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Case 23-2009: A 13-Year-Old Boy with Headache, Nausea, Seizures, and Hypertension
Michael J.G. Somers, M.D., Amita Sharma, M.D., P. Ellen Grant, M.D., Alexander R. Guimaraes, M.D., Ph.D., and Eveline E. Schneeberger, M.D.

Pr e sen tat ion of C a se
A 13-year-old boy was admitted to the hospital because of headache, nausea, seizures, renal failure, and hypertension. The patient had been well until approximately 3 weeks earlier, when intermittent left-sided headaches and fatigue developed, followed by nasal congestion and anorexia. He began to nap daily after school. During the week before admission, nausea and vomiting occurred approximately every other day. Five days before admission, facial and periorbital swelling developed. He saw his primary care physician. A test for streptococcal pharyngitis was reportedly negative; amoxicillin was prescribed for presumed sinusitis. He continued to feel unwell and was not as energetic as usual, although he was able to play lacrosse 3 days before admission. He reported constipation and mild epigastric and periumbilical abdominal pain, he vomited intermittently, and he slept much of the day. On the morning of admission, nausea, vomiting, and abdominal pain developed while the patient was at school. At 11:15 a.m., his mother took him to the doctor’s office. Blood was drawn for laboratory tests, and he was sent to another hospital for a radiograph of his abdomen. En route to the car, at approximately noon, he reported numbness of the right leg and dizziness, and he became disoriented, with difficulty walking and coordinating his legs, but with no clear weakness; the episode lasted 5 minutes. During the car ride, he returned to his baseline mental status; numbness of the right leg persisted. At the hospital, radiography was performed, laboratory-test results revealed azotemia, and he was referred to the emergency department of another hospital. He began vomiting. On examination in the emergency department, the patient was awake, oriented, and vomiting intermittently. The blood pressure was 170/120 mm Hg, the pulse 63 beats per minute, the temperature 37°C, the respiratory rate 16 breaths per minute, the oxygen saturation 98% while he was breathing ambient air, and the weight 45.5 kg. The skin was pale and facial edema was present; the remainder of the examination was normal. Laboratory-test results are shown in Table 1. Screening tests for mononucleosis and hepatitis A, B, and C were negative. Labetalol and
n engl j med 361;4 nejm.org july 23, 2009

From the Division of Nephrology, Children’s Hospital (M.J.G.S.); the Departments of Pediatrics (A.S.), Radiology (P.E.G., A.R.G.), and Pathology (E.E.S.), Massachusetts General Hospital; and the Departments of Pediatrics (M.J.G.S., A.S.), Radiology (P.E.G., A.R.G.), and Pathology (E.E.S.), Harvard Medical School — all in Boston.
N Engl J Med 2009;361:389-400.
Copyright © 2009 Massachusetts Medical Society.

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The New England Journal of Medicine Downloaded from nejm.org on September 22, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

500.0 0.28–3.0 13.3–13.5 0.1–34.org on September 22.1 8.0 8.2 458 181 24 15 0.0–0. Hematologic and Biochemical Laboratory Data.0–16.7–1.7 On Admission.5 9.4 5. For personal use only.6 14. 2009 The New England Journal of Medicine Downloaded from nejm.000 8. This Hospital 24.6–1. .3 1. Copyright © 2009 Massachusetts Medical Society. 2012.02 4.89) 0.4 135–145 3.5 0–17 (men) 22.500 150.0–37.0 4.000 4500–13. No other uses without permission.4 (ref 0.0 11.0–39.58–1.6 102 16.5 166 (ref 25–125) 0.5 10–60 15–350 10–40 10–55 193 (ref 30–300) 32 20 701 (ref 95–180) 2.0) 10.3 2.9 8–25 0.0 134 5.8 100–108 23.0 123 16.300.86 (ref 0.7 Day of Admission.* Variable Hematocrit (%) Hemoglobin (g/dl) Red cells (per mm3) White cells (per mm3) Platelets (per mm3) Mean corpuscular volume (μm3) Mean corpuscular hemoglobin (pg/red cell) Mean corpuscular hemoglobin concentration (g/dl) Red-cell distribution width (%) Erythrocyte sedimentation rate (mm/hr) Activated partial-thromboplastin time (sec) Prothrombin time (sec) International normalized ratio Sodium (mmol/liter) Potassium (mmol/liter) Chloride (mmol/liter) Carbon dioxide (mmol/liter) Urea nitrogen (mg/dl) Creatinine (mg/dl) Glucose (mg/dl) Bilirubin (mg/dl) Total Direct Protein (g/dl) Total Albumin Globulin Phosphorus (mg/dl) Magnesium (mmol/liter) Calcium (mg/dl) Parathyroid hormone (pg/ml) Alkaline phosphatase (U/liter) Aspartate aminotransferase (U/liter) Alanine aminotransferase (U/liter) Lactate dehydrogenase (U/liter) Lipase (U/dl) Amylase (U/liter) Troponin I (ng/ml) Thyrotropin (μIU/ml) Thyroxine. All rights reserved.0–4. free (ng/dl) 1.4 (specimen not hemolyzed) 96 19.0 10.9 9.0 15.4 1.64) 1.8 48 32.0 31.4–4.2 1.4 6.71 (ref 0.3 134 6.The n e w e ng l a n d j o u r na l of m e dic i n e Table 1.4 1. Age-Adjusted† 37. Other Hospital 26.5–10.0 3–100 0.1 110 390 n engl j med 361.000–5.3 2.2 6.1 38.000 84 32.0 2.100 114.4 95 21 134 15.5 70–110 Reference Range.3–1.2) 1.org july 23.3–6.9 3.1 3.0–0.910.6 0.3–5.5–14.6 (ref 25.3 3.000–450.000 127.4 nejm.2 23.6–4.0–8.6 6.1 8.000 86.000 78–98 25.0–35.0–49.0–1.0–31.

