Kidney international最新文献

Unauthorized immigrants and permanent residents may experience challenges in accessing kidney transplantation due to limited healthcare access, socioeconomic and cultural barriers. Understanding the United States (US) national landscape of kidney transplantation for non-citizens may inform policy changes. To evaluate this, we utilized two cohorts from the US national registry (2013-2023): 287,481 adult candidates for first transplant listing and 190,176 adult first transplant recipients. Citizenship was categorized as US citizen (reference), permanent resident, and presumed unauthorized immigrant. Negative binomial regression was used to quantify the incidence rate ratio over time by citizenship status. Cause-specific hazards models, with clustering at the state of listing/transplant, were used to calculate the adjusted hazard ratio of waitlist mortality, kidney transplant, and post-transplant outcomes (mortality/death-censored graft failure) by citizenship category. The crude proportion of presumed unauthorized immigrants listed increased over time (2013:0.9%, 2023:1.9%). However, after accounting for case mix and waitlist size, there was no change in listing over time. Presumed unauthorized immigrants were less likely to experience waitlist mortality (adjusted Hazard Ratio 0.54, 95% Confidence Interval: 0.46-0.62), were more likely to obtain deceased donor kidney transplant (1.11: 1.05-1.18), but less likely to receive live donor (0.80: 0.71-0.90) or preemptive kidney transplant (0.52: 0.43- 0.62). When stratified by insurance status, presumed unauthorized immigrants on Medicaid were less likely to receive deceased donor kidney transplants compared to their citizen counterparts; however, presumed unauthorized immigrants with Private insurance or Medicare were more likely to receive deceased donor kidney transplants. Presumed unauthorized immigrants were less likely to experience post-transplant death (0.56: 0.43-0.69) and graft failure (0.69: 0.57-0.84). Residents had similar pre- and post-transplant outcomes. Despite the barriers to kidney transplantation faced by presumed unauthorized immigrants and residents in the US, better post-transplant outcomes for presumed unauthorized immigrants compared to citizens persisted, even after accounting for differences in patient characteristics.

Chronic kidney disease (CKD) is a global health epidemic that greatly increases mortality due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiac injury in CKD. High serum levels of fibroblast growth factor (FGF) 23 in patients with CKD may contribute mechanistically to the pathogenesis of LVH by activating FGF receptor (FGFR) 4 signaling in cardiac myocytes. Mitochondrial dysfunction and cardiac metabolic remodeling are early features of cardiac injury that predate development of hypertrophy, but these mechanisms have been insufficiently studied in models of CKD. We found in wild-type mice with CKD induced by adenine diet, that morphological changes occurred in mitochondrial structure and cardiac mitochondrial and that metabolic dysfunction preceded the development of LVH. In bioengineered cardio-bundles and neonatal rat ventricular myocytes grown in vitro, FGF23-mediated activation of FGFR4 caused mitochondrial pathology, characterized by increased bioenergetic stress and increased glycolysis that preceded the development of cellular hypertrophy. The cardiac metabolic changes and associated mitochondrial alterations in mice with CKD were prevented by global and cardiac-specific deletion of FGFR4. Our findings indicate that metabolic remodeling and mitochondrial dysfunction are early cardiac complications of CKD that precede structural remodeling of the heart. Mechanistically, FGF23-mediated activation of FGFR4 causes mitochondrial dysfunction, suggesting that early pharmacologic inhibition of FGFR4 might serve as novel therapeutic intervention to prevent development of LVH and heart failure in patients with CKD.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) presents with extra-skeletal calcification and renal osteodystrophy (ROD). However, the pathophysiology of ROD remains unclear. Here we examine the hypothesis that stalled mitophagy within osteocytes of CKD-MBD mouse models contributes to bone loss. RNA-seq analysis revealed an altered expression of genes associated with mitophagy and mitochondrial function in tibia of CKD-MBD mice. The expression of mitophagy regulators, p62/SQSTM1, ATG7 and LC3 was inconsistent with functional mitophagy, and in mito-QC reporter mice with ROD, there was a two to three-fold increase in osteocyte mitolysosomes. To determine if uremic toxins were potentially responsible for these observations, treatment of cultured osteoblasts with uremic toxins revealed increased mitolysosome number and mitochondria with distorted morphology. Membrane potential and oxidative phosphorylation were also decreased, and oxygen-free radical production increased. The altered p62 /SQSTM1 and LC3-II expression was consistent with impaired mitophagy machinery, and the effects of uremic toxins were reversible by rapamycin. A causal link between uremic toxins and the development of mitochondrial abnormalities and ROD was established by showing that a mitochondria-targeted antioxidant (MitoQ) and the charcoal adsorbent AST-120 were able to mitigate the uremic toxin-induced mitochondrial changes and improve bone health. Overall, our study shows that impaired clearance of damaged mitochondria may contribute to the ROD phenotype. Targeting uremic toxins, oxygen-free radical production and the mitophagy process may offer novel routes for intervention to preserve bone health in patients with CKD-MBD. This would be timely as our current armamentarium of anti-fracture medications for patients with severe CKD-MBD is limited.

