Sunday, May 11, 2008: Free Communications

Introduction and Aims:The discrepancy between the vasculature size of small paediatric renal allograft recipients and their adult-sized kidney grafts leads to renal hypoperfusion and decrease in absolute glomerular filtration rate, referred to as functional adaptation of these kidneys to the recipients' size.It was reported recently that this functional adaptation is not completely reversible in the smallest recipients and is associated with irreversible histological damage (interstitial fibrosis, tubular atrophy and tubular microcalcifications), but the underlying mechanisms remain unknown.Methods: We selected 21 paediatric recipients (age 9.1±6.8years; range 1.0-21) of an adult-sized kidney who did not have delayed graft function or rejection episodes.Protocol biopsies were obtained at implantation and at 3 months after transplantation and scored according to the Banff classification.Whole-genome expression profiles of the biopsies obtained at 3 months were assessed using Affymetrix cDNA microarrays.Results: Biopsies obtained at implantation were of pristine histological condition, all but 2 kidney grafts were obtained from living donors (age 32±11 years).Graft function at 3 months after transplantation was highly variable, with an absolute creatinine clearance of 63±23 mL/min (range 31.2-106.1).In concordance with previous studies, absolute creatinine clearance (mL/min) was lowest in the youngest recipients (p<0.0001).Using quantitative Significance Analysis of Microarrays (FDR <0.05), 1051 probesets (724 unique identified genes) correlated with creatinine clearance (mL/min).Ingenuity canonical pathway analysis identified significant overrepresentation of relevant and overlapping pathways (Fig. 1; all p<0.05) involved in regulation of intracellular Ca 2+ and in cAMP signaling, important for the regulation of renal vascular tone and blood flow, as well as multiple growth factor signaling pathways.Expression of these overlapping genes correlated significantly with absolute creatinine clearance at 3 months (all q-values <0.05). Conclusions:The adaptation of adult-sized kidney grafts to the paediatric recipients' size is not only an automatic, passive physiological consequence of low renal blood flow, but is associated with gene expression alterations likely involved in the regulation of renal vascular resistance and GFR autoregulation, which could add to the irreversible tubulointerstitial injury observed in the smallest recipients.In addition to maintaining a hyperdynamic blood flow in the smallest paediatric renal allograft recipients, therapeutic measures targeting the described pathways could further extend the graft survival benefit of adult-sized kidneys transplanted into small children.