Renal Function - Filtration

Cells are surrounded by ________ fluid.

What is exchanged between them?

interstitial fluid

• Plasma components freely exchanged, except proteins

What influences the stability of the ECF compartment?

• Stable plasma composition

What are the principles functions of the kidney?

• Regulate volume/composition of ECF (which will affect ICF) - Osmoregulation, Blood pressure and volume

• Regulate concentrations of ions in ECF

• Excretion - endogenous waste/metabolites, toxins, drugs

• Acid base balance

Describe the endocrine functions of the kidney.

• Renin, counteracts reduction in ECF volume and BP

• Erythropoietin - formation and maturation of RBCs

• Calcitriol - calcium homeostasis

• Glucose - protect blood sugar during starvation

The kidney contributes to homeostatic control via cooperative functionality with ______ and ______ systems.

circulatory, respiratory

What is the functional unit of the kidney?

nephron

The cortex has the same osmolarity as the ____ ____ - ______.

blood supply - isosmotic

Describe the relative location of the cortical nephrons.

How about the juxtamedullary nephrons?

• Loop of Henle barely enters the medulla, primarily in cortex

• Loop of Henle passes deep into the medulla

Where is the glomerulus and bowman's capsule typically located within the kidney?

Cortex

For desert-dwelling animals where water retention is very important, what type of nephrons will likely be present in higher quantities?

Juxtamedullary nephrons

• Such as camels

What three fundamental processes or functions occur within the nephron?

1.) Filtration

2.) Reabsorption

3.) Secretion

What happens to the cell types along the length of the nephron?

Highly differentiated along length due to differing functions

Describe the cell types in the distal convoluted tubule and collection duct.

• Principal Cells - reabsorb Na+, Cl-, and secrete K+

• Intercalated Cells - reabsorb K+ and transfer H+

Where does filtration occur in the nephron?

Level of the glomerulus - bowman’s capsule (Solute/Fluid management)

• Blood enters under relatively high pressure due to high resistance in efferent arterioles

• Water, glucose, electrolytes, low molecular weight proteins, waste, drugs (Glomerular filtrate 20% of plasma) are all filtered out

  • Absorbed via the tubular network

• Content, cellular components, medium to high MW proteins, water exit via the efferent arteriole

Because large MW proteins and molecules are not typically asborbed at the level of the glomerulus, large waste products have the potential to be retained. However, what occurs in the Proximal Convoluted Tubule to combat this?

Secretion

• Elimination of non-filtered solutes or increased removal of substances from bloodstream to filtrate, from peritubular cells to filtrate (secreted substances produced in cells)

Another “problem” with the glomerulus is that we could potentially lose significant amounts of water, how do we combat this?

• Where does this occur

Reabsorption (Partial/total), recovery or required components from filtrate

• Occurs in proximal convoluted tubule, Loop of henle, distal convoluted tubule, collection duct

What conditions may result from low/medium MW proteins (As opposed to low MW proteins normally absorbed by the glomerulus) being absorbed?

• They are too large to be absorbed later in the nephron

• May lead to Proteinuria, Albuminuria, Haemoglobinuria

What regulates the rate of filtration in the kidney?

Hydrostatic and Osmotic Forces

**REMINDER

• What are the four starling’s forces?

• Capillary Hydrostatic Pressure (From Aorta, pushing OUT)

• Oncotic Pressure (Osmotic pressure due to plasma proteins pulling IN)

• Osmotic Pressure (Small pressure pushing OUT due to interstitial fluid proteins)

• Interstitial Fluid Hydrostatic Pressure (Small force pushing IN)

Why is TTbs effectively zero?

BOWMAN’S SPACE ONCOTIC PRESSURE

πbs is the oncotic pressure in the Bowman's space, caused by proteins in the filtrate. It is essentially zero because the Bowman's space contains very few proteins, as the glomerular filtration barrier prevents most proteins from passing into the filtrate.

What is the equation for net filtration and what does each variable mean?

P_uf = P_gc - (P_bs + TT_gc)

• Pgc is the glomerular hydrostatic pressure (outward force)

  • This is typically the blood pressure in the glomerulus, which drives fluid and solutes out of the capillaries and into the Bowman's capsule.

• Pbs is the Bowman's space hydrostatic pressure (inward force)

  • This pressure is the force exerted by the fluid that accumulates in the Bowman's capsule. As the space fills with filtrate, the pressure increases and it tends to push fluid back into the glomerular capillaries, opposing filtration.

• πGC is the plasma oncotic pressure (inward force)

  • Osmotic pressure, or oncotic pressure, results from the presence of plasma proteins (like albumin) that cannot pass through the glomerular filtration barrier. These proteins exert an inward pull on the fluid, drawing water back into the capillaries and opposing the filtration process.

What determines the Glomerular Filtration Rate (GFR)?

GFR = P_uf x (permeability of the filter, surface area (of filtration barrier))

• **Reminder: P_uf = net ultrafiltration pressure

• Affected by differences in hydrostatic pressure and plasma protein osmotic pressure

What regulates GFR?

Principally regulated by changes in blood flow, protein osmotic pressures and hydrostatic pressure.

How does a low blood flow affect GFR?

Lower blood flow - more water leaves (initial segments) - greater increase in osmotic pressure across the glomerular capillary bed (despite similar hydrostatic pressure), water 'held' in later parts of capillaries and overall decreased GFR

Low blood flow decreases glomerular filtration rate (GFR) primarily because it reduces the glomerular capillary hydrostatic pressure (P₍GC₎), which is the main driving force for filtration.

