Renal function at the time of nephrology referral but not dialysis initiation as a risk for death in patients with diabetes mellitus

Renal function at the time of nephrology referral but not dialysis initiation as a risk for death... Clinical Kidney Journal, 2018, 1–7 doi: 10.1093/ckj/sfy032 Original Article OR I G I N AL A R T I C L E Renal function at the time of nephrology referral but not dialysis initiation as a risk for death in patients with diabetes mellitus 1 1,2 1 1 Ce ´ dric Pinier , Philippe Gatault , Maud Franc ¸ois , Christelle Barbet , 1 1 1 1 He ´le ` ne Longuet , Nolwenn Rabot , Johann Noble , Elodie Bailly , 1,2 1,3,4 1,2,3 Matthias Buchler ,Be ´ne ´ dicte Sautenet and Jean-Michel Halimi 1 2 Service de Ne ´ phrologie-Immunologie clinique, Ho ˆ pital Bretonneau, CHU Tours, Tours, France, EA4245, Franc ¸ois-Rabelais University, Tours, France, FCRIN INI-CRCT Cardiovascular and Renal Clinical Trialists, France and INSERM U1246, Franc ¸ois-Rabelais University, Tours, France Correspondence and offprint requests to: Jean-Michel Halimi; E-mail: halimi@med.univ-tours.fr ABSTRACT Background: Renal patients with diabetes mellitus are at very high risk of death before and after chronic dialysis initiation. Risk factors for death in this population are not clearly identified. Methods: We performed a retrospective survival analysis in 861 patients with diabetes mellitus consecutively followed up in the 2000–13 period in a nephrology setting. Results: The mean age was 70 6 10 years [men 65.2%; diabetes duration 13.7 6 10.3 years; mean estimated glomerular filtration rate (eGFR) 42.4 6 21.0 mL/min/1.73 m ). During follow-up (median 60 months; up 15 years), 263 patients died (184 before and 79 after dialysis initiation) and 183 started chronic dialysis. In multivariate analyses, age, elevated systolic and low diastolic arterial pressures, peripheral artery disease, cancer, loop diuretic use and atrial fibrillation at baseline and acute kidney injury (AKI), heart failure (HF) and amputation during follow-up were identified as risk factors for death. After adjustments on these parameters, eGFRs at the time of the first outpatient visit—eGFR <45 mL/min/1.73 m {hazard ratio [HR] 1.58 [95% confidence interval (CI) 1.15–2.17]}, P¼ 0.005 and eGFR <30 [HR 1.53 (1.05–2.05)], P¼ 0.004, but not eGFR <60—were powerful risk factors for death. When initiation of dialysis was entered into the multivariate models, it was not associated with a risk of premature death [HR 1.19 (95% CI 0.91–1.55), P¼ 0.2069], even in patients >80 years of age [HR 1.08 (95% CI 0.64–1.81), P¼ 0.7793]. Conclusions: In patients with diabetes mellitus, high systolic and low diastolic arterial pressure, peripheral artery disease and development of AKI and HF are significant risk factors for death. In addition to these parameters, eGFR <45 mL/min/ 1.73 m at the time of referral is also a powerful risk factor for death. Keywords: diabetes, dialysis, epidemiology, renal function, risk of death Received: 11.9.2017. Editorial decision: 7.3.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| C. Pinier et al. Hospitalier Universitaire, Ho ˆ pital Bretonneau, Tours, France). The INTRODUCTION study was approved by the Ethics Committee of Human Research In 2014, at least 387 million people worldwide were living with of our hospital (approval number 2016-21). diabetes [1], and nearly 600 million people are expected to be di- Type 2 diabetes was defined according to the American abetic in 2035 [2]. Diabetes increases the risk of premature death Diabetes Association (ADA) criteria [10]. Data were retrieved and reduces life expectancy by nearly 15 years [3]. The risk of from files at baseline and during follow-up. They included age, death in patients with diabetes mellitus is markedly increased gender, comorbid conditions and diabetes duration. when renal function is impaired, and even more in end-stage At baseline, systolic and diastolic blood pressures and body renal disease (ESRD) and dialysis [4, 5]. mass index (BMI) were measured and information regarding the Optimal management of these renal patients with diabetes use of antihypertensive drugs [including renin–angiotensin sys- mellitus poses numerous problems, including the optimal time tem (RAS) blockers], glucose-lowering agents, lipid-lowering to nephrology referral and the need for dialysis (especially agents and antiplatelet medications were collected. when renal transplantation is not feasible). Some studies indi- Baseline laboratory results (including serum creatinine and cate that late referral to nephrologists is associated with re- glycated haemoglobin) were obtained. Baseline albuminuria duced survival [6]. The Kidney Disease: Improving Global was defined based on urine dipstick or by 24-h urine protein; Outcomes (KDIGO) guidelines suggest referring patients with an proteinuria was converted in albuminuria as described previ- estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m , ously [11]. GFR was estimated using the Modification of Diet in macrolbuminuria or rapid renal function decline (RRFD, i.e. Renal Disease (MDRD) equation [12]. eGFR decrease >5 mL/min/year) to nephrologists [7]. However, no specific guideline applies to the diabetic population. Follow-up and outcomes Whether earlier referral is justified in patients with diabetes All files were individually (manually) reviewed. Acute kidney in- mellitus and chronic kidney disease (CKD) is unknown, as the progression of renal disease may be slow. After referral, neph- jury (AKI) in hospitalization during follow-up was diagnosed us- ing the KDIGO criteria [7]. Only serum creatinine criteria were rologists face difficulties in the management of these elderly used to diagnose AKI, thus, urinary output criteria were omitted. patients with diabetes mellitus, as survival of these patients may be reduced after initiation of dialysis [8]. Some studies ad- Baseline serum creatinine was considered the lowest creatinine value (i.e. the reference creatinine value). We identified AKI by vocate that a conservative approach should be discussed in el- comparing the highest creatinine value found during hospitaliza- derly patients, especially those with diabetes [9]. With this in mind, it may be difficult for clinicians to refer these patients tion with the reference serum creatinine value. AKI was defined earlier to nephrologists as they feel that the patients may die as a serum creatinine level of 150% or þ0.3 mg/dL (þ26.5 mmol/L) versus the reference serum creatinine level [13]. before they need dialysis, that the duration of follow-up before reaching ESRD is uncertain and may be extremely long in some Stroke was defined in patients as focal neurological abnor- malities associated with ischaemic or haemorrhagic tissular patients and that chronic dialysis may precipitate death [9]. lesions found on computed tomography scan and/or magnetic However, referral to nephrologists is not only useful to delay ESRD, but it is important to optimize management of CKD resonance imaging. Amputation was defined as a lower limb amputation above the metatarsophalangeal joint. We also patients and therefore improve patient survival before and after recorded revascularization of coronary arteries (angioplasty, dialysis initiation. The late referral issue is important; however, coronary artery bypass grafting or coronary stent) and revascu- at the time of referral, it is not usually possible to know pre- larization of peripheral arteries (angioplasty or bypass of aortic cisely the duration of follow-up before dialysis or transplanta- or lower limb arteries). tion becomes necessary. From a practical point of view, the