Renal hemodynamics

Renal Hemodynamics” KLAUS

THURAU,

M.D.~

Giittingen, Germany

T

HIS review is concerned with the basic pattern of renal hemodynamics. No attempt has been made to include the extensive body of information dealing with renal hemodynamics in disease, a field of obvious and paramount importance, but one which I do not consider myself competent to discuss and treat critically. The material considered herein is that most pertinent to intrarenal blood flow distribution and regulation. A hypothesis concerning the latter is included, and some of its consequences discussed. Methods recently developed for measurements of renal blood flow and intrarenal blood flow distribution are described in the “Addendum.” Some degree of arbitrary selection of the material was necessary since in a review of this size all conflicting evidences cannot be sorted, weighed and considered.

almost entirely contributed by these two vascular segments. This conclusion is derived from micropuncture studies of peritubular capillary pressures which in the nondiuretic rat kidney average 16.1 mm. Hg [P-3]. Unfortunately, direct measurements of glomerular capillary pressure are not available, and the correct distribution of resistance to flow between preglomerular and postglomerular arterioles cannot be calculated. It is a reasonable but unproved assumption, however, that glomerular capillary pressure is in the range of 70 mm. Hg [4,5]. The hydrostatic pressure drop along the preglomerular arteriole is therefore of the same order of magnitude as along the postgiomerular arteriole (Fig. l), and resistance to flow is almost equally distributed between these two segments. The pressure drop from the large to small peritubular capillaries of 4.7 mm. Hg [z] indicates only a small resistance to flow created by this segment. A final pressure drop has been found at the intrarenal to extrarenal border of the renal veins [56,7]. In Figure 1 the pressure profile along the nephron has also been marked to portray schematically the average intrarenal pressures which are commonly recorded by a fine hypodermic needle pierced into the renal parenchyma. The needle pressure often is used as a measure of renal tissue pressure. However, if arterioles are ruptured by the needle, the needle pressure may reach much higher values. The significance of the needle pressure in respect to intrarenal pressures always remains somewhat questionable. Intrarenal Regulation of Renal Blood Flow. Renal blood flow is subject to a type of control which seems to be more highly developed in the kidney than in other organs, As arterial pressure is increased above 90 mm. Hg, renal blood flow does not follow the increase in blood pressure

TOTAL RENAL BLOOD FLOW It is generally assumed that the kidney is perfused by an unusually high blood flow rate per gram of tissue. This holds true, however, only for the renal cortex, with 400 to 500 ml. per 100 gm. per minute. In contrast, the renal medulla is perfused with 120 ml. per 100 gm. per minute in its outer zone, and 25 ml. per 100 gm. per minute in its inner zone (see section on “Medullary BloodfFlow”). Since up to 75 per cent of the kidney consists of cortical tissue, 93 per cent of total renal blood flow perfuses the renal cortex; the term renal blood refers primarily to cortical flow, therefore, blood flow rate. The special features of medullary hemodynamics are discussed in a later section. Pressure Gradients Along the Renal Vascular Bed. Both preglomerular and postglomerular arterioles are muscular vessels, and total renal resistance to flow under normal conditions is

* From the Department of Physiology, University of Gettingen, Germany. The work referred to herein of the author and his associates has been generously supported by the U. S. Department of the Army through its European Research Office and the Deutsche Forschungsgemeinschaft. t Currently American Heart Association Visiting Scientist, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

698

AMERICAN

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Renal Hemodynamicsbut stays almost constant. Since this increase in resistance to flow has been found in innervated, denervated and isolated kidneys, and during blockade of intrarenal ganglia [ 72-791, resistance changes appear to be wholly controlled by the kidney. This phenomenon, which is called autoregulation of renal bloodjow, has been investigated by numerous laboratories in the last decade, and it is still a matter of great controversy. The stimulating observation of Forster and Maes [72], later confirmed by others [ 73,74, 20,271, that not only renal blood flow is autoregulated but also glomerular filtration rate, suggested that the resistance changes are located in the preglomerular vascular segment. Further evidence for the preglomerular localization is derived from micropuncture measurements of pressures in peritubular capillaries and proximal and distal convolutions of the nephron in rats [3]. When arterial blood pressure was varied between 90 and 190 mm. Hg, these postglomerular pressures were constant in the range of 15 mm. Hg. (Fig. 2.) This is also true when postglomerular pressures are measured by the needle technic in dogs [22,23], rats, guinea pigs, cats and rabbits [24], or when estimated even more indirectIy from that ureteral pressure which must be applied in order to produce a diminution of urine flow [251. The effect of drugs that paralyze smooth muscle upon autoregulation suggests that the autoregulatory resistance changes are of myogenie origin. Ochwadt [76] first showed that the pressure/flow curve remains linear above 90 mm. Hg arterial blood pressure when potassium cyanide or novocain was added to the inflowing blood. The same was found by Thurau and Kramer [20] using papaverine, and by Waugh and Shanks [79] using procaine or chloral hydrate. Some have inferred that the increase in renal blood flow caused by these drugs is due to opening of arteriovenous shunt vessels, in which case peritubular capillary pressures should fall or remain constant. Pressures in cortical peritubular capillaries as well as in proximal and distal convolutions of the nephron, however, increase during the action of drugs that paralyze smooth muscle and become linearly correlated to arterial blood pressure above 90 mm. Hg [3]. These data indicate that blood flow is increased in all parts of the cortical vascular system. Moreover, the fact that the autoregulation of glomerular filtration rate is also abolished during the action of VOL.

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papaverine [a] may be taken as evidence against a non-uniform intrarenal distribution of blood flow, as would be expected if arteriovenous shunts were opened. In a recent extensive anatomic study, von Kiigelgen et al. 117741 could not confirm earlier findings of arteriovenous shunt vessels in the renal parenchyma. Finally, it is noteworthy that muscle-paralyzing drugs do not increase renal blood flow at blood pressures below 80 mm. Hg [76,20]. This indicates that under normal conditions myogenic tone of renal vessels is nonexistent at low arterial pressure and that the onset of an increasing vascular tone with increasing blood pressure appears at a pressure range at which glomerular filtration rate becomes normal. The question arises as to what stimulates the smooth muscle to constrict when blood pressure increases above 90 mm. Hg. Perhaps the most popular hypothesis, outlined in 1902 by Bayliss, is that myogenic reactions are brought about by changes in vessel wall tension [26]. The estimation of vessel wall tension is based upon the simplified La Place equation: T~~II = r(pi,

-

pout)

(1)

where “r” = inner vessel radius, Pi, = intravascular pressure and Pout = extravascular pressure (tissue pressure). Since “r” varies only with

120

v

100 issw

_

80 Pressure fmmHg’60

40 20 0 FIG. 1. Hydrostatic pressure gradients in the renal vascular and tubular systems during antidiuresis.

