Sodium and Potassium Content of Foods Consumed in an Italian Population and the Impact of Adherence to a Mediterranean Diet on Their Intake.

High sodium and low potassium intakes are associated with increased levels of blood pressure and risk of cardiovascular diseases. Assessment of habitual dietary habits are helpful to evaluate their intake and adherence to healthy dietary recommendations. In this study, we determined sodium and potassium food-specific content and intake in a Northern Italy community, focusing on the role and contribution of adherence to Mediterranean diet patterns. We collected a total of 908 food samples and measured sodium and potassium content using inductively coupled plasma mass spectrometry. Using a validated semi-quantitative food frequency questionnaire, we assessed habitual dietary intake of 719 adult individuals of the Emilia-Romagna region. We then estimated sodium and potassium daily intake for each food based on their relative contribution to the overall diet, and their link to Mediterranean diet patterns. The estimated mean sodium intake was 2.15 g/day, while potassium mean intake was 3.37 g/day. The foods contributing most to sodium intake were cereals (33.2%), meat products (24.5%, especially processed meat), and dairy products (13.6%), and for potassium they were meat (17.1%, especially red and white meat), fresh fruits (15.7%), and vegetables (15.1%). Adherence to a Mediterranean diet had little influence on sodium intake, whereas potassium intake was greatly increased in subjects with higher scores, resulting in a lower sodium/potassium ratio. Although we may have underestimated dietary sodium intake by not including discretionary salt use and there may be some degree of exposure misclassification as a result of changes in food sodium content and dietary habits over time, our study provides an overview of the contribution of a wide range of foods to the sodium and potassium intake in a Northern Italy community and of the impact of a Mediterranean diet on intake. The mean sodium intake was above the dietary recommendations for adults of 1.5-2 g/day, whilst potassium intake was only slightly lower than the recommended 3.5 g/day. Our findings suggest that higher adherence to Mediterranean diet patterns has limited effect on restricting sodium intake, but may facilitate a higher potassium intake, thereby aiding the achievement of healthy dietary recommendations.

Rapid development of vasopressin resistance in dietary K+ deficiency.

The association between diabetes insipidus (DI) and chronic dietary K+ deprivation is well known, but it remains uncertain how the disorder develops and whether it is influenced by the sexual dimorphism in K+ handling. Here, we determined the plasma K+ (PK) threshold for DI in male and female mice and ascertained if DI is initiated by polydipsia or by a central or nephrogenic defect. C57BL6J mice were randomized to a control diet or to graded reductions in dietary K+ for 8 days, and kidney function and transporters involved in water balance were characterized. We found that male and female mice develop polyuria and secondary polydipsia. Altered water balance coincided with a decrease in aquaporin-2 (AQP2) phosphorylation and apical localization despite increased levels of the vasopressin surrogate marker copeptin. No change in the protein abundance of urea transporter-A1 was observed. The Na+-K+-2Cl- cotransporter decreased only in males. Desmopressin treatment failed to reverse water diuresis in K+-restricted mice. These findings indicate that even a small fall in PK is associated with nephrogenic DI (NDI), coincident with the development of altered AQP2 regulation, implicating low PK as a causal trigger of NDI. We found that PK decreased more in females, and, consequently, females were more prone to develop NDI. Together, these data indicate that AQP2 regulation is disrupted by a small decrease in PK and that the response is influenced by sexual dimorphism in K+ handling. These findings provide new insights into the mechanisms linking water and K+ balances and support defining the disorder as "potassium-dependent NDI."NEW & NOTEWORTHY This study shows that aquaporin-2 regulation is disrupted by a small fall in plasma potassium levels and the response is influenced by sexual dimorphism in renal potassium handling. The findings provided new insights into the mechanisms by which water balance is altered in dietary potassium deficiency and support defining the disorder as "potassium-dependent nephrogenic diabetes insipidus."

Rise in Potassium Deficiency in the US Population Linked to Agriculture Practices and Dietary Potassium Deficits.

