Search

SIGNIFICANCE STATEMENT: The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict 2- and 5-year risk of kidney failure in populations with eGFR

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Risk stratification for chronic kidney is becoming increasingly important as a clinical tool for both treatment and prevention measures. The goal of this review is to identify how machine learning tools contribute and facilitate risk stratification in the clinical setting.The two key machine learning paradigms to predictively stratify kidney disease risk are genomics-based and electronic health record based approaches. These methods can provide both quantitative information such as relative risk and qualitative information such as characterizing risk by subphenotype.The four key methods to stratify chronic kidney disease risk are genomics, multiomics, supervised and unsupervised machine learning methods. Polygenic risk scores utilize whole genome sequencing data to generate an individual's relative risk compared with the population. Multiomic methods integrate information from multiple biomarkers to generate trajectories and prognostic different outcomes. Supervised machine learning methods can directly utilize the growing compendia of electronic health records such as laboratory results and notes to generate direct risk predictions, while unsupervised machine learning methods can cluster individuals with chronic kidney disease into subphenotypes with differing approaches to care.

PURPOSE OF REVIEW: We seek to determine recent advances in kidney pathophysiology that have been enabled or enhanced by artificial intelligence. We describe some of the challenges in the field as well as future directions. RECENT FINDINGS: We first provide an overview of artificial intelligence terminologies and methodologies. We then describe the use of artificial intelligence in kidney diseases to discover risk factors from clinical data for disease progression, annotate whole slide imaging and decipher multiomics data. We delineate key examples of risk stratification and prognostication in acute kidney injury (AKI) and chronic kidney disease (CKD). We contextualize these applications in kidney disease oncology, one of the subfields to benefit demonstrably from artificial intelligence using all if these approaches. We conclude by elucidating technical challenges and ethical considerations and briefly considering future directions. SUMMARY: The integration of clinical data, patient derived data, histology and proteomics and genomics can enhance the work of clinicians in providing more accurate diagnoses and elevating understanding of disease progression. Implementation research needs to be performed to translate these algorithms to the clinical setting.

Background and objectives AKI treated with dialysis initiation is a common complication of coronavirus disease 2019 (COVID-19) among hospitalized patients. However, dialysis supplies and personnel are often limited. Design, setting, participants, & measurements Using data from adult patients hospitalized with COVID-19 from five hospitals from the Mount Sinai Health System who were admitted between March 10 and December 26, 2020, we developed and validated several models (logistic regression, Least Absolute Shrinkage and Selection Operator (LASSO), random forest, and eXtreme GradientBoosting [XGBoost; with and without imputation]) for predicting treatment with dialysis or death at various time horizons (1, 3, 5, and 7 days) after hospital admission. Patients admitted to the Mount Sinai Hospital were used for internal validation, whereas the other hospitals formed part of the external validation cohort. Features included demographics, comorbidities, and laboratory and vital signs within 12 hours of hospital admission. Results A total of 6093 patients (2442 in training and 3651 in external validation) were included in the final cohort. Of the different modeling approaches used, XGBoost without imputation had the highest area under the receiver operating characteristic (AUROC) curve on internal validation (range of 0.93–0.98) and area under the precision-recall curve (AUPRC; range of 0.78–0.82) for all time points. XGBoost without imputation also had the highest test parameters on external validation (AUROC range of 0.85–0.87, and AUPRC range of 0.27–0.54) across all time windows. XGBoost without imputation outperformed all models with higher precision and recall (mean difference in AUROC of 0.04; mean difference in AUPRC of 0.15). Features of creatinine, BUN, and red cell distribution width were major drivers of the model’s prediction. Conclusions An XGBoost model without imputation for prediction of a composite outcome of either death or dialysis in patients positive for COVID-19 had the best performance, as compared with standard and other machine learning models. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_07_09_CJN17311120.mp3

BACKGROUND AND OBJECTIVES: Genetic variants in NAT8, a liver- and kidney-specific acetyltransferase encoding gene, have been associated with eGFR and CKD in European populations. Higher circulating levels of two NAT8-associated metabolites, N-δ-acetylornithine and N-acetyl-1-methylhistidine, have been linked to lower eGFR and higher risk of incident CKD in the Black population. We aimed to expand upon prior studies to investigate associations between rs13538, a missense variant in NAT8, N-acetylated amino acids, and kidney failure in multiple, well-characterized cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted analyses among participants with genetic and/or serum metabolomic data in the African American Study of Kidney Disease and Hypertension (AASK; n=962), the Atherosclerosis Risk in Communities (ARIC) study (n=1050), and BioMe, an electronic health record–linked biorepository (n=680). Separately, we evaluated associations between rs13538, urinary N-acetylated amino acids, and kidney failure in participants in the German CKD (GCKD) study (n=1624). RESULTS: Of 31 N-acetylated amino acids evaluated, the circulating and urinary levels of 14 were associated with rs13538 (P

Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had devastating effects worldwide. Patients with kidney failure on dialysis may have a higher risk of worse outcomes. Reports from China found that these patients with SARS-CoV-2 had fewer

