Fractional Excretion Of Lithium Research Articles

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes.

SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.

Claudin-10a Deficiency Shifts Proximal Tubular Cl- Permeability to Cation Selectivity via Claudin-2 Redistribution.

The tight junction proteins claudin-2 and claudin-10a form paracellular cation and anion channels, respectively, and are expressed in the proximal tubule. However, the physiologic role of claudin-10a in the kidney has been unclear. To investigate the physiologic role of claudin-10a, we generated claudin-10a-deficient mice, confirmed successful knockout by Southern blot, Western blot, and immunofluorescence staining, and analyzed urine and serum of knockout and wild-type animals. We also used electrophysiologic studies to investigate the functionality of isolated proximal tubules, and studied compensatory regulation by pharmacologic intervention, RNA sequencing analysis, Western blot, immunofluorescence staining, and respirometry. Mice deficient in claudin-10a were fertile and without overt phenotypes. On knockout, claudin-10a was replaced by claudin-2 in all proximal tubule segments. Electrophysiology showed conversion from paracellular anion preference to cation preference and a loss of paracellular Cl- over HCO3- preference. As a result, there was tubular retention of calcium and magnesium, higher urine pH, and mild hypermagnesemia. A comparison with other urine and serum parameters under control conditions and sequential pharmacologic transport inhibition, and unchanged fractional lithium excretion, suggested compensative measures in proximal and distal tubular segments. Changes in proximal tubular oxygen handling and differential expression of genes regulating fatty acid metabolism indicated proximal tubular adaptation. Western blot and immunofluorescence revealed alterations in distal tubular transport. Claudin-10a is the major paracellular anion channel in the proximal tubule and its deletion causes calcium and magnesium hyper-reabsorption by claudin-2 redistribution. Transcellular transport in proximal and distal segments and proximal tubular metabolic adaptation compensate for loss of paracellular anion permeability.

Clinic and ambulatory blood pressure in relation to the interaction between plasma advanced glycation end products and sodium dietary intake and renal handling.

Advanced glycation end product (AGE) clearance may cause renal tubular injuries, such as changes in sodium reabsorption. We hypothesize that AGEs interact with sodium metabolism to influence blood pressure (BP). The study participants were outpatients who were suspected of having hypertension but had not been treated with antihypertensive medication. Clinic and ambulatory blood pressures were measured at baseline (n = 989) and during follow-up (median, 4.4 years, n = 293). Plasma AGE concentrations were measured by enzyme-linked immunosorbent assay. Twenty-four-hour urine was collected for measurements of creatinine, sodium and lithium. In a cross-sectional analysis (n = 989), subjects in the top quintile versus quintiles 1-4 of plasma AGE concentration had significantly (P ≤ 0.004) lower fractional excretion of lithium (18.3% vs. 21.6%) and fractional distal reabsorption rate of sodium (95.0% vs. 95.8%) but similar BP (P ≥ 0.25). However, there was an interaction between plasma AGE concentration and urinary sodium excretion in relation to diastolic BP (P ≤ 0.058). Only in participants with low urinary sodium chloride excretion (≤6 grams/day, n = 189), clinic (84.3 vs. 80.2 mmHg), 24-h (83.9 vs. 80.4 mmHg), daytime (87.8 vs. 84.8 mmHg) and nighttime (75.1 vs. 72.1 mmHg) diastolic BP at baseline were higher (P ≤ 0.05) in the top quintile than in quintiles 1-4 of plasma AGE concentration. In the longitudinal study (n = 383), similar trends were observed, with significant (P ≤ 0.05) differences in the increment in daytime diastolic BP (6.8 vs. -1.7 mmHg) and incidence of ambulatory and treated hypertension (hazard ratio 3.73) during follow-up. In conclusion, AGEs were associated with high BP, probably via enhanced proximal sodium handling and on low dietary sodium intake.

Acute decrease of urine calcium by amiloride in healthy volunteers under high-sodium diet.

