[en] INTRODUCTION: Growth failure is considered the most important clinical outcome parameter in childhood chronic kidney disease (CKD). Central to the pathophysiology of growth failure is the presence of a chronic proinflammatory state, presumed to be partly driven by the accumulation of uremic toxins. In this study, we assessed the association between uremic toxin concentrations and height velocity in a longitudinal multicentric prospective pediatric CKD cohort of (pre)school-aged children and children during pubertal stages. METHODS: In a prospective, multicentric observational study, a selection of uremic toxin levels of children (aged 0-18 years) with CKD stage 1 to 5D was assessed every 3 months (maximum 2 years) along with clinical growth parameters. Linear mixed models with a random slope for age and a random intercept for child were fitted for height (in cm and SD scores [SDS]). A piecewise linear association between age and height was assumed. RESULTS: Data analysis included data from 560 visits of 81 children (median age 9.4 years; 2/3 male). In (pre)school aged children (aged 2-12 years), a 10% increase in concurrent indoxyl sulfate (IxS, total) concentration resulted in an estimated mean height velocity decrease of 0.002 SDS/yr (P < 0.05), given that CKD stage, growth hormone (GH), bicarbonate concentration, and dietary protein intake were held constant. No significant association with height velocity was found in children during pubertal stages (aged >12 years). CONCLUSION: The present study demonstrated that, especially IxS contributes to a lower height velocity in (pre)school children, whereas we could not find a role for uremic toxins with height velocity during pubertal stages.
Disciplines :
Pediatrics Urology & nephrology
Author, co-author :
Snauwaert, Evelien; Department of Pediatric Nephrology, Ghent University Hospital, Ghent, Belgium.
De Buyser, Stefanie; Biostatistics Unit, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Van Biesen, Wim; Department of Nephrology, Ghent University Hospital, Ghent, Belgium.
Raes, Ann; Department of Pediatric Nephrology, Ghent University Hospital, Ghent, Belgium.
Glorieux, Griet; Department of Nephrology, Ghent University Hospital, Ghent, Belgium.
Collard, Laure ; Université de Liège - ULiège > Département des sciences cliniques > Médecine générale ; Department of Pediatric Nephrology, CHC Liège, Ghent, Belgium.
Van Hoeck, Koen; Department of Pediatric Nephrology, Antwerp University Hospital, Antwerp, Belgium.
Van Dyck, Maria; Department of Pediatric Nephrology, University Hospital Leuven, Leuven, Belgium.
Godefroid, Nathalie; Department of Pediatric Nephrology, University Hospital Saint-Luc, Brussels, Belgium.
Walle, Johan Vande; Department of Pediatric Nephrology, Ghent University Hospital, Ghent, Belgium.
Eloot, Sunny; Department of Nephrology, Ghent University Hospital, Ghent, Belgium.
Language :
English
Title :
Indoxyl Sulfate Contributes to Impaired Height Velocity in (Pre)School Children.
Furth, S.L., Hwang, W., Yang, C., Neu, A.M., Fivush, B.A., Powe, N.R., Growth failure, risk of hospitalization and death for children with end-stage renal disease. Pediatr Nephrol 17 (2002), 450–455, 10.1007/s00467-002-0838-x.
Ku, E., Fine, R.N., Hsu, C.Y., et al. Height at first RRT and mortality in children. Clin J Am Soc Nephrol 11 (2016), 832–839, 10.2215/CJN.08250815.
Furth, S.L., Stablein, D., Fine, R.N., Powe, N.R., Fivush, B.A., Adverse clinical outcomes associated with short stature at dialysis initiation: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatrics 109 (2002), 909–913, 10.1542/peds.109.5.909.
Rosenkranz, J., Reichwald-Klugger, E., Oh, J., Turzer, M., Mehls, O., Schaefer, F., Psychosocial rehabilitation and satisfaction with life in adults with childhood-onset of end-stage renal disease. Pediatr Nephrol 20 (2005), 1288–1294, 10.1007/s00467-005-1952-3.
