Rituximab or plasmapheresis for prevention of recurrent focal segmental glomerulosclerosis after kidney transplantation: A systematic review and meta-analysis

Table 1 Characteristics of included studies evaluating the outcomes of preemptive plasmapheresis

Ref.	Country	Design	n (%)	Population	Age	PP protocol	Def of recurrence	Recurrence	Graft survival	Quality assessment
Kawaguchi et al[20], 1994	Japan	Retrospective	14	FSGS children	2-12 yr at FSGS Dx	2-3 sessions immediately before KT (-5, -3, and -1 d) ATG 7-14 d pre-op	N/A	3/8 (38%) vs 4/6 (67%)	93% graft survival in overall cohort	Fair, 4-1-2
Otsubo et al[21], 1999	Japan	Retrospective	37	FSGS undergoing KT	22 yr at KT	N/A	Clinical and biopsy in all cases	4/19 (21%) vs 9/18 (50%)	75%at 5 yr, 63% at 10 yr	Fair, 4-1-2
Iguchi et al[32], 1997	Japan	Prospective cohort	11	FSGS undergoing KT	33.3 (20-43) yr	3 sessions of pre-op PP within 3 d before KT	Clinical and/or pathologic	1/3 (33%) vs 4/8 (50%)	100% vs 63.6%	Fair, 4-2-2
Ohta et al[33], 2001	Japan	Retrospective	21	FSGS children	Age of FSGS onset 69.5 ± 36.4 mo (range 9-134 mo)	1-2 sessions immediately before KT (-5, -3, and -1 d). Therapeutic PP until reduction of proteinuria	Clinical and/or pathologic	5/15 (33%) vs 4/6 (67%)	13/15 vs 3/5 (1 death with functioning graft in Non-PP)	Fair, 4-2-2
Somers and Baum[34], 2009	United States	Retrospective	52	FSGS children	12.5 yr	N/A	N/A	5/19 (26%) vs 18/33 (55%)	Overall, 11/52 graft loss	Fair, 4-1-2
Gonzalez et al[35], 2011	United States	Retrospective	34	FSGS children	Age at KT: 13 ± 5 yr. Age at FSGS diagnosis: 5.3 yr (n = 19, recurrence group), 6.9 yr (n = 15, no recurrence group)	1-10 sessions	Clinical and/or pathologic	9/17 (53%) vs 10/17 (59%)	Graft loss at 3 yr: 25% in recurrence group vs 20% in non-recurrence	High, 4-2-3
Miyauchi et al[25], 2011	Japan	Prospective cohort	25	FSGS undergoing KT	N/A	N/A	N/A	3/9 (33%) vs 2/4 (50%)	N/A	Low, 3-1-1
Park et al[26], 2014	South Korea	Retrospective	27	FSGS undergoing KT	Age at KT: 39 ± 14 yr and 36 ± 11 yr	PP and IVGV infusion after each session of PP prior to transplantation	Clinical confirmed by biopsy	1/4 (25%) vs 5/18 (27%)	FSGS with recurrence had less graft survival than those without recurrence (P = 0.01)	High, 4-2-3
Okumi et al[27], 2015	Japan	Retrospective	38	FSGS undergoing KT	N/A	N/A	N/A	4/10 (40%) vs 2/5 (40%)	5/38 graft loss overall	Low, 3-1-1
Verghese et al[36], 2018	United States	Retrospective	57	FSGS children	Age at KT: 13.2 ± 4.5 yr (after 2006 with PP) vs 10.4 ± 5.4 yr (before 2006, no PP)	LDKT: 3 sessions PP pre-op. DDKT: 1 session of PP pre-op. Post-op: 5 sessions of PP every other day starting POD1	Biopsy; if unable to do biopsy, persistent nephrotic range proteinuria	7/26 (27%) vs 8/31 (26%)	Death-censored graft survival not sig different (P = 0.61)	High, 4-2-3
Koyun et al[37], 2019	Turkey	Retrospective	46	FSGS children	Age at KT: 7.2 ± 1.2 yr (PP) vs 10.7 ± 4.5 yr (no PP)	LDKT: 2-5 sessions of PP pre-op. DDKT: 1 session of PP pre-op. Post-op: 5 session of early PP	N/A	3/6 (50%) vs 5/40 (12.5%)	N/A	Low, 3-1-1
Campise et al[38], 2019	Italy	Retrospective	73	FSGS undergoing KT	Age at FSGS Dx: 27 (15-35) yr. Age at KT: 41 (38-52) yr	2003-2008: post-transplant PP only 2008-2014: 1 session immediately before surgery and 3 sessions per week for 3 consecutive weeks from POD1	Post-transplant proteinuria; confirmed by biopsy	Biopsy-proven: 5/21 (24%) vs 12/52 (23%)	Death-censored graft survival: 81% (17/21) vs 84% (44/52) (P = 0.7022)	High, 4-2-3
Uffing et al[8], 2020	United States, Europe, Brazil	Retrospective, multicenter	176	FSFS adults undergoing KT	Age at KT: 38 (29–47) yr. Age at FSGS Dx: 27 (17-40) yr	N/A	N/A	9/22 (41%) vs 48/154 (31%)	Graft failure 15% w/o recurrence and 39% with recurrence	High, 4-2-3

