Role of the macrophage migration inhibitory factor in the pathophysiology of pre-eclampsia

Proinflammatory cytokines are produced in pregnancy in response to the invading pathogens and/or nonmicrobial causes such as damage-associated molecules and embryonic semi-allogenic antigens. While inflammation is essential for a successful pregnancy, an excessive inflammatory response is implicated in several pathologies including pre-eclampsia (PE). This review focuses on the proinflammatory cytokine macrophage migration inhibitory factor (MIF), a critical regulator of the innate immune response and a major player of processes allowing normal placental development. PE is a severe pregnancy-related syndrome characterized by exaggerated inflammatory response and generalized endothelial damage. In some cases, usually of early onset, it originates from a maldevelopment of the placenta, and is associated with intrauterine growth restriction (IUGR) (placental PE). In other cases, usually of late onset, pre-pregnancy maternal diseases represent risk factors for the development of the disease (maternal PE). Available data suggest that low MIF production in early pregnancy could contribute to the abnormal placentation. The resulting placental hypoxia in later pregnancy could produce high release of MIF in maternal serum typical of placental PE. More studies are needed to understand the role of MIF, if any, in maternal PE

A Systematic Review on Materno-Foetal Outcomes in Pregnant Women with IgA Nephropathy: A Case of “Late-Maternal” Preeclampsia?

Background: IgA nephropathy is the most common primary glomerulonephritis in pregnancy and shares with other immunologic diseases and kidney diseases a relationship with adverse maternal outcomes, whose entity and pattern is only partially quantified. Recent studies provide new information and a systematic review regarded progression of kidney disease. The discussion of the outcomes with respect to low-risk pregnancies may help to perfect the estimation of the risks, and to identify specific research needs. Methods: A search strategy was built on Medline, EMBASE and the Cochrane review for the period January 2000-April 2017, aimed at retrieving both case series (defined as with at least 6 pregnancies in women with IgA nephropathy) and case reports, to look into rare occurrences. All papers, with or without control groups, were selected if they reported on at least one pregnancy outcome, or on long-term kidney function. Search strategy, paper selection and data extraction were done in duplicate (PROSPERO N 42016042623). Meta-analysis of case series was performed with Metanalyst Beta 3.13. Case reports were analysed narratively. Results: The search retrieved 556 papers, of which 27 were included (13 series and 14 case-reports). The case series report on 581 women with 729 pregnancies. The analysis was performed in comparison to the available control groups: 562 non-pregnant controls were available for the analysis of progression of kidney disease. As for pregnancy related outcomes (preeclampsia (PE), pregnancy induced hypertension (PIH), preterm birth, small babies), we meta-analyzed the data with respect to the only series of low-risk pregnancies (1418 pregnancies). When compared with women who never got pregnant after diagnosis of IgA nephropathy, in the present meta-analysis pregnancy in women with IgA nephropathy was not associated with a higher risk of progression of kidney disease, possibly due to the overall preserved kidney function at baseline: end-stage kidney disease (OR 0.68; CI 0.28-1.65). Conversely, the incidence of adverse pregnancy-related outcomes was increased compared to low-risk controls: PE and PIH were more than ten-fold increased (OR 11.80; CI 7.53-18.48 and OR 10.39; CI 5.45-19.80), while the increase in risk of preterm birth and "low birth weight babies" was less marked (OR 3.37; CI 1.91-5.95 and OR 2.36; CI 1.52-3.66), a discrepancy suggesting the occurrence of "late" or "maternal" PE, that may affect less severely foetal growth or shorten gestation. In conclusion, in the present meta-analysis IgA nephropathy was not associated with an increased progression of kidney disease. The more than ten-fold increased risk of PIH and PE, in combination with a doubled risk of small babies, suggests the occurrence of "late" or "maternal" PE, usually less affecting early foetal growth. This finding may be of help in defining control policies, while further research is needed to guide clinical management

Pregnancy, Proteinuria, Plant-Based Supplemented Diets and Focal Segmental Glomerulosclerosis: A Report on Three Cases and Critical Appraisal of the Literature.

