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PubMed1999

L-arginine reverses severe nephrosclerosis in aged spontaneously hypertensive rats.

OBJECTIVE: Acute and prolonged effects of L-arginine on systemic and renal hemodynamics and on renal pathological changes were examined in 85-week-old spontaneously hypertensive rats (SHR). RESULTS: After 3 weeks of L-arginine administration (n = 9; 2 g/l in drinking water), mean arterial pressure remained unchanged, although the cardiac index increased (187 +/- 26 versus 263 +/- 15 ml/min per kg; P < 0.05) and total peripheral resistance decreased (1.15 +/- 0.18 versus 0.67 +/- 0.06 AU; P < 0.05); the glomerular filtration rate increased (0.41 +/- 0.07 versus 0.79 +/- 0.07 ml/min; P < 0.01). Control untreated, aged SHR (n = 10) demonstrated severe nephrosclerosis histologically, but those treated with L-arginine demonstrated a markedly reduced glomerular injury score (164 +/- 22 versus 83 +/- 9; P < 0.005), and their urinary protein excretion (39 +/- 5 versus 19 +/- 5 mg/100 g body weight per day; P < 0.05) and serum creatinine concentration (1.4 +/- 0.1 versus 0.9 +/- 0.1 mg/dl; P < 0.05) diminished. Intravenous L-arginine (300 mg/kg body weight) given to untreated SHR reduced mean arterial pressure, increased the cardiac index (+98 versus +1%; P < 0.05) and decreased total peripheral resistance (+56 versus +13%, P < 0.005); however, these variables remained unchanged after 3 weeks of L-arginine treatment. CONCLUSIONS: Three weeks of treatment with L-arginine improved systemic hemodynamics, renal function and renal histologic changes in aged SHR with naturally occurring nephrosclerosis. These data provide an important insight into the pathophysiology of nephrosclerosis in hypertension and with aging, which is seen clinically.

Animals↗
PubMed2002

N- and L-type calcium channel antagonist improves glomerular dynamics, reverses severe nephrosclerosis, and inhibits apoptosis and proliferation in an l-NAME/SHR model.

OBJECTIVE: To determine the responses of the new dihydropyridine N- and L-type calcium antagonist, cilnidipine, on systemic and renal hemodynamics, glomerular dynamics, renal function, and histopathology in an Nomega-nitro-l-arginine methylester spontaneously hypertensive rat (l-NAME/SHR) model of nephrosclerosis. METHODS: Five groups of 20-week-old male SHR were studied using renal micropuncture techniques and histopathological analyses: group 1, control; group 2, cilnidipine (10 mg/kg per day) by gavage, for 3 weeks; group 3, l-NAME (50 mg/l) in drinking water, for 3 weeks; group 4, combination of l-NAME and cilnidipine, for 3 weeks; group 5, l-NAME for 3 weeks, followed by cilnidipine for a subsequent 3 weeks. RESULTS: Cilnidipine significantly reduced mean arterial pressure, total peripheral resistance and renal vascular resistance, while increasing effective renal blood flow and glomerular filtration rate (P < 0.01) in l-NAME/SHR. These hemodynamic changes were associated with significantly increased single nephron glomerular filtration rate (SNGFR) and plasma flow (SNPF) and decreased afferent glomerular arteriolar resistances when cilnidipine was used alone, and with increased SNGFR and SNPF, but decreased glomerular capillary pressure, afferent and efferent arteriolar resistances, urinary protein excretion, serum creatinine and uric acid concentrations (at least P < 0.05) in l-NAME-exacerbated SHR nephrosclerosis. In addition, glomerular and arteriolar injuries were markedly reversed (both P < 0.01), and glomerular apoptosis and cellular proliferation were inhibited and associated with glomerular tuft enlargement and an increase in cell number. CONCLUSION: Cilnidipine not only prevented, but reversed, the severe renal hemodynamic and glomerular dynamic changes, including apoptosis and glomerular cellular proliferation, in l-NAME/SHR-exacerbated nephrosclerosis. This dual-channel calcium antagonist thus exerted renoprotective pathophysiological effects in the l-NAME/SHR.

Animals↗
PubMed2004

Aldosterone antagonism ameliorates proteinuria and nephrosclerosis independent of glomerular dynamics in L-NAME/SHR model.

