Fibromuscular dysplasia of the renal artery with medial dissection

Fibromuscular Dysplasia of the Renal Artery with Medial Dissection A Case Simulating Polyarteritis Nodosa

DAVID

S. MEYERS,

CLARENCE

E. GRIM,

W. FORD KEITZER, Columbia.

M.D. M.D.* M.D.

Missouri

A 31 year old man with fibromuscular dysplasia of the renal artery presented with rash, hypertension of sudden.onset, seizures and an elevated erythrocyte sedimentation rate. Renal arteriography revealed an aneurysm of the left renal artery which was interpreted as secondary to polyarteritis nodosa. Renal vein renin determinations suggested a unilateral, renindependent, surgically amenable cause of the hypertension. Nephrectomy resulted in prompt and sustained return of blood pressure to within normal limits. Three distinct patterns of fibromuscular dysplasia were present in the renal artery. We recently studied a patient with fibromuscular dysplasia of the renal artery who manifested a polymorphous clinical picture simulating that of polyarteritis nodosa. CASE REPORT

From the Departments of Pathology, Medicine and Surgery, University of Missouri Medical Center, and Veterans Administration Hospital, Columbia, Missouri. This study was supported in part by U.S.P.H.S. Grant FR of Missouri Medical University 00287, School, (FR 5387-O) Missouri Regional Medical Program. Requests for reprints should be addressed to Dr. David S. Meyers, Department of Pathology, University of Missouri Medical Center, Columbia, Missouri 65201. Manuscript accepted October 12, 1973. Indiana University * Present address: School of Medicine, Indianapolis, Indiana 46202.

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A previously healthy, 31 year old male data processor was initially hospitalized at another institution because of severe bilateral flank pain, fever, chills, cough and weakness. Blood pressure and urinalysis were reported as within normal limits, and the white blood cell count was 13,000/mm3. The patient was discharged with a diagnosis of acute gastroenteritis but returned 2 weeks subsequently because of epistaxis, myalgias and fatigue. Blood pressure at that time was 240/140 mm Hg and the erythrocyte sedimentation rate was 38 mm/hour. There was no family history of hypertension. After initial antihypertensive therapy and the initiation of prednisone therapy (80 mg/day), he was transferred to the University of Missouri-Columbia Medical Center with the tentative diagnosis of polyarteritis nodosa. On admission on March 14, 1972, blood pressure was 180/120 mm Hg; all other vital signs were normal. An erythematous rash was noted on the neck, chest and shoulders. The fundi were free of papilledema, hemorrhages and exudates. An abdominal ,bruit was not heard. Electrocardiogram showed nothing abnormal. Urinalysis was within normal limits except for trace protein. The white blood cell count was 14,900/mm3 with 88 per cent neutrophils and the hematocrit value was 44 per cent. Initial erythrocyte sedimentation rate (Westergren method) was 18 mm/hour. Shortly after admission the patient had two grand mal seizures. Immediately thereafter, blood pressure was 180/130 mm Hg and neurologic examination gave nor-

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mal results. A 24-hour urine collection contained 0.7 g of protein. A renal arteriogram revealed an aneurysm of the left renal artery proximal to the hilus of the kidney (Figure 1) and questionable, small aneurysms of the intralobular arteries of the left kidney. The left kidney was 2!.3 cm shorter than the right kidney. The radiologist’s impression was polyarteritis nodosa. The following investigative procedures gave normal results: lupus erylhematous test, fluorescent antinuclear antibody test, deltoid muscle biopsy, repeated erythrocyte sedimentation rate, serial serum creatinine phosphokinase, brain scan, electroencephalogram and cerebrospinal fluid examination. On March 30, 1973, renal vein catheterization was performecl to investigate the relation between the aneurysm of the renal artery and the hypertension. The results are shown in Table I. Renin was measured by the method of Cohen et al. [l]. At the time of the study the patient was receiving the following drugs: prednisone, alpha-methyldopa, hydralazine, phenobarbital, guanethidine and diphenylhydantoin. Peripheral plasma renin activity was 77.4 ng Al/ml/hour. The lack of laboratory evidence of polyarteritis nodosa and the 4:l ratio of renin activity of left versus right renal veins suggested that the symptom complex was secondary to renal ischemia caused by the renal artery aneurysm. Initial management consisted of a tapering off of the prednisone therapy, antihypertensive drug therapy (guanethidine and hydrochlorothiazide) and discontinuan& of all other medication. Within 2 weeks, the rash had cleared and the patient was discharged with a blood pressure of 160/90 mm Hg. The prednisone therapy was gradually withdrawn with no adverse sequelae, and the blood pressure varied from 160/80 to 190/100 mm Hg. After steroid withdrawal, the patient underwent sur-

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gical correction in January 1973. During operation arterial pressures were monitered continuously by means of a cannula in the left radial artery ancl a Statham SP37@ transducer. After dissection of the left renal artery and its branches leading to the parenchyma of the kidney, inspection and palpation of the vessels demonstrated significant progression of the vascular disease from that suggested by arteriographic appearance 9 months previously. A normal appearing branch arose 15 mm distal to the origin of the main artery. This branch supplied the normal appearing upper pole of the kidney (Figures 2 and 3). Immediately distal to

TABLE

I

Results of Renal (ng Al*/ml/hour)

Vein

Position Supine After 20 min tilt *Angiotension

Renin

Determinations

Left

Right

272

121

396

102

I

Figure 2. Surgical specimen. the aneurysm and long arrows ing proximally.

Note aneurysm (short arrows) 1. Arteriogram. and branches arising proximal to the aneurysm (long arrows).

ARTERY-MEYERS

Small arrows indicate indicate branches aris-

Figure

Figure 3. Diagram. Numbered arrows indicate tions represented in Figures 4, 5, 6 and 7.

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stenotic zones showing periFigure 4. Proximal medial and intimal fibroplasia (arrows). Gomori’s trichrome stain; original magnification X 16, reduced by 28 per cent. the origin there

and

of the

followed

palpably

terminated Figure tion.

branch a

to the

25 mm

thickened in a fusiform

3).

The

Distal

was

aneurysm

posteriorly

to

The right

kidney.

explored

supply

and found

Intraarterial

the

of the

kidney

dilatation

firm

and

(B

without

the artery

divided into three branches inferior two thirds of the arose immediately proximal the

pole

aneurysmal

aneurysm

to the

upper

segment that was irregular (A in Figure 3). This portion in

pulsa-

(C in Figure

3)

which supplied the anterokidney. A branch which to the aneurysm passed

posteroinferior

kidney

and

two

its blood

thirds

supply

of

were

to be normal.

pressures

the aneurysm in the and a mean pressure

were

measured

stenotic gradient

proximal

to

branch (A in Figure 3) of 55 mm Hg was docu-

mented. Because of the extensive artery disease, reconstruction was

nature of the renal impossible and left

nephrectomy was performed. While the right kidney was being explored, the left renal artery was clamped for

20 min.

During

this

time,

there

was

no change

the systemic pressure and, indeed, the vascular pearance of the left kidney remained unchanged. sequently, a large periureteral collateral artery identified.

Five

clamped,

the

170/120

to

minutes

systemic 120/75

after blood

mm

the

left

pressure

Hg.

The

renal

vein

decreased

postoperative

in

apSubwas was from blood

pressure was 120/80 mm Hg. During the operation, peripheral plasma renin activity was determined every 15 min. Prior to nephrectomy, the plasma renin activity

averaged

18

ng

Al/ml/hr;

the

hour

after

ne-

phrectomy, it decreased to an average of 8 ng Al/ml/ hour. Seven weeks after operation, blood pressure was 120/70 mm Hg and other than moderate arteriolar narrowing seen on fundoscopy, physical examination showed no abnormalities. At this writing, 9 months after operation, the patient is well and normotensive without the use of antihypertensive medication. RESULTS

Pathologic g

Examination.

and measured

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10

The

kidney

cm in length.

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weighed

90

The inferior

two

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thirds was mildly atrophic whereas the upper pole appeared normal. Proximal to the origin of the branch to the upper pole of the kidney, the main artery was normal with a 3.5 mm lumen. The following 24 mm (A in Figure 3) was indurated with a stenotic central lumen of 1 mm in diameter. The branch to the upper pole of the kidney was normal with a lumen measuring 1 mm in diameter. Serial sections through the aneurysmal portion of the artery (B in Figure 3) demonstrated a dissecting aneurysm that had eccentrically displaced the true lumen. The aneurysm was 5 mm in diameter and 9 mm long. A branch originating at the proximal border of the aneurysm appeared normal except for a narrowing of its ostium. The distal portion of the renal artery (C in Figure 3) had a severely narrowed, centrally located lumen. This portion also contained numerous mural aneurysms. The branches of the terminal trifurcation were normal. Representative sections of the arteries were embedded in paraffin after formalin fixation, sectioned and stained with hematoxylin and eosin, Gomori’s trichrome, periodic acid-Schiff and Verhoeff’s elastic methods. Sections from the kidney and an adrenal biopsy specimen were processed for routine study and for immunofluorescent and electron microscopic study. Random portions of renal cortex from both the normal and the atrophic areas of the kidney were stained with hematoxylin and eosin, periodic acid-Schiff and Bowie’s stain [2]. Histologic Findings. The branches arising from the main renal artery were normal on histologic study. The proximal stenotic portion of the main artery (A in Figure 3) had a diffusely thickened media caused by proliferation of fibrous tissue (Figure 4); this change was most marked in the outer portion of the media (perimedial fibroplasia). Sections taken from the aneurysm revealed a false lumen in the media that was diffusely altered by fibroplasia (Figures 5, 6 and 7). At the proximal and distal points of the dissection, a disruption of the internal elastic lamina could be demonstrated (Figures 5 and 7). The distal stenotic portion (C in Figure 3) demonstrated medial fibroplasia with focal disruption of the internal elastic lamina forming mural aneurysms. There were no changes suggestive of active or healed arteritis in either extra- or intraparenchymal vessels. The ischemic portions of the renal cortex had marked tubular atrophy and a mild, diffuse, lymphocytic interstitial infiltrate. The nonischemic parenchyma was normal. A juxtaglomerular cell count comparing the ischemic and nonischemic areas was taken by the method of Turgeon and Sommers [3]. A total of 206 cells were counted in 25 juxtaglomerular bodies in the nonischemic 56

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upper pole compared with 281 in the ischemic part. In addition. a higher proportion of cells in the ischemic portion had intracytoplasmic granules when stained by the Bowie method [2,3]. The difference in the juxtaglomerular cell count between the two portions of the kidney is statistically significant (p < 0.005). lmmunofluorescent and ultrastructuiral studies of the kidney sections and the adrenal biopsy specimen gave normal results. COMMENTS The sudden hypertension, rash, abdominal pain, elevated erythrocyte sedimentation rate, seizures and proteinuria in this patient led to an initial diagnosis of polyarteritis nodosa. However, the lack of supportive data and the presence of an aneurysm of the renal artery suggested a renovascular origin for the symptom complex. Renal vein renin determin,ations supported this thesis, and surgical intervention demonstrated that the patient, indeed, had a renovascular lesion. The striking decrease in plasma renin activity and blood pressure associated with nephrectomy combined with the ipsilateral preoperative elevation in renal vein renin activity suggests that this patient’s hypertension was “renin-dependent.” Most of the features in the patient’s symptom complex are clearly consistent with sudden, severe hypertension and a dissecting aneurysm. The rash is a less clear feature, but its disappearance after discontinuance of phenobarbital, diphenylhydantoin and hydralazine suggests that it was drug-induced. The results of juxtaglomerular (cell count agree with those of Cracker [4] who fouind the juxtaglomerular cell count to be uniformly elevated above 225 cells in ischemic renal tissue from 23 patients with stenosis of the renal artery. The significant difference in the juxtaglomerular ceil count between the ischemic and nonischemic cortex suggests juxtaglomerular cell hyperplasia in response to decreased perfusion. Similar morphologic changes in obstruction in a branch of the renal artery have been associated with elevated renin levels in the ischemic cortex

Figure 5. Point of aneurysm formation. Note the medial fibroplasia and marked disruption of the internal elastic lamina. Verhoeff’s elastic stain; original magnification X 16. reduced by 28 per cent.

