Objectives: Pre-eclampsia (PE) is a leading cause of obstetric morbidity, with no definitive therapy other than delivery. We aimed to compare complement markers in maternal and fetal circulation, and placental tissue, between women with PE and healthy pregnant controls. Study Design: Maternal and umbilical cord blood was tested for iC3b, C3, C4, properdin, Ba and C5b-9, and placental tissue for C3d, C4d, C9 and C1q, from women with PE (n = 34) and healthy pregnant controls (n = 33). Maternal properdin and Ba tests were repeated in a separate validation cohort (PE n = 35; healthy pregnant controls n = 35). Main Outcome Measures: Complement concentrations in maternal and umbilical cord blood, and placental immunohistochemical complement deposition. Results: Women with PE had significantly lower concentrations of properdin (mean: 4828 vs 6877 ng/ml, p < 0.001) and C4 (mean: 0.20 vs 0.31 g/l, p < 0.001), and higher Ba (median: 150 vs 113 ng/ml, p = 0.012), compared to controls. After controlling for gestational age at blood draw, average properdin concentration was 1945 ng/ml lower in PE vs controls (95 % CI: 1487-2402, p < 0.001). Of the cord blood markers assessed, only Ba differed significantly between PE and controls (median: 337 vs 233 ng/ml, p = 0.004). C4d staining of the syncytiotrophoblast membrane was increased in PE vs controls (median immunoreactivity score 3 vs 0, p < 0.001). Maternal properdin and C4 were significantly negatively correlated with placental C4d staining. Conclusions: Our data confirm excessive placental complement deposition associated with significant concurrent changes in maternal and fetal circulating complement biomarkers in PE. Inhibition of complement activation is a potential therapeutic target.

Journal of the American Society of Nephrology 33(11S):p 502, November 2022. | DOI: 10.1681/ASN.20223311S1502b

Abstract Background and Aims The latest consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends metformin and lifestyle intervention as first-line therapy for type 2 diabetes. Second-line therapy recommendation is the use sodium-glucose cotransporter 2 (SGLT 2) inhibitors (if estimated glomerular filtration rate [eGFR] is adequate) or GLP-1 receptor agonists if eGFR is inadequate (or SGLT-2 inhibitors not tolerated). No recommendation is made for dipeptidyl peptidase-4 (DPP-4) inhibitors. Therapy choices are limited for patients with both type 2 diabetes and moderate-to-severe chronic kidney disease (CKD) and it is unclear from published data if observed cardiovascular benefits of new anti-diabetic agents extend to the CKD cohort. The aim of this study was to undertake a systematic review of all published CVOT trials using new anti-diabetic agents (GLP-1 receptor agonist, DPP-4 inhibitor, SGLT 2 inhibitor). Method We searched MEDLINE (via PubMed and the Cochrane Central Register of Controlled Trials) up to 1st December 2019. Data was stratified by trial entry eGFR into normal (eGFR ≥60 ml/min) and CKD (eGFR &lt;60 ml/min), with data extracted for primary major cardiovascular event (MACE) rates such as cardiovascular death, stroke and/or myocardial infarct. A meta-analysis with random effects model was performed to estimate overall hazard ratios (HRs) for MACE with new anti-diabetic agents stratified by eGFR. Inter-study heterogeneity was assessed with the I2 index and Cochran’s Q test. Results We analysed 13 studies from 16 that were eligible after our search strategy, with 2 excluded due lack of data stratified by eGFR and 1 excluded due to combined MACE/renal outcomes. The studies (GLP-1 agonists, n=6; DPP-4 inhibitors, n=4; SGLT 2 inhibitors, n=3) had a combined total of 128,266 participants (22.1% with eGFR &lt;60 ml/min). HR for MACE with GLP-1 agonists for participants with eGFR ≥60 ml/min was 0.87 (95% CI 0.77-0.98; p=0.02) and for participants with eGFR &lt;60 ml/min was 0.90 (95% CI 0.78-1.04; p=0.14). HR for MACE with DPP-4 inhibitors for participants with eGFR ≥60 ml/min was 0.99 (95% CI 0.92-1.07; p=0.86) and for participants with eGFR &lt;60 ml/min was 0.99 (95% CI 0.91-1.08; p=0.86). HR for MACE with SGLT 2 inhibitors for participants with eGFR ≥60 ml/min was 0.98 (95% CI 0.88-1.10; p=0.78) and for participants with eGFR &lt;60 ml/min was 0.82 (95% CI 0.70-0.96; p=0.01). Significant heterogeneity was observed in the meta-analyses for each new anti-diabetic therapy drug class stratified by eGFR. Conclusion Among the new anti-diabetic agents, our study suggests efficacy for prevention of MACE in the setting of CKD exists only for SGLT 2 inhibitors and not with GLP-1 receptor agonists or DPP-4 inhibitors. Targeted CVOT studies incorporating participants with diabetes and CKD are critical to guide glycaemic management in these high-risk patients. Until then, we suggest recommendations for second-line therapy in patients with type 2 diabetes and renal impairment should be amended to reflect the current evidence base supporting prevention of MACE with SGLT 2 inhibitors versus other new anti-diabetic agents.

