Discussion
These analyses demonstrate that retinopathy is common and present in approximately half of a group of patients with type 2 diabetes mellitus, moderate anemia, and moderate to severe CKD. In TREAT, nearly 30% of patients had advanced diabetic retinopathy as assessed by a history of laser photocoagulation, higher than the 15% found in the RIACE cohort,15 but still lower than the prevalence in patients with type 1 diabetes.16 Similar to prior cohorts of patients with type 2 diabetes,15 ,17 we found that when present, retinopathy identified patients who were younger had a longer known duration of diabetes, worse glycemic control, more insulin use, and a higher prevalence of hypertension. Diabetes is a systemic disease, and as expected from the baseline characteristics, individuals with retinopathy also had higher rates of all other microvascular complications including not only nephropathy but also neuropathy.
Several studies have found diabetic retinopathy to be associated with mortality and incident CV disease in patients with type 2 diabetes mellitus.2–7 In a recent analysis of the ACCORD trial, Gerstein et al4 demonstrated a positive relationship between baseline severity of retinopathy and incident CV events. The relationship persisted after adjustment for prior CV disease, HbA1c, systolic blood pressure, and several other baseline variables; however, neither renal function nor proteinuria was included in their model. Only a few of the prior studies took proteinuria into account in their multivariable models and none corrected for eGFR.5–7 Our data, incorporating these factors, do not confirm the prior findings, and suggest that adjustment for renal complications would explain much of the contribution from retinopathy in those prior studies.
Although retinopathy was associated with a higher likelihood of the development of the renal composite endpoint and ESRD in unadjusted analyses, once the baseline eGFR, urine protein/creatinine ratio, blood pressure, and diabetes severity were accounted for, this was no longer the case. This finding was consistent with the results of an analysis from the RENAAL trial, which also showed that individuals with retinopathy had a similar risk of progressing to ESRD or death that was mitigated by the addition of proteinuria and eGFR in multivariate analysis.18 Neither retinopathy nor laser photocoagulation as a marker of advanced disease was independently associated with a higher risk of renal morbidity or mortality in TREAT. Future studies such as DIACORE,19 a prospective cohort study of 6000 patients with type 2 diabetes mellitus for incident microvascular and macrovascular complications with a focus on renal events, should help to further elucidate the relationship between retinopathy and the development of ESRD in type 2 diabetes.
In a subset of patients who had cardiac biomarker analysis, we found that significantly more patients with retinopathy had detectable troponin levels than those without retinopathy, though there was no difference seen in NT-proBNP. This finding is hypothesis generating, and the increase in TnT in patients with retinopathy may be related to changes in cardiac structure and function, as Aguilar et al20 have shown that more severe diabetic retinopathy is associated with increased left ventricular mass, and lower left ventricular ejection fraction. Alternatively, elevations in cardiac biomarkers have also been shown to increase in relation to proteinuria, and may reflect systemic factors associated with CKD progression and a shared progression of CV and renal disease.13
The strengths of this study include the large number of participants and events and the masked endpoint adjudication process. There were 668 patients who progressed to ESRD in TREAT over the 2.4 years of follow-up. A limitation of this analysis is the presumably mixed etiology of CKD in TREAT; however, 64% of TREAT patients had proteinuria (>200 mg/g) and prior work has shown that the presence of albuminuria is associated with biopsy-proven diabetic glomerulosclerosis in 77% of cases.21 In addition, the presence of diabetic retinopathy in patients with albuminuria strongly suggests that diabetic glomerulopathy is the cause of albuminuria.21 ,22 We cannot make assumptions about the homogeneity of renal disease in TREAT. The investigator report of retinopathy status and a history of laser therapy, rather than the use of retinal photography, is another limitation of this analysis. The discrimination of the etiology of retinopathy is limited as well. However, the physician report was internally consistent with trends in other microvascular complications, and the 47% prevalence was similar to the 49% prevalence reported in the CRIC study of patients with type 2 diabetes mellitus and CKD that based the diagnosis on retinal photography.23 ,24 The potential for residual confounding due to an unmeasured covariate is also a limitation, though we selected variables to best fit a parsimonious model that is reflective of our clinical judgment and the statistical evidence. Because this is a selected population of patients with type 2 diabetes mellitus who have moderate to severe renal dysfunction and anemia, the results may not be applicable to other populations such as those with type 1 diabetes mellitus or less severe CKD.
In summary, retinopathy identified a group of patients who were younger, yet had a longer known duration of diabetes with worse glycemic control and higher rates of insulin use. Although it is common and the leading cause of blindness in the developed world, the presence of retinopathy in patients with type 2 diabetes mellitus, moderate to severe CKD, and anemia did not provide additional prognostic information about CV or renal events after taking into consideration baseline renal function/status.