CASE REPORTS
Asymptomatic IgA Nephropathy Associated with Pulmonary Hemosiderosis
A glomerular lesion identical to that of IgA nephropathy was demonstrated unexpectedly in a 17 year old boy who presented with clinical manlfestations of pulmonary hemoslderosis and with no evidence of renal disease. This subclinical glomerular lesion would have remained undetected in this patient unless kidney tissue was obtained and examined by immunofluorescence or electron microscopy. It is unknown if the glomerular lesion in this case is causally related to pulmonary hemosiderosis.
MOO NAHM YUM, M.D. LAWRENCE M. LAMPTON, M.D. PHILLIP M. BLOOM, M.D.’ JOSHUA L. EDWARDS,
M.D.
Indianapolis, Indiana
Idiopathic pulmonary hemosiderosis has been regarded as a clinical entity since its introduction to the medical literature by Ceelan in 1931. It has, however, become apparent that a number of renal diseases and systemic disorders may be associated with pulmonary lesions and that their manifestations may be indistinguishable from those of idiopathic pulmonary hemosiderosis. It is now essential to have extensive immunopathologic studies and a long follow-up to exclude the possibility of Goodpasture’s syndrome, systemic lupus erythematosus and other immune disorders before establishing a diagnosis of “idiopathic” pulmonary hemosiderosis [ 11. Patients with Goodpasture’s syndrome [2,3] and systemic lupus erythematosus [4-61 may present with purely pulmonary manifestations that mimic closely those of idiopathic pulmonary hemosiderosis. We have followed a young man for the last two and a half years who might have been considered as having idiopathic pulmonary hemosiderosis on clinical grounds, but who was found to have an unsuspected glomerular lesion that is identical to that of immunoglobulin A (IGA) nephropathy
by immunofluorescence
and electron
micros-
copy.
CASE REPORT A 17 year old boy was referred to Indiana University Hospital for evaluation of recurrent respiratory insufficiency in February 1975. In April 1974, he had
From the Departments of Pathology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Requests for reprints should be addressed to Dr. M. N. Yum, Department of Pathology, Indiana University Medical Center, 1100 West Michigan Street, Indianapolis. Indiana 46202. Manuscript accepted November 28, 1977. * Present address: Metroqolitan Medical Center, 701 Park Avenue, Minneapolis, Minnesota 55415.
1056
June 1976
The American
a flu-like myalgia.
illness with symptoms of fever, nonproductive cough, diarrhea and He denied having skin rash or dark urine at the time. He was ap-
parently
given an antibiotic
and remained
he was asked to obtain a pre-employment normal, and he was referred to a .ohvsician for “pneumonia”.
Failing
to respond
well until November
1974, when
chest roentgenogram. It was abwho treated him with antibiotics
to this, he was hospitalized
for pro-
gressive respiratory insufficiency. He reportedly had an increased white blood cell count of 20,400/mm3 and an oxygen tension (PO,) of 15 mm Hg, an oxygen saturation of 85 per cent, a carbon dioxide Hg and a pH of 7.39 with a fractional concentration
tension (PCOp) of 32 mm of inspired oxygen (Fi02)
of 0.2 1. Mechanically assisted ventilation with high FiO*‘s and therapy with antibiotics, digitalis, diuretics and corticosteroids was instituted. His condition
Journal of Medicine
Volume 64
IGA NEPHROPATHV AND PULMONARY
HEMOSIDEROSIS-VUM
ET AL.