Amiloride is a competitive blocker of the epithelial sodium (Na) channel in the renal collecting duct. It is a less potent diuretic than thiazides or loop diuretics, but is often used in association with its potassium (K)-sparing profile. Whether amiloride has a hypocalciuric effect similar to thiazides remains unclear. Animal studies and experiments on cell lines suggested that amiloride increases calcium (Ca) reabsorption in the distal nephron, but human studies are scarce. We performed a post hoc analysis of a study with 48 healthy males (mean ± standard deviation age, 23.2 ± 3.9 years) who were assigned to a high-Na/low-K diet for 7 days before receiving 20 mg of amiloride orally. Urinary excretions of electrolytes were measured at 3 and 6 h afterwards; we calculated the relative changes in urinary excretion rates after amiloride administration. The high-Na/low-K diet led to an expected suppression of plasma renin and aldosterone. Amiloride showed a mild natriuretic effect associated with a decreased kaliuresis. Urinary Ca excretion dropped substantially (by 80%) 3 h after amiloride administration and remained low at the sixth hour. At the same time, fractional excretion of lithium decreased by a third, reflecting an increased proximal tubular reabsorption. During a high-Na/low-K diet, amiloride had a strong acute hypocalciuric effect, most probably mediated by increased proximal Ca reabsorption, even though a distal effect cannot be excluded. Further studies should establish if chronic amiloride or combined amiloride/thiazide treatment may decrease calciuria more efficiently and be useful in preventing kidney stones.

RENAL SODIUM HANDLING IN RELATION TO ENVIRONMENTAL AND GENETIC FACTORS IN UNTREATED CHINESE

Objective: Renal tubular sodium handling plays a key role in blood pressure regulation. Several studies reported association between higher proximal tubule fractional reabsorption of sodium and genetic variations response to blood pressure, but no previous study evaluated the contributions of environmental and genetic cues to renal sodium handling in a population-based study. Design and method: Our study subjects were suspected hypertensive patients being off antihypertensive medication for at least 2 weeks and referred to our hypertension clinic for 24-hour ambulatory blood pressure monitoring. We collected serum and 24-hour urine for measurement of sodium, creatinine and lithium concentration. Sodium and creatinine concentrations were measured by coupled plasma mass spectrometry. Fractional excretion of lithium (FELi) and fractional distal reabsorption rate of sodium (FDRNa) were calculated as markers of proximal and distal sodium handling, respectively. We used the ABI SNapShot method and genotyped 12 SNPs from candidate genes (ADD1, ADD2, ADD3, LSS, ABCB1, HSD3B1, NEDD4L, AGTR1 and WNK1) and 6 SNPs (rs10502933, rs2345088, rs12513375, rs16817782, rs2461911, rs16893522) generated from a genome wide association study. Results: The 1409 study participants included 664 men and had a mean age of 51.0 years. In adjusted analysis, FELi was positively associated with age but negatively with the total-to-high density lipoprotein cholesterol ratio. FDRNa was negatively associated with current smoking and waist circumference (P < = 0.003). Both indexes were also significantly associated with season and humidity explaining with ∼1.3% and ∼3.5% of the variance, respectively. After adjustment for host and environmental factors and Bonferroni multiple testing, among the 19 studied genetic variants, only rs12513375 potentially play a role in sodium reabsorption and was significantly associated with either FELi or FDRNa of the variance and explained about 1.7% of the variance. Conclusions: In conclusion, renal sodium handling as measured by endogenous lithium clearance was sensitive to major host, environmental and genetic factors.

Renal Sodium Handling in Relation to Environmental and Genetic Factors in Untreated Chinese.

We investigated proximal and distal renal tubular sodium handling, as assessed by fractional excretion of lithium (FELi) and fractional distal reabsorption rate of sodium (FDRNa), in relation to environmental and genetic factors in untreated patients. Our study participants were suspected hypertensive patients being off antihypertensive medication for ≥2 weeks and referred for 24-hour ambulatory blood pressure monitoring. We collected serum and 24-hour urine for measurement of sodium, creatinine, and lithium concentration, and calculated FELi and FDRNa. We genotyped 19 single-nucleotide polymorphisms associated with renal sodium handling or blood pressure using the ABI SNapShot method. The 1,409 participants (664 men, 47.1%) had a mean (±SD) age of 51.0 ± 10.5 years. After adjustment for host factors, both FELi and FDRNa were significantly (P ≤ 0.01) associated with season and humidity, explaining ~1.3% and ~3.5% of the variance, respectively. FELi was highest in autumn and lowest in summer and intermediate in spring and winter (P = 0.007). FDRNa was also highest in autumn but lowest in winter and intermediate in spring and summer (P < 0.001). Neither FELi nor FDRNa was associated with outdoor temperature or atmospheric pressure (P ≥ 0.13). After adjustment for host and environmental factors and Bonferroni multiple testing, among the 19 studied genetic variants, only rs12513375 was significantly associated with FELi and FDRNa (P ≤ 0.004) and explained about 1.7% of the variance. Renal sodium handling as measured by endogenous lithium clearance was sensitive to major environmental and genetic factors. Our finding is toward the use of these indexes for the definition of renal tubular dysfunction.

