Regression of asymptomatic cardiomyopathy and clinical outcome of renal transplant recipients: a long-term prospective cohort study.

BACKGROUND: Asymptomatic left ventricular hypertrophy (LVH) is highly prevalent and associated with an adverse outcome in renal transplant recipients (RTRs). Nonetheless, there are currently no available studies analyzing the effect of LVH regression on solid clinical endpoints in these patients. METHODS: This study is the prospective observational extension of two randomized controlled trials aimed at assessing the effect of active intervention on post-transplant LVH in RTRs. We evaluated the incidence of a composite of death and any cardiovascular (CV) or renal event in 60 RTRs in whom LVH regression was observed and in 40 whose LVH remained unchanged or worsened. RESULTS: During an 8.4 ± 3.5-year follow-up, 8 deaths, 18 CV events and 6 renal events occurred in the entire cohort. Multivariable analysis showed that age [hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.03-1.12 each 1 year, P = 0.002] and LVH regression (HR 0.42, 95% CI 0.22-0.87, P = 0.019) were significant predictors of the composite endpoint. Kaplan-Meier estimates showed better survival rates in patients in whom actual LVH regression was achieved (P < 0.001, log-rank test). Age (HR 1.09, 95% CI 1.03-1.15 each 1 year, P = 0.004), better graft function (HR 0.95, 95% CI 0.91-0.99 each 1 mL/min/1.73 m(2) increase in estimated glomerular filtration rate, P = 0.03) and LVH regression (HR 0.41, 95% CI 0.22-0.79, P = 0.01) were significant predictors of the CV endpoint. Patients with a left ventricular mass index decrease also showed better cardiac event-free survival (P = 0.0022, log-rank test). CONCLUSIONS: This is the first study to demonstrate that LVH regression, regardless of the therapeutic strategy adopted to achieve it, portends better long-term clinical outcome in RTRs.

Is left ventricular hypertrophy a powerful predictor of progression to dialysis in chronic kidney disease?

BACKGROUND: The role of cardiovascular factors in predicting renal outcome has not been extensively elucidated. Herein, we report a prospective evaluation of the impact of left ventricular hypertrophy (LVH) on outcome in non-diabetic patients with chronic kidney disease (CKD). METHODS: We studied 144 patients (99 men; age 62±14 years) with stage 3-4 CKD, with baseline assessment of left ventricular mass index (LVMi) by echocardiography, estimated glomerular filtration rate (eGFR) by MDRD equation, 24-h blood pressure profile and 24-h proteinuria. Combined end point was progression to ESRD requiring dialysis, or death within 5 years. RESULTS: Forty-nine patients (34%) progressed to dialysis, 24 (17%) died, 57 (39%) were dialysis-free after 5 years and 14 were lost to follow-up. Multivariate Cox proportional hazards analysis showed that increased LVMi (HR 1.28, 95% CI 1.17-1.40 for each 10-g/m2 increase, P<0.0001) and reduced eGFR (5% risk increase for each 1-mL/min reduction, P=0.027) were the significant predictors of the combined end point in stage 3 CKD patients, whereas LVMi proved to be the only significant predictor of the combined end point in patients with stage 4 CKD (HR 1.19, 95% CI 1.09-1.31, P<0.0001). The same analysis showed that LVMi was the only significant predictor of progression to dialysis in stage 3 CKD patients (HR 1.42, 95% CI 1.23-1.64 for each 10-g/m2 increase, P<0.0001), while a 20% increase in the risk of progression to ESRD was observed for each 10-g/m2 increase in LVMi (P<0.0001), and a 10% increase for each 1-mL/min reduction in eGFR (P=0.046) in patients with stage 4 CKD. When evaluating the predictive role of LVMi on outcome using AUC-ROC curves, the overall performance of the model including LVMi (AUC 0.877, 95% CI 0.8-0.954) was superior to the model including eGFR (AUC 0.737, 95% CI 0.656-0.817) for the end point of progression to dialysis (P=0.026, Hanley test). CONCLUSIONS: LVH proved to be the strongest predictor of the risk of progression to dialysis in non-diabetic CKD, especially among patients with less advanced renal dysfunction. Regardless of whether it is a simple marker or a pathogenetic factor, LVH encompasses all factors possibly affecting renal and general outcome in CKD patients.

Effect of sirolimus on left ventricular hypertrophy in kidney transplant recipients: a 1-year nonrandomized controlled trial.

