Sodium-glucose co-transporter 2 inhibitors for all-cause and cardiovascular death in people with different stages of CKD: A systematic review and meta-analysis.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors (SGLT2is) reduce cardiovascular risk in people with diabetes and established cardiovascular disease, but emerging studies in chronic kidney disease (CKD) have inconsistent results. In this systematic review, we evaluate the effects of SGLT2is on cardiovascular mortality in people with CKD as a whole and across subgroups stratified by baseline kidney function and among people at low, moderate, high and very high risk according to KDIGO- CKD classification system. METHODS: Literature search was conducted in PubMed/MEDLINE, Cochrane/CENTRAL, Scopus and Web of Science up to 30 November 2023. We included randomized controlled trials assessing the effect of SGLT2is on cardiovascular mortality in people with CKD. Secondary outcomes included all-cause mortality and major adverse cardiac events (MACE). RESULTS: Eleven studies (n = 83,203 participants) were included. In people with CKD, treatment with SGLT2is compared to placebo reduced the risk of cardiovascular death by 14% (hazard ratio [HR] .86; 95%CI .79-.94), all-cause death by 15% (HR .85; 95%CI .79-.91) and MACEs by 13% (HR .87; 95%CI .81-.93). A consistent treatment effect was observed across eGFR-subgroups (≥60 mL/min/1.73 m2: HR .82, 95%CI .65-1.02; <60 mL/min/1.73 m2: HR .86, 95%CI .77-.96, p-subgroup difference = .68) and KDIGO risk-categories (low, moderate, high and very high) (p-subgroup difference = .69) for cardiovascular death; reduction in the risk of all-cause death tended to be greater in the highest KDIGO risk categories. A consistent treatment effect on cardiovascular mortality was observed for different SGLT2is agents studied. Sensitivity analysis for cardiovascular mortality endpoint including studies in diabetic people yielded similar results (HR .86; 95%CI .77-.97). CONCLUSIONS: Treatment with SGLT2is led to a significant reduction in the risk of cardiovascular and all-cause mortality in people with different CKD stages. These findings support the use of SGLT2is as an adjunct cardiovascular protective therapy in CKD. PROSPERO REGISTRATION NUMBER: PROSPERO registration number: CRD42022382863.

The association of sex differences in ambulatory blood pressure with cardiovascular events and mortality in dialysis patients.

Male patients with pre-dialysis chronic kidney disease (CKD) have worse ambulatory blood pressure (BP) control than females; this is associated with higher mortality. Male hemodialysis patients have higher ambulatory BP levels than females. This analysis aimed to investigate the association of sex differences in ambulatory BP with cardiovascular events and mortality in hemodialysis individuals. 129 male and 91 female hemodialysis patients with valid 48-h BP monitoring were followed for 53.4 ± 31.1 months. The primary endpoint was cardiovascular mortality; the secondary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, resuscitation after cardiac arrest, heart failure-hospitalization, coronary or peripheral revascularization. Cumulative freedom from the primary endpoint was lower for women (logrank-p = 0.032), while cumulative-freedom from the secondary endpoint did not differ significantly between-groups (logrank-p = 0.644). The crude risk for cardiovascular mortality was significantly higher in women (HR = 1.613, 95% CI [1.037, 2.509]). The crude risk for the combined endpoint was not different between the two groups (HR = 0.918, 95% CI [0.638, 1.320]). After adjusting for major risk factors (age, diabetes, dialysis vintage, coronary disease and hemoglobin) no significant differences in the risk for both the primary and the secondary endpoint were observed between women and men (primary: HR = 1.295 (95% CI [0.808, 2.078]), secondary: HR = 0.763 (95% CI [0.521, 1.118])). After additional adjustment for 44-h systolic BP the above relationships did not alter (primary: HR = 1.329 (95% CI [0.826, 2.137]), secondary: HR = 0.808 (95% CI [0.551, 1.184])). In conclusion, female hemodialysis patients have higher crude but similar adjusted cardiovascular mortality rates compared to male counterparts. In contrast to pre-dialysis CKD, the neutral relationship between gender and adverse cardiovascular outcomes in hemodialysis is not further affected by ambulatory BP.