Broyer, M., Le Bihan, C., Charbit, M., et al. Long-term social outcome of children after kidney transplantation. Transplantation 77 (2004), 1033–1037, 10.1097/01.tp.0000120947.75697.8b.
Harambat, J., Bonthuis, M., van Stralen, K.J., et al. Adult height in patients with advanced CKD requiring renal replacement therapy during childhood. Clin J Am Soc Nephrol 9 (2014), 92–99, 10.2215/CJN.00890113.
Behnisch, R., Kirchner, M., Anarat, A., et al. Determinants of statural growth in European children with chronic kidney disease: findings from the cardiovascular comorbidity in children with chronic kidney disease (4C) study. Front Pediatr, 7, 2019, 278, 10.3389/fped.2019.00278.
Rodig, N.M., McDermott, K.C., Schneider, M.F., et al. Growth in children with chronic kidney disease: a report from the chronic kidney disease in children study. Pediatr Nephrol 29 (2014), 1987–1995, 10.1007/s00467-014-2812-9.
Fine, R.N., Martz, K., Stablein, D., What have 20 years of data from the North American pediatric renal transplant cooperative study taught us about growth following renal transplantation in infants, children, and adolescents with end-stage renal disease?. Pediatr Nephrol 25 (2010), 739–746, 10.1007/s00467-009-1387-3.
Carbajo, E., López, J.M., Santos, F., Ordóñez, F.A., Niño, P., Rodríguez, J., Histologic and dynamic changes induced by chronic metabolic acidosis in the rat growth plate. J Am Soc Nephrol 12 (2001), 1228–1234, 10.1681/ASN.V1261228.
Gurevich, E., Segev, Y., Landau, D., Growth hormone and IGF1 actions in kidney development and function. Cells, 10, 2021, 3371, 10.3390/cells10123371.
Rees, L., Shaw, V., Nutrition in children with CRF and on dialysis. Pediatr Nephrol 22 (2007), 1689–1702, 10.1007/s00467-006-0279-z.
Farquharson, C., Ahmed, S.F., Inflammation and linear bone growth: the inhibitory role of SOCS2 on GH/IGF-1 signaling. Pediatr Nephrol 28 (2013), 547–556, 10.1007/s00467-012-2271-0.
Rees, L., Mak, R.H., Nutrition and growth in children with chronic kidney disease. Nat Rev Nephrol 7 (2011), 615–623, 10.1038/nrneph.2011.137.
Pass, C., MacRae, V.E., Huesa, C., Faisal Ahmed, S., Farquharson, C., SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis. J Bone Miner Res 27 (2012), 1055–1066, 10.1002/jbmr.1544.
Mårtensson, K., Chrysis, D., Sävendahl, L., Interleukin-1beta and TNF-alpha act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones. J Bone Miner Res 19 (2004), 1805–1812, 10.1359/JBMR.040805.
MacRae, V.E., Farquharson, C., Ahmed, S.F., The restricted potential for recovery of growth plate chondrogenesis and longitudinal bone growth following exposure to pro-inflammatory cytokines. J Endocrinol 189 (2006), 319–328, 10.1677/joe.1.06609.
Tan, J.C., Rabkin, R., Suppressors of cytokine signaling in health and disease. Pediatr Nephrol 20 (2005), 567–575, 10.1007/s00467-004-1766-8.
Landau, D., Assadi, M.H., Abu Hilal, R., Chen, Y., Rabkin, R., Segev, Y., SOCS2 silencing improves somatic growth without worsening kidney function in CKD. Am J Nephrol 51 (2020), 520–526, 10.1159/000508224.
Pecoits-Filho, R., Sylvestre, L.C., Stenvinkel, P., Chronic kidney disease and inflammation in pediatric patients: from bench to playground. Pediatr Nephrol 20 (2005), 714–720, 10.1007/s00467-005-1891-z.
Cai, D., Frantz, J.D., Tawa, N.E. Jr., et al. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119 (2004), 285–298, 10.1016/j.cell.2004.09.027.
