KDIGO GN Suppl Online Tables May 2012 PDF

KDIGO CLINICAL PRACTICE GUIDELINE
FOR GLOMERULONEPHRITIS
Online Supplementary Tables

May 2012
Table of Contents
Supplementary table 1. Evidence profile of studies examining IV vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome
Supplementary table 2. Existing systematic review on IV vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome
Supplementary table 3. Summary tables of studies examining IV vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome
(categorical outcomes)
Supplementary table 4. Summary table of RCT examining MMF vs. CsA in frequently relapsing nephrotic syndrome in children (categorical outcomes)
Supplementary table 5. Summary table of RCT examining MMF vs. CsA in frequently relapsing nephrotic syndrome in children (continuous outcomes)
Supplementary table 6. Summary table of RCT examining low vs. fixed dose CsA treatment in children with frequently relapsing nephrotic syndrome
Supplementary table 7. Summary table of RCT examining low vs. fixed dose CsA treatment in children with frequently relapsing nephrotic syndrome
(continuous outcomes)
Supplementary table 8. Evidence profile of RCTs examining CsA vs. placebo in steroid-resistant nephrotic syndrome in children
Supplementary table 9. Meta-analyses and systematic reviews on steroid-resistant nephrotic syndrome in children
Supplementary table 10. Evidence profile of studies examining CsA vs. Cyc treatment in children with steroid-resistant nephrotic syndrome
Supplementary table 11. Summary table of studies examining CsA vs. Cyc treatment in children with steroid-resistant nephrotic syndrome (categorical
outcomes)
Supplementary table 12. Evidence profile of RCTs examining ACE-I treatment for steroid-resistant nephrotic syndrome in children
Supplementary table 13. Summary table of RCTs examining ACE treatment for steroid-resistant nephrotic syndrome in children (continuous outcomes)
Supplementary table 14. Evidence profile of studies examining p.o. Cyc plus steroid vs. steroid in steroid-resistant nephrotic syndrome and/or FSGS in
children
Supplementary table 15. Summary table of studies examining p.o. Cyc plus steroid vs. steroid in children with SRNS or FSGS (categorical outcomes)
Supplementary table 16. Summary table of studies examining p.o. Cyc plus steroid vs. steroid in children with SRNS or FSGS (continuous outcomes)
Supplementary table 17. Summary table RCTs examining IV vs. p.o. Cyc treatment in children with steroid-resistant nephrotic syndrome (continuous
outcomes)
Supplementary table 18. Summary table of RCT examining TAC vs. CsA treatment in children with steroid-resistant nephrotic syndrome (categorical
outcomes)
Supplementary table 19. Summary table of RCT examining TAC vs. CsA treatment in children with steroid-resistant nephrotic syndrome (continuous
outcomes)
Supplementary table 20. Summary table of RCT examining CsA vs. steroid treatment after first relapse in adults with minimal change disease (categorical
outcomes)
Supplementary table 21. Summary table of RCT examining CsA vs. steroid treatment after first relapse in adults with minimal change disease (continuous
outcomes)
Supplementary table 22. Evidence profile of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous
nephropathy
Supplementary table 23. Existing systematic review on alkylating agents vs. control for idiopathic membranous nephropathy in adults with nephrotic
syndrome
Supplementary table 24. Summary table of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy
Supplementary table 25. Summary table of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy
Supplementary table 26. Summary table of RCTs examining alkylating agents plus steroid treatment vs. ACTH in patients with membranous nephropathy
Supplementary table 27. Summary table of RCTs examining alkylating agents plus steroid treatment vs. ACTH in patients with membranous nephropathy
Supplementary table 28. Evidence profile of RCTs examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy
Supplementary table 29. Existing systematic reviews on CsA/TAC treatment vs. placebo for idiopathic membranous nephropathy in adults with nephrotic
syndrome
Supplementary table 30. Summary table of RCT examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy (categorical outcomes)
Supplementary table 31. Summary table of RCT examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy (continuous outcomes)
Supplementary table 32. Evidence profile of RCTs examining MMF treatment vs. control for idiopathic membranous nephropathy in adults with nephrotic
syndrome
Supplementary table 33. Summary table of RCTs examining MMF treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome
Supplementary table 34. Summary table of RCTs examining MMF treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome
Supplementary table 35. Evidence profile of RCTs examining alternate-day prednisone treatment vs. control in adults and children with MPGN
Supplementary table 36. Summary table of studies examining alternate-day prednisone treatment vs. control in patients with MPGN (categorical
outcomes)
Supplementary table 37. Summary table of studies examining alternate-day prednisone treatment vs. control in patients with MPGN (continuous
outcomes)
Supplementary table 38. Summary table of studies examining dipyridamole plus aspirin treatment vs. placebo in patients with MPGN (categorical
outcomes)
Supplementary table 39. Summary table of studies examining dipyridamole plus aspirin treatment vs. placebo in patients with MPGN (continuous
outcomes)
Supplementary table 40. Summary table of study examining warfarin plus dipyridamole treatment vs. control in patients with MPGN (categorical outcomes)
Supplementary table 41. Summary table of study examining warfarin plus dipyridamole treatment vs. control in patients with MPGN (continuous outcomes)
Supplementary table 42. Summary table of studies examining prednisone or CsA treatment vs. control in patients with schistosoma and nephropathy
Supplementary table 43. Summary table of studies examining prednisone or CsA treatment vs. control in patients with schistosoma and nephropathy
Supplementary table 44. Evidence profile of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy
Supplementary table 45. Summary table of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy (categorical outcomes)
Supplementary table 46. Summary table of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy (continuous outcomes)
Supplementary table 47. Evidence profile of RCTs examining steroid regimens in biopsy-proven IgA nephropathy
Supplementary table 48. Meta-analyses and systematic reviews on immunosuppression for IgA nephropathy
Supplementary table 49. Summary table of RCTs examining steroid regimens in biopsy-proven IgA nephropathy (categorical outcomes)
Supplementary table 50. Summary table of RCTs examining steroid regimens in biopsy-proven IgA nephropathy (continuous outcomes)
Supplementary table 52. Summary table of RCTs examining steroid and immunosuppressive regimens in biopsy-proven IgA nephropathy (categorical
outcomes)
Supplementary table 53. Summary table of RCTs examining steroid and immunosuppressive regimens in biopsy-proven IgA nephropathy (continuous
outcomes)
Supplementary table 54. Evidence profile of RCTs examining AZA in combination vs. AZA alone in biopsy-proven IgA nephropathy
Supplementary table 55. Summary table of RCT examining AZA in biopsy-proven IgA nephropathy (categorical outcomes)
Supplementary table 56. Summary table of RCT examining AZA in biopsy-proven IgA nephropathy (continuous outcomes)
Supplementary table 57. Evidence profile of RCTs examining MMF in biopsy-proven IgA nephropathy
Supplementary table 58. Meta-analyses and systematic reviews on MMF therapy for IgA nephropathy
Supplementary table 59. Summary Table of RCTs examining MMF in biopsy-proven IgA nephropathy (categorical outcomes)
Supplementary table 60. Summary Table of RCTs examining MMF in biopsy-proven IgA nephropathy (continuous outcomes)
Supplementary table 61. Evidence profile of studies examining omega-3 fatty acid treatment in IgA nephropathy
Supplementary table 62. Meta-analyses and systematic reviews on fish oil treatment in IgA nephropathy
Supplementary table 63. Summary table of RCTs examining omega-3 fatty acids in biopsy-proven IgA nephropathy (categorical outcomes)
Supplementary table 64. Summary table of RCTs examining omega-3 fatty acids in biopsy-proven IgA nephropathy (continuous outcomes)
Supplementary table 65. Meta-analyses and systematic reviews on antiplatelet therapy for IgA nephropathy
Supplementary table 66. Summary table of RCT examining immunosuppression and anti-platelets in biopsy-proven IgA nephropathy (categorical
outcomes)
Supplementary table 67. Summary table of RCT examining immunosuppression and anti-platelets in biopsy-proven IgA nephropathy (continuous
outcomes)
Supplementary table 68. Summary table of RCT examining antiplatelet treatments in biopsy-proven IgA nephropathy (continuous outcomes)*
Supplementary table 69. Summary table of RCTs examining miscellaneous treatments in biopsy-proven IgA nephropathy (categorical outcomes)
Supplementary table 70. Summary table of RCTs examining miscellaneous treatments in biopsy-proven IgA nephropathy (continuous outcomes)
Supplementary table 71. Evidence profile of RCTs of MMF vs. Cyc for induction therapy in lupus nephritis
Supplementary table 72. Summary table of RCTs examining MMF vs. IV Cyc for induction therapy in patients with lupus nephritis (categorical outcomes)
Supplementary table 73. Summary table of RCTs examining MMF vs. IV Cyc for induction therapy in patients with lupus nephritis (continuous outcomes)
Supplementary table 74. Existing systematic review on Cyc vs. AZA for induction treatment in patients with lupus nephritis
Supplementary table 75. Summary table of RCT examining Cyc vs. AZA for induction treatment in patients with lupus nephritis (categorical outcomes)
Supplementary table 76. Summary table of RCT examining Cyc vs.AZA for induction treatment in patients with lupus nephritis (continuous outcomes)
Supplementary table 77. Summary table of RCT examining low vs. high dose IV Cyc in patients with lupus nephritis (categorical outcomes)
Supplementary table 78. Existing systematic review on IV vs. p.o. Cyc treatment in patients with lupus nephritis
Supplementary table 79. Summary table of RCT examining IV Cyc vs. p.o. Cyc in patients with lupus nephritis (categorical outcomes)
Supplementary table 80. Summary table of RCT examining Cyc vs. AZA for maintenance therapy in patients with lupus nephritis (categorical outcomes)
Supplementary table 81. Summary table of RCT examining Cyc vs. AZA for maintenance therapy in patients with lupus nephritis (continuous outcomes)
Supplementary table 82. Summary table of RCT examining IV Cyc vs. prednisone in patients with membranous lupus nephritis (categorical outcomes)
Supplementary table 83. Summary table of RCT examining IV Cyc vs. prednisone in patients with membranous lupus nephritis (categorical outcomes)
Supplementary table 84. Summary table of RCT CsA vs. IV Cyc in patients with membranous lupus nephritis (categorical outcomes)
Supplementary table 85. Summary table of RCT examining rituximab + Cyc vs. rituximab in patients with proliferative lupus nephritis (categorical
outcomes)
Supplementary table 86. Summary table of RCT examining rituximab + Cyc vs. rituximab in patients with proliferative lupus nephritis (continuous
outcomes)
Supplementary table 87. Summary table of RCT examining TAC vs. placebo in patients with lupus nephritis (categorical outcomes)
Supplementary table 88. Summary table of RCT examining TAC vs. placebo in patients with lupus nephritis (continuous outcomes)
Supplementary table 89. Summary table of a study examining TAC vs. standard protocols of steroid + p.o. Cyc or AZA in patients with class V lupus
Supplementary table 90. Summary table of a study examining TAC vs. standard protocols of steroid + p.o. Cyc or AZA in patients with class V lupus
Supplementary table 91. Summary table of a study examining AZA vs. IV Cyc maintenance therapy in patients with lupus nephritis (categorical outcomes)
Supplementary table 92. Summary table of a study examining MMF vs. IV Cyc maintenance therapy in patients with lupus nephritis (categorical outcomes)
Supplementary table 93. Evidence profile of studies examining MMF vs. AAZA maintenance therapy in patients with lupus nephritis
Supplementary table 94.Summary table of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis (categorical outcomes)
Supplementary table 95. Summary table of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis (continuous outcomes)
Supplementary table 96. Evidence profile of IV vs. p.o. Cyc for ANCA vasculitis
Supplementary table 97. Existing systematic review of Induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis
Supplementary table 98. Summary table of RCT examining induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis (categorical
outcomes)
Supplementary table 99. Summary table of RCT examining induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis (continuous
outcomes)
Supplementary table 100. Evidence profile of RCTs examining induction with rituximab vs. Cyc in patients with ANCA vasculitis
Supplementary table 101. Summary table of RCTs examining induction with rituximab vs. Cyc in patients with ANCA vasculitis (categorical outcomes)
Supplementary table 102. Summary table of RCTs examining induction with rituximab vs. Cyc in patients with ANCA vasculitis (continuous outcomes)
Abbreviations and Acronyms for Supplementary Tables
∆ Change MDRD Modification of Diet in Renal Disease
↓ Decrease MN Membranous nephropathy
↑ Increase MMF Mycophenolate mofetil
ACTH Adrenocorticotropic hormone MP Methlyprednisolone
ACE-I Angiotensin-converting enzyme inhibitors N Number
AE Adverse events N&V Nausea and vomiting
ALP Alkaline phosphatase NA Not applicable
ANCA Anti-neutrophil cytoplasmic antibody NaCl Sodium chloride
ARB Angiotensin receptor blockade nd Not documented
ARR Absolute relative risk NNT Number needed to treat
ASN American Society of Nephrology NS Not significant
AZA Azathioprine OR Odds ratio
BP Blood pressure p.o. Oral
CR Complete remission PR Partial remission
CrCl Creatinine clearance Pred Prednisone
CsA Cyclosporine pts Patients
Cyc Cyclophosphamide RCT Randomized controlled trial
DBP Diastolic blood pressure RD Risk difference
D/C Discontinued RPGN Rapidly progressive glomerulonephritis
DM Diabetes mellitus RR Relative risk
eGFR Estimated glomerular filtration rate RRT Renal replacement therapy
ESRD End-stage renal disease SCr Serum creatinine
ESRF End-stage renal failure SLE Systemic lupus erythematosus
ERT Evidence review team SRNS Steroid-resistant nephritic syndrome
FRNS Frequently relapsing nephritic syndrome SSNS Steroid sensitive nephritic syndrome
FSGS Focal segmental glomerulonephritis TAC Tacrolimus
GFR Glomerular filtration rate TB Tuberculosis
GI Gastrointestinal UACR Urine albumin creatinine ratio
HbA1c Hemoglobin A1c UI Unique identifier
HR Hazards ratio UK United Kingdom
HSP Henich-Schoenlein purpura UPCR Urine protein creatinine ratio
HSV Herpes simplex virus UPE Urine protein excretion
HTN Hypertension US United States
IMN Idiopathic membranous nephropathy UTI Urinary tract infection
IU International units WGM Work group member
i.v. Intravenous WMD Weighted mean difference
LFT Liver function test
LN Lupus Nephritis
Supplementary table 1. Evidence profile of studies examining i.v. vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome
Directness of Summary of findings
# of studies Methodological
Total N Consistency the evidence Other
Outcome and quality of studies
(treatment) across studies generalizability/ considerations Quality of evidence for Qualitative and quantitative description of Importance
study design per outcome outcome effect of outcome
applicability
Mortality 0 RCTs -- -- -- -- -- -- -- Critical
ESRD 0 RCTs -- -- -- -- -- -- -- Critical
1 Non-RCT 19 Some limitations
No important
(Moderate) (10) (-1) Direct Sparse Benefit for monthly i.v. cyclophosphamide at 6
Relapse inconsistencies Low High
1 SR 83 Some limitations (0) (-1) but not at end of study.
(0)
(2 RCTs) (41) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Kidney
function 0 RCTs -- -- -- -- -- -- -- High
(categorical)
ΔProteinuria
0 RCTs -- -- -- -- -- -- -- Moderate
(continuous)
ΔKidney
function 0 RCTs -- -- -- -- -- -- -- Moderate
(continuous)
1 Non-RCT 19 Some limitations
More nausea and vomiting with i.v.
(Moderate) (10) (-1)
Adverse events cyclophosphamide; more infections with p.o. Moderate
1 SR 48 Some limitations
cyclophosphamide.
(1 RCT) (26) (-1)
Balance of potential benefits and harm: Quality of overall evidence:
No difference between monthly i.v. cyclophosphamide and oral cyclophosphamide Low
Supplementary table 2. Existing systematic reviews on i.v. vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome
Study, Year, RefID Study Eligibility Criteria Interventions (Studies) Outcomes Conclusions Comments Yes/No
Hodson[34] Inclusion: 1. i.v. vs. oral cyclophosphamide regimens # children relapse within 6 Oral or i.v. cyclophosphamide, Is eligibility criteria similar to Yes
1) Children aged three months to (Abeyagunawardena 06b; Prasad 2004) months oral chlorambucil, cyclosporin the guideline
Date Base: 18 years with relapsing SSNS (i.e. Other interventions were included in the and levamisole substantially
CENTRAL(Cochrane Renal the child became oedema-free and meta-analysis and are the subject of other # children relapse within 12- reduce the incidence of relapse
Group), MEDLINE and his/her urine protein was = 1+ on summary tables 24 months in children with relapsing SSNS.
EMBASE dipstick or <4 mg/m²/h for three
Search Dates: consecutive days while receiving Mean relapse rate/pt/y The benefit of non-corticosteroid Are there any limitations to No
Central: (Sept 2007) corticosteroid therapy). Relapse of agents is sustained beyond the systematic review
Medline: (1966-Sept 2007) nephritic syndrome is defined as Adverse Events: on-treatment period for the methodology
EMBASE: (1980-Sept 2007) the recurrence of proteinuria HTN alkylating agents but rarely with
N Studies: measured semi-quantitatively on Leukopenia cyclosporin and levamisole.
26 trials included in this urine analysis or quantitatively Infections However there are inadequate
update using albumin or protein to Alopecia data available to determine
N Subjects: creatinine ratios or timed urine N&V/ GI which agent should be preferred Is limitation to evidence Yes
1173 children specimens. A renal biopsy initially. Thus the decision as to clearly addressed by the
diagnosis of minimal change which medication should be authors
disease was not required. used in a child with frequently
Exclusion: relapsing or steroid dependent
1) First episode of SSNS SSNS will largely depend on
2) Steroid-resistant nephritic patient and physician
syndrome preference following discussion
3) Other renal or systemic forms of of the possible side effects and
nephritic syndrome defined on the costs of courses of
renal biopsy, clinical features or alkylating agents and those of
serology (e.g. post-infectious prolonged courses of
glomerulonephritis, Henoch- cyclosporin or levamisole.
Schonlein nephritis, systemic lupus Clinically important differences
erythematosus). in efficacy are possible and
further comparative studies are
still needed.
Description of limitations of evidence by authors Small sample size
N studies Test for heterogeneity

Author, Year,
Intervention Control Outcome (N intervention Pooled RR (95% CI) P-value
RefID I2 Statistic (%) P-value
group/ total N)
2
Hodson 2008[34] i.v. Cyc p.o. Cyc Relapse within 6 months 0.54 [ 0.34, 0.88 ] 0.01 0 0.82
(41/83)
Continuing FRNS or SDNS at 6 1
i.v. Cyc p.o. Cyc 0.40 [ 0.18, 0.89 ] nd NA NA
months (26/47)
2
i.v. Cyc p.o. Cyc Relapse by end of study 0.99 [ 0.76, 1.29 ] 0.9 0 0.86
(41/83)
2
i.v. Cyc p.o. Cyc AE: All infections 0.14 [ 0.03, 0.72 ] nd NA NA
(41/83)
2
i.v. Cyc p.o. Cyc AE: Leukopenia 0.37 [ 0.09, 1.51 ] nd NA NA
(41/83)
2
i.v. Cyc p.o. Cyc AE: Hair Loss 0.19 [ 0.04, 1.03 ] nd NA NA
(41/83)
2
i.v. Cyc p.o. Cyc AE: Nausea & Vomiting 4.07 [ 0.21, 80.51 ] nd NA NA
(41/83)
Supplementary table 3. Summary tables of studies examining i.v. vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome (categorical outcomes)
Duration Description No. Analyzed (Enrolled) Results
Study, Year Outcome Events (%)
Outcome GFR/SCr Proteinuria P value Quality
Country measurement Intervention Control Intervention Control Intervention RR/OR/HR
(Treatment) [Control]
Relapse
Bircan
Patients without a 2y i.v. Cyc and p.o. Cyc and 10 9 5 (50%) RR 1.50
2003[8] nd nd <0.05 Fair
relapse (12 wk) prednisone prednisone (10) (9) [3 (33%)] (0.49-4.56)1
Turkey
Adverse events
0%
AE-oral thrush -- nd Fair
Bircan [22%]
2y i.v. Cyc and p.o. Cyc and 10 9
AE-upper 2003[8] nd nd
(12 wk) prednisone prednisone (10) (9) 0%
respiratory Turkey -- nd Fair
[22%]
infections
1 Calculated by ERT
Supplementary table 4. Summary table of RCT examining MMF vs. CsA in frequently relapsing nephrotic syndrome in children (categorical outcomes)
Study, Year Outcome No. Events (%)
Country measurement Intervention Control Intervention Control Intervention RR
Relapse
Dorresteijn
2008[21] 12 mo 12 12 GFR 125 5 (42%) 5.0
No relapses MMF CsA nd NS Fair
Netherlands (12 mo) (15) (16) ml/min/1.73 m2 [1 (8%)] (0.68, 36.66)
and Belgium
Adverse events
0 (0%)
AE-diarrhea -- -- Poor
[0 (0%)]
1 (8%) 0.25
AE-HTN NS Poor
Dorresteijn [4 (33%)] (0.03-1.92)
2008[21] 12 mo 12 12 GFR 125 0 (0%)
AE-Leukopenia2 MMF CsA nd -- -- Poor
Netherlands (12 mo) (15) (16) ml/min/1.73 m2 [0 (0%)]
and Belgium 0 (0%)
AE-hypertrichosis -- nd Poor
[3 (38%)]
AE- Gingival 0 (0%)
-- nd Poor
Hyperplasia [6 (60%)]
2 Leucocytes <4.0×1000 cells/mm3 in >1 measurement.

Supplementary table 5. Summary table of RCT examining MMF vs. cyclosporine in frequently relapsing nephrotic syndrome in children (continuous outcomes)
Study, Year Outcome Baseline ∆ P
Outcome GFR/SCr Proteinuria Quality
Country measurement Intervention Control Intervention Control Units Intervention Intervention value
(Treatment) (Control) (Control)
Relapse
Dorresteijn
2008[21] 12 mo 12 12 GFR 125 per patient- 0.83 NS
Relapse Rate MMF CsA nd -- Fair
Netherlands (12 mo) (15) (16) ml/min/1.73 m2 year (0.08) (0.08)
and Belgium
Kidney function
3 mo -2
(12 mo) (-11)
Dorresteijn 6 mo +1
2008[21] (12 mo) 12 12 GFR 125 ml/min/ 1.73 125 (-16)
∆GFR MMF CsA nd 0.03 Poor
Netherlands 9 mo (15) (16) ml/min/1.73 m2 m2 (123) 0
and Belgium (12 mo) (-9)
12 mo +6
(12 mo) (-14)
Supplementary table 6. Summary table of RCT examining low vs. fixed dose CsA treatment in children with frequently relapsing nephrotic syndrome (categorical outcomes)
Outcome GFR/SCr Proteinuria RR/OR/HR P value Quality
Country measurement Intervention2 Control2 Intervention Control Intervention
(95% CI)
Sustained remission
24 20 50% HR 0.37
In all patients 0.01 Good
(29) (27) [15%] (0.18–0.79)
Ishikura
Among patients 24 mo Low dose Fixed dose
2008[41] nd nd
without relapse (24 mo) CsA CsA 23 19 57% HR 0.43 NS
Japan Good
during first 6 (29) (27) [25%] (0.17–1.09) (0.08)
mo
Biopsy results
Mild arteriolar 4 (20%) RR 3.0
NS Poor
hyalinosis Ishikura [1 (7%)] (0.37-24)
24 mo Low dose Fixed dose 20 15
Striped fibrosis 2008[41] nd nd
(24 mo) CsA CsA (29) (27) 0%
or tubular Japan -- -- Poor
[0%]
atrophy
Adverse events3
25% RR 2.5 NS
AE-HTN Fair
[10%] (0.57-11) (0.20)
Ishikura
AE- 24 mo Low dose Fixed dose 24 20 17% RR 1.11
2008[41] nd nd NS Poor
hypertrichosis (24 mo) CsA CsA (29) (27) [15%] (0.28-4.4)
Japan
AE- gingival 8% RR 0.42
NS Poor
hyperplasia [20%] (0.08-2.0)
3Also no difference in headache, gastric pain, elevation of ALP, hyperuricemia, transient elevation of SCr.
2 All
patients received 6 months of cyclosporine targeting a trough level of 80-100 ng/ml. In the subsequent 18 months, patients randomized to low dose had their dose adjusted to maintain trough cyclosporine levels 60-80
ng/mL while those randomized to fixed dose received 2.5mg/kg/day
Supplementary table 7. Summary table of RCT examining low vs. fixed dose CsA treatment in children with frequently relapsing nephrotic syndrome (continuous outcomes)
Relapse Rates
Ishikura
Per patient 24 mo Low dose Fixed dose 24 20 3.1 -2.76
2008[41] nd nd -- nd Good
year (24 mo) CsA CsA (29) (27) (3.6) (-2.67)
Japan
Rate of progression to FRNS
Ishikura
Per patient 24 mo Low dose Fixed dose 24 20 0.14
2008[41] nd nd -- -- nd Good
year (24 mo) CsA CsA (29) (27) (0.42)
Japan
Height
Mean s.d. Ishikura
24 mo Low dose Fixed dose 23 17 -0.70 +0.60
score for 2008[41] nd nd -- nd Fair
(24 mo) CsA CsA (29) (27) (-0.62) (+0.58)
height Japan
Supplementary table 8. Evidence profile of RCTs examining CsA vs. placebo in steroid-resistant nephrotic syndrome in children
(treatment) across studies generalizability/ considerations Quality of evidence for Qualitative and quantitative Importance
study design per outcome outcome description of effect of outcome
applicability
No important Benefit of cyclosporine for complete
3 RCTs4 49 No limitations5 Direct Sparse
Remission consistencies Moderate remission as compared with placebo or High
(High) (26) (0) (0) (-1)
(0) no treatment
Relapse 0 RCTs -- -- -- -- -- -- -- High
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Kidney
(categorical)
ΔProteinuria
0 RCTs -- -- -- -- -- -- -- Moderate
(continuous)
∆Kidney
(continuous)
No nephrotoxicity or hirsuitism reported
3 RCTs6 49 although these are well known side
Adverse events Moderate
(High) (26) effects of cyclosporine. These studies
involved small numbers.
Benefit of cyclosporine in inducing complete remission Moderate
4 One of the RCTs has only been published in abstract form (Ponticelli 1993a) but was included in the Cochrane Systematic Review (Hodson 2006[33])
5 The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the independent review of trials by the ERT.
6 One of the RCTs has only been published in abstract form but was included in the Cochrane Systematic Review (Ponticelli 1993a)
Supplementary table 9. Meta-analyses and systematic reviews on steroid-resistant nephrotic syndrome in children
Hodson 2006[33] Inclusion criteria 1) Cyclosporine vs. 1) Complete remission during and 1) Cyclosporine when Is eligibility criteria Yes
Children aged three months to 18 years with placebo/no treatment (Garin following therapy (i.e. oedema free compared with placebo similar to the
Database: corticosteroid-resistant nephrotic syndrome 1988, Lieberman 1996, and urine protein was <1+ on or no treatment guideline
Cochrane (central) (i.e. persistent proteinuria >3+ on dipstick, Ponticelli 1993a) dipstick, urine protein-creatinine significantly increased
Search Dates: This is urinary protein-creatinine ratio >0.2 g/mmol or <0.02 g/mmol or <4mg/m²/h for three the Are there any No
an update to original >40 mg/m²/h after four weeks or more of daily or more consecutive days). number who achieved limitations to
search performed corticosteroid agent). Where a renal biopsy Secondary outcomes complete remission systematic review
Cochrane (2002, was performed, only children with biopsy • Partial remission with reduction in methodology
issue 2) diagnoses of MCNS, MPGN or FSGS were proteinuria
Medline 1966 – April included. (i.e. proteinuria <2+ , urine protein-
2002 creatinine ratio <0.2 g/mmol or <40
Embase 1980-April Exclusion criteria mg/m²/h) and an increase in serum
2002 steroid-responsive nephrotic syndrome, albumin levels.
Updated with congenital nephrotic syndrome or other renal • Changes in renal function (serum
Cochrane Central or systemic forms of nephrotic syndrome creatinine, creatinine
Registry up to Jun defined on renal biopsy, clinical features or clearance)
2005 serology (e.g. post-infectious • Number reaching end stage renal
N Studies: glomerulonephritis, Henoch-Schönlein failure
11 nephritis, systemic lupus erythematosus, • Adverse effects of therapy
N Subjects: membranous glomerulopathy or Is limitation to Yes
312 mesangiocapillary evidence clearly
glomerulonephritis) addressed by the
authors
Trials were generally small and of variable quality. Large confidence intervals – uncertainty in summary estimates.
Description of limitations of evidence by authors
Most trials did not provide data on the duration of remission, on renal dysfunction, the number progressing to end stage renal failure or mortality.

