Associations of Biomarkers of Tubular Injury and Inflammation with Biopsy Features in Type 1 Diabetes

Abstract

Background: Whether biomarkers of tubular injury and inflammation indicate subclinical structural kidney pathology early in type 1 diabetes remains unknown.

Methods: We investigated associations of biomarkers of tubular injury and inflammation with kidney structural features in 244 adults with type 1 diabetes from the Renin-Angiotensin System Study, a randomized, placebo-controlled trial testing effects of enalapril or losartan on changes in glomerular, tubulointerstitial, and vascular parameters from baseline to 5-year kidney biopsies. Biosamples at biopsy were assessed for kidney injury molecule 1 (KIM-1), soluble TNF receptor 1 (sTNFR1), arginine-to-citrulline ratio in plasma, and uromodulin and epidermal growth factor (EGF) in urine. We examined cross-sectional correlations between biomarkers and biopsy features and baseline biomarker associations with 5-year changes in biopsy features.

Results: Participants' mean age was 30 years (SD 10) and diabetes duration 11 years (SD 5); 53% were women. The mean GFR measured by iohexol disappearance was 128 ml/min per 1.73 m 2 (SD 19) and median urinary albumin excretion was 5 μ g/min (interquartile range, 3-8). KIM-1 was associated with most biopsy features: higher mesangial fractional volume (0.5% [95% confidence interval (CI), 0.1 to 0.9] greater per SD KIM-1), glomerular basement membrane (GBM) width (14.2 nm [95% CI, 6.5 to 22.0] thicker), cortical interstitial fractional volume (1.1% [95% CI, 0.6 to 1.6] greater), fractional volume of cortical atrophic tubules (0.6% [95% CI, 0.2 to 0.9] greater), and arteriolar hyalinosis index (0.03 [95% CI, 0.1 to 0.05] higher). sTNFR1 was associated with higher mesangial fractional volume (0.9% [95% CI, 0.5 to 1.3] greater) and GBM width (12.5 nm [95% CI, 4.5 to 20.5] thicker) and lower GBM surface density (0.003 μ m 2 / μ m 3 [95% CI, 0.005 to 0.001] lesser). EGF and arginine-to-citrulline ratio correlated with severity of glomerular and tubulointerstitial features. Baseline sTNFR1, uromodulin, and EGF concentrations were associated with 5-year glomerular and tubulointerstitial feature progression.

Conclusions: Biomarkers of tubular injury and inflammation were associated with kidney structural parameters in early type 1 diabetes and may be indicators of kidney disease risk.

Clinical trial registry name and registration number: Renin Angiotensin System Study (RASS/B-RASS), NCT00143949.

Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_11_17_CJN0000000000000333.mp3.

Graphical abstract

Figure 1

Spearman correlations of tubular biomarkers with kidney structural parameters at baseline. AER, albumin excretion rate; Arg/Cit, arginine-to-citrulline ratio; EGF, epidermal growth factor; GBM, glomerular basement membrane; iGFR, GFR measured by iohexol disappearance; KIM-1, kidney injury molecule 1; sTNFR1, soluble TNF receptor 1; UMOD, uromodulin.

Figure 2

AUC for prediction of abnormal values of mesangial fractional volume and cortical interstitial fractional volume using iohexol GFR, AER, and tubular biomarkers. Abnormal values for structural parameters in the Renin-Angiotensin System Study cohort were defined as values greater than the mean value of the structural parameter in the healthy control group ±2×SD. (A) Table depicting AUC values (and bootstrapped 95% CIs) for individual tubular biomarkers added to iohexol GFR and AER. (B) Receiver operating characteristic curves showing the true-positive rate versus the false-positive rate at different biomarker cut points. Three models are shown: (1) model 1, including iohexol GFR and AER; (2) model 1+sTNFR1; and (3) model 1+all tubular biomarkers. Circles represent Youden's index. AUC, area under the receiver operating characteristic curve; CI, confidence interval.