Complement involvement in kidney diseases: From physiopathology to therapeutical targeting

Table 1 Representative abnormalities in complement leading to renal disease

Components/related molecules	Diseases
Complement C3	C3 glomerulopathy (DDD), aHUS
Factor H	C3 glomerulopathy (DDD/C3GN), aHUS
Factor I	C3 glomerulopathy (C3GN), aHUS
MCP	aHUS
Factor B	aHUS
CFHR5	Familial C3 glomerulopathy (CFHR5 nepropathy)
CFHR3-1	Familial C3 glomerulopathy
CFHR1/3	IgA nephropathy, aHUS
Factor B autoantibody	C3 glomerulopathy (DDD)
Factor H autoantibody	C3 glomerulopathy (DDD/C3GN)
Bb (activated factor B)	HUS, ANCA-associated vasculitis
C3Nef	C3 glomerulopathy (DDD, C3GN)
Soluble C5b-9	HUS, TTP, ANCA-associated vasculitis
C3a	ANCA-associated vasculitis, TTP
C5a	ANCA-associated vasculitis
C1q/C1qR	C1q nephropathy
Properdin	TI injury due to massive proteinuria
C5	ANCA-associated vasculitis
Factor B	ANCA-associated vasculitis
CRaR	TI inflammation, IRI
C5aR	IRI
Factor H	IRI
C5b-9	IRI
CD59	IRI

DDD: Dense deposit disease; aHUS: Atypical hemolytic uremic syndrome; C3GN: C3 glomerulonephritis; MCP: Membrane co-factor protein; CFHR5: Complement factor H-related protein; ANCA: Anti neutrophil cytoplasmic antibody; C3Nef: C3 nephritic factor; TTP: Thrombotic thrombocytopenic purpura; TI: Tubulo-interstitial; IRI: Ischemia-reperfusion-injury.

Table 2 Some of the molecules aimed to target complement, phase of the trial and renal diseases related

Compound name	Complement target	Compound class	Phase/indication
C1 inhibitor (Berinert)	C1r, C1s, MASP1, MASP2	Regulator	P 1/2 transplant
Cp40, AMY 101			PC transplant , aHUS, DDD
sCR1, CDX-1135	C3 conv, C4b, C3b	Regulator	P 1 DDD
Mirococept, APT070	C3 conv, C4b, C3b	Regulator	P 1/2 transplant
Eculizumab	C5	Ab	P 4 aHUS, P 2/3 STEC-HUS, P 2 ANCA vasculitis, P 1 transplant
Mubodina	C5	Ab	PC aHUS, DDD
Ergidina	C5	Ab	PC transplant
CCX168	C5aR	Small molecule	P 2 ANCA vasculitis
ADC-1004	C5aR	Protein	PC transplant

MASP1: Mannan-binding lectin-associated serine protease; P: Phase; PC: Preclinical; aHUS: Atypical hemolytic uremic syndrome; DDD: Dense deposit disease; sCR1: Soluble complement receptor 1; Ab: Antibodies; STEC-HUS: Shiga toxin producing Escherichia Coli-hemolytic uremic syndrome.

Table 3 Trials ongoing with eculizumab in renal diseases and in renal transplantation

Rank	Identifier	Status	Study name
1	NCT01221181	Active	Eculizumab therapy for dense deposit disease and C3 nephropathy
2	NCT02093533	Recruiting	Eculizumab in primary MPGN
3	NCT01275287	Active	Targeting complement activation in ANCA-vasculitis
4	NCT00844545	Completed	Open label controlled trial of eculizumab in adult patients with plasma therapy-resistant aHUS
5	NCT00844844	Completed	Open label controlled trial of eculizumab in adolescent patients with plasma therapy-resistant aHUS
6	NCT00844428	Unknown	Open label controlled trial of eculizumab in adolescent patients with plasma therapy-sensitive aHUS
7	NCT00838513	Unknown	Open label controlled trial of eculizumab in adult patients with plasma therapy-sensitive aHUS
8	NCT01194973	Unknown	An open-label, multi center clinical trial of eculizumab in adult patients with aHUS
9	NCT01193348	Unknown	An open label, Multi center clinical trial of eculizumab in pediatric patients with aHUS
10	NCT01755429	Unknown	The safety and efficacy of eculizumab in Japanese patients with aHUS
11	NCT01522170	Enrolling	aHUS observational long term follow up
12	NCT01522183	Recruiting	aHUS registry
13	NCT01770951	Completed	A retrospective, observational, non-interventional trial to assess eculizumab treatment effect in patients with aHUS
14	NCT02205541	Not yet recruiting	Eculizumab in shiga-toxin related hemolytic and uremic syndrome pediatric patients
15	NCT01410916	Completed	Safety and efficacy study of eculizumab in shiga-toxin producing Escherichia coli (STEC-HUS)
16	NCT01406288	Completed	Completed outbreak of HUS linked to Escherichia coli of serotype 0104:H4
17	NCT01756508	Recruiting	Eculizumab for prevention and treatment of kidney graft reperfusion injury
18	NCT01919346	Recruiting	Eculizumab for prevention of DGF in kidney transplantation
19	NCT01403389	Active	A study of the activity of eculizumab for prevention of DGF in deceased donor transplant
20	NCT02142182	Recruiting	A trial for prevention of DGF after kidney transplantation
21	NCT01567085	Active	Safety and efficacy of eculizumab in the prevention of AMR in sensitized recipients of a kidney transplant from a deceased donor
22	NCT02113891	Not yet recruiting	Eculizumab therapy for subclinical antibody-mediated rejection in kidney transplantation
23	NCT01095887	Active	Eculizumab added to conventional treatment in the prevention of antibody-mediated rejection in blood group incompatible living donor kidney transplantation
24	NCT01106027	Active	Dosing regimen of eculizumab added to conventional treatment in positive crossmatch deceased kidney yransplant
25	NCT01895127	Recruiting	Efficacy and safety of eculizumab for treatment of antibody-mediated rejection following renal transplantation
26	NCT00670774	Active	Dosing regimen of eculizumab added to conventional treatment in positive crossmatch living kidney transplant
27	NCT01399593	Active	Safety and efficacy of eculizumab to prevent AMR in living donor kidney transplant recipients receiving desensitization
28	NCT01327573	Active	Eculizumab therapy for chronic complement-mediated injury in kidney transplantation
29	NCT01029587	Recruiting	Eculizumab to enable renal transplantation in patients with history of catastrophic antiphospholipid antibody syndrome

MPGN: Membrano-proliferative glomerulonephritis; ANCA: Anti neutrophil cytoplasmic antibody; aHUS: Atypical hemolytic uremic syndrome; STEC-HUS: Shiga-toxin producing escherichia; DEGF: Delayed graft function; AMR: Antibody mediated rejection.