ONLINE-ONLY SUPPLEMENTAL MATERIAL
Supplemental Table 1 Definition of nephrotic syndrome used in each study Supplemental Table 2 Baseline characteristics of the included studies
Supplemental Table 3 Details of the three trials entered in more than more comparison category
Supplemental Table 4 Immunosuppression for adult nephrotic syndrome and idiopathic membranous nephropathy
Supplemental Figure 1 Risk of bias summary: A review of the authors' judgment about each risk of bias item for each study.
Supplemental Figure 2 Risk of bias graph: A review of the authors' judgment about each risk of bias item for each study presented as percentages.
Supplemental Figure 3 Subgroup analysis of immunosuppression versus no treatment or ACEI on “all-cause mortality or risk of ESKD” according to the presence or absence of industrial support.
Supplemental Figure 4 Subgroup analysis of immunosuppression versus no treatment/ACEI on “all-cause mortality or risk of ESKD” according to the presence or absence of sample size estimation.
Supplemental Figure 5 Subgroup analysis of immunosuppression versus no treatment or ACEI on “all-cause mortality or risk of ESKD” according to the presence or absence of impaired baseline renal function.
Supplemental Figure 6 Publication bias of immunosuppressive treatments versus no treatment or ACEI: “all-cause mortality or risk of ESKD” (Harbord test) (A);
“complete or partial remission” (Harbord test) (B); “all-cause mortality or risk of
Supplemental Table 1 Definition of nephrotic syndrome used in each study
Trials Proteinuria Hypoalbuminemia Edema Hyperlipidemia
Ahmed 1994 (26) >3.5 g/24 h <25 g/L Not mentioned Not mentioned Arnadottir 2006 (12) Not mentioned Not mentioned Not mentioned Not mentioned Branten 1998 (27) Not mentioned Not mentioned Not mentioned Not mentioned Braun 1995 (28) >3.5 g/24 h Not mentioned Not mentioned Not mentioned Cameron 1990 (29) >3.5 g/24 h <30 g/L Not mentioned Not mentioned Cattran 1989 (31) >3.0 g/24 h Not mentioned Not mentioned Not mentioned Cattran 1995 (32) >3.5 g/24 h Not mentioned Not mentioned Not mentioned Cattran 2001 (30) >3.5 g/24 h Not mentioned Not mentioned Not mentioned Chan 2007(11) >3.0 g/24 h Not mentioned Not mentioned Not mentioned
Chen 2010 (14) >3.5 g/24 h <30 g/L Necessary Not necessary
Coggins 1979 (25) >3.5 g/24 h Not mentioned Not mentioned Not mentioned Donadio 1974 (33) Not mentioned Not mentioned Not mentioned Not mentioned Dussol 2008 (15) >3.0 g/24 h <30 g/L Not mentioned Not mentioned
Falk 1992 (34) >3.5 g/24 h <20 g/L Necessary Necessary
Hofstra 2010 (35) >3.5 g/24 h <35 g/L Not mentioned Not mentioned
Jha 2007 (18) >2.5 g/24 h <25 g/L Necessary Necessary
Jurubita 2012 (48) >8.0 g/24 h* Not mentioned Not mentioned Not mentioned Koshisawa 1993 (36) >3.5 g/24 h <30 g/L Not mentioned Not mentioned Kosmadakis 2010 (17) >3.5 g/24 h Necessary Necessary Necessary Liu 2009 (19) >3.5 g/24 h <30 g/L Not mentioned Not mentioned Murphy 1992 (37) Not mentioned Not mentioned Not mentioned Not mentioned Naumovic 2011 (16) >3.5 g/24 h Not necessary Not necessary Not necessary Pahari 1993 (38) >2.0 g/24 h Not mentioned Not mentioned Not mentioned Pisoni 2000 (39) >3.0 g/24 h Not mentioned Not mentioned Not mentioned Ponticelli 1992 (41) >3.5 g/24 h <25 g/L Not mentioned Not mentioned Ponticelli 1995 (42) >3.5 g/24 h <25 g/L Necessary Not mentioned Ponticelli 1998 (40) >3.5 g/24 h <25 g/L Not mentioned Not mentioned Ponticelli 2006 (13) >3.5 g/24 h <25 g/L Not mentioned Not mentioned Praga 2007 (10) >3.5 g/24 h <30 g/L Not mentioned Not mentioned Reichert 1994 (43) Not mentioned Not mentioned Not mentioned Not mentioned Saito 2009 (49) Not mentioned Not mentioned Not mentioned Not mentioned
Senthil 2008 (44) >2.5 g/24 h <22 g/L Necessary Necessary
Shibasaki 2004 (45) >3.5 g/24 h <30 g/L Not mentioned Not mentioned Silverberg 1976 (24) >3.0 g/24 h Not mentioned Not mentioned Not mentioned Tiller 1981 (46) Not mentioned Not mentioned Not mentioned Not mentioned Xu 2010 (47) >5.0 g/24 h* <25 g/L Not mentioned Not mentioned
*Severe nephrotic syndrome was defined using this cut-off value.
