| IntroductionChronic kidney disease (CKD) is an important public health problem and accurate estimation of the glomerular filtration rate (GFR) is essential for evaluating the stage of kidney function of patients with CKD. The current Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines stratify CKD into five stages, also based on GFR estimations. Normal or increase in GFR (stage 1 of CKD;GFR≥90ml/min/1.73m2). Mild reduction in GFR was defined as CKD only in the presence of kidney damage (stage 2 of CKD;GFR 89-60 ml/min /1.73m2). Moderate (stage 3 of CKD;GFR 59-30 ml/min/1.73m2) to severe (stage 4 of CKD;GFR 29-15 ml/min/1.73m2) reduction in GFR and kidney failure (stage 5 of CKD;GFR <15 ml/min/1.73m2) were defined as CKD, irrespective of the presence of kidney damage.Glomerular filtration rate (GFR) is defined as the volume of plasma that can be completely cleared of a particular substance by the kidneys in a unit of time. The "gold standard" for determining GFR is to measure the clearance of exogenous substance such as inulin and 51Cr-EDTA. These techniques, however, are time-consuming, labor-intensive, and expensive, and they require administration of substances that make them incompatible with routine monitoring. Thus, the measurement of endogenous blood substances to estimate GFR is a common practice.Properties of an ideal endogenous blood substance to estimate GFR should include release into the blood stream at a constant rate, free filtration by the glomerulus, no reabsorption or secretion by the renal tubules, unbound to plasma proteins and no exclusive elimination via the kidneys.In clinical practice, serum creatinine (SCr) has been widely used in estimation of GFR. SCr circulates in the blood unbound to any plasma proteins and is freely filtered by the proximal tubules, but is secreted in small amounts. As plasma concentration increases, tubular secretion of SCr increases, leading to an overestimation of GFR in patients with moderate to severe decreases in GFR. SCr is also insensitive for detecting small decreases in GFR because of the nonlinear relationship between plasma concentration and GFR, and the outpatients with mild impairment of kidney function are easy to been misdiagnosed.Besides SCr, other small proteins such as (32-microglobulin ((32-MG) , retinol - binding protein (RBP) have been proposed to estimate GFR. They have the adventage of can being freely filtered by the glomerulus and then almost completely reabsorbed and catabolized by proximal tubular cells, however, the influencing factors such as sex, inflammation, fever and body pathological state restrict their clinical use.Recently, serum cystatin C (CysC) was proposed as a new endogenous marker of GFR. This protease inhibitor with a low molecular weight is produced at a constant rate by all nucleated cells.It is freely filtered across the glomerular membrane and is reabsorbed and metabolized in the proximal tubule, so that it does not return to the blood flow. Some studies suggested that the blood concentration of cysC does not depend on sex, age, weight, nutrition, muscle mass,inflammation and infection and it is close to be the "ideal" endogenous marker.The value of cysC in estimate of GFR is still been disputed today. Most studies have found cysC to be a better marker of GFR than serum creatinine , although others considered that the diagnostic accuracy of cysC was not superior to serum creatinine.It is very important to find out and get rid of the cause of degressive GFR and reduce the impairment of kidney function. Is there more advantageous of cysC for detecting early impairment of kidney function?The aim of our study was to determine the reference scope of CysC, (52-MG, RBP, SCr in health adults and to evaluate the diagnostic value of serum cysC in GFR measurement in comparison with other endogenous markers in CKD patients with mild to moderate impairment of GFR. The standard method for the estimation of GFR is plasma clearance of 99mTc-DTPA.Patients and methods1. Patients1.1. Control groupOne hundred and fifty health adults (75 M and 80 F;aged 21-50 years) participated in this study. The blood was withdrawn from the vein before breakfast and the centrifugal serum samples were stored bellow-76 °C.1.2. Patients groupCKD was diagnosed and classified according to K/DOQI clinical practice guidelines. Seventy-five patients with CKD stages 2-3 (GFR 30-89ml/min/1.73m2) who had performed 99mTc-DTPA clearance were enrolled, and their sex, age, and body weight were recorded. Of the total patients, 42 (56%) were men and 33 (44%) were women. The age of patients ranged from 26 to 77 years, giving a mean of 48 years (49.1 years for men and 46.5 years for women).Their heights ranged from 145 to 181 cm and the mean height was 163.1 cm (167.1 cm for men and 158 cm for women). The weight of patients ranged from 39 to 85kg, giving a mean of 60.4 kg (65 kg for men and 54.6 kg for women) with.In all patients included in the study, 99mTc-DTPA clearance was estimated. On the day that the 99mTc-DTPA clearance was estimated,the blood was withdrawn from the patients' veins before breakfast and the centrifugal serum samples were stored bellow -76°C. Patients with acute kidney function deterioration, edema, skeletal muscle atrophy, dialysis, thyroid dysfunction, heart failure, or whose glucocorticoids were currently administered were excluded.2. Methods2.1. Measurement of serum concentration of cystatin C, f}2-micro-globulin, retinol - binding protein, and creatinine.Serum cystatin C level was measured by particle enhanced immunenephelometry (BN-II ,Dade Behring);Serum (32-microglobulin and retinol - binding protein levels were both measured by immune-nephelometry (BN-II ,Dade Behring);Serum creatinine level was measured by an autoanalyzer method (Automatic Analyzer for Hitachi 7600).2.2. Measurement of renal functionGlomerular filtration rate was measured by dual plasma sampling method of 99mTc-DTPA plasma clearance.A dose of 3mci(l 1 lMBq)/0.5 ml of 99mTc-DTPA was injected as a bolus in an antecubital vein. 3 ml of blood samples were withdrawn 2h and 4h post-injection respectively,and radioactivities of 1 ml plasma were measured. GFR was calculated by dual plasma sampling method and the results were all standardized with the body surface.3. Statistical analysisIn our study, mean ± standard deviation (SD) values were presented for each measurement. Data were analyzed using SPSS 13.0. A P value <0.05 was considered statistically significant.Results1. The reference scopes of CysC n (32-lv^ RBP> SCr in health adults: The concentration of serum CysC and the other endogenousmarkers was significant different between the male and female adults (p<0.01) : CysC 0.49-0.87mg/L for males and 0.33-0.78 mg/L for females;(32-MG 0.96-1.74 mg/L for males and 0.33-0.78 mg/L for females;SCr 55.1-94.5umol/L for males and 40.6-75.4umol/L for females;RBP 0.019-0.057g/L for males and 0.01-0.04g/L for femaleso2. The correlation coefficients between serum endogenous markers and GFRDTPA: * p<0.05;** p<0.01The correlation coefficients were -0.803** (-0.799** for males,-0.839** for females) for CysC, -0.792** (-0.764** for males, -0.827** for females) for(32-MG, -0.688** (-0.671** for males, -0.75** for females) for SCr, -0.45** (-0.39* for males, -0.51** for females) for RBP.The p value between (32-MG, SCr, RBP correlation coefficients and CysC correlation coefficient were 0.8561 (0.6908 for males and 0.8793 for females), 0.1148 (0.211 for males and 0.343 for females), 0.0002** (0.0025** for males and 0.0112* for females) respectively.3. The sensitivities of all endogenous markers in CKD patients with mild to moderate impairment of GFR:The sensitivities were 93.3% (97.6% for males, 87.9% for females) for CysC, 96% (100% for males, 90.9% for females) for|32-MG;81.3% (81% for males, 81.8% for females) for SCr, 52% (40.5% for males, 66.7% for females) for RBP.4. Diagnostic accuracy (area under the ROC curves, AUC) at cut-off value for GFR 60 ml/min/ 1.73m2 of serum cystatin C, p2-microglo-bulin, creatinine and retinol - binding: * p<0.05;** p<0.01The area under the ROC curves were 0.916** (0.925** for males, 0.908** for females) for CysC, 0.901** (0.914** for males and 0.896** for females) for(32-MG, 0.883** (0.918** for males, 0.86** for females) for SCr, 0.775** (0.789** for males, 0.727** for females) for RBP.The p value between AUC of(32-MG, SCr, RBP and AUC of CysC were 0.558 (0.768 for males and 0.737 for females), 0.356 (0.868 for males and 0.425 for females), 0.007** (0.0139* for males and 0.012* for females) respectively.Conclusions1. The concentration of serum cystatin C % |32-microglobulim retinol - binding protein and serum creatinine was significant difference between the male and female adults.2. Retinol-binding protein was not an adequate marker of glomerular filtration rate.3. The sensitivity of cystatin C and p2-microglobulin waff better than serum creatinine,it indicated that they could reflect the decrease of GFR earlier than serum creatinine in patients with mild to moderate kidney dysfunction.
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