Fractional Proximal Sodium Reabsorption Research Articles

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 < 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 < 0.05). The total fractional sodium excretion increased significantly after venom perfusion throughout experiments, while significant reductions (p < 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.

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.

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)

Interactions between subtotal nephrectomy and salt: effects on blood pressure and renal function in pregnant and nonpregnant ewes

The effects of high salt intake on blood pressure and renal function were studied in nine subtotally nephrectomized pregnant ewes (STNxP) and seven intact pregnant ewes (IntP) in late gestation and in eight subtotally nephrectomized nonpregnant ewes (STNxNP) and seven intact nonpregnant ewes (IntNP). STNxP had higher mean arterial pressures (P < 0.02) and plasma creatinine levels (P < 0.001) than IntP. High salt (0.17 M NaCl as drinking water for 5 days) did not change blood pressure in either STNxP or IntP. STNxNP had higher mean arterial pressures (P = 0.03) and plasma creatinine levels (P < 0.001) than IntNP. In STNxNP, blood pressure increased with high salt intake and there was a positive relationship between diastolic pressure and sodium balance (r = 0.497, P = 0.05). This relationship was not present in IntNP, STNxP, or IntP. Because high salt intake did not cause an increase in blood pressure in STNxP, it is concluded that they were protected by pregnancy from further rises in blood pressure. The observed increase in glomerular filtration rate (P < 0.03) and depression of fractional proximal sodium reabsorption (P = 0.003) that occurred in STNxP, but not in STNxNP, in response to high salt may have contributed to this protection. As well, the increased production of vasorelaxants in pregnancy may selectively protect against the occurrence of salt-sensitive hypertension in pregnancy.

Renal response to an acute protein challenge in pregnant women with borderline hypertension

The renal reserve (RR), assessed after an oral protein challenge or the intravenous administration of amino acids, is still present in healthy pregnant women (NP), although resting glomerular filtration rate (GFR) and renal plasma flow (RPF) increase progressively throughout normal gestation. No studies have addressed this issue in hypertensive gravidas; the aim of this trial was to evaluate renal response to an acute protein load (PL) in NP and pregnant women with borderline hypertension (HP). Five NP, eight HP and eight healthy non-pregnant women (CG) were evaluated. After fasting overnight, all subjects received an oral water load (20 mL/kg of body weight), the urinary output was then replaced orally with equal volumes of water. After two 30 min periods, an 80 g PL was provided. Creatinine clearance (CCr) was measured every 30 min from 1 h before and for 4 h following PL. Participants remained recumbent during the study, bladder emptiness was assessed by ultrasound immediately after each micturition. Baseline CCr was taken as the average of two 30 min periods before PL and peak Ccr as the maximal CCr recorded thereafter. The groups were similar with regard to age, weight or gestation age. Baseline CCr (NP: 118.5+/-6.0, HP: 127.4+/-6.7 and CG: 99.8+/-2.9 mL/min, P=0.004 (CG vs NP and HP), increased after PL to NP: 223.5+/-9.8 to HP: 178.5+/-13 and to CG: 149.1+/-4.0 mL/min, P<0.0004 (CG vs HP, CG vs NP and NP vs HP)). Peak minus baseline CCr was 97.3+/-10.1; 46.3+/-12.7 and 48.3+/-4.8 for NP, HP and CG, respectively (P<0.006 HP vs CG and NP). The peak CCr was obtained significantly earlier in both pregnant groups (Period 3) compared with the healthy non-pregnant women (Period 5) (P=0.02). The fractional proximal reabsorption of sodium (FPRNa+) at peak CCr was similar in the groups (NP: 0.74+/-0.01 HP: 0.78+/-0.02 and CG: 0.74+/-0.03, P=not significant (NS)) as was the distal delivery of sodium (DDNa+) (NP: 5.8+/-0.5; HP: 4.1+/-0.5 and CG: 4.3+/-0.4 meq/min, P=NS). Fractional excretion of urea (%) increased from 91.4+/-5.5 to 105.5+/-9.8%; 80.7+/-8.0 to 97.3+/-9.8; and 44.4+/-7.8 to 86.0+/-7.1 in NP, HP and CG, respectively (P=NS). There was a trend towards a poorer maternal and fetal outcome in the HP group. Mid-term borderline HP failed to increase CCr as much as NP did after a protein challenge, suggesting altered functional response of the nephron or lessened sensitivity of renal vasculature to additional vasodilator stimuli. These results support the interest of additional prospective studies with a larger number of patients to confirm these findings and evaluate the value of RR tests as predictors of outcome of pregnancies at risk.

