Sodium-glucose cotransporter 2 inhibitor (SGLT2i), a glucosuric agent initially approved for use as an antidiabetic agent, was unexpectedly found to confer cardio-and reno-protective effects in individuals with or without type 2 diabetes mellitus. Despite mounting evidence suggesting that SGLT2i provides cardio- and reno-protective benefits in both diabetic and non-diabetic and in chronic kidney disease (CKD) patients in the general population, reservations for its use in the transplant setting persist due to concerns for increased risk of genital mycotic and urinary tract infections. A comprehensive review of the literature on the efficacy and safety of SGLT2i use in diabetic kidney transplant recipients is herein presented followed by authors’ opinion on its optimal use in this patient population. In patients without hyperglycemia, the glomerular filtered load of glucose is relatively low, thereby limiting the extent of glucosuria and inherently minimizes hypoglycemic risk   AND [transplant]  AND  ) yielded 223 articles. Full-text articles selected for inclusion in our review included randomized controlled trials, retrospective studies, cohort studies, and prospective and retrospective case series. A total of 10 studies evaluating the efficacy and safety of SGLT2i in diabetic kidney transplant recipients with pre-existing type 2 diabetes or PTDM were identified. Of the 10 studies, seven were included in a systematic review and meta-analysis . One additional study included in the systematic review and meta-analysis was in abstract format and was graded as fair quality.2), and stable immunosuppressive therapy. Forty-four eligible patients with PTDM were randomized to receive either empagliflozin (n=22) or placebo (n=22) for 24 weeks. A statistically significant reduction in A1C and body weight was observed among empagliflozin-treated patients compared with their placebo-treated counterparts . There were no significant differences in adverse events, immunosuppressive drug levels, or eGFR between the two treatment groups . Study inclusion criteria included more than one year after transplant, stable renal function  and body weight  at end of study compared with baseline levels –16. No s2, p=0.8831 and 1 mL/min/1.73m2, p=0.1478, respectively). Of the 50 patients enrolled in the study, half were started on therapy within the first year after transplant with a median time to drug initiation of 319 days. The incidence of UTIs was not significantly different from that reported historically in this high-risk patient population . There was one case of genital yeast infection. No cases of diabetic ketoacidosis (DKA), amputations, or AKI were seen. Study inclusion criteria included absence of AKI within 30 days prior to the initiation of SGLT2i, freedom from any UTIs 6 months prior to SGLT2i initiation, and eGFR ≥ 30 mL/min/1.73m2 at the time of SGLT2i initiation  and improvement in magnesium concentration  were observed at 6-month follow-up. Overall insulin requirements decreased by -3.7 units . There was no statistically significant change in eGFR at three and six months after SGLT2i initiation . Non-statistically significant weight loss occurred in 15 patients with a recorded weight at both baseline and 3 months post SGLT2i initiation . Median time from kidney transplant to SGLT2i initiation was 28 months (range 16-60 months). Of 39 patients studied, 27 remained on therapy for at least 1 year. In patients with follow-up data, no statistically significant changes in kidney function (n=35) or tacrolimus exposure was observed (n=24). Ten patients (25%) experienced an adverse event while on SGLT2i therapy, with UTI being the most common . Five of six patients with UTI had a history of UTI prior to SGLT2 initiation. Four continued therapy without UTI recurrence. Urosepsis and pyelonephritis leading to SGLT2i discontinuation occurred in patients with prior history of recurrent UTIs. One patient developed diabetic ketoacidosis (due to uncontrolled diabetes) and concurrent UTI. Two patients developed complications from diabetic foot ulcers, both of whom had known peripheral vascular disease and prior history of diabetic foot ulcer. Two patients developed AKI more than 90 days after SGLT2i initiation determined by independent investigators to be unrelated to SGLT2i therapy. No episode of Fournier gangrene, genital mycotic infection, or bone fractures were identified during the study period .2, respectively, p=0.459). During a mean follow-up of 62.9 ± 42.2 months, a significantly lower risk of the primary composite outcome of all-cause mortality, death-censored graft failure, and serum creatinine doubling were observed among SGLT2i users compared with non-users in multivariate and propensity score-matched models . All three individual components of the outcome were significantly lower in SGLT2i users compared with non-users. A transient dip of more than 10% decline in eGFR occurred in 15.6% of SGLT2i-treated group during the first month but gradually recovered thereafter. Risk factors for eGFR dip were shorter time from transplantation to SGLT2i usage and higher mean tacrolimus trough levels. Post hoc analysis showed no difference in eGFR between the dipper and non-dipper groups at all time points. A significant decrease in urine protein-to-creatinine ratio was observed in both dipper (p=0.003) and non-dipper groups (p < 0.001). The incidence of any bacterial or fungal urinary tract infections were similar between SGLT2i users and non-users and no case of euglycemic ketoacidosis was identified. The study findings suggest that SGLT2i confers a renoprotective effect in diabetic kidney transplant recipients and its use is safe in such population , raising concerns that SGLT2i adverse events or deterioration in allograft function may have led to the discontinuation of therapy in these patients . NonetheAngiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) use was more common in SGLT2i users vs. non-users . Nonetheless, although the cardiorenal protective effects of ACEI and ARB have been well-described in the general population, their favorable impact on patient and graft survival in the transplant setting has not been consistently demonstrated .Studies evaluating the efficacy and safety of SGLT2i use in diabetic kidney transplant recipients are summarized in SGLT2i use in diabetic kidney transplant recipients results in modest decrease in A1c without increased risk for genitourinary infectious complications or euglycemic DKA. However, it should also be noted that patients with history of recurrent UTIs, urosepsis or genital mycotic infections were generally excluded from these studies. Furthermore, in most studies, patients selected for SGLT2i therapy were more than 1-year post-transplantation because of concerns for fluctuating kidney allograft function and increased infection risk in the early post-transplantation period. Nonetheless, the potential beneficial effects of SGLT2i including weight loss, renoprotection, metabolic and electrolyte benefit, and lack of significant drug-drug interaction with calcineurin inhibitor render SGLT2i an attractive treatment option for kidney transplant recipients. Of interest, an experimental animal model of tacrolimus-induced diabetes demonstrated that empagliflozin improves hyperglycemia and suppressed the tacrolimus-induced twofold increase in the expression of SGLT2 . FurtherSimilar to the general population, the use of SGLT2i in the transplant setting can cause an acute transient dip in eGFR, thought to be due to SGLT2i induced afferent arteriolar vasoconstriction. It is suggested that the natriuretic effect of SGLT2i leads to increased tubuloglomerular feedback and afferent arteriolar vasoconstriction even in denervated kidney allograft. Whether the resultant reduction in intraglomerular hypertension and hyperfiltration play a role in reducing proteinuria and preserving eGFR in diabetic kidney transplant recipients warrants further investigation.To date, there has been no case of Fournier gangrene associated with SGLT2i use in diabetic kidney transplant recipients. One case of new diabetic foot ulcer/osteomyelitis occurring years after starting empagliflozin leading to distal limb amputation has been reported. Notably, the patient had a history of peripheral vascular disease and prior history diabetic foot ulcers . It has In the authors’ opinion, SGLT2i use in diabetic kidney transplant recipients appears safe and effective in selected candidates. Based on currently available literature, optimal use of SGLT2i in kidney transplant recipients with pre-existing diabetes or PTDM is suggested in P-PT and P-PC contributed equally to searching the literature, writing the manuscript, and designing the tables. 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.


