Case 7- Chronic kidney disease Flashcards
What are the 4 main functions of the kidney?
- Maintenance of extracellular fluid volume, primarily through regulating Na+ (water follows)
- Excretion of metabolic waste: inc urea and creatinine
- Acid-base balance
- endocrine; hormone secretoin
What is the endocrine function of the kidney?
- RAAS: renin produced by the kidney, involved in production of Ang II and regulates BP
- Erythropoietin: RBC production and regulation
- Vitamin D: calcium regulation
What 2 processes does the process of concentrating urine rely on?
- Counter current multiplier: in the Loop of Henle
- Counter current exchanger: vasa recta
How do the ascending and descending limb vary in their permeability?
Descending= impermeable to NaCl = only H2O reabsorbed
Ascending= impermeable to water, only NaCl reabsorbed
What is the max gradient possible between tubular fluid and surrounding interstitial fluid?
200 mOsm/Kg
Compare the osmolalities of very dilute urine and the max concentrated urine
Very dilute= 100
Max concentration= 1200
How does the osmolality of tubular fluid change throughout the nephron?
End of PCT= isotonic
bottom of Loop of Henle= hypertonic
Before DCT= hypotonic
(then altered to suit hydration needs)
What does reabsorption throughout the PCT rely on?
Electrochemical gradient from Na+/K+ ATPase.
What does the PCT reabsorb?
- Na+ via SGLT2 (some by SGLT1) and then K+/Na+ ATPase
- Glucose via SGLT2 (some by SGLT1) and then GLUT2
- HCO3-
- Citrate
- Amino acids
- K+ (paracellular route)
- H2O (paracellular route)
What is responsible for Na+ absorption in the PCT?
NHE-3 = Na+/H+ exchanger on the apical membrane
What does the PCT excrete?
Bile salts
What is reabsorbed in the thin ascending limb and how?
Na+ = passively via ENaC
Cl- = passively by Cl- channels
What is reabsorbed/ excreted in the thick ascending limb and how?
Active process; Na+/K+ ATPase sets gradient:
- NKCC2 on apical side, reabsorbs Na+, K+ and 2Cl-
K+ is excreted (recycled) by ROMK2 (passive), as it has built up from NKCC2
What is reabsorbed in the early DCT?
Na+, Cl- and Ca2+ (impermeable to water):
- NCC: reabsorbs Na+ with Cl- (apical)
- TRPV5 reabsorbs Ca2+ (apical)
- NCX1: Na+/ Ca2+ exchanger reabsorbs Ca2+ for Na+ (basolateral)
- PMCA1b (Ca2+ ATPase pump) on basolateral side
- Na+ reabsorbed via Na/K+ ATPase
What are the 2 types of cells present in the late DCT and early CD? Give their net effect / function
Principal cells (bulk): uptake of Na+ into blood and extrude K+ in urine via ROMK1/3
Intercalated cells: involved in acid base balance:
- Type A = use H+ ATPase and H+/K+ ATPase to secrete H+ into urine
- Type B= secrete HCO3- and reabsorb H+
What are the effects of aldosterone on resorption in the collecting duct?
Increases ENaC = more resorption of Na+ (so water can follow)
Stimulates ROMK1/3 opening
Reverses the basolateral K+ channel, so K+ can be excreted (resorbed into cell, then leaves apical side via ROMK1/3)
What transporter in the CD is stimulated with a high plasma K+?
Cl-/ K+ co-transporter (in principal cell)
Why doesn’t aldosterone itself cause water retention?
If ADH isnt present, then we cannot absorb water as there are no AQP2’s present. Aldosterone only causes water retention indirectly by creating an osmotic gradient
What do the intercalated cells in the collecting duct help protect against? How do they do so?
Help protect against hypokalaemia and acidosis:
- If low plasma K+ is detected then H+/K+ ATPases are activated to reabsorb K+
- if acidosis is detected, then H+ ATPases are activated to excrete H+
Describe the permeability of the late DCT and CD to water, how can it vary?
