NT-proBNP and stem cell factor plasma concentrations are independently associated with cardiovascular outcomes in end-stage renal disease hemodialysis patients.

Aims: End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine. Methods and results: The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths. Conclusions: Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.

Outcome in biopsy-proven Lupus nephritis: Evaluation of biopsies from the Norwegian Kidney Biopsy Registry.

Objective To evaluate long-term mortality and end-stage renal disease (ESRD) in a cohort of Norwegian patients with biopsy-proven lupus nephritis (LN). Methods Renal biopsies were obtained from 178 patients with LN from 1988 until 2007. Mortality rate and death causes were provided by Statistics Norway and ESRD data were provided by the Norwegian Renal Registry. Risk factors for all-cause mortality were evaluated by Cox regression. Standardized mortality ratio (SMR) was compared to observed deaths in a matched general population sample. Results Mean age was 37.6 (±14.4) years, and median time of follow-up was 8.5 years (0-26.2). Thirty-six patients (20.2%) died during follow-up. The SMR for all-cause mortality was 5.6 (Confidence interval [CI] 3.7-7.5). In an adjusted multivariate analysis proliferative glomerulonephritis (LN class IV) was independently associated with all-cause mortality; hazard ratio (HR) 2.6 (Confidence interval [CI] 1.2-5.7 p = 0.017). Main causes of death were infections (47.2%) and cardiovascular events 8 (22.2%). Thirty-six patients (20.2%) reached ESRD. Conclusions Biopsy-proven LN is associated with increased mortality compared to the general population. LN class IV is associated with all-cause mortality. Infections and cardiovascular events were the most common causes of death. Patients with LN have a high incidence of ESRD.

Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study.

Genome-wide association studies (GWAS) are designed to investigate single nucleotide polymorphisms (SNPs) and the association with a clinical phenotype. A previous GWAS performed in 300 renal transplant recipients identified two SNPs (rs3811321 and rs6565887) associated with serum creatinine and clinical outcome. We sought to validate these findings. Genotyping of the two SNPs was performed using Taqman assays in 1638 Caucasians participating in the Assessment of LEscol in Renal Transplant (ALERT) study. Primary endpoint was death-censored graft loss, and secondary endpoint was all-cause mortality. Applying Cox regression, no crude association to graft loss was found for rs3811321 on chromosome 14 (hazard ratio [HR] 0.87, 95% CI 0.59-1.29, p = 0.50) or rs6565887 on chromosome 18 (HR 0.88, CI 0.62-1.25, p = 0.48). Multivariable adjustments did not change results, nor did evaluation of the number of risk alleles formed by the two SNPs. No association with mortality was detected. In conclusion, an impact of two SNPs on chromosomes 14 and 18 on death-censored graft survival or all-cause mortality was not confirmed. Our results emphasize the importance of validating findings from high-throughput genetics studies and call for large collaborative research initiatives in the field of transplantation outcomes.

Serum Calcification Propensity Is a Strong and Independent Determinant of Cardiac and All-Cause Mortality in Kidney Transplant Recipients.

Calcification of the vasculature is associated with cardiovascular disease and death in kidney transplant recipients. A novel functional blood test measures calcification propensity by quantifying the transformation time (T50 ) from primary to secondary calciprotein particles. Accelerated T50 indicates a diminished ability of serum to resist calcification. We measured T50 in 1435 patients 10 weeks after kidney transplantation during 2000-2003 (first era) and 2009-2012 (second era). Aortic pulse wave velocity (APWV) was measured at week 10 and after 1 year in 589 patients from the second era. Accelerated T50 was associated with diabetes, deceased donor, first transplant, rejection, stronger immunosuppression, first era, higher serum phosphate and lower albumin. T50 was not associated with progression of APWV. During a median follow-up of 5.1 years, 283 patients died, 70 from myocardial infarction, cardiac failure or sudden death. In Cox regression models, accelerated T50 was strongly and independently associated with both all-cause and cardiac mortality, low versus high T50 quartile: hazard ratio 1.60 (95% confidence interval [CI] 1.00-2.57), ptrend = 0.03, and 3.60 (95% CI 1.10-11.83), ptrend = 0.02, respectively. In conclusion, calcification propensity (T50 ) was strongly associated with all-cause and cardiac mortality of kidney transplant recipients, potentially via a cardiac nonAPWV-related pathway. Whether therapeutic improvement of T50 improves outcome awaits clarification in a randomized trial.