slowly improved but, as his medications were being tapered, he again had an episode of dyspnea for which he required ventilatory assistance. At the time of transfer in February 1975, he was grossly cyanotic with FiOa of 0.40. There was no pertinent previous medical history, family history or history of allergy. On initial examination he was noted to be obese (82 kg) with decreased breath sounds and bibasilar rales. Otherwise, his physical examination, electrocardiogram and echocardiogram were within normal limits. His chest roentgenograms revealed bilateral patchy infiltrates primarily in both lower lung fields. His hemoglobin level was 12.6 g/100 ml, hematocrit value 38 per cent, mean corpuscular hemoglobin concentration (MCHC) 32.5 per cent, mean corpuscular hemoglobin (MCH) 21.8 pg, mean corpuscular volume 67 p3, reticulocytes 2.4 per cent, white blood cell count 9,100/mm3 with a normal differential, and platelets were normal in number. There was moderate anisocytosis and slight poikilocytosis on peripheral blood smear. His blood urea nitrogen was 13/mg/lOO ml, creatinine clearance 128 ml/min; electrolytes were normal. Repeated urinalysis showed no red blood cells or protein. Twenty-four hour urine protein was 1.O mg. The erythrocyte sedimentation rate, serum haptoglobin, total iron-binding capacity, third and fourth components of (C3 and C4) were all within normal limits. Repeated lupus erythematosus preparations, antinuclear antibody and rheumatoid arthritis latex test results were negative throughout the course until January 1977, when the patient was last seen at Indiana University Hospital. Numerous sputum cultures grew no pathogenic organisms. Two weeks after admission he underwent a right thoracotomy, and a wedge biopsy of lower lobe of the right lung was obtained for pathologic examination. Subsequent treatment with 60 mg of prednisone over the following month resulted in partial clearing of the infiltrates in both lower lung fields and improvement of arterial blood gases (PO*, 62 mm Hg; oxygen saturation, 93 per cent; PC02, 33 mm Hg; pH 7.45). Following his discharge, the patient remained dependent on steroids for recurring hypoxemia. He returned to Indiana University Hospital in October 1975, for reevaluation of increasing hypoxemia. Arterial blood gases on admission were as follows: PO2 48 mm Hg, oxygen saturation 85 per cent, PC02 32 mm Hg and pH 7.44 with FiO*, 0.21. Sputum had numerous hemosiderin-laden macrophages. His hemoglobin level was 12.9 g/100 ml, blood urea nitrogen 16 mg/lOO ml and creatinine clearance 94 ml/min. Serum total protein was 6.5 g/100 ml and immune diffusion revealed IgG 1,480 mg, IgA 500 mg and IgM 110 mg/lOO ml, respectively. The serum was negative for circulating antiglomerular basement membrane antibodies (via Dr. Curtis B. Wilson of the Scripps Institute in La Jolla, California). To complete the prognostic evaluation, a percutaneous renal biopsy was performed without complication during this hospitalization. Steroid therapy was again instituted and slowly tapered by the time of discharge.
and pH 7.46. His chest film showed partial clearing of the infiltrates, particularly in the lower lobe of the left lung, but also persisting interstitial fibrosis.
The patient was most recently seen in January 1977, when his hemoglobin level was 15.6 g/ 100 ml and his blood urea nitrogen, creatinine, electrolytes and urinalysis were within normal limits. His arterial gases with an Fi02 of 0.21 were PO* 66 mm Hg, oxygen saturation 9 1 per cent, PC02 30 mm Hg
? lung biopsy spt men shows hemosiderin-laden macrophages and red blood ceils in the alveoli, enlarged alveolar cells and moderate interstitial fibrosis. Hematoxylin and eosin stain, magnification x 100.
MATERIALS
AND METHODS
Lung and kidney tissues were fixed in buffered 4 per cent formaldehyde, and paraffin sections cut at 3 to 4 1 were stained with hematoxylin and eosin, periodic acid-Schiff, silver methenamine, trichrome and elastic stains. For immunofluorescence, frozen sections were stained with fluorescein-conjugated monospecific antiserums to human IgG, IgA, IgM, IgE, C3, C4 and fibrinogen. For electron microscopy, tissues were fixed in 3 per cent glutaraldehyde, postfixed in osmium tetroxide, dehydrated in graded alcohols and embedded in Epon@ 812. Thin sections were stained with uranyl acetate and lead citrate, and examined with a Philipps 300 EM electron microscope. RESULTS
Lung Biopsy. In addition to scattered red blood cells, numerous hemosiderin-laden macrophages were found in the alveoli that were lined with hypettrophic epithelial cells (Figure 1). There was moderate fibrosis without inflammatory changes in the interstitial tissue. No vasculitis was observed. lmmunofluorescence was completely negative. Electron microscopy confirmed light microscopic findings and showed no evidence of microorganisms, basement membrane changes such as “clean breaks” [7] or “multilayering” [B]. Kidney biopsy. Eleven glomeruli were examined on 50 serial sections. All were considered normal on light
June 1978
The American Journal of Medicine
Volume 84
1057
IGA NEPHROPATHY AND PULMONARY HEMOSIDEROSIS-YUM
ET AL.
