Kidney International, Vol. 67, Supplement 94 (2005), pp.

S128S132

BLUEPRINTS FOR PREVENTION OF PROGRESSIVE RENAL FAILURE

The need for early nephrology referral

MOSES D. WAVAMUNNO and DAVID C.H. HARRIS
Centre for Transplantation and Renal Research, Millenium Institute, The University of Sydney at Westmead, Westmead, Australia

The need for early nephrology referral. The incidence of endstage renal disease is increasing. Progression to end stage can be
slowed if kidney damage is detected at an early stage. Prognosis and outcomes in patients with chronic kidney disease have
been related to the quality of predialysis care and the timing of
referral. Many patients with chronic kidney disease are referred
to a nephrologist close to commencement of renal replacement
therapy. This leads to suboptimal management of complications
of chronic renal insufficiency, and increased morbidity and mortality of patients on renal replacement therapy.
This article addresses the evidence that examines the view
that patients need to be referred early in order to avoid complications of chronic renal insufficiency.
Early referral can be achieved through improved communication between primary health care givers and nephrology
services. A multidisciplinary approach has a significant impact
on outcomes. In the face of rising incidence of chronic kidney
disease, early referral of all patients is not possible. Therefore,
identification of patients at risk for rapid deterioration of renal
function is important in order to rationalize and reduce health
care expenditure.

Timing of referral of patients with chronic kidney disease (CKD) to a nephrology service affects their outcomes. The majority of patients with renal disease are
referred close to the time of initiation of renal replacement therapy (RRT), which contributes to poor patient
outcomes on RRT. There are now several measures that
have proven efficacy for slowing progression of CKD and
a number of treatments that are effective at preventing
and reversing the morbidity of CKD. Timely referral can
allow RRT to be initiated at higher levels of residual renal
function, which may be beneficial as residual renal function is a predictor of mortality and morbidity in patients
with end-stage renal disease on RRT programs.
This article will address evidence that examines the
view that patients need to be referred early to ameliorate
the effects of CKD.
EARLY INITIATION OF DIALYSIS
Early referral does not necessarily mean early initiation of RRT. The optimal time for initiation of dialysis
Key words: chronic kidney disease, early referral, mortality.


C

2005 by the International Society of Nephrology

is unknown, and it is currently being examined in the

IDEAL trial (Initiating Dialysis Early And Late), a multicenter trial being conducted in dialysis units in Australia
and New Zealand [1]. At this stage, there is no convincing evidence that the reduced morbidity and mortality of
early referral is due to early initiation of RRT.
HOW COMMON IS LATE REFERRAL?
Depending on the definition of early referral with respect to months predialysis, and taking into account confounding factors such as presentations in acute renal
failure, 25% to 50% of patients worldwide who commence RRT are referred late to a nephrology service. In
a review of referral patterns of European patients with
type 2 diabetes mellitus who were starting RRT, 25% to
30% patients were referred to a nephrologist less than
1 month before initiation of dialysis.[2] Data from the
Australia and New Zealand Transplant Registry (ANZDATA) show that of 2300 patients starting RRT in 2002,
26% were referred less than 3 months prior to commencing dialysis [3].
DETERMINANTS OF LATE REFERRAL
There is some inconsistency in reports examining
factors that determine timing of referral (Table 1).
Winkelmayer et al [4] reviewed the risk factors for referral within 90 days of commencing RRT. In that study,
late referral was associated with older age, and absence
of comorbidity, including hypertension, coronary artery
disease, malignancy, and diabetes mellitus. It is possible
that the absence of comorbidity may provide a false sense
of security about the true risk for individual patients. Patients who were not black or white were also referred
later. However, in studies of Roderick [5] and Jungers [6],
the presence of comorbidity such as cardiovascular disease and diabetes was associated with late referral. Moreover, Steele [7] found that patients who were white and
younger were referred later. General internists tended to
refer later than family physicians or primary care physicians. In another study, Arora [8] found that patients in
health maintenance organizations were likely to be referred late compared to those in the Medicare system. In

