Systemic Implications in Dental practice

Cyclosporine therapy may cause gingival hyperplasia

Gingival growth occurs in patients taking phenytoin.

Patients with cardiac disease should receive dental treatment in minimal stressful environment. Anxiety,exertion and pain should be minimized.

Irregular pulse, engorged jugular veins and tachypnea may indicate the presence of cardiac disease.A history of hypertension, ischemic heart disease or any other cardiac problem particularly congenital heart disease and drug intake (anticoagulant, aspirin) should be sought.Angina may present as pain in the mandible, teeth and other oral Tissues Epinephrine in the local anesthesia may raise the blood pressure and precipitate dysarrhythmias.In patients with IHD, facilities for medical help, oxygen and nitroglycerine should be Available General anesthesia should be avoided for at least three months in patients with recent onset angina

Patient’s with Cushing’s syndrome more prone to get infections.(candidiasis)

Elective dental surgery should be deferred for 6 months following acute MI.Prophylaxis for infective endocarditis is mandatory in cases where there is a risk.Cardiac patients on anticoagulant drugs or aspirin are at increased risk of bleeding following dental procedures.Hence, these drugs should preferably be stopped a week before the procedure.Calcium channel blockers may cause gingival swelling and lichenoid lesions in the oral cavity. ACE inhibitorscan cause loss of taste, burning sensation in oral cavity,and angioedema. Dry mouth can result due toantihypertensive drugs such as d

Rifampicin can cause red saliva.

Elective dental care is avoided in patients with acuterenal failure

Elective dental procedures are better tolerated on non-dialysis days

Blood pressure measurement is advised at every visit.

Brown to black macular pigmentation in oral mucosa can be suspected for Addison disease.

Gonorrhea may present uncommonly with oral manifestations like tonsillitis, lymphadenitis, and painful oral and pharyngeal ulcers.

Oral manifestations in peptic ulcer disease are rare.However erosive dental lesions could be appreciated on lingual surface of lower incisors or palatal surface of upper maxillary teeth.

Corticopapillary Osmotic Gradient

  • The corticopapillary osmotic gradient is the osmotic gradient of the renal interstitium
  • It allows the nephrons to adjust the osmolarity of the tubular fluid, and ranges from 300 milliosmoles/liter in the cortex to up to 1200 milliosmoles in the inner medulla

The physiological processes that create the gradient are:

  • Medullary countercurrent multiplication
  • Urea recycling

Maintenance of the corticopapillary osmotic gradient relies on the vasa recta and countercurrent exchange.

Parts of the nephron:

  • Renal corpuscle
  • Proximal tubule
  • Nephron loop, specify its descending and ascending limbs; recall that the ascending limb is impermeable to water.
  • Distal tubule
  • Collecting duct
  • It is surrounded by the renal interstitium, which comprises tissues and fluids.
  • The corticomedullary junction marks where the cortex becomes the medulla
  • The proximal and distal tubules lie within the cortex, and the nephron loop lies within the medulla.
  • The corticopapillary osmotic gradient (the osmolarity of the interstitium) increases from the cortex to the medulla.

CREATION OF THE CORTICOPAPILLARY OSMOTIC GRADIENT

Medullary countercurrent multiplication

The thick ascending limb actively pumps sodium chloride into the medullary interstitium to create the osmotic gradient:

  • Isosmotic tubular fluid enters the descending limb of the nephron loop; its osmolarity is similar to that of blood plasma, 300 milliosmoles/liter.
  • Water is passively reabsorbed in the descending limb;
  • Consequently, by the time it reaches the bend of the nephron loop, the tubular fluid is hyperosmotic, with osmolarity as high as 1200 milliosmoles/liter; this is because water has left the tubular fluid; solutes have not been added to the tubular fluid.
  • The hyperosmotic tubular fluid is “pushed” into the ascending limb by the arrival of new tubular fluid; recall that tubular fluid is constantly flowing through the nephrons.
  • Then, as it passes through the ascending limb, sodium chloride is actively reabsorbed from the tubular fluid, which lowers its osmolarity.
  • Thus, as it exits the nephron loop, the tubular fluid is hypo-osmotic, at approximately 100 milliosmoles/liter. In other words, the nephron loop has created relatively dilute urine.

