Late referral for end-stage renal disease: a region-wide survey in the south west of England

Paul Roderick1,, Chris Jones1, Nick Drey1, Sara Blakeley2, Premila Webster3, Jonathan Goddard1, Sue Garland2, Linda Bourton4, Juan Mason2 and Charlie Tomson4

1 Health Care Research Unit, University of Southampton, Southampton General Hospital, Southampton, 2 Renal Unit, St Mary's Hospital, Portsmouth, 3 Health Services Research Unit, University of Oxford, Oxford and 4 Richard Bright Renal Unit, Southmead Hospital, Bristol, UK



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The proportion of patients referred for renal replacement therapy (RRT) at a late stage of disease appears to be similar to that first described nearly 20 years ago. This study investigated the current scale of the problem in a large region in England, identifying the prior health care, patient characteristics, referral pattern, and outcomes of those accepted onto RRT.

Methods. Three hundred and sixty-one (88%) out of 411 patients accepted for RRT in six renal units in the South and West Region of the UK between 1 June 1996 and 31 May 1997 were studied retrospectively. We examined the history of chronic renal failure, referral path to nephrologist, management of chronic renal failure (CRF) and patient outcomes. Patients were categorized as ‘late’ if they were referred to the renal unit either within 4 months or within 1 month of requiring RRT.

Results. One hundred and twenty-four (35%) patients were referred within 4 months of RRT, and 84 (23%) within 1 month. The main differences between patients referred later and other patients was seen for those referred within 1 month. These patients were older and had more co-morbidity, significantly worse laboratory parameters at the start of RRT, were less likely to have received standard treatments for CRF, had less permanent dialysis access in place at the start of RRT (18% vs 47%, P=0.001), and had a significantly longer hospital stay (18 vs 10 days, P=0.001). Seventy-four (19%) patients died in the first 6 months: 27 (32%) in the 1-month group, 46 (16%) in all others (P=0.002). We found no evidence that patients referred late had defaulted from nephrology follow-up or had an excess of rapidly progressive disease. Though data were incomplete, there was evidence of prior CRF of over 1 year in all late referral groups.

Conclusion. Nearly a quarter of patients are referred for specialist nephrology treatment at a very late stage, within 1 month of RRT. They are less likely to receive interventions that could alter the progression of CRF or reduce its associated co-morbidity, have a worse clinical state at the start of RRT, longer hospitalization and poorer survival. These differences were much less marked for those referred within 1–4 months of starting RRT, although this is an insufficient time to prepare for RRT. Further research is needed to determine the missed opportunities for more proactive diagnosis and management of CRF.

Keywords: chronic renal failure; early intervention; end-stage renal disease; late referral; renal replacement therapy



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
End-stage renal disease (ESRD) is inevitably fatal without renal replacement therapy (RRT), whether by dialysis or transplantation. As in other developed countries, the RRT programme in the UK has expanded significantly in the last decade and it is already estimated to cost 1.5% of NHS resources [1]. Moreover, demand in the UK is likely to double during the next 10–20 years until a steady state is reached [2].

Whilst chronic renal failure (CRF) can be difficult to detect unless actively searched for, opportunities for detection exist. Hypertension, urine and blood tests are all useful in detecting renal disease, especially in those from groups at increased risk of impairment such as diabetic and hypertensive patients. Timely referral of patients with CRF is essential, since for some individuals the progression of CRF to end stage can be delayed, halted or even reversed [3], and intervention may also ameliorate the morbidity associated with CRF. Timely referral also allows more time to inform patients of the RRT options and to establish dialysis access. The UK Renal Association has recommended referral of all patients to a nephrologist once serum creatinine is repeatedly above 150 µmol/l [4].