Supplemental Table 2 Baseline characteristics of the included studies
Studies Groups Follow-
Up(mo) N Age (yr)
Male Sex n (%)
Pathology (III-IV)
(%)
Proteinuria (g/24 h)
Albumin (g/L)
Hyper- tension n (%)
Serum Creatinine
(mg/dl)
GFR (ml/min
per 1.73 m2)
Previous Immune- suppressive
Therapy
Sample Size Calculation
Financial Support
Source CORTICOSTEROID MONOTHERAPY VERSUS NO TREATMENT
Coggins 1979 (25)
Prednisone
24 34
39(16-65) 22(65%) 9(26%) 9.4±6.0
- - 1.1±0.2
>60 NO NO Academic
Placebo 38 20(53%) 8(21%) 8.3±4.0 1.0±0.2
Cameron 1990 (29)
Prednisone
48 52 45±12 43(83%)
34(33%) 10.8±5.9 26.0±6.0 9(17%) 1.3±0.5 87±30
NO NO Unclear
Placebo 51 44±12 43(84%) 10.4±5.3 25.0±5.0 16(31%) 1.3±0.5 89±34
Cattran 1989 (31)
Prednisone
48 64 46(18-77) 48(75%) 33(52%) 6.8 27.0(10.0-60.0) 22(34%) 1.3(0.6-6.2) 72(15-156)
Corticosteroids YES Academic No treatment 56 45(16-83) 32(57%) 25(45%) 5.6 30.0(17.0-47.0) 17(30%) 1.1(0.6-6.5) 90(15-168)
ALKYLATING AGENT MONOTHERAPY VERSUS NO TREATMENT Donadio
1974 (33)
Cyclophosphamide
12 11 41(25-74) 9(82%) 1(9%) 7.8 27.0(19.0-34.0) 2(18%) 1.2(0.8-1.9) 75(44-117)
Corticosteroids NO Academic No treatment 11 48(34-69) 8(73%) 1(9%) 7.6 23.0(16.0-37.0) 2(18%) 1.1(0.8-2.2) 81(33-112)
Murphy 1992 (37)
Cyclophosphamide
24 13 47(26-66) 8(62%) 1(8%) 5.0 28.0(16.0-42.0) 4(31%) 1.2(0.6-3.2)
- NO NO Unclear
No treatment 13 40(18-65) 9(69%) 1(8%) 3.9 30.0(19.0-41.0) 4(31%) 1.0(0.6-2.3)
Tiller 1981 (46)
Cyclophosphamide
36 27
- - - 5.0
- - <4.0 - NO YES Academic
No treatment 27 4.2
ALKYLATING AGENTS + CORTICOSTEROIDS VERSUS NO TREATMENT OR ACEI OR CORTICOSTEROIDS Braun
1995 (28)
Cyclosporine+Steroids
60
44 43±16 21(48%) 13(30%) 7.2±3.9 27.0±5.0 33(75%) 1.2±0.4 102±43
NO NO NO
Chlorambucil+Steroids 31 43±14 25(81%) 8(26%) 9.3±6.3 27.0±6.0 13(42%) 1.0±0.3 103±31
No treatment 22 47±16 13(59%) 6(27%) 6.5±5.4 31.0±5.0 9(41%) 1.0±0.4 107±33
Jha 2007 (18)
Cyclophosphamide+Steroids
120 51 38±14 33(65%) 0(0%) 6.1±2.5 23.4±5.8 5(10%) 1.2±0.3 89±26
NO NO NO
No treatment 53 37±12 31(58%) 0(0%) 5.9±2.2 24.2±8.1 8(15%) 1.2±0.2 84±22
Ponticelli 1995 (42)
Cyclophosphamide+Steroids
120 42 44(15-70) 34(81%) 10(24%) 6.2±3.0
- 8(19%) 1.1±0.2
- NO NO Academic
No treatment 39 42(16-74) 29(74%) 9(23%) 5.3±2.8 12(31%) 1.1±0.3
Kosmadakis 2010 (17)
Cyclosporine+Steroids 9
10 51±5 8(80%) -
6.6±1.0 27.0±7.0 0(0%)
-
82±8
Unclear NO NO
Cyclophosphamide+Steroids 8 55±3 4(50%) 7.0±0.7 28.0±2.0 0(0%) 52±7
ACEI 10 52±5 5(50%) 5.2±0.8 22.0±1.4 0(0%) 66±6
Ahmed 1994 (26)
Chlorambucil+Steroids
15 10 32±7 8(80%)
- 6.1±1.9
- 0 (0%) 1.4±0.1
- NO NO Unclear
Prednisolone 10 38±14 8(80%) 7.6±2.0 2 (20%) 1.2±0.2
Falk 1992 (34)
Cyclophosphamide+Steroids
29 13 43±15 9(69%)
- 12.4±9.9
- - 2.3±1.0
- Corticosteroids NO Academic
Prednisone 13 46±14 7(54%) 11.1±6.7 2.7±1.6
Ponticelli 1992 (41)
Chlorambucil+Steroids
54 45 46(14-65) 32(71%) 18(40%) 7.6±4.2
- 15(33%) 1.0±0.3
- NO YES Unclear
Methylprednisolone 47 47(14-64) 27(57%) 18(38%) 7.0±4.1 14(30%) 1.0±0.3
Pahari 1993 (38)
Cyclophosphamide+Steroids
46 42 35±16 29(69%)
- - - - <2.0 - Unclear NO Unclear
Prednisolone 48 32±20 33(69%)
CYCLOPHOSPHAMIDE + CORTICOSTEROIDS VERSUS CHLORAMBUCIL + CORTICOSTEROIDS Reichert
1994 (43)
Chlorambucil+Steroids
15 10 45(31-65) 10(100%) 2(20%) 8.5±2.5 22.9±6.4 8(80%) 2.9±1.3
