Renal Physiology

Describe normal renal blood flow and its control, including the concept of autoregulation.

The kidneys receive approximately 25% of cardiac output or 1250ml/min via the renal arteries. The kidneys have a high oxygen consumption of 18ml/oxygen/minute but a low oxygen extraction of 10%. Therefore, the high renal blood flow is due to the need for filtration rather than due to metabolic demand. Each renal artery branches into smaller arteries and eventually into the afferent arterioles. Each afferent arteriole then forms a network of capillaries called the glomerulus which is drained by an efferent arteriole that subsequently forms peritubular capillaries and drain into the venous system. The medullary nephrons have specialised peritubular capillaries that surround the loop of Henle called the vasa recta and participates in counter current exchange of solutes and water. The renal circulation is unique in that it has two arterioles, the efferent and afferent, and two capillary beds; the glomerular and peritubular capillaries. The glomerular capillaries have a high hydrostatic pressure which allows for rapid fluid filtration while the peritubular capillaries have much lower hydrostatic pressures which permits rapid resorption of fluid. The renal cortical nephrons receive over 10 times the blood flow of the medullary nephrons which is one of the factors allowing for maintenance of the medullary osmotic gradient necessary for the countercurrent multiplication system to function.    

Renal blood flow is determined by the pressure gradient between the renal artery and the renal vein divided by the total renal vascular resistance. Therefore, blood flow is proportional the difference in pressure between the renal artery and vein, and is inversely proportional to the renal vascular resistance. The main way renal blood flow is controlled is by altering the vascular resistance. 

Renal blood flow is kept constant over a wide range of blood pressures in order to maintain a relatively constant glomerular filtration rate and allow precise control of water and electrolyte balance. This is known as autoregulation. Without autoregulation an increase in blood pressure by 25mmHg would result in about a 25% increase in GFR.

Autoregulation:

• It generally occurs between a MAP of about 60 – 100mmHg but this range may be shifted to a higher value in those with chronic hypertension
• Autoregulation occurs through two main mechanisms
  • Tubuloglomerular feedback
    • This is a feedback mechanism whereby changes in sodium chloride concentration at the macula densa results in changes in renal arteriolar resistance
    • The macula densa is part of the juxtoglomerular apparatus and lies in the walls of the junction between the ascending loop of Henle and the distal convoluted tubule. If there is decreased blood flow there is decreased flow in the loop of Henle and increased reabsorption of sodium chloride in the ascending loop of Henle. The macula densa senses a decrease in the sodium chloride concentration within the distal tubule and does two things;
      • decreases adenosine and ATP release which then causes afferent arteriolar dilatation and reduces resistance, thus increasing renal blood flow and GFR
      • increases renin release from the juxtaglomerular apparatus. Renin increases the formation of angiotensin 2 which constricts the efferent arterioles thereby increasing renal blood flow and GFR
  • Myogenic mechanism
    • This describes the intrinsic constriction of the afferent arteriole in response to an increased transmural pressure
    • The increased pressure increases the stretch on the vascular wall which then increases the intracellular movement of calcium ions resulting in constriction
    • The constriction increases resistance and thus decreases blood flow

Renal blood flow is also controlled by other factors.

• Sympathetic nervous system:
  • The kidneys are innervated by noradrenergic sympathetic nerves. Alpha receptor stimulation results in both afferent and efferent arteriolar constriction which reduces renal blood flow
  • B1 stimulation results in the release of renin from the juxtaglomerular apparatus which activates the renin-angiotensin-aldosterone system. Angiotensin 2 has an interesting effect on blood flow and GFR. It preferentially constricts efferent arterioles which decreases renal blood flow but increases glomerular hydrostatic pressure thus increasing GFR.
• Hormonal or autacoid factors
  • Catecholamines and endothelin generally cause vasoconstriction and decrease renal blood flow
  • Nitric oxide, prostacyclin and bradykinins results in vasodilatation, decreasing renal vascular resistance and increasing blood flow

What is GFR? Discuss the physiological factors that influence it

Glomerular filtration rate is the amount of plasma filtered into the tubules by all of the glomeruli over time, and is normally approximately 125ml/minute or 180L/day. The factors influencing GFR are Starling forces where GFR = glomerular ultrafiltration coefficient multiplied by the net filtration pressure.

The glomerular ultrafiltration coefficient is the glomerular capillary permeability multiplied by the effective filtration surface area. This coefficient is very high mainly due to high permeability.

Glomerular permeability: this depends on

• Molecular weight: substances are freely filtered if they are less than 7000 Da and are not filtered if they are over 70 000 Daltons. Between these two values filtration decreases with increasing molecular weight
• Electrical charge: the basement membrane is negatively charged and therefore repels other negatively charged molecules. Positively charged molecules are filtered more.

