The effect of mean arterial pressure titration to a higher level on microcirculation in septic shock patients with previous hypertension remains unknown. Our goal is to assess the effect of mean arterial pressure titration to a higher level on microcirculation in hypertensive septic shock patients.This is a single-center, open-label study. Hypertensive patients with septic shock for less than 24 hours after adequate fluid resuscitation and requiring norepinephrine to maintain a mean arterial pressure of 65 mmHg were enrolled. Mean arterial pressure was then titrated by norepinephrine from 65 mmHg to the normal level of the patient. In addition to hemodynamic variables, sublingual microcirculation was evaluated by sidestream dark field imaging.P = 0.002), cardiac output , and central venous oxygen saturation . There were significant increases in small perfused vessel density , proportion of small perfused vessels , and small microvascular flow index  when compared with a mean arterial pressure of 65 mmHg.Nineteen patients were enrolled in the study. Increasing mean arterial pressure from 65 mmHg to normal levels was associated with increased central venous pressure  contains supplementary material, which is available to authorized users. Septic shock is a major cause of death in critically ill patients and is characterized by hypotension and hypoperfusion . AlthougMaintaining sufficient perfusion pressure might be an important way to improve the microcirculatory perfusion . As one The optimal MAP target in septic shock patients, especially in patients with previous hypertension, is still unknown . The guiOur goal was to assess the effect on the microcirculation of MAP titration to normal levels in septic shock patients with previous hypertension. We hypothesized that the increase in MAP from 65 mmHg to the normal levels of patients is associated with improved sublingual microcirculation.This was a single-center, prospective, open-label study conducted in the intensive care unit of a tertiary care teaching hospital. The study protocol was approved by the Ethics Committee  of Zhongda Hospital, School of Medicine, Southeast University, and informed consent was given by each patient or their next of kin.Trial registration: Clinicaltrials.gov NCT01443494; registered 28 November 2011.Patients admitted to the intensive care unit who met the following inclusion criteria were enrolled in the study: 1) patients with septic shock for less than 24 hours with a history of previous hypertension ; 2) fluExclusion criteria were: pregnancy; age <18 years; inability to acquire the usual level of MAP; refusal of consent by the patient or relative; participation in other trials during the last 3 months; and hypertensive patients without antihypertensive therapy.As chronic hypertensive patients are supposed to have undergone more blood pressure measurements in daily life than normotensive patients, the average MAP acquired from a patient’s physical examination records over the last 2 years was taken to be the target MAP. If the medical records were incomplete, a detailed enquiry about the target MAP to their next of kin was performed. In addition, age, gender, duration of shock prior to inclusion, Acute Physiology And Chronic Health Evaluation II score, intensive care unit length of stay, in-hospital mortality, source of infection and comorbidities were also recorded.After stabilization for 30 minutes, basal measurements including hemodynamic and microcirculatory measurements were taken 20 minutes apart, and the NE doses were increased to titrate MAP to the target level. Patients were allowed to stabilize for 30 minutes before new measurements were taken. Thus, there was 50 minutes between the baseline and the second measurement. During the process, no other changes in treatment were allowed. The decision to stop the research was made by the treating intensivist according to predetermined safety limits for each patient. The detailed safety limits are reported in Additional file Serial measurements of NE dose, MAP, heart rate and CVP were performed. Noninvasive bioreactance cardiac output and stroke volume monitoring were obtained using the NICOM system . Arterial and central venous gases were obtained to determine arterial pH, hemoglobin, lactate, arterial partial pressure of oxygen, arterial partial pressure of carbon dioxide, arterial hemoglobin saturation, arterial oxygen partial pressure to fractional inspired oxygen ratio and central venous hemoglobin saturation.Measurements of the sublingual microcirculation were obtained using sidestream dark field . The SDF probe was placed under the sublingual area without pressure after removal of secretions. Video sequences of 20 seconds each were recorded from three different sublingual sites. These images were stored and later renumbered by an identifier blinded to the clinical course. Videos were converted to the AVI (audio video interleaved) file format with video processing software, and analysis for each image was performed by two different investigators. Finally, all the variables were averaged to yield a single value for statistical analysis. The microcirculatory flow index (MFI), based on determination of the predominant type of flow in four quadrants for small vessels and total vessels, was determined with a semi-quantitative methodology. Flow was characterized as no flow = 0, intermittent = 1, sluggish = 2, and continuous = 3, to reflect blood velocity, identical to that described in consensus conference recommendations . MFI wast test or Wilcoxon signed-rank test were used. Differences were considered significant at P < 0.05.Statistical analysis of the data was performed using SPSS 16.0 . Histograms and normal-quantile plots were examined and Kolmogorov-Smirnov test was performed to verify the normality of the distributions of the data. Data are presented as the mean ± SD if normally distributed or median (interquartile range) if not normally distributed. Categorical variables are presented as number and percentage. For continuous data, paired The main characteristics of the 19 patients are presented in Table P < 0.001) by augmenting NE dose was associated with significantly increased CVP , cardiac output  and central venous oxygen saturation  , proportion of small perfused vessels , and small MFI  compared with a MAP of 65 mmHg (Table Although the vascular density and heterogeneity index were not significantly altered, there were significant increases in small perfused vessel density (from 10.96 ± 2.98 to 11.99 ± 2.55 vessels/mmHg Table .Table 3Meanwhile, little interindividual variability in small perfused vessel density Figures  and 3, pThe main finding of our study suggested that increasing MAP to the usual levels in early resuscitated hypertensive septic shock patients was associated with considerable microcirculatory improvements, characterized by increased perfused vessel density, a higher proportion of small perfused vessels and elevated MFI. Meanwhile, little individual variability developed.Microcirculatory dysfunction plays an important role in the development of tissue hypoperfusion in patients with septic shock. Although early goal-directed therapy is reported to improve their outcome , the rouAn adequate MAP is typically essential to restore effective perfusion pressure and organ perfusion in septic shock patients. As the most common pre-existing condition in patients with septic shock , the SurHypertension could cause a rightward shift in cerebral pressure-flow autoregulation , which sIn our study, increasing MAP from 65 mmHg to the usual levels of the patients resulted in improved microcirculatory function in these septic shock patients with previous hypertension, although the cause and effect are unclear. NE was used to titrate MAP to the usual level. As the key vasoactive agent recommended for restoring MAP in the treatment of septic shock, NE might not only perform as the vasopressor but also affect preload and tissue perfusion. Increasing the dose of NE significantly augments cardiac output by 11 to 17% , suggestAn NE-induced cardiac output effect might be another reason for the improvement in the microcirculation: rapidly achieving a sufficient perfusion pressure could increase cardiac output in septic shock patients . GeorgerIn our study, fluid resuscitation was performed according to the guidelines to maintain a CVP of more than 8 mmHg and central venous oxygen saturation of more than 70% before patients were enrolled, and the basal measurements were taken after a MAP of 65 mmHg was achieved by fluids and NE. This differs from other studies where baseline measurements were taken in the unresuscitated septic shock patients. As a result, the sublingual microcirculation at baseline in our study seems to be less altered when compared with other studies. However, they were similar to microcirculatory parameters in resuscitated septic shock patients ,12,22.Considerable microcirculatory interpatient variations are reported in septic shock patients after MAP titration despite fluid resuscitation ,26, whicOur study has some limitations. Firstly, cardiac output was monitored by the NICOM system to minimize operative invasion. Although the most widely trusted technology for measuring cardiac output is still bolus thermodilution, NICOM is found to have similar monitoring capabilities compared with bolus thermodilution ,28. SecoIt is also important to note that this study is not a controlled study, and lacks a control group and a return to baseline blood pressure. Each patient, therefore, served as his/her own control when increasing MAP from 65 mmHg to the usual level. In addition, the lack of normotensive controls makes the results difficult to extend to normotensive subjects. However, there are several studies ,12 focusIn this open-label intervention study, increasing MAP from 65 mmHg to the usual level in patients was associated with improved microcirculatory function in septic shock patients with previous hypertension.Increasing MAP from 65 mmHg to the usual level in patients by NE was associated with increased CVP, cardiac output and central venous oxygen saturation in hypertensive septic shock patients.Increasing MAP from 65 mmHg to the usual level in patients by NE was associated with increased small perfused vessel density, proportion of small perfused vessels, and small microvascular flow index in hypertensive septic shock patients.


