Angiotensin Blockade and Diabetic Nephropathy

June 30, 2009

The July 2 issue of the New England Journal of Medicine has an article on the prevention of diabetic nephropathy and retinopathy that will elicit much attention. It concludes “Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy.” An accompanying editorial reached the same conclusion. This finding is surprising. Angiotensin blockade is standard treatment for patients with diabetic nephropathy at any stage and is often given to diabetic patients before they show signs of kidney disease.

I’ll just focus on the renal findings. The conclusion is misleading on two counts. The first is that the design of the study excluded patients who were most likely to benefit from angiotensin blockade and the second is that the data are, in my view, improperly interpreted.

The exclusion criteria were microalbuminuria, hypertension, and a glomerular filtration rate (GFR) of less than 90 ml/min. Thus the patients followed were at lower risk to show major progression of diabetic nephropathy than those who already had clear signs of it. But let’s ignore this and just look at the data in the study.

The primary renal endpoint of the study was a change in mesangial fractional volume (MFV). Increasing MFV is an early marker of the progression of diabetic nephropathy. The patients had renal biopsies at baseline and after 5 years of follow-up. Secondary end points included changes in microalbuminuria and GFR. The data show that “MFV between baseline and five years increased by 0.016 unit in the placebo group (p=0.004) and 0.026 unit in the losartan group (p<0.001) but did not change significantly (0.005 units) in the enalapril group.”

This is the key finding that is ignored both by the study authors and the editorialists. Angiotensin inhibition with enalapril prevented mesangial expansion. The authors try to explain away this critical observation by saying that the MFV at five years was not significantly different across the three groups. So what! Mesangial expansion did not occur in patients treated with an ACE inhibitor. These data indicate that angiotensin blockade with an ACE inhibitor but not with and angiotensin receptor blocker prevents progression of diabetic nephropathy. This important observation is thrown away. It’s also missed by the three editorial writers. Doubtless the press and many physicians will also miss it.

Progression of microalbuminuria was a secondary outcome. None of the groups had microalbuminuria (defined as 20 to 200 µg/min ) at the start of the study and none had it at the end, though it did go from 6.5 to 10.6 in the losartan group. This is statistically significant, but seems likely to be of little or no clinical significance as it’s not even close to being outside the normal range.  Yet the editorialists say “Inhibition of the renin-angiotensin system did not reduce the incidence of microalbuminuria…” They doubtless were looking at how many patients within each group developed proteinuria even though albumin excretion was not abnormal in any group.

At the end of five years 18% of the losartan group had (see figure) microalbuminuria. Figure 2In the placebo group 6% had increased albumin excretion, while only 4% of the enalapril group had an increase and no patients on enalapril developed it over the last 2.5 years of the study. This again suggests a beneficial effect of ACE inhibition and a possible deleterious effect of the ARB. This makes the above statement seem a big stretch.

“The GFR decreased similarly in all three groups; by 6.6 to 8.9 ml/min (p<0.002 in all three).” But the GFR was still at least 120 ml/min. These data require an interpretation not offered in either the paper or the editorial. The blood pressure was lower in the two treatment groups. Angiotensin blockade can lower GFR at the same time it’s preserving glomerular function. I can’t be sure, but it is nevertheless possible that enalapril lowered GFR because of both a greater effect on blood pressure and a direct renoprotective effect on the glomerulus, while GFR in the placebo group fell because of disease progression. In other words, if the study were longer the GFR might have been much lower in the placebo group than in the enalapril treated patients.

What to make of this ambiguous study? I think that current treatment of patients with incipient diabetic nephropathy, regardless of whether type 1 or type 2, is best done with ACE inhibition. At the very least more study is indicated to resolve the issues I’ve discussed and which this paper leaves uncertain.

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Maria Cebotari Sings…

June 28, 2009

Cebotari

Maria Cebotari was born in in Romania in 1910. She studied singing at the Chişinău Conservatory but joined the Moscow Art Theater as an actress in 1929. She didn’t stay in Moscow long. By 1931 she was singing Mimi in Dresden. Her combination of good looks, acting skill, and most importantly a beautiful voice that could sing almost anything made her an immediate success.

