Nephrol Dial Transplant (2002) 17: 672-674
© 2002 European Renal Association-European Dialysis and Transplant Association
Teaching Point
Nephrotic syndrome in early pregnancy—is renal biopsy always necessary?
(Section Editor: K. Kühn)
1 Department of Renal Medicine and 2 Department of Obstetrics and Gynaecology, Royal Preston Hospital, Sharoe Green Lane, Fulwood, Preston, UK
Keywords: early pregnancy; hypertension; nephrotic syndrome; partial mole; pre-eclampsia; renal biopsy; triploidy
Introduction
Increased proteinuria in pregnancy is common, ranging from a slight elevation to nephrotic amounts. In early pregnancy, nephrotic proteinuria with hypertension is considered suggestive of native renal disease rather than pre-eclampsia [1]. Diagnosis and proper management are very important for maternal and fetal health [2]. Overall, glomerular lesions associated with pre-eclampsia are the commonest findings in pregnant renal biopsies and the changes are reversible without any long-term sequelae [3].
Here we present a case of early nephrotic syndrome with hypertension associated with a triploid fetus and a placenta with a partial mole. Nephrotic syndrome and hypertension resolved when the pregnancy was terminated. Renal biopsy and steroids were not required.
Case
A 24-year-old primigravid woman with oedema and hypertension was referred for nephrological opinion after an ultrasound confirmed 15 weeks of gestation. She had noticed facial and periorbital oedema at 13 weeks gestation. There was a family history of Henoch–Schonlein purpura. On examination her blood pressure was 150/100 mmHg. The jugular venous pressure was raised. She had lower limb and sacral oedema. Clinical urinalysis showed proteinuria +++ and blood +. Her blood pressure rose to 178/110 mmHg over the following few days. Laboratory investigations showed serum sodium 131 mmol/l, potassium 4.3 mmol/l, urea 5.4 mmol/l, creatinine 72 mmol/l, albumin 26 g/l, 24 h urinary protein 3.72 g, haemoglobin 9.4 g/dl. MCV was 86.9 fl; serum vitamin B12 and folate levels and immunological screen were normal except low IgG 4.75 g/l (6–16 g/l). The ultrasound scan of her kidneys showed 10.2 cm size with normal echotexture. Bilateral pleural effusions were noticed. Echocardiogram was normal. Chest X-ray showed signs of fluid overload.
The routine ultrasound scan of the fetus at 12 weeks was reported as a single fetus, fetal heart and movements were seen, membranes were close to fetal head but separate from it. Her beta chorionic gonadotropin (bhCG) level was 209000 IU/l (normal <40 IU/l) and maternal alpha fetoprotein (AFP) levels were raised. She was treated with i.v. labetolol, low-salt diet, fluid restriction, and frusemide 40 mg daily. Oral labetolol was started once her blood pressure was stabilized. Low molecular weight heparin was given prophylactically once a day. There was a strong suspicion of renal disease. Renal biopsy was considered and deferred. The fetal anomaly ultrasound scan, performed at 18 weeks, showed a large echogenic placenta suggestive of a partial mole, with an elongated fetal head and distorted cerebellum. Facial anatomy was not clearly defined. Triploidy was suspected as partial mole can be associated with this condition. At this stage her haemoglobin was 7.9 g/dl, white cell count 7.1x109/l and platelets 81x109/l. Clotting was normal. She was admitted with pyrexia 38.2 °C. A cervigem pessary was inserted and the pregnancy was terminated. The placenta was not delivered completely and needed evacuation. Pathology showed a male fetus with various abnormalities including small cystic dysplastic kidneys. The placenta showed features of partial mole. Chromosome analysis confirmed triploidy (trisomy or extra set of chromosome 69, XXY). She was registered with the Jessop Hospital in Sheffield (Regional center for trophoblastic diseases) because of the partial mole and she was advised to avoid pregnancy until her bhCG levels are normal.
Two weeks post-termination she was seen in the renal clinic. Her 24 h urinary protein excretion was down to 1.09 g. Her blood pressure was 120/80 mmHg without any medication. Platelets returned to normal. Ten weeks post-termination her urinary protein was 0.39 g/day, with blood pressure 90/70 mmHg. Seven months post-termination she was referred again to the nephrologists with a 7-week pregnancy. Her urine dipstick was negative for protein and blood pressure was normal. She was seen again in the renal clinic at 14 weeks and 30 weeks of pregnancy. The parameters were normal. She delivered a normal baby at full term.
Discussion
Nephrotic syndrome occurs in 0.012–0.025% of all pregnancies [4]. The incidence of pregnancy-induced hypertension is 3% and eclampsia is 0.1%. The usual causes are pre-eclampsia, glomerulonephritis, diabetes, renal vein thrombosis, amyloidosis, and hereditary nephritis.
Occasionally it is necessary to treat the nephrotic syndrome with steroids. In pregnancy, steroid treatment has additional maternal and fetal problems. Sometimes nephrotic syndrome does not respond to steroids, which can aggravate the problems related to nephrotic syndrome. Thus, it is important to know the histology before starting treatment [2].
Generally nephrotic syndrome in pregnancy causes few problems if there is no hypertension or abnormal renal function. Physiological changes during pregnancy may cause a diagnostic dilemma as they mimic exacerbation of the disease. Physiological urinary protein excretion in pregnancy is increased to 0.39 g/day. Serum albumin is reduced by 5–10 g/l normally. Further reduction of serum albumin due to nephrotic syndrome can cause fluid retention. Because of the relative decrease in intravascular volume, diuretic therapy can compromise uteroplacental blood flow or cause increased tendency to thrombotic episodes significantly. Decreased serum albumin can be associated with low birth weight babies or poor fetal outcome.
