Kidney international最新文献

During the last 20 years, the disease burden attributable to metabolic disorders increased by 49.4%. Metabolic disorders are established risk factors for both chronic kidney disease (CKD) and cardiovascular disease (CVD). A concept of cardiovascular-kidney-metabolic (CKM) syndrome has recently been proposed to underscore the pathophysiological interrelatedness of the metabolic risk factors, CKD, and CVD. Two major adverse outcomes of the metabolic disorder associated kidney disease are cardiovascular disease, and to a less extent, kidney failure. This review aims to briefly summarize the traditional metabolic risk factors for kidney disease; to introduce the concept of CKM health; to present the methods for risk assessment for CKD progression and CVD, with focus on validated and clinically applicable prediction tools; and to discuss the key gaps in the current tools for the risk stratification. In summary, in general clinical settings, the CKM health and associated risk in patients with the metabolic disorder associated kidney disease can be assessed by combining the CKM staging model, the CKD Prognosis Consortium equations for CKD progression, and the PREVENT equations for CVD. More efficient risk prediction tools, potentially incorporating multimodal data, are needed for more accurate and early identification of individuals at high risk and better personalized management of the disease.

The link between immigrant status, a key social determinant of health, and kidney disease remains uncertain. To evaluate this, we compared incident adverse kidney outcomes between immigrants and non-immigrants using Canadian provincial health administrative data. We conducted a population-based observational cohort study of all adult Ontario residents (immigrants and non-immigrants) with normal baseline kidney function (estimated glomerular filtration rate (eGFR) 70 mL/min/1.73m² or more). Multivariable Cox proportional hazard regression modeling was used to evaluate the relationship between immigrant status and the composite adverse kidney outcome of 40% eGFR decline or kidney failure. The study cohort included 10,440,210 individuals with 22% immigrants and 78% non-immigrants. The mean (Standard Deviation) age and eGFR were 45 (17) years and 102 (16) mL/min/1.73m², respectively. Immigrants experienced a 27% lower hazard for the composite adverse kidney outcome (adjusted hazard ratio 0.73 [95% Confidence Interval 0.72-0.74]) compared to non-immigrants which was primarily driven by 40% eGFR decline. However, immigrants also experienced a 12% lower hazard for incident kidney failure (0.88 [0.84-0.93]) compared to non-immigrants. Results were consistent upon accounting for the competing risk of death and adjusting for baseline albuminuria. As has been demonstrated with other chronic diseases, these novel findings suggest that a "healthy immigrant effect" also extends to kidney disease. Differential kidney disease outcomes were identified among immigrants based on refugee status and world region of origin which may inform health policy decision-making toward targeted screening strategies and more cost-effective resource allocation for immigrant populations.

Anti-nephrin autoantibodies have been discovered in patients with minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS), especially in those with active nephrotic syndrome. Here, we investigated the prevalence and clinical significance of anti-nephrin antibodies in 596 adult Chinese patients (436 with MCD and 160 with primary FSGS) diagnosed by kidney biopsy. Anti-nephrin IgG and IgM were detected using ELISA, with validation through antigen-inhibition ELISA and Western blotting. Clinical data at biopsy and during the follow-up period were analyzed. Anti-nephrin antibodies were detected in 43% of all patients, with 30% testing positive for anti-nephrin IgG, 26% for anti-nephrin IgM, and 13.1% for both antibodies. The prevalence of anti-nephrin antibodies was higher in patients with nephrotic-range proteinuria who were not receiving steroids or immunosuppressants (51.1%). Patients with positive anti-nephrin antibodies exhibited more severe nephrotic syndrome, higher rates of relapse, and a shorter relapse-free period compared to those negative for these antibodies. Clinical features were similar between those with IgG and IgM. Notably, patients with both anti-nephrin IgG and IgM had the most severe proteinuria and the highest relapse frequency, suggesting a dose-dependent effect. Longitudinal analysis revealed that anti-nephrin antibodies significantly decreased during clinical remission, while they reappeared preceding proteinuria relapse. Our study shows that anti-nephrin antibodies, including IgG and IgM, are detectable in adult patients with MCD and primary FSGS and are associated with active nephrotic syndrome and frequent relapse. These antibodies may serve as valuable biomarkers and potential therapeutic targets.

Introduction: A recent chronic kidney disease (CKD) progression hierarchical composite endpoint (HCE) utilizes the glomerular filtration rate (GFR) slope for participants without a dichotomous event. Here, we evaluated clinical interpretations when HCE analyses are driven by GFR slope comparisons.

