Men had increased responses of diastolic blood pressure (P = 0.01), mean arterial pressure (P = 0.05), and a more pronounced decrease in effective renal plasma flow (P = 0.009) than women. We measured the changes in proteinuria and blood pressure in response to chronic administration (200 ng/kg/min for 3 weeks) of angiotensin II in rats. Male rats had an increased response of proteinuria compared with females . Male, but not female, angiotensin II-treated rats had increased numbers of renal interstitial macrophages compared to sham-treated rats (P < 0.001). In conclusion, gender differences are present in the response to acute and chronic infusion of angiotensin II. Difference in angiotensin II sensitivity could play a role in gender differences in progression of renal disease.Women with renal disease progress at a slower rate to end stage renal disease than men. As angiotensin II has both hemodynamic and direct renal effects, we hypothesized that the female protection may result from gender differences in responses to angiotensin II. Therefore, we studied gender differences in response to angiotensin II, during acute (human) and chronic (rats) angiotensin II administration. In young healthy men ( Women generally have a lower risk for developing cardiovascular disease (CVD) and chronic kidney disease (CKD) than men. They also progress slower to end stage renal disease (ESRD) after a renal insult (Silbiger and Neugarten 1-R) blocker to achieve the same blood pressuring lowering effect as women  on standardized sodium intake, we studied the responses of blood pressure and renal hemodynamics to an acute graded ang II infusion. The effects of ang II on blood pressure, proteinuria, and morphological markers of proinflammatory pathways and fibrosis in the kidney were studied in healthy young male and female rats after 3 weeks of chronic ang II infusion.n = 18; men, n = 18). Women were studied in the RETAP project, and compared with men from the Gene-Environment project  were excluded. Physical examination and electrocardiography did not reveal any abnormalities. None of the women were users of oral contraceptive medication. Both studies were approved by the local medical ethical committee , and all subjects gave written informed consent in accordance with the Declaration of Helsinki. The RETAP study was registered in the Netherlands National Trial Register  as REsponse To Angiotensin II in formerly Preeclamptic women (RETAP) study.The study population was recruited from the ongoing Groningen Renal Hemodynamic Cohorts (GRECO) program. The GRECO program hosts and harmonizes studies on renal hemodynamics at the renal function unit of the University Medical Center Groningen, by standardization of methodology, including harmonization of study protocols and calibration over time. This allows combined analyses in subjects from different substudies. The current study population consisted of 36 healthy, Caucasian subjects . For assessment of dietary compliance and the achievement of a stable sodium balance, 24 h-urine was collected at day 3 and day 6. As both renal hemodynamics and ang II responsiveness are greatly influenced by female sex hormones  plus an extra bolus of 0.06 MBq of 125I-iothalamate was given, followed by constant infusion at 12 mL/h of the same solutions. After a 2 h stabilization period, stable plasma concentrations of both tracers were attained, and the clearance periods started. The clearances were calculated using the formula U*V/P for GFR and I*V/P for ERPF. U*V represents the urinary excretion of the tracer, I*V represents the infusion rate of the tracer, and P represents the tracer value in plasma at the end of each clearance period. The urinary clearance of 125I-iothalamate was multiplied by the ratio of plasma-to-urinary clearance of 131I-hippuran to correct for voiding errors  and ERPF were measured from the clearance of constantly infused radio-labeled tracers, Blood pressure and heart rate were measured by using an automated sphygmomanometer . The appropriate blood pressure cuff was determined on the basis of arm circumference. Mean arterial pressure (MAP) was calculated as diastolic pressure plus one-third of the pulse pressure.Baseline values for blood pressure, GFR and ERPF were obtained from 10 am to 12 pm at 15 min intervals. Between 12 pm and 3 pm ang II  was administered intravenously at a constant rate in doses of 0.3, 1 and 3 ng/kg/min each during 1 h. During these ang II infusions blood pressure was measured at 5-min intervals.Urine samples were drawn from the 24 h-urine collected by all subjects. The levels of urinary sodium, potassium, and urea were assessed by an automated clinical chemistry analyzer .n = 25) and male (n = 19) Wistar rats  were kept in a 12-h light–dark cycle and constant room temperature, with food and water freely available in the home cages. Both female and male rats were divided in two groups: one sham-pump-treated group , and one group receiving ang II infusion continuously via an osmotic minipump . The infusion rates of ang II infusion were similar between males and females, that is, we infused ang II at a rate of 200 μg/min/kg . For minipump implantation rats were anesthetized with isoflurane and oxygen and minipumps were implanted intraperitoneally . In all rats, blood pressure and proteinuria were measured at baseline  and at weekly intervals after pump implantation . Subsequently, after 3 weeks of infusion (day 21) rats were sacrificed and the left kidney was collected. Parts of the kidney were harvested and fixed in 4% paraformaldehyde in PBS or snap frozen.Experiments were conducted under protocols approved by the Animal Ethical Committee of the University of Groningen. Four-month-old female . All rats were conscious during the measurements. In order to reduce spontaneous variation in blood pressure, rats were extensively trained for a period of 4 weeks on a daily basis to get used to the tail-cuff method. Prior to blood pressure readings, rats were optimally warmed using a warmth lamp to induce vasodilation of the tail vein. Readings were repeated 10 times and after excluding the lowest value, the average of the lowest three values for systolic blood pressure were used for further analysis.μmol)*(urine volume/1440)).Twenty-four-hour urine samples were collected from all rats. To this purpose, rats were placed in metabolic cages on days -1, 7, 14, and 21. Urinary concentration of protein  was determined as previously described  and CD206-positive macrophages  were stained as previously described , was detected using a murine monoclonal antibody  as previously described . The “Positive pixel Count V9” algorithm was used to analyze α-SMA-positive pixels in 30 randomly selected cortical fields per kidney after excluding vessels and glomeruli. The positive surface area (number of positive pixels) was divided by the total area of the field measured, providing a number of α-SMA-positive pixels corrected for the area analyzed. Researchers were blinded for group allocation of the rats while analyzing the kidney slides.The prefibrotic marker for myofibroblast transformation, alpha-smooth muscle actin (1-R) and the angiotensin II type 2 (AT2-R) receptors were obtained from Applied Biosystems . The sequence for 18S (M11188)  was: CGGCTACCACATCCAAGGA, CCAATTACAGGGCCTCGAAA, CGCGCAAATTACCCACTCCCGA.Total kidney RNA from homogenized renal cortex was isolated with TRIzol Reagent (Invitrogen) following the manufacturer’s instructions. Total RNA was quantified using a NanoDrop ND1000 spectrophotometer . cDNA synthesis was performed as described before . Parametric data are presented as mean ± standard deviation (SD) or mean ± standard error of the mean (SEM) in text, table, and figures and analyzed using Student t-test. Nonparametric data are presented as median (25th–75th percentile) and analyzed using Mann–Whitney U-test or Kruskal–Wallis test.Statistical analysis was performed using P ≤ 0.05.The responses to ang II infusion in humans  and rats (blood pressure and proteinuria) were analyzed by generalized estimating equations (GEE) analysis. Variables with a skewed distribution were log transformed to fulfill the criteria for GEE analysis. Statistical significance was accepted at Baseline characteristics of the men and women are shown in TableP = 0.01) and MAP (P = 0.05). After correction for baseline value, the gender difference in MAP responses became borderline significant (P = 0.08), but the gender difference in diastolic blood pressure response to ang II remained statistically significant (P = 0.01).The responses of blood pressure to increasing doses of ang II infusion in men and women are shown in FigureP = 0.001). Analyzing the dose–response curves as a whole by GEE analysis indicated that the response was significantly different between men and women for GFR .FigureP = 0.009; corrected for baseline value).ERPF significantly and progressively decreased during increasing doses of ang II in men and women. Analyzing the dose–response curve as a whole by GEE analysis indicated that the response was significantly different between men and women for ERPF (P < 0.001).The baseline body weight was significantly higher in male rats compared to female rats, while ang II treatment did not affect body weight . When corrected for body weight, proteinuria was still higher in males than in females (data not shown). Creatinine clearance corrected for body weight was not different between the four groups  after 3 weeks of treatment.In the sham-treated rats no significant changes in proteinuria were observed during the 3 weeks of treatment (results not shown). During 3 weeks of ang II infusion, which was similar in males and females, both male and female rats showed a significant increase in proteinuria, starting after the first week .In order to evaluate possible kidney damage, kidney sections were stained for -SMA Fig.. Figure41-R and AT2-R expression in kidney and aorta were evaluated (Fig.1-R in the kidney was found between sham-treated female and male rats and ang II infusion did not affect AT1-R expression in the kidney either. The mRNA expression for AT2-R in the kidney, however, was higher in female rats than in male rats, with again no effect of ang II treatment.ATated Fig. and B. NIn this translational study we found differences in the response to ang II infusion in both healthy human subjects and in healthy rats. In humans, men showed an increased blood pressure and ERPF response, and a slightly decreased GFR response to acute ang II infusion compared with women. We showed that chronic ang II infusion resulted in a higher blood pressure in male compared with female rats, which confirms previous studies. However, we also showed an increased proteinuria response to chronic ang II infusion in male rats compared with female rats. This was previously only shown in spontaneous hypertensive rats (SHR; Sullivan et al., 1-R, due to an upregulation of this receptor in a less active intrarenal RAAS system (Visser et al. Our human data showed a higher blood pressure response to acute ang II infusion in men compared with women. These results differ from those from Miller et al. and Gandhi et al. (Gandhi et al. To evaluate the effect of chronic ang II infusion we studied the proteinuria and blood pressure response to 3 weeks of ang II infusion in male and female rats. In accordance with the acute effects of ang II on blood pressure in our human study and with results of other rat studies (Sampson et al. Inflammatory processes and/or fibrosis may also be involved in the sex differences in ang II-induced proteinuria (Noronha et al. αSMA. These changes were not different between males and females. In the present study, the subtle pro-fibrotic damage after 3 weeks of ang II infusion appeared to be blood pressure related since there was a strong relationship between αSMA and blood pressure. There was no difference in blood pressure after 3 weeks of ang II treatment between males and females, this may also explain why we did not detect a sex difference in profibrotic kidney damage. However, we cannot exclude that infusion of ang II of longer duration, or with higher doses would have result in larger sex differences in proteinuria and blood pressure and in sex differences in profibrotic markers. This should be subject of further research.Despite the higher proteinuria in males there were little interstitial profibrotic changes in the kidney, as measured by 1-R and AT2-R and in the balance between the two. Although in the kidney the mRNA expression for the AT1-R was not different in males and females, AT2-R mRNA was higher in female rats compared with male rats. The increased expression of the AT2-R in females is in line with studies of the group of Denton et al., who suggested that the AT2-R plays a role in the decreased responsiveness to ang II of females (Sampson et al. Differences in responsiveness to ang II between males and females could be due to difference in expression of the AT2-R, could be an explanation for the gender differences in development of renal disease. Further research is required to elucidate these gender differences in RAAS regulation, which might contribute to a better view on the differences in renal risk profile and treatment recommendations between men and women.In conclusion, in both humans and rats, males seem to have a higher vascular and renal sensitivity to ang II compared to females. In response to acute ang II infusion, men have a stronger rise in blood pressure and a stronger ERPF response, but a decreased GFR response than women. In rats, pressor responses during chronic ang II infusion are also larger in males than in females, and associated with a higher increase of proteinuria and intrarenal inflammation in males. This study showed that differences in function of the RAAS between males and females, including differences in presence and function of the AT


