Clinical and Experimental Nephrology最新文献

Chronic kidney disease (CKD), a condition affecting over 850 million people worldwide, is a major global health issue. CKD leads to multimorbidities and disease complexity, expediting the aging process and increasing mortality rates-a phenomenon sometimes referred to as "renal senescence." The leading cause of death in patients with CKD is cardiovascular disease (CVD), accounting for one-third to one-half of all deaths, in stark contrast to cancer, which is the primary cause of death in the general population. While previous studies on kidney disease have focused extensively on urinary extracellular vesicles due to their potential as non-invasive diagnostic tools and their origin from kidney cells, our research highlighs the significance of circulating small extracellular vesicles (cEVs). We demonstrated that cEVs act as key mediators in the pathological intercellular and inter-organ communication between the kidneys and vascular smooth muscle cells (VSMCs). However, the biogenesis, cargo, and biological functions of cEVs remain incompletely understood under physiological and pathological conditions, including CKD. We identified microRNA (miRNA) transcriptomic signatures encapsulated in cEVs from CKD animal models, which were validated in human CKD samples. Notably, the depletion of specific miRNAs in CKD-derived cEVs promoted osteogenic differentiation of VSMCs and the deposition of calcium-phosphate crystals in vessels. In contrast, miRNAs enriched in cEVs from healthy individuals suppress these pathological processes, acting as a safeguard. These findings and future research could pave the way for the development of diagnostic and therapeutic platforms leveraging cEVs in nephrology.

Approximately, 1.2 million deaths occur each year from chronic kidney disease worldwide. The incidence is increasing and current treatments have limited efficacy. Many patients with kidney disease inevitably end up with kidney replacement therapy. mRNA has revolutionized the world of molecular therapy and spotlighted the attention of the medical community on its potential clinical application. Currently, mRNA-based therapies have started to emerge in the kidney field. In this review, we describe recent advances in renal mRNA-based therapies and discuss future possibilities for using mRNAs to treat kidney diseases.

Background: Proteinuria is often assessed by a single measurement, but persistent proteinuria has seldom been studied. Therefore, we investigated its association with cigarette smoking.

Methods: We prospectively followed 9,220 middle-aged Japanese men without renal dysfunction, proteinuria, diabetes, antihypertensive treatment, or cancer at baseline. Smoking status, daily cigarette consumption, and pack-years were assessed by questionnaire. Participants were grouped as nonsmokers, past smokers, or current smokers. Current smokers were classified by daily consumption (1-20 or ≥ 21) and cumulative exposure (0.1-40.0 or ≥ 40.1 pack-years). Persistent proteinuria was defined as proteinuria detected at ≥ 3 consecutive annual examinations. We used Cox proportional hazards models.

Results: There were 1972 nonsmokers, 2007 past smokers, and 5241 current smokers. During the 11-year follow-up, persistent proteinuria developed in 181 participants (28, 30, and 123 in each group), corresponding to incidence rates of 1.6, 1.7, and 2.6 per 1,000 person-years, respectively. In multivariate models, current smoking, daily cigarette consumption, and cumulative smoking consumption were significantly associated with the risk of persistent proteinuria, compared with nonsmoking. For daily cigarette consumption, multiple-adjusted HRs of persistent proteinuria for those who smoked 1-20, and ≥ 21 cigarettes per day were 1.59 (95% CI, 1.01-2.50), and 1.83 (1.15-2.91), respectively (P for trend = 0.011). For cumulative smoking exposure, the corresponding HRs for those with a pack-year of 0.1- 40.0, and ≥ 40.1 were 1.56 (1.00 -2.41), and 2.09 (1.26 -3.45), respectively (P for trend = 0.003).

Conclusions: In middle-aged Japanese men, cigarette smoking was associated with persistent proteinuria, and the risk rose with daily and cumulative smoking.

Background: Proteinuria reduction is considered a potential surrogate endpoint predictive of reflecting long-term kidney prognosis in IgA nephropathy (IgAN), but quantitative evidence in Japanese patients is limited. We aimed to examine the association between short-term proteinuria reduction at 12 months and long-term kidney outcomes in Japan IgA Nephropathy Cohort Study (J-IGACS).