Background and objectives Sepsis-associated AKI is a heterogeneous clinical entity. We aimed to agnostically identify sepsis-associated AKI subphenotypes using deep learning on routinely collected data in electronic health records. Design, setting, participants, & measurements We used the Medical Information Mart for Intensive Care III database, which consists of electronic health record data from intensive care units in a tertiary care hospital in the United States. We included patients ≥18 years with sepsis who developed AKI within 48 hours of intensive care unit admission. We then used deep learning to utilize all available vital signs, laboratory measurements, and comorbidities to identify subphenotypes. Outcomes were mortality 28 days after AKI and dialysis requirement. Results We identified 4001 patients with sepsis-associated AKI. We utilized 2546 combined features for K-means clustering, identifying three subphenotypes. Subphenotype 1 had 1443 patients, and subphenotype 2 had 1898 patients, whereas subphenotype 3 had 660 patients. Subphenotype 1 had the lowest proportion of liver disease and lowest Simplified Acute Physiology Score II scores compared with subphenotypes 2 and 3. The proportions of patients with CKD were similar between subphenotypes 1 and 3 (15%) but highest in subphenotype 2 (21%). Subphenotype 1 had lower median bilirubin levels, aspartate aminotransferase, and alanine aminotransferase compared with subphenotypes 2 and 3. Patients in subphenotype 1 also had lower median lactate, lactate dehydrogenase, and white blood cell count than patients in subphenotypes 2 and 3. Subphenotype 1 also had lower creatinine and BUN than subphenotypes 2 and 3. Dialysis requirement was lowest in subphenotype 1 (4% versus 7% [subphenotype 2] versus 26% [subphenotype 3]). The mortality 28 days after AKI was lowest in subphenotype 1 (23% versus 35% [subphenotype 2] versus 49% [subphenotype 3]). After adjustment, the adjusted odds ratio for mortality for subphenotype 3, with subphenotype 1 as a reference, was 1.9 (95% confidence interval, 1.5 to 2.4). Conclusions Utilizing routinely collected laboratory variables, vital signs, and comorbidities, we were able to identify three distinct subphenotypes of sepsis-associated AKI with differing outcomes.

Background Early reports indicate that AKI is common among patients with coronavirus disease 2019 (COVID-19) and associated with worse outcomes. However, AKI among hospitalized patients with COVID-19 in the United States is not well described. Methods This retrospective, observational study involved a review of data from electronic health records of patients aged ≥18 years with laboratory-confirmed COVID-19 admitted to the Mount Sinai Health System from February 27 to May 30, 2020. We describe the frequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aORs) with mortality. Results Of 3993 hospitalized patients with COVID-19, AKI occurred in 1835 (46%) patients; 347 (19%) of the patients with AKI required dialysis. The proportions with stages 1, 2, or 3 AKI were 39%, 19%, and 42%, respectively. A total of 976 (24%) patients were admitted to intensive care, and 745 (76%) experienced AKI. Of the 435 patients with AKI and urine studies, 84% had proteinuria, 81% had hematuria, and 60% had leukocyturia. Independent predictors of severe AKI were CKD, men, and higher serum potassium at admission. In-hospital mortality was 50% among patients with AKI versus 8% among those without AKI (aOR, 9.2; 95% confidence interval, 7.5 to 11.3). Of survivors with AKI who were discharged, 35% had not recovered to baseline kidney function by the time of discharge. An additional 28 of 77 (36%) patients who had not recovered kidney function at discharge did so on posthospital follow-up. Conclusions AKI is common among patients hospitalized with COVID-19 and is associated with high mortality. Of all patients with AKI, only 30% survived with recovery of kidney function by the time of discharge.

PURPOSE OF REVIEW: The universal adoption of electronic health records, improvement in technology, and the availability of continuous monitoring has generated large quantities of healthcare data. Machine learning is increasingly adopted by nephrology researchers to analyze this data in order to improve the care of their patients. RECENT FINDINGS: In this review, we provide a broad overview of the different types of machine learning algorithms currently available and how researchers have applied these methods in nephrology research. Current applications have included prediction of acute kidney disease and chronic kidney disease along with progression of kidney disease. Researchers have demonstrated the ability of machine learning to read kidney biopsy samples, identify patient outcomes from unstructured data, identify subtypes in complex diseases, and discuss the potential benefits on drug discovery. We end with a discussion on the ethics and potential pitfalls of machine learning. SUMMARY: Machine learning provides researchers with the ability to analyze data which was previously inaccessible. While still burgeoning several studies show promising results which will enable researchers to perform larger scale studies and clinicians the ability to provide more personalized care. However, we must ensure that implementation aids providers and does not lead to harm to patients.

BACKGROUND: Pregnancy-related AKI (PR-AKI) is increasing in the United States. PR-AKI is associated with adverse maternal outcomes. Disparities in racial/ethnic differences in PR-AKI by race have not been studied. METHODS: This was a retrospective cohort study using the National Inpatient Sample (NIS) from 2005 to 2015. We identified patients who were admitted for a pregnancy-related diagnosis using the Neomat variable provided by the NIS database that indicates the presence of a maternal or neonatal diagnosis code or procedure code. PR-AKI was identified using ICD codes. Survey logistic regression was used for multivariable analysis adjusting for age, medical comorbidities, socioeconomic factors, and hospital/admission factors. RESULTS: From 48,316,430 maternal hospitalizations, 34,001 (0.07%) were complicated by PR-AKI. Hospitalizations for PR-AKI increased from 3.5/10,000 hospitalizations in 2005 to 11.8/10,000 hospitalizations in 2015 with the largest increase seen in patients aged ≥35 and black patients. PR-AKI was associated with higher odds of miscarriage (adjusted odds ratio [aOR], 1.64; 95% CI, 1.34 to 2.07) and mortality (aOR, 1.53; 95% CI, 1.25 to 1.88). After adjustment for age, medical comorbidities, and socioeconomic factors, blacks were more likely than whites to develop PR-AKI (aOR, 1.17; 95% CI, 1.04 to 1.33). On subgroup analyses in hospitalizations of patients with PR-AKI, blacks and Hispanics were more likely to have preeclampsia/eclampsia compared with whites (aOR, 1.29; 95% CI, 1.01 to 1.65; and aOR, 1.69; 95% CI, 1.23 to 2.31, respectively). Increased odds of mortality in PR-AKI compared with whites were only seen in black patients (aOR, 1.61; 95% CI, 1.02 to 2.55). CONCLUSIONS: The incidence of PR-AKI has increased and the largest increase was seen in older patients and black patients. PR-AKI is associated with miscarriages, adverse discharge from hospital, and mortality. Black and Hispanic patients with PR-AKI were more likely to have adverse outcomes than white patients. Further research is needed to identify factors contributing to these discrepancies.