The global prevalence of chronic kidney disease (CKD) is increasing. In children, CKD exhibits unique etiologies and can have serious impacts on children’s growth and development. Therefore, an aggressive approach to preventing the progression of CKD and its complications is imperative. To improve the understanding and management of Asian pediatric patients with CKD, we designed and launched KNOW-Ped CKD (KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease), a nationwide, prospective, and observational cohort study of pediatric CKD with funding from the Korean government.From seven major centers, 450 patients <20 years of age with CKD stages I to V are recruited for the comprehensive assessment of clinical findings, structured follow-up, and bio-specimen collection. The primary endpoints include CKD progression, defined as a decline of estimated glomerular filtration rate by 50 %, and a requirement for renal replacement therapy or death. The secondary outcomes include the development of left ventricular hypertrophy or hypertension, impairment of growth, neuropsychological status, behavioral status, kidney growth, and quality of life.With this study, we expect to obtain more information on pediatric CKD, which can be translated to better management for the patients.NCT02165878 , submitted on June 11, 2014. Globally and locally, the prevalence of chronic kidney disease (CKD) is increasing along with prolonged lifespans and over-nutrition in many areas of the world . The devTo treat failed kidneys, nephrologists use powerful tools, namely dialysis and allograft kidney transplantation, to keep patients alive. However, the long-term prognosis and quality of life of patients who depend on renal replacement therapy (RRT) are poor, and healthcare expenses related to RRT are rapidly increasing along with the number of patients with end-stage renal disease (ESRD) . TherefoWe introduce a pediatric cohort study in Korea, KNOW-Ped CKD (KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease), a nationwide, ten-year prospective, observational cohort study of pediatric CKD that was launched in 2011 as a sub-cohort of KNOW-CKD, which was funded by the Korean government . The aimwww.knowkidney.org) upon completion of data collection.Seven major pediatric nephrology centers in Korea have participated in the study and enroll 450 children with CKD for comprehensive assessments of clinical findings, structured follow-up, and bio-specimen collection. To obtain follow-up data from more than five years, the patients are recruited during the first five years of this study. This study was approved by the institutional review boards of the participating centers, namely Seoul National University Hospital, Asan Medical Center, Kyungpook National University Hospital, Severance Hospital, Samsung Medical Center, Jeju University Hospital, and Pusan National University Children’s Hospital, and is included with the designation NCT02165878 at clinicaltrials.gov . The annual reports summarizing the data of this study will be available at our website  guidelines as either kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 mThe inclusion and exclusion criteria are presented in Table After obtaining informed consent, the following clinical information is collected: medical history, anthropometric measurements, laboratory tests and imaging studies according to the schedule presented in Table Serum creatinine, blood urea nitrogen, cystatin C, parathyroid hormone, vitamin D, and urine chemistry  are measured at a central laboratory  within one day after sampling to avoid inter-laboratory variation. At the central laboratory, serum creatinine is measured using the isotope dilution mass spectrometry (IDMS)-traceable method, and cystatin C is determined using immunonephelometry. Change in kidney volume is estimated by serial ultrasonography as previously reported . In a suA DNA sample is collected at the time of enrollment in the study. Serum and urine specimens are collected annually and stored in a deep freezer for further studies.The primary endpoints of KNOW-Ped CKD are the progression of CKD, which is defined as a decline of eGFR by ≥50 %; a requirement for renal replacement therapy; and death. The secondary outcomes include the development of left ventricular hypertrophy (left ventricular mass/height^2.7 >95th percentile for age and sex), hypertension , impairment in growth (height Z score <−1.88 or weight Z score <−1.65), deviation from the Korean average ranges of neuropsychological and behavioral status, stunted growth of renal volume, and quality of life as well as changes from the baseline values.The continuous variables of characteristics are presented using descriptive statistics with mean ± standard deviation for continuous variables and number and proportion for categorical variables. These variables will be compared using a one-way analysis of variance or Kruskal-Wallis test for the continuous variables and a chi-squared test or Fisher’s exact test for the categorical variables as appropriate. The time-to-event analysis will be the primary statistical method for analyzing the relationship between clinical characteristics and outcome variables, such as the progression of CKD, development of left ventricular hypertrophy, development of hypertension and impairment of growth. To analyze the primary outcome, we will apply the sub-distribution hazard models to our dataset with the competing risk event (progression of CKD or death without CKD) to evaluate the relative effects of covariates and cumulative incidence function .From July 2011 to December 2013, 322 patients 218:104) were enrolled in the study. The average age at the time of enrollment was 10.0 ± 5.4 years (yrs). The etiologies of CKD included congenital renal dysplasia/hereditary disease (49 %), reflux nephropathy/chronic pyelonephritis (22 %), primary glomerular diseases (16 %), secondary glomerular diseases (4 %), and others. The stages of CKD were I for 15 %, II for 19 %, IIIa for 17 %, IIIb for 17 %, IV for 19 %, and V for 13 % of the cases. The following proportions of participants according to age group were noted: 10 % of patients were <2 years, 16 % were 2 to 5 years, 28 % were 6 to 11 year, and 47 % were 12 to 19 years. One-third of enrolled patients had histories of urinary tract infection, and 9 % exhibited developmental delay. At baseline, hypertension was noted in 27 % of patients, hyperlipidemia in 49 %, anemia in 45 %, and iron deficiency in 25 %. Growth delay was observed even in the early stage of CKD, with mean height and weight Z scores of −0.88 and −0.91, respectively, especially in younger (<6 years) patients with advanced CKD (IV and V). The baseline characteristics of the participants are summarized in Table  were enrKNOW-Ped CKD is a prospective cohort study on Asian pediatric CKD with long-term follow-up. Although several investigations of school urinary screening and CKD have been reported, comprehensive studies on CKD have been rare in Asian countries , 42–49. Although advanced CKD tends to progress to ESRD, many children remain at stage I or II for a long time. The risk factors for progression in these patients remain unknown. In some children, at least transiently, renal function appears to recover. With the KNOW-Ped CKD study, we will investigate the determinants of prognosis for CKD stages I and II. Additionally, annual measurements of the kidney size in this study will answer the following questions: 1) Does the kidney volume in CKD correlate with renal function? 2) How much kidney growth is necessary for functional improvement? With KNOW-Ped CKD, we will be able to delineate the characteristics of Asian pediatric CKD, which will lead to a better understanding of the entire progression of CKD in children. We will also identify the similarity and differences among different ethnicities in pediatric CKD, enabling us to customize therapeutic management.Another characteristic of KNOW-Ped CKD is that this study enrolls the majority of pediatric pre-dialysis CKD patients in Korea. According to the data from Health Insurance Review and Assessment Service of the Korean National Health Insurance Program, a unique and obligatory public healthcare program in Korea, CKD patients <20 years of age numbered approximately 700 in 2014 . ExcludiStaging of CKD in KNOW-Ped CKD is based on the bedside CKiD equation. Although this equation has not yet been validated in Korean children, the bedside CKiD equation is simple and easy and therefore useful in clinical practice. Therefore, the authors expect that findings based on this equation, after validation via the KNOW-Ped CKD study, can be readily applied in patient care. Measuring GFR using the clearance of injected isotopic material is performed in a subset of the participants to investigate whether known pediatric eGFR estimation equations are applicable in Korean children. Regarding the staging of CKD, categorizing CKD stages in older children cannot be applied for children <2 years because the normal GFR is lower in children <2 years of age . AlthougThree years after launching the KNOW-Ped CKD study, more than 300 children with CKD have participated in this study. Additional analysis will be conducted upon the completion of enrollment; however, the distribution of the etiology of CKD is similar to that of previous reports, including CKiD and the Japanese nationwide survey study , 54. TheAlthough this study has some limitations, such as the use of the operational definition of CKD staging for younger patients and eGFR equations that have not yet been verified in Korean children, we expect that KNOW-Ped CKD, a prospective cohort study in pediatric CKD for a long-term period in an Asian country, will reveal more comprehensive characteristics of pediatric CKD, especially in its earlier stage, and the risk factors of progression that can be translated into better management of these patients through international collaboration with existing cohort studies.This study was approved by the institutional review boards of the participating centers, namely Seoul National University Hospital, Asan Medical Center, Kyungpook National University Hospital, Severance Hospital, Samsung Medical Center, Jeju University Hospital, and Pusan National University. Children <20 years of age with CKD are enrolled in this study after informed consent is obtained from parents or guardians.Not applicable.All data is included within the article.


Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy.Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations.2 concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR.The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin ELoxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, with acknowledged efficacy and safety over a wide range of clinical conditions. Despite their many useful therapeutic applications, substantial evidence has shown that NSAIDs can have deleterious effects on kidney function. For example, a nested case-controlled study using the General Practice Research Database from the United Kingdom showed that NSAID users in the general population were at threefold greater risk for a first-ever diagnosis of clinical acute kidney injury (AKI) than non-NSAID users. In addition, history of heart failure, hypertension, and diabetes were associated with a greater risk of AKI in this population .Combination therapy with NSAIDs and renin–angiotensin system (RAS) inhibitors increases the risk of kidney damage –4. Since2 (PGE2) is the most abundant vasodilatory prostaglandin in the human renal vascular bed. NSAIDs decrease PGE2 concentration by inhibiting cyclooxygenase-2 (COX-2). Adverse effects of NSAIDs may be avoided by administering these drugs as transdermal patches. These adhesive patches, which are applied to the skin at the site of pain, slowly release medication through the skin. Although NSAID patches are regarded as safe and are frequently used in patients with chronic kidney disease (CKD), the effects of NSAID patches on renal circulation in these patients have not been investigated. Loxoprofen-containing patches are one of the most widely used adhesive patches in Japan. We therefore analyzed the effects of topically applied loxoprofen sodium on kidney function in patients with diabetic nephropathy.NSAIDs can affect renal function by, for example, inhibiting the synthesis of important renal prostaglandins, especially those involved in solute homeostasis and maintenance of renal blood flow –8. ProstThis open-label, single-arm, single-dose study was performed at the Shiga University of Medical Science Hospital. In patients with type 2 diabetes and overt proteinuria [urinary albumin–creatinine ratio (ACR) >300 mg/g] who had knee and/or low back pain were recruited. We enrolled 20 patients with type 2 diabetes complicated by diabetic nephropathy stage III to IV. Patients with diabetic nephropathy were classified by the Ministry of Health, Labour and Welfare of Japan . The 20 ® tape) were applied to the back or knee of each patient, depending on the site of pain, for 24 h per day for five consecutive days (one patch per day). The degree of pain was assessed using a visual analogue scale (VAS) [Adhesive skin patches containing 100 mg loxoprofen  of each patient was calculated using the simplified equation of the Japanese Society of Nephrology, a version of the Modification of Diet in Renal Disease study equation modified for Japanese patients . GFR wasThe study protocol was approved by the Ethics Committee of Shiga University of Medical Science , and all participants provided written informed consent.t test was used to compare values at different time points. Pearson’s or Spearman’s rank correlation coefficients were calculated to determine the correlations between variables. Values were expressed as mean ± SD, and P < 0.05 was considered statistically significant.Data were analyzed using SPSS version 17.0 . The distribution of variables was analyzed by checking histograms and normal plots of the data, and normality was tested using the Kolmogorov–Smirnov and Shapiro–Wilk tests. Student’s 2, respectively. Two of the patients applied the LX-P on their knee and 18 applied the patch on their back.The 20 patients enrolled in this study consisted of 11 males and 9 females, ranging in age from 34 to 80 years (median age 61.6 years). The average height of the patients was 157.6 ± 10.8 cm, the average body weight was 69.8 ± 18.6 kg, and their average HbA1c was 7.2 ± 1.4 %. Their mean eGFRcre and eGFRcys were 24.8 ± 17.7 and 35.0 ± 21.1 mL/min/1.73 mP = 0.211 and P = 0.843, respectively). Pain assessed on a 10-point VAS was significantly reduced by LX-Ps   or after  treatment with LX-Ps (data not shown).PGE2 concentrations in fasting urine before and after the administration of LX-Ps did not differ significantly  to severe renal impairment (<30 mL/min/1.73 m2). Serum concentration of loxoprofen sodium and its trans-OH metabolite following a single oral dose of 60 mg have been reported to be 5.04 ± 0.27 and 0.85 ± 0.02 μg/mL, respectively [We found that short-term administration of LX-Ps was effective in treating knee and lower back pain in Japanese patients with diabetic nephropathy, without negatively affecting renal function. All 20 of our patients had overt protein in urine, but their eGFRcre ranged from normal , or between the trans-OH metabolite and urinary PGE2 (P = 0.370) (data not shown). We postulated that this is because the concentrations of loxoprofen sodium and its trans-OH metabolite were so low and in such a narrow range.We analyzed the correlation between the concentration of loxoprofen sodium or its trans-OH metabolite and urinary PGE2. There was no correlation between the concentrations of loxoprofen sodium and urinary PGE2 (NSAIDs are associated with elevated blood pressure and a higher incidence of hypertension –19 becauIn conclusion, in contrast to orally administered loxoprofen sodium, topically administered LX-Ps did not increase serum loxoprofen concentrations or decrease urinary PGE2 concentrations in Japanese patients with type 2 diabetes and renal impairment. Topical LX-Ps had no effect on renal function or on blood pressure in these patients. Although our study was limited by the small number of patients, topical LX-Ps showed good short-term safety and efficacy results in patients with diabetic nephropathy. However, additional large-scale and long-term studies are needed to clarify the safety of LX-Ps in patients with chronic kidney diseases. Furthermore, the effect of LX-Ps in patients on dialysis therapy is currently unclear, suggesting the need for further studies to clarify these effects.


