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Renal artery dysplasia in a patient with membranoproliferative glomerulonephritis
Renal Artery Dysplasia in a Patient with Membranoproliferative Glomerulonephritis
BRUCE R. LESLIE, M.D.* ROBERT J. HAMBURGER, M.D. MAGDA M. STILMANT, M.D. WALTER FLAMENBAUM, M.D. Boston, Massachusetts
A 27 year old man with nephrotic syndrome due to memhranoproliferative glomerulonephritis had multifocal stenoses of the renal and intestinal arteries. The arterial lesions demonstrated by angiography closely resembled those of medial fibromuscular dysplasia. The dysplasia progreaPedover a five year period to involve both renal arteries from their extrarenal segments through ‘their interlobar branches. Low serum levels of complement components C3 and C4, focal reduplication of the glomerular basement membrane on light microscopy, and the patterns of glomerular localization of IgG and C3 by immunofluorescence were characteristic of type I membranoproliferative glomerulonephritis. The development of the arterial dysplasia in a patient with chronic glomerulonephritis suggests a common immunologic pathogenesis of both disorders. Fibromuscular dysplasia is recognized as a cause of renal artery stenosis [l]. It can be identified by its characteristic angiographic appearance [2]. This report describes a patient with a progressive deformity of the renal arteries who also had membranoproliferative glomerulonephritis. The roentgenographically demonstrated “string of beads” pattern in the renal arteries was also seen in the jejunal branches of the superior mesenteric artery. The appearance was typical of that of medial fibromuscular dysplasia [3]. The development of these vascular changes in a patient with chronic hypocomplementemic glomerulonephritis suggests an immunologic pathogenesis of the arterial lesion. CASE REPORT
From the Renal Section and Department of Pathology, Boston Veterans Administration Hospital and the Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts. Requests for reprints should be addressed to Dr. Robert J. Hamburger, Renal Section, Boston VA Hospital, 150 S. Huntington Avenue, Boston, Massachusetts 02130. Manuscript accepted August 9.1978. * Present address: Rogosin Kidney Center, The New York’ Hospital- Cornell Medical Center, 525 East 68th Street, New York, New York 10021.
528
March 1979
In a 19 year old white man pharyngitis. fever and brown urine developed during Army basic training in 1969. Physical examination showed a blood pressure of 130/80 mm Hg, diffuse pharyngeal erythema and no peripheral edema, Urinalysis revealed 3+ proteinuria, 100 erythrocytes/high power field (hpf), and 0 to 4 leukocytes/hpf, as well as red cell and granular casts. Culture of a throat swab was negative for beta-hemolytic streptococci. Other laboratory data were blood urea nitrogen 17 mg/dl, creatinine 0.9 mg/dl, total protein 6.2 g/dl, albumin 4.8 g/dl, cholesterol 269 mg/dl, antistreptolysin 0 titer 250 Todd units/ml and a urinary protein excretion of 2.6 g/24 hours. A percutaneous renal biopsy was performed and interpreted as showing “subacute glomerulonephritis.” Proteinuria and microscopic hematuria persisted during the next eight years, and hypertension, dependent edema and lipiduria developed. The patient was first seen at the Boston Veterans Administration Hospital at age 27, in 1973. His blood pressure was 182/150 mm Hg; there were grade 2 Keith-Wagener-Barker funduscopic changes without signs or symptoms of
The American Journal of Medicine
Volume 66
RENAL ARTERY
DYSPLASIA
IN MEMBRANOPROLIFERATIVE
hypertensive encephalopathy. There was no history of renal trauma and no family history of hypertension or renal disease. No carotid or abdominal bruits were heard and the peripheral pulses were normal. The blood urea nitrogen was 18 mg/dl, creatinine 1.3 mg/dl, albumin 3.0 g/dl, cholesterol 352 mg/dl. urine protein 5.6 g/24 hours and creatinine clearance 70 ml/min. A right open renal biopsy was performed in April 1973 (Figure 11. Because a renal sonogram suggested a mass in the right kidney, an aortogram and selective right renal arteriogram were performed. These did not demonstrate a mass but did reveal multifocal stenoses of the right renal and jejunal arteries. During the next five years, increasing doses of furosemide, propranolol, methyldopa and hydralazine were required to control the patient’s hypertension and peripheral edema. In September 