He lived with his parents and brothers. on routine examination. multiply by 0. and the blood pressure decreased to 132/83 mm Hg. rash.35–7. and no evidence of acute stroke or hemorrhage. hydrocephalus. the pulse was 80 beats per minute. After the episodes.250. All rights reserved. multiply by 88. without shaking or body movement. arthralgias. one associated with incontinence.0–4. To convert the values for phosphorus to millimoles per liter. the blood pressure was 100/70 mm Hg and pubertal development had begun. † Reference values are affected by many variables. a prominent temporal horn. unexposed smokers. including the patient population and the laboratory methods used. To convert the values for creatinine to micromoles per liter. To convert the values for glucose to millimoles per liter. The weight was 45 kg and the blood pressure ranged between 150/60 and 170/115 mm Hg. (Continued. . This Hospital 103 204 279 26 5. He did not have sore throat. the temperature 36. One year before admission.org on September 22. and a normal third ventricle.4 lergies.org 391 The New England Journal of Medicine Downloaded from nejm. His mental status returned to normal after he slept. There was no family history of an autoimmune disorder. Other Hospital On Admission. Age-Adjusted† 45–160 228–428 30–300 >32. The electrocardiogram showed normal sinus rhythm with no peaked T waves. multiply by 0. After the CT scan.05551.. ill-defined focus of decreased density in the right parietal region and no other evidence of focal or diffuse lesions. shortness of breath. at approximately 3 p. and 4 p. He had no aln engl j med 361. 2012. multiply by 0. For personal use only. No other uses without permission.m. epistaxis. arthritis. Copyright © 2009 Massachusetts Medical Society.0–12. On examination. hemorrhage. hematuria. 1. multiply by 0. he required surgery for pyloric stenosis. The ranges used at Massachusetts General Hospital are age-adjusted for patients who are not pregnant and do not have medical conditions that could affect the results. 2009 nejm. with the occipital horn of the lateral ventricle larger on the left side than on the right.4.m. and they were thought to show asymmetric ventricles. divide by 0. 3. hemoptysis. desired Unexposed nonsmokers. The physical examination was unchanged. ‡ The composition of the patient’s inspired gas was not reported. To convert the values for magnesium to milligrams per deciliter. who were healthy. CT images from the other hospital were reviewed. At 3 weeks of age.45 35–42 80–100 24–30 Negative 1.case records of the massachusetts gener al hospital Table 1.5°C. he was somnolent but oriented.48 29 120 22 * Ref denotes reference range. They may therefore not be appropriate for all patients. photosensitivity.3229. He had been born via vaginal delivery after a fullterm gestation. To convert the values for urea nitrogen to millimoles per liter. Computed tomography (CT) of the head showed a small.1 Arterial blood gas analysis‡ Base excess (mmol/liter) pH Partial pressure of carbon dioxide (mm Hg) Partial pressure of oxygen (mm Hg) Bicarbonate (mmol/liter) 7. and the oxygen saturation 93 to 98% while he was breathing ambient air. Laboratory-test results are shown in Tables 1 and 2. There was minimal urine output. To convert the values for calcium to millimoles per liter. the patient was intermittently somnolent but arousable and oriented. Radiographs of the chest and abdomen july 23.0 Day of Admission.357. Both grandfathers had had prostate cancer. myalgias. He was transferred to the pediatric intensive care unit of this hospital.6 7. He had received all immunizations and took no medications.4114. Specimens of blood and urine were cultured. ondansetron were administered. or focal bone lesions. he had two episodes of blank staring.) Variable Iron (μg/dl) Iron-binding capacity (μg/dl) Ferritin (ng/ml) 25-Hydroxyvitamin D (ng/ml) Thiocyanate (μg/ml) Reference Range. the respiratory rate between 10 and 20 breaths per minute. and there was a family history of migraine headaches. or fever.0.