The aim of the study is to evaluate the relationship between Humphrey visual field progression and peripheral vascular endothelial function in patients with open-angle glaucoma (OAG), assessed by noninvasive endothelium-dependent flow-mediated vasodilation (FMD).Forty OAG patients, among which 22 had normal-tension glaucoma (NTG) and 18 had primary open-angle glaucoma (POAG) were enrolled. Each enrolled patient underwent a thorough ophthalmological examination including the Humphrey visual field test and measurement of FMD via high-resolution 2-dimensional ultrasonographic imaging of the brachial artery. Blood samples were evaluated for biochemistry and lipid profiles as well as levels of high-sensitivity C-reactive protein (hsCRP). The annual change of threshold sensitivity of the visual field in each test location were analyzed with pointwise linear regression. The correlation between long-term visual field progression and FMD was evaluated.P = 0.37). However, only the annual sensitivity change of the inferior peripheral field showed correlation with baseline FMD. There was no significant difference in the change slope of visual field between NTG and POAG patients.A mean follow-up of 7.47 ± 1.84 years revealed a faster progression rate over the superior visual field in all 40 OAG patients (superior field −0.24 ± 0.67 dB/y, inferior field −0.10 ± 0.59 dB/y, A correlation between baseline brachial artery FMD and visual field progression was observed in the inferior peripheral field in patients with NTG and POAG. This result suggests that peripheral vascular endothelial dysfunction may be related to glaucoma progression. Glaucoma refers to a group of conditions typically characterized by a loss of retinal ganglion cells (RGC) with changes to the retinal nerve fiber layer and optic nerve head (ONH), which manifest themselves as a particular pattern of visual field loss. Traditionally, intraocular pressure (IOP) is considered the most important and the only modifiable risk factor for glaucomatous damage. The presence of normal-tension glaucoma (NTG), however, challenges the long-held pathophysiological concept of glaucoma based only on IOP. One hypothesis proposes that vascular factors contribute to NTG.4 Several reports have identified compromised vascular endothelial cell function in glaucoma patients.9 The vascular endothelial function can be assessed in several ways, and 1 well-established noninvasive method uses ultrasound to measure endothelium-dependent flow-mediated vasodilation (FMD) in brachial artery.10 This technique involves creating transient brachial arterial occlusion by cuff inflation followed by a sudden deflation, upon which a brief high-flow state is induced, which in turn increases shear stress of the brachial artery wall and triggers endothelial nitric oxide (NO) release and vasodilation.11 FMD is judged as the vascular response to NO and can be quantified as an index of vasomotor function.11 We previously reported that patients with open-angle glaucoma (OAG) had impaired FMD, and the impairment was greater in those with NTG than with POAG.9 The extent to which this dysfunction contributes to the glaucomatous progress is unknown, however. The purpose of the present study is to investigate the relationship between long-term visual field progression and vascular endothelial dysfunction measured by FMD in brachial artery.The vascular endothelium–smooth muscle complex is a complicated organ that maintains vascular homeostasis and regulates vascular tone via autocrine, paracrine, and endocrine properties. Endothelial dysfunction is considered an important factor for developing systemic diseases such as atherosclerosis, hypertension, and heart failure.Forty patients with OAG (22 NTG and 18 POAG) were recruited from the glaucoma clinic of Chang Gung Memorial Hospital for this study. The diagnostic criteria for POAG were as follows: pretreatment IOP exceeded 21 mm Hg, open anterior chamber angles on gonioscopy, glaucomatous optic disc cupping , and typical glaucomatous visual field loss on Humphrey perimetry using the 30-2 Swedish interactive threshold algorithm (SITA) standard program , which were reproducible in 2 consecutive tests. The diagnostic criteria for NTG were identical to those for POAG except that the untreated IOP never exceeded 21 mm Hg measured at varying intervals from 8 AM to 5 PM. Eyes with previous ocular trauma, ocular surgery, or ocular diseases other than glaucoma were excluded. We also excluded patients with systemic diseases, for example, diabetes mellitus, hypertension, congestive heart failure, hypercholesterolemia, cerebral vascular accident (CVA), or autoimmune diseases. Thus, none of our patients were taking systemic medications such as antihypertensive drugs, cholesterol-lowering agents, aspirin, or nitrates, and none were receiving hormone replacement therapy. The study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital. All participants provided both verbal and written informed consent.Visual field tests of the Humphrey 30-2 SITA standard program were performed at regular intervals every 6 months. The enrolled patients should have at least 5 reliable tests for progression analysis, each defined as < 20% fixation losses, < 33% false-positive errors, and < 33% false-negative errors. The raw data of retinal sensitivity (in dB) of the left eyes were exported for analyses. After excluding edge points  and the 2 points corresponding to the blind spot, threshold sensitivity of 52 test points were analyzed with pointwise linear regression.All participants received blood tests for biochemical profiles. Venous blood samples were collected after 12 hours of overnight fasting and processed for the following tests: fasting blood glucose, serum cholesterol, triglyceride, creatinine, alanine aminotransferase (ALT), uric acid, and the high-sensitivity C-reactive protein (hsCRP) levels.11 Briefly, using an Acuson L7 7.5 MHz linear array transducer on an Acuson Aspen ultrasound system , 2D images of the left brachial artery and pulsed Doppler flow velocity signals were obtained. Imaging was performed in a dimly lit and quiet room at a temperature of 22° to 25° C. Before the first scan, patients were rested in the supine position for at least 10 minutes and remained supine until the final recording was completed with electrocardiogram continuous monitoring. Blood pressure was measured from the right arm before imaging. Images were obtained 3 to 5 cm above the antecubital fossa. First, baseline 2D images were acquired, followed by pulsed Doppler blood flow velocity. To induce hyperemia, we used a 5.6-inch wide blood pressure cuff inflated to 250 mm Hg at the forearm to occlude the arterial blood flow completely. The arterial occlusion was maintained for 5 minutes before the cuff was deflated rapidly. At the same time, the transducer was carefully placed in an identical position. Pulsed Doppler velocity signals were then recorded at 5 to 10 seconds immediately after the deflation. At 60 seconds after cuff deflation, 2D images of the brachial artery were recorded for 5 seconds. To determine the endothelium-independent, nitroglycerin-mediated vasodilation (NMD), the patients were rested for another 10 minutes, followed by sublingual nitroglycerin spray (400 μg). Repeated brachial artery scans were performed at the same position 4 minutes after nitroglycerin administration.All participants were referred to the vascular laboratory for the vascular ultrasound study after fasting for at least 8 hours. The brachial artery FMD was measured by high-resolution 2-dimensional (2-D) ultrasonic imaging as previously described.hyperemia–VDbaseline)/VDbaseline] × 100%FMD = [(VDnitroglycerin–VDbaseline)/VDbaseline] × 100%NMD = [ at the end diastole coinciding with the R-wave on the electrocardiogram. The diameter was calculated as the average of 3 end-diastolic frames. The FMD and NMD were calculated as the percentage change in brachial artery diameter in response to hyperemia and to nitroglycerin respectively:http://www.r-project.org) was used to carry out large-scale pointwise linear regression analyses. For subtypes of glaucoma, the Mann–Whitney test was used to compare group means and the chi-square test for categorical data. For relationship between FMD and visual field progression on each test location, the Spearman correlation coefficient was calculated. A P value <0.05 was considered statistically significant.Data were expressed as mean ± SD for continuous variables and percentage for categorical variables. The computational statistical environment R (P = 0.017).A total of 40 eyes from 40 individuals were included in the analyses: 18 were POAG and 22 were NTG. Table P = 0.92. The superior hemifield progresses faster than the inferior hemifield: superior hemifield −0.24 ± 0.67 dB/y, inferior hemifield −0.10 ± 0.59 dB/y, but statistically insignificant: P = 0.37.Figure Figure The present study demonstrates that FMD is correlated with visual field progression in the inferior peripheral area. To our knowledge, this is the first study to describe a relationship between peripheral vascular endothelial dysfunction and long-term visual field changes in patients with NTG and POAG.12 One such examples is the commercially available guided progression analysis (GPA) software from the Humphrey Field Analyser. In contrast, a trend-based analysis detects temporal progression over serial measurements based on linear regression. The trend-based analysis can be a very powerful tool especially when numerous observations are available, and subtle changes can be spotted early on. The Humphrey Field Analyser also provides software for trend-based assessments of temporal progression for the mean deviation (MD) and the visual field index (VFI). Both progressive changes in MD and VFI represent a global evaluation of visual function, and localized defect in early glaucoma may be neglected. In this study, we evaluated the threshold sensitivity at each test location in the visual field by detecting changes over time using massive pointwise linear regression (PLR). We also assessed regional changes of the visual field according to the GHT clusters, in order to correlate zonal changes with vascular factors.Detection of functional progression plays a central role in the treatment of glaucoma. Albeit at present the Zeiss Humphrey Field Analyser remains the method of choice for monitoring functional changes, there is still a lack of consensus on the standard criterion for glaucoma progression assessment. Several algorithms have been proposed to identify visual field progression over time and they are either event-based or trend-based. In event-based analysis, the difference between baseline and follow-up examinations is compared to the test–retest variability from a separate sample of patients. When the observed changes exceed the predefined test–retest limit, progression was flagged based on a chosen cut-off range.18 For example, Zink et al reported that lower blood volume in the inferior temporal neuroretinal rim is associated with greater corrected pattern standard deviation (CPSD) in standard automated perimetry (SAP).19 Using optical coherence tomography angiography, Jia et al showed that the disc flow index is reduced remarkably in glaucoma and is highly correlated with pattern standard deviation (PSD) of the visual field.20 Deokule et al reported that although the parapapillary blood flow does not correlate with visual field loss, the variance in mean parapapillary blood flow is significantly larger in OAG with visual field loss, suggestive of vascular abnormality.21 Both CPSD and PSD measure global changes of the visual field, and the correlation between vascular factors and focal visual field changes cannot be established using either of these measurements. In this study we used PLR to assess regional variation by measuring temporal change at each test location. The FMD represents a global vascular endothelial function and is considered as an index of vasomotor response for vital organs. Similar to earlier reports, our data showed a faster progression in the superior field,24 but only progression in the inferior peripheral field was correlated with FMD. Whether this finding implies that the superior peripheral retinal territory is more susceptible to vasomotor dysregulation remains to be elucidated. Second, our patients were relatively early glaucomas (MD = −6.18 ± 6.47 in the NTG and −6.63 ± 5.19 dB in the POAG group), their temporal changes of visual field loss might not be significant enough to show any difference in the early stage. As glaucoma progresses slowly, a longer follow-up is needed for further verification.Alterations in ocular blood flow have been found to correlate with structural and functional changes in OAG.To sum up, our study demonstrates that the brachial artery FMD is significantly correlated with inferior peripheral visual field progression, suggesting there is a regional difference in the visual field in terms of vulnerability to vascular dysregulation.


