1Department of Nephrology, Dialysis and Transplantation, Lyon Sud Hospital, Claude Bernard University, 2Service of Biostatistic, Hospices Civils de Lyon, Claude Bernard University, 3Department of Nephrology, Dialysis and Transplantation, Saint Etienne University Hospital and 4Department of Nephrology, Dialysis and Transplantation, Grenoble University Hospital, France
Correspondence and offprint requests to: Emmanuel Villar, Department of Nephrology, Dialysis and Transplantation, Lyon Sud Hospital, 165 chemin du Grand Revoyet, 69495 Pierre Bénite Cedex, France. Email: emmanuel.villar{at}chu-lyon.fr
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Abstract |
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Methods. In a cohort of 549 patients who reached end-stage renal disease (ESRD) between 1995 and 1998 in these units, we analysed the rates of pre-transplant evaluation (PTE), the duration of PTE, the rates of exclusion from transplantation by PTE and the rates of WLR. With Cox regression model, we identified the characteristics that have independent and significant effects on the likelihood of being registered after the first renal replacement therapy (RRT).
Results. In this cohort, 185 patients (33.7%) were wait-listed by 31.03.00 and no patient 70 years was evaluated or registered. In univariate analysis, PTE and WLR rates were lower in the elderly (21.5 and 20.0%, respectively) than those <60 years (79.1 and 70.2%, P < 0.001) and in D2 (33.0 and 24.2%) than in non-D2 (65.8 and 60.6%, P < 0.001). The duration of PTE was longer in D2 than in non-D2 (12.7 ± 11.0 vs 7.5 ± 7.1 months, P < 0.01). Among patients excluded from PTE, more patients without relevant co-morbidities [e.g. rapidly progressive ESRD, cardiovascular disease (CVD), malignancy] were present in the elderly (
70 years: 14.8%; 6069 years: 17.0%; <60 years: 6.4%) and in D2 (18.0%) than in non-D2 (10.9%). The adjusted relative risks (aRR) of being wait-listed after first RRT were significantly lowered by age and D2 (aRR, 95% CI): 6064 year olds (0.44%: 0.260.75), 6569 year olds (0.07%: 0.030.20) and D2 (0.41%: 0.240.69). Other conditions associated with a lower aRR were rapidly progressive ESRD (0.21%: 0.080.55), CVD (0.59%: 0.360.94), malignancy (0.13%: 0.040.46) and psychosis (0.05%: 0.010.35).
Conclusion. Advanced age and D2 were associated with low PTE and WLR rates even after adjustment for other patient characteristics.
Keywords: elderly; end-stage renal disease; recipient selection; renal transplantation; type 2 diabetes; waiting list registration
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Introduction |
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In view of the shortage of kidneys, recipient selection and equitable access to renal transplantation should be the cornerstones of the transplantation process. Surveys of the process to select patients for renal transplantation have detected significant variations in the evaluation of candidates both in European and in US transplant centres [8,9]. Moreover, previous studies in the US have showed that African-Americans, women, the elderly and diabetics were less likely to receive a renal transplant [1015].
Therefore, a multicentre study was designed to analyse the pre-transplant evaluation (PTE) and the process of waiting list registration (WLR) and to analyse the influence of patients medical characteristics and co-morbid conditions on the likelihood of their being registered on the national kidney transplantation waiting list managed by EfG. This study focused on elderly patients and on patients with type 2 diabetes (D2), two groups that are increasing dramatically in the ESRD population [1517].
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Subjects and methods |
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The process of registration on the renal transplantation waiting list in the studied units
In two nephrology departments, PTE was initiated and performed by the patients attending physicians. The decision in each department to register a patient on the national kidney transplantation waiting list was made by one of the physicians responsible for renal transplantation after a review of the patient's PTE. There was no systematic review of patients with chronic renal failure in those departments.
In one nephrology department, all patients with chronic renal failure followed-up in the unit were identified and listed. Twice a month, during a medical meeting, the question of pre-PTE was routinely raised for each patient, and selection for PTE was made after discussion of doubtful cases. PTE was performed by the patients attending physicians. All patients undergoing PTE were identified and listed. The decision to register a patient on the national kidney transplantation waiting list was made in a second bimonthly medical meeting after a complete PTE and following discussion of doubtful cases.
Study population
All patients who were followed in the three nephrology units for ESRD (defined as a need for dialysis or pre-emptive renal transplantation) between 01.01.95 and 31.12.98 were included. Patients who were referred by other health care providers only for renal transplantation and patients temporarily dialysed for acute renal failure were excluded. The study cohort consisted of 549 patients, with an exhaustiveness of 98.6%: eight patients were not included because their medical records had been lost. The numbers of patients in each nephrology department were: 209 in Saint Etienne University Hospital, 195 in Lyon Sud University Hospital and 145 in Grenoble University Hospital.
