The Kinetics of Cystatin C: A Marker for Dialysis Adequacy

When 90% or more of native kidney function is lost, renal replacement therapy must be initiated to sustain life. Renal transplantation is the preferred method, but availability is limited. The ideal dialysis prescription remains elusive. Small molecular weight molecules (such as urea and creatinine) have been used as markers of both kidney (native and transplant) and dialysis toxin clearance (function), but there are pitfalls in using these markers to assess total ‘renal’ dose (kidney plus dialysis). Body weight, gender and other factors also affect the concentrations of these small molecules, but not cystatin C. Furthermore, cystatin C has been shown to be a better marker for estimating kidney function than creatinine, and is associated with cardiovascular morbidity and mortality. Studies have shown that it is removed by dialysis. Therefore, we investigated the use of cystatin C, a naturally occurring endogenous protein, as a marker for estimating dialysis adequacy and renal clearance. This investigation was comprised of four studies to understand the kinetics of cystatin C in patients with advanced kidney disease with or without dialysis. We found that the amount of cystatin C reduction was influenced positively by hemodialysis blood flow rate and treatment time, and negatively by ultrafiltration rate. We further demonstrated that renal hyperfiltration significantly influenced the error of creatinine-based glomerular filtrate rate equation, but not for the cystatin C equation. Therefore, cystatin C appears to be a useful marker for the assessment of kidney function in patients with advanced kidney disease but not yet on dialysis. This was taken further in our third study where we developed an equation, which gave a better estimate of residual renal function than previously published equations in patients on dialysis but who have some remaining kidney function. Finally, we confirmed our hypothesis that cystatin C is cleared during dialysis by both diffusion and convection. It is distributed mainly in the extracellular space but equilibrates slowly between the extravascular and intravascular spaces. Furthermore, we have shown that cystatin C while cleared by dialysis is stable between dialysis treatments rather than being influenced by a single dialysis treatment. It is a marker for both dialysis and renal clearances and, thus, gives a stable index of total renal clearance. The long term goal will be to define the cystatin C threshold level that influences patient morbidity and mortality and to allow better dialysis prescriptions for patients with varying (and changing) residual renal function

Residual renal function assessment with cystatin C

Su Jin Kim and coworkers from Korea published an important study on the relationship of residual renal function (RRF) and cystatin in pediatric peritoneal dialysis (PD) patients in this issue of Pediatric Nephrology, both in anuric patients and patients with RRF. Based on a lack of correlation between cystatin C and standard small solute-based dialysis adequacy parameters such as Kt/Vurea but a significant correlation with RRF, the authors concluded that cystatin C may be a good tool to monitor RRF. The editorial reviews the available literature in adults, the different handing between urea and cystatin C, and the determinants of cystatin C clearance in dialysis patients. In adults, cystatin C levels are determined predominantly by RRF, but not exclusively. In anephric hemodialysis and PD patients, there is a correlation with standard weekly Kt/Vurea. Cystatin C levels will also depend on ultrafiltration. Despite these factors that affect cystatin C levels beyond RRF, cystatin C is a useful parameter for monitoring PD patients that may be more closely related to long-term outcomes than small solute adequacy parameters. © 2010 IPNA

Estimation of GFR using β-trace protein in children

Background and objectives Sexmay affect the performance of smallmolecularweight proteins as markers of GFR because of differences in fat mass between the two sexes. The hypothesis was that the diagnostic performance of b-trace protein, a novel marker of GFR, would be significantly better in boys than in girls. Design, setting, participants, & measurements GFR, height, weight, serum creatinine, and β-trace protein were measured in 755 children and adolescents (331 girls) undergoing 99technetium diethylenetriamine penta–acetic acid renal scans from July of 1999 to July of 2006. Boys and girls were separated into formula generation cohorts (284 boys and 220 girls) and formula validation cohorts (140 boys and 111 girls). GFRestimating formulas on the basis of β-trace protein, creatinine, and height were derived using stepwise linear regression analysis of log-transformed data. The slope of the regression lines of the sex-specific eGFRswere compared. Bland–Altman analysis was used for testing agreement between 99technetium diethylenetriamine penta–acetic acid GFR and calculated GFR both with this equation in boys and girls as well as previously established Benlamri, White, and Schwartz formulas. Results In the stepwise regression analysis, β-trace protein (R2=0.73 for boys and R2=0.65 for girls) was more important than creatinine (which increased R2 to 0.81 for boys and R2 to 0.75 for girls) and height (which increased R2 to 0.88 for boys and R2 to 0.80 for girls) in the data generation groups. GFR can be calculated using the following formulas: formula present Bland–Altman analysis showed better performance in boys than in girls. The new formulas performed significantly better than the previous Benlamri, White, and Schwartz formulas with respect to bias, precision, and accuracy. Conclusions Improved and sex-specific formulas for the estimation of GFR in children on the basis of β-trace protein, serum creatinine, and height are now available

