Renal

Mark Cobb, BIMS Revision Lecture 2021

Learning Outcomes

1. Demonstrate an understanding of the functional anatomy and histology of the renal and urinary system.�
2. Demonstrate an integrated understanding of the functional properties of the renal and urinary system.

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• Understand the role of the kidneys in controlling the composition and volume of the body fluids.�
• Demonstrate an understanding of bladder function and the control of micturition.�
• Demonstrate an understanding of the role of the kidneys as endocrine organs.�
• Demonstrate an appreciation of the common pathological processes that can affect the renal and urological system, and their manifestations and management.

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From Gray's Anatomy

Hilum at L1 level (transpyloric plane)

Very vascular region so worst place for injury

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Fascia compartmentalises bleeds so contained

Retroperitoneal

• Renal arteries originate directly from abdominal aorta
• Right renal artery slightly longer, inferior to IVC
• Renal veins drain directly into IVC
• Left renal vein slightly longer, anterior to aorta

Converting Units

Body Fluids

• Interstitial fluid is between cells
• Extracellular fluids = plasma + interstitial fluid

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• Most water is within cells
• Total body water greater in men than in women, and reduces with age

Volume of Distribution

• ‘Theoretical volume of fluid needed to contain the total amount of an administered drug at the same concentration of that in plasma’

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• V_d can indicate which body compartment the drug distributes in
• Drugs with V_d <10 L are mainly confined to plasma
• V_d 12-20 L distributed in extracellular compartment
• Large V_d accumulate within cells

Terminology

• Osmole = number of molecules that a compound dissociates into when dissolved in solution
• E.g. NaCl gives 2 osmoles, CaCl₂ gives 3 osmoles
• Osmolality = number of osmoles per unit mass of the solvent (Osm.kg^-1)
• (Osmolarity = number of osmoles per unit volume of solvent (Osm.L^-1))
• Osmotic pressure = pressure that would be required to oppose osmosis

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• Oncotic pressure = osmotic pressure caused by proteins (albumin) in blood
• Bulk flow = movement of water and solutes together due to a pressure gradient

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• Isosmotic = two solutions sharing the same osmolality
• Isotonic = has the same osmolarity as ECF (applying solution to cells wouldn’t cause net movement)

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Function of the Kidney

Nephron

Glomerular Filtration

• 20% of cardiac output goes to kidneys
• Most of the movement is due to bulk flow

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Bowman’s Capsule

• Endothelial cells have fenestrations between them
• These cells have a glycocalyx (-ve charge) creating a charge barrier – particularly effective for proteins
• BM also has –ve charge

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• Podocytes = epithelial cells
• Have filtration slits allowing small molecules through

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GFR

• GFR is around 120 ml.min^-1
• Cr,u = creatine in urine
• Cr,p = creatine in plasma
• V = rate of production of urine
• Creatinine produced by body at a steady rate
• eGFR often used in practice as doesn’t require 24hr urine sample

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• NB – nephron flow rate = GFR

2 x no. of nephrons

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Vasa Recta

• Vasa recta are a series of blood vessels surrounding nephron
• Have high oncotic pressure and low hydrostatic pressure, promoting passive movement into the capillaries

Proximal Tubule

• Large amount of reabsorption occurs here
• Reabsorption can be paracellular or transcellular
• Na⁺ key driver of absorption
• Na⁺/K⁺ ATPase creates electrochemical gradient for Na⁺
• Only on basolateral membrane

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• Water follows gradient paracellularly
• Some also goes transcellularly through AQP1

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Glucose Reabsorption

• Na⁺ glucose symporter transports glucose and sodium into cell – passive transport
• Glucose then absorbed through into interstitial space through GLUT2/1
• There is a tubular maximum load for glucose reabsorption i.e. reabsorption plateaus

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• SGLT2 inhibitors used in type 2 Diabetes Mellitus e.g. empagliflozin

Bicarbonate Reabsorption

• Acetazolamide – weak diuretic
• Blocks CA – carbonic anhydrase
• As less bicarbonate reabsorbed, urine becomes more alkaline. Can result in a metabolic acidosis

