associated with small vessel dysfunction (AIx), an established predictor of CVD mortality. Measurements of arterial stiffness after transplantation may help to more accurately stratify the future risk of CVD mortality in kidney transplant recipients. Larger longitudinal studies examining the association between glucose regulation, arterial stiffness and hard CVD clinical endpoints in kidney transplant recipients are required prior to considering whether interventional clinical trials in those with early abnormal glucose regulation could reduce the risk of future CVD events.The authors declare that they have no competing interests.WL designed the study. AV wrote the article and prepared figures. AV and WL were responsible for interpretation, statistical analysis of data and have responsibility for the final content. AV, WL, KY, HN collected data. WL, DC, SD, KY, GW and HN revised the article critically for important intellectual content. All authors read and approved the final manuscript.


Extrapolation to national level suggests that about 18% of primary care patients may suffer from CKD. CKD prevalence in a primary care population is therefore high, and preventive interventions may be advisable, in particular as CKD prevalence is likely to rise over the next decades.Chronic kidney disease (CKD) often remains clinically silent and therefore undiagnosed until a progressed stage is reached. Our aim was to estimate the prevalence of CKD in a primary care setting in Switzerland. A multicenter, cross-sectional study with randomly selected general practitioners was performed. Adults visiting their general physician’s cabinet during defined periods were asked to participate. Baseline information was reported on a questionnaire, urine and blood samples were analyzed in a central laboratory. Renal status was assessed using the Kidney Disease: Improving Global Outcomes (KDIGO) classification. Extrapolation of results to national level was adjusted for age and gender. One thousand individuals  with a mean age of 57±17 years were included. Overall, 41% of the patients had normal estimated glomerular filtration rate (eGFR) and albumin creatinine ratio (ACR), whereas 36% of the subjects had slightly reduced excretory renal function with physiological albuminuria based on normal ACR. Almost one fourth of the subjects (23%) had either a substantially reduced eGFR or high levels of ACR. About 10% of the patients had a substantially reduced eGFR of <60 ml/min/1.73 m Chronic kidney disease (CKD), defined as renal damage with persistent and usually progressive deterioration of ultrafiltration, is a worldwide public health problem 2) or slightly reduced (GFR 60–89 ml/min/1.73 m2), respectively, with evidence of renal damage (e.g. proteinuria). In CKD stages 3 and 4, functional impairment is moderate (GFR 30–59 ml/min/1.73 m2) or severe (GFR 15–29 ml/min/1.73 m2), respectively. Finally, CKD stage 5 is defined by kidney failure (GFR <15 ml/min/1.73 m2) or dialysis, and is also termed end-stage renal disease (ESRD) 2 or urinary albumin to creatinine ratio (ACR) >30 mg/g The classification of CKD is mainly based on measured or estimated glomerular filtration rate (GFR). In CKD stages 1 and 2, kidney function is normal . ESRD patients usually present with many complications, high mortality, strongly reduced quality of life, and high health care expenditures Unfortunately these interventions are expensive and not always available. Hemodialysis costs amount to 530 Swiss Francs per session Except for RRT, there is no other treatment for CKD patients with ESRD. Even at early stages, actual treatment options mainly aim to prevent or slow disease progression by controlling risk factors such as hypertension, diabetes, and obesity One of the biggest issues in CKD prevention is actually disease awareness. In the Kidney Early Evaluation Program (KEEP), a community-based screening program, only 10.0% of the 26,213 participants were aware of suffering from CKD. The proportion in awareness was particularly low for early CKD, with 5.1%, 6.3%, and 10.0% for stages 1 to 3, respectively. In contrast, almost 40% of the patients with CKD stage 4, and 60% of those with CKD stage 5 were aware of having renal disease One of the first steps to improve CKD management is knowledge about CKD prevalence. Consequently, in the last few years, research has focused on the epidemiology of CKD A cross-sectional, multicentre, non-interventional study was conducted in seven of the 26 Swiss cantons, including all five Swiss cantons with university affiliated medical faculties , the largest canton in central Switzerland (Lucerne), and the Italian speaking canton of Ticino. The selected cantons were home to nearly 60% of the entire Swiss population in 2010 and represent all three major language regions in Switzerland  Labormedizinisches Zentrum Dr. Risch) using overnight delivery service by the Swiss Postal Service. Laboratory analysis was performed on the day the samples were received. Laboratory parameters were determined on an Abbott ARCHITECT ci4100 analyzer platform , a Sysmex XT-5000 hematology analyzer , and a Bio-Rad D-10 HPLC system for the determination of glycated haemoglobin . The following parameters were measured to assess kidney function and damage: serum and urinary creatinine using the Jaffé method, cystatin C in the serum and urinary albumin . In our hands, the intra-assay coefficient of variation  for creatinine was 1.5% at 60 µmol/L, 1.0% at 168 µmol/L, and 0.7% at 624 µmol/L. The respective CV’s were 1.8% at 0.7 mg/L and 2.0% at 3.5 mg/L for cystatin C, and 1.6% at 32.5 mg/L, 1.5% at 119.5 mg/L for urinary albumin.Socio-demographic variables, clinical status and co-morbidities were reported on a questionnaire. Urine and blood samples were sent to a central laboratory for analysis. A spot urine was collected in a Greiner Vacuette tube without preservatives , whereas venous blood was collected in Sarstedt Monovette EDTA tubes and in serum tubes containing separation gel . After serum sample centrifugation, the samples were mailed to the central laboratory , as reported by the Swiss Federal Statistical Office Generalized linear models were fitted to control for factors that may be related to reduced eGFR or elevated ACR. In the first model, age, gender, and clinical characteristics of the study population were entered. In the second model, the laboratory parameters were analyzed. All variables showing significant results were used in a third model. The variables confirming significance in the third generalized linear model were finally combined in a simple linear regression analysis. The coefficient of determination (R square) and Pearson correlation coefficients were calculated. Significant variables were tested for multicollinearity by calculating the variance inflation factors (VIFs).Among the 1,000 individuals recruited, 57% were female, and the mean age was 57±17 years. The main socio-demographic and clinical characteristics of the patients according to gender are shown in The results of the laboratory analysis showed that mean values of many parameters were significantly different between males and females , cystatin C, total cholesterol, high-density lipoprotein (HDL), high sensitive troponin, folic acid, ferritin, chloride, inorganic phosphate, HbA1c, alanine and aspartate transaminase, gamma-glutamyl transpeptidase, bilirubin total, and albumin). However, the majority of the laboratory parameters were within normal range for both genders . For bot2) with physiological albuminuria based on normal ACR (<30 mg/g). About one tenth of the patients had a substantially reduced eGFR of <60 ml/min/1.73 m2, and 17.1% showed relevant proteinuria (ACR ≥30 mg/g). Almost one fourth of the analyzed subjects had CKD, i.e. they had either a substantial reduction in renal function or high levels of proteinuria , gender (p<0.001), and heart failure (p<0.001) were significantly and independently correlated with eGFR. In the second model, statistically significant correlations with eGFR were found for cystatin C (p<0.001), total cholesterol (p<0.001), HDL (p<0.001), high sensitive C-reactive protein , brain natriuretic peptide , folic acid (p = 0.001), sodium (p<0.001), inorganic phosphate (p<0.001), HbA1c (p<0.001), alanine transaminase (p = 0.001), and albumin (p = 0.024). In the third model combining all significant factors, gender, age, cystatin C, HDL, BNP, sodium, inorganic phosphate, HbA1c, and albumin remained significantly correlated with eGFR. The combination of the variables from the third model in a simple linear regression model confirmed a strong relationship with the eGFR . Particularly strong correlations were found for age (Pearson correlation coefficient ρ = −0.648) and cystatin c (ρ = −0.667). No multicollinearity problems were found .For ACR, the first model showed significant correlations with gender (p = 0.019), age (p = 0.036), heart rate (p = 0.021), diabetes (p = 0.001), and heart failure (p = 0.016). In the second model, significant results were found for urinary NGAL (p = 0.001), cystatin C (p = 0.001), BNP (p<0.001), and HbA1c (p<0.001). After combining all significant factors in a third model, gender, heart rate, diabetes, heart failure, urinary NGAL, cystatin C, BNP, and HbA1c remained significantly and independently correlated