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Renal blood flow, glomerular filtration and plasma clearance
PHYSIOLOGY
Renal blood flow, glomerular filtration and plasma clearance
Learning objectives After reading this article, you should be able to: C understand how the structure of the glomerular capillary wall affords the selectivity of the ultrafiltration process C describe the interaction of the Starling forces acting across the glomerular capillary wall to produce the ultrafiltrate of plasma, and understand how this interaction differs from that across a systemic capillary C describe the factors that can modify ultrafiltration rate and the mechanisms involved C define what is meant by the term ‘renal clearance’ and describe the usefulness and limitations of clearance measurements to the understanding of kidney function
John C Atherton
Abstract Homeostatic and excretory functions of the kidney depend on blood flow (w25% cardiac output) and glomerular ultrafiltration (w20% renal plasma flow). Blood flow distribution is not uniform, with only 10% reaching the medulla. Selectivity of ultrafiltration is related to molecular size, shape and electrostatic charge of molecules, and structure of the glomerular capillary barrier with its negatively charged glycoproteins. Ultrafiltration, determined by the balance between hydrostatic and colloid osmotic pressures (Starling forces) in the glomerular capillary and Bowman’s space, occurs along the length of the capillary: hydrostatic pressure is relatively unchanged and always exceeds plasma colloid osmotic pressure plus pressure in Bowman’s space. Ultrafiltration is influenced by changes in renal plasma flow, altered surface area (mesangial cell activity) and changes in vascular resistance afforded by afferent and efferent arterioles (mediated by sympathetic nerve activity, vasoconstrictors and vasodilators). Autoregulation of renal plasma flow minimizes changes in ultrafiltration (hence, filtered load). Myogenic and tubuloglomerular feedback mechanisms are responsible for autoregulation, but their relative contribution is yet to be resolved. Clearance measurements are used to assess renal plasma flow (RPF), glomerular filtration rate (GFR) (creatinine, inulin), filtration fraction (GFR/RPF), net reabsorption or secretion, and proximal and distal nephron function (lithium, free-water) but all have their limitations.
Keywords
Autoregulation;
blood
flow;
clearance
flow is 600e650 ml/minute, of which 100e140 ml/minute is filtered (glomerular filtration rate (GFR)) across the glomerular capillary wall into Bowman’s space. The magnitude and selectivity of the filtration process is possible because of the arrangement of the capillaries within Bowman’s space, the
The nephron and its blood supply
Distal convoluted tubule
Bowman’s capsule Glomerular capillaries Proximal convoluted tubule
glomerulus;
Peritubular capillaries
ultrafiltration
Veins
Normal functioning of the kidneys to subserve homeostasis and excretion of metabolic waste products depends on: an adequate blood supply; production of an ultrafiltrate of plasma; and the ability to modify the composition of the filtrate through reabsorption from and secretion into the tubule. About 25% of cardiac output (>1 litre/minute) is directed to the kidneys, but the distribution is not uniform. Almost 100% supplies the cortex, through the glomerular capillaries and peritubular capillaries that surround the proximal and distal convoluted tubules (Figure 1). Only about 10% enters the medulla, of which less than 3% reaches the inner medulla. Renal plasma
Cortex Medulla
Efferent arteriole Afferent arteriole
Collecting duct Loop of Henlé
Thin descending limb Vasa recta John C Atherton PhD was Senior Lecturer in Physiology at Manchester University. He graduated from Newcastle upon Tyne and gained his PhD at Manchester. His research interests focused on renal physiology with particular interest in urinary concentrating mechanisms, renal function in pregnancy, and assessment of nephron function. He is now Senior Lecturer in Medical Education at Keele University. Conflicts of interest: none declared.
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Thin ascending limb
Thick ascending limb
Figure 1
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PHYSIOLOGY
structure of the capillary wall, and the visceral epithelial layer (podocytes) of Bowman’s capsule with which it is in intimate contact (Figure 2a). The three main barriers (Figure 2b) to filtration are: the fenestrated capillary endothelium with pores (diameter 70 nm) that acts as a gross filter preventing the passage of blood cells; the basement membrane consisting of a porous matrix of extracellular proteins; and an epithelial layer with podocytes and foot-like processes (pedicels) that surround the glomerular capillaries. Thin membraneous sheets containing pores (4 nm by 14 nm) span the gaps (filtration slits, width 25e60 nm) between the pedicels. The passage of large molecules is limited, but haemoglobin (molecular diameter 6.5 nm) and some small plasma proteins (e.g. albumin; molecular diameter about 7 nm) can pass through the filtration barrier, albeit in small amounts. However, electrostatic charge is as important as the size and shape of the molecule. In general, neutral molecules with a molecular diameter less than 4 nm are freely filtered, but molecules (irrespective of charge) with diameters exceeding 8 nm are not filtered. Between
4 and 8 nm diameter the extent of filtration depends on size and charge. This can be explained by the presence of negatively charged glycoproteins on the filtration barriers (Figure 2b). Thus, for molecules of similar size but opposite charge, cationic molecules pass more readily through the barrier; but negatively charged plasma proteins with molecular diameters less than 8 nm do not pass easily. Mesangial cells found between capillaries within the glomerular tuft have at least three important functions in the filtration process. They exhibit contractile properties, thereby influencing the surface area over which ultrafiltration occurs. They have a structural role in the glomerular tuft and can secrete extracellular matrix. They are actively phagocytic, preventing accumulation within the extracellular matrix of macromolecules that have escaped through the basement membrane of the capillaries (i.e. they keep the filter clean). They also secrete prostaglandins and cytokines that may enhance the inflammatory response to invasion of the extracellular matrix by immune complexes (the basement membrane surrounds only part of the glomerular capillaries).
