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STEPH Glom Diseases > FSGS > Flashcards

FSGS Flashcards

1
Q

FSGS

Background

A

FSGS is the most common cause of nephrotic syndrome in African American adults and most common cause of GN-related ESRD in Black and White patients in the United States.

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2
Q

FSGS

Background

A

FSGS refers to a morphologic pattern of glomerular injury that may arise from a primary podocytopathy or secondary adaptive process involving nephron mass reduction, reflux nephropathy, viral or drug toxicity, genetic mutations, or other glomerular disease.

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3
Q

FSGS

Background

A

Histopathologic findings: segmental increase of mesangial matrix with obliteration of capillaries, sclerosis, hyalinosis, foam cells, podocyte hypertrophy with or without hyperplasia, and adhesions between glomerular tuft and Bowman capsule.

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4
Q

FSGS

Background

A

NOTE:
The deep inner juxtamedullary glomeruli are preferentially affected in early primary FSGS. Renal biopsies containing <15 glomeruli or only cortical glomeruli cannot exclude FSGS.

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5
Q

FSGS

Classification of FSGS

FSGS arising from primary alteration of glomerular epithelial cell:

A

Occurs with podocytopathies (e.g., genetic disorders), drugs, viral infections and primary FSGS. See Etiologies of FSGS below.

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6
Q

FSGS

Classification of FSGS

FSGS arising from primary alteration of glomerular epithelial cell:

A

Sudden onset edema and proteinuria

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7
Q

FSGS

Classification of FSGS

FSGS arising from primary alteration of glomerular epithelial cell:

A

Nephrotic syndrome (proteinuria > 3.5 g/d and serum albumin < 3.5 g/dL)

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8
Q

FSGS

Classification of FSGS

FSGS arising from primary alteration of glomerular epithelial cell:

A

Widespread foot process effacement of nonsclerotic glomeruli on EM

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9
Q

FSGS

Classification of FSGS

FSGS arising from reduced nephron mass or glomerular adaptations to injurious insults.

A

Development of edema and proteinuria are usually slowly progressive.

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10
Q

FSGS

Classification of FSGS

FSGS arising from reduced nephron mass or glomerular adaptations to injurious insults.

A

Does not typically present with nephrotic syndrome

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11
Q

FSGS

Classification of FSGS

FSGS arising from reduced nephron mass or glomerular adaptations to injurious insults.

A

EM generally reveals <80% segmental foot process effacement of nonsclerotic glomeruli.

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12
Q

FSGS

Classification of FSGS

A

FSGS arising from focal proliferative GN or hereditary nephropathies such as Alport syndrome.

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13
Q

FSGS

Genetic Predisposition to FSGS

A

APOL1: located on chromosome 22, in linkage disequilibrium with MYH9, codes for apolipoprotein L-1

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14
Q

FSGS

Genetic Predisposition to FSGS

A

Missense mutations of APOL1 are thought to predispose patients of African descents (rather than MYH9 in earlier reports) to an excess risk of FSGS, HIVAN and chronic hypertensive nephrosclerosis. Greatest risk: mutation of 2 alleles.

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15
Q

FSGS

Genetic Predisposition to FSGS

A

The same APOL1 mutations are protective against Trypanosoma brucei, a parasite spread by tsetse flies in Africa.

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16
Q

FSGS

Etiologies of FSGS

Primary FSGS:

A

Presence of the soluble form of urokinase receptor (suPAR) was previously thought to be a candidate in the pathogenesis of primary FSGS. This has been largely disproved.

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17
Q

FSGS

Etiologies of FSGS

Primary FSGS:

A

Cardiotropin-like cytokine circulating factor has also been implicated in primary FSGS.

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18
Q

FSGS

Etiologies of FSGS

Primary FSGS:

A

Pathogenic circulating factor for primary FSGS remains unknown.

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19
Q

FSGS

Etiologies of FSGS

All other etiologies of FSGS:

A

Familial/genetic: mutations including nephrin (NPHS1), podocin (NPHS2), α-actinin 4, transient receptor potential cation 6 (TRPC6), WT1, informin-2, SCARB2 (LIMP2), formin (INF2), CD2-associated protein, mitochondrial cytopathies

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20
Q

FSGS

Etiologies of FSGS

All other etiologies of FSGS:

A

Virus: human immunodeficiency virus type-1, parvovirus B19, simian virus 40, CMV, Epstein–Barr virus

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21
Q

FSGS

Etiologies of FSGS

All other etiologies of FSGS:

A

Drugs: heroin, interferons α, β, and γ), lithium, pamidronate, alendronate, sirolimus, anabolic steroids, CNIs

Adaptive structural–functional responses

22
Q

FSGS

Etiologies of FSGS

All other etiologies of FSGS:

A

Reduced renal mass: low birth weight, oligomeganephronia, premature birth, unilateral kidney agenesis, reflux uropathy, chronic allograft nephropathy, advanced renal disease with reductions in functioning nephrons

23
Q

FSGS

Etiologies of FSGS

All other etiologies of FSGS:

A

Initially normal renal mass: hypertension, DM, atheroemboli/acute vaso-occlusive process, obesity, increased lean body mass, anabolic steroids (body builders), cyanotic congenital heart disease, sickle cell anemia

24
Q

FSGS

Etiologies of FSGS

All other etiologies of FSGS:

A

Malignancy (lymphoma)

Association with any underlying glomerular diseases: IgAN, LN, pauci-immune focal necrotizing and crescentic GN, hereditary nephritis (Alport syndrome), membranous glomerulopathy, TMA

25
Q

FSGS

Histopathology of FSGS Variants

Not-otherwise-specified (NOS) FSGS:

A

Generic form of FSGS, not meeting any variant below

26
Q

FSGS

Histopathology of FSGS Variants

Not-otherwise-specified (NOS) FSGS:

A

Associations: most common subtype, can occur with primary or secondary including genetic forms; other forms can evolve into NOS over time

Clinical features: variable

27
Q

FSGS

Histopathology of FSGS Variants

Perihilar FSGS:

A

Lesions at glomerular vascular pole thought to reflect increased filtration pressures at the afferent arterioles associated with compensatory demand, glomerular hypertrophy, foot process effacement typically not severe and segmental

28
Q

FSGS

Histopathology of FSGS Variants

Perihilar FSGS:

A

Associations: adaptive FSGS (see Etiologies of FSGS)

Clinical features: typically subnephrotic proteinuria and normal serum albumin levels

29
Q

FSGS

Histopathology of FSGS Variants

Cellular FSGS:

A

Least common variant

Expansile segmental lesion with endocapillary hypercellularity, often including foam cells and infiltrating leukocytes; variable glomerular epithelial cell hyperplasia

30
Q

FSGS

Histopathology of FSGS Variants

Cellular FSGS:

A

Severe foot-process effacement typical on EM

Associations: usually primary, but may be seen with secondary causes

31
Q

FSGS

Histopathology of FSGS Variants

Cellular FSGS:

A

May represent early stage in the evolution of FSGS or tip lesion without proper glomerular orientation

Clinical features: typically nephrotic syndrome

32
Q

FSGS

Histopathology of FSGS Variants

Tip lesion FSGS:

A

Segmental lesion involving tubular pole, with either adhesion to tubular outlet or confluence of hypertrophic podocytes and tubular epithelial cells, may herniate into proximal tubule, often foam cells.

33
Q

FSGS

Histopathology of FSGS Variants

Tip lesion FSGS:

A

Compared with other variants, tip lesion has the least tubular atrophy and interstitial fibrosis; severe foot-process effacement is typical.

Tip lesion is more common in white race.

34
Q

FSGS

Histopathology of FSGS Variants

Tip lesion FSGS:

A

Associations: usually primary; thought to be mediated by physical stresses on paratubular segment due to convergence of protein-rich filtrate on tubular pole.

35
Q

FSGS

Histopathology of FSGS Variants

Tip lesion FSGS:

A

Clinical features: usually abrupt onset of nephrotic syndrome; best prognosis, highest rate of response to glucocorticoids compared to all other FSGS variants.

36
Q

FSGS

Histopathology of FSGS Variants

Collapsing FSGS:

A

Implosive glomerular-tuft collapse with hypertrophy and hyperplasia of overlying epithelial cells; hyperplastic glomerular epithelial cells may fill urinary space, resembling crescents; severe tubular injury; tubular microcysts common; severe foot-process effacement

37
Q

FSGS

Histopathology of FSGS Variants

Collapsing FSGS:

A

Associations: primary or secondary

Clinical features: most aggressive variant of primary FSGS, black racial predominance and severe nephrotic syndrome; worse prognosis, poor response to glucocorticoids.

