Pregnancy in women with nephrotic-range proteinuria: A retrospective cohort study.

Background: Obstetric and kidney outcomes following detection of nephrotic-range proteinuria in early pregnancy have not been well described. Methods: A retrospective cohort study of chronic kidney disease (CKD) in pregnancy between 2008 and 2018. Outcomes in those with nephrotic-range proteinuria before 20 weeks' gestation were compared to those without nephrotic-range proteinuria. Results: The study included 37 women with nephrotic-range proteinuria and 62 women without. Pre-pregnancy estimated glomerular filtration rate (eGFR) was similar. Nephrotic-range proteinuria was associated with higher rates of preterm (odds ratio [OR] 1.77, 95% confidence interval [CI]: 1.07-2.92) and early preterm delivery (OR 2.63, 95% CI: 1.12-6.2), and with a requirement for renal replacement therapy at 3 years post-partum (OR 10.72, 95% CI: 2.58-44.47). Tubulointerstitial scarring on kidney biopsy was associated with early preterm delivery and progression to advanced CKD, independent of pre-pregnancy eGFR. Conclusion: Compared to CKD without nephrotic-range proteinuria, nephrotic-range proteinuria early in pregnancy is associated with higher rates of pre-term delivery and progression to advanced CKD.

Reassuring pregnancy outcomes in women with mild COL4A3-5-related disease (Alport syndrome) and genetic type of disease can aid personalized counseling.

Individualized pre-pregnancy counseling and antenatal care for women with chronic kidney disease (CKD) require disease-specific data. Here, we investigated pregnancy outcomes and long-term kidney function in women with COL4A3-5 related disease (Alport Syndrome, (AS)) in a large multicenter cohort. The ALPART-network (mAternaL and fetal PregnAncy outcomes of women with AlpoRT syndrome), an international collaboration of 17 centers, retrospectively investigated COL4A3-5 related disease pregnancies after the 20th week. Outcomes were stratified per inheritance pattern (X-Linked AS (XLAS)), Autosomal Dominant AS (ADAS), or Autosomal Recessive AS (ARAS)). The influence of pregnancy on estimated glomerular filtration rate (eGFR)-slope was assessed in 192 pregnancies encompassing 116 women (121 with XLAS, 47 with ADAS, and 12 with ARAS). Median eGFR pre-pregnancy was over 90ml/min/1.73m2. Neonatal outcomes were favorable: 100% live births, median gestational age 39.0 weeks and mean birth weight 3135 grams. Gestational hypertension occurred during 23% of pregnancies (reference: 'general' CKD G1-G2 pregnancies incidence is 4-20%) and preeclampsia in 20%. The mean eGFR declined after pregnancy but remained within normal range (over 90ml/min/1.73m2). Pregnancy did not significantly affect eGFR-slope (pre-pregnancy ß=-1.030, post-pregnancy ß=-1.349). ARAS-pregnancies demonstrated less favorable outcomes (early preterm birth incidence 3/11 (27%)). ARAS was a significant independent predictor for lower birth weight and shorter duration of pregnancy, next to the classic predictors (pre-pregnancy kidney function, proteinuria, and chronic hypertension) though missing proteinuria values and the small ARAS-sample hindered analysis. This is the largest study to date on AS and pregnancy with reassuring results for mild AS, though inheritance patterns could be considered in counseling next to classic risk factors. Thus, our findings support personalized reproductive care and highlight the importance of investigating kidney disease-specific pregnancy outcomes.

Exploring biopsychosocial correlates of pregnancy risk and pregnancy intention in women with chronic kidney disease.

