Gudrun Nyberg

Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial

BACKGROUND Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. METHODS We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4.0-9.0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, non-fatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. FINDINGS After a mean follow-up of 5.1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0.83 [95% CI 0.64-1.06], p=0.139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0.65 [0.48-0.88] p=0.005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. INTERPRETATION Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.

Long‐term Cardiac Outcomes in Renal Transplant Recipients Receiving Fluvastatin: The ALERT Extension Study

Renal transplant recipients (RTR) have an increased risk of premature cardiovascular disease. The ALERT study is the first trial to evaluate the effect of statin therapy on cardiac outcomes following renal transplantation. Patients initially randomized to fluvastatin or placebo in the 5–6 year ALERT study were offered open‐label fluvastatin XL 80 mg/day in a 2‐year extension to the original study. The primary endpoint was time to first major adverse cardiac event (MACE). Of 1787 patients who completed ALERT, 1652 (92%) were followed in the extension. Mean total follow‐up was 6.7 years. Mean LDL‐cholesterol was 98 mg/dL (2.5 mmol/L) at last follow‐up compared to a pre‐study level of 159 mg/dL (4.1 mmol/L). Patients randomized to fluvastatin had a reduced risk of MACE (hazards ratio [HR] 0.79, 95% CI 0.63–0.99, p = 0.036), and a 29% reduction in cardiac death or definite non‐fatal MI (HR 0.71, 95% CI 0.55–0.93, p = 0.014). Total mortality and graft loss did not differ significantly between groups. Fluvastatin produces a safe and effective reduction in LDL‐cholesterol associated with reduced risk of MACE in RTR. The lipid‐lowering and cardiovascular benefits of fluvastatin are comparable to those of statins in other patient groups, and support use of fluvastatin in RTR.

Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT Study

Renal transplant recipients have a greatly increased risk of premature cardiovascular disease. The ALERT study was a multicenter, randomized, double‐blind, placebo‐controlled trial of fluvastatin (40–80 mg/day) in 2102 renal transplant recipients followed for 5–6 years. The main study used a composite cardiac end‐point including myocardial infarction, cardiac death and cardiac interventions. Although reduced by fluvastatin, this primary end‐point failed to achieve statistical significance thus precluding analysis of predefined subgroups. Therefore, in the present survival analysis, we used an alternative primary end‐point of cardiac death or definite nonfatal myocardial infarction (as used in other cardiac outcome trials) which was significantly reduced by Fluvastatin therapy and permits subgroup analysis. Fluvastatin reduced LDL‐cholesterol by 1 mmol/L compared with placebo, and the incidence of cardiac death or definite myocardial infarction was reduced from 104 to 70 events (RR 0.65; 95% CI 0.48, 0.88; p = 0.005). Fluvastatin use was associated with reduction in cardiac death or nonfatal myocardial infarction, which achieved statistical significance in many subgroups. The subgroups included patients at lower cardiovascular risk, who were younger, nondiabetic, nonsmokers and without pre‐existing CVD. These data support the early introduction of statins following renal transplantation.

Impact of metabolic control in progression of clinical diabetic nephropathy

SummaryRenal clearance of 51Cr-EDTA as a measure of glomerular filtration rate was followed prospectively for 21 months in 18 Type 1 (insulin-dependent) patients with juvenile-onset diabetes and nephropathy. Hypertension was treated aggressively, attaining a mean blood pressure of 154/88 mmHg in the supine and 126/82 mmHg in the standing position. The mean glycosylated haemoglobin value (HbA1c) during the observation period was found to correlate well with the mean of random blood glucose values (r=0.72). It also correlated to the rate of glomerular filtration rate decline over time, whether the latter was calculated as slope coefficient for all available data (r=-0.52, p<0.05) or based on the first and last observations only (r=-0.57, p<0.05). In a multiple linear stepwise regression analysis also including mean arterial blood pressure, the correlation between glomerular filtration rate decline and HbA1c was significant at p<0.01; this explained one-third of the progression, while mean arterial pressure could not be shown to contribute. It is concluded that hyperglycaemia, contrary to the general belief, is a risk factor for the progression of clinical diabetic nephropathy with reduced glomerular filtration rate.

