NaCl-induced renal vasoconstriction in salt-sensitive African Americans: antipressor and hemodynamic effects of potassium bicarbonate. (1/2318)

In 16 African Americans (blacks, 14 men, 2 women) with average admission mean arterial pressure (MAP, mm Hg) 99.9+/-3.5 (mean+/-SEM), we investigated whether NaCl-induced renal vasoconstriction attends salt sensitivity and, if so, whether supplemental KHCO3 ameliorates both conditions. Throughout a 3-week period under controlled metabolic conditions, all subjects ate diets containing 15 mmol NaCl and 30 mmol potassium (K+) (per 70 kg body wt [BW] per day). Throughout weeks 2 and 3, NaCl was loaded to 250 mmol/d; throughout week 3, dietary K+ was supplemented to 170 mmol/d (KHCO3). On the last day of each study week, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) using renal clearances of PAH and inulin. Ten subjects were salt sensitive (SS) (DeltaMAP >+5%) and 6 salt resistant (SR). In NaCl-loaded SS but not SR subjects, RBF (mL/min/1.73 m2) decreased from 920+/-75 to 828+/-46 (P<0.05); filtration fraction (FF, %) increased from 19. 4+/- to 21.4 (P<0.001); and renal vascular resistance (RVR) (10(3)xmm Hg/[mL/min]) increased from 101+/-8 to 131+/-10 (P<0.001). In all subjects combined, DeltaMAP varied inversely with DeltaRBF (r =-0.57, P=0.02) and directly with DeltaRVR (r = 0.65, P=0.006) and DeltaFF (r = 0.59, P=0.03), but not with MAP before NaCl loading. When supplemental KHCO3 abolished the pressor effect of NaCl in SS subjects, RBF was unaffected but GFR and FF decreased. The results show that in marginally K+-deficient blacks (1) NaCl-induced renal vasoconstrictive dysfunction attends salt sensitivity; (2) the dysfunction varies in extent directly with the NaCl-induced increase in blood pressure (BP); and (3) is complexly affected by supplemented KHCO3, GFR and FF decreasing but RBF not changing. In blacks, NaCl-induced renal vasoconstriction may be a pathogenetic event in salt sensitivity.  (+info)

Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioproliferative glomerulonephritis. (2/2318)

BACKGROUND: The renin-angiotensin system is thought to be involved in the progression of glomerulonephritis (GN) into end-stage renal failure (ESRF) because of the observed renoprotective effects of angiotensin-converting enzyme inhibitors (ACEIs). However, ACEIs have pharmacological effects other than ACE inhibition that may help lower blood pressure and preserve glomerular structure. We previously reported a new animal model of progressive glomerulosclerosis induced by a single intravenous injection of an anti-Thy-1 monoclonal antibody, MoAb 1-22-3, in uninephrectomized rats. Using this new model of progressive GN, we examined the hypothesis that ACEIs prevent the progression to ESRF by modulating the effects of angiotensin II (Ang II) on the production of transforming growth factor-beta (TGF-beta) and extracellular matrix components. METHODS: We studied the effect of an ACEI (cilazapril) and an Ang II type 1 receptor antagonist (candesartan) on the clinical features and morphological lesions in the rat model previously reported. After 10 weeks of treatment with equihypotensive doses of cilazapril, cilazapril plus Hoe 140 (a bradykinin receptor B2 antagonist), candesartan, and hydralazine, we examined systolic blood pressure, urinary protein excretion, creatinine clearance, the glomerulosclerosis index, and the tubulointerstitial lesion index. We performed a semiquantitative evaluation of glomerular immunostaining for TGF-beta and collagen types I and III by immunofluorescence study and of these cortical mRNA levels by Northern blot analysis. RESULTS: Untreated rats developed massive proteinuria, renal dysfunction, and severe glomerular and tubulointerstitial injury, whereas uninephrectomized control rats did not. There was a significant increase in the levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III in untreated rats. Cilazapril and candesartan prevented massive proteinuria, increased creatinine clearance, and ameliorated glomerular and tubulointerstitial injury. These drugs also reduced levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III. Hoe 140 failed to blunt the renoprotective effect of cilazapril. Hydralazine did not exhibit a renoprotective effect. CONCLUSION: These results indicate that ACEIs prevent the progression to ESRF by modulating the effects of Ang II via Ang II type 1 receptor on the production of TGF-beta and collagen types I and III, as well as on intrarenal hemodynamics, but not by either increasing bradykinin activity or reducing blood pressure in this rat model of mesangial proliferative GN.  (+info)

Glomerular size-selective dysfunction in NIDDM is not ameliorated by ACE inhibition or by calcium channel blockade. (3/2318)

BACKGROUND: In patients with insulin-dependent diabetes mellitus (IDDM) and overt nephropathy glomerular barrier size-selectivity progressively deteriorates with time and is effectively improved by angiotensin converting enzyme (ACE) inhibition. Whether similar glomerular functional changes develop in proteinuric patients with non-insulin-dependent diabetes mellitus (NIDDM), and whether antihypertensive agents can favorably affect glomerular filtration of macromolecules in these patients, has not been documented yet. METHODS: We investigated renal hemodynamics and fractional clearance of neutral dextrans of graded sizes, in nine proteinuric patients with NIDDM and renal biopsy findings of typical diabetic glomerulopathy. Six healthy volunteers served as controls. We also investigated the effects of an ACE inhibitor and of a calcium channel blocker, both given in doses targeted to achieve a comparable level of systemic blood pressure control, on glomerular hemodynamics and sieving function. Theoretical analysis of glomerular macromolecule transport was adopted to evaluate intrinsic glomerular membrane permeability properties. RESULTS: Fractional clearance of large macromolecules (42 to 66 A in radius) was significantly higher in diabetic patients than in controls, and the distribution of membrane pore radii was calculated to be shifted towards larger pore sizes in diabetics (mean radius increased from 55 to 60 A). Despite effective blood pressure control, neither antihypertensive affected glomerular hemodynamics to any significant extent. Fractional clearance of dextrans, as well as of albumin and IgG, and total urinary proteins were not modified by either treatments. CONCLUSIONS: These data indicate that patients with NIDDM and overt nephropathy develop abnormalities in size-selective function of the glomerular barrier and, at variance to IDDM, such changes were not ameliorated either by ACE inhibition or calcium channel blockade.  (+info)

Acute haemodynamic and proteinuric effects of prednisolone in patients with a nephrotic syndrome. (4/2318)

BACKGROUND: Administration of prednisolone causes an abrupt rise in proteinuria in patients with a nephrotic syndrome. METHODS: To clarify the mechanisms responsible for this increase in proteinuria we have performed a placebo controlled study in 26 patients with a nephrotic syndrome. Systemic and renal haemodynamics and urinary protein excretion were measured after prednisolone and after placebo. RESULTS: After i.v. administration of 125-150 mg prednisolone total proteinuria increased from 6.66+/-4.42 to 9.37+/-6.07 mg/min (P<0.001). By analysing the excretion of proteins with different charge and weight (albumin, transferrin, IgG, IgG4 and beta2-microglobulin) it became apparent that the increase of proteinuria was the result of a change in size selectivity rather than a change in glomerular charge selectivity or tubular protein reabsorption. Glomerular filtration rate rose from 83+/-34 ml to 95+/-43 ml/min (P<0.001) after 5 h, whereas effective renal plasma flow and endogenous creatinine clearance remained unchanged. As a result filtration fraction was increased, compatible with an increased glomerular pressure, which probably contributes to the size selectivity changes. Since corticosteroids affect both the renin-angiotensin system and renal prostaglandins, we have evaluated the effects of prednisolone on proteinuria after pretreatment with 3 months of the angiotensin-converting enzyme inhibitor lisinopril or after 2 weeks of the prostaglandin synthesis inhibitor indomethacin. Neither drug had any effect on prednisolone-induced increases of proteinuria. CONCLUSIONS: Prednisolone increases proteinuria by changing the size selective barrier of the glomerular capillary. Neither the renin-angiotensin axis nor prostaglandins seem to be involved in these effects of prednisolone on proteinuria.  (+info)

Neovascularization at the vascular pole region in diabetic glomerulopathy. (5/2318)

BACKGROUND: Diabetic nephropathy is associated with renal structural changes involving all of the compartments. Most characteristic is the diabetic glomerulopathy. Studies of the histological changes during the early phases of nephropathy have included the glomerulopathy and also the juxtaglomerular structures. Neovascularization, well-known in diabetic retinopathy, has also been observed in the kidney. The present study concerns estimates of frequency of neovascularization at the vascular pole region in early stages of diabetic nephropathy. METHODS: Extra efferent arterioles at the glomerular vascular pole were detected during measurements of the vascular pole area applying 1-microm serial sections through kidney biopsies. It was observed that more than one efferent arteriole existed occasionally. The present study was carried out with the aim of estimating the frequency of this phenomenon in diabetic patients and in non-diabetic controls, the diabetic patients categorized according to the level of albumin excretion rate. RESULTS: Neovascularization was first observed in IDDM patients with microalbuminuria. Some of the cases presented the phenomenon in all of the glomeruli studied. As the examinations of many kidney biopsies continued the phenomenon was observed also in the non-diabetic control group and in one IDDM patient with normoalbuminuria. However, the frequency was statistically highly significantly increased in patients with elevated albumin-excretion. Within this group a strong correlation between frequency of neovascularization and the severity of diabetic glomerulopathy is seen. CONCLUSIONS: The vascular abnormality localized to the vascular pole region is observed occasionally in the normal kidney, but the frequency is increased in patients with diabetic glomerulopathy. The abnormality may develop as a consequence of a long-standing diabetic glomerulopathy and might lead to less pronounced elevation of albumin excretion.  (+info)

Increased renal resistive index in patients with essential hypertension: a marker of target organ damage. (6/2318)

BACKGROUND: Increased renal resistance detected by ultrasound (US) Doppler has been reported in severe essential hypertension (EH) and recently was shown to correlate with the degree of renal impairment in hypertensive patients with chronic renal failure. However, the pathophysiological significance of this finding is still controversial. METHODS: In a group of 211 untreated patients with EH, we evaluated renal resistive index (RI) by US Doppler of interlobar arteries and early signs of target organ damage (TOD). Albuminuria was measured as the albumin to creatinine ratio (ACR) in three non-consecutive first morning urine samples. Left ventricular mass was evaluated by M-B mode echocardiography, and carotid wall thickness (IMT) by high resolution US scan. RESULTS: RI was positively correlated with age (r=0.25, P=0.003) and systolic blood pressure (SBP) (r=0.2, P=0.02) and with signs of early TOD, namely ACR (r=0.22, P=0.01) and IMT (r=0.17, P<0.05), and inversely correlated with renal volume (r=-0.22, P=0.01) and diastolic blood pressure (r=-0.23, P=0.006). Multiple linear regression analysis demonstrated that age, gender, ACR and SBP independently influence RI and together account for approximately 20% of its variations (F=8.153, P<0.0001). When clinical data were analysed according to the degree of RI, the patients in the top quartile were found to be older (P<0.05) and with higher SBP (P<0.05) as well as early signs of TOD, namely increased ACR (P<0.002) and IMT (P<0.005 by ANOVA), despite similar body mass index, uric acid, fasting blood glucose, lipid profile and duration of hypertension. Furthermore, patients with higher RI showed a significantly higher prevalence of microalbuminuria (13 vs 12 vs 3 vs 33% chi2=11.72, P=0.008) and left ventricular hypertrophy (40 vs 43 vs 32 vs 60%, chi2=9.25, P<0.05). CONCLUSIONS: Increased RI is associated with early signs of TOD in EH and could be a marker of intrarenal atherosclerosis.  (+info)

Immediate and early renal function after living donor transplantation. (7/2318)

BACKGROUND: In order to assess the immediate renal function after living donor transplantation, renal function was compared in eight renal allograft recipients and their living related kidney donors during the first 24 h after transplantation. METHODS: Substantial and comparable intraoperative volume loading with Ringer's acetate and mannitol was performed together with the administration of frusemide. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were estimated by the clearances of inulin and p-aminohippurane, respectively. Tubular reabsorptive function and injury were estimated from the clearance of lithium, the fractional excretion of sodium and the urinary excretion of N-acetyl-beta-glucosaminidase. RESULTS: One hour after completion of surgery, GFR (54 +/- 7 ml/min) and ERPF (294 +/- 35 ml/min) were only 30% lower in the grafts than in the remaining donor kidneys, increasing to similar levels within 3 h. Only minor tubular dysfunction and injury were revealed in the grafted kidneys, and these tended to normalize within 24 h. CONCLUSIONS: By the present transplantation procedure comprising short ischaemia time and substantial volume expansion combined with mannitol and frusemide administration, kidneys from living donors regain nearly normal function within a few hours after transplantation.  (+info)

Nitric oxide mediates sympathetic vasoconstriction at supraspinal, spinal, and synaptic levels. (8/2318)

The purposes of this study were to investigate the level of the sympathetic nervous system in which nitric oxide (NO) mediates regional sympathetic vasoconstriction and to determine whether neural mechanisms are involved in vasoconstriction after NO inhibition. Ganglionic blockade (hexamethonium), alpha1-receptor blockade (prazosin), and spinal section at T1 were used to study sympathetic involvement. NO was blocked with Nomega-nitro-L-arginine methyl ester (L-NAME). Regional blood flow in the mesenteric and renal arteries and terminal aorta was monitored by electromagnetic flowmetry in conscious rats. L-NAME (3-5 mg/kg iv) increased arterial pressure and peripheral resistance. Ganglionic blockade (25 mg/kg iv) significantly reduced the increase in resistance in the mesentery and kidney in intact and spinal-sectioned rats. Ganglionic blockade significantly decreased hindquarter resistance in intact rats but not in spinal-sectioned rats. Prazosin (200 micrograms/kg iv) significantly reduced the increased hindquarter resistance. We concluded that NO suppresses sympathetic vasoconstriction in the mesentery and kidney at the spinal level, whereas hindquarter tone is mediated at supraspinal and synaptic levels.  (+info)