Osmolarity of the interstitial fluid:

  • Interstitial fluid of the cortex is isosmotic with blood plasma, at 300 milliosmoles/liter
  • Osmolarity increases incrementally as we move towards the inner medulla, where, like the tubular fluid, its osmolarity can be as high as 1200 milliosmoles/liter.
  • This gradient is created by the continuous reabsorption of water and sodium chloride in the nephron loop:
  • Recall that, because water was reabsorbed in the descending limb, the tubular fluid that enters the ascending limb has a very high solute concentration;
  • Higher tubular fluid solute concentration leads to increased solute reabsorption, which raises the osmolarity of the medullary interstitium.
  • However, as the tubular fluid ascends through the outer medulla and cortex, continuous solute reabsorption reduces its osmolarity.
  • Thus, less solutes are available for transport to the interstitium, so its osmolarity decreases as we move superficially.

Urea recycling

Urea is reabsorbed from the medullary collecting ducts and contributes to the corticopapillary osmotic gradient.

  • Urea reabsorption relies on the presence of anti-diuretic hormone (ADH, aka, arginine, vasopressin), thus it is most prominent in water depletion states: when circulating ADH levels are high.
  • ADH increases water permeability, but has no effect on urea transport.
  • As a result of water reabsorption, urea concentration in the tubular fluid increases.
  • Then, in the inner medullary collecting duct, indicate that ADH increases both water permeability and urea transport;
  • The diffusion of urea into the interstitial fluid increases the osmolarity of the inner medulla, which adds to the corticopapillary osmotic gradient.
  • Urea can be secreted into the nephron loop, or, taken up by the vasa recta.

CORTICOPAPILLARY OSMOTIC GRADIENT

  • The corticopapillary osmotic gradient is the osmotic gradient of the renal interstitium
  • It allows the nephrons to adjust the osmolarity of the tubular fluid, and ranges from 300 milliosmoles/liter in the cortex to up to 1200 milliosmoles in the inner medulla
The physiological processes that create the gradient are:
  • Medullary countercurrent multiplication
  • Urea recycling
Maintenance of the corticopapillary osmotic gradient relies on the vasa recta and countercurrent exchange.

Parts of the nephron:

  • Renal corpuscle
  • Proximal tubule
  • Nephron loop, specify its descending and ascending limbs; recall that the ascending limb is impermeable to water.
  • Distal tubule
  • Collecting duct
  • It is surrounded by the renal interstitium, which comprises tissues and fluids.
  • The corticomedullary junction marks where the cortex becomes the medulla
  • The proximal and distal tubules lie within the cortex, and the nephron loop lies within the medulla.
  • The corticopapillary osmotic gradient (the osmolarity of the interstitium) increases from the cortex to the medulla.

CREATION OF THE CORTICOPAPILLARY OSMOTIC GRADIENT

Medullary countercurrent multiplication

The thick ascending limb actively pumps sodium chloride into the medullary interstitium to create the osmotic gradient:
  • Isosmotic tubular fluid enters the descending limb of the nephron loop; its osmolarity is similar to that of blood plasma, 300 milliosmoles/liter.
  • Water is passively reabsorbed in the descending limb;
  • Consequently, by the time it reaches the bend of the nephron loop, the tubular fluid is hyperosmotic, with osmolarity as high as 1200 milliosmoles/liter; this is because water has left the tubular fluid; solutes have not been added to the tubular fluid.
  • The hyperosmotic tubular fluid is “pushed” into the ascending limb by the arrival of new tubular fluid; recall that tubular fluid is constantly flowing through the nephrons.
  • Then, as it passes through the ascending limb, sodium chloride is actively reabsorbed from the tubular fluid, which lowers its osmolarity.
  • Thus, as it exits the nephron loop, the tubular fluid is hypo-osmotic, at approximately 100 milliosmoles/liter. In other words, the nephron loop has created relatively dilute urine.

