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Although hyperkalemia (HK) is often associated with adverse clinical outcomes in renal patients, few studies are available in the setting of kidney transplantation. Therefore, we evaluated prevalence and clinical correlates of HK in stable kidney transplant recipients (KTRs) on standard of care immunosuppressive therapy. We studied 160 stable KTRs (post-transplant vintage 46.6 ± 16.6 months), most of whom (96.2%) on calcineurin inhibitor (CNI)-based immunosuppressive therapy. HK was defined as plasma potassium levels above 5 mEq/L, confirmed in two consecutive samples. Office blood pressure was measured, and renal graft function was expressed by estimated glomerular filtration rate (eGFR), calculated according to the CKD-EPI formula. HK prevalence was 8.8%, and plasma K above 5.5 mEq/L was found in 2.5% of all KTRs. In the univariate logistic regression analysis HK was significantly associated with serum urea concentration (OR 1.03, 95% CI 1.01–1.05 for each 1 mg/dL increase), tCO2 (OR 0.77, 95% CI 0.66–0.90 for each 1 mmol/L increase), the presence of arterial hypertension (OR 4.01, 95% CI 1.3–12.64), the use of RAAS inhibitors (OR 5.26, 95% CI 1.6–17.7), and eGFR less than 30 ml/min/1.73 m2 (OR 7.51, 95% CI 2.37–23.77). By multivariable backward stepwise regression analysis, the presence of metabolic acidosis (OR 0.83, 95% CI 0.69–0.99, P = 0.04), arterial hypertension (OR 4.65 95% CI 1.01–17.46 P = 0.03), and to be administered RAAS inhibitors (OR 6.11, 95% CI 1.03–25.96 P = 0.03) remained significantly associated with HK. We conclude that in stable KTRs the prevalence of HK is about 9%, slightly lower than previously reported. Moreover, it is not associated with eGFR, but with metabolic acidosis, arterial hypertension, and the use of RAAS inhibitors.

Tacrolimus is a cornerstone in the immunosuppressive therapy of kidney transplantation. The once-daily formulation of tacrolimus has been shown to improve adherence of patients without affecting short-term efficacy. However, long-term proof of once-daily tacrolimus efficacy and safety is still lacking. From January 2009 to November 2013, 170 clinically stable kidney transplant patients were offered to change from the ongoing twice-daily tacrolimus (TDT) formulation to a once-daily tacrolimus (ODT) regimen. Kidney transplant recipients agreeing to the change to be treated with an ODT regimen (n = 105, estimated glomerular filtration rate [eGFR] 57.1 ± 1.6 mL/min/1.73 m2) and patients continuing on a TDT formulation (n = 65, eGFR 52.0 ± 2.2 mL/min/1.73 m2) were prospectively followed (median follow-up time 10.4 and 12.6 years in the ODT and TDT groups, respectively, P = not significant). At the end of the follow-up, patients in both groups experienced similar eGFR (50.4 ± 2.2 vs 48.0 ± 2.7 mL/min/1.73 m2 in the ODT and TDT groups, respectively, P = not significant). No differences were observed in biopsy-proven acute rejection, overall graft survival, doubling of serum creatinine, and new onset of proteinuria. The 2 groups also had a comparable rate of death, sepsis, and neoplasia. In conclusion, ODT appears safe and effective in stable kidney graft recipients even 10 years after transplantation. These findings support the use of ODT as a primary tacrolimus formulation in patients with kidney transplantation.

Macrophage infiltration is associated with unfavorable kidney graft outcome in protocol biopsies, but few studies have evaluated its impact on clinical practice. We therefore prospectively evaluated 37 kidney transplant recipients (KTRs) who underwent kidney biopsy due to slight increases in serum creatinine, or mild proteinuria (>0.3 g/24 hr), in the first post-transplant year. Banff score, CD68+ count (score 0-3) by immunohistochemistry, and 1-year DSA were assessed. DGF was reported in 10 (27%) patients, 6 (16%) had normal biopsy, 7 (19%) borderline lesions, 13 (35%) IFTA, and 11 (30%) other lesions. Fifteen KTRs had grade 3 CD68+ infiltration, and 47% developed de novo DSA. During a 6.2 ± 2.7 year follow-up, four patients (11%) suffered from biopsy-proven T-cell rejection, 17 KTRs (46%) lost their graft (12 in the grade 3 CD68+ group). Graft survival was lower in KTRs with grade 3 CD68+ infiltration (P = 0.0074; log-rank test). Grade 3 CD68+ infiltrate was an independent predictor of graft loss (HR 5.41, 95% CI 1.74-16.8; P = 0.003), together with more severe graft dysfunction at biopsy (HR 6.41, 95% CI 2.57-16; P

A changing paradigm of treatment of kidney transplant recipients is a new, wider approach to immunosuppression, which should take into account both antiviral and anticancer effects, in addition to cardiovascular protection. Recent observations suggest that the early introduction of mammalian target of rapamycin inhibitors (mTORi) in association with low dose CNI may offer many of these effects. The present manuscript summarizes benefits and contraindications of combinations with mTORi in kidney transplant immunosuppressive strategies.

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.

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.

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.

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/m 2 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/m 2 increase, P < 0.0001), while a 20% increase in the risk of progression to ESRD was observed for each 10-g/m 2 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.

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 þ 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

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.

To date, few studies have used ambulatory pressure monitoring (ABPM) in patients with chronic kidney disease (CKD) before the start of dialysis treatment. The aim of this study was therefore to ascertain the correlates of arterial hypertension assessed by ABPM in CKD patients at their first referral to a nephrologist.We studied 244 (164 men; mean age 63 years) nondiabetic patients with CKD. Each patient had blood pres-sure (BP) measured by 24-hour ABPM, creatinine clearance (CrCl) estimated according to the Cockcroft-Gault formula, and Hgb concentration, serum lipids, iPTH, daily urinary protein (Uprot) and sodium (UNa) excretion assessed using routine methods.According to ABPM data analysis, 81 patients were normotensives, 78 were stable hypertensives, 26 had day-time hypertension and 59 had nocturnal hypertension. ANOVA showed both lower CrCl (p=0.0033), and higher Uprot (p0.0001) in stable and nighttime hypertensives as compared with normotensives and daytime hypertensives. In the whole group each set of both systolic (SBP) and pulse pressure (PP) readings was directly associated with both age and Uprot (p0.05), and inversely with both CrCl and Hgb (p0.05). In multivariate analysis, however, Uprot emerged among modifiable risk factors, as the most significant predictor of both SBP and PP; the strength of this association was in the order nighttime PPnighttime SBP24-hour PPdaytime PPdaytime SBP24-hour SBP.In CKD patients, proteinuria is the strongest correlate of arterial hypertension and particularly of increased nocturnal PP, possibly as an expression of vascular damage. On the basis of these results, ABPM appears to be the most reliable tool for detecting the associations between raised BP (particularly nighttime hypertension) and renal damage in CKD patients not yet on renal replacement therapy (RRT).

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.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.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 (P0.05) 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 (P0.00002) 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).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.

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. © 2002 by the National Kidney Foundation, Inc.

OR-48 Key Words: Chronic Kidney Disease, Left Ventricular Hypertrophy, Arterial Hypertension