Faculty Bibliography

Biomarkers of tubular function such as epidermal growth factor (EGF) may improve prognostication of participants at highest risk for chronic kidney disease (CKD) after hospitalization. To examine this, we measured urinary EGF (uEGF) from samples collected in the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study, a multi-center, prospective, observational cohort of hospitalized participants with and without AKI. Cox proportional hazards regression was used to investigate the association of uEGF/Cr at hospitalization, three months post-discharge, and the change between these time points with major adverse kidney events (MAKE): CKD incidence, progression, or development of kidney failure. Clinical findings were paired with mechanistic studies comparing relative Egf expression in mouse models of kidney atrophy or repair after ischemia-reperfusion injury. MAKE was observed in 20% of 1,509 participants over 4.3 years of follow-up. Each 2-fold higher level of uEGF/Cr at three months was associated with decreased risk of MAKE (adjusted hazards ratio 0.46, 95% confidence interval: 0.39-0.55). Participants with the highest increase in uEGF/Cr from hospitalization to three-month follow-up had a lower risk of MAKE (adjusted hazards ratio 0.52; 95% confidence interval: 0.36-0.74) compared to those with the least change in uEGF/Cr. A model using uEGF/Cr at three months combined with clinical variables yielded moderate discrimination for MAKE (area under the curve 0.73; 95% confidence interval: 0.69-0.77) and strong discrimination for kidney failure at four years (area under the curve 0.96; 95% confidence interval: 0.92-1.00). Accelerated restoration of Egf expression in mice was seen in the model of adaptive repair after injury, compared to a model of progressive atrophy. Thus, urinary EGF/Cr may be a biomarker of distal tubular health, with higher concentrations and increased uEGF/Cr post-discharge independently associated with reduced risk of MAKE in hospitalized patients.

BACKGROUND:Children who require surgery for congenital heart disease have increased risk for long-term chronic kidney disease (CKD). Clinical factors as well as urine biomarkers of tubular health and injury may help improve the prognostication of estimated glomerular filtration rate (eGFR) decline. METHODS:We enrolled children from 1 month to 18 years old undergoing cardiac surgery in the ASSESS-AKI cohort. We used mixed-effect models to assess the association between urinary biomarkers (log2-transformed uromodulin, NGAL, KIM-1, IL-18, L-FABP) measured 3 months after cardiac surgery and cyanotic heart disease with the rate of eGFR decline at annual in-person visits over 4 years. RESULTS:per month). CONCLUSIONS:At 3 months after cardiac surgery, children with lower urine uromodulin and IL-18 concentrations experienced a significantly faster decline in eGFR. Children with cyanotic heart disease had a lower median eGFR at all time points but did not experience faster eGFR decline. A higher-resolution version of the Graphical abstract is available as Supplementary information.

KEY POINTS:Two genetic variants in the DISP1-TLR5 gene locus were associated with risk of AKI. DISP1 and TLR5 were differentially regulated in kidney biopsy tissue from patients with AKI compared with no AKI. BACKGROUND:Although common genetic risks for CKD are well established, genetic factors influencing risk for AKI in hospitalized patients are poorly understood. METHODS:We conducted a genome-wide association study in 1369 participants in the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI Study; a multiethnic population of hospitalized participants with and without AKI matched on demographics, comorbidities, and kidney function before hospitalization. We then completed functional annotation of top-performing variants for AKI using single-cell RNA sequencing data from kidney biopsies in 12 patients with AKI and 18 healthy living donors from the Kidney Precision Medicine Project. RESULTS: CONCLUSIONS:, suggesting this region as a novel risk for AKI susceptibility.

BACKGROUND:AKI is a heterogeneous syndrome. Current subphenotyping approaches have only used limited laboratory data to understand a much more complex condition. METHODS:We focused on patients with AKI from the Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI). We used hierarchical clustering with Ward linkage on biomarkers of inflammation, injury, and repair/health. We then evaluated clinical differences between subphenotypes and examined their associations with cardiorenal events and death using Cox proportional hazard models. RESULTS:We included 748 patients with AKI: 543 (73%) of them had AKI stage 1, 112 (15%) had AKI stage 2, and 93 (12%) had AKI stage 3. The mean age (±SD) was 64 (13) years; 508 (68%) were men; and the median follow-up was 4.7 (Q1: 2.9, Q3: 5.7) years. Patients with AKI subphenotype 1 ( N =181) had the highest kidney injury molecule (KIM-1) and troponin T levels. Subphenotype 2 ( N =250) had the highest levels of uromodulin. AKI subphenotype 3 ( N =159) comprised patients with markedly high pro-brain natriuretic peptide and plasma tumor necrosis factor receptor-1 and -2 and low concentrations of KIM-1 and neutrophil gelatinase-associated lipocalin. Finally, patients with subphenotype 4 ( N =158) predominantly had sepsis-AKI and the highest levels of vascular/kidney inflammation (YKL-40, MCP-1) and injury (neutrophil gelatinase-associated lipocalin, KIM-1). AKI subphenotypes 3 and 4 were independently associated with a higher risk of death compared with subphenotype 2 and had adjusted hazard ratios of 2.9 (95% confidence interval, 1.8 to 4.6) and 1.6 (95% confidence interval, 1.01 to 2.6, P = 0.04), respectively. Subphenotype 3 was also independently associated with a three-fold risk of CKD and cardiovascular events. CONCLUSIONS:We discovered four AKI subphenotypes with differing clinical features and biomarker profiles that are associated with longitudinal clinical outcomes.

BACKGROUNDLongitudinal investigations of murine acute kidney injury (AKI) suggest that injury and inflammation may persist long after the initial insult. However, the evolution of these processes and their prognostic values are unknown in patients with AKI.METHODSIn a prospective cohort of 656 participants hospitalized with AKI, we measured 7 urine and 2 plasma biomarkers of kidney injury, inflammation, and tubular health at multiple time points from the diagnosis to 12 months after AKI. We used linear mixed-effect models to estimate biomarker changes over time, and we used Cox proportional hazard regressions to determine their associations with a composite outcome of chronic kidney disease (CKD) incidence and progression. We compared the gene expression kinetics of biomarkers in murine models of repair and atrophy after ischemic reperfusion injury (IRI).RESULTSAfter 4.3 years, 106 and 52 participants developed incident CKD and CKD progression, respectively. Each SD increase in the change of urine KIM-1, MCP-1, and plasma TNFR1 from baseline to 12 months was associated with 2- to 3-fold increased risk for CKD, while the increase in urine uromodulin was associated with 40% reduced risk for CKD. The trajectories of these biological processes were associated with progression to kidney atrophy in mice after IRI.CONCLUSIONSustained tissue injury and inflammation, and slower restoration of tubular health, are associated with higher risk of kidney disease progression. Further investigation into these ongoing biological processes may help researchers understand and prevent the AKI-to-CKD transition.FUNDINGNIH and NIDDK (grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, K01DK120783, and R01DK093771).

RATIONALE & OBJECTIVE/OBJECTIVE:The role of plasma soluble tumor necrosis factor receptor (sTNFR)1 and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown. STUDY DESIGN/METHODS:Prospective cohort. SETTING & PARTICIPANTS/METHODS:Hospital survivors from the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) and AKI Risk in Derby (ARID) with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements. PREDICTORS/METHODS:We measured sTNFR1 and sTNFR2 obtained 3 months post-discharge. OUTCOMES/RESULTS:The associations between biomarkers with longitudinal kidney disease incidence and progression, heart failure and death were evaluated. ANALYTICAL APPROACH/METHODS:Cox proportional hazard models. RESULTS:Among 1474 participants with plasma biomarker measurements, 19% developed kidney disease progression, 14% had later heart failure, and 21% died over a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs per doubling in concentration were 2.9 (2.2-3.9) for sTNFR1 and 1.9 (1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the adjusted HRs per doubling in concentration were 1.9 (1.4-2.5) for sTNFR1 and 1.5 (1.2-2.0) for sTNFR2. For mortality, the adjusted HRs were 3.3 (2.5-4.3) for sTNFR1 and 2.5 (2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar for the magnitude of association between biomarkers and outcomes. LIMITATIONS/CONCLUSIONS:Different biomarker platforms, AKI definitions, limited generalizability to other ethnic groups. CONCLUSION/CONCLUSIONS:Plasma sTNFR1 and sTNFR2 measured 3 months after discharge were independently associated with clinical events, regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

Rationale & Objective: Acute kidney injury (AKI) is a heterogeneous clinical syndrome with varying causes, pathophysiology, and outcomes. We incorporated plasma and urine biomarker measurements to identify AKI subgroups (subphenotypes) more tightly linked to underlying pathophysiology and long-term clinical outcomes. Study Design: Multicenter cohort study. Setting & Participants: 769 hospitalized adults with AKI matched with 769 without AKI, enrolled from December 2009 to February 2015 in the ASSESS-AKI Study. Predictors: 29 clinical, plasma, and urinary biomarker parameters used to identify AKI subphenotypes. Outcome: Composite of major adverse kidney events (MAKE) with a median follow-up period of 4.7 years. Analytical Approach: Latent class analysis (LCA) and k-means clustering were applied to 29 clinical, plasma, and urinary biomarker parameters. Associations between AKI subphenotypes and MAKE were analyzed using Kaplan-Meier curves and Cox proportional hazard models. Results: Among 769 AKI patients both LCA and k-means identified 2 distinct AKI subphenotypes (classes 1 and 2). The long-term risk for MAKE was higher with class 2 (adjusted HR, 1.41 [95% CI, 1.08-1.84]; P = 0.01) compared with class 1, adjusting for demographics, hospital level factors, and KDIGO stage of AKI. The higher risk of MAKE among class 2 was explained by a higher risk of long-term chronic kidney disease progression and dialysis. The top variables that were different between classes 1 and 2 included plasma and urinary biomarkers of inflammation and epithelial cell injury; serum creatinine ranked 20th out of the 29 variables for differentiating classes. Limitations: A replication cohort with simultaneously collected blood and urine sampling in hospitalized adults with AKI and long-term outcomes was unavailable. Conclusions: We identify 2 molecularly distinct AKI subphenotypes with differing risk of long-term outcomes, independent of the current criteria to risk stratify AKI. Future identification of AKI subphenotypes may facilitate linking therapies to underlying pathophysiology to prevent long-term sequalae after AKI.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Contrast-associated AKI may result in higher morbidity and mortality. Intravenous fluid administration remains the mainstay for prevention. There is a lack of consensus on the optimal administration strategy. We studied the association of periprocedure fluid administration with contrast-associated AKI, defined as an increase in serum creatinine of at least 25% or 0.5 mg/dl from baseline at 3-5 days after angiography, and 90-day need for dialysis, death, or a 50% increase in serum creatinine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:We conducted a secondary analysis of 4671 PRESERVE participants who underwent angiographic procedures. Although fluid type was randomized, strategy of administration was at the discretion of the clinician. We divided the study cohort into quartiles by total fluid volume. We performed multivariable logistic regression, adjusting for clinically important covariates. We tested for the interaction between fluid volume and duration of fluid administration, categorized as <6 or ≥6 hours. RESULTS:. The range of fluid administered was 89-882 ml in quartile 1 and 1258-2790 ml in quartile 4. Compared with the highest quartile (quartile 4) of fluid volume, we found a significantly higher risk of the primary outcome in quartile 1 (adjusted odds ratio, 1.58; 95% confidence interval, 1.06 to 2.38) but not in quartiles 2 and 3 compared with quartile 4. There was no difference in the incidence of contrast-associated AKI across the quartiles. The interaction between volume and duration was not significant for any of the outcomes. CONCLUSIONS:We found that administration of a total volume of 1000 ml, starting at least 1 hour before contrast injection and continuing postcontrast for a total of 6 hours, is associated with a similar risk of adverse outcomes as larger volumes of intravenous fluids administered for periods >6 hours. Mean fluid volumes <964 ml may be associated with a higher risk for the primary outcome, although residual confounding cannot be excluded.