Nej m Cpc 1201412

case records of the massachusetts general hospital

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 367;16 nejm.org october 18, 20121540

Founded by Richard C. CabotNancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., EditorJo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate EditorSally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor

Case 32-2012: A 35-Year-Old Man with Respiratory and Renal Failure

Richard J. Glassock, M.D., Leila Khorashadi, M.D., and Yael B. Kushner, M.D.

From the Department of Medicine, David Geffen School of Medicine at the Univer-sity of California Los Angeles, Los Angeles (R.J.G.); and the Departments of Radiolo-gy (L.K.) and Pathology (Y.B.K.), Massa-chusetts General Hospital, and the De-partments of Radiology (L.K.) and Pathology (Y.B.K.), Harvard Medical School — both in Boston.

N Engl J Med 2012;367:1540-53.

DOI: 10.1056/NEJMcpc1201412Copyright © 2012 Massachusetts Medical Society.

Pr esen tation of C a se

Dr. Omar H. Maarouf (Nephrology): A 35-year-old man was admitted to this hospital because of dyspnea, anemia, and renal failure.

The patient had been well until several weeks before admission, when fatigue developed. Two days before admission, dyspnea developed and worsened, without fever, cough, or chest pain. Early on the day of admission, he went to an urgent care clinic affiliated with this hospital. On examination, the patient was in respi-ratory distress; the temperature was 37.1°C, the blood pressure 152/79 mm Hg, the pulse 102 beats per minute, the respiratory rate 36 breaths per minute, and the oxy-gen saturation 91% while he was breathing ambient air. The conjunctivae were pale. Auscultation of the chest revealed no rales or wheezing. Oxygen (15 liters per minute) was administered by face mask; the oxygen saturation initially rose to 95%, fell to 81% with oxygen (6 liters per minute), and rose to 100% with oxygen (15 liters per minute). He was transferred by ambulance to the emergency depart-ment at this hospital, arriving 50 minutes after his initial presentation.

The patient reported fatigue, shortness of breath, and, during the previous 2 days, decreased urination. He did not have cough, chest pain, a change in symptoms with position, hemoptysis, fevers, chills, night sweats, headaches, visual loss, dry eyes, dry mouth, or joint pain. His wife reported that during the previous 6 months, the patient had had episodes of bilateral finger, ankle, and facial swelling, without pain or change in color. Four years before admission, he had been evaluated because of back and suprapubic pain, fatigue, and a temperature of 38.6°C. Urinalysis showed hematuria and proteinuria; other laboratory-test results are shown in Table 1. Cul-ture of the urine grew 1000 to 10,000 colonies of mixed flora; testing for Chlamydia trachomatis and Neisseria gonorrhoeae was negative. Ceftriaxone was prescribed, and the patient was advised to follow up with his primary care provider, but he did not. Six years before admission, testing for rapid plasma reagin was positive at a titer of 1:8; testing for antibodies to Treponema pallidum and the human immunodeficiency virus (HIV) was negative, as was a Mantoux tuberculin skin test. The patient took no medications or herbal supplements, and he had no allergies. He was born in Central America, had immigrated to the United States 6 years before admission, was married with no children, and was physically active in his job. He had no history of recent travel, exposure to sick persons, blood transfusions, or previous surgery. He did not smoke, drink alcohol, or use illicit drugs.

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case records of the massachusetts gener al hospital

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On examination, the temperature was 36.9°C, the blood pressure 173/89 mm Hg, the pulse 95 beats per minute, the respiratory rate 36 breaths per minute, and the oxygen saturation 88% while he was breathing ambient air and 100% while he was breathing high-flow oxygen through a nonrebreather face mask. The skin and conjunctivae were pale, with slight brownish injections in the conjunctivae, and there were hypopigmented macules on the right temple and both lower cheeks and hyperpigmented macules on the bridge of the nose. There were bibasilar rales in the lungs, and the remainder of the ex-amination was normal.

Blood levels of magnesium, total and direct bilirubin, and lactate were normal, as were re-sults of liver-function tests and red-cell indexes. Serum protein electrophoresis revealed a diffuse increase in the IgG level, and testing for rheu-matoid factor and screening of the blood and urine for toxins were negative; other test results are shown in Table 1. Testing for hepatitis B and

C viruses and autoantibodies against histones was negative, as was parvovirus B19 nucleic acid test-ing. The stool was brown and positive for blood. An electrocardiogram (ECG) showed sinus tachy-cardia, counterclockwise rotation, and nonspe-cific ST-segment and T-wave abnormalities.

Furosemide was administered intravenously, nitroglycerin was administered by continuous in-fusion, and oxygen supplementation was contin-ued with bilevel positive airway pressure. The ABO blood type was A, Rh positive, with positive anti-body screening; a cold autoantibody was identi-fied. A prewarmed antibody screening was nega-tive. A chest radiograph showed bilateral central opacities, which extended peripherally and were confluent in the right lower lobe, and slight car-diomegaly; there were no pleural effusions. Trans-thoracic cardiac ultrasonography revealed nor-mal global cardiac function and right-ventricular size, no evidence of a pericardial effusion, and findings that were consistent with pulmonary edema.

