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case records of themassachusetts general hospital

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 361;4 nejm.org july 23, 2009 389

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

From the Division of Nephrology, Chil-drens Hospital (M.J.G.S.); the Depart-ments of Pediatrics (A.S.), Radiology(P.E.G., A.R.G.), and Pathology (E.E.S.),Massachusetts General Hospital; and theDepartments of Pediatrics (M.J.G.S., A.S.),Radiology (P.E.G., A.R.G.), and Pathology(E.E.S.), Harvard Medical School all inBoston.

N Engl J Med 2009;361:389-400.Copyright 2009 Massachusetts Medical Society.

Presentation of Case

A 13-year-old boy was admitted to the hospital because of headache, nausea, sei-zures, renal failure, and hypertension.

The patient had been well until approximately 3 weeks earlier, when intermit-tent left-sided headaches and fatigue developed, followed by nasal congestion andanorexia. He began to nap daily after school. During the week before admission,nausea and vomiting occurred approximately every other day. Five days before admis-sion, facial and periorbital swelling developed. He saw his primary care physician.A test for streptococcal pharyngitis was reportedly negative; amoxicillin was pre-scribed for presumed sinusitis. He continued to feel unwell and was not as ener-getic as usual, although he was able to play lacrosse 3 days before admission. Hereported constipation and mild epigastric and periumbilical abdominal pain, he vom-ited intermittently, and he slept much of the day.

On the morning of admission, nausea, vomiting, and abdominal pain developedwhile the patient was at school. At 11:15 a.m., his mother took him to the doctorsoffice. Blood was drawn for laboratory tests, and he was sent to another hospitalfor a radiograph of his abdomen. En route to the car, at approximately noon, hereported numbness of the right leg and dizziness, and he became disoriented, withdiff iculty walking and coordinating his legs, but with no clear weakness; the epi-sode 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 per-formed, laboratory-test results revealed azotemia, and he was referred to theemergency 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 63beats per minute, the temperature 37C, the respiratory rate 16 breaths per minute,the oxygen saturation 98% while he was breathing ambient air, and the weight45.5 kg. The skin was pale and facial edema was present; the remainder of theexamination was normal. Laboratory-test results are shown in Table 1. Screeningtests for mononucleosis and hepatitis A, B, and C were negative. Labetalol and

Case 23-2009: A 13-Year-Old Boywith 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.

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.

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n engl j med 361;4 nejm.org july 23, 2009390

Table 1. Hematologic and Biochemical Laboratory Data.*

VariableReference Range,

Age-AdjustedDay of Admission,

Other HospitalOn Admission,This Hospital

Hematocrit (%) 37.049.0 26.9 24.5

Hemoglobin (g/dl) 13.016.0 9.7 9.3

Red cells (per mm3) 4,500,0005,300,000 2,910,000

White cells (per mm3) 450013,500 6,000 8,100

Platelets (per mm3) 150,000450,000 127,000 114,000

Mean corpuscular volume (m3) 7898 86.7 84

Mean corpuscular hemoglobin (pg/red cell) 25.035.0 32.1

Mean corpuscular hemoglobin concentration(g/dl)

31.037.0 38.0

Red-cell distribution width (%) 11.514.5 16.2 15.8

Erythrocyte sedimentation rate (mm/hr) 017 (men) 48

Activated partial-thromboplastin time (sec) 22.134.0 23.6 (ref 25.039.0) 32.6

Prothrombin time (sec) 10.313.2 10.4 14.2

International normalized ratio 1.0 1.3Sodium (mmol/liter) 135145 134 134

Potassium (mmol/liter) 3.44.8 5.4 6.4 (specimen nothemolyzed)

Chloride (mmol/liter) 100108 95 96

Carbon dioxide (mmol/liter) 23.031.9 21 19.0

Urea nitrogen (mg/dl) 825 134 123

Creatinine (mg/dl) 0.61.5 15.6 16.1

Glucose (mg/dl) 70110 102 110

Bilirubin (mg/dl)

Total 0.01.0 1.4 (ref 0.31.2) 1.6

Direct 0.00.4 0.4

Protein (g/dl)