with ACR. The combination of these variables in a linear regression analysis showed a weak relationship . The highest Pearson correlation coefficients were found for BNP (ρ = 0.322), cystatin c (ρ = 0.247), and HbA1c (ρ = 0.215). Again, no multicollinearity problems were found .2) and/or relevant proteinuria (ACR ≥30 mg/g).In the extrapolation of CKD prevalence to the national level we made the assumption, that about 60% of the Swiss population visit a primary care physician at least once yearly . Of thos2 and an ACR <30 mg/g. About one third of the subjects showed slightly reduced filtration rate (eGFR 60–89 ml/min/1.73 m2) with physiological ACR, whereas 23% of the patients fulfilled the criteria of CKD (i.e. eGFR <60 ml/min/1.73 m2 and/or ACR >30 mg/g), as defined by KDIGO This study shows that CKD prevalence and/or renal function impairment in the general Swiss population is considerably high. In our sample only about 40% of the patients had a normal renal function with an eGFR ≥90 ml/min/1.73 m2, and a 25.6% prevalence of hypertension  Our study sample, which was derived from a primary care population, is nevertheless comparable to that of the Swiss Survey on Salt, and, to some extent, to the general Swiss population. In the Swiss Survey on Salt, a prospective, nationwide survey conducted in 2010–2011 with a random sample of 1,377 subjects, the mean age was 47.3 years, with 51.2% females, 17.3% current smokers, a mean BMI of 25.1 kg/m2. The difference of almost 3% may be explained by diverse recruitment strategies: whereas in our study the subjects were recruited in a primary care setting, in the Swiss Survey on Salt, the participants were recruited using a list of randomly selected households from the major Swiss telecommunication company’s home phone directory. For each household, one person was randomly selected and invited to participate in the study. It is reasonable to suppose that this sample was not only younger if compared to our study population, but also healthier and therefore less likely to suffer from CKD and other diseases. In the US National Health and Nutrition Examination Survey (NHANES) 1999–2006, a representative cross-sectional national survey, 9,536 participants were interviewed at home and/or received standardized medical examination in mobile study centers By extrapolation to national level, and after adjustment for age and gender, the percentage of patients in primary care that may have CKD is high, with almost 19% of the primary care population having substantially reduced renal function and/or relevant proteinuria. These results, again, are comparable to those found in the Swiss Survey on Salt, with a reported prevalence of about 7.7% of the included population for CKD stage 3 or higher. In our study, 10.4% of the patients had an eGFR <60 ml/min/1.73 mThe generalized linear regression models showed that both eGFR and ACR are strictly correlated with gender, cystatin C, BNP, and HbA1c. It is interesting to note that whereas eGFR was correlated with age and several blood/urine parameters , ACR was age independent and directly correlated to diabetes and heart failure. These results emphasize the importance of ACR as screening and prognostic factor for young patients and for patients with diabetes and/or heart failure. For example, in the Kidney Early Evaluation Program (KEEP) Annual Data Report 2007, it has been shown that ACR is the predominant positive screening test for younger age groups: in KEEP, about 80% and 60% of the CKD patients aged 18–30 and 31–45 years, respectively, showed elevated ACR with normal eGFR. Even higher percentages were found in the NHANES cohort from 1999–2004 2 and in 83.6% of those with eGFR ≥ 60 ml/min/1.73 m2 a stable level of renal filtration function was found at follow up 2 per year 2 was within the 25th and 50th percentile for men and women >65 years. In another study including more than 10,000 individuals 66 years of age or older, eGFR reductions of 0.8–1.4 and 2.1–2.7 ml/min/1.73 m2 per year were reported for non-diabetic and diabetic subjects, respectively 2 or ACR >30 mg/g (i.e. a suspected CKD) further tests should be performed to determine the type and duration of kidney disease. If the duration is >3 months, CKD is formally established. For elderly patients with slight to moderate reduction of renal function it is particularly important to monitor for rapid progression, defined as a sustained decline in eGFR of more than 5 ml/min/1.73 m2 per year Some limitations of the study have to be considered. Firstly, screened subjects were volunteers and therefore not necessarily representative for the overall primary care population in Switzerland. In this study, emergency patients were excluded for ethical reasons. Moreover, it is possible that patients visiting the GP with a relatively serious/painful disease tend to refuse to participate. This may have resulted in an underestimation of the true CKD prevalence. A second limitation concerns the use of a creatinine based estimation for renal filtration function. In the last years, many formulas have been developed to calculate eGFR: the Modification of Diet in Renal Disease (MDRD) formula, the Mayo Quadratic formula, and the CKD-EPI formula In summary, CKD prevalence in a primary care population in Switzerland is high. The growing proportion of elderly people among the Swiss population and the increasing prevalence of many risk factors will result in an increase of CKD prevalence over the next decades. Implementation of prevention and screening programs will be crucial in the managing strategies of many healthcare systems, especially in western countries. In addition, overcoming the lack of CKD awareness must become part of future strategies. Unlike the United States, where educational efforts have been made to increase CKD awareness in the general population ,


Despite available guidelines on hypertension (HTN), use of antihypertensives is variable. This study was designed to ascertain frequency of patients on monotherapy and > 1 antihypertensive therapy and also to ascertain proportion of patients on diuretic therapy.It was a crossectional study conducted on 1191 adults(age > 18 yrs)hypertensive patients selected by computerized International Classification of Diseases -9-coordination and maintenance (ICD-9-CM) presenting to a tertiary care hospital in Pakistan. Data on demographics, comorbids, type of antihypertensive drug, number of antihypertensive drug and mean duration of antihypertensive drug was recorded over 1.5 year period (2008-09). Blood pressure was recorded on admission. Primary outcome was use of combination therapy and secondary outcome was use of diuretic therapy.A total of 1191 participants were included. Mean age(SD) was 62.55(12.47) years, 45.3%(540) were males. Diabetes was the most common comorbid; 46.3%(551). Approximately 85% of patients had controlled hypertension. On categorization of anti hypertensive use into 3 categories;41.2%(491) were on monotherapy,32.2%(384) were on 2 drug therapy,26.5%(316) were on ≥3 drug therapy. Among those who were on monotherapy for HTN;34%(167) were on calcium channel blockers,30.10%(148) were on beta blockers, 22.80%(112) were on Angiotensin converting enzyme (ACE) inhibitors,12%(59) were on diuretics and 2.20%(11) were on Angiotensin receptor blockers(ARB). Use of combination antihypertensive therapy was significantly high in patients with ischemic heart disease(IHD)(p < 0.001). Use of diuretics was in 31% (369) patients. Use of diuretics was significantly less in patients with comorbids of diabetes (p 0.02), Chronic kidney disease(CKD)(p 0.003), IHD (p 0.001) respectivelyMost patients presenting to our tertiary care center were on combination therapy. Calcium channel blocker is the most common anti hypertensive drug used as monotherapy and betablockers are used as the most common antihypertensive in combination. Only a third of patients were on diuretic as an antihypertensive therapy. Hypertension is a leading contributor to the global burden of cardiovascular morbidity and mortality . DespiteSeveral reasons have been highlighted as cause of such high rates of uncontrolled hypertension. Apart from unhealthy lifestyles, lack of awareness about hypertension, distorted public health systems, physicians treating hypertension also lag behind in treating hypertension according to standard guidelines ,6. Non cSeventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) recommends diuretic to be used as preferred initial antihypertensive agent alone or in combination [The bination . On the bination ,10. All bination ,11. Hencbination . Four clbination -15.Data on the use of antihypertensive in individual specialty practices has been reported from the Indo-Asian region. There have been studies advocating the use of ACEIs in stroke patients and use of ARB in normotensive diabetic patients. Hence this data is specific to a certain patient population ,17. Currhttp://www.aku.edu. Ethical approval from the ethics review committee of the Aga Khan University (letter dated 16-08-2009) was taken for conduct of the studyThis was a cross sectional 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 with the help of professional staff and facilities that are among the best in the region. Care is available to all patients in need. Those who are