Hemodiafiltration is associated with reduced inflammation and increased bone formation compared to conventional hemodialysis in children - the HDF, Heart and Height (3H) study

IntroductionChronic kidney disease (CKD) is associated with nearly universal disturbances in mineral bone disease (MBD)

Bacchetta, J., Harambat, J., Cochat, P., Salusky, I. B. & Wesseling-Perry, K. The consequences of chronic kidney disease on bone metabolism and growth in children. Nephrol Dial Transplant 27, 3063-3071, doi:gfs299 [pii];10.1093/ndt/gfs299 [doi] (2012).

,Defective skeletal mineralization in pediatric CKD. manifesting as bone painSevere bone disease and low bone mineral density after juvenile renal failure., deformitiesSevere bone disease and low bone mineral density after juvenile renal failure., growth retardation in childrenEffect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure., fracturesSevere bone disease and low bone mineral density after juvenile renal failure.,

Denburg, M. R. et al. Fracture Burden and Risk Factors in Childhood CKD: Results from the CKiD Cohort Study. J Am Soc. Nephrol 27, 543-550, doi:ASN.2015020152 [pii];10.1681/ASN.2015020152 [doi] (2016).

and also vascular calcification

Shroff, R., Long, D. A. & Shanahan, C. Mechanistic insights into vascular calcification in CKD. J Am. Soc. Nephrol 24, 179-189, doi:ASN.2011121191 [pii];10.1681/ASN.2011121191 [doi] (2013).

. Although assessment of bone health is integral to the care of patients with CKD, it remains a major challenge for physiciansBone evaluation in paediatric chronic kidney disease: clinical practice points from the European Society for Paediatric Nephrology CKD-MBD and Dialysis working groups and CKD-MBD working group of the ERA-EDTA.. Histomorphometric analysis of bone biopsies is the gold standard for diagnosis of renal bone diseaseK/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease., but is invasive and not suited for screening and longitudinal monitoring. On the other hand, radiological bone assessment such as conventional x-rays or dual-energy X-ray absorptiometry (DXA), although non-invasive and widely available, has limited sensitivity and specificity in predicting changes in bone turnover and mineralizationAssessing bone mineralisation in children with chronic kidney disease: what clinical and research tools are available?.,Routine serum biomarkers, but not dual-energy X-ray absorptiometry, correlate with cortical bone mineral density in children and young adults with chronic kidney disease..Circulating biomarkers, reflecting global skeletal activity, are recognized as important toolsBiochemical markers of bone turnover: why theory, research, and clinical practice are still in conflict.,Using biochemical markers of bone turnover in clinical practice. to detect changes in bone homeostasis, enabling the assessment of both bone formation and resorptionPaediatric reference values for the C-terminal fragment of fibroblast-growth factor-23, sclerostin, bone-specific alkaline phosphatase and isoform 5b of tartrate-resistant acid phosphatase.,

Doyon, A. et al. Markers of bone metabolism are affected by renal function and growth hormone therapy in children with chronic kidney disease. PLoS One 10, e0113482, doi:10.1371/journal.pone.0113482 [doi];PONE-D-14-07739 [pii] (2015).

