RNU Flashcards
1
Q
Outline the process of erythropoietin (EPO) production
A
EPO is mainly secreted by interstitial cells of the kidneys in response to hypoxia
Blood around Loop of Henle and interstitium is relatively hypoxic
Cells are sensitive to changes in overall oxygen delivery; when low tissue oxygenation is detected, EPO is produced
Stimulates the production of red blood cells in red bone marrow
Minor contributions of EPO from the liver
2
Q
Summarise the functions of the kidney and relate them to the consequences of kidney failure
A
- Excretion of small solutes
Failure: increased plasma concentration of solutes e.g. urea, creatinine - Excretion of drugs
Failure: drug toxicity - Control of water and salt balance
Failure: ECF volume overload (tissue/pulmonary oedema, raised JVP) or depletion (dry mucous membranes, reduced skin turgor, decreased JVP and BP) - Control of blood pressure
Failure: hypertension - Control of electrolyte balance
Failure: hypo/hyperkalaemia etc - Control of acid/base balance
Failure: metabolic acidosis - EPO production
Failure: anaemia - Vitamin D activation
Failure: hypocalcaemia and secondary hyperparathyroidism
*A WET BED, helps one remember kidney functions:
A) maintenance of ACID-base balance;
W) maintenance of WATER balance;
E) balance of ELECTROLYTES;
T) removal of TOXINS;
B) control of BLOOD pressure;
E) production of ERYTHROPOIETIN; and
D) metabolism of vitamin D
3
Q
Outline the mechanism of action of Loop diuretics providing examples, clinical uses and adverse effects
A
- Examples: furosemide, bumetanide
- Mechanism of action
Inhibit Na/K/2Cl co-transporter in the thick ascending limb of the Loop of Henle
Increase excretion of K/Mg/Ca
High potency, rapid onset, short duration - Adverse effects
Can include metabolic alkalosis, hypokalemia and ototoxicity - Clinical uses
Oedema
Acute renal failure
Hypertension
Hypercalcaemia
4
Q
Describe how kidney function is measured
A
Glomerular filtration rate is the unit measure of kidney function
Creatinine is a normal product of muscle metabolism
* Produced constantly
* (almost) freely filtered at the glomerulus
* Neither secreted nor reabsorbed (almost) in the tubule
* Can be used to provide an estimate of the glomerular filtration rate
Plasma concentration of creatinine depends on muscle mass, kidney function and recent protein intake
Creatinine clearance can be measured using 24H urine collection
Estimated glomerular filtration rate (eGFR) can be measured using creatinine concentration from a blood sample
2 formulae
- Cockgroft & Gault: estimates creatinine clearance
* MDRD 4-variable: eGFR
Based on serum creatinine but corrects for age & sex
5
Q
Outline the disadvantages of the eGFR
A
Uses serum creatinine:
- Inverse relationship between serum creatinine and eGFR leads to slow recognition of loss of first 70% of kidney function
* Surprise at sudden rise in creatinine
* Overestimation of muscle mass in those with lower muscle mass e.g. elderly patients
* Not accurate when eGFR > 60mL/min/1.73m2 or in individuals < 18 y/o
6
Q
List typical values for renal blood flow, glomerular filtration rate and urine production
A
Renal blood flow
1.25L/min or 625ml/100g/min
GFR
100-120mL/min/1.73m2
Urine production
Minimum: 1mL/min or 0.4L/day
Maximum: 20mL/min or 12L/day
7
Q
Where does lymph from the kidneys drain to?
A
Para-aortic nodes
8
Q
Outline the mechanism of action of potassium-sparing diuretics providing examples, clinical uses and contraindications
A
Examples
* Amiloride: blocks ENaC channel in the collecting duct
* Spironolactone: mineralocorticoid receptor antagonist
Mechanism of action
Act on collecting duct and distal convoluted tubule
Low potency, slow onset & long duration
Contraindication: renal failure
Dangerous as renal failure is associated with hyperkalemia
Clinical uses
Oedema
K-conservation
Hypertension
Hyperaldosteronism
Heart failure
Cirrhosis
9
Q
Describe the pathophysiology of renal stones and list the main types of stones
A
aka renal calculus/nephrolithiasis
Renal stones are solid concretions of crystal aggregates
They are formed from the combination of excreted/secreted ions within the glomerular filtrate
Supersaturation of the filtrate leads to the formation of crystals
Types:
* Calcium-containing (80%, high density)
Calcium oxalate, calcium phosphate
* Struvite (magnesium, ammonium, phosphate - low density)
Associated w/ UTIs
* Uric acid
* Cysteine
* Mixed
10
Q
Outline treatment options for kidney stones depending on their location
A
- Nephrolithiasis
< 2cm:
Expectant management
Extracorporeal shock wave lithotripsy (eswl)
> 2cm:
Expectant management
Percutaneous ultrasonic lithotripsy (pul)
Large branched “staghorn” stones may require both pul and eswl
Cysteine stones: pul or open nephrolithotomy - Ureterolithiasis
<7mm:
Expectant management
Lower ureter-ureteroscopic stone removal
Mid-upper ureter eswl
>7mm:
Eswl
Ureteroscopic stone fragmentation
Open surgery
Ureteric stenting
11
Q
Name causes of chronic kidney disease (CKD)
A
- Diseases of the arterial supply
- Glomerular diseases
- Tubulo-interstitial diseases
- Obstructive uropathy
- Following acute kidney injury (AKI)
12
Q
Explain the role of citrate in the inhibition of renal stone formation
A
Citrate reduces urinary supersaturation of calcium salts
Forms soluble complexes with calcium
Inhibits crystal growth and aggregation
Increases activity of macromolecules in the urine which inhibit CaOx aggregation
Alkalinising effect inhibits urate and cysteine stones
Citrate can be increased by a low Na diet
13
Q
Explain the role of the kidney in the control of blood osmolality
A
Dehydration implies an increase in plasma osmolality
This increase is detected by osmotically active cells of the hypothalamus, which secrete ADH