BACKGROUND: Left ventricular hypertrophy (LVH) after renal transplantation may be affected by immunosuppressive therapy. STUDY DESIGN: Nonrandomized controlled trial evaluating the effect of sirolimus (SRL) on LVH of renal transplant recipients (RTRs). SETTING & PARTICIPANTS: 13 RTRs without diabetes who had received a single-kidney transplant from a deceased donor with chronic allograft dysfunction and biopsy-proven allograft nephropathy who were converted from calcineurin-inhibitor (CNI) to SRL treatment; 26 controls matched for age and year of transplantation who were not converted from CNI to SRL treatment. INTERVENTION: Conversion from CNI to SRL therapy. OUTCOMES & MEASUREMENTS: Left ventricular mass determination by using echocardiography at baseline and again 1 year later. Blood pressure (BP), hemoglobin level, serum creatinine level, uric acid level, lipid levels, trough levels of immunosuppressive drugs, and daily proteinuria were assessed at least twice monthly. Conventional antihypertensive therapy was used to achieve BP of 130/80 mm Hg or less. RESULTS: The study population included 26 men and 13 women (age, 25 to 66 years). Changes in BP were similar in the 2 groups (between-group difference, -4 +/- 5 mm Hg; P = 0.5 for systolic BP; -2 +/- 3; P = 0.6 for diastolic BP), whereas left ventricular mass significantly decreased in the SRL group alone (between-group difference, 8.6 +/- 2.4 g/m(2.7); P < 0.001) because of a decrease in both the interventricular septum and left ventricular posterior wall. LVH regressed in 12 of 13 patients on SRL therapy and 10 of 26 controls (P = 0.002). LIMITATIONS: Nonrandomized design. Single-center study with small sample size. CONCLUSIONS: Conversion from CNI to SRL therapy may regress LVH in RTRs regardless of BP changes, mainly by decreasing left ventricular wall thickness, thus suggesting nonhemodynamic-effect mechanisms of SRL on left ventricular mass.

ACE inhibitors and persistent left ventricular hypertrophy after renal transplantation: a randomized clinical trial.

BACKGROUND: Interventional studies of left ventricular hypertrophy (LVH) in renal transplant recipients are scarce and to date evaluated only patients immediately after renal transplantation. STUDY DESIGN: Randomized controlled trial that assessed the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in regressing persistent LVH after successful transplantation. SETTING & PARTICIPANTS: 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. INTERVENTION: Subjects were randomly assigned to either lisinopril (ACE-inhibitor group; 36 patients) or no therapy (control group; 34 subjects). OUTCOMES: Main outcome was change in left ventricular mass index (LVMi) at month 18. RESULTS: 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). LIMITATIONS: Single-center study with small sample size. Interaction of ACE inhibitors with cyclosporine treatment emerged from post hoc analysis. CONCLUSION: 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.

Associations of Left Ventricular Hypertrophy and Geometry with Adverse Outcomes in Patients with CKD and Hypertension.

BACKGROUND AND OBJECTIVES: Left ventricular hypertrophy (LVH) and abnormal left ventricular (LV) geometry predict adverse outcomes in the general and hypertensive populations, but findings in CKD are still inconclusive. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We enrolled 445 patients with hypertension and CKD stages 2-5 in two academic nephrology clinics in 1999-2003 who underwent both echocardiography and ambulatory BP monitoring. LVH (LV mass >100 g/m(2) [women] and >131 g/m(2) [men]) and relative wall thickness (RWT) were used to define LV geometry: no LVH and RWT≤0.45 (normal), no LVH and RWT>0.45 (remodeling), LVH and RWT≤0.45 (eccentric), and LVH and RWT>0.45 (concentric). We evaluated the prognostic role of LVH and LV geometry on cardiovascular (CV; composite of fatal and nonfatal events) and renal outcomes (composite of ESRD and all-cause death). RESULTS: Age was 64.1±13.8 years old; 19% had diabetes, and 22% had CV disease. eGFR was 39.9±20.2 ml/min per 1.73 m(2). LVH was detected in 249 patients (56.0%); of these, 125 had concentric LVH, and 124 had eccentric pattern, whereas 71 patients had concentric remodeling. Age, women, anemia, and nocturnal hypertension were independently associated with both concentric and eccentric LVH, whereas diabetes and history of CV disease associated with eccentric LVH only, and CKD stages 4 and 5 associated with concentric LVH only. During follow-up (median, 5.9 years; range, 0.04-15.3), 188 renal deaths (112 ESRD) and 103 CV events (61 fatal) occurred. Using multivariable Cox analysis, concentric and eccentric LVH was associated with higher risk of CV outcomes (hazard ratio [HR], 2.59; 95% confidence interval [95% CI], 1.39 to 4.84 and HR, 2.79; 95% CI, 1.47 to 5.26, respectively). Similarly, greater risk of renal end point was detected in concentric (HR, 2.33; 95% CI, 1.44 to 3.80) and eccentric (HR, 2.30; 95% CI, 1.42 to 3.74) LVH. Sensitivity analysis using LVH and RWT separately showed that LVH but not RWT was associated with higher cardiorenal risk. CONCLUSIONS: In patients with CKD, LVH is a strong predictor of the risk of poor CV and renal outcomes independent from LV geometry.