BACKGROUND: The renin-angiotensin-aldosterone system participates importantly in the progression of hypertensive renal disease. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists have been demonstrated to afford renoprotection in L-NAME-exacerbated nephrosclerosis in SHR rats. This study was designed to examine the effects of the aldosterone antagonist eplerenone on systemic and renal hemodynamics, glomerular dynamics, renal function and histopathology in L-NAME/SHR, and determine whether aldosterone antagonism would enhance the effectiveness of ACE inhibition. METHODS: Six groups of 20-week-old SHR were studied using renal micropuncture and histopathological techniques after 3 weeks of treatment: SHR control (tapwater, n = 10); SHR + eplerenone (101 +/- 8.3 mg/kg/day, n = 10); SHR + L-NAME (5.0 +/- 0.12 mg/kg/day, n = 9); SHR + L-NAME + eplerenone (n = 8); SHR + L-NAME + lisinopril (3 mg/kg/day, n = 9), and SHR + L-NAME + eplerenone + lisinopril (n = 9). RESULTS: L-NAME-treated SHR developed massive proteinuria, severe hypertensive nephrosclerosis, and tubulointerstitial damage. Eplerenone significantly reduced proteinuria (127.4 +/- 26.5 vs. 51.9 +/- 16.7 mg/24 h, p < 0.01), improved glomerular and arteriolar injuries (65 +/- 9 vs. 29 +/- 9 score/100 glomeruli, p < 0.01; 116 +/- 18 vs. 41 +/- 13 score/100 arterioles, p < 0.01, respectively), and decreased tubulointerstitial damage index (1.43 +/- 0.07 vs. 0.39 +/- 0.07, p < 0.01) without altering mean arterial pressure or glomerular dynamics. Combined therapy of eplerenone with lisinopril produced no further benefits than lisinopril alone. CONCLUSION: The aldosterone antagonist eplerenone significantly ameliorated proteinuria and nephrosclerosis in the L-NAME/SHR model, independent of hemodynamic effects.

Animals↗
PubMed1985

Marked proteinuria in hypertensive nephrosclerosis.

Heavy proteinuria in patients with essential hypertension raises the question of underlying primary renal disease. While malignant hypertension may be associated with proteinuria in the nephrotic range, it is generally held that protein excretion in benign nephrosclerosis is almost invariably less than 0.5-1.0 g/24 h. We report 18 patients with biopsy-proven hypertensive nephropathy and heavy proteinuria, of which only 6 had malignant hypertension. In the remaining 12 patients with benign nephrosclerosis, protein excretion reached up to 6.5 g/24 h, and nephrotic range proteinuria was present in 3 patients. All patients with heavy proteinuria suffered from long-standing moderate or severe, poorly controlled hypertension and were azotemic. We suggest that hypertensive nephrosclerosis be included in the differential diagnosis of massive proteinuria accompanying azotemia in poorly controlled hypertensives.

Adult↗
PubMed2001

Hypertensive nephrosclerosis as a relevant cause of chronic renal failure.

It is currently unclear whether hypertensive nephrosclerosis (HN), usually diagnosed solely on clinical grounds, is a relevant cause of end-stage renal disease. We biopsied 81 hypertensive outpatients (blood pressure >/=160/95 mm Hg) with moderate renal insufficiency, who were referred to our service from 1988 to 1998. Patients with known causes of hypertension, systemic disorders, rheumatic disease, or nephrotic syndrome were excluded. In 65% of patients, HN was the sole histological abnormality associated with renal dysfunction. Benign nephrosclerosis (BN), defined as isolated arteriolar hyalinosis and/or intimal fibrosis, was found in 18 HN patients (22%), whereas malignant nephrosclerosis (MN), denoted mainly by myointimal cell proliferation, appeared in 35 HN patients (43%). Previously undiagnosed primary nephritis (PN) was found in 13 patients (16%), whereas focal and segmental glomerulosclerosis, which might be either primary or secondary to hypertension, appeared in 15 patients (19%). These findings suggest that HN, in both its BN and MN forms, can be a definite cause of chronic renal insufficiency and that a substantial fraction of patients with renal insufficiency and clinical diagnosis of HN may actually have PN.

