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International Journal of Health Sciences and Research www.ijhsr.org ISSN: 2249-9571

Review Article

Pulmonary Renal Syndrome: Update Article

N.S.Neki1, Satpal Aloona2

1Professor, 2Assistant Professor, Department of Medicine, Govt. Medical College/ Guru Nanak Dev Hospital, Amritsar, India- 143001

Corresponding Author: N.S. Neki

Received: 08/01/2017 Revised: 24/01/2017 Accepted: 30/01/2017

ABSTRACT

The pulmonary–renal syndrome (PRS) refers to the combination of diffuse alveolar haemorrhage and rapidly progressive (RPGN). Pulmonary-renal syndrome can originate from various systemic autoimmune diseases. ANCA-associated vasculitides account for approximately 60%, Goodpasture's Syndrome for approximately 20% of the cases. It is almost always autoimmune in nature, therefore and other immunosupressants have role in its treatment. The underlying renal pathology is a form of focal proliferative glomerulonephritis. The lung pathology is in form of diffuse alveolar hemorrhages.

Key Words: Pulmonary renal syndrome; Wegener's granulomatosis; microscopic polyangiitis; systemic erythematosus.

INTRODUCTION collagen. [3,4] The pulmonary-renal Pulmonary–renal syndrome (PRS) is syndrome (PRS) is a rare and life- defined as the combination of diffuse threatening condition. The clinical picture of alveolar haemorrhage (DAH) and PRS includes (not always glomerulonephritis. [1,2] PRS are caused by a present) due to alveolar hemorrhages, acute- wide variety of diseases, including various onset and renal abnormalities forms of primary systemic ranging from isolated urinary abnormalities (Wegener‟sgranulomatosis and microscopic to rapidly progressive glomerulonephritis. A polyangiitis), Goodpasture's syndrome significant number of patients will present which is associated with to with rapid clinical deterioration and require the alveolar and glomerular basement admission to the intensive care unit (ICU) membrane and systemic lupus This is attributed either to exacerbation of erythematosus. The diagnosis is mainly the disease activity itself, or to infectious based on the identification of particular complications secondary to severe patterns of clinical, pathologic, radiologic immunosuppressive treatment Diffuse and laboratory features. The majority of alveolar haemorrhage is characterized by cases of pulmonary-renal syndrome are the presence of a haemorrhagic associated with ANCAs, either c-ANCA or bronchoalveolar lavage (BAL) in serial p-ANCA, due to autoantibodies against the BAL samples. In the clinical setting of an target antigens proteinase-3 and acute nephritis syndrome, percutaneous respectively. The antigen renal biopsy is commonly performed for target in Goodpasture's syndrome is type IV histopathology and immunofluorescence

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N.S. Neki et. al. Pulmonary renal syndrome: update article studies. Treatment of generalized ANCA- A) Pulmonary–renal syndrome associated vasculitis consists of associated with anti-GBM and immunosuppressive : Goodpasture‟s syndrome agents. [5-7] (GPS) Pathology B) Pulmonary–renal syndrome in The underlying pulmonary lesion in the ANCA-positive majority of cases of pulmonary–renal 1. Wegener‟s granulomatosis(WG) syndrome is small-vessel vasculitis which is 2. Microscopic polyangiitis characterized by a destructive and 3. Churg–Strauss syndrome(CSS) inflammatory process that involves 4. Other vasculitis arterioles, venules and alveolar capillaries C) Pulmonary–renal syndrome in which. [8] These vasculitis have a ANCA-negative systemic vasculitis heterogeneous pathogenesis and there are 1. Henoch–Schönlein three different pathophysiological 2. Mixed cryoglobulinaemia mechanisms of injury. [9] 3. Behçet‟s disease 1. mediated by anti--cytoplasmic 4. IgA nephropathy antibodies (ANCA), D) ANCA-positive pulmonary–renal 2. immune-complex mediated vasculitis of syndrome without systemic small vessels or vasculitis: Idiopathic pulmonary– 3. by antibodies against the glomerular renal syndrome basement membrane (Goodpasture Pauci-immune necrotizing syndrome). glomerulonephritis and pulmonary In the kidney, a rapidly progressive capillaritis glomerulonephritis (RPGN) is caused by E) Pulmonary–renal syndrome in drug- damage of the capillaries and basal associated ANCA-positive vasculitis membranes with leakage of erythrocytes, 1. Propylthiouracil which is followed by an influx of 2. D-Penicillamine macrophages, fibrinogen and the formation 3. Hydralazine of crescents.In the lungs, a diffuse alveolar 4. Allopurinol hemorrhage is caused by a pulmonary 5. Sulfasalazine capillaritis. [10] F) Pulmonary–renal syndrome in anti- In the case of ANCA-associated systemic GBM-postive and ANCA-positive vasculitis the ANCA is detected in about patients 80% of patients. Besides the correlation of G) Pulmonary–renal syndrome in ANCA titers with disease activity there is autoimmune rheumatic diseases evidence of a pathogenetic role of ANCA. (immune complexes and/or ANCA The ANCA is formed against two proteis mediated) named myeloperoxidase (MPO) and 1. Systemic lupus erythematosus proteinase 3 (Pr3) and these are detected in 2. Scleroderma (ANCA?) the cytoplasm of non-stimulated 3. Polymyositis . Finally cell necrosis and 4. apoptosis contribute to vascular 5. Mixed collagen vascular disease process.In Pauci-immune H) Pulmonary–renal syndrome in glomerulonephritis there is absence of thrombotic microangiopathy immune-complex deposition, 1. Antiphospholipid syndrome immunoglobulins or complement within the 2. Thrombotic thrombocytopenic biopsy sample. [11] purpura Classification of PRS according to the 3. Infections pathogenetic mechanism involved 4. Neoplasms (Etiopathological classification) [12]