Pooled RR1 Grading of
Author, Year, RefID Intervention Control Outcome (N intervention P-value
(95% CI) I2 Statistic P-value Reference
group/ total N)
Garin 1988,
Poor
Failure to achieve
Placebo/ no 3 Lieberman
Hodson 2006[33] Cyclosporine complete remission 0.66 [ 0.48, 0.91 ] 0.012 0 0.82
treatment 26/49 1996 Fair
(all pathologies)
Ponticelli
1993a Fair
Failure to achieve
Placebo/ no 2
Cyclosporine complete remission 0.70 [ 0.50, 0.99 ] 0.045 0 0.76
treatment 16/33
(FSGS only)
Failure to achieve
Placebo/ no 3
Cyclosporine complete or partial 0.18 [ 0.01, 3.32 ] 0.25 77.0 0.04
treatment 26/49
remission (all pathologies)
Failure to achieve
Placebo/ no 1
Cyclosporine complete or partial 0.05 [ 0.00, 0.73 ] 0.029 NA NA
treatment 12/24
remission (FSGS)
Supplementary table 10. Evidence profile of studies examining CsA vs. Cyc treatment in children with steroid-resistant nephrotic syndrome
applicability
1 Non-RCT 14 Serious limitations Direct Sparse
ESRD NA Very low Insufficient evidence Critical
(Moderate) (4) (-2) (0) (-1)
1 RCT 32 Some limitations Sparse
No important
(High) (15) (-1) Direct (-1) Possible benefit for CsA for remission at
Remission inconsistencies Very low High
1 Non-RCT 14 Serious limitations (0) Imprecision 12 weeks.
(0)
(Moderate) (4) (-2) (-1)
Sparse
1 Non-RCT 14 Serious limitations Direct (-1)
Relapse NA Very low Insufficient evidence High
(Moderate) (4) (-2) (0) Imprecision
(-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Kidney
(categorical)
ΔProteinuria
0 RCTs -- -- -- -- -- -- -- Moderate
(continuous)
ΔKidney
(continuous)
Adverse events 0 RCTs -- -- Moderate

Insufficient evidence Very low
Supplementary table 11. Summary table of studies examining CsA vs. Cyc treatment in children with steroid-resistant nephrotic syndrome (categorical outcomes)
RRT
Hafeez
12 mo 4 10 0 (0%)
Renal failure 2005[31] CsA7 Cyc8 nd >40 mg/m2/hr -- nd Poor
(12 wk) (4) (10) [0 (0%)]
India
Remission
2 (13%) RR 2.3 NS
Complete Fair
[1 (6%)] (0.23-23)11 (0.58)
12 wk 15 17 7 (47%)
Partial nd12 0.04 Fair
(48 wk) (15) (17) [2 (12%)]
Complete or 9 (60%)
nd13 0.03 Fair
Partial [3 (18%)]
2 (15%) RR 0.92
Complete NS Poor
Plank [1 (17%]) (0.10-8.3) 14
2008[62] 24 wk 13 6 GFR 191 9 (69%) RR 1.38
Partial CsA9 i.v. Cyc101 217 mg/m2/h NS Poor
Germany, (48 wk) (15) (17) ml/min/1.73 m2 [3 (50%)] (0.58-3.3) 15
Complete or Austria 11 (85%) RR 1.27
NS Poor
Partial [4 (67%)] (0.69-2.3) 16
2 (20%) RR 0.3
Complete NS Poor
[2 (67%)] (0.07-1.31) 17
48 wk 10 3 8 (80%) RR 1.20
Partial NS Poor
(48 wk) (15) (17) [1 (33%)] (0.51-2.83) 18
Complete or 10 (100%) RR 1.00
-- Poor
partial [3 (100%)] (1.00-1.00) 19
3 (75%) RR 1.50
Complete Hafeez NS Poor
12 mo 4 10 [5 (50%)] (0.65-3.47) 20
2005[31] CsA Cyc nd >40 mg/m2/hr
(12 wk) (4) (10) 1 (25%) RR 2.50
Partial India nd Poor
[1 (10%)] (0.20-31.00) 21
7 CsA 7-10 mg/kg/d in 2 divided doses X 12 mo

8 p.o. cyclophosphamide 2.5 mg/kg/d X 12 wk
9 Sandimmune targeting a trough level of 150 ng/mL X 12 wk and if proteinuria remained >40 mg/m2/h targeted a cyclosporine trough level of 350 ng/mL x 12 wk
10 IV Cyclophosphamide 500-1000 mg/m2 monthly X 12 wk and if proteinuria >40 mg/m2/h treated with IV MP pulses repeated monthly x 12 wk
11 Calculated by ERT
12 Not calculated since confidence intervals of calculated relative risk is not significant however, reported p values from published article show significance. This probably due to an adjusted analysis that was not described.
13 Not calculated since confidence intervals of calculated relative risk is not significant however, reported p values from published article show significance. This probably due to an adjusted analysis that was not described.
Complete or 4 (100%) RR 2.00
nd Poor
partial [5 (50%)] (1.08-3.72) 22
Relapse
Hafeez
12 mo 4 10 1 (25%)
After treatment 2005[31] CsA Cyc nd >40 mg/m2/hr -- nd Poor
(12 wk) (4) (10) [0 (0%)]
India
Supplementary table 12. Evidence profile of RCTs examining ACE-I treatment for steroid-resistant nephrotic syndrome in children
applicability
Remission 0 RCTs -- -- -- -- -- -- -- High
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Kidney
(categorical)
No important
ΔProteinuria 2 RCTs 95 No limitations Direct Sparse Benefit of ACE-I; high dose greater than low
consistencies Moderate Moderate
(continuous) (High) (50) (0) (0) (-1) dose greater than placebo
(0)
∆Kidney
1 RCT 45 No limitations Direct Sparse
function N/A Moderate Insufficient evidence Moderate
(High) (25) (0) (0) (-1)
(continuous)
Adverse events 0 RCTs -- -- Moderate

Benefit of ACE-I Moderate
Supplementary table 13. Summary table of RCTs examining ACE-I treatment for steroid-resistant nephrotic syndrome in children (continuous outcomes)
Study, Year Outcome Baseline ∆
Country measurement Intervention Control Intervention Control Units Intervention Intervention
Proteinuria
4 wk -2.69
Good
24 h Yi 2006[88] (12 wk) Fosinopril + 25 20 SCr 0.56 3.94 (-1.92)
Prednisone 3.94 g/d g/d <0.05
Proteinuria China 12 wk prednisone (30) (27) mg/dl (4.44) -2.84
Good
(12 wk) (-2.39)
Median %
reduction in
2-10 wk 34.8
UACR nd Good
(8 wk) (-7.9 to 76.6)
(low to high
dose)
Median %
reduction in
12-20 wk 37.2
UACR nd Good
(8 wk) Enalapril Enalapril (11.3–59.8)
(low to high
Bagga 0.2 to 0.6 0.6 to 0.2
dose) 25 25 SCr 0.6
2004[5] mg/kg/d mg/kg/d UACR 3.9 % NA
Median % (25) (25) mg/dl
India [Low to high [High to low
reduction in
2-10 wk dose] dose] 62.9
UACR nd Good
(8 wk) (40.6–71.6)
(high to low
dose )
Median %
reduction in
12-20 wk 33.3
UACR nd Good
(8 wk) (-20 to 58.7)
(high to low
dose)
SCr/GFR/CrCl
Yi 2006[88] 12 wk Fosinopril + 25 20 SCr 0.56 ml/min/ 91.3 -2.51
CrCl Prednisone 3.94 g/d NS Good
China (12 wk) prednisone (30) (27) mg/dl 1.73 m2 (96.1) (-2.03)
Supplementary table 14. Evidence profile of studies of p.o. Cyc plus steroid vs. steroid in steroid-resistant nephrotic syndrome and/or FSGS in children
applicability
Sparse
1 RCT 60 Some limitations23 Direct (-1)
Mortality N/A Very Low No difference Critical
(High) (35) (-1) (0) Imprecision
(-1)
Serious No important
2 Non-RCTs 70 Direct Sparse
ESRD limitations24 inconsistencies Very Low No difference Critical
(Moderate) (40) (0) (-1)
(-2) (0)
2 RCTs 93 Some limitations25
(High) (53) (-1) No important
Direct None
Remission Serious inconsistencies Moderate No difference High
2 Non-RCTs 70 (0) (0)
limitations26 (0)
(Moderate) (40)
(-2)
Relapse 0 RCTs -- -- -- -- -- -- --
Proteinuria
0 RCTs -- -- -- -- -- -- --
(categorical)
1 RCT 60 Some limitations28
Progression of (High) (35) (-1) Some
Direct None
kidney Serious inconsistencies Low No difference Moderate
1 Non-RCT 54 (0) (0)
disease27 limitations29 (-1)
(Moderate) (30)
(-2)
ΔProteinuria
0 RCTs -- -- -- -- -- -- --
(continuous)
Kidney
function 0 RCTs -- -- -- -- -- -- --
(continuous)
93 Some limitations30
2 RCTs
(53) (-1) Alopecia, hemorrhagic cystitis, leucopenia,
70 Some limitations31 infections more likely with cyclophosphamide
2 Non-RCTs
(40) (-1)
23 The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the ERT’s independent review of the trials.
27 Defined in the RCT as increase in serum creatinine from baseline of ≥30% or >0.4 mg/dl or onset of renal failure as evidenced by serum creatinine >4.0 mg/dl, maintenance on chronic dialysis, or renal transplantation; not
defined in the NRCS

applicability

No difference; more adverse effects with cyclophosphamide Moderate
Supplementary table 15. Summary table of studies examining p.o. Cyc plus steroid vs. steroid in children with SRNS or FSGS. Based on data reported in Hodson 2006. (categorical outcomes)
Study,
Outcome Events (%) P
Outcome Year GFR/SCr Proteinuria Quality
measurement Intervention Control Intervention Control Intervention RR value
Country
Mortality
Tarshish
12 mo p.o. Cyc and p.o. 35 25 GFR 118 3 (9%) RR 0.98 NS
12 mo 1996[82] Prednisone 161 mg/m2/h Fair
(12 mo) prednisone (35) (25) ml/min [2 (10%)] (0.18-5.40) 32 (>0.1)
US
ESRD
Methyl-
prednisolone
Hafeez
12 mo p.o. Cyc x 12 wk 33 >12 mo + 10 6 0 (0%)
12 mo 2005[31] nd >40 mg/m2/hr -- nd Poor
(12 mo) p.o. steroids x 12 mo p.o. (10) (6) [1 (17%)34]
India
prednisone
>12 mo
Martinelli
86 mo p.o. Cyc and p.o. p.o. 30 24 3 (10%) RR0.40 NS
86 mo 2004[55] nd nd Poor
(4 mo) prednisone prednisone (30) (24) [6 (25%)] (0.11-1.44) 35 (>0.1)
Brazil
Remission
Tarshish
12 mo p.o. Cyc and p.o. 32 21 GFR 118 8 (25%) RR0.88 NS
Complete 1996[82] Prednisone 161 mg/m2/hr Fair
US
ISKDC
1974[1] 24 mo p.o. Cyc and p.o. 18 15 10 (56%) RR 1.39 NS
Complete Prednisone nd >40 mg/m2/h Fair
EU, North (90 days) prednisone (18) (15) [6 (40%)] (0.66-2.93) 37 (>0.05)
America
Complete Methyl- 5 (50%) RR 1.50 NS
remission prednisolone [2 (33%)] (0.41-5.45)39 (0.54)
Hafeez
12 mo p.o. Cyc x 12 wk 38 >12 mo + 10 6
2005[31] nd >40 mg/m2/hr Poor
Partial (12 mo) p.o. steroids x 12 mo p.o. (10) (6) 1 (10%) RR 0.60 NS
India
remission prednisone [1 (17%)] (0.05-7.92)40 (0.698)
>12 mo
Complete 8 (27%) RR 2.13
Martinelli NS Poor
remission 86 mo p.o. Cyc and p.o. p.o. 30 24 [3 (13%]41) (0.63-7.18) 42
2004[55] nd nd
Partial (4 mo) prednisone prednisone (30) (24) 6 (20%) RR 2.40
Brazil NS Poor
remission [2 (8%)43] (0.53-10.84) 44
33 Some converted partially or fully to oral steroids. Cyclophosphamide added if “response was not satisfactory”.
34 Showed no response to therapy. Had FSGS. “Developed renal failure over a period of 1 year.”
38 Some converted partially or fully to oral steroids. Cyclophosphamide added if “response was not satisfactory”.
41 The data reported in the article appear to be for combined (Prednisone alone) + (Cyc + Pred). These numbers are derived from subtracting (Cyc + Pred) from “Prednisone”.
Study,
Outcome Events (%) P
Outcome Year GFR/SCr Proteinuria Quality
measurement Intervention Control Intervention Control Intervention RR value
Country
Progression of Renal Disease16
Tarshish
12 mo p.o. Cyc and p.o. 35 25 GFR 118 20 (57%) RR 1.59 NS
12 mo 1996[82] Prednisone 161 mg/m2/hr Fair
US
Martinelli
86 mo p.o. Cyc and p.o. p.o. 30 24 5 (17%) RR 0.50
86 mo 2004[55] nd nd NS Poor
(4 mo) prednisone prednisone (30) (24) [8 (33%]) (0.19-1.33) 46
Brazil
43 The data reported in the article appear to be for combined (Prednisone alone) + (Cyc + Pred). These numbers are derived from subtracting (Cyc + Pred) from “Prednisone”.
16 Defined as increase in serum creatinine from baseline of ≥30% or >0.4 mg/dl or onset of renal failure as evidenced by serum creatinine >4.0 mg/dl, maintenance on chronic dialysis, or renal transplantation.
Supplementary table 16. Summary table of studies examining p.o. Cyc plus steroid vs. steroid in children with SRNS or FSGS (continuous outcomes)
Time to Remission
ISKDC
1974[1] 2y 18 15 38.4
2 years p.o. Cyc Prednisone nd nd d NA <0.05 Fair
EU, North (90 d) (18) (15) (95.5)
America
Supplementary table 17. Summary table RCT examining i.v. vs. p.o. Cyc treatment in children with steroid-resistant nephrotic syndrome (continuous outcomes)
Proteinuria
Mantan
Median 6mo 26 23 GFR 101 UPCR 5.9 5.9 -4.3 NS
2008[54] i.v. Cyc p.o. Cyc mg/mg Poor
UPCR (18 mo) (27) (25) ml/min/1.73 m2 mg/mg (8.9) (-4.4) (0.2)
India
SCr/GFR/CrCl
Mantan
6 mo 26 23 GFR 101 UPCR 5.9 ml/min/1. 101 +2 NS
Median GFR 2008[54] i.v. Cyc p.o. Cyc Poor
(18 mo) (27) (25) ml/min/1.73 m2 mg/mg 73 m2 (107) (0) (0.2)
India
Serum Albumin
Median Mantan
6 mo 26 23 GFR 101 UPCR 5.9 2.2 +1.8 NS
serum 2008[54] i.v. Cyc p.o. Cyc g/dl Poor
(18 mo) (27) (25) ml/min/1.73 m2 mg/mg (1.7) (+1.9) (0.7)
albumin India
Supplementary table 18. Summary table of RCT examining TAC vs. CsA treatment in children with steroid-resistant nephrotic syndrome (categorical outcomes)
Remission
Complete 43% 0.85 NS
Fair
remission [50%] (0.44-1.65) (0.6)
6 mo 43% 1.42 NS
Partial remission Fair
(12 mo) [30%] (0.62-3.2) (0.4)
Complete or partial 86% 1.07 NS
Fair
remission [80%] (0.81-1.41) (0.6)
Complete Choudhry GFR 105 48% 0.86 NS
21 20 Fair
remission 2009[14] Tacrolimus CsA ml/min UPCR 9.8 g/g [55%] (0.47-1.57) (0.6)
(21) (20)
India SCr 0.56 mg/dl 38% 1.90 NS
Partial remission Fair
[20%] (0.67-5.34) (0.2)
12 mo
Complete or partial 86% 1.14 NS
(12 mo) Fair
remission [75%] (0.84-1.55) (0.4)
Relapse after
11% 0.22
achieving 0.03 Fair
[50%] (0.06-0.90)
remission
Nephrotoxicity
5% 0.48 NS
Persistent Choudhry GFR 105 Fair
12 mo 21 20 [10%] (0.05-4.9) (0.5)
2009[14] Tacrolimus CsA ml/min UPCR 9.8 g/g
(12 mo) (21) (20) 33% 0.67 NS
Reversible India SCr 0.56 mg/dl Fair
[50%] (0.32-1.41) (0.3)
Adverse Events
AE-worsening of 10% 0.89 NS
Fair
HTN [0%] (0.14-5.6) (0.9)
0%
AE-hypertrichosis -- <0.001 Fair
[95%]
AE-gingival 5% 0.07
<0.001 Fair
hyperplasia [60%] (0.01-0.51)
Choudhry GFR 105
12 mo 18 16 29% 5.3
AE-diarrhea 2009[14] Tacrolimus CsA ml/min UPCR 9.8 g/g NS Fair
(12 mo) (21) (20) [5%] (0.72-40)
India SCr 0.56 mg/dl
AE-sepsis/ 5% 0.89 NS
Fair
pneumonia [5%] (0.06-13) (0.9)
0% NS
AE-headache -- Fair
[5%] (0.3)
0% NS
AE-paresthesia -- Fair
[5%] (0.3)
Supplementary table 19. Summary table of RCT examining TAC vs. CsA treatment in children with steroid-resistant nephrotic syndrome (continuous outcomes)
Proteinuria
GFR 105
Choudhry
12 mo 19 16 ml/min UPCR 9.8 9.8 -9.3 NS
UPCR 2009[14] Tacrolimus CsA g/g Fair
(12 mo) (21) (20) SCr 0.56 g/g (8.0) (-7.4) (0.8)
India
mg/dl
Scr/GFR/CrCl
0.56 +0.12 NS
12 mo GFR 105 g/dl Fair
Choudhry (0.51) (+0.12) (0.3)
12 mo 19 16 ml/min UPCR 9.8
2009[14] Tacrolimus CsA -14.4 (-12%)
Schwartz (12 mo) (21) (20) SCr 0.56 g/g ml/min/1. 104.6 NS
India [-16.2 (-11%) Fair
GFR mg/dl 73 m2 (115.5) (0.1)
]
Albumin
GFR 105
Choudhry
12 mo 19 16 ml/min UPCR 9.8 1.8 +2.6 NS
12 mo 2009 [14] Tacrolimus CsA g/dl Fair
(12 mo) (21) (20) SCr 0.56 g/g (1.6) (+2.3) (0.08)
India
mg/dl
Supplementary table 20. Summary table of RCT examining CsA vs. steroid treatment after first relapse in adults with minimal change disease (categorical outcomes)
Remission
2 wk 20 (77%) RR 1.8247
0.02
(6 mo) [11 (42%)] (1.11-2.99)
4 wk 25 (96%) RR 1.2548
Eguchi nd
Complete (6 mo) CsA + 26 26 SCr 0.9 [20 (77%)] (1.00-1.56)
2010[23] Prednisolone 6.7 g/d Fair
remission 3 mo prednisolone (26) (26) mg/dl 24 (92%) RR 1.0049
Japan nd
(6 mo) [24 (92%)] (0.85-1.17)
6 mo 21 (81%) RR 1.0550
nd
(6 mo) [20 (77%)] (0.79-1.39)
Relapse
2 wk 0 (0%)
-- nd
(6 mo) [0 (0%)]
4 wk 0 (0%)
Eguchi -- nd
(6 mo) CsA + 26 26 SCr 0.9 [1 (4%)]
Relapse 2010[23] Prednisolone 6.7 g/d Fair
3 mo prednisolone (26) (26) mg/dl 2 (8%) RR 1.0051
Japan nd
(6 mo) [2 (8%)] (0.15-6.57)
6 mo 5 (19%) RR 0.8352
nd
(6 mo) [6 (23%)] (0.29-2.39)
Supplementary table 21. Summary table of RCT examining CsA vs. steroid treatment after first relapse in adults with minimal change disease (continuous outcomes)
Proteinuria
2 wk -5.9
<0.05
(6 mo) (-5.1)
4 wk -6.4 NS
Eguchi
(6 mo) CsA + 26 26 SCr 0.9 6.4 (-6.5) (0.1)
∆Proteinuria 2010[23] Prednisolone 6.7 g/d g/d Fair
3 mo prednisolone (26) (26) mg/dl (6.9) -6.2 NS
Japan
(6 mo) (-6.7) (0.9)
6 mo -5.8 NS
(6 mo) (-6.4) (0.7)
Supplementary table 22. Evidence profile of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy
applicability
2 RCT 174 Some limitations
No important
(High) (89) (-1) Direct Imprecision
Mortality consistencies Low Insufficient evidence Critical
1 SR 196 No limitations (0) (-1)
(0)
(4 trials) (103) (0)
No important
(High) (89) (-1) Direct Imprecision
ESRD consistencies Low Benefit for alkylating agents plus steroids Critical
1 SR 196 No limitations (0) (-1)
(0)
(4 trials) (103) (0)
No important
(High) (89) (-1) Direct None
Remission inconsistencies Moderate Benefit for alkylating agents plus steroids High
1 SR 176 No limitations (0) (0)
(0)
(4 trials) (94) (0)
No important
2 RCT 174 Some limitations Direct None
Relapse inconsistencies Moderate Benefit for alkylating agents plus steroids High
(High) (89) (-1) (0) (0)
(0)
Proteinuria 1 RCT 81 Some limitations Direct Sparse
NA Low Harm for alkylating agents plus steroids High
(categorical) (High) (42) (-1) (0) (-1)
Kidney
1 RCT 81 Some limitations Direct Sparse Possible benefit for alkylating agents plus
function NA Low High
(High) (42) (-1) (0) (-1) steroids
(categorical)
ΔProteinuria 1 RCTs 93 Some limitations Direct Sparse Possible benefit for alkylating agents plus
NA Low Moderate
(continuous) (High) (47) (-1) (0) (-1) steroids
∆Kidney
1 RCTs 93 Some limitations Direct Sparse
function NA Low No difference Moderate
(High) (47) (-1) (0) (-1)
(continuous)
174
2 RCTs Higher incidence of patient discontinuation
(89)
Adverse events due to adverse events for alkylating agents Moderate
1 SR 196
plus steroids.
(4 trials) (103)
Benefit of alkylating agents plus steroids Moderate
Supplementary table 23. Existing systematic reviews on alkylating agents vs. control for idiopathic membranous nephropathy in adults with nephrotic syndrome
Study, Year, Study Eligibility Criteria Interventions (Studies) Outcomes Conclusions Comments Yes/No
RefID
Schieppati Randomized controlled trials and quasi- The following classes of Definite endpoints This review failed to show any Is eligibility criteria Yes
2004[71] RCTs comparing any immunosuppressive treatments • death long-term effect of similar to the guideline
Date Base: immunosuppressive interventions for were considered: • ESRF which requires the initiation of immunosuppressive treatment
Cochrane Renal, the treatment of IMN in adults. • glucocorticoids (alone) dialysis or kidney transplantation. on patient and/or renal
Cochrane Inclusion criteria • alkylating agents (alone or in Surrogate endpoints survival. There was an
CENTRAL, • The selected patients were adult association with glucocorticoids) • “Partial remission” increased number of
MEDLINE, Pre- subjects with IMN, aged 16 years or • calcineurin inhibitors (alone or in • “Complete remission” discontinuations due to
MEDLINE, older, with nephrotic syndrome. association with glucocorticoids) • “Final proteinuria”, measured as g/24 h adverse events in
EMBASE • The diagnosis of IMN was • anti-proliferative agents (alone) • “Final serum creatinine”, measured as immunosuppressive treatment
Search Dates: histologically proven. Control groups were given placebo μmol/L groups. Within the class of Are there any No
1966-2003 • The assessment of “nephrotic or no treatment in addition to • “Final GFR”, measured as ml/min/1.73 alkylating agents there is weak limitations to systematic
syndrome” relies on that chosen by the supportive therapy. m2. evidence supporting the review methodology
authors in the single studies. It must be The following outcome measures for efficacy of cyclophosphamide
N Studies: 18 said that this definition can be safety were evaluated: as compared to chlorambucil.
heterogeneous. In trials that included a Side effects On the other hand,
minority of non-nephrotic subjects, • Proportion of patients experiencing any cyclophosphamide had fewer
N Subjects: 1025 when possible, analyses will be side effect leading to patient withdrawal. side effects leading to patient Is limitation to evidence No
restricted to nephrotic patients only. In Side effects might include, but are not withdrawal than chlorambucil. clearly addressed by
absence of an explicit definition of limited to, leukopaenia, cushingoid the authors
“nephrotic syndrome”, the cut-off point features, gastric disorders.
of urinary protein excretion above 3.5
g/24 h was used.

Author, Year, RefID Intervention Control Outcome (N intervention Pooled RR1(95% CI) P-value
I2 Statistic P-value
group/ total N)
4
Schieppati 2004[71] Alkylating agents Placebo Death 0.94 (0.14-6.22) 1 0.0% 0.33
(103/196)
4
Study Years : 1966-2003 Alkylating agents Placebo ESRD 0.44 (0.11-1.80) 0.30 0.0% 0.44
(103/196)
4
Alkylating agents Placebo ESRD or Death 0.56 (0.18-1.70) 0.30 0.0% 0.40
(103/96)
4
Alkylating agents Placebo Final proteinuria -2.36 (-4.27, -0.46) 0.02 35.8% 0.21
(103/196)
4
Alkylating agents Placebo Partial remission 1.22 0.60 50.1% 0.11
(94/176)
4
Alkylating agents Placebo Complete remission 2.37 (1.32-4.25) 0.004 0.0% 0.37
(94/176)
Complete or partial 4
Alkylating agents Placebo 1.55 (0.72-3.34) 0.30 79.9% 0.002
remission (94/176)
2 -38.37 (-117.67,
Alkylating agents Placebo Final SCr 0.60 87.4% 0.005
(55/107) 100.93)
Author, Year, RefID Intervention Control Outcome (N intervention Pooled RR1(95% CI) P-value
group/ total N)
1
Alkylating agents Placebo Final GFR 1.00 (-18.86, 20.86) 0.90 N/A N/A
(11/22)
4
Alkylating agents Placebo D/C due to AEs 5.97 (1.08-32.86) 0.04 0.0% 0.90
(103/196)
Supplementary table 24. Summary table of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy (categorical outcomes)
Mortality
Supportive
therapy with
SCr
Jha dietary sodium
10 y Alternate-month 47 46 1.21 mg/dl 1 (2%) RR 0.33
Death 2007[42] restriction, 6.11 g/d nd Good
(6 mo) steroid and Cyc (51) (53) GFR [3 (7%)] (0.04-3.02) aaa
India diuretics and
89 ml/min
anti-HTN
agents
Symptomatic
therapy with
Ponticelli dietary sodium
10 y Methylprednisolone 42 39 SCr 93.8 UPE 6.18 1 (2%) RR 0.31
Death 1995[63] restriction, nd Fair
(6 mo) and chlorambucil (42) (39) μmol/L g/d [3 (8%)] (0.03-2.85) bbb
Italy diuretics and
anti-HTN
agents
RRT
Supportive
therapy with
SCr
Jha dietary sodium
10y dialysis-free 10 y Alternate-month 47 46 1.21 mg/dl 89%
2007[42] restriction, 6.11 g/d -- 0.016 Good
survival (6 mo) steroid and Cyc (51) (53) GFR [65%]
India diuretics and
89 ml/min
anti-HTN
agents
Symptomatic 2 (5%) RR 0.21
RRT nd Fair
therapy with [9 (23%)] (0.05-0.90) ccc
Cumulative Ponticelli dietary sodium
10 y Methylprednisolone 42 39 SCr 93.8 UPE 6.18
probability of 1995[63] restriction,
(6 mo) and chlorambucil (42) (39) μmol/L g/d 0.92 (0.83-1.00)
being alive with Italy diuretics and -- 0.0038 Fair
[0.60 (0.42-0.78)]
functioning anti-HTN
kidney at 10 y agents
Remission
Complete Supportive 15 (32%) RR 2.94
<0.0001 Good
remission therapy with [5 (11%)] (1.16-7.42) ddd
SCr
Jha Alternate-month dietary sodium
10 y 47 46 1.21 mg/dl
2007[42] steroid and restriction, 6.11 g/d
Partial (6 mo) (51) (53) GFR 19 (40%) RR 1.69
India cyclophosphamide diuretics and <0.0001 Good
remission 89 ml/min [11 (24%)] (0.91-3.15) eee
anti-HTN
agents
aaa
Calculated by ERT
bbb
Calculated by ERT
ccc
Calculated by ERT
ddd
Calculated by ERT
eee
Calculated by ERT
Complete or Symptomatic
35 (83%) RR 2.17
partial therapy with nd Fair
[15 (38%)] (1.42-3.30) fff
remission Ponticelli dietary sodium
10 y Methylprednisolone 42 39 SCr 93.8 UPE 6.18
Complete 1995[63] restriction, 17 (40%) RR 7.89
(6 mo) and chlorambucil (42) (39) μmol/L g/d nd Fair
remission Italy diuretics and [2 (5%)] (1.95-31.97) ggg
Partial anti-HTN 9 (21%) RR 0.76
nd Fair
remission agents [11 (28%)] (0.35-1.63) hhh
Relapse
Supportive
therapy with
SCr
Jha dietary sodium
10 y Alternate-month 47 46 1.21 mg/dl 4 of 34 (12%) RR 0.24
Relapse 2007[42] restriction, 6.11 g/d nd Good
(6 mo) steroid and Cyc (51) (53) GFR [8 of 16 (9%)] (0.08-0.67) iii
India diuretics and
89 ml/min
anti-HTN
agents
Ponticelli
10 y Methylprednisolone Symptomatic 42 39 SCr 93.8 UPE 6.18 4 of 35 (10%)
Relapse 1995[63] -- nd Poor
(6 mo) and chlorambucil therapy (42) (39) μmol/L g/d [nd]
Italy
Proteinuria
Supportive
Patients with therapy of low
Ponticelli
nephrotic 10 y Methlyprednisolone salt diet, 42 39 SCr 93.8 UPE 6.18 9 (21%) RR 0.46
1995[63] nd Fair
syndrome at (6 mo) and chlorambucil diuretics and (42) (39) μmol/L g/d [6 (15%)] (0.15-1.42) jjj
Italy
last follow-up anti-HTN
medication
Kidney function
Supportive
therapy of low
Ponticelli
10 y Methlyprednisolone salt diet, 42 39 SCr 93.8 UPE 6.18 4 (10%) RR 1.39
↑SCr ≥50% 1995[63] nd Fair
(6 mo) and chlorambucil diuretics and (42) (39) μmol/L g/d [8 (21%)] (0.55-3.55) kkk
Italy
anti-HTN
medication
Adverse Events
Supportive SCr 7 (15%) RR 0.62 NS
AE-infections Jha Good
10 y Alternate-month therapy with 47 46 1.21 mg/dl [11 (24%)] (0.26-1.47) lll (0.35)
2007[42] 6.11 g/d
AE-thrombotic (6 mo) steroid and Cyc dietary sodium (51) (53) GFR 3 (6%) RR 0.73
India nd Good
episodes restriction, 89 ml/min [4 (8%)] (0.17-3.10) mmm
fff
Calculated by ERT
ggg Calculated by ERT
hhh Calculated by ERT
iii Calculated by ERT
jjj Calculated by ERT
kkk Calculated by ERT
lll Calculated by ERT
mmm
Calculated by ERT
diuretics and
0 (0%)
AE-malignancy anti-HTN -- nd Good
[0 (0%)]
agents
D/C due to AE
4 (10%)
in treatment -- nd Poor
[nd]
group
Supportive
AE-moderate 2 (5%)
therapy of low -- nd Poor
leukopenia Ponticelli [nd]
10 y Methlyprednisolone salt diet, 42 39 SCr 93.8 UPE 6.18
1995[63] 2 (5%)
AE-tremors (6 mo) and chlorambucil diuretics and (42) (39) μmol/L g/d -- nd Poor
Italy [nd]
anti-HTN
2 (5%)
AE-cramps medication -- nd Poor
[nd]
2 (2%)
AE-anxiety -- nd Poor
[nd]
Supplementary table 25. Summary table of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy (continuous outcomes)
No. Analyzed
Duration Description Results
(Enrolled)
Study, Year Outcome
Outcome GFR/SCr Proteinuria Baseline ∆ P value Quality
Country measurement
Intervention Control Intervention Control Units Intervention Intervention
(Treatment)
(Control) (Control)
Proteinuria
Supportive
therapy with
Jha dietary sodium
10 y Alternate-month 47 46 SCr 1.21 mg/dl 6.11 -5.21
Proteinuriannn 2007[42] restriction, 6.11 g/d g/d nd Fair
(6 mo) steroid and Cyc (51) (53) GFR 89 ml/min (5.91) (-3.31)
India diuretics and
anti-HTN
agents
SCr/GFR/CrCl
Supportive
therapy with
Jha dietary sodium
MDRD 10 y Alternate-month 47 46 SCr 1.21 mg/dl 89 -27
2007[42] restriction, 6.11 g/d ml/min nd Fair
eGFRooo (6 mo) steroid and Cyc (51) (53) GFR 89 ml/min (84) (-32)
India diuretics and
anti-HTN
agents
nnn Estimated from graph

