An observational study of the effectiveness of darbepoetin alpha administered in dialysis patients once every 2 weeks for 12 months.

AIMS: Erythropoiesis-stimulating agents (ESAs) are recommended for managing renal anemia. ALTERNATE is an observational study in European and Australian dialysis patients evaluating darbepoetin a (DA) once every 2 weeks (Q2W) in clinical practice. METHODS: Adult dialysis patients initiating treatment with DA Q2W were eligible regardless of previous/current ESA use. Data were collected 6 months before and 12 months after Q2W initiation. The primary endpoint was hemoglobin (Hb) concentration 12 months after initiation. RESULTS: A total of 6,112 patients were enrolled; 6,104 were eligible (87% hemodialysis, 12% peritoneal dialysis). Before initiation, 77.3%, 8.8%, and 7.8% of patients were receiving DA, epoetin beta, and epoetin alpha, respectively; 6% were ESA naïve. Mean (95% CI) Hb (g/dl) was 11.68 (11.63-11.72) 6 months before initiation, 12.00 (11.97-12.04) at initiation, and 11.62 (11.58-11.66) 12 months after initiation. Geometric mean (95% CI) weekly ESA dose (µg/wk) was 27.27 (26.62-27.93) immediately before initiation, 23.69 (23.28 - 24.10) at initiation, and 26.80 (26.12-27.49) 12 months after initiation. At month 12, 77.3% of patients were receiving DA Q2W. CONCLUSIONS: This large observational study demonstrates that Hb concentrations can be effectively maintained over 12 months in a general dialysis population with DA Q2W without an increase in ESA dose.

Mortality due to bleeding, myocardial infarction and stroke in dialysis patients.

Essentials Mortality due to bleeding vs. arterial thrombosis in dialysis patients is unknown. We compared death causes of 201 918 dialysis patients with the general population. Dialysis was associated with increased mortality risks of bleeding and arterial thrombosis. Clinicians should be aware of the increased bleeding and thrombosis risks. SUMMARY: Background Dialysis has been associated with both bleeding and thrombotic events. However, there is limited information on bleeding as a cause of death versus arterial thrombosis as a cause of death. Objectives To investigate the occurrence of bleeding, myocardial infarction and stroke as causes of death in the dialysis population as compared with the general population. Methods We included 201 918 patients from 11 countries providing data to the ERA-EDTA Registry who started dialysis treatment between 1994 and 2011, and followed them for 3 years. Age-standardized and sex-standardized mortality rate ratios for bleeding, myocardial infarction and stroke as causes of death were calculated in dialysis patients as compared with the European general population. Associations between potential risk factors and these causes of death in dialysis patients were investigated by calculating hazard ratios (HRs) with 95% confidence intervals (CIs) by the use of Cox proportional-hazards regression. Results As compared with the general population, the age-standardized and sex-standardized mortality rate ratios in dialysis patients were 12.8 (95% CI 11.9-13.7) for bleeding as a cause of death (6.2 per 1000 person-years among dialysis patients versus 0.3 per 1000 person-years in the general population), 13.4 (95% CI 13.0-13.9) for myocardial infarction (22.5 versus 0.9 per 1000 person-years), and 12.4 (95% CI 11.9-12.9) for stroke (14.3 versus 0.7 per 1000 person-years). Conclusion Dialysis patients have highly increased risks of death caused by bleeding and arterial thrombosis as compared with the general population. Clinicians should be aware of the increased mortality risks caused by these conditions.

Preservation of renal function after heart transplantation: initial single-center experience with sirolimus.

