Needle in a Haystack
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《新英格兰医药杂志》
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows.
A 63-year-old man presented to the emergency department because of shortness of breath that had begun the evening before, after he had gone to bed, and worsened progressively during the night. He had had no fevers, chills, cough, hemoptysis, chest pain, or peripheral edema, and there was no history of congestive heart failure. Five months earlier, a pulmonary embolus was diagnosed; the patient received warfarin maintenance therapy; the results of prothrombin-time testing, expressed as an international normalized ratio (INR), were consistently above 2.0. The patient did not think that his current symptoms were similar to those he had experienced with the pulmonary embolism.
Many disorders can present with a sudden onset of shortness of breath, some of which are medical emergencies. Priority should be given to evaluating the possible diagnoses of an acute myocardial infarction or unstable angina. Congestive heart failure precipitated by malignant hypertension, supraventricular or ventricular arrhythmias, and acute valvular diseases such as endocarditis should also be ruled out. Noncardiac diseases that may be characterized by shortness of breath at presentation, such as pneumonia, pneumothorax, acute airway obstruction, sepsis, and renal disease, should also be considered. In this case, despite nearly six months of therapeutic warfarin, pulmonary embolism must remain in the differential diagnosis because of the patient's history and the potentially dire consequences of missing that diagnosis.
The patient's medical history included a horseshoe kidney (a structural renal malformation), mild hypertension that was not treated with medication, depression; and an anxiety disorder. The patient had been a heavy smoker for more than 50 years and continued to smoke one pack per day. He did not use recreational drugs or alcohol, lived alone, and worked as a custodian. His medications included mirtazapine and lorazepam. He also reported taking up to two 200-mg tablets of ibuprofen daily during the previous week for generalized malaise.
On physical examination, he appeared cachectic and chronically ill and was in distress, with a respiratory rate of 22 breaths per minute and an oxygen saturation of 90 percent while he was breathing ambient air. He was afebrile; his blood pressure was 189/115 mm Hg; and his heart rate was 128 beats per minute and regular. A cardiopulmonary examination revealed no jugular venous distention or peripheral edema; breath sounds were equal bilaterally with wet rales but no wheezes, and an S4 heart sound was present, without a murmur or rub. The pulses were equal and symmetric; however, bruits were heard in both femoral arteries, which were rigid to palpation.
The patient's history of smoking and hypertension in conjunction with evidence of peripheral vascular disease on physical examination increases the likelihood of coronary artery disease complicated by congestive heart failure. Malignant hypertension could also precipitate acute pulmonary edema. Pericardial effusion with cardiac tamponade seems an unlikely diagnosis because of the elevated blood pressure, absence of jugular venous distention, and presence of rales. In addition, there is little evidence to support a diagnosis of pneumonia, pleural effusion, pneumothorax, or sepsis. The cachexia, which may or may not relate to the current acute presentation, will also require further evaluation.
A chest radiograph revealed bilateral perihilar alveolar infiltrates and borderline cardiomegaly, suggestive of cardiogenic pulmonary edema (Figure 1). An electrocardiogram revealed sinus tachycardia at 120 beats per minute, left ventricular hypertrophy, and no evidence of ischemia or infarction. The white-cell count was 9600 cells per cubic millimeter, with 70 percent neutrophils, 20 percent lymphocytes, 6 percent monocytes, and 4 percent eosinophils; the hemoglobin level was 13.7 g per deciliter; and the platelet count was 178,000 cells per cubic millimeter. The creatine kinase level was 69 U per liter, and the troponin T level was 0.02 ng per milliliter. Levels of electrolytes, calcium, magnesium, phosphorus, and liver enzymes were normal. The INR was 2.2. The urea nitrogen level was 25 mg per deciliter (8.9 mmol per liter), and the serum creatinine level was 2.7 mg per deciliter (240 μmol per liter); five months earlier, the urea nitrogen level had been 12 mg per deciliter (4.3 mmol per liter), and the creatinine level had been 1.2 mg per deciliter (110 μmol per liter). The patient was treated with oxygen given nasally and nitroglycerin, furosemide, and morphine given intravenously. His symptoms resolved during the next 12 hours, after a diuresis of 1.5 liters. His blood pressure fell to 140/90 mm Hg, and his oxygen saturation rose to 98 percent. Oral metoprolol was added to the treatment regimen, and he was admitted to the medical service. During his hospitalization, no arrhythmias were noted on telemetry.
Figure 1. Anteroposterior Radiograph of the Chest, Demonstrating Interstitial Pulmonary Edema and Borderline Cardiomegaly.
