Genome-wide polygenic risk score for retinopathy of type 2 diabetes.

Diabetic retinopathy (DR) is a common consequence in type 2 diabetes (T2D) and a leading cause of blindness in working-age adults. Yet, its genetic predisposition is largely unknown. Here, we examined the polygenic architecture underlying DR by deriving and assessing a genome-wide polygenic risk score (PRS) for DR. We evaluated the PRS in 6079 individuals with T2D of European, Hispanic, African and other ancestries from a large-scale multi-ethnic biobank. Main outcomes were PRS association with DR diagnosis, symptoms and complications, and time to diagnosis, and transferability to non-European ancestries. We observed that PRS was significantly associated with DR. A standard deviation increase in PRS was accompanied by an adjusted odds ratio (OR) of 1.12 [95% confidence interval (CI) 1.04-1.20; P = 0.001] for DR diagnosis. When stratified by ancestry, PRS was associated with the highest OR in European ancestry (OR = 1.22, 95% CI 1.02-1.41; P = 0.049), followed by African (OR = 1.15, 95% CI 1.03-1.28; P = 0.028) and Hispanic ancestries (OR = 1.10, 95% CI 1.00-1.10; P = 0.050). Individuals in the top PRS decile had a 1.8-fold elevated risk for DR versus the bottom decile (P = 0.002). Among individuals without DR diagnosis, the top PRS decile had more DR symptoms than the bottom decile (P = 0.008). The PRS was associated with retinal hemorrhage (OR = 1.44, 95% CI 1.03-2.02; P = 0.03) and earlier DR presentation (10% probability of DR by 4 years in the top PRS decile versus 8 years in the bottom decile). These results establish the significant polygenic underpinnings of DR and indicate the need for more diverse ancestries in biobanks to develop multi-ancestral PRS.

Genome-first recall of healthy individuals by polygenic risk score reveals differences in coronary artery calcium.

Genetic risk for coronary artery disease (CAD) is commonly measured with polygenic risk scores (PRS); yet, the relationship of atherosclerotic burden with PRS in healthy individuals not at high clinical risk for CAD (ie, without a high pooled cohort equations [PCE] score) is unknown. Here, we implemented a novel recall-by-PRS strategy to measure coronary artery calcium (CAC) scores prospectively in 53 healthy individuals with extreme high PRS (median [IQR] PRS = 94% [83-98]) and low PRS (median [IQR] PRS = 3.6% [1.2-10]). The high PRS group was associated with a 2.8-fold greater CAC than the low PRS group, adjusted for age, sex, BMI, smoking, and statin use, and had a 6.7-fold greater proportion of individuals with CAC exceeding 300 HU. These findings reveal that extreme PRS tracks with CAD risk even in those without high clinical risk and demonstrate proof of principle for recall-by-PRS approaches that should be assessed prospectively in larger trials.

Unplanned 30-Day Readmission Rates for Autosomal Dominant Polycystic Kidney Disease: Insight from the Nationwide Readmissions Database.

