A non-randomized trial of conversion from ciclosporin and tacrolimus to tacrolimus MR4 in stable long-term kidney transplant recipients: Graft function and influences of ABCB1 genotypes.

TRIAL REGISTRATION: PEP Study: Ethics committee N° 393/2004, EudraCT 2004-004209-98. PEP-X Study: Ethics committee amendment application N° 154/01/2008. ClinicalTrials.gov NCT03751332.

The Effect of ABCB1 Polymorphisms on Serial Tacrolimus Concentrations in Stable Austrian Long-Term Kidney Transplant Recipients.

BACKGROUND: The multidrug resistance 1 gene (ABCB1) encodes P-glycoprotein (PGP), mainly expressed in the liver and engaged in metabolism of drugs including the immunosuppressant tacrolimus (TAC). ABCB1 single nucleotide polymorphisms (SNP) may significantly alter pharmacokinetics and influence TAC concentrations of kidney transplant recipients (KTR). METHODS: The genotype distribution of ABCB1 1236C>T, 2677G>T/A and 3435C>T was investigated among 96 Austrian KTR who were converted from cyclosporin to TAC. Dose adjusted TAC trough levels and L/D ratios were assessed at week 1, 2, 4, and 8, and month 3, 12, and 24, and the influence of ABCB1 genotypes on dose adjusted TAC trough levels and level to dose (L/D) ratios were analyzed. RESULTS: The genotype distributions for ABCB1 1236C>T were CC 36.4%, CT 5.2%, TT 58.3%, for ABCB1 2677G>T/A GA 2%, GG 63.5%, GT 20.8%, TA 1%, TT 12.5%, and for ABCB1 3435C>T CC 20.8%, CT 7.2%, TT 71.8%. Dose adjusted TAC trough levels and L/D ratios were independent of ABCB1 genotypes except for ABCB1 1236C>T at a single time point (week 2: 0.02599 [CC] vs. 0.05704 [CT] vs. 0.03218 [TT]; p = 0.024). CONCLUSIONS: Serial analyses of TAC trough levels revealed no significant association with important ABCB1 genotypes among stable long-term Austrian KTR.

Late Conversion of Kidney Transplant Recipients from Ciclosporin to Tacrolimus Improves Graft Function: Results from a Randomized Controlled Trial.

BACKGROUND: Tacrolimus (TAC) to ciclosporin A (CSA) conversion studies in stable kidney transplant recipients have reported varying effects on graft function. Here we study graft function (eGFR) trajectories using linear mixed models, which provide effect estimates on both slope and baseline level of GFR and offer increased statistical power. METHODS: Secondary analysis of a randomized controlled trial of CSA treated kidney transplant recipients with stable graft function assigned to receive 0.1 mg/kg/day TAC (target 5-8 ng/ml) or to continue CSA based immunosuppression (target 70-150 ng/ml) at a 2:1 ratio. Renal graft function was estimated via the MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) formulas. RESULTS: Forty-five patients continued CSA and 96 patients were converted to TAC with a median follow up of 24 months. Baseline demographics (except for recipient age) including native kidney disease, transplant characteristics, kidney graft function, medication use and comorbid conditions did not differ between groups. In respect to long-term renal graft function, linear mixed models showed significantly improved eGFR trajectories (eGFRMDRD: p<0.001, eGFRCKD-EPI: p<0.001) in the TAC versus CSA group over 24 months of follow up. Estimated eGFRCKD-EPI group differences between TAC and CSA were -3.49 (p = 0.019) at 3 months, -5.50 (p<0.001) at 12 months, and -4.48 ml/min/1.73m2 (p = 0.003) at 24 months of follow up. Baseline eGFR was a significant predictor of eGFR trajectories (eGFRMDRD: p<0.001, eGFRCKD-EPI: p<0.001). Significant effects for randomization group were evident despite short-term trough levels in the supratherapeutic range (27% (n = 26) of TAC patients at week one). Median TAC trough levels were within target range at week 4 after conversion. CONCLUSION: Conversion of CSA treated kidney transplant recipients with stable graft function to TAC (target 5-8 ng/ml) showed significantly improved long-term eGFR trajectories when compared to CSA maintenance (target 70-150 ng/ml). TRIAL REGISTRATION: ClinicalTrials.gov NCT00182559 EudraCT identifier: 2004-004209-98.

