letters to the editor

bodies and MPO-ANCA was established. She underwent intermittent

hemodialysis, and immunosupressive therapy with metilprednisolone
(15 mg/kg/day, 3 days, IV) followed
by oral prednisone (1 mg/kg/day),
cyclophosphamide (750 mg/m 2,
monthly, IV), and plasma exchange
with daily exchange of one volume
of plasma for 5% human albumin for
14 days was initiated. She also received red blood cell transfusions. Two
weeks later, the patient was asymptomatic, recovered diuresis, and improved renal function. At hospital
discharge (day 38), uremia and creatinemia
were 148 mg/dl and 2.5 mg/dl, respectively,
and hemoglobin was 10.9 g/dl. She had no
clinical or laboratorial evidence of disease relapse, and she remains out of dialysis.
This case illustrates several interesting points. The patient presented
with symptoms and signs in other organs suggesting systemic vasculitis.
Serologic tests revealed coexistence
of anti-GBM antibodies and MPOANCA, and histology showed CGN
with linear deposition of IgG along
the glomerular capillaries. Although
the patient presented with renal failure requiring dialysis, there was renal function recovery after immunosupression with plasma exchange,
without evidence of disease relapse.
In a substantial proportion of patients with CGN double-positivity
for anti-GBM antibodies and ANCAs
(mostly MPO-ANCA) is detected. 1-5
Double-positive patients may have a
clinical course and response to treatment more typical of vasculitis than
of anti-GBM disease, and have possibly developed anti-GBM antibodies secondary to vasculitic glomerular damage. Some patients have
symptoms and signs in other organs
suggesting systemic vasculitis, and
renal function recovery may be more
likely if ANCAs are present.1 Recent
observations 3-5 however, have failed
to detect the differences described
earlier. Rutgers et al. 4 reviewed 46
MPO-ANCA-positive, 10 double-positive and 13 anti-GBM-positive pa-

tients with CGN. Creatinemia was

lower in ANCA-positive patients
compared to double-positive or antiGBM-positive patients (5.0, 10.3,
9.6 mg/dl, respectively; P = .01), and
renal survival was different among
the 3 groups (65%, 10%, and 15% of
dialysis at 1 year, respectively; P =
.04). Levy et al. 3 analyzed 27 patients with CGN and double-positivity for anti-GBM antibodies and
ANCAs (mostly MPO-ANCA), and
described patient and renal survival
rates of 52% and 26%, respectively,
at one year. Sixty-eight percent of patients were dialysis-dependent at presentation, and none of these recovered
renal function, despite immunosuppression with or without plasma exchange.
Although patients with CGN and double-positivity for anti-GBM antibodies
and ANCAs may have a poor prognosis when presenting with severe disease, behaving more like anti-GBM disease than vasculitis, and recovery from
severe renal failure may be rare, this
case highlights that immunosupressive
therapy with plasma exchange can improve patient and renal outcome in
such patients.
1. Bolton WK. Goodpastures syndrome.
Kidney Int 1996;50:1753-66.
2. Jannette
JC.
Rapidly
progressive
crescentic glomerulonephritis. Kidney Int
2003;63:1164-77.
3. Levy JB, Hammad T, Coulthart A, Dougan
T, Pusey CD. Clinical features and
outcome of patients with both ANCA
and anti-GBM antibodies. Kidney Int
2004;66:1535-40.
4. Rutgers A, Slot M, Van Paassen P, Van
Breda Vriesman P, Heeringa P, Tervaert
JW. Coexistence of anti-glomerular
basement membrane antibodies and
myeloperoxidase-ANCAs in crescentic
glomerulonephritis. Am J Kidney Dis
2005;46:253-62.
5. Yang G, Tang Z, Chen Y, Zeng C, Chen
H, Liu Z, et al. Antineutrophil
cytoplasmic antibodies (ANCA) in
Chinese patients with anti-GBM
crescentic glomerulonephritis. Clin
Nephrol 2005;63:423-8.

