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Cystatin C Predicts Renal Recovery Earlier Than Creatinine Among Patients With Acute Kidney Injury
Accepted Manuscript Cystatin C Predicts Renal Recovery Earlier Than Creatinine Among Patients With Acute Kidney Injury Kamel A. Gharaibeh, MD, Abdurrahman M. Hamadah, MD, Ziad M. El-Zoghby, MD, John C. Lieske, MD, Timothy S. Larson, MD, Nelson Leung, MD PII:
S2468-0249(17)30430-8
DOI:
10.1016/j.ekir.2017.10.012
Reference:
EKIR 253
To appear in:
Kidney International Reports
Received Date: 26 May 2017 Revised Date:
10 October 2017
Accepted Date: 30 October 2017
Please cite this article as: Gharaibeh KA, Hamadah AM, El-Zoghby ZM, Lieske JC, Larson TS, Leung N, Cystatin C Predicts Renal Recovery Earlier Than Creatinine Among Patients With Acute Kidney Injury, Kidney International Reports (2017), doi: 10.1016/j.ekir.2017.10.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Cystatin C Predicts Renal Recovery Earlier Than Creatinine Among
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Patients With Acute Kidney Injury
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Kamel A. Gharaibeh, MD
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Abdurrahman M. Hamadah, MD
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Ziad M. El-Zoghby, MD
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John C. Lieske, MD
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Timothy S. Larson, MD
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Nelson Leung, MD
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Author Affiliations: Division of Nephrology and Hypertension (Drs
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Gharaibeh, Hamadah, El-Zoghby, Lieske, Larson, and Leung), Division of
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Clinical Core Laboratory Services (Drs Lieske and Larson), Department of
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Physiology and Biomedical Engineering (Dr Lieske), and Division of
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Hematology (Dr Leung), Mayo Clinic, Rochester, Minnesota.
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Corresponding Author: Ziad M. El-Zoghby, MD, Division of Nephrology
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and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN 55905
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Email: [email protected]
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Phone: 507-266-1046
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Fax: 507-255-7891
Running title: Cystatin C and Acute Kidney Injury
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Author Contributions
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Kamel A. Gharaibeh, MD — Study design, data collection, and manuscript
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writing
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Abdurrahman M. Hamadah, MD — Study design, data collection, and
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manuscript writing
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Ziad M. El-Zoghby, MD — Study design, manuscript writing, and data
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analysis. Dr. El-Zoghby has had full access to data in the study and final
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responsibility for the decision to submit for publication.
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John C. Lieske, MD—Study design and review of the manuscript
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Timothy S. Larson, MD—Review of the manuscript
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Nelson Leung, MD—Study design and review of the manuscript
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Abstract
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Introduction: Serum cystatin C increases earlier than creatinine during acute
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kidney injury. However, whether cystatin C decreases earlier during
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recovery is unknown. This retrospective study aimed to determine the
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temporal trend between creatinine and cystatin C in acute kidney injury.
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Methods: We identified hospitalized patients with nonoliguric acute kidney
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injury who had serial creatinine and cystatin C values measured between
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May 2015 and May 2016. Demographic and laboratory data, causes of acute
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kidney injury, and relevant comorbidity data were collected through chart
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review.
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Results: For the 63 identified patients, mean (standard deviation) age was
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58.7 (13.9) years; male sex, 62%; white race/ethnicity, 95%. Baseline
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median (range) creatinine was 1.1 (0.5-3.0) mg/dL; 13% were kidney
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transplant recipients and 37% received corticosteroids. Comorbidities
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included malignancy (38%), diabetes mellitus (33%), heart failure (19%),
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and thyroid disorder (16%). The cause of kidney injury was acute tubular
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necrosis in 71%, 61% had acute kidney injury stage III, and 33.3% required
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dialysis. Cystatin C began to decrease before creatinine in 68% of patients: 1
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day earlier, 46%; 2 days earlier, 16%; and 3 days earlier, 6%. In 24% of
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cases, both began decreasing on the same day; in only 8%, cystatin C decreased after creatinine. Overall, cystatin C mean (95% confidence interval) decrease was 0.92 (0.65-1.18) days before creatinine (P<.001).
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Conclusion: In summary, cystatin C decreases before creatinine in most
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hospitalized patients with acute kidney injury. If confirmed in large
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prospective studies, these findings may have important management
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implications, possibly shortening hospital stay and reducing costs.
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Keywords: Acute Kidney Injury; Cystatin C; Creatinine
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Abbreviations
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AKI, acute kidney injury
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CysC, serum cystatin C
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CRRT, continuous renal replacement therapy
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eGFR, estimated glomerular filtration rate
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GFR, glomerular filtration rate
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IQR, interquartile range
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IHD, intermittent hemodialysis
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KeGFR, kinetic estimated glomerular filtration rate
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RRT, renal replacement therapy
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Scr, serum creatinine
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Introduction In acute kidney injury (AKI), sudden decrement in renal function takes place within hours and days, resulting in fluid and electrolyte
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abnormalities that may require hospitalization and renal replacement therapy
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(RRT). The annual incidence of AKI is increasing, especially in the United
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States (1). AKI is common among hospitalized patients, its incidence
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between 2004 and 2012 is reported to be as high as 20%, and it is associated
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with substantially increased morbidity and mortality rates (2). AKI severity
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can range from mild renal dysfunction to severe renal failure that requires
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RRT. A study of the Nationwide Inpatient Sample database reported an
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increased incidence rate of AKI requiring dialysis (3). Renal recovery after
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AKI can occur spontaneously and is defined as improved kidney biomarker
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levels. The thresholds to start and to discontinue RRT for AKI are highly
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variable. Although no clear consensus exists to define renal recovery in
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severe AKI that requires dialysis, the term is generally defined as no further
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need of RRT (4). Renal recovery is an important criterion for hospital
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discharge. A patient is usually discharged when convincing evidence shows
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declining serum creatinine (Scr) concentration.