Potent Inhibition of Biphasic Tubular Reabsorption of Lithium by Acetazolamide and Foscarnet in Rats.

Lithium is mainly excreted into urine, and a large fraction of lithium filtered through glomeruli is reabsorbed in the proximal tubule. However, the mechanisms responsible for lithium reabsorption remain unclear. We previously reported that the reabsorption of lithium was biphasic in rats, and that foscarnet inhibited lithium reabsorption with a high affinity type. We herein evaluated the effects of acetazolamide and foscarnet on the renal excretion of lithium in rats treated with lithium chloride at 2 doses. In rats intravenously injected with a bolus of 25 mg/kg lithium chloride, acetazolamide facilitated the urinary excretion of lithium, and increased the fractional excretion of lithium from 0.446 to 0.953, near the theoretically maximum value. At a dose of 2.5 mg/kg lithium chloride, the fractional excretion of lithium was 0.241 in control rats, 0.420 in rats administered acetazolamide, and 0.976 in rats administered acetazolamide and foscarnet. These results showed the potent inhibition of lithium reabsorption by acetazolamide and foscarnet in rats. And, it was exhibited that the effects of acetazolamide on lithium reabsorption differed with the dosages of lithium administered.

Acute and Chronic Effects of SGLT2 Inhibitor Empagliflozin on Renal Oxygenation and Blood Pressure Control in Nondiabetic Normotensive Subjects: A Randomized, Placebo-Controlled Trial.

BackgroundThe sodium/glucose cotransporter 2 inhibitor empagliflozin has cardiorenal protective properties through mechanisms beyond glucose control. In this study we assessed whether empagliflozin modifies renal oxygenation as a possible mechanism of renal protection, and determined the metabolic, renal, and hemodynamic effects of empagliflozin in nondiabetic subjects.Methods and ResultsIn this double‐blind, randomized, placebo‐controlled study, 45 healthy volunteers underwent blood and urine sampling, renal ultrasound, and blood‐oxygenation‐level–dependent magnetic resonance imaging before and 180 minutes after administration of 10 mg empagliflozin (n=30) or placebo (n=15). These examinations were repeated after 1 month of daily intake. Cortical and medullary renal oxygenation were not affected by the acute or chronic administration of empagliflozin, as determined by 148 renal blood‐oxygenation‐level–dependent magnetic resonance imaging examinations. Empagliflozin increased glucosuria (24‐hour glucosuria at 1 month: +50.1±16.3 g). The acute decrease in proximal sodium reabsorption, as determined by endogenous fractional excretion of lithium (−34.6% versus placebo), was compensated at 1 month by a rise in plasma renin activity (+28.6%) and aldosterone (+55.7%). The 24‐hour systolic and diastolic ambulatory blood pressures decreased significantly after 1 month of empagliflozin administration (−5.1 and −2.0 mm Hg, respectively). Serum uric acid levels decreased (−28.4%), hemoglobin increased (+1.7%), and erythropoietin remained the same.ConclusionsEmpagliflozin has a rapid and significant effect on tubular function, with sustained glucosuria and transient natriuresis in nondiabetic normotensive subjects. These effects favor blood pressure reduction. No acute or sustained changes were found in renal cortical or medullary tissue oxygenation. It remains to be determined whether this is the case in nondiabetic or diabetic patients with congestive heart failure or kidney disease. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03093103.

