Case 38-2005 — A 29-Year-Old Pregnant Woman with the Nephrotic Syndrome and Hypertension
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《新英格兰医药杂志》
Presentation of Case
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 of both 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 the joint 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 nephritis, 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 hospital. Laboratory-test results are shown in Table 1, Table 2, Table 3, and Table 4; the same treatment regimen that she was already following was continued. Eighteen months before admission, another renal biopsy, performed at this hospital, revealed class IV lupus nephritis, diffuse 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 Table 1, Table 2, Table 3, and Table 4. The patient declined the option of cyclophosphamide therapy because of a desire to preserve fertility. Azathioprine was discontinued, and mycophenolate mofetil was added to prednisone therapy.
Table 1. Hematologic Laboratory Data.
Table 2. Urine Chemical Values.
Table 3. Immunologic Laboratory Data.
Table 4. Blood Chemical Values.
Five months before admission, the patient reported that during the preceding month she had had unprotected intercourse; she also said she had had lightheadedness. The blood 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 gonadotropin was negative. Two months later, the patient still had not menstruated; repeated testing for quantitative serum levels of the beta subunit of human chorionic gonadotropin was positive at 162,000 U per liter.
Two months before admission, the patient was seen in the high-risk obstetrical clinic for prenatal care, at 11 weeks 6 days of gestation as determined by ultrasonographic measurement. The vital signs and physical examination were normal. Laboratory-test results are shown in Table 1, Table 2, Table 3, and Table 4. Supplementary prenatal vitamins, folic acid, and calcium were begun, and treatment with prednisone was continued at 10 mg a day.
Six weeks before admission, the patient's weight was 53.5 kg. Two weeks later, the weight was 60.3 kg, and 3+ pedal edema was noted. One week later, 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 jugulovenous distention. The results of an examination of the heart and lungs were normal; the uterine fundus was compatible with a gestational age of five months. There was 2+ pitting edema of the ankles and mild sacral edema. The results of laboratory tests are shown in Table 2. The patient was advised to wear antiembolic stockings and to restrict her intake of fluids to 1500 ml per day.
At follow-up visits with the obstetrician and the nephrologist on the day of admission, the patient had fatigue and weakness. An examination showed 3+ edema of the thighs. She was admitted to the hospital.
The patient had had an episode of herpes zoster infection two and a half years earlier and a bacille Calmette–Guérin 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 erythematosus or kidney disease.
On physical examination, the patient's skin was pale. The temperature was normal, the blood pressure 110/60 mm Hg, the pulse 96 beats per minute, and the weight 62.1 kg. An examination of the lungs revealed 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 age of 20 weeks. There was 3+ edema extending to the thighs. Results of laboratory tests are shown in Table 1 and Table 4.
The patient was placed on bed rest, and her vital signs were monitored. Methylprednisolone (250 mg per day) was administered intravenously for three days, followed by prednisone (60 mg per day). Fluids were restricted to 1500 ml per day. The option of pregnancy termination was discussed and declined by the patient. An ultrasonogram of the uterus obtained on the second hospital day revealed a normal fetus and normal volume of amniotic fluid. Treatment with epoetin alfa was begun, 3000 IU three times per week. On the third hospital day, the blood pressure ranged from 107/59 to 138/78 mm Hg. On the seventh hospital day, the weight was 64.1 kg and the blood pressure 140/80 mm Hg. An ultrasonogram of the patient's kidneys revealed no evidence of renal-vein thrombosis.
On the eighth hospital day, the blood pressure ranged from 120/60 to 150/70 mm Hg. Subcutaneous heparin, 5000 IU twice per day, was begun. On the ninth day, the blood pressure was 140/80 to 140/90 mm Hg, and the weight 65.0 kg. Treatment with azathioprine was again added to the patient's regimen. The results of laboratory tests from the 10th hospital day are in Table 1, Table 2, Table 3, and Table 4. Two units of packed red cells were transfused.
On the 14th hospital day, the patient's weight was 67.3 kg; it remained stable thereafter. Ultrasonography 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 minutes later the blood pressure was 140/80 and remained stable. On the 24th day, the blood pressure had risen to 174/100 mm Hg; the results of laboratory tests are shown in Table 1 and Table 4. Betamethasone, 12 mg intramuscularly, was given daily for two days.
On the 25th hospital day (24 weeks 2 days of gestation), a diagnostic procedure was performed.
Differential Diagnosis
Dr. Jeffrey L. Ecker: Pregnancy in a patient such as this with renal disease should ideally begin with consideration of potential problems before conception and an informed decision to pursue pregnancy. This patient did not have a preconception visit, but at her first prenatal visit I explained that the risk of fetal growth restriction and preeclampsia in patients with lupus nephritis may be as high as 30 percent1 for each condition and that either complication might necessitate an early delivery. Outcomes might be worse in women with antiphospholipid antibodies, such as lupus anticoagulant and anticardiolipin antibodies; these titers were not elevated in this patient. The patient's titers of anti-Ro (SS-A) were elevated (Table 3), and this antibody has been linked to an increased risk of neonatal complications, including neonatal lupus and congenital heart block.
