Pulmonary-Renal vasculitic disorders: Differential diagnosis and management

Pulmonary-renal syndrome (PRS) is a combination of diffuse pulmonary hemorrhage and glomerulonephritis. Pulmonary-renal syndrome is not a single entity and is caused by a variety of conditions, including Goodpasture’s syndrome associated with autoantibodies to the glomerular and alveolar basement membranes, various forms of primary systemic vasculitis associated with serum positivity for antineutrophil cytoplasmic antibodies (ANCA), cryoglobulinemia, systemic lupus erythematosus, systemic sclerosis, antiphospholipid syndrome, environmental factors, and drugs. The majority of cases of PRS are associated with ANCAs. The antigen target in Goodpasture’s syndrome is the alpha-3 chain of type IV collagen. The antigen target in PRS associated with systemic vasculitis is proteinase-3 and myeloperoxidase. Pulmonary-renal syndrome has been observed from the first to the ninth decade of life. The widespread adoption of serologic testing performed in an appropriate clinical context hopefully will limit diagnostic delay. The goals of treatment in PRS are to remove the circulating antibodies, to stop further production of autoantibodies, and to remove any antigen that stimulates antibody production. Treatment is based on plasmapheresis, steroids, and cyclophosphamide; however, infections are frequent contributors to death, and less toxic alternatives may improve outcome and prognosis resulting in a long-term survival. The degree of renal function and the percent of crescents on renal biopsy are better predictors of outcome. Renal transplantation can be safely carried out in PRS.     

28-year-old woman with Goodpasture's syndrome and nonspecific colitis

Goodpasture's syndrome usually becomes manifest with progressive glomerulonephritis and pulmonary hemorrhage. The diagnostic hallmark is the demonstration of anti-basement membrane anti-alpha3 type IV collagen antibodies (anti-GMB antibodies) in patient sera. Herein is reported the case of 28-year-old woman with Goodpasture's syndrome who developed the acute symptoms of nonspecific colitis which required surgical intervention. Immunosuppression along with plasmapheresis was successful in the treatment of life-threatening pulmonary hemorrhage, but not for the improvement of renal function.     

Pulmonary-renal syndrome in systemic sclerosis: a report of three cases and review of the literature

We describe three cases of acute renal failure with diffuse alveolar hemorrhage, which is designated pulmonary-renal syndrome (PRS), in systemic sclerosis (SSc) and review the literature to better define this rare but severe complication of SSc. The clinical course of three SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage are reported, and the literature published between 1967 and 2005 is reviewed following a PubMed search. Including our cases, a total of 19 SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage have been reported. Pulmonary-renal syndrome developing in SSc patients can be categorized clinicopathologically into three entities: PRS with thrombotic microangiopathy, PRS with small vessel vasculitides accompanied with SSc, and d-penicillamine-induced Goodpasture-like syndrome. Patients with scleroderma PRS with thrombotic microangiopathy, to which group our all patients belong, often developed diffuse alveolar hemorrhage after receiving high-dose corticosteroid therapy. Pulmonary-renal syndrome is a fatal complication of SSc and results from different pathogenic processes. Prompt differential diagnosis between the subsets is critical, because therapeutic strategy may differ in the use of high-dose corticosteroid and plasma exchange between the subsets of PRS. Clinical courses of the patients with PRS with thrombotic microangiopathy suggest that high-dose corticosteroid therapy is a trigger of diffuse alveolar hemorrhage in patients with diffuse SSc with signs of thrombotic microangiopathy.     

A case of chronic relapsing ANCA-associated microscopic polyangiitis successfully treated with plasma exchange

We report the case of a 4.5-year-old girl with microscopic polyangiitis (MPA) manifesting antineutrophil cytoplasmic autoantibody (ANCA)-positive necrotizing crescentic glomerulonephritis and pulmonary hemorrhage. She was initially on induction therapy with corticosteroids and azathioprine. Plasma exchange (PE) combined with immunosuppressants was used to treat an episode of recurrent pulmonary hemorrhage, and achieved remission. At 9.8 years of age her kidney disease relapsed, associated with renal dysfunction and increased proteinuria. To minimize the toxic effects of immunosuppressants, she was treated with PE again, and her renal dysfunction resolved. Plasma exchange was effective in reducing the risk of death and preserving long-term renal function without the severe adverse effects of immunosuppressants. Our preliminary results indicate that PE is likely to be a treatment option for children in acute phase of ANCA-associated MPA, who should be protected from the toxic effects of immunosuppressants.     

