Browsing by Subject "NEPHROPATHY"

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  • van Zuydam, Natalie R.; Ahlqvist, Emma; Sandholm, Niina; Deshmukh, Harshal; Rayner, N. William; Abdalla, Moustafa; Ladenvall, Claes; Ziemek, Daniel; Fauman, Eric; Robertson, Neil R.; McKeigue, Paul M.; Valo, Erkka; Forsblom, Carol; Harjutsalo, Valma; Perna, Annalisa; Rurali, Erica; Marcovecchio, M. Loredana; Igo, Robert P.; Salem, Rany M.; Perico, Norberto; Lajer, Maria; Karajamak, Annemari; Imamura, Minako; Kubo, Michiaki; Takahashi, Atsushi; Sim, Xueling; Liu, Jianjun; van Dam, Rob M.; Jiang, Guozhi; Tam, Claudia H. T.; Luk, Andrea O. Y.; Lee, Heung Man; Lim, Cadmon K. P.; Szeto, Cheuk Chun; So, Wing Yee; Chan, Juliana C. N.; Ang, Su Fen; Dorajoo, Rajkumar; Wang, Ling; Clara, Tan Si Hua; McKnight, Amy-Jayne; Duffy, Seamus; Pezzolesi, Marcus G.; Marre, Michel; Gyorgy, Beata; Hadjadj, Samy; Hiraki, Linda T.; Tuomi, Tiinamaija; Groop, Per-Henrik; Groop, Leif C. (2018)
    dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
  • Surrogate Markers Micro-Macro-Vasc (2018)
    Purpose Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. Methods Results A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 x 10(-9). Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 x 10(-8) and 1.23 x 10(-8), respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429). Conclusion This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.
  • Limonte, Christine P.; Valo, Erkka; Montemayor, Daniel; Afshinnia, Farsad; Ahluwalia, Tarunveer S.; Costacou, Tina; Darshi, Manjula; Forsblom, Carol; Hoofnagle, Andrew N.; Groop, Per-Henrik; Miller, Rachel G.; Orchard, Trevor J.; Pennathur, Subramaniam; Rossing, Peter; Sandholm, Niina; Snell-Bergeon, Janet K.; Ye, Hongping; Zhang, Jing; Natarajan, Loki; de Boer, Ian H.; Sharma, Kumar (2020)
    Background: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict. Methods: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of >= 3 and
  • Harjutsalo, Valma; Maric-Bilkan, Christine; Forsblom, Carol; Groop, Per-Henrik; FinnDiane Study Grp (2016)
    Aims/hypothesis The aim of this study was to evaluate the relationship among age at onset of diabetes, age at onset of menarche and risk of diabetic nephropathy and laser-treated retinopathy in type 1 diabetes. Methods Data related to age at menarche were collected through questionnaires and were available for 1,304 women who participated in the Finnish Diabetic Nephropathy Study (FinnDiane). A possible association between age at menarche and diabetic nephropathy and retinopathy was investigated. Results There was an inverse relationship between the age at onset of diabetes and age at menarche: the younger the age at onset of diabetes, the higher the age at menarche (p <0.0001). A non-linear relationship between the age of menarche and risk of diabetic microvascular complications was found in patients with diabetes onset before menarche, but there was no such association in patients with diabetes onset after menarche. Women with delayed menarche (> mean age+ 2 years) had a 2.30 (95% CI 1.27, 4.17; p <0.006) times higher risk of nephropathy compared with the women who underwent menarche at the mean age +/- 2 years. Delayed menarche also increased the risk of retinopathy (OR 2.34 [95% CI 1.36, 4.01]). After excluding patients with nephropathy, the OR for retinopathy was 2.11 (95% CI 1.15, 3.90). Earlier menarche (<mean age-2 years) did not have any effect on this risk. Conclusions/interpretation Delayed menarche was associated with an increased risk of diabetic nephropathy and retinopathy, whereas early menarche was not. Delayed menarche may be used as a new tool to identify women at risk of diabetic microvascular complications.
