Renal 04: Pathology 2

Front 1

What systemic diseases are associated with Nephrotic Syndrome?

Back 1

- Diabetic Nephropathy
- Amyloidosis
- Light Chain Deposition Disease

Front 2

What are the hereditary glomerular diseases?

Back 2

- Alport syndrome
- Thin basement membrane disease

Front 3

What is the leading cause of ESRD in most western societies?

Back 3

Diabetic Nephropathy (related to DM type I and II)
30-40% of patients will develop nephropathy

Front 4

How does Diabetes Mellitus relate to Nephropathy?

Back 4

- Both DM type 1 and 2
- Risk is related to duration of disease

Front 5

How long does it take after first diagnosis of diabetes to get proteinuria?

Back 5

- Takes 5-10 years until some people start getting proteinuria
- At 25 years after diagnosis, ~50% have proteinuria

Front 6

How long after onset of proteinuria with DM does it take to get renal failure?

Back 6

- Once proteinuria begins, you can get renal failure at any time
- 5 years after onset, ~50% have renal failure

Front 7

When should a person with DM be worried about renal failure?

Back 7

Once they start getting proteinuria

Front 8

How is the nephron affected by DM?

Back 8

- Dilated afferent arteriole (glucose-dependent, via vasoactive mediators VEGF, NO, TGF-B)
- Constricted efferent arteriole (increased pressure)
- Glomerular loss of proteins
- Proteins stored in cytoplasm cause cell activation and inflammation

Front 9

What are the implications of a dilated afferent arteriole and a constricted efferent arteriole in DM? Is this fixable?

Back 9

- Causes hyperfiltration
- Increases colloid osmotic pressure in post-glomerular capillaries
- Increases Na+ reabsorption in PT

- Can be corrected w/ good glycemic control

Front 10

How does angiotensin II affect nephron?

Back 10

Causes hypertrophic PT growth

Front 11

What are the changes to kidney function in diabetic nephropathy?

Back 11

- Hyperfiltration
- Hypertrophy of kidney (may increase by several cm)
- Mesangial changes (increase in number and size)
- Proteinuria
- Fibrosis

Front 12

What is hypertrophy of the kidney in DM/diabetic nephropathy associated with?

Back 12

Increase in number of mesangial cells and capillary loops (increases filtration surface area)

Front 13

How does the mesangium change in diabetic nephropathy? What mediates this?

Back 13

- Mesangial expansion (increase in cell number and size)
- Nodular diabetic glomerulosclerosis (increased deposition of extracellular matrix)

- Mediated by both glucose and glucose-derived AGEs (Advanced glycation end products)

Front 14

What causes proteinuria in Diabetic Nephropathy?

Back 14

- Widening of GBM (accumulation of type IV collagen and net reduction in negatively charged heparin sulfate)
- Podocyte changes (increased width of foot processes, apoptosis, reduced migration preventing coverage of BM)

* Serum proteins cross the BM d/t disrupted texture, gaps, and holes *

Front 15

What causes apoptosis of podocytes in diabetic nephropathy? Implications?

Back 15

- Triggered by AngII and TGF-B
- Leads to changes in podocytes that causes proteinuria

Front 16

What causes reduced migration of podocytes in diabetic nephropathy? Implications?

Back 16

- Reduced by AngII
- Prevents coverage of BM by podocytes, leading to proteinuria

Front 17

What is normal / abnormal?

Back 17

- Left: normal BM and podocyte
- Right: BM and podocyte changes associated with diabetic nephropathy

Front 18

What kind of fibrosis is seen in Diabetic Nephropathy? Cause? Implications?

Back 18

- Tubulointerstitial fibrosis (correlates w/ prognosis)
- Caused by release of TGF-β and AngII
- Tubular cells change their phenotype and become fibroblasts
- High glucose conc. and AGEs (Advanced glycation end products) further stimulate this process

Front 19

What are the stages of Diabetic Nephropathy?

Back 19

- Pre (1 and 2)
- Incipient (3)
- Overt (4)
- ESRD (5)

Front 20

What happens to GFR across the stages of Diabetic Nephropathy?

Back 20

- Pre (1 and 2): GFR ↑ (25-50%)
- Incipient (3): returns to normal level
- Overt (4): GFR ↓
- ESRD (5): very low GFR

Front 21

What happens to albuminuria across the stages of Diabetic Nephropathy?

