Tubular Sodium Handling Research Articles

Erythropoietin down‐regulates proximal renal tubular reabsorption and causes a fall in glomerular filtration rate in humans

Recombinant human erythropoietin (rHuEPO) elevates haemoglobin concentration both by increasing red blood cell volume and by a decrease in plasma volume. This study delineates the association of rHuEPO-induced changes in blood volumes with changes in the renin–aldosterone system and renal function. Sixteen healthy males were given rHuEPO for 28 days in doses raising the haematocrit to 48.3±4.1%.Renal clearance studieswith urine collections (N = 8) were done at baseline and at days 4, 11, 29 and 42. Glomerular filtration rate (GFR) was measured by 51Cr-EDTA.Renal clearance of lithium (CLi)was used as an index of proximal tubular outflow and to assess segmental renal tubular handling of sodium and water. rHuEPO-induced increases in haematocrit occurred from day 10 onwards and was caused by both an increase in red cell volume and a fall in plasma volume. Well before that (from day 2 and throughout the treatment time), rHuEPO decreased plasma levels of renin and aldosterone (N = 8) by 21–33% (P < 0.05) and 15–36% (P < 0.05), respectively. After cessation of rHuEPO, values returned to baseline. On days 11 and 29, CLi increased (P < 0.02) indicating a significant 10–16% decrease in absolute proximal reabsorption of sodium and water (APR = GFR − CLi, P < 0.05). GFR decreased slightly, albeit significantly, on day 4 (P < 0.05). In conclusion, rHuEPO promptly, and before any changes in blood volumes and haematocrit can be detected, causes a down-regulation of the renin–aldosterone system. The results are compatible with a rHuEPO-induced reduction in proximal reabsorption rate leading to activation of the tubuloglomerular feedback mechanism and a fall in GFR. Therefore, treatment with rHuEPO may result in suppression of endogenous EPO synthesis secondary to a decrease in intrarenal oxygen consumption.

Renal programming: cause for concern?

Development of the kidney can be altered in utero in response to a suboptimal environment. The intrarenal factors that have been most well characterized as being sensitive to programming events are kidney mass/nephron endowment, the renin-angiotensin system, tubular sodium handling, and the renal sympathetic nerves. Newborns that have been subjected to an adverse intrauterine environment may thus begin life at a distinct disadvantage, in terms of renal function, at a time when the kidney must take over the primary role for extracellular fluid homeostasis from the placenta. A poor beginning, causing renal programming, has been linked to increased risk of hypertension and renal disease in adulthood. However, although a cause for concern, increasingly, evidence demonstrates that renal programming is not a fait accompli in terms of future cardiovascular and renal disease. A greater understanding of postnatal renal maturation and the impact of secondary factors (genes, sex, diet, stress, and disease) on this process is required to predict which babies are at risk of increased cardiovascular and renal disease as adults and to be able to devise preventative measures.

Sodium, Potassium, and Target Organ Damage

The relationship between blood pressure (BP) and sodium intake is well documented. Large observational studies have shown that sodium chloride (NaCl) intake is directly related to BP, whereas various interventional studies demonstrated a relationship between the reduction in NaCl intake and magnitude of BP reduction. Similarly, a low-potassium diet is associated with high BP and increased cardiovascular risk. In the Intersalt Study, urinary potassium excretion (a surrogate for intake) was associated with a lower BP after adjustment for various confounders, including urinary sodium excretion. The effects of dietary sodium and potassium on BP are closely related. The first strain of rats bred by Dahl for the trait of “salt sensitivity” demonstrated less NaCl-induced hypertension when potassium intake was high. Well-controlled human studies subsequently showed that the BP-rising effect of extremely high NaCl intake can be blunted by potassium supplementation. Clinical trials showed that potassium supplementation modestly reduces BP, an effect that is, however, enhanced in blacks and in the presence of a high-sodium diet. Conversely, hypertension in potassium deficiency is associated with increased renal sodium reabsorption, whereas sodium restriction may prevent the development of hypertension induced by potassium restriction. Recent literature has identified regulatory pathways of tubular sodium and potassium handling (eg, those mediated by with-no-lysine-kinase 1)1 that may, at least partially, mediate interactions between dietary sodium and potassium on extracellular volume and BP. Importantly, whereas high-sodium/low-potassium intake are associated with hypertension, both have been shown to predict an increased cardiovascular risk even after adjustment for brachial BP and other observed factors, indicating that unmeasured factors played a role. Accumulating evidence indicates that central arterial pulsatile hemodynamic abnormalities predict cardiovascular risk independent of brachial BP in various populations.2 It should be noted that there is a highly variable relationship between brachial pulse pressure (PP) and aortic pulsatile hemodynamics. …

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.

