Proteinuria In Preeclampsia Research Articles

Acute and Transient Podocyte Loss and Proteinuria in Preeclampsia

Glomerular podocytes are known to regulate proteinuria and podocyturia correlated with proteinuria. Podocyturia, the urinary excretion of viable podocytes (glomerular epithelial cells), has been associated with proteinuria in preeclampsia. This study is the first to investigate the time course alterations of podocyturia in patients with preeclampsia (11 cases) and normotensive pregnant women (45 cases). Urinalysis was performed at 35 weeks of gestation, 4 days after delivery, and 1 month after delivery. In patients with preeclampsia, podocyturia was evident at 35 weeks of gestation and 4 days after delivery, while proteinuria had already decreased at 4 days after delivery. At 1 month after delivery, almost no patients exhibited podocyturia. In control cases, proteinuria was not significant throughout the study period. However, 9 of the 45 controls exhibited transient and mild podocyturia at 4 days after delivery without proteinuria or hypertension. Statistics indicated a correlation between urinary podocyte number and blood pressure, but not with proteinuria. In conclusion, podocyturia in preeclampsia is transient and almost synchronous with heavy proteinuria. The results suggest that acute podocyte loss implicates podocyturia as the possible mechanism of proteinuria in women with preeclampsia.

Effect of Antihypertensive Therapy with Alpha Methyldopa on Levels of Angiogenic Factors in Pregnancies with Hypertensive Disorders

BackgroundAntihypertensive drugs are believed to lower blood pressure in pre-eclampsia by direct or central vasodilatory mechanisms. However, they could also act by decreasing production of anti-angiogenic proteins involved in the pathophysiology of hypertension and proteinuria in pre-eclampsia (PE). The aim of our study was to evaluate the impact of antihypertensive therapy with alpha methyldopa on maternal circulating levels and placental production of soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng), vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in hypertensive disorders of pregnancy.Methodology/Principal FindingsIn a study conducted at University College Hospital and the Homerton University Hospital in London, we recruited 51 women with PE, 29 with gestational hypertension (GH), and 80 matched normotensive controls. Eight (16%) of the women with PE had severe disease. Placental samples were obtained from a further 48 women (14 PE, 10 GH and 24 matched controls). Serum levels of angiogenic factors were measured before and 24–48 hours after commencing antihypertensive therapy with alpha methyldopa for clinical indications. The same parameters were measured in placental extracts. In both PE (P<0.0001) and GH (P<0.05), serum sFlt-1 was increased and PlGF reduced at all gestations (P<0.001) compared to controls. Serum sEng levels were also increased in PE. Placental concentration of sFlt-1 and sEng was significantly higher in women with PE compared to controls and women with GH (P<0.0001). The concentration of PlGF was significantly lower in the placental tissue of women with PE compared to GH (P = 0.008). Antihypertensive treatment was associated with a significant fall in serum and placental content of sFlt1 and sEng in PE only.ConclusionsOur data suggest that alpha methyldopa may have a specific effect on placental and/or endothelial cell function in pre-eclampsia patients, altering angiogenic proteins.

Urinary Podocyte Excretion as a Marker for Preeclampsia

The proteinuria of preeclampsia is associated with glomerular endotheliosis, and a role for damaged and lost podocytes (glomerular epithelial cells) in the development of proteinuria has received support from studies of patients with glomerular diseases. This study asked whether urinary excretion of viable podocytes, quantified by the expression of podocin and other podocyte-specific proteins, is observed in pregnant women with clinically confirmed preeclampsia. In addition, levels of angiogenic factors implicated in the pathogenesis of preeclampsia were estimated. They included soluble receptor for vascular endothelial growth factor, also called fms-like tyrosine kinase receptor-1 (sFlt-1); placental growth factor (PIGF); and serum soluble endoglin. The cross-sectional study recruited 33 pregnant women with preeclampsia, 11 with HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and 23 normotensive pregnant women. All of the 15 preeclamptic women evaluated and also those with HELLP syndrome, but not normotensive control subjects, had podocin-positive cells in their urine. Podocyturia was 100% sensitive and 100% specific for the diagnosis of preeclampsia, and the degree of proteinuria correlated positively with podocyturia. The positive predictive value of urinary podocyte excretion for the presence of preeclampsia was greater than that of sFlt-1, PIGF, or endoglin. Nevertheless, serum levels of sFlt-1 were significantly higher in women with preeclampsia or HELLP syndrome than in normotensive control women, and the same was the case for serum levels of soluble endoglin. Women with preeclampsia or HELLP syndrome had lower serum levels of free PlGF than did normotensive pregnant women. Urine levels of PlGF did not differ from those in normal women. Podocyturia is a very sensitive and specific marker for preeclampsia, and it may contribute to the development of proteinuria in affected women. Further studies may clarify the effects of dysregulated vascular endothelial growth factor on mechanisms regulating podocyte attachment.

