Diabetic Nephropathy Flashcards
diabetes mellitus - defined
*a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both
*the chronic hyperglycemia is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, KIDNEYS, etc
type 1 diabetes mellitus
*autoimmune disease characterized by:
-antibody and cell-mediated destruction of pancreatic islet cells, resulting in ABSOLUTE DEFICIENCY OF INSULIN SECRETION & absence of circulating c-peptide
*all patients eventually require insulin treatment
*may occur at any age but commonly in childhood and prior to age 30
type 2 diabetes mellitus
*insulin resistance + insulin deficiency
*part of the metabolic syndrome, along with HTN, HLD, obesity
*usually older adults but prevalence increasing in children
*largest and fasting growing group requiring RRT (dialysis)
leading cause of kidney disease & ESRD in the US
diabetic nephropathy
diabetic nephropathy - overview
*occurs in T1DM, T2DM, and secondary forms of DM (pancreatitis, pancreatectomy)
*glomerulopathy characterized by structural and functional changes:
-structural: thickened GBM, expansion of mesangial matrix, glomerular sclerosis
-functional: persistent albuminuria, worsening HTN, progressive decline in GFR
diabetic nephropathy - pathogenesis (overview)
- hyperglycemia → nonenzymatic glycation of tissue proteins → mesangial expansion → GBM thickening and increased permeability
- hyperfiltration (glomerular HTN and increased GFR) → glomerular hypertrophy and glomerular scarring (glomerulosclerosis) → further progression of nephropathy
diabetic nephropathy: glomerular hyperfiltration
*commonly seen in early diabetes
*result of afferent arteriolar dilation / efferent vasoconstriction
*mechanism: glucose-dependent effects on arteriole; range of vasoactive mediators
→ increase in glomerular hydrostatic pressure
→ increased protein spilling in filtrate
→ increased inflammation due to tubular loading
effect of ACEi or ARB on diabetic nephropathy
*ACEi / ARB block Ang II-mediated constriction of the efferent arteriole
*helps to lower glomerular hypertension and hydrostatic pressure
*helps to reduce progression of nephropathy
diabetic nephropathy: renal hypertrophy
*early hyperfiltration is associated with organomegaly and glomerulomegaly
1. organomegaly: diabetic kidneys are increased in size (by several centimeters)
2. glomerulomegaly: increased number of capillary loops and filtration surface due to hypertrophy
diabetic nephropathy: mesangial expansion & nodule formation
*hyperglycemia directly promotes mesangial expansion and injury
*high blood sugar → increased intracellular glucose → increased mesangial expansion and increased matrix production
*over time, leads to increased advanced glycation end products (AGEs)
diabetic nephropathy: development of proteinuria
*widening of GBM results from:
-accumulation of type IV collagen
-net reduction in negatively charged proteoglycans (loss of charge barrier)
*results in leakage of proteins into the urine
diabetic nephropathy: tubulointerstitial fibrosis
*important structural changes that correlate to progression of DN are:
-degree of mesangial expansion
-severity of tubulointerstitial disease
*tubulointerstitial changes start early in process and not only correlate with renal function but also with prognosis
*mechanism: release of factors (esp. TGF-beta) and other cytokines from glomerulus → tubular reabsorption of endocytosed protein → renal ischemia/hypoxia from progressive hyalinosis
natural history of diabetic nephropathy
- renal hypertrophy & hyperfiltration
-elevated GFR and urine albumin excretion rate; associated with glomerular and tubular hypertrophy and enlarged kidneys - normoalbuminuria with an elevated GFR (5-10 years)
-increased mesangial matrix - microalbuminuria (5-15 years)
-30 to 300 mg albumin/24 hours
-increase in GBM thickness and mesangial volume - overt proteinuria (10-20 years)
-300+ mg albumin/g of creatinine - decline in GRF (15-25 years)
-ESRD (after 5 to 7 years of nephrotic-range proteinuria)
risk factors for developing diabetic nephropathy
*incidence greater in:
-race: African Americans (3-6x), Pima Native Americans
-genetics: those with a diabetic sibling or parent with diabetic nephropathy
-increased duration of diabetes
-males slightly higher
-higher systemic blood pressures
screening for diabetic nephropathy
- check urine microalbumin levels (early morning sample, at least 2 occasions)
- 24hr collection - gold standard
- untimed MICROALBUMIN/CREATININE RATIO
note - persistent microalbuminuria = 30-300 mg/day
