Glomerular Dynamics and Morphology of Aged Spontaneously Hypertensive Rats
Effects of Angiotensin-Converting Enzyme Inhibition
Abstract Relationships between glomerular dynamics and renal injury, micropuncture and histological studies were assessed in 73 week-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats divided into untreated and angiotension-converting enzyme inhibitor–treated (quinapril; 3 mg/kg/day; for 3 weeks) groups. Urinary protein excretion (UPE) and histologic arteriolar (AIS) and glomerular (GIS) injury scores were determined. Mean arterial pressure (MAP) of untreated SHR was increased compared with WKY (200±6 vs 119±4 mm Hg; P<0.01), effective renal plasma flow (ERPF) was reduced (1.47±0.21 vs 3.06±0.26 ml/min/per g; P>0.01), and filtration fraction (FF) and total renal vascular resistance (RVR) of SHR were increased (P<0.01). Single-nephron plasma flow (SNPF) of untreated SHR was decreased (174±17 vs 80±9 ml/min; P<0.01), and single-nephron filtration fraction and afferent arteriolar resistance (RA) were increased (19.4±1.8 vs 30.0±2.5% and 1.90±0.25 vs 9.05±1.35 U, respectively; both P<0.01). Despite reduced SNPF, glomerular capillary pressure (PG) increased (49.7±0.7 vs 53.8±1.3 mm Hg; P<0.05), the result of efferent arteriolar constriction (1.15±0.18 vs 2.84±0.36 U; P<0.01). Untreated SHR had higher UPE (13.9±1.5 vs 42.8±3.2; mg/100 g per day; P<0.01) and GIS and AIS scores than WKY (4.3±1.1 vs 64.3±8.4 and 16.6±3.1 vs 96.3±14.4; both P<0.01). Quinapril reduced SHR MAP (to 173±7 mm Hg), FF and RVR (all P<0.01) and increased ERPF (to 2.40±0.26 ml/min per g; P<0.05), and PG decreased (to 49.1±1.1 mm Hg; P<0.01); in association with RA and RE (to 5.18±0.8 U; P<0.01 and 1.74±0.31 U; P<0.05). Although quinapril reduced UPE (to 23.6±1.8 mg/100 g per day; P<0.01) with GIS and AIS (P<0.05) in SHR, these indices remained higher than in WKY. These data demonstrate that SHR naturally develop glomerular hypertension and ischemia with arteriolar constriction and glomerular sclerosis, and that intrarenal hemodynamic, pathologic, and proteinuric changes begin to reverse after 3 weeks of treatment.
- intrarenal hemodynamics
- renal micropunctures
- rats, inbred SHR
- rats, inbred WKY
- angiotensin-converting enzyme inhibitors
Antihypertensive drug therapy over the past two decades has reduced morbidity and mortality from stroke, congestive heart failure, and coronary heart disease in patients with hypertension, but it has been apparently ineffective in reducing end-stage renal disease.1 In this respect, it is unclear whether any one antihypertensive agent reduces or even exacerbates renal microcirculatory involvement in patients with essential hypertension. Studies of several animal models of renal disease with hypertension have shown that glomerular hypertension and hyperfiltration are associated with leakage of protein molecules across the glomerular capillary wall, leading to progressive functional deterioration and glomerulosclerosis.2 3 These findings have been derived from studies of rats with renal failure or from experimental models that required removal of one kidney with extirpation of tissue from the remaining kidney, renal infarction, or nephrotoxic drugs or chemicals. Extrapolation from these foregoing studies to the situation of patients with essential hypertension who have two normally functioning kidneys is obviously inappropriate. This information may be assessed better in the spontaneously hypertensive rat (SHR) with intact kidneys, but the relation between glomerular dynamics and pathological changes is not clear in this experimental model.
We have reported intrarenal glomerular dynamic changes in the 21-week-old SHR using micropuncture techniques but did not evaluate the relation of these functional changes with histopathology because there was no evidence of elevated glomerular hydrostatic pressure, efferent arteriolar resistance, or proteinuria at that age.4 5 However, others have reported proteinuria, glomerular injury, and impaired renal functions in 1-year-old SHR, but they did not report glomerular dynamics.6 Angiotensin II also produces generalized renal vasoconstriction that may induce renal injury.7 Feld et al8 examined the effects of the angiotensin-converting enzyme (ACE) inhibitor enalapril in old SHR and concluded that this ACE inhibitor delayed the onset of renal disease. The effects of the ACE inhibitor quinapril on intrarenal hemodynamics in rats with cardiac failure and in SHR have been reported from our laboratory,5 9 but its effects on intrarenal hemodynamics, proteinuria, and histopathology are still unclear in the aged SHR.