Diabetes mellitus (DM) is the most common cause of chronic kidney disease and end stage renal disease. New onset diabetes mellitus after transplant (NODAT) has been described in approximately 30% of non-diabetic kidney-transplant recipients many years post transplantation. DM in patients with kidney transplantation constitutes a major comorbidity, and has significant impact on the patients and allografts’ outcome. In addition to the major comorbidity and mortality that result from cardiovascular and other DM complications, long standing DM after kidney-transplant has significant pathological injury to the allograft, which results in lowering the allografts and the patients’ survivals. In spite of the cumulative body of data on diabetic nephropathy (DN) in the native kidney, there has been very limited data on the DN in the transplanted kidney. In this review, we will shed the light on the risk factors that lead to the development of NODAT. We will also describe the impact of DM on the transplanted kidney, and the outcome of kidney-transplant recipients with NODAT. Additionally, we will present the most acceptable data on management of NODAT. As the epidemic of diabetes mellitus (DM) is growing, diabetic nephropathy (DN) remains the leading cause of end stage renal disease (ESRD) in the American population [US Renal Data System (USRDS) data 2012]. DN and ESRD as its consequence, poses a major healthcare problem especially in developed countries, and as such it represents a great financial burden to the society. In the United States, over 21 million people, or 7% of the general population, are estimated to have diabetes. To date, despite aggressive research conducted in the early diagnosis and treatment of DN, the vast majority of diabetic patients eventually progress to ESRD. For these patients, either dialysis or renal transplantation remain the only options of survival.de novo after kidney or any other solid organ transplantation in transplant recipients.Renal transplantation has been considered the therapy of choice in suitable ESRD or pre-ESRD patients since it confers a better survival benefit to these patients compared to dialysis –3. DespiDiabetic nephropathy was the etiology of ESRD in approximately 23% of kidney-transplant recipients in the United States in 2008 . These nThe incidence of new onset diabetes mellitus after transplant (NODAT) is variable, ranging between 10 and 46% depending on the study design and the definition of NODAT –7. More P < 0.0001), whereas, individuals ≥60 years had a risk of 2.6   .2) have an RR for NODAT of 1.73 , this being, along with age, one of the most consistent risk factors  , especially in a setting of uncontrolled viremia, poses a risk factor for NODAT development. The USRDS registry confirmed that the 1-year incidence of NODAT in HCV-positive patients at transplantation was significantly higher compared to the HCV-negative patients  . InterfeIn addition to the above mentioned factors influencing NODAT development, several immunosuppressive agents that are commonly used in the transplant arena have been noted to have diabetogenic potential. Herein, commonly used drugs include glucocorticoids, calcineurin inhibitors (CNIs) including tacrolimus (TAC) and cyclosporine (CYC), as well as the mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus). The diabetogenic effect of all of these drugs has been explored in detail and their effect on development of NODAT has been elucidated in several major studies.In vivo and in vitro animal studies demonstrate initiation of glucocorticoid related insulin signaling cascade in skeletal muscles, resulting in reduced glucose uptake and glycogen synthesis  vs. 10/86 (11.6%), = 0.049] . On the ischarge .Calcineurin inhibitors are also commonly prescribed drugs in the transplant arena. Both CYC and TAC administration correlates strongly with NODAT development, however, TAC appears to have more pronounced diabetogenic effect as demonstrated in prospective and retrospective studies , 32. Thi2+ concentration thus interfering with glucose-stimulated insulin secretion  signaling. CNIs regulate the dephosphorylation of (NFAT) protein and CREB (cAMP-responsive element-binding transcription factor) activity-2 (TORC2). The dephosphorylation of these proteins regulates several target genes , which are critical in β-cell survival, replication, and function. TAC binds intracellularly to FK506-binding protein 1B (FKBP1B) before docking in the calcineurin binding site (Cnb1) of calcineurin, thus inhibiting calcineurin and its downstream pathways and decreasing β-cell replication and survival . Moreoveecretion , 35.Finally, even though with less frequency, mTOR inhibitors continue to be used among transplant patients despite clinical evidence of their use being associated with greater risks of allograft failure and recipient death compared with a CNI-based regimen . AdditioIn vitro sirolimus is noted to increase the insulin content in human islet cells ; however, as expected, the duration of diabetes was similar in the two groups at the time of histologic findings of DN   .The pathological findings of DN post kidney transplantation are in most part similar to those of typical DN in native kidneys. Thickening of GBM and the tubular basement membrane constitutes the first sign of DN. Mesangial matrix expansion develops later on. The extracellular matrix accumulates over time and forms nodular mesangial changes that gradually lead to the compression of the associated glomerular capillaries resulting in glomerular sclerosis and obliteration of capillary lumina. Hyalinosis in the afferent and efferent arteriolar occurs simultaneously with the glomerular lesions leading also to tubulointerstitial chronic changes . DN in tIn spite of the extensive data on the pathways that lead to DN in the native kidney, there is still a paucity of such data on DN after kidney transplantation. Although, we believe that the same mechanisms lead to DN in native kidney contribute to the development of post transplant DN, there have been no studies confirming these mechanisms in the transplanted kidney. However, there are few pathways that have been described in the initiating and developing of DN; these may have some significance in the transplanted kidney. Herein, will discuss two of these pathways.Recently, there have been major changes in our understanding of DN development in the native kidney, with a major focus on the podocyte as the initial site of injury , which lin vitro  that is known as one of the culprits in native and recurrent Focal and Segmental Glomerulosclerosis (FSGS) has recently been shown to play an active role in patients with DN . There, The management of NODAT requires a multifaceted approach given that this condition affects multiple organs other than the allograft itself. Other than extensive counseling of pre-transplant patients regarding the higher odds of developing NODAT  and recommendation for implementation of general pre-transplant measures , most of the transplant centers in the United States have abandoned the screening of transplant recipients with oral glucose tolerance test as this would possibly affect the candidacy for transplantation. Post transplantation screening for NODAT is, however, recommended for all solid organ recipients. Namely, most of the transplant centers would screen the recipients after transplant with weekly fasting glucose testing in the first month after transplantation and continue screening at 5, 6, and 12 months. After this period even though the risk of NODAT is somewhat lower, at least yearly testing with either glycosylated hemoglobin or fasting glucose is recommended.Early diabetes specialist referral, adequate glycemia control as well as treatment of comorbid conditions remain the backbone of medical approach to this condition. Further, good control of glycemia may even decrease the risk for rejection . In patiEven though the two main causes of kidney-transplant loss are chronic allograft nephropathy and death with a functioning allograft, NODAT is strongly associated with impaired patient survival , 52 as wThe mechanism by which NODAT influences the allograft survival is not well understood, other than predisposing patients to recurrent infections and acute rejection especially when attempts are made to decrease immunosuppression in order to minimize the diabetogenic effect of medications like TAC. In addition to this, NODAT likely contributes to recurrence of DN in the allograft. Similar to the general population, diabetic complications are also commonly encountered in patients with NODAT including ketoacidosis, neurologic, and ophthalmic complications as well as recurrent hypoglycemia and shock .In summary, NODAT is a common and serious condition that affects the overall health and the survival of a transplant recipient. Inability to control NODAT is associated with significant allograft failure as well as overall transplant recipient morbidity. Strenuous efforts must be undertaken to minimize its detrimental effect on the comorbid conditions that develop as a consequence of NODAT. We are looking forward to newer transplant protocols and medications that do not have the diabetogenic side effects of the ones currently used among the transplant patients and many such are currently underway.Jochen Reiser is an inventor on pending and issued patents related to the modification of suPAR. He stands to gain royalties from their commercialization. The rest of the authors have no conflict of interest.