S. Gonalves1, S. Jorge1
Nephrology and Renal Transplantation
Department. Hospital de Santa Maria.
Lisboa (Portugal)
1

Anatomical Pathology Department.

Hospital de Santa Maria. Lisboa (Portugal)
Correspondence: J.A. Lopes
Nephrology and Renal Transplantation
Department. Hospital de Santa Maria.
Av. Prof. Egas Moniz, 1649-035 Lisboa. Portugal.
jalopes93@hotmail.com
2

Treatment with
rituximab
for a patient with
p-ANCA
glomerulonephritis,
alveolar bleeding
and multiple relapses
on haemodialysis
Nefrologia 2010;30(6):710-12
doi:10.3265/Nefrologia.pre2010.Aug.10535

To the Editor,
The treatment of vasculitis associated with ANCA is still a topic of interest. Corticosteroids and cyclophosphamide are still the
cornerstone in the treatment of vasculitis associated with ANCA. We
must also point out the use of rituximab, a chimeric anti-CD20 antibody which has already been studied in several series of patients and
which seems to have a beneficial effect on refractory patients or those
with intolerance to the first-line
therapy. It has also been used with
other types of primary glomerulonephritis.
Several outbreaks seem to appear during the course of vasculitis associated with ANCA.
In patients with an established
chronic disease on dialysis or
kidney transplant recipients, relapse from the baseline disease
i s u s u a l l y u n l i k e l y, b u t n o t i m possible.

P. Fernandes1, J.A. Lopes1, L. Correia2,

710

Nefrologia 2010;30(6):698-713

letters to the editor

We present the case of a patient diagnosed with vasculitis associated
with ANCA with lung and kidney
disease being treated with renal replacement therapy with haemodialysis. He suffered multiple outbreaks
despite treatment with cyclophosphamide, corticosteroids and mycophenalate sodium. However, on
beginning treatment with rituximab,
he achieved full remission from the
disease and ANCA levels returned to
normal.
A male of 65 years of age, ex-smoker, diabetic was admitted to hospital
in 2005 due to minor haemoptysis,
oedemas on lower limbs, polyneuropathy, deterioration in renal function, and creatinine levels of 6 mg/dl.
He was found to have severe
anaemia together with impaired renal
function, proteinuria of 1.5 g/day,
haematuria with dysmorphic red
blood cells; he was positive for mpoANCA with a titre of 68.34 U/ml. A
kidney biopsy was performed showing extracapillary glomerulonephritis with fibrinoid necrosis and crescent formations with negative
immunofluorescence. In view of the
diagnosis of pauci-immune extracapillary glomerulonephritis with pulmonary involvement, treatment was
begun with 3 bolus of methylprednisolone at 1 g/day and monthly cyclophosphamide bolus. The patient
was discharged with creatinine level
of 2.9 mg/dl, and continued the treatment with monthly bolus cyclophosphamide and corticosteroids.
A year after the diagnosis, in 2006,
still in treatment with cyclophosphamide and corticosteroids, he had
a new outbreak of vasculitis with a
deterioration in renal function (Cr of
10.4 mg/dl), an increase in proteinuria and p-ANCA levels (188 U/l),
with no evidence of alveolar bleeding. He was treated with methylprednisolone bolus. In view of the severity of the outbreak and the lack of
renal function improvement, he was
given renal replacement therapy with
haemodialysis.
Nefrologia 2010;30(6):698-713

