Changes in serum metabolomic profile affect eGFR in patients with type 1 diabetes.
The rate of progression to end-stage renal disease (ESRD) increases in type 1 diabetes (T1D) patients with impaired renal function. Although chronic kidney disease (CKD) also increases the risk for ESRD, the risk varies depending on the rate of progression. The factors and the mechanisms affecting this variation are unknown, but progressive renal decline is the clinical manifestation that feeds the development of diabetic nephropathy. The study confirmed through global profiling in type 2 diabetes (T2D) some metabolites predict the occurrence of ESRD after 10 years. No study by far has examined metabolomic profiles of patients with T1D who progress to ESRD, the ultimate outcome of diabetic nephropathy. Thus, the purpose of this study was to examine metabolomic profiles in T1D patients to evaluate the risk for ESRD.
The study population included residents in New England between the ages of 21 and 54 years old with serum metabolomic profiles associated with variation in renal function decline with T1D (the Joslin Kidney Study prospective cohort). Out of 3,500 adult participants with T1D, 158 patients with proteinuria and CKD stage 3 were selected and followed for an average of 11 years to determine the estimated glomerular filtration rate (eGFR) slopes from serial measurements of serum creatinine (SCr) and to determine onset of ESRD by linear model procedure. Baseline serum samples were subjected to global metabolomic profiling. Blood and urine specimens were collected every 2 years and stored at -85°C for analysis, whereas other research specific specimens were collected during routine visits. The abnormality in urinary albumin excretion was evaluated by albumin and creatinine ratio (ACR) for the preceding two-year interval of baseline examination.
The clinical characteristics were differentiated by ANOVA for continuous variables and x2 test for categorical variables. Global metabolic profiling in at least 80% of the study population was further analyzed. Multiple comparisons were adjusted with a positive false discovery rate and the Cox regression model estimated the independent effect of a metabolite for ESRD progression. Spearman rank correlation coefficients expressed the correlation between baseline eGFR, baseline measures, and subsequent eGFR slopes. Principal component analysis was used to create a metabolite index and C statistics assessed the discrimination abilities of the risk prediction models. Effects of metabolite concentration on the progression to ESRD were expressed as the hazard ratio per 1 standard difference.
ESRD developed in 99 participants (63%) and median eGFR slope was -5.0 mL/min/1.73 m2 per year. Rapid eGFR decline occurred in younger diabetes patients for a shorter period with worse glycemic control and higher albuminuria. Global metabolomics profiling detected 110 amino acids and purine and pyrimidine metabolites in at least 80% of participants. Creatinine was the main metabolite associated with baseline eGFRs, but moderately correlated with subsequent eGFR slope. However, serum levels of seven modified metabolites (C-glycosyl tryptophan, pseudouridine, O-sulfo tyrosine, N-acetyl threonine, N-acetylserine, N6-carbamoyl threonyl adenosine, and N6-acetyllysine) remained significant in fully adjusted models and were associated with renal function decline and time to ESRD (P < 0.001) independent of the relevant clinical covariates. These metabolites associated with one another and with the manifestations of tubular injury.
The prospective cohort study was conducted in subjects with T1D, proteinuria, and CKD stage 3 at baseline monitored for over 10 years to assess changes in their eGFR and to identify time to onset of ESRD. It included a well-characterized population with a prolonged follow-up and ascertainment of ESRD with eGFR slopes, but it was conducted in Caucasians. Thus, this study may not be generalized to other ethnic populations. Another advantage is the non-targeted metabolomic approach used to examine the metabolites comprehensively and rank their alterations depending on disease progression. Although the global metabolomics profiling resulted in 9 metabolite biomarkers with potential risks of developing ESRD in T1D, their effects were independent of glycemic control, renal function, and albuminuria. Few studies have reported that C-glycosyl tryptophan, pseudouridine, and O-sulfotyrosine are the main risk metabolites to predict GFR-based renal outcome.
Overall, the study demonstrated that patients with increased circulating levels of certain modified metabolites experience faster renal function decline resulting in ESRD. However, whether these candidate metabolites are risk factors or just prognostic biomarkers of progression to ESRD in T1D needs to be determined. Future studies should expand on the mechanisms underlying the increase in acetylation or C-glycosylation of metabolites in high-risk patients for renal disease.
- Patients with T1D proteinuria, and impaired renal function at baseline demonstrated increased serum metabolites associated with faster decline in renal function leading to ESRD.
- Creatinine is the top metabolite associated with baseline eGFRs, but moderately correlated with subsequent eGFR slope.
- Seven out of nine metabolites (C-glycosyl tryptophan, pseudouridine, O-sulfo tyrosine, N-acetyl threonine, N-acetylserine, N6-carbamoyl threonyl adenosine, and N6-acetyllysine) were associated with renal function decline.
American Diabetes Association. Standards of medical care in diabetes–2017. Diabetes Care. 2017; 40(Suppl. 1): S6-S10
Krolewski AS. Progressive renal decline: the new paradigm of diabetic nephropathy in type 1 diabetes. Diabetes Care 2015;38:954–962
Niewczas MA, Mathew AV, Croall S, Byun J, Major M, Sabisetti VS, et al. Circulating Modified Metabolites and a Risk of ESRD in Patients with Type 1 Diabetes and Chronic Kidney Disease. Diabetes Care. March 2017;40:383-390