Association Between Arterial Properties and Renal Sodium Handling in a General Population

Mean arterial pressure drives pressure-natriuresis and determines arterial structure and function. In a population sample, we investigated the relation between arterial characteristics and renal sodium handling as assessed by the clearance of endogenous lithium. We ultrasonographically measured diameter, cross-sectional compliance (CC) and distensibility (DC) of the carotid, brachial, and femoral arteries in 1069 untreated subjects (mean age: 41.6 years; 50.1% women; 18.8% hypertensive subjects). While accounting for covariates and standardizing for the sodium excretion rate in both sexes, CC and DC of the femoral artery increased with higher fractional distal sodium reabsorption. Differences associated with a 1-SD change in fractional distal reabsorption of sodium were 51.7 mm(2)/kPax10(-3) (95% CI: 23.9 to 79.5; P=0.0002) and 0.56x10(-3)/kPa (95% CI: 0.17 to 0.94; P=0.004) for femoral CC and DC, respectively. In women as well as in men, a 1-SD increment in fractional proximal sodium reabsorption was associated with decreases in femoral and brachial diameter, amounting to 111.6 mum (95% CI: 38.2 to 185.1; P=0.003) and 52.5 mum (95% CI: 10.0 to 94.9; P=0.016), respectively. There was no consistent association between the properties of the elastic carotid artery and renal sodium handling. In conclusion, higher fractional sodium reabsorption in the distal nephron is associated with higher femoral CC and DC, and higher proximal sodium reabsorption is associated with decreased brachial and femoral diameters. These findings demonstrate that there might be an influence of renal sodium handling on arterial properties or vice versa or that common mechanisms might influence both arterial and renal function.

Effects of 7-day amino acid infusion on renal growth, function, and renin-angiotensin system in fetal sheep

These experiments examined whether renal growth and the fetal renin-angiotensin system could be stimulated by infusion of amino acids and whether chronic amino acid infusions restored glomerulotubular balance, which had been disrupted during 4-h infusions. Five fetal sheep aged 122 +/- 1 days gestation received an infusion of alanine, glycine, proline and serine in 0.15 M saline at 0.22 mmol/min for 7 days. Six control fetuses were given saline at the same rate (5 ml/h). Kidney wet weights after amino acid infusion were 28% larger than control fetuses (P < 0.05), and renal angiotensinogen mRNA levels were approximately 2.6-fold higher (P < 0.005). Circulating renin levels and renal renin mRNA levels were suppressed (P < 0.05), and renal renin protein levels tended to be lower. Arterial pressure was increased, and there was a marked, sustained natriuresis and diuresis. Glomerular filtration rate and filtered sodium were approximately two-fold higher throughout infusion (P < 0.05). Fractional proximal sodium reabsorption, suppressed at 4 h (from 73.4 +/- 6.5 to 53.7 +/- 10.2%), did not return to control levels (36.1 +/- 3.4% on day 7, P < 0.05). Distal sodium reabsorption was markedly increased (from 79 +/- 25 to 261 +/- 75 mumol/min by day 7, P < 0.005), but this was not sufficient to restore glomerulotubular balance. The resultant high rates of sodium excretion led to hyponatremia and polyhydramnios. In conclusion, long-term amino acid infusions increased renal angiotensinogen gene expression, kidney weight, and distal nephron sodium reabsorptive capacity but failed to restore proximal and total glomerulotubular balance.

Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion

Glomerular hyperfiltration plays a role in the pathophysiology of diabetic nephropathy. An increase in the glomerular filtration rate (GFR) could result from primary actions at the glomerular/vascular level or could be the consequence of a primary increase in proximal tubular sodium reabsorption resulting in systemic volume expansion. Recently it was hypothesized that an increase in sodium reabsorption may lead to glomerular hyperfiltration through the tubulo-glomerular feedback mechanism (tubular-hypothesis) without volume expansion. We have studied 54 normoalbuminuric patients with type 1 diabetes. The GFR was measured by inulin clearance. Proximal and distal sodium reabsorption were calculated according to standard formulas using the free water clearance technique. Plasma volume, measured by the (125)I-albumin method, atrial natriuretic peptide (ANP) and the second messenger cyclic guanosine-3,5-monophosphate (c-GMP) were used as markers of extracellular volume expansion. Glomerular hyperfiltration (GFR >or= 130 mL min(-1) 1.73 m(-2)) was present in 14 out of 55 patients with diabetes (25%). There were no differences in plasma volume between normo-(NF) and hyper-filtrating (HF) patients (2933 +/- 423 in NF vs. 3026 +/- 562 mL in HF, NS). Also plasma ANP and c-GMP levels were not significantly different between the groups. The fractional proximal reabsorption of sodium was significantly increased in HF [fPRNa(+) (%) 90.1 +/- 2.0 vs. 91.5 +/- 1.6, P = 0.02]. There were no differences in distal sodium reabsorption or distal sodium load (approximately macula densa concentration of NaCl) in both groups. Our data suggest that the primary event in diabetic glomerular hyperfiltration is an increase in proximal tubular sodium reabsorption. They do not support the hypothesis that systemic volume expansion or ANP mediate glomerular hyperfiltration in patients with normoalbuminuric type 1 diabetes. As such, changes in tubular sodium handling most probably influence tubulo-glomerular feedback.

Renal Interstitial Guanosine Cyclic 3′, 5′-Monophosphate Mediates Pressure-Natriuresis Via Protein Kinase G

Pressure-natriuresis is the physiological protective mechanism whereby elevation of blood pressure induces a rapid increase in renal sodium (Na+) excretion. Pressure-natriuresis abnormalities are common to all forms of hypertension. We tested the hypothesis that pressure-natriuresis is mediated by renal interstitial (RI) cGMP and protein kinase G (PKG). We used anesthetized, uninephrectomized Sprague-Dawley rats and a standard pressure-natriuresis model in which bilateral adrenalectomy and renal denervation was done on rats. Renal perfusion pressure (RPP) was adjusted by manipulating clamps above and below the renal artery, and RI cGMP was quantified by microdialysis. RI cGMP increased from 3.1+/-0.5 to 5.5+/-0.4 fmol/min (P<0.05) when RPP was raised from 100 to 140 mm Hg. This increase in RI cGMP was eliminated by RI infusion of soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ). Raising RPP from 100 to 140 mm Hg increased urinary sodium excretion from 0.2+/-0.1 to 0.8+/-0.1 micromol/min, fractional sodium excretion from 0.2+/-0.1% to 0.8+/-0.1%, and fractional lithium excretion from 20.1+/-3.0% to 62.7+/-3.7% (all P<0.05). These responses were eliminated by RI infusion of nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester, ODQ, and PKG inhibitors Rp-8-pCPT-cGMP and Rp-8-Br-cGMP. Increasing RPP from 100 to 140 mm Hg decreased fractional proximal sodium reabsorption without influencing fractional distal Na+ reabsorption or glomerular filtration rate. In conclusion, pressure-natriuresis is mediated by RI cGMP and a PKG signaling pathway in target renal proximal tubule cells.

Cardiorenal actions of a unique chimeric peptide to CNP and BNP in experimental chronic heart failure