Information regarding major cardiovascular events such as issue of the GFR cut-off value associated with a risk of deleteri- acute coronary syndrome (ACS), atrial fibrillation (AF) or hospi- ous outcome is also important. The two issues are of course talization for heart failure (HF) as well as infections requiring interconnected. However, it is easier for clinicians to identify hospitalization and cancer during follow-up was recorded. GFR values than a time to dialysis, which remains elusive in Patients were followed until death or the end of the study most cases. Earlier referral than the one indicated in the KDIGO period (15 November 2015). The main outcome of the study was guidelines may appear useful. all-cause death (whether or not death occurred in patients who Finally, the right timing for referral is unclear despite the started chronic dialysis). Deaths were identified using the KDIGO guidelines and the benefit of dialysis is unproven in national death register and medical records from our centre or many instances in elderly CKD patients with diabetes mellitus. primary care physicians. In this population, whether earlier referral is justified is unknown and whether dialysis initiation is detrimental is unclear. Statistical analyses In the present retrospective study, we estimated whether di- Results are presented as mean (standard deviation (SD)) for con- alysis initiation and the eGFR value of patients at the time of re- tinuous variables [or median and interquartile range (IQR) if the ferral are associated with risk factors for death in a large cohort distribution of the variable was skewed] and as percentages for of renal patients with diabetes mellitus followed up to 15 years. categorical variables. We performed univariate and multivariate Cox models to ex- MATERIALS AND METHODS amine the association between baseline characteristics and risk of death. Analyses were performed in the whole population and Study population sensitivity analyses were performed in subgroups of patients In the present study we retrospectively analysed 861 consecutive with advanced age (age 70,75 and80 years) because it was patients with type 2 diabetes who were referred as outpatients to suggested in the literature that the risk of death associated with nephrologists in our hospital during the 2000–13 period (Centre dialysis initiation was greater in older patients. We examined Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 GFR, dialysis initiation and death in diabetes | 3 Table 1. Baseline characteristics whether age at dialysis was a risk factor for death in patients who started dialysis. We also performed univariate and multi- Clinical characteristics (n ¼ 861) variate analyses to evaluate whether major events (cardiovas- Age (years) 70.36 10.0 cular events, stroke, hospitalization for infection, AKI) during Sex (male) 65.2 follow-up were risk factors for death; these events were consid- 2 BMI (kg/m ) 30.76 5.9 ered as time-dependent parameters. We only considered the Systolic/diastolic arterial pressure (mmHg) 1496 23/786 12 first event even when it occurred several times during follow- Diabetes duration (years) 13.76 10.3 up. A stepwise descending procedure was used to determine ev- Main reason for first outpatient visit in nephrology ward ery final multivariate model (all conventional variables were in- CKD 54.3 Albuminuria 15.6 cluded in the models: all univariate significant variables were Hypertension 3.4 included in a maximized multivariate model, then we deter- Other 26.7 mined an optimized model with a backward procedure). Comorbid conditions Kaplan–Meier curves were constructed and compared using a Hypertension 93.5 log-rank test. Analyses were performed using SAS version 9.3 Coronary artery disease 26.6 (SAS Institute, Cary, NC, USA). A P-value <0.05 was considered HF 20.4 to be statistically significant. Peripheral artery disease 19.2 AF 20.1 Stroke 7.0 RESULTS Renal artery stenosis 3.4 Baseline characteristics Smoking (active/former) 8.2/33.1 Diabetic retinopathy 24.0 The mean age was 70.3 6 10.0 years and most patients were Biological data men (65.2%). Overall, eGFR was 42.4 6 21.0 mL/min/1.73 m Serum creatinine (mmol/L) 1766 124 (Table 1). Of note, 334 (44.3%) patients had a history of major eGFR (mL/min/1.73 m ) 42.46 21.0 cardiovascular disease. Albuminuria was present in 98.1% of CKD stage patients and macroalbuminuria was present in 49% of patients. 1 or 2 15.6 Among the 556 patients with eGFR<60 mL/min/1.73 m , nor- 3a 19.7 moalbuminuria, microalbuminuria and macroalbuminuria were 3b 35.7 present in 22.1, 29.7 and 48.2% of patients, respectively. 4 22.8 Despite a significant proportion of patients with CKD, only 5 6.2 207 (24%) had diabetic retinopathy. Angiotensin-converting en- Albuminuria (mg/day or mg/g of urine creatinine) 9556 1794 Normoalbuminuria 21.4 zyme inhibitor and/or angiotensin receptor blocker (ARB) were Microalbuminuria 29.6 used in the most patients, and half of the patients received in- Macroalbuminuria 49.0 sulin (Table 1). Haemoglobin A1c 7.256 1.5 Antihypertensive therapy Baseline and follow-up parameters associated with the ACE inhibitor/ARB/both 33.5/42.5/3.7 risk of death Calcium-channel blocker 50.4 Loop diuretic 39.0 Patients were followed up for a median duration of 60 months Thiazide 23.5 (IQR 39–78 months, range 4.5–193 months, total observation Beta-blocker 46.0 time 6113 patient-years). During this period, 263 patients died Spironolactone 3.5 (including 79 after dialysis); the 5- and 10-year risks of death Others 22.1 were 24.2 and 44.6%, respectively. Of note, 183 patients started Glucose-lowering therapy chronic dialysis, whereas 13 patients had a conservative treat- Insulin 45.5 ment [mostly due to comorbid conditions (61.5%) or the Oral agents 53.0 patient’s choice (31.0%)] during follow-up. Diet only 7.5 In univariate and multivariate analyses, baseline parameters Other treatments associated with the risk of death included age, diastolic arterial Statin 57.7 pressure, peripheral artery disease, cancer, use of loop diuretics Fibrate 8.8 Antiplatelet drug 51.0 and AF (Table 2). Other parameters such as AKI were signifi- cantly associated with the risk of death in univariate and multi- Results are presented as percentage or mean 6 SD. variate analyses (Table 2). Albuminuria: values after conversion of proteinuria in albuminuria when only proteinuria was available [11]. Initiation of chronic dialysis, age and risk of death Albuminuria classes were defined as normoalbuminuria: albuminuria <30 mg/ day, <30 mg/g or <20 mg/L; microalbuminuria: albuminuria 30 and <300 mg/ In this analysis we assessed whether initiation of dialysis could day; 30 and <300 mg/g or 20 and <200 mg/L; macroalbuminuria: albuminuria accelerate the risk of death. 300 mg/day, 300 mg/g or 200 mg/L. In univariate analysis, dialysis was not associated with the CKD Stages:1–2:eGFR 60 mL/min/1.73 m ; 3a: 45–59.9; 3b: 30–44.9; 4: 15–29.9; 5: <15. risk of death (Table 3). The mean age at dialysis was 73.5 6 9.2 years in the 183 patients who initiated chronic dialysis In multivariate analyses, there was no significant associa- (Table 3). Similar results were observed when the analysis was tion between initiation of dialysis and the risk of death after restricted to older patients (70, 75 or 80 years at baseline); adjustments on baseline and/or follow-up risk factors for for these age groups, the mean age at dialysis was 77.1 6 4.6, death (Table 3). 79.8 6 3.5 and 83.1 6 2.8 years, respectively (Table 3). Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| C. Pinier et al. Table 2. Baseline and follow-up parameters associated with the risk of death during follow-up Univariate analysis Stepwise multivariate analysis Parameters HR 95% CI P-value HR 95% CI P-value Baseline Gender (men versus women) 1.09 0.84–1.42 0.5114 – Age (per 10 years) 2.16 1.85–2.52 <0.0001 1.94 1.64–2.29 <0.0001 Systolic arterial pressure (per þ10 mmHg) 0.97 0.92–1.03 0.2724 – Diastolic arterial pressure (per þ10 mmHg) 0.76 0.68–0.85 <0.0001 0.88 0.79–0.99 0.0127 BMI (kg/m ) 1.00 0.99–1.00 0.4494 – Haemoglobin (per þ1 g/L) 0.99 0.98–0.99 0.0003 – Smoking (ever versus no smoking) 1.14 0.89–1.47 0.2955 – Diabetic retinopathy 1.05 0.81–1.38 0.7106 – Coronary artery disease 1.63 1.27–2.10 0.0001 – Peripheral vascular disease 1.99 1.53–2.58 <0.0001 1.84 1.39–2.42 <0.0001 Lower limb amputation 1.89 1.06–3.37 0.0319 – Hospitalization for HF 2.43 1.88–3.15 <0.0001 – Cancer 1.74 1.26–2.40 0.0009 1.84 1.31–2.57 0.0004 Loop diuretic use 2.03 1.59–2.59 <0.0001 1.75 1.34–2.27 <0.0001 AF 1.83 1.83–3.14 <0.0001 1.68 1.25–2.26 0.0006 Glycosylated haemoglobin (per þ1%) 0.99 0.90–1.09 0.8040 – RAS blockers 0.74 0.57–0.96 0.0245 – Follow–up AKI 3.25 2.53–4.18 <0.0001 2.12 1.58–2.85 <0.0001 AF 0.99 0.70–1.40 0.9513 – Acute coronary syndrome 1.70 1.16–2.48 0.0062 – HF 3.63 2.83–4.66 <0.0001 2.44 1.83–3.27 <0.0001 Stroke 1.53 1.01–2.31 0.0449 – Lower limb amputation 2.35 1.31–4.20 0.0040 1.93 1.08–3.45 0.0275 Hospitalization for serious infection 3.64 0.51–26.1 0.1985 – Table 3. Chronic dialysis initiation and risk of death during follow-up Information regarding patients Information regarding patients who started chronic dialysis who died during follow-up during follow-up Age at Number of patients Age at Age at Number of Age at dialysis who died (before/after baseline death patients who baseline initiation HR 95% CI P-value dialysis initiation) (years) (years) started dialysis (years) (years) Risk of death associated with chronic dialysis initiation (univariate analysis) All patients (n ¼ 861) 1.19 0.91–1.55 0.2069 263 (184/79) 74.46 8.8 79.46 8.5 183 70.46 8.9 73.56 9.2 Sensitivity analyses (subgroup analyses) Age 70 years (n ¼ 474) 1.13 0.82–1.56 0.4621 187 (135/52) 78.76 5.3 83.36 5.6 101 77.16 4.6 79.96 5.0 Age 75 years (n ¼ 314) 1.07 0.73–1.58 0.7304 135 (99/36) 81.26 4.1 85.76 4.3 64 79.86 3.5 82.66 4.1 Age 80 years (n ¼ 139) 1.08 0.64–1.81 0.7793 74 (54/20) 84.16 3.1 88.16 3.3 27 83.16 2.8 85.26 3.3 Risk of death associated with chronic dialysis initiation (multivariate analysis) Model 1 1.19 0.89–1.58 0.2443 Model 2 1.40 0.42–4.71 0.5839 Model 3 1.69 0.47–6.13 0.4228 Age is presented in mean 6 SD. Baseline parameters: age, diastolic arterial pressure, peripheral vascular disease, cancer, use of loop diuretics and AF. Follow-up parameters: AKI, HF and amputation during follow-up. Adjustments on baseline parameters (Model 1), follow-up parameters (Model 2) or both (Model 3). Risk of death according to renal function value or Among patients who started dialysis, age at dialysis was sig- decline at the time of referral nificantly associated with the risk of premature death in univar- iate and multivariate analyses [univariate: HR per þ10 years 1.36 In univariate analyses, eGFR <30 mL/min/1.73 m (versus eGFR (95% CI 1.05–1.77), P¼ 0.0212; multivariate: 1.50 (1.10–2.05), 30) at the time of referral was significantly associated with the P¼ 0.0104]. risk of death (Table 4). However, eGFR <60 mL/min/1.73 m Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 GFR, dialysis initiation and death in diabetes | 5 Table 4. eGFR at the time of referral as a risk of death HR 95% CI P-value Univariate analysis Baseline eGFR <60 (versus 60) 2.88 1.78–4.64 <0.0001 Baseline eGFR <45 (versus 45) 2.18 1.63–2.91 <0.0001 Baseline eGFR <30 (versus 30) 1.84 1.44–2.36 <0.0001 Multivariate analysis Model 1: adjustment on baseline parameters Baseline eGFR <60 (versus 60) 1.40 0.83–2.38 0.2114 Baseline eGFR <45 (versus 45) 1.63 1.20–2.23 0.0020 Baseline eGFR <30 (versus 30) 1.49 1.14–1.95 0.0034 Model 2: adjustment on follow-up parameters Baseline eGFR <60 (versus 60) 2.25 1.39–3.65 0.0010 Baseline eGFR <45 (versus 45) 2.13 1.58–2.87 <0.0001 Baseline eGFR <30 (versus 30) 2.03 1.54–2.68 <0.0001 Model 3: adjustment on baseline and follow-up parameters Baseline eGFR <60 (versus 60) 1.30 0.76–2.23 0.3425 Baseline eGFR <45 (versus 45) 1.58 1.15–2.17 0.0053 Baseline eGFR <30 (versus 30) 1.53 1.53–2.05 0.0040 eGFR denotes eGFR (determined using the MDRD equation (in mL/min/1.73 m ). Baseline parameters: age, diastolic arterial pressure, peripheral vascular disease, cancer, use of loop diuretics and AF. Follow-up parameters: AKI, HF and amputation during follow-up. 1.00 0.75 0.50 P<0.0001 0.25 0.00 0 25 50 75 100 125 150 175 200 Follow-up (months) 2 2 FIGURE 1: Risk of death in patients with eGFR<45 mL/min/1.73 m (versus45) at the time of referral. Symbols in red: patients with eGFR <45 mL/min/1.73 m at the time of referral to the nephrologist. Symbols in black: patients with eGFR 45 mL/min/1.73 m at the time of referral to the nephrologist. (versus eGFR 60) and <45 mL/min/1.73 m (versus eGFR 45) factors for dialysis initiation [HR 7.12 (95% CI 5.28–9.60) were also significant (Table 4 and Figure 1). P<0.0001; HR 6.04 (3.76–9.70), P<0.0001; HR 20.7 (5.2–83.2), In multivariate analyses, only eGFR<45 mL/min/1.73 m P<0.0001, respectively]; similar findings were observed for (versus eGFR 45) and eGFR<30 mL/min/1.73 m (versus microalbuminuria versus normoalbuminuria [HR 2.03 (95% CI eGFR 30) remained significant (Table 4), even when patients 1.07–3.84), P¼ 0.0297] and for macroalbuminuria versus microal- with baseline eGFR<15 mL/min/1.73 m were excluded from the buminuria [HR 2.84 (1.97–4.11), P<0.0001]. analysis [HR 2.72 (95% CI 1.68–4.40), P <0.0001 and HR 2.05 (1.53– 2.750), P <0.0001, respectively]. DISCUSSION RRFD (eGFR change >5 mL/min/1.73 m /year) [HR 1.45 (95% CI 0.88–2.39), P¼ 0.1479] and macroalbuminuria (versus In the present study conducted in elderly patients with diabetes normoalbuminuria or microalbuminuria) [HR 1.14 (95% CI mellitus who were followed up in a nephrology setting, almost 0.89–1.46), P¼ 0.3021] were not risk factors for death during half of the patients died after 10 years of follow-up. Major risk follow-up. factors for death were age, diastolic arterial pressure, peripheral As expected, eGFR<30 mL/min/1.73 m (versus eGFR 30), artery disease, cancer, use of loop diuretics and AF at baseline, <45 (versus eGFR 45) and <60 (versus eGFR 60) were risk and AKI, HF and lower limb amputation during follow-up. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| C. Pinier et al. Initiation of chronic dialysis did not precipitate death, regard- population, but it should be noted that this figure is much less of adjustments. An eGFR <45 mL/min/1.73 m (CKD Stage greater than those reported in other French studies focused on 3b or worse) at the time of nephrology referral was a powerful renal risk in diabetes mellitus [19]. risk of death, after multiple adjustments, but not eGFR <60 mL/ Of note, AKI remained significantly associated with the risk min/1.73 m . These findings support the view that referral to of death in multivariate analyses. Recently it was reported that nephrologists may be warranted not only in patients with CKD AKI, in addition to GFR and albuminuria, was a strong predictor Stage 4 but also in patients with CKD Stage 3b. of cardiovascular and non-cardiovascular death in a large co- The results of the present study indicate that dialysis initia- hort of patients with diabetes mellitus. We noted that low dia- tion did not accelerate the risk of death, even in older patients stolic blood pressure was a risk factor for death in our (age 70–80 years). In a