Preventing disease progression is a vital part of the federal response to kidney disease. Acute kidney injury (AKI) is a common condition among hospitalized patients that is associated with long-term mortality, accelerates kidney disease progression, is a risk factor for cardiovascular disease, and worsens quality of life. The incidence of AKI is growing rapidly and with it, the number of survivors at risk for these outcomes. Developing optimal care strategies for this population will require better understanding of the interim outcomes and processes of care provided to these patients in the post-hospitalization period.
The overarching goal of this proposal is to better characterize the outcomes experienced by AKI survivors and identify modifiable risk factors that may favorably or adversely influence the risk for these outcomes. The objectives of this proposal are: 1) To characterize the long-term patterns of renal recovery and recurrent AKI, determine their association with kidney disease progression, and identify poor outcomes experienced by AKI survivors 2) To identify modifiable risk factors that may impact the risk factors for recurrent AKI, poor recovery, and other poor outcomes among AKI survivors. These findings will improve knowledge of the transition between AKI and future kidney disease, how AKI impacts the delivery of care, inform current clinical decision-making, and inform future clinical studies needed to reduce the poor outcomes of AKI.
We will perform a series of studies with a cohort of patients hospitalized between 2004 and 2012. Adults with and without AKI, defined using changes in serum creatinine in accordance with consensus criteria will be eligible. The assembly of the cohort will leverage the VA Informatics and computing Infrastructure (VINCI), which encompasses a national electronic data warehouse pooling data from all VA hospitals and the VA information Resource Center (VIREC), providing Center for Medicare Services (CMS) data intersected with the electronic medical records of Veterans. The CMS data in VIREC will be linked to VINCI observations to ensure capture of the outcome of end-stage renal disease (ESRD) or dialysis via cross-linkage with the United States Renal Data Systems (USRDS).
Aim #1: Identifying poor intermediate and long-term outcomes associated with AKI and how patterns of recovery may affect long-term outcomes.
We have examined the association between AKI and the following outcomes:
1. Recurrent AKI: We have examined the incidence of recurrent AKI among a retrospective cohort of 11,683 survivors of AKI. Recurrent AKI was defined as a 0.3 mg/dl or 50% increase from a baseline creatinine measure and time to recurrent AKI was examined using Cox Regression. Among 11,683 qualifying AKI hospitalizations, 2954 patients (25%) were hospitalized with recurrent AKI within 12 months of discharge. Median time to recurrent AKI within 12 months was 64 (interquartile range 19-167) days. The mean±SD and median (IQR) number of admissions without recurrent AKI were 0.6±1.1 and 0 (IQR, 0-1), respectively, with a range of 0-13. The total 1-year mortality from the time of discharge was 23%. Patients who experienced recurrent AKI had a higher 1-year mortality (35%) than patients who did not experience recurrent AKI (18%), P<0.001. These findings have been published in the Journal of the American Society of Nephrology 2016; 27(4):1190-2000. PMID: 26264853, PMCID: 4814177.
2.Incident Heart Failure. In a national cohort of 300,868 patients without a previous history of heart failure, we examined the association between AKI and the development of incident heart failure. There were 150,434 matched pairs in the study. Patients with and without AKI during the index hospitalization were well matched, with a median preadmission estimated glomerular filtration rate of 69mL/min/1.73m2. The overall incidence rate of heart failure was 27.8 (95% CI, 19.3-39.9) per 1,000 person-years. The incidence rate was higher in those with compared with those without AKI: 30.8 (95% CI, 21.8-43.5) and 24.9 (95% CI, 16.9-36.5) per 1,000 person-years, respectively. In multivariable models, AKI was associated with 23% increased risk for incident heart failure (HR, 1.23; 95% CI, 1.19-1.27). These findings suggest a link between AKI and cardiovascular outcomes and suggests the need to identify potential mechanisms that explain this association and the identification of modifiable risk factors. These findings were published in the American Journal of Kidney Diseases 2018; Feb;71(2):236-245.
3. To determine and understand patterns of recovery from AKI, we have constructed a cohort of 69,701 patients who survived KDIGO Stage II and III AKI and survived to 90 days following peak hospitalized serum creatinine without experiencing ESRD, death, or recurrent AKI. We have characterized the timing of recovery and are currently examining their association with poor outcomes.
