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case records of the

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The

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Founded by

Richard C. CabotNancy Lee Harris, m.d.,

Editor

Jo-Anne O. Shepard, m.d.

,Associate Editor

Stacey M. Ellender,Assistant Editor

Sally H. Ebeling,Assistant Editor

Christine C. Peters,Assistant Editor

Case 38-2005: A 29-Year-Old Pregnant Womanwith the Nephrotic Syndrome and Hypertension

Winfred W. Williams, Jr., M.D., Jeffrey L. Ecker, M.D., Ravi I. Thadhani, M.D., M.P.H.,and Aliyah Rahemtullah, M.D.

From the Division of Nephrology, Depart-ment of Medicine (W.W.W., R.I.T.), andthe Departments of Transplant Surgery(W.W.W.), Obstetrics, Gynecology, and Re-productive Biology (J.L.E.), and Pathology(A.R.), Massachusetts General Hospital;and the Division of Nephrology, Depart-ment of Medicine (W.W.W., R.I.T.), and theDepartments of Obstetrics, Gynecology,and Reproductive Biology (J.L.E.), and Pa-thology (A.R.), Harvard Medical School.

N Engl J Med 2005;353:2590-600.

Copyright 2005 Massachusetts Medical Society.

A 29-year-old pregnant woman with systemic lupus erythematosus was admitted to the

hospital because of renal failure at 20 weeks 6 days of gestation.The patient, a native of Panama, had been in good health until she was 21 years of age,

when pain and swelling developed in the distal and proximal interphalangeal joints ofboth hands and feet. An evaluation at a hospital in her native country led to a diagnosis

of systemic lupus erythematosus. Low-dose prednisone was administered, and thejoint inflammation resolved.

Approximately three years before admission, the nephrotic syndrome developed.

A renal biopsy performed at the other hospital revealed evidence of class IV lupus ne-phritis, according to the World Health Organization (WHO) classification (class I to

class V). Prednisone (10 mg), azathioprine (25 mg), furosemide (20 mg), and enalapril(15 mg) were administered daily. The patient immigrated to the United States about

four months after the diagnosis and transferred her care to a nephrologist at this hos-pital. Laboratory-test results are shown in Tables 1 through 4; the same treatment reg-imen that she was already following was continued. Eighteen months before admission,

another renal biopsy, performed at this hospital, revealed class IV lupus nephritis, dif-fuse proliferative type. One year before admission, the blood pressure was 85/50 mm Hg

and the weight 50.3 kg. Laboratory-test results are shown in Tables 1 through 4. Thepatient declined the option of cyclophosphamide therapy because of a desire to pre-

serve fertility. Azathioprine was discontinued, and mycophenolate mofetil was addedto prednisone therapy.

Five months before admission, the patient reported that during the preceding month

she had had unprotected intercourse; she also said she had had lightheadedness. Theblood pressure was 92/48 mm Hg and the pulse more than the 80 beats per minute.

The mycophenolate mofetil was discontinued and enalapril was withheld temporarily.Testing for quantitative serum levels of the beta subunit of human chorionic gonado-

tropin was negative. Two months later, the patient still had not menstruated; repeatedtesting for quantitative serum levels of the beta subunit of human chorionic gonado-

tropin was positive at 162,000 U per liter.Two months before admission, the patient was seen in the high-risk obstetrical

pres en t at i on of cas e

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clinic for prenatal care, at 11 weeks 6 days of gesta-tion as determined by ultrasonographic measure-

ment. The vital signs and physical examinationwere normal. Laboratory-test results are shown in

Tables 1 through 4. Supplementary prenatal vita-

mins, folic acid, and calcium were begun, and treat-ment with prednisone was continued at 10 mg a day.

Six weeks before admission, the patients weightwas 53.5 kg. Two weeks later, the weight was

60.3 kg, and 3+ pedal edema was noted. One weeklater, the blood pressure was 132/74 mm Hg, the

pulse 88 beats per minute, and the weight 62.1 kg.There was mild pallor, no icterus, and no jugulo-venous distention. The results of an examination of

the heart and lungs were normal; the uterine fun-dus was compatible with a gestational age of five

months. There was 2+ pitting edema of the anklesand mild sacral edema. The results of laboratory

tests are shown in Table 2. The patient was advisedto wear antiembolic stockings and to restrict her in-take of fluids to 1500 ml per day.

At follow-up visits with the obstetrician and thenephrologist on the day of admission, the patient

had fatigue and weakness. An examination showed

3+ edema of the thighs. She was admitted to thehospital.

