Intrarenal angiotensin and bradykinin peptide levels in the remnant kidney model of renal insufficiency

BACKGROUND: The remnant kidney model of renal failure is associated with normal or suppressed plasma renin and angiotensin (Ang) II levels when hypertension is established. However, the hypertension responds to angiotensin-converting enzyme (ACE) inhibition and Ang II receptor antagonism, suggesting a role for Ang II in the hypertensive process. Bradykinin (BK) is a potent vasoactive peptide that may also participate in this model. METHODS: Ang II and BK peptides were measured in the ischemic peri-infarct portion and the intact portion of the remnant kidney at two, five, and seven weeks after surgery. Plasma Ang II, renin, angiotensinogen, and aldosterone levels were also measured. RESULTS: Ang II levels in the peri-infarct portion were higher than in the intact portion at all time points and were higher than in sham-operated kidney at two weeks. Ang II levels in the intact portion were similar to the levels in kidneys of sham-operated rats at two and five weeks and were suppressed at seven weeks. BK levels were increased in the peri-infarct portion at all time points and in the intact portion at two and five weeks. Plasma Ang II and aldosterone levels were also elevated at two weeks. CONCLUSIONS: Peri-infarct renal tissue Ang II levels and plasma Ang II and aldosterone levels increase transiently during the evolution of hypertension in the remnant kidney model. Sustained hypertension is associated with an increase in intrarenal BK levels but not with persistent increases in intrarenal or circulating Ang II levels.     

The effect of different antihypertensive drugs on cavernous tissue in experimental chronic renal insufficiency

BACKGROUND: Male erectile dysfunction increases in prevalence in patients with severe chronic renal failure. Since arterial hypertension induces significant damage in cavernous tissue (CT), and considering that hypertension is extremely common in patients with end-stage renal disease (ESRD), the aim of this study was to evaluate the effect of the most conventionally employed antihypertensive drugs on CT in a rat model of renal insufficiency. METHODS: Five groups of male rats with subtotal nephrectomy (STNx) and 1 with sham operations were studied over 6 months: STNx without treatment, STNx with benazepril (BZ), STNx with losartan (LS), STNx with amlodipine (AML) and STNx with atenolol (AT) plus the sham group. All rats were sacrificed at 6 months after STNx, and penises processed for LM and immunohistochemical studies. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries and the amount of collagen type III were evaluated. RESULTS: All groups with antihypertensive drugs showed similar control in blood pressure throughout the study. Un-treated STNx, STNx with AML and STNx with AT presented significant (p<0.01) hypertrophy in both VSM and CSM, together with an increased amount of collagen type III in CT. Conversely, STNx with either BZ or LS showed a substantial (p<0.01) reduction in all of these variables, with values not different from the sham group. There was a significant (p<0.01) negative correlation between creatinine clearance and the amount of VSM, CSM and collagen type III deposition in CT in untreated STNx, STNx with AML and STNx with AT, but not in STNx with BZ, STNx with LS and sham. CONCLUSION: These results suggest that the interactions against the renin-angiotensin system (RAS) either by ACE inhibitors or angiotensin AT1 receptor blockers produce considerable benefits regarding structural abnormalities in CT in this animal model of renal insufficiency beyond blood pressure control.     