This randomized clinical trial investigates the effect of coronary venous pressure on myocardial resistances in patients with microvascular disease. How does coronary venous pressure influence myocardial resistances in patients with microvascular disease?In this blinded, physiology end point, sham-controlled randomized clinical trial that included 20 adults with microvascular disease, an increase in coronary venous pressure led to significantly decreased resting and hyperemic microvascular resistances.In patients with microvascular angina, the coronary venous circulation may be a novel therapy target. The role of the coronary venous circulation in regulating myocardial perfusion and its potential in treating microvascular angina is unexplored.To evaluate whether an increase in coronary venous pressure modifies microvascular resistance in patients with microvascular angina.This was a blinded, sham-controlled, crossover, randomized clinical trial that enrolled participants between November 2021 and January 2023. Participants for this physiology end point study were recruited from the Cardiology Center of the University of Medicine in Mainz, Germany. Patients with moderate/severe angina pectoris (Canadian Cardiovascular Society class 2-4) due to microvascular dysfunction (as defined by the thermodilution-based index of microvascular resistance >25 mm Hg × s). Exclusion criteria were epicardial coronary disease, second- and third-degree atrioventricular block, severe valvular heart disease, cardiomyopathy, and pulmonary or kidney disease.balloon and the deflated balloon in the right atrium, referred to as sham. Measurements were performed at rest and during maximal coronary hyperemia. Both patients and final assessors were blinded to the randomization sequence.Inflation of an undersized balloon placed in the cardiac coronary sinus (CS), hereafter referred to as Hemodynamic parameters, including aortic (Pa) and distal (Pd) coronary pressure, coronary sinus pressure (Pcs), right atrial pressure (Pra), and the mean transit time (inverse of blood flow [Tmn]), were measured.P < .001), a decrease in hyperemic distal coronary pressure  and mean transit time . As a result, CS occlusion led to a decrease in both resting coronary resistance  and the primary end point hyperemic coronary resistance .A total of 20 patients  were included in the study. Two patients (10%) had diabetes, 6 (30%) had hypercholesterolemia, 15 (75%) had hypertension, and 3 (15%) were active smokers. The inflation of the CS balloon caused a significant increase in CS pressure at rest and during hyperemia (300% and 317% increase, respectively, compared with sham, both Increased coronary venous pressure led to a reduction of microvascular resistances in patients with microvascular angina, a mechanism with potential implications for the therapy of this complex disease.NCT05034224ClinicalTrials.gov Identifier:  This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.This study was a sham-controlled, crossover, randomized clinical trial to investigate the effect of changes in coronary venous pressure on microvascular resistances. The protocol  without epicardial stenosis, reversible ischemia on noninvasive testing, and evidence of microvascular dysfunction (index of microvascular resistance [IMR] ≥25 mm Hg × s). Main exclusion criteria were second- or third-degree atrioventricular block, any valvular heart disease, any cardiomyopathy, and pulmonary or kidney disease.Vasoactive therapies were suspended for more than 12 hours before measurements were taken. Patients were randomly assigned 1:1 to 1 of 2 arms , with each patient undergoing invasive measurements at rest and during hyperemia in both conditions . For the6Coronary microvascular function assessments were performed with a wire-based thermodilution method using Pressure Wire X (Abbott Vascular) as per instructions for use; the same hyperemic agent was used for the 2 sets of measurements in each patient . The mean transit time (Tmn), coronary flow reserve (CFR), and IMR were measured. The absence of drift was confirmed at the end of the measurements. Patients were blinded to the randomization sequence, and hemodynamic data were encoded in the CoroFlow software (Coroventis) and collected by blinded assessors. Coronary flow capacity was measured to identify 4 different regions of myocardial ischemia (eMethods in Pd − Pcs) × Tmn] where Pd is the distal intracoronary pressure, Pcs the pressure in the coronary sinus, and Tmn the inverse of flow.The study’s primary end point was the (hyperemic) IMR during the inflation of the CS balloon as compared with sham. IMR was calculated as [(8 Assuming a mean (SD) IMR of 33 (13) mm Hg × s, an effect size of approximately 0.69, and a power of 80%, 19 patients were needed for the analysis.Randomization was performed by a computer-generated random sequence with permuted blocks. The power calculation was based on previous articles investigating the effect of acute administration of fasudil and enalaprilat on IMR.P values were 2-sided, and P < .05 was considered statistically significant. Data were analyzed using MedCalc software, version 15 .The primary analysis was performed as a within-participant comparison of the primary parameter using a linear mixed-regression model with a patient random intercept, condition, and period as well as their interaction as fixed factors and age and sex as covariates. Secondary end points were analyzed using the Wilcoxon test. Data are presented as median (IQR). All A total of 20 patients  were enrolled in this physiology end point study (eTable in P < .001) and during hyperemia , but it was not associated with a change in right atrial pressure. A decrease in hyperemic distal coronary pressure was also observed  along with a decrease in Tmn . Balloon inflation provoked a decrease in both resting coronary resistance  and hyperemic coronary resistance  (P < .001). Balloon inflation also caused a decrease in fractional flow reserve .Hemodynamic data are presented in the  < .001) . The est2R = 0.67; P < .001)  and an increase in blood flow.Many patients undergoing diagnostic coronary angiography for angina have microvascular disease.11 In the healthy circulation, increases in venous blood pressure elicit myogenic vasoconstrictor response of precapillary vessels and capillary derecruitment.12 In patients with severe vascular disorders, however, an increase in venous pressure has been associated with a rise in capillary  pressure, leading to an increase in capillary diameter and density  and a reduction in viscosity.13 Based on the Poiseuille law, volume flow rate is directly proportional to the fourth power of the vessel’s radius and inversely proportional to dynamic viscosity. Following an increase in CS pressure, even small increases in capillary recruitment/diameter and viscosity may, therefore, result in relevant improvements in microvascular resistance in patients with MVA, with a proportionally larger effect during hyperemia  disease will have to be investigated. Also, the mechanisms hypothesized are based on evidence from animal models or human in vivo models of the extracardiac circulation.In this crossover randomized clinical trial, the current findings that an acute increase in CS pressure led to a decrease in microvascular resistance and an increase in blood flow allow hypothesizing that the venous vasculature may be leveraged to improve coronary resistances in patients with MVA. This may have implications for therapy with a coronary sinus reducer.


Arterial hypertension (AH) after renal transplantation (RTX) is correlated with worse cardiovascular and renal outcomes, with loss of renal function, decreased graft survival and higher mortality. RTX recipients have discrepant blood pressure (BP) values when measured in the office or by systematic methodologies, such as Ambulatory Blood Pressure Monitoring (ABPM), with significant prevalence of no nocturnal dipping or nocturnal hypertension, white coat hypertension and masked hypertension. The aim of the present study was to review the issue of hypertension in RTX, addressing its multifactorial pathophysiology and demonstrating the importance of ABPM as a tool for monitoring BP in these patients. Treatment is based on lifestyle changes and antihypertensive drugs, with calcium channel blockers considered first-line treatment. The best blood pressure target and treatment with more favorable outcomes in RTX are yet to be determined, through well-conducted scientific studies, that is, in terms of AH in RTX, we currently have more questions to answer than answers to give. Arterial Hypertension (AH) is categorized in Brazil as a non-communicable chronic disease, defined by persistent elevation of blood pressure (BP), with Systolic Blood Pressure (SBP) ≥ 140 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 90 mmHg , using the correct technique, on at least in two different occasions without the use of antihypertensive medicationsAccording to the Kidney Disease Improving Global Outcomes (KDIGO) 2021The prognostic classification of the renal transplant patient, according to the glomerular filtration rate estimated by formulas such as the Modification Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology (CKD-EPI), follows the same logic as the CKD patient who includes them in stages 1 to 5, comparing them also according to the degree of albuminuriaAlthough RTX corrects many of the pre-transplant changes, AH remains a challenge to be faced in at least 50% of patients, both as an etiology of CKD and as a consequence of the disease, called “de novo hypertension”. This prevalence is quite variable among the different studies in the literature, so that it may be present in up to 70% to 90% of patients who received RTXAH after RTX is related to the kidney disease that determined the loss of function of the primitive kidneys and its continuity depends on the disease that affected them. As nephrectomy of primitive kidneys is not usually indicated, they may continue to produce vasopressor substances that maintain the hypertensive process, such as renin, activating the renin-angiotensin-aldosterone system (RAAS)Kidney transplant recipients are usually affected by numerous comorbidities of different natures, such as diabetes mellitus (DM), dyslipidemia, obesity, Metabolic Syndrome, among others, in addition to a higher prevalence of adverse events resulting from the use of immunosuppressive drugs, particularly calcineurin inhibitors (CIN) and glucocorticoids, which worsen blood pressure controlThe role of immunosuppressive therapy is vital in preventing rejection and prolonging graft survival, but it can cause AH, DM, dyslipidemia, electrolyte disorders and, paradoxically, nephrotoxicity. Glucocorticoids and CIN can increase sensitivity to vasoconstrictors, activating the RAAS, endothelin and thromboxane A2 (TXA2), in addition to determining sympathetic hyperactivity and sodium retention. On the other hand, they inhibit the synthesis of nitric oxide and prostacyclin, which may increase the formation of free radicals. It has also been reported that CIN can cause thiazide-sensitive sodium chloride cotransporter hyperactivity. Together, these processes cause endothelial dysfunction and contribute to the impairment of organ functionLike the CIN, glucocorticoids are important drugs, preventing graft rejection, but they are independent risk factors for the development of AH with a dose-dependent effect, due to the activation of mineralocorticoid receptors, leading to water retentionA promising line of research is the study of the development of HA post-transplantation when donors are hypertensive and recipients become hypertensive. A systematic review with meta-analysis concluded that this condition increases the risk of post-transplant AH and loss of the transplanted kidney, although more studies are needed to establish this relationshipThe presence of genetic mutations in the Apolipoprotein L1 (APOL1) and Caveolin-1 (CAV-1) genes, present in the donor and in the recipient, is associated with worse outcomes for the renal graft and the development of HA after RTXAnother key point is the quality of the transplanted kidney, which can be evaluated through the number of normal and sclerosed glomeruli in the renal biopsy and the calculation of the Kidney Donor Profile Index (KDPI), which uses clinical and laboratory data to classify the donated kidney as normal or expanded criteria kidney, the latter having worse outcomes and greater possibility of AHThe age factor adds risk to the recipient. It is estimated that for each 10-year increase in donor age, the risk of post-transplant AH increases by 28%After RTX, some factors may also be related to the appearance or worsening of HA in the recipient, such as, for example, the presence of