KEY POINTS: Inclisiran for LDL cholesterol reduction was analyzed post hoc in patients with CKD. Mean percentage LDL cholesterol reduction from baseline was around 50% regardless of eGFR in phase 3 trials. Inclisiran sho...KEY POINTS: Inclisiran for LDL cholesterol reduction was analyzed post hoc in patients with CKD. Mean percentage LDL cholesterol reduction from baseline was around 50% regardless of eGFR in phase 3 trials. Inclisiran showed sustained and effective LDL cholesterol-lowering in patients across various levels of eGFR values, without new safety findings. BACKGROUND: Lowering LDL cholesterol reduces the risk of atherosclerotic cardiovascular disease in patients with CKD. The efficacy and safety of inclisiran versus placebo in patients without and with CKD were investigated in a post hoc pooled analysis of three phase 3 trials (ORION-9, ORION-10, and ORION-11). METHODS: Patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease or its risk equivalent, and elevated LDL cholesterol were randomized 1:1 to subcutaneous inclisiran or placebo on days 1 and 90 and every 6 months thereafter for 540 days. Patients were stratified based on baseline eGFR (by CKD Epidemiology Collaboration equation): ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 . Coprimary end points were percentage change in LDL cholesterol at day 510 and time-adjusted percentage change after day 90 and through day 540. Safety was also evaluated. RESULTS: Of 3660 patients, 1610 (44%) had eGFR ≥90, 1608 (44%) 60 to <90, 300 (8%) 45 to <60, and 142 (4%) 15 to <45 ml/min per 1.73 m 2 . The mean (95% confidence interval) placebo-corrected percentage changes in LDL cholesterol from baseline at day 510 in patients with eGFR ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 were -49.9% (-53.2 to -46.6), -51.2% (-54.4 to -48.0), -54.7% (-62.5 to -47.0), and -44.7% (-57.6 to -31.8), respectively ( P < 0.001); the corresponding mean (95% confidence interval) time-adjusted placebo-corrected percentage changes in LDL cholesterol from baseline after day 90 through day 540 were -48.4% (-50.8 to -46.1), -51.8% (-54.2 to -49.4), -55.6% (-61.0 to -50.2), and -50.4% (-59.3 to -41.5; each P < 0.001). Significant decreases in total cholesterol, apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) occurred in all eGFR groups. Inclisiran was well tolerated without new safety findings. CONCLUSIONS: Inclisiran demonstrated sustained and effective LDL cholesterol reduction in patients with or at risk of atherosclerotic cardiovascular disease, regardless of baseline eGFR as low as 15 ml/min per 1.73 m 2 , without new safety findings. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, ORION-9 ( NCT03397121 ), ORION-10 ( NCT03399370 ), and ORION-11 ( NCT03400800 ).
J Am Soc Nephrol
· 2026 Apr · PMID 41591826
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Knowledge of kidney function is a key component for diagnosing CKD and initiating treatment. The eGFR, which is most commonly used in clinical practice as an approximation of kidney function, is the most practical for ev...Knowledge of kidney function is a key component for diagnosing CKD and initiating treatment. The eGFR, which is most commonly used in clinical practice as an approximation of kidney function, is the most practical for everyday use. It has, however, disadvantages because the two most common biomarkers used in eGFR calculations, creatinine and cystatin C, are influenced by patient characteristics such as body composition, inflammation, and many others, leading to significantly inaccurate GFR estimation at times. In patients who are prone to distorted eGFR values, measured GFR (mGFR) should be considered to ensure accurate assessment of kidney function. mGFR is not as influenced by patient characteristics as it uses exogenous biomarkers instead of endogenous ones. It is, however, more complex to perform and has also its limitations. Several different mGFR measurement methods exist. The one that has become most widely accepted and is the only method for which there is an internationally standardized protocol is plasma iohexol clearance. Other mGFR markers include iothalamate, mostly applied as urinary clearance and radioactive markers. Newer techniques that measure GFR transdermally have been developed, although they have yet to be sufficiently externally validated.
KEY POINTS: Targeting METTL3 with the heat shock protein 90 inhibitor 17-DMAG mitigated kidney fibrosis in CKD. The drug repositioning through differentially expressed gene and enrichment analyses identified 17-dimethyla...KEY POINTS: Targeting METTL3 with the heat shock protein 90 inhibitor 17-DMAG mitigated kidney fibrosis in CKD. The drug repositioning through differentially expressed gene and enrichment analyses identified 17-dimethylaminoethylamino-17-demethoxygeldanamycin as a potential agent to alleviate kidney fibrosis. The N -terminal heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin suppressed c-Jun-METTL3 signaling, attenuating N 6-methyladenosine methylation and kidney fibrosis. BACKGROUND: Kidney fibrosis is a major pathological feature of CKD, characterized by excessive deposition of extracellular matrix proteins, leading to progressive loss of kidney function. N 6-methyladenosine (m6A) RNA methylation has emerged as a crucial epigenetic modification implicated in various diseases, including kidney fibrosis. METTL3, an m6A writer, plays a key role in promoting fibrosis by stabilizing profibrotic gene expression. Therefore, targeting METTL3 represents a promising therapeutic strategy for CKD treatment. In this study, we explored the therapeutic potential of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in regulating METTL3 to mitigate kidney fibrosis. METHODS: Through transcriptome-based drug repositioning, we identified 17-DMAG as a potential inhibitor of METTL3. Differentially expressed gene analysis was performed to assess the enrichment of 17-DMAG in CKD-related gene expression profiles. The antifibrotic effects of 17-DMAG were evaluated in in vitro and in vivo models. The mechanism by which 17-DMAG downregulates METTL3 was also investigated. RESULTS: 17-DMAG significantly reduced METTL3 expression in renal epithelial cells in a dose-dependent and time-dependent manner. In in vivo mouse models of kidney fibrosis, 17-DMAG treatment attenuated METTL3 levels, reduced total m6A modification, and effectively mitigated fibrosis, as evidenced by decreased collagen deposition and profibrotic marker expression. Mechanistically, 17-DMAG, a heat shock protein 90 (HSP90) N -terminal inhibitor, induced a heat shock response that sequentially upregulated HSP70 expression. The elevated HSP70 levels inhibited c-Jun N -terminal kinase activity, thereby suppressing the c-Jun transcription factor and ultimately leading to the downregulation of METTL3 expression. MeRIP-Seq analysis revealed that 17-DMAG reversed unilateral ischemia-reperfusion injury-induced m6A epitranscriptomic changes in fibrosis-related genes, including GSK3B , which is involved in fibrotic pathways. CONCLUSIONS: N -terminal HSP90 inhibition, along with subsequent c-Jun suppression, contributed to the mechanism underlying 17-DMAG-induced METTL3 downregulation. Through this regulatory pathway, 17-DMAG effectively suppressed METTL3 expression and attenuated kidney fibrosis in both in vitro and in vivo models.
