American Journal of Nephrology最新文献

Objective: This study aimed to investigate the effects of cumulative exposure to plasma aldosterone concentration (PAC) and its time course on chronic kidney disease (CKD) in hypertensive patients, with the goal of providing insights for preventing future CKD events, especially in younger hypertensive patients.

Methods: This study enrolled a total of 7142 hypertensive participants, each of whom had undergone at least two PAC measurements before the age of 60. We calculated annual PAC area under the curve (AUC) and used Cox regression analyses to examine the association between annual PAC_AUC and CKD risk. We also explored how the timing course of PAC accumulation affected CKD risk, as different stages of PAC accumulation, even with the same annual PAC_AUC, may lead to varying risks. Additionally, we conducted a comparative analysis to assess the predictive performance of annual PAC_AUC versus single PAC measurements.

Results: During a median follow-up of 5.83 years, 754 participants developed CKD. The results showed a progressive increase in CKD risk with higher annual PAC_AUC [hazard ratio: 1.19; 95% confidence interval: 1.17, 1.21]. Moreover, the timing course of PAC accumulation modulates this risk; Kaplan-Meier curves indicated that participants with similar annual PAC_AUC but earlier PAC exposure had a higher CKD risk compared to those exposed later (Log-rank test, p < 0.001). Furthermore, annual PAC_AUC outperformed single PAC measurements in predictive accuracy.

Conclusion: CKD risk is influenced by both annual PAC_AUC and the timie course of PAC exposure. Participants exposed to elevated PAC earlier had a higher CKD risk than those exposed later, even at the same annual PAC_AUC. This highlights the importance of early PAC control to prevent CKD.

Introduction: Patients with primary membranous nephropathy (PMN) are at high risk of developing venous thromboembolic events (VTEs), while whether neutrophils are involved in the onset of VTEs in PMN remains unclear.

Methods: The association of neutrophils with VTEs was retrospectively analyzed in a large cohort of patients with PMN. Plasma cfDNA levels were evaluated in PMN patients with and without VTEs. In addition, we established a rat model of passive Heymann nephritis (PHN) by immunization with sheep anti-rat Fx1A serum. The inferior vena cava (IVC) was ligated to establish the deep vein thrombosis model. Thrombus weight and length were evaluated at 4 hours after IVC stenosis in rats. GSK484 was administered via intraperitoneal injection to assess the role of NETosis inhibition in thrombosis formation in PHN rats.

Results: Circulating neutrophils in PMN patients with VTEs were significantly higher than in patients without VTEs. Neutrophil counts were positively correlated with the activity of factor IX, factor XI, protein C, protein S, and AT-III (r=0.328, p=0.002; r=0.378, p<0.001; r=0.380, p<0.001; r=0.243, p=0.029; r=0.254, p=0.020). In multivariate logistic regression, neutrophils were the independent risk factors for VTEs in PMN patients (OR=1.608, 95%CI: 1.293-2.000; p<0.05). Significantly increased plasma levels of cfDNA were detected in PMN patients, especially in PMN patients with VTEs, relative to controls. In animal experiments, the plasma cfDNA levels elevated significantly after IVC stenosis in PHN rats, and GSK484 decreased the plasma cfDNA levels in PHN rats with IVC stenosis. 4 hours after IVC stenosis surgery, thrombi formed in PHN rats were both longer and heavier compared to those observed in control rats, and GSK484 administration significantly inhibits the thrombus formation in PHN rats.

Conclusion: This study preliminarily indicated that neutrophils were involved in the hypercoagulation state and increased thrombosis propensity in PMN, offering novel insights into the pathogenesis of thrombosis formation in PMN and potential therapeutic targets for its management.

Background: In primary membranous nephropathy (MN), 80% of patients harbor antibodies against phospholipase A2 receptor 1 (PLA2R1), closely linked to disease prognosis. Prior research has validated the correlation between antibodies directed towards the cysteine-rich(CysR) and C-type lectin 1, 7, and 8(CTLD1, CTLD7, and CTLD8) domains of PLA2R1 and outcomes in MN.

Methods: In a prospective cohort of 52 patients with newly diagnosed PLA2R1-MN, with urine protein ≥ 3.5 g/24 hours and estimated glomerular filtration rate ≥30 mL/min/1.73 m², we studied epitope-spreading patterns and domain-specific PLA2R1-Ab clinically using western blot and ELISA. The primary outcome was a combination of remission at 12 months. Kaplan-Meier curves and Multivariable Cox regression were employed to compare the single and multiple epitope patients.

