Viva G4(ii)e

This viva tests Section G4(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the distribution of blood volume and flow in the various regional circulations and explain the factors that influence them, including autoregulation. These include, but not limited to, the cerebral and spinal cord, hepatic and splanchnic, coronary, renal and uteroplacental circulations."

Specifically, this viva is all about renal blood flow.

Describe the blood supply of the kidneys.
  • Each kidney is supplied by a renal artery
  • Each is about 4-5 cm in length and 5-10 mm in diameter,
  •  Just before entering the parenchyma, the human renal arteries tend to divide into anterior and posterior main branches, which in turn divide into segmental arteries.
  • Inside the kidney, there is no anastomosis between these arteries, i.e each branch is an end-branch
  • Ischaemia of one segmental artery will create regional ischaemia in the territory of its distribution
  • The kidneys receive about 20% of the total cardiac output (about 1000ml/min)
    • 95% goes to the cortex, 5% goes to the medulla
    • Medullary blood flow must remain low to maintain the urea concentration gradient, to facilitate the concentration of urine
Describe the blood vessels of the kidney, from the renal artery to the renal vein
  • Renal artery, a branch of the aorta
  • Anterior and posterior main branches of the renal artery
  • Segmental arteries (large end arteries)
  • Interlobar arteries, which enter the renal tissue at the border between the cortex and medulla
  • Arcuate arteries, which run an arc-like course between the cortex and medulla
  • Cortical radial arteries, which ascend radially from the centre towards the renal capsule
  • Afferent arterioles, which supply the glomerulus
  • Glomerular capillaries
  • Efferent arterioles, which drain the glomerulus and descend into the medulla
  • Peritubular capillaries, which surround the cortical tubules
  • Vasa recta,  the descending and ascending straight vessels which surround the loop of Henle along its path into the renal medulla
  • Arcuate veins, into which the ascending vasa recta drain
  • Interlobular veins, which collect blood from the arcuate veins
  • Renal vein, which drains into the inferior vena cava
Describe the microcirculation of the renal medulla
  • The renal circulation has two capillary networks:
    • A high-pressure capillary network, being the glomerular capillaries
    • A low-pressure capillary network, the peritubular capillaries
  • The resistance of the afferent and efferent arterioles, on either side of the high-pressure glomerular capillaries, is an important mechanism of control for glomerular filtration
  • Afferent arterioles supply the glomerulus
  • Glomerular capillaries
  • Efferent arterioles drain blood from the glomerulus, and are thick and muscular 
    • Cortical nephron efferent arterioles branch into peritubular capillaries
    • Juxtaglomerular nephron efferent arterioles branch into vasa recta
  • Peritubular capillaries:
    • Thin-walled fenestrated capillaries, similar to systemic capillaries
    • Surround the proximal convoluted tubule and distal convoluted tubule
    • Main role is reabsorption and active secretion of solutes
  • Vasa recta:
    • Main role is concentration of urine
    • Descending vasa recta:
      • Thicker walls, more smooth muscle;
      • Mainly involved in countercurrent exchange of water
    • Ascending vasa recta: 
      • Thin-walled fenestrated capillaries, similar to systemic capillaries
      • Mainly involved in reclaiming reabsorbed water from the medulla
Explain the function of the vasa recta
  • The microcirculation of the medulla is a system designed to trap salt and urea in the innermost renal medulla, and to carry away only the reabsorbed water.
  • These are long straight vessels which travel alongside the descending limbs of the loop of Henle.
  • Descending vasa recta have thicker walls
    • They deliver blood to the medulla
    • Blood which flows into the medulla ends up becoming highly concentrated because medullary interstitial salt and urea diffuse into it
  • Ascending vasa recta are thin-walled,
    • histologically resemble peritubular and systemic capillaries (highly fenestrated)
    • These vessels drain reabsorbed fluid from the medulla
    • Medullary interstitial salt and urea diffuse out of the blood because the capillaries are highly fenestrated
    • Blood leaving the medulla is more dilute than blood entering the medulla, because a net removal of fluid is taking place
    • One descending vasa recta vessel begets several ascending ones, to maintain a low pressure gradient and slow flow, so that this increased flow due to fluid removal can occur without a high pressure being generated.
How is renal blood flow related to renal metabolic activity?

Renal metabolic activity scales in response to changes in blood flow, rather than the other way around.

  • In total, the kidneys only extract about 10-15% of the delivered oxygen
  • Renal venous oxygen saturation is therefore relatively high (~ 85%)
  • Total renal blood flow is high for reasons of filtration rather than metabolism
  • Most of this blood flow (95%) goes to the glomerulus.
  • The renal medulla is disproportionately metabolically active for its size, but receives only 5% of the blood flow:
    • It is only 0.5% of the total body mass, but it uses 7% of the total oxygen. 
    • The medulla receives only 20-100ml/min of blood flow so as not to wash out the urea concentration gradient, and has a very high oxygen extraction ratio.
    • This extreme metabolic activity is because 99.5% of the filtered sodium needs to be reclaimed by active transport
    • Sodium delivery is dependent on blood flow (which determines the GFR)
    • Thus, the more blood flow, the more sodium is delivered, and therefore the more metabolic demand is placed on the medulla.
    • As the result, renal oxygen extraction does not vary overmuch with different rates of blood flow (i.e. it stays stable)
How is renal blood flow autoregulated?

Blood flow to the kidneys remains constant against arterial blood pressures from 75 – 160 mmHg.

renal blood flow autoregulation - ubiquitous graph

This autoregulation occurs at the level of the afferent arteriole, just before the blood enters the glomerulus.

There are three main mechanisms:

  • Myogenic response (rapid, responsible for 50% of the total autoregulatory response)
    • Vasoconstriction in response to wall stretch
    • This is a stereotyped vascular smooth muscle response, not unique to the kidney
  • Tubuloglomerular feedback (slower, responsible for 35%)
  • Other mechanisms involving angiotensin-II and NO (even slower, <15%)
How does tubuloglomerular feedback influence renal blood flow?
  • Salt reabsorption from the loop of Henle is an active process
  • This process is highly dependent on the amount of salt available, i.e. on the rate of tubular fluid flow
  • Increased glomerular blood flow increases the flow of tubular fluid (as it increases glomerular filtration)
  • Thus, increased glomerular blood flow increases the amount of salt reabsorbed by the loop of Henle, and this increases the delivery of salt to the macula densa
  • Changes in salt concentration are sensed by the macula densa via the Na+-K+-2Cl cotransporter (NKCC2) in its luminal membrane.
  • This produces an increase in ATP release from macula densa cells
  • The ATP then either activates specific purine receptors on the afferent arteriole, or is converted to adenosine (which then acts on A1-adenosine receptors).
  • The net effect is that increased salt delivery to the nephron results in decreased glomerular blood flow, which decreases salt delivery (i.e. this is a negative feedback mechanism
What humoral factors influence renal blood flow?
  • ​​​​Vasoconstrictor stimuli:
    • Angiotensin II: increases filtration fraction by constricting the efferent arteriole, i.e. renal blood flow decreases bu glomerular filtration remains stable
    • Endothelin has the net effect of vasoconstriction, even though it acts as a vasodilator in the renal medulla.
  • Vasodilator stimuli:
    • Prostaglandins 
    • Bradykinin 
    • Amino acids
    • Blood glucose
How does the autonomic nervous system influence renal blood flow?
  • The vascular structures of the kidney are innervated by sympathetic fibres arising from around T11-L3
  • The sympathetic nervous system increases or decreases renal blood flow in response to systemic stresses
  • There is a resting sympathetic tone which is mainly vasoconstrictor in character
  • Sympathetic activation leads to:
    • Vasoconstriction of renal vessels 
    • Increased sodium and water reabsorption at the tubule
    • Increased renin release from the juxtaglomerular cells
  • This vasoconstriction changes the shape of the autoregulation curve, such that the "plateau" of stable pressure shifts right; i.e. there is less blood flow at a lower pressure than there was previously:

change in renal blood flow due to sympathetic activation

  • With enough noradrenaline, renal blood flow can decrease to 10% of normal.
How does noradrenaline affect glomerular filtration?
  • At modest doses, minimally.
  • The decrease in glomerular filtration is not as great as the decrease in renal blood flow
  • This is because the efferent tubule constricts much more than the afferent, forcing more blood through the glomerulus even as renal blood flow decreases
How do tubuloglomerular feedback and sympathetic stimulation interact?
  • Sympathetic nervous system decreases renal blood flow, and therefore salt delivery.
  • Tubuloglomerular feedback would normally increase renal blood flow in response to the reduced salt delivery to the macula densa
  • Under most conditions of sympathetic activation (eg. hypovolemia), this would be counterproductive (as it would oppose the effort to conserve volume)
  • Angiotensin II  modulates the reactivity of the TGF mechanism, decreasing the reactivity of the afferent arteriole in response to adenosine.
  • The result is a progressive loss of tubuloglomerular feedback reactivity in response to progressive volume loss

References

Just, Armin. "Mechanisms of renal blood flow autoregulation: dynamics and contributions." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292.1 (2007): R1-R17.

Stein, Jay H. "Regulation of the renal circulation." Kidney international 38.4 (1990): 571-576.

Bertram, John F. "Structure of the renal circulation." Advances in Organ Biology Volume 9, 2000, Pages 1-16 (2000)

Hansell, Peter, et al. "Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension." Clinical and Experimental Pharmacology and Physiology 40.2 (2013): 123-137.

Epstein, Franklin H. "Oxygen and renal metabolism." Kidney international 51.2 (1997): 381-385.

Leichtweiss, H-P., et al. "The oxygen supply of the rat kidney: Measurements of intrarenal pO 2." Pflügers Archiv 309.4 (1969): 328-349.

Burke, Marilyn, et al. "Molecular mechanisms of renal blood flow autoregulation." Current vascular pharmacology 12.6 (2014): 845-858.

Schubert, Rudolf, and Michael J. Mulvany. "The myogenic response: established facts and attractive hypotheses." Clinical science 96.4 (1999): 313-326.

Vallon, Volker. "Tubuloglomerular feedback and the control of glomerular filtration rate." Physiology 18.4 (2003): 169-174.

Kon, Valentina. "Neural control of renal circulation." Mineral and electrolyte metabolism 15.1-2 (1989): 33-43.

Johns, Edward J., Ulla C. Kopp, and Gerald F. DiBona. "Neural control of renal function." Comprehensive Physiology 1.2 (2011): 731-767.

Dibona, Gerald F., and Linda L. Sawin. "Functional significance of the pattern of renal sympathetic nerve activation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 277.2 (1999): R346-R353.

Mills, Lewis C., John H. Moyer, and Carrol A. Handley. "Effects of various sympathicomimetic drugs on renal hemodynamics in normotensive and hypotensive dogs.American Journal of Physiology-Legacy Content 198.6 (1960): 1279-1283.

SPENCER, MERRILL P., ADAM B. DENISON JR, and HAROLD D. GREEN. "The direct renal vascular effects of epinephrine and norepinephrine before and after adrenergic blockade." Circulation Research 2.6 (1954): 537-540.

Pallone, Thomas L., Zhong Zhang, and Kristie Rhinehart. "Physiology of the renal medullary microcirculation." American Journal of Physiology-Renal Physiology 284.2 (2003): F253-F266.

Zimmerhackl, Bernd, Channing R. Robertson, and Rex L. Jamison. "The microcirculation of the renal medulla." Circulation research 57.5 (1985): 657-667.

Just, Armin, et al. "Role of angiotensin II in dynamic renal blood flow autoregulation of the conscious dog." The Journal of physiology 538.1 (2002): 167-177.