Helena Strevens

Glomerular endotheliosis in normal pregnancy and pre‐eclampsia

Objective To investigate the proportion of women with findings characteristic for pre‐eclampsia, as opposed to renal disease, in a controlled study of hypertensive pregnant women undergoing antepartum renal biopsy.

The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System

Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as “preeclampsia.” Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (&Dgr;BP: 31.6±0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (&Dgr;BP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (&Dgr;BP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension.

Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre‐eclamptic pregnancies

Objective To study the correlation between serum cystatin C levels and renal structural changes in normal, hypertensive and pre‐eclamptic pregnancy to evaluate it as a marker of the degree of renal involvement in pre‐eclampsia.

Serum cystatin C for assessment of glomerular filtration rate in pregnant and non-pregnant women. Indications of altered filtration process in pregnancy

Serum cystatin C is believed to reflect the glomerular filtration rate (GFR) more closely than serum creatinine in many contexts and a reference interval for serum cystatin C in term pregnancy has been defined to enable its use also in pregnant women. However, serum cystatin C levels were not found to be decreased in term pregnancy, though GFR of low molecular mass substances is known to increase by at least 40% by the third trimester. The aim of this study was therefore to determine whether serum cystatin C is a reliable GFR marker also in pregnant women. GFR was determined by measurement of plasma clearance of iohexol in 48 previously healthy women in their third trimester and in 12 healthy nonpregnant women, and was compared with their serum levels of cystatin C and creatinine. Both serum cystatin C and creatinine levels were significantly related to GFR for both pregnant and non-pregnant women. However, the correlation between cystatin C and GFR was set at different levels for pregnant and nonpregnant women. Our results indicate a physiological difference between the filtration processes in kidneys of pregnant and non-pregnant women, whether it is size-dependent, configuration-dependent or charge-dependent. Nevertheless, serum cystatin C seems to reflect GFR reliably in both non-pregnant and pregnant, healthy and hypertensive women.

Serum cystatin C is a better marker for preeclampsia than serum creatinine or serum urate

Altered renal function is an essential component of the pathophysiological process in preeclampsia. The kidneys play a significant part in the turnover of most low molecular weight substances such as creatinine, urate and cystatin C. The present work was undertaken to investigate if the serum levels of these components are altered in characteristic ways in preeclampsia, and can be used to assist in the diagnosis of this condition. The serum levels were therefore determined in samples from 100 healthy women at term as well as in 45 samples of patients with preeclampsia (diastolic blood pressure >90 mmHg; urinary albumin excretion >300 mgL(-1)). The levels of all three components were significantly higher in samples from preeclamptic patients with the mean+SD being 1.55+/-0.29 vs. 1.05+/-0.19 mg L(-1) for cystatin C, 70+/-23 vs. 56+/-9.7 micromol L(-1) for creatinine, and 413+/-128 vs. 305+/-61 micromol L(-1) for urate. Receiver operating characteristic analysis demonstrated that the serum level of cystatin C had a superior diagnostic accuracy for preeclampsia compared to those of serum urate and creatinine and that the diagnostic accuracy of serum urate was better than that of serum creatinine.Altered renal function is an essential component of the pathophysiological process in preeclampsia. The kidneys play a significant part in the turnover of most low molecular weight substances such as creatinine, urate and cystatin C. The present work was undertaken to investigate if the serum levels of these components are altered in characteristic ways in preeclampsia, and can be used to assist in the diagnosis of this condition. The serum levels were therefore determined in samples from 100 healthy women at term as well as in 45 samples of patients with preeclampsia (diastolic blood pressure > 90 mmHg; urinary albumin excretion > 300 mg L -1 ). The levels of all three components were significantly higher in samples from preeclamptic patients with the mean - SD being 1.55 - 0.29 vs. 1.05 - 0.19 mg L -1 for cystatin C, 70 - 23 vs. 56 - 9.7 mumol L -1 for creatinine, and 413 - 128 vs. 305 - 61 mumol L -1 for urate. Receiver operating characteristic analysis demonstrated that the serum level of cystatin C had a superior diagnostic accuracy for preeclampsia compared to those of serum urate and creatinine and that the diagnostic accuracy of serum urate was better than that of serum creatinine.

Temporal changes of the plasma levels of cystatin C, beta-trace protein, beta(2)-microglobulin, urate and creatinine during pregnancy indicate continuous alterations in the renal filtration process

Objective. To determine the plasma levels of the renal functional markers creatinine, urate, cystatin C, β2‐microglobulin and β‐trace protein in samples from the first, second, early third and late third trimesters of 398 healthy women with uncomplicated singleton pregnancies. Material and methods. Plasma samples from 58 healthy non‐pregnant women served as controls. The creatinine levels were significantly lower at all time‐points in pregnancy, whereas the urate levels were lower during the first and second trimesters but increased in the late third trimester. The cystatin C, β2‐microglobulin and β‐trace protein levels displayed similar changes with increased levels in the third trimester but unaltered levels during the first and second trimesters. Results. The results indicate an increased filtration of low‐molecular weight molecules during pregnancy, particularly during the first and second trimesters, whereas filtration of 10–30 kDa molecules is decreased in the third but unaltered in the first and second trimesters. The levels of albumin and α2‐macroglobulin were measured in the same samples. Conclusions. The albumin levels decreased in the second and third trimesters, whereas the levels of α2‐macroglobulin were unchanged, which is compatible with a virtually unaltered transfer of α2‐macroglobulin between the intra‐ and extravascular space during pregnancy and a significantly increased extravascular fraction of albumin.

Female genital mutilation – an exported medical hazard

Background Female circumcision (FC) has remained a common practice in the countries where it has traditionally been performed. Following increased global mobility, it has also become a common medical issue in the predominantly non-Islamic countries where an increasing number of immigrants from regions where FC is still traditional, have settled. Objectives To investigate types of FC found in a group of immigrants from northern Africa with a current domicile in Scandinavia. To characterize these women with regard to education, socio-economic status and experienced complications and sequelae. To report attitudes to FC among the women and their husbands. Methods An autoquestionnaire was distributed to 220 immigrant women (16–42 years old), who belonged to an African community in Scandinavia and who had all been circumcised. Information was also gathered concerning 76 of their daughters (aged 1–13 years). Of the womens husbands, 95 were asked about their attitudes to FC. Results Of the 140 women, who had been circumcised in their home country before they migrated, 78 (35%) had been clitoridectomized, 38 (17%) had been subjected to genital excision and 24 (11%) to infibulation. The corresponding percentages in the remaining women, who had had FC when returning home for a visit, were 0%, 14% and 22%, respectively. Of the daughters, 15 (19%) had been circumcised whilst living in Scandinavia; all had been clitoridectomized. Twenty-eight (13%) women reported having experienced late complications or post-FC sequelae. A positive attitude to stopping the tradition of FC was reported twice as often by the husbands (69%) as by the circumcised women (35%). Religion (95% of the responders were Muslims and 5% Christians), cultural tradition, and increased chance of marriage or of continued health were the reasons put forward in favor of the continuation of FC by 58%, 27%, 10% and 4 %, respectively. Five per cent could not supply an opinion. Conclusions FC is performed in immigrant women even after settling in areas where this practise is legally banned. Circumcised immigrant women experience medical and sexual problems which have to be dealt with in their new domicile country. Many African Islamic women, who have migrated to Scandinavia, seem still to be in favour of the continuation of circumcision for varying reasons.

Folate and vitamin B12 in idiopathic male infertility.

Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B(12) (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case-control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmö and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P=0.01 and P=0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l(-1); P=0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.

