Pediatr Nephrol (2005) 20:17561761

DOI 10.1007/s00467-005-2040-4

ORIGINAL ARTICLE

Tanja Kersnik Levart Rajko B. Kenda

avic Duan Ferluga
Mojca Avgutin C
Anastazija Hvala Alenka Vizjak

C1Q nephropathy in children

Received: 4 April 2005 / Revised: 25 June 2005 / Accepted: 27 June 2005 / Published online: 25 October 2005

IPNA 2005

Abstract C1q nephropathy (C1qNP) is a peculiar form of

glomerulonephritis characterized by mesangial immunoglobulin and complement deposits, predominantly C1q,
with no evidence of systemic lupus erythematosus. We
describe the incidence, manifestation, histopathologic
findings, follow-up, treatment and outcome of C1qNP.
Twelve C1qNP patients were identified among 131 children who had undergone renal biopsy, accounting for a
9.16% incidence of C1qNP. Light microscopy examination showed focal segmental glomerulosclerosis (FSGS)
with or without diffuse mesangial proliferation (n=6),
minimal change disease (MCD) (n=4) or focal glomerulonephritis (n=2). C1q deposits were found in all, while
electron microscopy revealed visible deposits in nine
cases. Eight children presented with nephrotic syndrome,
while one had nephrotic proteinuria and renal insufficiency that progressed to end-stage renal failure. The remaining three patients presented with nonnephrotic proteinuria associated with microhematuria, hypertension or
renal insufficiency. Only one nephrotic syndrome patient
responded excellently to corticosteroids, while four became corticosteroid dependent, and three were corticosteroid resistant, showing a very poor response to other
immunosuppressive therapy as well. Patients with nonnephrotic proteinuria demonstrated fixed laboratory
findings. Most C1qNP patients had FSGS or MCD, the
majority of them presenting with corticosteroid-dependent or corticosteroid-resistant nephrotic syndrome. The
latter showed a very poor response to any immunosup avic
T. Kersnik Levart ()) R. B. Kenda M. Avgutin C
Department of Pediatric Nephrology,
University Medical Centre,
Stare pravde 4, 1000 Ljubljana, Slovenia
e-mail: Tanja.Kersnik@guest.arnes.si
Tel.: +386-1-5229600
Fax: +386-1-5229620
D. Ferluga A. Hvala A. Vizjak
Institute of Pathology,
Faculty of Medicine, University of Ljubljana,
Ljubljana, Slovenia

pressive therapy and high risk for progressive renal insufficiency.

Keywords C1q nephropathy Clinical manifestation
Histopathologic findings Follow-up Treatment
Outcome Children

Introduction
C1q nephropathy (C1qNP) is a poorly understood and still
very controversial entity. It is a relatively rare glomerulonephritis of unknown etiopathogenesis, characterized by
mesangial immunoglobulin and complement deposits,
predominantly C1q, with no clinical or serological evidence of systemic lupus erythematosus (SLE) [1]. The
incidence of C1qNP among patients who have undergone
renal biopsy varies from 0.21% [2] to 16.50% [3]. C1qNP
usually presents with proteinuria or full-blown nephrotic
syndrome, but other presenting features are also possible.
C1qNP may show only minor changes by light microscopy. According to some authors, in addition to diffuse
mesangial proliferation (DMP) and IgM nephropathy,
C1qNP represents a variant of minimal change disease
(MCD), while others believe it is often a separate condition [4]. However, more recent data suggest that C1qNP
may be more closely associated with focal segmental
glomerulosclerosis (FSGS) [2]. There is no known optimal therapy for C1qNP. The majority of patients with
C1qNP show poor response to oral corticosteroid therapy
[1, 3]. Moreover, in some patients, there is no consistent
evidence of any response to immunosuppressive therapy
[5]. On the other hand, some patients may show good
response to pulse corticosteroid therapy [3].
The outcomes of C1qNP are diverse. They are particularly poor in patients with nephrotic syndrome and
histological findings of FSGS. However, patients with
nephritic syndrome or nonnephrotic proteinuria and other
histological findings (MCD, DMP) may preserve their
normal renal function despite the absence of treatment
[3].

