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NDT Advance Access originally published online on January 5, 2006
Nephrology Dialysis Transplantation 2006 21(4):962-967; doi:10.1093/ndt/gfk030
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Clinical Nephrology

Late referral – a major cause of poor outcome in the very elderly dialysis patient

Vedat Schwenger1, Christian Morath1, Alex Hofmann1, Oskar Hoffmann2, Martin Zeier1 and Eberhard Ritz1

1 Department of Internal Medicine, Ruperto Carola University, Heidelberg, Germany and 2 Section of Medical Informatics, FH Gießen/Friedberg, University of Applied Sciences, Friedberg, Germany

Correspondence and offprint requests to: Dr med. Vedat Schwenger, Division of Nephrology, Department of Internal Medicine, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany. Email: vedat.schwenger{at}med.uni-heidelberg.de



   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Background. The population of incident dialysis patients is progressively ageing and dialysis outcome is particularly poor in the elderly. There is little documentation whether late referral is more frequent in the very elderly (≥75 years) as compared with non-elderly patients and whether it contributes, at least in part, to their particularly poor outcome.

Methods. In a retrospective single center study we assessed all consecutive patients (n = 254) who had been admitted to haemodialysis between 1998 and 2001. Outcome in relation to the interval between the time of referral and start of dialysis was compared in very elderly and non-elderly patients. According to a previous analysis in our center major adverse outcome is seen in patients referred ≤8 weeks before the start of dialysis. For the present study this time interval was therefore operationally defined as ‘late referral’.

Results. Expectedly 1 year after start of dialysis mortality was higher (31%) in the very elderly compared with younger patients (19%). The interval between referral and first dialysis was less in patients ≥75 years (median interval 3.5 weeks) compared with patients <75 years (median 20.5 weeks; P = 0.007). The difference in 1 year mortality between timely (>8 weeks) vs late (≤8 weeks) referral, however, was as high in the very elderly (42% vs 16%) as in the younger patients (34% vs 9%). The relative risk of death conferred by late referral was also not significantly different in the very elderly (RR 1.80) compared with the younger (RR 2.32) patient. Using multivariate analysis timing of referral proves to be an independent factor with regard to the outcome and time of survival.

Conclusions. We conclude that late referral is more frequent in the very elderly. Although the relative risk of death conferred by late referral is similar in the very elderly and non-elderly, due to higher frequency of late referral it accounts for a large proportion of excess mortality in the very elderly.

Keywords: elderly; haemodialysis; late referral; mortality; vascular access



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
The dialysis population is graying. An increasing proportion of incident patients requiring dialysis are above age 75 years [1–3]. According to the European Renal Association registry (ERA) between 1985 and 2002, 48% of incident patients (n = 18 920) were above the age of 65 years. The German national registry (‘Quasi Niere’) noted that between 1996 and 2003, the median age of incident patients (from 63 to 69 years) and prevalent patients (from 59 to 64 years) rose progressively [4].

Survival is known to be less in the elderly dialysis patient. We had recently identified late referral as a major determinant of poor dialysis outcome in our local population [5]. It was the aim of the present study to assess

  1. whether in very elderly patients late referral was more frequent and contributed more markedly to the total mortality than in younger patients and specifically,
  2. whether in the very elderly the increase of mortality associated with late referral, i.e. relative risk, was greater (interaction between age and late referral) and/or accounted for a greater proportion of death,
  3. whether timing of referral was an independent factor both for patient outcome and time of survival after initiation of dialysis.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
Study design
We identified all consecutive 254 patients starting haemodialysis between 1 January 1998 and 31 December 2001 at the Department of Nephrology at Heidelberg University. Patients starting on CAPD (n = 26) were not included. During this interval only one patient underwent preemptive transplantation.

A total of 46 patients received longterm chronic haemodialysis in the University Hospital and 208 patients were started in the University Hospital and subsequently transferred to neighbouring centres. The latter patients are included in the present analysis. Follow-up until 31 January 2003 was complete. The time of referral was identified from patient records.

The following data were recorded: demographic factors, date of referral, co-morbidity (i.e. diabetes mellitus, ischaemic heart disease, peripheral vascular disease, hypertension) and cause of ESRD. Blood pressure, body weight and laboratory data (urea, creatinine, phosphate triglycerides, cholesterol, haemoglobin) were recorded at the time of referral and at the start of dialysis. At the time of referral, creatinine clearance was measured in all patients using 24 h urine collections. From patient records we collected information concerning medication, type and timing of vascular access and medical complications. According to a previous analysis in our centre [5] the major adverse impact of late referral on outcome is seen in patients referred ≤8 weeks prior to the first dialysis. For this reason in the present study an interval ≤ 8 weeks was operationally defined as ‘late referral’ and this concerned 47% (n = 119) of all patients.