* Analyte Sodium (mmol/liter) Potassium (mmol/liter) Chloride (mmol/liter) Urea nitrogen (mg/dl) Creatinine (mg/ml) Calcium (mg/dl) Glucose (g/dl) Color Turbidity pH Specific gravity Screening dipstick White cells Bilirubin Urobilinogen Nitrites Albumin Glucose Ketones Blood Leukoesterase Urine sediment Hyaline casts (per low-power field) Granular casts (per low-power field) Red cells (per high-power field) White cells (per high-power field) Squamous epithelial cells (per highpower field) Bacteria (per high-power field) Budding yeast (per high-power field) 0–2 0–2 Negative Negative Few 0–5 4 4 94 15 50–100 5–10 Negative Few 0–2 Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Normal (ref normal) Negative 4+ Negative Negative 3+ Negative 1+ 1+ Negative Negative 3+ Trace Trace 3+ Reference Range. To convert the value for calcium to millimoles per liter. granular. 2009 nejm. † Reference values are affected by many variables. To convert the value for urea nitrogen to millimoles per liter. Other Hospital On Admission.250. To convert the value for creatinine to micromoles per liter.org The New England Journal of Medicine Downloaded from nejm. The ranges used at Massachusetts General Hospital are age-adjusted for patients who are not pregnant and do not have medical conditions that could affect the results.4 and waxy casts. Age-Adjusted† Diet-dependent Diet-dependent Diet-dependent Diet-dependent Diet-dependent Diet-dependent <0. Labetalol and ondansetron were continued. 392 n engl j med 361. Analysis of the urine sediment by a nephrologist revealed red-cell. revealed increased perihilar markings with a butterfly pattern of vasculature suggestive of mild congestive heart failure and a moderate amount of stool in the colon with a nonobstructive gas pattern. multiply by 55. They may therefore not be appropriate for all patients. This Hospital 38 68. they were otherwise normal.The n e w e ng l a n d j o u r na l of m e dic i n e Table 2. Results of Urinalysis.357. For personal use only. mixed-cellular. To convert the value for glucose to millimoles per liter. .05 Yellow Clear 5. and dextrose were given intravenously. and a continuous intravenous infusion of nitroprusside was begun.8 49 275 1.51. 2012.83 2.0–9.035 Yellow Hazy 6. No other uses without permission. Copyright © 2009 Massachusetts Medical Society.025 Day of Admission.001–1. multiply by 0. insulin. multiply by 0. Emergency hemodialysis was perjuly 23. including the patient population and the laboratory methods used.org on September 22.031 * Ref denotes reference range. An arterial catheter was inserted. All rights reserved.5 1.0 1. multiply by 8840. calcium gluconate. with a goal of systolic pressures below 140 mm Hg. and hydralazine.5 1.7 Negative Yellow Turbid 5.

With a lack of renal function. On the third day. Copyright © 2009 Massachusetts Medical Society. which indicated that they represented edema. Indirect immunofluorescence testing for antineutrophil cytoplasmic antibodies (ANCAs) and anti–glomerular basement membrane antibodies was negative. which suggested necrosis. hypocalcemia. With normal muscle turnover. and occipital regions. features compatible with mild congestive heart failure. 1A) showed diffuse echogenicity and a moderate increase in the size of both kidneys. Somers: This child presented with hematuria and proteinuria. the creatinine generally rises by 2 mg per kilogram of body weight per day. A diagnostic procedure was performed. midazolam. and cellular and granular casts. His serum creatinine level of 16 mg per deciliter could thus reflect a complete lack of glomerular filtration for about a week.4 The duration of the renal insufficiency is useful information in sorting out the differential diagnosis of the renal failure. analysis of a specimen of urine revealed a protein level of 27. parathyroid hormone. which may suggest a problem in addition to the decline in the GFR.4 cm in length and the left kidney 10. with dysmorphic erythrocytes. a slow chronic decline. The elevated serum creatinine level precludes new-onset kidney injury. The degree of metabolic acidosis. and oliguria leading to volume overload. With a normal glomerular filtration rate (GFR) and adequate hydration. or a chronic decline with superimposed acute decline. moderate free fluid in the pelvis. most of the T2-weighted bright areas had normal signal intensity. Ultrasonography performed on the second day (Fig. no evidence of free air. A review of the history and results of laboratory tests offer clues to the chronicity of this process. Fluid was restricted to 1 liter per day. Alexander R. with only small areas of increased signal on diffusion-weighted imaging. which suggests that the duration of severely reduced renal function is relatively short.G. and no hydronephrosis or solid-appearing mass lesions. this child generates about 15 mg of creatinine per kilogram of body weight per day that would normally be excreted in the urine. corresponding to areas of low attenuation seen on CT. No other uses without permission. frontal. On diffusion-weighted imaging. severe azotemia.3 mg per milliliter (20. most marked in the upper pole of the left kidney. The analysis of urine sediment supports this pattern of kidney injury. and a mild increase in interstitial opacities. Guimaraes: A chest film on admission showed clear lungs. Magnetic resonance imaging (MRI) of the brain showed areas of increased T2-weighted signal intensity in the subcortical white matter in the frontal. resulting in a stable serum creatinine level. Somers: May we review the radiology studies? Dr. 2012. 0 to 135) and a creatinine level of 2.org on September 22.0 mmol per liter. pyuria. There were no pleural effusions. parietal. and a moderate amount of stool throughout the colon. An abdominal radiograph showed a normal pattern of bowel gas. 1B) in the subcortical white matter in the n engl j med 361. and methylprednisolone and ranitidine were begun. and hyperphosphatemia is moderate. The effects of a decreased GFR on homeostasis of growth hormone. P. All rights reserved. which was not dilated.280 mg per liter (reference range. The right kidney was 9. The marked renal insufficiency and hypertension and the accompanying proteinuria make diffuse glomerular involvement likely. A sagittal view showed a moderate amount of fluid in the pelvis.case records of the massachusetts gener al hospital formed. with very little mass effect. Michael J. These areas were bright on both T2-weighted (Fig. Ellen Grant: MRI of the brain on the third day showed areas of increased signal intensity (Fig. parietal. normal heart size. and levels of IgG and IgM anticardiolipin antibodies were normal. This constellation of findings constitutes a nephritic pattern of renal disease. For personal use only. Mannitol.332 μmol per liter).3 cm in length. and erythropoietin also affect clinical facjuly 23. 2009 nejm. On the second hospital day. tests for lupus anticoagulant were negative. In contrast. this creatinine burden is excreted. Cultures of the blood and urine were sterile. Dr. 1D). which appear to represent increased fluid in the subcortical white-matter region. Duration of kidney insufficiency Differ en t i a l Di agnosis Dr. there is pronounced hyperkalemia. and fentanyl citrate were added. Dr. Ultrasonography of the kidney revealed mildly increased echogenicity of the renal parenchyma. and occipital regions. 1C) and fluid-attenuated inversion recovery images (Fig.org 393 The New England Journal of Medicine Downloaded from nejm. with a predominantly normal signal on diffusionweighted imaging. . Magnesium was administered as needed to maintain a level greater than 1.