INTRODUCTION: Women with Chronic Kidney Disease (CKD) are at increased risk of adverse pregnancy and renal outcomes. It is unknown how women with CKD understand their pregnancy risk. This nine-centre, cross-sectional study aimed to explore how women with CKD perceive their pregnancy risk and its impact on pregnancy intention, and identify associations between biopsychosocial factors and perception of pregnancy risk and intention. METHODS: Women with CKD in the UK completed an online survey measuring their pregnancy preferences; perceived CKD severity; perception of pregnancy risk; pregnancy intention; distress; social support; illness perceptions and quality of life. Clinical data were extracted from local databases. Multivariable regression analyses were performed. Trial registration: NCT04370769. RESULTS: Three hundred fifteen women participated, with a median estimated glomerular filtration rate (eGFR) of 64 ml/min/1.73m2 (IQR 56). Pregnancy was important or very important in 234 (74%) women. Only 108 (34%) had attended pre-pregnancy counselling. After adjustment, there was no association between clinical characteristics and women's perceived pregnancy risk nor pregnancy intention. Women's perceived severity of their CKD and attending pre-pregnancy counselling were independent predictors of perceived pregnancy risk. Importance of pregnancy was an independent predictor of pregnancy intention but there was no correlation between perceived pregnancy risk and pregnancy intention (r = - 0.002, 95% CI - 0.12 to 0.11). DISCUSSION: Known clinical predictors of pregnancy risk for women with CKD were not associated with women's perceived pregnancy risk nor pregnancy intention. Importance of pregnancy in women with CKD is high, and influences pregnancy intention, whereas perception of pregnancy risk does not.

Developing evidence-based guidelines for the safety of symptomatic drugs in multiple sclerosis during pregnancy and breastfeeding: A systematic review and Delphi consensus.

BACKGROUND: Multiple sclerosis (MS) is frequently diagnosed in people of reproductive age, many of whom will become pregnant following diagnosis. Although many women report an improvement in symptoms and relapses during pregnancy, symptoms such as fatigue and spasticity are commonly reported and can worsen. Prescribing medications during pregnancy and breastfeeding presents unique challenges and guidance on the use of symptomatic therapies is limited. OBJECTIVES: This paper aims to provide a consensus on the current evidence base to facilitate informed decision-making and optimise pre-conception counselling. METHODS: A list of most commonly prescribed medications for symptom management in MS was created using pregnancy and MS-related READ codes in the Welsh GP Dataset, followed by a review by MS neurologists. RESULTS: A final list of 24 medications was generated for review. Searches were performed on each medication, and evidence graded using standardised criteria. Evidence-based recommendations were developed and distributed to experts in the field and revised according to feedback using modified Delphi criteria. CONCLUSIONS: Our guidelines provide evidence-based recommendations on the safety of symptomatic therapies during pregnancy and breastfeeding for general practitioners and specialist teams working with people with MS who are hoping to embark on pregnancy or are currently pregnant. Individual risk-benefit ratios should be considered during pre-conception counselling to optimise symptom burden and minimise harm to both parent and child.

Glomerular diseases in pregnancy: pragmatic recommendations for clinical management.

Our understanding of the various aspects of pregnancy in women with kidney diseases has significantly improved in the last decades. Nevertheless, little is known about specific kidney diseases. Glomerular diseases are not only a frequent cause of chronic kidney disease in young women, but combine many challenges in pregnancy: immunologic diseases, hypertension, proteinuria, and kidney tissue damage. An international working group undertook the review of available current literature and elicited expert opinions on glomerular diseases in pregnancy with the aim to provide pragmatic information for nephrologists according to the present state-of-the-art knowledge. This work also highlights areas of clinical uncertainty and emphasizes the need for further collaborative studies to improve maternal and fetal health.

Severe hypertension in pregnancy.

Severe hypertension in pregnancy is defined as a sustained systolic blood pressure of 160 mmHg or over or diastolic blood pressure of 110 mmHg or over and should be assessed in hospital. Severe hypertension before 20 weeks' gestation is rare and usually due to chronic hypertension; assessment for target organ damage and exclusion of secondary hypertension are warranted. The most common cause of severe hypertension in pregnancy is pre-eclampsia, which presents after 20 weeks' gestation. This warrants more rapid control of blood pressure due to the risk of haemorrhagic stroke, and intravenous antihypertensive agents may be required. Treatment is determined by licensing, availability and clinician experience, with no high-level evidence to guide prescribing. Labetalol is the agent most commonly used, both orally and intravenously, in pregnancy in the UK. Severe hypertension is a risk factor for sustained hypertension after pregnancy. Hypertension in pregnancy is associated with increased cardiovascular risk.

