Converting-enzyme inhibitor versus calcium antagonist in cyclosporine-treated renal transplants. Regression of left ventricular hypertrophy by lisinopril after renal transplantation: role of ACE gene polymorphism. ACE inhibitors and persistent left ventricular hypertrophy after renal transplantation: a randomized clinical trial. Calcium channel blockade and preservation of renal graft function in cyclosporine-treated recipients: a prospective randomized placebo-controlled 2-year study. A randomized trial comparing losartan with amlodipine as initial therapy for hypertension in the early post-transplant period. Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial. Effect of angiotensin II receptor blocker on plasma levels of TGF-beta 1 and interstitial fibrosis in hypertensive kidney transplant patients. Hypertension after renal transplantation. Calcium channel or converting enzyme blockade? Influences of educational interventions and adverse news about calcium-channel blockers on first-line prescribing of antihypertensive drugs to elderly people in British Columbia.
The influence of antihypertensive treatment on the long-term evolution of arterial pressure and renal function was studied in a prospective controlled trial conducted in renal transplant recipients treated by cyclosporine. Within six months after transplantation, patients were randomly allocated to treatment by the angiotensin-converting enzyme inhibitor, lisinopril (ACEI, alone or associated with frusemide; N = 14), or the calcium antagonist, nifedipine (CA, alone or associated with atenolol; N = 11). Glomerular filtration rate (TcDTPA clearance) and effective renal plasma flow (hippuran clearance) as well as 24-hour urinary excretion of electrolytes and albumin were estimated at about 1 and 2.5 years of follow-up. Before initiation of antihypertensive therapy, the two groups were similar with regards to mean arterial pressure (119 +/- 2 vs. 120 +/- 4 mm Hg), effective renal plasma flow (285 +/- 26 vs. 248 +/- 33 ml/min/1.73 m2) and glomerular filtration rate (59 +/- 4 vs. 61 +/- 8 ml/min/1.73 m2 in the ACEI and CA groups, respectively). Both ACEI and CA treatments were associated with no change in renal function, a similar change in mean arterial pressure (ACEI -18 +/- 3; CA -13 +/- 5 mm Hg) and identical trough blood levels of cyclosporine. Urinary albumin excretion did not change significantly in any groups. Of interest, only in the ACEI group did filtration fraction significantly decrease (from 0.22 +/- 0.01% to 0.19 +/- 0.01% at final studies). These results indicate that in cyclosporine-treated transplant recipients, a satisfactory control of hypertension is obtained by chronic ACEI, which is as effective on arterial pressure as a combination of CA and atenolol.(ABSTRACT TRUNCATED AT 250 WORDS) Cardiac complications are the main cause of death in renal transplantation (RT), and left ventricular hypertrophy (LVH) may play an important role in these patients. The unfavorable genotype of the angiotensin-converting enzyme (ACE) gene has been associated with cardiovascular disease, including LVH. ACE inhibitors (ACEIs) reduce LVH, but little is known about the effects of ACEIs on LVH in RT patients with different insertion/deletion (I/D) genotypes of the ACE gene.
                We prospectively studied 57 stable nondiabetic RT patients with hypertension and echocardiographic LVH as well as a functional graft for 69.5 +/- 5.6 months. Patients randomly received either lisinopril 10 mg/day (group A, N = 29; 5 were excluded due to reversible acute renal failure) or placebo (group B, N = 28) for 12 months. Echocardiography (M-mode, 2-B, and color flow Doppler) was performed at baseline and 6 and 12 months later by the same examiner without previous knowledge of the genetic typing. The ACE genotype (I or D alleles) was ascertained by polymerase chain reaction (PCR; group A, DD = 10 and ID/II = 14; group B, DD = 15 and ID/II = 13).
