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Antiglomerular Basement Membrane Disease: The Long-Term Pulmonary Outcome
Antiglomerular Basement Membrane Disease: The Long-Term Pulmonary Outcome Peter J. Conlon, Jr, MB, MRCPI, MRCP(UK), J. Joseph Walshe, PhD, FACP, Conal Daly, MB, MRCPI, Michael Carmody, MD, FRCPI, Brian Keogh, MD, FRCPI, John Donohoe, MD, FRCPI, and Shane O'Neill, MD, FRCPI • We have evaluated long-term pulmonary function in 14 patients who were treated for anti-glomerular basement membrane disease at our institution during the last 17 years. Eight of these patients had evidence of pulmonary involvement, as manifested by hemoptysis, pulmonary infiltrates on chest x-ray film, or anemia. These patients were compared with a control group of 15 patients who had renal disease and who were matched for degree and duration of renal disease, age, smoking history, and method of renal replacement. The following variables were measured in each patient: forced vital capacity, forced expiratory volume in 1 minute, vital capacity, total lung capacity, residual volume, functional residual capacity, single-breath carbon monoxide transfer factor, and single-breath carbon monoxide transfer factor corrected for alveolar volume (KCO). These patients also participated in a graded exercise test and measurements of oxygen uptake, carbon dioxide production, minute ventilation, and oxygen saturation were taken. Patients with anti-glomerular basement membrane disease and a prior history of pulmonary hemorrhage had a significantly reduced KCO (46% ± 10% v 68.7% ± 14.7%) compared with the control group. There was no difference in any of the other measured parameters. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: Anti-glomerular basement membrane disease; Goodpasture's syndrome; lung function.
~ CUTE glomerulonephritis in association
f t with anti-glomerular basement membrane
(GBM) antibodies is referred to as anti-GBM disease. Pulmonary involvement can occur in up to 65% of these patients! (ie, those with Goodpasture's syndrome). Evidence of Goodpasture's syndrome may be signalled by the development of hemoptysis, dyspnoea, pulmonary infiltrates, and/or anemia. Pulmonary hemorrhage is usually confirmed by an increased lung diffusing capacity.2 The acute effects of this syndrome on both pulmonary and renal function have been widely reported. 3-8 In recent years, the early detection and treatment of anti-GBM disease with immunosuppressive agents and plasma exchange have greatly improved the renal prognosis. To date, reports on the pulmonary manifestations of this condition have been confined to the acute presentation or autopsy findings. 9 ,10 What has not been described is long-term pulmonary outcome. Consequently, we undertook a study to examine
From the Departments of Nephrology and Respiratory Medicine, Beaumont Hospital, Dublin, Ireland; and the Department of Nephrology, Meath Hospital, Dublin, Ireland. Received September 13, 1993; accepted in revised form February 9, 1994. Address reprint requests to Peter 1. Conlon, Jr, Division of Nephrology, Duke University Medical Center, Durham, NC 27710. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2306-0004$3.00;0 794
the long-term pulmonary effects of anti-GBM disease. PATIENTS AND METHODS Over a 17-year period we managed 26 patients with antiGBM disease. Of the 17 patients who continue to survive, 14 agreed to participate in the present study. The protocol involved patients attending the pulmonary function laboratory after a 4-hour fast, and they had the following variables measured using the Sensor Medics 2400 System: forced vital capacity, forced expiratory volume in I minute, vital capacity, total lung capacity, residual volume, functional residual capacity (using helium), single-breath carbon monoxide transfer factor corrected for hemoglobin (lung diffusing capacity), and single-breath carbon monoxide transfer factor corrected for alveolar ventilation (KCO). Recorded values were compared with reference standards. 11 Patients then participated in a graded exercise test according to the Bruce protocol using a Gould 9000 respiratory exercise system measuring oxygen uptake, carbon dioxide production, expired minute ventilation, and oxygen saturation using a pulse oximeter. A control group of 15 patients was constructed from patients attending our renal clinics. The subjects in the control group had renal disease of a nonsystemic nature and had no overt pulmonary disease. The control group was controlled for age, sex, smoking habit, degree and duration of renal impainnent, method of renal replacement, and duration of dialysis. Clinical data were obtained retrospectively from the patients' case notes. Clinical and demographic data relating to the study and control populations are summarized in Table I. To avoid distribution assumptions, Wilcoxon's rank sum test was used for statistical analysis.
