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(Clinical Chemistry. 2002;48:850-858.)
© 2002 American Association for Clinical Chemistry, Inc.

Diagnostic Value of Plasma Cystatin C as a Glomerular Filtration Marker in Decompensated Liver Cirrhosis

Rocco Orlando1, Michele Mussap2, Mario Plebani2, Pierpaolo Piccoli3, Sara De Martin3, Maura Floreani3, Roberto Padrini3 and Pietro Palatini3a

Departments of
1 Medical and Surgical Sciences and
3 Pharmacology and Anesthesiology, University of Padua, Largo E. Meneghetti 2, 35131 Padua, Italy.
2 Department of Laboratory Medicine, University Hospital of Padua, 35128 Padua, Italy.

aAuthor for correspondence. Fax 39-049-8275093; e-mail pietro.palatini{at}unipd.it.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Plasma creatinine concentration and calculated creatinine clearance are of limited value as glomerular filtration rate (GFR) markers in patients with decompensated liver cirrhosis. We assessed plasma cystatin C as an indicator of GFR in such patients.

Methods: We studied 36 patients with decompensated liver cirrhosis and 56 noncirrhotic controls, both groups including individuals with normal and impaired renal function. GFR was measured in all individuals by inulin clearance, with values <72 mL · min-1 · 1.73 m-2 considered decreased. We measured cystatin C and creatinine in plasma and calculated (from plasma concentrations) and measured creatinine clearances, using for them decision points of 1.25 mg/L, 115 µmol/L, and 72 and 72 mL · min-1 · 1.73 m-2, respectively.

Results: Plasma cystatin C concentrations were similar in controls and cirrhotics and, at the usual cutpoint, could detect decreased GFR with similar sensitivities in the two groups (73% and 88%, respectively). Serum creatinine was markedly lower in cirrhotics and remained mostly within the reference interval at all GFR values; the diagnostic sensitivity of creatinine was much lower in cirrhotics than in controls (23% vs 64%). Lower diagnostic sensitivity was also observed for calculated creatinine clearance (53% vs 100% in controls), whereas similar sensitivities were found for measured creatinine clearance (86% and 81%) in controls and cirrhotics, respectively. ROC analysis showed that all four variables had similar diagnostic accuracies in cirrhotic patients. However, it also revealed that good diagnostic accuracies for plasma creatinine and calculated creatinine clearance can be obtained only if reference intervals different from those used for the general population are adopted.

Conclusions: Plasma cystatin C concentration is an accurate GFR marker in cirrhotic patients. Plasma creatinine concentration and calculated creatinine clearance are of no practical value, as their reference values vary with the severity of the liver disease.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Various endogenous substances are being investigated as potential reliable markers of renal function. Inulin clearance (CIn) 1 is regarded as the "gold standard" for evaluating glomerular filtration rate (GFR), but cost and technical difficulties preclude its routine use in clinical practice (1). Single-sample creatinine values in serum are the most widely used indirect measure of GFR, but they are inaccurate as GFR indicators. Cystatin C values in serum have been proposed as a marker for GFR [see Randers and Erlandsen (2) and Price and Finney (3) for recent reviews]. Cystatin C, a low-molecular-weight protein produced at a constant rate by all nucleated cells, is freely filtered across the glomerular membrane and is neither secreted nor reabsorbed along the nephron. Because cystatin C is almost completely catabolized in the proximal tubule, its renal clearance cannot be measured, but its concentration in serum or plasma reflects the GFR. Several studies have reported that the reciprocal of cystatin C correlates better with GFR than does the reciprocal of creatinine, but equivalent diagnostic accuracies have often been reported (4)(5)(6). An advantage of cystatin C over creatinine is that the concentration of the former in serum is independent of sex, muscle mass, and age, so that the same reference interval applies to the whole population. However, cystatin C values may be adjusted for age, sex, and body mass by the use of algorithms such as the Cockcroft–Gault formula (7), which according to some studies, may provide GFR estimates that are similar to or better than those provided by measurement of 24-h creatinine clearance (CCr) (8). To date, there has been no systematic comparison of the less expensive method of Cockcroft and Gault (7) with the more expensive determination of cystatin C, as pointed out by Deinum and Dierkx (9).

