Year : 2008 | Volume
: 19 | Issue : 6 | Page : 918--923
Serum cystatin C as a marker of renal function in patients with acute renal failure
N Tarif1, JS Alwakeel1, AH Mitwalli1, Hammad Durdana2, NA Memon1, A Askar1, AR Chaudhary1, AC Isnani2,
1 Department of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia
2 Research Center, King Khalid University Hospital, Riyadh, Saudi Arabia
J S Alwakeel
Department of Medicine, King Khalid University Hospital, P.O. Box 2925, Riyadh 11461
Serum creatinine level is the traditionally used tool to detect changes in renal function. Serum cystatin C (CC) has been suggested to be an equally effective marker of renal function. We measured the serum levels of creatinine and CC in 73 patients with acute renal failure (ARF) and 300 age and sex matched healthy controls. The serum CC was measured by particle enhanced nephlometric immunoassay (PENIA). As expected, the serum creatinine and CC levels were significantly higher in ARF patients than the healthy controls and serum CC levels correlated significantly with serum creatinine (r= 0.47, p < 0.0001). This correlation further increased for multiple measurements, (r = 0.51, p < 0.0001). No gender difference was noted. Serum CC also correlated significantly with calculated GFR. Correlation of serum CC with serum creatinine and calculated GFR was much greater in patients with deteriorating renal function, compared to patients with improving renal function (p < 0.0001). Our study further suggests that the serum CC is a good marker of renal function in ARF patients, especially those with worsening renal function. Further larger studies are needed to evaluate its role in detecting early ARF and institute possible intervention.
|How to cite this article:|
Tarif N, Alwakeel J S, Mitwalli A H, Durdana H, Memon N A, Askar A, Chaudhary A R, Isnani A C. Serum cystatin C as a marker of renal function in patients with acute renal failure.Saudi J Kidney Dis Transpl 2008;19:918-923
|How to cite this URL:|
Tarif N, Alwakeel J S, Mitwalli A H, Durdana H, Memon N A, Askar A, Chaudhary A R, Isnani A C. Serum cystatin C as a marker of renal function in patients with acute renal failure. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2021 Jul 28 ];19:918-923
Available from: https://www.sjkdt.org/text.asp?2008/19/6/918/43465
The reported incidence of acute renal failure (ARF) in hospitalized patients is 4-7% and constitutes 1% of all hospitalizations. ,, Correct diagnosis and early detection can influence the outcome.  The gold standard method of detection of ARF is inulin clearance or nuclear isotope clearance.  Changes in serum creatinine are used for detection of acute kidney dysfunction.  Recently, the diagnosis of ARF was defined as increase in serum creatinine of > 44.2 gmol/L (0.5 mg/dL) from a baseline value of  In patients with raised serum creatinine > 221 gmol /L (2.5 mg/dL), any further rise of > 20% is defined as ARF. 
The serum creatinine levels are dependent on different factors, the most important being the muscle mass. In advanced renal failure, a significant amount of creatinine in urine is due to secretion rather than filtration.  These factors may influence the serum creatinine levels and result in falsely high or low values. Cystatin C (CC) is a small, non-glycosylated 13 KD basic protein that belongs to the family 2 of the cystatin super family of proteins. ,, The function of CC is to regulate the activity of cystein proteinases and it seems to be the main cysteine proteinase inhibitor of most investigated human biological fluids. CC is filtered by the glomeruli and is followed by tubular reabsorption and degradation resulting in excretion of a minute amount in the urine. It is not secreted in the tubules and also not reabsorbed back into the serum and therefore, its serum levels reflect the amount of glomerular filtration. This makes serum CC an alternative marker for glomerular filtration; hence it has been extensively studied for this purpose.  We studied 73 patients with ARF to assess the utility of serum CC as a marker of renal function. The purpose of the study was to evaluate whether serum CC is as good a marker of renal function deterioration as serum creatinine.
Materials and Methods
Over a period of three years (Jan 2001-Dec 2003), patients who were diagnosed to have ARF at hospitalization or, developed ARF (according to the definition stated above) during hospitalization, were included in the study (n = 78). The study was performed at the King Khalid University Hospital, Riyadh, Saudi Arabia. Consecutive multiple daily serum collections were performed. None of the patients was on corticosteroids at the time of sampling. The study protocol was approved by the College of Medicine Research Center Ethics Committee.
The serum creatinine and blood urea levels were measured by auto analyzers. The serum CC was measured using the Particle Enhanced Nephelometric Immunoassay (PENIA).  This assay was validated in our research laboratory by sampling more than 300 healthy volunteers. The serum CC was measured using BN 100 Nephlometer and N Latex cystatin C assay kits (Dade Behring, Germany), according to the procedure recommended by the manufacturer. Briefly, all the reagents and the serum samples were brought to room temperature. About 250300 µL of serum was placed in cups and loaded onto the sample racks. Serial dilutions of samples (1:10 and 1:100) were prepared by the built-in auto-diluter. 75 µL of diluted sample and 7.5 µL of N cystatin C reagent (lyophilized polystyrene particles coated with rabbit antibodies to human cystatin C) were mixed together in a reaction cuvette. Agglutination was measured at 840 nm and the results (mg /L) were evaluated by the machine using external reference sera and pre-programmed logitlog function. Serum samples were analyzed in duplicates and the mean of the two readings was used in the statistical analysis.