Background Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich α -2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF- β /activin receptor-like kinase 1 (ALK1) signaling. However, LRG1’s role in the kidney, particularly in the setting of DKD, has been unclear. Methods We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes. Results LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes. Conclusions These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.

Background and objectives Patients are informed of the risk of kidney biopsy–related complications using data from nonhospitalized patients, which may underestimate the risk for hospitalized patients. We evaluated the rate and risk factors of kidney biopsy–related complications in hospitalized patients with acute kidney disease (AKD) to better estimate the risk in this population. Design, setting, participants, & measurements We used data from the Yale biopsy cohort to evaluate rates of kidney biopsy–related complications including adjudicated procedure-related bleeding requiring blood transfusions or angiographic interventions, medium- or large-sized hematomas, reimaging after biopsy including abdominal ultrasonography or computed tomography, and death in hospitalized patients with AKD (including AKI). We evaluated univariable and multivariable association of risk factors with transfusions. We compared rates of complications between hospitalized and nonhospitalized patients. Results Between 2015 and 2017, 159 hospitalized patients underwent a kidney biopsy for AKD evaluation, of which 80 (51%) had stage 1 AKI, 42 (27%) had stage 2 (or higher) AKI, and 27 (17%) had AKD (without AKI). Of these, 12 (8%; 95% confidence interval [95% CI], 5% to 15%) required a transfusion, three (2%; 95% CI, 1% to 5%) required an intervention, 11 (7%; 95% CI, 4% to 12%) had hematoma, and 31 (20%; 95% CI, 14% to 26%) required reimaging after biopsy. Of the four (3%; 95% CI, 1% to 6%) deaths during hospitalization, none were related to the biopsy. Female sex, lower platelet count, and higher BUN were associated with postbiopsy transfusions on univariable and multivariable analyses. Trainee as proceduralist and larger needle gauge were associated with transfusions in univariable, but not multivariable, analysis. Nonhospitalized patients had lower rates of transfusion than hospitalized patients, although the latter also had lower prebiopsy hemoglobin and greater surveillance after biopsy. Conclusions Hospitalized patients experience higher risk of postbiopsy complications than previously reported and several factors, such as lower platelet count, female sex, and higher BUN, are associated with this risk.

Introduction: The pathogenesis of peripheral artery disease (PAD) and critical limb ischemia (CLI) are poorly understood. Hypothesis: We hypothesize that genetic factors related to abnormalities in coagulation or fibrinolysis, in addition to atherosclerosis, could play an important role in PAD patients and PAD with CLI patients. Methods: A genome-wide association study (GWAS) was performed testing for associations between single-nucleotide variants (SNVs) and PAD case-control (3,190 cases and 463,495 controls) and subgroup analysis of PAD with CLI case-control (142 cases and 3,048 controls) in the UK Biobank cohort. To further validate the results, we selected SNVs with the most significant Cochrane-Armitage trend p values without evidence of strong linkage disequilibrium (r2 > 0.8) for PAD with CLI case-control in the BioMe Biobank. We tested for association using BOLT-LMM with adjustment for age, sex, BMI, and the first ten principal components to control for population structure. The SNV association tests' significance level was set at P < 5x10–8 after Bonferroni correction. Results: 363 SNVs from 81 genetic loci reached the threshold for statistical significance based on a Bonferroni correction (p PLG and CDKN2B ) were independent for PAD with CLI. On pathway analyses, we identify several new loci that implicate thrombotic, inflammation, glycosaminoglycan synthesis, coagulation, and fibrinolytic pathways involved in PAD along with known atherosclerosis pathways (p Conclusions: We show that PLG gene related to coagulation pathways in PAD may play an important role in coagulation-related PAD pathogenesis.

