Competing risk of death and end-stage renal disease in incident chronic kidney disease (stages 3 to 5): the EPIRAN community-based study

Chronic kidney disease (CKD) is a common condition and the increased incidence of end-stage renal disease (ESRD) is a growing public health challenge worldwide [1‐6]. Less than 2 % of CKD patients in all stages except stage 4 progress to ESRD and undergo renal replacement therapy (RRT) [7]. CKD is associated with a markedly increased risk of cardiovascular morbidity and mortality and it is clear that the majority of CKD patients, especially those aged 75 and over, dies before reaching ESRD largely due to worsening heart disease [7‐12].

The early identification of patients at increased risk for CKD or in the early stages is therefore critical and could facilitate timely therapeutic interventions to slow both progression of CKD to ESRD and cardiovascular diseases with benefits on both kidney and patient survival [13, 14]. Thus screening strategies to increase early recognition of individuals at risk were developed implementing surveillance of elevated plasma creatinine, microalbuminuria, and more recently routine reporting of estimated glomerular filtration rate (eGFR) in a high-risk target population [3, 15‐22]. Family general practitioners (GPs) are responsible for CKD screening and timely referral to nephrologist. This creates opportunity for coordinated and optimal management of CKD to reduce morbidity and mortality [23].

Epidemiological data on incident CKD in the general population are the only ones permitting non-biased prognostic studies to be carried out, but they are scarce [5]. A recent literature review highlighted substantial heterogeneity between prevalence studies related to a wide range of study designs, criteria used for the selection of patients, and methods for measuring renal function [2]. Among the 43 selected studies, 6 high-quality studies allowed an estimate of the prevalence in a range of 1.7 to 8.1 %.

The objectives of the present community-based study was to determine the number of patients residing in a well-defined geographical area having a first serum creatinine value ≥1.7 mg/dL after January 1^st, 2004 and still present for at least 3 months, and to describe their primary care, outcomes and risk factors associated with outcomes using competing risks analyses.

A total of 49,114 creatinine values ≥1.7 mg/dL were reported in the UCGN from January 1^st, 2004 to June 30^th, 2006. Among the 4,409 individuals, 35 patients refused to be enrolled and 110 were excluded because of lack of a second creatinine measurement; 1,012 patients with a serum creatinine ≥1.7 mg/dL reported prior to January 1^st 2004 were considered as prevalent CKD patients; 2,621 patients had an acute deterioration of renal function, and creatinine level lowered back to below 1.7 mg/dL during the follow-up; finally, 631 were diagnosed incident CKD patients after validation by the expert committee (Fig. 1).

The first serum creatinine measurement with a value ≥1.7 mg/dL was initiated by a GP for 45.0 % of the 631 cases, a non nephrologist specialist for 49.5 %, and a nephrologist for only 5.5 %. Reasons why a specialist ordered a creatinine blood test were mostly a standard medical checkup on planned admission to hospital (57.8 %), on emergency visit (15.7 %), on pre-anesthesia assessment (12.8 %) and a routine follow-up for a chronic condition (13.7 %). A period of time was needed before confirmation of diagnosis by a second creatinine determination, and was similar for GPs and non nephrologist specialists (7 ± 4.2 and 6.4 ± 4.3 months, respectively).

In the population-based EPIRAN study, we detected patients having two consecutive serum creatinine values ≥1.7 mg/dL over a three-month period. Each case was critically reviewed by an expert committee. The annual incidence rate of CKD (stage 3 to 5 CKD defined as eGFR < 60 ml/min/1.73 m²/year) was estimated to 977.7 pmp using routine blood testing systematically reported by clinical laboratories of an urban territory with a population of 250,000. The incidence was two-fold higher in men than in women. This result is not surprising given the fact that the same cut-off was used in both genders. The identified patients were elderly with multiple comorbidities. Our results were close to that previously observed [40]. Studies conducted to define incidence for CKD are scarce, most of studies evaluate its prevalence [3‐5, 40]. Prevalence studies indicate CKD burden whereas incidence studies contribute to the implementation of longitudinal follow-up and the monitoring of CKD progression, and may therefore suggest prevention strategies.

