Patients affected by psychotic disorders are more likely to develop high rates of co-morbidities, such as obesity, type 2 diabetes, dyslipidemias, hypertension, metabolic syndrome, myocardial infarction, stroke etc., in the long-term. These morbidities have a significant impact on the life-expectancy of these patients. Patients with chronic psychoses show a 2–3-fold increased risk of death mostly from cardiovascular and metabolic diseases. Although there may be an independent link, between schizophrenia and metabolic conditions the cardio-metabolic risk is mostly related to an unhealthy lifestyle and the usage of antipsychotic agents  even when these remain effective treatments in the management of major psychoses. Recently, many international organizations have developed screening and monitoring guidelines for the control of modifiable risk factors in order to reduce the rate of co-morbidity and mortality among patients affected by schizophrenia. This paper is a review of current knowledge about the metabolic issues of patients affected by schizophrenia and describes clinical characteristics and medical management strategies for such conditions. Patients diagnosed with psychotic disorders report a reduced expectancy of life and show higher rate of physical co-morbidities said to be mostly due to an unhealthy life style and as a result of treatment by antipsychotic drugs  have been shown to greatly influence those modifiable risk factors leading to weight gain and metabolic changes among all patients treated  appear to induce more weight gain and metabolic abnormalities than First Generation Antipsychotics (FGAs) , serotonin 2C receptor (HTR2C), leptin, neuropeptide Y (NPY) and cannabinoid receptor 1 (CNR1)  includes the increase of low-density lipoprotein cholesterol (LDL-C) and/or decrease of high-density lipoprotein cholesterol (HDL-C). Studies have shown that the usage of antipsychotic drugs is associated with an increase of LDL-C and a decrease of HDL-C  constitutes of a cluster of different clinical conditions, including abdominal obesity, insulin resistance, dyslipidaemias, and elevated blood pressure. All components of the MetS have been recognized as independent risk factors for cardiovascular disease, pro-thrombotic state, pro-inflammatory state, non-alcoholic fatty liver disease and reproductive disorders  produced the definitions in 1985, European Group for the Study of Insulin Resistance in 1999, National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) in 2001 (modified in 2003), American Association of Clinical Endocrinologists in 2003 and finally by the International Diabetes Federation (IDF) in 2006 ;Elevated triglycerides (≥150 mg/dl) or drug treatment for dyslipidaemia;Reduced high-density lipoprotein (HDL) (< 40 mg/dl) or being on drug treatment for hypercholesterolaemia;Elevated blood pressure  or a history of hypertension or drug treatment for hypertension;Elevated levels of fasting glucose (≥100 mg/dl) or being on medication treatment for hyperglycaemia.MetS is diagnosed when 3 out of the following 5 criteria are recognized in the same patients:Papanastasiou  observedRecently it has been reported that MetS may influence the cognitive functioning in patients with chronic psychosis–especially in immediate memory, delayed memory, and attention  which is greater than that for olanzapine (2–20%) which is higher than that related to quetipaine (not significant increase) which is higher than that for aripiprazole = ziprasidone (not significant increase)  and repolarization (K+ output) of the ventricles. QT is corrected for heart rate (QTc) derived from the heart rate (HR) as 60 beats per minute according to Bazzett's formula.Using electro-cardiogram the functioning of the heart is assessed and in this context, QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization  is strongly associated with arrhythmias and torsade de pointes (TdP).Although QT may vary according to age, sex, circadian rhythms; a lengthened QT interval is a marker for the potential of ventricular tachyarrhythmias like Antipsychotic agents may prolong QTc interval depending on their binding- potency to IKr channels of ventricle repolarization (HERG channels). Second generation antipsychotic mostly involved with QTc- prolongation are ziprasidone, risperidone, paliperidone, clozapine, quetiapine. aripiprazole, olanzapine, and asenapine are associate with lower variations in QTc- interval  or other risky conditions  . Also, patients treated with chlorpromazine or fluphenazine may develop myocarditis. If clinical signs of myocarditis are suspected , the drug should be stopped immediately  and waist circumference; fasting blood glucose levels; fasting blood lipids: total cholesterol, triglycerides, LDL cholesterol  and HDL-C; blood pressure (measured twice and average taken), heart rate, heart and lung auscultation, foot pulses; ECG  /<88 cm (women), blood pressure ≤140/90 mmHg—triglycerides < 190 mg/dL—LDL < 115 mg/dL in non-diabetic patients. The, glycosylated hemoglobin < 7%—blood pressure ≤ 130/80 mmHg—triglycerides < 175 mg/dL—LDL < 100 mg/dL should be the recommended levels in patients with diabetes. Patients with diabetes should have their glycosylated hemoglobin levels measured 3-monthly and microalbuminuria, renal functioning, ophtalmological and feet examination yearly  perspective. Specific treatments may be required to reduce the cardiovascular risk. Clinicians have to involve general practitioners in order to collaborate with them in managing the risk factors. EPA guidelines recommend that BMI should be ≤25 kg/mMetabolic consequences of treatment with antipsychotic medication increase the risk of mortality among patients affected by chronic psychosis and many of the factors are preventable. Patients with psychoses appear to show higher levels of cardiometabolic co-morbidites in comparison with general population and 2–3-fold increased risk of premature death. Clinicians need to employ international guidelines and procedures to screen and monitor these co-morbid conditions in order to reduce mortality rates among patients affected by psychotic disorders and improve the outcome of illness, including patients' global functioning and quality of life.The research has been conducted in the absence of grant funding.The reviewer Marcello Nardini declares that, despite having collaborated on an article with authors Antonio Ventriglio and Antonello Bellomo in 2014, the review was conducted objectively and no conflict of interest exists. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Vespa affinis is a hornet widely distributed in Sri Lanka and it is responsible for the highest number of deaths related to Hymenoptera stings. Apart from the early reactions, victims often die in hospital many hours later due to complications such as myocardial infarction and multiple organ failure. Increased microvascular permeability and acute pulmonary oedema as the primary pathology is less known in hornet envenoming.Here, we report clinical and postmortem findings of two Sinhalese patients, a 48-year-old husband and his 46-year-old wife, who both died following a massive attack by hornets 32 hours and 9 hours after the incidence respectively. At postmortem examination, both patients had pleural effusions, acute pulmonary oedema and red cell casts in their urine. Their coronary arteries and histology of myocardium were normal.Early recognition of acute pulmonary oedema in hornet stings is needed with implementation of crucial treatments to avert deaths. Vespa affinis or Debara in Sinhala which belongs to the genus Vespa[The order Hymenoptera represents ants, wasps and bees. The family Vespidae includes stinging social wasps represented by 860 species worldwide. The subfamily Vespinae includes the hornets and yellow jackets,2. The cnus Vespa. Hornetsnus Vespa,2. The snus Vespa. A hornenus Vespa.Vespa affinis or Debara.Hornet stinging is a common environmental hazard in Sri Lanka. When disturbed, these insects in swarm, attack people in the vicinity causing multiple sting injuries. The majority of victims recover in hospitals, but an unaccountable number of them die due to acute complications which are unpredictable. The hisA 46-year-old Sinhalese woman went to the nearby wood to collect firewood at approximately 1 p.m. in the afternoon and pulled a branch of a tree without noticing a hornet nest attached to it. She then came under massive attack by hornets until her husband came to rescue her. Within half an hour of the attack she was admitted to a local hospital where she was found to have a blood pressure of 90/50mmHg. She received initial resuscitation with isotonic saline and medications such as hydrocortisone, chlorpheniramine maleate and promethazine and she was transferred to the nearest tertiary care hospital in 3 hours. At that time her blood pressure was 138/83mmHg and her radial pulse rate was 114 beats per minute. She was not in respiratory distress and her lungs were clear. An indwelling catheter was inserted that drained 250mL of normal colour urine. At 6 p.m., 5 hours after she was stung, her blood pressure was 160/115mmHg, her pulse rate was 100 beats per minute, her oxygen saturation was 98% and she was drowsy with a Glasgow coma scale of 11/15. She was given another dose of hydrocortisone and chlorpheniramine maleate. Her serum sodium was 136mmol/L, potassium was 3.0 mmol/L, and an electrocardiogram (ECG) showed sinus tachycardia. At 7.30 p.m., 6.5 hours after she was stung, she became oliguric and passed blood-stained urine and became restless. At 9 p.m., 8 hours after she was stung, she became dyspnoeic with a respiratory rate of 32 breaths per minute. Her radial pulse rate was 96 beats per minute, her blood pressure was 86/50mmHg and she had central cyanosis and fine crepitations in her lungs suggestive of pulmonary oedema. She was given high-flow oxygen via a face mask, an intravenous dose of frusemide and infusion of dobutamine while awaiting an intensive care bed. However, in the next 15 minutes she developed a cardiac arrest and underwent continuous resuscitation including intubation and assisted ventilation until she was pronounced dead at 10 p.m. Prior to this incidence she was in good health and was not taking any medication including beta-blockers or angiotensin-converting enzyme (ACE)-inhibitors. At autopsy, her skin had 40 sting marks distributed in her face, neck, chest, abdomen and limbs which were circumscribed and punctated. More than 100mL of blood-stained fluid was found in each pleural space and her lungs were oedematous and showed frothy fluid. Her kidneys were congested. Her myocardium was pale and her coronary arteries were normal. No abnormalities were found in other organs including her brain.9/L, blood urea was 48mg/dL, clotting time was over 10 minutes, international normalised ratio (INR) was 2, pH was 6.95, serum potassium was 5.3mmol/L, serum sodium was 143mmol/L and he was positive for D-dimer. Prior to this incidence he was in good health and was not taking any medication including beta-blockers or ACE-inhibitors. The autopsy examination found approximately 130 circumscribed punctated sting marks distributed all over his body (Figure The husband of Case 1 who is a 48-year-old Sinhalese man became a victim of a massive attack by hornets when he tried to rescue his wife. He was admitted to the same local hospital within half an hour of the attack and received the same medications as his wife had received. However, his blood pressure was 80/50mmHg