NephMadness 2015: Obstetric Nephrology Region

Joel Topf, MD; Matthew Sparks, MD; Phyllis August, MD, MPH

Disclosures

March 02, 2015

Editorial Collaboration

Medscape &

In This Article

Phyllis August, MD, MPH, Selection Committee, Obstetric Nephrology Region

Editor's Note: The following "Scouting Report" will help you complete your bracket in the NephMadness Tournament. Read it carefully to make your selections, and discuss your thoughts in our Comments section. This article first appeared on the AJKD BLOG.

Meet the Competitors: Podocyturia vs sFlt1 in Preeclampsia

Preeclampsia represents the intersection between nephrology and obstetrics. Some have even suggested that it is the most common glomerular disease in the world.

The last two decades have seen some significant advances to understanding both the treatment and pathophysiology of this disease. Nephrologists were at the center of many of these advances. Preeclampsia affects ~3-5% of all pregnancies worldwide and contributes to significant maternal and fetal morbidity and mortality.

sFlt1 really jumped on the scene first in 2002 in a JCI paper (a nephrology fellow at the time, Dr. Maynard, was the first author!) and then in 2004 with this publication by Levine et al in the NEJM. sFlt1 is like the UNLV of the mid-90s. The news of sFlt1 radiated throughout all of medicine, not just nephrology and obstetrics. It was a major breakthrough.

Team podocyte is starting to emerge as a serious contender as well. Let’s take a look at this intriguing matchup a little closer.

Podocyturia in Preeclampsia

Podocyturia is all the rage in almost every form of kidney disease, from diabetes to FSGS, to lupus to glomerulonephritis. In fact, recent evidence is pointing to the presence of low level podocyturia even in normal individuals. A recent JASN paper discusses the possibility of using podocytes captured in the urine for genetic testing. Studies have demonstrated the presence of podocyte protein markers in the urine of women with preeclampsia.

To further explore whether the presence of urinary podocyte shedding would predict the onset of preeclampsia, a study published in the journal Hypertension in 2013 looked at 3 groups of women, all of whom were followed prospectively from their initial clinic visit. The researchers matched in a 3:1 ratio normotensive controls (n=44) against patients with gestational hypertension (n=15) and the study group who eventually developed preeclampsia (n=15).

What did they find at the end of the second trimester? 100% of patients who eventually developed preeclampsia had podocyturia. None of the normotensive or gestational hypertensive patients did!

This equals 100% sensitivity and 100% specificity. Unbelievable! This paper also measured angiogenic factors (sFlt1, PIGF, and Endoglin). These produced much more heterogeneous data and it was difficult to predict which patients would eventually go on to develop preeclampsia.

Since 2007, there have been ~11 studies (mostly small) that have demonstrated podocyturia in patients with preeclampsia, according to a review published in Kidney International in 2014.

So, why are patients with preeclampsia losing podocytes?

Since the presence of podocyturia predates the development of high blood pressure, it stands to reason that this might be a very proximal event. This also suggests that the defect leading to preeclampsia also represents more than just endothelial injury and the podocyte might be involved as well. It has been postulated that the loss of podocytes could prompt glomerular destabilization, resulting in more podocyte loss and ultimately proteinuria. However, this is a small study that needs to be reproduced in a larger population. Advances in detection could help make the detection of podocytes in the urine a viable test.

sFlt1 in Preeclampsia

The identification of sFlt1 as a "biomarker" and a potential "pathogenic" factor was a huge advance in the field.

What is sFlt1? It is soluble fms-like tyrosine kinase-1. It is actually a splice variant of the better known vascular endothelial growth factor receptor 1 (VEGF-R1). sFlt-1 freely circulates and reduces the level of both VEGF and placental growth factor (PIGF). A paper in JCI and another in NEJM solidified its role in preeclampsia. These publications demonstrate increasing levels of sFlt-1 and decreasing levels of PIGF in preeclampsia.

What is really happening here? Is it the actual sFlt1 causing preeclampsia, or is it preeclampsia itself leading to increased sFlt1 levels?

Evidence has pointed to the production of excess sFlt-1 by the hypoxic/ischemic placenta. The sFlt-1 acts as a sort of sink for VEGF, not allowing it to bind to VEGF-R1 on the cell surface of the vasculature, further leading to generalized systemic endothelial dysfunction, and possibly worsening placental ischemia. In a real tour de force, Karumanchi and colleagues demonstrated that the administration of sFlt1 to pregnant rats induces the classic lesion of preeclampsia:

  • Hypertension

  • Proteinuria

  • Glomerular endotheliosis

These results argue that sFlt-1 is "the" pathogenic entity responsible for causing the renal lesion of preeclampsia. This heralded great potential to actually offer novel treatment beyond blood pressure control, magnesium, and delivery.

In 2010 another breakthrough came. A pilot study published in Circulation attempted to remove sFlt-1 with the use of apheresis treatment; however, this was not a randomized study. The authors examined the efficacy of using a negatively charged dextran sulfate cellulose column to adsorb sFlt-1 in 5 women with preterm preeclampsia and increased sFlt-1 levels. They showed that with one apheresis treatment, levels of sFlt-1 decreased.

They also treated 3 women with very preterm preeclampsia and elevated circulating sFlt-1 levels with multiple rounds of apheresis. Again, they observed decreased sFlt-1 levels, reduced proteinuria, and stabilization of blood pressure without any evident adverse events. Just to note that there was no control group in this study.

However, since this report nothing more has surfaced. A quick look at ClinicalTrials.gov shows a few trials that are currently in various stages of recruiting. Team sFlt-1 will be a difficult challenge for any team in this year’s NephMadness. A real UNLV from the Jerry Tarkanian era.

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