Total 6.08.3 5.9

Albumin 3.35.0 3.3

Globulin 2.64.1 2.6

Phosphorus (mg/dl) 3.04.5 6.3

Magnesium (mmol/liter) 0.71.0 1.1 1.1

Calcium (mg/dl) 8.510.5 8.4 8.2

Parathyroid hormone (pg/ml) 1060 458

Alkaline phosphatase (U/liter) 15350 193 (ref 30300) 181

Aspartate aminotransferase (U/liter) 1040 32 24

Alanine aminotransferase (U/liter) 1055 20 15

Lactate dehydrogenase (U/liter) 701 (ref 95180)

Lipase (U/dl) 1.36.0 2.5

Amylase (U/liter) 3100 166 (ref 25125)

Troponin I (ng/ml) 0.00.4 0.02

Thyrotropin (IU/ml) 4.86 (ref 0.283.89)

Thyroxine, free (ng/dl) 0.71 (ref 0.581.64)




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case records of the massachusetts general hospital


ondansetron were administered, and the bloodpressure decreased to 132/83 mm Hg. Computedtomography (CT) of the head showed a small,ill-defined focus of decreased density in the rightparietal region and no other evidence of focal ordiffuse lesions, hemorrhage, hydrocephalus, or fo-cal bone lesions. After the CT scan, at approxi-mately 3 p.m. and 4 p.m., he had two episodes ofblank staring, one associated with incontinence,without shaking or body movement. After the epi-sodes, he was somnolent but oriented. His mentalstatus returned to normal after he slept. Therewas minimal urine output. He was transferred tothe pediatric intensive care unit of this hospital.

He did not have sore throat, rash, arthralgias,arthritis, myalgias, photosensitivity, epistaxis, he-moptysis, shortness of breath, hematuria, or fever.He had been born via vaginal delivery after a full-term gestation. At 3 weeks of age, he requiredsurgery for pyloric stenosis. One year beforeadmission, on routine examination, the bloodpressure was 100/70 mm Hg and pubertal devel-opment had begun. He had received all immuni-zations and took no medications. He had no al-

lergies. He lived with his parents and brothers,who were healthy. Both grandfathers had hadprostate cancer, and there was a family historyof migraine headaches. There was no family his-tory of an autoimmune disorder.

On examination, the patient was intermittentlysomnolent but arousable and oriented. The weightwas 45 kg and the blood pressure ranged between150/60 and 170/115 mm Hg; the pulse was 80beats per minute, the temperature 36.5C, the re-spiratory rate between 10 and 20 breaths per min-ute, and the oxygen saturation 93 to 98% while hewas breathing ambient air. The physical examina-tion was unchanged. Laboratory-test results are

shown in Tables 1 and 2. Specimens of blood andurine were cultured. The electrocardiogram showednormal sinus rhythm with no peaked T waves.CT images from the other hospital were reviewed,and they were thought to show asymmetric ven-tricles, with the occipital horn of the lateral ven-tricle larger on the left side than on the right, aprominent temporal horn, and a normal thirdventricle, and no evidence of acute stroke or hem-orrhage. Radiographs of the chest and abdomen

Table 1. (Continued.)

VariableReference Range,



Iron (g/dl) 45160 103

Iron-binding capacity (g/dl) 228428 204

Ferritin (ng/ml) 30300 279

25-Hydroxyvitamin D (ng/ml) >32, desired 26

Thiocyanate (g/ml) Unexposed nonsmokers,1.04.0; unexposedsmokers, 3.012.0

5.1

Arterial blood gas analysis

Base excess (mmol/liter) Negative 1.6

pH 7.357.45 7.48

Partial pressure of carbon dioxide (mm Hg) 3542 29

Partial pressure of oxygen (mm Hg) 80100 120

Bicarbonate (mmol/liter) 2430 22

* Ref denotes reference range. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To con-vert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for glucose to millimolesper liter, multiply by 0.05551. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To con-vert the values for magnesium to milligrams per deciliter, divide by 0.4114. To convert the values for calcium to milli-moles per liter, multiply by 0.250.

Reference values are affected by many variables, including the patient population and the laboratory methods used. Theranges used at Massachusetts General Hospital are age-adjusted for patients who are not pregnant and do not havemedical conditions that could affect the results. They may therefore not be appropriate for all patients.

