Effect Of Volume Depletion Research Articles

Hypomagnesemia-induced Hypokalemia Is Associated with Higher Activities of ENaC and ROMK

Background: Hypokalemia occurs in 40 to 60% of patients with hypomagnesemia, and can result in cardiac arrhythmia and sudden death. Along the distal nephron, a decrease in intracellular Mg2+ has been proposed to release Mg2+-mediated inhibition of renal outer medullary K+ (ROMK) channels, increasing urinary K+ excretion. However, hypomagnesemia alone is not suffcient to cause hypokalemia. Higher activity of the epithelial Na+ channel (ENaC), which provides the driving force for K+ secretion via ROMK, has been proposed to be an additional requirement. We tested the hypothesis that hypomagnesemia-induced hypokalemia is associated with higher activities of ENaC and ROMK. Methods: C57/BL6 mice were fed normal (NL) [Mg2+ 0.15%/NaCl ~0.49% (wt/wt)], low Mg2+ (LM) [Mg2+ 0.0015– 0.003% (wt/wt); NaCl ~0.49%], low sodium (LS) [Na+ <0.001% (wt/wt)], or combined low sodium and low Mg2+ (LS/LM) [Mg2+ 0.0015-0.003%/Na+ <0.001% (wt/wt)] diets for 3 or 7 days. All diets contained diet [K+ ~0.8% (wt/wt)]. Kidneys and blood were harvested for Western blotting and measurement of plasma [K+]. DCT2/CNT from mice on NL or LS/LM diet were microdissected for measurement of ROMK activity via patch-clamping of split open tubules. Results: Plasma [K+] was only significantly lower than in mice on NL diet in mice on LS/LM diet. Abundances of cleaved α- and γ-ENaC, which correlate with ENaC activity, were lower on a LM diet compared with NL diet. Consistent with lower ENaC activity, the urinary Na+:K+ ratio following acute amiloride administration was lower in mice on LM diet than in mice on NL. While abundances of cleaved α- and γ-ENaC abundances were higher on LS diet than on LS/LM or NL diets, they did not differ between mice on LS/LM or NL diets. As expected, mice on LS diet displayed higher plasma aldosterone than mice on NL diet, but plasma aldosterone did not differ between mice on LS/LM or control diets. ROMK activity along DCT2/CNT was higher in mice on LS/LM diet than compared with mice on NL diet. Conclusions: While LM diet lowered and LS diet stimulated ENaC cleavage compared with controls, ENaC cleavage was similar in mice on LS/LM or NL diets, suggesting dietary Na+ and Mg2+ deficiency counteract each other with regard to ENaC activation. Other studies have shown that the inhibitory effect of hypokalemia on aldosterone secretion may be more potent than the effect of volume depletion on promoting aldosterone secretion, which may explain the lower plasma aldosterone in mice on LS/LM diet than in mice on LS diet. Overall, our data suggest that both ENaC and disinhibition of ROMK are required for the development of hypokalemia in the context of hypomagnesemia. Y.M., Uehara Foundation; J.M., NIDDK DK132066; W-H.W., NIDDK DK133220. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A review of sotagliflozin for use in type 1 diabetes.

Type 1 diabetes is a challenging disease that is largely managed with the use of insulin. The risk of hypoglycemia, side effects of weight gain, and high glucose variability associated with insulin use have prompted researchers to explore additional therapies to treat this condition. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of medications that lower glucose in type 2 diabetes patients independent of insulin action, and have been studied for use in the type 1 diabetes population. Sotagliflozin is an SGLT2 inhibitor that demonstrates a unique binding affinity for the SGLT1 receptor. A total of three phase III clinical trials (inTandem1, inTandem2, and inTandem3) were conducted to evaluate the safety and efficacy of sotagliflozin in type 1 diabetes. A modest hemoglobin A1C reduction of 0.3–0.4% was observed, with secondary benefits of reduced glucose variability, reduced insulin dosage, and positive weight loss effects. Overall there was a reduction in the risk of severe hypoglycemia with sotagliflozin, but a higher rate of ketone formation and risk of diabetic ketoacidosis was observed, along with increased mycotic infections and volume depletion effects.

