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ORIGINAL ARTICLE
Year : 2004  |  Volume : 52  |  Issue : 3  |  Page : 205-10
 

Macular ischaemia as a marker for nephropathy in diabetic retinopathy.


Aravind Eye Hospital & Postgraduate Institute of Ophthalmology, 1 Anna Nagar, Madurai 625 020, Tamil Nadu, India

Date of Submission13-Jun-2003
Date of Acceptance23-Jan-2004

Correspondence Address:
D Shukla
Aravind Eye Hospital & Postgraduate Institute of Ophthalmology, 1 Anna Nagar, Madurai 625 020, Tamil Nadu
India
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PMID: 15510459

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   Abstract 

PURPOSE: To determine whether diabetic macular ischaemia is associated with ischaemic heart disease (IHD), hyperlipidaemia, hypertension (HTN) and nephropathy. METHODS: Prospective case-control study from January to December 2001, involving 102 type 2 diabetic patients (aged 40-80 years), 59 with unilateral / bilateral macular ischaemia and 43 concurrent controls. Diabetic retinopathy was graded and macular ischaemia assessed by fundus examination, central fundus photography and fluorescein angiography. Systemic examination and laboratory investigations were done to evaluate systemic diseases. The associations were analysed by Chi-square test and Student's t-test. The significance of the variables as independent risk factors was tested by logistic regression analysis. RESULTS: Macular ischaemia was not associated with IHD (P=1.00); HTN (P=1.00) and hyperlipidaemia (P=0.30). Nephropathy was significantly associated with macular ischaemia (P=0.025; odds ratio [OR]: 2.62; 95% confidence interval [CI]: 1.16-5.9). The association remained significant after controlling for age, gender, duration of diabetes, severity of retinopathy, HTN, IHD and hyperlipidaemia. Further, the association with nephropathy was not affected by the presence of macular isachaemia in one or both the eyes (P=0.39). CONCLUSION: Macular ischaemia may serve as a marker for nephropathy in type 2 diabetes mellitus irrespective of the severity of retinopathy.


Keywords: Adult, Aged, Aged, 80 and over, Case-Control Studies, Diabetes Mellitus, Type 2, complications, Diabetic Nephropathies, complications, Diabetic Retinopathy, complications,


How to cite this article:
Shukla D, Kolluru CM, Singh J, John RK, Soman M, Gandhi B, Kim R, Perumalsamy N. Macular ischaemia as a marker for nephropathy in diabetic retinopathy. Indian J Ophthalmol 2004;52:205

How to cite this URL:
Shukla D, Kolluru CM, Singh J, John RK, Soman M, Gandhi B, Kim R, Perumalsamy N. Macular ischaemia as a marker for nephropathy in diabetic retinopathy. Indian J Ophthalmol [serial online] 2004 [cited 2014 Apr 16];52:205. Available from: http://www.ijo.in/text.asp?2004/52/3/205/14590


A diabetic patient is known to lose vision by two primary mechanisms: proliferative diabetic retinopathy (PDR) and its attendant complications, and diabetic macular oedema (DME).[1],[2] Although ischaemic maculopathy ranks low as a cause for blindness in persons with diabetes due to its relative rarity,[2],[3] the condition is important because it is not amenable to treatment, unlike PDR and DME. Most studies consider it merely the macular involvement in the setting of a generalised capillary drop-out and retinal ischaemia, and not a unique entity per se . [4],[5],[6] However, macular ischaemia may have associations independent of the severity of diabetic retinopathy (DR).

Concomitant systemic diseases are known to aggravate diabetic retinopathy and increase the risk of visual loss through DME and PDR.[1] Hyperlipidaemia is known to affect specific parameters like retinal hard exudates.[7] We designed to study a similar correlation between macular ischaemia and selected systemic diseases: hypertension, renal disease, ischaemic heart disease and hyperlipidaemia. These diseases were selected because of their common association, known effects on DME and PDR, similar microangiopathy and ischaemic pathology. [1],[8]


   Materials and Methods Top


We recruited subjects for the study from among patients presenting at the retina service of a tertiary eye care centre.

Common inclusion criteria

1. Patient able and willing to give informed consent to participate in the study.

2. Presence of retinopathy attributable to type 2 diabetes mellitus.

3. Feasibility of high-quality fluorescein angiograms, with well-defined foveal avascular zone (FAZ).

Inclusion criteria for Cases

The above criteria, and presence of macular ischaemia in at least one eye confirmed by fundus fluorescein angiography (FFA).

