No abstract

The Oxford Classification of IgA nephropathy (IgAN) includes the following four histologic components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). These combine to form the MEST score and are independently associated with renal outcome. Current prediction and risk stratification in IgAN requires clinical data over 2 years of follow-up. Using modern prediction tools, we examined whether combining MEST with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than current best methods that use 2 years of follow-up data. We used a cohort of 901 adults with IgAN from the Oxford derivation and North American validation studies and the VALIGA study followed for a median of 5.6 years to analyze the primary outcome (50% decrease in eGFR or ESRD) using Cox regression models. Covariates of clinical data at biopsy (eGFR, proteinuria, MAP) with or without MEST, and then 2-year clinical data alone (2-year average of proteinuria/MAP, eGFR at biopsy) were considered. There was significant improvement in prediction by adding MEST to clinical data at biopsy. The combination predicted the outcome as well as the 2-year clinical data alone, with comparable calibration curves. This effect did not change in subgroups treated or not with RAS blockade or immunosuppression. Thus, combining the MEST score with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than our current best methods.

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...