Uromodulin biology.

Uromodulin is a kidney-specific glycoprotein which is exclusively produced by the epithelial cells lining the thick ascending limb and early distal convoluted tubule. It is currently recognized as a multifaceted player in kidney physiology and disease, with discrete roles for intracellular, urinary, interstitial and serum uromodulin. Among these, uromodulin modulates renal sodium handling through the regulation of tubular sodium transporters that reabsorb sodium and are targeted by diuretics, such as the loop diuretic-sensitive Na+-K+-2Cl- cotransporter type 2 (NKCC2) and the thiazide-sensitive Na+/Cl- cotransporter (NCC). Given these roles, the contribution of uromodulin to sodium-sensitive hypertension has been proposed. However, recent studies in humans suggest a more complex interaction between dietary sodium intake, uromodulin and blood pressure. This review presents an updated overview of the uromodulin's biology and its various roles, and focuses on the interaction between uromodulin and sodium-sensitive hypertension.

Autonomic Nervous System Dysfunction in Peritoneal Dialysis Patients: An Underrecognized Cardiovascular Risk Factor?

BACKGROUND: In patients with end-stage kidney disease (ESKD) receiving peritoneal dialysis (PD), cardiovascular events represent the predominant cause of morbidity and mortality, with cardiac arrhythmias and sudden death being the leading causes of death in this population. Autonomic nervous system (ANS) dysfunction is listed among the non-traditional risk factors accounting for the observed high cardiovascular burden, with a plethora of complex and not yet fully understood pathophysiologic mechanisms being involved. SUMMARY: In recent years, preliminary studies have investigated and confirmed the presence of ANS dysfunction in PD patients, while relevant results from cohort studies have linked ANS dysfunction with adverse clinical outcomes in these patients. In light of these findings, ANS dysfunction has been recently receiving wider consideration as an independent cardiovascular risk factor in PD patients. The aim of this review was to describe the mechanisms involved in the pathogenesis of ANS dysfunction in ESKD and particularly PD patients and to summarize the existing studies evaluating ANS dysfunction in PD patients. KEY MESSAGES: ANS dysfunction in PD patients is related to multiple complex mechanisms that impair the balance between SNS/PNS, and this disruption represents a crucial intermediator of cardiovascular morbidity and mortality in this population.

Impact of public restrictive measures on hypertension during the COVID-19 pandemic: existing evidence and long-term implications.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that was first identified in December 2019 and emerged into an ongoing global pandemic. Both the pandemic itself and the associated public restrictive measures of social mobility established with different intensity over different periods in various countries have significantly affected the everyday activities and lifestyles of people all over the world. The impact of lockdown and quarantine measures on hypertension incidence and blood pressure (BP) control is an important topic that requires further investigation. The aim of this review is: a) to present the current evidence regarding the actual effects of public restrictive measures on BP levels and control, originating primarily from studies investigating the impact of public restrictive measures on BP control with the use of various BP phenotypes; b) to summarize the possible pandemic-related effects of factors known to affect BP levels, including both traditional (e.g. dietary habits including alcohol and sodium intake, body weight, smoking and physical activity) and non-traditional (e.g. sleep patterns, air pollution, environmental noise, delayed diagnosis and medication adherence) ones.

Renal artery stenting in the correct patients with atherosclerotic renovascular disease: time for a proper renal and cardiovascular outcome study?

