Renal Tubular Acidosis Flashcards
Normal acid-base balance
around 1 mmol/kg/day acid intake needs to be excreted
Base reabsorption (NaHCO3) at proximal tubule and acid secretion (NH3, H+) at distal tubule
Base reabsorption: cytoplasmic CA II and membrane-bound CA IV needed; H+ secreted at luminal by Na/H exchanger, Na-CO3 cotransporter at basolateral
Acid secretion: H+ ATPase, H/K ATPase – H+ secreted is trapped by NH3 or HPO4 and excreted; HCO3 generated and absorbed into blood by Cl-HCO3 exchanger
Normal response to acidosis and RTA
Respiratory: hyperventilation
Renal: reabsorb all filtered HCO3 and increase H excretion by increasing excretion of ammonium ions
–> urine pH <5.5
==> defects in ability of renal tubules to achieve this = RTA
Recall NAGMA diagnostic algorithm
HypoK vs HyperK
HyperK (URINE PH <5.5) - early uraemia acidosis, type 4 RTA, infusion of NH4Cl or HCl
HypoK
- URINE PH >5.5 – Type 1 RTA
- URINE PH VARIABLE – Type 2 RTA, CA inhibitors, diarrhoea
- uterosigmoidostomy
Although urine pH is a poor diagnostic tool, pH <5.5 generally rules out Type I RTA
Type 2 (proximal) RTA: defect, severity, effects on urine pH
Reduced HCO3 reabsorptive capacity in the proximal tubule –> leak to urine
Fall in [HCO3]p is SELF-LIMITED
- wasting only occurs when the [HCO3]p is above the reabsorptive threshold
- [HCO3]p usually 12-20 mmol/L
Distal acidification mechanisms intact –> urinary pH <5.5 during acidosis ([HCO3]p less than reabsorptive threshold)
–> when given HCO3, urinary pH increases
Type 2 RTA HypoK mechanism
Increased Na loss (less reabsorption with HCO3) –> secondary hyperaldosteronism to increase Na reabsorption and K secretion (modest effect)
When NaHCO3 given –> further increase distal HCO3 load (which draws more Na and increases flow rate)
=> further increase K secretion ==> HYPOKALAEMIA
MUST GIVE K SUPPLEMENT WHEN TREATING WITH ALKALI!!
Type 2 RTA Associations, Effects, Causes
Commonly a/w generalised proximal tubular dysfunction – Fanconi Syndrome
–> glucosuria, aminoaciduria, phosphaturira, tubular proteinuria
Effects:
- failure to thrive
- hypovolaemia/ dehydration –> polyuria, polydipsia
- hypoK –> muscle weakness, constipation, sudden death
Causes of Fanconi:
- children - cystinosis
- monoclonal gammopathies (excessive Ig accumulate and damage kidneys - MM, AL amyloidosis)
- heavy metals e.g. Pb, Hg, Cd
- nephrotoxic drugs e.g tenofovir, gentamicin
- Wilson’s disease, hyperPTH
Isolated:
- CA inhibitors (impair HCO3 reabsorption) e.g. acetozalamide, topiramate
Type 2 RTA Investigations
Single urinary measurement –> Fractional excretion of HCO3 >15%
(normal is <5% is [HCO3]p low)
HCO3 loading test (gold standard)
- if unsure
- normal response in acidosis = no change in HCO3 in urine since most is reabsorbed
- proximal RTA ==> URINARY HCO3 RISES AND URINARY PH >7.5
(also test urine for glucose, amino acids, phosphate etc.)
Type 1 (distal) RTA: defect, severity, effects on urine pH
Inability to excrete daily acid load in the collecting tubules
(low H+ ATPase activity, backleak of H+)
[HCO3]p may fall to <10 mmol/L
Abnormally high urine pH >5.5 during systemic acidosis
Type 1 RTA HypoK mechanism and effects of alkali therapy
Increased K secretion as compensation for lack of H+ secretion
Effects of alkali therapy:
- increased NaHCO3 distal delivery raises urine pH and allows relatively more H+ to be secreted
- expands ECV (effect of Na) –> decreased aldosterone and Na reabsorption –> resolves hypoK
Type 1 RTA causes
Primary
(children – genetic, drugs)
- persistent with neurosensorial deafness, HCO3 wasting in AR disease
Secondary
(adults – autoimmune diseases, hypercalciuria, drugs)
- genetic: sickle-cell, Wilson’s
- hypercalciuria: primary hyperPTH, vitamin D intoxication
- amyloidosis
- AI: Sjogren’s syndrome, RA, SLE, PBC
- drugs: amphotericin B, Li, analgesic abuse, ifosfamide
Type 1 RTA clinical features and investigations
Clinical features (children)
- poor growth/ osteomalacia (bone buffer)
- polyuria
- hypercalcuria
- nephrocalcinosis (CKD if progress)
- K depletion (muscle weakness)
Ix
- spot urine pH inappropriately high
- NH4Cl loading test (gold standard) only if necessary as can be dangerous
- -> urine pH won’t decrease as expected
- -> urine NH4 measured indirectly by urinary anion gap (UAG)
UAG = Na + K - Cl (normal = 20-90 mmol/L)
- normal response to NH4Cl = NH4 excretion in urine drags more Cl out –> U[Cl] increases –> UAG less positive
- impaired NH4 secretion = NH4 load not present in urine to drag Cl with it –> inappropriately positive UAG
Limitations of UAG
- false positive: increased urinary unmeasured anions e.g ketoacids
- invalid in volume depletion (reduced Na flow impairs distal acidification)
(can also do radiological exam for any renal stones)
Type 1 RTA treatment
Continuous alkali administration
- resume normal growth, arrest nephrocalcinosis and preserve renal function
Type 4 RTA Pathophysiology, diagnosis and management
Aldosterone deficiency or tubular resistance to aldosterone action
HyperK
Appropriately acidic urine <5.5 (since other distal acidification mechanisms are intact)
Plasma HCO3 >17 mmol/L (mild disturbance)
Diagnosis
- plasma renin and aldosterone levels
- drug hx
Management:
- withdraw K sparing diuretics
- restrict dietary K
- diuretics (K wasting)
- fludrocortisone (replace aldosterone function)
Type 4 RTA causes
Primary
- early childhood hyperK (transient)
Secondary
- mineralocorticoid deficiency e.g. Addison’s disease, hyporeninaemic hypoaldosteronism in chronic nephropathy e.g. diabetic nephropathy
- mineralocorticoid resistance e.g. genetic pseudohypoaldosteronism, chronic interstitial nephropathies such as obstructive uropathy
- drug-induced hyperK e.g. impaired RAAS by ACEi, COX inhibitors; inhibitors of K secretion such as diuretics (spironolactone)