Statistics
Demographic and clinical variables are reported as mean (M) and standard deviation (SD) or median and 10–90th percentile as appropriate. Survival and mortality rates were obtained for both groups using the Kaplan–Meier method (log rank test). The two-tailed Wilcoxon test was used for comparisons between groups. The zero hypothesis was rejected at P<0.05.

For analysis of influence of comorbidities on outcome, multivariate logistic regression was used. For time dependent death rate d(t) (or hazard rate) the Cox regression analysis (proportional hazards regression) was used.

For determination of relative risk we consider a 2 x 2 table like


Treatment Control
Risk a b
No risk c d
Total s1 s2

The relative risk of the treatment group compared with the control group can be estimated by

Formula
For the calculation of a confidence interval we estimate the standard error (SE) of the (normally distributed) logarithm of RR by

Formula



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
Demographic and laboratory data (Tables 1 and 2)
Between January 1998 and December 2001, a total of 254 incident patients started dialysis treatment in our unit. Of these, 58 patients (22.8%) were ≥75 years of age (in the following referred to as very elderly) and 196 (77.2%) were <75 years (in the following referred to as non-elderly patients). The mean age of very elderly was 79.6±4.3 years (range 75–89) and of non-elderly patients 58.1±12.3 years (range 20–74). Diabetes was present in the majority of the very elderly, i.e. 44/58 (76%), but not of non-elderly patients, i.e. 89/196 (45%). The concentrations of urea and haemoglobin as well as BMI and diastolic blood pressure at the time of referral were significantly different between very elderly and non-elderly patients.


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  		Table 1. Demographic and laboratory data of haemodialysis patients below and ≥75 years at referral and at the start of dialysis

 

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  		Table 2. Demographic and laboratory data at referral and at the start of dialysis in very elderly patients according to the time interval between referral and start of dialysis

 
Timing of referral and type of vascular access
Overall, the median time interval between referral and first dialysis was 14 weeks (10th–90th percentile 1–239). The median interval between referral and first dialysis was 3.5 weeks (10th–90th percentile 1–129) in very elderly and 20.5 weeks (1–272) in non-elderly patients (P = 0.007).

According to the above definition referral was late i.e. ≤8 weeks, in 35/58 of the very elderly patients (60.3%) compared with 84/196 of the non-elderly patients (42.9%) (P = 0.019).

The proportion of patients who started dialysis using a dialysis catheter was higher in very elderly (69.0%) than in the non-elderly patients (45.6%; P = 0.05).

Outcome according to age, timing of referral and vascular access are shown in Figures 1, 2 and Tables 3, 4 and 5.


Figure 1
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  		Fig. 1. Survival of very elderly (≥75 years) compared with non-elderly patients (<75 years) according to time of referral (≤8 vs >8 weeks prior to start of dialysis) (P = 0.0001, log-rank-test). Non-elderly <8w: non-elderly patients who started dialysis ≤8 weeks after referral; non-elderly >8w: non-elderly patients who started dialysis >8 weeks after referral; very elderly <8 w: very elderly patients who started dialysis ≤8 weeks after referral; very elderly >8w: very elderly patients who started dialysis >8 weeks after referral.

 

Figure 2
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  		Fig. 2. Survival of very elderly patients ≥75 years – use of Brescia-Cimino fistula or graft vs use of a central venous line (P = 0.04, log-rank-test). CVL: patients who started dialysis using a central venous line; BC: patients who started dialysis using a Brescia-Cimino fistula or a synthetic graft.

 

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  		Table 3. Logistic regression analysis of outcome (only significant factors displayed)

 

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  		Table 4. Proportional hazards regression analysis of survival (only significant factors displayed)

 

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  		Table 5. Relative risk (RR) of death according to timing of referral in very elderly and non-elderly haemodialysis patients

 
After a median follow-up of 88.5 weeks after initiation of dialysis (9–173) 53.2% of the very elderly patients were alive as opposed to 76.5% of the non-elderly patients (log-rank test 0.007).