  • Finndiane Study Grp (2018)
    Aims/hypothesis This study aimed to assess the use of ambulatory BP monitoring (ABPM) to identify the presence of masked, nocturnal and white-coat hypertension in individuals with type 1 diabetes, patterns that could not be detected by regular office-based BP monitoring alone. We also analysed associations between BP patterns and arterial stiffness in order to identify individuals at cardiovascular risk. Methods This substudy included 140 individuals with type 1 diabetes from the Helsinki metropolitan area, who attended the Finnish Diabetic Nephropathy Study (FinnDiane) Centre in Helsinki between January 2013 and August 2017. Twenty-four hour ABPM and pulse wave analysis were performed simultaneously using a validated non-invasive brachial oscillometric device (Mobil-O-Graph). Definitions of hypertension were based on the European Society of Hypertension guidelines. Masked hypertension was defined as normal office BP (BP obtained using a standardised automated BP device) but elevated 24 h ABPM, and white-coat hypertension as elevated office BP but normal 24 h ABPM. Results A total of 38% of individuals were normotensive and 33% had sustained hypertension, while 23% had masked and 6% had white-coat hypertension. About half of the cohort had increased absolute levels of night-time BP, half of whom were untreated. In the ambulatory setting, central BP and pulse wave velocity (PWV) were higher in participants with masked hypertension than in those with normotension (p <0.001). In a multivariable linear regression model adjusted for age, sex, BMI, antihypertensive treatment and eGFR, masked hypertension was independently associated with higher 24 h PWV ((3 0.50 [95% CI 0.34, 0.66]), but not with PWV obtained during resting conditions (adjusted 13 0.28 [95% CI -0.53, 1.10]), using normotension as the reference group. Conclusions/interpretation ABPM analysis revealed that one-quarter of the participants with type 1 diabetes had masked hypertension; these individuals would not have been detected by office BP alone. Moreover, arterial stiffness was increased in individuals with masked hypertension. These findings support the use of ABPM to identify individuals at risk of cardiovascular disease.
  • Ahola, Aila J.; Saraheimo, Markku; Freese, Riitta; Forsblom, Carol; Mäkimattila, Sari; Groop, Per-Henrik; FinnDiane Study Grp (2017)
    Aims: Inflammation plays an important role in the pathogenesis of cardiovascular diseases. Diet, as a modifiable risk factor, may in turn impact systemic inflammation. We therefore assessed whether adherence to the dietary recommendations is associated with high-sensitivity C-reactive protein (hs-CRP) concentrations in type 1 diabetes. Methods: Cross-sectional data from 677 FinnDiane study participants (48% men, mean +/- standard deviation age 46 +/- 13 years) were included. Dietary intake was assessed with a self-administered questionnaire. A diet score, with higher values denoting better adherence to the recommendations, was calculated. Serum hs-CRP concentration was measured, and individuals with hs-CRP <1.0 mg/l, and hs-CRP > 3.0 but <10.0 mg/l were compared. Results: Men and women with high hs-CRP had higher BMI, waist circumference, and triglyceride concentration, but lower HDL-cholesterol concentration. Adjusted for BMI, mean diet score was higher in the low hs-CRP group, both in men (10.8 +/- 3.6 vs. 9.9 +/- 3.8, p = 0.023) and women (12.7 +/- 3.4 vs. 11.6 +/- 3.5, p = 0.021). After further adjustments with potential confounding factors, the difference remained significant only in men. Conclusions: A diet that more closely adheres to the dietary recommendations is associated with lower hs-CRP in men. A prudent diet may help reduce systemic inflammation in type 1 diabetes. (C) 2017 Elsevier B.V. All rights reserved.