RESULTS
Eight of the 14 patients with anti-GBM disease had evidence of pulmonary hemorrhage at initial
American Journal of Kidney Diseases, Vol 23, No 6 (June), 1994: pp 794-796
LONG-TERM LUNG FUNCTION IN ANTI-GBM DISEASE Table 1. Clinical and Demographic Data of Study and Control Patients Anti-GBM Patients (n = 14)
Group
795 100~%-------------------------------------
-
Control Patients (n = 15) 60
Method of renal replacement Renal impairment (serum creatinine> 1.7 mgJdL) Renal transplant Hemodialysis Mean age (yr) Duration of renal replacement Range Cigarette smokers Male Female
;~
p·o.ooeo 3 5 6 41.8 ± 13.3 7.8 ± 5.6 1-17 yr 7 7 7
3 5 7 36 ± 8.6 6.3 ± 4.9 1-10 yr 8 7 8
presentation or subsequently. No patient required mechanical ventilation for respiratory support. Within 7 days of commencing plasmapheresis, clinical and radiologic evidence of pulmonary hemorrhage had resolved in all patients. There was no difference in the smoking history between the group of patients with and without pulmonary hemorrhage. Patients with anti-GBM disease who had pulmonary hemorrhage had a significantly reduced KCO (46% ± 10% v 68.7% ± 14.7%) when compared with a control group of patients (P = 0.006) (Fig 1). There was no difference in any of the other measured parameters between the study and control patients (Table 2). While there was a reduced KCO in the group of patients with pulmonary hemorrhage, this was not reflected in a reduced oxygen saturation on exercise.
0
No Pulm Haem
oontrol
Pulm Ha.m
Fig 1. KCO values for control patients, patients with pulmonary hemorrhage, and patients without pulmonary hemorrhage. The thick horizontal lines represent mean values.
tween cigarette smoking and subsequent pulmonary involvement. Chronic uraemia also has been shown to have a number of effects on the lungs, most marked of which is a reduction in the diffusing capacity.13.14 However, this cannot be the reason for the reduced KCO, as we had also matched for the degree and duration of uraemia in our control group. Lung pistology and immunofluorescence studies in patients with acute pulmonary hemorrhage related to anti-GBM disease lO ,15 have demonstrated immunoglobulin G deposition on Table 2. Results of Lung Function Studies and Exercise Tests Anti·GBM
Group
Hemorrhage
No Hemorrhage
Control
DISCUSSION
Our results have shown that in patients with anti-GBM disease, among a battery of pulmonary physiologic tests, KCO was the only variable to be significantly reduced; this finding was only present in patients who had a history of pulmonary hemorrhage. While cigarette smoking has been well described to reduce KCO, this cannot be the explanation for our findings, since the patients and controls were carefully matched for, among other variables, their smoking history. It also has been suggested that pulmonary hemorrhage in antiGBM disease is a consequence of cigarette smoking. 12 Again, we did not find any association be-
FVC FEV, VC TLC RV DLCO KCO
73 74 78.3 83.8 91.8 61 46
± ± ± ± ± ± ±
19.3 19.8 11.8 17.8 35 16.4 10
V02 max Vemax Lowest saturation Percentage of maximum heart rate achieved
61.8 ± 22 60.9 ± 16 89 ± 2.9
64.6 ± 13 71 ± 12 87 ± 4.3
85±13.2 81.8 ± 13.2 83.8 ± 10.8 81.8 ± 13.7 79 ± 14.7 70.9 ± 17.5 68.7 ± 14.7 P = 0.006 65 ± 12 57 ± 11 88 ± 3.1
78 ± 16
80 ± 14
75 ± 21
75 ± 14 78 ± 13.7 81.4 ± 11.2 78.4 ± 13.2 79±15.6 70 ± 11 60.8 ± 12.8
Abbreviations: FVC, forced vital capacity; FEV" forced expiratory volume in 1 minute; VC, vital capacity; TLC, total lung capacity; RV, residual volume; DLCO, lung diffusing capacity; V02 , oxygen uptake; Ve, expired minute ventilation.