700

Renal Hemodynamics-

the fourth root of resistance changes, it can be considered constant. TNart then depends primarily on Pi, - Pout, the transmural pressure difference. Furthermore, “r” of the individual arterioIe is not known, and only T,V,rr of an analogue vessel, which develops the same resistance to flow as the numerous parallel arterioles, can be calculated using Poiseuille’s law. In the following discussion, changes of transmural pressure difference are therefore taken as a first approximation of changes in vessel wall tension. As mentioned earlier, postarteriolar tissue pressures remain constant during elevated blood pressure. Since the muscular arterioles are surrounded by this tissue, transmural pressure difference and thus wall tension of the arterioles will vary with blood pressure. If an increase in tension causes smooth vascular muscle cells to contract, as has been found in the smooth muscles of Taenia coli by Biilbring [27], changes in resistance during autoregulation may be well explained by this mechanism. This hypothesis is supported by studies of Thurau and Kramer [77], Waugh [79], Semple and de Wardener CL%],and Schmid and Spencer [Z9], who found the time delay between a sudden increase in arterial pressure and the onset of vasoconstriction in the range of 5 to 10 seconds, which would be in accordance with neurophysiological studies. The nature of this vasoconstrictor reaction to stretch is myogenic since papaverine [ZO] and chloral hydrate [ 791 abolish the vascular reaction to stretch. If, as seeems reasonable from these results, wall tension is the major determinant of vascular

I 0

I so

Arferml BP wo

150

.tW mm&

FIG. 2. Pressures in peritubular capillaries and tubules of antidiuretic rat kidneys at various arterial blood pressures. (Micropuncture results from Thurau and Wober L3l.J

T/m-au

tone in the kidney, an arteriolar dilation should occur when transmural pressure difference is lowered by increasing extravascular tissue pressure at constant intravascular pressure (see equation 1). To test this concept renal tissue pressure was elevated by means of osmotic diuresis and ureteral occlusion in both antidiuresis and osmotic diuresis. Figure 3 summarizes data obtained in dog experiments in which the needle pressure was used as an estimate of tissue pressure. It is evident that renal blood flow is increased at high intrarenal tissue pressure. A more detailed analysis of hemodynamic changes in the course of increasing tissue pressure is illustrated in Figure 4. The results were obtained in a dog during mannitol diuresis. During ureteral occlusion the needle pressure increased from 35 to 72 mm. Hg while blood pressure remained constant; thus the transmural pressure difference of the muscular arterioles was lowered by 40 mm. Hp. This is accompanied by an increase in renal blood flow from 4.9 to 7.6 ml. per gm. per minute, which does not seem to reflect the entire arteriolar dilation which occurred. Figure 4 shows that pressure in inter-lobular veins increases simultaneously with the increase in tissue pressure, indicating that venous compression occurs at the intrarenal to extrarenal border when tissue pressure is increased [8]. Despite this increase in venous resistance, renal blood flow increases and it is apparent that arteriolar dilation must be of such a magnitude as to effect a net increase in renal blood flow. If this view is correct, a further increase in renal blood flow should occur immediately after release of the stop flow, as the elevated tissue pressure is lowered abruptly to abolish the venous resistance built up during the ureteral occlusion. Since the reaction time of smooth muscle contraction is of the order of 5 to 10 seconds, renal blood flow during this period should reflect the arteriolar dilation which was present at the end of a period of ureteral occlusion, but which was partially compensated by the increase in venous resistance. An overshoot in renal blood flow following the release of a ureteral occlusion has indeed been found [30,37,33] and is documented in the second panel of Figure 4. In view of these results it is necessary to postulate that even a constant renal blood flow during ureteral occlusion [.X&3&36] implies arteriolar vasodilation because of the concomitant increase in venous resistance. AMERICAN JOURNAL OF

MEDICINE

Renal

Hemodynamics-

These results clearly indicate that the kidney does not depress its own blood flow by an increase in tissue pressure as long as the vascular smooth musculature is reactive. A different view has been outlined by Selkurt (371, who also found an increase in renal blood Decreased flow during ureteral occlusion. para-amino hippurate (PAH) extraction suggested to him that medullary shunt of blood flow might be of significance during ureteral occlusion. This hypothesis, however, cannot be entirely accepted in the light of recent results which showed a decreased blood flow rate in the medulla during ureteral occlusion in mannitol diuresis (see section on “Medullary Blood Flow”). The low PAH extraction during stop flow could also be due to a limiting tubular fluid/plasma PAH-concentration gradient reached because the fluid was stagnant in the tubules; it does not necessarily represent diversion of blood flow from the cortex to the medulla. Whereas the myogenic nature of the changes in resistance during autoregulation seems to be well established, it is an unproved hypothesis presently favored by many [23,31)-32,38,39] that tangential wall tension is the major determinant of myogenic vascular tone in the kidney and responsible for the constancy of renal blood flow and glomerular filtration rate. Another possibility will be discussed subsequently. A number of models have been proposed which describe renal autoregulation on the basis of physical forces. In 1956 Pappenheimer and Kinter [40] suggested that red cells are progressively separated from plasma by a process of plasma skimming in the interlobular arteries, the degree of separation depending on the kinetic energy of arterial blood pressure. The increase in resistance to flow with increasing blood pressure is thought to be due to an increase in hematocrit within the vessels through which the cell-rich moiety of the blood is presumed to pass. For a number of reasons to be outlined, this attractive hypothesis does not explain autoregulation, although it is likely that cell separation occurs in the juxtamedullary region or along the vasa recta: (1) The cell separation hypothesis depends entirely on the presence of red cells in the perfusate, and a cell-free perfusion of the kidney should not exhibit the autoregulation phenomenon. As shown by Waugh [ 791, Thurau and Kramer [ZO], and Weiss et al. [47], autoregulation can be demonstrated in the VOL.

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absence of red cells. Although it is true that autoregulation deteriorates after 5 to 10 minutes when the kidney is perfused with an artificial perfusate [79,20], the addition of cell-free plasma to the artificial perfusate prevents the

FREEFLOW

100

101

90

9-

80

8-

70

7a $6. ? $5-

$60

I LM

340

$4-

30

3-

20

2-

!O

I-

0

O-

FIG. 3. Increase in renal blood flow accompanying increased intrarenal tissue pressure (INP). FreeJaw, increase in INP produced by osmotic diuresis during free urine flow. Antidiuresis, increase in INP produced by ureteral occlusion during antidiuresis. Osm. (osmotic) diuresir, increase in INP produced by ureteral occlusion during osmotic diuresis. Renal blood flow measured by noncannulating electromagnetic flow meter in dogs. Numbers at lower right of each graph represent the mean per cent increase. (Data from Thurau and Henne.)

702

Renal Hemodynamics-

- Thurau

RBF --

INP

f 5k.pflow

I min.

5 min.

m

+

3 min.

FIG. 4. Renal blood flow and intrarenal pressures before and during ureteral occlusion and after its release in osmotic diuresis. IRVP = intrarenal venous pressure. BP = arterial blood pressure. INP = intrarenal needle pressure. UP = ureteral pressure. Renal blood flow measured by electromagnetic flow meter. Tracings of sections of original records. (From Thurau and Henne, PJCgers Arti. ges. Physiol. in press.) -

deterioration of autoregulation [79]. It is clear from these results that a vasoactive plasma factor is involved, rather than red cells. That there is a delay in abolition of autoregulation during perfusion with a nonplasma fortified artificial perfusate is consistent with the assumption (see footnote on page 705) that the plasma factor (or factors) is present in the intercellular fluid, and has to be washed out. (2) The cell separation theory predicted a low intrarenal/systemic hematocrit ratio of 0.48 which would be inversely related to arterial blood pressure. Lilienfield and Rose [&‘I and Ochwadt [&I, however, using mean passage time measurements from renal artery to vein for labeled erythrocytes and plasma, calculated this ratio to be 0.9. (3) The low oxygen saturation of cell-poor peritubular capillary blood, as predicted by Pappenheimer and Kinter, was not found by Kramer and Ullrich [@I. The oxygen saturation of cortical capillary blood was essentially the same as renal venous blood. It should be emphasized that plasma skimming may be of some significance for the medullary circulation. It has been shown by micropuncture analysis of vasa recta blood that the

hematocrit of vasa recta blood/systemic blood is in the range of 0.37 to 0.48 [45,46].* Even though part of the low hematocrit is due to cell shrinkage in the hyperosmotic environment of the medulla [46], this does not account quantitatively for the reduction in cell volume, especially since up to 50 per cent of the osmotically active substances in vasa recta blood is urea which enters red cells [47]. Therefore, a plasma skimming mechanism may exist either at the beginning of the vasa recta or along the descending limb of the vascular loop. The demonstration of an unchanged hematocrit in vasa recta blood during osmotic diuresis [70], when medullary blood flow rate is known to be increased [48], and a rise in medullary red cell content during pharmacologic dilation [709] make it difficult * Caution should be exercised when using these micropuncture data as evidence of the true intravascular hematocrit. Besides technical difficulties in sampling blood by micropipettes, the hematocrit found in the samples represents only the ratio of cell flow rate to plasma flow rate entering the micropipette. For instance, if the dynamic intravascular hematocrit is 0.25, but the cells flow twice as fast as the plasma (Fahroeus effect), the cell volume sample would be identical with the plasma volume sampled, and the measured hematocrit would be 0.5. AMERICAN