Back 21

- Pre (1 and 2): little change
- Incipient (3): small increase
- Overt (4): greater climb
- ESRD (5): very high

Front 22

What are the functional and structural characteristics of Pre (Stage 1) Diabetic Nephropathy?

Back 22

Onset of Diabetes:
- GFR ↑ d/t glomerular hyper-filtration
- Glomerular hypertrophy seen on biposy
- Renal size ↑
- Reversible, transient albuminuria

Front 23

What are the functional and structural characteristics of Pre (Stage 2) Diabetic Nephropathy?

Back 23

Clinically Asymptomatic, but Biopsy shows:
- Mesangial expansion
- GBM thickening

Front 24

What are the functional and structural characteristics of Incipient (Stage 3) Diabetic Nephropathy?

Back 24

Early Nephropathy
- Development of HTN
- Persistent micro-albuminuria by 24-hr collection
- Urinary albumin excretion 30-300 mg/day

Front 25

What are the functional and structural characteristics of Overt (Stage 4) Diabetic Nephropathy?

Back 25

Overt Proteinuria:
- Urinary albumin > 300 mg/day
- GFR starts to decline
- 50% of patients will reach ESRD within 7-10 years
- Retinopathy presents in 90-95% patients

Front 26

What are the functional and structural characteristics of ESRD (Stage 5) Diabetic Nephropathy?

Back 26

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%)

Front 27

What are Kimmelstiel-Wilson lesions?

Back 27

- Acellular
- Nodular diabetic glomerulosclerosis

Front 28

What are the co-morbidities of DM?

Back 28

- HTN
- Neuropathy
- Vascular changes
- Increased mortality

Front 29

What features of DM lead to HTN?

Back 29

- Obesity
- Sympathetic activation d/t insulin resistance and hyperleptinemia
- Microvsculopathy d/t hyperglycemia
- AngII d/t hyperglycemia, macrovasculopathy, and dyslipidemia

Front 30

How common is Diabetic Retinopathy?

Back 30

- Almost all patients w/ Type 1 diabetes w/ nephropathy
- In 50-60% of Type 2 diabetes w/ nephropathy

Front 31

What are the characteristics / syptoms of neuropathy in diabetic nephropathy?

Back 31

- Sensory polyneuropathy: diabetic foot
- Autonomic polyneuropathy: silent angina, gastroparesis, erectile impotence, detrusor paresis

Front 32

What are the macrovascular complications seen in diabetic nephropathy?

Back 32

- Stroke
- Coronary heart disease
- Peripheral vascular disease

Front 33

How does microalbuminuria and macroalbuminuria affect diabetic nephropathy mortality?

Back 33

Macroalbuminuria >> Microalbuminuria >> Normoalbuminuria

Front 34

How do you treat Diabetic Nephropathy?

Back 34

- HTN therapy
- Glucose control
- Reduction of proteinuria
- Lipid lowering therapy
- Life style modification

Front 35

How does HTN relate to DN?

Back 35

- In DM patients w/ DN, HTN is almost always present
- Uncontrolled HTN associated with more rapid progression of DN and increased risk of fatal and nonfatal CV events

Front 36

What is the goal BP for diabetics? How do anti-HTN therapies affect survival?

Back 36

- Goal: 130/80 mmHg (or lower)
- Anti-HTN therapies improve survival in both type 1 and 2 DM w/ DN

Front 37

How does glucose control affect DN?

Back 37

- Good glycemic control (HbA1c < 7%) decreases risk of DM type 1 developing ESRD after 25 years from 40% to 9%
- Reduces progression to microalbuminuria
- Decreases microvascular complications (ie retinopathy)
- Decreases CV sequelae (even after later deterioration in glycemic control)

Front 38

How do you reduce proteinuria?

Back 38

Renin-angiotensin-aldosterone system blockade

Front 39

How does renin-angiotensin-aldosterone system blockade affect DN?

Back 39

- Reduces proteinuria
- Renoprotective independent of BP
- May cause up to 30% decline in GFR, but reno-protective in long-term
- Works through renal hemodynamic changes and blocking non-hemodynamic effects of AngII

Front 40

What are the typical lipid levels in DN?

Back 40

- Low HDL
- High TGs
- Smaller LDL particles

Front 41

How are lipids controlled in DN? Guidelines?

Back 41

- In type 2 DM w/ DN, tx w/ statins provides substantial CV benefit
- Goal: LDL <100 mg/dl in general and <70 mg/dl w/ CVD

Front 42

What lifestyle modifications should patients w/ DN do? Implications?