ooo Estimated from graph
Supplementary table 26. Summary table of RCTs examining alkylating agents plus steroid treatment vs. ACTH in patients with membranous nephropathy (categorical outcomes)
Remission
15 (93%) RR 1.07
Remission NS Poor
[14 (87%)] (0.86-1.34)68
Ponticelli Methlyprednisolone
Complete 12 mo Tetracosactide 16 16 SCr 0.9 5 (31%) RR 0.50
2006[64] and chlorambucil or 5.5 g/d NS Poor
remission (6 mo) (ACTH) (16) (16) mg/dl [10 (63%)] (0.22-1.14) 69
Italy Cyc
Partial 10 (63%) RR 2.50
NS Poor
remission [4 (25%)] (0.99-6.33) 70
Adverse Events
1 (6%)
AE-leukopenia -- nd Poor
[0 (0%)]
0 (0%)
AE-dizziness -- nd Poor
[1 (6%)]
AE-glucose 2 (13%)
-- nd Poor
intolerance [2 (13%)]
Ponticelli Methlyprednisolone
12 mo Tetracosactide 16 16 SCr 0.9 0 (0%)
AE-diarrhea 2006[64] and chlorambucil or 5.5 g/d -- nd Poor
(6 mo) (ACTH) (16) (16) mg/dl [1 (6%)]
Italy Cyc
AE- 0 (0%)
-- nd Poor
onycodystrophy [1 (6%)]
0 (0%)
AE-folliculitis -- nd Poor
[1 (6%)]
AE-bronzing of 0 (0%)
-- nd Poor
skin [1 (6%)]
Supplementary table 27. Summary table of RCTs examining alkylating agents plus steroid treatment vs. ACTH in patients with membranous nephropathy (continuous outcomes)
No. Analyzed
(Enrolled)
Study, Year Outcome P
Outcome GFR/SCr Proteinuria Baseline ∆ Quality
Country measurement value
(Treatment)
(Control) (Control)
Proteinuria
Ponticelli
12 mo Tetracosactide 16 16 SCr 0.9 5.1 -3.0
Median 2006[64] Methlyprednisolone 5.5 g/d g/d NS Poor
(6 mo) (ACTH) (16) (16) mg/dl (6.0) (-5.7)
Italy
SCr/GFR/CrCl
Ponticelli
12 mo Tetracosactide 16 16 SCr 0.9 0.9 +0.1
Median SCr 2006[64] Methlyprednisolone 5.5 g/d mg/dl NS Poor
(6 mo) (ACTH) (16) (16) mg/dl (0.9) (+0.1)
Italy
Supplementary table 28. Evidence profile of RCTs examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy
(treatment) across studies generalizability/ considerations Quality of evidence for Qualitative and quantitative description Importance
study design per outcome outcome of effect of outcome
applicability
No important
1 SR 104 Some limitation Direct Imprecision
Mortality inconsistencies Low Insufficient evidence Critical
(3 RCTs) (63) (-1) (0) (-1)
(0)
No important
1 SR 104 Some limitation Direct Imprecision
ESRD inconsistencies Low Insufficient evidence Critical
(3 RCTs) (63) (-1) (0) (-1)
(0)
1 RCT 48 No limitations
Important
(High) (25) (0) Direct None Benefit for tacrolimus in one RCT. No
Remission inconsistencies Low High
1 SR 104 Some limitation (0) (0) difference for cyclosporine.
(-1)
(2 RCTs) (63) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Kidney
function N/A Moderate Benefit for tacrolimus High
(High) (25) (0) (0) (-1)
(categorical)
No important
ΔProteinuria 1 RCT 48 No limitations Direct Sparse
inconsistencies Moderate Benefit for tacrolimus. Moderate
(continuous) (High) (25) (0) (0) (-1)
(0)
∆Kidney
(continuous)
48
1 RCT
(25) Possible increase in glucose intolerance
1 SR 104 with tacrolimus.
(3 RCTs) (63)
Benefit for tacrolimus. No difference for cyclosporine. Low
Supplementary table 29. Existing systematic reviews on CsA/TAC treatment vs. placebo for idiopathic membranous nephropathy in adults with nephrotic syndrome
RefID
Schieppati Randomized controlled trials and The following classes of Definite endpoints This review failed to show Is eligibility criteria Yes
2004[71] quasi-RCTs comparing any immunosuppressive treatments • death any long-term effect of similar to the guideline
Date Base: immunosuppressive interventions for were considered: • ESRF which requires the initiation of immunosuppressive
Cochrane Renal, the treatment of IMN in adults. • glucocorticoids (alone) dialysis or kidney transplantation. treatment on patient and/or
Cochrane Inclusion criteria • alkylating agents (alone or in Surrogate endpoints renal survival. There was an
CENTRAL, • The selected patients were adult association with glucocorticoids) • “Partial remission” increased number of
MEDLINE, Pre- subjects with IMN, aged 16 years or • calcineurin inhibitors (alone or • “Complete remission” discontinuations due to
MEDLINE, older, with nephrotic syndrome. in association with • “Final proteinuria”, measured as g/24 adverse events in
EMBASE • The diagnosis of IMN was glucocorticoids) h immunosuppressive
Search Dates: histologically proven. • anti-proliferative agents (alone) • “Final serum creatinine”, measured treatment groups. Within the Are there any No
1966-2003 • The assessment of “nephrotic Control groups were given as μmol/L class of alkylating agents limitations to
syndrome” relies on that chosen by placebo or no treatment in • “Final GFR”, measured as there is weak evidence systematic review
the authors in the single studies. It addition to supportive therapy. ml/min/1.73 m2. supporting the efficacy of methodology
N Studies: 18 must be said that this definition can The following outcome measures for cyclophosphamide as
be heterogeneous. In trials that safety were evaluated: compared to chlorambucil.
included a minority of non-nephrotic Side effects On the other hand,
N Subjects: 1025 subjects, when possible, analyses will • Proportion of patients experiencing cyclophosphamide had fewer Is limitation to No
be restricted to nephrotic patients any side effect leading to patient side effects leading to patient evidence clearly
only. In absence of an explicit withdrawal. Side effects might include, withdrawal than chlorambucil. addressed by the
definition of “nephrotic syndrome”, the but are not limited to, leukopaenia, authors
cut-off point of urinary protein cushingoid features, gastric disorders.
excretion above 3.5 g/24 h was used.
N studies Pooled RR71 Test for heterogeneity

Author, Year, RefID Intervention Control Outcome P-value
(N intervention group/ total N) (95% CI) I2 Statistic P-value
3
Schieppati 2004[71] CsA Placebo Death 2.70 (0.13-58.24) 0.50 N/A N/A
(63/104)
CsA 3
Study Years : 1966-2003 Placebo ESRD 0.88 (0.21-3.66) 0.90 42% 0.18
(63/104)
Declining renal function at baseline: CsA
3
No: 1 study Placebo ESRD or Death 0.93 (0.32-2.71) 0.90 20% 0.29
(63/104)
Yes: 2 studies
Use of ACE-I during follow-up: CsA
2 WMD72
Yes, confounding effect: 2 studies Placebo Final proteinuria 1 87% 0.005
(19/38) -0.08 (-9.29, 9.13)
No confounding effect: 1 study
CsA 2
Mean follow-up: 12, 15, and 21 mo Placebo Partial remission 1.08 (0.76-1.55) 0.70 0% 0.60
(54/87)
CsA 2
Grading: 2 A and 1 B Placebo Complete remission 1.10 (0.41-2.96) 0.80 0% 0.46
(54/87)
CsA Complete or partial 2
Placebo 1.00 (0.72-1.40) 1 0% 0.39
remission (54/87)
71 RR is equal to Intervention/Control
72 Weighted Mean Difference is equal to Intervention minus Control
CsA WMD
1
Placebo Final SCr 11.50 (-50.19, 0.70 N/A N/A
(10/21)
73.19)
CsA WMD
2
Placebo Final GFR 8.31 (-10.83, 0.40 35% 0.21
(19/38)
27.45)
CsA 3
Placebo D/C due to AEs 5.45 (0.29-101.55) 0.30 N/A N/A
(63/104)
Supplementary table 30. Summary table of RCT examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy (categorical outcomes)
Remission (PR or CR)
2 mo 9 (36%) RR 4.14
2 mo <0.04 Good
(18 mo) [2 (9%)] (1.00-17.19) 73
6 mo SCr 0.98 14 (56%) RR 4.29
6 mo Praga <0.01 Good
(18 mo) 25 23 mg/dl [3 (13%)] (1.41-13.04) 74
2007[69] Tac Control 7.2 g/d
12 mo (25) (23) GFR 104 18 (72%) RR 3.31
12 mo Spain <0.001 Good
(18 mo) ml/min [5 (22%)] (1.47-7.47) 75
18 mo 19 (76%) RR 2.91
18 mo 0.003 Good
(18 mo) [6 (30%)] (1.41-6.00) 76
Probability of PR or CR
6 mo 58%
6 mo -- Good
(18 mo) SCr 0.98 [10%]
Praga
12 mo 25 23 mg/dl 82%
12 mo 2007[69] Tac Control 7.2 g/d -- <0.00001 Good
(18 mo) (25) (23) GFR 104 [24%]
Spain
18 mo ml/min 94%
18 mo -- Good
(18 mo) [35%]
Mean time to PR or CR
SCr 0.98
Praga
Mean time 18 mo 25 23 mg/dl 6.1
2007[69] Tac Control 7.2 g/d -- 0.003 Good
(mo) (18 mo) (25) (23) GFR 104 [11.3]
Spain
ml/min
Kidney function
SCr 0.98
Praga
18 mo 25 23 mg/dl 1 (4%) RR 0.15
↑SCr 50% 2007[69] Tac Control 7.2 g/d 0.03 Good
(18 mo) (25) (23) GFR 104 [6 (26%)] (0.02-1.18) 77
Spain
ml/min
Adverse Events
AE-glucose 4 (16%) RR 1.84
nd Good
intolerance [2 (9%)] (0.37-9.12) 78
AE-chest 0 (0%)
-- nd Good
pain SCr 0.98 [2 (9%)]
Praga
18 mo 25 23 mg/dl 2 (8%)
AE-diarrhea 2007[69] Tac Control 7.2 g/d -- nd Good
(18 mo) (25) (23) GFR 104 [0 (0%)]
Spain
AE- gouty ml/min 1 (4%)
-- nd Good
arthritis [0 (0%])
0 (0%)
AE- UTI -- nd Good
[1 (4%)]
73
Calculated by ERT
74
Calculated by ERT
75
Calculated by ERT
76
Calculated by ERT
77
Calculated by ERT
78
Calculated by ERT
1 (4%)
AE- nausea -- nd Good
[0 (0%])
AE- 1 (4%)
-- nd Good
headache [0 (0%])
1 (4%)
AE-tremor -- nd Good
[0 (0%])
Supplementary table 31. Summary table of RCT examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy (continuous outcomes)
Proteinuria
SCr 0.98 7.2 -5.6
12 mo 0.045 Fair
Praga mg/dl (8.4) (-4.3)
12 mo 25 23
2007[69] Tac Control GFR 7.2 g/d g/d
(18 mo) (25) (23) 7.2 -5.3
18 mo Spain 104 0.048 Fair
(8.4) (-5.2)
ml/min
Supplementary table 32. Evidence profile of RCTs examining MMF treatment vs. control for idiopathic membranous nephropathy in adults with nephrotic syndrome
applicability
Sparse
No important
3 RCTs 73 Some limitations Direct (-1)
Remission inconsistencies Very low Insufficient evidence High
(0)
(-1)
Sparse
Important
2 RCT 41 Some limitations Direct (-1)
Relapse inconsistencies Very low Insufficient evidence High
(-1)
(-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Sparse
Kidney Important
function inconsistencies Very low Insufficient evidence High
(categorical) (-1)
(-1)
Important
ΔProteinuria 3 RCTs 73 Some limitations Direct Sparse
inconsistencies Low No difference Moderate
(continuous) (High) (37) (-1) (0) (-1)
(0)
∆Kidney No important
2 RCT 41 Some limitations Direct Sparse
function inconsistencies Low No difference Moderate
(High) (22) (-1) (0) (-1)
(continuous) (-1)
52 Higher incidence of adverse events and
Adverse events 2 RCT Moderate
(26) serious adverse events with MMF

Insufficient evidence Very low
Supplementary table 33. Summary table of RCTs examining MMF treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome (categorical outcomes)
Remission
Complete Conservative 1 (6%) NS
Fair
remission treatment with SCr 1.01 [0 (0%)] (0.3)
MMF and
6 mo ACE-I, statins, 15 17 mg/dl RR 1.25
conservative 6.2 g/d
(12 mo) low-salt and low- (19) (17) GFR 92 4 (27%) (0.65-2.40) NS
Partial remission treatment Fair
protein diet, and ml/min [3 (18%)] (0.8)
Dussol loop diuretic
2008[22]
Complete Conservative 1 (6%) NS
France Fair
remission treatment with SCr 1.01 [2 (12%)] RR 0.92 (0.5)
MMF and
12 mo ACE-I, statins, 15 17 mg/dl 6 (40%) (0.48-1.75) NS
Partial remission conservative 6.2 g/d Fair
(12 mo) low-salt and low- (19) (17) GFR 92 [5 (29%)) (0.9)
treatment
protein diet, and ml/min 37%
Remissions -- nd Fair
loop diuretic [41%]
NS Fair
remission [3 (33%)] (0.22-3.11) 79
4 (36%) RR 1.09
Partial remission NS Fair
Chan [3 (33%)] (0.33-3.66) 80
15 mo MMF and Modified Ponticelli 11 9
Composite 2007[11] 100 μmol/L 5.7 g/d
(6 mo) prednisone regimen (11) (9) 64%
endpoint of CR China -- NS Fair
[68%]
or PR
Time to 5
-- NS Fair
remission (mo) [6]
Conventional nd Good
remission UPCR 4.68 [3 (30%)] (0.48-4.77) 81
therapy with
Nayagam 12 mo MMF and 11 10 GFR 86 mg/mg 2 (18%) RR 0.36
Partial remission methlyprednisolon nd Good
2008[59] India (6 mo) prednisone (11) (10) ml/min (MN and [5 (50%)] (0.09-1.47) 82
e and p.o.
Time to FSGS) 9.2
prednisone -- nd Good
remission (wk) [10.4]
Relapse or Failure
4 (36%) RR 1.09
Treatment failure NS Fair
[3 (33%)] (0.33-3.66) 83
Chan
15 mo MMF and Modified Ponticelli 11 9 2 (18%) RR 2.27
Relapse 2007[11] 100 μmol/L 5.7 g/d NS Fair
(6 mo) prednisone regimen (11) (9) [1 (11%)] (0.23-22.56) 84
China
Relapse in CR or
3 (23%) -- nd Fair
PR (n=13)
Nayagam 12 mo MMF and Conventional 11 10 GFR 86 UPCR 4.68 0 (0%)
Relapse -- nd Good
2008[59] India (6 mo) prednisone therapy with (11) (10) ml/min mg/mg [1 (10%)]
methlyprednisolon (MN and
e and p.o. FSGS)
prednisone
Kidney Function
Conservative
treatment with SCr 1.01
Dussol MMF and
12 mo ACE-I, statins, 15 17 mg/dl 0 (0%)
↑SCr 20% 2008[22] conservative 6.2 g/d -- nd Fair
(12 mo) low-salt and low- (19) (17) GFR 92 [0 (0%)]
France treatment
protein diet, and ml/min
loop diuretic
2 (18%)
≥15% ↑SCr Chan -- nd Poor
15 mo MMF and Modified Ponticelli 11 9 [0 (0%)]
2007[11] 100 μmol/L 5.7 g/d
(6 mo) prednisone regimen (11) (9) 3 (27%) 2.45
≥15% ↓SCr China nd Poor
[1 (11%)] (0.31-19.74) 85
Adverse Events
3 (20%)
Serious AEs -- nd Fair
[0 (0%)]
AE-muscular 4 (27%) RR 0.91
nd Fair
pain [5 (29%)] (0.30-2.71) 86
2 (13%) RR 2.27
AE-anemia nd Fair
Conservative [1 (6%)] (0.23-22.56) 87
AE- treatment with SCr 1.01 2 (13%) RR 2.27
Dussol MMF and nd Fair
nausea/vomiting 12 mo ACE-I, statins, 15 17 mg/dl [1 (6%)] (0.23-22.56) 88
2008[22] conservative 6.2 g/d
(12 mo) low-salt and low- (19) (17) GFR 92 1 (7%) RR 1.13
AE-hypotension France treatment nd Fair
protein diet, and ml/min [1 (6%)] (0.08-16.59) 89
loop diuretic 1 (7%) RR 0.57
AE-cough nd Fair
[2 (12%)] (0.06-5.64) 90
AE-acute 0 (0%)
-- nd Fair
bronchitis [1 (6%)]
1 (7%)
AE-cytolysis -- nd Fair
[0 (0%)]
3 (27%) RR 1.23
AE-infection nd Poor
Chan [2 (22%)] (0.26-5.82) 91
15 mo MMF and Modified Ponticelli 11 9
AE-leucopenia 2007[11] 100 μmol/L 5.7 g/d 6 (30%) -- nd Poor
(6 mo) prednisone regimen (11) (9)
AE-new onset China 1 (9%) RR 0.82
nd Poor
DM [1 (11%)] (0.06-11.33) 92
0 (0%)
AE-death -- nd Poor
[0 (0%)]
Supplementary table 34. Summary table of RCTs examining MMF treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome (continuous outcomes)
Outcome GFR/SCr Proteinuria Units Quality
Country measurement Intervention Control Intervention Control Intervention Intervention value
Proteinuria
Conservative
treatment with SCr 1.01
Dussol MMF and
12 mo ACE-I, statins, low- 15 17 mg/dl 4865 +213.07
Mean UPCR 2008[22] conservative 6.2 g/d nd 0.3 Fair
(12 mo) salt and low-protein (19) (17) GFR 92 (6548) (-1834.6)
France treatment
diet, and loop ml/min
diuretic
Chan
15 mo MMF and Modified Ponticelli 11 9 100 5.3 -3.8
Proteinuria 2007[11] 5.7 g/d g/d nd Poor
(6 mo) prednisone regimen (11) (9) μmol/L (6.6) (-6.2)
China
Conventional
UPCR 4.68
Nayagam therapy with
12 mo MMF and 11 10 GFR 86 mg/mg 5.3 -4.6
∆UPCR 2008[59] methlyprednisolone mg/mg nd Fair
(6 mo) prednisone (11) (10) ml/min (MN and (5.1) (-4.0)
India and p.o.
FSGS)
prednisone
SCr/GFR/CrCl
100.1 20.3
SCr Chan μmol/L nd Poor
15 mo MMF and Modified Ponticelli 11 9 100 (95.4) (-5.8)
2007[11] 5.7 g/d
(6 mo) prednisone regimen (11) (9) μmol/L 71.5 5.0
CrCl China ml/min nd Poor
(91.3) (5.9)
Conventional
Nayagam therapy with
12 mo MMF and 11 10 GFR 86 UPCR 4.68 85 -4
MDRD GFR 2008[59] methlyprednisolone ml/min nd Good
(6 mo) prednisone (11) (10) ml/min mg/mg (80) (-4)
India and p.o.
prednisone
Supplementary table 35. Evidence profile of RCTs examining alternate-day prednisone treatment vs. control in adults and children with MPGN
(treatment) across studies generalizability/ considerations Quality of evidence for Qualitative and quantitative Importance of
study design per outcome outcome description of effect outcome
applicability
1 RCT 77 Serious limitations Direct Sparse

Mortality N/A Very low No difference Critical
(High) (44) (-2) (0) (-1)
Sparse
ESRD N/A Very low Benefit with prednisone Critical
(-1)
Sparse
Remission N/A Very low Insufficient evidence High
(-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Kidney No important
2 RCTs 95 Some limitations Direct Sparse Possible benefit with prednisone in
function inconsistencies Low High
(High) (52) (-1) (0) (-1) Type I and III
(categorical) (0)
ΔProteinuria 1 RCT 18 Serious limitations Direct Sparse
N/A Very low Possible benefit with prednisone Moderate
(continuous) (High) (8) (-2) (0) (-1)
∆Kidney
1 RCT 18 Serious limitations Direct Sparse
function N/A Very low Benefit with prednisone Moderate
(High) (8) (-2) (0) (-1)
(continuous)
Higher incidence of hypertensive
1 RCT 77
Adverse events encephalopathy and steroid toxicity with Moderate
(High) (44)
prednisone.
Potential benefit for prednisone Very low
Supplementary table 36. Summary table of RCTs examining alternate-day prednisone treatment vs. control in patients with MPGN (categorical outcomes)
Mortality
Tarshish
GFR 112 RR 0.38
1992[81] 63 mo Alternate-day 44 33 2 (5%)
Death Placebo ml/min/1.73 m2 122 mg/h/m2 (0.07-1.93) 0.240 Poor
US, Europe, (41 mo) prednisone (47) (33) [4 (12%)]
(62 µmol/L) 93
Mexico
ESRD
Mota-
Hernandez 2-5 y Alternate-day 8 10 0 (0%)
ESRD Lactose SCr 0.78 mg/dl 99 mg/h/m2 -- nd Fair
1985[58] (nd) prednisone (8) (10) [4 (40%])
Mexico
Remission
Mota-
RR 0.63
Hernandez Up to 8 y Alternate-day 8 10 1 (13%)
1, 2, or 8 y Lactose SCr 0.78 mg/dl 99 mg/h/m2 (0.07-5.72) 0.677 Fair
1985[58] (nd) prednisone (8) (10) [2 (20%)] 94
Mexico
Kidney Function
Mota-
“Moderate” Hernandez 5y Alternate-day 8 10 3 (38%)
Lactose SCr 0.78 mg/dl 99 mg/h/m2 -- nd Poor
increase in SCr 1985[58] (nd) prednisone (8) (10) [0 (0%)]
Mexico
RR 0.67
63 mo 16 (36%)
(0.40-1.10) 0.112
(41 mo) [18 (55%)]
44 33 95
130 mo (47) (33)

59%
(survival -- 0.07
↑SCr ≥30% or [88%]
analysis)
≥0.4 mg/dl (35 Tarshish Fair
Type I, III GFR 112 RR 0.45
µmol/L) 1992[81] Alternate-day 9 (29%)
Placebo 31 26 ml/min/1.73 m2 122 mg/h/m2 (0.23-0.90) 0.035
US, Europe, prednisone [15 (58%)]
(33) (26) (62 µmol/L) 96
Mexico
Type II RR 0.93
63 mo 5 (56%)
9 5 (0.37-2.33) 0.870
(41 mo) [3 (60%)]
(9) (5) 97
RR 0.70
SCr≥4.0 mg/dl 44 33 13 (30%)
(0.38-1.28) 0.241 Fair
(350 µmol/L) (47) (33) [14 (42%)] 98
Adverse Events
AE- RR 1.13
3 (6%)
Hypertensive Tarshish (0.20-6.35) 0.894 Fair
GFR 112 [2 (6%)]
encephalopathy 1992[81] 63 mo Alternate-day 44 33 99
Placebo ml/min/1.73 m2 122 mg/h/m2
AE-Steroid US, Europe, (41 mo) prednisone (47) (33)
(62 µmol/L) 2 (4%)
toxicity requiring Mexico -- nd Fair
[0 (0%)]
discontinuation
Supplementary table 37. Summary table of RCTs examining alternate-day prednisone treatment vs. control in patients with MPGN (continuous outcomes)
Proteinuria
Mota-
Hernandez 6.5 y Alternate-day 8 10 SCr 0.78 99 -3.63
Proteinuria Lactose 99 mg/h/m2 mg/h/m2 nd Poor
1985[58] (nd) prednisone (8) (10) mg/dl (97) (-0.05)
Mexico
SCr/GFR/CrCl
Mota-
Hernandez 6.5 y Alternate-day 8 10 SCr 0.78 0.78 -0.50
SCr Lactose 99 mg/h/m2 mg/dl nd Poor
1985[58] (nd) prednisone (8) (10) mg/dl (0.82) (+4.09)
Mexico
Supplementary table 38. Summary table of studies examining dipyridamole plus aspirin treatment vs. placebo in patients with MPGN (categorical outcomes)
No. Analyzed
Duration Description Time to Results
(Enrolled)
Study, Year Outcome outcome P
Outcome GFR/SCr Proteinuria Events (%) Quality
Country measurement Intervention value
Intervention Control Intervention Control Intervention RR/OR/HR
[Control]
ESRD
Mean 62
Donadio 100 RR 0.030
ESRD ≤7 y Dipyridamole 21 19 GFR 69.5 (range 3 (14%)
1984[19] Placebo 5.9 g/d (0.10-0.95) 0.03102 Fair
(dialysis) (12 mo) and aspirin (25) (25) ml/min/1.73 m2 37-70) mo [9 (47%)]
US 101
[33 (10-63)]
Kidney Function
Donadio 103 RR 0.39
↓GFR by 12 mo Dipyridamole 21 19 GFR 69.5 3 (14%)
1984[19] Placebo 5.9 g/d -- (0.12-1.29) <0.05 Fair
≥25% (12 mo) and aspirin (25) (25) ml/min/1.73 m2 [7 (37%)]
US 104
No. of Dipyridamole
12 mo Protein 30%
nephrotic aspirin, -- nd Fair
Zauner (36 mo) restriction (100%)
patients protein 10 8
1994[92] and anti- SCr 1.79 mg/dl 8.28 g/d --
No. of restriction (10) (8)
Germany 36 mo HTN 10%
nephrotic and anti- -- nd Fair
(36 mo) therapy (75%)
patients HTN therapy
Adverse Events
AE- painful 5%
-- nd Fair
ecchymosis [0%]
AE-
recurrent
5%
gastric ulcer -- nd Fair
[0%]
with
Donadio 105
bleeding 12 mo Dipyridamole 21 19 GFR 69.5
1984[19] Placebo 5.9 g/d --
AE-rectal (12 mo) and aspirin (25) (25) ml/min/1.73 m2 5%
US -- nd Fair
bleeding [0%]
AE-acute
interstitial
0%
nephritis -- nd Fair
[5%]
due to
furosemide
100 Subsequent publication (Donadio JV. 1989 AJKD Dec 14(5): 445) indicated that results are heavily influenced by lead-time bias, so no evidence profile was made.
102 Calculated by ERT. Odds ratio
Supplementary table 39. Summary table of studies examining dipyridamole plus aspirin treatment vs. placebo in patients with MPGN (continuous outcomes)
Outcome
Study, Year Baseline ∆
Outcome measuremen GFR/SCr Proteinuria P value Quality
Country Intervention Control Intervention Control Units Intervention Intervention
t
(Control) (Control)
(Treatment)
Proteinuria
Dipyridamol Protein 8.28 -5.72
12 mo g/d nd Poor
e aspirin, restricti (7.11) (-1.7)
Zauner
12 mo protein on and 10 8 SCr 1.79
1994[92] 8.28 g/d
(36 mo) restriction anti- (10) (8) mg/dl 8.28 -6.67
36 mo Germany g/d nd Poor
and anti- HTN (7.11) (-2.77)
HTN therapy therapy
SCr/GFR/CrCl
ml/min/1. -1.3 0.05
∆GFR 12 mo Donadio 106 GFR 69.5 NA Poor
12 mo Dipyridamol 18107 18 73 m2 (-19.6) <0.02108
1984[19] Placebo ml/min/1.73 5.9 g/d
(12 mo) e and aspirin (25) (25) +0.18
∆SCr 12 mo US m2 mg/dl NA NS Poor
(+1.1)
Dipyridamol Protein
e aspirin, restricti
Zauner
36 mo protein on and 10 8 SCr 1.79 1.79 -0.01
SCr 1994[92] 8.28 g/d mg/dl nd Poor
(36 mo) restriction anti- (10) (8) mg/dl (1.79) (-0.18)
Germany
and anti- HTN
HTN therapy therapy
107 Restricted to those without treatment complications.
108 By 2-sample t-test and by rank-sum test, respectively.
Supplementary table 40. Summary table of study examining warfarin plus dipyridamole treatment vs. control in patients with MPGN (categorical outcomes)
Country measurement Intervention Control Intervention Control Intervention OR/RR/HR
ESRD
Zimmerman
12 mo Warfarin and No 8 10 0 (0%)
ESRD 1983[93] SCr 1.6 mg/dl 2.91 g/d -- nd Poor
(12 mo) dipyridamole treatment (11) (11) [2 (20%)]
US
Kidney function
1 (13%) RR 0.21 0.06
↑SCr >0.2 mg/dl Poor
[6 (60%)] (0.03-1.40) (X2)
2 (25%)
↓SCr >0.2 mg/dl Zimmerman -- nd Poor
12 mo Warfarin and No 8 10 [0 (0%)]
1983[93] SCr 1.6 mg/dl 2.91 g/d
“Significant” ↓1/ (12 mo) dipyridamole treatment (11) (11) 0 (0%)
US -- <0.03 Poor
SCr (P<0.05) [5 (50%)]
0 (0%)
Doubling of SCr -- nd Poor
[4 (40%)]
Supplementary table 41. Summary table of study examining warfarin plus dipyridamole treatment vs. control in patients with MPGN (continuous outcomes)
Proteinuria
Zimmerman
12 mo Warfarin and No 8 10 6.2 -3.0 NS
Urine protein 1983[93] SCr 1.6 mg/dl 2.91 g/d g/d Poor
(12 mo) dipyridamole treatment (11) (11) (6.8) (-0.1) (<0.10)
US
SCr/GFR/CrCl
1.6 -0.2
SCr Zimmerman mg/dl <0.01 Poor
12 mo Warfarin and No 8 10 (1.6) (+2.0)
1983[93] SCr 1.6 mg/dl 2.91 g/d
(12 mo) dipyridamole treatment (11) (11) +0.091
1/SCr slope US dl/mg -- <0.025 Poor
(-0.208)
Supplementary table 42. Summary table of studies examining prednisone or CsA treatment vs. control in patients with schistosoma and nephropathy (categorical outcomes)
Remission
Oxamniquine
Oxamniquine 10 2 (20%)
+praziquantel SCr 0.99 4.47 g/d -- nd Poor
+praziquantel (10) [0 (0%)]
Complete + prednisone
remission Oxamniquine
Sobh +praziquantel (8) [0 (0%)]
12 mo +CsA 8
1989[74]
(3 d) Oxamniquine (8) RR 2.40
Netherlands Oxamniquine 10 3 (30%)
+praziquantel SCr 0.99 4.47 g/d (0.30- nd Poor
Partial + prednisone 18.90)109
remission Oxamniquine RR 1.00
+praziquantel SCr 0.68 2.92 g/d (0.07-13.37) nd Poor
+CsA 110
Kidney Function
Oxamniquine
+ prednisone
↑SCr
Oxamniquine RR 1.00
+praziquantel SCr 0.68 2.92 g/d (0.07-13.37) nd Poor
12 mo +CsA 8 111
1989[74]
(3 d) Oxamniquine (8)
+ prednisone
↓SCr
Oxamniquine
+CsA
Adverse Events
Oxamniquine
Drug 12 mo + prednisone 8
1989[74]
toxicity (3 d) Oxamniquine (8)
+CsA

