INTRODUCTION
Hemolytic uremic syndrome (HUS) is a rare disease characterized by thrombocytopenia
and acute renal failure. Atypical HUS (aHUS) accounts for approximately 10% of all
HUS cases. The pathogenesis of aHUS is mainly associated with gene mutations in complement
factor H, complement factor I, and membrane cofactor protein (MCP). The prognosis
of aHUS is generally poor. Totally, 60% of patients develop renal failure or even
die within 1 year. The efficacy of blood transfusion, dialysis, or plasmapheresis
is not excellent. Kidney transplantation is an important method for treating end-stage
renal diseases. Studies from other countries show that for patients with complement
system function disorders caused by aHUS, the transplantation success rate is low
and the postoperative aHUS recurrence rate is high.[1
2
3] With the introduction of the complement component 5 (C5) monoclonal antibody eculizumab
(Alexion, CT, USA), the long-term survival of patients significantly improves.[1]
We reported a 45-year-old male with aHUS caused by H factor gene mutation. We performed
successful kidney transplantation with the perioperative application of eculizumab.
During the 6-month follow-up, the function of the transplanted kidney was stable,
recurrence of aHUS did not occur, and no other complications were noted.
MEDICAL RECORDS
In January 2012, a 42-year-old male presented with 3-week history of cough, wheezing,
and edema. The laboratory examination showed the following results: hemoglobin (HGB)
65 g/L, platelet (PTL) 79 × 109/L, serum creatinine (Scr) 1089 μmol/L, blood urea
nitrogen 50.4 μmol/L, complement C3 0.44 g/L, and complement C4 0.24 g/L. Thoracic
X-ray suggested diffuse interstitial disease in both lungs. The main diagnoses were
severe pneumonia and acute renal failure. After treatment with respiratory support,
hormone pulse, hemodialysis, PTL transfusion, and antibiotics for 2 weeks, the respiratory
symptoms of the patient disappeared, and his body temperature returned to normal.
Gene detection analysis results suggested a factor H gene mutation. In addition, anti-factor
H antibody was not detected in his blood. Renal biopsy showed thrombotic microangiopathy.
In January 2014, he continued to receive regular hemodialysis and symptomatic treatment
in our hospital. The medication regimen with the complement C5 monoclonal antibody
(eculizumab) consisted of 900 mg/week for 4 continuous weeks, and then 1200 mg every
2 weeks until the surgery. Each tube of eculizumab was diluted with an equal volume
of 0.9% NaCl and intravenously infused at a speed of 150 ml/h. Then, we stopped the
plasmapheresis treatment. Because the application of eculizumab might induce a serious
Neisseria meningitidis infection, a meningitis vaccination was provided to the patient
before the start of the antibody therapy. In December 2014, he was stable. PLT level
had recovered to the normal range, and HGB level had increased to 98 g/L. After careful
preparation, he received a kidney transplant from a donor in January 2015. Laboratory
examination results were as follows: panel reactive antibodies I 22.5%, II 0%, total
13%; donor-specific antibody (−). The donor was a 31-year-old male with brain death.
We selected basiliximab (Novartis, Basel, Switzerland) (20 mg on day 0 and day 4)
for immune induction. The immunosuppressive regimen consisted of tacrolimus, mycophenolate
mofetil, and prednisone. He recovered well after the operation. The perioperative
eculizumab medication regimen consisted of 1200 mg 3 hours before surgery, 900 mg
each on day 1, day 8, day 15, and day 22 after surgery, 1200 mg on day 29, and 1200
mg every 2 weeks afterward to maintain the long-term inhibition of complement activity.
During the 6 months of postoperative follow-up, hematology examinations were regularly
performed every month. The complement C3 level of the patient gradually increased
to a normal level. The Scr, PLT, HGB, and complement C4 levels were within normal
ranges [Table 1].