Impermeable to water in the absence of ADH. When ADH is present, it binds to V2 receptors = insertion of AQP2 on apical membrane. Water can leave urine and enter the cell, then leave via AQP3/4 basolaterally (always there)
What AQP channels are present in the thick descending limb?
AQP1
How is K+ distributed in the body? Give the concentrations
- Most in cells (intracellular)= 98%, concentration 150-160mmol/L
- Remaining in ECF= 2%, at 4-5 mmol/L
How does hypo/hyperkalaemia affect depolarisation?
Hypokalaemia= hyperdepolarisatoin
Hyperkalaemia= depolarisation
Where is most of K+ reabsorbed?
PCT, then Loop of Henle (remaining amount is variable in CD/ late DCT)
What non-modifable factor determines concentration of urine?
Length of loop of Henle; if longer = more concentrated urine
What is the counter current exchanger?
Vasa recta surrounding the nephron has blood moving in the opposite direction to tubular fluid. As blood comes out the glomerulus, it is around 300. Then Na+ is taken up from tubular fluid. As it descends, blood osmolality is increased to 1200 (same as urine). As it ascends, it reabsorbs water.
(opposite to the tubular fluid mechanism)
How does diabetes cause polydipsia?
- high glucose, exceeds Tm (transport maximum), so glucose remains in the tubular fluid.
- glucose is osmotically active, so can attract water
- Glucose is in the tubular fluid and osmolality is high (1200), so encourages water to remain in the tubular fluid
- Osmotic diuresis and dehydration
- Detected by the hypothalamus = release of Ang II = thirst centre to drink more
Following head trauma, a patient develops central diabetes inspidus which is associated with a reduction in vasopressin secretion. The osmolality of a spot urine sample is expected to be…?
100, as this is what urine concentration is at DCT (before affected by ADH)
What is the distribution of Mg2+ and Ca2+ in the body?
99% of Ca2+ in bone, 1% in ECF
50% of Mg2+ in bone, 50% in ECF
How are Ca2+ and Mg2+ affected by osteoblasts/ osteoclasts?
Both Ca2+ and Mg2+ can be moved into the bone (from ECF) by osteoblasts
They can be moved out of bone into ECF via osteoclasts
How does Ca2+ affect depolarisation threshold?
Hypercalcaemia = raises depolarisation threshold
Hypocalcaemia = lowers depolarisation threshold
How does Mg2+ affect heart rate?
Hypermagnesaemia = lowers HR
Hypomagnesaemia = raises HR
How is Mg2+ and Ca2+ reabsorbed by the kidney?
Predominantly PCT and Loop of Henle (around 90% of both) via paraellular routes, then more selective reabsorption in DCT (remaining)
How is Ca2+ reabsorbed by the DCT?
- Enters via TRPV5, then bound to calbindin-D28K
- Transported to basolateral side and can exit by NCX1 (exchanged with Na+) or by PMCA1b (ATPase; pumped against concentration gradient)
What stimulates resorption of Ca2+?
TRPV5 is opened by:
- Parathyroid hormone, vitamin D and sex hormones (bind to receptors on basolateral side)
- Klotho from tubular fluid, can bind to it directly
How is Mg2+ reabsorbed by the kidney?
TRPM6 on apical side (so takes up Mg2+ from the urine into the cell). It is driven by an electrochemical gradient
What can stimulate Mg2+ absorption?
Epidermal growth factor
What is the average renal blood flow?
1L/min (around 20% of Q)
What achieves the filtration barrier of the kidneys?
- Podocytes on the epithelium: have foot processes (pedicles), stops larger molecules leaving the blood into tubular fluid.
- Endothelium: fenestrated
- Cells of the basement membrane have a negative charge; repels negatively charged ions
What type of blood vessels line the glomerulus?
Fenestrated capillaries
How does the PCT balance pH?
NHE-3 brings in a Na+ for H+ (goes into blood)
To balance the Na+, this transporter is linked to a Cl- transporter (Cl- is exchange with anion, i.e. HCO3-) so Cl- also enters
What transporter in the PCT is responsible for the regulation of cell volume?