  • Finndiane Study Grp (2018)
    Background and aims: In the general population, habitual coffee consumption is inversely associated with the metabolic syndrome, a syndrome that is rather common also in patients with type 1 diabetes. However, whether coffee intake is beneficially related to the metabolic syndrome also in type 1 diabetes, is not known. We, therefore, studied the potential association between coffee consumption and the metabolic syndrome in a large population of individuals with type 1 diabetes. Furthermore, we investigated whether coffee consumption is associated with insulin resistance (estimated glucose disposal rate, eGDR), kidney function (estimated glomerular filtration rate, eGFR), and low-grade chronic inflammation (high-sensitivity C-reactive protein, hsCRP). Methods and results: Data from 1040 participants in the Finnish Diabetic Nephropathy Study were included in these cross-sectional analyses. Metabolic syndrome was assumed if at least 3 of the following cardiovascular risk factors were present: central obesity, high blood pressure, low HDL-cholesterol concentration, high triglyceride concentration, and hyperglycaemia. Subjects were categorized based on self-reported daily coffee intake: non-consumers (= 1 cups/d <3), moderate (>= 3 cups/d <5), and high coffee consumption (>= 5 cups/d). In multivariable logistic regression analysis, moderate and high coffee consumption was associated with increased odds of the metabolic syndrome. Moreover, any level of coffee consumption was associated with increased risk of the blood pressure-component. An increasing trend was observed in the eGFR with increasing coffee consumption. Conclusions: In type 1 diabetes, high coffee intake is associated with the metabolic syndrome, and especially its blood pressure-component. (C) 2018 Published by Elsevier B.V.
  • Finndiane Study Grp; SDRN Type 1 Bioresource Collabora; Colombo, Marco; Valo, Erkka; Sandholm, Niina; Groop, Per-Henrik; Forsblom, Carol; Colhoun, Helen M. (2019)
    Aims/hypothesis We aimed to identify a sparse panel of biomarkers for improving the prediction of renal disease progression in type 1 diabetes. Methods We considered 859 individuals recruited from the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) and 315 individuals from the Finnish Diabetic Nephropathy (FinnDiane) study. All had an entry eGFR between 30 and 75 ml min(-1)[1.73 m](-2), with those from FinnDiane being oversampled for albuminuria. A total of 297 circulating biomarkers (30 proteins, 121 metabolites, 146 tryptic peptides) were measured in non-fasting serum samples using the Luminex platform and LC electrospray tandem MS (LC-MS/MS). We investigated associations with final eGFR adjusted for baseline eGFR and with rapid progression (a loss of more than 3 ml min(-1)[1.73 m](-2) year(-1)) using linear and logistic regression models. Panels of biomarkers were identified using a penalised Bayesian approach, and their performance was evaluated through 10-fold cross-validation and compared with using clinical record data alone. Results For final eGFR, 16 proteins and 30 metabolites or tryptic peptides showed significant association in SDRNT1BIO, and nine proteins and five metabolites or tryptic peptides in FinnDiane, beyond age, sex, diabetes duration, study day eGFR and length of follow-up (all at p <10(-4)). The strongest associations were with CD27 antigen (CD27), kidney injury molecule 1 (KIM-1) and alpha 1-microglobulin. Including the Luminex biomarkers on top of baseline covariates increased the r(2) for prediction of final eGFR from 0.47 to 0.58 in SDRNT1BIO and from 0.33 to 0.48 in FinnDiane. At least 75% of the increment in r(2) was attributable to CD27 and KIM-1. However, using the weighted average of historical eGFR gave similar performance to biomarkers. The LC-MS/MS platform performed less well. Conclusions/interpretation Among a large set of associated biomarkers, a sparse panel of just CD27 and KIM-1 contains most of the predictive information for eGFR progression. The increment in prediction beyond clinical data was modest but potentially useful for oversampling individuals with rapid disease progression into clinical trials, especially where there is little information on prior eGFR trajectories.
  • Finndiane Study Grp; Dahlström, Emma H.; Sandholm, Niina; Forsblom, Carol M.; Thorn, Lena M.; Jansson, Fanny J.; Harjutsalo, Valma; Groop, Per-Henrik (2019)
    Context: The relationship between body mass index (BMI) and mortality may differ between patients with type 1 diabetes and the general population; it is not known which clinical characteristics modify the relationship. Objective: Our aim was to assess the relationship between BMI and mortality and the interaction with clinically meaningful factors. Design, Setting, and Participants: This prospective study included 5836 individuals with type 1 diabetes from the FinnDiane study. Main Outcome Measure and Methods: We retrieved death data for all participants on 31 December 2015. We estimated the effect of BMI on the risk of mortality using a Cox proportional hazards model with BMI as a restricted cubic spline as well as effect modification by adding interaction terms to the spline. Results: During a median of 13.7 years, 876 individuals died. The relationship between baseline BMI and all-cause mortality was reverse J-shaped. When analyses were restricted to those with normal albumin excretion rate, the relationship was U-shaped. The nadir BMI (BMI with the lowest mortality) was in the normal weight region (24.3 to 24.8 kg/m(2)); however, among individuals with diabetic nephropathy, the nadir BMI was in the overweight region (25.9 to 26.1 kg/m(2)). Diabetic nephropathy, diabetes-onset age, and sex modified the relationship between BMI and mortality (P-interaction <0 . 05). Conclusions: Normal weight is optimal for individuals with type 1 diabetes to delay mortality, whereas underweight might be an indication of underlying complications. Maintaining normal weight may translate into reduced risk of mortality in type 1 diabetes, particularly for individuals of male sex, later diabetes-onset age, and normal albumin excretion rate.