Methods: Using CKD trial data, we calculated win odds using only GFR slope; dichotomous kidney events and GFR slope; all-cause mortality, dichotomous kidney events and GFR slope; and all-cause mortality with dichotomous kidney events.

Results: Win odds (95% confidence interval) calculated from pairwise GFR slope only comparisons were 1.44 (1.34-1.55), 1.60 (1.49-1.72), 1.19 (1.10-1.28), and 0.82 (0.78-0.86) in the DAPA-CKD, CREDENCE, SONAR, and ALTITUDE trials, respectively. Win odds were similar for the GFR slope only and full kidney HCE with and without mortality.

Conclusions: These results support incorporation of GFR slope into the CKD progression HCE and help to interpret the magnitude of treatment effect on kidney HCE estimated with win odds.

For decades, electron microscopy (EM) has been the primary method to visualize ultrastructural details of the kidney, including podocyte foot processes and the slit diaphragm. Despite its status as the gold standard, EM has significant limitations: it requires laborious sample preparation, works only with very small samples, is mainly qualitative, and is prone to misinterpretation due to section angle bias. Additionally, combining imaging and protein staining with antibodies poses a challenge, limiting EM's integration into routine research and diagnostic workflows. As imaging technology advances, super-resolution microscopy, with optical resolutions below 100 nm, presents a promising alternative for detailed insights into glomerular ultrastructure. This review explores various super-resolution techniques, particularly 3D-SIM, and demonstrates how they can be applied to standard histologic sections. The 3D-SIM-based measurement procedure PEMP offers a novel approach to quantifying podocyte foot process (PFP) morphology and can detect PFP changes even before proteinuria is present. Furthermore, PEMP can be combined with mRNA detection, multiplex staining, and deep learning algorithms, making it a powerful tool for kidney research, preclinical studies, and personalized diagnostics. This advancement has the potential to accelerate drug development and enhance therapeutic precision, heralding a new era of high-precision nephrology.

Human kidney organoids derived from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) have become novel tools for studying various kidney pathologies. Here, we transplanted ESC-derived kidney organoids into humanized mice with a mature human adaptive immune system developed through thymic education. As judged by histology and immunophenotyping, the transplanted HLA-mismatched kidney organoids trigged a robust alloimmune response, characterized by a dense immune cell infiltrate and enhanced memory T cell phenotype in the allograft 30 days post-transplantation. Multiplexed immunofluorescence revealed expression of functional markers of various immune cell infiltrates in response to organoid allografts, mimicking the T cell-mediated rejection process in humans. This validated our model as a novel platform to study various therapeutic strategies to control alloimmunity. Splenocytes isolated from organoid-transplanted hosts showed an alloantigen-specific memory response against 2D kidney organoids ex vivo. Overall, our study indicates that transplanting kidney organoids in humanized mice may be a valuable tool for studying human allogeneic immunity.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases featuring small blood vessel inflammation and organ damage, including necrotizing crescentic glomerulonephritis (NCGN). Persistent vascular inflammation leads to endothelial and kidney cell necrosis. Ferroptosis is a regulated cell death pathway executed by reactive oxygen species and iron-dependent lipid peroxidation culminating in cell membrane rupture. Here we show that ANCA-activated neutrophils induced endothelial cell (EC) death in vitro that was prevented by ferroptosis inhibition with Ferrostatin-1, Liproxstatin-1 and small inhibiting RNA against the enzyme AcylCoA Synthetase Long Chain Family Member 4 (ACSL4). In contrast, neither necroptosis nor apoptosis inhibition affected EC death. Moreover, both ferroptosis inhibitors alleviated lipid peroxide accumulation in EC. Increased lipid peroxidation was detected in kidney sections of AAV mice by immunohistochemistry. We generated MPO^-/- ACSL4^flox Tie2-Cre⁺ mice lacking ACSL4 specifically in EC (ACSL4^ΔEC) to study the significance of endothelial ferroptosis in vivo. ACSL4^ΔEC chimeric mice, but not control mice (ACSL4^WT), were protected from NCGN in a MPO-AAV bone-marrow transplantation model. These data establish that EC ferroptosis contributes to ANCA-induced glomerulonephritis. However, systemic pharmacological ferroptosis inhibition with Ferrostatin-1 or Liproxstatin-1 did not protect from NCGN in a murine AAV model. Ferrostatin-1 treatment both directly activated T cell proliferation and indirectly myeloid-mediated T cell proliferation and polarization in vitro. Conceivably, both effects may cancel the beneficial effect of endothelial ferroptosis inhibition. Mechanistically, we describe the importance of EC ferroptosis for the development of AAV. However, the lack of protection with systemic pharmacological ferroptosis inhibition should discourage clinicians from evaluating this treatment strategy in clinical AAV studies.