The composition of the patients inspired gas was not reported.




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revealed increased perihilar markings with a but-terfly pattern of vasculature suggestive of mildcongestive heart failure and a moderate amountof stool in the colon with a nonobstructive gaspattern; they were otherwise normal.

Analysis of the urine sediment by a nephrolo-gist revealed red-cell, mixed-cellular, granular,

and waxy casts. An arterial catheter was inserted,and a continuous intravenous infusion of nitro-prusside was begun, with a goal of systolic pres-sures below 140 mm Hg. Labetalol and ondanse-tron were continued, and hydralazine, calciumgluconate, insulin, and dextrose were given in-travenously. Emergency hemodialysis was per-

Table 2. Results of Urinalysis.*

AnalyteReference Range,



Sodium (mmol/liter) Diet-dependent 38

Potassium (mmol/liter) Diet-dependent 68.8

Chloride (mmol/liter) Diet-dependent 49

Urea nitrogen (mg/dl) Diet-dependent 275

Creatinine (mg/ml) Diet-dependent 1.83

Calcium (mg/dl) Diet-dependent 2.7

Glucose (g/dl)

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formed. Fluid was restricted to 1 liter per day,and methylprednisolone and ranitidine were be-gun. Mannitol, midazolam, and fentanyl citratewere added. Magnesium was administered asneeded to maintain a level greater than 1.0 mmolper liter. Indirect immunofluorescence testing forantineutrophil cytoplasmic antibodies (ANCAs)

and antiglomerular basement membrane anti-bodies was negative.

On the second hospital day, tests for lupusanticoagulant were negative, and levels of IgGand IgM anticardiolipin antibodies were normal.Ultrasonography of the kidney revealed mildlyincreased echogenicity of the renal parenchyma,most marked in the upper pole of the left kidney,moderate free fluid in the pelvis, and no hydro-nephrosis or solid-appearing mass lesions. Theright kidney was 9.4 cm in length and the leftkidney 10.3 cm in length. Cultures of the blood

and urine were sterile.On the third day, analysis of a specimen of

urine revealed a protein level of 27,280 mg perliter (reference range, 0 to 135) and a creatininelevel of 2.3 mg per milliliter (20,332 mol perliter). Magnetic resonance imaging (MRI) of thebrain showed areas of increased T

2-weighted

signal intensity in the subcortical white matterin the frontal, parietal, and occipital regions, witha predominantly normal signal on diffusion-weighted imaging. A diagnostic procedure wasperformed.

Differential Diagnosis

Dr. Michael J.G. Somers: May we review the radiologystudies?

Dr. Alexander R. Guimaraes: A chest film on ad-mission showed clear lungs, normal heart size,and a mild increase in interstitial opacities, fea-tures compatible with mild congestive heart fail-ure. There were no pleural effusions. An abdomi-nal radiograph showed a normal pattern of bowel

gas, no evidence of free air, and a moderateamount of stool throughout the colon, whichwas not dilated. Ultrasonography performed onthe second day (Fig. 1A) showed diffuse echoge-nicity and a moderate increase in the size of bothkidneys. A sagittal view showed a moderate amountof fluid in the pelvis.

Dr. P. Ellen Grant: MRI of the brain on the thirdday showed areas of increased signal intensity(Fig. 1B) in the subcortical white matter in the

frontal, parietal, and occipital regions, correspond-ing to areas of low attenuation seen on CT, whichappear to represent increased fluid in the sub-cortical white-matter region, with very little masseffect. These areas were bright on both T

2-weight-

ed (Fig. 1C) and fluid-attenuated inversion recov-ery images (Fig. 1D). On diffusion-weighted im-

aging, most of the T2-weighted bright areas hadnormal signal intensity, which indicated that theyrepresented edema, with only small areas of in-creased signal on diffusion-weighted imaging,which suggested necrosis.

