Assessing Nephrology Fellows' Skills in Communicating About Kidney Replacement Therapy and Kidney Biopsy: A Multicenter Clinical Simulation Study on Breaking Bad News.

RATIONALE & OBJECTIVE: Interpersonal communication skills and professionalism competencies are difficult to assess among nephrology trainees. We developed a formative "Breaking Bad News" simulation and implemented a study in which nephrology fellows were assessed with regard to their skills in providing counseling to simulated patients confronting the need for kidney replacement therapy (KRT) or kidney biopsy. STUDY DESIGN: Observational study of communication competency in the setting of preparing for KRT for kidney failure, for KRT for acute kidney injury (AKI), or for kidney biopsy. SETTING & PARTICIPANTS: 58 first- and second-year nephrology fellows assessed during 71 clinical evaluation sessions at 8 training programs who participated in an objective structured clinical examination of simulated patients in 2017 and 2018. PREDICTORS: Fellowship training year and clinical scenario. OUTCOME: Primary outcome was the composite score for the "overall rating" item on the Essential Elements of Communication-Global Rating Scale 2005 (EEC-GRS), as assessed by simulated patients. Secondary outcomes were the score for EEC-GRS "overall rating" item for each scenario, score < 3 for any EEC-GRS item, Mini-Clinical Examination Exercise (Mini-CEX) score < 3 on at least 1 item (as assessed by faculty), and faculty and fellow satisfaction with simulation exercise (via a survey they completed). ANALYTICAL APPROACH: Nonparametric tests of hypothesis comparing performance by fellowship year (primary goal) and scenario. RESULTS: Composite scores for EEC-GRS overall rating item were not significantly different between fellowship years (P = 0.2). Only 4 of 71 fellow evaluations had an unsatisfactory score for the EEC-GRS overall rating item on any scenario. On Mini-CEX, 17% scored < 3 on at least 1 item in the kidney failure scenario; 37% and 53% scored < 3 on at least 1 item in the AKI and kidney biopsy scenarios, respectively. In the survey, 96% of fellows and 100% of faculty reported the learning objectives were met and rated the experience good or better in 3 survey rating questions. LIMITATIONS: Relatively brief time for interactions; limited familiarity with and training of simulated patients in use of EEC-GRS. CONCLUSIONS: The fellows scored highly on the EEC-GRS regardless of their training year, suggesting interpersonal communication competency is achieved early in training. The fellows did better with the kidney failure scenario than with the AKI and kidney biopsy scenarios. Structured simulated clinical examinations may be useful to inform curricular choices and may be a valuable assessment tool for communication and professionalism.

Circulating Levels of sFlt1 Splice Variants as Predictive Markers for the Development of Preeclampsia.

Angiogenic biomarkers, including soluble fms-like tyrosine kinase 1 (sFlt1), are thought to be predictors of preeclampsia onset; however, improvement is needed before a widespread diagnostic test can be utilized. Here we describe the development and use of diagnostic monoclonal antibodies specific to the two main splice variants of sFlt1, sFlt1-1 and sFlt1-14. These antibodies were selected for their sensitivity and specificity to their respective sFlt1 isoform in a capture ELISA format. Data from this pilot study suggest that sFlt1-1 may be more predictive of preeclampsia than total sFlt1. It may be possible to improve current diagnostic platforms if more specific antibodies are utilized.

Gestational angiogenic biomarker patterns in high risk preeclampsia groups.