Background: CNP, a member of the natriuretic peptide system (NPS) of endothelial origin, is a potent venodilator with minimal natriuretic actions. CNP exerts venodilating actions via generation of cGMP after binding to the NPR-B receptor. BNP, a member of the NPS of myocardial origin, is the most potent natriuretic peptides and mediates its natriuretic properties via the NPR-A receptor. Both CNP and BNP possess a 17-amino acid ringed structure while BNP has a 6-amino acid COOH-terminus that CNP lacks. We recently designed and synthesized a novel 28-amino acid chimeric peptide termed “CBNP” which possesses the natriuretic actions of BNP and the venodilating actions of CNP. This chimeric protein possesses the 22-amino acid structure of CNP and the 6-amino acid COOH-terminus of BNP. To date its biological actions in experimental chronic heart failure (HF) are undefined. Methods: In 5 anesthetized dogs with experimental chronic HF produced by rapid ventricular pacing at 180 beats/min for 10 days, cardiorenal function was assessed in response to CBNP (50 ng/kg/min IV). Results: CBNP increased urinary sodium excretion (41±23 to 108±25 μEq/min∗), fractional sodium excretion (0.3±0.1 to 1.3±0.7 %∗) and glomerular filtration rate (29±5 to 39±4 ml/min∗), with a decrease in proximal fractional reabsorption of sodium (85±5 to 79±6 %∗). These renal responses were paralleled by increases in plasma cGMP (27±3 to 32±3 pmol/ml∗) and urinary cGMP excretion (1532±278 to 2344±589 pmol/min∗). In addition, CBNP also decreased right atrial pressure (5.8±0.4 to 3.4±0.8 mmHg∗), pulmonary capillary wedge pressure (18.9±0.9 to 15.6±0.5 mmHg∗) and cardiac output (2.7±0.3 to 2.0±0.2 l/min∗) consistent with a decrease in cardiac preload. Conclusion: These cardiorenal actions were unassociated with increases in plasma renin activity. The current study suggests that CBNP possess the venodilating actions of CNP and the natriuretic actions of BNP in experimental chronic HF. Thus, CBNP may have therapeutic potential as a venodilating and natriuretic agent in heart failure. (∗p<0.05 vs baseline)

Renal, cardiovascular and endocrine responses of fetal sheep at 0.8 of gestation to an infusion of amino acids.

Amino acid infusions increase renal blood flow (RBF) and glomerular filtration rate (GFR) and stimulate tubular reabsorption in adults. To characterize the effects of amino acids on fetal renal haemodynamics, tubular sodium reabsorption, acid-base homeostasis and plasma renin levels, 11 chronically catheterized fetal sheep aged 121 +/- 1 days (term ~150 days) were infused I.V. for 4 h with alanine, glycine, proline and serine (0.1, 0.1, 0.06 and 0.06 mmol min(-1), respectively) in 0.15 M saline at 0.165 ml min(-1). Eight control fetuses were given saline. During amino acid infusion, plasma amino acid levels increased up to 20-fold (P < 0.005). GFR increased by 50 +/- 8 % (P < 0.001); there was only a small transient increase in RBF. Proximal fractional sodium reabsorption fell from 74.6 +/- 2.9 to 55.5 +/- 5.4 % (P < 0.005). Distal sodium delivery increased, but a smaller percentage of this distal sodium load was reabsorbed (P < 0.005). Thus fractional sodium reabsorption fell from 95.5 +/- 0.9 to 81.4 +/- 2.0 % (P < 0.005). There was a large diuresis, natriuresis, kaliuresis and increase in osmolar excretion (P < 0.005). Plasma sodium and chloride concentrations fell (P < 0.005). Plasma osmolality did not change. Plasma renin levels fell (P < 0.05), cortisol levels increased (P < 0.05), and there was a compensated metabolic acidosis. Thus the fetal sheep kidney demonstrated a remarkable functional capacity to respond to amino acid infusion. The increase in filtration fraction and the lack of an increase in RBF suggest that efferent arteriolar vasoconstriction occurred, a very different response from the renal vasodilatation seen in adult animals.

Blood pressure lowering, renin suppressing and natriuretic properties of a new designer peptide BD-NP

