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
factors that can transiently increase urine albumin excretion rate (UAER)
*strenuous exercise
*oral protein intake
*UTI
*infection
who to screen for diabetic nephropathy?
*T1DM for > 5 years: screen annually
*T2DM, from time of dx: screen annually
*individuals with an elevated UAER > 30 mg/day should be screened every 6 months
advantage of screening for diabetic nephropathy
*MICROALBUMINURIA predicts HIGH renal and cardiovascular risk
diabetic nephropathy - clinical features
*persistent albuminuria
*worsening hypertension
*progressive decline in GFR
*microvascular and macrovascular complications
diabetic nephropathy - diagnosis
*based on presence of persistent albuminuria
*biopsy is the DEFINITIVE means of dx
*additional diagnostic support:
-ultrasound demonstrating large kidney size
-presence of diabetic retinopathy
-lack of RBC cast or macroscopic hematuria
-no evidence of other systemic illnesses
guidelines for diagnosis of diabetic nephropathy in T1DM pts
*microalbuminuria should be attributed to diabetes if:
-diabetic retinopathy is present
AND/OR
-diabetes duration is at least 10 years
guidelines for diagnosis of diabetic nephropathy in T2DM pts
*microalbuminuria should be attributed to diabetes if:
-diabetic retinopathy is present
OR
-patient progresses to macroalbuminuria
when to consider kidney biopsy in diabetic patients
*accelerated renal failure (rapid decline in renal function with minimal proteinuria)
*rapidly increasing protein excretion or acute onset nephrotic syndrome
*refractory HTN
*macroscopic hematuria or active urine sediment
*s/s of another systemic disease
diabetic nephropathy - pathology
*thickening of GBM
*mesangial matrix expansion
*glomerular sclerosis
*arteriolar hyalinosis (both afferent and efferent)
*decreased podocytes
*Kimmelstein-Wilson Nodules
diabetic nephropathy - treatments
*ACEi/ARB
*SGLT2 inhibitors
*goal: minimize risk factors for progression
risk factors for progression of diabetic nephropathy
*worsening proteinuria
*poor glycemic control
*hypertension
*genetic predisposition
*male sex
*other: HLD, tobacco use, obesity, low birth weight
proteinuria reduction in diabetic nephropathy
*ACEi/ARB = first line
*NDP CCBs (verapamil, diltiazem)
*aldosterone antagonists (spironolactone, eplerenone)
*goal = minimize proteinuria
glycemic control in diabetic nephropathy
*evidence for tight glycemic controlling in type 1 DM
*goal = HbA1C < 7.0
hypertension control in diabetic nephropathy
*goal < 130/80
*ACEi/ARB and salt restriction
hyperlipidemia control in diabetic nephropathy
*purpose: microalbuminuria is an INDEPENDENT risk factor for CV disease
*goal: LDL < 100 or < 70 (if other risk factors)
*statins
ways to slow progression of diabetic nephropathy - overview
- minimize proteinuria w/ ACEi or ARB
- glucose control
- control HTN w/ ACEi or ARB
- control HLD (statins)
- adjunct therapy
- RAAS blockade (ACEi/ARB)
- SGLT2 inhibitors