ADH increases the permeability of the collecting ducts
Binds to V2 receptor which stimulates cAMP
Promotes the release of preformed vesicles to release aquaporin II, which inserts into the tubular membrane
Aquaporin I allows the passage of water out into the interstitium
More water is reabsorbed, concentrated urine is product
14
Q
Outline the mechanism of action of thiazide diuretics providing examples, clinical uses and contraindications
A
Examples: bendroflumethiazide, metolazone, chlorothiazide, indapamide
Acts on the Na/Cl co-transporter in the cortical diluting segment of the distal convoluted tubule
Increase K/Mg excretion but decrease Ca excretion
Low potency, slow onset, long duration
Clinical uses
Oedema
Hypertension
Nephrogenic diabetes insipidus
Hypercalciuria (renal stones)
Contraindication: renal failure; ineffective
15
Q
Describe the flow of blood through the kidney
A
Renal artery branches off abdominal aorta posterior to renal vein
Gives off segmental arteries > interlobar arteries > arcuate arteries > interlobular arteries
Afferent arteriole > glomerular capillaries > efferent arteriole
Efferent arteriole gives rise to peritubular capillaries (cortical nephron) or vasa recta (juxtamedullary nephron)
Peritubular capillaries give rise to a stellate vein
> Interlobular vein > arcuate vein > interlobar vein > renal vein
16
Q
Describe the histology of the bladder
A
- Serosa
- Detrusor: 3 layers of smooth muscle (muscularis externa)
Inner longitudinal, middle circular, outer longitudinal - Trigone: area between 2 ureteric orifices
- Proximal sphincter mechanism
Bladder neck: internal sphincter is formed by thickening consisting of converging detrusor muscle fibres as they pass distally to become the smooth muscle of the urethra - Distal sphincter mechanism
Urethral smooth muscle
Intrinsic rhabdosphincter
Peri-urethral musculature - Lamina propria
- Transitional epithelium
17
Q
Explain the structure and function of umbrella cells
A
Umbrella cells are found in the epithelium of the bladder;
They are large, domed, ovoid cells with round nuclei, eosinophilic cytoplasm and scalloped edge
They contain intramembranous plaques (invaginations) which enable:
* Expansion of the epithelium
* Storage of chemically toxic urine in considerable volumes without damage to tissue
18
Q
Name the layers of the testis from deep to superficial
A
- Tunica albuginea (200-300 lobules, each with 1-4 seminiferous tubules)
- Tunica vaginalis
- Internal spermatic fascia aka transversalis fascia
- Cremaster muscle
- External spermatic fascia (continuation of external oblique)
- Dartos muscle
- Skin of scrotum
19
Q
State the function of Leydig cells
A
Leydig cells produce testosterone in the presence of luteinising hormone (LH) from the anterior pituitary
20
Q
State the functions of peritubular myoid cells
A
primary
21
Q
Describe the histological features which Sertoli cells are characterised by
A
- Sertoli cells have ovoid/triangular nuclei which contain fine sparse chromatin (pale stain)
- Sertoli cell cytoplasm extends from the basement membrane to the lumen of the tubule
- Cytoplasm of Sertoli cells is connected by continuous tight junctions, which separate the seminiferous tubule into 2 compartments
Basal: closest to basement membrane, immature cells found here (spermatogonia and early spermatocytes)
Adluminal: closest to lumen of tubule
After meiosis completes, the germ cells cross the blood-testis barrier to enter this compartment
22
Q
Describe the function of Sertoli cells
A
- Produce androgen-binding protein, anti-mullerian hormone and inhibin
- Mediate effects of testosterone and FSH
Express receptors for androgens (testosterone produced will move into testes and drive spermatogenesis) - Form the blood-testis barrier
- Provide mechanical support to germ cells
- Phagocytose excess cytoplasm from spermatids
23
Q
What is the “blood-testis barrier”?
A
The blood-testis barrier is formed by continuous tight junctions between Sertoli cells
The function of the blood-testis barrier is to prevent the autoimmune destruction of developing gametes
It restricts contact between post-meiotic cells (spermatids) and pre-meiotic germ cells (spermatogonia and spermatocytes)
24
Q
Explain the process of spermatogenesis
A
Spermatogenesis is the production of sperm in the testes
Spermatogonia divide by mitosis and produce 2 daughter cells
* Type A spermatogonia
Dark A: stem cell population; divide to form one dark A and one pale A
Pale A: mature into type B spermatogonia
* Type B spermatogonia
Divide by mitosis and differentiate into primary spermatocytes
Enter meiosis I to give 2 secondary spermatocytes
Secondary spermatocytes undergo second meiotic division to produce spermatids
Spermatids undergo spermiogenesis to become mature spermatozoa
25
Explain the process of spermiogenesis
During spermiogenesis, spermatids differentiate into mature spermatozoa by undergoing changes
* Cytoplasmic remodelling
Excess cytoplasm is phagocytosed by Sertoli cells
Become elongated spermatids
* Develop flagellum for propulsion
* Develop an acrosome to penetrate through oocyte coat
* Form a midpiece (central filamentous core with many mitochondria for energy)
* Nucleus contains compacted and inactive DNA
26
Name the boundaries of the inguinal canal
* Anterior
Internal and external oblique aponeurosis
* Superior
Internal oblique and transverse abdominis muscles
* Inferior
Lacunar and inguinal ligaments
* Posterior
Transversalis fascia and conjoint tendon
27
Describe the sources of mucus in the vagina
* Within the vagina: greater vestibular glands of Bartholin
- Above the vagina: glands of the uterine cervix produce mucus which moves down into the vagina to lubricate its surface
28
Which lymph nodes do the anal canal and external genitalia drain into?