recent single-centre observational population. Other studies suggest that there is a J curve rela- study, the risk of death was not different in patients 80 years tionship between diastolic blood pressure and the risk of death age choosing dialysis and in those receiving conservative treat- [20]. ment [14]. For this reason, it was proposed that dialysis initia- Our study has several limitations. It is a monocentric tion must be discussed on an individual basis [8, 9]. Our findings study and therefore our findings need to be replicated; how- suggest that the risk of death is not markedly accelerated in our ever, our cohort is large and the total observation period was elderly patients with diabetes mellitus in whom the decision of important. Files were individually (manually) reviewed and dialysis was made and therefore this decision was probably there was no inclusion bias, as these patients were consecu- adequate. tively included. In the present study, eGFR<45 mL/min/1.73 m (CKD Stage Our study also has some strengths. Multivariate analyses 3b) at the time of the first nephrology visit was a powerful risk were carefully designed to take into account potential con- of death. This issue of early referral to nephrologists has been founders, including baseline parameters as well as parameters extensively studied in patients with advanced CKD (usually during follow-up associated with the risk of death. All patients CKD Stage 5) [6]. Renal outcome and mortality were compared were followed in the same centre and we could therefore re- in patients with early versus later referral to nephrologists (in trieve all treatments, hospitalizations and biochemical evalua- most studies early was defined as follow-up before dialysis of tions. We believe that our cohort of patients is representative of 1–6 months) [6]. Using this definition, early referral was associ- the patients with diabetes mellitus followed up in nephrology ated with lower mortality as compared with later referral in the settings in France. In effect, renal function of the 986 outpa- Cochrane’s systematic review where 63 887 patients were ana- lysed [6]. However, these analyses were limited to patients with tients with diabetes mellitus who were referred to nephrologists low eGFR (CKD Stage 5), were not stratified according to the in the ALICE multicentre French study was comparable to that presence of diabetes mellitus and not all patients were man- found in our cohort [20]. The mortality rate of the 1341 patients aged in a nephrology setting [6]. Moreover, these analyses were with diabetes mellitus followed in French hospitals from the focused on the timing of referral but not on the value of eGFR at Survival, Type 2 Diabetes and Genetics study [21] was compara- the time of referral. Our results thus provide new evidence re- ble to that found in our cohort. Our mortality rate is lower than garding the right timing of referral using eGFR values. In effect, that found in the patients included in the UK Prospective the expected duration of follow-up before dialysis is an impor- Diabetes Study [22]. However, this study was conducted almost tant concept for nephrologists; however, the change of renal 20 years ago and the mortality rate has greatly diminished in function over time is difficult to ascertain for non-nephrologists recent years in this population [23]. and may vary considerably, especially in subjects with diabetes In conclusion, in the present study conducted in elderly mellitus [15, 16]. It was shown that the deterioration of renal patients with diabetes mellitus followed up in a nephrology function can be slow in many patients with diabetes mellitus, setting, the risk of death was not modified by the initiation of especially when low proteinuria is present [15, 17]. In contrast, dialysis and eGFR<45 mL/min/1.73 m (CKD Stage 3b) at the some patients exhibit much more rapid deterioration of renal time of the first nephrology visit was a powerful risk of death, function [15, 16]. Our findings are thus important, as they even in oldest patients. These findings support the view that focused on eGFR values and not on renal function changes over earlier referral of patients with diabetes mellitus to nephrolo- time. gists may be justified (at the CKD Stage 3b), even in the The KDIGO guidelines suggest referral of patients to nephrol- 2 absence of macroalbuminuria or rapid degradation of renal ogists in the following situations: eGFR<30 mL/min/1.73 m , function. macroalbuminuria or RRFD (yearly eGFR change >5 ml/min/ 1.73 m /year) [7] in order to optimize nephroprotection meas- ures and to accurately prepare patients for dialysis (including AUTHORS’ CONTRIBUTIONS the choice of techniques, the discussion regarding renal trans- P.C. was involved in the collection of data and design and plantation and the reduction of catheter use) [6, 7]. Our findings writing of the article. G.P., F.M., B.C.,L.H., R.N.,N.J.and B.E. suggest that referral to nephrologists should be prompted much were responsible for the analysis and discussion of the article. earlier (eGFR<45 mL/min/1.73 m ), not only to optimize nephro- B.M. contributed towards the writing and discussion of the ar- protection measures but primarily to improve the survival of ticle. S.B. provided the statistical analysis for the work de- patients, regardless of whether dialysis will be necessary in scribed. H.J-M. handled the design, writing and analysis of the these patients. Although macroalbuminuria and rapid deterio- article. ration of renal function were not associated with the risk of death during follow-up, these criteria remain useful to refer patients to nephrologists [18]. CONFLICT OF INTEREST STATEMENT In our study, 80% of patients were receiving RAS blockers. None declared. The results presented in this article have not The use of RAS blockers is advocated in patients with diabetes mellitus. Probably more patients should be using them in our been published previously in whole or part. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 GFR, dialysis initiation and death in diabetes | 7 13. Ronco C, House A, Haapio M. Cardiorenal syndrome: refining REFERENCES the definition of a complex symbiosis gone wrong. Intensive 1. Zimmet PZ, Magliano DJ, Herman WH et al. Diabetes: a 21st Care Med 2008; 34: 957–962 century challenge. Lancet Diabetes Endocrinol 2014; 2: 56–64 14. Verberne WR, Geers AB, Jellema WT et al. Comparative sur- 2. Guariguata L, Whiting DR, Hambleton L et al. Global esti- vival among older adults with advanced kidney disease mates of diabetes prevalence for 2013 and projections for managed conservatively versus with dialysis. Clin J Am Soc 2035. Diabetes Res Clin Pract 2014; 103: 137–149 Nephrol 2016; 11: 633–640 3. McKinlay J, Marceau L. 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Has the yearly increase in the renal N Engl J Med 2010; 362: 1575–1585 replacement therapy population ended? J Am Soc Nephrol 21. Joly D, Choukroun G, Combe C et al. Glycemic control accord- 2013; 24: 1367–1370 ing to glomerular filtration rate in patients with type 2 diabe- 10. American Diabetes Association. Classification and diagnosis tes and overt nephropathy: a prospective observational of diabetes. Diabetes Care 2015; 38: S8–S16 study. Diabetes Res Clin Pract 2015; 108: 120–127 11. Inker LA, Levey AS, Pandya K et al. Early change in protein- 22. Adler AI, Stevens RJ, Manley SE et al. Development and pro- uria as a surrogate end point for kidney disease progression: gression of nephropathy in type 2 diabetes: the United an individual patient meta-analysis. Am J Kidney Dis 2014; 64: Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 74–85 2003; 63: 225–232 12. Levey AS, Coresh J, Balk E et al. National Kidney Foundation 23. Tancredi M, Rosengren A, Svensson AM et al. Excess mortal- practice guidelines for chronic disease: evaluation, classifi- ity among persons with type 2 diabetes. N Engl J Med 2015; cation and stratification. Ann Intern Med 2003; 139: 137–147 373: 1720–1732 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Renal function at the time of nephrology referral but not dialysis initiation as a risk for death in patients with diabetes mellitus

