Original Article
Role of Plasminogen-Activator Inhibitor Type 1 in the Pathogenesis and Outcome of the Hemolytic Uremic Syndrome
N Engl J Med 1992; 327:755-759September 10, 1992
- Abstract
- Abstract
Background
Deposition of fibrin in glomeruli and renal failure are characteristic features of the hemolytic uremic syndrome. An inhibitor of glomerular fibrinolysis has been detected in plasma from children with this disorder. In this study, we define the inhibitor and show that its plasma level is correlated with the outcome of the disease.
Methods and Results
Plasminogen-activator inhibitor type 1 (PAI-1) in plasma was measured with an assay employing a specific monoclonal antibody in 40 consecutive children hospitalized with the hemolytic uremic syndrome: 12 who recovered adequate renal function (serum creatinine, ≤2.0 mg per deciliter [111 μmol per liter]) without dialysis, 23 who recovered adequate renal function after peritoneal dialysis, and 5 who did not recover adequate renal function after undergoing dialysis.
At presentation, plasma PAI-1 levels were higher in the patients with the hemolytic uremic syndrome than in nine children with other forms of acute renal failure. That the inhibitor was PAI-1 was indicated by the fact that it was a potent inhibitor of tissue plasminogen activator, was acid-resistant, and was not inhibited by denaturation (all unique traits of PAI-1) and that it was neutralized by an antibody specific for PAI-1. Multivariate discriminant-function analysis revealed that the duration of elevated PAI-1 activity was strongly correlated with the outcome of the disease (P<0.001). Peritoneal dialysis reduced plasma PAI-1 levels dramatically.
Conclusions
Our studies suggest that PAI-1 is the circulating inhibitor of fibrinolysis in the hemolytic uremic syndrome. Normalization of plasma PAI-1 levels (e.g., by peritoneal dialysis) is correlated with improvement in renal function. However, the possibility that increased plasma levels of PAI-1 are either causes or effects of the hemolytic uremic syndrome is not unequivocally established by these studies. (N Engl J Med 1992;327:755–9.)
Media in This Article
Figure 1
Plasminogen-Activator Inhibitor Activity, Lysis-Inhibitory Titers, and PAI-1 Antigen Levels in Plasma from a Typical Patient with the Hemolytic Uremic Syndrome Who Underwent One Course of Peritoneal Dialysis.Figure 2
Plasma Plasminogen-Activator Inhibitor Activity at Presentation in Patients with the Hemolytic Uremic Syndrome Who Underwent Dialysis and Did (○) or Did Not (●) Recover Adequate Renal Function, Patients with the Hemolytic Uremic Syndrome Who Did Not Undergo Dialysis (□), and Control Patients with Acute Renal Failure (
).Article Activity
- Article
THE hemolytic uremic syndrome is an important cause of acute and often of end-stage renal failure in children.1 The disease is characterized by glomerular fibrin deposition. An intrinsic glomerular fibrinolytic mechanism mediated by tissue plasminogen activator and urokinase may play a part in the removal of such deposits.2 In 1982, we described an inhibitor of glomerular fibrinolysis found in plasma from 17 children with the hemolytic uremic syndrome.3 Although no correlation was found between the titer of inhibitor and the hematocrit, the white-cell and platelet counts, the serum creatinine concentrations, or the antiplasmin level, there was a close correlation between levels of the inhibitor and the clinical course. Removal of the inhibitor from the plasma by peritoneal dialysis was associated with improvement in renal function.
Although our studies failed to reveal the precise nature of the inhibitor, it was distinct from the known physiologically important inhibitors of plasmin (alpha2-antiplasmin, C1 esterase inhibitor, alpha2-macroglobulin, and alpha1-antitrypsin). This suggested that inhibition could be directed against plasminogen activators.
Of the four recently described plasminogen-activator inhibitors,4 plasminogen-activator inhibitor type 1 (PAI-1), the primary inhibitor of both tissue plasminogen activator and urokinase in plasma,5 seemed the most likely candidate to be the inhibitor. We have now identified the inhibitor as PAI-1, measured PAI-1 levels in plasma from patients with the hemolytic uremic syndrome, and correlated the results with disease outcomes.