Forces involved in ultrafiltration
a
Forces involved in the formation of an ultrafiltrate of plasma are the Starling forces operating across the glomerular capillary wall (Figure 3). Forces that promote fluid movement out of the glomerular capillary are hydrostatic pressure in the glomerular capillary (PGC) and colloid osmotic pressure in Bowman’s space (pBS). The forces that oppose fluid movement from the glomerular capillary are colloid osmotic pressure (pGG) and intrarenal pressure (mainly hydrostatic pressure in Bowman’s space (PBS)). Thus, net ultrafiltration pressure can be represented as (PGC PBS) (pGC pBS). However, since large protein molecules do
Starling forces and ultrafiltration along a glomerular capillary 60
Pressure (mmHg)
b 40
πGC
PGC
20
PBS 0
Afferent arteriole
Figure 2 a Electron micrograph (24,000) through a glomerular capillary and surrounding podocytes. (a red blood cell; b capillary lumen; c endothelial cells) b Area of fenestrated glomerular capillary wall (70,000) (a podocyte; b pedicels; c filtration slits; d basement membrane; e Bowman’s space; f red blood cell. Negative charges on the pedicels, basement membrane and endothelial cells are indicated by bars).
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Glomerular capillary
Efferent arteriole
PGC and PBS, hydrostatic pressure in glomerular capillary and Bowman’s space, respectively; πGC, colloid osmotic pressure on glomerular capillary plasma.
Figure 3
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not traverse the glomerular capillary wall, pBS can be discounted. Hence, net ultrafiltration pressure and fluid movement out of the capillary (GFR) equal PGC (PBS þ pGC) and Kf (PGC (PBS þ pGC)), respectively, where Kf is the ultrafiltration coefficient that takes account of the surface area of the glomerular capillary as well as the permeability per unit of surface area. At the afferent arteriolar end of the capillary, net ultrafiltration pressure is about 10e15 mmHg. The ensuing fluid movement without significant protein movement results in a rise in pGC; net ultrafiltration pressure is reduced. Fluid moves out of the capillary until the forces promoting and opposing fluid movement from the capillary are equal. At this point (ultrafiltration pressure equilibrium) fluid movement from the capillary ceases. It is thought that this equilibrium is reached in some species (e.g. rat) but not in others (e.g. humans). The relationship between these forces operating across a glomerular capillary is different from a systemic capillary. Hydrostatic pressure declines along the length of the systemic capillary and there is no difference between the colloid osmotic pressure at the arterial and venous ends of the capillary. Fluid moves out of the capillary at the arteriolar end into the capillary at the venous end; fluid always moves out of the glomerular capillary. The reason for this difference is primarily because the glomerular capillary is in series with the afferent and efferent arterioles; the balance of vascular resistances is such that only a small decline in hydrostatic pressure occurs along the length of the glomerular capillary.
greater. The opposite changes occur if both afferent and efferent arterioles constrict. Changes in sympathetic nerve activity e renal nerves and the adrenal medulla affect afferent and efferent arteriolar resistance by a-adrenoceptor-mediated vasoconstriction, mainly on the afferent arteriole. Moderate stimulation lowers RPF without an equivalent change in GFR, suggesting that vasoconstriction of the efferent arteriole is the predominant effect. More intense stimulation of renal sympathetic nerves (e.g. following severe haemorrhage) dramatically reduces RPF and GFR, suggesting powerful and equivalent changes in resistance in afferent and efferent arterioles. Angiotensin II e the effects of this vasoconstrictor depend on the plasma concentration; efferent arterioles are more sensitive than afferent arterioles. At low concentrations any reduction in RPF may not be accompanied by an equivalent change in GFR, whereas at high concentrations both RPF and GFR are lower. The endothelial cells lining the renal arterioles produce a number of autacoids that have important vasodilator or vasoconstrictor actions. Endothelin has powerful vasoconstrictor effects on the afferent and efferent arterioles, which reduces RPF and GFR. These cells may also have angiotensin-converting enzyme on their cell surfaces, thereby converting angiotensin I, produced systemically or locally, to angiotensin II. Nitric oxide, released from endothelial cells, has significant vasodilator effects causing increases in RPF and GFR. Prostaglandins (PGE2, PGI2) produced locally, vasodilate afferent and efferent arterioles to increase RPF (not GFR), but their effects are manifest only during intense sympathetic nerve vasoconstrictor activity. Their primary role is to modulate the powerful vasoconstriction