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Assessment of renal recovery can be difficult, especially for patients
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receiving RRT. The biomarker Scr is commonly used to daily assess kidney function. However, Scr does not accurately reflect a true glomerular filtration rate (GFR) when renal function is not in a steady state, such as during an AKI episode. Cystatin C (CysC) is an endogenous biomarker of renal function
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produced by all nucleated cells at a near-constant rate, independent of
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muscle mass, and is cleared from circulation through glomerular filtration
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without reabsorption or secretion (5). CysC performs equally as Scr as a
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marker of renal function in most AKI cases and outperforms Scr in some
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cases (6). Limited evidence suggests that the concentration of CysC peaks
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earlier than Scr during AKI, and it may detect kidney dysfunction earlier
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than creatinine (7). Less is known about CysC level during the renal
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recovery phase. Predicting recovery of renal function following AKI is a
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highly sought-after issue in the AKI research field. Earlier identification of
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AKI recovery could result in less intensive resource utilization and earlier
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hospital discharge.
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We conducted an observational retrospective study to determine the
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relative time course of Scr and CysC levels of hospitalized patients with
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AKI. We hypothesized that serial measurement of CysC detects kidney
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function recovery before Scr by at least 24 hours in 30% of AKI patients.
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Methods
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Study Population
The study was approved by the Mayo Clinic Institutional Review
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Board. Using an institution wide clinical database, we identified all adult
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patients with AKI at Mayo Clinic in Rochester, Minnesota, between May 1,
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2015, and May 31, 2016, who had serial Scr and CysC values (at least 3 consecutives) measured during their hospitalizations. In this interval, CysC was measured with the routine laboratory tests as part of clinical care in
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nonoliguric patients (defined as urine output >400 mL/day) who had AKI
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and regardless of the AKI stage or the patient location (medical and surgical
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intensive care unit and non-intensive care unit). We excluded patients who
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were oliguric because the kidney function is not expected to recover during
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the time they were still oliguric. We also excluded patients who did not have
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at least 2 serial CysC test results available. AKI was defined on the basis of
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Acute Kidney Injury Network criteria (8). Baseline demographic data (age,
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race, and sex), body mass index, smoking status, other significant
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comorbidities (ie, heart failure, chronic kidney disease, hypertension,
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diabetes mellitus, thyroid disorder, history of kidney transplant, active
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malignancy, and active infection), corticosteroid use, and diuretics use were
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collected by review of health records. We also collected the cause of AKI,
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need for RRT, baseline Scr, eGFR using the Chronic Kidney Disease
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Epidemiology Collaboration equation, serial Scr and CysC, daily urine
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output, and the cause and duration of hospitalization.
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Statistical Analysis
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Continuous variables were summarized by mean and (SD) when
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normally distributed and as median (IQR) when skewed. Group comparisons
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for continuous variables were done with t test or Wilcoxon rank sum test for
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normally and nonnormally distributed data, respectively. Categorical
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variables were summarized by count and percentage, and groups were
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compared using the χ2 test. We then performed an exploratory univariate
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logistic regression analysis to determine variables associated with a decrease in serum CysC that preceded a decrease in serum creatinine. The dependant outcome was defined as a decline in the serum level of CysC that was at
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least 1 day earlier than a decrease in serum level of creatinine. The
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independent variables included were based on their associations with CysC
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based on prior studies and included age, sex, cause of AKI (acute tubular
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necrosis vs non–acute tubular necrosis), AKI stage, body mass index,
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diabetes mellitus, heart failure, infection, hypothyroidism, malignancy, and
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corticosteroid use (9, 10). All analyses were performed using JMP Pro
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software version 10.0. A p-value < 0.05 was considered statistically
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significant.
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Results
The study included 63 patients. Their clinical characteristics are
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summarized in Table 1. Mean (SD) age was 58.7 (13.9) years, 62% of the
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patients were men, and 95% were white. Baseline median (range) Scr before
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AKI was 1.1 (0.5-3.0) mg/dL; peak median (interquartile range [IQR]) Scr
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before recovery was 3.6 (2.8-5.2) mg/dL (range, 1.4-9.1 mg/dL). At
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discharge, Scr was 1.9 (1.4-2.9) mg/dL (range, 0.8-9.0 mg/dL). None of
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these patients were receiving dialysis at hospital discharge. Median (range)
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urine output was 1,950 (525-5,000) mL/day.
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Severity and Causes of AKI
The majority of patients had severe AKI; 38 (61.3%) had stage III
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AKI based on the Acute Kidney Injury Network classification (8) and 21
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(33.3%) required RRT (3 underwent only continuous renal replacement
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therapy (CRRT) , 10 underwent intermittent hemodialysis (IHD) only and 8 underwent CRRT followed by IHD) . Eighteen patients (29%) had stage II AKI and 6 (10%) had stage I AKI. The most common cause of AKI was
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acute tubular injury (n=45, 71%) followed by prerenal AKI (n=9, 14%)
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(Table 2).
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Renal Recovery Based on Serum CysC and Scr Serum CysC began to decrease before Scr for 43 patients (68%), on the same day for 15 (24%), and after Scr for 5 (8%) (Figure 1). Specifically,
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serum CysC declined 1 day earlier than Scr for 29 patients (46%), 2 days
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earlier for 10 (16%), and 3 days earlier for 4 (6%). Serum CysC declined 1
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and 2 days after Scr in 4 and 1 patient, respectively. Overall, the mean (95%
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CI) decrease in CysC was 0.92 (0.65-1.18) days before Scr (P<.001) and
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indicated recovery from AKI before or at the same time as Scr in 92% of
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patients. Figure 2 illustrates 3 examples of serial CysC and Scr in which
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serum CysC declined before, on the same day as, and after Scr. Of note,
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among the 21 patients who underwent RRT, Cys C began to decrease before
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Scr in all but 3 who received IHD alone.
