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Revista de la Facultad de Medicina Humana

versión impresa ISSN 1814-5469versión On-line ISSN 2308-0531

Rev. Fac. Med. Hum. vol.20 no.4 Lima oct./dic 2020

http://dx.doi.org/10.25176/rfmh.v20i4.3218 

Original Article

Red blood cell distribution width an inflammatory biomarker related to proliferative diabetic retinopathy

Juan Carlos Roque1  , Master in Medicine, Surgeon

Gabriela Quezada2  , Master in Ophthalmology, Surgeon

Claudia Saldaña1  , MSc, PhD, Medical Oncologist, Surgeon

Carolina Carrillo1  , Medical student

José Arturo Vargas1  , Master in teaching, Surgeon

Karla Arancibia3  4  , Doctor, Master of Public Health

1Universidad Científica del Sur, Departamento de Ciencias Básicas Morfofisiología, Lima-Perú.

2Servicio de Oftalmología Hospital Nacional Edgardo Rebagliatti Martins, Lima-Perú.

3Latin American Lifestyle Medicine Association, Lima-Perú.

4Lifestyle Medicine Centers, Lima-Perú.

INTRODUCTION

Diabetic retinopathy (DR), with a prevalence of 34%, is the most frequent microvascular complication among patients with type 2 diabetes mellitus. the third cause of blindness worldwide and the first in the economically active population(1,2). Its pathophysiology with cyclical events, in a crescendo of inflammation and oxidative stress generated by toxic levels of glucose in the retinal capillary, are crucial factors in its genesis and evolution(3,4); Neoangiogesis is a critical point for the early stages, nonproliferative diabetic retinopathy (NPDR), and late, proliferative diabetic retinopathy (PDR)(4,5,6).

The erythrocyte distribution width (RDW) is the coefficient of variation of the erythrocyte corpuscular volume, which represents in percentage terms the variability in erythrocyte size(7,8),which at present has been recognized as an inflammatory biomarker being found an association with inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate(9); this has been found associated with both infectious and non-infectious, acute and chronic inflammatory pathologies(10); and elevated in pathologies associated with neovessels, that is, neoplastic pathologies and associated with granulomas(11,12,13)

Recent studies have found an association between RDW and chronic complications associated with diabetes mellitus(14,15), especially diabetic nephropathy(16), a microvascular complication that has also been found associated with DR(17,18,19). In our bibliographic review, few studies have been carried out to date for the RDW and RD relationship, finding discrepancies in results(14,15,20). No studies were found for the RDW and PDR relationship.

The following article set out to determine the association between RDW and RDP in patients with type 2 diabetes mellitus. Determining this relationship will be essential for future preventive, prognostic, and therapeutic measures regarding this microvascular complication.

METHODS

Design

The present study had an unpaired case-control analytical design, prepared at the Research Institute in Biomedical Sciences of the Ricardo Palma University and carried out in the Ophthalmology department of the Hospital National Edgardo Rebagliatti Martins, in Lima, Peru, during the year 2017 between January to December.

All patients with diabetic retinopathy who had complete blood count and glycosylated hemoglobin exams updated within the last 3 months, an evaluation by the cardiology service, and an evaluation by the nephrology service to rule out complications to end organs were included. Those patients with type 1 diabetes mellitus, acute or chronic infections, systemic and/or ocular collagen disease, chronic obstructive pulmonary disease, history of cancer and/or treatment with radiation or chemotherapy were excluded from the study.

Procedures and variables

The diagnosis of diabetic retinopathy was made using a fundus examination using a slit lamp after pupillary dilation. RD was described and classified in RDNP and RDP according to the American Academy of Ophthalmology according to the eye in the most severe state. The diagnoses of congestive heart failure, arterial hypertension, and diabetic nephropathy were taken from the evaluation given by the cardiologist and endocrinologist. The RDW is the coefficient of variation of the corpuscular volume of the red blood cell, represented as a percentage, which allows us to determine its degree of variation, its cut-off point is 14.5% when it is high, anisocytosis is reported. HbA1c is the percentage representation of glucose bound to hemoglobin through non-enzymatic glycosylation, 6.5% is the cut-off point for the diagnosis of diabetes mellitus by the American Diabetes Association (ADA).

The complete blood count, glycosylated hemoglobin, history of arterial hypertension, diabetic nephropathy, and heart failure were obtained retrospectively, taking the medical history as a source of information. The weight and height data for the calculation of the body mass index were taken during the consultation with the patient, using a scale calibrated in kilograms using up to one decimal place and a standardized 1.99-meter wooden height rod using up to two decimal places for its measurement. respectively.