Patients with end-stage renal disease are susceptible to infection, particularly methicillin-resistant Staphylococcus aureus (MRSA). Although MRSA-related mortality and morbidity have been studied, methicillin-sensitive Staphylococcus aureus (MSSA) has not been investigated to the same degree. Five hundred and seventy-eight chronic hemodialysis patients were followed up retrospectively for 18 months. Routine screening for MRSA and MSSA was instigated. Two hundred and eighty-eight patients (49%) had at least one positive MSSA or MRSA swab. There was no statistical difference in age, Charlson index, diabetes, sex, ethnicity, deprivation index, or the duration of dialysis between the positive and negative groups. There were however, less fistulas and more lines in the positive patients (P = 0.025). Binary logistic regression revealed patients with a body mass index of greater than 30 had a significantly increased risk of Staphylococcus aureus colonization P = 0.044, odds ratio (OR) 1.856 (95% confidence interval 1.016-3.397). Those who entered the study using a temporary line for vascular access also conferred a greater risk of colonization P = 0.029, OR 2.174 (95% CI 1.084–4.359). Patients with positive swabs had significantly more admissions (P = 0.033) and in particular, more infection-related admissions (P = 0.001). They were less likely to survive the follow-up period (P = 0.012) and had substantially more bacteremia (P <0.001). Following multivariable analysis, swab positivity remained an independent risk factor for mortality. MRSA and MSSA colonization in patients is associated with significant mortality and morbidity in dialysis patients. Patients dialyzing with lines are also more likely to colonize compared to those with more permanent forms of vascular access.

PROBLEM:Pre-eclampsia (PE) is a leading cause of maternal and foetal morbidity worldwide. Given the implication of immune mechanisms, we compared markers of humoral immunity in PE and their relationship to circulating markers of inflammation, angiogenic factors, and renal function.METHOD OF STUDY:Serum samples from 88 previously healthy women admitted to hospital with PE and 107 healthy pregnant controls at term were analysed for serum immunoglobulins (Ig), including IgG subclasses and free light chain (sFLC) levels, beta-2 microglobulin (B2-M), high-sensitivity C-reactive protein (HS-CRP), albumin, complement proteins (C3 & C4), creatinine, cystatin-C and the ratio of soluble fms-like tyrosine kinase-1 (sFLT-1) and placental growth factor (PlGF).RESULTS:Compared to the controls, women with PE had significantly reduced renal function, serum IgG (subclass 1 & 3), albumin, and C4 levels, whilst concentrations of total sFLC, HS-CRP, B2-M, and sFLT-1:PlGF were raised. On multivariable analysis, sFLT-1:PlGF ratio (P < 0.001), sFLC (P < 0.001) and IgG1 (P < 0.024) were found to be independently associated with PE, after accounting for renal function, patient age, BMI, ethnicity, and parity. B2-M and sFLT-1:PlGF had comparable diagnostic association with PE (P = 0.184), and correlated strongly with each other (ρ = 0.588, P < 0.001) as well as with renal function and adverse clinical outcome.CONCLUSION:We describe for the first time that PE is independently associated with activation of the humoral immune system independent of deranged kidney function and angiogenic markers. The role of B2-M as a potential predictive marker of PE remains to be determined.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective and widely used antihypertensive drugs. Exposure to these agents is known to be harmful to the fetus in the second and third trimesters of pregnancy. Concerns have also been raised about the risk of congenital malformations if ACEIs or ARBs are taken during the first trimester of pregnancy. The evidence to date, however, is conflicting and observed malformations may be due to confounders such as undiagnosed diabetes or maternal obesity, other antihypertensive medications or the hypertension itself. Nonetheless, in women who become pregnant while taking an ACEI or ARB, the drug should be stopped as soon as possible. In women with chronic kidney disease and proteinuria, it may be appropriate to continue taking an ACEI or ARB until the pregnancy is confirmed because of the significant benefit to their kidney function and the lower fertility rate in these patients.