Erratum: Anti-Müllerian hormone concentrations in women with chronic kidney disease.

[This corrects the article DOI: 10.1093/ckj/sfz164.][This corrects the article DOI: 10.1093/ckj/sfz164.].

Placental and endothelial biomarkers for the prediction of superimposed pre-eclampsia in chronic kidney disease.

OBJECTIVES: To evaluate PlGF, sFlt-1, and novel endothelial biomarkers hyaluronan and vascular cell adhesion molecule (VCAM), for the prediction of superimposed pre-eclampsia in women with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study of pregnant women with CKD in UK. MAIN OUTCOME MEASURES: Outcomes including superimposed pre-eclampsia were based on predetermined criteria. Test performances of plasma PlGF, serum sFlt-1:PlGF, hyaluronan and VCAM concentrations were evaluated as area under the receiver-operating curve and at established and exploratory threshold concentrations. RESULTS: There were 232 pregnancies in 221 women with CKD. One third (76/232) developed superimposed pre-eclampsia. From 21 to 37 weeks' gestation, plasma PlGF was decreased among women that developed superimposed preeclampsia. Plasma PlGF levels < 150 pg/ml had the highest sensitivity (79% 95% CI: 58-91%) and negative predictive value (97%, 95% CI: 93-99%) for the prediction of delivery with superimposed pre-eclampsia within 14 days. Predictive performances of hyaluronan and VCAM were lower than for plasma PlGF. Low plasma PlGF, high hyaluronan and high VCAM concentrations had lower predictive performance in women with pre-pregnancy CKD stages 3-5 compared to stages 1-2. sFlt-1:PlGF > 38 did not usefully predict the need to deliver in women with CKD when measured in serum. CONCLUSIONS: Increased surveillance for the need for delivery should take place in women with CKD and plasma PlGF below 150 pg/ml after 20 weeks' gestation, with awareness that predictive value is reduced as excretory kidney function declines. Maternal endothelial dysfunction may alter the PlGF threshold at which superimposed pre-eclampsia manifests in women with CKD.

Anti-Müllerian hormone concentrations in women with chronic kidney disease.

BACKGROUND: Serum anti-Müllerian hormone (AMH) is a biomarker of ovarian reserve. There are limited data to guide the clinical interpretation of AMH in women with chronic kidney disease (CKD). The purpose of this study was to examine AMH concentrations in women with CKD compared with women without CKD. METHODS: We conducted a prospective cohort study of serum AMH concentrations in 163 non-pregnant women with CKD. Serum AMH concentrations were compared with age-specific AMH centiles from 887 healthy female controls. RESULTS: Participants included 30 women with Stage 1 CKD, 37 women with Stage 2 CKD, 26 women with Stage 3a CKD, 31 women with Stage 3b CKD and 39 women with Stages 4 and 5 CKD. The median estimated glomerular filtration rate (eGFR) was 51 (interquartile range 31-80) mL/min/1.73 m2. Serum AMH concentrations were lower in all CKD stages compared with women without CKD. Women ages 20-24 years with CKD had comparable serum AMH concentrations (median 1.959 ng/mL) to women ages 35-39 years without CKD (median 1.995 ng/mL). There was no evidence that eGFR was an independent modifier of serum AMH concentrations. More than half of women with CKD (58%) were predicted to have a low response to gonadotrophin stimulation. CONCLUSIONS: Women with CKD have a lower ovarian reserve and are predicted to have a lower ovarian response to gonadotrophin stimulation compared with women without CKD of a similar age. Women with CKD who fail to conceive within 6 months of regular unprotected intercourse should be considered for fertility assessment and intervention.

The impact of chronic kidney disease Stages 3-5 on pregnancy outcomes.

