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Background: An association between renal hemodynamic dysfunction and coronary artery disease (CAD) has been documented in chronic renal failure; however, no information is available in CAD patients with normal glomerular filtration rate (GFR). This study was aimed at evaluating early abnormalities and outcome of renal function in CAD patients., Methods: In 15 nondiabetic patients with normal renal function and no significant stenoses in renal arteries, and having undergone coronary arteriography, we studied systemic and renal hemodynamics before and after a vasodilating stimulus induced by aminoacid (AA) infusion. A control group (C) consisted of 15 sex- and age-matched kidney donors. The statistical adequacy of the sample size was preliminarily verified. Renal clearances were repeated after two years., Results: At baseline, GFR (mL/min/1.73 m2) averaged 81.4 +/- 3.8 in CAD and 83.7 +/- 1.4 in C (P= NS); RPF (mL/min/1.73 m2) was 297 +/- 22 in CAD and 456 +/- 15 in C (P < 0.0001); filtration fraction was higher in CAD (P < 0.001). Plasma renin activity was higher in CAD (P < 0.005). The number of coronary stenoses was inversely correlated with RPF but not with GFR. In CAD, at variance with C, AA did not induce any increment of GFR, while RPF increased without achieving the unstimulated value of C. Blood pressure was comparable in CAD and C at baseline and not modified by AA. After two years, a significant decrease in GFR (-14%, P < 0.001) and RPF (-15%, P < 0.001) occurred only in CAD, and in either group, the response to AA did not differ from that detected at baseline., Conclusion: In CAD patients with normal GFR, reduction in renal perfusion and absence of renal functional reserve likely represent early markers of progressive renal dysfunction.

Background: Rats of the Milan normotensive strain develop spontaneous glomerulosclerosis, whereas those of the Milan hypertensive strain are resistant to renal disease, possibly due to intrarenal artery hypertrophy protecting from systemic hypertension. To assess the role of hemodynamic versus metabolic factors in diabetic nephropathy, we investigated whether streptozotocin-induced diabetes accelerates glomerulosclerosis in Milan normotensive and/or removes (the hemodynamic) protection in Milan hypertensive rats by reducing preglomerular vascular resistance., Methods: Diabetic and nondiabetic Milan normotensive, hypertensive, and progenitor Wistar rats were followed for 6 months for the assessment of renal function and structure., Results: Proteinuria increased in nondiabetic and diabetic normotensive and, to a lesser extent, in diabetic Wistar, but not hypertensive rats. Serum creatinine increased and creatinine clearance decreased in nondiabetic and diabetic normotensive rats at 6 months. At 1.5 months, diabetic normotensive, but not hypertensive rats showed increased glomerular filtration rate and filtration fraction, suggesting glomerular hypertension. Diabetic nephropathy was detected in diabetic normotensive and Wistar, but not hypertensive rats. Glomerular extracellular matrix and TGF-beta mRNA levels increased with diabetes (and age) in normotensive, but not hypertensive rats. Arterioles and interlobular arteries showed increased media thickness in hypertensive versus normotensive rats, with diabetes reducing it only in the normotensive., Conclusion: These data show that Milan hypertensive rats are not susceptible to diabetic nephropathy, at variance with glomerulosclerosis-prone Milan normotensive rats, thus indicating the importance of genetic background. Our study suggests that the nature of this (genetic) protection might be hemodynamic, with intrarenal artery hypertrophy preventing diabetes-induced loss of autoregulation.

