Journal of The American Society of Nephrology最新文献

Background: It is imperative to critically evaluate the prognostic implications of Cardiovascular-Kidney-Metabolic (CKM) syndrome staging to inform clinical practice. The primary aims of this paper were to define the risk of mortality associated with each CKM syndrome stage and to determine the corresponding restricted mean survival time over a 15-year period.

Methods: This is a longitudinal study of 50,678 community-dwelling U.S. adults aged 20 and older with baseline data for CKM stage determination participating in the 1999-2018 National Health and Nutrition Examination Survey. CKM stages defined according to the American Heart Association presidential advisory. 15-year adjusted cumulative incidences of cardiovascular mortality were calculated for each stage from confounder-adjusted survival curves using the G-formula.

Results: Over a median 9.5-year follow-up, 2,564 participants experienced cardiovascular death. The 15-year adjusted cumulative incidences of cardiovascular mortality were: Stage 0, 5.5% (95% CI, 1.8-9.3); Stage 1, 5.7% (95% CI, 3.2-8.2); Stage 2, 7.9% (95% CI, 6.8-9.1); Stage 3, 8.7% (95% CI 6.7-10.8); Stage 4, 15.2% (95% CI, 13.6-16.8). The absolute risk difference between CKM Stage 4 and Stage 0 at 15 years was 9.6% (95% CI, 5.6-13.6). The survival difference between CKM stage 0 and Stage 4 at 15 years was 5.6 (95% CI, 5.5-5.7 months.

Conclusions: Our findings reveal a graded risk for cardiovascular mortality associated with higher CKM syndrome stage.

Background: Diabetic kidney disease (DKD) is characterized by progressive injury to glomerular podocytes due to sustained mechanical stress within the glomerulus. Piezo proteins, acting as cellular mechanosensors, play a pivotal role in mechanotransduction by sensing mechanical forces and regulating intracellular ion flux. This study investigates the role of Piezo1 in the progression of DKD and its mechanistic involvement in podocyte injury.

Methods: Podocyte-specific Piezo1 knockout mice were generated using the streptozotocin plus high-fat diet model of DKD. In vitro studies included the use of Piezo1 inhibitors to assess calcium influx, podocyte cytoskeletal rearrangement, and apoptosis under stiff matrix conditions. Additionally, nuclear factor of activated T cell cytoplasmic 1 (NFATc1) and transient receptor potential cation channel 6 (TRPC6) signaling pathways were explored to establish their role in Piezo1-mediated podocyte injury. Adeno-associated virus -TRPC6 was utilized to overexpress TRPC6 in podocyte-specific Piezo1 knockout mice to assess the in vivo interaction between Piezo1 and TRPC6.

Results: Podocyte-specific deletion of Piezo1 significantly ameliorated the progression of DKD in diabetic mice. Inhibition of Piezo1 reduced calcium influx, cytoskeletal rearrangement, and podocyte apoptosis in vitro. Mechanistically, Piezo1 activation triggered a signaling loop involving NFATc1 and TRPC6, leading to increased calcium influx, perpetuating podocyte injury. TRPC6 overexpression in vivo counteracted the protective effects of Piezo1 deletion, confirming the critical role of the Piezo1/NFATc1/TRPC6 axis in DKD progression.

Conclusions: Piezo1 plays a key mechanosensory role in podocyte injury during DKD progression by mediating calcium influx and activating the NFATc1/TRPC6 signaling pathway.

Background: Macrophages and tubular epithelial cell interactions are integral in kidney ischemia-incited interstitial inflammation leading to acute kidney injury. Ischemia/reperfusion injury riggers tubular epithelial cells to express IL-34, a macrophage growth factor, that promotes acute kidney injury and subsequent chronic kidney disease. IL-34 engages the cognate receptor, c-FMS, expressed by macrophages, and the recently discovered Protein-Tyrosine Phosphatase ζ (Ptprz). Ptprz, binds to multiple ligands other than IL-34 that progressively increase their expression in kidneys after ischemia/reperfusion injury.

Methods: We tested the hypothesis that signaling through Ptprz promotes macrophage-mediated acute kidney injury and subsequent chronic kidney disease, by comparing Ptprz knockout with wild-type mice after ischemia/reperfusion injury.

Results: Ptprz was expressed by leukocytes and in tubular epithelial cells after ischemia/reperfusion injury in mice. Using Ptprz knockout mice we determined that during acute kidney injury and chronic kidney disease kidney pathology, and loss of kidney function were ameliorated. Ptprz-dependent mechanisms mediated: (i) tubular epithelial cell expression of chemokines that fostered macrophage and T cell rich renal inflammation, and (ii) tubule injury and apoptosis, that resulted in the loss of tubules and interstitial fibrosis during chronic kidney disease . Mechanistically, Ptprz dependent tubule epithelial cells released mediators that:(i) promoted tubule cytotoxicity, and thereby, shortened tubule survival, and (ii) stimulated Ptprz expressing macrophages to generate mediators that induce kidney destruction. These findings are translational, as after ischemia reperfusion injury in human kidney transplants, PTPRZ and PTPRZ ligands were upregulated and expressed by the same cell populations as in mice. Moreover, PTPRZ levels in sera were elevated in kidney transplant patients.