- Corticosteroids NO Academic
Cyclophosphamide+Steroids 10 49(24-65) 9(90%) 3(30%) 9.8±4.8 25.9±9.7 6(60%) 2.5±1.0 Branten
1998 (27)
Chlorambucil+Steroids
32 15 51±12 15(100%)
- 9.0±2.6 22.0±5.6
- 2.5±0.8 46±17
NO NO Unclear
Cyclophosphamide+Steroids 17 53±14 15(88%) 11.0±5.3 22.0±6.0 3.1±1.4 43±23
Ponticelli 1998 (40)
Chlorambucil+Steroids
39 50 50(18-65) 37(74%) 18(36%) 8.0±5.2
- 15(30%) 1.1±0.3
- NO YES Academic
Cyclophosphamide+Steroids 45 48(17-55) 29(64%) 18(40%) 6.9±3.5 14(31%) 1.0±0.3
Supplementary Table 2 Baseline characteristics of included studies - continued
Cattran 2001 (30)
Cyclosporine+Prednisone 18
28 47±11 26(93%) -
9.7±5.3 28.0±6.0
-
1.3±0.5 95±37 Corticosteroids/
Alkylating agents
YES Company
Placebo+Prednisone 23 49±14 16(70%)) 8.8±4.7 27.0±6.0 1.1±0.3 90±27
Naumovic 2011 (16)
Cyclosporine+Steroids
36
10 39±13 9(90%) -
11.6±4.7 22.9±4.8
-
1.4±0.9 81±28 Corticosteroids/
Alkylating agents
NO Academic
Azathioprine+Steroids 13 48±8 10(77%) 7.0±2.7 28.3±6.4 1.4±0.5 76±31
CYCLOSPORINE (1.5 MG/KG TWICE A DAY) + CORTICOSTEROIDS VERSUS CYCLOSPORINE (3.0 MG/KG ONCE A DAY) + CORTICOSTEROIDS Saito
2009 (49)
Cyclosporine(twice a day)
12 16 - -
- 3.6±0.3
- - - -
Corticosteroids NO Company
Cyclosporine(once a day) 17 - - 3.7±0.5 - -
TACROLIMUS ± CORTICOSTEROIDS VERSUS NO TREATMENT OR CORTICOSTEROIDS + ALKYLATING AGENTS Praga
2007 (10)
Tacrolimus
30
25 44±12 20(80%) 3(12%) 7.2±3.3 27.0±8.0
-
1.0±0.2 104±26 Corticosteroids/
Alkylating agents
YES Company
No treatment 23 50±12 20(87%) 1(4%) 8.4±5.4 29.0±8.0 1.1±0.3 107±63
Chen 2010 (14)
Tacrolimus+Steroids
12 39 47±12 23(59%) 2(5%) 7.7±3.9 23.1±4.3
- 0.9±0.3 106±29
NO NO Unclear
Cyclophosphamide+Steroids 34 49±12 18(53%) 1(3%) 7.3±3.9 23.1±4.8 1.0±0.4 97±34
Xu 2010 (47)
Tacrolimus+Steroids
9 11 55±14 6(54%) -
>5.0 - - - -
NO NO Unclear
Cyclophosphamide+Steroids 13 55±14 9(69%) - - - -
MYCOPHENOLATE MOFETIL (MMF) ± CORTICOSTEROIDS VERSUS NO TREATMENT OR CORTICOSTEROIDS + ALKYLATING AGENTS Dussol
2008 (15)
MMF 12 19 48±15 17(89%) 0(0%) 6.2±3.5 23.2±7.3
- 1.0±0.3 92±30
NO YES Company
No treatment 17 56±15 15(88%) 0(0%) 9.5±5.8 20.2±6.0 1.1±0.4 81±25
Chan 2007 (11)
MMF+Steroids
15-24 11
50±14 13(65%) - 4.9(3.4-6.9) 26.6(24.1-29.1)
14(70%) 1.2±0.6 87±39
NO NO Company
Chlorambucil+Steroids 9 5.8(4.1-8.1) 26.4(23.2-29.5) 1.0±0.4 102±41
Senthil 2008 (44)
MMF+Steroids
16-18 11
- - - - 27.0±7.0
- - 85±11
NO NO Company
Cyclophosphamide+Steroids 10 27.0±4.0 80±13
MYCOPHENOLATE MOFETIL (MMF) + CYCLOSPORINE (2MG/KG/DAY) + CORTICOSTEROIDS VERSUS CYCLOSPORINE (5MG/KG/DAY) + CORTICOSTEROIDS Jurubita
2012 (48)
Cyclosporine(2mg/kg/day) +Steroids+MMF
12
9 - - - 10.4(8.4-14.9) - - -
>60 NO NO Unclear
Cyclosporine(5mg/kg/day)
+Steroids 9 - - - 10.3(8.0-14.1) - - -
ADRENOCORTICOTROPIC HORMONE (ACTH) Arnadottir
2006 (12)
ACTH
21 15
- - - - - - 1.2
- Unclear NO Unclear
No treatment 15 1.2
Ponticelli 2006 (13)
ACTH
22 16 48±13 12(75%) 2(13%) 6.7±2.8
- 9(56%) 1.0±0.4
- Unclear NO Academic
Alkylating agents+Steroids 16 51±10 7(32%) 4(25%) 5.5±2.0 9(56%) 0.9±0.2
AZATHIOPRINE Silverberg 1976 (24)
Azathioprine
12 5 41±15 3(60%) 1(20%) 12.2±4.9 24.0±5.0 2(40%) 1.1±0.4 95±37
NO NO Company
Placebo 4 45±18 3(75%) 0(0%) 9.1±5.9 25.0±3.0 1(25%) 1.5±0.5 74±22
MIZORIBINE Koshisawa