Supplementary table 43. Summary table of studies examining prednisone or cyclosporine treatment vs. control in patients with schistosoma and nephropathy (continuous outcomes)
Outcome GFR/SCr Proteinuria Race P value Quality
Proteinuria
Oxamniquine
Oxamniquine 10 4.47 -0.55
+praziquantel SCr 0.99 4.47 g/d nd Poor
Sobh +praziquantel (10) (3.9) (+0.09)
24-h 12 mo + prednisone 8
1989[74] nd g/d
proteinuria (3 d) Oxamniquine (8)
Netherlands Oxamniquine 8 2.92 +0.64
+praziquantel (8) (3.9) (+0.03)
+CsA
SCr/GFR/CrCl
Oxamniquine
Oxamniquine 10 0.99 -0.04
Sobh +praziquantel (10) (0.82) (+0.03)
12 mo + prednisone 8
SCr 1989[74] nd nd
(3 d) Oxamniquine (8)
Netherlands Oxamniquine 8 0.68 -0.14
+praziquantel (8) (0.82) (+0.03)
+CsA
Supplementary table 44. Evidence profile of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy
(treatment) across studies generalizability/ considerations Quality of evidence for Qualitative and quantitative description Importance
study design per outcome outcome of effect of outcome
applicability
Sparse
ESRD N/A Very low Insufficient evidence Critical
(-1)
Complete
0 RCTs -- -- -- -- -- -- -- High
remission
Partial
0 RCTs -- -- -- -- -- -- -- High
remission
Important
Proteinuria 2 RCTs 104 No limitations Direct None Benefit for ACE-I or ARB without steroids.
inconsistencies Moderate High
(categorical) (High) (52) (0) (0) (0) No difference with steroids
(-1)
Kidney No important
3 RCTs 148 Some limitations Direct None
function inconsistencies Moderate Benefit for ACE-I or ARB High
(High) (75) (-1) (0) (0)
(categorical) (0)
No important
ΔProteinuria 4 RCTs 227 Some limitations Direct None
inconsistencies Moderate Benefit for ACE-I or ARB Moderate
(continuous) (High) (116) (-1) (0) (0)
(0)
ΔKidney No important
function inconsistencies Moderate Benefit for ACE-I or ARB Moderate
(High) (213) (-1) (0) (0)
(continuous) (0)
149
Adverse events 2 RCTs No difference in major adverse event Moderate
(77)
Benefit of ACE-I or ARB Moderate
Supplementary table 45. Summary table of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy (categorical outcomes)
Outcome GFR Proteinuria RR/OR/HR P value Quality
Country measurement Intervention Control Intervention Control Intervention
(95% CI)
ESRD
Time to
Estimated NS
doubling of Li 2006[50] 2y Valsartan, 54 55 GFR 87 ml/min 1 (1%)
Placebo 1.8 g/d OR 0.23 (P -log-rank Fair
baseline SCr Hong Kong (2 y) 80 mg/d (54) (55) SCr 1.11 mg/dl [4 (7%)]
(0.03-2.21) test 0.18)
or ESRD
Proteinuria
Proteinuria
<500
41%
mg/d/1.73 m2 nd 0.0002
[9%]
lasting ≥6 mo
(All)
Proteinuria
<500
mg/d/1.73 m2 50%
nd nd
lasting ≥6 mo [11%]
(children
Coppo
only) 38 mo Benazepril 32 34 eGFR 116
2007[17] Placebo 1.6 g/d Good
Proteinuria (38 mo) 0.2 mg/kg/d (32) (34) ml/min/1.73m2
Europe
<160
13%
mg/d/1.73 m2 -- 0.02
[0 (0%)]
lasting ≥6 mo
(All)
Proteinuria
<160
mg/d/1.73 m2 2 (17%)
-- nd
lasting ≥6 mo [0 (0%)]
(children
only)
Losartan 50
Horita GFR 104 RR 1.08
↓Urine 24 mo mg/d, Prednisone 20 18 18 (90%) NS
2007[36] ml/min/1.73m2 1.6 g/d (0.84- Fair
protein ≥50% (24 mo) prednisone taper (20) (18) [15 (83%)] (0.551)
Japan SCr 0.8 mg/dl 1.39)112
taper
Kidney Function
3% NS
↓CrCl 30% nd Fair
[15%] (0.18)
Coppo
↓CrCl 30% or 38 mo Benazepril 32 34 eGFR 116
2007[17] Placebo 1.6 g/d RR 0.12
↑proteinuria (38 mo) 0.2 mg/kg/d (32) (34) ml/min/1.73m2 1 (3%) NS
Europe (0.02- Good
>3.5 g/d/1.73 [9 (27%)] (0.034)
0.88)113
m2
↑SCr 50% Praga 76 mo ACE-I No ACE-I 23 21 GFR 102 2 g/d 3 (13%)114 RR 0.23 0.010 Good

Outcome GFR Proteinuria RR/OR/HR P value Quality
(95% CI)
2003[68] (76 mo) 5-40 mg/d BP<140/90 (23) (21) ml/min (>3.5 g/d: [12 (57%)] (0.07-
Spain BP<140/90 SCr 1.0 mg/dl 11%) 0.70)115
0 (0%)
4y -- <0.05 Fair
[~6 (30%)]
RR 0.20
~2 (8%)
7y (0.05- 0.027 Fair
[~9 (45%)]
0.83)116
RR 0.25
SCr ≥1.5 mg 76 mo 3 (13%)117
(0.08- 0.016 Good
at last visit (76 mo) [11 (52%)]
0.77)118
Losartan 50
Horita GFR 104
24 mo mg/d, Prednisone 20 18 nd (0%?)
↑ SCr ≥50% 2007[36] ml/min/1.73m2 1.6 g/d RD -0.22119 nd Poor
(24 mo) prednisone taper (20) (18) [4 (22%)]
Japan SCr 0.8 mg/dl
taper
Adverse Event
Major RR 0.68
Li 2006[50] 2y Valsartan, 54 55 GFR 87 ml/min 2 (4%) NS
adverse Placebo 1.8 g/d (0.12- Good
Hong Kong (2 y) 80 mg/d (54) (55) SCr 1.11 mg/dl [3 (5%)] (0.664)
event 3.91)120
Losartan 50
Horita GFR 104
AE: Postural 24 mo mg/d, Prednisone 22 18 2 (9%)
2007[36] ml/min/1.73m2 1.6 g/d RD -0.09121 nd Fair
hypotension (24 mo) prednisone taper (22) (18) [0 (0%)]
Japan SCr 0.8 mg/dl
taper
114 SCr at baseline in the three enalapril-treated patients who reached the primary end point were 0.9, 1.4, and 1.4 mg/dl, corresponding to creatinine clearances of 120, 75, and 60 ml/min,
respectively.
117 Same 3 participants as for SCr 50% increase.
119 Calculated (P=0.02)
121 Calculated (NS)
Supplementary table 46. Summary table of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy (continuous outcomes)
No. Analyzed
(Enrolled)
Study, Year Outcome
Country measurement
(Treatment)
(Control) (Control)
Proteinuria
12 wk 1.80 0.35
0.005
(2 y) (2.35) (0.19)
24 wk 1.80 1.0
<0.001
(2 y) (2.35) (0)
52 wk 1.80 0.54
Proteinuria <0.001
(2 y) (2.35) (0.38)
Li 2006[50]
76 wk Valsartan, 80 54 55 GFR 87 ml/min 1.80 0.46
Hong Kong, Placebo 1.8 g/d g/d <0.001 Good
(2 y) mg/d (54) (55) SCr 1.11 mg/dl (2.35) (0.24)
China
104 wk 1.80 0.57
<0.001
(2 y) (2.35) (0.38)
Absolute 1.80 -0.66
<0.001
∆proteinuria 2y (2.35) (+0.08)
(2 y) 1.80 -33.5
%∆Proteinuria <0.001
(2.35) (+15.0)
76 mo -1.1
<0.001
Praga (76 mo) ACE-I GFR 102 2 g/d (+0.3)
No ACE-I 23 21 2.0
Proteinuria 2003[68] 5-40 mg/d ml/min (>3.5 g/d: g/d -0.8 (-36%) Good
BP<140/90 (23) (21) (1.7)
Spain 1y BP<140/90 SCr 1.0 mg/dl 11%) [+0.1 <0.001
(+23%)]
Shimizu GFR 72
“Antiplatelet 18 18 0.81 -0.36
Proteinuria 2008[73] 6 mo Losartan ml/min 0.81 g/d g/d NS Poor
agents” (18) (18) (0.73) (-0.10)
Japan SCr 1.0 mg/dl
Losartan 50
Horita GFR 104
24 mo mg/d, Prednisone 20 18 1.6 -1.3
Proteinuria 2007[36] ml/min/1.73m2 1.6 g/d g/24h <0.05 Fair
(24 mo) prednisone taper (20) (18) (1.6) (-1.1)
Japan SCr 0.8 mg/dl
taper
SCr/GFR/CrCl
Mean rates of
GFR 87 -5.62
0.01
throughout Li 2006[50] (78) (-6.98)
2y Valsartan, 80 54 55 GFR 87 ml/min
study period Hong Kong, Placebo 1.8 g/d ml/min/y Good
(2 y) mg/d (54) (55) SCr 1.11 mg/dl
Mean rates of China
87 -4.63
GFR 12 to 0.019
(78) (-6.92)
104 wks
102 -7
CrCl Praga ACE-I GFR 102 2 g/d ml/min <0.001
76 mo No ACE-I 23 21 (99) (-35)
2003[68] 5-40 mg/d ml/min (>3.5 g/d: Good
(76 mo) BP<140/90 (23) (21) 1.0 +0.2
SCr Spain BP<140/90 SCr 1.0 mg/dl 11%) mg/dl <0.001
(0.9) (+1.0)
Coppo
38 mo Benazepril 0.2 32 34 eGFR 116 1.6 g/d/1.73 ml/min/1.73 117.2 +8
∆CrCl 2007[17] Placebo 0.03 Good
(38 mo) mg/kg/d (32) (34) ml/min/1.73m2 m2 m2 (118.3) (-4)
Europe
Horita 24 mo Losartan 50 Prednisone 20 18 GFR 104 ml/min/1.73 104 -4
CrCl 1.6 g/d NS Fair
2007[36] (24 mo) mg/d, taper (20) (18) ml/min/1.73m2 m2 (103) (-19)
No. Analyzed
(Enrolled)
Study, Year Outcome
Country measurement
(Treatment)
(Control) (Control)
Japan prednisone SCr 0.8 mg/dl 0.8 0
SCr mg/dl
taper (0.7) (+0.2)
78.55 -9.4
CrCl ml/min
Shi (78.20) (-7.9)
Non ACE-I 44 39 GFR 78
2002[72] 18 mo ACE-I 1.98 g/d Follow-up: NS Poor
drug (65) (66) ml/min 125.07
SCr China μmol/L -8.01
(106.55)
(+47.85)
72.0 -0.2
GFR Shimizu GFR 72 ml/min NS
12 mo “Antiplatelet 18 18 (75.4) (+0.7)
2008[73] Losartan ml/min 0.81 g/d Poor
(12 mo) agents” (18) (18) 1.0 -0.1
SCr Japan SCr 1.0 mg/dl mg/dl NS
(0.9) (0)
Supplementary table 47. Evidence profile of RCTs examining steroid regimens in biopsy-proven IgA nephropathy
applicability*
No important
4 RCTs 336 Some limitations Some uncertainty None Benefit for steroids. No difference between
ESRD inconsistencies Low Critical
(High) (164) (-1) (-1) (0) low dose steroid and no steroid in one trial
(0)
No important
Proteinuria 3 RCTs 250 Some limitations Some uncertainty None
inconsistencies Low Benefit for steroid122 High
(categorical) (High) (121) (-1) (-1) (0)
(0)
Kidney No important
3 RCTs 179 Serious limitations Some uncertainty None
function inconsistencies Very low Benefit for steroids High
(High) (90) (-2) (-1) (0)
(categorical) (0)
No important
ΔProteinuria 6 RCTs 367 Some limitations Some uncertainty None
inconsistencies Low Benefit for steroid123 Moderate
(continuous) (High) (180) (-1) (-1) (0)
(0)
∆Kidney No important
5 RCTs 363 Some limitations Some uncertainty None
function inconsistencies Low Benefit of steroids Moderate
(High) (179) (-1) (-1) (0)
(continuous) (0)
60
Adverse events 1 RCT No serious adverse events Moderate
(29)
Benefit for steroids Low to Very low
* Generalizability was evaluated with regard to optimized therapy of proteinuria and hypertension with angiotensin converting enzyme (ACE-I) or angiotensin receptor blockage (ARB)
122 Among patients with a mean proteinuria of 2 g/d.

123 Among patients with a mean proteinuria of 2 g/d or more.
Study, Year Study Eligibility Criteria Interventions (Studies) Outcomes Conclusions Comments Yes/No
Samuels 2004[70] Head-to-head or placebo/no treatment Efficacy of steroids (7 trials) Risk of ESRD (need for Use of steroids in IgA Is Eligibility criteria similar Yes (biopsy
randomized trials evaluating the effects Efficacy of Immunosuppressive agents + dialysis) nephropathy significantly to the guideline proven IgA
Database: of different immunosuppressive agents steroids (3 trials) Doubling of serum creatinine reduced risk of ESRD, the nephropathy;
Medline, Embase, with biopsy proven IgA nephropathy. Efficacy of Immunosuppressive agents Glomerular filtration rate doubling of serum clinical trials)
Cochrane renal Both Adults and pediatric patients alone (3 trials) (GFR or CrCl) creatinine, and a
registry, ASN Urinary Protein Excretion significant reduction in
conference (g/24hr) urinary protein excretion.
Proceedings, Similar efficacy was not
Experts noted for kidney function
Search Dates: with use of Are there any limitations No
Until 2002 Immunosuppressive to systematic review
agents + steroids or methodology
N Studies: Immunosuppressive
13 trials (16 agents alone
publications) Immunosuppressive
agents alone were
N Subjects: associated with reduction Is limitation to evidence Yes
623 in urinary protein clearly addressed by the
excretion. authors
Lack of details on adverse events in published studies
Significant heterogeneity as a potential source for reduction in urinary protein excretion with Immunosuppressive agents, which had no significant
treatment effect on kidney function parameters.
Less applicable to early stages of IgA nephropathy
Suboptimal quality of trial reporting
Insufficient data to explore whether the duration of treatment or disease severity influenced the effect of treatment
N studies Test for

(N heterogeneity
Author, Year, Mean follow Baseline kidney Pooled
Intervention Control Outcome intervention P-value
RefID up function/proteinuria RR1(95% CI) I2 P-
group/ total
Statistic value
N)
2 studies: CrCl >25 6 0.44 (0.25,
Samuels 2004[70] Steroid No treatment/placebo ESRD 0.007 0% NS
ml/min/1.73m2 or (160/341) 0.80)
Study Years : Until Doubling of >70 ml/min 6 0.45 (0.29,
Steroid No treatment/placebo 0.0003 0% NS
2002 SCr 2 studies: SCr (160/341) 0.69)
No >136µmol/L 4 WMD 17.87
Steroid GFR 6-130 mo* 0.007 53.2% 0.09
treatment/placebo/dipyridamole 1 study: SCr <132 (67/138) (4.93, 30.82)
Urinary µmol/L
1 study: UPE WMD −0.49
No protein 5
Steroid <1.5g/d (−0.72, <0.0001 0% NS
treatment/placebo/dipyridamole excretion (127/263)
1 study: no data −0.25)
(g/24h)
Comments The systematic review did not report ACE-I use in the control arm or as co-medications
* Except for Shoji AJKD 2000, all studies had 6-130 mo follow-up. Shoji 2000 had 3 mo follow-up.
^ Except for Lai BMJ 1987, all studies had 23 mo and 36 mo follow-up. Lai 1987 had 3 mo follow-up.
Errors noted in text (page 179) and figure 6, 7.
Supplementary table 49. Summary table of RCTs examining steroid regimens in biopsy-proven IgA nephropathy (categorical outcomes)
Study, Year Outcome ACE-I or Events (%) P
Country measurement Intervention Control Intervention Control ARB use Intervention RR/OR/HR value
ESRD
Ramipril RR 0.16
Doubling of SCr Prednisone, 2 (4%)
Target BP (0.04- 0.011 Good
or ESRD ramipril [13 (27%)]
Manno <120–80 4 wk 0.66)124
8y Target BP <120– 48 49 GFR 100
2009[53] mmHg 1.7 g/d wash-out
(6 mo) 80 mmHg (48) (49) ml/min/1.73m2 RR 0.15
Italy 24-h 100% 1 (2%) NS
ESRD 24-h proteinuria to (0.02- Good
proteinuria to [7 (14%)] (0.067)
≤1.0 g 1.14)125
≤1.0 g
RR 1.30
2y 28 (97%)
(1.05- 0.018
(nd) SCr 1.1 mg/dl 4 wk [23 (76%)]
Lv 2009[51] 29 31 1.62)126
Kidney survival Cilazapril+steroid Cilazapril GFR 102 2.0 g/d wash-out Fair
China (30) (33) RR 1.58
3y ml/min/1.73 m2 100% 28 (97%)
(1.18- 0.002
(nd) [19 (66%)]
2.10)127
10-y kidney 97% RR 0.06
0.0003 Good
survival Pozzi [53%] (0.01-0.44)
10 y
2004[66] RR 0.20
(6 mo) Prednisone, anti- Anti-HTN, and 1 (2%)
RRT Italy (0.02- nd Fair
HTN, and antiplatelet 43 43 GFR 93 ml/min [5 (12%)]
2.0 g/d 14% 1.64)128
antiplatelet agents agents as (43) (43) SCr 97·2 μmol/L
Pozzi
as needed needed
1999[65] 5y 95%
Kidney survival 0.04 Fair
Italy (6 mo) [74%]
(Multicenter)
Katafuchi RR 1.09
5y Low dose steroid, 43 47 GFR 901 3 (7%)
ESRD 2003[46] Dipyridamole 252 mg/dl 2% (0.23- NS Fair
(2 y) dipyridamole (43) (47) ml/min/1.73 m2 [3 (6%)]
Japan 5.13)129
Proteinuria
Ramipril
Prednisone,
Target BP
ramipril
Manno <120–80 4 wk RR 1.11
↓Proteinuria 8y Target BP <120– 48 49 GFR 100 36 (75%) NS
2009[53] mmHg 1.7 g/24h wash-out (0.86- Good
<1g (6 mo) 80 mmHg (48) (49) ml/min/1.73m2 [33 (67%)] (0.407)
Italy 24-h 100% 1.44)130
24-h proteinuria to
proteinuria to
≤1.0 g
≤1.0 g

Study, Year Outcome ACE-I or Events (%) P
Country measurement Intervention Control Intervention Control ARB use Intervention RR/OR/HR value
RR 2.35
6 mo 22 (71%)
SCr 1.1 mg/dl 4 wk (1.36- nd
↓Proteinuria Lv 2009[51] (nd) 29 31 [10 (34%)]
Cilazapril+steroid Cilazapril GFR 102 2.0 g/d wash-out 4.08)131 Fair
>50% China (30) (33)
1y ml/min/1.73 m2 100% 81%
nd
(nd) (58%)
Minimal 6 mo 44% RR 2.11
0.037
response (6 mo) [21%] (1.08-4.13)
Good
↓<1g/d 1y 72% RR 2.38
Pozzi <0.001
proteinuria (6 mo) Supportive 43 43 GFR 93 ml/min [30%] (1.46-3.90)
2004[66] Steroids 2.0 g/d 14%
Optimal 6 mo therapy (43) (43) SCr 97·2 μmol/L 19% RR 4.00 NS
Italy
response (6 mo) [5%] (0.90-17.76) (0.089)
Good
↓<0.5g/d 1y 11 (26%) RR 5.50
0.014
proteinuria (6 mo) [2 (5%)] (1.30-23)
Kidney Function
↓Kidney Hogg Prednisone taper
3y 30 29 GFR 109 53% 2 (9.2%132) HR133 0.31
function, CrCl 2006[35] (80Æ40 mg every Placebo UPCR 2.2 NS Good
(2 y) (30) (29) ml/min/1.73 m2 [48%] [4 (8.7%)] (0.05, 1.8)
<60% baseline US, Canada other day
Pozzi
Progression of
1999[65] 5y 9 (21%) RR 0.41
renal disease Prednisone, anti- Anti-HTN, and 0.04
Italy (6 mo) [14 (33%)] (0.17-0.98)
(↑SCr 50%) HTN, and antiplatelet 43 43 GFR 93 ml/min
(Multicenter) 2.0 g/d 14% Fair
antiplatelet agents agents as (43) (43) SCr 97·2 μmol/L
Pozzi RR 0.08
Doubling of SCr 7y as needed needed 1 (2%)
2004[66] (0.01- nd
(↑SCr 100%)) (6 mo) [13 (30%)]
Italy 0.56)134
RR 0.67
CKD Lai 1986[48] 3y 17 17 2 (12%)
Prednisone No prednisone GFR 68 ml/min 6.5 g/d nd (0.13- nd Poor
(↓CrCl>15%) Hong Kong (4 mo) (17) (17) [3 (18%])
3.50)135
Adverse Events
SCr 1.1 mg/dl 4 wk
Major adverse Lv 2009[51] 7 mo 29 31 0 (0%)
Cilazapril+steroid Cilazapril GFR 102 2.0 g/d wash-out -- nd Fair
events China (nd) (30) (33) [0 (0%)]
ml/min/1.73 m2 100%

132 Estimated cumulative proportion of failures at 3 years
133 Controlled for baseline UPCR. Both also NS without adjusting for baseline UP/C
Supplementary table 50. Summary table of RCTs examining steroid regimens in biopsy-proven IgA nephropathy (continuous outcomes)
Study, Year Outcome ACE-I or Baseline ∆ P
Country measurement Intervention Control Intervention Control ARB use Units Intervention Intervention value
Proteinuria
Time SCr 1.1 mg/dl 4 wk
Lv 2009[51] 1y Cilazapril+st 29 31 2.5 -1.5
averaged Cilazapril GFR 102 2.0 g/d wash-out g/d 0.01 Good
China (nd) eroid (30) (33) (2.0) (-0.4)
proteinuria ml/min/1.73 m2 100%
Prednisone
Hogg taper
3y 30 29 GFR 109 53% 2.2
UPCR 2006[35] (80Æ40 mg Placebo UPCR 2.2 None nd <0.05 Poor
(2 y) (30) (29) ml/min/1.73 m2 [48%] (1.4)
US, Canada every other
day
Katafuchi Low dose
∆Urinary 5y Dipyridamol 43 47 GFR 91 252 -134
2003[46] steroid, 252 mg/dl 2% mg/dl nd Fair
protein (2 y) e (43) (47) ml/min/1.73 m2 (143) (-43)
Japan dipyridamole
Prednisone,
Anti-HTN,
Pozzi anti-HTN,
and
↓Proteinuria 1999[65] 5y and 43 43 GFR 93 ml/min 2.0 -1.2*
antiplatelet 2.0 g/d 14% g/d <0.05 Fair
(median) Italy (6 mo) antiplatelet (43) (43) SCr 97·2 μmol/l (1.8) (-1.0)
agents as
(Multicenter) agents as
needed
needed
Lai 1986[48] 3y No 17 17 6.5 -3.2
∆Proteinuria Prednisone GFR 68 ml/min 6.5 g/d nd g/d nd Poor
Hong Kong (4 mo) prednisone (17) (17) (4.7) (-1.4)
Alternate
Julian, 1y No 35 3.5 -2.2
∆Proteinuria day SCr 135 µmol/l nd 40% nd nd Fair
1993[44] US (1 y) prednisone (35) (3.2) (-1.4)
prednisone
Kidney Function
Prednisone,
Ramipril
ramipril
Target BP
Target BP
Mean rate Manno <120–80 4 wk ml/min/
8y <120–80 48 49 GFR 100 100.4 −0.56
↓kidney 2009[53] mmHg 1.7 g/24h wash-out 1.73m2 0.013 Good
(6 mo) mmHg (48) (49) ml/min/1.73m2 (97.5) (−6.17)
function Italy 24-h 100% /y
24-h
proteinuria
proteinuria to
to ≤1.0 g
≤1.0 g
Katafuchi Low dose
5y Dipyridamol 43 47 GFR 91 0.95 +0.4
∆SCr 2003[46] steroid, 252 mg/dl 2% mg/dl NS Fair
(2 y) e (43) (47) ml/min/1.73 m2 (0.95) (+0.6)
Japan dipyridamole
Prednisone
Hogg taper
3y 30 29 GFR 109 53% 1.0 0
SCr 2006[35] (80Æ40 mg Placebo UPCR 2.2 mg/dl nd Poor
(2 y) (30) (29) ml/min/1.73 m2 [48%] (0.8) (+0.3)
US, Canada every other
day
Alternate-
day
prednisolone Dipyridamol
Koike
2y 5–10 mg e or zilazep 24 24 0.92 0
∆SCr 2008[47] SCr 0.92 mg/dl 0.97 g/d 23% mg/dl NS Poor
(2 y) dipyridamole 150 or 300 (24) (24) (1.15) (+0.03)
Japan
or zilazep mg/d
150 or 300
mg/d
68.1 +6.0
∆CrCl ml/min
Lai 1986[48] 3y No 17 17 (68.2) (-3.6)
Prednisone GFR 68 ml/min 6.5 g/d nd nd Poor
Hong Kong (4 mo) prednisone (17) (17) 115.3 +11.6
∆SCr µmol/l
(125.5) (+5.2)
Alternate
Julian 1y No 35 135 -40 NS
∆SCr day SCr 135 µmol/l 3.5 g/d 40% µmol/l Fair
1993[44] US (1 y) prednisone (35) (138) (+19) (0.06)
prednisone
* estimated from figure
Samuels 2004[70] Head-to-head or placebo/no treatment Efficacy of steroids (7 trials) Risk of ESRD (need for Use of steroids in IgA Is Eligibility criteria similar Yes (biopsy
randomized trials evaluating the effects Efficacy of Immunosuppressive agents + dialysis) nephropathy significantly to the guideline proven IgA
Database: of different immunosuppressive agents steroids (3 trials) Doubling of serum creatinine reduced risk of ESRD, the nephropathy;
Medline, Embase, with biopsy proven IgA nephropathy. Efficacy of Immunosuppressive agents Glomerular filtration rate doubling of serum clinical trials)
Cochrane renal Both Adults and pediatric patients alone (3 trials) (GFR or CrCl) creatinine, and a
registry, ASN Urinary Protein Excretion significant reduction in
conference (g/24hr) urinary protein excretion.
Proceedings, Similar efficacy was not
Experts noted for kidney function
Search Dates: with use of Are there any limitations No
Until 2002 Immunosuppressive to systematic review
agents + steroids or methodology
N Studies: Immunosuppressive
13 trials (16 agents alone
publications) Immunosuppressive
agents alone were
N Subjects: associated with reduction Is limitation to evidence Yes
623 in urinary protein clearly addressed by the
excretion. authors
Lack of details on adverse events in published studies
Significant heterogeneity as a potential source for reduction in urinary protein excretion with Immunosuppressive agents, which had no significant
treatment effect on kidney function parameters.
Less applicable to early stages of IgA nephropathy
Suboptimal quality of trial reporting
Insufficient data to explore whether the duration of treatment or disease severity influenced the effect of treatment
N studies Test for