Methods
Materials
Bovine fibrinogen was obtained from Miles Laboratories (Elkhart, Ind.); [125I]sodium iodide from Amersham (Arlington Heights, Ill.); Triton X-100, Tween 80, and guanidine hydrochloride from Sigma Chemical (St. Louis); concanavalin A Sepharose from Pharmacia (Piscataway, N.J.); 24-well polystyrene tissue-culture cluster plates from Costar (Cambridge, Mass.); and polyclonal goat antihuman PAI-1 from American Diagnostica (New York).
Analytic Methods
Plasma was obtained by placing 4 ml of blood into a test tube containing 6 mg of EDTA and centrifuging it at 1000×g for 10 minutes. The plasma inhibitor was originally detected by measuring the lysis-inhibitory titer with a modified fibrin slide test.3 To quantitate the activity of plasminogen-activator inhibitor, 0.1 ml of plasma was incubated with 0.04 IU of tissue plasminogen activator (prepared as described elsewhere2) in 0.5 ml of 0.2M phosphate-buffered saline, pH 7.4, at 37°C for one hour and allowed to stand overnight at 4°C. Certain samples were acidified to pH 3.0 with 1N hydrochloric acid and were then neutralized to pH 7.0 with 1N sodium hydroxide.6 The mixture was centrifuged at 5000×g for 30 minutes at 4°C. Residual activity of tissue plasminogen activator was determined in 0.5 ml of the supernatant with a 125I-labeled fibrin film assay.2 The results are expressed as the percentage of inhibition (reduction) of the counts released by 0.04 IU of tissue plasminogen activator in phosphate-buffered saline. The concentration of PAI-1 antigen in plasma was measured with a specific mouse monoclonal-antibody enzyme-linked immunosorbent assay (ELISA) (American Diagnostica).
The inhibitor was characterized from 5 ml of plasma by concanavalin A Sepharose chromatography.7 The 1-ml column was eluted with 0.5M alpha-methyl-D-mannoside; 0.5-ml fractions were analyzed for activity of plasminogen-activator inhibitor (by a 125I-labeled fibrin film assay), PAI-1 concentration (by ELISA), and protein concentration.
The effect of denaturation on the activity of the inhibitor was studied in plasma specimens from eight randomly selected patients after exposure to guanidine hydrochloride.8 Inhibitor activity was measured by the 125I-labeled fibrin film assay.
Plasma (0.1 ml) from five randomly selected patients with the hemolytic uremic syndrome and two normal children was incubated with either 0.2 ml of polyclonal goat antihuman PAI-1 serum or phosphate-buffered saline for one hour at 37°C and overnight at 4°C. After centrifugation at 5000×g for 30 minutes at 4°C, the supernatants were studied for inhibitor activity by the 125I-labeled fibrin film assay.
Patients
Plasma specimens were collected from 40 consecutive children (28 girls and 12 boys) who presented with the hemolytic uremic syndrome; the activity of the inhibitor was measured in all the specimens collected daily from each patient during hospitalization and in those obtained during outpatient visits for one year after hospitalization. The patients ranged in age from 8 months to 12 years (mean, 4.2 years). Thirty-nine children presented with a history of diarrhea, which in 22 was bloody. All the patients had acute renal failure of sudden onset, microangiopathic hemolytic anemia, and thrombocytopenia, confirming the diagnosis of the hemolytic uremic syndrome. None had evidence of systemic lupus erythematosus, malignant hypertension, or renal-vein thrombosis.
Twenty-eight children required peritoneal dialysis. There were no significant differences in the mean (±SD) age (4.3±2.8 vs. 4.1±3.7 years, respectively; P = 0.85) or the percentage of patients with bloody diarrhea (50 percent vs. 72 percent, P = 0.19) among the children who required peritoneal dialysis and those who did not. Although 80 percent of the girls but only 53 percent of the boys required dialysis, the difference was not statistically significant (P = 0.07).