INTRODUCTION: Among end-stage kidney disease (ESKD) patients on dialysis with autosomal dominant polycystic kidney disease (ADPKD), relatively little is known about the epidemiology and risk factors for 30-day readmissions in the USA. Therefore, we evaluated the 30-day unplanned readmission rates and predictors and inpatient care costs among ESKD patients with and without ADPKD using a nationally representative, all-payer database. METHODS: We utilized the Nationwide Readmissions Database from 2013 to 2018 to identify patients admitted for ESKD on dialysis with and without ADPKD using ICD-9 and ICD-10 codes. The primary outcome was a 30-day, unplanned readmission rate. Secondary outcomes were readmission reasons and timing, mortality, cost of hospitalization and rehospitalization, and adjusted predictors of readmissions. We used χ2 tests, t tests, and Wilcoxon rank-sum tests for descriptive analyses and survey logistic regression to calculate adjusted odds ratios and 95% confidence intervals for associations with readmissions adjusting for confounders. RESULTS: From 2013 to 2018, in a cohort of 1,404,144 hospitalizations with ESKD on dialysis as the primary and secondary diagnosis on index admission, there were 8,213 (0.58%) patients with ADPKD and 1,395,932 patients without ADPKD. Those who had ADPKD during index admissions had fewer 30 days readmissions (18.8 vs. 23.8%, p < 0.0001). The cost of hospitalizations and readmissions in ESKD on-dialysis patients with ADPKD was higher than non-ADPKD patients. Compared to ESKD patients without ADPKD who were readmitted, readmitted ADPKD patients were more likely to be younger with a lower Elixhauser Comorbidity Index (ECI) score; have received kidney transplant, lower source of income, elective index admissions, private insurance; and be discharged routinely, admitted in hospitals with larger bed size, in teaching hospitals, and less likely to get admitted through the emergency department. Younger age (<75 years), higher ECI score, longer length of stay, Medicare and Medicaid insurance, self-pay, discharge to a short-term hospital, specialized care, home health care, and against medical advice were associated with significantly increased odds of readmission. ADPKD patients were 31% less likely to get readmitted and 43% less likely to die during readmissions. DISCUSSION/CONCLUSION: Nationwide, ESKD on-dialysis patients with ADPKD were less likely to have 30-day readmission than patients without ADPKD. Inpatient mortality during readmissions in patients admitted with ESKD on dialysis was lower with ADPKD as compared to those without ADPKD at the cost of higher health care expenses.

AKI in Hospitalized Patients with COVID-19.

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.

National Landscape of Unplanned 30-Day Readmission Rates for Acute Non-hemorrhagic Diverticulitis: Insight from National Readmission Database.

BACKGROUND: Early readmissions are an important indicator of the quality of care. Limited data exist describing hospital readmissions in acute diverticulitis. The study aimed to describe unplanned, 30-day readmissions among adult acute diverticulitis patients and to assess readmission predictors. METHODS: We analyzed the 2013 and 2014 United States National Readmission Database and identified acute diverticulitis admissions using administrative codes in adult patients older than 18 years of age. Our primary outcome was a 30-day, unplanned readmission rate. We used Chi-square tests, t tests, and Wilcoxon rank-sum tests for descriptive analyses and survey logistic regression to calculate adjusted odds ratios (aORs) and 95% confidence intervals for associations with readmissions adjusting for confounders. RESULTS: In the cohort of 364,511 hospitalizations with acute diverticulitis, as the primary diagnosis on index admission, 31,420 (8.6%) had at least one unplanned 30-day readmission. Sixty percent of the readmissions occurred within the first 2 weeks of the index admission. The most common reasons for unplanned 30-day readmission were due to diverticulitis of the colon (41.5%), postoperative infection (4.2%), septicemia (3.6%), intestinal infection due to Clostridium difficile (3%), and other digestive system complications such bleeding or fistula (2.8%). Multivariable analysis showed advance age (> 75 years), discharge against medical advice, comorbidities (renal failure, coronary artery disease, atrial fibrillation, congestive heart failure, hypertension, diabetes, obesity, weight loss, chronic lung disease, malignancy), blood transfusion, Medicare and Medicaid insurance, and increased length of stay (> 3 days) were associated with significantly higher odds for readmission. Patients who have undergone abdominal surgery during index admission were 31% less likely to get readmitted. CONCLUSIONS: On a national level, 1 in 11 hospitalizations for acute diverticulitis was followed by unplanned readmission within 30 days with most admissions occurring in the first 2 weeks. Multiple modifiable and non-modifiable factors influencing readmission rates were noted. Further studies should examine if strategies that address these predictors can decrease readmissions.

Hyperglycemia is Associated With Increased Mortality in Critically Ill Patients With COVID-19.

OBJECTIVE: To explore the relationship between hyperglycemia in the presence and absence of diabetes mellitus (DM) and adverse outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: The study included 133 patients with COVID-19 admitted to an intensive care unit (ICU) at an urban academic quaternary-care center between March 10 and April 8, 2020. Patients were categorized based on the presence or absence of DM and early-onset hyperglycemia (EHG), defined as a blood glucose >180 mg/dL during the first 2 days after ICU admission. The primary outcome was 14-day all-cause in-hospital mortality; also examined were 60-day all-cause in-hospital mortality and the levels of C-reactive protein, interleukin 6, procalcitonin, and lactate. RESULTS: Compared to non-DM patients without EHG, non-DM patients with EHG exhibited higher adjusted hazard ratios (HRs) for mortality at 14 days (HR 7.51, CI 1.70-33.24) and 60 days (HR 6.97, CI 1.86-26.13). Non-DM patients with EHG also featured higher levels of median C-reactive protein (306.3 mg/L, P = .036), procalcitonin (1.26 ng/mL, P = .028), and lactate (2.2 mmol/L, P = .023). CONCLUSION: Among critically ill COVID-19 patients, those without DM with EHG were at greatest risk of 14-day and 60-day in-hospital mortality. Our study was limited by its retrospective design and relatively small cohort. However, our results suggest the combination of elevated glucose and lactate may identify a specific cohort of individuals at high risk for mortality from COVID-19. Glucose testing and control are important in individuals with COVID-19, even those without preexisting diabetes.

Natural language processing of electronic health records is superior to billing codes to identify symptom burden in hemodialysis patients.

Symptoms are common in patients on maintenance hemodialysis but identification is challenging. New informatics approaches including natural language processing (NLP) can be utilized to identify symptoms from narrative clinical documentation. Here we utilized NLP to identify seven patient symptoms from notes of maintenance hemodialysis patients of the BioMe Biobank and validated our findings using a separate cohort and the MIMIC-III database. NLP performance was compared for symptom detection with International Classification of Diseases (ICD)-9/10 codes and the performance of both methods were validated against manual chart review. From 1034 and 519 hemodialysis patients within BioMe and MIMIC-III databases, respectively, the most frequently identified symptoms by NLP were fatigue, pain, and nausea/vomiting. In BioMe, sensitivity for NLP (0.85 - 0.99) was higher than for ICD codes (0.09 - 0.59) for all symptoms with similar results in the BioMe validation cohort and MIMIC-III. ICD codes were significantly more specific for nausea/vomiting in BioMe and more specific for fatigue, depression, and pain in the MIMIC-III database. A majority of patients in both cohorts had four or more symptoms. Patients with more symptoms identified by NLP, ICD, and chart review had more clinical encounters. NLP had higher specificity in inpatient notes but higher sensitivity in outpatient notes and performed similarly across pain severity subgroups. Thus, NLP had higher sensitivity compared to ICD codes for identification of seven common hemodialysis-related symptoms, with comparable specificity between the two methods. Hence, NLP may be useful for the high-throughput identification of patient-centered outcomes when using electronic health records.

Trends and Racial Disparities of Palliative Care Use among Hospitalized Patients with ESKD on Dialysis.

BACKGROUND: Study findings show that although palliative care decreases symptom burden, it is still underused in patients with ESKD. Little is known about disparity in use of palliative care services in such patients in the inpatient setting. METHODS: To investigate the use of palliative care consultation in patients with ESKD in the inpatient setting, we conducted a retrospective cohort study using the National Inpatient Sample from 2006 to 2014 to identify admitted patients with ESKD requiring maintenance dialysis. We compared palliative care use among minority groups (black, Hispanic, and Asian) and white patients, adjusting for patient and hospital variables. RESULTS: We identified 5,230,865 hospitalizations of such patients from 2006 through 2014, of which 76,659 (1.5%) involved palliative care. The palliative care referral rate increased significantly, from 0.24% in 2006 to 2.70% in 2014 (P<0.01). Black and Hispanic patients were significantly less likely than white patients to receive palliative care services (adjusted odds ratio [aOR], 0.72; 95% confidence interval [95% CI], 0.61 to 0.84, P<0.01 for blacks and aOR, 0.46; 95% CI, 0.30 to 0.68, P<0.01 for Hispanics). These disparities spanned across all hospital subtypes, including those with higher proportions of minorities. Minority patients with lower socioeconomic status (lower level of income and nonprivate health insurance) were also less likely to receive palliative care. CONCLUSIONS: Despite a clear increase during the study period in provision of palliative care for inpatients with ESKD, significant racial disparities occurred and persisted across all hospital subtypes. Further investigation into causes of racial and ethnic disparities is necessary to improve access to palliative care services for the vulnerable ESKD population.

Emergent colectomy rates decreased while elective ileal pouch rates were stable over time: a nationwide inpatient sample study.

PURPOSE: Despite advances in biologic therapy, approximately 10-15% of ulcerative colitis (UC) patients require surgery. We aimed to (1) examine the rates of emergent colectomy and elective ileal pouch anal anastomosis (IPAA) over time among UC patients in the USA and (2) investigate disparities in surgery rates by patient demographics. METHODS: Data from the Nationwide Inpatient Sample (NIS) from 2000 to 2014 were analyzed. Inclusion criteria were admissions with a primary UC ICD-9-CM diagnosis code and age > 18. Emergent cases were defined as those admitted through the emergency room with an outcome ICD-9-CM code for subtotal colectomy. Elective IPAA cases were defined with an outcome ICD-9-CM code for IPAA, used as a surrogate measure of colectomy. Patient and hospital-level demographics were analyzed. Temporal trends of colectomy were analyzed utilizing joinpoint-regression analysis with calculation of annual percentage change (APC). RESULTS: A total of 470,708 admissions were included over the 14-year period. Emergent colectomy rate significantly declined (APC - 7.35%, p = 0.0002), while the rate of elective IPAA remained stable (APC - 0.21%, p = 0.8). Emergent colectomy rates declined similarly across all demographics, though not as marked among patients age 50 and older and Medicare patients. Elective IPAA rates were significantly lower among blacks and patients with public insurance. CONCLUSIONS: There has been a significant decline in emergent UC colectomy rates in the USA; however, the overall need for surgery appears unchanged given stable IPAA rates. This suggests a limited impact on overall surgery rates with a shift from emergent to elective procedures.

National trends of endoscopic retrograde cholangiopancreatography utilization and outcomes in decompensated cirrhosis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) can be challenging in patients with decompensated cirrhosis (DC) due to increased risk of adverse events related to liver dysfunction. Limited data exist regarding its national utilization in patients with DC. We aim to determine the trends in utilization and outcomes of ERCP among patients with DC in US hospitalizations. METHODS: We identified hospitalizations undergoing ERCP (diagnostic and therapeutic) between 2000 and 2013 from the National Inpatient Sample (NIS) database and used validated ICD9-CM codes to identify DC hospitalizations. We utilized Cochrane-Armitage test to identify changes in trends and multivariable survey regression modeling for adjusted odds ratios (aOR) for adverse outcomes and mortality predictors. RESULTS: There were 43782 cases of ERCPs performed in DC patients during the study period. Absolute number of ERCPs performed in this population from 2000 to 2013 showed an upward trend; however, the proportion of DC patients undergoing ERCP remained stable. We noted significant decrease in utilization of diagnostic ERCP and an increase of therapeutic ERCPs (P < 0.01). There was a significant decrease in the mean length of stay for DC patients undergoing ERCP from 8.2 days in 2000 to 7.2 days in 2013 (P < 0.01) with an increase in the mean cost of hospitalization from $17053 to $19825 (P < 0.001). Mortality rates showed a downward trend from 2000 to 2013 from 13.6 to 9.6% (P < 0.01). Increasing age, Hispanic race, diagnosis of hypertension and diabetes mellitus, and private insurance were related to adverse discharges(P < 0.01). Increasing age, presence of hepatic encephalopathy, and sepsis were associated with higher mortality (P < 0.01). CONCLUSIONS: There is an increasing trend in therapeutic ERCP utilization in DC hospitalizations nationally. There is an overall decrease in mortality in DC hospitalizations undergoing ERCP. This improvement in mortality suggests improvement in both procedural technique and peri-procedural care as well as overall decreasing mortality in cirrhosis.

Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry.

Importance: Hereditary transthyretin (TTR) amyloid cardiomyopathy (hATTR-CM) due to the TTR V122I variant is an autosomal-dominant disorder that causes heart failure in elderly individuals of African ancestry. The clinical associations of carrying the variant, its effect in other African ancestry populations including Hispanic/Latino individuals, and the rates of achieving a clinical diagnosis in carriers are unknown. Objective: To assess the association between the TTR V122I variant and heart failure and identify rates of hATTR-CM diagnosis among carriers with heart failure. Design, Setting, and Participants: Cross-sectional analysis of carriers and noncarriers of TTR V122I of African ancestry aged 50 years or older enrolled in the Penn Medicine Biobank between 2008 and 2017 using electronic health record data from 1996 to 2017. Case-control study in participants of African and Hispanic/Latino ancestry with and without heart failure in the Mount Sinai BioMe Biobank enrolled between 2007 and 2015 using electronic health record data from 2007 to 2018. Exposures: TTR V122I carrier status. Main Outcomes and Measures: The primary outcome was prevalent heart failure. The rate of diagnosis with hATTR-CM among TTR V122I carriers with heart failure was measured. Results: The cross-sectional cohort included 3724 individuals of African ancestry with a median age of 64 years (interquartile range, 57-71); 1755 (47%) were male, 2896 (78%) had a diagnosis of hypertension, and 753 (20%) had a history of myocardial infarction or coronary revascularization. There were 116 TTR V122I carriers (3.1%); 1121 participants (30%) had heart failure. The case-control study consisted of 2307 individuals of African ancestry and 3663 Hispanic/Latino individuals; the median age was 73 years (interquartile range, 68-80), 2271 (38%) were male, 4709 (79%) had a diagnosis of hypertension, and 1008 (17%) had a history of myocardial infarction or coronary revascularization. There were 1376 cases of heart failure. TTR V122I was associated with higher rates of heart failure (cross-sectional cohort: n = 51/116 TTR V122I carriers [44%], n = 1070/3608 noncarriers [30%], adjusted odds ratio, 1.7 [95% CI, 1.2-2.4], P = .006; case-control study: n = 36/1376 heart failure cases [2.6%], n = 82/4594 controls [1.8%], adjusted odds ratio, 1.8 [95% CI, 1.2-2.7], P = .008). Ten of 92 TTR V122I carriers with heart failure (11%) were diagnosed as having hATTR-CM; the median time from onset of symptoms to clinical diagnosis was 3 years. Conclusions and Relevance: Among individuals of African or Hispanic/Latino ancestry enrolled in 2 academic medical center-based biobanks, the TTR V122I genetic variant was significantly associated with heart failure.

National Trends and Outcomes in Dialysis-Requiring Acute Kidney Injury in Heart Failure: 2002-2013.

BACKGROUND: Dialysis-requiring acute kidney injury (D-AKI) is a serious complication in hospitalized heart failure (HF) patients. However, data on national trends are lacking after 2002. METHODS: We used the Nationwide Inpatient Sample (2002-2013) to identify HF hospitalizations with and without D-AKI. We analyzed trends in incidence, in-hospital mortality, length of stay (LoS), and cost. We calculated adjusted odds ratios (aORs) for predictors of D-AKI and for outcomes including in-hospital mortality and adverse discharge (discharge to skilled nursing facilities, nursing homes, etc). RESULTS: We identified 11,205,743 HF hospitalizations. Across 2002-2013, the incidence of D-AKI doubled from 0.51% to 1.09%. We found male sex, younger age, African-American and Hispanic race, and various comorbidities and procedures, such as sepsis and mechanical ventilation, to be independent predictors of D-AKI in HF hospitalizations. D-AKI was associated with higher odds of in-hospital mortality (aOR 2.49, 95% confidence interval [CI] 2.36-2.63; P < .01) and adverse discharge (aOR 2.04, 95% CI 1.95-2.13; P < .01). In-hospital mortality and attributable risk of mortality due to D-AKI decreased across 2002-2013. LoS and cost also decreased across this period. CONCLUSIONS: The incidence of D-AKI in HF hospitalizations doubled across 2002-2013. Despite declining in-hospital mortality, LoS, and cost, D-AKI was associated with worse outcomes.

National Trends in Emergency Room Visits of Dialysis Patients for Adverse Drug Reactions.

BACKGROUND: Various medications are cleared by the kidneys, therefore patients with impaired renal function, especially dialysis patients are at risk for adverse drug events (ADEs). There are limited studies on ADEs in maintenance dialysis patients. METHODS: We utilized a nationally representative database, the Nationwide Emergency Department Sample, from 2008 to 2013, to compare emergency department (ED) visits for dialysis and propensity matched non-dialysis patients. Log binomial regression was used to calculate relative risk of hospital admission and logistic regression to calculate ORs for in-hospital mortality while adjusting for patient and hospital characteristics. RESULTS: While ED visits for ADEs decreased in both groups, they were over 10-fold higher in dialysis patients than non-dialysis patients (65.8-88.5 per 1,000 patients vs. 4.6-5.4 per 1,000 patients respectively, p < 0.001). The top medication category associated with ED visits for ADEs in dialysis patients is agents primarily affecting blood constituents, which has increased. After propensity matching, patient admission was higher in dialysis patients than non-dialysis patients, (88 vs. 76%, p < 0.001). Dialysis was associated with a 3% increase in risk of admission and 3 times the odds of in-hospital mortality (adjusted OR 3, 95% CI 2.7-2.3.3). CONCLUSIONS: ED visits for ADEs are substantially higher in dialysis patients than non-dialysis patients. In dialysis patients, ADEs associated with agents primarily affecting blood constituents are on the rise. ED visits for ADEs in dialysis patients have higher inpatient admissions and in-hospital mortality. Further studies are needed to identify and implement measures aimed at reducing ADEs in dialysis patients.

The Effect of Depression in Chronic Hemodialysis Patients on Inpatient Hospitalization Outcomes.

BACKGROUND/AIMS: Depression is common in patients with end-stage renal disease (ESRD) on hemodialysis (HD). Although, depression is associated with mortality, the effect of depression on in-hospital outcomes has not been studied as yet. METHODS: We analyzed the National Inpatient Sample for trends and outcomes of hospitalizations with depression in patients with ESRD. RESULTS: The proportion of ESRD hospitalizations with depression doubled from 2005 to 2013 (5.01-11.78%). Hospitalized patients on HD with depression were younger (60.47 vs. 62.70 years, p < 0.0001), female (56.93 vs. 47.81%, p < 0.0001), white (44.92 vs. 34.01%, p < 0.0001), and had higher proportion of comorbidities. However, there was a statistically significant lower risk of mortality in HD patients within the top 5 reasons for admissions. CONCLUSION: There were significant differences in demographics and comorbidities for hospitalized HD patients with depression. Depression was associated with an increased rate of adverse effects in discharged patients, and decreased in-hospital mortality.

Temporal trends of dialysis requiring acute kidney injury after orthotopic cardiac and liver transplant hospitalizations.

BACKGROUND: The epidemiology and outcomes of acute kidney injury (AKI) in prevalent non-renal solid organ transplant recipients is unknown. METHODS: We assessed the epidemiology of trends in acute kidney injury (AKI) in orthotopic cardiac and liver transplant recipients in the United States. We used the Nationwide Inpatient Sample to evaluate the yearly incidence trends (2002 to 2013) of the primary outcome, defined as AKI requiring dialysis (AKI-D) in hospitalizations after cardiac and liver transplantation. We also evaluated the trend and impact of AKI-D on hospital mortality and adverse discharge using adjusted odds ratios (aOR). RESULTS: The proportion of hospitalizations with AKI (9.7 to 32.7% in cardiac and 8.5 to 28.1% in liver transplant hospitalizations; ptrend<0.01) and AKI-D (1.63 to 2.33% in cardiac and 1.32 to 2.65% in liver transplant hospitalizations; ptrend<0.01) increased from 2002-2013. This increase in AKI-D was explained by changes in race and increase in age and comorbidity burden of transplant hospitalizations. AKI-D was associated with increased odds of in hospital mortality (aOR 2.85; 95% CI 2.11-3.80 in cardiac and aOR 2.00; 95% CI 1.55-2.59 in liver transplant hospitalizations) and adverse discharge [discharge other than home] (aOR 1.97; 95% CI 1.53-2.55 in cardiac and 1.91; 95% CI 1.57-2.30 in liver transplant hospitalizations). CONCLUSIONS: This study highlights the growing burden of AKI-D in non-renal solid organ transplant recipients and its devastating impact, and emphasizes the need to develop strategies to reduce the risk of AKI to improve health outcomes.

Integrated multiomics implicates dysregulation of ECM and cell adhesion pathways as drivers of severe COVID-associated kidney injury.

COVID-19 has been a significant public health concern for the last four years; however, little is known about the mechanisms that lead to severe COVID-associated kidney injury. In this multicenter study, we combined quantitative deep urinary proteomics and machine learning to predict severe acute outcomes in hospitalized COVID-19 patients. Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrated predictive power for both discovery and validation set with 87% and 79% accuracy, respectively. These predictive urinary biomarkers were recapitulated in non-COVID acute kidney injury revealing overlapping injury mechanisms. We further combined orthogonal multiomics datasets to understand the mechanisms that drive severe COVID-associated kidney injury. Functional overlap and network analysis of urinary proteomics, plasma proteomics and urine sediment single-cell RNA sequencing showed that extracellular matrix and autophagy-associated pathways were uniquely impacted in severe COVID-19. Differentially abundant proteins associated with these pathways exhibited high expression in cells in the juxtamedullary nephron, endothelial cells, and podocytes, indicating that these kidney cell types could be potential targets. Further, single-cell transcriptomic analysis of kidney organoids infected with SARS-CoV-2 revealed dysregulation of extracellular matrix organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters showed significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids. Collectively, these data suggest that extracellular matrix degradation and adhesion-associated mechanisms could be a main driver of COVID-associated kidney injury and severe outcomes.

The Association between Prevalence of Peritoneal Dialysis versus Hemodialysis and Patients' Distance to Dialysis-Providing Facilities.

Background: Accessibility to dialysis facilities plays a central role when deciding on a patient's long-term dialysis modality. Studies investigating the effect of distance to nearest dialysis-providing unit on modality choice have yielded conflicting results. We set out to investigate the association between patients' dialysis modality and both the driving and straight-line distances to the closest HD- and PD-providing units. Methods: All patients with ESKD who initiated in-center HD and PD in 2017, were 18-90 years old, and were on dialysis for ≥30 days were included. Patients in residence zip codes in nonconterminous United States or lived >90 miles from the nearest HD-providing unit were excluded. Results: A total of 102,247 patients in the United States initiated in-center HD and PD in 2017. Compared with patients on HD, patients on PD had longer driving distances to their nearest PD unit (4.4 versus 3.4 miles; P<0.001). Patients who lived >30 miles from the nearest HD unit were more likely to be on PD if the nearest PD unit was a distance equal to/less than that of the HD unit. PD utilization increased with increasing distance from patients' homes to the nearest HD unit. No change in this association was found regardless of if the PD unit was farther from/closer than the nearest HD unit. This association was not seen with straight-line distance analysis. Conclusions: With increasing distances from the nearest dialysis-providing units (HD or PD), PD utilization increased. Using driving distance rather than straight-line distance affects data analysis and outcomes. Increasing the number of PD units may have a limited effect on increasing PD utilization.

Kidney disease genetic risk variants alter lysosomal beta-mannosidase (MANBA) expression and disease severity.

More than 800 million people in the world suffer from chronic kidney disease (CKD). Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function; however, causal genes and pathways for CKD remain unknown. Here, we performed integration of kidney function GWAS and human kidney-specific expression quantitative trait analysis and identified that the expression of beta-mannosidase (MANBA) was lower in kidneys of subjects with CKD risk genotype. We also show an increased incidence of renal failure in subjects with rare heterozygous loss-of-function coding variants in MANBA using phenome-wide association analysis of 40,963 subjects with exome sequencing data. MANBA is a lysosomal gene highly expressed in kidney tubule cells. Deep phenotyping revealed structural and functional lysosomal alterations in human kidneys from subjects with CKD risk alleles and mice with genetic deletion of Manba Manba heterozygous and knockout mice developed more severe kidney fibrosis when subjected to toxic injury induced by cisplatin or folic acid. Manba loss altered multiple pathways, including endocytosis and autophagy. In the absence of Manba, toxic acute tubule injury induced inflammasome activation and fibrosis. Together, these results illustrate the convergence of common noncoding and rare coding variants in MANBA in kidney disease development and demonstrate the role of the endolysosomal system in kidney disease development.

Racial and Ethnic Disparities in Pregnancy-Related Acute Kidney Injury.

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.

Acute Kidney Injury in Hospitalized Patients with COVID-19.

IMPORTANCE: Preliminary reports indicate that acute kidney injury (AKI) is common in coronavirus disease (COVID)-19 patients and is associated with worse outcomes. AKI in hospitalized COVID-19 patients in the United States is not well-described. OBJECTIVE: To provide information about frequency, outcomes and recovery associated with AKI and dialysis in hospitalized COVID-19 patients. DESIGN: Observational, retrospective study. SETTING: Admitted to hospital between February 27 and April 15, 2020. PARTICIPANTS: Patients aged ≥18 years with laboratory confirmed COVID-19 Exposures: AKI (peak serum creatinine increase of 0.3 mg/dL or 50% above baseline). Main Outcomes and Measures: Frequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aOR) with mortality. We also trained and tested a machine learning model for predicting dialysis requirement with independent validation. RESULTS: A total of 3,235 hospitalized patients were diagnosed with COVID-19. AKI occurred in 1406 (46%) patients overall and 280 (20%) with AKI required renal replacement therapy. The incidence of AKI (admission plus new cases) in patients admitted to the intensive care unit was 68% (553 of 815). In the entire cohort, the proportion with stages 1, 2, and 3 AKI were 35%, 20%, 45%, respectively. In those needing intensive care, the respective proportions were 20%, 17%, 63%, and 34% received acute renal replacement therapy. Independent predictors of severe AKI were chronic kidney disease, systolic blood pressure, and potassium at baseline. In-hospital mortality in patients with AKI was 41% overall and 52% in intensive care. The aOR for mortality associated with AKI was 9.6 (95% CI 7.4-12.3) overall and 20.9 (95% CI 11.7-37.3) in patients receiving intensive care. 56% of patients with AKI who were discharged alive recovered kidney function back to baseline. The area under the curve (AUC) for the machine learned predictive model using baseline features for dialysis requirement was 0.79 in a validation test. CONCLUSIONS AND RELEVANCE: AKI is common in patients hospitalized with COVID-19, associated with worse mortality, and the majority of patients that survive do not recover kidney function. A machine-learned model using admission features had good performance for dialysis prediction and could be used for resource allocation.