# .center[.black[Adult tubulopathies (RTA)]]  <br> ### .center[.RWH_smaller_h3[UKKA Advanced Nephrology 2024 | Robert W Hunter]] ??? Image credit: https://discoveroxfordshire.com/galleries/spring-magdalen-college/ --- # Learning objectives - refresh adult tubulopathy syndromes - diagnostic work-up in hyperchloraemic acidosis (case 1) - principles of management in autoimmune RTA (case 2) ---  ---  ??? Could have chosen any of these to talk about – and perhaps commonest are RTA4 and NDI... …but RTA can be tricky --- # Case 1 Details redacted; was a case of aqcuired dRTA from Neurofen Plus dependancy. ??? Q: what are the mechanisms of hypoK and hypercalciuria in dRTA? (See RCPE presentation.) <br> ### Notes on UK uK:Cr should be < 2.5 mmol/mmol in hypoK. Threshold from Taiwanese cohort of HPP vs. Gitleman and dRTA (Lin Jama Int Med 2004). <br> ### Notes on measuring calcium excretion 24hr urine calcium excretion more reliable than random spot samples; there is considerable diurnal variation. Also remember effect of volume status: UNa and UCa correlated. Concentration in 24hr collections over 200 mg/L (5 mM) associated with high stone risk (Curhan, KI 2001). (My maths: assuming Cr excretion of 8 – 10 mmoles per day that would be 0.5 – 0.6 mmol/mmol.) The threshold for hypercalciuria in spot urine samples is 0.6 mmol / mmol( = 0.2 mg/mg). Classical thresholds are 300 mg per day (mean) and 250 mg per day (women) – but risks apparent at lower 24 hr excretion rates (Curhan). Normal is 1 – 4 mg per kg per day (so for 60 kg = 60 – 240 mg). ---  .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? ---  .RWH_footnote_right[.RWH_footer_style[Kwong et al. (2013), Urolithiasis]] ??? Pitfalls with urine pH: 1) measurement (issues with delayed samples, dipsticks inacurrate, urea-splitting organisms) – NB effect of CO2 diffusion around 0.1 pH unit (Yi, CJASN 2012) 2) apparent inability to acidify urine in some patients with chronic diarrhoea (Batlle, NEJM 1998; Palmer & Clegg, CJASN 2019)... …attributed to either UNa < 10 mM (Batlle, NEJM 1998; ESPN / ERKnet dRTA guidelines supplement) …or to high levels of ammonium in the urine raising pH – particularly if stimulated by hypoK (https://www.uptodate.com/contents/urine-anion-and-osmolal-gaps-in-metabolic-acidosis) …so need to check uNa and uAG Q: what is the normal renal response to chronic metabolic acidosis? ---  .RWH_footnote_right[.RWH_footer_style[Elkinton et al. (1960), Am J Med]] ??? NAE = V(uTA + uNH4 – HCO3) TA = phosphate, creatinine, citrate, ketones… Why is NH4+ upregulated to excrete an acid load and not TA? To keep urinary pH around 6.0. When urine pH very high, risk of CaHPO4 precipitation; when urine pH very low, risk of uric acid precipitation. <br> <br> ### Further details: Normally, kidney has to dispose ot 70 mmol non-volatile acid per day through TA and NH4. uNH4 therefore normally 30 – 40 mmol per day; up to 100 - 200 mmol per day after acid-loading (Kamel & Halperin, KI Reports 2021; Uribarri, AJKD 2022). uNH4 (directly-measured) higher on Western than plant-based diets (Uribarri AJKD 2022). ---  ??? Interpretation of uAG: - usually +ve 20 – 90 (dietary absorption of Na and K exceed that of Cl – and this has become more +ve in recent decades as diet has changed)… - …if zero, then NH4 excretion around 80 mmol per day (Kamel & Halperin, KI Reports 2021)… therefore +50 = 30 mmol per day - in context of HCMA: under –ve 20 = lots of NH4 (>100 mM) = appropriate = diarrhoea (“neg-GUT-tive”) - in context of HCMA: over +ve 20 = inappropriately low NH4 (<60 mM) = RTA - +/- 20 hard to interpret according to UpToDate ---  .RWH_footnote_right[.RWH_footer_style[Batlle et al. (2018), CJASN]] ??? Major criticism of this work is that giving NH4Cl = giving Cl without Na or K = will necessarily elevate uCl:uNa+K and cause a negative uAG! ---  .RWH_footnote_right[.RWH_footer_style[Uribarri et al. (2022), AJKD]] ??? A = controls; B = stone-formers Large commercial dataset from USA; subjects were NOT acidotic. Also had excluded subjects with very high uNH4:uSO4 as thought to be indicative of UTI with urease activity. ---  ??? Pitfalls with uAG: 1) main criticism that in steady state, UNa, K and Cl must reflect intake (Uribarri, JASN 2021) - so what is explanation for +ve uAG in dRTA? - likely in state of –ve K balance > high uK… …and also hypoK > impaired ammoniagenesis > high upH (see below) - …and explanation for –ve uAG in NH4Cl = unopposed Cl (see two slides