Case 20-2006 — An 84-Year-Old Man with Staphylococcal Bacteremia and Renal Failure
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《新英格兰医药杂志》
Presentation of Case
Dr. Alec D. Weisberg (Medicine): An 84-year-old man was transferred to this hospital because of staphylococcal bacteremia and renal failure. Two weeks before admission, fever, chills, nausea, vomiting, shortness of breath, productive cough, and generalized weakness developed. The patient went to the emergency department of a local hospital. The oxygen saturation was 88 percent while the patient was breathing ambient air. A radiograph of the chest showed patchy bilateral pulmonary infiltrates. He was admitted to the hospital. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus. He was treated with levofloxacin and cefotaxime for five days, and on the fifth day he was discharged home to complete a course of cephalexin. Five days later, a rash developed and he discontinued the cephalexin. Two days after that, his temperature rose to 39.2°C, with rigors. He was readmitted to the local hospital.
The patient reported no chest pain, shortness of breath, palpitations, abdominal pain, back pain, headache, visual changes, or joint pain and had a history of diabetes mellitus, cataracts, and sick sinus syndrome, for which a pacemaker had been placed seven years earlier. He was allergic to penicillin. He was a retired painter who had worked in shipyards, had quit smoking cigarettes more than 50 years previously, and did not drink alcohol. His medications were aspirin, atenolol, and glipizide.
On physical examination, the temperature was 38.5°C, the heart rate 111 beats per minute, the blood pressure 157/67 mm Hg, and the respiratory rate 24 breaths per minute. There were diminished breath sounds and bilateral chest crackles. A holosystolic murmur, grade 2/6, was heard at the apex radiating to the axilla. The abdomen was normal. There was a trace amount of peripheral edema in the legs and an erythematous, macular rash on the legs and face. Results of laboratory tests are shown in Table 1 and Table 2.
Table 1. Results of Hematology Laboratory Tests.
Table 2. Results of Chemistry Laboratory Tests.
Blood cultures were again positive for methicillin-sensitive S. aureus, and vancomycin was begun. On the second hospital day, a transthoracic echocardiogram revealed an ejection fraction of 55 percent, a thickened posterior leaflet of the mitral valve, mild mitral regurgitation, and left atrial enlargement. Computed tomography (CT) of the chest showed no infiltrates, but the presence of honeycombing at the lung bases with pleural calcification suggested exposure to asbestos. On the fourth hospital day, respiratory distress and hypoxemia developed; examination showed an elevated jugular venous pressure and diffuse crackles in both lungs. The patient was transferred to the medical intensive care unit. Furosemide was administered intravenously. Repeated CT of the chest revealed new bilateral patchy infiltrates in the upper lobes of the lungs, and the antibiotic treatment was broadened to include metronidazole and moxifloxacin. On the fifth hospital day, he was transferred to this hospital.
On admission, the temperature was 36.8°C, the pulse 96 beats per minute, the blood pressure 113/60 mm Hg, the respirations 24 breaths per minute, and the oxygen saturation 94 percent while the patient was breathing 4 liters per minute of oxygen by nasal cannula. The jugular venous pressure was 9 cm, and crackles extended halfway up both lung fields. Results of laboratory tests are shown in Table 1, Table 2, and Table 3. Lisinopril was started, and diuresis was continued. Moxifloxacin and metronidazole were discontinued. On the second hospital day, a transthoracic echocardiogram revealed an ejection fraction and valvular abnormalities similar to those noted at the other hospital, but no evidence of echogenicity on the mitral valve.
Table 3. Results of Immunology Laboratory Tests.
On the third day, petechial and palpable purpuric lesions developed on the patient's left great toe and the dorsum of the feet. During the next several days, the rash spread up his legs to his abdomen. Results of laboratory tests on days 3, 4, and 5 are shown in Table 4. On the fifth hospital day, a transesophageal echocardiogram showed no vegetations on the valves or pacemaker wire. On renal ultrasonography there was no hydronephrosis. Lisinopril was discontinued, and isosorbide dinitrate and hydralazine were started.
Table 4. Results of Laboratory Tests of Urine.
Microscopical examination of a punch-biopsy specimen of the skin of the abdomen obtained on the eighth hospital day showed a mild interface dermatitis with a superficial perivascular lymphocytic infiltrate. A cryoglobulin composed of heterogeneous IgG, IgA, and IgM, with a cryocrit of 1 percent was present in the blood. Tests for hepatitis B antigen and hepatitis B and C antibodies were negative. Results of laboratory tests are shown in Table 2 and Table 3. On the 10th day, vancomycin was discontinued because of concern about a hypersensitivity reaction, and daptomycin was initiated.
On the 13th day, the temperature rose to 38.3°C, with worsening hypoxemia and respiratory distress. Blood cultures were again positive for methicillin-sensitive S. aureus. On the 16th day, daptomycin was discontinued, and linezolid, rifampin, aztreonam, and levofloxacin were added. On the 18th day, the patient was taken to the operating room, where a transesophageal echocardiogram showed a vegetation on the right atrial pacemaker lead; the pacemaker was removed, and a bronchoalveolar lavage was performed.
Shortly thereafter, the oxygen saturation dropped to 80 percent while the patient was breathing 4 liters per minute of oxygen by nasal cannula. Tests of arterial blood gases while he was breathing 100 percent oxygen by way of a nonrebreathing face mask revealed a pH of 7.45, a partial pressure of carbon dioxide of 46 mm Hg, a partial pressure of oxygen of 112 mm Hg, and a bicarbonate level of 30 mEq per liter. The patient was transferred to the intensive care unit. The jugular veins were distended to the angle of the jaw, and diffuse crackles were heard in both lungs. After diuresis, the oxygen requirement fell to 4 liters of oxygen by nasal cannula. The patient was transferred back to the medical unit. Results of laboratory tests on days 19, 23, and 24 are shown in Table 1, Table 2, and Table 4.
On the 23rd hospital day, the purpuric lesions spread to the arms. A punch-biopsy specimen of the skin of the left upper arm obtained the next day showed necrotizing vasculitis with granular perivascular deposition of C3 (3+), fibrin (4+), IgM (1+), and trace IgG; IgA was not detected.
On the 25th day, the patient became somnolent and unresponsive. Cultures of the bronchoalveolar-lavage fluid yielded no growth of microorganisms, and levofloxacin and aztreonam were discontinued. Tests of arterial blood gases with the patient breathing supplemental oxygen revealed a pH of 7.22, a partial pressure of oxygen of 220 mm Hg, and a partial pressure of carbon dioxide of 80 mm Hg. The fractional excretion of sodium was less than 1 percent. He was transferred to the intensive care unit. Bilevel positive airway pressure was instituted. The creatinine level rose to 4.0 mg per deciliter (354 μmol per liter) on the 26th day. The urinary sediment contained dysmorphic red cells and red-cell casts. A repeated cryocrit was 2 percent. Results of other laboratory tests are shown in Table 1, Table 2, and Table 3. Methylprednisolone (1 g) was given intravenously, and plasmapheresis was initiated.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Mark D. Denton: May we see the imaging studies?