1977, serum complement component assay showed a C3 concentration of 66 mg/dl (normal 88 to 252 mg/dl] and C4 of 8.0 mg/dl (normal 10 to 75 mg/dl]. In March 1978. laboratory data included blood urea nitrogen 50 mg/dl, creatinine 2.4 mg/dl. albumin 1.9 g/dl, cholesterol 438 mg/dl, creatinine clearance 41 ml/minute and urine protein 25.8 g/24 hours. The C3 was 37 mg/dl and the C4 was less than 8 mg/dl. Latex fixation was positive at a dilution of l:40. Negative studies included a test for serum antinuclear antibody, lupus erythematosus preparation, serologic test for syphilis (VDRL), direct and indirect Coombs’ tests, Raji cell assay, and tests for hepatitis B surface antigen and cryoglobulins. There was no M component on serum or urine protein electrophoresis. Repeat aortography and renal arteriography were performed in March 1978. Venography was performed and samples for renin activities were obtained. Plasma renin activity (PRA) was determined as previously described [4] using the Gamma Coat Plasma Renin Activity Kit (Clinical Assays, Cambridge, Mass.]. At the time of sampling, the patient had been on a 2 g sodium diet without potassium restriction for one week and was taking 320 mg propranolol, 3 g methyldopa, 150 mg hydralazine and 160 mg furosemide/day. Attempts to reduce the doses of propranolol and methyldopa, and to substitute a nonrenin-suppressing drug prior to the procedure, were associated with unacceptable increases in blood pressure. Renal vein samples were obtained after a single intravenous dose of 80 mg furosemide in an attempt to stimulate renin release The results are presented in Table I.
RESULTS Renal Biopsy. The tissue was fixed in 10 per cent neutral buffered formalin, cut at 4 p, and stained with hematoxylin and eosin, periodic acid-Schiff and Jones’ silver methenamine stains. Direct immunofluorescence was carried out as described elsewhere [5] using monospecific fluorescein-conjugated antiserums for immunoglobulin G (IgG), immunoglobulin M (IgM), C3 and albumin (Cappel Laboratories, Downington, Pa.). The biopsy specimen contained over 50 glomeruli per section. The glomeruli were uniformly involved and showed diffuse proliferation, margination of polymorphonuclear leukocytes and club-shaped lobules with mesangial expansion. A few glomeruli exhibited small areas of necrosis but no crescents were evident
GLOMERULONEPHRITIS-LESLIE
ET AL.
Figure 1. Photomicrograph of right renal biopsy specimen. The glomerulus shows mesangial hypercellularity and increased mesangial matrix. There is segmental thickening of the basement membranes. Periodic acid Schiff stain; magnification approximately X 400, reduced by 24 per cent. Insert: Focal reduplication of the glomerular basement membrane. Jones’ silver methenamine stain; magnification approximately X 400, reduced by 24 per cent.
(Figure I]. The basement membranes were segmentally thickened and focal reduplication was demonstrated by Jones’ stain (Figure 1, insert). These findings are considered typical of type I membranoproliferative glomerulonephritis [6]. Staining with serums against IgG and C3 showed strong reaction in a coarse and irregular granular pattern predominantly along the peripheral capillary loops. The mesangium also contained faint granular deposits of the same reagents. All other antiserums tested were negative. There was a single right renal artery Angiography. which bifurcated 3 cm from its origin into upper and lower pole branches. Both of these vessels had multiple concentric narrowings giving a “string of beads” appearance. The involvement extended into the interlobar arteries (Figure 21. On the left, there were two renal arteries which were similarly involved. These findings were more extensive than those seen five years previously. The aortogram again showed multifocal stenoses of several jejunal branches of the superior mesenteric artery. These findings were typical of multifocal fibromuscular dysplasia.
TABLE I
March 1979
Plasma Renin Activities (PRA) Site
PRA (ng/ml/hr)
Inferior vena cava Right upper pole renal vein Left upper pole renal vein Right lower pole renal vein Left lower pole renal vein
4.7 7.4 6.6 6.2 6.7
The American Journal of Medicine
Volume 66
529
RENAL ARTERY
DYSPLASIA
IN MEMBRANOPROLIFERATIVE
GLOMERLJLONEPHRITIS-LESLIE
Figure 2. Right selective renal arteriogram, 1978. Multifocal stenoses extend from the main upper and lower pole arteries through the interlobar arteries.
