Fractional Sodium Reabsorption Research Articles

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.

ASSOCIATION OF HAEMOGLOBIN LEVELS DURING NORMOTHERMIC MACHINE PERFUSION OF PORCINE DONATION AFTER CARDIAC DEATH KIDNEYS WITH RENAL METABOLISM AND FUNCTION

Introduction: The shortage of kidneys for transplantation remains. Therefore, kidneys of suboptimal quality are used more often. These derive from expanded criteria donors (ECD) and donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) of these marginal donor kidneys is used to preserve and assess renal function. Although perfusion fluids are all based on red blood cells or alternative oxygen carriers, haemoglobin levels are mostly below 6 mmol/L. It is unknown to which extent oxygen carrying capacity is required to support kidney function during NMP. The aim of this study was to retrospectively evaluate the effect of haemoglobin levels on renal metabolism and function during NMP. Methods: Porcine kidneys obtained from a local slaughterhouse were considered eligible for this retrospective cohort study and were included when subjected to a warm ischemic time (WIT) ranging from 30 to 35 minutes and were subsequently preserved with oxygenated hypothermic machine perfusion (HMP) ranging from 3 to 24 hours. For all kidneys a 4 hours observation period with oxygenated NMP with an oxygen carrier was required. Kidneys were stratified according to haemoglobin concentrations (per 1 mmol/L increment). Variables measured were creatinine clearance, oxygen consumption, and fractional sodium reabsorption rates. Results: In total, 101 (84%) of 120 eligible kidneys were included. Preliminary results show that groups containing a haemoglobin level over 5 mmol/L or more result in higher oxygen consumption rates and increased reabsorption of sodium. Creatinine clearance seems to be improved in these groups as well.Conclusion: In this preliminary study, a minimum haemoglobin level of 5 mmol/l seems to be essential to effectively asses renal metabolism and function. It is unclear if lower haemoglobin levels result in renal injury.

Renal Nitric Oxide‐Dependent Mechanisms in Early Sunitinib‐Induced Hypertension

Sunitinib is an antiangiogenic receptor tyrosine kinase inhibitor used in cancer treatment. A major adverse effect of sunitinib is a rapidly developing hypertension associated with reduced renal nitric oxide (NO) availability and increased renal fractional sodium reabsorption (FRNa). We tested if NO‐dependent regulation of renal hemodynamics and FRNa are compromised and if nitrate supplementation has antihypertensive effects in early sunitinib‐induced hypertension.Male Wistar rats were treated with sunitinib at 15 mg/(kg*d). Four days after initiation of sunitinib treatment, renal hemodynamics and renal sodium excretion were investigated. Radiotelemetric experiments were performed to study the effects of nitrate supplementation and soluble guanylate cyclase (sGC) activation on arterial pressure. Nitric oxide synthase (NOS) as well as sGC mRNA and protein abundances were studied in renal tissue.Within four days, sunitinib elicited a 20–25 mmHg arterial pressure rise. NOS inhibition elicited similar reductions in total and renal medullary blood flow in sunitinib‐ and vehicle‐treated rats. NO‐dependent and independent components of endothelium‐dependent renal vasodilation were not compromised in early sunitinib‐induced hypertension. Low dose intrarenal NOS inhibition did not differentially affect FRNa in sunitinib‐ and vehicle‐treated rats. In sunitinib‐treated rats, renal nitrite/nitrate excretion was 60 per cent less than in controls (p < 0.05). However, nitrate supplementation did not reduce arterial pressure and renal sodium balance in sunitinib‐treated rats. While sunitinib treatment had no effects on renal NOS mRNA abundances, it significantly reduced renal cortical sGC α‐ and β‐subunit mRNA abundances as well as renal cortical guanylate cyclase protein expression. Pharmacological sGC activation caused a rapid 15–20 mmHg arterial pressure fall in sunitinib‐treated rats (p < 0.05).We conclude that the NO‐dependent regulation of renal hemodynamics is largely unaltered in early sunitinib‐induced hypertension despite evidence for reduced NO formation. Reduced renal sGC expression and activity may contribute to the early arterial pressure rise in sunitinib‐induced hypertension and cause its nitrate resistance.Support or Funding InformationSupported by the German Research Foundation, Grant‐No. KO 4936/2‐1.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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.