LETTER TO THE EDITOR

Objectives. To measure anteroposterior (AP) diameters, and to describe qualitative findings of the uterus and the uterine cavity in women with postpartum endometritis, after caesarean section (CS) and after manual evacuation of the placenta, and to compare these women with those in a normal puerperium. Methods. A prospective, descriptive, observational study of 103 postpartum women was conducted. Fifty-five women had clinical symptoms of postpartum endometritis, 28 had undergone CS, and 20 had manual placental evacuation. Ultrasound examinations were scheduled for days 1, 3, 7, 14, 28 and 56 postpartum. Women with endometritis underwent their first examination on the day they presented with clinical symptoms. Results. The AP diameters of the uterus and uterine cavity in all three groups overlapped considerably with the reference values. On day 56 postpartum, the uterus had achieved the same dimensions as found in our reference population. Compared with the reference group, during early puerperium, an empty cavity was less common among women with the three study conditions, and gas was present more often after CS and after manual evacuation of the placenta. An anteverted position of the uterus was less common among women with endometritis on day 14 and 28 postpartum, and among women delivered by CS on days 7, 14 and 28 postpartum. The incision site in the lower uterine segment was visible after CS. Conclusion. The ultrasonic findings in women with postpartum endometritis, after CS and after manual evacuation of the placenta, do not differ substantially from those during an uncomplicated puerperium. A delayed uterine involution process might explain the slight morphological differences observed.

Emerging Roles of Antiangiogenic and Angiogenic Proteins in Pathogenesis and Prediction of Preeclampsia

Hypertensive disorders are a major cause of maternal and fetal death, especially in developing nations, with the pregnancy-specific disease preeclampsia-eclampsia responsible for most of this mortality. Preeclampsia, recognized by ancient Greeks, was only sporadically investigated until late last century, current literature still labeling this disorder a “disease of theories.” Thus, not surprisingly, we have started the new millennium unable to predict or prevent preeclampsia, and management strategies remain but supportive, with pregnancy termination still the only definitive “therapy.” This may be about to change, as focused research, mainly in the past decade, has resulted in dramatic progress regarding pathogenesis of disease manifestations and risk assessment, while investigators have begun designing and testing definitive therapy.1 There are still a myriad of uncertainties and unanswered questions to address, but here we summarize the extent of 1 new and exciting chapter in preeclampsia research: the roles of angiogenic and antiangiogenic factors, to which an article in this issue by Rana and colleagues,2 contributes. A landmark report published in 2003 set the stage for all that followed.3 Dr Karumanchi’s laboratory, previously involved in renal cancer research, changed its focus to the kidney in preeclampsia. Using microarray chip technology, they probed gene expression profiles in placentas of women with preeclampsia and those with uncomplicated pregnancies. Of course many differences were noted, but one that caught the investigators’ attention was upregulation of the mRNA for the antiangiogenic protein soluble fms-like tyrosine kinase 1 (abbreviated as sFlt-1 or sVEGFR-1) in placentas from women with preeclampsia. Aware that de novo hypertension and proteinuria were 2 disturbing side effects of certain antiangiogenic compounds tested in cancer patients, these …

Urinary podocyte excretion as a marker for preeclampsia

The objective of this study was to examine whether podocyturia, which is the urinary excretion of viable podocytes (glomerular epithelial cells), is present in urinary sediments of patients with preeclampsia. We also aimed to compare the test characteristics of podocyturia to those angiogenic factors that have been shown to play an important role in the pathogenesis of preeclampsia (s-Flt-1, PlGF, and endoglin). Serum angiogenic factors were measured in 44 patients with preeclampsia and 23 normotensive control patients. In a patient subset (15 cases and 16 control patients), urinary proteinuria were identified and quantified on the basis of their expressions of podocyte-specific proteins. Urinary podocyte excretion occurred in all patients with preeclampsia. The positive predictive value for the diagnosis of preeclampsia was greater for podocyturia than for any of the measured angiogenic factors. Podocyturia is a highly sensitive and specific marker for preeclampsia. It may contribute to the development of proteinuria in preeclampsia.

