It is well known that morning blood pressure surge increases the risk of myocardial events in the first several hours post-awakening. This meta-analysis was performed to compare the antihypertensive efficacy of morning and bedtime dosing on decreasing morning blood pressure surge.Articles in 4 databases about clinical trials of ingestion time of antihypertensive drugs were searched and performed a meta-analysis to evaluate the different effects on morning blood pressure and absolute blood pressure (BP) reduction from baseline of between bedtime administration  and morning awaking administration (control group).The aim of this study is to compare the antihypertensive efficacy of morning and bedtime dosing on decreasing morning blood pressure surge.The bedtime will provide evidence support for clinicians and patients for reducing morning blood pressure surge.This study does not require ethical approval. The morning blood pressure surge has a significantly increased risk of cardiovascular events, so effective control on the morning blood pressure is of substantial clinical importance for the management of hypertension. In the HONEST study, cardiovascular risk was higher in patients with morning blood pressure [BP] > 145 mm Hg and office BP < 130 mm Hg  than in patients with morning home BP < 125 mm Hg and office BP < 130 mm Hg. A cohort study showed that a 1-mm Hg increase in morning BP was associated with a 2.1% increased risk of cardiovascular death.,4 Multiple prospective clinical trials indicate that improved normalization of asleep BP and 24 hours BP patterning – increase in sleep-time relative BP decline toward the more normal dipper profile – when administration with conventionally formulated single and combination hypertension medications at bedtime than upon awakening,,6 without an increase in adverse effects. Compared with morning dosing, taking antihypertensives at bedtime nearly halves cardiovascular deaths, according to recent studies.,8 In order to improve BP management, administration of antihypertensive drugs at bedtime has already been taken into account for the treatment strategy. Various researches focused on the influence of taking medicine before going to bed on 24 hours BP or cardiovascular events, and proposed that ingesting at least 1 antihypertensive medication at bedtime, compared with treatment with all medications upon awakening, gained a significant reduction in the 24-hours mean systolic BP (SBP)/diastolic BP (DBP) and the reduction was much more prominent during night time, decreasing the prevalence of non-dipping.–11 However, no consensus has been reached on the morning surge BP-lowering effect of this strategy.Hypertension is a global public health problem, causing many complications, especially cardiovascular events. The latest study (PURE) showed that hypertension was the largest risk factor and 22.3% of cardiovascular disease (CAD) cases and deaths were attributed to hypertension.Therefore, we conducted this meta-analysis to assess the effects of bedtime administration of BP-lowering agents on the morning surge in BP monitoring (ambulatory blood pressure measurement [ABPM]) results.22.1This NMA has been registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY). The registration number is INPLASY2020110126.2.2 The Literature search was performed in Pubmed, Embase, Cocharane, and ISI Web of Science without language restrictions, using the following search terms: Antihypertensive-drugs, Antihypertensive, Antihypertensive effect, Antihypertensive treatment, morning, awakening, blood pressure, Blood Pressure Monitoring, Ambulatory, bedtime, Morning blood pressure surge, Experimental trials, Treatment duration of antihypertensive drugs, Angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-blockers, diuretics, angiotensin receptor blockers, and alpha-blockers, ABPM, SBP, DBP, Randomized controlled trial, Controlled clinical trial, Randomized, random allocation, without imposed language restrictions. The reference lists of all retrieved articles were also reviewed to identify additional articles missed by using these search terms. The specific search strategy of the PubMed database is shown in Table This meta-analysis was conducted following  PRISMA guidelines.2.3Studies were included if they met the following criteria:1) including essential hypertension and secondary hypertension.Adult patients who satisfied diagnosis of hypertension using office measurements of blood pressure (SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg),2)Experimental trials with at least 6 weeks’ treatment duration of antihypertensive drugs .3)pm to 12:00 midnight), the control group was matched to the experimental group by drug and dose but with a morning regimen or in awaking time (from 6:00 am to 12:00 noon).Intervention was defined as one or more antihypertensive drugs administered at bedtime (from 5:00 4)Outcomes: Morning SBP and morning DBP.5) ABPM is recognized as a predictor of CV morbidity and mortality superior to office BP measurements.The pre- and post-treatment SBP and DBP of each patient were measured by ABPM, which is now the gold standard measurement and the most cost-effective strategy for diagnosing hypertension, evaluating true BP level.2.4We extracted the data from each study included: the first author, year of publication, study country, sample size, patient characteristics, interventions , and study design.2.5We resolved any discrepancies by discussion and examined the obtained data carefully for accuracy, and assessed the methodological quality of the included studies independently using the risk of bias tools according to the Cochrane Handbook version 5.1.0.2.6When there is heterogeneity between research results, we will conduct a comprehensive and systematic analysis of the reasons for heterogeneity and carry out hierarchical treatment according to different sources of heterogeneity. If it is due to the variation between studies, the intervention measures are consistent, and the research objects come from different populations. The following aspects will be used: age, course of the disease, gender.3 Six criteria were applied as follows:Risk of bias for each study was calculated in accordance with the Cochrane Handbook for Systematic Reviews of Intervention.1)selection bias ;2)performance bias (blinding of participants and personnel);3)detection bias (blinding of outcome assessment);4)attrition bias (incomplete outcome data);5)reporting bias (selective reporting);6)other bias.There were 3 potential bias judgments:1)low risk;2)high risk;3)unclear risk.A study was rated as having an unclear risk when insufficient details were reported regarding the methods and outcome, the risk of bias was unknown, a metric was not relevant to the study, particularly for assessing blinding and incomplete outcome data, or when the outcome assessed by the metric had not been measured in the study.4All included studies were grouped according to the intervention regimen. The data from each included trial were analyzed using Review Manager . The meta-analysis was performed using the generic inverse variance.5I2 and Q test statistic. Mild, moderate, and severe heterogeneity were defined by I2 values of 25%, 50%, and 75%, respectively. Sensitivity analysis was used to determine whether the included literature had a significant impact on the stability of the study.Statistical heterogeneity among studies was assessed using 6The funnel plot and Begger's test were used to assess the presence of publication bias.7,18 The mechanisms involved in the morning increase in cardiovascular events have been unclear, but recent clinical studies have shown that an exaggerated morning BP surge is a plausible factor involved in the triggering of cardiovascular events, particularly in the case of stroke.,19 1 mm Hg morning BP increase was associated with a 2.1% increased risk of cardiovascular death.,4 More and more evidences–22 show that the morning surge of blood pressure is closely related to cardiovascular events, stroke, and renal impairment. And for medication, guidelines suggest the long-term antihypertensive drugs of 24-hour stable blood pressure can control the large fluctuation of morning blood pressure and reduce the rise of morning peak blood pressure caused by failure to take medicine on time or missing. It could be suggested to non-dipper type or anti-dipper type hypertension patients to take long-term antihypertensive drugs before going to bed. A study showed that the morning surge of BP, a risk factor for stroke, was significantly reduced only after bedtime administration of nifedipine. Bedtime in comparison to awakening-time ingestion of nifedipine was also associated with a reduction in the incidence of edema from 13% to 1%. Taking antihypertensive drugs before going to bed can improve the compliance of patients, and some commonly used drugs, such as statins, in the same way, are suggested to be taken before going to bed. Especially for many elderly people who live a lifestyle of get up early and doing morning exercises tend to be affected by morning blood pressure surge.The incidence of cardiovascular events, such as myocardial infarction, sudden death, and stroke, is highest in the early hours after waking. showed that although no obvious difference was found in adverse drug reactions between the 2 groups (patients were provided with a single pill containing amlodipine/atorvastatin (5/20 mg) to be taken each night at 10 pmvs patients were taking amlodipine (5 mg) and atorvastatin (20 mg) each morning at 7 am), compliance was much better in the single-pill group than in patients taking 2 medications separately. The latest research showed that taking antihypertensives at bedtime nearly halved cardiovascular deaths when compared with morning dosing.Still, it is controversial. Some opposing views are that the sharp decrease in blood pressure at night would bring adverse effects on organ blood supply. A study,25 Circadian rhythms in gastric pH and emptying, gastrointestinal motility, biliary function and circulation, liver enzyme activity, and blood flow to the duodenum, kidney and other organs lead to PK and PD differences of antihypertensive medications due to different medication time.,25 In particular, the circadian pattern of the glomerular filtration rate, with a maximum during the day and a minimum at night, played a significant role in PK.,25,26 Antihypertensive drugs were eliminated more slowly overnight, potentially prolonging their duration of action when ingested at bedtime as compared to taken at awakening. The result of Hermida et al's study was consistent with the theory. The BP-lowering efficacy duration of spirapril was much longer when taken at bedtime (8 hours after ingestion) than in the morning (3 hours after ingestion). These studies indicated that antihypertensive drugs taken at bedtime demonstrated more effectively control on the morning surge of blood pressure. Moreover, the medications widely used in clinical conditions may have short half-life and duration of action and fail to provide a full 24 hours coverage, especially the morning surge of blood pressure, when taken in the morning.The mechanism for these observed time administration of antihypertensive drugs differences remains unclear, but it has been generally agreed that the pharmacokinetics (PK) and pharmacodynamics (PD) of the medications occurring about to with concerning the 24 hours cyclic processes were involved in BP regulation.Conceptualization: Peng Zhang, Chuanhua Yang.Formal analysis: Meiying Jin, Xuyu Song.Methodology: Xuyu Song, Zhao Wang.Project administration: Yuehua Jiang.Software: Peng Zhang, Xuyu Song.Writing – original draft: Peng Zhang.Writing – review & editing: Chuanhua Yang.