KEY POINTS: Lower kidney function is associated with higher concentrations of blood biomarkers for Alzheimer's disease and related dementia. Associations between kidney function and cerebrospinal fluid biomarkers for Alz...KEY POINTS: Lower kidney function is associated with higher concentrations of blood biomarkers for Alzheimer's disease and related dementia. Associations between kidney function and cerebrospinal fluid biomarkers for Alzheimer's disease and related dementia were heterogeneous and NS. Elevated blood biomarkers for Alzheimer's disease and related dementia in people with impaired kidney function may reflect reduced kidney clearance. BACKGROUND: Studies have shown that low kidney function may link to elevated Alzheimer's disease and related dementia fluid biomarkers, but the results are not consistent. This systematic review and meta-analysis aimed to investigate whether kidney function was associated with Alzheimer's disease and related dementia biomarkers (amyloid- β , tau, neurofilament light [NfL] protein, and glial fibrillary acidic protein [GFAP]) in blood and cerebrospinal fluid (CSF). METHODS: Human studies were identified through MEDLINE, EMBASE, Cochrane Library, and Web of Science (until May 2, 2025). Studies that reported the association between kidney function and Alzheimer's disease and related dementia biomarkers in blood or CSF among adults were included. Two authors independently screened and extracted data following preferred reporting items for systematic reviews and meta-analyses 2020 guidelines. Descriptive statistics and random-effects meta-analysis were used to analyze pooled effects. RESULTS: Of the 3024 studies screened, 93 met the inclusion criteria, encompassing 62,503 participants (mean age, 20-96 years; 54% female) from 21 countries. Ninety-one studies reported blood biomarkers, while ten reported CSF biomarkers. In meta-analysis of unadjusted correlation coefficients, kidney function (primarily eGFR) was inversely associated with concentrations of blood NfL, GFAP, Aβ40, β-amyloid 1-40 (A β 40), β-amyloid 1-42, and phosphorylated tau (p-tau181). In meta-analysis of adjusted regression coefficients, eGFR remained inversely associated with blood biomarker levels. Specifically, every 1 ml/min per 1.73 m 2 lower eGFR was associated with 0.19 pg/ml higher NfL (95% confidence interval [CI], 0.12 to 0.25), 0.11 pg/ml higher GFAP (95% CI, 0.04 to 0.18), and 0.29 pg/ml higher A β 40 (95% CI, 0.01 to 0.56). CSF biomarker findings were more heterogeneous and generally null. CONCLUSIONS: Low kidney function was associated with elevated blood biomarkers of Alzheimer's disease and related dementia (NfL, GFAP, and A β 40), whereas associations with CSF biomarkers were inconsistent and generally null.
J Am Soc Nephrol
· 2026 Jan · PMID 41568909
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KEY POINTS: Proximal tubular expression of hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) during ischemic injury increases kidney ketone and prostaglandin content. Kidney HMGCS2 deficiency emerged as both a biomarker and...KEY POINTS: Proximal tubular expression of hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) during ischemic injury increases kidney ketone and prostaglandin content. Kidney HMGCS2 deficiency emerged as both a biomarker and contributor to kidney disease. Renal ketogenesis supported the maintenance of proximal tubular fatty acid oxidation. BACKGROUND: Abnormal renal fatty acid oxidation in kidney disease suggests that dysregulated metabolism is a key component of kidney disease pathogenesis. While the liver is the main ketogenic organ, the rate-limiting enzyme for ketogenesis, mitochondrial hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), is induced in the proximal tubule of the kidney during fasting. We previously demonstrated that HMGCS2 induced in the kidney does not contribute to the circulating pool of ketones during fasting and cannot compensate for hepatic ketogenic deficiency. We hypothesized that kidney HMGCS2 may be acting locally within the kidney to maintain normal function during metabolic stress or injury. METHODS: Mice with kidney- or liver-specific deletion of Hmgcs2 were subjected to ischemia/reperfusion injury (IRI). Kidney histology, metabolomics, and lipidomics were analyzed. Mice were placed on a ketogenic diet for 4 days to increase plasma and kidney ketone content. Using novel mouse models with proximal tubular hemagglutinin-tagged mitochondria with or without Hmgcs2 deletion, proximal tubular-specific mitochondria were isolated, and fatty acid oxidation capacity was measured after IRI. RESULTS: Mice with kidney-specific Hmgcs2 deletion had significantly more kidney injury after IRI compared with wild-type controls. Kidneys lacking HMGCS2 exhibited a decrease in ketone content and an increase in lipid droplet accumulation after IRI. Proximal tubular-specific mitochondria lacking HMGCS2 had significantly lower fatty acid oxidation capacity both at baseline and after ischemic injury. Administration of a ketogenic diet for 4 days before IRI was sufficient to decrease kidney injury and augment mitochondrial fatty acid oxidation in kidney Hmgcs2 knockout mice. Kidney tissue lipidomics revealed that the loss of kidney HMGCS2 was associated with a decrease in both arachidonic acid containing phospholipids and prostaglandin levels. CONCLUSIONS: Loss of renal HMGCS2 and resultant ketogenesis increased ischemia-induced injury and decreased mitochondrial fatty acid oxidation capacity, suggesting a role in renal ketogenesis in limiting AKI.
