Associations of clinical features with kidney tubular biomarker trajectories in individuals with type 1 diabetes

Abstract

BackgroundIdentification of risk factors of tubular injury and dysfunction among individuals with type 1 diabetes (T1D) may provide insight into the mechanisms underlying tubulointerstitial pathology and allow for improved kidney health prognostication and treatment. MethodsWe examined associations of clinical characteristics and drug interventions on tubular biomarker trends in two T1D cohorts: (1) the Renin Angiotensin System Study (RASS, n=283) including adults with early T1D and no clinical evidence of kidney disease, randomized to enalapril, losartan, or placebo; and (2) the Preventing Early Renal Loss in Diabetes Study (PERL, n=530) including adults with longstanding T1D and chronic kidney disease (CKD) or at risk of kidney disease progression, randomized to allopurinol or placebo. Biomarkers were measured at 3 time points (baseline, mid-trial, closeout) over 5 years follow-up in RASS and 3 years follow-up in PERL. Measurements included: KIM-1, sTNFR1, arginine-citrulline ratio in plasma; EGF, UMOD in timed urine; a composite tubular secretion score reflecting clearances of 8 proximal tubular secreted solutes. ResultsAt baseline, RASS participants had a mean age of 30 years and 47% were male, with mean diabetes duration 11 years, hemoglobin A1c (HbA1c) 8.6%, iohexol-derived glomerular filtration rate (iGFR) 128 ml/min/1.73m2, and albumin excretion rate (AER) 6 ug/min. PERL participants had a mean age of 51 years and 66% were male, with mean diabetes duration 35 years, HbA1c 8.2%, iGFR 68 ml/min/1.73m2, and AER 286 ug/min. We observed significant changes in tubular biomarkers across both cohorts, suggesting progressive tubular injury and dysfunction. We identified baseline HbA1c and AER as factors associated with changes in multiple tubular biomarkers. Higher baseline HbA1c was associated with faster rise in KIM-1 (4.8 pg/mL increase per year, [95% CI 2.3, 7.3]), slower decline in arginine-citrulline ratio (0.02 unit slower decrease per year, [95% CI 0, 0.03]), and faster decline in EGF in RASS (194.7 ug/day decrease per year, [95% CI 6.8, 382.7]), and with faster rise in sTNFR1 in PERL (27.6 pg/mL increase per year, [95% CI 18.8, 36.5]). Higher baseline urinary albumin excretion rate was associated with faster declines in EGF (346.1 ug/day decrease per year, [95% CI 65.3, 626.8]) in RASS , and with faster rise in sTNFR1 (18.1 pg/mL increase per year, [95% CI 14.8, 21.4]) and faster declines in EGF (139.8 ug/day decrease per year [95% CI 31.9, 247.7]) and tubular secretion score (0.2 unit decrease per year, [95% CI 0.1, 0.3]) in PERL. Age, sex, and baseline age, diabetes duration, SBP, iGFR, and randomization to intervention versus placebo had limited associations with tubular biomarker trajectories. ConclusionLongitudinal changes in tubular biomarkers reflect progressive tubulointerstitial injury and dysfunction across the course of T1D DKD and are influenced by baseline glycemia and albuminuria.