Sadollah Abedini

Inflammation in Renal Transplantation

BACKGROUND AND OBJECTIVES Renal transplant recipients experience premature cardiovascular disease and death. The association of inflammation, all-cause mortality, and cardiovascular events in renal transplant recipients has not been examined in a large prospective controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients. Patients initially randomized to fluvastatin or placebo in the 5- to 6-yr trial were offered open-label fluvastatin in a 2-yr extension to the original study. The association between inflammation markers, high-sensitivity C-reactive protein (hsCRP), and IL-6 on cardiovascular events and all-cause mortality was investigated. RESULTS The baseline IL-6 value was 2.9 +/- 1.9 pg/ml (n = 1751) and that of hsCRP was 3.8 +/- 6.7 mg/L (n = 1910). After adjustment for baseline values for established risk factors, the hazard ratios for a major cardiac event and all-cause mortality for IL-6 were 1.08 [95% confidence interval (CI), 1.01 to 1.15, P = 0.018] and 1.11 (95% CI, 1.05 to 1.18, P < 0.001), respectively. The adjusted hazard ratio for hsCRP for a cardiovascular event was 1.10 (95% CI, 1.01 to 1.20, P = 0.027) and for all-cause mortality was 1.15 (95% CI, 1.06 to 1.1.25, P = 0.049). CONCLUSIONS The inflammation markers IL-6 and hsCRP are independently associated with major cardiovascular events and all-cause mortality in renal transplant recipients.

Asymmetrical dimethylarginine is associated with renal and cardiovascular outcomes and all-cause mortality in renal transplant recipients.

Increased plasma levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and predict the progression to dialysis and death in patients with chronic kidney disease. The effects of these increased ADMA levels in renal transplant recipients, however, are unknown. We used the data from ALERT, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients with stable graft function on enrollment. Patients who were initially randomized to fluvastatin or placebo in the 5- to 6-year trial were offered open-label fluvastatin in a 2-year extension of the original study. After adjustment for baseline values for established factors in this post hoc analysis, ADMA was found to be a significant risk factor for graft failure or doubling of serum creatinine (hazard ratio 2.78), major cardiac events (hazard ratio 2.61), cerebrovascular events (hazard ratio 6.63), and all-cause mortality (hazard ratio 4.87). In this trial extension, the number of end points increased with increasing quartiles of plasma ADMA levels. All end points were significantly increased in the fourth compared to the first quartile. Our study shows that elevated plasma levels of ADMA are associated with increased morbidity, mortality, and the deterioration of graft function in renal transplant recipients.

Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus : a randomized placebo-controlled study

OBJECTIVE Patients with systemic lupus erythematosus (SLE), with or without end-stage renal failure, are at increased risk of premature cardiovascular disease. Although statin therapy has been found to reduce cardiovascular risk in the general population, its effectiveness in kidney transplant recipients with SLE has not been examined. This study was undertaken to investigate the effect of fluvastatin on cardiac end points in a randomized controlled trial of renal transplant patients with SLE. METHODS Patients with SLE were identified from among participants in the Assessment of Lescol in Renal Transplantation trial, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin (40-80 mg/day) on cardiovascular outcomes in renal transplant recipients. Patients were randomized to either a group receiving fluvastatin or a placebo group for the duration of the 5-6-year trial, and then invited to continue in a 2-year open-label extension during which all participants, regardless of original group, received fluvastatin. Patients were followed up for a total of 7-8 years for assessment of the primary end point of major cardiac events, comprising nonfatal myocardial infarction, cardiac death, and coronary intervention procedures. RESULTS Fluvastatin reduced low-density lipoprotein cholesterol levels by 29.2% (95% confidence interval [95% CI] 18.3-40%), from a mean +/- SD of 4.0 +/- 0.9 mmoles/liter to 2.8 +/- 1.1 mmoles/liter, and total cholesterol by 19.6% (95% CI 11.7-27.5%), from 6.4 +/- 0.9 mmoles/liter to 5.1 +/- 1.1 mmoles/liter. Compared with placebo-treated patients, patients randomized to receive fluvastatin exhibited a 73.4% reduction in the risk of major cardiac events (relative risk 26.6 [95% CI 5.9-119.4], P = 0.064). CONCLUSION Our results indicate that the effect of fluvastatin on cardiac events in renal transplant recipients with SLE is similar to that observed with statin therapy in the renal transplant population as a whole.

Inflammation-associated graft loss in renal transplant recipients

BACKGROUND Although short-term graft survival has improved substantially in renal transplant recipients, long-term graft survival has not improved over the last decades. The lack of knowledge of specific causes and risk factors has hampered improvements in long-term allograft survival. There is an uncertainty if inflammation is associated with late graft loss. METHODS We examined, in a large prospective trial, the inflammation markers high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) and their association with chronic graft dysfunction. We collected data from the Assessment of Lescol in Renal Transplant trial, which recruited 2102 maintenance renal transplant recipients. RESULTS Baseline values were hsCRP 3.8 ± 6.7 mg/L and IL-6 2.9 ± 1.9 pg/mL. Adjusted for traditional risk factors, hsCRP and IL-6 were independently associated with death-censored graft loss, the composite end points graft loss or death and doubling of serum creatinine, graft loss or death. CONCLUSION The inflammation markers hsCRP and IL-6 are associated with long-term graft outcomes in renal transplant recipients.

Cerebrovascular events in renal transplant recipients.

Background. The incidence of stroke and risk factors for different subtypes of cerebrovascular (CBV) events in renal transplant recipients have not been examined in any large prospective controlled trial. Methods. The Assessment of Lescol in Renal Transplantation was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin (40–80 mg) daily on cardiovascular, and renal outcomes in renal transplant recipients. Patients initially randomized to fluvastatin or placebo in the 5 to 6 year trial was offered open-label fluvastatin in a 2-year extension to the original study. We investigated the incidence of stroke and risk factors for ischemic and hemorrhagic CBV events in 2102 renal graft recipients participating in the Assessment of Lescol in Renal Transplantation core and extension trial with a mean follow-up of 6.7 years. Results. The incidence and type of CBV events did not differ between the lipid lowering arm and the placebo arm. A total of 184 (8.8%, 95% confidence interval 4.6–12.9) of 2102 patients experienced a CBV event during follow-up, corresponding to an incidence of 1.3% CBV event per year. The mortality for patients experiencing a hemorrhagic stroke was 48% (13 of 27), whereas the mortality for ischemic strokes was 6.0% (8 of 133). Diabetes mellitus, previous CBV event, age, and serum creatinine were independent risk factors for cerebral ischemic events. The risk of a hemorrhagic cerebral event was increased by diabetes mellitus, polycystic kidney disease, left ventricular hypertrophy, and systolic blood pressure. Interpretation. Risk factors for CBV events in renal transplant recipients differ according to subtype.

Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism.

Background Hyperparathyroidism is reported in 10% to 66% of renal transplant recipients (RTR). The influence of persisting hyperparathyroidism on long-term clinical outcomes in RTR has not been examined in a large prospective study. Methods We investigated the association between baseline parathyroid hormone (PTH) levels and major cardiovascular events, renal graft loss, and all-cause mortality by Cox Proportional Hazard survival analyses in 1840 stable RTR derived from the Assessment of LEscol in Renal Transplantation trial. Patients were recruited in a mean of 5.1 years after transplantation, and follow-up time was 6 to 7 years. Results Significant associations between PTH and all 3 outcomes were found in univariate analyses. When adjusting for a range of plausible confounders, including measures of renal function and serum mineral levels, PTH remained significantly associated with all-cause mortality (4% increased risk per 10 units; P = 0.004), and with graft loss (6% increased risk per 10 units; P < 0.001), but not with major cardiovascular events. Parathyroid hormone above the upper limit of normal (65 pg/mL) indicated a 46% (P = 0.006) higher risk of death and an 85% higher risk of graft loss (P < 0.001) compared with low/normal values. Conclusions Hyperparathyroidism is an independent, potentially remediable, risk factor for renal graft loss and all-cause mortality in RTR.