Dr. Somers: This child presented with hematu-ria and proteinuria, severe azotemia, and oligurialeading to volume overload. This constellation offindings constitutes a nephritic pattern of renaldisease. The analysis of urine sediment supportsthis pattern of kidney injury, with dysmorphicerythrocytes, pyuria, and cellular and granular

casts. The marked renal insuff iciency and hyper-tension and the accompanying proteinuria makediffuse glomerular involvement likely.

Duration of kidney insufficiency

The duration of the renal insufficiency is usefulinformation in sorting out the differential diag-nosis of the renal failure. The elevated serumcreatinine level precludes new-onset kidney injury.With normal muscle turnover, this child gener-ates about 15 mg of creatinine per kilogram of bodyweight per day that would normally be excretedin the urine. With a normal glomerular f iltrationrate (GFR) and adequate hydration, this creatinineburden is excreted, resulting in a stable serumcreatinine level. With a lack of renal function, thecreatinine generally rises by 2 mg per kilogramof body weight per day. His serum creatininelevel of 16 mg per deciliter could thus reflect acomplete lack of glomerular filtration for abouta week, a slow chronic decline, or a chronic declinewith superimposed acute decline.

A review of the history and results of labora-

tory tests offer clues to the chronicity of this pro-cess. The degree of metabolic acidosis, hypocalce-mia, and hyperphosphatemia is moderate, whichsuggests that the duration of severely reducedrenal function is relatively short. In contrast,there is pronounced hyperkalemia, which maysuggest a problem in addition to the decline inthe GFR. The effects of a decreased GFR onhomeostasis of growth hormone, parathyroid hor-mone, and erythropoietin also affect clinical fac-




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tors such as growth rate, bone health, and red-

cell mass. The childs last routine examinationshowed normal adolescent development, but com-paring his recent rate of growth with normalranges might reveal a new delay in growth. Hismarkedly elevated parathyroid hormone level andthe hypocalcemia and hyperphosphatemia sug-gest chronic renal insufficiency. The hemoglobinlevel of less than 10 g per deciliter indicates ane-mia and may be related to renal failure, but incombination with mild thrombocytopenia, an

elevated serum lactate dehydrogenase level, and

indirect hyperbilirubinemia, it also suggests con-comitant microangiopathy, a process that couldcontribute to severe hyperkalemia.

Causes of Nephritis

There are four broad categories of renal diseasethat can lead to the acute nephritic pattern: acuteinterstitial nephritis, acute glomerulonephritis,chronic glomerulonephritis with exacerbation, andthe hemolyticuremic syndrome. Although idio-

l

A B

DC

Figure 1. Imaging Studies.

An ultrasound image of the abdomen (Panel A) shows a sagittal view of the right kidney. The kidney is enlarged anddiffusely echogenic without evidence of hydronephrosis. These findings are nonspecific but can be seen with renal

failure from a variety of causes. MRI of the brain shows areas of increased signal intensity on fluid-attenuated inver-

sion recovery (FLAIR) images (Panel B) in the subcortical white matter in the frontal, parietal, and occipital regions,corresponding to areas of low attenuation seen on CT, with very little mass effect. These areas were bright on both

T2-weighted (Panel C) and FLAIR (Panel D) images.




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pathic interstitial nephritis occurs rarely, mostepisodes in children arise from drug hypersensi-tivity. Commonly implicated medications includepenicillins, cephalosporins, and nonsteroidal an-tiinflammatory agents.1 Clinical and laboratorymanifestations vary widely. Onset is about a weekafter exposure, fever and rash are common, ede-

ma and hypertension are less common, and renaldysfunction is variable. Eosinophilia and eosino-philuria can occur, and pyuria with white-cellcasts is common. This boy has had no fever orrash and only brief exposure to amoxicillin. Theurine sediment is more active and the renal in-sufficiency more pronounced than usual. More-over, his renal impairment seems somewhat chron-ic and there may be a microangiopathy.

Hypertension is a common characteristic ofthe three other categories of renal disease thatpresent with a nephritic pattern. The degree of

hypertension can be pronounced, as in this boywho presented with probable hypertensive en-cephalopathy according to both clinical featuresand radiographic imaging.2 Headache, drowsiness,vomiting, visual changes, and seizures are com-mon, whereas focal neurologic deficits are lessfrequent. This boys presentation and imaging fitthe picture of a hypertensive encephalopathydriven by renal disease.