Fisher et al. in 1977 [3] looked retrospectively at 100 renal biopsies associated with pregnancy. Sixty-seven per cent of the biopsies showed changes of pre-eclampsia and one-third of pre-eclamptic biopsies had nephrotic range proteinuria. They concluded that nephrotic range proteinuria is not rare in pre-eclampsia and its onset does not herald deteriorating renal functions. Remote renal prognosis seems to be good. This is in contradistinction to a previous report by Weisman et al. [5]. The analysis of glomerular changes in pre-eclampsia by Kincaid-Smith in 1991 showed that subendothelial fibrinoid deposits in the glomerulus, the characteristic lesion of pre-eclampsia disappear gradually after delivery and may take up to 18 months [16]. Criscuolo et al. [2] examined 23 patients with nephrotic syndrome in the third trimester of pregnancy. Post-delivery, all the signs resolved and cure was achieved by 6 months.
Lindheimer and Davison in 1987 [17] and Lindheimer and Katz [18] in 1994 concluded from a review of literature and their own experience that although renal biopsy in pregnancy does not entail increased risks, it should be performed infrequently during gestation. The indications of its use are sudden renal insufficiency or massive nephrotic syndrome of unknown origin occurring prior to the final 2 months of pregnancy. While mild or moderate proteinuria in normotensive women and/or asymptomatic microscopic haematuria with well preserved renal function should be monitored closely and biopsy should be deferred to the postpartum period.
Fetoplacental factors are important determinants for abnormal pregnancy and pregnancy induced hypertension. These can be twin pregnancy, hydrops fetalis, hydatidiform mole, trisomies, triploidy, and tetraploidy. Twelve per cent of molar pregnancies have associated pre-eclampsia [6]. The onset of pre-eclampsia in molar pregnancies is classically earlier than that associated with a normal fetus [7]. Toxaemia prior to 24 weeks of pregnancy is a rare complication of pregnancy and when it occurs molar pregnancy must be considered even if a viable fetus is detected [8].
Cohen et al. [4] reported the first patient to have nephrotic syndrome due to pre-eclampsia associated with partial mole. After evacuation the patient had a reversal of her hypertension and nephrotic syndrome within 4 weeks. They concluded that complete resolution of nephrotic syndrome is consistent with a pregnancy-induced condition rather than underlying renal disease. With rapid evaluation and treatment, medical and obstetric complications can be avoided and the patient can return to her previous state of health without further sequelae. Rijhsinghani et al. in 1997 [9] retrospectively analysed 17 cases of triploidy identified between 1987 and 1996. Six (35%) had pre-eclampsia or hypertension with onset between 15 and 22.5 weeks. These patients had very high levels of bhCG and placentomegaly. Low levels of bhCG were not associated with pre-eclampsia. There is no detail about renal failure or nephrotic syndrome. Sorem et al. in 1995 [10] reported a case with advanced triploid pregnancy and pre-eclampsia at 26 weeks of pregnancy. Advanced triploid pregnancies are rare but have been associated with pre-eclampsia [11]. The vast majority of triploid pregnancies undergo early molar degeneration and abort early.
The association of abnormal karyotype with pre-eclampsia suggests that fetal and placental factors play a major role in the aetiology of this disease. Genetic, developmental, or immunological factors may contribute to the development of pre-eclampsia. The abnormal fetus can represent a genetic dose effect in which the fetus codes for excess factors such as basement membrane collagen or clotting factors on the extra chromosomes [12]. The paternal genetic component is essential for the development of extraembryonic tissue [13]. The diandric placenta may demonstrate an excess of paternal antigens that potentially contribute to the development of pre-eclampsia. Maternal serum AFP levels are greatly elevated in triploid pregnancies [14]. Very high levels of bhCG have been associated with severe and early pre-eclampsia [9]. Unconjugated estriol (E3) can be associated with pre-eclampsia [15]. Fluorescent in situ hybridization can be used to diagnose fetal abnormalities during pregnancy but definitive diagnosis is by fetal karyotype determination. Large placentas on ultrasound scan are associated with pre-eclampsia for the reasons as mentioned above [10].
In our case there was apparent pre-eclampsia at 12 weeks of gestation. Maternal AFP and bhCG were significantly elevated. The scan at 12 weeks was suspicious of fetoplacental abnormality. The anomaly scan at 18 weeks was highly suggestive of triploidy with partial mole. This was confirmed after termination. She was cured of nephrotic syndrome and hypertension after termination. Retrospectively the decision not to perform a renal biopsy was correct.
Teaching point
The message from this case report and review of literature is that early pregnancy pre-eclampsia and nephrotic syndrome does not warrant kidney biopsy. Pregnancy and associated factors like ultrasound scan of the fetus, levels of maternal AFP and bhCG should be taken into account. Fetal or placental abnormality should be excluded before renal biopsy. If this is confirmed, the main direction towards management is termination of pregnancy, which cures the renal condition. This can save patients from unnecessary renal biopsy or steroid treatment.
Notes
Supported by an educational grant from
Correspondence and offprint requests to: Dr Bhavna Pandya, 2 Higher Croft, Whitefield, Manchester M45 7LY, UK. 
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