If you’re here for the music you still might give this piece a glance. It’s on a subject of immense clinical importance that I’ve tried to present in a fashion accessible to layman while still having some content that might interest physicians. Some of the greatest work in medical pathophysiology has contributed to our current view of this system. This work should have been rewarded by several Nobel Prizes, but for some inscrutable reasons the Nobel committee has ignored it.

The story starts almost 200 years ago with the work of Richard Bright (1789-1858). Bright was one of the three great men of Guy’s Hospital in London. The other two were Thomas Hodgkin and Thomas Addison. All three had diseases named for them. Addison died a suicide. Today, doctors have the highest suicide rate of any profession. I may turn to this subject in a later post.

“Bright excelled at making meticulous clinical observations and correlating them with careful postmortem examinations. The results of his wide-ranging researches first appeared in Reports of Medical Cases (1827), in which he established edema (swelling) and proteinuria (the presence of albumin in the urine) as the primary clinical symptoms of the serious kidney disorder that bears his name. Bright’s subsequent papers on renal disease were published in a second volume of Reports (1831) and in the first volume of Guy’s Hospital Reports of 1836″ (from Encyclopedia Britannica entry on Bright). He also noted that patients with kidney disease often had enlarged hearts. He offered no explanation for this finding. The critical importance of cardiomegaly (enlarged heart) in this story was appreciated about a century latter.

The next important figure was Robert Tigerstedt (1853-1923). Tigerstedt was a Finn who did his most important work at the Karolinska Institute in Stockholm. He was a great physiologist who authored the definitive textbook of medical physiology of his time. He was a member of the initial Nobel Prize committee for Medicine and Physiology. He was unsuccessfully nominated for the prize twice. The reason his name survives is as the discoverer along with his student Per Bergman of renin. Bergman went into general practice after graduating from medical school. He never did another experiment, but if you do one like this you don’t have to.

What they did was make extracts of rabbit kidney and then infuse this extract into other rabbits. They showed that very small amounts of their extract caused large increases in blood pressure. They further showed that no then known substance was the causal agent for this increase in blood pressure. Accordingly, since it came from renal tissue they called it renin. They published their finding, in German, under the title ‘Niere und Kreislauf’ (Kidney and Circulation) in 1898 in the Scandinavian Archives of Physiology.

From “Niere und Kreislauf,” demonstrating in four rabbits the pressor effect of a crude saline extract of rabbit kidney.

The discovery of renin is one of the great achievements in medical physiology, but its initial report was greeted with monumental neglect. When Tigerstedt died in 1923 none of the memorial tributes to him mentioned renin. His reputation today rests solely on his discovery of this substance.

Harry Goldblatt (1891-1977) was an American pathologist who performed what in many observers, including me, think is the greatest physiological experiment of the 20th century. Parenthetically, the Wikipedia which has a bio on every 1 bit sports or entertainment figure you never heard of has no entry for Dr Goldblatt. Goldblatt started training as a surgeon but switched to pathology. In this latter capacity he noted that patients who had hypertension showed nephrosclerosis (hardening of the blood vessels within the kidney) on histologic examination of their kidneys. He thus formulated the theory that nephrosclerosis was the cause of hypertension rather than the other way around. Thanks to his and others’ work we now know that hypertension comes before nephrosclerosis and is its cause.

Harry Goldblatt and subject

But back to Goldblatt’s original thinking. Nephrosclerosis would result in diminished renal blood flow which in turn would cause hypertension. He couldn’t induce nephrosclerosis, but he could reduce renal blood flow by putting a clamp around each renal artery narrowing its diameter and thus causing, he postulated, increased blood pressure in an experimental animal. Today if you wanted to use his model you’d contact the nearest medical device supplier and ask for a Goldblatt clamp. Obviously, he had to construct the first such clamp. It took him several years to get the device right. Today he’d likely lose his extramural funding before he could do the experiment and we’d not have his momentous work.

When he had built a silver clamp which worked as desired, he used his surgical training to good advantage. Rather than do a midline incision on his dogs and put a clamp on each renal artery, he did a flank incision and put a clamp on one renal artery allowing the animal to recover from the surgery. He would then clamp the second renal artery. His initial hypothesis required both renal arteries to be clamped before hypertension developed. But to his surprise blood pressure rose immediately after one renal artery was narrowed.

Fortune favors the prepared mind and Goldblatt had such a mind. He  was one of the very few investigators aware of Tigerstedt and Bergman’s discovery of renin. He postulated that diminished perfusion of the clamped kidney was stimulating renin release which in turn raised blood pressure. To support this new hypothesis he developed a bioassay to measure renin. It’s values were in “Goldblatt Units” – if you invent the assay you can name the units after yourself. He showed that large amounts of renin were coming solely from the clamped kidney. When both kidneys were clamped the test animals were still hypertensive but renin values were not elevated. It took about 40 years to sort these two models out, but for a while it caused some investigators to think that renin was an epiphenomenon as an animal could be hypertensive with both low and high renins. The explanation for these findings is below. Regardless, Goldblatt and colleagues’ 1934 paper in the Journal of Experimental Medicine is a scientific landmark.

