Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study

Abstract

Research on early renal function decline in diabetes is hampered by lack of simple tools for detecting trends (particularly systematic decreases) in renal function over time when GFR is normal or elevated. This study sought to assess how well serum cystatin C meets that need. Thirty participants with type 2 diabetes in the Diabetic Renal Disease Study met these three eligibility criteria: GFR >20 ml/min per 1.73 m2 at baseline (based on cold iothalamate clearance), 4 yr of follow-up, and yearly measurements of iothalamate clearance and serum cystatin C. With the use of linear regression, each individual's trend in renal function over time, expressed as annual percentage change in iothalamate clearance, was determined. Serum cystatin C in mg/L was transformed to its reciprocal (100/cystatin C), and linear regression was used to determine each individual's trend over time, expressed as annual percentage change. In paired comparisons of 100/cystatin C with iothalamate clearance at each examination, the two measures were numerically similar. More important, the trends in 100/cystatin C and iothalamate clearance were strongly correlated (Spearman r = 0.77). All 20 participants with negative trends in iothalamate clearance (declining renal function) also had negative trends for 100/cystatin C. Results were discordant for only three participants. In contrast, the trends for three commonly used creatinine-based estimates of GFR compared poorly with trends in iothalamate clearance (Spearman r < 0.35). Serial measures of serum cystatin C accurately detect trends in renal function in patients with normal or elevated GFR and provide means for studying early renal function decline in diabetes.

Figure 1

Cross-sectional comparison of standardized iothalamate clearance with four indirect methods of measuring renal function in 30 Pima Indian participants with type 2 diabetes. The 30 participants contributed a total of 144 paired measurements for which iothalamate clearance and serum for the determination of GFR by the indirect methods were collected simultaneously. The shaded regions represent error margins of ±30% for agreement between methods. The 95% distribution of differences between the methods of estimation and the reference method, expressed as percentages by the methods of Bland and Altman, were −30 to 32% for 100/cystatin C, −29 to 79% for 100/creatinine, −42 to 73% for the Cockcroft-Gault formula, and −43 to 39% for the Modification of Diet in Renal Disease (MDRD) equation.

Figure 2

Correlation between estimates of the annual percentage change in renal function as determined from serial measurements of standardized iothalamate clearance and four indirect measures in 30 Pima Indian participants. Points in the lower right quadrant of a plot represent false-positive results for declining renal function (defined by an annual percentage change in iothalamate clearance <0 ml/min per 1.73 m²). Points in the upper left quadrant of a plot represent false-negative results for declining renal function (defined by an annual percentage change in iothalamate clearance ≥0 ml/min per 1.73 m²). Operating characteristics for trends in renal function estimated by cystatin C (A) are described in the text. The operating characteristics (sensitivity and specificity) of trends estimated by 100/creatinine (B), Cockcroft-Gault formula (C), and MDRD equation (D) were 50% and 70%, 60% and 60%, and 50% and 70%, respectively.

Figure 3

Serial determinations of renal function by standardized iothalamate clearance and by 100/cystatin C. The rate of change in renal function for each individual was estimated by linear regression of the determinations (transformed to the logarithmic scale) over time and expressed as the annual percentage change. (A) A participant with rapidly declining GFR. (B through D) Three individuals with disagreement between the trends in iothalamate clearance and 100/cystatin C for determining declining renal function. All examples illustrate the greater variability of standardized iothalamate clearance than 100/cystatin C. Within-individual SD for standardized iothalamate clearance was 14, 16, 16, and 9% for examples 1 through 4, respectively. For 100/cystatin C, it was 10, 11, 15, and 5%, respectively.