PubMed · 9280824
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T H Hostetter, C L Manske, M S Paller. 1997-09-04. Continuous hemofiltration.. https://pubmed.ncbi.nlm.nih.gov/9280824/
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Early transplant dysfunction and failure because of immunological and nonimmunological factors still presents a significant clinical problem for transplant recipients. A critical unmet need is the noninvasive detection and prediction of immune injury such that acute injury can be reversed by proactive immunosuppression titration. In this study, we used iTRAQ -based proteomic discovery and targeted ELISA validation to discover and validate candidate urine protein biomarkers from 262 renal allograft recipients with biopsy-confirmed allograft injury. Urine samples were randomly split into a training set of 108 patients and an independent validation set of 154 patients, which comprised the clinical biopsy-confirmed phenotypes of acute rejection (AR) (n = 74), stable graft (STA) (n = 74), chronic allograft injury (CAI) (n = 58), BK virus nephritis (BKVN) (n = 38), nephrotic syndrome (NS) (n = 8), and healthy, normal control (HC) (n = 10). A total of 389 proteins were measured that displayed differential abundances across urine specimens of the injury types (p < 0.05) with a significant finding that SUMO2 (small ubiquitin-related modifier 2) was identified as a "hub" protein for graft injury irrespective of causation. Sixty-nine urine proteins had differences in abundance (p < 0.01) in AR compared with stable graft, of which 12 proteins were up-regulated in AR with a mean fold increase of 2.8. Nine urine proteins were highly specific for AR because of their significant differences (p < 0.01; fold increase >1.5) from all other transplant categories (HLA class II protein HLA-DRB1, KRT14, HIST1H4B, FGG, ACTB, FGB, FGA, KRT7, DPP4). Increased levels of three of these proteins, fibrinogen beta (FGB; p = 0.04), fibrinogen gamma (FGG; p = 0.03), and HLA DRB1 (p = 0.003) were validated by ELISA in AR using an independent sample set. The fibrinogen proteins further segregated AR from BK virus nephritis (FGB p = 0.03, FGG p = 0.02), a finding that supports the utility of monitoring these urinary proteins for the specific and sensitive noninvasive diagnosis of acute renal allograft rejection.
The distribution of renal adenosine A(1) receptors was investigated in rats with glycerol- or mercuric chloride (HgCl(2))-induced acute renal failure. Receptors were localised by autoradiography using [(3)H]8-cyclopentyl-1,3-dipropylxanthine ([(3)H]DPCPX), a selective A(1) adenosine receptor antagonist. In saline-injected control animals, significant labelling with [(3)H]DPCPX was detected in glomeruli, the inner stripe of outer medulla, and the inner medulla. Sixteen hours following induction of glycerol-induced acute renal failure (ARF), a 34% increase in labelling in glomeruli was noted compared to saline-injected controls, and by 48 hr, glomerular labelling had increased by 200%. In addition, 48 hr following glycerol injection, significant labelling was now detected in the cortical labyrinth and medullary rays whilst, in the inner medulla, labelling had decreased by 34%. By contrast to glycerol-induced ARF, the only significant change noted 48 hr following induction of HgCl(2)-induced ARF was a 39% decrease in labelling in the inner medulla. It is concluded that glycerol-induced ARF results in differential expression of renal adenosine A(1) receptors with increased expression in the cortex and reduced expression in the inner medulla. Increased density of A(1) receptors in glomeruli may account, at least in part, for the increased renal vasoconstrictor response to adenosine and depressed glomerular filtration rate noted previously in this type of acute renal failure.
A male child, who presented at the age of 3.5 years with acute renal failure, was diagnosed as having partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8). The underlying HPRT mutation was unique in that the specific activity of HPRT in erythrocyte and in fibroblast lysates was normal, but the rate of uptake of hypoxanthine into nucleotides of intact cultured fibroblasts was markedly reduced (23% of normal). The low functioning of HPRT in the intact fibroblasts was associated with decreased utilization of endogenously generated hypoxanthine and with decreased utilization of the cosubstrate 5-phosphoribosyl-1-pyrophosphate (PRPP). The non-utilized hypoxanthine was excreted into the incubation medium. The accumulation of PRPP was indicated by the 2.3-fold increase in the rate of uptake of adenine into intact cell nucleotides and by the 7. 5-fold enhancement of the rate of de novo purine synthesis. Kinetic studies of HPRT activity in fibroblast lysates revealed reduced affinity of the enzyme for PRPP (apparent K(m) 500 microM in comparison to 25 microM in control lysates), manifested in low activity at low (physiological), but not at high PRPP concentrations. The apparent K(m) for hypoxanthine was normal (23 microM in comparison to 14.2 microM in control lysates). With allopurinol treatment, our patient has had no problems since presentation, and is developing normally at 5 years of age.