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Abstract

Clinical Kidney Journal, 2018, 1–7 doi: 10.1093/ckj/sfy032 Original Article OR I G I N AL A R T I C L E Renal function at the time of nephrology referral but not dialysis initiation as a risk for death in patients with diabetes mellitus 1 1,2 1 1 Ce ´ dric Pinier , Philippe Gatault , Maud Franc ¸ois , Christelle Barbet , 1 1 1 1 He ´le ` ne Longuet , Nolwenn Rabot , Johann Noble , Elodie Bailly , 1,2 1,3,4 1,2,3 Matthias Buchler ,Be ´ne ´ dicte Sautenet and Jean-Michel Halimi 1 2 Service de Ne ´ phrologie-Immunologie clinique, Ho ˆ pital Bretonneau, CHU Tours, Tours, France, EA4245, Franc ¸ois-Rabelais University, Tours, France, FCRIN INI-CRCT Cardiovascular and Renal Clinical Trialists, France and INSERM U1246, Franc ¸ois-Rabelais University, Tours, France Correspondence and offprint requests to: Jean-Michel Halimi; E-mail: halimi@med.univ-tours.fr ABSTRACT Background: Renal patients with diabetes mellitus are at very high risk of death before and after chronic dialysis initiation. Risk factors for death in this population are not clearly identified. Methods: We performed a retrospective survival analysis in 861 patients with diabetes mellitus consecutively followed up in the 2000–13 period in a nephrology setting. Results: The mean age was 70 6 10 years [men 65.2%; diabetes duration 13.7 6 10.3 years; mean estimated glomerular filtration rate (eGFR) 42.4 6 21.0 mL/min/1.73 m ). During follow-up (median 60 months; up 15 years), 263 patients died (184 before and 79 after dialysis initiation) and 183 started chronic dialysis. In multivariate analyses, age, elevated systolic and low diastolic arterial pressures, peripheral artery disease, cancer, loop diuretic use and atrial fibrillation at baseline and acute kidney injury (AKI), heart failure (HF) and amputation during follow-up were identified as risk factors for death. After adjustments on these parameters, eGFRs at the time of the first outpatient visit—eGFR <45 mL/min/1.73 m {hazard ratio [HR] 1.58 [95% confidence interval (CI) 1.15–2.17]}, P¼ 0.005 and eGFR <30 [HR 1.53 (1.05–2.05)], P¼ 0.004, but not eGFR <60—were powerful risk factors for death. When initiation of dialysis was entered into the multivariate models, it was not associated with a risk of premature death [HR 1.19 (95% CI 0.91–1.55), P¼ 0.2069], even in patients >80 years of age [HR 1.08 (95% CI 0.64–1.81), P¼ 0.7793]. Conclusions: In patients with diabetes mellitus, high systolic and low diastolic arterial pressure, peripheral artery disease and development of AKI and HF are significant risk factors for death. In addition to these parameters, eGFR <45 mL/min/ 1.73 m at the time of referral is also a powerful risk factor for death. Keywords: diabetes, dialysis, epidemiology, renal function, risk of death Received: 11.9.2017. Editorial decision: 7.3.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| C. Pinier et al. Hospitalier Universitaire, Ho ˆ pital Bretonneau, Tours, France). The INTRODUCTION study was approved by the Ethics Committee of Human Research In 2014, at least 387 million people worldwide were living with of our hospital (approval number 2016-21). diabetes [1], and nearly 600 million people are expected to be di- Type 2 diabetes was defined according to the American abetic in 2035 [2]. Diabetes increases the risk of premature death Diabetes Association (ADA) criteria [10]. Data were retrieved and reduces life expectancy by nearly 15 years [3]. The risk of from files at baseline and during follow-up. They included age, death in patients with diabetes mellitus is markedly increased gender, comorbid conditions and diabetes duration. when renal function is impaired, and even more in end-stage At baseline, systolic and diastolic blood pressures and body renal disease (ESRD) and dialysis [4, 5]. mass index (BMI) were measured and information regarding the Optimal management of these renal patients with diabetes use of antihypertensive drugs [including renin–angiotensin sys- mellitus poses numerous problems, including the optimal time tem (RAS) blockers], glucose-lowering agents, lipid-lowering to nephrology referral and the need for dialysis (especially agents and antiplatelet medications were collected. when renal transplantation is not feasible). Some studies indi- Baseline laboratory results (including serum creatinine and cate that late referral to nephrologists is associated with re- glycated haemoglobin) were obtained. Baseline albuminuria duced survival [6]. The Kidney Disease: Improving Global was defined based on urine dipstick or by 24-h urine protein; Outcomes (KDIGO) guidelines suggest referring patients with an proteinuria was converted in albuminuria as described previ- estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m , ously [11]. GFR was estimated using the Modification of Diet in macrolbuminuria or rapid renal function decline (RRFD, i.e. Renal Disease (MDRD) equation [12]. eGFR decrease >5 mL/min/year) to nephrologists [7]. However, no specific guideline applies to the diabetic population. Follow-up and outcomes Whether earlier referral is justified in patients with diabetes All files were individually (manually) reviewed. Acute kidney in- mellitus and chronic kidney disease (CKD) is unknown, as the progression of renal disease may be slow. After referral, neph- jury (AKI) in hospitalization during follow-up was diagnosed us- ing the KDIGO criteria [7]. Only serum creatinine criteria were rologists face difficulties in the management of these elderly used to diagnose AKI, thus, urinary output criteria were omitted. patients with diabetes mellitus, as survival of these patients may be reduced after initiation of dialysis [8]. Some studies ad- Baseline serum creatinine was considered the lowest creatinine value (i.e. the reference creatinine value). We identified AKI by vocate that a conservative approach should be discussed in el- comparing the highest creatinine value found during hospitaliza- derly patients, especially those with diabetes [9]. With this in mind, it may be difficult for clinicians to refer these patients tion with the reference serum creatinine value. AKI was defined earlier to nephrologists as they feel that the patients may die as a serum creatinine level of 150% or þ0.3 mg/dL (þ26.5 mmol/L) versus the reference serum creatinine level [13]. before they need dialysis, that the duration of follow-up before reaching ESRD is uncertain and may be extremely long in some Stroke was defined in patients as focal neurological abnor- malities associated with ischaemic or haemorrhagic tissular patients and that chronic dialysis may precipitate death [9]. lesions found on computed tomography scan and/or magnetic However, referral to nephrologists is not only useful to delay ESRD, but it is important to optimize management of CKD resonance imaging. Amputation was defined as a lower limb amputation above the metatarsophalangeal joint. We also patients and therefore improve patient survival before and after recorded revascularization of coronary arteries (angioplasty, dialysis initiation. The late referral issue is