  • Finndiane Study Grp; Eriksson, Marika; Summanen, Paula; Gordin, Daniel; Forsblom, Carol; Shams, Sara; Liebkind, Ron; Tatlisumak, Turgut; Putaala, Jukka; Groop, Per-Henrik; Martola, Juha; Thorn, Lena M. (2021)
    Introduction Cerebral small-vessel disease is common in neurologically asymptomatic individuals with type 1 diabetes. The retinal vasculature is thought to mirror the brain's vasculature, but data on this association are limited in type 1 diabetes. Our aim was to study associations between diabetic retinopathy severity and cerebral small-vessel disease in type 1 diabetes. Research design and methods For this cross-sectional study, we enrolled 189 participants with type 1 diabetes (median age 40 (33-45) years; 53% female; diabetes duration 21.6 (18.2-30.7) years) and 29 healthy age-matched and sex-matched controls as part of the Finnish Diabetic Nephropathy Study. Participants underwent a clinical investigation, brain MRI, and fundus imaging. Signs of cerebral small-vessel disease in brain MRIs were analyzed in relation to diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study (ETDRS) score). Results In type 1 diabetes, participants with cerebral small-vessel disease had higher ETDRS scores (35 (20-61) vs 20 (20-35), p=0.022) and a higher prevalence of proliferative diabetic retinopathy than those without cerebral small-vessel disease (25% vs 9%, p=0.002). In adjusted analysis, proliferative diabetic retinopathy was associated with cerebral small-vessel disease (OR 2.57 (95% CI 1.04 to 6.35)). Median ETDRS score (35 (20-65) vs 20 (20-35), p=0.024) and proliferative diabetic retinopathy prevalence were higher (29% vs 13%, p=0.002) in participants with versus without cerebral microbleeds. ETDRS scores increased by number of cerebral microbleeds (p=0.001), both ETDRS score (OR 1.05 (95% CI 1.02 to 1.09)) and proliferative diabetic retinopathy (8.52 (95% CI 1.91 to 37.94)) were associated with >2 cerebral microbleeds in separate multivariable analysis. We observed no association with white matter hyperintensities or lacunar infarcts. Conclusions Presence of cerebral small-vessel disease on brain MRI, particularly cerebral microbleeds, is associated with the severity of diabetic retinopathy.
  • Lithovius, Raija; Toppila, Iiro; Harjutsalo, Valma; Forsblom, Carol; Groop, Per-Henrik; Makinen, Ville-Petteri; FinnDiane Study Grp (2017)
    Aims/hypothesis Previously, we proposed that data-driven metabolic subtypes predict mortality in type 1 diabetes. Here, we analysed new clinical endpoints and revisited the subtypes after 7 years of additional follow-up. Methods Finnish individuals with type 1 diabetes (2059 men and 1924 women, insulin treatment before 35 years of age) were recruited by the national multicentre FinnDiane Study Group. The participants were assigned one of six metabolic subtypes according to a previously published self-organising map from 2008. Subtype-specific all-cause and cardiovascular mortality rates in the FinnDiane cohort were compared with registry data from the entire Finnish population. The rates of incident diabetic kidney disease and cardiovascular endpoints were estimated based on hospital records. Results The advanced kidney disease subtype was associated with the highest incidence of kidney disease progression (67.5% per decade, p <0.001), ischaemic heart disease (26.4% per decade, p <0.001) and all-cause mortality (41.5% per decade, p <0.001). Across all subtypes, mortality rates were lower in women compared with men, but standardised mortality ratios (SMRs) were higher in women. SMRs were indistinguishable between the original study period (19942007) and the new period (2008-2014). The metabolic syndrome subtype predicted cardiovascular deaths (SMR 11.0 for men, SMR 23.4 for women, p <0.001), and women with the high HDL-cholesterol subtype were also at high cardiovascular risk (SMR 16.3, p <0.001). Men with the low-cholesterol or good glycaemic control subtype showed no excess mortality. Conclusions/interpretation Data-driven multivariable metabolic subtypes predicted the divergence of complication burden across multiple clinical endpoints simultaneously. In particular, men with the metabolic syndrome and women with high HDL-cholesterol should be recognised as important subgroups in interventional studies and public health guidelines on type 1 diabetes.
