Renal Blood Flow in Health and Disease
The contribution to disordered renal function of deviations of renal blood flow from the normal obviously cannot be ascertained without definition of normal, which is far from a trivial problem. Renal perfusion is influenced by age, position, time of day, diet, activity and emotional state. These observations raise the question: What is ‘normal’ renal blood flow? For example, renal blood flow falls with increasing age, with assuming the upright position and with restriction of salt intake.
Obviously, renal blood flow in a recumbent 20-year-old healthy youth who eats 15 g of salt daily exceeds considerably that in a 70-year-old man who is standing, and who ingests 2 g of salt daily, but is neither more nor less normal in the former than in the latter. In both individuals renal function serves to maintain a normal internal milieu, although the limits over which the kidney will respond are narrowed in the elderly individual.
In some states such as severe hypotension (Selkurt 1946) or acute renal failure (Hollenberg et al. 1968) spectacular deviations from the normal occur. Detection and quantitation of the abnormality is straightforward. In states in which the abnormality is much more subtle but no less important, as in hepatic cirrhosis (Epstein et al. 1971) or benign essential hypertension (Hollenberg & Adams 1976) these factors become key.
Obviously, renal blood flow in a recumbent 20-year-old healthy youth who eats 15 g of salt daily exceeds considerably that in a 70-year-old man who is standing, and who ingests 2 g of salt daily, but is neither more nor less normal in the former than in the latter. In both individuals renal function serves to maintain a normal internal milieu, although the limits over which the kidney will respond are narrowed in the elderly individual.
In some states such as severe hypotension (Selkurt 1946) or acute renal failure (Hollenberg et al. 1968) spectacular deviations from the normal occur. Detection and quantitation of the abnormality is straightforward. In states in which the abnormality is much more subtle but no less important, as in hepatic cirrhosis (Epstein et al. 1971) or benign essential hypertension (Hollenberg & Adams 1976) these factors become key.
Glomerular filtration rate in neonates is considerably less than in the adult human (West et al. 1948), monkey (Chez et al. 1964), dog (Dicker 1952), sheep (Robillard et al. 1975), guinea pig (Spitzer & Edelmann 1971), pig (Gruskin et al. 1970) and rat (Dicker 1952). Renal blood flow increases progressively during the first weeks of life, along with spectacular changes in perfusion and function in various zones of the kidney.
The neonatal kidney is essentially a ‘juxtamedullary’ kidney. Juxtamedullary glomeruli and their tubular systems are morphologically more developed than outer cortical glomeruli at first, and structural maturation proceeds from the inner cortex outwards (Horster et al. 1971). Similarly, outer cortical blood flow and filtration rate increase more rapidly than that of the whole kidney during that interval (Horster et al. 1971, Spitzer & Brandis 1972), suggesting that functional maturation, like structural maturation, proceeds from the inner towards the outer cortex.
As more methods for assessing intrarenal blood flow distribution have become available, they have been applied to the assessment of the maturation process. Olbing et al. (1973) and Kleinman and Reuter (1973), independently employed microspheres to demonstrate that glomerular blood flow increases to the outer cortex dramatically with maturation in the puppy. In part this reflects the structural maturation of the glomeruli.
The possibility that functional factors play a role was raised by the observation that alpha adrenergic blocking agents influenced outer cortical perfusion strikingly in the puppy (Jose et al. 1972) whereas they have remarkably little influence in the resting mature animal or man. Angiotensin antagonists, conversely, do not influence renal blood flow in the neonate (Jose et al. 1975).
The neonatal kidney is essentially a ‘juxtamedullary’ kidney. Juxtamedullary glomeruli and their tubular systems are morphologically more developed than outer cortical glomeruli at first, and structural maturation proceeds from the inner cortex outwards (Horster et al. 1971). Similarly, outer cortical blood flow and filtration rate increase more rapidly than that of the whole kidney during that interval (Horster et al. 1971, Spitzer & Brandis 1972), suggesting that functional maturation, like structural maturation, proceeds from the inner towards the outer cortex.
As more methods for assessing intrarenal blood flow distribution have become available, they have been applied to the assessment of the maturation process. Olbing et al. (1973) and Kleinman and Reuter (1973), independently employed microspheres to demonstrate that glomerular blood flow increases to the outer cortex dramatically with maturation in the puppy. In part this reflects the structural maturation of the glomeruli.
The possibility that functional factors play a role was raised by the observation that alpha adrenergic blocking agents influenced outer cortical perfusion strikingly in the puppy (Jose et al. 1972) whereas they have remarkably little influence in the resting mature animal or man. Angiotensin antagonists, conversely, do not influence renal blood flow in the neonate (Jose et al. 1975).