Bellocq, A., Suberville, S., Philippe, C., et al. Low environmental pH is responsible for the induction of nitric-oxide synthase in macrophages. Evidence for involvement of nuclear factor-kappaB activation. J Biol Chem 273 (1998), 5086–5092, 10.1074/jbc.273.9.5086.
Zoccali, C., Vanholder, R., Massy, Z.A., et al. The systemic nature of CKD. Nat Rev Nephrol 13 (2017), 344–358, 10.1038/nrneph.2017.52.
Vanholder, R., Pletinck, A., Schepers, E., Glorieux, G., Biochemical and clinical impact of organic uremic retention solutes: a comprehensive update. Toxins (Basel), 10, 2018, 33, 10.3390/toxins10010033.
Vanholder, R., Schepers, E., Pletinck, A., Nagler, E.V., Glorieux, G., The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol 25 (2014), 1897–1907, 10.1681/ASN.2013101062.
Bugnicourt, J.M., Godefroy, O., Chillon, J.M., Choukroun, G., Massy, Z.A., Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc Nephrol 24 (2013), 353–363, 10.1681/ASN.2012050536.
Vanholder, R., Argilés, A., Jankowski, J., European uraemic toxin work group (EUTox) . European uraemic toxin work G. A history of uraemic toxicity and of the European uraemic toxin work group (EUTox). Clin Kidney J 14 (2021), 1514–1523, 10.1093/ckj/sfab011.
Tom, A., McCauley, L., Bell, L., et al. Growth during maintenance hemodialysis: impact of enhanced nutrition and clearance. J Pediatr 134 (1999), 464–471, 10.1016/s0022-3476(99)70205-2.
Geary, D.F., Piva, E., Tyrrell, J., et al. Home nocturnal hemodialysis in children. J Pediatr 147 (2005), 383–387, 10.1016/j.jpeds.2005.04.034.
Fischbach, M., Terzic, J., Menouer, S., Dheu, C., Seuge, L., Zalosczic, A., Daily on line haemodiafiltration promotes catch-up growth in children on chronic dialysis. Nephrol Dial Transplant 25 (2010), 867–873, 10.1093/ndt/gfp565.
Fischbach, M., Terzic, J., Menouer, S., et al. Intensified and daily hemodialysis in children might improve statural growth. Pediatr Nephrol 21 (2006), 1746–1752, 10.1007/s00467-006-0226-z.
Schwartz, G.J., Muñoz, A., Schneider, M.F., et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20 (2009), 629–637, 10.1681/ASN.2008030287.
Harris, P.A., Taylor, R., Minor, B.L., et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform, 95, 2019, 103208, 10.1016/j.jbi.2019.103208.
Harris, P.A., Taylor, R., Thielke, R., Payne, J., Gonzalez, N., Conde, J.G., Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42 (2009), 377–381, 10.1016/j.jbi.2008.08.010.
El Amouri, A., Snauwaert, E., Foulon, A., et al. Dietary fibre intake is associated with serum levels of uraemic toxins in children with chronic kidney disease. Toxins (Basel), 13, 2021, 225, 10.3390/toxins13030225.
Duranton, F., Cohen, G., De Smet, R., et al. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol 23 (2012), 1258–1270, 10.1681/ASN.2011121175.
Gryp, T., De Paepe, K., Vanholder, R., et al. Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease. Kidney Int 97 (2020), 1230–1242, 10.1016/j.kint.2020.01.028.
Snauwaert, E., Van Biesen, W., Raes, A., et al. Concentrations of representative uraemic toxins in a healthy versus non-dialysis chronic kidney disease paediatric population. Nephrol Dial Transplant 33 (2018), 978–986, 10.1093/ndt/gfx224.