Metabolic syndrome and cardiovascular risk in renal transplant recipients: effects of statin treatment.

Abstract:  Background:  Renal transplant recipients (RTR) have high risk for cardiovascular disease (CVD). They also have high prevalence of insulin resistance and metabolic syndrome (MS). Statin treatment reduces CVD risk in RTR. The aim was to study MS as CVD risk factor in RTR, and to investigate the effect of statin treatment in RTR with MS.

No detrimental effect on renal function during long-term use of fluvastatin in renal transplant recipients in the Assessment of lescol in renal transplantation (ALERT) study

Abstract:  Background:  Concerns have recently been raised regarding a potential harmful effect of statins on renal function. This study investigated the effect of fluvastatin treatment on renal function in renal transplant recipients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) trial.

Homoarginine and Clinical Outcomes in Renal Transplant Recipients: Results From the Assessment of Lescol in Renal Transplantation Study

Background Despite improvements in kidney transplantation, complications, including cardiovascular morbidity and graft loss, contribute to reduced graft and patient survival. The amino acid homoarginine exerts a variety of beneficial effects that may be relevant for cardiovascular and graft outcomes, which is investigated in the present study. Methods Homoarginine was measured in 829 renal transplant recipients participating in the placebo group of the Assessment of Lescol in Renal Transplantation study. Mean follow-up was 6.7 years. By Cox regression analyses, we determined hazard ratios (HRs) to reach prespecified, adjudicated endpoints according to baseline homoarginine levels: major adverse cardiovascular events (n = 103), cerebrovascular events (n = 53), graft failure or doubling of serum creatinine (n = 140), noncardiovascular mortality (n = 51), and all-cause mortality (n = 107). Results Patients mean age was 50 ± 11 years, homoarginine concentration was 1.96 ± 0.76 &mgr;mol/L, and 65% were men. Patients in the lowest homoarginine quartile (<1.40 &mgr;mol/L) had an adjusted 2.6-fold higher risk of cerebrovascular events compared to those in the highest quartile (>2.34 &mgr;mol/L) (HR, 2.56; 95% confidence interval [95% CI], 1.13–5.82). Similarly, the renal endpoint occurred at a significantly increased rate in the lowest homoarginine quartile (HR, 2.34; 95% CI, 1.36–4.02). For noncardiovascular and all-cause mortality, there was also increased risk associated with the lowest levels of homoarginine, with HRs of 4.34 (95% CI, 1.63–10.69) and 2.50 (95% CI, 1.38–4.55), respectively. Conclusions Low homoarginine is strongly associated with cerebrovascular events, graft loss and progression of kidney failure and mortality in renal transplant recipients. Whether interventions with homoarginine supplementation improve clinical outcomes requires further evaluation.

Graft loss risk in renal transplant recipients with metabolic syndrome: subgroup analyses of the ALERT trial.

BACKGROUND Several nonimmunologic risk factors for late renal graft loss (RGL) are also known components of metabolic syndrome (MS). We aimed to study MS as a risk factor for RGL. Also, the effect of statin treatment in reducing renal risk in renal transplant recipients (RTRs) with MS was studied. METHODS Nondiabetic RTRs (n=1,706) from the ALERT trial were followed for 7-8 years. MS was defined according to National Cholesterol Education Program Adult Treatment Panel III definition with waist girth replaced by BMI ≥30 (calculated as kg/m(2)). Renal end points included death-censored RGL and graft loss or doubling of serum creatinine. RESULTS During the follow-up, 284 patients experienced RGL, and there were 343 cases of graft loss or doubling of serum creatinine. Those with MS had increased risk for RGL (relative risk = 1.28, 95% confidence interval, 1.00-1.63; p=0.047), but not for the combined end point. After adjustment for other known and potential risk factors, MS was no longer associated with increased risk for RGL. The association between MS and RGL risk was attenuated once adjustment for creatinine was made. Statin treatment did not reduce the risk for renal end points in RTRs with or without MS. CONCLUSION MS had no independent association with RGL risk. Adjustment for renal function attenuated the association between MS and RGL.