The Goldblatt bioassay was replaced by the radioimmunoassay. The development of this technique resulted in a Nobel Prize. Important as it is, it’s just another way to measure something – it does not have the explanatory power of Goldblatt’s and successors’ work which was not rewarded by the Nobel Committee even though hypertension is the world’s most common disease. When I gave the Goldblatt Memorial Lecture at Cleveland’s Mount Sinai Hospital they were still measuring renin in Goldblatt units even though everyone else was using the radioimmunoassay.

A number of investigators worked out the details of how renin affected blood pressure over the next few decades. Renin is not a direct cause of increased blood pressure. It is an enzyme that works on a protein manufactured by the liver (angiotensinogen). Renin breaks the bond between two of the amino acids of this protein such that a 10 amino acid molecule is released (angiotensin I). Two more amino acids are cleaved by another enzyme, angiotensin converting enzyme (ACE), found mainly in the lung yielding an 8 amino acid long molecule (angiotensin II). Angiotensin II, depending on how you do the measurement, is the most potent naturally occurring vasoconstrictor – it contracts vascular smooth muscle and thus raises blood pressure. It also stimulates the adrenal gland to release aldosterone (Aldo) and the hypothalmus to form and the pituitary to release antidiuretic hormone (ADH).

Thus, angiotensin directly increases blood pressure by its effect on the arterial circulation and indirectly increases blood pressure by causing sodium retention secondary to Aldo release and water retention via ADH. The well known antihypertensive drugs – the ACE inhibitors – work by blocking the action of the enzyme just described. The retention of salt and water raises blood pressure by expanding blood volume.

John Laragh and colleagues working at Cornell Medical School completed this work by answering the questions that remained unclear from Goldblatt’s work of almost four decades earlier. If one kidney was clamped and the other untouched, renin release from the underperfused kidney was the cause of hypertension. If both kidneys were clamped or the normal kidney was removed leaving the clamped kidney in place the animal was still hypertensive, but renin levels were not increased. The difference between the two models is that 50% of the renal mass has decreased blood flow versus 100% in the two clamp or one clamp one kidney state. An underperfused kidney retains salt but the presence of a normal kidney allows this salt to be excreted such that there’s no perceptible increase in blood volume.

The Cornell investigators showed that the renin angiotensin system was responsible for the high blood pressure observed in the one clamp two kidney model – ie, a clamped kidney and a normal one. In the animal model of unilateral renal artery stenosis, removal of the non underperfused (normal) kidney results in a fall of the plasma renin activity to normal – nevertheless, hypertension perists. This form (a solitary underperfused kidney) of hypertension is associated with salt retention.

Treatment of animals having unilateral renal-artery stenosis with a specific angiotensin antagonist results in relief of the hypertension. This treatment has no effect on hypertension, however, when the uninvolved kidney has been removed. When such a one-kidney animal is salt-depleted, its blood pressure again becomes sensitive to the hypotensive action of a specific angiotensin antagonist.

When the entire renal mass is underperfused, the underperfused kidney or kidneys are responsible for maintaining sodium balance. It seems likely that the following events (see figure below) transpire when the entire renal mass is underperfused. Initially, there is an increase in renin release and salt retention, both secondary to renal underperfusion. These events result in hypertension and in extracellular volume expansion. Volume expansion increases blood pressure and eventually results in restoration of renal perfusion, suppression of accentuated sodium reabsorption, and inhibition of renin release. Thus, a new steady-state is reached that is characterized by hypertension on a volume rather than a pressor basis. Thus, renin dependent hypertension has been replaced by volume dependent hypertension.

When I was at the University of Illinois our group showed that the human equivalents (there are many and are not discussed here) of bilateral renal artery stenosis had low renin levels on an unrestricted salt diet and high renins when salt was withdrawn or depleted. Regardless of salt intake they were always hypertensive. When the renal vascular disease gets so bad that no amount of volume expansion can reperfuse the kidney the syndrome that develops is malignant hypertension.

The relationship of renin and blood volume when both kidneys are underperfused (Kurtzman, et al Arch Int Med 133:195, 1974)

Thus, what all this work says is that there are two ways to get high blood pressure either alone or in combination. Blood volume  might be elevated because the kidney retains too much salt. Anything that constricts the arterial vessels (like  angiotensin II) would also raise blood pressure. About 25% of hypertensive patients have volume mediated hypertension. About 10% have vasoconstrictor (or pressor) mediated high blood pressure. While the rest have a combination of the two mechanisms.

The formula for blood pressure is BP= CO x SVR. (CO=cardiac output; SVR= systemic vascular resistance). Thus there are only two general mechanisms that can raise blood pressure. CO is the volume term, if you retain salt CO goes up. SVR is the vasoconstrictor element. You’d have thought that any medical student looking at this simple formula would long ago have postulated what  took the greatest medical minds almost two centuries to formulate.