Renal Tubular Acidosis

2. RENAL TUBULOPATHIES

3. General notes
• There are on average 600,000 nephrons per kidney.
• By 36 weeks gestational age nephrogenesis is
complete, but glomerular filtration rate (GFR) is < 5% of
the adult value.
• The plasma bicarbonate concentration at which filtered
bicarbonate appears in the urine (bicarbonate
threshold) is low in the newborn (19-21 mmol/L),
increasing to mature values of 24-26 mmol/L by 4
years. Hence plasma bicarbonate values are lower in
infants
• Calculated Osmolality = 2XNa +Urea + Glucose

4. • Normal mature GFR values are 80-120
ml/min/1.73 m2, and are reached during the
second year of life
• 1.73 m2 is the surface area of an average
adult male.
• It is estimated from a calculated value using
the Schwartz formula:

5. Renal tubular physiology

6. Renal tubular physiology
• The renal tubules play a fundamental role in:
• • Maintaining extracellular fluid volume
• • Maintaining electrolyte and acid-base
homeostasis
• These processes are energy demanding and
render tubular cells most vulnerable to
ischaemic damage and acute tubular necrosis.
Renal tubular physiology

7. • The proximal tubule and Loop of Henle are
the sites of major reabsorption of most of the
glomerular filtrate.
• The distal tubule and collecting duct are
where 'fine tuning' of the final composition of
the urine occurs.
Renal tubular physiology

8. Proximal tubule
• The primary active transport system is the
Na+ -K+ -ATPase enzyme, reabsorbing 50% of
filtered Na+.
• Secondary transport involves coupling to the
Na+ -H+ anti porter, which accounts for 90%
of bicarbonate reabsorption with some Cl-.
Renal tubular physiology

9. • In addition:
• Glucose is completely reabsorbed
• Amino acids are completely reabsorbed
• Phosphate is 80-90% reabsorbed under the influence
of parathyroid hormone (PTH),
• Calcium is 95% reabsorbed - 60% in proximal tubule;
20% in Loop of Henle; 1 0% in distal tubule; 5% in
collecting duct
• A variety of organic solutes including creatinine and
urate, and some drugs, including trimethoprim and
most diuretics, are secreted in the proximal tubule
Renal tubular physiology

10. RENAL TUBULOPATHIES
• Proximal tubulopathies:
• Cystinuria.
• X-linked hypophosphataemic rickets.
• Proximal (type 2) RTA.
• Fanconi syndrome.
• Cystinosis.

11. Cystinuria
• Defect in reabsorption of, and excessive excretion of amino
acids cystine, ornithine, arginine and lysine (CAOL)
• Not to be confused with cystinosis
• Autosomal recessive.
• Cystine is poorly soluble in normal urine pH; has increased
solubility in alkaline urine
• Clinical manifestation is recurrent urinary stone formation
• Stones are extremely hard and densely radio-opaque
• Diagnosis based on stone analysis, or high cystine level in
timed urine collection
• Treatment based on high fluid intake and alkalinization of
urine with oral potassium citrate.

12. X-linked hypophosp hataemic rickets
vitamin-D-resistant rickets
• Mutation on X chromosome
• Isolated defect in PO4 reabsorption leading to:
• lnappropropriately low tubular reabsorption of PO4 - typically < 85% -
with a normal PTH and calcitriol level
• Hypophosphataemia (Plasma PO4 may be normal until 6-9 months of age)
• Earliest sign is ↑ alkaline phosphatase (by 3-4 months)
• have delayed growth, hypophosphataemia, ↑ alkaline phosphatase, and
radiological signs of rickets
• Other features include delayed dentition and recurrent dental abscesses
• Treatment is based on calcitriol or alfacalcidol, and phosphate
supplements
• Recent evidence suggests that addition of growth hormone treatment
may improve growth and biochemical disturbance

13. Proximal (type 2) RTA
• Failure to reabsorb filtered HC03-
• Renal bicarbonate threshold is low, i.e. HC03- is present in the urine
at levels of plasma HC03- lower than normal
• Distal tubular H+ excretion is intact so acid urine can be produced
• Normal acidification of urine in response to ammonium chloride
load .
• Ability to excrete acid from distal tubule, and the fact that calcium
salts are more soluble in acid urine, is the likely reason that
nephrocalcinosis is not a feature of proximal RTA .
• May occur as an isolated defect or as part of Fanconi syndrome.
• Symptoms include faltering growth, vomiting, short stature
• Treatment requires large doses of alkali (5-15 mmol/kg/day)

14. Fanconi syndrome
• Diffuse proximal tubular dysfunction, leading to excess
urinary loss of:
• Glucose - glycosuria with normal blood glucose
• Phosphate - hypophosphataemia, rickets
• Amino acids - no obvious clinical consequence
• HC03-- leading to proximal RTA
• K+ - causing hypokalaemia
• Na+, CI- and water - leading to polyuria and polydipsia,
chronic ECF volume depletion, faltering growth
• Tubular proteinuria - loss of low molecular weight
proteins including retinol binding protein.

