Glomerular crescents are associated with the risk of type 2 diabetic kidney disease progression: a retrospective cohort study.

BACKGROUND: Diabetic kidney disease (DKD) stands as the predominant cause of chronic kidney disease and end-stage kidney disease. Its diverse range of manifestations complicates the treatment approach for patients. Although kidney biopsy is considered the gold standard for diagnosis, it lacks precision in predicting the progression of kidney dysfunction. Herein, we addressed whether the presence of glomerular crescents is linked to the outcomes in patients with biopsy-confirmed type 2 DKD. METHODS: We performed a retrospective evaluation, involving 327 patients diagnosed with biopsy-confirmed DKD in the context of type 2 diabetes, excluding cases with other glomerular diseases, from nine tertiary hospitals. Hazard ratios (HRs) were calculated using a Cox regression model to assess the risk of kidney disease progression, defined as either ≥ 50% decrease in estimated glomerular filtration rates or the development of end-stage kidney disease, based on the presence of glomerular crescents. RESULTS: Out of the 327 patients selected, ten patients had glomerular crescents observed in their biopsied tissues. Over the follow-up period (median of 19 months, with a maximum of 18 years), the crescent group exhibited a higher risk of kidney disease progression than the no crescent group, with an adjusted HR of 2.82 (1.32-6.06) (P = 0.008). The presence of heavy proteinuria was associated with an increased risk of developing glomerular crescents. CONCLUSION: The presence of glomerular crescents is indeed linked to the progression of type 2 DKD. Therefore, it is important to determine whether there is an additional immune-mediated glomerulonephritis requiring immunomodulation, and it may be prudent to monitor the histology and repeat a biopsy.

Associations of MRI-derived kidney volume, kidney function, body composition and physical performance in ≈38 000 UK Biobank participants: a population-based observational study.

Background: Kidney volume is used as a predictive and therapeutic marker for several clinical conditions. However, there is a lack of large-scale studies examining the relationship between kidney volume and various clinicodemographic factors, including kidney function, body composition and physical performance. Methods: In this observational study, MRI-derived kidney volume measurements from 38 526 UK Biobank participants were analysed. Major kidney volume-related measures included body surface area (BSA)-adjusted total kidney volume (TKV) and the difference in bilateral kidneys. Multivariable-adjusted linear regression and cubic spline analyses were used to explore the association between kidney volume-related measures and clinicodemographic factors. Cox or logistic regression was used to identify the risks of death, non-kidney cancer, myocardial infarction, ischaemic stroke and chronic kidney disease (CKD). Results: The median of BSA-adjusted TKV and the difference in kidney volume were 141.9 ml/m2 [interquartile range (IQR) 128.1-156.9] and 1.08-fold (IQR 1.04-1.15), respectively. Higher BSA-adjusted TKV was significantly associated with higher estimated glomerular filtration rate {eGFR; ß = 0.43 [95% confidence interval (CI) 0.42-0.44]; P < .001}, greater muscle volume [ß = 0.50 (95% CI 0.48-0.51); P < .001] and greater mean handgrip strength [ß = 0.15 (95% CI 0.13-0.16); P < .001] but lower visceral adipose tissue volume [VAT; ß = -0.09 (95% CI -0.11 to -0.07); P < .001] in adjusted models. A greater difference in bilateral kidney volumes was associated with lower eGFR, muscle volume and physical performance but with higher proteinuria and VAT. Higher BSA-adjusted TKV was significantly associated with a reduced risk of CKD [odds ratio (OR) 0.7 (95% CI 0.63-0.77); P < .001], while a greater difference in kidney volume was significantly associated with an increased risk of CKD [OR 1.13 (95% CI 1.07-1.20); P < .001]. Conclusion: Higher BSA-adjusted TKV and lower differences in bilateral kidney volumes are associated with higher kidney function, muscle volume and physical performance and a reduced risk of CKD.

Risk of mortality and cause of death according to kidney function parameters: a nationwide observational study in Korea.

