Hemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children

<div><p>Randomized trials in adults have shown reduced all-cause and cardiovascular mortality on hemodiafiltration (HDF) compared to high-flux hemodialysis (HD), but the mechanisms leading to improved outcomes are not clear. We studied biomarkers of inflammation, oxidative stress, anti-oxidant capacity and endothelial dysfunction in 22 children (13 female, age 8–15 years). All children received HD for at least 3 months, and were then switched to HDF, keeping all dialysis related parameters and dialysis time constant. All the biomarkers of inflammation (ß2-microglobulin, IL-6, IL-10, high sensitive C-reactive protein [hsCRP]), oxidative stress (nitrotyrosine, advanced glycation end-products [AGEs], oxidized low density lipoprotein [ox-LDL] and anti-oxidant capacity) and endothelial dysfunction (asymmetric dimethyl arginine [ADMA], symmetric dimethyl arginine [SDMA]), were comparable between incident and prevalent patients on HD, suggesting that even a short dialysis vintage of 3 months on HD increases inflammation and endothelial stress. After 3 months of HDF therapy there was a significant reduction in ß2-microglobulin (p<0.001), hCRP, ADMA, SDMA, AGEs, ox-LDL (p<0.01 for all) and an increase in total antioxidant capacity (p<0.001) compared to HD. All children were maintained on the same dialyser, dialysis water quality, dialysis time and blood flow speeds suggesting that improved clearances on HDF led to an improved biomarker profile. Even in children with residual renal function there was a significant reduction in ß2 microglobulin, hsCRP, SDMA, ox-LDL and AGEs on HDF compared to HD. Children with a lower blood flow had higher inflammatory status (higher IL-6/IL-10 ratio; p = 0.04, r = -0.43). Children who achieved a higher convective volume (≥median 12.8L/m²) had lower ox-LDL (p = 0.02). In conclusion, we have shown that a significant improvement in inflammation, antioxidant capacity and endothelial risk profile is achieved even within a short time (3 months) on HDF compared to HD treatment.</p><p><b><i>Trial Registration</i>:</b> ClinicalTrials.gov: <a href="https://clinicaltrials.gov/ct2/show/NCT02063776" target="_blank">NCT02063776</a>.</p></div

Hemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children - Fig 3

<p>Percent increase in TAC and percent decrease in SDMA from HD to HDF was more pronounced in patients with higher blood flow rate (A,B). Higher blood flow rate was also associated with lower IL-6 to IL-10 ratio on HDF (C). Percent change = [(HDF-HD)/HD]*100.</p

Baseline characteristics of the patients.

<p>Baseline characteristics of the patients.</p

Comparison of biomarkers in children with and without residual renal function (RRF) on high-flux HD and HDF.

<p>Markers of oxidative stress (A), inflammation (B) and endothelial dysfunction (C) were significantly decreased in addition to a significant increase in anti-oxidant capacity on HDF compared to HD. This improvement was observed not only in patients without RRF but also in patients with RRF.</p

Demonstrating the molecular weights of the studied markers and comparison with albumin.

<p>AGEs are not shown in the figure because they are composed of several molecules, which are mostly middle molecules.</p

Dialysis related parameters of the patients.

<p>Dialysis related parameters of the patients.</p

Comparison of the inflammatory, oxidative stress and endothelial markers between HD and HDF in patients with and without residual renal function.

<p>Comparison of the inflammatory, oxidative stress and endothelial markers between HD and HDF in patients with and without residual renal function.</p

Table1_Magnetic resonance imaging based kidney volume assessment for risk stratification in pediatric autosomal dominant polycystic kidney disease.xlsx

IntroductionIn the pediatric context, most children with autosomal dominant polycystic kidney disease (ADPKD) maintain a normal glomerular filtration rate (GFR) despite underlying structural kidney damage, highlighting the critical need for early intervention and predictive markers. Due to the inverse relationship between kidney volume and kidney function, risk assessments have been presented on the basis of kidney volume. The aim of this study was to use magnetic resonance imaging (MRI)-based kidney volume assessment for risk stratification in pediatric ADPKD and to investigate clinical and genetic differences among risk groups.MethodsThis multicenter, cross-sectional, and case-control study included 75 genetically confirmed pediatric ADPKD patients (5–18 years) and 27 controls. Kidney function was assessed by eGFR calculated from serum creatinine and cystatin C using the CKiD-U25 equation. Blood pressure was assessed by both office and 24-hour ambulatory measurements. Kidney volume was calculated from MRI using the stereological method. Total kidney volume was adjusted for the height (htTKV). Patients were stratified from A to E classes according to the Leuven Imaging Classification (LIC) using MRI-derived htTKV.ResultsMedian (Q1-Q3) age of the patients was 6.0 (2.0–10.0) years, 56% were male. There were no differences in sex, age, height-SDS, or GFR between the patient and control groups. Of the patients, 89% had PKD1 and 11% had PKD2 mutations. Non-missense mutations were 73% in PKD1 and 75% in PKD2. Twenty patients (27%) had hypertension based on ABPM. Median htTKV of the patients was significantly higher than controls (141 vs. 117 ml/m, p = 0.0003). LIC stratification revealed Classes A (38.7%), B (28%), C (24%), and D + E (9.3%). All children in class D + E and 94% in class C had PKD1 variants. Class D + E patients had significantly higher blood pressure values and hypertension compared to other classes (p > 0.05 for all).DiscussionThis study distinguishes itself by using MRI-based measurements of kidney volume to stratify pediatric ADPKD patients into specific risk groups. It is important to note that PKD1 mutation and elevated blood pressure were higher in the high-risk groups stratified by age and kidney volume. Our results need to be confirmed in further studies.</p

Subject characteristics.

<p>Data are given as mean ± SD, median (interquartile range) or n (%) as appropriate.</p><p>At the time of bone marker assessment, 42 children (7.4%) were receiving rhGH treatment, excluding 4 patients who either started or stopped rhGH therapy within 3 months prior to analysis. 38 patients were consistently treated with rhGH during the follow-up period of 6–12 months. rhGH treated patients originated from 7 of the 12 participating countries, had a longer preceding duration of CKD (8.1±4.3 vs 5.9±4.5 years, p<0.003), were taller (-0.89±0.87 vs. -1.4±1.4 SDS, p<0.0002) and showed marginally better current growth rates (0.07±0.38 vs. -0.04±0.38, p = 0.08) compared to all non-rhGH treated patients.</p><p>Subject characteristics.</p

Predictors of baseline and prospective change in standardized height in total cohort; results of stepwise multiple linear regression analyses.

<p>The prospective change in height SDS during one year of observation was positively associated with higher BAP and TRAP5b SDS, lower baseline height SDS and rhGH therapy.</p><p>Interestingly, physical activity showed a positive association to prospective growth.</p><p>A case-control study was performed to obtain an unbiased analysis of the impact of rhGH on the bone marker pattern. For 41 rhGH treated patients an equal number of untreated control subjects matched by age, sex, country of residence, CKD duration, eGFR and serum phosphorus, iPTH and CRP was identified (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113482#pone.0113482.t005" target="_blank">Table 5</a>).</p><p>Predictors of baseline and prospective change in standardized height in total cohort; results of stepwise multiple linear regression analyses.</p