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Early identification and prognostic stratification of delayed graft function following renal transplantation has significant potential to improve outcome. Mass spectrometry analysis of serum samples, before and on day 2 post transplant from five patients with delayed graft function and five with an uncomplicated transplant, identified aminoacylase-1 (ACY-1) as a potential outcome biomarker. Following assay development, analysis of longitudinal samples from an initial validation cohort of 55 patients confirmed that the ACY-1 level on day 1 or 2 was a moderate predictor of delayed graft function, similar to serum creatinine, complementing the strongest predictor cystatin C. A further validation cohort of 194 patients confirmed this association with area under ROC curves (95% CI) for day 1 serum (138 patients) of 0.74 (0.67–0.85) for ACY-1, 0.9 (0.84–0.95) for cystatin C, and 0.93 (0.88–0.97) for both combined. Significant differences in serum ACY-1 levels were apparent between delayed, slow, and immediate graft function. Analysis of long-term follow-up for 54 patients with delayed graft function showed a highly significant association between day 1 or 3 serum ACY-1 and dialysis-free survival, mainly associated with the donor–brain–dead transplant type. Thus, proteomic analysis provides novel insights into the potential clinical utility of serum ACY-1 levels immediately post transplantation, enabling subdivision of patients with delayed graft function in terms of long-term outcome. Our study requires independent confirmation.

Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in ischemic injury to the heart, yet it is not known if these MMPs are involved in the injury that occurs to the transplant kidney. We therefore studied the pharmacologic protection of transplant kidneys during machine cold perfusion. Human kidney perfusates were analyzed for the presence of injury markers such as cytochrome c oxidase, lactate dehydrogenase, and neutrophil-gelatinase associated lipocalin (NGAL), and MMP-2 and MMP-9 were measured. The effects of MMP inhibitors MMP-2 siRNA and doxycycline were studied in an animal model of donation after circulatory determination of death (DCDD). Markers of injury were present in all analyzed perfusates, with higher levels seen in perfusates from human kidneys donated after controlled DCDD compared to brain death and in perfusate from kidneys with delayed graft function. When rat kidneys were perfused at 4°C for 22 hours with the addition of MMP inhibitors, this resulted in markedly reduced levels of MMP-2, MMP-9 and analyzed injury markers. Based on our study, MMPs are involved in preservation injury and the supplementation of preservation solution with MMP inhibitors is a potential novel strategy in protecting the transplant kidney from preservation injury.

Delayed graft function (DGF) is a frequent complication of renal transplantation, particularly in the setting of transplantation of kidneys derived from deceased donors and expanded-criteria donors. DGF results from tubular epithelial cell injury and has immediate and long term consequences. These include requirement for post-transplantation dialysis, increased incidence of acute rejection, and poorer long-term outcomes. DGF represents one of the clearest clinical examples of renal acute ischemia/reperfusion injury. Experimental studies have demonstrated that ischemia/reperfusion injury induces the synthesis of the full length secreted isoform of matrix metalloproteinase-2 (FL-MMP-2), as well as an intracellular N-terminal truncated MMP-2 isoform (NTT-MMP-2) that initiates an innate immune response. We hypothesized that the two MMP-2 isoforms mediate tubular epithelial cell injury in DGF. Archival renal biopsy sections from 10 protocol biopsy controls and 41 cases with a clinical diagnosis of DGF were analyzed for the extent of tubular injury, expression of the FL-MMP-2 and NTT-MMP-2 isoforms by immunohistochemistry (IHC), in situ hybridization, and qPCR to determine isoform abundance. Differences in transcript abundance were related to tubular injury score. Markers of MMP-2-mediated injury included TUNEL staining and assessment of peritubular capillary density. There was a clear relationship between tubular epithelial cell expression of both FL-MMP-2 and NTT-MMP-2 IHC with the extent of tubular injury. The MMP-2 isoforms were detected in the same tubular segments and were present at sites of tubular injury. qPCR demonstrated highly significant increases in both the FL-MMP-2 and NTT-MMP-2 transcripts. Statistical analysis revealed highly significant associations between FL-MMP-2 and NTT-MMP-2 transcript abundance and the extent of tubular injury, with NTT-MMP-2 having the strongest association. We conclude that two distinct MMP-2 isoforms are associated with tubular injury in DGF and offer novel therapeutic targets for the prevention of this disorder.

Introduction. Oxidative stress contributes to delayed graft function (DGF). Glutathione S-transferases (GSTs) are polymorphic genes which produce enzymes with protective effect against oxidative stress. This study aimed to investigate the association between donors' and recipients' GSTM1 and GSTT1 polymorphisms and DGF, creatinine clearance, and oxidative stress parameters in kidney allograft recipients. Materials and Methods. One hundred and eighty-two donor-recipient pairs were studied. Lipid peroxidation and total antioxidant capacity were measured in the recipients' plasma as the parameters of oxidative stress. Delayed graft function was determined based on at least 10% increase, no change, or less than 10% decrease in the serum creatinine level in 3 consecutive days during the 1st week after transplantation. Results. Lipid peroxidation was significantly greater in the recipients with DGF (P < .001). The frequency of GSTM1 null was significantly higher in the patients with DGF (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.17 to 0.86; P = .02). There was also a significant association between the donors' GSTM1 polymorphism and DGF (OR, 0.31; 95% CI, 0.14 to 0.68; P = .003). A significant association was detected between combination of recipients and donors' GSTM1 polymorphism and DGF (OR, 0.20; 95% CI, 0.07 to 0.64, P = .006). The recipients' GSTM1 polymorphism, alone and in combination with donors' GSTM1 and GSTT1, significantly affected the creatinine clearance on discharge day. Conclusions. These results suggest that the donors and recipients' GSTM1 polymorphism may be a major risk factor for oxidative stress and poor kidney allograft transplantation outcomes.

Mammalian target of rapamycin inhibitors (mTOR-I), everolimus and sirolimus, are immunosuppressive drugs extensively used in renal transplantation. Their main mechanism of action is the inhibition of cell signaling through the PI3 K/Akt/mTOR pathway. This interesting mechanism of action confers to these medications both great immunosuppressive potential and important anti-neoplastic properties. Although the clinical utility of this drug category, as with other antineoplastic/immunosuppressants, is clear, the use of mTOR-I commonly results in the development of several complications. In particular, these agents may determine severe renal toxicity that, as recent studies report, seems clearly correlated to dose and duration of drug use. The mTOR-I-induced renal allograft spectrum of toxicity includes the enhanced incidence of delayed graft function, nephrotoxicity in particular when co-administered with calcineurin inhibitors (CNI) and onset of proteinuria. The latter effect appears highly frequent in patients undergoing mTOR-I treatment and significantly associated with a rapid graft lost. The damage leading to this complication interests both the glomerular and tubular area. mTOR-I cause an inhibition of proliferation in podocytes and the epithelial-to-mesenchymal transition in tubular cells. Interestingly, all these side effects are mostly reversible and dose related. Therefore, it is unquestionable that these particular drugs should be administered at the lowest dose able to maintain relatively low trough levels, in order to maximize their important and specific therapeutic effects while minimizing or avoiding drug toxicities. Utilization of low dosages of mTOR-I should be encouraged not only in CNI-combined schemas, but also when administered alone in a CNI-free immunosuppressive protocol.