796
CONLON ET AL
the alveolar basement membrane with varying degrees of airspace fibrosis. This could provide a reason for the reduced KCO observed in our study. Support for the concept that prolonged, severe, or recurrent pulmonary hemorrhage in anti-GBM disease causes interstitial fibrosis comes from consideration of idiopathic pulmonary hemosiderosis. Multiple prolonged episodes ofpulmonary hemorrhage in idiopathic pulmonary hemosiderosis are associated with the development of interstitial fibrosis, restriction of lung volumes, reduced pulmonary diffusing capacity, and arterial hypoxemia. 16 While persistent or recurrent pulmonary hemorrhage in anti-GBM disease may be associated with more severe degrees of lung damage, due to the small number of patients in this study we were unable to correlate the severity of pulmonary hemorrhage with subsequent lung function studies. In this study, we have demonstrated a reduced KCO, reflecting reduced gas exchange, in longterm survivors of anti-GBM disease with a prior history of pulmonary hemorrhage. This finding suggests that these patients suffer from physiologically significant interstitial pulmonary fibrosis, and this needs to be taken into account in the long-term medical management of Goodpasture's syndrome.
REFERENCES I. Teague CA, Doak PB, Simpson IJ, Rainer SP, Herdson PB: Goodpasture's syndrome: An analysis of 29 cases. Kidney Int 113:492-504, 1979 2. Ewan PW, Jones HA, Rhodes CG, Hughes JMB: Detection of intrapulmonary hemorrhage with carbon monoxide uptake. Application in Goodpasture's syndrome. N Engl J Med 295:1391-1396.1976
3. Morgan PG, Turner-Warwick M: Pulmonary hemosiderosis and pulmonary hemorrhage. Br J Dis Chest 75:225242,1981 4. Sissons JGP, Evans DJ, Peters DK, Eisinger AJ, BoultonJones, Simpson IJ, Macanovic M: Glomerulonephritis associated with antibody to glomerular basement membrane. BMJ 4:11-14,1974 5. Briggs WA, JohnsonJP, Teichman S, YeagerHC, Wilson CB: Antiglomeru1ar basement membrane antibody-mediated glomerulonephritis and Goodpasture's syndrome. Medicine 58:348-361, 1979 6. Martinez J, Kohler PF: Variant "Goodpasture's syndrome"? Ann Intern Med 75:67-76,1971 7. Schachter EN, Finkelstein F, Bastl C, Walker Smith GJ: Diagnostic problems in pulmonary-renal syndromes. Am Rev RespirDis 115:155-159,1977 8. Holdsworth S, Boyce N, Thompson NM, Atkins RC: The clinical spectrum of acute glomerulonephritis and lung hemorrhage (Goodpasture's syndrome). Q J Med 55:75-86, 1985 9. Heptinstall RH, Salmon MV: Pulmonary hemorrhage with extensive glomerular disease of the kidney. J CIin Pathol 12:272-279, 1959 10. Koffler D, Sandson J, Carr R, Kunkel HG: Immunologic studies concerning the pulmonary lesions in Goodpasture's syndrome. Am J Pathol 54:293-299, 1969 II. Quanjer PH (ed): Standardized lung function testing. Report of the Working Party for Standardization of Lung Function Tests. European Community for Coal and Steel. Luxembourg. Bull Eur Physiol Pathol Respir 19:1-95, 1983 (suppI5) 12. Donaghy M, Rees AJ: Cigarette smoking and lung hemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane. Lancet 2: 1390-1393, 1983 13. Foreman JW, Ayers LN, Miller WC: Pulmonary diffusing capacity in chronic renal failure. Br J Dis Chest 75:8187, 1981 14. Lee HY, Stretton TB, Barnes AM: The lungs in renal failure. Thorax 30:46-53, 1975 15. Travis WD, Colby TV, Lombard C, Carpenter HA: A clinicopathological study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Patho1 14:1112-1125, 1990 16. Fulehan FJD, Abboud RT, Hubaytar R: Idiopathic pulmonary hemosiderosis. Am Rev Respir Dis 98:93-97, 1968