In liver cirrhosis, both plasma creatinine measurement and the Cockcroft–Gault method are of limited value as predictors of GFR. In particular, Papadakis and Arieff (10) and Caregaro et al. (11) found normal or low serum creatinine concentrations despite low GFR values. When they applied the Cockcroft–Gault formula, greatly overestimated GFR values were obtained for cirrhotic patients with reduced renal function. However, these studies did not include a control group and investigated only patients with severe liver dysfunction (10) or a heterogeneous patient population with compensated and decompensated cirrhosis (11). In a recent study (12) including both a control group and a patient population stratified according to the degree of liver dysfunction, we showed that the outcomes of these renal function tests differed in different stages of liver cirrhosis: in Child’s class A patients (with compensated cirrhosis), plasma creatinine and the Cockcroft–Gault method predicted GFR as accurately as in healthy individuals, whereas in patients with Child’s grade C (decompensated) liver cirrhosis, these tests overestimated GFR. These overestimated GFR values are caused by complications such as muscle wasting and ascites. Reductions in muscle mass and the ability to convert creatine to creatinine decrease creatinine concentrations in plasma. Ascites further contributes to overestimated GFR values by the Cockcroft–Gault formula because it increases body weight (but not muscle mass), which is included in the numerator of the formula.

In this study, we assessed cystatin C in serum as a GFR marker in decompensated cirrhosis to supplement a recent report on cystatin C in cirrhotic patients (13), which did not include a control group or comparison with the Cockcroft–Gault method. We also reevaluated the accuracy of CCr as a measure of GFR, as discrepant results have been reported for patients with liver cirrhosis (10)(11)(14).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study participants
After they gave informed, written consent, 36 male patients with biopsy-confirmed postviral liver cirrhosis and 56 noncirrhotic men participated in the study, whose design was approved by the local ethics committee in accordance with the Helsinki Declaration. All participants underwent a thorough clinical examination, including medical history, physical examination, urinalysis, and biochemical profile. All of the cirrhotic patients were in a decompensated state (Child’s class C). The functional reserve of the liver was scored according to Pugh et al. (15). Patients were excluded from the study if they had a history of recent gastrointestinal bleeding, refractory ascites, or severe encephalopathy. Controls included healthy volunteers and nephropathic patients with various degrees of renal insufficiency. Recognized causes of renal impairment were hypertension, glomerulonephritis, and polycystic kidney disease. Only patients with stable renal function were selected. Cirrhotic and nephropathic patients had no other disease. None of the healthy volunteers were taking medications, whereas pharmacologic treatment of cirrhotic and nephropathic patients was continued. However, none of the patients were taking drugs known to interfere with the tubular secretion of creatinine or its measurement.

study design
We performed this cross-sectional study in the Gastroenterology Unit of the University Hospital of Padua; the study included 36 consecutive, eligible cirrhotic patients who had been admitted to the unit from January 2000 to October 2001. Controls were recruited from the hospital staff, from healthy outpatient volunteers who were at the hospital for routine laboratory tests, and from patients in the Nephrology Unit (nephropathic patients). Each participant was studied for 3 consecutive days, during which the healthy volunteers stayed in the hospital from 0800 to 2000. All participants were fed a diet that provided sufficient energy (125–150 kJ · kg-1 · day-1) and protein (0.8–1.0 g · kg-1 · day-1) content.

On the first 2 study days, urine was collected from 0800 to 2000, and the creatinine concentration in plasma was measured at the beginning (after an overnight fast) and at the end (before the evening meal) of the collection period. The same plasma samples were used for the determination of cystatin C. Individual values for plasma creatinine and cystatin C were taken as the means of the four determinations. The mean intraindividual CV for cystatin C (11%) was somewhat greater than that for creatinine (5%), as reported previously (16).