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Renal Hemodynamics---Thurau explain the cell separation on the ljasis of Pappenheimer and Kinter’s hypothesis. In a series of papers, Hinshaw and associates \_9,&&5/] investigated the role played by tissue in regulating renal blood flow of pressure isolated kidneys perfused with a pump-lung From these studies it became apparatus. apparent that marked differences exist between isolated and nonisolated kidneys. In contrast to nonisolated kidneys, intrarenal tissue pressure varies with blood pressure and accounts for an increase in total renal resistance. It is interesting to note other pecularities which are consistent with results obtained by Winton [4] on isolated kidneys: renal blood flow is less than 50 per cent of normal, and renal vessels do not respond with vasodilation when chloral hydrate is added to the inflowing blood; renal blood flow in the isolated perfused kidneys decreases markedly when tissue pressure increases following occlusion of the ureter, whereas, as already mentioned, an increased or constant renal blood flow has been found in nonisolated kidneys. Data on glomerular filtration rate and tubular functions might help to explain the differences between isolated and nonisolated kidneys, but unfortunately little is known about this. An isolated kidney preparation with controlled excretory functions would be of great value, especially for studies of renal metabolism. The hernodynamic data suggest that in isolated perfused kidneys the smooth musculature develops irreversible contracture and does not respond to physiologic stimuli. Any satisfactory understanding of renal autoregulation must be based on an appreciation of the role which renal blood flow plays in urine formation. Under normal conditions, glomerular filtration rate and the proximal tubular sodium load are closely correlated with renal blood flow. It is pertinent to emphasize that practically all the filtered sodium has to be actively reabsorbed by the tubular cells and that this function determines the over-all metabolism in the kidney [52-541. The kidney is unusual in that blood flow, via the filtered sodium, appears to determine the metabolism, rather than metabolism determining blood flow, as in the heart or skeletal muscle. Should an increase in metabolism lead to an increase in renal blood flow, this in turn would lead to an increase in sodium load to the tubules and an even further increase in metabolism. It is clear that this kind of regulation would snowball and never lead to constancy to

VOL. 36, MAY

1964

of filtered sodium and of renal blood flow. Besides these theoretic objections to a dilating effect of increased metabolism, vasodilation has been found at reduced metabolic activity. When the ureter is occluded during osmotic diuresis, glomerular filtration rate and thus tubular sodium load fall rapidly, with a concomitant decrease in renal oxygen consumption but an increase in renal blood flow. (Table I.) Further evidence against a dilating effect of increased metabolic activity in the kidney has accumulated from studies on the effect of the metabolites of adenosine triphosphate (ATP) on renal blood flow. Substances such as adenylic acid, adenosine [55], inosine and guanosine, which all have a potent dilating effect on other vascular beds, lead to vasoconstriction in the kidney. (Fig. 5 and 6.) If, as has been established, active sodium reabsorption accounts for the major part of renal metabolism, and if the kidney responds with vasoconstriction when metabolism increases, this would lead to reduction in sodium load by means of decreased renal blood flow and glomerular filtration rate. According to this view, renal vascular resistance will also increase when blood pressure is elevated and lead to autoregulation of renal blood flow. Since it is most unlikely that metabolic substances per SC constrict renal blood vessels, it is attractive, on the basis of the following observations, to incorporate the renin-angiotensin system into the

TABLE BLOOD AND

FLOW,

ARTERIOVENOUS

OXYGEN

CONSUMPTION

DURING

URETERAL

I OXYGEN IN

THE

DIFFERENCE DOG

OCCLUSION

KIDNEY

IN

MANNITOLDIURESIS *

I

Period

Renal Blood Flow (ml./min.)

Duration (min’)

_. .____

I

= -I

Release.

I Oxygen Consumption (cc. /min.)

I-===)--

Control.

stop-flow.

Arteriovenous Oxygen Difference (vol. 50)

2

4 6

I

10 --1 4

402

2.52

498 498 454

1 1.92

412

0.93 ____~__ 2.60 2.86

1

1.43 0.93

320 320 I

10.10

I

9.60

7.14 4.22 3.86 8.30 8.60 I

* Courtesy of KRAMER, K. and DEETJEN,P.

Renal Hemodynamics-

704

Low sodium

R5F 2

( Angiotensin

Thurau

units 16.15 v/g

kidney

1

400,

Adenoftne

High sodium

SOY/min

(Angiotensin

i.o.

ren.

units 3.07/g

kidney)

FIG. 5. The effect on renal blood flow of renal intraarterial (i.a. rem) infusion of adenosine in dogs maintained on low and high sodium diets. Renin concentration was determined in each type of experiment, expressed in the figure as angiotensin units per gram of cortical tissue. Note the marked decline in renal blood flow during adenosine infusion in the kidney with low renin content. Tracings from original records. Renal blood flow measured by electromagnetic flow meter. (Data from Henne, Weichert, Thurau and Wolff.)

-T-

AMP

911

FIG. 6. Graded renal blood flow response to increasing single doses of adenylic acid injected into the renal artery of a dog on low sodium diet. Renal blood flow measured by electromagnetic flow meter. (Data from Henne, Weichert, Thurau and Wolff.)

phenomenon. Certain key facts are significant in developing this theory: (1) It seems well established that the granular cells of the juxtaglomerular apparatus are the site of renin production [56,57]. These cells are located in the medial layer of the afferent arteriole and are closely related to the macula densa cells which form part of the wall of the early distal convolution of the nephron. Together with intermixed l&s cells these three cell types make up the juxtaglomerular apparatus. Since each nephron is supplied with a juxtaglomerular apparatus, an anatomic and possibly a functional connection exists between the afferent arteriole and the early part of the distal convolution of each nephron [58-671. autoregulatory

(2) Changes in resistance during autoregulation deteriorate with synthetic perfusates and are restored by the inclusion of unzvashed red cells [SZ] or plasma [79]. Apparently a plasma factor is important for the changes in resistance. This could possibly be the renin substrate. (3) The secretory activity of the granular cells is closely related to regulation of sodium metabolism in the body but not to potassium metabolism [63]. (4) Renal autoregulation is closely connected with the formation of glomerular filtrate. Below a blood pressure of 60 mm. Hg, when glomerular filtration and therefore intratubular urine flow ceases, autoregulation is nonexistent [ 76,771. (5) Intratubular sodium concentration in the AMERICAN