This paper, for the first time, provides evidence that current practices that lead to agricultural crop removal of potassium are unsustainable and likely contributed to the decline in dietary potassium intake and rise in hypokalemia prevalence in the US population. Potassium concentrations in beef, pork, turkey, fruit, vegetables, cereal crops, and so forth decreased between 1999 and 2015 based on the examination of potassium values of food items of USDA standard reference. Ratios of potassium input to removal by crops between 1987 and 2014, potassium in topsoil, and crop-available soil potassium in US farms all declined in recent years. Reported reductions in dietary potassium intake correspond to these decreases in the food supply and to increases in hypokalemia prevalence in the US population. Results of this paper provide new understanding on links between potassium management in agricultural practices and potassium intake deficits, which is needed for combating increasing hypokalemia prevalence in the US population.

Experiences of the Dietary Management of Serum Potassium in Chronic Kidney Disease: Interviews With UK Adults on Maintenance Hemodialysis.

OBJECTIVE: Dietary potassium restrictions in kidney disease are complex to follow and may reduce quality of life. However, details on this impact are sparse. We therefore sought to explore patients' perspectives on the experienced impact of following low-potassium diets, to inform clinical practice and research. DESIGN AND METHODS: Qualitative semistructured interviews were undertaken in a UK teaching hospital with adults undergoing maintenance hemodialysis. Audio-recorded, transcribed interviews underwent thematic analysis. RESULTS: 34 adults (19 women, 15 men, and mean age 66.7 ± 10.9 years) with chronic kidney disease (CKD) participated. Our analysis identified three themes with subthemes: "What is left for me to eat now?"; "I'm obviously different"; "Food can be socially awkward", and one outlying theme: "Money doesn't grow on trees." Practical difficulties experienced when coming to terms with dietary restrictions meant testing out advice and experimenting with low- and high-potassium foods, to find a reasonable compromise, despite worries they could die from eating too much potassium. Interactions with food providers were dependent on pre-existing relationships, and maintaining these, at the expense of their dietary needs. Obtaining dietary requirements in restaurants often resulted in conflict with less concern for maintaining a relationship with those in the restaurant. Some individuals experienced financial difficulties, and decisions were made to prioritize family needs over their own dietary requirements. CONCLUSION: Low-potassium diets bring practical and psychosocial consequences which significantly impacts people living with CKD. Renal health professionals should offer more support to people on a low-potassium diet. Public education on dietary potassium requirements in CKD, particularly in the food service industry to increase awareness, may be a worthwhile intervention.

NBCe1-A is required for the renal ammonia and K+ response to hypokalemia.

Hypokalemia increases ammonia excretion and decreases K+ excretion. The present study examined the role of the proximal tubule protein NBCe1-A in these responses. We studied mice with Na+-bicarbonate cotransporter electrogenic, isoform 1, splice variant A (NBCe1-A) deletion [knockout (KO) mice] and their wild-type (WT) littermates were provided either K+ control or K+-free diet. We also used tissue sections to determine the effect of extracellular ammonia on NaCl cotransporter (NCC) phosphorylation. The K+-free diet significantly increased proximal tubule NBCe1-A and ammonia excretion in WT mice, and NBCe1-A deletion blunted the ammonia excretion response. NBCe1-A deletion inhibited the ammoniagenic/ammonia recycling enzyme response in the cortical proximal tubule (PT), where NBCe1-A is present in WT mice. In the outer medulla, where NBCe1-A is not present, the PT ammonia metabolism response was accentuated by NBCe1-A deletion. KO mice developed more severe hypokalemia and had greater urinary K+ excretion during the K+-free diet than did WT mice. This was associated with blunting of the hypokalemia-induced change in NCC phosphorylation. NBCe1-A KO mice have systemic metabolic acidosis, but experimentally induced metabolic acidosis did not alter NCC phosphorylation. Although KO mice have impaired ammonia metabolism, experiments in tissue sections showed that lack of ammonia does impair NCC phosphorylation. Finally, urinary aldosterone was greater in KO mice than in WT mice, but neither expression of epithelial Na+ channel α-, ß-, and γ-subunits nor of H+-K+-ATPase α1- or α2-subunits correlated with changes in urinary K+. We conclude that NBCe1-A is critical for the effect of diet-induced hypokalemia to increase cortical proximal tubule ammonia generation and for the expected decrease in urinary K+ excretion.

