Ravi Thadhani, M.D., M.P.H., chief of the Division of Nephrology at Massachusetts General Hospital and professor of medicine at Harvard Medical School, began with “a story that involves a bit of a dance, if you will, between medicine obstetrics and, I would say, a lot of luck,” at the Annual Irene Tamagna Lecture on Hypertension, held June 16.
Thadhani had a typical patient, 67 years old with a 20-year history of hypertension. “But she had one curious aspect of her history: pre-eclampsia,” he said.
Pre-eclampsia (PE), a widespread vascular disorder, typically occurs in the third trimester of a pregnancy and is marked by high blood pressure, protein in the urine, and signs of damage to other organs, most often the kidneys. As Thadhani explained, women tend to self-report a higher history of PE because it’s a topic for worry. “Women almost never forget if it was at least discussed,” he said, which is why his patient mentioned it. The patient had also had a kidney biopsy performed six years earlier and was diagnosed with kidney disease.
“Why does she have kidney disease and hypertension?” Thadhani asked. “Because her past history of pre-eclampsia predisposed her to these conditions. This, of course, serves as the premise of the discussion we’ll have: pre-eclampsia as a harbinger of disease many years later; what do we know about the disease; and can we diagnose this accurately and develop treatments for this condition.”
After developing PE in pregnancy, women have an increased risk of hypertension, stroke, and other cardiovascular conditions, Thadhani said. They also have a 40-fold increased risk of requiring a kidney biopsy and a higher risk of end-stage renal disease. In other words, “pregnancy uncovers [a] predisposition,” he explained, and the predispositions manifest in clinical conditions years later.
While PE may open a window to future medical issues, the disease itself is also cause for concern. It’s a factor in maternal mortality, both in the U.S. and around the world, and complications for babies and mothers can be long-lasting; consequences include premature deliveries, respiratory distress and cerebral palsy for babies, hypertensive encephalopathy and seizures for mothers, and death for both.
What makes PE tricky, as well, is that many women may not have typical risk factors, such as renal disease, HIV, or a family history of cardiovascular disease. Some women don’t display any risk factors at all. What has been clear, however, is that “when you deliver the placenta, the disease goes away,” Thadhani said. “There is something released that affects maternal signs and symptoms … and that affects the kidney, the liver, the brain, and all those organs and blood vessels.”
Several factors, Thadhani said, may be released from the placenta, but he focused on one: soluble fms-like tyrosine kinase-1 (sFLT-1), a serum protein that plays a role in vascular endothelial growth (endothelial cells create a thin layer that lines the interior of the heart and blood vessels). Women with PE typically have higher sFTL-1 levels. By looking at sFTL-1, as well as other signaling factors, like placental growth factor (PLGF) and vascular endothelial growth factor (VEGF), Thadhani found that it was possible to predict a pregnant woman’s likelihood of PE and potentially develop a therapeutic tool.
Using a baboon model, Thadhani experimented with infusions of PLGF and VEGF, but ultimately determined that antibodies were the key. “All we’re interested in doing is removing the protein of interest, in this case soluble FLT-1,” he said. “We actually made monoclonal antibodies; we covalently linked these antibodies using a variety of chemical reactions to technology that’s already been developed; and we created these cartridges the size of a hockey puck – you can actually fit that in the palm of your hand – and we then proceeded to try these cartridges in an extracorporeal fashion with our baboon model of pre-eclampsia.”
With the baboon model as proof of concept, Thadhani found that he could reduce sFLT-1 by 50 to 60 percent.
“Today, we have made human-sized cartridges, human monoclonal antibodies; we’ve put it on the cartridge; we’ve put it on the human machine; and my hope is, starting this fall, we’ll do healthy volunteers and then move this to pregnant patients,” he said.
Thadhani, however, was also “impatient,” he said, after 15 years of research, and he wanted to test his proof of concept. Going “back to basic chemistry,” and using a concept his high school-age daughter could point out, Thadhani figured, “Why not create a negatively charged column that allows me to remove the positively charged protein (sFLT-1)?”
Through apheresis, Thadhani was able to remove the positively charged sFLT-1 by passing it through a negatively charged dextran sulfate column. “The goal of our treatments,” he explained, “was to advance pregnancy in women coming in with very severe pre-term pre-eclampsia.”
Women with PE typically give birth earlier in the third trimester, at weeks 26 or 27, which can cause complications; by removing sFLT-1, Thadhani found that women were able to prolong their pregnancies, ensuring better health and safety of mother and child.
“My hope is, of course, to have a treatment available soon,” he said.