Diabetes Mellitus (DM) affects the cardiovascular response of patients. To study this effect, interbeat intervals (IBI) and beat-to-beat systolic blood pressure (SBP) variability of patients during supine, standing and controlled breathing tests were analyzed in the time domain. Simultaneous noninvasive measurements of IBI and SBP for 30 recently diagnosed and 15 long-standing DM patients were compared with the results for 30 rigorously screened healthy subjects (control). A statistically significant distinction between control and diabetic subjects was provided by the standard deviation and the higher moments of the distributions  with respect to the median. To compare IBI and SBP for different populations, we define a parameter, α, that combines the variability of the heart rate and the blood pressure, as the ratio of the radius of the moments for IBI and the same radius for SBP. As diabetes evolves, α decreases, standard deviation of the IBI detrended signal diminishes , skewness with respect to the median approaches zero , and kurtosis increases (fluctuations concentrate around the median). Diabetes produces not only a rigid heart rate, but also increases symmetry and has leptokurtic distributions. SBP time series exhibit the most variable behavior for recently diagnosed DM with platykurtic distributions. Under controlled breathing, SBP has symmetric distributions for DM patients, while control subjects have non-zero skewness. This may be due to a progressive decrease of parasympathetic and sympathetic activity to the heart and blood vessels as diabetes evolves. Cardiovascular dysfunction is a common Diabetes Mellitus (DM) complication due to autonomic neuropathy –5. It haThe quantification of cardiovascular function in DM usually is performed through the standard cardiovascular reflex tests established by the American Diabetes Association , 18: supThe objective of this study is to evaluate the influence of DM type II disease on the heart rate and blood pressure variability. Hence, we investigated how cardiac dynamics changes in patients with DM type II by analyzing in the time domain the characteristics of IBI and SBP records simultaneously taken from subjects during clinostatism, orthostatism and controlled breathing tests. As far as we know, this is the first global analysis involving simultaneous IBI and SBP variability data using measures in the time domain to compare control subjects, recently diagnosed and long-standing DM patients.All subjects provided written informed consent, underwent a screening history and physical examination. The patients with diabetes were part of a cohort of patients with metabolic syndrome who underwent a yearly glucose tolerance test. The Ethics’ Committee of the Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” approved the protocol for data recording. DM patients had a medical diagnosis by an expert, with blood glucose levels larger than 200 mg/dL at two hours in a glucose tolerance test, in agreement with the “Asociación Mexicana de Diabetes” and the 2011 “American Diabetes Association” recommendations .This study did not consider the effects of age and gender because HRV of healthy subjects only shows small differences in standard deviation between young and old subjects and are independent of gender . Body ma® device (The Netherlands) to record simultaneously the blood pressure and the heart rate from:Data were taken with a Portapres2 (with a mean and standard deviation of 24±3 kg/m2), and from 21 to 50 years old (33±8 yr). Subjects were classified as healthy if they did not smoke, had no cardiac diseases, and did not take medication. They were not hypertensive and had blood pressure levels of 120/80 mmHg or less.30 healthy control subjects, 17 female, 13 male, with a BMI from 19.1 to 28.5 kg/m2 (27±2 kg/m2), and between 38 and 48 years old (41±5 years). These recent DM patients have been screened regularly every year with an oral glucose tolerance test of 75 g for two hours. In their previous medical examination (done at most 2 years before the diagnosis), they were considered to have metabolic syndrome but did not take medications.30 patients with recently diagnosed DM type II, 16 female, 14 male, with BMI from 25.8 to 29.4 kg/m2 (27±6 kg/m2), and between 20 and 76 years of age (53±18 yr).15 patients with long-standing DM type II diagnosed 15±9 years previous to the present study, 10 female, 5 male, with BMI from 18.1 to 36.8 kg/m® equipment.Control subjects and DM patients abstained from caffeine, beta-blockers, anticholinergics, antihistamines, opioids and adrenergic medication for the 48 hours before the test. IBI and SBP were registered simultaneously while the subject was in supine position (clinostatic record) for 5 minutes. Subjects were made to stand up, relaxed for 1 minute and stayed in this position for a 5 minutes standing registration (orthostatic record). Finally, a controlled breathing test at 0.1 Hz was done . Data consisted of short-term 5 minutes recordings measured non-invasively with the PortapresSignals were detrended to avoid artificial contributions and to take out long oscillations with periods larger than the recording time of 5 min, i.e., with frequencies smaller than 0.04 Hz, known as very long frequency (VLF). In the literature it is recognized that VLF oscillations are due to regulatory mechanisms such as thermoregulation, while the autonomous nervous system is responsible of the heart rate oscillations from 0.04 to 0.4 Hz ,12. In FN is the number of data points recorded, summation is over all data points xi, and N). Since variance is equal to the total power of spectral analysis, it reflects all the cyclic components responsible for variability in the recording period [Traditionally, in the time domain, HRV is measured by the standard deviation (SD) of the interbeat intervals (IBI) , i.e. thg period .sk, as the third moment with respect to the median instead of the mean:m is the median, a quantity not as strongly affected by outliers or large deviations in the data, which is defined as the central value after the observations have been sorted in increasing order.In the temporal domain, histograms of IBI for control subjects have a marked asymmetry toward the right hand side of the distribution , 41. It Another useful measure of the distribution, not widely used to analyze IBI and SBP time series, is the kurtosis, κ (the fourth moment) , a measuFor a Gaussian , the kurtosis is zero, while positive κ corresponds to a leptokurtic distribution (more peaked than a Gaussian) and negative κ describes a platykurtic one (flatter than a Gaussian).® 2015, 64 bits and independently checked using a code written in Python® 2.7.7. We evaluated the first four moments for the IBI and SBP time series distributions. The IBI median is inversely proportional to the heart rate. Here we are interested only in the fluctuations of the heart rate, evaluated after the IBI time series is detrended. The standard deviation of the detrended IBI time series is one of the HRV measures of vagal and sympathetic modulation; skewness with respect to the median as a measure of symmetry reflects the balance of vagal and sympathetic effects, while the kurtosis measures the concentration of the data around the median and reflects the rigidity of the heart rate. Blood pressure variability is also analyzed through the SBP detrended time series, where also standard deviation, skewness with respect to the median and kurtosis are evaluated.Here, graphs and statistical parameter calculations were done mainly using OriginProIn order to compare the simultaneous IBI and SBP records, we define an α parameter as the ratio between the sk and κ are required to describe fine details of variability of a signal and the concept of sk-κ space. This is a useful way of synthesizing the various moments in a single measure in which the squaring of the quantities amplifies differences. Finally, SD has units whereas sk and κ are without units; therefore, we use the adimensional quantity SD/m  in order to be able to combined it with sk and κ in a single formula. This also allows to compare individuals with distinct heart rate baseline due to different SD on IBI.The definition of the α parameter can be explained as follows. A high heart rate variability (IBI) is considered being a protective factor for health and a low heart rate variability as a risk factor, whereas for blood pressure variability (SBP) the opposite appears to be true; therefore, we propose that in a single α parameter both heart rate and blood pressure risk factors can be quantified. Furthermore, as discussed above, successive moments of SD, ® normality test). Student’s t test was used to compare the different study groups of control subjects, recently diagnosed DM patients, and long-standing DM patients. A value of p<0.05 was considered statistically significant in the hypothesis test of different means of the moments  and the α parameter.Even when the histograms for each subject have tails and do not follow Gaussian distributions, the distributions of the moments for each group of study  are Gaussians  proved a statistically significant difference between control and long-standing DM patients, although there is an overlap due to the large variability in the statistics between subjects. Thus, the clinostatism test indicates that as DM evolves a more rigid cardiovascular response is produced, and IBI´s time series become more symmetric due to a loss of balance between vagal and sympathetic influence on the heart rate. The majority of the IBI values are on the right hand side with respect to the median reflecting a predominance of the vagal influence. In the standing up test only IBI’s kurtosis population average changes  under all tests for heart rate variability are summarized in  changes  from pos changes  from zersk proved a statistically significant difference between control, recently diagnosed and long-standing DM patients; under clinostatism and orthostatism κ population average is statistically significant different for control and long-standing DM subjects. There is no difference on SBP’s SD and on κ under controlled breathing test. For all tests, SBP’s skewness population average . It is important to note that long-standing DM patients usually take medications that regulate their glucose levels and blood pressure, and this could also help to adjust the fluctuations of their blood pressure as our measures of SBP variability show. In concordance with the physiological studies of Guyton and his group , 44 in dMoreover, the loss of balance between vagal and sympathetic influence on HRV also alters the high protective factor HRV and the low risk factor of the blood pressure variability in DM patients as reflected by the statistically significant difference between the α parameter for healthy subjects and DM patients under clinostatism. As DM evolves, the variability of the α parameter decreases reflecting that the system is more rigid. Thus, the α parameter seems to make a statistically significant distinction between healthy and DM individuals under clinostatism test. During this test, control subjects have higher values of α with large SD, indicating large intrapopulation variability. As DM evolves, α diminishes not only in value but also in variability, that is, the population becomes more homogeneous. The α parameter indicates that not only the heart response becomes more rigid, but also the variability of the blood pressure increases, in agreement with HRV being a protective health factor and blood pressure variability a risk factor.The analysis of IBI and SBP detrended time series in the time domain shows that all moments of the distribution are relevant parameters that allow significant differentiation between control subjects, recently diagnosed, and long-standing DM patients. In this paper it is shown that in the case of IBI, skewness and kurtosis with respect to the median are as effective parameters as the standard deviation in order to establish statistically significant differences between groups. As DM evolves, skewness with respect to the median tends to zero (increased symmetry), standard deviation decreases (higher rigidity), kurtosis also vanishes (data becomes more concentrated around the mean), and the distribution becomes more Gaussian. It is also important to notice that the dysfunction produced by DM gradually alters the relation between IBI and SBP response as shown by the decrease on α (defined here as the ratio between radius of IBI and SBP’s moments). The proposed α parameter can help to distinguish health from diabetes illness using a controlled breathing test. Moreover, for long-standing DM patients α has the same value under all tests reflecting the difficulty that these patients have in adapting to different stimulus. The data of this study shows that long-standing DM patients have considerable autonomic dysfunction. The heart rate variability data suggests that autonomic modulation of the heart is affected in long-standing diabetes, as shown by the reduction in standard deviation (increase in rigidity), skewness with respect to the median , and kurtosis (change to more leptokurtic distributions). Given that a reduction in heart rate variability indicators has been linked to an increased all-cause and cardiac mortality, it is quite likely that patients with diabetes who have a Gaussian HRV have deteriorated from an autonomic viewpoint and indicates that the autonomic neuropathy is progressive. These patients are probably at an increased risk of mortality. The analysis in this study is relatively simple to perform in patients, since it only employs the moments of the distributions and their ratios, so it can easily be adapted to clinical inspection.