Osmolarity of the interstitial fluid:

  • Interstitial fluid of the cortex is isosmotic with blood plasma, at 300 milliosmoles/liter
  • Osmolarity increases incrementally as we move towards the inner medulla, where, like the tubular fluid, its osmolarity can be as high as 1200 milliosmoles/liter.
  • This gradient is created by the continuous reabsorption of water and sodium chloride in the nephron loop:
  • Recall that, because water was reabsorbed in the descending limb, the tubular fluid that enters the ascending limb has a very high solute concentration;
  • Higher tubular fluid solute concentration leads to increased solute reabsorption, which raises the osmolarity of the medullary interstitium.
  • However, as the tubular fluid ascends through the outer medulla and cortex, continuous solute reabsorption reduces its osmolarity.
  • Thus, less solutes are available for transport to the interstitium, so its osmolarity decreases as we move superficially.

Urea recycling

Urea is reabsorbed from the medullary collecting ducts and contributes to the corticopapillary osmotic gradient.
  • Urea reabsorption relies on the presence of anti-diuretic hormone (ADH, aka, arginine, vasopressin), thus it is most prominent in water depletion states: when circulating ADH levels are high.
  • ADH increases water permeability, but has no effect on urea transport.
  • As a result of water reabsorption, urea concentration in the tubular fluid increases.
  • Then, in the inner medullary collecting duct, indicate that ADH increases both water permeability and urea transport;
  • The diffusion of urea into the interstitial fluid increases the osmolarity of the inner medulla, which adds to the corticopapillary osmotic gradient.
  • Urea can be secreted into the nephron loop, or, taken up by the vasa recta.

Potassium Reabsorption and Secretion

“Excitable” tissues

  • Rely on the potassium concentration gradient across cell membranes to establish resting membrane potentials.
  • Excitable tissues include: nerve, skeletal muscle, and cardiac muscle.

Two key forms of potassium balance:

Internal

  • Describes potassium distribution between the intra- and extracellular fluid compartments.

External

  • Describes the relationship between dietary intake of potassium and its renal excretion.

INTERNAL BALANCE

Homeostasis

  • ICF contains 98% of body’s total K+
  • ECF contains 2%
  • Sodium-potassium ATPase (aka, pump) maintains this homeostatic internal potassium balance.
  • Shifts in internal potassium balance can cause cardiac arrhythmia and muscle weakness.

Hypokalemia

Reduced extracellular potassium concentration

  • Potassium movement into the cell – intracellular potassium concentration increases and extracellular concentration increases.
  • External imbalance can cause hypokalemia from an increased potassium excretion-to-intake ratio.
  • Causes of increased intracellular concentration, include hormones, medications, and disease states.
  • Specific causes include:
    – Metabolic alkalosis.
    – Diarrhea-induced loss of potassium.
    – Medications
    – Hormones, such as:
    Aldosterone, which acts on the kidney’s reabsorption of potassium (an external balance mechanism).
    Beta-2 adrenergic stimulators and insulin, which drive potassium into the cell (an internal balance mechanism).

Clinical correlation

A rapid correction of hyperkalemia (elevated extracellular potassium) can be achieved with:
– An albuterol inhaler (a beta-2 adrenergic stimulator)
– insulin, which drives potassium from the plasma into the cell (an internal mechanism)
– Kayexylate, which produces a diarrhea-wasting of potassium (an external mechanism)

Hyperkalemia

Increased extracellular potassium concentration

  • Potassium movement out of the cell – intracellular potassium concentration decreases and extracellular concentration increases.
  • External imbalance can cause hyperkalemia from a reduced potassium excretion-to-intake ratio.
  • Specific causes include:
    – Metabolic acidosis.
    – Cell lysis (when the cell bursts, its contents are released) (an internal balance mechanism)
    – Increased ECF osmolarity (water will exit the cell, “dragging” potassium with it) (another internal balance mechanism)
    – Medications, such as:
    ACE Inhibitors, which acts on the kidney’s reabsorption of potassium in the opposite manner as aldosterone (an external balance mechanism).
    Beta-blockers prevent potassium entry into the cell (the opposite of beta-adrenergic stimulators).