We monitored the patient for hypertensive complications of pregnancy or worsening nephritis and scheduled her for frequent visits with her nephrologist and with me. Fetal growth was followed with ultrasonography. As she approached the 20th week of pregnancy, marked edema and weight gain occurred, with evidence of worsening renal function, which prompted us to admit the patient for fuller evaluation. Edema and proteinuria and rising blood pressure were present at the time of admission; this triad is the hallmark of preeclampsia, but each of these findings can also be associated with a flare of lupus nephritis.
At this point, the advice of a nephrology consultant was needed.
Dr. Nancy Lee Harris (Pathology): Dr. Williams was not involved in the care of this patient and is not aware of the diagnosis. We have invited him to discuss the differential diagnosis of this patient's renal disease.
Dr. Winfred W. Williams, Jr.: This 29-year-old woman had biopsy-proven lupus nephritis, WHO class IV. At 20 weeks' gestation, advancing renal insufficiency, rising blood pressure, and worsening proteinuria developed. The findings on urinalysis of heavy proteinuria, a sediment containing many white cells, red cells (with dysmorphic forms), and hyaline casts, are the first keys to narrowing the differential diagnosis. Despite the absence of cellular casts, these findings represent an "active," or nephritic, urinary sediment — indicative of glomerular injury (nephritis). The issue is whether she was having a flare of her lupus nephritis, preeclampsia, or both. These two possibilities require radically different management strategies and, therefore, must be sorted out as quickly and efficiently as possible. This is especially the case in a pregnancy in which renal failure and hypertension are progressing rapidly.
Preeclampsia
Preeclampsia typically is made manifest as new-onset hypertension and proteinuria after 20 weeks' gestation in a previously normotensive patient who does not have proteinuria. Eclampsia is the development of grand mal seizures in a woman with preeclampsia or gestational hypertension. Preeclampsia is classified as either mild or severe. In mild preeclampsia, the blood pressure is elevated to at least 140 mm Hg (systolic) or at least 90 mm Hg (diastolic) on at least two occasions and at least four to six hours apart. In severe preeclampsia, the blood pressure rises to at least 160 mm Hg (systolic), at least 110 mm Hg (diastolic), or both.2 Severe preeclampsia heralds the development of multiorgan-system involvement; patients who are affected may have abdominal pain, dysfunction of the central nervous system (headache, encephalopathy, blurred vision, or blindness), pulmonary edema, or hypoxia as another manifestation of capillary leak. The serum creatinine level is often greater than 1.2 mg per deciliter, which in most cases would represent a decrease of more than 50 percent in the glomerular filtration rate and substantial acute renal failure. There is a severe variant of preeclampsia — consisting of the triad of hemolysis (microangiopathic hemolytic anemia associated with an increased level of lactase dehydrogenase), abnormal results on liver-function tests, and a low platelet count, usually less than 100,000 per cubic millimeter — known as the HELLP syndrome. This patient, despite the development of severe thrombocytopenia and a rising level of lactase dehydrogenase, never had the full HELLP biochemical profile.
Lupus Nephritis in Pregnancy
Although there has been some controversy in the literature regarding whether flares in lupus activity actually occur during pregnancy,3 the current consensus is that pregnancy may exacerbate lupus activity. Flares occur in about 30 to 60 percent of patients with lupus who are pregnant,4,5 and flares in 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 in one series.4
In patients with lupus, a complete assessment of disease activity should be made as early as possible in pregnancy, or preferably before conception, in order to obtain a baseline for comparison as pregnancy progresses, as was done in this case. The evaluation includes blood pressure, renal function, and serologic measures associated with lupus, as well as an assessment of a 24-hour urine collection for protein and creatinine, and a simultaneous spot urine test from which the protein-to-creatinine ratio can be calculated and then correlated with the 24-hour protein excretion. Subsequently, the ratio of protein to creatinine can be monitored as an indication of protein excretion. Because of the marked increase in the risk of a lupus flare in women with active disease, it is imperative to attempt to achieve as complete a remission as possible before conception.
A Challenging Differential Diagnosis
How can we differentiate preeclampsia from a lupus flare in this case? Women with preeclampsia tend to be young and pregnant for the first time with a new onset of hypertension, as was the case in this patient, but the hypertension typically occurs later in pregnancy, in the third trimester. Hypertension associated with lupus is often chronic, and patients are often older than this one. Patients with lupus flares during pregnancy often have a history of antecedent disease activity, as did this patient. Serologic findings in lupus include evidence of complement activation, which this patient had, and elevated serologic markers; this patient had increasing titers of antinuclear antibodies, stable levels of anti–double-stranded DNA antibodies, and rising levels of 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 admission and throughout the patient's course in the hospital — a manifestation of severe nephrotic syndrome. The worsening, probably hemolytic, anemia and the thrombocytopenia with a platelet count of 84,000 per cubic millimeter can be seen both in advancing preeclampsia and in an active flare of systemic lupus erythematosus. Thus, this patient had features of both lupus flare and preeclampsia.
Because we do not yet have a sensitive and specific marker for either preeclampsia or lupus nephritis, renal biopsy is helpful to distinguish a condition that necessitates delivery from one that can be managed medically. Renal biopsies performed before gestation are not predictive of the renal outcome in pregnancy.6,7 Renal biopsy can be performed late in the second trimester and early into the third trimester with no complications to mother or fetus.8 In one series of patients with lupus who had undergone biopsy between 20 and 25 weeks' gestation, there were no serious complications and 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 perform renal biopsy.