Extensive data from many randomised, controlled trials have shown the benefit of treating hypertension (HTN). The target blood pressure (BP) for antihypertensive management is systolic < 140 mmHg and diastolic < 90 mmHg, with minimal or no drug side effects. Lower targets are no longer recommended. The reduction of BP in the elderly should be achieved gradually over one month. Co-existent cardiovascular (CV) risk factors should also be controlled.Reduction in risk of stroke, cardiac failure, chronic kidney disease and coronary artery disease.ab initio if the BP is ≥ 160/100 mmHg. In black patients, either a diuretic and/or a CCB is recommended initially because the response rate is better compared to an ACEI. In resistant hypertension, add an alpha-blocker, spironolactone, vasodilator or β-blocker.Correct BP measurement procedure is described. Evaluation of cardiovascular risk factors and recommendations for antihypertensive therapy are stipulated. Lifestyle modification and patient education are cornerstones of management. The major indications, precautions and contra-indications are listed for each antihypertensive drug recommended. Drug therapy for the patient with uncomplicated HTN is either mono- or combination therapy with a low-dose diuretic, calcium channel blocker (CCB) and an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB). Combination therapy should be considered The guideline was developed by the Southern African Hypertension Society 2014©. This is the sixth hypertension guideline published by the Southern African Hypertension Society (SAHS). Currently 30.4% of the adult population have hypertension (HTN),2The objective of this guideline was to promote evidencebased, accessible and comprehensive management of HTN by healthcare professionals in the public and private sectors. Applicable HTN and CVD treatment and prevention guidelines were reviewed as well as HTN trials reporting clinical end-points, including those with individuals with important co-morbidities such as diabetes mellitus and chronic kidney disease.9HTN is defined as a persistent elevation of office blood pressure (BP) ≥ 140/90 mmHg BP measurement is a vital clinical sign that is poorly performed by all healthcare professional categories. These recommendations apply to both clinic and self-measurement of BP. Failure to follow these guidelines leads to significant errors in BP measurement. BP should be recorded using an approved and calibrated electronic device or mercury sphygmomanometer Self BP measurement (SBPM) and ambulatory BP measurement (ABPM) are recommended in selected circumstances and target groups:11• suspected white-coat HTN (higher readings in the office compared with outside) or masked HTN • to facilitate diagnosis of HTN• to guide antihypertensive medication, especially in high-risk groups, e.g. elderly, diabetics• refractory HTN• to improve compliance with treatment (SBPM only).Masked HTN should be suspected if, despite a normal BP in the clinic, there is evidence of target-organ damage.http://afssaps.sante.fr.All devices used for SBPM and ABPM should be properly validated in accordance with the following independent websites: or In general, only upper-arm devices are recommended, but these are unsuitable in patients with sustained arrhythmias. For SBPM the patient should take two early morning and two late afternoon/early evening readings over five to seven days, and after discarding the first day readings, the average of all the remaining readings is calculated.Wrist devices are recommended only in patients whose arms are too obese to apply an upper arm cuff. The wrist device needs to be held at heart level when readings are taken.The advantages of SBPM measurement are an improved assessment of drug effects, the detection of causal relationships between adverse events and blood pressure response, and possibly, improved compliance. The disadvantages relate to increased patient anxiety and the risk of self-medication.ABPM provides the most accurate method to diagnose HTN, assess BP control and predict outcome.The appropriate cut-off levels for diagnosis of HTN by SBPM and ABPM are listed in 11Despite efforts to promote proper techniques in manual BP measurement, it remains poorly performed. Automated office BP measurement offers a practical solution to overcome the effects of poor measurement, bias and white coating.14The principle of assessing and managing multiple major risk factors for CVD is endorsed. However, because the practical problems in implementing previous recommendations based on the European Society of HTN (ESH) and the European Society of Cardiology (ESC) HTN guidelines, it has been decided to use a modification of this approach.9Once the diagnosis of HTN is established, patients with BP ≥ 160/100 mmHg should commence drug therapy and lifestyle modification. Patients with stage 1 HTN should receive lifestyle modification for three to six months unless they are stratified as high risk by the following criteria: three or more major risk factors, diabetes, target-organ damage or complications of HTN There has been considerable controversy about BP goals and SAHS accepts that to simplify management, a universal goal of antihypertensive treatment is < 140/90 mmHg regardless of CV risk and underlying co-morbidities.15SAHS does not support the JNC-8 committee recommendations of a goal BP < 150/90 mmHg for persons over 60 years without diabetes and CKD, as (1) increasing the target will probably reduce the intensity of antihypertensive treatment in a large population at high risk for cardiovascular disease, (2) the evidence supporting increasing the SBP target from 140 to 150 mmHg in persons aged 60 years or older was insufficient, (3) the higher SBP goal in individuals aged 60 years or older may reverse the decades-long decline in CVD, especially stroke mortality.16It is also essential to control hyperlipidaemia and diabetes through lifestyle and drug therapy, according to the Society for Endocrine Metabolism Diabetes of South Africa and South African Heart Association/Lipid and Atherosclerosis Society of Southern Africa guidelines, respectively.If the SBP is ≥ 180 mmHg or the DBP is ≥ 110 mmHg then refer to section 8 on severe (grade 3) HTN, as this section does not apply.All patients with HTN should receive lifestyle counselling as outlined in Before choosing an antihypertensive agent, allow for considerations based on the cost of the various drug classes, patient-related factors, conditions favouring use and contraindications, complications and target-organ damage (TOD) Tables , 7.ab initio if BP is ≥ 160/100 mmHg In otherwise uncomplicated primary HTN, the initial first choice of antihypertensive drug is a diuretic (thiazide-like or thiazide), ACEI or ARB, and/or CCB used as mono- or combination therapy In black hypertensive patients a diuretic and/or a CCB is recommended.Patients with severe HTN  may fall into one of three categories, which determine the urgency of their treatment. Patients should be managed or referred to the appropriate level of care and caregiver in accordance with local resources. Sustained, severe HTN requires immediate drug therapy and lifestyle modification, and close follow up.These patients are asymptomatic but have severe HTN without evidence of progressive TOD or complications. The patient must be kept in the care setting and BP measurement repeated after resting for one hour. If still elevated at the same level, commence oral therapy using two first-line drugs. Follow up within a week or earlier, with escalation of treatment as needed. Early referral is advised if BP is not controlled within two to four weeks.While not common, hypertensive emergencies and urgencies are likely to be encountered by all clinicians because of the high prevalence of chronic HTN. It is essential that all professionals are familiar with treatment. There is a paucity of information from well-conducted studies on the outcomes of various antihypertensive drugs and BP-lowering strategies.This level of HTN is symptomatic, usually with severe headache, shortness of breath and oedema. There are no immediate life-threatening neurological, renal, eye or cardiac complications, such as are seen in hypertensive emergencies. Ideally, all patients with hypertensive urgency should be treated in hospital.Commence treatment with two oral agents and aim to lower the diastolic BP to 100 mmHg slowly over 48 to 72 hours. This BP lowering can be achieved with the use of: (1) long-acting CCBs; (2) ACEI, initially used in very low doses, but avoid if there is severe hyponatraemia ; (3) β- blockers; and (4) diuretics.A hypertensive emergency is severe, often acute elevation of BP associated with acute and ongoing organ damage to the kidneys, brain, heart, eyes (grade 3 or 4 retinopathy) or vascular system. These patients need rapid (within minutes to a few hours) lowering of BP to safe levels. Hospitalisation is ideally in an intensive care unit (ICU) with experienced staff and modern facilities for monitoring. If an ICU is unavailable, the patient may be closely monitored and treated in the ward.Intravenous antihypertensive therapy, tailored to the specific type of emergency, has become the standard of care. Labetalol, nitroprusside or nitroglycerin are the preferred intravenous agents. Overzealous lowering of BP may result in stroke. A 25% reduction in BP is recommended in the first 24 hours. Oral therapy is instituted once the BP is more stable. Although most adult patients with a hypertensive emergency will have BP > 220/130 mmHg, it may also be seen at modest BP elevations; for example, in a previously normotensive woman during pregnancy (eclampsia) or in the setting of acute glomerulonephritis, especially in children.Severe HTN associated with ischaemic stroke and intracerebral haemorrhage should be managed according to the recommendations of the Neurological Association of South Africa.HTN that remains > 140/90 mmHg despite the use of three antihypertensive drugs in a rational combination at full doses and including a diuretic (hydrochlorothiazide 25 mg or indapamide 2.5 mg) is known as resistant HTN. Common causes of resistant HTN are listed in The therapeutic plan must include measures to ensure adherence to therapy and lifestyle changes. Unsuspected causes of secondary HTN are less common, but need to be considered based on history, examination and special investigations. It is essential to exclude pseudo-resistance by performing SBPM or 24-hour ABPM. Referral to a specialist is often indicated for a patient with resistant HTN.Once the issues relating to lifestyle, adherence to therapy, white coating, etc. outlined in Initial studies of renal denervation in patients with resistant HTN showed very promising results.31Blacks are more prone to complications of stroke, heart failure and renal failure, while the incidence of coronary heart disease, although increasing in frequency, is less common compared with that in whites and Asians.33Compared to whites, blacks respond poorly to ACEI and β-blockers as monotherapy, but this difference disappears once these drugs are combined with diuretics. Overall, CCBs show the most consistent response in blacks compared to other classes of drugs used as monotherapy.35HTN in children is an important issue beyond the scope of this guideline. In adolescents, the HTN is increasingly linked to obesity and affects up to 10% of people between the ages of 15 and 25 years.There are an estimated 5.8 million people living with HIV in South Africa. The co-existence of HIV with HTN and diabetes is increasing, and patients should be screened for associated glomerulonephritis.Two of the three major classes of antiretroviral drug, the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors, are involved in many drug interactions by inhibiting or inducing the key hepatic enzyme system, cytochrome P450. CCBs are the major class of antihypertensives affected by such drug interactions, leading to inhibition or induction of their metabolism.This national clinical guideline is a reference and educational document. The SAHS accepts no responsibility or liability arising from any information contained in or any error of omission from the protocol or from the use of any information contained in it.


Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease in developed countries and its prevalence has increased dramatically in the past few decades. These patients are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and the development of end-stage renal disease remain major concerns in diabetes. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) results in progressive renal damage. RAAS blockade is the cornerstone of treatment of DKD, with proven efficacy in many arenas. The theoretically-attractive option of combining these medications that target different points in the pathway, potentially offering a more complete RAAS blockade, has also been tested in clinical trials, but long-term outcomes were disappointing. This review examines the “state of play” for RAAS blockade in DKD, dual blockade of various combinations, and a perspective on its benefits and potential risks. In 1563, the earliest recorded mention of the adrenal gland is Bartolomeo Eustacchio’s copper-etched depiction of “glandulae Renibus incumentes” [In 1898, Robert Tigerstedt, a finnish medical scientist and physiologist, and his student, Per Bergman, made extracts of rabbit kidney, injected them into rabbits, and observed that even a very small amount of the extract increased blood pressure. Their results suggested the kidneys produced a protein, which they named renin, which caused a rise in blood pressure.In 1939, renin was found not to cause the rise in blood pressure by Irvine Page, but was an enzyme which catalyzed the formation of the substances that were responsible, namely “angiotonin or hypertenisin” (angiotensin), a pleiotropic hormone with several targets, including the kidneys, blood vessels, and nervous system.In 1953, aldosterone (“electrocortin”) was first isolated by Simpson and Tait.History of discovery and development of RAAS and their blockers is summarized in In a patient, it is now possible to inhibit renin directly with DRIs, to block the conversion of angiotensin I to angiotensin II with ACEIs, to block the major downstream targets of Angiotensin II with ARBs, and to blocks the action of aldosterone with AAs.Dysregulation of the RAAS has a critical role in the pathogenesis of CKD. There is an increase of glomerular capillary pressure due to continuous stimulation from the RAAS, which enhances oxidative stress and stimulates pro-inflammatory pathways. These mechanisms promote glomerular hypertrophy, which is present at an early stage of DKD and is the beginning of profibrotic cascade .ACEIs and ARBs block the production and formation of angiotensin II, therefore improving kidney and cardiovascular diseases . Reducinin vivo studies have shown that blockade of the RAAS with either ACEIs or ARBs leads to down-regulation of AGE, TGF-b, NADPH oxidase, ROS, reduced RAGE expression, reduced type IV collagen excretion, reduced mesangial extracellular matrix accumulation, reduced glomerulosclerosis, and albumin creatinine ratio [Several experimental, animal, and ne ratio ,9,10.These findings have been translated into several landmark clinical trials, demonstrating the beneficial effects of ACEIs and ARBs in DKD ,11,12.The rate of development of renal complications is thought to be more or less similar in type 1 (T1DM) and type 2 (T2DM) diabetes. However, after ten years of follow-up only 20% of T2DM patients with microalbuminuria progress to overt nephropathy in contrast to over 80% of T1DM patients. In addition, DKD can progress in the absence of albuminuria, suggesting that other tissue-destructive pathways might also have a role in the decline in renal function .Since the beginning of their use, several studies have demonstrated that ACEI therapy promotes regression to normoalbuminuria, decreases progression to overt DKD, and slows the rate of progression in DKD ,15, indeCollaborative Study Group trial [In 1993, the first trial to evaluate RAAS blockade on CKD progression was the up trial , perform [ [versus 23.1%). In one of these trials [In 1994 y Group)  and 1996y Group) , in two e trials , albumin trial [In 1994, EUCLID s) trial  was perfIn 2005, a systematic review of 11 trials  of normoData are lacking on the efficacy of ARBs in patients with T1DM and moderately increased albuminuria. It seems likely that these drugs are as effective as ACEIs given their proven benefit in patients with T2DM and either moderately increased albuminuria or overt nephropathy.(Renin Angiotensin System Study) [In 2009, RASS m Study)  trial wa [versus 5% and 16% versus 16% in the prevention and progression arms, respectively) or in the annual rate of increase in urinary albumin excretion. There was an overall trend to less severe retinopathy.In 2009, DIRECT  Trials)  was perfThere is no evidence that ACEIs or ARBs are effective for the primary prevention of moderately-increased albuminuria in T1DM patients who are normoalbuminuric and normotensive:Among T2DM patients with normal urine albumin excretion <30 mg/24 h) and preserved GFR, RAAS blockade has been demonstrated to prevent the development of albuminuria in the presence of hypertension, although not without hypertension ,29. Howe mg/24 h versus T1DM:et al. [In 1998, Ravid et al.  reported study [In the 2004, the BENEDICT l) study , was per trial [versus 23.6%) and severely increased albuminuria). However, no clear effect of the therapy on decline in estimated glomerular filtration rate (eGFR) was observed.In 2007, ADVANCE n) trial ,33 was pA similar benefit on the efficacy of ACEI therapy appears to be present in T2DM  trial [versus 9.8%) independently of blood pressure. However, an unexplained excess of cardiovascular mortality was observed in the olmesartan group.In 2011, the ROADMAP n) trial  performe study [In 2001, the IRMA-2 l) study  performe trial [In 2007, in the INNOVATION y) trial , telmisaAmong T2DM patients with microalbuminuria (30–300 mg/24 h), RAAS blockade has been demonstrated to reduce progression to macroalbuminuria (≥300 mg/24 h):Among T2DM patients with established DKD , RAAS blockade has been demonstrated to reduce risk of GFR loss, end-stage renal disease (ESRD), and death ,11,12.(The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study) trial [post hoc analysis [In 2001, RENAAL y) trial  was perfanalysis , albuminanalysis , neither [In 2005, IDNT y Trial) ,39 studyy Trial) ,41,42. trial [vs. 5.3%) was observed in the olmesartan group.In 2011, ORIENT l) trial , was perThere is more data available on the preferential renoprotective efficacy of ARBs:2, randomly assigned to enalapril or telmisartan. At five years, there was a not significant decline in GFR in the enalapril group (14.9 versus 17.9 mL/min per 1.73 m2 with telmisartan). Both groups had similar rates or findings for the secondary endpoints .In 2004, DETAIL trial  was perfACEIs are at least as effective as ARBs in diabetic patients with established DKD.In 2012, a meta-analysis by Hirst  of 49 rapost hoc analyses) involving 41,042 patients, reviewed whether RAAS blockade is beneficial for cardiovascular outcomes in patients with diabetes mellitus. RAAS blockade significantly reduced the risk of major cardiovascular events and myocardial infarction and there was no statistically significant trending towards fewer strokes and lower all-cause mortality.In 2012, another meta-analysis published by Nakao  of 19 raOnly a few long-term head-to-head studies have been designed to compare the effects of ARBs and ACEIs on the progression of DKD ,47. One In view of the existing evidence showing that RAAS blockade slows the progression of renal disease, ACEIs or ARBs are currently recommended for the treatment of early and late-stage DKD . The benAfter multiple studies showed the kidney-protective effects of RAAS inhibitors in patients with DKD and overt proteinuria, a common hypothesis was that combination therapy with an ARB and an ACEI would result in more complete inhibition of RAAS and, therefore, offer greater kidney and cardiovascular protection. If RAAS blockade monotherapy is good, the logical next question is, would combination therapy by acting on different points in the RAAS system be better? .Any single RAAS inhibitor does not completely block every step of the RAAS cascade. Greater down-regulation of the RAAS, as a whole, might be a consequence of RAAS blockade at different levels. In that order, potential lower doses of individual RAAS inhibitors could results in diminished adverse effects .During chronic ACEI therapy, the increase of angiotensin I levels can be converted to angiotensin II, this leads to further generation of aldosterone: adding an ARB could counteract the effects of the residual angiotensin II.During chronic ARB therapy, angiotensin II levels are elevated in addition to renin and angiotensin I, which can lead to angiotensin II competing with the ARB for the angiotensin II type 1 receptor, and angiotensin II binding to angiotensin II type 2 receptors on the adrenal glands, leading to the secretion of aldosterone .Finally, plasma potassium increases due to both the ACEIs and the ARBs .The “Aldosterone escape” was observed in many patients treated with a single RAAS blockade. Aldosterone baseline levels increased within 6–12 months in 30%–40% of the patients .During Many patients with macroalbuminuria despite being treated with single RAAS blockade presents “residual albuminuria”, setting a higher risk for the evolution of a chronic kidney disease, cardiovascular disease, and death ,53. ObseThe three pathophysiologic rationales for dual RAAS blockade are :Any sinThere are other drugs that reduce albuminuria but do not improve long-term renal and cardiovascular outcomes.Diabetic nephropathy can progress in the absence of albuminuria, suggesting that other tissue-destructive pathways might also have a role in the decline in renal function .This uncertainty is reflected by the US FDA’s reluctance to accept albuminuria reduction as an end point for approving new therapies and leaves the optimal clinical response to residual albuminuria unclear .Nevertheless, is albuminuria causally related to progressive kidney and cardiovascular disease, or is it simply a marker of intrinsic risk that cannot be modified with therapy?et al. [In 1997, Menard et al.  first re study, performed in 199 hypertensive, T2DM and microalbuminuric patients. After 12 weeks of treatment, the combination of submaximal doses of lisinopril (20 mg), and candesartan (16 mg) led to a 50% reduction in albuminuria as compared with monotherapy in maximal doses, leading to a reduction of 24% and 39%, respectively. Dual therapy resulted in ~9–11 mmHg and 5–6 mmHg reduction in systolic and diastolic BPs, over monotherapy.In 2000, Mogensen and colleagues  publisheIn 2003, Jakobsen and colleagues , in 24 p(The Irbesartan in the Management of Proteinuric Patients at High Risk for Vascular Events) study [In 2007, IMPROVE s) study , a randoversus placebo plus ARB, the addition of an ACEI-reduced albuminuria by 24%; and analyzing seven clinical trials of ARB plus ACEI versus placebo plus ACEI, the addition of an ARB reduced albuminuria by 22%. The authors concluded that dual RAAS blockade seemed more effective in reducing proteinuria than either class of agent alone, but they also concluded that many of the smaller studies did not provide reliable data on adverse events, limiting the clinical applicability of the concept at that time.In 2008, Kunz and