1757

Very few large series of C1qNP patients have been

reported so far, particularly in children. Iskandar et al. [3]
described the largest cohort of children with C1qNP. The
clinical, histological and prognostic features of 15 children were presented. Markowitz et al. [2] recently described 19 young adults with C1qNP, associated with
FSGS in 17 and MCD in 2 patients, which is the largest
single-center series of C1qNP so far.
To contribute some additional clinical experience to
the paucity of reports of C1qNP in children, we are reporting the second largest cohort of children with C1qNP.
The incidence of C1qNP among children who have undergone renal biopsy, the manifestation of the disease,
histopathologic findings, clinical follow-up, methods of
treatment and outcome are presented.

thus making a 9.16% incidence of this glomerular disease

among pediatric renal biopsises.
Manifestation of the disease
The manifestations of the disease are outlined in Table 1.
Most children (8/12) presented with nephrotic syndrome.
One presented with nephrotic proteinuria and renal insufficiency, while the other three presented with nonnephrotic proteinuria associated with microhematuria in
one, hypertension in one and renal insufficiency in one
child.
Histopathologic findings

Materials and methods

A total of 137 renal biopsies performed on 131 children at the
Department of Pediatric Nephrology, University Medical Center,
Ljubljana, from January 1994 to April 2004 were analyzed in a
retrospective study. C1qNP was characterized by mesangial immunoglobulin and complement deposits, with dominant or codominant C1q (demonstrated by the direct immunofluorescence
technique and semiquantitatively scored on a scale of 1 to 4+), in
patients without clinical or serological evidence of SLE, which was
carefully excluded. The anti-nuclear antibodies were negative, and
the serum complement concentrations were within normal limits.
Subsequently, 12 patients were identified as having C1qNP, 8 girls
and 4 boys, aged 4 to 16 years (mean 10.2 years). The patients
charts were reviewed retrospectively for manifestation of the disease, histopathologic findings, clinical follow-up, methods of
treatment and outcome. Light microscopy, immunofluorescence
and electron microscopy examinations were available in all 12
cases.
The nephrotic syndrome was characterized by nephrotic range
proteinuria (proteinuria exceeding 40 mg/m2/h), which led to hypoproteinemia/hypoalbuminemia, hyperlipidemia and edema.
Nonnephrotic proteinuria was defined as proteinuria ranging
from 4 to 40 mg/m2/h.
Hypoalbuminemia was defined as a serum albumin concentration below 25 g/l.
Hyperlipidemia was defined as an elevation of lipids above the
95th percentile for patient age and gender.
Renal insufficiency was defined by a calculated creatinine
clearance below normal values for patient age and gender.
Hypertension was defined as systolic or diastolic blood pressure
above the 95th percentile based on a childs gender, age and height
percentile.
Hematuria was defined by the presence of an abnormal quantity
of red blood cells in the urine, either microscopic or macroscopic.
Complete remission was defined as proteinuria below 4 mg/m2/
h and stable renal function at last follow-up.
Partial remission was defined by a reduction in proteinuria of at
least 50% and stable renal function at last follow-up.

Results
Incidence of C1q nephropathy
Twelve out of 131 children who had undergone renal
biopsy between January 1994 and April 2004 in a single
pediatric nephrology center met the criteria for C1qNP,

The histopathologic findings are presented in Table 1.

Light microscopy evaluation showed that the most common pattern of glomerular disease was FSGS with or
without DMP (Figs. 1, 2), presented in 6 out of 12 cases,
while MCD (Fig. 3) was found in 4/12 and mild focal
mesangial glomerulonephritis (FGN) in 2/12 cases. In
these last two cases, significant tubulointerstitial nephritis
and focal extraglomerular small vessel vasculitis (Fig. 4)
were also present.
Immunofluorescence revealed dominant or co-dominant staining for C1q in all 12 cases (Fig. 5), whereas C3
was found in 11/12 and C4 in 7/12 cases. There was a
positive staining for IgM in all 12 cases, whereas staining
for IgG (9/12) and IgA (7/12) was less consistent. A full
house pattern, revealing deposits of IgG, IgA, IgM, C1q
and C3, was found in 7/12 cases.
Electron microscopy revealed visible deposits in 9/12
cases. Their distribution was mesangial (Fig. 6) in 4/9,
mesangial and subedothelial in 3/9, mesangial, subepithelial and subendothelial in 1/9 and mesangial and subepithelial in 1/9 cases. Podocyte foot process effacement
(Fig. 3) was expressed in 8/9 children with nephrotic
syndrome or nephrotic proteinuria.
Clinical follow-up, methods of treatment and outcome
The clinical follow-up, methods of treatment and outcome
in relation to the manifestation of the disease and histopathologic findings are presented in Table 2. Eight out of
12 patients presented with nephrotic syndrome. Only one
of these, a patient with MCD, responded excellently to
corticosteroid therapy and experienced no relapse during
the 1-year follow-up period. Four patients, three with
MCD and one with FSGS associated with DMP, became
corticosteroid dependent, but responded very well to cyclophosfamide. Three patients with MCD experienced
complete remission, while in one patient with FSGS associated with DMP, partial remission was achieved. The
remaining three patients with nephrotic syndrome and
FSGS, two of them with associated DMP, were corticosteroid resistant and unfortunately also showed very poor