NHE-1, on basolateral side = pumps Na+ into cell and H+ into blood.
If cell is shrinking, it takes up Na+ so water can follow
What is the transport maximum (Tm) of glucose in the kidneys? At what glucose level is this exceeded?
1.25 mmol/min
Exceeded when plasma glucose >10 mmol/L
A diabetic patient with a low GFR and high plasma glucose has a filtered glucose rate of 0.48 mmol/L. Why might their dipstick urinalysis be positive for glucose if this doesnt exceed Tm?
- Have lost functioning nephrons, so the GFR isnt reflective of the single nephron GFR (likely to be higher)
- Low global GFR = build up of uraemic toxins (from urea - as not excreting it) = damage remaining nephrons. Splay increases
What is ‘splay’ and what is it caused by?
Splay is the concentration difference between a substance’s maximum renal reabsorption (i.e. Tm of glucose) vs. appearance (i.e. presence of glucose) in the urine
This is due to variation in the functioning of individual nephrons
How much glucose is produced by the kidney (as a % of body’s production)? Where is it produced?
20% glucose is produced by gluconeogenesis in the cortex, i.e. from lactate, pyruvate, oxaloacetate
How is the kidney’s production of glucose affected by diabetes?
300% increase in gluconeogenesis in the kidneys.
What factors do equations used to estimate GFR based on serum creatinine concentration take into account?
Age, sex, ethnicity
What is GFR? Give the average value
125ml/min; the volume of plasma filtered by the glomerulus per minute
Give the average total volume of plasma filtered at the glomerulus per day
125ml/min x 60 x 24 = 180L/d
What does the 3 layers of the glomerular basement membrane possess to aid filtration?
Has a middle layer with type IV collagen and laminins, then the outer layers both have heparin sulfate (glycan) which has a negative charge. This helps repel plasma proteins, i.e. albumin, as they have a negative charge.
What is the role of Mesangial cells?
- Phagocytose macromolecles that pass through
- Have contractile ability to control blood flow through the glomerulus
- Stimulate juxtaglomerular cells to secrete renin
How does the Bowman’s capsule structure control filtration?
Has podocytes; filtration slits between these allow substances of under 25-30nm to pass
After this is nephrin proteins, which have to be <7-9nm to pass
What are the 3 main contributing factors to GFR?
- Net filtration pressures
- Surface area
- Permeability of glomerulus
What are the 3 contributors to net filtration pressure?
- Glomerular hydrostatic pressure: i.e. pressure of blood that favours filtration (main force)
- Glomerular oncotic pressure: pressure of proteins which opposes filtration
- Bowman’s capsule hydrostatic pressure: opposes filtration
What are the normal values for pressures that contribute to overall net filtration pressure? (give the average NFP)
Glomerular hydrostatic= 55mHg
glomerular oncotic pressure= 30mmHg
Capsular hydrostatic= 15mmHg
NFP= 55 - (30+15) = 10mmHg
What alters glomerular hydrostatic pressure?
Blood pressure: high BP = higher hydrostatic pressure
What could alter glomerular hydrostatic pressure?
More proteins present in the blood, i.e. multiple myeloma
What could alter capsular hydrostatic pressure?
Kidney calculi
What is the filtration coefficient?
Product of the glomerular membrane’s permeability to water and the surface area of the membrane
How do you calculate renal clearance by the kidneys?
UV / P
U= Urinary concentration of X
V= urine volume per unit time
P= plasma concentration of X
What is autoregulation? How does it work?
Maintains renal blood flow and GFR despite changes in systemic pressure. If renal artery pressure increases, there is a corresponding increase in resistance to flow by the AFFerent arteriole (it constricts), but efferent remains the same.
This means glomerular capillary pressure stays constant = renal BF and GFR are maintained
What are the 2 mechanisms responsible for autoregulation?
Myogenic: vascular SM cell responds to stretch by vasoconstricting (reflex), thus if resistance increases, pressure is maintained
Tubuloglomerular feedback: DCT monitors what is going through it and regulates vasoconstriction/dilation as necessary
Where is the macula densa found?
