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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2009  |  Volume : 20  |  Issue : 2  |  Page : 227-231
Serum cystatin C: A surrogate marker for the characteristics of peritoneal membrane in dialysis patients


Department of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia

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   Abstract 

To evaluate whether cystatin C levels can be a surrogate marker of creatinine clearance and reflect the characteristics of peritoneal membrane in dialysis patients, we performed peritoneal equilibration tests (PET) in 18 anuric adult chronic peritoneal dialysis (PD) patients with a mean age of 39.7 ± 20 years. All the samples were analyzed for urea, creatinine, and cystatin C. Peritoneal transport, mass transfer, and peritoneal clearance of cystatin C were calculated. Correlation and regression analysis was done using cystatin C as a dependent variable and age, sex, height, weight, body surface area, and creatinine as independent variables. Cystatin C demonstrated a significant time dependent increase of dialysate concentration and decline in the serum concentrations during PET, and a strong correlation between serum creatinine and serum cystatin C concentrations(r: 0.62, p= 0.008). The trans-peritoneal clearance (mL/min/1.73 m 2 ) of cystatin C was related to its serum concentration and was similar to creatinine in its pattern but of smaller magnitude. Peritoneal mass transfer (mg/4 hr per 1.73 m 2 ) for cystatin C serum creatinine was 1.68 ± 0.67 and 73.3 ± 29.8, respectively. The dialysis/plasma D/P cystatin C concentration was > 0.1 at 4 hrs of PET denoted high peritoneal transport, while the values of < 0.1 denoted low transport type. We conclude that cystatin C follows the same pattern of peritoneal exchange as creatinine but the magnitude of transfer is many folds lower than creatinine. At present clinical utility of cystatin C in the evaluation of solute clearance is probably limited due to the minute amounts transferred across the membrane and the high renal clearance in the presence of residual renal function.

Keywords: Glomerular filtration rate, Cystatin C, Peritoneal dialysis, ESRD, Peritoneal clearance, Peritoneal equilibration test, Mass transfer, Middle molecular weight proteins

How to cite this article:
Al-Wakeel JS, Hammad D, Memon NA, Tarif N, Shah I, Chaudhary A. Serum cystatin C: A surrogate marker for the characteristics of peritoneal membrane in dialysis patients. Saudi J Kidney Dis Transpl 2009;20:227-31

How to cite this URL:
Al-Wakeel JS, Hammad D, Memon NA, Tarif N, Shah I, Chaudhary A. Serum cystatin C: A surrogate marker for the characteristics of peritoneal membrane in dialysis patients. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Nov 29];20:227-31. Available from: https://www.sjkdt.org/text.asp?2009/20/2/227/45527

   Introduction Top


Dialysis efficiency greatly influences the well­being, outcome and survival of patients on pe­ritoneal dialysis (PD). Therefore a close mo­nitoring and follow-up is essential so as to achieve the best outcome. Calculation of urea clearance by Kt/V, an indicator of small molecular weight solutes clearance, [1],[2],[3],[4] does not re­flect the middle molecules clearance in PD patients such as beta2 microglobulin and cys­tatin C. Accordingly, the referral range, serum concentrations and peritoneal clearance of these middle molecules need to be addressed.

Furthermore, serum creatinine estimates are not without fallacy in circumstances such as peritonitis, liver disease, and diabetes mellitus. In addition, serum concentration of creatinine is influenced by several factors including die­tary intake of meat, physical exercise, storage of samples, and concentration of glucose, fruc­tose, bilirubin, and antibiotics. [5],[6]

Cystatin C is an endogenous 13- KD protease inhibitor having single non-glycosylated poly­peptide chain with 120 amino acids. It is pro­duced at a constant rate by all nucleated cells. More than 99% of cystatin C is filtered by glo­meruli and metabolized in proximal tubules. [7] Cystatin C levels are more stable and increase in case of deteriorating renal function. It has been proposed as an alternative and more sen­sitive marker than serum creatinine. [8],[9],[10],[11],[12] Serum levels of cystatine C and its transport charac­teristics has not been studied in detail in PD patients.

The aim of our study is to determine peri­toneal transport characteristics and assess whe­ther cystatin C levels can be used as a surro­gate marker for creatinine clearance in PD patients.


   Patients and Methods Top


We performed peritoneal equilibration tests (PET) according to "Twardoski's"protocol [13] in 18 (11 males and 7 females) anuric chronic adult PD patients attending our dialysis center. The mean age was 39.7 ± 20 yrs (16-72yrs). A written informed consent was obtained from each patient.

Overnight, an 8-12 hr pre-PET PD exchange with 2 liters of 4.25% dialysate was performed. Next morning the overnight exchange was drained, and 2 liters of 2.5% dialysate were infused (zero Hr). At zero hrs, 2 hrs and 4 hrs of PET, 10 mL each of blood and dialysate samples were extracted for analysis. At the end of 4 hrs, dialysate was drained and its volume was measured. All the samples were analyzed for creatinine and cystatin C. Serum cystatin C was measured by using the particle enhanced nephelometric immunoassay (PENIA), [12] which was validated in our research laboratory by sampling more than 300 healthy volunteers. Serum cystatin C was measured using BN 100 Nephlometer and N Latex Cystatin C assay kits (Dade Behring, Germany) according to the procedure recommended by the manufacturer.