Potassium conservation is impaired in mice with reduced renal expression of Kir4.1.

To better understand the role of the inward-rectifying K channel Kir4.1 (KCNJ10) in the distal nephron, we initially studied a global Kir4.1 knockout mouse (gKO), which demonstrated the hypokalemia and hypomagnesemia seen in SeSAME/EAST syndrome and was associated with reduced Na/Cl cotransporter (NCC) expression. Lethality by ~3 wk, however, limits the usefulness of this model, so we developed a kidney-specific Kir4.1 "knockdown" mouse (ksKD) using a cadherin 16 promoter and Cre-loxP methodology. These mice appeared normal and survived to adulthood. Kir4.1 protein expression was decreased ~50% vs. wild-type (WT) mice by immunoblotting, and immunofluorescence showed moderately reduced Kir4.1 staining in distal convoluted tubule that was minimal or absent in connecting tubule and cortical collecting duct. Under control conditions, the ksKD mice showed metabolic alkalosis and relative hypercalcemia but were normokalemic and mildly hypermagnesemic despite decreased NCC expression. In addition, the mice had a severe urinary concentrating defect associated with hypernatremia, enlarged kidneys with tubulocystic dilations, and reduced aquaporin-3 expression. On a K/Mg-free diet for 1 wk, however, ksKD mice showed marked hypokalemia (serum K: 1.5 ± 0.1 vs. 3.0 ± 0.1 mEq/l for WT), which was associated with renal K wasting (transtubular K gradient: 11.4 ± 0.8 vs. 1.6 ± 0.4 in WT). Phosphorylated-NCC expression increased in WT but not ksKD mice on the K/Mg-free diet, suggesting that loss of NCC adaptation underlies the hypokalemia. In conclusion, even modest reduction in Kir4.1 expression results in impaired K conservation, which appears to be mediated by reduced expression of activated NCC.

Distal tubule basolateral potassium channels: cellular and molecular mechanisms of regulation.

PURPOSE OF REVIEW: Multiple clinical and translational evidence support benefits of high potassium diet; however, there many uncertainties underlying the molecular and cellular mechanisms determining effects of dietary potassium. Kir4.1 and Kir5.1 proteins form a functional heteromer (Kir4.1/Kir5.1), which is the primary inwardly rectifying potassium channel on the basolateral membrane of both distal convoluted tubule (DCT) and the collecting duct principal cells. The purpose of this mini-review is to summarize latest advances in our understanding of the evolution, physiological relevance and mechanisms controlling these channels. RECENT FINDINGS: Kir4.1 and Kir5.1 channels play a critical role in determining electrolyte homeostasis in the kidney and blood pressure, respectively. It was reported that Kir4.1/Kir5.1 serves as potassium sensors in the distal nephron responding to variations in dietary intake and hormonal stimuli. Global and kidney specific knockouts of either channel resulted in hypokalemia and severe cardiorenal phenotypes. Furthermore, knock out of Kir5.1 in Dahl salt-sensitive rat background revealed the crucial role of the Kir4.1/Kir5.1 channel in salt-induced hypertension. SUMMARY: Here, we focus on reviewing novel experimental evidence of the physiological function, expression and hormonal regulation of renal basolateral inwardly rectifying potassium channels. Further investigation of molecular and cellular mechanisms controlling Kir4.1 and Kir4.1/Kir5.1-mediating pathways and development of specific compounds targeting these channels function is essential for proper control of electrolyte homeostasis and blood pressure.

Randomized, Controlled Trial of the Effect of Dietary Potassium Restriction on Nerve Function in CKD.

BACKGROUND AND OBJECTIVES: Neuromuscular complications are almost universal in CKD by the time that a patient commences dialysis. Recent studies have indicated that chronic hyperkalemia may contribute to the development of neuropathy in CKD. This study was undertaken to determine whether dietary restriction of potassium intake may be a neuroprotective factor in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 24-month prospective, single-blind, randomized, controlled trial was undertaken in 47 consecutively recruited patients with stages 3 and 4 CKD. The intervention arm (n=23) was prescribed a diet focusing on potassium restriction to meet a monthly serum potassium level of ≤4.5 mEq/L, with oral sodium polystyrene sulfonate provided if dietary advice failed to achieve the target. The control arm (n=24) received dietary advice regarding general nutrition. The primary outcome was the change in the total neuropathy score evaluated by a blinded observer. Secondary outcomes included electrolyte levels, gait speed, neurophysiologic parameters, and health-related quality of life scores. Five patients withdrew before initiation of treatment, and final analysis consisted of n=21 in each group. RESULTS: There was a greater increase in total neuropathy score from baseline to final assessment in the control arm compared with the intervention arm (6.1±6.2-8.6±7.9 controls; 7.8±7.4-8.2±7.5 intervention; change 2.8±3.3-0.4±2.2, respectively; P<0.01). The intervention significantly reduced mean serum potassium compared with controls (4.6±0.1-4.8±0.1 mEq/L mean recorded every 6 months over the trial duration; P=0.03). There were no adverse changes in other nutritional parameters. Improved gait speed was also noted in the intervention arm compared with the control arm, with a mean increase of 0.15±0.17 m/s in the intervention group versus 0.02±0.16 m/s in the control group (P=0.01). CONCLUSIONS: Our results provide important preliminary evidence that dietary potassium restriction confers neuroprotection in CKD and should be confirmed in a larger multicenter trial.

Racial and Ethnic Differences in Mortality Associated with Serum Potassium in a Large Hemodialysis Cohort.

BACKGROUND: Hyperkalemia is observed in chronic kidney disease patients and may be a risk factor for life-threatening arrhythmias and death. Race/ethnicity may be important modifiers of the potassium-mortality relationship in maintenance hemodialysis (MHD) patients given that potassium intake and excretion vary among minorities. METHODS: We examined racial/ethnic differences in baseline serum potassium levels and all-cause and cardiovascular mortality using Cox proportional hazard models and restricted cubic splines in a cohort of 102,241 incident MHD patients. Serum potassium was categorized into 6 groups: ≤3.6, >3.6 to ≤4.0, >4.0 to ≤4.5 (reference), >4.5 to ≤5.0, >5.0 to ≤5.5, and >5.5 mEq/L. Models were adjusted for case-mix and malnutrition-inflammation cachexia syndrome (MICS) covariates. RESULTS: The cohort was composed of 50% whites, 34% African-Americans, and 16% Hispanics. Hispanics tended to have the highest baseline serum potassium levels (mean ± SD: 4.58 ± 0.55 mEq/L). Patients in our cohort were followed for a median of 1.3 years (interquartile range 0.6-2.5). In our cohort, associations between higher potassium (>5.5 mEq/L) and higher mortality risk were observed in African-American and whites, but not Hispanic patients in models adjusted for case-mix and MICS covariates. While in Hispanics only, lower serum potassium (<3.6 mEq/L) levels were associated with higher mortality risk. Similar trends were observed for cardiovascular mortality. CONCLUSIONS: Higher potassium levels were associated with higher mortality risk in white and African-American MHD patients, whereas lower potassium levels were associated with higher death risk in Hispanics. Further studies are needed to determine the underlying mechanisms for the differential association between potassium and mortality across race/ethnicity.

Calcineurin inhibitors block sodium-chloride cotransporter dephosphorylation in response to high potassium intake.

