Background

The incidence and temporal trends of moderate and severe albuminuria during recent decades are poorly described in type 1 diabetes. We aimed to assess diabetes duration-specific incidence rates, cumulative incidence, and secular trends of albuminuria in type 1 diabetes in Finland.

Methods

We conducted a population-based, retrospective cohort study of a stratified random sample (n=1500) of all individuals diagnosed with type 1 diabetes before age 15 years during 1970–99 in Finland. The sampling frame was the database of the Finnish Institute for Health and Welfare. Individuals with an atypical clinical course, presentation of non-diabetic kidney disease, insufficient albumin excretion rate measurements, or unavailable medical records were excluded (final sample n=1430). Study participants were followed up until death, the event of interest (moderate or severe albuminuria or kidney failure), or the most recent event-free date. Medical records retrieved up to Dec 31, 2020 were systematically reviewed for albuminuria determinations. Moderate and severe albuminuria were categorised on the basis of international reference limits (two of three consecutive urine samples). Kidney failure was defined as dialysis treatment or kidney transplant. Cohorts defined by calendar year of diabetes diagnosis (1970–79, 1980–89, and 1990–99) were assessed. Patterns of duration-specific incidences were evaluated by fitting generalised additive models to the data, which were split into multiple observations of half-year duration. Cumulative incidences were calculated with Kaplan-Meier analysis. In analyses with kidney failure as the endpoint, competing risk for mortality was incorporated.

Findings

In our stratified random sample, 462 individuals were diagnosed with diabetes in 1970–79, 481 were diagnosed in 1980–89, and 487 were diagnosed in 1990–99. The incidence rate pattern of severe albuminuria changed over time; a peak at 15–19 years since diabetes onset in the 1970–79 cohort was not replicated in those diagnosed later. In the combined 1980–99 diagnosis-year cohorts, the incidence rate rose during the first 14 years after diabetes onset, after which it levelled off to a plateau. Between the 1970–79 and 1980–89 diabetes diagnosis cohorts, the cumulative incidence of severe albuminuria had approximately halved (hazard ratio [HR] 0·55 [95% CI 0·42–0·72] with the 1970–79 cohort as reference, p<0·0001), whereas, between the 1980–89 and 1990–99 cohorts, no further decrease was observed (HR 0·83 [0·54–1·26] with the 1980–89 cohort as reference, p=0·38). The 25-year cumulative incidence for severe albuminuria was 26·8% (22·6–30·8) in the 1970–79 diagnosis cohort, 12·0% (9·0–15·0) in the 1980–89 cohort, and 10·8% (6·7–14·6) in the 1990–99 cohort. 15 years after onset of severe albuminuria, cumulative progression rate from severe albuminuria to kidney failure was 35·2% (27·4–43·0) in the 1970–79 cohort and 35·6% (24·3–47·0) in the 1980–99 cohorts combined (Gray's test p=0·37). In the cohorts with data on moderate albuminuria (1980–89 and 1990–99), cumulative incidence of moderate albuminuria showed no calendar effect between the earlier and later cohorts (HR 0·99 [0·78–1·28] with the 1980–89 cohort as reference, p=0·97). The incidence rate of moderate albuminuria increased until 10 years after diabetes onset, then remained mostly stable until starting to decrease at around 25 years after diabetes onset.

Interpretation

Our analyses show that the cumulative incidence of severe albuminuria has decreased between 1970–79 and 1980–99; however, whether this decrease solely denotes a delay in albuminuria, or also a true prevention of albuminuria, needs to be investigated further. Nevertheless, diabetic kidney disease remains a significant complication of type 1 diabetes. Due to the robust association of diabetic kidney disease with premature mortality, novel therapies to improve prognosis are needed.

Funding

Folkhälsan Research Foundation, Medical Society of Finland, Wilhelm and Else Stockmann Foundation, Finnish Diabetes Research Foundation, Waldemar von Frenckell Foundation, Liv och Hälsa Society, Academy of Finland, and Novo Nordisk Foundation.

Translations

For the Finnish and Swedish translations of the abstract see Supplementary Materials section.