BACKGROUND: Further study is warranted to determine the association between estimated glomerular filtration rate (eGFR) or albuminuria and the risk of death from diverse causes. METHODS: We screened >10 million general health screening examinees who received health examinations conducted in 2009 using the claims database of Korea. After the exclusion of those previously diagnosed with renal failure and those with missing data, 9,917,838 individuals with available baseline kidney function measurements were included. The primary outcome was mortality and cause-specific death between 2009 and 2019 identified through death certificates based on the diagnostic codes of International Classification of Diseases, 10th revision. Multivariable Cox regression analysis adjusted for various clinicodemographic and social characteristics was used to assess mortality risk. RESULTS: The hazard ratio of death was significantly high in both the eGFR <60 mL/min/1.73 m2 and in the eGFR ≥120 mL/ min/1.73 m2 groups in univariable and multivariable regression analyses when compared to those within the reference range (eGFR of 90-120 mL/min/1.73 m2). The results were similar for death by cardiovascular, cancer, infection, endocrine, respiratory, and digestive causes. We also found that albuminuria was associated with higher risk of death regardless of eGFR range, and those in the higher categories of dipstick albuminuria showed higher risk. CONCLUSION: We reconfirmed the significant association between eGFR, albuminuria, and mortality. Healthcare providers should keep in mind that albuminuria and decreased eGFR as well as kidney hyperfiltration are independent predictors of mortality.

Intradialytic hypotension and worse outcomes in patients with acute kidney injury requiring intermittent hemodialysis.

Background: Intradialytic hypotension (IDH) is a critical complication related to worse outcomes in patients undergoing maintenance hemodialysis. Herein, we addressed the impact of IDH on mortality and other outcomes in patients with severe acute kidney injury (AKI) requiring intermittent hemodialysis. Methods: We retrospectively reviewed 1,009 patients who underwent intermittent hemodialysis due to severe AKI. IDH was defined as either dialysis discontinuation due to hemodynamic instability or a decrease in systolic blood pressure (BP) of ≥30 mmHg, with or without a nadir systolic BP of <90 mmHg during the first session. The primary outcome was all-cause mortality, and transfer to the intensive care unit (ICU) due to unstable status was additionally analyzed. Hazard ratios (HRs) of outcomes were calculated using a Cox regression model after adjusting for multiple variables. Risk factors for IDH were evaluated using a logistic regression model. Results: IDH occurred in 449 patients (44.5%) during the first hemodialysis session. Patients with IDH had a higher mortality rate than those without IDH (40% vs. 23%; HR, 1.30; 95% confidence interval [CI], 1.02-1.65). The rate of ICU transfer was higher in patients experiencing IDH than in those without IDH (17% vs. 11%; HR, 1.43; 95% CI, 1.02-2.02). Factors such as old age, high BP and pulse rate, active malignancy, cirrhosis, and hypoalbuminemia were associated with an increased risk of IDH episodes. Conclusion: The occurrence of IDH is associated with worse outcomes in patients with AKI requiring intermittent hemodialysis. Therefore, careful monitoring and early intervention of IDH may be necessary in this patient subset.

Soluble suppression of tumorigenicity 2 is a potential predictor of post-liver transplant renal outcomes.

Acute kidney injury is considered an independent prognostic factor for mortality in patients with liver cirrhosis. Non-treated acute kidney injury can progress to hepatorenal syndrome with a poor prognosis. As suppression of tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor family that aggravates inflammation and fibrotic changes in multiple organs, we measured soluble ST2 (sST2) level in the serum and urine of liver-transplant recipients at the time of transplantation. The serum sST2 level significantly increased in liver-transplant recipients with suppressed kidney function compared with that in recipients with normal function. In recipients with severely decreased liver function (model for end-stage liver disease score ≥ 30), the serum sST2 level was higher than that in recipients with preserved liver function (model for end-stage liver disease score ≤ 20, P = 0.028). The serum sST2 level in recipients with hepatorenal syndrome was higher than that in liver-transplant recipients without hepatorenal syndrome (P = 0.003). The serum sST2 level in patients with hepatorenal syndrome was higher than that in recipients without a history of acute kidney injury (P = 0.004). Recipients with hepatorenal syndrome and recovered kidney function showed higher sST2 levels than those who did not recover (P = 0.034). Collectively, an increase in the serum sST2 level reflects a decrease in both kidney and liver functions. Thus, measuring sST2 level at the time of liver transplantation can help predict renal outcomes.

Spatially Aware Transformer Networks for Contextual Prediction of Diabetic Nephropathy Progression from Whole Slide Images.

