Objectives: The purpose of this study was to compare the effects of combined epidural-general anesthesia with those of general anesthesia alone on hemodynamic instability (intraoperative hypotension and hypertensive crisis) during pheochromocytoma and sympathetic paraganglioma surgery.Methods: A total of 119 patients' medical records were reviewed who were diagnosed as having pheochromocytoma and sympathetic paraganglioma on the basis of histological findings. Intraoperative hypotension was defined as a mean blood pressure < 60 mmHg or a decrease > 30% in baseline systolic blood pressure after adrenal vein ligation. Hypertensive crisis was defined as a systolic blood pressure > 200 mmHg or an increase > 30% in baseline systolic blood pressure during the operation. The predictor variables for intraoperative hypotension and hypertensive crisis were analyzed with logistic regression models. Data were presented as adjusted odds ratio with 95% confidence interval.Results: The independent predictors of intraoperative hypotension were an increased attenuation number on unenhanced computed tomography , a high baseline mean blood pressure , and the combined epidural-general anesthesia . In contrast, an increased attenuation number on unenhanced computed tomography was the only independent predictor of hypertensive crisis .Conclusions: The combined epidural-general anesthesia was not effective in attenuating hypertensive responses, but could have exacerbated intraoperative hypotension. These findings should be taken into account before selecting the anesthetic technique in pheochromocytoma and sympathetic paraganglioma surgery. Pheochromocytomas and sympathetic paragangliomas (PPGLs) are chromaffin cell tumors that produce, store, and secrete catecholamines 2, and tumor manipulation Surgical resection is the treatment of choice for PPGLs The combined epidural-general anesthesia technique (GE) has been widely used in PPGL resection. This technique has been reported to facilitate hemodynamic stability before tumor isolation and reduce pain and complications after surgery The primary purpose of this retrospective cohort study was to compare the effects of GE with those of general anesthesia alone (GA) on hemodynamic instability (intraoperative hypotension and hypertensive crisis) during PPGL surgery. We also investigated the risk factors for predicting hemodynamic instability in PPGL surgery.The institutional review boards of Pusan National University Hospital and Pusan National University Yangsan Hospital designated this retrospective cohort study as exempt (ID: H-1903-022-077 and 05-2019-055). The subjects of this study were patients who had been histologically diagnosed with PPGLs from January 2000 to December 2018 at Pusan National University Hospital or Pusan National University Yangsan Hospital. The following patients were excluded from the study: those with duplicated data, patients younger than 18 years, patients with head and neck paraganglioma, patients who underwent co-operative surgery, patients who had not undergone general anesthesia, and patients with more than 10% missing values.In the operating room, standard , depth of anesthesia , and intra-arterial blood pressure monitoring were performed. A central or large-bore peripheral intravenous catheter was inserted in all patients.Selection of anesthetic agents and techniques was made entirely by the attending anesthesiologists. In patients who underwent GE techniques, the epidural catheter was inserted into the lower thoracic epidural space (T8-12) according to the surgical incision site prior to general anesthesia induction. To provide adequate analgesia during surgery, local anesthetics (0.2% ropivacaine or 0.2% chirocaine) and supplemental opioid (3 mg of morphine sulfate or 50 mcg of fentanyl) were epidurally administered, and intravenous remifentanil infusion was occasionally added. The administration of the epidural loading dose was completed within 30 minutes after anesthesia induction, and no epidural medication was administered during the main surgical procedure. In patients undergoing GA techniques, intravenous opioid administration (remifentanil infusion or fentanyl bolus) was used for analgesia during induction and maintenance of anesthesia.Induction of general anesthesia was performed using an intravenous sedative hypnotic agent  and muscle relaxants . Anesthesia was maintained with continuous administration of sevoflurane, desflurane, isoflurane, or propofol, along with intermittent boluses of nondepolarizing muscle relaxants .Intraoperative hypotension and hypertensive crisis were defined before data collection and analysis. Intraoperative hypotension was defined as a mean intra-arterial blood pressure < 60 mmHg or a systolic intra-arterial blood pressure (SBP) reduction > 30% immediately before induction of anesthesia (SBPb) during the operation. Hypertensive crisis was defined by an SBP > 200 mmHg or an increase of > 30% in the SBPb during the operation.The following data were extracted from the electronic medical records: (1) baseline patient characteristics—age, sex, height, weight, clinical manifestations, American Society of Anesthesiologists (ASA) classification, left ventricular ejection fraction (LVEF), comorbidities; (2) preoperative computed tomography (CT) findings—The largest tumor diameter in the transverse plane and mean attenuation (Hounsfield unit: HU) on unenhanced CT. The mean attenuation number of the PPGL mass was measured using a circular region-of-interest (ROI) cursor. HU was measured in the central area while avoiding periadrenal retroperitoneal fat, and the mean HU value measured in two continuous sections was used; (3) preoperative catecholamine levels— plasma norepinephrine (pNE), plasma epinephrine (pEpi), urine vanillylmandelic acid (uVMA), and urine metanephrine (uMN) levels; (4) premedications— use of α-blocker and duration; (5) intraoperative data— anesthetic technique (GE vs. GA), induction and maintenance agents, use of remifentanil, method of surgery (laparoscopic or open), operation time, estimated blood loss, amount of fluid administration, urine output, and blood transfusion; (6) hemodynamic data—mean blood pressure before premedication (MBPpre), mean blood pressure immediately before induction of anesthesia (MBPb), and hemodynamic values during general anesthesia. Variables with data missing for more than 30% of the patients  were excluded from the analysis.All analyses were performed using IBM SPSS Statistics  and MedCalc . Continuous variables were presented as mean ± standard deviation (SD) or as median and interquartile range (IQR). Categorical data were reported as absolute numbers and percentages. The results of binary logistic regression analyses were presented as odds ratio (OR) or adjusted OR with 95% confidence interval (95% CI).Patient data were grouped according to anesthetic technique (GE vs. GA) and the occurrence of hemodynamic instability to compare preoperative patient demographics, tumor characteristics, and intraoperative variables. After the normality test, normally distributed data were analyzed using an independent t-test and non-parametric data were analyzed using the Mann-Whitney U test; categorical data were analyzed using the chi-squared test (with Yates' continuity correction for the 2 × 2 contingency table) or Fisher's exact test.First, univariate binary logistic regression analysis was performed to evaluate the association between predictor variables and outcome variables (intraoperative hypotension and hypertensive crisis). The predictor variables entered in the univariate analysis were baseline patient characteristics, preoperative CT findings, preoperative catecholamine level, premedications, intraoperative data, and preoperative hemodynamic data (MBPpre and MBPb).2 and the Hosmer-Lemeshow chi-squared statistics were calculated. The probability of each case was calculated and the area under the receiver operating characteristic curve (AUROC) was determined to evaluate the discriminative power of the multivariate logistic regression models; AUROC was also used to determine the optimal cut-off values for continuous predictor variables.The candidate predictors entered in the multivariate binary logistic regression analysis were predictor variables with p values less than 0.25 in the univariate analysis. The anesthetic technique (GE vs. GA) was also entered in the multivariate binary logistic regression analysis regardless of p value because it was our primary predictor variable. Predictor variable selection was performed by the backward elimination method based on the probability of the likelihood-ratio statistic, with p value ≥ 0.1 as the removal criterion. Patients with missing data for one or more predictors were excluded from the logistic regression analysis. To evaluate the usefulness and goodness-of-fit of the multivariate logistic regression model, Nagelkerke ROf the 119 patient records retrieved, 15 were excluded for the following reasons: duplication, three cases; patient age under 18 years, three cases; co-operative surgery, four cases; procedures without general anesthesia, one case; and missing values, four cases , 0.403, and 0.852 (95% CI: 0.765-0.938), respectively. The receiver operating characteristic (ROC) analysis to determine the cut-off values of continuous predictor variables showed that the optimal cut-off HU value on unenhanced CT and MBPb were 37 HU (AUROC [95% CI]: 0.654 [0.539-0.757]) and 93.7 mmHg (AUROC [95% CI]: 0.741 [0.646-0.822]).Univariate analysis presented 6 candidate predictors that might be independently associated with the occurrence of intraoperative hypotension Table . The folPreoperative patient demographics, tumor characteristics, and intraoperative variables of the groups stratified according to the occurrence of hypertensive crisis during PPGL resection are summarized in Table 2, and AUROC of the final model were 6.010 (p = 0.646), 0.198, and 0.727 , respectively. The ROC analysis to determine the cut-off value of the continuous predictor variable showed that the optimal cut-off HU value on unenhanced CT was 36 HU (AUROC [95% CI]: 0.667 [0.553-0.768]).Seven candidate predictors Table  and anesIn this retrospective chart review study, intraoperative hypotension was observed in 80 (76.9%) patients during PPGL resection. The independent predictors of intraoperative hypotension were an increased HU value on unenhanced CT, a high MBPb, and the GE technique. Hypertensive crisis occurred in 57 (54.8%) patients during PPGL resection. The only independent predictor of a hypertensive crisis was an increased HU value on unenhanced CT.The known risk factors for hemodynamic instability during PPGL surgery are increased preoperative urinary catecholamine levels, larger tumor size, and absence of the α-blocker premedication In the present study, a high MBPb was found to be associated with the occurrence of intraoperative hypotension, but not with hypertensive crisis during surgery. Before the resection of PPGLs, blood pressure should be optimized whenever possible, since uncontrolled preoperative hypertension in PPGL patients is known to increase the risk of perioperative complications In the present study, the GE technique was found to be associated with the occurrence of intraoperative hypotension during PPGL surgery. Epidural analgesia is frequently used in combination with general anesthesia in PPGL surgery for the attenuation of intraoperative hemodynamic response and postoperative pain control. Luo et al. Tumor manipulation is the most powerful factor to induce a catecholamine surge during PPGL surgery The present study has several other limitations. First, the intraoperative hemodynamic data used in the present study were extracted from electronic anesthetic records. Since these measurements are recorded every 5 minutes, the accuracy of the hemodynamic parameters could have been compromised. Second, due to the low prevalence rate of PPGLs, the recruitment period was over 18 years, and the development of surgical and anesthetic skills may have produced a bias. Finally, due to the low frequency of complications, we could not analyze the correlation between intraoperative hemodynamic instability and the patient's clinical outcome.In conclusion, in the present study, an increased HU value on unenhanced CT, a high MBPb, and the GE anesthetic technique were found to be independent predictors of intraoperative hypotension, while an increased HU value on unenhanced CT was found to be an independent predictor of hypertensive crisis during PPGL surgery. Since the GE anesthetic technique has the potential to cause intraoperative hypotension, anesthesiologists should consider these findings before selecting an anesthetic technique in PPGL surgery.


