Interview with Dr Hollenberg

Prof Norman K. Hollenberg Harvard Medical School Department of Radiology Brigham and Women's Hospital Boston, USA

Prof Zoccali: The renal response to changes in salt intake and its manipulation is perhaps your leading scientific interest. Could you tell us how this interest originated?

Dr Hollenberg: Our original renal blood flow studies were performed with radioxenon, injected into the renal artery at the time of angiography. We found a sharp difference in the normal kidney, in potential kidney donors, and in hypertensives who were being examined for renovascular disease. Because blood samples were being drawn from the renal vein as part of the evaluation in hypertensives, they were placed on a low-salt diet to activate the renin system: thus, we had to assess the affect of the low-salt intake in normals. The effect was striking. Much, if not all, of that renal response to restriction of salt intake reflects the local response of renin and AngII.

Prof Zoccali: You have a long, fruitful and much rewarding collaboration with Dr Gordon Williams. Not infrequently long collaboration brings also frictions and dissent. What was the good chemistry of this successful and enduring scientific alliance?

Dr Hollenberg: When our collaboration began, about thirty-five years ago, we had no long-term goals, no contract, and no commitment to anything except the next question. As we are a Committee that has only two members, there has never been a vote. We have to achieve consensus. It does help that we like each other, admire each other, and value each other. You will not be surprised that we have become rather good friends.

Prof Zoccali: You have lucidly delineated the “modulator” and “non-modulator” phenotypes. Beyond clinical research do you foresee a clinical application for this categorization?

Dr Hollenberg: Because nonmodulators show a large response to blockade of the renin-angiotensin-system with ACE inhibitors or ARBs, it would be attractive if we could identify them easily. Alas, we cannot identify them easily. We had examined approaches more simple than controlling salt intake and assessing the response to Ang II but only with limited success. For a time, sodium:lithium countertransport in RBCs was attractive. Later, the possibility that specific genotypes would identify nonmodulators was attractive. At the moment, it remains an interesting idea.

Prof Zoccali: Barker hypothesis is much intriguing and the number of epidemiological and experimental studies revolving around this hypothesis is rapidly increasing. Do you envisage a link between the dictate of this hypothesis and the modulator / non-modulator phenotype?

Dr Hollenberg: An interesting subject but rather difficult to study.

Prof Zoccali: Some believe that in the near future pharmacogenomics will dictate doctors choices but many remain skeptical about this perspective. What is your view on this problem?

Dr Hollenberg: It appears that a large number of genes are involved in the pathogenesis of hypertension, and current technology does not allow us to use the information clinically. Many of us continue to live with hope.

Prof Zoccali: The distance between basic and clinical research is widening. Do you think that it is more difficult now for young investigators to acquire a “from the bench to bedside” experience?

Dr Hollenberg: The broadening scope of the science, which now includes an extraordinary array of mechanisms and approaches has created many new opportunities for working directly from the bench to the bedside. Perhaps the most difficult issue is a practical one. The funds required to support clinical investigation have been increasingly difficult to find. As clinical research is inherently expensive, this step is almost always rate limiting.

Prof Zoccali: Do you believe that it has been a mistake for nephrology not having posed hypertension at centre stage in renal research 20-30 years ago? Why has nephrology for so long overlooked the problem of mild degrees of renal insufficiency in essential hypertensives?

Dr Hollenberg: Fashions in science, like fashions in every other part of life are impossible to control. Fortunately, the pendulum has swung, and interest in hypertension is a perfectly respectable stance for a nephrologist!

Prof Zoccali: Which is presently the research problem at the top of your interests?

Dr Hollenberg: I have been interested in the factors responsible for nephropathy in the patient with diabetes mellitus for the past fifteen years, with at least some success in identifying such factors. Diabetic nephropathy is a wonderful place to try to tease out the relationships between environmental factors, major genes, and polygenic effect. My second interest involves the biological effects of flavonoid-rich foods. As it turns out, flavanoid-rich cocoa activates vascular nitric oxide synthase in intact human beings -- including the blood supply to the extremity, the kidney, and the brain. The clinical implications are potentially enormous, and it is great fun to be working in a new area at my stage of live.

Prof Zoccali: Which is the scientific paper that had the greater impact on your scientific projects?

Dr Hollenberg: There have been a large number of papers, of course, that have influenced my work. When I first came to Boston a paper had just appeared from the physiology laboratory at Harvard Medical School written by Clifford Barger and his associates that described radioxenon transit through the dog kidney. I had become interested in acute renal failure and saw the potential of that method for studying the blood supply of the kidney in patients with acute renal failure from the moment that I read the paper. To accomplish the goals, I had to set up a new method in humans, teach myself to become an angiographer -- the radioxenon had to be injected into the renal artery -- and had to persuade the physicians involved and the patients to let me do the studies. Essentially all the good things that have happened to me since that time arose from the success of that first attempt to study the renal blood supply. In life, it is not only good to be lucky, it is best to be lucky early!

Prof Zoccali: Which is your favorite hobby?

Dr Hollenberg: I read, day and night, for work and for pleasure. When your questions arrived, I had just finished reading a novel, recently translated from the Italian by Umberto Eco entitled ”Baudolino”.