Outcomes were expressed in relation to the recovery of adequate renal function (arbitrarily defined as a serum creatinine concentration of ≤2.0 mg per deciliter [177 μmol per liter] without dialysis) after the acute phase of the disease. The average duration of follow-up was 3.1 years (range, 6 months to 11 years). On the basis of their outcomes, the patients could be divided into three groups: 12 patients who recovered adequate renal function without requiring dialysis, 22 patients who required dialysis before they recovered adequate renal function, and 5 patients who did not recover adequate renal function despite dialysis. In two patients from the last of these groups, the disease had progressed to end-stage renal failure as of this writing, whereas the other three had chronic renal insufficiency (a serum creatinine concentration exceeding 2.0 mg per deciliter). The patient who had no history of diarrhea was excluded from the outcome analysis because the date of onset of the disease (as defined by the onset of diarrhea) could not be determined, but the patient was included for the balance of the study. This patient did require dialysis before the recovery of adequate renal function.
Informed consent was obtained from the parents of all participants in the study, and the study protocol was approved by the institutional review board.
Control Patients
The activity of plasminogen-activator inhibitor was measured in plasma from nine children (age range, 2 to 13 years) who had other forms of acute renal failure. Three had acute tubular necrosis, two had poststreptococcal glomerulonephritis, two had acute interstitial nephritis, and one each had anaphylactoid purpura and rapidly progressive glomerulonephritis. In each patient, the diagnosis was confirmed by renal biopsy, and the plasma specimen was obtained at the time of the biopsy. There was no significant difference between the serum creatinine levels of the patients with acute renal failure (4.7±2.0 mg per deciliter [415±177 μmol per liter]) and those of the patients with the hemolytic uremic syndrome (4.4±2.7 mg per deciliter [389±239 μmol per liter]) (P = 0.65).
Peritoneal Dialysis
The indications for peritoneal dialysis included any combination of the following: fluid overload, hypertension,9 hyperkalemia, urine output less than 400 ml per square meter of body-surface area per day, and blood urea nitrogen concentration above 90 mg per deciliter (32 mmol per liter). Dialysis was carried out with commercial dialysis solutions used in volumes of 30 to 50 ml per kilogram of body weight. Peritoneal clearances were calculated with standard techniques10 and were corrected to a body-surface area of 1.73 m2.
Statistical Analysis
Results are expressed as means ± SD. The significance of differences between groups was determined with a t-test for small samples.11
In the evaluation of outcomes, statistical analyses were performed with the date of onset of the hemolytic uremic syndrome considered to be the date of onset of diarrhea, because that date was a historically fixed point in the course of the disease, rather than the inconstant date of the decision for hospitalization. The analyses considered the number of days from the onset of diarrhea to the occurrence of each of the following: the date of admission to the hospital, the determination of a platelet count exceeding 150×109 per liter, the normalization of plasma PAI-1 activity, the resumption of urine output (i.e., the duration of anuria), and the occurrence of a urine output exceeding 400 ml per square meter per day (i.e., the duration of oliguria). Comparisons were made by the usual pooled-variance t-test for two samples if the variances were not significantly different at the 10 percent level. Otherwise, a separate t-test of the variance was used with the Satterthwaite approximation for degrees of freedom.12
In addition, multivariate discriminant-function analysis was carried out to determine which variables might be correlated with disease outcome.
Results
Definition of the Inhibitor
Effects of Acidification and Denaturation on Inhibitor Activity
After acidification and neutralization, daily plasma samples from six randomly selected patients had similar levels of inhibitor activity as compared with plasma samples diluted equivalently with 1N sodium chloride.
After exposure to the denaturant guanidine hydrochloride, plasma specimens from eight patients with the hemolytic uremic syndrome showed no significant reduction in the inhibition of tissue plasminogen activator as compared with unexposed specimens. The denaturant did not significantly increase inhibitor activity, suggesting that in plasma from patients with the hemolytic uremic syndrome, PAI-1 is chiefly in the active form. Exposure to guanidine also had no effect on PAI-1 levels as determined by ELISA.