Methods: Participants from J-IGACS were categorized into tertiles based on their 12-month proteinuria-to-baseline proteinuria ratios. The primary outcome was a composite of ≥ 40% estimated glomerular filtration rate (eGFR) decline or initiation of kidney-replacement therapy. Associations between proteinuria ratio and outcomes were assessed using Cox proportional hazards models and restricted cubic splines. Multivariable analyses adjusted for age, sex, baseline eGFR, log-transformed proteinuria, Oxford classification scores, and use of corticosteroids and renin-angiotensin-aldosterone system inhibitors within 12 months.

Results: Among 792 patients, those in the greatest proteinuria reduction had significantly lower risk of the primary endpoint (P for trend < 0.001) and a more favorable eGFR slope. Spline analysis showed a continuous, dose-response association between proteinuria ratio and improved outcomes. These findings remained robust in sensitivity analyses restricted to patients likely qualifying for clinical trials. The results showed that patients with lower proteinuria ratios tended to have slower rates of eGFR decline (P for trend < 0.001).

Conclusion: Proteinuria reduction within the first-year post-diagnosis is independently associated with lower risk of adverse kidney outcomes and a slower decline in kidney function in patients with IgAN. These results support the use of proteinuria reduction as a surrogate endpoint in both clinical trials and disease management.

Background: Erythropoiesis-stimulating agents (ESA) hyporesponsiveness may be linked to malignancy, but studies examining this association are limited. We investigated whether initial ESA hyporesponsiveness and changes in responsiveness may serve as clinical markers reflecting undiagnosed malignancy in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD).

Methods: We used data from the BRIGHTEN, a prospective study of NDD-CKD patients with anemia. Initial ESA responsiveness was assessed using the erythropoietin resistance index (ERI-1B), calculated as the ratio of darbepoetin-alfa dose (μg) to hemoglobin concentration (g/dL) at 12 weeks after darbepoetin-alfa initiation. ESA responsiveness trends after 12 weeks were analyzed using a joint latent class model (JLCM). The associations of both initial ESA responsiveness and ESA responsiveness trends after 12 weeks with malignancy development were analyzed using a Cox proportional hazards model.

Results: Of the 1641 patients analyzed, 44 developed new malignancies. Patients with poor ESA response at 12 weeks (ERI-1B > 3.8 μg/g/dL) had a higher incidence of malignancy compared to those with better ESA response (adjusted hazard ratio [HR]: 2.07; 95% confidence interval [CI]: 1.07-4.00). Furthermore, based on the JLCM, patients in the poor response group, characterized by a faster decline in ESA responsiveness after 12 weeks, had a higher risk of malignancy than the good response group (adjusted HR: 2.01; 95% CI: 1.08-3.72).

Conclusion: Both initial ESA hyporesponsiveness and subsequent declines in responsiveness were significantly associated with the development of malignancy in patients with NDD-CKD. ESA hyporesponsiveness may serve as a clinical marker that reflects an increased risk of undiagnosed malignancy.

Background: Early reduction in proteinuria has been validated as a surrogate endpoint for IgA nephropathy (IgAN) in Western trials and is used for accelerated drug approval. However, its applicability to Japanese patients remains unclear. We aimed to evaluate the association between early proteinuria reduction and long-term renal outcomes in Japanese patients with IgAN.

Methods: This retrospective observational study used data from J-CKD-DB-Ex, a real-world database of CKD in Japan. Adult participants with IgAN, baseline urine protein/creatinine ratio (UPCR) ≥ 0.5 g/gCr, and eGFR ≥ 30 mL/min/1.73 m² were included. The exposure was a ≥ 30% UPCR reduction at 9-12 months after the index date (UPCR reduction group), vs participants without such reduction (non-UPCR reduction group). The primary endpoint was a composite of 40% decline in eGFR from baseline or onset of CKD stage G5. Cox proportional hazards and linear mixed-effects models evaluated the association between UPCR reduction, renal events, and eGFR slope.

Results: Among 385 participants (mean observation period 2,040 days), 245 achieved ≥ 30% reductions in UPCR. The UPCR reduction group showed significantly lower cumulative incidence of renal composite events than the non-UPCR reduction group. Annual eGFR decline was slower in the UPCR reduction group than that in the non-UPCR group (-1.9 vs -3.4 mL/min/1.73 m²/year). Greater UPCR reductions were linearly associated with more favorable eGFR slope.

Conclusions: Early proteinuria reduction is associated with decreased risk of renal failure and attenuated eGFR decline in Japanese patients with IgAN, supporting its validity as a surrogate endpoint for renal prognosis.