Background An early posttransplant biomarker/surrogate marker for kidney allograft loss has the potential to guide targeted interventions. Previously published findings, including results from the Clinical Trials in Organ Transplantation (CTOT)-01 study, showed that elevated urinary chemokine CXCL9 levels and elevated frequencies of donor-reactive interferon gamma (IFNγ)-producing T cells by enzyme-linked immunosorbent spot (ELISPOT) assay associated with acute cellular rejection within the first year and with lower 1-year posttransplant estimated glomerular filtration rate (eGFR). How well these biomarkers correlate with late outcomes, including graft loss, is unclear. Methods In CTOT-17, we obtained 5-year outcomes in the CTOT-01 cohort and correlated them with (a) biomarker results and (b) changes in eGFR (Chronic Kidney Disease Epidemiology Collaboration formula) over the initial 2 years posttransplant using univariable analysis and multivariable logistic regression. Results Graft loss occurred in 14 (7.6%) of 184 subjects 2 to 5 years posttransplant. Neither IFNγ ELISPOTs nor urinary CXCL9 were informative. In contrast, a 40% or greater decline in eGFR from 6 months to 2 years posttransplant independently correlated with 13-fold odds of 5-year graft loss (adjusted odds ratio, 13.1; 95% confidence interval, 3.0-56.6), a result that was validated in the independent Genomics of Chronic Allograft Rejection cohort (n = 165; adjusted odds ratio, 11.2). Conclusions We conclude that although pretransplant and early posttransplant ELISPOT and chemokine measurements associate with outcomes within 2 years posttransplant, changes in eGFR between 3 or 6 months and 24 months are better surrogates for 5-year outcomes, including graft loss.

Diabetes is a leading cause of ESKD worldwide, resulting in substantial patient morbidity and healthcare costs. Fenofibrate and other fibrate therapies may improve lipid profiles and prevent cardiovascular events in people with CKD, and thus may be useful as adjunctive therapies to reduce the risk

While increased obesity prevalence among persons of African ancestry (AAs) compared to persons of European ancestry (EAs) is linked to social, environmental and behavioral factors, there are no gene variants that are common and significantly associated with obesity in AA populations. We sought to explore the association between ancestry specific renal risk variants in the apolipoprotein L1 (APOL1) gene with obesity related traits in AAs.We conducted a genotype-phenotype association study from 3 electronic medical record linked cohorts (BioMe Biobank, BioVU, nuGENE); randomized controlled trials (genetic testing to understand and address renal disease disparities) and prospective cohort study (Jackson Heart Study). We analyzed association of APOL1 renal risk variants with cross-sectional measures of obesity (average body mass index (BMI), and proportion of overweight and obesity) and with measures of body composition (in Jackson Heart Study).We had data on 11,930 self-reported AA adults. Across cohorts, mean age was from 42 to 49 years and percentage female from 58% to 75.3%. Individuals who have 2 APOL1 risk alleles (14% of AAs) have 30% higher obesity odds compared to others (recessive model adjusted odds ratio 1.30; 95% confidence interval 1.16-1.41; P = 2.75 × 10-6). An additive model better fit the association, in which each allele (47% of AAs) increases obesity odds by 1.13-fold (adjusted odds ratio 1.13; 95% confidence interval 1.07-1.19; P = 3.07 × 10-6) and increases BMI by 0.36 kg/m2 (∼1 kg, for 1.7 m height; P = 2 × 10-4). APOL1 alleles are not associated with refined body composition traits overall but are significantly associated with fat free mass index in women [0.30 kg/m2 increment per allele; P = .03].Thus, renal risk variants in the APOL1 gene, found in nearly half of AAs, are associated with BMI and obesity in an additive manner. These variants could, either on their own or interacting with environmental factors, explain a proportion of ethnic disparities in obesity.

PURPOSE OF REVIEW: Current biomarkers for chronic kidney disease (CKD) are limited by lack of sensitivity and inability to prognosticate CKD progression. Significant recent research has better characterized novel biomarker candidates that are associated with CKD progression and cardiovascular mortality in CKD. This review discusses the most significant advances within the past year. RECENT FINDINGS: We discuss biomarkers for outcomes in CKD under two categories: (1) Emerging (defined as having been validated in an independent cohort) which include serum Cystatin C, serum β-trace protein, β2-microglobulin, suPAR, soluble Tumor Necrosis Factor Receptors 1/2, urinary monocyte chemotactic protein-1, neutrophil gelatin associated lipocalin, Kidney Injury Molecule-1 and Fibroblast Growth Factor-23 and (2) Novel (which have shown associations in smaller observational studies but have not been validated yet) which include indoxyl sulfate, p-cresyl sulfate, trimethylamine-N-oxide, inteleukin-18, Klotho, markers of endothelial dysfunction, vimentin and procollagen type III N-terminal propeptide. Further, we also discuss future directions for biomarker research including unbiased –omics approaches. SUMMARY: There are a number of promising biomarkers that can better prognosticate outcomes in and progression of CKD. Further research is warranted to examine whether these biomarkers validate independently as well and if their incorporation improves clinical practice and/or trial enrollment.

Hypertension (HTN) is a major cause of morbidity and mortality and a subset may be caused by monogenic mutations. We identified the prevalence of these mutations in a multiethnic cohort and determined their association with blood pressure, appropriate diagnosis, and adverse cardiovascular outcomes. In 27,972 individuals from the Bio Me Biobank (8304 European, 6993 African, 9985 Hispanic, and 2690 Other ancestry), we identified ClinVar mutations pathogenic for secondary hypertension using exome sequencing. 3125 individuals (11.2%) had pathogenic mutations with a majority in genes associated with catecholamine excess ( SDHD , SDHB , TMEM127 , RET ; n=1976) and sodium handling/hyperaldosteronism ( SCNN1G/ CYP11B1 ; n=384). (Fig 1A,B) In a linear model adjusted for sex, age, BMI, and 10 genetic principal components (PCs), individuals with mutations had elevated mean arterial pressure (β=0.7±0.6 mmHg; p=0.03) and increased odds of CAD (adjusted OR=1.12, 95% CI 1.0 to 1.3, p=0.04). Individuals with mutations in sodium handling/hyperaldosteronism genes had increased odds of CHF (adjusted OR = 1.44, 95% CI 1.04 to 1.97; p=0.02) adjusted for age, sex, 10 genetic PCs, and systolic blood pressure. The majority of individuals with mutations were diagnosed with essential HTN (54.2%) and only 7.8% had appropriate diagnoses of secondary HTN or received appropriate biochemical evaluation. (Figure 1C) Individuals with pathogenic mutations had higher blood pressures, elevated risk for CAD/CHF and the majority were not appropriately evaluated or diagnosed. These results suggest exome sequencing may have utility in hypertension diagnosis and management.

