Is intestinal transport dysfunctional in COVID-19-related diarrhea?

Diarrhea, often severe, is a recognized and frequently early symptom during acute COVID-19 infection and may persist or develop for the first time in patients with long-COVID, with socioeconomic consequences. Diarrheal mechanisms in these cases are poorly understood. There is evidence for disruption of intestinal epithelial barrier function and also for changes in the gut microbiome, which is critical for gut immunity and metabolism. Whether the SARS-CoV-2 virus has adverse effects on intestinal transport proteins is unclear. However, the ability of the virus to inhibit expression and activity of an aldosterone-regulated epithelial sodium (Na+) channel (ENaC) present in human distal colon, which is responsible for Na+ and water salvage, points to possible disruption of other intestinal transport proteins during COVID-19 infection. In this Perspective, we develop this idea by highlighting possible intestinal transport protein targets for the SARS-CoV-2 virus and discussing how their interactions might be explored in the laboratory.

Calmodulin Antagonist W-7 Enhances Intermediate Conductance Ca2+- Sensitive Basolateral Potassium Channel (IKCa) Activity in Human Colonic Crypts.

Intermediate conductance potassium (IKCa) channels are exquisitively Ca2+ sensitive, intracellular Ca2+ regulating channel activity by complexing with calmodulin (CaM), which is bound to the cytosolic carboxyl tail. Although CaM antagonists might be expected to decrease IKCa channel activity, the effect of W-7 in human T lymphocytes are conflicting. We therefore evaluated the effect of W-7 on basolateral IKCa channels in human colonic crypt cells. Intact crypts obtained from normal human colonic biopsies by Ca2+ chelation were used for patch clamp studies of basolateral IKCa channels in the cell-attached configuration. IKCa channel activity was studied when the bath Ca2+ concentration was changed from 1.2 mmol/L to 100 µmol/L and back to 1.2 mmol/L, as well as from 100 µmol/L to 1.2 mmol/L and back to 100 µmol/L, both in the absence and presence of 25 µmol/L W-7. Decreasing bath Ca2+ from 1.2 mmol/L to 100 µmol/L decreased IKCa channel activity reversibly in the absence of W-7, whereas there was a uniformly high level of channel activity at both bath Ca2+ concentrations in the presence of W-7. In separate experiments, increasing bath Ca2+ from 100 µmol/L to 1.2 mmol/L increased IKCa channel activity reversibly in the absence of W-7, whereas there was again a uniformly high level of channel activity at both bath Ca2+ concentrations in the presence of W-7. We, therefore, propose that W-7 has a specific stimulatory effect on basolateral IKCa channel activity, despite its ability to inhibit Ca2+/CaM-mediated, IKCa channel-dependent Cl- secretion in human colonic epithelial cells.

Vitamin D Reverses Disruption of Gut Epithelial Barrier Function Caused by Campylobacter jejuni.

Infections by the zoonotic foodborne bacterium Campylobacter jejuni (C. jejuni) are among the most frequent causes of bacterial gastroenteritis worldwide. The aim was to evaluate the relationship between epithelial barrier disruption, mucosal immune activation, and vitamin D (VD) treatment during C. jejuni infection, using intestinal epithelial cells and mouse models focused on the interaction of C. jejuni with the VD signaling pathway and VD treatment to improve C. jejuni-induced barrier dysfunction. Our RNA-Seq data from campylobacteriosis patients demonstrate inhibition of VD receptor (VDR) downstream targets, consistent with suppression of immune function. Barrier-preserving effects of VD addition were identified in C. jejuni-infected epithelial cells and IL-10-/- mice. Furthermore, interference of C. jejuni with the VDR pathway was shown via VDR/retinoid X receptor (RXR) interaction. Paracellular leakiness of infected epithelia correlated with tight junction (TJ) protein redistribution off the TJ domain and apoptosis induction. Supplementation with VD reversed barrier impairment and prevented inhibition of the VDR pathway, as shown by restoration of transepithelial electrical resistance and fluorescein (332 Da) permeability. We conclude that VD treatment restores gut epithelial barrier functionality and decreases bacterial transmigration and might, therefore, be a promising compound for C. jejuni treatment in humans and animals.