Rapidly Progressive Glomerulonephritis

This childs profound renal insufficiency raisesthe specter of a rapidly progressive glomerulone-phritis. The data suggest renal disease with a du-ration of no more than several months. The se-vere and rapid renal impairment, oliguria, edema,and hypertension are classic clinical features of arapidly progressive glomerulonephritis. Immune-complex diseases such as postinfectious nephri-tis, IgA nephropathy and HenochSchnlein pur-pura, and lupus nephritis constitute at least twothirds of cases.3-5 To help make a specific diagno-sis, the clinician should assess complement levels

and perform serologic tests for ANCA-associateddisease and lupus.This patient has no history of recent infection

to suggest postinfectious nephritis. ANCA-asso-ciated and antiglomerular basement membranedisease are unlikely because of the negative se-rologic tests. The child does not have the diag-nostic criteria for lupus, and he had a negativetest for anticardiolipin antibodies, a test that ispositive in up to three quarters of patients with

lupus; anticardiolipin antibodies are the usualcause of a lupus-induced thrombotic microan-giopathy.6 HenochSchnlein purpura is also un-likely, since most children with this syndromehave skin findings and 70% have gastrointesti-nal and joint symptoms; these are all absent inthis boy.7 Taken together, there is not compelling

evidence of a rapidly progressive glomerulonephri-tis related to either acute or chronic nephritis.

The HemolyticUremic Syndrome

As a result, we turn to the hemolyticuremic syn-drome as a possible cause of this childs renal in-jury. The suggestion of thrombotic microangiop-athy in the initial laboratory-test results makesthe hemolyticuremic syndrome an attractive uni-fying diagnosis, but it is important to determinewhether the microangiopathy is a primary pro-cess causing the renal dysfunction and hyperten-

sion or whether it is secondary to chronic glom-erulopathy or hypertension. Other than in casesof lupus, thrombotic microangiopathy is rare inchildren with chronic glomerular diseases, andwhen this entity has been described, it has beenin children with a nephrotic pattern of renal dis-ease. This leads to speculation that either the pro-coagulant state or endothelial injury linked tonephrosis caused the hemolyticuremic syndrome.8Since this child has no apparent preexisting glom-erular disease and does not have the nephroticsyndrome, it is unlikely that his hemolyticuremicsyndrome is linked to chronic glomerulopathy.

By activating the reninangiotensinaldoster-one system and causing shear stress, malignanthypertension contributes to endothelial-cell injuryand promotes thrombotic microangiopathy.9 A his-tory of severe hypertension with end-organ dam-age such as retinopathy or cardiac changes wouldincrease the clinical suspicion that the microan-giopathy is linked to blood pressure.10 Patientswith such hypertension-mediated thrombotic mi-croangiopathy have hematuria, proteinuria, and

renal insufficiency, and although most have ane-mia, a hemoglobin level below 10 g per deciliteris unusual,11 as is an elevated serum lactate dehy-drogenase or bilirubin level, thrombocytopenia,heavy proteinuria, or a severe decrease in GFR, allof which are prominent features in this child.

Table 3 summarizes conditions causing throm-botic microangiopathy and renal injury in children.This child has the classic triad of the hemolyticuremic syndrome: microangiopathic anemia, throm-




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bocytopenia without coagulopathy, and renal fail-ure. A negative Coombs test, a blood smear withmorphologic evidence of hemolysis, and serialmeasurements of markers of hemolysis, such aslactate dehydrogenase and haptoglobin, would beuseful data to support a diagnosis of the hemo-lyticuremic syndrome. The absence of fever, theabsence of neurologic abnormalities not associ-ated with hypertension, and severe renal insuffi-

ciency make thrombotic thrombocytopenic pur-pura less likely, as would normal levels of vonWillebrand factorcleaving protease (ADAMTS 13);the levels are deficient in most cases of throm-botic thrombocytopenic purpura.12