unable to pay for treatment, receive assistance through a variety of subsidies. AKUH is the first hospital in Pakistan and among the first few teaching hospitals in the world to be awarded the prestigious Joint Commission International Accreditation (JCIA) for practicing the highest internationally recognized quality standards in health care. Similarly, the Hospital also holds ISO 9001: 2008 certification for practicing consistent international standards of quality services All adult inpatients> 18 yrs), over a 1.5 year period(2008-2009), who were known hypertensive (diagnosed on having an average blood pressure of ≥140/90 mm Hg on at least 2 clinic visit)and were on antihypertensive therapy for at least 6 weeks were included [ yrs, ovePrimary outcome variable was use of combination antihypertensive therapy. It had three categories; monotherapy, two drug therapy and ≥three drug therapy. Secondary outcome was use of diuretics as an antihypertensive therapy. Data on demographics, co morbid conditions, type of antihypertensive drug, number of antihypertensive drugs and mean duration of antihypertensive drug therapy was recorded by trained data collectors. Records of antihypertensive drugs were extracted from the medical record of the patient. A two way approach was used for this purpose. Anti hypertensives documented on the initial assessment sheets filled at the time of admission was recorded. This was also reconfirmed from the record of the last clinic visit for every patient. In case the clinic visit was at some other hospitals, that prescription was used for the second confirmation. It was assumed that the patients were compliant to the medications written, however no additional measures were used to check compliance. Patients who used an antihypertensive medication with only 1 active ingredient were defined as receiving monotherapy. Those taking more than 1 active ingredient (either in 1 combination pill or in 2 different single pills) were defined as receiving polytherapy . A histoFirst two readings of blood pressure on admission were recorded. At the time of admission BP in the right arm were recorded using a mercury sphygmomanometer with the individual in the sitting position. Controlled blood pressure was defined as systolic blood pressure (SBP) < 140 mm Hg or diastolic blood pressure(DBP) < 90 mm Hg and uncontrolled blood pressure was defined as SBP > 140 mm Hg and DBP > 90 mm Hg . Any chaStatistical package for social sciences (SPSS) 17.1 was used for the analysis. Mean and standard deviation was used for quantitative variables and frequency and percentage for qualitative variables. Comparison of qualitative variables was done by chi square test and of quantitative variables by independent sample t test and analysis of variance. p value of < 0.05 was taken as significant.A total of 1191 participants were included. The mean age (SD) was 62.5(12.4) years, 45.3%(540) were males. Comorbids conditions and ovearall blood pressure readings are shown in Table On categorization of anti hypertensive into 3 categories; 41.2%(491) were on monotherapy,32.2%(384) were on 2 drug therapy and 26.5%(316) were on ≥3 drug therapy. Comparison is shown in Table Thirty one percent patients were on diuretic as antihypertensive therapy. Use of diuretics is significantly decreased in patients with the following comorbids(on diuretic v not on diuretic); diabetes , CKD , IHD  respectively. There was no significant difference in SBP (p 0.10) and DBP (p 0.50) of patients on diuretics compared to not on diuretics.This data of 1191 Southasian patients at atertiary care center show that, most hypertensive patients were on combination therapy. Patients with IHD, CKD were more likely to be on 2 drug combination antihypertensive therapy. Calcium channel blockers were used as the most common antihypertensive monotherapy and betablockers as most common antihypertensive in combination. Diuretics as monotherapy antihypertensive was used in one third of the patients.Recent clinical trials suggest that the approach of using monotherapy for the control of hypertension is not likely to be successful in most patients and especially in those with some comorbids conditions. . The achievement of BP goal typically requires 2 or more medications in various settings -24. ThisThe approach of combination therapy may be theoretically favored by the fact that multiple factors contribute to the hypertension and achieving control of BP with single agent and adding a second agent may lead to better control, acting by complimentary mechanism . Adherenantihypertensive drug class was angiotensin-converting enzyme inhibitors (30.1%), followed by beta-blockers (20.6%), calcium-channel blockers (17.9%), diuretics (15.4%) and angiotensin-receptor blockers (14%) [Calcium channel blockers have emerged as the most common monotherapy used for hypertension, whereas Beta blockers have been used as the most common combination therapy for hypertension. Calcium channel blockers have been the preferred monotherapy in many studies followed by beta blockers and ACE inhibitors -31. ACE rs 14%) . Hence crs (14%) ,34. Henc% . Hencers (14%) . The rears (14%) . Secondlrs (14%) .The strength of this study is the large sample size, and is the first study from this region to report figures on monotherapy, combination therapy and type of antihypertensives in hypertensives. However there are several limitations in our study. Firstly it has limited external validity as the sample is not representative for an entire population. It represents population visiting a standard hospital, hence is not representative of entire Pakistan. Secondly certain amount of recall bias may be involved as information about the antihypertensives was taken from the medical records. Thirdly the crossectional design of the study cannot strongly give a cause and effect association. Fourthly only one blood pressure reading has been taken into account, hence some of the patients may have been misclassified as controlled hypertensives. Also compliance and cost of antihypertensives was not assessed for each patient.Most patients presenting to our tertiary care center were on combination therapy. Calcium channel blocker is the most commonly used anti hypertensive drug used as monotherapy while betablockers is used as the most common combination therapy. Diuretics use in hypertensive patients is low and not keeping with the recommended guidelines.The authors declare that they have no competing interests.AA generated the idea, designed the study and was involved in analysis and first draft. SRI and AE were involved in the data management and analysis. AHK was involved in designing, proof reading and reviewing the draft. All authors read and approved the final manuscript


Type 1 diabetes mellitus (T1DM) is associated with cerebral compromise, typically found in patients with microangiopathy. Associations between subclinical macroangiopathy and the brain, whether or not in the presence of microangiopathy, have not been fully explored in T1DM. We hypothesized that subclinical macroangiopathy in adult T1DM may affect the brain and interacts with microangiopathy.In 51 asymptomatic T1DM patients with, 53 without proliferative retinopathy and 51 controls, right common carotid artery ultrasound was used to assess intima media thickness (cIMT) and distensibility (cD). Neuropsychological tests for cognitive functions, and magnetic resonance imagining for white matter integrity and functional connectivity, i.e. neuronal communication, were used.P = 0.071), whereas cD was not statistically significantly altered (P = 0.45). Patients with proliferative retinopathy showed the largest increase in cIMT and decrease in cD. In all participants, after adjustment for confounders, increased cIMT was related to decreased white matter integrity (β = −0.198 P = 0.041) and decreased functional connectivity in visual areas (β = −0.195 P = 0.046). For cognition, there was a significant interaction between cIMT and the presence of proliferative retinopathy after adjustment for confounding factors . Increased cIMT was associated with lower general cognitive ability , information processing speed  and attention  scores in patients without, but not in patients with proliferative retinopathy.After correction for confounders, cIMT was borderline significantly increased in all T1DM patients (These findings suggest that subclinical macroangiopathy may be a factor in the development of diabetes-related cognitive changes in uncomplicated T1DM, whereas in patients with advanced T1DM, proliferative retinopathy may rather be the driving force of cerebral compromise. Over the last decade, evidence has accumulated showing that adult type 1 diabetes mellitus (T1DM) is associated with decrements in mental efficiency -4. Both Besides microangiopathy, macrovascular changes are a common finding in T1DM, even in asymptomatic patients. Cross-sectional studies observed increased common carotid Intima Media Thickness (cIMT) in T1DM adolescents and adults as compared with controls ,9. AssocIt may be speculated that subclinical macroangiopathy negatively impacts the brain in T1DM, and that it may aggravate the effect of proliferative retinopathy on the brain. Therefore we investigated differences of subclinical macroangiopathy between healthy controls and T1DM