15. Fanconi syndrome
• Usual clinical features include :
• polyuria and polydipsia, chronic ECF volume depletion,
• faltering growth, constipation and rickets; with features of any
underlying condition in addition.
• Main causes of Fanconi syndrome:
1- Metabolic disorders
• Cystinosis
• Tyrosinaemia
• Lowe syndrome (oculo-cerebro-renal syndrome)
• Galactosaemia
• Wilson's disease
2- Heavy metal poisoning: lead and mercury
3- Idiopathic.

16. Cystinosis
• Autosomai recessive defect in the transport of cystine out of
lysosomes.
• Gene is localized to chromosome 17p and encodes an integral
membrane protein, cystinosin.
• Predominant early clinical features are of:
• Fanconi's syndrome
• Photophobia as the result of eye involvement with corneal cystine
crystals
• Hypothyroidism
• Late features include:
• Renal failure around 8-1 0 years of age, if untreated
• Pancreatic involvement with diabetes mellitus
• Liver involvement with hepatomegaly
• Gonadal involvement with reduced fertility
• Neurological deterioration and cerebral atrophy

17. Cystinosis
• Diagnosis is based on:
• Cystine crystals in cornea seen by slit lamp
• Peripheral blood white cell cystine level
• Antenatal diagnosis available for families with positive history
• Treatment is:
• Supportive - PO4, NaCI, K+, and NaHC03 supplements, and high
fluid intake;
• alfacalcidol; thyroxine
• Specific - cystearnine, which increases cystine transport out of the
lysosome;
• commencing treatment in early infancy appears to delay onset of
renal failure
• Other - indomethacin reduces the CFR, and hence the severe
polyuria and secondary polydipsia, and electrolyte wasting.

18. Loop of Henle
• A further 40% of filtered Na+ is reabsorbed via
the Na+ -K+ -2CI- cotransporter in the thick
ascending limb of the LoH
• The medullary concentration gradient is
generated here because this segment is
impermeable to water
• Loop diuretics block Cl- binding sites on the
cotransporter
• There is an inborn defect in Cl- reabsorption at
this same site in Bartter syndrome.
Renal tubular physiology

19. Loop of Henle
• Tubulopathy:
• Bartter syndrome.

20. Bartter syndrome
• This is caused by an inborn autosomal recessive defect, in
the Na+-K+-2CI- cotransporter in the thick ascending limb
of the loop of Henle, leading to NaCl and water wasting.
• Symptoms are polyuria, polydipsia, episodes of
dehydration, faltering growth and constipation;
• there may be maternal polyhydramnios with an affected
fetus
• The resultant ECF volume contraction causes secondary
renin secretion and raised aldosterone levels, with avid Na+
and water reabsorption in the distal tubule,
• and reciprocal K+ and H+ secretion into the urine. (Note
that the blood pressure is normal;
• the hyperreninaemia is a compensatory response to
maintain normal blood pressure in the presence of chronic
ECF volume depletion).
• There is also increased renal prostaglandin E2 production

21. Bartter syndrome
• The above changes produce the characteristic
biochemical disturbance of hypochloraemic
hypokalaemic metabolic alkalosis
• Crucial to the diagnosis is the finding of
inappropriately high levels of urinary CI- and Na+
- usually > 20 mmol/l; urine ca2+ is normal or
high (cf Gitelman syndrome )
• Therapy involves K+ supplementation combined
with prostaglandin synthetase inhibitors, usually
indomethacin.

22. Pseudo-Bartter syndrome
• The same plasma biochemistry - hypochloraemic hypokalaemic
alkalosis - but
• appropriately low levels of urine CI- and Na+ - < 10 mmol/L
• Main causes are:
• Cystic fibrosis - sweat loss of NaCl and water
• Congenital chloride diarrhoea - gastrointestinal loss
• Laxative abuse - gastrointestinal loss
• Cyclical vomiting
• NOTE:
• All the changes of Bartter syndrome, including the high urine
electrolyte levels, may be produced by loop diuretics, which block
the same site in the thick ascending limb of the loop of Henle.