and his pulse rate was 88 beats/minute and his lungs were clear. He was also transferred to the same tertiary care hospital along with his wife and on admission his blood pressure was 130/73mmHg, his pulse rate was 84 beats per minute, his oxygen saturation was 96% and his ECG was normal. He was in pain, but had stable clinical parameters. He started to pass blood-stained urine at 5 p.m., 4 hours after he had been stung, and he was mildly breathless with a respiratory rate of 22 breaths per minute. At 10 p.m., 9 hours after he had been stung, his blood pressure was 80/40mmHg, pulse rate was 90 beats per minute, respiratory rate was 38 breaths per minute and oxygen saturation dropped to72%. He was managed in the intensive care unit where he received inotropic drugs, high-flow oxygen and steroids. At 3 a.m., 14 hours after he had been stung, he became totally anuric and hypoxic, which required continuous mandatory assisted ventilation with 5mmHg positive end-expiratory pressure and he subsequently started peritoneal dialysis. His chest X-ray showed evidence of pulmonary oedema (Figure An unfortunate story of this nature highlights a social issue in which children loose both parents unexpectedly in an environmental accident. Also it proves the aggressive behaviour of disturbed hornets from which the victims find no way of escape. Hornets are ubiquitous in Sri Lanka, nesting close to human dwellings resulting in a constant conflict with humans. This results in immense human suffering and even leads to fatalities. Therefore, priority should be given to recognize hornet stings as an important health issue and to improve management strategies in hospitals thereby reducing the number of deaths. This needs the building up of a thorough knowledge base about possible complications of hornet stings, understanding of venom effects on body homeostasis and testing of different therapeutic regimens that would reverse the deranged physiological processes in the body. In this case study, both patients had similar macroscopic and histopathological findings suggesting an initiation of the same pathophysiological process as a result of envenoming that has progressed to an irreversible outcome.In both patients, acute pulmonary oedema had been the dominant manifestation detected both clinically and histopathologically that had contributed to their death within a short hospital stay. It is apparent that the development of pulmonary oedema took a few hours in both patients. However, fluid shift as a result of immediate anaphylaxis or anaphylactoid reaction would have started very early leading to the development of acute pulmonary oedema followed by a chain of events such as prolonged hypoxaemia, metabolic acidosis and cardiac dysfunction. During the early hours, onset of acute pulmonary oedema was not obvious clinically and detected later in advanced stages when the damage was irreparable. In the literature, wasp venom-induced massive acute pulmonary oedema has been reported in a 38-year-old Chinese woman in whom the causative mechanism was unexplained[In a series of 56 deaths after anaphylaxis studies in the UK, 23 cases had nothing indicative of an allergic pathology, and were attributed to severe shock secondary to anaphylaxis. The samOther than acute pulmonary oedema, development of acute venom-induced consumptive coagulopathy or disseminated intravascular coagulation occurred in Case 2 as suggested by increased blood clotting time, INR, thrombocytopenia and raised D-dimers in his blood. Both patients had developed acute kidney injury that was preceded by passing red-coloured urine. However, initial output and the colour of the urine were normal in the first patient. Microscopic finding of renal tissues showed red cell casts and tubular injury. Acute kidney injury and accumulation of toxic metabolites would have contributed to pulmonary oedema, myocardial dysfunction and metabolic acidosis and all these factors would have contributed to the fatal outcome. In Case 1, she had a cardiac arrest within a short time after development of pulmonary oedema. But in Case 2, the patient deteriorated over hours with multiple organ dysfunction and metabolic derangements. Multiple organ dysfunction and acute kidney injury has been reported after wasp stings,10-12. UThe immune mechanisms causing the histamine-releasing action of Hymenoptera stings are either Type 1 hypersensitivity that operates through immunoglobulin E-mediated mast cell degranulation leading to anaphylaxis or anaphylactoid reaction where immunoglobulins are not involved,5 or, ocBy doing critical analysis of these fatal cases one might find possible lapses in the management of them such as insufficient monitoring, missing onset of organ dysfunctions, delays in early intensive care and organ support and inappropriate therapeutic decisions and medications. Lack of standard management guidelines of Hymenoptera envenoming is a global problem which has an amplified effect on victims in resource-poor countries. Therefore, vigilance is needed from the time of stinging to detect all the complications and to institute proper management to increase the chances of survival of the victim. The severity of envenoming and the late complications are related to the number of stings as shown in these cases, but sometimes a single sting could be fatal in a sensitised individual. Hymenoptera stings and envenoming needs more global attention as it appears to be a neglected problem now.Early recognition of acute pulmonary oedema in hornet stings is needed with implementation of crucial treatments such as early use of assisted ventilation, organ support, dialysis, and medications such as adrenaline to avert deaths. Further studies are needed to understand the pathophysiological mechanisms of pulmonary oedema in Hymenoptera envenoming and to find out appropriate preventive treatments.Written informed consent was obtained from the patients’ next-of-kin for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.ACE: Angiotensin-converting enzyme; ECG: Electrocardiogram; INR: International normalised ratio.The authors declare that they have no competing interests.SAMK, KK and TK conceived and designed the study. AJK and KW collected data. AJN did autopsies and RW did histopathological studies. SAMK and RW drafted the report. All authors contributed to intellectual content, review and revision of the report, and have seen and approved the final version.


Mobile phone-assisted technologies provide the opportunity to optimize the feasibility of long-term blood pressure (BP) monitoring at home, with the potential of large-scale data collection.In this proof-of-principle study, we evaluated the feasibility of home BP monitoring using mobile phone-assisted technology, by investigating (1) the association between study center and home BP measurements; (2) adherence to reminders on the mobile phone to perform home BP measurements; and (3) referrals, treatment consequences and BP reduction after a raised home BP was diagnosed.We used iVitality, a research platform that comprises a Website, a mobile phone-based app, and health sensors, to measure BP and several other health characteristics during a 6-month period. BP was measured twice at baseline at the study center. Home BP was measured on 4 days during the first week, and thereafter, at semimonthly or monthly intervals, for which participants received reminders on their mobile phone. In the monthly protocol, measurements were performed during 2 consecutive days. In the semimonthly protocol, BP was measured at 1 day.R=0.72 for systolic BP and 0.72 for diastolic BP, both P<.001). Adherence was better in participants measuring semimonthly (71.4%) compared with participants performing monthly measurements . During the study, 41 (27.2%) participants were referred to their general practitioner because of a high BP. Referred participants had a decrease in their BP during follow-up .We included 151 participants (mean age [standard deviation] 57.3 [5.3] years). BP measured at the study center was systematically higher when compared with home BP measurements . Correlation of study center and home measurements of BP was high (Mobile phone-assisted technology is a reliable and promising method with good adherence to measure BP at home during a 6-month period. This provides a possibility for implementation in large-scale studies and can potentially contribute to BP reduction. High blood pressure contributes to the global burden of disease, accounting for 9.4 million deaths per year . With a The increasing availability of the Internet, mobile phones, and health sensors provides the potential to interactively administer health interventions at home. Recent surveys show that at least 75% of the European population uses the Internet on a regular basis, with almost half of them using a mobile phone to access the Internet (smartphone) . Adults The aim of this proof-of-principle study was to evaluate home blood pressure measurements using mobile phone-assisted technology. For this, we investigated (1) the association between study center and home blood pressure; (2) the adherence to perform home blood pressure measurements according to a monthly or semimonthly measurement protocol; and (3) referrals, treatment consequences and blood pressure reduction after a raised home blood pressure was diagnosed.iVitality is a Web-based research platform that consists of a Website, a mobile phone-based app, and sensors that are connected with or already integrated in the mobile phone to measure blood pressure . This iVWe chose to perform this study in people with a parental history of dementia because (1) they have a higher risk of both hypertension and dementia, making them a potentially suitable target group for large-scale preventive studies and (2) they are highly motivated to participate in preventive studies ,14,15. OParticipants were recruited through advertisements in memory outpatient clinics, nursing homes, general practices, and on the Website, and in the newsletter of the Dutch Alzheimer Foundation (Alzheimer-Nederland). If all of the inclusion criteria were met, participants received detailed study information in print. They visited the study center at Leiden University Medical Center or Academic Medical Center Amsterdam at baseline, where they received information about the study and baseline measurements were performed by a study physician or research nurse. Written informed consent was obtained from all participants. The medical ethical committee of Leiden University Medical Center, the Netherlands, approved the study.Enrolment and follow-up took place from September 2013 to January 2015. In preparation for the first visit to the study center, all participants completed a Web-based questionnaire on education, medical history, and medication use. During the visit to the study center, detailed information about the iVitality app and instructions on how to use it were given. History of hypertension and medication use was self-reported. Blood pressure was measured twice at baseline on the upper left arm, in sitting position with a fully automatic electronic blood pressure monitor. Participants were instructed in the use of the home blood pressure monitor.During a 6-month period, participants received automatic messages on preprogrammed days at self-chosen time points on their mobile phone, which reminded them to measure blood pressure. Participants with an Android mobile phone used an A&D blood pressure monitor  which was connected to the mobile