Nephrotoxicity is a potential adverse effect of anticancer treatment in childhood. Cytostatics, abdominal radiotherapy, total body irradiation (TBI) and some agents used in supportive care may induce acute kidney injury (AKI) or lead to chronic kidney disease (CKD). The aim of this study was to test the hypothesis whether urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are increased in acute lymphoblastic leukemia (ALL) survivors.The study cohort consisted of 86 patients  previously treated for ALL. The median time after cessation of treatment was 6.55 (IQR: 1.96–9.93) years and median age at the time of study: 12 (IQR: 6.76–16.00). The control group included 53 healthy peers. Immunoenzymatic ELISA commercial kits were used to measure urine KIM-1 and NGAL levels.p < 0.0001) and uKIM-1/creatinine ratio (p < 0.0001) were significantly higher in ALL survivors in comparison with healthy controls. Female patients had significantly higher levels of NGAL and NGAL/cr. than males . Of all the study participants, 11 (13%) presented eGFR below 90 mL/min/1.73 m2. The NGAL/cr. ratio seemed to be the best predictor of decreased eGFR (AUC = 0.65). The cumulative dose of methotrexate and cyclophosphamide did not predict the values of the urine NGAL, NGAL/cr., KIM-1/cr. and eGFR.The median levels of urine uNGAL (p < 0.05), uNGAL/creatinine (cr.) ratio (p < 0.01), uNGAL  and lower eGFR  in comparison with ALL survivors with the observation period of less than 5 years.Five years after the end of treatment, the patients had higher levels of uKIM-1 (1.02 ± 0.8 vs. 0.62 ± 0.6 ng/mL, , NGAL/cr. and uKIM-1/cr. ratio as compared to the control group. Further long-term follow-up studies are necessary to assess the significance of the NGAL and KIM-1 and their relationship to kidney damage after anticancer treatment in childhood.We demonstrated that ALL survivors have higher levels of urine NGAL In the last years, progress in the diagnosis and treatment of childhood cancer has resulted in up to 80% of patients achieving remission or permanent healing. Through long-term observations of patient cohorts, we have learned a lot about the early and long-term effects of anticancer treatment. Nowadays, the main goal, apart from achieving the best possible treatment outcome, is to maintain good health after therapy termination. Nephrotoxicity  is a potential late effect of cancer treatment in childhood. It is well known that some cytostatic agents such as cisplatin, ifosfamide and abdominal radiotherapy or total body irradiation (TBI) may induce acute kidney injury (AKI) and/or long-term deterioration of kidney function –5.Acute lymphoblastic leukemia (ALL) is the most common neoplastic disease in childhood and shows an overall survival between 80 and 98% depending on the risk group . The mosSerum creatinine level and estimated glomerular filtration rate (eGFR) are the simplest and most commonly used methods for assessing kidney function. On the other hand, several limitations of this method exist due to the influence of, among others, muscle mass, age, sex and hydration status. Moreover, the deterioration of kidney function may be very long unnoticed in clinical and laboratory tests, as it is often the case in chronic kidney disease (CKD). For this reason, new biomarkers are constantly being sought to reflect in particular the initial stage of kidney damage. In recent years, new biomarkers have been used to detect early onset of acute kidney injury, such as neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin family, and kidney injury molecule-1 (KIM-1), type 1 transmembrane glycoprotein.NGAL is detected in various types of human tissues including kidneys (monomeric form), gastrointestinal and respiratory tract. Furthermore, its neutrophil dimeric form also participates in the immunological response. In healthy subjects, it is present in serum and urine at very low levels. Due to the low molecular weight and low degradation, NGAL is excreted into the urine (uNGAL) and its concentration increases immediately in the first hours after AKI. In kidneys, NGAL is excreted from the loop of Henle epithelial cells, the proximal and distal tube, and its level increases in line with the degree of renal tubular damage  Kidney injury molecule-1 (KIM-1) is not detectable in health conditions. However, in the case of acute kidney damage, its excretion in proximal tubule cells in response to AKI is significantly increased –13. EsseThe available reports about the applicability of NGAL and KIM-1 as prognostic factors for early stages of chronic kidney damage are conflicting , 14–17. The aim of the present study was to test the hypothesis that urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are increased in survivors of childhood acute lymphoblastic leukemia many years after treatment.A total of 86 out of 106 patients treated between 1996 and 2007 in childhood for acute lymphoblastic leukemia were enrolled in the study. Eligible patients included any individual who visited the outpatient clinic for a follow-up after treatment completion. All of them were in complete first continuous remission. Exclusion criteria were: relapse, hematopoietic stem cell transplantation, solitary functional kidney, any congenital anomalies of kidney or urinary tract, and current infection. All the children were treated in accordance with the international Berlin–Frankfurt–Münster (BFM) protocols approved by the Polish Pediatric Leukemia and Lymphoma Group. Written informed consent was obtained from the participants or their parents/guardians. The study was approved by Ethical Committee of the Medical University of Bialystok in line with the Declaration of Helsinki (permission number: R-I-002/62/2018).2 [m2]. Blood pressure was measured using a standardized sphygmomanometer ; before the measurement, the participant rested peacefully for 5 min. The average values of the second and third measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were used for subsequent analyses. Hypertension (HT) was defined as a mean SBP and/or DBP level ≥ 95th percentile adjusted for age, sex and height [For all subjects, clinical history including demographic information, coexisting diseases, previous anticancer treatment, cumulative dosage of nephrotoxic drugs  and radiotherapy was obtained from medical records. The total cumulative glucocorticoids dosage was calculated with prednisone equivalent . Every pd height .The control group consisted of 53 healthy peers  with a pair of normal kidneys, who were offspring of the Pediatric and Nephrology Department’s employees and healthy school pupils recruited form the OLAF study . All the2) calculated using the updated Schwartz formula: eGFR = 0.413 × (height in cm / serum cr. in mg/dL). Clean catch urine samples were collected in the morning and stored at − 80ºC. Commercial immunoassays  were used to measure urine KIM-1 and NGAL levels and the values were expressed in nanograms per milliliter. All specimens were diluted to obtain the concentration for the optimal measurement in accordance with the instructions for the ELISA kit. Due to the fact that different urine dilutions may affect the concentration of the tested biomarkers, we calculated both urine KIM-1 and NGAL levels per milligram urine creatinine (cr.) . Urine albumin concentration was determined by Lowry’s method and the results were expressed in μg/mL. Children with a urinary albumin/creatinine ratio between 30 and 300 μg/mg were considered to have albuminuria. All the measurements were done after the end of anticancer treatment during follow-up visit (at least 6 months after completion of treatment).All laboratory tests were performed after 12-h night fasting. The biochemical analyses included an assessment of serum creatinine level (enzymatic method) and the estimated glomerular filtration rate (mL/min/1.73 mχ2) test were used. Continuous variables were compared with the Wilcoxon rank-sum or t Student test depending on the normal distribution. Univariate and multivariate logistic regression models with urine KIM-1/cr. and NGAL/cr. as independent variables were created. The correlations between variables were calculated by Spearman or Pearson correlation coefficients. The diagnostic value of the biomarkers and the optimum cut-off values were determined based on receiver operating characteristic (ROC) analysis, known as the area under the curve (AUC). Based on a rough classifying system, AUC was interpreted as follows: 90–100 (excellent), 80–90 (good), 70–80 (fair), 60–70 (poor), < 60 (fail). A p value below < 0.05 was considered significant.Statistical analysis was performed using STATA 12.1 version . Data were expressed as median (Me) and quartiles (Q) or mean and standard deviation (SD) when appropriate. All continuous variables were tested for normal distribution using Shapiro–Wilk or Kolmogorov–Smirnov tests. In the univariate analysis, Fisher exact test and Chi square , although the difference was not shown in the eGFR value . The summary of the biochemical parameters of all studied patients is presented in Table Compared to the control group, the ALL patients had higher values of creatinine level , but not KIM-1 . In CCS, we found a positive correlation between KIM-1 and NGAL concentration   but no differences in concentration of KIM-1 and KIM-1/cr. ratio were found.Both ratios, KIM-1/cr. and NGAL/cr., were significantly higher in ALL survivors in comparison with healthy controls, 01 Figs. . Moreove2 (Table p < 0.05). There were no differences in KIM-1 or KIM-1/cr. levels between groups depending on eGFR. Furthermore, no link was found between albuminuria and all the above parameters.Among all the study participants, there were 11 13%) who presented eGFR below 90 but over 60 mL/min/1.73 m% who pre2). We found that NGAL/cr. showed poor diagnostic factor profile, describing an area under curve (AUC) of 0.65 (95% CI: 0.49–0.79) with the best cut-off value of 19.14 ng/mg , whereas KIM-1/cr. turned out to be a fail predictor of reduced eGFR .ROC analyses were conducted to assess the diagnostic profile of KIM-1 and NGAL in identifying patients with an impaired renal function (eGFR < 90 mL/min/1.73 mp < 0.01), NGAL  and lower eGFR  as compared to those whose follow-up time did not exceed 5 years at the study time (38 patients) . No correlation was observed between high systolic and/or diastolic blood pressure and the investigated biomarkers.Given the fact that children in the first years of life might be more vulnerable to drug-induced nephrotoxicity, the study group was divided according to the time of diagnosis (0.5–3 years. vs. 3 years. and above); however, no differences in the concentration of the analyzed biomarkers were found. Interestingly, forty-eight subjects over 5 years after the end of treatment had higher levels KIM-1  did not show any significant differences. Summary