I think the diagnosis in this case is a pregnancy-induced flare of lupus nephritis, with superimposed preeclampsia, with the nephrotic syndrome, hemolytic anemia, and thrombocytopenia. I believe the procedure performed was the delivery of the infant.
Discussion of Management
Dr. Ecker: The cure for preeclampsia is simple and well known — delivery of the placenta. Cure for the mother, however, comes with risks to the newborn, which vary inversely with gestational age. The limit of viability is now from 22 to 24 weeks, but survivors at these early gestational ages almost uniformly have clinically important complications. Nonetheless, 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 22 weeks or continuing her pregnancy, with the attendant risk of worsening renal function. She elected to continue her pregnancy, in part because she recognized that her underlying disease and renal function were such that she could not reliably expect a better outcome in a future pregnancy. Anticipating a preterm delivery, we treated the patient with betamethasone at 24 weeks' gestation, to reduce the risk of neonatal complications, such as the respiratory distress syndrome and intracranial hemorrhage.
In patients in whom intercurrent medical disease may complicate the diagnosis of preeclampsia, we first optimize management of other conditions within the limits allowed by pregnancy. This patient received azathioprine and corticosteroids but not cyclophosphamide. We also seek to rule out other causes of any abnormal laboratory-test results, in this case discontinuing subcutaneous heparin in order to be sure that the decrease in platelets was not a result of heparin-induced thrombocytopenia. Having done this, we were still faced with rising blood pressure and decreasing platelet counts and concluded that there was an element of preeclampsia, which we thought was accurately classified as severe. Delivery is indicated in cases of severe preeclampsia with marked thrombocytopenia in order to protect the mother's health and before she is too sick to give birth safely, and because the in utero environment of such patients is unlikely to promote continued fetal health.
This patient underwent cesarean delivery because the fetus was in the breech presentation.
Dr. Harris: Dr. Steele, would you comment on your thinking as the nephrologist caring for this patient?
Dr. David J.R. Steele (Nephrology): When she initially presented to our clinic, this patient had been receiving immunosuppressant therapy, although not standard therapy, which would have included cyclophosphamide. She had stable, normal renal function, 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 treatment from azathioprine to mycophenolate mofetil, and she was counseled about the risks entailed by pregnancy. The patient had been on this protocol for approximately seven months when she alerted us to a possible pregnancy; mycophenolate mofetil was then discontinued.
As her pregnancy progressed, we believed that the development of nephrotic-range proteinuria and worsening renal function was due to a combination of preeclampsia and the recurrence of active lupus nephritis. We treated her with high-dose prednisone and added azathioprine in the hope of blunting the renal effects of lupus. We considered a renal biopsy to delineate which components of her renal disease were associated with lupus and which were associated with preeclampsia. However, in the setting of severe anemia followed by thrombocytopenia, we deemed that a biopsy would place her at high risk and deferred it.
Clinical Diagnosis
Pregnancy-induced flare of systemic lupus erythematosus.
Preeclampsia.
Dr. Winfred W. Williams, Jr.'s, Diagnosis
Pregnancy-induced flare of systemic lupus erythematosus.
Preeclampsia, with the nephrotic syndrome, thrombocytopenia, and hemolytic anemia.
Pathological Discussion
Dr. Aliyah Rahemtullah: The diagnostic and therapeutic procedure performed was delivery by cesarean section. The renal biopsy performed 18 months before admission (Figure 1) showed findings that were diagnostic of glomerulonephritis related to systemic lupus erythematosus. According to the revised classification of the International Society of Nephrology and the Renal Pathology Society for lupus nephritis, the findings on renal biopsy satisfy the criteria for both membranous lupus nephritis (class V) and diffuse segmental proliferative and sclerosing (class IV-S ) disease.10,11
Figure 1. Renal-Biopsy Specimen Obtained 18 Months before Admission.
Light-microscopical examination shows mesangial hypercellularity with increased mesangial matrix deposition and generalized capillary-wall thickening (Panel A, hematoxylin and eosin). More than 50 percent of the glomeruli show segmental adhesions with scarring (Panel B, periodic acid–Schiff 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 acid–Schiff stain). Direct immunofluorescence shows widespread granular staining 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 amorphous, electron-dense deposits in the glomerular basement membrane. In Panel D, the capillary space (asterisk) is recognizable 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).
After the delivery, the placenta weighed 95 g, less than the third percentile. On microscopical examination, the villi were hypermature with prominent syncytial knots (Figure 2A). The decidual arteries showed luminal narrowing with mural thickening, fibrinoid necrosis, and the accumulation of foamy macrophages and neutrophils (Figure 2B and Figure 2C). Increased numbers of immature intermediate trophoblast cells were distributed in a sheet-like fashion along the maternal floor (Figure 2D). These findings — a small placenta, decidual vasculopathy with or without acute atherosis, sheets of intermediate trophoblast cells, and hypermature villi — as well as acute and chronic infarcts and a small-diameter umbilical cord, are seen in conditions associated with chronic uteroplacental insufficiency, the best-recognized of which is preeclampsia. Similar findings can be seen in pregnancies affected by systemic lupus erythematosus and in other autoimmune diseases.12,13,14 Because the placental findings in pregnancies affected by preeclampsia and lupus are similar, it is difficult to distinguish between the two on the basis of placental pathology alone. It is possible to distinguish between an exacerbation of lupus and preeclampsia by performing a renal biopsy; in preeclampsia, renal biopsy shows the classic finding of glomerular endotheliosis.
