Diagnosing scleroderma renal crisis can sometimes be a challenge, particularly if it is the first presenting symptom of scleroderma.
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Explore This IssueFebruary 2021
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Entrance of the Ace Inhibitors
When the kidney senses it isn’t getting enough blood, it secretes renin, which acts on the protein angiotensinogen to produce angiotensin I. In the 1950s, researchers discovered the enzyme that could transform angiotensin I to angiotensin II, a powerful vasoconstrictor.7 Dr. Whitman explains, “All the blood vessels in your body start constricting, and let’s say you have a finite amount of salt and water and blood circulating. Your blood vessels go into spasms, and your blood pressure shoots up.”
This angiotensin-converting enzyme (ACE) eventually attracted attention as a drug target. This eventually led to the breakthrough development of the first successful oral ACE inhibitor, captopril, in the 1970s, which displayed a clear antihypertensive effect.7
John H. Laragh, MD, was one of the pioneers in the study of the renin-angiotensin system and hypertension. He and others were exploring the role of ACE inhibitors in the potential treatment of essential hypertension at the Hypertension-Cardiovascular Center at the New York Hospital–Cornell Medical Center.8
Researchers had hypothesized that elevated renin might play a pathological role in scleroderma renal crisis, based on animal studies and some earlier case reports. Dr. Steen says, “The ACE inhibitors were a brand-new class of medications. John Laragh was working on it for hypertension, and by around that time they knew that scleroderma was a renin-driven hypertension type of thing, so it was natural to try it.”
In 1977, Dr. Laragh and his colleagues published “Reversal of Vascular and Renal Crises of Scleroderma by Oral Angiotensin-Converting-Enzyme Blockade,” the first case report to describe the effects of an ACE inhibitor on scleroderma renal crisis.6 It detailed the stories of two scleroderma patients who displayed dramatic reversal of their renal crisis in response to captopril (SQ 14225), which had not yet been released publicly. The authors proposed that captopril, if used at the first sign of scleroderma renal crisis, might provide a powerful tool to protect against renin-induced vasoconstriction and so prevent life-threatening vascular damage.
Dr. Steen was pursuing a fellowship in rheumatology at the University of Pittsburgh, where she worked under the esteemed rheumatologist Gerald P. Rodnan, MD. She recalls that Dr. Rodnan was in communication with William A. D’Angelo, MD, a co-author and one of the physicians collaborating with Dr. Laragh.
As a fellow, Dr. Steen herself treated “patient 2,” a 25-year-old student with newly diagnosed severe scleroderma. She recounts that he and his family were in Florida over the holidays. “We got a call that he was in the emergency room with a blood pressure of 220 over 120. Dr. Rodnan had just found out about this drug and its availability, and he made it all happen.” They arranged to have him flown back to New York City for treatment. She adds, “We literally saved his life with this drug.”
Other reports soon followed. In 1981, another case study out of University of California, Los Angeles, described four patients with scleroderma renal crisis successfully treated with captopril.9 Another key study came out in 1982 from Dr. Laragh’s group working in collaboration with Dr. LeRoy: Variable Response to Oral Angiotensin-Converting-Enzyme Blockade in Hypertensive Scleroderma Patients.10
Dr. Whitman, the study’s first author, first began working with Dr. Laragh during a second-year resident elective at the Hypertension Center. Dr. Laragh asked his resident to study the response to captopril in his patients with scleroderma who had hypertension. He began treating these patients shortly before captopril’s FDA approval for essential hypertension.
Dr. Whitman analyzed seven patients with scleroderma renal crisis as well as a group of five patients with hypertensive urgency. Blockade of the angiotensin system effectively controlled blood pressure in all the patients. Five out of the seven patients with scleroderma renal crisis progressed to renal failure despite this, suggesting that their renal function had already been too compromised.10
Dr. Whitman explains, “If we didn’t get them on the captopril before their serum creatinine began to climb very rapidly, specifically a value about 2.5, they went ahead and went into renal failure. But if we gave them the medication before their serum creatinine got worse, we were able to stop them from getting malignant hypertension.”
Dr. Whitman notes that although this article received a lot of publicity, many other centers around the country were working on the topic, particularly the University of Pittsburgh. He adds, “We just happened to get more patients faster because we were working not only out of a rheumatology group of patients but also a hypertension center that was well known and run by Dr. Laragh, who was a very famous guy.”
Dr. Steen recounts that ACE inhibitors for scleroderma renal crisis moved into practice rapidly. Dr. Steen, Dr. Rodnan, Dr. D’Angelo and Dr. LeRoy planned to do a trial comparing captopril with minoxidil. She adds, “Then the drug came out, and nobody would enter anybody into the study, because people were finding out that the drug worked so miraculously that they wouldn’t even consider doing a controlled trial with another drug. You could give them this drug, and it was so dramatic—you could just see it. Particularly because, before then, almost everyone died.”