of the analyzed parameters depending on the dosage of chemotherapeutic agents is presented in Table 2, Ylinen et al. observed an elevated cystatin C concentration 36 h after the infusion, but no changes in NGAL level were noted [2 (according to the risk groups) found that patients who received doses higher then 3 g/m2 more often presented AKI with a parallel increase in urinary NGAL excretion. The authors suggested higher usefulness of the combination of serum creatinine ratio and serum NGAL (24 h after MTX infusion) for detecting AKI induced by a high dose of MTX compared with the serum creatinine ratio [The influence of anticancer treatment, especially radiotherapy and nephrotoxic agents such as ifosfamide and cisplatin, on kidney function is well known in patients with solid tumors treated in childhood , 3, 5. Tre noted . On the ne ratio .The results of NGAL and KIM-1 examinations in chronic kidney disease as markers of its development are controversial , 17, 30.2) in 1.7% of patients after 15 years of diagnosis, and in 6.6% after 35 years [In cancer survivors treated during childhood for different neoplasms, a decline in kidney function was observed mainly after treatment with nephrotoxic cytostatics. Mulder et al. in a study carried out on a large cohort of CCS (1122 subjects), almost half of whom were patients treated in childhood for leukemia and lymphoma, found glomerular deterioration  guidelines, CKD is defined by structural or functional abnormalities of the kidney for ≥ 3 months, with or without decreased eGFR or eGFR < 60 mL/min/1.73 m failure .There is a need to discover new biomarkers, preferably non-invasive  to predict deteriorating kidney function and identify patients in the early stages of the disease.2) were found in 13% of ALL survivors. We retrospectively checked data about eGFR measurement at least 3 months before the study time. All subjects with eGFR < 90 mL/min/1.73 during the study had also decreased eGFR three months earlier, but not < 60 mL/min/1.73 m2. None of participants met the criteria of CKD according to KDIGO guidelines. Considering the whole group of the patients studied, higher levels in urine NGAL (p < 0.05), NGAL/cr. ratio and KIM-1/cr. ratio were observed as compared to the control group (p < 0.0001). Higher values of NGAL/cr. (but not KIM-1/cr.) were found in the subgroup of patients with decreased eGFR in comparison with those who had normal eGFR; however, the sample size was small. ROC analyses revealed that among all analyzed parameters NGAL/cr. was the greatest predictor of decreased eGFR (< 90 mL/min/1.73 m2); however, the diagnostic profile was poor. It might be due to the low percentage of survivors with decreased eGFR and presumably quite young mean age at follow-up visits. We observed a correlation between NGAL and KIM-1 values but there was no correlation between the analyzed biomarkers and albuminuria. Lower eGFR and elevated tubular markers were found in ALL patients who survived more than 5 years after the end of treatment as compared to those whose follow-up time was less than 5 years. However, to determine whether the time after treatment affects the marker concentration, a longitudinal study should be performed on the same group of patients.In our study, lowered eGFR values  may predict worsening of kidney function many years after treatment. Elevated urine KIM-1 and NGAL levels indicate the possibility of subclinical tubular injury in those survivors who do not present “classical” chronic kidney disease as defined by KDIGO. These subtle changes in the eGFR, as well as in uNGAL and uKIM-1, may suggest the first subclinical sings of renal dysfunction and therefore may help identifying ALL survivors who are predisposed to progressive renal impairment. However, we realize that the time that has passed since the end of the therapy seems to be too short to draw final conclusions. Thus, further observational and longitudinal studies on the large cohort of ALL patients are required.The trend towards higher NGAL level in women was observed in our study group and was confirmed by some authors in healthy children and adults . Additio2, and only 11% of survivors had reduced GFR < 90 mL/min/1.73m2 [In our opinion, this is the first study concerning the analysis of tubular injury biomarkers in acute lymphoblastic leukemia survivors. Previous studies on other markers provided divergent results. Grönroos et al. in a prospective, but small study (28 survivors), evaluated glomerular and tubular function. They found a gradual decrease in GFR during follow-up but no changes in tubular function, i.e., normal blood electrolyte levels and normal urine α1- and β-2-microglobulin. Median eGFR value after the end of follow-up was 113.9 mL/min/1.73mn/1.73m2 . Dekkersn/1.73m2 . In one n/1.73m2 .MTX is considered the main factor damaging kidney function; however, it has been suggested that this decline in renal function is reversible . In our According to Grönroos et al. patients treated with methotrexate in combination with nephrotoxic antibiotics presented some late effects of deterioration of glomerular filtration and significant incidence of albuminuria . AdditioThere are several limitations of this study. It was a single-center analysis, with a relatively small number of patients. We did not evaluate the levels of urine NGAL and KIM-1 before the start of treatment, during exposure to chemotherapy or at the end of therapy, when possible recovery from MTX infusions may occur. The effects of other nephrotoxic drugs used in supportive care were not studied as well. The strengths of our research include the homogenous group of acute lymphoblastic leukemia survivors, relatively long follow-up time and no ethnic diversity., NGAL/cr. and uKIM-1/cr. ratio compared to the control group. Further longitudinal, prospective analyses of NGAL and KIM-1 levels in ALL survivors and their potential role as monitoring tools for kidney dysfunction remain to be performed.In conclusion, the results of this study demonstrated that ALL survivors have higher levels of urine NGAL


Design and Methods. A clinic-based cross-sectional study of 100 patients with T1DM aged 10-18 years. Patients with disease duration exceeding 5 years if the onset of diabetes was prepubertal and 2 years if it was postpubertal were included. Relevant sociodemographic, clinical, and biochemical information was obtained. Blood pressure was measured. The patients were screened for DN and DR using urinary microalbumin estimation and fundus photography, respectively.  Data on microvascular complications in children and adolescents with type 1 diabetes mellitus (T1DM) in Sudan are scarce. This study was aimed at determining the prevalence of diabetic nephropathy (DN) and retinopathy (DR) and their relationship to certain risk factors in children with T1DM attending the Sudan Childhood Diabetes Centre. p = 0.009) and longer diabetes duration (p = 0.02) than patients without retinopathy. Logistic regression showed that high HbA1c (odds ratio (OR) 0.83, confidence interval (CI) 0.68-1.00, p = 0.04), but not age, duration, ethnic group, BMI, blood pressure, and presence of nephropathy, was an independent risk factor for retinopathy. Likewise, high blood pressure , but not age, duration, ethnic group, BMI, HbA1c, and presence of retinopathy, was a predictor for nephropathy.  The frequency of microalbuminuria and diabetic retinopathy was 36% and 33%, respectively. Eleven percent had both retinopathy and microalbuminuria. Seven percent of the patients were found to be hypertensive. Patients with diabetic retinopathy had significantly higher HbA1c levels ( High prevalence of incipient DN and early stages of DR were observed in this study. Longer diabetes duration and higher HbA1c were associated with the presence of diabetic retinopathy. High blood pressure was a risk factor for DN. So regular screening for these complications and optimization of glycemic control are needed. Type 1 diabetes mellitus (T1DM) can lead to microvascular complications including nephropathy, retinopathy, and neuropathy. These chronic complications lower the quality of life and cause premature death in patients with diabetes . ClinicaThese microvascular complications of T1DM are associated with certain risk factors like age, ethnicity –6, age aOther modifiable risk factors include high blood pressure (BP) , 12, 13 There is a paucity of studies on microvascular complications in children and adolescents with T1DM in sub-Saharan Africa. However, all the African published studies showed high prevalence rates in patients with relatively short duration and at a young age –17. WhetThis study was aimed at determining the prevalence and risk factors for diabetic nephropathy and retinopathy among patients with T1DM attending the Sudan Childhood Diabetes Centre.This is a cross-sectional study of consecutively enrolled 100 children with T1DM aged 10-18 years attending the Sudan Childhood Diabetes Centre. The study lasted from February to September 2018. The Sudan Childhood Diabetes Centre is a specialized centre with a comprehensive multidisciplinary team that includes trained endocrinologists, dentists, ophthalmologists, diabetes nurses, diabetes educators, psychologists, dieticians, and social workers. The centre provides free insulin and glucometers either free or at a low cost. Ethical approval was obtained from the Sudan Childhood Diabetes Centre. Informed consent was obtained from the patient and/or his parents.The diagnosis of T1DM was mostly made by the treating paediatric endocrinologist in the centre clinically, as routine testing for autoantibodies or c-peptide is expensive.Patients aged ≥10 years with diabetes duration˃5 years if the onset was prepubertal and ˃2 years if it was postpubertal were included . AdditioAnthropometric measurements, pubertal staging, and blood pressure measurement were done during the interview.To assess blood pressure (BP), the patient sat down for a few minutes for rest before two measurements with a 5-10-minute interval, using an aneroid sphygmomanometer, were done. The Korotkoff phases I and V were the systolic and diastolic readings, respectively. Blood pressure was categorized according to BP tables from the fourth report of the national high blood pressure education program working group on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents, using age and height percentiles, with normotension defined as blood pressure under the 90th percentile, prehypertension systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) 90th to 95th percentile, and hypertension greater than the 95th percentile .Weight was measured using weighing scales to the nearest 0.1 kg. Height was measured using a stadiometer and was expressed in centimeters with no decimal. BMI was categorized according to the Centers for Disease Control and Prevention (CDC) age- and sex-specific growth charts. The following categories were used: underweight: <5th percentile, normal weight: 5th to 85th percentile, overweight: 85th to 95th percentile, and obese: >95th percentile . The sexThe most recent HbA1c was obtained from the patients' record. HbA1c was performed in the centre's laboratory with a point-of-care ichromἀ analyzer (company). Then, the patients were classified according to ISPAD 2018  guidelines which consider HbA1c < 7.5% to be the level for optimal control in resource-limited environments .Urine was examined for the presence of microalbumin in a spot random urine sample, using quantitative immunoturbidimetry of the HemoCue brand (company). Any reading less than 20 mg/l, between 20 mg/l and 200 mg/l, and more than 200 mg/l was considered negative, microalbuminuria, and macroalbuminuria, respectively. Testing on any febrile child, a child with a urinary tract infection, or menstruating female patients was postponed till the next visit. As per ISPAD Clinical Practice Consensus Guidelines 2018 , a patieRetinopathy was assessed by nonmydriatic two-field digital fundus photography using a fundus camera of the DRS brand  manufactured by CenterVue. The photography was carried out by an experienced optician, and the comments on the photos were made by an ophthalmologist experienced in diabetic retinopathy. Both the optician and the ophthalmologist were masked to the clinical status of the patient.The classification of diabetic retinopathy was based on the Early Treatment Diabetic Retinopathy Study (ETDRS) classification , which rt-tests for normally distributed continuous data, and Mann-Whitney U tests for skewed data. Comparison between more than two groups was performed using the Kruskal-Wallis test. The distribution of continuous data was tested for normality by the Kolmogorov-Smirnov test. Logistic regression was performed with the presence of DR and DN as dependent variables. The independent variables were age, diabetes duration, ethnic group, BMI, blood pressure, HbA1c, and the presence of the other complication (DR for DN and vice versa). Because of the significant collinearity between duration and age at onset and age and Tanner stage, age at onset and Tanner stage were omitted from the final model. Results are reported as odds ratio (OR) and 95% CI. All statistical tests were two-tailed with a p value < 0.05 considered significant. Data were analyzed using the Statistical Package for the Social Sciences program (IBM-SPSS) version 23.Descriptive statistics were reported as mean ± standard deviation when normally distributed and as median (interquartile range) for nonparametric data. Clinical characteristics and complication rates were compared using chi-square tests or Fisher's exact test for categorical variables, A total of one hundred patients with T1DM constituted the study population; their sociodemographic, ethnic, and clinical characteristics are shown in Most patients (95%) had a glucometer for home blood glucose monitoring, yet only 10% were checking daily and 39% check only when symptomatic. The rest do 2-3 readings per day in fixed 2 days per week.p ≤ 0.001). However, there was no statistically significant correlation between glycemic control and insulin regimen (p = 0.73), as well as insulin dose (p = 0.74).Regarding the glycemic control of the study population, the median HbA1c was 11.8% (IQR = 9-14), and only 10% had HbA1c < 7.5%. The analysis showed that there was a significant correlation between regular home blood glucose monitoring and glycemic control  were on a conventional insulin regimen, 5% were on an intensive regimen, none of the patients were using an insulin pump. The median (IQR) insulin dose in unit/kg was 0.9 (IQR = 0.8-1.1).The presence of incipient diabetic nephropathy  was observed in 36% of the participants. The youngest patient with microalbuminuria aged 11 years. Two patients had persistent macroalbuminuria . Diabetic retinopathy was observed in 33% of the patients. The youngest patient with diabetic retinopathy aged 10 years and 7 months. Most of the patients with diabetic retinopathy had very mild nonproliferative diabetic retinopathy (66.7%). 30% had mild nonproliferative diabetic retinopathy. Only one patient (0.3%) had moderate nonproliferative retinopathy. Eleven percent of the patients were found to have both diabetic nephropathy and retinopathy. The youngest of them was 11 years old.Out of the total study participants, only six patients were prepubertal. All of them had normal blood pressure. However, one of them had both microalbuminuria and bilateral very mild diabetic retinopathy. This patient whose age was 11 years had diabetes duration of only 3 years. Another patient whose age was 10 and a half with diabetes for 2 years had unilateral very mild diabetic retinopathy. This last patient had hypothyroidism, was overweight, and had a family history of T1DM and essential hypertension.p = 0.02) and higher HbA1c (p = 0.009) compared to patients without retinopathy. However, these two factors were not significantly different between groups with and without DN. There was no statistically significant difference between patients with and without any of the two microangiopathies regarding age, ethnic group, age at diabetes onset, BMI, puberty, and blood pressure.Characteristics of patients with and without any of the two microangiopathies are described in p = 0.03) was a predictor for the presence of DN, while the only variable that predicts DR was HbA1c level . Age, duration, ethnic group, BMI, and the presence of the other microangiopathy were not associated with any of the complications  were not achieving the target control (HbA1c less than 7.5%) . This fip ≤ 0.001). Although most of the patients are supplied with glucometers for free by the Sudan Childhood Diabetes Association (95% of the study group had a glucometer), most of the families could not afford to purchase the test strips as prices have increased tremendously over the last few years. In African cohort studies on children with diabetes, better metabolic control was achieved by frequent self-monitoring of blood glucose [In the current study, the poor glycemic control as measured by HbA1c was statistically strongly related to the lack of regular home blood glucose monitoring, caused by the unavailability of sustained glucometer's strip supply  had either one or both of the complications, and only 42 (42%) had neither of these complications. These findings concur with other African reports –17. AmonThe prevalence of microalbuminuria in the current study is much higher than that in a study carried out in Egypt which included wide age range participants with better glycemic control than ours . These tThe frequency of both of the microvascular complications in our study is higher than those reported from the developed world mostly due to better diabetes control and possibly genetic or ethnic variation , 36–38.In line with previous similar studies , 16, 35,In this study, 11 (11%) had combined diabetic retinopathy and nephropathy. No statistically significant relationship between the presence of diabetic nephropathy and retinopathy was found, a finding that contradicts many studies , 13, 39.p = 0.03). High blood pressure association with DN was found by many studies [Out of the total study participants, seven percent of patients had hypertension and 8% had prehypertension, a prevalence that is not very different from the prevalence of hypertension in healthy Sudanese school children . Compare studies , 38, 42. studies , 45. The studies , 46. No  studies , but in  studies , 42, 47. studies . HoweverNo relationship between the presence of any of the two microangiopathies and ethnicity was found in this study; this might be attributed to the fact that the participants were homogeneous regarding ethnic groups, as the majority (79%) belong to the Afro-Asiatic group. The role of ethnicity and genetics in the development of diabetic microvascular complications had been suggested by many studies that showed geographic as well as ethnic variation in the susceptibility to these complications , 14, 48.Moreover, no relation between age at onset and DN or DR was found, a finding that is in agreement with some studies , 9, but This study was relatively small and cross-sectional in design, yet it was able to show that patients with DR had significantly longer duration than patients without DR. However, the duration was not a predictor for DR when logistic regression was made. Many studies concluded that diabetes duration is a risk factor for DR development , 15, 47.Lastly, regarding glycemic control, patients with DR had significantly higher HbA1c than those without DR, and high HbA1c is a predictor for DR in the logistic regression, an observation that was also demonstrated by the landmark DCCT/EDIC  and numeThis study did not demonstrate any significant difference in glycemic control between groups with and without nephropathy so do most other available studies from sub-Saharan Africa , 44, 57.It is known that the risk factors involved in the development and progression of different diabetic microangiopathies in T1DM are overlapping but not identical . AdditioIn conclusion, in the present study, a high prevalence of early signs of diabetic nephropathy and retinopathy was demonstrated among children and adolescents at a relatively young age and short duration of T1DM, since more than half of the individuals included in this study suffered from at least one of these two chronic complications attributable to diabetes. The fact that the majority of our participants had poor glycemic control could partially explain this high prevalence. High blood pressure was found to be a predictor for diabetic nephropathy. Associations of diabetic retinopathy with longer disease duration and poor glycemic control were verified. However, no such association was found for diabetic nephropathy.This is the first exploratory study of diabetes-related microvascular complications in Sudanese children and adolescents. The rates we had found are high and suggest that health policymakers should prioritize diabetes care as a major component of health provision in Sudan to minimize the development of such costly and life-threatening complications, since the early stages of microvascular complications such as nephropathy and retinopathy are often asymptomatic. The primary clinical care emphasis on the prevention of vision loss or renal impairment must be appropriately directed at good glycemic control, early identification, accurate classification, and timely treatment of these complications. In this study, the proportion of patients with poor glycemic control was high, and therefore, focusing on glycemic control would be of great benefit. Large prospective studies are also necessary to validate the current findings.


