Anaemia is common and predicts mortality in diabetic nephropathy
From the Renal Unit and 1Diabetic Unit, Glasgow Royal Infirmary, Glasgow, UK
Address correspondence to Dr C. Stirling, Renal Unit, Glasgow Royal Infirmary, Castle Street, Glasgow G4 0SF, UK. email: cath.stirling{at}northglasgow.scot.nhs.uk
Received 8 December 2006 and in revised form 29 June 2007
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Summary |
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Background: Diabetes is the single largest cause of chronic renal failure, accounting for 18% of patients on renal replacement therapy in the UK.
Aim: To investigate the chronic kidney disease stage at which patients with diabetic nephropathy are referred to renal services, determine the prevalence of anaemia in patients with diabetic nephropathy, examine patient outcome and identity prognostic factors.
Design: Retrospective review.
Methods: Patients with diabetic nephropathy referred to our renal services between 1989 and 2004 were identified from electronic records. Estimated glomerular filtration rate (calculated using the MDRD formula) and haemoglobin at referral were collected. Times to renal replacement therapy and death were noted.
Results: We identified 508 patients. At referral, mean eGFR was 34 ml/min/1.73 m2 and 48% of patients were at CKD stages 4 and 5. Mean haemoglobin was 11.7 g/dl; 21% had a haemoglobin <10 g/dl at referral. Median survival was 37.9 months (95%CI 33.2–42.6); median survival independent of renal replacement therapy (RRT) was 21 months (95%CI 17.8–24.6). Of patients starting RRT, 38% did so within 1 year of referral. Older age (RR 1.02, 95%CI 1.01–1.04) and lower haemoglobin (RR 0.9, 95%CI 0.85–0.99) at referral predicted death on multivariate analysis.
Discussion: At referral to renal services, almost 50% of patients with diabetic nephropathy were at CKD stages 4 and 5. Anaemia was common and predicted mortality. All diabetic patients from CKD stage 3 should be screened for anaemia. We believe that patients with diabetic nephropathy should be discussed with renal services when they reach CKD stage 3 with evidence of progression of renal disease.
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Introduction |
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The combination of diabetes and chronic kidney disease has become a major health problem. The incidence of diabetes (mainly type 2) is increasing, and by 2010 the World Health Organization estimates that there will be 221 million people with diabetes worldwide.1 Diabetic nephropathy occurs in approximately 30% of patients with type 1 diabetes, and 20% of patients with type 2 diabetes, and is now the single largest cause of patients starting renal replacement therapy (RRT). In the UK, 18% of patients starting RRT have diabetes,2 while in the US this figure is 45%.3 Accelerated cardiovascular disease in patients with diabetic nephropathy results in many patients dying before requiring RRT. The publication of the St Vincent Declaration in 1989 recommended ‘implementation of effective measures’ to reduce the number of patients reaching end-stage renal failure by a third within 5 years.4 Since the declaration, many guidelines and standards have been published with the aim of improving the outcome of patients with diabetes and renal disease, but these have so far failed to achieve the goal of the Declaration. The National Service Framework for Renal Services Part I recommends timely referral to a renal unit at least 1 year prior to starting RRT, and Part II recommends identifying patients at high risk of chronic kidney disease and implementing treatment to slow progression.5 The UK Renal Association Chronic Kidney Disease guidelines recommend estimating glomerular filtration rate (eGFR) using the 4-point Modification of Diet in Renal Disease (MDRD) formula and classifying patients into five chronic kidney disease (CKD) stages.6
There is no consensus as to the optimal time of referral to renal services. Some propose referral when eGFR is <30 ml/min/1.73 m2, while others feel that this may be too late to have an impact on disease progression. Late referral to a renal unit is associated with a poorer outcome on RRT, loss of opportunity to slow progression of renal disease and under treatment of renal-specific complications, in particular renal anaemia.7,8 Anaemia has been shown to be associated with left ventricular hypertrophy,9 increased cardiovascular mortality10,11 and poorer quality of life,12 but correction of anaemia has not yet been shown to improve patient survival in a prospective randomized controlled trial. Various guidelines have been published recommending haemoglobin thresholds for the investigation of anaemia in CKD, and these are summarized in Table 1.13–17
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This study aimed to: (i) investigate at what stage of CKD patients with diabetic nephropathy are referred to renal services; (ii) investigate whether the stage of CKD at which patients with diabetic nephropathy are referred to a nephrologist has changed over the last 16 years; (iii) determine the prevalence of anaemia in a group of patients with diabetic nephropathy; (iv) measure the survival of patients with diabetic nephropathy and identify predictors of poor outcome; and (v) determine the percentage of patients who died before requiring RRT.
