By Arnaldo Lopez Ruiz, MD, and Alexander Niven, MD

Dr. Lopez Ruiz is Attending Physician, Division of Critical Care, AdventHealth Medical Group, AdventHealth Orlando, FL. Dr. Niven is Senior Associate Consultant, Division of Pulmonary/Critical Care Medicine, Mayo Clinic, Rochester, MN.

Dr. Lopez Ruiz and Dr. Niven report no financial relationships relevant to this field of study.

Pulmonary-renal syndrome (PRS) is a life-threatening condition that is characterized by acute kidney injury (AKI) caused by rapidly progressive glomerulonephritis (GN) and lung involvement, which often includes diffuse alveolar hemorrhage (DAH).1 PRS typically is the result of immune-mediated disease secondary to anti-glomerular basement membrane (anti-GBM) antibodies, anti-neutrophil cytoplasmic antibodies (ANCA), immune complexes (IC), and thrombotic microangiopathy (TMA).2

The three major ANCA-associated vasculitis (AAV) syndromes of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis polyangiitis (EGPA) account for 60% to 70% of PRS cases.3 Goodpasture’s syndrome is associated with DAH and rapidly progressive GN in the presence of anti-GBM antibodies. This condition is responsible for less than 20% of PRS cases.1 Systemic lupus erythematosus (SLE) is responsible for the majority (80%) of the 10% to 15% of PRS cases that are caused by IC disease. Clinical presentation is characterized by diffuse (Class IV) lupus GN associated with rapidly progressive DAH, often with severe hypoxemia.4 Other less frequent cases of PRS mediated by IC have been described in the context of systemic sclerosis (scleroderma), cryoglobulinemia, rheumatoid arthritis, polymyositis, dermatomyositis, and mixed connective tissue disease.4 Rare cases of PRS have been described in patients with immunoglobulin A (IgA) nephropathy, IgA vasculitis (Henoch-Schonlein purpura), acute endocarditis, or post-infectious GN.5 Despite its strong association with systemic thrombotic events, TMA secondary to catastrophic antiphospholipid syndrome (APS) and thrombotic thrombocytopenic purpura (TTP), often triggered by infections or malignancies, can induce PRS and is associated with a poor prognosis as the result of frequent brain, gastrointestinal, and heart involvement by TMA.

Certain medications (e.g., hydralazine, minocycline, allopurinol, propylthiouracil) have been associated with potentially reversible drug-associated AAV and PRS.6 Antinuclear antibodies (ANA) may be present, and hydralazine and minocycline both are associated with a lupus-like phenotype. Cases of PRS also have been reported during therapy with anti-tumor necrosis factor alpha (anti-TNF-α), with the development of monoclonal antibody-induced ANCA (e.g., adalimumab, etanercept, infliximab).6 Drug-induced AAV is more common in young women, presents with skin involvement, and while clinically similar to MPA, typically is less severe with a better prognosis.7 Cocaine adulterated with the anti-helminthic agent levamisole is a common cause of drug-induced AAV in the United States that can progress to PRS. It generally is associated with neutropenia, accompanied by skin, heart, and gastrointestinal involvement.8

AAV syndromes have a two-fold higher incidence in Caucasians, with a 1:1 male to female ratio, and a typical age of onset of 40-65 years. MPA is found most commonly in Asia, and GPA has a lower incidence in the Hispanic population. Goodpasture’s syndrome is extremely rare and predominantly affects young or middle-age Caucasians, with a slight male predominance. Environmental factors, such as smoking, infections, lithotripsy, and previous hydrocarbon exposure, have been implicated as triggers for this disease.7 PRS resulting from SLE and systemic sclerosis is observed more frequently in middle-age women (3:1 female to male ratio), with underlying lupus nephritis and pulmonary fibrosis, respectively.7,9 The course and severity of PRS related to SLE in the African American population have been associated with progression to end-stage renal disease (ESRD) and 60% to 70% mortality.10

CLINICAL PRESENTATION

Patients with PRS often present with evidence of severe AKI and respiratory symptoms, with rapid progression to hypoxemic respiratory failure prompting intensive care unit (ICU) admission. For many of these critically ill patients, the presentations represent an exacerbation of previously known disease, usually triggered by coexisting infection or inadequate immunosuppression.1,3 A considerable proportion of patients with PRS in the context of SLE have a concomitant viral or bacterial lung infection,9 and it has been reported that 34% to 40% of patients with GPA and pneumonia are infected with Staphylococcus aureus.11 However, up to 42% of AAV are new diagnoses. Clinical features of systemic inflammation, such as weight loss, fatigue, malaise, arthralgia, and myalgia, are common, and cannot effectively differentiate between AAV and IC disease.3

GPA commonly involves the sinuses, upper and lower respiratory tracts, and kidneys. Common associated complaints include a history of recurrent sinusitis, epistaxis, and otitis media. Nasal septal ulceration can lead to collapse of the nasal bridge, and subglottic and central airway inflammation can present as intubation difficulties. Lung involvement often results in progressive dyspnea, recurrent hemoptysis, or life-threatening pulmonary hemorrhage.7 Pulmonary hemorrhage is more common in GPA than in MPA and EGPA (42%, 29%, and 3%, respectively) and is associated with a worse prognosis.12

As a small vessel vasculitis, MPA shares many similar features to GPA. Although sinus involvement is less common in MPA, both conditions are associated with skin findings of leukocytoclastic angiitis, rapidly progressive GN, bowel ischemia and hemorrhage, myocardial ischemia, and mononeuritis multiplex. Differentiation often requires biopsy of an involved organ, with granulomatous inflammation in addition to small vessel vasculitis typical for GPA.13

EGPA often presents with peripheral eosinophilia, pulmonary infiltrates, and end organ dysfunction as a result of either eosinophilic infiltration or vasculitis after years of an atopic and asthma prodrome. The presence of diastolic cardiomyopathy due to eosinophilic infiltration contributes to high mortality in EGPA.7

Previous or concurrent evidence of thrombotic events involving the arterial and venous system, the presence of advanced hematologic malignancies, or persistent bacteremia favors the diagnosis of TMA induced by APS or TTP.1,14

DIAGNOSIS

DAH is defined by diffuse pulmonary opacities with varying degrees of respiratory failure, a decreasing hemoglobin level, and progressively bloody return (or with increasing red blood cell counts) on sequential bronchoalveolar lavage (BAL) aliquots. Alveolar hemorrhage is difficult to distinguish from pneumonia, especially in the roughly 30% of patients with DAH without hemoptysis.15 Hemosiderin-containing macrophages, erythrophagocytosis, and collections of free interstitial hemosiderin also can aid in distinguishing DAH from acute bleeding related to biopsy.15,16

Rapidly progressive GN presents with rapidly declining renal function, progressive oliguria, and an active urine sediment, with hematuria (including dysmorphic red cells), red cell casts, and nephritic range proteinuria (> 0.5 to 2 g/d). Urine microscopy should be performed on a fresh urine sample because red cell casts, indicators of heavy glomerular bleeding and glomerular necrosis, and dysmorphic red cells degenerate within 30 to 60 minutes. Renal ultrasound often will show normal to slightly enlarged kidneys with increased echogenicity.1,17

Serologic testing is important to both diagnose and categorize the underlying etiology of PRS. A cytoplasmic pattern of staining (cANCA) on immunofluorescence is associated most commonly with anti-PR3 antibodies by ELISA, whereas perinuclear staining (pANCA) is associated more commonly with the presence of anti-myeloperoxidase (MPO) antibodies.16 GPA is associated with a frequency of PR3-ANCA of 65% to 75%, and MPA has an association with MPO-ANCA of 55% to 65%, although both ANCA patterns have been associated with each disease.7 Eosinophilia (typically > 10%) is a classic finding in EGPA, and MPO-ANCA when present (30% to 40% of cases) is strongly related to GN.7 ELISA assays for anti-GBM antibodies are highly sensitive and specific for anti-GBM disease. Up to 30% of patients with anti-GBM disease have a concurrent positive MPO-ANCA, which is associated with a higher mortality rate than those with ANCA alone.18 Additional relevant serologic testing may include ANA, anti-dsDNA, cryoglobulins, complement levels, hepatitis serology, rheumatoid factor, anticyclic citrullinated peptide (anti-CCP), antiphospholipid antibodies, and serum protein immunoelectrophoresis.17

Given the frequency of a concurrent infectious process in this population that often is immunocompromised, blood cultures and BAL with cell count, Gram stain, serology, cultures for bacteria and fungus, and rapid polymerase chain reaction (PCR) assays for respiratory viruses and atypical bacteria are recommended.1,17

In critically ill patients, urgent kidney biopsy is preferred and indicated in the presence of AKI and an active urinary sediment, with or without evidence of pulmonary hemorrhage. (See Figure 1: https://bit.ly/3ppz2Th) Open lung biopsy has a greater diagnostic yield than transbronchial biopsy when the result of the kidney biopsy is inconsistent with the clinical and/or serologic profile, but it has a higher rate of complications.16,17

TREATMENT

The role of the intensivist in the management of PRS includes appropriate respiratory support and recognition and management of concurrent infection, hypovolemia, acute anemia, and coagulopathy. Co-management with consultants includes management of renal dysfunction and renal replacement therapy, and prompt initiation of immunosuppressive therapy when indicated.1,17 The goal of induction therapy is to achieve sustained remission by three months. Later remission, early relapse, or refractory renal dysfunction requiring RRT is associated with worse outcomes.16

The use of lung protective strategies is recommended in patients presenting with PRS and acute respiratory distress syndrome (ARDS) who require mechanical ventilation.19 Cases with mild to moderate hypoxemia (PaO2/FIO2 ratio > 150) and pulmonary infiltrates (< 50% of lung fields) without significant hemoptysis may be managed with high flow oxygen.20 The role of noninvasive ventilation in PRS has not been evaluated systematically.

