This study aimed to assess the effect of folic acid combined with pravastatin on atherosclerosis-related indexes in elderly patients with hypertension complicated with lacunar cerebral infarction.A total of 134 elderly hypertensive patients with lacunar cerebral infarction were randomly divided into 3 groups using the random number table method. Group A, the folic acid group, had 45 cases and received low-dose folic acid (0.8 mg/d) treatment on the basis of antihypertensive treatment. Group B, the pravastatin group, had 45 cases and received pravastatin (20 mg/d) treatment on the basis of antihypertensive treatment. Group C, the folic acid combined with the pravastatin group, had 44 cases. Members of this group received pravastatin (20 mg/d) and low-dose folic acid (0.8 mg/d) based on antihypertensive treatment. Levels of folic acid, homocysteine (Hcy), tumor necrosis factor alpha (TNF-a), matrix metallopeptidase 9 (MMP-9), cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were measured by ELISA before treatment in all 3 groups. Carotid intima-media thickness (IMT) was measured using ultrasound, and systolic and diastolic blood pressure were measured with a mercury column. After 8 weeks of treatment, the levels of folic acid, Hcy, TNF-a, MMP-9, TC, LDL-C, and systolic and diastolic blood pressure were compared among the 3 groups. IMT levels were measured at 12 weeks of treatment.P < .05). Patients in group C presented significantly decreased TNF-a, MMP-9, TC, and LDL-C levels and systolic and diastolic blood pressure after 8 weeks of treatment, compared with those in groups A and B (both P < .05). These patients also showed significantly decreased IMT levels compared with those in the other groups (P < .05).After 8 weeks of treatment, compared with group B, patients in groups A and C had folic acid levels significantly higher than baseline levels, with significantly lower Hcy levels (both Low-dose folic acid combined with pravastatin in elderly patients with lacunar cerebral infarction can reduce the level of homocysteine, improve the degree of carotid atherosclerosis, protect vascular endothelium, and reduce blood lipids and blood pressure, presenting better benefits than pravastatin alone. It is an ischemic stroke. It affects the sensory and motor systems and affects the brain's cognitive function, causing cognitive dysfunction in patients. The clinical manifestations of lacunar infarction are mild; as such, they are not valued.At present, small vessel atherosclerosis is the pathophysiological basis of lacunar cerebral infarction. Homocysteine (Hcy) is an important intermediate in the metabolism of methionine and cysteine in the human body. Its elevation can affect lipid metabolism and the autooxidation process, damage vascular endothelial cells, and promote the progression of atherosclerosis. Hcy has been determined as an independent risk factor for cardiovascular and cerebrovascular diseases; reduction of its levels contributes to the prevention and treatment of cerebrovascular diseases. and it protects against hypertension, atherosclerosis, and vascular endothelium. Many studies have confirmed that folic acid has a stabilizing effect on arterial plaque, and the supplementation of low-dose folic acid is also beneficial to lower total cholesterol and low-density lipoprotein (LDL).In elderly patients, folic acid absorption disorders are often caused by decreased food intake, reduced digestive function, and decreased absorption and utilization of nutrients. These lead to hyperhomocysteinemia, which increases the risk of stroke. Studies have confirmed that exogenous folic acid can reduce plasma Hcy levels and reduce the risk of hyperhomocysteinemia. It has a positive effect on the prevention and treatment of vascular diseases, Another study showed that folic acid can reduce the risk of in-stent restenosis after coronary intervention. These studies have shown that folic acid has a protective effect on the stability of arterial plaque, and its mechanism may be closely related to its anti-inflammatory effect. Folic acid can reduce the body's pro-inflammatory cytokine monocyte chemoattractant protein-1 level.,9 Monocyte chemoattractant protein-1 plays an important role in the formation and development of unstable plaques and can reduce the stability of plaques by promoting the aggregation of macrophages, the release of inflammatory factors, and the formation of foam cells. Therefore, folic acid may have a more positive effect on improving arteriosclerosis, promoting plaque stability, and lowering cholesterol. Tumor necrosis factor alpha (TNF-a) is currently recognized as a vascular endothelial inflammatory factor, a crucial factor in promoting vascular endothelial injury that leads to atherosclerosis. Matrix metallopeptidase 9 (MMP-9) plays a vital role in atherosclerosis and plaque formation. Therefore, increased folic acid intake in elderly hypertension patients with lacunar infarction not only reduces homocysteine but may also synergistically reduce LDL and promote plaque stabilization.A meta-analysis of 369,746 people observed in 11 prospective cohort studies showed that increasing folic acid intake can reduce the risk of coronary heart disease. Statins are the basic drug treatment for elderly patients with hypertension and lacunar infarction. Although statins are drugs that have been proven to stabilize plaque and reduce low-density lipoproteins, in clinical practice, the effect of single use of statins is often not favorable—patients’ LDL levels do not meet the standards, and the risk of cerebral infarction occurs again during medication. This phenomenon is more common in elderly patients.In addition to lowering lipids, statins can inhibit the vascular endothelial inflammatory reaction and delay the progression of arteriosclerosis, which has good application value.The elderly often suffers from a variety of chronic diseases and need to take a variety of medications. They also experience liver and kidney dysfunction and pharmacokinetic changes. To control the incidence of cardiovascular and cerebrovascular diseases among this patient population, there is a clinical need for increased statins to control low-density lipoproteins, which may lead to risks of liver damage, myolysis, renal insufficiency, etc. As a kind of vitamin, folic acid increases the intake without risk of liver and kidney dysfunction. There have been no studies in the literature addressing the potential effect of low-dose folic acid in elderly patients with hypertension and lacunar infarction.Therefore, this study investigated whether low-dose folic acid has a positive effect on vascular endothelial inflammatory factors, cholesterol, LDL, plaque stabilization, and blood pressure reduction in elderly patients with hypertension and lacunar infarction. We also assessed the effect of folic acid combined with pravastatin as a potential option for patients with lacunar infarction. The folic acid used in this study is the same as that used by pregnant women, which has no toxic side effects.–15 Fortifying foods with folic acid is an effective way to increase a woman's intake of folic acid without changing her dietary habits.Folic acid is a B vitamin. If a woman has enough folic acid in her body before and during early pregnancy, it can help prevent neural tube defects. Women need folic acid every day. In 1992, the U.S. Public Health Service recommended that all women of childbearing age capable of becoming pregnant consume folic acid daily to prevent neural tube defects. By 1998 in the United States, folic acid was added to all cereal grain products labeled as enriched, like breakfast cereals and corn grits. This process is called folic acid fortification. In the United States, fortification led to a 35% decrease in the rate of neural tube defects.To the best of our knowledge, this report evaluated the combined use of folic acid and pravastatin to determine its effectiveness in reducing the incidence of stroke without increasing the risk of liver and kidney dysfunction.22.1 and the diagnosis of lacunar infarction. Standard and diagnostic criteria for dyslipidemia were used. Patients were aged 60 to 80 years, had no previous history of cerebral infarction, and sex was not limited. The Hcy level was ≥10.0 μmol/L. All 3 groups had not received statins, folic acid, or B vitamins before 8 weeks to ensure the reliability of the test data. Patients had normal cognitive function, good compliance, informed knowledge about the study, and signed informed consent forms. We excluded acute stroke, disturbance of consciousness, intracranial, or systemic infection; patients with malignant tumors, autoimmune diseases; coronary heart disease, secondary hypertension, type 2 diabetes; patients with congestive heart failure; brain patients with trauma, post-epileptic state, poisoning, etc; severe liver or kidney, coagulopathy; history of trauma or surgery in the past 3 months; peripheral arterial occlusive disease; alcohol or drug dependence; those who are allergic to the research drugs; cognitive dysfunction or mental illness; or patients who were to be included in other clinical research. The study was approved by the ethics committee of Shanxi Bethune Hospital.We selected 134 patients with senile hypertension complicated with lacunar infarction who were admitted to our hospital from December 2014 to December 2016 as subjects. All patients met the diagnostic criteria for senile hypertensionDiagnosis of hypertension in the elderly: age ≥65 years old, blood pressure continuous or >3 times non-same day sitting systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. The diagnostic criteria for lacunar infarction were as follows: the onset of hypertension is mostly caused by arteriosclerosis, which is acute or subacute; in most cases no disturbance of consciousness occurs; computed tomography (CT) or magnetic resonance imaging (MRI) should be performed to confirm the diagnosis; and the clinical manifestations were not serious. The most common ones were pure sensory stroke, pure motor hemiplegia, ataxia hemiplegia, dysarthria hand clumsy syndrome, or sensorimotor stroke. Low-density lipoprotein cholesterol (LDL-C) <1.8 mmol/L and TC <3.1 mmol/L should be set as the target values of blood lipid control in elderly patients with hypertensive lacunar cerebral infarction, above this level is dyslipidemia.Before the grouping, each study subject was given 2.5 to 5 mg of amlodipine orally to maintain blood pressure below 140/90 mmHg. Due to individual differences, the amounts of amlodipine administered to each subject were different to maintain no difference in blood pressure before the study.Then, patients were divided into 3 groups A, B, and C using the random number table method, and all 3 patients continued to receive folic acid, pravastatin, or folic acid and pravastatin treatment on an oral basis of a certain amount of amlodipine until the end of observation.P > .05). Long-term smoking refers to smoking for >5 years. Long-term drinking refers to drinking liquor 2 to 3 times a week for at least 5 years.There were 45 cases in group A. The group included 23 men and 22 women, aged 60 to 77 (68.62 ± 5.14) years old. Among the participants, 10 had a personal history of long-term smoking, and 3 had a history of long-term drinking. There were 45 cases in group B. The group included 22 men and 23 women, aged 60 to 78 (69.02 ± 5.37) years old. Among the participants, 9 had a history of long-term smoking and 5 had a history of long-term drinking. In group C, there were 44 cases. The group included 23 men and 21 women, aged 60 to 80 (70.01 ± 5.22) years old. There were 8 participants with a history of long-term smoking and 4 participants with a history of long-term drinking. There were no significant differences in sex, age, and personal history  among 3 groups  of folic acid  each day, taken as an oral treatment after breakfast. Group B was given 20 mg of pravastatin  each day, taken before bedtime. Group C was treated with a low dose of folic acid  and pravastatin . All groups were treated for 12 weeks. During the study period, all 3 groups were given a uniform standard of diet and daily activity patterns.2.3Before treatment, fasting venous blood was taken from the participants. The plasma levels of folic acid (μg/L), Hcy (μmol/L), TNF-a (pg/mL), MMP-9 (ng/mL), cholesterol test (TC) (mmol/L), and LDL-C (mmol/L) were determined using enzyme-linked immunosorbent assay. The level of intima-media thickness (IMT) was measured by ultrasound, and the levels of systolic and diastolic blood pressure were measured by mercury column. Fasting