. Classical formation markers include bone alkaline phosphatase (BAP), a protein found on the surface of osteoblasts reflecting their activity. Bone resorption markers include tartrate-resistant acid phosphatase 5b (TRAP-5b), an enzyme produced by osteoclasts, reflecting their numberSkeletal remodeling in health and disease.Minireview: the OPG/RANKL/RANK system.Transcriptional networks controlling skeletal development.Kubota T. Michigami T. Ozono K. Wnt signaling in bone metabolism. and C-terminal telopeptide of type I collagen (CTX). In addition, sclerostin a canonical Wnt signaling pathway inhibitorFrom skeletal to cardiovascular disease in 12 steps-the evolution of sclerostin as a major player in CKD-MBD. was studied. More recently, the effects of chronic inflammation, which is common in patients with advanced CKD, has come into focus. Several conditions characterized by chronic inflammation are associated with excessive bone resorptionInflammation and functional iron deficiency regulate fibroblast growth factor 23 production.,Tsukasaki M. Takayanagi H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease., but the effects, if any, of different dialysis modalities on the inflammatory phenotype and CKD-related bone disease have not been studied.The ‘HDF-Hearts-Height’ (3H) study, a multicenter, longitudinal study in children receiving hemodiafiltration (HDF) compared to conventional hemodialysis (HD)Effect of haemodiafiltration vs conventional haemodialysis on growth and cardiovascular outcomes in children - the HDF, heart and height (3H) study., showed that subclinical cardiovascular disease is prevalent in children on dialysis, with attenuated progression of vascular changes in children receiving HDF compared to conventional HDEffects of Hemodiafiltration versus Conventional Hemodialysis in Children with ESKD: The HDF, Heart and Height Study.. In a cross-over trial when children on conventional HD were switched to HDF, keeping all other dialysis related parameters constant, a significant improvement in inflammation, antioxidant capacity and endothelial risk profile were seen even within a short time (3 months)Hemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children., but the effect of these biochemical changes on CKD-related bone disease were not explored. We present a post-hoc analysis of the 3H data to determine the changes in bone biomarkers in children on dialysis and the effect of different dialysis modalities on the evolution of MBD over a one-year follow-up.DiscussionDialysis is known to cause a pro-inflammatory milieu and is associated with profound dysregulation of mineral bone metabolism, but the impact of different dialysis modalities on CKD-MBD in adults and children remains largely undescribed. This prospective observational study, a post-hoc analysis of bone related outcomes in children on maintenance dialysis, has shown that children on HDF have an attenuated inflammatory profile, increased bone formation, stable sclerostin concentrations and lower FGF23/klotho ratios compared to those on conventional HD. The ∼25% reduction in FGF23 and a lower FGF23/klotho ratio in patients on HDF may explain the lower left ventricular mass in the 3H cohortEffects of Hemodiafiltration versus Conventional Hemodialysis in Children with ESKD: The HDF, Heart and Height Study. and reduced cardiovascular mortality in adult randomized studies comparing HDF to conventional HDHigh-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients.. HDF may achieve these effects through an improved clearance of the large middle-sized molecules (LMM) including pro-inflammatory cytokines and other ‘uremic toxins’ as well as reduce the production of these molecules in the more biocompatible milieu in HDF. There was no difference in residual renal function in HD and HDF cohorts, and this did not influence markers of mineral metabolism.While bone turnover is best described on bone histology from tetracycline-labelled bone biopsies, circulating biomarkers are useful surrogate measures: serum BAP levels are reflective of bone formation and TRAP5b of bone resorptionBone evaluation in paediatric chronic kidney disease: Clinical practice points from the European Society for Paediatric Nephrology CKD-MBD and Dialysis working groups and CKD-MBD working group of the ERA-EDTA.. Unlike other bone biomarkers, both BAP and TRAP5b are unaffected by CKD stageThe use of bone turnover markers in chronic kidney disease-mineral and bone disorders.. A large prospective observational study measuring a range of biomarkers in children with CKD stages 3 to 5 has shown a high bone turnover, with a clear increase in BAP z-score and a small but significant increase of TRAP5b z-score levels

Doyon, A. et al. Markers of bone metabolism are affected by renal function and growth hormone therapy in children with chronic kidney disease. PLoS One 10, e0113482, doi:10.1371/journal.pone.0113482 [doi];PONE-D-14-07739 [pii] (2015).

. We showed that the BAP-to-TRAP5b activity remained almost constant in children on HD, while children on HDF had an increase in the BAP/TRAP ratio that was comparable to that seen in healthy childrenPaediatric reference values for the C-terminal fragment of fibroblast-growth factor-23, sclerostin, bone-specific alkaline phosphatase and isoform 5b of tartrate-resistant acid phosphatase.. Although we did not see an association with growth hormone treatment, a previous study has shown that in children receiving recombinant growth hormone, BAP was higher and TRAP5b lower than in untreated controls

Doyon, A. et al. Markers of bone metabolism are affected by renal function and growth hormone therapy in children with chronic kidney disease. PLoS One 10, e0113482, doi:10.1371/journal.pone.0113482 [doi];PONE-D-14-07739 [pii] (2015).

, further strengthening the case for an increased BAP/TRAP5b ratio reflecting osteo-anabolism in the HDF cohort.We showed that the BAP/TRAP5b ratio inversely correlated with the inflammatory markers on univariable analysis. However, on multivariable analysis adjustment TNF-α attenuated but did not completely remove the difference between HD and HDF groups, suggesting that a reduction in the inflammatory milieu may contribute to, but is not the sole cause, of the observed improvement in the BAP/TRAP5b ratio in the HDF cohort. A similar inverse association of BAP and TRAP5b with CRP has been shown in children with CKD 3-5, implying that the effect of inflammation on reduced bone turnover is independent of the underlying renal disease or the effect of dialysis per se

Doyon, A. et al. Markers of bone metabolism are affected by renal function and growth hormone therapy in children with chronic kidney disease. PLoS One 10, e0113482, doi:10.1371/journal.pone.0113482 [doi];PONE-D-14-07739 [pii] (2015).