The effects of early glycosylation products (Amadori Products, AP) were investigated in male Munich-Wistar rats to establish whether AP play a role in the pathogenesis of glomerular hyperfiltration of early diabetic nephropathy. To mimic such a condition, normal rats were transfused with blood containing in vitro glycated serum (Group GLYC) to achieve plasma levels of Amadori products similar to those measured in rats with streptozotocin-induced diabetes. Rats transfused with normal blood were used as control (Group CON). Glomerular hemodynamics was evaluated in basal condition (B) and during acute hyperglycemia (HG). Blood transfusion did not alter basal hemodynamics. In Group CON, HG determined a rise of single nephron GFR (41.4 +/- 3.2 vs. 32.1 +/- 1.8 nl/min, P less than 0.005), secondary to the increase of afferent effective filtration pressure (EFPa, +19% vs. B, P less than 0.01). Rats of Group GLYC, in B, had values of SNGFR higher than those of Group CON B (46.8 +/- 3 nl/min, P less than 0.05, ANOVA). This increase was mediated by a significant reduction of glomerular afferent arteriole (Ra, -38% vs. Group CON B, P less than 0.05), a rise in hydrostatic gradient pressure in glomerular capillaries (delta P, +17%, P less than 0.05) and of EFPa (+31%, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: We investigated the role of atrial natriuretic factor (ANF) in the down-regulation of sodium excretion (UNaV). Seven subjects were sequentially studied while ingesting a normal-salt diet (220 mmol NaCl/day, NSD), a very low-salt diet (20 mmol NaCl/day, VLSD) for six days, and again at NSD for nine days. After one day of VLSD, a negative salt balance of 85 mmol was achieved and plasma ANF decreased from 19.1 (SE 2.5) to 7.2 (SE 2.1) pg/ml, whereas plasma renin activity (PRA) and plasma aldosterone (ALD) increased after the third and second day, respectively. During restoration of volemia (NSD), ANF increased after the third day; in contrast, PRA and ALD decreased earlier. Seven other subjects kept at low-salt diet (50 mmol NaCl/day) were studied during ANF infusion (at 2, 4, 8 ng/min/kg body wt). Increases of ANF from 10.3 (SE 0.9) pg/ml (basal condition) to levels of 24.0 (SE 1.9) pg/ml (infusion study), occurring physiologically in the same subjects after NSD, evoked increases in UNa V that accounted for 62% of UNa V rise necessary to balance the NSD, whereas PRA or ALD did not change. Plasma ANF, unlike PRA or ALD, was directly correlated with UNa V., In Conclusion: (a) ANF changes earlier than PRA and plasma aldosterone during VLSD; (b) PRA and ALD respond more promptly than ANF in the recovery from hypovolemia; (c) during ingestion of a low-salt diet, changes in plasma ANF by infusion account for more than half the increase in UNa V following the shift from low- to normal-salt diet independently of alterations in PRA and ALD.

The aim of this study was the evaluation, in healthy subjects, of the renal functional reserve (RFR), that is, the GFR increase induced by a combined infusion of amino acids (AA) and dopamine (D), in conditions of extracellular volume depletion caused by diuretic administration. In particular, this study was undertaken: a) to evaluate whether and to which extent, AA + D can reverse the functional GFR impairment induced by salt depletion, without volume restoration; b) to study whether any relationship may be found between the GFR in normal condition (the so-called "resting" GFR), and/or the renal functional reserve and the GFR impairment induced by salt depletion, in order to understand the role of both "resting" GFR and RFR in the degree of renal dysfunction induced by salt depletion. In control conditions the i.v. infusion of AA + D significantly increased RPF (+ 41% vs. baseline period) with a mean absolute increase of 211 ml/min. A similar pattern was observed in GFR behavior (+31.5% with 34 ml/min of mean absolute increase). A significant inverse exponential relationship was observed between GFR before AA + D i.v. infusion ("resting" GFR) and renal functional reserve (P less than 0.05), suggesting that, in normal conditions, these inversely related parameters may widely vary according to the tone of the glomerular arterioles. Following salt depletion, we observed a variable degree of GFR impairment. Both GFR and RPF were significantly decreased (-25.9%, P less than 0.05 and -29%, P less than 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

