American Journal of Nephrology最新文献

Background: Methotrexate (MTX) is an antimetabolite anticancer agent that has been used at doses ranging from 20 mg/m2 of body surface area to 33,000 mg/m2. High-dose methotrexate (HDMTX), defined as doses higher than 500 mg/m2, is used to treat acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, brain cancers, leptomeningeal spread of carcinomas, and other cancers. Depending on the dose and other factors, acute kidney injury occurs in 2%-39% of HDMTX courses and severe (Acute Kidney Injury Network grade 2 or higher) nephrotoxicity in approximately 2%, though incidence varies widely. Prompt recognition and treatment of delayed MTX elimination and renal dysfunction which includes increased hydration, high-dose leucovorin, and sometimes glucarpidase, is crucial to prevent life-threatening toxicities such as myelosuppression, mucositis, renal failure, and dermatitis.

Summary: In this article, we emphasize the importance of MTX pharmacokinetics and pharmacodynamics, highlight the cellular mechanisms of MTX anticancer activity, review the pathophysiology of MTX-induced renal injury, and explore strategies to prevent and manage MTX nephrotoxicity.

Key messages: Prompt recognition and effective treatment of renal and non-renal toxicities of HDMTX can improve outcomes, cancer prognosis, and survival.

Introduction: Prognostic value of glomerular hematuria in primary membranous nephropathy (PMN) patients with nephrotic syndrome (NS) has not been well understood. We investigated the earlier improvement of hematuria in PMN patients with NS receiving immunosuppressive (IS) therapies to illuminate its prediction capacity for the treatment response and remission status at 12 months.

Methods: This is a single-center retrospective study. From 1 January 2021 to 30 June 2024, patients with biopsy-proven PMN and NS starting IS therapy after renal biopsy were recruited. The main exposures were baseline hematuria and hematuria disappearing at 6 months. The outcome was nephrotic remission status at 12 months. Binary logistic regression models were used to estimate the relationship between exposures and outcomes. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive performance of exposures.

Results: Overall, 127 patients met the eligibility criteria. Overall, 112 patients (88.2%) had glomerular hematuria at the renal biopsy. Patients with hematuria had higher ages (57.2 ± 12.4 vs. 47.9 ± 12.7, p = 0.007), higher serum h-CRP levels (1.14 [0.66, 2.11] vs. 0.41 [0, 0.91], p = 0.004), and lower remission rate at 12 months (66/112 [58.9%] vs. 13/15 [86.67%], p = 0.037). In the subgroup of patients with glomerular hematuria, baseline hematuria levels were 18 (8, 25) RBC/μL. No significant correlations were found between baseline hematuria levels and other clinical indexes. At 6 months, 31 out of 112 (27.7%) patients had negative conversion of hematuria, and they had lower baseline PLA2R Ab titer (43.6 [0, 78.2] vs. 67.5 [10.8, 191.4], p = 0.025) and higher nephrotic remission rates at 12 months (26/31 [83.9%] vs. 40/81 [49.4%], p = 0.037), compared with those without. There were no significant differences among IS agents between the groups. Binary logistic regression demonstrated that hematuria disappearance at 6 months was an independent predictor for nephrotic remission at 12 months (OR = 0.211, 95% CI: 0.070-0.635, p = 0.006). ROC curve analysis revealed that the area under the curve for forecasting nephrotic remission at 12 months was 0.643 (p = 0.010) independently by the hematuria disappearance at 6 months and 0.781 (p < 0.001) combined with PLA2R Ab titer and IS therapeutic programs.

Conclusions: Patients with PMN and NS have high prevalence of glomerular hematuria. Patients without hematuria or negative conversion of hematuria at 6 months after IS treatment have higher nephrotic remission rates at 12 months. For patients with hematuria, hematuria disappearance at 6 months was an independent predictor for nephrotic remission at 12 months.

Introduction: Cardiovascular-kidney-metabolic (CKM) syndrome represents an integrated pathophysiological framework encompassing cardiovascular disease, kidney dysfunction, and metabolic disorders. The difference between cystatin C-based and creatinine-based estimated glomerular filtration rate (eGFRdiff) may reflect pathophysiological processes beyond kidney function, yet its prognostic significance across CKM syndrome stages remains poorly understood.

Methods: We examined records from 4,382 adult participants diagnosed with CKM syndrome (stages 0-3) extracted from the National Health and Nutrition Examination Survey database (1999-2004), with mortality surveillance continuing through December 2019. eGFRdiff was calculated using both absolute difference (eGFRabdiff) and the ratio (eGFRrediff) between cystatin C- and creatinine-based calculations. To investigate associations with overall and cardiovascular mortality outcomes, we employed Cox proportional hazard regression models with adjustments for demographic factors, clinical parameters, and biochemical indicators.

