Focal Segmental Glomerulosclerosis FSGS and the Kidney Transplant Patient

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Focal Segmental Glomerulosclerosis (FSGS)and the
Kidney Transplant Patient

• Cathleen E. Bailey-Vega RN, BSN, CCTC
• Margaret White RN, BSN, CCTC
• Ochsner Transplant Center

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Causes of ESRD (USRDS per million)

• Diabetes Mellitus 149
• Hypertension 90
• Glomerulonephritis 28
• Cystic Kidney 8
• Other 38
• Unknown 14
• Missing Disease 5

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Focal Segmental Glomerulosclerosis

• Initially described in 1972
• Zimmerman et al induced proteinuria in rats
  injected with serum from a patient with recurrent
  FSGS
• Dantal et al treated patients with recurrent FSGS
  with protein A immunoadsorption and demonstrated
  that the material eluted from the protein A
  column induced proteinuria when injected in rats

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Classifications of FSGS Primary vs. Secondary

• Permeability Factor (100 foot process
  effacement)
• Idiopathic
• Autoimmune (T-cell response)

• Toxins
• Genetic Abnormalities
• Infections (HIV, Parvo B-19)
• Obesicity
• Heroin Nephropathy
• Familial Disease
• Drug Toxicity (pamidronate)

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Diagnosis

• Blood Chemistries
• Urinalysis
• 24 hour urine for creatinine and protein
• Urine for protein/creatinine ratio
• Renal Biopsy
• Thorough history distinguish rate of onset and
  symptomatology

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Symptoms of FSGS Primary vs. Secondary

• Acute on set of nephrotic syndrome
• Peripheral edema
• Hypoalbuminemia
• Nephrotic Range proteinuria
• HTN
• Microscopic hematuria

• Non-nephrotic proteinuria
• Renal insufficiency
• Focal sclerosis
• Hypertrophy
• Hyperfiltration
• Renal scarring

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Histologic Variants

• To make the histologic Dx of FSGS the perihilar,
  cellular, tip and collapsing variants must be
  excluded.
• Light and Electron microscopy is necessary for
  accurate Dx.
• Light will show mesangial collapse and sclerosis.
• Electron will show diffuse fusion of the
  epithelial cell foot process.

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Podocyte-Slit Diaphragm Complex
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• Injury to visual epithelial cell orpodocyte,
  which attaches to the glomerular basement
  membrane by discrete foot process, appears to be
  the primary problem in most forms of FSGS
• Barrier to filtration is lost

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Prognostic Factors

• No Nephrotic Syndrome-85 10 yr survival
• Nephrotic Syndrome- 60-90 5 yr survival
  30-55 10 yr survival
• Massive Proteinuria- progress to ESRD w/in 5
  yrs
• Interstitial Fibrosis- poor renal survival
• Collapsing Variant- worse prognosis (HIV)
• Glomerular Tip Lesion- More likely to respond to
  steroid therapy

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Treatment of FSGS Primary vs. Secondary

• Corticosteroids, ACE inhibitors and ARBs
• If steroid resistant may try immunosuppressant
  agents such as Prograf, CYA, MMF or Rapa
• Lipid Lower Agents

• ACE and ARBs
• Treat the cause ieObesity- wgt loss HIV-HAART,
  drug toxicity
• Race may affect response to steroid therapy.

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Transplant and FSGS

• Recurrence rate as high as 50 (80 after a
  re-transplant)
• Occurs early post-Tx ( Days to 6-12 months)
• White race is a new recognized risk factor (4)
• Rapid recurrence is BAD
• In pediatric patients the benefit of living
  donation is lost (3,4)
• Age less that 15 years
• Rapid clinical course
• Mesangial proliferation or prior recurrence (1,2)
  
• Recurrence is less frequent in blacks
• (1) Senggutuvan et al Pediatr Nephrol, 1990 (2)
  Tejani et al, JASN 1992 (3)Baum et al Kidney Int
  2001, (4) Abbot et al, Am J Kidney Dis, 2001

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Clinical Presentation of FSGS Post Transplant

• Rapid onset of proteinuria (1)
• More frequent ARF (2)
• More frequent rejection (2)
• Graft loss is similar among living and cadaver
  donor recipients (3)
• Living donation is not a contra-indication. They
  DO better
• (1)Cheig et al, Kidney Int 1980, (2)Kim et al
  Kidney Int 1994, (3) Briganti et al N Engl J Med
  2002

