Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes

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1 Q J Med 2002; 95: Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes E.B. JUDE 1, S.G. ANDERSON 2, J.K. CRUICKSHANK 2, A. SRIVATSA 1, N. TENTOLOURIS 1, R. CHANDRASEKARAN 1,R.GOKAL 1 and A.J.M. BOULTON 1 From the 1 Department of Medicine, Manchester Royal Infirmary, and 2 Department of Epidemiology, Stopford Building, Manchester University, Manchester, UK Received 5 July 2001 and in revised form 21 March 2002 Summary Background: The causes and mechanisms of increased mortality of patients with diabetic nephropathy are unclear, and its natural history is poorly understood. Aim: To evaluate risk factors for mortality in type 2 diabetic patients with nephropathy. Design: Retrospective study of clinical and biochemical parameters in diabetic nephropathic patients and controls sampled from a secondary care register. Methods: We studied 170 type 2 diabetic patients (from 1987 to 1995) with nephropathy (proteinuria )0.5 g/24 h) and 170 non-nephropathic patients. Follow-up was until death or December Details of demographics, clinical and treatment history were obtained from medical records. Results: Mean follow-up was 5.3 years. Of the patients with nephropathy at baseline, 63 (37%) died compared with 14 (8%) non-nephropathic patients (x 2 = 53.8, p ). Age- and sexadjusted all-cause mortality rates were 8.1 (6.4, 9.8) Introduction Diabetic nephropathy is characterized by persistent proteinuria (total urinary protein )0.5 g/24 h), arterial hypertension, declining glomerular filtration rate and plasma lipid abnormalities. 1 In type 1 diabetes, proteinuria is associated with increased mortality as a consequence of uraemia and cardiovascular disease. 2 4 Type 2 diabetes mellitus is the leading cause of end-stage renal disease in the western world, 5 8 although individual risk is and 1.4 (0.5, 2.2) deaths per 100 person-years, respectively (rate ratio 5.8). Forty-four patients (57%) died from cardiovascular causes (rate ratio 5.4). Mortality was directly proportional to degree of proteinuria: g/24 h, 4.6 ( ); )2 g/ 24 h, 9.9 ( ) per 100 patient-years. A 36% (5 78%) excess risk of mortality was observed for each log unit increase in proteinuria. Multivariate Cox regression analyses confirmed a five-fold excess risk for all-cause and cardiovascular mortality in patients with nephropathy compared with those without. This was independent of other risk factors including baseline age w5% (1 8%)/yearx, creatinine w2.5 ( )/10 mmol/lx and glycaemic control (HbA 1c ) w15% (1 31%) per1% risex. Conclusions: Proteinuria is a potentially preventable and reversible risk factor associated with high mortality in type 2 diabetic patients. Prevention of the development of overt nephropathy and improvement in diabetes control may reduce mortality in these patients. relatively low, because patients die from cardiovascular disease before the terminal decline of renal function. In developing strategies to prevent the epidemic of diabetic renal disease, a key component is to identify and aggressively control the modifiable risk factors associated with the development and progression of diabetic nephropathy. There are very few longitudinal studies in type 2 diabetic patients with overt nephropathy In this Address correspondence to Dr E.B. Jude, Diabetes Centre, Tameside General Hospital, Fountain Road, Ashton-under-Lyne, Lancashire OL6 9RW. ejude@man.ac.uk ß Association of Physicians 2002

2 372 E.B. Jude et al. retrospective study, we examined the natural history of diabetic nephropathy and baseline factors associated with mortality in a cohort of patients in a secondary-care setting. Methods Study patients The study population comprised all eligible patients (inclusion criteria outlined below) with type 2 diabetes mellitus who attended the Manchester Diabetes Centre s Renal Clinic between 1 January 1987 and 31 December Participants in the nephropathic group included subjects who had dipstick proteinuria on two occasions (n = 170), and who were asked to collect a 24-h urine sample for the estimation of total urinary protein