Adolescent↗
PubMed2001

ACE inhibitors and appearance of renal events in hypertensive nephrosclerosis.

Nephrosclerosis constitutes a major cause of end-stage renal disease. Independently of blood pressure control, ACE inhibitors (ACEIs) are considered to be more nephroprotective than other antihypertensive agents. We have reviewed the long-term evolution of renal function in our series of essential hypertensive patients diagnosed as having nephrosclerosis when first seen in our unit. The analysis was performed depending on whether or not their antihypertensive therapy contained an ACEI alone or in combination for the whole follow-up. The end point was defined as the confirmation of a 50% reduction in creatinine clearance or entry in a dialysis program. A historical cohort of 295 patients was included in the analysis. Mean follow-up was 7.4+/-3.9 years. Diabetes prevalence was higher in ACEI-treated patients (25.7% versus 7.1%, P=0.000), but the diagnosis of diabetic nephropathy could not be confirmed on clinical grounds, including renal biopsy. Twenty-three out of 183 (12.6%) patients in the ACEI group and 23 out of 112 (20.5%) patients in the non-ACEI group experienced a renal event (P=0.0104 by log rank test). Similar results were observed when only nondiabetic patients were considered for the analysis. Cox regression analysis showed that baseline serum creatinine, absence of ACEI administration, mean proteinuria during follow-up, and age were independent predictors for the development of a renal event. In hypertensive nephrosclerosis, therapy containing an ACEI alone or in combination significantly reduces the incidence of renal events. This effect is independent of blood pressure control.

Adult↗
PubMedDate not supplied

Significance of increased accumulation of type VI collagen and transforming growth factor beta 1 in tubulointerstitial damage in hypertensive nephrosclerosis: an immunohistochemical study.

The distribution of type VI collagen and transforming growth factor beta 1 (TGF beta 1) was studied by immunohistochemistry in 12 renal biopsy specimens of hypertensive nephrosclerosis and five control cases. In control kidneys, the immunostaining of type VI collagen was found in the mesangium, glomerular basement membrane and tubular basement membrane. For TGF beta 1, mesangium, glomerular basement membrane, tubular basement membrane and tubular epithelial cells stained positively in the control kidneys. In contrast to the control cases, markedly increased immunostaining for both type VI collagen and TGF beta 1 was consistently observed in tubulointerstitial damage in hypertensive nephrosclerosis. These immunohistochemical findings provide the evidence for a parallel increase of both type VI collagen and TGF beta 1 during the process of tubulointerstitial injury in hypertensive nephrosclerosis. From the results of the present study, it is speculated that TGF beta 1 may contribute to the tubulointerstitial injury by stimulating increased synthesis of various extracellular matrix including type VI collagen.

Adult↗
PubMed2000

Calcium antagonist inhibits glomerular cell apoptosis and injuries of L-NAME exacerbated nephrosclerosis in SHR.

Increased apoptosis of glomerular cells, with progression of glomerulosclerosis, overactivity of the renin-angiotensin system and elevation of glomerular pressure, follows chronic nitric oxide synthase (NOS) inhibition in spontaneously hypertensive rats (SHR). To gain insight into the regulation of glomerular cell apoptosis in severe nephrosclerosis, we investigated apoptosis, the expression of proliferative cell nuclear antigen (PCNA) in glomeruli, and glomerular morphometric changes in 20-week-old SHR, SHR treated with NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 80 mg/l in drinking water), and SHR treated with L-NAME and the calcium antagonist, efonidipine (20 mg/kg per day), for 3 weeks. Apoptosis in non-sclerotic glomeruli was quantified by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. The increase in systolic blood pressure and the severe proteinuria with severe nephrosclerosis induced by chronic NOS inhibition were completely prevented by efonidipine. Furthermore, the glomerular area and capillary tuft area were markedly increased in rats treated with efonidipine compared with both control rats (+30 and +42%, respectively, p<0.01) and rats treated with L-NAME (+35 and +56%, respectively, p<0.01)-treated rats. This calcium antagonist also significantly inhibited the both increases of the glomerular cell apoptosis index (-72%) and the PCNA index (+44%), therefore the alteration between apoptosis and proliferation slightly increased the number of glomerular cells (subcapsular, +22%, p<0.01; juxtamedullary, +2%, not significant). Thus, the calcium antagonist efonidipine seems to play an important role in the regulation of apoptosis and proliferation of glomerular cells and may be effective in preventing nephrosclerosis exacerbated by NOS inhibition.