Microscopic polyangiitis presenting as a “pulmonary‐muscle” syndrome: Is subclinical alveolar hemorrhage the mechanism of pulmonary fibrosis?

Microscopic polyangiitis (MPA) may present with a syndrome that resembles idiopathic pulmonary fibrosis (IPF). We describe an MPA patient with the clinical presentation of a “pulmonary‐muscle” syndrome in which interstitial lung disease antedated the onset of myopathy. Identification of vasculitis on muscle biopsy was instrumental in recognizing clinical, radiographic, and histopathologic features that were more characteristic of MPA than of IPF. Institution of glucocorticoid and cyclophosphamide therapy led to the induction of a complete remission. The histologic findings in this case implicate subclinical episodes of alveolar hemorrhage as the mechanism of interstitial lung disease in MPA.     

Microscopic polyangiitis presenting as a "pulmonary-muscle" syndrome: is subclinical alveolar hemorrhage the mechanism of pulmonary fibrosis?

Microscopic polyangiitis (MPA) may present with a syndrome that resembles idiopathic pulmonary fibrosis (IPF). We describe an MPA patient with the clinical presentation of a "pulmonary-muscle" syndrome in which interstitial lung disease antedated the onset of myopathy. Identification of vasculitis on muscle biopsy was instrumental in recognizing clinical, radiographic, and histopathologic features that were more characteristic of MPA than of IPF. Institution of glucocorticoid and cyclophosphamide therapy led to the induction of a complete remission. The histologic findings in this case implicate subclinical episodes of alveolar hemorrhage as the mechanism of interstitial lung disease in MPA.     

Pulmonary-renal syndrome in systemic sclerosis

BACKGROUND AND OBJECTIVE: Renal failure, pulmonary hypertension, and interstitial lung disease are major causes of morbidity and mortality in systemic sclerosis (SSc). However, the concomitant occurrence of pulmonary hemorrhage associated with acute renal failure in SSc has been rarely described. The present study is the first analysis of pulmonary-renal syndrome in SSc. PATIENT AND METHODS: We present a 44-year-old woman with SSc who died of a fulminant course of acute renal failure associated with diffuse alveolar hemorrhage. We termed this uncommon and fatal complication of SSc scleroderma-pulmonary-renal syndrome (SPRS). A search of the English-written literature yielded reports of 10 additional similar cases. These patients, together with our present case, form the basis of the present analysis. RESULTS: The average age of the patients with SPRS was 46 years. The majority of the patients (80%) were women, and most had diffuse SSc. SPRS occurred an average of 6.4 years after disease onset and was associated with prior fibrosing alveolitis and/or D-penicillamine treatment. Interestingly, normotensive renal failure seems to characterize the scleroderma patients, because 9 of 11 (82%) had normal blood pressure. SPRS bears a poor prognosis: all of the 11 patients (100%) died within 12 months of admission. However, only 60% of the 5 patients for whom we have treatment data received corticosteroids. CONCLUSIONS: Pulmonary-renal syndrome is a rare but fatal complication of SSc. Because the treatment data are scarce and the prognosis is poor, aggressive treatment with pulse corticosteroids, cyclophosphamide, and possibly plasmapheresis is suggested.     

Development of Microscopic Polyangiitis in Patients with Chronic Airway Disease

Microscopic polyangiitis (MPA) is a rare systemic vasculitis syndrome, which is often accompanied by positive myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA). While pulmonary involvement of MPA consists mainly of diffuse alveolar hemorrhage and interstitial pneumonia, bronchiectasis has been reported as a pulmonary lesion in association with MPA. To investigate the clinical features of patients with MPA, focusing on the presence or the absence of preceding chronic airway diseases (CAD), we conducted a retrospective observational study of 26 patients in the last 13 years at Saga University Hospital. The clinical records and radiologic chest examinations were reviewed retrospectively. Pulmonary manifestations were alveolar hemorrhage in 3 patients (12%) and interstitial pneumonia in 5 (19%). Bronchiectasis, defined by the findings of chest radiograph and computed tomography, was found in 9 patients (35%). Four patients (15%) with bronchiectasis and one patient (4%) with chronic bronchitis had experienced chronic bronchial suppuration prior to the onset of MPA. Ten patients were classified as having chronic airway disease (CAD) before the onset of MPA. MPO-ANCA tended to be lower in the CAD group than in the non-CAD group. None of the patients in the CAD group had pulmonary hemorrhage or interstitial pneumonia. Only one patient (10%) in the CAD group died within 90 days of the onset of MPA, while 7 (43.8%) of the non-CAD group died. Our study suggests that MPA may result in part from CAD and that the clinical course of MPA with CAD may be different from MPA without CAD.     

Anti-glomerular basement membrane disease: outcomes of different therapeutic regimens in a large single-center Chinese cohort study

Anti-glomerular basement membrane (GBM) disease usually presents with rapidly progressive glomerulonephritis accompanied by pulmonary hemorrhage. The low incidence and fulminant course of disease preclude a large randomized controlled study to define the benefits of any given therapy. We conducted a retrospective survey of 221 consecutive patients seen from 1998 to 2008 in our hospital, and report here the patient and renal survival and the risk factors affecting the outcomes. Considering the similar clinical features of the patients, we could compare the effects of 3 different treatment regimens: 1) combination therapy of plasmapheresis and immunosuppression, 2) steroids and cytotoxic agents, and 3) steroids alone.The patient and renal survival rates were 72.7% and 25.0%, respectively, at 1 year after disease presentation. The serum level of anti-GBM antibodies (increased by 20 U/mL; hazard ratio [HR], 1.16; p = 0.009) and the presentation of positive antineutrophil cytoplasmic antibodies (ANCA) (HR, 2.18; p = 0.028) were independent predictors for patient death. The serum creatinine at presentation (doubling from 1.5 mg/dL; HR, 2.07; p < 0.001) was an independent predictor for renal failure.The combination therapy of plasmapheresis plus corticosteroids and cyclophosphamide had an overall beneficial effect on both patient survival (HR for patient mortality, 0.31; p = 0.001) and renal survival (HR for renal failure, 0.60; p = 0.032), particularly patient survival for those with Goodpasture syndrome (HR for patient mortality, 0.29; p = 0.004) and renal survival for those with anti-GBM nephritis with initial serum creatinine over 6.8 mg/dL (HR for renal failure, 0.52; p = 0.014). The treatment with corticosteroids plus cyclophosphamide was found not to improve the renal outcome of disease (p = 0.73). In conclusion, the combination therapy was preferred for patients with anti-GBM disease, especially those with pulmonary hemorrhage or severe renal damage. Early diagnosis was crucial to improving outcomes.     

Goodpasture's syndrome with normal renal function.

Two male patients with Goodpasture's syndrome manifesting as severe pulmonary hemorrhage with minimal renal abnormalities are described. Both patients had microscopic hematuria with normal renal function, and one had transient proteinuria. Renal glomerular histology was normal and electron microscopic findings revealed no electron-dense deposits, but immunofluorescence of immunoglobulin G (IgG) was positive in a linear fashion along glomerular capillary basement membranes in both patients. Pulmonary hemorrhage was arrested following prednisone therapy, and both patients have normal pulmonary and renal function at five and 13 months of follow-up. The literature on patients with Goodpasture's syndrome, pulmonary hemorrhage and normal renal function with minimal proteinuria is reviewed. It is suggested that a subset of patients with Goodpasture's syndrome have pulmonary hemorrhage as their major manifestation. Since prednisone seems to have an apparent beneficial effect on pulmonary hemorrhage, and relatively good prognosis, this diagnosis should be considered in patients with idiopathic pulmonary hemorrhage.     