Background and objectives Current measures for predicting renal functional decline in patients with type 2 diabetes with preserved renal function are unsatisfactory, and multiple markers assessing various biologic axes may improve prediction. We examined the association of four biomarker-to-creatinine ratio levels (monocyte chemotactic protein-1, IL-18, kidney injury molecule-1, and YKL-40) with renal outcome. Design, setting, participants, & measurements We used a nested case-control design in the Action to Control Cardiovascular Disease Trial by matching 190 participants with ≥40% sustained eGFR decline over the 5-year follow-up period to 190 participants with ≤10% eGFR decline in a 1:1 fashion on key characteristics (age within 5 years, sex, race, baseline albumin-to-creatinine ratio within 20 μ g/mg, and baseline eGFR within 10 ml/min per 1.73 m 2 ), with ≤10% decline. We used a Mesoscale Multiplex Platform and measured biomarkers in baseline and 24-month specimens, and we examined biomarker associations with outcome using conditional logistic regression. Results Baseline and 24-month levels of monocyte chemotactic protein-1-to-creatinine ratio levels were higher for cases versus controls. The highest quartile of baseline monocyte chemotactic protein-1-to-creatinine ratio had fivefold greater odds, and each log increment had 2.27-fold higher odds for outcome (odds ratio, 5.27; 95% confidence interval, 2.19 to 12.71 and odds ratio, 2.27; 95% confidence interval, 1.44 to 3.58, respectively). IL-18-to-creatinine ratio, kidney injury molecule-1-to-creatinine ratio, and YKL-40-to-creatinine ratio were not consistently associated with outcome. C statistic for traditional predictors of eGFR decline was 0.70, which improved significantly to 0.74 with monocyte chemotactic protein-1-to-creatinine ratio. Conclusions Urinary monocyte chemotactic protein-1-to-creatinine ratio concentrations were strongly associated with sustained renal decline in patients with type 2 diabetes with preserved renal function.

Background and Purpose— The epidemiology of dialysis requiring acute kidney injury (AKI-D) in acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) admissions is poorly understood with previous studies being from a single center or year. Methods— We used the Nationwide Inpatient Sample to evaluate the yearly incidence trends of AKI-D in hospitalizations with AIS and ICH from 2002 to 2011. We also evaluated the trend of impact of AKI-D on in-hospital mortality and adverse discharge using adjusted odds ratios (aOR) after adjusting for demographics and comorbidity indices. Results— We extracted a total of 3 937 928 and 696 754 hospitalizations with AIS and ICH, respectively. AKI-D occurred in 1.5 and 3.5 per 1000 in AIS and ICH admissions, respectively. Incidence of admissions complicated by AKI-D doubled from 0.9/1000 to 1.7/1000 in AIS and from 2.1/1000 to 4.3/1000 in ICH admissions. In AIS admissions, AKI-D was associated with 30% higher odds of mortality (aOR, 1.30; 95% confidence interval, 1.12–1.48; P P P P Conclusions— Incidence of AKI-D complicating hospitalizations with cerebrovascular accident continues to grow and is associated with increased mortality and adverse discharge. This highlights the need for early diagnosis, better risk stratification, and preparedness for need for complex long-term care in this vulnerable population.

Introduction: Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists have been introduced as novel antidiabetic agents, but their potential health impact in the US is unknown. We assessed the number of potentially eligible type 2 diabetes (T2D) patients, as well as projected changes in death and complication rates for nationwide use. Methods: Based on inclusion criteria of SGLT2i and GLP-1 receptor agonist RCTs, we determined eligibility in a weighted sample of 69.2M T2D patients from 2007-2014 National Health and Nutrition Examination Survey (NHANES) data. We employed a validated microsimulation model based on the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to simulate virtual life courses of eligible US patients. Pooled hazard ratios from meta-analyses of published RCTs were applied to model death and non-fatal adverse event rates with SGLT2i and GLP-1 receptor agonist use. Results: The proportion eligible in NHANES was 9.2% (95% CI 7.3-11.1), which translates into ~6.4M US adults. Simulated 10-year mortality (32.5%) decreased by 4.6% (95% CI 2.7-7.3) with SGLT2i and by 2.9% (95% CI 1.6-4.8) with GLP-1 receptor agonists. Mean life expectancy was 16.5 y, and increased by 1.3 y (95% CI 0.6-2.2) with SGLT2i and by 0.8 y (95% CI 0.4-1.5) with GLP-1 receptor agonists. With SGLT2i, lifetime heart failure risk decreased by 7.4% (95% CI 4.1-12.3) and end-stage renal disease (ESRD) risk decreased by 0.4% (95% CI -0.1-0.9). Improvements in these event risks were uncertain with GLP-1 receptor agonist use (Figure). With lifetime SGLT2i use, fracture risk increased from 16.9 to 22.4% (95% CI of Δ 2.5-9.6) and amputation risk rose from 5.7 to 11.2% (95% CI of Δ 2.3-9.5). Conclusions: Nationwide use of SGLT2i or GLP-1 receptor agonists may save over 8 or 5M life years, respectively. Moreover, SGLT2i may avoid over 470K new cases of heart failure and over 28K ESRD cases. Further research should illuminate whether these benefits outweigh additional costs and harms.