Figure 2. A representative glomerulus appears normal except for a slight mesangial expansion. Periodic acid-Schiff stain, magnification X 250.
Figure 3, A glomerulus stained with fluorescein-conjugated goat antiserum for human IgA. There are comma-shaped deposits predominantly localized in the mesangium. Magnification X 320.
microscopy, apart from very slight mesangial prominence in some glomeruli (Figure 2). A small focus of tubular atrophy was noted, suggesting a possible focal glomerular disease. However, even on multiple serial sectioning, a glomerular lesion which would account for the tubular atrophy could not be demonstrated. No evidence of vasculitis was present. lmmunofluorescent staining showed mesangial deposits of IgG, IgA and C3 (Figure 3) but no IgM, IgE, C4 or fibrin. Electron-dense deposits were readily found in the paramesangial regions (Figure 4). The glomerular capillary basement membrane was normal, and focal effacement of epithelial foot processes was noted over the dense deposits.
COMMENTS Although no pathognomonic criteria exist to allow certainty of diagnosis, the association of respiratory insufficiency with characteristic histologic changes in the lung biopsy specimen and hypochromic, microcytic anemia, albeit mild, along with absence of immunologic disorders such as systemic lupus erythematosus or rheumatoid arthritis and of urine abnormalities, would have strongly supported the diagnosis of idiopathic pulmonary hemosiderosis in this case. The negative results of immunofluorescence microscopy and the absence of any specific changes by electron microscopy in the lung biopsy specimen would be in agree-
Figure 4. An electron micrograph of a portion of a glomerulus showing electron-dense deposits (arrows) in the paramesangial and mesangial areas. Focal effacement of foot processes is present over the dense deposits. Magnification X 8,250, reduced by 32 per cent.
1058
June 1978
The American
Journal of Medicine
Volume 64
IGA NEPHROPATHYAND PULMONARY HEMOSIDEROSIS-YUM ET AL.
ment with those of others [9,10] and further support the diagnosis. The kidney biopsy specimen on immunofluorescence and electron microscopy, however, demonstrated glomerular lesions identical to those described in IgA nephropathy [9]. Similar immunofluorescence, light and electron microscopic patterns are found only in batients with anaphylactoid purpura and, rarely, in those with mild lupus nephritis [ 11,121, although IgA deposition in glomeruli may be found in various other glomerulopathies [ 131. There is no clinical or immunologic evidence suggestive of anaphylactoid purpura or systemic lupus erythematosus in the present case during the two and a half year follow-up. Since the first description by Berger and Hinglais in 1968 [ 141, IgA nephropathy has been widely accepted as a clinicopathologic entity whose essential feature is accumulation of IgA and C3 (often with IgG) in the glomerular mesangium demonstrable by immunofluorescent staining. The glomerular lesions by light microscopy are variable. The glomeruli may be normal, contain a focal-segmental proliferative lesion or show generalizeddiffuse mesangial proliferation. The patients are usually older children or young adults. They usually present with gross or microscopic hematuria, often shortly after an upper respiratory tract infection of undetermined etiology. No collagen vascular diseases or any other systemic diseases are known to be associated with this newly recognized disease entity [ 151. The absence of urine abnormalities in our case is difficult to explain. To our knowledge the deposition of IgA and C3 along with IGG in the glomerular mesangium has never been reported in normal subjects [ 11,161. However, most experimentally induced mesangial immune deposits are not associated with significant glomerular disease [ 17,181. The cause of this is unknown. It is possible that immune deposits in the glomerular mesangium are too few and that the glomerular injury is too mild to cause hematuria or proteinuria, or that the mesangial cells metabolize the immune complexes before a serious injury takes place. A brief review of literature indicates that a number of glomerular diseases may be associated with pulmonary hemosiderosis. Heptinstall and Salmon [ 191 reviewed the literature up to 1958 in search for renal lesions in patients with pulmonary hemosiderosis. Of the 69 recorded cases a renal lesion was documented