On the third day, CIn was determined by the single-injection method (17). In brief, at 0800 after an overnight fast, 5 g of inulin (Inutest; Laevosan GmbH) was infused over 1 min by a volumetric pump, and blood samples were taken from the opposite arm immediately before the infusion and 14 times thereafter until 8 h after injection. Blood was drawn into heparin-containing plastic tubes and immediately centrifuged. Urine was collected before and 0–8 h after inulin injection. Plasma and urine samples were stored at -40 °C until assayed. Before the CIn measurements were started, all participants were given 10 mL/kg tap water to drink. To maintain diuresis, urinary losses were replaced by equal amounts of water.

analytical methods
Creatinine was measured by the enzymatic PAP method (Boehringer), which is less sensitive than the Jaffe reaction to positive interference by nonspecific plasma chromogens and negative interference by bilirubin (12). Inulin was determined by a modification of the anthrone method of Jung et al. (18), as described recently (17). The limits of detection and CVs of the aforementioned assays have been reported (12)(17). Cystatin C was measured by a particle-enhanced turbidimetric immunoassay (19) with a commercially available Dako cystatin C PET reagent set (Dako) and a Hitachi 912 automated analyzer. The detection limit was 0.1 mg/L. The intra- and interassay CVs (n = 10) determined at 0.6 mg/L were <3.9% and <2.2% at 4 mg/L.

Plasma creatinine and cystatin C (evaluated tests) and CIn were determined in two different laboratories (Department of Laboratory Medicine and Department of Pharmacology, respectively) without each knowing the other’s results and without knowing the clinical status of the participants.

clearance calculations
The plasma inulin concentration-vs-time data were modeled with the use of GraphPad Prism software, Ver. 2.0 (GraphPad Software Inc.). In accordance with previous results (17), the best fit was obtained with a triexponential equation. The area under the plasma concentration–time curve was calculated from the coefficients and exponents of the best-fit equation. CIn was determined as the ratio of the amount excreted in urine to the area under the plasma concentration–time curve (17). Endogenous CCr was calculated from the standard formula: CCr = UV/P, where U is the urinary concentration, V is the urine flow rate, and P is the arithmetic mean of the concentrations in plasma at the beginning and end of the 12-h urine collection period. The clearance value for each individual was taken as the mean of the two determinations. The mean intraindividual CVs for CCr were similar in the two study groups (8% and 9% in cirrhotics and controls, respectively). To calculate the GFR from the CCr in plasma (predicted GFR), we used the Cockcroft–Gault formula, which currently provides the best GFR estimate (20). According to this formula: GFR = (140 - age) x weight (kg)/0.825 x plasma creatinine (µmol/L). All clearance values were normalized to a standard body surface area of 1.73 m2 by the formula of DuBois and DuBois (21).

statistical analysis
We performed a power analysis (CSS power assessment procedure; Statsoft Inc.) based on the difference between the sensitivities of cystatin C and creatinine in cirrhotic patients. This analysis indicated that with our sample size and a significance level ({alpha}) of 0.05, power (1 - ß) was >0.95. The results were then tested by the Wilk–Shapiro method (SAS univariate procedure, SAS release 6.03; SAS Institute) to ensure that the data were normally distributed and by the Levene test (CSS Levene test) for homogeneity of variances. Because a gaussian distribution of the data could not be rejected, inter- and intragroup comparisons were made by Student two-tailed unpaired and paired t-tests, respectively. Correlations were examined by linear regression analysis except those with Pugh scores, for which the Spearman rank correlation analysis was used. The significance of differences between correlation coefficients was estimated by a z transformation (22). The criterion for statistical significance was P <0.05. To assess the diagnostic accuracy of cystatin C in comparison with that of creatinine, CCr, and predicted GFR, ROC analysis was performed with Analyze-it software (Analyze-it Software Ltd.). The sensitivity and specificity of the tests were as currently defined (23).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The demographic and clinical features of the study participants are listed in Table 1 . There were no statistically significant differences between the two groups for age, weight, height, or body mass index. Liver function tests were all within reference limits in the control group. A reduced albumin concentration in some controls could be explained by their renal disease; in contrast, these test results were indicative of advanced hepatocellular insufficiency in cirrhotic patients.