colleagues  publisheFrom 2000s, several trials with hard outcomes demonstrated dual RAAS blockade, compared with either therapy alone, improved control of blood pressure and may induce a greater reduction in protein excretion ,56. ThesIn the case of dual RAAS blockade there was, for a long time, excitement about initial findings, and the treatment approach was adopted by many clinicians. Furthermore, as combination of ACEI and ARB has gained popularity in the primary care setting, the question of which patients now require withdrawal of combination therapy arises commonly . It is iDespite the lack of robust evidence on long-term efficacy and safety, dual RAAS blockade has been embraced as a treatment option and has been recommended by experts and even in some clinical guidelines: 2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC Task Force on the management of arterial hypertension , ACCF/AH trial [versus 2.2%) and higher rates of acute kidney injury requiring dialysis (1.4% versus 0.8%), hyperkalemia (11.3% versus 7.8%), hypotension (2.8% versus 1.9%) and diarrhea. They conclude “…The combination of the two drugs was associated with more adverse events without an increase in benefit…”.In 2008, the ONTARGET t) trial ,62 was p(Veterans Affairs Nephropathy in Diabetes) trial [2) and compare combination losartan (100 mg/d) and lisinopril (10 to 40 mg/d) therapy with losartan alone. It must be discontinued after a median of 2.2 years because of a significantly higher frequency of acute kidney injury requiring hospitalization (18% versus 11%) or severe hyperkalemia (9.9% versus 4.4%). They conclude “…the results of our study show that the use of combination therapy with an ACE inhibitor and an ARB in patients with proteinuric diabetic kidney disease is associated with an increased risk of adverse events and does not provide an overall clinical benefit…”.In 2013, the VA NEPHRON-D s) trial , was perEnthusiasm regarding the promising effects of dual RAAS blockade on surrogate outcomes in small, short-term studies has been tempered by the disappointing results of large trials with hard outcomes. Randomized studies designed to test additional renal protection and safety, unexpectedly showed increased risk of adverse outcomes and events such as AKI, hyperkalemia, and/or need for dialysis:versus placebo in the RENAAL trial [These data from large, independent clinical trials demonstrate that even in patients with established nephropathy, dual RAAS blockade fails to afford renoprotection. In addition, an interesting subgroup analysis of the ORIENT trial showed that olmesartan therapy provided renoprotection in the absence of background ACEI therapy . The 16%AL trial . HoweverAL trial .KDIGO clinical practice guidelines discourage the use of dual RAAS blockade for the prevention and treatment of DKD [Thus, it seems that combination therapy with an ACEI plus an ARB should not be used in patients with DKD: it does not prevent renal disease progression or death, and it increases the rate of serious adverse events. Therefore, the authors of the t of DKD .An increase in plasma renin activity during ACEI or ARB treatment as a result of compensatory mechanisms can limit the efficacy of these therapies . As reni trial [In 2008, AVOID s) trial , perform trial [versus 5.9%) and adverse events requiring cessation of therapy  were significantly more frequent (13.2% versus 10.2%) in the aliskiren group.In 2012, ALTITUDE s) trial , performIn 2012, Harel and colleagues  publishevs. valsartan monotherapy assessed blood pressure control. After two months combination therapy yielded significantly better blood pressure lowering. Safety events were similar in both groups, with no increased incidence of hyperkalemia in the combination therapy group.In 2013, the VIVID study , performInitial exploratory studies in patients with DKD showed that aliskiren reduces proteinuria and blood pressure, independently of each other . Moreovei.e., where GFR <60 mL/min). The European Medicines Agency has issued similar warnings.Thus, the use of aliskiren in combination with either an ACEI or ARB does not appear to preserve renal function and increases the risk of adverse events, at least in advanced nephropathy. In April 2012, the FDA recommended a new contraindication against the use of aliskiren with ARBs or ACEIs in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia, and a warning to avoid the use of aliskiren with ARBs or ACEIs in patients with moderate to severe renal impairment  on epithelial sodium channels, which are located on cortical collecting duct cells in the distal nephron. Additionally, there is increasing evidence that aldosterone is directly involved in the development and progression of renal disease via nonepithelial MR-mediated effects. Aldosterone exerts profibrotic effects through increased production of TGF-beta, reactive oxygen species, PAI-1 and increased collagen gene expression and synthesis, which can be abolished by MR blockade .RAAS blockade initially decreases circulating aldosterone levels, but suppression will not be sustained in 10%–50% of patients, a phenomenon called “aldosterone breakthrough” . This isIn line with this hypothesis, studies in patients with chronic kidney disease and early DKD show that MRA blockade on top of ACEI and/or ARB blockade exerts added renoprotective effects. Interestingly, the reduction in albuminuria induced by the addition of spironolactone to ACEI was related to aldosterone levels . This suIn spite of these encouraging results on albuminuria, long-term data on the efficacy of MR blockade on hard endpoints, for example the development of ESRD or patient survival, are still lacking.In 2006, the only long-term study performed to date of add-on spironolactone therapy in diabetic and nondiabetic patients with proteinuria showed that the agent induced an initial acute fall in eGFR that predicted a later beneficial effect on decline in renal function and a remarkable and sustained reduction in proteinuria .In 2008, effects on albuminuria were summarized in a systematic review . Fourteeversus losartan was not reported.In 2009, Medhi and colleagues published a placebo-controlled trial  performe2), already treated with an ACEI randomly assigned to eplerenone (50 or 100 mg/d) or placebo. Patients treated with eplerenone therapy present a significant reduction in albuminuria (40%–50% versus <10%). Severe hyperkalemia (>6 meq/L) occurred in 9% and 23% of patients receiving 50 and 100 mg/d of eplerenone, respectively, compared with 12% of patients in the placebo group.In 2006, Epstein and colleagues examined the efficacy and safety of eplerenone in a trial  of 268 pIn 2014, a meta-analysis of eight trials and 404 patients , combineThe eventual benefit of aldosterone blockade was then studied in various experimental models of diabetic nephropathy. MRAs appear to reduce proteinuria when used alone , and to There is no long-term data regarding the benefit with the combination of ACEI or ARB and MRA in terms of slowing the rate of loss of GFR, so the role of the aldosterone blocker is unclear in CKD progression. Reduction in albuminuria is not a validated surrogate for slowing nephropathy progression and the risk of inducing or aggravating hyperkalemia may limit the use of aldosterone antagonists although the risk of hyperkalemia may possibly be lower with an ARB . WhetherWith the publication of recent endpoint trials, the tide has shifted because of higher rates of side effects and no clear benefit. Although it can be argued that the ONTARGET study population is heterogeneous with a cardiovascular rather than kidney risk profile, that the ALTITUDE study is only investigating one possible combination of RAAS treatment, and that the VA NEPHRON D study was much smaller, the conclusion so far on the basis of three hard endpoint studies must be, until hard endpoint trials tells us otherwise or until we know more about which patients to select for combination treatment, that any combination using renin inhibition, ACEIs, or ARBs is not advisable. In the case of combinations with aldosterone receptor blockade, hard endpoint trials are still lacking; however, more data and information on this topic are sure to come .In a study  of 30 paA similar antiproteinuric effect has been demonstrated with combination therapy with verapamil and trandolapril . But theNondihydropyridine calcium channel blockers (diltiazem and verapamil) appear to be as effective as an ACEI or ARB in lowering protein excretion in diabetic patients ,80,81,82Dihydropyridine calcium channel blockers  have a variable effect ranging from increased protein excretion to no effect to a fall in protein excretion in different studies ,39,80,81High sodium intake has been found to blunt the antiproteinuric as well as the antihypertensive response to ACE inhibition, in albuminuric patients.post hoc analysis of the RENAAL and IDNT trials [Moderate salt restriction to 5–6 g/d  has beeT trials , ARB proincreased mortality in patients with heart failure on a very strict sodium diet treated with daily diuretics and fluid restriction, but this paper was retracted soon after publication because of concern over reporting of duplicate data and the inability of the authors to provide the original data for verification.Extremely aggressive sodium restriction on top of single or dual RAAS blockade might elicit adverse renal and cardiovascular events. A meta-analysis from Italy  concludeIf a low-sodium diet is not possible, diuretic therapy with increased furosemide dosage partially corrects the loss of antiproteinuric effect due to a high sodium intake, even in nephrotic patients .RAAS blockade is largely ineffective during states of volume excess or increased sodium intake. Sodium restriction and diuretic treatment increase the top of the dose-response curve to RAAS blockade, and therefore a larger maximum response can be obtained .High soU.S. Renal Data System (USRDS) 2013 Annual Data reported that anti-RAAS therapy, the single most important therapy for DKD, may be underutilized . DespiteThe usage of anti-RAAS treatment decreases as CKD advances. There are few reasons not to maximize anti-RAAS therapy, especially given the fact that these agents are beneficial in reducing albuminuria, in delaying the progression of DKD, in control hypertension, and in heart failure (a common companion of hypertensive DKD patients) . ParadoxThe main reasons wielded by some clinicians not to use RAAS blockade in DKD patients are All patients with DKD should be started on RAAS blockers.It is essential to individualize blood pressure (BP) targets and treatment regimens according to age, coexistent cardiovascular disease, and other comorbidities, risk of progression of CKD, presence or absence of retinopathy, other therapies and tolerance of treatment, with gradual escalation of treatment and close attention to adverse events related to BP treatment, including electrolyte disorders, acute deterioration in kidney function, orthostatic hypotension, and drug side effects.There is insufficient evidence to recommend combining an ACE-I with ARBs to prevent progression of CKD.○In normotensive normoalbuminuric T1DM and T2DM patients, RAAS-inhibiting agents for primary prevention is not justified.○In normotensive microalbuminuric T1DM and T2DM patients, an ARB or ACEI must be used.