Microscopic polyangiitis initiated with liver dysfunction, calf pain and fever of unknown origin

We report herein a case of microscopic polyangiitis (MPA), presenting onset with a spiking fever, liver/biliary dysfunction without jaundice and calf pain without elevation of serum creatine phosphokinase. During 1 month of careful examinations for initial diagnosis, the patient developed renal dysfunction and pulmonary hemorrhage. Based on the results of positive MPO-ANCA, renal and pulmonary involvements, the patient was diagnosed with MPA and treated with high-dose prednisolone and oral cyclophosphamide. Soon after initiation of the treatment, symptoms such as fever, calf pain, liver/biliary dysfunction and renal dysfunction disappeared with decrease of MPO-ANCA titer to the normal level.     

Circulating autoantibodies as serological markers in the differential diagnosis of pulmonary renal syndrome

Abstract. Objectives . Pulmonary renal syndrome (lung haemorrhage and glomerulonephritis) is a fulminant condition that warrants a rapid diagnosis and treatment to prevent mortality and preserve renal functions. However, the patients frequently present with non-specific pulmonary symptoms in the early phase of the syndrome and the diagnosis is often missed. Recently, several autoantibodies have been described in association with various forms of glomerulonephritis. We evaluated the association as well as the diagnostic and the prognostic significance of these antibodies in pulmonary renal syndrome. Design . Retrospective clinical study. Setting . University Hospital. Subjects . Forty consecutive patients with biopsy verified glomerulonephritis and overt haemoptysis or pulmonary infiltrates compatible with lung haemorrhage. Interventions . Analysis of proteinase 3 antineutrophil cytoplasm antibodies (PR3-ANCA), myeloperoxidase (MPO)-ANCA, antiglomerular basement membrane (GBM) and anti-entactin antibodies. Results . Thirty-six (90%) patients possessed one or more autoantibodies. Twenty-seven (70%) patients had ANCA (PR3-ANCA, MPO-ANCA or both). The remaining positive patients (n = 9) had anti-GBM antibodies. Only two patients had anti-entactin antibodies, suggesting a poor association of these antibodies with PRS. The majority of patients with anti-GBM antibodies had a very poor clinical outcome (five irreversible renal failure; three deaths). On the other hand, despite no significant difference in clinical features or renal morphology from patients with anti-GBM antibodies, 19 patients (70%) with ANCA recovered completely following treatment. Conclusions . Our study demonstrated that the presence of autoantibodies is a predominant feature of PRS and that the type of immunologic injury is of paramount importance in determining the course of illness in this syndrome. Analysis of the aforementioned antibodies can help in an early differential diagnosis and thus, in better management of PRS.     

Role of plasmapheresis performed in hemodialysis units for the treatment of anti-neutrophilic cytoplasmic antibody-associated systemic vasculitides

Anti‐neutrophilic cytoplasmic antibody (ANCA) positivity is seen in some systemic necrotizing vasculitides. Wegener's granulomatosis and microscopic polyangiitis are among the ANCA‐associated systemic vasculitides (AASV) and mortality is very high when renal failure occurs together with alveolar hemorrhage. The role of plasmapheresis in the treatment of these diseases has been studied retrospectively. Twelve patients with AASV who had plasmapheresis together with immunosuppressive medications have been involved. Primary diseases, immunosuppressive protocols, the number of plasmapheresis sessions, the amount of plasma that has been exchanged, urea and creatinine levels before and after treatment, pulmonary findings, the need for hemodialysis, and the outcome of patients were recorded. The mean age of patients was 52.9 ± 18.2 years. Wegener's granulomatosis was diagnosed in seven (58.3%) and microscopic polyangiitis in five (41.7%) patients. All patients had pulse cyclophosphamide and methylprednisolone followed by maintenance doses and plasmapheresis. Seven patients had hemodialysis at the beginning, and hemodialysis needed to be continued in three patients. Partial and complete remission was seen in 6 (50%) and 3 (25%) patients, respectively, and pulmonary findings regressed in all patients. End‐stage renal disease develops generally in AASV due to rapidly progressive glomerulonephritis causing severe irreversible glomerular damage. The mortality rate rises to 50% in cases of renal failure with diffuse alveolar hemorrhage; therefore, pulse immunosuppressive treatment with plasmapheresis may be life‐saving, as shown in our study.     

