Mechanisms of renal vasodilation and hyperfiltration during pregnancy

Glomerular filtration rate (GFR) and renal plasma flow (RPF) increase by 40-65% and 50-85%, respectively, during normal pregnancy in women. Studies using the gravid rat as a model have greatly enhanced our understanding of mechanisms underlying these remarkable changes in the renal circulation during gestation. Hyperfiltration appears to be almost completely due to the increase in RPF, the latter attributable to profound reductions in both the renal afferent and efferent arteriolar resistances. The major pregnancy hormone involved is relaxin. The mediators downstream from relaxin include endothelin (ET) and nitric oxide (NO). New evidence indicates that relaxin increases vascular gelatinase activity during pregnancy, thereby converting big ET to ET(1-32), which leads to renal vasodilation, hyperfiltration, and reduced myogenic reactivity of small renal arteries via the endothelial ET(B) receptor and NO. Whether the chronic volume expansion characteristic of pregnancy contributes to the maintenance of gestational renal changes requires further investigation. Additional studies are also needed to further delineate the molecular basis of these mechanisms and, importantly, to investigate whether they apply to women.     

Allograft enhancement during normal murine pregnancy

The immunizing effect of pregnancy was assessed using the cardiac allograft technique to estimate maternal reactivity against paternal antigens. In this study the following immunological activities were observed in pregnant or post partum mice. Cardiac allografts expressing paternal antigens were accepted in pregnant or post partum mice longer than in virgin recipients. The cardiac allograft enhancing effect was strain specific, was directly transferable by maternal lymphoid cells but not serum and could be shown to remain in effect in post partum female mice for at least five weeks after delivery.     

Systemic lupus erythematosus. Management during pregnancy.

The course of 27 pregnancies in 13 patients with systemic lupus erythematosus (SLE) is presented. The overall incidence of fetal wastage was 33.3%, a figure significantly higher than that observed in the general population. Although serum C3 complement levels rise during normal pregnancy, mean C3 levels remain within the normal range. Since it is a fall in complement levels in patients with SLE which may herald the onset of symptoms and provide a guide to therapy, assay of serum C3 complement levels remains a valid monitoring device in management of these patients during pregnancy. Flares of SLE during pregnancy generally should be treated vigorously with corticosteroids rather than by therapeutic abortion. Continuation of corticosteroid treatment during the first 2 months postpartum is advised to limit the incidence of exacerbation of SLE activity following delivery.     

Characterisation of the humoral immune response during murine pregnancy

Blood samples from female C57BL/10 mice mated with CBA/Ca males were obtained before, during and after both first and second pregnancies. A cellular enzyme-linked immunospecific assay (CELISA) was used to detect maternal antibodies against antigens on paternal splenocytes. Alloantibodies were detected in 48% of mice during or 9 days after a first pregnancy and in 82% of mice by the ninth day after the second pregnancy; these antibodies were first observed on day 10 of the first pregnancy. In two of four active multigravid sera tested, an increase in IgG1 concentration was detected; the level of all other isotypes remained within normal limits. Weak binding of alloantibody to an antigen of approximate molecular weight 44,000 was detected on CBA/Ca splenocytes by immunoblotting sera from multiparous animals. These sera also recognised an antigen of similar molecular weight on H-2b identical 129J splenocytes but not on splenocytes from the maternal strain. These results provide further information on the maternal humoral immune response during murine pregnancy.     

Changes in renal volume during normal pregnancy

Twenty-four healthy pregnant women with a normal pregnancy demonstrated a significant uniform enlargement of both kidneys. The renal volumes increased by a maximum of 30% during pregnancy. However, this could not be attributed to hydronephrosis, as the patients were selected in such a way that none with pelvectasia participated in the study. All regained normal renal volume within the first week after delivery. It is well known that a glomerular hyperfiltration takes place during normal pregnancy. Possible pathogenetic mechanisms are discussed.     

GnRHa flare and IVF pregnancy rates.

