Learning Objectives Flashcards
What is absorbed and secreted in the PCT?
Name the three types of cells in the DCT and what they’re involved with.
The glomerular filtration barrier is built of 3 layers arranged in series.
See image:
Filtration takes place from the glomerular capillaries (Cap) through:
- The pores of the endothelial cells (Endo)
- The glomerular basement membrane (GBM) consisting of the three layers:
Lamina rara interna (LRI) Lamina densa (LD) Lamina rara externa (LRE)
- The filtration slit membrane (arrows) between the foot processes (Fp) of the podocytes (Pod) into the urinary space (Us)
What two chemicals do podocytes secrete?
Podocin and Nephrin
What are the mesangial cells, what do they secrete, and what are they’re structural roles?
Mesangial cells are contractile cells that constitute the central stalk of the glomerulus.
Secrete Vasodilatory prostaglandins
Contractile
Structural support
Blood flow regulation (minor)
What is the difference between Glomerular Filtration Rate and Renal Clearance Rate?
Glomerular Filtration Rate
The rate at which fluid is filtered from the blood into Bowman’s space.
Assessed by measuring clearance of a substance that is freely filtered, and neither absorbed nor secreted.
Gold standard is inulin, but creatinine (waste product from muscle metabolism) is generally used to estimate in clinical practice.
GFR is inversely proportional to serum creatinine.
Renal Clearance
The rate at which a substance (often a drug) is removed from the plasma by the kidneys.
Varies depending on the substance.
Important for pharmacology.
Draw a diagram to explain the resulting effects of increased afferent or efferent pressure on GFR
Increased Afferent Pressure
(e.g. vasoconstriction)
Result: Reduced GFR
Increased Efferent Pressure
(e.g. vasoconstriction)
Result: Increased GFR
Name three keys factors that can affect GFR
- Hydrostatic / Oncotic pressure
- Blood flow and perfusion pressure
- Surface area
What are the 4 main ways that GFR is endogenously controlled?
Myogenic
Smooth muscle in the walls of the arterioles responds to pressure changes.
Tubuloglomerular feedback
The macula densa detects the rate of movement of Na+ and Cl- into cells, representing tubular flow rate.
A low flow rate induces:
- Dilation of the afferent arteriole
- Renin secretion. Angiotensin II -> constriction of the efferent arteriole.
Increased distal tubular Na**+ concentration causes…
- Swelling of the macula densa cells signals constriction of the nearby afferent arteriole so that the glomerular filtration of the same nephron is decreased.
- This forms a negative feedback loop in which the increased distal tubular load of Na+ is decreased by reducing the GFR and subsequently allowing more time for Na+ reabsorption because flow is slower.
For full explanation see below
Neural
Renin is released in response to noradrenaline acting on beta-1 receptors on juxtaglomerular cells
Hormonal
Angiotensin II increases GFR. ANP (Atrial Natriuretic Peptide) is secreted by the heart in response to increased pressure and causes increased excretion of sodium.
Tubuloglomerular Feedback
Distal tubule NaCl delivery is proportionate to glomerular filtration rate. Tubuloglomerular feedback adjusts GFR to maintain a relatively constant rate of distal tubule NaCl delivery. A drop in the delivery of Na+ or Cl− to the distal tubule is sensed at the macula densa. This signal is transmitted to the afferent arteriole. The afferent arteriole dilates, which increases glomerular capillary pressure. The afferent arteriole cells release renin, leading to intrarenal angiotensin II formation. Angiotensin II constricts preferentially the efferent arterioles, as the efferent arterioles are much more sensitive to angiotensin II. Efferent arteriolar constriction increases glomerular capillary pressure. Both vascular changes combine to cause an increase in GFR, which restores distal tubule Na+ or Cl− delivery.
Tubuloglomerular feedback results in the regulation of GFR. A drop in arterial blood pressure causes both a decrease in GFR and a decrease in renal blood flow. The drop in GFR causes a tubuloglomerular feedback—mediated arteriolar dilation, restoring GFR and also increasing renal blood flow. Consequently, the regulation of GFR also results in the autoregulation of renal blood flow.
Glomerulotubular balance ties peritubular capillary filtrate reabsorption to glomerular filtration rate. An increase in filtration at the glomerulus enhances filtrate reabsorption at the peritubular capillaries. Increased GFR increases the oncotic pressure of the blood exiting the glomerulus. When that blood enters the peritubular capillaries, the higher oncotic pressure increases reabsorption of filtrate from the renal tubules. An increase in GFR causes a proportionate increase in fluid reabsorption from the proximal tubules and loop of Henle. This balance is not perfect, so increase in GFR does increase fluid delivery to the late tubule segments
How do cells in the PCT control Acid-Base Balance?