phone and automatically transferred the results to the iVitality app by Bluetooth . ParticiCharacteristics of the study participants are reported as mean with standard deviation for continuous variables and as number with percentage for categorical variables. We used Pearson’s correlation coefficient to calculate the correlation between home and study center blood pressure measurements. To investigate agreement between study center and home blood pressure measurements, we computed the mean and the difference in study center and home blood pressure measurements and visualized this in a Bland–Altman plot.U test. In this proof-of-principle study, only participants who completed the 6-month period were used in the primary analysis. In a sensitivity analysis, we included all participants who were included at baseline.Adherence was defined as the actual performance of all blood pressure measurements within 1 week of the time point they were expected to perform their measurements and for which the participant received reminders through the mobile phone app. For each participant, we calculated the percentage of adherence during follow-up. Difference in adherence between the monthly and semimonthly measurement protocol was assessed using a Mann–Whitney t -test. For both blood pressure during the first week and final blood pressure, we calculated the mean values of all blood pressure measurements performed during the first and last week, with day 1 of both weeks being discarded  1.08) and diastolic blood pressure was 5.81 (0.68) mm Hg higher when compared with home blood pressure measurements (panel B). The Bland–Altman plot shows that the difference between the measurements was randomly distributed over the mean of the measurements, indicating that there was no systematic bias in agreement between the study center and home measurements. The 95% limits of agreement for the comparison were −16.82 to 32.82 mm Hg for systolic blood pressure and −9.71 to 21.33 mm Hg for diastolic blood pressure.The association between study center and home blood pressure during the first week is shown in P=.008). There was no difference in adherence between participants who entered their blood pressure measurements manually and participants who used a Bluetooth connection to transfer the measurements (data not shown). Furthermore, a sensitivity analysis in which we investigated the adherence of all 151 participants who were included at baseline, showed similar results: adherence was higher in participants who performed semimonthly blood pressure measurements (median adherence 85.7%) when compared with participants performing monthly measurements  and diastolic  blood pressure. There were 41 out of 151 (27.2%) participants who were referred to their GP because of a high blood pressure, of whom 35 (85.2%) actually visited their GP. In referred participants, blood pressure decreased significantly during the study, both systolic  and diastolic . Furthermore, no difference was found between final and initial blood pressure for both systolic and diastolic blood pressure between the monthly and semimonthly protocol (data not shown). In 7 out of 41 (17.1%) participants, blood pressure lowering medication had been started or changed.This proof-of-principle study, in which we evaluated the feasibility of home blood pressure measurements during a 6-month intervention period using mobile phone-assisted technology, has 3 main findings. First, study center and home blood pressure were highly correlated, although blood pressure measured at the study center was systematically higher when compared with home blood pressure. Second, adherence of all participants to perform blood pressure measurements was high and persisted during 6 months with better adherence in participants measuring semimonthly compared with participants who performed monthly measurements. Third, in participants who were referred to their GP because of a high blood pressure, systolic and diastolic blood pressure decreased significantly during the study, especially for those who started medication.Our finding that systolic and diastolic blood pressure at the study center was systematically higher when compared with home blood pressure measurements is in line with previous literature . A well-Previous studies on adherence to perform home blood pressure measurements show similar results to our findings ,24. In aHome-based blood pressure measurements using mobile phone-based technology may have several potential opportunities. First, other parameters derived from repeated blood pressure measurements, can easily be calculated, especially in a home-based setting. An example of such a parameter is blood pressure variability, of which we recently showed its association with cognitive decline . Second,In our study, blood pressure was lower at the end of follow-up when the participant was referred to the GP because of a high blood pressure at baseline. There are 2 possible explanations for this finding. First, the decrease in blood pressure may be the result of regression to the mean. This phenomenon occurs when repeated measurements tend to be followed by measurements that are closer to the mean. Although our baseline measurements were defined on repeated blood pressure measurements, it is still expected that the mean blood pressure during follow-up will go down, owing to regression toward the mean. Second, it may reflect a true effect of monitoring and subsequent treatment of blood pressure. Blood pressure lowering interventions by the GP and higher awareness of participants may all have contributed to a lower blood pressure. Although the fact that the effect on blood pressure was highest in those who initiated medication suggests the second explanation, we have not collected enough information on interventions in this proof-of-principle study to draw definite conclusions. An adequately powered randomized controlled trial may help to establish the effects of the interventions.For this proof-of-principle study, we selected highly motivated participants with a parental history of dementia. This may have introduced a selection bias toward better adherence and treatment effects, which reduces the external validity for other, broader defined populations. The strength of this study is that mobile phone technology was used to collect study data on blood pressure. This innovative method reduces the need for face-to-face contact and stimulates self-management. Now that this proof-of-principle study is promising, broader and larger populations can be included in future studies.This proof-of-principle study demonstrates that mobile phone-assisted technology can be used as a reliable and promising method to measure blood pressure at home during a 6-month period. This provides a possibility for implementation in large-scale studies and can potentially lead to blood pressure reduction and eventually reduction of cardiovascular disease.


This review examines the available evidence for targeting a specific mean arterial pressure (MAP) in sepsis resuscitation. The clinical data suggest that targeting an MAP of 65–70 mmHg in patients with septic shock who do not have chronic hypertension is a reasonable first approximation. Whereas in patients with chronic hypertension, targeting a higher MAP of 80–85 mmHg minimizes renal injury, but it comes with increased risk of arrhythmias. Importantly, MAP alone should not be used as a surrogate of organ perfusion pressure, especially under conditions in which intracranial, intra-abdominal or tissue pressures may be elevated. Organ-specific perfusion pressure targets include 50–70 mmHg for the brain based on trauma brain injury as a surrogate for sepsis, 65 mmHg for renal perfusion and >50 mmHg for hepato-splanchnic flow. Even at the same MAP, organs and regions within organs may have different perfusion pressure and pressure–flow relationships. Thus, once this initial MAP target is achieved, MAP should be titrated up or down based on the measures of organ function and tissue perfusion. In 1969, Weil and Shubin emphasized the importance of fluid resuscitation followed by cardiovascular support with vasoactive agents for the treatment of shock . The SurAlthough this strategy has been well established, blood pressure target in septic shock patients remains a subject of ongoing controversy. The Surviving Sepsis Campaign Guidelines recommend MAP target of 65 mmHg as a starting point , but thiIn 2004, Asfar et al. conducted a multicenter, randomized, open-label, prospective study involving 776 septic shock patients in French intensive care units (ICU) . The stuTaken together, the available evidence underscores the importance of personalizing the MAP target based on clinical responses of individual patients with septic shock. Heterogeneity, not only of patients, but their individual organs and microcirculation , 7 makesHumans, like other warm-blooded animals, maintain relatively high blood pressure at the expense of its multiple potentially negative consequences, such as myocardial ischemia, atherosclerosis, aneurysm or chronic kidney disease. This is because high blood pressure is necessary to allow autoregulation of organ blood flow to occur.Autoregulation is defined as the intrinsic ability of organs to maintain a constant blood flow despite changes in perfusion pressure . Since oOrgans can increase their own individual blood flow to meet their changing metabolic demands primarily by decreasing resistance, or vasodilation. Accordingly, both inflow pressure and intra-organ inflow resistance at the baseline must be sufficiently high to leave sufficient room for autoregulation of organ blood flow to occur. As a corollary, hypotension alone impairs local autoregulation independent of other factors like vasomotor tone and vascular responsiveness because without a sufficiently high inflow pressure, changes in local vascular resistance will not result in changes in local blood flow.Organ perfusion pressure is the difference between the inflow pressure and outflow pressure. In a totally vasodilated vasculature, outflow pressure approximates local venous pressure. Inflow and outflow pressures differ across vascular beds and can be altered by various diseases Table . AlthougUnder normal conditions, distribution of organ blood flow is determined by local metabolic demands. For example, cerebral blood flow increases in the cortex when the mind is actively thinking , and spl2 utilization of a whole body [This is because autoregulation, though central for normal blood flow homeostasis, is overruled in circulatory shock where baroreceptor-induced hypotension induces profound sympathetic nervous system output. Thus, in circulatory shock, sympathetic-induced vasoconstriction, not the metabolic-related vasoconstriction, becomes the primary determinant of organ blood flow distribution. The massive sympathetic discharge causes α-adrenergic receptor-based vascular vasoconstriction to occur as a function of the amount of vascular α-adrenergic receptor density and responsiveness of a given vascular region. Skin and skeletal muscle have large concentrations of α-adrenergic receptors and constrict markedly in response to circulatory shock. The gut has less α-adrenergic receptors and the kidneys lesser still. Importantly, the heart has minimal α-adrenergic receptors and the cerebral circulation none. Therefore, in case of severe systemic hypotension, organ blood flow will be diverted away from the skin, non-exercising skeletal muscles and splanchnic viscera to support