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I) Diffuse alveolar haemorrhage (RPGN) and it is associated with anti-GBM complicating idiopathic pauci- antibodies. It is rare, however this syndrome immune glomerulonephritis is responsible for about 20% of acute renal failure due to consequences of RPGN. The Epidemiologic Aspects [13-16] disease is hereditary in nature as it has been Goodpasture‟s syndrome is not common described in brothers and in identical twins. and has an incidence of approximately 0.5 More than 80% of patients carry the HLA to 1 case per million people per year. alleles DR15 or DR4 whereas the alleles Gender distribution is equal in both sexes DR7 and DR1 are rarely found. and there is no gender predisposition. Environmental factors, such as smoking, Goodpasture‟s syndrome has a bimodal age infections and previous hydrocarbon distribution, with a large number of patients exposure, have been implicated in triggering presenting at ages 20 to 30 and at ages 50 to the disease. In GPS, the target antigen is the 68. Whites are more frequently affected non-collagenous (NC1) domain of the α3 than blacks. Antineutrophil cytoplasmic (IV) collagen chain, it is of one of the six –associated vasculitis (ANCA) chains (alpha-1 to alpha-6 [α1 to α6]) which is the most common primary systemic small are entitled in making type IV collagen. vessel vasculitis to occur in adults. This target antigen is primarily found on the Although the etiology is sometimes inert aspect of the lamina densa, which is unknown, the incidence of vasculitis is the middle layer of the glomerular and increasing, and the diagnosis and alveolar basement membranes. Anti-GBM management of patients is challenging antibodies bind the glomerular basement because it is relatively infrequent, and has membrane, activating compliment and variable clinical expression. In patients proteases, resulting in the disruption of the presenting with PRS secondary to systemic filtration barrier and Bowman‟s capsule and vasculitis, pulmonary hemorrhage appears causing and crescent formation. in 40% of WG cases and 30% of (ii)Pulmonary–renal syndrome in ANCA- microscopic polyangitis (MPA) cases, and it positive systemic vasculitis [23-27] rises when renal involvement is severe. Circulating ANCA autoantibodies are Pulmonary hemorrhage in these disorders detected in the majority of patients carries a mortality rate of 10%. Diffuse presenting with PRS. ANCA is not alveolar hemorrhage in systemic lupus confirmatory for specific type but it leads to erythematosus (SLE) remains a devastating to three major pulmonary complication; mortality rates are systemic vasculitides syndromes which are around 45- 50%, and it occurs in less than associated with ANCA, includes: 2% of patients with SLE. Evidence for Wegener‟s granulomatosis, microscopic glomerular involvement is also present in polyangiitis and Churg–Strauss syndrome. large number of patients. Single-center The suspicion of a pulmonary-renal experience suggests that 60% to 70% of syndrome in an ANCA-associated systemic cases with PRS are associated with ANCAs, vasculitis can often be taken from a careful and 20% are associated with anti-GBM history and thorough clinical examination antibodies. [17,18] with detection of other vasculitic signs like Pathophysiology of PRS with respect to eye inflammation, intractable / each pathological type , skin rashes, arthralgia, myalgia or (i) PRS associated with anti-GBM polyneuropathy. antibodies: Goodpasture’s syndrome [19- Wegener‟s disease or Wegener‟s 22] granulomatosis (WG) is characterized by The term „Goodpasture‟s syndrome‟(GPS) the triad of systemic necrotizing vasculitis, includes diffuse alveolae hemorrhage and necrotizing granulomatous inflammation of rapidly progressive glomerulonephritis the upper and lower , and