PRENATAL MATERNAL FOOD RESTRICTION LEADS TO IMPAIRED RENAL SODIUM HANDLING IN ADULT RAT OFFSPRING: PP.9.361

Objective: Maternal food restriction (MFR) during pregnancy programmes the development of hypertension in the rat. The kidneys of MFR rats develop fewer nephrons suggesting that sodium retention may underlie the hypertension in this model. The aim of this study was to assess renal function in the MFR rat. Design and Methods: Control pregnant Wistar rats had access to food ad libitum (C n = 7); the food restricted group received 50% of the food consumed by control rats from day 1 of pregnancy until birth (MFR n = 6). Offspring had free access to food. At 9 weeks systolic blood pressure (SBP) and renal function were assessed in male rats housed in metabolism cages. Results and Conclusions: MFR offspring were significantly lighter at birth, but had caught up body weight by 9 weeks of age (Table 1). SBP was higher in the MFR animals. Food and water intake did not differ between MFR and control rats. Creatinine clearance was significantly lower in MFR rats, but neither urine flow nor sodium excretion rates were different from controls. However, fractional excretion of sodium was greater in MFR rats. These data suggest that renal tubular handling of sodium in MFR rats is altered. MFR rats filter less sodium than controls, but excrete proportionately more of the sodium that is filtered. Sodium retention may contribute to the higher SBP of these animals.

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.

In vivo stimulation of AMP-activated protein kinase enhanced tubuloglomerular feedback but reduced tubular sodium transport during high dietary NaCl intake

AMP-activated protein kinase (AMPK) is expressed in the apical membrane of cortical thick ascending limb, distal, and collecting tubules as well as macula densa cells of the kidneys. AMPK is an active modulator of epithelial Na(+) channels, Na(+)-2Cl(-)-K(+) cotransporter, and the ATP-dependent potassium channel. The present experiments explored whether AMPK participates in the regulation of tubuloglomerular feedback (TGF) and renal tubular sodium handling. To this end, renal clearance and micropuncture experiments were performed in anesthetized rats. Under normal NaCl diet, neither TGF response nor renal fluid and sodium excretion were altered by pharmacological activation of AMPK in vivo. However, under high NaCl diet, the TGF response was significantly enhanced after intravenous or intratubular application of the AMPK activator AICAR. Moreover, AICAR application significantly increased fractional delivery of fluid and sodium to the end of the proximal tubule. High dietary NaCl intake increased the renal transcript levels encoding the AMPK-alpha1 subunit, while it decreased the expression of AMPK-beta1 and AMPK-gamma2 subunits. Immunoblots revealed that high dietary NaCl intake reduced renal expression of activated AMPK by about three times compared to normal NaCl diet whereas additional AICAR application increased AMPK activity. Our results suggest that AMPK regulates tubuloglomerular balance as well as tubular transport upon change of renal work load.

Desmopressin Resistant Nocturnal Polyuria May Benefit From Furosemide Therapy Administered in the Morning

There is increasing evidence that a subgroup of patients with monosymptomatic nocturnal enuresis and nocturnal polyuria resistant to desmopressin may have an abnormal circadian rhythm of renal tubular sodium handling. The pathogenesis of this phenomenon remains to be elucidated. If the increased sodium excretion overnight results in desmopressin resistance, decreasing the sodium excretion overnight may result in subsequently better desmopressin response. We conducted a pilot study of the anti-enuretic and antidiuretic effects of desmopressin combined with 0.5 mg/kg furosemide daily in patients with desmopressin resistant nocturnal polyuria despite dietary sodium and protein restriction. Values were plotted against the reference frame of a desmopressin responsive enuresis group. Baseline values revealed significantly lower urinary osmolality and higher diuresis rate overnight compared to the reference population (monosymptomatic nocturnal enuresis desmopressin responders). Introduction of desmopressin resulted in normalization of nocturnal urinary osmolality. However, nocturnal polyuria persisted, despite reaching maximal urinary concentration overnight. Although protein and sodium restriction resulted in a significant decrease in urinary osmolality and diuresis rate, the difference was not clinically important enough to reach normal values or to achieve continence. Furosemide in the morning resulted in a significant increase in diuresis and osmotic and sodium excretion during the day, and decreased nighttime diuresis and osmotic excretion. In 9 of 12 patients the nocturnal antidiuretic effect resulted in an anti-enuretic effect, defined as enuresis less than 1 wet night per month. In 3 patients insufficient anti-enuretic effects were obtained despite significant antidiuresis. This pilot study clearly demonstrates that introduction of early morning furosemide results in a significantly lower nocturnal diuresis rate. Reduced diuresis associated with unchanged urinary osmolality results in decreased nocturnal osmotic excretion in compensation for increased osmotic (sodium) excretion during the daytime.