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Potential Treatments

• Protein adsorption and plasmapheresis (1)
• Plasmapheresis and cyclophosphamida (2)
• Preoperative plasmapheresis plus cyclosporine (3)
• Early plasmapheresis/ACEi, AIIRBs
• (1) Dantal et al N Eng J Med, 1994, (2) Cheong et
  al Nephro Dial Transplant, 2000

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Focal segmental glomerulosclerosis
(FSGS) Possible screening Bioassay for a
yet-to-be isolated serum protein Possible
prophylaxis Plasma exchange or adsorption Incidenc
e 2040 recurrence, 4050 graft
failure Rationale Although preliminary data
suggest that some patients may have a serum
protein that correlates with recurrent FSGS after
transplantation, no standardized assays are
available clinically. Some investigators have
suggested that the risk for recurrent FSGS may
be reduced with prophylactic plasma
exchange. Recommendations (A) Candidates with
FSGS should be warned that there is a 2040
risk of recurrence, and that 4050 with
recurrence lose their grafts. However, the risk
of recurrent FSGS need not preclude
transplantation. (B) A prior history of
graft loss from recurrent FSGS should be
considered at least a relative contraindication
to living donor transplantation, due to the
likelihood of recurrence (up to 80). (C)
Assays for a serum factor to predict recurrent
FSGS have not been standardized or validated
for clinical practice. (D) There are not yet
sufficient data for or against the use of
prophylactic plasma exchange or other measures
to prevent recurrent FSGS. AJT, 2001
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Case Studies on FSGS Post Kidney Transplant
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Case 1 DG 56yo CFOrg DX FSGS

• Recd Cad 0antigen mismatch10/30/07
• Sl Bcell CXM - thymo 100mg x6 d
• Bx proven FSGS
• Pre-op creat 9.7 on PD since 1/19/05
• Pre-op P/C ratio 6/07-3.64 10/07 2.2
• Creat on pre-op 9.7
• Creat and P/C ratio decreased daily
• Current Creat 0.9 P/C 0.19
• 11/5/07 begun Diovan (ARB)
• NO PLASMAPHERESIS

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Case 2 BF 22yo WmOrg Dx FSGS (collapsing
variant)

• massive protenuria treated with cytoxin,
  cyclosporine and steroids.
• PD since 11/04
• LD TX 3/29/06 - CXM
• Thymo 100mg x 4 , rapid steroid protocol.
• (off in 4 days.)
• Pre-op P/C not done. Creat 15.0
• Pre-op biopsy 10/04
• no segmental sclerosis, near 100 foot
  process effacement consistent with minimal change
  disease.
• Biopsy 2/05 Collapsing variant of FSGS

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Post-Op Course

• Kidney function decreased daily but slow
• Pt developed peripheral and pulmonary edema .

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POD P/C creat Plasmaphesis Med TX

• 1 0.9 8.7 N none
• 2 2.64 5.0 Y none
• 3 10.0 3. 7 Y Biopsy rec. FSGS
• 4 11.5 3.4 Y none
• 5 7.9 3.0 Y
  none
• 6 9.75 2.5 Y Diovan (ARB)
• 7 7.7 2.3 N no changes
• 8 8.8 2.1 Y added Altace (ACE)
• D/Cd on POD 8

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• Out pt Plasmapheresis M-W-F
• 6 days from d/c P/C 1.32 creat 1.8
• 13 days from d/c P/C 1.52 creat 2.3
• Plasmapheresis changed to 2x week
• 21 days from d/c stopped plasmapheresis P/C 1.32
  creat 1.8
• 7 day after stopping pheresis biopsy
• performed , foot process effacement 40-50
  capillary loops with significant decrease from
  biopsy of 4/1/06
• Current P/C 0.07 creat 1.9 remains on Diovan

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Case 3 TL 55yo Asian FOrg Dx FSGS

• Hemo since 12/04
• CAD kidney 4/21/07
• CXM
• Pre-op P/C 19.4 creat 8.1
• Pre-op Bx 12/03 FSGS 80 globally and
  segmentally sclerosed glomeruli, focally severe
  interstitial fibrosis and mod. vasc.sclerosis

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POD P/C Creat Plasmaphesis Med TX