The discrimination of acute tubular necrosis and prerenal azotemia using two biomarkers simultaneously

Introduction: The fractional excretion of sodium (FE Na) in urine has appeared as a helpful way to distinguish prerenal azotemia from acute tubular necrosis (ATN). Objectives: The urinary index of sodium has some limits. Lithium can be an additional careful indicator. The goal of our study was to assess the standards fractional excretion of sodium and lithium, (FE Na and FE Li) in distinguishing pre-renal azotemia (PRA) from ATN. Patients and Methods: Twenty-seven patients with prerenal azotemia, 25 patients with ATN and 20 healthy persons were included in this investigation. The plasma and urine sodium, creatinine and lithium levels were assessed. Additionally, FE Na and FE Li were calculated. To assess the diagnostic usefulness of FE Na and FE Li in discriminating prerenal azotemia from ATN, we created a receiver operating characteristic (ROC) curve. Results: The area under the curves (AUCs) of fractional excretion of Li and Na were 0.84 and 0.83 for distinguishing prerenal azotemia from ATN, respectively. There was a significant direct association between FE Na and FE Li in patients with ATN (P=0.001). No significant association of FE Na and FE Li in patients with prerenal azotemia was detected (p=0.26). By a cutoff point of 2.96%, the sensitivity and specificity for FE Na, were 68% and 75%, respectively for distinguishing PRA from ATN. By a cutoff point of 4.17%, the sensitivity and specificity of FE Li were 80% and 79%, respectively, for distinguishing prerenal azotemia from ATN. Conclusion: This investigation appeared a high AUC and accuracy of fractional excretion of sodium and lithium as a diagnostic method for distinguishing prerenal azotemia from ATN when used simultaneously. However, the discrimination of sensitivity and specificity of fractional excretion of lithium was greater than the fractional excretion of Na.

Effect of acetazolamide on lithium reabsorption and lithium-induced GSK3β phosphorylation in rat kidney.

Lithium promotes the phosphorylation of glycogen synthase kinase-3β (GSK3β), and this reaction protects against acute kidney injury mediated by renal apoptosis. Lithium is considered to be reabsorbed by sodium-phosphate cotransporters and sodium-proton exchanger NHE3. This study evaluated the relation between the lithium reabsorption and the phosphorylation of GSK3β, by using acetazolamide, an NHE3 inhibitor. In rats infused with lithium chloride, the plasma concentration of lithium was 4.77 mEq/l, and the renal clearance of lithium and its fractional excretion were calculated to be 2.29 ml/min/kg and 0.405, respectively. Coadministration of acetazolamide decreased creatinine clearance and the reabsorption rate of lithium, increased the fractional excretion of lithium, and did not affect its plasma concentration. Western blot analysis exhibited the facilitation of GSK3β phosphorylation in the kidney cortex by lithium infusion, and acetazolamide inhibited the lithium-induced phosphorylation of GSK3β. Lithium did not affect GSK3β phosphorylation in the liver and did not affect Akt in the kidney cortex and liver. These data show that lithium reabsorption contributes to GSK3β phosphorylation in the kidney cortex.

Abstract 081: Ghrelin is Produced by the Kidney and Mediates Distal Tubular Sodium Reabsorption in Rats

Ghrelin is a 28-amino acid peptide hormone that exerts powerful appetite-stimulating effects. Ghrelin receptor expression has been reported in the collecting duct, but the role of ghrelin in the kidney is unknown. The present studies confirmed ghrelin mRNA expression in inner medullary collecting duct cells (N=6) using RT PCR and sequencing of the 320-bp PCR product. Ghrelin peptide expression was also confirmed in these cells using immunohistochemistry and flow cytometry. To test intrarenal ghrelin action, 12-week-old uninephrectomized female Sprague-Dawley rats (N=26) received 3 bolus injections of ghrelin siRNA (N=7) or scrambled siRNA (N=7) into the renal interstitial (RI) space of the remaining kidney, each injection 48h apart. Following the last injection, rats received three, 1h RI infusions of 5% dextrose in water. Mean arterial pressure (MAP), urine sodium (Na + ) excretion (U Na V), glomerular filtration rate (GFR), fractional excretion of Na + (FE Na ), and fractional excretion of lithium (FE Li ) were calculated. In a separate set of rats, renal blood flow (RBF) was measured for 1h (N=6 for both ghrelin siRNA and scrambled siRNA). RI ghrelin siRNA-infused rats demonstrated significantly higher U Na V compared to scrambled siRNA-infused rats for all 3 periods (0.29±0.06 vs. 0.09±0.01, 0.35±0.09 vs. 0.11±0.03, and 0.27±0.07 vs. 0.09±0.02 μmol/min; P&lt;0.01, P&lt;0.05, and P&lt;0.05 respectively) and significantly increased FE Na compared to scrambled siRNA infused rats (0.26±0.05 vs. 0.11±0.02, 0.35±0.06 vs. 0.11±0.03, and 0.24±0.04 vs. 0.10±0.03%; P&lt;0.05, P&lt;0.01, and P&lt;0.05 respectively). There were no differences in in GFR, FE Li , MAP, or RBF. Since the increase in U Na V was not accompanied by similar increases in GFR, the effect of renal ghrelin inhibition suggested a tubular rather than hemodynamic, mechanism of action. To localize the specific tubular site, events distal to the renal proximal tubule were identified by changes in FE Na that occurred independently of changes in FE Li . RI ghrelin siRNA significantly increased FE Na without altering FE Li , suggesting distal nephron-dependent Na + reabsorption. Together, these data introduce ghrelin as a novel intrarenal peptide responsible for tonic Na + reabsorption at the level of the distal nephron.

