C Appendix 3 - what’s the mechanism?

C.1 Mechanisms in dRTA (see ESPN clinical practice points, NDT 2021):

Mechanism of hypoK in dRTA:

  1. response to systemic acidosis (inhibits PCT Na reabsorption and therefore stimulates RAAS)
  2. increased voltage gradient in CD (Na reabsorption not balanced by H excretion)
  3. sometimes also direct causes related to the underlying tubulopathy (e.g. amphoterocin)



Mechanism of hypoK in pRTA:

  1. increased HCO3 delivery and flow rate in distal nephron (Unwin 2001)

(…so this raises the question as to whether heavy HCO3 supplementation to target normalisation of systemic pH is necessarily helpful)



Mechansisms of hyperK and acidosis in RTA4:

  1. impaired ENaC activity – so reduced driving force for H+ and K+ secretion
  2. hyperK impairs ammoniagenesis



Mechanism of hypercalciuria in dRTA:

  1. release of Ca from bone (as protons are buffered by apatite)
  2. tubular resistance to the anti-calicuric effects of PTH



Mechanisms of stones / nephrocalcinosis in dRTA:

  1. hypercalciuria
  2. hypocituria (enhanced reabsorption of citrate in PCT; citrate inhibits stone formation)



C.2 Mechanisms in salt-wasting tubulopathy (See Dutta & Layton, AJP Renal 2024 – a modelling study)

Mechanisms of hypokalaemic alkalosis in Bartter and Gitelman:

  1. increased distal Na delivery > more electrogenic Na reabsorption favouring K+/H+ secretion
  2. volume depletion > secondary hyperaldosteronism


In Bartter syndrome, there is also:

  1. uncoupled tubuloglomerular feedback (in the absence of NaKCl uptake by MD cells, the MD behaves as if there is profound volume depletion, stimulating PGE2 and renin production - hence role for NSAIDs)



Mechanisms of Ca2+ and Mg2++ disturbance:

Remember that:

  • Ca2+ is reabsorbed 60 – 70% in PT, 25% in TALH (both passive paracellular) and 5 – 10% DCT via TRPV5 (stimulated by PTH)

  • Mg2+ reabsorbed 15 – 25% in PT, 60 – 70% in TALH (both passive paracellular) and 20% in DCT via TRPM6/7

  • Barrter = hypercalciuria, normal plasma Mg (unless type III)

  • Giltman = hypocalciuria, hypomagnesaemia


Therefore, mechanisms underlying Ca2+ disturbances in Bartter & Gitelman are relatively easy to explain: Ca2+ is reabsorbed paracellularly in the TALH (in response to a lumen +ve potential resulting from the combined actions of NKCC2-ROMK)…:

  • …so in Bartter syndrome, loss of Ca reabsorption through this route leads to calciuria

  • …whereas in Gitleman syndrome, there is relatively little direct effect on Ca transport in DCT so the effects of chronic volume depletion predominate (stimulating proximal Na and hence Ca reabsorption)


The mechanism underlying Mg2+ disturbances take a little more thought: one might expect to see something similar to Ca2+ in that acute inhibition of NKCC2 (loop diuretics) causes Mg2+ wasting but modelling suggests this is offset with chronic remodelling so that…:

  • …in Bartter, there is DCT hypertrophy, leading to increased Mg reabsorption via TRPM6/7 – so preventing hypoMg

  • …in Gitleman, there is DCT atrophy (causing Mg wasting); compensatory increases in proximal Na reabsorption drive hypocalciuria