OBJECTIVES: GnRH agonist administered early in the menstrual cycle (flare) causes an endogenous discharge of FSH and LH. Flare has been used in conjunction with gonadotropin ovarian stimulation for IVF 'poor responders'. There is an ongoing controversy regarding whether flare protocols improve pregnancy rates in 'poor responders'. The current study was designed to compare a GnRHa flare protocol with long suppression GnRHa IVF in 'poor responders'. METHODS: Seventy-three newly diagnosed poor responders who failed long GnRHa suppression IVF attempts were compared retrospectively with 128 age-matched IVF patients previously known poor ovarian responders treated with a long GnRHa suppression protocol. 'Poor responders' consisted of patients with peak E(2) less than 1000 pg/ml and/or less than five mature follicles with diameter >15 mm on the day of hCG administration. Student's t-test was used to analyze the data and the chi-squared test was used to compare fertilization and pregnancy rates. RESULTS: The flare protocol produced higher peak E(2) levels (1647+/-747 vs. 720+/-258 mIU/ml, P<0.05) and a larger number of mature follicles (5.8+/-2.2 vs. 4.0+/-1.0 P<0.05) in the study vs. the control group. A 30% pregnancy rate was achieved during this second IVF attempt using GnRHa flare protocol in the study group vs. 37 in the control group (P>0.05, NS). CONCLUSIONS: A comparison between the flare protocol group and the age-matched control group of poor ovarian responders subject to down regulation protocol, revealed higher peak E(2) levels and more mature follicles, respectively. However, both groups yielded comparable pregnancy rates. The use of high dose gonadotropin treatment in our study groups seems to be the only explanation for their subsequent successful outcome. We concluded that GnRH agonist flare protocol does not result in better IVF outcome compared with long GnRH agonist suppression protocol in IVF poor responders.     

Aging blunts remodeling of the uterine artery during murine pregnancy

OBJECTIVE: The progressive increase in uterine blood flow (UBF) during pregnancy is accommodated by morphologic changes in the uterine artery (UA) in a process defined as arterial remodeling. This process is accompanied by changes in cytoskeletal architecture of the arterial smooth muscle cells (SMCs) and surrounding extracellular matrix (ECM). Aging reduces flow-induced arterial remodeling. We studied changes in the murine UA during pregnancy and on the effects of aging on the capacity of the UA to remodel in response to pregnancy. METHODS: We determined morphologic and cytologic changes in UA from nonpregnant and pregnant mice aged 12 weeks (young) and 40 weeks (old) and correlated them with their reproductive performance. RESULTS: In young mice, pregnancy induced an early increase in UA wall mass, which preceded lumen widening. These changes were not accompanied by altered densities of elastin and collagen in the ECM of the medial layer. Smooth muscle cell proliferation increased in midpregnancy and was paralleled by a transient decrease in smoothelin and smooth muscle alpha-actin expression. In old mice, these pregnancy-dependent changes in the UA wall were either absent or markedly reduced. Although by day 11 of pregnancy litter size did not differ between both age groups, the number of viable pups in old mice by day 17 of pregnancy and at birth was 25% and 60% less than in young mice. CONCLUSION: Outward hypertrophic remodeling of the UA during pregnancy in young mice is characterized by transient phenotypic modulation and proliferation of SMCs and alterations in the composition of the ECM. In contrast, in older mice, UA remodeling is markedly reduced and accompanied with a loss of viable fetuses near term pregnancy.     

Neonatal lupus and IUGR following alpha-interferon therapy during pregnancy.

Interferon alfa-2a is a cytokine produced by recombinant DNA techniques and has antiproliferative, antiviral and immunomodulating effects. A number of case reports in the past have suggested relative safety of alpha-interferons during pregnancy with little or no effect on the fetus. A 15-year-old adolescent became pregnant while receiving alpha-interferon for essential thrombocythemia. She delivered a small-for-gestational age baby girl at 33 weeks gestation. The infant displayed a facial rash characteristic of neonatal lupus and transient thrombocytopenia; maternal and neonatal serologies were typical for drug-induced lupus. These findings suggest probable association between maternal use of alpha interferon and adverse effects in the fetus.     

妊娠合并系统性红斑狼疮患者孕期病情活动的影响因素及其与妊娠结局的关系

目的 探讨妊娠合并系统性红斑狼疮（SLE）患者孕期病情活动的影响因素及其与妊娠结局的关系.方法 对1991年至2005年收治的66例妊娠合并SLE患者的临床资料进行回顾性分析.结果 （1）孕前病情不稳定、孕期新发病及孕期泼尼松用药不规范者均出现SLE病情活动;孕期S比病情活动者32例（活动组）,非活动者34例（非活动组）.（2）活动组患者发生子痫前期9例、胎儿生长受限（FGR）13例、治疗性流产7例和早产15例,非活动组分别为1例、5例、1例和4例,两组分别比较,差异有统计学意义（P均＜0.05）.（3）活动组患者不同器官损伤中,以肾损害对妊娠的影响最大;用logistic回归前进法筛选变量结果显示,肾损害是子痫前期、FGR的独立危险因素.（4）孕期泼尼松用量每天≤15 mg者子痫前期及胎儿丢失发生率分别为4.7%（2/43）及9.3%（4/43）,用量每天≥20 mg者的子痫前期及胎儿丢失发生率分别为33.3%（6/18）及44.4%（8/18）,两者比较,差异有统计学意义（P＜0.01）.结论 孕前SLE比病情不稳定、孕期新发病及孕期泼尼松用药不规范为SLE病情活动的重要影响因素.孕期SLE病情活动特别是肾损害与不良妊娠结局有密切关系.孕期泼尼松用量每天≥20 mg者发生子痫前期及胎儿丢失的几率大于每天≤15 mg者.     