BACKGROUND: Contemporaneous data are required for women with chronic kidney disease (CKD) Stages 3-5 to inform pre-pregnancy counselling and institute appropriate antenatal surveillance. METHODS: A retrospective cohort study in women with CKD Stages 3-5 after 20 weeks' gestation was undertaken in six UK tertiary renal centres in the UK between 2003 and 2017. Factors predicting adverse outcomes and the impact of pregnancy in accelerating the need for renal replacement therapy (RRT) were assessed. RESULTS: There were 178 pregnancies in 159 women, including 43 women with renal transplants. The live birth rate was 98%, but 56% of babies were born preterm (before 37 weeks' gestation). Chronic hypertension was the strongest predictor of delivery before 34 weeks' gestation. Of 121 women with known pre-pregnancy hypertension status, the incidence of delivery before 34 weeks was 32% (31/96) in women with confirmed chronic hypertension compared with 0% (0/25) in normotensive women. The risk of delivery before 34 weeks doubled in women with chronic hypertension from 20% [95% confidence interval (CI) 9-36%] to 40% (95% CI 26-56%) if the gestational fall in serum creatinine was <10% of pre-pregnancy concentrations. Women with a urinary protein:creatinine ratio >100 mg/mmol prior to pregnancy or before 20 weeks' gestation had an increased risk for birthweight below the 10th centile (odds ratio 2.57, 95% CI 1.20-5.53). There was a measurable drop in estimated glomerular filtration rate (eGFR) between pre-pregnancy and post-partum values (4.5 mL/min/1.73 m2), which was greater than the annual decline in eGFR prior to pregnancy (1.8 mL/min/1.73 m2/year). The effect of pregnancy was, therefore, equivalent to 1.7, 2.1 and 4.9 years of pre-pregnancy renal disease in CKD Stages 3a, 3b and 4-5, respectively. The pregnancy-associated decline in renal function was greater in women with chronic hypertension and in those with a gestational fall in serum creatinine of <10% of pre-pregnancy concentrations. At 1 year post-partum, 46% (58/126) of women had lost ≥25% of their pre-pregnancy eGFR or required RRT. Most women with renal transplants had CKD Stage 3 and more stable renal function prior to pregnancy. Renal transplantation was not independently associated with adverse obstetric or renal outcomes. CONCLUSIONS: Contemporary pregnancies in women with CKD Stages 3-5 are complicated by preterm delivery, low birthweight and loss of maternal renal function. Chronic hypertension, pre- or early pregnancy proteinuria and a gestational fall in serum creatinine of <10% of pre-pregnancy values are more important predictors of adverse obstetric and renal outcome than CKD Stages 3-5. Pregnancy in women with CKD Stages 3-5 advances the need for dialysis or transplantation by 2.5 years.

Updates in Diagnosis and Management of Preeclampsia in Women with CKD.

It is estimated that women with CKD are ten times more likely to develop preeclampsia than women without CKD, with preeclampsia affecting up to 40% of pregnancies in women with CKD. However, the shared phenotype of hypertension, proteinuria, and impaired excretory kidney function complicates the diagnosis of superimposed preeclampsia in women with CKD who have hypertension and/or proteinuria that predates pregnancy. This article outlines the diagnoses of preeclampsia and superimposed preeclampsia. It discusses the pathogenesis of preeclampsia, including abnormal placentation and angiogenic dysfunction. The clinical use of angiogenic markers as diagnostic adjuncts for women with suspected preeclampsia is described, and the limited data on the use of these markers in women with CKD are presented. The role of kidney biopsy in pregnancy is examined. The management of preeclampsia is outlined, including important advances and controversies in aspirin prophylaxis, BP treatment targets, and the timing of delivery.

Diagnostic Indicators of Superimposed Preeclampsia in Women With CKD.