Data on the presentation of Autosomal Dominant Polycystic Kidney Disease (ADPKD) in children has been based on small/regional cohorts and practices regarding both asymptomatic screening in minors and genetic testing differ greatly between countries. To provide a global perspective, we analyzed over 2100 children and adolescents with ADPKD from 32 countries in six World Health Organization regions: 1060 children from the multi-national ADPedKD registry were compared to 269 pediatric patients from the United Kingdom (RaDaR) and 825 from the European Rare Kidney Disease Registry (ERKReg). Asymptomatic family screening was a common mode of presentation (48% in ADPedKD, 62% in ERKReg) with broad international variability (19%-75%), but fairly stable temporal trends in both registries with no correlation to genetic testing. The national rates of genetic testing varied and correlated significantly with healthcare expenditure (odds ratio 1.030 per 100 United States Dollars/capita/year, in the ERKReg cohort), with little variation over time. Diagnosis due to prenatal abnormalities was more common than anticipated at 14% increasing steadily from 2000 onward in both registries. Realistically, a high proportion of children were diagnosed with ADPKD by active screening, underlining that families affected by ADPKD have a high need for counselling on the complex issues around presymptomatic diagnosis. Regional variations in rate of genetic testing appeared to be driven by economic factors. However, large differences in rate of active screening were not correlated to healthcare spending and probably reflect the influence of different of cultural, legal and ethical frameworks on families and clinicians in different healthcare systems.

Kidney function, often assessed by estimated glomerular filtration rate (eGFR), declines naturally with age. However, there is a lack of eGFR reference values to describe normal and abnormal values for a specific age. The European Chronic Kidney Disease Burden Consortium is comprised of nine participating general population-based studies from seven European countries which provides European age- and sex-specific eGFR reference values in healthy adults using the European Kidney Function Consortium (EKFC) equation. Of 2,572,020 individuals, 1,535,253 (60%) were considered healthy, of which 45% were men. Ages ranged from 18 to 105 years old in men and 18 to 107 years old in women with a median age of 43 years in both sexes. At age 20 in men, the 5^th, 50^th and 95^th eGFR percentiles were 78 ml/min per 1.73 m², 99 ml/min per 1.73 m², and 119 ml/min per 1.73 m². In 20-year-old women this was 81 ml/min per 1.73 m², 101 ml/min per 1.73 m², and 121 ml/min per 1.73 m². Consequently, in men aged 80 years old, the 5^th, 50^th and 95^th eGFR percentiles were 49 ml/min per 1.73 m², 66 ml/min per 1.73 m², and 84 ml/min per 1.73 m². In 80 year old women this was 46 ml/min per 1.73 m², 63 ml/min per 1.73 m², and 81 ml/min per 1.73 m². Overall, our study shows that eGFR is not preserved with ageing in healthy individuals and these eGFR reference values can help determine abnormal and normal kidney function across the age range.

Novel transplantable organs need to be developed to address the global organ shortage. Transplantation of embryonic kidney tissue, or metanephros, facilitates glomerular and tubular maturation and offers partial organ functional support. However, adult environments do not permit exponential growth in size, limiting the life-supporting functionality and organ replacement effect of this approach. Here, we developed a novel strategy that combines the fusion of embryonic bladders with multiple anastomoses to the host ureter, enabling a significant increase in metanephros transplantation and urinary tract integration. By surgically anastomosing divided bladder segments, we reconstructed the excretory pathways by merging four metanephroi into each bladder and integrating them with the host ureter. Following the transplantation and integration of 20 metanephroi at the para-aortic region, anephric rats survived for over a month and generated approximately 50,000 nephrons in vivo. Ultrastructural and single-cell- transcriptomic analyses revealed that the maturity of the transplanted metanephroi was comparable to that of adult kidneys, although their small size likely contributed to their decreased urine concentration ability. Postoperative support helped normalize physiological homeostasis, including solute clearance, acid-base balance, electrolyte levels, and kidney hormone levels, within vital ranges. Our findings underscore the functional maturation capacity and dose-dependent therapeutic efficacy of embryonic kidney tissue, suggesting its potential as a transplantable organ system.