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Table 1 Manifestation of C1q nephropathy and histopathologic findings
Patient

Manifestation of disease

Light microscopy

Immunofluorescence

Deposits on electron microscopy

Nephrotic syndrome

MCD

Mesangial

Nephrotic syndrome

MCD

Nephrotic syndrome

MCD

Nephrotic syndrome

MCD

Nephrotic syndrome

FSGS

FSGS

7
8

Nephrotic proteinuria,
renal insufficiency
Nephrotic syndrome
Nephrotic syndrome

FSGS + DMP
FSGS + DMP

Nephrotic syndrome

FSGS + DMP

10

Proteinuria, hematuria

FSGS + DMP

11

Proteinuria, hypertension

FGN

12

Proteinuria, renal insufficiency

FGN

G(2+), A(1+), M(2+),

C3(2+), C1q(3+), C4(1+)
G(1+), M(1+),
C3(2+), C1q(3+)
M(2+), C3(1+),
C1q(2+), C4(1+)
G(2+), A(1+), M(1+),
C3(2+), C1q(4+), C4(1+)
G(2+), M(2+),
C3(1+), C1q(2+)
G(2+), A(1+), M(2+),
C3(1+), C1q(3+)
M(2+), C1q(2+)
G(2+), A(2+), M(3+),
C3(2+), C1q(3+), C4(2+)
G(3+), A(2+), M(3+),
C3(2+), C1q(3+), C4(1+)
G(3+), A(1+), M(2+),
C3(2+), C1q(3+), C4(2+)
M(1+), C3(3+),
C1q(3+)
G(3+), A(2+), M(3+),
C3(1+), C1q(4+), C4(2+)

No
Mesangial
Mesangial
Mesangial, subepithelial
No
Mesangial, subendothelial
Mesangial, subendothelial
Mesangial
Mesangial, subendothelial,
subepithelial
No
Mesangial, subendothelial

MCD minimal change disease; FSGS focal segmental glomerulosclerosis; DMP diffuse mesangial proliferation; FGN focal glomerulonephritis;
G immunoglobulin G; A immunoglobulin A; M immunoglobulin M; C3, C1q, C4 components of complement

Fig. 1 A glomerulus displays focal segmental glomerulosclerosis

not otherwise specified, associated with diffuse mesangial proliferation in patient 9 (PAS stain, 400)

response to other immunosuppressive therapy (cyclophosphamide, cyclosporine A, chlorambucil and mycofenolate mofetil). One of them progressed to end-stage
renal failure, one had transitory acute renal failure, while
in the last patient the follow-up was too short (6 months)
to predict the final outcome. In addition, end-stage renal
failure was observed in one patient with FSGS, who
presented with nephrotic proteinuria and renal insufficiency. Since her histopathologic findings showed a high
degree of chronicity, she was given no immunosuppressive treatment.

Fig. 2 One glomerulus shows collapsing focal segmental glomerulosclerosis surrounded by hypertrophic and hyperplastic podocytes, while the second glomerulus appears unremarkable in patient
5 (periodic acid-silver methenamine counterstained with Azan,
400)

The remaining 3/12 patients, who did not have nephrotic syndrome, showed fixed laboratory findings, regardless of whether they had had immunosuppressive
treatment. The patient with nonnephrotic proteinuria and
hematuria (with FSGS associated with DMP) was treated
with enalapril. The patient with nonnephrotic proteinuria
and hypertension (with FGN, extraglomerular vasculitis
and tubulointerstitial nephritis) responded very poorly to
antihypertensive therapy. She had been on corticosteroids

1759

Fig. 3 Electron micrograph shows moderate podocyte foot process

effacement of three peripheral glomerular capillary loops in patient
8 (osmium tetroxide fixation, uranyl acetate and lead citrate stain,
5,000)

Fig. 4 Acute necrotizing arteritis of the small interlobular artery,

accompanied by perivascular interstitial inflammation in patient 11
(H&E stain, 400)

and azathioprine because of autoimmune hepatitis 10

years before the renal disease was discovered. The patient
with nonnephrotic proteinuria and renal insufficiency
(with FGN, extraglomerular vasculitis and tubulointerstitial nephritis) was treated with cyclophosfamide, which
did not improve the degree of proteinuria, but a stable
renal function was achieved.