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 to five 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 indicate that the vessels have not undergone normal changes that usually take place early in pregnancy to allow for adequate 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 feature known 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 cardinal pathological feature of preeclampsia is that the spiral arteries of the mother do not undergo the normal spectrum of changes necessary for adequate oxygen and nutrient delivery to the placenta and fetus.15 A patient with lupus who is pregnant, in whom there is a greater risk of the development of preeclampsia, may exhibit similar findings. It has been suggested that pathogenic immune complexes may be deposited in the placental and uterine blood-vessel walls, leading to placental ischemia.16,17,18 To explain the systemic findings of proteinuria, hypertension, and coagulation abnormalities in the mother, it has been hypothesized that the ischemic placenta secretes one or more soluble factors into the maternal bloodstream that induce generalized endothelial dysfunction and the syndrome of preeclampsia. The soluble form of the vascular endothelial growth factor (VEGF) receptor, 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 that testing for sFlt-1 be performed on stored serum from this patient.
Dr. Ravi Thadhani: Serum samples taken from the patient at 20 and 22 weeks' gestation were sent to the laboratory of Dr. S. Ananth Karumanchi at Beth Israel 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 factors VEGF and PlGF, resulting in low levels of free VEGF and PlGF. The combination of elevated sFlt-1 and low levels of free PlGF in the serum appears to characterize preeclampsia.
Normal placental development requires the formation of placental blood vessels that are wide and distended and thus have low resistance to blood flow; abnormal angiogenesis is now thought to contribute to the development of preeclampsia. In animal models, sFlt-1 appears to be integral in the pathogenesis of preeclampsia.19,20 In humans,21 we have found that an elevation in serum levels of sFlt-1 and a decrease in serum levels of PlGF were present not only during clinical preeclampsia, but also four to five weeks before there was any clinical evidence of hypertension or proteinuria, suggesting that 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 control women without preeclampsia at similar stages of gestation are, at most, 900 to 1000 pg per milliliter (Figure 3).21 Levels of free PlGF were 432 pg per milliliter at 20 weeks' gestation and 399 pg per milliliter at 22 weeks' gestation. PlGF levels in control women without preeclampsia at that gestational age are near 700 pg per milliliter, whereas in early preeclampsia, levels of free PlGF are at or near 100 pg per milliliter. However, this patient had impaired renal function; PlGF is a small protein that is filtered in the kidney, and as a result of impaired renal function, serum levels may have been artificially elevated. Therefore, although the accuracy of these markers in the prediction and diagnosis of preeclampsia is still being studied, her serum levels of sFlt-1 and PlGF were consistent with preeclampsia, suggesting that preeclampsia was at least one component of her underlying condition.
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 gestational 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 clinical preeclampsia and those obtained at 33 to 41 weeks from women in whom preeclampsia later developed were also significant (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)
Dr. Robert B. Colvin (Pathology): Are levels of sFlt-1 elevated in patients with lupus?
Dr. Thadhani: The levels of sFlt-1 and PlGF have not been studied in lupus, but given that impaired renal function predisposes patients to preeclampsia, 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 patient's renal function continued to deteriorate rapidly, and her creatinine level peaked at 4.3 mg per deciliter (1.54 mmol per liter). Her platelet count normalized in four weeks, and the anemia improved. Her blood pressure normalized in six to eight weeks. The level of proteinuria remained above 10 g per 24 hours before starting to fall slowly. She continued to receive prednisone, 60 mg a day, and monthly pulsed intravenous 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 proteinuria improved, and the level of serum creatinine decreased to a low of 2.5 mg per deciliter but gradually increased again during a period of months. A repeated renal biopsy was then performed a year after her delivery, and it showed changes consistent with lupus nephritis, class VI (advanced sclerotic lupus nephritis), with tubulointerstitial and glomerular scarring.10,11 The patient is currently being evaluated for renal transplantation from a living donor.
Dr. Ecker: The baby boy had a birth weight of 600 g and was discharged from the hospital nearly 150 days after delivery, weighing 2500 g. His prolonged hospital course was complicated by retinopathy of prematurity, chronic lung disease, infection, and intraventricular hemorrhage (grade 2 of 4), but such a course is considered a good outcome for a fetus born at 24 weeks 2 days' gestation. He showed no signs of neonatal lupus. He is now home with his mother and by current reports is doing well.
Anatomical Diagnosis
Combined membranous (class V) and diffuse segmental proliferative and sclerosing (class IV-S ) lupus nephritis.
Small, hypermature placenta with severe decidual vasculopathy and acute atherosis, consistent with preeclampsia.
Dr. Thadhani reports having received income from Beckman Coulter and Abbott Diagnostics. He also reports that he is a coinventor on provisional patents filed by Massachusetts General Hospital for the use of cytokines in the diagnosis of gestational disorders that have been licensed to diagnostic companies.
Source Information
From the Division of Nephrology, Department of Medicine (W.W.W., R.I.T.), and the Departments of Transplant Surgery (W.W.W.), Obstetrics, Gynecology, and Reproductive Biology (J.L.E.), and Pathology (A.R.), Massachusetts General Hospital; and the Division of Nephrology, Department of Medicine (W.W.W., R.I.T.), and the Departments of Obstetrics, Gynecology, and Reproductive Biology (J.L.E.), and Pathology (A.R.), Harvard Medical School.
