Pulmonary capillaritis in IgA nephropathy.

Abstract: Pulmonary capillaritis presenting as diffuse alveolar hemorrhage is a rare manifestation in patients with IgA nephropathy. A 20-year-old male with hemodialysis dependent, end-stage renal failure presented with recurrent hemoptysis and respiratory failure. A histologic diagnosis of pulmonary capillaritis was established by transbronchial lung biopsy. He was successfully treated with intravenous methylprednisone and plasma exchange followed by oral prednisone and cyclophosphamide. This report highlights the independent renal and pulmonary manifestations of IgA nephropathy and the management of the resultant diffuse alveolar hemorrhage with aggressive immunosuppression.

Key Words: pulmonary capillaritis, diffuse alveolar hemorrhage, IgA nephropathy

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Pulmonary capillaritis is a rare systemic manifestation of IgA nephropathy that can result in life-threatening diffuse alveolar hemorrhage. (1) Renal and pulmonary manifestations usually occur concurrently, reflecting the same underlying immune process. (1-6) Therefore, the development of pulmonary capillaritis in a patient who had already progressed to end-stage renal failure is an exceptional situation. We describe such a case and highlight the use of cyclophosphamide as adjunctive therapy to steroids and plasma exchange.

Case Report

A 20-year-old Chinese male presented with a two-week history of small volume hemoptysis and progressive dyspnea. He had first presented with renal impairment and proteinuria 3 years earlier. Renal biopsy at that time had shown diffuse mesangial proliferative glomerulonephritis with positive immunofluorescence stainin-gof IgA. IgA nephropathy with sclerosis and crescents was diagnosed. As the patient defaulted follow-up on numerous occasions, he received no corticosteroids for treatment of IgA nephropathy, but intermittently got angiotensin receptor blockers, dipyridamole and Coumadin. His disease progressed to end-stage renal failure, and he had been initiated on hemodialysis 3 times per week 4 months earlier. He had no pulmonary symptoms or reported abnormalities on chest x-ray before this presentation.

Our patient was a nonsmoker with no known exposure to illicit drugs. His medications included iron, calcium and vitamin supplements, as well as biweekly subcutaneous erythropoietin 2000 IU. He denied any use of traditional or nonprescription medication. Review of systems revealed no gastrointestinal, joint or skin symptoms to suggest Henoch-Schonlein purpura.

On admission, our patient was febrile and in respiratory distress. Vital signs showed a heart rate of 105 beats per minute, blood pressure of 162/128 mm Hg and a respiratory rate of 28 breaths per minutes. Pulse oximetry was 96% on a Fi[O.sub.2] of 40%. He was clinically euvolemic and no vasculitic skin lesions were seen. Auscultatory examination of the chest revealed bilateral coarse crepitations, but no cardiac murmurs. Chest x-ray showed bilateral, lower zone alveolar infiltrates (Fig. 1).

Laboratory testing showed urea of 24.6 mmol/L, hemoglobin of 6.7 g/dL (baseline 8.7 g/dL) and leukocyte-count of 7.1 X [10.sup.9]/L with 94% polymorphs. Platelet counts and coagulation profile were normal.

He was aggressively hemodialyzed and given empiric treatment for severe community-acquired pneumonia. Although ultrafiltration to below dry weight was achieved during the hemodialysis sessions, bronchoal-veolar lavage yielded progressively bloodier returns. Abundant hemosiderin-laden macrophages were seen on cytology consistent with a diagnosis of diffuse alveolar hemorrhage. Lung biopsy was deferred because of progressive severity of respiratory distress.

An extensive microbiologic screen was unyielding. Serum antinuclear, antiglomerular membrane, antineu-trophil cytoplasmic (ANCA) and antiphospholipid antibodies were not identified, but total serum complement level was reduced at 41 CAE units (normal range 60-156). An-timyeloperoxidase and antiproteinase-3 antibodies that were subsequently performed were likewise negative.

The absence of any clinical response to antibiotics or dialysis, combined with a lack of circulating autoantibodies suggested a diagnosis of pulmonary vasculitis that was secondary to IgA nephropathy. Intravenous methylprednisone at 1 mg/kg/d and plasma exchange were instituted with rapid resolution of respiratory symptoms and hypoxemia. The patient was discharged without supplemental oxygen on an oral prednisone dose of 1 mg/kg/d.

The patient presented with recurrent hemoptysis and persistent chest x-ray infiltrates over the next two months. A transbronchial lung biopsy was performed and a histologic diagnosis of pulmonary capillaritis was made (Fig. 2). The alveolar hemorrhage was eventually controlled with cyclophosphamide at a dose of 2 mg/kg/d and prednisone 1 mg/kg/d. The prednisone was gradually tapered over twelve months to 5 mg/d. Cyclophosphamide was switched to azathioprine when he was six months into remission because of leucopenia.