The patient had had an episode of herpes zosterinfection two and a half years earlier and a bacille

CalmetteGurin vaccination as a child. She had no

allergies. She lived with a relative in the Boston area.She did not smoke cigarettes or drink alcohol. There

was no family history of systemic lupus erythema-tosus or kidney disease.

On physical examination, the patients skin waspale. The temperature was normal, the blood pres-

sure 110/60 mm Hg, the pulse 96 beats per minute,and the weight 62.1 kg. An examination of the lungsrevealed no abnormalities, and a 2/6 systolic ejection

murmur was heard at the upper left sternal border.The abdomen was soft, nontender, and gravid, with

a fundal height consistent with the gestational ageof 20 weeks. There was 3+ edema extending to the

thighs. Results of laboratory tests are shown in Ta-bles 1 and 4.

The patient was placed on bed rest, and her vital

signs were monitored. Methylprednisolone (250 mgper day) was administered intravenously for three

days, followed by prednisone (60 mg per day). Fluids

Table 1. Hematologic Laboratory Data.

Variable Before Admission Hospital Day

33 mo 18 mo 1 yr 3 mo 2 mo 2 days 1 3 10 24 25

Hematocrit (%) 38.8 31.3 26.8 25.3 22.9 20.1 22.4 20.4 19.5 23.3 22.8

Hemoglobin (g/dl) 13.5 11.2 9.8 8.8 8.1 7.1 7.7 7.3 6.9 8.0 7.9

White-cell count(per mm

3

)13,800 4800 8,300 8,800 10,200 14,300 11,000 16,700 21,200 18,600 15,800

Platelet count (per mm

3

) 347,000 277,000 209,000 244,000 282,000 295,000 326,000 271,000 106,000 84,000

Antiphospholipid anti-bodies

Negative Negative

Lupus anticoagulant Negative Negative

Urinalysis

Occult blood Negative 2+ 3+ 2+ 3+

Albumin 2+ 3+ 3+ 3+ 3+

Red cells (per high-power field)

35 02 1020 2050 >100

White cells (perhigh-power field)

None 1020 50100 2050 >100

Bacteria (per high-power field)

Few Moderate Few Many

Hyaline casts (perlow-power field)

1020 35 >29

Granular casts 02 35

Waxy casts 35


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were restricted to 1500 ml per day. The option ofpregnancy termination was discussed and declined

by the patient. An ultrasonogram of the uterus ob-tained on the second hospital day revealed a normalfetus and normal volume of amniotic fluid. Treat-

ment with epoetin alfa was begun, 3000 IU threetimes per week. On the third hospital day, the blood

pressure ranged from 107/59 to 138/78 mm Hg. Onthe seventh hospital day, the weight was 64.1 kg andthe blood pressure 140/80 mm Hg. An ultrasono-

gram of the patients kidneys revealed no evidenceof renal-vein thrombosis.

On the eighth hospital day, the blood pressureranged from 120/60 to 150/70 mm Hg. Subcuta-

neous heparin, 5000 IU twice per day, was begun.

On the ninth day, the blood pressure was 140/80 to140/90 mm Hg, and the weight 65.0 kg. Treatment

with azathioprine was again added to the patientsregimen. The results of laboratory tests from the

10th hospital day are in Tables 1 through 4. Twounits of packed red cells were transfused.

On the 14th hospital day, the patients weightwas 67.3 kg; it remained stable thereafter. Ultra-sonography of the uterus again showed a normal

fetus and normal volume of the amniotic fluid.That day the blood pressure rose transiently to

170/98 mm Hg, and the patient was dizzy; 30 min-utes later the blood pressure was 140/80 and re-

mained stable. On the 24th day, the blood pressurehad risen to 174/100 mm Hg; the results of labora-tory tests are shown in Tables 1 and 4. Betametha-

sone, 12 mg intramuscularly, was given daily fortwo days.

On the 25th hospital day (24 weeks 2 days of ges-tation), a diagnostic procedure was performed.

Dr. Jeffrey L. Ecker:

Pregnancy in a patient such as thiswith renal disease should ideally begin with con-sideration of potential problems before conception

and an informed decision to pursue pregnancy. Thispatient did not have a preconception visit, but at

her first prenatal visit I explained that the risk of fe-tal growth restriction and preeclampsia in patientswith lupus nephritis may be as high as 30 percent

1

for each condition and that either complicationmight necessitate an early delivery. Outcomes might

be worse in women with antiphospholipid antibod-ies, such as lupus anticoagulant and anticardiolipin

antibodies; these titers were not elevated in this pa-

tient. The patients titers of anti-Ro (SS-A) were ele-vated (Table 3), and this antibody has been linked

to an increased risk of neonatal complications, in-cluding neonatal lupus and congenital heart block.