(N heterogeneity
Author, Year, Mean follow Baseline kidney Pooled P-
Intervention Control Outcome intervention
RefID up function/proteinuria RR1(95% CI) value I2
group/ total P-value
Statistic
N)
Immunosuppressive 1 study: SCr
No 2 0.35 (0.04,
Samuels 2004[70] agents or ESRD >130µmol/l NS 0% NS
treatment/placebo/dipyridamole (total 106) 3.22)
cyclosporine alone 1 study: well
Urinary 24-72 mo preserved kidney
Immunosuppressive
Study Years: Until No protein function 3 WMD −0.94
agents or 0.0001 48.7% NS
2002 treatment/placebo/dipyridamole excretion 1 study: No clinical (63 / 122) (−1.43, -0.46)
cyclosporine alone
(g/24hr) inclusion criteria
Immunosuppressive No 2 0.59
ESRD 2 studies: No clinical NS nd nd
agents + steroids treatment/placebo/dipyridamole (total 152) (0.06, 6.03)
inclusion criteria
Urinary
23, 36 mo* 1 study: Proteinuria
Immunosuppressive No protein 3 WMD -1.25
>1.5 g/d or CrCl >5 0.09 97.3% <0.0001
agents + steroids treatment/placebo/dipyridamole excretion (79 / 153) (−2.71, 0.21)
ml/min/1.73m2
(g/24hr)
Comments The systematic review did not report ACE-I use in the control arm or as co-medications
* Except for Shoji AJKD 2000, all studies had 6-130 mo follow-up. Shoji 2000 had 3 mo follow-up.
^ Except for Lai BMJ 1987, all studies had 23 mo and 36 mo follow-up. Lai 1987 had 3 mo follow-up.
Errors noted in text (page 179) and figure 6, 7.
Supplementary table 52. Summary table of RCTs examining steroid and immunosuppressive regimens in biopsy-proven IgA nephropathy (categorical outcomes)
No. Analyzed
(Enrolled) ACE-I
Study, Year Outcome Quali
Outcome GFR/SCr Proteinuria or ARB Events (%) P value
Country measurement RR/OR ty
Intervention Control Intervention Control use Intervention
(Treatment) /HR
[Control]
ESRD
Prednisolone,
Renal Ballardie 5y BP <160/90 19 19 SCr 72%
cyclophosphamide 3.9 g/24h 26% 0.04 Poor
survival 2002[6] UK (2 y) mmHg (19) (19) >130µmol/l [5%]
BP <160/90 mmHg
Proteinuria
Patients with Harmankaya
5y Prednisolone, AZA DBP<90 21 22 SCr 0.8 0 (0%)
proteinuria 2002[32] nd 0% -- nd Poor
(4 mo) DBP<90 mmHg mmHg (21) (22) mg/dl [3 (14%)]
>500 mg/d Turkey
Adverse events
Treatment
discontinuation
due to mild
Yoshikawa Prednisolone,
AZA and Heparin, leukopenia or ↑
1999[89] 2y AZA, heparin, 40 34 SCr 0.64
warfarin warfarin, and 1.35 g/d 0% transaminase n=3 -- -- Fair
Japan (2 y) warfarin, and (40) (34) mg/dl
related AE dipyridamole [treatment
(Multicenter) dipyridamole
discontinuation
due to bleeding
n=2]
Supplementary table 53. Summary table of RCTs examining steroid and immunosuppressive regimens in biopsy-proven IgA nephropathy (continuous outcomes)
No. Analyzed
(Enrolled) ACE-I
Study, Year Outcome
Outcome GFR/SCr Proteinuria or ARB Baseline ∆ P value Quality
Country measurement
Intervention Control Intervention Control use Units Intervention Intervention
(Treatment)
(Control) (Control)
Proteinuria
Prednisolone,
Ballardie 5y BP <160/90 19 19 SCr >130 3.9 -3.6
↓Proteinuria cyclophosphamide 3.9 g/24h 26% g/24h nd Poor
2002[6] UK (2 y) mmHg (19) (19) µmol/l (4.6) (-0.63)
BP <160/90 mmHg
Yoshikawa Prednisolone, Heparin,
1999[89] 2y AZA, heparin, warfarin, 40 34 SCr 0.64 1.35 -1.13
UPE 1.35 g/d 0% g/d nd Fair
Japan (2 y) warfarin, and and (40) (34) mg/dl (0.98) (-0.10)
(Multicenter) dipyridamole dipyridamole
SCr/GFR/CrCl
Rate Prednisolone, µmol/l-
Ballardie 5y BP <160/90 19 19 SCr >130 -5.19 -1.07
↓kidney cyclophosphamide 3.9 g/24h 26% 1/d-1 x nd Poor
2002[6] UK (2 y) mmHg (19) (19) µmol/l (-4.85) (-5.12)
function BP <160/90 mmHg 10-6
Harmankaya
5y Prednisolone, AZA DBP<90 21 22 SCr 0.8 0.8 +0.1
∆SCr 2002[32] nd 0% mg/dl NS Poor
(4 mo) DBP<90 mmHg mmHg (21) (22) mg/dl (0.9) (+0.1)
Turkey
Yoshikawa Prednisolone, Heparin, ml/min
1999[89] 2y AZA, heparin, warfarin, 40 34 SCr 0.64 per 144 +3
CrCl 1.35 g/d 0% NS Fair
Japan (2 y) warfarin, and and (40) (34) mg/dl 1.73 (152) (-7)
(Multicenter) dipyridamole dipyridamole m2
Supplementary table 54. Evidence profile of RCTs examining AZA in combination vs. AZA alone in biopsy-proven IgA nephropathy
applicability
Mortality N/A Low No difference Critical
(High) (101) (0) (0) (-1)
ESRD N/A Low No difference Critical
(High) (101) (0) (0) (-1)
Important
Proteinuria 2 RCTs 287 No limitations Direct None
inconsistencies Moderate Possible harm High
(categorical) (High) (141) (0) (0) (0)
(-1)
Kidney Important
2 RCTs 287 No limitations Direct None
function inconsistencies Moderate No difference High
(High) (141) (0) (0) (0)
(categorical) (-1)
No
Proteinuria 2 RCTs 287 No limitations Direct None
inconsistencies High No difference Moderate
(continuous) (High) (141) (0) (0) (0)
(0)
ΔKidney
function N/A Moderate No difference Moderate
(High) (40) (0) (0) (-1)
(continuous)
207
Adverse events 1 RCT Treatment-related major side effects for AZA Moderate
(101)
Possible worsening, more side effects with AZA Low
Supplementary table 55. Summary table of RCTs examining AZA in combination vs. AZA along in biopsy-proven IgA nephropathy (categorical outcomes)
Study, Year Outcome ACE-I or Events (%)
Country measurement Intervention Control Intervention Control ARB use Intervention RR/OR/HR
Proteinuria
Proteinuria Yoshikawa AZA, warfarin, GFR 147 RR 1.24
24 mo 39 39 36 (92%)
disappearance 2006[90] dipyridamole, Prednisolone ml/min/1.73 m2 1.30 g/m2/d 0% (1.01- 0.039 Good
(24 mo) (40) (40) [29 (74%)]
(<0.1 g/m2/d) Japan prednisolone Scr 49 µmol/l 1.52)136
↓Proteinuria Pozzi 2010[67] AZA, GFR 66 RR 0.89
5y Prednisone 101 106 45 (45%)
>50% from Italy and prednisone ml/min/1.73 m2 2.0 g/d 46% (0.67- NS Good
(6 mo) alternate day (101) (106) [53 (50%)]
baseline Switzerland alternate day Scr 106 µmol/l 1.19)137
SCr/GFR/CrCl
Yoshikawa AZA, warfarin, GFR 147
CrCl <60 24 mo 39 39 0%
2006[90] dipyridamole, Prednisolone ml/min/1.73 m2 1.30 g/m2/d 0% -- NS Good
ml/min/1.73m2 (24 mo) (40) (40) [0%]
Japan prednisolone Scr 49 µmol/l
Pozzi 2010[67] AZA, GFR 66
↑SCr >50% 5y Prednisone 101 106 13 (13%) RR 1.14138
Italy and prednisone ml/min/1.73 m2 2.0 g/d 46% NS Good
from baseline (6 mo) alternate day (101) (106) [12 (11%)] (0.54-2.37)
Switzerland alternate day Scr 106 µmol/l
136
Calculated by ERT
137
Calculated by ERT
138
Calculated by ERT
Supplementary table 56. Summary table of RCTs examining AZA in combination vs. AZA alone in biopsy-proven IgA nephropathy (continuous outcomes)
Proteinuria
GFR 147
Yoshikawa AZA, warfarin, ml/min/1.73
2y 39 39 1.29 -1.19
UPE 2006[90] dipyridamole, Prednisolone m2 1.30 g/m2/d 0% g/m2/d NS Good
(2 y) (40) (40) (1.16) (-1.04)
Japan prednisolone Scr 49
µmol/l
GFR 66
Pozzi
AZA, ml/min/1.73
2010[67] 5y Prednisone 101 106 2.10 -0.94
UPE prednisone m2 2.0 g/d 46% g/d NS Good
Italy and (6 mo) alternate day (101) (106) (1.95) (-0.97)
alternate day Scr 106
Switzerland
µmol/l
SCr/GFR/CrCl
GFR 147
Yoshikawa AZA, warfarin, ml/min/1.73 ml/min/
24 mo 39 39 148 +8
CrCl 2006[90] dipyridamole, Prednisolone m2 1.30 g/m2/d 0% 1.73 m NS Good
(24 mo) (40) (40) (156) (-1)
Japan prednisolone Scr 49 2
µmol/l
Biopsy
Glomeruli
5.0 -0.4
showing nd
(3.1) (+11.5)
sclerosis
Glomeruli GFR 147
17.3 -15.6
showing Yoshikawa AZA, warfarin, ml/min/1.73 nd
24 mo 32 30 (19.1) (-18.2)
crescents 2006[90] dipyridamole, Prednisolone m2 1.30 g/m2/d 0% % Good
(24 mo) (40) (40)
Glomeruli Japan prednisolone Scr 49
showing µmol/l
5.2 +0.1
capsular nd
(3.6) (+1.4)
adhesion
s
Supplementary table 57. Evidence profile of RCTs examining MMF in biopsy-proven IgA nephropathy
applicability
Important
ESRD inconsistencies Low No difference for MMF vs. placebo Critical
(High) (58) (-1) (0) (0)
(-1)
Complete
0 RCTs -- -- -- -- -- -- -- High
remission
Partial
0 RCTs -- -- -- -- -- -- -- High
remission
Proteinuria 2 RCTs 72 Some limitations No Direct Sparse
Low No difference for MMF vs. placebo High
(categorical) (High) (37) (-1) inconsistencies (0) (-1)
Kidney Important
function inconsistencies Very Low No difference for MMF vs. placebo High
(High) (38) (-1) (0) (-1)
(categorical) (-1)
Proteinuria 2 RCTs 74 Some limitations No Direct Sparse
Low No difference for MMF vs. placebo Moderate
(continuous) (High) (41) (-1) inconsistencies (0) (-1)
ΔKidney Important
function inconsistencies Very Low No difference for MMF vs. placebo Moderate
(High) (41) (-1) (0) (-1)
(continuous) (-1)
106
Adverse events 3 RCTs Dose reduction due to side effects for MMF Moderate
(58)
No difference for MMF Low
Supplementary table 58. Meta-analyses and systematic reviews on MMF therapy for IgA nephropathy
Xu 2008[86] Included: only reports of RCTs that MMF 1.5-2.0 g/d (4 studies) Proteinuria (4 studies) 50% Decline Proteinuria: Is Eligibility criteria Yes
were conducted on adult humans and Control: steroids (1 study) and placebo Increase in Serum Creatinine Total events: 61 (MMF), 38 similar to the guideline
Database: which used MMF as the intervention. (3 studies) (3 studies) (control)
PubMed, Need for renal replacement RR 1.37 (0.79, 2.38)
Cochrane Excluded: Those that did not clearly (3 studies) 50% Increase in Scr: Total
(No language report the numbers of patients who events: 14 (MMF), 10
restriction) recovered, deteriorated or had renal- (control)
Search Dates: replacement treatment. RR 1.19 (0.62, 2.25) Are there any No
Until April 2008 Need for renal replacement limitations to
therapy: systematic review
Total events: 10 (MMF), 8 methodology
N Studies:
4 (control)
N Subjects: RR: 1.10 (0.46, 2.64) Is limitation to Yes
168 Authors advice against evidence clearly
routine use of MMF in IgAN addressed by the
authors
Smaller number of patients
Shorter duration of follow-up in a chronic disease condition
Both intervention and control groups received ACE-I
Studies are need to assess the effects of MMF alone or with ACE-I or ARBs
Individual study quality was rated using Jadad criteria of 5 items that ranged from 3-5
Comments
No serious side-effects noted from MMF therapy.

Treatment Baseline kidney Pooled
Author, Year Intervention Control Outcome (N intervention P-value I2
duration function/Proteinuria RR1(95% CI) P-value
group/ total N) Statistic
MMF 1.5-2.0 50% decline in 4 studies
Xu 2008[86] Steroids or placebo 1.37 (0.79, 2.38) 0.26 75.5% 0.007
g/d proteinuria (89/168)
50% Increase in 3 studies No data available in
18-36 mo the systematic 1.19 (0.62, 2.25 0.6 6.8% 0.34
SCr (58/106)
review 1.10 (0.46, 2.64) 0.83 0% 0.44
Comments: Both interventions and control groups used ACE-I
Supplementary table 59. Summary table of RCTs examining MMF in biopsy-proven IgA nephropathy (categorical outcomes)
No. Analyzed
(Enrolled)
Study, Year Outcome ACE-I or
Outcome GFR/SCr Proteinuria Events (%) P value Quality
Country measurement ARB use
(Treatment)
[Control]
ESRD
Frisch MMF 1000 Placebo 1000 Adjusted HR
2y 17 15 GFR 38 5 (29%)
ESRD 2005[28] mg 2x/d + mg 2x/d + 2.7 g/24hr Total 100% 1.74 NS Fair
(1 y) (17) (15) ml/min/1.73m2 [2 (13%)]
US ACE-I ACE-I 0.07–42.3
Placebo
MMF 2 g/d,
lactose cap,
Cumulative % Maes (<5 g NaCl/d),
3y (<5 g NaCl/d), 21 13 GFR 73 Total 89%
free of death 2004[52] ACE-I (aimed 1.9 g/d -- NS Fair
(3 y) ACE-I (aimed (21) (13) ml/min/1.73 m2 100%139 [92%]
or ESRD Belgium BP 125/75
BP 125/75
mmHg)
mmHg)
6y 2 (10%) RR 0.22
ESRD MMF 2 g/d 0.015 Fair
(6 mo) ACE-I or ARB [9 (45%)] (0.05- 0.90)140
Tang 2005, ACE-I or ARB
18 mo for target BP 20 20 GFR 75 1 (5%) RR 0.33 NS
2010[79;80] for target BP 1.8 g/d Total 100% Fair
Doubling of (6 mo) <125/85 (20) (20) ml/min/1.73 m2 [3 (15%)] (0.04-2.94) (0.323)
Hong Kong <125/85
SCr or ESRD 6y mmHg 3 (15%) RR 0.30
mmHg 0.037 Fair
(6 mo) [10 (50%)] (0.10-0.93)
Kidney Function
Adjusted HR
5 (29%)
↑SCr 50% 1.62 NS
Frisch MMF 1000 Placebo 1000 [2 (13%)]
2y 17 15 GFR 38 (0.07–35.6)
2005[28] mg 2x/d + mg 2x/d + 2.7 g/24hr Total 100% Fair
(1 y) (17) (15) ml/min/1.73m2 Adjusted HR
US ACE-I ACE-I 10 (59%)
↑SCr 0.5 mg/dl 2.84 NS
[7 (47%)]
(0.6–14.6)
↓Inulin Placebo
MMF 2 g/d, 33%
clearance ≥ lactose cap, nd NS
Maes (<5 g NaCl/d), [15%]
25% 3y (<5 g NaCl/d), 21 13 GFR 73 Total
2004[52] ACE-I (aimed 1.9 g/d Fair
(3 y) ACE-I (aimed (21) (13) ml/min/1.73 m2 100%141
Belgium BP 125/75 14%
↑SCr ≥ 50% BP 125/75 nd NS
mmHg) [0 (0%)]
mmHg)
Proteinuria
139 Higher doses of ACE-I in the MMF group

No. Analyzed
(Enrolled)
Outcome GFR/SCr Proteinuria Events (%) P value Quality
Country measurement ARB use
(Treatment)
[Control]
Frisch MMF 1000 Placebo 1000
↓24 h protein 2y 17 15 GFR 38 3 (18%) RR 1.32 NS
2005[28] mg 2x/d+ mg 2x/d + 2.7 g/24hr Total 100% Fair
excretion 50% (1 y) (17) (15) ml/min/1.73m2 [2 (13%)] (0.25-6.88)142 (0.739)
US ACE-I ACE-I
MMF 2 g/d
ACE-I or ARB
Tang ACE-I or ARB
Remission of 18 mo for target BP 20 20 GFR 75 16 (80%) RR 2.67
2005[79] for target BP 1.8 g/d Total 100% 0.006 Fair
proteinuria (6 mo) <125/85 (20) (20) ml/min/1.73 m2 [6 (30%)] (1.32-5.39)143
Hong Kong <125/85
mmHg
mmHg
Adverse Event
Frisch MMF 1000 Placebo 1000
Treatment 2y 17 15 GFR 38 2 (11%) RR 0.88 NS
2005[28] mg 2x/d+ mg 2x/d + 2.7 g/24hr Total 100% Fair
discontinuation (1 y) (17) (15) ml/min/1.73m2 [2 (13%)] (0.14-5.52)144 (0.894)
US ACE-I ACE-I
MMF 2 g/d
ACE-I or ARB
MMF dose Tang ACE-I or ARB Anemia (n=3)
18 mo for target BP 20 20 GFR 75
adjustment 2005[79] for target BP 1.8 g/d Total 100% Diarrhea (n=1) -- nd Fair
(6 mo) <125/85 (20) (20) ml/min/1.73 m2
due to AE Hong Kong <125/85 Infection (n=3)
mmHg
mmHg
Discontinuation
of MMF due to
TB (n=1)
Dose reduction
due to anemia
Placebo
MMF 2 g/d, (n=2)
lactose cap,
Maes (<5 g NaCl/d), Transient
3y (<5 g NaCl/d), 21 13 GFR 73 Total
Adverse event 2004[52] ACE-I (aimed 1.9 g/d leucopenia -- nd Fair
(3 y) ACE-I (aimed (21) (13) ml/min/1.73 m2 100%145
Belgium BP 125/75 (n=1)
BP 125/75
mmHg) [Placebo
mmHg)
pregnancy
uneventful n=1
Rectal
carcinoma
n=1)

Supplementary table 60. Summary table of RCTs examining MMF in biopsy-proven IgA nephropathy (continuous outcomes)
Duration No. Analyzed
Description Results
Outcome (Enrolled) ACE-I
Study, Yea
Outcome measuremen GFR/SCr Proteinuria or ARB Baseline ∆ P value Quality
r Country Interventio
t Intervention Control Control use Units Intervention Intervention
n
Proteinuria
18 mo MMF 2 g/d 1.8 -0.66
ACE-I or ARB 0.009 Fair
Tang 2005 (6 mo) ACE-I or ARB GFR 75 (1.87) (+0.53)
Mean urine for target BP 20 20 Total
2010[79;80] for target BP ml/min/1.73 1.8 g/d g/d
protein loss 2y - 6 y <125/85 (20) (20) 100% 1.8
Hong Kong <125/85 m2 nd NS Poor
(6 mo) mmHg (1.87)
mmHg
Placebo
MMF 2 g/d,
lactose cap,
Maes (<5 g NaCl/d), GFR 73 Total
∆Proteinuri 3y (<5 g NaCl/d), 21 13 1.9 -0.3
2004[52] ACE-I (aimed ml/min/1.73 1.9 g/d 100% g/d NS Fair
a (3 y) ACE-I(aimed (21) (13) 1.3 (-0.3)
Belgium BP 125/75 m2 146
BP 125/75
mmHg)
mmHg)
SCr/GFR/CrCl
Annualized Placebo
MMF 2 g/d, 1.46 +0.11
median lactose cap, mg/dl/y NS
Maes (<5 g NaCl/d), GFR 73 Total (1.39) (+0.05)
∆SCr 3y (<5 g NaCl/d), 21 13
2004[52] ACE-I (aimed ml/min/1.73 1.9 g/d 100% Fair
(3 y) ACE-I (aimed (21) (13)
∆Inulin Belgium BP 125/75 m2 147 ml/min/1. 73 -13
BP 125/75 NS
clearance mmHg) 73 m2 (69) (-2)
mmHg)
Annual
18 mo 1.53 -0.013
rates of MMF 2 g/d mg/dl/yr NS
(6 mo) ACE-I or ARB (1.65) (+0.108)
∆SCr Tang 2005 ACE-I or ARB GFR 75
for target BP 20 20 Total
2009[79;80] 18 mo for target BP ml/min/1.73 1.8 g/d -3.76 Good
Annual <125/85 (20) (20) 100% NS
Hong Kong (6 mo) <125/85 m2 ml/min/1. 75 (-1.0)
rates of mmHg
6y mmHg 73 m2 (69) -1.125
∆CrCl 0.021
(6 mo) (-3.812)

Supplementary table 61. Evidence profile of RCTs examining omega-3 fatty acid treatment in IgA nephropathy
applicability*
No important
ESRD inconsistencies Low Benefit of purified omega-3 fatty acid Critical
(High) (69) (-1) (-1) (0)
(0)
Proteinuria 1 RCT 30 Some limitations Some uncertainty Sparse
N/A Very low Benefit of purified omega-3 fatty acid High
(categorical) (High) (15) (-1) (-1) (-1)
Kidney Important
function inconsistencies Very low Possible benefit of omega-3 fatty acid High
(High) (99) (-1) (-1) (0)
(categorical) (-1)
No important
∆Proteinuria 5 RCTs 240 Some limitations Some uncertainty None
inconsistencies Low Possible benefit of omega-3 fatty acid Moderate
(continuous) (High) (127) (-1) (-1) (0)
(0)
ΔKidney Important
Function inconsistencies Very low Possible benefit of omega-3 fatty acid Moderate
(High) (144) (-1) (-1) (0)
(continuous) (-1)
Adverse events 0 RCTs -- -- -- -- -- -- -- Moderate
Benefit of omega-3 fatty acid Low to very low
* Generalizability was evaluated with regard to optimized therapy of proteinuria and hypertension with angiotensin converting enzyme (ACE-I) or angiotensin receptor blockage (ARB)
Supplementary table 62. Meta-analyses and systematic reviews on fish oil treatment in IgA nephropathy
Strippoli 2003[76] RCTs and quasi RCTs evaluating the Fish oil (3 studies) Deterioration in kidney Fish oils are not beneficial Is Eligibility criteria similar yes
effects of different treatment function: 50% increase in in IgA nephropathy. to the guideline
Database: regimens for IgA nephropathy on serum creatinine level from
Medline, EMBASE, kidney function and proteinuria baseline value or serum
Cochrane Renal creatinine level >1.5 mg/dl
Registry [132.6 µmol/l] at end of
Search Dates: treatment or reaching Are there any limitations no
Until 2002 ESRD requiring dialysis to systematic review
therapy or transplantation at methodology
N Studies: any time during treatment
Total 10 Daily proteinuria: grams of
Fish oil 3 protein per 24 hours
N Subjects: Is limitation to evidence yes
Fish oil 87 clearly addressed by the
authors
Suboptimal reporting of quality of individual trials
Language restrictions may have limited the results
Inclusion of RCTs and peer reviewed publication may have led to conclusions contrary to the evidence based recommendations published in 1997, and
1999.
¥ Only data for the fish oil intervention is extracted. For steroids and Immunosuppressive agents, more recent/comprehensive review by Samuels 2004 is selected.

Weighted mean Baseline kidney Pooled
Author, Year, RefID Intervention Control Outcome (N intervention P-value I2
Follow-up function/Proteinuria RR1(95% CI) P-value
None/ corn 2 1 study: normal or 0.63
Strippoli 2003[76]¥ Fish oil Kidney function NS nd 0.09
oil/olive oil (60/120) impaired SCr (but (0.30, 1.31)
Study Years : until None/ corn 3 <4.0 mg/dl) or WMD −0.12
Fish oil SCr NS nd 0.01
2002 oil/olive oil (47/92) absence and (−0.50, 0.25)
presence of
proteinuria
20.7 mo
1 study: SCr <3.0
None/ corn oil/ 2 mg/dl or daily WMD −0.57
Fish oil Proteinuria NS nd 0.09
olive oil (Total 137) proteinuria >1 g (−1.59, 1.45)
1 study: Daily
proteinuria
>0.5 g
¥ Only data for the fish oil intervention is extracted. For steroids and Immunosuppressive agents, more recent/comprehensive review by Samuels 2004 is selected.
Supplementary table 63. Summary table of RCTs examining omega-3 fatty acids in biopsy-proven IgA nephropathy (categorical outcomes)
Study, Year Outcome ACE-I or Events (%)
Country measurement Intervention Control Intervention Control ARB use Intervention RR/OR/HR
ESRD
Purified Supportive
Alexopoulos
4y omega-3 therapy 14 14 SCr 2.2 mg/dl 61% 1 (7%) RR 0.15 NS
ESRD 2004[2] 2.0 g/d Fair
(4 y) fatty acids (not (18) (16) GFR 48 ml/min [31%] [6 (43%)] (0.02-1.10)148 (0.062)
Greece
3g/d described)
Fish oil 12 g, Olive oil
Cumulative % Donadio ACE-I for ACE-I for GFR 82 RR 0.33
2y 55 51 Total 5 (10%)
of death or 1994[20] target BP target BP ml/min/1.73m2 2.5 g/d (0.13- 0.022 Fair
(2 y) (55) (51) 61% [14 (40%)]
ESRD Multicenter 140/85 140/85 SCr 1.4 mg/dl 0.85)149
mmHg mmHg
Proteinuria
Purified 11 (73%) RR 0.92 NS
%↓Proteinuria Fair
omega-3 fatty [2 (11%)] (0.62-1.36)150 (0.667)
Ramipril 10
Ferraro acids 3 g/d,
6 mo mg/d, 15 15 Total
2009[25] ramipril 10 GFR 91 ml/min 1.3 g/d
↓Proteinuria (6 mo) irbesartan (15) (15) 100% 12 (80%) RR 4.0
Italy mg/d, 0.002 Fair
≥50% 300 mg/d [3 (20%)] (1.4-11.3)
irbesartan
300 mg/d
Kidney Function
Purified Supportive 1 (7%) RR 0.15 NS
↑SCr >50% Alexopoulos Fair
4y omega-3 therapy 14 14 SCr 2.2 mg/dl 61% [6[43%]] (0.02-1.10)151 (0.077)
2004[2] 2.0 g/d
(4 y) fatty acids 3 (not (18) (16) GFR 48 ml/min [31%] 1 (7%) RR 0.13
↓GFR <50% Greece 0.041 Fair
g/d described) [7 (50%)] (0.02-0.92)152
30 29 GFR 109 8 (19%) HR 1.3
↓CrCl <60% Hogg 2.1 g/d NS Good
3y (30) (29) ml/min/1.73 m2 53% [4 (9%)] (0.4, 4.5)
2006[35] Fish oil 4 g/d Placebo
↓CrCl <60% (2 y) 23 13 [48%] 6 (24%) RR 1.70 NS
US, Canada nd UP/C 1-3 Fair
SUBGROUP (23) (13) [2 (16%)] (0.40-7.22)153 (0.438)
Donadio ACE-I for ACE-I for GFR 82
2y 55 51 Total 3 (6%) RR 0.20
↑Scr ≥50% 1994[20] target BP target BP ml/min/1.73m2 2.5 g/d 0.008 Fair
(2 y) (55) (51) 61% [14 (33%)] (0.06-0.65)154
Multicenter 140/85 140/85 SCr 1.4 mg/dl
mmHg mmHg

Supplementary table 64. Summary table of RCTs examining omega-3 fatty acids in biopsy-proven IgA nephropathy (continuous outcomes)
No. Analyzed
(Enrolled)
Country measurement Interventio Interventio ARB use
Control Control Units Intervention Intervention
(Treatment) n n
(Control) (Control)
Proteinuria
Purified Supportive SCr 2.2 2.0 -1.2
Proteinuria Alexopoulos nd Fair
4y omega-3 therapy 14 14 mg/dl 61% (1.6) (-0.7)
2004[2] 2.0 g/d g/d
Annual (4 y) fatty acids 3 (not (18) (16) GFR 48 [31%] 2.0 -0.70
Greece <0.04 Fair
∆proteinuira g/d described) ml/min (1.6) [-0.19]
Purified
omega-3
Ramipril 10
Ferraro fatty acids 3
6 mo mg/d, 15 15 GFR 91 Total 1.3 -9.4
UPE 2009[25] g/d, ramipril 1.3 g/d g/d <.001 Fair
(6 mo) irbesartan (15) (15) ml/min 100% (1.5) (-0.9)
Italy 10 mg/d,
300 mg/d
irbesartan
300 mg/d
Hogg GFR 109
2y 30 29 53% 2.1 NS
UPCR 2006[35] Fish oil 4 g/d Placebo ml/min/1.7 2.1 g/d -- nd Poor
(2 y) (30) (29) [48%] (1.4) (0.10)
US, Canada 3 m2
GFR 82
Median Donadio ACE-I for ACE-I for
2y 55 51 ml/min/1.7 2.5 -0.23 (-15%)
annual 1994[20] target BP target BP 2.5 g/d Total 61% g/d NS Fair
(2 y) (55) (51) 3m2 SCr 3.2 (-0.10 (-7%)
∆UPE Multicenter 140/85 140/85
1.4 mg/dl
mmHg mmHg
Cr-EDTA
Pettersson,
6 mo Corn oil 6 15 17 63 40% 1.8 -0.1
∆Proteinuria 1994[61] Fish oil 6 g 1.8 g/d g/d NS Fair
(6 mo) g (15) (17) ml/min/1.7 [59%] (2.0) (-0.2)
Sweden
3m2
Kidney Function
2.2 +0.1
SCr nd Fair
(2.8) (+3.1)
mg/dl
Purified Supportive SCr 2.2 2.2 0.2
Annual ∆SCr Alexopoulos <0.01 Fair
4y omega-3 therapy 14 14 mg/dl 61% (2.8) [0.1]
2004[2] 2.0 g/d
(4 y) fatty acids 3 (not (18) (16) GFR 48 [31%] 46 -5
GFR Greece nd Fair
g/d described) ml/min (45) (-11)
ml/min
Annual 46 -1.4
<0.001 Fair
∆GFR (45) [-3.0]
Purified
omega-3 fatty
Ramipril 10
Ferraro acids 3 g/d,
6 mo mg/d, 15 15 GFR 91 Total 91 +3.3 NS
eGFR 2009[25] ramipril 10 1.3 g/d ml/min Fair
(6 mo) irbesartan (15) (15) ml/min 100% (73) (-5.1) (0.1)
Italy mg/d,
300 mg/d
irbesartan
300 mg/d
Hogg GFR 109 0
2y 30 29 53% 0.9
SCr 2006[35] Fish oil 4 g/d Placebo ml/min/1.7 2.1 g/d mg/dl +0.2 nd Poor
(2 y) (30) (29) [48%] (0.8)
US, Canada 3 m2 +0.3
No. Analyzed
(Enrolled)
Country measurement Interventio Interventio ARB use
Control Control Units Intervention Intervention
(Treatment) n n
(Control) (Control)
Bennett
2y Fish oil 17 20 SCr 0.09 – 80 -23
CrCl 1989[7] No fish oil 1.3 – 2.5 g/d nd ml/min nd Poor
(2 y) 10g/d (17) (20) 0.2 mmol/l 76 (-21)
Australia
Annual Fish oil 12 g, Olive oil 1.4 +0.03
GFR 82 mg/dl 0.001
median ∆SCr Donadio ACE-I for ACE-I for (1.5) (+0.14)
2y 55 51 ml/min/1.7
Annual 1994[20] target BP target BP 2.5 g/d Total 61% Fair
(2 y) (55) (51) 3m2 SCr 1.4 ml/min/ 82 -0.3
median Multicenter 140/85 140/85 0.009
mg/dl 1.73m2 (81) (-7.1)
∆CrCl mmHg mmHg
131 +8
∆SCr µmol/l nd
Cr-EDTA (120) (+1)
Pettersson
6 mo Corn oil 6 15 17 63 40% 91 -12
∆CrCl 1994[61] Fish oil 6 g 1.8g/d ml/min <0.01 Fair
(6 mo) g (15) (17) ml/min/1.7 [59%] (99) (0)
Sweden
Annual rate 3m2 ml/min/ 63 -4
<0.05
↓GFR 1.73m2 (59) (-1)
Supplementary table 65. Meta-analyses and systematic reviews on antiplatelet therapy for IgA nephropathy
Taji 2006[78] Included: Studies of antiplatelet Dipyridamole (5) Level of proteinuria Antiplatelet agents Is eligibility criteria similar No (we only
intervention with a concurrent control Dilazep (1) Renal function (introduction resulted in reduced to the guideline include only
Database: group, Human adults, prospective Aspirin (1 study included both of RRT, creatinine proteinuria and protected RCTs for this
Medline, studies. Studies that used cytotoxic dipyridamole and aspirin) clearance, serum renal function in patients topic)
Cochrane, agents or steroids in both arms were Trimetazidine dihydrochloride (1) creatinine) with IgA nephropathy.
EMBASE, Ityu-shi included. Side effects Headache was reported in
(Japanese medical the dipyridamole group in
database) Excluded: Studies that did not clearly one study.
Search Dates: report data on the number of patients, Are there any limitations Yes
1970-2005 dialysis population, and those with to systematic review
cytotoxic agents or steroids in only one methodology
N Studies: arm.
7
N Subjects: Is limitation to evidence Yes

458 clearly addressed by the
authors
Suboptimal quality of individual controlled trials
Most studies did not assess true outcome of renal death
Long-term follow-up studies may yield different set of results
The effect of antiplatelet agents alone could not be discerned because patients received other concomitant therapies.