Gliflozin monotherapy for type 2 diabetes: a review of NICE Technology Appraisal 390

Gliflozin monotherapy for type 2 diabetes: a review of <scp>NICE</scp> Technology Appraisal 390

EFFECTS OF VOLUME DEPLETION AND NaHCO3 LOADING ON THE EXPRESSION OF Na+/H+ EXCHANGER ISOFORM 3, Na+ : HCO COTRANSPORTER TYPE 1 AND NITRIC OXIDE SYNTHASE IN RAT KIDNEY

1. The effects of volume depletion and NaHCO(3) loading on the expression of Na(+)/H(+) exchanger isoform 3 (NHE3), Na(+) : HCO(3)(-) cotransporter type 1 (NBC1) and neuronal (n) and inducible (i) isoforms of nitric oxide synthase (NOS) were determined in rat kidney. 2. Adult male Sprague-Dawley rats were used. Rats were divided into four groups: (i) euvolaemic (EC); (ii) hypovolaemic (HC); (iii) euvolaemia with NaHCO(3) loading (EB); and (iv) hypovolaemia with NaHCO(3) loading (HB). The expression of NHE3, NBC1, nNOS and iNOS proteins was determined in the cortex of the kidney by immunoblotting and immunohistochemistry. Tissue content of nitric oxide (NO) metabolites (NO(x)) were also determined in the cortex using a colourimetric assay. 3. Compared with the EC group, the expression of NHE3 and NBC1 was increased in the HC group and decreased in the EB group. Comparing the EB and HB groups, the expression of NHE3 and NBC1 was higher in the latter group. The expression of NHE3 was decreased and that of NBC1 was increased in the HB group compared with the HC group. The NO(x) content and nNOS expression were decreased in the hypovolaemic (HC) and NaHCO(3)-loaded (EB and HB) rats. Moreover, the expression of iNOS was decreased in the HB group compared with the other groups. 4. An altered volume status and NaHCO(3) loading may affect the regulation of NHE3 and NBC1 in the kidney and the endogenous NO system may play a role in the observed effects.

Risk factors and outcome of hospital-acquired acute renal failure: Clinical Epidemiologic Study

In order to evaluate potential risk factors for the development of hospital-acquired acute renal failure, a case-control study was performed, comparing patients with hospital-acquired acute renal failure with control subjects matched on age, sex, hospital, service of admission, and baseline renal function. The same patients were then reanalyzed utilizing a cohort study design to investigate outcomes from this syndrome. The following elevated odds ratios (95 percent confidence interval) were found while simultaneously adjusting for possible confounding variables using logistic regression: volume depletion, 9.4 (2.1 to 42.8); aminoglycoside use, 5.6 (1.3 to 23.7); congestive heart failure 9.0 (2.1 to 38.9); radiocontrast exposure, 4.9 (1.2 to 19.7); and septic shock, approached infinity, p <0.0001. The effect of volume depletion was markedly accentuated in those with diabetes (odds ratio = 116.7) and decreased in those without diabetes (odds ratio = 1.9) (p <0.05). The risk from aminoglycoside use markedly increased with increasing age (p <0.002). Finally, the development of hospital-acquired acute renal failure was associated with a marked increase in the risk of dying—the relative risk (95 percent confidence interval) was 6.2 (2.6 to 14.9)—and a marked increase in length of stay, from a median of 13 days in control subjects to a median of 23 days in case subjects (p = 0.005). In conclusion, hospital-acquired acute renal failure is a serious illness. Attempts to prevent it should focus on proved risk factors.

Effect of volume depletion on the afferent arterioles in the avian kidney.

Nine white leghorn chickens were injected i.m. with furosemide (10 to 60 mg/kg body weight) twice daily for 18 days. The birds were then anesthetized with a combination of equithesin and diazepam and the kidneys perfused via the heart. Kidney tissue was sectioned serially and the granular epithelioid cells were counted in the juxtaglomerular apparatuses of the furosemide treated birds and in 3 normal chickens. Hyperplasia and hypergranulation of the epithelioid cells was found to occur in the juxtaglomerular apparatuses of both mammalian and reptilian type nephrons (with and without Henles loop) in the furosemide treated group. This finding was interpreted as an effect of hypovolaemia on the juxtaglomerular apparatuses. Furosemide caused an immediate stop in weight gain, an increase in the erythrocyte volume fraction and a sudden drop in blood pressure. The blood pressure later rose to subnormal levels. The heart rate was not altered. Plasma sodium and chloride fell significantly one day after furosemide administration and remained low throughout the experiment. Potassium fell during the second part of the experimental period. Captopril was injected after 18 days of furosemide treatment and lowered the blood pressure significantly. This was interpreted as indirect evidence for the presence of renin in the granular epithelioid cells and indicates the importance of the renin angiotensin system in maintaining the blood pressure in hypovolaemic conditions.