International Journal of Health Sciences & Research (www.ijhsr.org) 296 Vol.7; Issue: 2; February 2017 N.S. Neki et. al. Pulmonary renal syndrome: update article necrotizing glomerulonephritis. The disease included in the etiology of PRS are D- usually involves Caucasians (80–97%) with Penicillamine, allopurinol and sulfasalazine. a mean age at the time of diagnosis of 40– If the causative drug is discontinued, it 55 years, although persons of every age may causes regression of the disease; however, be affected. The lungs are involved in 90% some patients continue to present positive of cases. In a small percentage of patients, a ANCA or even recurrent disease and may limited form of the disease that spares the require long-term immunosuppressive kidney. In active disease in about 90% of treatment. In general, drug-induced disease cases c-ANCA are directed against has a more benign course than ANCA proteinase 3. positive pulmonary–renal syndrome of other Microscopic polyangiitis (MPA) is a aetiology. systemic small-vessel vasculitis manifested (iv) Pulmonary–renal syndrome in by pauci-immune necrotic autoimmune rheumatic diseases [30-33] glomerulonephritis (80–100% of patients), These may be immune complexes mediated pulmonary capillaritis (10–30%), skin and/or ANCA mediated. These include lesions and arthralgias. Microscopic systemic lupus erythematosus, scleroderma, polyangiitis is characterized by a polymyositis rheumatoid arthritis and mixed necrotizing vasculitis of small vessels with collagen vascular disease. Pulmonary–renal minimal or missing immune deposits and an syndrome has been reported more inflammation of the pulmonary capillaries. commonly in systemic lupus erythematosus Typically, there is p-ANCA directed against and systemic sclerosis, and rarely in myeloperoxidase. rheumatoid arthritis and mixed connective The Churg-Strauss syndrome (CSS) tissue disease. Pulmonary hemorrhage is a is characterized by recurrent attacks rare complication of SLE (2%), and is and allergic rhinitis, and a detectable associated with high mortality rates (60%). (> 1500/mm3) and necrotizing Acute alveolar hemorrhage in SLE usually and / or necrotizing arteritis occurs as a PRS. In most cases, the lung with a Wegner's granulomatosis-like showed “bland” alveolar hemorrhage with presentation. c-ANCA or anti-PR3-Ab little or no inflammation. Alveolar detected rarely while p-ANCA and anti- hemorrhage in SLE is characterized by MPO-Ab can be detected in up to 62% of bland alveolar wall changes and seems to be cases. The Churg-Strauss syndrome can be similar pathogenically to the lupus distinguished clinically from Wegener`s microangiopathy of the kidney. Pulmonary– granulomatosis or Microscopic polyangiits renal syndrome is a rare but lethal by asthma attacks and eosinophilia. In complication of systemic sclerosis, and Churg–Strauss syndrome, renal involvement pulmonary fibrotic disease often coexists is milder compared with Wegener‟s disease, with it. ANCA, more commonly the Goodpasture‟s syndrome and microscopic perinuclear ANCA or MPO ANCA, have polyangitis. been detected in some systemic sclerosis (iii) Pulmonary–renal syndrome in drug- patients. Systemic sclerosis-PRS has a poor associated ANCA-positive vasculitis [28,29] prognostic indication; that is, all patients Drugs are one of the reversible causes of died within 12 months of admission. ANCA-positive vasculitis. The drugs most (v) PRS in thrombotic microangiopathy frequently implicated in the pathogenesis of [34,35] the syndrome are propylthiouracil and Pulmonary–renal syndrome may occur in hydralazine. ANCA are detected in 22% of conditions like antiphospholipid syndrome patients receiving propylthiouracil, but very (APS), thrombotic thrombocytopenic patients develop clinical manifestations of purpura, malignancies and infections. systemic vasculitis including pulmonary– renal syndrome. Other drugs which are

