Diabeteksen munuaistaudin ilmaantuvuus, progressio ja regressio tyypin 1 diabeteksessa

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.Viimeisten vuosikymmenien aikana tyypin 1 diabeteksen hoitostrategiat ovat parantuneet. Tästä huolimatta tautia sairastavia henkilöitä kuormittaa edelleen lisääntynyt ennenaikaisen kuolleisuuden riski, etenkin riski kuolla kardiovaskulaaritauteihin. Kohonneesta riskistä kertovat erityisesti diabeteksen munuaistaudin esiintyminen ja sen vaikeusaste. Diabeteksen munuaistaudin ennustetaan kehittyvän joka kolmannelle tyypin 1 diabetesta sairastavalle henkilölle, mutta nykyinen taudin tyypillinen kulku ei ole täysin selvä. Tämän väitöskirjan tavoitteena oli siten selvittää kokonaiskuva diabeteksen munuaistaudin ilmaantuvuudesta, progressiosta ja regressiosta. Tutkimme lisääntyneen ja selvästi lisääntyneen albuminurian (diabeteksen munuaistaudin ensimmäisten kliinisten vaiheiden) ilmaantuvuuskuvioita, kumulatiivisia ilmaantuvuuksia sekä ajallisia trendejä väestöpohjaisessa tutkimuksessa. Tutkimuskohortti koostui ositetusta satunnaisotoksesta (n=1500) kaikista tyypin 1 diabetekseen 0-14 vuoden iässä sairastuneista henkilöistä vuosina 1970-99 Suomessa. Tutkimme eroja kolmen kohortin välillä, jotka oli määritelty diabetesdiagnoosin kalenterivuoden mukaan (1970-79, 1980-89 ja 1990-99). Albuminurian progressiota ja regressiota arvioitiin valtakunnallisessa Finnish Diabetic Nephropahy (FinnDiane) Study -monikeskustutkimuksessa. Diabeteksen munuaistaudin progressiota tutkittiin tarkastellen jäännöskolesterolia ja apolipoproteiini C-III:a (apoC-III), jotka ovat triglyseridirikkaiden lipoproteiinien aineenvaihdunnan keskeisiä osatekijöitä. Albuminurian regressio määriteltiin munuaistaudin luokituksen palaamisena vähemmän edenneelle tasolle ennen FinnDianen ensimmäistä tutkimuskäyntiä. Tutkimme regression ja kardiovaskulaaritapahtumien sekä kuolleisuuden välistä yhteyttä. Tutkimuksessa havaittiin, että selvästi lisääntyneen albuminurian ilmaantumistiheys diabeteksen keston suhteen oli muuttunut ajan saatossa; 1970-79-kohortissa todettiin ilmaantuvuushuippu 15-19 vuoden kohdalla diabeteksen puhkeamisesta, mutta tämä huippu ei enää ollut havaittavissa myöhemmin diagnosoiduilla. Selvästi lisääntyneen albuminurian kumulatiivinen ilmaantuvuus puolittui diagnoosikohorttien 1970-79 ja 1980-89 välillä, kun taas 1980-89 ja 1990-99 välillä ei ollut todettavissa muutosta. Myöskään lisääntyneen albuminurian kumulatiivinen ilmaantuvuus ei osoittanut merkkejä kalenterivaikutuksesta vuosien 1980-89 ja 1990-99 välillä. Lisääntyneen albuminurian ilmaantuvuus nousi 10 vuoden ajan pysyen sen jälkeen vakaana, kunnes se alkoi laskea noin 25 vuoden kohdalla diabeteksen puhkeamisesta. Albuminurian regressioaste FinnDiane-kohortissa oli 23 %. Albuminurian regressioon liittyi kardiovaskulaaritapahtumien riskin sekä kuolleisuuden riskin lasku vähemmän edenneen munuaistaudin luokitusta vastaavalle tasolle. Jäännöskolesterolin pitoisuus liittyi vahvasti munuaistaudin etenemiseen. ApoC-III:n pitoisuus oli lähinnä yhteydessä lisääntyneen albuminurian progressioon, mutta tämäkään yhteys ei ollut riippumaton jäännöskolesterolista. Yhteenvetona voidaan todeta, että albuminurian ilmaantuvuus on vähentynyt ajan saatossa, mutta lasku on tasaantunut 1980-luvun jälkeen. Näin ollen munuaistauti on edelleen merkittävä riski tyypin 1 diabeteksessa. Albuminurian regressio on yleistä ja tähän liittyy parantunut kokonaisennuste. Triglyseridirikkaiden lipoproteiinien metabolia näyttää olevan osallisena diabeteksen munuaistaudissa tyypin 1 diabeteksessa. ApoC-III saattaa vaikuttaa taudin etenemiseen jäännöskolesterolin kautta

Incidence rate patterns, cumulative incidence, and time trends for moderate and severe albuminuria in individuals diagnosed with type 1 diabetes aged 0-14 years : a population-based retrospective cohort study

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 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. Copyright (C) 2022 Elsevier Ltd. All rights reserved.Peer reviewe

Apolipoprotein C-III predicts cardiovascular events and mortality in individuals with type 1 diabetes and albuminuria