  • Peddinti, Gopal; Cobb, Jeff; Yengo, Loic; Froguel, Philippe; Kravic, Jasmina; Balkau, Beverley; Tuomi, Tiinamaija; Aittokallio, Tero; Groop, Leif (2017)
    Aims/hypothesis The aims of this study were to evaluate systematically the predictive power of comprehensive metabolomics profiles in predicting the future risk of type 2 diabetes, and to identify a panel of the most predictive metabolic markers. Methods We applied an unbiased systems medicine approach to mine metabolite combinations that provide added value in predicting the future incidence of type 2 diabetes beyond known risk factors. We performed mass spectrometry-based targeted, as well as global untargeted, metabolomics, measuring a total of 568 metabolites, in a Finnish cohort of 543 nondiabetic individuals from the Botnia Prospective Study, which included 146 individuals who progressed to type 2 diabetes by the end of a 10 year follow-up period. Multivariate logistic regression was used to assess statistical associations, and regularised least-squares modelling was used to perform machine learning-based risk classification and marker selection. The predictive performance of the machine learning models and marker panels was evaluated using repeated nested cross-validation, and replicated in an independent French cohort of 1044 individuals including 231 participants who progressed to type 2 diabetes during a 9 year follow-up period in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study. Results Nine metabolites were negatively associated (potentially protective) and 25 were positively associated with progression to type 2 diabetes. Machine learning models based on the entire metabolome predicted progression to type 2 diabetes (area under the receiver operating characteristic curve, AUC = 0.77) significantly better than the reference model based on clinical risk factors alone (AUC = 0.68; DeLong's p = 0.0009). The panel of metabolic markers selected by the machine learning-based feature selection also significantly improved the predictive performance over the reference model (AUC = 0.78; p = 0.00019; integrated discrimination improvement, IDI = 66.7%). This approach identified novel predictive biomarkers, such as alpha-tocopherol, bradykinin hydroxyproline, X-12063 and X-13435, which showed added value in predicting progression to type 2 diabetes when combined with known biomarkers such as glucose, mannose and alpha-hydroxybutyrate and routinely used clinical risk factors. Conclusions/interpretation This study provides a panel of novel metabolic markers for future efforts aimed at the prevention of type 2 diabetes.
  • Tikkanen-Dolenc, Heidi; Waden, Johan; Forsblom, Carol; Harjutsalo, Valma; Thorn, Lena M.; Saraheimo, Markku; Elonen, Nina; Rosengård-Bärlund, Milla; Gordin, Daniel; Tikkanen, Heikki O.; Groop, Per-Henrik; FinnDiane Study Grp (2017)
    Aims/hypothesis Cardiovascular disease (CVD) is the most common cause of premature death and disability among patients with type 1 diabetes. Diabetic nephropathy accounts for the increased cardiovascular morbidity and mortality of these patients. We recently showed that the intensity of exercise predicts the incidence and progression of diabetic nephropathy in patients with type 1 diabetes. Little is known about the relationship between physical activity and CVD. Therefore, we studied how physical activity affects the risk of CVD events in patients with type 1 diabetes. Methods A 10 year follow-up study including 2180 type 1 diabetes patients from the nationwide multicentre Finnish Diabetic Nephropathy Study (FinnDiane). Leisure time physical activity (LTPA) was assessed by a previously validated self-report questionnaire. A CVD event was defined as a verified myocardial infarction, coronary procedure or stroke. Patients were analysed separately for the risk of developing a first ever CVD event and for the risk of a recurrent CVD event following a baseline event. Results A total of 206 patients had an incident CVD event during follow-up. A higher total LTPA and higher intensity, frequency and duration of activity were associated with a lower risk of incident CVD events. The observed association between exercise frequency and incident CVD remained significant when adjusted for classic risk factors. Exercise intensity also had a borderline effect on the recurrence-free time in patients with a major CVD event at baseline. Conclusion/interprelation This study suggests that exercise, particularly high frequency and high intensity exercise, may reduce the risk of CVD events in patients with type 1 diabetes.