Knowledge-based immunosuppressive therapy for kidney transplant patients--from theoretical model to clinical integration.

Immunosuppressive therapy is a risky necessity after a patient received a kidney transplant. To reduce risks, a knowledge-based system was developed that determines the right dosage of the immunosuppresive agent Tacrolimus. A theoretical model, to classify medication blood levels as well as medication adaptions, was created using data from almost 500 patients, and over 13.000 examinations. This model was then translated into an Arden Syntax knowledge base, and integrated directly into the hospital information system of the Vienna General Hospital. In this paper we give an overview of the construction and integration of such a system.

Urine Osmolarity and Risk of Dialysis Initiation in a CKD Cohort.

BACKGROUND: Several experimental studies in rats and a few association studies in humans suggest that the antidiuretic action of vasopressin may accelerate the progression of chronic kidney disease. We undertook a retrospective analysis in a monocentric cohort of 273 patients with chronic kidney disease stages 1-4, focusing on a strong variable of interest, urinary osmolarity, and a strong endpoint, dialysis initiation. Data was analyzed in a multivariate proportional sub-distribution hazards model for competing risk data with appropriate co-variates. MAIN RESULTS: Over a median follow-up period of 92 months, dialysis was initiated in 105 patients. After adjustments for baseline creatinine clearance, and other confounding factors, a higher risk for initiation of dialysis was found in patients with higher urinary osmolarity. After 72 months, the estimated adjusted cumulative incidence probability for dialysis initiation was 15, 24, and 34% in patients with baseline urinary osmolarity of 315, 510, and 775 mosm/l, respectively (p = 0.033). Key Messages: In this retrospective, longitudinal study, a higher baseline urinary osmolarity was strongly associated with a higher risk of end-stage renal disease (after appropriate adjustments). Further, prospective studies are required to evaluate the possible benefit of interventions aiming at reducing urinary osmolarity as a potential treatment for slowing chronic kidney disease progression.

PSHREG: a SAS macro for proportional and nonproportional subdistribution hazards regression.

We present a new SAS macro %pshreg that can be used to fit a proportional subdistribution hazards model for survival data subject to competing risks. Our macro first modifies the input data set appropriately and then applies SAS's standard Cox regression procedure, PROC PHREG, using weights and counting-process style of specifying survival times to the modified data set. The modified data set can also be used to estimate cumulative incidence curves for the event of interest. The application of PROC PHREG has several advantages, e.g., it directly enables the user to apply the Firth correction, which has been proposed as a solution to the problem of undefined (infinite) maximum likelihood estimates in Cox regression, frequently encountered in small sample analyses. Deviation from proportional subdistribution hazards can be detected by both inspecting Schoenfeld-type residuals and testing correlation of these residuals with time, or by including interactions of covariates with functions of time. We illustrate application of these extended methods for competing risk regression using our macro, which is freely available at: http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/statistical-software/pshreg, by means of analysis of a real chronic kidney disease study. We discuss differences in features and capabilities of %pshreg and the recent (January 2014) SAS PROC PHREG implementation of proportional subdistribution hazards modelling.

Augmented backward elimination: a pragmatic and purposeful way to develop statistical models.

Statistical models are simple mathematical rules derived from empirical data describing the association between an outcome and several explanatory variables. In a typical modeling situation statistical analysis often involves a large number of potential explanatory variables and frequently only partial subject-matter knowledge is available. Therefore, selecting the most suitable variables for a model in an objective and practical manner is usually a non-trivial task. We briefly revisit the purposeful variable selection procedure suggested by Hosmer and Lemeshow which combines significance and change-in-estimate criteria for variable selection and critically discuss the change-in-estimate criterion. We show that using a significance-based threshold for the change-in-estimate criterion reduces to a simple significance-based selection of variables, as if the change-in-estimate criterion is not considered at all. Various extensions to the purposeful variable selection procedure are suggested. We propose to use backward elimination augmented with a standardized change-in-estimate criterion on the quantity of interest usually reported and interpreted in a model for variable selection. Augmented backward elimination has been implemented in a SAS macro for linear, logistic and Cox proportional hazards regression. The algorithm and its implementation were evaluated by means of a simulation study. Augmented backward elimination tends to select larger models than backward elimination and approximates the unselected model up to negligible differences in point estimates of the regression coefficients. On average, regression coefficients obtained after applying augmented backward elimination were less biased relative to the coefficients of correctly specified models than after backward elimination. In summary, we propose augmented backward elimination as a reproducible variable selection algorithm that gives the analyst more flexibility in adopting model selection to a specific statistical modeling situation.