DCT
How does the kidney respond to an increase in arterial pressure?
- Increases glomerular pressure and renal plasma flow = raised GFR
- Increased plasma colloid osmotic pressure (as proteins are dissolved in less fluid) attempts to decrease GFR (minor effect)
- more fluid enters PCT, which increases reabsorption in the PCT and LOH to counteract this (glomerulotubular feedback)
- Macula densa in DCT detects high flow rate, releases a transmitter (thought to be adenosine)
- Afferent arteriole constricts (adenosine binds to AT1 receptor)
- Pre-glomerular resistance increases
= GFR is lowered
How does the kidney respond to a lowered arterial pressure?
Same detection mechanisms (but opposite), however prostaglandin E2 is released instead. This causes efferent arteriole to constrict = raise glomerular pressure and GFR
What factors would make an ideal marker for GFR?
- Must be freely filtered (i.e not affected by size or charge barrier)
- Not reabsorbed in the PCT
- Not secreted in the DCT
- Excreted in the urine
What can be used as a marker for GFR? Give their disadvantages
- Creatinine = affected by diet, gender, age, ethnicity
- Insulin= not endogenous, needs to be infused into blood
- Cystatin C= currently in trials, also affected by age, gender and ethnicity
What comprises the juxtaglomerular apparatus?
- Macula densa
- JG cells (modified SM)
- Mesangial cells
What is ACR used to measure?
glomerular damage, as it helps decide if a patient is in a state of proteinuria
How is pH calculated? What is it normally in arterial blood?
pH = -log10 [H+]
Normally 7.4
What is the Henderson-Hasselbauch equation?
pH = pK + log10 [HCO3-]/[CO2]
Works out pH using concentration of HCO3- and Co2
What is pK?
Constant at 6.1
Compare respiratory/ metabolic acidosis/ alkalosis
Respiratory acidosis: increased CO2, if lungs cant compensate the kidneys excrete acid
Respiratory alkalosis: low CO2, i.e. hyperventilation or altitude
Metabolic acidosis: low HCO3-
Metabolic alkalosis: high HCO3-
What values of CO2 (mmHg) and HCO3- (mM) would maintain pH at 7.4?
CO2= 40mmHg
HCO3-= 24mM
What are the 3 mechanisms for buffering H+?
- Resorption of filtered HCO3-
- Excretion of H+ as titratable acid (TA)
- Excretion of H+ as NH4 (ammonium)
How is HCO3- reabsorbed into the blood?
- H+ secreted across the apical membrane reacts with HCO3- to form CO2 and H2O via carbonic anhydrase IV
- CO2 diffuses into cell, reacts with H2O to form HCO3- and H+ via CA II
- HCO3- can leave via basolateral membrane into blood
How is H+ excreted as ‘titratable acid’?
- In the blood H+ reacts with to HCO3- to form H2O and CO2
- CO2 enters and reacts via CA II to form H+ and HCO3-
- HCO3- leaves basolaterally to neutralise blood, H+ goes into urine
- H+ binds to HPO4- to form H2PO4-
How is H+ excreted as NH4-?
Glutamine metabolism releases OH- and NH4-. The OH- reacts with CO2 to form HCO3-, released into blood
NH4- dissociates into NH3 and H+, can freely diffuse into tubular fluid
Recombines= excreted as acid
Where are the carbonic anhydrases relevant to the kidney found?
CA II = soluble so in cytoplasm
CA IV = bound to membrane (extracellualr)
Where is HCO3- reabsorbed throughout the kidney?
Most in the PCT (80%)
Small amounts in thick ascending limb (10%), DCT (6%) and CD (4%)
How much ammonium and titratable acid needs to be secreted each day? Where is this mainly?
Ammonium: 40 mmol, mainly PCT
TA: 30mmol, mainly PCT, some CD and then small in DCT
What are the 4 types of renal tubule acidosis?
Type 1: distal RTA
Type 2: proximal RTA
Type 3: mix of type 1 and 2
Type 4: hyperkalaemia
Which type of renal tubule acidosis occurs with hypoaldosteronism?
Type 4- hyperkalaemia
The NHE3 and H+ ATPase transporters are unable to work past what pH?
NHE3= pH 6
H+ ATPase= pH 4-5
Other than NHE3 and H+ ATPase, what transporter is present in the TAL and DCT for acid base balance?
AE2: basolateral HCO3- and Cl- exchanger, i.e. reabsorbs HCO3- into blood
Type A (alpha) intercalated cells in the DCT and CD have 2 isoforms of specific transporters, name them
kAE1 (same as AE2): basolateral HCO3- exchanger with Cl-
V-type H+/K+ ATPase: allows reabsorption of K+ too
What channels reabsorb NH4+ in the TAL?
NKCC1: ammonium can take place of K+, i.e. Na+, 2Cl- and NH4- is taken up into cell (apical)
ROMK2: apical reabsorption
Can also use Na+/K+ ATPase
what is the kNBCe1 transporter responsible for?
HCO3- efflux over basolateral membrane: 3 HCO3- transported with Na+ (has electrogenic potential)
What happens in type 1 renal tubular acidosis? Can it be treated?
Defective H+ secretion in the distal nephron, leads to metabolic acidosis. Can be autosomal dominant or recessive, and is due to multiple mutations: kAE1, V-type H+ ATPase, CAII. Treatable with HCO3-
What happens in type 2 renal tubular acidosis? Can it be treated?
Autosomal recessive condition where HCO3- reabsorption is impaired (proximal nephron), leads to metabolic acidosis. Associated with mutated kNBCe1 (i.e. 3 HCO3- with Na+)
If respiratory or metabolic acidosis is chronic, what changes can it lead to? Why?
Increased expression of NHE3 in PCT: in attempt to excrete H+ (exchanges it with Na+)
Increased expression of kNBCe1 in PCT, in attempt to reabsorb more HCO3-
If respiratory or metabolic alkalosis is chronic, what changes can it lead to? Why?
More type B (beta) intercalated cells in the collecting tubule, as these secrete HCO3- into urine
What is the typical first sign of diabetic kidney disease?
Persistant leakage of protein
How is the filtration barrier affected by diabetic kidney disease?
- Thickening of basement membrane
- Flattening of podocytes (foot processes)
- Mesengial cell proliferation and expansion of matrix, leads to sclerosis (nodular -> advanced)
What is nephrotic syndrome characterised by?
This is a clinical presentation (not a disease itself):
- Massive proteinuria
- Low protein in the blood (including albumin), which leads to…
- Oedema
What is a normal protein:creatinine ratio (PCR)? What values might be seen in nephrotic syndrome?
<20 mg/mmol
Nephrotic syndrome: >200mg/mmol
Why is PCR used for proteinuria assessment, not just the total level of protein?
Normalise/ correct it for concentration of the urine, i.e. excrete creatinine a lot
PCR is often used for children to assess proteinuria, what test might be used for adults or in diabetes monitoring? Give normal & nephrotic values
Albumin: creatinine ratio (ACR):
- >3mg/mmol normal
- >30 mg/mmol nephrotic syndrome
What % of diabetics develop diabetic nephropathy?
40%
Which ethnicity has increased risk for diabetic nephropathy?
Indian
What are the stages of injury following diabetes leading to DKD?
1: Hyperfiltration- i.e. from hyperglycaemia
2: Microalbuminuria
3: Macroalbuminuria
4: Proteinuria: unselective loss of protein
5: Declining renal function
How could you treat diabetic nephropathy?
-Glycaemic control
- RAAS blockade
- Lipid lowering
- Diuretics
- SGLT2 inhibitors= T2D
What drugs may be used to inhibit RAAS for diabetic nephropathy? Give examples
ACE-inhibitors= ramipril etc.