Study period
Patients were identified at the onset of renal replacement therapy (RRT) that included centre haemodialysis, out-centre haemodialysis, peritoneal dialysis or pre-emptive renal transplantation, and were followed until 03.31.00. The minimum duration of follow-up was 15 months after the first RRT.
Study end point
The end point of the study was each subject's status of registration on the French national kidney transplantation waiting list. There were three possibilities for each patient: being registered before the first RRT, being registered after the first RRT or not being registered before or on 31.03.00.
Studied parameters
Age, gender, country of birth, date of the first RRT, rapidly progressive ESRD, late referral, original nephropathy, co-morbid conditions at the time of the first RRT, modality of RRT, PTE performance and WLR were parameters collected retrospectively from patients medical records between 01.04.00 and 30.06.00.
The country of birth was taken as a dichotomous variable: birth in France or outside France. Rapidly progressive ESRD was defined as a patient's normal renal function 6 months before the first RRT. Late referral was defined as a first referral to a nephrologist <6 months before the first RRT. Original nephropathies included diabetic nephropathy, renal-vascular disease, primary and secondary glomerulonephritis (diabetic nephropathy being excluded from secondary glomerulonephritis), polycystic kidney disease, chronic tubulo-interstitial nephritis, malformative uropathy, other causes and unknown causes. Concomitant conditions associated with the first RRT included: type 1 diabetes; D2; arterial hypertension (blood pressure >140/90 mmHg or anti-hypertensive medication); carotid artery disease (defined as a stenosis >50%); peripheral vascular disease (defined as one or more of clinical claudication, a peripheral amputation or a peripheral artery stenosis >50%); coronary disease (angina, myocardial infarction); congestive heart failure (acute pulmonary oedema or left-ventricular ejection fraction <50% in echocardiography, or both); cerebrovascular accident; malignancy; alcohol addiction; hepatitis B or C; hepatic insufficiency (defined as a coagulation factor V <50%); HIV infection; chronic bacterial infections (defined as a history of bacterial infection treated with antibiotics during >3 months in the 2 years before ESRD or infections relapsing after antibiotic discontinuation); urological disease other than cancer; vasculitis and related diseases (auto-immune diseases); and psychosis. Cardiovascular disease (CVD) encompasses one or more cardiovascular co-morbid conditions, hypertension excepted. The cohort of 391 patients without D2 included 374 non-diabetics and 17 patients with type 1 diabetes. The modality of RRT was the one in use 3 months after the first RRT. PTE was defined as a complete evaluation of the patient in preparation for renal transplantation (including in particular cardiovascular, urologic and anaesthesiologic evaluations). The date of WLR, if any, was the date of the administrative registration on the national list managed by EfG. The duration of PTE was the time between the date of HLA group determination and the date of registration on the waiting list, and was documented only for patients with PTE leading to WLR.
Statistical analysis
Analyses performed included: (i) tabulation of patients characteristics and co-morbid conditions in the studied population; (ii) analysis of PTE and WLR processes in the entire cohort, in the elderly and in patients with D2; (iii) analysis of the medical characteristics of patients without PTE, by categories of age and in D2 vs patients without D2; (iv) comparisons of characteristics of registered vs non-registered patients with calculations of non-adjusted relative risk (NA RR) of being wait-listed by patient characteristics and co-morbid conditions (univariate analysis); (v) analysis of factors having independent effects on the likelihood of being registered on the waiting list (multivariate analysis).
Comparisons were done using the 2 test or Fischer exact test when needed for category variables and using the Student's t-test for continuous variables. One-year survival rates after the first RRT were determined by the KaplanMeier method. The Log-rank test was used to compare 1-year survival rates. Univariate analysis used the
2 or Fischer exact tests when needed to compare PTE and WLR rates according to patient characteristics, co-morbid conditions and RRT modalities.