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early part of the distal convolution under all circumstances is then lower than the plasma concentration, and variable [64,6s]. On the basis of these facts it is not unreasonable to postulate that the macula densa segment of the nephron and the afferent arteriole are functionally connected in such a way that the chemical composition of the intratubular urine at the macula densa site, once it has passed the proximal convolution and the loop of Henle, regulates renin release, thus affecting the tone of the afferent arteriole. The composition of the urine at the macula densa segment depends ceterisparibus on tubular activity and glomerular filtration rate. Let us assume the kidney showed no autoregulation; then an increase in arterial blood pressure would increase renal blood flow, glomerular filtration rate and tubular sodium load. In order not to lose the excess filtered sodium, the metabolically linked tubular reabsorption of sodium in the proximal tubule would have to increase instantaneously. Even if equal fractions of filtered sodium were reabsorbed in the proximal tubule [65,66], a greater amount of sodium during increased glomerular filtration rate would be delivered to the more distal tubular segments. The composition of the urine at the macula densa segment would therefore reflect the increased glomerular filtration rate and renal blood flow. In contrast to that in the proximal convolution, the sodium concentration at the macula densa segment of the nephron under normal conditions is below the plasma concentration [64,65l. It is this low concentration which makes it possible that sodium concentration increase or decrease with glomerular filtration rate without exceeding plasma values. It is suggested, therefore, that a high sodium concentration at the macula densa segment stimulates renin release and a low sodium concentration inhibits renin release. There is indeed experimental evidence for such a mechanism. If the sodium concentration at the early distal convolution is kept below normal by procedures such as mannitol diuresis and urea diuresis [64], vasodilation occurs [67-691. Renal blood flow is also increased in hypertonic sodium diuresis in which the sodium concentration in early distal tubular urine would be expected to increase. Giebisch [64, however, found the sodium concentration at this site of the nephron as low as in control animals. The mean value was even somewhat lower, but the difference was not statistically VOL.

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significant. On the other hand, a vasoconstriction [70] and reduction in glomerular filtration rate [77] has been found during the action of saluretic drugs, by which proximal sodium reabsorption is reduced and more sodium is delivered into the macula densa segment. On the basis of this suggested mechanism, renal autoregulation would primarily be a phenomenon which keeps constant the sodium load, the major determinant for renal metabolism, and autoregulation of blood flow under normal conditions would be a necessity of such regulation. This would be consistent with the observation by Elpers and Selkurt [72] that under certain experimental conditions, such as albumin infusions in dogs, glomerular filtration rate is far better autoregulated than renal blood flow. Guyton [67] recently postulated that the osmolality of the urine at the macula densa segment of the nephron controls blood flow to the glomerulus. He proposed that a low osmolality leads to preglomerular constriction, whereas more concentrated urine causes dilation. When the hypothesis, as described [60], was first formulated this possibility was rejected because of the micropuncture results of Gottschalk and Mylle [73]: (1) In hypertonic sodium chloride diuresis the osmolality of the urine in the early distal convolution is lower than in hydropenic animals. (2) In mannitol diuresis the osmolality at this site is essentially the same as in hydropenic animals. In both types of diuresis a vasodilation occurs without an increase in osmolality of the urine in the early distal convolution. The theory outlined herein includes the renin-angiotensin mechanism as part of the regulation. * Renal autoregulation, therefore, was investigated in dogs kept on a high sodium diet for an average of eight weeks. It is well known that the renin content of renal tissue is diminished under these circumstances [75], * It has occasionally been inferred that renin has to be secreted into the blood stream in order to catalyze the reaction of renin-substrate to angiotensin I, which is converted by an enzyme to angiotensin IL In this case, the locus of secretion at the end of the afferent arteriole would indeed be almost ineffective in respect to preglomerular resistance changes, since the vasoactive angiotensin II then is formed distal to the a&rent arteriole. However, so long as the renin substrate and the converting enzyme are also present in the intercellular fluid of the vessel wall, the liberation and action of angiotensin II would be highly localized in the last part of the afferent arteriole.

706

Renal Hemodynamics---

FIG. 7. Cortical

distribution of pressor material per glomerulus relative to that found in layer B. (Modified from Peart [74].)

and it was found that autoregulation was invariably greatly diminished, and in some instances even completely abolished. Peart [74] recently measured the renin distribution in the renal cortex and correlated renin content with the number of glomeruli found in different depths. Since the number of glomeruli is identical with the number of juxtaglomerular apparatus, renin content per juxtaglomerular apparatus in different layers of the cortex can be calculated. (Fig. 7.) The renin content per juxtaglomerular apparatus is very low in the juxtamedullary portion of the cortex. It is interesting to note that the medullary vessels are virtually postglomerular capillaries derived from juxtamedullary glomeruli. Some years ago it was found in this laboratory that the medullary blood flow is not autoregulated [&I, a result which could not be explained at that time, but which now seems consistent with the theory of renin-angiotensin regulation of precapillary resistance. Finally, the constrictive effect of ATP metabolites is much more pronounced in kidneys with a high renin content. In the experiments depicted in Figure 5,50 pg. adenosine per minute was constantly infused into the renal artery of a dog kept on a low sodium diet and of a dog kept on a high sodium diet. The renin content in the kidneys, expressed in angiotensin units, was 16.15 and 3.0 pg. angiotensin per gm. kidney, respectively. Whereas the kidney with a high renin content responds with marked

Thmau

vasoconstriction, this response in the kidney with a low renin content is only initial and transient. In the individual kidney the vasoconstriction depends on the amount of ATPmetabolites injected. (Fig. 6.) In summary, it is suggested that vasoconstriction in the kidney is linked to metabolism in such a way that renin-angiotensin could be the transmitter system between change in metabolism and the vascular smooth muscle cell. Whether the local metabolism at the macula densa segment of the nephron, or the sodium concentration at this site, or the over-all metabolism of the kidney stimulates renin release is unknown. It is most unlikely that a definite answer to these questions will be found before the physiologic meaning of the juxtaglomerular apparatus is more precisely characterized. Autoregulation should be considered not only as a circulatory phenomenon, but also in its relation to over-all renal function and metabolism. NERVOUS

AND

HUMORAL BLOOD

CONTROL

OF RENAL

FLOW

It is widely accepted that under normal conditions there is little or no neurogenic sympathetic constrictor tone in the kidney, since acute surgical and pharmacologic denervation, as well as chronic denervation of the kidney, does not change renal blood flow and glomerular filtration rate [76]. The most convincing demonstration comes from results obtained on transplanted kidneys in human subjects with renal blood flow and glomerular filtration rate values in the normal range [77]. Neurogenic vasoconstriction has been found in severe hypoxia, with reduction both in renal blood flow and glomerular filtration rate. The neurogenie origin was demonstrated in experiments with one innervated and one denervated kidney, the latter being without response to hypoxia [76,78]. Further evidence is provided from experiments in which renal vasoconstriction was inhibited when aortic and carotid sinus baroreceptors were stimulated [79]. Consistent with neurogenic rather than humoral induction of renal constriction in hypoxia are the results of Korner [SO], who found almost no decrease in renal blood flow following denervation of the carotid sinus region and section of the depressor nerves. Thus, renal vasoconstriction in hypoxia appears to be reflexly mediated with excitation of the carotid and aortic chemoreceptors. AMERICAN

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Renal

B

Hemodynamics--

-_._

-___-

RBF mflmin

400

zw

12 L-

0 200

I”‘..’

100 0

BPmmHg

532

Treadmill

9 mph

%-A

f

FIG. 8. A, renal blood flow in a conscious dog in normal standing and in head-up positions. B, renal blood flow and arterial blood pressure in a conscious dog during rest and exercise. Renal blood flow measured by electromagnetic flow meter, implanted on the left renal artery. Blood pressure recorded via Teflon@ tube implanted into the aorta above the origin of the renal arteries. Implantations three weeks prior to the experiment. (Data from Thurau and Henne.)