Discussion
Since C1qNP is still a very controversial and poorly
understood entity and our understanding of it has been
hindered by the paucity of any large studies, it seems
reasonable to report new cohorts of C1qNP patients in

Fig. 5 Immunofluorescence staining shows dominant (4+) global

glomerular mesangial C1q deposition in patient 8 (400)

Fig. 6 Electron micrograph shows mesangial-paramesangial electron-dense deposits surrounding the mesangial cell in patient 1
(osmium tetroxide fixation, uranyl acetate and lead citrate stain,
8,000)

order to improve our understanding of this rare condition.

The incidence of C1qNP among patients who have
undergone renal biopsy is quite diverse in different papers, ranging from 0.21% [2] to 16.50% [3] and was
9.16% in our study. We believe this should not be attributed to the varying incidence of C1qNP, but rather to
the difference in indications for renal biopsy, the inconsistent use of C1q staining as a part of immunofluorescence analysis and the differences in the age of patients
included in various studies. It is well recognized that indications for renal biopsy are not unanimously agreed
upon and that many institutions do not include C1q
staining as a routine part of histopathologic analysis. An
informal survey of renal pathologists in the UK in 1998
showed that only 50% of them undertook routine C1q

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Table 2 Clinical follow-up, methods of treatment and outcome in relation to the manifestation of C1q nephropathy and histopathologic
findings
Patient

Manifestation
of disease

Renal biopsy
findings

Corticosteroid
response

Other therapy

Follow-up
(years)

Outcome

1
2
3
4
5

Nephrotic
Nephrotic
Nephrotic
Nephrotic
Nephrotic

MCD
MCD
MCD
MCD
FSGS

Good
Dependent
Dependent
Dependent
Resistant

1
17
5
5
9

Complete remission
Complete remission
Complete remission
Complete remission
End-stage renal failure

Nephrotic proteinuria,
renal insufficiency
Nephrotic syndrome
Nephrotic syndrome

FSGS

Not given

None
Cyclophosphamide
Cyclophosphamide
Cyclophosphamide
Cyclophosphamide,
cyclosporine A,
chlorambucil,
enalapril
Enalapril

7
8

9
10
11
12

syndrome
syndrome
syndrome
syndrome
syndrome

Nephrotic syndrome
Proteinuria, hematuria
Proteinuria, hypertension
Proteinuria,
renal insufficiency

FSGS + DMP Dependent

FSGS + DMP Resistant

FSGS + DMP Resistant

FSGS + DMP Not given
FGN
Not given*
FGN
Not given

Cyclophosphamide
Cyclophosphamide,
cyclosporine A,
chlorambucil,
mycofenolate mofetil,
enalapril
Cyclophosphamide
Enalapril
Nifedipine, enalapril*
Cyclophosphamide

2.5

End-stage renal failure

1.5
1

Partial remission
Transient acute renal
failure; fixed nephrotic
syndrome

0.5
2.5
2
1.5

Fixed
Fixed
Fixed
Fixed

nephrotic syndrome
laboratory findings
laboratory findings
laboratory findings

MCD minimal change disease; FSGS focal segmental glomerulosclerosis; DMP diffuse mesangial proliferation; FGN focal glomerulonephritis
*Corticosteroids and other immunosuppressive therapy were not given for renal disease, but the patient was on corticosteroids and
azathioprine for 10 years because of autoimmune hepatitis

staining [5]. Since C1qNP shows the association with a

variety of glomerular diseases that are not uniformly
distributed in different age groups, it seems that the age of
patients also plays an important role in the diverse incidences of C1qNP [3, 4].
C1qNP usually presents with proteinuria, which is
frequently in the nephrotic range or, together with other
features, composes a nephrotic syndrome. Other presenting features (hematuria, renal insufficiency and hypertension), together with proteinuria, are also possible [1, 2,
3]. It seems that the majority of children with C1qNP
present with nephrotic syndrome [3], as was also observed
in our study.
The patterns of glomerular disease seen by light microscopy are diverse, but FSGS and MCD predominate,
FSGS being more often reported in adults [1, 2] and MCD
in children [3]. However, FSGS was a more common
pattern of glomerular disease than MCD in our large series of children with C1qNP. In addition, two children in
our study of C1qNP revealed a histological picture of
FGN associated with tubulo-interstitial lesions and focal
extraglomerular small vessel vasculitis, being peculiar in
clinical and pathohistological presentation. Considering
the definition of C1qNP, which includes predominant or
co-dominant glomerular deposits of C1q in patients
without any evidence of SLE, they both, one after a 1.5and the other after a 2-year follow-up period, still meet
the criteria for C1qNP. However, we should consider the
possibility that they might have different diseases, most
likely autoimmune, that had not yet fully presented. Imai
et al. [6] reported a similar case of a 35-year-old patient
with proteinuria, hematuria and hypocomplementemia