Angiotensin II receptor blockers= end in ‘sartan’ i.e. candesartan
What type diuretics may be used in diabetic kidney disease? Give their MOA and an example
Loop diuretics: inhibit NKCC2 in thick ascending limb to increase excretion of NaCl = more water excreted. Example= furosemide
Thiazide diuretics: inhibit NCC in DCT, so more water excreted. Risk. of hypercalcaemia. Example= indapamide
K+ sparing diuretics: in distal DCT, block ENaC to reduce Na+ reabsorption. Example= amiloride
Aldosterone receptor antagonist: blocks Na+/K+ ATPase and ENaC by reducing aldosterone action. Example= spironolactone
What do SGLT2 inhibitors drug names end in?
Flozin
Why aren’t SGLT2 inhibitors approved for T1D with diabetic kidney disease?
Risk of diabetic ketoacidosis
What are some options for renal replacement therapy?
Peritoneal dialysis: tube into abdomen, linked to hypertonic fluid to allow fluid to enter abdomen, then leaves with waste products
Haemodialysis: access circulation, blood gets cleaned
Surgery
What are some advantages of peritoneal dialysis?
- gentle; no anti-coagulation
- Less likely to cause hypotension or fluid shifts
- Cheap
- Immediate use
- Continuous use
What are some advantages/ disadvantages of haemodialysis?
- increased solute clearance (efficient)
- intermittent; not tolerant when haemodynamically active
- Need anti coagulation
- Requires specialist care
- 4 hour session 3x a week
What glucose transporters are present in the early vs late PCT and why?
Early PCT: SGLT2 and GLUT2, as these have low affinity and high capacity as there is lots of glucose to reabsorb
Late PCT: SGLT1 and GLUT1, as these have high affinity and low capacity, as there is not much glucose to reabsorb
What is the effect of calcitonin on Ca2+ reabsorption?
Calcitonin lowers Ca²⁺ reabsorption to try and reduce blood levels of Ca²⁺
i.e. calciTONIN, “tones in” (i.e. lowers) the blood Ca²⁺
What is the first line of treatment for hypertension?
If patient >55 or of african or afro-carribean origin: Calcium-channel blocker, i.e. amplodipine
If patient is <55 or has type II diabetes (or not of African origin): ARB or ACE-i
What are the targets of advanced glycation end-products?
Can lead to glycation of basement membrane (endothelial cells), especially in the efferent arteriole = hyaline arteriosclerosis, increased obstruction to blood flow= high GFR = hyperfiltration
Name what Na+ transporters are present in each part of the nephron
PCT — Na/AA, SGLT, NHE
Loop of Henlé — NKCC2
Early DCT — NCC
Late DCT — ENaC and Na⁺/K⁺-ATPase
Where is ADH synthesised/ released from?
Synthesised in hypothalamus, released from posterior pituitary
What channel do the macular densa cells possess? Why?
NKCC2: Allows the macula densa cells to sense the NaCl concentration in the tubular fluid. When the GFR increases = higher flow rate of fluid = higher delivery of NaCl to the macula densa
What are the 5 stages of Tervaet classification for diabetic nephropathy? Give what clinical sign may be present
Stage I: thickening of GBM
Stage IIA: mild mesengial expansion (i.e. microalbuminuria, ACR >3mg/mmol)
Stage IIB: severe mesengial expansion (i.e. macroalbuminuria, ACR>30mg/mmol)
Stage III: Nodular sclerosis: PCR >200mg/mmol
Stage IV: Advanced diabetic nephropathy = declined renal function
What is nephritis syndrome? What is it characterised by?
Reduction in kidney function:
- Haematuria
- Proteinuria, but less than nephrotic syndrome
What are some physiological effects of acute kidney injuries?
- Water and salt overload = oedema and HTN
- Excessive retention of K+
- Metabolic acidosis (unable to secrete H+)
How are organ transplants matched?
HLA type A, B and C on chromosome 6. Don’t have to fully match, but the less they match the more likely it is to fail. May require lifelong immunosuppression
For each of the following conditions, state what may be found in the urine:
- Glomerular disease
- Renal tubular disease
- Tubular dysfunction
Glomerular disease= RBC and protein
Renal tubular disease= high H+ ions
Tubular dysfunction= amino acids and glucose
What is the most common cause for chronic renal failure?
Diabetes: accounts for 30-40% of those needing dialysis
(second most common= hypertension)