We monitored the patient for hypertensive com-plications of pregnancy or worsening nephritis and

scheduled her for frequent visits with her nephrol-ogist and with me. Fetal growth was followed withultrasonography. As she approached the 20th week

of pregnancy, marked edema and weight gain oc-curred, with evidence of worsening renal function,

which prompted us to admit the patient for fullerevaluation. Edema and proteinuria and rising blood

pressure were present at the time of admission;this triad is the hallmark of preeclampsia, but eachof these findings can also be associated with a flare

of lupus nephritis.At this point, the advice of a nephrology con-

sultant was needed.

Dr. Nancy Lee Harris

(Pathology): Dr. Williams was

di fferen t i al di ag n os i s

Table 2. Urine Chemical Values.

Variable Before AdmissionHospital

Day

38 mo 33 mo 18 mo 1 yr 4 mo 2 mo 6 wk 1 wk 10

Urine creatinine (mg/ml) 0.59 0.84 1.61 1.13 0.21 0.82 1.24

Urine protein (mg/liter) 1660 1590 2740 2530 2390 4340 18,200

Protein-to-creatinine ratio 1.70 2.24 11.38 14.68

Albumin (g/dl) 712.8

Albumin-to-creatinine ratio 8692.7

24-hr urine specimen

Protein (mg) 6700 2656 2465 8289

Creatinine (mg) 944 1302

Volume (ml) 1600 1550 1910


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not involved in the care of this patient and is not

aware of the diagnosis. We have invited him to dis-cuss the differential diagnosis of this patients renal

disease.

Dr. Winfred W. Williams, Jr.:

This 29-year-oldwoman had biopsy-proven lupus nephritis, WHO

class IV. At 20 weeks gestation, advancing renal in-sufficiency, rising blood pressure, and worsening

proteinuria developed. The findings on urinalysisof heavy proteinuria, a sediment containing manywhite cells, red cells (with dysmorphic forms), and

hyaline casts, are the first keys to narrowing thedifferential diagnosis. Despite the absence of cellu-

lar casts, these findings represent an active, ornephritic, urinary sediment indicative of glo-

merular injury (nephritis

)

. The issue is whether she

was having a flare of her lupus nephritis, preeclamp-sia, or both. These two possibilities require radical-

ly different management strategies and, therefore,must be sorted out as quickly and efficiently as pos-

sible. This is especially the case in a pregnancy inwhich renal failure and hypertension are progress-

ing rapidly.

preeclampsia

Preeclampsia typically is made manifest as new-onset hypertension and proteinuria after 20 weeks

gestation in a previously normotensive patient whodoes not have proteinuria. Eclampsia is the develop-

ment of grand mal seizures in a woman with pre-eclampsia or gestational hypertension. Preeclamp-sia is classified as either mild or severe. In mild

preeclampsia, the blood pressure is elevated to atleast 140 mm Hg (systolic) or at least 90 mm Hg

(diastolic) on at least two occasions and at leastfour to six hours apart. In severe preeclampsia, the

blood pressure rises to at least 160 mm Hg (systol-

ic), at least 110 mm Hg (diastolic), or both.

2

Severepreeclampsia heralds the development of multi-

organ-system involvement; patients who are affect-ed may have abdominal pain, dysfunction of thecentral nervous system (headache, encephalopathy,

blurred vision, or blindness), pulmonary edema, orhypoxia as another manifestation of capillary leak.

The serum creatinine level is often greater than1.2 mg per deciliter, which in most cases wouldrepresent a decrease of more than 50 percent in the

glomerular filtration rate and substantial acute re-nal failure. There is a severe variant of preeclamp-

sia consisting of the triad of hemolysis (micro-angiopathic hemolytic anemia associated with an

increased level of lactase dehydrogenase), abnor-

mal results on liver-function tests, and a low plate-let count, usually less than 100,000 per cubic mil-

limeter known as the HELLP syndrome. Thispatient, despite the development of severe throm-

bocytopenia and a rising level of lactase dehydro-genase, never had the full HELLP biochemical

profile.

lupus nephritis in pregnancy

Although there has been some controversy in theliterature regarding whether flares in lupus activity

actually occur during pregnancy,

3

the current con-sensus is that pregnancy may exacerbate lupus ac-

tivity. Flares occur in about 30 to 60 percent of pa-tients with lupus who are pregnant,

4,5

and flaresin renal-disease activity are more common among

those who had active renal disease at conception(39 percent) than in those in remission (5 percent).

4

Preeclampsia occurred in 15 percent of patients inone series.

4

* ELISA denotes enzyme-linked immunosorbent assay.

