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Indian Pediatr 2013;50: 793-794
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Atypical Hemolytic Uremic Syndrome with
Membranoproliferative Glomerulonephritis
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*Kumud Mehta, Vaishali More, Arun Chitale and Shaila Khubchandani
From the *Department of Pediatric Nephrology, Jaslok
Hospital and Research Center and Department of Pediatrics, Nephrology
Division, Dr. D.Y.Patil Medical College, Hospital and Research Center,
Nerul, Navi-Mumbai, Maharashtra, India.
Correspondence to: Dr Vaishali More, 201, M-5, C-wing,
Palm Acres CHS, Pratiksha Nagar, Sion, Mumbai 400 022, India, Email:
[email protected]
Received: May 05, 2012;
Initial review: May 31, 2012;
Accepted: April 27, 2013
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Atypical hemolytic uremic syndrome (aHUS) associated with
membranoproliferative glomerulonephritis (MPGN) is an uncommon clinical
presentation, especially in children. We report a 8-year-old-boy who
presented like aHUS but the kidney biopsy showed MPGN
type 1.
Keywords: Atypical hemolytic uremic syndrome,
Hypocomplementemia, Membranoproliferative glomerulonephritis.
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Atypical hemolytic uremic syndrome (aHUS)
and membranoproloiferative glomerulo-nephritis (MPGN) are
uncommon diseases. Both these conditions are widely studied and
reported to be associated [1,2]. Previously they were considered
to be chance association but now there are reports of the role
of factor H in the etiopathogenesis of MPGN and aHUS.
Case Report
An 8-year-old boy was brought with the
complaints of decreased urine output, generalized edema and
fever since one week. He had no history of similar episodes in
the past or history suggestive of chronic kidney disease in the
family. There was no history of diarrhea, sore throat, rash or
hematuria preceding this illness. Examination revealed anasarca,
periorbital puffiness and pallor. Patient did not have rash,
joint involvement or purpura. Blood pressure was normal. He had
abdominal distension due to ascites. Liver was tender and
palpable 4 cm below the subcostal margin with a span of 10 cm.
Spleen was not palpable.
Investigations on admission, revealed
hemoglobin level of 4.6 g/dL, reticulocyte count of 2%,
leukocyte count of 12,200/cu mm with 67% neutrophils, 25%
lymphocytes and platelets 1,72,000/cu mm. Peripheral smear
showed microcytosis, anisocytosis, schistocytes, few tear drop
and target cells. Blood level of albumin was 3.1 g/dL, total
proteins 5.6 g/dL, pH 7.4, pCO 2
26 mm Hg and bicarbonate 16.1 mEq/L, creatinine 1.2 mg /dL, urea
nitrogen 65 mg/dL, sodium 136 mEq/L and potassium 5.7 mEq/L.
Antistreptolysin O (ASO) was negative, C3 was 28 mg/dL and
hepatitis B and C serology were negative. Urinalysis showed 3+
proteinuria, 10-15 red cells /hpf and 5-10 leukocytes/hpf.
Prothrombin time was 17 seconds (control 19 seconds) and aPTT
was 27 seconds. Lactate dehydrogenase and D-dimer were 772 IU/L
and 2000 ng/dL, respectively. Serum C4 was normal and
antinuclear antibodies anti-ds, DNA were negative. A diagnosis
of acute renal failure with microangiopathic hemolytic anemia
due to HUS was made. There was a steady increase in blood urea,
creatinine and potassium with a fall in urine output over the
next two days. Peritoneal dialysis was done for 72 hours
following which these levels normalized and the urine output
improved.
Renal histology showed ten enlarged glomeruli
with diffusely thick basement membrane, proliferation of
mesangial cells, fewer endothelial cells and neutrophil
infiltration. The loops were obliterated. The tubules showed
focal necrosis, hydrophobic changes and atrophy. The vessels
showed mild luminal narrowing due to myointimal thickening. The
interstitium revealed few lymphocytes. Immunofluorescence
revealed deposition of IgM, C 3
and C1q in the mesangium and capillary loops. IgG
and IgA were negative. Electron microscopy revealed
proliferation of endothelial and mesangial cells. The lamina
densa showed excess of basement membrane material with zones of
interpositioning and subendothelial electron dense deposits. The
foot processes were flat. The findings were suggestive of
membranoproloiferative glomerulonephritis (MPGN) type 1.
The patient was treated with oral
prednisolone at a dose of 2 mg/kg/day and fresh frozen plasma
for the first few days followed by alternate day transfusions to
which patient responded well. These were then tapered and
stopped when the activity of HUS decreased. During the course of
prednisolone therapy, blood pressure increased requiring
multiple agents. Urine albumin reduced, but 5 months later
showed significant albuminuria. Therapy with mycophenolate
mofetil resulted in decrease in proteinuria.
Two months later, he was admitted with fever,
vomiting, diarrhea and abdominal pain and 4+ proteinuria. He
rapidly developed septicemia with hypotension and multiorgan
failure, and died after four days of intensive care and
ventilator support.
Discussion
HUS with MPGN has been widely studied and
reported in the past [1,3]. The earliest reports just mention it
as a chance association or as HUS secondary to MPGN whereas,
recent reports implicate the role of factor H which is an
important component of the alternate complement pathway in both
HUS as well as MPGN [1,2]. Ten percent of HUS patients are due
to atypical form which is distinct and different from the
typical HUS. The atypical form of HUS has a poor prognosis and
terminal renal insufficiency occurs in over 50% with death rates
close to 25% [3].
Our patient had a clinical presentation of
aHUS on admission and his renal biopsy was suggestive of MPGN
type I. There was no evidence of HUS on the biopsy findings, yet
the patient responded well to plasma infusions. The co-existence
of HUS with MPGN can be explained on the basis of factor H
deficiency.
Mutations in the factor H gene are associated
with severe and diverse diseases including the rare renal
disorders of HUS and MPGN, and and the more frequent age related
macular degeneration
[4-6]. In a study on 19 patients of
glomerulonephritis with C3 deposits, assays were performed for
factor H, factor I and membrane cofactor protein to determine
whether they share a common genetic susceptibility. The study
suggested that dysregulation of the complement alternative
pathway is probably associated with a wide spectrum of diseases
ranging from HUS to MPGN with C3 deposits [6]. The clinical clue
to the diagnosis of MPGN in this case was persistent low C3
complement, which is found only in factor H deficient or
complement associated HUS. In a study of 16 factor H-deficient
patients, six had a homozygous deficiency of which four
presented with MPGN and two had aHUS. Patients with heterozygous
mutations in factor H gene are also reported to develop aHUS
[7].
Treatment options include control of
hypertension, plasma infusions or plasmapheresis and use of
steroids, which will help in control of MPGN as well as a HUS.
Eculizimab has also been used in the treatment of refractory
MPGN [8] and has been found useful in patients where
mycophenolate mofetil does not result in a satisfactory
response.
Competing interests: None stated;
Funding: None.
References
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