Correlations and time course of FGF23 and markers of bone metabolism in maintenance hemodialysis patients.

OBJECTIVE: Parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF23) are elevated in secondary hyperparathyroidism. In hemodialysis, higher dialysate calcium (1.5 mmol/L) induces intradialytic suppression of iPTH, whereas its impact on FGF23 and markers of bone metabolism is unknown. We assessed the time course of FGF23 and markers of bone metabolism in relationship to dialysate calcium. DESIGN AND METHODS: In this prospective cohort study of 19 patients on maintenance hemodialysis, we measured serum calcium (sCa), inorganic phosphate (iP), blood urea nitrogen (BUN), ß2-microglobulin (ßMG), iPTH, FGF23, aminoterminal propeptide type 1 procollagen (P1NP), C-telopeptide of type I collagen for bone degradation (CTX-I), osteocalcin (OC), bone specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase (TRAP5b) during a single hemodialysis session at baseline, 1, 2, and 3h of dialysis. The time course of measured parameters was compared according to groups of prescribed dialysate calcium of 1.25 mmol/L and 1.5 mmol/L. RESULTS: iPTH declined in the 1.5 mmol/L dialysis group as serum calcium increased whereas it tended to increase in the 1.25 mmol/L group without significant changes in serum calcium. Patients on long-term dialysate calcium of 1.5 mmol/L had significantly lower CTX-I levels and tended to lower levels of iPTH, FGF23, OC, P1NP and TRAP5b at the start of dialysis compared to those on 1.25 mmol/L. CTX-I, FGF23 and OC but not BALP, P1NP and TRAP5b decreased during dialysis independent of dialysate calcium. CONCLUSIONS: In spite of immediate effects on iPTH, dialysate calcium does not acutely affect other parameters of bone and mineral metabolism. SHORT SUMMARY: Dialysate calcium concentration is known to have both immediate and longer-term impact on parathyroid hormone levels in hemodialysis patients. Little is known about the acute impact of dialysate calcium on bone metabolism. In this cross-sectional study of prevalent hemodialysis patients, we found no evidence of immediate short-term dialysate calcium-induced changes of fibroblast growth factor 23 or anabolic and catabolic markers of bone turnover during hemodialysis. However, differences in CTX-I and to a lesser extent other parameters between groups of higher and lower dialysate calcium suggest a longer-term effect that remains to be validated.

Urine osmolarity and risk of dialysis initiation in a chronic kidney disease cohort--a possible titration target?

BACKGROUND: Increasing evidence is linking fluid intake, vasopressin suppression and osmotic control with chronic kidney disease progression. Interestingly, the association between urine volume, urine osmolarity and risk of dialysis initiation has not been studied in chronic kidney disease patients before. OBJECTIVE: To study the relationship between urine volume, urine osmolarity and the risk of initiating dialysis in chronic kidney disease. DESIGN: In a retrospective cohort analysis of 273 patients with chronic kidney disease stage 1-4 we assessed the association between urine volume, urine osmolarity and the risk of dialysis by a multivariate proportional sub-distribution hazards model for competing risk data according to Fine and Gray. Co-variables were selected via the purposeful selection algorithm. RESULTS: Dialysis was reached in 105 patients over a median follow-up period of 92 months. After adjustment for age, baseline creatinine clearance, other risk factors and diuretics, a higher risk for initiation of dialysis was found in patients with higher urine osmolarity. The adjusted sub-distribution hazard ratio for initiation of dialysis was 2.04 (95% confidence interval, 1.06 to 3.92) for each doubling of urine osmolarity. After 72 months, the estimated adjusted cumulative incidence probabilities of dialysis were 15%, 24%, and 34% in patients with a baseline urine osmolarity of 315, 510, and 775 mosm/L, respectively. CONCLUSIONS: We conclude that higher urine osmolarity is associated with a higher risk of initiating dialysis. As urine osmolarity is a potentially modifiable risk factor, it thus deserves further, prospective research as a potential target in chronic kidney disease progression.