Bicarb Buffer System
- CAH converts H and HCO3- to CO2 and H20
- Both of which are able to move across apical membrane
- Converted by CAH back to H and HCO3-
- So that HCO3- can be reabsorbed via Na+ co-transporter back into blood.
H+ is then involved in…
Protein Metabolism
- Proteins such as Glutamine (an A.A.) is deaminated to form Glutamate + NH4+
- Then converted to a-glutamate (an a-ketoacid) + NH4+
- The ketoacid is then involved in krebs cycle to produce more HCO3-
- The bicarb is the reabsorbed via Na+ co-transporter
- The NH4 is then excreted back into the filtrate.
How do the Intercalated cells in the DCT and Collecting Duct affect Acid-Base Balance?
Same as PCT but without Protein metabolism element.
Instead
H+ is pumped back into filtrate to take part in the Phosphate buffer system, and bicarb is also reabsorbed vis chloride shift mecahnism in addition to Na+ transporter
Give an overview of AKI, including a table of criteria for stages 1, 2 and 3
Acute Kidney Injury
Can be defined as:
Decreased GFR + Decreased Renal Function + Reversibility
KDIGO guidelines (Kidney Disease: Improving Global Outcomes) defines AKI as:
- A RISE in serum creatinine >26umol/L within 48 hours
- A RISE in creatinine >1.5x (50% increase) from baseline (i.e. BEFORE the AKI) within 7 days.
- URINE OUTPUT <0.5mL/kg/h for >6 consecutive hours (oliguria)
What are the main risk factors for AKI?
What are the three main types of AKI, and how can Urinalysis help to different between them diagnostically?
- Pre-Renal
- Intra-Renal
- Post-Renal
Creatinine is re-absorbed in very small amounts, whereas quite a bit of the Urea is absorbed (roughly about 20%) hence the usefulness of the BUN:Creatinine ratio.
Pre-Renal AKI
Results from decreased renal perfusion which can cause impaired oxygenation of renal tissue.
Symptoms
- Symptoms of hypovolemia: thirst, dizziness, tachycardia, oliguria, or anuria.
- Orthopnoea and paroxysmal nocturnal dyspnoea may occur if advanced cardiac failure is present.
- Azotaemia = presence of nitrogenous products in the blood (i.e. urea and creatinine).
Aetiology
- Hypovolaemia – e.g. haemorrhage, severe diarrhoea or vomiting, or burns
- Reduced effective circulating volume (actual volume not lost, but poor distribution or poor cardiac output) – e.g. heart failure or sepsis
- Renal Hypoperfusion – can be a result of renal artery stenosis, AAA, hepatorenal syndrome
- Drugs (ACE inhibitor, ARBs, NSAIDs) - Triple Whammy!
NOTES
- Renal artery stenosis - ACE inhibitors might cause a drop in intraglomerular pressure
- Reducing glomerular pressure is generally a good thing - high pressure can lead to long term chronic conditions.
- NSAIDS - Prostaglandins reduce pressure in the afferent artery - can be dangerous!
Draw a diagram to explain the effects of
ACE-i/ARB and NSAIDS on the Renal Capsule
Give an overview of NSAIDS, and highlight how they affect Renal function.
These causes affect the KIDNEY ITSELF. However, both pre-renal and post-renal causes can lead to intra-renal AKI. There are
1. Glomerular Nephritis
Damage is done to the glomerulus.
Common in Systemic Lupus Erythematous, where antibody- antigen complexes deposit in tissues, causing local inflammation and complement-related damage.
This is a Type III Hypersensitivity reaction. •
2. Acute Tubular Necrosis (ATN) - See image
The MOST COMMON cause of intra-renal AKI
Usually follows prolonged ischaemia (i.e. pre- renal AKI).
Can also be due to nephrotoxins (aminoglycoside antibiotics, methotrexate, radiocontrast)
3. Acute Interstitial Nephritis
Inflammation of the interstitial space.
Can be seen in allergies and infections. Ampicillin and rifampicin can cause a cell-mediated hypersensitivity reaction within the tubular interstitium.
4. Vascular
Adhesion of neutrophils and other inflammatory cells can cause afferent constriction. Vasculitis can also be a cause, and Renal Artery Stenosis (via atherosclerosis).
What is tested on a urine dipstick?
What are the four main functions of the Kidney?
What percentage of the Nephrons in a kidney are cortical, and how many are juxtamedullary?
Cortical: 85%
Juxtamedullary: 15%
Draw a diagram of the transcellular transport that takes place in the PCT, and explain how it is specially designed histologically for this function.
- Highly metabolic, numerous mitochondria for active transport
- Extensive brush border on luminal side ⇒ large surface area for rapid exchange
Give an outline of Fanconi’s Syndrome
What are the differences between the thin descending and thick ascending limbs of the Loop of Henle
Thin descending
Thin epithelial cells, no brush border, few mitochondria & low metabolic activity.
Freely permeable to water
Thick Ascending
Thick epithelial cells, extensive lateral intercellular folding, few microvilli, many mitochondria
⇒ high metabolic activity
Where is ADH/Vasopressin produced and where is it stored?
Produced in Hypothalamus
Stored in Posterior Pituitary Gland
What are the two intrinsic and one extrinsic mechanisms for controlling GFR
Draw a diagram to show the gradual drop in blood pressure as we move down the renal blood circulation
Draw a diagram outlining the three levels of physical filtration barriers present in the glomerulus
Outline the development of the formula for determining GFR
- The rate of filtration can be said to be:
The Concentration of I in plasma x GFR
[I]p x GFR
- The rate of filtration through Glomerulus per minute = Rate of entry into bladder per minute
Therefore
[I]p x GFR = [I]u x V*
(see image for definition of urine flow rate)
- Finally this means:
GFR = [I]u x V* / [I]p
UNITS - Very Important!
GFR = glomerular filtration rate; ml.min-1
Pin = plasma inulin concentration; mg.ml-1
Uin = urine inulin concentration; mg.ml-1
V* = urine flow rate; ml.min-1
Give a definition, formula and units for Renal Clearance
Outline what it means for a substance to have a greater, lesser or equal renal clearance to GFR, and give an example of substance in each case.
What is eGFR, what info is it based on, and what is its advantage over full urine collection and the full GFR calculation?
Estimation of GFR based on…(see image)
Isn’t as good as measuring it (i.e. 24h urine collection), but is much simpler as it requires just one blood test.
Current gold standard method is called
CKD-EPI
What are the stages and criteria for stages 1,2 and 3 for Chronic Kidney Disease?
Draw the graph to illustrate the handling of glucose by the kidneys, including concepts such as Transport Maximum and Renal Threshold
How is glucose reabsorbed in the tubule?
Why are SGLT2 inhibitors to treat diabetes (reducing glucose in blood) and diabetes-related CKD - Dapagliflozin (Europe) & Canagliflozin (USA)?
In assessing the effectiveness of a buffer solution, how does the henderson-hasselbach equation help us?
pK of a compound = Equilibrium constant between protonated/deprotonated form
Therefore, the closer the pK is to the desired pH of the environment, the better it acts as a buffer
Give an outline of the reabsorption of Bicarb in the proximal convoluted tubule
Note: Occurs in the PCT only - because it is the only part of the tubule in which the brush border enzymes include Carbonic Anhydrase
How do acetazolamide and other T-L Diuretics affect water output?
- They inhibit the activity of Carbonic Anhydrase
- This leads to less activity of the Na/H+ anti-porter
- Urine is more acidic, and less Na+ is absorbed meaning less water follows and water output is increased
How does the phosphate buffer system work, and where does it take place?
In the intercalated cells of the DCT
How does the Ammonia buffer system work, and in what part of the nephron does it take place?
The intercalated cells of the DCT
Give an overview of the respiratory system’s role in regulating blood pH
Give an overview of the how the body attempts to compensate for an acidotic state
Give an overview of the how the body attempts to compensate for an alkalotic state
Draw a table to summarise the body’s compensatory mechanisms for acid-base balance whether its of a respiratory or metabolic causes
How can increased activity of SGLT-2 transporters lead to increased GFR?
THE AMAZING SLIDE OF DIFFERENT DRUGS AND WHERE THEY WORK ON THE KIDNEY
AMAZING DIAGRAM OF DIFFERENT TYPES OF KIDNEY INJURY
MANAGEMENT OF AKI
Why does kidney injury usually lead to hyperkalemia?
AEIOU Indications for haemodialysis
Basic Functions of the Kidney