Role of intrarenal angiotensin II in glucocorticoid-induced renal vasodilation

Background. Although glucocorticoids elicit systemic hypertension, they are also demonstrated to cause marked increases in renal blood flow. The mechanism of this alteration, however, remains undetermined. Methods. Dogs were treated with dexamethasone (DEX) for 7 days, and renal, as well as systemic hemodynamic, responses to DEX were assessed. In addition, the role of intrarenal angiotensin (ANG) II in mediating the glucocorticoid-induced renal vasodilation was examined in conscious unrestrained dogs. Results. Seven-day treatment with DEX caused prominent increases in mean arterial pressure (MAP; from 80 ± 2 to 98 ± 5 mmHg) and in renal plasma flow (RPF; from 142 ± 4 to 191 ± 7 ml/min), with decreases in renal vascular resistance [RVR; from 0.26 ± 0.01 to 0.22 ± 0.01 mmHg/(ml/min)] and in the filtration fraction (FF; from 0.24 ± 0.01 to 0.20 ± 0.01). DEX treatment did not alter plasma ANG II levels, but enhanced candesartan-induced reduction in MAP. In contrast, the candesartan-induced increase in RPF (19 ± 2% increase) was completely abolished by DEX. DEX treatment markedly reduced renal tissue ANG II content (from 1.09 ± 0.07 to 0.71 ± 0.04 pg/mg tissue), which paralleled the response of renal tissue angiotensin-converting enzyme (ACE) activity (−20 ± 4%). Finally, intravenous ANG II administration caused a greater reduction in RPF during the DEX treatment period (−17 ± 2% vs −11 ± 1% in the control period). Conclusions. Glucocorticoids cause hypertension, but they also cause a paradoxical decrease in RVR and increase in RPF. The renal responses to candesartan and exogenous ANG II during DEX treatment suggest that the attenuation of intrarenal ANG-mediated vascular tone plays an important role in the altered renal hemodynamics. The decreased ANG tone is likely caused by reduced ANG II formation, resulting in part from suppressed ACE activity, but not from decreased sensitivity to ANG II. Received: November 1, 2000 / Accepted: April 5, 2001     

Zonal heterogeneity in action of angiotensin-converting enzyme inhibitor on renal microcirculation: role of intrarenal bradykinin.

The present study examined the role of intrarenal bradykinin in angiotensin-converting enzyme inhibitor (ACEI)-induced dilation of renal afferent (AFF) and efferent arterioles (EFF) in vivo, and further evaluated whether ACEI-stimulated bradykinin activity differed in superficial (SP) and juxtamedullary nephrons (JM). Arterioles of canine kidneys were visualized with an intravital charge-coupled device camera microscope. E4177 (an angiotensin receptor antagonist, 30 microg/kg) dilated AFF and EFF in SP (15 +/- 3% and 19 +/- 5%) and JM (15 +/- 3% and 18 +/- 4%). Subsequently, cilazaprilat (30 microg/kg) caused further dilation of both AFF (29 +/- 4%) and EFF (36 +/- 4%) in JM, whereas in SP it dilated only EFF (29 +/-3%). Similarly, in the presence of E4177, cilazaprilat caused further increases in sodium excretion. This cilazaprilat-induced vasodilation and natriuresis was abolished by a bradykinin antagonist (N(alpha)-adamantaneacetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]b radykinin). In parallel with these results, cilazaprilat increased renal bradykinin content, more greatly in the medulla than in the cortex (5.7 +/- 0.4 versus 4.6 +/- 0.1 ng/g). Similarly, cilazaprilat elicited greater bradykinin-dependent increases of nitrite/nitrate in the medulla. In conclusion, zonal heterogeneity in renal bradykinin/nitric oxide levels and segmental differences in reactivity to bradykinin contribute to the diverse responsiveness of renal AFF and EFF to ACEI. ACEI-enhanced kinin action would participate in the amelioration of glomerular hemodynamics and renal sodium excretion by ACEI.     