Diabetic nephropathy (DN) in the context of type 2 diabetes is the leading cause of end-stage renal disease (ESRD) in the United States. DN is graded based on glomerular morphology and has a spatially heterogeneous presentation in kidney biopsies that complicates pathologists' predictions of disease progression. Artificial intelligence and deep learning methods for pathology have shown promise for quantitative pathological evaluation and clinical trajectory estimation; but, they often fail to capture large-scale spatial anatomy and relationships found in whole slide images (WSIs). In this study, we present a transformer-based, multi-stage ESRD prediction framework built upon nonlinear dimensionality reduction, relative Euclidean pixel distance embeddings between every pair of observable glomeruli, and a corresponding spatial self-attention mechanism for a robust contextual representation. We developed a deep transformer network for encoding WSI and predicting future ESRD using a dataset of 56 kidney biopsy WSIs from DN patients at Seoul National University Hospital. Using a leave-one-out cross-validation scheme, our modified transformer framework outperformed RNNs, XGBoost, and logistic regression baseline models, and resulted in an area under the receiver operating characteristic curve (AUC) of 0.97 (95% CI: 0.90-1.00) for predicting two-year ESRD, compared with an AUC of 0.86 (95% CI: 0.66-0.99) without our relative distance embedding, and an AUC of 0.76 (95% CI: 0.59-0.92) without a denoising autoencoder module. While the variability and generalizability induced by smaller sample sizes are challenging, our distance-based embedding approach and overfitting mitigation techniques yielded results that suggest opportunities for future spatially aware WSI research using limited pathology datasets.

Discovery of Biomarkers Related to Interstitial Fibrosis and Tubular Atrophy among Kidney Transplant Recipients by mRNA-Sequencing.

Interstitial fibrosis and tubular atrophy (IF/TA) after kidney transplantation causes a chronic deterioration of graft function. IF/TA can be diagnosed by means of a graft biopsy, which is a necessity as non-invasive diagnostic methods are unavailable. In this study, we identified IF/TA-related differentially expressed genes (DEGs) through next-generation sequencing using peripheral blood mononuclear cells. Blood samples from kidney transplant recipients undergoing standard immunosuppressive therapy (tacrolimus/mycophenolate mofetil or mycophenolate sodium/steroid) and diagnosed as IF/TA (n = 41) or normal (controls; n = 41) at their one-year protocol biopsy were recruited between January of 2020 and August of 2020. DEGs were derived through mRNA sequencing and validated by means of a quantitative real-time polymerase chain reaction. We identified 34 DEGs related to IF/TA. ADAMTS2, PLIN5, CLDN9, and KCNJ15 demonstrated a log2(fold change) of >1.5 and an area under the receiver operating characteristic curve (AUC) value of >0.6, with ADAMTS2 showing the largest AUC value and expression levels, which were 3.5-fold higher in the IF/TA group relative to that observed in the control group. We identified and validated DEGs related to IF/TA progression at one-year post-transplantation. Specifically, we identified ADAMTS2 as a potential IF/TA biomarker.

Causal effects from tobacco smoking initiation on obesity-related traits: a Mendelian randomization study.

BACKGROUND: There is a widespread notion that tobacco smoking controls weight based on the appetite suppressive effect of nicotine. However, the causal relationship between smoking initiation and obesity-related traits in the general population are unclear. METHODS: This Mendelian randomization analysis utilized 378 genetic variants associated with tobacco smoking initiation (usually in adolescence or young adulthood) identified in a genome-wide association study (meta-analysis) of 1.2 million individuals. Outcome data for body mass index, waist circumference, hip circumference, and waist-to-hip ratio were extracted from the 337,138 white British-ancestry UK Biobank participants aged 40-69 years. Replication analyses were performed for genome-wide association study meta-analysis for body mass index, including the GERA/GIANT data including 364,487 samples from mostly European individuals. In addition, summary-level Mendelian randomization by inverse variance weighted method and pleiotropy-robust Mendelian randomization methods, including median-based and MR-Egger regression, was performed. RESULTS: Summary-level Mendelian randomization analysis indicated that genetically predicted smoking initiation is causally linked to higher body mass index [+0.28 (0.18-0.38) kg/m2], waist circumference [+0.88 (0.66-1.10) cm], hip circumference [+0.40 (0.23-0.57) cm], and waist-to-hip ratio [+0.006 (0.005-0.007)]. These results were consistent with those of the pleiotropy-robust Mendelian randomization analysis. Additionally, in replication analysis, genetically predicted smoking initiation was significantly associated with a higher body mass index [+0.03 (0.01, 0.05] kg/m2). CONCLUSION: Tobacco initiation may lead to worse obesity-related traits in the general 40- to 69-year-old individuals. Therefore, tobacco-use initiation as a long-term weight-control measure should be discouraged.