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Exploratory Analysis
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The logistic univariate analyses did not suggest an association between patient characteristics (ie, age, sex, acute tubular necrosis vs non–
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acute tubular necrosis, AKI stage, body mass index, diabetes mellitus, heart
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failure, infection, hypothyroidism, malignancy, and corticosteroid use) and
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the timing of CysC decrease compared with Scr decrease, except for a lower
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baseline estimated GFR (eGFR). Indeed, CysC was more likely to decrease before Scr for patients with a lower baseline eGFR (beta estimate, −0.35 per 15 mL/min increment in eGFR; 95% CI, −0.71 to −0.04; P=.04).
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Discussion Creatinine is derived from the metabolism of creatine in skeletal muscle and from dietary meat intake, which explains the variations in Scr
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level observed among different age-groups and geographic, ethnic, and
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racial groups. Creatinine is freely filtered across the glomerulus and is
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neither reabsorbed nor metabolized by the kidney. Creatinine level rises and
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it accumulates when the GFR suddenly decreases (11). The published GFR
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formulas can only be used to calculate eGFR when kidney function is stable
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(12). These formulas do not accurately calculate eGFR when Scr is
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increasing or decreasing. For example, early in the course of AKI, GFR is
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significantly reduced, but there has not been enough time for creatinine to
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accumulate. Therefore, Scr does not reflect the degree of renal dysfunction,
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and eGFR formulas overestimate the real GFR. This effect is also true in the
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early phase of AKI recovery, when Scr level stays high initially and does not
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reflect GFR accurately. Hence, eGFR formulas underestimate the real GFR.
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Use of Scr to estimate GFR has multiple limiting factors. These include
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variations in creatinine production, tubular secretion, and extrarenal
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creatinine excretion and the issues associated with creatinine measurement
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(11).
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Given these limitations with Scr, serum CysC has been analyzed to
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more precisely calculate GFR. Serum CysC level may correlate better with
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GFR than Scr level (13). Multiple studies identified serum CysC as a more
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accurate marker for mild reductions in kidney function than Scr alone (14). Combining Scr and CysC into a single equation provides a better estimate of GFR than equations that use either creatinine or CysC alone (15, 16). Chen proposed a simple formula to estimate GFR in the clinical
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setting of nonsteady renal function called kinetic eGFR (KeGFR)(17). The
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KeGFR formula requires the initial creatinine, creatinine production rate, the
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difference between consecutive plasma creatinine over a specified time, and
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volume of distribution. Although KeGFR calculations were developed early
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(since 1972), they are not widely used or taught (18). The KeGFR has been
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simplified recently for use at the bedside in the assessment of AKI recovery.
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This approach to characterize clearance is adaptable to alternative circulating
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filtration biomarkers, including serum CysC (17). Serum CysC is only
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distributed in extracellular fluid, not in total body water (19). It has a smaller
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distribution volume than Scr (almost one-third), and therefore it approaches
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steady state 3 times faster than Scr after GFR is altered, which reflects a
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more cohesive relationship between real GFR (kinetic) and eGFR (20).
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However, like creatinine based equation, estimated GFR based on the
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cystatin C is difficult to interpret in unstable conditions in which there is an
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acute change in GFR (21).
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The present study compared the temporal trend of serum CysC and Scr in nonoliguric patients with AKI. It found that serum CysC indicated
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renal recovery by at least 1 day earlier than Scr in 68% of patients and
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performed similarly to or better than Scr in 92% of the study population. CysC is a useful discovery marker of AKI and may detect AKI 1 or 2
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days earlier than Scr (7, 22). The literature that evaluates CysC in renal
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recovery is spare. Hall et al. concluded from their research that CysC
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performed better than Scr in predicting early graft function after deceaseddonor kidney transplant (6). Our study is one of the first to investigate CysC as a potential biomarker for renal recovery in humans. In our study, CysC
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failed to indicate renal recovery before Scr for only 5 patients (8%). On
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review of these 5 patients, we hypothesized that for 3 patients, several
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reasons may explain this CysC failure. One patient was receiving
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chemotherapy and may have internally released CysC from the destroyed
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nucleated cells. Another patient had evidence of bone marrow engraftment,
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resulting in rapid increase in the nucleated cells, with possible release of
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CysC in the serum. The third patient had bilateral ureteral obstruction, and
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severe pyelonephritis eventually developed, which could have resulted in
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slower CysC metabolism and clearance by the damaged renal tubular cells.
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We believe that the use of CysC holds considerable promise in the monitoring and management of AKI in the hospital, compared with the
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current standard of care using Scr. The use of CysC affected the care of
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several patients in this study, which led to a shorter hospital stay, fewer
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dialysis sessions, and avoidance of unnecessary kidney biopsies for some
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patients (Table 3). Figure 3 illustrates the case of a patient who could have
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been discharged from the hospital earlier on the basis of a serum CysC trend
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that indicated kidney function recovery 2 days before Scr. However, this
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patient had other medical issues that required further inpatient care.
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While not routinely used in clinical practice even among nephrologists, we computed serial kinetic eGFR and compared it to CysC.
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Renal function recovery was predicted earlier, at the same time and later
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with KeGFR in 24%, 52% and 24% of the patients respectively (data not
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shown). Of note, 4 of the 63 patients were excluded from the calculation
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because baseline creatinine was not available. Based on this data, kinetic eGFR appears to provide additional information to CysC however it is cumbersome to use by busy clinicians and requires calculation and data
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input by the clinician on a day to day basis to assess the eGFR trajectory. Of
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interest, compared to serum creatinine, KeGFR predicted kidney function
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recovery earlier, the same day and later in 58%, 37% and 5%, respectively.
