Pathology: Kidney 3 Flashcards
Systemic diseases associated with nephrotic syndrome
– Diabetic nephropathy
– Amyloidosis
– Light chain deposition disease
Hereditary glomerular disease
– Alport syndrome
– Thin basement membrane disease
Diabetic Nephropathy is the leading cause of what?
-Leading cause of ESRD in most Western societies
diabetic nephropathy caues/risk
-Can occur in both DM Type I and Type II
– Risk is related to duration of disease
-Risk is multifactorial
– 30-40% of patients will develop nephropathy
pathogenesis of diabetic nephropathy-characteristic of DN
hyperfiltration
hyperfiltration characteristics
- Common in early diabetes
- ↑ GFR due to glucose- dependent afferent arteriolar dilation
- Angiotensin II mediated constriction of the efferent arteriole
- Hyperfiltration increases colloid osmotic pressure in the post-glomerular capillaries
- ↑Na reabsorption in the PT
- Angiotensin II causes hypertrophic PT growth
- Can be corrected with good glycemic control
pathogenesis of hypertrophy in diabetic nephropathy
- Seen early in onset
- The size of the kidney may increase by several centimeters.
- Associated with an increase in the number of mesangial cells and of capillary loops
- Increasing filtration surface area.
pathogenesis of mesangial changes in diabetic nephropathy
- The hallmarks of DN
- mesangial expansion
- nodular diabetic glomerulosclerosis (the acellular Kimmelstiel-Wilson lesion),
- Early mesangial lesion is characterized by a increase in mesangial cell number and size and increased deposition of extracellular matrix.
- Mesangial expansion is mediated by both glucose and glucose-derived AGEs.
pathogenesis of proteinuria in diabetic neuropathy
• Widening of the GBM
• accumulation of type IV collagen and net reduction in negatively charged heparin sulfate.
• The podocyte changes
• Increased width of the foot
processes.
• Apoptosis triggered by ANG II and TGF-B
• Migration reduced by ANG II preventing coverage of the BM
• Serum proteins cross the BM due to the disrupted texture, gaps, and holes
diabetic nephropathy on EM
BM and podocyte changes
pathogenesis of fibrosis in diabetic nephropathy
• Tubulointerstitial fibrosis is seen early in DN
• correlates with prognosis.
• Caused by release of growth factors:
• TGF-β, ANG II
• Tubular cells change their phenotype and
become fibroblasts.
• High glucose concentration and AGEs further stimulate this process.
features of stage 1 of DN
Stage 1: Onset of diabetes • GFR increase due to glomerular hyperfiltration • glomerular hypertrophy seen on biopsy • renal size • Reversible, transient albuminuria
features of stage 2 of DN
Stage 2: Clinically asymptomatic, but biopsy shows
• mesangial expansion
• GBM thickening
features of stage 3 of DN
Stage 3: Early nephropathy
• development of hypertension
• persistent microalbuminuria by 24-hr collection
• Urinary albumin excretion 30-300 mg/day
features of stage 4 of DN
Stage 4: Overt proteinuria
• urinary albumin > 300 mg/day
• GFR starts to decline
• 50% of patients will reach ESRD within 7-10 years
• Retinopathy present in 90-95% of patients
features of stage 5 DN
Stage 5: End-stage renal disease
• Renal replacement therapy necessary
• Occurs a mean of 15 years after onset of Type 1 DM in patients who develop proteinuria (30%)
co-morbidities of DM
- HTN
- Neuropathy
- Vascular changes
- Increased mortality
DN and HTN-potential mechanisms leading to HTN in T2DM
exogenous factors–>obesity–>insulin resistance, hyperleptinemia–>sympathetic activation–>HTN
genetic factors–>obesity, T2DM–>insulin resistance, hyperleptinemia–>sympathetic activation–>HTN
genetic factors–> T2DM–> hyperglycemia–> microvasculopathy, AngiotensinII–> HTN
genetic factors–>T2DM–>dyslipidemia–> microvasculopathy–>HTN
DN and complications
- Diabetic retinopathy
- Polyneuropathy
- Macrovascular complications
Diabetic retinopathy
- in almost all patients with type 1 diabetes and nephropathy.
- In 50% to 60% of type 2 diabetes with nephropathy
Polyneuropathy
- Sensory polyneuropathy: Diabetic foot
- Autonomic polyneuropathy
- Silent angina
- Gastroparesis
- erectile impotence
- detrusor paresis
Macrovascular complications
(5X more frequent)
• Stroke
• coronary heart disease
• peripheral vascular disease
DN and mortality with normoalbuminuria, microalbuminuria, and macroalbuminuria
- low mortality rates with normoalbuminuria
- higher mortality rates with microalbuminuria
- mortality greatly increased with macroalbuminuria!
treatment of DN
- HTN therapy
- Glucose control
- Reduction of proteinuria • Lipid lowering therapy
- Life style modification
HTN prevelance in DM pts with DN
In DM pts with DN, HTN is almost always present
uncontrolled HTN is associated with…
- more rapid progression of DN
- increased risk of fatal and nonfatal CV events.
- antihypertensive therapies improve survival in both type 1 and type 2 diabetics with DN.
The current recommended blood pressure target for all diabetics?
is below 140/90 mm Hg
• Was 130/80 before JNC 8
glucose control and DN
•Studies suggest that with good glycemic control helps
• Decrease risk of progression
•Results from the Diabetes Control and Complications Trial
(DCCT)
• reduction in progression from normoalbuminuria to microalbuminuria
• Decrease in and other microvascular complications, specifically retinopathy
• Decrease in cardiovascular (CV) sequelae, this persisted despite later deterioration of the glycemic control.
