Short summary

Based on the entire population in the Region of Southern Denmark we investigate the following questions:

1. What is the incidence of moderate to severe CKD are there in the Region of Southern Denmark
2. Do these patients have an increased cardiovascular risk?
3. How many of these patients are referred to a nephrologist?
4. Is there a CKD-specific cut-off level for Troponin?

Rationale

Introduction

Chronic kidney disease (CKD) is an important health challenge with 10% of the population affected worldwide. All stages of CKD are associated with premature death, decreased quality of life and/or increased risks of cardiovascular morbidity. Only a minority of patients with CKD are aware of their diagnosis. The incidence of acute myocardial infarction (AMI) is particularly increased in patients with CKD. However, since there is a high prevalence of persistently elevated troponin in CKD patients, diagnosing AMI is very difficult in this patient group.

Background

Chronic kidney disease (CKD) is defined by The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) as abnormalities of kidney structure or function, persistent for more than 3 months. It is classified based on cause, glomerular filtration rate (GFR), and the degree of albuminuria. This classification divides CKD into 5 stages and uses the combination of an index of kidney function, GFR, and markers of kidney damage to define the stages. Stages 3-5 are defined by a GFR less than 60 ml/min/1.73  with or without markers of kidney damage, on at least 2 separate occasions separated by a period of at least 90 days. One of the biggest challenges is that large proportions of individuals with CKD remain undiagnosed. Data from the US National Kidney Foundation's Kidney Early Evaluation Program indicate that only 9% of patients with CKD are aware of their diagnosis. Early identification of individuals with CKD, followed by the implementation of evidence-based interventions can slow or prevent the progression to advanced stages of the disease and reduce the risk of cardiovascular disease.

For several reasons, patients with renal CKD merit particular attention. CKD is an independent risk factor for the development of coronary artery disease (CAD). A small angiographic study suggests that the prevalence of significant stenosis exceeded 50% in asymptomatic patients at the start of renal replacement therapy. Accordingly, a nearly 4.5-fold increased risk of AMI has been reported in CKD patients. One study suggests that for every 10mL/min per 1.73 m decline in GFR, there is a 5% higher cardiovascular risk. However, studies are often based on selected patients hindering conclusion regarding the prognostic value of duration and severity of CKD, treatment and preexisting co-morbidity. Despite of the increased risk of cardiovascular disease the CKD population is largely ignored by large cardiovascular trials. More than 80% of trials excluded subjects with end-stage renal disease and 75% excluded patients with CKD.

Moreover, the diagnosis of AMI in CKD patients is complicated by an atypical clinical presentation. According to the third universal definition of myocardial infarction, the criteria for AMI are met when there is a rise and/or fall of cardiac biomarkers (preferably troponin), along with supportive evidence in the form of typical symptoms, suggestive electrocardiographic (ECG) changes, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. However, left ventricular hypertrophy is common in CKD patients and often mimics ECG changes seen in AMI. Most importantly, the biomarker of choice, cardiac troponin is  elevated in up to 80% of patients with CKD per se making guidelines unfeasible in this patient group. According to a large scale American observational study with 29,319 patients with advanced CKD stage 4-5 from 2012, only 23% with AMI were accurately diagnosed on admission. In line with this, a recent review found only a limited diagnostic value of troponin in CKD patients, due to varying estimates of sensitivity and specificity. This was in part due to the interchangeably use of troponin I and troponin T.

A study only based on 75 CKD patients with eGFR < 60 ml/min found improved specificity when using a troponin t cut off that was more than twice as high as according to current AMI-guidelines. Others have shown that a second measurement of troponin results in improvement of sensitivity and specificity but at the expense of diagnostic delay and this probably worsened the prognosis. The attempt to find a cut-off level for troponin in CKD has been worked in a recent prospective study. They reported increasing troponin cut-off values with increasing CKD stage. However, the study was rather small including only 201 CKD patients. Another recent study looked at troponin cut-off levels for the different CKD stages. This was a single center study with 489 patients where only troponin t levels were measured although troponin I may be more specific in CKD. Still more solid data are needed defining a diagnostic cut-off value in this underdiagnosed high-risk population to improve both exclusion and identification of AMI to minimize the risk of diagnostic delay and thus improving outcome. Ideally positive and negative predictive values for both Troponin T and I according to CKD-group are needed. 

Description of the cohort

We include individuals over 18 years of age living in Denmark (i.e. possessing a national identity number) who had blood samples analysed for creatinine in the Region of Southern Denmark from 2006 until the end of 2013.

Data and biological material

Our study is designed as an observational cohort study utilizing The Danish Civil Registration System (DCRS) and The Danish National Patient Register (DNPR).

Laboratory data will be gathered from the respective laboratories of the Region of Southern Denmark (LRSD). The LRSD includes data from general practitioners and hospitals in the Region of Southern Denmark. All data are recorded according to the individual CPR-number, which allows record linking with the abovementioned databases.  

Collaborating researchers and departments

Department of Endocrinology, Hospital of Southern Jutlan

• Frans Brandt Kristensen, MD PhD

Department of Nephrology, Roskilde University Hospital

• James Heaf, MD PhD

Department of Cardiology Odense University Hospital

• Hans Mickley, MD, DMSc 

Research center for emergency medicine, Hospital of Southern Jutland Aabenraa

• Christian Backer Mogensen, MD PhD