Self-reported ancestry, genetically determined ancestry, and APOL1 polymorphisms are associated with variation in kidney function and related disease risk, but the relative importance of these factors remains unclear. We estimated the global proportion of African ancestry for 9048 individuals at Mount Sinai Medical Center in Manhattan (3189 African Americans, 1721 European Americans, and 4138 Hispanic/Latino Americans by self-report) using genome-wide genotype data. CKD-EPI eGFR and genotypes of three APOL1 coding variants were available. In admixed African Americans and Hispanic/Latino Americans, serum creatinine values increased as African ancestry increased (per 10% increase in African ancestry, creatinine values increased 1% in African Americans and 0.9% in Hispanic/Latino Americans; P≤1x10(-7)). eGFR was likewise significantly associated with African genetic ancestry in both populations. In contrast, APOL1 risk haplotypes were significantly associated with CKD, eGFR

Objective: The objective of this study was to describe the incidence of acute kidney injury (AKI) requiring renal replacement therapy (’dialysis-requiring AKI’) and the impact on in-hospital mortality among hospitalized adults with HIV infection. Design: A longitudinal analysis of a nationally representative administrative database. Methods: We reviewed the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample Database, a large, nationally representative sample of inpatient hospital admissions, to identify all adult hospitalizations with an associated diagnosis of HIV infection from 2002 to 2010. We analysed temporal trends in the incidence of dialysis-requiring AKI and the associated odds of in-hospital mortality. We also explored potential reasons behind temporal changes. Results: Among 183 0041 hospitalizations with an associated diagnosis of HIV infection, the proportion complicated by dialysis-requiring AKI increased from 0.7% in 2002 to 1.35% in 2010. This temporal rise was completely explained by changes in demographics and an increase in concurrent comorbidities and procedure utilization. The adjusted odds of in-hospital mortality associated with dialysis-requiring AKI also increased over the study period, from 1.45 [95% confidence interval (95% CI) 0.97–2.12] in 2002 to 2.64 (95% CI 2.04–3.42) in 2010. Conclusion: These data suggest that the incidence of dialysis-requiring AKI among hospitalized adults with HIV infection continues to increase, and that severe AKI remains a significant predictor of in-hospital mortality in this population. The increased incidence of dialysis-requiring AKI was largely explained by ageing of the HIV population and increasing prevalence of chronic non-AIDS comorbidities, suggesting that these trends will continue.

The population incidence of dialysis-requiring AKI has risen substantially in the last decade in the United States, and factors associated with this temporal trend are not well known.We conducted a retrospective cohort study using data from the Nationwide Inpatient Sample, a United States nationally representative database of hospitalizations from 2007 to 2009. We used validated International Classification of Diseases, Ninth Revision codes to identify hospitalizations with dialysis-requiring AKI and then, selected the diagnostic and procedure codes most highly associated with dialysis-requiring AKI in 2009. We applied multivariable logistic regression adjusting for demographics and used a backward selection technique to identify a set of diagnoses or a set of procedures that may be a driver for this changing risk in dialysis-requiring AKI.From 2007 to 2009, the population incidence of dialysis-requiring AKI increased by 11% per year (95% confidence interval, 1.07 to 1.16; P0.001). Using backward selection, we found that the temporal trend in the six diagnoses, septicemia, hypertension, respiratory failure, coagulation/hemorrhagic disorders, shock, and liver disease, sufficiently and fully accounted for the temporal trend in dialysis-requiring AKI. In contrast, temporal trends in 15 procedures most commonly associated with dialysis-requiring AKI did not account for the increasing dialysis-requiring AKI trend.The increasing risk of dialysis-requiring AKI among hospitalized patients in the United States was highly associated with the changing burden of six acute and chronic conditions but not with surgeries and procedures.

Background: The incidence of Intracranial Hemorrhage (ICrH) in HIV patients is on the rise in the United States, especially after the development of newer antiretroviral drugs. This study determines the trends of ICrH in HIV patients in the United States. Design/Methods: Data from the Nationwide Inpatient Sample (NIS) and Healthcare Cost and Utilization Project (HCUP) were analyzed for years 2002-2012.Hospitalizations with HIV positive status were identified using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes 042, V08 and ICrH by 430.xx-432.xx. Cochrane Armitage trend test and multivariate regression were used to analyze temporal trends and the potential reasons for temporal changes over the years. Results: A total of 2,584,548 hospitalizations with HIV status were made from 2002 to 2012. Of these, 10,292 (0.40%) admissions were due to ICrH or developed ICrH during hospitalization. Concurrent trend of ICrH and HIV increased from 0.34% to 0.45% in 2012 (p trend Conclusions: These data suggest that the incidence of ICrH among hospitalized adults with HIV infection continue to increase. This increasing ICrH was explained by an aging HIV population, changing demographics and chronic comorbidities, but questions still remain regarding unexplained factors which merit in-depth study.