• 1 4.3 3.8 N
  none
• 3 2.57 1.3 N Lisinopril
  (ACE)
• 5 26.7 1.0 Y
  same
• 6 21.3 1.0 Y Sol. 500mg x
  3
• biopsy mild cellular and vasc. Rej C4D stains
  neg. recurrent FSGS
• 7 ND 1.5 Y
  same
• 8 5.49 1.6 Y
  same
• 9 7.69 1.6 Y
  same
• 10 4.8 1.6 Y
  same
• 11 4.9 1.4 N Diovan
  (ARB)
• 12 3.7 1.3 N
  same
• 13 2.5 1.4 N D/Cd same
• Cur 0.28 0.9 N Diovan
  /Lisinopril

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Case 4 BR 46yo WMOrg Dx FSGS

• Pre-dialysis
• Ld transplant 10/15/07
• CXM
• Pre-op P/C 2.83 creat 3.9
• Pre-op biopsy 6/03 changes suggestive of focal
  and segmental glomeralosclorosis , sub acute and
  chronic tubulo-interstital nephritis

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POD P/C Creat Plasmaphesis Med TX

• 1 1.4 2.4 N none
• 2 2.79 1.7 N none
• 3 3.54 1.4 Y none
• 4 3.31 1.3 N biopsy ATN and recurrent
  FSGS 60 foot process effacement
• 5 1.9 1.4 Y none
• 6 1.89 1.4 N none
• 7 0.49 1.7 Y none
• 8 1.21 1.4 Y none
• 9 0.45 1.6 N D/Cd none

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• NO Diovan 2 creatine fluctuations
• POD 15 P/C 0.58 creat 2.0
• Biopsy Acute cellular rejection
  treated with solumedrol 500mg x 3 days.
• No further Plasmapheresis
• Current P/C 0.08 creat 1.6

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Case 5 LC 61yo CFOrg Dx FSGS

• Hemo 9/22/05
• LD with Bil Neph 2 protienuria 8/28/06
• Pre-op creat 5.2 no P/C ratios
• Creat dropped daily D/Cd POD 4 creat 1.4
• POD 5 readmitted decrease Phos and dehydration
  D/cd on POD 8

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POD P/C Creat Plasmaphesis Med
TX

• 9 3.71 2.1 N
  readmitted
• 10 3.0 2.0 N Bx vasc rejection
  FSGS
• 11 3.24 2.0 Y sol 200/ thymo 100
• 12 24 urine pro 2137 creat 2.0 sol/thymo
• 13 ND 2.3 N thymo
  100
• 14 2.08 2.1 N No
  thymo
• 15 3.8 1.9 N thymo
  100
• 16 ND 1.7 N No
  thymo
• 17 3.3 1.8 Y
  thymo 100
• 18 3.2 1.6 Y No
  thymo Diovan
• 19 3.3 1.5 Y
  thymo 100
• 20 2.6 1.5 N No
  thymo

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POD P/C Creat Plasmaphesis Med
TX

• 21 ND 1.5 Y thymo 100
• 22 3.77 1.4 Y No thymo
• 23 ND 1.4 Y No thymo
• 24 1.56 1.5 D/Cd continue plasma
  pheresis 3x week Stopped Pod 30. 1.3 2.2
• POD 31 biopsy no ACR
• Restarted PP on POD 34 3xweek.
• P/C continues to increase runs 3.9-13.11 with
  intermittent pheresis
• Creat jumping around 1.8-2.6

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• 9 weeks PO added Lisinopril
• 10 weeks biopsy ACR Sol 400mg x3 days with new
  pred taper
• Week 14 pheresis x 3
• Month 7 pheresis x 3 new pred taper 40 daily P/C
  12.3 creat 1.3
• Month 9 Pheresis MWF P/C 14.4 creat 1.7
• Current P/C 10.7 creat 3.2
• Pt considering re-transplant.

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Conclusion

• Candidates with FSGS should be warned that there
  is a 2040 risk of recurrence, and that 4050
  with recurrence lose their grafts. However, the
  risk of recurrent FSGS need not preclude
  transplantation.
• A prior history of graft loss from recurrent
  FSGS should be considered at least a relative
  contraindication to living donor transplantation,
  due to the likelihood of recurrence (up to 80).
• Assays for a serum factor to predict recurrent
  FSGS have not been standardized or validated for
  clinical practice.
• There are not yet sufficient data for or against
  the use of prophylactic plasma exchange or other
  measures to prevent recurrent FSGS. AJT, 2001