Our results confirm and expand, with longer follow-up, previously published findings by the FinnDiane group[8
] demonstrating that in the absence of renal disease, individuals with type 1 diabetes experience mortality rates similar to those in the general population. Thus, although the risk of death among participants with normoalbuminuria at study entry was twice the risk of death in the age- and sex-matched general population after 20 years of follow-up, restricting analyses to individuals maintaining normoalbuminuria throughout the duration of the study produced mortality rates not dissimilar to those in the general population. Correspondingly, a much greater proportion of deaths was due to non-diabetes related causes among deceased who had remained normoalbuminuric, whereas individuals with renal disease died primarily from acute and chronic diabetes complications.
It has long been known that the development of overt nephropathy in type 1 diabetes bears excess mortality risk,[17
] although the importance of microalbuminuria has been less clear, both because of its often transient nature and also because its sensitivity in identifying those at risk of progressive renal function loss in diabetes has been questioned.[20
] Nevertheless, we have previously shown that although moderately decreased estimated renal function (e.g., glomerular filtration rate) can occur in type 1 diabetes in the absence of preceding or concurrent albuminuria, this event is rare, particularly when the Cockcroft-Gault formula is used as opposed to the Modification of Diet in Renal Disease (MDRD) study formula to estimate renal function.[23
] Moreover, the importance of microalbuminuria was further emphasized in a recent analysis of risk factors for major outcomes of type 1 diabetes, comprising the aggregate of coronary artery disease, renal failure and diabetes-related death, where it emerged as the single best predictor from all individual measures studied, including HbA1
] In the present report, the presence of albuminuria at study entry was associated with an increased risk of mortality during follow-up. Indeed, mortality risk increased linearly with worsening of albuminuria, reaching, among those with ESRD, 30 times the mortality observed in the age- and sex-matched general population.
Considerable focus has been placed on the search for potential mechanisms linking renal disease with excess mortality in diabetes and a large body of literature has addressed the association between renal and cardiovascular disease. However, although renal damage (albuminuria) is a risk factor for cardiovascular outcomes, whether this relationship can be attributed to abnormalities caused by renal disease leading to atherosclerosis, or simply worsening of known cardiovascular risk factors is unclear.[24
] In addition, a further potential mechanism may reflect the “common soil” hypothesis, i.e. both renal and cardiovascular states result from the same predisposing factor. In fact, insulin resistance has been proposed as one such factor underlying both renal and cardiovascular complications,[25
] and thus, could potentially explain much of the link between renal and cardiovascular outcomes. Nonetheless, we have previously shown that overt nephropathy is a strong independent risk factor for incident “hard” CAD events (but not total CAD), even after allowing for standard risk factors including lipid and blood pressure levels as well as a measure of insulin resistance.[25
Of particular note is the finding that the vast majority of deaths in the renal disease group (93%) were related to diabetes, whereas nearly half of the deaths in those without renal disease were clearly not associated with diabetes at all. It should be stressed that these cause of death classifications were made before these analyses were conceived and performed and thus no potential bias exists. However, half the deaths in the normoalbuminuric group appear to be diabetes related (i.e., acute and chronic diabetes complications). We thus cannot totally exclude a minor increased mortality risk in the absence of renal disease, although any such increase is likely to be very small. Interestingly, two of the seven “diabetes-related” deaths in the NA group had significant concomitant conditions (alcohol abuse and asthma).
Although these results, along with the recently published findings from the FinnDiane study,[8
] are encouraging and suggest that prevention of kidney disease virtually eliminates the excess mortality associated with this diabetes type, analyses of complication rates over time within the EDC study demonstrate that still much work has to be done in preventing renal disease. For while ESRD has declined dramatically and a declining trend in the incidence of overt nephropathy was also noted, this latter improvement was lost with longer follow-up, suggesting that advanced renal disease incidence is merely being delayed, not prevented.[27
] In addition, CAD event rates have also not shown a fall after 30 years of follow-up,[27
] although a recent comparative analysis of the DCCT and EDC cohorts suggest that intensive therapy may reduce 30 year cardiovascular disease incidence.[28
] Considerable effort should then be aimed at the control of modifiable risk factors, including hyperglycemia, dyslipidemia, and hypertension.
The EDC study has several strengths for evaluating the relationship between renal disease and mortality, including its prospective design with biennial examinations to assess albuminuria status, its long-term follow-up to ascertain mortality, and its detailed classification of cause of death, including death certificates, autopsy and hospital records and review by an expert committee, using a standardized protocol to determine the primary cause of death and to rank contributory causes.[17
] Ascertainment of numerous relevant demographic and clinical variables also allowed us to incorporate these into our analysis to minimize confounding. The longitudinal nature of the data also allows the assessment of the effect of progression from normoalbuminuria to renal disease on mortality. Renal disease classifications were based on multiple samples (and confirmed by persistence or progression at the next examination) using identical protocols throughout the study period. Our data are remarkably consistent with those previously published from the FinnDiane study, thus strengthening the overall validity, particularly given the different socioeconomic and healthcare backgrounds from which both cohorts derive.[8
However, this study is not without limitations. Our cohort is hospital-based; however, a comparison of the EDC population with the Allegheny County type 1 diabetes registry found the EDC cohort to be epidemiologically representative of the local type 1 diabetes population.[11
] Also, the EDC population consists of individuals with long-standing diabetes. Thus, these data partially reflect outdated diabetes management and care, and may not be generalizable to individuals recently diagnosed with type 1 diabetes, whose experience may more closely resemble that of the DCCT intensive therapy cohort, as recently described.[28
In conclusion, our results demonstrate that in long-term follow-up, renal disease, including persistent microalbuminuria, is a key determinant of long-term excess mortality in type 1 diabetes, but that individuals with type 1 diabetes who avoid renal disease appear to achieve long-term mortality similar to, or only marginally higher, than seen in the general population. These results and those of the FinnDiane study should help focus attention on the identification of those at risk of microalbuminuria[31
] and the development of appropriate prevention strategies.