The hemolyticuremic syndrome in children isclassified into two categories: typical hemolyticuremic syndrome with a diarrheal prodrome (D+),and atypical hemolyticuremic syndrome unas-sociated with diarrhea (D). Up to 90% of chil-

dren with the hemolyticuremic syndrome havetypical disease, generally presenting before theyare school age, with acute onset occurring afterbloody diarrhea precipitated by verotoxin-produc-ing bacteria such as Escherichia coli O157:H7.13Although many affected children have severeacute kidney injury, the majority regain effectivefunction.14

Atypical hemolyticuremic syndrome occurs

at any age, and the onset tends to be insidious,often with marked hypertension; relapses occurthat lead ultimately to end-stage renal disease.14There is no specific prodromal illness, althoughatypical hemolyticuremic syndrome may occurafter or concurrently with illness, and 30 to 40%of pediatric cases are associated with severe pneu-mococcal disease.3 Some types of Streptococcuspneumoniaeproduce a neuraminidase that cleavessialic acid residues from renal endothelial cells,

Table 3. Thrombotic Microangiopathies Commonly Leading to Renal Injury.

VariableThrombotic Thrombo-

cytopenic PurpuraTypical HemolyticUremic Syndrome

Atypical HemolyticUremic Syndrome

Clinical characteristics

Prodromal illness Possible Diarrhea, usually entero-hemorrhagic

Escherichia coli

Variable

Fever Common Variable Variable

Neurologic abnormalities Common Rare Variable

Acute oliguria or anuria Rare Common Rare

Severe hypertension Possible Variable Common

Early laboratory findings

Severe thrombocytopenia (platelets,25,000/mm3)

Common Variable Variable

Severe anemia (hemoglobin, 6 g/dl) Possible Common Variable

Severe azotemia (blood urea nitrogen,>100 mg/dl [36 mmol/liter])

Possible Common Variable

Genetic associations ADAMTS 13 deficiencyor autoantibody None Complement regulatoryfactor mutation orautoantibody (factorH, factor I, membranecofactor protein)

Utility of plasma infusion or plasmapheresis Yes No Variable

Prognosis

Rapid resolution of acute illness No Yes No

Chronic renal failure within 1 yearof onset (% of patients)

25 5

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thereby exposing the ThomsenFriedenreich (T)antigen to an anti-T immunoglobulin commonlyfound in the plasma, leading to endothelial dam-age and thrombotic microangiopathy.15 Atypicalhemolyticuremic syndrome may also occur afterexposure to drugs that mediate endothelial-celldamage by various mechanisms, such as quinine,

mitomycin C, oral contraceptives, and the cal-cineurin inhibitors cyclosporine and tacrolimus.7This patient had no known exposure to S. pneu-moniae or relevant drugs.

In the past decade, up to half of the cases inchildren have been shown to involve abnormali-ties of complement factor H (CFH), factor I, ormembrane cofactor protein (MCP).16 Either a genemutation or an autoantibody directed against oneof these regulatory proteins leads to an inabilityto dampen alternative complement-cascade activ-ity, mediating renal endothelial-cell injury and

the initiation of thrombotic microangiopathy.Mutations in CFH often lead to severe disease.17Few cases of factor Ilinked disease have beendescribed, and MCP-associated disease seems tomanifest as the least severe phenotype.16 It is notclear what triggers the onset of disease in chil-dren with these genetic predispositions.

Approaches to therapy include plasma infu-sion to introduce functional factors and plasma-pheresis to remove autoantibodies. In this childwith the hemolyticuremic syndrome triad but nodiarrheal prodrome, atypical hemolyticuremicsyndrome must be considered. The absence ofprevious drug exposure, specific infection, or sys-temic illness puts atypical hemolyticuremic syn-drome associated with complement dysregulationhigh on the list of disorders in the differentialdiagnosis. A percutaneous renal biopsy will helpclarify the diagnosis.

Clinical Diagnosis

Atypical hemolyticuremic syndrome.

Dr. Michael J.G. Somerss

Diagnosis

Atypical hemolyticuremic syndrome.

