NEPHROLOGY 2008; 13, 730–736
doi:10.1111/j.1440-1797.2008.01023.x
Original Article
Slowing renal function decline in chronic kidney disease patients after nephrology referral SZU-CHIA CHEN,1,2 JER-MING CHANG,1,2,3 MING-CHIN CHOU,4 MING-YEN LIN,2 JUI-HSIN CHEN,4 JIA-HUI SUN,5 JINN-YUH GUH,2,3 SHANG-JYH HWANG2,3 and HUNG-CHUN CHEN2,3 Departments of 1Internal Medicine and 4Nursing, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, 2Department of Internal Medicine, Division of Nephrology, 5Department of Nursing, Kaohsiung Medical University Hospital, and 3Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan SUMMARY: Aim: Late referral of chronic kidney disease (CKD) patients to nephrologists is associated with increased morbidity and mortality and is still quite common and seldom studied in Taiwan because of unique sociocultural factors. We aimed to study the decline in renal function and factors related to the change in renal function before and after referral. Methods: We retrospectively reviewed the changes of estimated glomerular filtration rate (eGFR) in 213 new referrals of patients with CKD stages 3–5 to the nephrology divisions of one medical centre and one regional hospital from 2001–2006. Data on demographics and laboratory investigations were collected for study. Results: The rates of annual eGFR decline slowed significantly from -7.38 1 0.84 before referral to -1.02 1 0.45 mL/min per 1.73 m2/year after referral (mean 1 standard error of the mean, P < 0.001). The nephrology referral was the most significant factor associated with the slowing of renal function progression, as was younger age and female sex. After nephrology referral, patients with diabetes had an increase in eGFR compared to those without diabetes (P = 0.034). Patients had better control of diastolic blood pressure, sugar and lipid, more frequent use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and statins, less frequent use of non-steroidal anti-inflammatory drugs, and more serum creatinine measurements after nephrology referral. Conclusion: Slowing renal functional decline in CKD patients after referral addresses the importance of nephrology referral for CKD care, which should be strongly promoted in CKD prevention projects in Taiwan. KEY WORDS:
chronic kidney disease, estimated glomerular filtration rate, nephrology referral.
Chronic kidney disease (CKD) has recently attracted much attention, because it is recognized not only as the reservoir of end-stage renal disease (ESRD) but also for its association with increased morbidity and mortality.1 Early detection and treatment of CKD may delay progression to end stage.2,3 The quality of predialysis care and the timing of referral to nephrologists are associated with prognosis and outcomes in patients with CKD.4–7 Previous studies have reported that Correspondence: Dr Shang-Jyh Hwang, Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan. Email:
[email protected] Accepted for publication 26 July 2008. © 2008 The Authors Journal compilation © 2008 Asian Pacific Society of Nephrology
early nephrology referral results in better preserved renal function.8–10 In Taiwan, there are also some reports showing improvement in clinical outcome by early nephrology referral.6,11–13 However, most studies were conducted retrospectively on those patients who have received renal replacement therapy, rather than predialysis CKD patients. Acceleration in the rate of decline in estimated glomerular filtration rate (eGFR) as manifested by a change in the slope of the regression line or converted into the magnitude of eGFR change/year could be used to assess the efficacy of interventions designed to slow the progression of CKD. We conducted a before and after study to determine whether declining renal function slowed after nephrology referral in patients with moderate to advanced CKD (stages 3–5).
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Nephrology referral slows progression
METHODS Subjects All the study subjects were ambulatory patients followed up at the Outpatient Department from 2001–2006. Data were obtained by reviewing the medical records and also through medical informatics systems in a medical centre, the Kaohsiung Medical University Hospital, and a regional hospital, the Municipal Kaohsiung Hsiao-Kang Hospital, in southern Taiwan. Both of the two hospitals used the same system of medical staff and administrative management with comparable care quality. After converting the serum creatinine data into eGFR using the simplified formula in the Modification of Diet in Renal Disease (MDRD) study,14 patients were included for study when: (i) the eGFR was less than 60 mL/min per 1.73 m2 at the time of referral; (ii) they had been followed at departments other than nephrology for more than 1 year before referral or the nephrology division after referral; and (iii) at least three serum creatinine levels were available before and after nephrology referral. Those patients with acute renal failure or entering dialysis therapy within 1 year after nephrology referral were excluded to avoid acute effect or incomplete observation of change in renal function related to nephrologist care.
Definition of CKD stages According to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines,15 we classified those patients with evidence of kidney damage lasting for more than 3 months to be CKD stages 3, 4 and 5, based on eGFR levels (mL/min per 1.73 m2) of 30–59, 15–29 and less than 15, respectively. Further, we subdivided the group of CKD stage 3 into CKD stage 3A for those with eGFR levels of 45–59 and CKD stage 3B for those with eGFR levels of 30–44 mL/min per 1.73 m2.