antibody-mediated rejection events, late graft function, and the possibility of partial obstruction of the renal artery at the site of the anastomosis, which implies RAAS hyperactivity, with worsening of the hypertensive process and the need for surgical interventionIn addition, the inertia of physicians following these patients is highlighted, a phenomenon recognized in the treatment of primary hypertension, even when BP is outside the pressure targetFinally, another relevant issue is the arteriovenous fistula (AVF), the main access route to hemodialysis, which determines a modest but significant decrease in BP, as observed in a meta-analysis of 14 studies. On the other hand, ligation of the AVF after transplantation may determine an increase in BPPost-transplant AH is correlated with negative cardiovascular and renal outcomes, with loss of renal function, decreased graft survival and higher mortality from these causes in different countries and continentsRTX recipients often present discrepant BP values when it is measured in the office or by systematic methodologies, such as Home Blood Pressure Monitoring (HRBP) or Ambulatory BP Monitoring (ABPM). It is therefore recommended that blood pressure control in kidney transplant recipients be performed using these tools for greater diagnostic and therapeutic safety, considering the AH phenotype foundThe 24-hour MAP allows a rigorous analysis of blood pressure behavior, enabling the detection of attenuation or absence of nocturnal dipping, or even the appearance of hypertension during sleep, common conditions in chronic kidney patients and transplant recipients, which determine greater cardiovascular risk and which can be minimized with the use of chronotherapy, as demonstrated in several studiesA satisfactory nocturnal dip is considered to be a drop in SBP and DBP between 10-20% during sleep. When the decrease in BP during sleep remains between 1-10%, it is called attenuated nocturnal dipping; when negative or equal to zero, it is designated nocturnal descent or riser; and when it is present and >20%, it is classified as extreme nocturnal dippingSignificant prevalence of white coat hypertension (WCH) and masked hypertension (MAH) are frequent in ABPM, which can also occur in the general population and are described as blood pressure variations only observed when measurements are taken outside the office. WCH is characterized when BP is elevated in the office but is normal outside of it. MAH, in contrast, occurs when BP is normal in the office, but high in measurements performed away from this environmentSustained AH, also called True Hypertension (TH), occurs when BP is altered in the office and is equally high during HRBP or ABPM. When the BP is within the limits established in the office and in home monitoring (ABPM or HMBP), it is called True Normotension (TN)An integrative literature review was carried out using the Newcastle-Ottawa scale to search for clinical studies available in the last 10 years, in English and Portuguese, that portray the theme of arterial hypertension in kidney transplant recipients. Searches were carried out in PubMed, Medline and SciELO electronic databases and search filters were used to include articles published after 2012, with the following descriptors: Renal Transplantation, Arterial Hypertension and Ambulatory Blood Pressure Monitoring. The survey was carried out by two independent researchers in order to answer the question: What are the main ABPM studies in kidney transplant recipients?This summary can be viewed in Korogiannou et al.Nguyen et al.Gluskin et al.The study by Mallamaci et al.In Turkey, Kendirlinan Demirkol et al.Ahmed et al.Another Turkish study by Kayrak et al.2, serum creatinine < 2.5 mg/dL and follow-up of 5.5 years. Mean office SBP and DBP were 140.2 and 80.4 mmHg, respectively; and 66% of office measurements were ≥ 130/80 mmHg. The mean 24-hour ABPM was 131.5 and 77.4 mmHg for SBP and DBP, respectively. According to ABPM, only 36.5% of the recipients had controlled BP (mean 24 hours < 130/85 mmHg), 65% were considered to have a WCH phenotype. Considering the results, the authors recommend ABPM for medication adjustment and adequate BP control.The multicenter RETENAL study conducted in Spain by Fernandez Fresnedo et al.Ibernon et al.Wen and GourishankarNational data published in 2011 by Agena et al.A point to be stressed is the high complexity of the ABPM analytical report and the dependence of a qualified physician to report the exam, which is susceptible to interpretive errorsIn conclusion, although with different prevalence, it is correct to say that renal transplant patients should always be followed up with regular ABPM, which is an international recommendation. Phenotypes other than what is considered normal are prevalent, and these patterns may be correlated with worse cardiovascular and graft outcomes, possibly also with mortality, as in non-transplanted hypertensive adults, for reasons that are still unknownThis statement is also supported by a systematic review with meta-analysis by Pisano et al., which included 22 studies . Among 12 studies that evaluated data on renal outcomes, ten indicated that BP assessed by ABPM was a better predictor of decline in renal function than office measurements. Twelve studies analyzed the relationship between different BP records and target organ damage, and found robust correlations between echocardiographic abnormalities and vascular damage markers with 24h ABPM but not with office BP. In addition, the abnormal circadian BP pattern (non-dippers and reverse dippers) identified RTX receptors at risk for loss of renal function and cardiovascular abnormalitiesThe phenotypes diagnosed by ABPM are associated with more adequate decision-making and with outcomes, such as target organ damage and adverse renal events, translated into worsening proteinuria, progressive decrease in glomerular filtration rate and cardiovascular compromise.Studies that assess AH in RTX contribute to a better understanding of this frequent situation in transplant patients, and approaches aimed at controlling the different phenotypes have the potential to minimize damage.In the absence of specific randomized and controlled studies in this population, comparing different long-term treatments in relation to renal and cardiovascular outcomes, we should use existing blood pressure targets for uncontrolled hypertensives4.It is interesting to note that the ESC/ESH – European Society of Cardiology and European Society of Hypertension 2018)81 did noLifestyle changes (LSC) are always the first measures known to be effective in the treatment of AH in RTX, which do not differ from those recommended for AH in the general populationIdeally, every renal transplant patient should be treated by a multidisciplinary team, which is not always the reality of the services that carry out this follow-up. Thus, it is extremely important for the patient to be part of the process, as their lifestyle can directly affect hard outcomes, such as RTX function and mortality2; restriction of alcohol consumption and smoking cessation; in addition to guidance on medications that should be avoidedBriefly, LSC include a healthy diet, rich in fruits and vegetables, low in saturated fat and cholesterol, with grains, low in protein and low in sodium; regular physical activity, according to cardiovascular and respiratory capacity, preferably 150 minutes/week; maintenance of body mass index < 25 kg/ mIn recent years, several dietary trends have emerged aimed at reducing cardiovascular risk, anti-inflammatory effects and weight loss. Among them, plant-based diets, intermittent fasting, low-carbohydrate/keto diet and juices of different compositions have received media attention, but care and knowledge about the potential risks and benefits in kidney transplant recipients are neededA non-pharmacological measure that is widely encouraged and universally recommended for hypertensive patients is the use of a low-sodium diet, a change that is easy to implement, effective and cost-free. The 2021 KDIGO document suggests that sodium intake should be < 2 g of sodium per day  in patients with AH and CKD, with no specific recommendation for transplant recipientsIt is noteworthy that studies in the general population, but also in kidney transplant recipients, have associated the Mediterranean Diet with favorable clinical outcomesRegarding the DASH diet, in a prospective cohort study with 632 clinically stable renal transplant recipients, greater compliance to the DASH diet was associated with a lower risk of renal function decline , as well as lower mortality for all causes Physical exercise seems to be safe in RTX recipients and itis associated with a better quality of life and exercise capacityPharmacological treatment should be individualized and include antihypertensive drugs of different pharmacological classes until the recommended goals are reached. Risk-modifying variables such as sociodemographic profile, presence of comorbidities, stage of CKD and presence of albuminuria should always be compared. In addition, dosage convenience, availability, greater efficacy and tolerability, and fewer adverse effects are considered. Often, AH will be characterized as resistant or refractory, requiring the association of drugs with synergistic effects, which may be an option from the beginning, including in associationKDIGO 2021, as well as other authors, including a systematic review with meta-analysis and the 2021 European Society of Hypertension consensus, indicate that the first-line drugs are calcium channel blockers (CCB), as they improve graft function and reduce its loss. Its nocturnal use has shown good performance in reversing the altered sleep pattern. They are indicated especially in the first few months of RTX when the risk of acute kidney injury is greater, and RAAS blockers, particularly angiotensin II AT1 receptor blockers (ARBs), when renal function is stable, because these drug classes reduce graft loss when compared to the others. However, they make it clear that there is a lack of studies that support an evidence-based recommendation, since kidney transplant recipients are very often excluded from randomized clinical trials comparing outcomesTransplant patients with coronary heart disease and/or arrhythmias may benefit from beta-blockers or alpha and beta-blockers such as carvedilol. In benign prostatic hyperplasia, alpha-blockers are well indicated. In all cases in which hypervolemia or edematous states occur, thiazide or loop diuretics can be associated, including mineralocorticoid receptor antagonists, always with monitoring of serum potassium levels and kidney functionSGLT2 inhibitors and selective mineralocorticoid receptor antagonists are promising for use in RTX, as they cause nephroprotection, regardless of antihypertensive action, and can potentially be beneficial, but this is still a hypothesis to be unveiled, opening the way for studies with that population.The main aspects of treatment are summarized in Transplantation represents an alternative treatment for CKD, improving the quality and quantity of life and reducing the risk of cardiovascular complications, outcomes related to chronic diseases, in addition to avoiding adverse events related to the dialysis procedure itself. In addition, it allows the reintegration of the individual into social life, increases the possibility of returning to work practices, in addition to improving physical and mental conditionThus, like other chronic patients, transplant patients require close medical monitoring and a multidisciplinary team, compliance to an individualized care plan and to LSC, with constant checking of associated and controllable factors, such as hypertension and DM, both of which are highly prevalent in these individuals, as cause or consequenceIn this sense, it is worth mentioning the complexity of compliance to treatment of an individual with a chronic disease in their self-careThe correct diagnosis of AH by ABPM is able to unmask phenotypes that are impossible to determine without this resource, providing better blood pressure control. Although we still have many questions about the best way of diagnosing AH in kidney transplant recipients, the data in the literature enable us to advocate emphatically in favor of its use, or alternatively, HMBP when ABPM is unavailable, for diagnosis and follow-upTechnologies such as renal sympathetic denervation and baroreceptor stimulation, not discussed here, should not be used routinely, but can be considered in cases of resistant or refractory AH.Finally, we conclude that the best blood pressure target and treatment with more favorable outcomes in RTX are yet to be determined, that is, we currently have more questions to answer than answers to give in this complex tangle.