Incidence of hypertension in individuals with different blood pressure salt-sensitivity: results of a 15-year follow-up study

To evaluate the incidence of hypertension and the rate of decline in renal function in a sample of 47 Olivetti Heart Study (OHS) participants whose blood pressure (BP) salt-sensitivity and renal tubular sodium handling had been assessed in 1987-88. During the 2002-04 OHS follow-up examination, medical history, physical examination and blood and urine sampling were performed in 36 of the 47 participants to the baseline study (age 60 +/- 6 years; average follow-up = 15.1 +/- 0.6 years). The renal length was measured in 23 participants by kidney ultrasonography. Based on the baseline salt-sensitivity evaluation, the subjects were classified into a lower salt-sensitivity (LSS, n = 20) and a higher salt-sensitivity group (HSS, n = 16). In comparison with the LSS group, HSS participants had a significantly higher incidence of hypertension (87.5 versus 50.0%, P = 0.02), a higher glomerular filtration rate (median, first to fourth quartile: 81.9, 72.3-95.2 versus 72.3, 59.9-81.2 ml/min; P = 0.03) and greater kidney length (median, first to fourth quartile: 68.2, 63.3-72.1 versus 61.9, 58.7-62.7 mm/m of height; P = 0.003). The incidence of hypertension remained significantly higher in HSS individuals after adjustment for age, intercurrent changes in body mass index and baseline blood pressure on low sodium diet (P = 0.04). Our findings indicate that individuals with higher BP salt-sensitivity have a higher rate of incident hypertension and suggest an altered renal tubular sodium handling involving a trend to increased glomerular filtration rate and blood pressure over time as a possible mechanism.

Context Dependency of Serum and Urinary Lithium: Implications for Measurement of Proximal Sodium Reabsorption

To the Editor: As reported previously in this journal, the endogenous lithium clearance is a marker of proximal tubular sodium handling.1,2 To investigate the context dependency of the endogenous lithium clearance, we measured by electrothermal atomic absorption spectrophotometry the lithium concentrations in serum and in exactly timed urine samples in 745 whites (51.5% women) and …

Genetics of salt-sensitive hypertension

Excess dietary salt intake represents a predominant cause of hypertension. However, individual blood pressure response to salt is heterogeneous, possibly due to different inherited susceptibility. The early identification of rare monogenic forms of hypertension associated with abnormalities of renal tubular sodium handling and response to diuretics highlighted the important role of renal alterations in salt-sensitive hypertension. Thereafter, interest has concentrated on the identification of more common allelic variants of candidate genes for hypertension in relation to the salt-sensitivity phenotype. By now, relatively large numbers of such variants have been described, and the pathogenic role of gene-gene interaction has received increasing attention. The alternative approach, consisting of the search for quantitative trait loci in the human genome linked to the transmission of salt-sensitive hypertension, has so far been less successful and cost-effective. This review summarizes consolidated knowledge and discusses the most recent novel findings on the impact of genetic variance on salt-sensitivity of blood pressure.

Renal sodium handling in patients with normal pressure glaucoma

Low BP (blood pressure) is a recognized risk factor for some patients with NPG (normal pressure glaucoma). We have shown previously that patients with orthostasis have impaired circadian renal handling of sodium, which may contribute to the low BP. Therefore the aim of the present study was to examine the renal handling of sodium, the circadian variations in BP and the neurohormonal response to an orthostatic test in a selected subpopulation of 18 patients with NPG with vasospastic and orthostatic symptoms, and in 24 healthy control subjects. The variations in BP and renal tubular sodium handling were evaluated using 24 h ambulatory BP recordings, 24 h urine collections and determination of endogenous lithium clearance as a marker of proximal sodium reabsorption. The neurohormonal and BP responses to changes in posture were also determined in a 30 min orthostatic test. This selected group of patients with NPG had lower 24 h ambulatory BPs (P<0.001), and a more pronounced fall in BP when assuming an upright position (P<0.001) compared with controls. FE(Li) (fractional excretion of lithium) was higher in patients with NPG than controls during the day (36.6+/-21.8 compared with 20.4+/-8.7% respectively; P<0.01; values are means+/-S.D.) as well as during the night (38.8+/-41.9 compared with 19.7+/-10.8% respectively; P<0.02), suggesting a reduced reabsorption of sodium in the proximal tubule. This was compensated for by an increased distal reabsorption of sodium in patients with NPG (P<0.01). These data demonstrate that patients with vasospastic NPG have a high excretion of lithium, suggesting reduced sodium reabsorption in the proximal tubule, in spite of a low BP. The abnormal renal sodium handling might contribute to the maintenance of arterial hypotension and progression of the optic nerve damage in these patients.