Renal elimination of sclerostin increases with declining kidney function.

CONTEXT: Sclerostin serum levels are increased in patients with chronic kidney disease (CKD). Osteoporosis and CKD often occur simultaneously. Currently antisclerostin antibodies are in clinical development for the treatment of osteoporosis. OBJECTIVE: The objective of this study was to study the renal handling of sclerostin. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a university hospital and outpatient renal clinic. PATIENTS: One hundred twenty men and women with CKD stage 1-5 participated in the study. INTERVENTION: Measurements of sclerostin in urine and serum (ELISA), renal function [estimated glomerular filtration rate (eGFR)], electrolytes, α1-microglobulin, PTH, vitamin D, and markers of bone turnover were conducted. Eight human kidney biopsies were stained for sclerostin using immunohistochemistry. MAIN OUTCOME MEASURE: Urinary excretion of sclerostin was measured. RESULTS: Urinary sclerostin excretion increased with declining eGFR (R=-0.75, P<.001), from 10.4 (±12.7) pmol/L in patients with eGFR greater than 90 mL/min per 1.73 m2 (CKD stage 1) to 117.9 (±65.4) pmol/L in patients with eGFR less than 15 mL/min per 1.73 m2 (CKD stage 5, P<.001). Fractional excretion of sclerostin increased with declining eGFR (R=-0.83, P<.001) from 0.45% (±0.6%) in CKD 1 to 26.3% (±17.6%) in CKD 5 (P<.001). Fractional excretion of sclerostin correlated with fractional excretion of α1-microglobulin (R=0.82, P<.001). No association between serum sclerostin and fractional excretion of phosphorus was found in a multivariate analysis. Sclerostin was detected in proximal tubular cells, showing a diffuse cytoplasmic staining pattern. CONCLUSION: Increased sclerostin serum levels in CKD patients are not due to decreased renal elimination. On the contrary, renal elimination increases with declining kidney function. Whether this has consequences on antisclerostin antibody dosing, efficacy, or safety in patients with CKD remains to be determined.

Pretransplant risk stratification for early survival of renal allograft recipients.

BACKGROUND: Baseline comorbidities influence patient outcomes in renal transplantation. Identification of high-risk recipients for patient death and early allograft loss might lead to superior stratification. MATERIAL AND METHODS: In this retrospective study, risk stratification models were developed in a cohort of 392 kidney transplant recipients and validated in an independent cohort to predict short-term (2 year) outcomes. RESULTS: Peripheral arterial disease [OR 7·7 (95% confidence interval (CI): 2·45-24·60); P < 0·001], use of oral anticoagulation [OR 18·68 (95% CI: 3·77-92·46); P < 0·0001], smoking [OR 5·15 (95% CI: 1·67-15·84); P = 0·004], recipient age > 60 years [OR 7·28 (95% CI: 2·33-22·69; P = 0·001)], serum albumin < 40 g/L [OR 5·08 (95% CI: 1·82-14·19); P = 0·002], serum calcium ≥ 2·42 mM [OR 6·47 (95% CI: 1·37-30·58); P = 0·02] living donation [OR 2·95, (95% CI: 0·31-28·29); P = 0·34)] and previous haemodialysis [OR 3·33, (95% CI: 0·39-28·11); P = 0·27)] were included in the model. The validated model discriminated between low- (< 3 points) and high-risk recipients (> 8·5 points) with mortality rates of 0% vs. 54%. The comparison of the model with the Charlson comorbidity index (CCI) yielded significantly better receiver operating characteristic (ROC) areas (Novel Score ROC: 0·87 vs. CCI: 0·72, P = 0·0012). Early allograft loss was associated with presensitization [OR 3·02 (95% CI: 1·29-7·09); P = 0·011] and presence of hepatitis C antibodies [OR 2·42 (95% CI: 1·09-5·34); P = 0·029]. A risk model (ROC: 0·62) for allograft loss could not be developed. CONCLUSION: Risk stratification based on the novel score might identify high-risk recipients with disproportional risk of early patient death and lead to optimized strategies.