venous blood was taken from the 3 participant groups after 8 weeks of treatment. Plasma folate, Hcy, TNF-a, MMP-9, TC, and LDL-C were measured using enzyme-linked immunosorbent assay. The systolic and diastolic blood pressures of the 3 groups were measured 8 weeks after treatment. IMT level was detected by ultrasound Doppler at 12 weeks of treatment.Blood pressure readings were collected by 3 health care providers following the blood pressure measurement specifications stipulated in the hypertension guidelines. During the study period, blood pressure data were measured by the same mercury column blood pressure meter, and 3 providers shared one-third of each group of blood pressure measurements. Similarly, another 3 providers followed the operating practice process and used the same ultrasound instrument to measure the carotid intima-media thickness in one-third subgroup of each group of patients.2.4P < .05 was considered statistically significant.Statistical data processing was performed using the SPSS 23.0 software package (SPSS inc.). The measurement data were expressed as mean ± standard deviation. The comparison between groups was analyzed using analysis of variance. The comparison within the group was done using repeated measurement data, and the data of counting were analyzed by F-test. 3P > .05; Table P < .05); Hcy was significantly decreased, and the difference was statistically significant (P < .05). Compared with groups A and B, TNF-a, MMP-9, TC, and LDL-C were significantly decreased in group C, and the difference was statistically significant (P < .05).There was no significant difference in the levels of folic acid, Hcy, TNF-a, MMP-9, TC, and LDL-C among 3 groups before treatment (P > .05). After 8 weeks of treatment, the systolic and diastolic blood pressure of group C was lower compared with groups A and B. Both systolic and diastolic blood pressure decreased, and the difference between baseline and after treatment values was statistically significant (P < .05).Three groups of systolic and diastolic blood pressure measurements were compared. The results are shown in Table P > .05). After 12 weeks of treatment, compared with groups A and B, the IMT level of group C was significantly lower (P < .05).Table 2 = 0.093, P > .05). The loss of appetite was a short-term symptom, which appeared early and was gradually improved without affecting the health of patients.An evaluation of adverse reactions revealed that none of the 3 groups had allergic reactions, liver, and kidney function damage, increased creatine kinase, or acute cardiovascular and cerebrovascular events. The main manifestations were gastrointestinal symptoms. In group A, there were 2 cases of loss of appetite, 2 cases of nausea, and 3 cases of abdominal distension, with a total incidence rate of 15.56%. In group B, there were 3 cases of loss of appetite, 1 case of nausea, and 4 cases of abdominal distension, with a total incidence rate of 17.78%. In group C, there were 2 cases of loss of appetite, 2 cases of nausea, and 3 cases of abdominal distension, with a total incidence rate of 15.9%. There was no significant difference in the incidence of adverse reactions among the 3 groups , and their early diagnosis and treatment can greatly control patients’ conditions.Lacunar infarction is a common type of cerebral infarction in the elderly. It is often secondary to senile hypertension. It is ischemic cerebral infarction caused by occlusion of deep perforating branches in the cerebral hemisphere or brain stem. Mild, clinical symptoms of lacunar infarction are not typical, only manifesting as cortical dysfunction or emotional changes. As a result, they are easy to ignore and eventually lead to the formation of multiple areas or even large areas of cerebral infarction, resulting in cognitive decline or disability and death.,21The pathophysiological basis of lacunar infarction is atherosclerosis. The vascular wall gradually calcifies, with increased stiffness and decreased compliance. An abnormal activation of the inflammatory response leads to local infiltration of macrophages and phagocytosis of arterial intima deposits. Lipids become foam cells, forming the earliest lipid streaks of atherosclerotic lesions. Hemodynamic changes, including damaged arterial intima endothelial cells and platelet adhesion and aggregation and activation of platelet activating factor, are observed. On the intima, thrombus is formed, and a large number of inflammatory cytokines are released. These cytokines enter the blood vessel wall and promote smooth muscle cell proliferation. With the accumulation and migration of a large number of inflammatory cells and the proliferation of smooth muscle cells, inflammatory cells continue to release various cytokines and chemokines, ultimately leading to the formation of atherosclerotic plaques. Therefore, the inflammatory response and smooth muscle cell proliferation play a vital role in the formation and progression of atherosclerosis. As observed in animal studies, Hcy next damages the vascular endothelium by mediating oxidative stress, promoting smooth muscle cell proliferation, and increasing foam cell production promotes atherosclerosis. Lastly, it promotes platelet aggregation, thrombosis, and the deposition of fibrin and thrombus in arterial blood vessels.Hcy is a sulfur-containing amino acid, an important intermediate in the metabolism of methionine and cysteine in the human body. Hcy is a risk factor for atherosclerosis, hypertension, and thromboembolic diseases. The incidence of cardiovascular and cerebrovascular diseases is increasing in China. About 75% of elderly hypertensive patients in China show an increase in Hcy. This increase can cause poor blood pressure control and may lead to vascular endothelial dysfunction in the body, resulting in atherosclerosis. Hcy promotes atherosclerosis by initiating a 3-step mechanism. First, it triggers the release of various cytokines and active cell substances, leading to damage of the arterial wall. Similarly, studies have shown that hyperhomocysteinemia is associated with the occurrence of lacunar infarction, which involves Hcy in its development process. Therefore, the reduction of Hcy with drugs based on conventional antihypertensive, lipid-lowering, anti-platelet therapy, etc, can help control patients with hypertension and lacunar infarction.Older hypertensive patients with increased Hcy may have a 5-fold higher risk of atherosclerosis than persons with uncomplicated hypertension.TNF-a is an important member of the tumor necrosis factor family. It is a pro-inflammatory factor produced by monocytes and macrophages, and acts on vascular endothelial cells, damaging endothelial cells or causing vascular dysfunction and damage. Thrombosis plays a crucial role in the development of arteriosclerosis.Previous studies suggest that MMP-9 is involved in the formation of plaque fibrous caps, which can lead to plaque instability and are closely related to atherosclerosis, the severity of cerebral infarction, cognitive decline, and the prognosis of cerebrovascular disease. Studies have confirmed that MMP-9 gene polymorphism is associated with the increased prevalence of cerebral infarction.Pravastatin is a third-generation statin lipid-lowering drug. It can inhibit inflammatory cytokines, reduce the expression of leukocytes and endothelial cell adhesion molecules, and has anti-inflammatory effects. It improves vascular endothelial function, reduces plaque tension, improves the stability of atherosclerotic plaque, improves platelet function, reduces the formation of thrombosis, and prevents the formation of atherosclerosis through various mechanisms. The drug was suitable for our study because of its water solubility. Pravastatin metabolism is independent of the liver's drug metabolism, and its metabolites have no drug activity. Therefore, its side effects on the liver are relatively small. Moreover, elderly patients often need to take many drugs at the same time. Drug metabolism occurs through the cell P450 system, and because pravastatin is not metabolized by this system, the drug interaction is lower, making it safer for elderly patients. Oral supplementation with folic acid is a safe and effective method for reducing Hcy. The combined use of antihypertensive drugs and folic acid in patients with hypertension and elevated levels of Hcy can improve blood pressure control and reduce Hcy levels.,31 Pushpakumar et al studied the protective effects of folic acid in hypertension and confirmed that folic acid supplementation has a protective effect on cardiovascular events in hypertension. Other studies, including experiments in rats, have shown that low-dose folic acid as a supplement can significantly reduce their Hcy, TC, and low-density lipoprotein concentrations and lower the incidence of atherosclerosis, suggesting that low-dose folic acid can be used as an atheroma and primary prevention of sclerosis in subjects with risk factors for atherosclerosis. Related studies have also confirmed that the addition of an appropriate amount of folic acid can reduce the occurrence of aortic aneurysm and inhibit the formation of venous thrombosis while protecting against the occurrence of aortic dissection.Folic acid is a water-soluble B vitamin. It is involved in the body's synthesis and metabolism under the catalysis of methylenetetrahydrofolate reductase. When the body is deficient in folic acid or methylenetetrahydrofolate reductase, it will cause abnormal Hcy metabolism. The accumulation of Hcy in the body damages the endothelial cells of the wall, leading to atherosclerosis and causing structural and functional disorders along the vessel wall.Current research suggests that the anti-atherosclerosis effect of folic acid may be related to its anti-inflammatory effects, but the specific mechanism is still unclear, and folic acid has rarely been reported in the study of atherosclerosis in elderly hypertensive patients with lacunar infarction. This study investigated the effect of 0.8 mg/d folic acid combined with pravastatin 20 mg/d on arteriosclerosis to assess the possible beneficial effects in elderly patients with hypertension and lacunar infarction. The impact of diet and activities was minimized by ensuring the same healthy diet and healthy activity patterns among the 3 groups. There is no statistical difference among the 3 groups before the experiment.Compared with folic acid (group A) or pravastatin (group B) alone, patients administered folic acid combined with pravastatin (group C) had significantly low Hcy, TNF-a, MMP-9, and blood lipid levels, and their carotid intima-media thickness was also significantly improved after 12 weeks of treatment. Systolic and diastolic blood pressure were also significantly reduced, indicating that folic acid combined with pravastatin has a synergistic anti-inflammatory effect and improved arteriosclerosis. Our findings also showed that folic acid reduced Hcy levels after 8 weeks of treatment, demonstrating that supplementation with small doses of folic acid can achieve cardiovascular benefits. Folic acid alone can reduce Hcy, TNF-a, and MMP-9 to improve vascular endothelial function, reduce inflammation, lower lipid levels, and blood pressure, and result in other beneficial effects.Blood pressure fluctuations are present in elderly hypertension patients. To ensure that the blood pressure was kept in a relatively safe range during the study and that there was no significant difference in blood pressure among 3 groups, patients were given the same medicines to maintain their blood pressure below 140/90 mmHg. However, the dose of amlodipine varied to accommodate individual differences.A few limitations exist in this investigation. Whether the oral dose of amlodipine level had an effect on the combined folic acid and pravastatin treatment is not clear. Further studies are needed to determine the effects of other drugs taken by elderly patients with hypertension and lacunar infarction on folic acid treatments. We were also limited by the small sample size and short observation time. The exact mechanism of the effects and theoretical verification will need to be further confirmed by a large sample and randomized controlled study.Conceptualization: Xingpeng Bu.Data curation: Chunxia Li, Xingpeng Bu.Formal analysis: Chunxia Li.Funding acquisition: Yaru Liu.Investigation: Chunxia Li.Methodology: Chunxia Li, Xingpeng Bu.Resources: Xingpeng Bu, Yaru Liu.Supervision: Yaru Liu.Validation: Xingpeng Bu.Visualization: Yaru Liu.Writing – original draft: Chunxia Li, Xingpeng Bu.Writing – review & editing: Chunxia Li.