Background and objectives: Obstructive sleep apnea-hypopnea syndrome (OSAHS) and chronic obstructive pulmonary disease (COPD) are independently linked to an increase in cardiovascular disease (CVD). Only a few studies have been published linking the association between overlap syndrome and congestive heart failure (CHF). This review highlights the interplay between overlap syndrome (OSAHS-COPD) and CHF. Materials and methods: We thoroughly reviewed published literature from 2005 to 2022 in PubMed, Google Scholar, and Cochrane databases to explore the link between overlap syndrome and cardiovascular outcomes, specifically congestive heart failure. Results: Research indicates that individuals with overlap syndrome are more likely to develop congestive heart failure than those with COPD or OSA alone. Congestive heart failure is a common comorbidity of overlap syndrome, and it has a two-way connection with sleep-related breathing disorders, which tend to occur together more frequently than expected by chance. Conclusions: CHF seems to have a strong relationship with OS. Further research is required to understand the relationship between OS and CHF. In 1985, David C. Flenely first used the term “overlap syndrome” (OS) to characterize the combination of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA). The overall prevalence of COPD and OSA alone is high, and studies have revealed a higher prevalence of COPD coexisting with OSA ,3. PatieWe performed a literature search of PubMed, Google Scholar, and Cochrane databases to identify the literature reporting association of overlap syndrome with cardiovascular outcomes, particularly CHF . LiteratKeywords used for the literature search were ‘Overlap Syndrome (OR (Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea)) AND (Heart Failure OR Congestive Heart Failure OR CHF).’We carefully reviewed several studies and found 206 studies relevant to our topic. After removing duplicates, we screened 188 studies to find the data we needed for our review. Of those, we excluded some studies that did not meet our criteria and ended up with 8 full-text articles to include in our study. We excluded studies that lacked relevant information, had inaccessible full-text articles, or contained similar data already obtained from other studies.2 compared to OSA-only patients. The severity of COPD was similar in the OS group and COPD-only group, however FEV1/FVC ratio was lower in the OS group. This study showed that in comparison to patients with OSA alone or COPD alone, OS patients had higher prevalence rates of heart failure  and pulmonary arterial hypertension . Adle et al. [p = 0.01). The strength of this study is the large sample size, objective assessment, and subgroup analysis of COPD and OSA patients, however it is possible that there is a selection bias due to the fact that only a large subset of patients underwent pulmonary function tests, rather than the entire population referred for suspicion of OSA.A literature search  suggestsp = 0.002) and PH (aHR: 2.006 (1.005–4.004); p = 0.048). Among 43 heart failure patients, 28 had OS, 14 had COPD only, and 1 had OSAS. There was no statistically significant difference in severity of COPD and OSA when comparing these groups to the OS group; however, the OS group were more likely to require CPAP, suggesting more chance of developing comorbidities in this group. The incidence of heart failure was significantly higher in the OS group (35.4%) than the COPD group (8.9%) and OSA group (0.6%). This study provides insights regarding CHF in OS; however, this is a retrospective, single center study. Some patients were diagnosed as having OSA during treatment of coronary heart disease, which may have overestimated the risk of CHF in OSA patients. The retrospective cohort study by Tang et al.  in 6554 The prospective cohort study of 10,149 patients by Kendzerska et al. [The systematic review by Czerwaty et al.  suggestsIn a prospective, observational study conducted by Bhalla et al. , 77 consOn the other hand, patients with NYHA class 2 had a higher prevalence of OSA (51.4%) compared to NYHA class 3 (37.8%) and NYHA class 4 (10.8%). It is recommended that sleep apnea screening be implemented in the evaluation and follow-up of heart failure patients. However, it should be noted that the study’s assessment of sleep-disordered breathing (SDB) was limited to using a specific device and not complete lab polysomnography, so the prevalence and severity of SDB in the cohort may have been underestimated. Despite some limitations, this study gives important insights into the bidirectional relationship between CHF and OSA.2 vs. 11 6 g/m2, p = 0.02). Patients with COPD who are over the age of 18 and are at least in GOLD stage 2, and have a smoking history of at least 10 pack-years were considered for inclusion. They underwent overnight laboratory-based polysomnography to determine if they had OSA. Those with an apnea-hypopnea index (AHI) greater than 10 per hour were identified as having overlap syndrome. Adult COPD patients (GOLD stage 2 or higher) with at least 10 pack-years of smoking history were included. Overnight laboratory-based polysomnography was performed to test for OSA. Subjects with an apnea-hypopnea index (AHI) >10/h were classified as having overlap syndrome. When comparing the overlap syndrome group to the COPD-only group, the RV remodeling index (RVRI) was greater in the overlap syndrome group . The severity of oxygen desaturation was correlated with the level of RV remodeling in overlap syndrome participants .Sharma et al.  performeThe study by Chen et al.  includinIt is becoming increasingly clear through research that there is a strong connection between OSA, COPD, and CHF. While these conditions have their own distinct origins and clinical features, they often coexist due to shared risk factors such as age, obesity, smoking, and systemic inflammation. Moreover, each condition’s pathophysiological mechanisms can exacerbate the others. Thus, a vicious cycle of worsening symptoms and outcomes is created. This interplay involves many factors, including the impact of OSA on COPD exacerbations and how COPD can affect cardiac function in CHF patients. Additionally, both OSA and COPD can contribute to systemic inflammation, oxidative stress, endothelial dysfunction, and neurohormonal abnormalities, which substantially increase the risk of CHF. Furthermore, CHF itself is a risk factor for OSA.The pathogenesis of cardiovascular outcomes, including CHF in OS, is multifactorial and characterized by a cascade of events, as discussed below. Hypoxia triggers a chain of oxidative stress, systemic inflammation, and vascular dysfunction, which is further compounded by sympathetic overactivity. The influence of modifiable risk factors such as obesity and smoking further exacerbates this process. Patients with COPD experience decreased oxygen levels and breathing difficulties during sleep, especially during the REM (rapid eye movement) phase, due to relaxed intercostal muscles and limited chest wall movement. In contrast, patients with OSA encounter episodes of breathing cessation and reduced breathing primarily caused by the collapse of the upper airway, reduced pressure within the chest, and the activation of the sympathetic nervous system. This leads to frequent awakenings during the night and excessive sleepiness during the day . IndividWhen cells experience low oxygen levels (hypoxia) as in congestive heart failure, it triggers the activation of a protein called HIF-1α. This protein is involved in various cellular processes, such as controlling cell death, regulating blood vessel constriction, managing energy usage, and promoting the growth of new blood vessels (angiogenesis). In addition to HIF-1α, hypoxia also activates another protein called HIF-2α, which is responsible for triggering the production of pro-inflammatory cytokines (molecules that promote inflammation). The resulting release of IL-1, IL-6, TNF-alpha, and reactive oxygen species (ROS) creates oxidative stress within the vessel wall. This oxidative stress is the driving force behind the development of atherosclerosis, as it initiates endothelial dysfunction (damage to the inner lining of blood vessels), promotes the breakdown of fats in the blood (lipid peroxidation), and sustains the disease process through angiogenesis ,15,16. Research has demonstrated that individuals who have both obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) exhibit elevated sympathetic activity and decreased parasympathetic activity, as evidenced by measurements of heart rate modulation. Additionally, this could promote an increase in cardiac morbidities . FurtherObesity is considered the key risk factor for OSA. Patients with COPD and OSA are more susceptible to nocturnal desaturation because of the narrowing of the upper airways caused by neck obesity. Truncal obesity may weaken the respiratory muscles and diminish the compliance of the chest wall, which could lead to ventilation-perfusion mismatches and ventilatory dysfunctions. Such disturbance in ventilatory capacity results in the retention of carbon dioxide, which can be detrimental to the cardiovascular system . CigaretCongestive heart failure (CHF) and sleep-related breathing disorders have a two-way relationship. If sleep-disordered breathing is left untreated, it can have a negative impact on the function of the left ventricle, ultimately leading to CHF . AccordiThe existing studies suggest that patients with OS are at greater risk of developing CHF. However, only limited studies are available which explain the association between these two. We could analyze only few papers and data to conclude the result. Through an extensive literature search, we found a potential strong association