The role of circulating biomarkers, genetics, and diet in kidney function
Abstract: Today, between 8% and 16% of all individuals worldwide suffer from chronic kidney disease (CKD), which is becoming a growing public health issue. Creatinine and cystatin C are commonly used markers for kidney function, and estimated glomerular filtration rate (eGFR) and albuminuria are used to stage CKD. However, creatinine and eGFR are rather insensitive in identifying individuals at high risk of future CKD. Several biomarkers have been proposed to play a role, yet the clinical evidence, particularly from longitudinal studies, is limited. During the recent years, several genetic markers associated with kidney function have been identified by genome-wide association studies. However, the question of whether genetic markers may aid in improving prediction on the top of the commonly used clinical risk factors remains open. Environmental factors, such as diet, have been suggested to be of importance for kidney function, but current knowledge from individuals free of CKD is limited.Therefore, this thesis aimed to investigate if 1) circulating biomarkers (studies I-III) or 2) information on genetic predisposition (study IV) may show advantages in the prediction of future kidney function deterioration after a long-term follow-up. Furthermore, we studied if 3) dietary intake at baseline associates with future kidney function (study V). The work in this thesis was conducted within the setting of the Malmö Diet and Cancer Study, a population-based cohort of middle-aged individuals from Southern Sweden.In studies I-III we observed that in participants with an eGFR > 60 mL/min/1.73m2 elevated plasma levels of pro-enkephalin (study I), soluble urokinase receptor (study II), or kidney injury molecule-1 (study III), were each associated with an ~20% increased risk of incident CKD stage 3A per increase in one SD of the respective biomarker, independently of known risk factors (OR 1.17 95 %CI=1.05-1.30; 1.25 95 %CI=1.10-1.41, and 1.21 95 %CI=1.08-1.34, respectively).In study IV, we report that adding a genetic risk score composed of 53 SNPs, previously identified by GWAS to associate with kidney function, to a risk model including clinical risk factors, may be helpful in evaluating the risk of incident CKD (OR per risk allele 1.04, 95%CI 1.01-1.07; NRI 17.7.% P=0.0007).In study V, we investigated the association between dietary intakes and occurrence of CKD in participants with a preserved kidney function at baseline. We investigated reported intakes of 15 food groups focusing on different sources of protein, and intakes of macronutrients and three beverages. We observed that lower sucrose intake as well as higher fiber and coffee intake associated with favorable long-term kidney function. In conclusion, the studies included in this PhD-thesis demonstrate that novel circulating and genetic biomarkers may be clinically useful in estimating future kidney function, and emphasize genetic susceptibility and diet as important determinants of longitudinal kidney function.
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