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Activation of the renin system in acute pancreatitis
Activation of the Renin System in Acute Pancreatitis
ROBERT J. GREENSTEIN, M.D. LAWRENCE R. KRAKOFF, M.D. KATHERINE FELTON, MS. New York, New York
From the Department of Surgery and the Hypertension Division, Department of Medicine, Mount Sinai Hospital, New York, New York. Requests for reprints should be addressed to Dr. Lawrence R. Krakoff, Hypertension Division, Annenberg 23-32, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, New York 10029. Manuscript submitted February 3, 1986, and accepted June 25, 1986.
Activity of the renin-angiotensin system was assessed in patients with acute pancreatitis. Measurements of active plasma renin and inactive plasma renin were made in normal subjects, patients with acute pancreatitis, and patients with acute abdominal pain syndromes exclusive of pancreatitis. Active plasma renin values were significantly increased in acute pancreatitis, nearly 500 percent higher than in the other two groups. inactive plasma renin values were similar in the three groups. In a subgroup of patients with acute pancreatitis, measurements were made on presentation and after recovery. The elevated active plasma renin values on admission fell significantly with recovery, in parallel with changes in serum amylase values. Inactive plasma renin values changed variably; there was a significant inverse regression relationship between the changes in active and inactive plasma renin values with recovery. The results indicate that the renin-angiotensin system is activated in acute pancreatitis to a significantly greater extent than in other syndromes with acute abdominal pain. The increased active plasma renin in acute pancreatitis is most likely due to renal release secondary to the reduced circulating volume and hypotensive effect of this disease. However, changes in the relationship between active and inactive plasma renin in some patients suggest that activation of inactive renin by proteolytic enzymes released in acute pancreatitis might play an additional role. Inflammation in acute pancreatitis results from release into peripancreatic spaces and absorption into the circulation of digestive enzymes. These include glandular kallikrein and trypsin. This leads to vasodilation and “third-space” sequestration of fluid with circulatory hypovolemia [ 11. Normal plasma contains inactive or “pro-” renins [2]. These are activated in vitro by exposure to proteolytic enzymes, including trypsin [3] and kallikrein [4]. It is thought that under normal circumstances, potent inhibitors of these enzymes prevent activation of pro-renin in circulating plasma [5]. We hypothesized that acute pancreatitis should cause activation of the renin-angiotensin system. Such a change could be mediated by hypovolemia, any vasodilation-induced hypotension, proteolytic activation of pro-renin to renin, or a combination of these mechanisms. To evaluate these, we compared active plasma renin and inactive plasma renin (pro-renin) in normal subjects, patients with acute abdominal pain without pancreatitis, and patients with acute pancreatitis during the acute and convalescent periods of their illness. SUBJECTS AND METHODS Three groups of subjects were studied. Group I consisted of 12 ambulatory healthy normal subjects (20 to 40 years old) with normal sodium balance as
assessed by dietary history and 24-hour urine excretion of sodium. Group II consisted of 15 patients (mean age, 51 years; range, 24 to 95)
March
1987
The American
Journal
of Medicine
Volume
82
401
RENIN
IN PANCREATITIS-GREENSTEIN
TABLE I
ET AL
Renin Measurements
in Normal
Subiects
and Patients
with Acute Pancreatiltis
Plasma Renin (mg/ml/hour) Grout I II Ill
Active 1.6 f 1.8 f 9.8 f
-Normal (n = 12) Abdominal pain (n = 15) Acute pancreatitis (n = 14)
Results expressed as mean f SEM. p
inactive 0.2 0.3 3.0”
5.3 f 4.2 f 6.4 f
COMMENTS Acute pancreatitis causes in situ activation of digestive enzymes, autodestruction, peripancreatic inflammation, and necrosis. Activated trypsin may occupy a central role in this process, in part, by activating other enzyme systems such as phospholipases, kallikrein, and elastase [I]. Active forms of these enzymes are found in tissue and exudate in clinical and experimental acute pancreatitis [9, lo]. The resultant inflammation and necrosis lead to local vasodilation and “third-space sequestration” of body fluids in peripancreatic tissues, causing hypovolemia