Table 3. Immunologic Laboratory Data.*

VariableNormalRange Before Admission

HospitalDay

33 mo 1 yr 5 mo 2 mo 10

Antinuclear-antibody titer Negative 1:640speckled

>1:5120speckled

1:640speckled

>1:5120speckled

1:2560speckled

Antidouble-stranded DNA antibody titer Negative 1:640 1:160 1:80 1:40

Anti-Ro (SS-A) antibody, as measured byELISA (OD units)

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In patients with lupus, a complete assessment

of disease activity should be made as early as possi-ble in pregnancy, or preferably before conception,

in order to obtain a baseline for comparison as preg-nancy progresses, as was done in this case. Theevaluation includes blood pressure, renal function,

and serologic measures associated with lupus, aswell as an assessment of a 24-hour urine collection

for protein and creatinine, and a simultaneous spoturine test from which the protein-to-creatinine ratio

can be calculated and then correlated with the 24-

hour protein excretion. Subsequently, the ratio ofprotein to creatinine can be monitored as an indi-

cation of protein excretion. Because of the markedincrease in the risk of a lupus flare in women with

active disease, it is imperative to attempt to achieveas complete a remission as possible before con-

ception.

a challenging differential diagnosis

How can we differentiate preeclampsia from a lupusflare in this case? Women with preeclampsia tend

to be young and pregnant for the first time with anew onset of hypertension, as was the case in this

patient, but the hypertension typically occurs laterin pregnancy, in the third trimester. Hypertensionassociated with lupus is often chronic, and patients

are often older than this one. Patients with lupusflares during pregnancy often have a history of

antecedent disease activity, as did this patient. Sero-

logic findings in lupus include evidence of comple-

ment activation, which this patient had, and elevat-ed serologic markers; this patient had increasing

titers of antinuclear antibodies, stable levels of antidouble-stranded DNA antibodies, and rising levelsof anti-Ro antibodies. Finally, the signs of active

disease in the urinary sediment suggest nephritis;in preeclampsia, the urinary sediment is typically

bland without indicators of disease activity.Marked dyslipidemia was documented on admis-

sion and throughout the patients course in the hos-

pital a manifestation of severe nephrotic syn-drome. The worsening, probably hemolytic, anemia

and the thrombocytopenia with a platelet count of84,000 per cubic millimeter can be seen both in ad-

vancing preeclampsia and in an active flare of sys-temic lupus erythematosus. Thus, this patient had

features of both lupus flare and preeclampsia.Because we do not yet have a sensitive and spe-

cific marker for either preeclampsia or lupus nephri-

tis, renal biopsy is helpful to distinguish a condi-tion that necessitates delivery from one that can be

managed medically. Renal biopsies performed be-fore gestation are not predictive of the renal out-

come in pregnancy.

6,7 Renal biopsy can be per-formed late in the second trimester and early intothe third trimester with no complications to mother

or fetus.

8

In one series of patients with lupus whohad undergone biopsy between 20 and 25 weeks

gestation, there were no serious complications and

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter,multiply by 88.4. To convert the values for cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides to millimoles perliter, multiply by 0.02586.

Table 4. Blood Chemical Values.*

Variable Before Admission Hospital Day

33 mo 18 mo 1 yr 2 mo 2 days 1 3 10 23 24

Urea nitrogen (mg/dl) 23 18 24 18 18 25 36 34 39 44

Creatinine (mg/dl) 0.8 0.8 0.8 0.7 1.5 1.4 1.8 1.8 2.3 2.0

Protein (g/dl)Total 7.0 4.7 4.1 3.7 3.7

Albumin 3.1 2.9 3.0 1.8 1.1 1.2 1.1 1.1

Globulin 2.6 2.6

Lactate dehydrogenase (U/liter) 154 399

Cholesterol (mg/dl) 283 339 325

High-density lipoprotein 45 60 51

Low-density lipoprotein 179

Triglycerides 295 562 490 845


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all patients ultimately had a definitive diagnosis:

the most common finding was lupus nephritis.

9

The presence in this patient of thrombocytopenia

was probably a factor in the decision not to performrenal biopsy.

I think the diagnosis in this case is a pregnancy-

induced flare of lupus nephritis, with superim-posed preeclampsia, with the nephrotic syndrome,

hemolytic anemia, and thrombocytopenia. I believethe procedure performed was the delivery of the

infant.

Dr. Ecker:

The cure for preeclampsia is simple and

well known delivery of the placenta. Cure for themother, however, comes with risks to the newborn,

which vary inversely with gestational age. The limitof viability is now from 22 to 24 weeks, but survi-

vors at these early gestational ages almost uniform-ly have clinically important complications. None-theless, early delivery may still be necessary to

protect maternal health.When this patient was admitted, she was offered

the option of pregnancy interruption at 20 to 22weeks or continuing her pregnancy, with the atten-dant risk of worsening renal function. She elected to

continue her pregnancy, in part because she recog-nized that her underlying disease and renal function

were such that she could not reliably expect a betteroutcome in a future pregnancy. Anticipating a pre-

term delivery, we treated the patient with betametha-

sone at 24 weeks gestation, to reduce the risk ofneonatal complications, such as the respiratory dis-

tress syndrome and intracranial hemorrhage.In patients in whom intercurrent medical disease

may complicate the diagnosis of preeclampsia, wefirst optimize management of other conditions

within the limits allowed by pregnancy. This pa-tient received azathioprine and corticosteroids butnot cyclophosphamide. We also seek to rule out oth-

er causes of any abnormal laboratory-test results, inthis case discontinuing subcutaneous heparin in

order to be sure that the decrease in platelets wasnot a result of heparin-induced thrombocytopenia.

Having done this, we were still faced with risingblood pressure and decreasing platelet counts andconcluded that there was an element of preeclamp-

sia, which we thought was accurately classified assevere. Delivery is indicated in cases of severe pre-

eclampsia with marked thrombocytopenia in order

to protect the mothers health and before she is too

sick to give birth safely, and because the in uteroenvironment of such patients is unlikely to promote

continued fetal health.This patient underwent cesarean delivery be-

cause the fetus was in the breech presentation.

Dr. Harris:

Dr. Steele, would you comment onyour thinking as the nephrologist caring for this

patient?

Dr. David J.R. Steele

(Nephrology): When she ini-

tially presented to our clinic, this patient had beenreceiving immunosuppressant therapy, althoughnot standard therapy, which would have included

cyclophosphamide. She had stable, normal renalfunction, proteinuria that was not progressive and

not in the nephrotic range, and no hypertension.She had persistently positive serologic findings and

low complement titers. We switched her treatmentfrom azathioprine to mycophenolate mofetil, and

she was counseled about the risks entailed by preg-nancy. The patient had been on this protocol forapproximately seven months when she alerted us

to a possible pregnancy; mycophenolate mofetilwas then discontinued.

As her pregnancy progressed, we believed thatthe development of nephrotic-range proteinuria andworsening renal function was due to a combina-

tion of preeclampsia and the recurrence of activelupus nephritis. We treated her with high-dose

prednisone and added azathioprine in the hope ofblunting the renal effects of lupus. We considered a

renal biopsy to delineate which components of her

renal disease were associated with lupus and whichwere associated with preeclampsia. However, in the

setting of severe anemia followed by thrombocyto-penia, we deemed that a biopsy would place her at

high risk and deferred it.

Pregnancy-induced flare of systemic lupus erythe-

matosus.Preeclampsia.

Pregnancy-induced flare of systemic lupus erythe-

matosus.Preeclampsia, with the nephrotic syndrome,

thrombocytopenia, and hemolytic anemia.

di s cus s i on of m an ag em en t

cli n i cal di ag n os i s

dr. w i n fred w . w i lli am s , jr. s ,di ag n os i s


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Dr. Aliyah Rahemtullah:

The diagnostic and therapeu-

tic procedure performed was delivery by cesareansection. The renal biopsy performed 18 months be-fore admission (Fig. 1) showed findings that were

diagnostic of glomerulonephritis related to system-ic lupus erythematosus. According to the revised

classification of the International Society of Ne-phrology and the Renal Pathology Society for lupus

nephritis, the findings on renal biopsy satisfy thecriteria for both membranous lupus nephritis (classV) and diffuse segmental proliferative and scleros-

ing (class IV-S [A/C]) disease.

10,11

After the delivery, the placenta weighed 95 g, less

than the third percentile. On microscopical exami-nation, the villi were hypermature with prominent

syncytial knots (Fig. 2A). The decidual arteriesshowed luminal narrowing with mural thickening,fibrinoid necrosis, and the accumulation of foamy

macrophages and neutrophils (Fig. 2B and 2C). In-creased numbers of immature intermediate tropho-

blast cells were distributed in a sheet-like fashionalong the maternal floor (Fig. 2D). These findings

a small placenta, decidual vasculopathy with orwithout acute atherosis, sheets of intermediate tro-phoblast cells, and hypermature villi as well as

acute and chronic infarcts and a small-diameter

pat h olog i cal di s cus s i on

Figure 1. Renal-Biopsy Specimen Obtained 18 Months before Admission.

