CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

Richard C. Cabot, Founder, Nancy Lee Harris, M.D., Editor, Jo-Anne O. Shepard, M.D., Associate Editor, Eric S. Rosenberg, M.D., Associate Editor, Alice M. Cort, M.D., Associate Editor, Sally H. Ebeling, Assistant Editor, Christine C. Peters, Assistant Editor

Case 20-2012 — A 77-Year-Old Man with Leg Edema, Hematuria, and Acute Renal Failure

Hasan Bazari, M.D., Alexander R. Guimaraes, M.D., Ph.D., and Yael B. Kushner, M.D.

N Engl J Med 2012; 366:2503-2515June 28, 2012

Article

References

PRESENTATION OF CASE

Dr. Jonathan Reisman (Internal Medicine): A 77-year-old man was transferred to this hospital because of leg edema, hematuria, and acute renal failure.

The patient had a history of hypertension, atrial fibrillation, and an aortic aneurysm. He had been in his usual health until approximately 1 month before admission, when bilateral lower-leg edema developed, followed by a red rash on the feet. He saw his physician, who noted worsening hypertension; the patient's antihypertensive medications were changed, including discontinuation of amlodipine, a short trial of atenolol (which caused increased shortness of breath and wheezing), and initiation of diltiazem, without improvement in blood-pressure control and peripheral edema. Twenty days before admission, he saw his cardiologist and reported leg swelling and dyspnea. On examination, the blood pressure was 156/90 mm Hg and the pulse 70 beats per minute (irregularly irregular rhythm), with 3+ lower-leg edema. Diltiazem was stopped, and chlorthalidone begun. At a follow-up visit 5 days later, the patient reported slight improvement in dyspnea, his weight had decreased 3.6 kg, and the blood pressure was 146/80 mm Hg. The blood urea nitrogen level was 34 mg per deciliter (12.1 mmol per liter) (reference range, 8 to 25 mg per deciliter [2.9 to 8.9 mmol per liter]), and the creatinine, which reportedly had been 1.4 mg per deciliter (123.8 μmol per liter) the previous year, was 2.7 mg per deciliter (238.7 μmol per liter) (reference range, 0.60 to 1.50 mg per deciliter [53.0 to 132.6 μmol per liter]). Chlorthalidone and lisinopril were stopped, and follow-up was scheduled. Medications also included aspirin (81 mg), terazosin, and a combination of oxycodone and acetaminophen.

During the next week, subjective fevers and shaking chills developed; chest tightness occurred occasionally, but dyspnea on exertion lessened. Six days before this admission, two episodes of vomiting, with nonbilious emesis, and one episode of hemoptysis occurred. The urine appeared dark red. The next day, the patient went to the emergency department at another hospital. On examination, the height was 170 cm, the weight 72.1 kg, the blood pressure 141/85 mm Hg, the pulse 80 beats per minute and irregular, the temperature 36.7°C, the respiratory rate 22 breaths per minute, and the oxygen saturation 98% while the patient was breathing ambient air. There were fine crackles at the base of the left lung and a papular rash on the legs, without pretibial edema; the remainder of the examination was normal. Blood levels of total protein, phosphorus, magnesium, total bilirubin, creatine kinase, amylase, lipase, uric acid, IgA, IgG, and complement (C3 and C4) were normal, as were tests of coagulation and liver function. Testing was negative for antibodies to glomerular basement membrane (GBM) and for antineutrophil cytoplasmic antibodies (ANCA), including those with a cytoplasmic pattern of staining (c-ANCA, antibodies to serine proteinase 3) and those with a perinuclear pattern of staining (p-ANCA, antibodies to myeloperoxidase); other test results are shown in Table 1TABLE 1

Laboratory Data.

. Specimens of urine and blood were cultured, and intravenous fluids and ceftriaxone were administered. The patient was admitted to the other hospital.

Renal ultrasonography reportedly showed an abdominal aortic aneurysm of 8 cm. Computed tomography (CT) of the abdomen and pelvis, without the administration of contrast material, reportedly showed a circumferential fusiform aneurysm (8.3 cm) of the infrarenal abdominal aorta and another aneurysm (2 cm) in the right iliac artery. Terazosin, Lactobacillus acidophilus, heparin, clonidine, omeprazole, ferrous sulfate, nifedipine, and a polyvalent pneumococcal vaccine were administered. The blood level of creatinine rose daily. On the third day, testing for antinuclear antibodies was negative, and no monoclonal immunoglobulin was detected; other test results are shown in Table 1. On the second, third, and fourth hospital days, methylprednisolone (500 mg daily) was administered. On the third day, insulin was added. A unit of leukocyte-poor packed red cells was transfused. On the fifth hospital day, blood cultures drawn on admission remained sterile. A renal biopsy was performed. The next afternoon, pathological examination of the biopsy tissue revealed mild proliferative glomerulonephritis with crescents, segmental nodular glomerulosclerosis, diffuse linear immunofluorescence reactivity for IgG along the GBM, and signs of active and healed mesangiolysis, moderate tubular atrophy, and widespread endothelial-cell injury. The patient was transferred to this hospital.

The patient had a history of intermittent hemoptysis during the previous 5 years and reported no recent headache, changes in vision, malaise, fatigue, chest or abdominal pain, or diarrhea. He had hypertension, atrial fibrillation (for which he had declined anticoagulation therapy), hepatic and renal cysts, benign prostatic hypertrophy, and an aneurysm (4.3 cm by 4.4 cm) of the ascending thoracic aorta as revealed by CT imaging 2 years earlier. He had had orthopedic surgery, an appendectomy, and a deep venous thrombosis that was treated with heparin. He was married, had children, and was retired from the construction industry. He was a current cigarette smoker (55 pack-years), drank alcohol occasionally, and did not use illicit drugs. His father died at 58 years of age of myocardial infarction, his mother died at 67 years of age of breast cancer, a daughter had breast cancer, and two children had diabetes mellitus.

On examination, the blood pressure was 135/85 mm Hg and the pulse 85 beats per minute and irregular; the temperature, respiratory rate, and oxygen saturation were normal. He had faint crackles in both lungs, 3+ pitting edema to the knees, and a nonpalpable, pink, blanching macular rash on both medial malleoli; the remainder of the examination was normal. Blood levels of protein, albumin, globulin, phosphorus, and magnesium were normal, as were tests of coagulation and liver function; other test results are shown in Table 1. A chest radiograph showed focal, patchy opacification in the right lower lobe.

Diagnostic test results were received, and management decisions were made.

DIFFERENTIAL DIAGNOSIS

Dr. Hasan Bazari: May we review the imaging studies?

Dr. Alexander R. Guimaraes: The initial chest radiograph (Figure 1AFIGURE 1

Imaging Studies.

) showed increased reticulonodular opacities at both lung bases, more on the left lung than on the right lung. A high-resolution CT scan of the chest (Figure 1B and 1C) showed centrilobular emphysema at the apexes of the lungs; at the bases, where the crackles were heard, there were small reticular opacities without gross consolidation (Figure 1C). Ground-glass opacities and interlobular septal thickening (in a “crazy paving” pattern), which are considered suggestive of pulmonary hemorrhage, were not seen. A CT scan of the abdomen without intravenous contrast material (Figure 1D and 1E) showed a heavily calcified aneurysm of the infrarenal abdominal aorta that measured approximately 8 cm in maximal cross-sectional diameter.

Dr. Bazari: I am aware of the diagnosis in this case. This 77-year-old man presented with progressive renal failure, leg edema, and hemoptysis. He meets the criteria for the syndrome known as rapidly progressive glomerulonephritis, which is defined as a loss of renal function of at least 50% in less than 3 months and evidence of glomerular injury, with hematuria and proteinuria.1 The hematuria is of upper tract origin, with dysmorphic red cells and often red-cell casts in the sediment. The pathological correlate of the clinical syndrome of rapidly progressive glomerulonephritis is crescentic glomerulonephritis, in which crescents are formed by extracapillary proliferation of epithelial cells and more than 50% of the glomeruli are affected.2

Rapidly Progressive Glomerulonephritis

Rapidly progressive glomerulonephritis is caused by three major categories of disease: anti-GBM disease (in approximately 10% of cases), pauci-immune crescentic glomerulonephritis (in approximately 60%), and immune-complex glomerulonephritis (in approximately 30%). The clinician will need to decide on the risks and benefits of empirical therapy with immunosuppression while the evaluation is in progress. Our patient was empirically treated with glucocorticoids because of the results of the urinalysis and the presence of dysmorphic red cells in the sediment.