骨化三醇对糖尿病大鼠肾脏血管紧张素转换酶与血管紧张素转换酶2的影响

目的观察血管紧张素转换酶（angiotensinconvertingenzyme,ACE）和血管紧张素转换酶2（angiotensinconvertingenzyme2,ACE2）在糖尿病大鼠肾脏的表达及骨化三醇对其的影响。方法6～8周龄Wistar大鼠被随机分为3组,分别为对照组、糖尿病组、骨化三醇组（O．03μg·kg-1·d-1）。16周后处死各组大鼠,留取标本。放射免疫法检测尿胆微球蛋白（p2-microglobulin,p2-MG）、尿白蛋白（urinaryalbumin,Alb）、血全段甲状旁腺素（intactparathyrin,iPTH）;分光光度法检测尿肌酐（urinecreatinine,UCr）;苦味酸法检测血肌酐（serumcreatinine,SCr）;全自动生化仪检测血钙（Ca）和血磷（P）。PAS染色观察肾脏病理改变并进行半定量统计学分析。实时定量基因扩增荧光（quan—titativepolymerasechainreaction,QPCR）检测肾脏中ACE和ACE2mRNA表达。免疫组织化学法检测肾脏中ACE和ACE2蛋白表达。结果与糖尿病组相比,骨化三醇组尿陀一MG、尿Alb／UCr降低（P〈0．05）,内生肌酐清除率（endogenouscreatinineclearancerate,CCr）升高（P〈O．05）。各组大鼠血Ca、血P及iPTH差异无统计学意义（P〉0．05）。PAS病理染色及半定量分析结果提示,与糖尿病组相比,骨化三醇组大鼠肾脏肾小球硬化程度及肾小管间质纤维化程度有所减轻（P〈0．05）。与对照组比较,糖尿病组大鼠肾脏ACE与ACE2mRNA和蛋白表达均升高（P〈O．05）,ACE／ACE2升高（P〈0．05）。与糖尿病组比较,骨化三醇组大鼠肾脏ACEmRNA和蛋白的表达降低（P〈O．05）,ACE2mRNA和蛋白的表达升高（P〈（）．05）,ACE／ACE2降低（P〈0．05）。相关分析结果显示,尿82-MG、Alb／ucr与ACE／AcE2呈正相关（P〈0．05）,CCr与ACE／ACE2呈负相关（P〈0．05）。结论骨化三醇降低糖尿病大鼠蛋白尿、升高CCr,改善病理损伤,其肾脏保护作用可能与调节ACE和ACE2的表达有关。     

Effects of antihypertensive therapy on the renal function in spontaneously hypertensive rats (SHR) with renal ablation

To determine whether pharmacological control of blood pressure could affect the renal function and its deterioration in SHR with renal ablation, we studied effects of oral administration of captopril (50 mg/kg/day) and ramipril (10 mg/kg/day), angiotensin converting enzyme inhibitors (ACEI), nilvadipine (10 mg/kg/day) and benidipine (3-6 mg/kg/day), calcium channel blockers (CCB), and indapamide (10 mg/kg/day), a non-thiazide diuretic, for 2 and 12 weeks on systolic blood pressure (SBP), blood urea nitrogen (BUN) and serum creatinine (Scr), endogenous creatinine clearance (Ccr), and urinary protein excretion (UP) in SHR subjected to 5/6 nephrectomy a week before. Three weeks after the surgery, SBP (mmHg) in the untreated group was 253 +/- 8.9 (n = 11), captopril group 156 +/- 8.9 (n = 7, p less than 0.05), ramipril group 176 +/- 12 (n = 7, p less than 0.05), nilvadipine group 146 +/- 8.8 (n = 7, p less than 0.05), and benidipine group 197 +/- 8.5 (n = 7, p less than 0.05). Monotherapy with indapamide (206 +/- 4.8, n = 7, p less than 0.05) induced only a slight decrease in the SBP. Thirteen weeks after the surgery, SBP in the untreated group was 270 +/- 6.9 (n = 14), in the captopril group 191 +/- 4.8 (n = 7, p less than 0.05), in the ramipril group 160 +/- 9.5 (n = 7, p less than 0.05), in the nilvadipine group 177 +/- 13.2 (n = 7, p less than 0.05), and in the benidipine group 150 +/- 4.9 (n = 7, p less than 0.05). BUN was lower in the captopril and nilvadipine groups but not in the other treatment groups compared with the untreated group. Scr was lower in the ACEI groups. Ccr was higher in the ACEI and benidipine groups. UP was lower in all treatment groups. These results indicate that the similar reduction of SBP by ACEI and CCB has the potential to preserve renal function and to lessen renal damage in this model. Furthermore, they also suggest that ACEI have the potential to ameliorate renal function in this model. However, it remains to be determined why, despite the similar effects on SBP, deterioration of renal function in this model was prevented only by treatment with the ACEI, but not with the CCB.     