Diabetes mellitus (DM) is one of the fastest growing chronic diseases in the world and one of the main causes of vision loss. Whether or not diabetic choroidopathy (DC) is involved in the initiation and progression of diabetic ocular complications needs to be explored. We included 54 diabetic eyes from 36 diabetic patients, and 54 healthy eyes from 32 control subjects after propensity scores matching. All of the subjects were given pupil light and dark adaptation examination and optical coherence tomography angiography (OCTA). Scotopic pupil diameter (SPD), pupil contraction amplitude, and velocity of pupil contraction of the diabetic group were significantly lower than that of the healthy control group (P < 0.05).Choroidal thickness at temporal quadrant (at 750 μm) and superior quadrant (at 1500 μm and 2250 μm) increased in diabetic group compared to control group(P < 0.05).In the diabetic group, choriocapillaris blood flow signal density (CCBFSD) in the macular area (diameter = 2000 μm) were significantly decreased compared with the healthy control group (P < 0.05). Apparent changes in pupil and choroidal blood flow were observed in the diabetic patients. According to the World Health Organization (WHO), the total number of people with DM will grow from 171 million in 2000 to 366 million in 20302. At present, the pathological mechanisms of diabetic retinopathy are mainly explained by the effects of vascular leakage, vascular abnormalities, neuronal cell dysfunction, and inflammatory mechanisms3.Diabetes mellitus (DM) is one of the fastest growing chronic diseases in the world and one of the leading causes of vision loss4. Histopathological studies revealed a variety of choroidal changes secondary to DM7. The choroid accounts for more than 85% of the retinal blood supply and supplies all the nutrients for the retinal pigment epithelium and photoreceptors9. It has been reported that photoreceptors die rapidly when the choroidal blood flow decline drastically10. The regulation of choroidal blood flow includes neuromodulation, autoregulation, and local choroidal ganglion regulation13.The concept of diabetic choroidopathy was proposed by Saracco et al. as early as 198214. Studies have shown that nerve modulation of the uvea affects blood flow in the iris, ciliary body, and choroid16.Diabetic autonomic neuropathy (DAN) refers to a disorder of the autonomic nerves caused by DM, which involves diseases related to multiple systems including orthostatic hypotension, tachycardia, gastroparesis, diarrhea, constipation, etc. Its ocular complications include a reduction of scotopic pupil diameter and an Argyll-Robertson-like pupil21, little research on diabetic choroidal blood flow and its relation to pupil lesions is currently available. Previous studies have shown that the blood flow of choroidal capillaries in diabetic patients is significantly lower than that of healthy people23. Some studies have shown that their blood flow further decreases as the severity of the disease increases24.Both the choroid and the iris are parts of the uvea, and they have an inseparable relationship in anatomy, structure, and development of each other. Although there is a lot of evidence confirming the presence of pupillary lesions and changes in choroidal thickness caused by diabetic autonomic nerve damage25. OCT angiography (OCTA) is a recently developed technique that allows noninvasive visualization of vascular structures28. Moreover, the higher speed of the new OCT equipment has facilitated the optical reconstruction of complex vascular structures25. This feature of OCTA makes it an extremely valuable tool for studying choroidal blood flow29.In recent years, advances in optical coherence tomography (OCT) technology has revolutionized retinal research and clinical practiceA total of 108 eyes  were included for final analysis after PSM. The demographic and clinical characteristic details can be identified in Table 2, 1 cd/m2, 10 cd/m2, and 100 cd/m2, pupil contraction amplitude (PCA), velocity of pupil contraction (PCV) and velocity of pupil dilation (PDV) are shown in Table 2, 10 cd/m2, 100 cd/m2, and PDV were not significantly different from those in the healthy control group (P > 0.05).The details of the diabetic and healthy control groups for pupil diameters at light intensities of 0 cd/mChoroidal thickness (CT) at different locations of the fundus of the diabetic and the control groups is shown in Fig. CCBFSD in the macular area in the diabetic group were significantly lower than that in the healthy control group (P < 0.05). The details are shown in Fig. 21. We consider that this difference may result from pupillary autonomic nerve disorders in diabetic patients, suggesting that hyperglycemia damages the autonomic nerves of the iris.Our study showed that SPD, PCA, and PCV in the diabetic group were all lower than those in the healthy control group, which is consistent with results of previous studies31; however, some conflicting results suggest early thinning, late thickening19, or completely contrast choroidal thickening34. Some of these studies have their own characteristics that may explain the heterogeneity of the results. Querques et al. only compared CT in the central region18, and we know that choroidal changes in diabetes not only affect the central region but, more importantly, affect the circumference. The Vujosevic’s study included all stages of DR, including some patients with PDR17. In Esmaeelpour’s study, some patients had a history of hypertension and were taking medications30, which could affect choroidal circulation.We found that the CT at temporal quadrant (at 750 μm) and superior quadrant (at 1500 μm and 2250 μm) in the diabetic group significantly increased compared with the healthy control group. For this point, previous studies have had different results. Some clinical findings suggest choroidal thinning of early diabetic retinopathy (DR)OCTA, as a method for non-invasive visualization technique of fundus blood vessels, can provide a more comprehensive assessment of choroidal circulation. Compared with OCT, it provides a richer amount of blood flow information. Although OCTA has been frequently used clinically, it is rarely used as a tool for the study of DC. This is an innovative aspect of this research.Compared with previous studies, choriocapillaris blood flow signal density assessment method has been further updated. We use the self-programmed code to position and analyze each image. First of all, we perform batch analysis of pictures based on code, which can reduce manual errors and have good repeatability. Secondly, the code can accurately calculate the blood flow signal of each picture, thus forming 512 B-scan pictures into a "map" representing the choriocapillaris blood flow volume in the macular area, and finally calculating the percentage of choriocapillaris capillary blood signal density in this area.35. We speculate that there are two reasons for decreased CCBFSD in the macular area with diabetes. Firstly, decreased CCBFSD in diabetic patients is caused by vascular damage and blood flow decreasing due to long-term hyperglycemia. Secondly, although it is not realistic to completely exclude the effect of bleeding and exudation on signal acquisition, the patients we included were all patients with no DR, and mild or moderate DR whose bleeding and exudation were not severe. It should be noted that there is no evidence that slight retinal hemorrhage could significantly affect the collection of choroidal blood flow signals.Our study showed a lower CC perfusion in diabetic eyes compared with healthy eyes. Previous study has illustrated that eyes with NPDR are affected by macular hypoperfusion and photoreceptor damage and a lower CC perfusion may be associated with a greater damage of photoreceptorAt the same time, the increase of choroidal thickness and the decrease of SPD occurred in the diabetic group, and both were regulated by autonomic nerves, suggesting that this may be related to diabetic autonomic nerve damage. As we know, the decline of SPD is related to autonomic nerve damage. Furthermore, the middle vascular layer and large vascular layer of choroid also have autonomic and trigeminal innervation. The mechanism and their correlation deserve further research.36. It might suggest that an increased choroidal thickness may be associated with a lower CC perfusion, which is not surprising. Increased choroidal thickness and decreased choriocapillaris perfusion in patients with central serous chorioretinopathy, similar to the results in our study of patients with diabetes38. This reminds us that there may be some similar mechanisms in these two diseases. Firstly, thicker choroid may be caused by increased choroidal vessel wall permeability in an inflammatory state in both diseases. Secondly, choriocapillaris hypoperfusion may be caused by mechanical stress resulting from compression based on focal or diffusely enlarged choroidal vessels37.A previous report by Borrelli et al. demonstrated that a further dilation of the area occupied by medium-sized and larger-sized choroidal vessels and/or choroidal stroma appears to be associated with a progressive reduction in CC perfusion in healthy eyesCompared with previous studies, we better matched certain factors, such as age, gender, intraocular pressure, axial length and refractive status, to minimize the effect of these confounding factors on CT. At the same time, the OCT examination is performed at a constant time period of a day, which reduces the influence of the daily rhythm on the choroidal measurement.At the same time, we also need to consider the following points. First, differences in choroid assessment methods may lead to conflicting results. Diabetic choroidal vascular abnormalities are most common in the mid-circumference. However, OCT examinations focus on the macular/foveal area, so the results of these studies may not accurately reflect the actual situation. Second, OCTA has limitations as well: that is, only the velocity of blood flow within a certain range can be detected by the equipment. The velocity of choroidal capillaries may occasionally be too low to generate a disassociation signal, preventing OCTA from recording blood flow signals in capillaries. Thirdly, compared with the choroidal capillary layer, it is difficult to accurately evaluate blood flow of medium and large choroidal vessels because of the occlusion of retinal vessels and choroidal capillaries, and high blood flow velocity in these vessels.In short, with the advent of the latest OCTA technology, DC has become one of the most compelling diseases to study for ophthalmological researchers. Nonetheless, the relationship between DC and DR, and the role of DC in diabetic ocular diseases remain unknown. This important field requires further research.This study was performed according to the Declaration of Helsinki and was approved by the Ethics Committee of Tongji Hospital. Informed consent was obtained from all study participants before examination.We included 47 diabetic patients (84 eyes) and 48 healthy people (89 eyes) from the Department of Ophthalmology and Department of Endocrinology of Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology. Because the baselines of age, intraocular pressure, sex and spherical equivalent (SE) in two groups were not well matched, propensity scores matching was used. 54 diabetic eyes from 36 diabetic patients and 54 healthy eyes from 32 control subjects were included for final analysis after propensity scores matching, which were used to balance the two groups according to several baseline variables, including age, sex, intraocular pressure, SE. DM was diagnosed according to the 1999 WHO diagnostic criteria.Diabetic patients were included who had no signs of DR, or those diagnosed with mild or moderate non-proliferative diabetic retinopathy (NPDR).These included: (1) hypertension, kidney disorders, and other systemic diseases that may affect fundus circulation; (2) glaucoma, cataract, and history of ocular surgery; (3) vitreous opacity; (4) high myopia; (5) age-related macular degeneration, choroidal neovascularization, central serous retinal choroidopathy, and other eye diseases that affect the fundus circulation; (6) DM patients treated with laser and intraocular anti-vascular endothelial growth factor (VEGF), or macular edema; (7) patients with a history of ocular trauma.2 OCTA scanning, and foveal OCT line scan. Subjects with B-scan OCT image quality lower than 30 and OCTA quality lower than 35 were excluded.All subjects underwent visual acuity (VA), intraocular pressure (IOP), slit lamp examination, ophthalmoscopy, optometry, fundus photography, examination of pupil light and dark adaptation, parafoveal 3 × 3 mm2, 1 cd/m2, 10 cd/m2, and 100 cd/m2), pupil contraction amplitude (PCA), velocity of pupil contraction (PCV), velocity of pupil dilation (PDV).Pupil function tests were performed using a comprehensive pupillometer . Examinations were performed by the same ophthalmologist, including pupil diameter (PD) at different light intensities  was used to analyze the choriocapillaris blood flow signal in this region. The OCT B-scan was performed horizontally and vertically through the fovea. CT at the nasal, superior, temporal, and inferior choroid quadrants  and subfoveal choroidal thickness (SFCT) were recorded. Mean CT is their average. Choroidal thickness was measured as the perpendicular distance between the hyperreflective outer border of the retinal pigment epithelial/Bruch’s membrane layer and the sclero-choroidal interface, manually drawn blindly by the examiner. OCTA and OCT examinations were performed using the Heidelberg SPECTRALIS OCT equipment in 8:30 a.m.