in five: the lesion was described as a focal glomerulonephritis or glomerulitis in four and as the microscopic form of polyar-teritis nodosa in the fifth. Heptinstall and Joekes [20] describe a case of focal glomerulonephritis and hemoptysis in which a repeat biopsy two years later showed the same type of healed lesion in glomeruli as is seen in Schoenlein-Henoch syndrome. The association of pulmonary hemorrhage and glomerulonephritis in Goodpasture’s syndrome is well known. In most of the patients with this syndrome, the glomeruli show extensive crescent formation, although the early lesion may take the form of a focal glomerulonephritis. Wilson and Dixon [2] observed linear deposits of immunoglobulins along the alveolar, as well as the glomerular, capillary basement membranes in a patient who was clinically diagnosed as having idiopathic pulmonary hemosiderosis. Despite the immunofluorescence demonstration of antibasement membrane antibodies in the glomeruli, this patient remained asymptomatic, without clinical evidence of renal disease. Another similar case has been reported more recently by Mathew et al [3]. An unusual manner of presentation of systemic lupus erythematosus is pulmonary hemorrhage, as well illustrated by two reported cases [461. The demonstration of asymptomatic glomerular lesions in the cases of Wilson and Dixon [ 21, Mathew et al [3] and our own raises the question of how often unsuspected glomerular lesions may accompany the clinical syndrome of pulmonary hemosiderosis. We have herein described an additional unsuspected glomerular lesion in a patient with pulmonary hemosiderosis. It remains, however, to be seen if these lesions are associated, more than by chance and most of all, pathogenetically. It is noteworthy that the serum IgA level in this patient was high. High serum IgA levels were found in some cases of idiopathic pulmonary hemosiderosis [21] and of IgA nephropathy [22,23]. One is attracted to speculate in our case that an initial injury of the respiratory tract, that caused pulmonary hemorrhage, has stimulated an immune response resulting in the formation of circulating immune complexes rich in IgA and that these complexes were taken up and, in some unknown manner, metabolized efficiently by the glomerular mesangial cells.
REFERENCES 1. 2. 3.
Thomas HM, Irwin RS: Classification of diffuse intrapulmonary hemorrhage. Chest 68: 483, 1975. Wilson CB, Dixon FJ: Diagnosis of immunopathologic renal disease. Kidney Int 5: 389, 1974. Mathew TH, Hobbs JB, Kalowski S, et al.: Goodpasture’s syndrome: normal renal diagnostic findings. Ann Intern Med 82: 215, 1975.
4.
5.
June 1978
Elliott ML, Kuhn C: Idiopathic pulmonary hemosiderosis. UItrastructural abnormalities in the capillary walls. Am Rev Respir Dis 102: 895, 1970. Kuhn C: Systemic lupus erythematosus in a patient with ultrastructural lesions of the pulmonary capillaries previously reported in the Review as due to idiopathic pulmonary hemosiderosis. Am Rev Respir Dis 106: 931, 1972.
The American Journal of Medicine
Volume 84
1059
IGA NEPHROPATHYAND PULMONARY HEMOSIDEROSIS-YUM ET AL.
9.
10.
11. 12. 13.
14.
1060
Byrd RB, Trunk G: Systemic lupus erythematosus presenting as pulmonary hemosiderosis. Chest 64: 128, 1973. Hyatt RW, Adelstein ER, Halazun JF, et al.: Ultrastructure of the lung in idiopathic pulmonary hemosiderosis. Am J Med 52: 822, 1972. Gonzalez-Crussi F, Hull MT, Grosfeld JL: Idiopathic pulmonary hemosiderosis. Evidence of capillary basement membrane abnormality. Am Rev Respir Dis 114: 669, 1976. Irwin RS, Cottrell TS, Hsu KC, Griswold WR, Thomas HM: Idiopathic pulmonary hemosiderosis. An electron microscopic and immunofluorescent study. Chest 65: 41. 1974. Donlan CJ, Strodes CH, Duffy FD: Idiopathic pulmonary hemosiderosis. Electron microscopic, immunofluorescent, and iron kinetic studies. Chest 68: 577, 1975. Berger J: IgA glomerular deposits in renal disease. Transplant Proc 1: 939, 1969. McCluskey RT: The value of immunofluorescence in the study of human renal disease. J Exp Med 134: 2428, 1971. Hyman LR, Wagnild JP, Beirne GJ, et al.: Immunoglobulin-A distribution in glomerular disease. Analysis of immunofluorescence localization and pathogenic significance. Kidney Int 3: 397, 1973. Berger J, Hinglais N: Les depots intercapillaires d’lgA-IgG. J
June 1978
The American Journal of Medicine
Volume 84
15.