Dietary potassium intake is inversely related to blood pressure and mortality. Moreover, the sodium-chloride cotransporter (NCC) plays an important role in blood pressure regulation and urinary potassium excretion in response to potassium intake. Previously, it was shown that NCC is activated by the WNK4-SPAK cascade and dephosphorylated by protein phosphatase. However, the mechanism of NCC regulation with acute potassium intake is still unclear. To identify the molecular mechanism of NCC regulation in response to potassium intake, we used adult C57BL/6 mice fed a 1.7% potassium solution by oral gavage. We confirmed that acute potassium load rapidly dephosphorylated NCC, which was not dependent on the accompanying anions. Mice were treated with tacrolimus (calcineurin inhibitor) and W7 (calmodulin inhibitor) before the oral potassium loads. Dephosphorylation of NCC induced by potassium was significantly inhibited by both tacrolimus and W7 treatment. There was no significant difference in WNK4, OSR1, and SPAK expression after high potassium intake, even after tacrolimus and W7 treatment. Another phosphatase, protein phosphatase 1, and its endogenous inhibitor I-1 did not show a significant change after potassium intake. Hyperkaliuria, induced by high potassium intake, was significantly suppressed by tacrolimus treatment. Thus, calcineurin is activated by an acute potassium load, which rapidly dephosphorylates NCC, leading to increased urinary potassium excretion.

Modified Nutritional Recommendations to Improve Dietary Patterns and Outcomes in Hemodialysis Patients.

The renal diet has traditionally been regarded as one of the most complex medical nutrition therapies to teach, understand, and implement. Specifically, patients are instructed to limit fruits, vegetables, nuts, legumes, dairy, and whole grains because of both phosphorus and potassium concerns. Furthermore, hemodialysis patients are often encouraged to decrease fluid intake to control interdialytic weight gain. These restrictions can result in frustration, lack of autonomy, and the perception that there is nothing left to eat. It is possible that the traditional renal diet may be liberalized, with a focus on whole foods low in sodium and phosphorus additives, to afford patients greater choices and ultimately improved outcomes. Therefore, the objective of this review is to concisely assess the evidence in support of a renal diet focused primarily on reducing the intake of sodium and inorganic phosphorus. Finally, the limited evidence for restrictions on dietary potassium intake is summarized.

Bioavailability of potassium from potatoes and potassium gluconate: a randomized dose response trial.

BACKGROUND: The bioavailability of potassium should be considered in setting requirements, but to our knowledge, the bioavailability from individual foods has not been determined. Potatoes provide 19-20% of potassium in the American diet. OBJECTIVE: We compared the bioavailability and dose response of potassium from nonfried white potatoes with skin [targeted at 20, 40, and 60 milliequivalents (mEq) K] and French fries (40 mEq K) with potassium gluconate at the same doses when added to a basal diet that contained ∼60 mEq K. DESIGN: Thirty-five healthy, normotensive men and women with a mean ± SD age of 29.7 ± 11.2 y and body mass index (in kg/m(2)) of 24.3 ± 4.4 were enrolled in a single-blind, crossover, randomized controlled trial. Participants were partially randomly assigned to the order of testing for nine 5-d interventions of additional potassium as follows: 0 (control; repeated at phases 1 and 5), 20, 40, and 60 mEq K/d consumed as a potassium gluconate supplement or as unfried potato or 40 mEq K from French fries completed at phase 9. The bioavailability of potassium was determined from the area under the curve (AUC) of serial blood draws and cumulative urinary excretion during a 24-h period and from a kinetic analysis. The effects of the potassium source and dose on the change in blood pressure and augmentation index (AIx) were determined. RESULTS: The serum potassium AUC increased with the dose (P < 0.0001) and did not differ because of the source (P = 0.53). Cumulative 24-h urinary potassium also increased with the dose (P < 0.0001) and was greater with the potato than with the supplement (P < 0.0001). The kinetic analysis showed the absorption efficiency was high across all interventions (>94% ± 12%). There were no significant differences in the change in blood pressure or AIx with the treatment source or dose. CONCLUSIONS: The bioavailability of potassium is as high from potatoes as from potassium gluconate supplements. Future studies that measure the effect of dietary potassium on blood pressure will need to evaluate the effect of various dietary sources on potassium retention and in both normal and hypertensive populations. This trial was registered at clinicaltrials.gov as NCT01881295.

A green algae mixture of Scenedesmus and Schroederiella attenuates obesity-linked metabolic syndrome in rats.