BACKGROUND: Long-term survivors of heart transplantation are often confronted with chronic kidney disease, by definition related to the intake of calcineurin-inhibitors. Sirolimus is increasingly proposed as an alternative immunosuppressive agent due to its absence of nephrotoxicity. METHODS: Between November 2002 and November 2003, 9 adult heart transplant candidates with moderate to severe chronic renal disease were switched from cyclosporine to sirolimus. The conversion scheme consisted of an immediate stop of cyclosporine and an 8-mg loading dose of sirolimus, followed by 3 mg/d; after 1 week, the sirolimus dose was adjusted to maintain trough levels between 5 and 15 microg/L. The majority of patients were on corticosteroids, and on either azathioprine or mycophenolate mofetil. At conversion, the mean serum creatinine level was 2.11 (+/-0.4) mg/dL and the mean glomerular filtration rate (GFR) was 32 (+/-7) mL/min/1.73 m(2). Prior to conversion, the renal dysfunction was predominantly stable. RESULTS: After conversion, there were 7 dropouts (75%) due to several side effects related to sirolimus: edema (n = 2), general discomfort (n = 2), delayed wound healing (n = 1), cardiac thrombus (n = 1), and diarrhea (n = 1). The median treatment time with Sirolimus, therefore, was only 4.0 months. While on sirolimus, the renal function of all patients remained unchanged or showed even some improvement. Retrospective nephrological review revealed severe renal artery stenoses in 2 patients and serious generalized abdominal and renal atheromatosis in 7 patients. No cardiac dysfunction was seen. CONCLUSION: Conversion from cyclosporine to sirolimus was problematic due to sirolimus side effects, occurring at any time after the switch. One should also question whether chronic kidney disease after heart transplantation is routinely caused by the administration of calcineurin-inhibitors, in view of the generalized renal and abdominal atheromatosis.

The outcome of kidney grafts from multiorgan donors and kidney only donors.

From 1988 to 1994, 15356 renal cadaveric transplantations have been performed within the Eurotransplant area (Austria, Belgium, Germany, Luxembourg and The Netherlands); 8746 kidneys were obtained from multiorgan donors and 6610 from kidney only donors. To evaluate the impact of the procurement policy, multiorgan donor (MOD) versus kidney only donor (KOD), on renal graft survival, an observational study has been performed. Multivariate analysis using Cox's proportional hazards model served to quantify the role of the procurement policy on renal graft survival after adjustment for other prognostic factors. The kidneys obtained from MODs had a significantly better graft survival at 1, 3, and 5 years after transplantation than the kidneys obtained from KODs (85%, 75%, and 58% versus 78%, 68%, and 46% (P=0.0001). In the Cox model, patients transplanted with a KOD kidney had a 1.28 times higher risk of losing their graft than patients transplanted with a MOD kidney. This benefit in graft survival for MOD kidneys could not be explained by the fact that the MODs were younger and male, and that UW was used as preservation solution. A plausible explanation is that MODs, on average, because of the nonrenal transplants, are better supervised. We expect that optimal donor management will contribute to a better outcome of all renal grafts.

Analysis of the renal transplant waiting list: application of a parametric competing risk method.

BACKGROUND: The strong competition for scarce renal graft resources jeopardizes an individual patient's chances of a transplantation within a reasonable time scale. This study was undertaken to quantify these chances of receiving a transplant. METHODS: All patients registered for their first renal allograft between January 1980 and December 1993 (n=40,636) in Eurotransplant were selected. The influence of patient characteristics, such as age, HLA phenotype frequency, % panel-reactive antibodies, period of registration, and ABO blood group, on the waiting list outflow was studied. The competing risk method was applied, and Poisson models were built to estimate the risk factor effects. RESULTS: The chance of transplantation within 10 years after registration was overestimated by Kaplan-Meier (84%); using the competing risk method it was only 74%. The predicted chance for death on the waiting list was overestimated by 33% (45% Kaplan-Meier vs. 12% competing risk). A time-varying covariate effect on the chances of waiting list outflow was observed. Favorable factors for quick transplantation, such as blood group AB or a common HLA phenotype, were no longer seen to be driving forces for transplantation once 5 to 6 years of waiting time had been accrued. CONCLUSION: When multiple outcomes exist, Kaplan-Meier estimates should not be interpreted as survival rates, while competing risk estimates yield appropriate chances. A significantly decaying effect of the usual allocation parameters is observed with ongoing waiting time. This phenomenon is the statistical basis for redesigning allocation strategies. Organ exchange algorithms should have the potential to adapt to these time-varying effects.

The new Eurotransplant Kidney Allocation System: report one year after implementation. Eurotransplant International Foundation.