excretion. Control subjects (n = 170) were randomly selected from the general diabetes clinic database using a computer-generated program. This database included all type 2 patients who did not have proteinuria at, or within, the next 6 months after referral. All patients were regularly followed up in this multi-disciplinary diabetic renal clinic, the main secondary-care referral centre in this region. Follow-up was from the first visit to the diabetic renal clinic until death or until 31 December Patients who died during the study period had their death certificates retrieved from the Office of National Statistics. The cause and date of death was noted from the certificate. Inclusion criteria Patients with type 2 diabetes were included, regardless of sex or ethnicity. Ethnicity was selfdefined by the patient or if missing, by birthplace, and recorded as White European, South Asian (for all people of Indian subcontinent origin) or African-Caribbean (Caribbean origin and African descent). Type 2 diabetes was defined as diabetes treated either with diet alone or diet combined with oral hypoglycaemic agents or insulin treatment (started )2 years after diagnosis of diabetes), with onset after the age of 40 years. Patients with proteinuria )0.5 g/24 h were included as cases, and controls were patients who were dipstixnegative at baseline. Patients who were already on renal replacement therapy at referral to the diabetic renal clinic were excluded. Clinical and biochemical parameters All patients had sitting blood pressure, measured twice, in the right arm using a Dinamap (Critikon), after resting for 10 min. Hypertension was defined according to older WHO criteria (systolic )160 mmhg and/or diastolic )95 mmhg, or on antihypertensive treatment at baseline). Body mass index was weight in kg/(height in m) 2. Direct ophthalmoscopy was performed through dilated pupils for retinopathy, which was classified as none, background, or proliferative. Present medication and history of smoking were noted. Coronary artery disease was determined by 12-lead ECG, hospital records of confirmed myocardial infarction, definite history of angina or coronary artery bypass grafting. Cerebrovascular disease was assessed by history and clinical examination, and hospital records of definite stroke. Peripheral vascular disease was determined by history of intermittent claudication and ankle brachial pressure index (normal )0.9) using a multi-doppler machine (Huntleigh Nesbit Evans Healthcare). Peripheral nerve function was assessed by vibration perception threshold using a biothesiometer (Biomedical Instrument); neuropathy was defined as a threshold )25 V. 13 A mean of three readings was taken for each patient at the apex of the right hallux. Laboratory measurements Blood for HbA 1c, glucose, creatinine and cholesterol taken at routine clinics was analysed at baseline. At the first visit, a urine sample was checked for protein. If 01qprotein was present, urinary tract infection was excluded by urine culture if necessary. If infection was ruled out, 24-h urinary protein was measured on two separate occasions. Statistical analysis Statistical analyses were performed using programs available in the Intercooled Stata 6.0 statistical package. Student s t-test and ANOVA were used to assess differences in continuous variables while the x 2 test was used for categorical variables. The all-cause mortality hazards ratios for both continuous and categorical variables were based on Kaplan-Meier estimates and compared by log-rank test. Cox proportional hazards multiple regression analyses were performed to examine the baseline variables predictive of all-cause and cardiovascular mortality. The models used included those baseline variables that were a priori considered to be important predictors of all-cause mortality and included: sex, age, serum creatinine, cholesterol, proteinuria, presence of nephropathy, ischaemic heart disease, hypertension and retinopathy. Proteinuria and creatinine were log-transformed,