Goodpasture's Syndrome

This patient had a history of intermittent hemoptysis and was a smoker. Ernest Goodpasture described two cases of pulmonary hemorrhage with systemic vasculitis in 1918, which he ascribed to the influenza epidemic.3 Goodpasture's syndrome was later shown to be due to autoantibodies to the noncollagenous 1 (NC1) domain of type IV collagen in the GBM.4,5 Patients with Goodpasture's syndrome (also known as anti-GBM disease) often present with the abrupt onset of oliguria, hematuria, and acute renal failure, as this patient did.6 The age distribution is bimodal — young men who smoke present with a pulmonary–renal syndrome, and women in their sixth and seventh decades present with disease limited to the kidney.7 Lung involvement occurs in patients who smoke, such as this patient, presumably because of lung injury and the exposure of new epitopes to the immune system. Diagnosis is made by the detection of the antibody in the blood and of the deposition of IgG on the GBM on biopsy.

This patient could have anti-GBM disease, on the basis of acute glomerulonephritis and the history of hemoptysis. However, the test for anti-GBM antibody was negative.

Pauci-Immune Glomerulonephritides

The more common causes of rapidly progressive glomerulonephritis are the pauci-immune necrotizing glomerulonephritides, including the ANCA-associated vasculitides — microscopic polyangiitis, granulomatosis with polyangiitis (formerly Wegener's granulomatosis), and the Churg–Strauss syndrome. Microscopic polyangiitis is a vasculitis of the small and medium vessels8 that typically is manifested by prolonged constitutional symptoms,9 with renal involvement in 80% of patients10 and pulmonary involvement in 20 to 55% of patients.11 Mononeuritis multiplex and cutaneous lesions occur less frequently.12 Patients present with hematuria with or without proteinuria, occasionally in the nephrotic range, and 10 to 46% require dialysis.9,10,12 Circulating ANCA directed against myeloperoxidase (p-ANCA) are found in 50 to 75% of patients.10,13,14 The positive predictive value of the test for ANCA for a diagnosis of microscopic polyangiitis in patients with active renal disease ranges from 47 to 99%.15

Granulomatosis with polyangiitis typically involves the upper and lower respiratory tracts and is associated with glomerulonephritis. The disease can be indolent, with involvement of the sinuses (chronic sinusitis), the ears (otitis media), and the trachea (tracheal stenosis),16 before the onset of systemic vasculitis. The disease mostly affects white men and women in the fifth decade.17,18Most patients have upper-airway or lung involvement, which varies from nodules that cavitate to diffuse alveolar hemorrhage. Eye disease occurs in one third to one half of patients. Skin involvement can include a vasculitic rash and nonhealing ulcers. This patient had hemoptysis and a rash but no upper airway disease. Most patients have a positive test for ANCA directed against proteinase 3, with the immunofluorescence staining in a cytoplasmic distribution (c-ANCA).19 The ANCA tests have a sensitivity up to 90% and a specificity up to 98%. In this case, the negative ANCA test argues against the diagnosis of granulomatosis with polyangiitis but does not rule it out.

The third ANCA-associated disease is Churg–Strauss syndrome, characterized by asthma, eosinophilia, granulomatous vasculitis, and tissue eosinophilic infiltration.20-22 It occurs in patients in their 30s and 40s, unlike this patient, with a slight male predominance. The renal involvement is typically mild, unlike in this case.23 ANCA directed against myeloperoxidase (p-ANCA) can be detected in 65% of patients. Eosinophilia and elevated IgE levels are characteristic features. Our patient did not have any asthma or eosinophilia, making the Churg–Strauss syndrome unlikely.