Light-microscopical examination shows mesangial hypercellularity with increased mesangial matrix deposition and gen-eralized capillary-wall thickening (Panel A, hematoxylin and eosin). More than 50 percent of the glomeruli show segmen-

tal adhesions with scarring (Panel B, periodic acidSchiff stain) and glomerular-basement-membrane fragmentation

(arrow) and duplication in the regions of scarring. Very few glomeruli had evidence of active lesions of cellular crescent

formation (Panel B, inset, arrow, periodic acidSchiff stain). Direct immunofluorescence shows widespread granularstaining of the glomerular basement membrane and mesangium for IgG (Panel C). Similar staining was seen for C3, and

less-intense staining for the presence of IgM, IgA, and C1q. Electron microscopy shows widespread deposition of amor-

phous, electron-dense deposits in the glomerular basement membrane. In Panel D, the capillary space (asterisk) is rec-ognizable by the presence of red cells in the lumen, and the large deposits are mostly localized on the subepithelial

aspect of the glomerular basement membrane (arrows).

A B

C D

*


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umbilical cord, are seen in conditions associated

with chronic uteroplacental insufficiency, the best-recognized of which is preeclampsia. Similar find-

ings can be seen in pregnancies affected by system-ic lupus erythematosus and in other autoimmunediseases.

12-14

Because the placental findings in

pregnancies affected by preeclampsia and lupus aresimilar, it is difficult to distinguish between the two

on the basis of placental pathology alone. It is pos-sible to distinguish between an exacerbation of lu-

pus and preeclampsia by performing a renal biopsy;in preeclampsia, renal biopsy shows the classic find-ing of glomerular endotheliosis.

A cardinal pathological feature of preeclampsia

is that the spiral arteries of the mother do not under-go the normal spectrum of changes necessary for

adequate oxygen and nutrient delivery to the pla-centa and fetus.

15

A patient with lupus who is preg-nant, in whom there is a greater risk of the develop-

ment of preeclampsia, may exhibit similar findings.It has been suggested that pathogenic immune

complexes may be deposited in the placental anduterine blood-vessel walls, leading to placental is-

chemia.

16-18

To explain the systemic findings ofproteinuria, hypertension, and coagulation abnor-malities in the mother, it has been hypothesized

Figure 2. Pathological Findings of the Placenta (Hematoxylin and Eosin).

There are a greater number of syncytial knots (arrows, Panel A) than would be expected for the gestational age of 24

weeks, including detached knots in the maternal space without other components of villous structure findings that

are characteristic of villous hypermaturity. Normally, a term placenta contains one to two syncytial knots for every four tofive villi. Arteries of the decidualized endometrium (Panel B) show luminal narrowing with thickened walls composed of

residual smooth-muscle cells within the arterial media. Normally, vessels at this stage of pregnancy have an attenuated

or absent media and luminal distention. The findings observed here are characteristic of decidual vasculopathy and in-dicate that the vessels have not undergone normal changes that usually take place early in pregnancy to allow for ade-

quate blood flow to the fetoplacental unit. More severe changes consisting of decidual vasculopathy with fibrinoid

necrosis and accumulation of large, foamy lipid-filled macrophages and neutrophils within the vessel wall, a featureknown as acute atherosis, were also seen (Panel C). Increased numbers of immature intermediate trophoblast cells

along the maternal floor are also characteristic of an underperfused placenta (Panel D, arrows).

A B

C D


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that the ischemic placenta secretes one or more

soluble factors into the maternal bloodstream thatinduce generalized endothelial dysfunction and

the syndrome of preeclampsia. The soluble form ofthe vascular endothelial growth factor (VEGF) re-ceptor, sFlt-1, has been identified as one candidate

factor.

19,20

Dr. Harris:

We decided we needed an answer in

this case before this conference, so we asked thattesting for sFlt-1 be performed on stored serum

from this patient.

Dr. Ravi Thadhani

: Serum samples taken from thepatient at 20 and 22 weeks gestation were sent to

the laboratory of Dr. S. Ananth Karumanchi at BethIsrael Deaconess Medical Center in Boston to test

for both sFlt-1 and placental growth factor (PlGF),a VEGF family protein. sFlt-1 is an antiangiogenic

protein that acts by binding the pro-angiogenic fac-tors VEGF and PlGF, resulting in low levels of free

VEGF and PlGF. The combination of elevated sFlt-1and low levels of free PlGF in the serum appears tocharacterize preeclampsia.

Normal placental development requires the for-

mation of placental blood vessels that are wide and

distended and thus have low resistance to bloodflow; abnormal angiogenesis is now thought to

contribute to the development of preeclampsia. Inanimal models, sFlt-1 appears to be integral in thepathogenesis of preeclampsia.