between OS and CHF. However, several gaps remain in our understanding. We propose following future research directions to advance knowledge in this field. To better understand potential triple overlap, it is crucial to conduct large-scale epidemiological studies determining its prevalence, incidence, and associated risk factors. Longitudinal studies can be useful in identifying the causal factors and patterns of disease progression between OSA, COPD, and CHF.Conducting molecular studies, animal models, and in vitro experiments can aid in comprehending the shared pathophysiological pathways, such as chronic inflammation, oxidative stress, endothelial dysfunction, and autonomic dysregulation. Identifying specific biomarkers and genetic predispositions can facilitate prompt detection and targeted treatments.Standardized diagnostic criteria and comprehensive assessment tools are necessary to identify and characterize a potential triple overlap syndrome accurately. Research must focus on developing validated screening questionnaires, diagnostic algorithms, and imaging techniques that consider this association’s unique challenges.Researching the most effective ways to manage this situation is imperative. Future studies must determine the safety and effectiveness of interventions that target each aspect. Exploring new treatments, such as upper airway stimulation and upcoming medicine options, is highly recommended to determine if they can treat this condition.Long-term predictive studies are required to determine the impact of this suggested triple overlap on patient outcomes, including morbidity, mortality, and health-related quality of life.Future research should explore the effectiveness of educational interventions and shared decision-making approaches in managing patients with OS and CHF.Based on the review of prevailing literature on OS, there seems to be a significant association between CHF and OS. The mutual existence of all three of these conditions can be a significant cause of morbidity and mortality. Compared to COPD-only and OSAHS-only groups, OS patients possibly have worse diastolic dysfunction, more right ventricular mass index, more severe oxygen desaturation, and more frequent CHF. Due to the significant interplay between these entities, the triple overlap of OSAHS, COPD (OS), and CHF might have to be viewed as a single spectrum in the right clinical context. Due to paucity of data, further literature is needed to establish this association with more clarity. Identifying patients at risk of concomitant prevalence of all three of these conditions is important to initiate a timely management strategy and prevent complications.


This study investigated the effect of a continuous infusion of ketamine during thoracic surgery on arterial oxygenation , plateau airway pressure (Pplat), dynamic compliance, and shunt fraction (Qs/Qt) were recorded during two-lung ventilation as a baseline and at 30  and 60 (OLV-60) minutes during one-lung ventilation.Thirty patients older than 40 years, diagnosed with chronic obstructive pulmonary disease, and undergoing lobectomy were recruited for this study. Patients were allocated randomly to 1 of 2 groups. At the induction of anaesthesia, group K received intravenous (iv) 1 mg kg2, PaCO2, PaO2/FiO2 values, and Qs/Qt ratio were similar between the 2 groups at OLV-30 minute . However, at OLV-60 minute, PaO2, PaO2/FiO2 values were significantly increased, and Qs/Qt ratios were significantly decreased in group K than in group S .PaO2/FiO2) and decrease shunt fraction.Our data suggest that a continuous infusion of ketamine and desflurane inhalation in patients with chronic obstructive pulmonary disease during one-lung ventilation increase arterial oxygenation (PaO Chronic obstructive pulmonary disease is defined by chronic airflow limitation, incompletely reversible.One-lung ventilation applied for lung resection produces gas exchange abnormalities and increased intrapulmonary shunt, deepening hypoxemia in chronic obstructive pulmonary disease patients during surgery.Ketamine changes respiratory mechanics, provides airway relaxation, and alleviates bronchospasm in patients with pulmonary disease.2/FiO2) and decreases shunt fraction.The continuous infusion of ketamine in patients with chronic obstructive pulmonary disease undergoing lung cancer surgery during one-lung ventilation increases arterial oxygenation  and FEV1/FVC  ratio and results in hypoxemia and hypercapnia due to ventilation-perfusion (VA/Q) mismatch.2Chronic obstructive pulmonary disease (COPD) is defined by chronic airflow limitation, incompletely reversible. Pathologic changes include obstructive bronchiolitis in the small airways, parenchymal destruction, reduced elastic recoil due to emphysema, endothelial dysfunction, and arterial stiffening in the pulmonary vasculature.3 Furthermore, conventional methods such as high external positive end-expiratory pressure (PEEP) and high peak pressures may deteriorate oxygenation and respiratory mechanics during OLV because of high intrinsic PEEP (PEEPi) and the development of air trapping in patients with COPD. Additionally, the individual response of patients with COPD to external PEEP cannot be predicted.4One-lung ventilation (OLV) during thoracic surgery is a frequently chosen technique to provide ideal surgical exposure. However, during OLV, intrapulmonary shunt and dead space increase because of continued perfusion of the non-dependent lung and insufficient expansion of the dependent lung. Anaesthetics and the lateral decubitus position may also increase the shunt ratio and inhibit hypoxic pulmonary vasoconstriction (HPV).5 and decreasing the production of inflammatory cytokine in pulmonary tissues.6 Continuous infusion of ketamine in patients with asthma has been reported to improve gas exchange and chest compliance significantly.7Ketamine has been reported to change respiratory mechanics, provide airway relaxation, and alleviate bronchospasm in patients with the pulmonary disease by blocking the reuptake of catecholamines into presynaptic sympathetic neurons,9In the literature, although many agents  have been proposed to improve gas exchange and oxygenation during OLV, as far as we know, no studies have evaluated the effect of ketamine during thoracic surgery on arterial oxygenation and the shunt fraction in patients with COPD undergoing lung cancer surgery.2/FiO2) and the shunt fraction (Qs/Qt) in patients with COPD undergoing lung cancer surgery. We hypothesised that ketamine infusion during thoracic surgery would significantly improve oxygenation and decrease the shunt fraction in patients with COPD undergoing lung cancer surgery.This study was undertaken to investigate the effect of a continuous infusion of ketamine during thoracic surgery on arterial oxygenation , severe liver or kidney disease, or obesity [body mass index (BMI) ≥30 kg m-2] were excluded from the study. Demographic variables  and BMI values were evaluated and recorded preoperatively. The categories of COPD, medications used, comorbidities, preoperative spirometry data, duration of OLV and operation, right/left lobectomy ratios, and the number of cigarettes used by patients in the groups were also recorded.This prospective, randomised, double-blinded, controlled study was approved by the Ethical Committee of Çukurova University Medical Faculty (IRB = 56/6), and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrolment at clinicaltrials.gov (NCT02962999). The study was performed at the Department of Anesthesiology at the Hospital of Çukurova University Medical Faculty, Adana, Turkey. Forty-two patients undergoing lobectomy due to lung cancer were recruited in this study. The inclusion criteria included age over 40 years, American Society of Anesthesiologists (ASA) physical status II to III, and patients diagnosed with COPD according to the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease (GOLD) criteria.2), non-invasive blood pressure (NIBP), end-tidal CO2 pressure (ETCO2), bispectral index (BIS), core temperature, urine output, and ventilator settings such as tidal volume, respiratory rate, peak airway pressure (Ppeak), plateau airway pressure (Pplat), and dynamic compliance. Ventilator settings were adjusted based on pulse oximetry and measurements of arterial-blood gas analyses.Standard monitoring in the operating room included lead II-V electrocardiogram (ECG), pulse oximetry . Patients were monitored using the BIS index to titrate the desflurane concentration and the level of anaesthesia; we aimed to keep a BIS index between 40 and 60. If the BIS index increased above 60, the concentration of desflurane was increased. Patients were intubated with a double-lumen tube , and the position of the tube was confirmed using a fiberoptic bronchoscope . After induction of anaesthesia, the radial artery was catheterised to monitor continuous arterial pressure and analyse blood gas samples, and a central venous catheter was placed in the right internal jugular vein to evaluate central venous pressure.Two intravenous accesses with an 18-gauge peripheral intravenous catheter were established in all patients. General anaesthesia was induced with propofol , fentanyl , and rocuronium  and maintained using 4%-6% desflurane  + 60% air + 40% O-1, Ketalar flakon, Pfizer, New York, ABD) or 0.9% saline. Both syringes and solutions were labelled “study drug” and coded to maintain the double-blind nature of the study. Ketamine was supplied in 10 mL vials at a 50-mg mL-1 concentration and diluted with 100 mL normal saline to a 5 mg mL-1 concentration. The placebo saline solution was prepared similarly.Fifteen minutes before induction of anaesthesia, the patients were allocated randomly to 1 of 2 groups. A computer-generated random number table was used for