Table 1. Laboratory Data.*

VariableReference Range,

Adults†4 Yr before Admission On Admission 2nd Day

Blood

Hematocrit (%) 41.0–53.0 32.2 13.4 29.8

Hemoglobin (g/dl) 13.5–17.5 11.3 4.5 10.4

White-cell count (per mm3) 4500–11,000 11,300 11,500 5000

Differential count (%)

Neutrophils 40–70 84 89

Band forms 0–10 3

Lymphocytes 22–44 4 8

Monocytes 4–11 9 3

Platelet count (per mm3) 150,000–400,000 319,000 236,000 134,000

Erythrocyte count (per mm3) 4,500,000–5,900,000 3,770,000 1,480,000 3,440,000

Reticulocytes (%) 0.5–2.5 2.9

d-Dimer (ng/ml) <500 6908

Erythrocyte sedimentation rate (mm/hr) 0–17 97

Activated partial-thromboplastin time (sec)

21.0–33.0 35.2 32.6

Prothrombin time (sec) 11.0–13.7 15.3 14.2

International normalized ratio for pro-thrombin time

1.3 1.2

Fibrinogen (mg/dl) 140–400 764

Sodium (mmol/liter) 135–145 139 137

Potassium (mmol/liter) 3.4–4.8 4.8 3.7





Table 1. (Continued.)



Chloride (mmol/liter) 100–108 100 97

Carbon dioxide (mmol/liter) 23.0–31.9 6.6 16.2

Anion gap (mmol/liter) 3–15 32 24

Urea nitrogen (mg/dl) 8–25 158 91

Creatinine (mg/dl) 0.60–1.50 30.65 16.80

Estimated glomerular filtration rate (ml/min/1.73 m2)

≥60 (if patient is black, multiply results by 1.21)

2 3

Glucose (mg/dl) 70–110 126 173

Protein (g/dl)

Total 6.0–8.3 7.0 6.0

Albumin 3.3–5.0 2.9 2.4

Globulin 2.3–4.1 4.1

Calcium (mg/dl) 8.5–10.5 3.6 6.0

Ionized calcium (mmol/liter) 1.14–1.30 0.55 0.77

Phosphorus (mg/dl) 2.6–4.5 16.5 11.6

Lipase (U/liter) 13–60 159

Amylase (U/liter) 3–100 171

Creatine kinase (U/liter) 60–400 3169

Creatine kinase MB isoenzymes (ng/ml)

0.0–6.9 10.5

Troponin T (ng/ml) <0.03 0.12

Troponin I Negative Negative

Iron (μg/dl) 45–160 29

Iron-binding capacity (μg/dl) 230–404 197

Ferritin (ng/ml) 30–300 258

Anticardiolipin IgG (GPL) 0–15 101.2

Anticardiolipin IgM (MPL) 0–15 14.0

C3 (mg/dl) 86–184 59

C4 (mg/dl) 16–38 10

25-Hydroxyvitamin D (ng/ml) 33–100 12

Parathyroid hormone (pg/ml) 10–60 739

Osmolality (mOsm/kg of water) 280–296 341

Haptoglobin (mg/dl) 16–199 372

Blood gases (venous) while breathing high-flow oxygen by non-rebreather mask

pH 7.30–7.40 7.10

Partial pressure of carbon dioxide (mm Hg)

38–50 25

Partial pressure of oxygen (mm Hg) 35–50 33

Oxygen saturation (%) 44

Base excess (mmol/liter) −20.1





After 2 hours, tachypnea developed, the pa-tient appeared to be fatigued, and there had been no urine output. Propofol and fentanyl were ad-ministered; the trachea was intubated, and me-chanical ventilation was begun. He was admit-

ted to the intensive care unit (ICU). A radial arterial catheter, left internal jugular triple-lumen intravenous catheter, and hemodialysis catheter were placed, and hemodialysis was begun. Leuko-cyte-reduced red cells (8 units during 23 hours)

Table 1. (Continued.)



Urine

pH 5.0–9.0 5.5 6.0

Specific gravity 1.001–1.035 1.015 1.020

Color Yellow Yellow Yellow

Turbidity Clear Cloudy Clear

Screening-dipstick test

Glucose Negative Negative 1+ (250 mg/dl)

Bilirubin Negative Negative Negative

Ketones Negative Negative Negative

Occult blood Negative 3+ 3+

Albumin Negative 3+ 3+

Urobilinogen Negative Negative Negative

Nitrites Negative Negative Negative

White cells Negative Negative Negative

Sediment

Red cells (per high-power field) 0–2 3–5 20–50

White cells (per high-power field) 0–2 0–2 10–20

Bacteria (per high-power field) Negative Negative Few

Hyaline casts (per low-power field) 0–5 10–20

Granular casts (per low-power field) None 0–2

Squamous epithelial cells (per high-power field)

None None Few

Mucin (per low-power field) None Present

Muddy casts (per low-power field) None Few

Osmolality (mOsm/kg of water) Not defined 333

Sodium (mmol/liter) Not defined 54

Potassium (mmol/liter) Not defined 35.4

Chloride (mmol/liter) Not defined 51

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the values for ionized calcium to milligrams per deciliter, divide by 0.250. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for iron and iron-binding capacity to micromoles per liter, multiply by 0.1791. To convert the val-ues for 25-hydroxyvitamin D to nanomoles per liter, multiply by 2.496.

† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.





were transfused. Potassium chloride, calcium gluconate, and bicarbonate were administered. Gram’s staining of sputum revealed abundant leukocytes, very few squamous cells, and a few mixed gram-positive and gram-negative organ-isms. Ultrasonography of the abdomen revealed normal renal size, position, and echotexture and normal arterial blood flow.

