Very few studies have been conducted to determine the correlation of non-ocular factors such as CKD secondary to diabetes with various morphological patterns of DME seen on OCT. [12,20,21] Also the previous studies conducted were single centre studies with a relatively small sample size. None of the studies performed have demonstrated the impact of CKD on the recently described visual prognostic biomarkers in DME and correlated them. This study bridges this gap in knowledge which may help in better management.
On review of literature several studies have used proteinuria as a marker of nephropathy and found a relation between disease severity and proteinuria. [12,21,22] However an inconsistent relation has been reported between the two and therefore in our study we have used eGFR as a marker of nephropathy which is possibly a better marker for nephropathy as ethnic variations and age of the patient are used for its determination. Also, eGFR is possibly the earliest marker for nephropathy and albuminuria is an inconsistent marker that may regress or progress. [20,23]
In our group of patients, the average duration of diabetes was 12 years or more with stage 3,4 or 5 CKD and the proportion of different morphological patterns of DME on OCT did not significantly vary across various CKD stages. However, the most common morphological pattern found in the study cohort was cystoid pattern 42% (95% CI: 36-49) followed by mixed pattern 31% (95% CI: 24-38) and then the spongiform pattern in 16% (95% CI: 11-22). This is in contrast to what has been reported by Koo et al. in their retrospective study on 93 korean patients of DME with renal dysfunction. They found that the serous macular edema occurred most commonly (67%) and this possibly is due to albumin and other extracellular fluid leaking into the sub-retinal space leading to serous detachment. Romero et al. in a series of 112 Spanish patients of type-1 DM of which 23 patients had DR and nephropathy, found spongiform DME to be the most common pattern in 78% patients(18 out of 23) followed by cystoid pattern in 9%(2 out of 23). Ciardella et al. have reported a case of mixed type (serous and cystoid) macular edema in patients with albuminuria. This shows the variability in the morphological pattern of the DME found on OCT in patients with CKD and no single pattern can be correlated with it.
There is paucity of information in literature regarding the correlation of sight threatening DR with stages of CKD. [7,8] We found sight threatening DR to increase from 70% in CKD stage-3 to 82% in CKD stage-4 and 5. This was found to be statistically significant and consistent (p=0.03). It was also noted that the percentage of sight threatening DR was significantly different across all morphological patterns. The highest percentage risk was seen with VMT (100%) followed by SRD (92%), spongiform (82%), mixed (78%) and minimal in cystoid (69%). This highlights the fact that with advancement in the stage of CKD the patient has an increased risk of loss of vision.
In our study on subgroup analysis of patients on renal dialysis (19 out of 234 patients) spongiform pattern was not found in any patient and cystoid pattern was the commonest though not found to be statistically significant. This is in contrast to what has been reported by Takamura et al. who in their series of 118 eyes of patients on hemodialysis found spongiform pattern of DME to be the most common pattern in 53% (62 out of 118 eyes).
Longer duration of DM, age, hypercholesterolemia, poor glycaemic control (elevated HbA1C), hypertension and the use of insulin are regarded as major risk factors for manifestation of DME. In our study glycosylated haemoglobin (HbA1c) was found to be in the higher range >10mg% in patients with more advanced stage of CKD and on correlating level of HbA1c with the morphological pattern of DME. it was found that cystoid pattern was the most common irrespective of the level of the HbA1c. However, this was not found to be statistically significant. An observation was made that 50% of the patients with HbA1c >10mg% (poorly controlled diabetes) showed VMT. This possibly could be due to the primary insult of hyperglycemia leading to the development and acceleration of advanced glycation end products (AGEs) which promotes leukostasis and cause damage to both pericytes and endothelial cells. They are also believed to promote mechanical changes in the vitreous and at the vitreous-retinal interface promoting VMT and subsequent DME. [26,27] This highlights the fact that the patients with poorly controlled diabetes are likely to have more VMT causing a higher risk of sight threatening DR.
To the best of our knowledge there is a lacunae in literature regarding the impact of CKD on various OCT biomarkers. In our study on correlating the OCT biomarkers with stage of CKD we found ELM-EZ defects showed a direct correlation with the stage of CKD. They were present in 17 out of 27 patients (63%) in CKD stage-5 and in 30 out of 52 (58 %) and 24 out of 83 patients (29%) with CKD stage-4 and stage-3 respectively. This was found to be highly statistically significant. DRIL and HRD showed no correlation. This suggests that patients suffering from diabetes and end stage CKD show more ELM-EZ defects on OCT causing poorer visual prognosis. In a patient suffering from diabetes if on evaluation of OCT one finds ELM-EZ defects then it is important to check the renal function in such patients, if they are not aware of it.
Knudsen et al. studied DME in 20 patients with type-2 DM and found a strong correlation between increased retinal thickness on OCT and increased urinary albumin excretion rate. Acan D et al. in their study of 53 patients with DME found that diffuse retinal thickness (62%) was much higher with micro or macro albuminuria compared to cystoid macular edema (42%) and SRD (21%). They also found that the HbA1c levels were higher in the diffuse retinal thickness group. We found a direct correlation between foveal subfield thickness and stage of CKD. Maximum mean foveal sub-field thickness of 524.6 ± 178.8 µm was found in CKD stage-5. It was noted to be 463.3 ± 220 µm and 455.82 ± 166.36 µm in CKD stage-4 and 3 respectively. This was found to be statistically significant.
All the previous studies conducted were single centre studies with a relatively small sample size. The present study is the first from the Indian subcontinent and the largest multicentric series till date. It is also the first study to correlate eGFR with the morphological pattern of DME, sight threatening DR and OCT biomarkers with stage of CKD. The limitations of this study are as follows- it is a retrospective study, there was no control group with no CKD for comparison, the sample size of patients on renal dialysis was small to draw conclusions thereby requiring a further study with larger sample size.