The relationship between blood pressure and sodium (Na) excretion is less steep in hypertension caused by increased renal tubular reabsorption. We recently demonstrated that one mutation in rat alpha-adducin gene: (1) is responsible for approximately 50% of the hypertension of MHS rats, and (2) stimulates tubular Na-K pump activity when transfected in renal epithelial cell, suggesting that its pressor effect may occur because an increased tubular reabsorption. Linkage and association studies demonstrated that the alpha-adducin locus is relevant for human hypertension. A point mutation (G460W) was found in human alpha-adducin gene, the 460W variant (G/W) is more frequent in hypertensives than in normotensives. The aim of this study was to test whether acute changes in body Na may differently affect blood pressure in humans as a function of alpha-adducin genotype. The pressure-natriuresis relationship was analyzed in 108 hypertensive using two different acute maneuvers: Na removal (furosemide 25 mg p.o.) and, two days later, Na load (310 mmoles i.v. in 2 hr). We found that 80 patients were wild-type homozygous (G/G), 26 were G/W heterozygous, and 2 were W/W homozygous with similar blood pressure, age body mass index, gender, plasma and urinary sodium and potassium. In basal condition G/W-W/W patients showed a lower plasma renin activity and fractional excretion of Na. In either case the pressure-natriuresis relationship was less sleep in G/W-W/W than in G/G patients, obviously negative for Na depletion with furosemide (-0.011 +/- 0.004 vs. -0.002 +/- 0.002 mm Hg/mumol/min, P < 0.03), and positive for Na load (0.086 +/- 0.02 vs. 0.027 +/- 0.007 mm Hg/mumol/min, P < 0.001). The finding of reduced slope after Na depletion or Na load supports the hypothesis that, as MHS rats, humans bearing one W alpha-adducin variant display an increased of renal tubular sodium reabsorption.

Abstract-Abnormalities in renal sodium reabsorption may be involved in the development and maintenance of experimental and clinical hypertension. Adducin polymorphism is thought to regulate ion transport in the renal tubule. It has recently been shown that there is a significant linkage of ␣-adducin locus to essential hypertension and that the 460Trp allele is associated with hypertension. Patients with this allele display larger blood pressure changes with body sodium variation. The aim of this study was to test whether ␣-adducin polymorphism is involved in abnormalities of renal function. Because proximal tubular reabsorption has been shown to be tightly coupled to renal perfusion pressure, this segmental tubular function was investigated in 54 (29 Gly/Gly and 25 Gly/Trp) untreated hypertensive patients in basal conditions with the use of endogenous lithium concentration and uric acid. Fractional excretions of lithium and uric acid were significantly decreased in the Gly/Trp hypertensive patients compared with the Gly/Gly hypertensives. The contribution of ␣-adducin to fractional excretion of lithium was investigated by multiple regression analysis. Adducin genotype was significantly (R 2 ϭ0.11, Fϭ6.5; PϽ0.01) and directly related to fraction excretion of lithium; gender, age, urinary Na ϩ , urinary uric acid, mean blood pressure, and plasma renin activity were not related. In conclusion, the adducin gene can be considered to be a 'renal hypertensive gene' that modulates the capacity of tubular epithelial cells to transport Na ϩ and hence contributes to the level of blood pressure. (Hypertension. 1999;33:694-697.) Key Words: lithium Ⅲ genes Ⅲ human Ⅲ renal function Ⅲ blood pressure Ⅲ adducin Ⅲ hypertension, genetic C ross-transplantation studies in rat models of primary hypertension have shown that at least a portion of hypertension follows the kidney. This finding has been obtained in all strains in which such an experiment has been carried out, suggesting that the kidney contributes significantly to hypertension. 1 Data consistent with those in rats have also been obtained in humans. 2 Many abnormalities in kidney function and cell membrane ion transport have been described in hypertensive rats and humans. 3 The logical sequence of events going from a genetic-molecular abnormality to a cellular abnormality that causes hypertension via a modification of kidney function is difficult to prove. In Milan hypertensive (MHS) rats we showed that (1) hypertension develops because of a primary increase in renal tubular sodium reabsorption 4 ; (2) a significant portion of blood pressure difference between MHS and normotensive animals (MNS) is due to a functional point mutation within the gene coding for ␣-adducin 5 ; (3) transfection of either MHS or MNS ␣-adducin cDNA into rat renal epithelial cells showed that cells expressing MHS adducin had a significantly greater Na ϩ pump activity at Vmax and a larger number of Na ϩ pump units expressed on the cell surface 6 ; and (4) studies in a cell-free system have shown that...

Background and objective Time-average proteinuria (TAp) is the strongest predictor of renal survival in IgA nephropathy (IgAN). Little is known about the utility and safety of corticosteroids (CS) to obtain TAp,1 g/d in patients with advanced IgAN. This study sought to evaluate TAp at different degree of baseline renal function and histologic severity during CS use and to investigate treatment safety.Design, setting, participants, & measurements We performed one-stage individual-patient data meta-analysis among 325 patients with IgAN enrolled in three prospective, randomized clinical trials. Patients were divided into three groups according to treatment: no treatment (NT; supportive therapy), CS, and CS plus azathioprine (CS+A). Associations of TAp with histologic grading, treatment, and eGFR at baseline were performed with linear regression models for repeated measures. The median follow-up duration was 66.6 months (range, 12-144 months).Results In the first 6 months, proteinuria did not change in the NT group and decreased substantially in the other groups(CS: from a mean6SD of 2.2061.0 to 0.8 [interquartile range, 0.4-1.2] g/d; CS+A: from 2.87662.1 to 1.0 [interquartile range, 0.5-1.7] g/d), independent of the degree of histologic damage and baseline eGFR. The percentage of patients who maintained TAp,1 g/d was 30.2% in the NT, 67.3% in the CS, and 66.6% in the CS+A group. Thirty-four patients experienced adverse events: none in the NT, 11 (6.4%) in the CS, and 23 (20.7%) in the CS+A group. The risk of developing adverse events increased with decreasing levels of eGFR (from 2.3% to 15.4%). The addition of azathioprine to CS further increased the percentage of patients with adverse events (16.8% versus 5.7% in study 2 and 30.0% versus 15.4% in study 3; overall P,0.001).Conclusions In patients with IgAN, CS can reduce proteinuria and increase the possibility of maintaining TAp,1 g/d, regardless of the stage of CKD and the histologic damage. The risk of major adverse events is low in patients with normal renal function but increases in those with impaired renal function and with the addition of azathioprine.

BackgroundChronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease.Methods174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6–9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease.ResultsCarriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p = 0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p = 0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square = 6.84, p = 0,03). Cox regression showed that -374 T/A RAGE polymorphism (p = 0.037), albuminuria (p = 0.01) and LDL cholesterol (p = 0.038) were directly associated with CKD progression. HDL cholesterol (p = 0.022) and BMI (p = 0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline.Conclusions-374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression.

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