Pulmonary renal syndrome: A 4-year, single-center experience

Pulmonary Renal Syndrome: A 4-Year, Single-Center Experience Hugh Gallagher, MBBS, Jonathan T.C. Kwan, MD, and David R.W. Jayne, MD ● Pulmonary renal syndrome (PRS), defined as a combination of diffuse pulmonary hemorrhage and glomerulonephritis (GN), represents a severe syndrome for which minimal outcome data are available in the literature. We present a retrospective study of 14 consecutive patients from 1996 to 2000. Mean patient age was 65 ⴞ 2.1 (SEM) years, and 7 patients were women. At presentation, PO2 on air was 6.0 ⴞ 0.5 kPa, and creatinine level was 554 ⴞ 70 ␮mol/L. Thirteen patients had systemic vasculitis, and 1 patient had systemic lupus erythematosus (SLE). Five patients were cytoplasmic antineutrophil cytoplasmic autoantibody (C-ANCA) positive, and 7 patients were perinuclear ANCA (P-ANCA) positive; 2 of the latter patients also were positive for anti– glomerular basement membrane antibodies. Renal biopsy was performed in 10 patients. Histological examination showed membranous GN in the patient with SLE and segmental necrotizing crescentic GN in the other 9 patients examined. Twelve of 14 patients were initially dialysis dependent, and 8 of 14 patients required ventilatory support. All patients were treated with corticosteroids, 8 of 14 patients were administered intravenous methylprednisolone, 13 of 14 patients were administered daily cyclophosphamide, and 12 of 14 patients underwent plasma exchange. Patients were followed up for 22 ⴞ 9 months. Early reduction in cyclophosphamide dosage was required in 9 patients for neutropenia. Seven patients were alive at the end of follow-up, but 5 patients (36%) died in the first month. Of the survivors, 85% and 67% were alive after 1 and 2 years of completed follow-up: 83% and 75% of these survivors were dialysis independent, respectively. Five relapses were seen in 4 patients. One patient died of progressive pulmonary fibrosis. Sepsis was a major factor in 6 of 7 deaths. This patient group was older than those previously reported. Findings confirm previous suggestions that PRS requiring intensive care treatment has high mortality, and early survivors have good 1- and 2-year outcomes. Cyclophosphamide-associated neutropenia and infection were frequent contributors to death, and less toxic alternatives may improve outcome in PRS. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Pulmonary renal syndrome (PRS); antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis; anti– glomerular basement membrane (anti-GBM) disease; therapy; outcome; intensive care; respiratory failure.

T

HE COMBINATION OF pulmonary hemorrhage and glomerulonephritis (GN) was first described by Goodpasture in 1919.1 The term Goodpasture’s syndrome was adopted in 19582 to define a group of patients with similar characteristics, and the pathogenetic role of anti– glomerular basement membrane (anti-GBM) antibodies in some cases of pulmonary hemorrhage and GN was proven 10 years later.3 It has become clear that several different pathogenetic mechanisms underlie this clinical syndrome, and the eponymous description of Goodpasture’s syndrome has been abandoned. Instead, the term pulmonary renal syndrome (PRS) is used to describe a combination of diffuse pulmonary From the SW Thames Renal Unit, St Helier Hospital, Carshalton, Surrey; and the Department of Medicine, Addenbrooke’s Hospital, Cambridge, UK. Received June 5, 2001; accepted in revised form August 10, 2001. Address reprint requests to Hugh Gallagher, MBBS, SW Thames Renal Unit, St Helier Hospital, Wrythe Lane, Carshalton, Surrey SM5 1AA, UK. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/3901-0006$35.00/0 doi:10.1053/ajkd.2002.29876 42

hemorrhage and GN occurring as the presenting manifestation of multisystem autoimmune disease.4 Single-center experience suggests that 60% to 70% of cases with PRS are associated with autoantibodies to neutrophil cytoplasmic antigens (ANCAs) and 20% are associated with anti-GBM antibodies.5,6 PRS is a rare complication of systemic lupus erythematosus (SLE),7 and other autoimmune associations have been noted in individual cases.4 ANCA-associated systemic vasculitis (AASV), which can be subdivided into microscopic polyangiitis (MPA) and Wegener’s granulomatosis,8 and anti-GBM disease are rare conditions, with estimated incidences of 20 million/y for AASV and 1 million/y for anti-GBM disease.4 Pulmonary infiltrates with diffuse pulmonary hemorrhage are seen in 40% of patients with AASV,9 and a fulminant presentation requiring assisted ventilation occurs in approximately 5%.10 Outcome data for PRS remain confined to small studies with limited follow-up. We therefore performed a retrospective analysis of all cases seen in a single tertiary center over a 4-year period.