Dr. Subba R. Digumarthy: A chest radiograph obtained on the eighth day (Figure 1A) shows decreased lung volumes, multiple reticular opacities predominantly in the lung bases with cystic lucencies consistent with pulmonary fibrosis, and multiple ground-glass opacities predominantly in the upper lobes.
Figure 1. Radiograph (Panel A) and CT (Panels B and C) of the Chest.
A chest radiograph obtained with the use of portable equipment on the eighth hospital day (Panel A) shows decreased lung volumes with diffuse reticular opacities suggestive of pulmonary fibrosis. There are bilateral asymmetric air-space opacities predominantly in the upper lobes. CT of the chest (Panel B) shows bilateral asymmetric ground-glass opacities predominantly affecting the upper lobes (arrows). There are reticular opacities, honeycombing, and traction bronchiectasis predominantly affecting the lower lobes (Panel C), and a calcified pleural plaque is evident over the right hemidiaphragm (arrow).
CT of the chest performed three days after admission (Figure 1B and 1C) shows calcification of the diaphragmatic pleura consistent with previous asbestos exposure, multiple cystic areas predominantly in the lower lobes consistent with honeycombing, subpleural reticular opacities, architectural distortion, and traction bronchiectasis suggestive of pulmonary fibrosis. There are multiple ground-glass opacities that are bilateral and asymmetric and predominantly affect the upper lobes. A follow-up CT obtained on the 16th hospital day showed further progression of the ground-glass opacities also involving the lower lobes.
Dr. Sarah Chua: The transthoracic echocardiogram obtained on the second hospital day showed thickening of the posterior mitral annulus. A transesophageal echocardiogram (Figure 2A, and Video Clip 1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org) obtained on the fifth hospital day showed increased echodensity originating from the posterior mitral annulus extending toward the mitral leaflet, suggestive of posterior mitral annular calcification. A color Doppler study showed a reverse systolic flow from the left ventricle to the left atrium, compatible with mild mitral regurgitation. No vegetation was seen on the valves or on the pacemaker lead.
Figure 2. Echocardiographic Images.
A transesophageal echocardiogram obtained on the fifth hospital day (Panel A) shows increased echodensity that originates from the posterior mitral annulus and extends into the mitral leaflet, consistent with the presence of posterior mitral annular calcification (PMAC) (arrow). An intraoperative transesophageal echocardiogram obtained on the 18th day (Panel B) shows a pacemaker lead in the right atrium (RA) with an abnormal, shaggy mobile lesion attached to its tip (arrow), seen on the midesophageal view. Panel C shows an enlarged view of the right atrium with the mobile mass (arrow) attached at the tip of the right atrial pacemaker lead (arrowhead). LA denotes left atrium, LV left ventricle, and RV right ventricle.
An intraoperative transesophageal echocardiographic study done 12 days later (Figure 2B and 2C, and Video Clips 2 and 3 in the Supplementary Appendix) shows an echodense mobile mass attached to the pacemaker lead in the right atrium, which is consistent with a vegetation.
Dr. Denton: This patient had a prolonged illness characterized by persistent and inadequately treated staphylococcal bacteremia, hypoxemic episodes requiring transfer to the intensive care unit, and a steady decline in renal function. In a patient with acute renal failure, it is useful to consider prerenal, intrinsic, and postrenal causes. Prerenal causes are unlikely in this patient, on the basis of clinical findings. Postrenal causes can largely be dismissed given the absence of hydronephrosis on imaging. In the setting of recurrent sepsis and hypoxemia, acute tubular injury seems likely. The use of penicillin-based antibiotics raises the possibility of acute interstitial nephritis. The eventual occurrence of dysmorphic red cells and red-cell casts in the urinary sediment and the severe proteinuria, together with the presence of purpuric skin lesions, is highly suggestive of an active glomerulonephritis.
Differential Diagnosis
In this patient with persistent methicillin-sensitive S. aureus infection, an infection-related immune-complex–mediated glomerulonephritis seems most likely. Other causes of palpable purpura and glomerulonephritis include Henoch–Sch?nlein purpura, antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis, systemic lupus erythematosus, and essential mixed cryoglobulinemia. Atheroembolic disease causes palpable purpura and may cause renal failure, but the renal failure is due to a tubulointerstitial lesion, not glomerulonephritis. Nonpalpable purpura resulting from thrombocytopenia can be seen with the hemolytic–uremic syndrome and sepsis-associated disseminated intravascular coagulation. The hemolytic–uremic syndrome is associated with renal failure and sometimes nephrotic-range proteinuria, but not with red-cell casts. Other causes of renal failure and nonblanching skin lesions are amyloidosis and Waldenstr?m's macroglobulinemia.
Staphylococcal Infection and Glomerulonephritis
There are two principal clinical presentations of staphylococcus infection associated with glomerulonephritis.1 Chronic low-grade S. epidermidis infection of central nervous system shunts results in an immune-complex–mediated glomerulonephritis associated with a membranoproliferative histologic pattern, so-called shunt nephritis, frequently associated with severe proteinuria. S. aureus infection is also associated with immune-complex–mediated glomerulonephritis, but because of the acute nature of the infection, the histologic finding is usually a focal or diffuse proliferative glomerulonephritis, which may be associated with a rapid deterioration of renal function and variable proteinuria.
Staphylococcal Superantigen–Associated Glomerulonephritis
Several reports have described a third clinical entity, termed "staphylococcal superantigen–associated glomerulonephritis,"2 characterized by rapidly progressive glomerulonephritis and nephrotic-range proteinuria, purpura, elevated serum levels of IgA and IgG, and normal complement levels. In these reports, the patients had a variety of S. aureus infections, but a common link was a prolonged and persistent infection despite antimicrobial therapy, as seen in this case.3 A role for bacterial superantigen is suggested by the detection of a high frequency of T cells positive for T-cell receptor–V 5 and 8 in the peripheral circulation.4 The glomerular lesions included mesangial proliferation, membranoproliferative glomerulonephritis, and diffuse proliferative glomerulonephritis. All cases showed extensive IgA deposition in glomeruli,5 and in patients with purpura, IgA was also seen in the skin lesions,2,6 leading to a pathological diagnosis of Henoch–Sch?nlein purpura. This patient had persistent staphylococcal septicemia, glomerulonephritis with palpable purpura, elevated serum levels of IgA and IgG, and normal complement levels, consistent with the presence of staphylococcal superantigen–associated glomerulonephritis.
Henoch–Sch?nlein Purpura
Henoch–Sch?nlein purpura is a clinical syndrome characterized by a rash, arthralgias, abdominal pain, and renal disease. It is most common in children but can occur later in life, usually with a worse renal prognosis. This systemic vasculitis with a prominent cutaneous component is characterized by the tissue deposition of IgA-containing immune complexes. Renal involvement consists of an immune-complex–mediated glomerulonephritis with abundant IgA deposition. Complement levels are usually normal, as in this case. The clinical picture in this case, however, does not fit entirely with this diagnosis. First, there is no arthralgia or abdominal pain. Second, the distribution of the rash is slightly atypical; in this disease, it is usually concentrated on the back of the legs and buttocks and almost never affects the upper torso or back. Finally, the absence of IgA deposits in the skin-biopsy specimen argues against the diagnosis of Henoch–Sch?nlein purpura. The absence of IgA on the biopsy specimen may be due to the disappearance of IgA if the area from which the biopsy specimen was obtained represents an old lesion.