Bacillus anthracis Edema Toxin Increases Fractional Free Water and Sodium Reabsorption in an Isolated Perfused Rat Kidney Model.

Bacillus anthracis edema toxin (ET) consists of protective antigen (PA), necessary for host cell toxin uptake, and edema factor (EF), the toxic moiety which increases host cell cyclic AMP (cAMP). Since vasopressin stimulates renal water and sodium reabsorption via increased tubular cell cAMP levels, we hypothesized the ET would also do so. To test this hypothesis, we employed an isolated perfused rat kidney model. Kidneys were isolated and perfused with modified Krebs-Henseleit buffer. Perfusate and urine samples were obtained at baseline and every 10 min over 150 min following the addition of challenges with or without treatments to the perfusate. In kidneys perfused under constant flow or constant pressure, compared to PA challenge (n = 14 or 15 kidneys, respectively), ET (13 or 15 kidneys, respectively) progressively increased urine cAMP levels, water and sodium reabsorption, and urine osmolality and decreased urine output (P ≤ 0.04, except for sodium reabsorption under constant pressure [P = 0.17]). In ET-challenged kidneys, compared to placebo treatment, adefovir, an EF inhibitor, decreased urine cAMP levels, water and sodium reabsorption, and urine osmolality and increased urine output, while raxibacumab, a PA-directed monoclonal antibody (MAb), decreased urine cAMP levels, free water reabsorption, and urine osmolality and increased urine output (P ≤ 0.03 except for urine output with raxibacumab [P = 0.17]). Upon immunohistochemistry, aquaporin 2 was concentrated along the apical membrane of tubular cells with ET but not PA, and urine aquaporin 2 levels were higher with ET (5.52 ± 1.06 ng/ml versus 1.51 ± 0.44 ng/ml [means ± standard errors of the means {SEM}; P = 0.0001). Edema toxin has renal effects that could contribute to extravascular fluid collection characterizing anthrax infection clinically.

The Effect of Glutamine plus Gluthatione as Substrates for the Hypothermic Preservation of the Isolated Perfused Rabbit Kidney.

Rabbit kidneys were perfused with a high K+ and Mg++ solution as previously described with addition of substrates and hypothermia. Briefly the animals were anesthetized with urethane and sodium pentobarbital and the left kidney perfused at 37ºC with a previously dialyzed solution (4g% albumin) in an artificial heart-lung machine. Several functional parameters were evaluated such as perfusate and urine flow, GFR, %TNa, %TK, perfusion pressure and vascular resistance. The experiments lasted 2 hours. Two identical groups were perfused in normothermia (98,6oF) or hypothermia (73,4oF). The concentration of subtrates in the perfusion solution were 2mM of glutation and 1mM of glutamine. To measure kidney function creatinine was added to the perfusate and Na,K, and osmolarities were measured every ten minutes.Urinary flow in normothermic group is 16,7% higher than in hypothermic group. The same trend was observed with GFR that was, in normothermia, 39,5% higher than in hypothermia. The fractional sodium reabsorption was 9,67% lower in hypothermic group comparated to normothermic group. No changes were observed in the fractional transport of potassium. During hypothermic perfusion there is a reduction of renal metabolism, while maintaining good renal perfusion parameters. These substrates could be important metabolic support when kidneys were perfused for transplantation in lower temperatures.

Blood pressure and arterial stiffness in patients with high sodium intake in relation to sodium handling and left ventricular diastolic dysfunction status.