                All patients maintained a good renal function (serum creatinine <2.5 mg/dL) during the follow-up and both groups received a similar proportion of antihypertensive drugs (beta-blockers 83 vs. 79%; Ca antagonists 66 vs. 68%; alpha1-adrenoreceptor antagonists 50 vs. 67%) during the study. As expected, mean arterial blood pressure and hemoglobin levels showed a higher percentage reduction in group A versus group B (-4 +/- 2.8 vs. 2.1 +/- 2.6%, P = 0.07, and -11.5 +/- 1.5 vs. -0.5 +/- 2.3%, P < 0.01, respectively). Group A patients showed a significantly higher decrement in LV mass index (LVMI) than group B at the end of follow-up, after adjusting for age, baseline LVMI, time after grafting and changes in systolic blood pressure, renal function, and hemoglobin levels (group A, -9.5 +/- 3.5% vs. group B, 3 +/- 3.2%, P < 0.05). As a result, 46% of group A and only 7% of group B patients showed a reduction of LVMI >/=15% (P < 0.01). The beneficial effect of lisinopril on LVMI reduction was more evident in DD patients (placebo DD, 8.4 +/- 4.1% vs. lisinopril DD, -7.2 +/- 5.3, P < 0.05), and a trend was observed in patients with other genotypes (placebo ID/II, 2.8 +/- 5.4% vs. lisinopril ID/II, -11.4 +/- 5%, P = 0.33).
                Lisinopril decreases LVM in renal transplant patients with hypertension and LVH, and the ACE gene polymorphism may predict the beneficial effect of this therapy. This finding may be important in targeting prophylactic interventions in this population. Interventional studies of left ventricular hypertrophy (LVH) in renal transplant recipients are scarce and to date evaluated only patients immediately after renal transplantation.
                Randomized controlled trial that assessed the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in regressing persistent LVH after successful transplantation.
                70 renal transplant recipients (47 men; age, 30 to 68 years) without diabetes previously randomly assigned to either cyclosporine or tacrolimus therapy, with LVH persisting 3 to 6 months after transplantation.
                Subjects were randomly assigned to either lisinopril (ACE-inhibitor group; 36 patients) or no therapy (control group; 34 subjects).
                Main outcome was change in left ventricular mass index (LVMi) at month 18.
                A consistent decrease in both systolic (SBP) and diastolic blood pressure (DBP) was observed in both groups (between-group differences, -1.7 +/- 3.3 mm Hg; 95% confidence interval [CI], -4.8 to 8.2; P = 0.6 for SBP; 0.3 +/- 2.2 mm Hg; 95% CI, -4.8 to 4.1; P = 0.9 for DBP), whereas LVMi regressed more in the ACE-inhibitor group (between-group difference, 10.1 +/- 16.3 g/m(2.7); 95% CI, 4.2 to 16.1; P < 0.01). A significant interaction of ACE inhibitors with cyclosporine in affecting LVMi change was shown by means of post hoc multiple regression analysis (P < 0.01; differences between cyclosporine and tacrolimus group, 13.3 +/- 3.9 g/m(2.7); 95% CI, 5.3 to 21.2; P < 0.01 in the ACE-inhibitor group; 3.7 +/- 4.2 g/m(2.7); 95% CI, -4.7 to 12.2; P = 0.4 in the control group).
                Single-center study with small sample size. Interaction of ACE inhibitors with cyclosporine treatment emerged from post hoc analysis.
                A prolonged course of ACE-inhibitor therapy is effective in regressing the persistent LVH of renal transplant recipients by mechanisms independent of effects on BP. This regression seems to be at least in part the effect of an interaction between ACE inhibitors and cyclosporine. Studies have provided conflicting results as to the protective role of calcium channel blockers (CCB) in cyclosporine-treated patients with regard to blood pressure control and preservation of renal graft function. Lacidipine is a dihydropyridine CCB that possesses antioxidative, anti-atherosclerotic, and anti-adhesion properties and was shown to prevent cyclosporine-induced nephrotoxicity in a rat model.
                We conducted a multicenter prospective, randomized, placebo-controlled study in 131 de novo recipients of a cadaveric renal allograft on cyclosporine therapy. The aim of this 2-year study was to assess the effects of lacidipine on graft function (plasma iohexol clearance), renal plasma flow, anastomotic arterial blood flow, deterioration of renal function, blood pressure, acute rejection, and hospitalization rate.