Parallel intermediate conductance K+ and Cl- channel activity mediates electroneutral K+ exit across basolateral membranes in rat distal colon.

Transepithelial K+ absorption requires apical K+ uptake and basolateral K+ exit. In the colon, apical H+-K+-ATPase mediates cellular K+ uptake, and it has been suggested that electroneutral basolateral K+ exit reflects K+-Cl- cotransporter-1 (KCC1) operating in parallel with K+ and Cl- channels. The present study was designed to identify basolateral transporter(s) responsible for K+ exit in rat distal colon. Active K+ absorption was determined by measuring 86Rb+ (K+ surrogate) fluxes across colonic epithelia under voltage-clamp conditions. With zero Cl- in the mucosal solution, net K+ absorption was reduced by 38%, indicating that K+ absorption was partially Cl--dependent. Serosal addition of DIOA (KCC1 inhibitor) or Ba2+ (nonspecific K+ channel blocker) inhibited net K+ absorption by 21% or 61%, respectively, suggesting that both KCC1 and K+ channels contribute to basolateral K+ exit. Clotrimazole and TRAM34 (IK channel blockers) added serosally inhibited net K+ absorption, pointing to the involvement of IK channels in basolateral K+ exit. GaTx2 (CLC2 blocker) added serosally also inhibited net K+ absorption, suggesting that CLC2-mediated Cl- exit accompanies IK channel-mediated K+ exit across the basolateral membrane. Net K+ absorption was not inhibited by serosal addition of either IbTX (BK channel blocker), apamin (SK channel blocker), chromanol 293B (KV7 channel blocker), or CFTRinh172 (CFTR blocker). Immunofluorescence studies confirmed basolateral membrane colocalization of CLC2-like proteins and Na+-K+-ATPase α-subunits. We conclude that active K+ absorption in rat distal colon involves electroneutral basolateral K+ exit, which may reflect IK and CLC2 channels operating in parallel.NEW & NOTEWORTHY This study demonstrates that during active electroneutral K+ absorption in rat distal colon, K+ exit across the basolateral membrane mainly reflects intermediate conductance K+ channels operating in conjunction with chloride channel 2, with a smaller, but significant, contribution from K+-Cl- cotransporter-1 (KCC1) activity.

Segmental differences in upregulated apical potassium channels in mammalian colon during potassium adaptation.

Rat proximal and distal colon are net K+ secretory and net K+ absorptive epithelia, respectively. Chronic dietary K+ loading increases net K+ secretion in the proximal colon and transforms net K+ absorption to net K+ secretion in the distal colon, but changes in apical K+ channel expression are unclear. We evaluated expression/activity of apical K+ (BK) channels in surface colonocytes in proximal and distal colon of control and K+-loaded animals using patch-clamp recording, immunohistochemistry, and Western blot analyses. In controls, BK channels were more abundant in surface colonocytes from K+ secretory proximal colon (39% of patches) than in those from K+-absorptive distal colon (12% of patches). Immunostaining demonstrated more pronounced BK channel α-subunit protein expression in surface cells and cells in the upper 25% of crypts in proximal colon, compared with distal colon. Dietary K+ loading had no clear-cut effects on the abundance, immunolocalization, or expression of BK channels in proximal colon. By contrast, in distal colon, K+ loading 1) increased BK channel abundance in patches from 12 to 41%; 2) increased density of immunostaining in surface cells, which extended along the upper 50% of crypts; and 3) increased expression of BK channel α-subunit protein when assessed by Western blotting (P < 0.001). Thus apical BK channels are normally more abundant in K+ secretory proximal colon than in K+ absorptive distal colon, and apical BK channel expression in distal (but not proximal) colon is greatly stimulated as part of the enhanced K+ secretory response to dietary K+ loading.