3 Diabetic nephropathy in type 2 diabetes 373 as the underlying data was skewed. The hazard ratios for these variables therefore correspond to a 10-fold increase in concentration. The results are presented as hazard ratios (relative risk). Results We studied 340 patients with type 2 diabetes, 170 with proteinuria. Controls were older than cases, but mean baseline duration of diabetes and of follow-up were comparable (Table 1). In the proteinuric group, 79 (46%) patients were treated with ACE inhibitors. Controls were less obese and had lower blood pressures. Prevalence of hypertension, retinopathy, neuropathy, coronary and peripheral vascular disease was higher in patients with nephropathy, but smoking did not differ. Proteinuric patients had higher cholesterol, creatinine and HbA 1c concentrations (Table 1). Mortality Baseline variables were compared for patients who died during follow-up vs. survivors (Table 2). Of 77 patients who died during follow-up, 63 (37%) Table 1 had nephropathy at baseline; 14 (8%) were non-proteinuric controls (x 2 = 53.8, p ). Patients who died were younger in those with nephropathy, had a shorter known duration of diabetes, and higher baseline serum creatinine concentrations even after adjusting for age. Differences in cholesterol and HbA 1c were not significant (Table 2). Within the proteinuric patients, the prevalence of retinopathy, neuropathy and ischaemic heart disease was significantly higher in the patients who died. Cardiovascular disease was the major cause of death in both groups: 48% (n = 30) in the proteinuric patients, and 57% (n = 8) in the controls (Table 3). Uraemia was the cause of death in 14 (22%) proteinuric patients. Age- and sex-adjusted all-cause mortality rates were 8.1 (6.4, 9.8) and 1.4 (0.5, 2.2) deaths per 100 person years in proteinuric vs. control patients (rate ratio 5.8). Forty-four patients (57%) died from cardiovascular or cerebrovascular causes, with rates of 4.9 (3.5, 6.2) and 0.9 (0.2, 1.7) respectively, a similar rate ratio of 5.4. Kaplan-Meier survival curves showed poorer survival at 5 and 10 years of 58% and 19% for severely proteinuric patients ()2 g/24 h) compared with those with Baseline anthropometric and clinical variables in patients with and without proteinuria Nephropathy (n = 170) Non-nephropathic (n = 170) p Sex (M/F) (n) 117/53 109/61 Age (years) 58.2 (56.6, 59.8) 63.3 (62.2, 64.4) Ethnicity* (n) 101/43/26 126/29/ (x 2 = 8.42) Diabetes duration (years) 4.9 (4.5, 5.3) 5.3 (4.0, 6.5) 0.6 Follow-up (years) 5.1 (4.7, 5.5) 5.5 (5.1, 5.9) 0.1 Smoker % 22.3 (16, 29) 22.9 (17, 29) 0.8 Hypertension % 95.2 (92, 99) 47.6 (40, 55) Retinopathy % 78.1 (72, 84) 35.3 (26, 45) Neuropathy % 67.6 (61, 75) 41.8 (34, 49) IHD % 48.8 (41, 56) 25.3 (19, 32) PVD % 27.1 (20, 34) 6.5 (3, 10) BMI (kg/m 2 ) Male 28.7 (28, 30) 26.7 (26, 27.6) Female 31.9 (30, 34) 28.1 (27, 29.7) Systolic BP (mmhg) Male 169 (166, 172) 148 (144, 153) Female 174 (169, 179) 161 (155, 168) Diastolic BP (mmhg) Male 92 (90, 94) 84 (81, 86) Female 90 (87, 93) 85 (82, 88) 0.01 Cholesterol (mmol/l) 6.5 (6.2, 6.8) 5.9 (5.7, 6.1) HbA 1c % 10.6 (10.2, 11.0) 9.8 (9.4, 10.2) Serum creatinine (mmol/l) (128, 155) 92.7 (90, 96) Proteinuria (g/24 h) 2.9 (2.5, 3.3) Data shown as numbers, or mean (95%CI). *White European/Asian/African-Caribbean.

4 374 E.B. Jude et al. Table 2 Baseline variables and risk factors in type 2 diabetes patients stratified by nephropathy and survival status Nephropathy No nephropathy Alive Died Alive Died n (% of total) 107 (63%) 63 (37%) 156 (92%) 14 (8%) Age (years) 56.5 (54.3, 58.7) 61.1 (58.9, 63.2)** 63.0 (61.8, 64.2) 65.9 (63.4, 68.4) Duration DM (years) 5.1 (4.6, 5.6) 4.6 (3.7, 5.4) 5.1 (3.8, 6.4) 6.9 (3.3, 10.5) Duration follow-up (years) 5.5 (4.9, 5.9) 4.3 (3.7, 4.9) 5.7 (5.3, 6.1) 4.4 (2.6, 6.1) Hypertension, n (%) 100 (93) 62 (98) 77 (49) 4 (29) Retinopathy, n (%) 75 (70) 57 (92)*** 45 (29) 3 (21)** Neuropathy, n (%) 61 (57) 54 (86)*** 62 (40) 9 (64) IHD, n (%) 44 (41) 39 (62) 41 (26) 2 (14) PVD, n (%) 26 (24) 20 (32) 8 (5) 3 (21)* BMI (kg/m 2 )y 30.0 (28.8, 31.1) 27.9 (26.4, 29.6) 27.5 (26.7, 28.3) 26.0 (23.3, 28.7) Systolic BP (mmhg)y 152 (149, 155) 154 (143, 165) 170 (166, 175) 172 (168, 178)** Diastolic BP (mmhg)y 91 (89, 93) 91 (88, 94) 84 (82, 86) 87 (82, 93) Serum