On the basis of the presentation, radiographic findings, and rapid response to therapy, pulmonary edema appears to be the most likely diagnosis. There is no evidence of acute myocardial infarction or arrhythmia, and a recurrent pulmonary embolism seems unlikely. An unexpected finding is the renal failure, which, on the basis of the previous tests, is subacute to acute. Although mild, rapidly reversible acute renal failure can accompany congestive heart failure, the triad of renal failure, hypertension, and alveolar infiltrates raises the possibility of a pulmonary–renal syndrome such as Goodpasture's syndrome or a vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA). The absence of hemoptysis and prompt resolution of the shortness of breath after the administration of diuretics argue against pulmonary hemorrhage as the cause of the alveolar infiltrates. However, patients with these and other vasculitides can present with isolated rapidly progressive glomerulonephritis. Evidence of dysmorphic red cells, red-cell casts, and proteinuria on the urinalysis would provide support for this diagnosis.
Other diagnoses to consider at this point are malignant hypertension, which can be characterized at presentation by both acute renal failure caused by renal microvascular ischemia and congestive heart failure caused by diastolic dysfunction and ischemia. We are not told whether the patient had retinal hemorrhages or papilledema, but the rapid and dramatic decrease in blood pressure in response to diuretics argues against the presence of malignant hypertension. Patients with myeloma can present with cardiac and renal involvement, and that diagnosis should also be considered. Bilateral renal-artery stenosis can also be characterized initially by pulmonary edema because of a combination of volume overload and diastolic dysfunction. In this patient's age group, atherosclerotic disease is the most common cause of renal-artery stenosis, and his lengthy smoking history, along with the presence of bilateral femoral bruits, makes this an important consideration. It would be unusual for the creatinine level to increase so quickly because of isolated renovascular disease, unless the patient was concomitantly using angiotensin-converting–enzyme inhibitors, angiotensin-receptor blockers, nonsteroidal antiinflammatory drugs (NSAIDs), or cyclooxygenase-2 inhibitors; this patient had been taking ibuprofen for a week. Finally, renal obstruction, interstitial nephritis, and acute tubular necrosis caused by medications or exposure to other potentially toxic agents are diagnostic considerations.
Renal ultrasonography revealed fused, low-lying kidneys, without hydronephrosis or increased echogenicity. Oliguria was not present, but the serum creatinine level rose from 2.5 to 3.0 mg per deciliter (220 to 270 μmol per liter) by the third hospital day. On further questioning, the patient reported constipation during the previous year, along with a diminished appetite and an unintentional weight loss of more than 30 kg (his weight decreased from 90.9 kg to 59.1 kg) during the previous six months. He had not had fevers, chills, night sweats, nausea, rash, arthralgias, abdominal pain, hematuria, or other urinary tract symptoms. Further physical examination revealed a lower midline abdominal mass, but there was no hepatosplenomegaly, ascites, lymphadenopathy, rash, edema, or arthritis. A urinalysis revealed a specific gravity of 1.020, a pH of 7.0, and the presence of leukocyte esterase (2+), protein (2+), and trace amounts of blood. Review of the sediment by a nephrologist revealed no casts or crystals; rare white cells and nondysmorphic red cells were seen. A 24-hour urine collection contained 308 mg of protein. A test for antinuclear antibodies (ANA) was positive at 1:640, with a speckled pattern. Tests for ANCA and antibodies against glomerular basement membrane and phospholipids were negative, as were serologic tests for hepatitis B and C viruses. Blood cultures were negative. The serum complement levels were normal, with no monoclonal spikes in the serum or urine electrophoresis.
The serologic workup is essentially negative, and the analysis of the urinary sediment effectively rules out rapidly progressive glomerulonephritis. The positive ANA test does not raise my level of suspicion of nephritis associated with systemic lupus erythematosus, because the complement levels are normal and should be low in active immune-complex diseases such as lupus. The weight loss, constipation, abdominal mass, and recent pulmonary embolism raise the possibility of an underlying cancer such as colorectal carcinoma, which can be associated with renal complications, including obstruction, tumor infiltration, and tumor-associated glomerular disease. The most common presentation of tumor-associated glomerular disease is the nephrotic syndrome, but this syndrome is ruled out by the absence of substantial proteinuria. Horseshoe kidneys can be associated with focal segmental glomerulosclerosis with proteinuria, but the progression of renal disease is typically much slower than in this case, and the patient has only minimal proteinuria. Acute renal failure associated with cancer is often due to obstruction by pelvic or retroperitoneal masses or by lymphadenopathy. Just as important is the fact that partial obstruction, even with preserved urinary output, can also cause renal failure. Therefore, the absence of hydronephrosis does not rule out obstruction, especially in patients with malignant tumors that encase the renal pelvis and ureters and thereby restrict their dilatation. Thus, the absence of oliguria and hydronephrosis on ultrasonography would not deter me from further pursuing a diagnosis of obstruction, especially since the unremarkable findings on the analysis of the urinary sediment are consistent with the presence of obstruction. The horseshoe kidney may also limit the reliability of the ultrasound examination to rule out obstruction.