Results: Throughout a median surveillance period spanning 201.8 months, we documented 1,034 fatalities (15.69% of the cohort), with cardiovascular events accounting for 230 deaths (22.2% of all deaths, representing 3.24% of the entire cohort). After comprehensive adjustment in our statistical models, participants exhibiting a negative absolute eGFRdiff (eGFRabdiff <-15 mL/min/1.73 m2) demonstrated significantly elevated all-cause mortality risk (hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.34-2.29) compared to those with intermediate eGFRabdiff values (-15 to 15 mL/min/1.73 m2). Conversely, subjects with positive eGFRabdiff (≥15 mL/min/1.73 m2) showed a protective association (HR 0.65, 95% CI: 0.54-0.80). Quantitatively, each standard deviation reduction in eGFRabdiff corresponded to a 42% mortality risk increase (HR 1.42, 95% CI: 1.28-1.59) and 57% higher cardiovascular mortality (HR 1.57, 95% CI: 1.36-1.82). The relative difference metric yielded similar patterns, with eGFRrediff <1 associated with elevated risks for both all-cause (HR 1.79, 95% CI: 1.48-2.17) and cardiovascular mortality (HR 1.71, 95% CI: 1.23-2.38) versus eGFRrediff ≥1. Notably, these associations were significant in CKM syndrome stages 2-3 but not in stages 0-1.

Conclusion: eGFRdiff is inversely associated with all-cause and cardiovascular mortality in populations with CKM syndrome stages 0-3, with stronger associations in more advanced stages. eGFRdiff may serve as a valuable prognostic marker in CKM syndrome, potentially reflecting underlying inflammatory, oxidative stress, and endothelial dysfunction processes that contribute to adverse outcomes.

Introduction: Parathyroid hormone (PTH) induces browning of adipose tissue, leading to increased resting energy expenditure and loss of adipose and muscle tissues in animal models of kidney failure. However, its clinical significance in humans remains unclear. This study aimed to investigate whether PTH-lowering therapy with upacicalcet, a novel injectable calcimimetic, affects serum albumin levels as a surrogate marker of protein-energy wasting in patients on hemodialysis with secondary hyperparathyroidism (SHPT).

Methods: This was a post hoc analysis of a phase 3, double-blind, placebo-controlled study of upacicalcet for the treatment of SHPT in patients on hemodialysis. Participants were randomized in a 2:1 ratio to receive either upacicalcet or placebo after each hemodialysis session for 24 weeks. Longitudinal changes in serum albumin levels were compared between groups using mixed-effects models for repeated measures. The rate of change (slope) in serum albumin over time was also estimated using a linear mixed-effects model.

Results: A total of 99 patients in the upacicalcet group and 46 patients in the placebo group were included in the analysis. While serum albumin levels tended to decline in the placebo group, they remained relatively stable in the upacicalcet group, with a significant treatment-by-time interaction. In the linear mixed-effects model, the slope was less steep in the upacicalcet group than in the placebo group, although the between-group difference (0.09 g/dL per year; 95% CI, -0.04 to 0.23) did not reach statistical significance.

Conclusion: These findings raise the hypothesis that PTH suppression with upacicalcet mitigates the gradual decline in serum albumin levels over time. Further studies are warranted to investigate the long-term impact of PTH control on protein-energy wasting and related clinical outcomes.

Introduction: Previous studies found that frailty was an important risk factor for cardiovascular disease (CVD). However, the relationship between frailty and CVD risk across different cardiovascular-kidney-metabolic (CKM) syndrome stages remains poorly understood. This study investigated the association between frailty and incident CVD in populations with CKM syndrome stages 0-3.

Methods: We analyzed 6,049 middle-aged and older adults without pre-existing CVD data from the China Health and Retirement Longitudinal Study (2011-2020). Participants were categorized into CKM syndrome stages 0-3 based on the American Heart Association's criteria. Frailty was assessed using the frailty index (FI) and classified as robust, pre-frail, or frail. Cox proportional hazard models examined the association between frailty and incident CVD.

Results: During a median follow-up of 7.5 years, 1,441 participants developed CVD. Compared to robust individuals, pre-frail and frail participants had multivariable-adjusted hazard ratios of 1.58 and 2.13 for incident CVD, respectively. Each standard deviation increase in FI was associated with a 28% higher risk of incident CVD. A dose-response relationship was observed between FI and CVD risk, with no significant nonlinearity was detected. These associations remained consistent across all CKM syndrome stages, although significant effect modifications were observed by age, gender, and hypertension status. Sensitivity analyses yielded consistent results.