and therefore to protect the kidney from renal ischaemia. Other hormones are implicated in the control of RPF and GFR in pathophysiological conditions but their role in normal regulation has yet to be defined. Examples are direct vasodilator (dopa-mine, atrial natriuretic peptide) or vasoconstrictor (adenosine) effects on afferent and/or efferent arterioles or indirect effects via the release of nitric oxide from the endothelial cells (bradykinin, adenosine triphosphate (ATP), histamine). Mesangial cells may also be involved in the regulation of RPF and GFR; their contractile elements respond to autacoids in a similar way to arteriolar smooth muscle cells. They might influence GFR by controlling flow through glomemlar capillaries
Factors influencing GFR Changes in GFR can be mediated by changes in Kf and/or changes in the Starling forces. Renal plasma flow (RPF) is also an important determinant of GFR. The arrangement of the glomerular capillaries, in series between two sets of arterioles, the resistances of which can be changed independently, means that it is possible to produce changes in GFR that are both in parallel to and divergent from changes in RPF (Table 1) As flow along the glomerular capillary increases, the difference between PGC and pGC does not decrease at the same rate as at lower flow (Figure 3); the increase in pGC is smaller and therefore net ultrafiltration pressure is greater at all points along the capillary; ultrafiltration pressure disequilibrium at the efferent arteriolar end of the capillary is
Effect of changing renal arteriole resistance
Afferent arteriole resistance
Efferent arteriole resistance
Renal plasma flow
Glomerular capillary pressure
Glomerular filtration rate
Decreased Unchanged Unchanged Increased Decreased Increased
Unchanged Decreased Increased Unchanged Decreased Increased
[ [ Y Y [ Y
[ Y [ Y )/ )/
[ Y [ Y [ Y
Table 1
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PHYSIOLOGY
and by affecting the surface area available for ultrafiltration (an important determinant of Kf). Autoregulation (Figure 4) e kidneys regulate blood flow by adjusting vascular resistance to changes in perfusion pressure (blood pressure): renal blood flow ¼ perfusion pressure/renal vascular resistance. Within 80e200 mmHg, increments in blood pressure are not accompanied by significant changes in RPF or GFR. The mechanism underlying this is thought to comprise two components that collectively lead to a proportionate change in preglomerular vascular resistance: the renal myogenic response and tubuloglomerular feedback (TGF). The myogenic feedback mechanism ensures that when blood pressure rises, the ensuing stretching of muscle instigates contraction of the muscle, and RPF and GFR are relatively constant. The underlying mechanisms, though not fully resolved, involve depolarization, activation of voltage-gated L-type Ca2þ channels and Ca2þ entry triggering a rapid vasoconstriction. The tubuloglomerular feedback mechanism depends on the macula densa sensing tubular flow (or some function of changing flow such as changing sodium load). This sensing mechanism initiates a sequence of events leading to altered afferent arteriolar resistance. If GFR increases, flow past the macula densa increases, the afferent arteriole constricts, and RPF and GFR decrease. The converse occurs when GFR declines. This maintains constancy of the filtered load delivered to the reabsorptive sites. The traditional view is that the myogenic mechanism and TGF always work in concert to effect autoregulation of GFR, and hence have a central role in volume homeostasis despite fluctuations in mean arterial blood pressure. This view is now being questioned because there is little evidence of disturbed volume regulation in animal models where autoregulation is impaired. However, impaired autoregulation has been associated with increased susceptibility to hypertensive damage. An emerging concept is that the myogenic mechanism regulates afferent arteriolar tone in response to systolic (rather than mean) arterial
blood pressure to protect the glomerular capillary from damage due to increased hydrostatic pressure. This can lead to fluctuations in GFR, which, in turn, are compensated by TGF. In the emerging model, although the myogenic response and TGF can work in concert, this is more by luck than design and there are circumstances where TGF may modulate myogenic activity when a protective vasoconstriction to elevated systolic blood pressure disrupts the regulation of fluid delivery to the distal nephron. The suggestion in the new model is that the regulation of GFR is more approximate than originally thought in the traditional model and that long-term homeostasis is served by a series of slowerresponding mechanisms. The emerging view is currently supported by a range of models and in vitro studies but definitive evidence from in vivo and clinical studies is yet to be established.