Bronchoscopic examination revealed thick, red mucus in the main-stem and right-lower-lobe bronchi; the carina and airways of the left lung were normal. Bronchoalveolar lavage on the right, with four serial aliquots of normal saline, re-vealed increasingly red return, with 300 and 24,500 red cells per cubic millimeter and 975 and 1475 white cells per cubic millimeter in the first and fourth tubes, respectively. In the fourth tube, the white-cell differential count revealed 84% polymorphonuclear leukocytes, 1% lympho-cytes, 7% monocytes, and 8% macrophages or lining cells. Gram’s staining of the aspirate re-vealed leukocytes, without organisms; fungal wet preparation, staining for acid-fast and modified acid-fast bacilli, and testing for respiratory viruses were negative. Cytologic examination showed evidence of acute inflammation and pulmonary macrophages, with no malignant cells. Speci-mens of the sputum and swabs of the nasal mucosa and rectum were cultured. Methylpred-nisolone (1 g daily for 3 days) was administered.

On the second day, the sputum culture grew very few klebsiella; vancomycin, cefepime, and ciprofloxacin were administered. Testing was negative for Pneumocystis jiroveci, heterophile anti-bodies, and antibodies to streptolysin O, strep-tococcal DNase B, T. pallidum, and HIV. Other test results are shown in Table 1. Computed to-mography (CT) of the chest, performed accord-ing to the protocol for a pulmonary embolus, revealed bilateral perihilar ground-glass opaci-ties (more prominent on the right side than on the left side), mild interlobular septal thicken-ing, a small right pleural effusion, and no pul-monary emboli.

Results of additional diagnostic test were re-ceived, and a diagnostic procedure was per-formed.

Differ en ti a l Di agnosis

Dr. Richard J. Glassock: This patient presented with advanced renal failure of uncertain duration, he-

maturia, proteinuria, and hypocomplementemia. Progressive respiratory distress developed, and features observed on imaging and bronchoscopy indicated alveolar hemorrhage and inflammation. Severe anemia suggested acute blood loss into the lung parenchyma, combined with shortened red-cell survival. No microangiopathic features were noted. No infectious explanation for these findings was found.

May we review the imaging studies?Dr. Leila Khorashadi: An anteroposterior view of

the chest (Fig. 1A) shows predominantly perihilar and central air-space opacities that extend pe-ripherally and are confluent in the right lower lobe. There is slight cardiomegaly. The radio-graph obtained after intubation (Fig. 1B) shows increased confluence of the opacities, particu-larly the perihilar opacities. The right hemidia-phragm is partially obscured, and there is most likely a small right pleural effusion. In an intu-bated patient, lung volumes may be lower and some changes related to atelectasis can be ex-pected. Therefore, the overall appearance may be due to a combination of progression of the un-derlying process and atelectasis. The radiographic findings are nonspecific, and the differential diagnosis includes pulmonary edema, pulmonary hemorrhage, and acute respiratory distress syn-drome. Renal ultrasonography revealed normal renal size and echotexture.

Figure 1 (facing page). Chest Imaging Studies.

An anteroposterior radiograph of the chest on admis-sion (Panel A) with the patient in the upright position shows bilateral central opacities, which are more con-fluent in the right lower lung zone than elsewhere. Slight cardiomegaly is present. There is no pleural effusion. A repeat radiograph obtained 3 hours after admission (Panel B) shows that the patient has been intubated (arrow) and that a nasogastric tube (arrow-head) is in place. Central and perihilar patchy opacities persist, and there is increased confluence of the opaci-ties in the right lower lobe. The medial aspect of the right diaphragm is obscured. An axial image from CT angiography that was performed according to the pro-tocol for a pulmonary embolus (Panel C) shows a small right pleural effusion (arrow); a nasogastric tube is noted in the esophagus (arrowhead). On lung windows (Panel D), there are bilateral ground-glass opacities, confluent and consolidated opacities in the right lower lobe, and mild interlobular septal and fissural thicken-ing (arrow). A coronal view (Panel E) shows bilateral predominantly central ground-glass opacities; the arrowhead indicates the nasogastric tube.





Because of persistent hypoxemia, CT angiog-raphy of the chest was performed (Fig. 1C, 1D, and 1E). There are bilateral ground-glass opaci-ties corresponding to the central and perihilar opacities noted on the radiographs, and there is air-space consolidation in the right lower lobe. There is interlobular septal and fissural thicken-

ing, a feature that suggests fluid in the inter-lobular septa and the fissure. There is a small right pleural effusion and subsegmental relax-ation atelectasis.

Dr. Glassock: Taken together, these findings indicate a process in the general category of a pulmonary–renal syndrome and in the more spe-

A B

DC

E





cific group of disorders known as diffuse alveo-lar hemorrhage accompanied by glomerulone-phritis, often of a rapidly progressive variety.1-4 The term Goodpasture’s syndrome has histori-cally been applied to this constellation of find-ings. Ernest W. Goodpasture reported in 1919 (while serving as a lieutenant in the Navy Medi-cal Corps assigned to the Chelsea Naval Hospital near Boston) on the autopsy findings in the case of an 18-year-old man who had died of massive lung hemorrhage and crescentic glomerulonephri-tis during the height of the influenza pandemic.5 Goodpasture also observed splenic necrosis, most likely indicating a systemic vasculitis. These ob-servations were neglected until Stanton and Tange6 rediscovered them in 1958 and coined the now familiar eponym. Goodpasture appar-ently did not believe that the eponym was ap-propriate, since he was more interested in find-ing the cause of influenza than attempting to establish a link between lung hemorrhage and nephritis.7,8

The term Goodpasture’s syndrome is applied to the combination of lung purpura and nephritis, regardless of the underlying pathogenesis. We now recognize that diverse mechanisms underlie Goodpasture’s syndrome, so more precise termi-nology linked to pathogenesis is now preferred for the specific diseases. There are numerous pos-sible causes of Goodpasture’s syndrome in this case (Table 2). A useful clinical approach to dif-ferential diagnosis9 involves serologic categori-zation.