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Wavamunno and Harris: The need for early nephrology referral

Table 1. Risk factors for late referral

Age: young [7], old [4]
Race: non-black or white [4], white [7]
Comorbidity: presence [5, 6], absence [7]
Health maintenance organization [8]
Lack of health insurance [9]

contrast, Kinchen [9] found that late referral was common

in patients without insurance. The apparent inconsistency
in these reported risk factors for late referral is probably
attributable to local differences in patient socioeconomic
status and nephrologic resources.
WHAT DO THE GUIDELINES SAY?
In an attempt to address the risk determined by timing
of referral, a number of expert panels have developed
guidelines about when patients with CKD should be referred to a nephrology service. For example, the CARI
(Caring for Australians with Renal Insufficiency) guidelines [10] recommend that: (1) patients with a serum creatinine >150 (mol/L should have a creatinine clearance
calculated by the Cockroft-Gault equation or measured
by a 24-hour urine collection. Creatinine should be corrected for body surface area; and (2) patients with a creatinine clearance of <30 mL/min/1.73m2 are at a high risk
of progressive deterioration of renal function and should
be referred to a nephrology service for specialist management of renal failure, and to allow time for adequate
preparation for dialysis. Earlier referral should be considered in patients who are hypertensive or who have
significant proteinuria (>1 g/24hr) as these clinical features suggest that residual renal function may deteriorate
rapidly.
The aim of these guidelines is to achieve a late referral rate of <20%, a goal that will be monitored by
ANZDATA. It should be noted that both of these guidelines are based on level B evidence.
CONSEQUENCES OF LATE REFERRAL
The above recommendations are based on a number
of studies that together have shown that late referral of
patients is associated with increased patient morbidity
and mortality, increased need for and duration of hospital admission, and increased initial cost of care following
commencement of dialysis (Table 2).
There have been numerous retrospective studies, but
to date, only one prospective study has shown increased
mortality and morbidity among late referrals. The increased mortality and morbidity is partly explained by
complications related to vascular access. In a 3-center,
5-year prospective, observational study, Lorenzo et al
[11] evaluated the effect of presentation mode (planned
or unplanned) and type of access on mortality in 538
patients initiating RRT. Presentation and initiation of

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Table 2. Consequences of late referral

Increased mortality and morbidity [1116]
Increased cost and duration of hospitalization [17]
More temporary vascular access [8]
Increased need for urgent dialysis [19]
Suboptimal management for end-stage renal disease [18]
Reduced access to renal transplantation services [21]

dialysis was unplanned in 257 patients, and of these,

70% initiated dialysis with a temporary catheter. In this
study, unplanned presentation and initiation of dialysis
with a temporary catheter were independently associated
with increased mortality and morbidity. Vascular access
related admissions were more frequent among patients
initiating therapy with a temporary catheter. The combination of unplanned presentation and use of a temporary
catheter for initiation of dialysis was associated with even
greater morbidity and mortality.
Other studies have shown that timing of referral is associated with increased mortality. Waqar et al [12] performed a propensity score analysis on 2195 patients, and
demonstrated that late referral was associated with a
higher risk of death in the first year after initiation of
dialysis. Sesso et al [13] reviewed outcomes of 205 patients with nondiabetic nephropathy. Of these, 106 were
referred within 1 month of starting RRT, and 99 were
referred more than 3 months prior to starting therapy.
Survival at 6 months was significantly lower in the late referral group, and the risk of death was 2.77 times higher.
Khan et al [14] compared 52 patients who died within
90 days of commencing RRT to age- and sex-matched
controls who survived more than 90 days on RRT. A short
period of predialysis management was associated with increased mortality. Innes et al [15] reported a similar experience in 44 patients who died within 1 year of starting
dialysis compared to age- and sex-matched patients who
survived more than 1 year. Patients in the early mortality
group were characterized by late referral to a nephrologist. However, this small study also found that referral
time had no influence on survival beyond 1 year of starting RRT. In contrast, Cass et al [16] showed that there was
an increased risk of mortality even beyond the first year
on dialysis in patients referred less than 3 months predialysis compared to those referred more than 3 months
predialysis.
Ratcliffe et al [17] also reported increased morbidity
among late referrals. In a group of 56 patients, 23 of
whom were referred within1 month of starting RRT, serious complications that significantly prolonged the length
of stay in hospital were more frequent in the late referral group. In a similar study of 250 patients, Jungers et al
[18] reported that the duration and cost of hospitalization
were lower in patients referred early rather that late.
Late referral can imply suboptimal end-stage renal failure care. In a retrospective review of 135 patients in