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Patient evaluation and clinical features renal impairment is not a feature of this [36-42] disorder.(Fig1) These disorders exhibit considerable heterogeneity in clinical presentation both in severity and prognosis. Early recognition needs a high index of clinical suspicion combined with a full assessment of the clinical picture, available serology, radiology and histology, and exclusion of alternative diagnoses. Frequent presentation of PRS includes patient presenting with breathlessness and with pulmonary infiltrates seen on a chest radiograph. Many patients deteriorate rapidly and present with Fig. 1: X-ray image showing diffuse alveolar hemorrhages. life threatening respiratory and/or renal failure. Similarities exist with presentation Blood test abnormalities may include a of or severe cardiac failure with normochromic, normocytic anaemia with pulmonary oedema. Clinically apparent features of acute kidney injury in the form haemoptysis secondary to diffuse alveolar of raised blood urea and serum creatinine haemorrhage (DAH) occurs in about 55% of levels. Underlying thrombotic thrombocyto- cases. In one-third of cases of DAH penic purpura (TTP) is suggested by however, haemoptysis does not manifest evidence of haemolysis with fragmented red clinically. Haemoptysis is usually of small blood cells on peripheral blood film. Serum volume (<200 ml/24 h) and may be antibody detection of anti-GBM, ANA accompanied by a low grade fever, and/or ANCA is key to diagnostic work-up breathlessness and cough. if a PRS is suspected. However the level of Acute kidney injury may be apparent ANCA titre is not considered part of the from blood levels of blood urea and serum diagnostic criteria in systemic vasculitis. creatinine which carries greater diagnostic Whilst the presence of a positive significance in the presence of an active cytoplasmic ANCA (cANCA) (directed urinary sediment. In urine complete against PR3 antigen) correlates with analysis, proteinuria is more common than underlying Wegener‟s granulomatosus haematuria but when both are present, this is (present in 90% of cases), perinuclear indicative of glomerular membrane damage ANCA (pANCA) (directed against MPO) due to glomerulonephritis. Proteinuria is may be helpful in clinicopathological usually below the nephrotic range. Urine classification (Table 1). Anti-GBM microscopy may show red cell casts or antibodies detected using different dysmorphic red cells. immunoassays including immunoperoxidase Plain chest radiography or computed labelling have a sensitivity of 95 to100% tomography of the chest may reveal a with a specificity of 90e100% for distribution of infiltrates from perihilar Goodpasture‟s disease. Only 35 to70% of shadow extending towards the lower zones patients with CSS has a positive cANCA to frank consolidation mimicking an ARDS with 10% being positive for PR3. In fact appearance. In 25% of cases, chest CSS is more often ANCA negative than radiography may be normal. A rare but positive, and where positive, usually it is important cause of DAH which should be associated with c-ANCA or p-ANCA. ruled out is idiopathic pulmonary Flexible bronchoscopy is generally haemosiderosis which may result in used in the exclusion of infection and prolonged diffuse alveolar hemorrhages but confirmation of diffuse alveolar hemorrhages. Classically serial bronchial

International Journal of Health Sciences & Research (www.ijhsr.org) 298 Vol.7; Issue: 2; February 2017 N.S. Neki et. al. Pulmonary renal syndrome: update article washings show blood stained lavage fluid haemosiderin-laden macrophages. and cytology of the washings may show

Disease Proteinase-3- Myeloperoxidase ANCA Anti-GBM- (MPO-)-Antibody negative Ab Wegener`s 70 % 20 % 10 % <10% Granulomatosis Microscopic 30 % 60 % 10 % <10% Polyangiitis Churg-Strauss- 10 % 60 % 30 % <10% Syndrome Goodpasture <10% <30% 70% 95% Syndrome Table 1. Showing serology and sensitivity of different form of ANCA positive vasculitis and .

The diagnosis of RPGN is done by renal cmH2O with permissive hypercapnia may biopsy: in light microscopy there is a reduce lung injury to these patients. glomerulonephritis with crescent formation Drug Therapy in the Bowman's capsule (extracapillary (A) ANCA associated PRS: [43-46] proliferation) in more than 50% of the (a) Induction of remission glomeruli. In immunohistology, the type of The introduction of in immunoglobulins and the deposition pattern conjunction with steroids in the differ viz. capillary, mesangial, glomerular management 5-year mortality was lowered or linear along the glomerular basement from 50% with treatment membrane. Only in Goodpasture syndrome, alone to 12% with combination therapy. linear deposits are found along the Induction of remission is most commonly glomerular basement membrane. In case of achieved with high dose intravenous an ANCA triggered form, immune deposits methylprednisolone (0.5 ge1 g/day) for 3 to are missing (pauci-immune RPGN). In 5 days for which there is no substantial contrast, in immune-complex vaculitis, there evidence base. This is coupled with pulsed can be found a different picture, usually intravenous cyclophosphamide administered with granular deposition of IgG, IgM, IgA every 2 to3 weeks (15 mg/kg/pulse) on 6 to or complement. 9 occasions or as a daily oral regime (1 to 2 Specific management of PRS mg/kg/day).With this treatment, about 85% Patients with vasculitis frequently of patients achieve remission. Transition to die of sepsis. The risk of hospital aquired maintenance therapy may occur 6–12 infection in these patients is very high due months after the initiation of induction to immune-suppression. therapy or after clinical remission. Respiratory and airway management (b) Maintenance of remission In Wegener‟s granulomatosus there may be The most effective method of maintenance subglottic stenosis therefore intubation may of remission is also the subject of ongoing be difficult and require smaller endotracheal trials and there is considerable inter- tube inexperienced hands. In acute lung practitioner variability over both choice of injury due to diffuse alveolar haemorrhage immunosuppression and duration of large tidal volumes or pressure changes may treatment are continued at exacerbate damage to pulmonary low dose for a minimum of 18 months along microvasculature. Lung protective with a cytotoxic agent. Relapse will occur in ventilation, as used in the management of 11–57% of patients in remission. Some ARDS, with tidal volumes of 6 ml/kg and relapses are severe, resulting in end-organ inspiratory plateau pressures below 30 damage. Female or black patients and those patients with severe kidney disease, lung

International Journal of Health Sciences & Research (www.ijhsr.org) 299 Vol.7; Issue: 2; February 2017 N.S. Neki et. al. Pulmonary renal syndrome: update article disease or upper airway disease and anti- mortality exceeded 90% before the Pr3serum antibodies are shown to be more application of . But if resistant to initial treatment. In these cases, plasmapheresis is initiated early the the use of alternative agents must be response to treatment is 80%. If considered. Recent investigation suggested plasmapheresis treatment is delayed plasma TNF-α inhibitors, B-cell depletion agents, transfusion for von Willebrand factor mycophenolate mofetil(MMF), leflunomide cleavage protein are indicated. and antithymocyte globulin for treatment. Despite rigorous treatment, almost New agents are shown to be effective in 66% of patients with small-vessel vasculitis certain cases but are followed by high and pulmonary–renal syndrome will need relapse and complication rates. renal transplantation within less than 4 years (B) Goodpasture’s syndrome [47] of initial presentation. Immunosuppressive treatment should also be urgently initiated. Daily plasma exchange CONCLUSION should be started. Plasmapheresis should be Clinical suspicion is key to diagnosis discontinued if tests for anti-GBM as the symptom complex of PRS is often antibodies are found negative. A mean of 14 non-specific. The disorder has a wide range courses of treatment is usually needed until of severity of presentation from the general the anti-GBM antibody titre is normalized. outpatient clinic to the ICU setting. Prompt and aggressive plasmapheresis for Pulmonary renal syndrome in the ICU is a ANCA-positive anti-GBM-positive patients life-threatening entity with an acute onset may be needed for renal recovery and with a fulminant course if left untreated. (C) Systemic lupus erythematosus [48-50] Appropriate management of such patients Pulmonary haemorrhage in the case of lupus includes early and accurate diagnosis, nephritis carries a poor prognosis. Urgent exclusion of infection, close monitoring and immunosuppression should be given with specialized immunosuppressive treatment high dose methylprednisolone and along with plasma exchange in certain cyclophosphamide. New therapies such as cases. Relapses are quite common in treated and MMF are in trial stages patients. Newer immunomodulatory agents which bring about successful remission could confer life-saving options for in80% of cases. Relapse rates are high refractory disease in the future. Renal however despite the improved toxicity transplantation remains the only alternative profile. To avoid the severe side effects of for patients with pulmonary–renal syndrome the treatment of systemic lupus who develop end-stage renal disease. erythematosus, including bone marrow suppression, haemorrhagic cystitis, Source of funding- nil opportunistic infections, malignant diseases Conflict of interest- none declared and prematuregonadal failure, new agents such as mycophenolate mofetil and REFERENCES rituximab are under investigation. 1. Gallagher H, Kwan J, Jayne RW: Pulmonary renal syndrome: a 4-year, (D) Acute catastrophic antiphospholipid [51] single center experience. Am J Kidney syndrome Dis. 2002; 39:42-47. In pulmonary–renal syndrome related to 2. Stanton MC, Tange JD: Goodpasture‟s acute catastrophic antiphospholipid syndrome (pulmonary haemorrhage antibody syndrome (APS), the mainstay of associated with glomerulonephritis). therapy is anticoagulation. Australas Ann Med 1958; 7:132-44. (E) Thrombotic thrombocytopenic 3. Lerner RA, Glassock KJ, Dixon FJ: The purpura [52] role of antiglomerular basement In cases of pulmonary–renal syndrome and membrane antibody in the pathogenesis thrombotic thrombocytopenic purpura,

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How to cite this article: Neki NS, Aloona S. Pulmonary renal syndrome: update article. Int J Health Sci Res. 2017; 7(2):294-303.

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