This study investigated the responses to a green algae mixture of Scenedesmus dimorphus and Schroederiella apiculata (SC) containing protein (46.1% of dry algae), insoluble fibre (19.6% of dry algae), minerals (3.7% of dry algae) and omega-3 fatty acids (2.8% of dry algae) as a dietary intervention in a high carbohydrate, high fat diet-induced metabolic syndrome model in four groups of male Wistar rats. Two groups were fed with a corn starch diet containing 68% carbohydrates as polysaccharides, while the other two groups were fed a diet high in simple carbohydrates (fructose and sucrose in food, 25% fructose in drinking water, total 68%) and fats (saturated and trans fats from beef tallow, total 24%). High carbohydrate, high fat-fed rats showed visceral obesity with hypertension, insulin resistance, cardiovascular remodelling, and nonalcoholic fatty liver disease. SC supplementation (5% of food) lowered total body and abdominal fat mass, increased lean mass, and attenuated hypertension, impaired glucose and insulin tolerance, endothelial dysfunction, infiltration of inflammatory cells into heart and liver, fibrosis, increased cardiac stiffness, and nonalcoholic fatty liver disease in the high carbohydrate, high fat diet-fed rats. This study suggests that the insoluble fibre or protein in SC helps reverse diet-induced metabolic syndrome.

A systematic review of vascular and endothelial function: effects of fruit, vegetable and potassium intake.

AIM: To review the relationships between: 1) Potassium and endothelial function; 2) Fruits and vegetables and endothelial function; 3) Potassium and other measures of vascular function; 4) Fruits and vegetables and other measures of vascular function. DATA SYNTHESIS: An electronic search for intervention trials investigating the effect of potassium, fruits and vegetables on vascular function was performed in MEDLINE, EMBASE and the Cochrane Library. Potassium appears to improve endothelial function with a dose of >40 mmol/d, however the mechanisms for this effect remain unclear. Potassium may improve measures of vascular function however this effect may be dependent on the effect of potassium on blood pressure. The effect of fruit and vegetables on endothelial function independent of confounding variables is less clear. Increased fruit and vegetable intake may improve vascular function only in high risk populations. CONCLUSION: Increasing dietary potassium appears to improve vascular function but the effect of increasing fruit and vegetable intake per se on vascular function is less clear.

Salt loading has a more deleterious effect on flow-mediated dilation in salt-resistant men than women.

BACKGROUND AND AIMS: Dietary sodium loading has been shown to adversely impact endothelial function independently of blood pressure (BP). However, it is unknown whether dietary sodium loading impacts endothelial function differently in men as compared to women. The aim of this study was to test the hypothesis that endothelial-dependent dilation (EDD) would be lower in men as compared to women in response to a high sodium diet. METHODS AND RESULTS: Thirty subjects (14F, 31±2y; 16M, 29±2y) underwent a randomized, crossover, controlled diet study consisting of 7 days of low sodium (LS; 20 mmol/day) and 7 days of high sodium (HS; 300-350 mmol/day). Salt-resistance was determined by a change in 24-hr mean arterial pressure (MAP) ≤ 5 mm Hg between HS and LS as assessed on day 7 of each diet. Blood and 24-hr urine were also collected and EDD was assessed by brachial artery flow-mediated dilation (FMD). By design, MAP was not different between LS and HS conditions and urinary sodium excretion increased on HS diet (P < 0.01). FMD did not differ between men and women on the LS diet (10.2 ± 0.65 vs. 10.7 ± 0.83; P > 0.05) and declined in both men and women on HS (P < 0.001). However, FMD was lower in men as compared to women on HS (5.7 ± 0.5 vs. 8.6 ± 0.86; P < 0.01). CONCLUSIONS: HS reduced FMD in both men and women. In response to an HS diet, FMD was lower in men compared to women suggesting a greater sensitivity of the vasculature to high sodium in men.

Increasing plasma [K+] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis.

