Table 2.
The prevalence of rare variants in complement genes (i.e., CFH, CFI, CD46, CFB, C3, THBD, and CFHR1-CFHR5) and disease course in patients with secondary TMA confirm normal complement regulation. Single case reports have not been included.
| Genetics/FHAA a | Treatment | |||||
|---|---|---|---|---|---|---|
| Condition Ref. (Patients) | Rare Variants b | Pathogenic | Dialysis at Presentation | Kidney Outcome c | Standard of Care (SoC) | Eculizumab |
| STEC-HUS | 9/125, 7% | 3/125, 2% | >50% | 1–7% ESKD; no relapse d | Kidney response is common | Efficacy unproven |
| Ref. [67] (79) | 6/75 | 3/75 | 56% (median, 9 d) | 1% ESKD | Kidney response is common | Similar to SoC (n = 12) |
| Ref. [68] (25) | 1/25 | 0/25 | 80% (mean, 7 d) | - | - | - |
| Ref. [69] (26) | 2/25 | 0/25 | 65% (average, 16 d) | - | - | - |
| Ref. [70] (298) | - | - | 54% (mean, 10 d) | 1% ESKD | Kidney response is common | Similar to SoC (n = 67) |
| Ref. [71] (770) | - | - | 57% | 7% RRT at discharge | Kidney response is common | - |
| Ref. [72] (491) | - | - | 57% | 4% RRT at discharge | Kidney response is common | Similar to SoC (n = 193) |
| Post-diarrheal HUS | ||||||
| Ref. [67] (33) | 2/23, 9% | 1/33, 3% | 41% (median, 9 d) | 0% ESKD; no relape | Kidney response is common | Efficayc unproven; similar to SoC (n = 3) |
| Pneumococcal HUS | 3/5, 60% | 2/5, 40% | >50% | 14–23% ESKD; no relapse | Kidney response is common | Efficacy unproven |
| Ref. [73] (5) | 3/5 | 2/5 | 80% | - | - | - |
| Ref. [74] (37) | – | – | 73% (median, 15 d) | 23% ESKD | Kidney response is common | - |
| Ref. [75] (14) | - | - | 57% | 14% RRT at discharge | Kidney response is common | - |
| Drug-induced TMA | 2/62, 3% | 1/62; 2% | Variable | <16% ESKD; no relapse d | Kidney response is common | Efficacy unproven |
| Ref. [66] (32) | 2/32 | 1/32 | 22% | 16% ESKD | Kidney response is common | Similar to SoC (n = 13) |
| Ref. [76] (11) | 0/2 | 0/2 | 45% | - | Kidney response is common | - |
| Ref. [77] (15) | 0/15 | 0/15 | 33% | No ESKD | - | Kidney response is common |
| Ref. [78] (14) | 0/13 | 0/13 | - | No ESKD | Kidney response is common | - |
| Ref. [79] (19) | - | - | 90% | 17% ESKD | Kidney response is common | - |
| Cancer | 2/11, 18% | 1/11, 9% | Variable | ESKD competes with survival; no relapse | Kidney response is common | Efficacy unproven |
| Ref. [66] (11) | 2/11 | 1/11 | 55% | 30% ESKD | Kidney response is common | Similar to SoC (n = 8) |
| Ref. [80] (154) | - | - | 17% | - | - | - |
| Autoimmunity | 2/34, 6% | 0/34, 0% | Variable | Variable: ~10% (i.e., CAPS) [81] to >50% ESKD [82]; no relapse | Poor prognosis | Efficacy unproven |
| Ref. [66] (26) | 1/26 | 0/26 | 52% | 61% ESKD | Poor prognosis | No response (n/N = 8/9) |
| Ref. [77] (8) | 1/8 | 0/8 | 63% | 57% ESKD | Poor prognosis | No response (n/N = 6/7) |
| Ref. [83] (10; CAPS) | 1/10 | 0/10 | - | - | - | - |
| Ref. [84] (11; SLE) | 2/10 | 0/10 | 73% | 27% ESKD | - | No response (n/N = 4/11) |
| HSCT-TMA | 7/64, 11% | 0/64, 0% | 23% | Most surviving patients had CKD G3-4 [85,86]; no relapse | Poor prognosis with 1-year survival of 17% [87] | May be considered; 1-year survival of 66% [88] |
| Ref. [89] (34) | 3/34 | 0/34 | - | - | - | - |
| Ref. [88] (30) | 4/30 | 0/30 | 23% | - | - | - |
| DGKE-HUS | 3/72, 4% | 0/72, 0% | 50–69% | “late” ESKD; relapse is common | Kidney response is common | Efficacy unproven |
| Refs. [90,91] (44) | 3/44 | 0/44 | 52% | 23% ESKD (~12 yr); 70% relapse | Kidney response is common | Similar to SoC (n = 3) |
| Ref. [92] (15) | 0/15 | 0/15 | 50% (i.e., <3 Wk) | 13% ESKD (>20 yr); 53% relapse | Kidney response is common | Similar to SoC (n = 6) |
| Ref. [93] (13) | 0/13 | 0/13 | 69% | 31% ESKD (>10 yr); 77% relapse | Kidney response is common | Similar to SoC (n = 1) |
| Cobalamine C deficiency | ||||||
| Ref. [94] (36) | 2 e/15, 13% | 0/15, 0% | 22% | High mortality; no relapse | Kidney response is common | Efficacy unproven; no response (n/N = 4/5) |
| Monoclonal gammopathy | ||||||
| Ref. [95] (20) | - | - | 55% | 50% ESKD; no relapse | Kidney response is common | Efficacy unproven; no response (n/N = 1/1) |
a Rare variants indicate those with a minor allele frequency of <0.1%; detailed characteristics can be found in Table S1. b Number indicates pathogenic variants and variants of uncertain significance. c ESKD often within 1 year unless stated otherwise. d TMA recurrence linked to rare variant in complement genes. e Factor H autoantibodies were found in 1 patient with normal copies of CFHR1 and CFHR3, and thus these antibodies may not be relevant. CAPS, catastrophic antiphospholipid syndrome. CKD, chronic kidney disease (i.e., estimated GFR <60 mL/min/1.73 m2). D, days. DGKE, diacylglycerol kinase epsilon. TMA. ESKD, end-stage kidney disease. FHAA, factor H autoantibodies. HSCT, hematopoietic stem cell transplantation. SLE, systemic lupus erythematosus. STEC, Shiga toxin-producing E. coli. TMA, thrombotic microangiopathy. Wk, weeks.