Clinical correlation

Chronic kidney failure patients (who can’t excrete potassium) can develop hyperkalemia if they become constipated: they rely on the GI tract for external balance of potassium.

EXTERNAL BALANCE

  • Potassium reabsorption and secretion in the distal nephron are hormonally regulated to ensure that renal excretion matches dietary intake, which varies widely both intra- and inter-individually from day to day.
  • Potassium is freely filtered within the glomerulus.
  • Approximately 67% of the filtered load of potassium is reabsorbed from the proximal tubule.
  • 20% is reabsorbed from the thick ascending limb.
    – Recall that potassium reabsorption in these segments is linked with sodium reabsorption, and is, therefore, relatively constant.
  • Variable amount of potassium is reabsorbed from the distal tubule to conserve it when dietary intake is low; when dietary intake is high, potassium is secreted into the nephron.

Alpha-intercalated cells

  • In the distal nephron, conserve potassium when dietary intake is low.
  • Reabsorb potassium down the electrochemical gradient created by hydrogen-potassium ATPase (aka, pumps).
  • The hydrogen-potassium ATPase on the luminal membrane moves hydrogen to the tubule lumen while sending potassium into the tubule cell.
  • Potassium then diffuses through the basolateral membrane into the interstitium and capillaries.

Principal cells

  • Return excess potassium to the tubular lumen when dietary intake is high.
  • Secrete potassium down the electrochemical gradient created by sodium-potassium ATPase.
  • Sodium-potassium ATPase moves potassium from the blood into the cell, while projecting sodium from it.
  • Potassium then diffuses out of the cell, into the lumen to be excreted in the urine.

Glucose Reabsorption and Titration Curve

  • Typical plasma glucose concentration is between 70-100 milligrams/deciliters.
  • Glucose is completely reabsorbed from the proximal tubule via secondary active transport mechanisms as long as plasma glucose concentrations do not exceed this concentration.

REABSORPTION

  • Sodium-potassium ATPase extrudes sodium from the cell in exchange for potassium.
    – This exchange creates the electrochemical gradient that drives the SGLT co-transportation of sodium and glucose into the cell.
  • As sodium moves down its concentration gradient, glucose moves against its concentration gradient.
  • From here, GLUT transporters facilitate glucose diffusion out of the cell to return it to the blood (again, there are multiple types of GLUT transporters, but here we’ll simply generalize).
    – Within the healthy physiological glucose range, these transporters can completely reabsorb glucose from the proximal tubule; however, as we’ll see, at higher plasma concentrations, the transporters are overwhelmed, glucose is incompletely reabsorbed, and thus is excreted in the urine.

GLUCOSE TITRATION CURVE

Explains relationships between glucose plasma concentration, reabsorption, and excretion.

  • Filtered load of glucose increases in proportion to plasma glucose levels; this makes sense, because we know that glucose is freely filtered within the renal corpuscle. (A)
  • Glucose reabsorption follows filtration until plasma glucose concentration reaches approximately 200 milligrams per deciliter. (B)
    – At that point, the glucose reabsorption curve begins to bend because glucose transporters are approaching saturation.
  • At plasma glucose concentrations above 350 milligrams per deciliter, glucose reabsorption plateaus as the transporters reach full saturation. (D)
  • Glucose excretion remains near zero until glucose plasma concentration rises above 200 milligrams per deciliter (C)
    – Once this threshold is surpassed, glucose begins to appear in the urine (aka, glucosuria).
  • Then, when plasma glucose concentration rises above of 350-400 milligrams per deciliter, excretion rises in parallel with filtered load. (E)

Summary of some key points in the glucose titration curve.