ANCA-Associated Vasculitis
ANCA-associated vasculitis may present with isolated purpuric rash and glomerulonephritis. It is also associated with normal complement levels. S. aureus infection has been shown to be a risk factor for relapse of Wegener's granulomatosis. However, ANCA-associated vasculitis is ruled out by the absence of ANCA on serial immunofluorescence testing and enzyme-linked immunosorbent assay.
Systemic Lupus Erythematosus
Although the antinuclear antibody titer is high, a diagnosis of systemic lupus erythematosus is unlikely in view of the patient's male sex, absence of prior symptoms, negative test for double-stranded DNA, and normal complement levels. Also, histologic examination of a skin-biopsy specimen would usually show evidence of IgG, IgA, and IgM deposition.
Other Causes of Renal Injury
Acute Tubular Injury
Hospital-associated acute renal failure is frequently multifactorial. Although I am convinced that a glomerular process exists here, I would argue that a large component of the renal dysfunction in this case is due to acute tubular injury. The initial deterioration in this patient's renal function occurred when respiratory distress and hypoxemia prompted admission to the intensive care unit at the first hospital. Although his blood pressure at that time was not mentioned, it was low on transfer to this hospital. This period of hypoxemia and probable hypotension in the setting of S. aureus bacteremia is likely to cause tubular injury in an elderly patient with diabetes and is probably responsible for the early deterioration in renal function. The high level of urinary sodium is in keeping with the presence of tubular injury. The urinary sediment should be examined for granular casts.
Acute Interstitial Nephritis
Acute interstitial nephritis should be considered in a patient with a rash after exposure to cephalosporins. However, this disease is usually associated with an erythematous rash, white-cell casts in the urine, and kidneys that appear enlarged on ultrasound study; these findings were not present in this case. The low-grade eosinophiluria seen later was probably caused by the glomerular inflammation.
Septic Emboli
Thickening of the mitral valve was seen on echocardiograms, a finding that could indicate a vegetation. Autopsy studies have shown that septic emboli and small foci of cortical necrosis are common in patients with infective endocarditis.7 However, for renal emboli to cause a clinically important deterioration in renal function, there would have to be a substantial reduction in the blood flow to both kidneys from large emboli. Such an event would be rare and would be accompanied by hematuria, flank pain, and an elevated level of lactate dehydrogenase; these features were not present in this case.
Summary
I believe this patient had staphylococcal superantigen–mediated glomerulonephritis, complicated by acute tubular injury. I predict that examination of a renal-biopsy specimen in this case will show both evidence of tubular injury and a proliferative glomerulonephritis with predominant IgA deposition. Although this pathological description is also typical of Henoch–Sch?nlein purpura, I prefer to call this condition staphylococcal superantigen–mediated glomerulonephritis to emphasize the etiologic importance of the persistent S. aureus bacteremia.
Dr. Nancy Lee Harris (Pathology): Dr. Haupert, can you give us your thoughts as you cared for this patient?
Dr. Garner T. Haupert, Jr. (Nephrology): The clinical situation suggested renal failure due to prerenal azotemia or acute tubular injury, although we did not see any casts in the sediment that suggested the latter. This patient's clinical condition would not have allowed us to perform a renal biopsy according to the standard method, in which the patient must lie prone without moving and be able to hold his or her breath during the biopsy.
The team considered the diagnosis of immune-complex–mediated glomerulonephritis associated with endocarditis; however, the test for rheumatoid factor was negative and the complement levels were normal. On the 26th hospital day, the urinalysis finally showed dysmorphic red cells and red-cell casts, which are diagnostic of glomerulonephritis, and the cryoglobulin was characterized as type 3. Although this type is less frequently associated with glomerulonephritis than is type 2, in 10 to 12 percent of cases, renal injury can occur. Because the patient's condition was deteriorating and we were not certain that we could perform a renal biopsy right away, we elected to start plasma-exchange and pulsed corticosteroid therapy.
The diagnostic procedure was a renal biopsy that was performed at the bedside by interventional radiology with the use of imaging guidance.
Clinical Diagnosis
Glomerulonephritis, possibly due to mixed cryoglobulinemia, type 3.
Dr. Mark D. Denton's Diagnoses
Staphylococcal superantigen–associated glomerulonephritis.
Acute tubular necrosis.
Pathological Discussion
Dr. Robert B. Colvin: Light-microscopical examination of the renal-biopsy specimen revealed normal architecture. Tubular atrophy and fibrosis affected about 20 percent of the cortex. The arteries showed mild intimal fibrosis, and the arterioles had hyaline material in their walls, indicative of long-standing mild vascular disease. No vasculitis was found. Red-cell casts were evident in medullary tubules (Figure 3A). Mild acute tubular injury was present, characterized by flattening and vacuolization of the epithelium; glomeruli showed mild, diffuse mesangial hypercellularity and focal accumulation of neutrophils in capillary loops (Figure 3B). One glomerulus had segmental endocapillary hypercellularity with necrosis and karyorrhexis (Figure 3C). No crescents or globally sclerotic glomeruli were found. Pseudothrombi, typical of cryoglobulinemia, were not seen. Staining with periodic acid–Schiff (PAS) revealed a normal glomerular basement membrane, without thickening or duplication. PAS-positive granules were evident in the mesangium in most glomeruli (Figure 3D). IgA-containing deposits can be PAS-positive because of the stain's relatively high carbohydrate content, and this is a clue to the presence of IgA nephropathy.
Figure 3. Light-Microscopical Examination of the Renal-Biopsy Specimen.
The medulla (arrow) has tubules with hemolyzed red-cell casts (Panel A, hematoxylin and eosin). The cortex (Panel B, hematoxylin and eosin) shows acute tubular injury with loss of brush borders, cellular debris in the lumen, and thinning of the cytoplasm (arrows). The glomerulus shows mild mesangial hypercellularity and occasional neutrophils in capillary loops. A glomerulus (Panel C, hematoxylin and eosin) has segmental necrosis and karyorrhexis (arrow). Deposits positive on periodic acid–Schiff staining are present in the mesangium (Panel D).
Immunofluorescence microscopy confirmed the presence of IgA deposits (2+ to 3+) in the glomerular mesangium and focally along the glomerular basement membrane (Figure 4A). These deposits also stained for C3 (3+ to 4+) and fibrin (1+ to 2+); lambda light chains were also present and were more numerous than kappa light chains. The deposits did not stain for IgG, IgM, or C1q.
Figure 4. Immunofluorescence and Electron-Microscopical Examination of the Renal-Biopsy Specimen.
