Acute Kidney Injury Ascertainment Is Affected by the Use of First Inpatient Versus Outpatient Baseline Serum Creatinine

An important methodological issue concerning acute kidney injury (AKI) definitions1Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO Clinical Practice Guideline for Acute Kidney Injury.Kidney Int Suppl. 2012; 2: 1-138Abstract Full Text Full Text PDF Scopus (2005) Google Scholar is the choice of “baseline” serum creatinine (SCr).2De Rosa S. Samoni S. Ronco C. Creatinine-based definitions: from baseline creatinine to serum creatinine adjustment in intensive care.Crit Care. 2016; 20: 69Crossref PubMed Scopus (59) Google Scholar, 3Siew E.D. Ikizler T.A. Matheny M.E. et al.Estimating baseline kidney function in hospitalized patients with impaired kidney function.Clin J Am Soc Nephrol. 2012; 7: 712-719Crossref PubMed Scopus (175) Google Scholar, 4Siew E.D. Matheny M.E. Ikizler T.A. et al.Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury.Kidney Int. 2010; 77: 536-542Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar The most recent consensus definition proposes a rolling 48-hour window for AKI ascertainment during hospitalization, or the use of a baseline value that is “known or presumed to have occurred in the past 7 days.”1Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO Clinical Practice Guideline for Acute Kidney Injury.Kidney Int Suppl. 2012; 2: 1-138Abstract Full Text Full Text PDF Scopus (2005) Google Scholar However, significant misclassification in assigning AKI status can occur when admission or nadir inpatient SCr (as has been done in a number of studies) is used rather than a preadmission outpatient baseline.4Siew E.D. Matheny M.E. Ikizler T.A. et al.Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury.Kidney Int. 2010; 77: 536-542Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar A well-recognized concern with the use of admission SCr to define baseline kidney function is that it will be higher than a patient’s true baseline if community-acquired AKI is present, and therefore community-acquired AKI will be missed if the admission SCr is used to define baseline. However, animal and human studies have recently shown that creatinine generation can also quickly fall with acute illness, so falsely low readings may result.5Doi K. Yuen P.S. Eisner C. et al.Reduced production of creatinine limits its use as marker of kidney injury in sepsis.J Am Soc Nephrol. 2009; 20: 1217-1221Crossref PubMed Scopus (287) Google Scholar, 6Wilson F.P. Sheehan J.M. Mariani L.H. et al.Creatinine generation is reduced in patients requiring continuous venovenous hemodialysis and independently predicts mortality.Nephrol Dial Transplant. 2012; 27: 4088-4094Crossref PubMed Scopus (33) Google Scholar It is unknown whether changes in creatinine generation affect AKI ascertainment. Therefore, to quantitate variation in first inpatient SCr level and the impact on AKI ascertainment (Figure 1a), we compared preadmission baseline and first inpatient SCr in a large, population-based, hospitalized cohort. We also identified predictors of lower first inpatient SCr. We identified all hospitalized adults without end-stage renal disease at 21 Kaiser Permanente Northern California hospitals between 2006 and 2011 (Supplementary Figure S1); only the first eligible hospitalization per subject was included. Kaiser Permanente Northern California is a large integrated health care delivery system caring for > 4.1 million persons in the San Francisco Bay Area that is highly representative of the statewide population.7Gordon N.P. Characteristics of adult health plan members in the northern California region membership, as estimated from the 2011 Member Health Survey. Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA2013Google Scholar The study was approved by the institutional review boards of the Kaiser Foundation Research Institute and the University of California, San Francisco. Baseline SCr was the most recent outpatient SCr from a maximum of 365 days and a minimum of 7 days preadmission.8Go A.S. Parikh C.R. Ikizler T.A. et al.The Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study: design and methods.BMC Nephrol. 2010; 11: 22Crossref PubMed Scopus (119) Google Scholar We selected this as the gold standard because this definition has been used in prior studies examining the impact of baseline SCr on AKI ascertainment, including the prospective Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study.4Siew E.D. Matheny M.E. Ikizler T.A. et al.Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury.Kidney Int. 2010; 77: 536-542Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 8Go A.S. Parikh C.R. Ikizler T.A. et al.The Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study: design and methods.BMC Nephrol. 2010; 11: 22Crossref PubMed Scopus (119) Google Scholar A peak inpatient SCr ≥ 50% relative, ≥ 0.3 mg/dl absolute increase from the outpatient baseline, or need for acute dialysis defined AKI for this analysis.1Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO Clinical Practice Guideline for Acute Kidney Injury.Kidney Int Suppl. 2012; 2: 1-138Abstract Full Text Full Text PDF Scopus (2005) Google Scholar Covariates included demographics, comorbidities, severity of illness,9Escobar G.J. Greene J.D. Scheirer P. et al.Risk-adjusting hospital inpatient mortality using automated inpatient, outpatient, and laboratory databases.Med Care. 2008; 46: 232-239Crossref PubMed Scopus (227) Google Scholar preadmission estimated glomerular filtration rate (eGFR), and proteinuria. Comorbidities (diabetes, hypertension, cancer, coronary disease, chronic heart failure, prior ischemic stroke) were ascertained for up to 5 years before hospitalization using previously validated methods based on inpatient and ambulatory diagnoses and procedures, laboratory results, and pharmacy databases (codes available upon request).10Go A. Chertow G. Fan D. et al.Chronic kidney disease and risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9021) Google Scholar, 11Smith D.H. Thorp M.L. Gurwitz J.H. et al.Chronic kidney disease and outcomes in heart failure with preserved versus reduced ejection fraction: the Cardiovascular Research Network PRESERVE Study.Circ Cardiovasc Qual Outcomes. 2013; 6: 333-342Crossref PubMed Scopus (91) Google Scholar We identified coronary revascularization, sepsis, and acute heart failure occurring during the index hospitalization using relevant diagnosis and procedure codes. To further describe acute severity of illness, we determined whether patients were admitted to the intensive care unit during their stay and calculated the Laboratory-based Acute Physiology Score (LAPS) and COmorbidity Point Score (COPS), along with a validated predicted mortality score based on automated inpatient, outpatient and laboratory data.9Escobar G.J. Greene J.D. Scheirer P. et al.Risk-adjusting hospital inpatient mortality using automated inpatient, outpatient, and laboratory databases.Med Care. 2008; 46: 232-239Crossref PubMed Scopus (227) Google Scholar Preadmission eGFR (in ml/min per 1.73 m2) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation12Levey A.S. Stevens L.A. Schmid C.H. et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (16087) Google Scholar and baseline SCr information described previously. We ascertained proteinuria based on a urine dipstick result of 1+ or greater (in the absence of a concomitant urinary tract infection).10Go A. Chertow G. Fan D. et al.Chronic kidney disease and risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9021) Google Scholar The first inpatient SCr was expressed as a percentage change compared with baseline SCr. We used multivariable logistic regression to identify predictors of a first inpatient SCr that was < 90% of baseline SCr stratified by AKI status. Analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC). Of 214,802 eligible hospitalizations, 37,827 (17.6%) met our AKI criteria. AKI was associated with a higher prevalence of sepsis (20% vs. 7%), diabetes mellitus (40.3% vs. 26.3%), hypertension (79.5% vs. 65.5%), and chronic kidney disease (51.6% vs. 28.8%) (all P < 0.001) (Supplementary Table S1). Among all patients, 21.7% had a first inpatient SCr that was ≥ 110% above outpatient baseline (Table 1 and Figure 2). Not surprisingly, a greater proportion of patients with AKI (74.6%) experienced this pattern.Table 1Distribution of change between baseline and first inpatient serum creatinine (SCr) concentration, overall and stratified by acute kidney injury (AKI) statusaOverall P value < 0.001.Ratio between first inpatient and outpatient baseline SCrOverall(N = 214,802)AKIbIt should be noted that among those with AKI, a ratio between first inpatient and outpatient baseline SCr > 1.1 may or may not meet criteria for AKI. For example if the baseline SCr is 1.0 mg/dl, 110% of baseline would be 1.1 mg/dl and would not meet criteria for AKI; such an individual might have evolving AKI and a subsequent rise in SCr that meets criteria for AKI. In contrast, if the baseline SCr is 3.1 mg/dl, 110% of baseline would be 3.41 mg/dl, and this individual would meet criteria for AKI, which would be community acquired.