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Wavamunno and Harris: The need for early nephrology referral

Table 3. Chronic kidney disease: A clinical action plan (K/DOQI)

Stage

Description
At increased risk

GFR (mL/min/1.73m2 )
>90 (with CKD risk factors)

Kidney damage

Normal GFR>90

2
3
4
5

Kidney damage
Moderate decrease GFR
Severe decrease GFR
Kidney failure

6089
3059
1529
<15 (or dialysis)

Action
Screening
CVD risk reduction
Diagnosis and treatment
Treatment of comorbid conditions
Slowing progression
CVD risk reduction
Estimating progression
Evaluation/treating complications
Preparation for RRT
Replacement (if uremia present)

Abbreviations are: CVD, cardiovascular disease; RRT, renal replacement therapy. National Kidney Foundation, Kidney Disease Outcomes Quality Initiative,
www.kidney.org [32].

which late referral was defined as first nephrology referral

within 4 months of starting RRT, Arora et al [8] found that
patients referred late were less likely to have permanent
hemodialysis access. Avorn et al [19] analyzed 2398 incident hemodialysis patients and found that 35% had their
first referral to a nephrologist less than 90 days prior to initiation of dialysis. Patients referred late were 42% more
likely to require central venous access for hemodialysis
compared to those seen early, thus increasing the burden
of disease in this population as a result of inadequate development of vascular access for RRT. Another study has
shown that patients referred late are less likely to receive
EPO, have longer and more frequent episodes of acute
pulmonary edema, and usually require urgent dialysis.
In a cohort of 242 patients, Goransson [20] showed
that those who started RRT less than 3 months after
their first nephrology referral had worse biochemistry,
including lower serum albumin, whereas the early referral group had greater use of antihypertensive medication,
phosphate binders, and sodium bicarbonate.
Late referral also affects access to renal transplantation services. Data from the Australian and New Zealand
Registry showed that of 3000 patients starting RRT between 1995 and 1998, late referral patients were less likely
to be put on the waiting list for, or to be offered, a renal
transplant [21].
QUALITY OF REFERRAL
Most studies have examined timing of referral but have
not looked specifically at the effect of referral quality on
outcomes of patients with CKD. Recent studies show that
the frequency of visits to a nephrologist, the actual duration of care, and a multidisciplinary approach can have
an effect on outcomes and choice of dialysis modality.
Jungers et al [6] looked retrospectively at the effect of
graded durations of nephrologic care on patient survival
and found that, in a cohort of 1057 patients starting dialysis, regular predialysis nephologic care was associated
with improved long-term survival. Five-year survival was
lower in patients with predialysis nephrologic care of less