Disease mediated by Anti–glomerular Basement Membrane antibodies

Although disease mediated by anti–glomerular basement membrane (GBM) antibodies (anti-GBM disease) is one of the less common causes of lung purpura and nephritis, it must be considered in this case because of the potential implications for management.10 Anti-GBM disease is commonly associated with lung hemorrhage, mostly in young men. The severity of the lung hemorrhage varies greatly, but it can be life-threatening, as it was in this case. Pulmonary irritants (e.g., cigarette smoke, hydrocarbon fumes, or freebase cocaine) or lung infections can precipitate lung hemorrhage. No such events were documented in this case. Sys-temic manifestations (e.g., fever and hyperten-sion) other than those attributable to uremia or

respiratory insufficiency are usually absent, as in this case. Renal failure is common and usually rapidly progressive, as was suspected in this pa-tient. In anti-GBM disease, the renal lesion is most often a necrotizing and crescentic glomerulone-phritis, and the pulmonary lesion is most often a bland, noninflammatory alveolar hemorrhage. Both hemorrhage and inflammation were evi-dent in the bronchoalveolar lavage in this case.

Iron-deficiency anemia may be due to pulmo-nary bleeding. Serum complement levels are typi-cally normal, unlike in this case. The diagnostic hallmarks of anti-GBM disease are the presence of autoantibodies (typically IgG and only occa-sionally IgA) directed to well-defined conforma-tional epitopes expressed on type IV collagen.11 Approximately 20 to 30% of patients may also be shown to have antineutrophil cytoplasmic auto-antibodies (ANCA).

This patient had had proteinuria and hematu-ria several years earlier and presented with hy-pocomplementemia, and bronchoalveolar lavage revealed inflammation and hemorrhage — all of which would argue against the diagnosis of anti-GBM disease.

ANCA-associated disease

Since ANCA-associated vasculitis is the single most common cause of the syndrome of lung purpura and nephritis (Table 2),9 the diagnosis must be con-sidered in this patient. Of patients with granuloma-tosis with polyangiitis (formerly known as Wegen-er’s granulomatosis) and microscopic polyangiitis, 85 to 90% have antibodies to neutrophil cyto-plasmic constituents (myeloperoxidase or protein-ase 3).9,12,13 Systemic features, such as fever, my-algias, arthralgias, and skin lesions (palpable purpura and leukocytoclastic vasculitis), are also common but were absent in this patient.

The pulmonary lesion in ANCA-associated vas-culitis is diffuse alveolar damage, hemorrhage, and focal inflammatory vasculitis. In granuloma-tosis with polyangiitis, there may also be lesions in the upper airways (e.g., tracheitis, sinusitis, and otitis), necrotic pulmonary lesions, and hilar lymphadenopathy. Splenic necrosis can also be observed. The serum complement levels are typi-cally normal or elevated, unlike in this case, and the erythrocyte sedimentation rate and C-reactive protein levels are also elevated. Iron-deficiency anemia may be present if the pulmonary bleeding





is severe and chronic. This patient did not have systemic symptoms, upper airways were not in-volved, and he had hypocomplementemia, findings that argue against an ANCA-associated vasculitis.

A variety of disorders not associated with anti-GBM antibodies or ANCA may cause lung

purpura and nephritis (Table 2). Only a few need to be considered in this case.

Uremic Pneumonitis

In the era before dialysis, patients with advanced renal failure often presented with symptoms and

Table 2. Differential Diagnosis of Diffuse Alveolar Hemorrhage and Nephritis (Goodpasture’s Syndrome).

Immune-mediated disorders

Microscopic polyangiitis (with kidney and lung involvement only or multisystem involvement), usually positive for ANCA (most commonly antimyeloperoxidase)

Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), usually positive for ANCA (most commonly anti proteinase 3)

Anti-GBM disease

Combined anti-GBM disease and ANCA-associated disease (most commonly antimyeloperoxidase)

Systemic lupus erythematosus (with or without ANCA, anti-GBM antibody, or antiphospholipid autoantibody)

Churg–Strauss syndrome (eosinophilic granulomatous vasculitis)

Henoch–Schönlein purpura

IgA nephropathy (rare)

Mixed cryoglobulinemia (consisting of both IgG and IgM)

Behçet’s syndrome

Polymyositis

Mixed connective-tissue disease

Progressive systemic sclerosis

Idiopathic pulmonary hemosiderosis (with delayed anti-GBM disease)

Hypersensitivity to drugs (e.g., nitrofurantoin, penicillamine, hydralazine, propylthiouracil, or phenytoin)

Infectious disorders

Human immunodeficiency virus infection

Disseminated cryptococcosis

Legionnaires’ disease (with interstitial nephritis)

Other pulmonary or systemic infections, or both, with accompanying glomerulonephritis or interstitial nephritis (e.g., CMV infection, zygomycosis, streptococcal or staphylococcal sepsis, aspergillosis, leptospirosis, paragonimiasis)

Other disorders

Hemolytic–uremic syndrome (with glomerular thrombotic microangiopathy)

Malignant hypertension (with glomerular fibrinoid necrosis)

Membranoproliferative glomerulonephritis

Advanced diabetic nephropathy

Focal and segmental glomerulosclerosis

Acute tubular necrosis

Lung cancer (with associated glomerular disease)

Silica dust exposure (with anti-GBM antibody or ANCA)

Multiple pulmonary emboli and a coexistent renal disease (e.g., membranous glomerulopathy)