~ CUTE glomerulonephritis in association
f t with anti-glomerular basement membrane
(GBM) antibodies is referred to as anti-GBM disease. Pulmonary involvement can occur in up to 65% of these patients! (ie, those with Goodpasture's syndrome). Evidence of Goodpasture's syndrome may be signalled by the development of hemoptysis, dyspnoea, pulmonary infiltrates, and/or anemia. Pulmonary hemorrhage is usually confirmed by an increased lung diffusing capacity.2 The acute effects of this syndrome on both pulmonary and renal function have been widely reported. 3-8 In recent years, the early detection and treatment of anti-GBM disease with immunosuppressive agents and plasma exchange have greatly improved the renal prognosis. To date, reports on the pulmonary manifestations of this condition have been confined to the acute presentation or autopsy findings. 9 ,10 What has not been described is long-term pulmonary outcome. Consequently, we undertook a study to examine
From the Departments of Nephrology and Respiratory Medicine, Beaumont Hospital, Dublin, Ireland; and the Department of Nephrology, Meath Hospital, Dublin, Ireland. Received September 13, 1993; accepted in revised form February 9, 1994. Address reprint requests to Peter 1. Conlon, Jr, Division of Nephrology, Duke University Medical Center, Durham, NC 27710. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2306-0004$3.00;0 794
the long-term pulmonary effects of anti-GBM disease. PATIENTS AND METHODS Over a 17-year period we managed 26 patients with antiGBM disease. Of the 17 patients who continue to survive, 14 agreed to participate in the present study. The protocol involved patients attending the pulmonary function laboratory after a 4-hour fast, and they had the following variables measured using the Sensor Medics 2400 System: forced vital capacity, forced expiratory volume in I minute, vital capacity, total lung capacity, residual volume, functional residual capacity (using helium), single-breath carbon monoxide transfer factor corrected for hemoglobin (lung diffusing capacity), and single-breath carbon monoxide transfer factor corrected for alveolar ventilation (KCO). Recorded values were compared with reference standards. 11 Patients then participated in a graded exercise test according to the Bruce protocol using a Gould 9000 respiratory exercise system measuring oxygen uptake, carbon dioxide production, expired minute ventilation, and oxygen saturation using a pulse oximeter. A control group of 15 patients was constructed from patients attending our renal clinics. The subjects in the control group had renal disease of a nonsystemic nature and had no overt pulmonary disease. The control group was controlled for age, sex, smoking habit, degree and duration of renal impainnent, method of renal replacement, and duration of dialysis. Clinical data were obtained retrospectively from the patients' case notes. Clinical and demographic data relating to the study and control populations are summarized in Table I. To avoid distribution assumptions, Wilcoxon's rank sum test was used for statistical analysis.