Several studies have shown that late referral (variably defined as starting dialysis within 1 month, or 3–4 months from first referral to a dialysing nephrologist) occurs in approximately 23–48% [58] and 22–51% [911] of patients respectively. The consequences are worse biochemical parameters [11] and patient co-morbidity prior to starting RRT [7], higher rates of emergency dialysis [8], longer hospitalization [9], increased early mortality [9] and reduced chances of receiving a kidney transplant [8]. Health care costs are consequently increased [6]. Most studies of late referral have been in single centres and have focused on the size of the problem and its consequences. We present here the results of a large retrospective analysis of patients accepted for RRT in six renal dialysis units in the South and West Region of England, an area with a largely Caucasian population of approximately 6.6 million. We investigated the scale of the problem of late referral, dividing our sample by the two definitions used in previous studies (starting dialysis within 1 month or 4 months of referral). We compared the prior care, referral patterns, patient characteristics and outcomes of patients referred.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
All patients with ESRD accepted onto the renal replacement programmes of the six established units in the South and West Region between 1 June 1996 and 31 May 1997, were eligible. One unit was excluded as it had only recently opened. Patients with acute renal failure, those transferred in from other units already on dialysis, and returns to dialysis from failed transplants were excluded. Potentially eligible patients were identified by the clinical director of the renal units.

A retrospective analysis of ESRD patients’ clinical history was carried out using renal unit records, both clinical notes and computerized records. Data were collected using a standard questionnaire and short outcome profile devised by an expert panel including a geriatrician, a general practitioner, a diabetologist, two nephrologists involved in dialysis, and one physician with a special interest in nephrology. This included details on prior history of CRF (serum creatinine and urinalysis), referral history, the use of anti-hypertensive drugs including angiotensin-converting enzyme (ACE) inhibitors to delay progression of CRF, biochemical measures of CRF severity (e.g. creatinine), the use of measures to treat renal co-morbidity (e.g. phosphate binders), start of RRT, and outcomes including hospitalization and survival up to 6 months after the start of RRT. The risk index used by Khan et al. [12] was also used to classify patients into high-, medium- and low-risk groups using age, and presence of vascular disease, diabetes, myeloma or other organ diseases. The prescription of low-protein diets was not collected because dietary information was poorly recorded.

The participating renal units provided a list of all patients starting renal replacement therapy in the study period. Forty-one (9%) of 452 patients initially identified were excluded: 27 patients had moved units and were already on dialysis, five had recovered renal function, five had restarted dialysis following a failed transplant, and four had acute renal failure, which recovered. Of the remaining 411,361 (88%) had medical records available and, following questionnaire completion, were entered into the analysis. The definition of CRF used in the study was persistently raised serum creatinine above 150 µmol/l and/or recorded diagnosis in the medical notes. The initial definition of late referral used was that described previously [911], namely patient starting RRT within 4 months of referral to a nephrologist. Patients were then sub-divided into periods from referral to RRT of less than 1 month, 1–4 months, 4–12 months, and greater than 12 months. This allowed comparison with other late referral studies that used dialysis within 1 month of referral as their definition and investigation of how late referral has changed over time.

As well as the six renal units, the South and West Region also has some physicians with a special interest in nephrology based at District General Hospitals. Whilst these physicians have expertise in the management of renal disease, they do not have access to RRT programmes or dialysis access facilities.

Statistics
Statistical analysis included the comparison of patient group characteristics (here presented as referral under or over 1 month to the start of RRT) using tests appropriate to their data and distribution ({chi}2 test, t-test, Mann–Whitney). Regression analysis was used to identify factors predictive of death. P values of <0.05 were accepted as significant. All data were analysed using SPSS for Windows version 8.0.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The median age of the 361 patients was 64 years (range 15–89) and 218 (60%) were male. Age and sex data were available for 39 of the 50 with no medical records; age and gender did not differ (median 67 years, range 30–87; 59% male).

One hundred and twenty-four (35%) patients were referred within 4 months of RRT, 84 (23%) within 1 month. In all units except the smallest, over 28% of patients were referred within 4 months.