Transplantation (e.g., effects after lung transplantation or stem-cell transplantation)

Uremic pneumonitis (and advanced renal failure)

* ANCA denotes antineutrophil cytoplasmic autoantibody, CMV cytomegalovirus, and GBM glomerular basement membrane.





signs due to the effects of uremia on organ func-tion, including lung function. Cases of dyspnea, hypoxemia, and pulmonary infiltrates, sometimes accompanied by frank hemoptysis, were often seen. Many of these cases were most likely due to car-diogenic pulmonary edema secondary to chronic hypertension or expanded intravascular fluid vol-ume (or both), but cases with normal cardiac function were also described and were called “uremic pneumonitis.”14 It was thought that se-vere uremia could alter pulmonary capillary per-meability, resulting in noncardiogenic pulmonary edema. This patient has advanced renal failure and clinical and radiographic features that are compatible with uremic pneumonitis, but I be-lieve that other causes of respiratory insufficiency are more likely.

Thromboembolic disease

Dyspnea, hypoxemia, fever, and pulmonary infil-trates can be a manifestation of multiple pulmo-nary emboli or thromboses. The antiphospholipid antibody syndrome, a prothrombotic diathesis accompanying the nephrotic syndrome, or anti-proteinase 3–positive vasculitis15 can predispose to pulmonary thromboembolism. Typically, pa-tients with pulmonary thromboembolic disease have high right-sided cardiac pressures, abnormali-ties on ECG that indicate right-sided heart strain, hypoxemia that does not improve with increased inspired oxygen, and chest pain, none of which this patient had. The elevated d-dimer levels can be explained by the advanced renal failure.16

Uncommon causes

A variety of both systemic and pulmonary micro-bial infections can be accompanied by pulmonary hemorrhage and renal disease, including nephritis (Table 2).9 In one exceptional case, Goodpasture’s syndrome was evoked by legionnaires’ disease.17 No infections could be implicated in this patient, despite a vigorous search. Diffuse alveolar hemor-rhage and nephritis or renal failure have also been observed in many uncommon noninfectious dis-orders (Table 2), but a cause-and-effect relation-ship is uncertain, and I will not consider them further.1-4

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE), with both re-nal and pulmonary involvement, should be given serious consideration in this patient, even though

pulmonary involvement occurs in only 0.5 to 5% of patients with SLE.18-23 Diffuse alveolar dam-age with hemorrhage is among the more common manifestations of pulmonary involvement in SLE, and approximately 50% of patients with pulmo-nary involvement have overt hemoptysis. Lung hemorrhage in patients with SLE is nearly always associated with lupus nephritis and is commonly associated with antiphospholipid autoantibod-ies,9,24,25 as in this case, or polyangiitis.25 The lung lesions can be bland alveolar hemorrhage or a localized inflammatory pulmonary capillaritis, with bland lesions usually predominating over the inflammatory lesions. This patient had evidence of both hemorrhage and inflammation. Other fea-tures that this patient had that were compatible with SLE were hypopigmented and hyperpigment-ed skin lesions on sun-exposed areas, polyclonal hyperglobulinemia, hypocomplementemia, a pos-itive direct Coomb’s test (due to adsorbed C3dg, the main fragment of C3), biologic false positive tests for syphilis, positive tests for anticardiolipin antibodies, and possible lupus anticoagulant. Ar-thritis, arthralgia, serositis, neuropsychiatric in-volvement, warm-antibody hemolytic anemia, throm bocytopenia, and thrombotic microangi-opathy can also be present in SLE but were not prominent in this patient.

Patients who have SLE with renal and pulmo-nary involvement can have anti-GBM disease or disease associated with ANCA (almost always antimyeloperoxidase).17,26 These diseases can be diagnosed only with appropriate serologic tests or immunopathological studies of tissue, such as biopsy specimens from a kidney or possibly a lung. Diffuse polyangiitis unaccompanied by ANCA can also explain some cases of proliferative glo-merulonephritis in patients with SLE, particu-larly when segmental necrotizing features are present on examination of renal-biopsy speci-mens.27 Finally, myocardial involvement (myo-carditis, nonbacterial endocarditis, or valvular disease) can occur in patients with SLE. This patient had elevated levels of creatine kinase, creatine kinase MB isoenzymes, and troponin T, but it cannot be easily determined whether the elevated levels were due to renal failure or to vasculitic cardiac involvement. However, the pa-tient’s normal levels of troponin I and the nor-mal findings on cardiac ultrasonography make cardiac vasculitis unlikely. The patient also had elevated serum amylase and lipase levels, which





could be due to severe renal failure or pancre-atic involvement in association with a condition related to SLE, such as visceral vasculitis.

Summary

In summary, the clinical and laboratory findings in this case point strongly toward SLE with alveo-lar hemorrhage and severe proliferative lupus glo-merulonephritis, probably of a crescentic form. It is possible that antecedent membranous or focal proliferative lupus nephritis had transformed into an aggressive variety of the disease, but the nor-mal kidney size and echotexture imply that the disease was not chronic. The hematuria and pro-teinuria that the patient had 4 years earlier may have heralded the onset of lupus nephritis. I can find no direct clinical evidence for a thrombotic microangiopathy, such as thrombocytopenia or a microangiopathic hemolytic anemia, although the positive tests for anticardiolipin antibody, the biologic false positive test for syphilis, and the prolonged activated partial-thromboplastin time and prothrombin time may indicate a propensity for the development of this complication.