creatinine (mmol/l)y 140 (120, 160) 242 (216, 266)*** 93 (77, 109) 95 (39, 150) Proteinuria (g/24 h) 2.5 (2.0, 3.0) 3.5 (2.8, 4.2)** Cholesterol (mmol/l)y 6.4 (6.2, 6.7) 6.6 (6.1, 7.0) 5.9 (5.7, 6.2) 6.2 (5.3, 7.1) HbA 1c (%)y 10.3 (9.7, 10.8) 10.7 (10.0, 11.3) 9.8 (9.4, 10.3) 11.2 (9.7, 12.6) Data shown as n (%) or mean (95%CI), except yage-adjusted means (95%CI). IHD, ischaemic heart disease; PVD, peripheral vascular disease; BP, blood pressure. *p-0.05; **p-0.01; ***p Table 3 Causes of death Cause of death No proteinuria Proteinuria* Total Cardiovascular 8 (57) 30 (48) 38 (49) Cerebrovascular 1 (7) 5 (8) 6 (8) Renal 14 (22)** 14 (18) Others 4 (29) 11 (17) 15 (19) Data are numbers (%). Cause of death not known in 4 patients. *)0.5 g/24 h. **Of the 14 who died of uraemia, eight had continuous ambulatory peritoneal dialysis and one underwent renal transplantation. moderate proteinuria (0.5 2 g/24 h) (85% and 50%, respectively) (Figure 1). Age-adjusted mortality per 100 person years virtually doubled with increasing grade of proteinuria from 5.7 (3.1, 8.4) for g/24 h to 9.6 (8.1, 11.4) for )2 g/24 h. Cox survival analysis In univariate analyses, age, treatment with insulin, presence of hypertension, retinopathy, neuropathy, IHD, PVD, systolic BP and log serum creatinine were each associated with all-cause and cardiovascular mortality (Table 4). A 36% excess risk of mortality was observed for each ln unit increase in proteinuria whr = 1.36 (1.05, 1.78); p = 0.02x. Multivariate Cox regression analyses (Table 5) indicated that patients with nephropathy were still about five times as likely to die from any cause or from cardiovascular causes than those without nephropathy. This was independent of the association per year of increasing age and per ln unit creatinine. Each 1% increase in HbA 1c was associated with only a 15% increased risk of cardiovascular mortality. Including systolic BP, instead of hypertension, in a separate model, the risk of all-cause mortality for subjects with nephropathy was decreased slightly whazard ratio, HR = 3.69 ( ); p = 0.008x. In a separate model, excluding ethnicity and hypertension, a 1-unit increase in cholesterol whr = 1.21 (1.02, 1.45)x, creatinine w4.9 (3.0, 8.0)x, and HbA 1c w1.12 (1.01, 1.25)x were each associated with an increased risk of all-cause mortality, irrespective of subjects nephropathic status, after adjusting for age, sex, and duration of diabetes at baseline. Discussion Mortality is elevated in patients with type 2 diabetes mellitus (type 2 DM). 14 The dysmetabolic changes which accompany type 2 DM, including abnormalities in lipid metabolism, fuel flux, and endothelial function, have a greater impact on mortality in patients with nephropathic disease, than in those without. In this retrospective clinic-based study, we observed five-fold excess mortality in subjects with nephropathy (37% vs. 8% mortality) 10 years after diagnosis of diabetes; this is similar to previous

5 Diabetic nephropathy in type 2 diabetes 375 Figure 1. Kaplan-Meier estimates of the survival curves, considering all-cause mortality, for non-proteinuric and proteinuric patients with g and )2 g/24 h. Log rank tests for the equality of the survivor function across groups: A vs. B: x (p = ); B vs. C: x (p = 0.007); A vs. C: x (p ). Table 4 Hazard ratios (HRs) for risk of death for patients with type 2 diabetes by univariate Cox regression analysis Variable All-cause mortality Cardiovascular mortality HR 95%CI p HR 95%CI p Sex female Age 1 year Known duration of diabetes Treatment Diet alone Oral hypoglycaemic agent(s) Insulin Haemoglobin A 1c 1% Body mass index 1kg/m Pre-existing hypertension Retinopathy (any) Pre-existing neuropathy Pre-existing IHD Pre-existing PVD Pre-existing CVA Systolic BP 1 mmhg Diastolic BP 1 mmhg ln Serum creatinine Current smokers Serum cholesterol 1 mmol/l reports. 15,16 Baseline serum creatinine and proteinuria were also independent risk factors associated with mortality. Reduced survival rates in type 2 DM nephropathic patients compared to non-nephropathic patients (29% vs. 39%, respectively) have previously been reported. 