19,20 In humans,

21

we have found that an elevation in serum levels ofsFlt-1 and a decrease in serum levels of PlGF were

present not only during clinical preeclampsia, butalso four to five weeks before there was any clinical

evidence of hypertension or proteinuria, suggestingthat they play a role in the human disease as well.

At 20 weeks gestation, the sFlt-1 level in this

patient was 3177 pg per milliliter, and at 22 weeks,it was 6466 pg per milliliter, consistent with clinical

preeclampsia. Levine et al. showed that levels in con-trol women without preeclampsia at similar stages

of gestation are, at most, 900 to 1000 pg per milli-liter (Fig. 3).

21

Levels of free PlGF were 432 pg per

milliliter at 20 weeks gestation and 399 pg per mil-liliter at 22 weeks gestation. PlGF levels in controlwomen without preeclampsia at that gestational

age are near 700 pg per milliliter, whereas in early

Figure 3. Mean (SD) sFlt-1 Levels in Pregnancy and Preeclampsia.

The mean sFlt-1 concentrations are shown, before and after the onset of clinical preeclampsia according to the gesta-tional age of the fetus. I

bars represent standard errors. The P values given are for the comparisons, after logarithmic

transformation, with specimens from controls obtained during the same gestational-age interval; the differences, after

logarithmic transformation, between the specimens obtained at 33 to 41 weeks from women who already had clinicalpreeclampsia and those obtained at 33 to 41 weeks from women in whom preeclampsia later developed were also sig-

nificant (P=0.004 for the comparison at 33 to 36 weeks and P= 0.02 for the comparison at 37 to 41 weeks). (Reprinted

from Levine et al.

21

)

Controls

Women with clinicalpreeclampsia Women who later

had preeclampsia

Women who hadpreeclampsia>5 wk later

sFIt-1(pg/ml)

5000

3000

4000

2000

1000

0812 1316 1720 2124 2528 2932 3336 3741

Gestational Age (wk)

No. of specimensControlsBefore preeclampsia>5 wk before preeclampsiaDuring preeclampsia

211926

70578

14

2123192

727571

966

444343

565656

202121

P=0.04

P=0.008

P

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preeclampsia, levels of free PlGF are at or near 100

pg per milliliter. However, this patient had im-paired renal function; PlGF is a small protein that is

filtered in the kidney, and as a result of impaired re-nal function, serum levels may have been artificial-ly elevated. Therefore, although the accuracy of

these markers in the prediction and diagnosis ofpreeclampsia is still being studied, her serum lev-

els of sFlt-1 and PlGF were consistent with pre-eclampsia, suggesting that preeclampsia was at

least one component of her underlying condition.

Dr. Robert B. Colvin

(Pathology): Are levels ofsFlt-1 elevated in patients with lupus?

Dr. Thadhani:

The levels of sFlt-1 and PlGF havenot been studied in lupus, but given that impaired

renal function predisposes patients to preeclamp-sia, it is possible that levels of these biomarkers are

altered in women with lupus-related kidney disease.

Dr. Harris:

Dr. Steele and Dr. Ecker, can you tell

us how the mother and child are doing?

Dr. Steele

: After the birth, the patients renal func-tion continued to deteriorate rapidly, and her creat-

inine level peaked at 4.3 mg per deciliter (1.54 mmolper liter). Her platelet count normalized in four

weeks, and the anemia improved. Her blood pres-sure normalized in six to eight weeks. The level ofproteinuria remained above 10 g per 24 hours be-

fore starting to fall slowly. She continued to receiveprednisone, 60 mg a day, and monthly pulsed in-

travenous administration of cyclophosphamide(with the dose adjusted for renal failure) was added

for six months. Her treatment was then switched

back to mycophenolate mofetil. The level of pro-

teinuria improved, and the level of serum creatinine

decreased to a low of 2.5 mg per deciliter but grad-ually increased again during a period of months. A

repeated renal biopsy was then performed a yearafter her delivery, and it showed changes consistentwith lupus nephritis, class VI (advanced sclerotic

lupus nephritis), with tubulointerstitial and glomer-ular scarring.

10,11

The patient is currently being

evaluated for renal transplantation from a livingdonor.

Dr. Ecker:

The baby boy had a birth weight of 600 gand was discharged from the hospital nearly 150days after delivery, weighing 2500 g. His prolonged

hospital course was complicated by retinopathy ofprematurity, chronic lung disease, infection, and in-

traventricular hemorrhage (grade 2 of 4), but sucha course is considered a good outcome for a fetus

born at 24 weeks 2 days gestation. He showed nosigns of neonatal lupus. He is now home with his

mother and by current reports is doing well.