We therefore designed the present study with two purposes in mind: first, to investigate the relation between glomerular dynamics and renal pathological changes in old SHR with naturally occurring genetic hypertension in which both kidneys remained intact; and second, to determine the effects of ACE inhibition on these intrarenal hemodynamics and pathophysiological changes.
Male SHR and Wistar-Kyoto rats (WKY) (Charles River Co) were studied at 73 weeks of age. All were purchased at 15 weeks of age and then maintained in plastic cages until study. They were given normal rat chow and allowed full access to tap water ad libitum. When the protocol was begun, the SHR, then 69 weeks of age, were divided into two subgroups: an untreated hypertensive control group and a group treated for 3 weeks with the ACE inhibitor quinapril. The WKY served as a normotensive control group. All rats were allowed free access to water and standard rat chow. The experimental protocol was approved by our institutional animal care committee.
Before study, all rats were subjected to 24-hour urinary protein excretion studies using individual metabolic cages. Urinary protein was determined using the method of Lowry et al.10 Quinapril treatment (3 mg/kg) was instituted after measurement of protein excretion and was administered daily for 3 weeks by gastric gavage. This dosage and treatment period had been shown previously to reduce arterial pressure and cardiac mass significantly in 21-week-old SHR.11 After the 3-week treatment period, measurement of daily urinary protein excretion was repeated.
Each rat was studied by a renal micropuncture technique as reported previously.4 5 9 In brief, after overnight fasting, the rats were anesthetized with thiobutabarbital (70 mg/kg IP, Byk-Gulden), after which they were placed on a heating pad to maintain body temperature at 37°C throughout the study. The right femoral artery was cannulated, and approximately 120 μL of arterial blood was collected to serve as a baseline blank for p-aminohippurate assay. This arterial catheter was used for subsequent blood sampling and to measure directly mean arterial pressure (MAP) and heart rate. Tracheostomy was performed to ensure adequate and stable ventilation. Catheters were also inserted into the left jugular and right femoral veins. The left jugular vein was used for infusion of [3H]inulin (850 μCi/mL, DuPont–New England Nuclear) at a rate of 0.1 mL/100 g body wt per hour. The right femoral vein was used for infusion of saline (containing 5.6% p-aminohippurate, Merck Sharp & Dohme) at a rate of 0.2 mL/100 g body wt per hour and 12.5% albumin (0.8 mL/100 g body wt per hour) for the initial 60 minutes of the preparatory surgical procedures; the maintenance rate was 0.15 mL/100 g body wt per hour thereafter.
The left kidney was exposed through a subcostal incision. Once isolated, it was separated carefully from surrounding peritoneal fat, and the left ureter was catheterized with PE-10 tubing. The kidney was then mounted in a Lucite holder, covered with 2% agar, and immersed in a small pool of saline to the renal surface. The bladder was cannulated for measurement of the urine volume from the right kidney. Urine was collected over two 30-minute periods, and blood samples were withdrawn at the midpoint of each collection. If the glomerular filtration rate (GFR) of the two kidneys differed by more than 30%, the results from these experiments were discarded.
The following micropuncture measurements were made: (1) efferent arteriolar blood was withdrawn by direct puncture of two to three superficially located “star vessels,” (2) precisely timed (90 seconds) samples of fluid were collected from four to six randomly selected superficial proximal tubules for determination of single-nephron glomerular filtration rate (SNGFR), and (3) efferent arteriolar (PE), proximal tubular (PT), and stop-flow (SFP) pressures were measured12 by a servo-null system (Instrumentation for Physiology & Medicine). PT and PE measurements were obtained from proximal convoluted tubules and star vessels, respectively, both selected randomly. Because SHR glomerular capillaries are not located on the renal surface, glomerular capillary pressure (PG) was considered to be the sum of SFP and the systemic colloid osmotic pressure.13 These PE, PT, and SFP measurements were made at least three times, and average values were calculated.4 5 9
Tubular fluid, urine, and plasma samples were counted in a β-scintillation counter for [3H]inulin activity by placing these samples in 10-mL scintillation vials (Bio-Safe II). GFR and SNGFR were calculated from the standard clearance formula. Hematocrit was determined in all arterial samples. Effective renal plasma flow (ERPF) was determined from p-aminohippurate clearance. Arterial plasma protein concentration was measured refractometrically.