R Core Team. R: A language and environment for statistical computing. 2021, R Foundation for Statistical Computing, Vienna, Austria https://www.R-project.org/. (Accessed 16 April 2024)
Eloot, S., Van Biesen, W., Roels, S., et al. Spontaneous variability of pre-dialysis concentrations of uremic toxins over time in stable hemodialysis patients. PLoS One, 12, 2017, e0186010, 10.1371/journal.pone.0186010.
Cirillo, F., Lazzeroni, P., Sartori, C., Street, M.E., Inflammatory diseases and growth: effects on the GH-IGF axis and on growth plate. Int J Mol Sci, 18, 2017, 1878, 10.3390/ijms18091878.
MacRae, V.E., Wong, S.C., Farquharson, C., Ahmed, S.F., Cytokine actions in growth disorders associated with pediatric chronic inflammatory diseases (review). Int J Mol Med 18 (2006), 1011–1018, 10.3892/ijmm.18.6.1011.
Schaefer, F., Chen, Y., Tsao, T., Nouri, P., Rabkin, R., Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia. J Clin Invest 108 (2001), 467–475, 10.1172/JCI11895.
Troib, A., Landau, D., Kachko, L., Rabkin, R., Segev, Y., Epiphyseal growth plate growth hormone receptor signaling is decreased in chronic kidney disease-related growth retardation. Kidney Int 84 (2013), 940–949, 10.1038/ki.2013.196.
Dobie, R., Ahmed, S.F., Staines, K.A., et al. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF-1. J Cell Physiol 230 (2015), 2796–2806, 10.1002/jcp.25006.
Kim, H.Y., Yoo, T.H., Cho, J.Y., Kim, H.C., Lee, W.W., Indoxyl sulfate-induced TNF-α is regulated by crosstalk between the aryl hydrocarbon receptor, NF-κB, and SOCS2 in human macrophages. FASEB J 33 (2019), 10844–10858, 10.1096/fj.201900730R.
Rico-Bautista, E., Flores-Morales, A., Fernández-Pérez, L., Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine Growth Factor Rev 17 (2006), 431–439, 10.1016/j.cytogfr.2006.09.008.
Matsuo, K., Yamamoto, S., Wakamatsu, T., et al. Increased proinflammatory cytokine production and decreased cholesterol efflux due to downregulation of ABCG1 in macrophages exposed to indoxyl sulfate. Toxins (Basel) 7 (2015), 3155–3166, 10.3390/toxins7083155.
Eloot, S., Schneditz, D., Cornelis, T., et al. Protein-bound uremic toxin profiling as a tool to optimize hemodialysis. PLoS One, 11, 2016, e0147159, 10.1371/journal.pone.0147159.
Meyer, T.W., Sirich, T.L., Fong, K.D., et al. Kt/Vurea and nonurea small solute levels in the hemodialysis study. J Am Soc Nephrol 27 (2016), 3469–3478, 10.1681/ASN.2015091035.
Sirich, T.L., Meyer, T.W., Intensive hemodialysis fails to reduce plasma levels of uremic solutes. Clin J Am Soc Nephrol 13 (2018), 361–362, 10.2215/CJN.00950118.
Kalim, S., Wald, R., Yan, A.T., et al. Extended duration nocturnal hemodialysis and changes in plasma metabolite profiles. Clin J Am Soc Nephrol 13 (2018), 436–444, 10.2215/CJN.08790817.
Susantitaphong, P., Siribamrungwong, M., Jaber, B.L., Convective therapies versus low-flux hemodialysis for chronic kidney failure: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant 28 (2013), 2859–2874, 10.1093/ndt/gft396.
Shroff, R., Bayazit, A., Stefanidis, C.J., et al. Effect of haemodiafiltration vs conventional haemodialysis on growth and cardiovascular outcomes in children - the HDF, heart and height (3H) study. BMC Nephrol, 19, 2018, 199, 10.1186/s12882-018-0998-y.
Snauwaert, E., Van Biesen, W., Raes, A., et al. Haemodiafiltration does not lower protein-bound uraemic toxin levels compared with haemodialysis in a paediatric population. Nephrol Dial Transplant 35 (2020), 648–656, 10.1093/ndt/gfz132.
