Goodpastures (Anti-GBM disease)

Goodpasture’s disease (anti-GBM disease)

I. What every physician needs to know.

Anti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune disease in which anti-GBM antibodies are directed against the NC1 domain of the alpha -3 chain of type IV collagen of glomerular and alveolar basement membranes and clinically may result in rapidly progressing glomerulonephritis and pulmonary hemorrhage.

The eponyms Goodpasture’s disease and Goodpasture’s syndrome hail from Dr. Ernest Goodpasture, an American pathologist. Goodpasture detailed autopsy findings in a case report of an 18 year old hospital-corps man who succumbed to pulmonary hemorrhage and glomerulonephritis during the 1919 influenza pandemic. The patient’s renal biopsy revealed “glomerular nephropathy with a fibrinous exudate in Bowman’s capsule and cellular proliferation of glomerular tufts,” and “some urinary tubules are filled with erythrocytes.” Though he recognized influenza as a factor in the pathogenesis, it would take decades before these findings were recognized as one of the earliest described autoimmune diseases.

The term Goodpasture’s disease is used when anti-GBM antibodies are identified as the etiology of the nephritis and/or pulmonary hemorrhage. Goodpasture’s syndrome classically describes the pulmonary-renal syndrome, sometimes without reference to the anti-GBM antibodies. These three terms are often employed interchangeably in medical literature. Based on current understanding of the pathophysiology, anti-GBM disease is more precise nomenclature and will be used primarily. The 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides groups anti-GBM disease in the category of small-vessel vasculitis.

Antibodies recognize the alpha-3 chain of Type IV collagen in 85% of patients exclusively, but the antibodies recognize alpha-5(IV) and alpha-4(IV) monomers to lesser degrees. It has been shown that natural anti-GBM autoantibodies exist in normal human sera, though at lower levels and with less avidity for the alpha-3 (IV) chain and with different IgG subtypes.

Though basement membranes are ubiquitous, only alveolar and renal basement membranes are affected, possibly due to greater accessibility of the epitopes. Environmental factors have been implicated in this process. Initial insults such as smoking, infections, cocaine, hydrocarbons may allow for antibodies to access the basement membrane in pulmonary and renal tissues.

Genetic predisposition is also recognized in Goodpasture disease, with an increased prevalence of HLA-DR15, DRB1*04 alleles, and decrease frequency of DRB*01 and DRB*07 alleles.

Fibrinoid necrosis, microthrombi and crescentic glomerulonephritis are characteristic histologic findings in patients with anti-GBM disease affecting the kidneys. Underlying these findings is the classic type II reaction in the Gell and Coombs classification, resulting from complement activation and recruitment of polymorphonuclear cells and monocytes to these tissues.

Glomerular destruction results in hematuria and proteinuria, although typically less than nephrotic in range. In the pulmonary vasculature, destruction manifests as incompetence of pulmonary capillaries, extravasation of blood into the alveolar space that clinically manifests as diffuse alveolar hemorrhage.

Immunofluorescent microscopy reveals linear deposition of the immunoglobulin binding along the basement membranes. IgG predominates, primarily the IgG1 and IgG4 subtypes, which function by fixing complement and binding macrophages. Less frequently, IgA and IgM antibodies are pathogenic (Figure 1).

Figure 1.

The presence of anti-GBM antibodies appear to correlate more closely with renal dysfunction rather than pulmonary hemorrhage. This was suggested by data from a retrospective study of patients with high titers of anti-GBM antibodies, collected between 1987 and 1996. Of the 77 patients studied, 27 patients died, 31 patients were on chronic dialysis and 19 were living with native kidneys at six months. Antibody titers correlated with progression to end stage renal disease, whereas a similar correlation was not observed with pulmonary hemorrhage.

Case reports of anti-GBM disease with other autoimmune diseases, including multiple sclerosis, thrombotic thrombocytopenic purpura, and dermatomyositis, among others, have also been published. Anti-GBM disease has also been reported in approximately 5% of post renal transplant patients with Alport syndrome, and in those with membranous nephropathy and systemic vasculitis.