important; however, coronary artery bypass grafting or coronary stent) and revascu- at the time of referral, it is not usually possible to know pre- larization of peripheral arteries (angioplasty or bypass of aortic cisely the duration of follow-up before dialysis or transplanta- or lower limb arteries). tion becomes necessary. From a practical point of view, the Information regarding major cardiovascular events such as issue of the GFR cut-off value associated with a risk of deleteri- acute coronary syndrome (ACS), atrial fibrillation (AF) or hospi- ous outcome is also important. The two issues are of course talization for heart failure (HF) as well as infections requiring interconnected. However, it is easier for clinicians to identify hospitalization and cancer during follow-up was recorded. GFR values than a time to dialysis, which remains elusive in Patients were followed until death or the end of the study most cases. Earlier referral than the one indicated in the KDIGO period (15 November 2015). The main outcome of the study was guidelines may appear useful. all-cause death (whether or not death occurred in patients who Finally, the right timing for referral is unclear despite the started chronic dialysis). Deaths were identified using the KDIGO guidelines and the benefit of dialysis is unproven in national death register and medical records from our centre or many instances in elderly CKD patients with diabetes mellitus. primary care physicians. In this population, whether earlier referral is justified is unknown and whether dialysis initiation is detrimental is unclear. Statistical analyses In the present retrospective study, we estimated whether di- Results are presented as mean (standard deviation (SD)) for con- alysis initiation and the eGFR value of patients at the time of re- tinuous variables [or median and interquartile range (IQR) if the ferral are associated with risk factors for death in a large cohort distribution of the variable was skewed] and as percentages for of renal patients with diabetes mellitus followed up to 15 years. categorical variables. We performed univariate and multivariate Cox models to ex- MATERIALS AND METHODS amine the association between baseline characteristics and risk of death. Analyses were performed in the whole population and Study population sensitivity analyses were performed in subgroups of patients In the present study we retrospectively analysed 861 consecutive with advanced age (age 70,75 and80 years) because it was patients with type 2 diabetes who were referred as outpatients to suggested in the literature that the risk of death associated with nephrologists in our hospital during the 2000–13 period (Centre dialysis initiation was greater in older patients. We examined Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 GFR, dialysis initiation and death in diabetes | 3 Table 1. Baseline characteristics whether age at dialysis was a risk factor for death in patients who started dialysis. We also performed univariate and multi- Clinical characteristics (n ¼ 861) variate analyses to evaluate whether major events (cardiovas- Age (years) 70.36 10.0 cular events, stroke, hospitalization for infection, AKI) during Sex (male) 65.2 follow-up were risk factors for death; these events were consid- 2 BMI (kg/m ) 30.76 5.9 ered as time-dependent parameters. We only considered the Systolic/diastolic arterial pressure (mmHg) 1496 23/786 12 first event even when it occurred several times during follow- Diabetes duration (years) 13.76 10.3 up. A stepwise descending procedure was used to determine ev- Main reason for first outpatient visit in nephrology ward ery final multivariate model (all conventional variables were in- CKD 54.3 Albuminuria 15.6 cluded in the models: all univariate significant variables were Hypertension 3.4 included in a maximized multivariate model, then we deter- Other 26.7 mined an optimized model with a backward procedure). Comorbid conditions Kaplan–Meier curves were constructed and compared using a Hypertension 93.5 log-rank test. Analyses were performed using SAS version 9.3 Coronary artery disease 26.6 (SAS Institute, Cary, NC, USA). A P-value <0.05 was considered HF 20.4 to be statistically significant. Peripheral artery disease 19.2 AF 20.1 Stroke 7.0 RESULTS Renal artery stenosis 3.4 Baseline characteristics Smoking (active/former) 8.2/33.1 Diabetic retinopathy 24.0 The mean age was 70.3 6 10.0 years and most patients were Biological data men (65.2%). Overall, eGFR was 42.4 6 21.0 mL/min/1.73 m Serum creatinine (mmol/L) 1766 124 (Table 1). Of note, 334 (44.3%) patients had a history of major eGFR (mL/min/1.73 m ) 42.46 21.0 cardiovascular disease. Albuminuria was present in 98.1% of CKD stage patients and macroalbuminuria was present in 49% of patients. 1 or 2 15.6 Among the 556 patients with eGFR<60 mL/min/1.73 m , nor- 3a 19.7 moalbuminuria, microalbuminuria and macroalbuminuria were 3b 35.7 present in 22.1, 29.7 and 48.2% of patients, respectively. 4 22.8 Despite a significant proportion of patients with CKD, only 5 6.2 207 (24%) had diabetic retinopathy. Angiotensin-converting en- Albuminuria (mg/day or mg/g of urine creatinine) 9556 1794 Normoalbuminuria 21.4 zyme inhibitor and/or angiotensin receptor blocker (ARB) were Microalbuminuria 29.6 used in the most patients, and half of the patients received in- Macroalbuminuria 49.0 sulin (Table 1). Haemoglobin A1c 7.256 1.5 Antihypertensive therapy Baseline and follow-up parameters associated with the ACE inhibitor/ARB/both 33.5/42.5/3.7 risk of death Calcium-channel blocker 50.4 Loop diuretic 39.0 Patients were followed up for a median duration of 60 months Thiazide 23.5 (IQR 39–78 months, range 4.5–193 months, total observation Beta-blocker 46.0 time 6113 patient-years). During this period, 263 patients died Spironolactone 3.5 (including 79 after dialysis); the 5- and 10-year risks of death Others 22.1 were 24.2 and 44.6%, respectively. Of note, 183 patients started Glucose-lowering therapy chronic dialysis, whereas 13 patients had a conservative treat- Insulin 45.5 ment [mostly due to comorbid conditions (61.5%) or the Oral agents 53.0 patient’s choice (31.0%)] during follow-up. Diet only 7.5 In univariate and multivariate analyses, baseline parameters Other treatments associated with the risk of death included age, diastolic arterial Statin 57.7 pressure, peripheral artery disease, cancer, use of loop diuretics Fibrate 8.8 Antiplatelet drug 51.0 and AF (Table 2). Other parameters such as AKI were signifi- cantly associated with the risk of death in univariate and multi- Results are presented as percentage or mean 6 SD. variate analyses (Table 2). Albuminuria: values after conversion of proteinuria in albuminuria when only proteinuria was available [11]. Initiation of chronic dialysis, age and risk of death Albuminuria classes were defined as normoalbuminuria: albuminuria <30 mg/ day, <30 mg/g or <20 mg/L; microalbuminuria: albuminuria 30 and <300 mg/ In this analysis we assessed whether initiation of dialysis could day; 30 and <300 mg/g or 20 and <200 mg/L; macroalbuminuria: albuminuria accelerate the risk of death. 300 mg/day, 300 mg/g or 200 mg/L. In univariate analysis, dialysis was not associated with the CKD Stages:1–2:eGFR 60 mL/min/1.73 m ; 3a: 45–59.9; 3b: 30–44.9; 4: 15–29.9; 5: <15. risk of death (Table 3). The mean age at dialysis was 73.5 6 9.2 years in the 183 patients who initiated chronic dialysis In multivariate analyses, there was no significant associa- (Table 3). Similar results were observed when the analysis was tion between initiation of dialysis and the risk of death after restricted to older patients (70, 75 or 80 years at baseline); adjustments on baseline and/or follow-up risk factors for for these age groups, the mean age at dialysis was 77.1 6 4.6, death (Table 3). 