A matter of controversy is the renal vascular response due to exercise. Most results come from PAH clearance measurements which must be interpreted with some caution since PAH extraction may change during exercise. PAH clearance in these cases has usually been determined immediately after the end of exercise with the subject in a recumbent position, and it is known that renal blood flow may decrease in the change to the upright position due to an orthostatic reaction [76]. It is interesting to note that Freeman et al. [87] found a decrease in PAH clearance in man exercising in the upright position, but a constant PAH clearance when exercising in the recumbent position. These results suggest that a major part of the vasoconstriction found during exercise may be due to an orthostatic effect. This is consistent with results obtained in conscious dogs in which renal blood flow was recorded continuously by means of an implanted electromagnetic flow meter. Whereas a decrease in renal blood flow during head-up position was an invariable finding, renal blood flow was essentially unchanged during exercise in the normal recumbent position. (Fig. 8.) In isolated kidney preparations and by VOL. 36,

MAY

1964

707

Thurnu

experiments involving constant infusion into the renal artery in situ, it has been demonstrated that drugs that paralyze smooth muscle increase renal blood flow [76,77,79]. The action of these drugs on renal blood flow after a single injection, however, may be very different in the intact organism, since changes in systemic hemodynamics occur simultaneously, thus initiating powerful nervous constriction in the kidney. For instance, when papaverine is injected in a single dose into the aorta above the renal artery of a conscious dog, vasodilation occurs only initially. This is followed by a marked vasoconstriction, probably induced by the decrease in systemic blood pressure (Fig. 9), since the constrictive phase is prevented after pretreatment with ganglionic blocking drugs, which is in accordance with a reflexly induced increase in resistance. There is not much evidence that the sustained renal vasoconstriction following hemorrhagic shock or an ischemic period is of neurogenic origin. Folkow [82] found a relative unresponsiveness of the autonomic nervous system control of the renal vasculature, which is in accordance with a sustained renal blood flow at a normal range during the initial hemorrhage [83,84]. The vasoconstriction occurring during severe hemorrhage and following transfusion suggests a humoral component of vasoconstriction. It is not known whether this is due to increased output of catecholamines or to intrarenal liberation of angiotensin or other substances. Peart’s finding of a high renin content in the outer layer of the cortex and a low concentration RBF ml/m,n

; IltMw-ty?r.-.‘-’

-1

4w

mmHg 100

I

A.

FIG. 9. The effect on renal blood flow of injecting papaverine into the aorta above the origin of the renal arteries. Technics for measurement as for Figure 8, conscious dog.

Renal

Hernodynamics-

T/m-au

JOm fq

* (lOOg~minl* *

cantrats Awlic clampirg tfyperl. No Cl Sdyf~ll 0 119 HypoXiU

Na - Reabsorption 0

5

20 l4 m Eq (lCWg-min r’

h

FIG. 10. Correlation

of renal oxygen consumption with renal blood flow (left) and tubular sodium reabsorption (right). Note the exponential increase of oxygen consumption at low renal blood flow-values. Sodium reabsorption was varied by decreasing glomerular filtration rate (aortic clamp), hypteronic sodium chloride infusion, saluretic drugs and hypoxia. (From Kramer and Deetjen [5.7].) in the deeper zone (Fig.

7) should be considered in future work related to this problem. It is reported from several laboratories that mannitol infusion during hemorrhagic shock or during the course of extensive surgery leads to renal vasodilation and may thus prevent the development of renal failure [68,85-881. The vasodilation is thought to be due to an “osmotic or pharmacologic effect” upon vascular muscle cells. In the presence of mannitol, however, intratubular urine flow at a given reduction of arterial blood pressure and glomerular filtration rate is greater than without mannitol, and ceases at a lower blood pressure. If, as already indicated, a tubular-arteriolar feedback mechanism via the juxtaglomerular apparatus exists, the sustained urine flow in the macula densa segment of the nephron may possibly be an important factor in preventing complete renal shutdown. Investigators studying renal function by micropuncture technics agree that the distal convolution does not collapse completely when glomerular filtration rate ceases. It is a reasonable assumption that the fluid remaining in the distal convolution has a higher than normal

sodium concentration. According to our hypothesis, this would stimulate a release of renin and establish a humorally-induced vasoconstriction, independent of extrarenal factors. RENAL

BLOOD OXYGEN

FLOW

AND

RENAL

CONSUMPTION

In 1939 Kramer and Winton [67] demonstrated that the arteriovenous oxygen difference is constant in the kidney when renal blood flow changes above a blood pressure of 60 mm. Hg; in other words, oxygen consumption increases with increase in renal blood flow. The observation of Zerahn [89] that the oxygen uptake of an isolated frog skin above a resting level is proportional to active sodium transport paved the way for an explanation of the direct relation between renal blood flow and oxygen consumption. It is well established that renal sodium reabsorption is an active process and represents the overwhelming fraction of all tubular processes. Since glomerular filtration rate varies with renal blood flow under normal conditions, tubular sodium reabsorption is high at high rates of renal blood flow and accounts for the elevated AMERICAN

JOURNAL

OF

MEDICINE

Renal Hemodynamicsoxygen consumption. (Fig. 10.) The constant arteriovenous difference of oxygen noted only above 60 mm. Hg blood pressure is consistent with the onset of glomerular filtration at this range of blood pressure, whereas below this pressure the arteriovenous difference of oxygen is inversely correlated to renal blood flow, as in most other organs [52,53]. It is clear that a direct correlation between renal blood flow and oxygen consumption is obtained only as long as glomerular filtration rate changes with renal blood flow. In osmotic diuresis and during ureteral occlusion, oxygen consumption is lowered at an increased renal blood flow since glomerular filtration rate is diminished [54]. (Table I.) The unchanged renal arteriovenous oxygen difference when renal blood flow is reduced as much as 70 per cent suggested to Kramer [92] that hypoxia of renal tissue might not account for the development of renal failure following circulatory shock unless renal blood flow is further reduced. This hypothesis is supported by the work of Munck et al. [93] who found the oxygen saturation of peritubular capillary blood in the renal cortex of dogs unchanged when arterial blood pressure was lowered to 50 mm. Hg by hemorrhage. MEDULLARY

BLOOD

MAY

1964

709

[95] of the vascular pattern in the outer and inner medulla of the rat indicates that this concept has to be modified. By pretreatment with papaverine these investigators were able to inject the medullary vessels almost completely with Neoprene@ and dye. Between the bundles in the outer medulla, they observed a rich capillary plexus, which is fed by vessels leaving the bundles at different levels. They found a similar but less extensive capillary plexus with elongated meshes between the straight limbs of the vasa recta in the inner medulla. Thus there is an abrupt transition between outer and inner medulla. (Fig. 11.) The straight limbs of the vasa recta are scattered throughout the inner medulla, no longer form bundles and terminate at various levels in the elongated capillary network. No descending vasa recta were found looping back to form ascending (venous) vasa recta without breaking up into a capillary network. Unfortunately, little is known about the spatial arrangement of the descending and ascending limbs in the bundles of the outer medulla.