Immune-Complex Glomerulonephritides

The immune-complex glomerulonephritides that need to be considered include the hypocomplementemic and normocomplementemic groups. Disorders associated with low C3 levels include systemic lupus erythematosus, poststreptococcal glomerulonephritis, membranoproliferative glomerulonephritis, endocarditis, visceral abscesses, and shunt nephritis. The major disorder associated with low C4 levels is cryoglobulinemia. Normocomplementemic glomerulonephritides include mainly IgA nephropathy, Henoch–Schönlein purpura, and fibrillary glomerulonephritis.

Postinfectious glomerulonephritis occurs after an upper respiratory tract infection or skin infection.24,25 There was no preceding infection to explain this patient's disease. An immune complex glomerulonephritis caused by endocarditis was much more common in the pre-antibiotic era than it is now.26-29 We have seen cases of Henoch–Schönlein purpura triggered by infection with bacteria, including Staphylococcus aureus.30 In this patient, there was no evidence of infection or sepsis.

Cryoglobulinemia of any of the three types (type I, monoclonal; type II, monoclonal plus polyclonal; and type III, polyclonal)31 involves the skin, with petechial rash, livedo reticularis, ulceration, and digital ischemia. Other manifestations include arthritis, central nervous system involvement, cardiac involvement, gastrointestinal vasculitis, and pulmonary involvement. This patient had a rash and renal disease, raising the possibility of cryoglobulinemia. However, he had no risk factors for and no clinical manifestations of an infection, such as hepatitis C,32,33 or a clonal or malignant hematologic disorder, which is typically associated with cryoglobulinemia.

Systemic lupus erythematosus is most often manifested in young women but can also occur in the elderly and in men. The manifestations include skin, joint, serosal, gastrointestinal, renal, psychiatric, pulmonary, and hematologic manifestations. The symptoms in patients with lupus nephritis can range from none to rapidly progressive glomerulonephritis. This elderly male patient had none of the classic features of systemic lupus erythematosus.

IgA nephropathy and Henoch–Schönlein purpura are IgA-deposition diseases that cause glomerulonephritis. IgA nephropathy34 is the most common cause of glomerulonephritis, and symptoms range from asymptomatic hematuria to rapidly progressive glomerulonephritis.35Proteinuria, hypertension, older age, male sex, black race, and the presence of scarring and crescents on examination of a renal-biopsy specimen are all associated with a poor prognosis in patients with IgA nephropathy.36 Patients with Henoch–Schönlein purpura and renal disease have palpable purpura and gastrointestinal manifestations, including abdominal pain, bleeding, infarction, and intussusceptions.37 This patient with rapidly progressive glomerulonephritis and a rash could have an IgA-mediated process; however, the renal-biopsy specimen did not show IgA deposition.

Summary

In a patient with rapidly progressive renal failure, the finding of red-cell casts allows for a clinical classification of rapidly progressive glomerulonephritis. We can perform a sequential serologic evaluation (Figure 2FIGURE 2

Sequential Approach to the Diagnosis of Rapidly Progressive Glomerulonephritis.

), but the pattern of organ involvement may help define the pretest probability of a certain disease (Table 2TABLE 2

Anatomical Sites Involved in Conditions that Can Cause Rapidly Progressive Glomerulonephritis.

). Anti-GBM antibodies are highly sensitive and specific and their presence can be confirmed by Western blot analysis. Similarly, ANCA-associated vasculitis may be diagnosed when the clinical syndrome is classic, and a confirmatory tissue diagnosis may not be necessary. In this patient, the serologic evaluation was negative, but results of examination of a kidney-biopsy specimen were interpreted as anti-GBM disease.

Confronted with a negative serologic assay and a biopsy specimen showing anti-GBM disease, one has to explore the limitations of the test and consider whether the result may be a false negative. The ELISA may be spuriously negative, or the biopsy specimen may have shown nonspecific binding of IgG instead of true anti-GBM antibody. In addition, even a test that is 98% sensitive will be negative in 2% of patients with anti-GBM disease. We considered the possibility that this patient had antibodies that bound mainly to the kidney with high affinity and circulated only in low levels, below the sensitivity of the ELISA.38 Higher-avidity antibodies have been shown to be associated with more severe disease.39 Another possibility is that the target antigen for the anti-GBM antibody was not NC1. In patients with Alport's syndrome, who have mutations in the type IV collagen gene, anti-GBM disease may develop after transplantation in response to the normal antigen in the allograft. There is also a case report of anti-GBM disease in which the antigen was a renal 59-kD antigen.40 These new autoantibodies should be detected by Western blot analysis, in which the patient's serum is screened for an autoantibody to the Goodpasture's antigen.