Cystatin C reduction ratio depends on normalized blood liters processed and fluid removal during hemodialysis

Background and objectives: A negative correlation between the weekly standard Kt/V (urea) and serum cystatin C level (CysC) in functionally anephric dialysis patients has been previously demonstrated. Our objective was to measure the per dialysis CysC reduction ratio (CCRR) and to compare it with other indices of dialytic functions. Design, setting, participants, & measurements: In a pilot cross-sectional study of 15 functionally anephric patients on conventional high-flux high-efficiency hemodialysis three times per week, CysC levels were drawn pre-, mid-, and postdialysis over 1 week. CCRR was compared with single-pool Kt/V (Sp Kt/V) using urea kinetic modeling, urea reduction ratio (URR), creatinine reduction ratio (CRR), normalized liters processed (LP/kg), and ultrafiltration volume (UF). Normally distributed data (Shapiro-Wilks test) were described as mean ± SD, otherwise as median and interquartile range. Results: The mean pre- and post-CysC levels were 6.0 ± 1.0 and 4.7 ± 1.1 mg/L. The Sp Kt/V and Std Kt/V were 1.5 ± 0.2 and 2.6. The URR, CRR, and CCRR were 70.2% ± 9.0%, 64.5% ± 8.2%, and 26.1% ± 11.8%, respectively. There was no correlation between the CCRR, and the Sp Kt/V, URR, and CRR, whereas CCRR correlated with LP/kg and UF. Multiple regression analysis with these two parameters provided a model that explained 81% of the variance. Conclusions: Our data suggest that normalized liters processed and ultrafiltration volume explain most of the variance of CCRR. Therefore, CCRR may be an excellent method to monitor dialysis efficiency of low molecular weight proteins. Copyright © 2011 by the American Society of Nephrology

Euvolemia in hemodialysis patients: a potentially dangerous goal?

Dialysis patients have high mortality rate and the leading cause of death is cardiovascular disease. Uremic cardiomyopathy differs from that due to conventional atherosclerosis, where cardiovascular changes result in ineffective circulation and lead to tissue ischemia. Modern dialysis has significant limitations with fluid management probably the most challenging. Current evidence suggests that both volume overload and aggressive fluid removal can induce circulatory stress and multi-organ injury. Furthermore, we do not have accurate volume assessment tools. As a result, targeting euvolemia might result in more harm than benefit with conventional hemodialysis therapy. Therefore, it might be time to consider a degree of permissive over-hydration until we have better tools to both determine ideal weight and improve current renal replacement therapy so that the process of achieving it is not so fraught with the current dangers

Can the new CKD-EPI BTP-B2M formula be applied in children?

Although measuring creatinine to determine kidney function is currently the clinical standard, new markers such as beta-trace protein (BTP) and beta-2-microglobulin (B2M) are being investigated in an effort to measure glomerular filtration rate more accurately. In their recent publication, Inker et al. (Am J Kidney Dis 2015; 67:40–48) explored the use of these two relatively new markers in combination with some commonly available clinical characteristics in a large cohort of adults with chronic kidney disease. Their research led them to develop three formulae using BTP, B2M, and a combination of the two. The combined formula is particularly attractive as it removes all gender bias, which applies to both serum creatinine and cystatin C. Using data from a cohort of 127 pediatric patients from our center, we sought to determine whether these formulae would be equally as effective in children as in adults. Unfortunately, we found that the formulae cannot be applied to the pediatric population

A cross-sectional study measuring vanadium and chromium levels in paediatric patients with CKD

Objectives Although many secondary effects of high levels of vanadium (V) and chromium (Cr) overlap with symptoms seen in paediatric patients with chronic kidney disease (CKD), their plasma V and Cr levels are understudied. Design Ancillary cross-sectional study to a prospective, longitudinal, randomised controlled trial. Setting Children\u27s Hospital of Western Ontario, London Health Sciences Centre, London, Ontario, Canada. Participants 36 children and adolescents 4-18 years of age with CKD. Interventions 1-6 trace element measurements per patient. Cystatin C (CysC) estimated glomerular filtration rate (eGFR) was calculated using the Filler formula. Plasma V and Cr levels were measured using high-resolution sector field inductively coupled mass spectrometry. Anthropomorphic data and blood parameters were collected from our electronic chart programme. Water Cr and V data were obtained from the Ontario Water (Stream) Quality Monitoring Network. Primary and secondary outcome measures Primary outcomes: Plasma Cr and V. Secondary outcomes: Age, season, CysC, CysC eGFR, and Cr and V levels in environmental water. Results The median (IQR) eGFR was 51 mL/min/1.73 m 2 (35, 75). The median V level was 0.12 μg/L (0.09, 0.18), which was significantly greater than the 97.5th percentile of the reference interval of 0.088 μg/L; 32 patients had at least one set of V levels above the published reference interval. The median Cr level was 0.43 μg/L (0.36, 0.54), which was also significantly greater than the established reference interval; 34 had at least one set of Cr levels above the published reference interval. V and Cr levels were moderately correlated. Only some patients had high environmental exposure. Conclusions Our study suggests that paediatric patients with CKD have elevated plasma levels of V and Cr. This may be the result of both environmental exposure and a low eGFR. It may be necessary to monitor V and Cr levels in patients with an eGFR \u3c30 mL/min/1.73 m2

