John M. Davison

New Aspects in the Pathophysiology of Preeclampsia

Preeclampsia, the de novo occurrence of hypertension and proteinuria after the 20th week of gestation, continues to exert an inordinate toll on mothers and children alike. Recent clinical trials, new physiologic insights, and novel observations on pathogenesis have altered the thinking about preeclampsia. The mechanisms surrounding relaxin and its effects on the circulation and on matrix metalloproteinases have been elucidated. The growth factors receptor, fms-like tyrosine kinase 1, has been shown to exist in a soluble form that is able to inactivate vascular endothelial-derived growth factor and human placental growth factor. Compelling evidence has been brought forth suggesting that fms-like tyrosine kinase 1 is a circulating factor that can cause preeclampsia. Preeclamptic women have high circulating levels of asymmetric dimethyl arginine that could account for the generalized endothelial dysfunction observed in preeclampsia. Preeclamptic women also produce novel autoantibodies that may serve to activate angiotensin receptors. These new observations raise the possibility that the treatment of preeclamptic women will soon be improved.

Dialysis, Transplantation, and Pregnancy

Women on regular dialysis are usually infertile, but contraception should not be neglected. Pregnancy is invariably complicated and poses excessive risks, with an uncertain and low chance of success. Even when therapeutic abortion is excluded, the live birth outcome at best is 19%. Renal transplantation usually reverses abnormal reproductive function and comprehensive pre-pregnancy counseling is essential, with discussion of all implications, including the harsh realities of long-term maternal survival. In this survey of 2,309 pregnancies in 1,594 women, therapeutic abortion was undertaken in 27% of conceptions and the spontaneous abortion rate was 13%. Of the conceptions that continued beyond the first trimester, 92% ended successfully. In most, renal function was augmented in pregnancy, with transient deterioration in late pregnancy (with or without proteinuria). Permanent renal impairment occurred in 15% of pregnancies. There was a 30% chance of developing hypertension, preeclampsia or both. Preterm delivery occurred in 50%, and intrauterine growth retardation in 25% of pregnancies. Despite its pelvic location, the transplanted kidney rarely produced dystocia and was not injured during vaginal delivery. Cesarean section should be reserved for obstetric reasons only. Neonatal complications include respiratory distress syndrome, leukopenia, thrombocytopenia, adrenocortical insufficiency, and infection. No predominant or frequent developmental abnormalities have been described and data on infancy and childhood are encouraging. For the future more work is needed to improve pre-pregnancy assessment criteria, to understand the mechanisms of gestational renal dysfunction and proteinuria, to assess the side effects and implications of immunosuppression in pregnancy, and to elucidate the remote effects of pregnancy on both renal prognosis and the offspring.

Chronic kidney disease in pregnancy

Pregnant women with chronic renal disease adapt poorly to a gestational increase in renal blood flow. This may accelerate their decline in renal function and lead to a poor pregnancy outcome

Pregnancy following renal transplantation

Pregnancy is not contraindicated in renal transplant recipients with stable renal function, and a successful and healthy obstetric outcome can be expected in 95% of such cases. The incidence of both maternal and fetal complications is related to the degree of graft dysfunction and/or hypertension prior to pregnancy. Poorer prognosis is associated with poorer renal function. If complications (usually hypertension, renal deterioration, and/or rejection) occur before 28 weeks, then successful obstetric outcome is reduced by 20%. More information is needed about the intrauterine effects and neonatal consequences of maternal immunosuppression, which appears harmless at maintenance levels. From the data available it seems that pregnancy does not compromise long‐term transplant prognosis. In the absence of prospective controlled studies transplant pregnancy registries are the only viable means of providing clinicians with timely and relevant information on pregnancy outcomes on which to base management guidelines.