On the basis of the clinical presentation, we believed that the patient had a low-titer, high-affinity antibody that was causing anti-GBM disease. Therefore, we requested a Western blot analysis to look for an antibody in the patient's serum to bind to the 27-kD and 54-kD proteins present in a collagenase digestion of the GBM, which form monomers and dimers in the NC1 domain of the α3 chain of type IV collagen.41,42 In case immunofluorescence with anti-IgG2 and anti-IgG3 would yield better staining than the traditional IgG1 staining, a subclass analysis was also sought.

Dr. Eric S. Rosenberg (Pathology): Dr. Reisman, would you tell us what you and your team were considering when this patient arrived?

Dr. Reisman: When this patient arrived at 1 a.m., we were aware of his rapidly progressive kidney failure, which was confirmed with a biopsy examination showing crescentic glomerulonephritis. The differential diagnosis included ANCA-associated vasculitis, anti-GBM disease, lupus, poststreptococcal glomerulonephritis, Henoch–Schönlein purpura, and IgA nephropathy. The patient's history of one episode of hemoptysis suggested Goodpasture's syndrome, whereas the vomiting suggested Henoch–Schönlein purpura with gastrointestinal involvement. On examination, the rash on his legs was not palpable. However, he said with certainty that if he had run his hand over the rash with his eyes closed 1 or 2 weeks ago, he would have felt a texture to it. We awaited the serologic test results, and microscopical examination of a urine sample showed proteinuria, hematuria, and numerous granular casts. The patient had already received glucocorticoids to halt the kidney-function decline; the more immediate concern that first night involved controlling his hypertension, especially given his enlarged abdominal aortic aneurysm.

DR. HASAN BAZARI'S DIAGNOSIS

Goodpasture's syndrome.

PATHOLOGICAL DISCUSSION

Dr. Yael B. Kushner: A kidney biopsy was performed at the other hospital, and a specimen was sent for review. Light-microscopical examination of formalin-fixed tissue showed glomeruli with numerous cellular and fibrocellular crescents within the urinary space (Figure 3AFIGURE 3

Renal-Biopsy Specimen.

). The underlying glomeruli had a proliferative appearance, with occasional formation of well-developed mesangial nodules (Figure 3B). Some glomeruli had a loss of mesangial-cell nuclei and a lacy, disrupted appearance of the mesangial matrix, known as mesangiolysis (Figure 3C). Other glomeruli showed segmental or global sclerosis and adhesions to Bowman's capsule. The GBM was focally duplicated with periodic acid–Schiff staining. There was a minimal interstitial inflammatory infiltrate. Chronic changes were also identified in the tubulointerstitial compartment, with interstitial fibrosis and tubular atrophy. Renal tubules showed mild acute injury with epithelial-cell vacuolization and regenerative changes. A few arterioles showed marked edema with focal luminal occlusion and intramural fragmented red cells. Arterioles contained some intramural hyalinosis.

Immunofluorescence studies performed on frozen tissue (Figure 3D) showed relatively strong staining with IgG in a linear pattern along the GBM. Fibrin was seen within cellular crescents. IgM and C3 were seen in segmentally scarred glomeruli. Electron microscopy (not shown) revealed widespread effacement of podocyte foot processes. In addition, the endothelial cells were markedly edematous with focal subendothelial electron-lucent material. Deposits were not seen, and there were no tubuloreticular inclusions or other signs of immune-complex glomerulonephritis or autoimmune disease.

Cellular crescents seen on examination of a renal-biopsy specimen are the pathological equivalent of the clinical syndrome of rapidly progressive glomerulonephritis. Distinction among anti-GBM disease, pauci-immune (ANCA-associated) glomerulonephritis, and immune-complex glomerulonephritis is made on the basis of the pattern of immunofluorescence. In this case, the presence of linear immunofluorescence reactivity for IgG along the GBM is diagnostic of anti-GBM disease, which in the presence of pulmonary manifestations is referred to as Goodpasture's syndrome. In this patient, although the initial ELISA for anti-GBM antibodies was negative, anti-GBM antibody was subsequently detected with the use of Western blot analysis (Figure 3E).