FLOW

The formulation of the countercurrent theory by Kuhn, Wirz and Hargitay has greatly advanced our understanding of the renal concentrating mechanism. It has become apparent, however, that a complete understanding of this process requires consideration of medullary hemodynamics [94]. The interrelationship between medullary blood flow and countercurrent mechanism has been discussed elsewhere and will not be considered here, only the hemodynamic pattern of medullary blood flow. Medullary vasa recta are postglomerular capillaries derived from efferent arterioles of juxtamedullary glomeruli, which also supply the outer medullary capillary network. Juxtamedullary glomeruli may have two efferent arterioles, one breaking into an adjacent capillary network, the other passing into the medulla as vasa recta [95]. It follows, therefore, that not all the blood leaving the juxtamedullary glomeruli enters the vasa recta. The straight limbs of the vasa recta are in bundles in the outer zone of the medulla, and are generally assumed to form loops in the inner medulla [I/]. A recent study by Moffat and Fourman VOL. 36,

Thurau

FIG. 11. Section to show the abrupt transition between the outer and inner zones of the medulla in the rat kidney. Above is the outer medullary plexus with vascular bundles surrounded by a capillary plexus. Below lies the elongated capillary plexus of the inner medullary zone. (From Moffat and Fourman [95].)

Renal Hemodynamics

EVIMSBIUB FIG. 12. medulla diuresis ADH. t Deetjen

Dye dilution CUI‘VCSin the cortex and inncl of a dog kidney during antidiuresis, water and during inhibition of the water diuresis by = medullary circulation time. (From Thurau, and Kramer [.#].‘I

Smooth muscle cells have not been found in the vasa recta [96], and the term arteriole should not be used in connection with the descending limbs. There are, however, differences in the wall structure of descending and ascending limbs which indicate different functional characteristics. According to Longley et al. [!%I, the walls of the descending limbs are thick, and those of the ascending limbs thin and porous. The pressure profile in the medullary circulation is different from that in the cortex. Micropuncture measurements of pressure in the vasa recta at different points of the accessible part of the vascular loops yielded a pressure drop per millimeter descending limb of 6.5 mm. Hg, and a pressure of 7 mm. Hg at the bend of the loop [ 701. Assuming the same decrease in pressure per millimeter length in the nonaccessible two thirds of the vascular loop, the pressure at the beginning of the vasa recta would be in the order of 50 mm. Hg. This high postglomerular vascular pressure in the juxtamedullary region is in accordance with the presence of large efferent arterioles leaving the juxtamedullary glomeruli [ 771. The drop in postglomerular pressure, which occurs in the cortex along the short efferent arteriole, apparently takes place in the medullary region over the entire length

- ?‘humu

of the descending limbs of the vasa recta. ‘The low intravascular pressure found at the tip of the papilla indicates a lower resistance to flow in the ascending limb than in the descending limb. Whether this low ascending resistance is due to large vessel bores or to a larger number of vessels is not known. Kramer and associates [971 presented the first quantitative data demonstrating lower rates of blood flow in the inner medulla than in the cortex. Dye dilution curves recorded simultaneously at the surface of the cortex and in the inner medulla, after a single itrjection into the renal artery, revealed a high flow velocity in the cortical vessels and a much slower velocity in the medullary vessels. (Fig. 12.) Table II summarizes mean circulation times calculated from those curves, together with data obtained more recently for the outer medulla by the same laboratory [98]. Blood flow rates were calculated for the cortex and the outer and inner medulla from regional blood volumes and circulation times. Table II also includes data obtained by Thorburn et al. [99] utilizing the different technic of Ks5-washout in unanesthetized dogs, and the data obtained by Lilienfield et al. [XXI]. Blood flow rates in the outer and inner medulla per unit tissue weight are considerably lower than in the cortex and together account only for 6 or 7 per cent of total renal blood flow. The inner medulla is perfused by approximately 1 per cent of total renal blood flow and has the lowest perfusion rate per unit tissue of these areas. Ochwadt [707], using the washout technic of labeled erythrocytes and plasma in isolated dog kidneys, found the blood flow rate in his slow compartment III to be 3.1 per cent of total renal blood flow, which is similar to the value determined for the inner medulla. (Table II.) Although Ochwadt’s compartment III has not been localized within the kidney, it is reasonable to assume that it represents primarily inner medulla and parts of outer medulla. This is supported by the mean passage time through compartment III of 1.1 minute for erythrocytes and 1.4 minutes for albumin. These somewhat prolonged passage times are easily explained by the fact that renal blood flow in the isolated kidney preparation is only 50 per cent of that of the nonisolated kidney. The low medullary blood flow is not due to a poorly developed vascular bed. Vascular volume per unit tissue is essentially the same in any area of the kidney; if anything, the vascular volume AMERICAN

JOURNAL

OP

MEDICINE

Renal

Hemodynamics-

c,=c”+“+

ON INTRARENAL AND

I

I Source

Cortex. Outer

medulla.

Inner

medulla..

Compartment Compartment

~ .I

1+

_.

1,.

III.

* Figures in parentheses t Corrected as outlined VOL..

36,

Intrarenal Circulation Times* (min.)

Weight (% of total kidney)

MAY

1964

70 75 20 15 10 10

1 / I

Vascular

19.2 1 o’.Z “’ 22.0

0.095 (0.073) (1.1) 1.4

rlli

x )

- (Pm,P . Illi

TIMES, VASCULAR

Volume

ml./100 gm. Kidney

13.5 3.9 2.2

/

(2)

Blood Flow Rates

ml./100 gm. Tissue/Min.

458 472 112 132 29 17 22

17.3 :: :::

x2

VOLUMES

RATES

’ %of

0.086 0.75t

FLOW

ml./100 gm. Tissue

0.021

‘.’

P

II

CIRCULATION

BLOOD

I

(

1+2TL

F2

TABLE DATA

721

blood flow per unit tissue weight is about fifteen times that in resting muscle and approximately 50 per cent that in the brain and 30 per cent that in the heart under basal conditions. In contrast to the cortex, inner medullary blood flow measured as dye passage time in dogs is not autoregulated and therefore increases with increasing blood pressure [&I. The autoregulation phenomenon has not been investigated in the outer zone of the medulla. The fact that total renal blood flow is essentially unchanged when blood pressure increases above 90 mm. Hg indicates that the nonautoregulated fraction of total renal blood flow is quite small. Since blood flow rates in the outer and inner medulla together account for only 6 per cent of total renal blood flow, outer medullary blood flow may also not be autoregulated. Thurau and Deetjen [705] explained the loss of renal concentrating ability accompanying an increase in blood pressure on the basis of nonautoregulation of medullary blood flow. (Fig. 13.) This is in agreement with a mathematical treatment of Giinzler [705], who showed that the osmolar concentration at the tip of the medulla is inversely proportional to a value of blood flow between F and F* when all other factors remain constant:

in the inner medulla is greater than in the cortex. (Table II.) The low blood flow is probably accounted for by the high resistance to flow created by the extraordinary length of the medullary vessels, which in the dog is about 40 mm. According to the hydrostatic pressure profile, the resistance seems to be localized almost entirely in the descending limbs of the vasa recta. This is consistent with the results obtained by Meier et al. [ 7021 on the distribution of vascular volume between descending and ascending medullary vessels. Using an ingenious variation of the photoelectric method, they recorded dye dilution curves at different levels of the medulla, and calculated the descending vascular volume to be only 37 per cent of total medullary volume and the descending flow velocity of plasma to be 0.65 mm. per second. The increase in plasma protein concentration in the medullary vessels from the base to the tip of the papilla, as found by micropuncture studies [45-47,703] and more indirectly by tissue analysis [ 7041, may also contribute to the high resistance by virtue of an increased viscosity. A quantitative calculation, however, is complicated by the fact that the vasa recta hematocrit may fall over the length of the loops [7U,d5,&] and that shrinkage of the erythrocytes in the hyperosmotic environment [&I may create unpredictable flow characteristics in the vasa recta. Nevertheless, the term low medullary blood flow is strictly relative only, in comparison to the renal cortex. After all, inner medullary

COLLECTED

Thurau

6,.,1

ml./100 gm. Kidney/Min.