Effective renal blood flow (ERBF), glomerular filtration fraction (FF), and total renal vascular resistance were calculated using ERPF, GFR, and MAP. All data for ERPF, ERBF, and GFR were normalized using the left kidney weight after decapsulation at the conclusion of each study. Single cortical nephron hemodynamics (single-nephron plasma flow [SNPF], single-nephron blood flow [SNBF], and single-nephron filtration fraction [SNFF]), plasma protein concentration and efferent and afferent osmotic pressures, and afferent and efferent arteriolar resistances (RA and RE) were calculated using equations described previously.4 5 9 The pressure gradient across the glomerular capillary wall (ΔP) was calculated as ΔP=PG−PT. The ultrafiltration coefficient (Kf) was calculated to according to the equation detailed by Deen et al14 as modified by Arendshorst and Gottschalk.15
After rats were killed with excess pentobarbital, the hearts were removed immediately and cleaned, and the atria were carefully excised free from the ventricles. The free wall remained as part of the left ventricle. Wet masses of the blotted ventricles were carefully determined on a grammatic balance. Left and right ventricular masses were then expressed as the ratio of ventricular weight (milligrams) to body weight (grams).
The kidneys were fixed in 10% neutral buffered formalin and embedded in paraffin for light microscopic studies. Sections were cut at thicknesses of 2 to 3 μm and stained with hematoxylin and eosin, periodic acid–Schiff, and periodic acid–methenamine-silver. Histological examination was performed by two observers in a blinded fashion. For semiquantitative evaluation, glomerular and arteriolar injury scores were examined as follows.
Glomerular Injury Score
Approximately 50 subcapsular and 50 juxtamedullary glomeruli from each specimen were examined for glomerular injury score using the sections stained with periodic acid–Schiff. Each glomerulus was graded from 1 to 4 by a modification of the method of Raij and associates16 : grade 1, normal glomerulus by light microscopy; grade 2, involvement of up to one third of the glomerular area; grade 3, involvement of one to two thirds of the glomerulus; and grade 4, two thirds to global sclerosis. Each score was then calculated according to the formula Glomerular Injury Score=[(1×number of grade 2 glomeruli)+(2×number of grade 3 glomeruli)+(3×number of grade 4 glomeruli)]×100/(number of glomeruli observed).
Arteriolar Injury Score
Forty to 50 afferent arterioles were examined from each specimen for arteriolar injury score using the serial sections stained with periodic acid–Schiff. Grading was performed as described by Mai et al17 as follows: grade 1, no arteriolar changes; grade 2, hyalinosis of the arteriolar wall up to 50% of its circumference; grade 3, 50% to 100% hyalinosis of the wall circumference but without luminal narrowing; and grade 4, complete hyalinosis of the wall with luminal encroachment. Each score was then calculated according to the formula Arteriolar Injury Score=[(1×number of grade 2 arterioles)+(2×number of grade 3 arterioles)+(3×number of grade 4 arterioles)]×100/(number of afferent arterioles observed). Total injury score was calculated by adding the glomerular and arteriolar injury scores of each rat.
One-way ANOVA followed by the Duncan multiple range test was performed between groups, and linear regression analysis was used to examine for correlation between morphological and micropuncture data.18 19 All data are expressed as mean±SEM; a probability level of 5% was considered statistically significant.
Body and Organ Weights
Although body weight was less in the untreated (control) SHR, left kidney weight was not significantly different between WKY and untreated SHR. For this reason, the ratio of left kidney weight to body weight was increased in the untreated SHR. Similarly, the ratio of right ventricular to body weight was increased in control SHR. On the other hand, left ventricular weight and the ratio of left ventricular to body weight was significantly increased in these SHR. These organ weights were no different in the quinapril-treated SHR than in the untreated SHR. Although quinapril decreased left ventricular weight and the ratio of left ventricular to body weight, these values were still greater than in the WKY. Right ventricular weight was unaffected by quinapril (Table 1⇓).