Kerr, P.B., Argilés, A., Flavier, J.L., Canaud, B., Mion, C.M., Comparison of hemodialysis and hemodiafiltration: a long-term longitudinal study. Kidney Int 41 (1992), 1035–1040, 10.1038/ki.1992.157.
Locatelli, F., Mastrangelo, F., Redaelli, B., et al. Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters. The Italian cooperative dialysis study group. Kidney Int 50 (1996), 1293–1302, 10.1038/ki.1996.441.
Ward, R.A., Schmidt, B., Hullin, J., Hillebrand, G.F., Samtleben, W., A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study. J Am Soc Nephrol 11 (2000), 2344–2350, 10.1681/ASN.V11122344.
Agbas, A., Canpolat, N., Caliskan, S., et al. Hemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children. PLoS One, 13, 2018, e0198320, 10.1371/journal.pone.0198320.
Marquez, I.O., Tambra, S., Luo, F.Y., et al. Contribution of residual function to removal of protein-bound solutes in hemodialysis. Clin J Am Soc Nephrol 6 (2011), 290–296, 10.2215/CJN.06100710.
Sirich, T.L., Funk, B.A., Plummer, N.S., Hostetter, T.H., Meyer, T.W., Prominent accumulation in hemodialysis patients of solutes normally cleared by tubular secretion. J Am Soc Nephrol 25 (2014), 615–622, 10.1681/ASN.2013060597.
Ganesan, L.L., O'Brien, F.J., Sirich, T.L., et al. Association of plasma uremic solute levels with residual kidney function in children on peritoneal dialysis. Clin J Am Soc Nephrol 16 (2021), 1531–1538, 10.2215/CJN.01430121.
Chadha, V., Blowey, D.L., Warady, B.A., Is growth a valid outcome measure of dialysis clearance in children undergoing peritoneal dialysis?. Perit Dial Int 21 (2001), S179–S184, 10.1177/089686080102103S30.
Haffner, D., Zivicnjak, M., Pubertal development in children with chronic kidney disease. Pediatr Nephrol 32 (2017), 949–964, 10.1007/s00467-016-3432-3.
Schaefer, F., Seidel, C., Binding, A., et al. Pubertal growth in chronic renal failure. Pediatr Res 28 (1990), 5–10, 10.1203/00006450-199007000-00002.
Kim, H.S., Ng, D.K., Matheson, M.B., et al. Delayed menarche in girls with chronic kidney disease and the association with short stature. Pediatr Nephrol (Berlin, Germany) 35 (2020), 1471–1475, 10.1007/s00467-020-04559-7.
Kalra, P.S., Sahu, A., Kalra, S.P., Interleukin-1 inhibits the ovarian steroid-induced luteinizing hormone surge and release of hypothalamic luteinizing hormone-releasing hormone in rats. Endocrinology 126 (1990), 2145–2152, 10.1210/endo-126-4-2145.
Kao, K.T., Denker, M., Zacharin, M., Wong, S.C., Pubertal abnormalities in adolescents with chronic disease. Best Pract Res Clin Endocrinol Metab, 33, 2019, 101275, 10.1016/j.beem.2019.04.009.
Nappi, R.E., Rivest, S., Effect of immune and metabolic challenges on the luteinizing hormone-releasing hormone neuronal system in cycling female rats: an evaluation at the transcriptional level. Endocrinology 138 (1997), 1374–1384, 10.1210/endo.138.4.5044.
Rivier, C., Vale, W., Cytokines act within the brain to inhibit luteinizing hormone secretion and ovulation in the rat. Endocrinology 127 (1990), 849–856, 10.1210/endo-127-2-849.
van Huis, M., Bonthuis, M., Sahpazova, E., et al. Considerable variations in growth hormone policy and prescription in paediatric end-stage renal disease across European countries-a report from the ESPN/ERA-EDTA registry. Nephrol Dial Transplant 31 (2016), 609–619, 10.1093/ndt/gfv105.