Results: All patients had anti-CysR antibodies. 26(50.0%) exhibited multi-domain recognition, with one patient specifically recognizing the CTLD8 domain. A significant association was observed between PLA2R1-Ab and CysR-Ab(r = 0.869, P ＜0.001), as well as with anti-CTLD1 antibody(r = 0.803, P ＜0.001). During a median follow-up of 11 months(IQR, 6.0-17.0), 27 patients(65.9%) experienced complete or partial nephrotic syndrome remission. Notably, the multi-domain recognition exhibited a reduced remission rate compared to the single-domain(44.44% vs 82.61%, P = 0.011, alongside higher concentrations of anti-PLA2R1 antibodies. A higher baseline level of anti-CTLD1 was notably linked to a lower likelihood of remission. In a univariate analysis, multi-domain recognition decreases the probability of remission[HR, 0.38 (95% CI, 0.16-0.87), P = 0.022]. After the Kaplan-Meier analysis, the multi-domain group showed lower remission rates than the single-domain group at various time points.

Conclusion: The PLA2R1 epitope spreading is a potent tool for monitoring disease severity and stratifying patients based on renal outcomes for prognostic purposes. Hence, we advocate evaluating epitope spreading at the baseline stage when determining early therapeutic interventions for individuals diagnosed with MN.

Introduction: The pharmacokinetic data on dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, is limited in patients with severe renal impairment. We aimed to evaluate the pharmacokinetic properties and safety of dapagliflozin in patients with chronic kidney disease (CKD) stage 4.

Methods: This was a single center, open label, pharmacokinetic trial involving single and multiple doses. Patients with an estimated glomerular filtration rate (eGFR) of 15-<30 mL/min/1.73m2 were enrolled. The single-dose group received 10mg of oral dapagliflozin once daily, while the multiple-dose group received 10mg daily for five days. Pharmacokinetic parameters, pharmacodynamic response and tolerability were assessed.

Results: A total of 12 participants completed the single-dose study, and 9 participants completed the multiple-dose study. The mean eGFR was 23.4 and 23.2 mL/min/1.73m2 in single and multiple dose group, respectively. In the single dose group, dapagliflozin was rapidly absorbed and metabolized to produce dapagliflozin 3-O-glucuronide (D3OG) , with a mean Tmax of 0.7 hours and 1.8 hours, and a mean T1/2 of 16.7 hours and 14.9 hours, respectively. Participants with an eGFR of 15-24 mL/min/1.73m2 exhibited higher AUC0-∞ and mean residence time (MRT) for D3OG compared to those with an eGFR of 25-30 mL/min/1.73m2. In the multiple-dose group, there was no significant accumulation of dapagliflozin, as indicated by the ratio of AUCTau (918.6 ± 155.2 h×ng/mL) to AUC0-24h (917.1 ± 154.7 h×ng/mL) was close to 1. In the multiple-dose group, UACR decreased by 21% and 24-hour urinary protein decreased by 23% from baseline to 24 hours after the last dose.

Conclusion: In conclusion, no clinically significant accumulation of dapagliflozin was observed in patients with stage 4 CKD.

Introduction: Multimorbidity, defined as the presence of two or more chronic conditions, is associated with poor outcomes and increased cardiovascular risk in the general population. However, the effect of multimorbidity on patients with chronic kidney disease (CKD), a group of patients already at high risk for cardiovascular disease, is not well understood.

Methods: We analyzed data from 4,420 patients with non-dialysis CKD enrolled in the Fukuoka Kidney disease Registry Study. We identified 23 comorbidities, including cardiometabolic and non-cardiometabolic conditions. The patients were categorized into four groups according to the number of comorbidities: Group 1 (0-1 comorbidities), Group 2 (2 comorbidities), Group 3 (3 comorbidities), and Group 4 (≥4 comorbidities). We examined the associations between the number of comorbidities and the incidence of major adverse cardiovascular events (MACE) and all-cause mortality using Cox proportional hazards models.

Results: Over a 5-year follow-up, 229 patients experienced MACE and 456 died. The risk of MACE increased with the number of comorbidities. The multivariable-adjusted hazard ratios (95% confidence intervals) for MACE were 1.40 (0.80-2.44) for Group 2, 2.27 (1.33-3.88) for Group 3, and 3.53 (2.11-5.91) for Group 4 compared with Group 1. The all-cause mortality risk also increased with the number of comorbidities, with adjusted hazard ratios of 1.13 (0.77-1.66), 1.75 (1.22-2.51), and 2.53 (1.80-3.54) for Groups 2, 3, and 4, respectively.