References
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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 of both 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 the joint 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 nephritis, 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 hospital. Laboratory-test results are shown in Table 1, Table 2, Table 3, and Table 4; the same treatment regimen that she was already following was continued. Eighteen months before admission, another renal biopsy, performed at this hospital, revealed class IV lupus nephritis, diffuse 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 Table 1, Table 2, Table 3, and Table 4. The patient declined the option of cyclophosphamide therapy because of a desire to preserve fertility. Azathioprine was discontinued, and mycophenolate mofetil was added to prednisone therapy.
Table 1. Hematologic Laboratory Data.
Table 2. Urine Chemical Values.
Table 3. Immunologic Laboratory Data.
Table 4. Blood Chemical Values.
Five months before admission, the patient reported that during the preceding month she had had unprotected intercourse; she also said she had had lightheadedness. The blood 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 gonadotropin was negative. Two months later, the patient still had not menstruated; repeated testing for quantitative serum levels of the beta subunit of human chorionic gonadotropin was positive at 162,000 U per liter.
Two months before admission, the patient was seen in the high-risk obstetrical clinic for prenatal care, at 11 weeks 6 days of gestation as determined by ultrasonographic measurement. The vital signs and physical examination were normal. Laboratory-test results are shown in Table 1, Table 2, Table 3, and Table 4. Supplementary prenatal vitamins, folic acid, and calcium were begun, and treatment with prednisone was continued at 10 mg a day.
Six weeks before admission, the patient's weight was 53.5 kg. Two weeks later, the weight was 60.3 kg, and 3+ pedal edema was noted. One week later, 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 jugulovenous distention. The results of an examination of the heart and lungs were normal; the uterine fundus was compatible with a gestational age of five months. There was 2+ pitting edema of the ankles and mild sacral edema. The results of laboratory tests are shown in Table 2. The patient was advised to wear antiembolic stockings and to restrict her intake of fluids to 1500 ml per day.
At follow-up visits with the obstetrician and the nephrologist on the day of admission, the patient had fatigue and weakness. An examination showed 3+ edema of the thighs. She was admitted to the hospital.
The patient had had an episode of herpes zoster infection two and a half years earlier and a bacille Calmette–Guérin 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 erythematosus or kidney disease.
On physical examination, the patient's skin was pale. The temperature was normal, the blood pressure 110/60 mm Hg, the pulse 96 beats per minute, and the weight 62.1 kg. An examination of the lungs revealed 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 age of 20 weeks. There was 3+ edema extending to the thighs. Results of laboratory tests are shown in Table 1 and Table 4.
The patient was placed on bed rest, and her vital signs were monitored. Methylprednisolone (250 mg per day) was administered intravenously for three days, followed by prednisone (60 mg per day). Fluids were restricted to 1500 ml per day. The option of pregnancy termination was discussed and declined by the patient. An ultrasonogram of the uterus obtained on the second hospital day revealed a normal fetus and normal volume of amniotic fluid. Treatment with epoetin alfa was begun, 3000 IU three times per week. On the third hospital day, the blood pressure ranged from 107/59 to 138/78 mm Hg. On the seventh hospital day, the weight was 64.1 kg and the blood pressure 140/80 mm Hg. An ultrasonogram of the patient's kidneys revealed no evidence of renal-vein thrombosis.
On the eighth hospital day, the blood pressure ranged from 120/60 to 150/70 mm Hg. Subcutaneous heparin, 5000 IU twice per day, was begun. On the ninth day, the blood pressure was 140/80 to 140/90 mm Hg, and the weight 65.0 kg. Treatment with azathioprine was again added to the patient's regimen. The results of laboratory tests from the 10th hospital day are in Table 1, Table 2, Table 3, and Table 4. Two units of packed red cells were transfused.
On the 14th hospital day, the patient's weight was 67.3 kg; it remained stable thereafter. Ultrasonography 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 minutes later the blood pressure was 140/80 and remained stable. On the 24th day, the blood pressure had risen to 174/100 mm Hg; the results of laboratory tests are shown in Table 1 and Table 4. Betamethasone, 12 mg intramuscularly, was given daily for two days.
On the 25th hospital day (24 weeks 2 days of gestation), a diagnostic procedure was performed.
Differential Diagnosis
Dr. Jeffrey L. Ecker: Pregnancy in a patient such as this with renal disease should ideally begin with consideration of potential problems before conception and an informed decision to pursue pregnancy. This patient did not have a preconception visit, but at her first prenatal visit I explained that the risk of fetal growth restriction and preeclampsia in patients with lupus nephritis may be as high as 30 percent1 for each condition and that either complication might necessitate an early delivery. Outcomes might be worse in women with antiphospholipid antibodies, such as lupus anticoagulant and anticardiolipin antibodies; these titers were not elevated in this patient. The patient's titers of anti-Ro (SS-A) were elevated (Table 3), and this antibody has been linked to an increased risk of neonatal complications, including neonatal lupus and congenital heart block.
We monitored the patient for hypertensive complications of pregnancy or worsening nephritis and scheduled her for frequent visits with her nephrologist and with me. Fetal growth was followed with ultrasonography. As she approached the 20th week of pregnancy, marked edema and weight gain occurred, with evidence of worsening renal function, which prompted us to admit the patient for fuller evaluation. Edema and proteinuria and rising blood pressure were present at the time of admission; this triad is the hallmark of preeclampsia, but each of these findings can also be associated with a flare of lupus nephritis.