Data collections The age, sex, CKD stage and underlying disease for each patient were recorded at the time of nephrology referral. In addition, laboratory data and medication information of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), statins and nonsteroidal anti-inflammatory drugs (NSAIDs) during the study period were obtained from hospital informatics. Serum creatinine was measured in the central laboratory using equipment adapted with method of Jaffe reaction (Cobas Integra 400; Roche Diagnostics, Mannheim, Germany). Data of serum creatinine were defined as acute changes with the level of serum creatinine elevated over 30% compared to the last data within 3 months were excluded, which may partly exclude an unstable effect in a regression line. The total number of serum creatinine measurements during the 12 month period before and after referral were recorded, respectively. Proteinuria was tested semiquantitatively using dipsticks (Hema-Combistix; Bayer Diagnostics, Leverkusen, Germany) and recorded at referral and 6 months after referral or later. A test result of 1+ or more was defined as positive.
Definitions of decline in eGFR and annual eGFR change The eGFR data from individual patients across the time were converted into a regression line. At least three eGFR measurements during the 1 year period before and after referral were required to estimate a preand post-referral eGFR change. The linearity in the individual eGFR line was assessed, and the regression coefficient of time against eGFR © 2008 The Authors Journal compilation © 2008 Asian Pacific Society of Nephrology
was used to define the eGFR decline in mL/min per 1.73 m2/year for each individual. The outcome of nephrology referral on the aspect of slowing decline of renal function was evaluated based on the magnitude of the annual eGFR changes calculated from the regression line.
Definitions of disease status and drug treatment Study subjects were defined as having diabetes mellitus (DM) if the claimed data had an International Classification of Diseases Ninth Revision (ICD-9) disease code of 250.00–250.90, or presence of a fasting blood glucose level was greater than 126 mg/dL, or presence of hypoglycaemic agents in drug prescription for control blood glucose levels. A similar definition was applied to hypertension with an ICD-9 code of 401.9 diagnosed by a physician, systolic blood pressure (BP) of 140 mmHg or more, diastolic BP of 90 mmHg or more, or using antihypertensive medications irrespective of the BP. We defined the use of ACEI, ARB, statins and NSAIDs as patient exposure to these drugs for at least 3 months.
Definitions of changes in BP, haemoglobin A1c, triglyceride and total cholesterol levels The mean of measured systolic and diastolic BP (five times for averaging or at least once for those with fewer BP measurements) before and after nephrology referral, respectively, were recorded. Serum haemoglobin A1c, triglyceride and total cholesterol levels measured before and after nephrology referral were collected. The averages of these measures were defined as pre- and post-referral biomarkers to assess the impacts of BP and biomarkers changes on the rates of eGFR decline.
Statistical analysis Data are expressed as numbers and percentages, mean 1 standard deviation or mean 1 standard error of mean (SEM). The differences in items between pre- and post-referral stage were checked by the McNemar test for categorical variables, or by paired Student’s t-test for continuous variables. To examine further whether nephrology referral was associated with the progression of renal insufficiency, generalized estimating equations were used in longitudinal multivariate analysis. P < 0.05 was considered significant. Statistical analysis was performed using Statview ver. 5.1 software (SAS Institute, Cary, NC, USA).
RESULTS Clinical characteristics There were 213 patients that fitted the inclusion criteria for study. The clinical characteristics of these patients are listed in Table 1. Male sex compromised 64.8% of the patients. More than half had advanced CKD (stages 4–5, 55.9%) and 145 (68.1%) had proteinuria. The two most common underlying causes of CKD were diabetic kidney disease (120 cases, 56.3%) and non-diabetic glomerular diseases (56 cases, 26.3%). The average of the total times serum creatinine was measured before and after referral was 8.1 1 6.4 times (range, 3–55) and 10.0 1 6.9 times (range, 3–58), respectively, for calculating the rate of eGFR change (mL/min per 1.73 m2/year). The percentage distributions of the numbers of serum creatinine levels available for data analysis during the ‘before referral’ period were 22.5% (>10 serum
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Table 1 Characteristics of the study group Characteristics Age, years Male sex, n (%) Proteinuria at referral, n (%) eGFR at referral, mL/min per 1.73 m2 Stage of CKD, n (%) Stage 3 Stage 3A Stage 3B Stage 4 Stage 5 Underlying diseases of CKD, n (%) Diabetic kidney disease Hypertension Non-diabetic glomerular disease Cystic kidney disease Tubulointerstitial disease Others Diabetes Hypertension Referral sources Department of Family Medicine Department of Internal Medicine (except Division of Nephrology) Department of Neurology Department of Surgery Department of Urology Others
Value 64.8 1 12.4 138 (64.8) 145 (68.1) 27.4 1 14.3 94 28 66 60 59 120 9 56 2 20 6 124 178
(44.1) (13.1) (31.0%) (28.2) (27.7) (56.3) (4.2) (26.3) (0.9) (9.4) (2.8) (58.2) (83.6)
21 (9.9) 126 (59.1) 14 19 23 10
(6.6) (8.9) (10.9) (4.7)
Data are expressed as numbers and percentages, or mean 1 standard deviation. Estimated GFR (eGFR) was estimated using the simplified Modification of Diet in Renal Disease (MDRD) formula, expressed as mL/min per 1.73 m2. Chronic kidney disease (CKD) stage 3A, eGFR 45–59; CKD stage 3B, eGFR 30–44; CKD stage 4, eGFR 15–29; CKD stage 5, eGFR