Mean Follow- Baseline Kidney Pooled
Author, Year, RefID Intervention Control Outcome (N intervention P-value I2
up function/Proteinuria RR1(95% CI) P-value
Any antiplatelet Placebo/no 5
Taji 2006 [78] Proteinuria 0.61 (0.39, 0.94) 0.03 nd 0.007
therapy treatment/carbazochrome (218/399)
Study Years : 1970- Any antiplatelet Placebo/no 6
Renal function 2 studies: Moderate 0.74 (0.63, 0.87) 0.0 nd NS
2005 therapy treatment/carbazochrome (161/261)
to severe stage (lab
Any antiplatelet Placebo/no 5 ARR 0.26
Proteinuria or biopsy diagnosis)
therapy treatment/carbazochrome (218/399) NNT 3.9
6-60 mo* 5 studies: Either
Any antiplatelet Placebo/no 6 ARR 0.18
Renal function UPE in the range of
therapy treatment/carbazochrome (161/261) NNT 5.4
1.1-2.0 g/d
Placebo/no 3 Or CCr 51-88 ml/min
Dipyridamole Proteinuria 0.50 (0.36, 0.69) 0.0 nd NS
treatment/carbazochrome (92/182)
Placebo/no 4
Dipyridamole Renal function 0.69 (0.52, 0.92) 0.01 nd 0.1
treatment/carbazochrome (75/155)
* Except for Yagami 1986 Tokai J Exp Clin Med, studies had a range 6-60 mo follow-up. Yagami 1986 had 3.4 mo follow-up
Supplementary table 66. Summary table of RCT examining immunosuppression and anti-platelets in biopsy-proven IgA nephropathy (categorical outcomes)
ESRD
Cyclophosphamide
Walker RR 0.54
5y 1-2 mg/kg/d, No 25 27 SCr 0.10 1 (4%) NS
ESRD 1990[83] 1.67 g/d (0.05- Fair
(2 y) dipyridamole 400 treatment (25) (27) mmol/l [2 (7%)] (0.605)
Australia 5.59)155
mg/d, warfarin
Adverse events
Amenorrhea
(n=1)
Cyclophosphamide Oligospermia
In Walker
5y 1-2 mg/kg/d, No 25 27 SCr 0.10 (n=1)
treatment 1990[83] 1.67 g/d -- nd Fair
(2 y) dipyridamole 400 treatment (25) (27) mmol/l Hematuria (n=1)
group Australia
mg/d, warfarin Hemiplegic
migrainous
episode (n=1)

Supplementary table 67. Summary table of RCT examining immunosuppression and anti-platelets in biopsy-proven IgA nephropathy (continuous outcomes)
Proteinuria
Cyclophospham
Walker ide 1-2 mg/kg/d,
5y No 25 27 SCr 0.10 1.67 -0.53
∆UPE 1990[83] dipyridamole 1.67 g/d g/d nd Fair
(2 y) treatment (25) (27) mmol/l (1.76) (+0.13)
Australia 400 mg/d,
warfarin
SCr/GFR/CrCl
Cyclophospham
Walker ide 1-2 mg/kg/d,
5y No 25 27 SCr 0.10 0.10 +.02
∆SCr 1990[83] dipyridamole 1.67 g/d mmol/l nd Fair
(2 y) treatment (25) (27) mmol/l (0.12) (+.01)
Australia 400 mg/d,
warfarin
Supplementary table 68. Summary table of RCT examining antiplatelet treatments in biopsy-proven IgA nephropathy (continuous outcomes)*
SCr/GFR/CrCl
Slope 1/cr v Slow release -0.088 -0.008
none NS
time plots aspirin 650 (0.001) (+0.0007)
Chan Vitamin
~3 y mg/d, 19 19 SCr 77 0.125 +0.073
SCr 1987[9] B 1.57 g mmol/l NS Fair
(nd) dipyridamole (19) (19) ml/min (0.13) (+0.069)
Hong Kong complex
25-75 mg 77 +1
CrCl ml/min NS
3x/d (73) (-1)
* Based on discussions with WGM, the only Medline indexed study was data extracted.
Supplementary table 69. Summary table of RCTs examining miscellaneous treatments in biopsy-proven IgA nephropathy (categorical outcomes)
Partial remission
Patients Yoshikawa GFR 130 RR 4.38
2y 46 48 21 (46%)
showing 1997[91] Sairei-to Control ml/min/1.73m2 0.39 g/d (1.80- <0.001 Fair
(2 y) (50) (51) [5 (10%)]
normal urine Japan SCr 0.59 mg/dl 10.65)156
Proteinuria
Urokinase
↓Urine Chen 100,000 IU i.v.
1y Benazepril 35 36 25 (71%) RR1.6
protein 2004[13] 10 d/mo, SCr 107 µmol/l 1.82 g/d 0.027 Fair
(1 y) 10 mg/d (35) (36) [16 (44%)] (1.05-2.45)157
≥50% China benazepril 10
mg/d
Kidney function
Urokinase
Chen 100,000 IU i.v.
1y Benazepril 35 36 0 (0%)
↑SCr ≥50% 2004[13] 10 d/mob SCr 107 µmol/l 1.82 g/d -- nd Fair
(1 y) 10 mg/d (35) (36) [3 (8%)]
China benazepril 10
mg/d

Supplementary table 70. Summary table of RCTs examining miscellaneous treatments in biopsy-proven IgA nephropathy (continuous outcomes)
Outcome
Study, Year Baseline ∆
Outcome measuremen GFR/SCr Proteinuria P value Quality
Country Intervention Control Intervention Control Units Intervention Intervention
t
(Control) (Control)
(Treatment)
Proteinuria
Urokinase
Chen 100,000 IU i.v.
Urine 1y Benazepril 35 36 1.82 -1.20
2004[13] 10 d/mo, SCr 107 µmol/l 1.82 g/d g/24h <0.05 Fair
protein (1 y) 10 mg/d (35) (36) (1.79) (-0.50)
China benazepril 10
mg/d
Kano Fluvastatin 20 mg, GFR 108 1.3
Urinary 1y Dipyridamol 15 15 g/24 h/1. 1.3 -0.2
2003[45] dipyridamole 5 ml/min/1.73 m2 g/24 h/1.73 NS Fair
protein (1 y) e 5 mg/kg (15) (15) 73 m2 (1.2) (+0.1)
Japan mg/kg SCr 47 µmol/l m2
Defibrotide
Prednisolon
Frasca 10mg/kg/d,
2y e 0.5 10 10 GFR 56 ml/min 1.0 -0.6
UPE 1997[27] prednisolone 0.5 1.0 g/d g/d 0.02 Poor
(2 y) mg/kg/altern (10) (10) SCr 1.84 mg/dl (0.7) (+0.2)
Italy mg/kg/alternate
ate day
day
SCr/GFR/CrCl
Urokinase 78.9 +2.9
CrCl ml/min <0.05
Chen 100,000 IU i.v. (81.6) (-10.0)
1y Benazepril 35 36
2004[13] 10 d/mo, SCr 107 µmol/l 1.82 g/d Fair
(1 y) 10 mg/d (35) (36) 107 -1.0
SCr China benazepril 10 µmol/l NS
(112) (+33.3)
mg/d
ml/min/1 107.9 +25.2
CrCl Kano Fluvastatin 20 mg, GFR 108 1.3 0.001
1y Dipyridamol 15 15 .73 m2 (113.2) (-2.7)
2003[45] dipyridamole 5 ml/min/1.73 m2 g/24 h/1.73 Fair
(1 y) e 5 mg/kg (15) (15) 46.9 -5.4
SCr Japan mg/kg SCr 47 µmol/l m2 µmol/l NS
(45.1) (+3.5)
Defibrotide ml/min/1 56 +14%
%∆GFR Prednisolon 0.003
Frasca 10mg/kg/d, .73m2 (64) (-12%)
2y e 0.5 10 10 GFR 56 ml/min
1997[27] prednisolone 0.5 1.0 g/d Poor
(2 y) mg/kg/altern (10) (10) SCr 1.84 mg/dl 1.8 -14%
%∆SCr Italy mg/kg/alternate mg/dl 0.007
ate day (1.7) (+9%)
day
Supplementary table 71. Evidence profile of RCTs of MMF vs. Cyc for induction therapy in lupus nephritis
(treatment) across studies generalizability/ considerations Quality of evidence for Qualitative and quantitative Importance of
study design per outcome outcome description of effect outcome
applicability
No important
Mortality inconsistencies Moderate No difference Critical
(High) (307) (-1) (0) (0)
(0)
No important
2 RCTs 184 Some limitations Direct Imprecision
ESRD inconsistencies Low No difference Critical
(High) (90) (-1) (0) (-1)
(0)
Important
Remission inconsistencies Low Possible benefit for MMF158 High
(High) (340) (-1) (0) (0)
(-1)
Relapse NA Moderate No difference High
(High) (71) (0) (0) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Kidney
(categorical)
No important
ΔProteinuria 4 RCTs 152 Some limitations Direct None
inconsistencies/ Moderate No difference Moderate
(continuous) (High) (123) (-1) (0) (0)
(0)
function inconsistencies Moderate No difference Moderate
(High) (123) (-1) (0) (0)
(continuous) (0)
6 RCTs 683 More alopecia and infections with
(High) (340) cyclophosphamide.
No difference Low
158 Four of the 6 trials showed no benefit with MMF for complete remission when used for induction therapy. Two trials show increased probability of complete remission with MMF. Three of the 4
trials did not show a benefit with MMF for partial remission when used for induction therapy. One trial showed MMF is more likely to induce partial remission.
Supplementary table 72. Summary table of RCTs examining MMF vs. i.v. Cyc for induction therapy in patients with lupus nephritis (categorical outcomes)
Mortality
Appel White 40% RR 1.76
6 mo 184 180 9 (5%) NS
Death 2009[3] MMF i.v. Cyc SCr 1.1 mg/dl 4.1 g/d Asian 33% (0.60- Good
(6 mo) (185) (185) [5 (3%)] (0.29)
Multicenter Other 27% 5.15)159
Wang
6 mo 9 11 0 (0%)
Death 2007[85] MMF i.v. Cyc SCr 1.65 mg/dl 4.7 g/24h nd -- NS Poor
(6 mo) (9) (11) [0 (0%)]
China
RR 0.49
6 mo Black 61% 4 (6%)
Ginzler (0.15-1.54) nd Good
(6 mo) 71 69 White 17% [8 (3%)]
Death 2005[29] MMF i.v. Cyc SCr 1.06 mg/dl 4.1 g/d 160
(71) (69) Hispanic 14%
US 36 mo 4 (6%) RR 0.48
Asian 8% nd Good
(6 mo) [8 (11%)] (0.15-1.60)
6 mo 0 (0%)
-- NS Fair
Ong (6 mo) Malaysian 42% [0 (0%)]
19 25 SCr 96.5 µmol/l
Death 2005[60] MMF i.v. Cyc 1.8 g/d Chinese 53% RR 1.32
36 mo (26) (28) GFR 97 ml/min 1 (6%) NS
Malaysia Indian 5% (0.09-19.71) Fair
(6 mo) [1 (6%)] 161 (0.88)
El-Shafey SCr 132 µmol/l
6 mo 24 23 0 (0%)
Death 2010[24] MMF i.v. Cyc GFR 73.8 1.98.g/d Egyptian 100% -- nd Good
(6 mo) (24) (23) [1 (4%)]
Egypt ml/min
RRT
Black 61%
Ginzler
36 mo 71 69 White 17% 4 (6%) RR 0.53
Renal failure 2005[29] MMF i.v. Cyc SCr 1.06 mg/dl 4.1 g/24h nd Fair
(6 mo) (71) (69) Hispanic 14% [7 (10%)] (0.15-1.81)
US
Asian 8%
Ong Malaysian 42%
6 mo 19 25 SCr 96.5 µmol/l 1 (4%)
ESRD 2005[60] MMF i.v. Cyc 1.8 g/d Chinese 53% -- nd Fair
(6 mo) (26) (28) GFR 97 ml/min [0 (0%)]
Malaysia Indian 5%
Remission
Appel White 40% RR 1.07
Complete 6 mo 185 185 16 (9%)
2009[3] MMF i.v. Cyc SCr 1.1 mg/dl 4.1 g/d Asian 33% (0.54-2.09) nd Good
remission (6 mo) (185) (185) [15 (8%)]
Multicenter Other 27% 162
Complete 6 mo 4 (44%)
-- 0.026 Poor
remission (6 mo) [0 (0%)]
Partial Wang 3 mo 4 (44%)
9 11 -- 0.026 Poor
remission 2007[85] (6 mo) MMF i.v. Cyc SCr 1.65 mg/dl 4.70 g/24h nd [0 (0%)]
(9) (11)
China RR 0.81
Partial 6 mo 2 (22%)
(0.19-3.87) nd Poor
remission (6 mo) [3 (27%)] 163

RR 0.98
Complete 24 (73%)
Chan (0.74-1.30) NS Fair
remission 6 mo 32 30 SCr 1.28 mg/dl [23 (74%)]
2005[12] MMF Cyc 5.32 g/24h nd 164
(6 mo) (33) (31) GFR 72 ml/min
Partial China 24%
-- NS Fair
remission [23%]
Ong Malaysian 42% RR 2.19
Complete 6 mo 19 25 SCr 96.5 µmol/l 5 (26%) NS
2005[60] MMF i.v. Cyc 1.8 g/d Chinese 53% (0.60-8.06) Fair
remission (6 mo) (26) (28) GFR 97 ml/min [3 (12%)] (0.22)
Malaysia Indian 5% 165
RR 3.89
Complete 16 (23%)
Black 61% (1.37-11.05) nd Good
remission Ginzler [4 (6%)]
6 mo 71 69 White 17% 166
2005[29] MMF i.v. Cyc SCr 1.06 mg/dl 4.1g/d
(6 mo) (71) (69) Hispanic 14% RR 1.20
Partial US 21 (30%)
Asian 8% (0.69-2.07) nd Good
remission [17 (25%)] 167
RR 1.15
Complete 6 (25%) NS
(0.41-3.25) Good
remission El-Shafey SCr 132 µmol/l [5 (23%)] (0.53)
6 mo 24 23 168
2010[24] MMF i.v. Cyc GFR 73.8 1.98.g/d Egyptian 100%
(6 mo) (24) (23) RR 1.10
Partial Egypt ml/min 8 (33%) NS
(0.47-2.35) Good
remission (7 (30%)] 169 (0.54)
Relapse
Black 61%
First renal flare Ginzler
36 mo 71 69 White 17% 8 (11%) RR 0.98
after induction 2005[29] MMF i.v. Cyc SCr 1.06 mg/dl 4.1 g/24h nd Fair
(6 mo) (71) (69) Hispanic 14% [8 (11%)] (0.37-2.61)
therapy US
Asian 8%
Adverse Events
126 (69%) NS
Infections -- Good
[111 (62%)] (0.17)
Appel White 40% 61%
GI disorders 6 mo 185 185 -- nd Good
2009[3] MMF i.v. Cyc SCr 1.1 mg/dl 4.1 g/d Asian 33% [67%]
(6 mo) (185) (185)
Multicenter Other 27% RR 0.31
20 (11%)
Alopecia (0.20-0.49) nd Good
[64 (40%)] 170
Ginzler Black 61% RR 0.16

Severe 6 mo 71 69 1 (1%)
2005[29] MMF i.v. Cyc Scr 1.06 mg/dl 4.1 g/d White 17% (0.02-1.31) nd Good
infections (6 mo) (71) (69) [6 (9%)]
US Hispanic 14% 171

Pyogenic Asian 8%
nd RR 0.36 0.03 Good
infections
0 (0%)
Amenorrhea -- nd Good
[2 (3%)]
0 (0%)
Alopecia -- nd Good
[8 (11%)]
RR 0.62
18 (22%)
Lymphopenia (0.38-1.02) nd Good
[28 (37%)] 172
37% NS
Leukopenia -- Fair
[52%] (0.32)
Oligo- 0 (0%)
-- nd Fair
menorrhea Ong Malaysian 42% [1 (4%)]
6 mo 19 25 SCr 96.5 µmol/l
Pneumonia/ 2005[60] MMF i.v. Cyc 1.8 g/d Chinese 53% 3 (16%)
(6 mo) (26) (28) GFR 97 ml/min -- NS Fair
septicemia Malaysia Indian 5% [3 (12%)]
GI AE,
0.08 NS
episodes/pt. -- Fair
[0.07] (0.68)
mo
RR 0.17
1 (11%)
Herpes zoster (0.03- 0.025 Poor
[7 (64%)]
1.17)173
Wang 0 (0%)
Leukopenia 6 mo 9 11 -- nd Poor
2007[85] MMF i.v. Cyc SCr 1.65 mg/dl 4.70 g/24h nd [2 (18%)]
(6 mo) (9) (11)
China 0 (0%)
GI symptoms -- nd Poor
[3 (27%)]
0 (0%)
Elevated LFTs -- nd Poor
[1 (9%)]
RR 0.60
6 (26%)
GI symptoms (0.26-1.38) nd Poor
[10 (44%)] 174
Hu 2002[40] 6 mo 23 23 RR 0.57
MMF Cyc SCr 178.9 µmol/l 3.88 g/d nd 4 (17%)
Infection China ( 6 mo) (23) (23) (0.19-1.69) nd Poor
[7 (30%)] 175
0 (0%)
Leukopenia -- nd Poor
[2 (9%)]
El-Shafey SCr 132 µmol/l RR 0.96
Severe 6 mo 24 23 2 (8%)
2010[24] MMF i.v. Cyc GFR 73.8 1.98.g/d Egyptian 100% (0.15- nd Good
infections (6 mo) (24) (23) [2 (9%)]
Egypt ml/min 6.25)176

RR 1.28
4 (17%)
Leukopenia (0.32-
[3 (13%)]
5.10)177
RR 2.40
5 (21%)
Diarrhea (0.52-
[2 (9%)]
11.14)178

Supplementary table 73. Summary table of RCTs examining MMF vs. i.v. Cyc for induction therapy in patients with lupus nephritis (continuous outcomes)
Proteinuria
Wang
6 mo 9 11 4.7 1.35
Proteinuria 2007[85] MMF i.v. Cyc SCr 1.65 mg/dl 4.70 g/24h nd g/24h 0.001 Poor
(6 mo) (9) (11) (3.6) (2.2)
China
Black 61%
Ginzler White 17%
6 mo 71 69 4.1 2.03
Urine protein 2005[29] MMF i.v. Cyc Scr 1.06 mg/dl 4.1 g/24h Hispanic g/24 h nd Fair
(6 mo) (71) (69) (4.4) (1.46)
US 14%
Asian 8%
Malaysian
Ong
6 mo 19 25 SCr 96.5 µmol/l 42% 1.8 1.1
∆Proteinuria 2005[60] MMF i.v. Cyc 1.8 g/24h g/24h 0.04 Fair
(6 mo) (26) (28) GFR 97 ml/min Chinese 53% (3) (1.9)
Malaysia
Indian 5%
El-Shafey
6 mo 24 23 SCr 132 µmol/l Egyptian 1.98 1.30 NS
Proteinuria 2010[24] MMF i.v. Cyc 1.98.g/d g/d Good
(6 mo) (24) (23) GFR 73.8 ml/min 100% (2.09) (1.37) (0.82)
Egypt
SCr/GFR/CrCl
Wang
6 mo 9 11 1.65 1.38
SCr 2007[85] MMF i.v. Cyc SCr 1.65 mg/dl 4.70 g/24h nd mg/dl NS Poor
(6 mo) (9) (11) (0.94) (0.85)
China
Black 61%
Ginzler White 17%
6 mo 71 69 1.06 0.91
SCr 2005[29] MMF i.v. Cyc Scr 1.06 mg/dl 4.1 g/24h Hispanic mg/dl nd Fair
(6 mo) (71) (69) (1.08) ( 0.85)
US 14%
Asian 8%
Malaysian
Ong
6 mo 19 25 SCr 96.5 µmol/l 42% 96.5 109.5
SCr 2005[60] MMF i.v. Cyc 1.8 g/d µmol/l NS Fair
(6 mo) (26) (28) GFR 97 ml/min Chinese 53% (64) (94.4)
Malaysia
Indian 5%
El-Shafey
6 mo 24 23 SCr 132 µmol/l Egyptian 73.8 29.4 NS
eGFR 2010[24] MMF i.v. Cyc 1.98.g/d ml/min Good
(6 mo) (24) (23) GFR 73.8 ml/min 100% (69.1) (20.0) (0.16)
Egypt
Supplementary table 74. Existing systematic review on Cyc vs. AZA for induction treatment in patients with lupus nephritis
Flanc 2004[26] RCTs and quasi-RCTs comparing Trials with the following treatment Dichotomous: Induction with Cyclophosphamide Is eligibility Yes, included
treatments for proliferative lupus options were considered: 1. All cause mortality; and steroids is probably an criteria similar RCTs
Date Base: nephritis in both adult and pediatric 1. corticosteroids - including 2. ESRD (need for RRT) acceptable therapy as there is to the guideline
1. Cochrane patients with biopsy proven Class III, prednisolone, prednisone and 3. Doubling of Scr more data on cyclophosphamide
Central IV, Vc, Vd lupus nephritis were methyl-prednisolone 4. Stable renal function - <20% as an induction agent. Lack of
Register of included. 2. other immunosuppressive worsening of Scr data on other agents and the lack
Controlled All treatments were considered. agents - including Azathioprine, 5. Deterioration of renal function - of direct comparison of
Trials cyclophosphamide, MMF and >20% worsening of Scr azathioprine to
2. Medline and cyclosporine 6. Relapse of LN. cyclophosphamide make it
preMedline 3. plasma exchange or Toxicity: difficult to recommend other
3. Embase plasmapheresis; 1. major infection rate (all cause agents until further research
Search Dates: 4. Other agents (e.g. infection excluding HSV) becomes available. Given the risk Are there any No
CENTRAL - immunoglobulins). 2. HSV infection of infertility, it is reasonable that limitations to
issue 2, 2003 5. Non-specific treatment options 3. Ovarian failure the minimal effective cumulative systematic
1966 -2003 (e.g. antihypertensive 4. Bone toxicity ( avascular dose of cyclophosphamide be review
1980- 2003 agents)were not included in the necrosis or fracture) used. It is not possible to be more methodology
N Studies: present analysis as these do 5. bladder toxicity (haemorrhagic specific about optimal dosing
25 not specifically relate to LN but cystitis) schedules. Based on this review
more broadly to preventing the 6. Development of malignancy. plasma exchange cannot be
N Subjects: progression of CKD Remission of proteinuria according to recommended. Is limitation to Yes
915 the definitions of Chan 2000: evidence
complete remission: urinary protein clearly
excretion <0.3g/24 h. addressed by
Continuous outcomes : the authors
1. Scr (µmol/l)
2. CrCl (ml/min);
3. 24 h urinary protein excretion)
(g/24 h);
Trial quality varied greatly amongst RCTs. The small size of many of the included trials causes this analysis to have small numbers overall. Subjects
Description of limitations of evidence by authors differed between studies. The severity of renal impairment and the proportion of patients with Class IV LN differed amongst trials. Whilst some RCTs had
very long periods of follow-up, others were much shorter and inadequately powered to detect events.