Back 42

- Smoking cessation - decreases progression of micro to macro albuminuria
- Weight reduction - possibly improves renal outcome via reduction in proteinuria

Front 43

In Type 1 DM, how should you manage a patient with normoalbuminuria / normotension?

Back 43

Optimize glycemic control (target HbA1c < 7%)

Front 44

In Type 1 DM, how should you manage a patient with normoalbuminuria and hypertension?

Back 44

- Consider ACE-I or ARB as anti-HTN agent (target BP < 130/80 mmHg)
- Dietary Na+ restriction +/- diuretic therapy

Front 45

In Type 1 DM, how should you manage a patient with microalbuminuria and normotension?

Back 45

- Start ACE-I or ARB
- Titrate dose as tolerate to normoalbuminuria

Front 46

In Type 1 DM, how should you manage a patient with microalbuminuria and hypertension?

Back 46

- Titrate ACE-I or ARB as tolerated

- Consider addition of:
-- Selective aldosterone receptor antagonist (eg, spironolactone, eplerenone)
-- Non-dihydropyridine CCB (eg, diltiazem or verapamil)
-- Direct renin inhibitor (eg, aliskiren)

- Dietary Na+ restriction +/- loop or thiazide diuretic

- Treat to normoalbuminuria and BP < 130/80 mmHg

Front 47

In Type 1 DM, how should you manage a patient with overt proteinuria?

Back 47

- Continue management as for microalbuminuria and hypertension w/ aggressive BP control
- Treat CV risks and consider aspirin therapy and statin therapy
- Lifestyle modifications: smoking cessation and weight reduction as appropriate

Front 48

In Type 1 DM, how should you manage a patient with declining GFR?

Back 48

- Provide nutrition counseling regarding Na+, K+, and phosphorus restriction
- Avoid protein-calorie malnutrition
- Treat anemia
- Prepare for dialysis or transplantation when GFR <20ml/min

Front 49

What are the non-diabetic nephrotic syndromes?

Back 49

- Amyloidosis
- Light chain deposition disease

Front 50

What is Amyloidosis?

Back 50

- Generic term for a family of diseases defined by morphologic criteria
- Characterized by deposition in extracellular spaces of a proteinaceous material

Front 51

What kind of proteins cause amyloidosis in the kidney?

Back 51

- Light chains (secreted by a single clone of B cells)
- Lambda light chains (AL)

Front 52

What are light chains released from? What is it associated with?

Back 52

- Secreted by a single clone of B cells
- 20% of cases associated with multiple myeloma
- Type of amyloidosis affecting the kidney

Front 53

What causes systemic amyloidosis?

Back 53

Chronic inflammation

Front 54

What are the kidney manifestations of amyloidosis?

Back 54

- Enlarged
- Proteinuria, mainly albuminuria
- Absence of microscopic hematuria
- Tubular defects from amyloid deposits
- Renal tubular acidosis (Fanconi syndrome)
- Polyuria - polydipsia

Front 55

What syndrome is renal tubular acidosis a part of?

Back 55

Fanconi syndrome

Front 56

How can you diagnose Amyloidosis?

Back 56

- LM: deposits
- Congo-red stain - apple green birefringence
- IM: staining for light chain

Front 57

Which organs can be affected by amyloidosis?

Back 57

May infiltrate any organ other than the brain

Front 58

What are the extra-renal manifestations of amyloidosis?

Back 58

- Restrictive CM (1/3)
- GI: motility disturbances, malabsorption, hemorrhage, or obstruction
- Macroglossia (large tongue)
- Splenomegaly
- Peripheral nerve: sensory polyneuropathy, autonomic neuropathy (orthostatic HTN), lack of sweating, bladder dysfunction, impotence
- Skin: purpura (around eyes), papules, nodules, and plaques, occurring usually on face and upper trunk
- Joint: shoulder pain and swelling

Front 59

What component of immunoglobulin can be deposited in the kidney?

Back 59

Usually κ light chain

Front 60

What is light chain deposition disease associated with?

Back 60

50% of cases coexist w/ multiple myeloma

Front 61

What symptoms do patients with light chain deposition disease develop?

Back 61

- Proteinuria
- Hematuria
- Chronic renal insufficiency

Front 62

How can you diagnose light chain deposition disease develop?

Back 62

- LM: nodular glomerulosclerosis
- IF: light chain staining (κ)
- EM: granular deposits along GBM

Front 63

How can you distinguish the types of amyloidosis?