OBJECTIVE: Several conditions are associated with increased preeclampsia (PE) risk. Whether altered maternal angiogenic factor levels contribute to risk in these conditions is unknown. Our objective was to compare angiogenic biomarker patterns in high-risk pregnancies and low-risk controls. STUDY DESIGN: We conducted a planned secondary analysis of a 2-center observational study of angiogenic biomarkers in high-risk women. A total of 156 pregnant women with a PE risk factor and 59 low-risk controls were studied. Serial maternal serum samples were collected during 3 gestational windows: 23-27 weeks, 28-31 weeks, and 32-35 weeks. Soluble fms-like tyrosine kinase 1 (sFlt1), soluble endoglin (sEng), and placental growth factor (PlGF) were measured by enzyme-linked immunosorbent assay. Geometric mean angiogenic biomarker levels and angiogenic ratio (sFlt1 + sEng):PlGF were compared with low-risk controls for each risk group, at each gestational window. RESULTS: Gestational biomarker patterns differed in PE risk groups as compared with low-risk controls. Women with multiple gestations had markedly higher sFlt1 and sEng at all gestational windows. Women with prior PE had higher sFlt1 and angiogenic ratio, and lower PlGF, from 28 weeks onward. Women with chronic hypertension had significantly higher angiogenic ratio for all 3 gestational windows, but differences disappeared when women with PE were excluded. Obese and nulliparous women had significantly lower PlGF, but no differences in the angiogenic ratio. CONCLUSION: High-risk groups have altered angiogenic biomarker patterns compared with controls, suggesting that altered production or metabolism of these factors may contribute to PE risk, particularly in women with multiple gestations and prior PE.

Pregnancy and the kidney.

Nephrologists are frequently called on to diagnose and treat renal disorders in pregnant women. In this review, we update recent literature pertinent to pregnancy and renal disease. We initially begin by describing the application of common clinical estimators of GFR and proteinuria in pregnancy and then summarize recent studies regarding pregnancy in women with chronic kidney disease and the latest information on the use of common renal medications in pregnancy. In the final section, we describe advances in our understanding of the pathophysiology of preeclampsia and the potential clinical implications of these discoveries for screening, prevention, and treatment of preeclampsia.

Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.

BACKGROUND: Alterations in circulating soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and placental growth factor (PlGF), a proangiogenic protein, appear to be involved in the pathogenesis of preeclampsia. Since soluble endoglin, another antiangiogenic protein, acts together with sFlt1 to induce a severe preeclampsia-like syndrome in pregnant rats, we examined whether it is associated with preeclampsia in women. METHODS: We performed a nested case-control study of healthy nulliparous women within the Calcium for Preeclampsia Prevention trial. The study included all 72 women who had preterm preeclampsia (<37 weeks), as well as 480 randomly selected women--120 women with preeclampsia at term (at > or =37 weeks), 120 women with gestational hypertension, 120 normotensive women who delivered infants who were small for gestational age, and 120 normotensive controls who delivered infants who were not small for gestational age. RESULTS: Circulating soluble endoglin levels increased markedly beginning 2 to 3 months before the onset of preeclampsia. After the onset of clinical disease, the mean serum level in women with preterm preeclampsia was 46.4 ng per milliliter, as compared with 9.8 ng per milliliter in controls (P<0.001). The mean serum level in women with preeclampsia at term was 31.0 ng per milliliter, as compared with 13.3 ng per milliliter in controls (P<0.001). Beginning at 17 weeks through 20 weeks of gestation, soluble endoglin levels were significantly higher in women in whom preterm preeclampsia later developed than in controls (10.2 ng per milliliter vs. 5.8 ng per milliliter, P<0.001), and at 25 through 28 weeks of gestation, the levels were significantly higher in women in whom term preeclampsia developed than in controls (8.5 ng per milliliter vs. 5.9 ng per milliliter, P<0.001). An increased level of soluble endoglin was usually accompanied by an increased ratio of sFlt1:PlGF. The risk of preeclampsia was greatest among women in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone. CONCLUSIONS: Rising circulating levels of soluble endoglin and ratios of sFlt1:PlGF herald the onset of preeclampsia.

Circulating angiogenic factors in singleton vs multiple-gestation pregnancies.

OBJECTIVE: Placental soluble fms-like tyrosine kinase-1 may contribute to the pathogenesis of preeclampsia. Here we describe alterations in serum angiogenic factor levels in women with multiple gestation pregnancies, a major preeclampsia risk factor. STUDY DESIGN: We collected serial serum specimens from 101 pregnant women at high preeclampsia risk between 22 and 36 weeks' gestation. Soluble fms-like tyrosine kinase-1 and placental growth factor were measured by enzyme-linked immunosorbent assay. Women who had preeclampsia or gestational hypertension develop were excluded. RESULTS: Maternal soluble fms-like tyrosine kinase-1 was higher in multiple gestation (n = 20) compared with high-risk singleton (n = 81) pregnancies for each gestational age range examined. Maternal placental growth factor was significantly higher in multiple vs high-risk singletons before 31 weeks' gestation, whereas the soluble fms-like tyrosine kinase-1/placental growth factor ratio was higher in multiple vs high-risk singletons after 27 weeks. CONCLUSION: Alterations in circulating angiogenic factors are present in women with multiple gestations and may contribute to higher preeclampsia risk in this population.