Brain natriuretic peptide (BNP) is a 32-amino-acid peptide of cardiac origin with natriuretic and vasodilatory properties which is currently being developed for the treatment of congestive heart failure (CHF). Dendroaspis natriuretic peptide (DNP) is a recently discovered 38-amino-acid peptide structurally similar to ANP, BNP and CNP with potent natriuretic and vasoactive actions whose immunoreactivity is present in human plasma and elevated in human CHF. Data suggest that DNP is the natriuretic peptide most resistant to degradation by neutral endopeptidase due to its long C-terminus. Based upon the potent biological properties of both peptides we designed and synthesized a chimeric peptide BD-NP which consists of the 26 amino acid ring structure of BNP and the 15 amino acid C-terminus of DNP. We then assessed the cardiorenal actions of synthetic BD-NP in normal dogs in vivo. The therapeutic potential of parenterally administered BD-NP was assessed upon cardiorenal and endocrine function in 6 anesthetized dogs and compared with the placebo control group (n=7) which received saline. Intravenous synthetic BD-NP was infused after baseline measurements at 10 and 50 ng/kg/min. * p<0.05 vs. Baseline. Administration of low and high dose BD-NP decreased MAP (from baseline 133±6 to 122±4 and 104±3* mmHg), RAP (from 2.8±0.4 to 1.7±0.3* and 1.2±0.3* mmHg), PAP (from 16.7±0.8 to 15.3±0.5 and 12.4±0.4* mmHg) and PCWP (from 5.2±0.5 to 3.5±0.5* and 1.8±0.4* mmHg). BD-NP increased GFR (from 31±3 to 46±5* and 46±4* ml/min) without changes in RBF. BD-NP enhanced natriuresis (UNaV from 14.8±10 to 121.8±52* and 158.8±57* μEq/min) and diuresis (UV from 0.27±0.1 to 1.25±0.3* and 2.22±0.5* ml/min) with a decrease in proximal fractional reabsorption of sodium (from 83.8±5.0 to 68.6±3.8* and 61.7±3.8* %). Both doses of BD-NP decreased plasma renin activity (from 8.7±1.0 to 4.1±0.6* and 5.8±1.0* ng/ml/hr). In contrast, all parameters were unchanged with placebo. We report that this new designer peptide BD-NP potently lowers blood pressure, reduces cardiac filling pressures, increases glomerular filtration rate, augments natriuresis and diuresis and possesses renin-suppressing properties. These findings support a possible therapeutic role for this new designer peptide in the treatment of cardiovascular diseases such as hypertensive crisis and acute decompensated CHF.

Normal Responses of Atrial Natriuretic Factor and Renal Tubular Function to Sodium Loading in Hypertension-Prone Humans

Background: In order to explore the hypothesis of an atrial natriuretic factor (ANF) deficiency in prehypertension, we compared the response to sodium loading on ANF and renal function in subjects with positive and negative histories of hypertension. Methods: Twenty-two offspring of hypertensive parents (OH) and 20 offspring of normotensive parents (ON) were studied after 4 days of low (50 mmol/day) or high (300 mmol/day) dietary sodium intake. The diets were allocated randomly. Blood pressure (BP), renal function, plasma concentration of ANF, cyclic guanosine monophosphate (cGMP), renin, angiotensin I and II, aldosterone, endothelin and catecholamines were determined during a clearance period of 90 min on both diets. Neurohormones were measured by radioimmunoassays. Renal function was determined by simultaneous measurements of 51Cr-ethylenediaminetetraacetate (a marker of glomerular filtration rate), lithium and sodium clearances. Results: Supine systolic and diastolic BPs were significantly elevated in OH, with both low and high dietary sodium intake. There was no difference in ANF and cGMP concentrations on the low sodium diet. Increasing sodium intake caused a similar increase in ANF in OH and ON but cGMP did not change significantly. As expected the activity of the renin-angiotensin-aldosterone system was decreased by enhancing sodium intake but with both low and high sodium intake plasma renin concentration was significantly higher in OH than in ON. Activation of the sympathetic nervous system with low sodium intake was indicated by a moderate increase in plasma concentrations of epinephrine and norepinephrine in both groups. The renal effects were characterized by significant increases in GFR, lithium and sodium clearances with increasing sodium intake. There were no differences between OH and ON. Estimated values of fractional proximal and distal tubular sodium reabsorption decreased significantly and in a similar way in both OH and ON. Conclusion: These results indicate that the renal and neuroendocrine responses to dietary sodium loading are similar in both OH and ON. The only difference was a higher BP and an elevated plasma renin concentration on both dietary regimens in OH compared with ON. In particular, in OH and ON an identical increase in plasma ANF concentration in response to sodium loading was found. Thus, this study cannot support the hypothesis of a dysregulation of ANF in hypertension-prone humans.

Changes in renal hemodynamics and tubular function of surgically cured primary hyperparathyroid patients are probably due to chronic hypercalcemic nephropathy.