Liddle-Mutation of the ß-Subunit, but not the γ-Subunit, Attenuates Protein Kinase C-Mediated Inhibition of Human Epithelial Sodium Channels (hENaC).

Mammalian distal nephron and distal colon, prime sites for Na(+) homeostasis, contain amiloride-sensitive epithelial sodium channels (ENaC). Protein kinase C (PKC) inhibits ENaC by phosphorylating serine and threonine residues within COOH termini of the ß- and/or γ-subunits. Although some of these phosphorylation sites are close to the PY motifs, it is unclear whether they remain susceptible to PKC in Liddle-mutated ENaC ß- and/or γ-subunits, where PY motifs are truncated, resulting in increased apical ENaC expression. We therefore studied the effects of PKC in wild-type and Liddle-mutated human epithelial Na(+) channels (hENaC) expressed in Xenopus oocytes, using the dual-electrode voltage clamp technique. PKC activation using 500 nmol/l phorbol 12-myristate 13-acetate (PMA) decreased amiloride-sensitive Na(+) currents by 80 % in oocytes expressing wild-type hENaC, an effect largely prevented by co-exposure to 50 µmol/l calphostin C (a specific inhibitor of PKC), whereas 500 nmol/l phorbol didecanoate (PDD), an inactive phorbol ester which does not stimulate PKC, had no effect. In oocytes expressing hENaC containing the Liddle-mutated ß-subunit, PMA elicited a 54 % decrease in amiloride-sensitive Na(+) currents, significantly (P < 0.0025) less than that in oocytes expressing wild-type hENaC. By contrast, in oocytes expressing hENaC containing the Liddle-mutated γ-subunit, PMA elicited a 68 % decrease in amiloride-sensitive Na(+) current, similar (P = 0.10) to that in oocytes expressing wild-type hENaC. We conclude that hENaC incorporating the Liddle-mutated ß-subunit lacks one or more PKC phosphorylation sites, thereby significantly reducing the inhibitory effect of PKC on Na(+) channel activity, whereas hENaC incorporating Liddle-mutated γ-subunits remains as susceptible to PKC as wild-type hENaC.

Evidence that two distinct crypt cell types secrete chloride and potassium in human colon.

BACKGROUND: Human colon may secrete substantial amounts of water secondary to chloride (Cl(-)) and/or potassium (K(+)) secretion in a variety of diarrhoeal diseases. Ion secretion occurs via Cl(-) and K(+) channels, which are generally assumed to be co-located in the colonocyte apical membrane, although their exact cellular sites remain unclear. OBJECTIVE:  To investigate the location of apical Cl(-) (CFTR) and apical K(+) (large conductance; BK) channels within human colonic epithelium. DESIGN: Whole-cell patch clamp recordings were obtained from intact human colonic crypts. Specific blockers of K(+) channels and CFTR identified different types of K(+) channel and CFTR under resting conditions and after stimulating intracellular cAMP with forskolin. The BK channel ß3-subunit was localised by immunostaining. RESULTS: Two types of crypt cells were identified. One (73% of cells) had whole-cell currents dominated by intermediate conductance (IK) K(+) channels under resting conditions, which developed large CFTR-mediated currents in response to increasing intracellular cAMP. The other (27% of cells) had resting currents dominated by BK channels inhibited by the BK channel blocker penitrem A, but insensitive to both forskolin and the IK channel blocker clotrimazole. Immunostaining showed co-localisation of the BK channel ß3-subunit and the goblet cell marker, MUC2. CONCLUSIONS: In human colon, Cl(-) secretion originates from the dominant population of colonocytes expressing apical CFTR, whereas K(+) secretion is derived from a smaller population of goblet cells expressing apical BK channels. These findings provide new insights into the pathophysiology of secretory diarrhoea and should be taken into account during the development of anti-diarrhoeal drugs.

Calcium rapidly down-regulates human renal epithelial sodium channels via a W-7-sensitive mechanism.

