Background: People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. Methods: The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, –4.27 to –2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61–0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59–0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. Conclusions: In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02065791.

Background: The discrepancy between glycosylated hemoglobin (HbA_1c) and fasting plasma glucose (FPG) in clinical practice may be related to factors such as acute stress, renal dysfunction, and anemia, and its relationship with in-hospital outcomes is uncertain. The aim of this study was to investigate the association between the type of discrepancy between HbA_1c and FPG and in-hospital outcomes in patients with acute coronary syndrome (ACS) and diabetes. Methods: The Improving Care for Cardiovascular Disease in China - Acute Coronary Syndrome (CCC-ACS) project is a national, hospital-based quality improvement project with an ongoing database. Patients with ACS, diabetes and complete HbA_1c and FPG values at admission were included. The consistent group included patients with HbA_1c < 6.5% and FPG < 7.0 mmol/L or HbA_1c ≥ 6.5% and FPG ≥ 7.0 mmol/L. The discrepancy group included patients with HbA_1c ≥ 6.5% and FPG < 7.0 mmol/L (increased HbA_1c group) or HbA_1c < 6.5% and FPG ≥ 7.0 mmol/L (increased FBG group). Results: A total of 7762 patients were included in this study. The numbers of patients in the consistent and discrepancy groups were 5490 and 2272 respectively. In the discrepancy group, increased HbA_1c accounted for 77.5% of discrepancies, and increased FPG accounted for 22.5% of discrepancies. After adjusting for confounders, patients in the increased FPG group had a 1.6-fold increased risk of heart failure (OR, 1.62; 95% CI, 1.08–2.44), a 1.6-fold increased risk of composite cardiovascular death and heart failure (OR, 1.63; 95% CI, 1.09–2.43), and a 1.6-fold increased risk of composite major adverse cardiovascular and cerebrovascular events (MACCEs) and heart failure (OR, 1.56; 95% CI, 1.08–2.24) compared to patients in the increased HbA_1c group. Conclusions: Patients with an increased FPG but normal HbA_1c had a higher risk of in-hospital adverse outcomes than those with increased HbA_1c but normal FPG. This result may indicate that when HbA_1c and FPG are inconsistent in patients with ACS and diabetes, the increased FPG that may be caused by stress hyperglycemia may have a more substantial adverse effect than increased HbA_1c, which may be caused by chronic hyperglycemia. These high-risk patients should be given more attention and closer monitoring in clinical practice. Trial registry: Clinicaltrial.gov, NCT02306616. Registered 29 November 2014.

Key Points: Endothelin receptor antagonists should be applied for patients with CKD whose proteinuria and high risk of kidney function decline remains insufficiently controlled. We recommend that endothelin A receptor-selective endothelin receptor antagonists should be preferable for patients with CKD with consideration for combination therapy with sodium-glucose cotransporter-2 inhibitors. Background: Endothelin receptor antagonists (ERAs) are considered a potential effective treatment to reduce proteinuria and protect kidney function for patients with CKD; however, they may cause fluid retention. We conducted this meta-analysis to quantify the efficacy and safety of ERAs in CKD. Methods: We searched Cochrane Library, Ovid Medline, and Ovid Embase for randomized controlled trials up to January 2025. Continuous and dichotomous data were reported as standardized mean differences (SMDs) with 95% confidence intervals (CIs) and risk ratios (RRs) with 95% CIs, respectively. Results: Fourteen trials enrolling 6412 patients were included. Compared with the control group, ERAs decreased the risk of ESKD (RR=0.76, 95% CI [0.61 to 0.96]), reduced the urine protein-to-creatinine ratio (SMD=−0.56, 95% CI [−0.78 to −0.35]) and urine albumin-to-creatinine ratio (SMD=−0.64, 95% CI [−0.75 to −0.53]), achieved more frequent complete proteinuria remission (RR=2.61, 95% CI [1.84 to 3.71]) and partial proteinuria remission (RR=1.51, 95% CI [1.32 to 1.73]), slowed the decline of eGFR in the subgroup with a follow-up duration of at least 1 year (SMD=0.18, 95% CI [0.04 to 0.32]), improved the chronic eGFR slope (SMD=0.15, 95% CI [0.01 to 0.30]), and decreased systolic BP (SMD=−0.53, 95% CI [−0.76 to −0.30]) and diastolic BP (SMD=−0.78, 95% CI [−1.18 to −0.38]). Although the risk was increased in B-type natriuretic peptide (SMD=0.08, 95% CI [0.01 to 0.16]) and body weight (SMD=0.15, 95% CI [0.01 to 0.29]), ERAs did not increase the incidence of edema, fluid retention, or heart failure. The risk of hypotension was higher with ERAs compared with the control group (RR=1.92, 95% CI [1.36 to 2.70]). Conclusion: These findings suggest that ERAs may reduce proteinuria, prevent kidney disease progression, and lower BP in individuals with CKD.