Publisher Copyright: © 2021 The Association for the Publication of the Journal of Internal MedicineObjectives: We studied apolipoprotein C-III (apoC-III) in relation to diabetic kidney disease (DKD), cardiovascular outcomes, and mortality in type 1 diabetes. Methods: The cohort comprised 3966 participants from the prospective observational Finnish Diabetic Nephropathy Study. Progression of DKD was determined from medical records. A major adverse cardiac event (MACE) was defined as acute myocardial infarction, coronary revascularization, stroke, or cardiovascular mortality through 2017. Cardiovascular and mortality data were retrieved from national registries. Results: ApoC-III predicted DKD progression independent of sex, diabetes duration, blood pressure, HbA1c, smoking, LDL-cholesterol, lipid-lowering medication, DKD category, and remnant cholesterol (hazard ratio [HR] 1.43 [95% confidence interval 1.05–1.94], p = 0.02). ApoC-III also predicted the MACE in a multivariable regression analysis; however, it was not independent of remnant cholesterol (HR 1.05 [0.81–1.36, p = 0.71] with remnant cholesterol; 1.30 [1.03–1.64, p = 0.03] without). DKD-specific analyses revealed that the association was driven by individuals with albuminuria, as no link between apoC-III and the outcome was observed in the normal albumin excretion or kidney failure categories. The same was observed for mortality: Individuals with albuminuria had an adjusted HR of 1.49 (1.03–2.16, p = 0.03) for premature death, while no association was found in the other groups. The highest apoC-III quartile displayed a markedly higher risk of MACE and death than the lower quartiles; however, this nonlinear relationship flattened after adjustment. Conclusions: The impact of apoC-III on MACE risk and mortality is restricted to those with albuminuria among individuals with type 1 diabetes. This study also revealed that apoC-III predicts DKD progression, independent of the initial DKD category.Peer reviewe

The pattern-recognition molecule H-ficolin in relation to diabetic kidney disease, mortality, and cardiovascular events in type 1 diabetes

H-ficolin recognizes patterns on microorganisms and stressed cells and can activate the lectin pathway of the complement system. We aimed to assess H-ficolin in relation to the progression of diabetic kidney disease (DKD), all-cause mortality, diabetes-related mortality, and cardiovascular events. Event rates per 10-unit H-ficolin-increase were compared in an observational follow-up of 2,410 individuals with type 1 diabetes from the FinnDiane Study. DKD progression occurred in 400 individuals. The unadjusted hazard ratio (HR) for progression was 1.29 (1.18-1.40) and 1.16 (1.05-1.29) after adjustment for diabetes duration, sex, HbA(1c), systolic blood pressure, and smoking status. After adding triglycerides to the model, the HR decreased to 1.07 (0.97-1.18). In all, 486 individuals died, including 268 deaths of cardiovascular causes and 192 deaths of complications to diabetes. HRs for all-cause mortality and cardiovascular mortality were 1.13 (1.04-1.22) and 1.05 (0.93-1.17), respectively, in unadjusted analyses. These estimates lost statistical significance in adjusted models. However, the unadjusted HR for diabetes-related mortality was 1.19 (1.05-1.35) and 1.18 (1.02-1.37) with the most stringent adjustment level. Our results, therefore, indicate that H-ficolin predicts diabetes-related mortality, but neither all-cause mortality nor fatal/non-fatal cardiovascular events. Furthermore, H-ficolin is associated with DKD progression, however, not independently of the fully adjusted model.Peer reviewe

Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations

Background: Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits. Methods: We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy. Results: The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10-8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10-4), apolipoprotein B (p=5.6×10-4), and LDL cholesterol (p=9.5×10-4) concentrations. Conclusions: We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD. Keywords: APOB; Apolipoprotein A1; Apolipoprotein C-III; GTF3C5; LIPC; Lipidomics; MARCHF10; RBM47; RYR3; Whole-exome sequencing.Peer reviewe

Progression and regression of kidney disease in type 1 diabetes

Peer reviewe

Higher HbA(1c) variability is associated with increased arterial stiffness in individuals with type 1 diabetes

Correction: Volume22, Issue1 Article Number: 83 DOI: 10.1186/s12933-023-01813-8 Published:APR 8 2023Peer reviewe

Prognosis after first-ever myocardial infarction in type 1 diabetes is strongly affected by chronic kidney disease

     Objective: To study the prognosis after a first-ever myocardial infarction (MI) in type 1 diabetes, as well as how different MI- and diabetes-related factors affect the prognosis and risk of secondary cardiovascular events.  Research Design and Methods: Observational follow-up study of 4,217 individuals from the Finnish Diabetic Nephropathy Study with no prior MI or coronary revascularization. We verified 253 (6.0%) MIs from medical records or death certificates. Mortality from cardiovascular or diabetes-related cause was our main endpoint, while hospitalization due to heart failure, coronary revascularization, and recurrent MI were secondary endpoints, while accounting for death as a competing risk. Results: Of the individuals, 187 (73.9%) died during the median post-MI follow-up of 3.07 (IQR 0.02–8.45) years. Independent risk factors for cardiovascular and diabetes-related mortality were eGFR categories G3 (hazard ratio, HR 3.27 [confidence interval 1.76–6.08]), G4 (3.62 [1.69–7.73]), and G5 (4.03 [2.24–7.26]), prior coronary heart disease diagnosis (1.50 [1.03–2.20]), and older age at MI (1.03 [1.00–1.05]). Factors associated with lower mortality were acute revascularization (HR 0.35 [0.18–0.72]), and subacute revascularization (0.39 [0.26–0.59]). In Fine-Gray competing-risk analyses, kidney failure was associated with a higher risk of recurrent MI (subdistribution hazard ratio 3.27 [2.01–5.34]), heart failure (3.76 [2.46–5.76]), and coronary revascularization (3.04 [1.89–4.90]). Conclusions: Individuals with type 1 diabetes have a high cardiovascular and diabetes-related mortality after their first-ever MI. Particularly poor kidney function is associated with high mortality and excessive risk of secondary cardiovascular events. </p