A Holistic Approach to Risk for Early Kidney Injury in Indigenous Youth With Type 2 Diabetes: A Proof of Concept Paper From the iCARE Cohort

Abstract

Background: Indigenous youth with type 2 diabetes (T2D) are disproportionately affected by early onset albuminuria and are at high risk of kidney failure in early adulthood. Traditional biological approaches have failed to fully explain the renal morbidity seen in this population. The improving renal Complications in Adolescents with type 2 diabetes through REsearch cohort (iCARE) study was therefore designed in collaboration with patients, to more holistically evaluate risk factors for renal morbidity. We hypothesize that both biological factors and mental health influence renal outcomes, mediated via inflammatory pathways. Objective: The objective of this study was to evaluate the iCARE analytic framework which evaluates relationships between biological factors, mental health, inflammation, and albuminuria utilizing a structural equation modeling (SEM) approach. Methods: The first 187 youth with T2D (10-25 years) from the Manitoba iCARE cohort are presented here to evaluate our theoretical and analytic framework. An SEM was chosen to evaluate the statistical significance of proposed associations. The primary outcome was a nonorthostatic urine albumin:creatinine ratio ≥2 mg/mmol. Main exposures (ie, latent factors) included psychological health (distress, perceived stress, positive mental health and resilience), hypertension (24 hour monitored), and inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], fibrinogen). Hemoglobin A1c (HbA1c) and duration of diabetes were covariates. Results: Within the initial cohort (median age = 15 years, duration of diabetes = 2.3 years, 66.8% female), 30.5% (n = 57) had nonorthostatic albuminuria (ALB), and the majority of ALB was persistent (confirmed in 2/3 samples over a 6-month period; n = 47). Youth with ALB had higher HbA1c (10.9% vs 8.9%; P < .001), more hypertension (94.2% vs 78•2%; P = .02), longer duration of diabetes (3.4 vs 2.4 years; P = .01), higher distress (9.2 vs 7.3; P = .02), and stress scores (28.7 vs 26.4; P = .03), and elevated inflammatory markers (CRP: 4.9 vs 3.1 mg/L; P = .01, fibrinogen: 3.7 vs 3.3 µmol/L; P = .02). Factors directly associated with ALB in the SEM were hypertension (0.28; P = .001), inflammation (0.41; P < .001), and HbA1c (0.50; P < .001). Psychological health was independently associated with inflammation (−0.20; P < .001) but not directly associated with ALB. Conclusions: Albuminuria is highly prevalent in Indigenous youth with T2D. This preliminary analysis supports a theoretical framework linking glycemic control, hypertension, and inflammation, potentially mediated by psychological factors with albuminuria. These data support the need for more holistic models of evaluation and care for youth with T2D and multifactorial interventions to prevent complications. Abrégé Contexte: L'albuminurie à déclenchement précoce affecte de façon disproportionnelle les jeunes autochtones atteints de diabète de type 2 (T2D). Ces derniers présentent également un risque plus élevé d'insuffisance rénale au début de l'âge ...

Prevalence of Hypertension and Albuminuria in Pediatric Type 2 Diabetes

“…Forty-six studies reported hypertension prevalence ( Table 1 ). 4 , 15 , 17 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 The reported age at diagnosis of type 2 diabetes ranged from 7.1 to 20.0 years, 46 , 47 , 49 , 72 and the duration of diabetes ranged from inclusion at diagnosis 40 , 41 , 43 , 51 , 52 ,…”

An evaluation of renin‐angiotensin system markers in youth with type 2 diabetes and associations with renal outcomes

“…The kidney complications associated with youth onset T2D start earlier 1‐4 and progress more rapidly compared to type 1 and older onset type 2 populations 5,6 . Risk factors for progression have been evaluated in a few large cohorts such as the TODAY, 28,29 and SEARCH 30 studies and our own Canadian cohort 17 .…”

“…In contrast, the association between hypertension and albuminuria has not been consistent. Additional biopsychosocial risk factors 1 are emerging as important additional risk factors potentially linked to inflammatory pathways. Biopsy studies have shown that glomerular hypertrophy and focal glomerulosclerosis are important early histologic lesions in youth with T2D and albuminuria 31 .…”

“…ACE2 is a monocarboxypeptidase that serves as a protective arm of the RAS, since it cleaves angiotensin II (thereby reducing its deleterious effects) to angiotensin, 1‐7 a vasodilatory peptide 37 . ACE2 is highly expressed in the kidney, particularly in the brush border of the proximal tubule where it is hypothesized to be a regulator of angiotensin peptide metabolism 38 .…”

“…Youth with type 2 diabetes (T2D) have a specific phenotype that is, distinct from both adult onset and youth onset type 1 diabetes, with albuminuria affecting between 5% and 30% of individuals early in their disease course. [1][2][3][4] Rates of progression to end stage renal disease (ESRD) are also significantly higher as compared to type 1 and older onset type 2 populations. 5,6 Youth onset T2D is an evolving clinical condition with increasing prevalence, especially in socioeconomically disadvantaged populations.…”