38
Q

FSGS

Management of FSGS

A

Routine therapy for all FSGS variants: RAAS inhibition and dietary sodium restriction

39
Q

FSGS

Management of FSGS

Primary FSGS with subnephrotic proteinuria:

A

If no response or worsening of disease to routine therapy above, add glucocorticoids daily or alternate × at least 4 weeks, continue high dose up to a maximum of 16 week trial (prednisone 1 mg/kg (maximum 80 mg) daily or 2 mg/kg (maximum 120 mg) alternate day

40
Q

FSGS

Management of FSGS

Primary FSGS with subnephrotic proteinuria:

A

If still no improvement or intolerance to glucocorticoids, (e.g., uncontrolled diabetes, psychiatric conditions, severe osteoporosis), consider CNI.

41
Q

FSGS

Management of FSGS

Primary FSGS with subnephrotic proteinuria:

A

Once remission is achieved (complete remission: proteinuria < 0.3 g/d, normal SCr and serum albumin > 3.5 g/dL; partial remission: proteinuria 0.3 to 3.5 g/d, stable SCr or change in SCr by <25%), taper steroids slowly over 6 months.

42
Q

FSGS

Management of FSGS

Primary FSGS with subnephrotic proteinuria:

Steroid-resistant FSGS (persistence of nephrotic syndrome after 4 months of prednisone at 1 mg/kg/d): CNI plus prednisone.

A

Cyclosporine is thought to exert an antiproteinuric effect on the podocyte actin cytoskeleton independent of its immunosuppressive effect.

43
Q

FSGS

Management of FSGS

Primary FSGS with subnephrotic proteinuria:

Steroid-resistant FSGS (persistence of nephrotic syndrome after 4 months of prednisone at 1 mg/kg/d): CNI plus prednisone.

A

Cyclosporine 3 to 5 mg/kg/d in divided doses (target levels 125 to 175 ng/mL) for at least 4 to 6 months (or TAC 0.1 to 0.2 mg/kg/d in two divided doses (target levels 5 to 10 ng/mL).

44
Q

FSGS

Management of FSGS

Primary FSGS with subnephrotic proteinuria:

Steroid-resistant FSGS (persistence of nephrotic syndrome after 4 months of prednisone at 1 mg/kg/d): CNI plus prednisone.

A

If complete or partial remission, continue CNI for at least 12 months, followed by slow taper (reduce dose by 25% every 2 months).

45
Q

FSGS

Management of FSGS

Primary FSGS with subnephrotic proteinuria:

Steroid-resistant FSGS (persistence of nephrotic syndrome after 4 months of prednisone at 1 mg/kg/d): CNI plus prednisone.

A

If no remission by 6 months, discontinue therapy.

46
Q

FSGS

Management of FSGS

Primary FSGS with subnephrotic proteinuria:

Steroid-resistant FSGS (persistence of nephrotic syndrome after 4 months of prednisone at 1 mg/kg/d): CNI plus prednisone.

A

For steroid resistant FSGS and cyclosporine intolerance, combination of MMF and high-dose dexamethasone (0.15 mg/kg/d for 4 to 6 months, then taper off over 4 to 8 weeks) is suggested. Other options: ACTH gel (ACTHAR), rituximab, pirfenidone (anti-fibrotic agent), fresolimumab (anti-TGFβ antibody)

47
Q

FSGS

Management of FSGS

Primary FSGS with subnephrotic proteinuria:

Steroid-resistant FSGS (persistence of nephrotic syndrome after 4 months of prednisone at 1 mg/kg/d): CNI plus prednisone.

A

Steroid dependent FSGS: two relapses during or within 2 weeks of completing steroid therapy: treatment is similar to relapsing MCD in adults. Relapse is defined as proteinuria > 3.5 g/d after complete remission has been obtained.

48
Q

FSGS

Management of FSGS

Primary FSGS with nephrotic range proteinuria:

A

Glucocorticoids daily or alternate day × 16 week trial

If no improvement or intolerance to glucocorticoids, consider CNI.

49
Q

FSGS

Management of FSGS

Primary FSGS with nephrotic range proteinuria:

A

Adaptive FSGS: no immunosuppressive therapy; encourage weight loss if obese.

Secondary FSGS: treat underlying disease or removal of etiologic agents

50
Q

FSGS

Kidney Transplantation

A

Recurrence occurs in 20% to 50% of primary FSGS.

51
Q

FSGS

Kidney Transplantation

A

Risks for recurrence:

Children younger than 15 years old

Rapid course of ESRD (<3 years in native kidneys)

Heavy proteinuria prior to transplantation

Loss of previous allografts to recurrence

52
Q

FSGS

Kidney Transplantation

A

Plasmapheresis used in the early course of disease recurrence have been met with variable success.

STEPH Glom Diseases (23 decks)

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