  • The FinnDiane Study Group; Tikkanen-Dolenc, Heidi; Wadén, Johan; Forsblom, Carol; Harjutsalo, Valma; Thorn, Lena M.; Saraheimo, Markku; Elonen, Nina; Hietala, Kustaa; Summanen, Paula; Tikkanen, Heikki O.; Groop, Per-Henrik (2020)
    The aim of this study was to investigate whether leisure-time physical activity (LTPA) is associated with the development of severe diabetic retinopathy in individuals with type 1 diabetes.
  • Lipska-Zietkiewicz, Beata Stefania; Ozaltin, Fatih; Hölttä, Tuula; Bockenhauer, Detlef; Berody, Sandra; Levtchenko, Elena; Vivarelli, Marina; Webb, Hazel; Haffner, Dieter; Schaefer, Franz; Boyer, Olivia (2020)
    Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders presenting with massive proteinuria within the first 3 months of life almost inevitably leading to end-stage kidney disease. The Work Group for the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Pediatric Nephrology (ESPN) has developed consensus statement on genetic aspects of CNS diagnosis and management. The presented expert opinion recommends genetic diagnostics as the key diagnostic test to be ordered already during the initial evaluation of the patient, discusses which phenotyping workup should be performed and presents known genotype-phenotype correlations.
  • Sandholm, Niina; Groop, Per-Henrik (2018)
    Diabetic kidney disease and other long-term complications are common in diabetes, and comprise the main cause of co-morbidity and premature mortality in individuals with diabetes. While familial clustering and heritability have been reported for all diabetic complications, the genetic background and the molecular mechanisms remain poorly understood. In recent years, genome-wide association studies have identified a few susceptibility loci for the renal complications as well as for diabetic retinopathy, diabetic cardiovascular disease and mortality. As for many complex diseases, the genetic factors increase the risk of complications in concert with the environment, and certain associations seem specific for particular conditions, for example, SP3-CDCA7 associated with end-stage renal disease only in women, or MGMT and variants on chromosome 5q13 associated with cardiovascular mortality only under tight glycaemic control. The characterization of the phenotypes is one of the main challenges for genetic research on diabetic complications, in addition to an urgent need to increase the number of individuals with diabetes with high quality phenotypic data to be included in future genetic studies.