Table 1
Laboratory test results during the 6-month follow-up
Time since transplantation (months)
Serum creatinine (μmol/L)
Platelet (×109/L)
Complement C3 (g/L)
Complement C4 (g/L)
−12
860.10
33.00
0.44
0.24
−1
726.30
132.00
0.59
0.25
0
233.70
142.00
0.59
0.25
1
69.10
156.00
0.60
0.25
2
57.80
151.00
0.61
0.25
3
72.20
146.00
0.72
0.25
4
70.30
160.00
0.72
0.24
5
75.60
178.00
0.77
0.25
6
66.10
173.00
0.79
0.25
Minus represent preoperation and zero represents the day of surgery. C3: Component
3; C4: Component 4.
During the follow-up, he did not show obvious signs of graft rejection, aHUS recurrence,
or infection.
DISCUSSION
The typical symptoms, laboratory test results, clear factor H gene mutation, and renal
biopsy evidence prompted us to confirm the diagnosis of aHUS. Literature from other
countries reported that eculizumab was the most effective way to treat aHUS.[4]
As we know, there are three pathways to activate complement system in human body,
including classic pathway, alternative pathway, and mannose-binding lectin pathway.
Under normal physiological conditions, C3 interacts with factor B and factor D to
produce a very small amount of C3b and C3bBb (i.e., the C3 convertase in the alternative
pathway). However, factor H, factor I, and MCP can mediate the conversion of C3b into
the inactive form C3bi, to block the complement reaction activated by the alternative
pathway and to prevent the body from being attacked by the complement system. If a
patient has a genetic defect in factor H, factor I, or MCP, or if a patient has autoantibodies
against factor H, factor I, and MCP, C3b cannot be inactivated, and the excessively
activated complement system in the alternative pathway will attack PTLs and endothelial
cells to cause the typical clinical manifestation of aHUS. Eculizumab can specifically
block the pyrolysis of complement C5 and inhibit the formation of C5a and C5b, to
prevent the release of the inflammatory factor C5a and to stop the formation of C5b-9.[4]
A study by Cugno et al. shows that the half-life of eculizumab is approximately 11
days and the complement activity is significantly inhibited after 2–3 weeks of application.
However, starting at week 4, the inhibitory effect gradually decreases. Therefore,
the factor H-deficient patient in this case requires long-term maintenance treatment
at least for 6 months.[1
5]
In this case, two issues captured our attention:
Mutation of the factor H gene produce a congenital disease. Most patients exhibited
disease onset in childhood or adolescence. However, this patient had disease onset
at the age of 42
Eculizumab is a complement C5 monoclonal antibody. It exerts a regulatory function
on the complement system by blocking the final pathway. However, it does not affect
the formation of C3 convertase in the alternative pathway. C3b can still label red
blood cells, which are cleared by the reticuloendothelial system, thus causing the
persistent destruction of HGB. However, in this case, we found that after eculizumab
application and kidney transplantation, the levels of HGB and complement C3 in the
patient gradually increased to normal range. The underlying mechanism still requires
further clinical and basic research as well as drug exploration.[6]
According to a literature review and a summary of our experiences, kidney transplantation
is an important measure for treating kidney failure caused by aHUS. Perioperative
eculizumab treatment is a safeguard for successful kidney transplantation, and long-term
maintenance treatment is crucial for the prevention of aHUS recurrence. However, our
conclusion is obtained from one single case. The detailed mechanisms of immunological
and genetic pathogenesis require further investigation. It is still unclear whether
all patients with factor H mutations require lifelong medication. In particular, further
clinical research is required to determine the efficacy and safety of perioperative
and long-term preventive applications of eculizumab in China for the treatment of
aHUS.[7]
Financial support and sponsorship
This work is supported by grants from Project Yangfan–Special Funds for the Development
of Clinical Medicine of Beijing (No. ZYLX201408), and Outstanding Personnel Training
Funds of Beijing (No. 2013D003034000044).
Conflicts of interest
There are no conflicts of interest.