At this point, the advice of a nephrology consultant was needed.
Dr. Nancy Lee Harris (Pathology): Dr. Williams was not involved in the care of this patient and is not aware of the diagnosis. We have invited him to discuss the differential diagnosis of this patient's renal disease.
Dr. Winfred W. Williams, Jr.: This 29-year-old woman had biopsy-proven lupus nephritis, WHO class IV. At 20 weeks' gestation, advancing renal insufficiency, rising blood pressure, and worsening proteinuria developed. The findings on urinalysis of heavy proteinuria, a sediment containing many white cells, red cells (with dysmorphic forms), and hyaline casts, are the first keys to narrowing the differential diagnosis. Despite the absence of cellular casts, these findings represent an "active," or nephritic, urinary sediment — indicative of glomerular injury (nephritis). The issue is whether she was having a flare of her lupus nephritis, preeclampsia, or both. These two possibilities require radically different management strategies and, therefore, must be sorted out as quickly and efficiently as possible. This is especially the case in a pregnancy in which renal failure and hypertension are progressing rapidly.
Preeclampsia
Preeclampsia typically is made manifest as new-onset hypertension and proteinuria after 20 weeks' gestation in a previously normotensive patient who does not have proteinuria. Eclampsia is the development of grand mal seizures in a woman with preeclampsia or gestational hypertension. Preeclampsia is classified as either mild or severe. In mild preeclampsia, the blood pressure is elevated to at least 140 mm Hg (systolic) or at least 90 mm Hg (diastolic) on at least two occasions and at least four to six hours apart. In severe preeclampsia, the blood pressure rises to at least 160 mm Hg (systolic), at least 110 mm Hg (diastolic), or both.2 Severe preeclampsia heralds the development of multiorgan-system involvement; patients who are affected may have abdominal pain, dysfunction of the central nervous system (headache, encephalopathy, blurred vision, or blindness), pulmonary edema, or hypoxia as another manifestation of capillary leak. The serum creatinine level is often greater than 1.2 mg per deciliter, which in most cases would represent a decrease of more than 50 percent in the glomerular filtration rate and substantial acute renal failure. There is a severe variant of preeclampsia — consisting of the triad of hemolysis (microangiopathic hemolytic anemia associated with an increased level of lactase dehydrogenase), abnormal results on liver-function tests, and a low platelet count, usually less than 100,000 per cubic millimeter — known as the HELLP syndrome. This patient, despite the development of severe thrombocytopenia and a rising level of lactase dehydrogenase, never had the full HELLP biochemical profile.
Lupus Nephritis in Pregnancy
Although there has been some controversy in the literature regarding whether flares in lupus activity actually occur during pregnancy,3 the current consensus is that pregnancy may exacerbate lupus activity. Flares occur in about 30 to 60 percent of patients with lupus who are pregnant,4,5 and flares in 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 in one series.4
In patients with lupus, a complete assessment of disease activity should be made as early as possible in pregnancy, or preferably before conception, in order to obtain a baseline for comparison as pregnancy progresses, as was done in this case. The evaluation includes blood pressure, renal function, and serologic measures associated with lupus, as well as an assessment of a 24-hour urine collection for protein and creatinine, and a simultaneous spot urine test from which the protein-to-creatinine ratio can be calculated and then correlated with the 24-hour protein excretion. Subsequently, the ratio of protein to creatinine can be monitored as an indication of protein excretion. Because of the marked increase in the risk of a lupus flare in women with active disease, it is imperative to attempt to achieve as complete a remission as possible before conception.
A Challenging Differential Diagnosis
How can we differentiate preeclampsia from a lupus flare in this case? Women with preeclampsia tend to be young and pregnant for the first time with a new onset of hypertension, as was the case in this patient, but the hypertension typically occurs later in pregnancy, in the third trimester. Hypertension associated with lupus is often chronic, and patients are often older than this one. Patients with lupus flares during pregnancy often have a history of antecedent disease activity, as did this patient. Serologic findings in lupus include evidence of complement activation, which this patient had, and elevated serologic markers; this patient had increasing titers of antinuclear antibodies, stable levels of anti–double-stranded DNA antibodies, and rising levels of 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 admission and throughout the patient's course in the hospital — a manifestation of severe nephrotic syndrome. The worsening, probably hemolytic, anemia and the thrombocytopenia with a platelet count of 84,000 per cubic millimeter can be seen both in advancing preeclampsia and in an active flare of systemic lupus erythematosus. Thus, this patient had features of both lupus flare and preeclampsia.
Because we do not yet have a sensitive and specific marker for either preeclampsia or lupus nephritis, renal biopsy is helpful to distinguish a condition that necessitates delivery from one that can be managed medically. Renal biopsies performed before gestation are not predictive of the renal outcome in pregnancy.6,7 Renal biopsy can be performed late in the second trimester and early into the third trimester with no complications to mother or fetus.8 In one series of patients with lupus who had undergone biopsy between 20 and 25 weeks' gestation, there were no serious complications and 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 perform renal biopsy.
I think the diagnosis in this case is a pregnancy-induced flare of lupus nephritis, with superimposed preeclampsia, with the nephrotic syndrome, hemolytic anemia, and thrombocytopenia. I believe the procedure performed was the delivery of the infant.