Inclusion criteria for Controls

Common inclusion criteria, and presence of a normal FAZ in both eyes confirmed by FFA.

Exclusion criteria

1. Type 1, or indeterminate diabetes mellitus.

2. FFA not possible either due to medical reasons or refusals

3. Hazy ocular media precluding a good view of the retina

4. Any prior photocoagulation in the macular region

5. Macular ischaemic status doubtful after FFA

6. Concomitant fundus pathology that could potentially affect FAZ (e.g., arterial/venous occlusions)

7. Concomitant ocular pathology that could potentially influence the progression of retinopathy (glaucoma, high myopia, retinitis pigmentosa, other causes of optic atrophy, etc.)

8. A history of radiation to the head or neck region

9. Carotid vascular disease detected by clinical examination

10. Patients on haemo-/peritoneal dialysis.

All patients received a detailed work-up including a medical history, anterior segment slitlamp biomicroscopy, applanation tonometry and fundus examination with indirect ophthalmoscopy and biomicroscopy. We graded diabetic retinopathy based on an abbreviated ETDRS severity scale (mild, moderate and severe non-proliferative diabetic retinopathy [NPDR]; early and high risk PDR).[8] Fundus fluorescein angiography was done in a standard fashion using 3ml of 20% sodium fluorescein dye. An observer masked to the systemic findings assessed the FAZ from the frames centred on the fovea showing the highest quality capillary phase. Subsequently, a physician who was masked to the findings of ocular examination and FFA evaluated each subject for systemic diseases with special attention to hypertension, renal disease, ischaemic heart disease and hyperlipidemia.

Diabetes mellitus was diagnosed when a fasting plasma glucose of 126 mg/dL (6.99 mmol/L) or a non-fasting plasma glucose of 200 mg/dL (11.1 mmol/L)[9] was detected; or when the patient was already using medication for diabetes. Type 2 diabetes mellitus was determined on the basis of a diagnosis of diabetes mellitus after the age of 40 years, with the patient not having been on insulin for at least the first year after diagnosis. The blood pressure was measured with the patients in sitting position, after 5 minutes of rest. We defined systemic hypertension as either a systolic blood pressure 140 mm Hg and/or a diastolic blood pressure 90 mm Hg,[10] or the current use of systemic antihypertensive medications. The carotid pulse status was evaluated by digital palpation on both sides of the neck. All patients had an electrocardiogram (ECG); those who had changes suggestive of cardiac abnormalities not confirmed by ECG received an echocardiogram. We diagnosed IHD based on evidence of previous myocardial infarction or ischaemic changes (elevation/depression of S-T segment, inversion of T-wave) on ECG supported by clinical history and/or echocardiogram, or a history of cardiovascular surgery or angioplasty for IHD. We defined hyperlipidaemia as a fasting total plasma cholesterol of > 200 mg/dL (5.2 mmol/L).[11] We defined nephropathy as urine albumin 1+ (30 mg/dL, indicating gross proteinuria)[12] by bromophenol dipsticks, and/or blood urea >40 mg /dL (14.28 mmol/L),[13] and/or serum creatinine > 1.5 mg/dL (133 micromoles/L).[14] All the biochemical tests were done on an auto-analyser (Photometer 5010, Boehringer Mannheim, Mannheim, Germany).

We used the criteria described by Bresnick et al to define macular ischaemia. [4] The minimum criterion for diagnosing macular ischaemia was moderate FAZ irregularities. Moderate irregularities was defined as abnormally dilated and tortuous capillaries budding into the FAZ, terminal arterioles/venules directly abutting FAZ margins, and enlarged intercapillary spaces around the FAZ.[4] The size was a minor criterion compared to the irregularity of FAZ. Ischaemia was diagnosed only when the longest diameter of FAZ was 1000 (the measurements were made digitally using a telecentric FF 450plus fundus camera [VISUPAC system, Carl Zeiss, Germany]. Severe FAZ irregularities was defined as the destruction of the FAZ architecture: grossly enlarged FAZ with "pruned off" arterioles. Normal FAZ was defined as an FAZ <1000 in the longest diameter, regular and round/horizontally oval in shape. Mild undulations of FAZ were also considered normal.[4]

We used STATA version 7.0 software package (College Station, TX, USA) for statistical analyses. We performed a person-wise analysis to explore associations with systemic diseases (we considered the status of retinopathy in the worse eye for this analysis), and an eye-wise analysis to explore associations with the severity of diabetic retinopathy. We looked for significance of associations using Student's t-test and Chi-square test. Calculation of odds ratio (OR) with 95% confidence interval (95% CI) and multivariate logistic regression analysis were performed to assess the significance of variables as risk factors. The study was conducted in accordance with principles laid down for human research in the Helsinki Declaration.