A questionnaire survey on the diagnosis and treatment of Fabry nephropathy in clinical practice.

BACKGROUND: Fabry nephropathy is characterized by a deficiency of lysosomal alpha-galactosidase A, which results in proteinuria and kidney disease. The ineffectiveness of enzyme replacement therapy (ERT) for severe kidney failure highlights the need for early detection and meaningful markers. However, because the diagnosis and treatment of Fabry disease can vary according to the expertise of physicians, we evaluated the opinions of Korean specialists. METHODS: A questionnaire regarding the management of Fabry nephropathy was emailed to healthcare providers with the experience or ability to treat individuals with Fabry nephropathy. RESULTS: Of the 70 experts who responded to the survey, 43 were nephrologists, and 64.3% of the respondents reported having treated patients with Fabry disease. Pediatricians are treating primarily patients with classic types of the disease, while nephrologists and cardiologists are treating more patients with variant types. Only 40.7% of non-nephrologists agreed that a kidney biopsy was required at the time of diagnosis, compared with 81.4% of nephrologists. Thirty-eight of 70 respondents (54.3%) reported measuring globotriaosylsphingosine (lyso-Gb3) as a biomarker. The most common period to measure lyso-Gb3 was at the time of diagnosis, followed by after ERT, before ERT, and at screening. For the stage at which ERT should begin, microalbuminuria and proteinuria were chosen by 51.8% and 28.6% of respondents, respectively. CONCLUSION: Nephrologists are more likely to treat variant Fabry disease rather than classic cases, and they agree that ERT should be initiated early in Fabry nephropathy, using lyso-Gb3 as a biomarker.

Genetic variations in HMGCR and PCSK9 and kidney function: a Mendelian randomization study.

BACKGROUND: The genetically predicted lipid-lowering effect of HMGCR or PCSK9 variant can be used to assess drug proxy effects on kidney function. METHODS: Mendelian randomization (MR) analysis-identified HMGCR and PCSK9 genetic variants were used to predict the low-density lipoprotein (LDL) cholesterol-lowering effects of medications targeting related molecules. Primary summary-level outcome data for log-estimated glomerular filtration rate (eGFR; creatinine) were provided by the CKDGen Consortium (n = 1,004,040 European) from a meta-analysis of CKDGen and UK Biobank data. We also conducted a separate investigation of summary-level data from CKDGen (n = 567,460, log-eGFR [creatinine]) and UK Biobank (n = 436,581, log-eGFR [cystatin C]) samples. Summary-level MRs using an inverse variance weighted method and pleiotropy-robust methods were performed. RESULTS: Summary-level MR analysis indicated that the LDL-lowering effect predicted genetically by HMGCR variants (50-mg/dL decrease) was significantly associated with a decrease in eGFR (-1.67%; 95% confidence interval [CI], -2.20% to -1.13%). Similar significance was found in results from the pleiotropy-robust MR methods when the CKDGen and UK Biobank data were analyzed separately. However, the LDL-lowering effect predicted genetically by PCSK9 variants was significantly associated with an increase in eGFR (+1.17%; 95% CI, 0.10%-2.25%). The results were similarly supported by the weighted median method and in each CKDGen and UK Biobank dataset, but the significance obtained by MR-Egger regression was attenuated. CONCLUSION: Genetically predicted HMG-CoA reductase inhibition was associated with low eGFR, while genetically predicted PCSK9 inhibition was associated with high eGFR. Clinicians should consider that the direct effect of different types of lipid-lowering medication on kidney function can vary.

Discovery of Novel Digital Biomarkers for Type 2 Diabetic Nephropathy Classification via Integration of Urinary Proteomics and Pathology.