Author, Year, RefID Intervention Control Outcome (N intervention Pooled OR (95% CI) P-value
group/ total N)
Flanc 2004[26] Mortality
Study Years: Cyc AZA All cause mortality 1 (38/57) 0.79 [ 0.36, 1.70 ] 0.5 NA NA
1966-2003 ESRD/ Doubling of Scr
ESRD 1 (38/57) 0.42 [ 0.15, 1.19] 0.1
Doubling of Scr 1 (38/57) 0.56 [ 0.26, 1.22 ] 0.1
Cyc AZA NA NA
Stable renal function 1 (38/57) 1.32 [ 0.86, 2.01 ] 0.2
Deterioration of renal function 1 (20/30) 0.67 [ 0.18, 2.42] 0.5
Adverse events
Major infection 1 (38/57) 1.25 [ 0.27, 5.86] 0.8
Herpes Zoster 1 (38/57) 2.75 [ 0.68, 11.18] 0.2
Cyc AZA Ovarian failure 1 (27/45) 3.33 [ 1.12, 9.88 ] 0.03 NA NA
Bladder toxicity 1 (38/57) 3.59 [ 0.19, 66.14 ] 0.4
Malignancy 1 (38/57) 0.75 [ 0.14, 4.12] 0.7
Supplementary table 75. Summary table of RCT examining Cyc vs. AZA for induction treatment in patients with lupus nephritis (categorical outcomes)
Mortality
Grootscholten
6y 50 37 SCr 112 µmol/l 2 (4%) RR 0.49 NS
Death 2006[30] Cyc AZA 4.3 g/24h White 70% Fair
(2 y) (50) (37) GFR 65 ml/min [3 (8%)] (0.09-2.81) (0.426)
Netherlands
ESRD/ Doubling of Scr
0 (0%)
ESRD Grootscholten -- nd
6y 50 37 SCr 112 µmol/l [1 (3%)]
2006[30] Cyc AZA 4.3 g/24h White 70% Fair
(2 y) (50) (37) GFR 65 ml/min 2 (4%) RR 0.25 NS
Doubling of SCr Netherlands
[6 (16%)] (0.05–1.15) (0.075)
Remission
Grootscholten
2y 50 37 SCr 112 µmol/l
Remission 2006[30] Cyc AZA 4.3 g/24h White 70% *nd nd NS Fair
(2 y) (50) (37) GFR 65 ml/min
Netherlands
Relapse
Grootscholten
6y 50 37 SCr 112 µmol/l 2 (4%) RR 0.15
Renal relapse 2006[30] Cyc AZA 4.3 g/24h White 70% 0.010 Fair
(2 y) (50) (37) GFR 65 ml/min [10 (27%)] (0.03-0.64)
Netherlands
Adverse events
Premature 6y 2 (4%) RR 0.74 NS
ovarian failure (2 y) [2 (5%)] (0.03-0.64) (0.758)
Infection rate
18
(events/100 -- nd
[37]
patient y) Grootscholten
50 37 SCr 112 µmol/l
Herpes zoster 2006[30] Cyc AZA 4.3 g/24h White 70% Fair
2y (50) (37) GFR 65 ml/min 3
(events/100 Netherlands -- nd
(2 y) [12]
patient y)
Hospital
RR 1.1
admission for nd NS
(0.6–2.0)
infections
*Only Kaplan Meier curves showing cumulative incidence of partial and complete remission
Supplementary table 76. Summary table of RCT examining Cyc vs. AZA for induction treatment in patients with lupus nephritis (continuous outcomes)
Outcome Interventio GFR/SCr Proteinuria Race P value Quality
Country measurement Intervention Control Control Units Intervention Intervention
n
Proteinuria
Grootscholten
6y 50 37 SCr 112 µmol/l White 4.3 0.2
Proteinuria 2006[30] Cyc AZA 4.3 g/24h g/24h NS Fair
(2 y) (50) (37) GFR 65 ml/min 70% (3.2) (0.4)
Netherlands
SCr/GFR/CrCl
Grootscholten
6y 50 37 SCr 112 µmol/l White 112 80
SCr 2006[30] Cyc AZA 4.3 g/24h µmol/l NS Fair
(2 y) (50) (37) GFR 65 ml/min 70% (109) (86)
Netherlands
Supplementary table 77. Summary table of RCT examining low vs. high dose i.v. Cyc in patients with lupus nephritis (categorical outcomes)
Outcome GFR/SCr Proteinuria Race RR/OR/ P value Quality
HR
Mortality
41 mo
2 (5%)
Houssiau (3 mo low; 12 Caucasian -- nd
[0 (0%)]
2002[38], mo high) Low dose High dose 44 45 84%
Death SCr 1.15 mg/dl 3.03 g/dl Fair
2011[39] Cyc Cyc (44) (46) Asian 7% RR 2.62
5 (12%)
Europe 10 y follow-up Black 9% (0.54- nd
[2 (4%)]
12.77)179
ESRD/ doubling of SCr
41 mo
(High dose 12 RR 0.54
1 (2%)
ESRD mo (0.05- nd
[2 (4%)]
Low dose 3 5.70)180
mo)
73 mo
1 (2%) HR 0.35 NS
ESRD (3 mo low; 12
Houssiau [3 (7%)] (0.04-3.37) (0.34)
mo high) Caucasian 84%
2002[38], Low dose High dose 44 45
73 mo SCr 1.15 mg/dl 3.03 g/dl Asian 7% Fair
Doubling of 2011[39] Cyc Cyc (44) (46) 7 (17%) HR 2.2 NS
(3 mo low; 12 Black 9%
SCr Europe [1 (2%)] (0.66-7.27) (0.19)
mo high)
RR 0.52
2 (4%)
ESRD (0.10-
[4 (9%)]
2.71)181
10 y follow-up nd
Sustained RR 1.26
6 (14%)
Doubling of (0.42-
[5 (12%)]
SCr 3.81)182
Remission
Houssiau 41 mo Caucasian 84%
Renal Low dose High dose 44 45 30 (71%) HR 1.26 NS
2002[38] (3 mo low; 12 SCr 1.15 mg/dl 3.03 g/dl Asian 7% Fair
remission Cyc Cyc (44) (46) [22 (54%)] (0.72-2.21) (0.36)
Europe mo high) Black 9%
Adverse events
Severe 7 (11%) NS
HR 0.5
infection [17 (22%)] (0.2)
Houssiau Caucasian RR 1.02
41 mo 5 (11%)
Leukopenia 2002[38], Low dose High dose 44 45 84% (0.32- nd
(3 mo low; 12 SCr 1.15 mg/dl 3.03 g/dl [5 (11%)] Fair
2011[39] Cyc Cyc (44) (46) Asian 7% 3.29)183
mo high)
Europe Black 9% RR 1.02
2 (4%)
Menopause (0.15- nd
[2 (4%)]
6.94)184

Outcome GFR/SCr Proteinuria Race RR/OR/ P value Quality
HR
RR 1.02
Transient 1 (2%)
(0.07- nd
amenorrhea [1 (2%)]
15.85)185
RR 6.29
6 (15%) NS
Cancers (0.79-
10 y [1 (2%)] (0.10)
50.04)186
(3 mo low; 12
RR 0.79
Cardiac/arter mo high) 3 (7%)
(0.19- NS
ial events [4 (9%)]
3.30)187

Supplementary table 78. Existing systematic review on i.v. vs. p.o. Cyc treatment in patients with lupus nephritis
Flanc 2004[26] RCTs and quasi-RCTs comparing Trials with the following treatment Dichotomous: Induction with Is eligibility Yes, included
treatments for proliferative lupus options were considered: 7. All cause mortality; Cyclophosphamide and steroids criteria similar RCTs
Date Base: nephritis in both adult and pediatric 6. corticosteroids - including 8. ESRD (need for RRT) is probably an acceptable to the guideline
4. Cochrane patients with biopsy proven Class III, prednisolone, prednisone and 9. Doubling of Scr therapy as there is more data on
Central IV, Vc, Vd lupus nephritis were methyl-prednisolone 10. Stable renal function - <20% cyclophosphamide as an
Register of included. 7. other immunosuppressive worsening of Scr induction agent. Lack of data on
Controlled All treatments were considered. agents - including Azathioprine, 11. Deterioration of renal function - other agents and the lack of
Trials cyclophosphamide, MMF and >20% worsening of Scr direct comparison of azathioprine
5. Medline and cyclosporine 12. Relapse of LN. to cyclophosphamide make it
preMedline 8. plasma exchange or Toxicity: difficult to recommend other
6. Embase plasmapheresis; 7. major infection rate (all cause agents until further research
Search Dates: 9. Other agents (e.g. infection excluding HSV) becomes available. Given the Are there any No
CENTRAL - immunoglobulins). 8. HSV infection risk of infertility, it is reasonable limitations to
issue 2, 2003 10. Non-specific treatment options 9. Ovarian failure that the minimal effective systematic
1966 -2003 (e.g. antihypertensive 10. Bone toxicity ( avascular cumulative dose of review
1980- 2003 agents)were not included in the necrosis or fracture) cyclophosphamide be used. It is methodology
N Studies: present analysis as these do 11. bladder toxicity (haemorrhagic not possible to be more specific
25 not specifically relate to LN but cystitis) about optimal dosing schedules.
more broadly to preventing the 12. Development of malignancy. Based on this review plasma
N Subjects: progression of CKD Remission of proteinuria according to exchange cannot be Is limitation to Yes
915 the definitions of Chan 2000: recommended. evidence
complete remission: urinary protein clearly
excretion <0.3g/24 h. addressed by
Continuous outcomes : the authors
4. Scr (µmol/l)
5. CrCl (ml/min);
6. 24 h urinary protein excretion)
(g/24 h);
Trial quality varied greatly amongst RCTs. The small size of many of the included trials causes this analysis to have small numbers overall. Subjects
Description of limitations of evidence by authors differed between studies. The severity of renal impairment and the proportion of patients with Class IV LN differed amongst trials. Whilst some RCTs had
very long periods of follow-up, others were much shorter and inadequately powered to detect events.
Author, Year, RefID Intervention Control Outcome (N intervention Pooled OR1(95% CI) P-value
group/ total N)
Flanc, 2004[26] Mortality
Study Years: 1
i.v. Cyc p.o. Cyc All cause mortality 0.51 [ 0.18, 1.47 ] 0.2 NA NA
1966-2003 (20/38)
ESRD/ doubling of Scr
1
ESRD 0.23 [ 0.03, 1.83 ] 0.2 NA NA
(20/38)
1
Doubling of Scr 0.72 [ 0.23, 2.27 0.6 NA NA
(20/38)
i.v. Cyc p.o. Cyc
1
Stable renal function 1.11 [ 0.77, 1.59] 0.6 NA NA
(20/38)
Deterioration of renal 1
0.72 [ 0.23, 2.27 ] 0.6 NA NA
function (20/38)
Adverse events
1
Major infection 0.60 [ 0.11, 3.19 ] 0.5 NA NA
(20/38)
1
Herpes Zoster 0.75 [ 0.28, 2.04 ] 0.6 NA NA
(20/38)
1
i.v. Cyc p.o. Cyc Ovarian failure 0.67 [ 0.35, 1.28 ] 0.2 NA NA
(17/27)
1
Bladder toxicity 0.13 [ 0.01, 2.34 ] 0.2 NA A
(20/38)
1
Malignancy 1.20 [ 0.31, 4.65] 0.8 NA NA
(20/38)
Supplementary table 79. Summary table of RCT examining i.v. Cyc vs. p.o. Cyc in patients with lupus nephritis (categorical outcomes)
Mortality
White 31%
Yee Daily p.o. Asian 8% RR 2.46
2y 13 16 2 (15%)
Death 2004[87] i.v. Cyc Cyc + nd nd Afro Caribbean (0.25-24.22) nd Poor
(2 y) (13) (16) [1 (6%)]
Europe AZA 0% 188
Unknown 62%
RRT/ doubling of SCr
White 31% 0 (0%)
Doubled SCr -- Poor
Yee Daily p.o. Asian 8% [1 (6%)]
2y 13 16 NS
2004[87] i.v. Cyc Cyc + nd nd Afro Caribbean
(2 y) (13) (16) 0 (0%) (0.49)
Dialysis Europe AZA 0% -- Poor
[2 (13%)]
Unknown 62%
Adverse Events
RR 0.41
1 (8%)
Neutropenia (0.05-3.49) nd Poor
[3 (19%)] 189
RR 3.69
Nausea 3 (23%)
(0.43-31.43) nd Poor
vomiting [1 (6%)] 190
White 31%
RR 1.54
Yee Daily p.o. Asian 8% 5 (39%)
Infections 2y 13 16 (0.52-4.59) nd Poor
2004[87] i.v. Cyc Cyc + nd nd Afro Caribbean [4 (25%)]
(2 y) (13) (16) 191
Europe AZA 0%
Hemorrhagic 0 (0%)
Unknown 62% -- nd Poor
cystitis [1 (6%)]
1 (8%)
Malignancy -- nd Poor
[0 (0%)]
RR 1.23
Permanent 1 (8%)
(0.08-17.83) nd Poor
amenorrhea [1 (6%)] 192

Supplementary table 80. Summary table of RCT examining CsA vs. AZA for maintenance therapy in patients with lupus nephritis (categorical outcomes)
Renal flare
RR 0.61
Proteinuric 4 (11%)
(0.19- nd
flares [6 (18%)]
Moroni 4y 36 33 GFR 93 ml/min 1.98)193
Cyc AZA 2.8 g/24h Fair
2006[57] Italy (4 y) (36) (33) SCr 0.9 mg/dl RR 0.92
1 (3%)
Nephritic flare (0.06-14.07) nd
[1 (3%)] 194
RR 2.75
Undetectable Moroni 4y 36 33 GFR 93 ml/min 15 (42%)
Cyc AZA 2.8 g/24h (1.12-6.73) 0.045 Fair
proteinuria 2006[57] Italy (4 y) (36) (33) SCr 0.9 mg/dl [5 (15%)] 195
Adverse events
RR 0.37
4 (11%)
Leukopenia (0.13- nd
[10 (30%)]
1.06)196
RR 0.46
7 (19%)
Infections (0.21- nd
[14 (42%)]
0.99)197
RR 0.92
5 (14%)
Anemia (0.29- nd
[5 (15%)]
2.88)198
Moroni 4y 36 33 GFR 93 ml/min
Cyc AZA 2.8 g/24h RR 1.28 Fair
2006[57] Italy (4 y) (36) (33) SCr 0.9 mg/dl 7 (19%)
Hypertension (0.45- nd
[5 (15%)]
3.65)199
RR 0.46
Hyperlipidemi 2 (6%)
(0.09- nd
a [4 (12%)]
2.34)200
Gum 2 (6%)
-- nd
hyperplasia [0 (0%)]
2 (6%)
Hypertrichosis -- nd
[0 (0%)]

0 (0%)
Diabetes -- nd
[1 (3%)]
1 (3%)
Hyperkalemia -- nd
[0 (0%)]
Hypertensive 1 (3%)
-- nd
crisis [0 (0%)]
RR 4.28
14 (39%)
Arthralgias (1.35- nd
[3 (9%)]
13.56)201
RR 3.36
11 (31%)
GI disorders (1.03- nd
[3 (9%)]
11.00)202

Supplementary table 81. Summary table of RCT examining CsA vs. AZA for maintenance therapy in patients with lupus nephritis (continuous outcomes)
Proteinuria
2y 2.8 0.38
Moroni
(2 y) 36 33 GFR 93 ml/min (2.2) (0.53)
∆Proteinuria 2006[57] Cyc AZA 2.8 g/24h g/d NS Poor
4y (36) (33) SCr 0.9 mg/dl 2.8 0.23
Italy
(4 y) (2.2) (0.33)
SCr/GFR/CrCl
2y 92.5 82.6
Moroni 0.044
(2 y) 36 33 GFR 93 ml/min (104.1) (09.9)
∆CrCl 2006[57] Cyc AZA 2.8 g/24h ml/min Poor
4y (36) (33) SCr 0.9 mg/dl 92.5 -6.9
Italy NS
(4 y) (104.1) (-5.1)
Supplementary table 82. Summary table of RCT examining i.v. Cyc vs. prednisone in patients with membranous lupus nephritis (categorical outcomes)
Remission
RR 2.25
9 (60%)
Remission (0.88- 0.04 Fair
Austin Black 64% [4 (27%)]
12 mo 15 15 GFR 83 5.73)203
2009[4] Cyc Prednisone 5.4 g/d White 29%
(12 mo) (15) (15) ml/min/1.73m2 RR 3.00
Complete US Hispanic 7% 6 (40%)
(0.72-12.55) nd Fair
remission [2 (13%)] 204

Austin Black 64% RR 0.50
12 mo 15 15 GFR 83 1 (8%)
Doubling of SCr 2009[4] Cyc Prednisone 5.4 g/d White 29% (0.05-4.94) nd Fair
(12 mo) (15) (15) ml/min/1.73m2 [2 (13%)]
US Hispanic 7% 205
Adverse Events
0 (0%)
Leukopenia -- nd Fair
[0 (0%)]
0 (0%)
Amenorrhea -- nd Fair
[0 (0%)]
Nausea/anorexi 2 (17%)
-- nd Fair
a [0 (0%)]
↑BP with or 9 (75%)
-- nd Fair
without ↑SCr [0 (0%)]
Gingival
8 (67%)
hyperplasia/ Austin Black 64% -- nd Fair
12 mo 15 15 GFR 83 [0 (0%)]
↑facial hair 2009[4] Cyc Prednisone 5.4 g/d White 29%
(12 mo) (15) (15) ml/min/1.73m2
Paresthesia/ US Hispanic 7% 4 (33%)
-- nd Fair
tremor [0 (0%)]
RR 1.75
7 (58%)
Infections (0.64-4.75) nd Fair
[4 (27%)] 206
RR 2.00
2 (17%)
Pneumonia (0.20-19.78) nd Fair
[1 (7%)] 207
0 (0%)
Herpes zoster -- nd Fair
[0 (0%)]

RR 1.67
5 (42%)
Other (0.48-5.76) nd Fair
[3 (20%)] 208
Osteoporosi
RR 0.50
s/ hip 2 (17%)
(0.11-2.33) nd Fair
avascular [4 (27%)] 209
necrosis
Basal cell 0 (0%)
-- nd Fair
skin cancer [0 (0%)]

Supplementary table 83. Summary table of RCT examining i.v. CsA vs. prednisone in patients with membranous lupus nephritis (categorical outcomes)
Study, Year Outcome Events (%) P
Outcome GFR/SCr Proteinuria Race Quality
Country measurement Intervention Control Intervention Control Intervention RR/OR/HR value
Remission
RR 3.13
10 (83%)
Remission (1.30-7.51) 0.002 Fair
Austin Black 64% [4 (27%)] 210
12 mo 12 15 GFR 83
2009[4] CsA Prednisone 5.4 g/d White 29%
(12 mo) (12) (15) ml/min/1.73m2 RR 3.75
(0.92- nd Fair
remission [2 (13%)]
15.34) 211
12 mo 12 15 GFR 83 1 (7%)
Doubling of SCr 2009[4] CsA Prednisone 5.4 g/d White 29% (0.06-6.09) nd Fair
(12 mo) (12) (15) ml/min/1.73m2 [2 {13%)]
US Hispanic 7% 212
Adverse Events
2 (13%)
[0 (0%)]
0.25 (25%)
[0 (0%)]
3 (20%)
Nausea/anorexia -- nd Fair
[0 (0%)]
RR 3.13
10 (67%)
[4 (27%)]
Austin Black 64% 213
12 mo 12 15 GFR 83
2009[4] CsA Prednisone 5.4 g/d White 29% 0 (0%)
Pneumonia (12 mo) (12) (15) ml/min/1.73m2 -- nd Fair
US Hispanic 7% [1 (7%)]
2 (13%)
[0 (0%)]
RR 3.33
8 (53%)
[3 (20%)] 214
Osteoporosis/ hip RR 0.94

3 (20%)
avascular (0.26-3.41) nd Fair
[4 (27%)]
necrosis 215

Basal cell skin 1 (7%)
-- nd Fair
cancer [0 (0%)]
Supplementary table 84. Summary table of RCT CsA vs. i.v. Cyc in patients with membranous lupus nephritis (categorical outcomes)
Remission
RR 1.39
10 (83%)
Remission (0.86- nd Fair
Austin Black 64% [9 (60%)]
12 mo 12 15 GFR 83 2.25)216
2009[4] CsA Prednisone 5.4 g/d White 29%
(12 mo) (12) (15) ml/min/1.73m2 RR 1.25
(0.54-2.89) nd Fair
remission [6 (40%)] 217

12 mo 12 15 GFR 83 1 (7%)
Doubling of SCr 2009[4] CsA Prednisone 5.4 g/d White 29% (0.09- nd Fair
(12 mo) (12) (15) ml/min/1.73m2 [1 (8%)]
US Hispanic 7% 17.98) 218
Relapse
Incidence of Austin Black 64%
12 mo 12 15 GFR 83 2
relapse/100 2009[4] CsA Prednisone 5.4 g/d White 29% -- 0.02 Fair
(12 mo) (12) (15) ml/min/1.73m2 [0.2]
patient mo US Hispanic 7%
Adverse Events
0 (0%)
[2 (13%)]
0 (0%)
(1/4 (25%)]
RR 0.83
2 (17%)
Nausea/anorexia (0.16-4.21) nd Fair
[3 (20%)] 219
↑BP with/without Austin Black 64% 9 (75%)

12 mo 12 15 GFR 83 -- nd Fair
↑SCr 2009[4] CsA Prednisone 5.4 g/d White 29% [0 (0%)]
(12 mo) (12) (15) ml/min/1.73m2
Gingival US Hispanic 7%
8 (67%)
hyperplasia/ -- nd Fair
[0 (0%)]
↑facial hair
Paresthesia/ 4 (33%)
-- nd Fair
tremor [0 (0%)]
RR 0.88
7 (58%)
[10 (67%)] 220

2 (17%)
Pneumonia -- nd Fair
[0 (0%)]
0 (0%])
[2 (13%)]
RR 0.78
5 (42%)
[8 (53%)] 221
Osteoporosis/hip RR 0.83
2 (17%)
avascular (0.16-4.21) nd Fair
[3 (20%)]
necrosis 222
Basal cell skin 0 (0%)

-- nd Fair
cancer [1 (7%)]

Supplementary table 85. Summary table of RCT examining rituximab + cyclophosphamide vs. rituximab in patients with proliferative lupus nephritis (categorical outcomes)
Remission
2 (20%) RR 0.90
Complete response nd Poor
[2 (22%)] (0.16-5.13) 223
5 (50%) RR 0.75
Partial response nd Poor
Li 2009[49] 48 wk Rituximab + 10 9 SCr 134.8 [6 (66%)] (0.35-1.62) 224
Rituximab 3.8 g/24h
Complete or partial Hong Kong (48 wk) Cyc (10) (9) µmol/l 7 (70%) RR 0.79
nd Poor
response [8 (88%)] (0.49-1.26) 225
Total sustained
4 (21%) -- nd Poor
complete response
Adverse events
5 (50%) RR 0.64
AE- Infections nd Fair
[7 (77%)] (0.32-1.31) 226
0 (0%)
AE-Cramps -- nd Fair
[4 (44%)]
4 (40%) RR 1.20
AE-Ankle swelling nd Fair
[3 (33%)] (0.36-3.97) 227
2 (20%)
AE-Insomnia -- nd Fair
[0 (0%)]
2 (20%)
AE-Pruritis -- nd Fair
[0 (0%)]
Li 2009[49] 48 wk Rituximab + 10 9 SCr 134.8 2 (20%)
AE-Dyspepsia Rituximab 3.8 g/24h -- nd Fair
Hong Kong (48 wk) Cyc (10) (9) µmol/l [0 (0%)]
2 (20%)
AE-Urticaria -- nd Fair
[0 (0%)]
1 (10%)
AE-Chest pain -- nd Fair
[0 (0%)]
AE-Abdominal 1 (10%)
-- nd Fair
distension [0 (0%)]
0 (0%)
AE-Depression -- nd Fair
[1 (11%)]
1 (10%)
AE-Malaise -- nd Fair
[0 (0%)]

Supplementary table 86. Summary table of RCT examining rituximab + cyclophosphamide vs. rituximab in patients with proliferative lupus nephritis (continuous outcomes)
Proteinuria
Li 2009[49] Hong 48 wk Rituximab + 10 9 SCr 134.8 3.8 nd
Proteinuria Rituximab 3.8 g/24h g/24h NS Poor
Kong (48 wk) Cyclophosphamide (10) (9) µmol/l (4.1) (nd)
SCr/GFR/CrCl
Li 2009[49] Hong 48 wk Rituximab + 10 9 SCr 134.8 64.2 nd
CrCl Rituximab 3.8 g/24h µmol/l NS Poor
Kong (48 wk) Cyclophosphamide (10) (9) µmol/l (81.4) (nd)
Supplementary table 87. Summary table of RCT examining TAC vs. placebo in patients with lupus nephritis (categorical outcomes)
Proteinuria
Miyasaka
Daily UPE <0.3 28 wk 27 33 GFR 101 ml/min 4 (15%) RR 4.89
2009[56] Tacrolimus Placebo 1.6 g/d NS Fair
g/24h (28 wk) (28) (35) SCr 0.67 mg/dl [1 (3%)] (0.58-41.20) 228
Japan
Kidney function
Miyasaka
Maintenance of 28 wk 27 33 GFR 101 ml/min 22 (92%) RR 1.03
2009[56] Tacrolimus Placebo 1.6 g/d NS Fair
normal SCr (28 wk) (28) (35) SCr 0.67 mg/dl [26 (90%)] (0.80-1.33) 229
Japan
Adverse events
16 (57%) RR 0.86
All infections NS
[20 (57%)] (0.59-1.26) 230
2 (7%) RR 2.15
Serious infections NS
[1 (3%)] (0.21-22.37) 231
2 (7%) RR 0.72
Hyperlipidemia NS
[3 (9%)] (0.13-3.96) 232
Miyasaka
28 wk 27 33 GFR 101 ml/min 4 (14%)
↑Blood glucose 2009[56] Tacrolimus Placebo 1.6 g/d -- <0.05 Fair
(28 wk) (28) (35) SCr 0.67 mg/dl [0 (0%)]
Japan
2 (7%)
↑HbA1c -- NS
[0 (0%)]
4 (14%)
Nausea -- <0.05
[0 (0%)]
2 (7%) RR 0.72
Hypertension NS
[3 (9%)] (0.13-3.96) 233

Supplementary table 88. Summary table of RCT examining TAC vs. placebo in patients with lupus nephritis (continuous outcomes)
SCr/GFR/CrCl
12 wk 79.1
Miyasaka 0.005
(28 wk) 27 33 GFR 101 ml/min 101.4 [93.4]
CrCl 2009[56] Tacrolimus Placebo 1.6 g/d ml/min Fair
28 wk (28) (35) SCr 0.67 mg/dl [95.8] 78.2
Japan 0.060
(28 wk) [92.9]
Disease activity
Lupus nephritis Miyasaka
28 wk 27 33 GFR 101 ml/min 5.3 -1.8
disease activity 2009[56] Tacrolimus Placebo 1.6 g/d nd <0.001 Fair
(28 wk) (28) (35) SCr 0.67 mg/dl [5.2] [0.0]
index Japan
Supplementary table 89. Summary table of a study examining TAC vs. standard protocols of steroid + p.o. Cyc or AZA in patients with class V lupus (categorical outcomes)
Remission
Complete 28% NS
--
remission 12 wk [16%] (0.5)
Poor
Partial (6 mo) Standard 50% NS
Szeto --
remission protocols of 18 19 SCr 93 mg/dl [47%] (0.5)
2008[77] TAC 4.57 g/d
Complete steroid + p.o. (18) (19) GFR 103 ml/min 39% NS
China --
remission 24 wk Cyc or AZA [37%] (0.5)
Poor
Partial (6 mo) 44% NS
--
remission [58%] (0.5)
Adverse events
3 (17%) RR 1.58
Infection nd
[2 (11%)] (0.30-8.40) 234
Elevated 1 (6%) RR 1.06
nd
LFTs Standard [1 (6%)] (0.07-15.64) 235
Szeto
12 wk protocols of 18 19 SCr 93 mg/dl 1 (6%)
Angioedema 2008[77] TAC 4.57 g/d -- nd Poor
(6 mo) steroid + p.o. (18) (19) GFR 103 ml/min [0 (0%)]
China
Cyc or AZA 2 (11%)
Tremor -- nd
[0 (0%)]
8 (44%)
Dyspepsia -- nd
[0 (0%)]

Supplementary table 90. Summary table of a study examining TAC vs. standard protocols of steroid + p.o. Cyc or AZA in patients with class V lupus (continuous outcomes)
Study, Yea Outcome Baseline ∆ P Qualit
Outcome GFR/SCr Proteinuria
r Country measurement Intervention Control Intervention Control Units Intervention Intervention value y
Proteinuria
Standard
Szeto SCr 93 mg/dl
12 wk protocols of 18 19 4.57 76%
∆Proteinuria 2008[77] TAC GFR 103 4.57 g/d g/d 0.03 Poor
(6 mo) steroid + p.o. (18) (19) (3.62) (47%)
China ml/min
Cyc or AZA
SCr/GFR/CrCl
Standard
Szeto SCr 93 mg/dl
12 wk protocols of 18 19 ml/min/1. 102.8 NS
∆eGFR 2008[77] TAC GFR 103 4.57 g/d nd Poor
(6 mo) steroid + p.o. (18) (19) 73m2 (103.1) (0.7)
China ml/min
Cyc or AZA
Supplementary table 91. Summary table of a study examining AZA vs. i.v. Cyc maintenance therapy in patients with lupus nephritis (categorical outcomes)
Description No. Analyzed (Enrolled) Results
Duration
No. Events
Outcome GFR/SCr Proteinuria Race (%) Quality
Country measurement Intervention Control Intervention Control RR/OR/HR value
Intervention
(Treatment)
[Control]
Mortality
0 (0)%
Mortality -- 0.02 Fair
[4 (20%)]
Cumulative 30 mo 80%
rate of renal (30 mo) -- nd Fair
[74%]
survival
Event-free Contreras Black 47% nd 0.009
AZA + i.v. Cyc + 19 20
survival for 2004[15] SCr 1.7 mg/dl 5.7 mg/mg Hispanic 42%
steroids steroids (19) (20)
composite end 2005[16] US White 11%
60-72 mo 89% -- Fair
point of death nd
or chronic renal (30 mo) [80%]
failure236
Relapse free 30 mo NS
nd -- Fair
survival (30 mo) (0.12)
Contreras Black 47% RR 0.35
Chronic renal 30 mo AZA + i.v. Cyc + 19 20 1 (5)%
2004[15] SCr 1.7 mg/dl 5.7 mg/mg Hispanic 42% (0.04-3.09) nd Fair
failure 237 (30 mo) steroids steroids (19) (20) [3 (15%)]
2005[16] US White 11% 238
Relapse
30 mo AZA + i.v. Cyc + 19 20 6 (32%)
Relapse 2004[15] SCr 1.7 mg/dl 5.7 mg/mg Hispanic 42% (0.34-1.85) nd Fair
(30 mo) steroids steroids (19) (20) [8 (40%)]
2005[16] US White 11% 239
Adverse events
29%
Infection -- 0.002 Fair
[77%]
Contreras Black 47%
30 mo AZA + i.v. Cyc + 19 20 8%
Amenorrhea 2004[15] SCr 1.7 mg/dl 5.7 mg/mg Hispanic 42% -- 0.03 Fair
(30 mo) steroids steroids (19) (20) [32%]
2005[16] US White 11%
6%
Leukopenia -- 0.43 Fair
[10%]
236
ESRD, transplant or doubling of SCr from lowest value achieved during induction
237
Supplementary table 92. Summary table of a study examining MMF vs. i.v. Cyc maintenance therapy in patients with lupus nephritis (categorical outcomes)
Duration
No. Events
Intervention
(Treatment)
[Control]
Mortality
RR 0.25
1 (5%) NS
Mortality (0.03-2.05) Fair
[4 (20%)] 240 (0.11)
Cumulative rate 29 mo 95%
-- nd Fair
of renal survival (29 mo) [74%]
Contreras
Event-free Black 45%
2004[15] i.v. Cyc + 20 20
survival for MMF SCr 1.6 mg/dl 4.7 mg/mg Hispanic 50% nd 0.005
2005[16] steroids (20) (20)
composite end White 5%
US -- Fair
point of death or
60-72 mo 89%
chronic renal nd
(29 mo) [45%]
failure241
Relapse free 29 mo
nd -- 0.02 Fair
survival (29 mo)
Contreras
Black 45% RR 0.33
Chronic renal 2004[15] 29 mo i.v. Cyc + 20 20 1 (5)%
MMF SCr 1.6 mg/dl 4.7 mg/mg Hispanic 50% (0.04-2.94) nd Fair
failure242 2005[16] (29 mo) steroids (20) (20) [3 (15%)]
White 5% 243
US
Relapse
Contreras
Black 45% RR 0.38
2004[15] 29 mo i.v. Cyc + 20 20 3 (15%)
Relapse MMF SCr 1.6 mg/dl 4.7 mg/mg Hispanic 50% (0.12-1.21) nd Fair
2005[16] (29 mo) steroids (20) (20) [8 (40%)]
White 5% 244
US
Adverse events
32%
Infection 0.005 Fair
Contreras [77%]
Black 45%
2004[15] 29 mo i.v. Cyc + 20 20 6%
Amenorrhea MMF SCr 1.6 mg/dl 4.7 mg/mg Hispanic 50% 0.03 Fair
2005[16] (29 mo) steroids (20) (20) [32%]
White 5%
US 2% NS
Leukopenia Fair
[10%] (0.15)