Conclusion: In patients with CKD, multimorbidity is associated with an increased risk of MACE and all-cause mortality.

Introduction: Little is known about the biofluid specificity of microRNAs (miRNAs) in systemic lupus erythematosus (SLE) and the biofluid influence on miRNA diagnosis and prognosis accuracy. Our aim was to analyze the effect of biofluid on miRNA expression and to identify a specific miRNA profile in plasma exosomes related to SLE activity, renal damage and disease flares over a 60-month follow-up period.

Methods: Non-coding RNA sequencing analysis was used to determine miRNA in plasma and plasma exosomes in a discovery cohort of SLE patients and healthy subjects. Potential miRNAs were selected based on the differential expression between biofluids and were validated by quantitative polymerase chain reaction in a higher validation cohort.

Results: From the small RNA-sequencing, the 25 miRNAs with the highest fold-change expression between biofluids were identified. Nine miRNAs were validated in a larger cohort (n=115, of whom 30 had nephritis), and were found to be increased in exosomal fraction and patient groups. Further analysis revealed a panel combining three miRNAs for lupus nephritis diagnosis (miR-101-3p, miR-144-5p and miR-15a-5p) gave an area under the curve that improves the readout of the single miRNAs (0.964, p<0.0001). However, only miR-15a-5p had a strong discriminatory power of renal injury between patients (0.81, p<0.0001). Finally, exosomal miR-15a-5p was associated with histological features, chronicity index and flares (odds ratio 4.24, p<0.001), high levels being a strong independent predictor of 60-month follow-up flares (hazard ratio 4.24, p<0.001).

Conclusion: This novelty study demonstrated a biofluid exosome specificity of miRNA profile related to SLE with nephritis. Highlighting, exosomal miR-15a-5p levels with a strong association with proteinuria, renal histological features and high accuracy in the diagnosis of renal damage and detection of lupus flares. The detection of altered miRNAs levels in exosome-enriched fraction improved the diagnostic accuracy of renal damage in SLE.

Introduction: Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, and edema, though not all patients present with edema. This study investigates edema prevalence and its association with venous thromboembolism, kidney failure, and mortality in patients with nephrotic-range albuminuria and hypoalbuminemia.

Methods: We conducted a Danish multicenter cohort study, including patients with plasma albumin <30 g/L and nephrotic-range albuminuria in the Central Denmark Region (2012-2022). Patients were identified using the laboratory information system and followed until death, lost to follow-up, or end of study. Data on demographics, comorbidities, biochemical markers, medical treatment, renal pathology, edema venous thromboembolism, bleeding, kidney failure, and death were collected.

Results: Among 1,219 patients, 758 (62%) had edema at diagnosis. Patients with edema had higher urine albumin-creatinine ratio (4,245 mg/g [3,046-6,079] vs. 3,546 mg/g [2,691-5,125]) or higher 24-h urine albumin excretion rate (4,559 mg/day [3,146-6,591] vs. 3,546 mg/day [2,828-5,578]) and lower plasma albumin (26 g/L [22-28] vs. 28 g/L [26-29]) than those without edema. Venous thromboembolism occurred in 54 (4%) patients, with an incidence rate of 15 (95% CI, 11-21) per 1,000 person-years in patients with edema versus 10 (95% CI, 10-17) in patients without edema. Edema was also associated with faster kidney failure progression (edema: 188 days (IQR, 28-581), non-edema 364 days (IQR, 116-920), and higher 1-year all-cause mortality (edema: 19%; non-edema: 16%).

Conclusion: Edema affects approximately 60% of patients with nephrotic-range albuminuria and hypoalbuminemia, associated with increased risk of venous thromboembolism, faster kidney failure progression, and higher 1-year all-cause mortality, highlighting its prognostic information in NS.

Introduction: IgA nephropathy is the most common primary kidney disease in the world and has a highly variable clinical presentation. While studies have indicated a link between glomerular disease and infections, large-scale studies on IgA nephropathy are missing.

Methods: In our study, IgA nephropathy was defined as having a kidney biopsy record 1997-2011 in Sweden. Each IgA nephropathy patient was matched with five reference individuals based on age, sex, calendar year, and county of residence. We excluded individuals with earlier organ transplants, HIV, immunodeficiency, or end-stage kidney disease. Linear and Cox regressions, adjusted for age, sex, education, and diabetes, were performed to analyze total infections and antimicrobial treatments in both patients and reference individuals. Sibling analyses were also performed.

