While working in several Baltimore hospitals from 1996 to 2002, something struck nephrologist Macaulay Onuigbo, MD, MSc, as odd: Certain patients who presented with indisputable renal failure, while on concurrent ACE inhibitor and/or ARB therapy, did not exhibit any of the usual previously reported accompanying characteristics: no serious heart failure, no hypotension, no dehydration, no use of nonsteroidal anti-inflammatory drugs (NSAIDs) or COX inhibitors, and no evidence of renal artery stenosis on conventional angiograms.

“There was no known reason for the observed kidney failure,”recalled Dr. Onuigbo (pronounced on-oh-WEE-bo), then an internal medicine resident and subsequently a nephrology research fellow at Johns Hopkins School of Medicine (volunteer), and finally a clinical nephrology fellow at the University of Maryland Medical School, Baltimore.

“But when we would stop the ACE inhibitor, patients would get better. That got me thinking that perhaps, sometimes, these drugs were causing kidney damage, not protecting from it.”

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The reason he and his colleagues considered RAAS blockade a potential culprit was a report discussing microvascular arteriolar narrowing in the renal vasculature that was observable in histopathological studies but not evident in conventional angiography (QJM 1990:77:997-999).

Testing the theory

In 2002, Dr. Onuigbo joined the Mayo Health System’s Midelfort Clinic in Eau Claire, Wis., as a nephrologist, transplant physician, and hypertension specialist. He received permission to conduct a prospective cohort “mini-study” of sorts to test his theory that perhaps renin angiotensin system blockade had drawbacks that had been overlooked.

Starting in September 2002, Dr. Onuigbo enrolled any patient whose serum creatinine level had risen by at least 25% over baseline during the preceeding three months, and who had been on an ACE inhibitor, an angiotensin receptor blocker (ARB), or both, for periods greater than three months before the increase was recorded.

“In addition to my usual treatment for kidney failure, I would stop the ACE inhibitor or ARB,” said Dr. Onuigbo, an Adjunct Assistant Professor at the Mayo Clinic College of Medicine in Rochester, Minn., and the Regional Director, Northwestern Region, Mayo Health System Practice-Based Research Network (MHS-PBRN).

By 2006, Dr. Onuigbo was able to perform subgroup analyses on nearly 100 patients. with kidney failure, some of them with irreversible ESRD. Interestingly, 75% of the cohort was older than 65 years, 65% were older than 70, and 23% were older than 80. He identified five patients with clear renal failure that, in his opinion, could be explained only by the fact that they had been using an ACE inhibitor. All patients improved when the drug was discontinued.

A difficult reception

Acceptance of his hypothesis remains elusive. After agreeing to travel to the Mayo Clinic’s Rochester headquarters in late 2006 to present his data at grand rounds, Dr. Onuigbo was warned by his department chief that he was in for a difficult reception, which proved to be true. “It was like a candidate giving a speech to members of an opposing political party,” he joked.

When he got back to Eau Claire, he had two or three e-mail messages commending him on a good presentation. But most responses to his presentation were critical, as he had anticipated. He had only hoped for an open academic discussion of the issues. Dr. Onuigbo related, “The general knee-jerk response was, essentially, ‘This can’t be true.’”

The worst was yet to come. His grand rounds presentation earned him an invitation to write up his findings for the Mayo Clinic Proceedings .Dr. Onuigbo said he spent months perfecting his manuscript before submitting it, then more months complying with a multitude of requested revisions. After turning in the final product in March 2007, he received what still stands as the worst rejection he has received in more than 20 years of publishing. “They made it clear that this was a hard rejection: ‘Not to consider resubmitting.’”

But Dr. Onuigbo told this story with humor rather than bitterness, perhaps because it does have a significant bright side: “The hard rejection kicked me into high gear,” he explained. “I said, ‘Okay, if this is the last thing I’ll be able to achieve academically, I’m going to put in every ounce of effort that I have.’”

Deciding that perhaps one comprehensive report encompassing all his controversial angles might prove too much for others to absorb, Dr. Onuigbo made his offerings more bite-sized.

“For example, I talked about my five patients with what I call LORFFAB—late-onset renal failure from angiotensin blockade—in one paper with our postulated hypothesis for the presence of microvascular renal artery stenosis (mRAS), another seven patients with accelerated contrast-induced nephropathy while on concurrent RAAS blockade in another paper, and the 26 with MRA evidence of renal artery stenosis who had presented with new unreported findings in yet another. I thought it would be easier to convince people to consider my findings a little bit at a time.”

Making headway

Dr. Onuigbo’s work was eventually published in various journals. “In 2008, we were able to publish a total of eight papers on related topics in good internal medicine and nephrology specialty journals,” he said.

Although the use of the pronoun “we” in his reports implies that at least one colleague collaborated with him in exploring his unpopular study objectives, his co-author is actually his wife, a database analyst who helps him tabulate his data and create graphics that showcase his statistics. (“I could never get another MD to put his name on this because up until recently the whole concept was viewed as taboo,” he said with a laugh.)

Various journal editors who reviewed Dr. Onuigbo’s submitted articles asked what happened to the patient’s proteinuria when the ACE inhibitor or ARB was discontinued. When they learned it increased, they questioned how Dr. Onuigbo could then claim the kidneys were getting better.

In his most recent published paper , he provides a figure showing the dissociation between simultaneous changes in estimated glomerular filtration rate (eGFR) and proteinuria after discontinuing lisinopril in a LORFFAB patient (QJM. 2009:102:155-167) .

“After being on the ACE inhibitor for several years, that patient’s eGFR went from about 35 [mg/mL/1.73 m2] to maybe 15,” Dr. Onuigbo recounted.

“We stopped the lisinopril in September 2004, and his creatinine clearance went back up to 35 and remained there. At the same time the protein in his urine increased, so the two don’t necessarily have to go together.” In 1994, Tsalamandris et al had demonstrated a dissociation of trends between kidney function as measured by creatinine clearance versus proteinuria as measured by 24-hour urine protein excretion (Diabetes 1994:43:649-655).

Furthermore, studies have shown that proteinuria per se does not necessarily translate to good or bad outcomes, and that would explain why the combination therapy used in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) reduced proteinuria but did not improve outcomes, according to Dr. Onuigbo.