In 1935, she sang the role of Aminta in the world premiere of Richard Strauss’ opera Die Schweigsame Frau under Karl Böhm. Her versatile voice allowed her to sing Carmen, Salome, Violetta, Mimi, Butterfly, Susana and the Countess, Sophie, and Zerlina among others.

Her voice is dark and smooth though she sang many light roles. Her high notes are characteristic of the German style soprano who sings a lot of Mozart and Strauss. There’s sometimes a charming ambiguity of pitch and support to them similar to the high notes of Schwartzkopf and Della Casa.

Cebotari died of pancreatic cancer at age 39. She never sang in the US. The only negative about her career was that it was mainly based in Nazi Germany. What her relationship with the Third Reich was is unclear to me. She was blacklisted from the Salzburg Festival after the war. She was said to have been the mistress of Nazi state commissar Hans Hinkel. She divorced her first husband, Alexander Virudov, in 1938 the same year she married her second, actor Gustav Diessl.

Here’s Dove sono from Mozart’s Figaro. Then the Boheme Act 1 finale (in German); the bright tenor is Marcel Wittrisch. Finally, Es gibt ein Reich from Strauss’ Ariadne auf Naxos.

Cebotari made numerous recording, many of which are still in print. She also appeared in several films. She was a great artist who is known only to opera aficionados. Her work deserves serious attention.

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The Ghost in the Machine – A Cautionary Tale

June 25, 2009

This piece has been floating around the internet for a while. I decided that I might as well have it on my own site. I’ll also put it under Commentary.

It all started a couple of years ago on a Saturday afternoon. I turned on the radio to listen to the weekly Metropolitan Opera broadcast, forgetting that Parsifal was scheduled. Being comfortably settled in a stuffed reclining chair, I was too lazy to turn the radio off. Besides, nothing can put you to sleep faster than Wagner. No sooner had
the music started than I conked out. A couple of hours later, I woke up with a terrible toothache. The first act of Parsifal was still oozing from my speakers. I called my dentist who agreed to see me immediately; the weather was too bad for golf, which explained his availability. A few minutes later, I was in his chair after having had enough
X-rays to cure two cancers.

“Root canal,” he said after looking at the films.

“You always say that,” I opined. He ignored my comment and proceeded to fill a syringe with enough anesthetic to make me numb to the waist.

“Wait,” I said, unwilling to be narcotized for a week. “Turn on the radio.” He did. The first act of Parsifal was still on. “God never made a pain that could stand up to that,” I said pointing to the radio.

The dental work took an hour. I felt nothing. Wagner’s slow, slower, and slowest tempos had turned my brain to Jell-O. I wondered if I shouldn’t have opted for the anesthetic after all. When I left the dentist’s office, the first act of Parsifal was still coming from my car radio which I always leave on.

After entering my house, my jaw started to ache. I turned on my stereo, set the volume as loud as my three amplifiers (1200 watts) and six speakers would reach allowing me to get the maximum anesthetic effect that the first act of Parsifal could deliver. It worked. I was immediately numb. Three hours later, the first act of Parsifal still not concluded, I figured could handle any residual pain sans Wagner. I turned off the stereo and went about my usual Saturday night activities.

On Sunday, I stayed home. Monday morning, I got into my car to drive to work. The radio started up as usual. The first act of Parsifal was still on. Strange, I thought, I don’t remember it being this long. But I really had never paid much attention to the opera, so maybe it was just a little bit longer than the rest of Wagner’s oeuvre. That evening as I drove home, the first act of Parsifal was still coming from my radio. Now I was sure something untoward was afoot. I turned the radio off to allow my brain to clear sufficiently to analyze what had happened. No explanation came to mind.

When I entered my house, I was afraid to turn on the radio for fear that the first act of Parsifal might still be on. But eventually, curiosity got the better of me and I turned the thing on. You can imagine my relief when not a trace of Wagner emanated from my speakers. KOHM was in the middle of a Frank Bridge festival. Thus, the problem seemed solved even if I could not explain it.