The impact of an adverse prenatal environment such as famine exposure on the development of adulthood non-communicable chronic illnesses, including diabetes and hypertension has been well articulated in the recent past and supported by evidence. However, there exist few longitudinal studies conducted on the long term consequences of prenatal famine exposure on adulthood kidney function. Hence, we set out to examine whether prenatal exposure to the Ethiopian Great Famine (1983–1985) was associated with changes in estimated glomerular filtration rate (eGFR) and the risk of developing chronic kidney disease (CKD) later in adult life.The study was conducted in 219 famine exposed and 222 non exposed cohorts in Raya Kobo district, North Wollo Zone, Northern Ethiopia. Estimated GFR was computed from standardized serum creatinine using the CKD Epidemiology Collaboration (CKD-EPI) equation. The definition of CKD includes those with an eGFR of less than 60 ml/min/1.73 m2 on at least in two occasions of 90 days apart (with or without markers of kidney damage). Linear and logistic regression analyses were employed to examine the independent effect of prenatal famine exposure on eGFR and CKD respectively.The mean (SD) serum creatinine of exposed and non-exposed groups were 0.78 (0.2) and 0.75 (0.2) respectively. The mean (SD) eGFR of exposed groups was 107.95 (27.49) while the non-exposed 114.48 (24.81) ml/min. In linear regression, the unadjusted model to examine the association between famine exposure and eGFR resulted in a significant negative beta coefficient . Adjusting the exposure for outstanding covariates of kidney health, including systolic blood pressure, fasting blood sugar and blood glucose did not alter the inverse relationship . In the unadjusted bivariate logistic regression model, famine exposure resulted in nearly 2.7 times higher odds of developing CKD . The odds remained equivalent after adjusting for systolic blood pressure, fasting blood glucose and body mass index .In the study setting, prenatal exposure to the Great Ethiopian Famine was associated with decreased eGFR and higher risk of developing CKD among survivors. These findings may imply that famine in early life may play a significant role in the development of kidney dysfunction in adulthood.The online version contains supplementary material available at 10.1186/s12937-021-00675-8. Mortality and burden of disease related to suboptimal kidney functioning are the major contributors to global ill health [estimated 5–10 million people die annually from kidney disease [l health . The wor disease . Accordi disease . Contrar disease , 4. DespDirect measurement of GFR to determine CKD status is complicated in clinical as well as survey settings as it requires substantial time and resource , 6, 7. AAlthough often considered as a comorbidity of diabetes or hypertension, CKD has numerous complex causes –5. SpannThe impact of adverse prenatal famine or starvation on late adulthood chronic illness including diabetes, hypertension and CVD has been well articulated in the recent past and supported by evidence –16. As i2) among adults in Wollo, North-East part of Ethiopia.If risk groups are identified early, chronic kidney disease can be prevented and or worsening of kidney function can be slowed or averted by known interventions –4. The W2 and has a total population of 228,798 of which 147,837 are females [The study was conducted in 36 Kebeles of Raya Kobo district, North Wollo Zone, Northern Ethiopia. The district covers an area of 2001.57 km females . A histoThe sample size was calculated by applying two population proportion assuming a prevalence of type two diabetes mellitus as proxy risk factor for CKD in fetal exposed group (22.6%) and non-exposed group (9.8%) . Accordi2The exposure variable was the great Ethiopian famine of the 1983–1985 G.C. Other sociodemographic, biochemical including fasting blood glucose, lipids and lipoproteins and anthropometric variables were also assessed. The outcome variable eGFR was computed from standardized serum creatinine using the CKD Epidemiology Collaboration (CKD-EPI) equation where eGFR (estimated glomerular filtration rate) expressed as ml/min/1.73 mCr (standardized serum creatinine) in mg/dL, κ = 0.7  or 0.9 , α = − 0.329  or − 0.411 , min = indicates the minimum of SCr/κ or 1, max = indicates the maximum of SCr/κ or 1, age = years [Where S = years .The data collection procedure and measurements were guided by standard operating procedures outlined by the WHO STEPwise approach to surveillance (STEPS) manual . The datPretested structured questionnaire was used to collect sociodemographic data of the participants using face-to-face interview. The questionnaire was first prepared in English and then translated into Amharic  and back into English to ensure consistency. Eight trained clinical nurses collected the data.Fasting total cholesterol, plasma glucose, triglycerides and high-density lipoproteins were measured. Five milliliters of venous blood was collected in plane test tubes after overnight fasting participants (8–12 h). The analysis was made using A-25 bio-system® clinical chemistry analyzer. Low density lipoprotein (LDL) level was determined using Freidwald formula . StandarThe height of participants was measured to the nearest 0.1 cm using a stadiometer  with the subjects positioned at the Frankfurt Plane and the four points  touching the vertical stand and their shoes taken off. Weight was measured using portable battery operated Seca® digital scale. All anthropometric measurements were done in triplicate and the average value was used for further analyses . The weiBlood pressure was measured using a digital blood pressure apparatus in triplicate, with 5 minutes of rest in between measurements. The subsequent measurements were done 5 min apart. During data analysis, the mean of the second and third readings were calculated .Data were double-entered using EpiData 3.1 and exported to SPSS for windows version 25 . Student’s t - test was used to evaluate the mean score difference between prenatal famine exposed and non-exposed cohorts.p value of 0.05 was used to declare a significant difference. The results were presented as crude as well as adjusted odds ratio or beta coefficients and their 95%confidence intervalsLinear and logistic regressions were employed to examine the relationship between famine exposure in prenatal life and eGFR or CKD respectively. In order to account for the effect of outstanding biologic covariates four different regression models were evaluated. The first models in both regressions present unadjusted coefficients while model two, three and four were adjusted in a stepwise approach for fasting blood glucose, systolic hypertension and body mass index, respectively. Hosmer-Lemeshow test greater than 0.05 and maximum standard errors (SE) greater than 2 were used to check model fitness and multicollinearity, respectively. Potential effect modification was assessed by interaction terms. All analyses were two sided and Ethical clearance was obtained from Jimma University Institutional Review Board (IRB) as per protocol number IHRPGD/443/2018. Written informed consent was taken from each participant. The study participants were assured that they are free to withdraw their consent and discontinue participation without any form of prejudice. Privacy and confidentiality of collected data was ensured throughout the study. Copy of laboratory results were given to the respective participants and referral to the nearby public health facility were made for individuals with laboratory findings beyond the reference range.The socio-demographic details of the study participant were published elsewhere  sup. 1)1 presentOut of the famine exposed cohorts 20 participants and 8 for the non-exposed has CKD. Chi square test indicates a significant difference between the groups’ in terms of proportion of CKD  (model 1). In model 2, adjusted for fasting blood sugar, GFR is reduced by −.115 with the exposure . In model three further adjustment was made for fasting blood glucose in addition for systolic blood pressure where exposure to famine remained to have a negative beta coefficient . The last model, adjusted for fasting blood sugar, systolic blood pressure and BMI resulted in a reduction of eGFR by −.114 with prenatal famine .)  (model 1). Model two and three also showed in almost equivalent positive odds of having CKD with exposure  and  respectively. In the final model, adjusted for systolic BP, fasting blood sugar and BMI resulted in equivalent odds with model 2 and 3; OR (CI): 2.61 95% CI:  Table .Table 4In our previous studies in the same study setting, we have reported the positive association between prenatal exposure to famine in early life and the risk of metabolic syndrome and cognitive malfunctioning late in adulthood , 23. FurThe present finding indicates that exposure to prenatal famine had an association with the reduction in eGFR. We also found that, compared to non-exposed groups, adults who were exposed to famine in their fetal period had a higher proportion of CKD. In both of the above case scenarios, adjusting for classic outstanding covariates of CKD –4  among famine exposed groups compared to controls . HoweverApart from observational studies, findings from reviews of animal experimental studies reported that exposure to maternal global nutritional restriction during pregnancy to have unfavorable effects such as decreased kidney weight, lower nephron endowment, larger glomerular size, and lower GFR . Taking The implication of our findings should be interpreted considering the prevalent under nutrition in low income countries, which could have close or similar consequences on the health of the kidney during adulthood. Careful monitoring of CKD in hunger spots should be critical undertaking through early kidney disease detection programs and appropriate treatment of CKD risk factors such as obesity, high systolic blood pressure and elevated glucose levels.This study has some limitations. Fasting blood glucose and creatinine was obtained based on a single measurement, so the prevalence of CKD might be overestimated. We also estimated GFR using CKD-EPI equation as we don’t have any locally adapted equation. Furthermore, due to paucity of data we have not included other important prenatal factors such as as gestational age, maternal nutritional and health conditions, mother’s smoking and drinking habits.Prenatal exposure to the Great Ethiopian Famine of 1984–85 was associated with decreased eGFR and greater risk of CKD among survivors. These findings may imply that famine in early life may play a significant role in the development of kidney dysfunction late in adulthood.Additional file 1: Supp. Table 1. Background characteristics of Ethiopian great famine exposed and non-exposed groups in North Wollo Zone, Raya Kobo district, Northeast Ethiopia, 2019. Supp. Figure 1. Flow diagram representing sample recruitment.