As pointed out by Olbing et al. (1973), there are a number of potentially important functional implications of the pattern of perfusion and filtration in the neonatal kidney. The limited capacity of the neonatal kidney to respond to a salt load may reflect the reduced filtration and extreme immaturity of the outer cortical nephrons. In contrast the ability to respond to a water load with appropriate and effective urinary dilution is well developed in the neonate, perhaps due to the greater maturity of the juxtamedullary nephron population.
At the other end of the age spectrum, the kidney participates in the process of senescence with a decrease in mass, characteristic morphologic changes and a progressive reduction in blood flow and functional capacity (McDonald et al. 1951, Shock 1952, Wesson 1969). The morphologic and functional changes have frequently been attributed to the local vascular pathology that accompanies aging, but other factors have been suggested including active renal vasoconstriction (Shock 1952, Lee et al. 1966).
Inert gas washout has revealed a reduction in flow per unit tissue mass with advancing age (Hollenberg et al. 1974) indicating a larger blood flow reduction than reduction in mass---the anticipated finding if the flow reduction were primary in the genesis of atrophy. Increasing age also reduced the vasodilatation consequent to administration of vasodilators or a sodium load in the same study, also consistent with a fixed lesion of the vessels.
Responses to vasoconstrictors appear not to be modified by age. On the one hand, wall thickening with a reduced lumen would be expected to increase the response to vasocohstrictors. On the other hand, smooth-muscle atrophy might be anticipated to reduce the response. An unchanged response to. constrictors with age suggests that these two phenomena are precisely matched, and may well be linked.
The morphologic data and the characteristics of blood flow suggest that agerelated atrophy involves the renal cortical vasculature more than it involves the medulla, with a special influence on the outer cortical glomeruli. There are a number of similarities in the functional organization of the senescent and neonatal kidney, perhaps on a similar basismpreferential perfusion and filtration in the inner cortex.
Inert gas washout has revealed a reduction in flow per unit tissue mass with advancing age (Hollenberg et al. 1974) indicating a larger blood flow reduction than reduction in mass---the anticipated finding if the flow reduction were primary in the genesis of atrophy. Increasing age also reduced the vasodilatation consequent to administration of vasodilators or a sodium load in the same study, also consistent with a fixed lesion of the vessels.
Responses to vasoconstrictors appear not to be modified by age. On the one hand, wall thickening with a reduced lumen would be expected to increase the response to vasocohstrictors. On the other hand, smooth-muscle atrophy might be anticipated to reduce the response. An unchanged response to. constrictors with age suggests that these two phenomena are precisely matched, and may well be linked.
The morphologic data and the characteristics of blood flow suggest that agerelated atrophy involves the renal cortical vasculature more than it involves the medulla, with a special influence on the outer cortical glomeruli. There are a number of similarities in the functional organization of the senescent and neonatal kidney, perhaps on a similar basismpreferential perfusion and filtration in the inner cortex.
Diet also has a quantitatively important influence on renal perfusion and renal function. In animals a protein load sustained for several days results in a large increase in renal blood flow, but this phenomenon has not been demonstrable in man (Wesson 1969). In man, restriction of sodium and potassium intake both result in a reproducible reduction in renal blood flow (Hollenberg 1972, 1975).
Angiotensin antagonists have been utilized to assess the role of angiotensin in the renal response in the dog (Freeman et al. 1973), in the rabbit (Mimran et al. 1974), and in man (personal observation). In all three species angiotensin antagonists increase renal blood flow when sodium intake is restricted, but not when free access to sodium is allowed. The renal vascular response to sodium restriction, therefore, is very likely to be due to activation of the renin-angiotensin system.
Since restriction of potassium intake also activates the renin-angiotensin system and blunts the renal vascular response to angiotensin II (Hollenberg et al. 1975), features shared with restriction of sodium intake, it seems likely that the renal response in this setting also is due to angiotensin. Unfortunately, sodium intake and potassium intake have rarely been controlled in studies on renal blood flow in human disease.
Angiotensin antagonists have been utilized to assess the role of angiotensin in the renal response in the dog (Freeman et al. 1973), in the rabbit (Mimran et al. 1974), and in man (personal observation). In all three species angiotensin antagonists increase renal blood flow when sodium intake is restricted, but not when free access to sodium is allowed. The renal vascular response to sodium restriction, therefore, is very likely to be due to activation of the renin-angiotensin system.
Since restriction of potassium intake also activates the renin-angiotensin system and blunts the renal vascular response to angiotensin II (Hollenberg et al. 1975), features shared with restriction of sodium intake, it seems likely that the renal response in this setting also is due to angiotensin. Unfortunately, sodium intake and potassium intake have rarely been controlled in studies on renal blood flow in human disease.
