1. Recurrent and de-novo focal and segmental glomerulosclerosis (FSGS) in renal allografts Ingeborg M. Bajema
Good afternoon ladies & gentleman. I would like to present our research on chimerism in kidneys with lupus nephritis.

2. Focal Segmental Glomerulosclerosis (FSGS)
FSGS is a common cause of ESRD in adults and children
FSGS presents with nephrotic range proteinuria, elevated serum creatinine, hypertension
FSGS progresses to ESRD in approximately 30-50%

3. Etiologic classification of FSGS (d’Agati et al, 2004)
Primary (idiopathic) FSGS
Secondary FSGS
1. Familial/genetic (mutations)
2. Virus-associated (HIV, parvovirus)
3. Drug-induced
4. Mediated by adaptive structural- functional responses, e.g.:
- Chronic allograft nephropathy
- Any advanced renal disease with reduction in functioning nephrons

4. Columbia classification of FSGS
FSGS can be classified according to the Columbia classification
Five variants:
Tip lesion
Cellular variant
Collapsing variant
Perihilar variant
FSGS not otherwise specified

6. Tip lesion and cellular variant
Tip lesion: located near the origin of the proximal convoluted tubule
Cellular variant: endocapillary hypercellularity

7. Collapsing and perihilar variant
Collapsing lesion: collapse of the glomerular tuft with epithelial cell hypertrophy and hyperplasia
Perihilar variant: predominantly located at the vascular pole

8. Hierarchical classification: Fogo, Fundamentals of Renal Pathology, 2006

9. FSGS variants and outcome, Chapel Hill study:
Adult patients with biopsy-proven FSGS diagnosed between March 1982 and July 2001
Cellular, N=6
Collapsing, N=22
Tip lesion, N=34
Perihilar, N=52
FSGS nos, N=83
Thomas et al, 2006

10. FSGS variants and outcome, Chapel Hill study:
Adult patients with biopsy-proven FSGS diagnosed between March 1982 and July 2001
Cellular, N=6
Collapsing, N=22: younger, black patients; higher proteinuria
Tip lesion, N=34: higher proteinuria; better renal function; less severe ti injury
Perihilar, N=52
FSGS nos, N=83
Median follow-up: 1.8 years:
23% of patients on dialysis, 28% had renal failure.
Collapsing FSGS had worse 1-year (74%) and 3-year (33%) renal survival compared to other variants
Overall cohort renal survival at 1 and 3 years: 86 and 67%
Thomas et al, 2006

11. FSGS and renal transplantation
All variants can lead to ESRD
After transplantation, circa 30% of patients develop recurrent FSGS

12. Recurrent FSGS Ingulli & Tejani, 1991:
28 children, 6 recurrent FSGS, mostly in very young
Fujisawa et al, 2002:
13 children, recurrent FSGS in 5, graft function preserved
Crosson, review, in 2007:
recurrent FSGS in 20-30% of transplants
risk factor: rapid decline in renal function in native FSGS
young children
plasmapheresis: not always succesful
high chance of recurrence in 2nd graft
Sener, et al, 2009:
recurrent FSGS associated with bilateral nephrectomy,
severity of native FSGS, female gender, living donation

13. Recurrent FSGS Hickson et al, 2009:
30 children and adults, recurrent FSGS in 47%
plasmapheresis in combination with rituximab induced
prolonged remission
Canaud et al, 2009:
With high dose steroids, intravenous cyclosporine and
intensive and prolonged course of plasma exchange,
complete/sustained remission can be attained in a high
proportion of patients with recurrent FSGS (9/10)

14. Does the same sub-class recur in the renal transplant?
Research question
Does the same sub-class recur in the renal transplant?