the brain, heart and kidney blood flow . This reole body . ImportaUnder normal conditions, if inflow pressure were to be abruptly decreased, organ blood flow would also decrease and then cease at an inflow pressure higher than outflow venous pressure. This organ-specific stop-flow pressure is called critical closing pressure (Pcc) and it was first proposed by Burton . Pcc is Under normal resting conditions, perfusion pressure is the difference between inflow pressure and Pcc, and outflow venous pressure does not influence organ blood flow . This phIt is critically important to identify patients whose perfusion pressure is below the autoregulation threshold because from the point downward, organ blood flow is usually inadequate and organ perfusion will solely depend on perfusion pressure. This is the rationale for using vasopressors to restore organ perfusion pressure during acute resuscitation in fluid resuscitated patients with septic shock. Regrettably, there is not one threshold MAP because each organ system has a different inflow and outflow pressures and internal control systems linked to their individual physiologic roles . For exaAlthough the Surviving Sepsis Guidelines recommend using vasopressor to support an initial MAP target of 65 mmHg followed by individualized titration , this reLooking specifically at renal function, however, other studies found that targeting an MAP higher than 70 mmHg might be beneficial , 25. FurIn this context, Asfar et al. conducted a multicenter, randomized, stratified, open-label study called the Assessment of Two Levels of Arterial Pressure on Survival in Patients with Septic Shock (SEPSISPAM) to determine whether targeting an MAP of 65–70 mmHg was more or less effective than targeting a higher MAP of 80–85 mmHg [Importantly, targeting a higher MAP in all patients was not without risk. Although this study was underpowered to detect any differences in incidence of most of the adverse events, which were rare, the majority of adverse events (mainly tachyarrhythmias) were reported higher in the high-MAP target group who required higher infusion rates and duration of vasopressors .The study supports the recommendation that targeting an initial MAP of 65–70 mmHg in a patient without prior chronic hypertension is a reasonable first approximation, after which time MAP levels should be adjusted up or down as end-organ function dictates. Whereas in the patient with chronic hypertension, targeting a higher MAP around 80–85 mmHg appears to be a reasonable first step, but it should be done with caution because of the potential risk of adverse events due to higher doses and duration of vasopressors that would be necessary. Although no study to date has shown the impact of the dose and duration of vasopressors on survival, studies have consistently shown the risk of adverse events due to vasopressor use, ranging from 10 to 12 % –29.These findings underscore the importance of personalizing target MAP based on individual patient’s clinical response. There is no “one-size fits all” when it comes to optimal MAP for septic shock patients. This may seem to be an obvious conclusion, since MAP is not organ perfusion pressure, as described above. In fact, organ perfusion pressure is highly heterogeneous, not only between patients, but also within the same patient over time and among their organs and microcirculation during the evolution of septic shock , 7. ThisAfter the SEPSISPAM study was published, two review articles were published analyzing blood pressure targets for septic shock patients. Leone et al. reviewed 12 studies including 7 comparative studies that addressed different blood pressure goals on patient outcomes . They coD’Aragon et al. also reviewed 12 studies including two randomized control studies, which were the SEPSISPAM study and a Czech study, and 10 crossover studies . They reThe issue of vasopressor choice needed to support a given target MAP is also relevant to this discussion. It had been suggested that dopamine might increase splanchnic blood flow in well-resuscitated patients with septic shock , but SOA2 or iloprost) infusion showed improvement in both cardiac output and hepato-splanchnic blood flow [Meanwhile, it has been suggested that vasodilators such as prostacyclin may improve hepato-splanchnic circulation . In a smood flow . NotablyAs early as the time of Hippocrates more than 2500 years ago, sepsis has been known to affect brain function . Sepsis-Cerebral perfusion pressure (CPP) is defined as the difference between MAP and either CVP or intracranial pressure (ICP), whichever is higher. Under normal conditions, the brain maintains a high degree of autoregulation . NotablyA study using transcranial Doppler and near-infrared spectroscopy showed that cerebral autoregulation is disturbed in severe sepsis, presumably due to vascular endothelial dysfunction . Cerebra2 saturation, jugular venous oxygen saturation, transcranial Doppler and cerebral microdialysis studies, autoregulation threshold for CPP is thought to be around 50–60 mmHg [There are no clinical studies looking specifically at optimal MAP for the brain in severe sepsis, but a growing body of evidence looking at the relationship between CPP and outcomes in patients with traumatic brain injury (TBI) may prove helpful. Based on multiple indices such as brain tissue O–60 mmHg , 47.Accordingly, Brain Trauma Foundation recommends a target CPP between 50 and 70 mmHg . Within One exciting development in the management of CPP in TBI patients is the emergence of autoregulation-based therapy using cerebrovascular reactivity, which can be determined by looking at response of ICP to changes in MAP . Loss ofSepsis-induced myocardial depression is common and it tends to appear later in the course of the disease. Initially, patients with severe sepsis present with reduced CO, despite the preserved left ventricular ejection fraction because stroke volume is reduced as a result of decreased preload and vasomotor tone , 56. BotLater in their course, typically within the first 72 h, 40–50 % of these patients develop myocardial depression . Their CPathophysiology of sepsis-induced myocardial depression is complicated and involves various mechanisms, such as downregulation of β-adrenergic receptors, decreased sensitivity to calcium or increased nitric oxide production , 60–62. These findings led to a hypothesis that perhaps sepsis-induced myocardial depression is an adaptive response by which human heart attempt to prevent activation of cell death pathways and to allow full functional recovery by reducing energy expenditure .If that would be the case, the best management of heart in sepsis may be to avoid further stresses on the heart. Interestingly, recent randomized control trial showed improved clinical outcome using β-blockers in septic shock patients . While iRenal function may be the most studied with regard to target blood pressure in patients with severe sepsis or septic shock. Early animal study by Robertson et al. had shown that autoregulation threshold of kidneys might be around 80 mmHg . At leasMore recent studies seemed to favor somewhere in the middle. A larger, but retrospective clinical study by Dünser et al. showed that MAP below 75 mmHg was associated with a higher requirement of renal replacement therapy . NotablyIn elderly patients or patients with hypertension, atherosclerosis or chronic kidney diseases, the autoregulation curve of kidneys can be shifted significantly to the right , 73. ThiTo confirm this, Asfar et al. stratified their study population at the time of randomization according to whether or not they had a history of chronic hypertension . More thNotably, what is missing in all of these studies is the consideration of IAP. The renal perfusion pressure becomes the difference between MAP and IAP when IAP exceeds CVP. IAP can be measured at the bedside using bladder pressure , 75. IAHGiven the current state of evidence, MAP target of 65 mmHg may be reasonable in septic shock patients without any heightened susceptibility to AKI, such as preexisting chronic hypertension, atherosclerosis, chronic kidney disease or advanced age. In contrast, septic shock patients with these risk factors may benefit from higher target MAP of 80 mmHg. In patients with IAH, further increase in MAP target may be necessary, depending on their IAP. Notably, multiple other conditions including the use of medications such as nonsteroidal anti-inflammatory drugs can also impair kidney’s autoregulation and may benefit from higher MAP.Vasopressor of choice to achieve desired MAP is norepinephrine. Norepinephrine reduces renal blood flow in normal condition, but increases in sepsis by both decreasing renal vascular resistance and Pcc . VasopreThe liver plays a critical role in severe sepsis and septic shock for two reasons . First, Unlike the other organs, but like the lungs, the liver receives both arterial and venous blood flow. Hepatic artery supplies 25–50 % of hepatic blood flow and portal vein supplies the remainder . RegulatSevere sepsis affects the liver in two stages . In the Often, hepatic and splanchnic circulations are studied together due to technical difficulties in isolating one from another , and stuThe available evidence suggests that targeting an MAP of 65–70 mmHg in a patient with septic shock who does not have chronic hypertension is a reasonable first approximation. Whereas in a patient with chronic hypertension, targeting an MAP of 80–85 mmHg appears to be a reasonable first step. It must be done with caution, however, because the use of vasopressors is associated with adverse events. After these initial treatments, MAP should be titrated up or down based on the individual patient’s response, but heterogeneity, not only of patients, but of organs and microcirculations affected by septic shock makes it challenging. Caution needs to be taken in all patients in using MAP alone as surrogate of organ perfusion pressure, especially under conditions in which intracranial or intra-abdominal pressure may be elevated.If sepsis-associated delirium is the primary concern, a growing body of evidence regarding the management of traumatic brain injury patients suggests that MAP target between 50 and 70 mmHg is needed. Further titration of MAP based on multi-modal monitoring including pressure-reactivity index may worth further investigation.Sepsis-induced myocardial depression, though challenging in its management, may be an adaptive response by the heart in sepsis. Because coronary blood flow is increased, MAP target should not guide its management. Rather, it is important not to stress the heart any further by avoiding excessive or prolonged use of vasopressors. Recent study suggests promising role of β-blockers.Target MAP in septic shock is most studied in relation to sepsis-associated AKI. In patients without chronic hypertension, atherosclerosis, chronic kidney disease or advanced age, MAP target of 65 mmHg may be reasonable. For patients with these risk factors, MAP target of 80 mmHg may be better. It should be noted, however, that recent evidence suggests that hypotension may not be the primary mechanism of sepsis-associated AKI.Finally, hepatic dysfunction or mesenteric ischemia that can be associated with septic shock may not only result from the disease, but also from excessive use of vasopressors. MAP target as low as 60 mmHg may be reasonable to reduce vasopressor requirement. Furthermore, there may be a role of vasodilator in the management of hepato-splanchnic blood flow.