16. 17.
18.
19.
20. 21.
22. 23.
Urol Nephrol (Paris) 74: 694, 1968. Jenis EH, Lowenthal DT: IgA nephropathy, Chap 10. Kidney Biopsy Interpretation, Philadelphia, F.A. Davis, 1977, p 115. Bloom PM, Filo RS, Smith EJ: lmmunofluorescent deposits in normal kidneys (abstract). Kidney Int 10: 539, 1976. Michael AF, Fish AJ, Good RA: Glomerular localization and transport of aggregated proteins in mice. Lab Invest 17: 14, 1967. Kelley VE, Cotran RS: Mesangial and subepithelial localization of ferritin immune complexes in mouse glomerulus. Lab Invest 27: 144, 1972. Heptinstall RH, Salmon MV: Pulmonary hemorrhage with extensive glomerular disease of the kidney. J Clin Pathol 12: 272, 1959. Heptinstall RH, Joekes AM: Focal glomerulonephritis. A study based on renal biopsies. 0 J Med 28: 329, 1959. Valassi-Adams H, Rouska A, Karpouzas J, et al.: Raised IgA in idiopathic pulmonary hemosiderosis. Arch Dis Child 50: 320, 1975. Zimmerman SW, Burkholder PM: lmmunoglobulin A nephropathy. Arch Intern Med 135: 1217, 1975. Whitworth JA, Liebowitz S, Kennedy MC, et al.: IgA and glomerular disease. Clin Nephrol 5: 33, 1976.
Asymptomatic IgA Nephropathy Associated with Pulmonary Hemosiderosis
A glomerular lesion identical to that of IgA nephropathy was demonstrated unexpectedly in a 17 year old boy who presented with clinical manlfestations of pulmonary hemoslderosis and with no evidence of renal disease. This subclinical glomerular lesion would have remained undetected in this patient unless kidney tissue was obtained and examined by immunofluorescence or electron microscopy. It is unknown if the glomerular lesion in this case is causally related to pulmonary hemosiderosis.
MOO NAHM YUM, M.D. LAWRENCE M. LAMPTON, M.D. PHILLIP M. BLOOM, M.D.’ JOSHUA L. EDWARDS,
M.D.
Indianapolis, Indiana
Idiopathic pulmonary hemosiderosis has been regarded as a clinical entity since its introduction to the medical literature by Ceelan in 1931. It has, however, become apparent that a number of renal diseases and systemic disorders may be associated with pulmonary lesions and that their manifestations may be indistinguishable from those of idiopathic pulmonary hemosiderosis. It is now essential to have extensive immunopathologic studies and a long follow-up to exclude the possibility of Goodpasture’s syndrome, systemic lupus erythematosus and other immune disorders before establishing a diagnosis of “idiopathic” pulmonary hemosiderosis [ 11. Patients with Goodpasture’s syndrome [2,3] and systemic lupus erythematosus [4-61 may present with purely pulmonary manifestations that mimic closely those of idiopathic pulmonary hemosiderosis. We have followed a young man for the last two and a half years who might have been considered as having idiopathic pulmonary hemosiderosis on clinical grounds, but who was found to have an unsuspected glomerular lesion that is identical to that of immunoglobulin A (IGA) nephropathy
by immunofluorescence
and electron
micros-
copy.
CASE REPORT A 17 year old boy was referred to Indiana University Hospital for evaluation of recurrent respiratory insufficiency in February 1975. In April 1974, he had
From the Departments of Pathology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Requests for reprints should be addressed to Dr. M. N. Yum, Department of Pathology, Indiana University Medical Center, 1100 West Michigan Street, Indianapolis. Indiana 46202. Manuscript accepted November 28, 1977. * Present address: Metroqolitan Medical Center, 701 Park Avenue, Minneapolis, Minnesota 55415.
1056
June 1976
The American
a flu-like myalgia.
illness with symptoms of fever, nonproductive cough, diarrhea and He denied having skin rash or dark urine at the time. He was ap-
parently
given an antibiotic
and remained
he was asked to obtain a pre-employment normal, and he was referred to a .ohvsician for “pneumonia”.