Back 63

- Biopsy of superficial organ / kidney specimen
- Congo-Red Stain:
→ +: amyloidosis (lambda light chains usually)
→ -: stain w/ anti-κ/λ (light chain deposition disease)

Front 64

What are the types of hereditary glomerular disease?

Back 64

- Alport syndrome
- Thin Basement Membrane

Front 65

How is Alport syndrome inherited?

Back 65

- 80% X-linked recessive
- Can be autosomal recessive too

Front 66

What mutation causes Alport Syndrome? What does it encode? Implications?

Back 66

- COL4A5 gene on chromosome Xq22
- Encodes α5 chain of type IV collagen
- Leads to defect in basement membrane

Front 67

What are the renal symptoms of Alport Syndrome?

Back 67

- Hematuria
- Proteinuria
- HTN
- ESRD in all affected males w/ X-linked AS (90% by age 40)

Front 68

What are the characteristics of hematuria in Alport Syndrome?

Back 68

- Males have persistent microscopic hematuria
- Episodic gross hematuria, precipitated by URI
- First 2 decades of life
- More than 90% of females w/ X-linked AS have persistent or intermittent microscpic hematuria (but 7% of obligate heterozygotes never manifest hematuria)

Front 69

What are the characteristics of proteinuria in Alport Syndrome?

Back 69

- Absent early
- Develops eventually in all males w/ X-linked AS and females w/ Autosomal-Recessive AS

Front 70

What determines the rate of development of ESRD in Alport Syndrome?

Back 70

- Rate determined by underlying COL4A5 mutation
- 12% females w/ X-linked AS develop ESRD before age 40, 30% by 60, 40% by 80
- 90% of males w/ X-linked AS develop ESRD by age 40

Front 71

Is Alport Syndrome more severe in males or females?

Back 71

Males
- 12% females w/ X-linked AS develop ESRD before age 40, 30% by 60, 40% by 80
- 90% of males w/ X-linked AS develop ESRD by age 40

Front 72

What are the extra-renal manifestations of Alport Syndrome?

Back 72

- Cochlear defects
- Ocular defects
- Leiomyomatosis

Front 73

What are the characteristics of cochlear defects in Alport Syndrome? Who is affected more by it?

Back 73

- Adherence defect of organ of Corti to basilar membrane
- 80% of males
- 20-30% of females

Front 74

What are the characteristics of ocular defects in Alport Syndrome? Who is affected more by it?

Back 74

- Anterior lenticonus, pathognomic
- Maculopathy, whitish or yellowish flecks or granulations in a perimacular distribution
- 30-40% of XLAS males
- 15% of XLAS females

Front 75

What are the characteristics of leiomyomatosis in Alport Syndrome? Who is affected more by it?

Back 75

Esophagus and tracheobronchial tree

Front 76

How do you diagnose Alport Syndrome?

Back 76

- LM: early in disease glomeruli may appear normal; later global and segmental glomerulosclerosis, interstitial fibrosis

- IF: negative or non-specific IgM, C

- EM: variable thickening, thinning, basket weaving, and lamellation of GBM

Front 77

How do you treat Alport Syndrome?

Back 77

- No-disease specific therapy (RAAS blockade)
- Renal replacement is eventually necessary
- Transplant: 2-3% will get anti-GBM disease

Front 78

What is the other name for thin basement membrane disease?

Back 78

Benign Familial Hematuria

Front 79

How is thin basement membrane disease (benign familial hematuria) inherited?

Back 79

Usually autosomal dominant inheritance

Front 80

What are the features of thin basement membrane disease (benign familial hematuria)?

Back 80

- Continuous or intermitten microhematuria
- With or without gross hematuria
- Generally no renal insufficiency
- Previously considered benign (proteinuria, HTN, and ESRD are unusual)
- Extra-renal features are rare

Front 81

How do you diagnose thin basement membrane disease (benign familial hematuria)?

Back 81

** EM: thin GBM (usually ≤ 200 nm)

- LM: normal glomeruli

- IF: negative

Front 82

How do you treat thin basement membrane disease (benign familial hematuria)?

Back 82

- Reassurance
- Should be followed: BMP, urinalysis, and BP monitored every 1-2 years

Front 83

Does thin basement membrane disease (benign familial hematuria) progress to ESRD?

Back 83

Very small, but real, risk of progression to ESRD

Front 84

What is the most common cause of end-stage renal disease in US?

Back 84

Diabetes Mellitus