© Borgis - Postępy Nauk Medycznych 6/2014, s. 364-368
*Jerzy Jaroszewicz, Magdalena Rogalska-Taranta, Magdalena Płońska-Rogalska, Tomasz Szulżyk, Paweł Kozłowski, Tadeusz W. Łapiński, Robert Flisiak
Cystatyna C w przewlekłych chorobach wątroby – nie tylko wskaźnik upośledzenia funkcji nerek
Serum cystatin C in chronic liver disorders – not a simple marker of renal function impairment
Department of Infectious Diseases and Hepatology, Medical University of Białystok
Head of Department: prof. Robert Flisiak, MD, PhD
Streszczenie
Wstęp. Postępująca dysfunkcja nerek jest jedną z istotnych cech przewlekłych chorób wątroby. Rutynowo stosowane sposoby obliczania wskaźnika przesączania kłębuszkowego (GFR) oparte na kreatyninie mogą prowadzić do zawyżania rozpoznania przewlekłej dysfunkcji nerek. W ostatnich latach podkreśla się przydatność oznaczania cystatyny C (cys C) w surowicy krwi jako wczesnego wskaźnika upośledzenia wydolności nerek.
Cel pracy. Celem pracy była ocena przydatności pomiaru stężenia cys C u chorych z marskością wątroby oraz subklinicznym upośledzeniem funkcji nerek, jak również jej przydatności jako wskaźnika rokowniczego progresji marskości wątroby.
Materiał i metody. Stężenie cystatyny C oznaczono w surowicy 77 chorych z marskością wątroby o różnej etiologii za pomocą zestawu ELISA (BioVendor GmbH, Niemcy). Stężenia korelowano z GFR, jak również ze wskaźnikami upośledzenia funkcji wątroby. Sześćdziesięciu dwóch chorych poddano dalszej obserwacji celem ustalenia progresji choroby wątroby.
Wyniki. Stężenie cys C było niezależne od wieku, wagi, stężenia bilirubiny, aktywności ALT, INR, HgB oraz liczby płytek krwi. Stwierdzono dodatnią zależność ze stężeniem kreatyniny (B = 0,83; P < 0,001), ale też negatywny związek ze stężeniem albumin (B = -0,48; P = 0,01). Co więcej, zaobserwowano wyższe wyjściowe stężenia cys C u chorych, którzy w dalszej obserwacji rozwinęli niewydolność wątroby (351,6 ± 73,3 vs. 794,1 ± 234,3 ng/mL; P = 0,005) lub zmarli z jej powodu (359,2 ± 62,7 vs. 1,235 ± 486,6 ng/mL; P = 0,04).
Wnioski. Przeprowadzone badania wskazują na podwyższone stężenia cystatyny C w surowicy krwi chorych z marskością wątroby oraz na związek ze stopniem wydolności wątroby. Dodatkowo stężenie cystatyny C może wiązać się z niekorzystnym rokowaniem w marskości wątroby, co powinno być uwzględnione w skalach rokowniczych.
Summary
Introduction. Progressive renal function impairment is a pitfall of chronic liver disorders. Routinely used estimates of glomerular filtration rate (GFR) based on serum creatinine may potentially lead to the overdiagnosis of chronic kidney dysfunction. In recent years, serum cystatin C (cys C) has been proposed as an early marker of kidney dysfunction.
Aim. The aim of current study was to assess value of serum cystatin C in liver cirrhotics with subclinical kidney dysfunction and its possible usefulness in liver cirrhosis progression prediction.
Material and methods. Cystatin C was measured in sera of 77 patients with liver cirrhosis (48 males; age 52 yrs) by ELISA (BioVendor GmbH, Germany). Cys C was correlated with creatinine based GFR but also markers of liver dysfunction. Moreover, in 62 patients follow-up information on future decompensation or death was available.
Results. Serum cystatin C was independent of age, weight, bilirubin concentration, ALT, INR, hemoglobin and platelets count. We observed a positive correlation with serum creatinine (B = 0.83, P < 0.001) but also negative with albumins (B = -0.48, P = 0.01). Interestingly, cys C levels were higher in patients who developed liver decompensation (351.6 ± 73.3 vs. 794.1 ± 234.3 ng/mL, P = 0.005) or died due to its complications (359.2 ± 62.7 vs. 1.235 ± 486.6 ng/mL, P = 0.04) in the follow-up period.
Conclusions. This study showed the increase of serum cystatin C in liver cirrhotics with subclinical renal function impairment, but also suggests its association with the level of liver impairment. Our results point towards cystatin C as potential, clinical marker useful in predicting the development of liver cirrhosis complications.
Introduction
Progressive renal function impairment is a pitfall of chronic liver disorders. Hepatorenal syndrome in liver cirrhotics yields high mortality despite of novel treatment possibilities: terlipressin and albumins (1-3). Progressive renal dysfunction may eventually lead to acute tubular necrosis, interstitial fibrosis and tubular atrophy which remain irreversible. In fact, the diagnosis and cause of renal failure is independently associated with prognosis in liver cirrhosis, together with MELD score (Model For End-Stage Liver Disease), serum sodium, and hepatic encephalopathy (4). On the other hand, renal function impairment is not solely confined to end stage liver disease. In chronic hepatitis C a variety of kidney disorders can be observed, including the most common cryoglobulinemic glomerulopathy, and also other types of immune globulin associated nephropathies, membranoproliferative glomerulonephritis, diabetic nephropathy or focal glomerular sclerosis (5, 6).
MELD score including serum bilirubin and creatinine levels and International Normalized Ratio (INR) for prothrombin time is a current gold standard in prognosis assessment (7, 8) and replaces Child-Pugh classification of liver cirrhosis (9). On the other hand, routinely used estimates of glomerular filtration rate (GFR) which are based on serum creatinine may potentially lead to the overdiagnosis of chronic kidney dysfunction. First, several chromogens, among them bilirubin, glucose, uric acid and certain antibiotics interfere with creatinine quantity (10). Second, serum creatinine may be influenced by several factors unrelated to renal function: creatinine dietary intake, state of hydration as well as total pool body creatinine – muscle mass (11).
In recent years, serum cystatin C (cys C) has been proposed as a marker of early detection of kidney dysfunction (12). Cystatin C is a nonglycosylated low molecular weight (13 kDa) basic protein that is a member of the cystatin superfamily of cysteine protease inhibitors. It is a secreted protein ubiquitously expressed in all tissues. Therefore, it has a stable production rate even if there is an inflammatory response and is freely filtered by the glomeruli. Moreover, as opposed to serum creatinine, serum cystatin C concentration is not affected by dietary protein intake, and there is no interference of proteins and bilirubin present in serum during the estimation process.
Several investigators have previously reported that serum cystatin C correlates well with GFR and is especially useful in diagnosis of early, subclinical renal function impairment (13-15). We showed that serum cystatin C may reflect mild renal dysfunction in HIV-infection (16). Significant experience on the association between cys C levels and creatinine estimated GFR (Cr-GFR) was gained in another persistent viral disease, HIV-infection. Results from two large studies by Odden et al. (17) including 1008 participants and Jones et al. (18) including 250 subjects agreeably showed that serum creatinine levels may overestimate GFR in HIV-infection and kidney dysfunction is more prevalent than previously expected.
Aim
The aim of our study was to assess serum concentrations of cystatin C in liver cirrhosis of various aetiologies with early, subclinical kidney dysfunction. Moreover we addressed the possible usefulness of cystatin C measurement as a prognostic marker of in liver cirrhosis progression and its complications development.
Material and methods
Patients
Cystatin C was measured in sera of 77 Caucasian patients with liver cirrhosis (29 females and 48 males; median age: 52.0, min. 21, max. 82). Alcohol-related liver cirrhosis (ALC) was diagnosed in 37, primary biliary cirrhosis (PBC) in 14, hepatitis C virus related liver cirrhosis (HCV-LC) in 12, whereas role of hepatitis B virus (HBV-LC) as an etiologic factor was established in 14 subjects. None of patients included had HRS diagnosed, based on criteria proposed by Salerno et al. (19), nor pre-existing renal disorders detected by use of urinalysis or ultrasonography. Degree of liver insufficiency was established according to Child-Pugh classification (9). Ascites, encephalopathy, prothrombin index, as well as concentrations of bilirubin and albumin were evaluated for this purpose. Patients were scored as follows: 5-6 points as class (group) A, 7-9 points as class (group) B, and 10-15 points as class (group) C. Moreover, MELD score based on serum creatinine, albumins and bilirubin concentration was calculated (7). Clinical characteristic of studied population is presented in table 1. In the group of 62 patients with liver cirrhosis follow-up information was available (median 25 months) and clinically significant events, including liver cirrhosis decompensation or death due to the liver disease were recorded.
Table 1. Characteristics of studied population.
| Age (median, min.-max.), years | 52.0 (21-82) |
| Men/Women | 48/29 |
| Liver cirrhosis etiology | ALD, n = 37
HBV-LC, n = 14
HCV-LC, n = 12
PBC, n = 14 |
| Child-Pugh class | A, n = 19
B, n = 28
C, n = 30 |
| Child-Pugh score, pts. (median, min.-max.) | 9 (5-13) |
| ALT [U/L], mean ± SE | 92.1 ± 23.2 |
| Bilirubin [mg/dL], mean ± SE | 5.6 ± 0.9 |
| INR, mean ± SE | 1.7 ± 0.3 |
| Albumin [g/dL], mean ± SE | 3.0 ± 0.1 |
| RBC [106/uL], mean ± SE | 3.9 ± 0.1 |
| WBC [103/uL], mean ± SE | 7.1 ± 0.8 |
| PLT [103/uL], mean ± SE | 120.3 ± 9.2 |
| Creatinine [mg/dL], mean ± SE | 0.9 ± 0.1 |
| GFR by Cockroft-Gault formula1 [mL/min], mean ± SE | 86.7 ± 6.3 |
| GFR by MDRD2 [mL/min], mean ± SE | 104.6 ± 5.8 |
Cystatin C serum concentration was measured by sandwich enzyme immunoassay (BioVendor GmbH, Heidelberg, Germany). According to manufacturer information cystatin C assay limit of detection is 0.2 ng/mL, intra-assay CV is 5.0-9.6% and inter-assay CV is 4.8-6.2%. Creatinine, urea, albumin concentrations were measured in serum from the same sample. The glomerular filtration rate (GFR) was estimated using the Cockcroft-Gault and Modification of Diet in Renal Disease Study (MDRD) formula: GFR=170 x [serum creatinine concentration (mg/dL)] - 0.999 x [Age] - 0.176 x [0.762 if subject is female] x [serum urea nitrogen (mg/dL)] - 0.17 x [serum albumin concentration (g/dL)] + 0.318 with normal range of 90-120 mL/min per 1.73 m2 (11). Serum cystatin C concentrations in liver cirrhosis were compared with those obtained in 15 healthy volunteers (5 females and 10 males; median age: 42.0, min. 27, max. 62). The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 1983. The study was approved by the Bioethical Committee of the Medical University of Białystok. Informed consent was obtained from each patient.
Statistical analyses
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