–13:00 p.m. for reducing choroidal changes with daily rhythm.The 3 × 3 mmWe used SPECTRALIS Software Version 6.9a to layer the acquired images. We would make manual adjustments if the automatic segmentation was incorrect, and then used the self-written code to calculate choriocapillaris blood flow signal density (CCBFSD) in the macular area , which is the percentage of the yellow signal to the total area. Choriocapillaris was segmented with an inner boundary Bruch membrane and an outer boundary 49 μm below the Bruch membrane. The positioning method of the choroidal capillary area for calculation in the 256th image of 512 pictures is described detailly in Fig. All the data in this study were analyzed using IBM SPSS Statistics ver.26.0 . The propensity score was estimated using a logistic regression model with 1:1 nearest neighbour matching without replacement, based on an acceptable caliper width of 0.25 times. Kolmogorov–Smirnov test was used for the normality test. Independent sample t-test was used to compare the data between these two groups that satisfied the normal distribution; if it did not, non-parametric test was used. Chi-square test was used for gender comparison between the two groups. Measurement data were expressed as mean ± standard deviation. P < 0.05 was considered statistically significant.


We performed this randomized controlled study protocol to investigate the efficacy and adverse effects of furosemide vs torasemide in patients with heart failure (HF).The present study was authorized by the local research ethics committee of Shanxi Cardiovascular Hospital (no. 48736645) and informed consent was obtained from all patients. Patients were enrolled in a consecutive prospective manner on a voluntary basis. Patients who were aged 18 years and older with HF who were eligible to enroll in this randomized trial. All patients had evidence of left ventricular systolic dysfunction, confirmed by echocardiographic or nuclear imaging. The exclusion criteria were left ventricular diastolic dysfunction only, or receipt of medical or pharmaceutical care in other health systems. The primary efficacy end point was the change in procollagen type I carboxyterminal peptide (PICP) serum levels between baseline and final visit. Secondary efficacy variables included parameters related to the clinical course of HF, such as body weight, presence of edema, signs and symptoms of HF, electrocardiogram and echocardiographic evaluation, amino-terminal pro brain-type natriuretic peptide (NT-proBNP) serum levels measured by ELISA method, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and renal function.One hundred patients who met the inclusion criteria were included in our study, Table 1Fluid overload is the primary cause of hospitalization among patients with HF. Preventing circulatory congestion requires careful control of dietary sodium and chronic administration of loop diuretics. Torasemide and furosemide are representatives of loop diuretics with an identical diuretic mechanism, but different pharmacokinetic properties and additional effects. There is a need for reliable conclusion regarding the comparison of furosemide and torasemide in patients with HF. Several limitation should be noted:1.the small number of participants did not enable assessment of the impact of torasemide and furosemide in different clinically relevant subgroups that is, elderly, patients with chronic kidney disease, dilated cardiomyopathy;2.short-term follow up might lead to underestimation of the complications;3.methodological weakness in study design may affect the results. Future high quality studies were still required. HF is characterized by several symptoms, including breathlessness, ankle swelling, and fatigue, and several signs such as jugular distension, pulmonary crackles, and peripheral edema.,6 It is usually the result of structural defects and/or elevated intracardiac pressures at rest or during stress. Diuretics are recommended to reduce fluid and sodium retention in the body and relieve the symptoms of HF.,8 Previous clinical trial has concluded that in patients with chronic HF, loop and thiazide diuretics appear to decrease the risk of death and deterioration compared to placebo, and they also appear to improve exercise in comparison with active control. Loop diuretics including torasemide and furosemide act on the thick ascending limb of the loop of Henle leading to Na-K-2Cl cotransporter inhibition leading to effective inhibition of sodium reabsorption and therefore reduction in water reabsorption. Furosemide is the most often used loop diuretic for HF. However, present data suggest potential pharmacologic and antifibrotic advantages with torsemide. The bioavailability varies between 76% to 96% and 10% to 90% for torasemide and furosemide, respectively. In addition, a longer duration of action and improved tolerability for torasemide over furosemide have been demonstrated in some clinical studies.,13 However, no reliable evidence has been reached due to the poor study design and small sample size. We performed this randomized controlled study protocol to investigate the efficacy and adverse effects of furosemide vs torasemide in patients with HF.Heart failure (HF) is a widely prevalent clinical syndrome that has a huge burden on health care systems worldwide.2The present study was authorized by the local research ethics committee of Shanxi Cardiovascular Hospital (no. 48736645) and informed consent was obtained from all patients. Patients were enrolled in a consecutive prospective manner on a voluntary basis. The study was registered in the public trial registry (researchregistry 6455).Patients who were aged 18 years and older with HF who were eligible to enroll in this randomized trial. All patients had evidence of left ventricular systolic dysfunction, confirmed by echocardiographic or nuclear imaging. The exclusion criteria were left ventricular diastolic dysfunction only, or receipt of medical or pharmaceutical care in other health systems.Following a screening period, eligible patients were randomly assigned in a ratio of 1:1 to receive torasemide (10 mg daily) or furosemide (40 mg daily), in addition to their existing HF therapy. Treatment allocation was performed in blocks, following the randomization list previously generated by a central statistician, and sequentially assigned to each center. The dose of torasemide or furosemide could be uptitrated at follow-up visits if the patient did not respond to the treatment. Maximum doses allowed were 40 mg/d for torasemide and 160 mg/d for furosemide. Patients received the assigned treatment until the end of the study at week 32 .The primary efficacy end point was the change in procollagen type I carboxyterminal peptide (PICP) serum levels between baseline and final visit. Serum PICP was determined by specific ELISA in a central laboratory. Secondary efficacy variables included parameters related to the clinical course of HF, such as body weight, presence of edema, signs and symptoms of HF, electrocardiogram and echocardiographic evaluation, amino-terminal pro brain-type natriuretic peptide (NT-proBNP) serum levels measured by ELISA method, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and renal function. Arterial BP was measured in the morning, after 10 minutes in the supine position, using a mercury column sphygmomanometer. Additionally, incidence of cardiovascular events during the follow-up period of the study was monitored. The quality of life of the patients included in the study was measured using the Minnesota Living with Heart Failure Questionnaire.t test for quantitative, normally distributed variables, and the Mann–Whitney U test for quantitative, non-normally distributed variables . For all analyses, a P value of less than .05 was considered statistically significant.Continuous and ordinal variables were expressed as a median (interquartile range). Categorical data were presented as a number of patients and percentages. Group comparisons were performed using the Fisher exact test for qualitative variables and 3One hundred fifty patients who met the inclusion criteria were included in our study, Table 4 Preventing circulatory congestion requires careful control of dietary sodium and chronic administration of oral loop diuretics.,16 When patients with HF deteriorate, it is often presumed that they have lapsed in their adherence to diet or to use of diuretics. Poor absorption of a diuretic, however, coupled with continuous sodium intake can also cause an inexorable accumulation of sodium and water. Cardiac remodeling is an indicative of a progressive course of HF. Hemodynamic load and many other factors can influence the status of cardiac remodeling. Therefore, drugs that decrease the load can contribute to preventing or slowing cardiac remodeling, and this is one of the primary aims of HF therapy.Fluid overload is the primary cause of hospitalization among patients with HF.,18 However, the clinical evidence remains unclear. In this study, we aimed to compare clinical outcomes and adverse effects of therapy with furosemide vstorasemide in patients with HF. Several limitation should be noted:Torasemide and furosemide are representatives of loop diuretics with an identical diuretic mechanism, but different pharmacokinetic properties and additional effects. Compared to furosemide, torasemide has greater bioavailability, a higher degree of protein binding, and a longer half-life. These properties make that torasemide works faster, longer, and less frequently causes rapid micturition than furosemide. According to previous studies, torasemide decreases rates of HF hospitalizations and hospital stay, improves exercise tolerance, quality of life, left ventricular function, cardiac sympathetic nerve activity, myocardial fibrosis, pulmonary congestion, peripheral edema, and blood pressure compared with furosemide.1.the small number of participants did not enable assessment of the impact of torasemide and furosemide in different clinically relevant subgroups that is, elderly, patients with chronic kidney disease, dilated cardiomyopathy;2.short-term follow up might lead to underestimation of the complications;3.methodological weakness in study design may affect the results. Future high quality studies were still required.Conceptualization: Yifan Li.Data curation: Zhipeng Guo.Formal analysis: Li Li.Funding acquisition: Shunye Zhang.Writing – original draft: Yifan Li.