Circulating Levels of the Antiangiogenic Marker Soluble FMS-Like Tyrosine Kinase 1 Are Elevated in Women With Pregestational Diabetes and Preeclampsia

Preeclampsia is characterized by the development of proteinuria and hypertension after 20 weeks gestation, and it is associated with maternal and fetal morbidity. Preeclampsia affects ∼5% of pregnancies, though women with preexisting diabetes are three to four times more likely to develop preeclampsia (1). Preeclampsia is associated with altered angiogenic factors, including increased levels of circulating soluble FMS-like tyrosine kinase 1 (sFlt1) and reduced levels of vascular endothelial growth factor and placental growth factor (PlGF). Hypertension and proteinuria of preeclampsia may be caused by an imbalance of these angiogenic factors (2–10). Circulating sFlt1, an antiangiogenic protein, binds to proangiogenic proteins, vascular endothelial growth factor, and PlGF, preventing their interaction with endothelial cell receptors and inducing endothelial dysfunction. Rats given sFlt1 develop proteinuria, hypertension, and glomerular endotheliosis, which are hallmarks of preeclampsia (3). Alterations in sFlt1 and PlGF are observed several weeks before symptoms (2). It is unknown whether alterations in sFlt1 and PlGF are present in women with diabetes who then develop preeclampsia or whether a different pathway is responsible. Ultimately, it would be helpful to have a way to diagnose and predict preeclampsia in women with pregestational diabetes, as they frequently have preexisting hypertension and/or proteinuria, which make it difficult to differentiate superimposed preeclampsia. We evaluated a small group of women with diabetes and compared levels of sFlt1 and PlGF at delivery in both those who developed preeclampsia and those …

Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia

Preeclampsia is a pregnancy-specific disorder characterized by hypertension and proteinuria. In other disease states, proteinuria has been linked to altered expressions of podocyte foot-process proteins, but this has not been studied in women with preeclampsia. We sought to test the hypothesis that proteinuria in preeclampsia is associated with dysregulated expression of the podocyte cytoskeleton and/or tight junction proteins. Renal tissue was obtained from autopsy material from seven women who had severe preeclampsia during the second half of their pregnancies up to 48 h after delivery, and who subsequently died. As controls, we used autopsy material from two women who died accidentally during the second half of their otherwise normal pregnancies. Immunohistochemical stains for nephrin, synaptopodin and podocin were performed on representative sections prepared from paraffin-embedded material. Expression of both nephrin and synaptopodin was markedly decreased in preeclamptic compared with control kidney sections. By contrast, both cases and controls demonstrated strong staining for podocin. We conclude that down-regulation of nephrin and synaptopodin is associated with proteinuria in women with preeclampsia. Recent studies have demonstrated that soluble vascular endothelial growth factor receptor 1 (sFlt-1) levels are elevated in preeclampsia compared with normal pregnancy. Studies in mice have shown that sFlt-1 may play a role in inducing proteinuria by neutralizing vascular endothelial growth factor (VEGF) and suppressing nephrin. Proteinuria and elevations of sFlt-1 in preeclampsia are temporally related, further supporting a possible role of sFlt-1 in the dysregulation of podocyte foot-process proteins.

Hypertension During Pregnancy

Hypertension during pregnancy remains a common and potentially devastating complication.1,2 Hypertension can be isolated (gestational hypertension) or associated with proteinuria (preeclampsia) and, rarely, can manifest as a consequence of either preexisting or new onset renal (usually glomerular) disease. Preeclampsia is a particularly worrisome diagnosis, because it carries increased risk for morbidity to the mother and child and may accelerate to the condition of eclampsia in which seizures develop in association with a high risk for fetal and maternal mortality. Although, ideally, the diagnosis of these conditions should involve the use of biomarkers that reflect the underlying pathophysiology of the disease process, the lack of clinically available assays has forced the clinician to diagnose the condition based solely on the clinical presentation. Unfortunately, although establishing cut points for elevated blood pressure and urine protein excretion appears to be straightforward, these continuous variables lend themselves to arbitrary definitions, and this likely explains why the precise definition of preeclampsia has changed several times and why different organizations continue to classify preeclampsia differently.3 A recent report from the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy3 nicely summarized the current status of diagnosing preeclampsia: “Although our current understanding of this syndrome has increased, the criteria used to identify the disorder remain subject to confusion and controversy. The confusion doubtless reflects the fact that preeclampsia is a syndrome, which means that attempts at definition use arbitrarily selected markers rather than changes of pathophysiologic importance.” Adding to this confusion is the fact that a …

