No effect of enalapril on progression in autosomal dominant polycystic kidney disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are capable of reducing proteinuria and microalbuminuria with preservation of renal function in diabetic and non-diabetic renal disease. We designed a study investigating the effect of enalapril on the protection of renal function in autosomal dominant polycystic kidney disease (ADPKD). METHODS: We studied 61 normotensive and 28 hypertensive ADPKD patients. The normotensive group participated in a randomized double-blind placebo-controlled study, using enalapril. The hypertensive group was randomized for open label treatment with enalapril or the beta-blocker atenolol. The follow-up was 3 years, and renal function was established repetitively by measuring the clearance of inulin. RESULTS: In the normotensive group, renal function at baseline was 112 +/- 3 ml/min and decreased by -8 +/- 2 ml/min (P < 0.001). The loss of renal function in the patients treated with enalapril or placebo was similar (-7 +/- 3 vs -9 +/- 1 ml/min; P = 0.4). Although blood pressure significantly decreased with enalapril treatment, it had no effect on microalbuminuria. In the hypertensive group, renal function at baseline was 89 +/- 2 ml/min. The mean decline in renal function was -12 +/- 2 ml/min (P < 0.001), and was equal in patients treated with enalapril and those treated with atenolol. The patients treated with atenolol required more additional treatment to control blood pressure, but no difference on microalbuminuria was observed between the two treatments. CONCLUSION: This study was unable to detect a beneficial effect of ACE inhibition on loss of renal function in ADPKD patients.     

Elevated levels of plasma von Willebrand factor and the risk of macro- and microvascular disease in type 2 diabetic patients with microalbuminuria.

BACKGROUND: The purpose of this study was to examine the concept suggesting that microalbuminuria in combination with high levels of plasma von Willebrand factor is a stronger predictor for cardiovascular disease and microvascular complications than microalbuminuria alone in type 2 diabetic patients. METHODS: One hundred and sixty patients with type 2 diabetes mellitus and persistent microalbuminuria were followed for an average of 3.8 (SD 0.3) years. 70% of the patients were treated with angiotensin converting enzyme (ACE)-inhibitors. Patients in this subanalysis were divided into two groups according to baseline plasma von Willebrand factor levels below or above the median. The main outcome was cardiovascular disease (cardiovascular mortality, non-fatal stroke, non-fatal myocardial infarction, coronary artery bypass graft and revascularization or amputation of legs), progression to diabetic nephropathy or progression in diabetic retinopathy. RESULTS: At baseline the two groups were comparable for HbA(1c), fasting levels of s-total-cholesterol, s-HDL-cholesterol and s-triglycerides, systolic and diastolic blood pressure, gender, known diabetes duration, smoking habits, previous cardiovascular disease and antihypertensive therapy as well as retinopathy. Odds ratio for cardiovascular disease was 1.11 (95% CI 0.45-2.73, P=0.82) (multiple logistic regression), odds ratio for progression to nephropathy was 1.08 (0.41-2.85, P=0.87) and odds ratio for progression in retinopathy was 0.96 (0.46-2.00, P=0.92), all with plasma von Willebrand factor levels above the median. CONCLUSIONS: Our results do not support the suggestion that the combination of high plasma levels of von Willebrand factor and microalbuminuria is a stronger predictor for cardiovascular disease, progression to diabetic nephropathy or progression in diabetic retinopathy than microalbuminuria alone in patients with type 2 diabetes and persistent microalbuminuria.     

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. BACKGROUND: In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. METHODS: After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). RESULTS: In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (beta = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (beta = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta = -0.211, P = 0.006). CONCLUSION: In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.     

Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes

A mutation of endothelial nitric oxide synthase (ecNOS)-a key enzyme of the endogenous nitrovasodilator system that is essential for the regulation of blood flow and blood pressure-may aggravate the progression to diabetic nephropathy and/or retinopathy. To investigate the association of ecNOS tandem repeat polymorphism with diabetic nephropathy, the ecNOS genotype was assessed in 82 Japanese type 2 diabetic patients without nephropathy, 94 patients with microalbuminuria, 39 patients with nephropathy, and 155 healthy control subjects. The analysis revealed that type 2 diabetic patients with nephropathy (not with microalbuminuria) were significantly different from type 2 diabetic patients without nephropathy and healthy control subjects in genotype distribution (P = 0.0423) and frequency of the ecNOS4a allele (19.2% vs. 7.3 and 7.1%, respectively; P = 0.0078). The odds ratio of progression to diabetic nephropathy in diabetic patients who carry the mutated allele is about 2.87 compared with noncarriers. The stepwise multiple regression analysis in these patients showed that hypertension (F = 9.760) and ecNOS gene polymorphism (F = 5.298) are the relevant variables for nephropathy. However, no association was found between the ecNOS4a allele and hypertension or diabetic retinopathy. These results imply that the ecNOS gene polymorphism may be associated with progression to diabetic nephropathy in Japanese type 2 diabetic patients.     