Chronic kidney disease (CKD) is increasingly recognized in pregnant patients. Three characteristics are associated with a risk of preterm delivery or small for gestational age babies; kidney function reduction, hypertension, and proteinuria. In pregnancy, the anti-proteinuric agents (ACE–angiotensin converting enzyme-inhibitors or ARBS -angiotensin receptor blockers) have to be discontinued for their potential teratogenicity, and there is no validated approach to control proteinuria. Furthermore, proteinuria usually increases as an effect of therapeutic changes and pregnancy-induced hyperfiltration. Based on a favourable effect of low-protein diets on proteinuria and advanced CKD, our group developed a moderately protein-restricted vegan-vegetarian diet tsupplemented with ketoacids and aminoacids for pregnant patients. This report describes the results obtained in three pregnant patients with normal renal function, nephrotic or sub-nephrotic proteinuria, and biopsy proven diagnosis of focal segmental glomerulosclerosis, a renal lesion in which hyperfiltration is considered of pivotal importance (case 1: GFR (glomerular filtration rate): 103 mL/min; proteinuria 2.1 g/day; albumin 3.2 g/dL; case 2: GFR 86 mL/min, proteinuria 3.03 g/day, albumin 3.4 g/dL; case 3: GFR 142 mL/min, proteinuria 6.3 g/day, albumin 3.23 g/dL). The moderately restricted diet allowed a stabilisation of proteinuria in two cases and a decrease in one. No significant changes in serum creatinine and serum albumin were observed. The three babies were born at term (38 weeks + 3 days, female, weight 3180 g-62th centile; 38 weeks + 2 days, female, weight 3300 g-75th centile; male, 38 weeks + 1 day; 2770 g-8th centile), thus reassuring us of the safety of the diet. In summary, based on these three cases studies and a review of the literature, we suggest that a moderately protein-restricted, supplemented, plant-based diet might contribute to controlling proteinuria in pregnant CKD women with focal segmental glomerulosclerosis. However further studies are warranted to confirm the potential value of such a treatment strategy

Type 1 diabetes, diabetic nephropathy, and pregnancy: a systematic review and meta-study

BACKGROUND: In the last decade, significant improvements have been achieved in maternal-fetal and diabetic care which make pregnancy possible in an increasing number of type 1 diabetic women with end-organ damage. Optimal counseling is important to make the advancements available to the relevant patients and to ensure the safety of mother and child. A systematic review will help to provide a survey of the available methods and to promote optimal counseling. OBJECTIVES: To review the literature on diabetic nephropathy and pregnancy in type 1 diabetes. METHODS: Medline, Embase, and the Cochrane Library were scanned in November 2012 (MESH, Emtree, and free terms on pregnancy and diabetic nephropathy). Studies were selected that report on pregnancy outcomes in type 1 diabetic patients with diabetic nephropathy in 1980-2012 (i.e. since the detection of microalbuminuria). Case reports with less than 5 cases and reports on kidney grafts were excluded. Paper selection and data extraction were performed in duplicate and matched for consistency. As the relevant reports were highly heterogeneous, we decided to perform a narrative review, with discussions oriented towards the period of publication. RESULTS: Of the 1058 references considered, 34 fulfilled the selection criteria, and one was added from reference lists. The number of cases considered in the reports, which generally involved single-center studies, ranged from 5 to 311. The following issues were significant: (i) the evidence is scattered over many reports of differing format and involving small series (only 2 included over 100 patients), (ii) definitions are non-homogeneous, (iii) risks for pregnancy-related adverse events are increased (preterm delivery, caesarean section, perinatal death, and stillbirth) and do not substantially change over time, except for stillbirth (from over 10% to about 5%), (iv) the increase in risks with nephropathy progression needs confirmation in large homogeneous series, (v) the newly reported increase in malformations in diabetic nephropathy underlines the need for further studies. CONCLUSIONS: The heterogeneous evidence from studies on diabetic nephropathy in pregnancy emphasizes the need for further perspective studies on this issue

A best-practice position statement on pregnancy after kidney transplantation: focusing on the unsolved questions. The Kidney and Pregnancy Study Group of the Italian Society of Nephrology