Immunosuppression in pregnancy: Choices for infant and maternal health

Successful pregnancy outcomes are possible after all types of solid organ transplantation and thousands of successful pregnancies in such women have been reported. As immunosuppressive medications are required to maintain adequate graft and maternal survival, major concerns are the effect of these agents on the fetus and the effect of pregnancy on the well being of mother and graft, against a background of continuing advances and modifications in immunosuppressive therapy.Women should avoid unnecessary medications during pregnancy but clinicians worry most about teratogens; agents (environmental, pharmaceuticals or other chemicals) that cause abnormal development, whether this be an overt structural birth defect or more subtle derangements of embryonic or fetal development. A concern is that any agent or combination of agents and maternal condition(s) may be teratogenic, a risk that is increased in the transplant population. The goal of immunosuppression is to ensure graft and patient survival by preventing acute rejection. Combinations of agents allow for synergistic effects while minimising drug toxicities. No specific combination has been deemed optimal and the effects of more recently available combinations require further study.Although there are known theoretical risks to mother and fetus, successful pregnancies are now the rule in transplant recipients. This is without an apparent increase in the type or incidence of malformations in the newborns, and usually with no evidence of graft dysfunction and/or irreversible deterioration either related to prepregnancy graft problems or unpredictable gestational factors.For immunosuppression, what is best for the mother and her survival should ensure the best outcome for the fetus and, although no specific malformation pattern has been reported to date, there are some interesting trends worthy of continued analyses. A balance of good maternal and graft outcome with the lowest risk of fetal toxicity must be the goal of management.

Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes.

Successful pregnancy outcomes are possible after solid organ transplantation. While there are risks to mother and fetus, there has not been an increased incidence of malformations noted in the newborn of the transplant recipient. It is essential that there is closely coordinated care that involves the transplant team and an obstetrician in order to obtain a favourable outcome.Current data from the literature, as well as from reports from the National Transplantation Pregnancy Registry (NTPR), support the concept that immuno suppression be maintained at appropriate levels during pregnancy. At present, most immunosuppressive maintenance regimens include combination therapy, usually cyclosporin or tacrolimus based. Most female transplant recipients will be receiving maintenance therapy prior to and during pregnancy. For some agents, including monoclonal antibodies and mycophenolate mofetil, there is either no animal reproductive information or there are concerns about reproductive safety.The optimal (lowest risk) transplant recipient can be defined by pre-conception criteria which include good transplant graft function, no evidence of rejection, minimum 1 to 2 years post-transplant and no or well controlled hypertension. For these women pregnancy generally proceeds without significant adverse effects on mother and child.It is of note that the epidemiological data available to date on azathioprine-based regimens are favourable in the setting of a category D agent (i.e. one that can cause fetal harm). Thus, there is still much to learn regarding potential toxicities of immunosuppressive agents. The effect of improved immunosuppressive regimens which use newer or more potent (and potentially more toxic) agents will require further study.

Pregnancy after transplantation

The National Transplantation Pregnancy Registry (NTPR) was established in 1991 to study the outcomes of pregnancies in female transplant recipients and pregnancies fathered by male transplant recipients. Data from the NTPR have helped to endorse the reassurances from publications of smaller experiences that successful pregnancies are possible in the transplant population. In our last review for this journal (2000), we noted that important future issues would include the reassessment of prepregnancy guidelines, gestational and organ-specific problems, the role of new immunosuppressive drugs, and the long-term effects of pregnancy on both graft and child. Data collected by the NTPR over the last 7 years have addressed these issues, thus providing additional information for health care providers of transplant recipients of childbearing age. There has been some refinement of prepregnancy guidelines, but there is a need for additional data collection so that organ-specific outcomes and risks can further be identified. To date, the outcomes of the children followed have been encouraging, and specific remote effects have not been identified, but continued surveillance is still vital. Of special concern are the new immunosuppressive drugs, specifically for mycophenolate mofetil (CellCept, Roche Laboratories Inc., Nutley, New Jersey), where data reported to the NTPR and through postmarketing surveillance have shown an increased incidence of nonviable outcomes and a specific pattern and increased incidence of malformation in the newborn, which has resulted in a pregnancy category change. Newer information points to an increased need for vigilance among centers and continued monitoring of pregnancy outcomes in this population. As the first reported pregnancy after transplantation occurred in a kidney recipient 50 years ago, in March 1958, this review also highlights the first reported pregnancies in other solid organ recipients.