J Am Soc Nephrol
· 2026 Jun · PMID 41568892
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Ferroptosis is a distinct necrotic form of regulated cell death caused by a breakdown in membrane redox homeostasis. Accumulating evidence highlights a central role for ferroptosis in both acute and chronic kidney diseas...Ferroptosis is a distinct necrotic form of regulated cell death caused by a breakdown in membrane redox homeostasis. Accumulating evidence highlights a central role for ferroptosis in both acute and chronic kidney diseases, with proximal tubule cells being the primary target. It is tightly controlled by an intricate network of metabolic pathways for iron, lipid, and redox homeostasis, all of which are highly affected by kidney diseases. Moreover, recent studies have demonstrated that several human kidney disease genes modulate cellular susceptibility to ferroptosis by altering these metabolic pathways, underscoring ferroptosis as a potential therapeutic target to improve patient outcomes. Mechanistic studies have defined the cysteine-glutathione-glutathione peroxidase 4 (GPX4) axis as the central defense against ferroptosis. GPX4 detoxifies membrane phospholipid hydroperoxides, thus preventing iron-dependent lipid peroxidation chain reactions and damage to the plasma membrane. When GPX4 is overwhelmed, toxic lipid peroxides accumulate and disrupt membrane integrity-a process known as ferroptotic stress-ultimately leading to plasma membrane rupture and cell death. In this review, we provide a conceptual framework for understanding how ferroptotic stress contributes to kidney disease progression and how it can be therapeutically targeted. We highlight recent evidence that ferroptotic stress not only triggers cell death but also significantly affects the surviving proximal tubule cells. We discuss sex-specific differences in ferroptosis and explore the implications of female resilience to ferroptosis for identifying new therapeutic strategies. By integrating mechanistic insights into ferroptotic stress with new experimental observations, this review underscores ferroptosis as both a pathogenic driver and a promising therapeutic target in kidney disease.
KEY POINTS: Women with preeclampsia had a higher risk of incident albuminuria >300 mg/g, eGFR <60 ml/min per 1.73 m 2 , or the composite outcome. The higher risk extended across multiple outcomes, including CKD diagnoses...KEY POINTS: Women with preeclampsia had a higher risk of incident albuminuria >300 mg/g, eGFR <60 ml/min per 1.73 m 2 , or the composite outcome. The higher risk extended across multiple outcomes, including CKD diagnoses and nephrology referrals. Despite these risks, postpartum monitoring of kidney function was infrequent, limiting opportunities for early detection and intervention. BACKGROUND: Preeclampsia, a systemic hypertensive disorder of pregnancy, has been associated with the risk of kidney failure, an outcome that may take decades to develop. However, its association with early kidney disease, which could be targeted for intervention, remains underexplored. Here, we quantified the risk of CKD, defined by laboratory markers of kidney damage, in women who had a pregnancy complicated by preeclampsia versus a pregnancy without preeclampsia. METHODS: This was a population-based cohort study in Stockholm, Sweden, using inverse probability of treatment weights to minimize confounding. All nulliparous women who had at least one pregnancy ending in live or stillbirth between January 1, 2006, and December 31, 2020, were identified, excluding preexisting hypertension, diabetes, or CKD. Primary outcomes were ( 1 ) albuminuria defined by urine albumin-creatinine ratio >300 mg/g, ( 2 ) eGFR <60 ml/min per 1.73 m 2 , and ( 3 ) composite of albuminuria >300 mg/g and/or eGFR <60 ml/min per 1.73 m 2 . RESULTS: The study included 171,693 pregnancies (170,192 women: mean [SD] age, 29 [5] years), of whom 10,538 (6%) had at least one pregnancy complicated by preeclampsia. During a median follow-up of 7.0 years (interquartile range, 3.3-10.5), albuminuria >300 mg/g occurred after 775 pregnancies (0.5%), eGFR <60 ml/min per 1.73 m 2 occurred after 248 pregnancies (0.1%), and the composite outcome occurred after 985 pregnancies (0.6%). Incidence rates per 1000 person-years were higher after preeclampsia versus no preeclampsia for albuminuria >300 mg/g (1.53 versus 0.57), eGFR <60 ml/min per 1.73 m 2 (0.52 versus 0.18), and the composite outcome (2.00 versus 0.73). Weighted hazard ratios were 2.53 (95% confidence interval [CI], 2.04 to 3.13) for albuminuria >300 mg/g, 2.18 (95% CI, 1.49 to 3.19) for eGFR <60 ml/min per 1.73 m 2 , and 2.43 (95% CI, 2.01 to 2.95) for the composite outcome. In the first postpartum year, 2080 (20%) and 1043 (10%) of women with preeclampsia had serum creatinine or urine albumin testing, respectively. CONCLUSIONS: Preeclampsia was associated with a higher risk of laboratory signs of early kidney damage. There were low rates of postpartum kidney function monitoring.
Xu C, Cheung CY, Zhong J
… +8 more, Lin Y, Fong CH, Jiang X, Jia X, Lui DT, Lee CH, Lam KS, Xu A
J Am Soc Nephrol
· 2026 Apr · PMID 41563825
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KEY POINTS: Proteomics analyses consistently identified nine independent protein predictors for CKD in both Chinese and European participants with type 2 diabetes. A novel prediction model, "eGFR+five-protein panel predi...KEY POINTS: Proteomics analyses consistently identified nine independent protein predictors for CKD in both Chinese and European participants with type 2 diabetes. A novel prediction model, "eGFR+five-protein panel predicting CKD," reliably predicted CKD with good performance (area under the receiver operating characteristic curve ≥0.80). The new "eGFR+five-protein panel predicting CKD" model exhibited superior performance over traditional clinical models. BACKGROUND: Currently, there is a lack of reliable biomarkers for noninvasive prediction of CKD in patients with diabetes. This study aimed to identify novel protein predictors and construct a prediction model for incident CKD in participants with type 2 diabetes applicable across different populations. METHODS: A targeted Olink plasma proteomics profiling analysis, involving 368 proteins, was conducted in a nested case-control study comprising 132 incident CKD cases and 132 non-CKD controls, matched for age, sex, duration of diabetes, and eGFR, recruited from a long-term prospective cohort of Chinese type 2 diabetes participants (median approximately 9-year follow-up). False discovery rate was applied for multiple testing corrections. A q -value <0.2 was considered statistically significant. Three machine-learning approaches (Boruta, support vector machine, and eXtreme gradient boosting) were used for feature selection. Independent associations of proteins with incident CKD with adjustments for conventional clinical risk factors were examined in the training set ( n =1580, including 173 incident CKD cases and 1407 non-CKD controls; 70%) of the UK Biobank Pharma Proteomics Project (UKB-PPP) (median approximately 13.5-year follow-up). The least absolute shrinkage and selection operator-based Cox-regression analysis was used to develop the prediction model, which was subsequently validated in the testing set ( n =677, including 85 incident CKD cases and 592 non-CKD controls; 30%) of UKB-PPP. RESULTS: Among the 18 identified protein features predictive of incident CKD, 12 showed significant associations with consistent direction of effects in both cohorts. A prediction model ("eGFR+five-protein panel predicting CKD [eGFR+FPPC]") combining eGFR and five proteins (α-1-microglobulin/bikunin precursor, matrix metallopeptidase 7, placental growth factor, TNF-related apoptosis-inducing ligand receptor 2, and kidney injury molecule-1) was constructed and validated in the testing and training sets of the UKB-PPP, respectively. The "eGFR+FPPC" model achieved superior predictive performance in both training (area under the receiver operating characteristic curve [95% confidence interval]: 0.82 [0.79 to 0.85]) and testing (area under the receiver operating characteristic curve [95% confidence interval]: 0.80 [0.74 to 0.86]) sets of UKB-PPP and yielded fewer indeterminate results compared with conventional clinical models. CONCLUSIONS: The "eGFR+FPPC" model performed better than conventional clinical models in predicting incident CKD in type 2 diabetes participants across different populations.