Polymorphic genes for kinin receptors,nephropathy and blood pressure in type 2 diabetic patients

BACKGROUND/AIMS: There is evidence that hereditary predisposition contributes to the development of diabetic nephropathy and hypertension. Polymorphisms in the genes for bradykinin receptors (B(1)R and B(2)R) were found to be associated with decreased risk of the development of end-stage renal disease. This study examines whether B(1)R G(-699)C and B(2)R C(181)T polymorphisms are associated with microalbuminuria or overt nephropathy, or blood pressure variation in type 2 diabetic subjects. METHODS: B(1)R and B(2)R polymorphisms were determined in 153 type 2 diabetic patients with microalbuminuria, 132 with overt nephropathy (macroalbuminuria or chronic renal failure), and 161 patients with normoalbuminuria despite diabetes duration longer than 10 years. RESULTS: Distributions of the examined polymorphisms did not differ between patients with microalbuminuria or overt nephropathy, compared to normoalbuminuric control subjects. Patients carrying the B(2)R T allele had lower DBP, compared with non-carriers: 83.6 +/- 12.0 vs. 87.4 +/- 12.1 mm Hg, p < 0.05. Among patients not receiving ACEI, both SBP and DBP was significantly lower in B(2)R T allele carriers, compared to non-carriers (137.2 +/- 20.3 vs. 146.5 +/- 21.7 mm Hg, and 80.3 +/- 11.9 vs. 85.8 +/- 11.6 mm Hg, p < 0.05). CONCLUSIONS: Examined polymorphisms are not associated with the increased risk of incipient or overt nephropathy in type 2 diabetic patients. B(2)R C(181)T polymorphism may contribute to blood pressure variation in these subjects.     

Progression of diabetic nephropathy

BACKGROUND: Diabetic nephropathy is a major cause of renal failure. The decline in glomerular filtration rate (GFR) is highly variable, ranging from 2 to 20, with a median of 12 mL/min/year. The risk factors of losing filtration power (progression promoters) have not been clearly identified. Furthermore, information on optimal arterial blood pressure, glycemic control, and cholesterol levels are lacking. METHODS: We measured GFR with (51)Cr-EDTA plasma clearance technique, blood pressure, albuminuria, glycosylated hemoglobin A1c, and serum cholesterol every year for seven years (range 3 to 14 years) in 301 consecutive type 1 diabetic patients with diabetic nephropathy recruited consecutively during 1983 through 1997. Diabetic nephropathy was diagnosed clinically if the following criteria were fulfilled: persistent albuminuria> 200 microg/min, presence of diabetic retinopathy, and no evidence of other kidney or renal tract disease. In total, 271 patients received antihypertensive treatment at the end of the observation period. RESULTS: Mean arterial blood pressure was 102 +/- 0.4 (SE) mm Hg. The average decline in GFR was 4.0 +/- 0.2 mL/min/year and even lower (1.9 +/- 0.5 mL/min/year) in the 30 persistently normotensive patients, none of whom had ever received antihypertensive treatment (P < 0.01). A multiple linear regression analysis revealed a significant positive correlation between the decline in GFR and mean arterial blood pressure, albuminuria, glycosylated hemoglobin A(1c), and serum cholesterol during follow-up (R(adj)(2) = 0.29, P < or = 0.001). No threshold level for blood pressure, glycosylated hemoglobin A(1c), or serum cholesterol was demonstrated. A two-hit model with mean arterial blood pressure and glycosylated hemoglobin A(1c) below and above the median values (102 mm Hg and 9.2%, respectively) revealed a rate of decline in GFR of only 1.5 mL/min/year in the lowest stratum compared with 6.1 mL/min/year in the highest stratum (P < 0.001). CONCLUSIONS: The prognosis of diabetic nephropathy has improved during the past decades, predominantly because of effective antihypertensive treatment. Genuine normotensive patients have a slow progression of nephropathy. Several modifiable variables have been identified as progression promoters.     

Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac disease.

BACKGROUND: Hypertension is a recognized complication of partial correction of anemia with recombinant human erythropoietin (epoetin) in hemodialysis patients. We used interdialytic ambulatory blood pressure (ABP) monitoring to study the effects of partially corrected anemia versus normal hematocrit (hct) on BP in hemodialysis patients. METHODS: Repeated interdialytic ABP monitoring was performed for up to one year in 28 chronic hemodialysis patients with cardiac disease who were randomized to achieve and maintain normal hct levels (42 +/- 3%, group A) or anemic hct levels (30 +/- 3%, group B) with epoetin. Routine BP measurements obtained at dialysis treatments were also evaluated. RESULTS: Mean hct levels were 30.7 +/- 0.7% in group A and 30.6 +/- 0.7% in group B at baseline, then 39.3 +/- 1.2% (group A) and 33.5 +/- 0.6% (group B) at four months, and 42.0 +/- 1.1% (group A) and 30.4 +/- 1.0% (group B) at 12 months. Baseline ABP and routine dialysis unit BP levels were not different between the groups. At 2, 4, 8, and 12 months of follow-up, there were no statistically significant differences in any BP parameters between groups or increases in any BP parameters in either group A or group B patients compared with baseline. At 12 months, the mean nighttime diastolic BP (DBP) in group A patients was slightly but significantly lower than the mean daytime DBP (daytime DBP 76.6 +/- 1.9 mm Hg vs. nighttime DBP 72.9 +/- 2.1 mm Hg, P < 0.05). The mean daytime and nighttime BPs were not different from each other at two, four, and eight months in group A or at any time in group B, and in both groups, most patients had little diurnal change in BP. CONCLUSION: Correction of hct to normal with epoetin in chronic hemodialysis patients with cardiac disease did not cause increased BP as assessed by interdialytic ABP monitoring or by the measurement of routine predialysis and postdialysis BP. There was little diurnal change in systolic or diastolic BP at baseline or after correction of anemia to normal levels, and although mean nighttime DBP was lower than mean daytime DBP at 12 months in group A, the maintenance of normal hct levels did not affect the abnormal diurnal BP pattern seen at moderately anemic hct levels in most patients.     

Appropriate blood pressure control in hypertensive and normotensive type 2 diabetes mellitus: a summary of the ABCD trial

The hypertensive and normotensive Appropriate Blood Pressure Control in Diabetes (ABCD) studies were prospective, randomized, interventional clinical trials with 5 years of follow-up that examined the role of intensive versus standard blood pressure control in a total of 950 patients with type 2 diabetes mellitus. In the hypertensive ABCD study, a significant decrease in mortality was detected in the intensive blood pressure control group when compared with the standard blood pressure control group. There was also a marked reduction in the incidence of myocardial infarction when patients were randomly assigned to initial antihypertensive therapy with angiotensin-converting-enzyme inhibition rather than calcium channel blockade. The results of the normotensive ABCD study included associations between intensive blood pressure control and significant slowing of the progression of nephropathy (as assessed by urinary albumin excretion) and retinopathy, and fewer strokes. In both the hypertensive and normotensive studies, mean renal function (as assessed by 24 h creatinine clearance) remained stable during 5 years of either intensive or standard blood pressure intervention in patients with normoalbuminuria (<30 mg/24 h) or microalbuminuria (30-300 mg/24 h) at baseline. By contrast, the rate of creatinine clearance in patients with overt diabetic nephropathy (>300 mg/24 h; albuminuria) at baseline decreased by an average of 5 ml/min/year in spite of either intensive or standard blood pressure control. Analysis of the results of 5 years of follow-up revealed a highly significant correlation of all-cause and cardiovascular mortality with left ventricular mass and severity of albuminuria.     

Prediction of hypertension in chronic hemodialysis patients.