Glomerular epithelial foot processes and filtration slits in IDDM patients

SummaryDiabetic nephropathy is associated with functional changes in the glomerular filtration barrier but the structural counterpart remains unknown. Width of glomerular epithelial cell foot processes and of filtration slits were determined by morphometric methods in 11 non-diabetic kidney donors and in 28 diabetic patients with albumin excretion rates ranging from normal to proteinuria. Foot process width was estimated from the ratio of tuft surface density to length density of slits. At high magnification independently sampled, perpendicularly cut slits were classified. Foot process width on peripheral basement membrane was increased in microalbuminuric compared to normoalbuminuric diabetic patients (p<0.05) but showed no significant correlation with the level of albumin excretion when patients with increased barrier permeability were considered. Width of filtration slits in normo- and microalbuminuric diabetic patients exceeded that in non-diabetic control subjects (p<0.05). Filtration slits were narrower in patients with overt proteinuria than in patients with microalbuminuria (p<0.05) and correlated with glomerular filtration rate in all of the diabetic patients (r=0.65, p<0.005). The results show that insulin-dependent diabetic patients with nephropathy present changes of epithelial cells and filtration slits, demonstrable already in the stage of microalbuminuria. The mechanism of albumin leakage is not achieved by these measures. The dimension of filtration slits may play a contributing role in the level of glomerular filtration rate in diabetic patients.

Becoming a living kidney donor.

Earlier investigations of attitudes of living kidney donors have been performed in retrospect. We saw a need to investigate in depth those motives and feelings that are relevant in potential kidney donors. With a phenomenologic approach, interviews were performed with 12 potential donors. Seven categories of motives were identified: a desire to help, increased self-esteem from doing good deeds, identification with the recipient, self-benefit from the relative’s improved health, mere logic, external pressure, and a feeling of moral duty. In the individual, these categories interacted to create a perception of donation being the only option.

Advanced Diabetic Glomerulopathy: Quantitative Structural Characterization of Nonoccluded Glomeruli

Quantitative ultrastructural data were obtained from kidney biopsy material of 12 long-term insulindependent diabetics. All patients had overt diabetic nephropathy with increased urinary albumin excretion and reduced glomerular filtration rate. Renal clearance of 51Cr-EDTA was in the range of 16-50 ml · min−1 · 1.73 m−2. All patients received antihypertensive treatment. A combined light- and electron-microscope study was performed. A significant proportion of the glomeruli was totally occluded (mean 36%, range 24-67%). Structural data presented relate only to the open, still-functioning glomeruli. Comparison with data previously obtained showed that 1) the thickness of the peripheral basement membrane [647 nm, coefficient of variation (C.V.) 0.22] was more than twice the normal value (310 nm, C.V. 0.08); 2) the width of epithelial foot processes (352 nm, C.V. 0.07) was significantly greater than in normal biopsies (224 nm, C.V. 0.06); and 3) the mean volume of the open glomeruli was markedly increased compared with normal and clearly exceeded that in the early diabetic hypertrophy. Total mesangial volume and total basement membrane material per open glomerulus were increased by 277 and 614%, respectively. However, capillary length and surface per open glomerulus were similar to those observed in early diabetic hypertrophy. These findings suggest that a late glomerular hypertrophy with preservation of capillary surface occurs as a compensatory phenomenon, prolonging renal survival for diabetic nephropathy patients.