Hemolytic uremic syndrome with intracranial hemorrhage following mitomycin C administration

A 50-year-old woman treated for breast cancer with mitomycin C developed severe hypertension, followed by deep coma 3 days later. Computed tomography of the brain showed frontoparietal intracranial hemorrhage accompanied by subarachnoid hemorrhage. The patient was diagnosed additionally with hemolytic uremic syndrome (HUS) based on hemolytic anemia with schistocytosis, thrombocytopenia, and acute renal failure. The patient underwent hemodialysis and plasmapheresis with no improvement. We present the pathologic findings of the general vessels, which has been reported rarely. This case represents the first reported intracranial hemorrhage in HUS following mitomycin C administration. We emphasize the need to control blood pressure in patients with HUS.     

Two cases of pulmonary disease with perinuclear anti-neutrophil cytoplasmic antibody]

We encountered two cases of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA). The first was a case of idiopathic interstitial pneumonia diagnosed in a 73-year-old man since 1998. He was admitted to our hospital because of renal failure and anemia. The serum level of p-ANCA on admission was 264 EU, and specimens obtained by percutaneous renal biopsy showed crescentic glomerulonephritis and vasculitis due to p-ANCA. He was treated with prednisolone pulse therapy and prednisolone (PSL), however interstitial pneumonia occurred during PSL tapering. We treated him for pulmonary fibrosis with plasmapheresis, methylprednisolone (mPSL) and cyclophosphamide (CPA), which suppressed the progress of the interstitial pneumonia. The second case was one of massive pulmonary hemorrhage in a 68-year-old man who was admitted to our hospital. Physical examination revealed anemia: the laboratory data, renal failure; and the serum level of p-ANCA was elevated to 611 EU. The specimens obtained by percutaneous renal biopsy showed crescentic glomerulonephritis and vasculitis. The renal failure was not improved by PSL, but, together with the inflammation, responded to the combination of PSL and CPA. However, both patients died of serious infection. They were regarded as compromised patients because of the therapy mentioned above. No standard therapy has been established against p-ANCA positive pulmonary disease with renal failure. The treatment should control the progression of interstitial pneumonitis and pulmonary hemorrhage. It is important to consider the possibility of serious infection.     

Hemocholecyst complicated in a hemodialysis patient with microscopic polyangiitis

Microscopic polyangiitis (MPA) is a systemic vasculitis associated with antineutrophil cytoplasmic antibodies, and it involves multiple organs, including the kidneys and lungs. We report on the case of a 72-year-old woman with MPA who developed hemocholecyst in addition to alveolar hemorrhage and rapidly progressive glomerulonephritis. Although her renal function was not salvaged, the alveolar hemorrhage and hemocholecyst were treated conservatively. Clinicians should consider the possibility of hemocholecyst in patients with MPA complaining of abdominal pain.     

Pulmonary alveolar hemorrhage in patients with rheumatic diseases in Korea

Pulmonary alveolar hemorrhage (PAH) is a rare and often fatal presenting feature of rheumatic diseases, with high mortality rate ranging from 40% to 90%. This study was undertaken to review the clinical manifestations, disease course, prognosis, and treatment of PAH in rheumatic diseases in Korea. A retrospective analysis was performed from October 1995 to March 1999 at the Samsung Medical Center. Ten cases were diagnosed as having pulmonary hemorrhage with rheumatic diseases that comprised the following: 6 systemic lupus erythematosus (SLE), 3 microscopic polyangiitis (MPA), and 1 mixed connective tissue disease (MCTD). In 80% of the patients in the present series, PAH was the first clinical manifestation of rheumatic diseases. The most consistent systemic manifestation occurring in conjunction with PAH was renal involvement (80%). The overall patient mortality rate was 50% (5/10) in the current series. Our study suggests that PAH often occurs as the first clinical manifestation of rheumatic diseases and needs urgent medical treatment including plasmapheresis in addition to cyclophosphamide and methylprednisolone.     

Metabolic alkalosis due to plasmapheresis

Progressive metabolic alkalosis developed in two patients undergoing daily plasmapheresis for diffuse intrapulmonary hemorrhage associated with glomerulonephritis (Goodpasture's-like syndrome). The metabolic alkalosis promptly resolved when the plasmapheresis procedure was altered so that 3 percent albumin and cryoprecipitate rather than fresh frozen plasma were used as replacement for the removed patient plasma. The development of metabolic alkalosis during plasmapheresis can be explained by the large sodium citrate load given during the procedure. Severe metabolic alkalosis may develop in patients with decreased renal function when they are treated with plasmapheresis. The metabolic alkalosis can be prevented by appropriate modifications in the plasmapheresis protocol.     

Antiglomerular basement membrane antibody-mediated glomerulonephritis and Goodpasture's syndrome.

The originally dismal prognosis associated with anti-GBM Ab-mediated GN and Goodpasture's syndrome may be changing as we recognize a broader spectrum of disease, improve general supportive care, and improve specific treatment. Immunosuppressive therapy, if started early in the course of disease, may prevent or allow recovery from renal failure and may also result in cessation of recurrent pulmonary hemorrhage in most patients with this form of Goodpasture's syndrome. The administration of pharmacologic doses of corticosteroids intravenously can result in cessation of and dramatic recovery from severe pulmonary hemorrhage and obviate the need for emergency bilateral nephrectomy. Plasmaspheresis may represent a useful therapeutic procedure for the immediate and long term reduction in amounts of circulating anti-GBM Ab, but the definition of its true value and role awaits completion of controlled, prospective trials. Immunosuppressive therapy, with or without plasmapheresis, can reduce quantities of anti-GBM Ab in serum to undetectable levels without nephrectomy. Thus, it is likely, but not proven, that nephrectomy can be discontinued as a routine pretransplantation procedure in patients with anti-GBM Ab mediated GN. Finally, in patients who suffer irreversible renal failure, renal transplantation can be successfully undertaken with minimal risk of recurrent disease, when circulating anti-GBM Ab becomes undetectable.     

A Case Report of Efficiency of Double Filtration Plasmapheresis in Treatment of Goodpasture's Syndrome

Goodpasture's syndrome is characterized by pulmonary hemorrhage, rapid progressive glomerulonephritis and the presence of anti‐glomerular basement membrane (anti‐GBM) antibodies. Here, we report a case of Goodpasture's syndrome that we treated with double filtration plasmapheresis (DFPP) combined with immunosuppression therapy. The patient was a 32‐year‐old man with the main complaints of low‐grade fever, general fatigue and dyspnea. The clinical diagnosis was renal‐pulmonary syndrome based on pulmonary hemorrhage on chest X‐ray, rapid progressive renal insufficiency, and elevated C‐reactive protein (CRP). Goodpasture's syndrome was diagnosed because the patient was negative for MPO‐ANCA and PR3‐ANCA, and positive for anti‐GBM antibodies. Renal biopsy showed crescentic glomerulonephritis. Hemodialysis, immunosuppression therapy (methylprednisolone and cyclophosphamide) and DFPP were performed. Anti‐GBM antibodies were followed pre‐ and post‐DFPP, and removal efficiency, cost performance and complications were evaluated. The antibody levels were 121 and 84 EU/mL before and after the first DFPP procedure, respectively, giving a removal efficiency of 24%. Subsequently, the removal efficiencies were 52%, 55% and 60% after the second, third and fourth DFPP procedures. For comparison, the immunoglobulin G (IgG) removal efficiencies were 53%, 57%, 60% and 55% after the four respective DFPP procedures; therefore, the removal efficiencies were similar for anti‐GBM antibodies and IgG in all except the first DFPP procedure. The serum anti‐GBM antibody and IgG concentrations decreased from pre‐ to post‐DFPP, indicating that DFPP may be an effective therapeutic approach in Goodpasture's syndrome.