Discussion of Management
Dr. Ecker: The cure for preeclampsia is simple and well known — delivery of the placenta. Cure for the mother, however, comes with risks to the newborn, which vary inversely with gestational age. The limit of viability is now from 22 to 24 weeks, but survivors at these early gestational ages almost uniformly have clinically important complications. Nonetheless, 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 22 weeks or continuing her pregnancy, with the attendant risk of worsening renal function. She elected to continue her pregnancy, in part because she recognized that her underlying disease and renal function were such that she could not reliably expect a better outcome in a future pregnancy. Anticipating a preterm delivery, we treated the patient with betamethasone at 24 weeks' gestation, to reduce the risk of neonatal complications, such as the respiratory distress syndrome and intracranial hemorrhage.
In patients in whom intercurrent medical disease may complicate the diagnosis of preeclampsia, we first optimize management of other conditions within the limits allowed by pregnancy. This patient received azathioprine and corticosteroids but not cyclophosphamide. We also seek to rule out other causes of any abnormal laboratory-test results, in this case discontinuing subcutaneous heparin in order to be sure that the decrease in platelets was not a result of heparin-induced thrombocytopenia. Having done this, we were still faced with rising blood pressure and decreasing platelet counts and concluded that there was an element of preeclampsia, which we thought was accurately classified as severe. Delivery is indicated in cases of severe preeclampsia with marked thrombocytopenia in order to protect the mother's health and before she is too sick to give birth safely, and because the in utero environment of such patients is unlikely to promote continued fetal health.
This patient underwent cesarean delivery because the fetus was in the breech presentation.
Dr. Harris: Dr. Steele, would you comment on your thinking as the nephrologist caring for this patient?
Dr. David J.R. Steele (Nephrology): When she initially presented to our clinic, this patient had been receiving immunosuppressant therapy, although not standard therapy, which would have included cyclophosphamide. She had stable, normal renal function, 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 treatment from azathioprine to mycophenolate mofetil, and she was counseled about the risks entailed by pregnancy. The patient had been on this protocol for approximately seven months when she alerted us to a possible pregnancy; mycophenolate mofetil was then discontinued.
As her pregnancy progressed, we believed that the development of nephrotic-range proteinuria and worsening renal function was due to a combination of preeclampsia and the recurrence of active lupus nephritis. We treated her with high-dose prednisone and added azathioprine in the hope of blunting the renal effects of lupus. We considered a renal biopsy to delineate which components of her renal disease were associated with lupus and which were associated with preeclampsia. However, in the setting of severe anemia followed by thrombocytopenia, we deemed that a biopsy would place her at high risk and deferred it.
Clinical Diagnosis
Pregnancy-induced flare of systemic lupus erythematosus.
Preeclampsia.
Dr. Winfred W. Williams, Jr.'s, Diagnosis
Pregnancy-induced flare of systemic lupus erythematosus.
Preeclampsia, with the nephrotic syndrome, thrombocytopenia, and hemolytic anemia.
Pathological Discussion
Dr. Aliyah Rahemtullah: The diagnostic and therapeutic procedure performed was delivery by cesarean section. The renal biopsy performed 18 months before admission (Figure 1) showed findings that were diagnostic of glomerulonephritis related to systemic lupus erythematosus. According to the revised classification of the International Society of Nephrology and the Renal Pathology Society for lupus nephritis, the findings on renal biopsy satisfy the criteria for both membranous lupus nephritis (class V) and diffuse segmental proliferative and sclerosing (class IV-S ) disease.10,11
Figure 1. Renal-Biopsy Specimen Obtained 18 Months before Admission.
Light-microscopical examination shows mesangial hypercellularity with increased mesangial matrix deposition and generalized capillary-wall thickening (Panel A, hematoxylin and eosin). More than 50 percent of the glomeruli show segmental adhesions with scarring (Panel B, periodic acid–Schiff 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 acid–Schiff stain). Direct immunofluorescence shows widespread granular staining 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 amorphous, electron-dense deposits in the glomerular basement membrane. In Panel D, the capillary space (asterisk) is recognizable 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).
After the delivery, the placenta weighed 95 g, less than the third percentile. On microscopical examination, the villi were hypermature with prominent syncytial knots (Figure 2A). The decidual arteries showed luminal narrowing with mural thickening, fibrinoid necrosis, and the accumulation of foamy macrophages and neutrophils (Figure 2B and Figure 2C). Increased numbers of immature intermediate trophoblast cells were distributed in a sheet-like fashion along the maternal floor (Figure 2D). These findings — a small placenta, decidual vasculopathy with or without acute atherosis, sheets of intermediate trophoblast cells, and hypermature villi — as well as acute and chronic infarcts and a small-diameter umbilical cord, are seen in conditions associated with chronic uteroplacental insufficiency, the best-recognized of which is preeclampsia. Similar findings can be seen in pregnancies affected by systemic lupus erythematosus and in other autoimmune diseases.12,13,14 Because the placental findings in pregnancies affected by preeclampsia and lupus are similar, it is difficult to distinguish between the two on the basis of placental pathology alone. It is possible to distinguish between an exacerbation of lupus and preeclampsia by performing a renal biopsy; in preeclampsia, renal biopsy shows the classic finding of glomerular endotheliosis.