Background: The heterogeneous phenotype of diabetic nephropathy (DN) from type 2 diabetes complicates appropriate treatment approaches and outcome prediction. Kidney histology helps diagnose DN and predict its outcomes, and an artificial intelligence (AI)-based approach will maximize clinical utility of histopathological evaluation. Herein, we addressed whether AI-based integration of urine proteomics and image features improves DN classification and its outcome prediction, altogether augmenting and advancing pathology practice. Methods: We studied whole slide images (WSIs) of periodic acid-Schiff-stained kidney biopsies from 56 DN patients with associated urinary proteomics data. We identified urinary proteins differentially expressed in patients who developed end-stage kidney disease (ESKD) within two years of biopsy. Extending our previously published human-AI-loop pipeline, six renal sub-compartments were computationally segmented from each WSI. Hand-engineered image features for glomeruli and tubules, and urinary protein measurements, were used as inputs to deep-learning frameworks to predict ESKD outcome. Differential expression was correlated with digital image features using the Spearman rank sum coefficient. Results: A total of 45 urinary proteins were differentially detected in progressors, which was most predictive of ESKD (AUC=0.95), while tubular and glomerular features were less predictive (AUC=0.71 and AUC=0.63, respectively). Accordingly, a correlation map between canonical cell-type proteins, such as epidermal growth factor and secreted phosphoprotein 1, and AI-based image features was obtained, which supports previous pathobiological results. Conclusions: Computational method-based integration of urinary and image biomarkers may improve the pathophysiological understanding of DN progression as well as carry clinical implications in histopathological evaluation.

Impact of ABO incompatibility and early antibody-mediated rejection on chronic antibody-mediated rejection in kidney transplant patients.

INTRODUCTION: Early antibody-mediated rejection has been reported to increase chronic antibody-mediated rejection and decrease graft survival in kidney transplantation. However, the impact of early antibody-mediated rejection in ABO-incompatible kidney transplantation remains unclear. METHODS: We retrospectively analyzed living-donor kidney transplantation patients from two Korean centers. Patients were categorized based on ABO compatibility and early antibody-mediated rejection within 1 year. The primary outcome was chronic antibody-mediated rejection. The secondary outcomes were production of de novo donor-specific antibody and composite kidney outcome, defined as graft loss or a decline in estimated glomerular filtration rate to below 30 mL/min/1.73 m2. RESULTS: A total of 1639 patients were analyzed, including 1292 patients who underwent ABO-compatible kidney transplantation and 347 patients who underwent ABO-incompatible kidney transplantation. ABO-incompatible kidney transplantation had a lower risk of de novo donor-specific antibody production (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.48-0.95) and chronic antibody-mediated rejection (HR 0.33, 95% CI 0.12-0.92) with a comparable risk of the composite kidney outcome (HR 1.06, 95% CI 0.71-1.59) compared to ABO-compatible kidney transplantation. When outcomes of ABO-incompatible kidney transplantation were analyzed according to early antibody-mediated rejection, ABO-incompatible kidney transplantation without antibody-mediated rejection had a lower risk of de novo donor-specific antibody production (HR 0.60, 95% CI 0.41-0.88) and chronic antibody-mediated rejection (HR 0.28, 95% CI 0.09-0.91) than ABO-compatible kidney transplantation without antibody-mediated rejection. However, ABO-incompatible kidney transplantation with antibody-mediated rejection showed a higher risk of de novo donor-specific antibody production and similar risk of chronic antibody-mediated rejection compared to ABO-compatible kidney transplantation without antibody-mediated rejection. CONCLUSIONS: ABO-incompatible kidney transplantation showed a lower risk of de novo donor-specific antibody production and chronic antibody-mediated rejection compared to ABO-compatible kidney transplantation; however, early antibody-mediated rejection abrogated these beneficial effects of ABO-incompatible kidney transplantation.

Comparison of cardiovascular event predictability between the 2009 and 2021 Chronic Kidney Disease Epidemiology Collaboration equations in a Korean chronic kidney disease cohort: the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease.