Renal clearance measurements Renal clearance of a solute (CX) is defined as the volume of plasma passing through the kidneys from which all the solute has been removed and excreted in the urine in unit time. Thus CXPX ¼ UXV, where: CX is clearance of solute x, UX and PX are the urinary and plasma concentrations of x; and V is urine flow rate. Hence CX ¼ UXV/PX. Measuring RPF: to apply this principle to measurement of RPF it is essential to identify a solute that is completely removed from the plasma as it flows through the kidney (i.e. it is filtered and secreted to the extent that the renal venous concentration of the solute is zero) and it is not metabolized in the kidney. The amount delivered to the kidney equals the amount excreted (RPF.PX ¼ UXV). Such a solute is p-aminohippuric acid (PAH), but it is not endogenous and has to be administered. The kidney excretes this organic acid by ultrafiltration and by a proximal tubular anion secretory mechanism that can actively transport up to a maximum amount per minute (i.e. it can be saturated). When the plasma concentration increases, the amount delivered to the transport sites increases, the transport maximum may be exceeded and renal venous plasma concentration will not be zero. Use of CPAH to measure RPF will not be valid in these circumstances unless both systemic plasma and renal venous PAH concentrations are measured. It is important, therefore, that the secretory transport mechanism is not saturated. RPF is calculated as CPAH ¼ UPAHV/PPAH. However, even at low plasma PAH concentrations, a small amount of PAH escapes secretion because some of the tissues perfused do not possess PAH secretory mechanisms. Measurement of CPAH is referred to as the effective renal plasma flow (ERPF) e plasma flow through renal tissues that effectively remove PAH from the plasma passing through. This assumption underestimates the RPF by about 10%.
GFR (ml/minute)
RPF (ml/minute)
Relationship between renal arterial pressure, renal plasma flow (RPF) and glomerular filtration rate (GFR) 700
RPF 500
100
GFR
Measuring GFR: to apply this principle to measurement of GFR it is essential to identify a solute that is freely filtered and excreted unchanged. Thus, amount filtered ¼ amount excreted (GFR.PX ¼ UXV). Such a solute is inulin; a polysaccharide of fructose that is not endogenous so has to be administered. GFR is calculated as Cinulin ¼ UinulinV/Pinulin. Inulin has to be administered intravenously over several hours to achieve steady-state plasma concentrations before accurate measurements of GFR can be obtained. For this reason, endogenous plasma creatinine (derived from the muscle protein creatine) and 24-hour urinary
0 80
180
Renal arterial pressure (renal perfusion pressure) (mmHg) Figure 4
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creatinine measurements are used instead but they have the disadvantage that some creatinine is secreted by organic cation secretory mechanisms in the proximal tubule. It is usually claimed that this overestimate of GFR is ‘balanced’ by the error in measuring plasma creatinine that is high owing to the presence of non-specific chromogens. Some data indicate that creatinine clearance can overestimate GFR by 10e30%, suggesting that tubular secretion might make a more significant contribution to excreted creatinine. Plasma creatinine concentration alone is used to assess kidney function in the clinical setting. This might detect significant changes in GFR, but small changes could pass unnoticed. Creatinine production is relatively constant and must equal excreted creatinine if plasma creatinine is to remain constant (i.e. creatinine production ¼ GFR.Pcreat ¼ UcreatV). If GFR decreases, a transient decrease in UcreatV occurs and Pcreat increases until equality of production and output is re-established at the lower GFR. Therefore, with a continual chronic reduction in GFR, plasma creatinine concentration increases exponentially (i.e. an initial small reduction
in GFR produces only a small increase in plasma creatinine concentration). Only when there is a relatively large reduction in GFR will plasma creatinine increase dramatically (Figure 5). Renal clearance is not restricted to measurement of GFR, RPF and filtration fraction (GFR/RPF). Renal clearances of any solute can be measured and, when compared with GFR, its handling by the kidney can be assessed. For example, if the clearance of a solute is less than Cinulin there has been net reabsorption of the solute whereas if the clearance is greater than Cinulin there has been net secretion. Proximal and distal nephron function can be estimated using clearances of lithium and free water (CH2O, calculated as V-Cosm), respectively, but neither is entirely satisfactory. When proximal tubule reabsorption is altered, Clithium, a marker of fluid delivery from the proximal tubule, changes in the predicted direction. However, this underestimates fluid delivery because some lithium (12e15%) is reabsorbed in the loop of Henle. CH2O (measured during a maximal water diuresis when ADH secretion is suppressed) is used to estimate Naþ reabsorption in the water impermeable ascending limb of the loop of Henle and early distal tubule. However, because significant reabsorption of this ‘freed water’ occurs in the collecting duct even in the absence of ADH, CH2O provides an underestimate of Naþ absorption. A
Hyperbolic relationship between glomerular filtration rate (GFR) and plasma creatinine concentration (P creat ) 1200
FURTHER READING Bagshaw SM, Gibney RTN. Conventional markers of kidney function. Crit Care Med 2008; 36(Suppl.): S152e8. Boron WF, Boulpaep EL. Medical physiology. Philadelphia: Elsevier Science, 2003. Cupples WA. Interactions contributing to kidney blood flow autoregulation. Curr Opin Nephrol Hypertens 2007; 16: 39e45. Lote CJ. Principles of renal physiology. 3rd edn. London: Chapman & Hall, 1975. Loutzenhiser R, Griffin K, Williamson G, Bidani A. Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms. Am J Physiol Regul Integr Comp Physiol 2006; 290: R1153e67. Seldin DW, Giebisch G, eds. The kidney: physiology and pathophysiology. 3rd edn. Philadelphia: Lippincott, Williams and Wilkins, 2000. Valtin H, Schafer JA. Renal function. 3rd edn. Boston: Little, Brown and Company, 1995.