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 to five 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 indicate that the vessels have not undergone normal changes that usually take place early in pregnancy to allow for adequate 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 feature known 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 cardinal pathological feature of preeclampsia is that the spiral arteries of the mother do not undergo the normal spectrum of changes necessary for adequate oxygen and nutrient delivery to the placenta and fetus.15 A patient with lupus who is pregnant, in whom there is a greater risk of the development of preeclampsia, may exhibit similar findings. It has been suggested that pathogenic immune complexes may be deposited in the placental and uterine blood-vessel walls, leading to placental ischemia.16,17,18 To explain the systemic findings of proteinuria, hypertension, and coagulation abnormalities in the mother, it has been hypothesized that the ischemic placenta secretes one or more soluble factors into the maternal bloodstream that induce generalized endothelial dysfunction and the syndrome of preeclampsia. The soluble form of the vascular endothelial growth factor (VEGF) receptor, 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 that testing for sFlt-1 be performed on stored serum from this patient.
Dr. Ravi Thadhani: Serum samples taken from the patient at 20 and 22 weeks' gestation were sent to the laboratory of Dr. S. Ananth Karumanchi at Beth Israel 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 factors VEGF and PlGF, resulting in low levels of free VEGF and PlGF. The combination of elevated sFlt-1 and low levels of free PlGF in the serum appears to characterize preeclampsia.
Normal placental development requires the formation of placental blood vessels that are wide and distended and thus have low resistance to blood flow; abnormal angiogenesis is now thought to contribute to the development of preeclampsia. In animal models, sFlt-1 appears to be integral in the pathogenesis of preeclampsia.19,20 In humans,21 we have found that an elevation in serum levels of sFlt-1 and a decrease in serum levels of PlGF were present not only during clinical preeclampsia, but also four to five weeks before there was any clinical evidence of hypertension or proteinuria, suggesting that 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 control women without preeclampsia at similar stages of gestation are, at most, 900 to 1000 pg per milliliter (Figure 3).21 Levels of free PlGF were 432 pg per milliliter at 20 weeks' gestation and 399 pg per milliliter at 22 weeks' gestation. PlGF levels in control women without preeclampsia at that gestational age are near 700 pg per milliliter, whereas in early preeclampsia, levels of free PlGF are at or near 100 pg per milliliter. However, this patient had impaired renal function; PlGF is a small protein that is filtered in the kidney, and as a result of impaired renal function, serum levels may have been artificially elevated. Therefore, although the accuracy of these markers in the prediction and diagnosis of preeclampsia is still being studied, her serum levels of sFlt-1 and PlGF were consistent with preeclampsia, suggesting that preeclampsia was at least one component of her underlying condition.
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 gestational 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 clinical preeclampsia and those obtained at 33 to 41 weeks from women in whom preeclampsia later developed were also significant (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)
Dr. Robert B. Colvin (Pathology): Are levels of sFlt-1 elevated in patients with lupus?
Dr. Thadhani: The levels of sFlt-1 and PlGF have not been studied in lupus, but given that impaired renal function predisposes patients to preeclampsia, 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 patient's renal function continued to deteriorate rapidly, and her creatinine level peaked at 4.3 mg per deciliter (1.54 mmol per liter). Her platelet count normalized in four weeks, and the anemia improved. Her blood pressure normalized in six to eight weeks. The level of proteinuria remained above 10 g per 24 hours before starting to fall slowly. She continued to receive prednisone, 60 mg a day, and monthly pulsed intravenous 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 proteinuria improved, and the level of serum creatinine decreased to a low of 2.5 mg per deciliter but gradually increased again during a period of months. A repeated renal biopsy was then performed a year after her delivery, and it showed changes consistent with lupus nephritis, class VI (advanced sclerotic lupus nephritis), with tubulointerstitial and glomerular scarring.10,11 The patient is currently being evaluated for renal transplantation from a living donor.
Dr. Ecker: The baby boy had a birth weight of 600 g and was discharged from the hospital nearly 150 days after delivery, weighing 2500 g. His prolonged hospital course was complicated by retinopathy of prematurity, chronic lung disease, infection, and intraventricular hemorrhage (grade 2 of 4), but such a course is considered a good outcome for a fetus born at 24 weeks 2 days' gestation. He showed no signs of neonatal lupus. He is now home with his mother and by current reports is doing well.
Anatomical Diagnosis
Combined membranous (class V) and diffuse segmental proliferative and sclerosing (class IV-S ) lupus nephritis.
Small, hypermature placenta with severe decidual vasculopathy and acute atherosis, consistent with preeclampsia.
Dr. Thadhani reports having received income from Beckman Coulter and Abbott Diagnostics. He also reports that he is a coinventor on provisional patents filed by Massachusetts General Hospital for the use of cytokines in the diagnosis of gestational disorders that have been licensed to diagnostic companies.
Source Information
From the Division of Nephrology, Department of Medicine (W.W.W., R.I.T.), and the Departments of Transplant Surgery (W.W.W.), Obstetrics, Gynecology, and Reproductive Biology (J.L.E.), and Pathology (A.R.), Massachusetts General Hospital; and the Division of Nephrology, Department of Medicine (W.W.W., R.I.T.), and the Departments of Obstetrics, Gynecology, and Reproductive Biology (J.L.E.), and Pathology (A.R.), Harvard Medical School.
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