INTRODUCTION: Diagnosis of superimposed preeclampsia in women with chronic kidney disease (CKD) is complicated by the presence of hypertension and proteinuria due to renal disease. The aims of this study were to determine mechanistic links between superimposed preeclampsia and renin-angiotensin system activation, endothelial pathology, complement dysfunction, and tubular injury, and to explore the role of diagnostic indicators of superimposed preeclampsia. METHODS: Plasma and urinary biomarkers derived from the renin-angiotensin system (active renin, angiotensinogen), endothelial glycocalyx (hyaluronan, intercellular adhesion molecule, vascular cell adhesion molecule [VCAM], P-selectin, E-selectin), complement activation (C3a, C5a, complement factor H, C5b-9), and tubular injury (kidney injury molecule-1, urinary lipocalin-2) were quantified in 60 pregnant women with CKD including 15 women at the time of superimposed preeclampsia diagnosis and 45 women who did not develop superimposed preeclampsia, 18 women with preeclampsia, and 20 normal pregnancies. Correlation with placental growth factor was assessed. RESULTS: Plasma concentrations of hyaluronan (67.5 ng/ml vs. 27.5 ng/ml, P = 0.0017, receiver operating characteristic area 0.80) and VCAM (1132 ng/ml vs. 659 ng/ml, P < 0.0001, receiver operating characteristic area 0.86) distinguished women with CKD and superimposed preeclampsia from those without superimposed preeclampsia, and correlated with placental growth factor concentration. The diagnostic discrimination of markers of the renin-angiotensin system was reduced by adjustment for chronic hypertension, antihypertensive drug use, and black ethnicity. Other markers offered limited or no diagnostic discrimination for superimposed preeclampsia. CONCLUSION: This study suggests that endothelial dysfunction contributes to the pathophysiology of superimposed preeclampsia and a diagnostic role for plasma hyaluronan and VCAM is hypothesized.

Serum Creatinine in Pregnancy: A Systematic Review.

INTRODUCTION: Standard assessment of renal function in pregnancy is by measurement of serum creatinine concentration yet normal gestational ranges have not been established. The aim of this systematic review was to define the difference in serum creatinine in a healthy pregnancy compared with concentrations in nonpregnant women to facilitate identification of abnormal kidney function in pregnancy. METHODS: Medline, PubMed, Embase, Web of Science, theses, key obstetric texts, and conference proceedings were searched to July 2017. Eligible studies included quantification of serum creatinine concentration in a pregnant cohort, with either a reported local laboratory reference range or matched quantification in a nonpregnant cohort. The outcomes of interest were the mean and upper reference limits for creatinine in pregnancy, measured as a ratio of pregnant:nonpregnant values. Study heterogeneity was examined by meta-regression analysis. RESULTS: Forty-nine studies were identified. Data synthesis included 4421 serum creatinine values in pregnancy, weighted according to cohort size. Mean values for serum creatinine in pregnancy were 84%, 77%, and 80% of nonpregnant mean values during the first, second, and third trimesters, respectively. The 97.5th centile (upper limit of the 95% reference range) for serum creatinine in pregnancy was 85%, 80%, and 86% of the nonpregnant upper limit in sequential trimesters. CONCLUSION: Based on a nonpregnant reference interval of 45-90 µmol/l (0.51-1.02 mg/dl), a serum creatinine of >77 µmol/l (0.87 mg/dl) should be considered outside the normal range for pregnancy. Future work can use this value to explore correlation of adverse pregnancy outcomes with serum creatinine concentration. PROSPERO registration: CRD42017068446.

Dialysis in pregnancy.

Although kidney disease impacts on fertility, increasing numbers of pregnancies are reported in women on dialysis. Despite a trend of increasing live birth rates over recent decades, pregnancies on dialysis remain high risk with increased rates of adverse pregnancy outcomes including pregnancy loss, pre-eclampsia, pre-term delivery, low birth weight and higher levels of neonatal care. This article describes the prevalence of dialysis and pregnancy in women of childbearing age, with relevant information regarding the effects of end-stage renal disease on fertility in women. Pregnancy outcomes for women on dialysis are summarised, including their association with dialysis intensity. A guide to pre-pregnancy counselling, and the management of pregnancy on dialysis is provided. Factors that inform the decision to commence dialysis in pregnancy are examined. The advantages and disadvantages of peritoneal dialysis in pregnancy are discussed.

Glomerular Disease in Women.