I was halfway to work the next morning when I turned the car radio back on, hoping to miss the end of whatever NPR was playing when to my amazement I encountered the first act of Parsifal. It now hit me that my car radio had contracted a persistent infection. I had heard about people being infected by Wagner, but never a machine. What might the cure be? The only thing I could think of was to put the radio at prolonged rest. So I turned it off, planning to keep it inactive for at least a month. Again I was amazed; it wouldn’t go off. Not only would it not quit, but the first act of Parsifal was now coming from every position on the dial. The infection had spread. The only way I could make the thing shut up was to turn off the ignition. That was not a long-term solution, however. In fact, it proved not to be a short-term fix either. When I turned off the ignition upon returning home that night, the first act of Parsifal continued to drone from the car’s speakers. What was I to do now? You could hear lugubrious leitmotifs all over the house. If I moved the car out of the garage onto the street, the neighbors would probably call the police. After a while, my dogs started to howl, the cat ran away, the parrot went permanently mute, and all my tropical fish died. I had to get rid of the car, but who would buy a car that was chronically infected with the first act of Parsifal?

After the worst night of my life, I called the National Kidney Foundation. They have a program that accepts used cars as donations. They were really interested when I described my almost new car, until I got to the Parsifal problem.

“This type of disease is outside the purview of the NKF,” said the foundation’s spokesman. He then hung up the phone before I could beg him to take the car.

The only course was euthanasia. I took the car to my vet and had him put it to sleep. It was a total loss. I immediately bought a new car, but only after trying out its radio. To my relief, the Frank Bridge festival was still being broadcast by KOHM.

When I got home, I turned on the TV to watch Sesame Sweet, but the picture tube was dark while the first act of Parsifal snaked from the set’s speaker. The first act of Parsifal was also on every radio and TV in the house. It was even on the house’s intercom. I had destroyed the car too late to prevent contagion. I turned off every device in the house attached to a speaker and darkened the house. The place was quiet for a few days. I felt comfortable enough to turn the lights on. The calm persisted. At six the next morning, my alarm clock went off as usual, but instead of the electronic beep, I was roused by the first act of Parsifal. Like a string of firecrackers, every speaker in the house took up the first act of Parsifal in a sequence of belching tubas and guttural barks masquerading as singing. I dressed as fast as I could and fled my contaminated house.

What was I to do? Burning down your own home is illegal – I think. Before I could ponder my predicament further, the first act of Parsifal came unbidden from the speakers of my new car’s stereo system like quicksand at a Tupperware party. The revelation of Oedipus’s descent was a mere bagatelle compared to the emotion that this sound provoked in my breast. My old car had infected my house, which in turn had infected my new car. I was in an abyss of despair. I abandoned the car in the middle of the road and walked to work.

The rest of the day passed like the final recollections of a drowning man. I couldn’t go home knowing what was waiting for me there, so I checked into the cheapest motel I could find hoping that it would not have a radio or a TV in it. Even at $12 a night there was a television set in the room. Of course, I didn’t turn it on. In fact, I unplugged it and left it in the parking lot.

I finally fell into a frenzied sleep, seething with primal fear. Then I awoke with a shudder. A sound filled the inside of my head; it was the first act of Parsifal. It was coming from the fillings in my teeth. They were acting like a crystal radio. I had become Parsifal positive. Despite the hour, I called my dentist. He was quite huffy about being disturbed at such a premature time until I told him that Wagner was coming out of my teeth – and not just any Wagner, but the first act of Parsifal.

“I’ve heard about cases like yours,” he said, “but I never thought I’d see one.”

“You haven’t seen it yet,” I said, hoping to encourage him to prompt action.

“Okay,” he said, “meet me at my office in 20 minutes.”

I was there in five.

“I’m afraid there’s only one thing that can be done for you.” The dentist was gowned and gloved; he wore a lead apron and protective headgear and leggings. He breathed through a portable oxygen apparatus. His office music system played Rossini overtures which he felt would protect the place from the infection. “All your teeth have to
come out.

“Will that cure me?”

“Who knows,” he shrugged, “but it’s all science has to offer.”

Two years or so have passed since I last showed signs of the first act of Parsifal.
I’m toothless, homeless, carless, and on permanent leave from my job. I won’t be allowed back until I’m symptom-free for at least five years. My health insurance has been canceled. My friends and family have abandoned me. I am a shell of a man.

Mama, don’t let your babies grow up to be Wagnerians.

Originally published:
Kurtzman NA: The Ghost in the Machine – A Cautionary Tale. Lubbock Magazine (August):34-35, 1997.

