Journal of Nephrology
https://doi.org/10.1007/s40620-020-00925-8
LESSONS FOR THE CLINICAL NEPHROLOGIST
Atypical hemolytic uremic syndrome due to DGKE mutation
and response to eculizumab: lessons for the clinical nephrologist
Danya Husain1 · Brian Barron2 · Anya Golkowski Barron2 · Ibrahim Sandokji1,3 · Olivera Marsenic4 · Jillian K. Warejko1
Received: 4 June 2020 / Accepted: 16 November 2020
© Italian Society of Nephrology 2021
Keywords  Atypical hemolytic uremic syndrome (aHUS) · Complement · Complement inhibitors · Pediatrics · Genetics
The case
An 18-month-old white boy presented with non-bloody
diarrhea and pallor and one week of cough and nasal con-
gestion. On examination, he was hypertensive (115/99) and
tachycardic (140 bpm). Pertinent labs included normocytic
hemolytic anemia with hemoglobin (Hb) 5.7 g/dL, mean
corpuscular volume (MCV) 84 fL, thrombocytopenia (plate-
let count 153 × ­103/μL, nadir of 127 × 1,000/μL), serum cre-
atinine 1.3 mg/dL, lactate dehydrogenase (LDH) 3,800 U/L,
markedly increased schistocytes (> 6/hpf), undetectable hap-
toglobin levels (< 10 mg/dL), microscopic hematuria (20–30
red blood cells (RBCs)/hpf), and proteinuria (3 +). Further
studies demonstrated a negative direct Coombs test, normal
levels of complement C3 and C4, and normal activity of dis-
integrin and metalloproteinase with a thrombospondin type
1 motif, member 13 (ADAMTS13) (Table 1). Stool PCR was
negative for pathogens associated with diarrhea + hemolytic
uremic syndrome (HUS) including Shiga toxin-producing
E. coli, Shigella, Salmonella, Campylobacter, Vibrio and Y.
enterocolitica. Infectious workup was notable for leukocy-
tosis 22 × ­103/μL, elevated erythrocyte sedimentation rate
(ESR) 92 mm/h, negative blood culture, negative respira-
tory viral panel, and negative chest X-ray. Given the concern
for atypical hemolytic uremic syndrome (aHUS), empiric
* Jillian K. Warejko
Jillian.warejko@yale.edu
1
Pediatric Nephrology, Department of Pediatrics, Yale
University School of Medicine, P.O. Box 208064,
New Haven, CT 06520‑8064, USA
2
Yale University School of Medicine, New Haven, CT, USA
3
Pediatric Department, College of Medicine, Taibah
University, Medina, Saudi Arabia
4
Pediatric Nephrology, Lucile Packard Children’s Hospital,
Stanford University School of Medicine, Stanford, USA
eculizumab therapy was initiated with a 600 mg loading
dose administered within 24 h of presentation, while await-
ing the thrombotic microangiopathy (TMA) profile per the
Kidney Disease: Improving Global Outcomes (KDIGO)
guidelines [7]. Given the trend of worsening hematologic
parameters, worsening renal function (stage 3 AKI) and
hypertension, eculizumab was given to treat his thrombotic
microangiopathy.
Complement analysis (drawn prior to administration of
eculizumab) showed elevated levels of factor Bb at 7.92
mcg/mL (1.32–4.18) and C5a at 18.66 ng/mL (2.74–16.33)
(Table 1). The patient’s hematologic and renal function
parameters improved while eculizumab therapy was con-
tinued (Fig.  1). Serial peripheral blood smears showed
improvement of schistocytosis. An aHUS gene panel later
demonstrated two heterozygous mutations in diacylglycerol
kinase epsilon (DGKE), including the known truncating
allele c.966G > A, p.322Trp* [1] and one novel c.171del,
p.Ser58fs. The genes in this panel included C3, CFB, CFH,
CFHR1, CFHR3, CFHR5, CFI, DGKE, MCP, THBD,
MLPA, CFHR1/CFHR3 deletion. This patient did not carry
at-risk haplotypes in CFH, CD46 and s. In reviewing the
Human Gene Mutation Database (HGMD) Biobase, the
c.171del allele is a novel mutation that results in a frameshift
mutation with likely premature protein termination. Parental
segregation was notable for the mother being heterozygous
for c.966G > A, wild type for c.171del and the father being
heterozygous for c.171 del, wild type for c.966G > A.
The patient was discharged on eculizumab infusions
every two weeks, prophylactic penicillin, antihypertensives
(labetalol and amlodipine), and enalapril for its antihyper-
tensive and antiproteinuric effects. After one month, anti-
hypertensive medications were weaned, except enalapril
which was continued for proteinuria (urine protein-to-cre-
atinine ratio of 1.5–2.5 mg/mg). He continues on antibiotic
prophylaxis and was fully vaccinated for pneumococcus
13
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 Journal of Nephrology

and meningococcus. The patient continues to have inter-

Ab Antibody, Bb complement Bb, C complement component, CFH complement factor H, CFI complement factor I, MCP methyl-accepting chemotaxis protein, SMAC soluble membrane attack
Normal expression on neutrophils
mittent microhematuria and high-normal LDH (370–438;
[ref 180–435 U/L]). His most recent creatinine was 0.2 mg/
dL, hemoglobin 11.2 g/dL, platelets 325,000/ml, LDH 362
U/L, and urine protein: creatinine ratio of 2.2. At the time
of this report, the patient has been on eculizumab therapy
for > 2 years with the frequency of infusions having gradu-
ally been decreased to every 4 weeks after 1 year with no
aHUS recurrence. Adequate suppression of complement
MCP

activity was maintained throughout his therapy and moni-

tored via total complement (CH50 < 15.5 [ref > 41 U/mL])
 < 244 ng/mL

and SC5b-9 levels (65–186 [ref 72–244] U/mL).

SMAC

261

Lessons for the clinical nephrologist

4.18 µg/

Most aHUS is caused by complement pathway dysregula-

1.32–

mL
7.92
Bb

tion; however, non-complement inherited disorders such as

recessive mutations in DGKE have been well-recognized
31.5 mg/

[1–4]. DGKE, on chromosome 17q22, is the first gene impli-

13.3–

cated in aHUS that is not part of the complement cascade

CFB

dL
16.5

[1, 5]. DGKE-associated aHUS typically presents in the

first year of life with multiple HUS episodes and is impli-
2.4–4.9 mg/dL

cated in ~ 27% of other aHUS cases at age < 12 months [1,

3]. Some patients develop nephrotic syndrome a few years
after diagnosis, and the majority progress to end-stage renal
CFI

3.7

disease in the second decade of life [1]. DGKE-associated

aHUS is typically refractory to the standard therapies of
 < 22 U/mL
CFH Ab

aHUS, including eculizumab and plasmapheresis [1].

 < 22

DGKE is expressed in podocytes and controls the intra-

cellular concentration of diacylglycerol (DAG), a com-
ponent of the phosphatidylinositol (PI) cycle that partici-
68.0 mg/

pates in multiple cellular functions such as lipid-mediated

37.0–
CFH

dL
46.1

intracellular signaling [6]. Although the pathophysiology

of DGKE-associated aHUS remains unclear, loss of gene
16.3 ng/

function appears to cause a prothrombotic state with micro-

thrombi formation in the glomerulus independent of alterna-
2.75–

mL
18.6
C5a

tive complement cascade activation [1]. Renal biopsies often

demonstrate features of chronic TMA [1, 3].
Table 1  Patient’s complement profile on presentation

39.0 mg/

We present a child with a novel DGKE mutation who

11.8–

responded to eculizumab without disease recurrence,

dL
17.1
C4

with a discussion on the clinical decision-making sur-

rounding continuation of long-term therapy. The mutation
88.2 ng/

c.966G > A, p.322Trp* is well established in the literature

25.0–

mL
59.4
C3a

[1]. The novel c.171del mutation is predicted to cause a

premature truncation due to frame shift and, therefore,
71–150 mg/dL

would be considered deleterious. At present, the knowl-

edge of the full phenotype of this gene is still evolving.
Furthermore, our patient presented with concomitantly
121

elevated C5a, Bb, and SC5b-9 levels. Patients with DGKE-

C3

associated aHUS typically do not exhibit complement

complex
range

abnormalities; however, some studies have shown that

ence
Refer-

complement derangements may be present at diagnosis

13
Journal of Nephrology

Fig. 1  Patient laboratory values throughout the disease course. An reference range (- -) 150–465 × 1,000//μL. B. Serum LDH and creati-
arrow () indicates that a dose of eculizumab was given on that day nine levels; LDH reference range (- -) 180–435 U/L; creatinine refer-
and a star () indicates packed RBC transfusion. A. Hemoglobin and ence range 0.2–0.8 ml/dL
platelet levels; Hemoglobin reference range 12.0–15.0  g/dL; Platelet

