Predict sight-threatening complications from diabetes

DR Biomarker


RetmarkerDR is a biomarker for Diabetic Retinopathy progression in a mild non-proliferative stage, predicting sight-threatening Diabetic Retinopathy through the quantification of microaneurysms turnover ratios, namely for Clinically Significant Macular Edema and Proliferative Retinopathy.
RetmarkerDR is a class IIa medical device in Europe.

How RetmarkerDR Biomarker works?

RetmarkerDR consistently tracks each microaneurysm as a single entity in a specific location, with identifiable coordinates, providing valuable information.
The MA is classified as New (Red), Old (Green) or Disappeared (Yellow).

Retmarker also allows detailed image analysis and annotation. You can extend the automated results with manually marked Microaneurysms.
Number of MAs found in the baseline visit.
Number of MAs found in a follow-up visit, identifying which
ones are NEW, OLD or DISAPPEARED in this visit
Turnover: MA Formation & Dissapearance rates
The Image Explorer provides tools that allow to look at the same anatomical region of the eye… and you can even zoom in!
The software helps you to manually mark additional MAs.
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MicroAneurysms (MA) are fundamental to deal with Diabetic Retinopathy
Klein et al. looked at the relationship between retinal microaneurysms and the progression of diabetic retinopathy over a 4-year period. In their study the number of microaneurysms at the baseline examination was positively associated with significant progression of retinopathy.
On fundus photography, microaneurysms and small hemorrhages are the initial changes detected in the diabetic retina. They may be counted, and retinal microaneurysms counting has been suggested as an appropriated marker of retinopathy progression.
1989 Klein R, Meuer SM, Scot E Moss MA, Klein BEK (1989) The relationship of Retinal Microaneurysms Counts to the 4-Year Progression of Diabetic Retinopathy. Arch Ophthalmol 107: 1780-1785.
1995 Klein R, Klein B, Moss SE, Cruickshanks KJ (1995) The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. Ophthamology 102:7-16.
1999 Kohner AM, Stratton IM, Aldington SJ, Turner RC, Matthews DR for the UK Prospective Study Group (1999) Microaneurysms in the development of diabetic retinopathy (UKPDS). Diaetologia 45:1780-1785.
Retinal microaneurysms are important lesions of diabetic retinopathy and even one or two microaneurysms in an eye should not regarded as unimportant.
MA Turnover discriminates Diabetic Retinopathy progression
Sharp et al. found that Microaneurysm turnover values vary widely between eyes that have similar Early Treatment Diabetic Retinopathy Study (ETDRS) grading value.
Systemic Markers of Diabetes such as duration of the disease, poor glycemic control, increased blood pressure and lipid levels are relevant factors but they do not identify Diabetic Retinopathy progression. It is fundamental to identify lesions, their number and dynamics.
2003 Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, Wallece S, Goatman K, Grant A, Waugh N, McHardy K, Forrester JV (2003) The value of digital imaging in diabetic retinopathy. Health Technol Assess 7:1-119
2006 Hove MN, Kristensen JK, Lauritzen T, and Bek T. The relationships between risk factors and the distribution of retinopathy lesions in type 2 diabetes. Acta Ophthalmologica Scandinavica, 8(5), 619-623
2008 Csaky KG, Richman EA, Ferris FL (2008) Report from the NEI/FDA Ophthalmic Clinical Trials Design and Endpoints Symposium. Invest Ophthalmol Vis Sci 49:479-489
Retinal microaneurysm counting has been suggested as an appropriate marker of retinopathy progression.
MA Turnover, computed in Color Fundus Photographs, is predictive of DME
Over a 10-year follow-up period, microaneurysm turnover determined in the first 2 years identifies the patients at risk of progression to Clinically Significant Macular Edema and vision loss.
RetmarkerDR computer-assisted earmarking of microaneurysms allows quantification of the microaneurysm turnover.
2009 Nunes S, Pires I, Rosa A, Duarte L, Bernardes R, Cunha-Vaz J, "Microaneurysm Turnover Is a Biomarker for Diabetic Retinopathy Progression to Clinically Significant Macular Edema: Findings for Type 2 Diabetics with Nonproliferative Retinopathy", Ophthalmologica 2009;223:292–297
2009 Bernardes R, Nunes S, Pereira I, Torrent T, Rosa A, Coelho D, Cunha-Vaz J, "Computer-Assisted Microaneurysm Turnover in the Early Stages of Diabetic Retinopathy", Ophthalmologica 2009;223; 284–291
Complementary Evidences
Sjolie et al. showed that microaneurysms counts were predictive of an increased risk of retinopathy.
Low microaneurysm turnover values identify well the eyes that are less likely to develop CSME in a 2-year period.