  • Filtered load increases in proportion to plasma glucose concentrations (even when outside of the typical physiological range).
  • Reabsorption matches filtered load when plasma glucose concentrations remain below 200 milligrams per deciliter.
  • Above this threshold, glucose begins to appear in the urine (aka, glucosuria).
  • Once plasma glucose concentration rises above 350 milligrams per deciliter, all glucose transporters are saturated.
  • Transport maximum (Tm) is reached, and glucose reabsorption plateaus.
  • Once transport maximum is reached, excretion rate rises linearly with filtered load.
  • Because of a phenomenon called splay, threshold occurs before Tm because of variation in the transport maximum of individual nephrons due to differences in transport number and types.

Clinical causes of glucosuria.

  • Glucosuria occurs when the filtered load of glucose exceeds the resorptive capabilities, and glucose is excreted in the urine.
  • Diabetes mellitus, the body’s inability to make and/or use insulin results in excessive plasma glucose concentrations, which increases its filtered load.
  • Some women experience pregnancy-related glucosuria when increased GFR increases filtered load. This is often benign, and is not synonymous with gestational diabetes.

Sodium Reabsorption in the Distal Nephron

  • Key function of the kidneys is to ensure sodium balance:
    Sodium intake = sodium excretion.

Sodium Reabsorption by Segment:

  • 67% of filtered load is reabsorbed in proximal tubule.
  • 25% in thick ascending limb
  • 5% in the early distal tubule
  • 3% in the late distal tubule and collecting duct.
  • Less than 1% of the filtered load is excreted in the urine.

Load-dependent Sodium Reabsorption

  • In the distal segments, ensures that reabsorption rate remains relatively constant despite changes in filtered load.

Thick ascending limb:

  • Sodium reabsorption is linked to potassium and chloride reabsorption.
  • Sodium-potassium ATPase on basolateral membrane pumps sodium out of cell, potassium into it.
  • Drives cotransport of sodium, potassium, and chloride into the cell.
    In presence of ADH, activity of cotransporter is increased;
    In presence of Loop diuretics, chloride-binding site is blocked, cotransport ceases, and sodium is not reabsorbed.
  • Chloride and potassium diffuse out of the cell through the basolateral membrane;
    some potassium “leaks” back into the lumen.
  • Thick ascending limb is impermeable to water.

Early distal tubule:

  • Sodium and chloride reabsorption are linked.
  • Sodium-potassium ATPase creates electrochemical gradient that drives cotransport of sodium and chloride from lumen into cell.
    – Thiazide diuretics block chloride binding site on contransporter, so sodium is not reabsorbed.
  • Chloride exits via simple diffusion.
  • Early distal tubule is impermeable to water.

Late distal tubule and collecting duct:

  • Principal cells link sodium reabsorption to potassium secretion.
  • Sodium-potassium ATPase creates electrochemical gradient that drives sodium diffusion via epithelial sodium channels.
  • Potassium is secreted into lumen.
  • Aldosterone increases sodium reabsorption and potassium secretion.
  • Late distal tubule and collecting duct are only permeable to water in presence of ADH, which increases aquaporin-2 water channels.
  • Water exits cell via aquaporin 3 and 4 water channels.
    – K-sparing diuretics act on late distal tubule and collecting ducts to reduce sodium reabsorption and potassium secretion.

Sodium Reabsorption in the Proximal Nephron

  • Sodium reabsorption in the proximal nephron tubule is coupledwith reabsorption of other key solutes and water, and with secretion of hydrogen.
  • Sodium reabsorption maintains sodium balance, so that sodium intake equals sodium excretion.
    – This is one of the most important functions of the kidney because:
    As the major cation of the extracellular fluid, the amount of sodium determines extracellular fluid volume (because water follows osmotic gradients), and extracellular fluid volume determines plasma volume, blood volume, and blood pressure, which are critical physiological determinants.
  • Two-thirds of sodium reabsorption occurs within the proximal tubule, which comprises both early and late segments.