BACKGROUND: Upon the availability of a cadaveric donor kidney, a delicate allocation process precedes every transplantation. A remodeled Eurotransplant Kidney Allocation System (ETKAS)-derived from simulation studies-was installed in March 1996. The purpose was to adjust long waiting times and international exchange balances, while aiming at an optimal HLA-mismatch distribution. The new ETKAS consisted of a point-score system that was 100% patient oriented. METHODS: The impact of the new ETKAS on the composition of the waiting list, and the outcome of the allocation procedures during its first year, were evaluated and compared with the results obtained in 1995. RESULTS: The percentage of long-waiting patients and of patients with poorly matchable HLA phenotype increased significantly, from 9% to 19% and from 19% to 29%, respectively. Zero HLA-A-, HLA-B-, HLA-DR-mismatched patients still comprised 23% of the kidney transplant activity. The kidney exchange of the different Eurotransplant countries became balanced within 4 months; this persisted during the rest of the year. Pediatric patients had a high transplantation rate due to an assignment of extra points. The composition of the waiting list showed, after 1 year, fewer long-waiting patients and fewer patients with rare HLA phenotypes. CONCLUSIONS: The new ETKAS was able in its first year to meet the goals set at its introduction. In comparison with the old ETKAS, there was a better trade-off between HLA matching and waiting time. The value of computer simulation studies has been demonstrated impressively in the context of organ allocation.

Cross-reactive group matching does not lead to a better allocation and survival of donor kidneys.

BACKGROUND: In cadaveric renal transplantation HLA-A, -B, -DR matching of donor and recipient is beneficial for graft survival. However, allocation based on HLA matching seems to favor recipients with more frequently occurring HLA antigens. In this study we investigated whether matching on the basis of cross-reactive groups (CREGs), defined according to the United Network for Organ Sharing (UNOS), would be a good alternative for the allocation of kidneys without negatively influencing graft survival. Theoretically, this approach would provide more recipients with an immunologically well-matched donor organ. METHODS: The influence of CREG matching on graft survival was studied in univariate analyses using the Eurotransplant database. RESULTS: No beneficial effect of CREG matching was observed, whereas a significant HLA matching effect was observed in the 0 CREG mismatched donor/ recipient combinations. Only in the small subgroup with 1 MM for HLA-A, -B and 0 MM for HLA-DR, a significantly better survival was observed, when this mismatch belonged to the 0 or 1 MM CREG group versus two or more MM CREG group. However, this subgroup concerns only 8% of the transplants performed. CONCLUSIONS: In contrast to other reports, our study showed that HLA matching is by far more beneficial than CREG matching. In the homogenous Eurotransplant population, adjusting the matching criteria toward CREG matching would not lead to an improved graft survival.

Mortality rates after heart transplantation: how to compare center-specific outcome data?

BACKGROUND: Studies of outcome in cardiac transplantation have focused primarily on identifying patient- and donor-related factors associated with patient mortality. Less consideration has been given to the impact of the transplant center. This study was undertaken to assess variability in heart transplantation outcome in Eurotransplant centers to provide a framework for auditing. METHODS AND RESULTS: In a 2-year period, 1,401 adult patients underwent heart transplantation in 45 centers. The 1-year patient survival rate was 76% (95% CI, 74%-78%) with a range of 0% to 100% at the center level. The risk-adjusted center effect on mortality was estimated by calculating a standardized difference between the observed number of deaths 1 year after transplantation and the expected number of deaths based on the case mix. By assessing within- and between-center variations with empirical Bayes (EB) methods, after adjustment for all registered prognostic factors, an improved estimate of the true center effect was obtained. Compared with the standard risk-adjusted center effect method, fewer outlying centers were identified with the EB method. CONCLUSION: EB methods, because they are known to incorporate more information from the data, enable a more precise and realistic portrayal of heart transplant centers' performances, compared with other risk-adjusted center effect methods. In the context of auditing procedures, EB methods should preferably be used for the identification of centers that deviate significantly from quality standards.

Permanent detrimental effect of nonimmunological factors on long-term renal graft survival: a parsimonious model of time-dependency.

PURPOSE: We attempted to model and test the pattern of effects of prognostic factors on renal graft survival during the posttransplantation time course. PATIENTS AND METHODS: Patients who received a cadaveric kidney-only transplant between January 1990 and December 1995 in Eurotransplant, who received cyclosporine as induction therapy, and who had a complete follow-up at the time of analysis were included in the study (n= 10614). An index summarizing all covariate information was calculated and used for modeling the time-dependent effects with relation to graft failure. RESULTS: The immunological factors (HLA mismatch and % panel-reactive antibody) were seen to have a slowly decreasing negative effect on renal graft survival. The cold ischemic trauma (>24 hr) exerted a permanent detrimental effect on the grafts. The use of organs obtained from old donors was associated with a constant higher risk of graft loss. CONCLUSIONS: An analysis of determinants of human allograft dysfunction should also study the interaction between the effects and time. Nonimmunological factors had a constant detrimental effect on graft failure, whereas the impact of the immunological factors--although remaining important for late graft loss--very slowly decreased. In the context of marginal transplants, clustering of unfavorable factors should be avoided to prevent late graft losses.