A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism.

Persistent hyperparathyroidism (HPT) after kidney transplantation (KTx) is associated with hypercalcemia, hypophosphatemia and abnormally high levels of parathyroid hormone (PTH). In this randomized trial, cinacalcet was compared to placebo for the treatment of hypercalcemia in adult patients with persistent HPT after KTx. Subjects were randomized 1:1 to cinacalcet or placebo with randomization stratified by baseline corrected total serum calcium levels (≤11.2 mg/dL [2.80 mmol/L] or >11.2 mg/dL [2.80 mmol/L]). The primary end point was achievement of a mean corrected total serum calcium value<10.2 mg/dL (2.55 mmol/L) during the efficacy period. The two key secondary end points were percent change in bone mineral density (BMD) at the femoral neck and absolute change in phosphorus; 78.9% cinacalcet- versus 3.5% placebo-treated subjects achieved the primary end point with a difference of 75.4% (95% confidence interval [CI]: 63.8, 87.1), p<0.001. There was no statistical difference in the percent change in BMD at the femoral neck between cinacalcet and placebo groups, p=0.266. The difference in the change in phosphorus between the two arms was 0.45 mg/dL (95% CI: 0.26, 0.64), p<0.001 (nominal). No new safety signals were detected. In conclusion, hypercalcemia and hypophosphatemia were effectively corrected after treatment with cinacalcet in patients with persistent HPT after KTx.

Improved patient survival with simultaneous pancreas and kidney transplantation in recipients with diabetic end-stage renal disease.

AIMS/HYPOTHESIS: We aimed to determine whether simultaneous pancreas and kidney (SPK) transplantation would improve patient and kidney graft survival in diabetic end-stage renal disease (ESRD) compared with kidney transplantation alone (KTA). METHODS: Follow-up data were retrieved for all 630 patients with diabetic ESRD who had received SPK or KTA at our centre from 1983 to the end of 2010. Recipients younger than 55 years of age received either an SPK (n = 222) or, if available, a single live donor kidney (LDK; n = 171). Older recipients and recipients with greater comorbidity received a single deceased donor kidney (DDK; n = 237). Survival was analysed by the Kaplan-Meier method and in multivariate Cox regression analysis adjusting for recipient and donor characteristics. RESULTS: Patient survival was superior in SPK compared with both LDK and DDK recipients in univariate analysis. Follow-up time (mean ± SD) after transplantation was 7.1 ± 5.7 years. Median actuarial patient survival was 14.0 years for SPK, 11.5 years for LDK and 6.7 years for DDK recipients. In multivariate analyses including recipient age, sex, treatment modality, time on dialysis and era, SPK transplantation was protective for all-cause mortality compared with both LDK (p = 0.02) and DDK (p = 0.029) transplantation. After the year 2000, overall patient survival improved compared with previous years (HR 0.40, 95% CI 0.30, 0.55; p < 0.001). Pancreas graft survival also improved after 2000, with a 5 year graft survival rate of 78% vs 61% in previous years (1988-1999). CONCLUSIONS/INTERPRETATION: Recipients of SPK transplants have superior patient survival compared with both LDK and DDK recipients, with improved results seen over the last decade.

Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation.

In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent.

Prognostic model for total mortality in patients with haemodialysis from the Assessments of Survival and Cardiovascular Events (AURORA) study.

OBJECTIVES: Risk factors of mortality in patients with haemodialysis (HD) have been identified in several studies, but few prognostic models have been developed with assessments of calibration and discrimination abilities. We used the database of the Assessment of Survival and Cardiovascular Events study to develop a prognostic model of mortality over 3-4 years. METHODS: Five factors (age, albumin, C-reactive protein, history of cardiovascular disease and diabetes) were selected from experience and forced into the regression equation. In a 67% random try-out sample of patients, no further factors amongst 24 candidates added significance (P < 0.01) to mortality outcome as assessed by Cox regression modelling, and individual probabilities of death were estimated in the try-out and test samples. Calibration was explored by calculating the prognostic index with regression coefficients from the try-out sample to patients in the 33% test sample. Discrimination was assessed by receiver operating characteristic (ROC) areas. RESULTS: The strongest prognostic factor in the try-out sample was age, with small differences between the other four factors. Calibration in the test sample was good when the calculated number of deaths was multiplied by a constant of 1.33. The five-factor model discriminated reasonably well between deceased and surviving patients in both the try-out and test samples with an ROC area of about 0.73. CONCLUSIONS: A model consisting of five factors can be used to estimate and stratify the probability of death for individuals The model is most useful for long-term prognosis in an HD population with survival prospects of more than 1 year.