Diabetes is the most common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in most parts of the world. 20 to 30% of diabetic patient have diabetic nephropathy in type 1 and type 2. Hyperglycemia is the key of nephropathy creation. Hyperglycemia also by production of toxic materials, advanced glycosylated end product (AGE), increased activity of aldose reductase has some role. Some metabolites of arachidonic acid, hemodynamic derangements and genetic factors have also some role. Although diabetic nephropathy is most common cause of nephropathy in these patients, but diabetic patients are also prone to other urinary tract and renal parenchymal disease and should not be confused with renal failure due to diabetic nephropathy. The principle of treatment of diabetic nephropathy is based on tight control of hyperglycemia, tight control of blood pressure and glomerular pressure, control of dyslipidemia, restriction of protein intake and smoking withdrawal. Diabetes is the most common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in most parts of the world. 20 to 30% of diabetic patient have diabetic nephropathy in type 1 and type 2. The principle of treatment of diabetic nephropathy is based on tight control of hyperglycemia, tight control of blood pressure and glomerular pressure, control of dyslipidemia, restriction of protein intake and smoking withdrawal.Kidneys are one of the important organs that are involved in diabetes. Diabetes is the most common cause of end-stage renal disease (ESRD) in most parts of the world. Kidney involvement both directly and indirectly increase involvement of other organs and increase morbidity and mortality in diabetic patients.Since with untreated diabetic nephropathy, a significant decrease in life expectancy of patients happens; therefore, prevention of this debilitating condition and if there is, early diagnosis and treatment is important.Due to the increasing industrialization of societies, increased immobility and changes in diet and lifestyle and increasing prevalence of obesity, insulin resistance and type 2 diabetes prevalence is increasing.Because many of the classic symptoms of diabetes in type 2 diabetes, unlike type 1 diabetes, do not occur, the importance of screening methods for identifying these patients and screening them for kidney involvement is very important.Diabetic nephropathy is now the most common cause of chronic kidney disease (CKD). Both types of diabetes can lead to chronic kidney disease and eventually ESRD. But given the much higher prevalence of type 2 diabetes than type 1, often patients with ESRD have type 2 diabetes.The overall incidence 20 years after diagnosis is approximately 4 to 17% and after 30 years is about 16%.According to some studies, the incidence of nephropathy in type 1 diabetes is decreasing  production. In hyperglycemia some excess glucose binds with amino acids in blood or tissue proteins and ultimately leads to the production of AGE .1c.AGE binds to collagen and cause microvascular complications and renal complications .Long-term hyperglycemia causes structural changes in some proteins that biological activity of these new compounds are high, like HbAStudies show that proteins containing AGE increase protein kinase C activity and appearing of TGFβ. Protein kinase C provides an important role in cell proliferation and differentiation, and apoptosis. This enzyme increases extracellular matrix and cytokines and production of endothelin. This changes causes thickening of the glomerular basement membrane and obstruction of arteries and increased glomerular permeability.Another important enzyme in the pathogenesis of diabetic nephropathy is aldose reductase. This enzyme converts glucose to sorbitol. Long-term hyperglycemia increases the enzyme activity and sorbitol production, which increases the extracellular matrix. Accumulation of extracellular matrix in the mesangium and glomerular basement membrane (GBM) increase mesangium volume and thickening of GBM.Some metabolites of arachidonic acid by activating the receptor TXA2 (thromboxane A2) lead to oxidative stress and glomerular injuries .The earliest histological change is thickening of GBM . ApproxiIn overt nephropathy, both GBM thickening and increased mesangial matrix often are present. Mesangial matrix expansion leads to glomerular sclerosis. In about half of patients glomerular sclerosis has nodular pattern which is known as Kimmelstiel-Wilson nodules that shows severe glomerular sclerosis. Histological lesions pathogenesis are the same in type 1 and 2 diabetes. The main pathological lesions that lead to clinical albuminuria and nephropathy is increased mesangial matrix.Mesangial matrix expansion strongly increases the development of systemic hypertension and urinary albumin excretion ,13. The Other glomerular lesion is podocyte separation of the GBM and decreased foot process that will lead to worsening of proteinuria -17.Another important factor in the development of glomerular lesions is hemodynamic derangements. Auto-regulation of renal blood flow is impaired in diabetic nephropathy, so abnormal dilation of afferent arteriole leads to increased glomerular filtration and this can lead to glomerular sclerosis in long term.After developing sclerosis blood flow in remaining intact glomeruli increases and causes rise in glomerular pressure so eventually sclerosis.Systemic blood pressure can also directly transfer to the glomeruli and causes glomerular sclerosis. In type 1 diabetes with microalbuminuria, systemic blood pressure will begin to increases, although it may still be within normal range. Many patients with type 2 diabetes also have essential hypertension that increases after beginning of renal lesions.Many patients with long-term hyperglycemia have no nephropathy while others with not very long disease course have clinical nephropathy. This may be due to predisposing factors including genetic.Risk of diabetic nephropathy increases in type 1 and type 2 diabetic patients with a history of diabetic nephropathy in one of their first degree relatives.One of the genetic factors is angiotensin type 2 receptor gene on the X chromosome.Male patients with type 1 diabetes who are homozygous for the gene have lower glomerular filtration than heterozygous groups . AnotherIn a study on type 2 diabetic patients with proteinuria, 95% of individuals with the DD genotype reach ESRD in 10 years and after starting dialysis, patients with DD genotype had higher mortality.Diabetic patients who have a family history of hypertension or cardiovascular disease are more likely to develop nephropathy. Also the polymorphisms of genes related to insulin resistance plays a role in the development of diabetic nephropathy.There are various methods for screening of diabetic nephropathy in patients. It actually starts to prove microalbuminuria, to prevent its progress toward macroalbuminuria , or even turn it into normoalbuminuria status.Microalbuminuria defines as urinary excretion of 30-300 mg of albumin in the 24 hours urine collection continuously. Macroalbuminuria of clinical nephropathy is when albumin excretion in 24 hours urinary collection be greater than 300 mg continuously.Some evidence indicates that the onset of type 1 diabetes before puberty may play a role in creating microvascular complications including nephropathy. Therefore, clinical judgment about when to start screening on every patient should be considered individually. If hyperglycemia, hypertension and lipid disorders are not well controlled, in type 1 diabetic patients, microalbuminuria may develop in less than five years from the onset of diabetes . It is lThere are two conventional methods for microalbuminuria screening:1) Measuring the Alb/Cr ratio in a random urine sample which the morning sample is better.2) 24-hour urine collection and measurement of albumin.It should be noted that conventional strip test is not able to detect microalbuminuria. Therefore, negative urine protein analysis with this method does not reject microalbuminuria.It should be considered that some drugs such as ACEIs and ARBs and non-dihydropyridine calcium channel blockers  decrease urinary albumin excretion and may cause the tape test be negative . Some conditions like high and uncontrolled blood pressure, fever, heavy physical activity, uncontrolled hyperglycemia and acute infections increase transiently in urinary excretion of albumin .Because of the large daily changes in urinary albumin excretion rate, to prove the existence of microalbuminuria, test should be repeated three times at intervals of 3-6 months. It needs to demonstrate persistent microalbuminuria with at least two positive tests.Classification of clinical stages of diabetic nephropathy is as follows:Since the beginning of diabetes, glomerular filtration and renal blood flow increases and the kidneys enlargement  is also seen. The urine albumin excretion (UAE) rate was still less than 30 mg in 24 hour and blood pressure is also normal. The first pathological result is thickening of the GBM. Whatever hyperfiltration rate is more, developing of nephropathy is higher. If the initial glomerular filtration rate (GFR) is more than 150 ml per minute it will increase the chance of diabetic nephropathy .With the progression of kidney involvement, UAE will also increases. It is also called, hidden or subclinical nephropathy. In this stage the conventional strip test is often negative. At this stage the risk of cardiovascular disease begins to increase. Changes in albuminuria rate in time is associated with different risk of decreased kidney function, so in microalbuminuric patients that the rate of albumin exertion increased, constant or decreased, the risk of decreased GFR is very high, moderate and low respectively . In typeDiagnosis at this stage is a very good opportunity to prevent progression to clinical nephropathy or even back to the normoalbuminuria situation. But without treatment, the risk of developing clinical nephropathy in type 1 diabetic patients after 10-15 years (more than 75%) and in type 2 after 15-20 years (20-40%) is high.In a study on 75 adult patients with type 1 diabetes who were normoalbuminuric and had normal blood pressure during a follow-up of more than five years, the UAE and their blood pressure were monitored. 