Immunologic Specificity
When plasma from patients with the hemolytic uremic syndrome was incubated with goat antihuman PAI-1 serum, there was a sharp decline (P<1.01) in inhibitor activity to the level of the two normal subjects (Table 1Table 1
Effect of Goat Antihuman PAI-1 Serum on Plasma Inhibitor Levels.*). No significant change was detected in the activity of the inhibitor in plasma from the normal children after incubation with goat antihuman PAI-1 serum.Concanavalin A Sepharose Chromatography
Randomly selected acidified and nonacidified plasma specimens obtained from six patients on the first day of hospitalization, from three patients on the day of discharge, and from three normal children were analyzed for inhibition of tissue plasminogen activator, PAI-1 concentration, and protein level. The plasma specimens were acidified to remove antiplasmin activity, because previous studies3 found that the levels of the antiplasmins alpha1-antitrypsin and alpha2-macroglobulin were elevated, although their levels did not correlate with the lysis-inhibitory titer. Nonacidified plasma obtained during the acute phase of disease had elevated peaks of inhibitor activity and PAI-1 antigen, which coincided with the elution of glycoprotein. Both plasma obtained during convalescence and normal plasma had normal levels of inhibitor activity and PAI-1 antigen. Identical results were obtained in acidified plasma.
To confirm that PAI-1 was the previously reported3 circulating inhibitor of glomerular fibrinolysis, we measured lysis-inhibitory titers, PAI-1 activity, and PAI-1 antigen levels in plasma specimens obtained daily from three patients over the course of their hospitalizations. The results, as shown for one patient in Figure 1Figure 1
Plasminogen-Activator Inhibitor Activity, Lysis-Inhibitory Titers, and PAI-1 Antigen Levels in Plasma from a Typical Patient with the Hemolytic Uremic Syndrome Who Underwent One Course of Peritoneal Dialysis., demonstrated striking similarities among the three curves.Plasma PAI-1 Levels and Clinical Manifestations
PAI-1 Levels at Presentation of the Hemolytic Uremic Syndrome
As compared with control patients with acute renal failure, all 40 patients with the hemolytic uremic syndrome had increased (P<0.001) plasma PAI-1 activity at the time of presentation (Fig. 2Figure 2
Plasma Plasminogen-Activator Inhibitor Activity at Presentation in Patients with the Hemolytic Uremic Syndrome Who Underwent Dialysis and Did (○) or Did Not (●) Recover Adequate Renal Function, Patients with the Hemolytic Uremic Syndrome Who Did Not Undergo Dialysis (□), and Control Patients with Acute Renal Failure ().). Inhibitor activity was significantly higher (P<0.001) in the patients who subsequently had peritoneal dialysis than in those who did not (Fig. 2). There was no difference (P = 0.13) in PAI-1 activity at presentation in the patients undergoing dialysis who did and did not recover adequate renal function.PAI-1 Levels and Disease Outcome
When the patients who recovered adequate renal function after dialysis were compared with those who did not require dialysis, there were no significant differences in the number of days from the onset of diarrhea to the hospital admission, normalization of the platelet count, or normalization of plasma PAI-1 activity. Whereas the patients requiring dialysis had anuria for an average of 12 days, none of those who recovered without dialysis had anuria. As might be expected, patients requiring dialysis before recovery took significantly longer (16±6 days) to recover from oliguria than those not requiring dialysis (7±1 days, P<0.001).
When the patients who underwent dialysis were compared with respect to whether they did or did not recover adequate renal function, there were no significant differences in the number of days between the onset of diarrhea and admission to the hospital, the normalization of the platelet count, or the duration of oliguria. However, the patients undergoing dialysis who did not recover had anuria longer (17±4 vs. 12±4 days for those who did recover, P = 0.029) and required significantly more time (38±8 vs. 16±4 days, P = 0.003) to regain normal plasma PAI-1 activity. Multivariate discriminant-function analysis revealed that only one variable, duration of elevated PAI-1 activity, was correlated with clinical outcome (P<0.001).
Removal of PAI-1 by Peritoneal Dialysis
Peritoneal dialysis resulted in dramatic reductions in plasma inhibitor activity and PAI-1 antigen levels in all patients who had this treatment. Peritoneal dialysis was customarily carried out for two to three days, stopped, and then resumed as warranted on the basis of the patients' clinical status and the results of biochemical studies. Of 23 patients treated in this manner, 13 received only one course of dialysis, and all of these recovered. During dialysis, PAI-1 activity declined to normal and remained normal thereafter (Fig. 1). Ten patients required two to four courses of dialysis. The five patients who recovered adequately received only two courses, whereas the five patients who did not recover adequately received two, three, three, four, and four courses. In the patients who required multiple courses of dialysis, PAI-1 levels rebounded after the first course. Since these patients did not recover renal function, dialysis was resumed, and plasma PAI-1 levels declined to normal. The last five study patients to undergo dialysis followed a routine of continuous hourly exchanges for five to nine days, by which time their PAI-1 levels had declined to normal (and remained so thereafter), the urine output had increased, and recovery of renal function was apparent. Patients whose plasma PAI-1 activity declined to normal within 16 days after hospitalization recovered (whether or not dialysis was performed), whereas patients who still had elevated levels after this time did not.
The peritoneal clearance of PAI-1 and albumin was measured in two patients during the first 24 hours of dialysis. The PAI-1 clearance rate was 14.6 and 16.8 ml per minute per 1.73 m2, as compared with the albumin clearance of 0.07 and 0.25 ml per minute per 1.73 m2. The ratios of the clearance of PAI-1 to that of albumin in the two patients were 208:1 and 67:1.
Discussion
PAI-1, a glycoprotein with a molecular weight of approximately 52,000, is normally present at low concentrations (approximately 5 ng per milliliter) in plasma,4 where it functions as the primary inhibitor of tissue plasminogen activator and urokinase.5 It appears in two forms, active and latent (inactive). The latent form does not inhibit tissue plasminogen activator or urokinase, but it can be converted to the active form by denaturants, such as guanidine and sodium dodecyl sulfate.8 PAI-1 activity is not inhibited by acidification to pH 3.0 or exposure to denaturants.6 , 8 In contrast, the plasminogen-activator inhibitors PAI-2, PAI-3, and protease nexin are rarely found in plasma, are inefficient inhibitors of tissue plasminogen activator, do not bind to concanavalin A Sepharose, and are inhibited by acidification and treatment with denaturants.4 , 13
It appears that the inhibitor of fibrinolysis that is correlated with outcome in the patients with the hemolytic uremic syndrome is PAI-1. The source of this substance is not known. PAI-1 in normal plasma is functionally and immunologically similar to PAI-1 produced by endothelial cells and platelets.4 In plasma from patients with the hemolytic uremic syndrome, it is found in the active form for the most part. Because PAI-1 released from platelets is primarily found in the inactive form,14 , 15 PAI-1 in plasma from patients with the hemolytic uremic syndrome may be derived chiefly from endothelial cells.
PAI-1 can be removed from the circulation by peritoneal dialysis, and normalization of plasma levels within 16 days after hospitalization was associated with recovery. The peritoneal clearance of PAI-1 in two patients in this study was 208 and 67 times that of albumin. Its molecular weight is nearly that of albumin, and it seems possible that PAI-1 may have some characteristic aside from molecular weight that facilitates its removal by peritoneal dialysis.
Although our results demonstrate that plasma PAI-1 levels are correlated with clinical outcome, they do not resolve the question of whether increased PAI-1 activity is a cause or a consequence of disease activity. The possibility that an increased plasma concentration of PAI-1 is of pathogenetic importance in hemolytic uremic syndrome remains to be established.
Supported by grants from the James Whitcomb Riley Memorial Association and the American Heart Association, Indiana Affiliate.
We are indebted to Dr. James A. Norton for assistance with the statistical analysis, and to Mrs. Carol Teets for assistance in the preparation of the manuscript.
Source Information
From the Departments of Pediatrics (J.M.B., M.R.) and Medicine (N.U.B.) and the Lilly Research Laboratories (N.U.B.), Indiana University School of Medicine, Indianapolis. Address reprint requests to Dr. Bergstein at the James Whitcomb Riley Hospital for Children, 702 Barnhill Dr., Indianapolis, IN 46202–5225.
- References
References
1
United States Renal Data System 1990 annual report. 4. Pediatric ESRD . Am J Kidney Dis 1990;16:Suppl 2:65–77.
Web of Science2
Bergstein
CrossRef | Web of Science | Medline3
Bergstein
CrossRef | Web of Science | Medline4
Hekman
CrossRef | Web of Science | Medline5
Kruithof
Web of Science | Medline6
Loskutoff
CrossRef | Web of Science | Medline7
Erickson
CrossRef | Web of Science | Medline8
Erickson 9
Task Force on Blood Pressure Control in Children
Web of Science | Medline10
Krediet
CrossRef | Medline11
Bancroft H. Introduction to biostatistics. New York: Hoeber-Harper, 1962.
12
Rosner B. Fundamentals of biostatistics. 2nd ed. Boston: Duxbury Press, 1986.
13
Sprengers
Web of Science | Medline14
Declerck
Web of Science | Medline15
Booth
CrossRef | Web of Science | Medline
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CrossRef10
Chris Van Geet, Willem Proesmans, Jef Arnout, Jos Vermylen, Paul J. Declerck. (1998) Activation of both coagulation and fibrinolysis in childhood hemolytic uremic syndrome. Kidney International 54:4, 1324-1330
CrossRef11
Maya T. Anthony, Zella R. Zeigler, John Lister, Jane M. Raymond, Richard K. Shadduck, Robert E. Kramer, Jeffrey F. Gryn, P. B. Rintels, Emmanuel C. Besa, James N. George, Bernard Silver, Robert Joyce, David Bodensteiner. (1998) Plasminogen activator inhibitor (PAI-1) antigen levels in primary TTP and secondary TTP post-bone marrow transplantation. American Journal of Hematology 59:1, 9-14
CrossRef12
Franco Musio, Erin M. Bohen, Christinana M. Yuan, Paul G. Welch. (1998) Review of thrombotic thrombocytopenic purpurain the setting of systemic lupus erythematosus. Seminars in Arthritis and Rheumatism 28:1, 1-19
CrossRef13
Principal discussant:Barbara J. Bal. (1998) Endothelial cell activation. Kidney International 53:6, 1810-1826
CrossRef14
Paul Warwicker, Timothy H.J. Goodship, Rosemary L. Donne, Yves Pirson, Anthony Nicholls, Roy M. Ward, Peter Turnpenny, Judith A. Goodship. (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney International 53:4, 836-844
CrossRef15
Douglas Shemin, Lance D. Dworkin. (1998) Clinical Outcome in Three Patients with Postpartum Hemolytic Uremic Syndrome Treated with Frequent Plasma Exchange. Therapeutic Apheresis and Dialysis 2:1, 43-48
CrossRef16
Tsuyoshi Oikawa, Michael Freeman, Wilbur Lo, Douglas E Vaughan, Agnes Fogo. (1997) Modulation of plasminogen activator inhibitor-1 in vivo: A new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. Kidney International 51:1, 164-172
CrossRef17
Seth L. Schulman, Bernard S. Kaplan. (1996) Management of patients with hemolytic uremic syndrome demonstrating severe azotemia but not anuria. Pediatric Nephrology 10:5, 671-674
CrossRef18
A. Pereira, R. Mazzara, J. Monteagudo, C. Sanz, L. Puig, A. Martínez, A. Ordinas, R. Castillo. (1995) Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: a multivariate analysis of factors predicting the response to plasma exchange. Annals of Hematology 70:6, 319-323
CrossRef19
Helmut G Rennke. (1995) Secondary membranoproliferative glomerulonephritis. Kidney International 47:2, 643-656
CrossRef20
Christopher D. Hillyer, Alexander Duncan, M. Ledford, Timothy J. Barrett, Sherry A. Klumpp, Daniel C. Anderson, Harold M. McClure, Elliot F. Winton. (1995) Chemotherapy-induced hemolytic uremic syndrome: Description of a potential animal model. Journal of Medical Primatology 24:2, 68-73
CrossRef21
(1993) Briefly Noted. Seminars in Dialysis 6:2, 148-148
CrossRef
