Introduction

Chronic Kidney Disease (CKD) is defined as a structural defect or decreased function of the kidney1. This disorder is diagnosed by having at least one of the following criteria: a Glomerular Filtration Rate (GFR) of < 60 ml/min/ 1.73 m, albuminuria, disturbances in urinary sedimentation, histologic or imaging evidence of renal injury, renal tubular disorders, and a history of renal transplantation for longer than 3 months2, 3.

Glomerular filtration is the process in which the blood passes from a glomerular capillary tuft inside the Bowman's capsule where it is cleared of waste products. However, erythrocytes, leukocytes, and plasma proteins are exceptions, so they remain inside the vessel4, 5. It has been shown that GFR gradually decreases with age. This reduction is affected by diet, muscular mass, gender, and race6. Based on the GFR, CKD is classified into 5 stages from mild to an advanced disease with End-Stage Renal Disease (ESRD) being the final stage. This is characterized by dramatically reduced GFR and a need for dialysis. In this stage, either peritoneal dialysis or hemodialysis is selected for the patient depending on their condition7, 8, 9, 10, 11.

D-dimer, one of the molecules that results from fibrin degradation, is very low in the blood of healthy individuals. As an indicator of increased fibrinolysis, elevated levels of D-dimer indicate intravascular coagulation and thrombotic disease. Given its high sensitivity and negative predictive value, D-dimer testing is routinely used in clinical practice as a primary assessment for patients with suspected VTE12, 13. A negative D-dimer test can definitely rule out VTE. Thus, there is no need for subsequent imaging and anticoagulant therapy13, 14. Although D-dimer is almost always elevated in VTE, it can also increase due to several other conditions including acute illness, recent trauma or surgery, active malignancies, severe atherosclerosis, and pregnancy, leading to its relatively low specificity and positive predictive value15. Moreover, the specificity of D-dimer testing for the VTE diagnosis is even lower in patients with mild or moderate CKD. In these patients, the D-dimer level is associated with the CKD stage and disease progression16, therefore positive D-dimer results have no definite diagnostic value for ESRD patients under hemodialysis17 because they often have several other comorbidities such as atherosclerosis and malignancy which are also associated with increased serum D-dimer levels18, 19. In addition, investigations have shown that the specificity of D-dimer testing for pulmonary embolism diagnosis is significantly reduced in CKD patients because the D-dimer levels are associated with the CKD stage16. Therefore, the present study aimed to investigate the serum D-dimer level and its relationship with GFR in patients with CKD.

Methods

The present cross-sectional study included 98 patients with the diagnosis of CKD who presented to the nephrology clinic of Shahid Beheshti Hospital in Hamadan, Iran from April 2019 to February 2021. The exclusion criteria were active malignancy, rheumatoid arthritis, systemic lupus erythematosus, sickle cell anemia, current history of thromboembolic events, pregnancy, post-partum conditions, recent abdominal, thoracic or orthopedic surgery, cocaine use, hemoptysis, thrombophilia, and a history of trauma in the last 4 weeks. The present study was approved by the Ethics Committee of the Hamadan University of Medical Sciences with the ethics code of IR.UMSHA.REC.1398.869.

The participants gave informed written consent. They then gave blood samples, which were used to proceed with a quantitative D-dimer assessment using the ELFA VIDAS kits by the Biomerieux Company. The cut-off value was 500 ng/ml for a quantitative D-dimer assessment. The GFR of the participants was calculated using the MDRD formula and their serum creatinine levels, which were obtained from the recent test results of the patients. The patients were classified into 2 groups based on the calculated GFR as follows:

The clinical and demographic data of the participants, including age, gender, educational level, BMI, the cause of renal failure, serum creatinine, D-dimer level, GFR, and CKD duration were recorded in the related checklists.

Data analysis was performed using the SPSS-24 software with a significance level of 0.05%. The Pearson's correlation, Spearman's correlation, t-test, and Mann-Whitney U test were used in the analytical part of this study.

Results

The present study investigated 98 patients diagnosed with CKD. According to our results, 52.04% of the participants were men. The mean ± SD of the participants' age was 58.14 ± 15.89 years with a range of 27 – 93. More than half of the patients were older than 60, and most of them were illiterate or had less than a high school diploma. Regarding BMI, 42.86% had a BMI of 18.5 - 25 kg/m (Table 1). In total, 52 (53.06%) patients were undergoing hemodialysis. The most common cause of renal failure was hypertension (45.92%), followed by diabetes (22.45%) (Table 2).

The mean ± SD values of serum creatinine and D-dimer levels were 4.96 ± 3.34 mg/dl and 1614.28 ± 1917.39 ng/ml, respectively. Moreover, the mean ± SD value for GFR was 20.27 ± 15.32 ml/min.1.73 m. The mean ± SD for CKD duration was 10.36 ± 6.54. Finally, for a total 98 participants, 75 (76.53%) had a positive D-dimer test, while 23 (23.47%) had a negative test.

The serum D-dimer level had a significant positive correlation with creatinine and age (P < 0.05), while it had a significant negative correlation with GFR (P < 0.05). Moreover, there was a significant negative correlation between GFR and creatinine level (Table 3).

Using the Mann-Whitney U test, we found a significant difference between the patients with moderate (30 ≤ GFR ≤ 59) and severe (GFR ≤ 29) CKD and the D-dimer levels (986.37 ± 943.68 vs. 1853.06 ± 2133.95, P = 0.024).

Discussion

According to our results, there was a significant relationship between serum D-dimer level and the patients' GFR and age. We also found a negative correlation between GFR and serum D-dimer level. Patients with a lower GFR had higher D-dimer levels. In addition, there was a direct correlation between age and serum D-dimer level, meaning that an increased age led to higher D-dimer levels.

The present study is compatible with most similar studies20, 21, 22, 23, 24. For example, a study by Robert-Ebadi . on 1,625 participants found a more significant relationship between D-dimer level and GFR in patients whose possibility of pulmonary embolism had been ruled out compared to those with a diagnosis of pulmonary embolism23. In a study of 1305 participants, 169 participants (13%) were affected by pulmonary embolism, Linder . showed there to be a significant relationship between the calculated GFR and D-dimer level21. A study by Gubensek . on 167 participants undergoing chronic hemodialysis reported a mean D-dimer level of 966 ng/ml in these patients. Moreover, 75% of the patients had a positive D-dimer test (> 500 ng/ml), and the D-dimer levels were significantly correlated with the participants' age25. These results are compatible with our results.

According to a study by Xi . involving 1784 participants, the mean D-dimer levels were 291.5 mg/L, 995.5 mg/L, and 1901.5 mg/L in the patients with normal renal function, mild renal disease, and moderate renal disease, respectively. They found a significant relationship between D-dimer level and GFR24. Huang . performed a study on 115 participants and found a significantly elevated D-dimer level in patients with CKD stages 3, 4, and 520.

Mohammed and Khalil performed a study on 49 patients with CKD and found there to be no significant relationship between D-dimer level and the patients' GFR and age. They reported a significant correlation between D-dimer level and CKD duration22.

The present study had some limitations. For example, our sample size was smaller than similar studies due to the limited financial resources. Moreover, some patients refused to participate due to the invasive sampling method used.

Conclusions

According to our results, there was a significant correlation between the serum D-dimer level and the patients' GFR and age in patients with CKD, including those affected by ESRD who underwent hemodialysis. Given the present study results, we recommend setting a GFR-adjusted cut-off for D-dimer testing in patients with GFR <60 ml/min.1.73 m to reduce the number of false-positive results. The patients with CKD will be less exposed to imaging modalities with contrast which may lead to contrast-related nephropathy, exacerbating the current renal dysfunction of the patients.

Abbreviations

BMI: Body Mass Index

CKD: Chronic Kidney Disease

ESRD: End-Stage Renal Disease

GFR: Glomerular Filtration Rate

SD: Standard Deviation

VTE: Venous Thromboembolism

Acknowledgments

This article was derived from a research project approved by the Esfarayen University of Medical Sciences, which was conducted with the financial support of this university. The researchers would like to express their gratitude to the University Research Council and all patients, who participated in this study.

Author’s contributions

VS, SK, and NAS developed the original idea and the protocol, abstracted, and prepared the manuscript. SK and VS participated in the study design and analyzed the data. VS, and NAS contributed to the data gathering. All authors read and approved the final manuscript.

Funding

This study was funded by the Hamadan University of Medical Sciences, Iran (Research ID: 9811158772).

Availability of data and materials

Data and materials used and/or analysed during the current study are available The data that support the findings of the study are available from the corresponding author in SPSS form upon reasonable request.

Ethics approval and consent to participate

This study was conducted in accordance with the amended Declaration of Helsinki. Institutional review board approval was obtained from the ethics committees of Hamadan University of Medical Sciences (Ethics code: IR.UMSHA.REC.1398.869), and all participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.