Superficial inguinal nodes
29
Describe the process of oogenesis
Oogenesis is the production of ova in the ovaries
During embryological development, a pool of oogonia are formed
Oogonia mature into primary oocytes and enter meiosis I, arresting in prophase I
Granulosa cells surround them to form follicles; they remain arrested until puberty, when menstruation starts
FSH triggers the maturation of some follicles, which will complete meiosis I
Produce one secondary oocyte and one polar body (remains in follicle, eventually degraded)
Secondary oocyte is arrested in metaphase II
Ovulation triggers the release of the secondary oocyte into the uterine tube
If fertilised by sperm, chemical changes will trigger the completion of meiosis II, forming a mature ovum and another polar body
Mature ovum fuses with sperm to produce a zygote
30
Describe the types of tissue within the penis, relating this to blood flow during sexual arousal
2 types of tissue
* Corpora cavernosa (2, dorsal)
Permeated by blood sinuses which can fill with large volumes of blood (from dorsal artery of penis)
Separating the sinuses are trabeculae of connective tissue and smooth muscle
* Corpus spongiosum (1, ventral)
Surrounds the penile urethra
Meshwork of erectile tissue is finer than in corpus cavernosum to avoid compression of urethra on erection
Blood drains into the dorsal vein
31
List the different parts of the uterine tube
* Infundibulum
* Ampulla
* Isthmus
* Interstitial/uterine part
32
Outline the function of the seminal vesicles
Produce alkaline viscous fluid to neuralise acidic environment of the vagina
The fluid also contains:
* Fructose: ATP production in sperm
* Prostaglandins: improve motility and viability of sperm, trigger muscle contractions in vagina & uterus
33
What type of epithelium is found in the
a) vagina
b) uterine tubes
a) non-keratinising stratified squamous epithelium
b) ciliated simple columnar epithelium
34
Uterus
* Arterial blood supply
* Venous drainage
* Lymphatic drainage
* Arterial blood supply:
Uterine artery, branch of internal iliac artery
* Venous drainage:
Uterine vein, branch of internal iliac vein
* Lymphatic drainage:
Body drains into para-aortic nodes
Cervix drains into internal iliac nodes
35
Describe the different layers which make up the endometrium of the uterus (superficial to deep)
* Stratum functionalis:
Lost and regrows every menstrual cycle
Contains top portion of tubular uterine glands
Vast blood supply, spiral arteries
Subdivided into 2 layers
Stratum compactum
Stratum spongiosum
Proliferation driven by oestrogen
* Stratum basalis
Contains bases of tubular glands
Vast blood supply, straight arteries
36
Describe the menstrual stage of the menstrual cycle
If a pregnancy does not occur, the corpus luteum degenerates and stops producing progesterone
Stratum functionalis shrinks, compressing spiral arteries, leading to tissue ischaemia
Vascular stasis occurs - blood trapped in arteries, tissue necrosis takes place
Blood vessels relax, backed up blood ejects, carrying away necrotic tissue - this is the menstrual period
Blood exits endometrial cavity via cervix and vagina
37
Describe the function of mesangial cells
Remove aggregated proteins from the glomerular basement membrane to keep it clear of debris
38
Differentiate between medullary rays, cortical labyrinths and renal corpuscles
Medullary rays are projections of the medulla into the cortex, consisting of Loops of Henle and collecting ducts
Cortical labyrinths are found between medullary rays and consist of proximal and distal convoluted tubules
Renal corpuscles consist of the glomerulus (capillary tuft) and Bowman’s capsule
39
Describe the different layers which allow filtration to take place in the nephron
* Fenestrated negatively charged capillary epithelium
* Negatively charged glomerular basement membrane
* Foot processes of podocytes (visceral layer of Bowman’s capsule)
Interdigitation of foot processes is the filtration step
* Filtration slits (slit diaphragm)
Glomerular ultrafiltrate enters Bowman’s space and goes to PCT
40
Compare the histological features of the proximal and distal convoluted tubules
PCT:
* Brush border with tall microvilli
* Irregular lumen, “star-shaped”
* Simple cuboidal epithelium (ion pumping)
DCT:
* No brush border
* Larger, round lumen
* Cells are smaller: more nuclei, fewer organelles
41
Explain the structure and function of the Loop of Henle
Function: further concentration of urine
Structure:
* Thin descending limb
Permeable to water and salt
* Thick ascending limb
Impermeable to water
Actively transports sodium, potassium and chloride
Creates a concentration gradient to promote water reabsorption in the descending limb
42
Describe the mechanism of action of the countercurrent multiplier system in the Loop of Henle
NKCC2 co-transporter: pumps 1 sodium, 1 potassium and 2 chloride ions out of ascending limb of the Loop of Henle into interstitium
Creates a concentration gradient to draw water out of the thin descending limb via osmosis
Osmolarity of filtrate increases towards the tip of the Loop and descends again as ions are pumped out of the ascending limb
Sodium ions are reabsorbed via the basal Na/K ATPase (sodium potassium pump)
Chloride moves down its own ion channel
If the potassium channel is open, potassium can leak back to the tubule down its concentration gradient
This creates a net positive charge which can allow other positively charged ions (calcium and magnesium) to pass through between the channels
43
Describe the function of the distal convoluted tubule
The distal convoluted tubule reabsorbs water and sodium under the influence of aldosterone
It contains a sodium-chloride co-transporter (NCC)
Transports sodium into the distal convoluted tubule
NaK ATPase pumps sodium into the interstitium
If more aldosterone is secreted, more sodium is reabsorbed in exchange for potassium
44
Describe the function of the cortical collecting duct (CCD)
* The cortical collecting duct gives the final filtrate concentration
* Aldosterone and ADH act here
2 columnar epithelial cells line the lumen
* Principal cells
Sodium enters the cell through an epithelial sodium channel (ENaC)
Excess potassium is excreted via the renal outer medullary potassium channel (ROMK)
* Intercalated cells
Reabsorb bicarbonate
Contain a hydrogen ion channel to excrete excess hydrogen ions
45
Explain the kidney’s role in the control of blood pressure
Osmoreceptors in the macula densa of the juxtaglomerular apparatus (DCT) detect:
* Low levels of sodium in the filtrate (low filtration pressure)
Produce prostaglandin E2 which is detected by juxtaglomerular cells
Juxtaglomerular cells produce renin, activating RAAS (renin-angiotensin-aldosterone system)
Renin cleaves angiotensinogen into angiotensin I
Angiotensin I converted into angiotensin II (powerful vasoconstrictor ) by ACE
Aldosterone is recruited from the zona glomerulosa of the adrenal gland, increasing water and sodium reabsorption
* High levels of sodium in the filtrate (high filtration pressure)
Produce adenosine
Constricts afferent arteriole to reduce blood flow to the nephron
46
Name the components of the juxtaglomerular apparatus
* Macula densa
* Mesangial cells
* Juxtaglomerular cells
* Smooth muscle cells of the afferent arteriole
47
Describe the mechanism through which the kidneys reabsorb filtered bicarbonate
Bicarbonate filtered at glomerulus
Hydrogen ions secreted by tubular cells into PCT lumen via NaH anti-porter or H+ ATPase
Filtered bicarbonate cannot cross apical membrane of PCT cell
Combines with secreted hydrogen to form carbonic acid in the presence of carbonic anhydrase, which dissociates into carbon dioxide and water