Renin release in turtles: effects of volume depletion and furosemide administration

To gain insight into the phylogenetic history of mechanisms controlling renin release, we conducted studies in the freshwater turtle Pseudemys scripta. Maneuvers known to stimulate renin release in mammals were evoked in the turtle, and the response was compared with that in mammals. Cumulative hemorrhage (30% blood vol) in anesthetized turtles failed to increase renin even though arterial pressure was reduced to 50% of control. An even more severe hemorrhage (60% blood loss) or hypotension induced by nitroprusside infusion in unanesthetized turtles also failed to evoke an enhanced level of renin. However, under identical experimental conditions, a 15% blood loss in rats increased renin at least fourfold (P less than 0.01). In other studies 48 h of furosemide administration in awake turtles increased renin more than threefold (P less than 0.05) and were accompanied by concomitant reductions in plasma sodium and potassium (P less than 0.05). The general conclusions drawn from these studies is that renin secretion in this primitive vertebrate is similar to that in mammals with respect to renal tubular and electrolyte mechanisms, but unlike all mammals tested these turtles do not possess an intrarenal baroreceptor component in renin control.

Effect of volume depletion and subsequent propranolol treatment on blood pressure and plasma renin activity in patients with essential and with renovascular hypertension.

1. In nineteen patients, five with unilateral renal artery stenosis and fourteen with essential hypertension (WHO grades I–II), blood pressure, plasma and extracellular fluid volumes and plasma renin activity were studied at the end of three sequential periods: (a) after at least 3 days on a 60 mmol Na+ diet; (b) after 3 days of salt depletion induced with a diuretic and sustained on a 20 mmol Na+ diet; (c) after 3 days during which the 20 mmol Na+ diet was continued and beta-receptor blockade was induced by increasing dosages of propranolol up to 320 mg daily. 2. After sodium depletion extracellular fluid volume and plasma volume decreased and plasma renin activity increased; blood pressure did not change significantly. 3. After adding propranolol, plasma volume and extracellular fluid volume remained low, and there was a significant decrease in plasma renin activity and blood pressure. 4. No correlation could be demonstrated between changes of blood pressure and plasma renin activity. 5. When the responses of the five patients with renal artery stenosis were compared with those of the fourteen patients with essential hypertension, no significant differences were found. 6. Propranolol has a strong anti-hypertensive effect after Na+ depletion, irrespective of the absolute activities of plasma renin.

Dual effect of potent diuretics on renal handling of phosphate in man.

Inorganic phosphate excretion appeared to reflect changes in reabsorptive activity within the proximal nephron following diuretic administration in man. Intravenous ethacrynic acid and furosemide both resulted in equivalent immediate phosphaturic responses. Phosphate excretion decreased significantly during the second hour after ethacrynic acid was injected when urinary losses were not replaced, but remained unchanged if the body weight was maintained constant by isotonic saline infusion. Phosphate excretion was unchanged during the second hour after the injection of furosemide when volume contraction occurred but increased significantly in the studies with saline repletion. Since ethacrynic acid depressed glomerular filtration rate (GFR) more than furosemide, even when urinary losses were replaced with saline, the quantitative differences between these agents' effects on phosphate excretion probably reflected the depressant effect of ethacrynic acid on GFR. The tendency toward relative phosphate retention during diuretic-induced volume contraction after the introduction of either agent could be reversed by isotonic saline infusion. During saline infusion, ultrafilterable plasma calcium concentrations did not vary reciprocally with phosphate excretion, sodium excretion fell from peak postdiuretic values, and urinary phosphate increased. The suppressive effect of volume depletion on inorganic phosphorus output seems best interpreted as a consequence of concomitantly increased fractional sodium and water reabsorption by the proximal nephron. In contrast, the immediate phosphaturia following the injection of ethacrynic acid or furosemide may reflect primary inhibitory actions of these agents on phosphate reabsorption further distally, possibly at the site in Henle's loop where they exert their major effect on sodium reabsorption, since volume contraction did not affect the magnitude of this immediate phosphaturic response unless GFR decreased concomitantly.