•Euglycemia that followed isolated transplantation of the pancreas was associated with a regression of the diabetic glomerulosclerosis. (N Engl J Med 1998; 339:69-75)
Reducing proteinuria in DN
- Renin-angiotensin-aldosterone system blockade
- Renoprotective independent of BP
- Reduces proteinuria
- May cause up to 30% decline in GFR but renoprotective in the longterm
- Works through renal hemodynamic changes and blocking non-hemodyanmic effects of Ang II
lipid control in DN
• Most patients with DN have:
– Low HDL
– High TGs
– Smaller LDL particle
• In type 2 diabetic patients with DN, treatment with statins provides substantial CV benefit
– Not seen in DN with ESRD
• Current guidelines
– LDL <70 mg/dl for diabetic patients with CVDLifestyle modifications for DN
• Smoking cessation
– Decreases progression of micro to macro albuminuria
• weight reduction
– Possibly improves renal outcome via reduction in proteinuria
Non-diabetic nephrotic
syndromes
Amyloidosis
Light chain deposition disease
Amyloidosis characterization
• Amyloidosis is a generic term for a family of diseases defined by morphologic criteria.
– Characterized by the deposition in extracellular spaces of a proteinaceous material
Amyloidosis affecting the kidney characteristics
– light chains, secreted by a single clone of B cells
• 20% of cases associated with multiple myeloma
– Usually lambda light chains (AL)
– Systemic amyloidosis (AA) results from chronic inflammation
• Not discussed
Kidney manifestations of amyloidosis
• kidney is often enlarged and hypertension is absent even when renal function is impaired.
• Proteinuria, mainly albuminuria, occurs in the absence of microscopic hematuria.
• Tubular defects from amyloid deposits
– Renal tubular acidosis (mostly as a part of Fanconi
syndrome)
– polyuria-polydipsia (resulting from urinary concentration defect)
amyloidosis on LM
deposits seen
amyloidosis with Congo-red stain
apple green birefringence
amyloidosis on IM
staining for light chain
Extra-renal manifestations of amyloidosis
• AL amyloidosis may infiltrate almost any organ other than the brain
– Restrictive cardiomyopathy in 1/3 of pts
– Gastrointestinal tract
• motility disturbances, malabsorption, hemorrhage, or obstruction
– Macroglossia
– Splenomegaly
– Peripheralnerve
• sensory polyneuropathy, autonomic neuropathy(orthostatic hypotension, lack of sweating, bladder dysfunction, impotence)
– Skin
• Purpura (around the eyes) papules, nodules, and plaques, occurring
usually on the face and upper trunk.
– Joint
• Shoulder pain and swelling
Light Chain Deposition Disease characteristics
• Deposition of excess immunoglobulin light chains in the kidney
– usually
– 50% of cases coexist with multiple myeloma
what do patients with light chain deposition disease develop?
– proteinuria
– hematuria
– chronic renal insufficiency
LCDD on LM
nodular glomerulosclerosis
LCDD on IF
light chain staining
• Kappa staining
LCDD on EM
granular deposits along GBM
Hereditary glomerular diseases
- Alport Syndrome
- Thin Basement Membrane
Alport Syndrome
• Most commonly X-linked recessive (80%) but can be autosomal recessive as well
• Mutation of the COL4A5 gene on chromosome Xq22 which encodes the alpha5 chain of type IV collagen
– defect in the basement membrane
renal manifestations of Alport Syndrome
• Hematuria
– Affected males have persistent microscopic hematuria
– episodicgrosshematuria,precipitatedbyURI
– Present in the first two decades of life.
– More than 90% of females with XLAS have persistent or intermittent microscopic hematuria, but about 7% of obligate heterozygotes never manifest hematuria
• Proteinuria is absent early but develops eventually in all males with XLAS and in both males and females with ARAS.
• Hypertension
• ESRD develops in all affected males with XLAS (90% by age 40)
–rate determined by the underlying COL4A5 mutation.
– Females with XLAS 12% developed ESRD before the age of 40, 30% by age 60 years, 40% by age 80 years
extra-renal manifestations of Alport Syndrome
• Cochlear defects
– adherence defect of the organ of Corti to the basilar membrane
– 80% of males
– 20-30% of female
• Ocular defects
– 30% to 40% of XLAS males
– 15% of XLAS females
– Anterior lenticonus, pathognomic (15% of males, associated with ESRD by 30 years)
– maculopathy, whitish or yellowish flecks or granulations in a perimacular distribution
• Leiomyomatosis (less common)
– esophagus and tracheobronchial tree
pathology of Alport Syndrome on LM
LM: Early in disease, glomeruli may appear normal. Later global and segmental glomerulosclerosis, interstitial fibrosis
pathology of Alport Syndrome on IF
IF: Negative or non-specific IgM, C
pathology of Alport Syndrome of EM
EM: variable thickening, thinning, basket weaving, and lamellation of the GBM
treatment of Alport Syndrome
• No disease-specific therapy
– RAAS blockade
• Renal replacement is eventually necessary
• Transplant
– 2-3% will get anti-GMB diseaseThin Basement Membrane Disease (Benign Familial Hematuria) characteristics
• Usually autosomal dominant inheritance
• Continuous or intermittent microhematuria, with or without gross hematuria, and generally no renal insufficiency
• Previously considered benign
– Proteinuria, HTN and ESRD are unusual
• Extra-renal features are rare
pathologic findings of TBMD on LM
LM: normal glomeruli
pathologic findings of TBMD on IF
negative
pathologic findings of TBMD on EM
___________???
treatment for TBMD
• Reassurance
• Should be followed
– Very small but real risk of progression to ESRD
– BMP, urinalysis and BP monitored every 1-2 years