How does a higher blood flow affect GFR?

Higher blood flow - smaller fraction filtered so osmotic pressure increases less, increased GFR

How can the resistance of renal arterioles be altered, what does this affect?

• Diameter can be altered which affects flow, hydrostatic pressure, and therefore affects GFR

What does constricting the afferent renal arterioles do to GFR?

• Increases the resistance of renal arterioles

• Decreases the blood flow - decreases hydrostatic pressure which lowers the GFR

What does dilating the afferent renal arterioles do to GFR?

• While constricting the efferent arteriole.

• Opposing effect so GFR is relatively unchanged

• Increases hydrostatic pressure but decreases flow rate

How is the GFR regulated if a moderate or acute change occurs to arterial BP?

• What is the ultimate aim?

• Aim - stabilise GFR to prevent unnecessary fluctuations in body fluid levels and urine output.

• Kidney is able to apply changes at a local level by: autoregulation:

  • Myogenic Reflex

  • Tubuloglomerular feedback

    • **Both occur at level of the afferent arterioles

What is the myogenic reflex in response to?

• Response to acute moderate changes in BP

How does the myogenic reflex work in response to high BP?

Stimulates stretch receptors in afferent arterioles

Reflex contraction of afferent arteriole

Flow and pressure in glomerulus stabilised, less blood flows through

NET RESULT 'Constant' blood flow + GFR

How does the myogenic reflex work in response to low BP?

Decrease in BP

Detected by stretch receptors

Reflex dilation of afferent arteriole

Flow and pressure in glomerulus stabilised, increasing flow

NET RESULT 'Constant' blood flow + GFR

What is tubuloglomerular feedback based on?

• Based on flow rate in the tubule

Describe the tubuloglomerular feedback based on a low GFR.

Decrease in GFR - Less fluid filters out of bowman’s capsule, less fluid throughout tubule

Fuid flow reaches DCT - at the macula densa (Junction between the afferent arteriole and DCT)

• Paracrine signals released from macula densa to dilate the afferent arteriole

• Causes more blood to flow, increasing the GFR and returning. tonormal

What will happen if there is a more chronic, systemic change to arterial BP?

Autoregulation is no longer enough, as afferent AND arteriole pressure is affected

• Aim is to alter GFR to protect the BP

• Renin Angiotensin Aldosterone System

Describe how the Renin Angiotensin Aldosterone System is activated in response to a low GFR (Stimulated by chronic/systemic change in BP). (End with prod. of Angiotensin II)

At level of the kidney

• Low GFR

• Flows through tubule

• Past macula densa senses decreased pressure and decreased NaCL concentrations

• Macula densa releases renin

At the level of the liver

• Renin acts on angiotensinogin produced by liver, converting it to angiotensin I

At the level of the Lungs

• ACE (Angiotensin Converting Enzyme) → converts angiotensin I to angiotensin II

What affects does angiotensin II have on the body?

• Increase sympathetic activity

  • Increased cardiovascular output ^^ GFR

• Tubular Na+, Cl- reabsorption and K+ excretion, H2O retention

• Adrenal Gland cortex to secrete aldosterone (Increases above effects)

• Arteriolar vasoconstriction, to increase BP

• Pituitary gland ADH secretion from PP

  • Stimulates thirst, helps water retention via collection duct H2O reabsorption

Ultimately:

Water and salt retention. Effective circulating volume increases. Perfusion of the juxtaglomerular apparatus increases.

• Constricts efferent arterioles to combat low BP, maintains GFR and waste clearance

• Subsequent low pressure in peritubular capillaries promotes reabsorption, increase BP

Summarize the mechanisms regulating GFR.

• Normal small/acute changes in BP

• Large/prolonged decrease in BP or marked reduction in volume

AUTOREGULATION - Adjusts arteriolar resistance

• Maintains excretion of water, wastes and salts

Sympathetic NS and Angiotensin II override 'autoregulation'.

• Maintain GFR to maintain waste excretion but increased water reabsorption → increased BP.

Why is GFR important in a clinical context?

Important clinical indicator of the extent and progress of renal disease

Describe how GFR can be calculated.

• **What substance is ideal and why?

• **What other substance can be used?

GFR = urinary excretion of a substance / minute plasma concentration of substance

• Substance must be freely filtered and neither reabsorbed nor secreted (From blood plasma → filtrate, and cannot be reabsorbed or secreted into filtrate)

• Inulin - a fructose polymer (MW 5200D) is ideal (Infuse to achieve steady plasma conc").

  • Downside = must be infused

• Endogenous creatinine often used clinically (but some secretion)

What is clearance?

An alternate value that is closely related to GFR and can be used as a numerical expression of renal efficiency.

Defined as the volume of plasma, that contains the amount of the substance excreted in the urine per minute (i.e. sum of filtered and secreted).

Clearance is the volume of plasma that would need to be "cleansed" (or cleared) to excrete a certain amount of a substance in one minute, including both the substances filtered and those actively secreted by the kidneys.

Describe how clearance is calculated.

Collect urine for a period of time (t) and measure [X].

Express excretion of X per minute.

Clearance of X= (urinary [x]) x ( (vol urine/min) / (plasma [X]) )

For inulin, GFR = _____.

clearance