79.8 6 3.5 and 83.1 6 2.8 years, respectively (Table 3). Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| C. Pinier et al. Table 2. Baseline and follow-up parameters associated with the risk of death during follow-up Univariate analysis Stepwise multivariate analysis Parameters HR 95% CI P-value HR 95% CI P-value Baseline Gender (men versus women) 1.09 0.84–1.42 0.5114 – Age (per 10 years) 2.16 1.85–2.52 <0.0001 1.94 1.64–2.29 <0.0001 Systolic arterial pressure (per þ10 mmHg) 0.97 0.92–1.03 0.2724 – Diastolic arterial pressure (per þ10 mmHg) 0.76 0.68–0.85 <0.0001 0.88 0.79–0.99 0.0127 BMI (kg/m ) 1.00 0.99–1.00 0.4494 – Haemoglobin (per þ1 g/L) 0.99 0.98–0.99 0.0003 – Smoking (ever versus no smoking) 1.14 0.89–1.47 0.2955 – Diabetic retinopathy 1.05 0.81–1.38 0.7106 – Coronary artery disease 1.63 1.27–2.10 0.0001 – Peripheral vascular disease 1.99 1.53–2.58 <0.0001 1.84 1.39–2.42 <0.0001 Lower limb amputation 1.89 1.06–3.37 0.0319 – Hospitalization for HF 2.43 1.88–3.15 <0.0001 – Cancer 1.74 1.26–2.40 0.0009 1.84 1.31–2.57 0.0004 Loop diuretic use 2.03 1.59–2.59 <0.0001 1.75 1.34–2.27 <0.0001 AF 1.83 1.83–3.14 <0.0001 1.68 1.25–2.26 0.0006 Glycosylated haemoglobin (per þ1%) 0.99 0.90–1.09 0.8040 – RAS blockers 0.74 0.57–0.96 0.0245 – Follow–up AKI 3.25 2.53–4.18 <0.0001 2.12 1.58–2.85 <0.0001 AF 0.99 0.70–1.40 0.9513 – Acute coronary syndrome 1.70 1.16–2.48 0.0062 – HF 3.63 2.83–4.66 <0.0001 2.44 1.83–3.27 <0.0001 Stroke 1.53 1.01–2.31 0.0449 – Lower limb amputation 2.35 1.31–4.20 0.0040 1.93 1.08–3.45 0.0275 Hospitalization for serious infection 3.64 0.51–26.1 0.1985 – Table 3. Chronic dialysis initiation and risk of death during follow-up Information regarding patients Information regarding patients who started chronic dialysis who died during follow-up during follow-up Age at Number of patients Age at Age at Number of Age at dialysis who died (before/after baseline death patients who baseline initiation HR 95% CI P-value dialysis initiation) (years) (years) started dialysis (years) (years) Risk of death associated with chronic dialysis initiation (univariate analysis) All patients (n ¼ 861) 1.19 0.91–1.55 0.2069 263 (184/79) 74.46 8.8 79.46 8.5 183 70.46 8.9 73.56 9.2 Sensitivity analyses (subgroup analyses) Age 70 years (n ¼ 474) 1.13 0.82–1.56 0.4621 187 (135/52) 78.76 5.3 83.36 5.6 101 77.16 4.6 79.96 5.0 Age 75 years (n ¼ 314) 1.07 0.73–1.58 0.7304 135 (99/36) 81.26 4.1 85.76 4.3 64 79.86 3.5 82.66 4.1 Age 80 years (n ¼ 139) 1.08 0.64–1.81 0.7793 74 (54/20) 84.16 3.1 88.16 3.3 27 83.16 2.8 85.26 3.3 Risk of death associated with chronic dialysis initiation (multivariate analysis) Model 1 1.19 0.89–1.58 0.2443 Model 2 1.40 0.42–4.71 0.5839 Model 3 1.69 0.47–6.13 0.4228 Age is presented in mean 6 SD. Baseline parameters: age, diastolic arterial pressure, peripheral vascular disease, cancer, use of loop diuretics and AF. Follow-up parameters: AKI, HF and amputation during follow-up. Adjustments on baseline parameters (Model 1), follow-up parameters (Model 2) or both (Model 3). Risk of death according to renal function value or Among patients who started dialysis, age at dialysis was sig- decline at the time of referral nificantly associated with the risk of premature death in univar- iate and multivariate analyses [univariate: HR per þ10 years 1.36 In univariate analyses, eGFR <30 mL/min/1.73 m (versus eGFR (95% CI 1.05–1.77), P¼ 0.0212; multivariate: 1.50 (1.10–2.05), 30) at the time of referral was significantly associated with the P¼ 0.0104]. risk of death (Table 4). However, eGFR <60 mL/min/1.73 m Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 GFR, dialysis initiation and death in diabetes | 5 Table 4. eGFR at the time of referral as a risk of death HR 95% CI P-value Univariate analysis Baseline eGFR <60 (versus 60) 2.88 1.78–4.64 <0.0001 Baseline eGFR <45 (versus 45) 2.18 1.63–2.91 <0.0001 Baseline eGFR <30 (versus 30) 1.84 1.44–2.36 <0.0001 Multivariate analysis Model 1: adjustment on baseline parameters Baseline eGFR <60 (versus 60) 1.40 0.83–2.38 0.2114 Baseline eGFR <45 (versus 45) 1.63 1.20–2.23 0.0020 Baseline eGFR <30 (versus 30) 1.49 1.14–1.95 0.0034 Model 2: adjustment on follow-up parameters Baseline eGFR <60 (versus 60) 2.25 1.39–3.65 0.0010 Baseline eGFR <45 (versus 45) 2.13 1.58–2.87 <0.0001 Baseline eGFR <30 (versus 30) 2.03 1.54–2.68 <0.0001 Model 3: adjustment on baseline and follow-up parameters Baseline eGFR <60 (versus 60) 1.30 0.76–2.23 0.3425 Baseline eGFR <45 (versus 45) 1.58 1.15–2.17 0.0053 Baseline eGFR <30 (versus 30) 1.53 1.53–2.05 0.0040 eGFR denotes eGFR (determined using the MDRD equation (in mL/min/1.73 m ). Baseline parameters: age, diastolic arterial pressure, peripheral vascular disease, cancer, use of loop diuretics and AF. Follow-up parameters: AKI, HF and amputation during follow-up. 1.00 0.75 0.50 P<0.0001 0.25 0.00 0 25 50 75 100 125 150 175 200 Follow-up (months) 2 2 FIGURE 1: Risk of death in patients with eGFR<45 mL/min/1.73 m (versus45) at the time of referral. Symbols in red: patients with eGFR <45 mL/min/1.73 m at the time of referral to the nephrologist. Symbols in black: patients with eGFR 45 mL/min/1.73 m at the time of referral to the nephrologist. (versus eGFR 60) and <45 mL/min/1.73 m (versus eGFR 45) factors for dialysis initiation [HR 7.12 (95% CI 5.28–9.60) were also significant (Table 4 and Figure 1). P<0.0001; HR 6.04 (3.76–9.70), P<0.0001; HR 20.7 (5.2–83.2), In multivariate analyses, only eGFR<45 mL/min/1.73 m P<0.0001, respectively]; similar findings were observed for (versus eGFR 45) and eGFR<30 mL/min/1.73 m (versus microalbuminuria versus normoalbuminuria [HR 2.03 (95% CI eGFR 30) remained significant (Table 4), even when patients 1.07–3.84), P¼ 0.0297] and for macroalbuminuria versus microal- with baseline eGFR<15 mL/min/1.73 m were excluded from the buminuria [HR 2.84 (1.97–4.11), P<0.0001]. analysis [HR 2.72 (95% CI 1.68–4.40), P <0.0001 and HR 2.05 (1.53– 2.750), P <0.0001, respectively]. DISCUSSION RRFD (eGFR change >5 mL/min/1.73 m /year) [HR 1.45 (95% CI 0.88–2.39), P¼ 0.1479] and macroalbuminuria (versus In the present study conducted in elderly patients with diabetes normoalbuminuria or microalbuminuria) [HR 1.14 (95% CI mellitus who were followed up in a nephrology setting, almost 0.89–1.46), P¼ 0.3021] were not risk factors for death during half of the patients died after 10 years of follow-up. Major risk follow-up. factors for death were age, diastolic arterial pressure, peripheral As expected, eGFR<30 mL/min/1.73 m (versus eGFR 30), artery disease, cancer, use of loop diuretics and AF at baseline, <45 (versus eGFR 45) and <60 (versus eGFR 60) were risk and AKI, HF and lower limb amputation during follow-up. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| C. Pinier et al. Initiation of chronic dialysis did not precipitate death, regard- population, but it should be noted that this figure is much less of adjustments. An eGFR <45 mL/min/1.73 m (CKD Stage greater than those reported in other French studies focused on 3b or worse) at the time of nephrology referral was a powerful renal risk in diabetes mellitus [19]. risk of death, after multiple adjustments, but not eGFR <60 mL/ Of note, AKI remained significantly associated with the risk min/1.73 m . These findings support the view that referral to of death in multivariate analyses. Recently it was reported that nephrologists may be warranted not only in patients with CKD AKI, in addition to GFR and albuminuria, was a strong predictor Stage 4 but also in patients with CKD Stage 3b. of cardiovascular and non-cardiovascular death in a large co- The results of the present study indicate that dialysis initia- hort of patients with diabetes mellitus. We noted that low dia- tion did not accelerate the risk of death, even in older patients stolic blood pressure was a risk factor for death in our (age 70–80 years). In a recent single-centre observational population. Other studies suggest that there is a J curve rela- study, the risk of death was not different in patients 80 years tionship between diastolic blood pressure and the risk of death age choosing dialysis and in those receiving conservative treat- [20]. ment [14]. For this reason, it was proposed that dialysis initia- Our study has several limitations. It is a monocentric tion must be discussed on an individual basis [8, 9]. Our findings study and therefore our findings need to be replicated; how- suggest that the risk of death is not markedly accelerated in our ever, our cohort is large and the total observation period was elderly patients with diabetes mellitus in whom the decision of important. Files were individually (manually) reviewed and dialysis was made and therefore this decision was probably there was no inclusion bias, as these patients were consecu- adequate. tively included. In the present study, eGFR<45 mL/min/1.73 m (CKD Stage Our study also has some strengths. Multivariate analyses 3b) at the time of the first nephrology visit was a powerful risk were carefully designed to take into account potential con- of death. This issue of early referral to nephrologists has been founders, including baseline parameters as well as parameters extensively studied in patients with advanced CKD (usually during follow-up associated with the risk of death. All patients CKD Stage 5) [6]. Renal outcome and mortality were compared were followed in the same centre and we could therefore re- in patients with early versus later referral to nephrologists (in trieve all treatments, hospitalizations and biochemical evalua- most studies early was defined as follow-up before dialysis of tions. We believe that our cohort of patients is representative of 1–6 months) [6]. Using this definition, early referral was associ- the patients with diabetes mellitus followed up in nephrology ated with lower mortality as compared with later referral in the settings in France. In effect, renal function of the 986 outpa- Cochrane’s systematic review where 63 887 patients were ana- lysed [6]. However, these analyses were limited to patients with tients with diabetes mellitus who were referred to nephrologists low eGFR (CKD Stage 5), were not stratified according to the in the ALICE multicentre French study was comparable to that presence of diabetes mellitus and not all patients were man- found in our cohort [20]. The mortality rate of the 1341 patients aged in a nephrology setting [6]. Moreover, these analyses were with diabetes mellitus followed in French hospitals from the focused on the timing of referral but not on the value of eGFR at Survival, Type 2 Diabetes and Genetics study [21] was compara- the time of referral. Our results thus provide new evidence re- ble to that found in our cohort. Our mortality rate is lower than garding the right timing of referral using eGFR values. In effect, that found in the patients included in the UK Prospective the expected duration of follow-up before dialysis is an impor- Diabetes Study [22]. However, this study was conducted almost tant concept for nephrologists; however, the change of renal 20 years ago and the mortality rate has greatly diminished in function over time is difficult to ascertain for non-nephrologists recent years in this population [23]. and may vary considerably, especially in subjects with diabetes In conclusion, in the present study conducted in elderly mellitus [15, 16]. It was shown that the deterioration of renal patients with diabetes mellitus followed up in a nephrology function can be slow in many patients with diabetes mellitus, setting, the risk of death was not modified by the initiation of especially when low proteinuria is present [15, 17]. In contrast, dialysis and eGFR<45 mL/min/1.73 m (CKD Stage 3b) at the some patients exhibit much more rapid deterioration of renal time of the first nephrology visit was a powerful risk of death, function [15, 16]. Our findings are thus important, as they even in oldest patients. These findings support the view that focused on eGFR values and not on renal function changes over earlier referral of patients with diabetes mellitus to nephrolo- time. gists may be justified (at the CKD Stage 3b), even in the The KDIGO guidelines suggest referral of patients to nephrol- 2 absence of macroalbuminuria or rapid degradation of renal ogists in the following situations: eGFR<30 mL/min/1.73 m , function. macroalbuminuria or RRFD (yearly eGFR change >5 ml/min/ 1.73 m /year) [7] in order to optimize nephroprotection meas- ures and to accurately prepare patients for dialysis (including AUTHORS’ CONTRIBUTIONS the choice of techniques, the discussion regarding renal trans- P.C. was involved in the collection of data and design and plantation and the reduction of catheter use) [6, 7]. Our findings writing of the article. G.P., F.M., B.C.,L.H., R.N.,N.J.and B.E. suggest that referral to nephrologists should be prompted much were responsible for the analysis and discussion of the article. earlier (eGFR<45 mL/min/1.73 m ), not only to optimize nephro- B.M. contributed towards the writing and discussion of the ar- protection measures but primarily to improve the survival of ticle. S.B. provided the statistical analysis for the work de- patients, regardless of whether dialysis will be necessary in scribed. H.J-M. handled the design, writing and analysis of the these patients. Although macroalbuminuria and rapid deterio- article. ration of renal function were not associated with the risk of death during follow-up, these criteria remain useful to refer patients to nephrologists [18]. CONFLICT OF INTEREST STATEMENT In our study, 80% of patients were receiving RAS blockers. None declared. The results presented in this article have not The use of RAS blockers is advocated in patients with diabetes mellitus. Probably more patients should be using them in our been published previously in whole or part. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018 GFR, dialysis initiation and death in diabetes | 7 13. Ronco C, House A, Haapio M. Cardiorenal syndrome: refining REFERENCES the definition of a complex symbiosis gone wrong. Intensive 1. Zimmet PZ, Magliano DJ, Herman WH et al. Diabetes: a 21st Care Med 2008; 34: 957–962 century challenge. Lancet Diabetes Endocrinol 2014; 2: 56–64 14. Verberne WR, Geers AB, Jellema WT et al. Comparative sur- 2. Guariguata L, Whiting DR, Hambleton L et al. Global esti- vival among older adults with advanced kidney disease mates of diabetes prevalence for 2013 and projections for managed conservatively versus with dialysis. Clin J Am Soc 2035. Diabetes Res Clin Pract 2014; 103: 137–149 Nephrol 2016; 11: 633–640 3. McKinlay J, Marceau L. 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Excess mortal- practice guidelines for chronic disease: evaluation, classifi- ity among persons with type 2 diabetes. N Engl J Med 2015; cation and stratification. Ann Intern Med 2003; 139: 137–147 373: 1720–1732 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy032/5032516 by Ed 'DeepDyve' Gillespie user on 12 July 2018

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Clinical Kidney JournalOxford University Press

Published: Jun 2, 2018

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