The patient underwent technetium-99m–mercaptoacetyltriglycine nuclear scanning of the kidneys with furosemide administration. The study revealed fused kidneys with prompt excretion of isotope, indicating no evidence of obstruction. The left part of the kidney accounted for 39 percent of the split renal function, and the right accounted for 61 percent. On palpation, the abdominal mass was believed to be the ectopic horseshoe kidney.
Ureteral obstruction has been ruled out. Patients with tubulointerstitial diseases such as acute tubular necrosis or acute interstitial nephritis caused by the ingestion of ibuprofen usually present with characteristic casts, along with leukocytes and red cells in the sediment; these were not seen. What else causes acute renal failure in the presence of a normal urinary sediment? Congestive heart failure is one cause, but the creatinine level generally improves when the acute episode is treated, just the opposite of the course in this case. Prerenal azotemia resulting from volume depletion is unlikely. The most likely explanation at this point is bilateral renovascular disease, presenting as acute renal failure precipitated by the use of NSAIDs. There is no history of recent exposure to angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers, which can precipitate a similar presentation.
Abdominal magnetic resonance angiography with gadolinium enhancement (Figure 2) revealed the horseshoe kidney and marked atherosclerotic disease of the abdominal aorta. There were two right and two left renal arteries, all of which were well visualized and widely patent. A transthoracic echocardiogram showed moderate mitral regurgitation and a dilated left atrium and ventricle with segmental wall-motion abnormalities. The ejection fraction was 45 percent, and there was no pericardial effusion. The ascending aorta was dilated, and a mobile protruding atheroma was noted.
Figure 2. Magnetic Resonance Angiograms of the Renal Arteries.
Panel A shows crossed, fused ectopia, with the left kidney attached to the lower pole of the right kidney. In Panel B, multiple renal arteries (arrows) originate from the aorta and both common iliac arteries that supply the horseshoe kidney. There is marked atherosclerosis of the abdominal aorta.
Renal magnetic resonance angiography is highly sensitive (although not highly specific) for renal-artery stenosis. It is especially useful in cases such as this one; the renal arteries were well visualized and normal, ruling out bilateral renal-artery stenosis. Nonetheless, the aortic segments visualized on both the echocardiogram and the magnetic resonance angiogram suggest a substantial atherosclerotic burden, albeit with sparing of the renal arteries. I suspect that the patient's risk factors, visualized atherosclerosis, and wall-motion abnormalities point to undiagnosed coronary artery disease. Cardiac ischemia precipitated by volume overload induced by NSAIDs or an exacerbation of hypertension could explain the initial pulmonary edema.
The presence of extensive aortic atherosclerosis raises the possibility of another diagnosis not previously considered, atheroembolic kidney disease. We have not been told of any cutaneous signs of atheroembolism, such as livedo reticularis, or overt emboli with the so-called blue toe syndrome. Also, cholesterol embolism is often associated with eosinophilia, hypocomplementemia, and granular casts and leukocytes on the urinalysis, but these were not present in this patient. However, these manifestations can vary widely, and this patient did present with systemic symptoms that complicate atheroembolism, including anorexia and weight loss. With no other suitable working diagnosis, I must strongly consider atheroembolic kidney disease. I would perform a kidney biopsy, but only after carefully discussing the risks of the procedure with the patient, including the risk of recurrent pulmonary embolism related to discontinuing warfarin.
The patient's renal function stabilized, with a creatinine level of 3.1 mg per deciliter (270 μmol per liter). Cardiac catheterization was deferred because of the renal failure. He left the hospital against medical advice but returned with recurrent pulmonary edema within two weeks. The serum creatinine level rose to 5.0 mg per deciliter (440 μmol per liter). There was no oliguria, and the results of a repeated review of the urinary sediment were unchanged. Subsequently, a percutaneous kidney biopsy was performed (Figure 3). Pathological examination under light microscopy revealed global sclerosis in two of six glomeruli; the remaining glomeruli were unremarkable. Coarse vacuolization was found in the epithelium of tubules, with loss of brush borders, suggesting ischemic injury. The arteries showed intimal thickening and fibrosis consistent with the presence of hypertension. The immunofluorescence study was negative, ruling out immune-complex disease. Electron microscopy showed minimal segmental effacement of podocyte foot processes and no electron-dense deposits. Two needle-shaped cholesterol crystals were identified in separate afferent arterioles, consistent with the presence of atheroembolic kidney disease. During the subsequent two months, uremia developed and hemodialysis was initiated.
Figure 3. Percutaneous-Biopsy Specimen of the Kidney.
Both the light-microscopical view (Panel A, hematoxylin and eosin) and the electron-microscopical view (Panel B) show needle-like clefts from atheroemboli to afferent arterioles.