Population and sample

The OpenEpi statistical package was used to calculate the sample size of unpaired case-control type design, with a statistical power of 80%, a 95% confidence interval, a percentage of exposed controls of 50%, a case-control ratio of 1: 1 and an expected Odds Ratio of 2.1. A sample size of 131 cases with PDR and 131 controls with PNR was obtained using the Fleiss formula with continuity correction.

Ethical Issues

It was approved by the ethics committee of the Hospital National Edgardo Rebagliatti Martins, the approval of the head of the retina service of said hospital, and the acceptance of INICIB to carry out the data collection.

Statistical analysis

The STATA statistical package was used for the univariate analysis of relative frequencies of the qualitative variables and the mean and standard deviation for quantitative variables. In the bivariate analysis for qualitative variables, the chi-square test was used for sample homogeneity between cases and controls, in turn for quantitative variables, the Shapiro-France normality test was used for normality, the non-parametric test for the difference of medians U of Mann Whitney, for these tests a critical value of 0.05 was taken; To determine the strength of association, the statistical model Odds ratio was used. In the multivariate analysis, an Odds ratio adjusted for confounding variables was performed.

RESULTS

The total sample consisted of 262 participants, of which 131 were cases with PDR and 131 controls with NPDR. The medical records of each of the study subjects were found when data collection was carried out, so there was no missing data.

In the quantitative analysis, the RDW test was of 14.41% ± 0.84% found for the cases and 13.49% ± 1.26% for the controls, a significant statistical difference of P = 0.0000 was found, at its Once the HbA1c had 6.88 +/- 0.55 for the cases and 6.53 +/- 1.12 for the controls, and one found a statistically significant difference of P = 0.0002,Table 1.

Table 1.  Quantitative univariate analysis 

Variables Cases Controls Normality test Shapiro France Statistical test Mann Whitney U
Age 64.58+/-5.02 61.67+/-6.16 0.00007 P=0.0001
RDW 14.41+/-0.84 13.49+/-1.26 0.00001 P=0.0000
Hemoglobin 13.44+/-1.23 13.56+/-1.03 0.03321 P=0.3782
Hba1c 6.88+/-0.55 6.53+/-1.12 0.00001 P=0.0002
BMI 29.34+/-1.97 28.74+/-2.22 0.00001 P=0.0023

Abbreviations: RDW. Red cell distribution width, HbA1c. Glycated hemoglobin, BMI. Body mass index.

For the qualitative analysis, a high RDW of 80.15% for the cases and 53.44% for the controls, finding a statistically significant difference (P = 0.000), in turn, a high HbA1c of 83.97% for the cases and 58.02% for the controls with a statistically significant difference (p = 0.000 ),Table 2.

Table 2.  Quantitative univariate analysis 

Variables Case Control Statistical test
HbA1c      
≥6.5 % 110(83.97%) Si: 76(58.02%) P= 0.000
<6.5 % 21(16.03%) No: 55(41.98%)
RDW      
≥ 14.5% Si: 105(80.15%) Si: 70(53.44%) P=0.000
< 14.5% No: 26(19.85%) No: 61(46.56%)
Anemia      
Hb <11 gr/dL 11(8.40%) 8(6.11%) P=0.475
Hb ≥ 11 gr/dL 120(91.60%) 123(93.89%)
Gender      
Male 67(51.15%) 71(54.20%) P=0.621
Female 67(51.15%) 71(54.20%)
Age group      
≥ 60 years 113(83.26%) 18(13.74%) P=0.009
< 60 years 18(13.74%) 35(26.72%)
Congestive heart failure      
Yes 26(19.85%) 22(16.79%) P=0.523
No 105(80.15%) 109(83.21%)
Hypertension      
Yes 79(60.31%) 70(53.44%) P=0.262
No 52(39.69%) 61(46.56%)
Diabetic nephropathy      
Yes 86(65.65%) 61(46.56%) P=0.002
No 45(34.35%) 70(53.44%)
Obesity      
BMI ≥30 77(58.78%) 64(48.85%) P=0.107
BMI <30 54(41.22%) 64(48.85%)

Abbreviations: Hb1Ac. Glycated hemoglobin, RDW. Red cell distribution width, Hb. Hemoglobin, BMI. Body mass index.

In the bivariate analysis, a statistically significant association was found between RDW and RDP (OR 3.79 P = 0.000 CI = 2.12-6.78), HbA1c and RDP (OR 3.52 P = 0.000 IC = 2.03-6.10), NFD (OR 2.19 P = 0.002 IC 1.33-3.61), Age Group (OR 2.29 P = 0.010 IC 1.22-4.30), inTable 3shows these and other results obtained.

Table 3.  Bivariate analysis 

Variables OR p IC
HbA1c 3.52 0.000 2.03-6.10
RDW 3.79 0.000 2.12-6.78
Age group 2.29 0.010 2.12-6.78
NFD 2.19 0.002 2.12-6.78

Abbreviations: HbA1c. Glycated hemoglobin, RDW. Erythrocyte distribution width, NfD. Diabetic nephropathy.

