Journal of The American Society of Nephrology最新文献

Background: A family history of health conditions may reflect shared genetic and/or environmental risk. It is not well known to what extent family history impacts outcomes among patients with chronic kidney disease (CKD). Herein, we studied the associations of family history of CKD, diabetes, and other conditions with common comorbidities and kidney disease progression among patients with CKD.

Methods: We carried out an observational study of two prospective CKD cohorts, 2,573 adults and children from the Cure Glomerulopathy Network (CureGN) and 3,939 Chronic Renal Insufficiency Cohort (CRIC) adult participants. Self-reported first-degree family history of CKD, diabetes, and other common diseases were tested for associations with the risk of comorbidities and CKD progression using multivariable models.

Results: Family history of common comorbid conditions was associated with higher risk of these conditions in the context of CKD, including approximately by over 3-fold for diabetes (adjusted OR 3.37, 95% C.I. 2.73-4.15), 48% for cancer (adjusted OR 1.48, 95% C.I. 1.05-2.09), and 69% for cardiovascular disease (adjusted OR 1.69, 95% C.I. 1.36-2.10 in combined cohorts). While polygenic risk score for CKD was associated with kidney disease progression (adjusted HR 1.11, 95% C.I. 1.06-1.16 in combined cohorts), family history of kidney disease was not an independent risk factor for disease progression in the context of existing CKD. In contrast, family history of diabetes was significantly associated with a higher risk of CKD progression independently of diabetes occurrence, or polygenic risk score for diabetes (adjusted HR 1.19, 95% C.I. 1.05-1.35 in combined cohorts).

Conclusions: Broad collection of family history in the context of CKD improved clinical risk stratification. Family history of diabetes was consistently associated with a higher risk of CKD progression independently of diabetes status or polygenic risk score for diabetes in both cohorts.

Background: Cystatin C has entered mainstream clinical care as a measure of kidney function, joining serum creatinine which has been used for almost a century. But many physicians notice that eGFRCr and eGFRCys values can differ considerably. Hospitalization with critical illness is known to acutely decrease eGFRdiff (eGFRCys - eGFRCr). However, whether this effect occurs in all-cause hospitalizations and persists after hospitalization is unknown.

Methods: Among 5,599 adult participants in the Chronic Renal Insufficiency Cohort (CRIC) study with serum creatinine and cystatin C measurements, we estimated the association of six categories of total days of hospitalization between annual study visits (never hospitalized, hospitalized <7 days, 7-<14 days, 14-<28 days, 28-<42 days, and ≥ 42 days) and changes in eGFRCr, eGFRCys, and eGFRdiff between those study visits.

Results: Compared to no hospitalization between study visits, increasing days of hospitalization were associated with decreases in eGFRCys (e.g., -3.30 [95% CI -5.48, -1.13] ml/min/1.73m2 for ≥ 42 days of hospitalization, test for trend p<0.001), while eGFRCr remained relatively stable (e.g., -1.12 [-2.77, 0.53] ml/min/1.73m2 for ≥ 42 days of hospitalization, test for trend p=0.21). The differential effect resulted in eGFRdiff becoming progressively more negative with more total days of hospitalization (test for trend p<0.001).

Conclusions: Prolonged or repeated hospitalization was associated with larger decreases in eGFRCys compared to eGFRCr on measurements months after hospital discharge.

Background: Cardiovascular-Kidney-Metabolic (CKM) syndrome highlights the interconnected nature of metabolic diseases, chronic kidney disease, and cardiovascular diseases, representing a significant and growing public health burden. This study aimed to quantify the global burden of CKM syndrome by examining its key components, including high body mass index (BMI), diabetes, chronic kidney disease, atrial fibrillation and flutter, lower extremity peripheral arterial disease, ischemic heart disease, and stroke.

Methods: Data were derived from the Global Burden of Disease (GBD) 2021 platform, which provided estimates for incidence, prevalence, mortality, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life years (DALYs). A decomposition analysis was performed to assess the contributions of population growth, aging, and epidemiological changes to the burden of CKM syndrome. A NORDPRED model was employed to project future trends in DALYs, YLLs, and YLDs through 2046.

Results: Globally, ischemic heart disease and stroke were the major contributors to the CKM syndrome-related burden in 2021. Regions with a middle Socio-Demographic Index (SDI), such as Southeast Asia and the Western Pacific, experienced the largest burden. However, age-standardized DALY rates were inversely related to SDI, with regions of lower SDI exhibiting higher rates. From 1990 to 2021, DALYs for the seven key components of CKM syndrome increased, primarily driven by population growth and aging. However, age-standardized DALY rates varied across components, with stroke (-38.7% [95% uncertainty interval (UI): -43.4% to -34.0%]), peripheral arterial disease (-30.1% [-33.5% to -27.2%]), and ischemic heart disease (-28.8% [-32.5% to -25.2%]) showing a declining trend, while diabetes (38.2% [29.7% to 47.0%]) and high BMI (25.5% [16.6% to 33.7%]) exhibited an increasing trend. Further projection analysis suggested a consistent trend in the changes in CKM syndrome-related burden from 2022 to 2046, with increases ranging from 55.9% for stroke to 105.7% for atrial fibrillation and flutter.