Kidney transplantation (KT) is often considered to be the method best able to restore fertility in a woman with chronic kidney disease (CKD). However, pregnancies in KT are not devoid of risks (in particular prematurity, small for gestational age babies, and the hypertensive disorders of pregnancy). An ideal profile of the potential KT mother includes “normal” or “good” kidney function (usually defined as glomerular filtration rate, GFR ≥ 60 ml/min), scant or no proteinuria (usually defined as below 500 mg/dl), normal or well controlled blood pressure (one drug only and no sign of end-organ damage), no recent acute rejection, good compliance and low-dose immunosuppression, without the use of potentially teratogen drugs (mycophenolic acid and m-Tor inhibitors) and an interval of at least 1–2 years after transplantation. In this setting, there is little if any risk of worsening of the kidney function. Less is known about how to manage “non-ideal” situations, such as a pregnancy a short time after KT, or one in the context of hypertension or a failing kidney. The aim of this position statement by the Kidney and Pregnancy Group of the Italian Society of Nephrology is to review the literature and discuss what is known about the clinical management of CKD after KT, with particular attention to women who start a pregnancy in non-ideal conditions. While the experience in such cases is limited, the risks of worsening the renal function are probably higher in cases with markedly reduced kidney function, and in the presence of proteinuria. Well-controlled hypertension alone seems less relevant for outcomes, even if its effect is probably multiplicative if combined with low GFR and proteinuria. As in other settings of kidney disease, superimposed preeclampsia (PE) is differently defined and this impairs calculating its real incidence. No specific difference between non-teratogen immunosuppressive drugs has been shown, but calcineurin inhibitors have been associated with foetal growth restriction and low birth weight. The clinical choices in cases at high risk for malformations or kidney function impairment (pregnancies under mycophenolic acid or with severe kidney-function impairment) require merging clinical and ethical approaches in which, beside the mother and child dyad, the grafted kidney is a crucial “third element”

International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project

Background: In 2006, WHO produced international growth standards for infants and children up to age 5 years on the basis of recommendations from a WHO expert committee. Using the same methods and conceptual approach, the Fetal Growth Longitudinal Study (FGLS), part of the INTERGROWTH-21st Project, aimed to develop international growth and size standards for fetuses. Methods: The multicentre, population-based FGLS assessed fetal growth in geographically defined urban populations in eight countries, in which most of the health and nutritional needs of mothers were met and adequate antenatal care was provided. We used ultrasound to take fetal anthropometric measurements prospectively from 14 weeks and 0 days of gestation until birth in a cohort of women with adequate health and nutritional status who were at low risk of intrauterine growth restriction. All women had a reliable estimate of gestational age confirmed by ultrasound measurement of fetal crown–rump length in the first trimester. The five primary ultrasound measures of fetal growth—head circumference, biparietal diameter, occipitofrontal diameter, abdominal circumference, and femur length—were obtained every 5 weeks (within 1 week either side) from 14 weeks to 42 weeks of gestation. The best fitting curves for the five measures were selected using second-degree fractional polynomials and further modelled in a multilevel framework to account for the longitudinal design of the study. Findings: We screened 13 108 women commencing antenatal care at less than 14 weeks and 0 days of gestation, of whom 4607 (35%) were eligible. 4321 (94%) eligible women had pregnancies without major complications and delivered live singletons without congenital malformations (the analysis population). We documented very low maternal and perinatal mortality and morbidity, confirming that the participants were at low risk of adverse outcomes. For each of the five fetal growth measures, the mean differences between the observed and smoothed centiles for the 3rd, 50th, and 97th centiles, respectively, were small: 2·25 mm (SD 3·0), 0·02 mm (3·0), and −2·69 mm (3·2) for head circumference; 0·83 mm (0·9), −0·05 mm (0·8), and −0·84 mm (1·0) for biparietal diameter; 0·63 mm (1·2), 0·04 mm (1·1), and −1·05 mm (1·3) for occipitofrontal diameter; 2·99 mm (3·1), 0·25 mm (3·2), and −4·22 mm (3·7) for abdominal circumference; and 0·62 mm (0·8), 0·03 mm (0·8), and −0·65 mm (0·8) for femur length. We calculated the 3rd, 5th 10th, 50th, 90th, 95th and 97th centile curves according to gestational age for these ultrasound measures, representing the international standards for fetal growth. Interpretation: We recommend these international fetal growth standards for the clinical interpretation of routinely taken ultrasound measurements and for comparisons across populations. Funding: Bill & Melinda Gates Foundation