Increases in intracellular calcium (Ca(2+)) inhibit renal sodium (Na(+)) absorption in cortical collecting ducts, but the precise mechanism is unclear. We, therefore, studied the effects of raising intracellular Ca(2+) (using 10 µmol/L A23187, a Ca(2+) ionophore) on wild-type and Liddle-mutated human epithelial Na(+) channels (hENaC) expressed in Xenopus oocytes, using the dual-electrode voltage clamp technique. A23187 decreased amiloride-sensitive Na(+) current by 55% in oocytes expressing wild-type hENaC, an effect prevented by co-exposure to 50 µmol/L W-7 (to inhibit the Ca(2+)/calmodulin complex). By contrast, co-exposure to 50 µmol/L calphostin (to inhibit protein kinase C) or 5 µmol/L KN-62 (to inhibit Ca(2+)/calmodulin-dependent protein kinase II) had no effect on the decrease in amiloride-sensitive Na(+) current elicited by A23187 alone. Whereas A23187 reduced amiloride-sensitive Na(+) current in oocytes expressing wild-type hENaC, it had no similar effect in those expressing Liddle-mutated hENaCs, suggesting that the activity of individual Na(+) channels in situ was unchanged by the rise in intracellular Ca(2+). These data suggest that the A23187-induced rise in intracellular Ca(2+) inhibited wild-type hENaC through a W-7-sensitive mechanism, which likely reflected enhanced removal of Na(+) channels from the cell membrane by endocytosis. We, therefore, propose that Na(+) absorption in cortical collecting duct cells is inhibited by Ca(2+), possibly when complexed with calmodulin.

Enhanced K(+) secretion in dextran sulfate-induced colitis reflects upregulation of large conductance apical K(+) channels (BK; Kcnma1).

Defective colonic Na(+) and Cl(-) absorption is a feature of active ulcerative colitis (UC), but little is known about changes in colonic K(+) transport. We therefore investigated colonic K(+) transport in a rat model of dextran sulfate-induced colitis. Colitis was induced in rat distal colon using 5% dextran sulfate sodium (DSS). Short-circuit current (Isc, indicating electrogenic ion transport) and (86)Rb (K(+) surrogate) fluxes were measured in colonic mucosa mounted in Ussing chambers under voltage-clamp conditions in the presence of mucosal orthovanadate (a P-type ATPase inhibitor). Serum aldosterone was measured by immunoassay. Control animals exhibited zero net K(+) flux. By contrast, DSS-treated animals exhibited active K(+) secretion, which was inhibited by 98, 76, and 22% by Ba(2+) (nonspecific K(+) channel blocker), iberiotoxin (IbTX; BK channel blocker), and TRAM-34 (IK channel blocker), respectively. Apical BK channel α-subunit mRNA abundance and protein expression, and serum aldosterone levels in DSS-treated animals, were enhanced 6-, 3-, and 6-fold respectively, compared with controls. Increasing intracellular Ca(2+) with carbachol (CCH), or intracellular cAMP with forskolin (FSK), stimulated both active Cl(-) secretion and active K(+) secretion in controls but had no or little effect in DSS-treated animals. In DSS-induced colitis, active K(+) secretion involves upregulation of apical BK channel expression, which may be aldosterone-dependent, whereas Cl(-) secretion is diminished. Since similar ion transport abnormalities occur in patients with UC, diarrhea in this disease may reflect increased colonic K(+) secretion (rather than increased Cl(-) secretion), as well as defective Na(+) and Cl(-) absorption.

Potential role of reduced basolateral potassium (IKCa3.1) channel expression in the pathogenesis of diarrhoea in ulcerative colitis.