24-hour blood pressure (ambulatory) of patients was controlled . In the Ratios equal to or less than 0.9; the natural drop in blood pressure at night, had negative predictive value of 91% for microalbuminuria. Furthermore, the risk of microalbuminuria in the group with equal or less than 0.9, was seventy percent less than the group with more than 0.9. The conclusion is that in type 1 diabetic patients increased systolic blood pressure at night (sleep), is a predictor of microalbuminuria in the future.If microalbuminuria is associated with retinopathy, the probability that the origin of microalbuminuria is due to diabetes, increases. Conversely, when there is no retinopathy, other causes of CKD are probable.However, the predictive value of microalbuminuria in diabetic nephropathy in type 1 diabetes is more than type 2,because many type 2 diabetic patients develop microalbuminuria because of hypertension and nephrosclerosis.This stage also called clinical nephropathy that occurs about 10-20 years after onset of diabetes, . In this stage coronary artery disease and cerebrovascular events also increases obviously compared to the previous stage. About 75% of patients in this stage have high blood pressure. Control of blood pressure in type 2 diabetic patients with previous hypertension, is more difficult.At this stage the conventional dipstick test is positive for proteinuria and urinary albumin excretion rate in 24h collection is more than 300 mg. After this, GFR decline, about 10-12 ml annually.With the onset of clinical nephropathy and in the absence of therapeutic interventions, progressive decline in kidney function occur and proteinuria increases that can reaches the nephrotic range. Diabetic retinopathy is very helpful to confirm the diagnosis of diabetic nephropathy. Hypertension and proteinuria, independently leads to reduce GFR and progression to ESRD.20% of type 2 diabetic patients before the onset of clinical nephropathy and 40% of them with clinical nephropathy have renal vascular disease .Tubulointerstitial fibrosis also begins at this stage, and if the extent and severity is more, renal lesions and prognosis will be worse.In clinical nephropathy patients develop hypoalbuminemia and edema. Serum albumin level in diabetic patients with nephrotic syndrome who have generalized edema is higher than non-diabetic patients with nephrotic syndrome; because glycated albumin in diabetic patients passes easily through the capillary wall, then water shifts from plasma to interstitial space.Basically this means that in diabetic patients with nephrotic syndrome the edema will develop with milder hypoalbuminemia than nondiabetic patients with nephrotic syndrome .In approAlmost 20-30 years after onset of diabetes,approximately 10 years after the onset of clinical nephropathy, the patient reaches this stage. The risk for type 1 is more than type 2 diabetes. But the prevalence of type 2 diabetes is 9 times more than type 1, so most diabetic patients with ESRD have type 2 diabetes.In these circumstances, the mortality rate in diabetic patients is more than nondiabetic patients. In addition cardiovascular and cerebrovascular disease in these patients is higher. In this stage, the incidence of diabetic foot ulcers is higher, which sometimes reach 25%.In the UKPDS report, annual chance of progression from diagnosis of diabetes to onset of microalbuminuria, from onset of microalbuminuria to overt nephropathy, and overt nephropathy to increase in serum creatinine or switching to renal replacement therapy, is respectively, 2, 2.8, 2.3%.In order to prove the diagnosis of diabetic nephropathy, the following criteria are used:1)Enough time: At least 10 years past the onset of diabetes, but this criterion is often not verifiable in type 2.2)Persistent albuminuria more than 300 mg in 24 hours: Given that almost all patients with type 1 diabetes with diabetic nephropathy have retinopathy, retinopathy in patients with first and second criteria, prove the diagnosis, and lack of it virtually excluded diagnosis.3)Diabetic retinopathy at the same timeConsidering that only 50-60% of type 2 diabetic have retinopathy at the time of diagnosis of nephropathy, the presence of diabetic retinopathy, confirms the diagnosis, however, its absence does not exclude the diagnosis. If retinopathy was not present, it must first ensure the absence of other renal diseases.Our study demonstrated that the prevalence of retinopathy in type 2 diabetic patients in microalbuminuria stage was 67% and in macroalbuminuria stage was 86% and the prevalence of diabetic nephropathy in patients with retinopathy was 72%.Also there is a significant relationship between the severity of nephropathy and retinopathy in the non-proliferative diabetic retinopathy but this relationship was not significant in the proliferative diabetic retinopathy .A fundamental question is whether a diabetic patient with advanced diabetic nephropathy have normal urinary albumin excretion rate? The answer is yes .Diabetic patients are also prone to other urinary tract and renal parenchymal disease and should not be confused with renal failure due to diabetic nephropathy. For example, the possibility of acute renal failure following acute pyelonephritis in these patients is more than general population. One of the problems that involves these patients frequently is bladder detrusor muscle dysfunction (neuropathic bladder), that can lead to obstructive nephropathy. In these patients due to renal artery stenosis at the same time, ischemic renal disease is likely, that can lead to acute and progressive or chronic kidney failure. In diabetic patients, type IV renal tubular acidosis  is probable, that exacerbate by renin-angiotensin- aldosterone system inhibitor and non-steroidal anti-inflammatory drugs.The risk of acute tubular necrosis (ATN) after using contrast agents, is high. Also, these patients because of diabetic neuropathy have gastroparesis and vomiting and are prone to hypovolemia and acute renal failure. Systolic heart failure in these patients is due to multiple risk factors that can lead to prerenal failure or ischemic tubular necrosis.Another major complication of diabetes is the papillary necrosis that can lead to obstructive acute renal failure in bilateral ureteral obstruction or unilateral obstruction in one kidney patients or in patients with underlying CKD.It should be noted that the majority of patients with diabetic nephropathy have neuropathy at the same time. It is not necessary for diagnosis of nephropathy but its absence diminishes the likelihood of diabetic nephropathy. Some criteria that should be mentioned for diagnosis of non-diabetic nephropathy are in It should be noted that microscopic hematuria without RBC cast is seen frequently in biopsy-proven diabetic nephropathy . In a stIt should be noted that many patients with CKD due to diabetic nephropathy does not have small kidneys. In other words, small kidneys  prove the diagnosis of chronic renal failure in diabetic nephropathy, but lack of small kidneys, does not exclude the diagnosis.Treatment of diabetic nephropathy is based on some principle:1)Tight control of hyperglycemia2)control of blood and glomerular pressure3)Control of dyslipidemia4)Restriction of protein intake5)Smoking withdrawal.1c<7% but some offer <6.5%.Tight control of glucose can prevent microalbuminuria, conversion of microalbuminuria to macroalbuminuria and may be leads microalbuminuria status to normoalbuminuria.The goal is to achieve a HbAThe exact treatment of hyperglycemia with insulin can return glomerular hypertrophy and hyperfiltration partially. However, both are risk factors for diabetic nephropathy.Treatment with insulin can reach blood glucose to almost normal range, so it reduces the onset or progression of nephropathy . Also, tHypertension and proteinuria, both progress nephropathy, and lead to ESRD.Considering the pro-fibrotic effects of angiotensin II on vascular system, inhibit the effect, reduce capillary pressure and also may prevent glomerular lesions.In addition to exact hyperglycemia control, by strict control of blood pressure and use of renin- angiotensin-aldosterone system inhibitors, risk of nephropathy progression clearly reduce.All antihypertensive medications are effective in reducing systemic blood pressure, but the most effective drugs in reducing intra-glomerular pressure, are renin-angiotensin-aldosterone inhibitors such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor inhibitors (ARBs).When type I diabetic patients suffer from high blood pressure, they usually have reached to clinical nephropathy. While about 30% of type 2 diabetic patients in time of diagnosis of diabetes and about 70% at beginning of diabetic nephropathy have high blood pressure.Using combination of ACEIs and ARBs reduce UAE in 35% and ESRD in 28% in diabetes type 2 compared using alone .In the prospective, open and controlled study was done by author, combination of losartan 100 mg daily and enalapril 40 mg daily has beneficial effects of antiproteinuria more than monotherapy with either of these drugs in patients with type 2 diabetes. This antiproteinuric effect is independent from antihypertensive effect and in short term can delays kidney failure. This dual therapy did not have risks and side effects more than single treatment .et al. evaluated 45 patients with idiopathic proteinuric nephropathy and showed combination of ACEIs and ARBs with lower doses also has similar role  or the sodium potassium exchange resins [kayexalate (sodium polystyrene)] can use. Both types of treatment in patients with cardiac decompensation may exacerbate previous failure .The most common lipid disorder in diabetes is increased triglycerides and reduced HDL. Although LDL levels in these patients is usually normal, but it has high atherogenic properties.Accompaniment of glucose intolerance or diabetes, high blood pressure, low HDL and high triglycerides, obesity and sometimes high LDL are known as metabolic syndrome, will lead to increased risk of cardiovascular disease.Due to the presence of hypertension, dyslipidemia and diabetes, there is a risk of nephropathy and its progression.Treatment of lipid disorders reduce microvascular (nephropathy and retinopathy) and macrovascular  complication in diabetic patients.Therapeutic purposes by the American diabetes association are: The blood triglyceride level of less than 150 mg/dL, HDL over 60 mg/dl and LDL less than 100 mg/dL.In diabetic patients over 40 years age, that their total cholesterol levels is >135 mg/dl, treatment with statins may be useful to reduce LDL by 30% from the baseline value (regardless of its amount) .In the Physician's Health Study that was conducted during fourteen-year follow-up, dyslipidemia was associated with increased risk of renal failure in men who initially had normal renal function .An interesting study was performed about the effects of LDL apheresis on improvement of kidney function in type 2 diabetic patients with nephrotic proteinuria (due to diabetic nephropathy). The first group included five men and three women with a mean age of 54.6 years and the second group included six men and four women, with mean age of 56.6 years. Both groups had prolonged nephrotic syndrome. LDL apheresis effect on proteinuria and urinary podocyte (podocyturia) was studied. The first group receives apheresis and at the end of the study was found that total cholesterol, LDL, LP (a), urea and serum creatinine were significantly lower and creatinine clearance was significantly increased. Also urinary protein excretion rate and urine podocyte decreased in these patients significantly .High protein intake can increase glomerular filtration and sclerosis. Studies have shown that reducing protein intake in diabetic patients can reduce proteinuria and slow the progression of renal failure. Protein restriction can lead to decrease symptoms of uremia and delay need for dialysis.The possible mechanism of effect of protein restriction is reduced hyperfiltration in healthy nephron.American diabetes association recommends the maximum daily intake of protein is 0.8 g protein per kg for patients who have increased urinary albumin excretion .However, it must be noted that severe protein restriction increases morbidity and mortality in ESRD patients.In a study effects of smoking on renal complications in 359 type 1 diabetic patients were evaluated. In those who were smokers, prevalence of UAE was higher (2.8 times) than non-smokers. After stopping of smoking, there was a clear improvement in the UAE. Similar results also obtained in type 2 diabetic patients with nephropathy.The principle of treatment of diabetic nephropathy is based on tight control of hyperglycemia, tight control of blood pressure and glomerular pressure, control of dyslipidemia, restriction of protein intake and smoking withdrawal.The authors wish to thanks the following people, staff of diabetes research center for their valuable help and contribution to this manuscript: Drs. Aleali and Drs. Yazdanpanah. We are also grateful to Dr. Rezaii for his unsparing help.All authors equally prepared the manuscript.The author declared no competing interests.Ethical issues  have been completely observed by the authors.None declared.