randomisation. An anaesthetist, blinded to the study groups, prepared 2 syringes and 2 solutions containing ketamine  as a bolus, followed by 0.5 mg kg-1 h-1 infusion until the end of the operation. Group S (n = 15) received the same amount of iv bolus but with 0.9% saline  at induction, followed by 0.5 mL kg-1 h-1 infusion of 0.9% saline until the end of the operation.At induction of anaesthesia, group K (n = 15) intravenously (iv) received 1 mg kg-1, ratio of inspirium:expirium (I:E) = 1:2.5, and PEEP = 5 cmH2O in both groups. Respiratory frequency was set to maintain an end-tidal carbon dioxide partial pressure in 5-6 kPa. Ppeak was limited to 30 cmH2O. During OLV, the dependent lung was ventilated with VCV, TV 5 mL kg-1, I:E = 1:2.5, PEEP = 5 cmH2O. Fraction of inspired oxygen (FiO2) was 40% initially and then adjusted to maintain SaO2 at 92% to 98%. In the event of desaturation (SaO2 <92%), FiO2 was increased step by step from 0.4 to 1.0 in 0.2 increments. If desaturation persisted despite the therapy above, the ventilation strategy was converted to TLV. Respiratory frequency during OLV was also set to maintain an end-tidal carbon dioxide partial pressure in 5-6 kPa.Following endotracheal intubation with double-lumen tubes, patients were ventilated with volume-controlled ventilation (VCV), tidal volume (TV) 8 mL kg2, EtCO2) were continuously monitored but recorded only just before the initiation of OLV (baseline) and at 30 (OLV-30) and 60 (OLV-60) minutes during OLV. PaO2 and PaCO2 values, FiO2, PaO2/FiO2 ratio, Ppeak, Pplat, static compliance, and the Qs/Qt ratio were recorded just before the initiation of OLV (as baseline) and at OLV-30 and OLV-60 minutes during OLV. Dynamic compliance was calculated using the following formula: Haemodynamic [heart rate (HR) and mean arterial pressure (MAP)] and respiratory variables (SpOpeak - PEEP)Dynamic compliance = tidal volume/ + 6.7 RI = respiratory index 2 - PaO2)/PaO2RI =  - PaCO2PAOPB = atmosphere pressure = 760 mmHg2O = water vapour pressure = 47 mmHgPH2, PaCO2, and PaO2/FiO2 values were measured routinely only at 20 minutes after arrival to the PACU to evaluate pulmonary function status. It was planned that if the patients experienced signs of dyspnoea or episodes of hypoxia (SpO2 <90%), they would be transferred to the intensive care unit (ICU). Patients were evaluated for 72 h postoperatively for the occurrence of pneumonia and atelectasis on X-ray and the beginning of acute lung injury (ALI). All other complications such as hypotension and atrial fibrillation were recorded after arrival in the ICU. Length of hospital stay and mortality rates at 30 days were recorded.All patients were followed-up routinely in the postoperative care unit (PACU) postoperatively. Patients were monitored regarding haemodynamic and respiratory variables to evaluate the postoperative pulmonary complications. PaO11 A PaO2/FiO2 ratio <300 mmHg, diffuse pulmonary infiltration at 72 h, and exclusion of hydrostatic pulmonary oedema because of other primary causes were defined as ALI.12In addition to clinically detected new or progressive lung infiltration on X-ray, 2 or more symptoms were regarded as pneumonia; fever >38°C or hypothermia, leucocytosis or leucopenia, and purulent secretion.2 and the PaO2/FiO2 ratio. The secondary outcome was regarded as shunt fraction, postoperative pneumonia, atelectasis, ALI, and the length of hospital stay.The primary outcome was accepted as improvement in oxygenation expressed as the PaO13 study in which the effect of ketamine on the PaO2 was investigated, the effect size was defined as 1.25, and it required 15 subjects per study group for a power of 0.9 and a significance level of .05. This study calculated the effect size assuming that PaO2 values would be 176 ± 31 mmHg in group K and 142 ± 22 mmHg in group S at 30 minutes. Therefore, the sample size was determined by supposing that the PaO2 values at 30 minutes would be 34 mmHg higher in group K.Power analysis for testing the hypothesis and determining sample size used a primary endpoint defined as improvement in oxygenation. Considering Rees and Gaines'st-test or the Mann–Whitney U-test was used depending on whether the statistical hypotheses were fulfilled. Repeated measures analysis of variance was applied to evaluate the change in the measurements obtained in the time interval. The normality of distribution for continuous variables was confirmed with the Shapiro–Wilk test. The statistical level of significance for all tests was P <.05. All analyses were performed using the IBM Statistical Package for Social Sciences Version 20.0  statistical software package. Categorical variables are expressed as numbers and percentages, and continuous variables are summarised as mean and standard deviation or median and minimum-maximum where appropriate. The Fisher exact test was used to compare categorical variables between the groups. To compare continuous variables between 2 groups, Student’s Forty-two patients undergoing lobectomy due to lung cancer were recruited in this study and randomised into the ketamine and saline groups. However, 12 patients were excluded from the study; 4 patients declined to participate, 3 because of missing data, and 5 due to changes in the surgical plan . Therefo2, PaCO2, Ppeak, Pplat, and dynamic compliance values at baseline and OLV-30 and OLV-60 minutes were similar between the 2 groups . However, at OLV-60 minutes, PaO2 and PaO2/FiO2 values were significantly increased, and Qs/Qt ratios were significantly decreased in group K compared with group S . However, there was not a statistically significant variation in group S (P = .999 for both).The over time changes of the measurements were examined and PaO2 and the PaO2/FiO2 ratio at the postoperative 20th minute were similar, and there was no significant difference between the 2 groups.Postoperative data are presented in 2 desaturation (SaO2 <90%) after extubation. In group S, 2 patients were transferred to the ICU without extubation because of insufficient respiratory effort after anaesthesia was turned off, and 1 patient was re-intubated in the PACU because of dyspnoea and O2 desaturation.One patient was transferred to the ICU in group K because of tachypnoea, dyspnoea, and OAlthough statistically not significant, 6 complications (atelectasis in 3 patients and ALI in 3 patients) were detected in group S during the follow-up period in the ICU, whereas none in group K. The length of hospital stay was found similar between the 2 groups.2/FiO2) and decreases shunt fraction in patients with COPD during OLV. In the present study, higher PaO2 and PaO2/FiO2 values were comparable to previously reported PaO2 levels in patients using intraoperative ketamine during OLV.14 However, Rees and Gaines13 reported significantly higher PaO2 levels with ketamine than we found.This study demonstrated that continuous infusion of ketamine and desflurane inhalation increases arterial oxygenation  and causes hypoxemia and hypercapnia. Furthermore, OLV applied for lung resection produces gas exchange abnormalities and increased intrapulmonary shunt, deepening hypoxemia and oxygen desaturation (<90%) during surgery.17 This level of desaturation raises concern that cellular organ function may be impaired or damaged due to reduced oxygen delivery.18 The interventions for improving oxygenation during OLV include an increase in the inspired fraction of oxygen followed by the recruitment of both lungs, PEEP application to the ventilated lung, and continuous positive airway pressure application to the nonventilated lung.19 However, complex physiology, diversity in patients’ underlying conditions, and the limitation of PEEP application to overcome the V/Q mismatch can render these attempts ineffective.20 Various therapeutic agents such as β-agonists or dexmedetomidine have been available in such situations, but limited studies support their use.8 Therefore, treatment options for hypoxemia in these patients during OLV are limited. Ketamine has been reported to produce bronchodilation by blocking both N-methyl d-aspartate receptor-induced bronchoconstriction and reuptake of catecholamines into presynaptic sympathetic neurons. Furthermore, it acts as a relaxant agent on bronchial smooth muscles by vagal inhibition and improves pulmonary compliance.5 In the present study, ketamine infusion decreased Qs/Qt ratios and improved arterial oxygenation (PaO2/FiO2) at OLV-60 minutes in patients with COPD during OLV.Chronic obstructive pulmonary disease is characterised by expiratory airflow limitation because of small airway inflammation (obstructive bronchiolitis), air trapping, and parenchymal destruction. These factors adversely affect the 21 In the present study, ketamine was chosen to increase PaO2/FiO2 values and decrease the Qs/Qt ratio. Previous studies demonstrated that ketamine acted as a relaxant agent on bronchial smooth muscles by vagal inhibition, improved pulmonary artery compliance, decreased V/Q mismatch, and provided haemodynamic stability.23 However, conflicting results have been presented in the literature. Ogawa et al24 investigated the effects of etomidate and ketamine on pulmonary vasorelaxation in response to receptor-dependent and independent endothelial activators and found that both etomidate and ketamine selectively attenuated receptor-mediated endothelium-dependent pulmonary vasorelaxation by inhibiting the nitric oxide and endothelium-derived hyperpolarising factor components of the response. Conflictingly, Weinreich et al14 reported that intrapulmonary shunting and arterial oxygen desaturation during OLV were decreased with ketamine anaesthesia, and cardiovascular stability improved during OLV. That study differed from ours because they had no patients with COPD, and the effect of