A glomerulus (Panel A, anti-IgA antibody) shows granular IgA deposits, primarily in the mesangium. An electron micrograph (Panel B) shows amorphous, electron-dense deposits in the glomerular mesangium (arrows), and scattered electron-dense deposits in the glomerular basement membrane. Repeated immunofluorescence microscopy of additional sections of the skin-biopsy specimen reveals occasional microvascular granular IgA deposits (Panel C, arrow; anti-IgA antibody).
Electron-microscopical examination of one glomerulus (Figure 4B) showed numerous amorphous, electron-dense deposits in the mesangium and occasional subendothelial and subepithelial deposits. The glomerular basement membrane showed segmental duplication, and podocytes had effacement of foot processes.
The results are diagnostic of either IgA nephropathy or Henoch–Sch?nlein purpura. The disease appears to be mild in this case, because no crescents were found. The glomerular disease does not explain the elevated creatinine level, which is more likely to be due to the tubular injury in kidneys with chronic vascular disease.
To distinguish IgA nephropathy from Henoch–Sch?nlein purpura, we need evidence of systemic involvement either from the clinical history or from biopsies of other organs. In this case, a biopsy of the purpuric rash was performed. No IgA was seen in the initial studies. We repeated the stains on deeper levels of the skin-biopsy specimen (Figure 4C) and found occasional vessels that had IgA. Involvement in Henoch–Sch?nlein purpura is typically focal, and this finding provides evidence for that diagnosis.
The pathogenesis of the disease is still obscure. An association with bacterial or viral infection has repeatedly been reported, including staphylococcal sepsis with or without endocarditis.4,8,9,10,11 Drug hypersensitivity may also be a cause.12,13 In one case, Henoch–Sch?nlein purpura developed while a patient was receiving vancomycin for an S. aureus infection.10 The drugs may act by promoting the breakdown of the organism to an antigenic form.8,10
Henoch–Sch?nlein purpura is generally limited to one acute episode, whereas IgA nephropathy tends to be chronic; however, the two disorders may be biologically related.14,15,16 How infections or drugs provoke an IgA response and the vasculitis is unknown. Patients have elevated plasma IgA levels and increased expression of T-cell receptor–V5.2–5.3 and V8 by T cells as well as a higher level of various cytokines, as compared with those in healthy persons.4 The IgA deposited is predominately the plasma form, polymeric IgA1, with no secretory component (normally added by epithelium); IgA2 is rarely detected.17,18 Lambda light chains are disproportionately present, as compared with kappa light chains, as was true in this case.19 Enhanced expression of the transferrin receptor (CD71), which also serves as a receptor for IgA1, has been found on mesangial cells.20
Pathological predictors of an adverse outcome include the presence of crescents, sclerotic glomeruli, necrotizing glomerular lesions, interstitial fibrosis, and arteriolar hyalinosis.21,22 This case had none of these markers.
Dr. Harris: Dr. Weisberg, would you describe the patient's subsequent course?
Dr. Weisberg: On the day after the biopsy, the patient's mental status worsened, he was unable to protect his airway, and the trachea was intubated. Anuria developed, with worsening acidosis and an electrolyte imbalance. Continuous venovenous hemofiltration was initiated. During three days of plasmapheresis and high-dose corticosteroids, the rash and urinary output improved and the creatinine level decreased to 1.8 mg per deciliter (159 μmol per liter); continuous venovenous hemofiltration was discontinued. The trachea was extubated on day 31; the next day, the patient was alert and oriented and was transferred to the medical unit. However, the next day his oxygen saturation levels fell, and he became unresponsive, was intubated, and was transferred back to the medical intensive care unit. During the next six days, the creatinine level rose to 3.1 mg per deciliter (274 μmol per liter). On day 39, while he was surrounded by his family, ventilator support was withdrawn and he died. An autopsy was not performed.
Anatomical Diagnoses
Henoch–Sch?nlein purpura associated with Staphylococcus aureus sepsis.
Acute tubular necrosis.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Renal Unit, Derriford Hospital, and the Department of Medicine, Peninsula Medical School — both in Plymouth, United Kingdom (M.D.D.); and the Departments of Radiology (S.R.D.), Cardiology (S.C.), and Pathology (R.B.C.), Massachusetts General Hospital; and the Departments of Radiology (S.R.D.), Medicine (S.C.), and Pathology (R.B.C.), Harvard Medical School — both in Boston.
References
Davison AM. Infection associated glomerulonephritis. In: Davison AM, Cameron JS, Grunfeld JP, Kerr DNS, Ritz E, Winearls CG, eds. Oxford textbook of clinical nephrology. 2nd ed. Vol. 1. Oxford, England: Oxford University Press, 1998:667-77.
Koyama A, Kobayashi M, Yamaguchi N, et al. Glomerulonephritis associated with MRSA infection: a possible role of bacterial superantigen. Kidney Int 1995;47:207-216.
Handa T, Ono T, Watanabe H, Takeda T, Muso E, Kita T. Glomerulonephritis induced by methicillin-sensitive Staphylococcus aureus infection. Clin Exp Nephrol 2003;7:247-249.
Hirayama K, Kobayashi M, Muro K, Yoh K, Yamagata K, Koyama A. Specific T-cell receptor usage with cytokinemia in Henoch-Schonlein purpura nephritis associated with Staphylococcus aureus infection. J Intern Med 2001;249:289-295.
Koyama A, Sharmin S, Sakurai H, et al. Staphylococcus aureus envelope antigen is a new candidate for the induction of IgA nephropathy. Kidney Int 2004;66:121-132.
Yoh K, Kobayashi M, Yamaguchi N, et al. Cytokines and T-cell responses in superantigen-related glomerulonephritis following methicillin-resistant Staphylococcus aureus infection. Nephrol Dial Transplant 2000;15:1170-1174.
Majumdar A, Chowdhary S, Ferreira M, et al. Renal pathological findings in infective endocarditis. Nephrol Dial Transplant 2000;15:1782-1787.
Montoliu J, Miro JM, Campistol JM, et al. Henoch-Sch?nlein purpura complicating staphylococcal endocarditis in a heroin addict. Am J Nephrol 1987;7:137-139.
Spector DA, Millan J, Zauber N, Burton J. Glomerulonephritis and Staphylococcal aureus infections. Clin Nephrol 1980;14:256-261.
Michail S, Vaiopoulos G, Nakopoulou L, et al. Henoch-Sch?nlein purpura and acute interstitial nephritis after intravenous vancomycin administration in a patient with a staphylococcal infection. Scand J Rheumatol 1998;27:233-235.
Arrizabalaga P, Saurina A, Sole M, Blade J. Henoch-Sch?nlein IgA glomerulonephritis complicating myeloma kidneys: case report. Ann Hematol 2003;82:526-528.
Garcia-Porrua C, Gonzalez-Gay MA, Lopez-Lazaro L. Drug associated cutaneous vasculitis in adults in northwestern Spain. J Rheumatol 1999;26:1942-1944.
Borras-Blasco J, Enriquez R, Amoros F, et al. Henoch-Sch?nlein purpura associated with clarithromycin: case report and review of literature. Int J Clin Pharmacol Ther 2003;41:213-216.