RESULTS
Eight of the 14 patients with anti-GBM disease had evidence of pulmonary hemorrhage at initial
American Journal of Kidney Diseases, Vol 23, No 6 (June), 1994: pp 794-796
LONG-TERM LUNG FUNCTION IN ANTI-GBM DISEASE Table 1. Clinical and Demographic Data of Study and Control Patients Anti-GBM Patients (n = 14)
Group
795 100~%-------------------------------------
-
Control Patients (n = 15) 60
Method of renal replacement Renal impairment (serum creatinine> 1.7 mgJdL) Renal transplant Hemodialysis Mean age (yr) Duration of renal replacement Range Cigarette smokers Male Female
;~
p·o.ooeo 3 5 6 41.8 ± 13.3 7.8 ± 5.6 1-17 yr 7 7 7
3 5 7 36 ± 8.6 6.3 ± 4.9 1-10 yr 8 7 8
presentation or subsequently. No patient required mechanical ventilation for respiratory support. Within 7 days of commencing plasmapheresis, clinical and radiologic evidence of pulmonary hemorrhage had resolved in all patients. There was no difference in the smoking history between the group of patients with and without pulmonary hemorrhage. Patients with anti-GBM disease who had pulmonary hemorrhage had a significantly reduced KCO (46% ± 10% v 68.7% ± 14.7%) when compared with a control group of patients (P = 0.006) (Fig 1). There was no difference in any of the other measured parameters between the study and control patients (Table 2). While there was a reduced KCO in the group of patients with pulmonary hemorrhage, this was not reflected in a reduced oxygen saturation on exercise.
0
No Pulm Haem
oontrol
Pulm Ha.m
Fig 1. KCO values for control patients, patients with pulmonary hemorrhage, and patients without pulmonary hemorrhage. The thick horizontal lines represent mean values.
tween cigarette smoking and subsequent pulmonary involvement. Chronic uraemia also has been shown to have a number of effects on the lungs, most marked of which is a reduction in the diffusing capacity.13.14 However, this cannot be the reason for the reduced KCO, as we had also matched for the degree and duration of uraemia in our control group. Lung pistology and immunofluorescence studies in patients with acute pulmonary hemorrhage related to anti-GBM disease lO ,15 have demonstrated immunoglobulin G deposition on Table 2. Results of Lung Function Studies and Exercise Tests Anti·GBM
Group
Hemorrhage
No Hemorrhage
Control
DISCUSSION
Our results have shown that in patients with anti-GBM disease, among a battery of pulmonary physiologic tests, KCO was the only variable to be significantly reduced; this finding was only present in patients who had a history of pulmonary hemorrhage. While cigarette smoking has been well described to reduce KCO, this cannot be the explanation for our findings, since the patients and controls were carefully matched for, among other variables, their smoking history. It also has been suggested that pulmonary hemorrhage in antiGBM disease is a consequence of cigarette smoking. 12 Again, we did not find any association be-
FVC FEV, VC TLC RV DLCO KCO
73 74 78.3 83.8 91.8 61 46
± ± ± ± ± ± ±
19.3 19.8 11.8 17.8 35 16.4 10
V02 max Vemax Lowest saturation Percentage of maximum heart rate achieved
61.8 ± 22 60.9 ± 16 89 ± 2.9
64.6 ± 13 71 ± 12 87 ± 4.3
85±13.2 81.8 ± 13.2 83.8 ± 10.8 81.8 ± 13.7 79 ± 14.7 70.9 ± 17.5 68.7 ± 14.7 P = 0.006 65 ± 12 57 ± 11 88 ± 3.1
78 ± 16
80 ± 14
75 ± 21
75 ± 14 78 ± 13.7 81.4 ± 11.2 78.4 ± 13.2 79±15.6 70 ± 11 60.8 ± 12.8
Abbreviations: FVC, forced vital capacity; FEV" forced expiratory volume in 1 minute; VC, vital capacity; TLC, total lung capacity; RV, residual volume; DLCO, lung diffusing capacity; V02 , oxygen uptake; Ve, expired minute ventilation.
