Correspondence

Research Letter

Calibration of Cystatin C in the National Health and Nutrition Examination Surveys (NHANES)

Chronic kidney disease (CKD) is a general term covering heterogeneous disorders with an overarching definition of having markers of kidney damage or decreased glomerular filtration rate (GFR). This definition has been widely accepted and unchanging since 2002. The staging of CKD now places GFR categories and albuminuria categories on an equal footing and relates them to risk of an increasing range of outcomes. The prevalence of CKD is recognized to be high globally at over 10%. Data quality is still a limited but improving and trends suggest an increase globally with some plateau in the rise in high income countries with an already high burden of disease.

We compared cystatin C in youth with versus without diabetes and determined factors associated with cystatin C in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D).

Youth (ages 12–19 years) without diabetes (N = 544) were ascertained from the NHANES Study 2000–2002 and those with T1D (N = 977) and T2D (N = 168) from the SEARCH for Diabetes in Youth Study. Adjusted means of cystatin C concentrations were compared amongst the 3 groups. Next, we performed multivariable analyses within the T1D and T2D SEARCH samples to determine the association between cystatin C and race, sex, age, diabetes duration, HbA1c, fasting glucose, and BMI.

Adjusted cystatin C concentrations were statistically higher in NHANES (0.85 mg/L) than in either the T1D (0.75 mg/L) or T2D (0.70 mg/L) SEARCH groups (P < 0.0001). Fasting glucose was inversely related to cystatin C only in T1D (P < 0.001) and BMI positively associated only in T2D (P < 0.01) while HbA1c was inversely associated in both groups.

Cystatin C concentrations are statistically higher in youth without diabetes compared to T1D or T2D, however the clinical relevance of this difference is quite small, especially in T1D. In youth with diabetes, cystatin C varies with BMI and acute and chronic glycemic control, however their effects may be different according to diabetes type.

The US prevalence of reduced estimated glomerular filtration rate (eGFR) based on serum creatinine level increased during the decade ending in 2002. National Health and Nutrition Examination Survey (NHANES) cystatin C measurements recently were calibrated to the international standard, allowing for an independent test of the trend in prevalence of reduced eGFR using cystatin C level.

Cross-sectional surveys performed during 2 periods.

Nationally representative subsamples of adult participants from NHANES III (1988-1994) and the NHANES 1999-2002 surveys.

Survey period.

Prevalence of reduced GFR, defined as eGFR <60 mL/min/1.73 m² based on levels of serum creatinine, cystatin C, or both (eGFR_cr, eGFR_cys, and eGFR_cr-cys), using estimating equations developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).

Serum cystatin C level, measured from stored samples in 2006, calibrated to the international standard in 2012.

Between 1988-1994 and 1999-2002, the prevalence of reduced eGFR_cr, eGFR_cys, and eGFR_cr-cys increased from 4.7% (95% CI, 4.1%-5.3%) to 6.5% (95% CI, 5.9%-7.1%) (P < 0.001), from 5.5% (95% CI, 4.6%-6.5%) to 8.7% (95% CI, 7.5%-10.0%) (P < 0.001), and from 4.4% (95% CI, 3.7%-5.2%) to 7.1% (95% CI, 6.2%-8.0%) (P < 0.001), respectively. The higher prevalence of reduced GFR in the later period was observed in all subgroups of age, race, sex, and GFR categories. After adjusting for changes in the US population by age, sex, race, diabetes, hypertension, and body mass index, prevalence ratios of reduced GFR in the later versus earlier survey were 1.24 (95% CI, 1.09-1.45), 1.34 (95% CI, 1.15-1.67), and 1.33 (95% CI, 1.17-1.65) using eGFR_cr, eGFR_cys, and eGFR_cr-cys, respectively.

Likely underascertainment of persons with GFR <15 mL/min/1.73 m²; GFR was estimated and not measured; comparability of laboratory assays based on a calibration subsample.

The prevalence of reduced eGFR_cys in the US civilian noninstitutionalized population increased between 1988-1994 and 1999-2002, confirming the increase observed in the prevalence of reduced eGFR_cr.

Our objective was to quantify short-term total within-person variability in standard and nontraditional kidney measures using national data.

Repeated examination study of serum and urine kidney measures.

Participants 18 years or older in the Third National Health and Nutrition Examination Survey (NHANES III) who had repeated blood and urine samples collected during visits occurring approximately 18 days apart.

Standardized serum creatinine, standardized cystatin C, β-trace protein (BTP), β₂-microglobulin (B2M), and urine albumin and creatinine. We calculated the within-person coefficient of variation (CV_w), which includes both biological and analytical variability. We also evaluated the impact of variability on estimates of the prevalence of reduced estimated glomerular filtration rate and albuminuria.

Serum cystatin C level demonstrated the lowest short-term within-person variability (CV_w = 6.8%). Serum creatinine and B2M levels (CV_w = 7.6% and 8.4%, respectively) also had low variability. BTP level had the most variability of the serum markers (CV_w = 11.6%). As expected, urine albumin and urine creatinine measurements showed high variability (CV_w >30% for both); however, albumin-creatinine ratio performed much better than either measure alone, with CV_w of 11.3%. The effect of short-term variability on the prevalence of reduced estimated glomerular filtration rate was moderate, with an ∼20% lower prevalence when defined based on single measurements compared to repeated application of the same test approximately 18 days apart. Repeated testing for albuminuria had a larger effect, showing a 33% lower prevalence of albuminuria when repeated testing was applied.

Only 2 measurements available. General population with low prevalence of kidney disease.

Our results suggest that creatinine, cystatin C, and B2M levels have similarly low short-term variability. BTP level was more variable compared with the other serum filtration markers. Urine albumin and creatinine levels were highly variable and may benefit from repeated assessments to reduce the misclassification of albuminuria.