Type 2 Pseudohypoaldosteronism: New Insights Into Renal Potassium, Sodium, and Chloride Handling

Type 2 Pseudohypoaldosteronism: New Insights Into Renal Potassium, Sodium, and Chloride Handling

Does Malfunction of Arachidonic Acid Epoxygenase Explain Salt-Sensitive Hypertension?: Salt-Sensitive Hypertension Is Associated with Dysfunctional Cyp4a10 Gene and Kidney Epithelial Sodium Channel. J Clin Invest 116: 1696-1702, 2006.

Does Malfunction of Arachidonic Acid Epoxygenase Explain Salt-Sensitive Hypertension?: Salt-Sensitive Hypertension Is Associated with Dysfunctional Cyp4a10 Gene and Kidney Epithelial Sodium Channel. J Clin Invest 116: 1696-1702, 2006.

Abnormal Circadian Rhythm of Diuresis or Nocturnal Polyuria in a Subgroup of Children With Enuresis and Hypercalciuria is Related to Increased Sodium Retention During Daytime

In a subgroup of children with enuresis an increase in nighttime water and solute excretion has been documented. To investigate if modifications in renal function are involved in nocturnal enuresis, we assessed circadian variation in natriuresis and tubular sodium handling in polyuric hypercalciuric children. A total of 10 children with proved hypercalciuria and nocturnal polyuria and 10 age matched controls were included in the study. A 24-hour urine collection was performed in 8 sampling periods for measurement of urinary sodium excretion. Segmental tubular sodium transport was investigated during a daytime oral water load test and calculated according to standardized clearance methodology. The children with enuresis showed a marked increase in the fractional excretion of sodium during the night (0.93% +/- 0.36%), while daytime sodium excretion was decreased (0.84% +/- 0.23%). Analysis of segmental tubular sodium transport revealed decreased delivery of sodium to distal tubule (C(H2O) + C(Na) = 10.7 ml/100 ml glomerular filtration rate), indicating increased proximal tubular sodium reabsorption but also stimulation of distal sodium reabsorption as demonstrated by increased fractional distal sodium reabsorption (92.9% +/- 2.2%, controls 90.5% +/- 2.9%). Increased distal reabsorption was associated with increased fractional potassium excretion (17.5% +/- 2.7%, controls 13.6% +/- 6.4%), indicating increased distal tubular sodium/potassium exchange. No intrinsic defect in renal tubular sodium transport was found, but during the day increased sodium reabsorption in proximal and distal tubules was observed, suggesting extrarenal factors to be involved in altered circadian variation in solute and water excretion by the kidney.

Abnormalities of renal sodium handling in the metabolic syndrome. Results of the Olivetti Heart Study

The mechanisms underlying high blood pressure in the framework of metabolic syndrome (MS) are not clarified: we thus analyzed the relationship of MS and its components to renal tubular sodium handling among participants of the Olivetti Heart Study, an epidemiological investigation of a representative sample of adult white male population in southern Italy. Proximal (FPRNa) and distal (FDRNa) fractional sodium reabsorption were estimated by the clearance of exogenous lithium in 702 participants aged 25-75 years examined in 1994-1995. Blood pressure and relevant anthropometric and biochemical variables were also measured. The diagnosis of MS was based on modified National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) criteria. FPRNa, but not FDRNa, was directly associated with body mass index (BMI), waist circumference, diastolic pressure, serum triglyceride and uric acid, independently of age and of antihypertensive treatment. After adjustment for age, FPRNa, but not FDRNa, was significantly greater in individuals with MS, as compared to those without [77.6% (95% confidence interval = 76.7-80.1) versus 74.4% (73.7-75.1), P < 0.001]. A similar difference was observed after the exclusion of participants on current antihypertensive treatment (P = 0.018). In untreated individuals, a significant interaction was observed between obesity and insulin resistance as related to FPRNa (P = 0.002): the highest age-adjusted levels of FPRNa were detected in obese hypertensive and obese insulin-resistant participants. In this sample of an adult male population, MS was associated with an increased rate of FPRNa. This finding is relevant to the pathophysiology of MS and possibly to the prevention of its cardiovascular and renal consequences.