Measurements of active plasma renin, inactive plasma renin, and percent active renin in the normal subjects (Group I), patients with acute abdominal pain (Group II),
1967
The American
Journal
f 2.9 f 3.7 f 7.9”
and patients with acute-phase pancreatitis (Group Ill) are given in Table I. The mean active plasma renin value in Group II was not significantly different from that in Group I. In contrast, the mean active plasma renin value in Group Ill was significantly higher (nearly six-fold) than that in the others. The percent active renin in Group Ill was also significantly higher than that in the other groups. However, inactive plasma renin values were not significantly different in comparisons among them. Thus, the higher percent active renin in Group Ill was due to the increase in active plasma renin, not an absolute reduction in inactive plasma renin. Systolic and diastolic blood pressure measurements in Groups II and Ill, made when blood samples were obtained in the emergency room, were not significantly different (Group II, 135 f 13/77 f 4 mm Hg; Group Ill, 141 f 6/80 f 4 mm Hg). Paired measurements of serum amylase, active plasma renin, inactive plasma renin, and percent active renin in patients with pancreatitis in the acute phase of the illness and after recovery are shown in Figure 1. The hyperamylasemia evident in the acute phase decreased significantly (307 f 88 units, p 10.01) with recovery. Active plasma renin also decreased significantly (3.7 f 1.7 rig/ml/hour, p 10.04) during this interval. The reduction in percent active renin of 23 f 11 percent was of borderline significance (p = 0.07), and the change in inactive plasma renin was clearly not significant (p = 0.2). The changes in inactive plasma renin compared with changes in active plasma renin in the same subjects are shown in Figure 2. Those patients with highest active plasma renin values in the acute phase had the greatest reductions with recovery and the greatest increases in inactive plasma renin, as reflected in the significant regression coefficient of Figure 2.
RESULTS
March
23.6 26.6 48.5
groups.
seen in the emergency room with acute abdominal pain in whom acute pancreatitis was excluded by the usual clinical and laboratory assessment; the diagnosis was diverticulitis in two, appendicitis in five (with perforation in two), choiecystitis in three, sickle cell crisis in two, and pyelonephritis in three. Group III consisted of 14 patients (mean age, 51 years; range, 27 to 84) with acute pancreatitis, eight of whom were studied both in the emergency room and during recovery three to five days later. Diagnosis was based upon a compatible history, findings on physical examination, and elevated serum amylase values. Venous blood samples were obtained from patients in groups II and Ill at the time of presentation by one of us (R.J.G.) before therapeutic measures were begun. Samples were drawn simultaneously for determination of the serum amylase level, as a diagnostic measure, and for measurement of active plasma renin. The latter samples were collected with sodium EDTA, transported on ice, and centrifuged for IO minutes at 3,000 X g at 6OC. The separated plasma was stored within 30 minutes at -2OOC in order to avoid cryoactivation of inactive plasma renin [6]. Blood pressure was measured within a few minutes of blood sample collection; routine clinical measurements and assessments necessary for diagnosis were recorded throughout each patient’s hospital stay. Active plasma renin was measured by radioimmunoassay of angiotensin I [7,8]. Activation of inactive plasma renin was achieved by utilizing trypsin (Sigma T-8253) at a concentration of 1 mg/ml incubated at 23OC for 30 minutes at pH 7.4. At the end of this phase, plasma pH was adjusted to pH 6.0 with 0.7 M malate buffer prior to assay of angiotensin I. Preliminary experiments with normal plasma indicated that maximal activation of renin occurred with 0.75 to 1.25 mg of trypsin added per 1.0 ml of plasma, in agreement with studies of Sealey et al [4]. inactive plasma renin was calculated by subtraction of active plasma renin from total renin activity in each plasma sample after trypsin activation. Percent active renin was calculated by dividing the active plasma renin value by the sum of the active and inactive plasma renin values and then multiplying by 100. Statistical comparison for differences among these three groups employed one-way analysis of variance (ANOVA). For paired studies, the t test was used. Regression relationships were calculated using the nonparametric Spearman rank correlation coefficient.