Intact parathyroid hormone levels in renal insufficiency

To define the onset of the rise in intact parathyroid hormone (PTH) levels in renal insufficiency, we conducted a cross-sectional study of parameters of mineral metabolism in patients with varying degrees of renal impairment. Using an immunoradiometric assay to measure intact PTH levels, we found elevations in intact PTH levels as creatinine clearance approaches 60 ml/minute (serum creatinine near 1.8) and a significant inverse relationship between indices of renal function and intact PTH levels (r=-0.60, P<0.001 for intact PTH and creatinine clearance). Calcium and phosphate levels correlate less strongly with the degree of hyperparathyroidism (r=-0.39, P<0.001 for total calcium; r=0.31, P<0.05 for phosphate). As a group, only patients with severe renal failure (creatinine clearance <20 ml/minute) had 1,25-dihydroxyvitamin D levels below normal (11±4 [SEM] pg/dl, normal range 15–60). Intact and n-terminal PTH measurements correlate well in this patient population with varying degrees of renal insufficiency (r=0.9, P<0.001). Intact PTH can be elevated in patients with mild to moderate renal insufficiency, thus efforts to prevent the development of secondary hyperparathyroidism in renal failure should be undertaken early in the course of renal insufficiency.     

Plasmapheresis in the intensive therapy of renal insufficiency

Results of the treatment of 12 patients operated on organs of the abdominal cavity for peritonitis and 2 patients with purulent pyelonephritis are described. The patients had different degrees of disturbances of the renal function (renal insufficiency included). The use of plasmapheresis improved the diuretic function of the kidneys, parameters of glomerular filtration and reduced azotemia. However in patients with the terminal renal insufficiency the including of plasmapheresis and hemofiltration proved to be unsuccessful.     

Effects of smoking on systemic and intrarenal hemodynamics: influence on renal function

In recent years, it has become apparent that smoking has a negative impact on renal function, being one of the most important remediable renal risk factors. It has been shown clearly that the risk for high-normal urinary albumin excretion and microalbuminuria is increased in smoking compared with nonsmoking subjects of the general population. Data from the Multiple Risk Factor Intervention Trial indicate that at least in men, smoking increases the risk to reach end-stage renal failure. Smoking is particularly "nephrotoxic" in older subjects, subjects with essential hypertension, and patients with preexisting renal disease. Of interest, the magnitude of the adverse renal effect of smoking seems to be independent of the underlying renal disease. Death-censored renal graft survival is decreased in smokers, indicating that smoking also damages the renal transplant. Cessation of smoking has been shown to reduce the rate of progression of renal failure both in patients with renal disease and in patients with a renal transplant. The mechanisms of smoking-induced renal damage are only partly understood and comprise acute hemodynamic (e.g., increase in BP and presumably intraglomerular pressure) and chronic effects (e.g., endothelial cell dysfunction). Renal failure per se leads to an increased cardiovascular risk. The latter is further aggravated by smoking. Particularly, survival of smokers with diabetes on hemodialysis is abysmal.     

Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients

Hypertension and hyperfiltration are two important risk factors for the development of chronic allograft nephropathy. Transforming growth factor-beta(1) (TGF-beta(1)) is the main cytokine involved in the fibrotic process that is involved in chronic rejection. Angiotensin II upregulates TGF-beta(1) production. Angiotensin II receptor antagonists therefore could not only control BP but also reduce TGF-beta(1) production in renal transplant patients. The aim of this study was to compare the effects of losartan and amlodipine on renal hemodynamics, as well as TGF-beta(1) and endothelin-1 (ET-1) plasma levels in a group of renal transplant patients who had normal renal function and who were treated with cyclosporine. Seventeen renal transplant patients who were receiving cyclosporine and who had normal graft function were included in a random 2 x 2 crossover trial with amlodipine and losartan (6 wk with each therapy). Three studies were performed (at baseline and at the end of both treatment periods) to determine renal hemodynamics, TGF-beta(1), and ET-1. Both treatments controlled BP to a similar degree, but only amlodipine increased GFR through an increase in the estimated glomerular hydrostatic pressure and filtration fraction. In contrast, losartan maintained GFR and reduced estimated glomerular hydrostatic pressure and filtration fraction significantly. Losartan and amlodipine had opposite effects on TGF-beta(1). Amlodipine did not affect TGF-beta(1) concentrations. In contrast, losartan reduced the plasma levels of TGF-beta(1) by approximately by 50% (from baseline, 5.2 to 2.6 ng/ml; P: = 0.01); the majority of the patients reached normal levels of TGF-beta(1). ET-1 concentrations were significantly higher during amlodipine compared with losartan treatment. The present study documents that with similar control of BP, losartan and amlodipine have opposite effects on renal hemodynamics and on TGF-beta1 concentrations. These differences could be important for the management of chronic allograft nephropathy.     