(n = 37,827)No AKI(n = 176,975)< 0.7017,573 (8.2)488 (1.3)17,085 (9.7)0.70–0.7932,351 (15.1)1056 (2.8)31,295 (17.7)0.80–0.8947,202 (22.0)1978 (5.3)45,224 (25.6)0.90–0.9940,338 (18.8)2618 (6.9)37,720 (21.3)1.00–1.0930,745 (14.3)3455 (9.1)27,290 (15.4)1.10–1.1915,379 (7.2)3459 (9.1)11,920 (6.7)1.20–1.298876 (4.1)4015 (10.6)4861 (2.7)1.30–1.395119 (2.4)3828 (10.1)1291 (0.7)1.40–1.493472 (1.6)3183 (8.4)289 (0.2)1.50–1.997283 (3.4)7283 (19.3)0 (0.0)≥ 2.006464 (3.0)6464 (17.1)0 (0.0)a Overall P value < 0.001.b It should be noted that among those with AKI, a ratio between first inpatient and outpatient baseline SCr > 1.1 may or may not meet criteria for AKI. For example if the baseline SCr is 1.0 mg/dl, 110% of baseline would be 1.1 mg/dl and would not meet criteria for AKI; such an individual might have evolving AKI and a subsequent rise in SCr that meets criteria for AKI. In contrast, if the baseline SCr is 3.1 mg/dl, 110% of baseline would be 3.41 mg/dl, and this individual would meet criteria for AKI, which would be community acquired. Open table in a new tab In all, 45% of the patients had a first inpatient SCr that was < 90% of the outpatient baseline; 9.4% of those with AKI experienced this pattern. Regardless of AKI status, older age, history of cancer, and intensive care unit admission were associated with a first inpatient SCr that was < 90% of outpatient baseline SCr (Table 2). Patients with diabetes mellitus, hypertension, sepsis, and greater severity of illness (measured by predicted mortality) were less likely to have a low first inpatient SCr, reflecting the fact that many of these patients present with AKI in evolution. It should be noted that several of these factors (e.g., sepsis and acute illness) are associated with acute reductions in creatinine generation, so the severity of AKI may be difficult to ascertain based on changes in SCr alone. In the future, novel biomarkers or real-time measurement of GFR may better define AKI severity.Table 2Correlates of having a first inpatient serum creatinine (SCr) value < 90% of outpatient baselineaMultivariable logistic regression was used to identify predictors of a first inpatient SCr < 90% of baseline and are expressed as odds ratios (95% confidence intervals).CharacteristicAKI(n = 37,827)No AKI(n = 176,975)Age, yr < 45REFREF 45–741.53 (1.28–1.84)1.33 (1.28–1.37) ≥752.06 (1.71–2.50)1.37 (1.32–1.43)Male gender0.95 (0.88–1.02)0.85 (0.83–0.87)Race/ethnicity WhiteREFREF Black/African American1.03 (0.92–1.16)0.88 (0.85–0.91) Asian/Pacific Islander1.12 (1.00–1.26)0.97 (0.94–1.00) Other/unknown199 (0.5)891 (0.5)Medical history Diabetes mellitus0.82 (0.76–0.89)0.93 (0.91–0.95) Hypertension0.90 (0.82–0.99)0.92 (0.90–0.94) Systemic cancer1.26 (1.15–1.37)1.06 (1.04–1.09) Coronary heart disease1.12 (0.97–1.28)1.01 (0.96–1.05) Chronic heart failure0.99 (0.87–1.13)0.91 (0.87–0.96) Ischemic stroke0.92 (0.71–1.19)1.11 (1.03–1.19)During index hospitalization Coronary revascularization1.43 (1.24–1.63)0.84 (0.80–0.88) Sepsis0.88 (0.80–0.97)0.67 (0.65–0.70) Heart failure0.91 (0.78–1.05)0.50 (0.48–0.53)Admitted to intensive care unit2.33 (2.15–2.52)1.26 (1.23–1.29)Predicted Mortality Score category < 0.1%REFREF 0.1 to < 0.5%1.08 (0.87–1.35)0.94 (0.90–0.97) 0.5 to < 2%1.04 (0.85–1.28)0.89 (0.85–0.92) 2 to < 5%0.83 (0.68–1.03)0.84 (0.80–0.87) 5 to < 10%0.61 (0.49–0.76)0.74 (0.70–0.77) 10 to < 15%0.44 (0.34–0.57)0.70 (0.65–0.74) 15 to < 30%0.39 (0.30–0.50)0.70 (0.66–0.75) ≥ 30%0.23 (0.16–0.33)0.54 (0.48–0.61) Unknown0.81 (0.64–1.04)0.80 (0.76–0.84)Prior documented proteinuria0.94 (0.84–1.04)0.87 (0.84–0.90)Outpatient baseline eGFR ≥ 60 ml/min per 1.73 m21.32 (0.81)1.00 (0.39) 45–59 ml/min per 1.73 m21.03 (0.94–1.14)1.38 (1.34–1.42) 30–44 ml/min per 1.73 m21.03 (0.92–1.14)1.52 (1.47–1.57) <30 ml/min per 1.73 m20.87 (0.76–0.99)1.57 (1.49–1.67)eGFR, estimated glomerular filtration rate; REF, reference.Boldface data represent statistically significant associations.a Multivariable logistic regression was used to identify predictors of a first inpatient SCr < 90% of baseline and are expressed as odds ratios (95% confidence intervals). Open table in a new tab eGFR, estimated glomerular filtration rate; REF, reference. Boldface data represent statistically significant