CO2 and H2O diffuse into the PCT cell and reform bicarbonate and a hydrogen ion
Bicarbonate diffuses through basolateral membrane > interstitial fluid > peritubular capillary blood
48
Describe the mechanism through which the kidneys excrete fixed acid
* Excretion of titratable acid
Tubular cells generate a new bicarbonate
This is absorbed along with a hydrogen that binds to (& is titrated by) a base other than HCO3 (mainly phosphate)
So the filtered phosphate anion is combined with H+ generated within the cell
Delivery of PO4 is not amenable to much regulation
* Excretion of ammonium (NH4+)
Ammonia (NH3) is generated from the metabolism of glutamine in the PCT (upregulated in acidosis)
Available to be titrated by hydrogen ions formed in the CCD, forming ammonium (NH4+), which is excreted in the urine
Each H+ excreted is matched by another HCO3 absorbed
49
Discuss the features of respiratory acidosis and alkalosis
* Respiratory acidosis
Increased pCO2, H+ may be normal due to renal retention of HCO3, pH may be low or normal
Response:
Acute - buffering (not HCO3) by haemoglobin, phosphate
Chronic - compensation, kidneys retain bicarbonate
Causes: increased generation of CO2 or reduced ventilation of CO2; COPD is a risk factor
* Respiratory alkalosis
Lowered pCO2, H+ may be normal, pH may be high or normal
Caused by hyperventilation
Response:
Renal excretion of bicarbonate
Acute alkalosis increases calcium binding to albumin, reducing ionised calcium, resulting in tetany
50
Outline the features and causes of metabolic acidosis
* Features
Lowered bicarbonate, increased or normal H+/pH, decreased pCO2 (respiratory compensation)
* Causes
* Addition of extra acid
Generation of extra acid through metabolism: lactic acidosis, ketoacidosis
Ingestion of acid: e.g. methanol, ethylene glycol
* Failure to excrete acid
Renal tubular acidosis
Chronic renal failure
- Loss of bicarbonate
In stool (diarrhoea) or urine (renal tubular acidosis)
51
Describe the pathophysiology of lactic acidosis
Lactic acid is produced as a byproduct of anaerobic respiration
Buffered by bicarbonate to produce lactate, which is metabolised by liver & kidney
In cases of tissue hypoperfusion and hypoxia, lactate production is greater than renal excretion of H+
2 main types
* Type A:
Evidence of tissue hypoperfusion in shock (septic, cardiogenic, hypovolaemic)
Reduced oxigen delivery (hypoxia, carbon monoxide poisoning)
Anaerobic muscle activity (e.g. sprinting)
* Type B: no clinical evidence of tissue hypoperfusion
B1: underlying diseases e.g. leukaemia, lymphoma
B2: drugs and toxins e.g. metformin, cyanide
B3: inborn errors of metabolism, congenital forms of lactic acidosis with enzyme defects e.g. pyruvate dehydrogenase deficiency
52
Explain what is meant by an “anion gap”
An anion gap (AG) is the difference in unmeasured cations and anions, adjusting for albumin
AG = Na - (Cl + HCO3)
The difference between Na and Cl + HCO3 reflects the presence of unmeasured anions
If this is Cl (hyperchloraemia), the anion gap will be unchanged
If it is not Cl, (normochloraemia), the anion gap will rise
Metabolic acidosis caused by:
- Excess volatile acids (except HCl) such as lactic acid or ketoacids
- Loss of bicarbonate
The AG is used to identify the cause of a metabolic acidosis
53
Outline the features and causes of a metabolic alkalosis
* Features
Increased HCO3, decreased or normal H+, increased or normal pH, normal or increased pCO2 (respiratory compensation)
* Causes
Volume depletion
* Gastric acid loss
* Diuretics
Volume repletion
* Mineralocorticoid excess
* Hyperaldosteronism
* Bartter’s, Cushing’s
* Profound K depletion
54
Explain how gastric acid loss can lead to a metabolic alkalosis
* Volume depletion
Sodium reabsorbed to replenish fluid volume; sodium reabsorption drives bicarbonate reabsorption, maintaining alkalosis
* Chloride depletion
Due to loss of hydrochloric acid
HCO3 reabsorption in DCT requires chloride secretion
If tubular chloride is reduced, the gradient to absorb bicarbonate increases
* Potassium depletion
Distal tubule hydrogen secretion occurs in potassium exchange; in trying to reabsorb potassium, more hydrogen ions are excreted causing alkalosis
Treatment: fluid resuscitation with 0.9% NaCl & treat cause
55
Outline the arterial blood supply and venous drainage of the bladder
Arterial blood supply
- Males
Superior and inferior vesical branches of the internal iliac artery
Middle rectal artery
* Females
Vaginal artery
Internal pudendal artery
Venous drainage
- Vesical venous plexus (empties into internal iliac veins)
56
Describe the sympathetic innervation of the bladder and sphincters
* Spinal nerve roots T10-L2
* Post-ganglionic outflow via sympathetic hypogastric nerves
* Direct contraction of smooth muscle of bladder base (pre-prostatic sphincter) and urethra
* Enhancement of bladder neck and urethral tone (alpha 1 adrenoceptors)
* Relaxation of bladder by:
Beta-3 adrenoceptor mediated detrusor relaxation (weak)
Inhibition of parasympathetic ganglia
57
Describe the parasympathetic innervation of the bladder and sphincters
* Spinal nerve roots S2-S4 from lateral horn intermediolateral nucleus
* Outflow via sacral parasympathetic pelvic splanchnic nerves (nervi erigentes)
* Detrusor muscle contraction (M3 receptors)
* Inhibitory to internal sphincter
58
Describe the somatic innervation of the bladder and sphincters
* Spinal nerve roots S2-S4 from anterior horn
* Onuf’s nucleus situated medially gives fibres which travel in pelvic nerves (pudendal nerve)
* After synapsing at pelvic ganglion innervate rhabdosphincter
* Sensory and motor to external sphincter
59
Explain the different phases of the bladder cycle
* Storage phase
Sympathetic effects dominate during bladder filling (compliance)
Fibres in the hypogastric nerve suppress contraction of the detrusor
Somatic fibres in the pudendal nerve control external sphincter
* Voiding phase
Parasympathetic effects dominate during voiding
Controlled by spinopontine-spinal reflex involving pontine micturition control centre (pons)
Fibres in the pelvic splanchnic nerve cause contraction of the detrusor
Somatic fibres going to external sphincter become less active
Bladder neck descends and opens (funnelling)
* Termination phase
Flow reduces & ends
Sphincter closes under voluntary control; urethra contracts forcing urine level back up into bladder
Cortical micturition centre takes control, returning to filling phase
60
Name the ligaments of the uterus and ovaries and describe their functions
Uterus:
- Broad ligament
Double layer of peritoneum draped over uterus and uterine tubes
Ovaries attached posteriorly via mesovarium
* Round ligament
Maintains anteflexion
Passes through inguinal canal and ends in labium majus
Ovaries:
- Ovarian ligament
Attaches upper pole of ovary to lateral uterine wall
* Suspensory ligament
Attaches ovary to lateral pelvic wall
Contains ovarian artery + vein
61
Describe the pouch of Douglas (rectouterine pouch) and the uterovesical pouch
* Pouch of Douglas
Double fold of peritoneum between posterior wall of uterus and anterior wall of rectum
Infection or fluids could potentially accumulate here
* Uterovesical pouch
Between uterus and bladder
62
Name the layers surrounding the kidney from superficial to deep
* Pararenal fat
* Renal fascia
* Perirenal fat
* Renal capsule
63
Describe the duct system of the testis
* Seminiferous tubules
* Straight tubules
* Rete testes
* Efferent ductules
* Epididymis
Storage and maturation of sperm
3 parts: head, body and tail
* Ductus deferens
64
What type of epithelium lines the ductus deferens?