BACKGROUND: The 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine-based estimated glomerular filtration rate (eGFRcr) equation contains a race component that is not based on biology and may cause a bias in results. Therefore, the 2021 eGFRcr and creatinine-cystatin C-based eGFR (eGFRcr-cysC) equations were developed with no consideration of race. This study compared the cardiovascular event (CVE) and all-cause mortality and CVE combined predictability among the three eGFR equations in Korean chronic kidney disease (CKD) patients. METHODS: This study included 2,207 patients from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease. Receiver operating characteristic (ROC) and net reclassification improvement (NRI) index were used to compare the predictability of the study outcomes according to the 2009 eGFRcr, 2021 eGFRcr, and 2021 eGFRcr-cysC equations. RESULTS: The overall prevalence of CVE and all-cause mortality were 9% and 7%, respectively. There was no difference in area under the curve of ROC for CVE and mortality and CVE combined among all three equations. Compared to the 2009 eGFRcr, both the 2021 eGFRcr (NRI, 0.013; 95% confidence interval [CI], - 0.002 to 0.028) and the eGFRcr-cysC (NRI, -0.001; 95% CI, -0.031 to 0.029) equations did not show improved CVE predictability. Similar findings were observed for mortality and CVE combined predictability with both the 2021 eGFRcr (NRI, -0.019; 95% CI, -0.039-0.000) and the eGFRcr-cysC (NRI, -0.002; 95% CI, -0.023 to 0.018). CONCLUSION: The 2009 eGFRcr equation was not inferior to either the 2021 eGFRcr or eGFRcr-cysC equation in predicting CVE and the composite of mortality and CVE in Korean CKD patients.

Spatially Aware Transformer Networks for Contextual Prediction of Diabetic Nephropathy Progression from Whole Slide Images.

Diabetic nephropathy (DN) in the context of type 2 diabetes is the leading cause of end-stage renal disease (ESRD) in the United States. DN is graded based on glomerular morphology and has a spatially heterogeneous presentation in kidney biopsies that complicates pathologists' predictions of disease progression. Artificial intelligence and deep learning methods for pathology have shown promise for quantitative pathological evaluation and clinical trajectory estimation; but, they often fail to capture large-scale spatial anatomy and relationships found in whole slide images (WSIs). In this study, we present a transformer-based, multi-stage ESRD prediction framework built upon nonlinear dimensionality reduction, relative Euclidean pixel distance embeddings between every pair of observable glomeruli, and a corresponding spatial self-attention mechanism for a robust contextual representation. We developed a deep transformer network for encoding WSI and predicting future ESRD using a dataset of 56 kidney biopsy WSIs from DN patients at Seoul National University Hospital. Using a leave-one-out cross-validation scheme, our modified transformer framework outperformed RNNs, XGBoost, and logistic regression baseline models, and resulted in an area under the receiver operating characteristic curve (AUC) of 0.97 (95% CI: 0.90-1.00) for predicting two-year ESRD, compared with an AUC of 0.86 (95% CI: 0.66-0.99) without our relative distance embedding, and an AUC of 0.76 (95% CI: 0.59-0.92) without a denoising autoencoder module. While the variability and generalizability induced by smaller sample sizes are challenging, our distance-based embedding approach and overfitting mitigation techniques yielded results that sugest opportunities for future spatially aware WSI research using limited pathology datasets.

Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia.

BACKGROUND: Ageing traits and frailty are important health issues in modern medicine. Evidence supporting the causal effects of tobacco smoking on various ageing traits is required. METHODS: This study performed Mendelian randomization (MR) analysis instrumenting 377 genetic variants associated with being an ever-smoker at a genome-wide significance level to test the causal estimates from tobacco smoking. The outcome data were obtained from 337 138 white British ancestry participants from the UK Biobank. Leucocyte telomere length, appendicular lean mass index, subjective walking pace, handgrip strength, and wristband accelerometry-determined physical activity degree were collected as ageing-related outcomes. Summary-level MR analysis was performed using the inverse variance-weighted method and pleiotropy-robust MR methods, including weighted median and MR-Egger. Observational association between the outcome traits and phenotypically being an ever-smoker was also investigated. RESULTS: Summary-level MR analysis indicated that a higher genetic predisposition for tobacco smoking was significantly associated with shorter leucocyte telomere length (twofold increase in prevalence of smoking towards standardized Z-score, -0.041 [-0.054, -0.028]), lower appendicular lean mass index (-0.007 [-0.010, -0.005]), slower walking pace (ordinal category, -0.047 [-0.054, -0.033]) and lower time spent on moderate-to-vigorous physical activity (hours per week, -0.39 [-0.56, -0.23]). The causal estimates were non-significant towards handgrip strength phenotype (kg, 0.074 [-0.055, 0.204]). Pleiotropy-robust MR results generally supported the main causal estimates. The observational findings also showed significant association between being an ever-smoker and the ageing traits. CONCLUSIONS: Genetically predicted and observational tobacco smoking status are significantly associated with poor ageing phenotypes. Healthcare providers may continue to reduce tobacco use, which may be helpful in reducing the burden of ageing and frailty.