Left ventricular hypertrophy in nondiabetic predialysis CKD.

BACKGROUND: Although left ventricular hypertrophy (LVH) is a strong predictor of mortality in patients with end-stage renal disease, few studies are available before the start of dialysis treatment. The purpose of this study is to evaluate the prevalence and clinical correlates of LVH in nondiabetic patients with chronic kidney disease (CKD) not yet undergoing renal replacement therapy. METHODS: We investigated 244 nondiabetic patients with CKD; 57 patients (42 men; age, 20 to 78 years) had stages 1 to 2 CKD and 187 patients (122 men; age, 18 to 77 years) had stages 3 to 5 CKD. Fifty-two normotensive healthy subjects served as controls. Each patient had blood pressure (BP) measured by means of 24-hour ambulatory BP monitoring and left ventricular mass index (LVMi) assessed by means of M-mode echocardiography. Creatinine clearance was estimated by means of the Cockcroft-Gault formula, and hemoglobin, serum lipid, and intact parathyroid hormone concentrations and daily urinary protein excretion were assessed by using routine methods. RESULTS: In the overall group, prevalences of arterial hypertension and LVH were 66% and 74%, respectively. LVMi was 160 +/- 50 g/m2 body surface area and associated directly with age (P = 0.0013), duration of arterial hypertension (P = 0.0075), 24-hour systolic BP (P = 0.0113), pulse pressure (P = 0.0003), daytime (P = 0.0206) and nighttime systolic BP (P = 0.0059), and urinary protein excretion (P < 0.05) and inversely with creatinine clearance (P = 0.0103) and hemoglobin level (P = 0.0276). In patients with CKD stages 1 to 2 (LVH prevalence, 51%), age, duration of arterial hypertension, pulse pressure, and urinary protein excretion were significant predictors of LVMi (P < 0.00002) by using stepwise regression analysis, whereas in those with CKD stages 3 to 5 (LVH prevalence, 78%), pulse pressure emerged as the sole predictor of LVMi (P = 0.0011). CONCLUSION: The prevalence of LVH in nondiabetic predialysis patients with CKD is greater than previously reported, and there is evidence that LVH already is present in the early stages of renal disease. Arterial hypertension is associated with LVH in patients with CKD, and the strong relationship between elevated pulse pressure and LVH in those with more advanced CKD suggests that increased arterial stiffness might have a role for LVH well before the start of dialysis therapy.

Left ventricular geometry and adverse cardiovascular events in chronic hemodialysis patients on prolonged therapy with ACE inhibitors.

BACKGROUND: In addition to the absolute magnitude of left ventricular (LV) mass (LVM), the geometric pattern of the left ventricle might help explain the different tendency toward LV hypertrophy (LVH) regression seen under effective therapy in chronic hemodialysis patients. METHODS: Forty-five hemodialyzed uremic subjects, 17 patients with concentric LVH and 28 patients with eccentric LVH, were followed up with yearly echocardiography over 3 years while on monotherapy with angiotensin-converting enzyme (ACE) inhibitors. Predialysis blood pressure (BP) and percentage of interdialytic weight gain recorded during the month the echocardiographic study was performed were retrieved and averaged. Any adverse cardiovascular events occurring during the 3-year follow-up period also were recorded. RESULTS: Significant regression of LVH (P = 0.0028) was observed in the group as a whole during the 3 years on ACE-inhibitor therapy, mainly accounted for by a reduction in pulse pressure (PP; r = 0.45; P = 0.0017). After subgrouping patients according to LV geometry, an LVM reduction was observed only in the 17 patients with concentric LVH (P = 0.0003), whereas no difference was detected in subjects with eccentric LVH despite the same degree of BP reduction and hemoglobin level and Kt/V increases in both groups. Moreover, a greater incidence of cardiovascular events was observed in patients with eccentric LVH than in those with concentric LVH during the 3-year follow-up period. CONCLUSION: The most important finding of this study is that eccentric LVH seems to be less responsive to ACE-inhibitor treatment and is associated with a greater incidence of adverse cardiovascular events compared with concentric LVH. Furthermore, the decrease in PP appears to be the main predictor of LVH regression in chronic hemodialysis patients on ACE-inhibitor therapy.