The results of serologic tests will be crucial in the determination of the diagnosis, the progno-sis, and the best course of therapy. Although oliguria and advanced renal failure are ominous signs, the normal kidney size and echotexture im-ply a potential for reversibility if effective treat-ment can be implemented quickly. A renal-biopsy specimen would provide the most useful diagnos-tic and prognostic information and would guide the therapy.

Dr. Nancy Lee Harris (Pathology): Dr. Maarouf, would you summarize the clinical thinking at the time?

Dr. Maarouf: When we initially saw the patient, we were most concerned about anti-GBM dis-ease and ANCA-associated vasculitis, resulting in renal disease and pulmonary hemorrhage. When we learned of the low complement levels, we also considered SLE. The diagnostic tests were the anti-GBM antibody and ANCA tests and serologic testing for lupus, followed by a renal biopsy.

Clinic a l Di agnosis

Alveolar hemorrhage and nephritis due to anti-GBM disease, ANCA-associated vasculitis, or sys-temic lupus erythematosus.

DR . R ICH A R D J. GL A SSO CK’S DI AGNOSIS

Systemic lupus erythematosus with alveolar hemorrhage and lupus nephritis (most likely pro-liferative and crescentic glomerulonephritis).

Pathol o gic a l Discussion

Dr. Yael B. Kushner: A kidney biopsy was performed on the fifth hospital day. Examination of forma-lin-fixed tissue by means of light microscopy (Fig. 2A and 2B) showed proliferative-appearing glomeruli with focal formation of cellular and fibrocellular crescents. The GBM was markedly thickened, imparting a “wire loop” appearance on the slides that were stained with hematoxylin and eosin. On periodic acid–Schiff staining (Fig. 2C), the GBM was duplicated. Many glomeruli were globally sclerosed, indicating disease chro-nicity. The renal tubules and the interstitium were also abnormal (Fig. 2D), with advanced tu-bular atrophy and interstitial fibrosis and an in-flammatory infiltrate composed primarily of mononuclear cells.

Immunofluorescence staining of frozen tis-sue (Fig. 3A and 3B) showed strong staining with IgG, IgM, IgA, C3, C1q, and kappa and lambda light chains in a granular pattern in the mesangium and along the GBM, with focal con-fluence of deposits, mirroring the wire-loop ap-pearance seen on light microscopy. There was granular staining for IgG, C3, and kappa and lambda light chains along the tubular basement membrane.

Electron microscopy (Fig. 3C and 3D) re-vealed massive subendothelial, mesangial, and intramembranous electron-dense immune-com-plex deposits. Rare subepithelial deposits were also seen. The deposits occasionally had a con-centric curvilinear substructure with a finger-print-like appearance. Tubuloreticular structures were seen in the endothelial-cell cytoplasm.

Lupus nephritis may have virtually any ap-pearance on conventional light microscopy. The common thread is the presence of immune-complex deposits that stain for multiple immu-noreactants, including C1q, in what is referred to as a “full house” pattern on immunofluores-cence. In this case, massive immune complex–type deposits were seen along the GBM and tu-bular basement membrane and even in Bowman’s





capsule. The classic full house was identified on immunofluorescence. In patients with lupus, the deposits often form a substructure in a concen-tric curvilinear fingerprint pattern, as was seen in this case. Such patients, including this one, frequently have tubuloreticular inclusions in the cytoplasm of the endothelial cells; it is unknown how they are formed.

The classification of lupus nephritis is based on the glomeruli alone.28 In this case, more than half the glomeruli were diseased (indicating dif-fuse glomerulonephritis) and there was global involvement, so the disease was classified as a diffuse proliferative and sclerosing lupus nephri-tis, with both active and chronic lesions, re-ferred to as class IV-G (A/C). The chronic tubu-lointerstitial changes suggested that the disease had been smoldering and was not acute. Al-though there were a few subepithelial deposits,

there were not enough to make an additional diagnosis of membranous lupus nephritis (class V) at the time of the biopsy.

Multiple small blood vessels (Fig. 2E and 2F) contained occlusive thrombi, which were seen on light microscopy and also stained with fibrin on immunofluorescence, confirming that they were fibrin thrombi. Some arterioles contained intramural fragmented red cells (schistocytes) and showed mucoid intimal change. These find-ings are diagnostic of thrombotic microangiopa-thy, most likely due to the presence of anticar-diolipin antibodies.29

Dr. Maarouf: Transfusion medicine was con-sulted regarding possible plasma exchange, pend-ing the results of the anti-GBM antibody and ANCA testing. Fortunately, the patient had a dra-matic improvement after the administration of glucocorticoids and was quickly weaned from

A B C

E FD

Figure 2. Light-Microscopical Examination of Renal-Biopsy Specimen.

The glomeruli have a vaguely lobular architecture (Panel A, hematoxylin and eosin) with diffusely thickened capillary walls and mild endocapillary proliferation. Cellular crescents are present (Panel B, arrow; hematoxylin and eosin). Some glomeruli show evidence of chronicity (Panel C, periodic acid–Schiff), with striking duplication of the glomer-ular basement membrane (arrows) and fibrocellular crescents (arrowheads). The tubulointerstitial compartment (Panel D, Masson’s trichrome) shows advanced tubular atrophy and interstitial inflammation, which are additional indications of chronicity. Arterioles focally contain occlusive fibrin thrombi (Panel E, arrow; hematoxylin and eosin), a feature that is diagnostic of thrombotic microangiopathy. Intramural fragmented red cells are present (Panel F, arrow; hematoxylin and eosin).





mechanical ventilation and was extubated within 48 hours after admission. Testing for ANCA, an-tibodies to proteinase 3 and myeloperoxidase, and Goodpasture’s antigen (NC1 domain of the α3 chain of type IV collagen) were negative. The antinuclear antibody titer was positive at 1:1280 and had a homogeneous pattern. The titer for antibodies to double-stranded DNA was positive at 1:80.