1993 (36)
Mizoribine
6 48
>15 - - - - - - >50 Corticosteroids NO Unclear
Placebo 41
Shibasaki 2004 (45)
Mizoribine
24 14
- - - - - - <2 - Corticosteroids NO Unclear
No treatment 11
TRIPTERYGIUM WILFORDII (TW) Liu
2009 (19)
TW+Steroids
12
43 41±12 31(72%) -
6.0±2.5 24.1±3.7 10(23%) 0.8±0.3
-
Corticosteroids/
Alkylating agents
NO Academic
TW 41 49±10 30(73%) 5.7±2.3 27.3±5.0 11(27%) 0.9±0.4
EARLY VERSUS LATE CYCLOPHOSPHAMIDE + CORTICOSTEROIDS Hofstra
2010 (35)
Early treatment
72 14 48±13 13(93%)
- 9.6(5.9-14.4) 22.6±4.8
- 1.1(0.8-1.4) 81±17
NO YES Academic
Late treatment 12 49±10 11(92%) 12.0(5.6-17.2) 22.3±3.8 1.1(0.8-1.4) 76±13
Supplemental Table 3 Details of the three trials entered in more than more comparison category
Trials Comparison Categories Braun
1995 (28)
Alkylating agents+corticosteroids versus no treatment or ACEI or corticosteroids
Cyclosporine ± corticosteroids versus no treatment or ACEI or corticosteroids ± alkylating agents/azathioprine Kosmadakis
2010 (17)
Alkylating agents+corticosteroids versus no treatment or ACEI or corticosteroids
Cyclosporine ± corticosteroids versus no treatment or ACEI or corticosteroids ± alkylating agents/azathioprine Naumovic
2011 (16)
Cyclosporine ± corticosteroids versus no treatment or ACEI or corticosteroids ± alkylating agents/azathioprine Azathioprine ± corticosteroids versus placebo or cyclosporine + corticosteroids
Supplemental Table 4 Immunosuppression for adult nephrotic syndrome and idiopathic membranous nephropathy Outcomes Follow-up
(months)
Patients (Studies)
Event Proportions RR/MD
(95% CI) P-value Absolute Risk with Controls
Risk Difference with Interventions (95% CI) Controls Interventions
Immunosuppressive treatments versus no treatment or ACEI (18 studies with 935 patients) (10, 12, 15, 17, 18, 24, 25, 28, 29, 31-33, 36, 37, 39, 42, 45, 46)
Death or ESKD 6-120 791 (15) 64/383 (16.7%)
36/408 (8.8%)
RR 0.58
(0.36 to 0.95) 0.03 167 per 1000 70 fewer per 1000 (from 8 fewer to 107 fewer) Death 6-120 791 (15) 16/383
(4.2%)
10/408 (2.5%)
RR 0.65
(0.29 to 1.44) 0.29 42 per 1000 15 fewer per 1000 (from 30 fewer to 18 more) ESKD 6-120 791 (15) 48/383
(12.5%)
26/408 (6.4%)
RR 0.55
(0.31 to 0.95) 0.03 125 per 1000 56 fewer per 1000 (from 6 fewer to 86 fewer) CR or PR 6-120 864 (16) 123/415
(29.6%)
198/449 (44.1%)
RR 1.31
(1.01 to 1.70) 0.04 296 per 1000 92 more per 1000 (from 3 more to 207 more) CR 6-120 761 (15) 38/364
(10.4%)
76/397 (19.1%)
RR 1.59
(0.87 to 2.88) 0.13 104 per 1000 62 more per 1000 (from 14 fewer to 196 more) PR 6-120 761 (15) 78/364
(21.4%)
111/397 (28.0%)
RR 1.16
(0.86 to 1.57) 0.33 214 per 1000 34 more per 1000 (from 30 fewer to 122 more)
Proteinuria 6-120 393 (9) - - MD -0.95
(-1.81 to -0.09) 0.04 - 0.95 g/24 h lower
(1.81 lower to 0.09 lower)
Adverse events leading to withdrawal or hospitalization
6-120 880 (16) 1/424 (0.2%)
33/456 (7.2%)
RR 5.35
(2.19 to 13.02) 0.0002 2 per 1000 10 more per 1000 (from 3 more to 28 more) Corticosteroid monotherapy versus no treatment (3 studies with 295 patients) (25, 29, 31)
Death or ESKD 24-48 295 (3) 22/145 (15.2%)
16/150 (10.7%)
RR 0.75
(0.34 to 1.63) 0.47 152 per 1000 38 fewer per 1000 (from 100 fewer to 96 more) Death 24-48 295 (3) 7/145
(4.8%)
4/150 (2.7%)
RR 0.58