PodoCount: A Robust, Fully Automated, Whole-Slide Podocyte Quantification Tool.

Introduction: Podocyte depletion is a histomorphologic indicator of glomerular injury and predicts clinical outcomes. Podocyte estimation methods or podometrics are semiquantitative, technically involved, and laborious. Implementation of high-throughput podometrics in experimental and clinical workflows necessitates an automated podometrics pipeline. Recognizing that computational image analysis offers a robust approach to study cell and tissue structure, we developed and validated PodoCount (a computational tool for automated podocyte quantification in immunohistochemically labeled tissues) using a diverse data set. Methods: Whole-slide images (WSIs) of tissues immunostained with a podocyte nuclear marker and periodic acid-Schiff counterstain were acquired. The data set consisted of murine whole kidney sections (n = 135) from 6 disease models and human kidney biopsy specimens from patients with diabetic nephropathy (DN) (n = 45). Within segmented glomeruli, podocytes were extracted and image analysis was applied to compute measures of podocyte depletion and nuclear morphometry. Computational performance evaluation and statistical testing were performed to validate podometric and associated image features. PodoCount was disbursed as an open-source, cloud-based computational tool. Results: PodoCount produced highly accurate podocyte quantification when benchmarked against existing methods. Podocyte nuclear profiles were identified with 0.98 accuracy and segmented with 0.85 sensitivity and 0.99 specificity. Errors in podocyte count were bounded by 1 podocyte per glomerulus. Podocyte-specific image features were found to be significant predictors of disease state, proteinuria, and clinical outcome. Conclusion: PodoCount offers high-performance podocyte quantitation in diverse murine disease models and in human kidney biopsy specimens. Resultant features offer significant correlation with associated metadata and outcome. Our cloud-based tool will provide end users with a standardized approach for automated podometrics from gigapixel-sized WSIs.

Nonlinear causal effects of estimated glomerular filtration rate on myocardial infarction risks: Mendelian randomization study.

BACKGROUND: Previous observational studies suggested that a reduction in estimated glomerular filtration rate (eGFR) or a supranormal eGFR value was associated with adverse cardiovascular risks. However, a previous Mendelian randomization (MR) study under the linearity assumption reported null causal effects from eGFR on myocardial infarction (MI) risks. Further investigation of the nonlinear causal effect of kidney function assessed by eGFR on the risk of MI by nonlinear MR analysis is warranted. METHODS: In this MR study, genetic instruments for log-eGFR based on serum creatinine were developed from European samples included in the CKDGen genome-wide association study (GWAS) meta-analysis (N=567,460). Alternate instruments for log-eGFR based on cystatin C were developed from a GWAS of European individuals that included the CKDGen and UK Biobank data (N=460,826). Nonlinear MR analysis for the risk of MI was performed using the fractional polynomial method and the piecewise linear method on data from individuals of white British ancestry in the UK Biobank (N=321,024, with 12,205 MI cases). RESULTS: Nonlinear MR analysis demonstrated a U-shaped (quadratic P value < 0.001) association between MI risk and genetically predicted eGFR (creatinine) values, as MI risk increased as eGFR declined in the low eGFR range and the risk increased as eGFR increased in the high eGFR range. The results were similar even after adjustment for clinical covariates, such as blood pressure, diabetes mellitus, dyslipidemia, or urine microalbumin levels, or when genetically predicted eGFR (cystatin C) was included as the exposure. CONCLUSION: Genetically predicted eGFR is significantly associated with the risk of MI with a parabolic shape, suggesting that kidney function impairment, either by reduced or supranormal eGFR, may be causally linked to a higher MI risk.

A Nanostructured Phthalocyanine/Albumin Supramolecular Assembly for Fluorescence Turn-On Imaging and Photodynamic Immunotherapy.