   Results Top


All 102 subjects (59 cases and 43 controls) with type 2 diabetes who met the criteria for inclusion in the study agreed to participate in the study. There were no significant differences in age, gender, and duration of diabetes or severity of retinopathy between cases and controls [Table - 1]. Bilateral macular ischaemia was present in 23 (39%) eyes. Although macular ischaemia was more common in severe stages of retinopathy (63% in eyes with early proliferative retinopathy and 70% in high-risk retinopathy), the association with severity of retinopathy was not significant by the person-wise analysis (P=0.24) or by eye-wise analysis (P=0.11). [Figure - 1], [Figure - 2]

Hypertension (OR: 1.05; 95% CI: 0.48 to 2.32), IHD (OR: 1.125; 95% CI: 0.45 - 2.82) and hyperlipidaemia (OR: 1.63; 95% CI: 0.72 - 3.70) were not significantly associated with macular ischaemia. Only nephropathy was significantly associated with the presence of macular ischaemia (OR: 2.62; 95% CI: 1.16 - 5.92) [Table - 1]. The retinal-renal association remained significant after adjusting for all variables including the potential confounders, i.e., age, duration of diabetes mellitus, severity of DR in the worse eye, HTN, IHD and hyperlipidaemia (OR: 2.83; 95% CI: 1.15 - 7.00) [Table - 2].


   Discussion Top


Data from our study suggest that diabetic patients with macular ischaemia are more likely to have nephropathy. Although the association between macular ischaemia and hypertension, ischaemic heart disease or hyperlipidaemia was not found to be statistically significant, the study sample did not have enough power to comment conclusively on this finding. Bresnick et al have previously reported the association between retinal ischaemia and nephropathy; 6 of 8 diabetic subjects with retinal and macular ischaemia had elevated serum creatinine.[15]

Severity of DR was a major confounding variable in our study. FAZ size and irregularities are known to increase with increasing severity of DR. [4],[5],[6] At the same time presence and severity of DR have been reported to be strongly associated with proteinuria in both type 1 and 2 DM. [16],[17],[18],[19],[20] Macular ischaemia and nephropathy were noted in 66.7 % of patients with PDR in our study. Therefore, severity of DR might have been the common link between macular ischaemia and nephropathy. Secondly, ECG-proven IHD has been shown to be associated with both severity of DR and nephropathy.[17],[18] Further, nephropathy has been linked with duration of diabetes, elevated serum triglycerides and total plasma cholesterol .[18],[19],[21] Lastly, in view of its known association with renal disease, hypertension could have increased the incidence of nephropathy in our patients; though Mansour et al[5] found no correlation of hypertension with FAZ irregularities. We found the ischaemia - nephropathy relationship valid after adjusting for age, gender, duration of diabetes mellitus, severity of DR, HTN, IHD and hyperlipidaemia by multivariate analysis [Table - 2].

Defining macular ischaemia may be difficult. Although various qualitative angiographic criteria like enlargement and irregularity of FAZ, disruption of perifoveal capillary network have been used, they have not been quantified. Thus, while gross macular ischaemia can be diagnosed with certainty, criteria for diagnosis of an early macular ischaemia are not known. The ambiguity is compounded by the frequent occurrence of enlarged and irregular FAZ in diabetic patients. [4],[5],[6] Bresnick et al attempted to quantify macular ischaemia as mild, moderate and severe FAZ abnormalities.[4] Mild irregularities consisted of small breaks in the margin of the FAZ seen as deep undulations. These might represent a grey area between the normal and ischaemic FAZ, and therefore patients with mild FAZ irregularities were excluded from the categories of both cases and controls in our study.