elevated serum lactate dehydrogenase level. PLEASE NOTE: Figure has been redrawn and type has been reset. and indirect hyperbilirubinemia. and red. but comparing his recent rate of growth with normal ranges might reveal a new delay in growth. 2009 The New England Journal of Medicine Downloaded from nejm. The hemoglobin level of less than 10 g per deciliter indicates anemia and may be related to renal failure. health.The n e w e ng l a n d j o u r na l of m e dic i n e A B C D Figure 1. . and occipital regions. Please check carefully. All rights reserved. with very little mass Revised These areas were bright on both corresponding to areas of low attenuation seen effect. These findings are nonspecific but can be seen with renal RETAKE 1st ICM failure from a variety of causes. bone cell mass. but in combination with mild thrombocytopenia. it also suggests conISSUE: 7-23-09 comitant microangiopathy. The child’s last routine examination JOB: 36104 showed normal adolescent development. and the hemolytic–uremic syndrome. Copyright © 2009 Massachusetts Medical Society. Causes of Nephritis There are four broad categories of renal disease that can lead to the acute nephritic pattern: acute interstitial nephritis. chronic glomerulonephritis with exacerbation. Imaging Studies. Although idio- n engl j med 361. acute glomerulonephritis. MRI of theAUTHOR Somers of increased signal intensity on fluid-attenuated inverbrain shows areas 2nd REG F FIGURE 1a-d white matter in the frontal. No other uses without permission. The kidney is enlarged and diffusely echogenic without evidence of hydronephrosis. a process that could contribute to severe hyperkalemia. parietal. His markedly elevated parathyroid hormone level and the hypocalcemia and hyperphosphatemia suggest chronic renal insufficiency. an 394 AUTHOR.org on September 22. SIZE Enon ARTIST: mst FILL H/T Combo H/T 33p9 tors such as growth rate. sion recovery (FLAIR) images (Panel B) in the subcortical 3rd CASE TITLE on CT.org july 23. EMail Line 4-C T2 -weighted (Panel C) and FLAIR (Panel D) images.4 nejm. 2012. An ultrasound image of the abdomen (Panel A) shows a sagittal view of the right kidney. For personal use only.

This leads to speculation that either the procoagulant state or endothelial injury linked to nephrosis caused the hemolytic–uremic syndrome. The Hemolytic–Uremic Syndrome This child’s profound renal insufficiency raises the specter of a rapidly progressive glomerulonephritis.4 As a result. All rights reserved. heavy proteinuria. a hemoglobin level below 10 g per deciliter is unusual. all of which are prominent features in this child. and seizures are common. and renal insufficiency. oliguria. it has been in children with a nephrotic pattern of renal disease. edema and hypertension are less common. By activating the renin–angiotensin–aldosterone system and causing shear stress. Rapidly Progressive Glomerulonephritis lupus. Eosinophilia and eosinophiluria can occur. proteinuria. drowsiness. it is unlikely that his hemolytic–uremic syndrome is linked to chronic glomerulopathy. . as in this boy who presented with probable hypertensive encephalopathy according to both clinical features and radiographic imaging. his renal impairment seems somewhat chronic and there may be a microangiopathy. or a severe decrease in GFR.org on September 22. The suggestion of thrombotic microangiopathy in the initial laboratory-test results makes the hemolytic–uremic syndrome an attractive unifying diagnosis. and hypertension are classic clinical features of a rapidly progressive glomerulonephritis. vomiting. visual changes. most episodes in children arise from drug hypersensitivity. 2009 nejm.10 Patients with such hypertension-mediated thrombotic microangiopathy have hematuria. we turn to the hemolytic–uremic syndrome as a possible cause of this child’s renal injury. Other than in cases of lupus. the clinician should assess complement levels and perform serologic tests for ANCA-associated disease and lupus. Commonly implicated medications include penicillins. Moreover.2 Headache. No other uses without permission. and renal dysfunction is variable. The urine sediment is more active and the renal insufficiency more pronounced than usual. This child has the classic triad of the hemolytic– uremic syndrome: microangiopathic anemia. and nonsteroidal antiinflammatory agents. thrombotic microangiopathy is rare in children with chronic glomerular diseases. Onset is about a week after exposure. 