Smart phototheranostic nanomaterials are of significant interest for high-quality imaging and targeted therapy in the precision medicine field. Herein, a nanoscale photosensitizer (NanoPcM) is constructed through the self-assembly of morpholine-substituted silicon phthalocyanine (PcM) and albumin. NanoPcM displays a turn-on fluorescence depending on the acid-induced abolition of the photoinduced electron transfer effect (change in molecular structure) and disassembly of the nanostructure (change in supramolecular structure), which enables low-background and tumor-targeted fluorescence imaging. In addition, its efficient type I photoreaction endows NanoPcM with a superior immunogenic photodynamic therapy (PDT) effect against solid tumors. The combination of NanoPcM-based PDT and αPD-1-based immunotherapy can efficiently inhibit tumor growth, reduce spontaneous lung metastasis, and trigger abscopal effects. This study should provide a perspective for the future design of nanomaterials as promising phototheranostics for cancer imaging and therapy.

Causal effects from non-alcoholic fatty liver disease on kidney function: A Mendelian randomization study.

BACKGROUND AND AIMS: An observational association between nonalcoholic fatty liver disease (NAFLD) and kidney function impairment has been reported. We aimed to investigate the causal effects from NAFLD on estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) study. METHODS: We first performed single-variant MR with rs738409 as a genetic instrument for NAFLD. Another genetic instrument was developed from a genome-wide association study for biopsy-confirmed NAFLD among individuals of European ancestry (1483 cases and 17 781 controls). The eGFR outcome was assessed in individuals of white British ancestry from the UK Biobank (N = 321 405). The associations were reassessed in the negative control subgroup (body mass index < 30 kg/m2 , absence of central obesity, and serum alanine aminotransferase level ≤ 20 IU/mL) with a low probability of developing NAFLD. As a replication analysis, a summary-level MR was performed with the European ancestry CKDGen dataset (N = 567 460). RESULTS: In the UK Biobank, a genetic predisposition for NAFLD, determined either by the single SNP rs738409 or by the group of variants, was significantly associated with a reduced eGFR even with adjustment for metabolic disorders. Although the associations were not significant in the negative control subgroup with a low probability of developing NAFLD, they were significant in the subgroup with a remaining risk of NAFLD, suggesting the absence of a horizontal pleiotropic pathway. The summary-level MR from the CKDGen dataset supported the causal effects of NAFLD on reduced eGFR. CONCLUSIONS: This MR analysis supports the causal reduction in kidney function by NAFLD.

Association between visit-to-visit blood pressure variability and risks of dementia in CKD patients: a nationwide observational cohort study.

Background: The association between visit-to-visit blood pressure (BP) variability and dementia risk in chronic kidney disease (CKD) patients has rarely been studied. Methods: In this retrospective observational study, individuals who received three or more general health screenings were identified in the nationwide database of Korea. Those with persistent non-dialysis-dependent CKD [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or dipstick albuminuria ≥1+] were included. The study exposure was systolic or diastolic BP variability, calculated as the variation independent of the mean and categorized into quartiles (Q4: the highest quartile; Q1: the lowest quartile). The risks of all-cause dementia, including Alzheimer's disease and vascular dementia, were analyzed by Cox regression adjusted for various clinical characteristics, including baseline BP and eGFR values. Results: We included 103 139 CKD patients and identified 7574 (7%) dementia events, including 5911 (6%) Alzheimer's disease cases, 886 (1%) vascular dementia events and 777 (1%) cases categorized as other types of dementia. Higher systolic BP variability was significantly associated with higher risks of all-cause dementia {[Q4 versus Q1], hazard ratio [HR] 1.173 [95% confidence interval (CI) 1.102-1.249], P for trend < .001}. The results were also significant for the risk of Alzheimer's disease [HR 1.162 (95% CI 1.083-1.248), P < .001] and vascular dementia [HR 1.282 (95% CI 1.064-1.545), P = .039]. The results were similar when diastolic BP variability was the exposure, as high diastolic BP variability was significantly associated with higher risks of all-cause dementia [HR 1.191 (95% CI 1.117,1.270), P < .001]. Conclusions: Higher visit-to-visit BP variability is significantly associated with a higher risk of dementia in CKD patients.