Conclusions: Frailty is independently associated with increased CVD risk across the spectrum of CKM syndrome stages, with a clear dose-response relationship.

Background: Physical activity levels in hemodialysis patients are low and continue to decline, increasing mortality risk. Intradialytic exercise improves hemodialysis patients' quality of life and enhances their physical and psychological health. But existing reviews fail to provide the best evidence for enhancing physical activity levels in this population. This study is to examine the efficacy and safety of intradialytic exercise for hemodialysis patients.

Methods: MEDLINE, Embase, the Cochrane Library, CINAHL, Web of Science, PubMed, Wan Fang data, and SinoMed were searched up to March 2025. The reference lists of eligible studies were systematically checked to ensure comprehensive coverage of the relevant literature. Two independent reviewers searched the databases, selected trials, conducted a bias assessment, and extracted the data. Meta-analysis was conducted using Review Manager version 5.4.1.

Results: Of the 3,880 studies that were screened, 23 studies involving 1,114 patients were identified. Three types of exercise, 7 exercise durations, and 4 exercise intensity standards were compared. Physical activity level, VO₂ peak, muscle strength, and muscle mass were reported. Statistically, in terms of exercise type, combined aerobic and resistance exercise improved physical activity levels (SMD = 0.99, 95% CI: 0.44-1.55) and VO₂ peak (SMD = 1.01, 95% CI: 0.56-1.46). Meanwhile, resistance exercise significantly improved muscle strength (SMD = 0.52, 95% CI: 0.24-0.81). In terms of exercise intensity, moderate exercise intensity significantly improved physical activity levels (SMD = 0.55, 95% CI: 0.22-0.88), VO₂ peak (SMD = 0.59, 95% CI: 0.12-1.07), and muscle strength (SMD = 0.37, 95% CI: 0.11-0.63). Additionally, higher-intensity exercise also significantly improved muscle strength (SMD = 1.02, 95% CI: 0.51-1.53). As for exercise duration, programs lasting up to 3 months positively impacted physical activity levels (SMD = 0.65, 95% CI: 0.17-1.13) and VO₂ peak (SMD = 0.70, 95% CI: 0.19-1.21). Furthermore, exercise extending up to 6 months significantly improved muscle strength in hemodialysis patients (SMD = 0.41, 95% CI: 0.18-0.64).

Conclusion: Evidence shows that intradialytic exercise interventions improve physical activity levels, VO₂ peak, and muscle strength in hemodialysis patients. Future clinical intervention studies could conduct direct comparisons of protocols with different exercise modalities, intensities, and durations.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) has an elevated prevalence of intracranial aneurysms compared to the general population. However, the risk of de novo aneurysm formation in these patients remains unclear, leading to a lack of consensus regarding whom and when to follow. Although the data from the general population tend to be referred, this assumption needs caution because patients with ADPKD have different characteristics, such as location tendency, aneurysm size at rupture, and gene mutation. Here, we investigate the incidence of de novo aneurysm in ADPKD patients to examine whether patients without intracranial aneurysms on initial imaging need frequent follow-up.

Methods: This is a retrospective cohort study conducted in two ADPKD referral centers in Japan. Consecutive samples of 2,117 adult patients with ADPKD from April 2003 to October 2024 were eligible. Of these, 850 patients without baseline brain imaging and 555 patients without follow-up brain imaging were excluded, leaving 712 patients included in this study. Patients were divided into two groups according to the presence of intracranial aneurysms on the initial image. The primary outcome was the incidence of de novo aneurysm formation during follow-up. Kaplan-Meier analysis and Cox proportional hazards models were used to estimate risks, adjusting for age, sex, hypertension, smoking history, and family history of subarachnoid hemorrhage or aneurysm.

Results: Of 712 patients, 181 had intracranial aneurysms on initial imaging (screening-positive) and 531 had none (screening-negative). The median age was 54 years (interquartile range, 45-62 years), and 398 (55.8%) were women. Over 4,580 person-years of follow-up, the overall incidence of de novo aneurysm formation was higher in the screening-positive group (1.2 per 100 person-years) than in the screening-negative group (0.26 per 100 person-years) (hazard ratio, 3.81; 95% confidence interval, 1.50-9.67, p = 0.005).

Conclusion: ADPKD patients without preexisting aneurysms on initial imaging are at relatively low risk of developing de novo aneurysms. Our findings help determine the adequate follow-up timing and its target in patients with ADPKD. However, caution is warranted in generalizing these results because the study population had a higher median age and more advanced kidney disease.

Introduction: The residual risk of chronic kidney disease (CKD) progression remains high in clinical trials of kidney protective drugs in patients with diabetic kidney disease (DKD).