2012. these are all absent in this boy. The data suggest renal disease with a duration of no more than several months. edema. anticardiolipin antibodies are the usual cause of a lupus-induced thrombotic microangiopathy. ANCA-associated and anti–glomerular basement membrane disease are unlikely because of the negative serologic tests. fever and rash are common. thrombocytopenia. and pyuria with white-cell casts is common. whereas focal neurologic deficits are less frequent.case records of the massachusetts gener al hospital pathic interstitial nephritis occurs rarely. The severe and rapid renal impairment. This boy’s presentation and imaging fit the picture of a hypertensive encephalopathy driven by renal disease.org 395 The New England Journal of Medicine Downloaded from nejm.6 Henoch–Schönlein purpura is also unlikely. Table 3 summarizes conditions causing thrombotic microangiopathy and renal injury in children. For personal use only.8 Since this child has no apparent preexisting glomerular disease and does not have the nephrotic syndrome. Immunecomplex diseases such as postinfectious nephritis. The degree of hypertension can be pronounced.9 A history of severe hypertension with end-organ damage such as retinopathy or cardiac changes would increase the clinical suspicion that the microangiopathy is linked to blood pressure. IgA nephropathy and Henoch–Schönlein purpura.3-5 To help make a specific diagnosis. and lupus nephritis constitute at least two thirds of cases. The child does not have the diagnostic criteria for lupus. and when this entity has been described. This boy has had no fever or rash and only brief exposure to amoxicillin. Hypertension is a common characteristic of the three other categories of renal disease that present with a nephritic pattern. Copyright © 2009 Massachusetts Medical Society. and he had a negative test for anticardiolipin antibodies.11 as is an elevated serum lactate dehydrogenase or bilirubin level.7 Taken together. but it is important to determine whether the microangiopathy is a primary process causing the renal dysfunction and hypertension or whether it is secondary to chronic glomerulopathy or hypertension. and although most have anemia. malignant hypertension contributes to endothelial-cell injury and promotes thrombotic microangiopathy. a test that is positive in up to three quarters of patients with n engl j med 361. since most children with this syndrome have skin findings and 70% have gastrointestinal and joint symptoms. This patient has no history of recent infection to suggest postinfectious nephritis.1 Clinical and laboratory manifestations vary widely. thromjuly 23. there is not compelling evidence of a rapidly progressive glomerulonephritis related to either acute or chronic nephritis. cephalosporins.

≤6 g/dl) Severe azotemia (blood urea nitrogen. and severe renal insufficiency make thrombotic thrombocytopenic purpura less likely.3 Some types of Streptococcus pneumoniae produce a neuraminidase that cleaves sialic acid residues from renal endothelial cells. Copyright © 2009 Massachusetts Medical Society.12 The hemolytic–uremic syndrome in children is classified into two categories: typical hemolytic– uremic syndrome with a diarrheal prodrome (D+).4 dren with the hemolytic–uremic syndrome have typical disease. and renal failure.org The New England Journal of Medicine Downloaded from nejm. 2012. Up to 90% of chil396 n engl j med 361. A negative Coombs’ test. Thrombotic Microangiopathies Commonly Leading to Renal Injury. ≤25.The n e w e ng l a n d j o u r na l of m e dic i n e Table 3. the levels are deficient in most cases of thrombotic thrombocytopenic purpura. usually enterohemorrhagic Escherichia coli Variable Rare Common Variable Variable Common Common None Variable Thrombotic Thrombocytopenic Purpura Typical Hemolytic– Uremic Syndrome Atypical Hemolytic– Uremic Syndrome Fever Neurologic abnormalities Acute oliguria or anuria Severe hypertension Early laboratory findings Severe thrombocytopenia (platelets. would be useful data to support a diagnosis of the hemolytic–uremic syndrome. a blood smear with morphologic evidence of hemolysis. and the onset tends to be insidious.14 Atypical hemolytic–uremic syndrome occurs at any age. All rights reserved.org on September 22. Variable Clinical characteristics Prodromal illness Possible Diarrhea. such as lactate dehydrogenase and haptoglobin. No other uses without permission. and 30 to 40% of pediatric cases are associated with severe pneumococcal disease. the majority regain effective function. the absence of neurologic abnormalities not associated with hypertension. generally presenting before they are school age. with acute onset occurring after bloody diarrhea precipitated by verotoxin-producing bacteria such as Escherichia coli O157:H7. as would normal levels of von Willebrand factor–cleaving protease (ADAMTS 13). For personal use only. The absence of fever. >100 mg/dl [36 mmol/liter]) Genetic associations Common Common Rare Possible Common Possible Possible ADAMTS 13 deficiency or autoantibody Variable Variable Rare Common Variable Variable Variable Complement regulatory factor mutation or autoantibody (factor H. july 23.14 There is no specific prodromal illness.13 Although many affected children have severe acute kidney injury. 2009 nejm. . factor I. relapses occur that lead ultimately to end-stage renal disease.000/mm3) Severe anemia (hemoglobin. although atypical hemolytic–uremic syndrome may occur after or concurrently with illness. often with marked hypertension. and serial measurements of markers of hemolysis. and atypical hemolytic–uremic syndrome unassociated with diarrhea (D−). membrane cofactor protein) Variable No <50 ≥50 <80 Utility of plasma infusion or plasmapheresis Prognosis Rapid resolution of acute illness Chronic renal failure within 1 year of onset (% of patients) Progression to end-stage renal disease (% of patients) Recurrence post-transplantation (% of patients) Yes No 25 <50 <50 No Yes 5 20 0 bocytopenia without coagulopathy.