During the follow-up, the patient

was diagnosed with bronchiectasis,
and was admitted on several occasions with superinfections of the
lung.
In 2007, a year after the onset of
haemodialysis and in remission from
the disease, he was re-admitted with
a new outbreak of vasculitis with an
episode of haemoptysis, muscle pain,
asthenia, and worsening of the
anaemia. ANCA levels were 100 U/l.
He was treated with corticosteroids
and i.v. cyclophosphamide, with a
remission in the outbreak. Six
months later, still in treatment with
cyclophosphamide, he had a new
outbreak characterized by fever, asthenia, haemoptysis and ANCA of
193 U/l. Treatment was begun with
corticosteroids
and
cyclophosphamide, and mycophenolate was
added as a maintenance therapy but
was badly tolerated due to a digestive disorder and was abandoned.
In view of the patients history of
outbreaks of vasculitis despite the
standard immunosuppressor treatment with cyclophosphamide, and
the fact that he was undergoing renal
replacement therapy with haemodialysis, it was decided to begin treatment with 4 doses (375 mg/m 2) of rituximab.
Later, the patient continued treatment
with 4 bolus of cyclophosphamide per
month, remaining in remission and with
ANCA negativisation 21 months after
beginning treatment with rituximab,
without any secondary complications to
date.
The pathogenesis of glomerulonephritis associated with ANCA is
not totally clear. ANCA have been
related with the pathogenesis of vasculitis, although the levels of ANCA
in circulation do not always correlate
with the level of activity of the disease. The generation of ANCA is determined by the activation of autoreactive B lymphocytes through the
chronic stimulation of T lympho-

cytes, which explains the relapsing

nature of the disease. Furthermore,
ANCA produce the liberation of free
radicals and proteolytic enzymes
which leads to damage of the vascular endothelium in adjacent tissues.1
Immunosuppressor treatment of the
outbreaks in patients on dialysis does
not differ from the normal treatment
for patients with a generalised disease. Regarding the maintenance
therapy, various options have been
attempted to reduce the toxicity associated with cyclophosphamide,
such as azathioprine, mycophenolate
mofetil, and leflunomide.2
In refractory cases, rituximab has
been shown to be effective in
achieveing remission from the disease in several series of patients. Rituximab is a chimeric anti-CD20 antibody
which
depletes
B
lymphocytes, so it has been proposed
as a rescue therapy in refractory disease, as the aetiopathogenetic importance of B cells in the generation of
ANCA is well known. 3
As we have mentioned above, relapse of vasculitis is relatively uncommon in patients on haemodialysis, and it is even rarer to find
patients such as ours with multiple
relapses in spite receiving standard
immunosuppressor therapy and
haemodialysis.
Little experience has been acquired
into the use of rituximab as a rescue
therapy in haemodialysis patients.
However, reviewing the bibliography, rituximab treatment was assayed in a patient with a history of
terminal
chronic
disease
on
haemodialysis as a lymphoma B cell
treatment, showing that therapeutic
levels of the drug remain in the blood
despite haemodialysis, so it is not
necessary to adjust the treatment
doses. 4 Another patient with nonHodgkin
lymphoma
requiring
haemodialysis was treated with rituximab with no evidence of an increase in side effects.5
711

letters to the editor

In our case, treatment began with
4 doses of rituximab accompanied with a monthly bolus of cyclophosphamide, with which remission from the vasculitis
outbreaks was achieved together
with the reduction and later negativisation of the levels of
ANCA. This suggests that rituximab may be an effective drug as
a rescue therapy in patients on
chronic haemodialysis with a
vasculitis relapse.
1. Csernok E, Ai M, Gross WL, et al. Wegener
autoantigen induces maturation of
dendritis cells and licences them for Th1
priming via the protease - activated
receptor-2
pathway.
Blood
2006;107(11):4400-8.
2. Jayne DR, Rasmussen N, Andrassy K, et al.
A randomized trial of maintenance therapy
for vasculitis associated with antineutrophil
cytoplasmic autoantibodies. N Engl J Med
2003;349(1):36-44.
3. Wong C. Rituximab in refractory
antineutrophil cytoplasmic antibodyassociated vasculitis: what is the
current evidence?. NDT 2007;22:32-6.
4. Jillella AP, Dainer PM, Kallab AM,
Ustun C. Treatment of a patient with
end-stage
renal
disease
with
Rituximab: pharmacokinetic evaluation
suggest Rituximab is not eliminated by
hemodialisis.
Am
J
Hematol
2002;71(3):219-22.
5. Feldman G, Nattermann J, Gerhart T,
Nhle CP, Spengler U, Woitas R. Partial
remission of a newly diagnosed diffuse
large B-cell Non Hodgkins lymphoma
in a hemodialysis patient after
administration
of
inmunochemotherapy with Rituximab-CHOP.
Int J Lab Hematol 2007;29(6):469-73.
M.A. Azancot, I. Agraz Pamplona, J.
Fort Ros, A. Marn Valencia, I. Gil
Carballeira,
J. Camps Domenech
Nephrology Department. Vall dHebron
Hospital. Barcelona, Spain.
Correspondence: I. Agraz Pamplona
Seccin de Nefrologa.
Hospital Vall dHebron. Barcelona. Spain.
iagraz@vhebron.net