Pathological Discussion

Dr. Eveline E. Schneeberger: A renal-biopsy specimenwas obtained. Most glomeruli displayed collapse

of capillary loops (Fig. 2A). Multiple arterioleshad swollen endothelial cells with luminal f ibrinand platelets and fragmented red cells within thelumens and in the walls (Fig. 2A, inset). Immuno-fluorescence microscopy revealed focal, trace, andirregular staining in the mesangium for IgM andthe complement protein C3. No fibrin was de-

tected in a relatively small number of examinedglomeruli. However, staining for IgM, C3, C1q,and fibrin was detected in the walls of severalsmall arteries and arterioles, some of which ap-peared to be thrombosed (Fig. 2B). Tubular reab-sorption droplets stained for IgG, albumin, andkappa and lambda light chains, indicating thepresence of increased glomerular permeability.Electron microscopical examination showed wide-spread collapse of glomerular capillary lumens,with wrinkling of glomerular basement mem-branes and podocyte foot-process effacement (Fig.

2C). Glomerular endothelial cells were swollen,with widespread loss of fenestrae, a feature con-sistent with endothelial-cell injury. Endothelial-cell injury was also present in arterioles and smallarteries. These showed partial occlusion of vas-cular lumens by the swollen endothelial cells,scattered platelets intermixed with fibrin, and redcells. Deposition of fibrin, fragmented red cells,and leukocytes were noted in arterial walls.

These pathological features indicate thromboticmicroangiopathy, a descriptive term that encom-passes the vascular pathology observed in thehemolyticuremic syndrome and thrombotic throm-bocytopenic purpura. The pathological features donot permit distinction between these two entitiesor between typical and atypical hemolyticuremicsyndrome.

Pathophysiology of the Hemolyticuremic

syndrome

Thrombotic microangiopathy follows endothelial-cell injury in multiple vascular beds. It may becaused by autoantibodies targeting components

of the coagulation or complement pathways, in-cluding antiphospholipid, antiADAMTS 13, andanti-CFH antibodies, or by genetic mutations incomponents of these pathways, including ADAMTS13, CFH, MCP, and factor I. In the hemolyticuremic syndrome, endothelial-cell damage is es-pecially prominent in the kidney. The injury maybe mediated by bacterial toxin, as in typical hemo-lyticuremic syndrome, or by drugs, as in somecases of atypical hemolyticuremic syndrome.




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Atypical hemolyticuremic syndrome due to ab-normalities in the complement pathway results

from complement-mediated endothelial injury.Normally, a small amount of C3b is deposited onall cells that are in contact with plasma. The con-certed actions of MCP and plasma CFH, togetherwith the proteolytic action of factor I, lead to theinactivation of deposited C3b on endothelialcells, thereby preventing propagation of the C3b-amplification loop. Mutations in any one of thesefactors leads to a failure to control C3 amplifica-

tion, resulting in endothelial-cell lysis and thedevelopment of thrombotic microangiopathy.18

Dr. Amita Sharma: In this patient, we stronglysuspected the diagnosis of atypical hemolyticuremic syndrome. Determination of plasma levelsof C3, CFH, complement factor I (CFI), comple-ment factor H receptor (CFHR), CFHR1, CFHR3,and complement factor B (CFB); the expressionof MCP; and screening for anti-CFH antibodiesis indicated in the evaluation of all patients withatypical hemolyticuremic syndrome. This patient

l

A B

DC

Figure 2. Renal-Biopsy Specimens.

In the first biopsy specimen (Panel A), the majority of glomeruli appeared collapsed, with only a few red cells pres-ent in glomerular capillaries. Fibrinoid necrosis with entrapped red-cell fragments (inset) is present in a number of

arterioles. Immunofluorescence microscopy (Panel B) shows infiltration of a small artery by fibrin and a luminal

thrombus. Electron microscopy of a glomerulus (Panel C) shows collapse of glomerular capillaries and swollen en-dothelial cells, with loss of fenestrae and trapped red cells. There is widespread podocyte foot-process effacement.

In the second biopsy, obtained 12 weeks later (Panel D), glomeruli are collapsed, partially sclerosed, or both. Thisis accompanied by focal interstitial fibrosis and tubular atrophy. The lumens of many arterioles are obliterated by

intimal fibrosis (inset).




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had normal antigenic levels of factor H, factor I,and MCP.

