Relationship between biomarkers of tubular injury and intrarenal hemodynamic dysfunction in youth with type 1 diabetes

Johnson, Melissa; Tommerdahl, Kalie L.; Vinovskis, Carissa; Waikar, Sushrut S.; Reinicke, Trenton; Parikh, Chirag R.; Obeid, Wassim; Nelson, Robert G.; Raalte, Daniël H. van; Pyle, Laura; Nadeau, Kristen J.; Bjornstad, Petter

doi:10.1007/s00467-022-05487-4

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…A statistically significant inverse association of RI and a latent variable indicating the risk for DKD in our study does not seem logical. It contradicts the findings of several other studies (8,35). Some researchers also did not find a statistically significant difference in RI values in children with DM-T1 and in the healthy population and no association between albuminuria and RI.…”

Section: Discussioncontrasting

confidence: 59%

Cystatin C, renal resistance index, and kidney injury molecule-1 are potential early predictors of diabetic kidney disease in children with type 1 diabetes

et al. 2022

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BackgroundDiabetic kidney disease (DKD) is the main cause of end-stage renal disease in patients with diabetes mellitus type I (DM-T1). Microalbuminuria and estimated glomerular filtration rate (eGFR) are standard predictors of DKD. However, these predictors have serious weaknesses. Our study aimed to analyze cystatin C, renal resistance index, and urinary kidney injury molecule-1 (KIM-1) as predictors of DKD.MethodsWe conducted a cross-sectional study in 2019 on a consecutive sample of children and adolescents (10–18 years) diagnosed with DM-T1. The outcome was a risk for DKD estimated using standard predictors: age, urinary albumin, eGFR, serum creatinine, DM-T1 duration, HbA1c, blood pressure, and body mass index (BMI). We conducted the analysis using structural equation modeling.ResultsWe enrolled 75 children, 36 girls and 39 boys with the median interquartile range (IQR) age of 14 (11–16) years and a median (IQR) duration of DM-T1 of 6 (4–9) years. The three focal predictors (cystatin C, resistance index, and urinary KIM-1) were significantly associated with the estimated risk for DKD. Raw path coefficients for cystatin C were 3.16 [95% CI 0.78; 5.53; p = 0.009, false discovery rate (FDR) < 5%], for renal resistance index were –8.14 (95% CI –15.36; –0.92; p = 0.027; FDR < 5%), and for urinary KIM-1 were 0.47 (95% CI 0.02; 0.93; p = 0.040; FDR < 5%).ConclusionCystatin C, renal resistance index, and KIM-1 may be associated with the risk for DKD in children and adolescents diagnosed with DM-T1. We encourage further prospective cohort studies to test our results.

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Section: Discussioncontrasting

confidence: 59%

Cystatin C, renal resistance index, and kidney injury molecule-1 are potential early predictors of diabetic kidney disease in children with type 1 diabetes

et al. 2022

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“…Kidney injury molecule-1 (KIM-1) present in the proximal tubules of the kidney is largely recognized as an important biomarker of the progressive renal damage in diabetes ( Papu John et al, 2019 ; Majumder et al, 2022 ). Further, Lipocalin-2 (LCN-2) also serves as a crucial prognostic marker of renal injury in diabetes and hypertension ( Johnson et al, 2022 ; Majumder et al, 2022 ). Therefore, we investigated whether diabetic conditions induced kidney damage and Nimbidiol treatment ameliorated renal injury in Akita mice.…”

Section: Resultsmentioning

confidence: 99%

Nimbidiol protects from renal injury by alleviating redox imbalance in diabetic mice

Juin,

Pushpakumar,

Sen

2024

Front. Pharmacol.