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  		Table 1. Demographic and clinical characteristics of study participants.1

As shown in Table 2 , both cirrhotic patients and controls were divided into two groups on the basis of their CIn values: those with GFR values within the reference interval and those with a reduced GFR, with 72 mL · min-1 · 1.73 m-2 as the lower limit of the GFR reference interval (24). CIn values were evenly distributed in each subgroup, and their mean values were similar in controls and cirrhotics. As expected, CCr overestimated GFR to a greater extent in individuals with reduced renal function, but the degree of overestimation was similar in cirrhotic and noncirrhotic individuals. In accordance with previous observations (12)(20), the calculated CCr (predicted GFR) underestimated the true GFR in controls with normal renal function, whereas it provided a good estimate of GFR in patients with renal impairment. On the other hand, application of the Cockcroft–Gault algorithm led to an overestimation of GFR in cirrhotic patients, especially those with renal insufficiency (+75%). Although their GFR values were comparable to those of controls, cirrhotic patients exhibited much lower plasma creatinine concentrations, but cystatin C concentrations did not differ significantly between the two groups. The clinical significance of these results is depicted in Fig. 1 : in the controls, plasma cystatin C and creatinine both increased in a hyperbolic fashion as GFR decreased and could detect renal failure with similar sensitivities (73% and 64%, respectively). Conversely, in cirrhotic patients, creatinine failed to detect reduced renal function, its sensitivity being only 23%, whereas cystatin C still exhibited good diagnostic sensitivity (88%).


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  		Table 2. Renal findings in controls and cirrhotics patients.1



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  		Figure 1. Relationships between CIn and plasma concentrations of cystatin C and creatinine.

The dotted lines represent the reference limits: 72 mL · min-1 · 1.73 m-2 for CIn (24), 1.25 mg/L for cystatin C (25), and 115 µmol/L for creatinine (Padua University Hospital Laboratory).

Correlation analysis (Fig. 2 ) showed that the reciprocals of plasma cystatin C and creatinine values correlated equally well with CIn in controls as has been reported previously (4)(5)(6). Similar correlations were also unexpectedly observed in cirrhotic patients, despite the significantly different performance of the two GFR markers in detecting renal insufficiency. Significantly better correlations were observed for CCr in both controls and cirrhotics (P <0.01 and 0.05, respectively, vs the correlation coefficients of the other three markers).



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  		Figure 2. Correlations between CIn and (from top to bottom) reciprocals of plasma cystatin C, reciprocal of plasma creatinine, CCr, and predicted GFR.

Solid lines indicate regression lines; dotted lines show the 95% confidence intervals for the regression lines. P <0.0001 for all correlations.

The curves obtained from ROC analysis are shown in Fig. 3 . Consistent with the results of correlation analysis, ROC curves showed equivalent diagnostic accuracies for plasma cystatin C and creatinine in both controls and cirrhotics. The areas under the ROC curves (95% confidence intervals) for cystatin C and creatinine were 0.927 (0.861–0.993) and 0.916 (0.842–0.991), respectively, in controls and 0.901 (0.803–0.999) and 0.907 (0.814–1.000) in cirrhotics (P >0.05 in both cases). In the controls, the diagnostic accuracies of CCr and predicted GFR were better (P <0.01 and 0.05, respectively) than those of cystatin C and creatinine, whereas all four markers had similar diagnostic accuracies in the cirrhotic group. The cutoff value that maximized the sum of sensitivity and specificity (26) and the corresponding sensitivity and specificity of each of the four renal function tests are listed in Table 3 . Diagnostic accuracies of cystatin C and creatinine were similar in both controls and cirrhotics. However, it should be noted that the cutoff limits for cystatin C were very similar in the two groups and very close to the upper reference limit for the general population. Only in controls was the cutoff limit for creatinine close to that conventionally applied to a male population. In cirrhotic patients, the cutoff limit was markedly lower. A similar difference in the cutoff limit was observed for predicted GFR. This is the consequence of lower plasma concentrations of creatinine in cirrhotic patients compared with controls with similar GFR values.