One of the major strengths of our study is the innovative nature of the methodology based on repeated measurement of serum creatinine to confirm the persistence of renal injury. Firstly, it is worth noting that the systematic and automated self-reporting of abnormal creatinine levels above the cut-off value by laboratories may help primary care physicians detect more accurately patients at increased risk for CKD or in early stages, particularly among elderly [16, 22, 41, 42]. Secondly, asserting incidence and chronicity of the condition is of major interest to differentiate CKD from acute kidney injury (AKI) and not misclassify patients with an acute deterioration as chronic. Nearly 60 % of patients with at least one increased value in creatinine level above 1.7 mg/dL had creatinine level under this cut-off value during the course of our study. All medical reports were appraised by an expert committee including nephrologists and epidemiologists. Study nurses systematically interviewed all clinical laboratories in order to track all measures under the cut-off value that would not have been reported. This work allowed us to assert the chronicity of renal disease. Thirdly, the large sample size and the prospective non interventional design with a longitudinal follow-up add to the robustness of our findings reflecting real life. Finally, competing risks analyses showed that most patients died prior to the stage of ESRD and allowed us to identify predictive factors associated to death and dialysis initiation. Age at diagnosis, presence of anemia, CHF and active neoplasia were independent risk factors for all-cause mortality. Our results are consistent with those previously reported [7]. Anemia develops as a frequent complication of CKD, and can have a deleterious effect not only on progression of CKD but also on progression of cardiovascular diseases and events [1]. In our study, 45.9 % of incident CKD patients (stages 3 to 5) experienced decline of their renal function during the course of the study, and those with a fast decline were more likely to reach ESRD or death, as previously shown among prevalent CKD patients [10, 43]. In addition, eGFR was not associated with risk of death that was inconsistent with previous findings [10, 44]. Go et al found non linear relations between the GFR and the risk of death [10]. In 38,520 non-dialysis-dependent CKD patients, each 5 mL/min/1.73 m² decline in eGFR was associated with higher risk of death due to cardiovascular disease (hazard ratio: 1.10; 95 % confidence interval: 1.08 to 1.12) [44]. The first possible explanation for our contradictory results is the selection of incident patients whereas those previous studies included prevalent patients. All the published data that correlated eGFR with death were observed in studies performed in prevalent CKD patients. Prevalent CKD patients are different from incident CKD patients because of a survival bias due to the non-inclusion of patients who have died before the study starts and to the fact that development of CKD increases the risk of death. A second explanation is supported by clinical characteristics of patients included in the EPIRAN study; they were mostly stage 3 CKD patients at the time of diagnosis and non progressors (54.1 %). From our point of view, progression of CKD played a major role when it was found to be associated with risk of death in prevalent patients. Finally, a completely different explanation could be supported by recent findings. Mandelli et al. assessed mortality prediction in the oldest old (aged 85 years and older) with five different equations to estimate GFR They showed that risk of mortality was significantly higher for reduced GFR estimated with the Berlin Initiative Study-1 and Cockroft-Gault equations over the short time, whereas the MDRD formula appeared a more consistent predictor after five years [45]. However, a significantly higher risk of death after 5 years was found in the oldest old with a very low eGFR (<30 mL/min/1.73 m²), irrespective of the equation. In addition, we found that independent risk factors significantly associated with dialysis initiation were age at diagnosis, presence of diabetes and GFR below 20 mL/min/1.73 m². Interestingly, elderly (>70 years) were less likely to undergo dialysis. This may be due to a bias towards nephrology referral and indication for dialysis, a low likelihood of experiencing progression of CKD to ESRD in elderly or a patient choice [46].