American Journal of Kidney Diseases, Vol 39, No 1 (January), 2002: pp 42-47

PULMONARY RENAL SYNDROME: 4-YEAR EXPERIENCE

METHODS Fourteen consecutive cases of PRS managed at a single center between 1996 and 2000 were studied. Thirteen of these were de novo presentations of PRS at this institution; the care of the other patient had been transferred from another center. Criteria for inclusion were diffuse pulmonary hemorrhage, GN with deteriorating renal function, and hypoxia (PO2 ⬍ 8.0 kPa). Diffuse pulmonary hemorrhage was defined as the presence of diffuse, bilateral, parenchymal infiltrates on chest radiograph, together with either hemoptysis or direct visualization of bleeding at bronchoscopy. Data were recorded for baseline characteristics (age, sex, comorbid conditions); length and features of prodromal illness; clinical, biochemical, and serological features at presentation; Birmingham Vasculitis Activity Score; initial and subsequent treatment; and complications of treatment. Outcome data concerning survival, dialysis dependence, serum creatinine level, and ANCA status were documented at 1 month, 3 months, 1 year, and 2 years. The occurrence, management, and outcome of relapsing disease, presence of lung dysfunction in remission, and cause of death, when relevant, also were noted.

RESULTS

Mean patient age was 65 ⫾ 2.1 (SEM) years, and seven patients were women. The mean duration of the prodromal illness, characterized by lethargy, weight loss, and arthralgia, was 2.9 ⫾ 0.4 (SEM) months. Two patients had previous diagnoses of cryptogenic fibrosing alveolitis (CFA), and one patient, mixed connective tissue disease. One of the two patients with CFA was ANCA positive, with myeloperoxidase (MPO)ANCA specificity. Two patients had a history of nephrotic syndrome. One of these patients, with positive double-stranded DNA binding and antinuclear antibodies (ANAs), previously had undergone a renal biopsy that showed typical changes of membranous nephropathy. Clinical, biochemical, serological, and histological features at presentation are listed in Tables 1 and 2. Both patients with serological positivity for anti-GBM antibodies were also perinuclear ANCA (P-ANCA) and MPO-ANCA positive. None of the ANCA-positive patients had the granulomatous lesions or respiratory tract features necessary for a firm diagnosis of Wegener’s granulomatosis8; therefore, all have been classified as MPA. One patient (Table 2, patient 7) had serological features more typical of SLE, with a low C4 count and positive ANAs, and two additional patients had positive ANAs in addition to ANCAs. Renal biopsy was performed in 10 patients.

43 Table 1.

Summary of Presenting Features

Clinical parameters Systolic blood pressure (mm Hg) Dialysis dependence (%) Assisted ventilation (%) Inotropic support (%) Birmingham Vasculitis Activity Score Biochemical parameters Hemoglobin (g/dL) Serum creatinine (␮mol/L) PO2 on air (kPa) PO2 on maximum oxygen therapy (kPa) Serological parameters C-ANCA/PR3-ANCA positivity (%) Isolated P-ANCA/MPO-ANCA positivity (%) Double P-ANCA/MPO-ANCA anti-GBM positivity (%)

140 ⫾ 5.5 86 57 57 28.7 ⫾ 1.4 8.2 ⫾ 0.6 554 ⫾ 70.4 6.0 ⫾ 0.5 9.0 ⫾ 0.6 36 36 14

NOTE. Results expressed as mean ⫾ SEM or percentage. Abbreviation: PR3, proteinase 3.

Light microscopy confirmed segmental necrotizing crescentic GN in 9 patients and membranous GN in the patient with positive ANAs and a low C4 count. Immunofluorescence was performed on all specimens showing crescentic change. Eight of nine specimens showed no evidence of immune deposition, confirming a renal histological diagnosis in these cases of pauci-immune rapidly progressive GN. One specimen showed heavy granular deposition of immunoglobulin and C3 along the GBM. This latter patient (Table 2, patient 9) had an 18-month history of nephrotic syndrome with no histological diagnosis. At the time of acute presentation with PRS, there was strong MPO-ANCA specificity, and renal biopsy showed a chronic mesangial proliferative process with granular deposition of immunoglobulin G (IgG), IgM, IgG, and C3 and superimposed acute necrotizing GN. All patients were treated with corticosteroids at a mean starting dose of 54 ⫾ 3.9 mg of prednisolone. In addition, 8 of 14 patients were administered intravenous methylprednisolone (1.5 to 3 g), 13 of 14 patients were administered daily cyclophosphamide (orally when possible; 9 patients, 2 mg/kg; 4 patients, 1 mg/kg), and 12 of 14 patients underwent therapeutic plasma exchange (6.1 ⫾ 0.7 sessions). Four of these 14 patients were administered sequential intravenous immunoglobulin after plasma exchange. During the study period, the use of pulsed meth-

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GALLAGHER, KWAN, AND JAYNE Table 2.

Serological and Histological Classification of Patients Histological Results

Patient No.

Serological Results

Light Microscopy

Immunofluorescence

Diagnosis

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Negative P-ANCA C-ANCA C-ANCA P-ANCA C-ANCA dsDNA, ANA, low C4 P-ANCA P-ANCA P-ANCA, ANA P-ANCA, ANA, anti-GBM P-ANCA, anti-GBM C-ANCA C-ANCA

Crescentic GN — Cresentic GN Crescentic GN Crescentic GN Crescentic GN Membranous GN — Crescentic GN* Crescentic GN — — Crescentic GN Crescentic GN

Negative — Negative Negative Negative Negative — — Granular Ig, C3* Negative — — Negative Negative

MPA (ANCA-negative) MPA MPA MPA MPA MPA SLE MPA MPA MPA MPA with anti-GBM antibodies MPA with anti-GBM antibodies MPA MPA

Abbreviations: dsDNA, double-stranded DNA; Ig, immunoglobulin. *Biopsy findings were of a chronic mesangial proliferative process with granular deposition of IgG, IgM, IgG, and C3 and superimposed acute necrotizing GN. Clinical findings are considered in the text.

ylprednisolone was reduced, and sequential plasma exchange and intravenous immunoglobulin were introduced in an attempt to reduce septic complications. Cyclophosphamide treatment was planned to continue for 3 (10 patients) or 6 months (3 patients), and patients were then maintained on azathioprine therapy. White blood cell counts were monitored daily at the onset of therapy and weekly intervals thereafter. Cytopenia frequently was associated with treatment. Neutrophil counts less than 3 ⫻ 109/L and 1 ⫻ 109/L were seen in 7 of 14 and 3 of 14 patients, respectively. Lymphocyte counts less than 0.5 ⫻ 109/L were documented in 13 of 14 patients. Early reduction in cyclophosphamide dose because of cytopenia was required in 9 patients. Patients were followed up for 22 ⫾ 9 months. Outcome data at 1 month, 3 months, 1 year, and 2 years are listed in Table 3. Notably, 7 of 14 Table 3.

Follow-Up

1 mon 3 mon 1y 2y

patients were alive at the end of follow-up, but 5 of 14 patients died in the first month; 4 of these patients had required assisted ventilation. Of patients surviving the first month, 6 of 7 patients (85%) survived to the end of 1 year of completed follow-up, and 4 of 6 patients (67%) were alive at the end of 2 years’ completed follow-up; 83% and 75% remained dialysis independent at these times, respectively. Of the 4 patients requiring mechanical ventilation who survived the first month, 3 patients were alive at the end of followup. Five relapses were seen in four patients. One relapse presented with new pulmonary infiltrates and a decline in renal function at 7 months in a patient who was initially C-ANCA positive and had undergone a 6-month course of cyclophosphamide therapy before being switched to azathioprine therapy. The relapse was successfully Outcome Data

Survivors (%)

Dialysis Dependence in Survivors (%)

Serum Creatinine in DialysisIndependent Survivors (␮mol/L)

ANCA Positivity (%)

64 64 50 36

56 22 17 25

230 ⫾ 16 231 ⫾ 37 194 ⫾ 28 167 ⫾ 23

89 67 17 25

NOTE. Results expressed as mean ⫾ SEM or percentage.