. A recent cross-sectional study in 63 children with CKD stages 2-5 has shown that TNF-α correlated with biomarkers of CKD-MBD and showed an inverse association with height z-score, suggesting that inflammation may contribute to growth impairment in pediatric CKDTumor necrosis factor-alpha is associated with mineral bone disorder and growth impairment in children with chronic kidney disease.. However, this study showed an unexpected positive correlation between TNF-α and both bone formation markers ALK and BAP, making the inhibitory effect of inflammatory cytokines on bone turnover difficult to reconcileTumor necrosis factor-alpha is associated with mineral bone disorder and growth impairment in children with chronic kidney disease.. Chronic inflammation is a multisystem disorder and there are several potential mechanisms by which inflammatory cytokines can aggravate bone disease in CKD. TNF-α inhibits the expression of RUNX2, a major transcription factor that blocks osteoblast differentiationTNF-alpha and IL-1beta inhibit RUNX2 and collagen expression but increase alkaline phosphatase activity and mineralization in human mesenchymal stem cells. and promotes osteoclastogenesisTNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand.. Receptor activator of nuclear factor κB ligand (RANKL; also known as TNF ligand superfamily, member 11) is an essential cytokine in osteoclastogenesis, but may play a paradoxical role in bone homeostasis by also increasing the expression of bone morphogenic protein 2 and stimulating the Wnt pathwayOsta B. Benedetti G. Miossec P. Classical and Paradoxical Effects of TNF-alpha on Bone Homeostasis.. Binding of RANKL to the RANK receptor leads to activation of TNF receptor-associated factors and upregulation of osteoclast target genesKrum S.A. Chang J. Miranda-Carboni G. Wang C.Y. Novel functions for NFkappaB: inhibition of bone formation.. TNF-α inhibitors are used in chronic inflammatory disorders of childhood such as inflammatory bowel disease and juvenile idiopathic arthritis, wherein children treated with TNF-α inhibitors showed improved trabecular bone mineral density and cortical structureImprovements in Bone Density and Structure during Anti-TNF-alpha Therapy in Pediatric Crohn's Disease., reduced bone lossSimonini G. Giani T. Stagi S. de Martino M. Falcini F. Bone status over 1 yr of etanercept treatment in juvenile idiopathic arthritis. and greater statural growthTynjala P. Lahdenne P. Vahasalo P. Kautiainen H. Honkanen V. Impact of anti-TNF treatment on growth in severe juvenile idiopathic arthritis.,The effects of anti-TNF-alpha treatment with adalimumab on growth in children with Crohn's disease (CD).. Our data suggest that high serum phosphate levels negatively influence bone turnover; this effect may be mediated via the PTH effect on RANKL directed osteoclastogenesis or even via stimulating inflammation. Dietary phosphate loading increased serum TNF-α in uremic ratsPhosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia.. After parathyroidectomy, bone expression of TNF-α significantly decreases in patients on HDSantos F.R. Moyses R.M. Montenegro F.L. Jorgetti V. Noronha I.L. IL-1beta, TNF-alpha, TGF-beta, and bFGF expression in bone biopsies before and after parathyroidectomy..Sclerostin, a potent inhibitor of the Wnt/ β-catenin pathwayDrueke T.B. Lafage-Proust M.H. Sclerostin: just one more player in renal bone disease?., showed an early reduction in plasma concentrations with convective clearanceHemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children.. In this study children on HDF had comparable sclerostin levels to those with moderate to severe CKD in the series published by Doyon et al

Doyon, A. et al. Markers of bone metabolism are affected by renal function and growth hormone therapy in children with chronic kidney disease. PLoS One 10, e0113482, doi:10.1371/journal.pone.0113482 [doi];PONE-D-14-07739 [pii] (2015).