Diabetes mellitus is the leading cause of end-stage renal disease worldwide. Microalbuminuria is the cornerstone for the diagnosis of diabetic nephropathy. However, it is an inadequate marker for early diagnosis. MicroRNAs are not only new and promising markers for early diagnosis but also, but they may also play a role in the prevention of disease progression.  This study included ninety patients with type 2 DM in addition to 30 control subjects. MicroRNA-451 expression in blood and plasma using real-time PCR was evaluated in addition to the classic diabetic nephropathy markers . p=0.0001. Patients with eGFR 60 ml/min/1.73 m2 showed a significantly higher plasma microRNA-451 (29.6 ± 1.6) and significantly lower urinary microRNA-451 (21 ± 0.9) in comparison to patients with eGFR >60 ml/min/1.73 m2 and p=0.0001. eGFR showed a positive correlation with urinary microRNA-451 and negative correlation with both plasma microRNA-451 and urinary albumin. Both plasma and urinary microRNA-451 are highly sensitive and specific markers for chronicity in diabetic nephropathy patients with sensitivity of 90.9% and 95.5% and specificity of 67.6% and 95.6%, respectively.  There was a significant difference between the studied groups versus control regarding serum creatinine, eGFR, urinary, and plasma microRNA-451 with  MicroRNA-451 is a promising early biomarker for chronic kidney disease in diabetic nephropathy with high sensitivity and specificity. There is an increased prevalence of diabetes mellitus (DM) all over the world. The major complications related to DM are attributed to the microvascular and macrovascular affections . DiabetiMolecular techniques with different accessible detection of biomarkers have been developed to use the new biomarkers as a target for early diagnosis of diabetic nephropathy .MicroRNAs (miRNAs) represent an appeal diagnostic biomarker for many diseases, including renal tumors , diabetiβ1 (TGF-β1) signal pathway and their impact on epithelial-mesenchymal transformation [β1 is the regulation of proliferation in the extracellular matrix, fibroblast, and myofibroblasts [β1 receptors increase with the initiation of fibrosis [MicroRNAs play an essential role in regulating cell proliferation, differentiation, apoptosis, neoplastic transformation, and apoptosis. The role of miRNAs in DN development is through the development of renal fibrosis . The stuormation , 14. Theroblasts . In renafibrosis . About tfibrosis . Urinaryfibrosis .The advantages of the use of miRNAs as a diagnostic biomarker are their stability in blood and urine samples and being noninvasive markers. Therefore, the quantitative measurement of miRNA in plasma and urine samples can be used as a diagnostic marker for monitoring the development of diabetic complications leading to the modification of the treatment with increased quality of life and the survival rates of the patients .To the best of our knowledge, this is the first study that evaluated urinary and blood levels of miRNA-451 as an early biomarker for the diagnosis of diabetic nephropathy and chronic kidney disease in diabetic patients.A case-control study including 90 diabetic patients recruited from outpatients' clinics from Mansoura University Hospital from January 2017 till November 2018 was conducted, in addition to 30 healthy subjects with normal kidney functions, normal blood glucose levels, and normal renal ultrasonography.Group 1, including 30 patients with normoalbuminuria and urinary albumin level <30 mcg/mg creatinineGroup 2, including 30 patients with microalbuminuria and urinary albumin level between 30 and 299 mcg/mg creatinineGroup 3, including 30 patients with macroalbuminuria and urinary albumin level >300 mcg/mg creatinineGroup 4, including 30 healthy individuals of the same age and sexPatients were classified according to the presence of albuminuria into four groups:2 and those with any abnormal renal ultrasonography finding were excluded. The Medical Ethical Committee of Mansoura Faculty approved the study. A voluntary informed consent was taken from all patients. Confidentiality and privacy were considered as regard personal, clinical, and laboratory data.The criteria for inclusion of the participant were age above 18 years with known DM type 2 and who are receiving their regular and routine antidiabetic medications, either orally or as an insulin therapy from the outpatients' clinics of Mansoura university hospitals with normal blood pressure, systolic blood pressure ≤140 mmHg and diastolic blood pressure ≤90 mmHg. Patients with congenital kidney diseases, malignancy, chronic glomerulonephritis, endocrinal diseases other than DM, and eGFR <30 ml/min/1.74 mEach subject had a complete medical history recording and comprehensive physical examination.2Group 2Group 2, including 22 patients with eGFR <60 ml/min/1.73 mPatients were reclassified according to the GFR level to the following:A urine sample was collected in a clean container from each subject and transported to the laboratory for complete urine analysis, including amount registration, glucose, ketone, creatinine, and albumin measurement. Quantitative measurement of urinary albumin and creatinine was carried out by using biosystem kits ; after that, an aliquot of urine was kept at −80°C for measurement of miRNA-451.The albumin in urine is measured by turbidimetry method as albumin binds to antihuman albumin coating agglutination latex particles. The quantity of albumin was measured at 505 wave length with RA analyzer 50.A ten-milliliter blood sample was obtained from each subject after eight hours of fasting and divided into three aliquots. One aliquot was used for complete blood counts by Sysmex system and HBA1c by Stanbio kit  by the use of quantitative colorimetric method using column chromatography for determination of glycohemoglobin in whole blood. From the other aliquot, serum was separated and subjected to laboratory measurement of serum creatinine, albumin, cholesterol, total triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), blood urea nitrogen (BUN), and fasting blood glucose level by autoanalyzer Dialab . Another blood sample was obtained after two hours for postprandial blood glucose levels. The serum was separated from the third aliquot and kept frozen at −80°C for the molecular study of miRNA-451 by a real-time polymerase chain reaction.2) = 175 × (Scr)−1.154 × (age)−0.203 × eGFR  using the A260/280 nm ratio.δCt values, where Ct = threshold cycle, δCt = (Ct target microRNA − Ct RNU6B).The expression of mature miR-451 was determined by qRT-PCR, as described in detail previously using the TaqMan Human MicroRNA Assay kit  and the real-time PCR system  . The endp < 0.05.Statistical analysis was carried out by the use of SPSS 22. Numerical Data are presented as mean ± SD for normally distributed values. ANOVA analyzed differences between the groups. Pearson's correlation coefficient was employed to test the correlations between different variables. Receiver operating characteristics (ROC) analysis was used to calculate the area under the curve (AUC) for microRNA-451 levels of serum and urine to find the best cutoff values for identifying renal impairment in diabetic patients. All results were considered significant if In the current study, patients were classified according to the level of albuminuria into three groups. There was no significant difference between the studied groups as regard age, sex, WBCs, platelets, and HDL .p=0.0001. Total cholesterol, LDL, and TGs showed a significant difference between the studied group with p-value, 0.0001, 0.0001, and 0.002, respectively. The eGFR had a significant difference among the studied groups (p=0.0001). Both urinary and plasma microRNA-451 showed a statistically significant difference in different patients' groups compared to the control group (p=0.0001). Diabetic patients with macroalbuminuria showed the highest level of plasma microRNA-451 and the lowest level of both urinary microRNA-451 and eGFR  were included in group [Sixty-eight patients (75.6%) showed eGFR >60 ml/min/1.73 mp-values 0.0001, 0.035, 0.036, and 0.0001, respectively, as shown in 2 (five patients) showed a significant increase in plasma microRNA-451 and decrease in urinary microRNA-451 in comparison to the control group with p-values 0.01 and 0.008, respectively.Comparison between the two groups showed no significant difference regarding age, sex, BUN, fasting blood sugar, HBA1c, total cholesterol, LDL, HDL, TGs, hemoglobin, WBCs, and platelets. On the other hand, there was a significant difference as regard creatinine, albuminuria, plasma microRNA-451, and urinary microRNA-451 with r = −0.491, p=0.0001 and r = −0.458, p=0.0001, respectively, and a positive correlation with urinary microRNA-451  as shown in The eGFR showed a significantly negative correlation with albuminuria and plasma microRNA-451, For the determination of sensitivity and specificity of microRNA-451 in blood and urine as biomarkers for early detection of diabetic nephropathy and chronic kidney disease in our patients, ROC analysis was used. The area under the curve was 0.427 for urinary microRNA-451 and 0.625 for plasma microRNA-451. The sensitivity of plasma microRNA-451 was 90.9% for cutoff 27.5 with a specificity of 67.7%, while the sensitivity of plasma microRNA-451 was 95.5% for cutoff 19.5 with specificity was 95.6%, as shown Diabetes mellitus is the leading cause of end-stage renal disease worldwide . Early dThe change in creatinine level, together with increased albumin in urine, appears as an attractive biomarker for the diagnosis of glomerular dysfunction associated with DM. However, these markers have many limitations, such as the tubular affection in DM, which may precede glomerular dysfunction leading to normal serum creatinine and normal level of urine albumin .Therefore, there is a need for new, easily accessible, and noninvasive biomarkers for early detection of diabetic nephropathy. Among these biomarkers is the microRNA expression, which are affected by the pathological conditions involving kidneys .In the present study, plasma microRNA-451 