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• Caffeine has a diuretic effect
• Acts on sodium-bicarbonate cotransporter

Amino acids

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• Many different transporters as in GIT
• Most are cotransporters that use Na⁺ gradient

Chloride

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• Exchanged with other anions across the apical membrane using antiporters e.g. HCOO^-
• Ions can also move with water paracellularly
• Less Cl^- than Na⁺ absorbed early on so its net concentration increases

Loop of Henle

• Descending limb goes into medulla
• Permeable to water – leaves due to osmotic force
• Thick ascending limb
• Can sustain an osmotic gradient of 200 mOsm.kg^-1
• Uses Na⁺/K⁺/2Cl^- cotransporter

Thick Ascending Limb

• Na⁺ requires pump for absorption
• K⁺ reverse leak allows more Na⁺ to be absorbed

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• Furosemide is a loop diuretic
• Blocks action of transporter
• Be wary of hypokalaemia

Countercurrent Multiplier

• Maintains a fixed osmolality – around 200 mOsm
• Allows for more reabsorption of ions than in a parallel system

Distal Tubule

• Na⁺/Cl^- cotransporter moves ions into cell
• Na⁺/K⁺ ATPase on basolateral surface
• K⁺/Cl^- cotransporter on basolateral surface

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• Thiazide and thiazide-like diuretics block the Na⁺/Cl^- cotransporter
• Often used as anti-hypertensives

Collecting Ducts

• K⁺ can be secreted here
• ADH regulates expression of AQP2 channels
• Aldosterone increases expression of Na⁺ channels and Na⁺/K⁺ ATPase

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• Spironolactone a diuretic which blocks effect of aldosterone
• K⁺ sparing diuretic

ADH (vasopressin)

• Synthesised in hypothalamus, released from post. Pituitary
• Acts at V₂ receptor, via G_s pathway
• cAMP stimulates AQP2 synthesis, packaged into vesicles
• PKA helps insertion of AQP2 by phosphorylation of vesicles
• Little ADH = dilute urine
• Lots of ADH = concentrated urine

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• UT-A1 channels are regulated in same way as AQP2
• These reabsorb urea
• Either absorbed into vasa recta or descending loop via UT-A2

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ADH disorders

Renal Blood Flow

• There is autoregulation of blood pressure in the kidneys
• Myogenic response – when the afferent arterioles are stretched, they contract – results in increased resistance and reduced flow rate
• Stretch-activated cation channels depolarise, increasing Ca²⁺ influx, causing contraction
• This allows for the GFR to be maintained

Tuboglomerular Feedback

• High Na⁺ in the distal tubule is sensed by the macula densa
• Macula densa cells release ATP
• ATP broken down into adenosine, which causes vasoconstriction of afferent arterioles

Renal Plasma Flow

PAH is not reabsorbed at all – all that is removed is lost in the urine

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NB – equation can also be used to work out substance clearance – substitute PAH with substance you are interested in

Measured in l.hr^-1 or ml.min^-1

Clearance

• First-order kinetics
• Clearance = dose/ area under curve

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• Clearance = k*V_d

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• t_1/2 = ln(2)/k

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Example

• The antibiotic gentamicin is injected intravenously as a bolus into a patient. Gentamicin has a volume of distribution of 17L and is renally cleared, with clearance of 4L.hr^-1. Given these values, calculate the half-life of gentamicin in the circulation.

Homeostasis

Osmoregulation

• Osmolality detected in the anterioventral third ventricle (AV3V) region
• Increase in osmolality results in increased ADH release
• Occurs when inadequate water intake
• Neurones from AV3V project to hypothalamus, increasing thirst

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• Decreased osmolality results in suppression of ADH and suppression of thirst

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• NB – kidneys can only concentrate urine up to 1400 mOsm.kg^-1

Hyperosmolar Hyperglycaemic State (HHS)

• In Diabetes Mellitus, the glucose conc. can increase so much that it contributes to the osmolality
• This gives a strong thirst drive
• Results in a dilutional hyponatraemia
• Can cause altered mental status, seizures and other neurological signs
• Occurs when blood glucose >33mM