Low absolute glomerular filtration rate in the living kidney donor: A risk factor for graft loss

Background. There is no defined lower acceptable level of glomerular filtration rate (GFR) in potential living kidney donors. Considerations focus on the risk for the donor. We wanted to evaluate the outcome in the recipient in relation to the GFR of the living donor. Methods. There were 344 living donated kidney transplantations performed January 1985 through February 1997 which were evaluated. Two thirds of the donors shared one haplotype with the recipient and 15% shared both. Of the donors 18% were above age 60. The median follow-up time (until graft loss) was 63 months. Before nephrectomy, the donors′ GFR had been measured by isotope clearance. Results. Twenty-six donors (7.6%) had an absolute GFR below 80 ml/min, i.e. not adjusted to 1.73 m2 body surface area (BSA). Cumulative graft survival, censored for graft loss because of death of the patient, was significantly reduced in recipients of grafts from donors with GFR <80 ml/min. A significant correlation between GFR and donor age was observed, but donor age per se was not identified as a risk factor for graft loss. In a Cox stepwise proportional hazards analysis, the relative risk for graft loss was 2.28 with a GFR below 80 ml/min (confidence interval 1.183–4.383, P =0.014) and with sharing one or both haplotypes 0.56 (0.313–0.988, P =0.046) and 0.36 (0.139–0.912, P =0.03), respectively. Conclusions. An absolute GFR below 80 ml/min in the living donor more than doubles the risk of graft loss. This fact should be considered when definitions of acceptable limits for donor GFR are discussed.

Can DXA Predict Fractures in Renal Transplant Patients

Renal transplant patients have a high prevalence of osteopenia, osteoporosis and fractures. The aim of the study was to investigate whether dual‐energy x‐ray absorptiometry (DXA) is of value to predict fractures. In 1995–2007, 238 renal transplant patients underwent 670 DXA investigations. Osteopenia (46.0%), osteoporosis (13.9%) and absolute bone mineral density (BMD) (median 0.9, range 0.4–2.0 g/cm2) in the hip region were used to evaluate fracture risk. Data on fractures were collected at the occasion of each DXA, and a questionnaire was filled in by 191 patients at regular outpatient visits. Reported fractures were verified by consultation of medical records. In all, 46 patients had 53 fractures. Cumulative hazard of fracture was significantly different among normal BMD, osteopenia and osteoporosis in the hip (p < 0.0001). A Cox proportional hazard analysis also including age, gender and diabetic nephropathy showed significantly increased fracture risk for osteoporosis (3.5 times, CI 1.8–6.4, p = 0.0001) as well as for osteopenia (2.7 times, 1.6–4.6, p = 0.0003). A significantly increased risk was also found with absolute BMD estimates below the median. Osteopenia and an absolute bone density below 0.9 g/cm2 in the hip region confer an increased risk of fracture.

Risk factors for reaching renal endpoints in the assessment of Lescol in renal transplantation (ALERT) trial

Background. The aim of the study was to identity risk factors for long-term renal transplant function and development of chronic allograft nephropathy (CAN) in renal transplant recipients included in the Assessment of Lescol in Renal Transplantation (ALERT) trial. Methods. The ALERT trial was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 and 80 mg/day, in renal transplant recipients who were randomized to receive fluvastatin (Lescol) (n=1,050) or placebo (n=1,052) over 5 to 6 years of follow-up. Renal endpoints including graft loss or doubling of serum creatinine or death were analyzed by univariate and multivariate regression analysis in the placebo group. Results. There were 137 graft losses (13.5%) in the placebo group, mainly caused by CAN (82%). Univariate risk factors for graft loss or doubling of serum creatinine were as follows: serum creatinine, proteinuria, hypertension, pulse pressure, time since transplantation, donor age, human leukocyte antigen-DR mismatches, treatment for rejection, low high-density lipoprotein cholesterol, and smoking. Multivariate analysis revealed independent risk factors for graft loss as follows: serum creatinine (relative risk [RR], 3.12 per 100-&mgr;M increase), proteinuria (RR, 1.64 per 1-g/24 hr increase), and pulse pressure (RR, 1.12 per 10 mm Hg), whereas age was a protective factor. With patient death in the composite endpoint, diabetes mellitus, smoking, age, and number of transplantations were also risk factors. Conclusions. Independent risk factors for graft loss or doubling of serum creatinine or patient death are mainly related to renal transplant function, proteinuria, and blood pressure, which emphasizes the importance of renoprotective treatment regimens in this population.