Effects of Dapagliflozin on Volume Status When Added to Renin-Angiotensin System Inhibitors.

Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart and kidney failure in patients with type 2 diabetes, possibly due to diuretic effects. Previous non-placebo-controlled studies with SGLT2 inhibitors observed changes in volume markers in healthy individuals and in patients with type 2 diabetes with preserved kidney function. It is unclear whether patients with type 2 diabetes and signs of kidney damage show similar changes. Therefore, a post hoc analysis was performed on two randomized controlled trials (n = 69), assessing effects of dapagliflozin 10 mg/day when added to renin–angiotensin system inhibition in patients with type 2 diabetes and urinary albumin-to-creatinine ratio ≥30 mg/g. Blood and 24-h urine was collected at the start and the end of treatment periods lasting six and 12 weeks. Effects of dapagliflozin compared to placebo on various markers of volume status were determined. Fractional lithium excretion, a marker of proximal tubular sodium reabsorption, was assessed in 33 patients. Dapagliflozin increased urinary glucose excretion by 217.2 mmol/24 h (95% confidence interval (CI): from 155.7 to 278.7, p < 0.01) and urinary osmolality by 60.4 mOsmol/kg (from 30.0 to 90.9, p < 0.01), compared to placebo. Fractional lithium excretion increased by 19.6% (from 6.7 to 34.2; p < 0.01), suggesting inhibition of sodium reabsorption in the proximal tubule. Renin and copeptin increased by 46.9% (from 21.6 to 77.4, p < 0.01) and 33.0% (from 23.9 to 42.7, p < 0.01), respectively. Free water clearance (FWC) decreased by −885.3 mL/24 h (from −1156.2 to −614.3, p < 0.01). These changes in markers of volume status suggest that dapagliflozin exerts both osmotic and natriuretic diuretic effects in patients with type 2 diabetes and kidney damage, as reflected by increased urinary osmolality and fractional lithium excretion. As a result, compensating mechanisms are activated to retain sodium and water.

Effect of renal ischemia on urinary excretion of lithium in rats.

Lithium, administered to patients with bipolar disorders, is mainly excreted in the urine, and tubular reabsorption is involved. This study characterized the renal excretion of lithium in rats subjected to renal ischemia for 60min or 90min. After intravenous injection of lithium chloride at 25mg/kg, the pharmacokinetic parameters of lithium were determined. In sham-operated rats, the renal clearance of lithium was calculated to be 1.49ml/min/kg, and its ratio to creatinine clearance (fractional excretion) was 43.4%. Renal ischemia inhibited the renal excretion of lithium, and did not affect its fractional excretion. The urinary pH of rats with renal ischemia for 90min was significantly higher than those of the other groups, and the linear regression with the fractional excretion of lithium in rats with renal ischemia showed a moderate correlation (r=0.650, p=0.00193). This study demonstrated the effect of renal ischemia on the renal excretion of lithium in rats. It was suggested that not only glomerular filtration but also the reabsorption of lithium was impaired by renal ischemia.