RAAS system

• Acts to increase BP by increasing Na⁺ reabsorption
• Water follows and so increases circulating volume

Can be inhibited in 4 ways

• ACE inhibitors e.g. enalapril, ramipril
• AT₁ receptor antagonists e.g. candesartan
• Aldosterone receptor antagonists e.g. spironolactone
• Renin inhibition e.g. aliskiren (not widely used)

Haemorrhage

• There is decreased circulating volume, resulting in a lower BP
• Sensed by afferent arteriole, causing a fall in wall tension and activation of RAAS
• Also sympathetic innervation of the afferent arteriole
• Vasoconstriction upstream of granule cells causes a further fall in wall pressure
• Direct stimulation of renin release
• Afferent a. vasoconstriction drops glomerular hydrostatic pressure to lower GFR
• Fall in BP results in lower BP in vasa recta
• Increased fluid uptake, resulting in more fluid loss from filtrate
• As a result, decreased Na⁺ delivery to distal tubule, further stimulating renin release

Haemorrhage

• Haemorrhage also results in ADH release
• Decreased cardiac filling activates the baroreceptor reflex
• This, along with central actions of ATII, increases release of ADH
• More water is reabsorbed to maintain circulating volume
• Na⁺ isn’t retained
• Acute response to haemorrhage involves hyponatraemia

ANP

• Increased venous return and atrial filling causes ANP release
• Acts on ANP_A,B receptors, activating cGMP
• Dilates afferent a., increasing GFR
• Decreases Na⁺/Cl^- cotransport activity
• Decreases ENaC and Na⁺/K⁺ ATPase activity
• NB – urodilatin is a similar peptide produced in the kidney

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• Net effect is increase in Na⁺ excretion in urine

Other influences on Na⁺

• Prostaglandins PGE₂ and PGI₂ produced tonically and increase Na⁺ excretion
• If system inhibited then Na⁺ retention
• E.g. NSAIDs

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• Dopamine synthesised in kidneys
• Acts via D₁ receptors, increasing cAMP and decreasing Na⁺/H⁺ activity
• Leads to increased Na⁺ excretion

K⁺ regulation

• Vast majority in intracellular space
• 4mM in extracellular space
• Addition of K⁺ buffered by uptake into cells, although takes time to develop
• Changes in K⁺ doesn’t have effect on osmolality as clearance is very high

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Hyperkalaemia

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• Causes
• End-stage renal failure, crush injuries, blood transfusion, cytotoxic drugs, insulin deficiency, K⁺ sparing diuretics
• Results in cardiac dysrhythmias
• Treat the cause

Hypokalaemia

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• Causes
• Diarrhoea, furosemide, insulin overdose
• Results in cardiac dysrhythmias
• Treat cause

Acid-Base regulation

pH = -log₁₀[H⁺]

• H⁺ is a waste product
• Reacts with bicarbonate to produce CO₂
• This results in a loss of bicarbonate, so the kidney requires to have a pH regulatory role

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• There is a net reabsorption of bicarbonate
• Clinically, very high levels of bicarbonate aren’t seen due to its tubular maximum limit
• Limit depends on H⁺ in PCT

H⁺ secretion

• Primary active transport dominant mechanism for H⁺ secretion
• H⁺/K⁺ ATPase
• H⁺ ATPase
• This occurs in the α-intercalated cells in the distal tubule

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• H⁺ needs to be buffered in the filtrate
• Done through hydrogen phosphate
• H₂PO₄^- forms in urine

Ammonia secretion

• In PCT
• Glutamine → glutamic acid → α-ketoglutarate
• NH₄⁺ byproduct at each step
• NH₄⁺ can’t leave the cell but NH₃ can

• Respiratory acidosis
• Hypoventilation → CO₂ increase → H⁺ increase → HCO₃^- production

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• Respiratory alkalosis
• Hyperventilation → CO₂ decrease → H⁺ decrease → reduced HCO₃^- production

• Metabolic acidosis
• Caused by anything other than CO₂
• E.g. renal failure, lactic acidosis