There has been no further relapse over two years and repeated ANCA serology was negative. Chest x-rays normalized after 4 months from initial presentation when pulmonary function testing showed normal spirometry ([FEV.sub.1] 3.83 L; 107.2% predicted and FVC 4.33 L; 97.9% predicted). There was a mild reduction in corrected diffusion capacity 1.21 mmol/min/kPa/L; 66% predicted. Chest x-rays and pulmonary function test results continued to remain stable throughout remission.

Discussion

Pulmonary capillaritis in IgA nephropathy can manifest independently of renal disease and, as this case illustrates, can occur after the renal pathology appears to have burnt out. Although isolated sporadic pulmonary capillaritis is a possible differential diagnosis that cannot be excluded in our patient, there are a number of biologic explanations that can attribute the alveolar hemorrhage to IgA nephropathy. Alveoli and glomeruli share a vascular histology of tortuous capillaries and similar antigens. (7) Suggested mechanisms of capillaritis include anti-basement membrane IgA deposition, (2) immune complex pneumonitis (3) and a variation of Henoch-Schonlein purpura, (8) ie, leukocytoclastic vasculitis. However, circulating antibodies have not been identified and IgA immunofluorescence staining of lung biopsy remains an inconsistent finding. (1) This implicates a pauci-immune pathology attacking alveolar capillaries and glomeruli. The resultant classic histopathological findings of pulmonary capillaritis are interstitial erythrocytes, capillary wall fibrinoid necrosis, inter-alveolar septal capillary occlusion, interstitial and alveolar space neutrophils, as well as interalveolar septal fibrin clots. (9)

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The reported mortality of diffuse alveolar hemorrhage associated with IgA nephropathy is 50%. (1-6) The use of steroids, (1-6) azathioprine (2) and plasma exchange (2,6) have had limited success. However, treatment with cyclophosphamide using a regimen similar to an ANCA-associated vasculitis was successful in our patient.

Conclusion

Pulmonary and renal manifestations of IgA nephropathy can occur independent of each other. Cyclophosphamide may be considered if diffuse alveolar hemorrhage is refractory to steroids.

References

1. Lai FM, Li EK, Suen MW, et al. Pulmonary hemorrhage: a fatal manifestation of IgA nephropathy. Arch Pathol Lab Med 1994;118:542-546.

2. Border WA, Baehler RW, Bhathena D, et al. IgA antibasement membrane nephritis with pulmonary hemorrhage. Ann Intern Med 1979;91:21-25.

3. Harland RW, Becker CG, Brandes JC, et al. Immunoglobulin A (IgA) immune complex pneumonitis in a patient with IgA nephropathy. Ann Intern Med 1992;116:220-222.

4. Yum MN, Lampton LM, Bloom PM, et al. Asymptomatic IgA nephropathy associated with pulmonary hemosiderosis. Am J Med 1978;64:1056-1060.

5. Travis WD, Colby TV, Lombard C, et al. A clinicopathological study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol 1990;14:1112-1125.

6. Afessa B, Cowart RG, Koenig SM. Alveolar hemorrhage in IgA nephropathy treated with plasmapharesis. South Med J 1997;90:237-239.

7. McCaughey WT, Thomas BJ. Pulmonary hemorrhage and glomerulonephritis: the relation of pulmonary hemorrhage to certain types of glomerular lesions. Am J Clin Pathol 1962;38:577-589.

8. Kathuria S, Cejfec G. Fatal pulmonary Henoch-Schonlein syndrome. Chest 1982;82:654-656.

9. Mark EJ, Ramirez JF. Pulmonary capillaritis and hemorrhage in patients with systemic vasculitis. Arch Pathol Lab Med 1985;109:413-418.

Devanand Anantham, MBBS, MRCP, Kenneth P.W. Chan, MBBS, FCCP, Khoon Leong Chuah, MBBS, FRCPA, Anantharaman Vathsala, MD, FRCP, and Philip Eng, MBBS, FCCP

From the Department of Respiratory and Critical Care Medicine, the Department of Pathology, and the Department of Renal Medicine, Singapore General Hospital, Singapore.

Reprint requests to Dr. Devanand Anantham, Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Outram Road, Singapore 169608. E-mail: [e-mail]

Accepted January 4, 2007.

RELATED ARTICLE: Key Points

* Pulmonary capillaritis is a rare manifestation of IgA nephropathy.

* Pulmonary capillaritis can occur independent of kidney disease in IgA nephropathy, long after the renal manifestations have apparently burnt out.

* Management requires prompt diagnosis and aggressive immunosuppression.