  • SUMMIT Consortium; DCCT EDIC Res Grp; GENIE Consortium; Salem, Rany M.; Todd, Jennifer N.; Sandholm, Niina; Valo, Erkka; Haukka, Jani K.; Harjutsalo, Valma; Groop, Leif C.; Forsblom, Carol; Groop, Per-Henrik; Florez, Jose C.; Panduru, Nicolae Mircea (2019)
    Background Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. Methods To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. Results Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1). Conclusions The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
  • Achhra, Amit C.; Mocroft, Amanda; Ross, Michael; Ryom-Nielson, Lene; Avihingsanon, Anchalee; Bakowska, Elzbieta; Belloso, Waldo; Clarke, Amanda; Furrer, Hansjakob; Lucas, Gregory M.; Ristola, Matti; Rassool, Mohammed; Ross, Jonathan; Somboonwit, Charurut; Sharma, Shweta; Wyatt, Christina; INSIGHT START Study Grp (2017)
    The impact of early ART initiation (versus deferring) on kidney function has not been studied. START was a randomised comparison of immediate versus deferred ART initiation among HIV-positive persons with CD4(+) (cellsimm(3)) counts >500. Serum creatinine and urine dipstick protein were measured at Months 0, 1, 4, 8 and 12, and annually thereafter. The two arms were compared for changes in eGFR (mL/min/1.73 m(2), calculated by CI94% and >19% of follow-up time, respectively. Overall, 89% started ART using a tenofovir-based regimen. Over 2.1 years median follow-up, mean eGFR was 056 (95% CI 0.003-1.11) higher in the immediate versus deferred arm, which was more prominent after adjustment for current tenofovir or bPI use (1.85, 95% CI 1.21-2.50) and in Black participants (30.1% overall) (3.90, 95% CI 2.84-4.97) versus non-Blacks (1.05, 95% CI 0.33-1.77) (P <0.001 for interaction). Relative risk for proteinuria in the immediate versus deferred arm was 0.74 (95% CI 0.55-1.00) (P = 0.049). In the short-term, immediate ART initiation was associated with a modestly higher eGFR and lower proteinuria risk versus deferring ART (more pronounced in Black participants). Whether this early benefit translates into a lower risk of CKD requires further follow-up. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
  • Heinjoki, Marjo; Karjalainen, Merja; Saltevo, Juha; Tiihonen, Miia; Haanpaa, Maija; Kautiainen, Hannu; Mäntyselkä, Pekka (2020)
    Background Due to these changes in kidney function, aging kidneys are more prone to drug-induced impairments in renal properties. Diabetes has been associated with the declined kidney function and an elevated risk of renal failure. The aim of this study is to compare kidney function and potentially nephrotoxic drug use among home-dwelling older persons with or without diabetes. Methods A total of 259 persons with and 259 persons without diabetes and aged >= 65 years were randomly selected to participate in a health examination with complete data gathered from 363 individuals (187 with diabetes and 176 without diabetes). The estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI equation. Each participant was categorized based on the nephrotoxic profile of their medications. Results There were no differences in mean eGFR values (77.5 +/- 18.8 vs. 80.5 +/- 14.8 ml/min/1.73m(2), p = 0.089) or in the proportion of participants with eGFR <60 ml/min/1.73m(2) among persons with diabetes (16% vs. 10%, p = 0.070), compared to persons without diabetes. Potentially nephrotoxic drug use was similar between the groups. The mean number of potentially nephrotoxic drugs was 1.06 +/- 0.88 in those with and 0.97 +/- 1.05 in those without diabetes (p = 0.39). Conclusions The kidney function of older persons with diabetes does not differ from that of older persons without diabetes and furthermore potentially nephrotoxic drug use seem to play only a minor role in the decline in kidney function among home-dwelling persons in the Inner-Savo district.
  • Haukka, Jani K.; Sandholm, Niina; Forsblom, Carol; Cobb, Jeffrey E.; Groop, Per-Henrik; Ferrannini, Ele (2018)
    Elevated urinary albumin excretion (microalbuminuria) is an early marker of diabetic nephropathy, but there is an unmet need for better biomarkers that capture the individuals at risk with higher accuracy and earlier than the current markers do. We performed an untargeted metabolomic study to assess baseline differences between individuals with type 1 diabetes who either developed microalbuminuria or remained normoalbuminuric. A total of 102 individuals progressed to microalbuminuria during a median follow-up of 3.2 years, whereas 98 sex-, age- and body mass index (BMI) matched nonprogressors remained normoalbuminuric during a median follow-up of 7.1 years. Metabolomic screening identified 1,242 metabolites, out of which 111 differed significantly between progressors and non-progressors after adjustment for age of diabetes onset, baseline glycosylated hemoglobin A1c (HbA(1c)), and albumin excretion rate (AER). The metabolites that predicted development of microalbumiuria included several uremic toxins and carnitine metabolism related molecules. Iterative variable selection indicated erythritol, 3-phenylpropionate, and N-trimethyl-5-aminovalerate as the best set of variables to predict development of microalbuminuria. A metabolomic index based on these metabolites improved the prediction of incident microalbuminuria on top of the clinical variables age of diabetes onset, baseline HbA1c and AER (ROCAUC = 0.842 vs 0.797), highlighting their ability to predict early-phase diabetic nephropathy.