patients with and without proliferative retinopathy. Second, associations between subclinical macroangiopathy and cognitive, white matter tract integrity and functional connectivity parameters were calculated in these participants. Last, to address the hypothesis that subclinical macroangiopathy may aggravate the effect of proliferative retinopathy on the brain, we tested whether the interaction terms of subclinical macroangiopathy with proliferative retinopathy were statistically significant for the brain measurements. Such significant interactions indicate that the effect of subclinical macroangiopathy differs according to proliferative retinopathy status, which was subsequently tested.2, alcohol or drug abuse, psychiatric comorbidity warranting treatment, centrally acting medication use, cardio- or cerebrovascular disease, head trauma, hepatitis, anaemia, thyroid dysfunction, pregnancy, epilepsy, contraindication for MRI or insufficient visual acuity to perform the neuropsychological tests. Additionally, controls were excluded in case of hypertension. Patients with proliferative retinopathy  and estimated IQ were included in this study. A detailed description of the study design can be found elsewhere . In shorfication  by a trafication ). Patienfication . HyperteOn the morning of the ultrasound, participants were instructed to have a standardised breakfast, not including eggs, coffee, tea or orange juice and not to smoke. Ultrasound of the right common carotid artery was performed by a single blinded research assistant, after participants rested for 10 minutes in the supine position. An arterial wall B-mode ultrasound imager with a 7.5 MHz linear-array transducer  was used. Measurement site was approximately 10 mm from the carotid bulb. The exact measurement site on the artery was determined in the B-mode, in a region free of plaque with a clearly identified double-line pattern.Then data acquisition was performed in the M-mode for 4 seconds, triggered by the R-top of the ECG. Offline, 2 components of subclinical macrovascular disease, i.e. cIMT and carotid Distensibility (cD) were calculated using vessel wall movement detection software . For each subject, to calculate the cIMT, 3 measurements were selected. A measurement was selected if the standard deviation of the mean diameter of the lumen was less than 1% of that mean diameter. For reproducibility purposes, measurements of 15 randomly selected participants were assessed a second time after a year by the same assistant. This yielded an absolute mean difference in cIMT of 0.0128 mm, with an interclass correlation coefficient κ of 0.985 with a 95% confidence interval: 0.955 – 0.995.−1]). The higher the change in lumen area of the carotid artery the more flexible the arterial wall, therefore, a low cD value is associated with increased arterial stiffness. As this is a functional measure, it is more sensitive to intra-personal circumstances and levels of cD can fluctuate within each participant. To prevent selection bias, it was decided to include cD values of all measurements made for each participant.Additionally, arterial stiffness was estimated by measuring the relative changes in lumen area for a given change in pressure  Diffusion Tensor Imaging, white matter tract integrity was assessed as previously described . Most prA detailed description of acquisition and analysis of resting-state functional MRI (fMRI) can be found elsewhere . IncreasP-value of <0.05 to indicate statistical significance was used. All analysis were performed using IBM-SPSS 20 .Demographic, anthropometric and medical variables were analysed using One-Way ANOVA with Bonferroni correction, Student’s t-test, Kurskal-Wallis test or chi-square, whether appropriate. Carotid IMT between patients and controls was compared using a MANCOVA corrected for age, sex, systolic blood pressure and multiple comparisons (Bonferroni). First, interaction terms between group  and subclinical macroangiopathy were tested for brain parameters. In case of a significant interaction effect, the association between those brain variables and subclinical macroangiopathy was analyzed in all patients and controls separately. In the absence of an interaction effect, these associations were calculated in a pooled analysis in all participants. For the pooled analysis, all associations were studied using linear regression, corrected for age, sex and systolic blood pressure and additionally for HbA1c, current smoking status and depressive symptomatology. Next, interactions of subclinical macroangiopathy and proliferative retinopathy on brain parameters were tested in all T1DM patients. In case of significant interaction terms, groups were analyzed separately. Linear regression was again used to determine associations between subclinical macroangiopathy and brain variables. These analyses in T1DM patients alone were corrected for age, sex and systolic blood pressure, diabetes duration, HbA1c, current smoking status and depressive symptomatology. For all tests a P < 0.05). They had higher systolic blood pressure relative to controls. Patients with, as compared to those without proliferative retinopathy, had longer disease duration, earlier onset age, more often hypertension and increased albumin:creatinine ratio .Echography of 1 control and 2 patients without microvascular complications did not result in reliable cIMT or cD values. Thus, they were excluded from the analyses. Table P = 0.071; Figure Carotid IMT, after correction for age, sex, systolic blood pressure and multiple comparisons, was borderline increased in all T1DM patients versus controls (Pinteraction > 0.05). Thus, all participants were used in a pooled analysis. Increased carotid intima media thickness was associated with white matter integrity of the right inferior fronto-occipital tract (β = −0.206 P = 0.027) and borderline associated with decreased visual network functional connectivity (β = −0.176 P = 0.064), after correction for age, gender and systolic blood pressure. These associations were similar after additional correction for current smoking, depressive symptomatology and HbA1c .There were no significant interaction effects between cIMT or cD and group  for cognition, white matter integrity or functional connectivity . After additional correction for diabetes duration, current smoking, depressive symptomatology, and HbA1c the results of the interaction analyses were similar . There were no significant interaction terms for white matter integrity or functional connectivity. There were no associations between cIMT and cognitive parameters in patients with proliferative retinopathy . Contrary, in T1DM patients without clinically manifest microvascular complications, there were significant associations between increased cIMT and poorer general cognitive ability .Next, the possible interaction between subclinical macroangiopathy and proliferative retinopathy was assessed in all T1DM patients. For general cognitive ability, information processing speed and attention, there were statistically significant interactions between cIMT, but not cD, and proliferative retinopathy, corrected for age, gender and systolic blood pressure  study showed decreased blood flow in adult patients with asymptomatic T1DM relative to controls [In addition to measures of cognition, brain functioning and white matter integrity, the relationship between subclinical macroangiopathy and parameters of cerebral blood flow would have been of interest. A recently published [controls . These pIn this study no effects were found for carotid distensibility. Contrary, a previous case–control study showed that in middle-aged T1DM patients without or with mild microvascular complications (mostly background retinopathy), increased aortic stiffness was related to lower total brain white matter volume and increased prevalence of white matter hyperintensities, i.e. ischemic brain damage ,22. SimiThe effects sizes of the observed associations were small to moderate, indicating a relatively moderate contribution of cIMT in T1DM-related cognitive dysfunction. From this study it cannot be determined why T1DM-related cerebral compromise in patients with proliferative retinopathy was not exacerbated by measures of subclinical macroangiopathy. However, based on our findings, one may speculate that early cognitive changes, i.e. before microvascular complications are present, may be in part mediated by increased cIMT, but that once microangiopathy has developed T1DM-related cerebral compromise, the effects of subclinical macrovascular disease is overruled. This differential effect of macro- and microvascular disease on CNS function and structure requires further study.The cross-sectional nature of this study pertains us to draw causal conclusions. Other limitations may include that fact that our patient with proliferative retinopathy had longer disease duration and earlier disease onset age than their counterparts without complications, both of which could constitute a confounder. Therefore, we corrected for diabetes duration in the analyses in T1DM patients. Additional correction for diabetes onset age is not possible due to co-linearity between the two variables. But removing diabetes duration from the analyses and adding diabetes onset age yielded similar results. This may indicate that our