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.

Circulating angiogenic factors and the risk of preeclampsia.

BACKGROUND: The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. METHODS: We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. RESULTS: During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. CONCLUSIONS: Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia.

Angiogenic factors for the prediction of preeclampsia in high-risk women.

OBJECTIVE: The objective of the study was to evaluate angiogenic factors for the prediction of preeclampsia in high-risk women. STUDY DESIGN: We collected serial serum specimens from 94 women at high preeclampsia risk between 22 and 36 weeks' gestation. Soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) were measured by enzyme-linked immunosorbent assay. RESULTS: Mean serum sFlt1 and the sFlt1/PlGF ratio were higher in subjects who developed early-onset (less than 34 weeks) preeclampsia, as compared with subjects without preeclampsia, from 22 weeks gestation onward. In subjects who developed late-onset (34 weeks or later) preeclampsia, sFlt1 was significantly increased after 31 weeks' gestation. The sFlt1/PlGF ratio at 22-26 weeks was highly predictive of early-onset preeclampsia. The within-woman rate of change of the sFlt1/PlGF ratio was predictive of overall preeclampsia risk. CONCLUSIONS: In high-risk women, serum sFlt1 and the sFlt1:PlGF ratio are altered prior to preeclampsia onset and may be predictive of preeclampsia. Larger studies are needed to confirm these findings.

Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women.

OBJECTIVE: The purpose of this study was to determine whether serum fms-like tyrosine kinase 1 (sFlt1) concentration during preeclampsia were associated with mid trimester blood pressure, other maternal characteristics, or pregnancy outcomes. STUDY DESIGN: We performed a nested case-control study within the Calcium for Preeclampsia Prevention study cohort. Each woman with preeclampsia (case) was matched to 1 normotensive control. A total of 120 pairs of women was chosen randomly. Serum concentrations of sFlt1 and placental growth factor were measured throughout pregnancy, but before labor and delivery. We focused on data from 40 women with blood specimens that were obtained after the onset of preeclampsia. After logarithmic transformation, we determined mean serum sFlt1 concentrations of all control specimens within gestational age windows during which case specimens had been obtained after the onset of preeclampsia. Within each of these gestational age windows, we computed an upper bound for the control specimens equal to 2 standard deviations above the mean. After the onset of preeclampsia, 16 women with log-transformed serum sFlt1 values greater than the upper bound of the control specimens were considered to have high preeclampsia serum sFlt1 levels. The 24 other women were considered to have low preeclampsia serum sFlt1 levels. RESULTS: Women with high or low concentrations of serum sFlt1 during preeclampsia (arithmetic means, 5746 and 3007 pg/mL, respectively) had similar pregnancy outcomes and similar maternal characteristics, except for blood pressure at Calcium for Preeclampsia Prevention study enrollment. Systolic and diastolic blood pressure at enrollment at 13 to 21 weeks of gestation were significantly higher in the 24 women with low serum sFlt1 concentrations during preeclampsia (systolic blood pressure, 114 mm Hg; diastolic blood pressure, 65 mm Hg) than in the 16 women who had preeclampsia at high serum sFlt1 concentrations (systolic blood pressure, 106 mm Hg; diastolic blood pressure, 59 mm Hg). Blood pressure at 13 to 21 weeks among the women with high preeclampsia serum sFlt1 concentrations was identical to the blood pressure among normotensive control subjects. In linear regression analyses of data from all 40 women, both systolic (P < .0001) and diastolic (P = .014) blood pressures at enrollment were correlated negatively with natural logarithm serum sFlt1 concentration after onset of preeclampsia. CONCLUSION: Women with higher mid trimester blood pressure had preeclampsia at lower serum sFlt1 concentrations. Because higher blood pressure may reflect occult endothelial damage, these observations may explain increased susceptibility to preeclampsia among women with pre-existing vascular disease.

