Abstract
The aims of my PhD were to understand physiological and pathophysiological factors that influence outcomes in reproductive health and pregnancy for women with chronic kidney disease (CKD) before, during and after pregnancy.Standard assessment of renal function in pregnancy is by measurement of serum creatinine concentrations yet normal gestational ranges had not been established. Serum anti-Müllerian hormone (AMH) is a biomarker of ovarian reserve, but the clinical interpretation of AMH in women with CKD is ambiguous and had not been examined in early stage CKD. There are limited contemporary data available to inform counselling and surveillance of women with moderate and severe kidney disease (CKD stages 3-5) undertaking pregnancy, with outcomes restricted to small and historical cohorts. Mechanistic links between superimposed pre-eclampsia and CKD include endothelial dysfunction, renin-angiotensin system activation, complement activation and tubular injury, which offer the potential for novel diagnostic indicators. Placental growth factor (PlGF) concentrations in isolation and in combination with soluble fms-like tyrosine kinase-1 (sFlt-1:PlGF) have been recently implemented as diagnostic adjuncts in women with suspected pre-eclampsia, yet data on the utility of these markers in women with CKD are limited. Given that the diagnosis of superimposed pre-eclampsia in women with CKD is complicated by the presence of hypertension and proteinuria due to kidney disease, an evaluation of the utility of PlGF, sFlt-1, and other novel biomarkers in the prediction of superimposed pre-eclampsia in women with CKD was warranted.
Methods used in this thesis included a systematic review and meta-analysis of 4421 serum creatinine concentrations in pregnancy, a prospective cohort study of AMH concentrations in 163 reproductive-age women with CKD, a retrospective cohort study of obstetric and renal outcomes in 178 pregnancies in women with pre-pregnancy CKD stages 3-5, a nested case-control study of novel biomarkers in the diagnosis of superimposed pre-eclampsia in women with CKD; and a prospective multicentre study of 232 pregnancies in women with CKD, examining the accuracy of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in predicting the need for delivery due superimposed pre-eclampsia.
The upper limits of the reference interval for serum creatinine in pregnancy were 85%, 80% and 86% of the upper limit outside of pregnancy in sequential trimesters. This means that for an upper reference limit of 90µmol/L for serum creatinine in non-pregnant females, values greater than 76µmol/L in the first trimester, 72µmol/L in the second trimester, and 77µmol/L in the third trimester should be considered abnormal in pregnancy, and warrant investigation to exclude a diagnosis of CKD or acute kidney injury in pregnancy.
Serum AMH concentrations in women with CKD aged less than 35 years were lower than in women without CKD, across all CKD stages. Women with CKD aged 20-24 years had comparable serum AMH concentrations to women aged 35 years and over without CKD.
Pregnancies in women with pre-pregnancy CKD stages 3-5 were complicated by preterm delivery, low birthweight and loss of maternal renal function. Chronic hypertension was the strongest predictor of delivery before 34 weeks’ gestation, with additional risk if the gestational fall in serum creatinine was less than 10% of pre-pregnancy values. Pre- or early pregnancy proteinuria was the strongest predictor of birthweight below the 10th centile. There was a step-decline in renal function in relation to pregnancy in most women with pre-pregnancy CKD stages 3-5, equivalent to between 1.7 and 4.9 years of background renal disease depending on pre-pregnancy CKD stage and rate of decline in kidney function prior to pregnancy. There was no evidence that renal transplantation conferred additional risk in women with pre-pregnancy CKD stages 3-5. Superimposed pre-eclampsia affected one third of women with CKD. Although plasma PlGF concentrations were lower in women with CKD who developed superimposed pre-eclampsia, mean concentrations did not fall below 100pg/ml. Plasma PlGF (Quidel) concentrations below 150pg/ml had the highest sensitivity and negative predictive value for the prediction of delivery due to superimposed pre-eclampsia in women with CKD. High plasma hyaluronan and VCAM concentrations discriminated both pre-eclampsia and superimposed pre-eclampsia from uncomplicated pregnancy, supporting existing pathogenic theories that pre-eclampsia is a disease of endothelial dysfunction. However, predictive performances for hyaluronan and VCAM were lower than for plasma PlGF concentrations. Quantification of PlGF, sFlt-1 and sFlt-1:PlGF ratio in serum did not usefully predict the need for delivery due to superimposed pre-eclampsia in women with CKD. There was no demonstrable diagnostic role for factors derived from the renin-angiotensin and complement systems.
This thesis was a multifaceted study of a heterogeneous disease. It addressed knowledge gaps for women with CKD across the spectrum of reproductive health including disease definition, pre-pregnancy assessment, diagnosis and prediction of superimposed pre-eclampsia in pregnancy, and long-term renal outcomes. It also formed the basis for the first national guideline for women with kidney disease in pregnancy in the UK.
| Date of Award | 1 Sept 2020 |
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| Original language | English |
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| Supervisor | Lucy Chappell (Supervisor), Liz Lightstone (Supervisor), Kate Bramham (Supervisor) & Catherine Nelson-Piercy (Supervisor) |