ketamine was primarily attributed to its positive inotropic and chronotropic effect. However, contrary to Weinreich et al’s14 trial, the increased oxygenation and decreased shunt fraction in our study were attributed to the bronchodilatory effect of ketamine because there was no significant difference in haemodynamic variables between the two groups.Hypoxic pulmonary vasoconstriction is less protective in patients with COPD due to a decrease in endothelium-dependent relaxation, leading to decreased pulmonary artery compliance and increased pulmonary artery stiffness.25 The present study could not demonstrate any beneficial effect of ketamine on PVR because we could not measure pulmonary arterial pressure and PVR.The efficiency of ketamine on pulmonary vasculature and perfusion is still under investigation. In some recent clinical studies, ketamine exhibited an ideal effect in patients with pulmonary hypertension with no increase in pulmonary vascular resistance (PVR).26 Previous studies of COPD mainly focused on hyperinflation and PEEPi because of air trapping during OLV.27 However, there is controversy regarding PEEPi and oxygenation during OLV in patients with COPD. Some authors support a negative correlation between PEEPi and oxygenation,4 whereas others advocate that PEEPi increases functional residual capacity and improves oxygenation in severe COPD.28 However, this statement should be considered according to the severity of COPD. In this study, we were not able to measure PEEPi but administered a longer expiration period (I/E: 1/2.5) than usual, which would decrease the possibility of PEEPi. In addition, we rarely observed decreased compliance and increased Ppeak and Pplat levels because most of our patients had mild-to-moderate COPD. Nevertheless, the effects of ketamine on respiratory mechanics cannot be underestimated, and the results of this study cannot be extrapolated.During the period of OLV in the lateral position, numerous factors influence arterial oxygenation. In addition to the increased right-to-left shunt through the non-dependent lung, the alveolar pressure in the dependent lungs may also affect arterial oxygenation.9 Huber et al7 demonstrated that ketamine was usually effective in reducing airway resistance in patients with existing pulmonary dysfunction, involving slightly, moderately, or severely increased airway resistance. In the present study, we observed no increased airway resistance in any patients with COPD, and this might be related to the relief of bronchospasm of ketamine evidenced by lower Pplat and Ppeak levels, although nonsignificant. However, Howton et al29 evaluated ketamine as a bronchodilator in patients with severe acute asthma and found no difference between the ketamine and placebo groups. Accordingly, ketamine was concluded to have had no bronchodilatory effect, despite satisfying or beneficial effects.Ketamine has long been used in treating patients with acute asthma as a bronchodilator and in managing anaesthesia.Pplat and Ppeak values were better, we failed to demonstrate any significant difference between the 2 groups, mainly due to the relatively small sample size. Second, we were not able to measure PEEPi. Lastly, the dose of ketamine might vary. In adults, the induction dose of ketamine has been reported as 1-2 mg kg-1 iv, and it should be given at a rate of around 0.1-0.5 mg kg-1 h-1 to maintain anaesthesia without producing significant cumulative effects.30 However, when used for refractory bronchospasm in operating rooms and refractory status asthmaticus in ICUs, a loading dose of 0.1-0.2 mg kg-1 is used, followed by an infusion of 0.15-2.5 mg kg-1 h-1.5 We aimed to evaluate the effects of ketamine on oxygenation and respiratory mechanics during OLV; we used a 1-mg kg-1 bolus dose of ketamine, followed by 0.5 mg kg-1 h-1 continuous infusion; however, lower or higher doses of ketamine could also be used.The present study has several limitations. First, although -1 h-1) and desflurane inhalation in patients with COPD undergoing lung cancer surgery during OLV increases arterial oxygenation (PaO2/FiO2) and decreases shunt fraction. Although Pplat and Ppeak values were better in the ketamine group, we failed to demonstrate any significant effect on these respiratory mechanics. Further studies with a more significant patient number are needed to demonstrate this effect.Continuous infusion of ketamine (0.5 mg kg


IgA nephropathy (IgAN) is the most common glomerular disease globally, andits susceptibility and the risk for the development of end-stage kidneydisease are related to genetic and environmental factors. IgAN recurrenceafter kidney transplantation is relatively common, impacting graft functionand survival. This study evaluated the risk factors and the clinical,laboratory, and histological characteristics of post-transplant IgANrecurrence based on the Oxford classification.Retrospective single-center cohort study including kidney transplantrecipients with biopsy-proven pre-transplantation IgAN, with analysis ofrisk factors and clinical, laboratory, and histological characteristics ofthe IgAN recurrence cases.53 patients fulfilled the inclusion criteria and were included in the study.The majority was male, white, eutrophic, with a mean age of 27 ± 9 years atIgAN diagnosis. Systemic arterial hypertension and proteinuria were frequentin the pretransplant period. Four recipients (7.5%) presented IgANrecurrence in a period of 6 to 122 months post-transplant. According to theOxford classification, they had high scores of mesangial hypercellularityand segmental glomerulosclerosis in the native kidney biopsies and there wasmesangial hypercellularity in all analyzed graft biopsies. None of thesepatients had received induction immunosuppression and all of them presentedgraft failure in the follow-up.In this series, there was a high prevalence of mesangial hypercellularity andsegmental glomerulosclerosis on native kidney biopsies, and mesangialhypercellularity occurred in all IgAN recurrence graft biopsies. Despite thelower incidence of recurrence of IgAN post-transplant compared to previousreports, progression to graft loss was of 100%. The susceptibility to IgAN and chronic kidney disease (CKD) risk are relatedto genetic and environmental factors. Coexisting risk factors, such as hypertension, smoking, and obesity,contribute to microvascular injury and disease progression, with CKD rates reaching20% after 20 years of follow-up. IgAN results from circulating and glomerular complexes comprised ofgalactose-deficient IgA1 directed against the hinge region O-glycans, leading toglomerular inflammation and mesangial proliferation. The clinical presentation of IgAN ranges from microscopic hematuria duringrespiratory or gastrointestinal tract infections in children and young adults toimpaired kidney function in older adults, with proteinuria and high blood pressure. IgAN recurrence after kidney transplantation is relatively common, with a15-year cumulative incidence of 15%. Several risk factors for recurrence of IgAN post-transplant have beendescribed, including younger age, recipients of zero-HLA mismatched living donors,steroid-avoidance or early steroid withdrawal, absence of inductionimmunosuppressive therapy, HLA allelic subtypes, crescentic and rapidly progressivenative IgAN, and shorter total ischemia time.IgA nephropathy (IgAN) is the most common glomerular disease globally, withprevalence varying geographically according to kidney biopsy indications. Electron microscopy usually shows electron-dense deposits in the mesangialand paramesangial areas and occasionally in the sub-endothelial and sub-epithelial regions. IgAN commonly presents with mesangial expansion and hypercellularity inlight microscopy, but focal glomerular necrosis, segmental sclerosis, and crescentsin Bowman's space may also be detected. The Oxford IgAN classification defines four histopathological features withprognostic value: mesangial hypercellularity (M), endocapillary hypercellularity(E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis(T), commonly referred to as the MEST score. A recent update added cellular and fibrocellular crescents (C) to previouscriteria, resulting in the MEST-C score.The hallmark of IgAN diagnosis is predominant IgA deposits in the mesangium, isolatedor associated with IgG and/or IgM, C3, properdin, C4 or C4d, mannose-binding lectin,and terminal complement complex (C5b-C9), while C1q is usually absentThe present study evaluated risk factors and clinical, laboratory, and histologicalcharacteristics of post-transplant IgAN recurrence based on the Oxford IgANclassification.This was a retrospective single-center cohort study including kidney transplantrecipients with biopsy-proven pre-transplantation IgAN. Patients younger than 18years and those without histologic confirmation of IgAN were excluded. Clinical,laboratory and histological data were retrospectively collected from medical recordsand renal transplant program databases at the time of transplantation and during thepost-transplant follow-up. Data were transcribed and organized into a Microsoft™Excel worksheet. The study was approved by the local ethics committee.Primary outcomes were risk factors for IgAN recurrence and clinical, laboratory, andhistological characteristics of these cases. The secondary endpoint comprisedanalysis of the histologic features of cases with an available description of Oxfordparameters in native kidney biopsies according to IgAN recurrence aftertransplantation.Induction immunosuppressive therapy consisted of basiliximab  in recipients with panel-reactive antibody (PRA) lower than 50%,without anti-HLA donor-specific antibodies (DSA) receiving a kidney from a standarddeceased donor. In cases of expanded criteria donors, non-identical HLA