Atherosclerotic renovascular disease (ARVD) represents the most common type of renal artery stenosis. In the last decade, a few large trials failed to demonstrate the superiority of standard medical therapy plus percutaneous transluminal renal angioplasty (PTRA) compared with medical therapy alone in lowering blood pressure levels or preventing adverse renal and cardiovascular outcomes in patients with ARVD. However, this issue remains controversial and an ongoing debate focusses on the benefits that selected patients could experience from renal revascularization procedures. In this regard, several pieces of observational data show that PTRA is associated with future cardiorenal benefits in patients presenting with high-risk ARVD phenotypes. Such evidence resulted in a progressive shift in relevant recommendations, with most recent not-graded suggestions supporting that revascularization should be offered in these high-risk subjects. Existing evidence clearly calls for a properly designed randomized controlled trial with selected patients presenting high-risk ARVD phenotypes, in order to confirm the superiority of PTRA versus non-invasive management in this patient group and objectively guide everyday clinical practice.

Advanced chronic kidney disease with life-threatening hypokalemia due to undiagnosed Gitelman syndrome.

We report a case of a 58-year-old woman presenting with symptoms of oliguria, fatigue, anorexia, constipation, hypovolemic signs, and laboratory tests showing severe hypokalemia (1.7 mEq/L), hyponatremia (120 mEq/L), high serum creatinine (SCr, 6.46 mg/dL) and urea (352 mg/dL). The patient had previously been diagnosed with chronic kidney disease (CKD), with SCr up to 2.58 mg/dL 1 year prior, and had in all her previous laboratory tests shown hypokalemia, which was treated with conservative measures and eplerenone despite low-normal blood pressure and normal heart function. A set of coordinated measures were applied to restore the potassium deficit, revert hypovolemic hyponatremia, and support renal function (including 4 dialysis sessions). In addition, a careful diagnostic approach revealed inappropriately high urine sodium and potassium losses, hypocalciuria, and hyperreninemic hyperaldosteronism leading to the diagnosis of Gitelman syndrome and hypokalemia-associated chronic tubulointerstitial nephropathy. Importantly, compliance with a simple set of instructions on high potassium and liberal sodium diet enabled the patient not only to remain euvolemic, free of symptoms, and with normal electrolytes, but also to recover a significant part of renal function and stabilize at an earlier CKD stage. Gitelman syndrome is a rare disorder that can be easily diagnosed and treated following simple measures; its early diagnosis is necessary to avoid life-threatening complications.

Effect of patient gender on short-term blood pressure variability in hemodialysis patients.

Increased blood pressure variability (BPV) is strongly associated with cardiovascular events in end-stage kidney disease patients. Male hemodialysis patients present higher cardiovascular risk compared with females. The aim of this study is to investigate sex differences in short-term BPV in hemodialysis patients. 129 male and 91 female hemodialysis patients that underwent 48-h ABPM were included in this analysis. Standard deviation (SD), weighted SD (wSD), coefficient of variation (CV), and average real variability (ARV) of SBP and DBP were calculated with validated formulas. Age, dialysis vintage and history of major comorbidities did not differ between men and women. 48-h SBP/DBP (137.2 ± 17.4/81.9 ± 12.1 mmHg vs 132.2 ± 19.2/75.9 ± 11.7 mmHg, p = 0.045/<0.001) was significantly higher in men than women. During the 48-h period, all systolic BPV indices were similar between men and women (48-h SBP-ARV: 12.0 ± 2.9 vs 12.1 ± 3.2 mmHg, p = 0.683); 48-h DBP-SD, DBP-wSD and DBP-ARV (9.1 ± 1.6 vs 8.4 ± 1.8 mmHg, p = 0.005) were higher in men. In conclusion, short-term diastolic BPV indices are higher in male than female hemodialysis patients. Increased BPV may impact on the higher incidence of cardiovascular events observed in male hemodialysis patients.

Ambulatory central BP and arterial stiffness in patients with and without intradialytic hypertension.