showed a significant increase in patients with DM and mild to moderate end-stage renal disease either with or without albuminuria. These findings were similar to the previous experimental study by Zhang et al. , 28.The increased expression of miR-451 has a protective role in DN that leads to the inhibition of glomerular and mesangial cell proliferation, in both in vivo and in vitro studies. This pathway is mediated through the downregulation of Ywhaz and p38 MAPK signal pathway. These are the target genes for miR-451, which downregulated the expression of Ywhaz  gene in the 3′ UTR. The overexpression of miR-451 caused the reduced activities of the two kinases (p38 MAPK and MKK3) and the suppression of Ywhaz . Therefo2 compared to the other group of patients with eGFR >60 ml/min/1.73 m2. Our result matched the previous study which reported a reduction of all miRNA levels as they decreased in parallel with the renal functions among patients with end-stage renal disease [On the other hand, urinary microRNA-451 in the present study showed a significant reduction in patients with eGFR <60 ml/min/1.73 m disease . The hig disease  and hype disease . These fThere was a significant positive correlation between the urinary microRNA-451 level and the eGFR value in association with a negative correlation between the plasma microRNA-451 level and eGFR, which supports the role of microRNA-451 as a predictor of disease progression and the development of renal fibrosis . PreviouThe question raised either from this study and/or the previous studies was about the use of microRNA-451 as a predictor for the disease progression and a therapeutic approach to prevent the development of DN. This approach can be mediated through miRNA mimics, miRNA expression vectors, miRNA-containing exosomes, and miRNA-inducing natural agents with the restoration of renal-protective miRNAs levels and subsequent protection from DN .2 compared to urinary microRNA-451, as shown in The present study has shown that both plasma and urinary microRNA-451 can be used as a sensitive and specific marker for the early diagnosis of DN. The sensitivity of plasma microRNA-451 was 90.9% with a specificity of 67.6%, while the sensitivity of urinary microRNA-451 was 95.5% with specificity 99.6%, which were in agreement with the results of Sayilar et al. . On the The present study's findings highlight the different expressions of microRNA-451 in blood and urine in different stages of diabetic nephropathy. There is a marked and gradual increase in blood level in different stages, denoting the potential role of this microRNA in the pathogenesis of this condition and its usefulness as an early biomarker for diagnosis. Moreover, the level of urinary microRNA-451 has a gradual reduction, reflecting the role played in the pathogenesis, and makes it a valuable biomarker for early diagnosis of diabetic nephropathy even in the absence of albuminuria. This study has its limitations, including a small sample size and the lack of renal biopsy and pathology, which we think will add a lot of value to our results.


Supplemental Digital Content is available in the text Hypertension becomes increasingly an alarming global health concern. There is a growing interest in treatment of traditional Chinese medicine (TCM), and tonifying kidney therapy  has been extensively used in the treatment of hypertension according to TCM theory. In this article, we outline the protocol of research projects and methods to examine comprehensively the effectiveness and safety of TKT in treating hypertensive patients.We will collect randomized controlled trails (RCTs) that report the application of TKT for patients with hypertension from electronic databases including PubMed, EMBASE, CENTRAL, CNKI, VIP, CBM, and Wanfang database. Time of literature retrieval is set from the beginning of database construction to the end of June, 2020. Two reviewers will independently perform literature screening, data extraction, and quality assessment of included literature, and any divergences will be worked out via discussion. The primary outcomes include total efficacy rate, systolic and diastolic blood pressure change will be assessed. The secondary outcomes include clinical symptoms and adverse events will also be assessed. RevMan5.3 software will be applied to analyzing data included studies.This study will synthesize and analyze all collated data in order to evaluate TKT for the treatment of hypertension involves different aspects in total efficacy rate, systolic and diastolic blood pressure change, clinical symptoms, and adverse events.This study will determine the efficacy of TKT in the treatment of hypertension and recommend its clinical value based on the evaluated the effectiveness and security results.INPLASY202050044. According to the latest Chinese hypertension screening survey, the prevalence of hypertension was 27.9% and the estimated number of adult hypertensive patients is 244.5 million, besides, another estimated 435.3 million with pre-hypertension.,6 In 2010, hypertension caused 9.4 million deaths, the number of adults diagnosed with hypertension was expected to rise to ∼1.56 billion by 2025.,8 Furthermore, with the environmental changes, ageing, unhealthy lifestyle such as excessive sodium consumption, insufficient intake of dietary potassium, smoking, drinking, unhealthy diet, overweight and obesity, and physical inactivity constantly spring up,,10 hypertension will continue to be an formidable challenge for the global healthcare industry. Hypertensive patients ought to consistently take conventional antihypertensive drugs, whereas those antihypertensive drugs are likely to develop certain side effects. Globally, the application of CAM to manage cardiovascular disease is on the rise.,12 And among patients who use CAM, the most common forms are antihypertensive herbal medicines.,13 Many previous studies have revealed that Chinese herbal medicines  associated with conventional therapy is further effective and safer for treating hypertension than conventional therapy only.–17Hypertension is currently defined as consistent elevated blood and the patients diagnosed with the disease have systolic blood pressure ≥140 mm Hg, and/or diastolic blood pressure ≥90 mm Hg.Inner Canon of Yellow Emperor . Kidney (shen) deficiency is one of the main mechanisms of hypertension,,19 especially for the elderly and long duration of hypertension. Kidney deficiency syndrome involves Yin deficiency syndrome and Yang deficiency syndrome. Owing to chronic diseases can involve the kidney, kidney deficiency syndrome is always associated with high blood pressure. Many systematic reviews has confirmed that Chinese medicine prescriptions representing the kidney-tonifying method, such as Liuwei Dihuang pill, Qiju Dihuang pill, and Shenqi pill,–23 have remarkable curative effects as an adjunctive therapy for reducing hypertension.According to TCM theory, hypertension coincides with the category of “vertigo” or “headache” on the basis of its clinical manifestations, which is originally documented in Although 1 systematic review on treating senile hypertensive patients with kidney-tonifying Chinese herbal formula was published 6 years ago, there have been many randomized controlled clinical studies published recently. In addition, further research is warranted to investigate the curative effect of hypertension with TKT regardless of age, sex or ethnic background. Therefore, we intend to perform this systematic review to update the clinical evidence of TKT in the treatment of hypertension based on its effectiveness and safety.22.1 If there are any adjustments of subtle details in this study, we intend to modify and update in the final publication.The study protocol was registered with INPLASY (registration number: INPLASY202050044). The procedure of this protocol will be conducted in compliance with guidelines of PRISMA-P.2.22.2.1We only collect RCTs that report the application of TKT for patients with hypertension, irrespective of whether using blind method or not.2.2.2Participants included must be diagnosed with hypertension, whether the diagnostic criteria were described in literature. There will be no restrictions on age, sex, or ethnic background.2.2.3Intervention measures included TKT alone or combined with conventional western medication in the experiment group, whereas the control group adopted conventional western medication only. Furthermore, we will not set limitations on dosages, formulation composition and course of treatment.2.2.4The primary outcome indicators involve total efficacy rate, systolic and diastolic blood pressure change. Clinical symptoms and adverse events will be ragarded as the secondary outcome indicators.2.32.3.1English online databases mainly include PubMed, EMBASE, CENTRAL; Chinese online databases mainly include CNKI, VIP, CBM, and Wanfang databases. Time of literature retrieval is set from the beginning of those database constructions to the end of June 2020. Literature must be published in English or Chinese. Finally, the search strategy of each database will be checked and modified according to our requirement. The retrieval strategy for PubMed will be presented as an example in Appendix A , and other databases will be referenced to the retrieval strategy of PubMed.2.3.2Grey literature and clinical trial registries will be retrieved to compensate for the deficiencies of electronic databases.2.42.4.1To import all literature into NoteExpress v3.2.0 software. Two reviewers (Zhuoran Tang and Yize Sun) will independently screen literature and conduct data extraction with pre-designed data extraction table and extraction results will be cross-checked by each other. Data extraction based on the following items: title, first author, publication year, diagnosis criteria, demographic information, study characteristics, sample size, interventions, outcomes, adverse events, etc. Divergences will be worked out via discussion with a third reviewer (Haibin Zhao). If relevant data is incomplete, we intend to contact the author of the original literature by telephone or email. We will