15. Recurrent FSGS in renal transplants
Multi-center study with 19 patients with renal transplantation after FSGS, with 23 allografts, 26 native kidney samples, 31 post-transplant biopsies and 4 transplantectomies.
Cooperating centers from:
- the Netherlands (Leiden, Utrecht Groningen, Rotterdam)
- Germany (Erlangen)
- USA: Boston Massachusetts

16. Patient demographics No. of patients (female / male) 19 (5 / 14)
Age at original diagnosis (2 to 59)
Time on dialysis before first transplant 22 months (5.7-79)
Age at first transplant years (3 - 60)
Age of transplant biopsy years (3 - 61)
Time to first post-transplant biopsy 108 days ( )

17. Histologic variants in native kidneys of patients with recurrent FSGS
19 patients, from which 26 biopsies from native kidneys were available:
16 patients had a single sample taken:
8: FSGS nos
5: collapsing variant
2: cellular variant
1: tip lesion
3 patients had multiple samples taken:
1st: MC, 2nd: FSGS nos
1st: MC, 2nd: FSGS nos, 3rd: collapsing
1st: cellular FSGS, 2nd: FSGS nos

18. Recurrent FSGS - 17 patients had recurrent FSGS in the 1st allograft
- 2 patients had recurrent FSGS in the 2nd allograft
(1 patient lost 1st graft to severe acute rejection;
1 patient had MCD in 1st allograft, 5 days post tx)
- 2 patients had recurrent FSGS in both 1st and 2nd allograft

19. Histologic variants of recurrent FSGS
8 / 10 patients with native FSGS nos, also had FSGS nos in at least one renal transplant biopsy
4 / 6 patients with native collapsing FSGS, also had collapsing FSGS in at least one renal tx biopsy
2 / 2 patients with native cellular FSGS, also had cellular FSGS in the renal allograft
1 / 1 patient with native tip lesion FSGS, had MC in the renal allograft (5 days post transplantation)

20. Recurrent FSGS after native FSGS nos
10 patients with native FSGS nos:
8 had recurrent FSGS nos, but 3 of these had a different variant before the biopsy which showed FSGS nos:
patients 1,2: MC within 3 wks after tx
FSGS nos in 3rd year after tx
patient 3: collapsing FSGS in 1st year after tx
2 patients had collapsing FSGS

21. Recurrent FSGS after collapsing FSGS
6 patients with collapsing FSGS:
4 had recurrent collapsing FSGS, but 2 of these had MC 2 days and 4 days after transplantation
2 patients had FSGS nos
One patient had recurrent collapsing FSGS in 3 renal transplant biopsies taken at 7, 63 and 645 days after transplantation

22. Patterns of recurrent FSGS
Recurrence of FSGS with fidelity:
- Type 1: same variant recurs
- Type 2: same variant recurs after intermediate stage with MC
Recurrence of FSGS with evolution:
- Type 3: different variant recurs
- early
- late: beware of other causes of FSGS
- Type 4: MC (in short-term follow-up)

23. Patterns of recurrent FSGS
Recurrence of FSGS with fidelity (81% of allografts):
- Type 1: same variant recurs (N = 11)
- Type 2: same variant recurs after intermediate stage with MC (N=4)
Recurrence of FSGS with evolution (19% of allografts):
- Type 3: different variant recurs (N=4)
- early (N=2, nos to collapsing)
- late: beware of other causes of FSGS (N=2, collapsing to nos)
- Type 4: MC in short-term follow-up (N=2)

24. Discussion points Caveats of this study:
No protocolized biopsies, transplant biopsies taken at variable time-points after transplantation
Sampling error: in all biopsies diagnosed with MC, at least 8 glomeruli were present (but some studies request 25)
Perihilar variant not included – probably because it only infrequently recurs
De novo FSGS in renal transplants? Cannot be excluded

25. Discussion points FSGS nos generally recurred as FSGS nos
Collapsing and cellular variants recur in their native forms, and in this study, there was no exchange between these two or evolution from one type to another
FSGS nos may represent a late phase of a number of variants of FSGS
MC can be an early phase of FSGS variants other than the tip lesion variant

26. Acknowledgments Leiden:
Daphne H.T. Ijpelaar, Emile de Heer, Jan A. Bruijn
Boston:
Alton B. Farris, Evan Farkash, Robert B. Colvin
Rotterdam: Natascha Goemaere
Erlangen: Kerstin Amann
Utrecht:
Roel Goldschmeding, Tri Q. Nguyen
Groningen: Marius C. van den Heuvel