CKD patients identified in our cohort were mainly stages 3-4 primary care patients, but the first abnormal creatinine level (above the cut-off value) was measured in a public or private hospital for 42.8 % of patients. For serum creatinine measurements ordered by a non nephrologist specialist, they were done mostly within a standard medical checkup that was not systematically transmitted to the family GP, and as a result, delayed CKD diagnosis. Clinical inertia in response to CKD diagnosis was seen in primary care but also with specialist care, whether they worked in healthcare institutions or not. The same phenomenon was observed for the check up to diagnose CKD. Proteinuria was sought only in 7.9 % of patients despite French recommendations for diagnosis and management of CKD and international guidelines advocating systematic screening for markers of kidney damage such as proteinuria [47‐50]. Proteinuria is predictive for CKD progression but also for progression to ESRD [5, 48, 51‐55]. Proteinuria was also shown to impact on the occurrence of cardiovascular events [56]. Reduction of proteinuria is therefore a major determinant for reducing the risk of CKD progression to ESRD and cardiovascular events [49, 57‐61]. Our study confirm that early identification of CKD patients on the basis of presence of reduced eGFR or proteinuria is desirable to permit early intervention for reducing risk of cardiovascular events, progression to kidney failure or death [62]. Over the past decade, the therapeutic arsenal to reduce CKD burden, such as prevention of complications, slowing progression, and prevention of cardiovascular risk, has markedly expanded [48, 50, 63]. However, practice patterns suggest that physicians remain unfamiliar with recommendations for detection and management of CKD as highlighted in several studies [64‐67]. The lack of acute awareness of clinical practice guidelines for CKD varies according to the type of registration status (nephrologist > specialist > GP) [65, 66]. As early detection is within the realm of the family GPs, they should feel more comfortable with making the initial diagnosis of CKD and providing appropriate primary and ongoing care to patients.

Regarding medical monitoring of patients, our findings demonstrated that only 28.3 % of patients were referred to a nephrologist after CKD diagnosis. There is probably a bias in nephrologist referral related to the age of patients. It is indeed possible that GPs chose not to refer elderly to nephrologists because 1) they felt that elderly could not be candidates for RRT, and 2) reduced GFR remained relatively stable in most of them. Several recent studies showed the benefit of conservative management in elderly as long as they remained asymptomatic [68]. A prospective, community-based study provided a compelling evidence for a causal relationship between pre-ESRD medical care and outcomes [69].

A recent literature review focusing on studies regarding changes in kidney function over time highlighted the importance of incorporating the rate of kidney decline in the staging of CKD for better risk stratification on mortality and cardiovascular outcomes for individual patients as CKD is a dynamic [70]. Although most CKD patients will die from cardiovascular disease rather than progress to kidney failure, it is of interest to develop prevention programs for patients who will progress to ESRD, such as tertiary preventive care and regular monitoring to detect early patients most likely to progress. This will let appropriate referral of patients who might benefit from a nephrology service while allowing the majority to remain in primary care, and prevent that local nephrology services become overwhelmed [71]. Nevertheless, it is mandatory to conduct medical surveillance in those remaining in primary care, and avoid all situations (iatrogenic and not) which may lead to worsening of renal function or decompensate.

The following limitations should be considered. First, we used a single creatinine cut-off value as inclusion criterion to define impaired renal function because French clinical laboratories did not calculate eGFR when we designed the study. Although French clinical laboratories were required to report eGFR for each creatinine value in 2005, we could not change this main inclusion criterion during the study. The creatinine cut-off value of 1.7 mg/dL was selected on the basis of the only published incidence study when the EPIRAN study was designed [40]. Drey et al. used this value as recommended by the Renal Association [72]. CKD diagnosis could only be assigned to patients who had had serum creatinine measurement, and more specifically those who had repeated measurement. As a result, incidence of CKD may be underestimated, because only patients with serum creatinine repeated measurement were included in our study. However, this cut-off value allowed to detect a majority of new patients having stage 3 CKD and avoid misclassification of healthy elderly people with eGFR <60 mL/min. Second, because of the non interventional design of our study, only patients who were prescribed creatinine measurement could be identified. Another limitation was the scarcity of proteinuria determination, although presence of proteinuria was recognized to predispose to ESRD, even with a normal renal function [3, 5, 13, 55, 57, 59, 60]. Our results were consistent with previous findings highlighting that special attention must be paid to improve albuminuria screening [3, 5]. Despite these limitations, a non interventional approach is the only possible way of studying management of patients in real life.

In conclusion, our study provided annual incidence rate of CKD stage 3 to 5 in a community-based population, confirmed that death was far more likely than advancement to RRT in CKD patients, identified predictors of death and dialysis initiation, and highlighted the need to improve the hands-on implementation of guidelines for the evaluation and management of CKD in primary care.