Commentary
As this case illustrates, the difficulty in diagnosing renal atheroembolism is often related to the fact that the diagnosis is never even considered. In this instance, the diagnosis was especially difficult, because there were initially no obvious signs or symptoms. Furthermore, in trying to identify a single, unifying disease to connect the pulmonary embolism to the subsequent renal presentation, the discussant did not consider that the treatment of the initial process may have been the link between the thromboembolism and the renal disease. Indeed, although invasive aortic manipulation is the leading cause of atheroembolism, spontaneous atheroembolism is often precipitated by thrombolysis or anticoagulation, which was the likely cause in this case.1,2 It was only after a detailed evaluation of other potential causes of renal failure proved fruitless and after magnetic resonance angiography and echocardiography, which were ordered for other reasons, showed evidence of diffuse atherosclerosis that the discussant considered the diagnosis of spontaneous atheroembolism and found the "needle in the haystack." In fairness, the discussant's approach highlighted the important principle of ruling out life-threatening diagnoses first and then evaluating patients for other treatable diagnoses. In this case, the delayed diagnosis had little clinical effect, since there are currently no effective treatments for atheroembolism.
Atheroembolic disease accounts for approximately 5 to 10 percent of cases of acute renal failure.3 These rates may actually underestimate the true prevalence of the disease, because the nonspecific symptoms and indolent nature of the syndrome render the diagnosis elusive, as shown in this case. Typical signs, including eosinophilia, hypocomplementemia, livedo reticularis, and cutaneous emboli, are highly variable and may be absent.4 Retinal emboli, known as Hollenhorst plaques, may provide clues to the diagnosis, but they occur only rarely.5 As in this case, the results of urinalysis may be unrevealing or may misleadingly suggest other diagnoses, such as interstitial nephritis, acute tubular necrosis, or even glomerulonephritis.6,7,8 Furthermore, most cases of atheroembolic kidney disease are triggered by angiography, in which case radiocontrast-induced nephropathy is easily invoked as an alternative diagnosis.5,9
Risk factors for atheroembolism include increased age, male sex, hypertension, a history of coronary or peripheral vascular disease, and a history of smoking.4 In studies of patients with biopsy-proven atheroembolic kidney disease, anticoagulation was thought to be a precipitating factor in 33 to 55 percent of cases.3,4,5 Anticoagulant agents are thought to destabilize atherosclerotic plaques by allowing cholesterol crystals that were previously covered by clot to be exposed to the circulation. The prognosis for patients with atheroembolic kidney disease is poor; in up to 25 percent, the condition progresses to end-stage renal disease, and in a recent prospective study, 38 percent died within five years.5
The identification of needle-shaped cholesterol clefts on examination of the renal-biopsy specimen is required to make the diagnosis (sites of atheroembolism dissolve during tissue fixation). However, even on renal biopsy, patchy involvement of the kidney can lead to a sampling error and a false negative finding. In addition, changes consistent with the presence of acute tubular necrosis, minimal change disease, and collapsing glomerulopathy, an aggressive subtype of focal segmental glomerulosclerosis, have been described in biopsy specimens from patients with atheroembolism.10,11 Even when cholesterol clefts are found on biopsy, the finding may be incidental in a patient with another primary diagnosis. However, an incidental finding was unlikely in this case, since the course of the renal failure is consistent with this diagnosis, other potential diagnoses were reasonably ruled out, and the patient's diffuse atherosclerosis and recent anticoagulant therapy are recognized risk factors for atheroembolism.
Atheroembolic disease is an important yet underdiagnosed component of the spectrum of kidney disease associated with atherosclerosis. Physicians should consider this diagnosis in patients with underlying vascular disease who present with renal failure.
No potential conflict of interest relevant to this article was reported.
We are indebted to Dr. Alan J. Greenfield in the Department of Vascular Radiology and Dr. R. Neal Smith in the Department of Pathology at Massachusetts General Hospital for providing the radiographic and pathological figures for this article.
Source Information
From the Renal Division, Department of Medicine, Brigham and Women's Hospital (K.R.P.); and the Nephrology Division, Department of Medicine, Massachusetts General Hospital (M.W.) — both in Boston.
Address reprint requests to Dr. Wolf at Massachusetts General Hospital, 55 Fruit St., Bartlett-917, Boston, MA 02114, or at mswolf@partners.org.
References
Moll S, Huffman J. Cholesterol emboli associated with warfarin treatment. Am J Hematol 2004;77:194-195.
Wong FK, Chan SK, Ing TS, Li CS. Acute renal failure after streptokinase therapy in a patient with acute myocardial infarction. Am J Kidney Dis 1995;26:508-510.
Mayo RR, Swartz RD. Redefining the incidence of clinically detectable atheroembolism. Am J Med 1996;100:524-529.
Thadhani RI, Camargo CA Jr, Xavier RJ, Fang LS, Bazari H. Atheroembolic renal failure after invasive procedures: natural history based on 52 histologically proven cases. Medicine 1995;74:350-358.
Scolari F, Ravani P, Pola A, et al. Predictors of renal and patient outcomes in atheroembolic renal disease: a prospective study. J Am Soc Nephrol 2003;14:1584-1590.