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The present study reports a single-center experience and has several limitations. Most of our patients were white, which makes the results
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difficult to generalize to different populations. Its small sample size did not
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allow us to perform multivariate analyses to evaluate factors that may be
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associated with a better or worse performance of CysC, such as various
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patient characteristics (eg, native kidneys vs kidney allografts). In addition,
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most patients in this study had severe AKI (stage III), and many required
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RRT. However, this population does not represent the majority of
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hospitalized patients with AKI. Lastly, CysC is easily obtainable at our
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center as part of routine clinical practice, but this option may not be
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available in most community hospitals to make timely clinical decisions. In
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addition, Cystatin C is more expensive than serum creatinine but the cost is
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less than or equivalent to the cost of other commonly ordered tests such as
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C-reactive protein, parathyroid hormone, 25-hydroxyvitamin D and
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Troponin T (23). This extra cost is easily offset by avoiding an extra dialysis
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treatment or shortening the length of hospitalization.
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In conclusion, the findings in this study suggest that CysC decreases earlier that Scr and thus is an earlier biomarker of AKI recovery in
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hospitalized patients (68%), with only 8% of patients showing delayed improvement of CysC compared with Scr. If confirmed by large prospective studies, these findings may have important clinical implications for
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managing AKI, with potential for shortened hospital stay and reduced
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resource utilization and costs.
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Disclosure
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The authors declare no conflicts of interest related to this publication.
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This work was presented in part at the Annual Meeting of the American
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Society of Nephrology on November 17, 2016 in Chicago, Illinoi, USA.
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Acknowledgements
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This publication was supported by Grant Number UL1 TR000135 from the
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National Center for Advancing Translational Sciences (NCATS). Its
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contents are solely the responsibility of the authors and do not necessarily
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represent the official views of the NIH.
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We thank the scientific publication staff at Mayo Clinic for editorial
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assistance.
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20.
Endre ZH, Pickering JW, Walker RJ. Clearance and beyond: the complementary
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roles of GFR measurement and injury biomarkers in acute kidney injury (AKI). Am
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J Physiol Renal Physiol. 2011;301(4):F697-707. 21.
Delanaye P, Cavalier E, Morel J, Mehdi M, Maillard N, Claisse G, et al. Detection
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of decreased glomerular filtration rate in intensive care units: serum cystatin C
389
versusserum creatinine. BMC Nephrology. 2014;15(1):9.
390
22.
Zhang Z, Lu B, Sheng X, Jin N. Cystatin C in Prediction of Acute Kidney Injury: A Systemic Review and Meta-analysis. American Journal of Kidney Diseases.
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2011;58(3):356-65.
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23.
Shlipak MG, Mattes MD, Peralta CA. Update on cystatin C: incorporation into clinical practice. Am J Kidney Dis. 2013;62(3):595-603.
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Table 1 - Characteristics of the 63 Study Patients Valuea
Variable
58.7 (13.9)
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Age, mean (SD), y Male sex
39 (61.9)
White race/ethnicity
60 (95)
Smoker or ex-smoker
29 (46)
BMI, median (IQR), kg/m2
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27.8 (25-35.5)
mL/min/1.73m2 Diabetes mellitus Heart failure Hypertension
Infection Hypothyroidism Malignancy
21 (33) 12 (19) 33 (52) 23 (37) 34 (54)
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Corticosteroids use
70 (27.4) (19-138)
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Baseline eGFR, mean (SD) (range),
10 (16) 24 (38) 8 (13)
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Kidney transplant
Serum creatinine, median (IQR), mg/dL
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1.1 (0.9-1.3)
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Baseline Peak
3.6 (2.8-5.2)
At discharge
1.9 (1.4-2.9)
Abbreviations: BMI, body mass index; eGFR, estimated glomerular
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filtration rate based on the Chronic Kidney Disease Epidemiology
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Collaboration equation; IQR, interquartile range.
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a
Values are presented as number and percentage of patients unless
specified otherwise.
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Table 2 - Causes of Acute Kidney Injury Among the 63 Patients
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Patients, No. (%)
Acute tubular necrosis
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Cause
45 (71.4)
Prerenal disease (including CRS and HRS) Contrast medium nephropathy
9 (14.3) 3 (4.8)
1 (1.6)
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Obstruction
Pigment nephropathy Cast nephropathy Acute interstitial nephritis Unknown
1 (1.6)
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1 (1.6) 1 (1.6) 1 (1.6)
1 (1.6)
Abbreviations: CRS, cardiorenal syndrome; HRS, hepatorenal
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syndrome.
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Table 3 - Clinical Implications of Use of Serum Cystatin C Instead of Serum
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Creatinine to Monitor Renal Recovery After Acute Kidney Injury
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Clinical Decision
Patients, No. (%)
Dialysis avoided
15 (24)
Drug dose more appropriate
10 (16) 6 (10)
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Kidney biopsy avoided
Earlier hospital discharge 413 414
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4 (6)
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Legends
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Figure 1 - Percentage of Patients in Whom Serum CysC Started to Decrease
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Before, the Same Day as, or After Scr. CysC indicates cystatin C; D-3, CysC
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peaked 3 days before Scr; D-2, CysC peaked 2 days before Scr; D-1, CysC
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peaked 1 day before Scr;D0, CysC peaked on the same day as Scr; D+1,
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CysC peaked 1 day after Scr; D+2, CysC peaked 2 days after Scr; Scr, serum
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creatinine.
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Figure 2 - Examples of Patients With Various Temporal Trends Between
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Serum CysC and Scr. Each Scr value (mg/dL) is represented as a red dot (as
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a triangle for Scr peak) and each serum CysC (mg/L) as a blue rectangle (as
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a triangle for CysC peak). CysC indicates cystatin C; Scr, serum creatinine.
