Individuals suffering from depressive disorders display a greater incidence of hypertension compared with the general population, despite reports of the association between depression and hypotension. This phenomenon may depend, at least in part, on the use of antidepressant drugs, which may influence blood pressure through different effects on adrenergic and serotoninergic pathways, as well as on histaminergic, dopaminergic, and cholinergic systems. This review summarizes extant literature on the effect of antidepressant drugs on blood pressure. Selective serotonin reuptake inhibitors are characterized by limited effects on autonomic system activity and a lower impact on blood pressure. Thus, they represent the safest class—particularly among elderly and cardiovascular patients. Serotonin–norepinephrine reuptake inhibitors, particularly venlafaxine, carry a greater risk of hypertension, possibly related to greater effects on the sympathetic nervous system. The norepinephrine reuptake inhibitor reboxetine is considered a safe option because of its neutral effects on blood pressure in long-term studies, even if both hypotensive and hypertensive effects are reported. The dopamine–norepinephrine reuptake inhibitor bupropion can lead to blood pressure increases, usually at high doses, but may also cause orthostatic hypotension, especially in patients with cardiovascular diseases. The norepinephrine–serotonin modulators, mirtazapine and mianserin, have minimal effects on blood pressure but may rarely lead to orthostatic hypotension and falls. These adverse effects are also observed with the serotonin-reuptake modulators, nefazodone and trazodone, but seldomly with vortioxetine and vilazodone. Agomelatine, the only melatonergic antidepressant drug, may also have limited effects on blood pressure. Tricyclic antidepressants have been associated with increases in blood pressure, as well as orthostatic hypotension, particularly imipramine. Oral monoamine–oxidase inhibitors, less frequently skin patch formulations, have been associated with orthostatic hypotension or, conversely, with hypertensive crisis due to ingestion of tyramine-containing food . Lastly, a hypertensive crisis may complicate antidepressant treatment as a part of the serotonin syndrome, also including neuromuscular, cognitive, and autonomic dysfunctions. Clinicians treating depressive patients should carefully consider their blood pressure status and cardiovascular comorbidities because of the effects of antidepressant drugs on blood pressure profiles and potential interactions with antihypertensive treatments. The World Mental Health Survey estimates that depression affects 322 million people worldwide with an overall prevalence of 4.4% while being higher in older age groups with more than 7.5% in females and 5.5% in males aged 55–75 years . DepressDepressed patients display a higher incidence of hypertension compared with the general population , 4. The The increase in blood pressure (BP) among depressed individuals may involve several mechanisms, including endothelial dysfunction, low-grade inflammation, hypercoagulation –11, alteGiven these premises, this review aims to discuss the effects on BP associated with antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), selective norepinephrine reuptake inhibitors, dopamine (DA)–norepinephrine reuptake inhibitors, norepinephrine–serotonin modulators, serotonin agonist/antagonist-reuptake inhibitors, tricyclic and tetracyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs), underscoring their pharmacological properties and how this information can be used in clinical practice.An extensive review of English language literature was performed to identify all relevant articles describing the BP changes induced by antidepressant drugs. We searched PubMed, EMBASETM, CINHAL, Web of Science, and Cochrane databases for relevant articles. Related search terms were used as follows:  OR (“antidepressant drugs” [Mesh]) OR (“orthostatic hypotension” [Mesh]) OR  OR (“major depression” [Mesh]) OR (“depressive disorders” [Mesh]) OR (“serotoninergic syndrome” [Mesh]) OR (“cheese reaction” [Mesh]) AND (“antihypertensive agents” [Mesh]) . Medicalvia a direct arterial constriction but also include different responses depending on the type of vascular bed and on the activation of 5-HT receptor subtypes. Vasoconstriction mainly relates to 5-HT2A and 5-HT1B/1D receptor activation  plays a major role in the pathogenesis of depressive disorders through its action on the central nervous system, whereas it also influences the peripheral cardiovascular system. 5-HT can act on multiple pathways, including the central and peripheral autonomic nervous systems, kidney sodium and water balance, and adrenal gland hormone secretion, all of which are involved in short- and long-term BP control. 5-HT effects on BP are various and start tivation . The efftivation . 5-HT altivation . 5-HT altivation . Both 5- release , but it ll in BP . NE is all in BP , whereasll in BP . NE can ll in BP . In factll in BP . DA affell in BP . At highIn the last decade, depression has been considered a risk factor for cardiovascular disease, independent of traditional risk factors , 30. MajSeveral pathogenetic mechanisms involved in BP regulation and the targets of effective and commonly prescribed antihypertensive drugs can be involved in the rise or reduction in depressive symptoms . HistoriSSRIs are most frequently used as first-line treatment of major depression  58). Th. Th58). 1A, thus facilitating 5-HT release , thereby enhancing and prolonging serotonergic neurotransmission. Other effects of SSRIs are related to presynaptic serotonin (5-HT) receptor desensitization, especially 5-HT release . Free ci release . Sertral release . Another release  12). Ca. Ca1A, t release . Because release . In animll in BP , 62. ThiChronic treatment with citalopram and escitalopram, its therapeutically active S-enantiomer, did not change systolic and diastolic BP levels  nor HR neither QT interval length in two studies on elderly depressed patients, with and without coronary artery disease , 74. In 2C receptors, which could lead to increases in both NE and DA neurotransmissions. A modest reduction in sitting and standing systolic (−2.9 and −2.6 mmHg) and diastolic BP (−2.3 and −1.5 mmHg) was observed after short periods (12 weeks) of treatment with fluoxetine in major depressive patients normotensive and hypertensive. A diversified pattern between hypertensive and normotensive subgroups was reported with hypertensive (diastolic BP between 90 and 95 mmHg) patients showing a larger BP reduction (−4.3 and −5.6 mmHg sitting and standing systolic BP and −4.8 and −3.9 mmHg for diastolic BP) than in normotensive with pretreatment diastolic BP values between 60 and 90 mmHg (−4.3 and −5.6 mmHg sitting and standing systolic BP and −4.8 and −3.9 mmHg for diastolic BP). The normotensive subjects with pretreatment diastolic BP < 60 mmHg had a modest increase in BP levels instead , and sedation and intubation in case of severe muscle rigidity and hyperthermia . A . A 2C re instead . This cleceptors  and indueceptors , 92, 93.eceptors . TreatmeSNRIs include venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran . The firVenlafaxine is indicated as a treatment for major depressive disease, generalized anxiety disorder, panic disorder, and social anxiety disease. Its half-life is 5 h, but its major and effective metabolite (O-desmethylvenlafaxine) has an 11-h half-life . This meDuloxetine is prescribed for major depressive disorder as well as diabetic peripheral neuropathic pain, chronic musculoskeletal pain, and fibromyalgia . DuloxetA recent review shows a low risk for venlafaxine to induce a rise in BP, and, on the contrary, a decreased or neutral effect of this drug on BP was reported more frequently . AnotherMilnacipran is prescribed not only for major depressive disease but also for fibromyalgia, and it can be an effective treatment for chronic fatigue syndrome and anxiety  129). L. L129). Reboxetine is prescribed for major depressive disease, dysthymia, and attention-deficit/hyperactivity disorder, with better tolerability than TCA  142). I. I142). In fact, according to the UK Medicines and Healthcare Products Regulatory Agency and the European Medicines Agency, both hypotension and hypertension have been reported as common undesirable effects observed in post-marketing data Atomoxetine is a selective inhibitor of NET and is prescribed in clinical practice for attention-deficit/hyperactivity disorder and in neurogenic orthostatic hypotension of multisystemic atrophy because of its ability to increase BP .Bupropion is a unicyclic aminoketone drug that enhances the release of NE and DA through NET and DAT inhibition. It is used to treat major depressive disease and for smoking cessation because of its activity as a non-competitive antagonist of nicotinic acetylcholine receptors. Because of renal and hepatic elimination, low doses should be used in patients with renal or hepatic failure . Elevate2A, 5-HT2C, 5-HT3, histamine-H1, and H2 receptor antagonist. It should be prescribed with caution in case of renal, cardiac, and hepatic impairments . B. B2A, 5-airments . Althougairments , there aairments , 164. Itairments . Mianserairments , even ifairments , 167. Orairments , in contairments  169)..2A, 5-HT2A receptor antagonism and on SERT inhibition . I. I2A recic drive .2A receptor antagonist but a low H1-histamine receptor and α1-adrenergic antagonist; at high doses, SERT inhibition and 5-HT2C antagonism are the drug's targets . At low doses, trazodone acts mainly as a potent 5-HT targets , 171. Ca targets . Orthost targets , 174. Se targets  175)..2A recep3, 5-HT7, and 5-HT1D receptor antagonist, a 5-HT1B partial agonist, a 5-HT1A receptor full agonist, and a SERT inhibitor. Vilazodone, another antidepressant launched 7 years ago, is a 5-HT1A partial agonist and a SERT inhibitor; it is indicated for major depressive disorders, anxiety disorder, and obsessive–compulsive disorder ..2B/5-HT22, and M1-cholinergic receptor antagonists), a wide spectrum of adverse effects can complicate their use. Tricyclic compounds include imipramine, amitriptyline, clomipramine, doxepin, trimipramine, desipramine, nortriptyline, and protriptyline . In. In2, aniptyline   –200, amiThe use of iproniazid, a non-selective, irreversible MAOI, originally prescribed for tuberculosis but found to have strong antidepressant effects, opened wide the clinical use for this class of drugs, suggesting that monoamine neurotransmission deficiencies play a central role in the development of major depression . TranylcTranylcypromine and phenelzine are non-selective irreversible MAOI, with hepatic metabolism and renal excretion . Tranylcvia patch because of limited clinical and experimental experience  for Parkinson's disease and higher doses as antidepressant treatment  55). Th. Th55). perience  226). H. Hvia paperience . No hypeperience . The samperience , suggestMoclobemide is a selective, reversible inhibitor of MAO-A, so the dietary restriction is not required during treatment –230. No This narrative review summarized the available studies on the effects of antidepressants on BP. Antidepressants act on several neurotransmitter systems that have direct or indirect effects on BP regulation. Thus, antidepressant drugs might lead individuals to develop hypertension, hypotension, and orthostatic hypotension through a wide array of mechanisms. Although general considerations can be made on different classes of antidepressants, each compound ultimately shows a very specific profile that should be considered before clinical use. Patient characteristics are another obvious source of variability for the effects of antidepressants on BP. In sum, the neutral effect on BP is a feature of SSRI, and this class represents a safe option for patients with preexisting cardiac disease. The occurrence of orthostatic hypotension should always be considered as a real risk in serotonin agonist/antagonist-reuptake inhibitor-trazodone-prescribed patients, but especially in TCA-prescribed patients, with the highest rate in those receiving imipramine and the lowest with nortriptyline. As with orthostatic hypotension, treatment with SNRI, dopamine–NE reuptake inhibitor, and MAOI should be carefully monitored in patients with preexisting hypertension due to their potential to raise BP and facilitate the incidence of hypertensive crisis. When prescribing an antidepressant, the clinician must carefully evaluate its risk/benefit ratio by taking into account the presence of cardiovascular and cerebrovascular diseases, as well as monitoring the effects of the chosen agents. Consideration must be given that an appropriate treatment for depression can ultimately reduce morbidity and mortality. Finally, SSRIs and other recent antidepressants rarely affect BP in a clinically meaningful way. Nonetheless, careful consideration must be given to patients with preexistent BP abnormalities, the elderly, and to individuals with physical comorbidities. Issues requiring particular attention include potential interactions with antihypertensive agents and factors affecting drug metabolism.ACal, IV, MA, and ACab conceived and designed the review. ACal, IF, IV, MB, PC, ST, MA, and ACab collected the data and contributed to the analysis of literature data. ACal, IF, IV, MB, ST, and ACab performed the analysis of all data. ACal, IV, MB, SZ, RV, PC, MA, and ACab discussion of the results. ACal, IV, MB, and ACab wrote the paper. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


