<br> <br> <br>  <br> # .black[Hyperkalaemia] ### UCL Physiology Course 2023 | Robert W Hunter --- # Learning objectives - overview of K⁺ homeostasis - K⁺ transport in skeletal muscle (& effects of pH) - K⁺ handling in the renal tubule - mechanism of the DCT 'K⁺ switch' - causes of hyperkalaemia - slides at: https://www.kidneyfish.net/talks/ .RWH_footer_pearl[clinical pearls] --- # A (boring) case 58M returning from theatre after a cadaveric (DBD) kidney transplant. ESKD from ADPKD; on peritoneal dialysis. Native urine output 300 ml per 24 hrs. Urine output 20 ml/hr post-op. K⁺ 6.3 mM. <br> What would you do? ??? Added complication: can no longer do PD (peritoneal breach) and promised SpR that post-op HD would not be required when he asked pre-op if we could get anaesthetics to stick a line in "just in case". ---  -- .RWH_footer_pearl[plasmalyte] ??? A small [RCT](https://pubmed.ncbi.nlm.nih.gov/29121282/) of 0.9% NaCl *vs* PL-148 in deceased donor KTRs found (statistically and clinically) significantly lower [K⁺] in the PL group (5.4 *vs.* 6.1 mM). The NaCl group were more acidaemic and hyperchloraemic. Therefore likely two-part mechanism for plasmalyte effect: i) cellular shifts ii) less chloride delivery to distal tubule, favouring electrogenic over electroneutral Na⁺ re-absorption. --- class: center, middle, inverse # .white[K⁺ transport in muscle] ---  ??? Easy to remember. ---  .RWH_footnote_right[.RWH_footer_style[Aronson & Giebisch (JASN 2011)]] ??? Acidosis opposes Na⁺ influx - causing a drop in [Na⁺]_i. This inhibits NaKATPas activity, tending to hyperkalaemia. ---  .RWH_footnote_right[.RWH_footer_style[Oster (AJP 1978)]] ??? Study in mongrel dogs: acid-loading causes hyperkalaemia for mineral, but not organic, acids. ---  .RWH_footnote_right[.RWH_footer_style[Aronson & Giebisch (JASN 2011)]] ??? Monocarboxylate co-transporter. Therefore H⁺ can enter cells without purturbing [Na⁺]_i. (Of course do get hyperK early on in DKA but that is not due to the acidosis, rather the lack of insulin!) --- class: center, middle, inverse # .white[K⁺ transport in the renal tubule] ---  ---  ---  -- .RWH_footer_pearl[Na⁺ delivery <br> SGLT2i <br> plasmalyte again] ??? Can we flip that switch? Protective effect of SGLT2is wrt hyperK confirmed in [meta-analysis](https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.057736) of RCTs in T2DM. Reduced risk of serious hyperK by 15%. Potential mechanisms: i) increased distal Na delivery ii) increased aldo iii) preservation of kidney function ---  ---  ---  ??? Kir4.1 and Kir5.1 form a heterotetramer 'K⁺ sensor' in the basolateral membrane (40 pS channel). Kir4.1 (Kcnj10) mutations in EAST syndrome (aka SESAME): epilepsy, ataxia, sensorineural deafness, tubulopathy (Gitelman-like). ---  .RWH_footnote_right[.RWH_footer_style[Wang (KI 2017)]] ??? Single-channel recording in DCT isolated from mice on normal / low / high K diet for 4 days. Channel open probability higher on low K. Went on to show that this caused hyperpolarisation (as expected). This then prompts [chloride efflux](https://doi.org/10.1016/j.cmet.2014.12.006). NB K-sensing in the adrenal is through an [analagous mechanism](https://doi.org/10.1016/j.cmet.2014.12.006). HyperK depolarises *zona glomerulosa* cells (Kcnj5 and TASK-2 channels) and DCT cells (Kir4.1/5.1). The ZG cells respond by opening V-gated Ca²⁺ channels, leading to aldosterone release. ---  ---  ??? Seminal paper from [Ellison group](https://doi.org/10.1016/j.kint.2017.10.023) using Kir4.1 knockout mice. K⁺ restriction activates Kir4.1/5.1 and hyperpolarises the cell membrane. This leads to a fall in intracellular chloride, activating the WNK / SPAK / NCC cascade. (And the converse in high K⁺ intake.) See also paper from [Welling group](https://doi.org/10.1152/ajprenal.00388.2014) using SPAK knockout mice. ---  .RWH_footnote_right[.RWH_footer_style[Wang (KI 2017)]] ??? Demonstration of the effects of dietary K on total and phospho-NCC; abolished in Kir4.1 knockout mice. ---  ??? WNK-SPAK network - master-coordinator of electrolyte transport - also intergrates other cues. ---  .RWH_footnote_right[.RWH_footer_style[Zhang (JCI Insight 2023)]] --- class: center, middle, inverse # .white[Causes of hyperkalaemia] ---  ---  -- .RWH_footer_pearl[diuretics <br> fludrocortisone] ??? CNIs activate NCC by [stimulating Kir1.4/1.5](https://doi.org/10.1172/jci.insight.165987). This may account for the observation that CNIs [activate the WNK/SPAK cascade](https://pubmed.ncbi.nlm.nih.gov/21963515/). Heparin can cause a [type IV RTA](https://doi.org/10.1136/bmj.h5531). Usually if additional RFs. Onset within 1 - 3 days. Reduces aldosterone synthesis by reducing density of AT₁Rs in adrenal *zona glomerulosa*. Fludrocortisone a rational therapy. --- # Take-home points - K⁺ flux influenced by acid-base status (hence plasmalyte helpful) - mineral acidoses cause hyperkalaemia; organic acidoses do not - distal Na⁺ delivery required for effective K⁺ secretion (hence SGLT2i) - 'K⁺ switch' in DCT sets balance between distal electroneutral and electrogenic Na⁺ re-absorption .RWH_footnote_right[.RWH_footer_style[slides at: https://www.kidneyfish.net/talks/; see presenter notes for suggestions for futher reading]] ??? ### Further reading: [Hunter & Bailey, NDT 2019](https://doi.org/10.1093/ndt/gfz206) [McDonough, Physiology 2017](https://doi.org/10.1152/physiol.00022.2016)