Not unexpectedly the Kaplan–Meier analysis showed a significant difference of survival between very elderly and non-elderly patients (P = 0.007). Nevertheless, when survival was plotted separately as a function of the interval between referral and start of dialysis (Figure 1), there was no difference of survival between early and late referral when the groups of the very elderly and non-elderly patients were compared. Accordingly, the relative risk of death conferred by late referral was not significantly different (P>0.05) between very elderly and non-elderly patients (Table 5). With the multivariate logistic regression analysis the following factors were identified as significantly influencing patient outcome: history of myocardial infarction, late referral and start of dialysis with a functioning Brescia-Cimino (BC) fistula (Table 3). Additionally, using the proportional hazard analysis both history of myocardial infarction and late referral were independent factors determining survival after start of dialysis (Table 4). One year after the start of dialysis, mortality in very elderly patients starting dialysis using a BC fistula or synthetic graft was lower compared with those patients starting dialysis using a dialysis catheter (23.1 and 35.2%, respectively; P = 0.04) (Figure 2).



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
The present analysis in a single European unit is in agreement with other reports from both sides of the Atlantic [3,6–9] showing that late referral is significantly more frequent in very elderly as compared with non-elderly patients. Surprisingly, so far it has not been examined whether advanced age is an independent determinant of late referral and whether outcome is more adversely affected by late referral in the very elderly compared with the non-elderly dialysis patient.

The present study shows that age is an independent determinant for the risk of late referral [3]. Not unexpectedly, the Kaplan–Meier analysis showed a significant difference of survival between very elderly and non-elderly patients [3,7]. Although late referral was more frequent in the very elderly, in contrast to the widely held opinion, the relative risk of death for late vs timely referral was not higher in the very elderly as compared with the non-elderly patients. In other words late referral was apparently no more deleterious in the very elderly. Nevertheless, because of the high frequency of late referral it made an important contribution to the excess mortality in the very elderly. Late referral was an independent factor influencing patient outcome.

An important point to consider is the high proportion of very elderly patients in whom dialysis had to be started using a central venous line. Our data identify vascular access as a predictor of outcome and confirm the observations of Xue et al. and Pastan et al. [10,11] that mortality is higher in very elderly dialysed using a central venous line.

Another point to discuss is the high prevalence of diabetes in the very elderly patients. Surprisingly, in this cohort the presence of diabetes was no longer an independent factor determining outcome after adjustment for comorbidity, particularly coronary heart disease. The excessive proportion of diabetics in this German dialysis population of elderly individuals differs from recent observations reported from other countries. Whether there are more fundamental biological reasons for this difference, or whether the observations from Germany in this case again are forerunners of what will later be observed in other countries as well [12,13] must be found out by future longitudinal comparisons in different European countries. One potential cause could have been better cardiovascular survival in recent years in the predialysis phase.

What conclusions for clinical practice can be drawn from these observations? To improve the poor outcomes of dialysis in the very elderly, it is important to identify potential causal factors other than age per se. The above data suggest that late referral is one decisive factor which is potentially modifiable [6,9,14–23]. Death is undoubtedly a strong endpoint which is easy to assess. It must not be forgotten, however, that quality of life (QOL) is an additional important aspect which cannot be assessed in a retrospective analysis. In a prospective study by Loos et al. [24] using the SF-36, the loss in QOL was particularly evident in elderly dialysis patients referred late, but elderly patients with timely referral had a QOL score which was almost equal to that of younger patients [24,25].

The present analysis has strengths and weaknesses. The single center character guaranteed complete data collection and homogeneity of treatment protocols. On the other hand the sample size is limited. Because during the observation period most patients received haemodialysis and the few patients on CAPD were excluded, specific conclusions concerning CAPD or transplantation cannot be drawn.

We tried to find out why very elderly patients were referred later than younger patients. There was no significant difference with respect to the relative proportion of patients referred by general practitioners and specialists (diabetologists, cardiologists, etc.). Nevertheless, approximately 70% had been seen regularly by their physicians, so that patient non-compliance is not a major causal factor. We assume that one major reason for late referral was underestimation of the severity of reduction of GFR when only serum creatinine concentration was taken into consideration. This underlines that the recent recommendations to estimate GFR by one of the validated equations are definitely appropriate [26].



   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
The present study has identified late referral as an independent, but modifiable cause of excess mortality on haemodialysis in very elderly patients. Apparently late referral is not intrinsically more deleterious in the very elderly; at least the relative risk of death for late vs timely referral was not higher in the very elderly compared with the non-elderly patients. Nevertheless, late referral makes a major contribution to excess mortality, mainly because late referral is more frequent in the very elderly.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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Received for publication: 9. 6.05
Accepted in revised form: 7.12.05


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