Combined membranous (class V) and diffuse seg-

mental proliferative and sclerosing (class IV-S[A/C]) lupus nephritis.

Small, hypermature placenta with severe decid-

ual vasculopathy and acute atherosis, consistentwith preeclampsia.

Dr. Thadhani reports having received income from BeckmanCoulter and Abbott Diagnostics. He also reports that he is a coinven-tor on provisional patents filed by Massachusetts General Hospitalfor the use of cytokines in the diagnosis of gestational disorders that

have been licensed to diagnostic companies.

an at om i cal di ag n os i s

references

1.

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2.

Sibai B, Dekker G, Kupermin C. Pre-eclampsia. Lancet 2005;365:785-99.

3.

Lockshin MD. Pregnancy does not causesystemic lupus erythematosus to worsen.Arthritis Rheum 1989;32:665-70.

4.

Moroni G, Quaglini S, Banfi G, et al.Pregnancy in lupus nephritis. Am J KidneyDis 2002;40:713-20.

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Petri M, Howard D, Repke J. Frequencyof lupus flare in pregnancy: the Hopkins Lu-pus Pregnancy Center experience. ArthritisRheum 1991;34:1538-45.

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Hayslett JP, Lynn RI. Effect of pregnancyin patients with lupus nephropathy. KidneyInt 1980;18:207-20.

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Imbasciati E, Surian M, Bottino S, et al.Lupus nephropathy and pregnancy: a studyof 26 pregnancies in patients with systemic

lupus erythematosus and nephritis. Neph-ron 1984;36:46-51.

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Meola M, Barsotti G, Cupisti A, Buon-cristiani E, Giovannetti S. Free-hand ultra-sound-guided renal biopsy: report of 650consecutive cases. Nephron 1994;67:425-30.

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Chen HH, Lin HC, Yeh JC, Chen CP. Re-nal biopsy in pregnancies complicated byundetermined renal disease. Acta ObstetGynecol Scand 2001;80:888-93.

10.

Weening JJ, DAgati VD, Schwartz MM,et al. The classification of glomerulone-phritis in systemic lupus erythematosus re-

visited. J Am Soc Nephrol 2004;15:241-50.[Erratum, J Am Soc Nephrol 2004;15:835-6.]

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Weening JJ, DAgati VD, Schwartz MM,et al. The classification of glomerulonephri-tis in systemic lupus erythematosus revisit-ed. Kidney Int 2004;65:521-30. [Erratum,Kidney Int 2004;65:1132.]

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Labarrere CA, Catoggio LJ, Mullen EG,Althabe OH. Placental lesions in maternalautoimmune diseases. Am J Reprod Immu-nol Microbiol 1986;12:78-86.

13.

Magid MS, Kaplan C, Sammaritano LR,Peterson M, Druzin ML, Lockshin MD. Pla-cental pathology in systemic lupus erythe-matosus: a prospective study. Am J ObstetGynecol 1998;179:226-34.

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Ogishima D, Matsumoto T, Nakamura Y,Yoshida K, Kuwabara Y. Placental pathologyin systemic lupus erythematosus with anti-phospholipid antibodies. Pathol Int 2000;50:224-9.

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Moffett-King A. Natural killer cells andpregnancy. Nat Rev Immunol 2002;2:656-63. [Erratum, Nat Rev Immunol 2002;2:975.]

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Guzman L, Avalos E, Ortiz R, Gurrola R,Lopez E, Herrera R. Placental abnormalitiesin systemic lupus erythematosus: in situ de-


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position of antinuclear antibodies. J Rheu-matol 1987;14:924-9.

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Hanly JG, Gladman DD, Rose TH,Laskin CA, Urowitz MB. Lupus pregnancy:a prospective study of placental changes. Ar-thritis Rheum 1988;31:358-66.

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Labarrere C, Alonso J, Manni J, Domen-ichini E, Althabe O. Immunohistochemicalfindings in acute atherosis associated with

intrauterine growth retardation. Am J Re-prod Immunol Microbiol 1985;7:149-55.

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Maynard SE, Min JY, Merchan J, et al. Ex-cess placental soluble fms-like tyrosine ki-nase 1 (sFlt1) may contribute to endothelialdysfunction, hypertension, and proteinuriain preeclampsia. J Clin Invest 2003;111:649-58.

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Thadhani R, Mutter WP, Wolf M, et al.

First trimester placental growth factor andsoluble fms-like tyrosine kinase 1 and riskfor preeclampsia. J Clin Endocrinol Metab2004;89:770-5.

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Levine RJ, Maynard SE, Qian C, et al.Circulating angiogenic factors and the riskof preeclampsia. N Engl J Med 2004;350:672-83.

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