BACKGROUND: There are no universally accepted criteria for the diagnosis of hypertension in hemodialysis (HD) patients. We sought to determine the clinical performance of predialysis and postdialysis systolic and diastolic blood pressure values (BPs) in diagnosing hypertension or assessing its control. METHODS: Seventy patients [77% African American, 46% females, mean age 59 +/- 17 (SD) years, 34% diabetics] on chronic HD underwent a single 44-hour interdialytic ambulatory blood pressure monitoring (ABPM) and concomitant recording of BP by conventional syphygmomanometer in the HD unit for two weeks. Hypertension was defined as systolic BP (SBP) > or =135 mm Hg or diastolic BP (DBP) > or =85 mm Hg on an average 44-hour ABPM. RESULTS: Average ABP was 144 +/- 22/81 +/- 11 mm Hg. Seventy-three percent of the patients had systolic hypertension; 40% had diastolic hypertension, and 24% were normotensive or had well-controlled BP. Area under the curve of receiver operating characteristic (ROC) curves exceeded 80% for all BPs, but the thresholds for best sensitivity and specificity were markedly different for predialysis and postdialysis BPs. A two-week averaged predialysis BP of > 150/85 mm Hg or a postdialysis BP of > 130/75 mm Hg had at least 80% sensitivity in diagnosing hypertension. Specificity of at least 80% was achieved if predialysis BP of > 160/90 mm Hg or postdialysis BP of > 140/80 mm Hg was used. There was poor agreement between HD unit BP and ABP values. CONCLUSIONS: HD unit BP values can be used to identify the presence or absence of hypertension, although prediction of ambulatory BPs from HD unit BP values cannot be made reliably in individual patients.     

Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial

Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme (ACE) inhibitors on the progression of IgA nephropathy (IgAN), but prospective and controlled studies demonstrating this effect are lacking. Forty-four patients with biopsy-proven IgAN, proteinuria > or = 0.5 g/d, and serum creatinine (SCr) < or = 1.5 mg/dl were randomly assigned either to receive enalapril (n = 23) or to a control group (n = 21) in whom BP was controlled with antihypertensives other than ACE inhibitors. Primary outcome was renal survival estimated by a 50% increase in baseline SCr. Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria. Baseline clinical findings were similar at baseline between enalapril-treated and control group, and there were no differences in BP control during follow-up. Mean follow-up was 78 +/- 37 mo in the enalapril group and 74 +/- 36 mo in the control group. Three patients (13%) in the enalapril group and 12 (57%) in the control group reached the primary end point (P < 0.05). Kaplan-Meier renal survival was significantly better in enalapril group than in control group: 100% versus 70% after 4 yr and 92% versus 55% after 7 yr (P < 0.05). Three patients in the enalapril group (13%) and 11 (52%) in the control group showed SCr > 1.5 mg/dl at the last visit (P < 0.05). Proteinuria significantly decreased in the enalapril group, whereas it tended to increase in the control group (P < 0.001 between groups). In conclusion, ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function.     

Comparison of indapamide and low-dose hydrochlorothiazide monotherapy in black patients with mild to moderate hypertension.

OBJECTIVES: To assess, using ambulatory blood pressure monitoring (ABPM), the antihypertensive efficacy of hydrochlorothiazide 12.5 mg and indapamide 2.5 mg given as a monotherapy over 3 months to black patients with mild to moderate essential hypertension. DESIGN: Single-centre, prospective, randomised open pilot study in three phases: (i) 1-week drug-free washout period; (ii) 2-week placebo run-in phase; and (iii) 3-month prospective open-label active treatment period. RESULTS: Forty-two black patients with mean daytime diastolic BP (DBP) > or = 90 mmHg and < or = 115 mmHg (mean age 57 +/- 11 years, 28 women/14 men) were enrolled into the study. Overall, a profound and sustained BP reduction was achieved with indapamide at 3 months (N = 20). The 24-hour BP decreased from 150 +/- 17/94 +/- 6 mmHg to 130 +/- 19/82 +/- 9 mmHg (P < 0.0001 for systolic BP (SBP) and DBP at 3 months versus baseline); the mean daytime BP decreased from 155 +/- 15/98 +/- 6 mmHg to 134 +/- 18/87 +/- 10 mmHg (P < 0.0001 for SBP and DBP at 3 months versus baseline). The overall control (mean daytime DBP < 90 mmHg) and response (decrease in daytime DBP > or = 10 mmHg) rates achieved with indapamide were 10/20 (50%) and 13/20 (65%), respectively. In contrast, monotherapy with hydrochlorothiazide resulted in more modest BP reduction and control and response rates at 3 months (N = 22). The 24-hour BP decreased from 147 +/- 14/94 +/- 7 mmHg to 139 +/- 19/88 +/- 2 mmHg (P < 0.05 for DBP at 3 months versus baseline, P = NS for SBP); the mean daytime BP decreased from 151 +/- 14/98 +/- 5 mmHg to 144 +/- 16/93 +/- 10 mmHg (P < 0.05 for DBP at 3 months versus baseline, P = NS for SBP). The corresponding control and response rates were 7/22 (32%) and 8/22 (36%). Both hydrocholorothiazide and indapamide caused significant hypokalaemia. CONCLUSIONS: Monotherapy with indapamide is associated with greater BP reduction and control and response rates than monotherapy with low-dose hydrochlorothiazide and may be an appropriate choice of antihypertensive diuretic therapy in black South African patients with mild to moderate hypertension.     