Animals↗
PubMed2002

Nipradilol prevents L-NAME-exacerbated nephrosclerosis with decreasing of caspase-3 expression in SHR.

The proliferative cell nuclear antigen (PCNA) is an auxiliary protein of DNA polymerase delta and appears to be required for both DNA synthesis and repair. Previously, we showed that prolonged NO synthase (NOS) inhibition produced severe nephrosclerosis with an increase of glomerular cell DNA fragmentation (apoptosis), glomerular ischemia and hypertension in spontaneously hypertensive rats (SHR). The objective of the present study was to investigate the effects of the vasodilating, nonselective, NO-releasing beta-adrenoceptor blocker nipradilol on DNA fragmentation and synthesis/repair of glomerular cells in this prolonged NOS blockaded SHR. Twenty-week-old SHR were administered an NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 80 mg/l in drinking water) or co-treated with the same dose of L-NAME and nipradilol (20 mg/kg/day) for 3 weeks. After this treatment, expression of apoptosis was histologically examined using caspase-3, an apoptosis inducer, in addition PCNA (DNA synthesis/repair), and examination of glomerular morphometric changes, including cell number and tuft area. Nipradilol reduced blood pressure and preserved creatinine clearance reduction in L-NAME/SHR. These effects were associated with normalization of the glomerular cell apoptosis index and caspase-3 score, an increase in PCNA index, and increases in glomerular cell numbers and glomerular tuft area, resulting in a decreased glomerular injury score. Thus, in SHR administered an NOS inhibitor, nipradilol improved nephrosclerosis in association with a decrease in apoptosis and an increase in DNA synthesis/repair of glomerular cells. These findings may provide important insights into DNA repair/repair and apoptosis in nephrosclerosis.

Adrenergic beta-Antagonists↗
PubMed2006

Synthetic/secreting and apoptotic phenotypes in renal biopsy tissues from hypertensive nephrosclerosis patients.

The major glomerular abnormalities in hypertensive nephrosclerosis are described as glomerular obsolescence (GO), glomerulosclerosis (GS), and glomerular collapse (GC). However, glomerular cellular changes caused by hypertensive insults have not been well analyzed. Using an immunoenzyme method, we examined eleven biopsy samples from patients with hypertensive nephrosclerosis for two synthetic and secreting phenotypes, a-smooth muscle actin (alpha-SMA) and collagen type III (Col. III), and two apoptotic phenotypes, pro-apoptotic molecule Bax and anti-apoptotic molecule BcI-2. Together with the glomerular and vascular changes and interstitial fibrosis (IF) area, the results were scored quantitatively and semi-quantitatively and compared to the clinical findings, which included systolic blood pressure (SBP), mean arterial pressure (MAP), serum creatinine levels (sCr) and creatinine clearance (Ccr), using univariate and multivariate analyses. As a result, GS was frequently observed in the mild-to-moderate hypertensive group (140 < or = SBP<180 mmHg), whereas GC was positively correlated with SBP. Furthermore, there was a positive correlation of GS with mesangial alpha-SMA and Col. III, suggesting that GS was the reflection of these synthetic and secreting phenotypic changes in mesangial cells. Endothelial Bax was positively correlated with Ccr (p<0.01); in contrast, podocytic Bax was positively correlated with sCr (p<0.05) and showed a tendency to correlate with MAP (p=0.054). In conclusion, these findings support the view that mesangial synthetic and secreting phenotypic changes may be a reflection of cellular activation caused by mild-to-moderate hypertension and that apoptotic phenotypic expression in podocytes, rather than endothelial cells, may be related to the development of a severe form of hypertensive nephrosclerosis.

Actins↗
PubMed2000

Increased fibrinogen levels and hemostatic abnormalities in patients with arteriolar nephrosclerosis: association with cardiovascular events.