analyze only available data of included literature when missing data cannot be obtained. PRISMA flow diagram will be applied to present the procedure of studies selection Fig. . Moreove2.4.2 to evaluate bias risk. The main details of assessment include: random sequence generation, allocation concealment, types of blinding, missing outcome data, and other bias. The overall risk-of-bias evaluation is divided into three criteria: “low,” “high,” and “unclear ” bias. Disagreements will be reached consensus via discussion.Two reviewers (Zhuoran Tang and Xiang Liu) will utilize RoB2 tool provided by the Cochrane Handbook version 6.02.4.3RevMan5.3 software will be used to integrate and analyze included studies. Dichotomous data will be reported as risk ratio (RR) with 95% confidence interval (CI), whereas continuous data will be reported as mean difference (MD) or standard mean difference (SMD) with 95% CI. Results of the meta-analysis will be visualised by forest plots.2.4.4χ2 test and I2test.Heterogeneity is influenced by many factors , and we plan to evaluate its degree through I2 statistic <50% and P value > .1, we will consider that there exists statistical heterogeneity can be ignored and adopt the fixed model to integrate the data. Conversely, the random effect model will be adopted when I2statistic ≥50% and P value < .1. Furthermore, we will conduct subgroup analysis or sensitivity analysis to investigate potential sources of heterogeneity.If 2.4.5Funnel plots will be applied to examine publication bias when at least 10 trials are identified.2.4.6If sufficient comparable studies are available, subgroup analysis will be conducted in terms of age, sex, intervention forms, treatment course, etc.2.4.7In order to ensure the robustness of analytical conclusions, we will utilize sensitivity analysis to examine the impact of low quality trials.2.4.8It requires no ethical approval for this study on the basis of collecting and collating documents. Findings will be disseminated through a peer-reviewed publication.2.4.9Conforming to the GRADE approach, we evaluate the strength of evidence for each outcome with rated as “high,” “moderate,” “low,’, and “very low.”3 found that Qin-Dan-Jiang-Ya-Tang (QDJYT) might be associated with inhibiting bFGFmRNA and its proteic productions to effectively lower blood pressure and improve vascular remodeling in spontaneous hypertensive rats. Xiong et al suggested that Bu-Shen-Jiang-Ya decoction (BSJYD) combined with conventional western medicine could effectively manage blood pressure and heart rate in order to reverse ventricular remodeling of spontaneous hypertensive rats via the mechanism that BSJYD may suppress EKR signaling pathway. In China, it is widely known among TCM clinicians that “kidney”(Shenzang) is vital to treat hypertensive patients, especially for patients diagnosed as “kidney deficiency” after based on syndrome differentiation of TCM need to adopt TKT. Hypertensive patients with “kidney deficiency” syndrome  such as nocturia, fatigue, vertigo, tinnitus, insomnia, hot flashes, waist soreness, and knee weakness could take Qiju Dihuang capsule or Jinkui Shenqi pill based on the difference of “ kidney yin deficiency” or “kidney yang deficiency”. Among antihypertensive drugs, diuretics and beta-blockers may lead to harmful impacts on sexual function. Besides, antihypertensive drugs can also lead to insomnia, fatigue, joint pain, dizziness, tinnitus, cold hands and feet. According to TCM theory, “kidney govern reproduction” and “kidney govern bone” illustrate that kidney is the basis of life, however hypertensive patients are usually accompanied by kidney damage. TKT in treating hypertensive patients based on diverse clinical manifestations, including tonifying kidney only, tonifying kidney and activating blood (Huoxue), tonifying kidney and soothing liver (Shugan) during clinical practice.In recent years, more and more people attach importance to TCM therapy, which has been proved to have a conspicuousness impact on blood pressure control in many previous clinical trials of TCM for hypertension. Animal experiments on TCM to treat hypertension are also being explored. Wang et alWith the emergence of many clinical trials on TKT for hypertension recently, we hope to provide higher evidence than the previous meta-analysis through analyzing the latest trials regarding this topic and expanding the sample size. However, there might be some deficiencies in this study, which may lead to heterogeneity due to small sample size, age, dosage, intervention forms, and treatment course.Conceptualization: Zhuoran Tang.Data curation: Chao Wang, Haibin Zhao.Formal analysis: Zhuoran Tang.Funding acquisition: Haibin Zhao, Di Ma.Investigation: Zhuoran Tang, Chao Wang.Methodology: Zhuoran Tang, Haibin Zhao.Project administration: Haibin Zhao.Resources: Zhuoran Tang, Yize Sun, Xiang Liu.Software: Xiang Liu, Xin Qi, Di Ma.Supervision: Haibin Zhao.Writing – original draft: Zhuoran Tang, Yize Sun.Writing – review & editing: Zhuoran Tang.


Background: Preventive medicine and primary health care are essential for patients with chronic kidney disease (CKD) because the symptoms of CKD may not appear until the renal function is severely compromised. Early identification of the risk factors of CKD is critical for preventing kidney damage and adverse outcomes. Early recognition of rapid progression to advanced CKD in certain high-risk populations is vital. Methods: This is a retrospective cohort study, the population screened and the site where the study has been performed. Multivariate statistical analysis was used to assess the prediction of CKD as many potential risk factors are involved. The clustering heatmap and random forest provides an interactive visualization for the classification of patients with different CKD stages. Results: uric acid, blood urea nitrogen, waist circumference, serum glutamic oxaloacetic transaminase, and hemoglobin A1c (HbA1c) were significantly associated with CKD. CKD was highly associated with obesity, hyperglycemia, and liver function. Hypertension and HbA1c were in the same cluster with a similar pattern, whereas high-density lipoprotein cholesterol had an opposite pattern, which was also verified using heatmap. Early staged CKD patients who are grouped into the same cluster as advanced staged CKD patients could be at high risk for rapid decline of kidney function and should be closely monitored. Conclusions: The clustering heatmap provided a new predictive model of health care management for patients at high risk of rapid CKD progression. This model could help physicians make an accurate diagnosis of this progressive and complex disease. Chronic kidney disease (CKD) poses a substantial challenge to global health policy because of its health and economic burden . PrimaryIdentification and staging of CKD rely on the measurement of glomerular filtration rate (GFR) and albuminuria. The calculation of actual GFR by measurement of external filtration markers is cumbersome and impractical. Moreover, clinical studies have found that external GFR markers are not reliable predictors of risk of advanced CKD because of the inconsistency in their levels at different stages of CKD ,5,6,7,8.Recently, machine learning techniques have showed success in prediction and diagnosis of numerous critical diseases. In fact, one study found that CKD can be diagnosed with an accuracy of 0.98, using supervised machine learning technique . HoFor heatmaps, we used Euclidean distance as the distance measure and Ward’s method for unsupervised clustering. The clustering may be upgraded using other measures or algorithms. In addition, the heatmap may be more robust and dynamic with adequate sample size of patients at different stages or by using other specific and remarkable variables. Accordingly, new patients could be assessed using this clustering heatmap system based on their health conditions; if the new patients, especially those in early stages of CKD, had patterns similar to those in advanced CKD groups, precautionary treatment could be administered. In the clustering of medical factors, GPT, GOT and UA were in the same cluster with a similar pattern, whereas HDL, being a sign of good health, had the opposite pattern.The CAP and E score by FibroScan are accurate non-invasive methods for assessing liver steatosis and fibrosis in patients with NAFLD . CKD andThe result on hyperuricemia can be explained by association with the acceleration of GFR decline and CKD progression ,36,37. PThere are several limitations in this study. First, this study investigated only health-conscious participants that underwent a self-paid health examination, and the number of patients with advanced CKD may be underrepresented. Having approximately the same percentage of patients across different CKD stages will establish a much better model, and hence repeating this study by selectively including more advanced CKD patients is one of the future goals of this study. Second, this is a retrospective study, and confounding cannot be excluded. Hence, the subsequent step is to conduct a large prospective study to test the accuracy and usefulness of the predictive model. Third, this study concerned mainly Han Chinese population residing in Taiwan, and the study results needs to be repeated and validated in other populations. Fourth, this study failed to include some new CKD diagnostics that may further improve the prediction of CKD staging. For example, it was recently found that salivary ferric ion reducing antioxidant parameter can distinguish patients with mildly to moderately decreased kidney function from those with severe renal impairment with an accuracy of 100% (AUROC) .Using machine learning technologies, we have generated a new predictive model of health care management for patients within the high-risk CKD group. However, considering the retrospective nature of this study, a sufficiently powered prospective cohort study is needed to conclusively address the usefulness of this predictive model to help physicians make an accurate diagnosis of the staging of CKD, which changes over time.


