A letter from Dr Kate Bramham, specialist registrar of nephrology and obstetric medicine.

 

I am a nephrologist and my passion for obstetric medicine originated early in my medical training, after a chance consultation with Prof Michael De Swiet over a complex patient.  Subsequently I was inspired by Prof Catherine Nelson-Piercy and embarked upon several clinical studies of women with chronic kidney disease in pregnancy.   I was then awarded a National institute of Health Research doctoral fellowship at King’s College London with Prof Lucilla Poston, who herself had originally trained as a renal physiologist and still has a passion for the nephron, and with Dr Lucy Chappell, who has guided my training fellowship with expertise. I have also been fortunate to be supported throughout by the proficiency and experience of Prof John Davison and Prof Liz Lightstone.

 

My overall research aim is to improve pregnancy outcomes for women with pre-existing chronic kidney disease and/or hypertension.  Recently we have published a meta-analysis and systematic review of pregnancy outcomes in women with chronic hypertension including a comparison with the general population, which highlighted the elevated risk of all adverse events in these women.  It also demonstrated the importance of clear and consistent research definitions which are currently lacking in this field. Superimposed pre-eclampsia was identified to be associated with the greatest fold increase compared with pre-eclampsia (seven-fold change). Subsequently I have focussed on trying to determine the contribution of maternal and placental factors to this syndrome in women with chronic kidney disease and/or hypertension in the PEACHES study (Pre-Eclampsia,And Chronic Hypertension and rEnal Study),  in which we undertook longitudinal sampling of 165 women recruited from two UK teaching hospitals with pre-existing disease and compared them with healthy controls and women with pre-eclampsia without risk factors. We have demonstrated that gestational changes in placental growth factor (PlGF) and soluble Fms-like tyrosine kinase-1 (sFlt-1) do not appear to be influenced by the presence of maternal disease.  Furthermore, our early work suggests that low PlGF may be diagnostic of placental disease in women with chronic kidney disease and/or chronic hypertension.  Ongoing work includes assessment of these biomarkers in women with more severe renal disease, but preliminary evaluation has not demonstrated any influence of reduced glomerular filtration. I presented some of this work at the recent ISSHP conference in New Orleans (2015), with considerable interest from a number of colleagues across several disciplines.

Many women with chronic kidney disease and/or hypertension have a ‘placental’ phenotype, with early onset disease and growth restriction.  A future aim is to determine whether trophoblastic invasion is impaired in these women, or whether maternal disease influences placental function later in pregnancy.

I am also exploring the impact of maternal factors on the development of superimposed pre-eclampsia.Through collaboration with the PREDO study group we have performed a case-control study of women with pre-existing hypertension with extensive exploration of subclinical glomerular, renal tubular, cardiac and endothelial dysfunction. Abnormalities in glomerular autoregulation were identified in women with chronic hypertension which were more pronounced in women who subsequently developed superimposed pre-eclampsia.  Endothelial injury was a predictor of subsequent disease.  An interesting finding included a reduction in shedding of the glycocalyx (endothelial surface) layer, prior to onset of superimposed pre-eclampsia, and we are now studying this pathway in more detail.

One of the major challenges of this work has been attempting to define and diagnose superimposed pre-eclampsia, which as yet remains elusive! In addition to assessment of the diagnostic performance of angiogenic factors in women with chronic hypertension and chronic kidney disease I have attempted to develop novel urinary markers through a proteomics work-flow.  Initial candidates have been identified with sensitivity and specificity for differentiating between women with pre-eclampsia from those with gestational hypertension, chronic kidney disease, chronic hypertension and healthy controls.  However, these candidates were poor diagnostic markers for superimposed pre-eclampsia.  It is likely that change in glomerular selectivity of proteinuria in superimposed pre-eclampsia is insufficient to discriminate between women with progression of pre-existing kidney injury and endothelial damage from maternal-placental factors.

Another enigma remains the differentiation between progression of renal disease and physiological changes in renal function at later gestations, and my current research is focussing on understanding mechanisms and identifying markers of acute kidney injury in women with chronic kidney disease.   Kate Wiles, a fellow nephrologist has recently started recruiting to the PAIRS study (Pregnancy Adaptations In Renal disease Study) at four UK centres (target recruitment of 160 women with chronic kidney disease stages 3 to 5 in three years).  This work is part of the National Institute of Health Research Rare Renal Diseases Registry (RaDAR) initiative and includes national data collection on renal disease progression and pregnancy outcomes which is ongoing until 2020.

Finally, I am interested in the long term renal consequences of pre-eclampsia, and in collaboration with colleagues at Imperial College, London, we are exploring the biopsy findings of 120 women identified to have renal disease after pregnancy.  Preliminary analysis has identified a typical pattern of secondary focal segmental glomerulosclerosis, and future work includes exploration of novel immunological factors in this disease process.

I am currently working as a clinical lecturer at King’s College London, and the associated hospitals (King’s College Hospital, and Guy’s and St Thomas’ NHS Foundation trust), completing my nephrology training and running a renal pregnancy service with Dr Nicolas Kametas, a maternal and fetal medicine expert with a specialist interest in hypertension.  I count myself lucky to have worked with so many inspirational figures in this field, who have stirred my interest in improving pregnancy outcomes for these high-risk pregnant women, nurtured my career and motivated me to continue exploring these complex challenges in pregnancy care for many years to come.