Vascular mechanical properties and endothelial function in pre-eclampsia with special reference to bilateral uterine artery notch

Objectives. To assess whether women with pre‐eclampsia (PE) have different properties of the blood vessel wall compared to healthy pregnant controls. Further, to evaluate endothelial function and vascular mechanical properties in women with PE with special regard to its association with bilateral uterine artery notch and placental histopathology. Participants. Some 57 Caucasian pregnant women: 23 with uncomplicated pregnancies and normal uterine artery Doppler, and 34 with PE, the PE group comprising 2 subgroups according to the presence (n = 20) or absence (n = 14) of bilateral uterine artery notches. Methods. Ultrasonic echo‐tracking assessed the elastic properties of the common carotid artery, abdominal aorta and popliteal artery. Flow‐mediated dilatation (FMD) of the brachial artery was measured by ultrasonography. Histopathological examination of the placenta was carried out in 46 pregnancies: 18 uncomplicated pregnancies, 15 with PE with bilateral notch, and 13 with PE without bilateral notch. Results. There were no significant differences in carotid, aortic or popliteal vessel wall stiffness either between women with PE and controls or within the PE group. FMD was significantly lower in women with PE than in controls (p = 0.03). The lowest FMD was observed in pre‐eclamptic women with bilateral uterine artery notches 9.5% (SD: 5.3) compared to 11.6% (SD: 5.4) in pre‐eclamptic women without bilateral uterine artery notch, and 13.4% (SD: 4.0) in controls (p = 0.01). Bilateral uterine artery notching was significantly associated with a lower FMD (OR: 0.87; 95% CI: 0.77–0.98). There were significantly more placentas with high ischaemic score in the bilateral notch group than in the group with PE and normal circulation. Conclusions. There were no differences in vessel wall stiffness between women with PE and healthy controls. Women with PE showed signs of endothelial dysfunction, significantly more pronounced in women with bilateral uterine artery notch. Bilateral uterine artery notch was associated with ischaemic pathology of the placenta. Notwithstanding, a significant number of placentas in the PE group failed to show noteworthy ischaemic or other morphological changes that could explain the role of the placenta in the development of PE.

Cystatin C, beta-2-microglobulin and beta-trace protein in pre-eclampsia.

Background. An altered renal function is an essential component of the patho‐physiology of pre‐eclampsia. The plasma levels of low molecular mass proteins, e.g. β‐trace protein, β‐2‐microglobulin and cystatin C, are increased in the third trimester of normal pregnancy. The plasma levels of cystatin C and β‐2‐microglobulin are further increased in pre‐eclampsia, and the cystatin C level has been reported to be a reliable marker for the disease. The aim of this investigation was to study the plasma levels of β‐trace protein, β‐2‐microglobulin and cystatin C in pre‐eclampsia, and to determine the diagnostic performance of these proteins compared to that of urate and creatinine. Methods. A case‐control study of 57 women diagnosed with pre‐eclampsia, and 218 healthy women with uncomplicated singleton pregnancies in the third trimester. Women in the catchment area of Lund, Sweden, were included during an 18‐month period from October 2003 to April 2005. Venous blood samples were drawn upon inclusion when diagnosis was made. The maternal plasma concentrations of the 3proteins were analysed by automated particle‐enhanced immunoturbidimetric assays. Results. The plasma levels of the 3 proteins were significantly higher in the third trimester of pre‐eclamptic patients compared to healthy pregnant women in the third trimester. The upper reference limits (parametric 97.5 percentile) were 2.57mg/l for β‐2‐microglobulin, 0.72mg/l for β‐trace protein and 1.37mg/l for cystatin C. ROC analysis showed similar diagnostic performance for the 3 proteins, with β‐trace protein displaying the best diagnostic performance of all the analytes. Conclusions. In this study, the maternal plasma levels of β2‐microglobulin, β‐trace protein and cystatin C were all significantly elevated in pre‐eclampsia compared to those of healthy pregnant women, and displayed similar diagnostic performance for diagnosing pre‐eclampsia. The results indicate that low molecular mass proteins are useful as markers of renal impairment in pre‐eclampsia.