CYP3A5 gene expression status is associated with tacrolimus dose requirement in renal transplant recipients.Tacrolimus is an approved first-line immunosuppressive agent for kidney transplantations. Part of interindividual and interethnic differences in the response of patients to tacrolimus is attributed to polymorphisms at CYP3A5 metabolic enzyme. CYP3A5*3 in 76 renal transplanted patients of Egyptian descent. Secondly, we evaluated the influence of the CYP3A5 gene variant on tacrolimus doses required for these patients as well on dose-adjusted tacrolimus trough-concentrations.In this study, we determined the allelic frequency of CYP3A5*3 variant was the most frequent allele detected at 85.53%. Additionally, our results showed that, mean tacrolimus daily requirements for heterozygous patients (CYP3A5*1/*3) were significantly higher compared to homozygous patients (CYP3A5*3/*3) during the first year after kidney transplantation.The CYP3A5 genotype.This is the first study in Egypt contributing to the individualization of tacrolimus dosing in Egyptian patients, informed by the  Chronic Kidney Disease (CKD) is a long-term, progressive, and irreversible condition characterized by functional and structural kidney damages lasting for at least 3 months . Kidney CYP3A5 gene explain 40–50% of the variability in tacrolimus metabolism and clearance  contributes significantly to the increase of CYP3A activity associated with recovery of renal function after transplantation  higher tacrolimus doses compared to CYP3A5 non-expressors those who are homozygous for the variant alleles   . HoweverCYP3A5*3 among Egyptian patients that have undergone transplantation and to evaluate the influence of this polymorphism on tacrolimus daily dose and on metabolism rate in adult patients during the first year after kidney transplantation.In this study, we aimed to determine the allelic frequency of For the present study, 76 unrelated kidney transplanted adult patients were enrolled in Urology and Nephrology Center at Mansoura University Hospital in Egypt. All patients underwent renal transplantation from living donors and were under tacrolimus immunosuppressive treatment for at least one year. Recipients received a standard bodyweight-based tacrolimus initial dose (day -1 before transplantation) of 0.1 mg/kg twice per day. Blood samples were collected into EDTA tubes and stored at -80°C till analyzed. Therapeutic drug monitoring was applied to all samples for dose adjustment. The target whole-blood concentration in early period after transplantation is 10–20 ng/ml and in the maintenance period (after 3 months) 5–10 ng/ml. Tacrolimus daily dose, tacrolimus blood levels, demographic, and clinical data were obtained from medical files of the patients at the beginning of the post-transplant period and at 12 months after transplantation. Patients with diarrhea or vomiting, liver disease, advanced renal dysfunction, or other disorders that could have altered the absorption of tacrolimus or patients that will be co-prescribed drugs that affect the pharmacokinetics of tacrolimus and its pharmacological effect  were excluded from the study.The study was conducted in compliance with the declaration of Helsinki and was approved by the Ethics Committee of the Mansoura University Hospital and written informed consent was obtained from all subjects.CYP3A5 single nucleotide polymorphism (SNP) – CYP3A5*3 (rs776746) was genotyped by PCR-restriction fragment length polymorphism (RFLP), using the SspI restriction endonuclease as previously described . Continuous variables are shown as mean and standard deviation and qualitative data are expressed as frequency and percentage.Continuous data were tested for normality using Kolmogorov-Smirnov and Shapiro-Wilk tests (p = 0.05) and visualized with Q-Q plots. Depending on the distribution, comparisons for variables between two groups were performed with two-tailed test or Wilcoxon test for related samples and with unpaired t-test or Mann-Whitney test for independent samples. The categorical data were analyzed using two-tailed Fisher’s exact test.In the present study patients were divided into two groups according to their genotype [CYP3A5 expressors (*1/*1 or *1/*3) and CYP3A5 non-expressors (*3/*3)]. Both groups were examined for statistically significant difference in dose requirements, tacrolimus blood levels, and C/D ratio (dose corrected trough concentration of Tac). These data were compared at different time points among related samples (patients with the same genotype) and at the same time points among independent samples (patients with different genotype).Statistical analysis was performed using SPSS Statistics 25.0 (IBM SPSS software) and GraphPad Prism 8.0. The significance level was set at p<0.05.A total of 76 kidney transplant recipients were included in this study and they all were adults and self-reported Egyptians. According to the date of the transplantation, there were missing data for 17 of the patients regarding tacrolimus dose. The characteristics of 59 recipients according to their CYP3A5 genotype are shown in CYP3A5*3/*3 genotype was observed in 55 (72.37%) cases, CYP3A5*1/*3 in 20 (26.32%) cases, and CYP3A5*1/*1 in 1 (1.32%) case. Total allelic frequency was 85.53% for CYP3A5*3 and 14.47% for CYP3A5*1 (2 = 0.58323 < 3.841).Of the 76 kidney transplant recipients, the CYP3A5*1 Figure 1CYP3A5*1 carriers and CYP3A5*3/*3 groups were 9.861 ± 2.182 (range: 6.0–14.0) and 6.756 ± 2.478 mg/day (range: 2.0–11.0), while doses one year after transplantation were 7.806 ± 3.158 (range: 2.5–13.0) and 4.207 ± 2.083 mg/day (range: 1.5–10.5), respectively. This shows a significant reduction of the dosage for both genotypic groups, 20.84% for expressors (CYP3A5*1/*3 or *1/*1) (P = 0.0017) and 37.73% for non-expressors (CYP3A5*3/*3) (P < 0.0001). Differences between initial and first-year doses are shown in For the 59 patients, tacrolimus initial doses (mean ± standard deviation) for CYP3A5*3/*3 and CYP3A5*1 carriers, mean dose for CYP3A5*1 carriers was significantly higher (45.96%) than for CYP3A5*3/*3 (P < 0.0001). One-year mean tacrolimus dose for CYP3A5*1 carriers was 85.55% higher than for CYP3A5*3/*3 (P < 0.0001) (Comparing the starting daily dose between  0.0001) Figure 3CYP3A5 non-expressors was higher in both time points compared with CYP3A5 expressors. However, there was no significant differences between the two groups neither at the early post-transplant period (p = 0.3035) nor at the maintenance period (p = 0.6373).Average tacrolimus blood concentrations in CYP3A5*1 recipients exhibited significantly lower C/D ratios (47.89% lower) than those homozygous for the variant allele (*3/*3) at one year of treatment . However, there was no significant difference between the two groups at the early post-transplant period (p = 0.0586). Significant increase was observed at C/D ratios comparing the two time points among CYP3A5*1 carriers (p = 0.0003) and among CYP3A5*3/*3 recipients (p = 0.0123)  compared to recipients homozygous for *3 allele (CYP3A5*3/*3)  the three genotypic groups, CYP3A5*1/*1, CYP3A5*1/*3, and CYP3A5*3/*3 were observed in 1.32, 26.32, and 72.37% respectively. The distribution of CYP3A5 gene showed that the CYP3A5*3 allele was 85.53%. In previous studies in the Egyptian population, different frequencies were reported for the CYP3A5*3 allele, ranging from as low as 11% to as high as 78%  . Our stuh as 78% . Studieseven 90% , whereaseven 90% .CYP3A5 variants on tacrolimus dosage and on tacrolimus blood concentrations normalized by the dose and proved that there is significant difference between renal transplant patients with the CYP3A5*1 allele compared to homozygotes for the CYP3A5*3 allele, especially during the early post-transplant phase . Concentration/dose ratio was significantly lower in CYP3A5*1 expressors. All these indicate that CYP3A5 expressors require a larger tacrolimus dose in order to maintain the same blood concentration.Several studies have been conducted in North Africans in order to evaluate the effect of nt phase . To our patients . Our resCYP3A5*3 variant seems to be higher as compared with previous studies in the Egyptian population and in agreement to that reported prevalence of this allele for other North African or Caucasian populations. Furthermore, comparison of tacrolimus dose requirement for renal transplant patients showed statistically significant difference among genotypes. It is important to draw up different treatment plan for different recipients. As CYP3A5 shows great heterogeneity in African population, there is a need for pharmacogenomic testing prior to tacrolimus administration after kidney transplantation to achieve genotype-guided dose and contribute to a better-individualized immunosuppressive therapy.Although there are minor limitations in our study, single center and small cohort, our results showed that frequency of the The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by Mansoura University Hospital. The patients/participants provided their written informed consent to participate in this study.EM, MMa, and GP conceded the study. MMa, AA, MMo, AR, EE, HHS, and HS provided samples and clinical data. EM performed the analysis. EM and GP compiled the draft manuscript. GP and HS provided funding. All authors contributed to the article and approved the submitted version.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.