Blunted renal dopaminergic system activity in puromycin aminonucleoside-induced nephrotic syndrome

A primary tubular sodium handling abnormality has been implicated in the edema formation of nephrotic syndrome. Dopamine synthesized by renal proximal tubules behaves as an endogenous natriuretic hormone by activating D(1)-like receptors as a paracrine/autocrine substance. We examined the time courses of the urinary excretion of sodium, protein and dopamine in puromycin aminonucleoside (PAN)-treated and control rats. The rats were sacrificed during greatest sodium retention (day 7) as well as during negative sodium balance (day 14) for the evaluation of renal aromatic l-amino acid decarboxylase (AADC) activity, the enzyme responsible for the synthesis of renal dopamine. Also, the influence of volume expansion (VE) and the effects of the D(1)-like agonist fenoldopam (10 microg/kg bw/min) on natriuresis and on proximal tubular Na(+),K(+)-ATPase activity were examined on day 7. The daily urinary excretion of dopamine was decreased in PAN-treated rats, from day 5 and beyond. This was accompanied by a marked decrease in the renal AADC activity, on days 7 and 14. During VE, the fenoldopam-induced decrease in proximal tubular Na(+),K(+)-ATPase activity was more pronounced in PAN-treated rats than in controls. However, the urinary sodium excretion during fenoldopam infusion was markedly increased in control rats but was not altered in PAN-treated animals. PAN nephrosis is associated with a blunted renal dopaminergic system activity which may contribute to enhance the proximal tubular Na(+),K(+)-ATPase activity. However, the lack of renal dopamine appears not to be related with the overall renal sodium retention in a state of proteinuria.

Evidence of a dynamic aldosterone‐independent distal tubular control of renal sodium excretion in compensated liver cirrhosis*

In preascitic cirrhosis increased sodium retention occurs in kidney distal tubule in spite of normal aldosterone plasma levels. No clearance technique can dissect the respective contribution to sodium retention exerted by Henle's loop, distal convoluted tubule and collecting duct, so we evaluated proximal and distal tubular sodium handling in preascites during two manoeuvres that temporarily increase aldosterone secretion. Ten patients with compensated cirrhosis and nine controls were studied in recumbency, during standing and after dopamine receptor blockade with metoclopramide through: 4 h renal clearances of sodium, potassium, lithium and creatinine; plasma levels of active renin and aldosterone. Whilst comparable in recumbency, aldosterone levels significantly rose during standing and after metoclopramide in both groups. In patients, dopaminergic blockade caused a fall of distal sodium delivery (P < 0.01) but urinary sodium excretion was unchanged because the reabsorbed fraction of distal sodium delivery also fell (P < 0.03). Cirrhotic patients showed the same findings in the passage from recumbency to standing. In preascitic cirrhosis, the distal tubular segments of the nephron are able to cope with decreases in tubular flow by reducing reabsorption at an aldosterone-independent site (possibly the loop of Henle).

Multiple gene approaches to delineate the role of the renin-angiotensin-aldosterone system in nephropathy

Multiple gene approaches to delineate the role of the renin-angiotensin-aldosterone system in nephropathy

More on the sodium saga.

The relationship between sodium (salt) intake and blood pressure has been convincingly established by epidemiological, observational, interventional, physiological, and some genetic evidence for some time. Yet the interaction remains the subject of passionate and heated debate. Even among those who are convinced of the salt–blood pressure interaction, some advocate a population-wide attempt to reduce dietary salt intake, arguing on the basis of epidemiological and interventional evidence, and others who suggest that such interventions should be targeted toward those most likely to benefit: the “salt-sensitive” subpopulation. Studies have characterized such subgroups on the basis of higher blood pressure, increased age or African-American ethnicity.1 The issue is rendered even more compelling by the findings that salt sensitivity can be identified among “normotensive” subjects (ie, those with blood pressure <140/90) as well as those with hypertension1 and the designation of those with blood pressure levels between 120 and 139 mm Hg systolic and 80 and 89 diastolic as prehypertensive2 and at increased risk for development of fixed hypertension and for cardiovascular events compared with those with lower blood pressure.3 Observational data have provided a starting point for the quantitative considerations of dietary salt intake. The most recent (1999–2000) NHANES survey provides an estimated dietary sodium intake based on food records, excluding discretionary sodium, of 135 to 204 mmol per day for men and 100 to 135 mmol per day for women in the United States.4 Questionnaires are acknowledged to underestimate actual intake, and urinary sodium excretion has been shown to provide a more accurate index of total sodium intake because it represents ≈93% of intake at steady-state conditions.5 A recent British survey reported that urinary sodium excretion averaged 187 mmol per day for men and 139 mmol per day for women.5 This was very similar to …