796
CONLON ET AL
the alveolar basement membrane with varying degrees of airspace fibrosis. This could provide a reason for the reduced KCO observed in our study. Support for the concept that prolonged, severe, or recurrent pulmonary hemorrhage in anti-GBM disease causes interstitial fibrosis comes from consideration of idiopathic pulmonary hemosiderosis. Multiple prolonged episodes ofpulmonary hemorrhage in idiopathic pulmonary hemosiderosis are associated with the development of interstitial fibrosis, restriction of lung volumes, reduced pulmonary diffusing capacity, and arterial hypoxemia. 16 While persistent or recurrent pulmonary hemorrhage in anti-GBM disease may be associated with more severe degrees of lung damage, due to the small number of patients in this study we were unable to correlate the severity of pulmonary hemorrhage with subsequent lung function studies. In this study, we have demonstrated a reduced KCO, reflecting reduced gas exchange, in longterm survivors of anti-GBM disease with a prior history of pulmonary hemorrhage. This finding suggests that these patients suffer from physiologically significant interstitial pulmonary fibrosis, and this needs to be taken into account in the long-term medical management of Goodpasture's syndrome.
REFERENCES I. Teague CA, Doak PB, Simpson IJ, Rainer SP, Herdson PB: Goodpasture's syndrome: An analysis of 29 cases. Kidney Int 113:492-504, 1979 2. Ewan PW, Jones HA, Rhodes CG, Hughes JMB: Detection of intrapulmonary hemorrhage with carbon monoxide uptake. Application in Goodpasture's syndrome. N Engl J Med 295:1391-1396.1976
3. Morgan PG, Turner-Warwick M: Pulmonary hemosiderosis and pulmonary hemorrhage. Br J Dis Chest 75:225242,1981 4. Sissons JGP, Evans DJ, Peters DK, Eisinger AJ, BoultonJones, Simpson IJ, Macanovic M: Glomerulonephritis associated with antibody to glomerular basement membrane. BMJ 4:11-14,1974 5. Briggs WA, JohnsonJP, Teichman S, YeagerHC, Wilson CB: Antiglomeru1ar basement membrane antibody-mediated glomerulonephritis and Goodpasture's syndrome. Medicine 58:348-361, 1979 6. Martinez J, Kohler PF: Variant "Goodpasture's syndrome"? Ann Intern Med 75:67-76,1971 7. Schachter EN, Finkelstein F, Bastl C, Walker Smith GJ: Diagnostic problems in pulmonary-renal syndromes. Am Rev RespirDis 115:155-159,1977 8. Holdsworth S, Boyce N, Thompson NM, Atkins RC: The clinical spectrum of acute glomerulonephritis and lung hemorrhage (Goodpasture's syndrome). Q J Med 55:75-86, 1985 9. Heptinstall RH, Salmon MV: Pulmonary hemorrhage with extensive glomerular disease of the kidney. J CIin Pathol 12:272-279, 1959 10. Koffler D, Sandson J, Carr R, Kunkel HG: Immunologic studies concerning the pulmonary lesions in Goodpasture's syndrome. Am J Pathol 54:293-299, 1969 II. Quanjer PH (ed): Standardized lung function testing. Report of the Working Party for Standardization of Lung Function Tests. European Community for Coal and Steel. Luxembourg. Bull Eur Physiol Pathol Respir 19:1-95, 1983 (suppI5) 12. Donaghy M, Rees AJ: Cigarette smoking and lung hemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane. Lancet 2: 1390-1393, 1983 13. Foreman JW, Ayers LN, Miller WC: Pulmonary diffusing capacity in chronic renal failure. Br J Dis Chest 75:8187, 1981 14. Lee HY, Stretton TB, Barnes AM: The lungs in renal failure. Thorax 30:46-53, 1975 15. Travis WD, Colby TV, Lombard C, Carpenter HA: A clinicopathological study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Patho1 14:1112-1125, 1990 16. Fulehan FJD, Abboud RT, Hubaytar R: Idiopathic pulmonary hemosiderosis. Am Rev Respir Dis 98:93-97, 1968