Effect of dilazep dihydrochloride on urinary albumin excretion in patients with autosomal dominant polycystic kidney disease

Proteinuria and microalbuminuria occur with a highly variable severity and are associated with progression of autosomal dominant polycystic kidney disease (ADPKD). Dilazep dihydrochloride, an antiplatelet drug, is effective in patients with immunoglobulin A nephropathy or diabetic nephropathy. We studied whether dilazep dihydrochloride affects the urinary albumin excretion (UAE) in normotensive and hypertensive patients with ADPKD. Twelve normotensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 6, group A) and a placebo group (n = 6, group B). In addition, 10 hypertensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 5, group C) and a placebo group (n = 5, group D). Treatment with dilazep was continued for a period of 6 months, at the end of which the UAE was reduced form 130 +/- 52 to 46 +/- 26 microg/min (p < 0.01) in group A. There was no reduction in group C. There were no changes in UAE in placebo groups B and D. These results suggest that dilazep dihydrochloride may be effective in reducing UAE in normotensive ADPKD patients with microalbuminuria.     

Efficacy and safety of valsartan, an angiotensin II receptor antagonist, in hypertension after renal transplantation: a randomized multicenter study

BACKGROUND: The prevalence of posttransplant hypertension is high, and it appears to be a major risk factor for graft and patient survival. The aim of this study was to assess the efficacy and safety of valsartan, an angiotensin-receptor blocker (ARB), in the treatment of posttransplant hypertension. METHODS: A multinational, multicenter, prospective, randomized, double-blind, placebo-controlled study was performed on the treatment of hypertension (systolic blood pressure [BP] >/= 140 and/or diastolic BP >/= 90 mm Hg) in adult cyclosporin-treated renal transplant recipients randomized to receive either valsartan (80 mg once daily) or a matching placebo for 8 weeks. After the first 4 weeks, furosemide 20 mg twice daily was added on a open basis if systolic BP remained >/= 130 mm Hg and/or diastolic BP remained >/= 85 mm Hg. RESULTS: One hundred fifteen (valsartan = 57, placebo = 58) uncontrolled hypertensive patients despite monotherapy for hypertension, other than angiotensin-converting enzyme inhibitor or ARB, were randomized. In the valsartan group, significant decreases were seen in systolic BP (from 153 +/- 11 to 140.9 +/- 18.35 mm Hg at 4 weeks, and 136.5 +/- 15 mm Hg at 8 weeks) and diastolic BP (from 93 +/- 9 to 85.2 +/- 11.28 mm Hg at 4 weeks, and 83.8 +/- 9.2 mm Hg at 8 weeks). There was no significant change in the placebo group. In the valsartan group, a statistically but not clinically significant reduction was observed in the mean hemoglobin concentration (12.9 +/- 1.6 g/dL versus 13.8 +/- 1.6 g/dL at 4 weeks, P < .01; and 12.3 +/- 1.6 versus 13.8 +/- 1.7 at 8 weeks; P < .001) as well as a significant increase in serum potassium (4.4 +/- 0.5 mmol/L versus 4.1 +/- 0.4 mmol/L at 4 weeks, P < .01) vs placebo. CONCLUSIONS: Valsartan is effective in the treatment of posttransplant hypertension and is well tolerated.     

Persistent renal hypertrophy and faster decline of glomerular filtration rate precede the development of microalbuminuria in type 1 diabetes

Soon after the onset of type 1 diabetes, renal hypertrophy and hyperfiltration become manifest, particularly among patients who will subsequently develop diabetic nephropathy. Whether these early renal dysfunctions are involved in the pathogenesis of diabetic nephropathy is currently unclear. We evaluated, during the same day, kidney volume and glomerular filtration rate (GFR) in 146 patients with type 1 diabetes and normal renal function. All the individuals were then monitored for a mean of 9.5 +/- 4.4 years for the development of microalbuminuria. Kidney volume and GFR were reevaluated in a subset of 68 patients 4 years after baseline. During follow-up, microalbuminuria developed in 27 of 146 diabetic patients. At baseline, kidney volume (312.8 +/- 52.6 vs. 281.4 +/- 46.1 vs. 236.8 +/- 41.6 ml/1.73 m(2), P < 0.05) but not GFR was increased in patients predisposed to microalbuminuria. Risk of progression was higher in patients with increased kidney volume (P = 0.0058). Patients predisposed to microalbuminuria showed a stable increase in kidney volume (P = 0.003), along with a faster decline of GFR (P = 0.01). Persistent renal hypertrophy and faster decline of GFR precede the development of microalbuminuria in type 1 diabetes. These findings support the hypothesis that renal hypertrophy precedes hyperfiltration during the development of diabetic nephropathy.     

Ambulatory blood pressure and left ventricular mass in normotensive patients with autosomal dominant polycystic kidney disease

Higher left ventricular mass (LVM) has been found in early stages of autosomal dominant polycystic kidney disease (ADPKD). The mechanisms involved in the increase of LVM are unknown. To investigate whether LVM in ADPKD may be influenced by abnormal diurnal BP variations, the 24-h ambulatory BP profile was analyzed in a group of young normotensive ADPKD patients. Ambulatory BP monitoring and two-dimensional echocardiography were performed in 26 young normotensive ADPKD with normal renal function and in 26 healthy control subjects. LVM index was higher in ADPKD patients than in controls (90.8+/-19.6 g/m2 versus 73.9+/-16.1 g/m2, P = 0.001). Average 24-h and daytime systolic, diastolic, and mean BP were similar in both groups. Nighttime diastolic and mean BP, but not systolic BP, were greater in ADPKD patients. The average and percent nocturnal decrease of systolic BP was lower in ADPKD patients than in control subjects (10.0 mm Hg [-3 to 24] versus 15.5 mm Hg [-4 to 31], P = 0.009, and 9.0% [-2 to 22] versus 14.2% [-2 to 25], P = 0.016, respectively). On the basis of their profile BP patterns, 54% of ADPKD subjects and 31% of controls were classified as nondippers (P = 0.092). There were no differences between dippers and nondippers in left ventricular wall thickness, chamber dimensions, and mass indexes. In ADPKD patients, simple regression analysis showed that LVM index was correlated with 24-h, daytime, and nighttime systolic BP. On multiple regression analysis, the 24-h systolic BP was the only variable linked to LVM index. It is concluded that young normotensive ADPKD patients have higher LVM that is closely related to the ambulatory systolic BP. The nocturnal fall in BP is attenuated in these patients, although it is not associated with the higher LVH that they present.     

Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. The Diabiopsies Group.

Renal interstitial expansion is now considered a useful marker of progression of several nephropathies. This study describes a multicenter, prospective, double-blind, placebo-controlled, randomized trial of the effects of Perindopril (4 mg/d) on kidney structure and function over 2 yr in 26 type 2 diabetic patients with proteinuria ranging from 70 to 4210 mg/d and relatively preserved GFR (creatinine clearance >60 ml/min). All patients underwent baseline renal biopsy, but four (15%) were not randomized because of the presence of nondiabetic nephropathy. The remaining 22 were randomized ( 11 to Perindopril [PE], 11 to placebo [PO]), and 19 (9 PE, 10 PO) underwent follow-up biopsy at 2 yr. BP was controlled equally in both groups throughout. Proteinuria increased in PO patients (+1562 mg/d) but declined in PE patients (-156 mg/d) (P < 0.05). Morphometric analysis was performed by light microscopy using a Biocom computer. Over the 2 yr, mean cortical interstitial fractional volume identical at baseline increased significantly in PO patients (31.7 +/- 5.3 versus 40.2 +/- 11.1%; P = 0.001) but was unchanged in PE patients (33.8 +/- 4.9 versus 34.7 +/- 6.6%; P = 0.50). It is concluded that: (1) nondiabetic nephropathy is present in approximately 15% of albuminuric type 2 diabetic patients; and (2) Perindopril prevents interstitial expansion in hypertensive patients with biopsy-proven diabetic glomerulopathy. These results support a role of angiotensin II in the progression of interstitial changes in type 2 diabetic patients with nephropathy.     