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Figure 3 - Temporal Evolution of Serum CysC and Scr After an Acute
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Kidney Injury Episode of a Patient Hospitalized for Resection of Total Hip
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Arthroplasty. Serum CysC (mg/L) started to decrease 2 days earlier than Scr
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(mg/dL) (vertical solid line and dashed line, respectively). Assuming no
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other reason to keep the patient in the hospital besides awaiting kidney
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function recovery, the patient could be discharged 2 days earlier on the basis
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of decrease in serum CysC (vertical blue line) rather than Scr (vertical green line). CysC indicates cystatin C; Scr, serum creatinine.
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S2468-0249(17)30430-8
DOI:
10.1016/j.ekir.2017.10.012
Reference:
EKIR 253
To appear in:
Kidney International Reports
Received Date: 26 May 2017 Revised Date:
10 October 2017
Accepted Date: 30 October 2017
Please cite this article as: Gharaibeh KA, Hamadah AM, El-Zoghby ZM, Lieske JC, Larson TS, Leung N, Cystatin C Predicts Renal Recovery Earlier Than Creatinine Among Patients With Acute Kidney Injury, Kidney International Reports (2017), doi: 10.1016/j.ekir.2017.10.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Cystatin C Predicts Renal Recovery Earlier Than Creatinine Among
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Patients With Acute Kidney Injury
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Kamel A. Gharaibeh, MD
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Abdurrahman M. Hamadah, MD
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Ziad M. El-Zoghby, MD
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John C. Lieske, MD
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Timothy S. Larson, MD
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Nelson Leung, MD
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Author Affiliations: Division of Nephrology and Hypertension (Drs
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Gharaibeh, Hamadah, El-Zoghby, Lieske, Larson, and Leung), Division of
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Clinical Core Laboratory Services (Drs Lieske and Larson), Department of
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Physiology and Biomedical Engineering (Dr Lieske), and Division of
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Hematology (Dr Leung), Mayo Clinic, Rochester, Minnesota.
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Corresponding Author: Ziad M. El-Zoghby, MD, Division of Nephrology
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and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN 55905
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Email: [email protected]
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Phone: 507-266-1046
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Fax: 507-255-7891
Running title: Cystatin C and Acute Kidney Injury
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Author Contributions
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Kamel A. Gharaibeh, MD — Study design, data collection, and manuscript
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writing
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Abdurrahman M. Hamadah, MD — Study design, data collection, and
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manuscript writing
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Ziad M. El-Zoghby, MD — Study design, manuscript writing, and data
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analysis. Dr. El-Zoghby has had full access to data in the study and final
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responsibility for the decision to submit for publication.
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John C. Lieske, MD—Study design and review of the manuscript
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Timothy S. Larson, MD—Review of the manuscript
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Nelson Leung, MD—Study design and review of the manuscript
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Abstract
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Introduction: Serum cystatin C increases earlier than creatinine during acute
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kidney injury. However, whether cystatin C decreases earlier during
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recovery is unknown. This retrospective study aimed to determine the
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temporal trend between creatinine and cystatin C in acute kidney injury.
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Methods: We identified hospitalized patients with nonoliguric acute kidney
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injury who had serial creatinine and cystatin C values measured between
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May 2015 and May 2016. Demographic and laboratory data, causes of acute
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kidney injury, and relevant comorbidity data were collected through chart
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review.
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Results: For the 63 identified patients, mean (standard deviation) age was
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58.7 (13.9) years; male sex, 62%; white race/ethnicity, 95%. Baseline
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median (range) creatinine was 1.1 (0.5-3.0) mg/dL; 13% were kidney
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transplant recipients and 37% received corticosteroids. Comorbidities
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included malignancy (38%), diabetes mellitus (33%), heart failure (19%),
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and thyroid disorder (16%). The cause of kidney injury was acute tubular
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necrosis in 71%, 61% had acute kidney injury stage III, and 33.3% required
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dialysis. Cystatin C began to decrease before creatinine in 68% of patients: 1
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day earlier, 46%; 2 days earlier, 16%; and 3 days earlier, 6%. In 24% of
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cases, both began decreasing on the same day; in only 8%, cystatin C decreased after creatinine. Overall, cystatin C mean (95% confidence interval) decrease was 0.92 (0.65-1.18) days before creatinine (P<.001).
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Conclusion: In summary, cystatin C decreases before creatinine in most
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hospitalized patients with acute kidney injury. If confirmed in large
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prospective studies, these findings may have important management
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implications, possibly shortening hospital stay and reducing costs.
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Keywords: Acute Kidney Injury; Cystatin C; Creatinine
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Abbreviations
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AKI, acute kidney injury
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CysC, serum cystatin C
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CRRT, continuous renal replacement therapy
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eGFR, estimated glomerular filtration rate
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GFR, glomerular filtration rate
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IQR, interquartile range
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IHD, intermittent hemodialysis
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KeGFR, kinetic estimated glomerular filtration rate
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RRT, renal replacement therapy
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Scr, serum creatinine
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81 82
Introduction In acute kidney injury (AKI), sudden decrement in renal function takes place within hours and days, resulting in fluid and electrolyte
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abnormalities that may require hospitalization and renal replacement therapy
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(RRT). The annual incidence of AKI is increasing, especially in the United
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States (1). AKI is common among hospitalized patients, its incidence
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between 2004 and 2012 is reported to be as high as 20%, and it is associated
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with substantially increased morbidity and mortality rates (2). AKI severity
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can range from mild renal dysfunction to severe renal failure that requires
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RRT. A study of the Nationwide Inpatient Sample database reported an
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increased incidence rate of AKI requiring dialysis (3). Renal recovery after
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AKI can occur spontaneously and is defined as improved kidney biomarker
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levels. The thresholds to start and to discontinue RRT for AKI are highly
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variable. Although no clear consensus exists to define renal recovery in
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severe AKI that requires dialysis, the term is generally defined as no further
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need of RRT (4). Renal recovery is an important criterion for hospital
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discharge. A patient is usually discharged when convincing evidence shows
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declining serum creatinine (Scr) concentration.