Position is also a quantitatively important determinant of renal perfusion (Smith 1951, Lee et al. 1966, Wesson 1969). Assuming the upright position results in a reduction in mean and cortical blood flow, and an increased renin secretion within minutes (Hollenberg et al. 1969). The reduction in renal blood flow is larger than the accompanying reduction in cardiac output (Lee et al. 1966).
Since mean arterial pressure does not fall in the standing position, active renal vasoconstriction must mediate the response. There is no direct information on whether angiotensin, norepinephrine or some other endogenous vasoconstrictor is responsible for the response in man.
Since mean arterial pressure does not fall in the standing position, active renal vasoconstriction must mediate the response. There is no direct information on whether angiotensin, norepinephrine or some other endogenous vasoconstrictor is responsible for the response in man.
Emotional states also appear to exert an important influence on renal blood flow (Smith 1951). Much of the information on the subject is anecdotal. Wolf et al. (1978) demonstrated a much larger fall in renal perfusion associated with emotional stress in patients with essential hypertension than in normal healthy control subjects.
Since the renal response was blunted by prior sympathectomy, the response was attributed to sympathetic nervous system activity by Wolf ' et al. (1948). Whether the neural activity was directed to alpha receptors in the vessels or led to renal vasoconstriction indirectly via activation of the renin-angiotensin system is not known.
Since the renal response was blunted by prior sympathectomy, the response was attributed to sympathetic nervous system activity by Wolf ' et al. (1948). Whether the neural activity was directed to alpha receptors in the vessels or led to renal vasoconstriction indirectly via activation of the renin-angiotensin system is not known.
Limitations of space make it impossible to review in detail what has been learned about disordered renal perfusion and its relationship to function in a host of disease states. Diseases in which an abnormality of renal perfusion probably plays a pathogenetic role include essential and secondary hypertension; the oedema states including congestive heart failure, cirrhosis of the liver and the nephrotic syndrome; and states characterized by a progressive reduction in glomerular filtration rate such as prerenal azotemia, acute renal failure and the hepatorenal syndrome.
In many of these conditions, well-documented abnormalities of renal perfusion, especially of the renal cortex, are sufficiently consistent and sufflciently large to account for many features of the disease process, as reviewed recently (Hollenberg 1975, Hollenberg & Adams 1976, Hollenberg, Mange] & Fung l976a).
In many of these conditions, well-documented abnormalities of renal perfusion, especially of the renal cortex, are sufficiently consistent and sufflciently large to account for many features of the disease process, as reviewed recently (Hollenberg 1975, Hollenberg & Adams 1976, Hollenberg, Mange] & Fung l976a).
It seems appropriate to complete this chapter with a quotation from Homer Smith (1951), since so many of the concepts presented arose in his laboratory. Smith suggested caution when interpreting studies performed with invasive techniques in anaesthetized animals subjected to major surgical trauma.
‘The technique of study of the renal circulation . .. in vogue consists of a series of Operations which might have been especially designed to excite autonomic nervous activity . . . anesthetic administered, the abdomen incised, viscera exposed, blood vessels dissected, . . . kidney forcibly freed of its attachments and manipulated. . . . If under these conditions vasoconstrictor activity does not approach a maximum level, it must indeed be because of the reign of chaos in the autonomic nervous system. . .
If emotional disturbance can so markedly influence the renal circulation in man, what must we say of procedures in laboratory animals which entail profound stimulation. . . . What I would plead is that the history of renal physiology has been in too large measure a history of traumatic procedures. . . . Perhaps it is not too much to suggest that so far as immediate experimental procedures are concerned, any observation that is too traumatic to be safely, reasonably and ethically carried out upon man is too traumatic, as far as physiological validity is concerned, to be carried out upon an experimental animal.’ These statements stand 25 years later.
‘The technique of study of the renal circulation . .. in vogue consists of a series of Operations which might have been especially designed to excite autonomic nervous activity . . . anesthetic administered, the abdomen incised, viscera exposed, blood vessels dissected, . . . kidney forcibly freed of its attachments and manipulated. . . . If under these conditions vasoconstrictor activity does not approach a maximum level, it must indeed be because of the reign of chaos in the autonomic nervous system. . .
If emotional disturbance can so markedly influence the renal circulation in man, what must we say of procedures in laboratory animals which entail profound stimulation. . . . What I would plead is that the history of renal physiology has been in too large measure a history of traumatic procedures. . . . Perhaps it is not too much to suggest that so far as immediate experimental procedures are concerned, any observation that is too traumatic to be safely, reasonably and ethically carried out upon man is too traumatic, as far as physiological validity is concerned, to be carried out upon an experimental animal.’ These statements stand 25 years later.