N: Number; ESKD: End-stage kidney disease; FSGS: Focal segmental glomerulosclerosis; PP: Plasmapheresis; KT: Kidney transplantation; RTX: Rituximab; N/A: Not available.

Table 2 Characteristics of included studies evaluating the outcomes of preemptive rituximab

Ref.	Country	Design	n (%)	Population	Age	Rituximab dose and protocol	Concurrent PP	Def of recurrence	Recurrence	Graft survival	Follow-up duration	Quality assessment
Burke et al[22], 2009	United States	Retrospective	29	FSGS undergoing KT	Age at KT: 6-21 yr	N/A	No	New onset proteinuria	6/18 (33%) vs 8/11 (72%)	No significant difference in graft survival	N/A	Fair, 3-1-2
Sagheshima et al[23], 2010	United States	Prospective	40	FSGS undergoing KT	Age at KT: 4-24 yr	N/A	No	UPCR > 3.5 post-transplant	8/29 (28%) vs 7/11 (64%)	N/A	N/A	Low, 3-1-1
Fornoni et al[24], 2011	United States	Retrospective	41	High-risk pediatric/young adult FSGS undergoing KT: (< 25 yr at FSGS Dx or progression to ESKD within 7 yr)	Age at KT: 15 ± 5.5 yr (rituximab), 12.3 ± 5.2 yr (control)	One dose of rituximab (375 mg/m2) within 24 h of kidney transplantation	No	UPCR > 3.5 within 30 d post-transplant or need for PP. Protocol biopsy in 20/27 (74%)	7/27 (26%) vs 9/14 (64%)	1-yr graft survival: 95.8% vs 85.7% (P = 0.26)	N/A	High, 4-1-3
Miyauchi et al[25], 2011	Japan	Prospective	25	FSGS undergoing KT	N/A	N/A	N/A	N/A	2/12 (17%) vs 5/13 (38%)	N/A	N/A	Low, 3-1-1
Park et al[26], 2014	South Korea	Retrospective	27	FSGS undergoing KT	Age at KT: 39 ± 14 yr (n = 7, recurrence), 36 ± 11 yr (n = 20, no recurrence)	PP and IVGV infusion after each session of PP prior to transplantation, and RTX (375 mg/m2) was administeredwithin 1 wk prior to transplantation	Yes	Clinical confirmed by biopsy	1/4 (25%) vs 5/18 (27%)	FSGS with recurrence had less graft survival than those without recurrence (P = 0.01)	N/A	High, 4-1-3
Okumi et al[27], 2015	Japan	Retrospective	38	FSGS undergoing KT	N/A	N/A	Yes	N/A	5/23 (22%) vs 6/15 (40%)	5/38 graft loss overall. Cr at yr 2 and 6 significantly lower in those who received both R + PP	N/A	Low, 3-1-1
Futamura et al[28], 2016	Japan	Retrospective	28	FSGS undergoing KT	N/A	N/A	Yes	N/A	3/7 (43%) vs 5/21 (24%)	N/A	N/A	Low, 3-1-1
Alasfar et al[29], 2018	United States	Prospective	64	High-risk FSGS undergoing KT (2 of: white, age ≤ 30 at Dx, progression to ESKD ≤ 5 yr. Albumin < 3 g/dL during disease course, h/o failed KT due to recurrence)	Age at FSGS Dx: 29.9 ± 17.2. Age at KT: 38 ± 16.5	Rituximab was given in 1 or 2 doses (375 mg/m2per dose)	Yes; 3-10 sessions of PP day-7 to POD 2	Clinical and biopsy	23/37 (62%) vs 14/27 (51%)	Trend toward better renal allograft survival in nonrecurrent group comparedto the recurrent group (P = 0.0662)	29.5 mo	High, 4-1-3
Lu et al[30], 2018	United States	Retrospective	55	High-risk FSGS undergoing KT considered (age ≤ 25 at Dx, proteinuria ≥ 5 g/d, progression to ESKD ≤ 5-7 yr)	Age at KT: 44	One dose of rituximab (375 mg/m2, max 100 mg)	No	Proteinuria and biopsy	4/7 (57%) vs 6/48 (13%)	Graft loss: 1/7 (14%) vs 8/48 (17%)	N/A	Fair, 3-2-2
Auñón et al[31], 2021	Spain	Retrospective, multicenter	34 (93 total cohort)	High-risk FSGS undergoing KT considered (hypoalbuminemia and NS at baseline); genetic form excluded	Age at KT: 35.0 ± 15.2 (R group), 42.4 ± 12.2 (non-R group)	Rituximab, 1 g at induction and 1 g on day 14 after transplantation	No	Recurrence of proteinuria, confirmed by biopsy	6/12 (50%) vs 9/22 (41%)	53.5% with recurrence vs 88.5% in non-recurrence group	N/A	High, 4-1-3
Mukku et al[39], 2021	United States	Retrospective	18	FSGS undergoing KT	Age at KT: 35 yr	N/A	Yes	Recurrence of proteinuria	0/8 vs 3/10 (30%)	8/8 vs 9/10	30 (1-36) mo	Low, 3-1-1