, although levels in both groups were lower than in age matched healthy childrenSclerostin levels during growth in children.. In healthy children serum sclerostin levels were inversely associated with cortical volumetric bone mineral density and cortical thicknessSclerostin levels during growth in children., and lower sclerostin levels were predictive of high bone turnover even in adults with CKDSclerostin and Dickkopf-1 in renal osteodystrophy..FGF23, a phosphaturic hormone produced by osteocytes, is a 32-kilodalton protein that is known to be cleared by HDF. Comparable to previous studies, we showed ∼25% lower FGF23 levels in HDFPerouse de Montclos T. et al.[Online hemodiafiltration in children and hypoparathyroidism: a single-centre series of cases]., whereas levels increased by over 100% in HD children. As seen with the dialytic clearance of other LMM compounds such as FGF-23, IL-6 and TNF-α, although an early reduction in plasma concentrations is seen with convective clearanceHemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children., this is not sufficient to further reduce plasma concentrations in the long-term, perhaps as production of these compounds overwhelms the clearance capacity of thrice-weekly dialysisCarlson N. Mortensen O.H. Axelsen M. Pedersen R.S. Heaf J.G. Clearance of Sclerostin, Osteocalcin, Fibroblast Growth Factor 23, and Osteoprotegerin by Dialysis.. Although protective in early CKD, FGF23 is known to have several “off-target” effects, independent of changes in mineral metabolism, on cardiac myocytesFGF23 induces left ventricular hypertrophy. with an increased prevalence of left ventricular hypertrophyFibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. and premature mortality in adults with all stages of CKDFibroblast growth factor 23 and mortality among patients undergoing hemodialysis., stressing the importance of reducing FGF23 levels by HDF. Importantly, these changes in FGF23 levels were independent of serum phosphate which did not change in the HD or HDF cohorts; nevertheless, serum phosphate levels are a poor proxy of phosphate exposure and other groups have shown that phosphate control is better in patients on HDF compared to HDImpact of convective flow on phosphorus removal in maintenance hemodialysis patients.. Similarly, FGF23 levels are significantly lower in patients on short daily HD compared to those on conventional three times a week HD, suggesting that FGF23 levels may be a more sensitive biomarker of cumulative phosphate burdenShort daily hemodialysis is associated with lower plasma FGF23 levels when compared with conventional hemodialysis..In acute inflammation FGF23 expression is markedly increased, but osteocytes are able to maintain normal serum levels of biologically active FGF23 despite the rise in FGF23 transcription, by commensurately increasing FGF23 cleavageInflammation and functional iron deficiency regulate fibroblast growth factor 23 production.. In contrast, chronic inflammation also increases biologically active intact FGF23 levels, perhaps as sustained periods of FGF23 overproduction overwhelm the capacity of the FGF23 cleavage apparatus in osteocytes. Measurement of FGF23 fragments may have revealed a stronger association between FGF23 concentrations and inflammation. Cytokine profiling in a cohort of adults with pre-dialysis CKD has shown that several cytokines may play a role in increasing the production of FGF23Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation.,Associations of Fibroblast Growth Factor 23 with Markers of Inflammation and Leukocyte Transmigration in Chronic Kidney Disease.. Furthermore, inflammation may also indirectly stimulate the production of FGF23 through the activation of hepcidin and induction of hypoferremiaInflammation and functional iron deficiency regulate fibroblast growth factor 23 production.. Thus, in patients on dialysis, FGF23 can aggravate the bone disease of CKD, and lose any protective role it may have in countering hyperphosphatemia in early stages of CKDLeifheit-Nestler M. et al.Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23.Leifheit-Nestler M. et al.Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease.Sharaf El Din U.A. Salem M.M. Abdulazim D.O. Is Fibroblast growth factor 23 the leading cause of increased mortality among chronic kidney disease patients? A narrative review.. Importantly, the relationship between inflammation and CKD-MBD may be bi-directional and self-perpetuating; FGF23 stimulates hepatocytes to increase secretion of IL-6 and CRP, and FGF23 may itself be affected by inflammatory cytokinesSharaf El Din U.A. Salem M.M. Abdulazim D.O. Is Fibroblast growth factor 23 the leading cause of increased mortality among chronic kidney disease patients? A narrative review.,Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease..Conventional hemodialysis evokes an inflammatory response by releasing inflammatory cytokines

Shroff, R., Long, D. A. & Shanahan, C. Mechanistic insights into vascular calcification in CKD. J Am. Soc. Nephrol 24, 179-189, doi:ASN.2011121191 [pii];10.1681/ASN.2011121191 [doi] (2013).

,Leurs P. Lindholm B. Stenvinkel P. Effects of hemodiafiltration on uremic inflammation.,Dai L. Golembiewska E. Lindholm B. Stenvinkel P. End-Stage Renal Disease, Inflammation and Cardiovascular Outcomes.. In our study the inflammatory cytokines IL-6, TNF-α and hs-CRP were higher in HD compared to HDF patients at baseline and continued to increase significantly in HD even after adjusting for baseline levels, but no change was seen in the HDF cohort over the 12-month follow-up. As with all dialysis studies, the ‘incident’ patients in our cohort were on dialysis for a median of one month in order to stabilize and achieve the optimal dialysis program before the first study measures were recorded. The inflammatory markers showed a strong correlation with ß2M, a prototype middle molecule, indicating that clearance on HDF largely accounted for lower levels in HDF. Similar results were shown in the CONTRAST study: although CRP and IL-6 concentrations increased in patients treated with HD over the 3-year study period, they remained stable in the HDF cohort, suggesting that HDF maintains a sustained reduction in inflammatory activityLeurs P. Lindholm B. Stenvinkel P. Effects of hemodiafiltration on uremic inflammation.,Is hemodiafiltration the technical solution to chronic inflammation affecting hemodialysis patients?.,Online hemodiafiltration reduces systemic inflammation compared to low-flux hemodialysis.

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