Empiric antibiotic coverage targeting gram-positive and gram-negative bacteria is common until diagnostic studies return, and antifungal coverage with an echinocandin should be considered in patients with risk factors.1,11,17 There is no indication that early initiation of RRT is beneficial in patients with GN and progressive AKI,21 and it is well-recognized that patients who require RRT have low rates of renal recovery.22 Acute blood loss anemia and coagulopathy are immune-mediated and often improve with immusuppression.1,17

Anti-GBM disease carries the greatest morbidity and mortality and, therefore, is treated very aggressively. Current treatment recommendations include high-dose glucocorticoids, cyclophosphamide, and plasma exchange (PLEX).23,24 Case reports suggest that rituximab may be useful in refractory cases of anti-GBM disease.25 The largest and best-documented experience in anti-GBM disease used high-dose prednisolone (1 mg/kg/day) tapered over six months, oral cyclophosphamide (2 mg/kg/day) for two to three months, and daily PLEX (60 mL/kg with albumin or fresh frozen plasma if bleeding is a risk) for 14 days or until anti-GBM antibody was no longer detectable.24,26 In a small randomized trial, the addition of PLEX to prednisolone and cyclophosphamide increased the proportion of patients with preserved renal function by 42%.27 The degree of crescent formation and interstitial injury on renal biopsy provides important prognostic information on the likelihood of renal recovery.27 Therefore, kidney biopsy is essential to guide immunosuppressive management in anti-GBM disease.23,24

In those patients with AAV and SLE presenting with PRS, pulse dose methylprednisolone (500 mg to 1,000 mg daily) for three days, followed by prednisone 1 mg/kg/day in combination with rituximab (375 mg/m2/week × four doses) has been shown to be noninferior to corticosteroids plus oral cyclophosphamide (2 mg/kg/day) and azathioprine (2 mg/kg/day to 3 mg/kg/day) [CYC-AZA] for two to three months.28,29 An important determinant of therapy selection is treatment toxicity. Cyclophosphamide toxicity may include leukopenia, hemorrhagic cystitis, bladder cancer, infertility, and opportunistic infections, limiting its utility in younger and relapsed patients. Patients receiving cyclophosphamide should ensure adequate hydration and be prescribed mercaptoethane sulfonate (recommended if cyclophosphamide dose is > 1 g) and trimethoprim-sulfamethoxazole to prevent hemorrhagic cystitis and Pneumocystis jiroveci pneumonia, respectively. Strategies that reduce cyclophosphamide exposure include intravenous administration, the use of alternative induction agents (such as rituximab), and early conversion to maintenance immunosuppression.30 Pulse intravenous cyclophosphamide has efficacy equivalent to daily oral therapy in terms of survival and remission induction. However, pulse therapy results in an approximately 50% lower cumulative dose of cyclophosphamide.31 Side effects of rituximab include infusion reactions, anaphylaxis, opportunistic infections such as reactivation of tuberculosis, and progressive multifocal leukoencephalopathy.30

Most authors recommend the use of PLEX (60 mL/kg) in patients with PRS secondary to AAV, SLE, TTP, and APS, or in those patients with PRS and presenting with severe AKI requiring RRT.1,2,17,32,33,34 The PEXIVAS trial randomized a large number of patients with AAV complicated with rapidly progressing GN or pulmonary hemorrhage to induction treatment with or without PLEX and high-dose vs. low-dose corticosteroids. The trial found that low-dose corticosteroids were not inferior and associated with less side effects, and also failed to show an improvement in renal outcomes with PLEX.35 Based on these results, PLEX should not be used in most patients with renal involvement. However, it is important to note that no GN patients in this study received a renal biopsy and only 9% had pulmonary hemorrhage. A subset of patients with severe, rapidly progressing GN and minimal chronic parenchymal damage still may derive benefit from PLEX, especially those with markedly elevated ANCA titers who are approaching or require RRT.36 PLEX also should be considered in patients with DAH given the trend toward benefit in this subgroup. Finally, patients who are double-seropositive for both ANCA and anti-GBM antibodies also should receive PLEX.37

Despite high rates of complete remission in the first 18 months of therapy, relapse remains common and affects 30% to 50% of patients treated with a cyclophosphamide-based regimen and 32% of patients receiving rituximab-based induction.29,30,38 The relapse risk predictably is increased in the presence of high ANCA titers and following reconstitution of the B cell population after rituximab therapy.39,40

CONCLUSION

AAV, anti-GBM disease, and IC-mediated disease are the three main causes of immune-mediated PRS. ICU physicians play a critical role in the early recognition and management of these patients, who have poor long-term renal outcomes and a significant mortality risk in untreated cases. The evaluation of PRS requires a comprehensive clinical assessment, urinalysis and microscopy, appropriate serologic tests, and histopathology via urgent kidney biopsy. Initial induction therapy should include corticosteroids plus rituximab or a combination of CYC-AZA-corticosteroids. Although recent data have not demonstrated a clear benefit of PLEX on renal outcomes, patients presenting with histologic evidence of rapidly progressing GN, severe pulmonary hemorrhage, or high titers of ANCA and/or anti-GBM antibodies still should be considered for this treatment.

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