[8]. The patient’s initial leukocytosis, elevated ESR, and studies may imply subtle activation, as another study dem-
symptoms of cough and rhinorrhea may suggest that these onstrated that a patient with aHUS presented with only
complement abnormalities were due to an acute phase elevated Bb and SC5b-9 levels [9]. Overall, it is difficult
reactant phenomenon. On the other hand, the complement to conclusively delineate between these two possibilities.

13

Our patient continues to exhibit an uncharacteristic
response to eculizumab, with absence of aHUS relapse and
near complete resolution of renal and hemolytic abnor-
malities. This response stands in contrast to earlier studies
that suggested partial or no response with eculizumab in
patients with DGKE-associated aHUS [1]. As of his last
office visit, he is 3 years old; to date, his renal function
and blood pressure remain normal, whilst he remains on
enalapril to control proteinuria. Our case contributes fur-
ther to the scientific community by providing day-to-day
laboratory trends in DGKE-associated aHUS. Similarly
to our patient, a child with DGKE-associated aHUS who
did not respond to plasmapheresis showed good response
to eculizumab [8, 9].
At present, there are limited therapies for aHUS, includ-
ing plasmapheresis, eculizumab, its longer acting formula-
tion ravulizumab, and liver and kidney transplantation. To
date, there are no other medications or monoclonal drugs
available to prevent or treat aHUS, but research is ongoing to
discover novel therapies such as avacopan, an orally-admin-
istered complement C5aR1 antagonist [3, 4]. This case, how-
ever, demonstrates that DGKE-associated aHUS could have
improved outcomes with eculizumab. This antibody binds
C5 preventing its cleavage, thus preventing the formation
of C5b which is necessary to form SMAC [4]. However,
the loss of ability to form SMAC is associated with infec-
tions by encapsulated organisms, such as life-threatening
meningococcal infections [4, 7]. Given the risk of recurrence
with stopping therapy versus the risk of infection and cost,
there is an ongoing debate on when, if ever, to decrease
frequency or discontinue therapy [3, 8]. At this time, our
patient is receiving eculizumab at increased time intervals,
while we closely monitor him. In the era of personalized
medicine, both the presence of mutations known to cause
aHUS and the clinical picture should continue to be taken
into consideration together when deciding on how to treat.
A limitation of this case report is that some individuals with
DGKE mutation achieve remission with supportive care,
(JASN 28:3066–3075, 2017), so we cannot be absolutely
certain of the cause-effect relationship between eculizumab
and remission.
In conclusion, we present a case of aHUS with a novel
DGKE mutation and concomitant elevated Bb and C5a levels
that responded to eculizumab therapy. This case highlights
the dilemma of initiating and continuing long-term eculi-
zumab therapy in a patient with DGKE-associated aHUS. At
this time, response to therapy and the individual’s mutations
should be taken into consideration together when deciding
on continued treatment. In the absence of recommenda-
tions for the use of eculizumab in DGKE-mutation associ-
ated aHUS, informed joint decision-making with family on
length of therapy is important, including a discussion of the
risks of aHUS relapses, as well as spontaneous remission.
13
Journal of Nephrology
Acknowledgements  We would like to acknowledge and thank the
patient and his family for their willingness to participate in this case
report.
Author contributions  Data acquisition: DH, BB, AGB, IS, JKW;
data interpretation: DH, BB, AGB, IS, OM, JKW; supervision: OM,
JKW. Each author contributed important intellectual content during
manuscript drafting and revision, accepts personal accountability for
the author’s own contributions, and agrees to ensure that questions
pertaining to the accuracy or integrity of any portion of the work are
appropriately investigated and resolved.
Funding  There was no funding/support source for this report.
Compliance with ethical standards 
Conflict of interest  The authors have no financial conflicts of inter-
est to disclose.
Ethical approval  This article does not contain any studies with
human participants or animals performed by any of the authors.
Consent for publication  Legal guardians signed informed consent
regarding publishing their data and photographs.
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