Beta 2-microglobulin levels in patients with renal insufficiency

beta 2-microglobulin (beta 2M) has been implicated in the pathogenesis of amyloidosis in long-term dialysis patients. beta 2M levels were measured in patients with chronic renal failure: before and after conventional hemodialysis in 30, before and after high-flux (HF) hemodialysis in 35, and during the first hemodialysis treatment in five patients, as well as in the serum and peritoneal fluid of 13 patients who were receiving continuous ambulatory peritoneal dialysis (CAPD) and in the serum and urine of three patients who had received kidney transplants. Dialysis patients had markedly elevated beta 2M levels; prehemodialysis values were not significantly different for patients receiving conventional v HF hemodialysis. Most of these patients were functionally anephric, and the beta 2M levels did not correlate with age, sex, or time on dialysis. In patients receiving conventional hemodialysis using cellulose acetate membrane, beta 2M levels increased 25.4% after hemodialysis, whereas in patients receiving HF hemodialysis using polysulfone membrane, beta 2M levels decreased significantly (43.0%) after hemodialysis. End-stage renal disease patients dialyzed for the first time had beta 2M values significantly lower than the other two groups because of residual glomerular filtration rate (GFR). CAPD patients also had lower values because they had an estimated loss of 80.4 mg/d of beta 2M in the dialysate fluid. In patients with chronic renal failure, beta 2M levels paralleled the increase in serum creatinine. Patients who received kidney transplants had a dramatic decrease in beta 2M levels that correlated with improvement in GFR. beta 2M correlated with the residual GFR, and its removal was membrane-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of renal replacement therapy on plasma lipoprotein(a) levels

Patients with end-stage renal disease (ESRD) have significantly higher levels of lipoprotein(a) [Lp(a)] when compared to control populations. Elevated levels of Lp(a) may play a role in the high incidence of cardiovascular disease in ESRD. We conducted a prospective study to test the hypothesis that plasma levels of Lp(a) decline rapidly after renal transplantation proportional to the improvement in renal function, but are not affected by hemodialysis. All adults that initiated hemodialysis or received a renal transplant from our institution during a 10-month period were invited to participate in the study. Lp(a) levels were obtained immediately prior to the initiation of renal replacement therapy. In transplant recipients, repeat Lp(a) measures were done at 3 days, 5 days, 1 week, 2 weeks, 3 weeks and 4 weeks post-transplant. In hemodialysis patients, repeat Lp(a) measures were done after 3 months. We used a mixed effects model to analyze the effect of time, race and creatinine on Lp(a) after transplant. Lp(a) levels decreased rapidly after renal transplantation. Mean Lp(a) levels at 2 weeks were 35.3% lower than prior to transplantation. Each reduction of 50% in creatinine was associated with a 10.6% reduction in Lp(a) (p < 0.001). In contrast, there was no significant change in Lp(a) after initiation of hemodialysis. The rapid decrease of Lp(a) levels after renal transplantation provides support for a metabolic role of the kidney in Lp(a) catabolism and suggests that the increase in Lp(a) seen in chronic kidney disease is due to loss of functioning renal tissue.     