Espejo B, Herrero JC, Torres A, et al. Immunoallergic interstitial nephritis vs. cholesterol atheroembolism: differentiating characteristics. Nefrologia 2003;23:125-30.
Scolari F, Tardanico R, Pola A, et al. Cholesterol crystal embolic disease in renal allografts. J Nephrol 2003;16:139-143.
Goldman M, Thoua Y, Dhaene M, Toussaint C. Necrotising glomerulonephritis associated with cholesterol microemboli. BMJ 1985;290:205-206.
Scolari F, Tardanico R, Zani R, et al. Cholesterol crystal embolism: a recognizable cause of renal disease. Am J Kidney Dis 2000;36:1089-1109.
Liss KA, Gaughan WJ, McCue PA, Burke JF. Coexistence of atheroemboli and minimal-change disease. Clin Nephrol 1997;47:125-128.
Greenberg A, Bastacky SI, Iqbal A, Borochovitz D, Johnson JP. Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: clinicopathological correlations. Am J Kidney Dis 1997;29:334-344.(Krishna R. Polu, M.D., an)
A 63-year-old man presented to the emergency department because of shortness of breath that had begun the evening before, after he had gone to bed, and worsened progressively during the night. He had had no fevers, chills, cough, hemoptysis, chest pain, or peripheral edema, and there was no history of congestive heart failure. Five months earlier, a pulmonary embolus was diagnosed; the patient received warfarin maintenance therapy; the results of prothrombin-time testing, expressed as an international normalized ratio (INR), were consistently above 2.0. The patient did not think that his current symptoms were similar to those he had experienced with the pulmonary embolism.
Many disorders can present with a sudden onset of shortness of breath, some of which are medical emergencies. Priority should be given to evaluating the possible diagnoses of an acute myocardial infarction or unstable angina. Congestive heart failure precipitated by malignant hypertension, supraventricular or ventricular arrhythmias, and acute valvular diseases such as endocarditis should also be ruled out. Noncardiac diseases that may be characterized by shortness of breath at presentation, such as pneumonia, pneumothorax, acute airway obstruction, sepsis, and renal disease, should also be considered. In this case, despite nearly six months of therapeutic warfarin, pulmonary embolism must remain in the differential diagnosis because of the patient's history and the potentially dire consequences of missing that diagnosis.
The patient's medical history included a horseshoe kidney (a structural renal malformation), mild hypertension that was not treated with medication, depression; and an anxiety disorder. The patient had been a heavy smoker for more than 50 years and continued to smoke one pack per day. He did not use recreational drugs or alcohol, lived alone, and worked as a custodian. His medications included mirtazapine and lorazepam. He also reported taking up to two 200-mg tablets of ibuprofen daily during the previous week for generalized malaise.
On physical examination, he appeared cachectic and chronically ill and was in distress, with a respiratory rate of 22 breaths per minute and an oxygen saturation of 90 percent while he was breathing ambient air. He was afebrile; his blood pressure was 189/115 mm Hg; and his heart rate was 128 beats per minute and regular. A cardiopulmonary examination revealed no jugular venous distention or peripheral edema; breath sounds were equal bilaterally with wet rales but no wheezes, and an S4 heart sound was present, without a murmur or rub. The pulses were equal and symmetric; however, bruits were heard in both femoral arteries, which were rigid to palpation.
The patient's history of smoking and hypertension in conjunction with evidence of peripheral vascular disease on physical examination increases the likelihood of coronary artery disease complicated by congestive heart failure. Malignant hypertension could also precipitate acute pulmonary edema. Pericardial effusion with cardiac tamponade seems an unlikely diagnosis because of the elevated blood pressure, absence of jugular venous distention, and presence of rales. In addition, there is little evidence to support a diagnosis of pneumonia, pleural effusion, pneumothorax, or sepsis. The cachexia, which may or may not relate to the current acute presentation, will also require further evaluation.
A chest radiograph revealed bilateral perihilar alveolar infiltrates and borderline cardiomegaly, suggestive of cardiogenic pulmonary edema (Figure 1). An electrocardiogram revealed sinus tachycardia at 120 beats per minute, left ventricular hypertrophy, and no evidence of ischemia or infarction. The white-cell count was 9600 cells per cubic millimeter, with 70 percent neutrophils, 20 percent lymphocytes, 6 percent monocytes, and 4 percent eosinophils; the hemoglobin level was 13.7 g per deciliter; and the platelet count was 178,000 cells per cubic millimeter. The creatine kinase level was 69 U per liter, and the troponin T level was 0.02 ng per milliliter. Levels of electrolytes, calcium, magnesium, phosphorus, and liver enzymes were normal. The INR was 2.2. The urea nitrogen level was 25 mg per deciliter (8.9 mmol per liter), and the serum creatinine level was 2.7 mg per deciliter (240 μmol per liter); five months earlier, the urea nitrogen level had been 12 mg per deciliter (4.3 mmol per liter), and the creatinine level had been 1.2 mg per deciliter (110 μmol per liter). The patient was treated with oxygen given nasally and nitroglycerin, furosemide, and morphine given intravenously. His symptoms resolved during the next 12 hours, after a diuresis of 1.5 liters. His blood pressure fell to 140/90 mm Hg, and his oxygen saturation rose to 98 percent. Oral metoprolol was added to the treatment regimen, and he was admitted to the medical service. During his hospitalization, no arrhythmias were noted on telemetry.