PULMONARY RENAL SYNDROME: 4-YEAR EXPERIENCE

treated with plasma exchange, intravenous immunoglobulin, and a change from azathioprine to mycophenolate mofetil therapy. The second relapse presented as progressive breathlessness in a patient with initial P-ANCA positivity, again shortly after the cessation of cyclophosphamide therapy; ANCA status at the time of relapse was borderline positive by immunofluorescence, but there was no clinical response to further immunosuppression, including a second course of cyclophosphamide. In a third patient, a late relapse manifest by hemoptysis and declining renal function was successfully treated with cyclophosphamide and plasma exchange. The fourth patient experienced two relapses; one relapse was dominated by features of central nervous system vasculitis at 1 month, whereas the other relapse was manifest by declining renal function at 3 years. In both cases, C-ANCA seropositivity was noted, and the early and late relapses were successfully treated with intravenous methylprednisolone and continuous cyclophosphamide therapy, respectively. Main causes of death in the first year were sepsis (three cases), pulmonary embolism, pericardial effusion, and massive pulmonary hemorrhage (one case each). One patient who was MPO-ANCA positive and had a previous diagnostic label of CFA died at 15 months of progressive pulmonary fibrosis. However, it should be emphasized that sepsis was believed to be a significant contributor in six of seven deaths. DISCUSSION

A firm diagnosis of PRS is best established by using a combination of clinical presentation, serological results, and histological results, although obtaining material for the latter may present practical difficulties in a critical care setting. Confirmation of diffuse lung hemorrhage by bronchoscopy often was helpful, and others also have used bronchoalveolar lavage in this setting. The occurrence of prodromal illness of significant duration in most cases indicates a need and opportunity for earlier diagnosis, and the widespread adoption of serological testing performed in an appropriate clinical context hopefully will limit diagnostic delay. The proportions of patients in this study with ANCA and antiGBM positivity are similar to those previously reported for PRS.5,6 Double anti-GBM and ANCA

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positivity is well recognized, and although the suggestion in the literature that these overlap cases have a more severe clinical phenotype11 is impossible to confirm or refute here on the basis of such small numbers, it may be relevant that neither of the patients with anti-GBM antibodies on this study regained independent renal function. The duration of prodromal illness and degree of renal dysfunction, assessed by serum creatinine level, also are in good accordance with values quoted in earlier series.5,10 Thus, in many respects, the study population is likely to be a group representative of patients with PRS as a whole. However, our patients have a mean age considerably older than those of Saxena et al5 and ter Maaten et al,10 and this would have contributed to a poorer outcome. The degree of pulmonary dysfunction evident in these patients is likely to be a more significant determinant of outcome; 57% required ventilatory support for massive pulmonary hemorrhage, representing an occurrence of respiratory failure in excess of that previously documented for PRS.10 There are no agreed-on criteria for PRS, and those used here were more stringent than those in other studies with respect to the severity of lung disease. Conclusions that can be drawn from this analysis will therefore have most relevance for patients at the severe end of the PRS spectrum. Although the small numbers involved preclude meaningful statistical analysis, the level of early mortality reported here is striking and far greater than the rate of 12% reported by Saxena et al.5 Differences in case mix are likely to underlie this discrepancy, and other studies have suggested similar early mortality rates of 50%6 and, for a subgroup of patients with PRS requiring assisted ventilation, 60%.10 In a recent study of 29 patients with MPA with alveolar hemorrhage, the 5-year survival rate was 68%.12 The degree of pulmonary hemorrhage in this group, assessed by mean hemoglobin level, was similar to that found here. However, patients of Lauque et al12 were younger, and only 28% and 10% required renal replacement therapy and mechanical ventilation, respectively. Interestingly, much of their mortality was attributed to active vasculitis, and it may be of relevance that 24% were treated with plasma exchange compared with 86% in our center. The outcome of patients with