Primary aldosteronism is a frequent form of secondary hypertension that had long been considered relatively benign. Experimental and clinical evidence collected in the last two decades, however, has clearly demonstrated that this endocrine disorder is associated with excess cardiovascular and renal complications as compared to essential hypertension. These complications reflect the ability of inappropriate elevation of plasma aldosterone to cause tissue damage beyond that induced by high blood pressure itself, thereby setting the stage for major cardiovascular and renal disease. Because of the impact of elevated aldosterone on organ damage, goals of treatment in patients with primary aldosteronism should not be limited to normalization of blood pressure, and prevention or correction of organ complications is mandatory. Treatment with mineralocorticoid receptor antagonists or unilateral adrenalectomy is the respective options for treatment of idiopathic adrenal hyperplasia or aldosterone-producing adenoma. Last years have witnessed a rapid growth in knowledge concerning the effects of these treatments on cardiovascular and renal protection. This paper is an overview of the cardiovascular and renal complications that occur in patients with primary aldosteronism and a summary of the results that have been obtained in the long term on cardiovascular and renal outcomes with either medical or surgical treatment. Aldosterone is secreted by the outermost portion of the adrenal cortex and contributes to regulation of blood pressure. Aldosterone acts at the distal tubular site of the nephron where it increases water and sodium reabsorption thereby leading to extracellular fluid expansion. Evidence collected in the last two decades indicates that, in addition to the regulatory role in body fluid and electrolyte balance, aldosterone affects a variety of cell functions that may result in tissue fibrosis. Expression of mineralocorticoid receptors has been detected in different cell types obtained from cardiac and vascular tissues  and robuPrimary aldosteronism (PA) is one of the most frequent forms of secondary hypertension and among patients with high blood pressure there is evidence of a much higher prevalence of this condition than the previously estimated frequency of less than one percent –5. HyperIdiopathic adrenal hyperplasia (IHA) and aldosterone secreting adrenal adenoma (APA) account for more than 95% of forms of PA and, with few exceptions, are characterized, respectively, by bilateral or unilateral involvement of the adrenal glands . Adminis+/K+ ATPase (ATP1A1) [2+ ATPase calcium channel (ATP2B3) [The last few years have witnessed an explosive growth in knowledge of the genetic basis of PA, and many different somatic mutations, all involving genes encoding ion channels, have been described in patients with APAs . After t(ATP1A1) , Ca2+ AT(ATP2B3) , and vol(ATP2B3)  have bee(ATP2B3) , 24. Det(ATP2B3) , 24 or r(ATP2B3) . Therefo(ATP2B3) . This paAs stated previously, current treatment for APA is adrenalectomy, because surgery apparently confers a greater possibility of cure and avoids the possible side effects of MR antagonists . ChronicInitial studies reported a low prevalence of cardiac complications in patients with PA  and subsIt is known that subclinical cardiac and vascular changes anticipate major cardiovascular events in patients with high blood pressure. In patients with PA, higher prevalence of a variety of cardiac abnormalities has been reported together with structural  and funcEchocardiographic investigations of cardiac changes after treatment of PA were initially confined to short-term studies performed after adrenalectomy and showed significant reduction of the left ventricular mass together with improvement of diastolic function . Later oHigh-affinity MR has been detected in cardiac myocytes and fibroblasts  and theiβ-hydroxysteroid dehydrogenase (11β-HSD2), the enzyme that converts cortisol to the receptor-inactive cortisone. Moreover, activity of 11β-HSD2 generates NADH from NAD and produces changes in the intracellular redox potential that might, in turn, inactivate the glucocorticoid-MR complex [β-HSD2 is not present in nonepithelial tissues including the heart, but in such tissues, changes of the intracellular redox potential can result from generation of reactive oxygen species and thereby affect the activity of the MR [ In vitro experiments have demonstrated that changes in the redox potential of cardiomyocytes by exposure to oxidized glutathione turn cortisol from being an MR antagonist to an agonist [MRs are found in epithelial and nonepithelial tissues with high affinity for aldosterone and glucocorticoid hormones. Under physiological conditions, the majority of MRs in nonepithelial tissues are bound to cortisol, whereas in epithelial tissues, binding of cortisol to MR is prevented by 11 complex . 11β-HSDf the MR . In vitr agonist . Recentl agonist  through  agonist  leading 2 in only 7% of 56 patients with PA [Although animal studies demonstrated that inappropriately elevated aldosterone levels for the salt status cause renal tissue damage , the cli with PA , whereas with PA . In pati with PA  to 24% [ with PA  a dispar with PA , prevale2/year) or EH (−1.06 mL/min/1.73 m2/year) were comparable. Urinary albumin losses did not differ between patients with PA or EH during the long-term phase of follow-up. Separate analysis of renal outcomes in patients with PA who were treated with spironolactone or adrenalectomy did not reveal significant differences.Crucial data on the role of the kidney in PA were reported in two prospective studies in which PA patients were followed in the short and long term after treatment. In 25 patients with adrenal adenoma who were followed for 6 months after adrenalectomy, Ribstein et al.  found a These two important prospective studies have consistently indicated that PA is characterized by a partially reversible renal dysfunction, suggesting that proteinuria might be the marker of a renal hemodynamic defect. Consistent with the findings of past investigations conducted on the effects of mineralocorticoid hormones on renal function  some of Similar to the heart, exposure to aldosterone levels that are inappropriate for the salt status or activation of MR can damage the kidney via mechanisms that are independent of blood pressure . ElevateAnother issue that is worth mentioning is related to prevalence of simple renal cysts in PA. In a first cross-sectional study, Torres et al.  used CT Current evidence unquestionably indicates a high rate of cardiovascular complications in patients with PA, showing that this condition is far from being benign. The high rate of complications in PA patients, however, is not merely explained by blood pressure elevation. Elevated aldosterone causes myocardial hypertrophy and fibrosis over that induced by high blood pressure itself and, together with vascular structural and functional changes, sets the stage for future cardiovascular events. With regard to the kidney, there are PA intrarenal hemodynamic changes leading to relative glomerular hyperfiltration and increased urinary protein losses. These functional changes are fully reversible until structural damage of intrarenal vessels ensues as the result of persistent hypertensive insult. Follow-up studies of patients with PA indicate that both medical and surgical treatments effectively lower blood pressure, correct subclinical organ damage, and decrease the risk of cardiovascular events and renal disease progression. In this view, timely identification of PA patients becomes mandatory to effectively prevent organ complications. Although during the last years many questions related to the effects of aldosterone on the cardiovascular and renal system have been satisfactorily answered, many others still await clarification.


Percutaneous renal biopsy (PRB) is a decisive diagnostic procedure for children and adolescents with renal diseases. Aim of this study was to evaluate retrospectively the complication rates of percutaneous kidney biopsies and their therapeutic consequences to assess the role of ultrasound-guidance including Doppler ultrasound examinations in preparation, execution and follow-up care and to present a recommended protocol.Institutional review board approved this retrospective study; informed consent was waived. Between 1997 and 2011 a total of 438 ultrasound-guided biopsies were performed in 295 patients, 169 of the biopsies were performed on kidney transplants. Average age of patients was 10.2+/−5.2 years (range of 15 days until age of 23). Before and post biopsy ultrasound examination including Doppler examination was carried out. Biopsy itself was ultrasound monitored. Complications were analysed with regard to age of patient, kidney transplants, year of occurrence, number of punctures, performing physician and time interval of occurrence to develop an optimized protocol for ultrasound-guidance.In 99% of cases successful PRB were performed, i.e. enough kidney parenchyma for histological analysis was obtained. No lethal or major complication that required surgical intervention occurred. Eighteen relevant complications were observed (complication rate: 4.1%). Except in one case in which additional MRI diagnostic was necessary, ultrasound examination after 4 hours post biopsy or even earlier when symptoms occurred, was able to detect complications and determine indications for intervention.Ultrasound-guided PRB is an established and effective method in children and adolescents, but shows a certain rate of complications and therefore should not be indicated without diligence. Ultrasound including Doppler ultrasound is a valuable tool in preparation, guidance of biopsy, detection of complications and in follow-up care. Ultrasound examinations (including Doppler) pre-, during and 4 hours post kidney biopsy and, depending from case, a few days until weeks after biopsy is recommended. Percutaneous renal biopsy (PRB) is an established diagnostic method and has been performed for plenty of years Ultrasound-guidance of renal biopsy is an often used but not yet generally regarded standard procedure. Data shown in a multi-centre study performed on behalf of the British Association of Paediatric Nephrology emphasize the need of protocol standardization for renal biopsies that allows comparing success and complications The purpose of our study was to analyse complications with regard to age of patient, kidney transplants, year of occurrence, number of punctures, performing physician and time interval of occurrence post biopsy to develop an optimized protocol for ultrasound-guidance in preparation, execution and follow-up care of biopsies.This retrospective study was approved by the ethics committee of the Medical Faculty of the University of Cologne, which waived the requirement to prove informed consent. Since the study is purely retrospective, no further ethics considerations apply.In the Department of Paediatrics of the University Hospital of Cologne kidney biopsies have been performed ultrasound-guided since 1993. From 1997 until 2005 biopsies were taken by two trained pediatric nephrologists, since 2005 residents in training were involved.Between 1997 and 2011 a total of 438 ultrasound-guided biopsies were performed in 295 patients (164 boys and 131 girls), 169 of the biopsies were performed on kidney transplants. The average age of patients was 10.2+/−5.2 years (range of 15 days until age of 23). Indications for kidney biopsies are shown in In preparation of kidney biopsy ultrasound and Doppler ultrasound examination of kidneys were performed in each patient, independent of native kidneys or kidney transplants. In these examinations kidneys, the retro-peritoneum and the bladder were inspected to assess possible biopsy difficulties and anatomical orientation.Depending from native kidney or kidney transplant, patients were in prone or in dorsal position during biopsy. Biopsies were carried out ultrasound-guided in local anaesthesia using “Core Tissue Biopsy Needles” (14–16 Gauge). Depending from age and compliance patients got a short anesthesia.Acuson 128 XP ultrasonic device, since 2007 a GE Logic 7 ultrasonic device was used. Examinations pre- and post-biopsy were carried out until 2003 with an ultrasonic device type Acuson 128 XP  or since 2003 with an ultrasonic device type Sequoia , since 2007 additionally the GE Logic 7 ultrasonic device was used. Vector or sector transducers (3.5 to 5 MHz) or for high resolution linear array transducers with higher frequencies (7.5 to 10 MHz) were used.Until 2007 ultrasound guidance of biopsies was performed with an As well as for pre-biopsy, post-biopsy examination of both kidneys with volumetric analysis and B-mode ultrasound was performed; also an examination of bladder and an examination of the retroperitoneal space were accomplished. Since first vascular complications were observed in 2003 colour Doppler examinations were performed mandatorily.Pre-biopsy and during biopsy the distance between the lower kidney pole, the destined localization of biopsy and the skin was determined see . In rareAfter a bandage was applied a sandbag was put on the puncture site until first ultrasound examination. From 1997 until 2003 bed rest for 24 hours was necessary and ultrasound examination after 4 and 24 hours was done.From 2003 until 2011 when biopsies were performed on an outpatient’s basis, bed rest for only 4 hours was performed; ultrasonic examination was done 4 hours after biopsy, if negative patients were able to go home. If positive e.g. for bleeding or AV fistula, or if laboratory values were abnormal, e.g. declining haemoglobin levels, patients were admitted for further controls.Slim, often falciform, perirenal hematomas until a width of approx. 