In a population with high sodium consumption, we assessed relation between brachial and central blood pressures, elastic properties of large arteries, echocardiographic left ventricular diastolic function and sodium reabsorption as fractional urinary lithium excretion in proximal (FELi) and fractional sodium reabsorption in distal tubules assessed using the endogenous lithium clearance. Mean±s.d. age of 131 treated hypertensive patients (66 men and 65 women) was 61.9±7.5 years. We found significant interaction between left ventricular diastolic function and FELi with respect to the values of brachial blood pressure: systolic (SBP), diastolic (DBP) and mean blood pressure (MBP) (all PINT<0.03). In patients with FELi below the median value and impaired left ventricular diastolic function, the values of SBP (149.3 vs 132.5 mm Hg; P=0.005), DBP (85.1 vs 76.1 mm Hg; P=0.001), MBP (106.5 vs 94.9 mm Hg; P=0.001), central SBP (SBPC) (137.4 vs 122.0 mm Hg; P=0.01), central DBP (DBPC) (84.8 vs 76.0 mm Hg; P=0.003), central MBP (MBPC) (106.9 vs 95.9 mm Hg; P=0.007), aortic pulse wave augmentation (18.0 vs 13.5 mm Hg; P=0.03), pulse wave velocity (14.6 vs 12.5 m s(-1); P=0.02) and central aortic pulse wave augmentation index (155.7% vs 140.9%; P=0.01) were significantly higher than in patients with normal left ventricular diastolic function. Such relationships were not observed in the entire group and patients with FELi above the median value. In the hypertensive population with high sodium intake, increased sodium reabsorption in proximal tubules may affect blood pressure parameters and arterial wall damage, thus contributing to the development of left ventricular diastolic function impairment.

Acute effect of Russell’s viper (Daboia siamensis) venom on renal tubular handling of sodium in isolated rabbit kidney

Abstract Background: The common complication in cases of poisoning by Russell’s viper (Daboia siamensis) venom (RVV) is acute renal failure, but the pathogenesis involved in the alteration of kidney function is still not well understood. Objective: To clarify the role of RVV in the pathogenesis of renal damage, the present study examines the functional short-term alterations acutely induced by RVV in isolated perfused rabbit kidney. Methods: Effects of RVV on renal tubular handling of sodium including mean perfusion pressure (PP), the renalvascular resistance (RVR), the glomerular filtration rate (GFR), the urinary flow (V) and osmolar clearance (Cosm) were studied in two groups of isolated perfused rabbit kidneys; each group had four isolated rabbit kidneys. RVV was added to the perfusion system to obtain the final concentration of 10 ⃞g/ml. Results: Immediate decreases in PP and RVR caused by the venom were significantly apparent (p &lt; 0.05) in the first 15 min after RVV administration. A gradual rise in both PP and RVR occurred 15 min after the initial reduction of the first phase, but its remained below pretreatment values. The GFR, V, and Cosm decreased significantly throughout experiments after venom perfusion (p &lt; 0.05). The total fractional sodium excretion increased significantly after venom perfusion throughout experiments, while significant reductions (p &lt; 0.05) of renal tubular handling of sodium were apparent for proximal absolute reabsorption of sodium and proximal fractional reabsorption of sodium including marked reductions of distal absolute reabsorption of sodium and distal fractional reabsorption of sodium of the venom treated kidney. Optical microscopy of treated kidney tissue showed acute tubular necrosis at the end of experiment. Conclusion: The present study suggests that an administration of RVV in the isolated rabbit kidney causes direct acute nephrotoxicity and acute alterations of main functional parameters that are probably mediated by either the direct action of venom components or an indirect effect from vasoactive mediators released from renal cells of the RVV-treated kidney.

The effect of glutamine, glutathione and glutamine plus glutathione as substrates for the preservation of the isolated perfused rabbit kidney (1063.3)

Rabbit kidneys were perfused with a high K+ and Mg++ solution as previously described (J S R 21(3);169,1976), with addition of substrates. Briefly the animals were anesthetized with urethane and sodium pentobarbital and the left kidney perfused at 37ºC with a previously dialyzed solution (4g% albumin) in an artificial heart‐lung machine. Several functional physiological parameters were evaluated such as perfusate and urine flow, GFR, %TNa, %TK, perfusion pressure and vascular resistance. The experiments lasted 2 hours. To measure kidney function creatinine was added to the perfusate and Na,K, and osmolarities were measured every ten minutes. Urinary flow increased 2.5‐fold in the Glutamine group when compared to control. This parameter increased 3 times in the Glutathione group and 2.1‐fold in the Glutamine + Glutathione group when compared to control. The same trend was observed with GFR that was enhanced 2.3 times in the Glutamine group, 4.1 times in the Glutathione group and 3 times in the Glutamine + Glutathione group. The fractional sodium reabsorption increased 5.0% with Glutamine, 13.0% with Glutathione and 17.0% with Glutamine + Glutathione. No changes were observed in the fractional transport of potassium. We conclude that these 2 substrates, isolated or combined, promote a great improvement in kidney function in this ex vivo model. These substrates could be important metabolic support when perfusing kidneys for transplantation.Grant Funding Source: CNPq/Brazil

The kidney in congestive heart failure: ‘are natriuresis, sodium, and diuretics really the good, the bad and the ugly?’