associations. Our results have important implications for AKI ascertainment. Of the patients, 45% had a first inpatient SCr that was < 90% of the outpatient baseline. Consequently, using the first inpatient SCr in place of the outpatient baseline may misclassify some individuals as having AKI when no AKI is, in fact, present (as the SCr rises back to the actual baseline) (Figure 1b). In fact, in our study population, 6605 individuals would have met AKI criteria, had the first inpatient SCr been used in place of the outpatient baseline (Figure 3). The inclusion of patients without actual AKI because of this misclassification can bias associations between AKI and true AKI risk factors towards the null. Even among those who met our criteria for AKI, nearly 1 in 12 had a first inpatient SCr that was < 90% of outpatient baseline; here, using an inpatient SCr that is lower than outpatient baseline may lead to misclassification of AKI severity. In contrast, using the outpatient baseline SCr identified 21,864 individuals who were not identified as having AKI using the first inpatient SCr, likely due to the presence of community-acquired AKI. A total of 15,963 individuals were identified as having AKI using either the outpatient baseline or first inpatient SCr. Thus, the overall incidence of AKI was higher when the outpatient baseline SCr was used (37,827 vs. 22,568). We note that, in some populations (i.e., those of older age and with cancer), the first inpatient SCr was more likely to be <90% of preadmission baseline, as might be expected, as these conditions are more likely to be associated with reductions in muscle mass over time. Further studies are needed to better understand whether these differences reflect ongoing malnutrition due to chronic illness, and, if so, how best to estimate baseline SCr in these populations. In clinical practice, careful evaluation of both the outpatient baseline SCr and first inpatient SCr in these populations who are more likely to have a low first inpatient SCr is warranted to help with the clinical ascertainment of AKI. Due to the presence of community-acquired AKI at admission, a significant proportion of patients who met our AKI definition would not have met criteria for AKI had the first inpatient SCr been used as baseline (Figure 3). Study strengths include the large number of patients with outpatient baseline SCr measurements within an integrated health care delivery system, which allowed for analysis of patient-level factors stratified by AKI status, an important determinant of admission SCr. Kaiser Permanente Northern California is highly representative of the local and statewide population, so results are likely more generalizable than those from specialized populations (e.g., the predominantly male Veterans Affairs population). A potential limitation is that we focused on individuals with an available outpatient SCr, so no inferences can be made about how to estimate baseline SCr without outpatient data. In those circumstances, given the importance of baseline SCr for AKI classification4Siew E.D. Matheny M.E. Ikizler T.A. et al.Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury.Kidney Int. 2010; 77: 536-542Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar and given the variation between first inpatient and outpatient baseline SCr that we have shown, clinicians should use all available resources to identify an outpatient baseline SCr. All the authors declared no competing interests. The authors would like to thank members of the ASSESS-AKI Consortium for helpful discussions. This work was supported by research grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): R01 DK101507, U01 DK082223. Contributions: Research idea and study design: KDL, CYH, JY, TCT, ASG; data acquisition and statistical analysis: JY, TCT, ASG; data interpretation: KDL, CYH, JT, TCT, SZ, JDO, ASG; manuscript preparation: KDL and ASG. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. KDL and ASG take responsibility that this study has been reported honestly, accurately, and transparently and that no important aspects of the study have been omitted. Download .docx (.05 MB) Help with docx files Figure S1Flow diagram of all Kaiser Permanente Northern California adult hospitalizations. A total of 214,802 hospitalizations were identified for this analysis, as described. Download .docx (.02 MB) Help with docx files Table S1Baseline characteristics of the overall cohort and by acute kidney injury status.