BACKGROUND: Increased arterial stiffness is suggested to be involved in the pathogenesis of intradialytic-hypertension (IDH). Ambulatory pulse-wave-velocity (PWV) is an independent predictor for all-cause-mortality in haemodialysis and its prognostic power is better than office PWV. This is the first study examining ambulatory central blood pressure (BP) and arterial stiffness parameters in patients with and without IDH. METHODS: This study examined 45 patients with IDH (SBP rise ≥10 mmHg from pre- to post-dialysis and post-dialysis SBP ≥150 mmHg) in comparison with 197 patients without IDH. All participants underwent 48-h ABPM with Mobil-O-Graph-NG; parameters of central haemodynamics, wave reflection and PWV were estimated. RESULTS: Age, dialysis vintage and interdialytic weight gain did not differ between-groups. IDH patients had higher 48-h cSBP (131.7 ± 16.2 vs. 119.2 ± 15.2 mmHg, p < 0.001), 48-h cDBP (86.7 ± 12.7 vs. 79.6 ± 11.5 mmHg, p < 0.001) and 48-h cPP (45.5 ± 10.4 vs. 39.8 ± 10.0 mmHg, p = 0.001) compared to patients without IDH. Similarly, during day- and nighttime periods, cSBP/cDBP and cPP levels were higher in IDH-patients compared to non-IDH. Forty-eight-hour augmentation pressure and index, but not AIx(75) were higher in IDH patients; 48-h PWV (10.0 ± 2.0 vs. 9.2 ± 2.1 m/s, p = 0.017) was significantly higher in patients with IDH. The two study groups displayed different trajectories in central BP and PWV over the course of the recording; IDH patients had steadily high values of the above variables during the 2 days of the interdialytic-interval, whereas non-IDH patients showed a gradual elevation, with significant increases from the 1st to 2nd 24 h. CONCLUSIONS: IDH patients have significantly higher levels of ambulatory central BP and arterial stiffness parameters and a different course over the 48-h period compared with non-IDH patients. Increased arterial stiffness could be a prominent factor associated with the high burden of cardiovascular disease in this population.

Sex differences in ambulatory blood pressure levels, control and phenotypes of hypertension in hemodialysis patients.

BACKGROUND AND AIMS: Ambulatory blood pressure (BP) control is worse in men than women with chronic kidney disease or kidney transplantation. So far, no study investigated possible sex differences in the prevalence, control, and phenotypes of BP according to predialysis and 48-h ambulatory blood pressure monitoring (ABPM) in hemodialysis patients. Further, no study has evaluated the diagnostic accuracy of predialysis BP in male and female hemodialysis patients. METHOD: One hundred and twenty-nine male and 91 female hemodialysis patients that underwent 48-h ABPM were included in this analysis. Hypertension was defined as: (1) predialysis SBP ≥140 or DBP ≥90 mmHg or use of antihypertensive agents, (2) 48-h SBP ≥130 or DBP ≥80 mmHg or use of antihypertensive agents. RESULTS: Predialysis SBP did not differ between groups, while DBP was marginally higher in men. 48-h SBP (137.2 ±â€Š17.4 vs. 132.2 ±â€Š19.2 mmHg, P  = 0.045), DBP (81.9 ±â€Š12.1 vs. 75.9 ±â€Š11.7 mmHg, P  < 0.001) and daytime SBP/DBP were higher in men. The prevalence of hypertension was not different between groups with the use of predialysis BP or 48-h ABPM (92.2% vs. 89%, P  = 0.411). However, concordant lack of control was more frequent in men than women (65.3% vs. 49.4%, P  = 0.023). The prevalence of white-coat and masked hypertension did not differ between groups; the misclassification rate with the use of predialysis BP was marginally higher in women. In both sexes, predialysis BP showed low accuracy and poor agreement with ABPM for diagnosing ambulatory hypertension [area-under-the-curve in receiver-operating-curve analyses (SBP/DBP): men, 0.681/0.802, women: 0.586/0.707]. CONCLUSION: Ambulatory BP levels are higher in male than female hemodialysis patients. Although hypertension prevalence is similar between sexes, men have worse rates of control. The diagnostic accuracy of predialysis BP was equally poor in men and women.

Association of peridialytic, intradialytic, scheduled interdialytic and ambulatory BP recordings with cardiovascular events in hemodialysis patients.