The patient was transferred out of the ICU on the third day. The administration of prednisone (60 mg daily) was begun. After the presence of active lupus nephritis was confirmed on examina-tion of the renal-biopsy specimen, we planned to treat the patient with 500 mg of cyclophospha-mide intravenously every 2 weeks for 3 months, followed by 50 mg orally daily. He received the first dose while in the hospital. While he was

A B

DC

Figure 3. Immunofluorescence and Electron-Microscopical Studies of Renal-Biopsy Specimens.

Immunofluorescence reveals abundant granular immune-complex deposition in the mesangium and along the glo-merular basement membrane in a classic “full house” pattern (Panel A, anti-IgG immunofluorescence). Immune-complex deposition is also seen along the tubular basement membrane and is a frequent finding in lupus nephritis (Panel B, anti-IgG immunofluorescence). With the use of electron microscopy, abundant electron-dense deposits are seen in a mesangial, intramembranous, subepithelial, and subendothelial distribution (Panel C). The deposits are mainly amorphous but occasionally have a curvilinear “fingerprint” substructure (inset), which is often seen in lupus nephritis. Endothelial cells contain tubuloreticular inclusions (Panel D, arrow), a common finding in lupus nephritis.





still in the hospital, the platelet count fell to a nadir of 90,000 per cubic millimeter. Because of the positive tests for lupus anticoagulant and an-ticardiolipin antibodies in this patient who had pathological evidence of thrombotic microangi-opathy in the kidney-biopsy specimen, plasma exchange was again considered, but the transfu-sion medicine team thought it was not indicated. Anticoagulation with low-molecular-weight hep-arin was then begun, followed by a transition to warfarin. The patient was discharged on the 11th day, with outpatient hemodialysis.

The patient did not follow up with the rheu-matology or nephrology service and therefore did not receive the additional planned cyclophospha-mide infusions. He began outpatient hemodialy-sis three times a week. At the dialysis clinic, the administration of oral cyclophosphamide (50 mg daily) was begun and prednisone (20 mg per day) was continued. The patient adhered poorly to the medications and declined to take warfarin. He discontinued cyclophosphamide after 6 months. After several months of dialysis, urine output re-sumed, the creatinine level declined, and dialysis was reduced to twice-weekly sessions. His renal function continued to improve, and 15 months after discharge, dialysis and prednisone were discontinued. Seven months after the discontinu-ation of dialysis, the urea nitrogen level was 29 mg per deciliter (10.4 mmol per liter), and the creati-nine 3.26 mg per deciliter (288.2 μmol per liter).

Dr. Harris: Are there any questions?A Physician: Do you use the complement C3 and

C4 assays in the differential diagnosis of renal disease?

Dr. Glassock: I use measurements of serum complement (C3 and C4) and sometimes total serum complement hemolytic activity (CH50) to help refine a differential diagnosis. In hepatitis C–related cryoglobulinemia with nephritis, the

C4 level is low and the C3 level may be normal. In hemolytic–uremic syndrome due to comple-ment factor H deficiency, the C3 level is low and the C4 level is normal. In lupus nephritis, both the C3 and C4 levels are low. Although these measurements are useful, other evidence must be weighed as well. In this case, there was abun-dant evidence, other than the C3 and C4 levels, that supported a diagnosis of SLE.

A nat omic a l Di agnosis

Systemic lupus erythematosus with diffuse pro-liferative lupus nephritis, with active and chronic lesions (class IV-G [A/C]), and pulmonary alveo-lar hemorrhage.

This case was presented at the Harvard Medical School post-graduate course MGH Nephrology Update (Directors, Drs. Mario F. Rubin, Hasan Bazari, and M. Amin Arnaout), sponsored by the Harvard Medical School Department of Continuing Edu cation.

Dr. Glassock reports receiving consulting fees from QuestCor, BioMarin, Novartis, Eli Lilly, Bristol-Myers Squibb, Genentech, Vifor, Genzyme-Sanofi, and American Renal Associates; receiv-ing fees for expert opinions for patients and caregivers in legal cases involving renal disease and for expert testimony for the defense in a lawsuit involving alleged renal injury from volatile hydrocarbons; receiving lecture fees from Renal Ventures and Genentech; receiving payment from Lighthouse Learning for the development of educational presentations; receiving editorial stipends from UpToDate; receiving royalties from Oxford Medi-cal Publishers and UpToDate; owning stock or stock options in Reata and La Jolla Pharmaceuticals; and serving as an unpaid board member for LABioMed and UKRO. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. Khorashadi is currently at the Department of Radiology, Mount Auburn Hospital, Cambridge, MA. Dr. Kushner is cur-rently at the Department of Pathology, Beth Israel Deaconess Medical Center, Boston.

We thank Drs. Hasan Bazari, Mario F. Rubin, Ednan K. Bajwa, and Andrew Liteplo for assisting in the preparation of the case history; Drs. Bazari and John H. Stone for review-ing the clinical discussion; Dr. Louis Ercolani for providing follow-up information; and Drs. Robert B. Colvin and R. Neal Smith for assisting in the preparation of the pathological dis-cussion.