World Health Organization (WHO) consultation experts recommend countries to have guidance to identify public health action points suitable for their country. The objective of the study was to evaluate different obesity indices to predict high blood pressure and its optimal cutoff values among the adult population.A total of 3368 individuals age from 25 to 64 years were included in this study. Data was collected based on the WHO Stepwise approach. Body mass index (BMI), waist circumference (WstC), waist to hip ratio (WHpR) and waist to height ratio (WHtR) were measured and calculated. High blood pressure was considered for those with systolic blood pressure above 135 mmHg, diastolic blood pressure above 85 mmHg or taking antihypertensive medications. To generate cutoff values, the receiver operator characteristic curve was generated with the maximum Youden index.P = 0.003), BMI (P = 0.036) and WHtR (P < 0.001) than men. Men had significantly higher WHpR (P = 0.027) than women. There were significantly higher BMI, WstC, WHpR, and WHtR among those with high blood pressure. The cutoff values for BMI, WstC, WHpR and WHtR were 22.86 kg/m2, 84.05 cm, 0.91 and 0.50 for men and 24.02 kg/m2, 79.50 cm, 0.91 and 0.51 for women, respectively.Women had a significantly higher hip circumference (BMI, WstC, WHpR, and WHtR are a useful predictor of high blood pressure among adults’ rural residents of southern Ethiopia. As the sensitivity for the cutoff values of most of indices were low, further surveys in different settings may need to be done before a conclusion can be drawn on whether or not to review the anthropometric cut offs for high blood pressure in Ethiopia. Anthropometric parameters that assess body fat are broadly utilized to foretell the increased risk of chronic disease both at individual and population levels . Body maHypertension is regarded as one of the major contributing factors for the global burden of diseases and a cardiovascular risk factor . PhysiolWHO identified a cutoff value for these anthropometric indicators commonly based on the body fat level. The risks of certain diseases are notably higher in some populations than would be expected , 14. AgaThe study was carried at Arba Minch Health and Demographic Surveillance System (HDSS) which is located in Arba Minch Zuria district Southern Ethiopia. Arba Minch, the administrative town of the district, located 505 km south from the capital city, Addis Ababa. Arba Minch HDSS includes nine Kebeles (the lowest administrative unit of Ethiopia) of Arba Minch Zuria District. Eight of the nine HDSS Kebeles are rural and one is semi-urban.A community-based cross-sectional survey was conducted from April to June 2017. The source population was adult residents (25–64 years old). Based on the 2016 Arba Minch HDSS site report, 24,800  eligible individuals, which was 33.5% of the total population, were included as source population. Pregnant mothers or women who have a history of recent delivery up to 8 weeks were excluded from the study [The sample size was determined based on the WHO stepwise (STEPS) approach to surveillance of chronic non-communicable disease risk . The estData collection instruments were adapted from STEPS instruments. From three levels of STEPS approach, only step one and two were applied in this study. Interview and measurement were conducted at the participants’ dwelling. Step one of the STEPS instruments is the questionnaire-based, which was designed to obtain core data on socio-demographic information with appropriate modifications in accordance with the STEPS manual . Blood pTraining was given for three days on data collection material and measurement procedures for 20 data collectors and four supervisors. The pre-test was conducted on 2% of the sample size and the finding was used to adjust the content and approach of the tools. Supervisors had monitored the whole data collection process and checked the data for completeness every day during the data collection time. To increase the response rate, the data collectors repeatedly visited (at least three times) those participants who were not present at the house during data collection time.BMI was generated by computing weight in kg per height in meter squared. WHpR and WHtR were computed by dividing the waist circumference by hip circumference and height, respectively. High blood pressure was considered for those with systolic blood pressure above 135 mmHg, diastolic blood pressure above 85 mmHg or if the participant reported that he/she is taking antihypertensive medications .P-value < 0.05 was considered significant.EPI-data version 3.1 statistical software was used for data entry and the data was exported to Stata version 14 for further management and analysis. Descriptive statistical analyses like mean, standard deviation, frequencies & percentages were computed. Pearson’s partial correlation coefficients were calculated to reflect the relationships between four obesity indexes, and to characterize how these indexes correlated with high blood pressure. The receiver operator characteristic (ROC) curve was generated to identify optimal cutoff values with the maximum Youden index (sensitivity plus specificity-1) for anthropometric indexes to blood pressure measurements and to determine the ability of anthropometric variables to discriminate high blood pressure. The area under the curve (AUC) was calculated to compare the effectiveness of the different indexes and P = 0.283). In addition, there was no significant difference between men and women concerning WstC (P = 0.406), systolic blood pressure (P = 0.837) and diastolic blood pressure (P = 8.99). However, women had a significantly higher hip circumference (P = 0.003), BMI (P = 0.036) and WHtR (P < 0.001) than men. Men had significantly higher WHpR (P = 0.027) than women  participated in the study with a response rate of 99.3%. The mean (SD) age of the participants was 44.59 11.17) years and there was no significant difference in age between both sexes . For women, there were significantly higher BMI, WstC, WHpR and WHtR among those with high blood pressure and diastolic blood pressure above 85 mmHg. Only significantly higher WHpR and WHtR was observed in systolic blood pressure above 135 mmHg in women  were apparently higher for high blood pressure. Similarly, a study conducted among 772 Chinese subjects showed that there was significantly higher mean value of BMI, WstC and WHtR for increased measurements of blood pressure. Contrary to the finding of this report, WHpR was not related . A studypressure . A studypressure . A reporpressure . As it ipressure –36.This study indicated that BMI, WstC, WHpR and WHtR useful indicators to identify the presence of high blood pressure in the adult population of the study setting. In addition, except BMI and WstC for systolic blood pressure above 135 mmHg for women, the other indicators showed that they had useful cutoff values for increased blood pressure measurements. Different studies showed the importance of these anthropometric indicators as a predictor of high blood pressure , 37, 38.2. The present study revealed that 22.86 kg/m2 and 24.02 kg/m2 were the cutoff values for indicating the presence of high blood pressure for men and women, respectively. Other Studies in Ethiopia and Asian countries showed similarly lower cutoff value than indicated by WHO based on the Caucasian population [2, 23.8 kg/m2 and 23.5 kg/m2, respectively, which are nearly similar to this finding. Similarly, for women, the cutoff values were 23.3 kg/m2, 24.1 kg/m2 and 26.2 kg/m2 for the Chines population of Liaoning Province, Hong Kong and Western Ethiopia, respectively [. A study from Taiwanese and Shandong of China showed that the cutoff value of BMI was 25.74 kg/m2 and 25 kg/m2 for men and 23.46 kg/m2 and 24.5 kg/m2 for women, respectively [The cutoff value recommended by the WHO for BMI is 25 kg/mpulation . For menectively , 37, 39.ectively , 40. Finectively . The higectively , 38–40.. The cutoff value for women WstC was similar to the WHO cutoff recommendation. For men, the cutoff value is lower than the recommended. Relatively the specificity for both men and women, and sensitivity for women is good, the sensitivity for the WstC cut-off value for men was by far lower even compared to other studies [The cutoff value for WstC to indicate high blood pressure of this study was lower than the cutoff value of WHO. The cutoff value by WHO is 94 cm for men and 80 cm for women . A study studies , 38–40.. Other studies, like Hong Kong, showed 0.89 for men and 0.84 for women as a predictor for high blood pressure [The cutoff value to predict high blood pressure by using WHpR was 0.91 for both sexes from this finding. A cutoff value for WHpR as a predictor for high blood pressure in Southwest Ethiopia was 0.86 and 0.89 for men and women employees of the University . Other spressure . Abdominpressure . The WHOpressure , 39.. A study among Taiwanese male adults showed that the cutoff value was 0.51 for men and 0.49 for women [. The specificity for the cutoff value for WHtR of this study was nearly similar to different studies. But the sensitivity was low for both men and women [In this study, the WHtR cutoff value of identifying individuals with high blood pressure was nearly 0.50 for both sexes. A study among Hong Kong showed 0.50 for men and 0.55 for women as a cutoff value for WHtR as a predictor for high blood pressure among adult males . A studyor women . A studyor women . A studyor women . The spend women –40.For this analysis, we consider measurements of blood pressure which is a part of metabolic syndrome. The data were collected mostly from rural residents within a district. As it is recommended to use different cutoff values for anthropometric indicators of metabolic syndrome, this finding gives a significant contribution.In conclusion, BMI, WstC, WHpR and WHtR are useful predictors of high blood pressure among adults of rural residents of southern Ethiopia. This report found that the cutoff value of BMI for blood pressure measurements lower than that of the WHO’s recommendation for overweight based on the Caucasian population. But the sensitivity and specificity of BMI cutoff values for determining high blood pressure were low. Regarding WstC, the cutoff value is similar to the WHO cutoff value for women, but it is lower than the cutoff value of the men participants. In addition, the sensitivity for assessing high blood pressure using WstC was low for men. WHO recommended the cutoff value for WHpR was similar for men but lower for the women population of the study site. For most of the anthropometric indicators, the cutoff value as a predictor of high blood pressure was lower in this population compared with the international cutoff values. In addition, the sensitivity for determining the cutoff values for most of the indices was low. Further surveys in different settings may need to be done before a conclusion can be drawn on whether or not to review the anthropometric cutoffs for high blood pressure in Ethiopia.Additional file 1.