○In hypertensive microalbuminuric T1DM and T2DM patients, ACEI or ARB monotherapy remains the mainstay of treatment.○Due to the lack of evidence supporting a target blood pressure of less than 130/80 mmHg, we recommend a goal of 140/90 mmHg.○The use of RAAS blockers and a blood pressure of less than 130/80 mmHg is not of proven value for slowing CKD progression.○Dual RAAS blockade should not be routinely applied.Patients with low or moderate risk for progressive kidney disease :○All patients should be treated on RAAS blockers especially those with advanced Stage 3 or higher CKD.○Hypertensive T1DM and T2DM patients must be treated with BP-lowering drugs to maintain a lower blood pressure of less than 130/80 mmHg especially those with more than 1 g of proteinuria and advanced Stage 3 or higher CKD.○Maintaining anti-RAAS therapy for its secondary stroke prevention and antiproteinuric effects must always remain a consideration.○It is recommended that temporary discontinuation of RAAS blockers in patients with GFR <60 mL/min/1.73 m2 who have serious intercurrent illness (particularly in a setting of dehydration such as diarrhoea and vomiting) that increases the risk of acute kidney failure.○Clinicians should carefully weigh the potential benefits of dual RAAS blockade against potential adverse effects including hyperkalemia on an individual basis.Patients at high risk :According to previous studies and the current KDIGO recommendations ,112,113 There are now well-powered primary and secondary trials clearly showing that combined RAAS blockade does not alter the natural history of DKD. Although RAAS blockade has formed the cornerstone of pharmacological management in diabetic nephropathy over the last two decades, we have continued to witness progression of CKD to ESRD. This is not surprising given that they do not block the multiple pathophysiological pathways leading to DKD. It is therefore necessary to look beyond this single pathway in strategies to prevent what is a complex and multifactorial condition.Very hypertensive patient (>160/100 mmHg), excluded from ONTARGET trial, requiring multi-agent therapy (including ACEI/ARB in combination), where CVD risk is directly correlated with BP, any BP lowering would be expected to translate to a significant reduction in CVD-related morbidity and mortality. In a case control study  of 600 pSome of the ONTARGET patients were using therapies proven to have beneficial effects on vascular risk , attenuating any additional benefit from combination ACEI/ARB therapy. However, in clinical practice, many patients do not or cannot take statin treatment and cannot use β-blockers or anti-platelet agents. It is theoretically possible that a greater RAAS blockade would be beneficial in this subgroup of patients who cannot have risk attenuated by other pharmacological means.However, “the devil is in the detail” as says Wong  in a rev“It would still be premature to sound the death knell for dual blockade” . LifestyHence, there remains a clear and growing need for emerging therapeutic strategies and, indeed, there are several agents currently under investigation, targeting other metabolic pathways.Several recent candidates have failed to meet expectations or are now being tested for therapy of DKD: prorenin receptor antagonists, inhibitors of AGE formation , aldose reductase inhibitors (sorbinol and tolerestat), triterpenoid activator of the transcription factor Nrf2 (bardoxolone methyl), glycosaminoglycan (sulodexide), selective vitamin D receptor activator , ET receptor blockers , antioxidant therapy , PKC-b inhibitor (ruboxistaurin), inhibitors of TGF-b production (pirfenidone), recombinant human anti-CTGF monoclonal immunoglobulin G antibody (FG-3019), methyl xanthine derivative (pentoxifylline), anti-TNF-a antibody (Infliximab), inhibitors of Janus kinases (JAK), AGE-crosslink breaker , non-steroidal mineralocorticoid receptor antagonist .The optimal qualities required from an effective novel agent in DKD would be clear additive effects to the benefits of renin-angiotensin aldosterone blockade, tolerability, safety and, ideally, benefits in terms of cardiovascular outcomes.


Blood pressure is one important risk factor for stroke prognosis. Therefore, continuous monitoring of blood pressure is crucial for preventing and predicting stroke. However, current blood pressure devices are mainly air-cuff based, which only can provide measurements intermittently. This study proposed a new blood pressure estimation method based on the pulse transit time to realize continuous monitoring. The proposed method integrated a linear model with a compensation algorithm. A calibration method was further developed to guarantee that the model was personalized for individuals. Variation and variability of pulse transit time were introduced to construct the compensation algorithm in the model. The proposed method was validated by the data collected from 30 healthy subjects, aged from 23 to 25 years old. By comparing the estimated value to the measurement from an oscillometry, the result showed that the mean error of the estimated blood pressure was −0.2 ± 2.4 mmHg and 0.5 ± 3.9 mmHg for systolic and diastolic blood pressure, respectively. In addition, the estimation performance of the proposed model is better than the linear model, especially for the diastolic blood pressure. The results indicate that the proposed method has promising potential to realize continuous blood pressure measurement. It has been reported that ambulatory blood pressure values were linearly related to stroke risk, which has stronger predictive power than screening blood pressure . The prePulse transit time (PTT) has been reported to be correlated with blood pressure, especially for the SBP –17, and Apart from the estimation accuracy, implementation of the estimation model in a device for clinical or healthcare use is the ultimate goal. The linear mapping between PTT and blood pressure has not been proved to provide the best blood pressure estimation. However, it is still the best applicable for coarse blood pressure trend indications . TherefoA previous study pointed out that PTT variability had high coherence with heart rate variability and blood pressure variability , both ofThis study involved 31 healthy subjects (aged from 23 to 25 years) without known cardiovascular abnormalities. The subjects were recruited in a university campus with submitting a written consent with full understanding of the experiment procedure. Each subject was asked to refrain from coffee and alcohol at least 2 hours and instructed about the procedures before conducting the experiment. Then the experiment was carried out in a temperature-controlled room (24 ± 2°C) for all the subjects.For the data collection, standard lead I ECG and reflective PPG signals were recorded simultaneously by a self-designed device at a sampling rate of 250 Hz for each channel and digitized by a 12-bit A/D converter. The ECG signal was collected from the index fingertip of left hand and the index and middle fingertips of right hand, while the PPG signal was collected from the index fingertip of right hand at the same time. Standard blood pressure was measured by an oscillometry  at subjects' left upper arms.The experiment procedure was arranged into four sessions, namely, pretest, calibration sitting, calibration standing, and estimation test. In pretest session, each subject was required to sit down and relax for 10 minutes to stabilize his/her blood pressure. During this time, the participant got prepared for the experiment, such as wearing the sensors. The rest of the three sessions followed a routine data collection procedure, which is shown in The experiment outline is summarized in Ninety-three datasets were finally recorded for the 31 subjects and processed offline. The raw data were first filtered by a sliding window with window length of 10 milliseconds. The beat-to-beat PTT was defined as the time interval between the R-wave of ECG and the peak of the PPG pulse within the same cardiac cycle see in . The flu a, b, c, and d are coefficient constants; PTT is the pulse transit time value for estimation; PTTV is the PTT variability during the signal recording, which is defined as PTTVBP=aPTT+bBP=aPTT+ba and b were further calibrated for each individual by calibration.Considering that the relationship between blood pressure and PTT varies from subject to subject, individual calibration is necessary for blood pressure estimation. Specifically, the coefficient constants in  should b Calibration-sitting and Calibration-standing sessions to derive the value of a and b in .The correlation between any paired variables was analyzed by the correlation coefficient R2 around 0.96 (P < 0.001) for the estimation results derived from two models. However, for the DBP, the proposed model showed a better performance with R2 of 0.71 (P < 0.001), while it is 0.27 (P < 0.01) for the linear model estimation results. The correlation analysis indicates that the proposed method provides better estimation performance on blood pressure especially for the DBP.The blood pressure measured by the oscillometry was regarded as the standard value. Correlation between estimated blood pressure values from the two estimation models and the standard value was first analyzed, as shown in The mean estimation error of the proposed model was −0.2 ± 2.4 mmHg and −0.5 ± 3.9 mmHg, while it was 0.1 ± 2.5 mmHg and 1.3 ± 7.4 mmHg from the linear model, for the SBP and DBP, respectively. The result again showed that the proposed method had a better performance on the DBP estimation. This is evident in the Bland Altman plot shown in Figures As an important risk factor, blood pressure has prognostic value for stroke. Continuous blood pressure measurement will assist for the preventing and predicting of stroke. The PTT-based blood pressure estimation provides the most practical solution for the continuous measurement since the required signal (ECG and PPG) can be obtained by wearable devices. The purpose of this study was to develop a PTT-based blood pressure estimation method with personalized model and easy implementation. The underlying mechanism blood pressure estimation is that pulse wave velocity, which is the inverse of PTT, is directly determined by the elasticity of vessel wall that is associated with blood pressure level . Wong etConsidering all above factors, we proposed a PTT-based blood pressure estimation method including a new model with compensation and calibration procedure. Hydrostatic effect has been approved to be influencing blood pressure level and included in current method in calibration to derive personalized coefficients in the estimation model for each individual , 47. SitIt is well known that the variability in heart rate and blood pressure carries important neural control information for the cardiovascular system –41. One The proposed model has shown promising potential for continuously monitoring blood pressure. As the risk of stroke is much dependent on the blood pressure level –7, such Although the current study shows promising results, there is one limitation. This study only tested the proposed method on healthy young subjects. It is well known that in hypertension patients, the blood pressure regulation is different from the healthy. Such method needs to be validated further on people with different conditions, such as patients with stroke and hypertension.