Effect of oral sodium bicarbonate supplementation on progression of chronic kidney disease in patients with chronic metabolic acidosis: study protocol for a randomized controlled trial (SoBic-Study).

BACKGROUND: Overt chronic metabolic acidosis in patients with chronic kidney disease develops after a drop of glomerular filtration rate to less than approximately 25 mL/min/1.73 m2. The pathogenic mechanism seems to be a lack of tubular bicarbonate production, which in healthy individuals neutralizes the acid net production. As shown in several animal and human studies the acidotic milieu alters bone and vitamin D metabolism, induces muscle wasting, and impairs albumin synthesis, aside from a direct alteration of renal tissue by increasing angiotensin II, aldosteron and endothelin kidney levels. Subsequent studies testing various therapeutic approaches in very selected study populations showed that oral supplementation of the lacking bicarbonate halts progression of decline of renal function. However, due to methodological limitations of these studies further investigations are of urgent need to ensure the validity of this therapeutic concept. METHODS/DESIGN: The SoBic-study is a single-center, randomized, controlled, open-label clinical phase IV study performed at the nephrological outpatient service of the Medical University of Vienna. Two-hundred patients classified to CKD stage 3 or 4 with two separate measurements of HCO3- of <21 mmol/L will be 1:1 randomized to either receive a high dose of oral sodium bicarbonate with a serum target HCO3- level of 24±1 mmol/L or receive a rescue therapy of sodium bicarbonate with a serum target level of 20±1 mmol/L. The follow up will be for two years. The primary outcome is the effect of sodium bicarbonate supplementation on renal function measured by means of estimated glomerular filtration rates (4-variable-MDRD-equation) after two years. Secondary outcomes are change in markers of bone metabolism between groups, death rates between groups, and the number of subjects proceeding to renal replacement therapy across groups. Adverse events, such as worsening of arterial hypertension due to the additional sodium consumption, will be accurately monitored. DISCUSSION: We hypothesize that sufficiently balanced acid-base homeostasis leads to a reduction of decline of renal function in patients with chronic kidney disease. The concept of an exogenous bicarbonate supplementation to substitute the lacking endogenous bicarbonate has existed for a long time, but has never been investigated sufficiently to state clear treatment guidelines. TRIAL REGISTRATION: EUDRACT Number: 2012-001824-36.

Effect of conversion from ciclosporin to tacrolimus on endothelial progenitor cells in stable long-term kidney transplant recipients.

BACKGROUND: Endothelial progenitor cell (EPC) counts are proposed surrogate markers for vascular function and cardiovascular risk. The effect of tacrolimus (TAC) on EPC is unknown. METHODS: In this randomized controlled trial, we assigned 148 stable long-term kidney transplant recipients (KTR) to maintaining ciclosporin (CSA) or to commencing TAC-based immunosuppression at a 2:1 ratio. EPC counts (CD34/KDR) after 24 months were defined as primary endpoint. RESULTS: The intent-to-treat analysis included 141 KTR (estimated glomerular filtration rate, 46.7 [40.1-61.8] mL/min per 1.73 m). Median (interquartile range [IQR]) EPC counts at baseline and month 24 were 6 (2-9) and 3 (1-9) cells and 4 (2-8) and 2 (0-5) cells per 5×10 mononuclear cells in CSA and TAC, respectively. Median (IQR) circulating angiogenic cells at baseline and month 24 were 28 (10.7-57) and 44.33 (14.6-59.8) cells and 22 (10.8-41) and 21 (9.7-49.5) cells per high-power field in CSA and TAC, respectively. Median (IQR) endothelial cell colony-forming units count per well at baseline and month 24 were 10.5 (3.3-34.3) and 4.38 (1.7-26.5) in CSA and significantly declined from 9.31 (1.8-29.3) to 4.13 (1.1-9.5) in TAC (P=0.003). There were no cardiovascular events in either group. CONCLUSION: Although late conversion from CSA to TAC appears safe in KTR, conversion to TAC has no favorable effect on EPC. Low EPC levels are associated with a higher risk of subsequent cardiovascular events and are therefore of prognostic value. Their trend to decline over time deserves further examination.

