Diabetic Nephropathy: Pathogenesis Type I or Type II Diabetes
↑ Glucose uptake & glycolysis in glomerular & tubular cells
Poor glycemic control = ↑ Glucose load
↑ Proximal tubule reabsorption of Na via Na/glucose co-transporter
↓ NaCl to distal tubule
Activation of tubulo- glomerular feedback at macula densa
to kidney
↑ Activation of renin- angiotensin system (RAS)
↑ Intrarenal angiotensin II
↑ Advanced glycation end products (AGE)
Shunting of glucose through non- glycolytic pathways (e.g. polyol)
Activation of Protein Kinase C (PKC) pathway
Excessive production and accumulation of glycolytic intermediates (e.g. sorbitol, hexosamine, succinate)
hyperglycemia
Succinate via GPR91
↑ Free radical production (oxidative stress)
Activation of cellular signalling, transcription factors and cytokines (e.g. TGF-β-Smad-MAPK, IGF-1, NF-κB)
↑NADPH oxidase activity
↑Blood volume ↑ Blood pressure ↑ Renal perfusion
Relative afferent arteriole dilatation, efferent arteriole constriction
Initial ↑ in glomerular filtration rate (GFR)
Podocyte loss/injury
Authors: Steven Chen Shannon Gui Yan Yu* Reviewers: Julia Heighton Ryan Brenneis Sophia Chou* * MD at time of publication
Initial glomerular hyperfiltration at time of diagnosis
↓ Production of matrix metallo- proteinases
Aberrant extracellular matrix (ECM) protein expression and accumulation
Sheer stress to glomeruli à pressure-induced damage
↑ Glomerular basement membrane permeability to proteins like albumin
↓ Extracellular matrix regulation
“Metabolic Pathway”
Mesangial matrix expansion
Kimmelstiel-
Wilson lesions (pink
hyaline nodules due to accumulation of damaged proteins)
Tubular fibrosis
Scarred glomeruli are less able to effectively filter blood
↓ in glomerular filtration rate (GFR)
Albuminuria
Usually occurs after ~5 years from time of diagnosis in T1DM; can occur at time of diagnosis in T2DM
Abbreviations
IGF: Insulin-like growth factor
MAPK: Mitogen-activated protein kinases NADPH: Nicotinamide adenine dinucleotide phosphate
NF-κB: Nuclear factor kappa-light-chain- enhancer of activated B cells
TGF-β: Transforming growth factor-β
Protein endocytosis into tubular cells causing inflammation
“Hemodynamic Pathway”
Diabetic Nephropathy
Overt diabetic nephropathy may take upwards of 15-25 years to develop
Note: The mechanisms presented here have been simplified. The cross- talk and signaling between the metabolic and hemodynamic factors do not manifest in a step-wise fashion, but rather occur in parallel.
Legend:
Pathophysiology
Mechanism
Sign/Symptom/Lab Finding
Complications
Published May 3, 2020 on www.thecalgaryguide.com