Purpose of review To review unique considerations in the epidemiology, diagnosis, and management of kidney disease in older adults with HIV. Recent findings HIV infection may accelerate the course of kidney disease associated with traditional risk factors, such as diabetes, which are more common in older adults. The risks of acute and chronic kidney disease are increased both with HIV infection and with older age. Although the prevalence of chronic kidney disease is higher among HIV-infected adults than among HIV-negative adults, the mean age at diagnosis of end-stage renal disease is similar. Recent studies have supported the use of newer creatinine-based kidney function estimates in HIV-infected adults, although data in older adults are limited. These estimates are susceptible to artifact in the setting of newer medications that interfere with the secretion of creatinine, including cobicistat and dolutegravir. The management of kidney disease in older adults with HIV infection may be complicated by polypharmacy and increased risk for medication toxicity. Summary With aging of the HIV-infected population, age-related comorbid conditions such as kidney disease are increasingly important causes of morbidity and mortality. Although recent data do not support premature aging of HIV-infected individuals with respect to kidney disease, the risk of acute and chronic kidney disease is increased by HIV infection and its treatment.

Approximately 1 in 4 individuals infected with the human immunodeficiency virus (HIV) in the United States is coinfected with the hepatitis C virus. Both conditions increase the risk for the development and progression of kidney disease. The effect, however, of coexisting HIV and hepatitis C infection on the spectrum and progression of kidney disease is not well known. To compare the clinical features, histopathologic kidney diagnoses, and proportion of individuals progressing to end-stage kidney disease (ESKD), we reviewed the clinical records of HIV-infected individuals with and without hepatitis C coinfection who underwent ultrasound-guided percutaneous kidney biopsies between February 7, 1995, and March 30, 2009.Of the 249 HIV-infected individuals included in this study, 58% were coinfected with hepatitis C. Coinfected individuals were older (mean age, 46 ± 7 vs. 44 ± 10 yr, respectively; p < 0.01) and more likely to have used illicit drugs (85% vs. 14%, respectively; p < 0.01) compared to HIV-infected individuals without hepatitis C. HIV-associated nephropathy was the most common histopathologic diagnosis in both groups. Immune-complex glomerulonephritides (ICGNs), including lupus-like nephritis, postinfectious glomerulonephritis, membranous glomerulopathy, membranoproliferative glomerulonephritis, IgA nephropathy, and nonspecific ICGNs, occurred more frequently in individuals coinfected with hepatitis C than in those not coinfected (22% vs. 11%, respectively; p = 0.02). Although the proportion of those who died was similar between the 2 groups, hepatitis C coinfection was independently associated with a greater risk of progression to ESKD (hazard ratio, 1.81; 95% confidence interval, 1.09-2.99; p = 0.02).The current study demonstrates that coinfection with hepatitis C in individuals infected with HIV predisposes these individuals to immune-complex glomerulonephritides and is associated with increased risk of ESKD in the biopsied population.

N-Methyl-3,4-methylenedioxyamphetamine (MDMA), also called "Ecstasy," is a commonly abused psychoactive drug among the American youth. We present the case of a 23-year-old Korean-American woman who presented with seizure, delirium, and rigidity after MDMA ingestion. She was febrile (38.7°C), tachycardic (188 beats/min), tachypneic (26 breaths/min) with a borderline blood pressure (95/43 mm Hg). Examination revealed generalized muscle rigidity, tremors, hyperreflexia, and ocular clonus, leading to the diagnosis of serotonin syndrome. Urine toxicology screen was only positive for amphetamines, consistent with the history of MDMA ingestion. Initial laboratory testing showed thrombocytopenia, further testing showed deranged prothrombin time, partial thromboplastin time, decreased fibrinogen, and elevated D-dimer, suggesting disseminated intravascular coagulation. Hepatic transaminases trended up dramatically reflecting acute hepatitis. The patient received supportive care and improved by hospital day 3. MDMA toxicity manifested as serotonin syndrome, hepatitis, and coagulopathy is exceedingly rare. MDMA is metabolized by the hepatic CYP2D6 enzyme. Certain populations, such as Koreans, Chinese, and Japanese have a high prevalence of a polymorphism that confers reduced enzyme activity. We discuss this hypothesis as a possible cause for this severe presentation in our patient after a single ingestion.

BACKGROUND: The association between Moyamoya disease and sickle cell disease is well recognized in the literature. However, there is limited data on inpatient admission of concurrent sickle cell disease and Moyamoya disease. We sought to determine the trend in incidence of admissions of concurrent Moyamoya and sickle cell disease as well as the most common presentation of these admissions. METHODS: We reviewed the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (NIS) database from 2000-2011 for concurrent Moyamoya and sickle cell admissions using the ICD 9-CM codes We obtained data on gender, clinical presentation, procedures, co-morbidities and patient outcomes RESULTS: From 2000 to 2011, an estimated patients 756 (weighted (n)=3692) with co-existing Moyamoya disease and sickle cell disease were admitted. The incidence of admission for concurrent disease increased significantly from 0.04/100,000 admissions in 2000 to 0.21/100,000 admissions in 2011(figure 1). This was very significant using the Cochrane Armitage trend test(p CONCLUSION: The number of hospitalizations due to concurrent Moyamoya and sickle cell disease has increased significantly over the last decade and are likely to present with a cerebrovascular accident. Thus, it is important to maintain a high degree of suspicion for Moyamoya disease in sickle cell disease patients presenting with neurological symptoms since this could potentially impact their management.