Pseudostratified columnar epithelium with stereocilia
65
Describe the arterial supply, venous drainage and lymphatic drainage of the testes
* Arterial blood supply: testicular artery
* Venous drainage: pampiniform venous plexus
* Lymphatic drainage
Testes: para-aortic nodes
Scrotum: superficial inguinal nodes
66
List the contents of the spermatic cord
* Nerves
Sympathetic branches of testicular plexus
Genital branch of genitofemoral nerve
Cremasteric nerve
* Arteries
Testicular artery
Artery to ductus deferens
Cremasteric artery
* Pampiniform venous plexus
* Ductus deferens
* Lymphatic vessels
67
Describe the structure of the prostate gland
* Made up of 30-50 individual tubuloalveolar glandular units
* Open up into separate branching ducts & open into prostatic urethra
* Embedded in a fibromuscular stroma which divides the prostate into lobules
* 3 zones
Peripheral
* Main body of the gland, located posteriorly
* Most prostate cancers originate here
Central
* Surrounds prostatic urethra
* Contains periurethral mucosal glands
* Most common location of BPH
Transitional
- Contains submucosal glands
68
Describe the substances found within prostatic secretions
Pseudostratified cuboidal/low columnar epithelial cells secrete an acidic fluid containing
* Citrate (used by sperm for ATP production)
* Zinc
* Acid phosphatase
* Prostate specific antigen
* Proteolytic enzymes (liquefy coagulated semen)
69
Describe the blood supply to the prostate gland
prostatic arteries,
(which are mainly derived from the internal iliac arteries)
Also branches from:
* Internal pudendal artery
* (Inferior vesical artery)
* Middle rectal arteries
70
Describe the different sections of the male urethra
* Pre-prostatic
Area leaving bladder and entering urethra, 1-1.5cm
* Prostatic
2-3cm, widest part of urethra
* Membranous
2cm, narrowest part of urethra
Contains sphincter urethrae muscle (external sphincter)
Contains Cowper (bulbourethral) glands which produce mucus + glycoproteins during sexual arousal
* Penile (pendulus)
Final part, longest (15-20cm)
Ends at external urethral meatus
71
Differentiate between primordial, primary, secondary and tertiary (Graafian) follicles
* Primordial
Single layer of squamous follicular cells surrounding oocyte
* Primary
Multiple layers of stratified cuboidal follicular cells surrounding oocyte
Zona pellucida develops
* Secondary
Development of fluid-filled intercellular spaces
Differentiation of follicular cells into theca and granulosa cells
* Tertiary (Graafian)
Development of fluid-filled antrum
Increase in size, will later undergo ovulation
72
Explain the function of the
a) granulosa cells
b) theca cells
a) Granulosa cells contain aromatase, an enzyme which converts androgens into oestrogens
b) 2 theca layer
Theca internal: produces androgens from cholesterol, inner layer in close proximity to granulosa cells
Theca external: outer fibrous layer
73
Describe the changes in the follicle in case of pregnancy
At the point of ovulation, only oocyte and some closely associated granulosa cells leave the ovary
Remaining follicle reorganises itself into the corpus luteum
Granulosa cells undergo hypertrophy and form the bulk of the corpus luteum as radiating cords of lutein cells
Theca cells also become lutein cells but remain in the periphery
If pregnancy occurs, corpus luteum maintains pregnancy by producing hormones
* Progesterone
* Oestrogens
* Relaxin
* Inhibin
Between radiating cords sinusoidal capillaries & larger blood vessels are found to transport hormones into bloodstream
74
Describe the pronephros
The pronephros is the first rudimentary, non-functional structure involved in kidney formation
Forms at 4 weeks in cervical region (7-10 segmented solid cell groups)
Degenerates at the end of week 4
75
Describe the mesonephros
Forms at the end of week 4 in the abdominal region
Non-functional but tubular structures are present which drain into mesonephric duct
Contributes cells to genital ridge as it degenerates where gonads will later develop
Duct system associated with the mesonephros is taken over by testes, becoming ductus deferens, epididymis and ejaculatory ducts
76
Describe the metanephros
Develops during week 5 in pelvic region
Fully functional by week 11-12 but nephrons are formed until birth
Excretory units develop from the metanephric mesoderm
Formed from 2 parts
* Ureteric bud
Protrusion of mesonephric duct
Source of duct system in kidneys, allows urine drainage from developing kidney
Becomes associated with cluster of cells in surrounding mesoderm (metanephric mesenchyme/cap/blastema)
* Metanephric cap
Provides excretory units
77
Describe the indifferent stage of genital duct development
2 pairs of genital ducts develop in weeks 5-6
- Gonads initially appears as a pair of longitudinal ridges (urogenital/gonadal ridges)
Primordial germ cells originating in the yolk sac migrate to the genital ridge via the dorsal mesentery, forming the primitive gonad
Sex differentiation starts in week 7
78
Describe the development of the gonads if the embryo is genetically male
The Y chromosome encodes testis-determining factor SRY
Acts on somatic cells, triggering the differentiation of
- Sertoli cells: produce anti-mullerian hormone, which degrades the mullerian duct
* Leydig cells: produce testosterone, which allows the formation of the ductus deferens, epididymis & ejaculatory duct from the mesonephric duct
Sex cords proliferate and become horseshoe-shaped (primitive germ cells & somatic cells)
Testis cords are solid till puberty
* Acquire a lumen to form seminiferous tubules, which join with rete testis & efferent ductules
* Rete testis and mesonephric duct link to form the ductus deferens
The tunia albuginea forms, separating the cords from surface epithelium
79
Describe the development of the gonads if the embryo is genetically female
Wnt 4 is the ovary-determining gene
Primordial germ cells divide by mitosis to form a pool of oogonia, enter meiotic arrest during 4th month
Paramesonephric (Mullerian) ducts form lateral to mesonephric ducts & gonads
Form funnel-shaped cranial ends which open into peritoneal cavity
Migrate caudally parallel to mesonephric ducts, reaching pelvic region
Approach each other in the midline
- Cranial portion forms uterine tubes
- Caudal portion forms uterovaginal primordium (uterus + superior vagina)
80
Describe the function of the cloaca
Posterior orifice that serves as the only opening for the intestinal, reproductive and urinary tracts at early stages
Hindgut (endodermal lining)
Continuous with developing gut
- Gut tube is covered by membranes: oropharyngeal and cloacal
Also exit for any digestive waste formed by embryo
Allantois emerges from cloaca
81
Describe the embryological development of the bladder
Urorectal septum divides the cloaca (week 4-7) by fusion with the cloacal membrane to form
* Anterior urogenital sinus
Bladder: cranial part of urogenital sinus
Exception - trigone (mesonephric duct)
Allantois forms a remnant - the urachus
* Posterior rectal/anal canal
82
Describe the embryological development of the accessory glands and the lower part of the vagina
* Accessory glands
Prostate gland develops as an outgrowth from the prostatic urethra
Bulbourethral glands develop as an outgrowth from the penile urethra
* Lower part of vagina
2 outgrowths from urogenital sinus - sinovaginal bulbs - fuse to form a vaginal plate
Hollows to form a cavity
83
Describe the embryological development of the external genitalia
Week 3 after fertilisation
* A pair of cloacal folds develop around the cloacal membrane
* Join to form the genital tubercle at the cranial end
* Caudally, cloacal folds are subdivided
* Urethral folds in front can form the labia minora and the ventral aspect of the penis
* Genital swellings appear on either side of urethral folds and can form scrotal swellings or the labia majora
* Anal folds behind
84
Describe the embryological development of the urethra
Middle pelvic part of urogenital sinus
Androgens from foetal testis cause the genital tubercle to elongate into the phallus
Phallus pulls urethral folds forwards
They form the lateral walls of the urethral groove and close over the urethral plate to form the penile urethra (erectile tissue will form around that)
External urethral meatus is derived from surface ectoderm
85
Discuss the role of kisspeptin in the reproductive tract
Kisspeptin is found in the hypothalamus and is the master regulator of the HPG axis as it controls the release of GnRH
* Kisspeptin neurons directly contact GnRH neurons which contain the kisspeptin receptor (GPR54)
* GnRH regulates the release of LH and FSH from the anterior pituitary
86
Discuss the role of feedback mechanisms in the control of kisspeptin
Kisspeptin secretion is controlled by feedback from the gonads
This feedback is via oestrogen, progesterone and testosterone
Positive feedback causing increased secretion of kisspeptin during the pre-ovulatory LH surge is due to oestrogen and progesterone
Negative feedback is a result of oestrogen and testosterone inhibiting this secretion to control reproduction
87
Discuss the role of kisspeptin during puberty
KiSS1 neurons increase in the hypothalamus
Kisspeptin secretion increases during puberty and becomes pulsatile with 60-minute intervals correlating with GnRH pulses
Amplified GnRH leads to increased levels of sex steroid hormones
88
Describe what happens when kisspeptin is dysregulated
* Precocious puberty
Activating kisspeptin mutations: HPG axis is reactivated earlier than it should
* Delayed puberty
Inactivating kisspeptin mutations lead to hypogonadotrophic hypogonadism
89
Describe the gross anatomy of the placenta
Weight: 400-650g
2 plates
- Basal plate
Maternal side of the placenta containing the maternal decidua
* Chorionic plate
Foetal side of placenta containing chorionic vessels feeding into the umbilical cord
Umbilical cord
- Contains 3 vessels
1 umbilical vein - transport oxygenated blood to foetus
2 umbilical arteries - transport deoxygenated blood away from foetus
- Wharton’s jelly protects vessels from damage
90
Describe the development of the placenta
Day 8-9
Blastocyst embeds into uterine wall and trophoblast layer differentiates into cytotrophoblasts and syncytiotrophoblasts
Day 12
Syncytiotrophoblasts develop lacunae (precursor of intervillous space)
Projections of syncytiotrophoblasts into maternal decidua form the primary villi
Secondary villi: contain cytotrophoblasts and extraembryonic mesenchyme, day 13-15
Tertiary villi: capillaries develop in mesenchymal core, week 3
These will form villous trees (foetal vessels) which will be in close proximity with the maternal circulation in intervillous spaces
Extravillous trophoblast cells remodel spiral arteries from coiled, high resistance low flow vessels to high flow low resistance vessels, allowing sufficient blood flow to foetus
91
Describe the functions of the placenta
* Metabolism: synthesis of glycogen, cholesterol, fatty acids, nutrients
* Endocrine
Produces hormones: progesterone, placental growth factor, oestrogen, hCG, human placental lactogen
- Transfer
O2, CO2, urea, bilirubin, electrolytes, carbohydrates
Drugs
Antibodies
Amino acids and glucose
Vitamins B, C, D
Viruses
92
Define the terms pre-eclampsia, eclampsia and foetal growth restriction
Pre-eclampsia: new onset hypertension with proteinuria after 20 weeks’ gestation, associated with oedema
Eclampsia: fits or convulsions associated with the features of pre-eclampsia, can lead to maternal and foetal death
Foetal growth restriction: failure to reach genetically pre-determined growth potential due to placental dysfunction
93
What is a placental cotyledon?
One of the lobes of the placenta containing villous trees, which are bathed in maternal blood
Allows close proximity of maternal and foetal circulations to permit the exchange of nutrients, gases and wastes in between
94
Name the layers of the placental barrier
* 4 layers
Foetal capillary endothelium
Connective tissue of the villi
Cytotrophoblast
Syncytiotrophoblast
95
Describe the pathophysiological mechanisms that underlie pre-eclampsia
3 step hypothesis
* Abnormal placentation
Abnormal remodelling of spiral arteries leads to poor uteroplacental blood flow; hypoxia & ischaemia-reperfusion injury
* Abnormal maternal response to placental trigger
Increased release of free radicals and inflammatory mediators in syncytiotrophoblast
Excess release of placental factors like soluble endoglin (sENG)
These sequester VEGF and PlGF (reduced concentration in maternal plasma)
Ultimately, maternal response to placental dysfunction
* Exaggerated inflammatory response
* Endothelial dysfunction
Manifests as renal and cardiovascular dysfunction
* Organ/systems failure
96
Describe the clinical features associated with pre-eclampsia
* Systolic > 140mmHg or diastolic > 90mmHg
* Protein:creatinine ratio >30mg/mmol
* Headaches
* Blurred/flashing vision
* Pain in upper right abdomen
* Heartburn
* Rapid oedema
97
Define “endothelial dysfunction” in the context of pre-eclampsia
Systemic pathological state characterised by an imbalance between vasodilator and vasoconstrictor molecules
Defective proliferation/survival of endothelial cells
Circulating factors:
* Placental debris (syncytiotrophoblast microvesicles/extracellular vesicles)
* Angiogenic factors (sFlt-1)
* Lipids/oxidation
* Inflammation
98
Outline current clinical guidelines for the management of pre-eclampsia
PlGF-based testing to diagnose suspected PE + standard clinical assessment
Symptomatic treatment
- Labetalol for hypertension
Others: nifedipine, methyldopa
Foetal monitoring
- Foetal cardiotocography at diagnosis
Monitor foetal heartbeat + uterine contractions
- Ultrasound for foetal growth and amniotic fluid volume assessment
- Umbilical artery Doppler velocimetry (blood flow)
Timing of birth - planned early birth if severe PE
99
Name the risk factors for pre-eclampsia
* Primigravidae (first pregnancy)
* BMI > 25
* Multiple pregnancy
* Age > 40
* Family history
* Existing hypertension, kidney problems, diabetes, thrombophilia
* Previous pregnancy with pre-eclampsia
* Use of barrier contraceptive methods/assisted reproduction
100
Describe the consequences of foetal growth restriction
Increased risk of stillbirth, childhood morbities and disease in adulthood
Barker hypothesis: inadequate nutrition in utero “programs” the foetus to have metabolic characteristics that can lead to future disease
101
Describe the functions of the gonadotrophins in males and females
Males
- FSH
Stimulates primary spermatocytes to undergo meiosis
Enhances production of androgen-binding protein in Sertoli cells
* LH
Acts on Leydig cells to regulate testosterone production
Females
- FSH
Inhibits recruitment of follicles
Supports growth of ovarian follicles (granulosa cells)
* LH
Supports ovarian theca cells
LH surge triggers ovulation
102
Explain the follicular phase in the menstrual cycle
10-14 days, pre-ovulatory
Characterised by growth of dominant follicle
Oestrogen is rising and progesterone is low
* Development of the primary follicle
* Development of the secondary follicle
LH levels increase, FSH levels increase until follicle reaches appropriate size
Once appropriate follicle size is reached, negative feedback - FSH and LH decrease
Granulosa cells produce inhibin which inhibits FSH but not LH
Oestrogen levels increase exponentially, switching to positive feedback, releasing stores of LH and FSH in anterior pituitary
LH surge triggers ovulation (day 14) and negative feedback is turned on again; oestrogen levels decrease
103
Explain the process of development of the primary follicle
Signals from ovarian stroma (particularly BMPs) act on primordial follicle
Make follicle cells produce kit ligand
Recruits stromal cells which become the outer theca layer (primary follicle)
Signals also instruct oocyte to make more signals:
GDF-9: signals to follicular cells to differentiate into granulosa cells and proliferate
104
Explain the process of development of the secondary follicle
FSH secretion increases, stimulating further growth of recruited follicles and development of antrum
Circulating LH levels increase slowly (1-2 days after FSH increase)
Affects theca cells, which gain an independent blood supply
Granulosa cells develop FSH, oestrogen and androgen receptors (follicle with most receptors becomes dominant)
Recruited follicles increase production of oestradiol, stimulating LH and FSH synthesis but inhibiting their secretion (FSH more so than LH)
FSH levels decrease once appropriate follicle size is reached
105
Describe the luteal phase of the menstrual cycle
Post-ovulatory, 14 days long
Formation of the corpus luteum from the follicle
Corpus luteum secretes primarily progesterone, which stimulates the development of the secretory endometrium
No pregnancy: corpus luteum degenerates into corpus albicans and disintegrates; oestrogen + progesterone decrease late in this phase
Pregnancy: implanting embryo produces hCG which signals to corpus luteum to keep producing progesterone
Levels of circulating oestrogen, progesterone and inhibin are high, so FSH and LH are low
106
Describe the endometrial changes taking place during the proliferative and secretory phases
* Proliferative
Driven by oestrogen
Tubular uterine glands of the endometrium are proliferating
Stratum functionalis is regrowing after last menstrual period
- Secretory
Driven by progesterone
Endometrium becomes thicker
Glands develop and become more secretory
Synthesise a carbohydrate-rich secretion to support developing embryo
107
Outline the clinical signs of polycystic ovarian syndrome (PCOS)
* Hirsutism
* Acne
* Irregular or absent menstrual periods
* Infertility
* Type II diabetes
* Weight gain
108
Describe the pathogenesis of PCOS
Ovaries appear enlarged and contain multiple fluid-filled structures under the ovarian capsule
These are normal antral follicles but present in much higher numbers than usual
Increased ovarian stroma
Inappropriate exposure of antral follicles to excessive androgen concentrations leading to inhibition of FSH release
Increased LH leads to hyperandrogenism (LH:FSH ratio > 2:1 is diagnostic)
109
Describe treatments for PCOS
* Weight loss
* Contraceptive pill: can induce regular periods
* Fertility treatment
Clomiphene: ovulation induction
IVF
* Spironolactone: anti-androgen
* Metformin: improves insulin sensitivity
* Finasteride and flutamide: reduce hirsutism
110
Describe the regulation of spermatogenesis
GnRH stimulates release of FSH and LH
LH stimulates testosterone production by Leydig cells
FSH and LH stimulate Sertoli function to support developing sperm
Once spermatogenesis reaches sufficient levels, Sertoli cells produce inhibin
Limits FSH production
Testosterone is also involved in negative feedback as it is detected by hypothalamus & pituitary
Downregulates GnRH > FSH and LH > testosterone
111
Define endocrine disruptors and explain how they affect reproduction
Exogenous substances which disrupt normal endocrine function
Can function as agonists (excessive hormone function by activating receptors) or antagonists (prevent binding of endogenous hormone)
Examples
- Phytoestrogens: oestrogenic effect (soy-derived products)
* Anabolic steroids: mild testosterone-like effects impact negative feedback in hypothalamus/pituitary leading to testis atrophy & sterility
* Phthalates: testicular dysgenesis syndrome (cryptorchidism, hypospadias…)
112
Describe the process of testicular descent
Begins in 10th week of pregnancy
* Transabdominal phase
Testes enlarge as the mesonephric kidneys regress
Each testis is anchored at its
* Superior pole: cranial suspensory ligament
* Inferior pole: gubernaculum
Atrophy of mullerian ducts allows transabdominal movement of testes into deep inguinal ring
* Inguino-scrotal phase
Testis moves from inguinal region to scrotum under the control of androgens e.g. testosterone and CGRP
Testes arrive at scrotum a few week before birth
113
Define cryptorchidism, including risk factors and long-term consequences
* Failure of descent of testes into scrotum
* Risk factors
Low birthweight / small for gestational age / prematurity
Maternal diabetes
Exposure to endocrine disruptors e.g. phthalates
* Long-term consequences
Testicular dysfunction
Testicular cancer risk
Persistent bilateral cryptorchidism in an adult: azoospermia
114
Discuss management for cryptorchidism
* Any undescended testis after 6 months: orchidopexy
Laparoscopic procedure for non-palpable testis
* Hormonal treatment
hCG stimulation test
LHRH test
115
Define hypospadias, include risk factors and management
Ectopically positioned external urethral meatus which lies proximal to the normal site on the ventral aspect of the penis
Chordee (head of the penis curved upwards/downward) and hooded foreskin are common
Associated with cryptorchidism and inguinal hernia
Risk factors: advanced maternal age, IVF, endocrine disruptors
Treatment:
Surgery (hormonal treatment prior)
116
Which qualities of sperm are analysed in relation to fertility?
* Volume: 1.5ml per ejaculate
* pH 7.2
* Sperm concentration
* Total count
* Motility
* Viability
* Morphology
117
Briefly describe the different types of ovulatory disorders
* Hypothalamic-pituitary failure
Due to lifestyle factors like rapid weight loss e.g. elite athletes, eating disorders
* Hypothalamic-pituitary-ovarian dysfunction
Includes PCOS
* Ovarian failure
Includes Turner’s syndrome, premature ovarian failure, cancer treatment
118
Name tests used to investigate infertility due to issues with the Fallopian tubes
* Laparoscopy and dye test (gold standard)
* HSG (hysterosalpingogram): X-ray, dye injected into uterus
* HyCoSy (hystero contrast sonography): ultrasound
119
Explain the steps in the in vitro fertilisation process
* Pituitary downregulation
With GnRH agonists or antagonists
* Ovarian hyperstimulation
Once natural cycle is suppressed, women take FSH so there are more eggs to be collected & fertilised
Injection of hCG before oocyte retrieval to achieve final follicular maturation
* Oocyte retrieval
Oocytes retrieved by direct needle puncture of each follicle (transvaginally with ultrasound guidance)
* Fertilisation
Oocytes inseminated in vitro with washed sperm or through ICSI
Embryos are cultured
* Implantation
Through embryo transfer into uterus
120
What is measured in urinalysis?
* Haemoglobin
* Leukocyte esterase and nitrites
* Ketones
* Bilirubin
* Urobilinogen
* Protein
* Glucose
* pH
* Specific gravity
121
Discuss the management of chronic kidney disease (CKD)
Symptomatic treatment
* EPO injections, ferrous sulphate: iron deficiency anaemia
* Calcichew (aka calcium carbonate, a phosphate-binding agent): hyperphosphataemia
* Calcitriol: hypocalcaemia
* Dialysis
Kidney transplants
122
Differentiate between haemodialysis and peritoneal dialysis
* Haemodialysis
Surgical creation of arteriovenous fistula (AVF)
Use radial artery + brachiocephalic vein
Blood passes through long capillary tubes made of a semipermeable membrane
Dialysate solution passes in countercurrent direction on other side, filters waste out of blood
3-4 hours 3x a week
* Peritoneal dialysis
Dialysate solution is inserted via a catheter implanted into peritoneal cavity
Blood flow through mesenteric capillaries can exchange electrolytes and solutes with the dialysate solution
Exchange 4x daily, leaving to dwell in peritoneum for 6h
123
Discuss the investigations used for renal stones
* Imaging
CT KUB (kidneys, ureters, bladder)
Ultrasound
* Urinalysis
Volume
pH (calcium & struvite < 7.0, uric acid and cysteine > 7.0)
Proteinuria, haematuria, nitrites/leukocyte esterase (signs of infection)
Urinary calcium, sodium, oxalate, citrate, creatinine, uric acid, cysteine
Crystal shape
- Serum
Calcium
Phosphate
Urate
PTH
Bicarbonate
124
Describe the countercurrent exchange mechanism in the vasa recta
The vasa recta are permeable to water and solutes; they run down the descending limb and up the ascending limb of the Loop of Henle
Allow extra solutes pulled from the interstitium near the descending limb to be returned near the ascending limb
Water diffused from the capillary into the interstitium returns
Maintains the corticopapillary gradient, which would otherwise be destroyed by osmosis
125
Describe the types of acute rejection
* Hyperacute rejection
Preformed anti-donor antibodies bind to graft endothelium immediately after transplantation
Immune activation > recruitment of complement > endothelial damage > pro-inflammatory cytokines > thrombosis and ischaemia > graft failure
Minutes-hours
* Acute cellular rejection
T cells destroy graft parenchyma & vessels by graft cytotoxicity and inflammatory reactions
Days-months
* Acute humoral rejection
Antibodies damage graft vasculature
Days-months
126
Describe the process of chronic rejection
Caused by poor Human Leukocyte Antigen (HLA) matching
HLA reactive antibodies can lead to acute rejection episodes, increasing risk of chronic loss of function
Dominated by atherosclerosis, T cell reactions, secretion of cytokines, proliferation of vascular smooth muscle and parenchymal fibrosis
Known as chronic allograft nephropathy in kidney transplants
Months-years
127
Describe the mechanisms involved in renal excretion of drugs
* Glomerular filtration
Protein binding affects the rate of filtration; increased free fraction means increased rate of filtration
* Tubular secretion
Independent of protein binding
Most drugs are actively secreted into the PCT
* Reabsorption
Influenced by the pKa of the drug (increased ionisation leads to decreased reabsorption)
Drugs which are excreted largely unchanged by the kidney e.g. lithium, cisplatin chemotherapy are usually nephrotoxic
128
Describe how impaired kidney function has an effect on drug metabolism and clearance
2 problems: toxicity and ineffective treatment
* Impaired drug absorption
* Altered pharmacokinetics
Impaired elimination
Decreased protein binding
Renal dysfunction impacts hepatic drug metabolism
* Altered drug effect
Increased sensitivity to CNS depressants, opiates…
Decreased sensitivity to diuretics, urinary antibacterial
* Enhancement of adverse effects e.g. metformin, digoxin
129
Explain the dose adjustments necessary in patients with compromised kidneys
Modify dose and monitor drug concentration
Consider:
* Therapeutic index
* Extent of renal decompensation
* Extent of renal elimination
* Concentration-dependent toxicity
130
State the embryological origin of the urogenital tract
intermediate mesoderm
131
Name the 3 sets of kidney structures during development and the region they are present in
* pronephros - cervical region
* mesonephros - abdo region
* metanephros - pelvic region