Doxazosin GITS trough to peak ratio and 24-hour blood pressure monitoring in the management of hypertension in renal transplant patients

We have studied 20 patients, 10 male, 10 female, mean age 52.5+/-10.9 years, who received a cadaver kidney transplant between June 1996 and January 1999. The patients presented with mild or moderate high BP and were treated on a maintained immunosuppression with an anti-calcineurin agent and steroids, associated or not to mycophenolate-mofetil. At baseline, a 24-hour ambulatory BP monitoring was performed. General biochemical parameters were determined and doxazosin GITS (Gastro-Intestinal Therapeutic System) in a single dose of 4 mg/d was started. Doxazosin GITS was titrated four weeks after up to 8 mg/d if the BP was greater than 140/90 mm Hg. At week 12, biochemical analysis were repeated as well as the 24-hour BP monitoring and the T/P ratio was calculated. RESULTS: The patients were divided in responders, T/P index >50%, n=10 or not-responders, T/P index <50%, n=10 patients). No differences in systolic BP (SBP), diastolic BP(DBP), plasma creatinine or proteinuria were seen at base-line. DBP was lower in responders than in non-responders (P=ns). Doxazosin doses were 5.5+/-3 mg/d vs 5.8+/-3 and T/P ratio 0.70+/-0.13 vs 0.17+/-0.14, (P=.001). There were no variations in pl. t. cholesterol, triglycerides, glucose or uric acid. CONCLUSIONS: Treatment was safe and efficient, not increasing metabolic adverse effects. Doxazosin GITS is a safe agent which can reduce cardiovascular risk. In our patients, the good T/P ratio has been associated with a best diastolic BP control. This good profile should be taken into account for 24-hour BP control in hypertensive renal transplant patients.     

Unilateral parenchymatous kidney disease and hypertension: results of nephrectomy and medical treatment

In the present study 43 patients with unilateral parenchymatous kidney disease and hypertension were investigated. 20 patients were nephrectomized, 23 treated with antihypertensive drugs. Both therapeutic approaches showed an excellent and sustained blood pressure-(BP)-lowering effect. BP fell from 185 +/- 27/116 +/- 13 to 138 +/- 20/86 +/- 10 mm Hg in the operated and from 194 +/- 32/116 +/- 13 to 149 +/- 22/95 +/- 12 mm Hg in the medically treated patients after 2 and 6 weeks, respectively (p less than 0.001). BP was 142 +/- 16/89 +/- 11 and 136 +/- 16/90 +/- 10 mm Hg at the long-term follow-up in the 2 subgroups. In the operated group 70% (n = 14) were cured, 20% (n = 4) were improved and 10% (n = 2) unimproved. In the medically treated group 65% (n = 15) were normotensive, 26% (n = 6) improved and 9% (n = 2) treatment resistant. No significant correlation between postoperative BP reduction and lateralization of renin secretion (PRA-ratio greater than or equal to 1.5) was found. Although cured patients showed a higher mean PRA-ratio, 4 patients with a PRA-ratio less than 1.5 were cured (n = 2) or improved (n = 2) postoperatively. Our results document an excellent and sustained antihypertensive effect of both nephrectomy and medical treatment in patients with unilateral parenchymatous kidney disease and hypertension. They further limit the predictive value of renal venous renin determination in the preoperative workup.     

