A B S T R A C T The isotopic method described previously for quantification of plasmin-jI by disc gel electrophoresis was modified by inclusion of euglobulin precipitation to expand its applicability to plasmas containing low radioactivity of plasmin-I and plasminogen-'I. It was found that the euglobulin precipitation method precipitates 72.4±2.1 (SD) % of both plasmin-'I and plasminogen-I. Using this method and plasminogen-I as a tracer, studies were first made of the effects of heparin and e-aminocaproic acid in dogs on plasmin-mI generation in responese to a single injection of urokinase and to venous injury; second, of the effects of venous occlusion and thrombosis on plasmin-'I generation; and third, in vitro studies of plasminogen-'I affinity to fibrin and its activation in blood clots. The venous injury was produced by the damage of venous endothelium by an injection of 90% phenol and the thrombosis by a thrombin injection into an occluded vein. Heparin and e-aminocaproic acid under the present experimental conditions inhibited about 78 and 100%, respectively of plasmin-I generation by the urokinase injection. Similar inhibitory effects of heparin and e-aminocaproic acid were observed on plasmin-;I generation in response to venous injury.The venous occlusion caused a small degree of plasmin-'I generation, but thrombin thrombosis did not seem to stimulate the generation of plasmin-;I.

Aims To summarize evidence from randomized controlled trials (RCTs) concerning the effects of dipeptidyl peptidase‐4 (DPP‐4) inhibitors on kidney outcomes in patients with type 2 diabetes mellitus (T2DM). Methods The Medline, EMBASE and Cochrane databases were searched for RCTs comparing DPP‐4 inhibitors with a placebo, active comparator or standard care, with at least 500 person‐years follow‐up in patients with T2DM and with reporting of kidney outcomes. Treatment effects were summarized using random‐effects meta‐analysis. Results Ten trials including 47 955 patients (mean estimated glomerular filtration rate [eGFR] 71 mL/min/1.73m2, mean follow‐up 10 762 patient‐years per trial) were eligible for inclusion. DPP‐4 inhibitors were compared with placebo (five trials), active comparator (three trials), and standard care (two trials). Overall, treatment with DPP‐4 inhibitors was associated with a greater decline in eGFR than treatment with the comparators (weighted mean difference −1.12 mL/min/1.73m2, 95% confidence interval [CI] −1.61, −0.62; high‐certainty evidence). There were no detectable effects of DPP‐4 inhibitors on rates of doubling serum creatinine (risk ratio [RR] 1.10, 95% CI 0.90, 1.34; high‐certainty evidence), end‐stage kidney disease (RR 0.97, 95% CI 0.77, 1.23; high‐certainty evidence), death from kidney causes (RR 1.81, 95% CI 0.67, 4.93; low‐certainty evidence), or all‐cause mortality (RR 1.01, 95% CI 0.95, 1.09; high‐certainty evidence). DPP‐4 inhibitors significantly reduced the risks of the surrogate kidney outcome of new albuminuria (RR 0.88, 95% CI 0.8, 0.98; moderate‐certainty evidence) and worsening albuminuria (RR 0.88, 95% CI 0.82, 0.94; moderate‐certainty evidence). There was no difference in the safety outcome of acute kidney injury (RR 1.04, 95% CI 0.57, 1.87; high‐certainty evidence). Conclusions Dipeptidyl peptidase‐4 inhibitors are associated with a greater decline in eGFR, despite reducing the development and progression of albuminuria, and have no clear effect on other key kidney outcomes.

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