The essay procedure included warming all the reagents and the serum samples to room tem­perature. Then, about 250-300 µL of serum was placed in cups and loaded onto the sample racks, and serial dilutions (1:10 and 1:100) of the samples were prepared by the built-in auto­diluter. Afterwards, 75 µL of a 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 nephlometer using ex­ternal reference sera and pre-programmed logit­log function. The serum samples were analyzed in duplicates and the mean of the two readings was used in the statistical analysis. Creatinine was measured by the Jaffe's technique.

Peritoneal mass transfer and clearance for cystatin C and creatinine were calculated by standard methods. [14],[19] as follows: Peritoneal Mass Transfer (mg/4 hrs) = Ve x Ce/T.P; Peri­toneal Clearance (mL/min) = Ve x Ce/t.P, where Ve = total dialysate effluent volume, Ce = concentration of protein or solute in dialysate effluent, T and t are the hrs dwell time in and minutes respectively, and P= serum concentration of solute or protein. [14],[15]

Statistical analysis

We used the statistical package program SPSS 10.0 for windows for the purposes of our study. Student's "t" test was done for continouos variables. Correlation and regression analysis was performed, and statistical significance was considered at a P-value of < 0.05.


   Results Top


[Table 1] shows the demographics and solutes basic levels. During PET, dialysate concentra­tion of cystatin C, demonstrated a significant time dependent increase from 0.17 ± 0.18, to 0.37 ± 0.2 (p= 0.002), and 0.58 ± 0.33 mg/L (p= 0.0000) at 0, 2, and 4 hours of PET, res­pectively, [Figure 1] and [Table 2]. A similar time dependent, but insignificant, decline in the serum concentrations of serum cystatin C was also observed from 8.12 ± 2 to 8.17 ± 2 and 8.05 ± 2 mg/L at 0, 2, and 4 hours of PET, respectively (p= 0.85). A time dependent de­cline in the serum concentrations of creatinine was also noted, [Table 2].

A strong correlation was found between serum creatinine and serum cystatin C concentrations throughout the PET, [Table 3]. Dialysate to plasma ratio (D/P) of cystatin C significantly increased during PET, [Table 4].

The Trans-peritoneal clearance (mL/min/1.73 m 2 ) of cystatin C was related to its serum con­centration and similar to the creatinine in its pattern, but of smaller magnitude. The peritoneal clearance of creatinine was 3.54 ± 2.06 mL/min, while that of cystatin C was 0.38 ± 0.2 mL/ min, [Table 5]. The peritoneal mass transfer (mg/ 4 hr/1.73 m 2 ) for cystatin C and serum crea­tinine was 1.68 ± 0.67 and 73.3 ± 29.8, respectively.

The D/P value > 0.1 (at 4 hrs of PET) of cystatin C indicated high peritoneal transport while the values < 0.1 denoted low transport type. These values were comparable to create­nine D/P value > 0.72 indicating high perito­neal transport and < 0.72 indicating low trans­port. Eighty-eight percent of our patients had low and 12% had high peritoneal transport, [Table 6].


   Discussion Top


In the present study, we demonstrated that serum cystatin C levels are high in peritoneal dialysis patients as other studies. [14],[15],[16],[17],[18] Correlation between serum cystatin C and creatinine were highly significant suggesting that serum cystatin C increased similar to creatinine in ESRD patients. The peritoneal transport cha­racteristics in our patients were similar to those as previously studied by Kabanda et al. [15],[16],[17],[18],[19],[20] We illustrated in our patients that peritoneal mass transfer and peritoneal clearance of cys­tatin C was significantly lower than creatinine. Moreover, the D/P ratio, which characterizes the peritoneal membrane, was significantly high at 2 and 4 hours suggesting mainly high trans­port. [15] Previous authors did not classify the patients as high or low transporters on the basis of D/P. In our study, the D/P ratio for creatinine and serum cystatin C was > 0.75 and > 0.15 at 4 hours consistent with high transporters in other studied populations. 14,15 Only 2 (12%) of our patients were high trans­porters with a D/P ratio of creatinine > 0.75 and cystatin C > 0.1.

Peritoneal mass transfer of cystatin C was small in magnitude compared to urea and crea­tinine and therefore it is difficult to use it as a surrogate marker for clearance. Recently, Montini et al have evaluated the peritoneal clearance and weekly solute removal in 17 pe­diatric patients on automated peritoneal dia­lysis. [16] They have confirmed the above finding and higher solute clearance in the presence of residual renal function. In our study, the pa­tients were anuric, and residual urine was not an issue. Furthermore, we have shown that the peritoneal characteristics for cystatin C to be similar to previous reports and also could pos­tulate that high and low transporters can be separated by using the cut off point value of D/P of > 0.1. However, we need further study in a larger patient population. At present clini­cal utility of cystatin C in the evaluation of solute clearance is probably limited due to the minute amounts transferred across the mem­brane and the high renal clearance in the pre­sence of residual renal function. [16]

We conclude that our study reveals that serum cystatin C levels are high similar to serum creatinine in PD patients. However, the peritoneal clearance and mass transfer of cys­tatin C is small due to its larger molecular size compared to creatinine. D/P ratio > 0.1 could be used to differentiate high from low trans­porters; this however needs further evaluation in a larger population.

Funded and Supported by King AbdulAziz City of Science and Technology (KACST) and King Saud University, Riyadh, Saudi Arabia

 
   References Top

1.National Kidney Foundation Dialysis Outcome Quality Initiative: NKF-K/DOQI clinical prac­tice guidelines for peritoneal dialysis Ade­quacy: Update 2000. Am J Kidney Dis 2000; 37(Suppl 1):S65-136.  Back to cited text no. 1    
2.National Kidney Foundation Dialysis Outcome Quality Initiative peritoneal dialysis adequacy Work Group: NKF-K/DOQI clinical practice guidelines for peritoneal dialysis adequacy: Am J Kidney Dis 1997;30(Suppl 2):S67.  Back to cited text no. 2    
3.Diaz-Buxo JA, Lowrie EG, Lew NL, et al. Associate of mortality among peritoneal dia­lysis patients with special reference to peri­toneal transport rates and solute clearance. Am J Kidney Dis 1999;33:523-34.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Leypoldt JK, Cheung AK, Carrol CE, et al. Removal of middle molecules enhances survival in hemodialysis. J Am Soc Nephrol 1996;7: 1454.  Back to cited text no. 4    
5.Bergman JM, Thorpe KE, Churchill DN. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: A Reanalysis of CANUSA Study. J Am Soc Nephrol 2001;12;2158-62.  Back to cited text no. 5    
6.Spenceer K. Analytical reviews in clinical biochemistry: The estimation of creatinine. Ann Clin Biochem 1986;23:1-25.  Back to cited text no. 6    
7.Simpson WJ. Plasma creatinine and the effect of delay in the separation of samples. Ann Clin Biochem 1992;:307-30.  Back to cited text no. 7    
8.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. 8    
9.Shimizu-Tokiwa A, Kobata M, Io H, et al. Serum cystatin C is more sensitive marker of glomerular function than serum creatinine. Nephron 2002;92(1):224-6  Back to cited text no. 9    
10.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(1):29-34.  Back to cited text no. 10    
11.Kyhse-Andersen J, Schmidt C, Noordin G, et al. Serum Cystatin C determined by a rapid, automated particle-enhanced turbitometric method is a better marker than serum crea­tinine for glomerular filtration rate. Clin Chem 1994;40:1921-6.  Back to cited text no. 11    
12.Vikas R, Charles K, Stevens G. Serum cystatin C is superior to serum creatinine as marker of kidney function: A meta analysis. Am J Kidney Dis 2002;40(2) 221-6.  Back to cited text no. 12    
13.Erlandsen EJ, Randers E, Kristensen JH. Eva­luation of the Dade Behring N Latex Cystatin C assay on the Dade Behring Nephlometer II System. Scand J Clin Lab Invest 1999;59:1-8.  Back to cited text no. 13  [PUBMED]  
14.Twardowski ZJ, Nolph KD, Khanna R, et al. Peritoneal equilibration test. Perit Dial Bull 1987;7:138-47.  Back to cited text no. 14    
15.Kabanda A, Goffin E, Bernard A, et al. Factors influencing serum levels and peritoneal clearance of low molecular weight proteins in continuous ambulatory peritoneal dialysis. Kidney Int 1995;48:1946-52.  Back to cited text no. 15  [PUBMED]  
16.Erlandsen EJ, Randers E, Kristensen JH. Reference intervals for serum cystatin c and serum creatinine in adults. Clin Chem Lab Med 1998;36:393-7.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Montini G, Amici G, Milan, et al. Middle molecule and small protein removal in children on peritoneal dialysis. Kidney Int 2002;61(3): 1153-9.  Back to cited text no. 17    
18.Blumenkrantz MJ, Gahl GM, Kopple JD, et al. Protein loses during peritoneal dialysis. Kidney Int 1981;19:593-602.  Back to cited text no. 18  [PUBMED]  
19.Mussap M, Plebani M. Biochemistry and clinical role of human cystatin C .Crit Rev Clin Lab Sci 2004:41(5-6):467-550.  Back to cited text no. 19    
20.Kagan A, Bar-Khaim Y, Schafer Z, Fainaru M. Kinetics of peritoneal protein loss during CAPD: Different characteristics for low and high molecular weight proteins. Kidney Int 1990;37(3):971-9.  Back to cited text no. 20    

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Correspondence Address:
Jamal S Al-Wakeel
Department of Medicine, King Khalid University Hospital, P.O. Box 2925, Riyadh 11461
Saudi Arabia
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PMID: 19237809

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    Figures

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