402
2.9 0.5 1.3
Percent Active Renin
of Medicine
Volume
82
RENIN
extending to hypotension and shock in more severely ill patients. Activation of the kallikrein-kinin system may also cause systemic vasodilation [ 1 l- 131. Both the tendency to intravascular hypovolemia and vasodilation might act as stimuli for renin release by the juxtaglomerular cells of the kidney as a compensatory mechanism in order to maintain arterial pressure by the vasoconstrictor action of angiotensin II [ 141. Although severe pain might cause renin release by neural mechanisms, we did not find that patients with abdominal pain syndromes had significant elevations of active plasma renin values compared with normal subjects. In contrast, the group with pancreatitis had an average active plasma renin value during the acute phase of the illness that was six times that in the normal subjects or patients with abdominal pain. During recovery from acute pancreatitis, active plasma renin decreased significantly. This probably reflects restoration of normal volume homeostasis due to intravenous fluid administration given as routine therapy. In addition to measurement of active plasma renin, the assay that is usually performed for assessment of the circulating renin-angiotensin system, we measured inactive plasma renin [2] by using trypsin activation. This was done to determine whether the known activation of various proteolytic enzymes in acute pancreatitis would cause in vivo conversion of inactive renin to active renin, leading to a predicted low inactive plasma renin value in acute pancreatitis. This was not found, as the mean inactive plasma renin value in patients with acute pancreatitis was no different from that in normal subjects or those with acute abdominal pain syndromes. However, in the subgroup of those with acute pancreatitis whose active and inactive plasma renin values were measured during the acute phase and after recovery, a significant inverse regression relationship was found between the change in active and inactive plasma renin. Our results indicate that patients with the highest active plasma renin values in the acute phase had the largest change toward normal (Figure 1) and also had the largest increase in inactive plasma renin with recovery (Figure 2). Perhaps then, those with the highest active plasma renin levels in acute pancreatitis do have some degree of conversion of inactive to active plasma renin. With recovery, the change in inactive plasma renin represents a recovery of this plasma factor toward normal from a lower level resulting from prior activation or “consumption” during the acute phase. Other patients with acute pancreatitis and smaller increases in active plasma renin during the acute phase do not exhibit this pattern. Changes in the level of plasma trypsin inhibitor concentration might also account for the relationship between changes in active and inactive plasma renin during recovery from acute pancreatitis. Plasma trypsin inhibitor concentration is reduced in the acute phase, presumably due to binding of trypsin that has reached the circulation [9]. In
March
IN PANCREATITIS-GREENSTEIN
ACUTE PANCREATITIS
ET AL
RECOVERY
ng/ml/hr PRA
15-
IPRA
. P=OO7
Figure f. Measurements of active renin (PRA), inactive renin (IPRA), serum amylase, and percent active renin during the symptomatic and recovery phases of acute pancreatitis. The mean values (2c SEM) are indicated on either side of the paired measurements.
I
AIPRA
\
\
\
\
20 \a \
16 \
\
12 \
\
. l
8
\
l
I
\, 4 I -20
I
I
I
-16 -12 -8
1
I\
-4
‘i
4
8
12
n
PRA
,%i
Figure 2. Relationship between the change in PRA (A PRA) and change in IPRA (A IPRA) with recovery in acute pancreatitis (Spearman rank correlation coefficient r, = 0.94; p
1987
The American
Journal
of Medicine
Volume
82
403
RENIN
IN PANCREATITIS-GREENSTEIN
ET AL
the assay for inactive plasma renin, addition of exogenous trypsin to plasma with subnormal amounts of trypsin inhibitors might inactivate renin to some extent [2] and give a false-low value for inactive plasma renin. With recovery and normalization of plasma trypsin inhibitors, activation of inactive plasma renin in the assay would again be optimal. We did not assess plasma trypsin inhibitor concentration to evaluate this possibility. However, this effect would only apply to measurement of inactive plasma renin and would not account for the increase in active plasma renin that we observed in the acute phase. There was no significant relationship between the changes in active plasma renin, inactive plasma renin, or percent active renin and serum amylase levels. However, it is well known that serum amylase measurements do not correlate well with severity of acute pancreatitis [I]. Activation of the renin-angiotensin system in acute pancreati-
tis may serve as a defense against the hypovolemia and hypotension that complicate this disease. However, excessive activation of the renin system by release of active renin from the kidney and perhaps by proteolytic conversion of inactive renin might cause inappropriate vasoconstriction. This sequence might account for the occasional observation of paradoxic arterial hypertension as a complicating event in acute pancreatitis [ 151. It is possible that the degree of angiotensin II-induced vasoconstriction, as reflected by the active plasma renin level, might be an independant determinant of outcome in acute pancreatitis. This study was not designed to assess that possibility in comparison with established predictors such as the “Ranson criteria” [16]. Our finding that active plasma renin is significantly increased in acute pancreatitis suggests, however, that this measurement be included in prospective studies to improve definition of the predictors of mortality and morbidity in acute pancreatitis.
REFERENCES 1. 2.
3.
4.
5. 6.
7
8.
404
Banks PA: Pancreatitis. New York: Plenum, 1979; 49-52. Sealey JE, Atlas SA, Laragh JH: Pro-renin and other large molecular weight forms of renin. Endocr Rev 1980; 1: 365-391. Cooper RM, Murray GE, Osmond DH: Trypsin-induced activation of renin precursor in plasma of normal and anephric man. Circ Res 1976: 4O(suppl 1): 171-179. Sealey JE, Atlas SA, Laragh JH, Oza NB, Ryan JW: Activation of a prorenin-like substance in human plasma by trypsin and by urinary kallikrein. Hypertension 1979; 1: 179-189. Leckie B: Endogenous activation of plasma-inactive-renin. Lancet 1978; II: 217-219. Sealey JE, Moon C, Laragh JH, Alderman M: Plasma prorenin: cryoactivation and relationship to renin substrate in normal subjects. Am J Med 1976; 61: 731-738. Krakoff L: Measurement of plasma renin substrate by radioimmunoassay of angiotensin I: concentration in syndromes associated with steroid excess. Clin Endocrinol Metab 1973; 37: 110-l 17. Kodish ME, Katz FH: Plasma renin concentration: comparison of angiotensinase inhibitors and correlation with plasma renin activity and aldosterone. J Lab Clin Med 1974;
March
1987
The American
Journal
of Medicine
Volume
9.
10.
11.
12.
13. 14. 15.
16.
82
83: 705-715. Geokas MC, Rinderknecht H: Free proteolytic enzymes in pancreatic juice of patients with acute pancreatitis. Am J Dig Dis 1974; 19: 591-598. Ohlsson K, Eddeland A: Release of proteolytic enzymes in bile-induced pancreatitis in dogs. Gastroenterology 1975; 69: 668-675. Sumi H, Takasugi S, Toki N: Studies on kallikrein-kinin system in plasma of patients with acute pancreatitis. Clin Chim Acta 1978; 87: 113-l 18. Ofstad E: Formation and destruction of plasma kinins during experimental acute hemorrhagic pancreatitis in dogs. Stand J Gastroenterol 1970; S(suppl 5); 10-44. Orlov V, Beyakov N: Blood kallikrein-kinin system in acute pancreatitis. Am J Gastroenterol 1978; 70: 645-648. Haber E: The role of renin in normal and pathological cardiovascular homeostasis. Circulation 1976; 54: 849-861. Sankaran S, Lucas GE, Walt AJ: Transient hypertension with acute pancreatitis. Surg Gynecol Obstet 1974; 138: 235-238. Ranson JHC, Pasternak BS: Statistical methods for quantifying the severity of clinical acute pancreatitis. J Surg Res 1977; 22: 79-91.
ROBERT J. GREENSTEIN, M.D. LAWRENCE R. KRAKOFF, M.D. KATHERINE FELTON, MS. New York, New York
From the Department of Surgery and the Hypertension Division, Department of Medicine, Mount Sinai Hospital, New York, New York. Requests for reprints should be addressed to Dr. Lawrence R. Krakoff, Hypertension Division, Annenberg 23-32, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, New York 10029. Manuscript submitted February 3, 1986, and accepted June 25, 1986.
Activity of the renin-angiotensin system was assessed in patients with acute pancreatitis. Measurements of active plasma renin and inactive plasma renin were made in normal subjects, patients with acute pancreatitis, and patients with acute abdominal pain syndromes exclusive of pancreatitis. Active plasma renin values were significantly increased in acute pancreatitis, nearly 500 percent higher than in the other two groups. inactive plasma renin values were similar in the three groups. In a subgroup of patients with acute pancreatitis, measurements were made on presentation and after recovery. The elevated active plasma renin values on admission fell significantly with recovery, in parallel with changes in serum amylase values. Inactive plasma renin values changed variably; there was a significant inverse regression relationship between the changes in active and inactive plasma renin values with recovery. The results indicate that the renin-angiotensin system is activated in acute pancreatitis to a significantly greater extent than in other syndromes with acute abdominal pain. The increased active plasma renin in acute pancreatitis is most likely due to renal release secondary to the reduced circulating volume and hypotensive effect of this disease. However, changes in the relationship between active and inactive plasma renin in some patients suggest that activation of inactive renin by proteolytic enzymes released in acute pancreatitis might play an additional role. Inflammation in acute pancreatitis results from release into peripancreatic spaces and absorption into the circulation of digestive enzymes. These include glandular kallikrein and trypsin. This leads to vasodilation and “third-space” sequestration of fluid with circulatory hypovolemia [ 11. Normal plasma contains inactive or “pro-” renins [2]. These are activated in vitro by exposure to proteolytic enzymes, including trypsin [3] and kallikrein [4]. It is thought that under normal circumstances, potent inhibitors of these enzymes prevent activation of pro-renin in circulating plasma [5]. We hypothesized that acute pancreatitis should cause activation of the renin-angiotensin system. Such a change could be mediated by hypovolemia, any vasodilation-induced hypotension, proteolytic activation of pro-renin to renin, or a combination of these mechanisms. To evaluate these, we compared active plasma renin and inactive plasma renin (pro-renin) in normal subjects, patients with acute abdominal pain without pancreatitis, and patients with acute pancreatitis during the acute and convalescent periods of their illness. SUBJECTS AND METHODS Three groups of subjects were studied. Group I consisted of 12 ambulatory healthy normal subjects (20 to 40 years old) with normal sodium balance as
assessed by dietary history and 24-hour urine excretion of sodium. Group II consisted of 15 patients (mean age, 51 years; range, 24 to 95)
March
1987
The American
Journal
of Medicine
Volume
82
401
RENIN
IN PANCREATITIS-GREENSTEIN
TABLE I
ET AL
Renin Measurements
in Normal
Subiects
and Patients
with Acute Pancreatiltis
Plasma Renin (mg/ml/hour) Grout I II Ill
Active 1.6 f 1.8 f 9.8 f
-Normal (n = 12) Abdominal pain (n = 15) Acute pancreatitis (n = 14)
Results expressed as mean f SEM. p
inactive 0.2 0.3 3.0”
5.3 f 4.2 f 6.4 f
COMMENTS Acute pancreatitis causes in situ activation of digestive enzymes, autodestruction, peripancreatic inflammation, and necrosis. Activated trypsin may occupy a central role in this process, in part, by activating other enzyme systems such as phospholipases, kallikrein, and elastase [I]. Active forms of these enzymes are found in tissue and exudate in clinical and experimental acute pancreatitis [9, lo]. The resultant inflammation and necrosis lead to local vasodilation and “third-space sequestration” of body fluids in peripancreatic tissues, causing hypovolemia
Measurements of active plasma renin, inactive plasma renin, and percent active renin in the normal subjects (Group I), patients with acute abdominal pain (Group II),
1967
The American
Journal
f 2.9 f 3.7 f 7.9”
and patients with acute-phase pancreatitis (Group Ill) are given in Table I. The mean active plasma renin value in Group II was not significantly different from that in Group I. In contrast, the mean active plasma renin value in Group Ill was significantly higher (nearly six-fold) than that in the others. The percent active renin in Group Ill was also significantly higher than that in the other groups. However, inactive plasma renin values were not significantly different in comparisons among them. Thus, the higher percent active renin in Group Ill was due to the increase in active plasma renin, not an absolute reduction in inactive plasma renin. Systolic and diastolic blood pressure measurements in Groups II and Ill, made when blood samples were obtained in the emergency room, were not significantly different (Group II, 135 f 13/77 f 4 mm Hg; Group Ill, 141 f 6/80 f 4 mm Hg). Paired measurements of serum amylase, active plasma renin, inactive plasma renin, and percent active renin in patients with pancreatitis in the acute phase of the illness and after recovery are shown in Figure 1. The hyperamylasemia evident in the acute phase decreased significantly (307 f 88 units, p 10.01) with recovery. Active plasma renin also decreased significantly (3.7 f 1.7 rig/ml/hour, p 10.04) during this interval. The reduction in percent active renin of 23 f 11 percent was of borderline significance (p = 0.07), and the change in inactive plasma renin was clearly not significant (p = 0.2). The changes in inactive plasma renin compared with changes in active plasma renin in the same subjects are shown in Figure 2. Those patients with highest active plasma renin values in the acute phase had the greatest reductions with recovery and the greatest increases in inactive plasma renin, as reflected in the significant regression coefficient of Figure 2.
RESULTS
March
23.6 26.6 48.5
groups.
seen in the emergency room with acute abdominal pain in whom acute pancreatitis was excluded by the usual clinical and laboratory assessment; the diagnosis was diverticulitis in two, appendicitis in five (with perforation in two), choiecystitis in three, sickle cell crisis in two, and pyelonephritis in three. Group III consisted of 14 patients (mean age, 51 years; range, 27 to 84) with acute pancreatitis, eight of whom were studied both in the emergency room and during recovery three to five days later. Diagnosis was based upon a compatible history, findings on physical examination, and elevated serum amylase values. Venous blood samples were obtained from patients in groups II and Ill at the time of presentation by one of us (R.J.G.) before therapeutic measures were begun. Samples were drawn simultaneously for determination of the serum amylase level, as a diagnostic measure, and for measurement of active plasma renin. The latter samples were collected with sodium EDTA, transported on ice, and centrifuged for IO minutes at 3,000 X g at 6OC. The separated plasma was stored within 30 minutes at -2OOC in order to avoid cryoactivation of inactive plasma renin [6]. Blood pressure was measured within a few minutes of blood sample collection; routine clinical measurements and assessments necessary for diagnosis were recorded throughout each patient’s hospital stay. Active plasma renin was measured by radioimmunoassay of angiotensin I [7,8]. Activation of inactive plasma renin was achieved by utilizing trypsin (Sigma T-8253) at a concentration of 1 mg/ml incubated at 23OC for 30 minutes at pH 7.4. At the end of this phase, plasma pH was adjusted to pH 6.0 with 0.7 M malate buffer prior to assay of angiotensin I. Preliminary experiments with normal plasma indicated that maximal activation of renin occurred with 0.75 to 1.25 mg of trypsin added per 1.0 ml of plasma, in agreement with studies of Sealey et al [4]. inactive plasma renin was calculated by subtraction of active plasma renin from total renin activity in each plasma sample after trypsin activation. Percent active renin was calculated by dividing the active plasma renin value by the sum of the active and inactive plasma renin values and then multiplying by 100. Statistical comparison for differences among these three groups employed one-way analysis of variance (ANOVA). For paired studies, the t test was used. Regression relationships were calculated using the nonparametric Spearman rank correlation coefficient.
402
2.9 0.5 1.3
Percent Active Renin
of Medicine
Volume
82
RENIN
extending to hypotension and shock in more severely ill patients. Activation of the kallikrein-kinin system may also cause systemic vasodilation [ 1 l- 131. Both the tendency to intravascular hypovolemia and vasodilation might act as stimuli for renin release by the juxtaglomerular cells of the kidney as a compensatory mechanism in order to maintain arterial pressure by the vasoconstrictor action of angiotensin II [ 141. Although severe pain might cause renin release by neural mechanisms, we did not find that patients with abdominal pain syndromes had significant elevations of active plasma renin values compared with normal subjects. In contrast, the group with pancreatitis had an average active plasma renin value during the acute phase of the illness that was six times that in the normal subjects or patients with abdominal pain. During recovery from acute pancreatitis, active plasma renin decreased significantly. This probably reflects restoration of normal volume homeostasis due to intravenous fluid administration given as routine therapy. In addition to measurement of active plasma renin, the assay that is usually performed for assessment of the circulating renin-angiotensin system, we measured inactive plasma renin [2] by using trypsin activation. This was done to determine whether the known activation of various proteolytic enzymes in acute pancreatitis would cause in vivo conversion of inactive renin to active renin, leading to a predicted low inactive plasma renin value in acute pancreatitis. This was not found, as the mean inactive plasma renin value in patients with acute pancreatitis was no different from that in normal subjects or those with acute abdominal pain syndromes. However, in the subgroup of those with acute pancreatitis whose active and inactive plasma renin values were measured during the acute phase and after recovery, a significant inverse regression relationship was found between the change in active and inactive plasma renin. Our results indicate that patients with the highest active plasma renin values in the acute phase had the largest change toward normal (Figure 1) and also had the largest increase in inactive plasma renin with recovery (Figure 2). Perhaps then, those with the highest active plasma renin levels in acute pancreatitis do have some degree of conversion of inactive to active plasma renin. With recovery, the change in inactive plasma renin represents a recovery of this plasma factor toward normal from a lower level resulting from prior activation or “consumption” during the acute phase. Other patients with acute pancreatitis and smaller increases in active plasma renin during the acute phase do not exhibit this pattern. Changes in the level of plasma trypsin inhibitor concentration might also account for the relationship between changes in active and inactive plasma renin during recovery from acute pancreatitis. Plasma trypsin inhibitor concentration is reduced in the acute phase, presumably due to binding of trypsin that has reached the circulation [9]. In
March
IN PANCREATITIS-GREENSTEIN
ACUTE PANCREATITIS
ET AL
RECOVERY
ng/ml/hr PRA
15-
IPRA
. P=OO7
Figure f. Measurements of active renin (PRA), inactive renin (IPRA), serum amylase, and percent active renin during the symptomatic and recovery phases of acute pancreatitis. The mean values (2c SEM) are indicated on either side of the paired measurements.