2011 Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, Bilous R, Aldington S, Chaturvedi N (2011) Retinal microaneurysms count predicts progression and regression of diabetic retinopathy. Post-hoc results from the DIRECT Programme. Diabet Medicine 28():345-351.
2012 Ribeiro ML, Nunes SG and Cunha-Vaz JG Microaneurysm turnover at the macula predicts risk of development of clinically significant macular edema in persons with mild nonproliferative diabetic retinopathy. Diabetes Care, vol. 36, no. 5, pp. 1254–9, May 2012.
2013 Ribeiro L, Nunes S, and Cunha-Vaz J. Microaneurysm turnover in the macula is a biomarker for development of clinically significant macular edema in type 2 diabetes. Current Biomarker Findings, 201;3:11–15.
2013 Ribeiro L and Cunha-Vaz J, "Surrogate outcomes for progression in the initial stages of diabetic retinopathy", Immunology, Endocrine & Metabolic Agents - Medicinal Chemistry, 13(1), 25-34, 2013
Microaneurysm turnover computed automatically in digital color fundus photographs is a good biomarker for worsening of retinopathy and development of clinically significant macular edema.
Microaneurysm turnover appears to be a biomarker of the risk of progression and a surrogate outcome for development of Clinically Significant Macular Edema.
Confirmation of MA Turnover predictive value
Using the RetmarkerDR software, the team from the LMU in Munich was able to identify patients with higher risk to develop CSME during a follow-up period of up to 5 years. The automated analysis may help to determine the individual risk of a patient to develop sight-threatening complications related to diabetic retinopathy.
“Micro-Aneurysm Formation Rate as calculated by a validated automated method seems a very promising biomarker for enriching a patient population at higher risk for the development of Clinically Significant Macular Oedema.”
2014 Haritoglou C, Kernt M, Neubauer A, Gerss J, Oliveira CM, Kampik A and Ulbig M Microaneurysm formation rate as a predictive marker for progression to clinically significant macular edema in nonproliferative diabetic retinopathy. Retina, vol. 34, no. 1, pp. 157–164, Jan. 2014.
2015 Letter of support for micro-aneurysm formation rate (MAFR) biomarker.
2018 Pappuru, Rajeev KR, et al. Microaneurysm turnover is a predictor of diabetic retinopathy progression , British Journal of Ophthalmology (2018).
New study with LV Prasad Eye Institute, India, confirms that Diabetic Retinopathy progression is predicted by Microaneurysm Turnover, a measure automatically computed by RetmarkerDR from the analysis of non-invasive field 2 images.
MA Turnover Phenotypes predicts vision-threatening DR
Progression risk for Macular Edema in Diabetic Retinopahy is identified by three Phenotypes based in Retinal Thickness and Microaneurysm turnover (computed with RetmarkerDR). Different Ethnical groups present different Phenotypes distributions.
MA Turnover-Based Phenotype identifies eyes at higher risk for development of vision– threatening complications (CSME or PDR). It is the only phenotype associated with PDR.
Four Independent Longitudinal Studies confirm Microaneurysm turnover-based Phenotypes as predictors of Macular Edema increased progression risk.
2017 Ribeiro, Luísa, et al. Different Phenotypes of Mild Nonproliferative Diabetic Retinopathy with Different Risks for Development of Macular Edema (C-TRACER Study). Ophthalmic research, 2017.
2017 Cunha-Vaz, José, et al. Diabetic Retinopathy Phenotypes of Progression to Macular Edema: Pooled Analysis From Independent Longitudinal Studies of up to 2 Years' Duration in Investigative ophthalmology & visual science 58.6 (2017): BIO206-BIO210.
2020 Marques IP, Madeira MH, Messias AL, et al. Retinopathy Phenotypes in Type 2 Diabetes with Different Risks for Macular Edema and Proliferative Retinopathy. J Clin Med. 2020;9(5):1433. Published 2020 May 12.
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Lobo C. et al.
"Patterns of progression in Diabetic Retinopathy correlation between phenotypes and genotypes"

Nunes S. et al.
"Phenotypes of Diabetic Retinopathy Progression to CSME based on non-invasive examinations"

Nunes S. et al.
"Cluster Analysis Identification Of Early Diabetic Retinopathy Phenotypes"

Nunes S. et al.
"Validation of a predictive model for diabetic retinopathy progression in type-2 diabetic patients with mild nonproliferative diabetic retinopathy"

Pires I. et al.
"Microaneurysms Formation Rate as a Predictor of DR Progression to CSME Needing Photocoagulation in Nonproliferative Retinopathy in Diabetes Type 2"

Bernardes R. et al.
"Earmarking Retinal Changes on a Color Fundus Photograph Time-Sequence"

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