Algoet C, Proesmans W. Renal biopsy 2-9 years after Henoch-Sch?nlein purpura. Pediatr Nephrol 2003;18:471-473.
Davin JC, Weening JJ. Henoch-Sch?nlein purpura nephritis: an update. Eur J Pediatr 2001;160:689-695.
Paynter HE, Banks RA. Evolution of IgA nephropathy into Henoch-Sch?nlein purpura in an adult. Clin Nephrol 1998;49:121-123.
Lomax-Smith JD, Zabrowarny LA, Howarth GS, Seymour AE, Woodroffe AJ. The immunochemical characterization of mesangial IgA deposits. Am J Pathol 1983;113:359-364.
Conley ME, Cooper MD, Michael AF. Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis, and systemic lupus erythematosus. J Clin Invest 1980;66:1432-1436.
Takatani T, Iwase H, Itoh A, et al. Compositional similarity between immunoglobulins binding to asialo-, agalacto-IgA1-Sepharose and those deposited in glomeruli in IgA nephropathy. J Nephrol 2004;17:679-686.
Haddad E, Moura IC, Arcos-Fajardo M, et al. Enhanced expression of the CD71 mesangial IgA1 receptor in Berger disease and Henoch-Sch?nlein nephritis: association between CD71 expression and IgA deposits. J Am Soc Nephrol 2003;14:327-337.
Pillebout E, Thervet E, Hill G, Alberti C, Vanhille P, Nochy D. Henoch-Sch?nlein purpura in adults: outcome and prognostic factors. J Am Soc Nephrol 2002;13:1271-1278.
Szeto CC, Choi PC, To KF, et al. Grading of acute and chronic renal lesions in Henoch-Sch?nlein purpura. Mod Pathol 2001;14:635-640.(Mark D. Denton, M.D., Ph.)
Dr. Alec D. Weisberg (Medicine): An 84-year-old man was transferred to this hospital because of staphylococcal bacteremia and renal failure. Two weeks before admission, fever, chills, nausea, vomiting, shortness of breath, productive cough, and generalized weakness developed. The patient went to the emergency department of a local hospital. The oxygen saturation was 88 percent while the patient was breathing ambient air. A radiograph of the chest showed patchy bilateral pulmonary infiltrates. He was admitted to the hospital. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus. He was treated with levofloxacin and cefotaxime for five days, and on the fifth day he was discharged home to complete a course of cephalexin. Five days later, a rash developed and he discontinued the cephalexin. Two days after that, his temperature rose to 39.2°C, with rigors. He was readmitted to the local hospital.
The patient reported no chest pain, shortness of breath, palpitations, abdominal pain, back pain, headache, visual changes, or joint pain and had a history of diabetes mellitus, cataracts, and sick sinus syndrome, for which a pacemaker had been placed seven years earlier. He was allergic to penicillin. He was a retired painter who had worked in shipyards, had quit smoking cigarettes more than 50 years previously, and did not drink alcohol. His medications were aspirin, atenolol, and glipizide.
On physical examination, the temperature was 38.5°C, the heart rate 111 beats per minute, the blood pressure 157/67 mm Hg, and the respiratory rate 24 breaths per minute. There were diminished breath sounds and bilateral chest crackles. A holosystolic murmur, grade 2/6, was heard at the apex radiating to the axilla. The abdomen was normal. There was a trace amount of peripheral edema in the legs and an erythematous, macular rash on the legs and face. Results of laboratory tests are shown in Table 1 and Table 2.
Table 1. Results of Hematology Laboratory Tests.
Table 2. Results of Chemistry Laboratory Tests.
Blood cultures were again positive for methicillin-sensitive S. aureus, and vancomycin was begun. On the second hospital day, a transthoracic echocardiogram revealed an ejection fraction of 55 percent, a thickened posterior leaflet of the mitral valve, mild mitral regurgitation, and left atrial enlargement. Computed tomography (CT) of the chest showed no infiltrates, but the presence of honeycombing at the lung bases with pleural calcification suggested exposure to asbestos. On the fourth hospital day, respiratory distress and hypoxemia developed; examination showed an elevated jugular venous pressure and diffuse crackles in both lungs. The patient was transferred to the medical intensive care unit. Furosemide was administered intravenously. Repeated CT of the chest revealed new bilateral patchy infiltrates in the upper lobes of the lungs, and the antibiotic treatment was broadened to include metronidazole and moxifloxacin. On the fifth hospital day, he was transferred to this hospital.
On admission, the temperature was 36.8°C, the pulse 96 beats per minute, the blood pressure 113/60 mm Hg, the respirations 24 breaths per minute, and the oxygen saturation 94 percent while the patient was breathing 4 liters per minute of oxygen by nasal cannula. The jugular venous pressure was 9 cm, and crackles extended halfway up both lung fields. Results of laboratory tests are shown in Table 1, Table 2, and Table 3. Lisinopril was started, and diuresis was continued. Moxifloxacin and metronidazole were discontinued. On the second hospital day, a transthoracic echocardiogram revealed an ejection fraction and valvular abnormalities similar to those noted at the other hospital, but no evidence of echogenicity on the mitral valve.
Table 3. Results of Immunology Laboratory Tests.
On the third day, petechial and palpable purpuric lesions developed on the patient's left great toe and the dorsum of the feet. During the next several days, the rash spread up his legs to his abdomen. Results of laboratory tests on days 3, 4, and 5 are shown in Table 4. On the fifth hospital day, a transesophageal echocardiogram showed no vegetations on the valves or pacemaker wire. On renal ultrasonography there was no hydronephrosis. Lisinopril was discontinued, and isosorbide dinitrate and hydralazine were started.
Table 4. Results of Laboratory Tests of Urine.
Microscopical examination of a punch-biopsy specimen of the skin of the abdomen obtained on the eighth hospital day showed a mild interface dermatitis with a superficial perivascular lymphocytic infiltrate. A cryoglobulin composed of heterogeneous IgG, IgA, and IgM, with a cryocrit of 1 percent was present in the blood. Tests for hepatitis B antigen and hepatitis B and C antibodies were negative. Results of laboratory tests are shown in Table 2 and Table 3. On the 10th day, vancomycin was discontinued because of concern about a hypersensitivity reaction, and daptomycin was initiated.
On the 13th day, the temperature rose to 38.3°C, with worsening hypoxemia and respiratory distress. Blood cultures were again positive for methicillin-sensitive S. aureus. On the 16th day, daptomycin was discontinued, and linezolid, rifampin, aztreonam, and levofloxacin were added. On the 18th day, the patient was taken to the operating room, where a transesophageal echocardiogram showed a vegetation on the right atrial pacemaker lead; the pacemaker was removed, and a bronchoalveolar lavage was performed.