Pcreat (μmol/litre)
900
600
300
0 50
0
100
GFR (ml/minute) Figure 5
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Renal blood flow, glomerular filtration and plasma clearance
Learning objectives After reading this article, you should be able to: C understand how the structure of the glomerular capillary wall affords the selectivity of the ultrafiltration process C describe the interaction of the Starling forces acting across the glomerular capillary wall to produce the ultrafiltrate of plasma, and understand how this interaction differs from that across a systemic capillary C describe the factors that can modify ultrafiltration rate and the mechanisms involved C define what is meant by the term ‘renal clearance’ and describe the usefulness and limitations of clearance measurements to the understanding of kidney function
John C Atherton
Abstract Homeostatic and excretory functions of the kidney depend on blood flow (w25% cardiac output) and glomerular ultrafiltration (w20% renal plasma flow). Blood flow distribution is not uniform, with only 10% reaching the medulla. Selectivity of ultrafiltration is related to molecular size, shape and electrostatic charge of molecules, and structure of the glomerular capillary barrier with its negatively charged glycoproteins. Ultrafiltration, determined by the balance between hydrostatic and colloid osmotic pressures (Starling forces) in the glomerular capillary and Bowman’s space, occurs along the length of the capillary: hydrostatic pressure is relatively unchanged and always exceeds plasma colloid osmotic pressure plus pressure in Bowman’s space. Ultrafiltration is influenced by changes in renal plasma flow, altered surface area (mesangial cell activity) and changes in vascular resistance afforded by afferent and efferent arterioles (mediated by sympathetic nerve activity, vasoconstrictors and vasodilators). Autoregulation of renal plasma flow minimizes changes in ultrafiltration (hence, filtered load). Myogenic and tubuloglomerular feedback mechanisms are responsible for autoregulation, but their relative contribution is yet to be resolved. Clearance measurements are used to assess renal plasma flow (RPF), glomerular filtration rate (GFR) (creatinine, inulin), filtration fraction (GFR/RPF), net reabsorption or secretion, and proximal and distal nephron function (lithium, free-water) but all have their limitations.
Keywords
Autoregulation;
blood
flow;
clearance
flow is 600e650 ml/minute, of which 100e140 ml/minute is filtered (glomerular filtration rate (GFR)) across the glomerular capillary wall into Bowman’s space. The magnitude and selectivity of the filtration process is possible because of the arrangement of the capillaries within Bowman’s space, the
The nephron and its blood supply
Distal convoluted tubule
Bowman’s capsule Glomerular capillaries Proximal convoluted tubule
glomerulus;
Peritubular capillaries
ultrafiltration
Veins
Normal functioning of the kidneys to subserve homeostasis and excretion of metabolic waste products depends on: an adequate blood supply; production of an ultrafiltrate of plasma; and the ability to modify the composition of the filtrate through reabsorption from and secretion into the tubule. About 25% of cardiac output (>1 litre/minute) is directed to the kidneys, but the distribution is not uniform. Almost 100% supplies the cortex, through the glomerular capillaries and peritubular capillaries that surround the proximal and distal convoluted tubules (Figure 1). Only about 10% enters the medulla, of which less than 3% reaches the inner medulla. Renal plasma
Cortex Medulla
Efferent arteriole Afferent arteriole
Collecting duct Loop of Henlé
Thin descending limb Vasa recta John C Atherton PhD was Senior Lecturer in Physiology at Manchester University. He graduated from Newcastle upon Tyne and gained his PhD at Manchester. His research interests focused on renal physiology with particular interest in urinary concentrating mechanisms, renal function in pregnancy, and assessment of nephron function. He is now Senior Lecturer in Medical Education at Keele University. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:7
Thin ascending limb
Thick ascending limb
Figure 1
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PHYSIOLOGY
structure of the capillary wall, and the visceral epithelial layer (podocytes) of Bowman’s capsule with which it is in intimate contact (Figure 2a). The three main barriers (Figure 2b) to filtration are: the fenestrated capillary endothelium with pores (diameter 70 nm) that acts as a gross filter preventing the passage of blood cells; the basement membrane consisting of a porous matrix of extracellular proteins; and an epithelial layer with podocytes and foot-like processes (pedicels) that surround the glomerular capillaries. Thin membraneous sheets containing pores (4 nm by 14 nm) span the gaps (filtration slits, width 25e60 nm) between the pedicels. The passage of large molecules is limited, but haemoglobin (molecular diameter 6.5 nm) and some small plasma proteins (e.g. albumin; molecular diameter about 7 nm) can pass through the filtration barrier, albeit in small amounts. However, electrostatic charge is as important as the size and shape of the molecule. In general, neutral molecules with a molecular diameter less than 4 nm are freely filtered, but molecules (irrespective of charge) with diameters exceeding 8 nm are not filtered. Between
4 and 8 nm diameter the extent of filtration depends on size and charge. This can be explained by the presence of negatively charged glycoproteins on the filtration barriers (Figure 2b). Thus, for molecules of similar size but opposite charge, cationic molecules pass more readily through the barrier; but negatively charged plasma proteins with molecular diameters less than 8 nm do not pass easily. Mesangial cells found between capillaries within the glomerular tuft have at least three important functions in the filtration process. They exhibit contractile properties, thereby influencing the surface area over which ultrafiltration occurs. They have a structural role in the glomerular tuft and can secrete extracellular matrix. They are actively phagocytic, preventing accumulation within the extracellular matrix of macromolecules that have escaped through the basement membrane of the capillaries (i.e. they keep the filter clean). They also secrete prostaglandins and cytokines that may enhance the inflammatory response to invasion of the extracellular matrix by immune complexes (the basement membrane surrounds only part of the glomerular capillaries).