Listing for lung transplantation: life expectancy and transplant effect, stratified by type of end-stage lung disease, the Eurotransplant experience.

BACKGROUND: Increased referral for lung transplantation, persistent shortage of donor lungs, and moderate transplant outcome call not only for adequate listing criteria, but also for an optimal allocation scheme. We used global cohort survival after listing and survival benefit from transplantation to study the effect of a lung allocation scheme, primarily driven by waiting time, on the different types of end-stage lung disease. METHODS: We followed all adult patients consecutively listed for first, lung-only transplantation between 1990 and 1996 (n = 1,208) for at least 2 years, with an additional 2-year follow-up after transplantation (n = 744). We used the competing risk method, the Kaplan-Meier method, and a time-dependent non-proportional hazards model to analyze waiting-list outcome and global mortality after listing, post-transplant survival, and transplant effect, respectively. Each analysis was stratified for type of end-stage lung disease. RESULTS: At 2 years, 57% of the total cohort had received lung transplants, whereas 25% had died on the waiting list. The 2-year survival post-transplant was 55%. The global mortality of the cohort, since listing, amounted to 46% at 2 years. Compared with continued waiting, patients experienced benefit from transplantation by Day 100, which lasted until the end of the 2-year analysis period. We noticed the highest global mortality rates for patients with pulmonary fibrosis and pulmonary hypertension (54% and 52%); emphysema patients had the lowest (38%). Patients with pulmonary fibrosis and cystic fibrosis had much earlier benefit from transplantation, 55 and 90 days, respectively. Transplantation also benefited emphysema patients by Day 260. CONCLUSIONS: Lung transplantation conferred transplant benefit in a Western European cohort of adults, in particular for patients with pulmonary fibrosis and cystic fibrosis, but also for patients with emphysema. The global survival rate, reflecting the real life expectancy for a newly listed transplant candidate, is poor for patients with pulmonary fibrosis and pulmonary hypertension. Allocation algorithms that lessen the impact of waiting time and take into account the type of end-stage lung disease should be developed.

Lung transplant waiting list: differential outcome of type of end-stage lung disease, one year after registration.

BACKGROUND: Donor lung scarcity, distinct natural courses of the different types of end-stage lung diseases, and lung allocation schemes demand appropriate candidate acceptance for a lung transplant and time of listing. This study was undertaken to investigate the association between type of end-stage lung disease and outcome, 1 year after a lung transplant candidate was put on the waiting list. METHODS: From 1990 to 1995, 1376 adult patients were registered for a first lung (n = 1006) or heart-lung (n = 370) transplantation in Eurotransplant. All patients were followed for at least 1 year. For each type of end-stage lung disease (cystic fibrosis, pulmonary fibrosis, emphysema, pulmonary hypertension, congenital heart disease, and other), chances of transplantation, of death on the waiting list, and of removal for other reasons, 1 year after listing, were calculated with the competing risks method. A multivariate Cox regression model was used to assess the influence of the type of end-stage lung disease on the waiting list outflow among other prognostic variables. RESULTS: Lung transplant candidates with emphysema and with pulmonary fibrosis had the highest chance of a transplant; however, patients with pulmonary fibrosis had also the highest probability of dying while waiting, while the emphysema patients and those with the type "other" had the lowest probability. In the multivariate analysis, the type of end-stage lung disease appeared as an independent prognostic factor for both outcomes. Compared to the patients with cystic fibrosis (reference group), only patients with pulmonary fibrosis had a significantly higher chance of a transplant (RR = 1.50); the lowest chance of death for the emphysema and the "other" patients was confirmed (RR = 0.53 and RR = 0.51, respectively). Recipient size, ABO blood group, country and epoch of listing also had a significant impact on the transplant chance, while country of listing and recipient age were the other factors independently influencing the chance of dying on the waiting list. On the heart-lung waiting list, the type of end-stage lung disease solely affected the chance of death prior to transplant. Compared with cystic fibrosis, pulmonary fibrosis had a significantly higher risk (RR = 2.93), closely followed by pulmonary hypertension (RR = 2.57). Factors crucial for the chance of a heart-lung transplant were recipient size, ABO blood group and country of listing. CONCLUSIONS: The type of end-stage lung disease is a distinctive factor for predicting survival on the lung and heart-lung transplant waiting list, and should be taken into account whenever assessing waiting list outcomes. When developing lung allocation schemes, it is medically justified to incorporate the type of end-stage lung disease.