Shortly thereafter, the oxygen saturation dropped to 80 percent while the patient was breathing 4 liters per minute of oxygen by nasal cannula. Tests of arterial blood gases while he was breathing 100 percent oxygen by way of a nonrebreathing face mask revealed a pH of 7.45, a partial pressure of carbon dioxide of 46 mm Hg, a partial pressure of oxygen of 112 mm Hg, and a bicarbonate level of 30 mEq per liter. The patient was transferred to the intensive care unit. The jugular veins were distended to the angle of the jaw, and diffuse crackles were heard in both lungs. After diuresis, the oxygen requirement fell to 4 liters of oxygen by nasal cannula. The patient was transferred back to the medical unit. Results of laboratory tests on days 19, 23, and 24 are shown in Table 1, Table 2, and Table 4.
On the 23rd hospital day, the purpuric lesions spread to the arms. A punch-biopsy specimen of the skin of the left upper arm obtained the next day showed necrotizing vasculitis with granular perivascular deposition of C3 (3+), fibrin (4+), IgM (1+), and trace IgG; IgA was not detected.
On the 25th day, the patient became somnolent and unresponsive. Cultures of the bronchoalveolar-lavage fluid yielded no growth of microorganisms, and levofloxacin and aztreonam were discontinued. Tests of arterial blood gases with the patient breathing supplemental oxygen revealed a pH of 7.22, a partial pressure of oxygen of 220 mm Hg, and a partial pressure of carbon dioxide of 80 mm Hg. The fractional excretion of sodium was less than 1 percent. He was transferred to the intensive care unit. Bilevel positive airway pressure was instituted. The creatinine level rose to 4.0 mg per deciliter (354 μmol per liter) on the 26th day. The urinary sediment contained dysmorphic red cells and red-cell casts. A repeated cryocrit was 2 percent. Results of other laboratory tests are shown in Table 1, Table 2, and Table 3. Methylprednisolone (1 g) was given intravenously, and plasmapheresis was initiated.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Mark D. Denton: May we see the imaging studies?
Dr. Subba R. Digumarthy: A chest radiograph obtained on the eighth day (Figure 1A) shows decreased lung volumes, multiple reticular opacities predominantly in the lung bases with cystic lucencies consistent with pulmonary fibrosis, and multiple ground-glass opacities predominantly in the upper lobes.
Figure 1. Radiograph (Panel A) and CT (Panels B and C) of the Chest.
A chest radiograph obtained with the use of portable equipment on the eighth hospital day (Panel A) shows decreased lung volumes with diffuse reticular opacities suggestive of pulmonary fibrosis. There are bilateral asymmetric air-space opacities predominantly in the upper lobes. CT of the chest (Panel B) shows bilateral asymmetric ground-glass opacities predominantly affecting the upper lobes (arrows). There are reticular opacities, honeycombing, and traction bronchiectasis predominantly affecting the lower lobes (Panel C), and a calcified pleural plaque is evident over the right hemidiaphragm (arrow).
CT of the chest performed three days after admission (Figure 1B and 1C) shows calcification of the diaphragmatic pleura consistent with previous asbestos exposure, multiple cystic areas predominantly in the lower lobes consistent with honeycombing, subpleural reticular opacities, architectural distortion, and traction bronchiectasis suggestive of pulmonary fibrosis. There are multiple ground-glass opacities that are bilateral and asymmetric and predominantly affect the upper lobes. A follow-up CT obtained on the 16th hospital day showed further progression of the ground-glass opacities also involving the lower lobes.
Dr. Sarah Chua: The transthoracic echocardiogram obtained on the second hospital day showed thickening of the posterior mitral annulus. A transesophageal echocardiogram (Figure 2A, and Video Clip 1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org) obtained on the fifth hospital day showed increased echodensity originating from the posterior mitral annulus extending toward the mitral leaflet, suggestive of posterior mitral annular calcification. A color Doppler study showed a reverse systolic flow from the left ventricle to the left atrium, compatible with mild mitral regurgitation. No vegetation was seen on the valves or on the pacemaker lead.
Figure 2. Echocardiographic Images.
A transesophageal echocardiogram obtained on the fifth hospital day (Panel A) shows increased echodensity that originates from the posterior mitral annulus and extends into the mitral leaflet, consistent with the presence of posterior mitral annular calcification (PMAC) (arrow). An intraoperative transesophageal echocardiogram obtained on the 18th day (Panel B) shows a pacemaker lead in the right atrium (RA) with an abnormal, shaggy mobile lesion attached to its tip (arrow), seen on the midesophageal view. Panel C shows an enlarged view of the right atrium with the mobile mass (arrow) attached at the tip of the right atrial pacemaker lead (arrowhead). LA denotes left atrium, LV left ventricle, and RV right ventricle.
An intraoperative transesophageal echocardiographic study done 12 days later (Figure 2B and 2C, and Video Clips 2 and 3 in the Supplementary Appendix) shows an echodense mobile mass attached to the pacemaker lead in the right atrium, which is consistent with a vegetation.
Dr. Denton: This patient had a prolonged illness characterized by persistent and inadequately treated staphylococcal bacteremia, hypoxemic episodes requiring transfer to the intensive care unit, and a steady decline in renal function. In a patient with acute renal failure, it is useful to consider prerenal, intrinsic, and postrenal causes. Prerenal causes are unlikely in this patient, on the basis of clinical findings. Postrenal causes can largely be dismissed given the absence of hydronephrosis on imaging. In the setting of recurrent sepsis and hypoxemia, acute tubular injury seems likely. The use of penicillin-based antibiotics raises the possibility of acute interstitial nephritis. The eventual occurrence of dysmorphic red cells and red-cell casts in the urinary sediment and the severe proteinuria, together with the presence of purpuric skin lesions, is highly suggestive of an active glomerulonephritis.
Differential Diagnosis
In this patient with persistent methicillin-sensitive S. aureus infection, an infection-related immune-complex–mediated glomerulonephritis seems most likely. Other causes of palpable purpura and glomerulonephritis include Henoch–Sch?nlein purpura, antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis, systemic lupus erythematosus, and essential mixed cryoglobulinemia. Atheroembolic disease causes palpable purpura and may cause renal failure, but the renal failure is due to a tubulointerstitial lesion, not glomerulonephritis. Nonpalpable purpura resulting from thrombocytopenia can be seen with the hemolytic–uremic syndrome and sepsis-associated disseminated intravascular coagulation. The hemolytic–uremic syndrome is associated with renal failure and sometimes nephrotic-range proteinuria, but not with red-cell casts. Other causes of renal failure and nonblanching skin lesions are amyloidosis and Waldenstr?m's macroglobulinemia.
Staphylococcal Infection and Glomerulonephritis
There are two principal clinical presentations of staphylococcus infection associated with glomerulonephritis.1 Chronic low-grade S. epidermidis infection of central nervous system shunts results in an immune-complex–mediated glomerulonephritis associated with a membranoproliferative histologic pattern, so-called shunt nephritis, frequently associated with severe proteinuria. S. aureus infection is also associated with immune-complex–mediated glomerulonephritis, but because of the acute nature of the infection, the histologic finding is usually a focal or diffuse proliferative glomerulonephritis, which may be associated with a rapid deterioration of renal function and variable proteinuria.