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IntroductionChronic hyperglycemia-induced oxidative stress plays a crucial role in the development of diabetic nephropathy (DN). Moreover, adverse extracellular matrix (ECM) accumulation elevates renal resistive index leading to progressive worsening of the pathology in DN. Nimbidiol is an alpha-glucosidase inhibitor, isolated from the medicinal plant, ‘neem’ (Azadirachta indica) and reported as a promising anti-diabetic compound. Previously, a myriad of studies demonstrated an anti-oxidative property of a broad-spectrum neem-extracts in various diseases including diabetes. Our recent study has shown that Nimbidiol protects diabetic mice from fibrotic renal dysfunction in part by mitigating adverse ECM accumulation. However, the precise mechanism remains poorly understood.MethodsThe present study aimed to investigate whether Nimbidiol ameliorates renal injury by reducing oxidative stress in type-1 diabetes. To test the hypothesis, wild-type (C57BL/6J) and diabetic Akita (C57BL/6‐Ins2Akita/J) mice aged 10–14 weeks were used to treat with saline or Nimbidiol (400 μg kg−1 day−1) for 8 weeks.ResultsDiabetic mice showed elevated blood pressure, increased renal resistive index, and decreased renal vasculature compared to wild-type control. In diabetic kidney, reactive oxygen species and the expression levels of 4HNE, p22phox, Nox4, and ROMO1 were increased while GSH: GSSG, and the expression levels of SOD-1, SOD-2, and catalase were decreased. Further, eNOS, ACE2, Sirt1 and IL-10 were found to be downregulated while iNOS and IL-17 were upregulated in diabetic kidney. The changes were accompanied by elevated expression of the renal injury markers viz., lipocalin-2 and KIM-1 in diabetic kidney. Moreover, an upregulation of p-NF-κB and a downregulation of IkBα were observed in diabetic kidney compared to the control. Nimbidiol ameliorated these pathological changes in diabetic mice.ConclusionAltogether, the data of our study suggest that oxidative stress largely contributes to the diabetic renal injury, and Nimbidiol mitigates redox imbalance and thereby protects kidney in part by inhibiting NF-κB signaling pathway in type-1 diabetes.

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“…These biomarkers have been suggested to reflect subclinical kidney disease, with studies demonstrating differences between KIM-1 in people with versus without diabetes, as well as correlations with features of glomerular hyperfiltration. 44,45 Higher plasma sTNFR1 and KIM-1 and lower urinary UMOD and EGF have all been associated with progressive kidney function decline, including among people with normal kidney function at baseline. [46][47][48] Linking tubular and inflammatory biomarkers with 5-year kidney structural changes early in the course of DKD in persons with type 1 diabetes further substantiates the theory that these biomarkers indicate ongoing subclinical pathology.…”

Section: Modelmentioning

confidence: 99%

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

Limonte,

Prince,

Hoofnagle

et al. 2023

CJASN

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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 tumor necrosis factor receptor 1 (sTNFR1), and arginine-to-citrulline ratio in plasma; uromodulin (UMOD) and epidermal growth factor (EGF) in urine. We examined cross-sectional correlations between biomarkers and biopsy features and baseline biomarker associations with 5-year change in biopsy features. Results Participants’ mean age was 30 years (SD 10) and diabetes duration 11 years (SD 5); 53% were female. Mean iohexol-GFR was 128ml/min/1.73m2 (SD 19) and median urinary albumin excretion was 5μg/min (IQR 3,8). KIM-1 was associated with most biopsy features: higher mesangial fractional volume (0.5% [95% CI 0.1,0.9] greater per SD KIM-1), glomerular basement membrane width (14.2nm [95% CI 6.5,22.0] thicker), cortical interstitial fractional volume (1.1% [95% CI 0.6,1.6] greater), fractional volume of cortical atrophic tubules (0.6% [95% CI 0.2,0.9] greater), and arteriolar hyalinosis index (0.03 [95% CI 0.1,0.05] higher). sTNFR1 was associated with higher mesangial fractional volume (0.9% [95% CI 0.5,1.3] greater) and glomerular basement membrane width (12.5nm [95% CI 4.5,20.5] thicker), and lower glomerular basement membrane surface density (0.003μm2/μm3 [95% CI 0.005,0.001] lesser). EGF and arginine-to-citrulline ratio correlated with severity of glomerular and tubulointerstitial features. Baseline sTNFR1, UMOD, 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 early type 1 diabetes and may be indicators of kidney disease risk.

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Relationship between biomarkers of tubular injury and intrarenal hemodynamic dysfunction in youth with type 1 diabetes

Cited by 8 publications

References 28 publications

Cystatin C, renal resistance index, and kidney injury molecule-1 are potential early predictors of diabetic kidney disease in children with type 1 diabetes

Cystatin C, renal resistance index, and kidney injury molecule-1 are potential early predictors of diabetic kidney disease in children with type 1 diabetes

Nimbidiol protects from renal injury by alleviating redox imbalance in diabetic mice

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

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