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diffuse pulmonary hemorrhage in the context of SLE is unclear, with small series reporting mortality rates with cyclophosphamide between 25%13 and 70%.14 Patients in our cohort surviving the acute presentation have a reasonable longer term outcome in terms of both survival and maintenance of independent renal function. The former observation is consistent with other reports suggesting that survivors of the acute phase of PRS have a similar prognosis to other subgroups of AASV, with 75% surviving 2 years,15 and the latter may reflect in part that none of the 14 patients here had disease mediated entirely by anti-GBM antibodies, a group less likely to regain independent renal function.16 Recovery of renal function generally postdated the institution of immunosuppressive therapy by several weeks. Of the 12 patients who were initially dialysis dependent, 5 patients died during the first month. Two of the survivors regained independent renal function during the first month, and 3 more patients became dialysis independent by 3 months. The two patients who did not recover renal function had serological positivity for anti-GBM antibodies. The incidence of immunosuppression-related adverse events in this study was remarkably high. Cyclophosphamide-associated neutropenia and infection were significant contributors to six of seven deaths, and only one patient died acutely of active vasculitic disease. Protocol changes during the study were introduced to reduce infective risk by avoiding pulsed methylprednisolone therapy and instituting immediate plasma exchange followed by intravenous immunoglobulin. This aimed to correct hypogammaglobulinemia and exploit the antivasculitic effect of immunoglobulin.17 Small numbers do not permit conclusions on the success of these modifications. It is hoped that outcome in PRS will be improved by earlier diagnosis, early aggressive therapy, and the pursuit of less toxic alternatives to cyclophosphamide. Current practice in this center includes the routine use of plasma exchange in patients with PRS, with a concomitant dose reduction or omission of cyclophosphamide. Although a firm evidence base for plasma exchange in this setting is lacking, a rationale for its adoption can be provided on both basic scientific and clinical grounds. The similarity in patho-

GALLAGHER, KWAN, AND JAYNE

logical changes of alveolar hemorrhage and crescentic GN is well recognized. There is a strong association of PRS with the presence of ANCA, believed by many authorities to be pathogenic on the basis of both association of ANCA titer with disease activity18 and in vitro and in vivo properties of these autoantibodies to, eg, activate neutrophils19 and induce generalized pulmonary tissue injury.20 Plasma exchange is indicated for antiGBM disease,16 and finally, evidence is accumulating for the role of plasma exchange in ANCAassociated rapidly progressive GN.21 Potential future refinements include the use of tumor necrosis factor blockade22 and autoantibody-specific immunoabsorption.23 REFERENCES 1. Goodpasture EW: The significance of certain pulmonary lesions in relation to the aetiology of pneumonia. Am J Med Sci 158:863-870, 1919 2. Stanton MC, Tange JD: Goodpasture’s syndrome (pulmonary haemorrhage associated with glomerulonephritis. Aust Ann Med 7:132-144, 1958 3. Lerner RA, Glassock KJ, Dixon FJ: The role of antiglomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med 126:989-1004, 1967 4. Jayne DR: Pulmonary-renal syndrome. Semin Respir Crit Care Med 19:69-77, 1998 5. Saxena R, Bygren P, Arvastson B, Wieslander J: Circulating autoantibodies as serological markers in the differential diagnosis of pulmonary renal syndrome. J Intern Med 238:143-152, 1995 6. Niles JL, Bottinger EP, Saurina GR, Kelly KJ, Pan G, Collins AB, McCluskey RT: The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med 156:440-445, 1996 7. Eagen JW, Memoli VA, Roberts JL, Matthew GR, Schwartz MM, Lewis EJ: Pulmonary hemorrhage in systemic lupus erythematosus. Medicine 57:545-560, 1978 8. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG: Nomenclature of systemic vasculitides. Arthritis Rheum 37:187-192, 1994 9. Haworth SJ, Savage CO, Carr D, Hughes JM, Rees AJ: Pulmonary haemorrhage complicating Wegener’s granulomatosis and microscopic polyarteritis. BMJ 290:1775-1778, 1985 10. ter Maaten JC, Franssen CF, Gans RO, van Schijndel RJ, Hoorntje SJ: Respiratory failure in ANCA-associated vasculitis. Chest 110:357-362, 1996 11. Jayne DR, Marshall PD, Jones SJ, Lockwood CM: Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int 37:965-970, 1990 12. Lauque D, Cadranel J, Lazor R, Pourrat J, Ronco P, Guillevin L, Cordier JF: Microscopic polyangiitis with alveolar hemorrhage. Medicine 79:222-233, 2000 13. Schwab EP, Schumacher HR, Freundlich B, Callegari

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