To understand the mechanisms responsible for the persistent hypercalciuria and reduced glomerular filtration rate (GFR) previously found in 6 of 10 patients surgically cured of primary hyperparathyroidism (PHPx), the tubular handling of lithium, sodium, calcium, and phosphate as well as the renal hemodynamics were evaluated in these 10 PHPx patients, in 10 control subjects, and in 5 patients with renal hypercalciuria (RH), during fasting and after an oral calcium load. A positive correlation between the fractional excretions of calcium and sodium was found in all groups, but the PHPx patients excreted more calcium for the same amount of sodium than control subjects. The fractional proximal sodium reabsorption (FPRNa), distal delivery, and fractional phosphate reabsorption were similar in all groups; a significant positive correlation was found between the fractional calcium reabsorption and the FPRNa, indicating that proximal tubular function was preserved and that the urinary calcium losses in RH and in the hypercalciuric PHPx patients (h-PHPx) occurred in the distal nephron. However, only h-PHPx patients had reduced renal plasma flow, renal blood flow, and GFR, as well as a high renal vascular resistance, which was even more evident after the calcium challenge. These findings lead us to conclude that RH and h-PHPx patients are very different, as far as kidney dysfunction is concerned, and that a hypercalcemic nephropathy is the most probable cause of the alterations in distal calcium reabsorption and renal hemodynamics found in the h-PHPx patients.

Proximal tubular reabsorption of growth hormone and sodium/fluid in normo- and microalbuminuric insulin-dependent diabetes mellitus.

Proximal tubular dysfunction may be implicated in the pathogenesis of diabetic nephropathy. An investigation of proximal tubular function was carried out by assessing proximal tubular sodium-reabsorption and low molecular weight protein excretion in a group of patients with type 1 diabetes mellitus. Normoalbuminuric [group A, n = 6, albumin excretion rate (AER) mean (range) 4 (0-10) micrograms/min], and microalbuminuric [group B, n = 6, AER 88 (35-198) micrograms/min] patients with type 1 diabetes were compared with matched controls. Simultaneous lithium and growth hormone (GH) clearance and urinary beta 2-microglobulin excretion were assessed. Fasting plasma glucose at the start of the study was [median (range)] 13 (10.2-15.1), 9.3 (5.9-15) and 4.1 (4.0-5.0) mmol/l in groups A, B and controls, respectively, with a mean coefficient of variation during the study of 3.9% (group A) and 5.2% (group B). There was no significant difference in plasma glucose levels between patients in groups A and B. Urinary GH excretion was raised in the patients with microalbuminuria (group B; P < 0.05), although there was no difference in serum GH clearance rate between the patient groups and controls. Urinary GH correlated with B 2-microglobulin in the diabetic subjects (r = 0.665, P < 0.05) and with the degree of microalbuminuria in group B patients (r = 1, P < 0.01). Urinary GH was also greater than 10 microU, the median value observed in the controls, in 5 of 6 (83%) patients in group A. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) measured by constant infusion of 51Cr-ethylene diamine tetra-acetic acid (EDTA) and I125-para-amino hippuric acid (PAH), respectively, showed relative hyperfiltration in the normoalbumiruric group compared with controls (P < 0.05) and group B (P < 0.05). Absolute proximal reabsorption of sodium and of water (APRNa and APRH2O) was significantly higher in group A patients (P < 0.05). Although GFR was significantly higher in group A patients, no differences were found in fractional proximal reabsorption of sodium and water (FPRNa+H2O) or end proximal delivery between the patient groups and controls. Therefore, the measurement of protein reabsorptive capacity provides a more sensitive marker of renal tubular impairment in type 1 diabetes than sodium/fluid reabsorptive capacity. In patients with microalbuminuria, both glomerular and tubular damage may coexist. Our results stress the usefulness of markers of renal tubular function in monitoring the course of diabetic nephropathy. This study also shows that assessment of GH clearance has promise as a marker of renal tubular protein reabsorptive capacity.