Increased plasma fibrinogen levels and hemostatic abnormalities suggestive of a prothrombotic state are present in patients with end-stage renal failure and could contribute to increased cardiovascular morbidity in these patients. We investigated the relationship between abnormalities of the hemostatic system and the degree of renal failure and whether these abnormalities are associated with increased prevalence of cardiovascular events in patients with arteriolar nephrosclerosis. In 425 patients recruited at a hypertension clinic we assessed the renal function by creatinine clearance, urinary protein excretion, and microalbuminuria, the prevalence of atherosclerotic disease, and measured prothrombin time, activated partial thromboplastin time. fibrinogen, prothrombin fragment 1+2 (F1+2), D-dimer, and antithrombin. Early impairment of renal function (creatinine clearance, 30 to 89 ml/min per 1.73 m2 of body surface area) caused by arteriolar nephrosclerosis was found in 172 patients. Patients with early renal failure were significantly older and had significantly greater values of blood pressure, plasma fibrinogen, F1+2, and D-dimer than patients with normal renal function. Elevated D-dimer and fibrinogen levels were independently associated with the presence of decreased creatinine clearance. Log fibrinogen, log F1+2, and log D-dimer were inversely correlated with creatinine clearance. The prevalence of coronary artery, cerebrovascular, and peripheral vascular disease was significantly greater in patients with mild renal failure than in those with normal renal function. Elevated levels of fibrinogen and D-dimer were associated with the presence of atherosclerotic disease independent of renal function and other risk factors. In conclusion, changes in hemostatic parameters occur early in the course of renal failure in patients with arteriolar nephrosclerosis, suggesting a prothrombotic state that may contribute to the risk for atherosclerotic disease at all levels of renal function.

Adult↗
PubMed1976

Nephrosclerosis postpartum and in women taking oral contraceptives.

The condition of a patient with postpartum nephrosclerosis improved during heparin therapy. Review of the literature disclosed 29 other patients with the same histopathologic characteristics, eight of whom also recovered substantial renal function after anticoagulation therapy. Also reported is a patient in whom renal failure occurred while she was taking oral anovulatory agents. Renal biopsy specimen showed the same histopathologic features, which raises the question of similar factors mediating the expression of this disease. We suggest a uniform terminology for this syndrome, either postpartum nephrosclerosis or nephrosclerosis in women taking oral contraceptives.

Adult↗
PubMed1989

[Current aspects of nephrosclerosis].

The most frequent form of nephrosclerosis in human kidneys is the so-called benign variant. It may develop subsequent to even short-lasting hypertensive episodes. The interlobular arteries may be primarily affected, occasionally accompanied by glomerular and tubulointerstitial lesions. Consequently, progressive renal damage may occur potentially aggravating renal diseases of different origin. Malignant nephrosclerosis became a rare disease. Experimentally, it was impossible to induce its early intimal changes exclusively by high blood pressure values. Therefore, it was assumed that previous adaptive vascular changes, in addition to further advancing hypertension, may also be prerequisites for the development of malignant nephrosclerosis.

Humans↗
PubMed1988

Two variants of nephrosclerosis separately related to age and blood pressure.

Two variants of nephrosclerosis, roughly corresponding to the arterial and the arteriolar forms, have been examined in a series of autopsy kidneys by five observers using quantitative morphometry. These two variants are both marked by fibroplastic intimal thickening and medial wastage in the arteries, but one of these affects vessels of sizes that are closer to the heart, whereas the other affects sizes that are more remote from the source of arterial pressure. Both types of nephrosclerosis were found to increase with aging in subjects without hypertension. Each year of aging added 0.15 units of intimal thickening to the close vessels and 0.11 to the remote vessels. Each millimeter of mercury of elevated blood pressure was equivalent to 1 year of aging in the close and 2 years in the remote levels of the arterial tree. The four variables, age, blood pressure, remote level intimal thickness, and close level intimal thickness, were found to hold complex curvilinear interrelationships when examined by regression analysis. A dynamic model was suggested by the following findings: The earliest changes shown by young normotensives are in the close vessels, possibly because of the aging effect of the normal pulse wave. Later, the changes extend into the remote level, perhaps because the thickened intima is rigid and propagates the pulse wave abnormally far into the smallest arteries. Hypertension could then be viewed either as a cause for an exaggeration of this normal process or as a consequence of its extension into the remote level vessels where resistance to blood flow is greater or both. The objective morphometric method showed good agreement in the findings by independent observers and is considered to be suitable for epidemiologic studies of nephrosclerosis.