Forces involved in ultrafiltration
a
Forces involved in the formation of an ultrafiltrate of plasma are the Starling forces operating across the glomerular capillary wall (Figure 3). Forces that promote fluid movement out of the glomerular capillary are hydrostatic pressure in the glomerular capillary (PGC) and colloid osmotic pressure in Bowman’s space (pBS). The forces that oppose fluid movement from the glomerular capillary are colloid osmotic pressure (pGG) and intrarenal pressure (mainly hydrostatic pressure in Bowman’s space (PBS)). Thus, net ultrafiltration pressure can be represented as (PGC PBS) (pGC pBS). However, since large protein molecules do
Starling forces and ultrafiltration along a glomerular capillary 60
Pressure (mmHg)
b 40
πGC
PGC
20
PBS 0
Afferent arteriole
Figure 2 a Electron micrograph (24,000) through a glomerular capillary and surrounding podocytes. (a red blood cell; b capillary lumen; c endothelial cells) b Area of fenestrated glomerular capillary wall (70,000) (a podocyte; b pedicels; c filtration slits; d basement membrane; e Bowman’s space; f red blood cell. Negative charges on the pedicels, basement membrane and endothelial cells are indicated by bars).
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Glomerular capillary
Efferent arteriole
PGC and PBS, hydrostatic pressure in glomerular capillary and Bowman’s space, respectively; πGC, colloid osmotic pressure on glomerular capillary plasma.
Figure 3
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not traverse the glomerular capillary wall, pBS can be discounted. Hence, net ultrafiltration pressure and fluid movement out of the capillary (GFR) equal PGC (PBS þ pGC) and Kf (PGC (PBS þ pGC)), respectively, where Kf is the ultrafiltration coefficient that takes account of the surface area of the glomerular capillary as well as the permeability per unit of surface area. At the afferent arteriolar end of the capillary, net ultrafiltration pressure is about 10e15 mmHg. The ensuing fluid movement without significant protein movement results in a rise in pGC; net ultrafiltration pressure is reduced. Fluid moves out of the capillary until the forces promoting and opposing fluid movement from the capillary are equal. At this point (ultrafiltration pressure equilibrium) fluid movement from the capillary ceases. It is thought that this equilibrium is reached in some species (e.g. rat) but not in others (e.g. humans). The relationship between these forces operating across a glomerular capillary is different from a systemic capillary. Hydrostatic pressure declines along the length of the systemic capillary and there is no difference between the colloid osmotic pressure at the arterial and venous ends of the capillary. Fluid moves out of the capillary at the arteriolar end into the capillary at the venous end; fluid always moves out of the glomerular capillary. The reason for this difference is primarily because the glomerular capillary is in series with the afferent and efferent arterioles; the balance of vascular resistances is such that only a small decline in hydrostatic pressure occurs along the length of the glomerular capillary.
greater. The opposite changes occur if both afferent and efferent arterioles constrict. Changes in sympathetic nerve activity e renal nerves and the adrenal medulla affect afferent and efferent arteriolar resistance by a-adrenoceptor-mediated vasoconstriction, mainly on the afferent arteriole. Moderate stimulation lowers RPF without an equivalent change in GFR, suggesting that vasoconstriction of the efferent arteriole is the predominant effect. More intense stimulation of renal sympathetic nerves (e.g. following severe haemorrhage) dramatically reduces RPF and GFR, suggesting powerful and equivalent changes in resistance in afferent and efferent arterioles. Angiotensin II e the effects of this vasoconstrictor depend on the plasma concentration; efferent arterioles are more sensitive than afferent arterioles. At low concentrations any reduction in RPF may not be accompanied by an equivalent change in GFR, whereas at high concentrations both RPF and GFR are lower. The endothelial cells lining the renal arterioles produce a number of autacoids that have important vasodilator or vasoconstrictor actions. Endothelin has powerful vasoconstrictor effects on the afferent and efferent arterioles, which reduces RPF and GFR. These cells may also have angiotensin-converting enzyme on their cell surfaces, thereby converting angiotensin I, produced systemically or locally, to angiotensin II. Nitric oxide, released from endothelial cells, has significant vasodilator effects causing increases in RPF and GFR. Prostaglandins (PGE2, PGI2) produced locally, vasodilate afferent and efferent arterioles to increase RPF (not GFR), but their effects are manifest only during intense sympathetic nerve vasoconstrictor activity. Their primary role is to modulate the powerful vasoconstriction and therefore to protect the kidney from renal ischaemia. Other hormones are implicated in the control of RPF and GFR in pathophysiological conditions but their role in normal regulation has yet to be defined. Examples are direct vasodilator (dopa-mine, atrial natriuretic peptide) or vasoconstrictor (adenosine) effects on afferent and/or efferent arterioles or indirect effects via the release of nitric oxide from the endothelial cells (bradykinin, adenosine triphosphate (ATP), histamine). Mesangial cells may also be involved in the regulation of RPF and GFR; their contractile elements respond to autacoids in a similar way to arteriolar smooth muscle cells. They might influence GFR by controlling flow through glomemlar capillaries