241
242
Supplementary table 93. Evidence profile of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis
Outcome and quality of studies Quality of evidence for Qualitative and quantitative description of Importance
(treatment) across studies generalizability/ considerations
applicability
Some No important
3 RCTs 156 Direct Imprecision
Mortality limitations inconsistencies Low No difference Critical
(High) (94) (0) (-1)
(-1) (0)
Imprecision
1 RCT 105 No limitations Direct (-1)
ESRD N/A Low No difference Critical
(High) (53) (0) (0) Sparse
(-1)
No important
3 RCTs 206 No limitations Direct Imprecision
Relapse inconsistencies Moderate No difference High
(High) (105) (0) (0) (-1)
(0)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Imprecision
Kidney
1 RCT 105 No limitations Direct (-1)
function N/A Low No difference High
(High) (53) (0) (0) Sparse
(categorical)
(-1)
Some
Proteinuria 1 RCT 62 Direct Sparse
limitations N/A Low No difference Moderate
(continuous) (High) (32) (0) (-1)
(-1)
Kidney Some
1 RCT 62 Direct Sparse
function limitations N/A Low No difference Moderate
(High) (32) (0) (-1)
(continuous) (-1)
Adverse 3 RCTs 206
No difference Moderate
events (High) (105)
No difference Low
Supplementary table 94. Summary table of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis (categorical outcomes)
Duration
No. Events
Intervention
(Treatment)
[Control]
Mortality
1 (5%) NS
Mortality -- Fair
[0 (0%)] (0.33)
Cumulative
95%
rate of renal 30 mo -- nd Fair
[80%]
survival (30 mo)
Event-free Contreras Black 45%
20 19 SCr 1.7 NS
survival for 2004[15] MMF AZA 4.7 mg/mg Hispanic 50% --
(20) (19) mg/dl (0.50)
composite end 2005[16] US White 5%
-- Fair
point of death
60-72 mo 89%
or chronic renal nd
(30 mo) [80%]
failure245
Relapse free 30 mo NS
-- -- Fair
survival (30 mo) (0.22)
i.v. Cyc + GFR 86
Chan
12 mo MMF+ prednisone, 21 21 ml/min 0 (0%) NS
Death 2000[10] 5.8 g/24h nd -- Fair
(12 mo) prednisone then AZA + (21) (21) SCr 1.2 [2 (10%)] (0.49)
China
prednisone mg/dl
i.v. Cyc + GFR 72
Chan
63 mo MMF+ prednisone, 32 30 ml/min 0 (0%) NS
Death/ESRD 2005[12] 5.32 g/24h nd -- Fair
(≥12 mo) prednisone then AZA + (33) (33) SCr 1.28 [4 (12%)] (0.062)
China
prednisone mg/dl
Houssiau White 42%
48 mo 53 52 SCr 1.01 2 (4%)
Death 2010[37] MMF AZA 3.63 g/24h Black 6% -- nd Good
(44 mo) (53) (52) mg/dl [0 (0%)]
Europe Asian 5%
Chronic renal 30 mo 20 19 SCr 1.7 1 (5)%
2004[15] MMF AZA 4.7 mg/mg Hispanic 50% (0.06-14.13) nd Fair
failure 246 (30 mo) (20) (19) mg/dl [1 (5%)]
2005[16] US White 5% 247
Houssiau White 42% RR 0.74

48 mo 53 52 SCr 1.01 3 (6%)
Doubling SCr 2010[37] MMF AZA 3.63 g/24h Black 6% (0.17- nd Good
(44 mo) (53) (52) mg/dl [4 (8%)]
Europe Asian 5% 3.13)248
245
246
Duration
No. Events
Intervention
(Treatment)
[Control]
RR 0.98
1 (2%)
ESRD (0.06-
1 (2%)
15.28)249
Relapse
30 mo 20 19 SCr 1.7 3 (15%)
Relapse 2004[15] MMF AZA 4.7 mg/mg Hispanic 50% (0.14-1.63) nd Fair
(30 mo) (20) (19) mg/dl [6 (32%)]
2005[16] US White 5% 250
RR 1.50
i.v. Cyc + GFR 86 3 (15%) NS
Relapse Chan (0.28-8.08)
12 mo MMF+ prednisone, 21 21 ml/min [2 (11%)] (0.15)
2000[10] 5.8 g/24h nd 251 Fair
(12 mo) prednisone then AZA + (21) (21) SCr 1.2
Time to China 40 NS
prednisone mg/dl --
relapse, wk [39] (0.70
HR 1.536
i.v. Cyc + GFR 72 11 (34%) NS
Relapse Chan (0.634-
63 mo MMF+ prednisone, 32 30 ml/min [9 (30%)] (0.342)
2005[12] 5.32 g/24h nd 3.722) Fair
(≥12 mo) prednisone then AZA + (33) (33) SCr 1.28
Time to China 20
prednisone mg/dl -- nd
relapse, wk [33]
Houssiau White 42%
48 mo 53 52 SCr 1.01 10 (19%) HR 0.75
Renal flare 2010[37] MMF AZA 3.63 g/24h Black 6% 0.49 Good
(44 mo) (53) (52) mg/d 13 (25%) (0.33-1.71)
Europe Asian 5%
Adverse events
32%
Infection -- NS
[29%]
Contreras 19 Black 45%
30 mo 20 1.7±1.6 4.7±4.3 6%
Amenorrhea 2004[15] MMF AZA (19) Hispanic 50% -- NS Fait
(30 mo) (20) mg/dl mg/mg [8%]
2005[16] US White 5%
2%
Leukopenia -- NS
[6%]
RR 0.57
4 (19%) NS
Infection (0.20-1.66)
i.v. Cyc + GFR 86 [7 (33%)] 252 (0.29)
Chan
12 mo MMF+ prednisone, 21 21 ml/min
2000[10] 5.8 g/24h nd 0 (0%) NS Fair
Hair loss (12 mo) prednisone then AZA + (21) (21) SCr 1.2 --
China [4 (19%)] (0.11)
prednisone mg/dl
Permanent 0 (0%) NS
--
amenorrhea [1 (8%)] (0.46)

Duration
No. Events
Intervention
(Treatment)
[Control]
0 (0%) NS
Leukopenia --
[2 (10%)] (0.49)
1 (5%) NS
Diarrhea --
[0 (0%)] (1.00)
1/234 pt-mo Rate Ratio
Incidence of NS
[1/102.5 pt- 2.28
infection (0.062)
mo] (0.96-5.43)
1/327.6
Incidence of Rate Ratio
pt.mo NS
hospitalized 1.85
[1/177 pt- (0.254)
infections (0.64-5.33)
mo]
i.v. Cyc + GFR 72 0 (0%)
Hair loss Chan -- nd
63 mo MMF+ prednisone, 32 30 ml/min [9 (29%)]
2005[12] 5.32 g/24h nd Fair
(≥12 mo) prednisone then AZA + (33) (33) SCr 1.28 4%
Amenorrhea China -- 0.004
prednisone mg/dl [36%]
Permanent 0%
-- nd
amenorrhea [56%]
0 (0%)
Leukopenia -- nd
[8 (26%)]
RR 2.81
3 (9%)
GI upset (0.31-25.58) nd
[1 (3%)] 253
RR 1.47
21 (40%)
Infection (0.84- nd
[14 (27%)]
2.57)254
Houssiau White 42% RR 0.18
48 mo 53 52 SCr 1.01 2 (4%)
Leukopenia 2010[37] MMF AZA 3.63 g/24h Black 6% (0.04- nd Good
(44 mo) (53) (52) mg/dl [11 (21%)]
Europe Asian 5% 0.77)255
RR 0.98
8 (15%)
Diarrhea (0.40- nd
[8 (15%)]
2.42)256

Supplementary table 95. Summary table of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis (continuous outcomes)
Study, Year Outcome Baseline ∆ Qualit
Outcome GFR/SCr Proteinuria Race P value
Country measurement Intervention Control Intervention Control Intervention Intervention y
Scr/GFR
1.13 -0.16
SCr, mg/dl i.v. Cyc + NS Fair
Chan (1.10) (-0.11)
12 mo MMF+ prednisone, 21 21 GFR 86 ml/min
Cr Cl, 2000[10] 5.8 g/24h nd
(12 mo) prednisone then AZA + (21) (21) SCr 1.2 mg/dl 86 +6
ml/min/1.73 China nd Fair
prednisone (77) (+5)
m2
i.v. Cyc + 1.27 -0.308 NS
SCr slope Chan Fair
63 mo MMF+ prednisone, 32 30 GFR 72 ml/min (1.28) (0.242) (0.914)
2005[12] 5.32 g/24h nd
(≥12 mo) prednisone then AZA + (33) (33) SCr 1.28 mg/dl 67.4 0.142 NS
CrCl slope China Fair
prednisone (74.9) (0.057) (0.131)
Proteinuria
i.v. Cyc +
Chan
12 mo MMF+ prednisone, 21 21 GFR 86 ml/min 5.8 -5.3
Proteinuria 2000[10] 5.8 g/24h nd nd Fair
(12 mo) prednisone then AZA + (21) (21) SCr 1.2 mg/dl (3.7) (-3.5)
China
prednisone
i.v. Cyc +
Chan
Proteinuria- 63 mo MMF+ prednisone, 32 30 GFR 72 ml/min 6.21 -0.085 NS
2005[12] 5.32 g/24h nd Fair
slope (≥12 mo) prednisone then AZA + (33) (33) SCr 1.28 mg/dl (4.44) (-0.055) (0.075)
China
prednisone
Supplementary table 96. Evidence profile of i.v. vs. p.o. Cyc for ANCA vasculitis
applicability
No important
(High) (76) (-1) Direct
Mortality inconsistencies None Moderate No difference for mortality Critical
1 SR 129 Some limitations (0)
(0)
(3 RCTs) (61) (-1)
No important
RRT inconsistencies None Moderate No difference for RRT Critical
(0)
(3 RCTs) (61) (-1)
Important
Remission inconsistencies None Low No difference for i.v. cyclophosphamide High
(-1)
(3 RCTs) (49) (-1)
No important
Relapse inconsistencies None Moderate Benefit for oral cyclophosphamide High
(0)
(3 RCTs) (57)) (-1)
Proteinuria
0 RCTs -- -- -- -- -- -- -- High
(categorical)
Kidney
(categorical)
ΔProteinuria
0 RCTs -- -- -- -- -- -- -- Moderate
(continuous)
function inconsistencies None Moderate No difference for change in kidney function Moderate
(continuous) (0)
(2 RCT s) (21) (-1)
1 RCT 149
(High) (76) Lower incidence of leukopenia with pulse
Adverse events
1 SR 129 cyclophosphamide
(3 RCTs) (61)
Benefit for oral cyclophosphamide in preventing relapse Moderate
Supplementary table 97. Existing systematic review of Induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis
RefID
Walters 2008[84] All RCTs and quasi-RCTs (RCTs in 1. Corticosteroids versus placebo. 1. Mortality at 1, 2 and 5 1. On current data, the use of Is eligibility Yes
which allocation to treatment was 2. Non-corticosteroid agents, years. pulse Cyc results in an criteria similar
Date Base: obtained by alternation, use of alternate including Cyc, AZA, plasma 2. Kidney function: SCr) increased risk of relapse to the
1. Cochrane medical records, date of birth or other exchange and immunoadsorption, level at 1, 2, 3, 6 and 12 when compared to guideline
Central predictable methods) looking at any with or without concurrent use of months then annually. continuous use but a
Register of intervention used for the treatment of other immunosuppressive agents. 3. Need for RRT at 1, 2, 3, reduced total dose.
Controlled renal vasculitis in adults. 3. Different doses and duration of 6 and 12 months then
Trials corticosteroid treatment. annually.
2. Cochrane Inclusion criteria 4. Different doses, duration and route 4. No. of patients
Renal Group All adult patients suffering from an of administration of non- relapsing (as defined by
Specialized episode of AKF and/or proteinuria and corticosteroid treatment the study).
Register, hematuria with a kidney biopsy showing 5. Any other agents evaluated in a 5. Adverse effects of each
3. MEDLINE severe acute GN with crescents, RCT drug (e.g. nausea,
EMBASE glomerular necrosis or other histological leukopenia, and
Search Dates: evidence of vasculitis. AKF was as infections). Are there any
1966-2008 defined by the included studies. 6. Cumulative doses of limitations to
steroid and other systematic
Exclusion criteria agents. review
N Studies:
1. RPGN with granular immune 7. Relapse of disease is methodology
13
deposits such as SLE, defined by the included
cryoglobulinemia, HSP. studies, but typically
N Subjects: 2. RPGN secondary to infections. included an increase in Is limitation to
702 3. Polyarteritis nodosa. BVAS score or a evidence
4. Churg Strauss disease. recurrence of symptoms clearly
5. Goodpasture’s disease of vasculitis. addressed by
the authors
The review is limited by the small number of available studies and some design features of the included studies. Several included diagnoses other than renal vasculitis.
Some date prior to the development of the ANCA assay. This will limit the validity of the data and diagnoses included in those studies. Other differences include those
Description of limitations of evidence by
between interventions, notably the regimens of immunosuppressive drugs and the number and volume of plasma exchanges utilized. Some of these may have had a very
authors
significant impact on the outcomes of studies and may explain the level of heterogeneity in some of our results
Author, Year, RefID Intervention Control Outcome (N intervention group/ total Pooled OR1(95% CI) P-value
N)
Walters 2008[84] Pulse Cyc Continuous Cyc Death at 3 months 1(12/32) 1.67 [ 0.27, 10.33 ] 0.58 NA NA
Study Yrs. :1980- Pulse Cyc Continuous Cyc Death at 6 months 1(12/32) 1.11 [ 0.22, 5.73 ] 0.90 NA NA
2007 Pulse Cyc Continuous Cyc Death at 1 year 2(39/82) 0.82 [ 0.25, 2.72] 0.75 44 0.18
Pulse Cyc Continuous Cyc Death at 2 years 3(61/129) 0.75 [ 0.21, 2.61 ] 0.65 56 0.11
Pulse Cyc Continuous Cyc Death at 5 years 0 0 NA NA NA
Pulse Cyc Continuous Cyc Death at final FU 3(61/129) 0.87 [ 0.42, 1.80] 0.71 32 0.23
Pulse Cyc Continuous Cyc Dialysis at 1 month 0 0 NA NA NA
Pulse Cyc Continuous Cyc Dialysis at 2 months 0 0 NA NA NA
Pulse Cyc Continuous Cyc Dialysis at 3 months 0 0 NA NA NA
Pulse Cyc Continuous Cyc Dialysis at 6 months 1(27/50) 6.00 [ 0.33, 110.43] 0.23 NA NA
Pulse Cyc Continuous Cyc Dialysis at 12months 0 0 NA NA NA
Pulse Cyc Continuous Cyc Dialysis end of study 3(61/129) 1.70 [ 0.78, 3.67 ] 0.18 0 0.66
Pulse Cyc Continuous Cyc Scr at 1 month 0 0 NA NA NA
Pulse Cyc Continuous Cyc Scr at 2 months 0 0 NA NA NA
Pulse Cyc Continuous Cyc Scr at 3 months 1(10/28) -4.58 [ -97.77, 88.61 ] 0.92 NA NA
Pulse Cyc Continuous Cyc Scr at 6 months 1(10/27) 51.69 [ -81.03, 184.41 ] 0.45 NA NA
Pulse Cyc Continuous Cyc Scr at 12 months 2(21/52) -9.78 [ -53.16, 33.61 ] 0.66 0 0.98
Pulse Cyc Continuous Cyc Scr at 2 years 2(21/52) 0 0.90 0 0.81

Author, Year,
Intervention Control Outcome (N intervention Pooled OR1(95% CI) P-value
RefID I2 Statistic P-value
group/ total N)
Pulse Cyc Continuous Cyc Remission at 6 months 1(27/50) 1.14 [ 0.88, 1.46 ] 0.32 NA NA
Walters 2008[84]
Pulse Cyc Continuous Cyc Untimed remission 1(22/47) 1.18 [ 0.98, 1.42 ] 0.077 NA NA
Study Years :1980-
Pulse Cyc Continuous Cyc Total 2(49/97) 1.17 [ 1.00, 1.35 ] 0.044 0 0.79
2007
Pulse Cyc Continuous Cyc Relapse at 1 year 1(22/47) 2.84 [ 0.61, 13.21 ] 0.18 NA NA
Pulse Cyc Continuous Cyc Relapse at 2 years 1(22/47) 1.89 [ 0.51, 7.03 ] 0.34 NA NA
Pulse Cyc Continuous Cyc Untimed relapse 3(57/119) 1.75 [ 1.00, 3.05 ] 0.050 0 0.54
Pulse Cyc Continuous Cyc Treatment failure 2(39/82) 1.36 [ 0.15, 12.56] 0.79 69 0.07
Pulse Cyc Continuous Cyc Serious infections 3(61/129) 0.71 [ 0.32, 1.58] 0.40 80 0.01
Pulse Cyc Continuous Cyc Leukopenia 3(61/129) 0.43 [ 0.22, 0.84 ] 0.014 0 0.54
Pulse Cyc Continuous Cyc Nausea 2(49/97) 2.51 [ 1.07, 5.89] 0.035 0 0.99
Supplementary table 98. Summary table of RCT examining the effect of induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis (categorical outcomes)
Mortality
SCr 225 µmol/l/
de Groot RR 0.53
6 mo Daily p.o. 76 73 SCr 2.55 mg/dl 5 (7%) NS
Death 2009[18] Pulse Cyc nd (0.19-1.52) Fair
(6 mo) Cyc (76) (73) GFR 38 [9 (2%)] (0.79)
EU/Mexico 257
ml/min/1.73 m2
RRT/ Doubling of Scr
SCr 225 µmol/l/
de Groot SCr 2.55 mg/dl RR 4.80
18 mo Daily p.o. 76 73 5 (7%) NS
ESRD 2009[18] Pulse Cyc GFR 38 nd (0.57-40.13) Fair
(6 mo) Cyc (76) (73) [1 (1%)] (0.105)
EU/Mexico ml/min/1.73 258
m2
Remission
RR 1.03
3 mo 72 65 49 (68%)
(0.81-1.30) nd Fair
(6 mo) (76) (73) [43 (66%)] 259
RR 1.01
6 mo 66 60 61 (92%)
(0.91-1.12) nd Fair
(6 mo) (76) (73) [55 (92%)] 260
RR 0.97
9 mo 63 58 SCr 225 µmol/l/ 61 (97%)
(0.93- nd Fair
de Groot (6 mo) (76) (73) SCr 2.55 mg/dl [58 (100%)]
Daily p.o. 1.01)261
Remission 2009[18] Pulse Cyc GFR 38 nd
Cyc RR 0.98
EU/Mexico 12 mo 62 55 ml/min/1.73 61 (98%)
(0.95-1.02) nd Fair
(6 mo) (76) (73) m2 [55 (100%)] 262
RR 0.98
15 mo 62 54 61 (98%)
(0.95-1.02) nd Fair
(6 mo) (76) (73) [54 (100%)] 263
RR 0.98
18 mo 62 54 61 (98%)
(0.95-1.02) nd Fair
(6 mo) (76) (73) [54 (100%)] 264
Relapse

SCr 225 µmol/l/
SCr 2.55 mg/dl
de Groot20091 >9 mo Daily p.o. 76 73 13 (17%) HR 2.01
Relapse Pulse Cyc GFR 38 nd nd Fair
EU/Mexico (6 mo) Cyc (76) (73) [6 (8%) (0.77- 5.30)
ml/min/1.73
m2
Adverse events
Any RR 0.99
58 (77%)
adverse (0.83-1.19) nd Fair
[56 (77%)]
event 265
RR 0.58
Leukopen 20 (26%)
(0.37-0.92) 0.016 Fair
ia [33 (45%)] 266
20 (26%) HR 0.41
Infection nd Fair
[21 (29%)] (0.23-0.71)
Serious/
SCr 225 µmol/l/
life- RR 0.67
de Groot SCr 2.55 mg/dl 7 (9%)
threatenin 9 mo Daily p.o. 76 73 (0.27-1.67) nd Fair
2009[18] Pulse Cyc GFR 38 nd [10 (14%)]
g (6 mo) Cyc (76) (73) 267
EU/Mexico ml/min/1.73
infection
m2
0 (0%)
Alopecia -- nd Fair
[2 (3%)]
1 (1%)
Cancer -- nd Fair
[1 (0%)]
Hemorrha RR 1.92
2 (3%)
gic (0.18-20.73) nd Fair
[1 (1%)]
cystitis 268
Amenorrh 1 (1%)
-- nd Fair
ea [0 (0%)]

Supplementary table 99. Summary table of RCT examining induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis (continuous outcomes)
SCr/GFR/CrCl
Median SCr 225 µmol/l/
de Groot ml/min/
eGFR 9 mo Daily p.o. 76 73 SCr 2.55 mg/dl 32 5 NS
2009[18] Pulse Cyc nd 1.73 Fair
improvem (6 mo) Cyc (76) (73) GFR 38 (29) (8) (0.36)
EU/Mexico m2
ent ml/min/1.73 m2
Supplementary table 100. Evidence profile of RCTS examining induction with rituximab vs. Cyc in patients with ANCA vasculitis
applicability
No important
2 RCTs 241 Some limitations Direct
Mortality inconsistencies None Moderate No difference Critical
(High) (132) (-1) (0)
(0)
ESRD 0 RCT -- -- -- -- -- -- -- Critical
No important
Remission inconsistencies None Moderate No difference High
(High) (132) (-1) (0)
(0)
Relapse N/A Moderate No difference High
(High) (33) (0) (0) (-1)
Proteinuria
0 RCT -- -- -- -- -- -- -- High
(categorical)
Kidney
function 0 RCT -- -- -- -- -- -- -- High
(categorical)
ΔProteinuria
0 RCT -- -- -- -- -- -- -- Moderate
(continuous)
function inconsistencies None Moderate No difference Moderate
(High) (132) (-1) (0)
(continuous) (0)
2 RCTs 241
Adverse events No difference Moderate
(High) (132)
No difference Moderate
Supplementary table 101. Summary table of RCTs examining induction with rituximab vs. Cyc in patients with ANCA vasculitis (categorical outcomes)
Mortality
12 mo
Jones i.v. Cyc
(6 mo for Rituximab + i.v. 33 11 GFR 20 6 (18%) RR 1.00269 NS
Death 2010[43] followed by nd Good
rituximab; 12 mo Cyc (33) (11) ml/min/1.73 m2 [2 (18%)] (0.24-4.25) (1.00)
EU & Australia AZA
for Cyc)
Stone Cyc +
6 mo i.v. rituximab + 99 98 1 (1%) RR 0.49
Death 2010[75] placebo- eCrCl 54 ml/min nd nd Fair
(6 mo) placebo Cyc (99) (98) [2 (2%)] (0.05-5.37)
Multi rituximab
Remission
12 mo
Jones i.v. Cyc
Sustained (6 mo for Rituximab + i.v. 33 11 GFR 20 25 (76%) RR 0.93270 NS
2010[43] followed by nd Good
remission rituximab; 12 mo Cyc (33) (11) ml/min/1.73 m2 [9 (82%)] (0.66-1.30) (0.68)
EU & Australia AZA
for Cyc)
70 (71%) RR 1.14 NS
Remission Fair
[61 (62%)] (0.93-1.39) (0.10)
ANCA 47%
-- 0.004 Fair
negative [24%]
Stone Cyc +
Proteinase 3- 6 mo i.v. rituximab + 99 98
2010[75] placebo- eCrCl 54 ml/min nd 15%
ANCA (6 mo) placebo Cyc (99) (98) -- <0.001 Fair
Multi rituximab [17%]
negative
Myeloperoxida
40% NS
se-ANCA -- Fair
[41%] (0.95)
negative
Relapse
12 mo
Jones i.v. Cyc GFR 20
(6 mo for Rituximab + i.v. 33 11 4 (27%) RR 1.33271 NS
Relapse 2010[43] followed by ml/min/1.73 nd Good
rituximab; 12 mo Cyc (33) (11) [1 (10%)] (0.17-10.70) (0.70)
EU & Australia AZA m2
for Cyc)
Adverse events
12 mo 2 (6%) RR 0.67272
Leukopenia Jones i.v. Cyc GFR 20 nd
(6 mo for Rituximab + i.v. 33 11 [1 (9%)] (0.07-6.66)
2010[43] followed by ml/min/1.73 nd Good
rituximab; 12 mo Cyc (33) (11) 12 (36%) RR 1.44273
All infections EU & Australia AZA m2 nd
for Cyc) [3 (27%)] (0.50-4.14)

Serious 6 (18%) RR 1.00274
nd
infection [2 (18%)] (0.24-4.25)
All infusion 2 (6%)
-- nd
reactions [0 (0%)]
2(6%)
Cancer -- nd
[0 (0%)]
Events
requiring
12 (36%) RR 1.00275
hospitalization nd
[4 (36%)] (0.41-2.47)
or life-
threatening
1 (1%) RR 0.99276
Cancer nd Fair
[1 (1%)] (0.06-15.61)
3 (3%) RR 0.30277
Leukopenia nd Fair
[10 (10%)] (0.08-1.05)
Thrombocytop 3 (3%) RR 2.97278
nd Fair
enia [1 (1%)] (0.31-28.06)
7 (7%) RR 0.99279
Infection nd Fair
[7 (7%)] (0.36-2.72)
Hemorrhagic 1 (1%) RR 0.99280
nd Fair
cystitis [1 (1%)] (0.06-15.61)
Hospitalization
Stone Cyc + 8 (8%) RR 3.96281
due to disease 6 mo i.v. rituximab + 99 98 nd Fair
2010[75] placebo- eCrCl 54 ml/min nd [2 (2%)] (0.86-18.18)
or treatment (6 mo) placebo Cyc (99) (98)
Multi rituximab
Infusion
reaction
preventing
1 (1%)
further -- nd Fair
[0 (0%)]
infusions of
investigational
medication
1035
All AEs -- nd Fair
[1016]
All serious 79
-- nd Fair
AEs [78]

Supplementary table 102. Summary table of RCTs examining induction with rituxamib vs. Cyc in patients with ANCA vasculitis (continuous outcomes)
SCr/GFR/CrCl
Jones 12 mo
i.v. Cyc
Median 2010[43] (6 mo for Rituximab + i.v. 33 11 GFR 20 ml/min/ ml/min/1 20 29 NS
followed by nd Good
↑eGFR EU & rituxamib; 12 mo Cyc (33) (11) 1.73 m2 .73 m2 (12) (27) (0.14)
AZA
Australia for Cyc)
Stone Cyc +
6 mo i.v. rituximab + 99 98 54 +11.2
∆eCrCl 2010[75] placebo- eCrCl 54 ml/min nd ml/min nd Fair
(6 mo) placebo Cyc (99) (98) (69) (+10.5)
Multi rituximab
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KDIGO CLINICAL PRACTICE GUIDELINE

Online Supplementary Tables

N studies Test for heterogeneity

2 Leucocytes <4.0×1000 cells/mm3 in >1 measurement.

N studies Test for heterogeneity

Balance of potential benefits and harm: Quality of overall evidence:

7 CsA 7-10 mg/kg/d in 2 divided doses X 12 mo

Adverse events 0 RCTs -- -- Moderate

Balance of potential benefits and harm: Quality of overall evidence:

defined in the NRCS

Balance of potential benefits and harm: Quality of overall evidence:

N studies Test for heterogeneity

nnn Estimated from graph

N studies Pooled RR71 Test for heterogeneity

Balance of potential benefits and harm: Quality of overall evidence:

1 RCT 77 Serious limitations Direct Sparse

130 mo (47) (33)

109 Calculated by ERT

112 Calculated by ERT

122 Among patients with a mean proteinuria of 2 g/d.

N studies Test for

124 Calculated by ERT

131 Calculated by ERT

N studies Test for

N studies Test for heterogeneity

139 Higher doses of ACE-I in the MMF group

142 Calculated by ERT

146 Higher doses of ACE-I in the MMF group

N studies Test for heterogeneity

148 Calculated by ERT

N Subjects: Is limitation to evidence Yes

N studies Test for heterogeneity

155 Calculated by ERT

156 Calculated by ERT

159 Calculated by ERT

Ginzler Black 61% RR 0.16

164 Calculated by ERT

172 Calculated by ERT

177 Calculated by ERT

N studies Test for heterogeneity

179 Calculated by ERT

185 Calculated by ERT

188 Calculated by ERT

193 Calculated by ERT

201 Calculated by ERT

ESRD/ doubling of SCr

203 Calculated by ERT

208 Calculated by ERT

Osteoporosis/ hip RR 0.94

210 Calculated by ERT

ESRD/ doubling of SCr

↑BP with/without Austin Black 64% 9 (75%)

216 Calculated by ERT

Basal cell skin 0 (0%)

221 Calculated by ERT

223 Calculated by ERT

228 Calculated by ERT

234 Calculated by ERT

240 Calculated by ERT

Remission 0 RCTs -- -- -- -- -- -- -- High

Houssiau White 42% RR 0.74

249 Calculated by ERT