It was recently found in traumatic brain injury (TBI) that ICP variability (ICPV) predicted favorable outcome. We hypothesized that ICPV may depend on intracranial compliance, unstable blood pressure and cerebral vasomotion. In this study, we aimed to further investigate the explanatory variables for ICPV and its relation to outcome. Data from 362 TBI patients were retrospectively analyzed day 2 to 5 post-injury. ICPV was evaluated in three ways. First, variability in the sub-minute time interval (similar to B waves) was calculated as the amplitude of the ICP slow waves using a bandpass filter, limiting the analysis to oscillations of 55 to 15 s (ICP AMP 55–15). The second and third ICPV measures were calculated as the deviation from the mean ICP averaged over 30 min (ICPV-30m) and 4 h (ICPV-4h), respectively. All ICPV measures were associated with a reduced intracranial pressure/volume state (high ICP and RAP) and high blood pressure variability in multiple linear regression analyses. Higher ICPV was associated with better pressure reactivity in the univariate, but not the multiple analyses. All ICPV measures were associated with favorable outcome in univariate analysis, but only ICP AMP 55–15 and ICPV-30m did so in the multiple logistic regression analysis. Higher ICPV can be explained by a reduced intracranial compliance and variations in cerebral blood volume due to the vessel response to unstable blood pressure. As ICP AMP 55–15 and ICPV-30m independently predicted favorable outcome, it may represent general cerebral vessel activity, associated with better cerebral blood flow regulation and less secondary insults. Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young adults worldwide . Post-trICP variability (ICPV) can be defined over various time intervals. The slow wave ICP amplitude, i.e. ICP oscillations with time periods at e.g. 15 to 55 s, is similar to “B waves” and is believed to represent the vasogenic response to blood pressure variations . ICPV maThe exact physiological mechanisms for ICP variability in short and long-term time intervals, their physiological information and relation to outcome are poorly studied. In this study, we aimed to investigate the differences in very short-term (sub-minute window), short-term (minutes) and long-term (hours) ICP variability, its relation to ICP and other physiological variables to determine how this information is associated with clinical outcome.The Department of Neurosurgery at the University Hospital in Uppsala, Sweden, provides neurosurgical care for a central part of Sweden, with a population of approximately two million people. Most patients are initially managed at local hospitals according to the advanced trauma life support (ATLS) principles and then referred to Uppsala  . Since 22 > 12 kPa, blood glucose 5–10 mmol/L, electrolytes within normal ranges together with normovolemia and body temperature < 38 °C.All patients were treated in accordance with a standardized ICP-oriented treatment protocol to avoid secondary insults , 9. Trea1-antagonist infusion  and repeated injections of a α2-agonist .All unconscious (GCS M 1-5) patients were intubated and sedated with propofol infusion  and morphine  for analgesia. The intracranial pressure was monitored in all unconscious patients with either an intraparenchymal sensor device  or an intraventricular catheter drainage system . Patients were initially hyperventilated (4.0–4.5 kPa), but normoventilated as soon as ICP allowed. In stable patients, neurological wake-up tests were repeatedly performed. In case of high ICP with simultaneous high blood pressure and tachycardia, stress was treated with a βIntracranial lesions with significant mass effect were surgically evacuated. In situations of increased ICP, despite basal treatment and if no mass lesion was present, cerebrospinal fluid was drained. If ICP still remained elevated, a thiopental infusion was started, and finally, if high ICP was still refractory, a decompressive craniectomy was performed.The ICP and arterial blood pressure data were recorded with the Odin software, developed at Uppsala University and University of Edinburgh . ICPV waPRx, which originally was described by Czosnyka et al., was calculated as a moving 5-min correlation of 10 s averages of ICP and MAP . We alsoThe RAP-index  was calculated as the moving 5-min correlation between ICP amplitude and ICP . ART AMPOutcome was assessed at 6 months following injury, by specially trained personnel with structured telephone interviews, using the Extended Glasgow Outcome Scale (GOS-E) , 15, conDemographic data were presented as the mean ± SD. Mean daily values for all three ICPV measures were generated for each patient the first 10 days in Odin, as illustrated in Fig. The explanatory variables for the three ICPV measures were analyzed with univariate correlation tests (Spearman) and multiple linear regression including demographic data  and physiological data  for day 2 to 5  with simple and multiple logistic regression analyses Table . The mulFurthermore, the ICPV measures were evaluated for association with intracranial hypertension. The mean ICPV measures for the first day post-injury and the proportion of good monitoring time (GMT) (%) of ICP > 20 mmHg were calculated for day 1 and day 2 to 5, respectively. The correlation between the ICPV measures on day 1 vs. GMT > 20 mmHg on day 1 and day 2 to 5 were analyzed with the Spearman correlation test Table .Table 3EThe effects of DC on ICPV was evaluated as the temporal trend the first 10 days post-injury, for patients treated with DC in relation to the patients that did not require DC treatment Fig. . Furtherp values < 0.05 were considered statistically significant.All procedures performed in the studies were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual patients included in the study or their next of kin.Three hundred sixty-two patients were included. Mean age was 47 (± 19) and 79% were male. Eight percent were GCS M 1–2 at admission, 20% had pupillary abnormalities (anisocoria and/or one/two unreactive pupils) and 66% had CT Marshall score diffuse injury I-III. Forty-six percent were operated with craniotomy, 11% treated with thiopental and 10% with DC. Fifty-six percent of the patients had favorable clinical outcome at 6 months following injury.Figure In the Spearman’s rank correlation analyses, both higher ICPV-30m and ICPV-4h were associated with younger age, whereas ICP AMP 55–15 had no correlation with age  in ICP AMP 55–15, 1.2 ± 0.5 vs. 0.9 ± 0.4 mmHg  in ICPV-30m and 1.9 ± 0.5 vs. 1.7 ± 0.6 mmHg  in ICPV-4h. Lower ICPV was also associated with unfavorable outcome in a simple logistic regression analysis , GMT  % ICP > 20 mmHg, GMT % 70 mmHg > CPP > 60 mmHg, PRx55–15 and blood pressure variability  and inclusion of RAP in the multiple logistic regression of unfavorable outcome attenuated the association between outcome with ICP AMP 55–15/ICPV-30m and RAP, respectively, to non-significant.All three ICPV measures on day 1 post-injury were strongly associated with ICP > 20 mmHg on the same day Table . Higher The temporal course for ICPV-30m for patients treated with DC (n = 37) and the non-DC (n = 325) population is illustrated in Fig. In this study, we found that ICPV, particularly high ICP AMP 55–15 and ICPV-30m, independently predicted favorable outcome. The ICPV measures had amplitudes around 0–5 mmHg and likely represented smaller changes in the cerebral blood volume, rather than small changes in mass lesion size or edema. Although higher ICPV was associated with negative factors such as intracranial hypertension and higher blood pressure variability, it also correlated with predictors for better outcome such as younger age, higher GCS M at admission and lower PRx/intact pressure reactivity. This indicates that ICPV is augmented by a reduced intracranial pressure/volume reserve and varies with the cerebral blood volume as a consequence of the vessel response to variable blood pressure. Thus, ICPV may via several mechanisms be associated with better cerebral blood flow regulation and less secondary insults.ICP variations have generated interest since the development of ICP monitoring in the NIC . Various2 and rhythmic brainstem oscillations that control the cerebral vessels [The origin of ICPV has been debated . Rosner  vessels , 18, 20.In line with these theories, we found that reduced intracranial volume/pressure reserve (high ICP and RAP) and high BPV (ART AMP 55–15/BPV-30m/BPV-4h) predicted high ICPV in the multiple linear regressions  independently predicted low ICPV for all time intervals. DC drastically changes the intracranial dynamics as the cranial vault is opened, with an increased intracranial pressure/volume reserve . Hence, Castellani et al. looked at ICPV in terms of plateau waves in severe TBI. Similar to our findings, high ICPV/plateau waves were associated with young age, diffuse rather than focal brain injury, high ICP/RAP and intact pressure autoregulation . We beliTraditionally, ICPV in terms of type A and B waves have been considered pathological , 23. HowIn this study, we evaluated three ICPV measures, i.e. very short-term (ICP AMP 55–15), short-term ICPV-30m) and long-term (ICPV-4h). For all three measures, higher values were associated with better outcome (higher GOS-E). However, only ICP AMP 55–15 and ICPV-30m independently predicted favorable outcome in the multiple logistic regression analysis  . SimilarAs ICPV is associated with the intracranial pressure/volume reserve and possibly the autoregulatory status , 17, 18,ICP variability was traditionally considered pathological in acute brain injuries. Contrary to earlier belief, we found that higher ICP variability in the 0–5 mmHg range in the subminute and 30-minute interval independently predicted favorable outcome in traumatic brain injury.Although higher ICPV was associated with higher intracranial hypertension and higher blood pressure variability, it also correlated with positive factors such as young age and high GCS M at admission. Our analysis led to the conclusion that the intracranial effects and the effect on outcome are both due to a controlled dilation of the cerebral vessels, probably in response to metabolic demand, with net positive effects.