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron's function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy-refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter-regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction-although not by conventional GFR measurements-is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function.

The effect of glutamine and alanylglutamine as substrates for the isolated perfused rabbit kidney

Rabbit kidneys were perfused with a high K+ and Mg++ solution as previously described (J S R 21(3);169,1976). Briefly the animals were anesthetized with urethane and pentobarbital and the left kidney perfused at 37ºC with a previously dialyzed solution in an artificial heart‐lung machine custom fabricated. Several functional physiological parameters were evaluated such as perfusate and urine flow, GFR, %TNa, %TK, osmolar clearance, perfusion pressure and vascular resistance. The experiments lasted 2 hours. To measure kidney function creatinine was added to the perfusate and Na,K, and osmolarities were measured every ten minutes. Urinary flow increased 6.5‐fold in AG group when compared to control. Glutamine increased this parameter 16.5 times. The same trend was observed with GFR that was enhanced 5.5 times in the AG group while Glut 1 increased 10.6%. The fractional sodium reabsorption increased 8.87% with AG while Glut increased 11.26%. No changes were observed in the fractional transport of potassium. We conclude that these 2 substrates promote a great improvement in kidney functional preservation in this ex vivo model. These substrates could be important metabolic support when perfusing kidney for transplantation.Financial support: CNPq and FUNCAP Brazil

Proximal tubular angiotensinogen in renal biopsy suggests nondipper BP rhythm accompanied by enhanced tubular sodium reabsorption

The renal capacity for sodium excretion is impaired by a reduction in the glomerular ultrafiltration coefficient and by enhancement of the fractional tubular sodium reabsorption (FRNa), leading to a nondipper circadian blood pressure (BP) rhythm. Angiotensin II in the systemic circulation can be easily filtered across the glomerular capillary walls and stimulates renal proximal tubular angiotensinogen (PT-AGT) production, leading to the activation of intrarenal angiotensin II, which is known to augment the FRNa in animal models. We performed an immunohistochemical investigation to determine the contribution of PT-AGT to enhancement of FRNa and the nondipper circadian BP rhythm in 40 consecutive patients with primary IgA nephropathy (IgAN). Immunostaining for PT-AGT was increased in the IgAN patients compared with control individuals (P = 0.04), and correlated directly with the FRNa (r = 0.39, P = 0.01) and the night/day ratio of BP (r = 0.38, P = 0.02), but not creatinine clearance (r = -0.008, P = 0.9). The night/day ratio of BP was determined by both creatinine clearance (r = -0.36, P = 0.03) and FRNa (r = 0.47, P = 0.006). Tubular sodium reabsorption is stimulated by intrarenal angiotensin II, as indicated by PT-AGT, and contributes to the genesis of the nondipper BP rhythm. Further studies are needed to evaluate whether or not treatment to prevent sodium retention is useful for patients who exhibit increased PT-AGT in renal biopsies.