Systemic and Whole-Kidney Hemodynamics
MAP was significantly elevated in the untreated SHR compared with the WKY. ERPF and ERBF of the control, untreated SHR were significantly reduced although there was no difference in GFR compared with the WKY. Consequently, FF and renal vascular resistance of the untreated SHR were increased significantly (Table 1⇑). It was of interest that serum creatinine and uric acid concentrations did not change significantly; however, creatinine was reduced within the short period of ACE inhibition therapy, and uric acid level was higher in the aged SHR and was reduced with that treatment.
SNPF of the untreated SHR was significantly reduced with respect to WKY (P<.01); this was associated with a slightly (but insignificantly) reduced GFR and a significantly increased SNFF and RA (Table 2⇓). Despite this decreased SNPF, SFP and PG were significantly (P<.05) increased, presumably the result of a significantly increased RE. All other intrarenal pressure measurements (PT, PE, efferent osmotic pressure, and ΔP) of the untreated SHR were significantly increased.
Quinapril significantly reduced MAP in SHR to levels that were less than those of the untreated SHR but still greater than those of the normotensive WKY. This pharmacologically induced hypotension in the SHR was associated with an increased ERPF and a decreased FF and renal vascular resistance; GFR was unaffected (Table 1⇑). In contrast to these whole-kidney SHR hemodynamic changes, quinapril caused no change in SNPF and SNFF. However, PG decreased, and this was associated with significant reductions in RE and RA. The ΔP and RA also decreased with treatment, and RA and RE remained greater than in the WKY, whereas Kf tended to increase (Table 2⇑).
Before treatment, there was no difference in urinary protein excretion between the two SHR groups (42.8±3.2 to 40.9±2.8 mg/100 g per day), and these protein excretory rates were much greater than in the WKY (P<.01). Treatment with the ACE inhibitor significantly reduced that protein excretion, although after this 3-week treatment period, it still remained greater than that of WKY (P<.01, Fig 1⇓).
The morphological appearance of arterioles, glomeruli, and interstitium remained normal in the 73-week-old normotensive control WKY compared with the untreated and quinapril-treated SHR (Fig 2⇓). Renal injury of the untreated SHR (compared with WKY) revealed segmental and global glomerular sclerosis and arterioarteriolar sclerosis associated with inflammatory cell infiltration, interstitial fibrosis, atrophic and dilated tubules, and tubular casts. In addition, these SHR demonstrated marked medial and intimal thickening, with proliferation of vascular smooth muscle cells in the interlobular arteries. The afferent arterioles showed hyalinosis with luminal encroachment; periarterial fibrosis with lymphocytic infiltration was also seen. Quinapril reduced this damage, especially in the glomeruli and interstitium (Fig 2⇓, right).
Glomerular and Arteriolar Injury Scores
The glomerular damage of the subcapsular lesions was mild in each group, and the arteriolar and glomerular changes were more severe in the juxtamedullary area (P<.01, Table 3⇓). With quinapril treatment, the severity of these lesions on the juxtamedullary glomeruli was significantly decreased (P<.01, Table 3⇓) compared with untreated SHR. Moreover, the total injury score (Fig 3⇓) was significantly greater in untreated SHR (164.0±22.6) and quinapril-treated SHR (110.1±12.4) than in WKY (22.7±3.9, P<.01). This total injury score was reduced significantly by quinapril treatment (P<.05). Finally, there was a strongly positive correlation between these two indexes (r=.827, P<.001).
Correlation Between Glomerular Injury Score and Glomerular Dynamics
There were strongly positive correlations between glomerular injury score and RA (Fig 4⇓, bottom left; r=.890, P<.001) and RE (Fig 4⇓, bottom right; r=.752, P<.001); there were negative correlations between glomerular injury score and SNPF (Fig 4⇓, top left; r=.639, P<.001) and SNGFR (Fig 4⇓, top right; r=.491, P<.05). PG did not correlate with glomerular injury score (r=.227).
The results of this study demonstrate three major points: (1) By 73 weeks of age the SHR demonstrate renal and glomerular hemodynamic changes demonstrating a natural progression of disease related to prolonged hypertension; (2) these changes were associated with markedly elevated urinary protein excretion and histological evidence of severe hypertensive nephrosclerosis; and (3) ACE inhibition promoted early reversal of these pathological changes within 3 weeks.