Gender differences exist in the prevalence of glomerular diseases. Data based on histological diagnosis underestimate the prevalence of preeclampsia, which is almost certainly the commonest glomerular disease in the world, and uniquely gender-specific. Glomerular disease affects fertility via disease activity, the therapeutic use of cyclophosphamide, and underlying chronic kidney disease. Techniques to preserve fertility during chemotherapy and risk minimization of artificial reproductive techniques are considered. The risks, benefits, and effectiveness of different contraceptive methods for women with glomerular disease are outlined. Glomerular disease increases the risk of adverse outcomes in pregnancy, including preeclampsia; yet, diagnosis of preeclampsia is complicated by the presence of hypertension and proteinuria that precede pregnancy. The role of renal biopsy in pregnancy is examined, in addition to the use of emerging angiogenic biomarkers. The safety of drugs prescribed for glomerular disease in relation to reproductive health is detailed. The impact of both gender and pregnancy on long-term prognosis is discussed.

Reproductive health and pregnancy in women with chronic kidney disease.

Chronic kidney disease (CKD) is associated with reduced fertility and an increased risk of adverse pregnancy outcomes. Rates of pre-eclampsia, fetal growth restriction and preterm delivery increase incrementally with the severity of CKD and proteinuria. Pre-pregnancy counselling can facilitate informed decision-making. Safe and effective contraception is required for women who wish to delay or avoid pregnancy. Pregnancy planning for women who wish to conceive involves appropriate substitution of known teratogens - including mycophenolate mofetil, angiotensin blockers and cyclophosphamide - and can aid optimization of disease control. However, pregnancy, which can occur in women with any stage of CKD, can exacerbate comorbidities such as anaemia, vitamin D deficiency and hypertension. Increased haemodialysis provision is associated with improved pregnancy outcomes for women on dialysis. Diagnosis of pre-eclampsia in women with CKD is complicated in patients with pre-existing hypertension and proteinuria but can be improved by the use of vasoactive biomarkers as well as placental and fetal Doppler ultrasound. Pregnancy data for newer drugs used in CKD are limited as pregnancy and CKD are common exclusion criteria for drug and intervention trials. Although prospective data may be available for older drugs, the use of most drugs in pregnancy is based on retrospective data and expert consensus.

Silent obstruction in a young woman with systemic lupus erythematosus: a case report and literature review on kidney injury from ureteral endometriosis.

INTRODUCTION: Endometriosis is the most common pelvic gynaecologic disorder affecting pre-menopausal women. However ureteral endometriosis (UE) especially intrinsic urinary tract endometriosis is a rare finding that is notorious for causing silent renal insult. The pathogenesis of endometriosis still remains a mystery but studies have suggested an association between endometriosis and systemic lupus erythematosus (SLE) suggesting an immunological aspect to endometriosis. There is very little recognition in the renal literature of the significance of UE leading to progressive kidney injury and the association with autoimmune conditions in particular SLE. CASE DESCRIPTION: We present a case of a 30-year old female with a background history of SLE with a silent progressive kidney injury due to an obstructive uropathy secondary to bilateral intrinsic UE and severe loss of her left kidney function that was treated with ureteric stenting. She subsequently underwent bilateral re-implantation of her ureters as a definitive treatment plan as she expressed a wish to conceive. DISCUSSION: Progressive kidney injury as a result of UE has been reported in the past, however its true incidence is not known. The time of diagnosis is crucial as it reflects renal prognosis. This article outlines the clinical implications from the renal perspective of the disease considering the relevant health problem UE can impose to women. This paper discusses the emerging evidence of an association between SLE and endometriosis that remains poorly understood. CONCLUSION: A high index of suspicion is required to diagnose UE as the disease occurs insidiously with non-specific symptoms leading to a silent obstructive uropathy. If missed it can ultimately lead to irreversible kidney dysfunction and mortality. We suggest that patients with endometriosis especially UE should be followed up regularly with renal function testing and imaging. Any health professionals dealing with patients suffering from SLE should consider appropriate investigations and referral if any symptom that suggests endometriosis is reported.