Effective filtration surface area is the surface area of the capillary bed. This can be altered by mesangial cell contraction which reduces the area or relaxation which increases the area.

• Agents causing contraction include: endothelin, angiotensin 2, vasopressin, noradrenaline, thromboxane A2
• Agents causing relaxation: ANP, dopamine, cAMP

Net filtration pressure is the balance between the capillary hydrostatic pressure which moves fluid out of the capillary versus the plasma oncotic pressure in the capillary and the hydrostatic pressure in Bowman’s capsule which opposes this movement. It is equal to the glomerular capillary hydrostatic pressure minus Bowman’s capsule hydrostatic pressure minus glomerular capillary oncotic pressure. The glomerular capillary hydrostatic pressure is determined by:

• Arterial pressure: increased pressure causes an increase in hydrostatic pressure and thus an increase in GFR, within the confines of autoregulation
• Afferent arteriolar resistance: increase in resistance causes a decrease in hydrostatic pressure and therefore a decrease in GFR
• Efferent arteriolar resistance: increased resistance causes an increase in hydrostatic pressure and therefore a small increase in GFR. However, this also reduces blood flow which increases the filtration fraction and therefore decreases GFR. The effect of changes in efferent arteriolar resistance are biphasic, moderate constriction causes an increase in GFR while severe constriction causes a decrease in GFR.

Bowman’s capsule hydrostatic pressure:

• Obstruction of the renal tract will increase Bowman’s capsule hydrostatic pressure and decrease GFR

Factors affecting glomerular capillary oncotic pressure:

• Renal blood flow: decreased blood flow will increase the oncotic pressure and decrease GFR
• Filtration fraction: is the fraction of the renal plasma flow that is filtered through the glomerular capillaries. This is normally 16-20% and is proportional to the oncotic pressure of the glomerular capillaries.
  • Increase in filtration fraction will increase oncotic pressure and decrease GFR
• Location
  • Due to the impermeability of the glomerular capillary to protein and the increased fluid reabsorption, the oncotic pressure within the capillary increases along its length.

Describe the renal handling of bicarbonate

The kidneys reabsorb about 4000-5000mmol/day of bicarbonate, most of which occurs within the proximal tubules. Normally, all filtered bicarbonate is reabsorbed.

Proximal tubular mechanism:

• The proximal tubular mechanism accounts for approximately 85% of bicarbonate reabsorption
• Filtered bicarbonate cannot cross the apical membrane of proximal tubular cells. Instead, hydrogen ions are transported into the tubule by a hydrogen/sodium antiporter and by a hydrogen/ATPase pump.
• The hydrogen then combines with bicarbonate and is converted to carbon dioxide and water by carbonic anhydrase which is present in the luminal brush border.
• Carbon dioxide and water can diffuse into the proximal tubule cell where it is converted back to hydrogen and bicarbonate under the influence of carbonic anhydrase.
• The hydrogen ions can be recycled back into the tubule and continue to resorb bicarbonate.
• The bicarbonate ions are transferred across the basolateral membrane into the bloodstream by a Na-Hco3 symporter which transfers three bicarbonate ions for every one sodium ion. The electrical imbalance that results is counteracted somewhat by a sodium potassium ATPase pump at the basolateral membrane which transports 3 sodium ions out for every 2 potassium ions in. This helps to maintain low intracellular sodium levels which preserves the concentration gradient required for the H+/Na+ antiporter at the apical membrane
• The net effect of this process is the reabsorption of one Hco3 and one Na ion from the tubular lumen into the bloodstream for every one H+ ion secreted

Loop of Henle:

• Approximately 10- 15% of bicarbonate reabsorption occurs within the Loop of Henle
• The tubular fluid within the loop of Henle is more concentrated due to the reabsorption of water in the proximal tubule. This causes an increase in intra-luminal HCO3 concentration, stimulating reabsorption.
• The process of reabsorption is very similar to that which occurs in the proximal tubule.

Distal tubular mechanism

• The distal tubules only have a limited capacity to reabsorb bicarbonate and only 0-5% of bicarbonate reabsorption occurs here
• Hydrogen is secreted into the distal tubules by a H+ATPAse pump in the intercalated cells. This combines with HCO3 and is reabsorbed as c02 + h20 via carbonic anhydrase and is converted back within the cell, like in the proximal tubules.
• The bicarbonate is then transferred across the basolateral membrane by a HCO3-Cl exchanger.