Results: The linear regression analysis revealed a significant association between IgA nephropathy and the overall frequency of infections compared to the general population (β = 0.44; 95% CI: 0.35-0.53) and siblings (β = 0.36; 95% CI: 0.23-0.49). Similarly, antimicrobial prescriptions, especially antibiotics, were more common in IgA nephropathy compared to the general population and to siblings. Cox regression showed an elevated risk of any infection (adjusted hazard ratio [aHR] = 2.00; 95% CI: 1.84-2.18) and sepsis (aHR = 3.18; 95% CI: 2.17-4.65) corresponding to one extra case of sepsis per 63 patients followed for 10 years. The strongest associations were seen for urinary tract infections; ear, nose, and throat infections; and musculoskeletal and gastrointestinal infections.

Conclusion: Conclusively, our study demonstrates an increased prevalence of infections and antibiotic prescriptions in IgA nephropathy patients. The increased risk of sepsis warrants clinical awareness and prevention.

Rationale & Objective: Clinical practice guidelines recommend lower (35.0°C-35.5°C) instead of standard dialysate temperature (36.5°C-37.0°C) to mitigate the risk of intradialytic hypotension. However, many studies have been available since the recommendations were published. Hence, the current study aims to provide an updated meta-analysis of clinical outcomes with cold versus standard dialysate.

Study design: Systematic review and meta-analysis of eligible articles indexed in PubMed, Cochrane, Web of Science, and Scopus.

Participants: Hemodialysis patients Exposure: Cooled versus standard dialysate.

Outcome: Intradialytic hypotension, mean arterial pressure, thermal-related discomfort, and body temperature.

Analytical approach: The random effects model was used for all outcomes due to high heterogeneity (I2: interdialytic hypotension=60%, mean arterial pressure=72%, symptoms of discomfort =41%, and decrease in body temperature=87%). The "leave-one-out" approach was used for sensitivity analysis, and the Cochrane risk-of-bias tool was used to evaluate study quality.

Results: Pooled data from 31 studies indicate that cooled dialysis may be associated with a lower risk of intradialytic hypotension [RR 0.67 (95%CI 0.48-0.93), p=0.02] and higher mean arterial pressure [MD 7.18 (95%CI 3.79-10.58), p<0.01] compared to standard temperature dialysis. However, cooled dialysis was associated with a higher risk of discomfort [RR 1.55 (95% CI 1.25-1.93], p<0.01] and a decrease in body temperature [MD -0.29 (95%CI -0.52--0.05), p=0.02]. Only five studies had a low risk of bias.

Limitations: Most included studies were from over a decade ago, had a small participant size, and did not report other critical long-term outcomes such as mortality, cardiovascular events, treatment discontinuation, or hospitalization rate.

Registration: Registered with ID CRD42024589307 at PROSPERO Conclusions: Using cooled dialysate might be a simple approach to reduce interdialytic hypotension risk and increase mean arterial pressure, albeit at the cost of patient discomfort. The limitations associated with the quality of included studies underscore the need for high-quality, multicenter studies with large/diverse study populations.

Introduction: Maintaining renin-angiotensin-aldosterone system inhibition (RAASi) in advanced chronic kidney disease (CKD) to delay CKD progression is still controversial. This is due to potential side effects associated with RAASi, such as a decline in glomerular filtration rate (GFR) and hyperkalemia. This study aimed to examine the effect of RAASi on progression of advanced CKD to kidney failure (estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, CKD stage 5) in a real-life outpatient cohort.

Methods: This single-center retrospective observational study presents data from 954 individuals with advanced CKD (eGFR 15-30 mL/min/1.73 m2), comparing 806 RAASi with 511 control intervals over a median follow-up period of 19 months. The endpoint was defined as time to manifestation of kidney failure. Univariate and multivariate time-to-event analyses were performed to assess effects of RAASi on endpoint probabilities.

Results: Univariate time-to-event analysis did not show a significant difference in the median time to kidney failure between RAASi and control intervals (7.6 vs. 7.0 years, p = 0.74). Covariate-adjusted multivariate regression models also demonstrated no association between RAASi treatment and progression to kidney failure in patients with advanced CKD (hazard ratio 0.92 [95% CI: 0.67-1.23], p = 0.63).

Conclusion: RAASi has no significant impact on the time to kidney failure in patients with advanced CKD. Hence, this study supports maintenance of RAASi in advanced CKD, if used for extrarenal indications such as cardiovascular protection.