Use of Protein:Creatinine Ratio Measurements on Random Urine Samples for Prediction of Significant Proteinuria: A Systematic Review

Proteinuria is recognized as an independent risk factor for cardiovascular and renal disease and as a predictor of end organ damage. The reference test, a 24-h urine protein estimation, is known to be unreliable. A random urine protein:creatinine ratio has been shown to correlate with a 24-h estimation, but it is not clear whether it can be used to reliably predict the presence of significant proteinuria. We performed a systematic review of the literature on measurement of the protein:creatinine ratio on a random urine compared with the respective 24-h protein excretion. Likelihood ratios were used to determine the ability of a random urine protein:creatinine ratio to predict the presence or absence of proteinuria. Data were extracted from 16 studies investigating proteinuria in several settings; patient groups studied were primarily those with preeclampsia or renal disease. Sensitivities and specificities for the tests ranged between 69% and 96% and 41% and 97%, respectively, whereas the positive and negative predictive values ranged between 46% and 95% and 45% and 98%, respectively. The positive likelihood ratios ranged between 1.8 and 16.5, and the negative likelihood ratios between 0.06 and 0.35. The cumulative negative likelihood ratio for 10 studies on proteinuria in preeclampsia was 0.14 (95% confidence interval, 0.09-0.24). The protein:creatinine ratio on a random urine specimen provides evidence to "rule out" the presence of significant proteinuria as defined by a 24-h urine excretion measurement.

Anti-Vascular Endothelial Growth Factor Receptor-2 Antibody Accelerates Renal Disease in the NZB/W F1 Murine Systemic Lupus Erythematosus Model

Anti-Vascular Endothelial Growth Factor Receptor-2 Antibody Accelerates Renal Disease in the NZB/W F1 Murine Systemic Lupus Erythematosus Model

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

Urinary heparan sulfate proteoglycan excretion in black African women with pre-eclampsia.

The heparan sulfate proteoglycan of the glomerular basement membrane is considered to be mainly responsible for the charge selectivity of the glomerular basement membrane. Decreased heparan sulfate proteoglycan results in a decreased anionic charge of the glomerular basement membrane with increased heparan sulfate proteoglycan in the urine, and is believed to be responsible for the proteinuria in pre-eclampsia. To determine the urinary heparan and chondroitin sulfate proteoglycan levels in women with pre-eclampsia. Eighty-four patients were studied: 28 were normotensive pregnant, 28 were nonproteinuric hypertensive, and 28 were pre-eclamptic. Urine samples were obtained and urinary glycosaminoglycan concentrations were determined using the dimethyl-methylene blue assay. Plotting absorbance against the concentrations of heparan and chondroitin sulfate proteoglycans drew a standard curve. The concentration of heparan and chondroitin sulfate proteoglycans was read-off from the linear portion of the standard curve. The standard solutions contained 25, 50, 100 and 200 mg/l heparan or chondroitin sulfate. The Mann-Whitney U-test was used to detect differences between the three groups, and the Pearson's correlation coefficient was calculated for clinical data correlation of the pre-eclamptic group. Urinary excretion of heparan sulfate proteoglycan (123.1 +/- 22.1 mg/l) was significantly increased in the pre-eclamptic group compared with the normotensive pregnant group (60.5 +/- 5.1 mg/l; p < 0.0001) and the hypertensive nonproteinuric group (63. 2 +/- 3.7 mg/l; p < 0.0001). Urinary chondroitin sulfate proteoglycan excretion followed a similar pattern, being significantly increased in the pre-eclamptic group (88.86 +/- 9.79 mg/l) compared with the normotensive pregnant group (49.1 +/- 8.49 mg/l; p < 0.0001) and the hypertensive nonproteinuric group (43. 9 +/- 5.7 mg/l; p < 0.0001). A significant Pearson's correlation between 24-h urine output vs. 24-h protein excretion (r = 0.51; p < 0.001), and between loss of HSPG versus 24-h urinary protein excretion (r = 0.72; p < 0.0001) was obtained in the pre-eclamptic group. This study demonstrates a reduction of glomerular charge in pre-eclampsia. The strong correlation between the severity of proteinuria and the loss of charge supports the hypothesis that the loss of glomerular charge induces structural changes of the filtration barrier, and may be the mechanism responsible for the proteinuria in pre-eclampsia. Furthermore, the elevated levels of urinary proteoglycan (heparan and chondroitin sulfate proteoglycans) in this disorder show a loss into the urine rather than a neutralization of these macromolecules.