References

1. Gallagher H, Kwan JT, Jayne DR. Pul-monary renal syndrome: a 4-year, single-center experience. Am J Kidney Dis 2002; 39:42-7.2. Leatherman JW, Davies SF, Hoidal JR. Alveolar hemorrhage syndromes: diffuse microvascular lung hemorrhage in im-mune and idiopathic disorders. Medicine (Baltimore) 1984;63:343-61.3. Green RJ, Ruoss SJ, Kraft SA, Duncan SR, Berry GJ, Raffin TA. Pulmonary capil-laritis and alveolar hemorrhage: update on diagnosis and management. Chest 1996;

110:1305-16. [Erratum, Chest 1997;112: 300.]4. Bolton WK. Pulmonary renal syn-drome and emergency therapy. Contrib Nephrol 2010;165:166-73.5. Goodpasture EW. Landmark publica-tion from the American Journal of the Medical Sciences: the significance of cer-tain pulmonary lesions in relation to the etiology of influenza. Am J Med Sci 2009; 338:148-51.6. Stanton MC, Tange JD. Goodpasture’s syndrome (pulmonary haemorrhage as-

sociated with glomerulonephritis). Aus-tralas Ann Med 1958;7:132-44.7. Collins RD. Dr Goodpasture: “I was not aware of such a connection between lung and kidney disease.” Ann Diagn Pathol 2010;14:194-8.8. Idem. Ernest William Goodpasture: scientist, scholar, gentleman. Franklin, TN: Hillsboro Press, 2002.9. Niles JL, Böttinger EP, Saurina GR, et al. The syndrome of lung hemorrhage and ne-phritis is usually an ANCA-associated con-dition. Arch Intern Med 1996;156:440-5.





10. Phelps RG, Turner AN. Antiglomeru-lar basement membrane disease and Goodpasture’s disease. In: Floege J, John-son RJ, Feehally J, eds. Comprehensive clinical nephrology. 4th ed. St. Louis: Saunders/Elsevier, 2010:282-91.11. Pedchenko V, Bondar O, Fogo AB, et al. Molecular architecture of the Good-pasture autoantigen in anti-GBM nephri-tis. N Engl J Med 2010;363:343-54.12. Falk RJ, Nachman PH, Hogan SL, Jen-nette JC. ANCA glomerulonephritis and vasculitis: a Chapel Hill perspective. Semin Nephrol 2000;20:233-43.13. Jennette JC, Falk RJ, Gasim AH. Pathogenesis of antineutrophil cytoplas-mic autoantibody vasculitis. Curr Opin Nephrol Hypertens 2011;20:263-70.14. Henkin RI, Maxwell MH, Murray JF. Uremic pneumonitis: a clinical, physio-logical study. Ann Intern Med 1962;57: 1001-8.15. Bautz DJ, Preston GA, Lionaki S, et al. Antibodies with dual reactivity to plas-minogen and complementary PR3 in PR3-ANCA vasculitis. J Am Soc Nephrol 2008; 19:2421-9.16. Karami-Djurabi R, Klok FA, Kooiman J, Velthuis SI, Nijkeuter M, Huisman MV. d-dimer testing in patients with suspect-ed pulmonary embolism and impaired re-nal function. Am J Med 2009;122:1050-3.

17. Case Records of the Massachusetts General Hospital (Case 17-1978). N Engl J Med 1978;298:1014-21.18. Schmidt HW, Hargraves MM, Ander-sen HA, Daugherty GW. Pulmonary changes seen in lung purpura and some of the other collagen diseases. Can Med Assoc J 1963;88:658-65.19. Eagen JW, Memoli VA, Roberts JL, Matthew GR, Schwartz MM, Lewis EJ. Pulmonary hemorrhage in systemic lupus erythematosus. Medicine (Baltimore) 1978;57:545-60.20. Zamora MR, Warner ML, Tuder R, Schwarz MI. Diffuse alveolar hemorrhage and systemic lupus erythematosus: clini-cal presentation, histology, survival, and outcome. Medicine (Baltimore) 1997; 76:192-202.21. Chang MY, Fang JT, Chen YC, Huang CC. Diffuse alveolar hemorrhage in sys-temic lupus erythematosus: a single cen-ter retrospective study in Taiwan. Ren Fail 2002;24:791-802.22. Shen M, Zeng X, Tian X, et al. Diffuse alveolar hemorrhage in systemic lupus erythematosus: a retrospective study in China. Lupus 2010;19:1326-30.23. Kwok SK, Moon SJ, Ju JH, et al. Dif-fuse alveolar hemorrhage in systemic lupus erythematosus: risk factors and clinical outcome: results from affiliated

hospitals of Catholic University of Korea. Lupus 2011;20:102-7.24. Deane KD, West SG. Antiphospholip-id antibodies as a cause of pulmonary capillaritis and diffuse alveolar hemor-rhage: a case series and literature review. Semin Arthritis Rheum 2005;35:154-65.25. Isono M, Araki H, Haitani T, et al. Diffuse alveolar hemorrhage in lupus ne-phritis complicated by microscopic poly-angiitis. Clin Exp Nephrol 2011;15:294-8.26. Yadla M, Krishnakishore C, Reddy S, et al. An unusual association of anti-GBM diseases and lupus nephritis presenting as pulmonary renal syndrome. Saudi J Kidney Dis Transpl 2011;22:349-51.27. Schwartz MM, Korbet SM, Katz RS, Lewis EJ. Evidence of concurrent immu-nopathological mechanisms determining the pathology of severe lupus nephritis. Lupus 2009;18:149-58.28. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomeru-lonephritis in systemic lupus erythemato-sus revisited. Kidney Int 2004;65:521-30. [Erratum, Kidney Int 2004;65:1132.]29. Appel GB, Pirani CL, D’Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol 1994; 4:1499-515.Copyright © 2012 Massachusetts Medical Society.

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