A13202 Renal sodium handling in relation to environmental and genetic factors in untreated Chinese

Objectives: To evaluate the contributions of environmental and genetic cues to renal sodium handling in a population-based study. Methods: Our study subjects were suspected hypertensive patients being off antihypertensive medication for at least 2 weeks and referred to our hypertension clinic for 24-hour ambulatory blood pressure monitoring. We collected serum and 24-hour urine for measurement of sodium, creatinine and lithium concentration. Sodium and creatinine concentrations were measured by coupled plasma mass spectrometry. Fractional excretion of lithium (FELi) and fractional distal reabsorption rate of sodium (FDRNa) were calculated as markers of proximal and distal sodium handling, respectively. We used the ABI SNapShot method and genotyped 12 SNPs from candidate genes (ADD1, ADD2, ADD3, LSS, ABCB1, HSD3B1, NEDD4L, AGTR1 and WNK1) and 6 SNPs (rs10502933, rs2345088, rs12513375, rs16817782, rs Results: Our study included 1409 untreated patients and 664 men (mean age, 51.0 years). In adjusted analysis, FELi was positively associated with age but negatively with the ratio of the total cholesterol and high density lipid (P ≤ 0.003). FDRNa was negatively with current smoking and waist circumference. After adjusting the host and environmental factors and after Bonferroni correction, among the 18 genetic variations, only AGTR1 rs2131127 was significantly associated with FELi (P = 0.032). In AGTR1 rs2131127 CC homozygotes (n = 162) had lower daytime systolic blood pressure than T allele carriers (131.4 vs. 133.6 mmHg, P = 0.04). Season and humidity together explained ∼1.3% and ∼3.5% of the variation of the fractional excretion of lithium and distal reabsorption of sodium, respectively, while genetic cues just 1.10% or less. Conclusion: Environmental compared with genetic cues are critical drivers of renal sodium handling.

HIGH SODIUM INTAKE IS ASSOCIATED WITH MASKED HYPERTENSION IN THE GENERAL POPULATION

Objective: We investigated the association between office (OBP) and daytime ambulatory blood pressure (ABP) and sodium dietary intake and renal handling, as assessed by 24-hour urinary sodium excretion (24hUVNa) and endogenous lithium clearance (FELi), respectively. Design and method: We recruited from general population 192 individuals, never treated with antihypertensive medications. We administered standardized questionnaires to obtain information on subjects’ medical history and life style. SpaceLab 90207 monitors were programmed to measure blood pressure each 15 min during daytime (6:00–22:00) and each 30 min night-time. In adjusted categorical analyses, normotension was the referent group (OBP < 140/90 and daytime ABP < 135/85 mmHg). White-coat hypertension was defined as OBP > = 140/90 and daytime ABP < 135/85 mmHg; masked hypertension as OBP < 140/90 and daytime ABP > = 135/85 mmHg; and sustained hypertension as OBP > = 140/90 and daytime ABP > = 135/85 mmHg. Blood and 24-hour urine samples were collected. We calculated fractional excretion of lithium (FELi) as the marker of proximal sodium handling. A higher FELi indicates that less sodium and water is reabsorbed in the proximal tubule. Results: The study group included 87 men and 105 women, mean age 40.5 years, office BP 124.3/84.0 mm Hg, 24hUVNa 160 mmol/24 h, 128 (66.7%) normotensives, 29 (15.1%) sustained hypertensives, 8 (4.2%) individuals with masked hypertension, 27 (14.0%) subjects with white coat hypertension. In adjusted analyses, we did not find any associations between office or daytime ambulatory BP and 24hUVNa (P > = 0.24) or FE Li (P > = 0.30). However, in categorical multivariate analyses, individuals with masked hypertension had higher 24hUVNa as compared to normotensives (197 vs 153 mmol/24 h; P = 0.04). There were no differences in 24hUVNa between white-coat hypertensives (P = 0.59) or sustained hypertensives (P = 0.44) and normotensive reference group. None of BP categories differed from normotensives in terms of FELi (P > = 0.19). Conclusions: Excessive sodium intake may play a part in the genesis of masked hypertension in the general population.

The role of distal tubule and collecting duct sodium reabsorption in sunitinib-induced hypertension.