Figure 1. Anteroposterior Radiograph of the Chest, Demonstrating Interstitial Pulmonary Edema and Borderline Cardiomegaly.
On the basis of the presentation, radiographic findings, and rapid response to therapy, pulmonary edema appears to be the most likely diagnosis. There is no evidence of acute myocardial infarction or arrhythmia, and a recurrent pulmonary embolism seems unlikely. An unexpected finding is the renal failure, which, on the basis of the previous tests, is subacute to acute. Although mild, rapidly reversible acute renal failure can accompany congestive heart failure, the triad of renal failure, hypertension, and alveolar infiltrates raises the possibility of a pulmonary–renal syndrome such as Goodpasture's syndrome or a vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA). The absence of hemoptysis and prompt resolution of the shortness of breath after the administration of diuretics argue against pulmonary hemorrhage as the cause of the alveolar infiltrates. However, patients with these and other vasculitides can present with isolated rapidly progressive glomerulonephritis. Evidence of dysmorphic red cells, red-cell casts, and proteinuria on the urinalysis would provide support for this diagnosis.
Other diagnoses to consider at this point are malignant hypertension, which can be characterized at presentation by both acute renal failure caused by renal microvascular ischemia and congestive heart failure caused by diastolic dysfunction and ischemia. We are not told whether the patient had retinal hemorrhages or papilledema, but the rapid and dramatic decrease in blood pressure in response to diuretics argues against the presence of malignant hypertension. Patients with myeloma can present with cardiac and renal involvement, and that diagnosis should also be considered. Bilateral renal-artery stenosis can also be characterized initially by pulmonary edema because of a combination of volume overload and diastolic dysfunction. In this patient's age group, atherosclerotic disease is the most common cause of renal-artery stenosis, and his lengthy smoking history, along with the presence of bilateral femoral bruits, makes this an important consideration. It would be unusual for the creatinine level to increase so quickly because of isolated renovascular disease, unless the patient was concomitantly using angiotensin-converting–enzyme inhibitors, angiotensin-receptor blockers, nonsteroidal antiinflammatory drugs (NSAIDs), or cyclooxygenase-2 inhibitors; this patient had been taking ibuprofen for a week. Finally, renal obstruction, interstitial nephritis, and acute tubular necrosis caused by medications or exposure to other potentially toxic agents are diagnostic considerations.
Renal ultrasonography revealed fused, low-lying kidneys, without hydronephrosis or increased echogenicity. Oliguria was not present, but the serum creatinine level rose from 2.5 to 3.0 mg per deciliter (220 to 270 μmol per liter) by the third hospital day. On further questioning, the patient reported constipation during the previous year, along with a diminished appetite and an unintentional weight loss of more than 30 kg (his weight decreased from 90.9 kg to 59.1 kg) during the previous six months. He had not had fevers, chills, night sweats, nausea, rash, arthralgias, abdominal pain, hematuria, or other urinary tract symptoms. Further physical examination revealed a lower midline abdominal mass, but there was no hepatosplenomegaly, ascites, lymphadenopathy, rash, edema, or arthritis. A urinalysis revealed a specific gravity of 1.020, a pH of 7.0, and the presence of leukocyte esterase (2+), protein (2+), and trace amounts of blood. Review of the sediment by a nephrologist revealed no casts or crystals; rare white cells and nondysmorphic red cells were seen. A 24-hour urine collection contained 308 mg of protein. A test for antinuclear antibodies (ANA) was positive at 1:640, with a speckled pattern. Tests for ANCA and antibodies against glomerular basement membrane and phospholipids were negative, as were serologic tests for hepatitis B and C viruses. Blood cultures were negative. The serum complement levels were normal, with no monoclonal spikes in the serum or urine electrophoresis.
