Chronic kidney disease (CKD) is a significant public health challenge, with diet and genetic predisposition playing crucial roles in its development and progression. However, the relationships between these factors and kidney function are only partially understood, especially in the context of prevention. This thesis aimed to address three objectives: (Objective 1) assess CKD prevalence and public awareness in the Val Venosta/Vinschgau district (South Tyrol, Italy); (Objective 2) identify dietary patterns (DPs) associated with kidney function and CKD risk, and (Objective 3) explore the interplay between DPs and genetic predisposition in relation to kidney dysfunction. Objective 1: We assessed CKD prevalence and awareness in the Val Venosta/Vinschgau district using data from the Cooperative Health Research in South Tyrol (CHRIS) study. We combined standard biomarkers, estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), with data from a custom-developed kidney health questionnaire. Findings revealed a gap between self-reported CKD prevalence and the prevalence of CKD defined according to clinical standards using measured markers, indicating a major lack of awareness or diagnosis in participants. Objective 2: The investigation was conducted from three distinct perspectives, each one covered by a dedicated project. In all projects, Reduced Rank Regression (RRR) was employed to derive CKD-related dietary patterns (DPs). First, we derived three RRR-based DPs using four nutrients (protein, phosphorus, potassium, and sodium) as mediators. DPs showed heterogeneous effects across kidney out-comes, possibly reflecting specificity to kidney function or damage. Notably, one DP (DP1), characterized by high levels of all four nutrients, was associated with lower eGFR levels in males, indicating poorer kidney function. Second, RRR was used to derive sex-specific DPs using nine cardio-renal-metabolic markers as mediators. In addition, an hypertension-oriented dietary index, the DASH score, was derived. In males, results generally corroborated previous evidence on the effects of the DASH-style diet. In females, the association between DPs and eGFR was influenced by menstrual status. Third, by leveraging prospective data from the Swedish National March Cohort (SNMC), we used RRR to replicate the nutrient-based DPs obtained in the cross-sectional CHRIS study and derived the DASH score and the Nordic Nutrition Recommendation (NNR) score. We then investigated the effects of all DPs on CKD incidence risk over a 19-year follow-up. Three RRR-DPs were identified and associations with CKD incidence were heterogenous across sexes. The NNR-score showed a protective effect on CKD risk, but the benefit plateaued at higher levels of adherence. The DASH-score was protective for CKD, but only in females. Objective 3: A polygenic score (PGS) was calculated based on genetic variants associated with eGFR in European ancestry individuals to investigate the interplay between genetic predisposition and the DPs in determining kidney function. Non-linear interactions be-tween PGS and dietary protein and phosphorus were detected. These results suggested that the impact of protein and phosphorus intake on eGFR may be modified by genetic predisposition. To summarise, this research provided new insights into the epidemiology of kidney diseases in the general population, CKD prevalence and awareness, as well as the effects of diet on kidney function, and the role of genetic predisposition in diet-renal health associations. While the beneficial effects of the DASH diet were confirmed, results also suggested that the optimal dietary approach may vary across different population subgroups and by sex. Therefore, using a flexible approach like the RRR to derive DPs can be particularly effective. Finally, findings indicated that genetic predisposition may influence the relationship be-tween diet and kidney function.
La malattia renale cronica (CKD) rappresenta una significativa sfida per la salute pubblica, in cui dieta e predisposizione genetica svolgono un ruolo cruciale nello sviluppo e nella progressione. Tuttavia, le relazioni tra questi fattori e la funzionalità renale sono solo parzialmente comprese, specialmente nel contesto della prevenzione. Questa tesi si propone di affrontare tre obiettivi: (Obiettivo 1) valutare la prevalenza e la consapevolezza della CKD nel distretto della Val Venosta/Vinschgau (Alto Adige, Italia); (Obiettivo 2) identificare i dietary patterns (DPs) associati alla funzionalità renale e al rischio di CKD; e (Obiettivo 3) esplorare l'interazione tra i DPs e la predisposizione genetica in relazione alla disfunzione renale. Obiettivo 1: Abbiamo valutato la prevalenza e la consapevolezza della CKD nel distretto della Val Venosta/Vinschgau utilizzando i dati dello studio Cooperative Health Research in South Tyrol (CHRIS). Sono stati combinati biomarcatori standard, come il tasso di filtrazione glomerulare stimato (eGFR) e il rapporto albumina-creatinina urinaria (UACR), con le risposte ad un questionario specifico sulla salute renale. I risultati hanno evidenziato un divario tra la prevalenza auto-riportata di CKD e quella definita secondo gli standard clinici utilizzando i marcatori misurati, suggerendo una scarsa consapevolezza o sottodiagnosi della malattia. Obiettivo 2: L’indagine è stata condotta da tre prospettive distinte, ciascuna trattata in un progetto dedicato. In tutti i progetti, è stata utilizzata la Reduced Rank Regression (RRR) per derivare i dietary patterns (DPs) legati alla CKD. In primo luogo, abbiamo derivato tre DPs basati sulla RRR utilizzando quattro nutrienti (proteine, fosforo, potassio e sodio) come mediatori. I DPs hanno mostrato effetti eterogenei sugli esiti renali, riflettendo probabilmente una specificità legata alla funzionalità o al danno renale. In particolare, un DP (DP1), caratterizzato da alti livelli di tutti e quattro i nutrienti, è stato associato a livelli inferiori di eGFR negli uomini, indicando una funzionalità renale ridotta. In secondo luogo, la RRR è stata utilizzata per derivare DPs specifici per sesso utilizzando nove marcatori cardio-renali-metabolici come mediatori. Inoltre, è stato derivato un indice dietetico orientato all’ipertensione, il DASH score. Negli uomini, i risultati