Two-chain urokinase was first isolated from human urine in 1965–1966^1,2). After this discovery, attention was directed to the potential usefulness of urokinase as a thrombolytic agent in thromboembolic diseases. But little is known about the role of plasminogen activator activity in normal renal physiology. Also, the site of plasminogen activator production is not known, nor is the change in urine fibrinolytic activity with declining renal function. It now seems clear that the glomerulus has an intrinsic mechanism for removing fibrin deposits³⁾. In the presence of massive intravascular fibrin deposion, glomerular survival depends upon glomerular fibrinolytic capacity⁴⁾. If this capacity to remove deposited fibrin is insufficient, necrosis results. On the other hand, adequate plasminogen activator activity will remove glomerular fibrin with restoration of glomerular integrity⁵⁾. The amount of plasminogen activator activity produced by remnant nephrons may be linked to the chronicity of renal disease or progression of renal failure.

A correlation was found between glomerular function as measured by creatinine clearance and urokinase excretion. When the creatinine clearance decreased, the urokinase excretion also decreased regardless of the etiology of kidney disease⁶⁾. Some investigators^7,8) were unable to detect plasminogen activator in the urine of uremia patients. However, it is not known how functional nephrons produce the plasminogen activator as the renal function progresses to renal failure. To answer this question, we measured the plasminogen activator activity of urine in patients of various renal function deterioration and attempted to measure the plasminogen activator activity production of remnant nephrons.

The plasminogen activator activity of the 12 consecutive urine samples from a healthy individual showed that the U-PA activity varied with time (Fig. 1), but there was no circadian rhythm. The U-PA activity correlated with the osmolality (r = 0.51, P<0.001) and creatinine (r = 0.56, P<0.001) of the urine (Fig. 2), suggesting that its origin is a proximal nephron and is concentrated at a distal nephron.

The purpose of this study was to evaluate the changes in urine plasminogen activator as renal failure progresses. We used the fibrin plate method. It is a simpler and more sensitive method than the fibrin tube method as described by white et al.²⁾ Many factors are involved in the pathogenesis and chronicity of renal failure¹⁰⁾, but there is good evidence that fibrin deposition and intravascular coagulation may be destructive to glomeruli¹¹⁾. Whatever the primary pathogenetic insult may be, the destructive glomerular process might be mediated in large part by coagulation, fibrin deposition and crescent formations within the glomerulus^12–14). Even though the precise mechanisms of fibrin deposition and removal are poorly understood, it is generally accepted that glomerulus possesses fibrinoltic activity mediated by the elaboration of a plasminogen activator³⁾. Since the plasma plasminogen activator in all probability is produced in the vascular wall^15–17), it seems likely that this is also from the glomerular endothelial cell. In normal circumstances, this activator will then be transported with the glomerular filtrate to the urinary tract. But until now there has been no evidence that glomerular plasminogen activator activity yields U-PA activity or U-PA activity reflects the glomerular plasminogen activator activity. Blood and U-PA activity are generally reported as diminished in glomerulonephritis and in both acute and chronic renal failure^18–22). In this study, we demonstrated that as the GFR decreases, the U-PA activity concentration and total U-PA activity also decrease. But total urine plasminogen activator activity/GFR increased suddenly when the GFR fell below about 25 L/day. The correlation between total U-PA activity/GFR and GFR was very similar to that of FeNa and GFR. The FeNa also increased abruptly as the GFR fell below 25 L/day. The increment of FeNa is due to the decreased reabsorption of filtered Na. Otherwise the urine plasminogen activator activity is not filtered but is produced in nephron. This increased U-PA excretion by remnant nephrons may be explained as follows: The overloading of solute or GFR itself, which remnant nephrons faced to, might be the stimulant of urine plasminogen activator activity production. Our study does not elucidate the physiologic role of this increased plasminogen activator production of remnant nephrons. It is possible that increased urine fibrinolytic activity is necessary for the remnant nephrons to function, but in some situations it may contribute to the progression of renal failure.