The serologic workup is essentially negative, and the analysis of the urinary sediment effectively rules out rapidly progressive glomerulonephritis. The positive ANA test does not raise my level of suspicion of nephritis associated with systemic lupus erythematosus, because the complement levels are normal and should be low in active immune-complex diseases such as lupus. The weight loss, constipation, abdominal mass, and recent pulmonary embolism raise the possibility of an underlying cancer such as colorectal carcinoma, which can be associated with renal complications, including obstruction, tumor infiltration, and tumor-associated glomerular disease. The most common presentation of tumor-associated glomerular disease is the nephrotic syndrome, but this syndrome is ruled out by the absence of substantial proteinuria. Horseshoe kidneys can be associated with focal segmental glomerulosclerosis with proteinuria, but the progression of renal disease is typically much slower than in this case, and the patient has only minimal proteinuria. Acute renal failure associated with cancer is often due to obstruction by pelvic or retroperitoneal masses or by lymphadenopathy. Just as important is the fact that partial obstruction, even with preserved urinary output, can also cause renal failure. Therefore, the absence of hydronephrosis does not rule out obstruction, especially in patients with malignant tumors that encase the renal pelvis and ureters and thereby restrict their dilatation. Thus, the absence of oliguria and hydronephrosis on ultrasonography would not deter me from further pursuing a diagnosis of obstruction, especially since the unremarkable findings on the analysis of the urinary sediment are consistent with the presence of obstruction. The horseshoe kidney may also limit the reliability of the ultrasound examination to rule out obstruction.
The patient underwent technetium-99m–mercaptoacetyltriglycine nuclear scanning of the kidneys with furosemide administration. The study revealed fused kidneys with prompt excretion of isotope, indicating no evidence of obstruction. The left part of the kidney accounted for 39 percent of the split renal function, and the right accounted for 61 percent. On palpation, the abdominal mass was believed to be the ectopic horseshoe kidney.
Ureteral obstruction has been ruled out. Patients with tubulointerstitial diseases such as acute tubular necrosis or acute interstitial nephritis caused by the ingestion of ibuprofen usually present with characteristic casts, along with leukocytes and red cells in the sediment; these were not seen. What else causes acute renal failure in the presence of a normal urinary sediment? Congestive heart failure is one cause, but the creatinine level generally improves when the acute episode is treated, just the opposite of the course in this case. Prerenal azotemia resulting from volume depletion is unlikely. The most likely explanation at this point is bilateral renovascular disease, presenting as acute renal failure precipitated by the use of NSAIDs. There is no history of recent exposure to angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers, which can precipitate a similar presentation.
Abdominal magnetic resonance angiography with gadolinium enhancement (Figure 2) revealed the horseshoe kidney and marked atherosclerotic disease of the abdominal aorta. There were two right and two left renal arteries, all of which were well visualized and widely patent. A transthoracic echocardiogram showed moderate mitral regurgitation and a dilated left atrium and ventricle with segmental wall-motion abnormalities. The ejection fraction was 45 percent, and there was no pericardial effusion. The ascending aorta was dilated, and a mobile protruding atheroma was noted.
Figure 2. Magnetic Resonance Angiograms of the Renal Arteries.
Panel A shows crossed, fused ectopia, with the left kidney attached to the lower pole of the right kidney. In Panel B, multiple renal arteries (arrows) originate from the aorta and both common iliac arteries that supply the horseshoe kidney. There is marked atherosclerosis of the abdominal aorta.
Renal magnetic resonance angiography is highly sensitive (although not highly specific) for renal-artery stenosis. It is especially useful in cases such as this one; the renal arteries were well visualized and normal, ruling out bilateral renal-artery stenosis. Nonetheless, the aortic segments visualized on both the echocardiogram and the magnetic resonance angiogram suggest a substantial atherosclerotic burden, albeit with sparing of the renal arteries. I suspect that the patient's risk factors, visualized atherosclerosis, and wall-motion abnormalities point to undiagnosed coronary artery disease. Cardiac ischemia precipitated by volume overload induced by NSAIDs or an exacerbation of hypertension could explain the initial pulmonary edema.
The presence of extensive aortic atherosclerosis raises the possibility of another diagnosis not previously considered, atheroembolic kidney disease. We have not been told of any cutaneous signs of atheroembolism, such as livedo reticularis, or overt emboli with the so-called blue toe syndrome. Also, cholesterol embolism is often associated with eosinophilia, hypocomplementemia, and granular casts and leukocytes on the urinalysis, but these were not present in this patient. However, these manifestations can vary widely, and this patient did present with systemic symptoms that complicate atheroembolism, including anorexia and weight loss. With no other suitable working diagnosis, I must strongly consider atheroembolic kidney disease. I would perform a kidney biopsy, but only after carefully discussing the risks of the procedure with the patient, including the risk of recurrent pulmonary embolism related to discontinuing warfarin.
The patient's renal function stabilized, with a creatinine level of 3.1 mg per deciliter (270 μmol per liter). Cardiac catheterization was deferred because of the renal failure. He left the hospital against medical advice but returned with recurrent pulmonary edema within two weeks. The serum creatinine level rose to 5.0 mg per deciliter (440 μmol per liter). There was no oliguria, and the results of a repeated review of the urinary sediment were unchanged. Subsequently, a percutaneous kidney biopsy was performed (Figure 3). Pathological examination under light microscopy revealed global sclerosis in two of six glomeruli; the remaining glomeruli were unremarkable. Coarse vacuolization was found in the epithelium of tubules, with loss of brush borders, suggesting ischemic injury. The arteries showed intimal thickening and fibrosis consistent with the presence of hypertension. The immunofluorescence study was negative, ruling out immune-complex disease. Electron microscopy showed minimal segmental effacement of podocyte foot processes and no electron-dense deposits. Two needle-shaped cholesterol crystals were identified in separate afferent arterioles, consistent with the presence of atheroembolic kidney disease. During the subsequent two months, uremia developed and hemodialysis was initiated.