中文翻译：

---

0-14 岁被诊断患有 1 型糖尿病的个体中度和重度蛋白尿的发病率模式、累积发病率和时间趋势：一项基于人群的回顾性队列研究

背景

近几十年来中度和重度蛋白尿的发生率和时间趋势在 1 型糖尿病中的描述很少。我们的目的是评估芬兰 1 型糖尿病患者的糖尿病病程特异性发病率、累积发病率和白蛋白尿的长期趋势。

方法

我们对 1970-99 年间在芬兰 15 岁之前诊断出患有 1 型糖尿病的所有个体的分层随机样本 (n=1500) 进行了一项基于人群的回顾性队列研究。抽样框架是芬兰健康和福利研究所的数据库。具有非典型临床过程、非糖尿病肾病表现、白蛋白排泄率测量不足或无法获得医疗记录的个体被排除在外（最终样本 n = 1430）。研究参与者被随访直至死亡、感兴趣的事件（中度或重度白蛋白尿或肾衰竭）或最近的无事件日期。对截至 2020 年 12 月 31 日检索到的病历进行了系统的审查，以测定白蛋白尿。根据国际参考限值（三个连续尿样中的两个）对中度和重度蛋白尿进行分类。肾衰竭被定义为透析治疗或肾移植。评估了按糖尿病诊断日历年（1970-79、1980-89 和 1990-99）定义的队列。通过将广义加性模型拟合到数据来评估持续时间特定发生率的模式，这些数据被分成半年持续时间的多个观察值。使用 Kaplan-Meier 分析计算累积发生率。在以肾衰竭为终点的分析中，纳入了死亡的竞争风险。通过将广义加性模型拟合到数据来评估持续时间特定发生率的模式，这些数据被分成半年持续时间的多个观察值。使用 Kaplan-Meier 分析计算累积发生率。在以肾衰竭为终点的分析中，纳入了死亡的竞争风险。通过将广义加性模型拟合到数据来评估持续时间特定发生率的模式，这些数据被分成半年持续时间的多个观察值。使用 Kaplan-Meier 分析计算累积发生率。在以肾衰竭为终点的分析中，纳入了死亡的竞争风险。

发现

在我们的分层随机样本中，1970-79 年有 462 人被诊断出患有糖尿病，1980-89 年有 481 人被诊断出患有糖尿病，1990-99 年有 487 人被诊断出患有糖尿病。严重蛋白尿的发病率模式随时间发生变化；1970-79 年队列中糖尿病发病后 15-19 年的峰值并未在后来诊断的人群中重现。在 1980-99 诊断年合并队列中，发病率在糖尿病发病后的前 14 年内上升，之后趋于平稳。在 1970-79 和 1980-89 糖尿病诊断队列之间，严重白蛋白尿的累积发生率大约减半（风险比 [HR] 0·55 [95% CI 0·42-0·72]，1970-79 队列为参考，p<0·0001)，而在 1980-89 和 1990-99 队列之间，未观察到进一步下降（HR 0·83 [0·54–1·26]，以 1980–89 队列为参考，p=0·38）。严重白蛋白尿的 25 年累积发生率在 1970-79 诊断队列中为 26·8% (22·6–30·8)，在 1980–89 队列中为 12·0% (9·0–15·0) , 和 10·8% (6·7–14·6) 在 1990–99 队列中。严重白蛋白尿发作 15 年后，从严重白蛋白尿到肾衰竭的累积进展率在 1970-79 队列中为 35·2% (27·4–43·0)，在 1970–79 队列中为 35·6% (24·3–47·0) ) 在 1980–99 年的队列中合并（格雷检验 p=0·37）。在有中度白蛋白尿数据的队列中（1980-89 和 1990-99），中度白蛋白尿的累积发生率在较早和较晚的队列之间没有日历效应（HR 0·99 [0·78–1·28] 与 1980 –89 队列作为参考，p=0·97)。

解释

我们的分析表明，严重蛋白尿的累积发病率在 1970-79 年和 1980-99 年间有所下降；然而，这种减少是否仅表示白蛋白尿的延迟，或真正预防白蛋白尿，需要进一步研究。然而，糖尿病肾病仍然是 1 型糖尿病的重要并发症。由于糖尿病肾病与过早死亡密切相关，因此需要新的疗法来改善预后。

资金

Folkhälsan 研究基金会、芬兰医学会、Wilhelm 和 Else Stockmann 基金会、芬兰糖尿病研究基金会、Waldemar von Frenckell 基金会、Liv och Hälsa 协会、芬兰科学院和诺和诺德基金会。

翻译

有关摘要的芬兰语和瑞典语翻译，请参阅补充材料部分。