who had mild mesangial glomerulonephritis, tubulo-interstitial nephritis and arteriolitis associated with immunofluorescent findings characteristic for C1qNP. They
speculated that this could be a very rare variant of C1qNP.
The criterion for inclusion in C1qNP is dominant or
co-dominant staining for C1q [1, 2, 3]. Dominant or codominant C1q was associated with deposits of immunoglobulins and other complement components, sometimes
as a full-house pattern, in our study as well as reported
by others [1, 2, 3, 5].
Different studies [1, 2, 3] have confirmed the presence
of electron dense deposits in all renal biopsy samples
having mesangial, paramesangial or subendotelial distribution, while in our study visible deposits were demonstrated by electron microscopy in 75% of the cases.
The overall impression when reading papers on
C1qNP is that the disease has a poor prognosis. However,
by analyzing papers on C1qNP precisely and also considering the results of this study, it appears evident that
the disease as such is not a uniform entity. It is therefore
understandable that the prognosis of C1qNP depends
largely on the manifestation of the disease and underlying
histopathologic findings. Our study and other reports
show that the patients with the poorest prognoses are
those with nephrotic syndrome and FSGS [3, 7, 8, 9].
Their nephrotic syndrome is usually corticosteroid-resistant, and also resistant to other immunosuppressive therapy. Patients with MCD or other patterns of glomerular
disease have a more favorable outcome according to our
results, as well as the results of other studies [3, 10].
When they present with nephrotic syndrome, it is usually
corticosteroid dependent, but a good response to cyclo-

1761

phosphamide or pulse corticosteroid treatment has been

noted. When the disease manifests with other presenting
features associated with nonnephrotic proteinuria (hematuria, renal insufficiency or hypertension), fixed laboratory findings are usually found in the patients follow-up
regardless of immunosuppressive treatment. Exceptions
are patients with advanced renal insufficiency, especially
if they have nephrotic proteinuria, where end-stage renal
failure is very likely to occur.
In conclusion, the results of this study confirm that
most C1qNP cases show a histological picture of FSGS/
MCD and that the majority of children with C1qNP
present with nephrotic syndrome that is either corticosteroid dependent or corticosteroid resistant. Corticosteroid-dependent nephrotic syndrome patients are mostly
those with MCD who seem to respond well to cyclophosphamide or pulse corticosteroid treatment. In corticosteroid-resistant nephrotic syndrome patients, the histopathologic findings are mostly those of FSGS. These
patients show a very poor response to other immunosuppressive therapy and therefore their cases portend a
poor prognosis. An optimal therapy for C1qNP is still
unknown, and additional studies will be needed to define
it more precisely.

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pathologic entity usually causing nephrotic syndrome. Am J
Kidney Dis 6:103110
2. Markowitz GS, Schwimmer JA, Stokes MB, Nasr S, Seigle RL,
Valeri AM, DAgati VD (2003) C1q nephropathy: a variant of
focal segmental glomerulosclerosis. Kidney Int 64:12321240
3. Iskadar SS, Browning MC, Lorentz WB (1991) C1q nephropathy: a pediatric clinicopathologic study. Am J Kidney Dis
18:459465
4. Burton DR, Gerald BA. (2004) Minimal change variants: mesangial proliferation; IgM nephropathy; C1q nephropathy. In:
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nephropathy from lupus nephritis. Nephrol Dial Transplant
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6. Imai H, Tadashi Y, Satoh K, Miura AB, Sugawara T, nakamoto
Y (1996) Pan-nephritis (glomerulonephritis, arteriolitis, and
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type of C1q nephropathy? Am J Kidney Dis 27:583587
7. Churg J, Bernstein J, Glassock RJ (1995) Renal disease: classification and atlas of glomerular diseases, 2nd edn. IgakuShoin Medical Publishers, New York
8. Jennette JC, Hipp CG (1985) Prognostic importance of glomerular C1q in idiopathic nephrotic syndrome due to mesangioproliferative glomerulonephritis. Am J Kidney Dis 6 (abstract): A7
9. Korbet SM, Schwartz MM, Lewis EJ (1994) Primary focal
segmental glomerulosclerosis: clinical course and response to
therapy. Am J Kidney Dis 23:773783
10. Davenport A, Maciver AG, Mackenzie JC (1992) C1q nephropathy: do C1q deposits have any prognostic significance in
the nephrotic syndrome? Nephrol Dial Transplant 7:391396