Our earlier renal hemodynamic and micropuncture studies4 5 9 focused on 20-week-old SHR and WKY because by this age left ventricular hypertrophy had developed and could be reversed by antihypertensive therapy.11 However, in those previous studies, the only evidence of renal involvement was increased total renal vascular and afferent glomerular arteriolar resistances4 5 9 and increased afferent and efferent arteriolar responsiveness to α1-adrenergic stimulation and inhibition.4 5 Glomerular hydrostatic pressure was not increased, nor was there significant proteinuria or morphological changes. In the present study of 73-week-old SHR, the increased total vascular and afferent glomerular arteriolar resistances had become more severely increased and were associated with increased efferent glomerular arteriolar resistance and glomerular hydrostatic pressure as well as reduced renal plasma flow (whole-kidney measurement and SNPF), increased FF, and marked proteinuria. Furthermore, these functional changes were associated with histological evidence of arteriolar and glomerular disease characteristic of hypertensive nephrosclerosis.20 Some of these pathological changes had been reported earlier by Freis and Ragan21 and Feld et al22 in 73- and 67-week-old SHR, respectively. However, neither of these latter two studies related their deleterious renal changes to glomerular dynamic alterations as assessed by renal micropuncture.
With respect to left ventricular weight, in the present study control SHR showed further increase in left ventricular hypertrophy, the magnitude of which had continued to increase by 73 weeks.23 In an earlier study from our laboratory,11 quinapril reduced left ventricular mass in 19-week-old SHR with two doses administered for 3 weeks each, a low subhemodynamic dose (1 mg/kg) and higher hemodynamically effective dose (3 mg/kg). These findings suggest that reduced left ventricular mass did not depend solely on reduced cardiac afterload. In the present study, we treated the SHR with the higher quinapril dose for 3 weeks, and left ventricular mass was less diminished than in the 19-week-old SHR studied earlier.11 These findings continue to provide further support for the thesis that the local tissue renopressor inhibitory effect may be involved by this treatment.
In contrast to the foregoing changes in left ventricular mass, renal injury was not evident in the 19-week-old SHR.4 5 11 Thus, many studies have required uninephrectomized rats for the investigation of renal injury and micropuncture and the changes caused by antihypertensive agents. In these models, glomerular hyperfiltration and hypertension were produced experimentally, and these changes were ameliorated by dietary protein restriction or pharmacotherapy.2 3 However, it is inappropriate to extrapolate from the foregoing studies in uninephrectomized rats to the SHR or to patients with essential hypertension, both of whom have intact kidneys with naturally progressive disease. Moreover, in contrast to the glomerular hypertension and hyperfiltration hypothesis for glomerular injury, hypertensive nephrosclerosis may also result from glomerular ischemia as a consequence of preglomerular arteriolar constriction with luminal narrowing and diminished glomerular blood flow even though the precise mechanism for the altered glomerular dynamics is unclear. It still remains possible that both alterations, glomerular hypertension and glomerular ischemia, coexist; and the present data support this thesis.
Indeed, not only was there evidence of increased PG, RA, and RE, but these alterations were associated with reduced ERPF and SNPF, with increased FF and severe proteinuria. Furthermore, the increased juxtamedullary glomerular and arteriolar injury scores provide further support for this concept in the SHR.
With respect to the nephrosclerosis of aged SHR, Feld et al6 had already demonstrated the development of renal injury with proteinuria during the first year of life. They also indicated that the juxtamedullary glomeruli, which appeared to be the major source of urinary protein, initially suffered the greatest damage. Our present data strongly support these findings and provide heretofore unavailable supportive intrarenal (ie, glomerular) and whole-kidney hemodynamic data. At present, there is no explanation as to why glomerular injury occurred primarily in the deep nephrons. In this regard, there are some morphological and physiological differences between the deep and superficial glomeruli. With respect to physiological differences, glomerular blood flow is increased significantly in the deep glomeruli, and this could be related to the greater degree of juxtamedullary renal injury.24 25 We studied only superficial glomeruli by renal micropuncture, and these glomeruli did not show severe pathological changes, as found in the deeper glomeruli. Hence, the more severe pathological damages in the deep nephrons may be expected to be associated with even more severe functional changes. Moreover, the impaired functional changes that were seen most likely precede the pathological changes. This concept certainly is in accord with the findings in earlier reports.20 24 In addition, Feld et al22 demonstrated that the initial lesions were confined to the juxtamedullary zone, sparing the outer cortex.