The association of macular ischaemia with nephropathy could possibly be explained on the basis of similar ischaemic microangiopathy in the two end-organs. Similar to the retinal capillaries in DR, renal glomeruli also exhibit basement membrane thickening early in diabetic renal disease, resulting in characteristic nodular, diffuse and exudative glomerular lesions. The common end point of these renal lesions is glomerular hyalinisation, primarily an ischaemic event.[22]

Klein et al (ARIC study group)[20] found a significant association of retinopathy with extracranial carotid artery stenosis and hypertension. However, the clinical correlates of atherosclerosis, notably coronary heart disease and hyperlipidaemia were not associated with the severity of DR. Similarly, we did not find any association of IHD and hyperlipidaemia with macular ischaemia, which is known to progress with increasing severity of DR. [4],[5],[6]

An important systemic variable, the carotid / ophthalmic artery stenosis, was not studied as a cause for macular ischaemia. Financial constraints prevented routine carotid doppler studies in our patients. The random one-time assessment of renal parameters might have affected the sensitivity and specificity of the diagnosis of nephropathy.[23] Supplementary tests like 24-hour urine studies may have given more accurate results. The limitation of a single non-stereo posterior pole photograph was partly offset by meticulous indirect ophthalmoscopy and slitlamp biomicroscopy, as well as a detailed angiography of the mid-periphery covering the extent of the 7 standard photographic fields. Clinical examination does not appear to match the sensitivity of 7-field assessment for detecting or grading DR, though specificity may be comparable.[24],[25] Single-field assessment of DR is reported to have a 78% sensitivity, and 86% specificity in comparison to the 7-field gold standard.[25] The Diabetes Control and Complications Trial (DCCT) found 7-field photography and central 2-field angiography comparable in sensitivity; but this study focussed on very early detection of lesions of DR and not the grading.[26] We hoped to achieve reasonably good sensitivity and specificity by combining the three methods : clinical examination, single-field photography and FFA. Finally, the cross-sectional design of the study (assessing macular ischaemia and systemic variables at a point of time) limited our ability to predict the temporal sequence of the reported associations. Our results need to be verified by a larger study including type 1 diabetic patients, who are known to have a higher prevalence of renal impairment.[21]

It has already been suggested that diabetic individuals with retinopathy (especially, severe retinopathy) should be screened for microalbuminuria and gross proteinuria. [1],[23] We further recommend that a diagnosis of macular ischaemia in a type 2 diabetic patient, irrespective of the severity of retinopathy, should alert the ophthalmologist to the possibility of nephropathy so that appropriate investigations and management strategies may be instituted.