11 The patients referred to this clinic with baseline 24-h proteinuria )2 g had a lower survival probability at 5 years (68%) than did patients with protein excretion rates between g/24 h (85%). Similar to the Wisconsin cohort, which reported proteinuria as an independent predictor of all-cause mortality, in this clinic-based cohort, baseline proteinuria was associated with a 36% excess risk of all-cause mortality. 17 Recently, Valmadrid et al. demonstrated that proteinuria was an independent risk factor for cardiovascular mortality, a finding which we have also observed. 12 Mortality is also associated with increasing levels of albuminuria, age, diabetes duration, serum creatinine 18,19 and high albumin excretion rates (i.e mg/min). 20

6 376 E.B. Jude et al. Table 5 Cox Proportional Hazards multivariate analyses Variable HR 95%CI p All-cause mortality Patients with nephropathy ln Serum creatinine Age 1 year Pre-existing IHD Haemoglobin A 1c 1% Serum cholesterol 1 mmol/l Known duration of diabetes 1 year Sex female Ethnicity Pre-existing hypertension Cardiovascular mortality Patients with nephropathy ln Serum creatinine Haemoglobin A 1c 1% Pre-existing IHD Age 1 year Known duration of diabetes 1 year Ethnicity Pre-existing hypertension Sex female HR, hazard ratio. Diabetic nephropathy is associated with high blood pressure, which is known to worsen renal function. While we did not observe a significant and independent association of blood pressure on mortality, systolic blood pressure is a significant predictor of cardiovascular mortality. 15 Any effect of blood pressure here may be confounded by the high proportion of patients (98%) on anti-hypertensive treatment at referral. Hypercholesterolaemia is an important risk factor for atherosclerosis and mortality in diabetic patients. 21 In one study of type 1 patients, hypercholesterolamia was a risk factor for deterioration of renal function and mortality. 22 Rapid loss of renal function rose with increasing levels of serum cholesterol, independent of blood pressure, but with blood pressure added to the multivariate analysis, the risk increased by a third. In another cohort, Ravid and colleagues 23 also reported decreased renal function in type 2 diabetic patients with hypercholesterolaemia. We found higher cholesterol levels in patients with diabetic nephropathy but the increased levels did not confer a significant excess mortality. This study is both retrospective and observational, and therefore potentially suffers from the limitations of such investigations. There may have been unrecognized biases in the selection of controls, but it is unlikely that these biases would have had a substantial impact on the associations between the risk factors reported here and adverse outcome. Secondly, because this study was conducted in a secondary referral centre, the results here may not be comparable with those from community-based studies. It also highlights the need to initiate specialist multi-disciplinary renal clinics to improve care of diabetic patients with nephropathy. The question as to whether referral to a diabetic clinic with special renal interests can reduce mortality, needs further study. The results of recent studies have provided adequate evidence that development and progression of diabetic nephropathy can be prevented through improvement in diabetes control, 24,25 optimization of blood pressure, 6,26 28 restriction of protein intake, 6,27,28 use of ACE inhibitors and/or angiotensin-ii receptor antagonists, 29,30 and when there is indication of lipid-lowering medications. 31 This study has shown that proteinuria is independently associated with increased mortality in subjects with type 2 diabetes. However, proteinuria may simply be a marker of high risk, and modification of the degree of proteinuria may not influence risk at all. In addition, the presence of other microvascular complications may indicate a higher risk of mortality in type 2 diabetic patients with proteinuria. In conclusion, we recommend earlier referral to the diabetic renal clinic, earlier initiation of appropriate treatment (e.g. with ACE inhibitors) and

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