A recent population analysis of anti-GBM cases in Ireland over an 11 year period to ascertain the national incidence of disease identified a clustering pattern over time and space. Ten of 79 patients were diagnosed in a 3-month period and 6 patients localized to four counties, further supporting a theory on environmental trigger for disease to manifest.

II. Diagnostic Confirmation: Are you sure your patient has Goodpasture’s disease?

Anti-GBM disease must be distinguished from other rapidly progressive glomerulonephritic disease and other causes of hemoptysis and alveolar hemorrhage. The sine qua non is the presence of circulating anti-GBM antibodies in conjunction with the clinical presentation. Patients may present with either a dominant pulmonary or renal constellation of findings. Consequently, early clinical manifestations vary considerably.

Enzyme-linked immunosorbent assays (ELISA) are commercially available and have 95% sensitivity in detecting anti-GBM antibodies. Specificity varies more broadly by assay, on the order of 91-100%. Western blot may offer confirmation through serologic testing.

In spite of the sensitivity and specificity of ELISA and Western blot assays, many experts argue that renal biopsy should be pursued in all cases unless contraindicated, to evaluate the extent of renal injury, and to guide therapy and prognosis. The recommendation is that diagnosis should be confirmed by immunofluorescence of renal tissue, or less frequently, lung. This technique reveals the classic linear deposits of immunoglobulin on the basement membrane, shown in Figure 1.

Patients with massive hemoptysis requiring ICU level care may be too ill to undergo invasive procedures during immediate presentation. In this scenario, renal biopsy may be reserved for cases of diagnostic uncertainty.

Indirect immunofluorescence lacks sensitivity and is rarely useful in making the diagnosis.

Novel chemiluminescence assays and dot-blot assays for both Anti-Neutrophil Cytoplasmic Autoantibody (ANCA) and anti-GBM show high sensitivity and specificity, though they are not routinely available.

ANCA positivity does not exclude the disease and its role in the pathogenesis of Goodpasture disease as distinguished from ANCA-associated vasculitis needs further elucidation. It is positive in up to 30% of patients with anti-GBM disease. ANCA positivity, at least in one study, was a favorable factor in patients’ initial prognosis and it may persist following clinical remission. Dual anti-GBM and ANCA positivity may also be implicated in disease relapse.

A. History Part I: Pattern Recognition:

The clinical presentation varies depending on the type of end organ damage. Respiratory symptoms include cough, dyspnea, and chest pain. Weight loss, fatigue, and fever may be endorsed but are more common in other vasculitidies or in association with concurrent infection.

Hemoptysis can be minimal or significant, leading to respiratory distress and failure. Antecedent pulmonary insults, ranging from pneumonia to recreational drug use such as crack cocaine, to hydrocarbon exposure are often elicited from patients with prominent pulmonary involvement. A case report implicated silica in one instance.

Evidence of overt renal failure includes nausea, vomiting, confusion, edema, dyspnea, and oliguria. Gross hematuria may be reported.

Roughly 60-80% present with the pulmonary-renal syndrome, while 20-40% exhibit kidney involvement alone. Fewer than 10% have lung disease only. Still unclear is why pulmonary disease alone is not frequently encountered. Anti-GBM antibody access to alveolar basement membrane appears to be limited in otherwise healthy individuals.

Hydrocarbon use has been shown to alter the accessibility of the basement membrane to antibodies in rat models. The other environmental factors discussed previously appear to contribute to pulmonary involvement, possibly in the same manner. Microscopic hematuria and proteinuria are often identified. Anemia may be significant and patients may report fatigue and exertional dyspnea.

Patients manifesting signs of acute renal failure with oliguria tend to have worse prognosis since the disease usually progresses insidiously before brought to medical attention.

B. History Part 2: Prevalence:

By most estimates, this rare disease occurs in one in every million people in the United States while from the UK suggest that the incidence of anti-GBM disease is 0.5 cases per million. Prevalence of reported end-stage renal disease (ESRD) with a primary diagnosis of Goodpasture’s was 0.2 percent of the nearly 550,000 patients with ESRD, per the United State Renal Data System Annual report for 2010. The median age was 52, with 26.8% over 65 years of age; 49.7 % were men and 90.7 % were white.