Early proximal tubule:

  • Sodium reabsorption is linked to reabsorption of nutrients, inorganic and organic acids, and the secretion of hydrogen.
  • Transport occurs via two pathways:
    – The transcellular pathway, which transports substances through tubule cells;
    – The paracellular pathway, which moves substances through “leaky” tight junctions between tubule cells.
  • Sodium-potassium ATPase (aka, pump) actively pumps sodium out of the tubule cell, and brings potassium into it.
    – This exchange creates the electrochemical gradient that drives secondary transport of sodium and other solutes across the luminal membrane and into the tubule cell.
  • Luminal membrane cotransporters couple movement of sodium into the cell with movement of other solutes, including:
    – Glucose
    – Amino acids
    – Inorganic and organic acids.
  • These solutes move out of the cell via facilitated diffusion.
  • As a general rule, water follows sodium:
    – Transcellularly, it passes through aquaporin 1 channelslocated on the luminal and basolateral membranes;
    – Paracellularly, it passes between the tight junctions of tubule cells.
  • Countertransporter exchanges sodium for hydrogen, which it secretes into the tubular lumen.
  • Reactions within the cell produce bicarbonate, which is reabsorbed via facilitated diffusion.

Late Proximal Tubule:

  • Sodium and chloride reabsorption are linked in the late proximal tubule.
    – To understand why this is so, consider that most other solutes were reabsorbed within the early proximal tubule; chloride is not, and, therefore, remains in the tubule fluid as it enters the late proximal tubule.
  • Sodium-potassium pump creates gradient that drives luminal membrane counter transporters:
    – One moves sodium into the cell and hydrogen into the lumen.
    – The other moves chloride into the cell and formate into the lumen (formate ions are metabolic byproducts).
  • Chloride then passes through the basolateral membrane down its concentration gradient via simple diffusion.
  • Both sodium and chloride pass through “leaky” tight junctions between the tubule cells; this is another example of the paracellular pathway.

Glomerulotubular balance

  • Maintains a nearly constant rate of sodium reabsorption, despite changes in GFR.
  • In response to changes in GFR, the proximal tubule alters the total amount of sodium it reabsorbs so that the rate of sodium reabsorption is held at ~67%.
  • However, glomerulotubular balance changes in response to changes in extracellular fluid volume:
    – When ECF volume contracts, total sodium and water reabsorption is increased; this reflects the body’s attempt to increase ECF volume.
    – When ECF volume expands, total sodium and water reabsorption is decreased; excess sodium and water are excreted in the urine in attempt to decrease ECF volume.

Overview of Reabsorption and Secretion in the Nephron

Reabsorption

  • Removes solutes and water from the tubular fluid and returns them to the blood;
  • It reclaims much of the water, ions, and nearly all of the nutrients that are filtered.

Secretion

  • Moves solutes from the blood and nephron tubule cells into the tubular fluid;
  • Secretion is important for removal of substances that aren’t filtered (such as drugs and metabolites) and for fine-tuning the final urine composition.

Key principles of transport:

  • Vasculature:
    – Efferent arteriole leaves glomerulus, gives rise to peritubular capillaries.
    – Peritubular capillaries give rise to vasa recta of juxtamedullary nephrons.
    – Vasa recta drains deoxygenated blood into the interlobular vien.

Reabsorption and Secretion by Segment:

  • Proximal tubule:
    Reabsorbs:
    Water
    Sodium
    Chloride
    Potassium
    Calcium
    Phosphate
    Urea
    Bicarbonate
    Glucose, amino acids, and other nutrients.
    Secretes:
    Hydrogen
    PAH (para-aminohippurate)
    Ammonium ions
    Certain drugs
    Organic acids and bases (such as creatinine)
  • Nephron loop:
    Concentrates or dilutes urine.
    Thin limb:
    Water is reabsorbed.
    Thick ascending limb:
    Sodium
    Potassium
    Chloride
    Calcium
    Bicarbonate
    Magnesium
    (no water reabsorption)
  • Distal tubule
    Reabsorption and secretion are hormonally regulated to fine-tune tubular fluid, to maintain ECF volume and osmolarity homeostasis.
    Early distal tubule, aka, diluting segment:
    Sodium
    Chloride
    Potassium
    Calcium
    (no water reabsorption).
    Late distal tubule:
    Reabsorbs:
    Water
    Sodium
    Chloride
    Bicarbonate
    Urea.
    Secretes:
    Potassium.
  • Collecting duct:
    Secretes OR Reabsorbs
    Potassium
    Hydrogen
    Bicarbonate
    Ammonium ions