2.5 cm, hematomas along the puncture channel and moderate pain were considered as normal consequences of the biopsy and were not regarded as complications. “Relevant complications“ were:Perirenal or retroperitoneal bleedings causing a drop in hemoglobin of more than 10% or hematomas with a size of more than 2.5 cm widthBleedings into the renal pelvis and urinary bladderArteriovenous fistulas in the puncture area (with or without bleedings)All data were collected and analysed retrospectively. Complications were analysed with regard to therapeutic consequences, age of patient, kidney transplants, year of occurrence, number of punctures, performing physician and time interval of occurrence. The focus of this analysis was the role of ultrasound examinations in pre-biopsy examination, ultrasound-guidance of biopsy and follow-up examinations.Association of number of complication and time period (either 1997–2002 vs 2003–2011 or 1997–2004 vs 2005–2011) or number of punctures per biopsy and time period were evaluated by Pearson’s chi-square test or Fisher’s exact test, contingent on expected cell counts below 5. Moreover, the association with the number of complications was adjusted for age, gender and kidney transplant by multiple logistic regression. We could not adjust for 30 different indications, nor could we identify a sensible subgrouping. The strength of association is summarized by the odds ratio. Calculations were done with SPSS Statistics .In 99% of cases biopsies were performed successfully, i.e. enough kidney parenchyma for histological analysis was obtained.No lethal complication occurred. No permanent loss or decrease of renal function was observed. Four specific groups of complications were distinguished :Perirenal/retroperitoneal bleeding with a drop in hemoglobin of more than 10% .Three patients received a blood transfusion but none of the patients needed interventional treatment. One patient showed clinical symptoms of an acute abdomen and CRP values increased rapidly. Clinical improvement after an antibiotic treatment was observed. Except for one patient, in whom bleeding was observed during first night after biopsy, bleeding occurred within the first four hours. The hematomas were detected sonographically and their size monitored sonographically.Bleeding in the urinary tract with hematuria or blood clots in the urinary bladder (n = 5).With one exception in which a patient had a drop of hemoglobin after three weeks (which was possibly not related to kidney biopsy), patients with this complication were clinically apparent within four hours. In one case it was necessary to cystoscopically remove a bladder tamponade, the other cases showed spontaneous recovery. The size of blood clots and bleeding was monitored sonographically. Ultrasound examination methods were employed to monitor/detect urinary obstructions.Arterio-venous (AV) fistula without relevant bleeding .Except from one case, fistulas were detected sonographically in the follow-up examination after four hours. In one patient without acute symptoms the AV fistula was discovered in a sonographic control examination after three months. Because of sonographic findings and a slightly decreased general condition and increase in serum creatinine, an interventional embolization was performed. In two patients fistulas showed a spontaneous recovery within a few months. One AV-fistula occurred in a kidney transplant with chronic transplant nephropathy; because of sonographic findings and increase of serum creatinine arterial embolization was performed.In the last case with AV-fistula arterial embolization was promptly necessary based on distinct sonographic findings: AV fistula at the lower pole of the left kidney with a large draining vein and an arterial signal (resistance index between 0.5 until 0.57).AV-fistulas with relevant bleedings in the urinary tract .In these two cases patients showed aggravated pain and hematuria within two hours after biopsy. The AV-fistula was detected by ultrasound; in addition a bladder tamponade was found, which threatened to cause an intrarenal obstruction. Cystoscopical removal of the bladder tamponade and angiographic embolization of the AV-fistula was performed in both patients.In total eighteen relevant complications occurred, adding to a complication rate of 4.1% see . Eleven Six post biopsy complications (five AV-fistulas and one bleeding) needed an angiographic or cystoscopic intervention (1.3%). Two AV-fistulas and ten bleedings showed a spontaneous regression see . Six of Time course of annual number of biopsies and annual complication rate is shown in From 1997 until 2002 when biopsies were performed with hospitalization the overall complication rate was 2.5%, from 2003 until 2011, when biopsies were performed on an outpatient’s basis, complication rate showed a little increase up to 4.7%, which was not statistically significant . However, we arguably observed a clearer trend towards a higher complication rate in 2005–2011 (5.5%) compared with 1997–2004 (2.5%), when residents in training were involved in kidney biopsies . When adjusting for possibly confounding variables  this “trend” did not change , but remained below statistical significance. Moreover, we could not find an association of incident complication and number of punctures . In fact, in the 13 biopsies with 4 to 7 punctures no complication occurred.For one case of an AV fistula which was very complex and indication for interventional treatment was not clear, additional MRI imaging was carried out. Except from this case angiography or cystoscopy were indicated because of ultrasound findings without further imaging. Most complications were found in ultrasound examination after 4 hours post biopsy or even earlier, when symptoms occurred.Percutaneous ultrasound-guided renal biopsy is an established and effective diagnostic method in children and adolescents since many years Despite reduction of complication rates and improvement of safety based on the use of ultrasound guidance Standards of the British Association of Pediatric Nephrology (BAPN) indicate that the complication rate should not be above 5% In our patients we observed a complication rate of 4.1% and thereby fulfilled the standards of BAPN. We monitored eleven bleedings (2.5%) and seven AV fistulas (1.5%). An interventional treatment was necessary in six patients (one bleeding and five AV fistulas). Spontaneous recovery was observed in two patients with an AV fistula. We performed an ultrasound guidance of biopsies and we had a prospective and strict protocol for ultrasound follow-up examinations, including Doppler ultrasound.The number of biopsies increased from 1997 to 2005 see . During Provided that the biopsy was performed with a functioning team of physicians there was no correlation between the person who performed the biopsy (e.g. pediatric nephrologist or resident) and the complication rate. The only “trend” observed was the frequent changes within the biopsy team since 2005, which could explain the increase in complication rate in 2007–2008. However, the complications could have also occurred as a coincidence because of the patient collective in these years, e.g. two patients with relevant bleedings had an increased bleeding disposition. Changes in the biopsy team also occurred in the further years, but from 2008 until 2010 no relevant complications that needed interventional treatment were observed. A statistical significant difference in complication rate was not observed comparing inpatient’s and outpatient’s biopsies. The total number of successful biopsies in our study corresponds to the standards of the BAPN. These standards indicate that in at least 95% of biopsies enough kidney parenchyma must be collected for histological analysis and that there should not be a difference between different punctures during biopsy.One of the largest studies about renal biopsies depicted data of 9288 biopsies (715 children and 8573 adults) Reports about kidney biopsies in children and adolescents and their complication rates are hard to find and they consist of smaller patient collectives, compared to adult studies see . For exaThere are a number of studies of kidney biopsies in children Very few studies in children and adolescents reported on AV fistulas An explicit recommendation for Doppler examinations in children and adolescents was given by Riccabona and colleagues In general AV fistulas are more frequently seen in kidney transplants. For example, Bilge and colleagues This increased prevalence of AV fistula after transplant kidney biopsies was confirmed in our series: in six of the seven patients with this complication a kidney graft biopsy was performed. In contrast, relevant bleedings were observed mostly in patients after native kidney biopsies. So in our opinion it is important especially for transplanted patients to perform a Doppler ultrasound examination before kidney biopsy to exclude the possibility of a preexisting AV fistula that was caused by earlier biopsies and post biopsy to detect fistulas that were caused by the current biopsy.There is a need to find the most adequate time interval for follow-up examinations, especially considering the differences in our outpatient treatment. A 4, 6 or even 11 hour time interval in which most of the relevant complications occurred were reported But also late complications like AV fistula are possible, with AV fistulas appearing days until weeks after biopsy until very late occurrences up until 15 months post biopsy In a multi-center study it was shown that 33% of complications were missed in a time interval of 8 hours Early sonographic detection of compressing subcapsular renal hematomas is of vital importance for the prognosis Late complication of a venous oozing bleeding with relevant drop of hemoglobin that showed symptoms 3 weeks after biopsy had no further consequences except from blood transfusion. Two asymptomatic AV fistulas were detected in later ultrasound follow-up examinations, the time interval at which follow-up ultrasound examinations were performed was chosen depending on patient’s condition, symptoms and prompt post biopsy problems. Indication for interventional treatment necessities were always based on the development of ultrasound findings.Even after changing from an inpatient to an outpatient setting no relevant complications between 4 and 24 hour post biopsy were observed. Hence, we recommend an early ultrasound follow-up examination 4 hours after biopsy. But there is a strong need for further follow-up to detect oozing bleedings and asymptomatic AV fistulas that might develop hemodynamic effects.In conclusion percutaneous ultrasound-guided renal biopsy is an established and effective method in children and adolescents, but has a certain rate of complications and therefore should not be done without careful consideration.Ultrasound examination is able to detect relevant complications and is essential for indication of interventional treatment (assessment of size and dynamics of a hematoma or a urinary obstruction). Especially in detection of asymptomatic AV fistula that need interventional treatment, ultrasound examination including Doppler is of great importance. However, no published standard operating procedure (SOP) is available. Therefore, development of such an SOP to avoid or at least to directly detect severe complications is definitively necessary.We recommend ultrasound examinations (including Doppler) pre-, during, 4 hours post kidney biopsy and, in case no direct complication is visible, a few weeks after biopsy for preparation, execution and follow-up of kidney biopsies in children and adolescents. A first sonographic follow-up examination 4 hours post biopsy is suitable for outpatients and has a good predictive value for early occurring relevant complications. Especially patients with kidney transplants are at risk for developing AV fistulas, therefore Doppler examinations are important. As AV fistula could occur a few weeks after biopsy a long-term ultrasound examination including Doppler ultrasound is essential. Following such a center specific SOP we were able to achieve a low complication rate of 4.1%.