Background Fibromuscular dysplasia (FMD) is the most frequent cause of renovascular hypertension in women of fertile age. We present a 36 year old identified in early pregnancy with severe resistant hypertension caused by bilateral FMD. Case A 36-year-old primigravida with no past medical history was referred to the renal-obstetric services at 11 weeks gestation with severe hypertension. Mean ambulatory blood pressure (BP) was 180/100 despite maximum treatment dose of nifedipine and labetalol. Renal function, ECG, plasma renin/aldosterone ratio and urinary catecholamine study was normal. Renal ultrasound identified a small left kidney and after careful MDT discussion with detailed patient consent catheter renal angiography was performed. Radiation dose to the fetus was minimised by reducing the X-ray frame rate, exposure time and lead screening. Selective renal angiography demonstrated classical bilateral renal FMD and bilateral angioplasty resulted in excellent immediate results without complications. BP rapidly improved and the patient had a successful term delivery. Conclusions Reports from the literature of FMD diagnosed in pregnancy are associated with poor pregnancy outcomes and there are few reports of antenatal angioplasty. FMD is a rare yet important diagnosis to exclude in women presenting with uncontrolled hypertension before fetal viability. In selected cases where the index of suspicion is high and after careful MDT discussion involving radiation protection specialists renal artery angioplasty can be effective in controlling BP. The longer-term risks to the child posed by antenatal radiation are small and outweighed by the greater, more immediate risk to mother and child during pregnancy of uncontrolled BP.

Introduction In 2001, the UK National Screening Committee advised that all pregnant mothers should be offered a screening test for Down’s syndrome (DS). This is performed at first (biomarkers and ultrasound) or second trimester (biochemical screen). There are limited data reporting pregnant women with chronic kidney disease (CKD) have higher false positive screening rates possibly because of reduced clearance of β-hCG (1–3). Our aim was to establish whether standard DS screening is appropriate in pregnant women with renal disease. Methods We performed a retrospective, single centre review of DS screening data for women attending a tertiary renal-antenatal clinic over the past 5 years and correlated with clinical outcome. Results A total of 240 women had renal function checked at the time of screening. Twenty-seven% had creatinine ≥60 µmol/L-above upper normal pregnancy value (range 24–544). There were a higher proportion of positive screens compared to the general population at first (5.7% vs 2%) and second trimester (9% vs 3.5%). No patient had a baby affected with DS. Increased creatinine was associated with higher levels of unconjugated oestriol (uE3), free and total β-hCG (p ≤ 0.01) and a higher DS risk score (p ≤ 0.01). Increased proteinuria also correlated with a higher β-hCG (p ≤ 0.01) and risk score (p ≤ 0.02). In patients with a high risk score; 30% had IUGR, 10% pre-term delivery and 56% delivered a small baby. Conclusion Renal function appears to affect levels of β-hCG and uE3and also independently influence the risk score in DS screening. Alternative screening may need to be considered in this group or renal impairment corrected for. References Cararach V, Casals E, Martinez S, Carmona F, Aibar C, Quinto LI, et al. Abnormal renal function as a cause of false-positive biochemical screening for Down’s syndrome. Lancet. 1997;350(9087):1295. Epub 1997/11/14 Cheng PJ, Liu CM, Chang SD, Lin YT, Soong YK. Elevated second-trimester maternal serum hCG in patients undergoing haemodialysis. Prenat Diagn. 1999;19(10):955–8. Epub 1999/10/16 Benachi A, Dreux S, Kaddioui-Maalej S, Czerkiewicz I, Fakhouri F, Thervet E, et al. Down syndrome maternal serum screening in patients with renal disease. Am J Obstet Gynecol. 2010;203(1):60 e1–4. Epub 2010/04/27

Introduction Pregnant women deemed to be at high risk of thrombo-embolic disease (TED) should be treated with prophylactic low molecular weight heparin (LMWH). LMWH is cleared by the kidneys and although guidelines exist for dose reduction in patients with chronic kidney disease (CKD) these are for outside of pregnancy. LMWH activity can be monitored by measuring anti-factor Xa levels. The purpose of our study was to review the safety and efficacy of LMWH dosing and the value of anti-factor Xa levels in pregnant women with CKD. Methods We conducted a retrospective, single centre review of pregnant women attending a tertiary renal-antenatal clinic who had received LMWH over 3 years. Results 31 pregnancies in 28 women were identified (median age 31y (range 17–38)). LMWH was started at 3.7–34 weeks gestation (mean 11.8). Indications for treatment included proteinuria (68%) and previous VTE (26%). Prophylactic dosing was used in all but 1 case. Anti-Xa levels were always within target range in 31% of patients. Women with CKD (creatinine >70 umol/l) had higher anti-Xa levels (0.25 IU/ml vs 0.19 IU/ml, P < 0.02) and were more likely to have had a supra-therapeutic measurement (67% vs 21%, P < 0.02) compared to women with normal renal function. Delivery was by caesarean section in 73% of patients and there were no cases of significant haemorrhage or VTE. Conclusions Prophylactic treatment with LMWH in pregnant women at high risk of VTE with CKD appears to be safe and effective. Measurement of anti-factor Xa may be helpful in guiding dosing in these patients.