Diarrhoea in ulcerative colitis (UC) mainly reflects impaired colonic Na(+) and water absorption. Colonocyte membrane potential, an important determinant of electrogenic Na(+) absorption, is reduced in UC. Colonocyte potential is principally determined by basolateral IK (KCa3.1) channel activity. To determine whether reduced Na(+) absorption in UC might be associated with decreased IK channel expression and activity, we used molecular and patch clamp recording techniques to evaluate IK channels in colon from control patients and patients with active UC. In control patients, immunolabelling revealed basolateral IK channels distributed uniformly along the surface-crypt axis, with substantially decreased immunolabelling in patients with active UC, although IK mRNA levels measured by quantitative PCR were similar in both groups. Patch clamp analysis indicated that cell conductance was dominated by basolateral IK channels in control patients, but channel abundance and overall activity were reduced by 53% (p = 0.03) and 61% (p = 0.04), respectively, in patients with active UC. These changes resulted in a 75% (p = 0.003) decrease in the estimated basolateral membrane K(+) conductance in UC patients compared with controls. Levels of IK channel immunolabelling and activity in UC patients in clinical remission were similar to those in control patients. We conclude that a substantial decrease in basolateral IK channel expression and activity in active UC most likely explains the epithelial cell depolarization observed in this disease, and decreases the electrical driving force for electrogenic Na(+) transport, thereby impairing Na(+) absorption (and as a consequence, Cl(-) and water absorption) across the inflamed mucosa.

Cyclic AMP-induced K+ secretion occurs independently of Cl- secretion in rat distal colon.

cAMP induces both active Cl(-) and active K(+) secretion in mammalian colon. It is generally assumed that a mechanism for K(+) exit is essential to maintain cells in the hyperpolarized state, thus favoring a sustained Cl(-) secretion. Both Kcnn4c and Kcnma1 channels are located in colon, and this study addressed the questions of whether Kcnn4c and/or Kcnma1 channels mediate cAMP-induced K(+) secretion and whether cAMP-induced K(+) secretion provides the driving force for Cl(-) secretion. Forskolin (FSK)-enhanced short-circuit current (indicator of net electrogenic ion transport) and K(+) fluxes were measured simultaneously in colonic mucosa under voltage-clamp conditions. Mucosal Na(+) orthovanadate (P-type ATPase inhibitor) inhibited active K(+) absorption normally present in rat distal colon. In the presence of mucosal Na(+) orthovanadate, serosal FSK induced both K(+) and Cl(-) secretion. FSK-induced K(+) secretion was 1) not inhibited by either mucosal or serosal 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34; a Kcnn4 channel blocker), 2) inhibited (92%) by mucosal iberiotoxin (Kcnma1 channel blocker), and 3) not affected by mucosal cystic fibrosis transmembrane conductance regulator inhibitor (CFTR(inh)-172). By contrast, FSK-induced Cl(-) secretion was 1) completely inhibited by serosal TRAM-34, 2) not inhibited by either mucosal or serosal iberiotoxin, and 3) completely inhibited by mucosal CFTR(inh)-172. These results indicate that cAMP-induced colonic K(+) secretion is mediated via Kcnma1 channels located in the apical membrane and most likely contributes to stool K(+) losses in secretory diarrhea. On the other hand, cAMP-induced colonic Cl(-) secretion requires the activity of Kcnn4b channels located in the basolateral membrane and is not dependent on the concurrent activation of apical Kcnma1 channels.

Over-expression of colonic K+ channels associated with severe potassium secretory diarrhoea after haemorrhagic shock.

A 67-year-old woman with end-stage renal disease (ESRD) was referred with chronic diarrhoea, severe hypokalaemia and recurrent colonic pseudo-obstructions following haemorrhagic shock. The cause of secretory diarrhoea was uncertain, but an ileostomy identified the colon as the source of the watery diarrhoea and potassium (K(+)) losses, and symptoms only resolved after colectomy. Immunohistochemistry of the colon revealed over-expression of high conductance K(+) (BK) channel protein in surface colonocytes and crypt cells compared with controls and other patients with ESRD. We hypothesize that colonic ischaemia during haemorrhagic shock led to increased BK channel expression and thus enhanced colonic K(+) and water secretion, resulting in severe hypokalaemia and colonic pseudo-obstruction.