Renal function in heart failure: a disparity between estimating function and predicting mortality risk.

AIMS: To compare the predictive value of estimated renal function calculated by the Chronic Kidney Disease Epidemiology Collaboration (eGFR(CKD-EPI)), four-variable Modification of Diet in Renal Disease (eGFR(MDRD-4)), and Cockcroft-Gault [estimated creatinine clearance (eCcr)] equation in terms of all-cause mortality in heart failure. Renal function is an important prognostic factor in heart failure. Established methods of estimating renal function are known to under-/overestimate true function in certain settings. METHODS AND RESULTS: A total of 800 systolic heart failure outpatients (mean age 57 ± 11.5 years, 82% male) were studied over a median follow-up of 121 (Q1-Q3: 110-130) months. The highest systematic difference was seen between eCcr and eGFR(MDRD-4) [+12.33 points (mean), 95% limits of agreement -22.35 to 47.01; generalized kappa = 0.36]. eGFR(MDRD-4) and eGFR(CKD-EPI) were the most similar [-4.16 points (mean), 95% limits of agreement -11.56 to 3.25; generalized kappa = 0.74]. Up to 35.4% of patients were reclassified into different estimated glomerular filtration rate (eGFR) categories when comparing eGFR(CKD-EPI) with eCcr and eGFR(MDRD-4). eGFR(CKD-EPI) performed marginally better in terms of predicting all-cause mortality than eGFR(MDRD-4), as univariate areas under the time-dependent receiver operating characteristic curves (AUC), marginal and partial proportions of explained variation (PEV), net reclassification improvement (NRI), and the integrated discrimination improvement (IDI) for 5 years of follow-up were significantly higher for eGFR(CKD-EPI) than for eGFR(MDRD-4). CONCLUSION: In this cohort of heart failure patients, eGFR(CKD-EPI) was marginally better in predicting all-cause mortality than eGFR(MDRD-4). Estimated function differed widely between equations and is likely to have an effect on therapy choice.

Clinical evaluation of two novel biointact PTH(1-84) assays in hemodialysis patients.

OBJECTIVES: In chronic kidney disease-mineral and bone disorder (CKD-MBD), most treatment decisions are guided by parathyroid hormone (PTH) levels. Here, we aimed at assessing the technical and clinical performance of two novel automated biointact PTH(1-84) assays, from Roche Diagnostics (Ro) and DiaSorin (DS), in hemodialysis patients. DESIGN AND METHODS: We recorded demographics, dialysis treatment characteristics, pharmacotherapy for CKD-MBD and laboratory work-up. Statistical methods included Passing-Bablok, and multiple linear regression. RESULTS: 121 patients, dialyzing on average for 3.5 years (range: 0.1-22.5), with serum phosphate 1.9±0.6 mmol/L (mean±SD), participated in the study. Median serum concentration for intact PTH was 223 ng/L (range: 5-2844), and for biointact PTH(1-84) was 136 ng/L (Ro; range: 1-1644), respectively 138 ng/L (DS; range: 4-1580). Both biointact assays were significantly correlated (r=0.98; Ro=0.87×DS+19.60). Bland-Altmann plots revealed an average bias ±2 SD of 10±27 ng/L below 200 ng/L, and -32±157 ng/L above 200 ng/L (Ro minus DS). The variably adjusted association between PTH and serum phosphate was very similar, regardless of the PTH assay, but this was not the case for PTH-derived measures (ratios biointact/intact; differences intact minus biointact). (Log)PTH concentrations as well as serum phosphate were significantly associated with serum creatinine, but only in patients with >0 mL urine per day. CONCLUSIONS: Results from Roche and DiaSorin biointact PTH(1-84) assays were well correlated, but showed increased deviations at higher concentrations. Biointact PTH(1-84) levels are roughly two third of intact PTH. The association between PTH and serum creatinine may depend on residual renal clearance of PTH and/or serum phosphate.

Knowledge-based tacrolimus therapy for kidney transplant patients.