Effect of ultrafiltration during hemodialysis on hepatic and total-body water: an observational study.

Background The hepatic circulation is involved in adaptive systemic responses to circulatory stress. However, it is vulnerable to both chronic hypervolemia and cardiac dysfunction. The influence of hemodialysis (HD) and ultrafiltration (UF) upon liver water content has been understudied. We conducted a detailed pilot study to characterize the effects of HD upon liver water content and stiffness, referenced to peripheral fluid mobilization and total body water. Methods We studied 14 established HD patients without liver disease. Magnetic resonance imaging (MRI) together with ultrasound-based elastography and bioimpedance assessment were employed to measure hepatic water content and stiffness, body composition, and water content in the calf pre- and post-HD. Results Mean UF volume was 8.13 ± 4.4 mL/kg/hr. Fluid removal was accompanied with effective mobilization of peripheral water (measured with MRI within the thigh) from 0.85 ± 0.21 g/mL to 0.83 ± 0.18 g/mL, and reduction in total body water (38.9 ± 9.4 L to 37.4 ± 8.6 L). However, directly-measured liver water content did not decrease (0.57 ± 0.1 mL/g to 0.79 ± 0.3 m L/g). Liver water content and IVC diameter were inversely proportional (r = - 0.57, p = 0.03), a relationship which persisted after dialysis. Conclusions In contrast to the reduced total body water content, liver water content did not decrease post-HD, consistent with a diversion of blood to the hepatic circulation, in those with signs of greater circulatory stress. This novel observation suggests that there is a unique hepatic response to HD with UF and that the liver may play a more important role in intradialytic hypotension and fluid shifts than currently appreciated

Statistical identification of gene association by CID in application of constructing ER regulatory network

<p>Abstract</p> <p>Background</p> <p>A variety of high-throughput techniques are now available for constructing comprehensive gene regulatory networks in systems biology. In this study, we report a new statistical approach for facilitating <it>in silico </it>inference of regulatory network structure. The new measure of association, coefficient of intrinsic dependence (CID), is model-free and can be applied to both continuous and categorical distributions. When given two variables X and Y, CID answers whether Y is dependent on X by examining the conditional distribution of Y given X. In this paper, we apply CID to analyze the regulatory relationships between transcription factors (TFs) (X) and their downstream genes (Y) based on clinical data. More specifically, we use estrogen receptor α (ERα) as the variable X, and the analyses are based on 48 clinical breast cancer gene expression arrays (48A).</p> <p>Results</p> <p>The analytical utility of CID was evaluated in comparison with four commonly used statistical methods, Galton-Pearson's correlation coefficient (GPCC), Student's <it>t</it>-test (STT), coefficient of determination (CoD), and mutual information (MI). When being compared to GPCC, CoD, and MI, CID reveals its preferential ability to discover the regulatory association where distribution of the mRNA expression levels on X and Y does not fit linear models. On the other hand, when CID is used to measure the association of a continuous variable (Y) against a discrete variable (X), it shows similar performance as compared to STT, and appears to outperform CoD and MI. In addition, this study established a two-layer transcriptional regulatory network to exemplify the usage of CID, in combination with GPCC, in deciphering gene networks based on gene expression profiles from patient arrays.</p> <p>Conclusion</p> <p>CID is shown to provide useful information for identifying associations between genes and transcription factors of interest in patient arrays. When coupled with the relationships detected by GPCC, the association predicted by CID are applicable to the construction of transcriptional regulatory networks. This study shows how information from different data sources and learning algorithms can be integrated to investigate whether relevant regulatory mechanisms identified in cell models can also be partially re-identified in clinical samples of breast cancers.</p> <p>Availability</p> <p>the implementation of CID in R codes can be freely downloaded from <url>http://homepage.ntu.edu.tw/~lyliu/BC/</url>.</p