From 2005 to 2011 Mazowe District recorded a gradual decline in prevalence of hypertension in the face of rising incidence of complications like stroke. This raised questions on whether diagnosis and management of hypertensive patients is being done properly.We conducted an analytic cross sectional study at three hospitals in Mazowe District where we randomly selected 201 of 222 patients from out patients departments and interviewed a convenience sample of 23 healthcare workers. Structured interviewer administered questionnaires were used to collect data on demographic characteristics and knowledge from patients, as well as knowledge and practices from health workers. Physical measurements were done on all patients. Frequencies; proportions, odds ratios, Chi square test and stratified & logistic regression analysis were done using Epi info version 3.5.4 while graphs were generated using Microsoft excel®. Calculations were done at 95% confidence interval.Prevalence, awareness, control, compliance, and complication rate of hypertension were: 69.7%, 56.2%, 22.0%, 59.8% and 20.7% respectively. Independent risk factors for hypertension were age , obesity , and previous high blood pressure reading . Complications included cardiac failure (8.6%), visual defects (4.3%) and stroke (3.6%). Co-morbid human immunodeficiency virus (10.7%) and diabetes mellitus (12.1%) were identified among respondents. Knowledge was poor in 47.7% of health workers.Risk factors found in this study are consistent with other studies. Health service factors are the main reasons for poor diagnosis and management of hypertension. Health workers need training on diagnosis and management of hypertension. Guidelines, digital sphygmomanometers and adequate drug supply are needed. District has since purchased digital BP machines and requested assistance with training on clinical features of hypertension, use of digital machines, and how to properly measure BP. A policy document on non-communicable diseases including hypertension was subsequently developed by the Ministry of Health and Child Care and currently awaiting endorsement by parliament. Hypertension is a chronic, sometimes acute, condition characterized by an abnormally raised blood pressure resulting in end organ damage. Hypertension is strictly limited to arterial blood pressure. Normally the maximum pressure exerted via blood on the arterial walls by the heart during a contraction (systolic pressure), is below 140 mmHg while the minimum pressure on the arterial wall when the heart is relaxing between contractions is below 90 mmHg (diastolic pressure).When the cause is unknown it is designated essential hypertension. This has a genetic link within families. Secondary hypertension is where the cause is identified as in: chronic kidney disease; adrenal gland disorders; pregnancy; or drug induced hypertension .Zimbabwe is experiencing an epidemiological transition where the prevalence of hypertension is rising due to Western diets and lifestyle .The impact of hypertension was previously ignored as institutions focused on communicable diseases (NCDs) such as HIV. With these communicable diseases becoming more controlled and life expectancy increasing, importance of NCDs is now being felt . BecauseRisk factors for developing hypertension can be modifiable , or non-modifiable .Hypertension tends to rise with increasing age due to the stiffening of the arterial walls . FemalesZimbabweans have adopted unhealthy eating habits and behaviours such as smoking cigarettes and alcohol abuse. According to the STEPwise survey done in 2005, 58% of men and 13.5% of women took alcohol while 33.4% of men and 5% of women used tobacco . The resHypertension is diagnosed by measuring BP using a sphygmomanometer. In Zimbabwe, three consecutive readings at least 4 hours apart are used for diagnosis after which a Medical Doctor can commence treatment. However a single systolic blood pressure (SBP) above 180 mmHg or a diastolic blood pressure (DBP) above 110 mmHg is indication for treatment . The waist circumference was measured in the mid-axillary line midway between the lower rib and the superior iliac crest using a standard stretch resistant dressmaker’s tape measure. Central obesity was defined as WHR above 0.85 and 0.95 for females and males respectively.SD CHeCK GOLD BLOOD GLUCOSE TEST MONITOR and STRIPS. A patient with RBS of at least 11.1 mmol/L was classified as having diabetes and further management recommended. Patients with RBS between 7 mmol/L and 11 mmol/L were classified as a suspected diabetic and a fasting blood sugar test recommended [RBS was done on all patients using ommended .Written informed consent was obtained from all patients while verbal consent was obtained from health workers. Permission was sought and granted from Provincial Medical Director (PMD), Mashonaland Central Province; District Medical Officer (DMO), Mazowe District; Health Studies Office (HSO), with ethical approval from the Joint Research and Ethics Committee (JREC/210/12) and Medical Research Council of Zimbabwe (MRCZ) approval number MRCZ/B/381.A feasibility study was done at Tsungubvi clinic and relevant adjustments made to the final data collection tools.Stepwise logistic regression analysis was then conducted to estimate measures of association of significant variables found in the bivariate analysis at the p = 0.25 level. We started with a single variable adding the other variables one by one at the 0.05 level (95% CI) eliminating all non-significant variables until all possible variables had been added.Prevalence, frequencies, proportions, odds ratios, stratified Chi square tests and logistic regression analysis were done using Epi info 3.5.3  and Microsoft Excel® 2007 was used to generate graphs. All calculations were made at 95% confidence interval (95% CI). Univariate analysis was initially done fitting information into previously prepared shell tables and graphs. This was followed by bivariate analysis to examine two variables comparing risk factors and outcomes. Stratified analysis was done for factors found to be statistically significant in the bivariate analysis to control for confounding and identify effect modification. We interviewed 201 of 222 patients giving a response rate of 90.5%. Thirteen were excluded (non-residents of Mazowe) while 8 refused to participate  (95% CI: 62.8%-75.9%), based on SBP and or DBP. Hypertension was slightly more prevalent in women (72.3% vs. 64.8%: 95% CI: 0.76-2.63) though not significant  as compared to urban (29.9%) and farming (20.9%). The remainder were peri-urban (5.5%) and mining areas (3%). After reclassifying into mainly urban and mainly rural residence most patients were in the mainly rural category . The prevalence of hypertension was 71.8% (95% CI: 59.9%-81.9%) in urban areas and 68.5% (95% CI: 59.7%-76.3%) in rural areas. Though not significant, patients staying in urban areas were at higher risk of having hypertension as compared to those in rural areas . Awareness was comparable between patients staying in urban (72.5%) and rural (76.4%) areas  as well as being on treatment; urban  vs rural  with POR 0.68; 9% CI: 0.30-1.57. Control was better among patients from rural areas (25%) as compared to patients from urban areas (13.8%) but this was not statistically significant .Awareness was higher among women in rural areas (79%) as compared to those in urban areas (71.9%)  while men in urban areas had higher awareness rate  . Treatment rate was higher among rural women (61.3%) and urban men (68.4%) as compared to urban women (50%) and rural men (55.6%). Control rate was higher among rural women (27%) and rural men (20%) as compared to urban women (12.5%) and urban men (15.4%).P < 0.001). There were no statistically significant differences between hypertensive and non-hypertensive patients with respect to marital status (P = 0.082), place of residence (P = 0.174), highest level of education (P = 0.642) and employment status (0.585). Though not significant patients older than 60 years were: less likely to be aware of their hypertension , more likely to be on treatment for hypertension , less likely to have controlled hypertension among those on treatment .Patients’ median age was 45 years (IQR: 35 yrs - 60 yrs) with most being younger than 60 years (73.6%). Median ages were 48 years and 36 years for hypertensive and non-hypertensive patients respectively (Most (70.6%) mentioned stress as a cause of hypertension. Clinical features mentioned were mainly headache and body weakness. Most (63.2%) thought stroke was the only complication of hypertension.P = 0.075).A high proportion of hypertensive patients were being attended to at local clinics (51.4%) as compared to hospitals (43.6%). Smaller proportions were consulting General Practitioners (3.6%) and traditional healers (1.4%)  material or guidelines for management of hypertension for use in the health facilities. Clinicians were using the Essential Drugs List in Zimbabwe as a reference text.P < 0.001) with obese patients being 4.15 times more likely to be hypertensive than non-obese patients.The prevalence of overweight and obesity in the study population was 28.9% and 27.9% respectively. Central obesity was found in 50.8% of women and 7.0% of men. Forty-nine (35%) hypertensive patients were obese. Among hypertensive patients women were more likely to be obese than men (32.3% vs. 19.7%) with POR 2.55; 95CI: 1.13-5.75). Obesity was associated with hypertension . Reasons for missing doses were mainly drug side effects, trying alternative treatment, and feeling better.Thirty-four (40.2%) hypertensive patients on treatment had ever missed at least two doses of medication. Patients missing doses were taking one 16 (48.5%); two 15 (45.5%); and three 2 (6.1%) types of antihypertensive >drugs. This did not affect compliance .Twenty-nine  hypertensive patients presented with a complication, such as congestive cardiac failure, visual problems, stroke or sensor y peripheral neuropathy. There were significant differences (20.7% vs. 3.3%) with hypertensive patients more likely to present with complications than non-hypertensive patients . Those with controlled hypertension were less likely to develop complications than those with poorly controlled hypertension (POR 0.31: P = 0.41).Eighty-three patients had co-morbid conditions. Ten percent had HIV while 12.1% (95% CI: 7.2-18.7) had diabetes mellitus. Eleven of the diabetic hypertensive patients were newly diagnosed. Diabetic patients were more likely to suffer from hypertension as compared to non-diabetic patients, however this was not statistically significant  hypertensive respondents mentioned having been given advice on lifestyle modification. Only 36 (25.7%) and 10 (16.4%) hypertensive and non-hypertensive respondents had been screened for diabetes mellitus.Twenty-four (11.9%) respondents were smokers. Of these only 4 were advised not to smoke. Hypertensive smokers were 15 (62.5%). Only 3 of these 15 were advised not to smoke. On the other hand 25 (14.1%) non-smokers currently hypertensive were advised not to smoke.P = 0.007).Consultation fees ranged from $0.00 to $10. Eighty-two respondents (58.6%)  paid for consultation. Patients not paying fees had better hypertension control  health workers. Only 4 (17.4%) correctly described the classification of hypertension. Knowledge on risk factors, symptoms and complications of hypertension was sought and the results are shown in Table Various case scenarios were presented to health workers to assess how they were managing patients. The correct method of measuring BP was described by 10 (43.5%) health workers. A patient presenting with BPs of 130/85 and 150/90 