The presence of prominent nodular glomerular changes raised the possibility of diabetic renal disease; this may have been an important pitfall in this case, because immunofluorescence studies of tissue specimens from patients with diabetes can also show a linear IgG pattern and the initial test for anti-GBM antibodies was negative in this patient. However, this patient does not have diabetes. What other possibilities exist for nodular glomerulosclerosis? Paraprotein deposition and immune-complex diseases with membranoproliferative patterns, such as membranoproliferative glomerulonephritis and cryoglobulinemia, can be ruled out on the basis of the findings on immunofluorescence and ultrastructural studies, as well as by the clinical history. An entity termed idiopathic nodular glomerulosclerosis has been described, typically in middle-aged men who have hypertension and who smoke.43 This diagnosis is possible in the presence of mesangiolysis, since healed mesangiolysis may later change to a nodular pattern.

The presence of arteriolar edema and luminal occlusion with intramural fragmented red cells along with ultrastructural signs of endothelial injury suggest subclinical thrombotic microangiopathy. Typical causes include malignant hypertension, antiphospholipid antibody syndrome (indicated by a positive test for lupus anticoagulant or other antiphospholipid, such as an anticardiolipin antibody or an antibody against B₂-glycoprotein 1), scleroderma, the hemolytic–uremic syndrome or thrombotic thrombocytopenic purpura, and drugs with vascular toxic effects. However, in this case, it is possible that the same injury (caused by smoking and hypertension) that led to the mesangiolysis and nodular glomerulosclerosis also led to arteriolar endothelial injury.

Dr. Bazari: Patients confirmed to have anti-GBM disease are treated with glucocorticoids, cyclophosphamide, and plasmapheresis.44 Aggressive treatment leads to better patient survival, approaching 85%. Renal survival with therapy is 65%, and poor prognostic criteria are oligoanuria and a serum creatinine level greater than 6 mg per deciliter (530.4 μmol per liter) at presentation.45Plasma exchange is continued until the antibody is no longer detected.

Dr. Rosenberg: Dr. Reisman, would you tell us what happened with this patient?

Dr. Reisman: We continued glucocorticoid therapy, used plasmapheresis to remove the anti-GBM antibodies, and started the administration of cyclophosphamide. The patient underwent open aortic aneurysm repair on the 10th hospital day, because of concern about rupture. At the time of discharge, on the 21st day, he had an undetectable level of anti-GBM antibodies in his serum, and his creatinine level was 3 mg per deciliter (265 μmol per liter). He presented 2 weeks later with progressive kidney failure that required hemodialysis. A month after that, a perforated viscus developed, and it was decided that surgical repair was not within his goals of care. He died soon thereafter.

Dr. Rosenberg: Are there any questions?

Dr. Lloyd Axelrod (Endocrinology): Dr. Bazari, I would be curious about your thoughts about the microangiopathic component and what the basis is for that finding.

Dr. Bazari: The patient did not have a microangiopathic hemolytic anemia. He had evidence of thrombotic microangiopathy in the kidney but not necessarily a systemic thrombotic microangiopathy. The presence of thrombotic microangiopathy on a biopsy specimen without the finding of a microangiopathic hemolytic anemia most likely results from local factors and is not a manifestation of a systemic disease.

A Physician: In the absence of the coexisting conditions that led to his death, what would the natural history of the kidney disease have been?

Dr. Bazari: The patient had stage 4 chronic kidney disease, with a creatinine level greater than 3 mg per deciliter. Anti-GBM disease tends to be self-limiting, and we usually treat for 3 to 6 months or until the anti-GBM antibody titer is undetectable. If there is end-stage renal disease, we still pay attention to the titer, since pulmonary hemorrhage can occur in association with the recurrence of the anti-GBM disease.

ANATOMICAL DIAGNOSIS

Goodpasture's syndrome.

Presented at the Medical Case Conference.

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