Staphylococcal Superantigen–Associated Glomerulonephritis
Several reports have described a third clinical entity, termed "staphylococcal superantigen–associated glomerulonephritis,"2 characterized by rapidly progressive glomerulonephritis and nephrotic-range proteinuria, purpura, elevated serum levels of IgA and IgG, and normal complement levels. In these reports, the patients had a variety of S. aureus infections, but a common link was a prolonged and persistent infection despite antimicrobial therapy, as seen in this case.3 A role for bacterial superantigen is suggested by the detection of a high frequency of T cells positive for T-cell receptor–V 5 and 8 in the peripheral circulation.4 The glomerular lesions included mesangial proliferation, membranoproliferative glomerulonephritis, and diffuse proliferative glomerulonephritis. All cases showed extensive IgA deposition in glomeruli,5 and in patients with purpura, IgA was also seen in the skin lesions,2,6 leading to a pathological diagnosis of Henoch–Sch?nlein purpura. This patient had persistent staphylococcal septicemia, glomerulonephritis with palpable purpura, elevated serum levels of IgA and IgG, and normal complement levels, consistent with the presence of staphylococcal superantigen–associated glomerulonephritis.
Henoch–Sch?nlein Purpura
Henoch–Sch?nlein purpura is a clinical syndrome characterized by a rash, arthralgias, abdominal pain, and renal disease. It is most common in children but can occur later in life, usually with a worse renal prognosis. This systemic vasculitis with a prominent cutaneous component is characterized by the tissue deposition of IgA-containing immune complexes. Renal involvement consists of an immune-complex–mediated glomerulonephritis with abundant IgA deposition. Complement levels are usually normal, as in this case. The clinical picture in this case, however, does not fit entirely with this diagnosis. First, there is no arthralgia or abdominal pain. Second, the distribution of the rash is slightly atypical; in this disease, it is usually concentrated on the back of the legs and buttocks and almost never affects the upper torso or back. Finally, the absence of IgA deposits in the skin-biopsy specimen argues against the diagnosis of Henoch–Sch?nlein purpura. The absence of IgA on the biopsy specimen may be due to the disappearance of IgA if the area from which the biopsy specimen was obtained represents an old lesion.
ANCA-Associated Vasculitis
ANCA-associated vasculitis may present with isolated purpuric rash and glomerulonephritis. It is also associated with normal complement levels. S. aureus infection has been shown to be a risk factor for relapse of Wegener's granulomatosis. However, ANCA-associated vasculitis is ruled out by the absence of ANCA on serial immunofluorescence testing and enzyme-linked immunosorbent assay.
Systemic Lupus Erythematosus
Although the antinuclear antibody titer is high, a diagnosis of systemic lupus erythematosus is unlikely in view of the patient's male sex, absence of prior symptoms, negative test for double-stranded DNA, and normal complement levels. Also, histologic examination of a skin-biopsy specimen would usually show evidence of IgG, IgA, and IgM deposition.
Other Causes of Renal Injury
Acute Tubular Injury
Hospital-associated acute renal failure is frequently multifactorial. Although I am convinced that a glomerular process exists here, I would argue that a large component of the renal dysfunction in this case is due to acute tubular injury. The initial deterioration in this patient's renal function occurred when respiratory distress and hypoxemia prompted admission to the intensive care unit at the first hospital. Although his blood pressure at that time was not mentioned, it was low on transfer to this hospital. This period of hypoxemia and probable hypotension in the setting of S. aureus bacteremia is likely to cause tubular injury in an elderly patient with diabetes and is probably responsible for the early deterioration in renal function. The high level of urinary sodium is in keeping with the presence of tubular injury. The urinary sediment should be examined for granular casts.
Acute Interstitial Nephritis
Acute interstitial nephritis should be considered in a patient with a rash after exposure to cephalosporins. However, this disease is usually associated with an erythematous rash, white-cell casts in the urine, and kidneys that appear enlarged on ultrasound study; these findings were not present in this case. The low-grade eosinophiluria seen later was probably caused by the glomerular inflammation.
Septic Emboli
Thickening of the mitral valve was seen on echocardiograms, a finding that could indicate a vegetation. Autopsy studies have shown that septic emboli and small foci of cortical necrosis are common in patients with infective endocarditis.7 However, for renal emboli to cause a clinically important deterioration in renal function, there would have to be a substantial reduction in the blood flow to both kidneys from large emboli. Such an event would be rare and would be accompanied by hematuria, flank pain, and an elevated level of lactate dehydrogenase; these features were not present in this case.
Summary
I believe this patient had staphylococcal superantigen–mediated glomerulonephritis, complicated by acute tubular injury. I predict that examination of a renal-biopsy specimen in this case will show both evidence of tubular injury and a proliferative glomerulonephritis with predominant IgA deposition. Although this pathological description is also typical of Henoch–Sch?nlein purpura, I prefer to call this condition staphylococcal superantigen–mediated glomerulonephritis to emphasize the etiologic importance of the persistent S. aureus bacteremia.
Dr. Nancy Lee Harris (Pathology): Dr. Haupert, can you give us your thoughts as you cared for this patient?
Dr. Garner T. Haupert, Jr. (Nephrology): The clinical situation suggested renal failure due to prerenal azotemia or acute tubular injury, although we did not see any casts in the sediment that suggested the latter. This patient's clinical condition would not have allowed us to perform a renal biopsy according to the standard method, in which the patient must lie prone without moving and be able to hold his or her breath during the biopsy.
The team considered the diagnosis of immune-complex–mediated glomerulonephritis associated with endocarditis; however, the test for rheumatoid factor was negative and the complement levels were normal. On the 26th hospital day, the urinalysis finally showed dysmorphic red cells and red-cell casts, which are diagnostic of glomerulonephritis, and the cryoglobulin was characterized as type 3. Although this type is less frequently associated with glomerulonephritis than is type 2, in 10 to 12 percent of cases, renal injury can occur. Because the patient's condition was deteriorating and we were not certain that we could perform a renal biopsy right away, we elected to start plasma-exchange and pulsed corticosteroid therapy.
The diagnostic procedure was a renal biopsy that was performed at the bedside by interventional radiology with the use of imaging guidance.
Clinical Diagnosis
Glomerulonephritis, possibly due to mixed cryoglobulinemia, type 3.
Dr. Mark D. Denton's Diagnoses
Staphylococcal superantigen–associated glomerulonephritis.
Acute tubular necrosis.
Pathological Discussion
Dr. Robert B. Colvin: Light-microscopical examination of the renal-biopsy specimen revealed normal architecture. Tubular atrophy and fibrosis affected about 20 percent of the cortex. The arteries showed mild intimal fibrosis, and the arterioles had hyaline material in their walls, indicative of long-standing mild vascular disease. No vasculitis was found. Red-cell casts were evident in medullary tubules (Figure 3A). Mild acute tubular injury was present, characterized by flattening and vacuolization of the epithelium; glomeruli showed mild, diffuse mesangial hypercellularity and focal accumulation of neutrophils in capillary loops (Figure 3B). One glomerulus had segmental endocapillary hypercellularity with necrosis and karyorrhexis (Figure 3C). No crescents or globally sclerotic glomeruli were found. Pseudothrombi, typical of cryoglobulinemia, were not seen. Staining with periodic acid–Schiff (PAS) revealed a normal glomerular basement membrane, without thickening or duplication. PAS-positive granules were evident in the mesangium in most glomeruli (Figure 3D). IgA-containing deposits can be PAS-positive because of the stain's relatively high carbohydrate content, and this is a clue to the presence of IgA nephropathy.