Background: Cerebral venous thrombosis (CVT) refers to a stroke subtype characterized by the disturbance of cerebral venous outflow caused by venous thrombosis. Previous studies have reported a range of factors that predict the prognosis of CVT. This study is aimed to find out whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) are suitable as potential indicators of the severity and clinical outcome in CVT patients.Methods: The CVT patients admitted to Xuanwu Hospital from January 2014 to December 2019 were enrolled. The severity of CVT was assessed by the National Institute of Health Stroke Scale (NIHSS) and intracranial pressure (ICP) at the time of admission. The modified Rankin score (mRS) was assessed at 6 months of follow-up.Results: One hundred fifty-six CVT patients were enrolled with a mean age of 35.8 ± 12.8 years. A percentage of 55.8% of the CVT patients recruited were female, and 17.3% were either pregnant or in perinatal period. Headache was the most common symptom. SBP and DBP were not correlated with NIHSS at admission. Furthermore, SBP and DBP had no impact on the disturbance of consciousness, epilepsy, intracranial hemorrhage, and mental disorders. However, SBP and DBP were positively correlated with ICP at admission. SBP > 129.5 mmHg and/or DBP > 77.5 mmHg suggested the presence of intracranial hypertension (IH). Based on current results, SBP was not correlated with mRS at 6 months of follow-up. However, DBP was found to be positively correlated with mRS at 6 months of follow-up. DBP in CVT patients with good prognosis was significantly lower than in those with poor prognosis. DBP > 79.5 mmHg was identified as a cutoff value to predict a poor clinical outcome. A higher mRS and a higher rate of poor clinical outcome were found in CVT patients with SBP > 146 mmHg or DBP > 79.5 mmHg compared to those with SBP ≤ 146 mmHg or DBP ≤ 79.5 mmHg.Conclusion: SBP > 129.5 mmHg and DBP > 77.5 mmHg suggested the presence of IH in CVT patients. DBP > 79.5 mmHg predicted a poor clinical outcome. Cerebral venous thrombosis (CVT) refers to a stroke subtype characterized by the cerebral venous outflow disturbance caused by venous thrombosis . In receIt is reported that 13.4% of CVT patients had poor prognosis . Also, aIt is widely recognized that high blood pressure (BP) is a significant risk factor for arterial stroke and an indicator of poor prognosis in arterial stroke patients . HoweverThe CVT patients admitted to Xuanwu Hospital from January 2014 to December 2019 were enrolled. This prospective study was approved by the Xuanwu Hospital ethnics committee. The inclusion criterion was CVT confirmed by magnetic resonance venography (MRV), computed tomography venography (CTV), digital subtraction angiography (DSA), or high resolution-magnetic resonance imaging (HR-MRI).2O was considered as intracranial hypertension (IH)  was detected by measuring CSF pressure with lumbar puncture. An ICP > 250 mmHion (IH) . In ordeion (IH) .t-test, while categorical data were expressed as a number (percentage) and processed using chi-square test. Pearson correlation coefficient and linear regression were used to predict the correlation between continuous variables. Logistic regression models were constructed using enter method. The cutoff points were calculated using receiver operating characteristic (ROC) curves. p < 0.05 was considered statistically significant.SPSS Version 16.0  was used for all statistical analyses. The continuous data following Gaussian distribution were expressed as mean ± standard deviation and analyzed with independent One hundred fifty-six CVT patients were recruited in this study, with a mean age of 35.8 ± 12.8 years. There were 87 (55.8%) female patients, and 27 (17.3%) patients were either pregnant or in the perinatal period. Twenty-one (13.5%) patients had hypertension, 7 (4.5%) had diabetes mellitus, 7 (4.5%) had hyperlipidemia, 4 (2.6%) had deep venous thrombosis, 4 (2.6%) had pulmonary embolism, and 3 (1.9%) had systemic infectious diseases. Seventeen (10.9%) patients had a history of smoking, and 17 (10.9%) patients had a history of alcohol. Headache (89.7%) was the most frequent symptom, followed by new-onset epilepsy (34.6%), limb weakness (33.3%), disturbance of consciousness (21.2%), visual impairment (19.9%), and tinnitus (5.8%). The average SBP and DBP were 122.8 ± 16.7 and 77.6 ± 10.8 mmHg, respectively .p = 0.107; p = 0.135, p = 0.009; p = 0.019, p = 0.0004, p = 0.024, NIHSS, clinical presentations, and ICP at admission were used to assess the severity of CVT. Our results showed that SBP and DBP were not correlated with NIHSS , the National Natural Science Foundation (81371289) and the Project of Beijing Municipal Top Talent of Healthy Work of China. This study was also funded by the Natural Science Foundation of Beijing Municipality (7212047). The grant number of Project of Beijing Municipal Top Talent of Healthy Work is 2014-2-015.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Hypertension is a major global cause of cardiovascular disease and death with rising worldwide prevalence, particularly in low-income countries. With low awareness, poor treatment, and low control of hypertension in Africans, there is an increased number of patients with target organ damage (TOD), especially chronic kidney disease (CKD), as a consequence of hypertension. The aim of our study is to assess the prevalence of CKD from studies in Africa reporting TOD related to hypertension.  We performed a search of PubMed/MEDLINE, Web of Science, EBSCOhost, and African Journals Online (AJOL) for studies reporting on CKD as TOD in patients with hypertension. The pooled estimate of CKD was then presented by subregions, age group, eGFR equations, and urban or rural location. p < 0.0001) and in studies conducted in urban settings (p < 0.001). CKD prevalence was not significantly different by type of GFR equation or age.  We identified 1,334 articles from which 12 studies were included for quantitative analysis. The studies included 5297 participants from 6 countries . The pooled prevalence of CKD was 17.8% (95% CI 13.0–23.3%), and CKD was significantly more prevalent in West Africa (21.3% (95% CI: 16.1–27.0); CRD42018089263. This study reports a high prevalence of CKD related to hypertension with a higher prevalence in urban than rural areas. This emphasizes the role of hypertension in causing kidney damage, and the need for strategies to improve awareness, treatment, and control of hypertension in Africans. This study is registered with PROSPERO registration number  Hypertension is a prevalent worldwide public health problem and an important modifiable risk factor for cardiovascular disease (CVD) and chronic kidney disease (CKD). The prevalence of hypertension in the global adult population was estimated to be 31.1% (95% CI: 30.0%–32.2%) in 2010, representing 1.38 billion people who were affected worldwide . The Uniβ) [There are subtle differences in the pathogenesis of hypertension between populations of African ancestry and Europeans, and such differences may account for the varied course of hypertension in these populations . For insβ)  and sociβ) .Given that blood pressure (BP) is a modifiable risk factor for CKD, it is important to identify the contribution of hypertension to CKD in Africans, especially as access to treatment for CKD and kidney failure is severely limited  with extCRD42018089263. Ethics approval was not required for this study.The Preferred Reporting Items for Systematic Review and Meta-Analysis , 20 was 2) as documented by the authors using any of the standard creatinine-based formulae to estimate the glomerular filtration rate (GFR): Chronic Kidney Disease Epidemiology (CKDEPI) [Published literature between January 1995 to December 2019 was included. We selected 1995 as the start year for our search as the definitions and stages of CKD were developed subsequently. We included all studies (without language restrictions) that reported CKD  as TOD of hypertension in adults 18 years or older and included studies conducted in Africa. Hypertension was defined as systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg . We repo(CKDEPI) , Modific(CKDEPI) , and Coc(CKDEPI) . We exclWe performed a search of PubMed/MEDLINE, Web of Science, EBSCOhost, and African Journals Online (AJOL). Medical subject headings (MESH), including “prevalence,” “hypertension,” blood pressure,” “hypertensive,” “hypertensive target organ damage,” “chronic kidney disease,” “kidney disease,” kidney damage,” kidney failure,” “target organ damage,” “Africa,” “sub-Saharan Africa,” ‘Africa South of Sahara,” and all African countries by names were used in the search and modified for each database, as necessary. We adapted the MEDLINE search strategy for other databases .Data extraction was done independently and in duplicates by SA and UE, and disagreement was resolved by consensus by SA and UE, and when necessary, in consultation with IGO. The following data variables were extracted from selected studies: first author's name, year of publication, country and subregion of study, race of study participants, study design, total sample size, sample size of study participants with hypertension, gender proportion, median age, mean body mass index (BMI), mean SBP, mean DBP, eGFR equation used for assessment, number, and proportion of participants with CKD.To assess the quality of methodology of the studies included for analysis, a modified 9-point rating system by Stanifer et al.  was usedSTATA 16  was used for statistical analysis.I2 statistic was used to determine the heterogeneity between studies [Q-test based on ANOVA. Comparison of prevalence of hypertension and TOD between age groups, gender, location , and region (West Africa versus East Africa versus Southern Africa) was done.The prevalence of TOD in hypertensives was performed using meta-analytic techniques. The study-specific estimates derived from the DerSimonian–Laird random-effects model  were poo studies . Subgroup value of the Egger test = 0.19 .The mean systolic blood pressure ranged from 135.9 mmHg  to 175.4I2 = 95.5%, p < 0.001)   . Four st p=0.65; . The prep=0.001) .p < 0.001, p=0.76, Supplementary p=0.95, Supplementary When assessed according to region, studies from West Africa had the highest pooled prevalence of CKD (21.3% (16.1–27.0)), while the one study from Southern Africa had the lowest (3.2% (95% CI: 1.7–5.5%)), with a significant difference in prevalence across regions . This is consistent with general population reports from previous studies showing higher CKD prevalence in West Africa [Our study also found that the West African subregion had the highest pooled prevalence of CKD (21.3% (16.1–27.0%); t Africa , 39, 47.t Africa . The APOt Africa , 50. We t Africa , 52.Furthermore, we also found a higher prevalence of CKD among the urban populations compared to rural populations. This is largely consistent with observations from studies in Africa of higher prevalence of hypertension in urban than rural settings . EpidemiFinally, our study identified nonsignificantly different CKD prevalence rates based on the different equations used for assessing CKD from the included studies. Given that the current equations in use were not developed in sub-Saharan African populations, uncertainties remain about the best equation for assessing GFR in Africans. The accuracy of current equations remains limited at an individual level, particularly due to differences in muscle mass. Other studies have also reported differences in CKD prevalence using these equations with an overestimation using the CG equation , 45. ThiThere were some limitations to our study. First, the absence of reporting serial measurements of serum creatinine and or GFR at least 3 months apart to define CKD is notable. Severe hypertension can be associated with acute kidney dysfunction; therefore, it may not be possible to distinguish such cases from CKD. Thus, the use of a single GFR estimation to assess CKD prevalence is likely to overestimate the prevalence . This haOur study shows that the prevalence of CKD is high amongst hypertensive patients in Africa, particularly for those in urban than in rural areas. Given that blood pressure is a modifiable risk factor for CKD, strategies to improve hypertension awareness, treatment, and control should be implemented in African countries. Such strategies should include strengthening NCD structures in each country and ensuring availability of cheap but effective drugs for hypertension treatment.