Living kidney donors represent a unique population of patients. Potential donors are selected based on the belief that their preoperative fitness is likely to mitigate the risks of long- and short-term harm following uninephrectomy. Studies performed on postdonation outcomes have largely focused on mortality and the risk of end-stage renal failure, but have also investigated secondary outcomes such as cardiovascular morbidity and hypertension. It has been postulated that hypertension is a possible outcome of living kidney donation. A variety of studies have been conducted to investigate the prevalence, epidemiology, mechanisms, treatment strategies, and long-term ramifications of hypertension postdonation. These studies are heterogeneous in their population, design, methodology, and outcome measures and have presented contradicting outcomes. Additionally, the absence of a well-matched control group has made it challenging to interpret and generalise the reported findings. As such, it is not possible to definitively conclude that hypertension occurs at a higher rate among donors than the general population. This article will review the evidence of postdonation hypertension prevalence, mechanisms, treatment, and complications. Kidney transplantation, for the majority of patients with end-stage renal failure, remains the treatment of choice of renal replacement therapy (RRT)  2]. Des. Des2]. A vast wealth of evidence exists on the long-term health complications associated with end-stage renal failure and dialysis, particularly regarding the effects on patient-related qualitative outcomes and cardiovascular mortality which adjusts following kidney transplantation –10. The Living kidney transplant donors represent a unique subset of the general population both pre- and postdonation. The process of performing a surgical procedure with the intent of harvesting a fully functioning organ from a healthy individual has historically been debated as a potentially ethical grey area, which is counterbalanced by the belief that the harm induced to the donor is negligible and comparatively outweighed by the potential benefit provided to the recipient .In an ideal setting, a robust selection process for kidney donors, including preoperative counselling and physical assessment, is aimed at identifying potential donors at the peak of health and exist at the upper end of the population normal distribution curve for their age- and sex-matched peers. Following donation, they represent a cohort of healthy individuals with solitary kidneys. These characteristics make this cohort of patients inherently challenging to effectively match to control groups from the general population, even when adjusted for age and gender. Conclusions drawn from this data on the quantitative and qualitative outcomes are therefore challenging to interpret or generalise .Additionally, the majority of donors are discharged from follow-up relatively quickly given the low incidence of perioperative morbidity and mortality , 14. In Another major pitfall in the existing literature on donors is a lack of transparency and uniform standardisation in the selection and fitness testing of potential donors. Uncertainty regarding the parameters of fitness among donors in previous literature dramatically increases the challenges faced in generalising the findings previously reported, particularly when counselling these patients in clinic. The diagnosis of hypertension is likely to be one of the indications for longer-term follow-up of donors, a phenomenon which may introduce bias by apparently inflating the proportion of hypertensive donors who are included in studies.It is noteworthy that biochemical evidence suggests that following nephrectomy, the circadian rhythm of the renin-angiotensin-aldosterone system (RAAS) undergoes significant remodelling . InconsiIn addition to the above, despite the apparent health of potential donors, the demographics of these patients is a key aspect which must be considered. The vast majority of studies on the topic of hypertension as a long-term outcome of living kidney donation do not discriminate between related and unrelated donors. Epidemiological data suggests that renal disease is predominantly seen in patients with diabetes and cardiovascular disease. These primary illnesses are also prevalent among lower socioeconomic groups. Living-related or partnered donors may share similar genetic and socioeconomic traits as their recipients and, as such, may be exposed to similar cardiovascular risks –20.What is also unclear from the literature is the blood pressure outcome of the recipients specifically from donors who develop de novo hypertension. Given that the blood pressure profile in transplant patients is heavily dependent on the phenotype of the transplanted kidney, hypertension among recipients may allude to an underlying process specific to the donor, rather than simply uninephrectomy.Understandably, controlled studies have yet to accomplish matching which accommodates beyond age and sex and also considers the role of shared socioeconomic and genetic factors in prognosis among this unique cohort. Alongside this, the qualitative aspect of the psychological stressors associated with living kidney donation has only recently become apparent and represents yet another aspect of hypertension prediction which has not been explored or appropriately matched in previous trials and studies –24.The literature regarding the incidence and prevalence of hypertension in the years following living kidney donation is characterised predominantly by inconsistency in study design and outcomes . While tAmong these studies, there is wide variability in the time point postdonation at which blood pressure is assessed and reported. Exclusion criteria vary between studies, occasionally, including individuals with predonation hypertension or subgroups with statistically significant variability in their predonation blood pressure , 25. TheThe definition and robustness of a diagnosis of hypertension vary, with some studies relying heavily on medication lists and only one study investigating the use of ambulatory blood pressure measurements (ABPM) in the diagnosis of hypertension. Holscher et al. assessed over 41000 patients with a relatively short follow-up period of two years divided into blocks from which statistical estimation was used to arrive at a diagnosis of hypertension given significant data gaps . They idp = 0.04), for the outcome of self-reported hypertension among donors compared to healthy controls [This study reported a hazard ratio of 1.19 , and blood pressure-matched controls, by Mjøen et al., informs the counselling of long-term renal failure outcomes in potential kidney donors . This stIt is unsurprising, given the above, that studies assessing the prevalence of hypertension following elective uninephrectomy in healthy donors have highly variable reported outcomes compared to either controls or age- and sex-matched individuals from general population epidemiological studies. Studies which have proposed that there is a significant risk of developing increased blood pressure following donation are faulted by poor design, the absence of a meaningful control group, and small sample size , 31, 32.p < 0.001). Despite the prospective design of this study, significant data gaps requiring sensitivity analyses were employed. 26% of patients were lost to follow-up, and this study design did not exclude patients from analysis who had significantly higher predonation systolic blood pressure.Among these studies, Thiel et al. reported on a prospective Swiss cohort of 1214 donors with a follow-up of 10 years and identified that compared to the Framingham data of age- and sex-matched controls, the risk of hypertension at 1 year was triplicated by kidney donation compared to the general population . This stp < 0.0001).Comparatively, similar limitations can be identified among studies suggesting that the prevalence of hypertension is equivalent to or less than that expected of the general population , 33–40. Over a period of forty-five years, a progressive rise in blood pressure was identified among all patients. In those who achieved hypertension, a rate of increase of 2.9 mmHg per decade in systolic pressure was recorded, compared to a rate of increase of 2 mmHg per decade among nonhypertensive patients. A progressive rise in blood pressure has previously been demonstrated among adults and has been attributed to age-related phenomena, genetic and environmental factors, and vascular remodelling.p < 0.001), smokers (p < 0.001), older donors (p < 0.001), lower estimated glomerular filtration rate (eGFR) (p < 0.001), and first-degree relatives of the recipient (p < 0.001). Additionally, this study identified that the risk of hypertension was exacerbated by the cumulative presence of these synergistic risk factors.The underlying characteristics of these patients were distinct, with higher end blood pressure identified among persons with higher BMI . Additionally, the adjusted Cox regression analysis end-stage renal disease after multiple imputation was 11.38 (p ≤ 0.001) for donors compared to controls. Importantly, this subgroup analysis compared 31 patients to 34522 controls. Despite its strong statistical significance, the validity of this finding is challenging to translate into practice.Mjøen et al. reported that the cumulative all-cause mortality and chronic kidney disease are inflated among donors . The rolEpidemiological data suggests cardiovascular disease to be a global pandemic directly associated with mortality . In contIt is well recognised from robust cardiovascular studies that following uninephrectomy, significant physical adaptations occur, inclusive of cardiac remodelling characterised by a statistically significant increase in ventricular mass among donors compared to controls . The rolThe evidence suggests that cardiovascular mortality in donors is no different from the general population in the first decade postdonation, suggesting that cardiac remodelling and cardiovascular adaptations may not carry the weight of clinical significance . AdditioIt is noteworthy however that these finding may be cushioned by the cherry-picking bias imposed on the literature by having pristinely healthy donors compared to the age- and sex-matched population, making generalisation of these findings largely misleading.Living kidney donation is associated with a robust series of assessments and counselling of potential donors. Predonation assessment and counselling need to develop on par with the developing awareness of the downstream sequelae of kidney donation including the physical and psychological elements. While there are studies assessing the risk of depression following kidney transplantation, there is undoubtedly a coexistent psychosocial benefit of kidney transplantation. These psychosocial elements and their outcome on the physical well-being of donors are yet to be unpicked. A propensity towards hypertension has been identified within certain subgroups within the donor population which may or may not have subsequent knock-on effects on cardiovascular mortality. As such, appropriate kidney donation must be accompanied by robust screening of potential donors for hypertension and cardiovascular mortality. These should not necessarily be barriers to donation, but should be used to inform potential donors of risks in a holistic way.The evidence suggests that uninephrectomy is not clearly a risk factor for the development of de novo hypertension for all donors. The outcome of hypertension appears to be the end result of the synergistic effects of kidney donation with modifiable and nonmodifiable risk factors. As such, predonation counselling should include a risk calculator in order to provide potential donors with evidence-based decisions.The development of hypertension and cardiovascular mortality, similar to that of the general population, is likely driven by a combination of modifiable and nonmodifiable factors. Donors should be counselled about salt restriction and monitoring of blood pressure at home. Given the uncertainty presented in the data on the long-term sequelae of hypertension among donors, it is unclear what target blood pressure should be recommended.Modifiable risk factors, such as smoking and elevated BMI, that impede the health and well-being of patients and appear to contribute to hypertension should be addressed, although these should not be considered per se a contraindication to donate . Older dIt is worth noting that by standard description, kidney donors do not fall into a category that is truly comparable to age- and sex-matched controls in the general population. Given that hypertension may well represent the end product of an adaptive process in an individual who is apparently at no greater risk of cardiovascular mortality, some studies have postulated that a reasonable degree of permissive hypertension is likely appropriate, rather than intensive blood pressure control .Further study is required to delineate the prevalence of hypertension among kidney donors, particularly given the changes in approach to identification, selection, and management of donors. One such study which may shed light on the role of uninephrectomy on the outcome of hypertension may include an analysis of recipients from donors who develop postdonation de novo hypertension. This may indicate a donor-specific phenomenon responsible for the genesis of hypertension.There remains significant uncertainty regarding the prevalence, pathophysiology, complications, and management of hypertension following living kidney donation. It is unclear whether or not there is a significant risk of hypertension in donors compared to the general population. It appears clear from the evidence that the propensity for hypertension is a heterogeneous phenomenon which affects donors to different degrees and may be related to ethnicity, age, time from transplant, and BMI.This data suggests that hypertension occurs following kidney donation most readily among certain subgroups of patients, particularly those with higher BMIs, smokers, and those with higher predonation creatinine and blood pressures. In the future, this could inform decision-making when assessing potential living donors, but requires further work.The mechanisms driving hypertension are likely to be inexorably linked with renal salt handling and a deficiency in nephron number contextualised to individual characteristics and are similarly likely to be part of an adaptive process following uninephrectomy. The long-term sequelae of hypertension among donors remain unclear.Overall, there may be a small to modest increase in blood pressure postdonation, which is more apparent in certain subgroups of donors, but the validity of these findings has consistently been hampered by the absence of a meaningful control group, significant bias, small sample size, retrospective design, and poor follow-up. Additionally, this propensity to developing de novo hypertension is likely reliant on a complex interplay of nephrectomy contextualised to individual risk factors. Among these patients, the risk of developing hypertension appears to result in significant cardiovascular remodelling. These outcomes do not appear at present to have a significant bearing on clinical outcomes, but further long-term data is required to resolve this matter conclusively.