The occurrence of rejection was associated with lower death-censored graft survival . Surveillance biopsies of kidney grafts experiencing DGF remain an essential tool for the care of kidney transplant recipients. The recipient’s age and duration of DGF are independent risk factors for acute rejection, while antibody-induction therapy with ATG is associated with protection from its occurrence.Delayed graft function (DGF) is a common complication of kidney transplantation and frequently leads to the necessity of surveillance biopsies. The purpose of this study is to describe the histological findings in surveillance biopsies of deceased donor kidney transplant recipients and evaluate the risk factors for graft outcomes. This is a monocentric, retrospective study including kidney transplant recipients that underwent a graft biopsy during the DGF period between January 2006 and July 2019. 356 biopsies were performed in 335 deceased donor transplant recipients. Biopsies were analyzed according to the Banff classification. The main histological findings were: acute tubular necrosis in 150 biopsies (42.1%), acute rejection in 96 biopsies (26.9%), and borderline findings in 91 biopsies (25.5%). In the multivariate analysis, recipient age ( Over the last decades, kidney transplantation became an effective lifesaving procedure for a substantial portion of patients with end-stage kidney diseases . BesidesDelayed graft function is currently most frequently characterized by the need for dialysis within the first week after transplantation . It occuDuring DGF graft injuries may go unnoticed due to the absence of graft functional parameters used for their monitoring and currently, the only reliable diagnostic tool in this setting is the graft surveillance biopsy. Moreover, the incidence of acute rejection is substantially higher in kidney grafts undergoing DGF , 14.Current transplant guidelines recommend graft tissue histologic evaluation every 7–10 days until the graft acquires function , 16. HowThe present study aimed to evaluate the utility of surveillance biopsies in uncovering graft injuries, other them those related to ischemia and reperfusion, that would lead to specific treatments, mainly acute cellular rejection and antibody-mediated rejection. We also evaluated the influence of the initial immunosuppressive regimen on the incidence of acute rejection in the surveillance biopsy and patient and graft survivals.The study included all adult kidney transplant recipients who received a deceased donor graft, developed DGF, and underwent a surveillance biopsy between January 2006 and July 2019 at Hospital de Clínicas de Porto Alegre, RS, Brazil. We excluded kidney-pancreas and kidney-liver transplant recipients and kidney transplants performed after another solid-organ transplantation. The study flowchart is shown in During the study period, 1,303 brain dead deceased donor kidney transplants were performed and the vast majority of these organs  were preserved by cold storage. Three hundred and thirty-five patients underwent 356 representative surveillance biopsies and were included in the study. Kidney allograft biopsies were performed at the attending team’s discretion every 7–14 days during DGF. Biopsies occurred under real-time ultrasonography guidance, through a semiautomatic gun with a 16-G biopsy needle. A renal pathologist analyzed slides stained with hematoxylin-eosin, periodic acid shift, and Masson’s trichrome and interpreted them according to the Banff classification in effect at the time of assessment.All patients received corticosteroids, calcineurin inhibitors, and mycophenolate as immunosuppressive therapy. Patients that did not receive antibody induction and patients treated with Basiliximab received immunosuppressive drugs at the usual initial doses. Patients treated with anti-thymocyte globulin (ATG) induction, at standard immunological risk, did not receive calcineurin inhibitors until the graft achieved function. Those at high immunological risk received an initially reduced dose. Cellular rejections were treated with corticosteroid pulses or ATG if scored Banff 2A or higher, antibody-mediated rejections were treated with plasmapheresis and polyclonal IV immunoglobulins. Treatment of patients with borderline findings on the surveillance biopsy was decided by the attending team based on the estimated risk of rejection.Delayed graft function was defined by the requirement of at least one dialysis session during the first week after transplantation , 13. DGFThe study was approved by the Ethics and Research Committee of the Hospital de Clínicas de Porto Alegre approved the study (protocol number 64239617.4.0000.5327). The clinical and research activities being reported are in accordance with the ethical standards of the Declaration Helsinki and Declaration of Istanbul on Organ Trafficking and Transplant Tourism.p-value ≤ 0.2 in the univariable analysis were included in the multivariable analysis model. For the multivariable analysis, prevalence ratios and confidence intervals were estimated by Poison’s regression with robust estimation of variance. We used Kaplan-Meier estimate tests for analyzing patients and grafts survivals and GraphPad Prism for data presentation . A p-value lower than 0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 18.0 software .Data is presented in absolute numbers, percentages, and frequencies. Continuous variables are presented as mean ± standard deviation, compared using ANOVA, with Tukey post hoc test. Categorical variables are presented as frequencies and compared using Chi-square tests. Sixteen variables were included in the risk analysis for acute rejection. Namely, donor and recipient age, donor and recipient ethnicity, recipient gender, donor final serum creatinine >1.5 mg/dl, expanded criteria donor (ECD), previous transplantation, panel reactive antibodies (PRA) > zero, HLA mismatches, DSA, cold ischemia time, vascular anastomosis time, DGF duration (days), positive historic B cell and presence and type of antibody induction . In the univariable analysis, prevalence ratio (PR) and 95% confidence intervals (CI) were calculated and the Chi-square test was used to assess their significance. Variables with a In the study period, 356 representative allograft biopsies were performed in 335 transplant recipients. Data of the recipients, donors, and transplant-related variables are shown in ®) and underwent 157 biopsies, 151 (45.1%) patients received ATG (Thymoglobulin®) and underwent 157 biopsies. Thirty-six patients did not receive antibody induction and underwent 42 biopsies. The most frequent maintenance regimen was tacrolimus, sodium mycophenolate, and steroids in 288 (85.9%) patients.The majority of the patients were male (61.2%), Caucasian (74.9%), and almost half were not HLA sensitized (48.9% zero PRA). All patients received an initial immunosuppressive regimen with steroids, calcineurin inhibitors (tacrolimus or cyclosporine), and anti-proliferative agents  with or without antibody induction. One hundred and forty-eight patients (44.1%) received monoclonal anti-α-chain IL-2 receptor antibodies , vascular anastomosis time (p = 0.0001), DGF duration (p < 0.05), and absence of induction therapy with ATG (p = 0.0001) were associated with acute rejection. These risk factors along with the recipient’s age (p < 0.2) were included in the multivariate analysis model, which showed that the recipient’s age, DGF duration, and absence of induction therapy with ATG were significantly associated with the occurrence of acute rejection (ejection .p = 0.005). For this analysis, we divided patients and biopsies into four groups according to DGF duration. In group 1, with DGF duration up to 7 days, 44 biopsies were performed in 43 patients with eight episodes of rejection identified (18.2%). In group 2, with DGF duration between 8 and 14 days, there were 93 biopsies in 83 patients with 20 rejection episodes (21.5%). In group 3, with DGF duration between 15 and 21 days, there were 76 biopsies in 70 patients with 19 rejection episodes (25.0%) and, in group 4, with DGF duration longer than 21 days, 143 biopsies were performed in 139 patients with 49 episodes of rejection (34.3%) (p = 0.126). However, patients treated with ATG had a significantly lower incidence of acute rejection than those in the other two groups (p = 0.0001).The type of immunosuppressive regimen was associated with the occurrence of acute rejection. In the group of 36 patients who did not receive antibody-induction therapy, acute rejection incidence was 36.1% (13 patients with cellular rejections). In the group of 148 patients treated with Basiliximab, the incidence was 37.8% (56 patients with cellular rejections), and, in the 151 patients who received ATG, an incidence of 17.9% of acute rejection was observed . No difference in acute rejection incidence was observed between patients treated with Baxiliximab and those without antibody-induction therapy (p = 0.001), higher class I PRA , higher class II PRA , higher frequency of re-transplants , and more patients with donor-specific anti-HLA antibodies , respectively for the ATG, Basiliximab and no-induction groups.p = 0.145) nor the use or type of antibody-induction therapy (p = 0.665) were associated with patient survival. Death censored graft survival was significantly lower in the group of patients with acute rejection (log-rank p = 0.009) and was not influenced by the use or type of antibody-induction therapy (log-rank p = 0.177) (Neither acute rejection (= 0.177) .p = 0.003), male gender (p = 0.045), and DGF duration were associated with graft loss. These risk factors along with donor’s ethnicity, cold ischemia time, and acute rejection were included in the multivariate analysis model, which showed that the recipient’s age, recipient’s male gender, DGF duration, and acute rejection were significantly associated with graft loss (p < 0.0095).aft loss . To furtGrafts were lost due to chronic graft failure in 40 cases , immunological causes (acute or chronic rejections) in 12 cases , vascular causes in 6 cases  and recurrent focal and segmental glomerulosclerosis in 1 case.In the present study, we analyzed the histological findings on surveillance graft biopsies of kidney transplant recipients experiencing DGF. The main findings were acute tubular necrosis and a high incidence of other graft injuries occurred, particularly acute cellular rejection and borderline findings. We also found that the occurrence of acute rejection during DGF leads to inferior graft survival.Delayed graft function is a frequent complication of brain-dead deceased donor kidney transplantation and is even more frequent in kidney transplants from donors on circulatory death . Kidney The incidence of DGF is highly variable worldwide. It varies from around one-fourth to approximately two-thirds of kidney transplants from brain-dead deceased donors –29. In BTwo-thirds of the recipients in the present study developed DGF by the definition adopted in the present study. This frequency is similar to the one found in the Brazilian multicenter study  and to pAs expected, the largest percentage of the biopsies obtained during the DGF period presented with a histological diagnosis of acute tubular necrosis. However, Banff grade IA or higher acute rejections occurred in one-fourth of the biopsies. A noteworthy overtime change occurred in the frequency of the histological lesions. The frequency of acute tubular necrosis decreased, and the frequency of rejection increased, reflecting the healing of ischemia and reperfusion injuries partially replaced by alloimmune injury, possibly acting for maintaining graft dysfunction. Vascular anastomosis time was highly significant at the univariate analysis but presented borderline statistical value in the multivariate analysis. In line with our findings, a recent publication by Lim et al. reported an important association between DGF duration and acute rejection. They described that three-quarters of the acute rejection episodes occurred in kidney transplant recipients whose DGF lasted longer than 2 weeks . MoreoveSome controversy remains on whether or not DGF is associated with an increased incidence of acute rejection and reduced graft survival. Such may be due to a lack of homogeneity of the study cohorts and the non-uniform DGF definitions , 14, 17.Perhaps the major hurdle of DGF is the inability to detect or even suspect the occurrence of acute rejection due to the lack of functional parameters usually used to monitor injuries. Importantly, in the absence of accurate