indicating the presence of increased glomerular permeability. These showed partial occlusion of vascular lumens by the swollen endothelial cells. including ADAMTS Atypical hemolytic–uremic syndrome. 2012. inset). Endothelialcell injury was also present in arterioles and small arteries. Eveline E. CFH. The pathological features do not permit distinction between these two entities or between typical and atypical hemolytic–uremic syndrome. leading to endothelial damage and thrombotic microangiopathy. All rights reserved.17 Few cases of factor I–linked disease have been described. Immunofluorescence microscopy revealed focal. and the calcineurin inhibitors cyclosporine and tacrolimus.org july 23. with widespread loss of fenestrae. C1q. scattered platelets intermixed with fibrin. or by genetic mutations in Di agnosis components of these pathways. atypical hemolytic–uremic syndrome must be considered. . In the hemolytic– uremic syndrome. It may be Atypical hemolytic–uremic syndrome.16 Either a gene mutation or an autoantibody directed against one of these regulatory proteins leads to an inability to dampen alternative complement-cascade activity. No fibrin was detected in a relatively small number of examined glomeruli.15 Atypical hemolytic–uremic syndrome may also occur after exposure to drugs that mediate endothelial-cell damage by various mechanisms. In the past decade. factor I. oral contraceptives. However. and kappa and lambda light chains. 13.4 nejm. MCP. The absence of previous drug exposure. or systemic illness puts atypical hemolytic–uremic syndrome associated with complement dysregulation high on the list of disorders in the differential diagnosis.case records of the massachusetts gener al hospital thereby exposing the Thomsen–Friedenreich (T) antigen to an anti-T immunoglobulin commonly found in the plasma. Copyright © 2009 Massachusetts Medical Society.G. In this child with the hemolytic–uremic syndrome triad but no diarrheal prodrome. as in typical hemoDr. and leukocytes were noted in arterial walls. some of which appeared to be thrombosed (Fig. C3. a feature consistent with endothelial-cell injury. mitomycin C. trace. and factor I. fragmented red cells. 2C). as in some was obtained. Cl inic a l Di agnosis n engl j med 361. up to half of the cases in children have been shown to involve abnormalities of complement factor H (CFH). and red cells. a descriptive term that encompasses the vascular pathology observed in the hemolytic–uremic syndrome and thrombotic thrombocytopenic purpura. 2009 397 The New England Journal of Medicine Downloaded from nejm.7 This patient had no known exposure to S. such as quinine. Glomerular endothelial cells were swollen.org on September 22. Most glomeruli displayed collapse cases of atypical hemolytic–uremic syndrome. These pathological features indicate thrombotic microangiopathy. with wrinkling of glomerular basement membranes and podocyte foot-process effacement (Fig. specific infection. and irregular staining in the mesangium for IgM and the complement protein C3. Multiple arterioles had swollen endothelial cells with luminal fibrin and platelets and fragmented red cells within the lumens and in the walls (Fig. 2A. caused by autoantibodies targeting components of the coagulation or complement pathways. Tubular reabsorption droplets stained for IgG. pneumoniae or relevant drugs.16 It is not clear what triggers the onset of disease in children with these genetic predispositions. No other uses without permission. Electron microscopical examination showed widespread collapse of glomerular capillary lumens. Mutations in CFH often lead to severe disease. or membrane cofactor protein (MCP). staining for IgM. including antiphospholipid. Approaches to therapy include plasma infusion to introduce functional factors and plasmapheresis to remove autoantibodies. mediating renal endothelial-cell injury and the initiation of thrombotic microangiopathy. Somer s’s anti-CFH antibodies. albumin. Schneeberger: A renal-biopsy specimen lytic–uremic syndrome. Pathophysiology of the Hemolytic–uremic syndrome Thrombotic microangiopathy follows endothelialcell injury in multiple vascular beds. A percutaneous renal biopsy will help clarify the diagnosis. For personal use only. of capillary loops (Fig. The injury may Pathol o gic a l Discussion be mediated by bacterial toxin. and MCP-associated disease seems to manifest as the least severe phenotype. and Dr . endothelial-cell damage is especially prominent in the kidney. Mich a el J. anti–ADAMTS 13. and fibrin was detected in the walls of several small arteries and arterioles. 2B). Deposition of fibrin. or by drugs. 2A).

complement factor I (CFI). the majority of glomeruli appeared collapsed. Please check carefully. Normally. we strongly suspected the diagnosis of atypical hemolytic– uremic syndrome.The n e w e ng l a n d j o u r na l of m e dic i n e A B C D Figure 2. Immunofluorescence microscopy (Panel B) shows infiltration of a small artery by fibrin and a luminal 2nd 2a-d thrombus. Electron microscopy of aREG F FIGURE glomerulus (Panel C) shows collapse of glomerular capillaries and swollen en3rd CASE trapped red cells. The concerted actions of MCP and plasma CFH. 2009 The New England Journal of Medicine Downloaded from nejm. ISSUE: 7-23-09 endothelial-cell lysis and the resulting in development of thrombotic microangiopathy. a small amount of C3b is deposited on all cells that are in contact with plasma.18 Dr.org on September 22. In the first biopsy specimen (Panel A). CFHR1. partially sclerosed. CFH. together with the proteolytic action of factor I.org july 23. AUTHOR. PLEASE NOTE: Figure has been redrawn and type has been reset. the expression of MCP. or both. lead to the inactivation of deposited C3b on endothelial cells.4 nejm. TITLE dothelial cells. and complement factor B (CFB). The H/T and tubular lumens of many arterioles are obliterated by FILL 33p9 Combo intimal fibrosis (inset). CFHR3. glomeruli are collapsed. Fibrinoid necrosis with entrapped red-cell fragments (inset) is present in a number of RETAKE 1st AUTHOR Somers ICM arterioles. This SIZE Enon H/T is accompanied by focal interstitial fibrosisARTIST: mst atrophy. Amita Sharma: In this patient. This patient 398 n engl j med 361. No other uses without permission. with loss of fenestrae and Revised EMail Line 4-C In the second biopsy. Mutations in any one of these factors leads to a failure to control C3 amplifica- tion. with only a few red cells present in glomerular capillaries. Determination of plasma levels of C3. 2012. Atypical hemolytic–uremic syndrome due to abJOB: 36104 normalities in the complement pathway results from complement-mediated endothelial injury. complement factor H receptor (CFHR). There is widespread podocyte foot-process effacement. . For personal use only. and screening for anti-CFH antibodies is indicated in the evaluation of all patients with atypical hemolytic–uremic syndrome. Renal-Biopsy Specimens. Copyright © 2009 Massachusetts Medical Society. All rights reserved. obtained 12 weeks later (Panel D). thereby preventing propagation of the C3bamplification loop.