1 I

I

I

Investigator

lEr,l B,ood

FIOW

321 .o 354.0 22.4 20.0 2.9 2.0

92.5 94.1 6.5 5.3 1.0 0.6

Kramer et al. 1971 Thorburn et al. [99] Deetjen et al. [98] Thorbum et al. [WI Kramer et al. [97] Thorburn et al. 1991 Lilienfield et al. [XX?]

209.5

96.9

Ochwadt Ochwadt Ochwadt Ochwadt

j:I

represent values for erythrocytes; all other values were obtained from plasma. in the “Addendum” (equation 7). This correction was not employed by Ullrich

1215

et al. [46].

“1.1

. _

[707] [707] [707] [7071

Renal

712

1

0

Hemodynamics-

Medullary Blood&v 250

500

750

,u//g.mtn

FIG. 13. Urine to plasma osmolal ratio as a function of medullary blood flow. (From Thurau and Deetjen W51.)

where cl = osmolar concentration

at the tip of the medulla, co = osmolar concentration of plasma, *m, = influx of osmotically active substances into vasa recta blood per unit length, Pmi = countercurrent diffusion of osmotically active substances per unit length, L = total length of loop, x = distance from beginning of the loop, and F = flow rate. Pinter and Shohet [706], assuming sodium transport only in the thick ascending part of Henle’s loop, calculated that the sodium concentration at the tip of the papilla would be inversely proportional only to flow rate. Both calculations, however, only approximate the changes which occur with changes in blood flow, because simplifying assumptions were necessary for mathematical treatment. As shown in Figure 13, final urine osmolality decreases below plasma values at high medullary blood flow rates. Since antidiuretic hormone (ADH) activity is unchanged in these experiments, it is suggested that the diluted urine from early distal nephrons has not become osmotically equilibrated with medullary interstitium during its passage through the collecting ducts, because of high tubular flow rates. In man, pharmacologic renal vasodilation results in a decrease in concentrating ability, which in part may be due to an increase in medullary blood flow rate [707]. As derived from equation 2 and from these experiments, changes in medullary blood flow are expected to have major effects on the final urine concentration. Therefore, it was of great interest to know what changes in medullary hemodynamics occur when renal function changes from antidiuresis to water diuresis or to osmotic diuresis. In both diuretic states a decrease in medullary circulation time was

Thurau

measured [@I. Figure 12 shows dye dilution curves in the inner medulla obtained in an anesthetized dog in antidiuresis, during water diuresis and following inhibition of the water diuresis with ADH. .4ssuming no change in 1 ~__is a relative vascular volume, circulation time measure of medullary blood flow. The assumption that medullary blood volume is not decreased during water diuresis is supported by measurements of red cell and albumin distribution spaces in frozen medullary tissue slices, which may in fact be increased during water diuresis [ 7081. Figure 14 summarizes such an experiment and indicates that, during water diuresis, medullary blood flow may increase by approximately 70 per cent. The cause of the increased medullary blood flow during water diuresis is unknown. An increase in blood flow in the inner medulla could in part be due to a decrease in shunting of water across the tops of the vascular loops by a lessened medullary osmolality. Such a mechanism would imply no change in inflow rates to the entire medulla, but would indicate that a greater part of the inflowing blood reaches the tip of the medulla. There is no evidence from which to determine whether or not ADH acts preferentially on medullary vessels. In numerous unpublished experiments Kramer and associates could not demonstrate a vasoactive effect of ADH in physiologic concentrations on medullary vessels. Using large doses of ADH, they noted vasoconstrictive activity on the cortical and medullary vessels. The increase in medullary blood flow during osmotic 200

I?

.5!

74

6~ GFR hi/aml

,“.

1

FIG. 14. Medullary blood flow, estimated as the reciprocal of medull& circulation time, in a dog during the development of a water diuresis, and its inhibition by ADH. (Modified from Thurau, Deetjen and Kramer

[@I.) AMERICAN

JOURNAL

OF

MEDICINE

Renal

Hemodynamics-

diuresis parallels the increase in total renal blood flow [&I. Lilienfield et al. [700], however, did not confirm these results. Medullary circulation was studied recently in dogs by Kramer, Deetjen and Sugioka (unpublished data) during ureteral occlusion in osmotic diuresis. The medullary circulation time became longer, and the fraction of injected dye which passed the medullary circulation decreased considerably. (Fig. 15A.) At the same medullary oxygen pressure measured time, by an oxygen-electrode inserted into the tissue of the inner medulla, decreased essentially to zero. (Fig. 15B.) These three facts together strongly indicate a reduction of medullary blood flow during stop-flow experiments. The mechanism by which the increase in pelvic pressure increases medullary resistance to flow is poorly understood. It is interesting to note that during the stop-flow period and reduced blood flow, papillary sodium, chloride and urea are depleted [ 777-7731. The

concentrating ability impairment in renal following stop-flow release [37] might in part be due to a markedly reduced blood flow and lack of oxygen during the stop flow period. Because of the technical difficulties involved in measuring medullary blood flow, nothing is known to date about medullary hemodynamics in man. Based on the assumption that PAH is not extracted from the blood perfusing the medulla, but completely extracted from blood perfusing the cortex, it was suggested that medullary blood flow could be calculated from the PAH extraction ratio [709]: Medullary

blood flow = RBF(l

-

E~AH)

(3)

For example, if 90 per cent of the PAH is extracted from blood flowing through the kidney (EPAn = 0.9), cortical blood flow would then be 90 per cent, and the blood perfusing the medulla 10 per cent of total renal blood flow. An arterial concentration of PAH in the medullary blood is a central requirement for this calcu-

Release (34 sec.)

Stop Flow (57sec.l

Control (32 sec.)

713

Thurau

FIG. 15A. Dye dilution curves in cortex and inner medulla of the dog kidney after injection of the same amount of dye

into the renal artery during free urine flow and ureteral occlusion in mannitol diuresis. Medullary circulation times, in parentheses, are corrected according to equation7. (Courtesy of Kramer and Deetjen.)

Adrenalin

iA.ren.

P,ug/mm

~ 1 mm

, I

62

59

FIG. 15B. Oxygen tension in the inner medulla of the dog kidney during free urine flow and ureteral occlusion in mannitol diuresis. Numbers indicate oxygen tension in mm. Hg. For comparison, the effect of adrenaline on medullary oxygen tension is included. (From Kramer and Deetjen [WI.) VOL.

