Chapter 1 RENAL HAEMODYNAMICS AND GLOMERULAR FILTRATION

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1 3 Chapter 1 RENAL HAEMODYNAMICS AND GLOMERULAR FILTRATION David Shirley, Giovambattista Capasso and Robert Unwin The kidney has three homeostatic functions that can broadly be described as excretory, regulatory and hormonal. Excretory and regulatory functions are closely related: elimination of unwanted and potentially toxic products of tissue metabolism on the one hand; and the excretion or conservation of water and solutes, and thus the control of fluid and electrolyte balance and circulating volume, on the other. Several processes, beginning with the ultrafiltration of plasma and including the selective reabsorption and secretion of solutes and production of concentrated or dilute urine, achieve these functions. Here we discuss the first of these processes. RENAL BLOOD FLOW The normal renal blood flow is ~1200 ml/min, equivalent to ~25% of the resting cardiac output. Given that the kidneys make up <0.5% of the body weight, this clearly represents a massive blood flow. The magnitude of the blood supply is required not for the kidneys metabolic needs but in order to maintain a high rate of glomerular filtration (ultrafiltration of blood plasma). A typical glomerular filtration rate is 120 ml/min (normal range ml/min per 1.73 m 2 ); i.e. ~20% of the plasma perfusing the kidneys is normally filtered 1. GLOMERULAR FILTRATION The Filtration Barrier Three layers separate the fluid in glomerular capillaries from that in Bowman s capsule (Figure 1). Plasma is forced through the fenestrations between glomerular endothelial cells (thereby excluding blood cells), then through the non-cellular basement membrane and the slits between the foot processes of the podocytes (glomerular epithelial cells) lining Bowman s capsule. As the plasma crosses the basement membrane and filtration slits, there is no hindrance to the passage of molecules with a diameter of <4 nm (<40 Å), while those with a diameter >8 nm are not filtered at all; between these figures there is graded filtration. Since most plasma constituents have a molecular diameter much less than 4 nm, while most plasma proteins are bigger than 1 Assuming a normal haematocrit, the renal plasma flow is slightly greater than half the renal blood flow.

2 4 Acute Renal Failure in Practice Figure 1. (A) Diagrammatic representation of the glomerular membranes; (B) Scanning electron micrograph of podocytes (P) as viewed from Bowman s space The foot processes are wrapped around capillary loops. Taken, with permission, from Tisher CC and Madsen KM. Anatomy of the kidney; in The Kidney 4th ed., Brenner BM and Rector FC (eds.), Saunders, Philadelphia, (A) Podocytes Basement membrane Endothelium Fenestration (B) 7 nm, the glomerular filtrate has a composition similar to plasma save for the virtual absence of protein (Table 1). The glomerular barrier does not discriminate on the basis of size alone. A layer of polyanionic glycoproteins that covers the surface of the components of the filtration barrier repels large anions (i.e. proteins with a net negative charge like albumin) without significantly affecting small anions such as chloride or bicarbonate. Normal average urinary excretion of albumin in men and women is ~7 mg/24 h2; detection of albumin by dipstix has a threshold concentration of 200 mg/l. If the fixed negative charges on the filtration barrier are lost, as in some forms of glomerular disease (e.g. minimal change nephropathy), the filterability of albumin increases significantly from its normal value of <0.1%, causing significant proteinuria. Some plasma 2Up to 18 mg/24 h in men and 32 mg/24 h in women. chapter01.p65 4 6/12/02, 10:51 AM

3 Renal Haemodynamics and Glomerular Filtration 5 Table 1. Relationship between molecular diameter and filtration across glomerular membranes Substance Sodium Chloride Glucose β 2 microglobulin Myoglobin Bence-Jones protein Haemoglobin Albumin γ-globulin Molecular diameter (nm) ~0.4 (hydrated) ~0.6 (hydrated) Filterability * (%) <0.1 0 % filterability indicates that the substance is freely filtered, i.e. its concentration in Bowman s space equals that in plasma. proteins, e.g. β 2 microglobulin (molecular diameter ~3.2 nm), are small enough to be filtered even under normal circumstances. Haemoglobin (molecular diameter ~6.5 nm), even if released into plasma, becomes bound to haptoglobin and very little is filtered. However, myoglobin (molecular diameter ~3.9 nm), if released into plasma due to muscle damage (see Chapter 12), undergoes major filtration (Table 1). Pressures Responsible for Glomerular Filtration Ultimately, the glomerular filtrate is forced across the glomerular membranes by the hydrostatic pressure in the glomerular capillaries (P GC ). This pressure is sufficient to overcome the opposing two pressures: the hydrostatic pressure in Bowman s capsule (P BC ) and the colloid osmotic (oncotic) pressure in the glomerular capillaries (π GC ) (Figure 2). The driving force for filtration is known as the net filtration pressure (NFP). The colloid osmotic pressure in Bowman s capsule is negligible, owing to the virtual exclusion of proteins from the filtrate. The rate of filtration (GFR) is determined by the product of NFP and the ultrafiltration coefficient (K f ), the latter being a composite of the surface area available for filtration (which is large) and the hydraulic conductance of the glomerular membranes (which is high). Although direct measurements of P GC and P BC are unavailable in humans, extrapolation from animal studies allows the following estimates of the pressures at the start (afferent end) of the glomerular capillary bed: Therefore, NFP ~10 mmhg. P GC ~50 mmhg P BC ~15 mmhg π GC ~25 mmhg