N: Number; ESKD: End-stage kidney disease; FSGS: Focal segmental glomerulosclerosis; PP: Plasmapheresis; KT: Kidney transplantation; RTX: Rituximab; N/A: Not available.

Table 3 Detailed characteristics of included studies evaluating the outcomes of preemptive plasmapheresis

Ref.	Country	Age	Genetic testing	Race	Time to ESKD	Repeat KT	Induction	IS	Donor types	Biopsy	Follow-up duration
Kawaguchi et al[20], 1994	Japan	2-12 yr at FSGS Dx	N/A	Asian	12–117 mo		ATG only in PP group	CS, CsA, AZA/mizolibine	13/14 living1/14 DDKT	N/A	N/A
Otsubo et al[21], 1999	Japan	22 yr at KT	N/A	Asian	N/A	N/A	CS, CsA/Tac	CS, CsA/Tac, AZA/mizolibine	34/37 LRKT, 4/37 DDKT	Per-cause biopsy	N/A
Iguchi et al[32], 1997	Japan	33.3 (20-43) yr	N/A	Asian	N/A	None	ATG during first 2 wk in PP group	CS, CsA, AZA	100% LRKT	Intra-op biopsy (1 h) in all cases then as clinically indicated	N/A
Ohta et al[33], 2001	Japan	Age of FSGS onset69.5 ± 36.4 mo (range 9-134 mo)	N/A	Asian	51.8 ± 29.6 mo (range 7-120)	1/21	None	CS, CsA/Tac, AZA/mizolibine	3/21 DDKT (14%) vs 18/21 (LRKT)	Intra-op biopsy (1 h) in all cases then as clinically indicated	62.7 (PP group), 41.6 mo (non-PP group)
Somers and Baum[34], 2009	Unite States	12.5 yr (85% white)	N/A	85% White	3 yr (median)	N/A	N/A	CsA-based regimen	42% living donor	N/A	N/A
Gonzalez et al[35], 2011	United States	Age at KT: 13 ± 5 yr	NPHS2 mutation testing on 10 patients (9 tested negative, 1 with heterozygous mutation)	29% White, 15% African, 44% Hispanic, 12% others	4.2 yr (n = 19, recurrence group), 3.1 yr (n = 15, no recurrence group)	Recurrence in previous graft 5/34	rATG (if ATN) or daclizumab	CS, CsA/Tac, MMF	15/34 living, 19/34 DDKT	Per-cause biopsy	N/A
Miyauchi et al[25], 2011	Japan	N/A	N/A	Asian	N/A	N/A	N/A	CS, CsA/Tac, AZA/mizolibine	N/A	N/A	N/A
Park et al[26], 2014	South Korea	Age at KT: 39 ± 14 yr (n = 7, recurrence), 36 ± 11 yr (n = 20, no recurrence)	N/A	Asian	46 ± 44 mo (n = 7, recur group), 68 ± 67 mo (n = 20, no recur group)	none	Basiliximab (20 mg) on days 0 and 4	CS, CsA/Tac, MMF	4/27 DDKT, 24/27 living (17/27 LRKT)	Per-cause biopsy	N/A