While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, they can elicit organ-related immune-related adverse events (irAEs) such as kidney injury. Here, our study evaluated the ability of a humanized immune system (HIS) tumor-bearing mouse model to investigate ICI-mediated kidney injury. Non-humanized (BRGS) and humanized (HIS-BRGS) mice were implanted with human breast cancer cells and treated with either nivolumab (anti-PD-1) or a combination of nivolumab and ipilimumab (anti-CTLA-4) for four weeks. Histopathological analysis revealed that HIS-BRGS mice treated with ICIs exhibited significant interstitial nephritis and vasculitis/periarteritis, consistent with kidney phenotypes observed in patients. Combination therapy resulted in more extensive kidney pathology than nivolumab alone and exhibited an accumulation of T helper cells in the affected areas. Importantly, our results suggest that HIS-BRGS mice can effectively recapitulate features of ICI-induced kidney injury observed in patients and can be used to study mechanisms and prevention strategies to limit irAEs.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe hepatorenal fibrocystic disorder. Its rareness and the variability of disease courses have been major obstacles for the establishment of clinical trials on treatment of kidney disease in ARPKD. In this observational study we characterized kidney disease progression in a very large cohort of up to 658 patients with the clinical diagnosis of ARPKD and identified risk factors associated with rapid kidney disease progression. The estimated probability of kidney failure by the age of 20 years was 50.1% (95% confidence interval 42.2%‒57.0%), with earlier kidney failure in specific subgroups. Mean yearly estimated glomerular filtration rate decline after the first year of life was 1.3 ml/min per 1.73m² during childhood and adolescence in the overall cohort, ranging from 0.5 to 2.2 ml/min per 1.73m² in various subgroups. Furthermore, we developed prediction models for the relative risk of early kidney failure to be applied at the age of two months in daily clinical life. The finally chosen predictor set for a score based on a Cox model encompassed five factors: gestational age at oligo- or anhydramnios, gestational age at birth, functional genotype, serum creatinine (mg/dl) as well as documentation of arterial hypertension at the age of two months. The derived simple prognostic score showed good prediction performance, especially in the first three years of life. It reliably identified patients who are not at risk of early kidney failure and may be helpful to identify patients at risk of more rapid disease progression that could benefit from novel therapeutic interventions.

Objective: Autoantibodies against the podocyte protein nephrin were recently identified in a pediatric cohort primarily comprising steroid-sensitive (SSNS) and steroid-dependent (SDNS) nephrotic syndrome (NS). However, their prevalence across all NS subtypes, particularly in steroid-resistant nephrotic syndrome (SRNS), and their relation to therapy response remain need to be determined to advance pathophysiological understanding and refine treatment strategies.

Methodology: A multicenter cohort study measuring anti-nephrin autoantibodies in samples from children with SSNS, SDNS, non-genetic and genetic SRNS was conducted.

Results: Sixty nine of 101 (68%) patients with SSNS, 19 of 67 (28%) patients with SDNS, 14 of 103 patients (14%) with non-genetic SRNS and one of 62 patients (2%) with genetic SRNS were positive for anti-nephrin autoantibodies. The prevalence of anti-nephrin autoantibodies increased with presence of active disease in cases of SSNS and SDNS. Within the group of non-genetic SRNS patients with active disease, anti-nephrin positivity was found in 13 of 74 (18%) patients responding to intensified immunosuppression compared to none of 17 patients with multidrug-resistant SRNS.

Conclusion: The prevalence of anti-nephrin antibodies is substantially higher in children with steroid responsive NS than in those with SRNS, suggesting that anti-nephrin antibodies primarily drive SSNS/SDNS. In contrast, NS due to podocyte gene mutations is primarily genotype-caused. Anti-nephrin autoantibodies may serve as a positive prognostic marker in pediatric NS, indicating a favorable response to immunosuppressive therapy.

Health research results are primarily disseminated through scientific peer-reviewed journals and are not readily accessible to patients and caregivers, which can impede informed decision-making and limit the impact of research on patient outcomes. The aim of the workshop was to identify strategies to disseminate research in chronic kidney disease (CKD) to patients and caregivers. The workshop involved patients, caregivers (n=27), and health professionals (n=54) from Australia (ten breakout groups). The transcripts were thematically analysed. Three themes (strategies) were identified. Generating interest encompassed emphasising the benefits and impacts of research, using engaging modes of delivery, increasing visibility in clinical settings, and harnessing popular culture. Eliminating barriers to access included ensuring free access to journal articles, translating into different languages, providing plain-language summaries, considering convenience in the context of CKD-related burdens, and maximising exposure. Demonstrating trustworthiness and repute entailed filtering for high-quality information and propagating through familiar networks and community-based channels. Ensuring ease of access to research; drawing attention; and prompting motivation; to engage in research, and instilling confidence in patients about the quality of research may support effective dissemination. Adopting patient prioritized models to increase translation of research may support shared decision-making in practice and improve care and patient outcomes.