Immunofluorescence studies showed minimal focal staining for IgM. and one had a fresh thrombus. Guimaraes reports receiving grant support from AstraZeneca. CFB and C3 is indicated. patients should be monitored during high-risk periods. The first four repeats include the major C3b binding site and regulate the fluidphase function. 2D). because of both the high risk of graft loss due to recurrent hemolytic–uremic syndrome. renal function. Dr. and advised to avoid known precipitants such as oral contraceptives. It has been 2 years since his initial presentation. In type I. and MCP. Many of the arteries were occluded by fibrous connective tissue (Fig. Sharma: Since examination of the biopsy specimen showed viable renal tissue. A nat omic a l Di agnosis Atypical hemolytic–uremic syndrome with complement factor H mutation.org on September 22. Approximately 8 weeks after initial presentation. The type II mutation seen in this patient led to decreased binding of C3b to endothelial cells.case records of the massachusetts gener al hospital had normal antigenic levels of factor H. if possible. obtained 12 weeks later. showed global sclerosis of one third of the glomeruli. This patient was treated initially with plasma exchange and subsequently with plasma infusion. Genotyping of CFH. the mutations lead to quantitative deficiency. Dr.24 Since CFH is synthesized predominantly in the liver. and hemolysis persisted. july 23. With peritoneal dialysis. the protein level is normal but one or more of its functions may be affected. whereas in type II (present in 25 to 75% of cases). the risk of the development of the hemolytic–uremic syndrome in a patient with a mutation cannot be quantified. even if plasma levels are normal. The other glomeruli showed wrinkled and segmentally thickened glomerular basement membranes and segmental collapse of glomerular capillaries (Fig. hypertension was easy to control with monotherapy. Combined liver and kidney transplantation with perioperative plasma infusion or exchange to elevate the level of wild-type complement regulators has been successful. 2D.25 Living-donor transplantation from family members is contraindicated. CFH consists of 20 contiguous modules called short consensus repeats. The family preference and likelihood that hemodialysis may have been contributing to ongoing hemolysis made us switch to peritoneal dialysis. The development of functional complement regulatory proteins by means of recombinant technology would also allow for infusions of these proteins as a new therapeutic approach to prevent disease activation or reactivation after transplantation. factor I. and MCP and. Copyright © 2009 Massachusetts Medical Society. and with the decline in renal function. kidney transplantation alone does not correct the deficiency. Dr. and fibrin in the glomeruli and some afferent arterioles. However. 2009 nejm. Schneeberger: The second biopsy specimen. missense mutation (S1191L) on short consensus repeat 20 of CFH.org 399 The New England Journal of Medicine Downloaded from nejm. such as when they have viral infections. he remained dependent on dialysis and had onn engl j med 361. hemolysis ceased. Nancy Lee Harris (Pathology): Would you consider genetic testing of family members? Dr. The defects in CFH can be classified as one of two types.20 Genetic testing in this patient disclosed a heterozygous. with intact fluid-phase function and normal protein levels in plasma. angiotensinconverting–enzyme inhibitors were added for control of hypertension. after another 6 weeks.4 going hemolysis. the patient’s hypertension remained difficult to control. inset). and the outcome of renal transplantation. the response to therapy. and the risk that related donors may share the recipient’s genetic predisposition. and he is doing well on peritoneal dialysis. CFI. and hemodialysis was continued. No other potential conflict of interest relevant to this article was reported. Somers: Genetic testing is indicated for relatives of an affected person who are considering donating a kidney to that person. However. Electron microscopical examination of a single glomerulus revealed features similar to those observed in the first biopsy. The role of more widespread genetic screening for relatives is unclear at this point.21-23 Current treatment of atypical hemolytic–uremic syndrome involves plasma exchange or plasma infusion. These factors prompted a repeat renal biopsy. C3. All rights reserved. aggressive plasma exchange was instituted.19 Identification of the specific mutation is also important because of differences in mortality. No other uses without permission. . Dr. 2012. Since mutations are predisposing rather than causal. For personal use only. The family is weighing the risk of combined liver and kidney transplantation against continued dialysis while awaiting the development of novel therapies that may use monoclonal antibodies or recombinant proteins to alter complement-cascade dysregulation. Tubular atrophy and interstitial fibrosis involved approximately 30% of the cortex.