To define the role of medullary damage and the influence of solute load and blood pressure (BP) in impairing urinary concentration, patients with chronic glomerulonephritis were investigated by histological and functional studies. In 59 biopsy specimens, the degree of medullary fibrosis was correlated inversely with urinary specific gravity and was significantly greater in hypertensive than in normotensive subjects. The following clearance studies were carried out in patients with a GFR of 15 to 40 ml/min in maximal antidiuresis: (1) Eight patients were studied while receiving a high sodium and protein diet and then after 1 week of low sodium, low protein diet; (2) ten patients were loaded with hypertonic saline (3%) to increase urine volume up to 25 to 30% of GFR; (3) the concentrating ability was compared in 15 normotensives and 15 hypertensives with comparable GFR; (4) the concentrating ability was studied in nine hypertensive patients before and after drug-induced normalization of BP. In (1) no change occurred in maximal urine osmolality (UOsm) even if fractional sodium excretion and filtered load of urea were reduced. In (2), values of UOsm fell below those of plasma osmolality. In (3), UOsm and negative free-water generation were lower in hypertensive than in normotensive subjects. In (4), normalization of BP was not associated with any change in UOsm. These results indicate that osmotic diuresis does not play a critical role in reducing urinary concentration. This defect is better accounted for by an intrinsic medullary damage, enhanced in hypertensive patients, which may impair the permeability of collecting ducts to water.

Glomerular dynamics were investigated by micropuncture in 15-day pregnant Munich-Wistar rats. Female non-pregnant rats were used as control. In hydropenia, single nephron glomerular filtration rate (SNGFR) averaged 37.2 nl/min/g kidney weight in pregnant rats, and 26.2 nl/min/g kidney weight in controls (P less than 0.0005). During pregnancy, mean glomerular plasma flow (GPF) rose from 63.0 to 104.5 nl/min (P less than 0.0005), and glomerular capillary hydrostatic pressure (PG) from 44.8 to 50.6 mm Hg (P less than 0.0005). This rise in PG accounted for an increase in effective filtration pressure (EFP). Mean EFP at the efferent end of the glomerulus rose from near zero to 9.7 mm Hg, indicating filtration pressure disequilibrium. After extracellular fluid volume expansion with saline, GPF and EFP were still greater during pregnancy. A filtration pressure disequilibrium occurred also in non-pregnant rats, allowing calculation of definite values of the ultrafiltration coefficient (Kf). During pregnancy, mean Kf was reduced from 0.0332 to 0.0285 nl/(sec X mm Hg) (P less than 0.005). SNGFR was moderately, but not significantly, increased. These results show that during pregnancy glomerular dynamics is characterized by a rise in GPF and EFP, and by a reduction in Kf. Following these changes, a plasma-flow dependent rise in SNGFR occurs in hydropenia. After expansion, instead, SNGFR is unmodified because the dependence of ultrafiltration on plasma-flow declines while the influence of Kf increases at high values of GPF.

Up to now, no studies have been performed in normal humans to investigate the role of renal hemodynamic abnormalities in relation to acute-cyclosporin A (CsA) renal dysfunction and to verify whether the specific renal vasodilator, dopamine, can counteract these abnormalities. Eight normal subjects were examined both (A) after oral CsA (12 mg/kg body wt) and (B) after oral CsA + dopamine infusion (2 mg/kg body wt/min), under water diuresis. Both in protocols A and in B, four basal renal clearances were performed before CsA and every twenty minutes for four hours after CsA administration. In protocol A, after CsA, inulin (GFR) and PAH clearance (RPF) fell by up to 27% and to 41%, respectively, so that filtration fraction (FF) increased (P less than 0.01). A slight (not significant) hypertension occurred while renal resistances were markedly raised (P less than 0.001). Fractional urine and Na+ excretion as well as CH2O decreased, while UOsm increased (P less than 0.01). In protocol B, dopamine was infused from 120 to 180 minutes after CsA (that is, when the maximal adverse effects of CsA on renal hemodynamics had been observed in A). Dopamine infusion could reverse completely the effects of CsA on RPF, GFR, fractional urine output and CH2O; only UOsm remained higher than normal in conclusion with an increased fractional excretion of sodium (P less than 0.01). No changes were observed in plasma renin activity, aldosterone and in urinary epinephrine and norepinephrine excretion both in protocols.(ABSTRACT TRUNCATED AT 250 WORDS)