Colonic Potassium Absorption and Secretion in Health and Disease.

The colon has large capacities for K+ absorption and K+ secretion, but its role in maintaining K+ homeostasis is often overlooked. For many years, passive diffusion and/or solvent drag were thought to be the primary mechanisms for K+ absorption in human and animal colon. However, it is now clear that apical H+ ,K+ -ATPase, in coordination with basolateral K+ -Cl- cotransport and/or K+ and Cl- channels operating in parallel, mediate electroneutral K+ absorption in animal colon. We now know that K+ absorption in rat colon reflects ouabain-sensitive and ouabain-insensitive apical H+ ,K+ -ATPase activities. Ouabain-insensitive and ouabain-sensitive H+ ,K+ -ATPases are localized in surface and crypt cells, respectively. Colonic H+ ,K+ -ATPase consists of α- (HKCα ) and ß- (HKCß ) subunits which, when coexpressed, exhibit ouabain-insensitive H+ ,K+ -ATPase activity in HEK293 cells, while HKCα coexpressed with the gastric ß-subunit exhibits ouabain-sensitive H+ ,K+ -ATPase activity in Xenopus oocytes. Aldosterone enhances apical H+ ,K+ -ATPase activity, HKCα specific mRNA and protein expression, and K+ absorption. Active K+ secretion, on the other hand, is mediated by apical K+ channels operating in a coordinated way with the basolateral Na+ -K+ -2Cl- cotransporter. Both Ca2+ -activated intermediate conductance K+ (IK) and large conductance K+ (BK) channels are located in the apical membrane of colonic epithelia. IK channel-mediated K+ efflux provides the driving force for Cl- secretion, while BK channels mediate active (e.g., cAMP-activated) K+ secretion. BK channel expression and activity are increased in patients with end-stage renal disease and ulcerative colitis. This review summarizes the role of apical H+ ,K+ -ATPase in K+ absorption, and apical BK channel function in K+ secretion in health and disease. © 2018 American Physiological Society. Compr Physiol 8:1513-1536, 2018.

Role of protein kinase C in aldosterone-induced non-genomic inhibition of basolateral potassium channels in human colonic crypts.

Aldosterone produces rapid, non-genomic, inhibition of basolateral intermediate conductance K(+) (IK(Ca)) channels in human colonic crypt cells but the intracellular second messengers involved are unclear. We therefore evaluated the role of protein kinase C (PKC) in aldosterone's non-genomic inhibitory effect on basolateral IK(Ca) channels in crypt cells from normal human sigmoid colon. Patch clamp studies revealed that in cell-attached patches, IK(Ca) channel activity decreased progressively to 38+/-8% (P<0.001) of the basal value 10 min after the addition of 1 nmol/L aldosterone, and decreased further to 23+/-6% (P<0.02) of the basal value 5 min after increasing the aldosterone concentration to 10 nmol/L. Pre-incubation of crypts with 1 micromol/L chelerythrine chloride or 1 micromol/L Gö 6976 (PKC inhibitors) prevented the inhibitory effect of aldosterone. Conversely, channel activity decreased to 60+/-9% (P<0.02) of the basal value 10 min after the addition of 500 nmol/L PMA (a PKC activator), whereas 4alpha-PMA (an inactive ester) had no effect. When aldosterone (10 nmol/L) and PMA were added together, IK(Ca) channel activity was inhibited to the same extent as with aldosterone alone. These results indicate that aldosterone's non-genomic inhibitory effect on the macroscopic basolateral K(+) conductance in human colonic crypts reflects PKC-mediated inhibition of IK(Ca) channels.

Infective and inflammatory diarrhoea: mechanisms and opportunities for novel therapies.