Figure 3. Light-Microscopical Examination of the Renal-Biopsy Specimen.
The medulla (arrow) has tubules with hemolyzed red-cell casts (Panel A, hematoxylin and eosin). The cortex (Panel B, hematoxylin and eosin) shows acute tubular injury with loss of brush borders, cellular debris in the lumen, and thinning of the cytoplasm (arrows). The glomerulus shows mild mesangial hypercellularity and occasional neutrophils in capillary loops. A glomerulus (Panel C, hematoxylin and eosin) has segmental necrosis and karyorrhexis (arrow). Deposits positive on periodic acid–Schiff staining are present in the mesangium (Panel D).
Immunofluorescence microscopy confirmed the presence of IgA deposits (2+ to 3+) in the glomerular mesangium and focally along the glomerular basement membrane (Figure 4A). These deposits also stained for C3 (3+ to 4+) and fibrin (1+ to 2+); lambda light chains were also present and were more numerous than kappa light chains. The deposits did not stain for IgG, IgM, or C1q.
Figure 4. Immunofluorescence and Electron-Microscopical Examination of the Renal-Biopsy Specimen.
A glomerulus (Panel A, anti-IgA antibody) shows granular IgA deposits, primarily in the mesangium. An electron micrograph (Panel B) shows amorphous, electron-dense deposits in the glomerular mesangium (arrows), and scattered electron-dense deposits in the glomerular basement membrane. Repeated immunofluorescence microscopy of additional sections of the skin-biopsy specimen reveals occasional microvascular granular IgA deposits (Panel C, arrow; anti-IgA antibody).
Electron-microscopical examination of one glomerulus (Figure 4B) showed numerous amorphous, electron-dense deposits in the mesangium and occasional subendothelial and subepithelial deposits. The glomerular basement membrane showed segmental duplication, and podocytes had effacement of foot processes.
The results are diagnostic of either IgA nephropathy or Henoch–Sch?nlein purpura. The disease appears to be mild in this case, because no crescents were found. The glomerular disease does not explain the elevated creatinine level, which is more likely to be due to the tubular injury in kidneys with chronic vascular disease.
To distinguish IgA nephropathy from Henoch–Sch?nlein purpura, we need evidence of systemic involvement either from the clinical history or from biopsies of other organs. In this case, a biopsy of the purpuric rash was performed. No IgA was seen in the initial studies. We repeated the stains on deeper levels of the skin-biopsy specimen (Figure 4C) and found occasional vessels that had IgA. Involvement in Henoch–Sch?nlein purpura is typically focal, and this finding provides evidence for that diagnosis.
The pathogenesis of the disease is still obscure. An association with bacterial or viral infection has repeatedly been reported, including staphylococcal sepsis with or without endocarditis.4,8,9,10,11 Drug hypersensitivity may also be a cause.12,13 In one case, Henoch–Sch?nlein purpura developed while a patient was receiving vancomycin for an S. aureus infection.10 The drugs may act by promoting the breakdown of the organism to an antigenic form.8,10
Henoch–Sch?nlein purpura is generally limited to one acute episode, whereas IgA nephropathy tends to be chronic; however, the two disorders may be biologically related.14,15,16 How infections or drugs provoke an IgA response and the vasculitis is unknown. Patients have elevated plasma IgA levels and increased expression of T-cell receptor–V5.2–5.3 and V8 by T cells as well as a higher level of various cytokines, as compared with those in healthy persons.4 The IgA deposited is predominately the plasma form, polymeric IgA1, with no secretory component (normally added by epithelium); IgA2 is rarely detected.17,18 Lambda light chains are disproportionately present, as compared with kappa light chains, as was true in this case.19 Enhanced expression of the transferrin receptor (CD71), which also serves as a receptor for IgA1, has been found on mesangial cells.20
Pathological predictors of an adverse outcome include the presence of crescents, sclerotic glomeruli, necrotizing glomerular lesions, interstitial fibrosis, and arteriolar hyalinosis.21,22 This case had none of these markers.
Dr. Harris: Dr. Weisberg, would you describe the patient's subsequent course?
Dr. Weisberg: On the day after the biopsy, the patient's mental status worsened, he was unable to protect his airway, and the trachea was intubated. Anuria developed, with worsening acidosis and an electrolyte imbalance. Continuous venovenous hemofiltration was initiated. During three days of plasmapheresis and high-dose corticosteroids, the rash and urinary output improved and the creatinine level decreased to 1.8 mg per deciliter (159 μmol per liter); continuous venovenous hemofiltration was discontinued. The trachea was extubated on day 31; the next day, the patient was alert and oriented and was transferred to the medical unit. However, the next day his oxygen saturation levels fell, and he became unresponsive, was intubated, and was transferred back to the medical intensive care unit. During the next six days, the creatinine level rose to 3.1 mg per deciliter (274 μmol per liter). On day 39, while he was surrounded by his family, ventilator support was withdrawn and he died. An autopsy was not performed.
Anatomical Diagnoses
Henoch–Sch?nlein purpura associated with Staphylococcus aureus sepsis.
Acute tubular necrosis.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Renal Unit, Derriford Hospital, and the Department of Medicine, Peninsula Medical School — both in Plymouth, United Kingdom (M.D.D.); and the Departments of Radiology (S.R.D.), Cardiology (S.C.), and Pathology (R.B.C.), Massachusetts General Hospital; and the Departments of Radiology (S.R.D.), Medicine (S.C.), and Pathology (R.B.C.), Harvard Medical School — both in Boston.
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Paynter HE, Banks RA. Evolution of IgA nephropathy into Henoch-Sch?nlein purpura in an adult. Clin Nephrol 1998;49:121-123.
Lomax-Smith JD, Zabrowarny LA, Howarth GS, Seymour AE, Woodroffe AJ. The immunochemical characterization of mesangial IgA deposits. Am J Pathol 1983;113:359-364.
Conley ME, Cooper MD, Michael AF. Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis, and systemic lupus erythematosus. J Clin Invest 1980;66:1432-1436.
Takatani T, Iwase H, Itoh A, et al. Compositional similarity between immunoglobulins binding to asialo-, agalacto-IgA1-Sepharose and those deposited in glomeruli in IgA nephropathy. J Nephrol 2004;17:679-686.
Haddad E, Moura IC, Arcos-Fajardo M, et al. Enhanced expression of the CD71 mesangial IgA1 receptor in Berger disease and Henoch-Sch?nlein nephritis: association between CD71 expression and IgA deposits. J Am Soc Nephrol 2003;14:327-337.
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Szeto CC, Choi PC, To KF, et al. Grading of acute and chronic renal lesions in Henoch-Sch?nlein purpura. Mod Pathol 2001;14:635-640.(Mark D. Denton, M.D., Ph.)