Introduction
Atypical HUS
Classification of atypical hemolytic uremic syndrome
Primary TMA: hereditary |
aHUS with complement gene mutation |
(CFH; CFI; CFB; C3; CD46; CFHR1 hybrid) |
TTP with ADAMTS13 mutation |
MMACHC TMA |
DGKE TMA |
Primary TMA: hereditary |
aHUS with complement autoantibodies |
(anti-FH; anti-FI) |
TTP with ADAMTS13 autoantibody |
Secondary TMAs |
TMA with glomerular disease |
(FSGS; IgAN, C3G/MPGN, MN, AAV) |
Malignancy associated TMA |
Drug induced TMA |
Direct toxicity (interferon B; bevacizumab) |
Immune mediated damage (e.g., quinine) |
TMA with autoimmune conditions |
(SLE, SRC, CAPS) |
De novo TMA after solid organ transplant |
HELLP |
Infection associated TMA |
STEC-HUS |
Pneumococcal HUS |
HIV associated aHUS |
Other |
Pathology
Inherited primary complement-mediated aHUS
Membrane cofactor protein
Complement factor I
Complement C3
Complement factor B
Thrombomodulin
Common genetic susceptibility factors
Acquired primary complement-mediated aHUS
Clinical presentation and outcome
Disease penetrance
Eculizumab in aHUS
Eculizumab non-responsive aHUS
DGKE
Inverted formin 2
Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type
Polymorphisms in C5 and the use of Coversin to treat TMA
C3 Glomerulopathy
Introduction
Classification and pathology of C3G
Overlap of C3G and MPGN
Immune-mediated glomerulonephritis
Monoclonal gammopathy of renal significance
Complement derangement in C3G and MPGN
FH deficiency
Gene | Effect | Variant | Gene | Effect | Variant | ||
---|---|---|---|---|---|---|---|
CFH
| Complete FH deficiency (homozygous) | P88T* |
CFH
| VUS (normal FH levels) | P26S | £ | |
R127L* | [73] | ΔG122-E128 | [65] | ||||
C431S | D130N | [65] | |||||
C597R | [65] | A161S | [65] | ||||
P621Y | [75] | IVS11 + 5 | [65] | ||||
C673S | [73] | G334A | £ | ||||
Y899X | [76] | G650V | [64], £ | ||||
Y1008X | [66] | F717L | [65] | ||||
W1096R* | £ | H878Y | 2 | ||||
Partial FH deficiency | P76X | [64] | A892V | 3 | |||
L77X | [65] | R1210V | [65] | ||||
V143I | [65] | VUS (FH levels not known) | R127C | [66] | |||
I216T | [77] | S199G/E1172X | £ | ||||
R232X | [65], £ | C431S | £ | ||||
C673R | [65] | N516K | [78] | ||||
K768X | [76] | V609I | £ | ||||
C1043X | [65] | M725X | [79] | ||||
Functional FH deficiency (homozygous) | R78G | [66] | V837I/E1145D | [78] | |||
ΔK224* | [80] | Q950H | [66] | ||||
R53C | T956M | ||||||
Functional FH deficiency | R83S* | [83] |
C3
| Gain of function | Δ923-924DG* | [84] | |
R1210C | I756T* | [85] | |||||
R53C | R161W | [87] | |||||
CD46
| VUS | K66N | VUS | R148Q | [87] | ||
V181M | [65] | A443S | [87] | ||||
CFI
| FI deficiency | G119R | L1100P | [87] | |||
A240G | L1318R | [87] | |||||
C309R | [65] | V86I | [66] | ||||
C327R | [65] | R505C | [66] | ||||
VUS | c.1-4C > T | [66] | V619M | [66] | |||
G57D | [66] | G637R | [66] | ||||
None | G261D | R1042Q | [66] | ||||
I306S | [65] | S1063N | [66] | ||||
CFB
| Gain of function | I242L | [87] | R1303H | [66] | ||
VUS | D279E | [87] | R1320Q | [66] | |||
S367R* | [95] | D1362N | [66] | ||||
G161R | [66] | C1518R | [66] | ||||
H451R | [66] | D1625H | [66] | ||||
R679W | [66] | None | K1051M | [66] |
FHR proteins
Genomic abnormalities in C3G
Abnormal FHR protein | Phenotype | Effect | Reference |
---|---|---|---|
FHR212FHR51–9 | DDD | Stabilizes C3bBb | |
FHR512FHR51–9 | CFHR5 nephropathy | De-regulates FH | |
FHR512FHR21–4 | C3GN | Not known | [101] |
FHR11234FHR11–5 | Low C3 | De-regulates FH | [102] |
FHR312FHR11–5 | C3GN | De-regulates FH | |
FHR1123FHR51–9 | DDD/C3GN overlap | De-regulates FH | [104] |
FHR512FHR21–4 | C3GN | De-regulates FH | [105] |