Genotyping of CFH, CFI, and MCP and, ifpossible, CFB and C3 is indicated, even if plasmalevels are normal. Since mutations are predispos-ing rather than causal, the risk of the developmentof the hemolyticuremic syndrome in a patient

with a mutation cannot be quantif ied. However,patients should be monitored during high-riskperiods, such as when they have viral infections,and advised to avoid known precipitants such asoral contraceptives.19 Identification of the specificmutation is also important because of differencesin mortality, renal function, the response to ther-apy, and the outcome of renal transplantation.20

Genetic testing in this patient disclosed aheterozygous, missense mutation (S1191L) onshort consensus repeat 20 of CFH. CFH consistsof 20 contiguous modules called short consen-

sus repeats. The first four repeats include themajor C3b binding site and regulate the fluid-phase function. The defects in CFH can be clas-sified as one of two types. In type I, the muta-tions lead to quantitative deficiency, whereas intype II (present in 25 to 75% of cases), the pro-tein level is normal but one or more of its func-tions may be affected. The type II mutation seenin this patient led to decreased binding of C3bto endothelial cells, with intact f luid-phase func-tion and normal protein levels in plasma.21-23

Current treatment of atypical hemolyticure-mic syndrome involves plasma exchange or plasmainfusion.24 Since CFH is synthesized predomi-nantly in the liver, kidney transplantation alonedoes not correct the deficiency. Combined liverand kidney transplantation with perioperativeplasma infusion or exchange to elevate the levelof wild-type complement regulators has been suc-cessful.25 Living-donor transplantation from fam-ily members is contraindicated, because of boththe high risk of graft loss due to recurrent hemo-lyticuremic syndrome, and the risk that related

donors may share the recipients genetic predis-position. The development of functional comple-ment regulatory proteins by means of recombi-nant technology would also allow for infusionsof these proteins as a new therapeutic approachto prevent disease activation or reactivation aftertransplantation.

This patient was treated initially with plasmaexchange and subsequently with plasma infusion.Approximately 8 weeks after initial presentation,he remained dependent on dialysis and had on-

going hemolysis. These factors prompted a repeatrenal biopsy.

Dr. Schneeberger: The second biopsy specimen,obtained 12 weeks later, showed global sclerosisof one third of the glomeruli. The other glomerulishowed wrinkled and segmentally thickened glom-erular basement membranes and segmental col-

lapse of glomerular capillaries (Fig. 2D). Many ofthe arteries were occluded by fibrous connectivetissue (Fig. 2D, inset), and one had a fresh throm-bus. Tubular atrophy and interstitial fibrosis in-volved approximately 30% of the cortex. Immuno-fluorescence studies showed minimal focal stainingfor IgM, C3, and fibrin in the glomeruli and someafferent arterioles. Electron microscopical exami-nation of a single glomerulus revealed featuressimilar to those observed in the first biopsy.

Dr. Sharma: Since examination of the biopsyspecimen showed viable renal tissue, aggressive

plasma exchange was instituted, angiotensin-convertingenzyme inhibitors were added forcontrol of hypertension, and hemodialysis wascontinued. However, after another 6 weeks, thepatients hypertension remained difficult to con-trol, and hemolysis persisted. The family prefer-ence and likelihood that hemodialysis may havebeen contributing to ongoing hemolysis made usswitch to peritoneal dialysis. With peritonealdialysis, hemolysis ceased, and with the declinein renal function, hypertension was easy to con-trol with monotherapy. It has been 2 years sincehis initial presentation, and he is doing well onperitoneal dialysis. The family is weighing therisk of combined liver and kidney transplantationagainst continued dialysis while awaiting the de-velopment of novel therapies that may use mono-clonal antibodies or recombinant proteins to altercomplement-cascade dysregulation.

Dr. Nancy Lee Harris(Pathology): Would you con-sider genetic testing of family members?

Dr. Somers: Genetic testing is indicated for rela-tives of an affected person who are considering

donating a kidney to that person. The role of morewidespread genetic screening for relatives is un-clear at this point.

Anatomical Diagnosis

Atypical hemolyticuremic syndrome with com-plement factor H mutation.

Dr. Guimaraes reports receiving grant support from AstraZeneca.No other potential conflict of interest relevant to this article wasreported.




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