Finally, a multivariate analysis was performed obtaining an adjusted OR with a statistically significant relationship for the RDW variables ( OR 2.15 P = 0.037 IC = 1.05-4.43) and HbA1c (OR 2.28 P = 0.026 IC = 1.10-4.69) in relation to the PDR,tabla 4shows these other results obtained.

Table 4.  Multivariate analysis 

Variables OR p IC 95%
HbA1c 2.28 0.026 1.10-4.69
RDW 2.15 0.037 1.05-4.43
Age group 1.65 0.142 0.84-3.23
NFD 0.97 0.925 0.50-1.86

Abbreviations: HbA1c. Glycated hemoglobin, RDW. Erythrocyte distribution width, NFD. Diabetic nephropathy.

DISCUSSION

Our study is the first to find an association for an RDW> 14.5% for PDR Both by bivariate and multivariate analysis, the main limitations of our study are that it was uni-centric, the data were collected only from one hospital, it was not possible to quantify other inflammatory markers such as C-reactive protein, fibrinogen, sedimentation rate for its Compared with RDW, the study design is not prospective and does not allow a causal relationship to be established.

DR is the most common microvascular complication of diabetes mellitus, and this complication is the leading cause of blindness in the economically active population(1,2,3). Its pathogenesis, not yet clarified, involves intermittent and sustained toxic levels of glucose in the retinal capillary, deleteriously affecting the retinal vascular lesions, that is, endothelium, pericytes, glia, and retinal neurons. By altering its function and predisposing to a retinal environment in favor of inflammation, thickening of the basement membrane and extracellular matrix increased capillary permeability, advanced glycosylation products, the formation of free radicals, thrombosis, necrosis and/or apoptosis of cells that make up said unit, chemotaxis of nuclear polymorphs and hypoxia. this will have a breaking point when this microenvironment begins to generate high values of pro-angiogenic and chemotactic molecules for fibroblasts(3,4,5,8,21). This induces the deposition of granulation tissue and the formation of neovessels, giving way to the late stage of diabetic retinopathy, the proliferative state(5,21), this inflammatory progression related to glycemia could explain why HbA1c and RDW are higher in PDR patients, the advanced stage.

An association has been reported between the microangiopathic complications of DR and diabetic nephropathy (DN)(18), finding DN as a risk factor in the development and progression of DR(16), which could be due to the deleterious effect of elevated systemic glucose levels that damage the hemiretinal and glomerular barriers(4,19), our study did not find a relationship for PDR and DN, which could be explained by its retrospective design.

In our bibliographic review, a discrepancy of results was found in the authors who have searched for the relationship between RD and RDW; Magri et al in 2013(15)reported an absence of statistically significant association when relating these variables, as did Malandrino et al(14)who divided the variable of the red cell distribution width into quartiles, finding no association in the 3rd quartile (OR 1.09 CI 0.61-1.97) or in the 4th quartile (OR 1.06 CI 0.37-3.03), unlike Kurtul et al(20)who in 2016 found a statistically significant association for RD and RDW (p = 0.036 OR 1.69 CI 1.036 -2,763), we propose that this discordance of results may be due to the presence of both stages of DR, the RDNP and RDP in the same group of analyzes, based on the fact that our results find a relationship between the RDW and RDP, taking the RDNP as control.

We recommend future prospective, multicenter studies, with higher statistical power, with the ability to confirm our results. The next step is to evaluate the possible relationship of RDW with angiogenic processes and biological markers of angiogenesis.

Our study suggests that RDW would not only be a strong predictor of diabetic retinopathy, but also a marker of microvascular progression, showing the transition from NPDR to PDR, serving the clinician as an additional factor in the progression of the disease.

CONCLUSION

This is the first study to establish a statistically significant relationship between RDW and RDP. A relationship was found for elevated levels of RDW and RDP by bivariate and multivariate analysis. We can conclude that the red cell distribution width could be a predictive biomarker for PDR and should be taken into account when evaluating patients with NPDR. We recommend prospective studies for the RDW and RDP relationship.

Acknowledgment:

The authors of this research wish to thank Dr. Jhony A. De La Cruz-Vargas, who directed the thesis and the development of the article.

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Funding: Self-financed.

Received: June 30, 2020; Accepted: July 20, 2020

Correspondence: Juan Carlos Ezequiel Roque Quezada Address: Carr. Panamericana Sur 19, Villa EL Salvador 15067, Lima-Perú. Telephone: 945558094 E-mail:100017716@ucientifica.edu.pe

Author’s Contributions: The author participated in the genesis of the idea, project design, data collection and interpretation, analysis of results, and preparation of the manuscript of the present research work.

Conflicts of interest: The author declares no conflict of interest in the publication of this article.

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