Tubular Disorders ✅ Flashcards
How much plasma does the adult kidney filter per day on average?
150L of plasma
How much sodium does the adult kidney filter per day on average?
22.5mmol
What % of filtered sodium is reabsorbed by the tubules?
99%
What do disorders in sodium handling affect?
BP
What effect does sodium-losing disorders have on BP?
Hypotension
What effect to sodium-retaining disorders have on BP?
Hypertension
What transporter is important in sodium homeostasis?
Na/K-ATPase
What cells is Na-K-ATPase present in?
All cells
What is the importance of Na/K-ATPase?
It is the driving force which generates a favourable eletrochemical gradient for Na entry into the cell
What does the sodium gradient allow?
Co-transport of other substances, such as glucose, amino acids, phosphate
What happens to fractional excretion of sodium in renal salt-wasting disorders?
It is almost always normal
Why is fractional excretion of sodium normal in almost all renal salt-wasting disorders?
Because sodium is the main determinant of intravascular volume, so in salt-wasting disorders there is activation of RAAS
What are the functions of the proximal tubule?
- Glucose transport
- Phosphate transport
- Amino acid transport
What renal tubular disorders affect the proximal tubule?
- Renal glycosuria
- Hypophosphataemic rickets
- Isolated, generalised aminoaciduria
What is generalised dysfunction of the proximal tubule called?
Fanconi syndrome
What is the function of the ascending limb of Henle?
Sodium, potassium, and chloride transport
What renal tubular disorder affects the ascending limb of Henle?
Bartter syndrome
What are the functions of the distal tubule?
- Proton (H+) secretion
- Sodium chloride transport
What renal tubular disorders affect the distal tubule?
Distal renal tubular acidosis
Gitelman syndrome
What are the functions of the collecting duct?
- Water transport
- Sodium and potassium transport
What renal tubular disorders affect the collecting duct?
- Nephrogenic diabetes insipdius
- Pseudohypoaldosteronism
- Liddle syndrome
What is Fanconi syndrome?
A generalised proximal tubular disorder
What happens to glomerular function in Fanconi syndrome?
It is at least initially well preserved
What can the causes of Fanconi syndrome be divided into?
- Congenital
- Acquired
- Renal
What are the cardinal clinical features of Fanconi syndrome?
- Growth faltering
- Polyuria
- Rickets
What is found biochemically in Fanconi syndrome?
- Normal plasma anion gap
- Metabolic acidosis
- Hypophosphataemia
- Hypokalaemia
- Generalised aminoaciduria
What is involved in supportive management of Fanconi syndrome?
- Salt, water, and nutritional supplementation
- Bicarbonate, electrolyte, and phosphate replacement
What are the congenital causes of Fanconi syndrome?
- Familial idiopathic form
- Cystinosis
- Tyrosinaemia
- Galactosaemia
What are the acquired causes of Fanconi syndrome?
- Medications
- Poisoning
- Renal transplantation
- Renal diseases
What medications can cause Fanconi syndrome?
- Aminoglycosides
- Sodium valproate
- 6-mercaptopurine
- Ifosfamide
What poisons can cause Fanconi syndrome?
- Toluene
- Paraquat
What renal diseases can cause Fanconi syndrome? -
- ATN
- Tubulointerstitial nephritis
- Focal and segmental glomeruloscerlosis
What phase of ATN might Fanconi syndrome occur in?
The recovery phase
What is the most common cause of Fanconi syndrome in Europe and North America?
Nephropathic cystinosis
What is nephropathic cystinosis?
A disorder of lysosomal cystine transport
What is the inheritance pattern of nephropathic cystinosis?
Autosomal recessive
What is the pathological process in nephropathic cystinosis?
Excessive intracellular accumulation of free cystine in many organs, including the kidney, eyes, and thyroids
How is nephropathic cystinosis managed?
Mercaptamine
How does mercaptamine treat nephropathic cystinosis?
It prevents accumulation of lysosomal cystine
What structure is involved in Bartter syndrome?
The thick ascending loop of Henle
What structure is involved in Gitelman syndrome?
The distal convulted tubule
What biochemical abnormalities are produced by Bartter and Gitelman syndromes?
- Hypokalaemia
- Hypochloraemia
- Metabolic alkalosis
- Salt wasting
What is the main problem in Bartter/Gitelman syndromes?
Tubular loss of sodium and chloride, and secondarily excess loss of potassium in the distal tubule associated with hyperreninaemia and hyperaldosteronism
What is sodium reabsorption linked to in the distal tubule?
Chloride reabsorption
What channel is disrupted in Bartter syndrome?
The sodium-potassium chloride channel (NKCC2)
Where is the NKCC2 channel located?
In the loop of Henle
What drug is the NKCC2 channel sensitive to?
Furosemide
What channel is disrupted in Gitelman syndrome?
The sodium-chloride channel (NCCT)
Where is the NCCT located?
In the early DCT
What drug is the NCCT channel sensitive to?
Thiazide
What are salt wasting disorders from the distal nephron always associated with?