Effects of chronic cyclosporine administration on renal blood flow and intrarenal blood flow distribution

Cyclosporine-induced decreases in renal blood flow (RBF) and glomerular function are well documented. Glomerular filtration and tubular function may be affected by changes in both total renal blood flow and cortical blood flow distribution (CBFD). The effect of CsA on RBF, CBFD, glomerular filtration rate, and tubular function was studied in conscious ewes receiving a mean CsA dose of 30 mg/kg/day for 28 days with mean CsA trough levels of 344 +/- 45 ng/ml. RBF and CBFD were determined by the injection of 15 microns radioactive microspheres before and after one month of treatment with CsA or its vehicle, olive oil. RBF decreased by 24% from 7.65 +/- 0.87 to 5.79 +/- 0.42 ml/min/g of kidney in CsA-treated ewes (P = 0.014), while no decrease was noted in the control group (7.92 +/- 1.10 vs. 7.62 +/- 0.71). Intracortical blood flow decreased in proportion to the fall in total renal blood flow--thus CsA treatment did not change the cortical distribution of flow. There was a 25% decrease in GFR, as determined by inulin clearance, in the CsA-treated group (80 +/- 6 vs. 62 +/- 3 ml/min; P = 0.027) while there was a nonsignificant increase in control animals (62 +/- 11 vs. 92 +/- 7 ml/min). There was no evidence of tubular dysfunction in either group. There were also no changes in urinary excretion rates of prostaglandins PGE2, 6-keto-PGF1 alpha or thromboxane B2, nor were there changes in plasma renin activity. CsA induced decreases in RBF occur red without redistribution of cortical blood flow, indicating that altered cortical distribution of blood flow is not responsible for the changes in GFR or tubular function that have been reported. The changes in renal blood flow and glomerular filtration rate are independent of changes in renal prostaglandin production, and are likely not associated with altered plasma renin activity.     

Immunoglobulin induction therapy in renal transplant recipients: Effects on immunoglobulin and regulatory antibody levels

We have previously shown that high pretransplant regulatory autoantibodies are associated with better kidney graft outcome. To analyze the effect of intravenous immunoglobulin (IVIG) induction therapy on these regulatory antibodies, we performed a prospective randomized study in 50 renal transplant recipients who were randomly assigned to receive 7 x 10 g IVIG or 7 x 10 g IV albumin infusions. Basic immunosuppressive therapy consisted of tacrolimus/azathioprine (n = 24) and tacrolimus/mycophenolate mofetil (n = 26), respectively. ELISA was used to assess IgG-/IgA-anti-Fab, -anti-F(ab)2 and -anti-hinge regulatory antibodies. IVIG induction therapy resulted in upregulation of serum IgG and IgA levels within the first 20 days posttransplant (P = .001, IgG; P = .04, IgA), so that a significant IgG deficiency was found only in non-IVIG patients (day 10: IgG <6 g/L: 7/25 (28%) non-IVIG versus 0/25 IVIG patients; P = .005). As the IVIG charges contained all of the regulatory antibodies tested, intravenous administration of these antibodies explain the elevated IgG- and IgA-anti-F(ab)2 antibody levels found in IVIG compared to non-IVIG patients on day 10 (P = .005 and P = .04, respectively). Our data indicated that IVIG induction prevented severe IgG deficiency in the early posttransplant period but had no impact on severe infectious complications. IVIG induction enhanced immunoregulatory antibody levels early posttransplant, which might provide graft protective effects.     

Combined peritoneal and haemodialysis therapy for chronic renal insufficiency

Twenty-three patients with chronic uraemia were treated for an average of 8.5 months with intermittent peritoneal dialysis. When hypervolaemia developed and/or the volume of low-molecular weight substances increased, the therapy was complemented by one or two sessions of haemodialysis per week. The combined treatment was carried on for 4.1 months on average, in consequence of which the general condition improved, body weight reached the optimum, blood pressure diminished, turned normal and could be controlled by drugs. In the wake of the therapy carbamide nitrogen and creatinine levels dropped significantly, serum total protein and albumin values increased. At the close of the observation period 3 patients remained under combined therapy, 2 had undergone cadaveric kidney transplantation, 18 were transferred to chronic haemodialysis. Thoughts are evolved about the advisability of intermittent peritoneal dialysis and combined therapy in the care for uraemic patients.