livingdonors, PRA > 50%, or presence of DSA, induction therapy was with IVanti-thymocyte globulin, 3-7 mg/kg, dose-adjusted by lymphocyte count. Allrecipients received 500 mg methylprednisolone IV at the time of transplantation andsteroid therapy during follow-up. Maintenance immunosuppression consisted of acalcineurin inhibitor (tacrolimus or cyclosporine) and an antiproliferative drug(sodium mycophenolate or azathioprine).. The IgAN recurrence was diagnosed by identifying a predominant deposition ofIgA in the immunofluorescence study of the post-transplant graft biopsy in patientswith pre-transplant IgAN diagnosis. The IgAN features were described according tothe presence of mesangial hypercellularity, endocapillary hypercellularity,segmental glomerulosclerosis, tubular atrophy, and crescents on light microscopy.The cell-mediated rejection cases were treated with steroid pulse therapy oranti-thymocyte globulin. The antibody-mediated rejection treatment consisted of 5-7sessions of plasmapheresis associated with 2g/kg intravenous immunoglobulin(IVIG).The post-transplant allograft biopsies were performed if serum creatinine increasedmore than 20% from baseline or if new-onset proteinuria occurred. Two experiencedrenal pathologists performed the histologic analysis. The rejection cases werediagnosed and categorized based on histological findings and blood DSA detectionaccording to the 2013 Banff classification, revised in 20152 tests. Values of p < 0.05 were consideredstatistically significant. Data were analyzed with the GraphPad Prism 7.0c™ for Mac.Statistical analysis: Continuous variables are reported as mean ± standard deviationor as median and range and/or percentages. Continuous variables were compared amongthe groups using the Kruskal-Wallis test, whereas categorical variables werecompared using Pearson χOf 2,870 kidney transplantations performed between 1999 and 2019, 53 fulfilled theinclusion criteria and were included in the study. The majority was male, white,eutrophic, with a mean age of 27 ± 9 years at IgAN diagnosis . Thirty-The mean age at transplantation was 37.7 ± 11.2 years, about ten years older than atIgAN diagnosis, and the majority of patients received a kidney from a deceased donor. In this series, three patients had previous kidney transplantation,one with graft loss due to chronic graft dysfunction and the others because ofarterial thrombosis. Thirty-two patients (60.4%) received immunosuppressiveinduction therapy, mainly thymoglobulin , associated to a routinemethylprednisolone injection. During post-transplant follow-up, renal graft biopsywas performed in 20 patients (57.1%) mainly because of renal dysfunction . Of these cases, four presented proteinuria (22.2%) and one hematuria (5.5%).One graft biopsy was indicated due to isolated proteinuria and there was no case ofgraft biopsy performed due to isolated hematuria. Acute rejection was diagnosed in12 patients (22.6%), being 11 classified as cell-mediated. The cell-mediatedrejection cases occurred 12.3 ± 30.2 months post-transplant, without a temporalrelationship with IgAN diagnosis. Only one patient presented histologic changescompatible with chronic rejection.2), while the non-recurrent patients were classified asoverweight, with a significantly higher mean BMI (p = 0.03). In this series, all theIgAN recurrence patients did not receive immunosuppressive induction therapy attransplant, and the immunosuppressive maintenance regimen included a calcineurininhibitor, an antiproliferative drug, and steroids. The mean dose of prednisone inthe IgAN recurrence group was 2.5 mg daily, while in the group without IgANrecurrence was 5 mg daily (p = 0.01). The native kidney biopsy registries of IgANrecurrence group showed mesangial hypercellularity in more than 50% of glomeruli(M1), segmental glomerulosclerosis (S1), and tubular atrophy and interstitialfibrosis in 26% to 50% of the cortical area (T1) [Four white patients (7.5%) with a mean age of 22 ± 4.76 years presented histologicfeatures of IgAN recurrence in a period ranging from 6 to 122 months aftertransplant. The IgAN recurrence group was younger at IgAN diagnosis in native kidney(p = 0.04) and at kidney transplant (p = 0.01) . These prea (T1) . One casLong term follow-up of renal transplants from patients with native IgAN showed 17(32%) graft failures 41.3+ 38.1 months after transplant, being four (23.5%) due toIgAN recurrence, six (35.3%) secondary to chronic graft dysfunction withoutrecurrence, and two (11.8%) due to acute rejection. Five patients died with afunctioning graft (29.4%).. Most patients had arterial hypertension and proteinuria at IgAN diagnosis innative kidneys, which are considered risk factors for the progression to chronickidney disease. Morphological analysis of native kidney biopsies showed mesangialhypercellularity in 42.8% of patients, and prevalence of segmentalglomerulosclerosis higher than 50%, evidencing its impact on the progression tokidney failure. Compared with other causes of CKD, patients with IgAN have betteraccess to kidney transplantation, since they are younger, have significantly fewercomorbidities, and have a shorter waiting-list time.The general characteristics of the patients with biopsy-proven IgAN in this study aresimilar to those of previous studies, with patients younger than other causes ofchronic kidney disease (CKD), differing according to the biopsy indication and length of post-transplant follow-up. In this series, the IgAN recurrence rate was 7.5%, possibly due to the lackof protocol graft biopsies, limiting the diagnosis of recurrence to cases of graftdysfunction or proteinuria. However, protocol biopsies performed exclusively todetect IgAN recurrence are not recommended, as no treatment has been shown to haltor slow the progression of clinical disease. In this series, the age at native IgAN diagnosis and transplantation weresignificantly lower in the IgAN recurrence group, similar to other studies. The determinants for IgAN recurrence are poorly understood, but severalcharacteristics have been identified as possible factors, such as younger age attransplantation, rapid progression of native IgAN, level of proteinuria, and donor characteristics. Several studies have shown the association between glomerular C4d andprogression of IgAN. In this series, however, the IgAN recurrence biopsies were performed beforeestablishing the C4d research protocol; therefore, we did not have this information.IgAN recurrence was associated with young age and long-term posttransplant follow-upin this series, concordant to previous studies. The BMI was significantly lower in the IgAN recurrence group. Althoughhigher body mass index (BMI) was associated with IgAN progression, little is known about its influence on IgAN recurrence.The post-transplant IgAN recurrence is relatively common, with recurrence ratesranging from 8% to 53%. A retrospective study of Berthoux et al. showed a 9% IgAN recurrence rate after anti-thymocyte globulin therapy, whilethe group without induction presented a 41% recurrence rate. Although the IgANrecurrence group did not receive induction immunosuppression and received asignificantly lower maintenance dose of steroids than the group without IgANrecurrence in this series, the IgAN recurrence rate was lower than that study. Wehypothesized that this could be related to all these cases taking aimmunosuppressive maintenance regimen with a calcineurin inhibitor,antiproliferative drugs, and steroids. However, the protective effect ofimmunosuppressive regimen in IgAN recurrence patients remains controversial since itwas not verified in some studies.The heterogeneity in immunosuppressive protocols seems to be also associated withIgAN recurrence, such as immunosuppressive protocols free of induction therapy,steroid-avoidance, or early steroid-withdrawal. In this series, the patients with IgAN recurrence did not receive additionalspecific treatment. Previous studies showed that treatment of IgAN recurrence withACEi, BRA, pulse steroids, or intravenous cyclophosphamide had no impact on the outcomes. In this series, all patients with high scores in the Oxford classificationwere associated with poor prognosis. Although the Oxford classification has been developed in native kidneys, ithas also been successfully applied for IgAN recurrence in transplant kidneys. The patients with IgAN recurrence presented high scores in the native kidneybiopsies, and mesangial hypercellularity was detected in all IgAN recurrence graftbiopsies. A multicenter, international, retrospective study by Uffing et al. showed that IgAN recurrence was associated with a 3.7-fold higher risk ofgraft loss. A study by Nijim et al. showed a mean graft survival of 6.5 ± 5.1 years. Graft survival time afterIgAN recurrence diagnosis was similar in this series, with a median survival of 68.5months. The limitations of this study are its single-center and retrospectivedesign. Besides this, the lack of protocol biopsies impaired the accuracy of thetrue prevalence of IgAN recurrence in the center, which was probably underestimatedin the present study.The optimal treatment for IgAN recurrence remains unknownIgAN is the most common glomerular disease with relatively common recurrences,varying widely according to biopsy indication and length of post-transplantfollow-up. In this series, IgAN recurrence was associated with younger age andlong-term post-transplant follow-up. According to the Oxford classification, therewas a high prevalence of mesangial hypercellularity and segmental glomerulosclerosison native kidney biopsies, and mesangial hypercellularity occurred in all IgANrecurrence graft biopsies. The progression to graft loss was 100% in the IgANrecurrence group, and lower doses of maintenance steroids were associated with aworse prognosis.