Renal venography showed right upper and lower pole veins inserting separately into the inferior vena cava. On the left, a single main renal vein divided into upper and lower pole veins. There was no evidence of renal vein thrombosis. COMMENTS The lesions demonstrated at arteriography in our patient closely resemble those seen in medial fibromuscular dysplasia. This patient, in addition, had nephrotic syndrome due to membranoproliferative glomerulonephritis. The chronically low serum levels of complement components C3 and C4, the glomerular morphology, and the patterns of IgG and C3 localization in glomeruli by immunofluorescence identify this case as type I membranoproliferative glomerulonephritis [6,7]. To our knowledge, this is the first report of the association of fibromuscular dysplasia with a defined form of glomerulonephritis. An immunologic mechanism has been implicated in the pathogenesis of some case of fibromuscular dysplasia. Meyers et al. [8] reported a case of fibromuscular dysplasia of the renal artery with medial dissection in a patient with fever, skin rash and abdominal pain, a symptom complex also seen in polyarteritis nodosa. Dornfield and Kaufman [9] reported a case of fibromuscular hyperplasia of the right renal artery in which sections of the vessel removed at operation contained intimal deposits of IgM, complement and fibrinogen.
530
March 1979
The American Journal of Medicine
ET AL.
It was hypothesized that some cases of fibromuscular hyperplasia may represent a response to localized inflammation induced by deposition of circulating immune complexes. In the present case, deposition of immune complexes may have occurred not only in glomeruli but also in the vasa vasorum or intima of medium-sized arteries. The inflammatory process thus initiated could ultimately have led to fibromuscular dysplasia. The coexistence of nephrotic syndrome and renal artery stenosis has been the subject of several case reports. Pasternack et al. [lo) described a 35 day old boy with the nephrotic syndrome and bilaterally narrow renal arteries which were structurally normal at autopsy. The three patients described by Berlyne and associates [Ill had atherosclerotic obstruction. The simultaneous presence of multifocal stenoses of the renal arteries and an immunologically defined glomerular disease distinguishes the present case from these previous reports. Aneurysms of the renal artery are also a feature of polyarteritis nodosa. However, polyarteritis usually involves intrarenal arteries and spares the larger extrarenal vessels. In addition, systemic symptoms such as fever, skin rash, arthralgia and abdominal pain frequently present in polyarteritis, were absent in the present patient. The glomerular lesions and the serum complement profile in polyarteritis are also different from those seen in in membranoproliferative glomerulonephritis [l&15]. The association of glomerulonephritis and fibromuscular dysplasia has been noted infrequently. Marks et al. [16] cited their experience of three cases of “fibroplasia of the renal artery” in association with “chronic nephritis.” Further details were not provided. It is unlikely that an immune mechanism is involved in all cases of fibromuscular dysplasia. Several other pathogenetic theories have been offered. In the first report of this condition as a cause of renal artery stenosis, Leadbetter and Burkland 1171 suggested that it was a congenital anomaly. The occurrence of the lesion in siblings is consistent with an inherited disorder [18,19]. It has also been reported in association with neurofibromatosis, a disease with an established genetic basis [ZO].The finding of excessive mobility of the kidneys of patients with fibromuscular dysplasia has led to the suggestion that this lesion is secondary to the repeated trauma of orthostatic stretching of the renal artery [21,22]. An unknown relation to estrogen metabolism has been invoked to explain the predominance of cases in females [l]. Although the right renal artery appeared more abnormal than the left, PRA was comparable in the renal veins from both sides. These results may have been complicated methyldopa. press renin
Volume 66
by the administration of propranolol and drugs which have been reported to supproduction [23,24]. Excessive renin pro-
KENAL ARTERY DYSPLASIA IN MEMBRANOPROLIFERATIVE GLOMERKJLONEPHRITIS--LESLIE ET AL.
duction has been associated with renal artery stenosis [x5]. Chronic glo~nerulonephritis may also result in persistent renin production despite increases in blood pressure and extracellular fluid volume [26]. The similar renin activities from both kidneys is consistent with symmetric renovascular disease or bilateral renal parenchymal disease. Progressive arterial dysplasia occurred in the present patient in association with active glomerular disease. We offer the hypothesis that an immunologic process may be the common cause of both entities, and that fibromuscular dysplasia may be present in other patients with membranoproliferative glomerulonephritis. The renal arteries of patients with membranoproliferative
glomerulonephritis and those with fibromuscular dysplasia, removed at operation or autopsy, should be examined for deposits of immunoglobulin and complement. In addition, the occurrence of proteinuria in patients with fibromuscular dysplasia may not necessarily be the consequence of hypertension alone but may, in some cases, reflect a simultaneous glomerular lesion. ACKNOWLEDGMENT
We would like to thank Dr. Robert Colvin of the Massachusetts General Hospital, Boston, Massachusetts, for performing the Raji cell assay, and Mrs. Hilda Siegel for secretarial assistance.
REFERENCES
2. 3. 4.
5. 6.
7. 8. 9.
10. 11.
12. 13.
Simon N. Franklin SS, Bleifer KH, et al.: Clinical characleristics of renovascular hypertension. JAMA 220: 1209, 1972. Harrison EC Jr, McCormack LJ: Pathologic classification of renal arterial disease in renovascular hypertension. Mayo Clinic Proc 46: 161.1971. Youngberg SP. Sheps SC, Strong CC: Fibromuscular disease of the renal arteries, Med Clin North Am 61: 623. 1977. Habcr E, Koerner T, Page LB, et al.: Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma rcnin activity in normal human subjects. J Clin Endocrinol29: 1349, 1969. Couscr WC, Lewis EJ: A method for preservation of immunofluorescence in renal tissue. Am J Chn Path01 61: 873, 1974. Jones DB: Membranoprolifcrative glomerulonephritis. One or many diseases? Arch Pathol Lab Med 101: 457, 1977. West CD: Pathogencsis and approaches to therapy of membranoprolifcrstive glomerulonephritis. Kidney Int 9: 1, 1976. Meyers DS, Grim (X, Kcitzer WF: Fibromuscular dysplasia of the renal artery with medial dissection. A case simulating polyarteritis nodosa. Am J Med 56: 412. 1974. Dornfield L. Kaufman JJ: Immunologic considerations in renovascular hypertension. Ural Clin North Am 2: 285, 1975. Pastcrnack A, Ekhmd J, Krohn K: Renal artery stenosis and the nephrotic syndrome. Acta Med Stand 181: 265, 1967. Berlyne GM, Tavill AS, Baker SBdeC: Renal artery stenosis and the nephrotic syndrome. Q J Med 33: 325,1964. ‘Leonhardt E’I’C,Jakobson H, Ringqvist CT: Angiographic and clinicophysiologic investigation of a case of polyarteritis ntrdosa. Am J Med 53: 242, 1972. Dornficld L, Lecky JW. Peter JR: Polyartcritis and intrarenal renal artery aneurysms. JAMA 215: 1950. 1971.
Davson J, Ball J, Platt R: The kidney in periarteritis nodosa. Q J Med 17: 175.1948. 15. Heptinstall RH: Pathology of the Kidney, 2nd ed, Boston, Little, Brown’& Co., 1974, p 603. 16. Marks LS, Smith RB, Kaufman JJ: The renal hypertensive suspect with coexistent lesions. Urology 4: 140.1974. 17. Leadbetter WF. Burkland CE: Hypertension in unilateral renal disease. J Urol39: 611,1938. 18. Halpern MM, Sanford HS, Viamonte M Jr: Renal-artery abnormalities in three hypertensive sisters. JAMA 194: 512, __ 14.
1965.
19.
20.
21. 22. 23.
Hansen J’,Holtcn C, Thorbog JV: Hypertension in two sisters caused by so-called fibromuscular hyperplasia of the renal arteries. Acta Met1 Stand 178: 461.1965. Schiirch W, Messerli FH, Genest J, et al.: Arterial hypertension and neurofibromatosis: renal artery stenosis and coarctation of abdominal aorta. Can Med Assoc J 113: 879, 1975. DeZecuw D, Donker AJM, Burema J: Nephroptosis and hypertension. Lancet 1: 213, 1977. Derrick JR, Hanna I? Abnormal renal mobility and hypertension Am 1Surg 106: 673, 1963. Biihlcr FR, La&h J‘H,Vaughan ED Jr, et al.: Antihypertensivc action of propranolot. Specific antirenin responses in high and normal renin forms of essential, renal, renovascuiar. and malignant hvpertcnsion. Am [ Cardiol 32: 511. _. 1973.
24. Shakil M. Fasola AF, Priviteria PJ, at al.: Effect of methyldopa on plasma renin activity in man. Circ Res 25: 543, 1969. 25. Cross F The rcnin-angiotensin system and hypertension. Ann Intern Med 75: 777, 197.1. 28. Schalekamp MA, Beevcrs DG, Brings JD, et al.: Hypertension in chronic renal failure. An abnormal relation between sodium and the renin-angiotensin system. Am J Med 55: 379, 1973.
March 1979
The American Journal of Medicine
Volume 66
531
BRUCE R. LESLIE, M.D.* ROBERT J. HAMBURGER, M.D. MAGDA M. STILMANT, M.D. WALTER FLAMENBAUM, M.D. Boston, Massachusetts
A 27 year old man with nephrotic syndrome due to memhranoproliferative glomerulonephritis had multifocal stenoses of the renal and intestinal arteries. The arterial lesions demonstrated by angiography closely resembled those of medial fibromuscular dysplasia. The dysplasia progreaPedover a five year period to involve both renal arteries from their extrarenal segments through ‘their interlobar branches. Low serum levels of complement components C3 and C4, focal reduplication of the glomerular basement membrane on light microscopy, and the patterns of glomerular localization of IgG and C3 by immunofluorescence were characteristic of type I membranoproliferative glomerulonephritis. The development of the arterial dysplasia in a patient with chronic glomerulonephritis suggests a common immunologic pathogenesis of both disorders. Fibromuscular dysplasia is recognized as a cause of renal artery stenosis [l]. It can be identified by its characteristic angiographic appearance [2]. This report describes a patient with a progressive deformity of the renal arteries who also had membranoproliferative glomerulonephritis. The roentgenographically demonstrated “string of beads” pattern in the renal arteries was also seen in the jejunal branches of the superior mesenteric artery. The appearance was typical of that of medial fibromuscular dysplasia [3]. The development of these vascular changes in a patient with chronic hypocomplementemic glomerulonephritis suggests an immunologic pathogenesis of the arterial lesion. CASE REPORT
From the Renal Section and Department of Pathology, Boston Veterans Administration Hospital and the Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts. Requests for reprints should be addressed to Dr. Robert J. Hamburger, Renal Section, Boston VA Hospital, 150 S. Huntington Avenue, Boston, Massachusetts 02130. Manuscript accepted August 9.1978. * Present address: Rogosin Kidney Center, The New York’ Hospital- Cornell Medical Center, 525 East 68th Street, New York, New York 10021.
528
March 1979
In a 19 year old white man pharyngitis. fever and brown urine developed during Army basic training in 1969. Physical examination showed a blood pressure of 130/80 mm Hg, diffuse pharyngeal erythema and no peripheral edema, Urinalysis revealed 3+ proteinuria, 100 erythrocytes/high power field (hpf), and 0 to 4 leukocytes/hpf, as well as red cell and granular casts. Culture of a throat swab was negative for beta-hemolytic streptococci. Other laboratory data were blood urea nitrogen 17 mg/dl, creatinine 0.9 mg/dl, total protein 6.2 g/dl, albumin 4.8 g/dl, cholesterol 269 mg/dl, antistreptolysin 0 titer 250 Todd units/ml and a urinary protein excretion of 2.6 g/24 hours. A percutaneous renal biopsy was performed and interpreted as showing “subacute glomerulonephritis.” Proteinuria and microscopic hematuria persisted during the next eight years, and hypertension, dependent edema and lipiduria developed. The patient was first seen at the Boston Veterans Administration Hospital at age 27, in 1973. His blood pressure was 182/150 mm Hg; there were grade 2 Keith-Wagener-Barker funduscopic changes without signs or symptoms of
The American Journal of Medicine
Volume 66
RENAL ARTERY
DYSPLASIA
IN MEMBRANOPROLIFERATIVE
hypertensive encephalopathy. There was no history of renal trauma and no family history of hypertension or renal disease. No carotid or abdominal bruits were heard and the peripheral pulses were normal. The blood urea nitrogen was 18 mg/dl, creatinine 1.3 mg/dl, albumin 3.0 g/dl, cholesterol 352 mg/dl. urine protein 5.6 g/24 hours and creatinine clearance 70 ml/min. A right open renal biopsy was performed in April 1973 (Figure 11. Because a renal sonogram suggested a mass in the right kidney, an aortogram and selective right renal arteriogram were performed. These did not demonstrate a mass but did reveal multifocal stenoses of the right renal and jejunal arteries. During the next five years, increasing doses of furosemide, propranolol, methyldopa and hydralazine were required to control the patient’s hypertension and peripheral edema. In September 1977, serum complement component assay showed a C3 concentration of 66 mg/dl (normal 88 to 252 mg/dl] and C4 of 8.0 mg/dl (normal 10 to 75 mg/dl]. In March 1978. laboratory data included blood urea nitrogen 50 mg/dl, creatinine 2.4 mg/dl. albumin 1.9 g/dl, cholesterol 438 mg/dl, creatinine clearance 41 ml/minute and urine protein 25.8 g/24 hours. The C3 was 37 mg/dl and the C4 was less than 8 mg/dl. Latex fixation was positive at a dilution of l:40. Negative studies included a test for serum antinuclear antibody, lupus erythematosus preparation, serologic test for syphilis (VDRL), direct and indirect Coombs’ tests, Raji cell assay, and tests for hepatitis B surface antigen and cryoglobulins. There was no M component on serum or urine protein electrophoresis. Repeat aortography and renal arteriography were performed in March 1978. Venography was performed and samples for renin activities were obtained. Plasma renin activity (PRA) was determined as previously described [4] using the Gamma Coat Plasma Renin Activity Kit (Clinical Assays, Cambridge, Mass.]. At the time of sampling, the patient had been on a 2 g sodium diet without potassium restriction for one week and was taking 320 mg propranolol, 3 g methyldopa, 150 mg hydralazine and 160 mg furosemide/day. Attempts to reduce the doses of propranolol and methyldopa, and to substitute a nonrenin-suppressing drug prior to the procedure, were associated with unacceptable increases in blood pressure. Renal vein samples were obtained after a single intravenous dose of 80 mg furosemide in an attempt to stimulate renin release The results are presented in Table I.
RESULTS Renal Biopsy. The tissue was fixed in 10 per cent neutral buffered formalin, cut at 4 p, and stained with hematoxylin and eosin, periodic acid-Schiff and Jones’ silver methenamine stains. Direct immunofluorescence was carried out as described elsewhere [5] using monospecific fluorescein-conjugated antiserums for immunoglobulin G (IgG), immunoglobulin M (IgM), C3 and albumin (Cappel Laboratories, Downington, Pa.). The biopsy specimen contained over 50 glomeruli per section. The glomeruli were uniformly involved and showed diffuse proliferation, margination of polymorphonuclear leukocytes and club-shaped lobules with mesangial expansion. A few glomeruli exhibited small areas of necrosis but no crescents were evident
GLOMERULONEPHRITIS-LESLIE
ET AL.
Figure 1. Photomicrograph of right renal biopsy specimen. The glomerulus shows mesangial hypercellularity and increased mesangial matrix. There is segmental thickening of the basement membranes. Periodic acid Schiff stain; magnification approximately X 400, reduced by 24 per cent. Insert: Focal reduplication of the glomerular basement membrane. Jones’ silver methenamine stain; magnification approximately X 400, reduced by 24 per cent.
(Figure I]. The basement membranes were segmentally thickened and focal reduplication was demonstrated by Jones’ stain (Figure 1, insert). These findings are considered typical of type I membranoproliferative glomerulonephritis [6]. Staining with serums against IgG and C3 showed strong reaction in a coarse and irregular granular pattern predominantly along the peripheral capillary loops. The mesangium also contained faint granular deposits of the same reagents. All other antiserums tested were negative. There was a single right renal artery Angiography. which bifurcated 3 cm from its origin into upper and lower pole branches. Both of these vessels had multiple concentric narrowings giving a “string of beads” appearance. The involvement extended into the interlobar arteries (Figure 21. On the left, there were two renal arteries which were similarly involved. These findings were more extensive than those seen five years previously. The aortogram again showed multifocal stenoses of several jejunal branches of the superior mesenteric artery. These findings were typical of multifocal fibromuscular dysplasia.
TABLE I
March 1979
Plasma Renin Activities (PRA) Site
PRA (ng/ml/hr)
Inferior vena cava Right upper pole renal vein Left upper pole renal vein Right lower pole renal vein Left lower pole renal vein
4.7 7.4 6.6 6.2 6.7
The American Journal of Medicine
Volume 66
529
RENAL ARTERY
DYSPLASIA
IN MEMBRANOPROLIFERATIVE
GLOMERLJLONEPHRITIS-LESLIE
Figure 2. Right selective renal arteriogram, 1978. Multifocal stenoses extend from the main upper and lower pole arteries through the interlobar arteries.
Renal venography showed right upper and lower pole veins inserting separately into the inferior vena cava. On the left, a single main renal vein divided into upper and lower pole veins. There was no evidence of renal vein thrombosis. COMMENTS The lesions demonstrated at arteriography in our patient closely resemble those seen in medial fibromuscular dysplasia. This patient, in addition, had nephrotic syndrome due to membranoproliferative glomerulonephritis. The chronically low serum levels of complement components C3 and C4, the glomerular morphology, and the patterns of IgG and C3 localization in glomeruli by immunofluorescence identify this case as type I membranoproliferative glomerulonephritis [6,7]. To our knowledge, this is the first report of the association of fibromuscular dysplasia with a defined form of glomerulonephritis. An immunologic mechanism has been implicated in the pathogenesis of some case of fibromuscular dysplasia. Meyers et al. [8] reported a case of fibromuscular dysplasia of the renal artery with medial dissection in a patient with fever, skin rash and abdominal pain, a symptom complex also seen in polyarteritis nodosa. Dornfield and Kaufman [9] reported a case of fibromuscular hyperplasia of the right renal artery in which sections of the vessel removed at operation contained intimal deposits of IgM, complement and fibrinogen.
530
March 1979
The American Journal of Medicine
ET AL.
It was hypothesized that some cases of fibromuscular hyperplasia may represent a response to localized inflammation induced by deposition of circulating immune complexes. In the present case, deposition of immune complexes may have occurred not only in glomeruli but also in the vasa vasorum or intima of medium-sized arteries. The inflammatory process thus initiated could ultimately have led to fibromuscular dysplasia. The coexistence of nephrotic syndrome and renal artery stenosis has been the subject of several case reports. Pasternack et al. [lo) described a 35 day old boy with the nephrotic syndrome and bilaterally narrow renal arteries which were structurally normal at autopsy. The three patients described by Berlyne and associates [Ill had atherosclerotic obstruction. The simultaneous presence of multifocal stenoses of the renal arteries and an immunologically defined glomerular disease distinguishes the present case from these previous reports. Aneurysms of the renal artery are also a feature of polyarteritis nodosa. However, polyarteritis usually involves intrarenal arteries and spares the larger extrarenal vessels. In addition, systemic symptoms such as fever, skin rash, arthralgia and abdominal pain frequently present in polyarteritis, were absent in the present patient. The glomerular lesions and the serum complement profile in polyarteritis are also different from those seen in in membranoproliferative glomerulonephritis [l&15]. The association of glomerulonephritis and fibromuscular dysplasia has been noted infrequently. Marks et al. [16] cited their experience of three cases of “fibroplasia of the renal artery” in association with “chronic nephritis.” Further details were not provided. It is unlikely that an immune mechanism is involved in all cases of fibromuscular dysplasia. Several other pathogenetic theories have been offered. In the first report of this condition as a cause of renal artery stenosis, Leadbetter and Burkland 1171 suggested that it was a congenital anomaly. The occurrence of the lesion in siblings is consistent with an inherited disorder [18,19]. It has also been reported in association with neurofibromatosis, a disease with an established genetic basis [ZO].The finding of excessive mobility of the kidneys of patients with fibromuscular dysplasia has led to the suggestion that this lesion is secondary to the repeated trauma of orthostatic stretching of the renal artery [21,22]. An unknown relation to estrogen metabolism has been invoked to explain the predominance of cases in females [l]. Although the right renal artery appeared more abnormal than the left, PRA was comparable in the renal veins from both sides. These results may have been complicated methyldopa. press renin
Volume 66
by the administration of propranolol and drugs which have been reported to supproduction [23,24]. Excessive renin pro-
KENAL ARTERY DYSPLASIA IN MEMBRANOPROLIFERATIVE GLOMERKJLONEPHRITIS--LESLIE ET AL.