The presence of Lindsay's nails in a patient with a risk factor for chronic kidney disease could be a valuable clue to an underlying long‐standing renal impairment, particularly when serum creatinine level is not at hand. The presence of Lindsay's nails in a patient with a risk factor for chronic kidney disease could be a valuable clue to an underlying long‐standing renal impairment, particularly when serum creatinine level is not at hand. As chronic kidney disease is usually silent, delays in diagnosis are not uncommon. Thus, a higher degree of suspicion is indispensable. Detection of Lindsay's nails in this hypertensive patient was a significant hint for chronic kidney disease.Chronic kidney disease (CKD) usually presents with persistently elevated serum urea and creatinine levels. However, due to the silent nature of CKD, the diagnosis can frequently be delayed if a timely renal function test is not carried out. Unfortunately, biochemical tests for the assessment of renal function may not be done in a patient for various reasons. Firstly, asymptomatic CKD patients tend not to seek medical help. Secondly, the test may not be requested in the first visit unless the patient is on a regular follow‐up for certain medical conditions. Thirdly, notably in resource‐limited settings, access to automated laboratory tests could be lacking in reasonable proximity. Hence, a higher degree of suspicion for renal impairment especially in those with risk factors is crucial. Utilizing all available clinical clues can also narrow down the differential diagnoses.Advanced CKD presents with uremia. Although uremia consists of myriad symptoms and signs that demonstrate renal insufficiency, most of them are nonspecific to kidney disease. Nail changes are one of these non‐specific signs. Nail disorders commonly associated with chronic renal impairment include absent lunula, half‐and‐half nails, and splinter hemorrhages.2A 50‐year‐old woman with a medical history of poorly controlled hypertension and right nephrolithiasis presented to the emergency room with the complaint of a new‐onset generalized tonic‐clonic seizure. She also complained of headache, nausea, restlessness, headache, light‐headedness, fatigue, and shortness of breath on exertion. The patient denied any urinary complaint. She was not on outpatient follow‐up, and she quit antihypertensive medication for three months.Her initial vitals were blood pressure 220/120 mm Hg, heart rate 113 beats per minute, respiratory rate 37 breaths per minute, and oxygen saturation 94% on room air. She was agitated but was alert and oriented. Her cardiopulmonary examination was notable for sinus tachycardia and tachypnea with normal breath sounds bilaterally.As the first episode of seizure occurred at home, emergency management focused on controlling blood pressure, which was initially assumed to be the probable cause of the convulsion. Sublingual drops of nifedipine resulted in minimal blood pressure decrease. Four hours later, the patient had an episode of generalized tonic‐clonic convulsion that was aborted at the second minute using diazepam 10 mg given intravenously after securing the airway. The subsequent blood pressure record was 203/111 mm Hg. Hydralazine 10 mg was slowly administered intravenously. Although no other episode of convulsion occurred, blood pressure was not adequately controlled with those available medications.Meanwhile, some nail color changes were incidentally noted during a meticulous assessment of the patient. The fingernails had a whitish proximal half with dark‐brown sharply demarcated distal half that does not fade on pressure, fitting the appearance of Lindsay's nails  Figure . Taking When renal function test became accessible during working hours, blood urea nitrogen (BUN) was found to be 183 mg/dL and serum creatinine 17.2 mg/dL. Complete blood count showed hemoglobin of 7.2 g/dL. Ultrasound of the kidneys revealed shrunken kidneys with loss of cortico‐medullary differentiation. The patient was soon referred for dialysis with the provisional diagnosis of ESRD secondary to hypertensive nephropathy. Being into hemodialysis within 16 hours of her presentation, the patient was clinically stabilized. Blood pressure was controlled, and the patient showed marked clinical improvement upon subsequent evaluation.3Nail changes are common in chronic kidney disease, affecting more than 75% of hemodialysis patients.The pathophysiology of half‐and‐half nails is not clearly elucidated. The proximal white band is thought to result from chronic anemia secondary to an increased wall thickness of capillaries or overgrowth of connective tissue between the nail and the bone with the reduction in blood in the subpapillary plexus. The distal brown band is caused by melanin deposits, possibly from increased β‐melanocyte‐stimulating hormone.Lindsay's nails are commonly associated, but not specific, with chronic kidney disease. There is no correlation between the presence of Lindsay's nails and the degree of renal impairment or blood urea nitrogen or creatinine levels. It is also found that it does not improve with hemodialysis, although the nail discoloration may regress after successful renal transplantation.Lindsay's nails should not be confused with other nail disorders particularly with Terry's nails. In Terry's nails, the distal 1‐2 mm of the nail shows a pink or brown band with the entire nail plate or proximal end whiteness. These changes have been noted in 25% of hospitalized patients, most commonly those with cirrhosis, chronic congestive heart failure, and adult‐onset diabetes, and in very elderly patients.4Lindsay's nails are relatively uncommon clinical examination findings and probably unheard‐of to many clinicians. With the advent of the rapid contemporary technological dependence in modern medicine, these signs might be considered obsolete and of no use. However, the present case report demonstrates the importance of subtle physical examination clues in the diagnosis of chronic kidney disease especially in the absence of relevant laboratory investigations. Although this patient with no prior follow‐up to a primary care physician presented with a complicated CKD, the emergency department is, in fact, not the ideal setting to look for these subtle signs.The recognition of these associated nail disorders might help early consideration of possible renal insufficiency in a patient with known risk factors even in cases where there is no significant rise in serum urea or creatinine considering the lack of its correlation with those laboratory parameters. On top of that, since the nail changes are associated with chronic kidney disease instead of acute kidney injury, the presence of half‐and‐half nails in the background of confirmed renal insufficiency would also make acute kidney injury unlikely, thereby assisting in differentiating chronic from acute. Therefore, clinicians should be aware of this clinical sign and look for it in their daily practice when appropriate. Nevertheless, it is prudent to keep in mind that, like many clinical signs, its presence is more clinically relevant and helpful in decision‐making than the absence of thereof.None declared.Saud Mohammed Raja detected the clinical sign, took the lead in the management of the patient, did the photography, and wrote the manuscript.Written informed consent was obtained from the patient for publication of this case report and the related photograph.


BackgroundThe global incidence and prevalence of chronic kidney disease (CKD) is skyrocketing. In Asia, the prevalence of CKD varies from 10%-18%. However, as Asia is largely populated by developing countries with nascent health care systems, there is a dearth of research and data. It is estimated that a large number of cases go unreported. As a result, the exact disease burden remains unclear. The knowledge about risk factors and their proportionate role in CKD is indispensable in regards to patient management and care. ObjectiveThe early recognition of the most important risk factors for end-stage renal disease (ESRD) is key to early diagnosis, successful treatment, and general heightened awareness regarding CKD. In developing countries, the provision of medical services, in general, and nephrological services, in particular, is wholly inadequate. The insufficiency of solid and regularly updated data compounds the problem. This research study aims to partake in catering to that need.MethodologyA structured questionnaire was used to obtain quantitative and categorical data from 119 ESRD patients in the nephrology ward, Allied Hospital, Faisalabad through non-probability sampling. Socio-demographic profile of the patients and information regarding the presence or absence of risk factors were collected. The resulting dataset was analyzed using R version 3.6.3  for data visualization and descriptive analysis.ResultsThe most common age group for ESRD presentation was 46-60 years (52.1%). Among the 119 ESRD patients, the most frequent risk factor was hypertension with 85.7% of the patients presenting with the condition, followed by diabetes mellitus (DM) in 54.6%, renal calculi in 28.6%, glomerulonephritis (GN) in 31.1%, Family history of CKD in 24.4%, and polycystic kidney disease (PKD) in 5% of the patients. Gender-wise distribution of the patients shows that the proportion of patients with hypertension, renal calculi, and family history of CKD varied very little among the two groups.ConclusionIn conclusion, our study has reinforced the existing body of knowledge and brought some fresh evidence regarding the prevalence of risk factors in ESRD to light. Hypertension and DM, together, represent the vast majority of cases with ESRD. However, hypertension far outpaces DM as the leading risk factor. Nephrolithiasis was also present in a considerable minority, with a figure much higher than previously reported. Finally, a relatively younger age group (45-60 years) formed the majority of the ESRD patients which is a concerning development. It points to early progression of CKD to ESRD. Long-term adequate control of these risk factors limits disease progression.  The global incidence and prevalence of chronic kidney disease (CKD) is skyrocketing. Kidney diseases have become the ninth leading cause of death in the United States, imposing a financial strain of 47.5 billion dollars in 2010 alone , which iCKD is a general term that refers to a variety of medical problems impacting the morphological structure and physiological function of the kidney . It is aStage 5 CKD is referred to as ESRD. It affects over 1500 people per million population (ppm) in countries with high prevalence, like Japan, Taiwan, and the United States . Nearly The common risk factors leading to ESRD in Pakistan include glomerulonephritis (GN) (37%), hypertension (12%), diabetes mellitus (DM 10%), and renal calculi (5%) . Other r%, and reIn Pakistan, insufficient attention has been paid to the prevention of kidney diseases. There is a lack of community-based nephrology services. The lack of healthcare infrastructure, limited education, and financial constraints have hamstrung efforts to address these problems . The earA structured questionnaire containing close-ended questions was used to obtain quantitative and categorical data from 119 ESRD patients in the nephrology ward, Allied Hospital, Faisalabad through non-probability sampling. Socio-demographic profile of the patients and information regarding the presence or absence of risk factors such as DM, hypertension, polycystic kidney disease (PKD), GN, and family history of renal disease were collected. The resulting dataset was analyzed using R version 3.6.3  for data visualization and descriptive analysis.Out of 119 patients, 67 (56.3%) were male and 52 (43.7%) were female. The male to female ratio was 1.28:1. Age distribution of patients included four categories  formed the majority of the ESRD patients which is a concerning development. It points to early progression of CKD to ESRD. Long-term adequate control of these risk factors limits disease progression. In addition, a higher level of education and awareness is associated with better health outcomes because such patients are more likely to seek medical attention and receive timely treatment, leading to greater control of the associated risk factors.


Instrumental gait analysis in nephrology is widely neglected, although patients with chronic kidney disease (CKD) show brain changes due to cerebrovascular disease and metabolic disorders that can potentially influence gait quality. Our study assesses the association between CKD stages and gait parameters, to understand the prevalent status of brain related gait parameters (i.e. variability) and of performance related parameters . We hypothesize that gait changes are detectable already in early stages of CKD.Forty-five participants distributed in 5 CKD severity groups underwent an instrumental gait analysis via a triaxial accelerometer affixed to the lower trunk under single- and dual-task conditions. In addition to spatio-temporal parameters, variability and dual-task cost of gait were extracted. A battery of clinical assessments was conducted with the aim of helping to better explain the findings of the gait analysis. A correlation analysis was made to investigate a linear relation between gait parameters and CKD severity.p < 0.01, r = -0.55, 95% CI ), stride length , step length  of step length , gait regularity , dual-task cost of gait speed  and dual-task cost of stride time . Adjustment for age and gender confirmed all results except for gait regularity. With increasing severity of renal failure, Handgrip strength, Time for the Expanded Timed Get Up and Go test, executive functions, haemoglobin, and haematocrit, worsen.Statistically significant correlations (Pearson correlation coefficient) with CKD severity were found for gait speed  and with variability of gait  supported by the results of the clinical assessments, suggests that gait disturbance in CKD patients is not only due to metabolic factors that lead to muscle wasting, but also to brain changes that affect motor control. This suggests that the treatment of renal disease should include cognitive aspects in addition to metabolic and functional factors.The online version contains supplementary material available at 10.1186/s12882-022-02697-8. Patients at end stage renal disease (ESRD) are known to be particularly frail . CompareOften the lower health status of ESRD has been explained with factors related to the renal replacement therapy (RRT) – mostly haemodialysis (HD) – in particular, a reduced physical activity level –12, and Currently there is not much detailed knowledge about the highly prevalent gait impairments seen in CKD and ESRD patients, and how these impairments affect gait quality . When gaA cross-sectional study design will allow assessment of the relationship between CKD exposure and gait outcomes, and consequently help determine whether a longitudinal study would be warranted . The aimThis is a cross-sectional observational study in an ambulant setting of 5 groups of CKD patients at different severity stages, based on the estimated glomerular filtration rate (eGFR) in accordance with K/DOQI guidelines  calculatWe recruited the patients in Canton Ticino – Switzerland, between July 2020 and May 2021. Medical doctors of two nephrology units of the multicentric public hospital , asked patients with a kidney disease about their interest in participating in the study. In case of a positive answer, their contact data were sent to the principal investigator who called the patient and fixed the date for a visit. Before starting their visit, inclusion and exclusion criteria were checked, the patients were informed orally, received written information, and signed the written informed consent form. Patients with normal kidney function (stage 1) or mild to severe kidney dysfunction (stages 2–5), who were able to understand information for executing assessments, and could walk for about 20 m alone and without a walking aid, were eligible for the study. Patients with an unstable or preterminal health status , diagnosis of depressive syndromes or dementia  were exGait was assessed following international guidelines that suggest to let the patient walk in a single- and a dual-task condition –35. The value/DTvalue, since this was expected to be lower in the dual-task condition) and for stride time .In addition to the spatio-temporal parameters , variability was assessed using the coefficient of variation (CV = standard deviation / mean) of stride and step both in the spatial and the temporal domain, and gait regularity  . Dual-taFor the description of the population, several clinical tests were assessed. A detailed description can be found in Additional file r = 0.50).Since previous studies gave a hint of the presence of at least a moderate inverse correlation (Pearson's rho > 0.50) between increasing CKD severity and worsening in motoric , 42 and Demographic, clinical, functional and gait characteristics of the subjects were described using mean and standard deviation, and reporting minimum and maximum values, for numerical variables, while sex was categorised numerically.s coefficient to confirm the existence of associations by relaxing the prerequisites of the parametric Pearson's r coefficient. Spearman's rs 95% CIs were obtained using a bias corrected bootstrap method with 1000 replications. The association between CKD and gait variables was studied, also controlling for age and sex, performing separate linear regressions for each gait variable: in this case a corrected regression coefficient  was reported. We did no include other possibly important covariates in the adjusted model due to the relatively low number of the collective, since including more variable could create multicollinearity problems.Although the CKD stage is not strictly a continuous variable, the number of stages (five) of CKD severity is relatively high, and previous projects were carried out using this approximation . Due to All participants completed the gait analysis and for all 45 participants all data are available. Missing data for clinical aspects  were not replaced and no adjustment of mean and standard deviation was carried out. We checked for the presence of outliers calculating a Mahalanobis distance on gait variables: one subject had a distance which was almost double relative to the second one. After inspecting the groups of variables, we found that the distance was almost entirely due to his dual task performance, where his Mahalanobis distance was almost five times the second one, therefore we decided to exclude him from parametric analyses in dual task analyses only, while retaining him in non-parametric analyses .p ≤ 0.05. Statistical analyses were performed using Stata 15.1 (StataCorp) and JMP Pro 15 (SAS Institute Inc.).Significance cut-off was set at n = 8); stage 3 (n = 9); stage 4 (n = 9); stage 5 not on dialysis (n = 10); 5 on HD (n = 9). The combined CKD group 1 & 2 was on average younger than the other three groups (60 vs. 74 years). Table  51 patients were asked by the nephrologist to participate. 1 person (CKD 5 not on HD) died before the principal investigator could fix the date for the visit. 5 patients change their mind once contacted by the principal investigator and denied to participate . No participant was excluded by the principal investigator during the visit. 45 patients accepted to participate in the study which led to an almost equal distribution of the participants in 5 CKD severity groups: stage 1–2  deteriorate in a linear way with the reduction of eGRF and suggests that already in early stages of CKD (namely stage 3) changes in the brain structure may influence gait quality. The other variability measures show no decline over the disease progression, however, the values observed for step time and stride length variability show values that are consistently high and are, when compared to benchmarks, to be considered in ranges attributable to pathologic walking behaviour . It can,It is widely known that CKD severity affects the health status both for physical and cognitive performance –3, 9 andGait disorders may be caused by muscular peripheral impairment, may have a neurologic central origin, or may be due to a combination of factors . Where lAlthough these results apparently also explain the slowdown of gait speed and shortening of stride length , 59, somIn our study we also calculated gait variability, that is known to be related to neurocognitive factors –80. As gThe aim of this study was to describe gait characteristics of CKD patients at different stages. We found statistically relevant correlations between a decline in gait speed, stride length and spatial and temporal variability. This can be explained on the one hand by muscle wastage, and on the other hand by cognitive decline, especially executive function, due to cerebrovascular disorders. As these changes start already in patients with a moderately reduced kidney function, interventions to prevent cognitive and physical decline should be offered early in form of training that stimulates both physical and cognitive domains.Our study is one of the first describing quantitatively the gait characteristics of CKD patients through all disease stages and should, therefore, be considered as a pilot study and our conclusion treated as exploratory. Firstly, the small number of participants in each group has the risk that a few outliers  and an increase in gait variability and dual-task cost of walking were found to be correlated with CKD severity. This finding confirms on the one hand the influence of metabolic changes in the muscle that leads to muscle wastage and, in turn, to a reduced physical walking speed performance, together with a higher degree of fatigue recorded in the participants with CKD ≥ 3. On the other hand, the poor results shown in neurocognitive tests, in dual-task cost of gait speed analysis, and in variability measures of gait in participants with a more impaired renal function, hint towards brain changes that influence gait quality of CKD patients. These results suggest that the treatment of CKD patients should be multidisciplinary and should take cognitive aspects into consideration in addition to the metabolic and muscle strength functional properties even though they were obtained in a relatively small sample of subjects and therefore deserve to be confirmed by other (possibly larger) studies. Longitudinal studies exploring the development of gait in CKD patients over time are warranted.Additional file 1.


The presence of a variant of the human peptide transporter 2 (PEPT2), with a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses, and the known clinical features of renal involvement in acute hepatic porphyrias.Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest under drastically different clinical pictures. The most dramatic presentation of the four congenital acute hepatic porphyrias  consists of potentially life-threatening neurovisceral attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a distinct, long-term degenerating condition with specific pathological and clinical features, for which a satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most commonly reported, though other pathologic features  are consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms possibly intervening in causing renal damage in AHPs are different: among others,  Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the metabolic pathway of heme biosynthesis . Accordiδ-aminolevulinic acid, porphobilinogen—PBG, or porphyrins) in plasma, urine, and/or feces, depending on the hydrophobicity of the different compounds. Since porphyrins are highly reactive to ultraviolet rays, when found in urine they cause it to turn to a reddish hue under sunlight exposure. At the same time, when porphyrins deposit in the skin, they are responsible for the painful phototoxic reactions of cutaneous porphyrias, mainly due to the light-dependent release of cytotoxic reactive oxygen species (ROS) in the course of type I/II photosensitized reactions [Each of the porphyrias is characterized by a specific pattern of accumulation of heme precursors  which, by putatively increasing the metabolic demand for heme, could trigger an APA. In the absence of randomized controlled trials or a shared consensus, periodic infusions of heme arginate have been implemented as a prophylactic therapy for APAs , whereasIn recent years, a novel siRNA-based drug, givosiran, has been approved for the treatment of acute hepatic porphyrias ,11: by s2 per year [While givosiran has represented a breakthrough in the management of acute porphyrias, it must not be overlooked that, other than acute attacks, patients with AHPs develop long-term complications such as chronic neuropathy, hepatocellular carcinoma, and chronic kidney disease (CKD) ,14. In fper year .The purpose of this review is to outline the known features of renal involvement in acute hepatic porphyrias: most of the knowledge on this subject is provided by studies on the most common AHP, acute intermittent porphyria, even though at least a few early observations on the South African cluster of variegate porphyria are available ,18.It is generally assumed that the kidney contributes to heme production as the third major synthesizing organ, after the bone marrow and the liver—which account, respectively, for 80% and 15% of total heme biosynthesis . In factprocess—an initial increase in the enzyme’s activity in the cytosol and a subsequent shift into the mitochondrial matrix- seems qualitatively similar to what has been observed in the liver, but its kinetics are much slower  [Compared to liver cells, ALAS in the kidney is somewhat more refractory to induction by porphyrinogenic stimuli. The induction minutes) . By contminutes) .This being considered, it might be of interest to estimate the amount of the “free” heme pool reserves in liver cells. Liver transplantation is deemed curative in AHPs : therefoSeveral observations have supported the idea that porphyrin excess in urine, e.g., during attacks, is of renal origin ,21,22,23Several factors may contribute to the decline in kidney function in patients with AHPs.In the first instance, it should be considered that hypertension is a common finding in patients with acute porphyrias ,26,27, aHMBS mutation (either AIP patients or asymptomatic carriers) confirmed a significant association between the diagnosis of acute intermittent porphyria and chronic kidney disease (CKD) independent of hypertension [HMBS mutations  and a greater eGFR decline  [An observational study on a few hundred patients with rtension . In partrtension . Comparertension . Quite iutation) .HMBS mutation, even if asymptomatic, has been demonstrated for a specific variant of the peptide transporter 2 (PEPT2). PEPT2 is expressed on the brush border of the tubular proximal cells in the S2 and S3 segments, where it acts as a proton-coupled symporter for the reabsorption of di- and tri-peptides, plus a number of peptide-like endogenous and exogenous compounds , including the highly hydrophilic ALA. The PEPT2*1 variant has a greater affinity to its substrates compared to PEPT2*2, and its presence has been independently associated in multivariate analysis with a worse decline in renal function and lower eGFR in patients with HMBS mutations, regardless of the presence of other symptoms of the disease. [PEPT2*1 variant in subjects exposed to a risk of lead toxicity  [A significant impact on the severity and evolution of CKD in individuals with disease.  Since PEdisease. , where irphyria) ,34. Notarphyria) , and therphyria) .2 to produce superoxide anion (O2), HO radical, and ALA radical (ALA); ALA, in the presence of oxygen, reduces iron and yields dioxo valeric acid (DOVA), a highly reactive oxidant [Among several mechanisms by which ALA is thought to cause cytotoxic damage, the kidney may be particularly susceptible—at least in its most metabolically active segments—to mitochondrial ALA-induced oxidation. At the intracellular level, ALA undergoes a phosphate-catalyzed auto-enolization, and becomes an oxidizing agent; it reacts with iron and O oxidant ,37. Seve oxidant ,39,40.Renal histopathological findings in patients with PAKD point toward chronic tubulointerstitial damage ,41,42,43Cell culture studies have shown that human endothelial cells (HUVECs), when incubated with ALA and PBG, do not appear to suffer direct damage from the porphyrin precursors . In contOn electron microscopy, HRECs incubated with PBG showed accumulation of electron-dense cytosolic granules, whereas light microscopy detected yellow-brown granular aggregates, negative for Perl’s stain, and numerous cytoplasmic osmiophilic granules within the proximal tubular cells . IntriguIt is then interesting, from a historical as well as a scientific perspective, that a few studies on acute porphyrias from the past century have reported histopathological findings suggestive of tubular deposition of porphyrins ,44,45,462−) [As a matter of fact, consistent pieces of evidence have been gathered concerning the cell-damaging effects of light-independent porphyrin-mediated toxicity : in part2−) ,53. It mIt must be remarked that when a mouse model of AIP was employed to investigate the effects of repeated phenobarbital-induced acute attacks on renal tissues  relativeFrom a clinical perspective, signs of proximal tubulointerstitial insufficiency  and of oxidative damage (increased urinary excretion of lipoperoxides), have been anecdotally signaled in porphyric patients ,43. A paHMBS mutation [Selectively higher urinary PBG values in association with a decreased kidney function have been observed in patients with mutation  and confmutation , where nmutation . This temutation , with a mutation .The reason for this selective accumulation of PBG is not entirely clear: it has been supposed that fairly high initial levels of plasma PBG, due to renal impairment, could exert an additional substrate inhibition on hepatic HMBS, precipitating substrate accumulation ,64. In fProbably due to their binding to plasma albumin and hemopexin , porphyrConcerning peritoneal dialysis, it has been recently reported  the inteKidney transplantation has been successfully attempted in patients with AHPs and ESRD ,72,73,74The beneficial effects of kidney transplantation alone are likely due to the interruption of the vicious cycle of accumulation of neuro- and nephrotoxic porphyrin precursors caused by the impairment in renal function. In fact, kidney allograft permitted a more effective clearance of ALA and PBG, which resulted in a reduction in their ratio toward values normally observed in AIP patients with normal kidney function. Moreover, transplanted kidneys are an exogenously implanted source of effective heme synthesis, and could provide some form of compensation for the deficiencies of the heme synthetic pathway at the hepatic level. In the setting of organ transplantation, several immunosuppressive drugs have proved safe in patients with porphyria ,72,73,74A novel siRNA-based agent, givosiran, exploits the native RNA-induced silencing complex (RISC) to specifically modulate liver ALAS1 mRNA translation ,11,12. GAt the same time, additional caution should be exercised as to avoid further deterioration in kidney function in patients treated with givosiran . In FranImportantly, none of the patients qualified for a diagnosis of acute kidney injury, based on the KDIGO criteria , and tho2/year in average), which could be likely explained by the natural history of PAKD; lastly, two patients experienced an abnormally deep decline in renal function (−5.8 mL/min/1.73 m2/year in average). Notably, a kidney biopsy was performed in one of the two patients with progressively declining renal function, yielding no specific signs of active tubular, glomerular, or arteriolar injury, only mild tubular atrophy and interstitial fibrosis were observed; additionally, no immune deposits or alterations of ALAS1 mRNA and protein expression were detected. In this patient, an interruption of treatment with givosiran (due to a pregnancy plan) resulted in a stabilization of renal function.Those patients who were followed up for 30 months could be split into the following groups: two patients did not suffer any reduction in the estimated glomerular filtration rate; three patients displayed a modest decline in renal function , soluble guanylyl cyclase (sGC) or other hemeproteins could impact the delicate microcirculatory balances of the kidney. These alterations could be engendered, if not by relative heme depletion, even by hemodynamic rearrangements because of givosiran interrupting the patients’ chronic exposure to high levels of ALA—a molecule with known vasoactive effects which, at least in the mouse brain, was shown to induce all three NOS isoforms .When heme depletion was induced in animal models by administration of succinyl acetone (another inhibitor of ALA dehydrogenase), the activities of renal nitric oxide synthase ,85 and sAdditionally, it should be mentioned that patients treated with givosiran have shown increased homocysteine levels, or a further aggravation of their basal hyperhomocysteinemia , nonetheGiven the effectiveness of givosiran as a treatment for prevention of APAs, it is highly relevant to precisely characterize the adverse events possibly associated with this therapy. Likewise, because of the intrinsic risk factors of patients with AHPs for developing CKD, postmarketing clinical data are probably necessary before giving a definitive answer for a putative additional decline in kidney function under siRNA-based therapy.The clinical manifestations of acute porphyrias are multifaceted and do not limit themselves to acute attacks. In particular, porphyria-associated kidney disease is a long-term, degenerating condition, for which a satisfactory treatment is still not available. A deeper understanding of the mechanisms of kidney damage in AHPs  is cruciIn fact, a baseline evaluation of kidney function should always be included in the diagnostic workup of AHPs, and we strongly recommend a periodic monitoring of the progression of kidney damage in these patients, whether they are under siRNA-based therapy or not.Since acute attacks are the most dramatic manifestation of AHPs, a great deal of the research in this field has focused on the pathogenesis and treatment of neurovisceral damage . In thisIn our opinion, the advent of an effective treatment for acute attacks emphasizes the importance of widening our knowledge on the chronic burden of AHPs, e.g., with additional studies on the several available animal models . FurtherFinally, it should not be overlooked that acute porphyrias represent a paradigm for the study of heme metabolism and its dysfunctions. Further research in the field of kidney damage related to derangements of heme biosynthesis could prove highly valuable in several contexts and pave the way for wider clinical applications.


Background and Purpose: Nocturnal non-dipping blood pressure and heart rate are associated with an increased risk of cardiovascular disease. The effects of such variance on cerebrovascular disease have not been well studied.Methods: The 24-h ambulatory blood pressure (ABPM) and heart rate were monitored with B-pro in patients with acute stroke within the initial week of hospital admission. The risk factor profiles, clinical presentation, imaging, and short-term prognosis were compared in nocturnal dippers and non-dippers  of blood pressure and heart rate.Results: We enrolled 234 patients in whom ABPM and MRI data were available. Heart rate data were available in 180 patients. Lacunar sub-cortical stroke was the most common acute lesion (58.9%), while hypertension (74%) and diabetes (41.5%) were the most common associated risk factors. ABPM revealed non-dipping in 69% of patients. On univariate analysis, Small Vessel Disease (SVD) was significantly more frequent in non-dippers vs. dippers . Silent strokes were also more frequent in non-dippers vs. dippers . Multivariate analysis revealed SVD to be significantly related to age, hypertension, blood pressure non-dipping, and severity of symptoms at index event.Conclusions: The presence of nocturnal non-dipping of blood pressure and heart rate are associated with an increased risk of silent stroke and SVD. Increased use of ABPM may allow for improved diagnosis of non-dippers. In 1988 O'Brian et al. reported in a study of 102 hypertensive patients that non-dippers (17% of enrolled subjects) were at a higher risk of stroke during follow-up . AlthougWhite matter hyperdensities and small vessel disease (SVD) increase with age and are increasingly being recognized in patients with hypertension and other vascular risk factors. The presence of SVD increases the risk of stroke, CAD, cognitive dysfunction and dementia, and mortality . SeveralWe have previously reported on the high incidence of SVD in multi-ethnic patients with acute stroke from Qatar. SVD was evident in 65% of subjects, with an even higher prevalence noted in patients with preexisting hypertension and diabetes . AmbulatIn this study, we report on the effects of nocturnal non-dipping of blood pressure and heart rate on the frequency of SVD in acute stroke patients. We studied the 24-h ambulatory blood pressure (ABPM) and heart rate in acute stroke patients in whom MRI scans were performed during admission. Our primary objective was to determine the frequency of non-dippers and quantify the severity of SVD in dippers vs. non-dippers. We also examined the association of SVD in non-dippers on the severity of symptoms at presentation and the 90-day prognosis.The study was approved by the Institutional Review Board at Hamad Medical Corporation . All acute stroke patients admitted to the Hamad General Hospital (HGH) from September 2018 to October 2020, were approached for the study. Following consent, the measurement of the ambulatory pressure was completed in most patient during the admission, usually during day 2–7 of the admission. The MRI was completed within 2–4 days of the admission. For the current study, we only included patients in whom ABPM and MRI were completed during the admission. The clinical data, laboratory investigations, and imaging information were collected prospectively and entered into the case record forms (CRFs).The clinical information was collected on all consented patients admitted to the HGH including prehospital modified Rankin Scale (mRS), risk factors for stroke, mode of presentation, the severity of symptoms , evaluation and investigations in the emergency department, complications in hospital, final diagnosis and prognosis at discharge and mRS following discharge at 90 days. The information was collected in a database. The details of the database have previously been described , 14.Cardiovascular risk factors were ascertained through direct examination and interviews conducted by trained clinical nurse specialists. Diabetes mellitus was defined by the current use of insulin or hypoglycemic agents or admission HbA1c more than 7.0%. Hypercholesterolemia was defined as a total serum cholesterol >5.2 mmolL, or the use of lipid-lowering medications. Body mass index was calculated using height and weight (kg/m2). Hospital admission systolic BP (SBP) and diastolic BP (DBP) were measured on the non-dominant arm in a lying position, using a sphygmomanometer calibrated against a reference mercury sphygmomanometer and with an arm cuff of appropriate size. BPs were recorded twice with a 5-min interval, and the average of the two recordings was used. Hypertension was defined as office SBP >140 mmHg or DBP >90 mmHg (mean of two readings), or prior antihypertensive medication use. We also included patients with no previous history of hypertension in whom the diagnosis was entertained when the blood pressure reading was consistently more than SEP >140 or DBP >90 during multiple readings during the admission.® HealthSTATS International, Singapore, Singapore) on the non-dominant arm. The methods of ambulatory BP monitoring with B-Pro have been compared to standard arm cuff devices with comparable results (Ambulatory blood pressure monitoring (ABPM) was performed with B-Pro  is urements . The B-Purements , 18. We The heart rate data was obtained from the B-pro monitors and was available for 180 of the patients. We used the methods as defined by Ogoyama et al.  for calcBrain images were obtained on a Siemens 3T MRI. The details of the methodology have been previously published in a report from Qatar in a similar population . Brieflyt-tests for continuous variables and chi-square tests for categorical variables were performed between the groups  and (SVD Absent vs. SVD present). Multivariable logistic regression analyses were used to evaluate the association of ABM measures with subclinical cerebrovascular disease. Multivariable models were adjusted for the factors associated with subclinical cerebrovascular disease at the P < 0.05 level in the univariable analyses of ABPM and brain MRI abnormalities patients. Odds ratios and 95% confidence interval were reported. ROC curve with c-statistics was presented to see the model accuracy for SVD. A p < 0.05 (two-tailed) was considered statistical significant level. SPSS 21·0 statistical package was used for the analysis.Descriptive results for all continuous variables were reported as mean ± standard deviation and numbers (percentage) for categorical variables. Median and Inter Quartile Range (IQR) were calculated for NIHSS score. Student There were 234 patients in whom ABPM was completed and MRI data was available. The 24-h pulse reading was available in 180 patients. In the remainder of subjects, the pulse recordings were not of sufficient quality to have an accurate determination of the daytime and nighttime measurements accurately and were therefore not utilized for further analysis.The demographics, risk factors, current medications at the time of admission, clinical diagnosis, and the severity of stroke symptoms are shown in p = 0.02). The differences in the severity of SVD changes were most evident in the brainstem region (19.8 vs. 8.3% p = 0.02). Periventricular changes were marginally higher in non-dippers (81.5 vs. 70.8% p = 0.069). Silent infarctions were significantly more frequently seen in non-dippers compared to dippers (40.7% vs. 26.4% P = 0.03). CMBs were also marginally increased in non-dippers but did not reach significance. In all, CMBs were evident in 21.4% of patients (non-dippers 23.5% and dippers 16.7% P = 0.24). Patients with nocturnal pulse dipping were also more likely to have significantly fewer silent strokes and small vessel disease as shown in Small vessel disease was evident in 121 of 234 (51.7%) patients as shown in p = 0.002), non-dippers , and NIHSS on admission  were found significantly associated with SVD.p = 0.003) and hypertensive on admission  were found significantly associated with SVD  and begins to rise in the morning as the person awakens (morning surge) . The revA recent meta-analysis reported on short and long-term prognosis following acute stroke and the use of ABPM. Higher blood pressures during the day or night were a marker of poor outcome whereas nocturnal dipping was associated with a good prognosis . The preSurprisingly, nocturnal heart rate non-dipping has received limited attention 40). It is associated with an increase in cardiovascular disease  and, inc. It is aOur study has limitations. The number of patients with ABPM was small and the 24-h heart rate measurements were available in an even smaller number of patients. A larger series of patients may have allowed for better characterization of trends noted in some additional variables. The patients in our series were young, and the majority had acute lacunar strokes with mild symptoms. This may not be representative of stroke in Western countries and the results cannot be generalizable. Other reports of ABPM within 24–48 h of an acute stroke have also shown the importance of nocturnal non-dipping and prognosis , 41. AnoIn summary, we present the 24-h ABPM, heart rate, and MRI findings in a series of patients with acute stroke. Our study shows that hypertension and nocturnal non-dipping of blood pressure and heart rate is associated with an increase in silent stroke and SVD in patients presenting with an acute stroke. We also show that patients with pre-existing silent SVD present with more severe symptoms. The lack of long-term follow-up in our study is a limitation but several previous studies suggest that non-dipping may be associated with slower recovery and a higher risk of recurrent strokes . There iThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by IRB of Hamad Medical Corporation. The patients/participants provided their written informed consent to participate in this study.NA and AS: concept, design, and draft. NA, BB, DM, SJ, RF, and MA: acquisition, analysis, interpretation of data, technical, and administrative support. SK, SA-J, and AS: critical review. RS and NA: statistical analysis. All authors contributed equally to the manuscript.The authors received funding for this study from the Hamad Medical Corporation to cover manpower and from Weil Cornell College of Medicine-Qatar for procedures and publications.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


A clear pathogenetic association exists between obesity and arterial hypertension, becoming even more evident in subjects with severe obesity. Bariatric surgery has proved to be the most effective treatment for severe obesity, with its benefits going beyond weight loss. The present review aimed to determine the effects of bariatric surgery on arterial hypertension evident in short- and long-term follow-ups. Moreover, the differences between surgical techniques regarding hypertension remission are described as well as the possible pathophysiologic mechanisms involved. In addition, the effects of bariatric surgery beyond blood pressure normalization are also analyzed, including those on target organs and cardiovascular morbidity and mortality. Hypertension (HTN) is one of the best known and most widely studied cardiovascular risk factors, and a close correlation between obesity and HTN has been extensively demonstrated . Thus, HConventional medical treatment for morbid obesity has previously achieved mild outcomes, which are probably related to limited long-term adherence to lifestyle modifications in some patients . By contIn this respect, owing to the widely known systematic review published by Buchwald et al.  in 2004,2. Subjects were randomized to GB plus medical therapy or medical therapy alone. The primary endpoint  occurred more frequently in the GB group (83.7%) compared to the control group (12.8%). Moreover, HTN remission 1 year after surgery, defined as systolic and diastolic blood pressure < 140 and 90 mmHg, respectively, with previous withdrawal of all medication, occurred in approximately one-half of the patients in the GB group and none in the conventional treatment group. It is noteworthy that the HTN remission rate after BS obtained in the GATEWAY trial [HTN remission in the short term <3 years) after BS has been widely analyzed in observational studies, some meta-analyses, and a few randomized controlled trials (RCT) ,6,7,8,9.AY trial  was loweAY trial ,6,9, inc years afLess evidence exists on the mid- (3–5 years) and long-term (>5 years) effects of BS on HTN remission compared to other obesity comorbidities such as type 2 diabetes, and this evidence is mainly available from observational studies ,12.The results obtained in the mid- and long-term after BS were more modest compared to those achieved with a shorter-term follow-up. Regarding this, our group had previously evaluated HTN remission after BS with a 36-month follow-up, observing that 68.1% of hypertensive patients showed HTN remission 1 year after the surgical procedure, 21.9% of whom had relapsed at 3 years [p = 0.06).However, BS still presents more beneficial outcomes in the mid- and long-term follow-up compared to conventional treatment. In this respect, various RCT ,14,15 cop < 0.001), with these results being in line with other previous studies [The superior results obtained with a surgical approach compared to lifestyle modifications have also been further confirmed with a longer-term follow-up. In this respect, the Swedish Obese Subjects cohort  observed studies ,16.p < 0.00001) and 46 reported HTN resolution .Systematic reviews and meta-analyses also confirmed the superiority of BS, which was previously observed with a short-term follow-up. In this respect, Vest et al.  in 2012 However, although studies with a longer follow-up confirmed the beneficial outcomes after BS in comparison to conventional treatment regarding HTN evolution, an RCT specifically focused on evaluating HTN remission at mid- and long-term after BS is lacking. Moreover, the possible differences among the most used surgical procedures  must not be ignored, as detailed below.Considering the different BS procedures, GB has been considered, until recently, the gold standard technique owing to its favorable results in both weight loss and comorbidity remission . HoweverIn order to shed light on the effects of both BS techniques, our group carried out a meta-analysis to evaluate 1 and 5-year HTN remission after both procedures . Thirty-Thus, although some studies obtained more promising results regarding HTN remission after GB compared to LSG, the superiority of GB must be further confirmed with longer-term follow-up (>5 years).Owing to the favorable results (which go beyond weight loss) of BS in obese subjects, the concept of metabolic surgery has gained importance in recent years , with th2 for comorbidity improvement, which was addressed in previous observational publications mainly aimed at glycemic improvement after surgery but also at achieving hopeful results regarding HTN remission [This fact has opened debate on whether BS should be indicated in patients with body mass index < 35 kg/memission ,25.2  and glucagon-like peptide-1 (GLP-1) could also play an important part due to their effects on the gastrointestinal system together with a diuretic and natriuretic effect on the kidney . FurtherFurthermore, adipokines and other inflammatory cytokines also appear to be related to HTN recovery. In this respect, previous studies observed a decline in leptin levels from 1 week up to 1 year after BS together with increasing adiponectin concentrations . MoreoveFinally, the resolution of other obesity comorbidities (which share pathophysiologic mechanisms with HTN) such as obstructive sleep apnea could also play a part in blood pressure improvement ,41.The underlying mechanisms related to the possible superiority of GB over LSG are also worth mentioning. The main accepted hypothesis is that these differences could be explained by the superior weight loss after GB in the mid- and long-term follow-up. As mentioned previously, the possible role of gastrointestinal hormones in HTN improvement after surgery gains value, as some studies observed a decrease in blood pressure levels within the first week post-BS and when weight loss was minimal . In thisPatients with morbid obesity have a higher prevalence of target organ damage than patients of normal weight, and HTN is clearly related to its development. These target organ alterations mostly refer to changes in heart, vessels, and kidney structure and function .2 higher body mass index is associated with an increased risk of aortic stenosis, heart failure, deep venous thrombosis, HTN, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism (estimates in the range of 6–13% higher risk). The findings for fat mass were broadly consistent. Specifically, the link between obesity and heart failure is known to be stronger than those for other cardiovascular disease subtypes and is uniquely unexplained by traditional risk factors [Regarding cardiac changes, several works reported echocardiographic alterations, both morphologic and functional, in obese patients ,46. The  factors . However factors .In relation to the mechanisms responsible for cardiac improvement after BS, several authors concur in that the effects of weight-loss surgery on cardiac function and morphology are either hormonally or centrally regulated, probably with an important role for leptin and other adipokines , as wellImportantly, these cardiovascular structure and function alterations have also proved to be reversible with weight loss strategies such as BS, resulting in lowered cardiovascular risk . The effOne of the main manifestations of vessel alteration is the development of arterial stiffness (AS). It is considered to be an independent cardiovascular risk factor  and is dRegarding the effect of BS on AS, several studies reported a significant decrease in both PWV and the augmentation index, another marker of AS, several months after BS ,64,65. TObesity is an independent risk factor for kidney disease, regardless of diabetes and HTN, both of which are driven largely by obesity . Hyperfi2, and albuminuria, biomarkers of kidney function and damage, respectively, characterize renal alterations in obese patients.Obesity also favors a deleterious adipocytokine pattern ,69 chara2, where the GFR was measured by the gold standard method, but these are not accurate in obesity classes II and III [2 since, after BS, patients lose not only fat but also muscle mass, which generates creatinine [The gold-standard method to assess the GFR is measurement of the renal clearance of an exogenous filtration tracer ; however, most studies use GFR (eGFR) estimations derived from prediction equations. These equations were obtained by regression analyses in various populations with body mass index < 30 kg/m and III . Thus, ieatinine . Furthereatinine . Cystatieatinine .p = 0.008) after surgery when analyzed as a dichotomous variable as well as statistically significant decreases. Moreover, drops were observed in the incidences of albuminuria and proteinuria after BS of 58% and 69%, respectively (p < 0.0001 for both). Data on the 4047 patients included in the Swedish Obese Subjects study [p < 0.001). Similarly, O’Brien et al. [Overall, patients with complicated obesity will likely benefit from the weight loss after BS . Li et ats study , comparin et al.  in a retn et al.  analyzedAs regards renal protective factors, Favre et al.  reportedThe mechanisms behind the improvement in risk factors following BS are not well understood. Glomerular function may be related to restoration in homeostasis of the renin–angiotensin system through better renal perfusion and to the restitution of normal insulin signaling in glomerular podocytes and attenuation of hyperfiltration. Additionally, this improvement may also be secondary to reductions in the pro-inflammatory state related to obesity  as measuObese patients who undergo BS may also experience some renal complications. Lieske et al.  reportedp = 0.002) during a median follow-up of 14.7 years. In that same cohort, the number of total fatal or non-fatal cardiovascular events  was also lower in patients undergoing BS. Other studies yielded similar results, thereby confirming the beneficial effects of BS on cardiovascular morbidity and mortality [Moving a step forward, the next question to answer is: what is the real impact of HTN improvement after BS in terms of cardiovascular morbidity and mortality reduction? It has previously been reported that BS reduces the number of cardiovascular events and mortality rates in patients with morbid obesity. For instance, the Swedish Obese Subjects Study Group  observedortality ,81.Although the observed reduction in cardiovascular disease prevalence after BS is probably multifactorial, it can be assumed that HTN improvement probably plays a key role, although this remains to be confirmed. In fact, the Swedish Cohort  failed tHowever, the possible “obesity paradox” must also be acknowledged. This refers to a more favorable evolution regarding cardiovascular or renal outcomes in patients with a higher body mass index. This possible paradoxical effect observed in some studies could be explained by increased tumor necrosis factor (TNF-α) receptors in adipose tissue or an earlier diagnosis of cardiovascular events in the obese population, among others. Despite this, the underlying mechanisms of this possible paradox in obese population are still being investigated in order to achieve more solid conclusions .BS has proved to be a highly effective treatment for obesity-associated HTN, achieving HTN remission in more than half of patients. However, a greater need for antihypertensive medication prior to BS and less weight loss during follow-up are both factors that may hinder the achievement of complete HTN remission.Moreover, a decline in cardiovascular morbidity and mortality has also been observed after BS in morbidly obese subjects. These favorable results regarding cardiovascular outcomes may be mediated by multiple mechanisms that go beyond weight loss, one of which may be improved blood pressure levels together with a decline in target organ damage. However, future studies are required in this field for more solid conclusions to be drawn.