BACKGROUND: Ambulatory-BP-monitoring (ABPM) is recommended for hypertension diagnosis and management in hemodialysis patients due to its strong association with outcomes. Intradialytic and scheduled interdialytic BP recordings show agreement with ambulatory BP. This study assesses in parallel the association of pre-dialysis, intradialytic, scheduled interdialytic and ambulatory BP recordings with cardiovascular events. METHODS: We prospectively followed 242 hemodialysis patients with valid 48-h ABPMs for a median of 45.7 months to examine the association of pre-dialysis, intradialytic, intradialytic plus pre/post-dialysis readings, scheduled interdialytic BP, and 44-h ambulatory BP with outcomes. The primary end-point was a composite one, composed of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, resuscitation after cardiac arrest, hospitalization for heart failure, coronary revascularization procedure or peripheral revascularization procedure. RESULTS: Cumulative freedom from the primary end-point was significantly lower with increasing 44-h SBP (group 1, < 120 mmHg, 64.2%; group 2, ≥ 120 to < 130 mmHg 60.4%, group 3, ≥ 130 to < 140 mmHg 45.3%; group 4, ≥ 140 mmHg 45.5%; logrank-p = 0.016). Similar were the results for intradialytic (logrank-p = 0.039), intradialytic plus pre/post-dialysis (logrank-p = 0.044), and scheduled interdialytic SBP (logrank-p = 0.030), but not for pre-dialysis SBP (logrank-p = 0.570). Considering group 1 as the reference group, the hazard ratios of the primary end-point showed a gradual increase with higher BP levels with all BP metrics, except pre-dialysis SBP. This pattern was confirmed in adjusted analyses. An inverse association of DBP levels with outcomes was shown with all BP metrics, which was no longer evident in adjusted analyses. CONCLUSIONS: Averaged intradialytic and scheduled home BP measurements (but not pre-dialysis readings) display similar prognostic associations with 44-h ambulatory BP in hemodialysis patients and represent valid metrics for hypertension management in these individuals.

Associations of Atrial Fibrillation Patterns With Mortality and Cardiovascular Events: Implications of the MISOAC-AF Trial.

AIM: This retrospective cohort study aimed to evaluate the prognostic implications of the distinct atrial fibrillation (AF) temporal patterns: first diagnosed, paroxysmal, and persistent or permanent AF. METHODS: In this post hoc analysis of the MISOAC-AF trial (NCT02941978), a total of 1052 patients with AF (median age 76 years), discharged from the cardiology ward between 2015 and 2018, were analyzed. Kaplan-Meier and Cox-regression analyses were performed to compare the primary outcome of all-cause mortality, the secondary outcomes of stroke, major bleeding and the composite outcome of cardiovascular (CV) mortality or hospitalization among AF patterns. RESULTS: Of patients, 121 (11.2%) had first diagnosed, 356 (33%) paroxysmal, and 575 (53.2%) persistent or permanent AF. During a median follow-up of 31 months (interquartile range 10 to 52 months), 37.3% of patients died. Compared with paroxysmal AF, patients with persistent or permanent AF had higher mortality rates (adjusted hazard ratio (aHR), 1.37; 95% confidence interval [CI], 1.08-1.74, P = .009), but similar CV mortality or hospitalization rates (aHR, 1.09; 95% CI, 0.91-1.31, P = .35). Compared with first diagnosed AF, patients with persistent or permanent AF had similar mortality (aHR, 1.26; 95% CI, 0.87-1.82, P = .24), but higher CV mortality or hospitalization rates (aHR, 1.35; 95% CI, 1.01-1.8, P = .04). Stroke and major bleeding events did not differ across AF patterns (all P > .05). CONCLUSIONS: In conclusion, in recently hospitalized patients with comorbid AF, the presence of persistent or permanent AF was associated with a higher incidence of mortality and morbidity compared with paroxysmal and first diagnosed AF.