The characteristics of the sample at first dialysis are shown in Table 1Go. Whilst there was little difference between those patients referred 1–4 months prior to RRT and early referrals in age, gender, or co-morbidity, those referred within 1 month of starting RRT were significantly older (68 vs 59 years, P=0.002) and had a greater degree of co-morbidity (26 (31%) vs 53 (19%), P=0.237) than those referred more than 1 month before RRT. The ‘final’ referral of the patient to a nephrologist based in the dialysing renal unit differed between these two groups, with referrals within 1 month more likely to be referred by a hospital physician, including a proportion directly from a physician with a special interest in nephrology, whilst GPs were the main referral source for those referred more than 1 month before RRT (P=0.034). The cause of ESRD did not differ significantly between any of the groups, with tests positive for vasculitis (ANCA) and rapidly progressive glomerulonephritis found for small, similar numbers in all groups. The characteristics of those late referral patients referred by a physician with a special interest in nephrology (n=22) and those from all other doctors (n=102) were compared. There was no difference between the two groups in gender, co-morbidity index, and biochemical values; patients in the ‘special interest in nephrology’ group were younger (median age 51 vs 67 years) and were more likely to have permanent access (68 vs 51%), to start dialysis as an outpatient (19 vs 13%), and to be discharged on peritoneal dialysis (26 vs 18%) rather than haemodialysis (68 vs 82%).


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Table 1.  Baseline characteristics of early and late referrals

 
Figure 1Go shows the distribution of known prior chronic renal failure by group. Although there was a large proportion of data unavailable (approximately 50% in each group) in all groups including the late referred, the proportion with a history of known CRF for greater than 1 year was over 60%.



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Fig. 1.  Duration of known CRF prior to referral by group.

 
At first referral, all those referred within 1 month of RRT had several significantly adverse laboratory measures including higher serum creatinine, phosphate and potassium, and lower bicarbonate, albumin, haemoglobin and cholesterol levels. This was not unexpected given the different stages of disease progression in the groups. Some differences persisted at the start of RRT (Table 2Go). This largely accounted for any differences seen in comparing all late referrals under 4 months with those referred earlier.


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Table 2.  Serum biochemical and haematological values at RRT

 
Those referred within 1 month of RRT were less likely to have received phosphate binders, sodium bicarbonate and vitamin D supplements, or to have received erythropoietin at the start of RRT (Table 3Go). The use of aspirin, a recognized secondary prevention measure, was low in both late and early referrals. At referral to a nephrologist, nine (24%) diabetics in the early referred group and six (25%) in the late group were prescribed ACE inhibitors. At dialysis this had changed to 13 (33%) in the early and five (21%, P=NS) in the late referrals. Analysis by smaller referral groups was not possible because of the very small numbers.


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Table 3.  Treatment prescribed at time of starting RRT

 
Mean systolic blood pressures in those referred more than 1 month and less than 1 month before RRT did not differ significantly either at first referral (160 vs 158 mmHg) or dialysis (153 vs 150 mmHg), and neither did diastolic blood pressure (at referral, 89 vs 85 mmHg; at RRT, 83 vs 82 mmHg). The proportion of patients with systolic blood pressures (SBP) <140 mmHg and diastolic (DBP) <80 mmHg did not differ between any of the referral groups at first referral or dialysis.

Overall, at referral, 22% of patients had a SBP <140 mmHg and 28% had a DBP <80 mmHg; this improved to 33 and 43% respectively at dialysis.

Those referred within 1 month of RRT were more likely to be on haemodialysis (Table 4Go) and to have temporary vascular access than all others. This included tunnelled catheters whose use was limited in all groups (5%). They were also less likely to have received a transplant at 6 months (0 vs 4%, P=0.001), less likely to have had a significantly longer initial hospital stay (18 vs 10 days, P=0.001), less likely to start dialysis as an outpatient (11 vs 28%, P=0.001), and had more hospitalization episodes within the first 6 months (mean 2.6 vs 1.7, P=0.001).


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Table 4.  Dialysis access and clinical outcomes of referral groups

 
Status at 6 months was available for 389 (95%) of the 411 patients. Overall 74 (19%) patients died in the first 6 months: 27 (32%) of those referred within 1 month, 46 (16%) of those more than 1 month (P=0.002) and one with unknown referral status.

Independent factors affecting survival at 6 months were found using regression analysis. Compared with being referred more than 1 month prior to RRT, referrals within 1 month were less likely to survive at 6 months, once age, co-morbidity and serum albumin levels were taken into account (OR, 1.5; 95% CI, 0.73–2.89), although this did not reach significance (P=0.293).

Having a high degree of co-morbidity was also related to poorer survival (OR, 1.8; 95% CI, 0.90–3.69), although again this was not significant (P=0.098). Increasing age by 1 year reduced 6-monthly survival by approximately 4% (P=0.005; 95% CI, 0.93–0.98) and increasing albumin levels by 1 g/l increased survival by 10% (P=0.001; 95% CI, 1.05–1.16).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This large multi-centre study has shown that in the late 1990s, in one region of the UK, over one-third of patients were still being referred to a renal unit less than 4 months before starting dialysis; 23% were starting dialysis within 1 month of referral, with 16 (12%) requiring immediate RRT on the day of referral. This is a similar figure to that described nearly 20 years ago [5]. However, this is not comparing like with like, as the case-mix of the populations studied has changed.

Figure 2Go shows the previous late referral studies characterized by year of study and definition of late referral, and this suggests that despite an increasingly elderly and more co-morbid population, when similar study definitions are used, the incidence of late referral may be falling [58,10,11,13,14]. The markedly small number of late referrals found by Arora et al. [11] may be due to their excluding patients with unrecovered acute renal failure.



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Fig. 2.  Late referral proportions (%LR) by study and definition (<1 month or <3–4 months), with sample age (mean) and diabetic data were known.

 
Whilst late referral leads to a poorer patient health state at the start of RRT, with less likelihood of receiving interventions to reduce co-morbidity associated with CRF and more emergency dialysis, these differences were largely due to those referred within 1 month of the start of RRT. Once separated, the differences between the other groups (1–4 months, 4–12 months and more than 12 months) were not significant for the type of doctor referring patients to nephrologists, the cause of renal disease, the clinical state of the patient and the use of renal therapies at RRT, dialysis access at RRT and method of RRT, and hospital length of stay and death at 6 months. Of course, such sub-group analyses have problems of small numbers leading to type 2 errors. Moreover, whatever the definition of late referral, it may deny these patients the opportunities for intervention that could potentially have reduced the progression of their renal failure. Although the detrimental effects of renal failure were most marked in the 1-month group, referral within 1–4 months of RRT reduced the duration with the various therapies for CRF-associated co-morbidity, and it may be insufficient time to properly prepare for life on RRT.

Albumin levels were significantly lower in those referred within 1 month; hypo-albuminaemia is a good marker of chronic illness and inflammation and is predictive of early death on dialysis [15]. Referrals within 1 month were more likely to have biochemical signs of renal bone disease such as higher phosphate and alkaline phosphatase [11,16]. They were also less likely to receive treatment for such complications. Haemoglobin levels were much lower in the late-referred group and they were less likely to receive erythropoietin treatment for anaemia. The control of anaemia is important in the reduction of left ventricular hypertrophy, itself a predictor of mortality, and is present long before patients reach ESRD [17].

Whilst we found no difference between the two groups for SBP or DBP, at referral only 22% of SBP and 28% of DBP measurements for the sample as a whole met the guidelines of the day (SBP <140 mmHg and DBP <80 mmHg), recommended in the second report of the British Hypertension Society [18].

We showed that those referred within 1 month of RRT had a poorer outcome, were more likely to start dialysis in an emergency, using temporary access [16], and required more access procedures [5,7,12]. This group also had increased hospital length of stay, poorer survival and less chance of early transplantation [7,14,19]. Despite their increasing popularity, we found the use of tunnelled catheters for vascular access was limited in this population.

We found a greater degree of co-morbid illness in those referred within 1 month of RRT, but this did not reach significance. This supports another study [12], which suggests that this may be one of the factors associated with late referral, as physicians are less likely to refer those with a complicated medical history. Logistic regression showed that, once age, co-morbidity and albumin levels were taken into account, referral within 1 month of RRT was associated with poorer survival at 6 months, but was not significant. This suggests that it is the condition of the patient at the start of RRT rather than the referral time that is important in predicting survival, a finding similar to that found in some [9,6,13] but not all [5,7,8] previous late referral studies.

Patients referred late may be subdivided into those for whom late referral is unavoidable (i.e. patients with rapidly progressive renal failure or late presenters who are asymptomatic until a late stage), and those involving avoidable factors. Most studies have not investigated these factors. One that did [7], found that of 65 patients referred within 1 month, 12 (18%) had been virtually asymptomatic until late in the disease, 27 (42%) had been referred to the renal unit but had discontinued follow-up, and 26 (40%) had been diagnosed with renal disease 2–11 years earlier and were not referred to a renal unit despite receiving family physician care. We were unable to find any confirmed cases of loss to follow-up from nephrology care, nor an excess of rapidly progressive renal failure, though this may have been under-ascertained due to the retrospective design of the study. We did find that over one-half of all patients for whom data were available had evidence of CRF over 1 year before referral, suggesting that there may be avoidable factors in late referral.

An important question then is under whose care late-referred patients are, prior to referral, as this might indicate where educational initiatives, shared care, or joint policies are required. However, retrospective data only gives the final referral. This period may be short-lived once advanced CRF is diagnosed, and therefore may not reflect the setting in which opportunities are missed. We found that 14% of late referrals were from a general practitioner, a similar proportion to others [10], and this suggests that these are not simply patients being held in the community. A large proportion of late-referred patients were referred by physicians with a special interest in nephrology. Although these physicians are able to provide expert advice on the management of renal failure, they do not have access to dialysis access facilities or pre-dialysis counsellors, important factors in preparing the patient for RRT. However, they do appear to prepare the patient better for dialysis, but due to the retrospective nature of the study we were unable to assess the likelihood of these physicians receiving patients in a very poor state and having to refer them immediately. An important point is that even if such patients are removed as a special case, that still leaves 29% of RRT patients being referred within 4 months of RRT.

Some might argue that a degree of late referral is understandable as clinicians may be more concerned with the competing risks, e.g. fatal cardiovascular disease. When this does not occur and renal function deteriorates the need for dialysis then becomes overriding and late referral ensues. This assumes that there are many more patients who would have developed ESRD had they not died of competing causes. The impact on pre-dialysis services of referring them all earlier is hard to quantify. We would argue that earlier nephrology referral would be beneficial in the treatment of CRF and its associated co-morbidity, and probably in cardiovascular management too, but the cost-effectiveness of earlier referral requires future research.

The strengths of the study are the large sample size with comprehensive population coverage and its attempt to investigate patient history. The major limitation was the retrospective design and its reliance on one source of data, renal unit records. All retrospective studies are unavoidably limited by the amount and accuracy of data available, particularly the medical notes. In our study, important information regarding referral patterns, duration of known renal failure, and patient history prior to referral was incomplete. This has limited our ability to assess the level of renal function at the start of RRT, an important factor, as it appears that even our ‘early referrals’ commence RRT more uraemic than current DOQI guidelines recommend [20]. It is with this in mind that a prospective follow-up study has been undertaken to collect data from multiple sources (referring hospitals, general practitioners, renal units, and patients themselves) to allow a more accurate assessment of the scale and nature of missed opportunities for management of CRF—for example whether raised serum creatinine results are acted upon.

The region studied has a generally healthy, predominantly Caucasian population and, as such, findings may not be applicable to a largely urban area or one with a significant proportion of ethnic minorities. Whilst the acceptance rate for this region has traditionally been lower than UK or English rates it is probably commensurate for the level of need for RRT.

In summary, late referral remains a feature of patients starting RRT, with adverse consequences especially if less than 1 month. Further work is ongoing to characterize the scale and nature of the missed opportunities. This should inform effective policies on the identification and diagnosis, and appropriate referral and treatment of patients with chronic renal failure, and ultimately may reduce the incidence of late referral and/or improve the cost-effectiveness of renal replacement therapy.



   Acknowledgments
 
We thank the staff of all the renal units that participated, and Drs Clive Hall, Tracy Villar and Peter White for participating in our expert group.



   Notes
 
Correspondence and offprint requests to: Dr Paul Roderick, Health Care Research Unit, Level B, South Academic Block, Southampton General Hospital, Southampton SO16 6YD, UK. Email: pjr{at}soton.ac.uk Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 21. 6.01
Accepted in revised form: 2. 2.02