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      Cystatin C is Indispensable for Evaluation of Kidney Disease

      EJIFCC

      The Communications and Publications Division (CPD) of the IFCC

      cystatin C, GFR, morbidity, mortality, renal, shrunken-pore-syndrome

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          Abstract

          The present minireview of the place of cystatin C in clinical medicine emphasizes, and discuss the evidence, that cystatin C-based GFR-estimating equations do not require the use of vague terms like race and sex, that cystatin C-based GFR-esti mating equations are useful for both children and adults, including the elderly, that the best GFR-estimation requires simultaneous use of both cystatin C- and creatinine-based equations, that cystatin C-based GFR-estimating equations are superior to creatinine-based equations in predicting end-stage renal disease, cardiovascular manifestations, hospitalisation and death, and, finally that cystatin C is required to diagnose the new syndrome “Shrunken Pore Syndrome” with its high mortality and morbidity, even in the absence of reduced GFR. When automated laboratory equipment is available, the cost of cystatin C is comparable to that of enzymatically determined creatinine.

          The conclusion is that cystatin C should be used at least as often as creatinine in clinical medicine.

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          Most cited references 39

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          Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD.

          Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables. Test of diagnostic accuracy. Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438). Measured GFR (mGFR). Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study. GFR was measured by using urinary clearance of iodine-125-iothalamate in the US studies and chromium-51-EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used. Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m(2) (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables. Study population composed mainly of patients with CKD. Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.
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            Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities.

            An equation from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) provides more accurate estimates of the glomerular filtration rate (eGFR) than that from the modification of diet in renal disease (MDRD) Study, although both include a two-level variable for race (Black and White and other). Since creatinine generation differs among ethnic groups, it is possible that a multilevel ethnic variable would allow more accurate estimates across all groups. To evaluate this, we developed an equation to calculate eGFR that includes a four-level race variable (Black, Asian, Native American and Hispanic, and White and other) using a database of 8254 patients pooled from 10 studies. This equation was then validated in 4014 patients using 17 additional studies from the United States and Europe (validation database), and in 1022 patients from China (675), Japan (248), and South Africa (99). Coefficients for the Black, Asian, and Native American and Hispanic groups resulted in 15, 5, and 1% higher levels of eGFR, respectively, compared with the White and other group. In the validation database, the two-level race equation had minimal bias in Black, Native American and Hispanic, and White and other cohorts. The four-level ethnicity equation significantly improved bias in Asians of the validation data set and in Chinese. Both equations had a large bias in Japanese and South African patients. Thus, heterogeneity in performance among the ethnic and geographic groups precludes use of the four-level race equation. The CKD-EPI two-level race equation can be used in the United States and Europe across a wide range of ethnicity.
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              Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality.

              A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied. To evaluate whether combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone. Prospective cohort study involving 26,643 US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ≥60 mL/min/1.73 m(2) and ACR of either <30 or ≥30 mg/g. All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years. Participants had a mean age of 65 years, 40% were black, and 54% were women. Of 26,643 participants, 1940 died and 177 developed end-stage renal disease. Among participants without CKD defined by creatinine, 24% did not have CKD by either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0-5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2-4.7) for those with CKD defined by creatinine and cystatin C, and 5.6 (95% CI, 3.9-8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 3863 (16%) had CKD detected by ACR or cystatin C. Compared with participants who did not have CKD by any measure, the HRs for mortality were 1.7 (95% CI, 1.4-1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9-2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4-3.7) for participants with CKD defined by both measures. Risk of incident end-stage renal disease was higher among those with CKD defined by all markers (34.1 per 1000 person-years; 95% CI, 28.7-40.5 vs 0.33 per 1000 person-years; 95% CI, 0.05-2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate was among persons missed by the creatinine measure but detected by both ACR and cystatin C (rate per 1000 person-years, 6.4; 95% CI, 3.6-11.3). Net reclassification improvement for death was 13.3% (P < .001) and for end-stage renal disease was 6.4% (P < .001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR. Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.
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                Author and article information

                Journal
                EJIFCC
                EJIFCC
                eJIFCC
                EJIFCC
                The Communications and Publications Division (CPD) of the IFCC
                1650-3414
                19 December 2017
                December 2017
                : 28
                : 4
                : 268-276
                Affiliations
                Department of Clinical Chemistry and Pharmacology, Laboratory Medicine, Lund University, Skåne University Hospital , Lund, Sweden
                Author notes
                Department of Clinical Chemistry and Pharmacology Laboratory Medicine Lund University Skåne University Hospital SE-22185 Lund Sweden +46 702393773 anders.grubb@ 123456med.lu.se

                Acknowledgement: This study was supported by grants from the Alfred Österlund Foundation, the Medical Faculty of the University of Lund and from Region Skåne.

                Conflict of interest: The author declares that there is no conflict of interest regarding the publication of this article.

                Article
                ejifcc-28-268
                5746836
                Copyright © 2017 International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All rights reserved.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 55, Pages: 9
                Categories
                Research Article

                shrunken-pore-syndrome, renal, mortality, morbidity, gfr, cystatin c

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