were correctly managed by six (26.1%) and eight (34.8%) health care workers respectively. Sixteen health workers could correctly outline the monitoring of a patient on treatment for hypertension.As shown in Tables Patients on treatment were more likely to have controlled hypertension than those who were not on treatment .modified by obesity as shown in Table Stratified analysis showed that the relationship between being on treatment and having controlled BP was Sex also modified the effect of older age on development of hypertension with women being more likely to have hypertension than men Table .Logistic regression analysis showed that independent determinants for developing hypertension in this study were age above 60 years, obesity and having a high BP reading in the previous 12 months as shown in Table Prevalence of hypertension was high in this study. Most patients were aware that they had hypertension and the majority were on treatment. There was, however, a gap between diagnosis and control of hypertension. The median age was higher among hypertensive patients as compared to the non-hypertensive patients.Independent risk factors for hypertension found among patients were age above 60 years, obesity, high BP in the previous 12 months. Patients with hypertension were more likely to have complications associated with hypertension than non-hypertensive patients with the most common complication being cardiac failure.Standard diagnostic tools such as dressmaker’s tape measure were either unavailable or not being used by health care workers. Simple errors in measuring BP were common among health care workers. Drug supply was erratic and dependent on the specific health centre with most patients relying on supplies from hospitals.Prevalence of hypertension was expected to be higher than population based studies done in Zimbabwe and abroad but in this study it was much higher than expected. In addition to the rising prevalence of hypertension in Zimbabwe this may have also been due to the nature of the study, a hospital based study. Therefore the proportion of patients who present with hypertensive is likely to be higher than the population based studies in literature.The prevalence of hypertension was slightly higher in women as compared to men, although this was not significant. We assume this may be due to the higher prevalence of obesity among women, a risk factor for hypertension. The STEPwise survey of 2005 also found a higher prevalence of hypertension in women. However there has been no consistence in the sex difference as shown by a study done in Mozambique where men had a higher prevalence of hypertension than women .Prevalence of hypertension rose with increasing age. This is biologically plausible as the age related arteriosclerosis of blood vessels lowers flexibility of blood vessels causing the heart to increase the force of myocardial contraction raising BP. Similar to the study in Mozambique increasing age was associated with increased risk of hypertension .Awareness of hypertension was very high in this study approaching proportions found in developed countries. The assumption is that study population had better health seeking behaviour. In addition all patients attending health facilities in Zimbabwe get BP checks where there are BP machines.Control of hypertension was very low with no significant difference between men and women. Other studies have found better control of hypertension among women as compared to men ,13,14. WThough not significant in this study higher education levels have been noted to amount to better understanding of health related issues and better health outcomes. Due to societal norms women tend to be less educated than men. However, despite being less educated than men, women usually understand health messages better as they are in constant contact with the health delivery system more than men. According to Pandit et al. lower education attainment and more limited literacy are important predictors of poorer hypertension knowledge and control .This realisation helps in development of educational tools to improve knowledge acquisition among patients.There was a high proportion of undiagnosed hypertension in this study, probably due to the poor health worker practices found in all hospitals. This high proportion of patients with previously undiagnosed of hypertension is worrisome considering the fatal consequences of hypertension. In an American study 8% of the American hypertensives were undiagnosed . In the The prevalence and awareness rate was higher in patients from urban areas while treatment and control rates were higher among patients from urban areas. This was however not significant. In comparison the awareness, treatment and control rates were significantly lower in patients from rural areas as compared to urban areas in the PURE study of which Zimbabwe was a part of.In our study both SBP and DBP tended to be within the same grade in hypertensive patients older than 50 years. However, hypertensive patients younger than 50 years tended to have their DBP in a higher grade than SBP. Williams et al. showed that patients younger than 50 years tended to have either isolated DBP or both high systolic and diastolic BP in 30-40% of cases .The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure has noted the importance of paying attention to SBP which is a major risk factor for cardiovascular diseases. According to the report most Physicians have been taught that diastolic pressure is more important than SBP thus they put more emphasis on DBP . SimultaPatient knowledge depends on the source of their information which is usually the local health practitioner. Stress has never been proven to be a direct cause of hypertension yet more than 70% of respondents believed it to be a cause. The only link between stress and hypertension is the temporary spikes in BP caused by stress via an upsurge of adrenaline from the adrenal glands ,23. ThisHealth workers knowledge on complications of hypertension was poor therefore patients may present with complications which health workers may fail to identify. Zibaeenezhad also found that knowledge on hypertension was poor among health workers in his study where only 20% of Physicians could properly manage a patient with hypertension . AnotherIncreasing age and setting in of musculoskeletal problems like arthritis may make walking to health facility difficult for patients. There is therefore need to uphold the primary health care approach and avail drugs and services at clinic level, not just hospitals. Unfortunately quality of services is threatened by persistent resource shortage. The good working relationship between health workers and patients is a good starting point for improving patient knowledge and compliance to treatment and follow up.Use of manual BP machine by poorly trained workers was one of the causes of poor diagnosis identified in this study. The WHO recommends use of digital BP machines to avoid such errors. Common avoidable errors were being made during BP measuring process in all hospitals resulting in missed diagnoses of hypertension. Simple tools for anthropometric measurements were not being used as health workers did not seem to understand the importance simple methods of assessing the cardiovascular risk of a patient. As a result patients may present late with complications like stroke, conditions that are very difficult to manage once they set in.Advice on lifestyle modification has been given to most patients but hypertensive patients were more likely to benefit than non-hypertensive patients. This may mean health care workers are not promoting primary prevention of hypertension.Consultation for chronic illnesses in Zimbabwe is free but patients in this study were made to pay. This may work against efforts to improve health care to hypertensive patients. Absence of drugs at clinic level worsens the situation for hypertensive patients as they are forced to travel to the hospitals. This study showed that free consultation enhanced control of hypertension making consultation fees an important barrier to care .A study done in Ethiopia showed that co-morbidity affected compliance and adherence with those with more than one co-morbid conditions having poor adherence . This waTaking antihypertensive treatment has been linked to reduction of BP level and risk of stroke among patients . In thisObesity affects the effect of treatment on control of hypertension. This is because obesity increases insulin release which then thickens blood vessels in addition to release of renin and aldosterone. A study in USA showed that obese patients are at greater risk of hypertension and its complications when associated with a higher WHR. Literature has shown that obesity can result in a patient presenting with complications of hypertension without a previous diagnosis of hypertension. This may occur even at lower BP levels .Risk factors found such as obesity are consistent with findings in other studies in Zimbabwe and other countries. In clinical trials obesity has been linked to cardiovascular risk factors such as diabetes mellitus and hyperlipidaemia. Hence weight reduction may work in the reverse direction to cause a decline in blood pressure irrespective of changes in salt intake as hypothesised by Hall et al. .Complications were more prevalent than initially anticipated with cardiac failure being common. Visual defects due to hypertension may have been underestimated as there were no provisions for fundoscopy. Strokes were only 3.6% which is lower than initially anticipated.A tenth of hypertensive patients had HIV. This is worrying as most Opportunistic Infections Clinic (OIC) staff tends to focus on HIV related ailments and ignore non-communicable diseases such as hypertension. This finding is very important as it enlightens the importance of measuring patients’ BP at every contact. In addition taking ARVs has been shown to induce metabolic syndrome where BP rises in association with abdominal adiposity.Co-morbid diabetes mellitus was high. This is worrying considering 74.3% of hypertensive respondents had never been screened for diabetes prior to this study. Due to a hypothesised genetic link, most patients with poorly controlled hypertension are assumed to develop diabetes and vice versa ,30. It iIndependent risk factors for hypertension are consistent with what is known about hypertension. Several studies have shown similar findings where increasing age and obesity were risk factors for developing hypertension. Central obesity was independently associated with poor control of hypertension for respondents on treatment. This is consistent with findings by Mahmood et al. in India ,28.Limitations included reluctance by local Doctors to participate in this study. During the study there was a tendency by other respondents to inform each other about the study. As a result there may have been an overestimation of the prevalence of hypertension in this study. Local Doctors tended to absent themselves on the days investigation was ongoing. Thus patients may have ended up participating in the study in an effort to get medical attention from the investigator. This may have distorted results of the study.White coat hypertension could not be ruled out in this study.We developed and used a non-standard system developed to grade health worker knowledge. The system assumed all responses were equally important which may not be the case in practice.The drug supply and control system in the hospitals was not assessed in this study.The prevalence of hypertension in this hospital based study was very high with the burden being higher in those living in urban areas, women, the