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Methods |
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We interrogated the electronic patient records at the renal unit in Glasgow Royal Infirmary to identify patients who were referred with diabetic nephropathy between 1989 and 2004. The diagnosis was made in patients with albuminuria >300 mg/day or urine albumin:creatinine ratio >30 mg/mmol, retinopathy and normal kidneys on ultrasound, or biopsy-proven diabetic nephropathy. Patients were referred either to the combined diabetic-renal clinic or the general renal clinic, from diabetic clinics and primary care. Data from audits of our local diabetic-renal clinic have previously been published.18,19 Age, gender, serum creatinine and haemoglobin at referral were collected. The haemoglobin concentrations 6 months after referral were retrieved. The eGFR was calculated using the 4-point Modification of Diet in Renal Disease (MDRD) formula.20 The dates of first referral, commencement of RRT, death and last clinic visit were collected. The eGFR and haemoglobin at starting RRT and at the visit prior to death were retrieved.
Statistics
Results were expressed as means (SD) or medians (IQR). Intergroup comparisons were made using Student's t test for normally distributed variables and the Mann-Whitney U test for variables with non-normal distribution. The 
2 test was used to compare categorical variables. Patient survival was calculated using Kaplan-Meier survival curves, and the log rank test was used to compare these curves. Predictors of mortality were analysed by univariate, then multivariate, Cox regression analysis. All statistical analyses used either Excel or SPSS for Windows (v. 11.5).
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Results |
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We identified 508 patients over a 16-year period. At referral, mean age was 60 years (SD 12), 52.8% were men and the mean eGFR was 34 ml/min/1.73 m2 (SD 20). Mean haemoglobin at referral was 11.7 g/dl (SD 2.1), and 105 patients (21%) had a haemoglobin <10 g/dl at referral. Sixty-six percent of patients met the European Best Practice guideline, 58% met the NKF-KDOQI guideline, and 40% met the NICE guideline for management of anaemia. Table 2 shows the stage of CKD, haemoglobin and degree of anaemia at referral. Figure 1 shows the relationship between haemoglobin and eGFR at referral (r2 = 0.31, p < 0.01)
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Changes with time
Table 3 shows the changes seen over the 16 years. Increasing numbers of patients were referred with time, and patients were older but fewer were referred in CKD stage 5 in the latter years. There was no difference in mean eGFR or haemoglobin at referral during the time period. The percentage of patients with a haemoglobin <10 g/dl 6 months after seeing a nephrologist fell from 26.3% to 10.9%.
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Outcome
Of the 508 patients referred to a renal unit since 1989, 243 (47.8%) have died. Forty-seven percent of deaths occurred in patients who were not on RRT. Mean eGFR at the clinic visit prior to death in those who did not start RRT was 22 ml/min/1.73 m2 (SD 15). Median survival after referral to a renal unit was 37.9 months (95%CI 33.2–42.6). One-year survival was 83.7% and five-year survival was 30.2%. Median survival was worse in women (30.9 months, 95%CI 22.5–39.2) than in men (40.8 months, 95%CI 33–48.5) (p = 0.01). Median survival was 53.8 months for those referred at CKD stage 1 and 2, 47.5 months for CKD stage 3, 31.4 months for CKD stage 4, and 35.6 months for CKD stage 5 (p = 0.007) (Figure 2).
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One hundred and eighty-seven patients (37%) started RRT. Mean eGFR starting RRT was 7.4 ml/min/1.73 m2 (SD 2.8), and mean haemoglobin was 9.4 g/dl (SD 1.6). Median (range) time from referral to starting RRT was 17 (0–191) months: 59 (16–191) months in those referred at CKD stage 1 and 2 (n = 8); 42 (9–109) months for those at CKD stage 3 (n = 39); 21 (1–121) months for those at CKD stage 4 (n = 59); and 6 (0–49) months for those at CKD stage 5 (n = 81). Seventy-one patients (38%) who started RRT did so within 1 year of referral to a renal unit. Of these patients, 76% (n = 54) were referred at CKD stage 5, 20% (n = 14) at CKD stage 4 and 4% (n = 3) at CKD stage 3. The patients who started RRT within 1 year were significantly older (59 vs. 55 years, p = 0.05) and were referred with significantly lower eGFR (12 vs. 30 ml/min/1.73 m2, p < 0.001) and haemoglobin (9.7 vs. 11.7 g/dl, p < 0.001). Median survival on RRT was 33.5 months (95%CI 26.9–40.1) and 1 and 5 year survivals were 75.2% and 26.9%, respectively.