A bimodal distribution was identified in a small case series from the 1980s. Men classically present in the second to third decade of life, while females in sixth to eighth decade.

C. History Part 3: Competing diagnoses that can mimic Goodpasture’s disease.

The breadth of the following differential diagnosis accounts for other pulmonary renal syndromes, glomerular disease and disease more commonly presenting with hemoptysis and renal failure. Initial work-up may lead the hospitalist clinician to exclude infection and malignancy, as well as thromboembolic disease. Rarer disease is included based on clinical or histologic similarities.

Anticytoplasmic antibody, ANCA-associated vasculitis

GPA (granulomatosis with polyangitis), nee’ Wegener’s granulomatosis (WG), a pauci-immune ANCA-associated autoimmune vasculitis of small and medium size vessels must be distinguished from anti-GBM disease. It is also a multiorgan disease. Both upper and lower respiratory tract involvement and glomerulonephritis dominate the clinical course. More common than anti-GBM disease, WG has a reported prevalence in the United States of approximately 3 per 100,000 people.

The majority of patients with GPA have antibodies to cytoplasmic antigen within neutrophils (c-ANCA) targeting proteinase 3 antigen (PR3-ANCA). In contrast with anti-GBM disease, clinical features include sinusitis, rhinitis, saddle-nose deformity, uveititis, arthritis and arthralgias, central nervous system involvement, as well as peripheral nervous system pathology (cranial nerve palsies, optic nerve vasculitis, mononeuritis multiplex).

Microscopic Polyangitis and Churg-Strauss (eosinophilic granulomatosis with polyangitis) are other ANCA-associated vasculitidies. Both are associated with perinuclear ANCA (P-ANCA), with antibody to myeloperoxidase, (Anti-MPO).

ANCA negative vasculitis

• Henoch Schoenlein Purpura

• Behcet’s

• Polyarteritis Nodosa

• Mixed Cryoglobulinemia

Glomerulonephritis

• Bacterial endocarditis

• Systemic lupus erythematosus

• IgA nephropathy

• Post-infectious glomerulonephritis

• Focal segmental glomerulosclerosis

Pulmonary-renal syndrome with thrombotic angiopathy

• Nephrotic syndrome with pulmonary embolism

• Thrombotic thrombocytopenic purpura

Other

• Diffuse Alveolar Hemorrhage

• Tuberculosis

• Coagulopathy

• Aortobronchial fistula

• Idiopathic pulmonary hemosiderosis

• Urinary tract malignancy

• Pulmonary malignancy

• Renal Infarct

• Alport’s post-transplantation nephritis

Drug-Associated vasculitidies

• Propylthiouracil

• D-penicillamine

• Hydralazine

• Allopurinol

• Sulfasalazine

D. Physical Examination Findings.

No specific physical examination findings accompany anti-GBM disease. General considerations for the clinician follow.

Pulmonary exam

The pulmonary exam may be normal, with auscultation revealing normal breath sounds. Tachypnea and accessory muscle use accompany respiratory distress and prompt immediate resuscitation. Asymmetric, increased tactile fremitus, dullness to percussion, crackles and egophany can be appreciated over areas of consolidation. Adventitious breath sounds are auscultated, specifically fine crackles over territories of alveolar hemorrhage.

Renal

Volume overload attends severe acute renal failure. Edema may be profound. Uremic patients exhibit confusion, and asterixes may be identified.

E. What diagnostic tests should be performed?

Radioimmunoassay (RIA) or enzyme-linked immuno-absorbent assays (ELISA) which identify anti-GBM antibodies are the most readily available and sensitive diagnostic assays. Sensitivity exceeds 95 % for most clinical assays. Specificity ranges from 90.9 -100%. Western blot assays, with higher specificity, can confirm the diagnosis, especially if renal biopsy is not pursued.

Most authorities recommend renal biopsy for diagnostic uncertainty and to help characterize the extent of renal disease. Antibody testing is not conclusive in immunocompromised patients, necessitating renal biopsy. Characterizing the extent of crescentic formation has prognostic value; standard therapy will not be effective in patients with high degree of crescentic formation.

