PubMed · 14594162
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Robin L Fainsinger, Catherina Fraser, Pablo Amigo, Gary Frank. 2003. Checking the facts.. https://doi.org/10.1177/026921630301700717
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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.
BACKGROUND: The outcome for patients presenting with acute renal failure and Burkitt lymphoma (BLARF) without dialysis is poor. This was a retrospective non-randomized comparative study designed to determine the outcome of two different treatment protocols. METHODS: One group of patients (TPA) received oral allopurinol, intravenous (IV) cyclophosphamide, vincristine, methotrexate, furosemide, 8.4% sodium bicarbonate, and intrathecal (IT) methotrexate; the other (TPB) alternate day IV infusion of low dose cyclosphosphamide (125 mg/m(2) x 4 doses), IT methotrexate (Days 1 and 5) and aggressive pre-emptive anti-tumor lysis syndrome therapy including oral allopurinol and calcium lactate, IV calcium gluconate, salbutamol, insulin and infusions of furosemide, sodium bicarbonate and glucose. RESULTS: Nine of 16 received TPA, 7 received TPB. Post chemotherapy anemia was more severe with TPA (P < 0.05). TPB patients received significantly more chemotherapy than those in TPA (P = 0.04). All 16 had tumor lysis syndrome (TLS). Six of nine patients with TPA died from this (three from other causes), two deaths in TPB were due to causes other than tumor lysis. Other evaluated outcome indices were similar in both groups. CONCLUSION: Slow IV infusion of low dose cyclophosphamide given on alternate days in addition to pre-emptive anti-TLS measures (TPB) were associated with better outcome in BLARF patients compared to a high dose multiple chemotherapy regimen (TPA).
Although ischemia is the leading cause of acute renal failure in human, there is little information on the remodeling the kidney endothelium matrix during ischemic injury. In this study, we investigated the activity and expression of MMP-2 and MMP-9, in an isolated endothelial fraction following an acute in vivo reversible ischemia induced in rats by vascular clamping. Ischemia increased serum creatinine levels 1.4-fold, hallmark of acute renal failure. Isolation of the endothelial cell fraction was performed by affinity chromatography using an anti-PECAM-1 antibody. The isolated fraction was assessed by Western blotting analysis of endothelial cell markers. The positively selected fractions were enriched in the endothelial markers eNOS and PECAM-1 by 128-fold and 44-fold, respectively. Gelatin zymography showed that ischemia strongly stimulated proteolytic activity of proMMP-2 (1.8-fold), proMMP-9 (3-fold) and MMP-9 (4-fold) in the endothelial fractions. Western blot analysis indicated that TIMP-2 protein level increased by 3.2-fold in the endothelial fractions during ischemia. Surprisingly, TIMP-1 was absent from the endothelial preparations but was easily detected in the non-endothelial cells. Levels of the endocytic receptor LRP were increased by 2-fold during ischemia in the endothelial fractions. Occludin, a known in vivo MMP-9 substrate, was partly degraded in the endothelial fractions during ischemia, suggesting that the MMP-9 which was upregulated during ischemia was functional. These data suggest that ischemia in kidney could lead to the degradation of the vascular basement membrane and to increased permeability. This suggests new therapeutic approaches for ischemic pathologies by targeting MMP-9 and its regulators.