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• Metabolic alkalosis
• Caused by anything other than CO₂
• E.g. vomiting

Synthesis

Erythropoietin (EPO)

• Produced by mesangial cells in renal cortex
• Production and release stimulated by
• Hypoxia
• Low iron levels
• B-adrenoreceptor and ATII

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• Binds to EPO receptor in bone marrow
• Increases proerythroblast production, increasing erythrocytes

Vitamin D metabolism

• Vitamin D obtained from diet/skin
• Liver converts this to 1,25-dihydroxycholecalciferol
• Kidney converts to 1,25-dihydrocholecalciferol or 1,25(OH)₂ vit D

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• Activated vit D
• Increases Ca and phosphate absorption from bowel
• Decreases Ca and phosphate excretion

Chronic Kidney Disease (CKD)

• eGFR used to monitor kidney function
• Decrease of function for 3+ months
• 5 stages

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• Think of CKD if:
• Diabetes
• Hypertension
• Multiple drugs, esp. NSAIDs
• Elderly

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Diabetic Nephropathy

• Associated with poor diabetic control and hypertension
• Pathology
• Thickening of BM
• Mesangial expansion
• Hyperglycaemia
• Stimulation of TGF-B release
• Glomerulosclerosis

CKD Consequences

• Failure of fluid homeostasis
• Hyperkalaemia
• Metabolic acidosis
• Bone disease and ectopic calcification
• Anaemia
• Accumulation of drugs

Dialysis and Transplant

Dialysis

• Indicated in CKD stage 5
• Doesn’t replace synthetic function of kidneys
• Filters fluid and solutes with a semipermeable membrane
• Fluid and solutes can be removed or added
• Only achieves GFR <15 mls.min^-1

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• Transplant replaces ALL function
• Risk of rejection
• Inserted in iliac fossa, connected to iliac vessels

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Peritoneal Dialysis

• Dialysis fluid put into abdominal cavity
• Peritoneum acts as semi-permeable e membrane
• Fluid contains dextrose/glucose to set an osmotic gradient
• Also some Na⁺ and K⁺
• Molecules move until no gradient left
• Fluid then removed and replaced

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• Lasts 8-10 yrs
• Needs permanent peritoneal catheter
• Risk of peritonitis
• Can be continuous or overnight

Haemodialysis

• 4 hrs 3x a week
• Usually done through arterio-venous fistula or central line
• Alkali buffer needs to be added

Acute Kidney Injury (AKI)

Shock

• Caused by problem with pump, blood or dissolved O₂
• Can lead to tissue ischaemia
• Brain, heart and kidneys most sensitive
• Measure lactate and urine output
• Urine output is a marker of tissue perfusion in kindey
• Increase in ADH and RAAS causes water retention

Ureters

• Run from hilum of kidney to bladder
• 3 areas of constriction:
• Ureteropelvic junction
• Ureteral crossing of iliac vessels
• Ureterovesical junction

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Urinary Bladder

• Temporary storage of urine, 400-600mls
• Assists in expulsion of urine
• Rectovesical pouch in males
• Rectouterine and vesciouterine pouches in female
• Trigone is a smooth area with no folds (rugae) – formed from opening of ureters and internal urethral orifice

Bladder Emptying

• Bladder wall formed from urothelium, lamina propria, detrusor smooth muscle, serosa
• High-resistance tight junctions between cells so no permeability
• Umbrella cells form another barrier
• Detrusor muscle cells run in an irregular ‘basket-weave’ pattern
• Innervated by autonomic nerves – paraNS – M3 muscarinic receptors
• SymNS acts on B3 adrenoceptors for relaxation

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• SymNS – hypogastric nerve (T12-L2)
• ParaNS – pelvic nerve (S2-S4)

Urethra

• Internal sphincter (in males ) – autonomic
• External sphincter – somatic NS – skeletal muscle

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• Falling off a bike compresses bulbous part of urethra against pubic symphysis
• Can bleed into superficial perineum
• Difficult urinating as urethra damaged
• If male damages hip and it separates, the prostate gets pulled up. Leads to a high-riding prostate with difficulty urinating