Figure 3. Percutaneous-Biopsy Specimen of the Kidney.
Both the light-microscopical view (Panel A, hematoxylin and eosin) and the electron-microscopical view (Panel B) show needle-like clefts from atheroemboli to afferent arterioles.
Commentary
As this case illustrates, the difficulty in diagnosing renal atheroembolism is often related to the fact that the diagnosis is never even considered. In this instance, the diagnosis was especially difficult, because there were initially no obvious signs or symptoms. Furthermore, in trying to identify a single, unifying disease to connect the pulmonary embolism to the subsequent renal presentation, the discussant did not consider that the treatment of the initial process may have been the link between the thromboembolism and the renal disease. Indeed, although invasive aortic manipulation is the leading cause of atheroembolism, spontaneous atheroembolism is often precipitated by thrombolysis or anticoagulation, which was the likely cause in this case.1,2 It was only after a detailed evaluation of other potential causes of renal failure proved fruitless and after magnetic resonance angiography and echocardiography, which were ordered for other reasons, showed evidence of diffuse atherosclerosis that the discussant considered the diagnosis of spontaneous atheroembolism and found the "needle in the haystack." In fairness, the discussant's approach highlighted the important principle of ruling out life-threatening diagnoses first and then evaluating patients for other treatable diagnoses. In this case, the delayed diagnosis had little clinical effect, since there are currently no effective treatments for atheroembolism.
Atheroembolic disease accounts for approximately 5 to 10 percent of cases of acute renal failure.3 These rates may actually underestimate the true prevalence of the disease, because the nonspecific symptoms and indolent nature of the syndrome render the diagnosis elusive, as shown in this case. Typical signs, including eosinophilia, hypocomplementemia, livedo reticularis, and cutaneous emboli, are highly variable and may be absent.4 Retinal emboli, known as Hollenhorst plaques, may provide clues to the diagnosis, but they occur only rarely.5 As in this case, the results of urinalysis may be unrevealing or may misleadingly suggest other diagnoses, such as interstitial nephritis, acute tubular necrosis, or even glomerulonephritis.6,7,8 Furthermore, most cases of atheroembolic kidney disease are triggered by angiography, in which case radiocontrast-induced nephropathy is easily invoked as an alternative diagnosis.5,9
Risk factors for atheroembolism include increased age, male sex, hypertension, a history of coronary or peripheral vascular disease, and a history of smoking.4 In studies of patients with biopsy-proven atheroembolic kidney disease, anticoagulation was thought to be a precipitating factor in 33 to 55 percent of cases.3,4,5 Anticoagulant agents are thought to destabilize atherosclerotic plaques by allowing cholesterol crystals that were previously covered by clot to be exposed to the circulation. The prognosis for patients with atheroembolic kidney disease is poor; in up to 25 percent, the condition progresses to end-stage renal disease, and in a recent prospective study, 38 percent died within five years.5
The identification of needle-shaped cholesterol clefts on examination of the renal-biopsy specimen is required to make the diagnosis (sites of atheroembolism dissolve during tissue fixation). However, even on renal biopsy, patchy involvement of the kidney can lead to a sampling error and a false negative finding. In addition, changes consistent with the presence of acute tubular necrosis, minimal change disease, and collapsing glomerulopathy, an aggressive subtype of focal segmental glomerulosclerosis, have been described in biopsy specimens from patients with atheroembolism.10,11 Even when cholesterol clefts are found on biopsy, the finding may be incidental in a patient with another primary diagnosis. However, an incidental finding was unlikely in this case, since the course of the renal failure is consistent with this diagnosis, other potential diagnoses were reasonably ruled out, and the patient's diffuse atherosclerosis and recent anticoagulant therapy are recognized risk factors for atheroembolism.
Atheroembolic disease is an important yet underdiagnosed component of the spectrum of kidney disease associated with atherosclerosis. Physicians should consider this diagnosis in patients with underlying vascular disease who present with renal failure.
No potential conflict of interest relevant to this article was reported.
We are indebted to Dr. Alan J. Greenfield in the Department of Vascular Radiology and Dr. R. Neal Smith in the Department of Pathology at Massachusetts General Hospital for providing the radiographic and pathological figures for this article.
Source Information
From the Renal Division, Department of Medicine, Brigham and Women's Hospital (K.R.P.); and the Nephrology Division, Department of Medicine, Massachusetts General Hospital (M.W.) — both in Boston.
Address reprint requests to Dr. Wolf at Massachusetts General Hospital, 55 Fruit St., Bartlett-917, Boston, MA 02114, or at mswolf@partners.org.
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