Effects of ACE inhibitors on long-term outcome of renal transplant recipients: a randomized controlled trial.

BACKGROUND: Available data on the role of renin-angiotensin system blockade in renal transplantation are inconclusive. Herein, we report the long-term results of a randomized controlled trial planned to evaluate the impact of angiotensin-converting enzyme inhibitors (ACE-i) on the cardiovascular outcome of renal transplant recipients (RTRs) receiving calcineurin inhibitors, steroids, and mycophenolate mofetil. METHODS: Thirty-six RTRs were allocated to receive ACE-i and 34 served as controls. Survival free of a composite endpoint consisting of death, major cardiovascular events, renal graft loss or creatinine doubling, and survival free of each single endpoint were analyzed in both groups according to a modified intention-to-treat analysis. RESULTS: During a 10-year follow-up, three patients died (one in the ACE-i group and two controls) and three lost their graft (two receiving ACE-i and one control). Three major cardiovascular events were observed in the ACE-i group and 12 among controls (P=0.008). At the end of observation, a significant increase in urinary protein excretion rate was only observed in controls (P=0.017).Compared with controls, RTRs administered ACE-i had significantly better survival free of the combined endpoint (P=0.0102, log-rank test) and free of major cardiovascular events (P=0.0027) without significant differences in renal outcome. By Cox regression analysis, ACE-i therapy resulted in the most powerful predictor of survival free of composite endpoint (hazard ratio, 0.165; 95% confidence interval, 0.053-0.512; P=0.0018) and survival free of major cardiovascular events (hazard ratio, 0.209; 95% confidence interval, 0.068-0.636; P=0.0059). CONCLUSIONS: Prolonged therapy with ACE-i was associated with better general and cardiovascular outcome of RTRs without detrimental effects on renal graft function.

Effect of everolimus on left ventricular hypertrophy of de novo kidney transplant recipients: a 1 year, randomized, controlled trial.

BACKGROUND: Although conversion from calcineurin inhibitors to mammalian target of rapamycin inhibitors proved to be effective in regressing left ventricular hypertrophy (LVH) in renal transplant recipients (RTRs) with chronic allograft dysfunction, there are currently no reports of randomized trials on this issue involving de novo RTRs administered everolimus (EVL). METHODS: This randomized, open-label, controlled trial evaluated the effect of EVL on the left ventricular mass index (LVMi) of 30 nondiabetic RTRs (21 men; age 28-65 years). Ten were allocated to EVL plus reduced-exposure cyclosporine A (CsA), and 20 to standard dose CsA. LVMi was assessed by echocardiography both at baseline and 1 year later. Blood pressure (BP), hemoglobin, serum creatinine, lipids, trough levels of immunosuppressive drugs, and daily proteinuria were also evaluated twice monthly. Antihypertensive therapy that did not include renin-angiotensin system blockers was administered to achieve BP less than or equal to 130/80 mm Hg. RESULTS: Changes in BP were similar in the two groups (between group difference 1.2 ± 5.7 mm Hg, P=0.84 for systolic, and -1.5 ± 3.7, P=0.69, for diastolic BP), whereas LVMi significantly decreased in the EVL group alone (between group difference 9.2 ± 3.1 g/m(2.7), P=0.005), due to a reduction in both the interventricular septum and the left ventricular posterior wall thickness. EVL therapy together with baseline LVMi were the only significant predictors of LVH regression according to a multivariate model that explained 49% of the total LVMi variance (P=0.0015). CONCLUSIONS: An immunosuppressive regimen consisting of EVL plus reduced exposure CsA proved to be effective in regressing LVH in RTRs regardless of BP, mainly by reducing left ventricular wall thickness.