obese, and the elderly.The diagnosis and management of hypertension is poor in Mazowe District with resultant high proportion of patients with undiagnosed hypertension. In addition a high proportion of patients on treatment are developing complications.The absence of standard guidelines has made the situation worse. Contributing to these complications is the poor compliance to medications among hypertensive patients.We recommend that in the short term health workers need on the job training and mentorship in proper diagnosis and management of hypertension. Guidelines for the management of hypertension need to be printed and availed to health workers to help improve their knowledge, practices and to also serve as a reference.Health workers need training in measuring and calculating WHR and BMI with guidance from the Non-Communicable Diseases Unit at MoHCC Head Office.The Mazowe District Health Executive and Hospital Management Teams should prioritize purchase of digital BP machines.In the medium term: National Pharmaceutical Company should provide drugs to health facilities. The Directorate of Pharmacy may need to relax the policy on second line antihypertensive drugs such as atenolol and avail them to clinics for resupply only to patients prescribed at higher levels.The National Office must come up with appropriate awareness messages on hypertension and disseminate through the provincial and district offices.The Province needs to set up Specialist NCDs clinics in the Province and ensure training of health staff.In the long term: DHE should conduct operational research on hypertension and other non-communicable diseases in the district to enable evidence based practices. Available data on non-communicable diseases need to be analysed and used for decision making locally.Subsequently the Directorate of Epidemiology and Disease Control drafted a policy document on non-communicable disease, a process leading to development of standard operating procedures for addressing the burden of non-communicable diseases in Zimbabwe. Currently the document is awaiting endorsement by parliament which will allow organizations such as the WHO to provide support for the directorate.The authors declare that they have no competing interests, both financial and non-financial.MM: conception, design, acquisition, analysis and interpretation of data and drafting the manuscript. PM: conception, design, acquisition, analysis and interpretation of data and drafting the manuscript. LT: conception, design, data collection, analysis, interpretation and reviewing of several drafts of the manuscript for important intellectual content. NT: conception, design, reviewing of several drafts of the manuscript for important intellectual content. MT and SR had oversight of all stages of the research and critically reviewed the final draft for important intellectual content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/14/102/prepub


Smoking is the most important reversible cardiovascular risk factor. It is well established that quitting smoking reduces coronary events. However, on several occasions, the cardiovascular safety of smoking cessation drugs has been questioned. Our goal is to evaluate the effects of smoking cessation drugs on blood pressure and heart rate in patients from a smoking cessation service in a cardiology hospital.p < 0.05).We examined the PAF database (Smoking Cessation Assistance Program database) between January 2008 and March 2014. We analyzed data from 900 patients who were compliant with the treatment . The most frequent clinical diagnoses were coronary artery disease (25.2 %), hypertension (57.2 %), and diabetes (13.4 %). Blood pressure, heart rate, and carbon monoxide (CO) concentration in exhaled air were analyzed at consecutive visits during the first 45 days of treatment (mean visits - 3). Analysis of repeated measures was used for the statistical analysis (Two hundred seventy one patients used nicotine replacement therapy (NRT) alone, 81 used bupropion alone, 154 used varenicline alone, 283 used NRT plus bupropion and 111 used bupropion plus varenicline. For all smoking cessation drugs, used alone or in combination, no increase occurred in the average value of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). Significant reductions in CO concentrations occurred in all smoking cessation drug groups.Smoking cessation drugs used in monotherapy or in combined regimens did not influence systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) in this group of patients during the observation period. Smoking cessation substantially lowers the risk of death in patients of all ages , includiThese medications demonstrated effectiveness in achieving complete smoking cessation , but theA recent network meta-analysis of 21 randomized clinical trials (RCTs) showed that bupropion was not harmful for MACEs and appeared to have a cardioprotective effect . VarenicThere are few studies evaluating combination of therapies for smoking cessation –15, noneWe examined CV effects of these drugs on blood pressure and heart rate in outpatient setting according to different combination therapies and the previous presence of hypertension, coronary artery disease, and/or acute myocardial infarction.We analyzed 900 outpatient subjects followed at the Smoking Cessation Program of the Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil. Most of the patients have cardiovascular diseases or high risk score. We used the PAF database (Smokers Assistance Program) between January 2008 and March 2014 and looked up subjects of both genders older than 18 years of age. The Ethics Committee for Research Project Evaluation (CAPPesq) of the Hospital das Clinicas – School of Medicine, University of Sao Paulo, approved the study. The study complied with the Declaration of Helsinki. They agreed with the informed consent form.n = 900) did not have significant differences in their SBP, DBP, HR and CO values  compared with data of the untreated patients (n = 891)  (p > 0.05).During the study period, 1791 patients were enrolled to the service. However, 891 patients were excluded because they did not come in the consecutive visits and their data for BP, HR, and/or CO were not available. However, patients with analyzed data , bupropion, and varenicline. In the first visit (baseline), the patient was not in use of any drug for smoking cessation. One of these drugs was prescribed as monotherapy according to the nicotine dependence level, previous use of smoking cessation drugs, availability of the medication and lack of absolute contraindication related to each drug. Varenicline was prescribed for patients who failed in previous attempts with NRT and/or bupropion, or who smoked one or more packs of cigarettes per day.The gap between follow-up visits was 2 to 3 weeks. In all visits the patient were questioned about smoking status, compliance and collateral effects of the medication prescribed, and we evaluated the vital signs, CO level, and withdrawal symptoms.In the second visit, the patients who achieved success with monotherapy and had no or mild withdrawal symptoms were kept with the same medication. The patients who did not achieve success and the patients who achieved complete cessation but with moderate or intense withdrawal symptoms had associated therapies .The data were categorized in 3 visits in sequential follow-up, called initial (baseline), second, and third visits. Variables from the database included in the analysis were: age; sex; smoking cessation; smoking cessation drugs used; smoker’s degree of nicotine dependence according to the Fagerström score  and Issap < 0.05.Categorical variables are presented as percentages and continuous variables are presented as means ± SD (standard deviation). Friedman’s test (repeated measures) was performed to analyze SBP, DBP, HR, and CO levels during visits, according to the prescribed pharmacotherapy and the presence of hypertension, CAD, or AMI. Friedman’s test was also performed to analyze SBP, DBP, and HR according with the CO cutoff (6 ppm) in the second and third visits and the presence of hypertension, CAD, or AMI. Statistical analyses were carried out using SPSS 16.0 software , with the level of significance set at During the study, 900 patients were included in the analysis. The median age of patients was 53 ± 17 and 50.5 % were male. Table Among these 900 patients, 271 patients used NRT alone, 81 used bupropion alone, 154 used varenicline alone, 283 used NRT + bupropion, and 111 used bupropion + varenicline.p > 0.05) during 3 sequential measures in follow-up, regardless of pharmacotherapy for smoking cessation used and the presence of hypertension, CAD, and/or previous AMI. The CO analysis showed a significant reduction (p < 0.001) in exhaled CO level in 3 sequential measures in follow-up in all the types of pharmacotherapy for smoking cessation used, alone or in combination.Table n = 900) according with a CO cutoff of 6 ppm in the second and third visits and the presence of hypertension, CAD, or AMI. There was no significant influence of this variable in change BP and HR in all smoking cessation drugs group.We also analyzed BP and HR of followed patients (It is well known that quitting smoking can reduce the risk of mortality from heart disease and acute myocardial infarction . HoweverWe did not observe any significant change in systolic or diastolic blood pressure and heart rate in 900 patients who used smoking cessation therapies and were followed at Heart Institute, a cardiac hospital with a large rate of patients with hypertension, CAD, and/or AMI. This result was regardless of the combination of pharmacotherapies used in the smoking cessation treatment and the presence or absence of cited comorbidities.In the literature, tachycardia is a well-established and benign adverse effect observed in a lot of studies using NRT . Some stConcerning bupropion, an increase in blood pressure could be an important cardiovascular side effect, regardless of pre-existing hypertension, because of the effect of bupropion on the reuptake of norepinephrine . HoweverIn the same way, Tonstad et al reported no changes in BP after 24 weeks of varenicline versus placebo. The mean HR remained similar in the varenicline group and decreased by 2 beats per minute in the placebo group . AdditioThere are some studies with the use of NRT in population of smokers without cardiovascular diseases or with hypertension alone , 28, whiThis study has some limitations. BP and HR were measured at 3 consecutive visits. Therefore, although it is enough to have a comparison, possible small changes might be seen in a more prolonged follow. Compliance with the treatment and smoking status were measured during the follow-up period by asking patients and by measuring exhaled CO level, which showed a significant reduction in comparison with basal CO level, regardless of pharmacotherapy used. It indicates reduction or cessation of smoking. We did not design a study with the objective and power to observe major CV events.Our findings of maintenance of BP and HR in a relatively large population of smokers with and without preexisting stable CV diseases using different combinations of smoking cessation therapies are important as a safety data for clinical practice. This result is in agreement with a recent meta-analysis of the use of NRT, bupropion and varenicline, which did not find an increase in major CV events with all drugs . In patiOur data from a real clinical practice suggest that, even in patients with hypertension, CAD, and/or AMI, there are no significant clinical change in blood pressure or heart rate during the use of NRT, varenicline, and/or bupropion.