(0.11 to 2.97) 0.51 48 per 1000 20 fewer per 1000 (from 43 fewer to 95 more) ESKD 24-48 295 (3) 15/145
(10.3%)
12/150 (8.0%)
RR 0.81
(0.34 to 1.93) 0.63 103 per 1000 20 fewer per 1000 (from 68 fewer to 96 more) CR or PR 24-48 295 (3) 33/145
(22.8%)
38/150 (25.3%)
RR 1.18
(0.64 to 2.16) 0.60 228 per 1000 41 more per 1000 (from 82 fewer to 264 more)
CR 24-48 192 (2) 15/94
(16.0%)
10/98 (10.2%)
RR 0.64
(0.29 to 1.42) 0.27 160 per 1000 57 fewer per 1000 (from 113 fewer to 67 more)
PR 24-48 192 (2) 11/94
(11.7%)
18/98 (18.4%)
RR 1.63
(0.62 to 4.25) 0.32 117 per 1000 74 more per 1000 (from 44 fewer to 380 more)
Proteinuria 36 43 (1) - - MD 0.00
(-1.99 to 1.99) 1.00 - 0.00 g/24 h lower/higher (1.99 lower to 1.99 higher)
Adverse events leading to withdrawal or hospitalization
24-48 295 (3) 1/145 (0.7%)
5/150 (3.3%)
RR 2.22
(0.38 to 13.12) 0.38 7 per 1000 8 more per 1000 (from 4 fewer to 84 more) Alkylating agent monotherapy versus no treatment (3 studies with 102 patients) (33, 37, 46)
Death or ESKD 12-36 102 (3) 3/51 (5.9%)
1/51 (2.0%)
RR 0.62
(0.03 to 12.27) 0.76 59 per 1000 22 fewer per 1000 (from 57 fewer to 663 more) Death 12-36 102 (3) 2/51
(3.9%)
1/51 (2.0%)
RR 0.75
(0.05 to 10.61) 0.83 39 per 1000 10 fewer per 1000 (from 37 fewer to 377 more)
ESKD 12-36 102 (3) 1/51 (2.0%)
0/51 (0.0%)
RR 0.33
(0.01 to 7.84) 0.50 20 per 1000 13 fewer per 1000 (from 19 fewer to 134 more) CR or PR 12-36 48 (2) 6/24
(25.0%)
13/24 (54.2%)
RR 2.14
(0.99 to 4.63) 0.05 250 per 1000 285 more per 1000 (from 2 fewer to 908 more)
CR 12-36 48 (2) 1/24
(4.2%)
2/24 (8.3%)
RR 2.00
(0.21 to 19.44) 0.55 42 per 1000 42 more per 1000 (from 33 fewer to 768 more)
PR 12-36 48 (2) 5/24
(20.8%)
11/24 (45.8%)
RR 2.19
(0.90 to 5.34) 0.09 208 per 1000 248 more per 1000 (from 21 fewer to 904 more)
Proteinuria 12 19 (1) - - MD -0.49
(-3.60 to 2.62) 0.76 - 0.49 g/24 h lower
(3.60 lower to 2.62 higher)
Adverse events leading to withdrawal or hospitalization
12-36 102 (3) 0/51 (0.0%)
11/51 (21.6%)
RR 7.18
(1.33 to 38.70) 0.02 0 per 1000 -
Corticosteroids + alkylating agents versus no treatment or ACEI or corticosteroid monotherapy (8 studies with 448 patients) (17, 18, 26, 28, 34, 38, 41, 42)
Death or ESKD 9-120 448 (8) 41/226 (18.1%)
17/222 (7.7%)
RR 0.44
(0.26 to 0.75) 0.002 181 per 1000 102 fewer per 1000 (from 45 fewer to 134 fewer) Death 9-120 448 (8) 7/226
(3.1%)
4/222 (1.8%)
RR 0.57
(0.16 to 1.98) 0.38 31 per 1000 13 fewer per 1000 (from 26 fewer to 30 more) ESKD 9-120 448 (8) 34/226
(15.0%)
14/222 (6.3%)
RR 0.45
(0.25 to 0.81) 0.008 150 per 1000 83 fewer per 1000 (from 29 fewer to 113 fewer) CR or PR 9-120 422 (7) 87/213
(40.8%)
140/209 (67.0%)
RR 1.46
(1.13 to 1.89) 0.004 408 per 1000 188 more per 1000 (from 53 more to 364 more)
CR 9-120 422 (7) 37/213 (17.4%)
89/209 (42.6%)
RR 2.32
(1.61 to 3.32) <0.00001 174 per 1000 229 more per 1000 (from 106 more to 403 more)
PR 9-120 422 (7) 50/213
(23.5%)
51/209 (24.4%)
RR 0.94
(0.56 to 1.57) 0.82 235 per 1000 14 fewer per 1000 (from 103 fewer to 134 more)
Proteinuria 9-120 279 (6) - - MD -1.25
(-1.93 to -0.57) 0.0003 - 1.25 g/24 h lower (1.93 lower to 0.57 lower)
Adverse events leading to withdrawal or hospitalization
9-120 448 (8) 7/226 (3.1%)
18/222 (8.1%)
RR 2.11