non-invasive methods or biomarkers of rejection in this setting, the only reliable tool to uncover alloimmune graft injury is the surveillance graft biopsy.In agreement with previous studies, our results demonstrated that the rejection rate decreases with age supporting the notion that immunosuppressive therapy may be reduced in elderly recipients due to the progressive decline in immune functions, leading to a lower risk of rejection and a higher risk of infectious complications –35.Antibody induction therapy with polyclonal anti-T cell antibodies is often used to prevent acute rejection, particularly in recipients with high immunological risk. In our study, the group of patients who received ATG was at higher immunological risk and, despite this, had a substantially lower incidence of rejection in the surveillance biopsy as compared to patients that received monoclonal anti-IL2 receptor antibodies or patients who did not receive antibody-induction therapy. Recently, Alloway and collaborators reported a reanalysis of the data from prior trials comparing ATG with anti-IL-2 receptor monoclonal antibodies, showing the superiority of such polyclonal antibodies in preventing acute rejection . MoreoveInterestingly a considerably high incidence of histological rejection occurred even in patients considered of lower immunological risk such as patients without anti-HLA sensitization, and patients without anti-donor HLA antibodies, receiving ATG induction and baseline immunosuppressive regimen with steroids, tacrolimus, and sodium mycophenolate. In the group of patients that did not receive antibody induction and in the group that received Basiliximab the incidence of rejection was very high despite the potent association of baseline immunosuppressive agents . These fA study by Hatoum and collaborators evaluated the utility of surveillance allograft biopsies during DGF in patients receiving antibody-induction therapy with ATG or Basiliximab and baseline immunosuppression with steroids, mycophenolate, and tacrolimus. They concluded that rejection episodes during DGF are uncommon and, therefore, the usefulness of serial surveillance biopsies is limited. These results differ from ours in some ways, including a much lower incidence of DGF, the inclusion of kidney recipients of living donors, and a higher proportion of African-American recipients . TherefoIt is conceivable that with a higher incidence of DGF and the use of organs from expanded criteria donors, the incidence of rejection would be higher . ImportaA recent study by Van Loon et al. also revealed a very high incidence of acute rejection in their subset of patients with DGF. In their study, the risk factors for rejection were HLA mismatches and pre-transplant HLA-DSA. The authors found that non-immune risk factors were not strong risk factors for early inflammation . This isThe association between prolonged vascular anastomosis time and DGF is long known and was confirmed in two recent studies , 27. HowThe present work, by selecting only biopsies of patients with DGF, does not allow the analysis of DGF risk factors, particularly cold ischemia time. However, in previous studies, cold ischemia time surfaced as an independent risk factor for acute rejection , 43. We Our study has limitations intrinsic to its retrospective and monocentric design. Early protocol biopsies of function kidney grafts, at a similar time as the surveillance biopsies in DGF, could also reveal unsuspected lesions. We did not analyze the outcomes of patients who had DGF but were not subjected to the surveillance biopsy. Also, caution is needed in the interpretation of the immunosuppressive regimen results due to the non-randomized design. Nevertheless, the timing of the biopsies was dictated by current guidelines and, a considerable incidence of acute cellular rejection occurred during the DGF period indicating that surveillance biopsies are instrumental for the clinical care of kidney transplant recipients.In conclusion, the surveillance biopsy of kidney grafts with DGF remains an essential tool for the clinical care of the kidney transplant recipient. These biopsies are even more important in settings where kidneys from expanded criteria donors and/or high KPDI donors are frequently utilized, with prolonged cold ischemia time and high incidence of DGF.


IntroductionVitamin D deficiency is a rising health issue in patients with chronic kidney disease (CKD). It can lead to serious issues such as rickets, periodontitis, osteoporosis, weakness, muscle ache, and depression. This study was conducted to determine the vitamin D status of patients with CKD in Pakistan and evaluate the correlation between serum vitamin D and renal function progression.MethodologyA retrospective study enrolled patients who visited Liaquat National Hospital, Karachi, Pakistan, from January 2015 to January 2021 with a primary diagnosis of CKD. Anthropometric, laboratory, and demographic data were collected from the hospital management information system (HMIS).ResultsA total of 513 patients with CKD were included in the study. More than 50% of the patients were from stage 3 to stage 5 of CKD while the rest were from stage 1 and stage 2. Significant differences are in relation to calcium, phosphate, and albumin across categories of severity of CKD. Calcium is lowest in stage 5 while phosphate is highest in stage 5. Vitamin D deficiency was found in all participants, but serum vitamin D concentration was lowest in stage 5, i.e., 8.14+6.00. The changing of vitamin D level was associated with the severity of CKD staging .ConclusionThe current study has shown that vitamin D deficiency, calcium deficiency, and hyperphosphatemia are more common in patients with CKD, but their severity is more common in advanced stages of CKD. Chronic kidney disease (CKD) is referred to as kidney damage and reduced renal function that can be categorized into five stages as per the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines . GloballVitamin D deficiency is a rising health issue in patients with CKD . It can In Pakistan, not many studies have been conducted to determine the association between vitamin D deficiency and CKD staging. Therefore, the treatment of CKD patients is often suboptimal or not well-targeted. Along with the deficiency of vitamin D, deficiency of inactive vitamin  is expected. Therefore, treatment needs to include active and nutritional vitamin D. In the case of early CKD, nutritional vitamin D is preferred . StudyinThis was a retrospective study that enrolled patients who visited Liaquat National Hospital, Karachi, Pakistan, from January 2015 to January 2021 with a primary diagnosis of CKD. CKD is defined as abnormalities structure or function of a kidney that has been present for more than three months and has health implications (not graded). Overall, 590 patients visited Liaquat National Hospital, Karachi, Pakistan, from January 2015 to January 2021 with a primary diagnosis of CKD. Fifty-one  did not fulfill the eligibility criteria and data of 26 (4.40%) patients were missing. In total, 513 patients with CKD were included in the study.2 and an albumin-creatinine ratio (ACR) of 30 mg/g or higher [The diagnostic thresholds were kept at an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 mr higher . CKD wasr higher .Patients were not included in the final analysis if they had acute kidney injury . Patients whose important data were missing were also excluded in the final analysis. All the variables were extracted from the hospital management information system (HMIS).2). Laboratory data at baseline included white blood cells (WBCs), hemoglobin, platelets, calcium, phosphate, albumin, cardiac reactive protein (CRP), parathyroid hormones (PTH), serum vitamin D, and creatinine were obtained from HMIS. eGFR was calculated by the CKD Epidemiology Collaboration (CKD-EPI) equation [Anthropometric, laboratory, and demographic data were collected from HMIS by the investigator. Body mass index (BMI) was calculated as body weight (kg)/squared height . Continuous variables were presented as mean and standard deviation while categorical variables were presented as frequency and percentage. The difference in the baseline characteristics of patients in five stages was determined using one-way analysis of variance (ANOVA) for continuous variables and the chi-square test of independence for categorical variables. Median and interquartile ranges were presented for hemoglobin, platelets, calcium, phosphate, albumin, c-reactive protein (CRP), parathyroid hormone (PTH), and their comparison was done in different stages of CKD using the Kruskal-Wallis test. Mean values were presented for vitamin D levels, and their association was seen with independent variables, including age, BMI, CKD, and gender using Pearson's coefficient, one-way ANOVA, and independent t-test as appropriate. Variables significantly associated with vitamin D are used to assess the relationship between CKD staging and vitamin D using multivariable linear regression analysis for controlling confounding variables. The correlation between estimated glomerular filtration rate (eGFR) and vitamin D was assessed using Pearson's correlation. A p-value of less than 0.05 was considered significant.In total, 513 patients with CKD were included in the study. Based on the eGFR values, participants were assigned into five different stages as per the classification criteria discussed in the methodology section. The characteristics of participants by CKD stages are shown in Table Hypertension was the most common comorbidity found among patients in the current study, followed by diabetes. Hypertension and diabetes were present among 80.31% and 70.37% of patients, respectively. The frequency of hypertension and diabetes are significantly higher in advanced stages than in lower stages . The incidence of all other comorbidities is significantly low and no significant difference was found in different stages as shown in Table Table Variables significant in univariate analysis were used to generate the final model using multivariable linear regression analysis. Table CKD has become a major public health issue worldwide, particularly in developing countries. In Pakistan, the prevalence of CKD among adults was 21.2% . Our stuDiabetes and hypertension are common comorbidities among CKD patients in the current study. CKD is a consequence of uncontrolled hypertension and a prevalent cause of hypertension. The hypertension prevalence in CKD patients could rise from 68% to 87%, along with declining eGFR in advanced stages. The study conducted by Wang et al. also reported similar findings in which the prevalence of hypertension in CKD stage 1 patients was 67% compared to the 92% in CKD stage 5 patients . BesidesIn CKD, vitamin D deficiency is frequent, and it is linked to the increasing increase in PTH that occurs as renal function declines. It can also increase cardiovascular risk, mineral bone disease, and hyperparathyroidism . Our stuA weak positive correlation between eGFR and vitamin D was reported in the current study, similar to the study conducted by Wang et al. . It indiIn this study, we have also compared the calcium, phosphate, and albumin levels in five stages of CKD. The findings showed a deficiency of calcium in advanced stages of CKD while phosphorus is in the normal range in stage 1 to stage 4 of CKD. In contrast, stage 5 has a significantly higher serum phosphorus level. Considering the impact of CKD staging on calcium and phosphate, correction of hyperphosphatemia and hypocalcemia should be addressed as a preliminary step. Calcitriol can be used to treat secondary hyperparathyroidism caused by CKD . PTH, asThe current study has certain limitations. First, data related to vitamin medications, vitamin supplements, enteral feeds, and dietary intake related to mineral and bone metabolism of patients were missing, making it difficult to analyze etiologic hypotheses. Second, it was a retrospective study; therefore, we were not able to analyze several other factors as well. Third, it used the data of only one tertiary care hospital. In the future, more prospective multicenter studies need to be conducted with a larger sample size, including inpatients and outpatients, to get more generalizable findings and reduce confounding factors and possible biases. Finally, we were not able to determine the causes of CKD among the patients in the current study.The current study has shown that vitamin D deficiency, calcium deficiency, and hyperphosphatemia are more common in patients with CKD. Still, their severity is more common in advanced stages of CKD. Health care professionals should educate and counsel CKD patients regarding nutritional sources of vitamin D and its monitoring. Primary care physicians are being urged to join nephrologists, endocrinologists, nutritionists, other specialists, and public health agencies in disseminating and implementing updated guidelines and recommendations to combat the growing epidemic of vitamin D deficiency, especially among the highly vulnerable CKD population.