36,

MAY

1964

714

Renal

n_

Hemodynamics-

Antiduresis Duresis

FIG. 16. Ratios of PAH concentrations of vasa recta plasma to arterial plasma during antidiuresis and diuresis (mannitol, ammonium chloride) in golden hamsters. (Micropuncture results from Schnermann and Thurau.)

lation. In micropuncture studies of PAH concentration in vasa recta blood, this assumption could not be confirmed. In golden hamsters with arterial plasma concentrations between 1.2 and 10 mg. per cent PAH, and renal extraction ratios up to 0.82, the PAH concentration ratio of vasa recta plasma/arterial plasma during antidiuresis is considerably higher than 1.0, ranging between 4 and 12. During diuresis (mannitol and ammonium chloride), this ratio ranged between 1.1 and 2.5. (Fig. 16.) Even though a countercurrent diffusion of PAH may exist in the vascular loop, a net influx of PAH from other sources must be postulated. This is most readily explained by assuming diffusion out of the loops of Henle and collecting ducts, in which PAH concentrations are high. The lowered vasa recta plasma/arterial plasma PAH ratio during diuresis is consistent with this assumption since urinary PAH concentrations, especiallv in the collecting ducts, are decreased in diuresis. These results, however, are inconsistent with the assumption made in equation 3. ADDENDUM

Methodology. In addition to the well known clearance technics, new methods have been developed to measure renal blood flow independent of urine flow, some of them applicable also in man. Brun et al. [ 7751 measured renal blood flow by a modified Kety method using kryptons5. This method made available for the first time data on renal blood flow in oliguric and anuric states, since only arterial and renal venous blood samples are necessary to calculate renal blood flow per 100 gram tissue. Recently, this method was critically evaluated by Renner et al. [776]. In general, errors result from the usually very small arteriovenous concentration difference of the inert gas used. Because of the small arteriovenous concentration

Thurau

difference, it is also difficult to determine accurately the time of final equilibration between arterial and venous concentration. Nevertheless, this method has made a great contribution to our present knowledge of renal hemodynamics in acute renal failure [777]. Recently Thorburn et al. [So] used the inert gas method in conscious dogs. After a single injection of Kra5 into the renal artery, the disappearance curve of the gamma emission was monitored with a scintillation probe placed on the body surface above the kidney. In contrast to the Kety method, which needs arterial and venous catheterization, only the renal artery has to be catheterized. Assuming an equilibration of krypton between blood and tissue in a single passage through the capillary bed, and assuming an extremely small recirculation, the rate of disappearance from the kidney will depend upon the nutrient or capillary blood flow (F): F (ml./100

gm./min.)

= k x “,”

loo

(4)

where F = arterial inflow rate per 100 gm. tissue, k = slope of the disappearance curve, X = partition coefficient for the inert gas between tissue and blood, and p = specific gravity of the tissue. In contrast to other organs, the decay curves obtained in the kidney are nonexponential and can be described by a series of exponentials, each associated with different blood flow rates through localized regions of the kidney. Four regions could be differentiated: (1) cortex, (2) juxtamedullary cortex and outer medulla, (3) inner medulla, and (4) perirenal and hilar fat. As long as removal of the test substance from the tissue is affected only by the capillary blood flow, this method is a valid measure of nutrient blood flow rate. As pointed out by these investigators, however, there is evidence that in the outer and inner medulla the removal of highly diffusible substances such as krypton is affected also by countercurrent exchange diffusion between descending and ascending limbs of both the vasa recta and the loops of Henle. This tends to give calculated blood flow rates smaller than the true value. The dye-dilution technic was used by Reubi et al. [ 7781 and Cohn and Gombos [779] for renal blood flow measurement in man. After a single injection of a known amount of dye (Evans blue, Cardio green) into one renal artery, the dye concentration curve in the renal venous blood was recorded. This method also requires catheters in the renal artery and vein. Since this technic is independent of urine flow, it is also applicable in acute renal failure. The last part of the dye-dilution curve also showed a nonexponential slope which, according to Reubi et al. [778], can be used to calculate medullary blood flow rate. The picture, however, is complicated by the fact that recirculating dye also affects the last part of the dilution curve [98,702]. AMERICAN

JOURNAL

OF

MEDICINE

Excluding

recirculating

dye in a dog preparation,

Deetjen et al. [98] differentiated a rapid and a slow flow component from the venous dye dilution curve. They found the slow component to be a constant fraction of total renal blood flow and of the same order of magnitude as blood flow rate measured in the outer and inner medulla [97-991. In recent years, the noncannulating electromagnetic flow meter technic has become a very useful tool for renal blood flow measurements in unanesthetized animals and in anesthetized animals and man. Because of the miniaturization of the flow probes [720], these units can be implanted in animals for months, thus allowing continuous recordings of renal blood flow in long-term experiments. The method is also applicable in man for continuous measurement of renal blood flow during the course of abdominal surgery [ 7271. Interest in renal hemodynamics for the past five years has been focused on intrarenal blood flow distribution. Several indirect methods were developed to determine blood flow rate in the cortex and outer and inner medulla. With the exception of the krypton method of Thorburn et al. [99], they are all applicable only to acute animal experiments. Kramer et al. [97] calculated regional blood flow rate by means of local blood volume and local circulation time : F (ml./100

gm./min.)

=

vascular

volume/100

mean circulation

gm. time (5)

Local ratio:

vascular

volume

was calculated

Hemoglobin

concentration

in tissue

Hemoglobin

concentration

in blood

= vascular

volume/100

utilizing

the

gm. tissue

(6)

Emery et al. [722]; Lilienfield et al. [97] and Ulfendahl [708] estimated regional blood volume using labeled erythrocytes and plasma. The concentration of red cells and plasma was measured in tissue slices taken from different regions. Since (labeled) albumin does not remain entirely in vessels but is distributed also in extravascular space, and since the concentration of protein in the medullary vessels is higher than in peripheral blood [45-47,703], the calculated intravascular volumes are too high. To obtain mean circulation times (see equation 5) of blood in the cortex and outer and inner medulla, dye-dilution curves in these areas were recorded simultaneously after a single injection of Evans blue or Cardio green dye into the renal artery. (Fig. 12.) Recordings were taken by small photoelectric probes placed on the cortical surface and on one side of the papilla or further up into a caIyx. Whereas in the cortex a photoelectric reflectometer was pierced under the capsule, the medullary photocells received VOL.

36,

MAY

1964

light transmitted from a small tungsten bulb at the tip of a hypodermic needle pierced through the tissue. Local mean circulation times were calculated from the dye-dilution curves. The definition of circulation time in the inner medulla needs special consideration. If regional blood flow rate is measured by means of vascular volume and circulation time, the latter should be calculated from dilution curves obtained at the end of vascular volume. In the medulla it would require a photocell placed at the end of the ascending vasa recta. This, however, is technically not feasible. Since the photocell is attached to the entire length of the papillary surface, it measures the dye passage at an infinite number of points along the vascular volume. The curve obtained by such a method represents the integration of the measurements made at all these points from the beginning to the end of the loop. Therefore, it is reasonable to assume that the mean circulation time calculated from such an integrated curve corresponds to the circulation time only at the mid-point of the vascular volume and that the total medullary circulation time is twice the time measured. Equation 5 applied to the medulla is therefore modified to: F

V Med”“s = 2t&du,le

(7)

Lilienfield et al. [700] estimated plasma flow of the inner medulla from the rate of 1131 accumulation in this area. Kidneys were rapidly removed and frozen at different time intervals following the beginning of an infusion of 1131-labeled albumin. Kidney slices were analyzed for activity in different portions of the medulla. Since only one point of the accumulation curve can be obtained in each individual kidney, this method gives only a first approximation of medullary blood flow rate, and changes in regional blood flow rate with changes in renal function cannot be measured in the individual kidney. In isolated dog kidneys the washout technic of labeled erythrocytes and plasma was used by Ochwadt [707] to calcuIate intrarenal distribution of blood flow rate and vascular volume. After perfusing the kidney for 20 to 30 minutes with blood containing CrQagged red ceils and PI-labeled albumin, the kidney was switched to nonradioactive blood and the decay curve of the labeled indicators computed in the outflowing venous blood. From the nonexponential slope of the decay curve, three intrarenal compartments with different blood flow rates were calculated and related to cortex, juxtamedullary region and medulla. REFERENCES 1. WIRZ, H. Druckmessungen in Kapillaren und Tubuli der Niere durch Mikropunktion. H&et. physiol. et pharmacol. acta, 13: 42, 1955. 2. GOTTSCHALK, C. W. and MYLLE, M. Micropuncture study of pressures in proximal tubules and

716

3.

4.

5.

6. 7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

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