Effects of enalapril and eprosartan on the renal vascular nitric oxide system in human essential hypertension

BACKGROUND: Experimental data in humans on the contribution of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers to the nitric oxide system of the renal vasculature are inconsistent. Enalapril and eprosartan, alone and in combination, were used to determine their short-term effects on the renal nitric oxide system and renal hemodynamics of human subjects with essential hypertension. METHODS: Twenty male, white patients (27 +/- 1 years) with mild essential hypertension (143 +/- 11/95 +/- 6 mm Hg) were included in a double-blind, randomized, placebo-controlled, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or combination of both drugs (10 and 300 mg/day, respectively) each over a one week period followed by a two-week washout phase. After each study phase the glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined. Basal nitric oxide synthesis of the renal vasculature was assessed by the decrease in RPF after inhibition of nitric oxide synthase with NG-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). RESULTS: After one week of therapy, the combination therapy decreased casual blood pressure by 5 +/- 2/3 +/- 1 mm Hg versus placebo (P < 0.01). Neither enalapril alone (-2 +/- 2/1 +/- 2 mm Hg, NS vs. placebo) nor eprosartan alone (-1 +/- 1/0 +/- 2 mm Hg, NS vs. placebo) had a clear-cut significant effect on casual blood pressure. In the combination phase, RPF increased by 123 +/- 36 mL/min (P < 0.01). Neither enalapril alone (+59 +/- 46 mL/min, P = 0.21) nor eprosartan alone (+113 +/- 51 mL/min, P = 0.06) had a clear-cut significant effect on RPF. Changes of RPF induced by treatment correlated with the L-NMMA induced decrease in RPF in the combination (r = 0.70, P < 0.01) and eprosartan phase (r = 0.86, P < 0.001), but not in the enalapril phase (r = -0.44, P = 0.10). Renal vascular resistance was reduced by each active treatment with the most prominent reduction in the combination phase. GFR was unaffected by any treatment. CONCLUSIONS: In contrast to the effects of either substance alone, a combination of half the dose of eprosartan with half the dose of enalapril had a prominent effect on renal perfusion. The effects of eprosartan on RPF are mediated, at least in part, by an increased bioavailability of nitric oxide in the renal vasculature.     

Renal function and structure in albuminuric type 2 diabetic patients without retinopathy.

BACKGROUND: In type 2 diabetic patients without retinopathy the cause of albuminuria is heterogeneous and our knowledge of the relationship between kidney structure and function in these patients is limited. Therefore, a long-term study evaluating the structural-functional relationship in albuminuric type 2 diabetic patients without retinopathy was performed. METHODS: Mesangial volume of total glomerular volume (Vv (mes/glom)), fractional area of focal interstitial fibrosis and tubular atrophy of cortical area (FF) and percentage of sclerosed glomeruli (S/G) were measured on kidney biopsies from 49 type 2 diabetic patients without retinopathy. Glomerular filtration rate (GFR) was determined at least 3 times (median 8 (range 3-20)) in each patient. Patients were followed for 7.0 (1.1-17) years. Albuminuria and blood pressure were measured every 3-6 months. RESULTS: Biopsies revealed diabetic glomerulopathy (DG-group) in 69% of the patients (27 male/7 female) and normal glomerular structure (n=9) or glomerulonephritis (n=6) were found in 31% (13 male/2 female) (NDG-group). In the DG-group GFR decreased from 97+/-5 to 66+/-5 ml/min/1.73 m(2) (mean+/-SE) (P<0.001), with a rate of decline in GFR of 5.3+/-0.8 ml/min/year and in the NDG-group from 93+/-7 to 74+/-11 ml/min/1.73 m(2) (P<0.01), with a rate of decline in GFR of 3.2+/-0.9 ml/min/year, P=0.09 between groups. Mean arterial blood pressure decreased from 109+/-2 to 100+/-2 mm Hg (P<0.001) (DG-group) and remained unchanged in the NDG-group. An association between Vv (mes/glom) and rate of decline in GFR was revealed mainly in the NDG-group (DG-group; r=0.31, P=0.07 and NDG-group; r=0.74, P<0.01). Furthermore, the rate of decline in GFR seemed to be associated with FF in the NDG group (r=0.48, P=0.07). Percentage of S/G was not associated with the rate of decline in GFR. Vv (mes/glom) was associated with mean albuminuria during follow-up in the DG group; r=0.38, P<0.03 (NDG group; r=0.51, P=0.09). Albuminuria was an independent predictor of the rate of decline in GFR in both groups (DG-group; r=0.40, P<0.05 and NDG-group; r=0.61, P<0.01). CONCLUSIONS: Our study revealed a tendency to a faster rate of decline in GFR in the DG-group compared to the much smaller NDG-group, characterized by marked heterogeneity of the underlying kidney lesions and rate of GFR loss. A large mesangial volume fraction was associated with increased albuminuria and loss in GFR. Albuminuria acted as a progression promoter in both groups.