Determination of the superficial glomerular dynamics was important to provide a mechanism for the glomerular injury. Thus, in aged SHR renal plasma flow and SNPF were significantly decreased, and GFR and SNGFR were unchanged. Furthermore, despite the decreased SNPF, PG was increased significantly, and this was associated with a significant increase in RE. These results demonstrated that glomerular ischemia and glomerular hypertension occurred in the aged SHR. It was very interesting that glomerular hypertension had occurred in our study without hyperfiltration. Using subtotally nephrectomized rats, Anderson et al26 reported that when glomerular hypertension was controlled, glomerular injury might be ameliorated even if hyperfiltration persisted. They also suggested that glomerular hypertension with glomerular ischemia but not necessarily with hyperperfusion or hyperfiltration is the most critical determinant of glomerular injury.
In an earlier study in 19-week-old SHR treated with quinapril, we demonstrated a decreased PG associated with vasodilation of afferent and efferent glomerular arterioles even though the pretreatment PG was normal. These results are consistent with those of the present study, in which an elevated PG was reduced with quinapril, suggesting the clinical, hemodynamic, and histological benefits of reducing PG in the early stages of antihypertensive therapy with the goal of preventing further renal injury from hypertensive vascular disease. Although we were not able to demonstrate such prevention in young SHR, we were able to show these beneficial effects of treatment in the old SHR in this study. Thus, with ACE inhibitor treatment, urinary protein excretion and arteriolar and glomerular injury scores improved in only 3 weeks, suggesting that this treatment began to reverse the pathophysiological changes associated with reduced glomerular pressure and increased glomerular flow. Feld et al8 also demonstrated the beneficial effects of ACE inhibition in aged SHR. In that study, enalapril decreased arterial pressure but only postponed the onset of kidney disease. Nordlander and Havu27 investigated the effects of a calcium antagonist in aged SHR, showing that felodipine reduced the proteinuria and glomerular sclerosis. On the other hand, Dworkin and associates28 showed that calcium antagonism and ACE inhibition reduced renal injury through different mechanisms in rats with remnant kidneys. In that study, administration of the calcium antagonist nifedipine also reduced arterial pressure despite the persistence of glomerular hypertension. Analysis of morphological changes showed that kidney weight, glomerular volume, and glomerular capillary radius all decreased in the nifedipine-treated rats. The authors concluded that the calcium antagonists inhibit compensatory renal growth, whereas the ACE inhibitors act via hemodynamic mechanisms by reducing glomerular capillary pressure. To our way of thinking, it is likely that the cause of glomerular injury in hypertension is multifactorial, and further studies are needed to define with greater certainty the mechanisms of that injury.
Finally, questions may be raised as to how the renal glomerular and arteriolar lesions reversed pathologically. There are two possibilities: reversibility of the arteriolar and glomerular lesions or disappearance of the injured lesions. Most current thinking seems to conclude that the injured glomerular lesions are irreversible, but the present findings suggest that this may not necessarily be the case. On the other hand, the latter possibility of the disappearance of lesions seems more unlikely. Our counting of glomeruli and the associated lesions do not support that contention. Thus, the concept of irreversibility of glomerular and arteriolar damage and disappearance of glomeruli may not be correct. It therefore seems more likely that glomerular and arteriolar damage is reversible. Recent literature dealing with myocardial and vascular lesions in hypertension support the thesis that cardiovascular lesions are at least in part reversible.29 30 31 Furthermore, Nordlander and Havu27 reported reversibility of glomerulosclerosis in aged SHR with the calcium antagonist felodipine. Therefore, the present study adds promise to the possibility that hypertensive renal disease can be reversed.
This study was supported by funds from the Hypertension Research Trust Fund, Alton Ochsner Medical Foundation. We also acknowledge the Parke Davis Research Laboratories for their generous supply of quinapril. We deeply appreciate the technical assistance and support of Gordon B. McFarland, MD, and Joan M. Kissinger, MT.
This manuscript from Alton Ochsner Medical Foundation was sent to Theodore Kotchen, MD, Consulting Editor, for review by expert referees, for editorial decision, and for final disposition.
- Received August 31, 1994.
- Revision received October 24, 1994.
- Accepted November 21, 1994.
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