The median time to the combined end-point of death or RRT was 21.2 months (95%CI 17.8–24.6), with 1-year survival independent of RRT 69.2% and 5-year survivals 14.1%. The patients who were alive and independent of RRT had higher eGFR (42 vs. 28 ml/min/1.73 m2, p < 0.001) and haemoglobin (12.5 vs. 11.3 g/dl, p < 0.001) at referral, but there was no difference in age or gender.
Predictors of death
Cox regression analysis was used to determine which factors at referral predicted death. The factors analysed by univariate analysis are shown in Table 4. Blood pressure, glycaemic control, cholesterol and smoking history was not available to enter into the analysis. The factors associated with death were older age at referral, female sex, lower eGFR and lower haemoglobin. Under multivariate analysis, only lower haemoglobin (RR 0.9, 95%CI 0.85–0.99) and older age (RR 1.02, 95%CI 1.01–1.04) were independent predictors of death.
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Discussion |
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There is raised awareness about the management of patients with chronic kidney disease following the recent publication of the Chronic Kidney Disease guidelines,6 the National Service Framework for Renal Disease5 and the recent reporting of estimated glomerular filtration rate. Diabetic nephropathy is the single largest cause of chronic renal failure, and accounts for 18% of patients on renal replacement programmes in the UK.2 The management aim in patients with diabetic nephropathy is to improve outcome by identifying patients early, addressing cardiovascular risk factors, initiating treatment to slow progression of renal disease, correcting renal specific complications and avoiding late referral. The rate of progression of renal failure in untreated diabetic nephropathy is 1 ml/min/month, but interventions can reduce this to 0.1 ml/min/month.21
Forty-eight percent of patients are referred to our renal service in chronic kidney disease stages 4 and 5, and the median time to RRT was 17 months. Despite increasing number of patients being referred to renal services, the percentage of patients referred late has fallen over the past 16 years. This may reflect changes in referral pattern following publication and dissemination of results from previous audits of our diabetic-renal clinic. However, between 2001 and 2004, almost 10% of patients were seen by our renal service for the first time in CKD stage 5. Patients referred late have limited options available to slow progression of renal disease, usually have established renal specific complications, start RRT with temporary access, and may not have the possibility of pre-emptive transplantation. It remains to be seen whether the publication of the CKD guidelines, the National Service Framework for Renal Services and the reporting of eGFR has a further impact on referral pattern. The publication of the SIGN guidelines on the management of diabetes in 199722 had little impact by 1999, but is likely to have played a role in the reduction of patients with advanced renal disease at referral and increase in use of ACEI in the latter time period. Locally, a managed clinical network for diabetes was set up in 2004. However, this will have minimal impact on the current study, as the time period studied was 1989–2004.
Our data also highlight the problem of anaemia in patients with diabetic nephropathy. Twenty-one percent of patients referred to our service had a haemoglobin <10 g/dl, including 50% of those in CKD stage 5. Small studies have established that patients with diabetic nephropathy are more anaemic than other patients with chronic renal failure for a given eGFR.23,24 In a larger study, for each CKD stage, haemoglobin was 1 g/dl lower in patients with diabetes than in the non-diabetic population.25 It has been suggested that erythropoietin synthesizing cells in the renal interstitium are more severely affected by diabetic nephropathy and do not respond to anaemia and hypoxia.26 Therefore, there is both loss of, and resistance to, erythropoietin. Our data confirm that anaemia is a significant problem at referral to a renal unit. Using the European Best Practice guidelines, 66% of patients meet the criteria for investigation of anaemia, 58% meet the NKF-KDOQI guidelines and 40% meet the recent NICE guidelines. In a comparable study, patients with diabetes who had a mean eGFR of 50 ml/min/1.73 m2 had a mean haemoglobin of 12.3 g/dl, and 41% of patients met the NKF-KDOQI guidelines for anaemia. Anaemia is associated with impaired sleep, impaired cognitive function, decreased exercise tolerance and a general decrease in quality of life.12 Anaemia is also associated with left ventricular hypertrophy9 and ischaemic heart disease,10,11 and predicts a faster rate of progression of renal disease.27 Even at CKD stage 3, 8% of patients had a haemoglobin <10 g/dl, 48% met the European Best Practice guideline target for investigation of anaemia, 31% met the NKF-KDOQI guidelines and 24% met the NICE guidelines.
Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers impair erythropoiesis and promote anaemia.28 The use of these medications has increased substantially over the 16 years of the study. In our most recent audit, 86% of patients were referred on one of these drugs. It is also possible that the increasing use of aspirin has a role in anaemia. During the time period of the study, aspirin prescription at referral increased from 38% to 85%. No patient was referred to the diabetic-renal clinic on erythropoietin. Erythropoeitin was available from the late 1980s, but its use was initially limited to patients on renal replacement therapy. Latterly, it has been used in patients with chronic renal failure. The reduction in the most recent time period in the percentage of patients with a haemoglobin <10 g/dl at 6 months after seeing a nephrologist, is likely to reflect this change in practice of erythropoietin use.
Median patient survival from referral to a renal unit was 37.9 months. Almost 50% of deaths occurred in patients who did not reached renal replacement therapy. These patients had an eGFR of 22 ml/min/1.73 m2 at the visit prior to death, implying that renal failure was not the cause of death. There was no difference in survival between those patients referred in CKD stage 4 and those in stage 5. This is disappointing, perhaps implying that treatment requires to be initiated earlier. The data emphasize the high mortality in patients with diabetic nephropathy, largely explained by a dramatic increase in cardiovascular disease. Although on univariate analysis, women had a worse survival, this likely reflects lead-time bias, as women were referred with more severe renal failure. Independent predictors of death included older age and lower haemoglobin at referral. Partial correction of anaemia has led to regression in left ventricular hypertrophy in end-stage renal disease patients,29 and improvements in left ventricular structure in patients with congestive heart failure and mild kidney impairment.30 In cohort studies, anaemia is associated with a worse outcome in dialysis patients31 and in patients with CKD stage 3 and 4.32
The haemoglobin target has been debated. Currently, there is no evidence that a high haemoglobin is beneficial. In a Cochrane review of anaemia, haemoglobin targets of 12 g/dl were associated with a lower risk of death in the population with cardiovascular disease and chronic kidney disease, as compared to haemoglobin targets of 13.3 g/dl.33 The recent NICE guideline recommends aiming for a stable haemoglobin concentration between 10.5 and 12.5 g/dl.17 As yet there has not been a prospective study showing improved survival with correction of anaemia. The Cardiovascular Risk Reduction by Early Anaemia Treatment with Erythropoietin Beta (CREATE) trial34 and the Correction of Haemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial35 have addressed the issue of haemoglobin target in patients with chronic kidney disease. In the CREATE trial, patients with an eGFR between 15 and 35 ml/min/1.73 m2 were randomized to a target haemoglobin value in the normal range (13–15 g/dl) or the subnormal range (10.5–11.5 g/dl). The higher haemoglobin target was not associated with any reduction in cardiovascular events, although quality of life improved.34 In the CHOIR trial, patients with an eGFR between 15 and 50 ml/min/1.73 m2 were randomized to a target haemoglobin of 13.5 g/dl or 11.3 g/dl. The higher haemoglobin target was associated with an increased risk of the primary composite endpoint of death, myocardial infarction, hospitalization for congestive cardiac failure and stroke with no improvement in quality of life.35
Almost 50% of patients in the CHOIR trial and 26% of patients in the CREATE trial had diabetes. However, recruitment is ongoing for two studies in patients with diabetes mellitus and CKD. The Anaemia Correction in Diabetes (ACORD) study will compare changes in left ventricular mass index, cardiac structure and function in patients with diabetic nephropathy. Patients with a creatinine clearance >30 ml/min/1.73 m2 will be randomized to receive erythropoietin to maintain a target haemoglobin of 13–15 g/dl, while the control group will be maintained with haemoglobin levels from 10.5 to 11.5 g/dl.36 The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) will compare erythropoietin therapy aiming for a target haemoglobin of 13 g/dl with a placebo group who will receive erythropoietin when haemoglobin is less than 9 g/dl. In this study, the primary endpoint will be overall mortality and non-fatal cardiovascular events.37
Who is to supervise the care of these high-risk patients has been debated. Locally, we have shown that combined diabetic-renal clinics and intensive management of patients with diabetic nephropathy is beneficial.19,38 In this study, 48% of patients were in CKD stages 4 and 5 at time of referral to renal services, and 38% of patients starting RRT did so within 1 year of referral. Anaemia was common, with 21% of patients referred with haemoglobin <10 g/dl. We believe that discussion with renal services should occur from CKD stage 3 in patients with evidence of progression of renal disease. This will allow the implementation of strategies to slow progression of renal disease, the identification and early treatment of renal specific complications and early planning of access for RRT. Anaemia should be looked for in all diabetic patients who have an eGFR <60 ml/min/1.73 m2, and anaemic patients should be referred to renal services for anaemia management. Patients with earlier stages of diabetic nephropathy or stable CKD stage 3 should be followed up in primary care or by diabetologists, who can target cardiovascular risk factors and implement strategies to delay progression of renal disease.
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References |
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