Immunofluorescence will differentiate anti-GBM disease, which shows a linear IgG deposition, from the granular immunoglobulin and complement deposition characteristic of systemic lupus erythematous and postinfectious glomerulonephritis, and from the necrotizing vasculitis of pauci-immune glomerulonephritis.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

In addition to testing for anti-GBM antibodies, the acute renal failure work-up entails urinalysis, urine culture, urine electrolytes, CPK, ANCA, and complement levels, and may include CRP and ESR and urine eosinophils, urine electrolytes and protein quantification. Urine cytology may be useful in older patients. Hematuria work-up should include urinalysis and examination for red blood cells and red blood cell casts, the latter more indicative of glomerular injury. Workup for infections may be indicated depending on patient’s presentation and history.

Low C3 and C4 complement levels suggest other causes of nephritic disease, as complement levels are usually normal in anti-GBM disease.

ANCA-associated vasculitidies will be evaluated with c-ANCA and p-ANCA. Many, as high as 30%, test positive for ANCA. Patients with anti-GBM disease will likely require basic hemolytic and coagulapathy work-up with peripheral blood smear, PT, INR and PTT, LDH, and haptoglobin.

Other appropriate tests include screening for HIV, hepatitis and screening ANA for systemic lupus erythematous. The erythrocyte sedimentation rate (ESR) is rarely elevated as opposed to the elevation encountered in the vasculitidies.

Prominent pulmonary involvement often warrants exclusion of malignancy with sputum cytology, and sputum for AFB when radiographic and clinical presentation is concerning for tuberculosis. Urine toxicology may identify cocaine use as an antecedent pulmonary insult.

Loss of anti-GBM antibody is associated with disease remission.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Chest X-ray

In a series of 25 patients with 39 episodes of pulmonary hemorrhage, all except two patients had findings of pulmonary hemorrhage. In 20 % of the films, no findings of alveolar hemorrhage were identified. Relapses occurred in conjunction with pulmonary infection, and occasionally, volume overload. Findings of coalescent or patchy alveolar infiltrates, primarily perihilar or in the mid to lower lung fields have been described. Resolution of hemorrhage can be expected in 3-4 days.

Thoracic computed tomography

Diffuse, bilateral areas of ground-glass or air-filling opacities implicate alveolar hemorrhage (Figure 2). Ventilation/ perfusion scan offers the ability to evaluate for pulmonary embolism, when contrasted studies cannot be performed.

Figure 2.

Computed tomography of abdomen and pelvis, if nephrolithiasis, renal infarction or malignancy is also suspected.

Other useful tests

• Renal ultrasound: enlarged kidneys, a nonspecific finding, may be visualized by ultrasound.

• Bronchoscopy is indicated following CT of the chest if patient is stable for diagnosis and management of hemoptysis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Not applicable.

III. Default Management.

Treatment delay attends delayed diagnosis in anti-GBM disease.

The KDIGO (Kidney disease improving global outcomes) glomerulonephritis guidelines published in 2012 address the management of anti-GBM disease and a formal prednisone taper regimen is outlined there.

These guidelines make four major recommendations:

• Initiate immunosuppression with high-dose corticosteroids and cyclophosphamide plus plasmapharesis in all with anti-GBM glomerulonephritis (GN) except those that have 100% crescent formation by renal biopsy and are dialysis dependent at time of presentation and who do not have pulmonary hemorrhage (Grade I B). Patients who have significant pulmonary hemorrhage should receive pharesis even in the setting of severe renal failure.

• Initiate treatment for anti-GBM GN without delay with high-dose corticosteroids and plasmapharesis. If the diagnosis is highly suspected, consider treatment while diagnosis is being confirmed (Not graded).

• No maintenance therapy for patient who have been treated for anti-GBM GN (Grade I D).

• Defer referral for kidney transplant until anti-GBM antibodies have cleared for 6 months (Not graded).