Patients with chronic kidney disease are at increased risk of cardiovascular disease and this often manifests clinically like heart failure. Conversely, patients with heart failure frequently have reduced kidney function. The links between the kidneys and cardiovascular system are being elucidated, with blood pressure being a key risk factor. Patients with heart failure have benefitted from many trials which have now established a strong evidence based on which to base management. However, patients with advanced kidney disease have often been excluded from these trials. Nevertheless, there is little evidence that the benefits of such treatments are modified by the presence or absence of kidney disease, but more direct evidence among patients with advanced kidney disease is required. Neprilysin inhibition is the most recent treatment to be shown to improve outcomes among patients with heart failure. The UK HARP-III trial assessed whether neprilysin inhibition improved kidney function in the short- to medium-term and its effects on cardiovascular biomarkers. Although no effect (compared to irbesartan control) was found on kidney function, allocation to neprilysin inhibition  did reduce cardiac biomarkers more than irbesartan, suggesting that this treatment might improve cardiovascular outcomes in this population. Larger clinical outcomes trials are needed to test this hypothesis. In addition, HF may worsen CKD by decreasing renal perfusion, causing renal venous congestion and activation of the sympathetic nervous system and renin–angiotensin–aldosterone system . Treatment for HF in CKD can be divided into two broad types: (i) treatments that intervene on pathophysiological links between CKD and HF to prevent HF and (ii) treatments known to improve prognosis in established HF among people without CKD.CKD is commonly associated with high BP, due to salt and water retention, activation of the sympathetic nervous and other neurohormonal systems and accumulation of endogenous vasopressors . StudiesAnaemia is a well-recognized complication of CKD and has been proposed as a direct cause of HF in patients with CKD following observational and non-randomized interventional studies, suggesting that anaemia is associated with LVH and correcting the anaemia reverses the LVH , 20. HowReducing parathyroid hormone concentrations with calcimimetic therapy might reduce the risk of non-atherosclerotic cardiovascular events (such as HF) among haemodialysis patients , 23. Suc2 but have excluded patients with more advanced stages of CKD (i.e. eGFR <30 mL/min/1.73 m2).The main objectives of HF therapy in CKD (as well as in non-CKD) patients are to decrease the preload and afterload and to reduce LVH, treat myocardial ischaemia and inhibit neurohumoral hyperactivity, especially the sympathetic nervous system and RAS . HoweverMany pharmacological and device treatments are recommended for HF with reduced ejection fraction (HFrEF) . The maiFor patients with HFrEF [with a left ventricular ejection fraction (LVEF) <35%] who remain symptomatic after optimization of ACEi and β-blocker therapy, guidelines recommend a mineralcorticoid receptor antagonist (MRA). This recommendation follows two large trials see . Again, post hoc analyses have suggested that patients recruited from certain geographic regions had significantly worse adherence to treatment , which may have made the overall result a ‘false negative’  degrades natriuretic and other vasoactive peptides  and therefore neprilysin inhibition (NEPi) enhances the activity of the natriuretic peptide system leading to natriuresis, diuresis, BP reduction and inhibition of RAS and the sympathetic nervous system . IsolateSacubitril/valsartan is a first-in-class ARNI that is rapidly metabolized after ingestion to the NEPi pro-drug sacubitril and the ARB valsartan. Sacubitril/valsartan reduces BP more than equivalent doses of valsartan alone . The ProSacubitril/valsartan has also been tested among patients with HFpEF. The PARAMOUNT trial compared sacubitril/valsartan with valsartan in 301 patients with change in NT-proBNP as the primary outcome . At 12 wIn addition to its known benefits in HFrEF , NEPi might also have beneficial effects on the kidney. Experiments using 5/6 nephrectomy models suggested that NEPi reduces proteinuria and histological markers of kidney damage more than ACE inhibition alone , 56. In 2 or their eGFR was ≥45–<60 mL/min/1.73 m2 and the urine albumin:creatinine ratio was >20 mg/mmol. Other pre-specified outcomes included albuminuria, BP and cardiac biomarkers. A total of 414 participants were randomized and the average eGFR was 35 mL/min/1.73 m2 and median urine albumin:creatinine ratio was 54 mg/mmol. Only 4 and 13% reported HF and coronary heart disease, respectively, at baseline.The UK Heart and Renal Protection (HARP)-III trial was designed to investigate the short- to medium-term effects of sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily on kidney function among patients with established CKD . Patient2 [The primary outcome of measured GFR at 12 months did not differ between the two groups: the difference in means was −0.1 (standard error 0.7) mL/min/1.73 m2 . AlbuminAlthough the effects on kidney function are not encouraging, they do not exclude a benefit on long-term progression of CKD . However, the effects on BP and cardiac biomarkers support the hypothesis that sacubitril/valsartan might reduce the risk of cardiovascular events (and in particular those related to HF) among patients with CKD, irrespective of whether they have known cardiac disease. The neutral effects on tolerability and safety outcomes in the UK HARP-III trial would also support further investigation of this hypothesis.The burden of HF among patients with CKD is considerable and contributes significantly to the excess of cardiovascular morbidity and mortality observed in this growing population. The anatomical substrates of HF develop early in the progression of CKD and strategies to prevent it have not been rigorously tested in the CKD population. Furthermore, trials among patients with known HF have usually excluded patients with moderate or advanced CKD, so the efficacy and—importantly—the safety of these treatments in the CKD population are uncertain. NEPi looks promising as a treatment that could reduce the risk of HF safely among patients with CKD, but clinical outcome trials are required. Newer treatments for HF, such as sodium glucose co-transporter-2 inhibitors, are being tested in large trials in both HF and CKD populations  and may www.ctsu.ox.ac.uk).RH, PK, WH and CB work at the Clinical Trial Service Unit, University of Oxford which received a grant from Novartis Pharma AG to conduct the UK HARP-III trial. CTSU has also received grants from Merck, Pfizer and Boehringer-Ingelheim for research in kidney disease. CTSU has a staff policy of not accepting honoraria or other payments from the pharmaceutical industry, except for the reimbursement of costs to participate in scientific meetings (www.ctsu.ox.ac.uk.The UK HARP-III trial was funded by a grant to the University of Oxford from Novartis Pharma. The trial was conducted, analysed and published independently of the funder. See