Factors influencing GFR Changes in GFR can be mediated by changes in Kf and/or changes in the Starling forces. Renal plasma flow (RPF) is also an important determinant of GFR. The arrangement of the glomerular capillaries, in series between two sets of arterioles, the resistances of which can be changed independently, means that it is possible to produce changes in GFR that are both in parallel to and divergent from changes in RPF (Table 1) As flow along the glomerular capillary increases, the difference between PGC and pGC does not decrease at the same rate as at lower flow (Figure 3); the increase in pGC is smaller and therefore net ultrafiltration pressure is greater at all points along the capillary; ultrafiltration pressure disequilibrium at the efferent arteriolar end of the capillary is
Effect of changing renal arteriole resistance
Afferent arteriole resistance
Efferent arteriole resistance
Renal plasma flow
Glomerular capillary pressure
Glomerular filtration rate
Decreased Unchanged Unchanged Increased Decreased Increased
Unchanged Decreased Increased Unchanged Decreased Increased
[ [ Y Y [ Y
[ Y [ Y )/ )/
[ Y [ Y [ Y
Table 1
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and by affecting the surface area available for ultrafiltration (an important determinant of Kf). Autoregulation (Figure 4) e kidneys regulate blood flow by adjusting vascular resistance to changes in perfusion pressure (blood pressure): renal blood flow ¼ perfusion pressure/renal vascular resistance. Within 80e200 mmHg, increments in blood pressure are not accompanied by significant changes in RPF or GFR. The mechanism underlying this is thought to comprise two components that collectively lead to a proportionate change in preglomerular vascular resistance: the renal myogenic response and tubuloglomerular feedback (TGF). The myogenic feedback mechanism ensures that when blood pressure rises, the ensuing stretching of muscle instigates contraction of the muscle, and RPF and GFR are relatively constant. The underlying mechanisms, though not fully resolved, involve depolarization, activation of voltage-gated L-type Ca2þ channels and Ca2þ entry triggering a rapid vasoconstriction. The tubuloglomerular feedback mechanism depends on the macula densa sensing tubular flow (or some function of changing flow such as changing sodium load). This sensing mechanism initiates a sequence of events leading to altered afferent arteriolar resistance. If GFR increases, flow past the macula densa increases, the afferent arteriole constricts, and RPF and GFR decrease. The converse occurs when GFR declines. This maintains constancy of the filtered load delivered to the reabsorptive sites. The traditional view is that the myogenic mechanism and TGF always work in concert to effect autoregulation of GFR, and hence have a central role in volume homeostasis despite fluctuations in mean arterial blood pressure. This view is now being questioned because there is little evidence of disturbed volume regulation in animal models where autoregulation is impaired. However, impaired autoregulation has been associated with increased susceptibility to hypertensive damage. An emerging concept is that the myogenic mechanism regulates afferent arteriolar tone in response to systolic (rather than mean) arterial
blood pressure to protect the glomerular capillary from damage due to increased hydrostatic pressure. This can lead to fluctuations in GFR, which, in turn, are compensated by TGF. In the emerging model, although the myogenic response and TGF can work in concert, this is more by luck than design and there are circumstances where TGF may modulate myogenic activity when a protective vasoconstriction to elevated systolic blood pressure disrupts the regulation of fluid delivery to the distal nephron. The suggestion in the new model is that the regulation of GFR is more approximate than originally thought in the traditional model and that long-term homeostasis is served by a series of slowerresponding mechanisms. The emerging view is currently supported by a range of models and in vitro studies but definitive evidence from in vivo and clinical studies is yet to be established.
Renal clearance measurements Renal clearance of a solute (CX) is defined as the volume of plasma passing through the kidneys from which all the solute has been removed and excreted in the urine in unit time. Thus CXPX ¼ UXV, where: CX is clearance of solute x, UX and PX are the urinary and plasma concentrations of x; and V is urine flow rate. Hence CX ¼ UXV/PX. Measuring RPF: to apply this principle to measurement of RPF it is essential to identify a solute that is completely removed from the plasma as it flows through the kidney (i.e. it is filtered and secreted to the extent that the renal venous concentration of the solute is zero) and it is not metabolized in the kidney. The amount delivered to the kidney equals the amount excreted (RPF.PX ¼ UXV). Such a solute is p-aminohippuric acid (PAH), but it is not endogenous and has to be administered. The kidney excretes this organic acid by ultrafiltration and by a proximal tubular anion secretory mechanism that can actively transport up to a maximum amount per minute (i.e. it can be saturated). When the plasma concentration increases, the amount delivered to the transport sites increases, the transport maximum may be exceeded and renal venous plasma concentration will not be zero. Use of CPAH to measure RPF will not be valid in these circumstances unless both systemic plasma and renal venous PAH concentrations are measured. It is important, therefore, that the secretory transport mechanism is not saturated. RPF is calculated as CPAH ¼ UPAHV/PPAH. However, even at low plasma PAH concentrations, a small amount of PAH escapes secretion because some of the tissues perfused do not possess PAH secretory mechanisms. Measurement of CPAH is referred to as the effective renal plasma flow (ERPF) e plasma flow through renal tissues that effectively remove PAH from the plasma passing through. This assumption underestimates the RPF by about 10%.