(0.77 to 5.79) 0.15 31 per 1000 34 more per 1000 (from 7 fewer to 148 more) Cyclophosphamide + corticosteroids versus chlorambucil + corticosteroids (3 studies with 147 patients) (27, 40, 43)
Death or ESKD 15-39 147 (3) 6/75 (8.0%)
8/72 (11.1%)
RR 1.17
(0.15 to 9.36) 0.88 80 per 1000 14 more per 1000 (from 68 fewer to 669 more) Death 15-39 147 (3) 0/75
(0.0%)
1/72 (1.4%)
RR 3.00
(0.14 to 65.90) 0.49 0 per 1000 -
ESKD 15-39 147 (3) 6/75
(8.0%)
7/72 (9.7%)
RR 1.09
(0.16 to 7.72) 0.93 80 per 1000 7 more per 1000 (from 67 fewer to 538 more) CR or PR 15-39 147 (3) 41/75
(54.7%)
55/72 (76.4%)
RR 1.64
(0.72 to 3.76) 0.24 547 per 1000 350 more per 1000 (from 153 fewer to 1000 more)
CR 15-39 147 (3) 12/75
(16.0%)
24/72 (33.3%)
RR 2.22
(0.76 to 6.47) 0.14 160 per 1000 195 more per 1000 (from 38 fewer to 875 more)
PR 15-39 147 (3) 29/75
(38.7%)
31/72 (43.1%)
RR 1.16
(0.58 to 2.31) 0.68 387 per 1000 62 more per 1000 (from 162 fewer to 507 more)
Proteinuria 32-39 118 (2) - - MD -2.74
(-7.71 to 2.23) 0.28 - 2.74 g/24 h lower
(7.71 lower to 2.23 higher)
Adverse events leading to withdrawal or hospitalization
15-39 147 (3) 18/75 (24.0%)
9/72 (12.5%)
RR 0.48
(0.26 to 0.90) 0.02 240 per 1000 125 fewer per 1000 (from 24 fewer to 178 fewer) Cyclosporine ± corticosteroids versus no treatment or ACEI or corticosteroids ± alkylating agents/azathioprine
(6 studies with 202 patients) (16, 17, 28, 30, 32, 39) Death or ESKD 9-60 202 (6) 10/91
(11.0%)
14/111 (12.6%)
RR 1.00
(0.47 to 2.15) 1.00 110 per 1000 0 fewer per 1000 (from 58 fewer to 126 more)
Death 9-60 202 (6) 2/91
(2.2%)
5/111 (4.5%)
RR 1.28
(0.35 to 4.66) 0.71 22 per 1000 6 more per 1000 (from 14 fewer to 80 more)
ESKD 9-60 202 (6) 8/91
(8.8%)
9/111 (8.1%)
RR 0.96
(0.37 to 2.53) 0.94 88 per 1000 4 fewer per 1000 (from 55 fewer to 135 more) CR or PR 9-60 185 (5) 39/83
(47.0%)
57/102 (55.9%)
RR 1.03
(0.73 to 1.44) 0.88 470 per 1000 14 more per 1000 (from 127 fewer to 207 more)
CR 9-60 185 (5) 12/83
(14.5%)
16/102 (15.7%)
RR 1.03
(0.52 to 2.03) 0.94 145 per 1000 4 more per 1000 (from 69 fewer to 149 more)
PR 9-60 185 (5) 27/83
(32.5%)
31/102 (30.4%)
RR 0.84
(0.54 to 1.31) 0.45 325 per 1000 52 fewer per 1000 (from 150 fewer to 101 more)
Proteinuria 9-60 131 (5) - - MD 0.61
(-0.87 to 2.09) 0.42 - 0.61 g/24 h higher
(0.87 lower to 2.09 higher)
Adverse events leading to withdrawal or hospitalization
9-60 202 (6) 2/91 (2.2%)
2/111 (1.8%)
RR 1.18
(0.06 to 23.79) 0.91 22 per 1000 4 more per 1000 (from 21 fewer to 501 more)
Cyclosporine (1.5 mg/kg twice a day) + corticosteroids versus cyclosporine (3.0 mg/kg once a day) + corticosteroids (1 study with 33 patients) (49)
CR 12 33 (1) 11/17
(64.7%)
11/16 (68.8%)
RR 1.06
(0.66 to 1.72) 0.81 647 per 1000 39 more per 1000 (from 220 fewer to 466 more)
Proteinuria 12 33 (1) - - MD -0.70
(-0.96 to -0.44) <0.00001 - 0.70 g/24 h lower (0.96 lower to 0.44 lower) Tacrolimus ± corticosteroids versus no treatment or corticosteroids + alkylating agents
(3 studies with 145 patients) (10, 14, 47) Death or ESKD 12-30 121 (2) 1/57
(1.8%)
0/64 (0.0%)
RR 0.31
(0.01 to 7.20) 0.46 18 per 1000 12 fewer per 1000 (from 17 fewer to 109 more)
Death 12-30 121 (2) 1/57
(1.8%)
0/64 (0.0%)
RR 0.31
(0.01 to 7.20) 0.46 18 per 1000 12 fewer per 1000 (from 17 fewer to 109 more)
ESKD 12-30 121 (2) 0/57
(0.0%)
0/64
(0.0%) not pooled - - -