Localization of Tubular Adaptation to Renal Sodium Loss in Gitelman Syndrome

Gitelman syndrome (GS) is a salt-wasting tubulopathy that results from the inactivation of the human thiazide-sensitive sodium chloride cotransporter located in the distal convoluted tubule. Tubular adaptation to renal sodium loss has been described and localized in the distal tubule in experimental models of GS but not in humans with GS. The tubular adaptation to renal sodium loss is described. Osmole-free water clearance and endogenous lithium clearance with furosemide infusion are used to compare 7 patients with genetically confirmed GS and 13 control participants. Neither endogenous lithium clearance nor osmole-free water clearance disclosed enhanced proximal fluid reabsorption in patients with GS. These patients displayed significantly lower osmole-free water clearance factored by inulin clearance (7.1 ± 1.9 versus 10.1 ± 2.2; P<0.01) and significantly lower fractional sodium reabsorption in the diluting nephron (73.2% ± 7.1% versus 86.1% ± 4.7%; P<0.005), consistent with the inactivation of the thiazide-sensitive sodium chloride cotransporter. The furosemide-induced reduction rate of fractional sodium reabsorption in the diluting segment was higher in patients with GS (75.6% ± 6.1% versus 69.9% ± 3.2%; P<0.039), suggesting that sodium reabsorption would be enhanced in the cortical part of the thick ascending limb of the loop of Henle in patients with GS. These findings suggest that tubular adaptation to renal sodium loss in GS would be devoted to the cortical part of the thick ascending limb of the loop of Henle in humans.

Counterpoint: Activation of the Intrarenal Renin-Angiotensin System is the Dominant Contributor to Systemic Hypertension

Our discussion regarding the dominant mechanism responsible for hypertension calls to mind the famous poem, “The Blind Men and the Elephant,” by John Godfrey Saxe based on an ancient fable from India. In essence, the blind men described the elephant based on their specific encounter, thus

PROXIMAL SODIUM REABSORPTION IS AN INDEPENDENT PREDICTOR OF HYPERTENSION: 2D.05

Objective: Given the association between salt-sensitivity of blood pressure (BP) and risk of future hypertension (HPT), we investigated the predictive role of alterations in segmental renal tubular sodium handling in the development of HPT during the 8 year follow-up of the Olivetti Heart Study participants. Methods: A selected sample (n = 314) of OHS population was examined at baseline and after 8 years. The participants were included if they were normotensive (SBP/DBP <140/90 mm Hg without anti-hypertensive treatment) and had normal renal function (creatinine clearance - CrCl> 60 ml/min) at baseline. Proximal and distal fractional tubular sodium reabsorption were calculated using the clearance of exogenous lithium. Results: The baseline sample characteristics were: age 49.3 ± 6.8 yrs, BMI 26.4 ± 2.8 kg/m2, SBP/DBP 119.8 ± 9.6/78.9 ± 6.4 mm Hg, CrCl 90.9 ± 18.2 mL/min (M ± SD). The HPT incidence in 8 years was 52%. The participants who developed HPT (group A) compared with those who did not (group B) had higher baseline SBP (122.4 ± 8.4 mm Hg vs 117.0 ± 10.0, p < 0.0001), DBP (80.6 ± 5.6 VS 77.1 ± 6.7 mm Hg, p < 0.0001), BMI (27.0 ± 2.9 vs 25.9 ± 2.6 kg/m2, p < 0.0001) and fractional proximal reabsorption of sodium (75.8 ± 6.3 vs 73.8 ± 7.3 %, p = 0.01). At logistic regression analysis using standardised variables, a 1SD-higher proximal sodium reabsorption at baseline predicted a 44% greater risk of HPT in 8 years (95% C.I. 13–84, p = 0.003), independently of baseline SBP (OR: 1.88, 95% C.I. 1.43–2.47, p < 0.001), BMI (OR: 1.51, 95% C.I. 1.16–1.95, p = 0.002), age and creatinine clearance used as an index of glomerular filtration rate. Conclusions: In this sample of healthy adult male population, proximal sodium reabsorption indexed to glomerular filtration rate was an independent predictor of future HPT.

FUNCTIONAL ANGIOTENSINOGEN -20C PROMOTER VARIANT IS ASSOCIATED WITH DIFFERENT RENAL TUBULAR SODIUM HANDLING IN NORMOTENSIVE AND HYPERTENSIVE MEN: PP.24.456