4 6 Acute Renal Failure in Practice Figure 2. Pressures involved in glomerular filtration afferent glomerulus efferent P GC π GC P BC Bowman s capsule GFR α NFP GFR = K f NFP NFP = P GC P BC π GC GFR = K f (P GC P BC π GC) Owing to the low resistance of the glomerular capillaries, P GC does not decrease appreciably along the capillary bed. However, as (protein-free) fluid is filtered, the protein concentration of unfiltered plasma remaining in the glomerular capillary increases, thereby raising π GC and reducing NFP. In some species, filtration equilibrium is achieved, whereby NFP = 0, before the end of the capillary bed (efferent end). In humans, it is thought that this situation is rarely, if ever, attained; nevertheless, NFP clearly decreases as the glomerular capillaries are traversed. If renal blood flow increases, the percentage of plasma filtered per unit length of capillary will decrease; therefore, π GC will rise less rapidly and NFP will fall more slowly. Thus the mean NFP along the capillary will be increased, resulting in a raised GFR. In this way, GFR is linked to renal blood flow. Although the average value for NFP is probably <10 mmhg, ~180 litres of glomerular filtrate are formed each 24 h. This points to the extraordinarily high K f of glomerular capillaries. AUTOREGULATION OF RENAL BLOOD FLOW AND GFR Given the low resting value for NFP, even small changes in any of the filtration pressures can have profound effects on GFR. Nevertheless, under normal circumstances, despite fluctuations in arterial pressure that would be expected to influence P GC, GFR changes very little. This is due to the phenomenon of autoregulation whereby, over a mean arterial pressure (MAP) range of ~ mmhg 3, the renal vascular resistance automatically changes as the blood pressure changes (Figure 3). The change in resistance occurs in the afferent s, which has the important consequence that not only is renal blood flow autoregulated but so is GFR, since only a small proportion of the change in MAP is transmitted to the glomerular capillaries, i.e. P GC changes only marginally (Figure 4). Without autoregulation, relatively small fluctuations in MAP would cause major changes in P GC and GFR, and in excretion rates. 3 MAP is calculated as 1/3 systolic BP + 2/3 diastolic BP; BP limits for autoregulation are approximately 90/70 and 260/140 mmhg.

5 Renal Haemodynamics and Glomerular Filtration 7 Figure 3. Renal autoregulation Renal blood flow (ml/min) Renal blood flow GFR GFR (ml/min) MAP (mmhg) Figure 4. Autoregulation of glomerular filtration rate artery afferent glomerular capillaries efferent Mean hydrostatic pressure MAP Constriction of afferent : bigger pressure drop MAP Dilatation of afferent : smaller pressure drop The intrarenal mechanism underlying autoregulation is not fully understood. It is probably in part a myogenic mechanism whereby the smooth muscle of the afferent arteriolar wall intrinsically responds to being stretched (due to a rise in MAP) by contracting, thereby increasing the vascular resistance. The other possible contributory factor is tubulo-glomerular feedback, a negative feedback mechanism whereby an initial increase in GFR (resulting from a raised MAP) leads to an increased delivery of NaCl in the tubular fluid arriving at the macula densa region of the nephron (last part of the thick ascending limb of the loop of Henle), which, by some unknown mechanism involving angiotensin II and other vasoconstrictors (such as adenosine and ATP), triggers vasoconstriction of the adjacent afferent.

6 8 Acute Renal Failure in Practice Table 2. Effects of vasoactive agents on glomerular haemodynamics Afferent resistance Efferent resistance Effect on NFP K f Effect on GFR Renal Sympathetic Nerves Angiotensin II or Epinephrine/Norepinephrine or or Atrial Natriuretic Peptide or Vasodilator Prostaglandins Thromboxanes Adenosine Endothelin-1 or Nitric Oxide () Dopamine N.B. The arrows represent directional changes seen when the agent is applied in high dose in isolation. The actual changes that occur will be influenced greatly by both dosage and experimental setting. Factors Affecting Renal Blood Flow and GFR Outside the autoregulatory range, e.g. in circulatory shock, renal blood flow and GFR change with blood pressure. Even within the autoregulatory range, blood pressure does have some influence on renal haemodynamics (Figure 3). Furthermore, a number of extrinsic factors can override the intrinsic influence of autoregulation. These extrinsic factors can affect renal blood flow and P GC by altering the resistance of afferent and/or efferent s; or they can change K f by inducing mesangial cell contraction or relaxation, thereby altering the glomerular surface area available for filtration (Table 2). Afferent arteriolar constriction will reduce renal blood flow and reduce P GC, causing a reduction in GFR. Efferent arteriolar constriction will reduce renal blood flow but increase P GC ; these changes act in opposite directions with respect to GFR and the net effect on GFR is minimal. A reduction in K f will reduce GFR. Any given vasoactive agent may have a spectrum of effects (on afferent/efferent arteriolar tone or K f ), making the net effect on GFR difficult to predict. Thus, angiotensin II, a major regulator of glomerular function, causes constriction of both afferent and efferent 4 s, as well as reducing K f. The overall outcome for GFR depends on the relative magnitudes of these actions, which vary in different pathophysiological conditions. 4 The efferent is particularly sensitive to angiotensin II, which is why blockade of its action can precipitate ARF in the setting of renal hypoperfusion.

7 Renal Haemodynamics and Glomerular Filtration 9 A period of renal hypoperfusion, systemic or local, underlies most cases of ARF. Therefore, an obvious therapeutic target is to reverse afferent arteriolar vasoconstriction, and/or mesangial cell contraction, but without significantly reducing efferent arteriolar tone. This selective approach is not easy to achieve in practice, although various experimental studies have reported beneficial effects of antagonists of endothelin and adenosine, and of nitric oxide donors. However, due to the varying aetiology and underlying complexity of even haemodynamic ARF, it is apparent that no single agent will be fully protective. For further reading please refer to the end of Chapter 2.