CR or PR 12-30 121 (2) 30/57 (52.6%)
41/64 (64.1%)
RR 1.19
(0.91 to 1.55) 0.20 526 per 1000 100 more per 1000 (from 47 fewer to 289 more)
CR 12-30 121 (2) 14/57
(24.6%)
14/64 (21.9%)
RR 0.91
(0.47 to 1.74) 0.77 246 per 1000 22 fewer per 1000 (from 130 fewer to 182 more)
PR 12-30 121 (2) 15/57
(26.3%)
29/64 (45.3%)
RR 1.60
(0.99 to 2.59) 0.05 263 per 1000 158 more per 1000 (from 3 fewer to 418 more)
Proteinuria 9-30 132 (3) - - MD -1.06
(-1.66 to -0.47) 0.0004 - 1.06 g/24 h lower (1.66 lower to 0.47 lower)
Adverse events leading to withdrawal or hospitalization
12-30 121 (2) 3/57 (5.3%)
6/64 (9.4%)
RR 1.74
(0.47 to 6.45) 0.40 53 per 1000 39 more per 1000 (from 28 fewer to 287 more) Mycophenolate mofetil ± corticosteroids versus no treatment or corticosteroids + alkylating agents
(3 studies with 77 patients) (11, 15, 44) CR or PR 12-24 77 (3) 19/36
(52.8%)
19/41 (46.3%)
RR 0.88
(0.58 to 1.35) 0.57 528 per 1000 63 fewer per 1000 (from 222 fewer to 185 more)
CR 12-24 77 (3) 7/36
(19.4%)
8/41 (19.5%)
RR 0.99
(0.35 to 2.82) 0.98 194 per 1000 2 fewer per 1000 (from 126 fewer to 354 more)
PR 12-24 77 (3) 12/36
(33.3%)
11/41 (26.8%)
RR 0.83
(0.41 to 1.70) 0.61 333 per 1000 57 fewer per 1000 (from 197 fewer to 233 more)
Proteinuria 15 19(1) - - MD 0.50
(-0.65 to 1.65) 0.39 - 0.50 g/24 h higher
(0.65 lower to 1.65 higher)
Adverse events leading to withdrawal or hospitalization
12-24 77 (3) 5/36 (13.9%)
6/41 (14.6%)
RR 0.81
(0.12 to 5.29) 0.83 139 per 1000 26 fewer per 1000 (from 122 fewer to 596 more) Mycophenolate mofetil + cyclosporine (2mg/kg/day) + corticosteroids versus cyclosporine (5mg/kg/day) + corticosteroids
(1 study with 18 patients) (48)
CR or PR 12 18 (1) 7/9
(77.8%)
9/9 (100.0%)
RR 1.27
(0.86 to 1.86) 0.23 778 per 1000 210 more per 1000 (from 109 fewer to 669 more)
CR 12 18 (1) 3/9
(33.3%)
4/9 (44.4%)
RR 1.33
(0.41 to 4.33) 0.63 333 per 1000 110 more per 1000 (from 197 fewer to 1000 more)
PR 12 18 (1) 4/9
(44.4%)
5/9 (55.6%)
RR 1.25
(0.49 to 3.19) 0.64 444 per 1000 111 more per 1000 (from 227 fewer to 973 more)
Adrenocorticotropic hormone versus no treatment or corticosteroids + alkylating agents (2 studies with 62 patients) (12, 13) Death or ESKD 21-22 32 (1) 0/16
(0.0%)
1/16 (6.3%)
RR 3.00
(0.13 to 68.57) 0.49 0 per 1000 -
Death 21-22 32 (1) 0/16
(0.0%)
0/16
(0.0%) not pooled - - -
ESKD 21-22 32 (1) 0/16
(0.0%)
1/16 (6.3%)
RR 3.00
(0.13 to 68.57) 0.49 0 per 1000 -
CR or PR 21-22 62 (2) 14/31 (45.2%)
28/31 (90.3%)
RR 2.55
(0.45 to 14.55) 0.29 452 per 1000 700 more per 1000 (from 248 fewer to 1000 more)
CR 21-22 62 (2) 5/31
(16.1%)
19/31 (61.3%)
RR 3.81
(0.75 to 19.27) 0.11 161 per 1000 453 more per 1000 (from 40 fewer to 1000 more)
PR 21-22 62 (2) 9/31
(29.0%)
9/31 (29.0%)
RR 1.03
(0.33 to 3.25) 0.96 290 per 1000 9 more per 1000 (from 195 fewer to 653 more)
Proteinuria 22 31 (1) - - MD -1.80
(-3.19 to -0.41) 0.01 - 1.80 g/24 h lower
(3.19 lower to 0.41 lower)
Adverse events leading to withdrawal or hospitalization
21-22 32 (1) 2/16 (12.5%)
1/16 (6.3%)
RR 0.5
(0.05 to 4.98) 0.55 125 per 1000 62 fewer per 1000 (from 119 fewer to 498 more) Azathioprine ± corticosteroids versus placebo or cyclosporine + corticosteroids (2 studies with 32 patients) (16, 24)
Death or ESKD 12-36 32 (2) 0/14 (0.0%)
1/18 (5.6%)
RR 2.36