Introduction: Management of intracerebral hemorrhage (ICH) requires urgent diagnostic and therapeutic procedures, which may not be uniformly available throughout the week. We attempt to define a "weekend effect" for ICH, which has not yet been fully established in this patient population. Hypothesis: We aimed to evaluate whether outcomes differ with respect to the day of admission in patients admitted with ICH. Methods: We reviewed the Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample (NIS) database from 2000 to 2011 for ICH using ICD 9-CM codes. NIS represents 20% of all US hospital pts and weighted numbers represent national estimates.We defined primary outcome as mortality and adverse outcome(composite of in-hospital mortality & discharge other than home). We utilized chi-square test for univariable analysis for categorical variables and generated hierarchical multilevel regression models to determine independent predictors of mortality and adverse outcome. Results: We included 161017 patients (weighted n=788641) with ICH, out of which 42996(weighted n= 210592) were admitted on weekend. After adjusting for confounders (demographics, Deyo’s modification of charlson’s co-morbidity index, admission type (elective or emergent), hospital region, hospital teaching status, hospital ICH volume and primary payer), the weekend admissions were still associated with 10 % higher mortality (OR 1.10, 95% CI 1.07-1.16, P=0.001) and 20% higher adverse outcome (OR 1.12, 95% CI 1.09-1.16, p=0.001). Conclusions: Thus, admission for ICH on the weekend was a significant and independent predictor of increased in hospital mortality and adverse outcomes as compared to weekday admission. The reasons for this are likely manifold and warrant further investigation both from a quantitative and qualitative standpoint.

Background: The impact of do-not-resuscitate (DNR) orders on outcomes has not been systematically evaluated in Intracerebral Hemorrhage (ICH). Hypothesis: We assessed the impact of DNR orders in ICH and its association to mortality/related adverse outcomes. Methods: We reviewed the Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample(NIS) database of 2011 for ICH using ICD 9-CM codes(431).This represents 20% of all US hospital patients and weighted numbers represent national estimates. We defined patients’ DNR status with ICD code V49.86 and comorbid conditions by Deyo’s modification of Charlson’s Comorbidity Index (CCI). We only included adult patients in our analysis. Our primary outcomes of interest were in-hospital mortality and adverse outcome (composite of mortality & discharge other than home). We utilized chi-square test for univariable analysis for categorical variables and generated hierarchical multilevel regression models to determine independent predictors of mortality and adverse outcome. Results: We analyzed a total of 13440 pts (weighted n= 64617) with ICH of which 2029 (weighted n=9713) patients had DNR status. The proportions of mortality (56% vs. 19%, p Conclusion: DNR status in patients admitted with ICH appears to be a independent and significant predictor of substantially increased hospital mortality and adverse outcomes. The reasons for this are multifactorial and likely involve patient as well as systematic factors.Further studies including both quantitative/qualitative aspects are warranted to investigate these factors in detail.

Background: Prior studies have demonstrated an association between ethnicity and symptom onset to presentation time (S2PT) among patients presenting with ST elevation MI (STEMI) in the USA, with a shorter S2PT among Caucasians when compared with other ethnicities. However, little is known regarding whether or not a patient's ability to comprehend English impacts the S2PT. Methods: Consecutive patients presenting to 4 hospitals in NYC with STEMI referred for primary angioplasty were included in the analysis. S2PT was recorded on the day of the infarct based on the patient's account of the onset of symptoms. We assessed a patient's ability to comprehend English through telephone interviews conducted during routine follow-up. Results: Among 210 patients, 83.8% (176 of 210) had either some English comprehension or were fluent in English (E) and 16.2% (34 of 210) reported no English comprehension (non-E). Of the non-E patients, 65% (22 of 34) spoke Spanish, 6% (2 of 34) spoke Russian, 6% (2 of 34) spoke Chinese and 23% (8 of 34) spoke another language. The baseline variables and mean S2PT are depicted in the table. Non-E patients had a significantly higher S2PT compared to E patients even after adjusting for differences in baseline variables. Increased odds were also observed among non-E patients with a longer S2PT (adjusted odds ratio for S2PT > 120 minutes 2.17; 95% CI 01.03-4.54; p=0.04). This association remained constant even after adjusting for confounders like age, sex, ethnicity, level of education and comorbidities (diabetes, previous history of MI and PCI). Conclusions: S2PT is strongly influenced by a patient's ability to comprehend English. This information emphasizes the need for more aggressive “multi-lingual” educational outreach and the use of multi-lingual emergency lines in an effort to decrease total ischemic time during STEMI. English Comprehension Fair or Good (N=176) No English Comprehension (N=34) P Age Mean (SD) 62 (14.2) 65 (11) 0.22 Male sex n (%) 129 (73) 26 (76) 0.70 Diabetes n (%) 25 (14) 9 (27) 0.09 Hypertension n (%) 107 (66) 20 (62.5) 0.70 Prior MI n (%) 21 (12) 2 (6) 0.284 Prior PCI or CABG n (%) 12 (6.8) 2 (6) 0.960 Education: n (%) 40 (23) 12 (35) 0.09 Less than HS 62 (35) 8 (23) HS Diploma 8 (4) 0 (0) College Diploma Unknown 66 (38) 14 (42) Mean S2P time (SD) 225 (315) 387 (820.6) 0.05 S2P time > 120 minutes n (%) 70 (40) 20 (62.5) 0.04