Antiangiogenic receptor tyrosine kinase inhibitors (RTKI) induce arterial hypertension which may limit their use. Renal fractional sodium excretion (FENa) is reduced in early RTKI-induced hypertension, whereas fractional lithium excretion is unaltered. Therefore, we tested the hypothesis that activated distal tubule and collecting duct sodium reabsorption contributes to RTKI-induced hypertension. Amiloride-sensitive and hydrochlorothiazide (HCTZ)-sensitive fractional sodium reabsorption (FRNa) and renal epithelial sodium channel (ENaC) as well as sodium chloride cotransporter (NCC) abundances were determined in sunitinib-treated and control rats. The antihypertensive effects of amiloride and HCTZ were investigated by radiotelemery. After 4 days of treatment, mean arterial pressure was 20 mmHg higher, FENa was lower (0.32 ± 0.08% vs. 0.65 ± 0.14%; P < 0.05), and renal medullary-ENaC protein abundance was higher in sunitinib-treated rats than in controls. Amiloride-sensitive FRNa was 2.37 ± 0.52% in sunitinib-treated rats vs. 2.66 ± 0.44% in controls (n.s.). HCTZ increased FENa by a similar magnitude without affecting amiloride-sensitive FRNa in both groups. After 14 days of treatment, renal medullary β-ENaC protein abundance was higher in rats that received sunitinib than in controls, whereas α-ENaC, γ-ENaC, and NCC abundances were similar in both groups. Amiloride and HCTZ reduced the sunitinib-induced mean arterial pressure rise by 8 ± 3 mmHg (P < 0.05) and 12 ± 2 mmHg (P < 0.05), respectively, without additive effects when combined. ENaC-dependent and thiazide-sensitive sodium-retaining mechanisms are not overactive in sunitinib-induced hypertension but ENaC blockers and in particular thiazides may be suitable for its treatment.

Compensatory Distal Reabsorption Drives Diuretic Resistance in Human Heart Failure.

Understanding the tubular location of diuretic resistance (DR) in heart failure (HF) is critical to developing targeted treatment strategies. Rodents chronically administered loop diuretics develop DR due to compensatory distal tubular sodium reabsorption, but whether this translates to human DR is unknown. We studied consecutive patients with HF (n=128) receiving treatment with loop diuretics at the Yale Transitional Care Center. We measured the fractional excretion of lithium (FELi), the gold standard for in vivo assessment of proximal tubular and loop of Henle sodium handling, to assess sodium exit after loop diuretic administration and FENa to assess the net sodium excreted into the urine. The mean±SD prediuretic FELi was 16.2%±9.5%, similar to that in a control cohort without HF not receiving diuretics (n=52; 16.6%±9.2%; P=0.82). Administration of a median of 160 (interquartile range, 40-270) mg intravenous furosemide equivalents increased FELi by 12.6%±10.8% (P<0.001) but increased FENa by only 4.8%±3.3%. Thus, only 34% (interquartile range, 15.6%-75.7%) of the estimated diuretic-induced sodium release did not undergo distal reabsorption. After controlling for urine diuretic levels, the increase in FELi explained only 6.4% of the increase in FENa (P=0.002). These data suggest that administration of high-dose loop diuretics to patients with HF yields meaningful increases in sodium exit from the proximal tubule/loop of Henle. However, little of this sodium seems to reach the urine, consistent with findings from animal models that indicate that distal tubular compensatory sodium reabsorption is a primary driver of DR.

Dipeptidyl Peptidase 4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1α1-67 in Patients With Type 2 Diabetes.