Background: The frontier of renal outcome modifications in Japan 10 (FROM-J10) study is a 10 year longitudinal cohort study evaluating the long-term outcomes of treatment according to the clinical guidelines for chronic kidney disease (CKD) by primary care physicians. This study aimed to identify distinctive trajectories of kidney function among patients with CKD and evaluate the patient characteristics associated with each trajectory using the FROM-J10 study data.

Method: This secondary study used 10 years of data from 2379 patients aged between 40 and 74 years with CKD stages from G1 to G5 in the FROM-J10 study. Group-based trajectory modeling was applied to the change in estimated glomerular filtration rate (eGFR) over time, and patients were classified into distinct groups that followed similar trajectories. Multivariate logistic analysis was performed for patient characteristics associated with each trajectory.

Results: In total, 2257 patients with at least three eGFR values were included in this study. Two distinct trajectories of eGFR decline were identified: progressive decline (n = 1240, 54.9%) and gradual decline (n = 1017, 45.1%). In multivariate logistic analysis with gradual eGFR decline as a reference, proteinuria was associated with progressive eGFR decline in CKD from G2 to G4 + 5; lower albumin in G2, G3a, and G4 + 5; and lower hemoglobin in G3a to G4 + 5.

Conclusions: In patients with CKD adequately treated by primary care physicians, kidney function declined very slowly over 10 years. We suggest that patient characteristics identified as progressive eGFR decline, proteinuria, and lower albumin and hemoglobin levels should be managed appropriately in clinical practice.

Background: Effectively managing a large numbers chronic kidney disease (CKD) cases requires collaboration between nephrologists and non-nephrologists. In 2024, the Japan physicians association conducted a third nationwide questionnaire survey on managing CKD. This study aimed to clarify the differences in managing CKD between nephrologists and non-nephrologists and identify remaining issues by comparing them with past surveys.

Method: In the 2024 surveys, 1003 general practitioners voluntarily participated and answered 20 questions about CKD care and treatment. They were divided into 2 groups: 835 non-nephrologists and 168 nephrologists, and the differences were analyzed. Furthermore, the 2024 survey results were compared with those from the 2013 and 2019 surveys.

Results: The use of CKD guidelines was significantly lower among non-nephrologists than nephrologists (55%/21% and 86%/60%, respectively; p < 0.001), and as in the past 2 surveys (p < 0.001). Estimated glomerular filtration rate assessment was widespread at 95%; nevertheless, 34% of non-nephrologists measured quantitative proteinuria compared to 82% of nephrologists (p < 0.001). This prevalence decreased with each survey and with the age of the non-nephrologists. While 75% of nephrologists prescribed renin-angiotensin system inhibitors for patients with CKD and hypertension, considering their renoprotective effects, 45% of non-nephrologists answered it (p < 0.001). While 61% of non-nephrologists prescribed sodium-glucose co-transporter 2 inhibitors to patients with CKD, regardless of diabetes complications, compared to 83% of nephrologists (p < 0.001).

Conclusion: The quality of CKD management by non-nephrologists partially improved in the past decade; however, the low use of guidelines and implementation of quantitative proteinuria measurements among non-nephrologists needs to be addressed in future.

Clinical nephrology research is increasingly challenged by the need to translate complex patient experiences, emerging biomarkers and treatments, and an expanding methodological tools into improvements in care. Clinical epidemiology provides a bridge between bedside questions and population science; however, its role is often narrowly perceived as clinical statistics rather than as a discipline centered on research conceptualization and design. In this invited review, I reflect on how clinical questions arising from routine nephrology practice can be systematically developed into clinically relevant research through a nephrologist-epidemiologist's lens. First, drawing on our experience and illustrative examples, I describe how rethinking care processes through established frameworks-such as the structure-process-outcome model-can support clinicians in formulating answerable questions that matter to patients. Second, I expand the lens beyond traditional nephrology to incorporate perspectives from social medicine, emphasizing trust, hope, and patient-reported outcomes as integral components of chronic kidney disease care. Finally, this review highlights how clinical questions can be embedded within clinical research design frameworks to clarify research objectives across diagnosis, treatment, prognosis, and etiology. In an era of rapid methodological diversification, the nephrologist-epidemiologist's unique contribution may lie in cultivating a sharpened lens: the ability to discern relevant clinical questions and sustain deep clinical reasoning. By doing so, clinical epidemiology can continue to guide research that advances comprehensive and patient-centered kidney care.