Plasma Levels of Middle Molecules to Estimate Residual Kidney Function in Haemodialysis without Urine Collection

© 2015 Vilar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/Licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BACKGROUND: Residual Kidney Function (RKF) is associated with survival benefits in haemodialysis (HD) but is difficult to measure without urine collection. Middle molecules such as Cystatin C and β2-microglobulin accumulate in renal disease and plasma levels have been used to estimate kidney function early in this condition. We investigated their use to estimate RKF in patients on HD. DESIGN: Cystatin C, β2-microglobulin, urea and creatinine levels were studied in patients on incremental high-flux HD or hemodiafiltration(HDF). Over sequential HD sessions, blood was sampled pre- and post-session 1 and pre-session 2, for estimation of these parameters. Urine was collected during the whole interdialytic interval, for estimation of residual GFR (GFRResidual = mean of urea and creatinine clearance). The relationships of plasma Cystatin C and β2-microglobulin levels to GFRResidual and urea clearance were determined. RESULTS: Of the 341 patients studied, 64% had urine output>100 ml/day, 32.6% were on high-flux HD and 67.4% on HDF. Parameters most closely correlated with GFRResidual were 1/β2-micoglobulin (r2 0.67) and 1/Cystatin C (r2 0.50). Both these relationships were weaker at low GFRResidual. The best regression model for GFRResidual, explaining 67% of the variation, was: GFRResidual = 160.3 · (1/β2m) - 4.2. Where β2m is the pre-dialysis β2 microglobulin concentration (mg/L). This model was validated in a separate cohort of 50 patients using Bland-Altman analysis. Areas under the curve in Receiver Operating Characteristic analysis aimed at identifying subjects with urea clearance≥2 ml/min/1.73 m2 was 0.91 for β2-microglobulin and 0.86 for Cystatin C. A plasma β2-microglobulin cut-off of ≤19.2 mg/L allowed identification of patients with urea clearance ≥2 ml/min/1.73 m2 with 90% specificity and 65% sensitivity. CONCLUSION: Plasma pre-dialysis β2-microglobulin levels can provide estimates of RKF which may have clinical utility and appear superior to cystatin C. Use of cut-off levels to identify patients with RKF may provide a simple way to individualise dialysis dose based on RKF.Peer reviewe

Relationship of GFR with the reciprocal of pre-dialysis plasma Cystatin C levels.

<p>GFR shown is calculated from the mean of urea and creatinine clearance. For the linear regression shown r² was 0.5.</p

Plasma levels of molecules at each study time-point

<p>SD Standard Deviation</p><p>Plasma levels of molecules at each study time-point</p

ROC analysis of pre-dialysis levels of Cystatin C, β2-microglobulin, urea and Cystatin C to identify patients with significant residual renal urea clearance ≥2ml/min/1.73m² BSA.

<p>The greatest area under the curve was for β2-microglobulin.</p

Demographics of the validation cohort.

<p>† Median</p><p>* Interquartile range (IQR)</p><p>Demographics of the validation cohort.</p

Baseline characteristics and dialysis parameters of the study population.

<p>Total Kt/V_urea represents the sum of residual renal and dialyser clearance which was used for incremental dialysis calculations and as target Kt/V (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0143813#sec006" target="_blank">methods</a>).</p><p>† Median.</p><p>* Interquartile range.</p><p>Baseline characteristics and dialysis parameters of the study population.</p

B2-microglobulin level cut-off levels that may be used to identify patients with residual renal function measured as GFR.

<p>AUC: Area Under the Curve</p><p>For various levels of GFR the cut-off β2 microglobulin level was determined that would yield a false positive rate (specificity) of 10%. For each GFR level area under the curve is shown for ROC analyses.</p

Bland-Altman analysis showing performance of Eq 1 for predicting GFR (ml/min/1.73m² BSA) based on pre-dialysis β2-microglobulin plasma concentration.

<p>Bland-Altman analysis showing performance of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0143813#pone.0143813.e004" target="_blank">Eq 1</a> for predicting GFR (ml/min/1.73m² BSA) based on pre-dialysis β2-microglobulin plasma concentration.</p

Relationship of GFR with the reciprocal of pre-dialysis β2 microglobulin levels.

<p>GFR shown is calculated from mean of urea and creatinine clearance. For the linear regression shown r2 was 0.67.</p

Correlation of pre-dialysis Cystatin C and β2 microglobulin plasma levels and their interdialytic rise with various measures of RKF

<p>GFR_Residual = the measured residual GFR (mean of urea and creatinine clearances).r² is the square of the Pearson correlation coefficient.</p><p>Correlation of pre-dialysis Cystatin C and β2 microglobulin plasma levels and their interdialytic rise with various measures of RKF</p