A single randomized trial in patients with anti-GBM disease conducted at Walter Reed Army Medical center, evaluated renal outcomes in 17 patients, who were primarily in their mid-second decade of life and who were primarily Caucasian men. Half were randomly assigned to immunosuppression with steroids and cyclophosphamide alone (group 1, serum Cr at presentation 4.6 mg/ dl) or immunosuppression plus plasmapharesis (group 2, serum Cr at presentation of 5.1 mg/ dl). Immunosuppression was done with prednisone, 2 mg/kg/ day for 1 week then 1 mg/ kg/ day for 3 weeks, then alternating day dosing for 3 months.

Cyclophosphamide dosing was 2 mg/kg/ day for 3 months, then 1 mg/ kg/ day for the remainder of treatment. 4L Plasma exchange was done every 3 days until anti-GBM antibody binding was less than 5% or until stable on hemodialysis for 30 days. Decreased serum creatinine and more rapid rate of disappearance of anti-GBM antibody were significant in the pharesis group. As in other studies, the percent of crescent formation (less than 30%) and preserved renal function portended a better prognosis independent of treatment with plasmapharesis. Renal prognosis was poor in either group when patients presented with a higher percentage of involved crescents and a higher serum creatinine at presentation.

In a larger trial of 137 patients with ANCA-associated systemic vasculitis, the primary end point of dialysis at three months was evaluated. Patients were randomly assigned to pulse steroids and cyclophosphamide, with or without plasmapharesis. Forty nine percent were not dependent on dialysis in the immunosuppression group alone, while 69% were independent of dialysis group in the plasmapharesis group. One year survival and adverse event rates were comparable between the two groups, suggesting the role of plasmapharesis in preventing end stage renal disease.

The recommended treatment regimens are thereby informed largely by case reports and reference to the use of plasmapharesis in other autoimmune disease. Generally, the plasmapharesis course will be a daily or every other daily schedule for two to three weeks until anti-GBM titers are in the normal range and hemoptysis has resolved.

Four liter exchanges with albumin as replacement are advised. If recent bleeding has occurred and following renal biopsy, one to two liters of fresh frozen plasma are administered to restore coagulation factors depleted with pharesis. Patients not requiring renal replacement therapy immediately, those with a serum creatinine less than 5-7 mg/dl., and less than 50% crescent formation on renal biopsy appear to respond most dramatically to plasmapharesis.

Patients with pulmonary hemorrhage or who are ANCA-positive should also be treated with plasmapharesis.

Induction therapy for anti-GBM includes pulse dose methylprednisolone, which should be started at (15-30 mg/kg) with a maximum dose of 1000 mg daily, intravenously for three days. Steroids are continued, generally as oral prednisone at 0.6-1 mg/kg daily for a month, followed with a long tapering maintenance taper, as per recent guidelines up through 6 months or disappearance of anti-GBM antibodies. Cyclophosphamide is started at 2 mg/kg daily, orally or intravenously, and generally continued for 3 to 6 months.

Novel therapeutic agents have shown promise in murine models. Atorvastatin and bezafibrate have been shown to attenuate anti-GBM glomerulonephritis and crescentic formation in rats. Prophylaxis for Pneumocystic jiroveci is advised while on immunosuppressive therapy.

A. Immediate management.

Immediate stabilization includes airway management and respiratory support. Hemodynamic support includes volume resuscitation, transfusion of blood products for symptomatic anemia. Attention to antecedent or concurrent pulmonary infections or insults, including recreational drugs is essential. Excluding other life-threatening etiologies of hemoptysis, including pulmonary embolism are appropriate.

In the setting of massive hemoptysis, typically defined as greater than 600ml/24 hours, bronchoscopy should be performed emergently. Though anti-GBM disease can be managed conservatively, vascular injury should be excluded. Computed Tomography should precede bronchoscopy unless the patient is unstable.

Bronchoscopy facilitates endobronchial tamponade of a hemorrhagic artery as a temporizing measure to definitive treatment of massive hemoptysis. Balloon arterial embolization (BAE) is a non-surgical option. Conditions warranting surgical intervention include thoracic vascular injury, arteriovenous malformation, aortobronchial fistulas.