Okumi et al[27], 2015	Japan	N/A	N/A	Asian	N/A	N/A	Basiliximab (after 2002)	CS, CsA/Tac, MMF	N/A	N/A	N/A
Verghese et al[36], 2018	United States	Age at KT: 13.2 ± 4.5 yr (after 2006 with PP) vs 10.4 ± 5.4 yr (before 2006, no PP)	NPHS2 mutation testing (for those with NPHS2 homozygous mutation, PP not indicated)	N/A	N/A	N/A	93% received lymphocyte depleting induction	Before 2006: AZA (90%), MMF (16%), CsA (97%), CS (97%). After 2006: AZA (12%), MMF (88%), CsA (62%)/Tac (38%), CS (12%)	DDKT 37% vs Living 63%	Per-cause biopsy	N/A
Koyun et al[37], 2019	Turkey	Age at KT: 7.2 ± 1.2 yr (PP) vs 10.7 ± 4.5 yr (no PP)	Genetic testing (unspecified gene panel): 2/6 + in PP group vs 14/40+ in control group	N/A	N/A	N/A	N/A	N/A	DDKT 20%, Living 80%	N/A	N/A
Campise et al[38], 2019	Italy	Age at FSGS Dx: 27 (15-35) yr. Age at KT: 41 (38-52) yr	Not done	100% White	5 (1-10) yr, 33% rapid (< 3 yr) progression to ESKD	(7/21) 33% in PP group; previous graft loss due to recurrence	Basiliximab (20 mg) on days 0 and 4	CS, Tac, MMF	100% DDKT	Per-cause biopsy	45 (30-107) mo
Uffing et al[8], 2020	Unites States, Europe, Brazil	Age at KT: 38 (29–47) yr. Age at FSGS Dx: 27 (17-40) yr	Not done in most patients	56% White, 11% Black, 5% Hispanic, 5% Asian, 10% mixed, Other or unknown 14%	38 (14–75) mo	25%; prior graft loss due to FSGS 9%	rATG (42%), basiliximab (42%), daclizumab (3%), none (13%)	CS + Tac + MMF (72%), CS + CsA + MMF (17%), Tac + MMF (5%), other 6%	67% DDKT, 22% LRKT, 15% LUKT	Per-cause biopsy	N/A

N: Number; ESKD: End-stage kidney disease; FSGS: Focal segmental glomerulosclerosis; PP: Plasmapheresis; KT: Kidney transplantation; RTX: Rituximab; N/A: Not available; LUKT: Living-related kidney transplantation; CS: Corticosteroids; CsA: Cyclosporine; Tac: Tacrolimus; MMF: Mycophenolate mofetil; AZA: Azathioprine; rATG: Rabbit anti-thymocyte globulin; DDKT: Deceased donor kidney transplantation; LRKT: Living-related kidney transplantation.