findings are independent of disease duration and diabetes onset age. Furthermore, an early disease onset age (i.e. <7 years of age) has been hypothesised to have more adverse effects on the brain than an onset later in life . In thisIn conclusion, in T1DM patients without, contrary to patients with proliferative retinopathy, cIMT as marker of subclinical atherosclerotic disease, but not cD, as marker of arterial stiffness, was related to poorer performance in cognitive domains. Furthermore, increased cIMT, but not cD, was related to decreased functional connectivity and white matter integrity. The underlying mechanisms contributing to these differential findings remain to be determined, but it might be that the consequences of microangiopathy on the diabetes brain overrule the more subtle effects of incipient macrovascular disease.cIMT: Carotid intima media thickness; cD: Carotid distensibility; T1DM: Type 1 diabetes; T2DM: Type 2 diabetes; CNS: Central nervous system; BMI: Body mass index; (f)MRI:  magnetic resonance imaging; ANOVA: Analysis of variance; MANCOVA: Multivariate analysis of covariance; ECG: Electrocardiogram.The authors declare that they have no competing interest.EvD took part in the design of this study, collected and analyzed the data, wrote the manuscript. FJS, MD, MK, RGIJ, AMW, FB participated in the design of the study. ACM rated the fundus photographs to ascertain proliferative or no retinopathy in diabetes patients. JB performed the ultrasound measurements, which was supervised by NJZ. MMS, PJP and FB supervised the MRI-analyses. All authors were involved in interpreting the data, drafting the manuscript and making revisions to the manuscript. All authors read and approved the final manuscript.


Objective: Congenital hypothyroidism (CH) increases the prevalence of kidney and urogenital malformations. There are limited studies considering different aspects of kidney function in well-controlled CH patients. We evaluated some features of kidney function in euthyroid children with CH who have been receiving thyroxine hormone since early life.Methods: This cross-sectional study was conducted in Isfahan, Iran, on 74 children aged 2-15 years old . Inclusion criteria for CH patients were euthyroidism at the time of the survey and initiation of replacement therapy during the early neonatal period. Kidney ultrasound evaluation was performed in all participants. Serum biochemistry included urea, creatinine, sodium (Na), potassium (K), magnesium, calcium, and cystatin C levels. Urine electrolytes, fraction excretion (FE) of electrolytes and microalbumin, and glomerular filtration rate (GFR) were also determined.Results: The male/female ratio was 0.8/1 and 1.5/1 in the patient and control groups, respectively. Mean age and height did not differ significantly between the two groups. Ultrasound evaluation of the kidney revealed that the anteroposterior diameter of the right kidney was significantly higher in CH patients as compared to healthy subjects. No significant difference was observed between GFRs in patients with CH and healthy children. The mean values for FENa and FEK were significantly higher in the patient group.Conclusions: Increased FENa and FEK may be a manifestation of impaired tubular maturation in CH. More longitudinal studies are needed to evaluate kidney function in CH patients. Conflict of interest:None declared. Thyroid hormones are of prime importance in human growth and development. Congenital thyroxine T4) deficiency or insufficiency in the newborn results in severe mental retardation ,2,3. Rep deficienThe incidence of several congenital malformations including cardiac, oral, neurologic, and urogenital anomalies have been reported to be higher in CH patients in comparison with a normal population ,9,10. CHThis cross-sectional study on 74 children aged 2-15 years was conducted in Isfahan, Iran, from March 2010 to October 2011. Thirty-six subjects were known cases of CH who met the inclusion criteria of being euthyroid at the time of the survey and having received replacement therapy initiated in the early neonatal period (within the first 14 days of life). Thirty eight age-, weight- and height-matched healthy children were selected as the control group. Information on this group was based on their medical records and interviews conducted with their parents. Due to the scarcity of poorly controlled CH patients in the community, we were not able to recruit such patients to the study as another control group.Kidney ultrasound was performed in each participant by the same experienced radiologist blinded to the diagnosis of CH using an ultrasound apparatus with 3 and 6 MHz curvy linear probes . All three dimensions of each kidney , as well as the anterior-posterior (AP) diameter of the pelvis, renal parenchymal thickness, and bladder wall thickness were measured. An AP diameter greater than 3 mm and a bladder wall thickness greater than 2 mm were accepted as high for all ages. Fasting blood samples were collected in all subjects to measure cystatin C, blood urea nitrogen (BUN), creatinine (Cr), magnesium (Mg), sodium (Na), potassium (K), and calcium (Ca). Urine Cr, Mg, Na, K, Ca, and microalbumin (MA) were measured in the fasting spot urine samples. MA was assessed by the nephelometric (turbidimetric) method, using a locally manufactured kit . A urine MA/Cr ratio greater than 30 was considered abnormally high. Serum Cr, Mg, Ca, and BUN were measured enzymatically on a Hitachi 7350 autoanalyzer. Serum cystatin C was measured by a particle-enhanced immunoturbidimetric method . Fractional excretion (FE) of Na and K (FENa and FEK) were used to detect presence of renal tubular dysfunction. Additionally FEMg was used as a marker of tubular injury . We used the following formulae to calculate FENa, FEK, and FEMg (13):X urinary (X)/serum (X) X urinary Cr] X100FE(X) = [serum Cr X urinary (Mg)/serum (Mg) X urinaryFEMg= [serum Cr X 0.7] X 100Cr It has been shown previously that FEMg measurements can be used to demonstrate any possible damage in the thick ascending limb of Henle’s loop which is one of the most energy-dependent sections of the renal tubule ,15.Glomerular filtration rate (GFR) was measured using the following formulae:X height (cm)/serum Cr1) GFR (Schwartz formula) = K (mg/dL) (K= 0.55 for girls and K= 0.7 for boys)2) (cystatin C-based Schwartzformula) = 39.1[height (m)/SCr(mg/dL)]0.516 [1.8/cystatinC (mg/L)]0.294 [30/BUN(mg/dL)]0.169 [1.099][height (m)/1.4]0.188 (2) GFR (mL/min/1.73 mX cystatin C(mg/L) −1.680 X 1.384 (3) GFR (cystatin C-based formula) = 84.69  X 1.384 4) Log GFR (cystatin C-based formula) =1.962+1.123 _ log (1/cystatin C) Using the above equations enabled us to compare the GFR results by sex, height, and age.Euthyroid state was defined as a normal response to thyroid-stimulating hormone (TSH) and normal T4 levels. In all CH patients included in the study, serum TSH values were kept at levels less than 5 mU/L and serum total T4 and free T4 during the first year of life within targeted values  .The study protocol was approved by the Research Ethics Committee at Isfahan University of Medical Sciences. Written consent was obtained from each subject’s parents or caregivers, and also oral consent was taken from the participants, when appropriate.There were 20 females and 16 males in the study group . There were 23 males and 15 females in the control group . The mean age did not differ significantly between the study and control groups . Mean ± standard deviation (SD) values for height in the study and control groups were 132.9 ± 21.7 cm and 131.0 ± 20.8 cm, respectively (p>0.05). Height SD scores were also similar in the study and control groups . The median age at diagnosis and treatment in CH male and female patients were 10 and 14 days, respectively.Kidney ultrasound results revealed that only AP diameter of the right kidney was significantly increased in CH patients as compared to healthy subjects . Kidney The mean levels of serum Na, K, Mg and Cr and the mean levels of urinary Na, K, Mg, and Cr were not significantly different between the study and control groups (data not shown). As shown in Since kidney measurements, serum Cr and GFR values all increase with age, we used SD scores to evaluate these parameters. Comparing SD scores for bladder wall thickness, serum Cr and GFR between the patient and control groups did not show any significant differences, except for the SD score of the kidney AP diameter being higher in the study group than in the control group . In this present study, we evaluated the anatomical and functional aspects of kidneys in well-treated CH children. Reports on evaluation of kidney function in uncontrolled CH are scarce and we were not able to compare our results in well-controlled CH cases with those on poorly controlled patients. Nonetheless, our results revealed kidney dysfunction in CH in addition to a bilateral mild increase in the AP diameter of the kidney in CH patients. However, no evidence of hydronephrosis (AP diameter of 10 mm or more) was found. Kumar et al  have repIn addition to the geometric parameters of the kidney, we also evaluated different aspects of kidney function, including GFR, urine MA , serum Cr levels, and FENa, FEK and FEMg. GFR assessment is one of the most important criteria for evaluation and detection of renal function impairment. Serum Cr-based Schwartz formula has been widely accepted to estimate GFR. Recently, a serum cystatin C-based equation has been developed to diminish the chance of overestimating GFR values measured by the Cr–based Schwartz formula . There aOur results showed normal renal function in well-controlled CH patients. Using various equations to measure GFR, no difference was observed in GFR levels between CH patients and age- and height-matched healthy children in the present study. We could show that appropriate management of CH newborns maintains renal function in the normal range. Nonetheless, the mean values for FENa and FEK were found to be higher in our patients as compared with the control group.It has been proposed that FENa can be used as a marker in assessing acute kidney injury ,30. Decr