Methods: In a prospective study, we assessed whether 16 plasma and 10 urine cytokine levels can inform the residual risk of CKD progression in 93 incident patients with DKD treated by nephrology according to clinical guidelines.

Results: Plasma and urine levels of 12 plasma and 7 urinary cytokines differed between patients with DKD and from healthy controls. Participants were categorized into CKD G1-G2 (preserved GFR) and CKD G3-G5 (GFR <60 mL/min/1.73 m2). After a median of 7.27 years (interquartile range, 5.34-9.56), 13/40 (32.5%) patients with CKD G1-G2 at baseline had progressed to CKD G3-G5. Progressors had higher plasma interleukin 22 (IL-22) and tumor necrosis factor-alpha (TNF-α) levels than nonprogressors. Plasma IL-22 and TNF-α levels in progressors were similar to those in patients already in CKD G3-G5 at baseline, suggesting that cytokine dysregulation precedes CKD progression. In patients with CKD G1-G2, cutoff points for plasma IL-22 and TNF-α predicted progression with an area under the curve of 0.76 and 0.77, respectively. Additionally, patients with CKD G1-G2 and plasma TNF-α or IL-22 levels equal to or above the cutoff value had significantly lower estimated glomerular filtration rate values at the end of follow-up and had more frequently progressed to a very high-risk KDIGO category. In cluster analysis, clusters displaying the highest urinary or plasma cytokine levels were associated with worse GFR outcomes.

Conclusion: Plasma IL-22 and TNF-α may help identify patients with early DKD with a high residual risk of CKD progression despite treatment.

Introduction: Anemia is common in hemodialysis patients, and iron supplementation is essential for its management. However, the impact of baseline inflammation on the efficacy of oral versus intravenous iron remains unclear.

Methods: This post hoc analysis of the IHOPE trial included 193 maintenance hemodialysis patients stratified by median baseline high-sensitivity C-reactive protein (hsCRP). Patients were randomized to receive intravenous iron sucrose (100 mg once biweekly) or oral polysaccharide-iron complex (150 mg twice daily) for 24 weeks. The primary outcome was hemoglobin level at 24 weeks. Secondary outcomes included hsCRP, oxidative stress markers, and iron parameters.

Results: At 24 weeks, patients with high baseline hsCRP had lower hemoglobin levels than those with low hsCRP (113.82 ± 12.04 vs. 118.05 ± 13.50 g/L, p = 0.038), despite similar baseline hemoglobin values. Among patients receiving intravenous iron sucrose, those with high hsCRP had significantly lower hemoglobin (112.90 ± 13.19 vs. 121.32 ± 13.46 g/L; p = 0.005) and higher hsCRP and superoxide dismutase levels, suggesting persistent inflammation and oxidative stress. In contrast, hemoglobin levels were similar between high and low hsCRP subgroups in the oral polysaccharide-iron complex group (p = 0.913). Iron parameters and adverse events were comparable across groups.

Conclusion: This post hoc analysis suggests baseline inflammation significantly modifies responses to specific iron formulations in hemodialysis patients. Patients with elevated hsCRP showed poorer hemoglobin responses to intravenous iron sucrose, while oral polysaccharide-iron complex maintained consistent efficacy across inflammatory states. These findings warrant prospective studies on inflammation-guided personalization of iron therapy.

Background: Artificial intelligence (AI) increasingly impacts medicine and medical specialties, including nephrology. Technologies such as large language models (LLMs), decision-support AI, and machine learning-powered predictive analytics enhance clinical care. These AI-driven tools show great potential in areas such as predicting the risk of chronic kidney disease (CKD), managing dialysis, supporting kidney transplantation, and treating CKD and diabetes-related kidney issues.

Summary: General AI platforms like ChatGPT, Bard, and Google Gemini are useful for education and synthesizing knowledge. In contrast, specialized medical AI systems such as KidneyIntelX and DreaMed Advisor provide clinically validated decision support systems that aid physicians in patient care. Retrieval-augmented generation (RAG) enhances LLMs by accessing real-time medical data and research insights, reducing misinformation risks, and ensuring accurate, verified medical responses. However, LLMs still face challenges in adapting to complex patient cases. The effectiveness of RAG depends on the quality of the data retrieved and adherence to ethical and confidentiality standards, with human oversight often necessary.

Key messages: (i) Improving AI accuracy, increasing model transparency, and ensuring seamless integration into clinical settings maximize AI benefits in nephrology. (ii) Regulatory approvals and validation are essential to build trust among patients, physicians, and healthcare institutions. (iii) When integrated correctly into clinical workflows, AI can transform nephrology practice by providing efficient, data-driven insights, improving patient outcomes, and reducing administrative burdens. (iv) Ethical, responsible adoption with stringent oversight is crucial for successfully implementing AI in nephrology.