than 6 months than for those receiving care for an average of 36 months, and predialysis nephrologic care of less
than 6 months was an independent predictive factor for
all-cause mortality.
In a retrospective review of patients with CKD, Ifudu
et al [22] found that patients seen by a nephrologist had
better biochemical parameters at initiation of RRT compared to those seen by a non-nephrologist physician and
those who did not receive medical care. There was an increase in short-term morbidity in patients not followedup by a nephrologist.
Frequency of follow-up also appears to affect outcomes. Avorn et al [23] reviewed patients starting RRT
over a 6-year period, and documented use of nephrology
services during the year before dialysis. Patients who saw
a nephrologist on less than 5 occasions in that year had
higher mortality compared to those who had 5 or more
visits.
Multidisciplinary teams have been found to be more effective in reducing the morbidity associated with CKD. In
a prospective nonrandomized study comparing patients
reviewed by individuals to those reviewed by a multidisciplinary team, there was a significant reduction in the
need for urgent dialysis and hospitalization rates among
those receiving multidisciplinary care [24].
Despite the evidence from these studies, a significant
proportion of patients with CKD still receive inadequate
pre-referral care, even when referred early. Of 411 patients reviewed by Cleveland et al, only 18% had a calculated GFR less than 15 mL/min, yet only 24% had optimal
blood pressure control, only 44% were on an angiotensinconverting enzyme inhibitor, 19% had serum calcium of
less than 2.15 mmol/L, and only 14% were on calcium
supplements. Thus, in this group of patients a significant
proportion of those referred well before the need for dialysis received inadequate pre-referral care [25].
THE ROLE OF PREDIALYSIS EDUCATION
Early referral enables patients and their families to
receive sufficient information and education about the

Wavamunno and Harris: The need for early nephrology referral

nature of end-stage renal disease and the options for

treatment. Predialysis education can assist the patient
in the choice of dialysis modality, and also can increase
patient awareness about many aspects of end-stage renal disease. A prospective trial of predialysis education
showed reduced cost at start of dialysis, need for urgent
dialysis, and days of hospitalization in the first month
on dialysis among patients who had predialysis education
[24]. Other studies of predialysis education have shown
improved patient function and psychologic well being, in
addition to greater rates of permanent hemodialysis, at
commencement of dialysis.
HOW TO REFER EARLIER
There are a number of approaches that can facilitate
achievement of the goal of earlier referral to nephrology services. These approaches include medical education, improved communication between the local medical
officer and the nephrologist, a team approach, providing patients with information, strict adherence to guidelines, and offering financial incentives to facilitate early
referrals.
Family physicians act as gatekeepers for the majority of
referrals. A survey in Canada, the United States, and the
UK showed that family physicians referred patients at a
serum creatinine of between 260 and 340 mmol/L regardless of patient age, whereas most nephrologists would
prefer to accept referrals at lower serum creatinines
[26].
LIMITATIONS
With the increasing incidence of end-stage renal disease, due largely to the increasing incidence of diabetes
mellitus as a cause of CKD, particularly in developing
countries, referral of all patients with CKD is unrealistic
and inappropriate. In fact, the majority of patients with
mild, moderate, and even severe renal failure die before
requiring dialysis [22], and renal function remains stable
in many [28]. Targeting patients with diabetes, hypertension, smokers, and those over 65 years of age will identify
those patients with kidney disease at risk of rapid deterioration of kidney function and most likely to benefit from
early referral.
CONCLUSION
Early referral to a nephrology service, and regular and
frequent follow-up using a multidisciplinary team approach reduces mortality and morbidity related to endstage renal disease, both in the short and long term. Early
referral enables identification of patients at risk of rapid
deterioration in renal function, and appropriate intervention for complications of CKD such as anemia, hyperten-

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sion, and risk factors for cardiovascular disease. A clinical

action plan should be developed for all patients based on
the stage of kidney disease, as defined by the K/DOQI
stages for CKD [29].
This approach has the potential to optimize patient care
and reduce costs of managing patients with CKD.
Reprint requests to Prof. David C.H Harris, Centre for Transplantation and Renal Research, Millennium Institute, University of Sydney at
Westmead, Westmead, NSW 2145, Australia.
E-mail: dch@medicine.usyd.edu.au

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