Urinary chloride loss
Why are salt wasting disorders from the distal nephron always associated with urinary chloride loss in excess of urinary sodium loss?
- All chloride reabsorption is linked with sodium, with twice as much chloride as sodium reabsorbed via NKCC2 (so if these receptors are disrupted, it has a bigger impact on chloride reabsorption)
- Sodium reabsorption but not chloride reabsorption can occur partly via the paracellular route
- There is no capacity for chloride reabsorption more distally within the nephron
What biochemical abnormalities are specific to Bartter syndrome?
Hypercalciuria
Why does Bartter syndrome cause hypercalciuria?
Because calcium reabsorption is a linked paracellular process
Does hypomagnesaemia occur in Bartter syndrome?
No
Why does hypomagnesaemia not occur in Bartter syndrome?
Because of compensatory reabsorption in the early DCT
What biochemical abnormalities are specific to Gitelman syndrome?
- Hypocalciuria
- Hypomagnesaemia
Why do you get hypocalcuria and hypomagnesaemia in Gitelman syndrome?
Because of a compensatory mechanisms in the early DCT which down-regulates cells expressing NCCT and an apical magnesium channel in favour of cells which reabsorb sodium and calcium
When does Gitelman syndrome present?
Typically in older children or adults
How does Gitelman syndrome present?
- Muscle weakness and cramps
- Short stature
What might Gitelman syndrome be diagnosed following the investigation of?
- Constipation
- Growth problems
- Enuresis
When does Bartter syndrome present?
Early childhood
How does Bartter syndrome present?
- Growth faltering
- Dehydration
- Hypotonia
- Lethargy
What is often present in the history in Bartter syndrome?
Maternal polyhydraminos
Is Gitelman or Bartter syndrome more severe?
Bartter
How does the kidney achieve acid-base balance?
- Bicarbonate reabsorption
- Acid secretion
Where does most bicarbonate reabsorption occur in the kidneys?
Proximal tubules
What % of filtered bicarbonate is reabsorbed in the proximal tubules?
Up to 90%
Which part of the nephron is principally responsible for acid secretion?
The distal collecting tubules
What is the minimal achievable urine pH?
4.5 to 5
What allows the excretion of the daily acid load within the limits of the minimal achievable urine pH?
Buffers in the tubular lumen bind free hydrogen ions
What are the main urinary buffers of hydrogen ions?
- Ammonia
- Phosphate
How is ammonia formed?
Amino acid metabolism
How does ammonia enter the tubular lumen?
It freely diffuses across tubular membranes
What is formed when ammonia combines with free hydrogen ions in the tubular lumen?
Ammonium (NH4+)
Can ammonium be reabsorbed?
No, it is trapped within the tubular lumen
What are the ways in which renal tubular acidosis can occur?
- Bicarbonate wasting in the proximal tubule
- Impairment in formation of ammonia
- Failure to adequately secrete hydrogen ions
What was RTA caused by bicarbonate wasting in the proximal tubule historically known as?
Type 2 RTA
What does RTA due to bicarbonate wasting in the proximal tubule almost always occur as part of?
Fanconi syndrome
What is RTA caused by an impairment in the formation of ammonia known as?
Type 4 RTA
What does type 4 RTA lead to?
Renal failure
What is the acidosis in type 4 RTA associated with?
Hyperkalaemia
What is RTA caused by a failure to adequately secrete hydrogen ions associated with?
Hypokalaemia
Are most cases of childhood distal RTA genetic or acquired?
Genetic
What might autosomal recessive forms of childhood distal RTA be associated with?
Sensorineural deafness
What gene is involved in autosomal recessive childhood distal RTA associated with sensorineural deafness?
ATP6V1B1
What gene is involved in autosomal recessive childhood distal RTA not associated with sensorineural deafness?
ATP6V0A4
What do mutated genes causing autosomal recessive childhood distal RTA code for?
Subunits of the H-ATPase apical hydrogen ion transporter
What gene is involved in autosomal dominant childhood distal RTA?
SLC4A1
What does the gene involved in autosomal dominant childhood distal RTA code for?
The chloride-bicarbonate exchanger on the basolateral membrane
How does the urine pH in distal RTA compare to proximal RTA?
In distal RTA it is always >5.5, whereas in proximal RTA it varies
What does the urine pH vary according to in proximal RTA?
Plasma bicarbonate
What should initial correction of acidosis take into account in distal RTA?
Potassium and calcium
Why do potassium and calcium need to be taken into account in the initial correction of acidosis in distal RTA?
Because they will both decrease in response to alkali treatment
What does maintenance treatment consist of in distal RTA?
Sodium bicarbonate or citrate (sodium and/or potassium)
How does the doses of base required in distal RTA compare to that in proximal RTA?
They are generally less than for proximal RTA
What is required long-term in distal RTA?
Lifelong follow up
Why is lifelong follow up required in distal RTA?
They are at risk of nephrolithiasis and long-term deterioration in renal function from the nephrocalcinosis
