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.

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%

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

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

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

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

Hierarchical classification: Fogo, Fundamentals of Renal Pathology, 2006

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

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

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

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

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)

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

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

Patient demographics No. of patients (female / male) 19 (5 / 14) Age at original diagnosis 35 (2 to 59) Time on dialysis before first transplant 22 months (5.7-79) Age at first transplant 38 years (3 - 60) Age of transplant biopsy 38 years (3 - 61) Time to first post-transplant biopsy 108 days (2 - 4015)

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

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

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)

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

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

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)

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)

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

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

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