ADORA2A  and one SNP of ADORA2B (rs7208480) were genotyped and an association between SNPs and clinical outcomes was evaluated. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. The rs4822489 was significantly associated with the severity of CHF after adjustment for traditional cardiovascular risk factors . However, the five SNPs as well as the haplotypes were not found to be associated with CHF susceptibility. The findings of this study suggest that rs4822489 may contribute to the severity of CHF in the northern Chinese. However, further studies performed in larger populations and aimed at better defining the role of this gene are required.The causes of chronic heart failure (CHF) and its progression are likely to be due to complex genetic factors. Adenosine receptors A2A and A2B  play an important role in cardio-protection. Therefore, polymorphisms in the genes encoding those receptors may affect the risk and severity of CHF. This study was a case-control comparative investigation of 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls. Four common single-nucleotide polymorphisms (SNPs) of  Chronic heart failure (CHF) is the end result of various insults to the myocardium, the most common of which is ischemic heart disease . The pred-ribofuranosyl-9-H-purine) [Adenosine is a naturally occurring endogenous purine nucleoside that is composed of an adenine molecule attached to a ribose sugar moiety (ribofuranose) via a β-N9-glycosidic bond (6-amino-9-β--purine) . Levels -purine) .1 (ADORA1), A2 (ADORA2), and A3 (ADORA3). In addition, ADORA2 was subsequently sub-divided according to the existence of distinct high-(ADORA2A) vs. low-affinity (ADORA2B) binding sites. Layland et al. [ADORA2A and the resultant increase in myocardial blood flow. Furthermore, deletion of the ADORA2A gene has been shown to reduce the heart rate [ADORA2B are particularly prone to myocardial ischemia [ADORA2A and ADORA2B play an important role in heart activity.Adenosine regulates cell function via four structurally related G-protein-coupled receptors: Ad et al.  revealedart rate , and in ischemia ,11,12,13ADORA2A and ADORA2B could be affected by gene polymorphisms in vivo. It is therefore reasonable to hypothesize that single-nucleotide polymorphisms (SNPs) in ADORA2A and ADORA2B can influence the activity of the adenosine A2 receptors, and further affect the susceptibility and progression of CHF. To the best of our knowledge, this hypothesis has not been investigated previously. We therefore investigated whether four selected ADORA2A SNPs  and one ADORA2B SNP (rs7208480) are associated with CHF risk or severity in a north Chinese population.The activities of p < 0.05).The baseline characteristics of the study subjects are listed in p > 0.05). The allele frequencies and genotype distribution of these five SNPs did not differ significantly between the CHF patients and healthy controls in a univariate analysis. After adjustment for age, sex, and traditional cardiovascular risk factors, there was still no evidence that the risk of CHF either increased or decreased significantly in the presence of any of the SNPs  were in strong LD with each other . Then, the association between inferred haplotypes and CHF risk among the individuals was analyzed. But no haplotype was found to be associated with the CHF susceptibility (Linkage disequilibrium (LD) analysis for the tibility .p = 0.047 and 0.025, respectively).The genotype distribution and allele frequencies of the five SNPs were investigated in relation to a CHF clinical subset . A signip = 0.024 and 0.020, respectively; p values of two variables (age and dyslipidemia) were <0.1 , and thus they were entered into a multivariable ordinal regression model. After that, only rs4822489 was significantly associated with the severity of CHF .Analysis of the association between the different genotype groups of each polymorphism and NYHA class in CHF patients revealed that the genotype distribution and allele frequencies differed significantly between rs4822489 and the NYHA class of the CHF patients  in a cohort of patients with type 1 diabetes. They found that carriers homozygous for the T allele of SNP rs4822489 were less likely to progress to PDR during follow-up than were carriers of any G allele. Hider et al. [ADORA2A polymorphisms on the outcome of methotrexate (MTX) treatment in rheumatoid arthritis (RA), but they did not identify any association between rs4822489 and adverse events in RA patients for this SNP because of the genotyping success rate of <85%. Three other ADORA2A SNPs were detected in the present study: rs2236624, rs2236625, and rs5751876. rs2236624 is an intronic SNP and is in linkage disequilibrium with 15 currently known SNPs, 4 of which are within exons but are synonymous coding SNPs; 5 are intronic, 6 lie in the 3' untranslated region, 1 is a nonsynonymous SNP, and another is a frame-shift polymorphism [ et al. [ et al. [ et al. [ et al. [It has been shown that the rs4822489 variant is associated with other diseases. Bashira et al.  explored[ et al.  found th[ et al. ,28,29 an[ et al. ,31. In a[ et al.  found th[ et al. ,34. HoweADORA2B is located on chromosome 21p12; the rs7208480 (intergenic) SNP of this gene was selected in this study to explore its effects on CHF. Desai et al. [i et al.  concludei et al. . It is ai et al. ,38,39. HIn this study, we also found that the prevalence of the rs2236625 CC genotype and C allele were significantly higher in smokers among CHF patients, which suggested that this SNP might have a certain effect on the cardiovascular function of smokers. It is reported that adenosine could increase myocardial contractility, which might be due to increased coronary blood flow through activation of ADORA2A receptors (Gregg’s phenomenon) ,41. SmokExploration of the HapMap database revealed that the minor allele frequencies of rs7208480 and rs5751879 in the Chinese Han population were both <0.05. The experimental results of this study show that subjects with the rs7208480TT genotype—the distribution of which in the control group deviated from the HWE—constituted only 0.023 in the entire study population. This may be due to the characteristics of genetic drift, since the subjects were from the same geographical area.ADORA2A polymorphism and the severity of CHF in a Chinese Han population; however, several limitations of the study need to be considered. First, the sample was relatively small, and so the reported results need to be validated in a larger sample; Second, the study subjects were drawn from a northern Chinese population, and similar studies in other populations were needed to confirm our findings; Third, we selected one SNP (rs7208480) that was found to be associated with PH by a literature search, without studying all the SNPs of ADORA2B [This study has produced interesting outcomes and the first evidence of a relationship between  ADORA2B ; FinallyChinese CHF patients (age > 18 years) were recruited in 2013 and 2014 from the First Affiliated Hospital, College of Medicine, Xi’an Jiaotong University. Patients were classified as having heart failure by experienced cardiologists using the Guidelines for Diagnosis and Treatment of Heart Failure in China (2013) and the cause of the disease was determined according to clinical assessment and echocardiography. The following patient exclusion criteria were applied: age ≤ 18 years, presence of severe hepatic or renal insufficiency, tumors or malignant disease, acute attack of CHF, severe acute infection, metabolic disorders, and acute myocardial infarction without revascularization within the previous 2 weeks. The sample collection was completed according to strict criteria by two visiting staff, and was reviewed by the Chief Physician of Cardiology. Eventually, 300 patients were enrolled.The healthy subjects, from the Medical Examination Center of the same hospital (age > 18 years) and without known personal or family history of cardiovascular disease, were invited to participate in this study as controls. To identify symptom-free subjects and exclude suspected cardiovascular disease subjects, a detailed interview was conducted in the framework of a physical examination by expert physicians. Four hundred controls were finally included, comparable for sex and ethnicity.To obtain data on demographic and clinical characteristics, such as gender, age, and traditional cardiovascular risk factors, interviewer-administered health-risk questionnaires were performed. Hypertensive patients were defined according to the Guidelines for Prevention and Treatment of Hypertension in China (2013). Someone taking antihypertensive drugs was also considered to have hypertension. In addition, dyslipidemia and diabetes were defined according to the Guidelines on Prevention and Treatment of Blood Lipid Abnormality in Chinese Adults (2007) and the Guidelines for Prevention and Treatment of Diabetes in China (2013), respectively. Information regarding smoking status was self-reported. Individuals were designated as “smokers” if they reported that they had smoked an average of at least five cigarettes daily for at least the past 12 months . The present study was performed with strict protocol under the Ethics Committee of the First Affiliated Hospital, College of Medicine, Xi’an Jiaotong University. A statement of informed consent was obtained from all participants after the procedure had been fully explained to them.i.e., rs2236625, rs2236624, and rs4822489), which captured most of the known common variations of ADORA2A according to the Chinese Han population data from HapMap (available online: http://www.hapmap.org), and one SNP (rs5751876) of ADORA2A yielded by a literature search were selected for the present study. In addition, we learned that rs7208480 of ADORA2B was associated with PH, which was common in CHF patients, so this SNP was also studied in this study. Sequenom MassARRAY Assay Design 3.0 software  was used to design a Multiplexed SNP MassEXTEND assay [The blood samples were collected into tubes containing ethylenediaminetetraacetic acid. After centrifugation, the samples were stored at −80 °C until analysis. The standard phenol-chloroform extraction method was used to extract genomic DNA from the whole blood. The concentration of DNA was measured by spectrometry . Three tag-SNPs  was used for the statistical analyses. Deviation of genotype distributions from Hardy-Weinberg equilibrium (HWE) was determined using the χhttp://bioinfo.iconcolgia.net).The association between haplotypes and CHF risk was analyzed using the Haploview soft version 4.2  and haplotype Stats software obtained from Catalan Institute of Oncology  with a retention p value of <0.10 in the univariate analysis were entered into a multivariable ordinal regression model to evaluate the association between SNPs and NYHA class. The cutoff for statistical significance was set at p < 0.05 (two-sided).Differences in parameters related to the severity of CHF, such as ejection fraction (EF), left-ventricular end-diastolic diameter (LVEDD), and left-ventricular end-systolic diameter (LVESD), were evaluated among patients, stratified according to the three different genotypes by analysis of variance, and significant differences among pairs of means were tested using Dunnett’s test. Differences in genotype distribution and allele frequency for the significant SNPs according to functional New York Heart Association (NYHA) class were also analyzed by χADORA2A and the severity of CHF, thus providing novel insight into the contribution of adenosine to heart function. Further functional studies and well-characterized, larger molecular epidemiological studies involving diverse ethnic populations of different countries are necessary to confirm these findings.In conclusion, the findings of this preliminary study have revealed an association between the rs4822489 SNP in