Table 4 Detailed characteristics of included studies evaluating the outcomes of preemptive rituximab

Ref.	Country	Age	Genetic testing	Race	Time to ESKD	Repeat KT	Induction	IS	DDKT	Follow-up duration
Burke et al[22], 2009	United States	Age at KT: 6-21 yr	N/A	N/A	N/A	N/A	rATG or daclizumab	CS, Tac, MMF	N/A	N/A
Sagheshima et al[23], 2010	United States	Age at KT: 4-24 yr	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Fornoni et al[24], 2011	United States	Age at KT: 15 ± 5.5 yr (rituximab), 12.3 ± 5.2 yr (control)	N/A	White 56%, Black 44%	3.4 ± 2.0 yr (rituximab group), 3.3 ± 2.1 (control)	N/A	Combined thymoglobulin (1 mg/kg, 3–5 doses) and daclizumab. Alemtuzumab in one patient.	CS, Tac, MMF	Preemptive: 3/27 (11%) in rituximab group, 2/14 (14%) in non-rituximab group	N/A
Miyauchi et al[25], 2011	Japan	FSGS undergoing KT	N/A	Asian	N/A	N/A	N/A	CS, CsA/Tac, AZA/mizolibine	N/A	N/A
Park et al[26], 2014	South Korea	Age at KT: 39 ± 14 (n = 7, recurrence), 36 ± 11 (n = 20, no recurrence)	N/A	Asian	46 ± 44 mo (n = 7, recur group), 68 ± 67 mo (n = 20, no recur group)	none	Basiliximab (20 mg) on days 0 and 4	CS, CsA/Tac, MMF	3/27 DDKT, 24/27 living	N/A
Okumi et al[27], 2015	Japan	N/A	N/A	Asian	N/A	N/A	Basiliximab (after 2002)	CS, CsA/Tac, MMF	N/A	N/A
Futamura et al[28], 2016	Japan	N/A	N/A	Asian	N/A	N/A	N/A	N/A	N/A	N/A
Alasfar et al[29], 2018	United States	Age at FSGS Dx: 29.9 ± 17.2. Age at KT: 38 ± 16.5	N/A	White 56%, Black 32%, Asian 7%, Hispanic 4%	4 (0–9) yr	37% (42/66 63% first transplant)	Depleting agent 92%	CS + Tac + MMF (92%), CS + CsA + MMF (8%)	DDKT 37%, LUKT 37%, LRKT 25%	29.5 mo
Lu et al[30], 2018	United States	Age at KT: 44	N/A	White 64%	N/A	0%	N/A	CS, Tac, MMF	N/A	N/A
Auñón et al[31], 2021	Spain	Age at FSGS Dx: 24.5 ± 18.5 (rituximab group), 30 ± 13.7 (non-rituximab group). Age at KT: 35.0 ± 15.2 (R group), 42.4 ± 12.2 (non-R group)	Excluded suspected genetic causes of FSGS	N/A	5.12 ± 4.44 (R group), 7.58 ± 7.11 (Non-R group)	7/34 (21%); recurrence in previous graft 2/12 (16.7%) in R group vs 2/22 (9.1%) In non-R group	Rituximab group: rATG 16.7%, basiliximab 50%. Non-rituximab group: rATG 40.9%, basiliximab 22.7%	CS + Tac + MMF (93.3%)	85.3% DDKT, 11.8% LRKT, 2.9% LUKT	N/A
Mukku et al[39], 2021	United States	Age at KT: 35 yr	N/A	White 39%, Black 27%	N/A	2/8 pre-emptive group vs 0/10	rATG (61%), alemtuzumab (22%), basiliximab (17%)	CS + Tac + MMF (83%), CS + CsA + MMF (17%)	89% DDKT	30 (1-36) mo

N: Number; ESKD: End-stage kidney disease; FSGS: Focal segmental glomerulosclerosis; RRT: Renal replacement therapy; PP: Plasmapheresis; IS: Immunosuppression; KT: Kidney transplantation; RTX: Rituximab; CS: Corticosteroids; CsA: Cyclosporine; Tac: Tacrolimus; MMF: Mycophenolate mofetil; AZA: Azathioprine; rATG: Rabbit anti-thymocyte globulin; DDKT: Deceased donor kidney transplantation; LRKT: Living-related kidney transplantation; LUKT: Living-related kidney transplantation; N/A: Not available.