et al. Kavanagh D. 16. et al. 25. as well as unpublished text slides. Pediatr Nephrol 2008. Intern Med 1999. Gulati S. 7. 20. 5th ed. Alon U. A clinico-pathologic study of crescentic glomerulonephritis in 50 children: a report of the Southwest Pediatric Nephrology Study Group. 1983:381-94. Amore A. Kavanagh D. Fujita T. 13. 2004:851-63. Xing C. EMBO J 2006. Brewster UC. Klein PJ.6:231-5.27: 450-8.108:1267-79. et al. ed. and cardiac studies. and diagrams. This slide set contains all of the images from the CPC. tables. Jaakola VP. Bulla M. eds.77-78:5-22. Pediatric nephrology. Mayo Clin Proc 2006.80:422-9. In: Avner ED. 2005:65-83. Massachusetts General Hospital. 11. CFH. 111:5307-15. and photomicrographs. Noris M. 3rd ed. For personal use only. Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides. Basel. or individual sets may be purchased for $50 each. Basel. In: Royer P.38:495-9. Thomsen-Friedenreich antigen in haemolytic-uraemic syndrome. Ståhl AL. Risdon RA. 2009 The New England Journal of Medicine Downloaded from nejm.org july 23. Blood 2006. Paris: Flammarion. Jokiranta TS. Kidney Int 1985. Atypical haemolytic uraemic syndrome. Philadelphia: Lippincott Williams & Wilkins. Glomerulonephrites a croissants diffuse.31:479-83. Leake J. 10. Barratt TM.11:213-8.24: 69-74. Br Med Bull 2006. 2005:85-109. and IF mutations on clinical presentation. 8. Nephrologie pediatrique. Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H. 17. not only those published in the Journal. Qian J. 18:506-14. Dillon MJ. Pärepalo M.28:89-95.8:216-21. Spectrum of radiological changes in hypertensive children with reversible posterior leucoencephalopathy. Application forms for the current subscription year. Every year 40 sets are produced. 12.204:1249-56. neurologic. 2004:817-31. 2. Richards A. Department of Pathology. All rights reserved. 21. Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation. MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners. including digital images. Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. FremeauxBacchi V. Coppo R. Blood 2008. Niaudet P. 9. and outcome. Tsai HM. Jalanko H. Pickering MC. Lapeyraque AL. 400 n engl j med 361.1:625-31. de Jorge EG. Wagner E. et al. Goodship TH. eds. 4. averaging 50-60 slides per set. Brioschi S. Boston. Jardim HM. et al. Goldman A. In: Avner ED. et al. with identifying legends. ed. 15. Crescentic glomerulonephritis in children. Garg S. J Am Soc Nephrol 2007.org. Nephrology (Carlton) 2006. Thrombotic mi- croangiopathy in malignant hypertension and hemolytic uremic syndrome (HUS)/ thrombotic thrombocytopenic purpura (TTP): can we differentiate one from the other? Hypertens Res 2005. Complement and kidney disease. Each set is supplied on a compact disc and is mailed to coincide with the publication of the Case Record. Niaudet P. 23. . Koskinen A. et al. Sun B. Switzerland: Birkhauser-Verlag. Hemolytic uremic syndrome associated with immunoglobulin A nephropathy: a case report and review of cases of hemolytic uremic syndrome with glomerular disease. Philadelphia: Lippincott Williams & Wilkins. Gupta RK. Kurien A. eds. Henoch-Schonlein purpura. Copyright © 2009 Massachusetts Medical Society. et al. et al. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. In: Zipfel P. No other uses without permission. Clin J Am Soc Nephrol 2007. shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. In: Zipfel PF. 18. The cost of an annual subscription is $600. Phan V. Habib R. Pediatr Nephrol 1992. 5th ed. 3.2:591-6. Caprioli J. may be obtained from the Lantern Slides Service. Renal thrombotic microangiopathies induced by severe hypertension. which began in January. Pediatric nephrology. Zhang B. 24. 81:593. Heinen S. Shibagaki Y. Non-shiga toxin-associated hemolytic uremic syndrome. Am J Transplant 2008. Complement and kidney disease. J Exp Med 2007. Zhao X. Broyer M.25:1784-94. Hypertens Res 2008. Rifkin BS. Structure of complement factor H carboxylterminus reveals molecular basis of atypi- cal haemolytic uremic syndrome. Switzerland: BirkhauserVerlag. Lancet 1977. 6. Amirlak I.4 nejm. Vaziri-Sani F. Heinen S. 14. are included. Tubulointerstitial nephritis. Yu X. Prasad N. Harmon WE. Mathiew H. Jozsi M.org on September 22. Efficacy of plasma therapy in atypical hemolytic uremic syndrome with complement factor H mutations.case records of the massachusetts gener al hospital References 1. Copyright © 2009 Massachusetts Medical Society. Richards A. response to treatment. Genetics of HUS: the impact of MCP. J Thromb Haemost 2003. Thrombotic microangiopathy associated with malignant hypertension. Noris M. Lehtinen MJ. Niaundet P. Hartmann A. Remuzzi G. Levy M. Radiographic. 2012. Jozsi M. gross specimens. Meri S. 5. Amirlak B. 19. Sakai T. Hemolytic uremic syndrome: a factor H mutation (E1172Stop) causes defective complement control at the surface of endothelial cells. et al. Morita S. Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. Peltonen S. Role of complement and factor H in hemolytic uremic syndrome. Harmon WE. Lupus anticoagulant and anticardiolipin antibodies in SLE with secondary antiphospholipid antibody syndrome. Newman RA.2: 1024-5. 22. Turk J Hematol 2007. MartinezBarricarte R. Br J Radiol 2007.23:1363-6. Haemolytic uraemic syndrome: an overview. Skerka C. Okamoto N.