Scarce information on outcomes of epidemic post infectious glomerulonephritis is available. This is a 10-year follow-up of the patients that developed acute glomerulonephritis in an epidemic outbreak caused by group C Streptococcus zooepidemicus in Brazil in 1998, that were also previously evaluated 2 and 5 years after the acute episode.In this prospective study 60 cases (out of 134 in 1998) were reevaluated after 10 years, as well as community controls matched by gender and age. They underwent clinical and renal function evaluation, including serum creatinine and cystatin C, estimated glomerular filtration rate (eGFR), albuminuria and hematuria.2 and/or albuminuria >30mg/g creatinine: 13.8% vs. 12.2%, respectively, p = 0.817) except for a higher frequency of hypertension in the cases . Comparing the same patients affected in the acute episode, 2, 5 and 10 years later, it was observed an improvement of median eGFR levels at 2 years and a trend toward subsequent stabilization in these levels, associated with decrease in albuminuria and increased hypertension rates in the last survey. At 10 years it was not observed additional reduction of renal function using serum creatinine, eGFR and cystatin C.Comparisons of clinical and renal function aspects of 60 patients and 48 community controls have not shown significant differences (eGFR <60 ml/min/1.73mDuring the acute episode of epidemic GN a considerable proportion of patients presented hypertension and reduced renal function; after 2 years and particularly at this 10-year follow-up survey there was no worsening of renal function parameters, except for persistent higher frequency of hypertension. Nevertheless, a longer follow up is necessary to confirm that progressive loss of renal function will not occur. Streptococcus zooepidemicus, a cause of bovine mastitis. Epidemiological investigation revealed that patients had consumed a locally produced cheese prepared with unpasteurized milk [In Brazil a large outbreak of acute glomerulonephritis (GN) occurred in 1998, associated to unpasteurized milk, when 253 cases of acute GN were reported in the state of Minas Gerais  [Outbreaks of post streptococcal glomerulonephritis (PSGN) have been rare since the 1970s  and scarThe files of the originally affected patients with their contact addresses and clinical information were kept recorded by the local nephrology team under the supervision of one of the authors (SWP). After 10 years of the outbreak a new clinical survey was conducted and 60 subjects were reevaluated in the present study. In addition, a control group was selected in the community; they were neighbors of the cases and matched to them by age and gender. The controls lived in the region during the outbreak in 1998 and did not have symptoms or signs of the disease at that occasion.Participants provide their written informed consent to participate in this study, that was approved by the ethics committee of the Universidade Federal de Minas Gerais.-1.19. GFR was considered reduced when lower than 60 mL/min/1.73m2.The medical team visited the cases and controls in their homes, collected the clinical information, and obtained early morning blood and urine samples for analyses. During each visit, a recently voided urine sample was collected for dipstick test  and albuminuria assessment; a blood sample was drawn ; an interim history was obtained; and a physical examination was performed. Blood pressure was measured with a mercury sphygmomanometer, while the patient was in the sitting position after 5 minutes of rest. The average of 3 measurements taken with a 1-minute interval was used in the analysis. Hypertension was defined when systolic blood pressure was higher or equal to 140 mmHg or diastolic blood pressure was higher or equal to 90 mmHg, or use of antihypertensive medication. Blood and urine samples were appropriately stored at 4°C and brought to the reference study laboratory. When examined within 1 day, urine samples were kept at 4°C; otherwise, they were frozen at −20°C. Blood samples were examined for serum creatinine  and cystatin C  and values were considered abnormal if greater than 30 mg/g creatinine. GFR was estimated (eGFR) based on serum creatinine (eGFR-creatinine) by the Modification of Diet in Renal Disease (MDRD) study equation, and based on serum cystatin C by the equation eGFR-cys = 76.7 x cystatin CThe chi-square test or Fisher’s exact test were used for the comparison of categorical variables. Student’s t-test or the Mann–Whitney tests (whenever appropriate) were used for the comparison of continuous variables. In the longitudinal analysis that involved eGFR in the years of 1998 (outbreak), 2000 (after 2 years), 2003 (after 5 years), and 2008 (after 10 years) the tests of Friedman and Wilcoxon were applied for numerical variables and the McNemar’s for categorical variables. Analysis of covariance was used to compare mean values of variables adjusted for age and gender. Tests were two-sided and statistical significance was set at p<0.05. The software used was the SPSS v. 15.0.Of the 134 confirmed cases of PSGN seen in 1998, 13 died: three in the acute phase of illness , six after resolution of the acute illness, with normal renal function , and four died on chronic dialysis program. Eleven cases required dialysis during the acute phase of illness and 3 of these died within 1 month of disease; 3 recovered renal function and stopped dialysis before 3 months of disease; 5 of them remained on chronic dialysis; of these, four died after more than 2 years on dialysis.After 10 years of the outbreak, considering the remaining 121 patients some cases could not be located (n = 52) or did not agree to undergo another medical evaluation (n = 9), thus leaving 60 cases for the current study. These cases did not differ at presentation from those not re-examined regarding several characteristics such as: mean age, gender, hospitalization rate, presence of edema, mean systolic and diastolic blood pressure, serum creatinine levels, and need for dialysis. We confirmed that during the follow-up, none of the non-reevaluated cases died or underwent chronic dialysis in the dialysis centers of the state of Minas Gerais.During the acute phase, renal biopsy was performed in nine patients. All specimens showed “diffuse proliferative glomerulonephritis” as expected in a context of PSGN. No patients received immunosuppressive drug therapy in the acute phase of disease; however, diuretics and anti-hypertensive drugs were frequently used. Immunosuppression including the use of glucocorticosteroids was never prescribed during the entire observation period of 10 years.Gender and age of patients and controls, as well as blood pressure measurements and laboratory parameters at follow-up are shown in After categorization considering the cutoffs that are indicative of altered results, the only variable that was statistically different between the groups was hypertension, whose prevalence was higher among cases than controls  . Even afMean±SE levels of systolic blood pressure were more elevated among cases than controls , adjusting for age and gender.In this assessment, the most commonly used antihypertensive medications were angiotensin converting enzyme inhibitors or angiotensin receptor blockers, in 28.3% (n = 17/60) of the cases and 12.5% (n = 6/48) of the controls followed by the diuretic hydroclorothiazide, in 8.3% (n = 5/60) and 8.3% (n = 4/48) of them, respectively. The cases did not report a frequent use of non-steroidal anti-inflammatory drugs or other nephrotoxic drugs. At 5 years of follow-up, angiotensin converting enzyme inhibitors or angiotensin receptor blockers were used by 7 of 56 (12.5%) cases.Detection of hematuria by dipstick test revealed 11.7% of positivity in the group of patients and 8.4% in the control group (p = 0.812).2 did not differ between cases and controls .The frequency of eGFR-creatinine lower than 60 mL/min/1.73mIn the longitudinal analysis of eGFR-creatinine measurements along the years of follow-up, it was observed a statistically significant difference in the median values, except between the years 2000 and 2003, with an increased median eGFR at the last evaluation compared to previous years .2 showed a higher proportion of patients with lower values in 1998 during the outbreak (42.0%) compared to the three subsequent surveys (p<0.001), but no statistically significant difference was observed between the 2-year, 5-year and 10-year surveys .The analysis using eGFR categorized as ≥ or <60 mL/min/1.73mNone of the patients had nephrotic syndrome. Increased albuminuria (>30 mg/g) was detected in 12% of the cases  and 8% of the controls (p = 0.508). Altogether 13.8% of the patients and 12% of the controls (p = 0.817) had increased albuminuria and/or reduced eGFR-creatinine.S. equi subspecies zooepidemicus is rare in humans but is a well-known cause of disease in cows and horses [S. zooepidemicus can cause PSGN [d horses . In humause PSGN ,7 affectuse PSGN ,8, assocuse PSGN ,7,9 , but after 10 years of follow-up complete recovery occurred in the great majority of cases.It is of note the severe presentation of this outbreak, as well as a high frequency of reduced renal function and/or microalbuminuria, involving almost 50% of the patients 2 years after the acute episode ,10. RenaStreptococcus [During the follow-up, hypertension and urinary abnormalities were more frequently detected in this series than in other outbreaks of PSGN associated with group A tococcus –14. In ftococcus  and 42% tococcus , respectFew months after the acute episode, it was observed 8% (n = 11/134) of cases with acute renal failure and 3.7% (n = 5/134) with end-stage renal disease, that represent a relatively high rate of loss of renal function in the acute phase of this post infectious GN.One of the strengths of this study is the use of serum creatinine, eGFR based on serum creatinine and serum cystatin C as additional tools to evaluate more precisely the renal function  of this As eventual study limitations is necessary to emphasize that the case ascertainment methods used in the earlier phase of such outbreak possibly would not have identified those cases that did not need hospital admission or referral to a nephrologist. Therefore, it is possible that we have studied cases with more severe symptoms and presentation. In addition, despite our efforts, we were not able to reexamine several patients initially affected, however their baseline characteristics were not different from those reassessed and we confirmed that none initiated chronic dialysis in the region during the follow-up. Overall, this sample had a low frequency of risk factors for adverse renal outcomes, as reflected in the very satisfactory renal function results. Also notable is the increasing use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers by the cases (12.5% at 5-yr and 28.3% at 10-yr follow-up), which have contributed to the preservation of kidney function.Besides the heterogeneity of the studies of PSGN most of them with group A streptococci makes comparison among available reports difficult. Even in group A cases short-term prognosis of GN is undoubtedly good , but lonEspecially for its preventable nature, the possible contribution of episodes of acute PSGN to increased risk of chronic kidney disease in later life is a matter of concern. This was investigated in an Aboriginal community in Australia . Of 1519Post infectious GN including PSGN in their different presentations are current kidney health problems all over the world, as a typical acute PSGN of childhood predominantly in developing countries or involving older adults in the industrialized ones.S. zooepidemicus as the etiological agent of acute PSGN, transmitted to humans by unpasteurized dairy products, and affecting mostly adults, as demonstrated in this and other outbreaks.Considering our studies and few others it is necessary to be aware to the possibility of S. zooepidemicus outbreak leading to PSGN. In the present study it is noteworthy that after the acute phase, characterized by severe clinical manifestations of this epidemic PSGN , it was observed a trend toward maintenance of renal function instead of progressive loss, especially after 2 years.Long-term reports on epidemic PSGN are scarce, reinforcing the relevance of following during 10 years this population affected by an Nevertheless, it is still possible that part of these patients have lost a substantial proportion of their nephrons during the acute glomerulonephritis episode and may have reduced nephron mass. The apparent slight improvement in eGFR at 10 years may be partly the consequence of glomerular hyperperfusion/ hyperfiltration injury, particularly considering the increasing percentage of patients with hypertension at this point. Thus, it is still necessary a longer follow-up to dismiss possible deleterious effects of PSGN.