(0.11 to 52.41) 0.59 0 per 1000 -
Death 12-36 32 (2) 0/14 (0.0%)
0/18
(0.0%) not pooled - - -
ESKD 12-36 32 (2) 0/14
(0.0%)
1/18 (5.6%)
RR 2.36
(0.11 to 52.41) 0.59 0 per 1000 -
CR or PR 12-36 32 (2) 8/14 (57.1%)
7/18 (38.9%)
RR 0.73
(0.39 to 1.38) 0.34 571 per 1000 154 fewer per 1000 (from 349 fewer to 217 more)
CR 12-36 32 (2) 3/17
(17.6%)
3/15 (20.0%)
RR 1.12
(0.20 to 6.28) 0.90 176 per 1000 21 more per 1000 (from 141 fewer to 932 more)
PR 12-36 32 (2) 4/14
(28.6%)
5/18 (27.8%)
RR 0.96
(0.35 to 2.68) 0.94 286 per 1000 11 fewer per 1000 (from 186 fewer to 480 more)
Proteinuria 12 9 (1) - - MD 1.10
(-2.79 to 4.99) 0.58 - 1.10 g/24 h higher
(2.79 lower to 4.99 higher)
Adverse events leading to withdrawal or hospitalization
12-36 32 (2) 0/14 (0.0%)
2/18 (11.1%)
RR 3.93
(0.21 to 73.71) 0.36 0 per 1000 -
Mizoribine versus no treatment (2 studies with 114 patients) (36, 45) CR or PR 6-24 114 (2) 9/52
(17.3%)
25/62 (40.3%)
RR 2.24
(1.14 to 4.38) 0.02 173 per 1000 215 more per 1000 (from 24 more to 585 more)
CR 6-24 114 (2) 1/52
(1.9%)
7/62 (11.3%)
RR 4.08
(0.73 to 22.81) 0.11 19 per 1000 59 more per 1000 (from 5 fewer to 419 more)
PR 6-24 114 (2) 8/52
(15.4%)
18/62 (29.0%)
RR 1.89
(0.90 to 3.97) 0.09 154 per 1000 137 more per 1000 (from 15 fewer to 457 more)
Adverse events leading to withdrawal or hospitalization
6-24 89 (1) 0/41 (0.0%)
2/48 (4.2%)
RR 4.29
(0.21 to 86.80) 0.34 0 per 1000 -
Tripterygium Wilfordii (1 study with 84 patients) (19)
CR or PR 12 84 (1) 15/41
(36.6%)
32/43 (74.4%)
RR 2.03
(1.31 to 3.16) 0.002 366 per 1000 377 more per 1000 (from 113 more to 790 more)
CR 12 84 (1) 2/41
(4.9%)
16/43 (37.2%)
RR 7.63
(1.87 to 31.13) 0.005 49 per 1000 323 more per 1000 (from 42 more to 1000 more)
PR 12 84 (1) 13/41
(31.7%)
16/43 (37.2%)
RR 1.17
(0.65 to 2.13) 0.60 317 per 1000 54 more per 1000 (from 111 fewer to 358 more)
Adverse events leading to withdrawal or hospitalization
12 84 (1) 4/41 (9.8%)
3/43 (7.0%)
RR 0.72
(0.17 to 3.00) 0.65 98 per 1000 27 fewer per 1000 (from 81 fewer to 195 more) Early versus late cyclophosphamide + corticosteroids (1 study with 26 patients) (35)
Death or ESKD 72 26 (1) 1/12 (8.3%)
1/14 (7.1%)
RR 0.86
(0.06 to 12.28) 0.91 83 per 1000 12 fewer per 1000 (from 78 fewer to 940 more)
Death 72 26 (1) 1/12
(8.3%)
0/14 (0.0%)
RR 0.29
(0.01 to 6.50) 0.43 83 per 1000 59 fewer per 1000 (from 82 fewer to 458 more)
ESKD 72 26 (1) 0/12
(0.0%)
1/14 (7.1%)
RR 2.6
(0.12 to 58.48) 0.55 0 per 1000 -
CR or PR 72 26 (1) 9/12
(75.0%)
12/14 (85.7%)
RR 1.14
(0.77 to 1.69) 0.50 750 per 1000 105 more per 1000 (from 173 fewer to 518 more)
CR 72 26 (1) 8/12 (66.7%)
7/14 (50.0%)
RR 0.75
(0.39 to 1.45) 0.39 667 per 1000 167 fewer per 1000 (from 407 fewer to 300 more)
PR 72 26 (1) 1/12
(8.3%)
5/14 (35.7%)
RR 4.29
(0.58 to 31.79) 0.15 83 per 1000 274 more per 1000 (from 35 fewer to 1000 more)
Proteinuria 72 26 (1) - - MD 0.59
(-0.64 to 1.82) 0.35 - 0.59 g/24 h higher
(0.64 lower to 1.82 higher)
Adverse events leading to withdrawal or hospitalization
72 26 (1) 6/12 (50.0%)
2/14 (14.3%)
RR 0.29
(0.07 to 1.16) 0.08 500 per 1000 355 fewer per 1000 (from 465 fewer to 80 more)
Supplementary Figure 1
Supplementary Figure 2
Supplementary Figure 3
Supplementary Figure 4
Supplementary Figure 5
Supplementary Figure 6