hanno generalmente confermato le evidenze precedenti sugli effetti della dieta DASH. Nelle donne, l’associazione tra i DPs e l’eGFR risultava influenzata dallo stato mestruale. Infine, sfruttando i dati prospettici della Swedish National March Cohort (SNMC), abbiamo replicato i DPs basati sui nutrienti ottenuti nello studio trasversale CHRIS utilizzando la RRR e derivato il DASH score e il Nordic Nutrition Recommendation (NNR) score. Successivamente, abbiamo studiato gli effetti di tutti i DPs sul rischio di incidenza di CKD in un follow-up di 19 anni. Sono stati identificati tre DPs basati sulla RRR, le cui associazioni con l’incidenza di CKD sono risultate eterogenee tra i sessi. Lo score NNR ha mostrato un effetto protettivo sul rischio di CKD, stabilizzandosi però a livelli di aderenza elevati. Il DASH score risultava protettivo, ma solo nelle femmine. Obiettivo 3: È stato calcolato uno score poligenico (PGS) basato su varianti genetiche associate all’eGFR in individui di ascendenza europea per investigare l’interazione tra predisposizione genetica e DPs nella determinazione della funzionalità renale. Sono state rilevate interazioni non lineari tra il PGS e l’assunzione di proteine e fosforo. Questi risultati suggeriscono che l’impatto dell’assunzione di proteine e fosforo sull’eGFR potrebbe essere modificato dalla predisposizione genetica. In sintesi, questa ricerca ha fornito nuove conoscenze sull’epidemiologia delle malattie renali nella popolazione generale, sulla prevalenza e consapevolezza della CKD, sugli effetti della dieta sulla funzionalità renale e sul ruolo della predisposizione genetica nelle associazioni tra dieta e salute renale. Sebbene gli effetti benefici della dieta DASH siano stati confermati, i risultati suggeriscono che l’approccio dietetico ottimale può variare tra diversi sottogruppi di popolazione e in base al sesso. Pertanto, l’uso di un approccio flessibile come la RRR per derivare i DPs può essere particolarmente efficace. Infine, i risultati indicano che la predisposizione genetica può influenzare la relazione tra dieta e funzionalità renale.
Chronic kidney disease in a population-based cohort: an analytical study of prevalence, dietary patterns, and gene-diet interactions affecting kidney function
BARBIERI, GIULIA
2025
Abstract
Chronic kidney disease (CKD) is a significant public health challenge, with diet and genetic predisposition playing crucial roles in its development and progression. However, the relationships between these factors and kidney function are only partially understood, especially in the context of prevention. This thesis aimed to address three objectives: (Objective 1) assess CKD prevalence and public awareness in the Val Venosta/Vinschgau district (South Tyrol, Italy); (Objective 2) identify dietary patterns (DPs) associated with kidney function and CKD risk, and (Objective 3) explore the interplay between DPs and genetic predisposition in relation to kidney dysfunction. Objective 1: We assessed CKD prevalence and awareness in the Val Venosta/Vinschgau district using data from the Cooperative Health Research in South Tyrol (CHRIS) study. We combined standard biomarkers, estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), with data from a custom-developed kidney health questionnaire. Findings revealed a gap between self-reported CKD prevalence and the prevalence of CKD defined according to clinical standards using measured markers, indicating a major lack of awareness or diagnosis in participants. Objective 2: The investigation was conducted from three distinct perspectives, each one covered by a dedicated project. In all projects, Reduced Rank Regression (RRR) was employed to derive CKD-related dietary patterns (DPs). First, we derived three RRR-based DPs using four nutrients (protein, phosphorus, potassium, and sodium) as mediators. DPs showed heterogeneous effects across kidney out-comes, possibly reflecting specificity to kidney function or damage. Notably, one DP (DP1), characterized by high levels of all four nutrients, was associated with lower eGFR levels in males, indicating poorer kidney function. Second, RRR was used to derive sex-specific DPs using nine cardio-renal-metabolic markers as mediators. In addition, an hypertension-oriented dietary index, the DASH score, was derived. In males, results generally corroborated previous evidence on the effects of the DASH-style diet. In females, the association between DPs and eGFR was influenced by menstrual status. Third, by leveraging prospective data from the Swedish National March Cohort (SNMC), we used RRR to replicate the nutrient-based DPs obtained in the cross-sectional CHRIS study and derived the DASH score and the Nordic Nutrition Recommendation (NNR) score. We then investigated the effects of all DPs on CKD incidence risk over a 19-year follow-up. Three RRR-DPs were identified and associations with CKD incidence were heterogenous across sexes. The NNR-score showed a protective effect on CKD risk, but the benefit plateaued at higher levels of adherence. The DASH-score was protective for CKD, but only in females. Objective 3: A polygenic score (PGS) was calculated based on genetic variants associated with eGFR in European ancestry individuals to investigate the interplay between genetic predisposition and the DPs in determining kidney function. Non-linear interactions be-tween PGS and dietary protein and phosphorus were detected. These results suggested that the impact of protein and phosphorus intake on eGFR may be modified by genetic predisposition. To summarise, this research provided new insights into the epidemiology of kidney diseases in the general population, CKD prevalence and awareness, as well as the effects of diet on kidney function, and the role of genetic predisposition in diet-renal health associations. While the beneficial effects of the DASH diet were confirmed, results also suggested that the optimal dietary approach may vary across different population subgroups and by sex. Therefore, using a flexible approach like the RRR to derive DPs can be particularly effective. Finally, findings indicated that genetic predisposition may influence the relationship be-tween diet and kidney function.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14242/207668
URN:NBN:IT:UNIVR-207668