Iso-risk curves as a tool for clinical decision-making: donor factors and medical urgency in cardiac transplantation.

UNLABELLED: BACKGROUND; No significant improvement of overall graft survival in cardiac transplantation has occurred during the past decade, notwithstanding the identification of several prognostic donor and recipient risk factors. By translating multivariate results into iso-risk curves plots, stratified for medical urgency, we attempt to present results in a more practical manner, to be used as guidelines at the time of donor heart offer and of allocation. METHODS: We analyzed all first heart-only transplants performed in adults and carried out between January 1, 1997, and June 30, 1998 (N = 1120). Before transplant, 687 patients were at home, 233 on hospital wards, and 200 on the intensive care unit. The overall Cox model yielded 5 independent factors associated with 1-year graft outcome: donor age, donor:recipient weight ratio, medical urgency, end-stage heart disease, and transplant country. We used the significant donor variables of donor age and donor:recipient weight ratio for the iso-risk curves; we calculated relative risks for all combinations of donor age and donor:recipient weight ratio. We obtained iso-risk curves by linking equal relative risks. RESULTS: All iso-risk curves showed that with older donor age, the donor:recipient weight ratio must be higher to obtain the same relative risk for all 3 medical urgency groups. The more urgent the heart transplant candidate, the higher the course of the iso-risk curve for all donor ages. CONCLUSIONS: Iso-risk curve is an elegant tool for presenting multivariate analyses in a more practical and patient-oriented manner. The more understandable prognostic factors become the more likely we are to achieve better results in cardiac transplantation and to use more optimally donor hearts. As an example, we have demonstrated the interaction between donor age, donor:recipient size ratio, and medical urgency.

Cardioscopy and robotic assistance for the diagnosis of intraventricular endocarditis.

A 44-year-old male patient with an undefined mass in the left ventricular endocardium was scheduled for minimally invasive cardiac surgery. Ventricular investigation and tissue biopsies were completed with the help of a voice-controlled robotic arm. Pathologic examination revealed non-bacterial thrombotic endocarditis. In addition to videoscopy, robotic assistance allows an easier diagnostic and therapeutic approach of intraventricular pathologies.

Demand, supply and allocation in Eurotransplant.

The main problem in organ transplantation is the continuing shortage of organ donors. Despite all efforts no major significant increases in organ availability are observed during the year 1996 in the participating Eurotransplant counties, while the demand i.e. the waiting lists are still increasing. Shortage of organs will also have its effects and constraints on the distribution i.e. the allocation of scarce organs. To meet the demand of the renal transplantation programs a special kidney allocation system was designed based upon many simulation studies. Already a few months after implementation of the new system very promising results were observed i.e. the discrepancies between the different countries in terms of kidney procurement and transplantation frequencies disappeared. Furthermore, twice as much long waiting kidney patients have been transplanted as previously and the percentage of well matched HLA donor-recipient combinations remained surprisingly high, nearly 24%.

Effect of receiving a heart transplant: analysis of a national cohort entered on to a waiting list, stratified by heart failure severity. Comparative Outcome and Clinical Profiles in Transplantation (COCPIT) Study Group.

OBJECTIVE: To determine whether there is a survival benefit associated with cardiac transplantation in Germany. DESIGN: Prospective observational cohort study. SETTING: All 889 adult patients listed for a first heart transplant in Germany in 1997. MAIN OUTCOME MEASURE: Mortality, stratified by heart failure severity. RESULTS: Within 1 year after listing, patients with a predicted high risk had the highest global death rate (51% v 32% and 29% for medium and low risk patients respectively; P<0.0001), had the highest risk of dying on the waiting list (32% v 20% and 20%; P=0.0003), and were more likely to receive a transplant (48% v 45% and 41%; P=0.01). Differences between the risk groups in outcome after transplantation did not reach significance (P=0.2). Transplantation was not associated with a reduction in mortality risk for the total cohort, but it did provide a survival benefit for the high risk group. CONCLUSION: Cardiac transplantation in Germany is currently associated with a survival benefit only in patients with a predicted high risk of dying on the waiting list. Patients with a predicted low or medium risk have no reduction in mortality risk associated with transplantation; they should be managed with organ saving approaches rather than transplantation.

