Incidence, progression, and regression of diabetic kidney disease in type 1 diabetes

Despite improved treatment strategies during the past decades, individuals with type 1 diabetes remain burdened with an increased risk of premature mortality, especially due to cardiovascular causes of death. The presence and severity of diabetic kidney disease (DKD) is a main driver of the risk. DKD is predicted to affect every third individual with type 1 diabetes; however, the contemporary natural history of DKD has been poorly described. Therefore, the aim of this doctoral thesis was to obtain a holistic view of the incidence, progression, and regression of DKD. We studied incidence rate patterns, cumulative incidences, and time trends for moderate and severe albuminuria (the first clinical stages of DKD) using a population-based study design. The cohort encompassed a stratified random sample (n=1,500) of all individuals diagnosed with type 1 diabetes at the age of 0-14 years during 1970-99 in Finland. Differences between three cohorts defined by the calendar year of diabetes diagnosis (1970-79, 1980-89, 1990-99) were assessed. Progression and regression of albuminuria were studied in the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) Study. The DKD progression was assessed in light of remnant cholesterol and apolipoprotein C-III (apoC-III), both key components of the triglyceride-rich lipoprotein metabolism. Regression of albuminuria was defined as a change to a less advanced stage of albuminuria before the FinnDiane baseline visit. We investigated the association between regression and incident cardiovascular events and mortality. We found that the diabetes duration-specific incidence rate pattern of severe albuminuria had changed over time; the incidence peak noted at 15-19 years of diabetes duration in the 1970-79 diagnosis cohort was not replicated in those diagnosed later. The cumulative incidence of severe albuminuria had approximately halved between the 1970-79 and 1980-89 cohorts, but no further decrease was noticed between 1980-89 and 1990-99. The incidence rate of moderate albuminuria increased until 10 years after diabetes onset, then remained stable until starting to decrease at around 25 years of duration. No signs of a calendar effect for moderate albuminuria between 1980-89 and 1990-99 appeared. The albuminuria regression rate was 23%, independent of the initial DKD stage. Regression of albuminuria was associated with reduced risk of cardiovascular events and mortality to the same level of those who did not progress in the first place. Remnant cholesterol was robustly associated with DKD progression. ApoC-III was primarily associated with the progression from moderate to severe albuminuria; however, not independent of remnant cholesterol. This thesis concludes that the incidence of albuminuria has decreased over time but has plateaued after the 1980s; hence, a substantial residual burden of DKD in type 1 diabetes remains. Regression of albuminuria is a frequent phenomenon, and it is associated with an overall improved prognosis. The triglyceride-rich lipoprotein metabolism appears to be implicated in the development and progression of DKD, with remnant cholesterol possibly mediating the effects of apoC-III.