There has recently been considerable interest in better understanding how blood pressure should be managed after an episode of hospitalized AKI, but there are scant data regarding the associations between blood pressure measured after AKI and subsequent adverse outcomes. We hypothesized that among AKI survivors, higher blood pressure measured three months after hospital discharge would be associated with worse outcomes. We also hypothesized these associations between blood pressure and outcomes would be similar among those who survived non-AKI hospitalizations.We quantified how systolic blood pressure (SBP) observed three months after hospital discharge was associated with risks of subsequent hospitalized AKI, loss of kidney function, mortality, and heart failure events among 769 patients in the prospective ASSESS-AKI cohort study who had hospitalized AKI. We repeated this analysis among the 769 matched non-AKI ASSESS-AKI enrollees. We then formally tested for AKI interaction in the full cohort of 1538 patients to determine if these associations differed among those who did and did not experience AKI during the index hospitalization.Among 769 patients with AKI, 42 % had subsequent AKI, 13 % had loss of kidney function, 27 % died, and 18 % had heart failure events. SBP 3 months post-hospitalization did not have a stepwise association with the risk of subsequent AKI, loss of kidney function, mortality, or heart failure events. Among the 769 without AKI, there was also no stepwise association with these risks. In formal interaction testing using the full cohort of 1538 patients, hospitalized AKI did not modify the association between post-discharge SBP and subsequent risks of adverse clinical outcomes.Contrary to our first hypothesis, we did not observe that higher stepwise blood pressure measured three months after hospital discharge with AKI was associated with worse outcomes. Our data were consistent with our second hypothesis that the association between blood pressure measured three months after hospital discharge and outcomes among AKI survivors is similar to that observed among those who survived non-AKI hospitalizations.The online version contains supplementary material available at 10.1186/s12882-021-02480-1. Patients who experience hospitalized AKI are more likely to experience long-term risks of more rapid loss of kidney function measured by estimated glomerular filtration rate (eGFR), subsequent hospitalization for heart failure and all-cause mortality –5. This Optimal BP targets may not be different after a hospitalization with AKI than after a hospitalization without AKI. Recent literature suggests that prognostic factors for adverse outcomes after AKI (such as proteinuria)  and riskMotivated by the lack of data to inform the design of potential post-AKI intervention trials, we analyzed data from a prospective parallel cohort study to test two hypotheses: (i) higher achieved BP measured 3 months after an index hospitalization would associate with subsequent adverse events and (ii) these associations would not be modified by whether or not AKI occurred during that index hospitalization.ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) is a parallel, matched, prospective cohort study of participants with and without AKI during hospitalization at four North American centers between December 2009 and February 2015. Details of the study have been published , 16. BriResting BP was measured for each participant at the 3-month post-hospitalization baseline visit by trained research personnel using an Omron automated oscillometric BP cuff. Three measurements were taken 30 s apart with the participant seated in a chair for 5 min prior to the first measurement. We performed analyses based on the mean of these three measurements.Follow-up continued until death, loss to follow-up, or study end on November 30, 2018. At each contact, the occurrence of any hospitalizations was ascertained by self-report and/or surveillance of electronic medical record systems with validation of clinical outcomes through physician adjudication of medical records as previously described , 16. SubAll covariates were measured at the baseline study visit including self-reported sociodemographic factors, smoking status, body mass index, medication use, and comorbidities. Blood samples were collected to measure SCr at the ASSESS-AKI Central Laboratory at the University of Minnesota using an isotope dilution mass spectrometry (IDMS)-traceable assay. Urine total protein was quantified using a turbidimetric method and urine albumin concentration using a nephelometric method in a central laboratory.For the 769 ASSESS-AKI participants who experienced AKI during the index hospitalization and the 769 participants who did not experience AKI, we built separate cubic polynomial spline models examining the association between systolic BP (SBP) observed 3 months after discharge and risk of subsequent AKI within the framework of proportional hazards regression models. We adjusted these models for center, age, gender, race, smoking status, history of myocardial infarction or revascularization, diabetes mellitus, heart failure, and 3-month baseline visit CKD-EPI eGFR, body mass index, urine protein:creatinine ratio, use of diuretics, blockers of the renin-angiotensin system, statins, beta blockers and calcium channel blockers. For each model, we constructed two cubic polynomial curves of the SBP that connected at the knot point of 120 mmHg. We imposed the conditions that the two splines, along with their first two derivatives, were continuous at the knot point for the sake of rendering a smooth curve. The same models were then used to examine association between SBP and risks of loss of kidney function, all-cause mortality, and hospitalization for heart failure. In addition, to illustrate an example of the relative hazards at a particular BP, we reported the model-based estimate of the hazard ratio, along with its confidence interval, for SBP 140 mmHg compared to SBP 120 mmHg. We selected 140 mmHg vs. 120 mmHg since these SBP targets might be considered for a future trial of blood pressure control among AKI survivors, and these were the SBP targets in the SPRINT trial  that fouTo formally test for interaction of AKI status during the index hospitalization on the shape of the spline curves for SBP and outcomes, we constructed interaction terms between AKI status and each component of the cubic polynomial spline in a model containing the full cohort of all 1538 patients. We then applied approximate t tests with the resultant partial maximum likelihood estimates of the interaction terms to assess their statistical significance.In secondary analyses, we examined the mean of the three baseline visit diastolic BP (DBP) measurements with the knot point of 80 mmHg. We also examined alternative definitions for subsequent hospitalized AKI episode with (1) AKI defined as a ≥ 50 % relative increase from the most recent outpatient study visit SCr (done within one year) to the peak inpatient SCr and (2) AKI defined as a≥ 50 % relative increase or ≥ 0.3 mg/dL absolute increase from the most recent outpatient study visit SCr to the peak inpatient SCr .Less than 0.5 % of data on covariates was missing. We performed a complete case analysis, excluding 27 participants with AKI during the index hospitalization and 20 participants without AKI during index hospitalization .The cohort of 1538 eligible adult participants included 769 who had AKI and a matched 769 who did not have AKI during their index hospitalization  and 27 % died. 18 % had heart failure events. Achieved SBP 3 months after hospitalization did not have a stepwise association with any of the four adverse outcomes examined Figs. . For subDuring follow-up among the 769 patients without AKI during the index hospitalization, 26 % experienced subsequent AKI, 5 % experienced loss of kidney function, 15 % died, and 10 % had heart failure events. In this group, achieved SBP 3 months after hospitalization also did not have a stepwise association with any of the four adverse outcomes examined Figs. . For subp = 0.27), loss of kidney function (p = 0.26), mortality (p = 0.55), or heart failure events (p = 0.52).Graphs of the adjusted hazard ratios for each outcome by continuous SBP were similar in patients with and without AKI during the index hospitalization Figs. , 3 and 4In adjusted analysis, achieved DBP 3 months post-hospitalization also had no stepwise association with of any of the four adverse outcomes examined . We obseWhen we repeated the analysis using alternative subsequent AKI definitions of (1) a 50 % relative increase or (2) either a 0.3 mg/dL absolute increase or 50 % relative increase from the most recent outpatient SCr to the peak SCr during a hospitalization, the incidences of AKI were 24 and 34 % respectively . Similar to the main analysis, lower achieved SBP 3-month post-hospitalization was not associated with stepwise higher risk of subsequent AKI . No effea priori hypothesis, we found that achieved SBP 3 months after hospitalization did not have a stepwise association with any of the four adverse outcomes examined among AKI survivors. This was true in particular within the range of SBP 110–150 mmHg, where targets for interventional trials would almost certainly be set. Associations between 3-month post-hospitalization SBP and subsequent risks of hospitalized AKI, loss of kidney function, all-cause mortality, and adjudicated heart failure events were similar in participants with and without AKI during the index hospitalization, confirming our second a priori hypothesis.In this prospective observational study of ASSESS-AKI participants, in contrast to our first Our results are not consistent with what one would expect based on the landmark SPRINT trial, which found that targeting a SBP of < 120 mmHg lowered all-cause mortality and major cardiovascular events compared with targeting a SBP of < 140 mmHg . In contAn important strength of this analysis is that it is the first and only one to our knowledge to explore how observed blood pressure measured systematically after discharge from hospitalizations complicated by AKI relates to subsequent adverse outcomes. To strengthen the rigor of our study, we analyzed information collected systematically as part of a structured research protocol, rather than relying on data collected as part of routine clinical care, thus reducing potential ascertainment bias and missing data. We evaluated three definitions of subsequent AKI and results were consistent across all definitions. We were able to systematically account for key covariates such as amount of proteinuria and eGFR—both quantified at a uniform time point relative to BP ascertainment and to the AKI episode for better control of confounding. We also had long-term follow-up for clinical outcomes (mean follow-up 4.6 years), comparable with large trials of BP targets. The ability to compare the association between BP and adverse outcomes in those who did and did not experience AKI during the index admission is another novel aspect of this work.Our study had several limitations. First, this was an observational study of achieved BP without any defined targets. Thus, in some instances, we compared outcomes of patients who were treated with antihypertensive medications to achieve a certain blood pressure with outcomes of patients who achieved the same blood pressure without medication . Although our model includes antihypertensive medication classes, we did not account for dosing differences and residual confounding is possible. We defined BP at a single point in time  and BP may have changed during follow-up. However, this approach has been commonly used in observational studies associating BP with clinical outcomes –23. WhilIn conclusion, in this prospective cohort study, AKI (predominantly stage 1 AKI) was not an effect modifier of the associations between BP and adverse outcomes after hospitalization. Furthermore, there was not a strong stepwise association between BP and subsequent adverse outcomes among AKI survivors.The opinions expressed in this article are the authors’ own and do not reflect the view of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, the Department of Health and Human Services, or the United States Government.Additional file 1.


Chronic kidney disease (CKD) is associated with higher risk of cardiovascular disease-related ischemic events, which includes peripheral arterial disease (PAD). PAD is a strong predictor of future cardiovascular events, which can cause significant morbidity and mortality. Resistin has been found to be involved in pathological processes leading to CVD. Therefore, we aim to investigate whether resistin level is correlated with PAD in patients with non-dialysis CKD stage 3 to 5. There were 240 CKD patients enrolled in this study. Ankle-brachial index (ABI) values were measured using the automated oscillometric method. An ABI value < 0.9 defined the low ABI group. Serum levels of human resistin were determined using a commercially available enzyme immunoassay. Thirty CKD patients (12.5%) were included in the low ABI group. Patients in the low ABI group were older and had higher resistin levels as well as higher diabetes mellitus, hypertension and habit of smoking, and lower estimated glomerular filtration rate than patients in the normal ABI group. After the adjustment for factors that were significantly associated with PAD by multivariate logistic regression analysis, age and serum resistin level were independent predictors of PAD. A high serum resistin level is an independent predictor of PAD in non-dialysis CKD stage 3 to 5. Importa2 2% had six2 2% had six m2 (4%) ,6.PAD is recognized as peripheral arteries obstruction due to atherosclerosis, which is highly prevalent in patients with CKD ,6. SymptResistin is a cysteine-rich peptide consisting of 108 amino acid sequences. Resistin is involved in different metabolic processes, acting as a proinflammatory factor, resulting in production of inflammatory cytokines and increased expressions of cell adhesion molecules . RecombiA total of 240 non-dialysis CKD stage 3 to 5 were recruited from a medical center in Hualien, Taiwan. The recruitment occurred between January 2020 and August 2020. Blood pressure (BP) measurements were obtained in the morning, after at least 10 min of rest and measurements were obtained by a trained staff, using an appropriately sized standard mercury sphygmomanometer. The average of 3 serial measurements taken 5 min apart was used. Patients were classified as hypertensive if their blood pressure recording ≥140/90 mmHg or had been treated with one or more antihypertensive agents in the past 2 weeks. Patient with diabetes mellitus (DM) were defined as fasting plasma glucose ≥126 mg/dL or had received one or more oral antihyperglycemic drugs or insulin. This study was approved by the Institutional Review Board of Tzu Chi Hospital (IRB108-219-A). All the patients provided written informed consent before participation. Exclusion criteria were dialysis, acute infection, malignancy, stroke, amputation, heart failure, treatment with cilostazol or pentoxifylline during blood sampling, elevated ankle-brachial index (ABI) > 1.4, or refusal to provide informed consent.Weight was measured in minimal clothing and without shoes, recorded to the nearest 0.5 kg. Height was also recorded to the nearest 0.5 cm. Waist circumference was measured midway between the lowest ribs and the hip bones with the hands placed on the hips. Body mass index (BMI) was calculated by dividing weight (in kg) by height (in meters squared) .g for 10 min and stored at 4 °C within 1 h of processing for biochemical analyses. Serum blood urea nitrogen, creatinine, fasting glucose, total cholesterol, low-density lipoprotein cholesterol, triglycerides, total calcium, and phosphorus were measured by autoanalyzer . Serum resistin values were analyzed by enzyme-linked immunosorbent assay  [Blood samples were obtained after overnight fasting. In each patient, approximately 5 mL blood was immediately centrifuged at 3000×  France) . The estAn ABI-form device  was used to measure the ABI values. Simultaneous measurement of the oscillometric blood pressures in the arms and ankles were obtained. Occlusion and monitoring cuffs were placed over all four extremities with the patient in supine position. ABI was calculated by dividing the lowest mean from the ankles by the mean in the arm. A low ABI value was defined by less than 0.9 (low ABI group). The diagnosis of PAD is established based on an ABI < 0.9 .p value less than 0.05 was considered to indicate statistical significance.The normal distribution of the results was assessed by using Kolmogorov–Smirnov test. Data with normal distribution were shown as mean ± standard deviation and comparisons between participants were conducted by using the Student’s independent t-test (two-tailed). Mann–Whitney U test was used to analyze the differences between non-normally distributed data and expressed as medians and interquartile ranges. PAD-associated variables were tested for independence by multivariate logistic regression analysis. Area under curve (AUC) was calculated using receiver operating curve (ROC) and determine serum resistin levels to predict PAD in CKD patients. Categorical variables were expressed as numbers with percentages and compared using the Chi-square test. All analyses were performed with the use of SPSS for Windows, version 19.0 . A n = 133; 55.4%), β-blockers , calcium channel blockers , statins , and fibrate .Baseline characteristics of all 240 patients with non-dialysis CKD stage 3 to 5 are summarized in p < 0.001) and had more DM (p = 0.033), hypertension (p = 0.023), and had ever smoked (p = 0.013). Patients in the low ABI group had significantly higher fasting glucose (p = 0.022) and serum resistin level (p < 0.001), but a lower eGFR level (p = 0.002), as compared to normal ABI group.A total of 30 patients with non-dialysis CKD stage 3 to 5 (12.5%) were included in the low-ABI group. There were no significant differences in gender distribution, BMI, serum lipids, creatinine, stage of CKD, coexisting glomerulonephritis, and the use of ARB, β-blockers, CCB, statin or fibrate were seen between either of the groups. Compared with participants in the control group, patients with low ABI were significantly older age (p = 0.001), and age  were independent predictors of PAD in patients with CKD (p = 0.0001)  revealed that increased serum resistin level  .This study demonstrates that non-dialysis CKD stage 3 to 5 patients with low ABI tended to be older aged, lower eGFR, and had DM, hypertension, used tobacco more and had markedly elevated serum resistin levels. Furthermore, we found that age and resistin levels were significantly associated with PAD in non-dialysis CKD stage 3 to 5 patients after we adjusted other cofounder factors.Age, male gender, tobacco use, DM, dyslipidemia, and hypertension are well recognized as established risk factors for PAD ,15. The The ABI is a simple and non-invasive diagnostic tool for detection of PAD ,19. Alth2 have PAD, whilst only 3.7% of individuals with creatinine clearance >60 mL/min/1.73 m2 have PAD [The prevalence of PAD is greater in patients with CKD, compared with individuals with normal renal function . Accordihave PAD . Furtherhave PAD . Currenthave PAD ,25,26.Resistin, initially described as an adipokine secreted by the adipocytes, has been suggested as a potential link between obesity, insulin resistance, and DM ,28. AlthThere are several limitations to this study that require consideration. Our study is cross-sectional in design and hence causality could not be drawn based on the current results. Second, the present study was conducted in a single center, with a specific community selected because of the high prevalence of CKD. Finally, we did not measure inflammatory markers such as C-reactive protein of these patients. Therefore, further longitudinal studies are needed to define the relationship between serum resistin and PAD in non-dialysis CKD patients before confirming the cause–effect relationship.The present study showed that higher resistin level and older age were the independent predictors of PAD in non-dialysis CKD stage 3 to 5 patients. Given the potential role of resistin acting as a biomarker and therapeutic target for atherosclerosis, further studies are essential to elucidate the detailed signaling pathways and complex biological effects of resistin .


Their appetite status was measured using the Council on Nutrition Appetite Questionnaire (CNAQ). We examined independent determinants of appetite impairment in these CKD patients using multiple regression analyses. Among 78 patients with CKD, 42.3% had CNAQ-identified impaired appetite. Those with an impaired appetite also had poorer physical performance, a higher degree of functional impairment, higher frail severities, lower serum sodium levels, less intact oral cavity, and a trend toward having less intact nasal structures than those without. Multiple regression analyses revealed that a higher frail severity, in the forms of increasing Study of Osteoporotic Fractures (SOF) scores (odds ratio (OR), 2.74; 95% confidence interval (CI), 1.15–6.57) and a less intact nasal structure  were associated with a higher probability of having an impaired appetite, while higher serum sodium  correlated with a lower probability. Based on our findings, in patients with CKD, the severity of frailty, serum sodium, and nasal structural integrity might modify appetite status. Therapies targeting these factors might be beneficial for appetite restoration in patients with CKD.Protein-energy wasting (PEW) is an important complication resulting from chronic kidney disease (CKD). Appetite impairment contributes significantly to PEW in these patients, but risk factors associated with having appetite impairment in patients with CKD remain elusive. Patients with an estimated glomerular filtration rate <60 mL/min/1.73 m Chronic kidney disease (CKD) is recognized based on abnormalities involving renal structure and/or function persisting for more than three months, and has gradually become a global public health concern since nearly two decades ago. Although a precise estimation of CKD prevalence is difficult due to its asymptomatic nature during its early stage, more than 10% of the population worldwide have CKD [A major CKD complication is protein-energy wasting (PEW), which describes the co-existence of depleting protein building blocks and energy stores accompanied by chronic inflammation. Approximately 10–50% of patients with CKD are found to have PEW, and PEW prevalence tends to increase, paralleling the severity of renal dysfunction . The preAnorexia occurs in more than one-third of patients with end-stage renal disease (ESRD)  and is rThe protocol of this study was approved by the Institutional Review Board of the National Taiwan University Hospital (No. 201710041RIND). All participants provided written informed consent. The conductance of this study adhered to the Declaration of Helsinki.2 for ≥2 times at out-patient settings at least three months apart, with or without hematuria or proteinuria, according to the Kidney Disease Improving Global Outcomes (KDIGO) recommendation [The recruitment procedure has been detailed previously . In brieendation . Exclusiendation ,10. For These participants were further inquired about their functional status and received frailty screening. Functional status was gauged using two indices, the Eastern Cooperative Oncology Group (ECOG) score and the Karnofsky performance scale. Scores from the former index range between 0 and 5, with higher scores indicating a poorer performance. Scores from the latter index range between 0 and 100, with higher scores indicating better performance. Frailty status was evaluated using the FRAIL scale and the Study of Osteoporotic Fractures (SOF) scale. The former scale operationalizes the concept of frailty using five dimensions, namely, Fatigue, Resistance, Ambulation, Illness, and Loss of weight , with a Therefore, in this study, we asked our participants to report whether they had anatomical or functional impairment regarding their smell and taste perceptions, based on a visual analogue scale (VAS) . Higher VAS scores indicate better ratings of the specified structure or function. Self-report questions for assessing nasal structure integrity were administered in the following format: “Do you rate your nasal cavity/structure as normal?”.After completing the interview, self-report questionnaires, and physical tests, all participants received blood tests to determine their hemogram and serum biochemical profiles, including nutritional features, electrolyte panels, and renal function tests. We calculated eGFR based on the Modification of Diet in Renal Disease (MDRD) formula .In this study, appetite status was assessed using the Council on Nutrition Appetite Questionnaire (CNAQ). The CNAQ is an eight-item questionnaire originally designed to evaluate recipients’ appetite and their eating behavior . Each itt-tests (for continuous variables) and chi-square tests , respectively. We first examined the distribution of the CNAQ scores among our CKD participants graphically. This was followed by categorizing participants into those with and without a CNAQ-defined impaired appetite. Univariate analyses were conducted by comparing clinical features, including demographic features, religious beliefs, comorbidities, physical parameters, performance status, sensory functions, frailty test results, and laboratory profiles between participants with and without an impaired appetite. Multiple logistic regression analyses were subsequently performed with an impaired appetite as the dependent variable, incorporating variables with a p-value < 0.1 during univariate analyses. We constructed two regression models: Model 1 included demographic features, comorbidities, physical parameters, performance status, frailty test results, and laboratory profiles in the analysis, while model 2 additionally included the sensory function results. SPSS version 19 was used in all analyses, and a two-sided p-value < 0.05 was considered statistically significant.We described continuous and categorical variables using means with standard deviations, as well as minimal and maximal values in parentheses and numbers with percentages. They were compared between groups using Student’s n = 63; 80.8%), followed by diabetes mellitus , prior cerebrovascular events , and malignancy . The mean systolic and diastolic BP, HR, and BMI were 129.0 ± 15.9 mmHg, 77.1 ± 13.1 mmHg, 75.3 ± 10.1 per min, and 25.3 ± 3.7 kg/m2, respectively. Their physical performance was mildly reduced, with mean TCS, TUG, and GS of 12.9 ± 5.5 s, 4.1 ± 3.2 s, and 0.9 ± 0.4 m/s, respectively. Participants with CKD were not anemic  and their serum albumin levels were 41 ± 3 g/L. Their mean eGFR levels were 31.0 ± 15.1 mL/min/1.73 m2.During the study period, a total of 78 participants with stage 3 or higher CKD were prospectively enrolled, after excluding two patients that could not comply with the study protocol. Only one patient had dialysis-dependent CKD. Their mean age was 72.0 ± 11.7 years, with 55 (70.5%) males. The most common comorbidity among the enrolled participants with CKD was hypertension (p = 0.03), had significantly poorer physical performance, including lower grip strength (p = 0.04) and longer TCS (p = 0.04), had a more severely impaired functional status , had higher frail severities, and had lower serum sodium levels (p = 0.02) compared to those without (p = 0.06) and longer TUG (p = 0.06) was observed n CKD patients with an impaired appetite than in those without. Interestingly, CKD patients with an impaired appetite had less self-reported intactness involving their taste function (p = 0.04) and oral cavity structure (p = 0.02) and had a trend of less intact nasal structure (p = 0.07) than those without , and discovered that higher SOF scores or an increased frail severity was significantly associated with an elevated probability of having an impaired appetite (odds ratio (OR), 3.42; 95% confidence interval (CI), 1.54–7.6), while hemoglobin levels exhibited a trend of an inverse relationship with the probability of having an impaired appetite  (p = 0.75) nor grip strength  were significant determinants of appetite impairment.We subsequently examined the independent determinants of having an impaired appetite among these with CKD using multiple regression analyses. In model 1, we accounted for variables with a univariate 57–1.01) . In mode57–1.01) . FinallyIn this study, we prospectively recruited a cohort of patients with CKD, among whom the independent determinants of developing appetite impairment were analyzed. After accounting for an exhaustive set of variables, we found that frailty, serum sodium levels, and self-reported less intact nasal function modulated the probability of having appetite impairment. These findings are expected to facilitate a deeper understanding of the origin of appetite status variation and impairment among patients with CKD, and potentially guide the selection of at-risk patients for pre-emptive nutritional care.Among our participants, 42.3% had an impaired appetite, a number comparable to that in patients with ESRD under chronic dialysis . RelativThe association between having more severe frailty and a higher probability of having appetite impairment is reasonable. Older adults with chronic illnesses and subjective complaints such as fatigue, a core component of frailty, are found to exhibit worse feeding behavior and have poorer meal quality and lower frequencies of food intake than those without such complaints. Physical restraints, including difficulty in ambulation and the associated sarcopenia, also correlate closely with having an impaired appetite, especially in older adults. The presence of frailty is frequently accompanied by a higher probability of depression in patients with CKD , and depIt is interesting that neither BMI or abdominal circumference differed between those with and without appetite impairment. Several reasons could be attributable, as provided below; first, the case number of each group was rather modest, and thereby the statistical efficiency for detecting differences could not be reached. Second, there was a possibility that patients with appetite impairment had a higher prevalence of sarcopenic obesity, which led to the manifestations of similar BMI and waist circumferences to those without appetite impairment, but poorer muscle strength.We also discovered that lower serum sodium levels are associated with a higher probability of having appetite impairment in patients with CKD . Prior rSensory perceptions, especially smell and taste intactness, impact heavily on the choices of food preferences and appetite . The finVital clinical implications can be derived from our findings. Strategies aiming to ameliorate frailty, including nutritional care, rehabilitation programs, and exercise sessions, may be harnessed to reduce the probability of developing appetite impairment among patients with CKD ,32,33. SOur study has its advantages and drawbacks. The focus of this study, to determine the independent determinants of an impaired appetite in patients with CKD, fills the research gap and enriches the existing literature by providing evidence on potential appetite modifiers in patients with CKD. We compiled a comprehensive set of variables for selecting the potential determinants of appetite impairment, defined in a standardized way, and some of the included factors  have not been examined before for such an appetite-influencing effect. However, several limitations should be kept in mind when interpreting our results. First, the findings from our study cannot affirm whether a causal relationship exists between the identified factors and the probability of having an impaired appetite in CKD patients. Our sample size was modest, but the large number of variables analyzed most likely negates the influence posed by statistical inefficiency. The assessment of appetite, although conducted using a structuralized instrument, remained subjective in nature and might not always be compatible with results using objective nutritional assessment methods. In addition, depression was not measured in this study. Finally, patients in our cohort mostly had stages 3 and 4 CKD, and extrapolating our results to those with dialysis-dependent CKD should be conducted very carefully. Nonetheless, a replicative study is still needed to verify our findings.In conclusion, we revealed several important yet under-recognized factors that independently influence the probability of having appetite impairment in patients with CKD. The severity of frailty, serum sodium levels, and the presence of nasal structural lesions all play a role in modifying appetite status. Therapies targeting these factors might become potential approaches for appetite restoration in these patients.