Immunosuppressive therapy is necessary when patients with chronic kidney disease receive a kidney transplant. Certain immunosuppressive agents need therapeutic drug monitoring. The goal of this paper was to identify adaptation rules for Tacrolimus therapy from a clinical data set. For knowledge acquisition, patient data from 1995 to 2008 from the Department of Nephrology and Dialysis of the Vienna General Hospital were used, including patient demographics, laboratory parameters, time since kidney transplantation and other immuno-suppressive drugs administered. Tacrolimus was chosen from the available immunosuppressive drugs. By applying a regression tree, we create homogeneous groups of data. Models were generated for these groups that can predict the level of the drug concentration for the next ward round. A knowledge base was developed on the basis of the determined models, which is used within a clinical decision support system for Tacrolimus therapy planning, which was integrated into clinical routine.

Routinely available biomarkers improve prediction of long-term mortality in stable coronary artery disease: the Vienna and Ludwigshafen Coronary Artery Disease (VILCAD) risk score.

AIMS: Previous risk assessment scores for patients with coronary artery disease (CAD) have focused on primary prevention and patients with acute coronary syndrome. However, especially in stable CAD patients improved long-term risk prediction is crucial to efficiently apply measures of secondary prevention. We aimed to create a clinically applicable mortality prediction score for stable CAD patients based on routinely determined laboratory biomarkers and clinical determinants of secondary prevention. METHODS AND RESULTS: We prospectively included 547 patients with stable CAD and a median follow-up of 11.3 years. Independent risk factors were selected using bootstrapping based on Cox regression analysis. Age, left ventricular function, serum cholinesterase, creatinine, heart rate, and HbA1c were selected as significant mortality predictors for the final multivariable model. The Vienna and Ludwigshafen Coronary Artery Disease (VILCAD) risk score based on the aforementioned variables demonstrated an excellent discriminatory power for 10-year survival with a C-statistic of 0.77 (P < 0.001), which was significantly better than an established risk score based on conventional cardiovascular risk factors (C-statistic = 0.61, P < 0.001). Net reclassification confirmed a significant improvement in individual risk prediction by 34.8% (95% confidence interval: 21.7-48.0%) compared with the conventional risk score (P < 0.001). External validation of the risk score in 1275 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up of 9.8 years) achieved similar results (C-statistic = 0.73, P < 0.001). CONCLUSION: The VILCAD score based on a routinely available set of risk factors, measures of cardiac function, and comorbidities outperforms established risk prediction algorithms and might improve the identification of high-risk patients for a more intensive treatment.

Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure.

BACKGROUND: Recent studies show associations between inorganic phosphate and risk of heart failure in the general population as well as between fibroblast growth factor 23 (FGF-23) and outcome in coronary heart disease. This study was carried out to assess whether circulating levels of inorganic phosphate and FGF-23, a new central hormone in mineral bone metabolism, predict outcome in systolic heart failure. MATERIALS AND METHODS: Ninety-nine consecutive outpatients with systolic heart failure were enrolled. Mean (SD) age was 61 years (11), mean left ventricular ejection fraction (LVEF) was 33% (10), 82 patients were men, median estimated creatinine clearance was 83 mL/min (Q(1) -Q(3) 58-106), median NTproBNP level was 803 pg/mL (Q(1) -Q(3) 404-2757), median inorganic phosphate was 1·12 mM (Q(1) -Q(3) 1·02-1·22), median FGF-23 was 39·02 pg/mL (Q(1) -Q(3) 32·45-55·86) and median follow-up was 35 months. Associations between inorganic phosphate, FGF-23 and endpoints were assessed using Cox regression analyses. RESULTS: Inorganic phosphate and FGF-23 levels were significantly higher (P < 0·001 and P = 0·009) in patients reaching the combined endpoint of cardiac hospitalization or death. FGF-23 (ln) predicted all-cause mortality (hazard ratio (HR) 5·042, P = 0·032) in a model adjusted for age, gender, estimated creatinine clearance, LVEF, New York Heart Association (NYHA) stage and NTproBNP level. Inorganic phosphate predicted heart failure hospitalization (HR 26·944, P = 0·021), cardiac hospitalization (HR 16·016, P = 0·017) and the combined endpoint (HR 13·294, P = 0·015) in models adjusted for the same co-variables. CONCLUSION: The results of this study demonstrate the independent prognostic value of inorganic phosphate and FGF-23 in heart failure even in the context of established risk markers.