The glomerular filtration rate (GFR) was estimated by the Cockcroft-Gault formula:
The modified MDRD formula was also used to compare with the Cockcroft and serum CC:
186.3 (serum Creatinine) -1.154 × (Age) -0.203) × 0.742 if females × 1.21 if black. ,
All data are presented as mean ± standard deviation. Data from ARF patients was compared with a cohort of 300 healthy people for serum CC, urea and creatinine, and calculated GFR by using student t test and ANOVA. These healthy subjects were evaluated as a part of a larger study evaluating serum CC levels in healthy Saudi population. Spearman's correlation coefficient was used to evaluate the relationships between variables. A p value of p > 0.05. However, females were younger, had lesser body weight and serum urea levels and also lower calculated GFR [Table 2].
Pearson correlation revealed significantly positive correlation among serum CC and creatinine [Table 3]. Compared to the GFR, the serum CC had a slightly lesser, although still significantly negative, correlation similar to serum creatinine. Age, weight and gender had no influence on the serum CC and creatinine levels. Patients with more than one blood sample were evaluated by separating them into progressively improving versus deteriorating renal function based on the serum creatinine level; similar degree of correlations were observed [Table 3].
It is clear from the large number of samples obtained in our patients with ARF that serum CC is as good a marker of renal function as serum creatinine. Similar relationship was observed when multiple samples were studied and further classified on the basis of progressively improving or deteriorating renal function. These findings are consistent with results of other studies both in healthy and kidney disease patients. ,,,, Other reports however, do not agree with these findings. , A more recent meta analysis by Dharmidharka et al and review by Laterza et al, evaluating studies using serum CC as a marker of renal function, concluded that serum CC has the same clinical utility as serum creatinine. , Laterza further observed that smaller changes in GFR are better predicted by serum CC than serum crea tinine levels. 
To date, only two studies, one by Hergert Rosenthal et al and another by Ahlstrom et al, have been performed to assess the utility of serum CC in detecting early changes of renal function in patients with ARF. , Both studies demonstrated similar correlation between serum creatinine and serum CC although showing conflicting results when it came to early detection of ARF. The study by HergertRosenthal et al demonstrated a rise in serum CC by 80% a day before the onset of ARF while the serum creatinine level rose only by 21%.  Thus, the serum CC was able to detect ARF clearly. This has a significant clinical importance since early detection of ARF, especially in the ICU setting, may alert the physician to avoid or change the dose of potentially nephrotoxic medications. Ahlstrom et al however, could not replicate these results despite similar patient population.  The difference may be due to the smaller number of patients (n = 29 vs. n = 44) in whom the serum CC and creatinine estimations were available three days prior to development of ARF.
In our patients with ARF, we were able to consolidate the findings of the two earlier studies that both serum CC and creatinine levels are equally effective in detecting established ARF. Our study is different than reported by Ahlstrom et al. since we excluded all patients requiring renal replacement therapy and therefore, present a true cohort of ARF patients.  As speculated by them, and recently confirmed by Campo et al and our own unpublished observations in hemodialysis (HD) patients, the serum CC levels increase post-HD during diffusive HD while convective dialysis decreases the levels significantly.  Our study therefore evaluates serum CC in patients with ARF without interference by the dialysis modality.
The calculation of GFR is influenced by markers that influence serum creatinine levels such as age, muscle mass, weight, gender and race. ,, Thus, the GFR may not be as accurate in ARF patients due to inaccurate measurement of weight as a result of administration of intravenous fluids and insensible losses, especially in the ICU setting. We therefore used two different formulae (CCG and MDRD) to estimate the GFR and both showed good correlation with serum creatinine and serum CC, although to a lesser degree with CC. In our patients, the serum CC and serum creatinine levels were similar in both genders; nevertheless females had significantly lower weight and consequently, the calculated GFR [Table 4]. We can speculate that this correlation difference is due to the lack of influence by patient's weight or muscle mass, on serum CC. 
Levels of serum CC may increase in patients on high dose of glucocorticoids and therefore, we did not include any patient who was on these medications. ,
Our patients had established ARF (serum creatinine 259.9 ± 129 umol/L), hence, we cannot confirm the utility of serum CC in detecting early ARF. We agree with HergertRosenthal et al that confirmation of this benefit of serum CC needs a larger multicenter study in the ICU setting.  Such patients have predisposing factors for the development of ARF such as congestive heart failure, sepsis, contrast studies and administration of potentially nephrotoxic medications such as aminoglycosides or amphotericin B.
Although we had a large number patients (n= 73), multiple samples were obtained in only 42 patients. We also did not use patients with underlying chronic kidney disease and therefore, this study data cannot be used for patients who develop acute on chronic kidney disease.
In conclusion, serum CC has the same clinical utility as serum creatinine in detecting ARF. The serum creatinine levels negatively correlated with calculated GFR while serum CC had a similar, although slightly lesser, correlation. A study in hospitalized patients with potential to develop ARF is needed to asses whether serum CC has a role in detecting early changes in GFR.
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