Acute Ureteral Obstruction and Glomerulotubular Function in Rats

Urinary tract obstruction is a common cause of acute renal failure (ARF). During unilateral ureteral obstruction (UUO) arteriolar vasoconstriction, increase in tubular pressure, and ultrafiltrate retrodiffusion occur. We studied renal function of rats with surgical UUO for 24 hr. After this period of UUO, the contralateral kidney was removed and the right ureter was deobstructed. The control uninephrectomized group consisted of normal rats submitted to left uninephrectomy (UNx). Functional studies were performed 12 and 24 hr, and 7 days after deobstruction and UNx. We measured creatinine clearance, and fractional excretion of sodium and lithium. Using conventional formulas we calculated fractional proximal and distal sodium reabsorption. Initially we observed a reduction in glomerular filtration rate (GFR) after deobstruction (12 and 24 hr). However, after 7 days, the GFR was significantly higher in deobstructed rats than in controls (340.3 ± 18.3 vs. 286.4 ± 9.3 μL/min/100 g, p < 0.01). The dry kidney weight was also increased in these rats. The fractional sodium excretion was increased in deobstructed rats, mainly in early studies (12 and 24 hr). Whereas fractional proximal reabsorption was reduced in both groups, the fractional distal reabsorption was significantly decreased in the deobstructed group compared to UNX controls (93.9 ± 0.9 vs. 98.9 ± 0.1% after 24 hr, p < 0.01). Our data showed that UUO influenced both glomerular and tubular functions. A salient finding was the overcorrection of GFR 7 days after deobstruction. The renal release of hormones and growth factors could mediate these alterations in renal function through their vascular, tubular, and proliferative actions.

The renal response to exogenous insulin in non-insulin-dependent diabetes mellitus in relation to blood pressure and cardiovascular hormonal status.

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by insulin resistance hyperinsulinaemia and a high frequency of hypertension. It has recently been shown that insulin exerts a sodium-retaining effect, which is preserved in NIDDM: We sought to determine whether insulin affected renal sodium handling differently in hypertensive and normotensive NIDDM patients. After a baseline period of 2 h, eight normotensive (N-) NIDDM patients and eight NIDDM patients with hypertension (H-) underwent a euglycaemic clamp with infusion of two sequential doses of insulin (50 and 500 mU/kg/h) or vehicle (time control) during 2-h periods each. Fractional clearances of sodium and lithium were determined according to standard methods. Fractional lithium clearance was used to assess segmental tubular sodium handling. Insulin induced similar decrements in fractional sodium excretion (N-NIDDM: 43+/-5.9 and 57+/-9.1%,H-N IDDM: 48+/-16.4 and 62+/-12.5%, low and high insulin dose respectively). Distal tubular sodium absorption increased simultaneously. A fall in fractional proximal sodium reabsorption was observed in N-NIDDM (4.4+/-2.7 and 29.8+/-5.1%, low and high insulin dose respectively), which was attenuated in H-NIDDM (-5.0+/-7.3 and -2.1+/-13.9% respectively). The latter appeared to be related to a defective atrial natriuretic factor (ANF) and renal cyclic GMP response. A modest decrease in blood pressure occurred during insulin infusion that was not related to changes in ANF or FeLi. The findings suggest that insulin-induced sodium retention may contribute to hypertension in NIDDM if the homeostatic response to offset this effect fails.

Modifications induced by -10 degrees Trendelenburg's posture in sodium tubular handling in patients with essential hypertension.

In essential hypertensive patients "exaggerated natriuresis" is a response to acute volume expansion. However, the underlying mechanisms for this remain to be determined. We studied 19 patients with essential hypertension (HP) and 9 normotensive subjects (NS). In all examined subjects the response to acute central volume expansion, without the plasma compositional change that Trendelenburg's position involves, was evaluated during 90 min (period T) after a similar period of deambulation (period D). Mean blood pressure (MBP), tubular sodium handling by the lithium clearance technique, plasma renin activity (PRA), plasma aldosterone (PA), plasma catecholamines and urine prostaglandine E2 and kallikrein were assessed after D and T. MBP was significantly higher in HP than in NS (p = 0.00001). HP showed "exaggerated natriuresis" after T (fractional excretion of sodium increased from 0.55 +/- 0.1% after D to 1.20 +/- 0.2% after T, p < 0.01). This was because of a decrease in their proximal fractional reabsorption of sodium (from 74.96 +/- 1.8% after D to 62.50 +/- 2.8% after T, p < 0.01). Plasma epinephrine and plasma dopamine after T were significantly lower than in standing position in HP (p < 0.01) but no in NS. The decrease in plasma renin activity after T in HP was 53%, and 32% in NS. There were not any significant differences between groups in the other neurohormonal systems studied. We conclude that the major determinant of "exaggerated natriuresis" in hypertensive patients is a higher stimulation of the cardiopulmonary receptors following Trendelenburg's position and consequently stronger reflex inhibition of sympathetic system activity and renin-angiotensin II activity. The "exaggerated natriuresis" after Trendelenburg's position in HP was an expression of abnormal pressure natriuresis.

Clinical assessment of renal proximal tubular function using lithium clearance method

Proximal and distal sodium reabsorption values were calculated from lithium clearance in 63 patients with renal diseases, 13 cirrhotic patients with ascites and 12 control subjects. In the patients with renal diseases, fractional excretion of lithium (FELi) and fractional proximal reabsorption of sodium (FPRNa) were not changed in patients whose glomerular filtration rate (GFR), was over 30 mL/min, but FELi was increased and FPRNa was decreased when the GFR was lower than 30 mL/min. Moreover, fractional distal reabsorption of sodium (FDRNa) was decreased in patients whose GFR was under 40 mL/min. These results indicate that proximal tubular function is well adapted to the degree of renal function even if the etiologies of renal diseases are different. Five patients with nephrotic syndrome (minimal change type) were subjected to lithium clearance method before and after steroid treatment. FPRNa in nephrotic patients was reduced after the treatment, though there was no significant difference in FDRNa. In cirrhotic patients, FELi, FPRNa and FDRNa did not differ from the values in the control subjects, which were not influenced by the decrease in GFR. Thus, the reduction of FPRNa with GFR which was observed in renal disease, was absent in liver cirrhosis. In conclusion, these data indicate that renal adjustment of sodium excretion in chronic renal disease at first takes place in the distal parts of the nephron and later in the proximal tubule, and in addition, that in appropriate reabsorption of sodium from the proximal tubule probably plays a role in ascites formation in cirrhotic patients.

Renal sodium transport in healthy elderly and elderly with systolic hypertension

It is accepted that lithium clearance expresses the delivery of sodium and water. This study was designed to investigate renal sodium transport in healthy and hypertensive elderly using lithium clearance (Cli) and fractional lithium clearance (FEli). The clearance studies were performed and analyzed in young healthy volunteers (n = 29, 26.2 ± 3.7 years), elderly with normal blood pressure (n = 49, 67.8 ± 6.1 years) and elderly with systolic hypertension (n = 37, 68.5 ± 7.2 years, blood pressure ≥ 160/95 mmHg). FENa of healthy elderly group was greater than that of young group (1.36 ± 0.49% vs. 1.06 ± 0.54%, P < 0.05), but there was no difference between the healthy elderly group and hypertensive elderly group. In the healthy elderly with normal GFR (subgroup 1, n = 27), FELi was still significantly higher than that of young group (26.1 ± 10.0 vs. 18.6 ± 4.0%, P < 0.001). The absolute proximal reabsorption of sodium (APRNa) and the fractional proximal reabsorption of sodium (FDRNa) in subgroup 1 were obviously lower than that of the young group (11.9 ± 1.8 vs. 13.3 ± 3.1 mmol/min, P < 0.05 and 76.5 ±6.4% vs. 81.5 ± 4.0%, P < 0.005). On the other hand, no significant difference was found in absolute or fractional distal reabsorption of sodium (ADRNa or FDRNa) between subgroup 1 and the young group. ADRNa/filtered sodium load (FLNa) in subgroup 1 was significantly higher than that of the young group (22.6 ± 6.8% vs. 17.6 ± 3.9%, P < 0.05), whereas there were no differences in CLi, FELi, APRNa, ADRNa, FDRNa or ADRNa/FLNa between the healthy elderly group and the aged systolic hypertensive group. It is concluded that in ageing, sodium reabsorption in the proximal nephron is reduced alone with a relative enhancement of sodium reabsorption in distal nephron, which might be a compensation in sodium balance of old persons. Abnormalities of sodium reabsorption were unlikely to be responsible for systolic hypertension in the elderly.