Urine formation

Filtration

  • The first step in urine formation is filtration, in which water and solutes, including ions and nutrients, are filtered from the blood to produce ultrafiltrate.
  • Filtration is a passive process, and relies on pressures within the renal blood vessels and nephron.
  • Ultrafiltrate passes through the nephron tubule as tubular fluid.

Reabsorption

  • Removes solutes and water from the tubular fluid and returns them to the blood;
  • It reclaims much much of the water, ions, and nearly all of the nutrients that are filtered are reclaimed via reabsorption.

Secretion

  • Moves solutes from the blood and nephron tubule cells into the tubular fluid;
  • Secretion is important for removal of substances that aren’t filtered (such as drugs and metabolites) and for fine-tuning the final urine composition.

Nephron segments

  • Renal corpuscle is where the blood is filtered and tubular fluid is formed. .
  • Proximal tubule is the primary site of reabsorption of water, ions, and nutrients.
    Specifically: sodium, potassium, water, and nutrients are reabsorbed from the proximal tubule; hydrogen, which plays a major role in acid/base balance, is secreted into the proximal tubule.
  • The nephron loops is the U-shaped segment:
    It comprises descending and ascending limbs.
    Water is reabsorbed from the descending limb; solutes are reabsorbed from the ascending limb. .
    This is where urine is either diluted or concentrated, depending on the body’s needs.
  • Distal tubule is the distal portion of the nephron.
  • The collecting duct delivers urine to the renal pelvis.
    In these last two segments, reabsorption and secretion are hormonally regulated to maintain water and ion homeostasis.

Specifically:

  • Sodium and water are reabsorbed from the distal tubule.
  • Hydrogen and potassium are secreted into it.
  • Sodium and water are reabsorbed from the collecting duct;
  • Potassium and hydrogen are either reabsorbed or secreted, depending on the body’s needs. It is also a primary site of secretion of substances that weren’t filtered but need to be excreted in the urine.
  • The nephron loop either dilutes or concentrates the tubular fluid, depending on the body’s needs.
  • Activity of the the distal tubule and collecting duct is hormonally regulated to maintain ECF volume and osmolarity homeostasis.

Key ways that reabsorption and secretion are regulated:

  • First, it’s important to recognize that, in general, water and other solutes follow sodium: when sodium is reabsorbed, they usually are, too (the exception is the ascending limb of the nephron loop).
  • Therefore, altering sodium reabsorption is an effective way to alter the reabsorption of other solutes and water.
  • This may be necessary, for example, in the case of high blood pressure:
  • To help reduce blood volume, diuretics reduce sodium reabsorption to facilitate increased excretion of solutes and water.
  • On the other hand, in cases of low blood pressure, the body needs to conserve solutes and water.
  • Two key hormones that facilitate this are:
  • Aldosterone increases reabsorption of sodium within the distal nephron; since water follows sodium, it also increases blood volume.
  • Anti-diuretic hormone directly increases the rate of water absorption in the distal nephron, and, therefore, blood volume.

Extrinsic GFR Regulation: Renin Angiotensin System

Renin-angiotensin system

(aka, renin-angiotensin-aldosterone system)

  • Extrinsic mechanism of GFR regulation that is activated when mean arterial pressure drops below 80 mmHg; recall that too-low blood pressure can cause tissue necrosis.
  • To raise blood volume and pressure, the renin-angiotensin system produces hormones that act on multiple organs, including the renal arterioles.
  • Because it requires the production, secretion, and transport of hormones throughout the blood circulation, it is a relatively slow mechanism of GFR regulation.
  • One of these hormones, angiotensin II, has dose-dependent effects on GFR:
    – At low levels, angiotensin II reduces renal blood flow but increases GFR.
    – At higher levels, it reduces both renal blood flow and GFR.