GFR (ml/minute)
RPF (ml/minute)
Relationship between renal arterial pressure, renal plasma flow (RPF) and glomerular filtration rate (GFR) 700
RPF 500
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GFR
Measuring GFR: to apply this principle to measurement of GFR it is essential to identify a solute that is freely filtered and excreted unchanged. Thus, amount filtered ¼ amount excreted (GFR.PX ¼ UXV). Such a solute is inulin; a polysaccharide of fructose that is not endogenous so has to be administered. GFR is calculated as Cinulin ¼ UinulinV/Pinulin. Inulin has to be administered intravenously over several hours to achieve steady-state plasma concentrations before accurate measurements of GFR can be obtained. For this reason, endogenous plasma creatinine (derived from the muscle protein creatine) and 24-hour urinary
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Renal arterial pressure (renal perfusion pressure) (mmHg) Figure 4
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PHYSIOLOGY
creatinine measurements are used instead but they have the disadvantage that some creatinine is secreted by organic cation secretory mechanisms in the proximal tubule. It is usually claimed that this overestimate of GFR is ‘balanced’ by the error in measuring plasma creatinine that is high owing to the presence of non-specific chromogens. Some data indicate that creatinine clearance can overestimate GFR by 10e30%, suggesting that tubular secretion might make a more significant contribution to excreted creatinine. Plasma creatinine concentration alone is used to assess kidney function in the clinical setting. This might detect significant changes in GFR, but small changes could pass unnoticed. Creatinine production is relatively constant and must equal excreted creatinine if plasma creatinine is to remain constant (i.e. creatinine production ¼ GFR.Pcreat ¼ UcreatV). If GFR decreases, a transient decrease in UcreatV occurs and Pcreat increases until equality of production and output is re-established at the lower GFR. Therefore, with a continual chronic reduction in GFR, plasma creatinine concentration increases exponentially (i.e. an initial small reduction
in GFR produces only a small increase in plasma creatinine concentration). Only when there is a relatively large reduction in GFR will plasma creatinine increase dramatically (Figure 5). Renal clearance is not restricted to measurement of GFR, RPF and filtration fraction (GFR/RPF). Renal clearances of any solute can be measured and, when compared with GFR, its handling by the kidney can be assessed. For example, if the clearance of a solute is less than Cinulin there has been net reabsorption of the solute whereas if the clearance is greater than Cinulin there has been net secretion. Proximal and distal nephron function can be estimated using clearances of lithium and free water (CH2O, calculated as V-Cosm), respectively, but neither is entirely satisfactory. When proximal tubule reabsorption is altered, Clithium, a marker of fluid delivery from the proximal tubule, changes in the predicted direction. However, this underestimates fluid delivery because some lithium (12e15%) is reabsorbed in the loop of Henle. CH2O (measured during a maximal water diuresis when ADH secretion is suppressed) is used to estimate Naþ reabsorption in the water impermeable ascending limb of the loop of Henle and early distal tubule. However, because significant reabsorption of this ‘freed water’ occurs in the collecting duct even in the absence of ADH, CH2O provides an underestimate of Naþ absorption. A
Hyperbolic relationship between glomerular filtration rate (GFR) and plasma creatinine concentration (P creat ) 1200
FURTHER READING Bagshaw SM, Gibney RTN. Conventional markers of kidney function. Crit Care Med 2008; 36(Suppl.): S152e8. Boron WF, Boulpaep EL. Medical physiology. Philadelphia: Elsevier Science, 2003. Cupples WA. Interactions contributing to kidney blood flow autoregulation. Curr Opin Nephrol Hypertens 2007; 16: 39e45. Lote CJ. Principles of renal physiology. 3rd edn. London: Chapman & Hall, 1975. Loutzenhiser R, Griffin K, Williamson G, Bidani A. Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms. Am J Physiol Regul Integr Comp Physiol 2006; 290: R1153e67. Seldin DW, Giebisch G, eds. The kidney: physiology and pathophysiology. 3rd edn. Philadelphia: Lippincott, Williams and Wilkins, 2000. Valtin H, Schafer JA. Renal function. 3rd edn. Boston: Little, Brown and Company, 1995.
Pcreat (μmol/litre)
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GFR (ml/minute) Figure 5
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