A Cox proportional hazards model was used to identify those patient characteristics and co-morbid conditions with independent effects on the probability of being wait-listed after the first RRT and to quantify their effects. The end-point was WLR after the first RRT, and the patients who were wait-listed before RRT (52 patients) were excluded. Patients older than 70 years on the first day of RRT (189 patients) and HIV-infected patients (two patients) were not included in the Cox regression analysis because none of them were wait-listed in this cohort. Up to that point, only 306 patients were included in the multivariate analysis. Patients not reaching WLR were right-censored at death or at their last follow-up of this study. Patient age in four categories (1549 years; 5059 years; 6064 years and 6569 years), gender, country of birth, rapidly progressive ESRD, late referral, nephropathy, co-morbidities at the first RRT (as described above), RRT modality, year of the first RRT and nephrology departments were introduced in the model to explore their effects on the likelihood of being wait-listed. Step-by-step analysis was done with both backward and forward introduction of variables to explore interactions between variables. Nephropathy and co-variables of the RRT modalities were not included in the final Cox regression model because of interactions between some co-morbidities and some original nephropathies (diabetes and diabetic nephropathy, CVD and renal-vascular nephropathy, urologic diseases and nephropathy related to malformative uropathy; P < 0.01) and between age and RRT modalities (P < 0.01). Age, D2 and CVD were studied as parameters of interest in several multivariate Cox regression models, with step-by-step adjustment for other variables. No difference was noted between the estimations of the adjusted relative risks (aRR) of being registered on the renal transplantation waiting list whatever the studied parameter. The result of multivariate analysis shown in Table 3 is the result of analyse using age in four categories as parameters of interest. Significance was defined as P < 0.05 for each analysis.
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Results |
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One-year survival rates after the first RRT were: 85.2% in the entire cohort; 92.9% in the 1559 year group; 83.7% in the 6069 year group and 77.2% in patients 70 years old (univariate analysis, P < 0.05). The 1-year survival rates after the first RRT were significantly lower in patients with D2 than in patients without: 78.5 vs 87.7% (univariate analysis, P < 0.05). Rapidly progressive ESRD (40 patients) was associated with a poorer 1-year survival rate, being 62.5 vs 86.8% in 509 patients without rapidly progressive ESRD (univariate analysis, P < 0.05).
Analysis of the PTE and the process of waiting list registration
Among the 549 patients studied, 207 (37.7%) were evaluated for renal transplantation and 185 (33.7%) were placed on the renal transplantation waiting list by 31.03.00. In this cohort, the oldest patient registered on the waiting list was 68.8 years old at the time of registration. As no patient older than 70 years was either evaluated or registered in this cohort, further analyses were focused on patients younger than 70 years (360 patients). In this sub-group, the rates of PTE and WLR were, respectively, 57.5 (207/360) and 51.4% (185/360). The rates of PTE and WLR and exclusion after PTE are shown in Figure 1. The duration of PTE was 8.1 ± 7.6 months in the entire cohort, 8.4 ± 8.1 months in 1559 year group and 6.8 ± 4.3 months in 6069 year group (NS). The duration of PTE was significantly longer in patients with D2 than in patients without: 12.7 ± 11.0 months vs 7.5 ± 7.1 months, respectively (P < 0.01).
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Patients without PTE
We identified 49 patients who were not evaluated and who had no apparent reason for exclusion before any PTE. Those patients had no co-morbidities at the first RRT (except D2 alone), no history of cardiovascular event, no diagnosed neoplasm and no deaths during the year after the first RRT. The rates for such patients were, respectively, in the 1559 year group, in the 6069 year group and in patients older than 70 years as follows: 6.4% (3/47 patients without PTE), 17.0% (18/106) (P = 0.07 in comparison with the1559 year group) and 14.8% (28/189) (P = 0.12 in comparison with the 1559 year group). In the 153 patients younger than 70 years who had no PTE, these rates were higher in patients with D2 than in patients without D2: 18.0% (11/61) vs 10.9% (10/92) (P = 0.21; analysis performed only in patients younger than 70 years).
Registration on the renal transplantation waiting list (univariate analysis)
Characteristics of registered patients vs non-registered patients and non-adjusted relative chance of being registered, by patient characteristics and co-morbidities, are shown in Table 2. In univariate analysis, factors associated with a low likelihood of registration were: age 60 years, D2, all cardiovascular co-morbidities, rapidly progressive ESRD, diabetic nephropathy, renal-vascular disease, neoplasm, alcohol addiction and in-centre haemodialysis as the RRT modality. Polycystic kidneys and malformative uropathy as original nephropathies, type 1 diabetes and urologic diseases (cancer excepted) as co-morbid conditions were associated with high rates of registration.
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Discussion |
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PTE, as defined in this study, was a process leading to a low rate of exclusion from renal transplantation (10% of the patients beginning PTE).
Patients older than 60 years were less frequently evaluated for renal transplantation, but the rate of exclusion resulting from PTE and the mean duration of PTE were not different from those in younger patients. PTE seemed to have been performed in only pre-selected elderly patients with a low rate of exclusion (<7%). The percentages of patients without obvious reasons for not being taken through PTE were twice as high in elderly patients than in young ones.