Adult↗
PubMed1983

Renal vascular lesions in severe hypertension. Transitional changes from benign to malignant nephrosclerosis.

Renal vascular changes in severe hypertension were studied. Twenty-five cases selected from 4,629 autopsies were classified into 2 groups according to the cause of death: group 1 (9 cases died of renal failure) and group 2 (16 cases of extra-renal death). Group 1 had been clinically diagnosed as malignant hypertension and had the hallmarks of malignant nephrosclerosis characterized by arteriolar fibrinoid necrosis and edematous intimal thickening. Group 2 had been clinically diagnosed as benign hypertension and basically exhibited the changes of benign nephrosclerosis. However, about half of the cases of group 2 had arteriolar fibrinoid necrosis, though the lesion was usually less extensive than in group 1. Immunofluorescence revealed similar deposits of immunoglobulins and fibrinogen in the site of fibrinoid necrosis observed in both groups. As for the changes of interlobular arteries, a quantitative analysis disclosed a distinctive difference between groups 1 and 2 with respect to the narrowing ratio of arterial lumina, though edematous intimal thickening was recognized on relatively rare occasions in the distal interlobular arteries in a few cases of group 2. From the results, the problem of transition from the benign to malignant nephrosclerosis was discussed.

Adult↗
PubMedDate not supplied

[Copper and zinc metabolic derangement in patients with chronic pyelonephritis developing nephrosclerosis and renal insufficiency].

Cu and Zn levels were measured (nuclear-absorption spectrophotometry) in the blood and urine from patients with chronic pyelonephritis (CP) in emergence of nephrosclerosis and renal insufficiency. CP patients were found to develop hypercupremia as early as initial stages of nephrosclerosis when renal insufficiency was not apparent. Blood Zn was low, especially in development of chronic renal insufficiency. Cu and Zn disbolism may contribute to formation of sclerotic lesions in the kidneys and to development of chronic renal insufficiency. Assay for Cu and Zn is proposed for early diagnosis of nephrosclerosis and provides objective clinical control over the disease course to make timely correction of the detected defects and valid prognosis.

Adult↗
PubMed1992

Nephrosclerosis and aortic atherosclerosis from age 6 to 70 years in the United States and Mexico.

With increasing age, the thoracic aorta shows progressive fibroplastic intimal thickening, which is thought to be pre-atheromatous. A similar progressive intimal thickening in the renal cortical arteries is the distinguishing feature of the nephrosclerosis which underlies essential hypertension. Therefore, the earliest detectable youthful precursors of atherosclerosis and hypertension show strong morphological resemblances to each other. In this study, close statistical associations have been shown between the two types of arterial intimal fibroplasia. Both conditions show similar sigmoid growth curves from ages 6 to 70 years, thereby generating correlations across age groups of r = 0.99 in New Orleans and r = 0.95 in Mexico City. Specimens gathered in New Orleans were found to have about 1.4 times greater arterial intimal thickening than specimens from Mexico City, and this excess was seen at all ages in both the aortas and the renal cortical arteries. It seems likely that intimal fibroplasia of arteries is reflecting similar biological principles at all levels of the vascular tree. Whatever etiological factors vary between New Orleans and Mexico City, those factors appear to act directly at a tissue level to promote the early precursors of atherosclerosis and of the nephrosclerosis that underlies hypertension.

Adolescent↗
PubMed1990

Cholinergic vasodilatory effect of an imidazoindole on the nephrosclerosis of hypertensive rats.

Pyridino [1,2-a] imidazo [5,4-b] indole (Compound 1) has been reported previously as an antihypertensive agent. Parenteral introductions of Compound 1 in spontaneously hypertensive rats (SHR) and in normotensive dogs have been found to reduce systolic blood pressure (SBP) in those animal models. Later studies have shown cholinomimetic effects of Compound 1 in animal tissue preparations and in live animals. Our experiments showed that daily oral administration of Compound 1 minimized the development of hypertensive nephrosclerosis and prevented premature death in male SHR. Compound 1 also potentiated cholinergic activity in isolated rabbit hearts. It is suggested that cholinergic vasodilation by Compound 1 is responsible for the hypotensive effect and prevention of nephrosclerosis in SHR.

Animals↗