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  		Figure 3. Nonparametric ROC plots for the diagnostic accuracy of plasma cystatin C, plasma creatinine, CCr, and predicted GFR in distinguishing between normal and reduced GFR (CIn <72 mL · min-1 · 1.73 m-2).


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  		Table 3. Calculated cutoff limits, sensitivities, and specificities (95% confidence intervals) of cystatin C, creatinine, CCr, and predicted GFR in control and cirrhotic groups.1


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Evaluation of renal failure is essential in patients with decompensated liver cirrhosis, because a significant proportion of them manifest reduced GFR. Careful assessment of GFR is critically important for prognosis because the indicators of renal function are sensitive markers of the severity of liver dysfunction in cirrhosis and are better predictors of patient survival than are measures that estimate hepatic function (27). Quantification of renal failure is also necessary to avoid excessive dosages of drugs, such as diuretics and nephrotoxic antibiotics, that may cause toxic side effects or aggravate renal dysfunction. However, this task is made difficult by the unreliability of the GFR markers traditionally used in clinical practice. The following conclusions can be drawn from available studies: (a) the creatinine concentration in serum is abnormally low in patients with decompensated cirrhosis; and (b) application of the Cockcroft–Gault formula overestimates the true GFR because of the low creatinine concentration and the occurrence of ascites and edema. On the other hand, no conclusion is yet possible regarding the reliability of CCr because conflicting results have been reported.

Our findings confirm the poor sensitivity of plasma creatinine in detecting reduced GFR [23%, in accordance with the 18.5% calculated by Caregaro et al. (11)] when the upper reference limit conventionally used in clinical practice (115 µmol/L) is applied. The significantly lower urinary creatinine excretion found in cirrhotic patients (Table 2Up ) also confirms that their lower steady-state creatinine concentrations are the consequence of a reduction in creatinine production rate. Consistent with the low creatinine, the Cockcroft–Gault method overestimated GFR, especially in cirrhotic patients with reduced renal function. As a consequence, this method also exhibited a low sensitivity in detecting renal impairment (53%), in good agreement with the value (51%) obtained by Caregaro et al. (11).

According to Papadakis and Arieff (10) and Caregaro et al. (11), CCr yields reasonably accurate estimates of GFR in cirrhotic patients with normal renal function, whereas it greatly overestimates the true GFR [by 100% (10) and 50% (11)] in cirrhotic patients with renal failure. Although they did not include a control group, these authors concluded that GFR overestimation by CCr is particularly pronounced in cirrhosis-associated renal failure. These conclusions have been challenged by the results of a more recent study (14) showing that the extent of GFR overestimation is related only to the degree of renal impairment, irrespective of etiology. However, the most recent study included a control (noncirrhotic) group of only five individuals. Our study, which compared control and patient groups of adequate sizes (statistical power >95%), definitely shows that the overestimation of GFR by CCr is no greater in cirrhosis-associated renal failure than in nephropathies of different etiology. The sensitivity of CCr in detecting reduced GFR was therefore consistently similar in controls and cirrhotics (86% and 81%, respectively).