Factors which increase bicarbonate reabsorption include:

• Biochemical factors
  • increased tubular bicarbonate concentration
  • increased paco2
  • decreased potassium levels
• Hormonal factors
  • Increased angiotensin 2
  • Increased aldosterone
• Renal factors
  • Increased luminal flow rate
  • Decreased extracellular volume

Briefly outline the role of the kidney in body water homeostasis

Water homeostasis is regulated so that there is adequate circulatory volume and so that plasma osmolality is maintained within a narrow range of 275-290 mOsmol, thus preserving normal cellular function. The kidneys role in body water balance is via the excretion of a concentrated or dilute urine. Urine volume can be reduced but the baseline solute load of 600mosmol/day that needs to be excreted means the minimum urine volume is 430ml/day as the maximum concentration capacity of urine is 1400mOsmol/kg. The mechanisms by which the kidneys change urine volume are:

• Changing glomerular filtration rate: we have already discussed the factors affecting GFR. Decreasing GFR will decrease renal water excretion
• Changing tubular reabsorption: this is mainly via mechanisms that alter the reabsorption of sodium and which alter the release of ADH.
  • 65% of water reabsorption occurs in the proximal convoluted mainly via osmosis due to the reabsorption of solutes, especially sodium
  • 15% is reabsorbed in the descending limb of the loop of Henle via osmosis. Therefore, factors increasing sodium reabsorption such as activation of the renin-angiotensin-aldosterone system increases water reabsorption
  • The remainder is absorbed from the distal convoluted tubule and collecting ducts under the influence of ADH.
    • ADH is a hormone produced in the supraoptic and paraventricular nuclei of the hypothalamus then transported to the posterior pituitary where it is secreted into the circulation
    • Secretion of ADH is stimulated by increased osmolarity which is detected by osmoreceptors in the hypothalamus. It is also stimulated by hypotension and hypovolemia via baroreceptors and by nausea, vomiting, pain and stress.
    • ADH causes the insertion of aquaporin 2 channels to the apical membranes of these tubules which increases their permeability to water, thus increasing water reabsorption.
• The countercurrent multiplier system
  • This is the process of using energy to generate an osmotic gradient that enables the reabsorption of water from tubular fluid. It occurs in the juxtamedullary nephrons and depends on the generation of a highly concentrated medullary interstitium. This generation depends on three important modification of the renal tubules:
    • The hairpin loop that is the loop of Henle allows solute and water exchange between the descending and ascending limb
    • The Na/K-ATPase and NaK2Cl co-transporters as well as the impermeability to water of the thick ascending limb drives solutes but not water into the medulla from the tubules
    • The increased concentration gradient in the medulla due to this increased solute concentration drives water from the descending limb, which is water permeable, into the medulla
  • These modifications mean that water is able to leave the descending limb down its concentration gradient, which progressively increases the concentration of tubular fluid as it descends. These solutes within the tubular fluids are then actively transported into the interstitium by the ascending loop of Henle. The fluid leaving the ascending loop of Henle therefore becomes more hypo-osmolar. Fluid keeps flowing through the tubules, these steps continue to repeat with the medullary interstitial osmolality increasing until a steady state is reached and there is a gradient of osmolality from the top to the bottom of the loop. The longer the length of the loop of Henle, the greater the osmolality that can be reached at the tip of the medulla.
  • Urea recycling in the inner medulla also contributes to the countercurrent multiplier.

List the physiological effects of renal failure

The renal system has a crucial role in the maintenance of homeostasis within the body. The effects of renal dysfunction include effects on:

• Acid base balance
  • Chronic metabolic acidosis occurs due to decreased excretion of hydrogen, decreased ammonia production, decreased tubular reabsorption of bicarbonate and retention of organic anions
• Water and electrolyte balance
  • Difficulty in sodium and water balance can lead to hyponatremia, hypertension, peripheral oedema and congestive cardiac failure
  • Hyperkalemia is common in end stage renal failure due to decreased excretion and transcellular shifts due to acidosis
  • Hyperphosphatemia is also common and results in secondary hyperparathyroidism
• Elimination of toxins and waste
  • Increased urea can result in pruritis, platelet dysfunction, decreased immune function, gastrointestinal dysfunction including bleeding and neurological changes including encephalopathy polyneuropathy
  • Increased uric acid can result in gout
• Endocrine function
  • There is decreased erythropoietin production leading to a normochromic normocytic anaemia
  • Decreased conversion of vitamin D into its active metabolite results in hypocalcemia and subsequently renal osteodystrophy. This is exacerbated by hyperphosphotemia.
  • Increased renin formation can lead to hypertension
• Metabolic function
  • Decreased breakdown of free fatty acids leads to hyperlipidemia, accelerated atherosclerosis and increased risk of ischemic heart disease
  • Uremia and inflammation induced insulin resistance in patients with renal failure increases the risk of diabetes whie decreased renal gluconeogenesis and decreased insulin metabolism can also increase the risk of hypoglycemia

Tagged as: Physiology, Renal, Kidney, GFR, ADH.