Kidney+Neuro exam preparation

Previous exam 2023

Questions 1-9 Neuro

Questions 10-17 Kidney

1) Information or resources Define the concept of “window of susceptibility”. (2p)

Windows of susceptibility refer to specific periods in an individual's life when they are more vulnerable to the effects of environmental health hazards.

From https://library.fiveable.me/key-terms/environmental-occupational-health/windows-of-susceptibility

Toxicants have different effects based on the timing of exposure during development and sensitivity changes with the development stage.  this is called windows of susceptibility.

From Rishi’s note, which is from tutor’s saying.

2) Neurotoxin Y blocks the Na/K ATP-ase. (2p)

3) Why is the nervous system more sensitive to neurotoxicants during development as compared to the adult state? Describe three specific features and motivate. (3p)

The immature NS is especially vulnerable to certain chemicals, and there are several factors that make the developing NS uniquely susceptible.

1. Window of susceptibility. Cell sensitivity differs with the developmental stage, leading to critical windows of vulnerability. Chemicals that alter the timing and formation of neural connections could result in permanent malformations, the consequences of which may be quite unlike the chemical’s effects in the adult NS.

2. Limited Cell Replacement. While synapto-genesis can continue throughout life, proliferation cannot; therefore, the CNS is unique in that damaged neural cells are not readily replaced.

3. Weaker Defenses. There are physiological and kinetic differences in the developing organism that may profoundly influence its sensitivity, including the slow formation of the blood–brain barrier and lack of key metabolic enzymes to protect the brain and eliminate toxicants.

From text book page 844. Summarized by ChatGPT.

4) Describe three neurotoxic mechanisms which can account for the developmental neurotoxicity of methylmercury (MeHg). (3p)

1. Oxidative Stress: Methylmercury (MeHg) increases reactive oxygen species, damaging neural cells during critical developmental stages.

2. Increased Intracellular Calcium: MeHg disrupts calcium homeostasis, impairing cell signaling and promoting cell death in developing neurons.

3. Mitochondrial Dysfunction: MeHg interferes with mitochondrial function, reducing energy production essential for neural growth and repair during development.

Answered by ChatGPT based on points from slides.

5) One of the following is NOT relevant for methyl mercury (MeHg) neurotoxicity. (1p) Select one alternative:

• increase in intracellular Calcium
• interference with glucocorticoid hormone signalling
• interference with thyroid hormone signalling
• oxidative stress

6a) Define excitotoxicity. (3p) 6b) Describe two circumstances which promote excitotoxicity.

Excitotoxicity is a condition of central neuronal death due to an excess of glutamate or related excitatory molecules binding to their respective receptors.
Promotor:
1. lack a full blood–brain barrier
2. structurally related amino acids

From https://www.sciencedirect.com/science/article/pii/S1054358916300096

7) Tetrodotoxin (TTx) is a neurotoxin which blocks voltage-gated Na channels (prevents them from opening). (2p)

7a) What effect does TTx have on resting membrane potential?

7b) What effect does TTx have on action potential?

7a) Effect on Resting Membrane Potential: Tetrodotoxin (TTx) does not affect the resting membrane potential because it only blocks voltage-gated sodium channels, which are not active at rest. 

7b) Effect on Action Potential: TTx prevents the initiation and propagation of action potentials by blocking voltage-gated sodium channels, stopping the influx of Na+ ions necessary for depolarization.

8) Which symptoms are associated with sarin gas intoxication? Select one or more alternatives:

• paralysis of skeletal muscles
• euphoria
• excessive salivation
• excessive sweating

9) Define the concept of “silent toxicity”. (2p)

“Silent neurotoxicity”, also called silent toxicity or silent damage to the nervous system, represents a persistent biochemical change or morphological injury to the nervous system that does not induce overt evidence of toxicity (i.e. remains clinically unapparent) unless unmasked by experimental or natural processes.

From https://www.sciencedirect.com/science/article/pii/S0892036216300162

10) What are the three main functions of the kidney and give one concrete example of each function. (3p)

1. Regulation of Blood: The kidney regulates blood pressure and electrolyte balance (e.g., adjusts sodium and water levels to control blood pressure).

2. Excretion of Waste and Foreign Substances: It removes metabolic waste like urea and toxins from the bloodstream (e.g., excretes urea in urine).

3. Hormone Production: The kidney produces hormones that regulate various body functions (e.g., erythropoietin stimulates red blood cell production).

Points from slides and concreted by ChatGPT.

11) The renal tubule has three different sections, which are these and in what order do they appear? (2p)

The three sections of the renal tubule, in order, are:

1. Proximal convoluted tubule
2. Loop of Henle
3. Distal convoluted tubule

From slides

12) The kidney secretes several hormones, name two of these hormones and explain one main function for each respective hormone. (2p)

Renin activates the renin-angiotensin-aldosterone system, thus
regulating blood pressure and Na+,K+ balance

Erythropoietin stimulates red blood cell formation by bone marrow

Prostaglandins/kinins bradykinin = vasoactive, leading to
modulation of renal blood flow & along with angiotensin II affect the
systemic blood flow

From slides

13) Mention two types of clinical tests that can be performed to detect glomerular and tubular damage, respectively. (2p)

Glomerular damage:
1. Serum creatinine test
2. Urinary protein (albumin) test
Tubular damage:
1. Urinary β2-micro-globulin test
2. Urinary RBP(retinol-binding protein) test

From slides

14) Give examples of two diuretic substances (natural or drug), and explain how they affect diuresis? (2p)

1. Caffeine. Caffeine can inhibits Na+ reabsorption
2. Furosemide. Furosemide can selectively inhibit Na+-K+-2CL- symporters in
the thick ascending limb of the loop of Henle

From slides

15) Development of chronic renal failure occurs progressively. (4p) a. What defines the last stage, referred to as end-stage renal disease? b. Give one example of a substance that has been associated with chronic kidney disease (CKD). c. Briefly describe one underlying mechanism by which your selected substance can cause kidney damage.

a.
End-stage renal disease – 90% of nephrons lost, GFR 10-15% of normal,
oliguria, further increase of nitrogen-containing waste and creatinine in
blood => need dialysis
b.
Pb
c.
At first, Pb enters the cells in proximal tubule(PT) by endocytosis after binding to low-molecular-weight proteins. In PT cells, Pb inhibits mitochondrial respiratory function, which lead to formation of ROS. ROS causes oxidative stress and depletes glutathione. Finally, PT cells apoptosis occurs and kidney is damaged.

From slides

16) Give two examples of occupations where individuals may be exposed to nephrotoxic substances, and state one substance for each occupational exposure and the main site of action for each respective substance in the kidney. (3p)

1.Electronic waste recycler; Cadmium; proximal tubular
2.Firefighter; inorganic dust and fumes; glomerulus

From PBL and slides.

17) What does the half-life of a drug mean and what are the two factors that the half-life is dependent on? Also, give one example of how the half-life of a drug can be affected by the presence of kidney failure? (2p)

Half-life (t1/2): The time it takes for the concentration of a chemical in the body to decrease by half.
The half-life of a drug is dependent on the volume distribution (VD) and the elimination rate (ER)
In kidney failure, the estimated glomerular filtration rate (eGFR) decreases, reducing the kidneys' ability to eliminate drugs. For drugs primarily excreted by the kidneys, such as gentamicin, a decreased eGFR slows drug clearance, leading to an increased half-life and a higher risk of accumulation and toxicity.

Definition and factors from slides. Example from slides and refined by ChatGPT.

Points from slides(Kidney)

Kidney structure

Order of urine production

Nephron => papillary ducts=> minor calyces => major calyces => renal pelvis => ureter => urine bladder

nephron

TWO parts:

• Renal corpuscle
  • Glomerulus - capillary network
  • Bowman’s capsule – double-walled cup surrounding the glomerular capillaries
• Renal tubule
  • Proximal convoluted tubule
  • Loop of Henle
  • Distal convoluted tubule

Urine production

• GOAL: to maintain homeostasis by regulating the volume and composition of blood.
• Involves excretion of solutes, especially waste products:
  1. Ammonia and urea: breakdown of amino acids (most abundant).
  2. Creatinine: breakdown of creatinine phosphate, important role in muscle contraction.
  3. Uric acid: recycling of nitrogenous bases from RNA molecules.