Failing
to respond
well until November
1974, when
chest roentgenogram. It was abwho treated him with antibiotics
to this, he was hospitalized
for pro-
gressive respiratory insufficiency. He reportedly had an increased white blood cell count of 20,400/mm3 and an oxygen tension (PO,) of 15 mm Hg, an oxygen saturation of 85 per cent, a carbon dioxide Hg and a pH of 7.39 with a fractional concentration
tension (PCOp) of 32 mm of inspired oxygen (Fi02)
of 0.2 1. Mechanically assisted ventilation with high FiO*‘s and therapy with antibiotics, digitalis, diuretics and corticosteroids was instituted. His condition
Journal of Medicine
Volume 64
IGA NEPHROPATHV AND PULMONARY
HEMOSIDEROSIS-VUM
ET AL.
slowly improved but, as his medications were being tapered, he again had an episode of dyspnea for which he required ventilatory assistance. At the time of transfer in February 1975, he was grossly cyanotic with FiOa of 0.40. There was no pertinent previous medical history, family history or history of allergy. On initial examination he was noted to be obese (82 kg) with decreased breath sounds and bibasilar rales. Otherwise, his physical examination, electrocardiogram and echocardiogram were within normal limits. His chest roentgenograms revealed bilateral patchy infiltrates primarily in both lower lung fields. His hemoglobin level was 12.6 g/100 ml, hematocrit value 38 per cent, mean corpuscular hemoglobin concentration (MCHC) 32.5 per cent, mean corpuscular hemoglobin (MCH) 21.8 pg, mean corpuscular volume 67 p3, reticulocytes 2.4 per cent, white blood cell count 9,100/mm3 with a normal differential, and platelets were normal in number. There was moderate anisocytosis and slight poikilocytosis on peripheral blood smear. His blood urea nitrogen was 13/mg/lOO ml, creatinine clearance 128 ml/min; electrolytes were normal. Repeated urinalysis showed no red blood cells or protein. Twenty-four hour urine protein was 1.O mg. The erythrocyte sedimentation rate, serum haptoglobin, total iron-binding capacity, third and fourth components of (C3 and C4) were all within normal limits. Repeated lupus erythematosus preparations, antinuclear antibody and rheumatoid arthritis latex test results were negative throughout the course until January 1977, when the patient was last seen at Indiana University Hospital. Numerous sputum cultures grew no pathogenic organisms. Two weeks after admission he underwent a right thoracotomy, and a wedge biopsy of lower lobe of the right lung was obtained for pathologic examination. Subsequent treatment with 60 mg of prednisone over the following month resulted in partial clearing of the infiltrates in both lower lung fields and improvement of arterial blood gases (PO*, 62 mm Hg; oxygen saturation, 93 per cent; PC02, 33 mm Hg; pH 7.45). Following his discharge, the patient remained dependent on steroids for recurring hypoxemia. He returned to Indiana University Hospital in October 1975, for reevaluation of increasing hypoxemia. Arterial blood gases on admission were as follows: PO2 48 mm Hg, oxygen saturation 85 per cent, PC02 32 mm Hg and pH 7.44 with FiO*, 0.21. Sputum had numerous hemosiderin-laden macrophages. His hemoglobin level was 12.9 g/100 ml, blood urea nitrogen 16 mg/lOO ml and creatinine clearance 94 ml/min. Serum total protein was 6.5 g/100 ml and immune diffusion revealed IgG 1,480 mg, IgA 500 mg and IgM 110 mg/lOO ml, respectively. The serum was negative for circulating antiglomerular basement membrane antibodies (via Dr. Curtis B. Wilson of the Scripps Institute in La Jolla, California). To complete the prognostic evaluation, a percutaneous renal biopsy was performed without complication during this hospitalization. Steroid therapy was again instituted and slowly tapered by the time of discharge.
and pH 7.46. His chest film showed partial clearing of the infiltrates, particularly in the lower lobe of the left lung, but also persisting interstitial fibrosis.
The patient was most recently seen in January 1977, when his hemoglobin level was 15.6 g/ 100 ml and his blood urea nitrogen, creatinine, electrolytes and urinalysis were within normal limits. His arterial gases with an Fi02 of 0.21 were PO* 66 mm Hg, oxygen saturation 9 1 per cent, PC02 30 mm Hg
? lung biopsy spt men shows hemosiderin-laden macrophages and red blood ceils in the alveoli, enlarged alveolar cells and moderate interstitial fibrosis. Hematoxylin and eosin stain, magnification x 100.