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The AARP and Newspeak

June 24, 2009

The AARP has hardly been a disinterested commentator on government provided healthcare given their stake in Medicare. Thus its article “8 myths About Health Care Reform” in its July/August 2009 magazine which describes itself as the “World’s Largest Circulation Magazine”. I’ll list the eight “myths” which would have made Orwell beam with pride. You decide whether these are myths or not. Of course the piece never does offer a concrete plan for reforming healthcare. Mephisto skulks in the fine print.

1. Health reform won’t benefit people like me who have insurance. (If the government does it you’ll likely be worse off.)
2. The boomers will bankrupt Medicare. (Of course they won’t my generation has already done it.)
3. Reforming our health care system will cost us more. (The government is going to save us money?)
4. My access to quality health care will decline. (Many physicians already refuse new Medicare patients.)
5. I won’t be able to visit my favorite doctor. (He’ll probably take early retirement.)
6. The uninsured actually do have access to good care – in the emergency room. (A real straw man. The uninsured use the ER no more often and sometimes less than patients with insurance.)
7. We can’t afford to tackle this problem now. (What’s a few more trillion dollars more at this point?)
8. We’ll end up with socialized medicine. (Precisely.)

I couldn’t resist throwing in a few comments. Just a few things to contemplate. Why does healthcare need reforming? There’s only one reason. It costs too much. So when the passion to reform strikes like anaphylaxis ask the question. If you can’t come up with the answer take a shot of epinephrine and rethink the issue. Also ponder how good government is at controlling costs. If the feds knew how to run a national healthcare program Medicare would not be virtually insolvent.

After you’ve come to grips with the cost of medical care, ponder how to increase coverage, make medical care affordable, while simultaneously making care readily available. When you’ve solved these problems reform away.

You could start with Medicare which has about $36 trillion (there are even higher estimates) in unfunded liabilities. Then move to the VA which has been described as a “shambles.” With these two government systems repaired you should be ready for the half of medical care that the government doesn’t yet control.

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Live Forever or Die in the Attempt

June 19, 2009

The world’s oldest man died. Long live the world’s oldest man. Have you noticed that being the world’s oldest man is a death sentence? You’re next to go. There’s no one in front of you. The article which notes this event mentions that Japan (the former world’s oldest man was Japanese) has the longest life expectancy in the world. This is typically attributed to the “healthy” Japanese diet which is rich in fish and rice.

No mention of the salt content of the average Japanese diet – the highest in the world. This taste for salt likely explains the high hypertension rate in Japan. Here too they lead the world. Also no mention of the country’s high smoking rate. The country which has the second highest life expectancy is Sweden where diabetes is rampant.

So diet and disposition only explain long life if you’re selective at what you examine and to what you attribute causality. It would be instructive to measure life expectancy in Japanese-Americans who eat a western diet and who tend to be taller and heavier.

The Honolulu Heart Program did just that. “The cohort of Japanese men in the Honolulu Heart Program studies has a life expectancy that is longer than their counterparts in Japan, and Japan has the longest life expectancy of any country in the world.” So I suppose you could conclude that eating an “unhealthy” American diet which Japanese-Americans tend to do lengthens your life expectancy if you start out with good genes.

Being the world’s oldest man is no plate of rice and fish balls. Remember Tithonus. He had a pretty rough deal. Eating a really boring diet may not make you live longer, but like the pilot in Catch 22 who only did boring things, your life will seem longer. Pizza and hamburgers are okay if you use a little common sense. Anybody know who is the current world’s oldest man?

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Recording of the Week – Thalberg/Rossini Variations

June 17, 2009

Rossini - Thalberg

I’ve mentioned Sigismond Thalberg’s fantasies on Italian operas before. They are a poetical take on the great Italian operas of the piano virtuoso’s time. Francesco Nicolosi has been a champion of Thalberg’s music for decades. Recorded in Budapest in March of 1992 Variations on Operas by Rossini contains fantasies on themes from four Rossini operas: Semiramide, La Donna del Lago, Il Barbiere di Siviglia, and Moïse.

