The vision was to explore the moments nephrology went off the rails in order to inoculate us from making the same mistake in the future. Its okay to make mistakes, as long as we don't keep making the same mistakes. The four missteps we chose each demonstrate a unique failure.
In chronologic order lets review the nature of the missteps.
Science is hard
A generation of patients suffered CNS, bone, and blood pathology from aluminum hydroxide prescribed to patients in order to prevent hyperphosphatemia. This was the young science of dialysis coming up against the limits of technology. Sure, there was the assumption that oral aluminum could not be absorbed, that was later shown to be false, but in the end, science is hard and mistakes are made when we are operating at the event horizon of knowledge. The lesson here should be that we should remain humble and maintain an open mind when operating at the edge of science. Long held assumptions can turn out to be wrong and harm can come from the most banal of sources. A phos binder. Really?
Steroids for Membranous
Statistics are a bitch
The positive finding in the Collaborative Study of Adult Nephrotic Syndrome is a cruel twist of fate. When examining the Missteps, I wanted to find a villain in each story I wanted each one to be a modern medical morality tale. I looked for a way to blame the greedy, or the arrogant, or the sloppy, but the story of membranous is just a story about bad luck affecting good people trying their hardest to do honest science. Dumb luck resulted in 9 of the most aggressive cases of membranous nephropathy all landing in the placebo group. The steroids didn't preserve function, the placebo group just crashed and burned for no good reason. Bad things happen to good science. It happens because statistics demands it. Our only defense is to be vigilant against over interpreting fragile results and single trials.
Duel ACEi and ARB for Proteinuric Chronic Kidney Disease
It is easiest to fool people who want to believeThe story of of combining of ACEi and ARB is the classic medical reversal. The physiology and pathology tells explain that proteinuria is toxic. Two drug classes ACEi and ARBs have each separately been shown to be safe, effective and kidney protective. Early data shows that combining them unlocks synergistic reductions in the consensus surrogate outcome, proteinuria. The story was only missing improved hard outcomes with ACEi ARB therapy. This was satisfied by the 2002 COOPERATE trial in the Lancet. The trial answered all the hopes and dreams of nephrologists. It showed successful retardation of proteinuria and delayed dialysis. But when the trial is everything you ever hoped for, it probably would be wise to take a second look and go through the results patient by patient. The COOPERATE trial turned out to be a fraud. What is the lesson from ACEi and ARB? Stories that fit together like a perfect little present probably don't and deserve special scrutiny.
Normalization of Hemoglobin
Don't be distracted by the perfect little story, keep your eyes on the prospective data
The story of the normalization of hemoglobin and the damage it did has been told over and over. Much of the blame is directed at the companies that profited from the drugs, but nephrologists have agency. We are not automatons that are incapable of individual thought. Beserab published the truth in 1998 and we let conflicted parties set the guidelines and agenda in opposition to that truth. There is fault enough for all, but before nephrologists can wag their collective finger at the editors at NEJM, or the authors of KDOQI, or the share holders of AMGEN, we need to come to terms with how we ignored what was right in front of our eyes. We wanted to believe that improving hemoglobin could magically erase the cardiovascular disease killing our patients. It was a nice fairy tale, but it wasn't true.
Medical marketing used to mean mugs, pens and ads in journals. Now it means thought leaders, surrogate outcomes, studies and guidelines.— Joel Topf, MD FACP (@kidney_boy) March 31, 2016