There have been significant advances in unravelling the cellular mechanisms of diarrhoea in common gut infections and colonic inflammation, as well as in the identification of targets for potential antidiarrhoeal drugs. Infective diarrhoea reflects activation of electrogenic Cl⁻ secretion, inhibition of electroneutral NaCl absorption and in some cases, downregulation of tight junctional proteins and increased apoptosis. In colonic inflammation, diarrhoea mainly reflects impairment of colonic Na⁺ and Cl⁻ absorption by inflammatory cytokines, leading to decreased water absorption. Stimulation of endogenous opiate-dependent pathways, manipulation of epithelial ion (Na⁺, K⁺ and Cl⁻) channels and suppression of proinflammatory cytokine production by a variety of drugs and novel molecules, offer opportunities to move evaluation of these potential antisecretory and anti-inflammatory agents from the laboratory into clinical trials.

Pathogenesis of diarrhea in ulcerative colitis: new views on an old problem.

BACKGROUND: Whereas water movement into the intestinal lumen occurs secondary to Cl secretion in secretory diarrheal diseases, defects in key transport processes lead to profound decreases in colonic Na, Cl, and water absorption in ulcerative colitis. STUDIES AND RESULTS: Recent studies indicate reduced expression/activity of apical Na channels and basolateral Na, K-ATPase, leading to loss of electrogenic Na absorption in the distal colon and rectum. There is also likely to be a decrease in electroneutral NaCl cotransport, which is present throughout the colon. Preliminary work on basolateral K channel abundance and activity in colonic epithelial cells suggests that whole-cell K conductance is decreased in ulcerative colitis, leading to epithelial cell depolarization, and further limitation of Na absorption. In addition, there is a marked reduction in colonic epithelial resistance, which reflects a decrease in the integrity of intercellular tight junctions and the presence of apoptotic foci. CONCLUSIONS: Impaired Na and Cl transport, combined with enhanced epithelial "leakiness," results in a profound decrease in the capacity of the inflamed colon to absorb salt and water. Transport abnormalities in ulcerative colitis may at least partly reflect the effects of proinflammatory cytokines, raising the possibility of novel approaches to the restoration of colonic absorptive capacity in this disease.

Dietary potassium and laxatives as regulators of colonic potassium secretion in end-stage renal disease.

BACKGROUND: In end-stage renal disease (ESRD), colonic potassium (K+) secretion increases as renal K+ excretion declines. The nature of this adaptive process is poorly understood, but post-prandial increases in plasma K+ concentration may be a determining factor. In addition, even though colonic K+ secretion increases in ESRD, interdialytic hyperkalaemia is a serious problem in haemodialysis patients, which might be reduced by stimulating colonic K+ secretion still further using laxatives. METHODS: Plasma K+ concentrations were measured in the fasting state, and for 180 min after the oral administration of 30 mmol of K+ to nine control subjects and 16 normokalaemic patients with ESRD (eight "predialysis" patients and eight patients undergoing continuous ambulatory peritoneal dialysis (CAPD)). Plasma K+ concentrations were also monitored for 180 min in fasting controls and ESRD patients who were not given the oral K+ load. To study the effect of laxatives on interdialytic hyperkalaemia, plasma K+ concentrations were measured in eight control subjects and 13 haemodialysis patients before and during 2 weeks treatment with bisacodyl (a cAMP-mediated laxative) and in five haemodialysis patients before and during 2 weeks treatment with lactulose (an osmotic laxative). RESULTS: Oral K+ loading caused plasma K+ concentration to rise within the normal range (3.5-5.1 mmol/l) in control subjects, while significantly higher concentrations were achieved in the "predialysis" patients and sustained hyperkalaemia developed in the CAPD patients. Bisacodyl treatment had no effect on plasma K+ concentrations in control subjects, but significantly decreased the mean interdialytic plasma K+ concentration (from 5.9+/-0.2 to 5.5+/-0.2 mmol/l, P<0.0005) in haemodialysis patients, whereas plasma K+ concentration did not change during lactulose treatment. CONCLUSIONS: Higher plasma K+ concentrations after food may help to maintain K+ homeostasis in ESRD by enhancing colonic K+ secretion. Bisacodyl may be useful for reducing interdialytic hyperkalaemia in patients undergoing haemodialysis.