                A total of 118 recipients were available for intention-to-treat analysis on efficacy (lacidipine: n=59; placebo: n=59). Graft function assessed by serum creatinine concentration and glomerular filtration rate measured as plasma iohexol clearance, was persistently better in lacidipine-treated patients from 1 year onwards (respectively, P<0.01 and P<0.05). Renal plasma flow and anastomotic blood flow were not significantly higher in lacidipine-treated patients. Three patients on lacidipine therapy and four on placebo experienced treatment failure defined as an increase in serum creatinine from baseline of more than 60% (log-rank test: P=0.57). Study groups did not differ in acute rejection rate, trough blood cyclosporine concentrations, blood pressure, number of antihypertensive drugs, hospitalization rate, and adverse event rate.
                The use of calcium channel blockers in cyclosporine-treated renal recipients results in a significantly better allograft function at 2 years and this effect is independent of blood pressure lowering. Blockade of the renin-angiotensin-aldosterone system in the early post-transplant period remains controversial. Angiotensin II-receptor blockers (ARB) have many benefits to the patient with chronic kidney disease and these benefits may also apply to the renal transplant recipient (RTR). Additionally, there are theoretical benefits of ARB use in RTR. This study was designed to investigate the safety of early ARB use after renal transplantation.
                RTR with serum creatinine levels <3.0 mg/dl were randomized to receive either ARB (n = 29) or calcium-channel blocker (CCB; n = 27) as initial therapy for post-transplant hypertension. Differences in potassium, creatinine and haemoglobin concentrations were compared at baseline, 3, 6 and 12 months after transplantation.
                Withdrawal from the assigned treatment was high: 12 in the ARB group (due to hyperkalaemia in six) and 17 in the CCB group (due to intractable oedema in seven and post-transplant erythrocytosis requiring an angiotensin-converting enzyme inhibitor in seven). There were no differences in blood pressure, haemoglobin or creatinine concentration at any time-points. Mean potassium concentrations were only slightly higher in the ARB vs CCB group (range: 4.2-4.3 vs 3.7-3.8 mEq/l, respectively, but clinically significant) and the number of patients with potassium values >6.0 mEq/l was higher in ARB (n = 7) vs CCB (n = 1).
                These data suggest that hyperkalaemia is the major complication that occurs with the use of ARB in the immediate post-transplant period. ARB use does not affect renal function or complicate the post-transplant management of RTR. Other than reducing the incidence of post-transplant erythrocytosis, ARB use does not cause an excess incidence of anaemia. Strategies to reduce the risk of hyperkalaemia may allow increased use of ARB immediately after kidney transplantation. Most hypertensive renal transplant recipients require two or more antihypertensive medications to achieve blood pressure control. However, which medications must be combined is still a matter of debate.
                A prospective randomized open-label blinded evaluation trial comparing the six-month effects of the amlodipine-enalapril combination (n = 32) vs. enalapril alone (n = 33) and vs. amlodipine alone (n = 34) on arterial pressure, renal function, albuminuria and tolerability.
                At six months, diastolic arterial pressure was more adequately controlled (i.e., <90 mmHg) in the combination group than in the amlodipine and enalapril groups (100% vs. 82.4% and 84.8%, respectively, p = 0.038). The same trend was observed for systolic arterial pressure (65.6% vs. 58.8% and 51.5%, NS). The six-month change in albuminuria was similar in the combination group and in the enalapril group (-64.7% vs. -59.5%); however, patients in the combination group exhibited a greater reduction in albuminuria than in the amlodipine group (-64.7% vs. -29.0%, p = 0.002). As compared with baseline values, serum creatinine and potassium remained unchanged in the combination group, whereas they increased by 9 +/- 12 micromol/L (p = 0.01) and by 0.2 +/- 0.4 mmol/L (p < 0.01), respectively, in the enalapril group. The cyclosporine trough levels remained unchanged in the combination group, but increased in the amlodipine group.
                Angiotensin-converting enzyme inhibitor (ACEI)-calcium-channel blocker (CCB) combination controls arterial pressure more adequately than ACEI alone or CCB alone, reduces albuminuria and may prevent the ACEI-induced initial rise in serum creatinine. Transforming growth factor-beta1 (TGF-beta 1) is involved in the pathogenesis of chronic allograft nephropathy after kidney transplantation. The aim of the study was to evaluate the effect of the angiotensin receptor blocker losartan on TGF-beta 1 plasma levels and proteinuria in hypertensive transplant recipients.