Conclusions: Intra-renal Ptprz-dependent macrophage and tubular epithelial cell mediated mechanisms promote acute kidney injury and subsequent chronic kidney disease.

Background: Acute kidney injury (AKI) is a syndrome characterized by a precipitous decline in kidney function, posing a significant threat to patient survival. The role of RNA binding protein (RBP) in AKI remains insufficiently understood and we found an important RBP, Lgals3, that may mediate the progress of AKI.

Methods: Lgals3-/- mice, Nr4a1-/- mice and cross-linking immunoprecipitation and high-throughput sequencing were performed to examine the role of Lgals3 in AKI and the targeted binding proteins.

Results: Lgals3 expression was notably elevated in vivo and in vitro AKI models. Inhibition of Lgals3 mitigated kidney injury in both in vivo and in vitro AKI models. Conversely, kidney-specific overexpression of Lgals3 exacerbated kidney damage. Mechanistically, Lgals3 bound to the 3'-untranslated region of Nr4a1 via AAUAAA, resulting in upregulation of Nr4a1 and subsequent enhancement of Bap1 transcription, facilitating ferroptosis in AKI. Moreover, knockout of Nr4a1 or inhibition of the region of AAUAAA by antisense oligonucleotide (ASO) conferred protection against Lgals3-induced ferroptosis in AKI models.

Conclusions: Lgals3 contributed to kidney injury by binding to the 3'UTR region of Nr4a1 via AAUAAA, leading to the activation of ferroptosis.

Background: The well-known accuracy limitations of estimated GFR (eGFR) currently employed in clinical practice present barriers to optimal care for patients with, or at-risk for, decreased kidney function. A point-of-care glomerular filtration rate (GFR) measurement methodology has the potential to address these limitations. We prospectively assessed transdermal detection of the novel fluorescent GFR tracer agent relmapirazin in participants having normal or impaired kidney function across all human skin colors on the Fitzpatrick Skin Scale (FSS).

Methods: A multi-center study comprising 74 participants with eGFR from normal to Stage 4 CKD was performed. Forty-six participants were FSS types I-III, and twenty-eight were FSS type IV-VI. A module containing an LED and photodetector to activate and collect transdermal relmapirazin fluorescence was attached adhesively to the upper chest of each participant. Relmapirazin (1.5mg/kg) was administered by intravenous push, and fluorescence emission was acquired for 12 hours. A two-compartment pharmacokinetic model fit the fluorescent intensity vs time data, and the fluorescence clearance rate (FCR) was extracted from the second (terminal) compartment. Plasma relmapirazin concentrations were measured contemporaneously and the corresponding plasma GFR for each participant was determined. Linear regression analysis was used to compare the FCR to the indexed plasma GFR.

Results: Participant age range was 23 to 80 years old, with 59% females. The two-compartment pharmacokinetic behavior was observed in the fluorescence intensity vs time data and a FCR was successfully deduced for every participant completing the 12-hour study. The FCR vs. the indexed plasma GFR yielded an excellent correlation over the range of GFR measured and for all skin colors with a r2 = 0.90 (95% confidence interval 0.85 to 0.94). No severe adverse events were reported.

Conclusions: Point-of-care transdermal detection of the fluorescent GFR tracer agent relmapirazin was feasible in patients with normal to impaired kidney function and for a range of skin color types.

Background: Natural, technological and other disasters cause significant human suffering, and kidney patients are uniquely vulnerable. The safe provision of kidney replacement therapies necessitates the consistent provision of resources. Robust disaster risk reduction and management (DRRM) can mitigate risks associated with resource disruption. Individual kidney care programs may benefit from an organized approach to developing context-specific protocols. We aimed to synthesize contemporary literature in kidney care to create a roadmap in DRRM.

Methods: We conducted a scoping review followed by a content analysis using the Framework Method. Literature that focused on lessons learned and proposed strategies or recommendations in DRRM was eligible. We contextualized this roadmap within the domains of disaster preparedness, response, and recovery.

Results: Of 3,973 titles and abstracts screened, 52 articles were included. We developed the following roadmap: 1) the 'ABC4s' of disaster preparedness: Assess needs, risks, and vulnerabilities (regional risks, patients at risk); Build a task force network; Capacity building (tangible resources, intangible resources, monetary considerations, transportation); Communication (network and protocol, patients' medical and dialysis information, contact information of all stakeholders, inclusive approach, reliable medium); Coaching (patients, caregivers, healthcare personnel, reinforce and repeat); Contingency planning (surge capacity, rationing care, resource distribution); and Strategic partnerships. 2) the 'DIAL' response: Damage and scope assessment; Initiate action plan (choose the plan, apply preparedness tenets, implications for receiving facilities); Appraise the action plan regularly (reassess, maintain ethical standards, address psychosocial needs); and Liaise, engage and update. 3) the 'ARC' to recovery: Assess damage; Return to the (new) norm; and Collect data to evaluate, improve, and share.

Conclusions: We propose a roadmap to disaster preparedness, response and recovery that can guide individual kidney care programs globally to develop context-specific protocols aimed at building capacities and facilitating processes toward DRRM.