B. Physical Examination Tips to Guide Management.

N/A

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

• Anti-GBM titers.

• CBC, daily or every other day.

• Renal profile, daily or every other day.

D. Long-term management.

• Anti-GBM titers

• CBC

• Renal profile

• Evaluation for proteinuria

E. Common Pitfalls and Side-Effects of Management

Methylprednisolone and prednisone

Immunosuppression, avascular necrosis, hypertension, hyperglycemia, psychosis, osteoporosis attend chronic steroid use. When steroids are administered for over three months, adequate calcium and vitamin D supplementation are warranted. Using the BMD (bone mineral density) index and clinical risk factors, the World Health Organization Fracture Assessment Tool (FRAX) developed in 2008 can guide pharmacologic treatment with bisphosphonates in high-risk patients. Smoking cessation and weight-bearing exercises should be encouraged.

Cyclophosphamide

Cyclophosphamide is contraindicated in the first trimester of pregnancy and in breast feeding. Adverse effects include sterility and amenorrhea, making this a potentially unattractive initial treatment option for woman of child-bearing age. Other adverse effects include hemorrhagic cystitis, immunosuppression, bladder fibrosis, and pancytopenia. In patients with a CrCl under 10, the dose is decreased by 25%, while those on hemodialysis require 50% of the standard dosing.

Plasmapharesis

Complications of plasmapheresis include hypotension, volume overload, citrate-induced paresthesia and metabolic alkalosis. Reactions occur more frequently when using fresh frozen plasma than with albumin, and may include urticaria, and less frequently, anaphylaxis. Exchange with albumin alone can deplete clotting factors and predispose to bleeding. FFP should be administered following renal biopsy or in patients with hemoptysis.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

Evaluate for other causes of renal insufficiency. Avoid nephrotoxic agents and redose other prescribed medications as indicated. General work-up and lab testing for hematuria, exclusion of nephrolithiasis may be appropriate. If pneumonia or other infections are present, antibiotic dosing adjustments are made accordingly. Based on degree of renal failure and proteinuria, ACE-I or ARB may be indicated at discharge or at early follow-up appointments.

B. Liver Insufficiency.

Other than correcting coagulopathy, no special considerations are unique to this population. Supportive care can be accomplished with fresh frozen plasma, blood products for active bleeding and coagulopathy.

C. Systolic and Diastolic Heart Failure

In one case report, standard treatment with plasmapharesis, pulse steroids and cyclophosphamide successfully resolved anti-GBM disease and dilated cardiomyopathy.

D. Coronary Artery Disease or Peripheral Vascular Disease

Severe anemia from massive hemoptysis causes demand on patients with significant or unstable coronary artery disease. Anemia has been shown to be a poor prognostic factor for patients with acute coronary syndrome. Transfusion thresholds for patients with acute coronary syndrome should be observed.

E. Diabetes or other Endocrine issues

Chronic steroid use requires diligent outpatient management by an internist or endocrinologist in managing diabetes and monitoring for secondary adrenal insufficiency if steroids are abruptly discontinued by a patient.

F. Malignancy

No specific considerations.

G. Immunosuppression (HIV, chronic steroids, etc.).

Chronic steroid use portends increased risk of infection in the immunocompromised patient. In addition, antibody testing for diagnostic purposes is unreliable in patients with HIV and renal biopsy should be pursued to establish suspected cases of anti-GBM disease. Prophylaxis for Pneumocystic jiroveci should be considered while on immunosuppressive therapy.

H. Primary Lung Disease (COPD, Asthma, ILD)

Recurrent pulmonary hemorrhage may lead to pulmonary fibrosis. Standard care for patients with coexisting COPD or asthma should be offered. No standard recommendations for outpatient pulmonary function tests exist, but these are warranted during followed-up patients who presented with diffuse alveolar hemorrhage.

I. Gastrointestinal or Nutrition Issues

Patient education on nutrition and diet based on degree of chronic kidney disease can be found at http://www.kidney.org/atoz/pdf/nutri_chronic.pdf.

J. Hematologic or Coagulation Issues

As in patients with liver disease and coagulopathy, immediate supportive care with fresh frozen plasma and packed red blood cells is imperative in a patient with hemoptysis. Work-up for coagulopathy as discussed previously, should be undertaken.

K. Dementia or Psychiatric Illness/Treatment

Steroid-induced psychosis, manifesting as hallucinations and delirium may require dose adjustment of discontinuation if symptoms are severe.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Pulmonary hemorrhage should be monitored closely in the intensive care unit. Shock and respiratory failure may ensue and require frequent monitoring.

The hospitalist should be aware of potential adverse effects encountered using plasmapharesis as described. Line infections should be minimized with attention to sterile technique and withdrawal of the venous access immediately after the conclusion of therapy.

B. Anticipated Length of Stay.

Duration of plasmapharesis dictates duration of inpatient management. This will be variable, but can involve two to three weeks of therapy.

C. When is the Patient Ready for Discharge?

Patients can be discharged after completing plasmapharesis, and once hemoptysis has been effectively controlled. Depending on hospital facility access and consultants ability for management, plasmapheresis may be able to be performed on an outpatient schedule for patients who are hemodynamically stable and able to follow an outpatient schedule.

D. Arranging for Clinic Follow-up

Treatment is interdisciplinary. Generally, a nephrologist and pulmonologist will follow the patient within a week of discharge. Rheumatologists may manage patients committed to chronic steroids and cytotoxic drugs.

1. When should clinic follow up be arranged and with whom.

In patients with renal failure, renal function should be followed on a weekly basis for at least the first month, then biweekly, then monthly intervals. Those on hemodialysis will have standard renal replacement sessions.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Renal profile, including chemistry, magnesium, phosphorus, CBC with differential, anti-GBM ELISA will be used from the time of the initial follow-up clinic visit through recovery.

E. Placement Considerations.

Those who progress to end-stage renal disease will need venous access and placement for renal replacement, and testing for hepatitis prior to placement. Coordination with a nephrologist and case manager will streamline this process. Temporary venous access should be established during hospitalization. Venous mapping and vascular surgery consultation are considerations for ultimate long-term hemodialysis access.

F. Prognosis and Patient Counseling.

Mortality exceeds 90% in untreated patients. Renal recovery is of primary concern. Those with serum creatinine greater than 6.6 mg/dL have the most dismal prognosis, 0-18% with renal recovery. Patients with fewer than 30% crescent formation and preserved renal function respond favorably and have long-term preservation of renal function.

Early diagnosis and treatment are essential and predictive of outcome. Patients with diffuse alveolar hemorrhage respond well to plasmapheresis. Those with ANCA positivity also appear to have better outcomes. Relapses are rare, including in those who have undergone renal transplantation.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

NO JCAHO core measures are exclusive to anti-GBM disease. For concomitant pneumonia, standard JCAHO guidelines include timing of antibiotic administration, generally within six hours of hospital arrival, drawing blood cultures prior to initial antibiotic administration, appropriate antibiotic administration, and vaccinating for influenza and pneumonia.

Based on revised 2006 CDC guidelines, routine voluntary screening for HIV should be accomplished for patients entering the health care setting, with an opt-out option, without requiring a separate consent form. These recommendations are directed at people between the ages of 13 and 64 unless undiagnosed HIV infection in the patient population has been documented to be below 0.1%.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

The length of stay may be considerable in a patient requiring plasmapharesis, and prophylaxis for venous thromboembolism will be required. Pharmacologic prophylaxis with heparin or low molecular weight heparins will be contraindicated in the setting of active hemoptysis. Non-pharmacologic prophylaxis will be required. Fall precautions may be indicated in patients with significant anemia and weakness.

The care of a patient with anti-GBM disease is interdisciplinary. Follow-up with a nephrologist, pulmonologist, a primary care physician and often a rheumatologist should be established during admission. Following renal function and anti-GBM titers can be handled as an outpatient. Nephrotic range proteinuria should prompt discussion with a nephrologist on timing and appropriateness of instituting an ACE inhibitor.

If applicable, smokers should be counseled and given resources on smoking cessation. Influenza and pneumococcal vaccinations are indicated prior to discharge.

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