Quality of life and dialysis decisions in critically ill patients with acute renal failure.

OBJECTIVE: To determine whether health-related quality of life (HRQL) in survivors of acute renal failure (ARF) occurring in intensive care is predictable from data available at the time of acute illness. DESIGN AND SETTING: Prospective pilot study in academic intensive care units. PATIENTS AND METHODS: Patients requiring renal replacement therapy for ARF while in intensive care over a 6-month enrollment period were included. The primary outcome measure was HRQL among survivors 6 months following hospital discharge, as assessed by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), and its association with Acute Physiology and Chronic Health Evaluation (APACHE) III score. We also asked survivors whether, in retrospect, they would choose to have dialysis again and what factors influenced this decision. RESULTS: Ninety-two percent (12/13) of participants surviving 6 months completed the follow-up interview. The mean mental and physical components of the SF-36 were comparable to and slightly lower than the age-matched general population, respectively. There was no correlation between APACHE III score at the time of dialysis initiation and SF-36 score at 6 months. Almost all patients, regardless of their HRQL, stated they would choose dialysis again. CONCLUSIONS: HRQL may not be predictable from data available at the time of dialysis initiation in this population. In retrospect, surviving patients agree with the decision to accept dialysis, even when their HRQL is poor.

Angiogenic biomarkers for prediction of early preeclampsia onset in high-risk women.

OBJECTIVE: Chronic hypertension, pregestational diabetes mellitus, history of prior preeclampsia and obese nulliparity are maternal conditions associated with increased preeclampsia risk. Whether altered maternal angiogenic factor levels allow for prediction of pending disease is unclear. Our objective was to evaluate angiogenic factors for early preeclampsia prediction in high-risk women. METHODS: Serial serum specimens were collected from 157 women at high preeclampsia risk and 50 low-risk controls between 23 and 36 weeks gestation in 3 windows (23-27.6, 28-31.6, and 32-35.6 weeks) in a two-center observational cohort. Soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) were measured by ELISA. RESULTS: Multivariate parsimonious logistic regression analyses using backward elimination for prediction of early-preeclampsia (diagnosed < 34 weeks) found the best-fitting model included the predictors (1) sFlt1 measured in the second window (28-31.6 weeks) with AUC 0.85, sensitivity 67% and specificity 96% and (2) sFlt1 measured in the first window (23-27.6 weeks) and sEng change between first and second window with AUC 0.91, sensitivity 86% and specificity 96%. CONCLUSIONS: Two-stage sampling screening protocol utilizing sFlt1 and sEng is promising for prediction of preeclampsia diagnosed before 34 weeks. Larger studies are needed to confirm these findings.

Angiogenic biomarkers for prediction of maternal and neonatal complications in suspected preeclampsia.

OBJECTIVE: To determine if maternal serum angiogenic factors predict maternal and neonatal complications in women presenting to an acute care setting with suspected preeclampsia. STUDY DESIGN: Maternal serum samples were prospectively collected from women with suspected preeclampsia at the time of initial presentation to hospital triage with signs or symptoms of preeclampsia. Soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin (sEng) were measured by ELISA. The primary outcome was a composite of maternal and neonatal complications. RESULTS: Of 276 women with suspected preeclampsia, 78 developed maternal or neonatal complications. Among women presenting prior to 37 weeks gestation, sFlt1, PlGF, and sEng were significantly different in women who developed maternal and neonatal complications as compared to women without complications. Higher levels of sFlt1, sEng, and the sFlt1:PlGF ratio were associated with an increased odds of complications among women presenting prior to 37 weeks. A multivariable model combining the sFlt1:PlGF ratio with clinical variables was more predictive of complications (AUC 0.91, 95% CI 0.85-0.97) than a model using clinical variables alone (AUC 0.82, 95% CI 0.79-0.90). CONCLUSION: Angiogenic biomarkers associate with maternal and neonatal complications in women with suspected preeclampsia, and may be useful for risk stratification.

Acute kidney injury in pregnancy: the thrombotic microangiopathies.