712

Kidney failure and

diabetes. Diagnostic
inertia?
Nefrologia 2010;30(6):712-3
doi:10.3265/Nefrologia.pre2010.Oct.10679

To the Editor,
Diabetes mellitus (DM) is a common
cause of kidney failure (KF), but this
pathology is not the only aetiology in
diabetic patients presenting with renal failure.
We present the case of a 62 year old
man with a history of arterial hypertension (AHT), duodenal ulcer, acute
myocardial infarction (AMI) and
type 2 DM, diagnosed in 2007.
In February 2008, he was admitted to
the internal medicine department with
pyelonephritis with acute KF (MDRD
21 ml/min), which were interpreted in
the context of the infection which was
made worse by taking non-steroidal
anti-inflammatory drugs (NSAIDs),
and continued on discharge. In September 2008, he was referred to the
nephrology department presenting
with grade 4 KF (MDRD 13.83
ml/min), proteinuria of 5 g/24 h, and
persistent microhematuria (negative
urine cultures and negative cytology
for malignancy). Of note in the rest of
the analysis were: Negative ANA,
ANCA, and Anti-GBM. Immunoglobulins, light chains, complements, and
proteinogram were normal. Blood
cultures for HCV, HBV, and HIV
were negative. Abdominal ultrasound:
kidneys of normal size with moderately cortical echogenicity with no
evidence of dilation of the excretory
tract. Normal ocular fundus.
In view of the rapid evolution of the
KF, without a clear aetiology being
known, a kidney biopsy was performed which revealed 21 glomeruli,
6 of them sclerotic and the rest with
glomerular mesangial expansion. A
crescent formation was observed in
one of these. Thickening of the tubular basal membrane and moderate in-

Figure 1. E.M: Postinfectious GN. Presence

of subepithelial electron-dense deposits
(humps).

terstitial inflammatory infiltrates

was seen, with a predominance of
plasma cells, polymorphonuclear
neutrophils, and lymphocytes. Immunofluorescence was negative. An
electronic microscope showed diffuse thickening of the glomerular
basal membrane with the presence of
subepithelial electron-dense deposits
forming the typical humps (Figure
1).
This finding lead to a diagnosis of
post-infectious glomerulonephritis
(PIGN)
complicating
a
nephropathy.
1. Pham TT, Sim JJ, Kujubu DA, et al.
Prevalence of nondiabetic renal disease
in diabetic patients. Am J Nephrol
2007;27:322.
2. Fingerhut D. KDOQI Clinical Practice
Guidelines and Clinical Practice
Recommendations for Diabetes and
Chronic Kidney Disease. Am J Kidney
Dis 2007;49(Suppl 2).
3. Coppo R, Gianoglio B, Porcellini MG,
Maringhini S. Frequency of renal
diseases and clinical indications for
renal biopsy in children (report of the
Italian National Registry of Renal
Biopsies in Children). Group of Renal
Immunopathology of the Italian Society
of Pediatric Nephrology and Group of
Renal Immunopathology of the Italian
Society of Nephrology. Nephrol Dial
Transplant 1998;13:293.
4. Haas
M.
Incidental
healed
postinfectious glomerulonephritis: a
Nefrologia 2010;30(6):698-713

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