Glomerular Ultrafiltration in Normal and Preeclamptic Pregnancy

GFR and renal plasma flow (RPF) decrease in preeclampsia, a serious hypertensive complication of pregnancy. Serial data derived in late pregnancy (LP) and >5 mo postpartum (PP) in 13 healthy controls and 10 preeclamptic women (13 and 5, respectively) returning PP for theoretical analysis of neutral dextran sieving curves (theta(D)), are presented and are used to calculate the key determinants of glomerular ultrafiltration. Normal LP hyperfiltration was associated with increases in RPF and the ultrafiltration coefficient (K(f)), as well as in the nondiscriminatory shunt pathway (omega(0)) and the SD of pore size (S). Preeclamptic LP showed the largest omega(0) and S values, indicating a loss of size-selectivity, accompanying reduced K(f) and RPF, both of which are implicated in the relative hypofiltration. Despite a 100-fold increase in urinary albumin excretion (UAE), LP preeclamptic theta(D) values were reduced for the equivalent neutral dextran (36A), providing indirect evidence for a loss of glomerular barrier charge-selectivity. All the determinants of GFR and all modeled parameters were comparable across both groups PP, strong evidence that preeclamptic glomerular dysfunction resolves.

Etiology of Non–Cystic Fibrosis Bronchiectasis in Adults and Its Correlation to Disease Severity

RATIONALE Testing for underlying etiology is a key part of bronchiectasis management, but it is unclear whether the same extent of testing is required across the spectrum of disease severity. OBJECTIVES The aim of the present study was to identify the etiology of bronchiectasis across European cohorts and according to different levels of disease severity. METHODS We conducted an analysis of seven databases of adult outpatients with bronchiectasis prospectively enrolled at the bronchiectasis clinics of university teaching hospitals in Monza, Italy; Dundee and Newcastle, United Kingdom; Leuven, Belgium; Barcelona, Spain; Athens, Greece; and Galway, Ireland. All the patients at every site underwent the same comprehensive diagnostic workup as suggested by the British Thoracic Society. MEASUREMENTS AND MAIN RESULTS Among the 1,258 patients enrolled, an etiology of bronchiectasis was determined in 60%, including postinfective (20%), chronic obstructive pulmonary disease related (15%), connective tissue disease related (10%), immunodeficiency related (5.8%), and asthma related (3.3%). An etiology leading to a change in patients management was identified in 13% of the cases. No significant differences in the etiology of bronchiectasis were present across different levels of disease severity, with the exception of a higher prevalence of chronic obstructive pulmonary disease-related bronchiectasis (P < 0.001) and a lower prevalence of idiopathic bronchiectasis (P = 0.029) in patients with severe disease. CONCLUSIONS Physicians should not be guided by disease severity in suspecting specific etiologies in patients with bronchiectasis, although idiopathic bronchiectasis appears to be less common in patients with the most severe disease.

Assessment of glomerular filtration rate during pregnancy using the MDRD formula

It is now recommended practice to use estimated glomerular filtration rate (eGFR) values to screen for and monitor chronic renal disease. The most frequently used formula in the general population is that described following the Modification of Diet in Renal Disease (MDRD) study whereby serum creatinine is adjusted for age, gender and race. This study evaluates the performance of the MDRD formula in pregnancy by comparing eGFR with measured values obtained by inulin clearance studies in early and late normal pregnancy and in pregnancies complicated by renal disease or pre‐eclampsia. Our results indicate that in all situations, MDRD substantially underestimates glomerular filtration rate during pregnancy and cannot be recommended for use in clinical practice.