Objectives: Angiotensinogen (AGT) gene is the most relevant in the genetics of human hypertension. Angiotensin II affects renal tubular sodium reabsorbtion at both proximal and distal tubular sites. The AGT -20C functional promoter variant is associated with higher AGT expression in human kidney medulla. To test whether A-20C variants are related to segmental tubular sodium handling, white male subjects participating in two follow-up examinations of the Olivetti Heart Study 8-years apart were genotyped and the results correlated with renal sodium handling evaluated by the clearance of exogenous lithium. Design and methods: Genotype analysis was performed in 407 subjects of which 230 normotensive and 177 hypertensive (≥ 140/90 mmHg). Clinical, anthropometric and biochemical analyses were performed at both visits. Results: Hypertensive men had significant higher BMI (P < 0.001), waist circumference (P < 0.001), total cholesterol (P < 0.001), LDL cholesterol (P < 0.01), triglycerides (P < 0.001) and glucose (P < 0.001) than normotensive men. The -20C allele frequencies were not different between normotensive and hypertensive subjects (28 vs. 25%). Among the normotensives, the −20C carriers had a lower sodium fractional excretion (NaFE) (P = 0.019), due to markedly elevated fractional distal sodium reabsorption (P = 0.001). This association was maintained after adjustment for age, BMI and SBP (P = 0.001) and was confirmed at the 8-year follow-up examination (P = 0.025). The association between the -20C variant and increased distal sodium reabsorption was not observed among hypertensive participants. Conclusions: The altered distal tubular sodium handling observed in normotensive −20C carriers may be related to higher AGT expression in kidney medulla induced by the −20C variant. The reason why the alteration was not apparent in hypertensive individuals is unclear but it might be speculated that the effect of the variant was masked by the increased adipose tissue AGT production associated with abdominal adiposity and overweight in the hypertensive population. In conclusion, the AGT -20C promoter variant is associated with a significant alteration of distal renal tubular sodium handling in normotensive men.

Diabetic Natriuresis is Due to the Loss of Insulin Dependent Proximal Tubular Sodium Reabsorption

This study tested the role of hypo‐insulinemia in mediating the natriuresis in Type I diabetes. A 6‐day diabetic period was induced using either decreased insulin administration to induce hyperglycemia (D group), or clamped insulin administration (DG group) at the control‐period infusion rate and hyperglycemia was induced by infusing glucose continuously i.v. During diabetes, blood glucose increased from normal to 449±40 mg/dl in the D group, and 470±56 mg/dl in the DG group. Control urinary sodium excretion averaged 71±5 mEq/day and 69±7 in the D and DG groups respectively. Urinary sodium excretion increased during diabetes in the D group averaging 125±24 by day 5 while decreased to 54±9 by day 5 in the DG group. Fractional sodium reabsorption (FNaR) decreased by day 5 in the D group (99.8±0.02 vs. 98.2±0.08%, p&lt;0.05) but tended to increase by day 5 in the DG group. Estimated proximal fractional sodium reabsorption (PFNaR) decreased from control during diabetes in the D group while PFNaR increased during the diabetic period in the DG group. This was corroborated by fractional lithium reabsorption, an indicator of PFNaR, which increased during the diabetic period in the DG group from 73±6% to 89±4 day 2 and 92±1 day 5, p&lt;0.05) These data suggest that the decrease in plasma insulin in Type I diabetes plays a significant role in mediating the diabetic natriuresis by decreasing proximal tubular sodium reabsorption. (HL56259)

Dietary sodium intake in a sample of adult male population in southern Italy: results of the Olivetti Heart Study

To assess dietary habitual sodium intake and the association between daily sodium intake and anthropometric indices, food habits and hypertension in the sample of adult male population participating in the Olivetti Heart Study. The study population was composed of 940 men participating in the 2002-2004 follow-up examination of the Olivetti Heart Study. Blood pressure, anthropometric indices, biochemical parameters and sodium excretion in a 24-h urine collection were measured. The frequency of consumption of selected foods was estimated by a food frequency questionnaire (FFQ) capturing the previous year data. In a subgroup of the study population (n=138), the fractional excretion of sodium was estimated by endogenous lithium clearance. Dietary sodium intake estimated by 24 h urinary excretion was 203+/-70 mmol/day. Sodium excretion was significantly lower in treated hypertensive patients and higher in overweight/obese participants when compared with normotensive and normal-weight individuals, respectively. In addition, the inverse correlation detected in normal-weight individuals (r=-0.321; P<0.05) between fractional proximal tubular sodium reabsorption and dietary sodium intake was disrupted in overweight/obese individuals (r=0.058; P=NS). The independent determinants of 24 h urinary sodium excretion were body mass index (BMI), the occurrence of antihypertensive treatment, and frequency of consumption of pasta and cold cuts. Habitual salt intake in this sample of male adult population in southern Italy was well above the recommended amounts. A higher salt intake and an altered renal sodium handling were observed in overweight and obese participants. Sodium intake was only slightly reduced in hypertensive participants on pharmacological therapy.

ANP-mediated inhibition of distal nephron fractional sodium reabsorption in wild-type and mice overexpressing natriuretic peptide receptor

Atrial natriuretic peptide (ANP) elicits natriuresis; however, the relative contributions of proximal and distal nephron segments to the overall ANP-induced natriuresis have remained uncertain. This study was performed to characterize the effects of ANP on distal nephron sodium reabsorption determined after blockade of the two major distal nephron sodium transporters with amiloride (5 microg/g body wt) plus bendroflumethiazide (12 microg/g body wt) in male anesthetized C57/BL6 and natriuretic peptide receptor-A gene (Npr1) targeted four-copy mice. The lower dose of ANP (0.1 ng x g body wt(-1) x min(-1), n = 6) increased distal sodium delivery (DSD, 2.4 +/- 0.4 vs. 1.6 +/- 0.2 mueq/min, P < 0.05) but did not change fractional reabsorption of DSD compared with control (86.3 +/- 2.0 vs. 83.9 +/- 3.6%, P > 0.05), thus limiting the magnitude of the natriuresis. In contrast, the higher dose (0.2 ng x g body wt(-1) x min(-1), n = 6) increased DSD (2.8 +/- 0.3 mueq/min, P < 0.01) and also decreased fractional reabsorption of DSD (67.4 +/- 4.5%, P < 0.01), which markedly augmented the natriuresis. In Npr1 gene-duplicated four-copy mice (n = 6), the lower dose of ANP increased urinary sodium excretion (0.6 +/- 0.1 vs. 0.3 +/- 0.1 mueq/min, P < 0.05) and decreased fractional reabsorption of DSD compared with control (72.2 +/- 3.4%, P < 0.05) at similar mean arterial pressures (91 +/- 6 vs. 92 +/- 3 mmHg, P > 0.05). These results provide in vivo evidence that ANP-mediated increases in DSD alone exert modest effects on sodium excretion and that inhibition of fractional reabsorption of distal sodium delivery is requisite for the augmented natriuresis in response to the higher dose of ANP or in Npr1 gene-duplicated mice.

Ethnic differences in proximal and distal tubular sodium reabsorption are heritable in black and white populations

Segmental handling of sodium along the proximal and distal nephron might be heritable and different between black and white participants. We randomly recruited 95 nuclear families of black South African ancestry and 103 nuclear families of white Belgian ancestry. We measured the (FENa) and estimated the fractional renal sodium reabsorption in the proximal (RNaprox) and distal (RNadist) tubules from the clearances of endogenous lithium and creatinine. In multivariable analyses, we studied the relation of RNaprox and RNadist with FENa and estimated the heritability (h) of RNaprox and RNadist. Independent of urinary sodium excretion, South Africans (n = 240) had higher RNaprox (unadjusted median, 93.9% vs. 81.0%; P < 0.001) than Belgians (n = 737), but lower RNadist (91.2% vs. 95.1%; P < 0.001). The slope of RNaprox on FENa was steeper in Belgians than in South Africans (-5.40 +/- 0.58 vs. -0.78 +/- 0.58 units; P < 0.001), whereas the opposite was true for the slope of RNadist on FENa (-3.84 +/- 0.19 vs. -13.71 +/- 1.30 units; P < 0.001). h of RNaprox and RNadist was high and significant (P < 0.001) in both countries. h was higher in South Africans than in Belgians for RNaprox (0.82 vs. 0.56; P < 0.001), but was similar for RNadist (0.68 vs. 0.50; P = 0.17). Of the filtered sodium load, black participants reabsorb more than white participants in the proximal nephron and less postproximally. Segmental sodium reabsorption along the nephron is highly heritable, but the capacity for regulation in the proximal and postproximal tubules differs between whites and blacks.