Purpose: In recent years, the incidence of malignancy patients with membranous nephropathy (MN) has gradually increased, but the clinical and pathological characteristics of these patients are still unclear. Our study aims at elucidating the clinical and pathological characteristics of malignancy patients with MN, especially the expression patterns of MN-specific antigens in both kidney and tumor tissue. Patients and Methods: A retrospective analysis was performed to summarize the clinical and pathological data of MN patients with malignancy at Beijing Anzhen Hospital from January 1, 2012, to December 31, 2022, followed by a thorough review of relevant literature published between May 1, 2000 to May 1, 2023 and case aggregation. Results: 19 patients in our center’s MN cohort and 21 patients from literature review were diagnosed with malignancy either before or after being diagnosed with MN. Among them, 16 (40.0%) and 17 (42.5%) patients tested PLA2R-only and THSD7A-only positive in renal tissue, respectively. And 16 of 26 patients showed similar staining in tumor and kidney tissues. Compared to the idiopathic membranous nephropathy (IMN) patients at our center, patients with malignancy were older, had a lower estimated glomerular filtration rate, and had a lower rate of partial or complete response to treatment. Renal tissue from MN patients with concomitant malignancy was less frequently PLA2R-positive, more frequently THSD7A-positive, and more often glomerular IgG subclass IgG2 (P = 0.033) but less frequently IgG4 (P < 0.001). Conclusion: The clinical and pathological characteristics of MN patients with concomitant malignancy are different from those of IMN patients. Active screening for malignancy should be performed in non-PLA2R-positive elderly MN patients with a poor therapeutic response. Staining for MN target antigens in kidney and tumor tissues may be inconsistent, and the role of MN target antigens needs to be further explored.

Key Points: Higher serum phospholipase A2 receptor antibody is an independent risk factor of arterial and venous thromboembolic events in patients with primary membranous nephropathy. The inflammatory system may play a role in this relationship. Background: This study investigated risk factors and possible mechanisms of arterial and venous thromboembolic events in patients with primary membranous nephropathy (pMN). Methods: Patients with pMN confirmed by renal biopsy from June 1, 2010, to March 3, 2023, were included, and the study outcome was set as a composite end point of acute coronary syndrome, heart failure, cerebral infarction, arrhythmia, pulmonary embolism, deep venous thrombosis, and all-cause mortality. Results: A total of 433 pMN patients with complete data were included, with a median follow-up time of 73 (45.5–101.6) months and a composite end point rate of 10.2%. We divided all patients with events into an early event group (events occurring in the first 2 years after renal biopsy) and a late event group (events occurring after 2 years after renal biopsy) according to the time of event. It showed a lower serum albumin and higher baseline value of serum phospholipase A2 receptor (PLA2R) antibody titer and mean value of each follow-up in the early event group compared with the late event group. Cox proportional hazards model showed that after adjusting for confounding factors, in addition to older age, history of deep vein thrombosis and higher urinary protein, higher baseline serum PLA2R antibody titers (odds ratio [OR], 1.034; 95% confidence interval [CI], 1.006 to 1.063; P = 0.015), and high high-sensitivity C-reactive protein level (OR, 1.049; 95% CI, 1.002 to 1.098; P = 0.041), renal pathology with segmental sclerotic lesions (OR, 3.480; 95% CI, 1.338 to 9.050; P = 0.011) were also independent risk factors for the occurrence of end point events. The results also showed that baseline serum IL-6 levels were significantly higher in the event group compared with the nonevent group (4.25 versus 3.21 pg/ml), and the difference was statistically significant (P = 0.009). Conclusions: In the early event group, higher serum PLA2R antibody and renal pathology with segmental sclerosis lesions may affect the occurrence of cardiovascular, cerebrovascular, and venous thrombotic events. The inflammatory system may play a role in this relationship.