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Assessment of renal recovery can be difficult, especially for patients
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receiving RRT. The biomarker Scr is commonly used to daily assess kidney function. However, Scr does not accurately reflect a true glomerular filtration rate (GFR) when renal function is not in a steady state, such as during an AKI episode. Cystatin C (CysC) is an endogenous biomarker of renal function
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produced by all nucleated cells at a near-constant rate, independent of
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muscle mass, and is cleared from circulation through glomerular filtration
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without reabsorption or secretion (5). CysC performs equally as Scr as a
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marker of renal function in most AKI cases and outperforms Scr in some
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cases (6). Limited evidence suggests that the concentration of CysC peaks
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earlier than Scr during AKI, and it may detect kidney dysfunction earlier
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than creatinine (7). Less is known about CysC level during the renal
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recovery phase. Predicting recovery of renal function following AKI is a
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highly sought-after issue in the AKI research field. Earlier identification of
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AKI recovery could result in less intensive resource utilization and earlier
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hospital discharge.
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We conducted an observational retrospective study to determine the
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relative time course of Scr and CysC levels of hospitalized patients with
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AKI. We hypothesized that serial measurement of CysC detects kidney
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function recovery before Scr by at least 24 hours in 30% of AKI patients.
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Methods
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Study Population
The study was approved by the Mayo Clinic Institutional Review
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Board. Using an institution wide clinical database, we identified all adult
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patients with AKI at Mayo Clinic in Rochester, Minnesota, between May 1,
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2015, and May 31, 2016, who had serial Scr and CysC values (at least 3 consecutives) measured during their hospitalizations. In this interval, CysC was measured with the routine laboratory tests as part of clinical care in
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nonoliguric patients (defined as urine output >400 mL/day) who had AKI
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and regardless of the AKI stage or the patient location (medical and surgical
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intensive care unit and non-intensive care unit). We excluded patients who
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were oliguric because the kidney function is not expected to recover during
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the time they were still oliguric. We also excluded patients who did not have
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at least 2 serial CysC test results available. AKI was defined on the basis of
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Acute Kidney Injury Network criteria (8). Baseline demographic data (age,
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race, and sex), body mass index, smoking status, other significant
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comorbidities (ie, heart failure, chronic kidney disease, hypertension,
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diabetes mellitus, thyroid disorder, history of kidney transplant, active
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malignancy, and active infection), corticosteroid use, and diuretics use were
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collected by review of health records. We also collected the cause of AKI,
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need for RRT, baseline Scr, eGFR using the Chronic Kidney Disease
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Epidemiology Collaboration equation, serial Scr and CysC, daily urine
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output, and the cause and duration of hospitalization.
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Statistical Analysis
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Continuous variables were summarized by mean and (SD) when
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normally distributed and as median (IQR) when skewed. Group comparisons
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for continuous variables were done with t test or Wilcoxon rank sum test for
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normally and nonnormally distributed data, respectively. Categorical
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variables were summarized by count and percentage, and groups were
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compared using the χ2 test. We then performed an exploratory univariate
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logistic regression analysis to determine variables associated with a decrease in serum CysC that preceded a decrease in serum creatinine. The dependant outcome was defined as a decline in the serum level of CysC that was at
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least 1 day earlier than a decrease in serum level of creatinine. The
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independent variables included were based on their associations with CysC
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based on prior studies and included age, sex, cause of AKI (acute tubular
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necrosis vs non–acute tubular necrosis), AKI stage, body mass index,
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diabetes mellitus, heart failure, infection, hypothyroidism, malignancy, and
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corticosteroid use (9, 10). All analyses were performed using JMP Pro
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software version 10.0. A p-value < 0.05 was considered statistically
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significant.
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Results
The study included 63 patients. Their clinical characteristics are
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summarized in Table 1. Mean (SD) age was 58.7 (13.9) years, 62% of the
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patients were men, and 95% were white. Baseline median (range) Scr before
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AKI was 1.1 (0.5-3.0) mg/dL; peak median (interquartile range [IQR]) Scr
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before recovery was 3.6 (2.8-5.2) mg/dL (range, 1.4-9.1 mg/dL). At
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discharge, Scr was 1.9 (1.4-2.9) mg/dL (range, 0.8-9.0 mg/dL). None of
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these patients were receiving dialysis at hospital discharge. Median (range)
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urine output was 1,950 (525-5,000) mL/day.
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Severity and Causes of AKI
The majority of patients had severe AKI; 38 (61.3%) had stage III
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AKI based on the Acute Kidney Injury Network classification (8) and 21
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(33.3%) required RRT (3 underwent only continuous renal replacement
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therapy (CRRT) , 10 underwent intermittent hemodialysis (IHD) only and 8 underwent CRRT followed by IHD) . Eighteen patients (29%) had stage II AKI and 6 (10%) had stage I AKI. The most common cause of AKI was
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acute tubular injury (n=45, 71%) followed by prerenal AKI (n=9, 14%)
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(Table 2).
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Renal Recovery Based on Serum CysC and Scr Serum CysC began to decrease before Scr for 43 patients (68%), on the same day for 15 (24%), and after Scr for 5 (8%) (Figure 1). Specifically,
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serum CysC declined 1 day earlier than Scr for 29 patients (46%), 2 days
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earlier for 10 (16%), and 3 days earlier for 4 (6%). Serum CysC declined 1
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and 2 days after Scr in 4 and 1 patient, respectively. Overall, the mean (95%
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CI) decrease in CysC was 0.92 (0.65-1.18) days before Scr (P<.001) and
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indicated recovery from AKI before or at the same time as Scr in 92% of
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patients. Figure 2 illustrates 3 examples of serial CysC and Scr in which
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serum CysC declined before, on the same day as, and after Scr. Of note,
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among the 21 patients who underwent RRT, Cys C began to decrease before
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Scr in all but 3 who received IHD alone.
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Exploratory Analysis
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The logistic univariate analyses did not suggest an association between patient characteristics (ie, age, sex, acute tubular necrosis vs non–
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acute tubular necrosis, AKI stage, body mass index, diabetes mellitus, heart
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failure, infection, hypothyroidism, malignancy, and corticosteroid use) and
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the timing of CysC decrease compared with Scr decrease, except for a lower
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baseline estimated GFR (eGFR). Indeed, CysC was more likely to decrease before Scr for patients with a lower baseline eGFR (beta estimate, −0.35 per 15 mL/min increment in eGFR; 95% CI, −0.71 to −0.04; P=.04).
206 207 208 209
Discussion Creatinine is derived from the metabolism of creatine in skeletal muscle and from dietary meat intake, which explains the variations in Scr
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level observed among different age-groups and geographic, ethnic, and
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racial groups. Creatinine is freely filtered across the glomerulus and is
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neither reabsorbed nor metabolized by the kidney. Creatinine level rises and
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it accumulates when the GFR suddenly decreases (11). The published GFR
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formulas can only be used to calculate eGFR when kidney function is stable
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(12). These formulas do not accurately calculate eGFR when Scr is
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increasing or decreasing. For example, early in the course of AKI, GFR is
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significantly reduced, but there has not been enough time for creatinine to
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accumulate. Therefore, Scr does not reflect the degree of renal dysfunction,
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and eGFR formulas overestimate the real GFR. This effect is also true in the
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early phase of AKI recovery, when Scr level stays high initially and does not
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reflect GFR accurately. Hence, eGFR formulas underestimate the real GFR.
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Use of Scr to estimate GFR has multiple limiting factors. These include
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variations in creatinine production, tubular secretion, and extrarenal
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creatinine excretion and the issues associated with creatinine measurement
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(11).
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more precisely calculate GFR. Serum CysC level may correlate better with
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GFR than Scr level (13). Multiple studies identified serum CysC as a more
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accurate marker for mild reductions in kidney function than Scr alone (14). Combining Scr and CysC into a single equation provides a better estimate of GFR than equations that use either creatinine or CysC alone (15, 16). Chen proposed a simple formula to estimate GFR in the clinical
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setting of nonsteady renal function called kinetic eGFR (KeGFR)(17). The
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KeGFR formula requires the initial creatinine, creatinine production rate, the
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difference between consecutive plasma creatinine over a specified time, and
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volume of distribution. Although KeGFR calculations were developed early
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(since 1972), they are not widely used or taught (18). The KeGFR has been
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simplified recently for use at the bedside in the assessment of AKI recovery.
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This approach to characterize clearance is adaptable to alternative circulating
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filtration biomarkers, including serum CysC (17). Serum CysC is only
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distributed in extracellular fluid, not in total body water (19). It has a smaller
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distribution volume than Scr (almost one-third), and therefore it approaches
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steady state 3 times faster than Scr after GFR is altered, which reflects a
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more cohesive relationship between real GFR (kinetic) and eGFR (20).
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However, like creatinine based equation, estimated GFR based on the
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cystatin C is difficult to interpret in unstable conditions in which there is an
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acute change in GFR (21).
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The present study compared the temporal trend of serum CysC and Scr in nonoliguric patients with AKI. It found that serum CysC indicated
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renal recovery by at least 1 day earlier than Scr in 68% of patients and
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performed similarly to or better than Scr in 92% of the study population. CysC is a useful discovery marker of AKI and may detect AKI 1 or 2
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days earlier than Scr (7, 22). The literature that evaluates CysC in renal
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recovery is spare. Hall et al. concluded from their research that CysC
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performed better than Scr in predicting early graft function after deceaseddonor kidney transplant (6). Our study is one of the first to investigate CysC as a potential biomarker for renal recovery in humans. In our study, CysC
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failed to indicate renal recovery before Scr for only 5 patients (8%). On
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review of these 5 patients, we hypothesized that for 3 patients, several
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reasons may explain this CysC failure. One patient was receiving
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chemotherapy and may have internally released CysC from the destroyed
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nucleated cells. Another patient had evidence of bone marrow engraftment,
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resulting in rapid increase in the nucleated cells, with possible release of
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CysC in the serum. The third patient had bilateral ureteral obstruction, and
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severe pyelonephritis eventually developed, which could have resulted in
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slower CysC metabolism and clearance by the damaged renal tubular cells.
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We believe that the use of CysC holds considerable promise in the monitoring and management of AKI in the hospital, compared with the
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current standard of care using Scr. The use of CysC affected the care of
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several patients in this study, which led to a shorter hospital stay, fewer
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dialysis sessions, and avoidance of unnecessary kidney biopsies for some
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patients (Table 3). Figure 3 illustrates the case of a patient who could have
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been discharged from the hospital earlier on the basis of a serum CysC trend
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that indicated kidney function recovery 2 days before Scr. However, this
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patient had other medical issues that required further inpatient care.
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While not routinely used in clinical practice even among nephrologists, we computed serial kinetic eGFR and compared it to CysC.
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Renal function recovery was predicted earlier, at the same time and later
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with KeGFR in 24%, 52% and 24% of the patients respectively (data not
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shown). Of note, 4 of the 63 patients were excluded from the calculation
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because baseline creatinine was not available. Based on this data, kinetic eGFR appears to provide additional information to CysC however it is cumbersome to use by busy clinicians and requires calculation and data
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input by the clinician on a day to day basis to assess the eGFR trajectory. Of
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interest, compared to serum creatinine, KeGFR predicted kidney function
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recovery earlier, the same day and later in 58%, 37% and 5%, respectively.