Patients with D2 were highly excluded at all stages of the selection process for registration on the renal transplantation waiting list. They were less frequently considered for PTE, more frequently excluded after PTE, with a longer PTE duration, and then less likely to be registered on the renal transplantation waiting list than patients without D2. In patients with D2, the diagnosis of CVD was the main reason for exclusion from transplantation after PTE. Cardiovascular investigations needed in patients with D2 [1820], such as invasive angiography or coronarography, may explain the longer PTE. Among patients without apparent reasons for exclusion from PTE, patients with D2 were twice as likely to be excluded than patients without.
Moreover, because the process of selection for renal transplantation starts before PTE, the combination of age 60 years and D2 seemed to be the most important reason for exclusion from renal transplantation before any PTE (Figure 2 top). Elderly patients with D2 were significantly less likely to be evaluated than elderly patients without D2. CVD seemed to have no significant effect on the decision to begin PTE in the elderly. This suggests that age and D2 were thought by clinicians to be limiting factors for renal transplantation, independently of other co-morbidities. Unfortunately, the reasons for patients being excluded from renal transplantation before any PTEfor example patient's choicewere documented in <50% of medical records, and those data were not analysed here.
Advanced age, D2 and CVD are linked characteristics [1517] and confounders in an analysis of factors influencing renal transplantation wait-listing. Multivariate analysis confirmed that old age and D2 have independent and significant effects on the likelihood of being registered on a renal transplantation waiting list. With equal co-morbidities, elderly patients and patients with D2 had a lower probability of being wait-listed than young patients and patients without D2.
Several other characteristics decreased the likelihood of being registered on the renal transplantation waiting listsuch as rapidly progressive ESRD, probably because of a high 1-year death rate. Other significant factors were the classic relative or absolute medical contraindications of renal transplantation [1820]: CVD, history of malignancy and psychosis.
In univariate analysis, type 1 diabetes was associated with a high rate of WLR: 14 of 17 patients in this cohort (82.3%). Those data are comparable with USRDS data [15]. This high rate could be explained by the registration of six of our patients on the kidneypancreas transplantation waiting list and their age at the first RRT (mean age: 40.6 ± 10.1 years). The lack of statistical power and adjustment for age may explain why this characteristic was not a significant factor in multivariate analysis.
No statistical association was noted in this study between registration and gender or country of birth. Previous American studies have shown that females, Native Americans, African-Americans and Asian patients had a lower probability of receiving a renal transplant than males and whites [1015]. National health care systems may explain the differences of data between France and USA.
Late referral was not a factor influencing the decision to wait-list a patient, after adjustment for patient characteristics and co-morbiditiesif, in case of late referral, the patient's characteristics and co-morbid conditions allowed wait-listing.
No difference in access to the renal transplantation waiting list was detected between the three nephrology units studied. These units are all in university hospitals where both dialysis and transplantation are performed and where the interest and the educational level of physicians in renal transplantation are widespread and high.
Although advanced age and D2 are not considered as contraindications for renal transplantation [15,78], we found that these conditions have influenced adversely the likelihood of being registered on renal transplant waiting list. In both conditions, renal transplantation is beneficial, with an increased survival and quality of life compared with dialysis [16]; but some studies have shown that because of higher rates of morbidity and mortality the prognosis of renal transplantation was poorer in those groups than in younger patients and in patients without D2 [14]. As a result, the collective benefit of renal transplantation might decrease when the elderly or patients with D2 are transplanted leading physicians to allocate kidneys to other patients given organ shortage. This utilitarian approach to kidney transplantation may explain our results, but it has to be discussed in view of actual epidemiological data on ESRD. In Western countries >50% of incident ESRD patients are older than 60 years (59% in our cohort) [15,17]. The incidence of patients with D2 in the ESRD population has increased in the last 20 yearsnow over 25% in Europe [16] (28.8% in this 19951998 university hospitals cohort) and >40% in USA [15]. A recent medico-economical study by Jassal et al. [4] showed that, compared with dialysis, the cost-effectiveness of cadaveric renal transplantation declines as age increases over 65 years and with prolonged waiting times in dialysis. Elderly patients may benefit if transplanted after a short time awaiting and with organs from living donors. To our knowledge, such a study is not available for patients with D2. When matched with respect to the year of transplantation, sex, age, immunological parameters and duration of graft cold-ischaemia, Boucek et al. [5] showed that transplantation outcomes were not different in highly selected patients with D2 compared with patients without D2.
Thus, in those patients, prognostic factors of renal transplantation have to be better analysed. The criteria for the selection of high-risk recipients should be discussed in the community of nephrology-transplantation physicians, in order to respect both individual and collective benefits, to improve equity and effectiveness of recipient selection and access to renal transplantation, to offer information to the elderly and patients with D2 regarding results of transplantation and, finally, to improve the cost-effectiveness of renal transplantation.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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