MATERIALS
AND METHODS
Lung and kidney tissues were fixed in buffered 4 per cent formaldehyde, and paraffin sections cut at 3 to 4 1 were stained with hematoxylin and eosin, periodic acid-Schiff, silver methenamine, trichrome and elastic stains. For immunofluorescence, frozen sections were stained with fluorescein-conjugated monospecific antiserums to human IgG, IgA, IgM, IgE, C3, C4 and fibrinogen. For electron microscopy, tissues were fixed in 3 per cent glutaraldehyde, postfixed in osmium tetroxide, dehydrated in graded alcohols and embedded in Epon@ 812. Thin sections were stained with uranyl acetate and lead citrate, and examined with a Philipps 300 EM electron microscope. RESULTS
Lung Biopsy. In addition to scattered red blood cells, numerous hemosiderin-laden macrophages were found in the alveoli that were lined with hypettrophic epithelial cells (Figure 1). There was moderate fibrosis without inflammatory changes in the interstitial tissue. No vasculitis was observed. lmmunofluorescence was completely negative. Electron microscopy confirmed light microscopic findings and showed no evidence of microorganisms, basement membrane changes such as “clean breaks” [7] or “multilayering” [B]. Kidney biopsy. Eleven glomeruli were examined on 50 serial sections. All were considered normal on light
June 1978
The American Journal of Medicine
Volume 84
1057
IGA NEPHROPATHY AND PULMONARY HEMOSIDEROSIS-YUM
ET AL.
Figure 2. A representative glomerulus appears normal except for a slight mesangial expansion. Periodic acid-Schiff stain, magnification X 250.
Figure 3, A glomerulus stained with fluorescein-conjugated goat antiserum for human IgA. There are comma-shaped deposits predominantly localized in the mesangium. Magnification X 320.
microscopy, apart from very slight mesangial prominence in some glomeruli (Figure 2). A small focus of tubular atrophy was noted, suggesting a possible focal glomerular disease. However, even on multiple serial sectioning, a glomerular lesion which would account for the tubular atrophy could not be demonstrated. No evidence of vasculitis was present. lmmunofluorescent staining showed mesangial deposits of IgG, IgA and C3 (Figure 3) but no IgM, IgE, C4 or fibrin. Electron-dense deposits were readily found in the paramesangial regions (Figure 4). The glomerular capillary basement membrane was normal, and focal effacement of epithelial foot processes was noted over the dense deposits.
COMMENTS Although no pathognomonic criteria exist to allow certainty of diagnosis, the association of respiratory insufficiency with characteristic histologic changes in the lung biopsy specimen and hypochromic, microcytic anemia, albeit mild, along with absence of immunologic disorders such as systemic lupus erythematosus or rheumatoid arthritis and of urine abnormalities, would have strongly supported the diagnosis of idiopathic pulmonary hemosiderosis in this case. The negative results of immunofluorescence microscopy and the absence of any specific changes by electron microscopy in the lung biopsy specimen would be in agree-
Figure 4. An electron micrograph of a portion of a glomerulus showing electron-dense deposits (arrows) in the paramesangial and mesangial areas. Focal effacement of foot processes is present over the dense deposits. Magnification X 8,250, reduced by 32 per cent.
1058
June 1978
The American
Journal of Medicine
Volume 64
IGA NEPHROPATHYAND PULMONARY HEMOSIDEROSIS-YUM ET AL.
ment with those of others [9,10] and further support the diagnosis. The kidney biopsy specimen on immunofluorescence and electron microscopy, however, demonstrated glomerular lesions identical to those described in IgA nephropathy [9]. Similar immunofluorescence, light and electron microscopic patterns are found only in batients with anaphylactoid purpura and, rarely, in those with mild lupus nephritis [ 11,121, although IgA deposition in glomeruli may be found in various other glomerulopathies [ 131. There is no clinical or immunologic evidence suggestive of anaphylactoid purpura or systemic lupus erythematosus in the present case during the two and a half year follow-up. Since the first description by Berger and Hinglais in 1968 [ 141, IgA nephropathy has been widely accepted as a clinicopathologic entity whose essential feature is accumulation of IgA and C3 (often with IgG) in the glomerular mesangium demonstrable by immunofluorescent staining. The glomerular lesions by light microscopy are variable. The glomeruli may be normal, contain a focal-segmental proliferative lesion or show generalizeddiffuse mesangial proliferation. The patients are usually older children or young adults. They usually present with gross or microscopic hematuria, often shortly after an upper respiratory tract infection of undetermined etiology. No collagen vascular diseases or any other systemic diseases are known to be associated with this newly recognized disease entity [ 151. The absence of urine abnormalities in our case is difficult to explain. To our knowledge the deposition of IgA and C3 along with IGG in the glomerular mesangium has never been reported in normal subjects [ 11,161. However, most experimentally induced mesangial immune deposits are not associated with significant glomerular disease [ 17,181. The cause of this is unknown. It is possible that immune deposits in the glomerular mesangium are too few and that the glomerular injury is too mild to cause hematuria or proteinuria, or that the mesangial cells metabolize the immune complexes before a serious injury takes place. A brief review of literature indicates that a number of glomerular diseases may be associated with pulmonary hemosiderosis. Heptinstall and Salmon [ 191 reviewed the literature up to 1958 in search for renal lesions in patients with pulmonary hemosiderosis. Of the 69 recorded cases a renal lesion was documented
in five: the lesion was described as a focal glomerulonephritis or glomerulitis in four and as the microscopic form of polyar-teritis nodosa in the fifth. Heptinstall and Joekes [20] describe a case of focal glomerulonephritis and hemoptysis in which a repeat biopsy two years later showed the same type of healed lesion in glomeruli as is seen in Schoenlein-Henoch syndrome. The association of pulmonary hemorrhage and glomerulonephritis in Goodpasture’s syndrome is well known. In most of the patients with this syndrome, the glomeruli show extensive crescent formation, although the early lesion may take the form of a focal glomerulonephritis. Wilson and Dixon [2] observed linear deposits of immunoglobulins along the alveolar, as well as the glomerular, capillary basement membranes in a patient who was clinically diagnosed as having idiopathic pulmonary hemosiderosis. Despite the immunofluorescence demonstration of antibasement membrane antibodies in the glomeruli, this patient remained asymptomatic, without clinical evidence of renal disease. Another similar case has been reported more recently by Mathew et al [3]. An unusual manner of presentation of systemic lupus erythematosus is pulmonary hemorrhage, as well illustrated by two reported cases [461. The demonstration of asymptomatic glomerular lesions in the cases of Wilson and Dixon [ 21, Mathew et al [3] and our own raises the question of how often unsuspected glomerular lesions may accompany the clinical syndrome of pulmonary hemosiderosis. We have herein described an additional unsuspected glomerular lesion in a patient with pulmonary hemosiderosis. It remains, however, to be seen if these lesions are associated, more than by chance and most of all, pathogenetically. It is noteworthy that the serum IgA level in this patient was high. High serum IgA levels were found in some cases of idiopathic pulmonary hemosiderosis [21] and of IgA nephropathy [22,23]. One is attracted to speculate in our case that an initial injury of the respiratory tract, that caused pulmonary hemorrhage, has stimulated an immune response resulting in the formation of circulating immune complexes rich in IgA and that these complexes were taken up and, in some unknown manner, metabolized efficiently by the glomerular mesangial cells.
REFERENCES 1. 2. 3.
Thomas HM, Irwin RS: Classification of diffuse intrapulmonary hemorrhage. Chest 68: 483, 1975. Wilson CB, Dixon FJ: Diagnosis of immunopathologic renal disease. Kidney Int 5: 389, 1974. Mathew TH, Hobbs JB, Kalowski S, et al.: Goodpasture’s syndrome: normal renal diagnostic findings. Ann Intern Med 82: 215, 1975.
4.
5.
June 1978
Elliott ML, Kuhn C: Idiopathic pulmonary hemosiderosis. UItrastructural abnormalities in the capillary walls. Am Rev Respir Dis 102: 895, 1970. Kuhn C: Systemic lupus erythematosus in a patient with ultrastructural lesions of the pulmonary capillaries previously reported in the Review as due to idiopathic pulmonary hemosiderosis. Am Rev Respir Dis 106: 931, 1972.
The American Journal of Medicine
Volume 84
1059
IGA NEPHROPATHYAND PULMONARY HEMOSIDEROSIS-YUM ET AL.
9.
10.
11. 12. 13.
14.
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