Mortality due to pulmonary embolism, myocardial infarction, and stroke among incident dialysis patients.

BACKGROUND: It is has been suggested that dialysis patients have lower mortality rates for pulmonary embolism than the general population, because of platelet dysfunction and bleeding tendency. However, there is limited information whether dialysis is indeed associated with a decreased mortality risk from pulmonary embolism. OBJECTIVE: The aim of our study was to evaluate whether mortality rate ratios for pulmonary embolism were lower than for myocardial infarction and stroke in dialysis patients compared with the general population. METHODS: Cardiovascular causes of death for 130,439 incident dialysis patients registered in the ERA-EDTA Registry were compared with the cardiovascular causes of death for the European general population. RESULTS: The age- and sex-standardized mortality rate (SMR) from pulmonary embolism was 12.2 (95% CI 10.2-14.6) times higher in dialysis patients than in the general population. The SMRs in dialysis patients compared with the general population were 11.0 (95% CI 10.6-11.4) for myocardial infarction, 8.4 (95% CI 8.0-8.8) for stroke, and 8.3 (95% CI 8.0-8.5) for other cardiovascular diseases. In dialysis patients, primary kidney disease due to diabetes was associated with an increased mortality risk due to pulmonary embolism (HR 1.9; 95% CI 1.0-3.8), myocardial infarction (HR 4.1; 95% CI 3.4-4.9), stroke (HR 3.5; 95% CI 2.8-4.4), and other cardiovascular causes of death (HR 3.4; 95% CI 2.9-3.9) compared with patients with polycystic kidney disease. CONCLUSIONS: Dialysis patients were found to have an unexpected highly increased mortality rate for pulmonary embolism and increased mortality rates for myocardial infarction and stroke.

Fluctuations of haemoglobinaemia in chronic haemodialysis patients.

In March 2008 and June 2009, an ad hoc working group of nephrologists discussed the status of anaemia therapy with erythropoiesis-stimulating agents [ESA] in patients on chronic haemodialysis, the phenomenon of fluctuations of haemoglobinaemia, and the need for individualisation of ESA treatment. The working group put together the following statements: (1) ESAs increase the haemoglobin concentration and adaptations of the ESA dose adjust the response according to a negative-feedback loop. The long lag time between an ESA dose change and its effect on erythropoiesis is cumbersome. The optimal haemoglobin target concentration is different for every haemodialysis patient; the lowest haemoglobin concentration upon which one could consistently demonstrate a positive subjective and objective clinical benefit in chronic dialysis is 11 g/dL, in contrast to the lowest haemoglobin concentration of 10 g/dL recommended in the current EMEA label for ESAs. (2) Intra-individual fluctuation of haemoglobinaemia over time is unavoidable, not only due to the ESA dose/haemoglobin response interaction, but also, and more importantly, due to the occurrence of acute illnesses and exacerbations of co-morbid conditions. Many different methodologies to characterise haemoglobin variability have been described but there is currently no universally applied definition of the phenomenon. (3) An impact of the haemoglobin level and the amplitude of the haemoglobin fluctuations on patient outcome has been observed. Without disclosing any causal relationship, worse outcomes were associated with haemoglobin fluctuations around the lower target level, but later on, more simply linked to the relative time spent below the haemoglobin concentration of 11 g/dL and to the administration of inappropriately high ESA doses in order to achieve the recommended haemoglobin target range. A plausible mechanism might be that acute illnesses blunt the patients' basal ESA sensitivity; this leads to subnormal and/or varying haemoglobin levels, currently initiating an ESA dose increase. The longer it takes the patient to recover from the acute illness, the more the prolongation of the clinically poor condition is to some extent maintained by the persistence of low haemoglobinaemia and/or by the administration of high ESA doses, and, as such, on their turn possibly contributing to an ultimate poor outcome. In the absence of clinical trials, recommendations should be offered how to proceed with the administration of ESAs as optimal as possible in periods of clinical instability.

Senescence rates in patients with end-stage renal disease: a critical appraisal of the Gompertz model.

The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age-specific mortality rates for European patients on dialysis (n=274 221; follow-up=594 767 person-years), for European patients with a functioning kidney transplant (n=61 286; follow-up=345 024 person-years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmic mortality curve for patients on dialysis compared with both patients with a functioning kidney transplant and the general population (P<0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded the highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation.