# .center[.black[Tubulopathies in adults]]  <br> ### .center[.RWH_smaller_h3[UKKA Advanced Nephrology 2025 | Robert W Hunter]] ??? ### Abstract Diseases caused by defects in any of the transporter proteins expressed by renal tubular epithelial cells are collectively termed the "tubulopathies". Our understanding of these diseases is largely influenced by inherited monogenic disorders, which usually present in childhood.[1]   In this presentation, I outline an approach to the adult patient with tubulopathy, covering when to consider a diagnosis, how to assess for acquired and inherited forms and principles of management. I illustrate key points using a clinical case and invite the audience to answer questions around diagnosis.   The first step towards diagnosis is to recognise the tubular "syndrome": acidosis, salt-wasting, mineralocorticoid resistance, apparent mineralocorticoid excess, water excess, nephrocalcinosis etc.[2] A spot urine sample sent for creatinine and electrolytes can be invaluable and should be sent before therapy commences or when the patient is stable during follow-up. The second step is to implicate the renal tubule, by demonstrating an inappropriate response to the physiological perturbation (e.g. finding an alkaline urine in a metabolic acidosis suggests RTA; a high FEMg in hypomagnesaemia suggests renal Mg wasting). Having excluded common causes of electrolyte disturbance (vomiting, diarrhoea, alcohol, endocrine disorders), the third step is to consider possible causes of the tubulopathy. In order of decreasing likelihood, these are: drugs [3], exogenous toxins, "endogenous toxins" such as paraproteins, autoimmune disorders, tubulointerstitial inflammation and inherited disease.   Management is largely supportive, although some specific therapies are emerging. There are national and international guidelines for the management of some tubulopathies.   References: [1] Downie et al. (2021); CJASN 16:620-630. [2] Bockenhauer & Kleta (2021); Pediatric Nephrology 36:2553-2561. [3] Zietse et al. (2009); Nat Rev Nephol 5(4):192-202. ---  ??? Traditional place to start when understanding tubulopathies. Problems: 1) really complicated and off-putting – so main aim today is to make the tubule accessible and share a simple approach that I have found useful 2) de-emphasizes inherited causes 3) patients don’t present with – and aren’t even referred with – suspected tubulopathy… …they have incidental electrolyte abnormalities… <br> <br> ### Notes FHHNC = familial hypomagnesaemia with hypercalciuria and nephrocalcinosis Inherited pRTA is very rare; inherited dRTA less so. Commonest cause of inherited Fanconi syndrome is cystinosis. XLD hypophosphataemic rickets is the commonest type; causes elevated FGF23 (phosphatonin). X-linked hypercalciuric nephrolithiasis = Dent’s disease, XLR nephrolithiasis, XLR hypophosphataemia rickets, LMWH proteinuria (all CLCn5 mutations). Encodes chloride channel involved in endosomal acidification – therefore impaired endocytosis by megalin / cubulin. Defective endocytosis of vitD and PTH lead to calciuria. <br> <br> Other disorders not depicted here: - ADTKD (e.g. HNF1b etc.) - FHH (CaSR) - ciliopathies (ADPKD etc.) - metabolic disorders (oxalosis etc.) - endocrine disorders (GRA etc.) ---  ??? Could have chosen any of these to talk about – and perhaps commonest are RTA4 and NDI... …but RTA can be tricky --- # Learning objectives - real life and exams - refresh (adult) tubulopathy syndromes - how to diagnose any tubulopathy - (and a very little bit about management) --- # Case 1 Details redacted; was a case of aqcuired dRTA from Neurofen Plus dependancy. --- class: black  ---  ??? Hypokalaemic acidosis = differential diarrhoea HypoK in pRTA from bicarbonaturia HypoK in dRTA from increased V-gradient in CD (Na reabsorption not balanced by H+ excretion) ---  ??? Hypokalaemic alkalosis = differential vomiting Differentiate vomiting from tubulopathy with FECl (< 0.5% excludes salt-losing tubulopathy). How to differentiate between Bartter and Gitelman? PMg low in Gitelman (with chondocalcinosis) UCaV = high in Bartter (with nephrocalcinosis) / low in Gitelman ---  ---  ??? HyperK and acidosis in RTA4 from: - loss of ENaC – so reduced driving force for H+ and K+ secretion - hyperK impairs ammoniagenesis ---  ??? Other phenotypes not shown: - NDI and SIAD - nephrocalcinosis / stones - CKD ---  ??? ### Testing Always a role for FE: - FECl <0.5% = not a salt-losing tubulopathy (and therefore purging instead) - FEMg >2 – 4% = renal wasting - FEPO4 >10 – 20% = renal wasting ---  .RWH_footnote_right[.RWH_footer_style[Trepiccione et al. (2021), NDT]] ??? Seems easy according to textbooks (although not always – sometimes FEHCO3 etc…) …but actually often problematic in practice. Let’s see why upH and uAG are unreliable. Q: how do you measure upH? ---  ??? Rarely a role for more specialist testing: - urinary acidification test for recurrent stone-formers / nephrocalcinosis (NOT for frank acidosis) - thiazide test for Gitelman or Gordon (FECl) - urinary drug screen - exome testing (available in Scotland for Bartter & Gitelman, Cystinuria, Nephrocalcinosis & Nephrolithiasis (large panel), PHA1 (paeds), tubulopathies and RTA panel (very large panel) --- # Take-home messages - always worth diagnosing acquired tubulopathies - careful history and old results - spot urine on admission (or deferred) - always send basic 'universal panel' - implicate tubule (upH, uAG, uOG, FE, uK:Cr...) - not a tubulopathy > DAPT > inherited --- class: center, middle, inverse # .white[Supplemental slides] ---  ---  ---  ---