Urinary heparan sulfate proteoglycan excretion in black African women with pre-eclampsia

Background. The heparan sulfate proteoglycan of the glomerular basement membrane is considered to be mainly responsible for the charge selectivity of the glomerular basement membrane. Decreased heparan sulfate proteoglycan results in a decreased anionic charge of the glomerular basement membrane with increased heparan sulfate proteoglycan in the urine, and is believed to be responsible for the proteinuria in pre-eclampsia. Aim. To determine the urinary heparan and chondroitin sulfate proteoglycan levels in women with pre-eclampsia. Materials and methods. Eighty-four patients were studied: 28 were normotensive pregnant, 28 were nonproteinuric hypertensive, and 28 were pre-eclamptic. Urine samples were obtained and urinary glycosaminoglycan concentrations were determined using the dimethyl-methylene blue assay. Plotting absorbance against the concentrations of heparan and chondroitin sulfate proteoglycans drew a standard curve. The concentration of heparan and chondroitin sulfate proteoglycans was read-off from the linear portion of the standard curve. The standard solutions contained 25, 50, 100 and 200 mg/l heparan or chondroitin sulfate. The Mann–Whitney U-test was used to detect differences between the three groups, and the Pearson's correlation coefficient was calculated for clinical data correlation of the pre-eclamptic group. Results. Urinary excretion of heparan sulfate proteoglycan (123.1 ± 22.1 mg/l) was significantly increased in the pre-eclamptic group compared with the normotensive pregnant group (60.5 ± 5.1 mg/l; p < 0.0001) and the hypertensive nonproteinuric group (63. 2 ± 3.7 mg/l; p < 0.0001). Urinary chondroitin sulfate proteoglycan excretion followed a similar pattern, being significantly increased in the pre-eclamptic group (88.86 ± 9.79 mg/l) compared with the normotensive pregnant group (49.1 ± 8.49 mg/l; p < 0.0001) and the hypertensive nonproteinuric group (43. 9 ± 5.7 mg/l; p < 0.0001). A significant Pearson's correlation between 24-h urine output vs. 24-h protein excretion (r = 0.51; p < 0.001), and between loss of HSPG versus 24-h urinary protein excretion (r = 0.72; p < 0.0001) was obtained in the pre-eclamptic group. Conclusion. This study demonstrates a reduction of glomerular charge in pre-eclampsia. The strong correlation between the severity of proteinuria and the loss of charge supports the hypothesis that the loss of glomerular charge induces structural changes of the filtration barrier, and may be the mechanism responsible for the proteinuria in pre-eclampsia. Furthermore, the elevated levels of urinary proteoglycan (heparan and chondroitin sulfate proteoglycans) in this disorder show a loss into the urine rather than a neutralization of these macromolecules.

Protein/creatine ratio in random urine specimens for quantitation of proteinuria in preeclampsia

Protein/creatinine ratio (mg/g) in random urine samples was measured in 35 preeclamptic patients and 70 healthy pregnant women. We found a close correlation between the protein/creatinine ratio in random urine samples and both the 24-hour protein excretion and the 24-hour protein/creatinine ratio in the preeclamptic patients. The ratio did not exceed 200 mg/g in any of the 70 healthy pregnant women; therefore, ratios below this value can be considered normal. We conclude that determination of the protein/creatinine ratio in random urine specimens may be a simple method for quantitation of proteinuria in preeclampsia.

