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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 6  |  Page : 918-923
Serum cystatin C as a marker of renal function in patients with acute renal failure


1 Department of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia
2 Research Center, King Khalid University Hospital, Riyadh, Saudi Arabia

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   Abstract 

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;19:918-23

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 2020 Nov 27];19:918-23. Available from: https://www.sjkdt.org/text.asp?2008/19/6/918/43465

   Introduction Top


The reported incidence of acute renal failure (ARF) in hospitalized patients is 4-7% and constitutes 1% of all hospitalizations. [1],[2],[3] Co­rrect diagnosis and early detection can in­fluence the outcome. [4] The gold standard me­thod of detection of ARF is inulin clearance or nuclear isotope clearance. [5] Changes in serum creatinine are used for detection of acute kidney dysfunction. [6] 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 < 221 gmol/L (2.5 mg/dL) over a period of less than two weeks. [7] In pa­tients with raised serum creatinine > 221 gmol /L (2.5 mg/dL), any further rise of > 20% is defined as ARF. [7]

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. [8] 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. [8],[9],[10] 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. [11] 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 Top


Patients

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.

Methods

The serum creatinine and blood urea levels were measured by auto analyzers. The serum CC was measured using the Particle Enhanced Nephelometric Immunoassay (PENIA). [12] 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. [13],[14]

Statistics

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 < 0.05 was taken as significant. The statistical analysis was done using the SPSS 10.0.5 for windows (SPSS, Chicago, IL, USA).


   Results Top


Of the 78 patients who were initially re­cruited for the study, five were excluded due to their data being incomplete; thus, samples from a total of 73 patients (31 females and 42 males) were available for final evaluation. The mean age of the study patients was 57.2 ± 18.7 years. A single sample could be obtained in 38 patients due either death of the patient, transfer to hemodialysis or because they were shifted to another hospital. More than one sample was obtained from 35 patients (2 samples: 15 patients, 3 samples: 16 patients, 4 samples: 4 patients). Thus, a total of 38 single and 94 multiple samples were obtained from the study group (total = 132 samples).

The mean serum CC, creatinine, urea and GFR were significantly different among pa­tients with ARF as compared to the healthy controls [Table 1]. There was no difference in the serum CC and creatinine values between males and females, 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].


   Discussion Top


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. [15],[16],[17],[18],[19] Other reports however, do not agree with these findings. [20],[21] 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. [22],[23] Laterza further observed that smaller changes in GFR are better predicted by serum CC than serum crea­ tinine levels. [23]

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. [24],[25] 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%. [24] 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. [25] 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. [25] 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. [26] 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. [13],[14],[27] 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. [28]

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. [29],[30]

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. [24] 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.

 
   References Top

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7.Mussap M, Dalla Vestra M, Fioretto P, et al. Cystatin C is a more sensitive marker than creatinine for the estimation of GFR in type 2 diabetic patients. Kidney Int 2002;61:1453-61.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
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10.Newman DJ, Thakkar H, Edwards RG, et al. Serum Cystatin C measured by automated immunoassay: a more sensitive marker of changes in GFR than serum creatinine. Kidney Int 1995;47:312-8.  Back to cited text no. 10  [PUBMED]  
11.Tenstad O, Roald AB, Grubb A, Aukland K. Renal handling of radiolabel led human cystatin C in the rat. Scand J Clin Lab Invest 1996;56:409-14.  Back to cited text no. 11  [PUBMED]  
12.Finney H, Newman DJ, Grubber W, Merle P, Price CP. Initial evaluation of cystatin C mea­surement by particle enhanced immuno nephe­lometry on the Behring nephelometry systems (BNA, BN II). Clin Chem 1997;43:1016-22.  Back to cited text no. 12    
13.Gault MA, Longerich LL, Harnett JD, Wesolowski C. Predicting glomerular function from adjusted serum creatinine. Nephron 1992; 62(3):249-56.  Back to cited text no. 13    
14.National Kidney Foundation. K/DOQI Clinical practice guidelines chronic kidney disease: Evaluation, classification and stratification. Am J Kidney Dis 2002;39:S1.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Coll E, Botey A, Alvarez L, et al. Serum cystatin C as a new marker for noninvasive esti­mation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis 2000;36:29-34.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Mazur MJ, Heilman RL. Early detection of acute renal failure by serum cystatin C: a new opportunity for a hepatologist. Liver Transpl 2005;11:705-7  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Randers E, Erlandsen EJ, Pederson OL, Hasling C, Danielsen H. Serum cystatin C as an endogenous parameter of the renal function in patients with normal to moderately impaired renal function. Clin Nephrol 2000;54:203-9.  Back to cited text no. 17    
18.Randers E, Ivarsen P, Erlandsen EJ, et al. Plasma cystatin C as a marker of renal function in liver cirrhosis. Scan J Clin Lab Invest 2000;62:129-34.  Back to cited text no. 18    
19.Le Bricon T, Thervet E, Benlakehal M, Bousquet B, Legendre C, Erlich D. Changes in plasma cystatin C after renal transplantation and acute rejection in adults. Clin Chem 1999;45:2243-9.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Hergert-Rosenthal S, Trabold S, Pietruck F, Holtmann M, Philipp T, Kribben A. Cystatin C: efficacy as screening test for reduced glomerular filtration rate. Am J Nephrol 2000;20:97-102.  Back to cited text no. 20    
21.Stickle D, Cole B, Hock K, Hruska KA, Scott MG. Correlations of plasma concentrations of cystatin C and creatinine to inulin clearance in a pediatric population. Clin Chem 1998;44: 1334-8.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Dharnidharka VR, Kwon C, Stevens G. Serum Cystatin C is superior to serum creatinine as a marker of kidney function: a met analysis. Am J Kidney Dis 2002;40:221-6.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Laterza OF, Price CP, Scott MG. Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 2002;48:699-707.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Hergert-Rosenthal S, Marggraf G, Husing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004;66:1115-22.  Back to cited text no. 24    
25.Ahlstrom A, Tallgren M, Peltonen S, Pettila V. Evolution and predictive power of serum cystatin C in acute renal failure. Clin Nephrol ;62(5):344-50.  Back to cited text no. 25    
26.Campo A, Lanfranco G, Gramaglia L, Goia F, Cottino R, Giusto V. Could plasma cystatin C be useful as a marker of hemodialysis low molecular proteins removal? Nephron Clin Pract 2004;98:c79-82.  Back to cited text no. 26  [PUBMED]  [FULLTEXT]
27.Finney H, Newman DJ, Price CP. Adult refe­rence ranges for serum cystatin C, creatinine and predicted creatinine clearance. Ann Clin Biochem 2000;37:49-59.  Back to cited text no. 27  [PUBMED]  [FULLTEXT]
28.Hoek FJ, Kemperman FA, Kriediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant 2003;18:2024-31.  Back to cited text no. 28    
29.Risch L, Herkoltz r, Blumberg G, Huber AR. Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clin Chem 2001;47:205-5­9.  Back to cited text no. 29    
30.Bokenkamp A, Van Wuk JA, Lentze MJ, Stoffel-Wagner B. Effects of corticosteroid therapy on serum cystatin C and (32 microglobulin concentrations. Clin Chem 2002;48:1123-6.  Back to cited text no. 30    

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Correspondence Address:
J S Alwakeel
Department of Medicine, King Khalid University Hospital, P.O. Box 2925, Riyadh 11461
Saudi Arabia
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PMID: 18974576

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