23. Distal tubule
• A further 5% of filtered Na+ is reabsorbed here, via a
Na+ -CI- co-transporter
• H+ secreted into urine by H+ -ATPase
• Aldosterone-sensitive channels (also present in the
collecting duct) are involved in regulating K+ secretion.
• K+ secretion is proportional to:
1- Distal tubular urine flow rate .
2- Distal tubular Na+ delivery: so natriuresis is associated with
increased K+ secretion and hypokalaemia (e.g. Bartter
syndrome; loop diuretics) .
3- Aldosterone level - so conditions of elevated aldosterone
are associated with hypokalaemia
4- [pH]-t
Renal tubular physiology

24. Distal tubule
• Tubulopathy :
• Gitelman syndrome.
• Type 1 (distal).

25. Gitelman syndrome
• This condition is considered a variant of Bartter syndrome
• There is an inborn autosomal recessive defect in the distal
tubule Na+-CI- cotransporter
• Often asymptomatic, with transient episodes of weakness
and tetany with abdominal pain and vomiting
• Patients have hypokalaemic metabolic alkalosis, raised
renin and aldosterone, and
• hypomagnesaemia with increased urinary magnesium
wasting,
• and hypocalciuria, a feature which helps distinguish it from
classical Bartter syndrome (in which urinary Ca2+ is normal
or high)
• Biochemical changes resemble those produced by thiazide
diuretics, which inhibit this distal tubule co-transporter

26. Collecting duct
• A final 2% of filtered Na+ is reabsorbed via
aldosterone-sensitive Na+ channels, in
exchange for K+
• Spironolactone binds to and blocks the
aldosterone receptor, explaining its diuretic
and K+ -sparing actions
• Anti-diuretic hormone (ADH) opens water
channels (aquaporins) to increase water
reabsorption
Renal tubular physiology

27. Renin -angiotensin -aldosterone
system
• Renin is released from the juxtaglomerular apparatus
in response to
• decreased perfusion to the kidney, leading to
increased angiotensin II levels (causing
vasoconstriction); and increased aldosterone release
(causing enhanced distal tubular sodium and water
conservation and hence extracellular fluid (ECF)
volume expansion)
• Abnormal renin release resulting in hypertension is
associated with most forms of secondary renal
hypertension, e.g. reflux nephropathy, renal artery
stenosis
Renal tubular physiology

28. Collecting duct
• Tubulopathy :
• Nephrogenic diabetes insipidus.
• Liddle syndrome.
• Pseudohypoaldosternism.

29. Nephrogenic diabetes insipidus
• Resistance to action of high circulating levels
of ADH
• Associated with ADH-receptor gene mutations
(X-linked nephrogenic diabetes insipidus),
• and aquaporin (water-channel) gene
mutations (autosomal recessive nephrogenic
diabetes insipidus)
• High volumes of inappropriately dilute urine
with tendency to hypernatraemic dehydration.

30. Liddle syndrome
• constitutive activation of amiloride-sensitive
distal tubular epithelial sodium channel:
• ECF volume expansion leading to renin and
aldosterone suppression, and hypokalaemia

31. Pseudohypoaldosteronism
• is constitutive inactivation of the amiloride-
sensitive distal tubular epithelial Na+ channel,
leading to excessive loss of salt and' water
with ECF volume depletion, and
hyperkalaemia;
• renin and aldosterone levels are high
secondary to the ECF volume depletion.
• There are transient and permanent forms.

32. • There are syndromes of low-renin
hypertension, including:
• Conn syndrome- primary
hyperaldosteronism: high aldosterone
leading to ECF volume expansion,
hypertension, hypokalaemia, and renin
supression
• Liddle syndrome

33. • Erythropoietin system
• Deficiency of EPO in renal disease is a major
cause of the associated anaemia
• Vitamin D metabolism
• Deficiency of renal production of calcitriol
underlies the rickets of renal failure

35. Metabolic Acidosis
• Approach:
• A. Calculate the Anion gap:
• Anion gap = Na (+ K) - (HCO3+ Cl)
• Normal = 12 ± 2 (± 4 if K included)
• High: Added or retained H+ or acid - when Cl-
will be normal, i.e. normochloraemic
• Normal: Loss of HCO3 compensated by
chloride “Hyperchloremia”

36. • B. High Anion gap M. Acidosis: Look at lactic
acid
• High: lactic acid
1. Type A: Hypoperfusion; hypoxia, dehydration,
shock & Ht. failure
2. Type B: NO hypoperfusion; renal failure,
starvation ± IEM
• Normal: lactic acid
• 1. Endogenous production of acid: DKA or IEM.
• 2. Exogenous acid gain: Poison / Toxin.

37. • C. Normal Anion gap M. Acidosis:
• Look at Urine Anion gap
• Urine Anion gap is
• negative if Cl > (Na + K)
• & Positive if Cl < (Na + K)
• Positive (less urine Cl) “Renal loss of HCO3”: RTA
• Negative (higher urine Cl) “GIT loss of HCO3”:
Persistent diarrhea
• Fractional excretion of HCO3 is <5% in GIT
• & >10% in RTA “Calculated like Na”

38. • D. Renal Tubular Acidosis “RTA”:
• Look to serum potassium
• K+ High: Type 4; check Aldosterone
• K+ low: Type 1 “dRTA" Urine PH >5.5 ±
Nephrocalcinosis ± deafness
• K+ low: Type 2 “pRTA" Urine PH <5.5 ± Fanconi
syndrome
• In type 4, Aldosterone may be low “True
Addison” or High “receptor defect” Pseudo.

40. Thanks