P = .04; hazard ratio 3.95, 95% CI 1.33‐ 11.79, P = .01, respectively), while only HR risers was shown to be correlated with a decline in eGFR≥ 50% , and decline in eGFR . No predictive value was found for HR dipping pattern to mortality and CV events. In conclusion, our study provided the first evidence that HR non‐dippers, especially risers were a risk factor for poor renal outcomes in hypertensive patients with CKD.The association of heart rate (HR) dipping pattern with renal outcomes in chronic kidney disease (CKD) patients with hypertension has never been investigated. In order to demonstrate if HR dipping pattern is a risk factor for renal outcomes, cardiovascular (CV) diseases, and mortality in hypertensive patients with CKD, we conducted the prospective longitudinal observational study. Patients were divided into three groups according to their nocturnal HR: HR dippers (night–day HR ratio ≤ 0.9), HR non‐dippers (0.9 < night–day HR ratio ≤ 1.0), and HR risers (night–day HR ratio > 1.0). The primary outcome was renal endpoint, a composite outcome of progression to end‐stage renal disease (ESRD) or estimated glomerular filtration rate (eGFR) decline ≥ 50%; the secondary outcomes included poor renal outcomes, CV events, and death. A total of 34 (11.3%) patients reached renal endpoint after a follow‐up of 34 ± 17 months. Both HR non‐dippers and HR risers were predictive to renal endpoint  1.04‐ 6.4,  Patients with albuminuria , or the estimated glomerular filtration rate (eGFR) < 60 mL/min / 1.73 m2, or abnormalities of kidney structure for over 3 months were diagnosed with CKD.http://www.ClinicalTrials.gov; TCTR20180313004). Written informed consent was obtained from all patients.This was a prospective longitudinal observational study including patients from two centers  in China. Adult patients were eligible if they: (1) had chronic kidney disease, (2) have been diagnosed with hypertension in the clinic, and (3) agreed to take 24h ABPM. Exclusion criteria were patients with 1) eGFR < 15 mL/min per 1.73 mPatients were collected from January 2014 to December 2019, a total of 304 CKD patients met the inclusion /exclusion criteria and completed the 24h ABPM. According to their nocturnal HR from 24h ABPM, the participants were divided into 3 groups, including HR dippers (night–day HR ratio ≤0.9), HR non‐dippers (0.9 < night–day HR ratio ≤1.0), and HR risers (night–day HR ratio > 1.0). Demographic data ), Medical history ), and laboratory tests  were recorded at baseline. Patients were followed up by checking the electronic databases in the hospital and phone calls; the follow up was from the day of ABP, until December, 2020, death, or CKD progression, and censored on the date they had the last clinic visit or phone answering. Only patients with follow‐up time for more than six months were included into the final analysis.2.2Office BP and HR were measured by experienced nurses at the time that the participants were admitted to our hospital; the mean value of three consecutive measurements at 5‐minute intervals with a mercury sphygmomanometer after patients rest quietly for 5 to 10 minutes was recorded. The twenty‐four‐hour ambulatory blood pressure (ABP) and heart rate monitoring was performed via The Space Labs 90217 device  in West China Hospital and ABPM 6100  in Chengdu 7th People's Hospital, with BP and HR readings set at 20‐minute intervals from 6:00 am to 10:00 pm, and 30‐minute or 60‐minute intervals from 10:00 pm to 6:00 am. The BP and HR of daytime, nighttime was defined as the mean values during the period from 6:00 am to 10:00 pm and 10:00 pm to 6:00 am, respectively; patients were instructed to take their usual activities and receive antihypertensive drugs as usual, and was encouraged to sleep no later than 10:00 pm, and get up at nearly 6:00 am. A measurement with at least 70% of diurnal and nocturnal BP and HR readings was regarded as a successful ABP. The ABP must be taken within three days after the measurement of office BP. Both office BP and ABP measurements were taken from the non‐dominant arm with an appropriate cuff size based on arm circumference at the time of enrollment.2.3Dipping pattern of BP and HR were calculated with the formula: mean night‐day ratio of systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR, patients were diagnosed with normal BP or HR dippers if the night‐day ratio was ≤0.9, or non‐dippers if the ratio was > 0.9 and ≤1.0,2.42 or dialysis), or eGFR decline ≥ 50%. The secondary outcome included (1) death; (2) deterioration of kidney function, including a composite of progression to ESRD, eGFR decline ≥ 30%; and individual components of the composite kidney outcomes; (3) the rate of change of eGFR from baseline, calculated as (eGFR at endpoint ‐ eGFR at baseline)/ eGFR at baseline; (4) CV events, which was defined as a fatal or nonfatal newly occurred CV disease, including coronary heart disease, myocardial infarction, heart failure, stroke, angina pectoris, whichever occurred first. Patients were followed up every 6 months by checking the electronic databases in the hospital and phone calls, mainly including disease progression and laboratory tests ; the follow‐up was from the day of ABP, until December 2020, death, or renal endpoints, and censored on the date they had the last clinic visit or phone answering.The primary outcome was a renal endpoint, which was defined as a composite of progression to ESRD . All data were expressed as mean ± standard deviation (SD) for normally distributed data, median values with their interquartile range for skewed data, and numbers (n) with percentage (%) for categorical variables. Data were analyzed by using the Chi‐square test or Fisher's exact test for categorical variables, Student's t‐test for normally distributed data, and Wilcoxon rank‐sum test for continuous skewed variables.P value < .05 was considered statistically significant.Kaplan‐Meier survival function estimates, the log‐rank test was applied to compare the incidence rates of events in different groups; Multivariable Cox regression model was used to investigate associations of HR dipping pattern with renal and CV outcomes. The proportional hazards (PH) assumption was tested by assessing the log‐minus‐log plots of survival. The multivariate linear regression model was applied to detect the association of HR dipping pattern with the rate of change of eGFR from baseline, the regression ß coefficient represented the contribution of the independent variables to the dependent variables. Hazard Ratios, 95% CIs (CIs) were calculated and a two‐tailed 33.12); 48 (15.9%), 45 (14.9%) patients were a current smoker or drinker, respectively. One hundred twenty‐two (40.4%) patients had a CV history, 82 (27.2%) of which had arrythmia, and 218 (72.2%) were complicated with diabetes mellitus (DM).Two (0.66%) of the included 304 patients at baseline were lost to follow up, finally, 302 hypertensive participants with CKD and good quality ambulatory BP/HR recordings  were analyzed ; those with HR risers had a higher possibility of CV history, using ß blocker, and a higher level of RBC, and lower level of hemoglobin, albumin (P < .05)  non dippers and 42 (13.9%) risers. Table 3.2Over a mean follow‐up of 34 ± 17 months, a total of 34 (11.3%) patients reached renal endpoint , 56 (18.5%) patients had an eGFR decline ≥30%.P < .05); cumulative survival of CKD progression was significantly lower in patients with HR non‐dippers (P = .034) and HR risers (P = .01) when compared to HR dippers  and HR risers (16.7%), versus HR dippers (5.6%) (3.8% and P < .05) and HR risers at night  were demonstrated to be associated with the renal endpoint, even after adjustment of basic clinical characteristics   and risers  showed strong predictive value to a composite renal outcome of ESRD or eGFR decline ≥30% (Table P < .05), and eGFR decline ≥30% ; while HR non‐dippers only showed association with eGFR decline ≥30%  ; the mean relative change rate of eGFR from baseline was 15%, 11%, and −1.69% in HR dippers, HR non dippers, and HR risers group, respectively. In the multivariate linear regression, HR risers was demonstrated to be negatively correlated with the relative change rate of eGFR from baseline  compared to HR dippers, the difference remained significant after adjustment of day HR, BP and SBP/DBP dipping pattern .During the follow‐up time, there are 8 7.4%), 11 (7.2%), and 4 (9.5%) death in the HR dippers, HR non‐dippers, and HR risers group; 37 (34.3%), 47 (30.9%) and 11 (26.2%) patients occurred new CV complications in the three groups, respectively. However, the difference in the incidence rate of death and CV events among the three groups was not significant in the analysis of the log‐rank test. In the Cox regression model, the HR non‐dipping pattern was not predictive of death and CV events  whereas HR non‐dippers had no correlation with change rate of eGFR compared to HR dippers .In the study, we also analyzed the association of HR dipping pattern with CV events. It is not established whether HR non‐dipping pattern can be risk factors of CV events, in contrast to the established relationship of non‐dippers of BP. A previous study of 2021 participants concluded that a non‐dipping pattern of HR was associated with preclinical cardiac damage and predictive to CV events (hazard ratio 1.8, 95% CI: 1.13–2.86, There are some strengths of our study. Firstly, previous published studies have mostly focused on the association of BP rather than HR dipping pattern with the renal and heart outcomes in CKD patientsOur study also has some limitations. First, with only 302 patients included into the study, the sample size is relatively small; second, the median follow‐up time is also not long enough with only 34‐month. Further prospective studies with larger sample sizes and long follow‐up periods are needed in the future.5Nocturnal HR non‐dipping pattern, especially HR rising, was associated with increased risk of renal endpoint, kidney function deterioration and decline in eGFR. The predictive value of HR non‐dippers for poor renal outcomes disappeared after further adjustment, while that of HR risers remained stable. Circadian rhythm of HR in hypertensive patients with CKD deserves further attention and research.The authors declared no potential conflicts of interest concerning the research, authorship, and/ or publication of this article.Xiang Liu, Huan Zhou, Yi Tang, and Wei Qin: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND drafting the work or revising it critically for important intellectual content; AND final approval of the version to be published; AND agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.Gen Li, Fangming Li, Lingqiu Dong, and Siqing Wang, Zheng Jiang, Jiaxing Tan, Aiya Qin: analysis and acquisition of data; AND drafting the work; AND final approval of the version to be published; AND agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