I
AIPRA
\
\
\
\
20 \a \
16 \
\
12 \
\
. l
8
\
l
I
\, 4 I -20
I
I
I
-16 -12 -8
1
I\
-4
‘i
4
8
12
n
PRA
,%i
Figure 2. Relationship between the change in PRA (A PRA) and change in IPRA (A IPRA) with recovery in acute pancreatitis (Spearman rank correlation coefficient r, = 0.94; p
1987
The American
Journal
of Medicine
Volume
82
403
RENIN
IN PANCREATITIS-GREENSTEIN
ET AL
the assay for inactive plasma renin, addition of exogenous trypsin to plasma with subnormal amounts of trypsin inhibitors might inactivate renin to some extent [2] and give a false-low value for inactive plasma renin. With recovery and normalization of plasma trypsin inhibitors, activation of inactive plasma renin in the assay would again be optimal. We did not assess plasma trypsin inhibitor concentration to evaluate this possibility. However, this effect would only apply to measurement of inactive plasma renin and would not account for the increase in active plasma renin that we observed in the acute phase. There was no significant relationship between the changes in active plasma renin, inactive plasma renin, or percent active renin and serum amylase levels. However, it is well known that serum amylase measurements do not correlate well with severity of acute pancreatitis [I]. Activation of the renin-angiotensin system in acute pancreati-
tis may serve as a defense against the hypovolemia and hypotension that complicate this disease. However, excessive activation of the renin system by release of active renin from the kidney and perhaps by proteolytic conversion of inactive renin might cause inappropriate vasoconstriction. This sequence might account for the occasional observation of paradoxic arterial hypertension as a complicating event in acute pancreatitis [ 151. It is possible that the degree of angiotensin II-induced vasoconstriction, as reflected by the active plasma renin level, might be an independant determinant of outcome in acute pancreatitis. This study was not designed to assess that possibility in comparison with established predictors such as the “Ranson criteria” [16]. Our finding that active plasma renin is significantly increased in acute pancreatitis suggests, however, that this measurement be included in prospective studies to improve definition of the predictors of mortality and morbidity in acute pancreatitis.
REFERENCES 1. 2.
3.
4.
5. 6.
7
8.
404
Banks PA: Pancreatitis. New York: Plenum, 1979; 49-52. Sealey JE, Atlas SA, Laragh JH: Pro-renin and other large molecular weight forms of renin. Endocr Rev 1980; 1: 365-391. Cooper RM, Murray GE, Osmond DH: Trypsin-induced activation of renin precursor in plasma of normal and anephric man. Circ Res 1976: 4O(suppl 1): 171-179. Sealey JE, Atlas SA, Laragh JH, Oza NB, Ryan JW: Activation of a prorenin-like substance in human plasma by trypsin and by urinary kallikrein. Hypertension 1979; 1: 179-189. Leckie B: Endogenous activation of plasma-inactive-renin. Lancet 1978; II: 217-219. Sealey JE, Moon C, Laragh JH, Alderman M: Plasma prorenin: cryoactivation and relationship to renin substrate in normal subjects. Am J Med 1976; 61: 731-738. Krakoff L: Measurement of plasma renin substrate by radioimmunoassay of angiotensin I: concentration in syndromes associated with steroid excess. Clin Endocrinol Metab 1973; 37: 110-l 17. Kodish ME, Katz FH: Plasma renin concentration: comparison of angiotensinase inhibitors and correlation with plasma renin activity and aldosterone. J Lab Clin Med 1974;
March
1987
The American
Journal
of Medicine
Volume
9.
10.
11.
12.
13. 14. 15.
16.
82
83: 705-715. Geokas MC, Rinderknecht H: Free proteolytic enzymes in pancreatic juice of patients with acute pancreatitis. Am J Dig Dis 1974; 19: 591-598. Ohlsson K, Eddeland A: Release of proteolytic enzymes in bile-induced pancreatitis in dogs. Gastroenterology 1975; 69: 668-675. Sumi H, Takasugi S, Toki N: Studies on kallikrein-kinin system in plasma of patients with acute pancreatitis. Clin Chim Acta 1978; 87: 113-l 18. Ofstad E: Formation and destruction of plasma kinins during experimental acute hemorrhagic pancreatitis in dogs. Stand J Gastroenterol 1970; S(suppl 5); 10-44. Orlov V, Beyakov N: Blood kallikrein-kinin system in acute pancreatitis. Am J Gastroenterol 1978; 70: 645-648. Haber E: The role of renin in normal and pathological cardiovascular homeostasis. Circulation 1976; 54: 849-861. Sankaran S, Lucas GE, Walt AJ: Transient hypertension with acute pancreatitis. Surg Gynecol Obstet 1974; 138: 235-238. Ranson JHC, Pasternak BS: Statistical methods for quantifying the severity of clinical acute pancreatitis. J Surg Res 1977; 22: 79-91.