Birth Weight and Thyroxine-Binding Globulin in Pre-Eclampsia

Plasma concentrations of thyroxine (T4) and thyroxine-binding globulin (TBG) as well as triiodothyronine uptake (T3U) were measured in 32 proteinuric pre-eclamptic patients and 24 normotensive pregnant women at similar gestations in the third trimester. The pre-eclamptic patients had slightly lower TBG, and significantly lower T4, concentrations, which were significantly correlated. They also had significantly lower infant birth weight which was correlated to the TBG and T3U values. There was no correlation between T4 and TBG or between birth weight and TBG or T3U in the normotensive women. It is likely that the correlation between TBG and birth weight in the pre-eclamptic patients reflects the severity of proteinuria in pre-eclampsia.

The significance of proteinuria in pre-eclampsia; proteinuria associated with low birth weight only in pre-eclampsia

To examine the significance of proteinuria in pre-eclampsia, we studied 87 nulliparous patients in whom pre-eclampsia was diagnosed clinically and whose blood pressure and urine findings returned to normal after delivery. There was no difference in the gestation at diagnosis, highest systolic and diastolic blood pressures before treatment/delivery, or the number given antenatal hypotensive therapy between patients with proteinuria (group A, n = 46) and without proteinuria (group B, n = 41). Group A patients had higher plasma urea concentration (p < 0.02), but similar creatinine and urate concentrations to group B patients. Group A patients had a higher rate of induction of labour (p < 0.04) and Caesarean section before labour (p < 0.04), and the mean gestation at delivery as well as the birth weight were less (p < 0.03 and p < 0.004, respectively). The results suggest that proteinuria in pre-eclampsia is associated with more severe fetal involvement and growth retardation only, but not with an increased severity of the maternal condition such as hypertension and a higher plasma urate concentration.

Nephrotic proteinuria with pre-eclampsia

During a retrospective study of 100 patients who underwent renal biopsy because of pregnancy complicated by hypertension, we found 19 patients in whom proteinuria exceeded 5.0 Gm. per 24 hours and an adoitional eight patients in whom excretion ranged between 3.5 and 5 Gm. per day. Of these 27 patients, 23 had the kidney lesion of pre-eclampsia, and three of them had superimposed hypertensive changes in the vasculature. The remaining four had other renal diseases. We located and re-examined 10 of the 23 pre-eclamptic women, 12 to 104 (mean, 36) months after delivery. Serum creatinine levels were normal in all but one, who was discovered to have polycystic kidney disease. During the same time period, we located the records of six women who had heavy proteinuria during gestation but were normotensive. Thus, at our institution, pre-eclampsia is the most common cause of the nephrotic syndrome in pregnancy. The frequency of nephrotic proteinuria in pre-eclampsia appears higher than previously suspected, but, despite this fact, recovery was complete in most instances.

THE ORIGIN AND EFFECTS OF PROTEINURIA IN PREGNANCY

Summary The proteinuria of nephrotic syndrome in pregnancy and pre-eclampsia was investigated by immunochemical techniques that enabled identification of individual proteins and estimated the renal clearance of proteins, and hence the selectivity of the proteinuria. It has been shown that the proteinuria of pre-eclampsia is a result of a leak through a damaged glomerular basement membrane with no apparent tubular cause for protein loss. The differential protein clearance in pre-eclampsia does not suggest that this will be a promising method for distinguishing pre-eclamptic nephropathy from most cases of chronic glomerulonephritis, but the proteinuria of pre-eclampsia does show some similarities to that in renal vein thrombosis. This suggests that the deposition of fibrinoid material in the glomerular basement membrane is the probable cause of proteinuria in pre-eclampsia. The heavy urinary protein loss in pre-eclampsia produces hypogammaglobulin-aemia in the fetus. A fall in serum albumin, transferrin and IgG, with an elevation of alpha2-macroglobulin and β-lipoprotein is found in the mother. These maternal protein changes are identical to those occurring in nephrotic syndrome and are a result of “molecular sieving” of proteins of intermediate molecular weight through the damaged basement membrane. It is postulated that these serum protein changes are in part responsible for some of the clinical complications of both conditions, and that a rise in the level of the two macroglobulins may, by their antiplasmin activity, exacerbate disseminated intervascular coagulation and deposition of fibrin within the kidneys of a patient with pre-eclampsia.