Deng P, Zhou H, Yu J
… +12 more, Li Y, Yang F, Zhang D, Zhou M, Luo J, Gao L, Bi E, Guo N, Nie J, Sun B, Hou FF, Hu Y
J Am Soc Nephrol
· 2026 Jun · PMID 41563819
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KEY POINTS: Extracellular matrix protein 1 is specifically expressed in glomerular mesangial cells in both human and mice. Loss of extracellular matrix protein 1 leads to excessive mesangial matrix expansion and disrupte...KEY POINTS: Extracellular matrix protein 1 is specifically expressed in glomerular mesangial cells in both human and mice. Loss of extracellular matrix protein 1 leads to excessive mesangial matrix expansion and disrupted glomerular architecture. Extracellular matrix protein 1 binds integrin α 8 β 1 to stabilize mesangial cell adhesion to the mesangial matrix and glomerular basement membrane. BACKGROUND: The mesangium consists of mesangial cells and mesangial matrix that maintain normal glomerular structure and function. The mechanisms by which mesangial cells regulate mesangial matrix dynamics remain poorly understood. This study investigated the role of mesangial cell-derived extracellular matrix protein 1 (ECM1) in regulating mesangial matrix homeostasis and glomerular structure in mice. METHODS: Immunofluorescence and single-nucleus RNA sequencing were used to clarify the ECM1 expression pattern in kidney. Global and tamoxifen-inducible Ecm1 -knockout (KO) mice demonstrated the in vivo function of Ecm1 . Immunoprecipitation, mass spectrometry, and RNA-seq were used to reveal the mechanism by which ECM1 regulates mesangial matrix homeostasis. RESULTS: snRNA-seq and immunofluorescence revealed that ECM1 was specifically expressed in glomerular mesangial cells and downregulated in diabetic kidney disease and IgA nephropathy. Genetic deletion of Ecm1 in mice resulted in mesangial matrix expansion at 4 and 8 weeks of age, whereas early stages appeared unaffected. Similarly, tamoxifen-induced global deletion of Ecm1 in 4-week-old mice led to a trend toward mesangial matrix expansion. Transcriptomic profiling and immunofluorescence confirmed substantial alterations of the mesangial matrix components in Ecm1 -KO kidneys. As a result, histological examination showed profound glomerular abnormalities in Ecm1 -KO mice. Ecm1 deficiency also elevated TGF β 1 expression and downstream signaling, likely contributing to the excessive collagen deposition in glomeruli. Mechanistically, ECM1 interacted with integrin α 8 β 1 to promote mesangial cell-matrix adhesion, and loss of this interaction led to mesangial cell disaggregation and detachment from glomerular basement membrane, thereby promoting glomerular pathology. Notably, adeno-associated virus-mediated ECM1 expression in vivo effectively rescued kidney dysfunction in Ecm1 -KO mice. CONCLUSIONS: ECM1 was highly expressed in glomerular mesangial cells. Loss of Ecm1 led to altered mesangial matrix composition, matrix expansion, and glomerular abnormalities, while restoration of ECM1 expression reversed these defects, demonstrating an essential role of mesangial cell-derived ECM1 in preserving normal mesangial homeostasis and glomerular structure in mice.