Of the four GFR markers examined, plasma cystatin C afforded the greatest sensitivity (88%) in detecting renal impairment in cirrhotic patients. In contrast to plasma creatinine measurements and the Cockcroft–Gault method, plasma cystatin C is a good discriminator between individuals with normal and reduced renal function who are also in decompensated cirrhosis, indicating that muscle wasting does not influence cystatin C values. This is consistent with the fact that cystatin C, unlike creatinine, is synthesized by all nucleated cells. In contrast, in cirrhotic patients the reciprocal of creatinine concentration and the predicted GFR correlated with CIn as well as did the reciprocal of cystatin C concentration. Moreover, ROC curves showed similar diagnostic accuracies in cirrhotics for these three renal function tests. The fact that, contrary to many previous studies (2)(3), we did not find the correlation and diagnostic accuracy of creatinine to be inferior to those of cystatin C may be attributable to methodologic reasons: we measured creatinine by the enzymatic PAP method, which is far less sensitive to interferences than the routinely used Jaffe reaction (see Materials and Methods), and our plasma creatinine values are the means of four determinations.

The following explanation is proposed for our observations: creatinine has poor diagnostic sensitivity when the conventional upper reference limit is used, not because its concentration in patients with decompensated cirrhosis fails to increase as GFR decreases [as suggested previously (10)], but because it is markedly lower than in noncirrhotics at all GFR values. The creatinine concentration varies inversely with GFR in cirrhotics as well (the slopes of the regression lines are equal for controls and cirrhotics; Fig. 2Up ) and can theoretically be used as a GFR marker. The data in Table 3Up confirmed that a diagnostic accuracy similar to that of controls could be obtained in our decompensated cirrhotics when an appropriately lower cutoff value was used. However, the degree of liver dysfunction varies considerably (Pugh score from 10 to 15) even within Child’s class C cirrhotics. In our patients, we found a significant correlation between creatinine production and Pugh score [Spearman correlation coefficient >0.60 (P <0.02) in cirrhotics with both normal and reduced GFR]. Thus, plasma creatinine concentrations are expected to vary even in patients with decompensated liver cirrhosis, making the determination of an appropriate reference range impossible. At variance with creatinine, the cutoff limits at which maximum diagnostic accuracy is observed for cystatin C are very similar in controls and cirrhotics. This implies that a single reference range can be used for healthy individuals and patients with decompensated cirrhosis. This considerable practical advantage makes cystatin C clearly preferable to creatinine as a marker for routine estimation of GFR in patients with severe liver dysfunction. Although only male patients were examined in our study, this conclusion also applies to female cirrhotic patients because cystatin C concentrations have been shown to be independent of sex (2)(3).

Our study also shows that although CCr overestimates GFR, its diagnostic accuracy in cirrhotic patients is roughly equivalent to that of plasma cystatin C if a cutoff of 72 mL · min-1 · 1.73 m-2 (24) is chosen to distinguish between individuals with normal and reduced GFR (Table 3Up ). It should be noted, however, that such diagnostic accuracy for CCr can be obtained only if accurate urine collections and creatinine measurements are performed. The mean intraindividual CV of CCr was <10% in our patients, in good agreement with the CV values (3–14%) previously observed when collection errors were eliminated (28).

In conclusion, at variance with previous studies with either no (10)(11)(13) or too exiguous (14) a control group and that examined a heterogeneous patient population, we compared renal markers in a pathologically homogeneous population of cirrhotic patients and a control group of adequate size. This allowed us to reach the following conclusions: (a) unlike creatinine, the plasma cystatin C concentration is not affected by decompensated cirrhosis and is as reliable a GFR marker in such patients as it is in healthy individuals; (b) plasma creatinine concentration and the Cockcroft–Gault method are not useful as GFR markers in cirrhotic patients because their use requires the determination of a suitable reference interval, a goal that is not feasible in practice; (c) the diagnostic accuracy of plasma cystatin C is similar to that of CCr in patients with decompensated cirrhosis, but it has an advantage over CCr because the need for inconvenient and frequently inaccurate urine collection is avoided.


   Acknowledgments
 
This work was supported by a grant from MURST (Ministero per l’Università e la Ricerca Scientifica e Tecnologica).


   Footnotes
 
1 Nonstandard abbreviations: CIn, inulin clearance; GFR, glomerular filtration rate; and CCr, creatinine clearance.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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