Acute kidney injury (AKI) is a rare but serious complication of pregnancy. Although prerenal and ischemic causes of AKI are most common, renal insufficiency can complicate several other pregnancy-specific conditions. In particular, severe preeclampsia/HELLP syndrome, acute fatty liver of pregnancy (AFLP) and thrombotic thrombocytopenic purpura (TTP) are all frequently complicated by AKI, and share several clinical features which pose diagnostic challenges to the clinician. In this article, we discuss the clinical and laboratory features, pathophysiology and treatment of these 3 conditions, with particular attention to renal manifestations. It is imperative to distinguish these conditions to make appropriate therapeutic decisions which can be lifesaving for the mother and fetus. Typically AFLP and HELLP improve after delivery of the fetus, whereas plasma exchange is the first-line treatment for TTP.

Angiogenic factors and preeclampsia.

Preeclampsia, a hypertensive disorder peculiar to pregnancy, is a systemic syndrome that appears to originate in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of phenotypic preeclampsia was largely unknown, but recent observations support the hypothesis that altered expression of placental anti-angiogenic factors are responsible for the clinical manifestations of the disease. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These anti-angiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and as of 2011 the role of angiogenic proteins in early placental vascular development was starting to be explored. The data linking angiogenic factors to preeclampsia have exciting clinical implications, and likely will transform the detection and treatment of preeclampsia.

Soluble endoglin for the prediction of preeclampsia in a high risk cohort.

OBJECTIVES: To evaluate soluble endoglin (sEng) and the soluble fms-like tyrosine kinase 1 (sFlt1) to placental growth factor (PlGF) ratio for the prediction of preeclampsia in high-risk women, and to evaluate differences in sEng between women with high-risk singleton and multiple gestation pregnancies. STUDY DESIGN: We collected serial serum specimens from 119 women at high preeclampsia risk. sEng, sFlt1 and PlGF were measured by ELISA. RESULTS: Among subjects who did not develop preeclampsia, mean serum sEng was significantly higher in those with multiple gestation pregnancies vs. high-risk singletons. Among women with singleton gestations, mean serum sEng was higher in subjects who developed early-onset (<34 weeks) and late-onset (>or= 34 weeks) preeclampsia, as compared with subjects without preeclampsia, from 22 weeks and 28 weeks gestation onward, respectively. The within-woman rate of change of sEng was also higher in women who later developed preeclampsia. CONCLUSIONS: sEng is higher in women with multiple gestations vs. high-risk singleton pregnancies. In high-risk women, serum sEng is increased prior to preeclampsia onset.

Misapplications of commonly used kidney equations: renal physiology in practice.

Equations for estimating GFR, quantifying urinary protein excretion, and assessing renal sodium handling are widely used in routine nephrology and general medical and surgical practice. If these equations are applied in circumstances inconsistent with the clinical situations for or extrapolated beyond the limits in which they were validated, clinicians can come to erroneous conclusions, which could be detrimental for patient care. This review uses clinical vignettes to demonstrate some of the common pitfalls that clinicians may encounter in the use of these equations and considers the physiologic principles underlying their use. Equations for assessing aspects of renal function should only be used in specific clinical situations, if the underlying assumptions regarding their calculations and values are satisfied.

Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia.

Preeclampsia, a pregnancy-specific syndrome of hypertension and proteinuria, is characterized by defective placental vasculogenesis and widespread maternal endothelial dysfunction. Although the manifestations of preeclampsia are primarily maternal, the burden of morbidity and mortality is often on the neonate, since the only effective treatment-delivery of the fetus and placenta-often results in iatrogenic prematurity. In this review, we summarize recent advances in our understanding of the pathophysiology of preeclampsia, including normal and aberrant placental vascular development and evidence for endothelial dysfunction. We describe recent evidence that supports a novel mechanism in which a maladaptive shift in placental production of angiogenic factors such as soluble fms-like tyrosine kinase 1 (a circulating antiangiogenic protein) may play an important role in the pathogenesis of preeclampsia.

Preeclampsia: a renal perspective.

Preeclampsia is a syndrome that affects 5% of all pregnancies, producing substantial maternal and perinatal morbidity and mortality. The aim of this review is to summarize our current understanding of the pathogenesis of preeclampsia with special emphasis on the recent discovery that circulating anti-angiogenic proteins of placental origin may play an important role in the pathogenesis of proteinuria and hypertension of preeclampsia.