Quality of life in kidney donors.

Reports on quality of life of kidney donors include small populations with variable response rates. The aim was to evaluate quality of life in kidney donors in a large cross-sectional study. Through the Norwegian Renal Registry we contacted all 1984 kidney donors in the period 1963-2007 with a response rate of 76%. All received the Short-Form-36 (SF-36) survey form and a questionnaire specifically designed for kidney donors. SF-36 scores for a subgroup (n = 1414) of kidney donors were not inferior to a general population sample, adjusted for age, gender and education. When asked to reconsider, a majority stated that they still would have consented to donate. Risk factors for having doubts were graft loss in the recipient (OR 3.1, p < 0.001), medical problems after donation (OR 3.7, p < 0.001), unrelated donor (OR 2.2, p = 0.01) and less than 12 years since donation (OR 1.8, p = 0.04). Older age at donation was associated with lower risk (OR 0.98, p = 0.03). Compared with other donors, those expressing doubts had inferior SF-36 scores. Norwegian kidney donors are mostly first-degree relatives. They are fully reimbursed and offered life-long follow-up. All inhabitants are provided universal healthcare. This should be considered when extrapolating these results to other countries.

Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial.

OBJECTIVES: In Incremental Decrease in Endpoints through Aggressive Lipid-lowering (IDEAL), we compared cardiovascular outcomes in patients with and without chronic kidney disease (CKD) (estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2)) and analysed relationships between lipoprotein components (LC) and major coronary events (MCE) and other cardiovascular (CV) events. DESIGN: Exploratory analysis of CV endpoints in a randomized trial comparing high dose of atorvastatin to usual dose of simvastatin on MCE. SETTINGS: Patients with CKD were compared with the non-CKD patients. Cox regression models were used to study the relationships between on-treatment levels of LC and incident MCE. FINDINGS: Chronic kidney disease was strongly associated with cardiovascular end-points including total mortality. In patients with CKD, a significant benefit of high dose atorvastatin treatment was found for any CV events, stroke and peripheral artery disease, but not for MCE. However, all cardiovascular end-points except stroke and CV mortality were reduced in the non-CKD group. Differential changes in LC or relationships to LC could not explain the different treatment outcomes in MCE in the two groups. INTERPRETATION: Chronic kidney disease was a powerful risk factor for all cardiovascular end-points. The reason why the significant reductions achieved by high-dose statin treatment in most CV end-points in the non-CKD group were only in part matched by similar reductions in the CKD patients is not apparent. This difference did not result from differential changes in or relations to LC, but limited power may have increased the possibility of chance findings.

Early, abrupt conversion of de novo renal transplant patients from cyclosporine to everolimus: results of a pilot study.

In a single-center study, 20 kidney transplant patients without prior rejection were abruptly converted from cyclosporine to everolimus at seven wk post-transplant. All patients received basiliximab induction with maintenance enteric-coated mycophenolate sodium and corticosteroids. Biopsy-proven acute rejection had occurred in three of 20 patients (15.0%) by the end of week seven post-conversion. All episodes were mild and reversible, with subsequent recovery of renal function. Calculated glomerular filtration rate (GFR) improved significantly (51 +/- 11 mL/min at time of conversion, 58 +/- 12 mL/min at week seven post-conversion, 57 +/- 17 mL/min at month six post-conversion; p = 0.001). No patient developed proteinuria in the nephrotic range. Twenty-two adverse events were reported in 10 patients, three of which had a suspected relationship to everolimus. Mean leukocyte and platelet count decreased significantly, and triglyceride level increased. This study suggests that kidney transplant patients without prior rejection can be converted abruptly from cyclosporine to everolimus at seven wk post-transplant, resulting in significantly improved renal function with no apparent increase, in risk of rejection and good tolerability.