Accomplished by filtration, reabsorption, secretion and excretion.

Rate of urinary excretion: glomerular filtration + secretion - reabsorption

Tubular reabsorption and secretion

• most reabsorption occur in proximal convoluted tubule

Glomerular filtration rate (GFR)

Is the amount of filtrate formed in all renal corpuscles of both kidneys each minute

Controlling GFR

• Auto-regulation

  • Myogenic mechanism (fast): ↑ blood pressure => stretching of smooth muscle in afferent arteriole wall => contraction => narrows lumen => ↓GFR
  • Tubuloglomerular feedback (slower): ↑ blood pressure => less reabsorption of Na+, Cl- and water => detected by macula densa cells => ↓ release of NO (vasodilation) by juxtaglomerular apparatus => contraction of afferent arteriole = ↓GFR

• Neural regulation

  • Sympathetic stimulation (exercise or hemorrhage) => release of norepinephrine => causes powerful vasoconstriction of afferent arterioles = ↓GFR.

• Hormonal regulation

  • Angiotensin II: potent vasoconstrictor => narrows both afferent and efferent arterioles => ↓ renal blood flow => ↓GFR.
  • Atrial natriuretic peptide (ANP): secreted by the heart at ↑ blood volume => ↑ capillary surface => ↑GFR

Renin – Angiotensin – Aldosterone System

Hormone production

• Renin activates the renin-angiotensin-aldosterone system, thus regulating blood pressure and Na+,K+ balance
• Prostaglandins/kinins bradykinin = vasoactive, leading to modulation of renal blood flow & along with angiotensin II affect the systemic blood flow
• Erythropoietin stimulates red blood cell formation by bone marrow

Effects to ADME when kidney failure occurs

• Absorption and bioavailability

In case of kidney failure, the motility of the stomach is decreased and intestinal edema may occur, decreasing the absorption of drugs such as the diuretic furosemide.

• Distribution and protein binding

In case of kidney failure, the protein binding of drugs is decreased mainly due to lower albumin concentrations in plasma moving the drug from the blood to organs, increasing the distribution of the drug. This leads to a decreased plasma concentration of such drugs but increased concentrations of the active form in organs. This in turn increases the half-life of the drug. Examples of such drugs are warfarin, phenytoin and morphine.

• Elimination

Elimination through the kidneys is mostly dependent on the eGFR. In case of decreased eGFR, the half-life of a drug increases

Toxicants lead to kidney failure

• NSAIDs

  NSAID can cause a decreased perfusion to the kidneys and decrease the eGFR in case of decreased blood pressure/hypovolemia, dehydration, heart failure.

• ACE-inhibitors(Angiotensin converting enzyme inhibitors)

  ACE-inhibitors can decrease the eGFR through a decrease of the glomerular capilar pressure.

• Metformin

Points from slides(Neuro)

Nervous system anatomy

• CNS (central nervous system)
• PNS (peripheral nervous system)
  • Somatic nervous system
  • Autonomous nervous system
    • parasympathetic nerves
    • sympathetic nerves

Action potential

1. Resting membrane potential
2. Depolarization (Na channels open)
3. Repolarization (K channels open)
4. Refractory period (Na/K pump re-establish membrane potential

Neurotoxicity Definition

Adverse change in the structure or function of the central or peripheral nervous system following exposure to a chemical or physical agent.

Neurological deficit Definition

Functional abnormality of a body area due to decrease in the function of the brain, spinal cord, nerves, or muscles.

How signaling across the synapse

Synaptic signaling between neurons involves diffusible chemical messengers (neurotransmitters) released by the presynaptic neuron into the synaptic cleft Neurotransmitters bind to receptors on the postsynaptic neuron and activate ion channels (ionotropic receptors) → local changes in membrane potential → action potential → propagation along the axon

Indirect neurotoxicity definition

neurologic alterations due to agents acting primarily on sites outside the nervous system(eg. CO; EDCs)

adult vs. developing nervous system

feature	adult CNS	developing CNS
state	static (?)	dynamic
main processes	electric signals; plasticity	proliferation and differentiation (plasticity)
functional reserve	large	small
structural reserve	small	large
damage	cell death;	altered progenitor proliferation and differentiation; reprogramming