 
   References Top

1.Aiello LP, Cahill MT, Wong JS. Perspective: Systemic considerations in the management of diabetic retinopathy. Am J Ophthalmol 2001;132:760-76.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Fong DS, Ferris FL III, Davis MD, Chew EY, for the Early Treatment Diabetic Retinopathy Study research group. Causes of severe visual loss in the early treatment diabetic retinopathy study: ETDRS Report 24. Am J Ophthalmol 1999;127:137-41.  Back to cited text no. 2    
3.Early Treatment Diabetic Retinopathy Study Research Group. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS Report 19. Arch Ophthalmol 1995;113:1144-55.  Back to cited text no. 3  [PUBMED]  
4.Bresnick GH, Condit R, Syrjala S, Palta M, Groo A, Korth K. Abnormalities of the foveal avascular zone in diabetic retinopathy. Arch Ophthalmol 1984;102:1286-93.  Back to cited text no. 4  [PUBMED]  
5.Mansour AM, Schachat A, Bodiford G, Haymond R. Foveal avascular zone in diabetes mellitus. Retina 1993;13:125-28.  Back to cited text no. 5  [PUBMED]  
6.Arend O, Wolf S, Jung F, Bertram B, Postgens H, Toonen H et al. Retinal microcirculation in patients with diabetes mellitus: dynamic and morphological analysis of perifoveal capillary network. Br J Ophthalmol 1991;75:514-18.  Back to cited text no. 6    
7.Chew EY, Klein ML, Ferris FL III, Remaley NA, Murphy RP, Chantry K et al, for the ETDRS research group. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22 . Arch Ophthalmol 1996;114:1079-84.  Back to cited text no. 7    
8.Aiello LM, Cavallerano J, Aiello LP. Diagnosis, management and treatment of non proliferative diabetic retinopathy and macular edema. In: Albert DM, Jakobiec FA, editors. Principles and Practice of Ophthalmology. 2nd ed. Philadelphia: W.B Saunders Company. 2000, Vol. 3, pp1900-14.  Back to cited text no. 8    
9.Jack SD. Diabetes mellitus and related disorders. In: Ahya SN, Kellie Flood, Subramanian P, editors. The Washington Manual of Medical Therapeutics. 30th edition. Lippincott William and Wilkins. 2001. pp 455-72.  Back to cited text no. 9    
10.Venkata Ram CS. Systemic hypertension. In: Sainani GS, Abraham P, Dastur FD, Joshi VR, Lele RD, Mehta PJ et al, editors. API Text book of Medicine. Mumbai: Association of Physicians of India; 1999, pp 403-14.  Back to cited text no. 10    
11.Brown MS, Goldstein JL. The hyperlipoproteinemias and other disorders of lipid metabolism. In: Issel Bacher KJ, Braunvald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, editors. Harrison's Principles of Internal Medicine. 13th edition. McGraw Hill, Inc; 1994, pp 2058-69.  Back to cited text no. 11    
12.Coe FL. Alterations in urinary functions. In: Issel Bacher KJ, Braunvald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, editors. Harrison's Principles of Internal Medicine. 13th edition. Mc Graw Hill, INC; 1994, pp 235-41.  Back to cited text no. 12    
13.Amaresan AS. Renal function tests. In: Sainani GS, Abraham P, Dastur FD, Joshi VR, Lele RD, Mehta PJ et al, editors. API Text book of Medicine . Mumbai: Association of Physicians of India; 1999, pp 623-28.  Back to cited text no. 13    
14.Appendix: Chemical constituents of blood. In: Issel Bacher KJ, Braunvald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, editors. Harrison's Principles of Internal Medicine . 13th edition. Mc Graw Hill, Inc. 1994, p 2490.  Back to cited text no. 14    
15.Bresnick GH, Venecia GD, Myers FL, Harris JA, Davis MD. Retinal ischaemia in diabetic retinopathy. Arch Ophthalmol 1975;93:1300-10.  Back to cited text no. 15    
16.Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy: V. Proteinuria and retinopathy in a population of diabetic persons diagnosed prior to 30 years of age. In: Friedman EA, L'Esperance FA (editors). Diabetic Renal - Retinal Syndrome. Orlando: Grune & Stratton Company; 1986. Vol. 3, pp 245-65.  Back to cited text no. 16    
17.West KM, Erdreich LJ, Stober JA. A detailed study of risk factors for retinopathy and nephropathy in diabetes. Diabetes 1980;29:501-8.  Back to cited text no. 17  [PUBMED]  
18.Collins VR, Dowse GK, Plehwe WE, Imo TT, Toelupe PM, Taylor HR. High prevalence of diabetic retinopathy and nephropathy in Polynesians of Western Samoa. Diabetes Care 1995;18:1140-49.  Back to cited text no. 18    
19.Lee KU, Park JY, Kim SW, Lee MH, Kim GS, Park SK. Prevalence and associated features of albuminuria in Koreans with NIDDM. Diabetes Care 1995;18:793-99.  Back to cited text no. 19    
20.Klein R, Sharrett AR, Klein BEK, Moss SE, Folsom AR, Wong TY et al. The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes. The Atherosclerosis risk in communities study. Ophthalmology 2002;109:1225-34.  Back to cited text no. 20    
21.Knuiman MW, Welborn TA, McCann VJ, Stanton KG, Constable IJ. Prevalence of diabetic complications in relation to risk factors. Diabetes 1986; 35:1332-39.  Back to cited text no. 21  [PUBMED]  
22.Herman WH, Teutsch SM. Renal disorders associated with diabetic mellitus. In: Friedman EA, L'Esperance FA (editors). Diabetic Renal - Retinal Syndrome . Orlando: Grune & Stratton Company; 1986, Vol. 3, pp 9-53.  Back to cited text no. 22    
23.Klein R, Klein BEK, Moss SE, Cruickshanks KJ. Ten-year incidence of gross proteinuria in people with diabetes. Diabetes 1995; 44:916-23.  Back to cited text no. 23    
24.Moss BE, Klein R, Kessler SD, Richie KA. Comparison between ophthalmoscopy and fundus photography in determining severity of diabetic retinopathy. Ophthalmology 1985; 92:62-67.  Back to cited text no. 24    
25.Lin DY, Blumenkranz MS, Brothers RJ, Grosvenor DM, for The Digital diabetic screening group. The sensitivity and specificity of single-field non-mydriatic monochromatic digital fundus photography with remote image interpretation for diabetic retinopathy screening: a comparison with ophthalmoscopy and standardized mydriatic color photography. Am J Ophthalmol 2002;134:204-13.  Back to cited text no. 25    
26.The Diabetes Control and Complications Trial research group. Color photography vs fluorescein angiography in the detection of diabetic retinopathy in the diabetes control and complications trial. Arch Ophthalmol 1987;105:1344-51.  Back to cited text no. 26  [PUBMED]  


Figures

[Figure - 1], [Figure - 2]

Tables

[Table - 1], [Table - 2]


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