Figure 6. Midportion centric displacement hoeff’s elastic stain; duced by 28 per cent.

of the aneurysm illustrating ecof the stenotic true lumen. Veroriginal magnification x 16, re-

151. Fibrornuscular dysplasia of the renal artery is a well described entity [6-lo]. Dissecting aneurysms of the renal artery are unusual as isolated lesions but relatively common in association with fibromuscular dysplasia. Dissecting aneurysms were found in 6 of 66 cases of idiopathic, nonatheromatous, medial dysplasia reviewed by Harrison et al. [6] from the Mayo Clinic. In a joint pathologic classification, Harrison and McCormack [7] estimated that 5 to 10 per cent of cases of fibromuscular dysplasia involve medial dissection. Dissecting (aneurysm of the renal artery has been associated with the onset of renin-dependent malig-

Figure 7. Reentry point of the aneurysm. ma/ fibroplasia. Arrows show internal elastica. Verhoeff’s elastic stain; original X 76. reduced by 28 per cent.

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nant hypertension [11,12]. In addition to the clinical features, this case is of interest because of its anatomic features: (1) the demonstration of the points of formation and reentry of the dissecting aneurysm; (2) three distinct patterns of fibromuscular dysplasia of the renal artery represented consecutively in a single artery (perimedial fibroplasia, medial dissection and medial fibroplasia

with mural aneurysm formation); (3) juxtaglomerular cell hyperplasia in the ischemic portion of the kidney. ACKNOWLEDGMENT Antibody to angiotension I was kindly provided by Drs. E. L. Cohen and J. W. Conn, Ann Arbor, Michigan.

REFERENCES 1.

2.

3.

4. 5.

6.

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Cohen EL, Grim CE, Conn JW, Blough WM, Guyer RB. Kern DC, Lucas CP: Accurate and rapid measurements of plasma renin activity by radioimmunoassay. J Lab Clin Med 77: 1025, 1971. Pitcock JA, Hartroft PM: The juxtaglomerular cells in man and their relationship to the level of plasma SOdium and to the zona glomerulosa of the adrenal cortex. Am J Pathol 34: 863, 1958. Turgeon C, Sommers SC: Juxtaglomerular cell counts and human hypertension. Am J Pathol 38: 227, 1961. Cracker DW: Bilateral juxtaglomerular cell counts in renal hypertension. Arch Pathol 93: 103, 1972. Geyskes GG, Misage JR, Bron K, Haas JE, Berg G, Shipiro AP: Malignant hypertension following renal artery branch obstruction. JAMA 22.2: 457, 1972. Harrison EG. Hunt JC, Bernatz PE: Morphology of fibromuscular dysplasia of the renal artery in renovascu-

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lar hypertension. Am J Med 43: 97, 1967. Harrison EG, McCormack LJ: Pathologic classification of renal arterial disease in renovascular hypertension. Mayo Clin Proc 46: 161, 1971. McCormack LJ, Poutasse EF, Meaney TF, Noto TJ, Dustan HP: A pathologic-arteriographic correlation of renal arterial disease. Am Heart J 72: 188, 1966. Cracker DW: Fibromuscular dysplasia of renal artery, Arch Pathol85: 602, 1968. Sheps SG. Kincaid OW, Hunt JC: Serial renal function and angiographic observations in idiopathic fibrous and fibromuscular stenoses of the renal arteries. Am J Cardiol 30: 55, 1972. Perry MO: Hypertension and dissecting aneurysm of the renal artery. Arch Surg 102: 216, 1971. Khanna OP, Nedwich A, Gonick P: Accelerated hypertension due to intramural dissection of accessory renal artery. Urology 1: 130, 1973.