                A total of 162 transplant recipients were included in the study. The patients were randomized into 3 groups: group 1 received losartan; group II received an angiotensin-converting enzyme inhibitor (captopril), and group III received a calcium channel blocker (amlodipine). All the parameters were recorded at the time of therapy initiation and at 1, 4 and 12 weeks and 12 months thereafter. Graft biopsy before the start and at the end of the study was done to evaluate histopathological progression.
                Blood pressure was controlled in the 3 groups; however, the need for other antihypertensive agents was significant in groups I and II. Treatment with losartan significantly decreased the plasma level of TGF-beta1, 24-hour urinary protein and serum uric acid (p < 0.05). No significant changes were seen in the hemoglobin or serum potassium levels. The rate of histopathological progression was significantly lower in the losartan group. No patient was discharged from the study due to side effects.
                After transplantation all drugs were able to control blood pressure with good safety and tolerability. The study demonstrates that ARB significantly decreases the plasma levels of TGF-beta1, proteinuria and uric acid. These results could play an important and decisive role in the treatment and prevention of chronic allograft nephropathy.
                Copyright 2003 S. Karger AG, Basel We compared the effects of 4 weeks of calcium channel blockade (amlodipine) or converting enzyme inhibition (lisinopril) on blood pressure and renal hemodynamics in a double-blind crossover trial in a group of 20 hypertensive cyclosporine-treated renal transplant patients. Amlodipine (10 mg) was more effective than the same dose of lisinopril in controlling hypertension (mean 24-hour arterial pressure, 111 +/- 9 and 115 +/- 9 mm Hg, respectively; P < .05). Blood pressure during both treatments was lower than during placebo (124 +/- 12 mm Hg, P < .05). Compared with placebo, amlodipine treatment was associated with a significant increase in glomerular filtration rate (10 +/- 20%, P < .05) and effective renal plasma flow (27 +/- 20%, P < .01) and a decrease in renal vascular resistance (23 +/- 18%, P < .01). Renal hemodynamics did not change during lisinopril. Neither drug had an effect on proteinuria. The data indicate that amlodipine is more effective than lisinopril in controlling hypertension in cyclosporine-treated patients and that treatment with amlodipine but not with lisinopril is accompanied by an increase in glomerular filtration rate and effective renal plasma flow and a decrease in renal vascular resistance. The data suggest that the renin-angiotensin system does not play a main role in determining cyclosporine-associated changes in renal hemodynamics and has a limited role in determining cyclosporine-associated hypertension. The way in which dissemination of evidence changes medical practice needs to be better understood. Controversy about calcium-channel blockers (CCB) in the past 3 years has provided a natural experiment, enabling assessment of the impact of media stories, a national warning letter, a teleconference, small group workshops, and newsletters on first-line prescribing of antihypertensive drugs.
                We included all physicians (4403) in British Columbia who prescribed a thiazide diuretic, beta-blocker, inhibitor of angiotensin-converting enzyme (ACE), or CCB as the first antihypertensive agent for 36,507 residents aged 66 years and over, with no previous or concurrent sign of underlying cardiovascular disease. We used a database covering all prescriptions to elderly people to measure the change in proportion of newly treated patients who received each class of drug as first-line therapy. We used a matched cohort design for assessment of the teleconference and workshops, a randomised community design for the newsletters, and time-series analysis for the media impacts.
                The proportion of patients who received a CCB as first-line therapy declined gradually from 22% in early 1994 to 15% in late 1996. This proportion was not affected by two waves of adverse news about CCBs in 1995, but fell by 5% for 5 months and by 3% for 1 month after two waves in 1996. The proportion of patients who received either a CCB or an ACE inhibitor as first-line therapy, contrary to guidelines, was still 42% overall in 1996. The workshops and newsletters were followed by shifts from first-line CCB to first-line thiazide prescribing.
                Changes in prescribing practices occur gradually with the accumulation of small impacts from educational interventions and lay media attention.
These data suggest that CCB may be preferred as first line agents for hypertensive kidney transplant recipients. ACEi have some detrimental effects in kidney transplant recipients. More high quality studies reporting patient centred outcomes are required.