Antihyperglycemic agents, such as empagliflozin, stimulate proximal tubular natriuresis and improve cardiovascular and renal outcomes in patients with type 2 diabetes. Because dipeptidyl peptidase 4 (DPP-4) inhibitors are used in combination with sodium-glucose cotransporter 2 (SGLT2) inhibitors, we examined whether and how sitagliptin modulates fractional sodium excretion and renal and systemic hemodynamic function. We studied 32 patients with type 2 diabetes in a prospective, double-blind, randomized, placebo-controlled trial. Measurements of renal tubular function and renal and systemic hemodynamics were obtained at baseline, then hourly after one dose of sitagliptin or placebo, and repeated at 1 month. Fractional excretion of sodium and lithium and renal hemodynamic function were measured during clamped euglycemia. Systemic hemodynamics were measured using noninvasive cardiac output monitoring, and plasma levels of intact versus cleaved stromal cell-derived factor (SDF)-1α were quantified using immunoaffinity and tandem mass spectrometry. Sitagliptin did not change fractional lithium excretion but significantly increased total fractional sodium excretion (1.32 ± 0.5 to 1.80 ± 0.01% vs. 2.15 ± 0.6 vs. 2.02 ± 1.0%, P = 0.012) compared with placebo after 1 month of treatment. Moreover, sitagliptin robustly increased intact plasma SDF-1α1-67 and decreased truncated plasma SDF-1α3-67. Renal hemodynamic function, systemic blood pressure, cardiac output, stroke volume, and total peripheral resistance were not adversely affected by sitagliptin. DPP-4 inhibition promotes a distal tubular natriuresis in conjunction with increased levels of intact SDF-1α1-67. Because of the distal location of the natriuretic effect, DPP-4 inhibition does not affect tubuloglomerular feedback or impair renal hemodynamic function, findings relevant to using DPP-4 inhibitors for treating type 2 diabetes.

Role of the renal sympathetic nerves in renal sodium/potassium handling and renal damage in spontaneously hypertensive rats.

Renal sympathetic nerve activity has an important role in renal disease-associated hypertension and in the modulation of fluid homeostasis. In the present study, changes in renal function and renal sodium/potassium handling were investigated in groups of 12-week-old male, spontaneously hypertensive rats with renal denervation (RDNX group) or sham denervation (sham group). The RDNX group excreted significantly more sodium than the sham group during the 2-week observation period (P<0.05). Following bilateral renal denervation, the fractional lithium excretion was elevated in the RDNX group compared with the sham group, but no significant effect was observed of renal denervation on the fractional distal reabsorption rate of sodium or the fractional excretion of potassium. Furthermore, the glomerular injury score and the wall-to-lumen ratio of the interlobular artery were significantly lower in the RDNX group than in the sham group (P<0.05). In conclusion, the present study indicates an involvement of the renal sympathetic nerves in the regulation of renal tubular sodium reabsorption in spontaneously hypertensive rats and in the renal damage associated with hypertension.

PS 18-16 Renal sodium handling in relation to plasma advanced glycation end products concentration in untreated subjects

Objective: previous experimental study showed that advanced glycation end products (AGEs) might enhance epithelial sodium channel in the renal cortical collecting duct cells. In the present study, we investigated renal sodium handling, as assessed by endogenous lithium clearance indexes, in relation to plasma AGEs concentration in subjects who did not take antihypertensive medication. Design and Method: The study subjects were previously never treated with or stopped antihypertensive medication for at least 2 weeks. We calculated fractional excretion of lithium and fractional distal reabsorption rate of sodium, as markers of proximal and distal sodium handling, respectively. Plasma AGEs concentration was measured by the enzyme-linked immunosorbent assay method and logarithmically transformed for statistical analysis. Results: The 1006 study participants (mean age 51.3 years) included 499 (49.6%) men and 40 (4.0%) diabetic patients. After adjustment for sex, age, body mass index, mean arterial pressure, pulse rate, current smoking and alcohol intake, plasma fasting glucose, serum triglycerides, serum total-to-high-density lipoprotein cholesterol ratio, plasma AGEs concentration (geometric mean [95% confidence interval] 13.4 [12.8 to 14.0] mg/mL) was significantly (P = 0.0007) associated with fractional lithium clearance (mean [±standard deviation] 21.7% ± 12.1%). For each 10-time increase in plasma AGEs concentration, fractional lithium clearance was 4.3% (absolute percentage change) lower. In tertile 3 of sodium urinary excretion, higher plasma AGEs concentration was also associated with lower fractional distal reabsorption rate of sodium (93.3% in tertile 3 vs. 95.1% in tertile 1 of plasma AGEs concentration, P = 0.002). Conclusions: Plasma AGEs concentration was positively associated with sodium renal reabsorption in the proximal tubule, as assessed by fractional lithium clearance. However, on the condition of high sodium intake, it was negatively associated with sodium reabsorption in the distal tubule, probably as a compensation of increased sodium intake and increased sodium reabsorption in the proximal tubule.