Conclusions: The findings of this study highlight the substantial and growing CKM syndrome-related burden, emphasizing the urgent need for comprehensive and targeted interventions.

Background: Kidney fibrosis, the excessive accumulation and dysregulated remodeling of the extracellular matrix, is the principal pathophysiological process in chronic kidney disease (CKD). Protein L-isoaspartyl/D-aspartyl methyltransferase (PCMT1) is crucial in repairing post-translational modifications of L-isoaspartyl residues, which are important for extracellular matrix proteins because of their low turnover rate and susceptibility to accelerating factors. This study aimed to reveal a novel role of PCMT1 in kidney fibrosis.

Methods: Kidney tissues from mice and humans were evaluated for PCMT1 expression and its association with fibrosis and kidney function. PCMT1's effects on the TGF-β1/Smad signaling were analyzed, and its functional role was assessed in tubule-specific Pcmt1 knockout murine models of kidney fibrosis. The ability of secreted PCMT1 to repair L-isoaspartyl residues on the ectodomain of transforming growth factor beta receptor 2 (TGFBR2) was investigated through immunoprecipitation, gene lentivirus overexpression or knockout, and post-translational modification mass spectrometry.

Results: PCMT1 expression was decreased in the tubules of human kidney biopsies from patients with CKD and murine fibrosis models. Renal tubule-specific PCMT1 deficiency in murine kidney fibrosis models worsened tubular injury, extracellular matrix protein deposition, myofibroblast activation, and TGF-β1/Smad signaling overactivation. Mechanistically, PCMT1 was unconventionally secreted and enzymatically inhibited TGF-β1-induced extracellular matrix protein deposition in vitro. PCMT1 interacted with TGFBR2, reversing N63 deamination on its ectodomain, which triggered TGFBR2 ubiquitination and degradation. PCMT1 supplementation in kidneys decreased TGFBR2 levels, attenuated TGF-β1/Smad overactivation, and impeded the profibrotic process.

Conclusions: Our study highlights the importance of PCMT1 in maintaining extracellular matrix homeostasis and mitigating kidney fibrosis by regulating TGFBR2 deamination and its protein stability, suppressing the TGF-β1/Smad signaling.

Background: Expanded hemodialysis (HD) using a medium cut-off dialyzer improves the clearance of middle-molecular toxins compared to conventional HD. This study evaluated the effect of expanded HD on preserving residual kidney function in incident HD patients.

Methods: Patients who initiated HD were randomized to receive dialysis with either a Theranova 400 (Baxter) or a high-flux dialyzer with a similar surface area over 12 months. The primary outcome was a change in glomerular filtration rate (GFR) over 12 months, as determined by the mean of urea and creatinine clearance. The secondary outcome was a change in 24-hour urine volume, middle molecules, and kidney injury markers.

Results: A total of 80 HD patients (mean age [SD]: 63 [12] years; male: 52 [65%]) underwent randomization. Over 12 months, the Theranova group demonstrated a significantly smaller decrease in GFR than the high-flux group (least-squares mean difference of change [95% confidence interval]: -1.4 [-2.4, -0.5] mL/min/1.73 m2). Theranova maintained greater 24-hour urine volume until 9 months, not at 12 months, compared to the high-flux dialyzer. The reduction ratio for κ/λ free light chains, TNF-α, and GDF-15 was higher in the Theranova group than in the high-flux group. The increase in the kidney injury marker, IGFBP7, was attenuated in the Theranova group. Hospitalization rate and mortality did not differ between the two groups.

Conclusions: This trial suggests that expanded HD using the Theranova dialyzer may slow decline in residual kidney function compared with a high-flux dialyzer in incident HD patients.

The treatment and management of kidney diseases present a significant global challenge, affecting over 800 million individuals and necessitating innovative therapeutic strategies that transcend symptomatic relief. The application of nanotechnology to therapies for kidney diseases, while still in its early stages, holds transformative potential for improving treatment outcomes. Recent advancements in nanoparticle-based drug delivery leverage the unique physicochemical properties of nanoparticles for targeted and controlled therapeutic delivery to the kidneys. Current research is focused on understanding the functional and phenotypic changes in kidney cells during both acute and chronic conditions, allowing for the identification of optimal target cells. In addition, the development of tailored nanomedicines enhances their retention and binding to key renal membranes and cell populations, ultimately improving localization, tolerability, and efficacy. However, significant barriers remain, including inconsistent nanoparticle synthesis and the complexity of kidney-specific targeting. To overcome these challenges, the field requires advanced synthesis techniques, refined targeting strategies, and the establishment of animal models that accurately reflect human kidney diseases. These efforts are critical for the clinical application of nanotherapeutics, which promise novel solutions for kidney disease management. This review evaluates a substantial body of in vivo research, highlighting the prospects, challenges, and opportunities presented by nanotechnology-mediated therapies and their potential to transform kidney disease treatment.