Stimuli for Renin Release:

  • Mechanoreceptors within the juxtaglomerular cells respond to reduced stretch of the afferent arteriole.
  • The macula densa of the distal tubule detects decreased salt concentration of the filtrate, and sends signals to the juxtaglomerular cells.
  • Sympathetic stimulation, which is activated by the baroreceptor reflex, activates beta 1 receptors of the juxtaglomerular cells. Notice that this pathway involves both the nervous and endocrine systems.

Steps of RAS:

  • First, reduced renal blood flow induces the juxtaglomerular cells to secrete renin, which is an enzyme.
  • Within the blood stream, renin catalyzes the conversion of angiotensinogen to angiotensin I, which is a hormone with only mild vasoconstrictor effects.
  • However, as it travels through the blood, *angiotensin-converting enzyme8 converts angiotensin I to angiotensin II.
  • Angiotensin II has widespread effects throughout the body that raise blood volume and pressure

GFR regulation:

  • Angiotensin II induces arteriole vasoconstriction, especially of the efferent arteriole, which has more angiotensin-sensitive receptors than the afferent arteriole does.
  • Reduced blood flow through the efferent arteriole raises hydrostatic capillary pressure within the glomerulus, which helps to maintain GFR within the homeostatic range.
  • However, if efferent arteriole blood flow is reduced too much, the oncotic capillary pressures overwhelm the hydrostatic pressures, and GFR is reduced (filtration pressures are discussed in detail, elsewhere).

Clinical Correlations:

  • RAS can be life-saving in the case of systemic hypotension, but consider the clinical consequences of renal artery stenosis, which reduces blood flow through the renal artery.
    – In response, the renin-angiotensin system activates to elevate blood volume and pressure throughout the body, which can cause renovascular hypertension and kidney damage.
  • A pharmacologic correlate, antihypertensive medications were developed to regulate the renin-angiotensin-aldosterone system, which reduce vasoconstriction and lower blood pressure.
    – Angiotensin converting enzyme inhibitors (ACE inhibitors); inhibit ACE.
    Unfortunately, ACE inhibitors can cause an irritating dry cough,
    So angiotensin 2 receptor inhibitors were also developed to block the angiotensin 2, type 1 receptors.

Extrinsic GFR Regulation: Sympathetic Nervous System

  • The sympathetic division of the nervous system is an extrinsic mechanism of GFR regulation.
  • It is activated when mean arterial blood pressure drops below 80 mmHg.
  • Sympathetic activation rapidly induces vasoconstriction of the arterioles to the glomerulus to reduce GFR and to divert blood away from the kidneys to support other body tissues: the kidneys typically receive 20-25 % of total cardiac output, when this extrinsic regulator is activated, the percentage is much less.
  • This is particularly important in response to hemorrhage, in which loss of blood volume lowers blood pressure, so blood is shunted away from the kidneys to avoid body tissue necrosis.

Sympathetic Regulation Steps:

  • Low blood pressure decreases carotid sinus activity.
  • Cardiovascular centers of medulla in brainstem respond by releasing norepinephrine via sympathetic nerves.
  • Norepinephrine activates alpha 1 receptors on arterioles, initiates vasoconstriction.
    – Because afferent arteriole has more alpha 1 receptors, it constricts to a greater degree.
    – This reduces renal blood flow, hydrostatic capillary pressure, and GFR.
  • Norepinephrine also activates beta 1 receptors of juxtaglomerular cells of afferent arteriole, which induces reninrelease.
  • In the bloodstream, renin catalyzes hormonal conversion that eventually leads to production of angiotensin II.
  • Angiotensin II induces vasoconstriction, especially of the efferent arteriole.
  • Ultimately, both RBF and GFR are reduced in response to sympathetic stimulation.