Introduction: Systems Biology of Kidney Disease

Sharma, Kumar; Suszták, Katalin; Pennathur, Subramaniam

doi:10.1016/j.semnephrol.2018.02.001

Cited by 3 publications

(4 citation statements)

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“…Similarly, there were inconsistent relationships between genes expressing KRIS proteins and histopathological indices of DKD in kidney biopsies obtained in the 1KGP project. Interestingly, the vast majority of current research utilizing high throughput technologies concentrates on the kidney as the primary driver of the disease 37 , our findings highlight the importance of non-kidney factors as important etiological drivers of DKD.…”

Section: Discussionmentioning

confidence: 72%

A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes

Niewczas

Pavkov

Skupień

et al. 2019

Nat Med

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Chronic inflammation is postulated to be involved in development of end stage renal disease (ESRD) in diabetes, but which specific circulating inflammatory proteins contribute to this risk remains unknown. To study this we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with Type 1 and Type 2 diabetes. In each cohort we identified an extremely robust K idney R isk I nflammatory S ignature (KRIS) consisting of 17 novel proteins enriched for TNF Receptor Superfamily members that was associated with a 10-year risk of ESRD. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying ESRD development in both types of diabetes. These proteins may be used as new therapeutic targets, new prognostic tests for high risk of ESRD and as surrogate outcome measures where changes in KRIS levels during intervention can reflect the tested therapy’s effectiveness.

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Section: Discussionmentioning

confidence: 72%

A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes

Niewczas

Pavkov

Skupień

et al. 2019

Nat Med

Self Cite

297

282

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“…Therefore, we can plausibly speculate that studies focusing on protection against diabetic kidney disease development will not only complement the current understanding of risk determinants, but will offer new and invaluable insights into the disease mechanisms.Over the last decade, metabolomics has emerged from a quiet biochemistry field into mainstream research. Given the metabolic nature of diabetes, metabolomics studies will likely offer insights into the mechanisms underlying chronic diabetic complications 8,9 . Metabolomics is a well-suited tool for such discoveries, as our…”

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confidence: 99%

“…Over the last decade, metabolomics has emerged from a quiet biochemistry field into mainstream research. Given the metabolic nature of diabetes, metabolomics studies will likely offer insights into the mechanisms underlying chronic diabetic complications 8,9 . Metabolomics is a well-suited tool for such discoveries, as our…”

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confidence: 99%

Circulating short and medium chain fatty acids are associated with normoalbuminuria in type 1 diabetes of long duration

Moon

Tsay

Lampert

et al. 2021

Sci Rep

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A substantial number of subjects with Type 1 Diabetes (T1D) of long duration never develop albuminuria or renal function impairment, yet the underlying protective mechanisms remain unknown. Therefore, our study included 308 Joslin Kidney Study subjects who had T1D of long duration (median: 24 years), maintained normal renal function and had either normoalbuminuria or a broad range of albuminuria within the 2 years preceding the metabolomic determinations. Serum samples were subjected to global metabolomic profiling. 352 metabolites were detected in at least 80% of the study population. In the logistic analyses adjusted for multiple testing (Bonferroni corrected α = 0.000028), we identified 38 metabolites associated with persistent normoalbuminuria independently from clinical covariates. Protective metabolites were enriched in Medium Chain Fatty Acids (MCFAs) and in Short Chain Fatty Acids (SCFAs) and particularly involved odd-numbered and dicarboxylate Fatty Acids. One quartile change of nonanoate, the top protective MCFA, was associated with high odds of having persistent normoalbuminuria (OR (95% CI) 0.14 (0.09, 0.23); p < 10–12). Multivariable Random Forest analysis concordantly indicated to MCFAs as effective classifiers. Associations of the relevant Fatty Acids with albuminuria seemed to parallel associations with tubular biomarkers. Our findings suggest that MCFAs and SCFAs contribute to the metabolic processes underlying protection against albuminuria development in T1D that are independent from mechanisms associated with changes in renal function.

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“…In addition, eGFR decline may precede the onset of albuminuria, suggesting the presence of disease activity before clinical signs are apparent [5, 7]. While various pathophysiological processes, including hyperglycemia, microvascular dysfunction, inflammation, and fibrosis, are implicated in DKD, the mechanisms underlying the observed differential decline in kidney function across individuals remain poorly understood [8, 9]. Insight into the mechanisms of eGFR decline in T1D is important for early identification of individuals at risk for DKD progression and for development of new therapies.…”

Section: Introductionmentioning

confidence: 99%

A Targeted Multiomics Approach to Identify Biomarkers Associated with Rapid eGFR Decline in Type 1 Diabetes

et al. 2020

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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 <1 mL/min/1.73 m2, respectively. Associations of demographic and clinical variables with rapid eGFR decline were tested using logistic regression, and prediction was evaluated using area under the curve (AUC) statistics. Targeted metabolomics, lipidomics, and proteomics are being performed using high-resolution mass-spectrometry techniques. Results: At baseline, the mean age was 43 years, diabetes duration was 27 years, eGFR was 94 mL/min/1.73 m2, and 62% of participants were normoalbuminuric. Over 7.6-year median follow-up, the mean annual change in eGFR in cases and controls was −5.7 and 0.6 mL/min/1.73 m2, respectively. Younger age, longer diabetes duration, and higher baseline HbA1c, urine albumin-creatinine ratio, and eGFR were significantly associated with rapid eGFR decline. The cross-validated AUC for the predictive model incorporating these variables plus sex and mean arterial blood pressure was 0.74 (95% CI: 0.68–0.79; p < 0.001). Conclusion: Known risk factors provide moderate discrimination of rapid eGFR decline. Identification of blood and urine biomarkers associated with rapid eGFR decline in T1D using targeted omics strategies may provide insight into disease mechanisms and improve upon clinical predictive models using traditional risk factors.

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Introduction: Systems Biology of Kidney Disease

Cited by 3 publications

References 0 publications

A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes

A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes

Circulating short and medium chain fatty acids are associated with normoalbuminuria in type 1 diabetes of long duration

A Targeted Multiomics Approach to Identify Biomarkers Associated with Rapid eGFR Decline in Type 1 Diabetes

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