Evaluation of the pharmacokinetic interaction between fluvastatin XL and cyclosporine in renal transplant recipients.

OBJECTIVE: To assess the pharmacokinetic interaction between cyclosporine and extended-release fluvastatin (fluvastatin XL), 80 mg for 7 days, in stable renal transplant recipients. METHODS: This was a single-center, open-label study. 17 renal transplant recipients received their standard cyclosporine therapy (Days 1 - 9) plus a once-daily single oral dose of fluvastatin XL, 80 mg (Days 2 - 8). Blood samples were collected and cyclosporine (whole blood) and fluvastatin (plasma) concentrations determined by radioimmunoassay and HPLC fluorescence detection, respectively. Pharmacokinetic parameters were calculated using non-compartment analysis and fluvastatin results were compared with historical controls. RESULTS: Treatment with fluvastatin XL, 80 mg for 7 days, had no significant effect on either the AUC0-12 (3,644 ng x h/ml in the absence of fluvastatin vs. 3,534 ng x h/ml in the presence of fluvastatin) or the Cmax of cyclosporine (983 ng/ml in the absence of fluvastatin vs. 945 ng/ml in the presence of fluvastatin). Co-administration of fluvastatin XL also had no effect on the tmax, t1/2 or apparent clearance (CL/F) of cyclosporine in renal transplant patients. The AUC and Cmax for fluvastatin XL in the presence of cyclosporine (AUC0-24 1,192 ng. x h/ml, Cmax 271 ng/ml) were approximately 2-fold higher compared with historical data for fluvastatin XL alone in healthy volunteers (AUC0-24 630 ng x h/ml, Cmax 102 ng/ml) but lower than the historical data for fluvastatin IR, 40 mg b.i.d. alone in healthy volunteers (AUC0-24 1,340 ng x h/ml, Cmax 443 ng/ml). Tmax, t1/2 and trough levels of fluvastatin in the presence of cyclosporine were also similar to the historical controls. Concomitant administration of cyclosporine and fluvastatin XL was well tolerated by renal transplant recipients. CONCLUSIONS: Fluvastatin XL, 80 mg, and cyclosporine do not show clinically relevant pharmacokinetic interactions.

The impact of early-diagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events.

The impact of early-diagnosed new-onset post-transplantation diabetes mellitus (PTDM) on cardiovascular (CV) disease is not well described. The objectives of the present prospective single-center observational study were to assess the long-term effects of early-diagnosed new-onset PTDM on major cardiac events (MCE; cardiac death or nonfatal acute myocardial infarction) and patient survival. Diabetic status and CV risk factors were assessed in 201 consecutive renal allograft recipients 3 months after transplantation (baseline) during a period of 16 months (1995-96). Follow-up data until January 1, 2004 were obtained from the Norwegian Renal Registry. The 8-year (range 7-9 years) cumulative incidence of MCEs was 7% (nine out of 138) in recipients without diabetes, 20% (seven out of 35) in patients with new-onset PTDM and 21% (six out of 28) in patients with diabetes mellitus before transplantation (DM). Proportional hazards regression analyses (forward stepwise regression) revealed that patients with PTDM had an approximately three-fold increased risk of MCEs as compared with nondiabetic patients (hazard ratio (HR)=3.27, 95% confidence interval (CI)=1.22-8.80, P=0.019). A total of 61 patients (30%) died. Eight-year patient survival was 80% in the nondiabetic group, 63% in the PTDM group and 29% in the DM group, respectively. Pretransplant diabetes (HR=5.09, 95% CI=2.60-9.96, P<0.001), age (HR=1.03, 95% CI=1.01-1.05, P=0.016), cytomegalovirus (CMV) infection (HR=2.66, 95% CI=1.27-5.53, P=0.009), and creatinine clearance (HR=0.98, 95% CI=0.96-1.00, P=0.046), but not PTDM (HR=1.20, 95% CI=0.58-2.49, P=0.621), were independent predictors of death in the multiple Cox regression model. Early-diagnosed PTDM is a predictor of MCEs, but not of all-cause mortality, the first 8 years after renal transplantation.

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.

Combined therapy with atorvastatin and calcineurin inhibitors: no interactions with tacrolimus.

Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback. Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4+PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors.