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      Utilizing Estimated Creatinine Excretion to Improve the Performance of Spot Urine Samples for the Determination of Proteinuria in Kidney Transplant Recipients

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          Abstract

          Background

          Agreement between spot and 24-hour urine protein measurements is poor in kidney transplant recipients. We investigated whether using formulae to estimate creatinine excretion rate (eCER), rather than assuming a standard creatinine excretion rate, would improve the estimation of proteinuria from spot urine samples in kidney transplant recipients.

          Methods

          We measured 24 hour urine protein and albumin and spot albumin:creatinine (ACR) and spot protein:creatinine (PCR) in 181 Kidney transplant recipients.” We utilized 6 different published formulae (Fotheringham, CKD-EPI, Cockcroft-Gault, Walser, Goldwasser and Rule) to estimate eCER and from it calculated estimated albumin and protein excretion rate (eAER and ePER). Bias, precision and accuracy (within 15%, 30% and 50%) of ACR, PCR, eAER, ePER were compared to 24-hour urine protein and albumin.

          Results

          ACR and PCR significantly underestimated 24-hour albumin and protein excretion (ACR Bias (IQR), -5.9 mg/day; p< 0.01; PCR Bias, (IQR), -35.2 mg/day; p<0.01). None of the formulae used to calculate eAER or ePER had a bias that was significantly different from the 24-hour collection (eAER and ePER bias: Fotheringham -0.3 and 7.2, CKD-EPI 0.3 and 13.5, Cockcroft-Gault -3.2 and -13.9, Walser -1.7 and 3.1, Goldwasser -1.3 and -0.5, Rule -0.6 and 4.2 mg/day respectively. The accuracy for ACR and PCR were lower (within 30% being 38% and 43% respectively) than the corresponding values estimated by utilizing eCER (for eAER 46% to 49% and ePER 46–54%).

          Conclusion

          Utilizing estimated creatinine excretion to calculate eAER and ePER improves the estimation of 24-hour albuminuria/proteinuria with spot urine samples in kidney transplant recipients.

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          Most cited references19

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          Prediction of creatinine clearance from serum creatinine.

          A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
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            Use of single voided urine samples to estimate quantitative proteinuria.

            Quantitation of urinary protein excretion is used extensively for diagnostic and prognostic purposes and to assess the effects of therapy. The method most commonly used to measure urinary protein relies on 24-hour urine collections, which are time consuming, cumbersome, and often inaccurate. We reasoned that the urinary protein/creatinine ratio in a single voided urine sample should correlate well with the quantity of protein in timed urine collections. In a study of 46 specimens we found an excellent correlation between the protein content of a 24-hour urine collection and the protein/creatinine ratio in a single urine sample. The best correlation was found when samples were collected after the first voided morning specimen and before bedtime. We conclude that the determination of the protein/creatinine ratio in single urine samples obtained during normal daylight activity, when properly interpreted by taking into consideration the effect of different rates of creatinine excretion, can replace the 24-hour urine collection in the clinical quantitation of proteinuria. In the presence of stable renal function, a protein/creatinine ratio of more than 3.5 (mg/mg) can be taken to represent "nephrotic-range" proteinuria, and a ratio of less than 0.2 is within normal limits.
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              Equations to estimate creatinine excretion rate: the CKD epidemiology collaboration.

              Creatinine excretion rate (CER) indicates timed urine collection accuracy. Although equations to estimate CER exist, their bias and precision are untested and none simultaneously include age, sex, race, and weight. Participants (n = 2466) from three kidney disease trials were randomly allocated into equation development (2/3) and internal validation (1/3) data sets. CER served as the dependent variable in linear regression to develop new equations. Their stability was assessed within the internal validation data set. Among 987 individuals from three additional studies the equations were externally validated and compared with existing equations. Mean age was 46 years, 42% were women, and 9% were black. Age, sex, race, weight, and serum phosphorus improved model fit. Two equations were developed, with or without serum phosphorus. In external validation, the new equations showed little bias (mean difference [measured - estimated CER] -0.7% [95% confidence interval -2.5% to 1.0%] and 0.3% [95% confidence interval -2.6% to 3.1%], respectively) and moderate precision (estimated CER within 30% of measured CER among 79% [76% to 81%] and 81% [77% to 85%], respectively). Corresponding numbers within 15% were 51% [48% to 54%] and 54% [50% to 59%]). Compared with existing equations, the new equations had similar accuracy but showed less bias in individuals with high measured CER. CER can be estimated with commonly available variables with little bias and moderate precision, which may facilitate assessment of accuracy of timed urine collections.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 December 2016
                2016
                : 11
                : 12
                : e0166547
                Affiliations
                [1 ]Department of Medicine, McMaster University, Hamilton, Canada
                [2 ]Division of Nephrology, Department of Medicine, Queens University, Kingston, Canada
                [3 ]Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, Canada
                [4 ]Kidney Research Centre, University of Ottawa, Ottawa, Canada
                [5 ]Clinical Epidemiology Program, University of Ottawa, Ottawa, Canada
                [6 ]Division of Nephrology, Department of Medicine, Mubarak AlKabeer Hospital, Kuwait City, Kuwait
                The University of Manchester, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: AA CW GK.

                • Data curation: AA CW GK.

                • Formal analysis: AA MW.

                • Funding acquisition: CW GK AA.

                • Investigation: AA CW GK NH.

                • Methodology: AA MW CW GK PB.

                • Project administration: AA.

                • Software: AA MW.

                • Supervision: AA GK.

                • Visualization: AA MW.

                • Writing – original draft: MW AA CW.

                • Writing – review & editing: AA MW CW PB NH SH GK.

                Author information
                http://orcid.org/0000-0002-1388-9799
                Article
                PONE-D-16-26874
                10.1371/journal.pone.0166547
                5135043
                27911917
                1606b0b2-45d6-4b3a-919c-56ac33749ab0
                © 2016 Wang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 July 2016
                : 31 October 2016
                Page count
                Figures: 0, Tables: 6, Pages: 11
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000241, Physicians' Services Incorporated Foundation;
                Award ID: R03-59
                Award Recipient :
                This study was supported by Physicians services incorporated foundation grant number R03-59, http://www.psifoundation.org/ (CW, GK). The funders did not have any role in data collection or data analysis or preparation of manuscript or decision to publish.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Urine
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Urine
                Biology and Life Sciences
                Physiology
                Body Fluids
                Urine
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Urine
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Excretion
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Excretion
                Biology and Life Sciences
                Biochemistry
                Proteins
                Albumins
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Organ Transplantation
                Renal Transplantation
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Urinary System Procedures
                Renal Transplantation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Proteinuria
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Proteinuria
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Creatinine
                Biology and Life Sciences
                Physiology
                Renal Physiology
                Glomerular Filtration Rate
                Medicine and Health Sciences
                Physiology
                Renal Physiology
                Glomerular Filtration Rate
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Custom metadata
                Due to ethical restrictions related to patient confidentiality, data are available after approval from the Ottawa Hospital Research Ethics Board for researchers who meet criteria for access to confidential data. Questions regarding this process my be directed to Ayub Akbari ( aakbari@ 123456ottawahospital.on.ca ).

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