Aim #2: To identify potentially modifiable risk factors that may impact future outcomes of AKI survivors:
1. New-onset or worsening proteinuria during the 12 months following hospitalizations. Patient with and without AKI were matched using Mahalnobis-distance matching with good resulting balance in demographics, comorbidities, antihypertensive use, and severity of illness. The distribution of proteinuria over one year post-discharge in the matched cohort was compared using inverse probability sampling weights. Subgroup analyses were based on diabetes, pre-admission ACEI/ARB use, and AKI severity. Among the 90,614 matched AKI and non-AKI pairs, the median estimated glomerular filtration rate was 62 mL/min/1.73m2. The prevalence of diabetes and hypertension were 48% and 78%, respectively. The odds of having one plus or greater dipstick proteinuria was significantly higher during each month of follow-up in patients with AKI than in patients without AKI (odds ratio range 1.20-1.39). Odds were higher in patients with Stage II or III AKI (odds ratios 1.32-1.81) than in Stage I AKI (odds ratios 1.18-1.32), using non-AKI as the reference group. Results were consistent regardless of diabetes status or baseline ACEI/ARB use. Thus, AKI is a risk factor for incident or worsening proteinuria, suggesting a possible mechanism linking AKI and future CKD. The results were published in Kidney International 2018;93(2):460-469
2. Hypoglycemia. We compared the risk for postdischarge hypoglycemia among hospitalized patients with diabetes who do and do not experience AKI. We identified 65,151 propensity score-matched pairs with and without AKI. The incidence of hypoglycemia was 29.6 (95% CI 28.9-30.4) and 23.5 (95% CI 22.9-24.2) per 100 person-years for patients with and without AKI, respectively. After adjustment, AKI was associated with a 27% increased risk of hypoglycemia (hazard ratio [HR] 1.27 [95% CI 1.22-1.33]). For patients with full recovery, the HR was 1.18 (95% CI 1.12-1.25); for partial recovery, the HR was 1.30 (95% CI 1.23-1.37); and for no recovery, the HR was 1.48 (95% CI 1.36-1.60) compared with patients without AKI. Across all antidiabetes drug regimens, patients with AKI experienced hypoglycemia more frequently than patients without AKI, though the incidence of hypoglycemia was highest among insulin users, followed by glyburide and glipizide users, respectively. These results suggest that patients with diabetes who survive an episode of AKI are at elevated risk for hypoglycemia suggesting the need to identify strategies to reduce this risk, including, but not limited to, careful review of their nutritional status and medication dosage. These findings were published Diabetes Care. 2018 Mar;41(3):503-512
3. We are examining how variations in practice may impact the risk for recurrent AKI, including ongoing how medication exposures may impact adverse outcomes.
The proposal will improve Veterans' care in a number of areas. The incidence for AKI is growing and optimal care has not been defined. This work will identify survivors at highest risk for poor intermediate and long-term outcomes. Findings to date illustrate that survivors of AKI are at risk for a variety of kidney-related outcomes (recurrent AKI, proteinuria) that may also be reasonable targets whose modification may reduce the risk for future kidney function decline suggested in previous studies. In addition, we have identified other clinically relevant outcomes not directly related to the kidney that survivors of AKI are at risk for including cardiovascular (heart failure) and potential adverse drug events (hypoglycemia). These findings suggest the need for a more comprehensive approach to the care of this growing population and the need to develop strategies that may reduce these risks. Future work in this proposal will examine the relationship between different recovery patterns and future outcomes and processes of care associated with poor recovery and recurrent AKI that may be amenable to quality improvement measures or formal clinical testing.
- Hung AM, Siew ED, Wilson OD, Perkins AM, Greevy RA, Horner J, Abdel-Kader K, Parr SK, Roumie CL, Griffin MR, Ikizler TA, Speroff T, Matheny ME. Risk of Hypoglycemia Following Hospital Discharge in Patients With Diabetes and Acute Kidney Injury. Diabetes Care. 2018 Mar 1; 41(3):503-512.
- Bansal N, Matheny ME, Greevy RA, Eden SK, Perkins AM, Parr SK, Fly J, Abdel-Kader K, Himmelfarb J, Hung AM, Speroff T, Ikizler TA, Siew ED. Acute Kidney Injury and Risk of Incident Heart Failure Among US Veterans. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2018 Feb 1; 71(2):236-245.
- Parr SK, Matheny ME, Abdel-Kader K, Greevy RA, Bian A, Fly J, Chen G, Speroff T, Hung AM, Ikizler TA, Siew ED. Acute kidney injury is a risk factor for subsequent proteinuria. Kidney international. 2018 Feb 1; 93(2):460-469.
- Silver SA, Siew ED. Follow-up Care in Acute Kidney Injury: Lost in Transition. Advances in chronic kidney disease. 2017 Jul 1; 24(4):246-252.
- Lipworth L, Abdel-Kader K, Morse J, Stewart TG, Kabagambe EK, Parr SK, Birdwell KA, Matheny ME, Hung AM, Blot WJ, Ikizler TA, Siew ED. High prevalence of non-steroidal anti-inflammatory drug use among acute kidney injury survivors in the southern community cohort study. BMC nephrology. 2016 Nov 24; 17(1):189.
- Parr SK, Siew ED. Delayed Consequences of Acute Kidney Injury. Advances in chronic kidney disease. 2016 May 1; 23(3):186-94.
- Siew ED, Parr SK, Abdel-Kader K, Eden SK, Peterson JF, Bansal N, Hung AM, Fly J, Speroff T, Ikizler TA, Matheny ME. Predictors of Recurrent AKI. Journal of the American Society of Nephrology : JASN. 2016 Apr 1; 27(4):1190-200.
- Brown JR, Rezaee ME, Nichols EL, Marshall EJ, Siew ED, Matheny ME. Incidence and In-Hospital Mortality of Acute Kidney Injury (AKI) and Dialysis-Requiring AKI (AKI-D) After Cardiac Catheterization in the National Inpatient Sample. Journal of the American Heart Association. 2016 Mar 15; 5(3):e002739.
Diagnosis, Treatment - Observational, Prognosis
Decision Support, Guideline Development and Implementation, Healthcare Algorithms, Models of Care, Practice Patterns/Trends