Evidence from prospective cardiovascular (CV) outcome trials in type 2 diabetes (T2DM) patients supports the use of sodium–glucose co-transporter-2 inhibitors (SGLT2i) to reduce the risk of CV events. In this study, we compared the risk of several CV outcomes between new users of SGLT2i and other glucose-lowering drugs (oGLDs) in Catalonia, Spain.CVD-REAL Catalonia was a retrospective cohort study using real-world data routinely collected between 2013 and 2016. The cohorts of new users of SGLT2i and oGLDs were matched by propensity score on a 1:1 ratio. We compared the incidence rates and hazard ratio (HR) for all-cause death, hospitalization for heart failure, chronic kidney disease, and modified major adverse CV event .After propensity score matching, 12,917 new users were included in each group. About 27% of users had a previous history of CV disease. In the SGLT2i group, the exposure time was 60% for dapagliflozin, 26% for empagliflozin and 14% for canagliflozin. The use of SGLT2i was associated with a lower risk of heart failure , all-cause death , all-cause death or heart failure , modified MACE , and chronic kidney disease .In this large, retrospective observational study of patients with T2DM from a Catalonia, initiation of SGLT-2i was associated with lower risk of mortality, as well as heart failure and CKD.The online version contains supplementary material available at 10.1186/s12933-021-01323-5. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus (T2DM) , 2. IndeSo far, meta-analyses of prospective CV outcome trials (CVOTs) have consistently shown that treatment with sodium–glucose co-transporter-2 inhibitors (SGLT2i) modestly reduces the incidence of major adverse cardiovascular outcomes (MACE) and have a consistent and robust beneficial effect on hospitalizations for heart failure and progression of kidney disease regardless of prior history of CVD or established CKD –12. BesiIn the real-world setting, several large multinational, observational studies assessed the comparative effectiveness of initiating treatment with a SGLT2i vs. other glucose-lowering drugs (oGLDs) . The results of the CVD-REAL 1 and 2 studies showed that the use of SGLT2i was associated with decreased risk of hospitalisation for HF and all-cause mortality in subjects with a broad range of CV risk , 19. MorAvailable observational, real-world studies suggested that there might be a class effect of SGLT2i on CV and renal outcomes, and that the benefits could be extended to a broader population with diabetes  , 28. As Based on the need to confirm the applicability of results from other observational, real-world studies, the primary aim of the present study was to investigate, in a primary care population database in Catalonia (Spain), whether the risk for HF among users initiating SGLT2i was different from those initiating oGLDs. Secondarily, we aimed to compare all-cause mortality, modified MACE , all-cause mortality or HF, MI, stroke, and CKD between these two groups of new users.This was a retrospective cohort study of adult subjects with T2DM between January 2013 and December 2016. Data from patients were extracted from the electronic medical records of the SIDIAP database (Information System for the development of Primary Care Research) and the CMDB register  from the Catalan Institute of Health (ICS) . The assTo identify patients initiating glucose-lowering treatment with either an SGLT2i  or oGLDs in our databases we used the codes of the Anatomical Therapeutic Chemical (ACT) classification system from the World Health Organization (WHO) . New useNew users were eligible if they initiated treatment with either an SGLT2i or oGLD between the 1st December 2013 and the 31st December 2016. In our approach, all episodes of SGLT-2i and oGLD initiation were eligible to be included, thus one patient might be included more than once and might have contributed with more than one episode of new glucose-lowering medication initiation for different drug classes  and at different time points. Furthermore, subjects were not selected hierarchically; therefore, the potential risk period from the oGLD group was removed, which could lead to mortality bias . This meVariables were captured for all patients at the index date inclusive or before (1 year prior to the index date). At baseline, we collected data for social-demographic characteristics, including age, gender, toxic habits (smoking), and deprivation index (DI). The DI assesses five socioeconomic indicators related with work and education  extracted from census tracks . It deteClinical characteristics included diabetes-related parameters , concomitant medications, comorbidities, and laboratory parameters . During the follow-up, we collected data (ICD10 diagnostic codes) on the following events as single outcomes: all-cause mortality, HF [hospitalisation for HF or diagnostic code (ICD10: I50), atrial fibrillation (ICD10: I48), stroke (ICD10: I60–I62), ischemic stroke (ICD10: I63–I64), MI (ICD10: I21–I22), and CKD  all-cause mortality or HF , and (b) modified MACE, defined as all-cause mortality, MI or stroke.The SGLT-2i group was matched to the oGLDs group (comparator) based on propensity score and calendar period of study entry. For matching, we used the nearest neighbour calliper width of 0.25 multiplied by the standard deviation (SD) of the propensity score distribution . The varhttps://www.r-project.org/). The source code is available at https://github.com/jrealgatius/CVD_REAL_OP2, and a dashboard with interactive Additional material at https://dapcat.shinyapps.io/CVD_REAL.The baseline characteristics for each cohort were summarised by frequencies and percentages for categorial variable, and as mean (± SD or median and quartiles) for continuous and count variables. For the main on treatment analysis, we calculated the person-time at risk for each patient as the length of the index exposure episode, defined as the number of days from the day after the index prescription start date to the last day of follow-up. For each outcome of interest, the crude incidence rate (IR) in each index exposure group was estimated as the number of incident events divided by the total number of patient-years (PY) at risk and was expressed as per 100 PY. The IRs for the SGLT2i group and oGLD group were then compared using a hazard ratio (HR) and the corresponding 95% confidence interval (CI). This analysis was performed using Cox proportional hazards regression by clusters (patient ID) with robust estimation of standard errors. Both crude and adjusted HR were estimated for all endpoints. As covariates for adjustment, we used gender, age, T2DM duration, hypertension, body mass index (BMI), use of antihypertensive drugs, and HF or MI  initiating treatment with and the remaining 13,281 with an SGLT2i (5.5%). Baseline characteristics before propensity-score matching are shown in Additional file http://dapcat.shinyapps.io/CVD_REAL). In the overall population, more than two-thirds of users at the moment of initiation with a new glucose-lowering drug had a diabetes duration of ≥ 5 years (77.7%), suboptimal glycemic control , and nearly two-thirds (65.1%) were on statins treatment  of HF, all-cause death, the combination of both outcomes, and modified MACE was lower in patients with T2DM receiving SGLT2i than in patients initiating oGLDs . Moreover, crude and adjusted Cox regression analyses  showed magnitude and effects similar to the ones detected in the on-treatment analysis approach .Similar results regarding the number of events and IRs were observed for all of the study outcomes in the sensitivity analysis using the intention-to-treat approach population .The subgroup analyses showed no statistically significant interactions with users’ characteristics, including age (≥ 65 years), gender, comorbidity profile , or CV and baseline medication . As such, none of the these variables modified the association between SGLT2i use and reduced risk of HF, all-cause death, all-cause death or HF, MACE, and CKD  and only 8% of initiators had values below 60 mL/min/1.73 m2. In that study, the annual rate of change in eGFR from baseline showed the benefit of initiating an SGLT2i regardless the eGFR subgroup, although the magnitude of the change was lower among those with compromised kidney function . Another RW study conducted in Italy, the DARWIN-T2D, assessed the albumin excretion rate (AER) as a surrogate of kidney outcome in T2DM patients treated with dapagliflozin vs. active comparators  [2 at baseline and the authors reported a decline of 37% in the AER irrespective of baseline eGFR, while there was no change among those who received a comparator. Lastly, a systematic review and meta-analysis of RCTs in patients with T2DM and CKD (defined as eGFR < 60 mL/min/1.73 m2) treated with SGLT2i found that these agents slowed the annual loss in kidney function (eGFR slope) and led to a 29% reduction in the risk of the composite outcome doubling serum creatinine, ESRD, or renal death [In the moment of realization of the study SGLT2i were not recommended in severe renal impairment, namely < 45 mL/min/1.73 mliflozin , 47. Regliflozin . On the icazide) . The meaal death . A reducal death . Besidesal death .The incident rates of non-fatal MI, stroke , and atrial fibrillation were not different between patients initiating SGLT2i or other oGLDs in our study. A neutral or small effect of SGLT2i on all of these particular outcomes has been as well observed in previous RW studies , 39, 49.The results of our study should be considered in the context of several potential strengths and limitations. The main strength of our study is a large number of patients included the representativeness of the diabetic population . MoreoveIn this real-world study of patients with T2DM attended in routine clinical practice from a South European region, new use of SGLT2i was associated with a lower risk of HF, mortality and renal events compared with the use of oGLDs. These results expand previous observational studies supporting the use of SGLT2i in patients with a broad CV risk profile in real-world clinical practice. Moreover, they show that the magnitudes of the associated CV and renal benefits are similar to those observed in other European geographical regions.Additional file 1: Figure S1. Flow chart of the patients included in the study. Figure S2. Pre and post propensity score matching and standardised differences. Table S1. Variables included in the propensity score. Table S2. Variables included in the adjustments of Cox regression analysis. Table S4. Number of patients and follow-up time (years). Table S5. Sensitivity crude analysis of intention-to-treat. Table S6. Sensitivity analysis of intention-to-treat output from Cox regression models. Figure S3. Subgroup analysis for heart failure outcome, including gender, age, chronic kidney disease, history of cardiovascular disease, cardiovascular and diabetes medications at baseline (ITT approach). Figure S4. Subgroup analysis for all-cause death or hearth failure outcome, including gender, age, chronic kidney disease, history of cardiovascular disease, cardiovascular and diabetes medications at baseline (ITT approach). Figure S5. Subgroup analysis for modified MACE outcome, including gender, age, chronic kidney disease, history of cardiovascular disease, cardiovascular and diabetes medications at baseline (ITT approach). Figure S6. Subgroup analysis for all-cause death outcome, including gender, age, chronic kidney disease, history of cardiovascular disease, cardiovascular and diabetes medications at baseline (ITT approach). Figure S7. Subgroup analysis for nonfatal myocardial infarction outcome, including gender, age, chronic kidney disease, history of cardiovascular disease, cardiovascular and diabetes medications at baseline (ITT approach). Figure S8. Subgroup analysis for non-fatal stroke outcome, including gender, age, chronic kidney disease, history of cardiovascular disease, cardiovascular and diabetes medications at baseline (ITT approach). Figure S9. Subgroup analysis for ischemic stroke outcome, including gender, age, chronic kidney disease, history of cardiovascular disease, cardiovascular and diabetes medications at baseline (ITT approach). Figure S10. Subgroup analysis for atrial fibrillation outcome, including gender, age, chronic kidney disease, history of cardiovascular disease, cardiovascular and diabetes medications at baseline (ITT approach). Figure S11. Subgroup analysis for chronic kidney disease outcome, including gender, age, chronic kidney disease, history of cardiovascular disease, cardiovascular and diabetes medications at baseline (ITT approach). Table S7. Specification of diseases codes used. Table S8. Specification of ATC/DDD codes used.