Hypertension is the most important preventable risk factor for premature death worldwide. It increases the risk of ischemic heart disease, strokes, peripheral vascular disease, and other cardiovascular diseases, including heart failure, aortic aneurysms, diffuse atherosclerosis, and pulmonary embolism. In childhood, hypertension can be determined according to a table adjusted for height, age and gender . A graphWe used a computerized calculation method to develop high-resolution graphics containing curves with 5,841 points each, to depict the main percentiles associated with high blood pressure for boys from 1 to 17 years old in the 50th percentile of height. Each point represents the calculation of the polynomial equation that includes the statistical processing of the last Report on Blood Pressure [Six monotonic curves of systolic BP for boys representing the 50th, 75th, 90th, 95th, 99th, and 99th +5 percentiles were built Figure . In relaThe adjustment of systolic BP for height is of little significance, and the updated graphic can be used to diagnose high systolic blood pressure for boys. Clinical studies are necessary to determine the systolic BP percentile that better represents clinically significant hypertension.


Many published epidemiologic studies confirm a marked increase in the prevalence of asthma and allergic rhinitis. The link between allergic rhinitis and asthma has been extensively studied and approximately 75% of patients with asthma have allergic rhinitis. The proportion of patients with asthma in populations of allergic rhinitis patients has not been well studied.The purpose of this study is to estimate the prevalence of undiagnosed asthma in a specific population of patients presenting to an Otolaryngologist with symptoms of allergic rhinitis.Prospective cohort study. Methods: Patients presenting with symptoms of allergic rhinitis to two tertiary care Rhinology practices in Northern Alberta were asked to undergo allergy skin testing, serum IgE quantification, and pulmonary functional testing. Patients with previous asthma screening or known history of reactive airway disease or asthma were excluded.107 patients with allergic rhinitis symptoms were recruited between September 2010 to January 2013. Patients predominantly had perennial or persistent rhinitis (64.5%) with moderate-severe symptoms (50.5%). While only 14.9% of patients had abnormal IgE levels, 68.8% had positive skin testing. Abnormal pulmonary function tests were obtained in 39.1% of patients and 26.1% of patients were diagnosed with asthma.There is a high prevalence of undiagnosed asthma in patients presenting to tertiary Rhinology care with moderate to severe allergic rhinitis symptoms. Screening lung function testing should be considered in this patient population. Many published epidemiologic studies examining populations in Europe over the last few decades have confirmed a marked increase in the prevalence of asthma and allergic rhinitis -3. One rSeveral explanations for this close relationship prevail in the literature. At the forefront is the unified airway hypothesis, which states that both upper and lower airway allergic symptoms are manifestations of the same atopic disease . Asthma The current understanding of shared pathophysiology between allergic rhinitis and asthma prompted the World Health Organization’s ARIA (Allergic Rhinitis and its Impact on Asthma) to recommend asthma screening in patients with allergic rhinitis. Nonetheless, it is not current practice by most Otolaryngology-Rhinology practitioners in Canada to order this screening routinely for patients with symptoms consistent with allergic rhinitis. The purpose of this cross-sectional study is to estimate the prevalence of undiagnosed asthma in a specific population of patients presenting to an Otolaryngologist with symptoms of allergic rhinitis.University of Alberta Research Ethics Board approval was obtained prior to commencement of study (Pro00032514). Adult patients (age ≥ 17 years of age) presenting to two Academic Otolaryngologists with rhinology practices at the University of Alberta with one or more symptoms of rhinitis were prospectively recruited between September 2010 and January 2013. Patients were diagnosed with allergic rhinitis if at least one symptom of nasal itching, sneezing, nasal obstruction, congestion, rhinorrhea, and/or hyposmia was present in association allergen exposure. Patients with concomitant diagnosis of chronic rhinosinusitis with or without polyposis were not excluded. Patients with known or previously diagnosed allergic asthma or reactive airway disease were excluded.http://www.whiar.org/Documents&Resources.php]. A four-point asthma-screening tool was also administered to each patient (Table http://www.ginasthma.org/). All data recorded were compared to norms based on age, gender, race, weight and height. All patients underwent testing at the same diagnostic laboratory. Results of testing were prospectively collected in a database.Severities of nasal symptoms were categorized as intermittent versus persistent and mild versus moderate-severe in accordance with the WHO Allergic Rhinitis and its Impact on Asthma 2008 Guidelines [nt Table . RecruitSPSS 20.0 was used for statistical analysis. Factors were examined for association with increased likelihood of asthma using Mantel-Haenszel tests followed by regression analysis using likelihood ratio tests. A significance level of p < 0.05 was used for all analysis.Asthma Screening Tool . Of the abnormal results, 24 patients had a diagnosis of asthma (26.1%) based on diagnostic criteria outlined in ‘Methods’. The distribution of severity of asthma is shown in Table Regression analysis failed to show any independent risk factors for increased risk of asthma diagnosis Table .This study found a high rate of undiagnosed asthma in a population of patients with allergic rhinitis presenting to tertiary care Rhinology in Northern Alberta. The results of this study support the existing evidence for a strong association between asthma and allergic rhinitis. It also supports studies that have demonstrated AR as an independent risk factor for asthma .To our knowledge, there are currently no other studies in the literature that examine the rate of undiagnosed asthma in allergic rhinitis patients. Also, no studies have examined, specifically, the value of asthma screening in this population despite recent ARIA guidelines, which recommended that persistent allergic rhinitis should be evaluated for asthma . We founOur study failed to identify any specific risk factors for abnormal pulmonary function test results in patients with allergic rhinitis. Specifically, a family history of atopy, positive allergy skin testing and answers to the 4-point allergy-screening tool failed to predict likelihood of asthma. Some authors have suggested that a serum IgE level > 140 IU/ml may be predictive of atopic disease , while oAdmittedly, this is a cross-sectional study with a relatively small sampling of patients in Alberta and is highly selected -- the patients in our study had significant nasal complaints as demonstrated by a high proportion of patients with moderate-severe (50.5%) and persistent rhinitis (64.5%). This is in contrast to the mild symptoms seen in the general population who are likely managed by primary care practitioners . In addiDespite these limitations, the results of this study remain useful to clinicians that treat patients with a spectrum of AR severity. It reinforces the fact that AR is not a trivial disease and should be managed aggressively to optimize progression of airway reactivity. In patients with persistent and severe disease, there is a high rate of undiagnosed, but clinically significant asthma and we feel this warrants consideration for increased asthma screening by practitioners who see allergic rhinitis patients. Future studies examining the cost-effectiveness of asthma screening in this population are necessary before widespread adoption.There is a high prevalence of undiagnosed asthma in patients presenting to tertiary Rhinology care with moderate to severe allergic rhinitis symptoms. Screening lung function testing may be considered in this patient population.The authors declare that they have no competing interests.DWJC, EDW, MB, and HV conceived and designed the study. DWJC, EDW, MB, HV, and CCJ collected the study data. CCJ analyzed the data and prepared the manuscript. DWJC, EDW, MB, HV, HS, and CCJ approved the final manuscript.


The Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events (CanPREDDICT) is a large, prospective, pan-Canadian, cohort study designed to improve our understanding of determinants of renal and cardiovascular (CV) disease progression in patients with chronic kidney disease (CKD). The primary objective is to clarify the associations between traditional and newer biomarkers in the prediction of specific renal and CV events, and of death in patients with CKD managed by nephrologists. This information could then be used to better understand biological variation in outcomes, to develop clinical prediction models and to inform enrolment into interventional studies which may lead to novel treatments.Commenced in 2008, 2546 patients have been enrolled with eGFR between 15 and 45 ml/min 1.73m2 from a representative sample in 25 rural, urban, academic and non academic centres across Canada. Patients are to be followed for an initial 3 years at 6 monthly intervals, and subsequently annually. Traditional biomarkers include eGFR, urine albumin creatinine ratio (uACR), hemoglobin (Hgb), phosphate and albumin. Newer biomarkers of interest were selected on the basis of biological relevance to important processes, commercial availability and assay reproducibility. They include asymmetric dimethylarginine (ADMA), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), troponin I, cystatin C, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6) and transforming growth factor beta 1 (TGFβ1). Blood and urine samples are collected at baseline, and every 6 monthly, and stored at −80°C. Outcomes of interest include renal replacement therapy, CV events and death, the latter two of which are adjudicated by an independent panel.The baseline distribution of newer biomarkers does not appear to track to markers of kidney function and therefore may offer some discriminatory value in predicting future outcomes. The granularity of the data presented at baseline may foster additional questions.The value of the cohort as a unique resource to understand outcomes of patients under the care of nephrologists in a single payer healthcare system cannot be overstated. Systematic collection of demographic, laboratory and event data should lead to new insights.2, 22% had eGFR values below 20 mL/min/1.73m2; 61% had uACR < 30. Serum albumin, hemoglobin, calcium and 25-hydroxyvitamin D (25(OH)D) levels were progressively lower in the lower eGFR strata, while parathyroid hormone (PTH) levels increased. Cystatin C, ADMA, NT-proBNP, hsCRP, troponin I and IL-6 were significantly higher in the lower GFR strata, whereas 25(OH)D and TGFβ1 values were lower at lower GFR. These distributions of each of the newer biomarkers by eGFR and uACR categories were variable.The mean age of the cohort was 68 years, 90% were Caucasian, 62% were male, and 48% had diabetes. Forty percent of the cohort had eGFR between 30–45 mL/min/1.73m Chronic kidney disease (CKD), defined as the presence of persistent reduction in kidney function (i.e. glomerular filtration rate (GFR) <60mL/min for more than 3 months) or evidence of chronic kidney damage (e.g. proteinuria), is a growing global health problem. CKD afflicts 10-13% of adults in North America, Europe and Australia . There iThe major causes of CKD in developed societies are hypertension, diabetes, atherosclerotic vascular disease, and certain glomerular diseases (e.g. IgA nephropathy). Even within etiological categories, however, there is wide variation in rates of progression -11: someThe variable prognosis of CKD is highly problematic for health systems, health practitioners, and patients alike. Patients very reasonably want to know what will happen to their kidneys down the road. Will dialysis be needed, and when? Uncertainty in prognosis is troubling for patients, hampers psychosocial adaptation to illness, and degrades quality of life -15. HealAlthough progress has been made in developing usable prediction models for risk of dialysis in CKD populations , much leThe Canadian study of Prediction of Risk and Evolution to Dialysis, Death and Interim CV events over Time (CanPREDDICT) was established in 2008 to address these questions of interest.CanPREDDICT is a large, prospective, pan-Canadian cohort study with the primary objective of describing the associations between traditional and newer biomarkers in the prediction of renal and CV events in patients with CKD managed by nephrologists. This information will then be used to better understand biological variation in outcomes, to develop clinical prediction models and to inform enrolment into interventional studies which may lead to novel treatments.2. Patients were excluded if they were unable to provide informed consent, had an organ transplant, were on immunomodulatory therapy for active vasculitis or glomerulonephritis, or who had a life expectancy of less than 1 year (e.g. due to cancer) in the opinion of their attending nephrologist .The study protocol was approved by the institutional review boards of all 25 participating centres, led by the University of British Columbia and Providence Health Care Research Institute as the coordinating site; and the research was conducted in accordance with the Declaration of Helsinki. The study was registered at The direct costs of the study are funded by an unrestricted educational grant from Janssen-Ortho Inc. The concept, design and execution of the study, including all data management and analysis, were entirely investigator driven. Statistical and methodological support is provided from University of British Columbia and the BC Provincial Renal Agency. Funding from the Kidney Foundation of Canada for ancillary studies (Bioimpedance in CKD) has been received, and other applications for peer-reviewed funding are pending.The main objectives of the CanPREDDICT study are 1) to examine the role of both traditional risk factors and a select panel of newer, non-traditional serum and urine biomarkers, in the progression of kidney and CV disease in patients with CKD, alone and separately and 2) to develop robust predictive models to discriminate between high and low risk patients.The main outcomes of interest in the CanPREDDICT study include renal endpoints: progression of CKD to renal replacement therapy (RRT), CV events (both heart failure and ischemic events) and death.RRT is defined as need for dialysis initiation or renal transplantation. Major CV events are defined as fatal or non-fatal myocardial infarction (MI), defined as chest pain, dynamic troponin change, cardiogenic shock and ECG to distinguish ST-elevated MI vs non-ST-elevated MI), ischemic stroke , or need for coronary revascularization . Congestive heart failure (CHF) is defined as dyspnea plus 2 of the following: bibasilar rales, raised jugular venous pressure or chest x-ray with evidence of interstitial or alveolar pulmonary edema. A panel of three physicians comprising a nephrologist, a cardiologist, and a neurologist independently adjudicated all CV outcomes based on source documentation.Follow-up was originally planned for 3 years, with completion of the main study in December 2012, but has been extended for an additional 2 years.Demographics, clinical status, medications, as well as blood and urine samples are collected at baseline and every 6 months at study visits for the first 3 years. An abbreviated set of data  will be collected annually during the 2-year extension.In addition to traditional clinical and laboratory risk factors for cardiac or renal disease progression, a select panel of newer biomarkers are also being measured: asymmetric dimethylarginine (ADMA), interleukin-6 (IL-6), high sensitivity C-reactive protein (hsCRP), cystatin C, transforming growth factor beta 1 (TGFβ1), troponin I, and N-terminal pro-brain natriuretic peptide (NT-pro-BNP). These biomarkers were chosen based on 1) established biological importance in disease processes of interest , 2) robust evidence of association with clinical