RNU Flashcards
Outline the process of erythropoietin (EPO) production
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
Summarise the functions of the kidney and relate them to the consequences of kidney failure
- 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
Outline the mechanism of action of Loop diuretics providing examples, clinical uses and adverse effects
- 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
Describe how kidney function is measured
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
Outline the disadvantages of the eGFR
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
List typical values for renal blood flow, glomerular filtration rate and urine production
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
Where does lymph from the kidneys drain to?
Para-aortic nodes
Outline the mechanism of action of potassium-sparing diuretics providing examples, clinical uses and contraindications
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
Describe the pathophysiology of renal stones and list the main types of stones
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
Outline treatment options for kidney stones depending on their location
- 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
Name causes of chronic kidney disease (CKD)
- Diseases of the arterial supply
- Glomerular diseases
- Tubulo-interstitial diseases
- Obstructive uropathy
- Following acute kidney injury (AKI)
Explain the role of citrate in the inhibition of renal stone formation
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
Explain the role of the kidney in the control of blood osmolality
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
Outline the mechanism of action of thiazide diuretics providing examples, clinical uses and contraindications
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
Describe the flow of blood through the kidney
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
Describe the histology of the bladder
- 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
Explain the structure and function of umbrella cells
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
Name the layers of the testis from deep to superficial
- 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
State the function of Leydig cells
Leydig cells produce testosterone in the presence of luteinising hormone (LH) from the anterior pituitary
State the functions of peritubular myoid cells
Peritubular myoid cells are contractile smooth muscle cells found at the outer tubular edge
Functions:
- Provide structural integrity to the tubule
- Secrete ECM molecules for the basement membrane
- Signal to Sertoli and Leydig cells
Describe the histological features which Sertoli cells are characterised by
- 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
Describe the function of Sertoli cells
- 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
What is the “blood-testis barrier”?
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)
Explain the process of spermatogenesis
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
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
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
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
Which lymph nodes do the anal canal and external genitalia drain into?
Superficial inguinal nodes
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
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
List the different parts of the uterine tube
- Infundibulum
- Ampulla
- Isthmus
- Interstitial/uterine part
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
What type of epithelium is found in the
a) vagina
b) uterine tubes
a) non-keratinising stratified squamous epithelium
b) ciliated simple columnar epithelium
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
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
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
Describe the function of mesangial cells
Remove aggregated proteins from the glomerular basement membrane to keep it clear of debris
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
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
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
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
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
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
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
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
Name the components of the juxtaglomerular apparatus
- Macula densa
- Mesangial cells
- Juxtaglomerular cells
- Smooth muscle cells of the afferent arteriole
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
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
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
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)
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
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