Specific immune tolerance during pregnancy after renal transplantation

Pregnancy is associated with specific immunological tolerance to fetal antigens suggesting that immunoregulatory processes during pregnancy can induce specific immunological unresponsiveness. We report a case of a female renal transplant recipient who stopped immunosuppressive therapy during first pregnancy. Despite histologically proven acute renal allograft rejection during the early course of transplantation, no immunological response was observed for 9 years after withdrawal of immunosuppression. Two further pregnancies within that time period did not evoke any renal complications, but were complicated by premature rupture of the amnion and by the development of preeclampsia. To our knowledge, there are no reports of such a long-term specific unresponsiveness to a renal allograft without immunosuppressive therapy. Natural and active immunoregulatory mechanism can be related for the development of specific immune tolerance to renal allograft in this case.     

Acute renal insufficiency during pregnancy with acute pancreatitis

According to current data the incidence of acute pancreatitis is from 1:1000 to 1:5000. Symptoms vary a lot, one of rare but most severe complications being acute renal failure. The case is a 24-year-old pregnant patients--30-th gestational week with symptoms of acute pancreatitis based most probably on hereditary hypertriglyceridemia and hypercholesterolemia. Parallel to acute inflammation of pancrease a hypercoagulation syndrome developed. It is possible that acute renal failure was caused by active thrombus formation. Because of danger for the life of mother and baby, an urgency preterm Cesarean Section was performed. Resussitation post-surgery care and drug therapy (lowmolecular anticoagulants, antibiotics, spasmolytics and analgetics, protease--inhibitors, inhibitors of protome pump, regulators and inhibitors of pancreas secretion normalize renal and pancreatic function if based on special dietary regimr. Coagulation status also normalizes.     

Blood pressure and renal function during normal pregnancy

In order to obtain reference values during normal pregnancy 24 women with strict criteria for health and normal pregnancy were studied. Greatest interest was focused on blood pressure (BP) measurements and renal function tests. Investigations were made in early second trimester and in the 30th, 33rd and 36th gestational weeks. Gestational age was estimated by ultrasound measurement of crown-rump length before the 14th gestational week. Both systolic and diastolic BP measured in the right arm were about 10 mmHg lower in the left lateral position than when supine or standing. The difference is suggested to be dependent on hydrostatic factors. Diastolic BP should be defined at the fourth phase of the Korotkoff sounds in order to be reliable because of the common phenomenon of late or non-disappearance of the sounds during pregnancy. Diastolic BP in phase IV increased in up to 25% of the cases with 15 mmHg or more from early second trimester to the 36th gestational week in all three positions. Serum creatinine concentration was low in early second trimester and did not change during pregnancy, while serum urea decreased and serum urate increased during pregnancy. The results emphasize the importance of using reference values from a normal pregnant population obtained at different gestational weeks for comparison in studies on certain pathological conditions during pregnancy, especially pre-eclampsia.     

Natural history of fetal cell microchimerism during and following murine pregnancy

In humans, fetal cells enter the maternal circulation during all pregnancies and can persist for decades. Human studies, however, are often limited by the number of subjects and the availability of healthy and diseased tissues for analysis. We sought to develop a murine model to establish the natural history of fetal cell microchimerism in various maternal tissues during and after healthy pregnancies resulting from congenic and allogenic matings. We bred C57BL/6J and DBA/2J virgin female mice to C57BL/6J males transgenic for the enhanced green fluorescent protein (GFP), which shows autosomal dominant inheritance with complete penetrance and is under the control of a ubiquitous chicken beta-actin promoter and a cytomegalovirus enhancer. During pregnancy and at different times after delivery, female mice were sacrificed. Tissues were collected and the presence of the gfp transgene and GFP+ cells was assessed by real-time quantitative PCR and by immunofluorescence. During pregnancy, microchimerism was detected in all tissues from mice carrying GFP+ fetuses. Fetal cells were often mononuclear. The frequency of fetal cells in the lungs was significantly higher compared to other tissues. The level of microchimerism was also significantly higher in congenic compared to allogenic matings. After delivery, the frequency of fetal cells decreased and fetal cells were undetectable at 2 and 3 weeks after the first delivery. However, some mice that had three gestations had detectable fetal cells 3 weeks after their last delivery. Using sensitive methods of detection, we demonstrate that fetal cell microchimerism occurs during all murine pregnancies. We describe a useful model for the study of the consequences of this phenomenon.