Effect of early conversion from CNI to sirolimus on outcomes in kidney transplant recipients with allograft dysfunction.

BACKGROUND: Studies evaluating the effect of conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) in renal transplant recipients (RTRs) have shown conflicting results, and only few short-term uncontrolled studies are available in patients with chronic allograft dysfunction. This is the first controlled study to evaluate long-term survival and both renal and cardiac outcomes in nondiabetic RTRs with allograft dysfunction who were converted from CNI to SRL. METHODS: We evaluated 13 RTRs with biopsy-proven allograft dysfunction who underwent early conversion from CNI to SRL, and 26 controls with normal graft function taking CNI. All continued both steroids and mycophenolate mofetil. SRL was titrated to trough levels of 4-8 ng/mL. Outcome measures included 3-year event-free survival, acute rejection rate and 3-year changes in Modification of Diet in Renal Disease (MDRD) Study equation estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMi) as assessed by echocardiography. RESULTS: Compared with controls, patients on SRL showed better 3-year event-free survival (p=0.024; log-rank test), significant eGFR increase (+5.5 ± 8.9 vs, -6.4 ± 14.7 ml/min per 1.73 m2, p=0.011), LVMi regression (-9.0 ± 7.6 g/m(2.7) vs. 1.0 ± 10.1 g/m(2.7), p=0.0038) and similar acute rejection rate. Three-year change in eGFR was the only significant predictor of event-free survival by Cox regression analysis (hazard ratio = 0.96; 95% confidence interval, 0.93-0.99; p=0.017), whereas SRL was the strongest predictor of both eGFR increase (beta coefficient, 0.342; p=0.01) and LVM reduction (beta coefficient, -0.609; p=0.0001) by multivariate regression analysis. CONCLUSIONS: Conversion from CNI to SRL in RTRs with allograft dysfunction proved to be associated with better survival, improved renal graft function and regression of cardiac hypertrophy.

The worsening of left ventricular hypertrophy is the strongest predictor of sudden cardiac death in haemodialysis patients: a 10 year survey.

BACKGROUND: Although the incidence of sudden cardiac death (SCD) is high among haemodialysis (HD) patients, there are few papers available on this topic. The aim of this study on a single-centre HD population observed over a 10 year period was to identify patient- and HD-related specific factors that might be associated with a higher risk of SCD. METHODS: The study included 123 patients (76 men; age 29-79 years) undergoing renal replacement therapy at our dialysis unit for at least 6 months. For each patient, routine laboratory tests were performed monthly, blood pressure was measured both at the start and the end of each dialysis session, haemoglobin and pre-dialysis serum K(+) were determined weekly, serum iPTH was assessed thrice yearly, and an echocardiographic study was performed annually to determine the left ventricular mass index (LVMi). The prevalence of cardiovascular (CV) co-morbidities, and the incidence of new events were also recorded. RESULTS: During the 10 years, 85 patients died-16 from SCD, 30 from cardiac causes (CC) other than SCD, and 39 from other causes (OC); 38 patients were still alive (AL) at the end of the observation period. Comparative analysis of SCD, CC, OC and AL, reveals that the male prevalence (13/3) was higher in SCD than in AL, while AL were younger than the deceased patients regardless of the cause of death (P<0.0001; ANOVA), the duration of arterial hypertension was higher in SCD (129+/-104 months; P = 0.0005; ANOVA), despite similar antihypertensive therapies, and the difference between LVMi at end-point and at inception (deltaLVMi) was significantly higher in SCD [+56+/-38 g/m(2) body surface area] compared with OC (-5+/-35), AL (-17+/-25) and even CC (7+/-30) (P<0.0001; ANOVA); finally, the prevalence of patients with ischaemic heart disease (IHD) was higher in the SCD group (11/5; P<0.0001, chi(2)). Univariate Cox regression analysis demonstrated that the factors increasing the risk of SCD were IHD (P = 0.002), the worsening of left ventricular hypertrophy (LVH) (P<0.0001), and the presence of long-lasting arterial hypertension (P = 0.001). An increase in LVH was the sole risk factor for SCD when comparing SCD with CC patients (P = 0.003). By multivariate Cox regression analysis deltaLVMi was identified as the strongest predictor of SCD (P<0.0001). CONCLUSION: While confirming the role of common CV risk factors for SCD in dialysis patients such as IHD and arterial hypertension, this study is the first to demonstrate that the worsening of LVH is the strongest predictor of sudden death.