Dietary potassium loading results in rapid kaliuresis, natriuresis, and diuresis associated with reduced phosphorylation (p) of the distal tubule Na(+)-Cl(-) cotransporter (NCC). Decreased NCC-p inhibits NCC-mediated Na(+) reabsorption and shifts Na(+) downstream for reabsorption by epithelial Na(+) channels (ENaC), which can drive K(+) secretion. Whether the signal is initiated by ingesting potassium or a rise in plasma K(+) concentration ([K(+)]) is not understood. We tested the hypothesis, in male rats, that an increase in plasma [K(+)] is sufficient to reduce NCC-p and drive kaliuresis. After an overnight fast, a single 3-h 2% potassium (2%K) containing meal increased plasma [K(+)] from 4.0 ± 0.1 to 5.2 ± 0.2 mM; increased urinary K(+), Na(+), and volume excretion; decreased NCC-p by 60%; and marginally reduced cortical Na(+)-K(+)-2Cl(-) cotransporter (NKCC) phosphorylation 25% (P = 0.055). When plasma [K(+)] was increased by tail vein infusion of KCl to 5.5 ± 0.1 mM over 3 h, significant kaliuresis and natriuresis ensued, NCC-p decreased by 60%, and STE20/SPS1-related proline alanine-rich kinase (SPAK) phosphorylation was marginally reduced 35% (P = 0.052). The following were unchanged at 3 h by either the potassium-rich meal or KCl infusion: Na(+)/H(+) exchanger 3 (NHE3), NHE3-p, NKCC, ENaC subunits, and renal outer medullary K(+) channel. In summary, raising plasma [K(+)] by intravenous infusion to a level equivalent to that observed after a single potassium-rich meal triggers renal kaliuretic and natriuretic responses, independent of K(+) ingestion, likely driven by decreased NCC-p and activity sufficient to shift sodium reabsorption downstream to where Na(+) reabsorption and flow drive K(+) secretion.

Basic research: Salt wasting in distal renal tubular acidosis-new look, old problem.

Acidosis affects sodium and potassium excretion, likely via the pH sensitivity of ion transporters. A recent paper shows that ß-intercalated cells with deleted H(+)-ATPase release ATP into urine, which induces the production of prostaglandin E2 (PGE2). PGE2 then reduces sodium absorption in the principal cells of the cortical collecting tubule and increases potassium secretion.

Renal ß-intercalated cells maintain body fluid and electrolyte balance.

Inactivation of the B1 proton pump subunit (ATP6V1B1) in intercalated cells (ICs) leads to type I distal renal tubular acidosis (dRTA), a disease associated with salt- and potassium-losing nephropathy. Here we show that mice deficient in ATP6V1B1 (Atp6v1b1-/- mice) displayed renal loss of NaCl, K+, and water, causing hypovolemia, hypokalemia, and polyuria. We demonstrated that NaCl loss originated from the cortical collecting duct, where activity of both the epithelial sodium channel (ENaC) and the pendrin/Na(+)-driven chloride/bicarbonate exchanger (pendrin/NDCBE) transport system was impaired. ENaC was appropriately increased in the medullary collecting duct, suggesting a localized inhibition in the cortex. We detected high urinary prostaglandin E2 (PGE2) and ATP levels in Atp6v1b1-/- mice. Inhibition of PGE2 synthesis in vivo restored ENaC protein levels specifically in the cortex. It also normalized protein levels of the large conductance calcium-activated potassium channel and the water channel aquaporin 2, and improved polyuria and hypokalemia in mutant mice. Furthermore, pharmacological inactivation of the proton pump in ß-ICs induced release of PGE2 through activation of calcium-coupled purinergic receptors. In the present study, we identified ATP-triggered PGE2 paracrine signaling originating from ß-ICs as a mechanism in the development of the hydroelectrolytic imbalance associated with dRTA. Our data indicate that in addition to principal cells, ICs are also critical in maintaining sodium balance and, hence, normal vascular volume and blood pressure.

Opening lines of communication in the distal nephron.

The distal nephron is composed of two main cell types: principal cells and intercalated cells. These cells have distinct morphologic features that allow them to be readily distinguished by light microscopy, as well as distinct suites of proteins that facilitate cell-specific transport properties. In this issue of the JCI, Gueutin and colleagues describe a new mechanism by which ß-intercalated cells, via release of ATP and prostaglandin E2 (PGE2), influence the activity of transporters in principal cells.