previous) - …and explanation for –ve uAG in diarrhea = preferential loss of K over Cl > lower uK - heavy dependence on diet (NB normal uAG from +40 to +70 since 1980s = more dietary K with organic anions – Uribarri JASN 2021) 2) other unmeasured anions – tend to give +ve AG (Batlle, CJASN 2018) - significant other urinary anions as above - …includes bicarbonaturia in pRTA on supplements - …and if upH > 6.5 then likely bicarbonaturia - so expect obligate +ve uAG in metabolic alkalosis 3) unmeasured cations (e.g. Li+) = tend to give –ve AG 4) dependance on upH (Uribarri JASN 2021) - at upH = 7: uHCO3 = 10 mM and significant increase in divalent uPO4 – so tend to +ve AG… - in alkaline urine, H2PO4- converted to HPO42- which is less soluble – hence greater stone risk 5) impaired ammoniagenesis - significant AKI or CKD (impaired ammoniagenesis from decreased PCT mass, hyperK, RAAS blockade and lower aldo) - volume depletion (UNa < 10 mM prevents acidification) 6) irrelevant ammoniagenesis - urea-splitting organisms CONCLUSIONS: - uNH4 is helpful; uAG is unreliable, with the balance argument being convincing… - …nevertheless can still help to differentiate between diarrhoea and RTA – just not for the reasons that we thought! ---  ??? Interpretation of uOG (https://www.uptodate.com/contents/urine-anion-and-osmolal-gaps-in-metabolic-acidosis): - normal 10 – 90 (= 5 – 45 mM NH4) - in context of HCMA: uOG > 400 = 200 mM NH4 = appropriate response = diarrhoea - in context of HCMA: uOG < 150 = 75 mM NH4 = inadequate response = dRTA …or for a more complex interpretation see Kamel & Halperin (KI Reports, 2021): multiply uNH4/uCr by estimated Cr excretion rate and deem >50 mmol NH4 per day an adequate response to acidosis Pitfalls (fewer than for uAG and crucially not subject to the theoretical balance criticism): - additional osmolytes as above - urease-producing organisms (will have lots of NH4 but does not represent NH4 generated by renal tubules)… - …so therefore caveat applies equally to directly measured NH4 <br> <br> See great correlation in Fujimaru (Nephron 2021): Japanese cohort with CKD (mean eGFR 25)… …but see also Raphael (CJASN 2018): terrible correlation in KTRs! ---  ---  .RWH_footnote_right[.RWH_footer_style[Walsh et al. (2007), KI]] --- # Diagnosis of dRTA - history and judgement! - upH > 5.5 (but check UNa) - positive uAG > +20; low uOG <150 - uCa:Cr >ULN, uK:Cr >2.5 mmol/mmol - USS - dynamic acidification testing - biopsy - urinary drug screens - exome sequencing ??? USS more sensitive than CT for nephrocalcinosis in the context of hypoparathyroidism… …but CT more specific (Boyce JCEM 2013) Plain films very insensitive. --- # Case 2 Details redacted; was a case of acquired dRTA in Sjogren syndrome. ??? Q: why do I have to take these disgusting supplements? Aims of treatment: bone health (Thai case series and extrapolation from paediatrics) – and remember K citrate improves bone density in normal subjects! stones dangerous hypoK CKD? Target normalization of K, HCO3, Cl, uCa. Prefer K citrate as this addresses hypoK and Na will exacerbate calciuria (theoretical; not borne out in practice). ---  ??? Evans et al (2015), Rheumatology. Renal involvement in pSS is 5% (retrospective series) or 25%+ in prospective studies - therefore under-recognized. Classic tubulocentric, lyphocytic TIN (= extraglandular epithelialitis) with CD4+ T-cell infiltrate. (Role for B-cells as evidenced by autoAbs etc.) 75% TIN; 25% GN dRTA associated with Ro, La, hypergammaglobulinaemia dRTA and NDI have similar prevalence (up to 25% in prospective series) – but NDI usually well compensated and therefore no Ix / Rx required. Classic GN is IC MPGN, of which 66% cryo (due to IgM production). Associated with lymphoma (as is pSS). ---  .RWH_footnote_right[.RWH_footer_style[DeFrance et al. (1995), JASN; Devuyst el al. (2009), KI]] ??? A = control; B = patient. Loss of H+-ATPase (but see similar non-specific signal in PCT brush borders). Other image = IgG from patient with Sjogren dRTA reacting with ICs in control human kidney. AutoAbs to H+-ATPase, AE1 and CAII have been described. --- # Take-home messages - always worth diagnosing acquired tubulopathies - trust history, old results, clinical judgement - use upH, uAG, uOG (but know limitations) - dynamic urinary acidification testing - drug history (any acquired tubulopathy) - look for Sjogren syndrome in tubulopathies and *vice versa* - treat for bone health and to prevent dangerous hypoK