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The present study reports a single-center experience and has several limitations. Most of our patients were white, which makes the results
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difficult to generalize to different populations. Its small sample size did not
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allow us to perform multivariate analyses to evaluate factors that may be
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associated with a better or worse performance of CysC, such as various
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patient characteristics (eg, native kidneys vs kidney allografts). In addition,
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most patients in this study had severe AKI (stage III), and many required
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RRT. However, this population does not represent the majority of
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hospitalized patients with AKI. Lastly, CysC is easily obtainable at our
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center as part of routine clinical practice, but this option may not be
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available in most community hospitals to make timely clinical decisions. In
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addition, Cystatin C is more expensive than serum creatinine but the cost is
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less than or equivalent to the cost of other commonly ordered tests such as
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C-reactive protein, parathyroid hormone, 25-hydroxyvitamin D and
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Troponin T (23). This extra cost is easily offset by avoiding an extra dialysis
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treatment or shortening the length of hospitalization.
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In conclusion, the findings in this study suggest that CysC decreases earlier that Scr and thus is an earlier biomarker of AKI recovery in
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hospitalized patients (68%), with only 8% of patients showing delayed improvement of CysC compared with Scr. If confirmed by large prospective studies, these findings may have important clinical implications for
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managing AKI, with potential for shortened hospital stay and reduced
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resource utilization and costs.
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Disclosure
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The authors declare no conflicts of interest related to this publication.
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This work was presented in part at the Annual Meeting of the American
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Society of Nephrology on November 17, 2016 in Chicago, Illinoi, USA.
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Acknowledgements
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This publication was supported by Grant Number UL1 TR000135 from the
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National Center for Advancing Translational Sciences (NCATS). Its
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contents are solely the responsibility of the authors and do not necessarily
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represent the official views of the NIH.
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We thank the scientific publication staff at Mayo Clinic for editorial
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assistance.
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Table 1 - Characteristics of the 63 Study Patients Valuea
Variable
58.7 (13.9)
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Age, mean (SD), y Male sex
39 (61.9)
White race/ethnicity
60 (95)
Smoker or ex-smoker
29 (46)
BMI, median (IQR), kg/m2
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27.8 (25-35.5)
mL/min/1.73m2 Diabetes mellitus Heart failure Hypertension
Infection Hypothyroidism Malignancy
21 (33) 12 (19) 33 (52) 23 (37) 34 (54)
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Corticosteroids use
70 (27.4) (19-138)
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Baseline eGFR, mean (SD) (range),
10 (16) 24 (38) 8 (13)
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Kidney transplant
Serum creatinine, median (IQR), mg/dL
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1.1 (0.9-1.3)
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Baseline Peak
3.6 (2.8-5.2)
At discharge
1.9 (1.4-2.9)
Abbreviations: BMI, body mass index; eGFR, estimated glomerular
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filtration rate based on the Chronic Kidney Disease Epidemiology
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Collaboration equation; IQR, interquartile range.
401 402
a
Values are presented as number and percentage of patients unless
specified otherwise.
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Table 2 - Causes of Acute Kidney Injury Among the 63 Patients
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Patients, No. (%)
Acute tubular necrosis
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Cause
45 (71.4)
Prerenal disease (including CRS and HRS) Contrast medium nephropathy
9 (14.3) 3 (4.8)
1 (1.6)
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Obstruction
Pigment nephropathy Cast nephropathy Acute interstitial nephritis Unknown
1 (1.6)
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Delayed transplant graft function
1 (1.6) 1 (1.6) 1 (1.6)
1 (1.6)
Abbreviations: CRS, cardiorenal syndrome; HRS, hepatorenal
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syndrome.
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Table 3 - Clinical Implications of Use of Serum Cystatin C Instead of Serum
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Creatinine to Monitor Renal Recovery After Acute Kidney Injury
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Clinical Decision
Patients, No. (%)
Dialysis avoided
15 (24)
Drug dose more appropriate
10 (16) 6 (10)
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Kidney biopsy avoided
Earlier hospital discharge 413 414
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4 (6)
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Earlier nephrology service sign-off
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Legends
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Figure 1 - Percentage of Patients in Whom Serum CysC Started to Decrease
418
Before, the Same Day as, or After Scr. CysC indicates cystatin C; D-3, CysC
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peaked 3 days before Scr; D-2, CysC peaked 2 days before Scr; D-1, CysC
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peaked 1 day before Scr;D0, CysC peaked on the same day as Scr; D+1,
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CysC peaked 1 day after Scr; D+2, CysC peaked 2 days after Scr; Scr, serum
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creatinine.
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Figure 2 - Examples of Patients With Various Temporal Trends Between
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Serum CysC and Scr. Each Scr value (mg/dL) is represented as a red dot (as
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a triangle for Scr peak) and each serum CysC (mg/L) as a blue rectangle (as
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a triangle for CysC peak). CysC indicates cystatin C; Scr, serum creatinine.
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Figure 3 - Temporal Evolution of Serum CysC and Scr After an Acute
430
Kidney Injury Episode of a Patient Hospitalized for Resection of Total Hip
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Arthroplasty. Serum CysC (mg/L) started to decrease 2 days earlier than Scr
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(mg/dL) (vertical solid line and dashed line, respectively). Assuming no
433
other reason to keep the patient in the hospital besides awaiting kidney
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function recovery, the patient could be discharged 2 days earlier on the basis
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of decrease in serum CysC (vertical blue line) rather than Scr (vertical green line). CysC indicates cystatin C; Scr, serum creatinine.
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