duction has been associated with renal artery stenosis [x5]. Chronic glo~nerulonephritis may also result in persistent renin production despite increases in blood pressure and extracellular fluid volume [26]. The similar renin activities from both kidneys is consistent with symmetric renovascular disease or bilateral renal parenchymal disease. Progressive arterial dysplasia occurred in the present patient in association with active glomerular disease. We offer the hypothesis that an immunologic process may be the common cause of both entities, and that fibromuscular dysplasia may be present in other patients with membranoproliferative glomerulonephritis. The renal arteries of patients with membranoproliferative
glomerulonephritis and those with fibromuscular dysplasia, removed at operation or autopsy, should be examined for deposits of immunoglobulin and complement. In addition, the occurrence of proteinuria in patients with fibromuscular dysplasia may not necessarily be the consequence of hypertension alone but may, in some cases, reflect a simultaneous glomerular lesion. ACKNOWLEDGMENT
We would like to thank Dr. Robert Colvin of the Massachusetts General Hospital, Boston, Massachusetts, for performing the Raji cell assay, and Mrs. Hilda Siegel for secretarial assistance.
REFERENCES
2. 3. 4.
5. 6.
7. 8. 9.
10. 11.
12. 13.
Simon N. Franklin SS, Bleifer KH, et al.: Clinical characleristics of renovascular hypertension. JAMA 220: 1209, 1972. Harrison EC Jr, McCormack LJ: Pathologic classification of renal arterial disease in renovascular hypertension. Mayo Clinic Proc 46: 161.1971. Youngberg SP. Sheps SC, Strong CC: Fibromuscular disease of the renal arteries, Med Clin North Am 61: 623. 1977. Habcr E, Koerner T, Page LB, et al.: Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma rcnin activity in normal human subjects. J Clin Endocrinol29: 1349, 1969. Couscr WC, Lewis EJ: A method for preservation of immunofluorescence in renal tissue. Am J Chn Path01 61: 873, 1974. Jones DB: Membranoprolifcrative glomerulonephritis. One or many diseases? Arch Pathol Lab Med 101: 457, 1977. West CD: Pathogencsis and approaches to therapy of membranoprolifcrstive glomerulonephritis. Kidney Int 9: 1, 1976. Meyers DS, Grim (X, Kcitzer WF: Fibromuscular dysplasia of the renal artery with medial dissection. A case simulating polyarteritis nodosa. Am J Med 56: 412. 1974. Dornfield L. Kaufman JJ: Immunologic considerations in renovascular hypertension. Ural Clin North Am 2: 285, 1975. Pastcrnack A, Ekhmd J, Krohn K: Renal artery stenosis and the nephrotic syndrome. Acta Med Stand 181: 265, 1967. Berlyne GM, Tavill AS, Baker SBdeC: Renal artery stenosis and the nephrotic syndrome. Q J Med 33: 325,1964. ‘Leonhardt E’I’C,Jakobson H, Ringqvist CT: Angiographic and clinicophysiologic investigation of a case of polyarteritis ntrdosa. Am J Med 53: 242, 1972. Dornficld L, Lecky JW. Peter JR: Polyartcritis and intrarenal renal artery aneurysms. JAMA 215: 1950. 1971.
Davson J, Ball J, Platt R: The kidney in periarteritis nodosa. Q J Med 17: 175.1948. 15. Heptinstall RH: Pathology of the Kidney, 2nd ed, Boston, Little, Brown’& Co., 1974, p 603. 16. Marks LS, Smith RB, Kaufman JJ: The renal hypertensive suspect with coexistent lesions. Urology 4: 140.1974. 17. Leadbetter WF. Burkland CE: Hypertension in unilateral renal disease. J Urol39: 611,1938. 18. Halpern MM, Sanford HS, Viamonte M Jr: Renal-artery abnormalities in three hypertensive sisters. JAMA 194: 512, __ 14.
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March 1979
The American Journal of Medicine
Volume 66
531