Here is Thalberg’s setting of the great canonic ensemble Qual mesto gemito which is the centerpiece of the extended finale to the opera’s first act. Semiramide is perhaps Rossini’s greatest opera, certainly among the serious works. It’s so rarely performed because of the extraordinary demands in makes on the singers, especially the mezzo-soprano and the bass. It’s even harder to cast than Il Trovatore. It’s only had 28 performance at the Met. The first in 1892, the last in 1993. The was a span of almost a century when it wasn’t done at all.

The Met had Marilyn Horne and Sam Ramey for the 1990 run. Their extraordinary performances made the best case possible for this wonderful work. Here’s Qual mesto gemito performed as Rossini intended. Without great singers this opera is best left on the shelf.

The rest of Nicolosi’s Rossini album is filled with beautiful playing of some of the Swan of Pessaro’s most inspired tunes.

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Effectiveness and Cost

June 14, 2009

There’s a growing sentiment that a solution to out of control medical costs might be to limit reimbursement of diagnostic and therapeutic procedures that are deemed to be of little or no effectiveness. I’ve written earlier that this is rationing of medical care in disguise. But let’s look at his issue in a little more detail.

To start, give Something’s Got to Give in Medicare Spending a read. It’s by Tyler Cowan an economist from George Mason University. As is typical in this field, he’s got the economic reality of federal healthcare funding down cold. He’s on less solid ground when he shifts to the medical half of the equation:

If we are willing to take comparative-effectiveness studies seriously, we could make significant cuts in Medicare costs right now. We could cut some reimbursement rates, limit coverage for some of the more speculative treatments, like some forms of knee and back surgery, and place more limits on end-of-life-care.

He realizes that this won’t happen, but the reasons he gives, while valid, leave out the most important reason why this type of rationing won’t work. What he doesn’t realize, and almost no one wishes to admit, is that much (perhaps most) of medical care lacks good evidence for its effectiveness.

Consider cancer treatment. Chemotherapy for treatment of solid tumors (this excludes leukemia and lymphomas) are of limited or no effectiveness. Are we willing to tell this to cancer patients and their families? While almost any doctor outside of oncology will concede the point in private, vanishingly few will say so in public. Mull the implications of this if you think it might be true. If we were to save money by limiting care it would have to include the big stuff – cancer, heart disease, diabetes. You can’t balance the medical budget with less back and knee surgery.

Next go to psychiatry. Most of what psychiatrists do lacks even the slimmest basis in science for its effectiveness. It is the very lack of good evidence supporting treatment in oncology and psychiatry that make them the two most important specialties in medicine. I’m not being facetious. The less we know about something the more we need an expert for its management. Before penicillin there was a medical specialty devoted to the treatment of syphilis. Once we had an effective treatment we no longer needed an expert for its management.

The public and the medical profession would no more forsake the treatment of important diseases no matter how ineffective than would the Rostovs forgo treating Natasha’s depression in War and Peace even though they, the patient, and the doctor all knew that the treatment was useless. I’ll post the entire scene later. It should be required reading for all. When people are sick something must be done. Whether it works is secondary. Note that Natasha’s doctor is paid in gold at the end of his visit. Everybody was satisfied with his appearance because something was done. Natasha eventually gets better on her own.

Cowan concludes his NY times piece on a pessimistic note: The most likely possibility is that the government will spend more on health care today, promise to realize savings tomorrow and never succeed in lowering costs. It is rare that governments successfully cut costs by first spending more money. “Rare” is an understatement.

Also consider that the AMA has come out against a national government run medical care scheme, hospitals are protesting President Obama’s proposed cuts in Medicare, as is the pharmaceutical industry. Meanwhile The Access to Medical Imaging Coalition is lobbying against plans to reduce the number of CTs and MRIs done. There are too many stakeholders who won’t give up any of their piece of the pie to allow real reform. Also how can anything intelligent survive passage through two houses of 535 politicians.

When your dog becomes unmanageable you take him to a professional trainer hoping that he can bring the beast under control. If the trainer fails euthanasia is the only remedy. The health care beast seem beyond management.

So is there any way out of this mess? Mancur Olson had one. The late economist posited that the only way to reform a really big system was to have it first collapse. Politics would prevent any other remedy. Collapse has the salutary effect of allowing you to start over. All the stakeholders start with nothing. I think that medical care in this country falls under this category – too big not too fail.

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