outcomes, and 3) commercial availability of assays -35. ImpoMeasurement details of the newer biomarkers are described in the Additional file The primary considerations for the sample size estimation were: 1) to ensure adequate power to demonstrate that inclusion of novel biomarkers in predictive models would enhance discrimination between subjects who will or will not experience outcomes; and 2) a high level of precision when assessing the discriminatory value of the new predictive models that include biomarkers. A sample size of 2500 would yield estimated standard errors of approximately 1%, which would provide 99% power to demonstrate that the novel biomarkers would be statistically significant predictors if the hypothesized increase in discrimination of 5% existed. Also, this sample size allowed quantification of the magnitude of the increase with high precision. As described in the Additional file As a longitudinal observational cohort study, clinical visits every 6 months for the initial 3 years, and then annually for an additional 2 years are planned. During the first 12 follow-up months, attrition was low, with 4% of the cohort lost to follow-up , congestive heart failure (CHF), cerebrovascular disease, peripheral arterial disease, chronic lung disease, chronic liver disease, chronic gastrointestinal disease and previous diagnosis of cancers. Blood pressure, height and weight, routine laboratory testing  were also obtained. Serum, plasma and urine samples are collected for analysis in a central laboratory at each visit. Patient follow-up continues after transition to dialysis or transplantation, until death or lost to follow-up. In addition to the demographic and clinical data described above, the six pre-specified newer biomarkers were selected for measurement. As described above, the selection was done on the basis of biological relevance, commercial availability of assays, and published data suggesting prognostic value for heart disease or kidney disease progression, or death. ADMA, a potent inhibitor of endothelial nitric oxide production, impairs vascular relaxation, contributes to hypertension, and is correlated with CV events and renal decline -25. NT-p2) and 60% of the cohort was in CKD Stage 4 at baseline, with 22% of the cohort with eGFR below 20 mL/min/1.73m2. Diabetes and hypertensive nephropathy were the most frequent primary kidney diseases (30% each), and 22% of patients had a history of cardiac disease (CHF or IHD) at entry. 68% had either diabetes or CV disease. Compared with patients in the higher eGFR strata, patients at lower eGFR were slightly younger and slightly less likely to be male. Diabetes was significantly more prevalent in the 20–29 mL/min/1.73m2 stratum than in the lower or higher strata. At each eGFR stratum, there was a similar distribution of those with diabetes, IHD, CHF or any combination thereof. Of note, only 32% of the cohort had neither diabetes nor CV comorbidities .Our observations on these newer biomarker distributions have both practical and research applications. As noted above, most biomarkers of inflammation and CV disease appear right-shifted in this CKD cohort, indicating that a higher proportion of patients with CKD have elevated values. For example, the lowest NT-pro-BNP value in the cohort in the cell of the highest eGFR and lowest uACR within the cohort Figure c is withThe main strength of CanPREDDICT is that it is a large, national, prospective observational study of referred CKD patients, with comprehensive data capture on risk factors for progressive renal and cardiac diseases in Canada. The dataset includes measures of six novel nontraditional biomarkers of cardiorenal disease progression. Biobanking of urine and blood samples will permit future genetic and proteomic analyses. While the CanPREDDICT cohort is qualitatively similar to other CKD cohorts, its sampling of patients at lower eGFR and its setting in the Canadian health system make it complementary to other national cohorts, and provides the basis for international comparisons and cross-validation of findings.The low prevalence of non-Caucasian individuals enrolled is a relative limitation. Although the proportion of non-white individuals in Canada is lower than in the US, for example, non-white individuals are still underrepresented in the CanPREDDICT Cohort relative to Canadian demographics as a whole. A funding application to extend and to enrich the cohort with non-white individuals so that it more closely reflects Canadian demographics is under review.As patients were recruited at nephrology clinics across Canada, the results of CanPREDDICT will be applicable to CKD patients seen and followed by nephrologists . This is an important group of patients to characterize and understand, and it is expected that the results of CanPREDDICT over time will inform management in these patients. However, CanPREDDICT results may not necessarily translate to CKD patients who are not referred to nephrologists, as they are not represented in this cohort. The logistics of identifying and intensively following non-referred CKD patients are considerable, and will have to be resolved in future studies. The pre-selected biomarkers, chosen for practical reasons, did not include FGF-23, which has been shown in multiple populations to predict CV outcomes and death. Arrangements to measure FGF-23 in an approved laboratory have been completed at the writing of this paper; results are pending.CanPREDDICT was designed at the outset to be a platform for further collaborations and studies. A 8 person steering committee, consisting of 6 nephrologists, a statistician and methodologist, and a laboratory physician evaluates all requests, based on a predefined set of criteria. To date, several sub-studies have been approved, including one looking at bioimpedance and outcome, and one reviewing urine protein evaluation and outcomes.Requests for collaboration may be directed to Dr. Adeera Levin, principal investigator and chair of the steering committee, at canpreddict@providencehealth.bc.ca.ADMA: Assymetric dimethyl arginine; CKD: Chronic kidney disease; CHF: Congestive heart failure; CV: Cardiovascular; eGFR: Estimated glomerular filtration rate; hsCRP: High-sensitivity C-reactive protein; IHD: Ischemic heart disease; IL-6: interleukin-6; NT-pro-BNP: Pro-brain naturietic peptide; RRT: Renal replacement therapy; TGFβ1: Transforming growth factor beta 1; uACR: Urine albumin to creatinine ratio; 25(OH)D: 25-hydroxyvitamin D; PTH: Parathyroid hormone; Hgb: Hemoglobin.The authors have no competing interests as regards to this manuscript or study. For full transparency, however listed below is additional information about each: AL receives grant/research funds from Kidney Foundation of Canada (KFoC), Canadian Institute of Health Research (CIHR), Merck, Abbott, Amgen, Otsuka; NM receives grant/research funds from Amgen, CIHR; CR receives funds from Manitoba Health Servcies and Kidney Foundation of Canada; CC receives funds from CIHR, KFoC, BB receives funds from CIHR, Amgen; FM receives funds from Federacion Recerche Sante de Quebec (FRSQ).The concept, rationale, design logistics and analysis were determined by the investigators. All analyses were conducted by OD, and all study materials remain property of the investigators. The sponsor had no role aside from funding the study. AL, CR, and OD developed and wrote the manuscript; BB, DH, NM, FM, CC, MT provided constructive criticism and edits of the drafts of the manuscripts. All contributed to the final product. OD was responsible for all analyses and presentation of the materials in the manuscript. As members of the steering committee, all are responsible for the integrity and running of the study from inception to current state. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/14/121/prepubAdditional information regarding study organization, measurement of biomarkers and sample size calculations.Click here for file