Sabato 27 ottobre 2012 - Pacini Editore

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risk of developing this life-threatening condition varies widely
among these disorders, being higher for patients affected by
Familial Mediterranean Fever (FMF), Tumor necrosis factor
Receptor-Associated Periodic Syndrome (TRAPS) and Muckle-
Wells Syndrome (MWS). In spite of an acute-phase response during
attacks, there are only few previous published reports of its
occurrence in Hyperimmunoglobulinemia D with periodic fever
Syndrome (HIDS). We report a case to describe the occurrence
of renal AA Amyloidosis causing nephrotic syndrome in a young
Italian man affected with HIDS.
Material and methods. The patient, a 29-year-old man of southern
Italian ancestry, was referred to us in April 2011. Since the
first months of life he had experienced recurrent attacks of fever
associated with sore throat, myalgias, vomiting and diarrhoea.
Later the attacks of fever reduced their frequency but in the last
year there was an increased frequency of febrile episodes with
proteinuria in the nephrotic range. Laboratory examinations performed
showed proteinuria 9.17 g/24 h, a raised erytrocite sedimentation
rate, a normal C-reactive protein, leukocytosis, serum
amyloid 3.67 mg/L, serum IgD 233 UI/ml, creatinine 1.09 mg/dl.
A kidney biopsy was performed.
Results. Microscopic examination revealed extensive weakly
eosinophilic amorphous material infiltrating the mesangium, capillary
walls, tubular basement membranes, interstitium and vessels
walls. After Congo red staining, the deposits showed intense
apple-green birefringence under polarized light, consistent with
the presence of amyloid. On immunohistochemistry, the amyloid
deposits were intensively and specifically stained with an antiamyloid
A antibody and were negative for antibodies against k
and λ light chains. A diagnosis of renal AA Amyloidosis was
made, Stage III, with diffuse and global glomerular involvement,
late phase, according to the Staging System of renal Amyloidosis
proposed by Helmut Hopfer and co-workers recently. Clinical
and laboratory findings suggested the diagnosis of HIDS. The
research of TNFRSF1A mutations was negative; the research for
MVK mutations was positive in heterozygosis and revealed the
presence of 2 mutations in MVK, namely, V377I and I268T, thus
confirming the clinical diagnosis of HIGD. The patient started
therapy with Anakinra.
Conclusions. Hereditary periodic fevers are a group of rare
Mendelian disorders characterized by recurrent, self-limited attacks
of fever and inflammation predominantly involving the
serosal membranes, the joints and the skin. Five different entities
belong to this nosologic category, namely, FMF, TRAPS,
MWS, HIDS and Familial Cold Autoinflammatory Syndrome.
Patients are at variable risk for the development of systemic
reactive (AA) Amyloidosis, leading to the nephrotic syndrome
and renal failure. HIDS is a recessively inherited autoinflammatory
condition predominantly found in patients originating
from northwestern Europe. It was described in 1984 in a group
of children of Dutch ancestry. The disease manifests in infancy
and is characterized clinically by recurrent attacks of fever typically
lasting 3-7 days and usually occurring 6-12 times a year.
These episodes are often accompanied by headache, cervical
lymphadenopathy, arthritis, diarrhea, vomiting and rash. Attacks
may be precipitated by immunizations or minor infections and
the disease usually ameliorates with age. Clinical features are
accompanied by an acute-phase response and polyclonal elevations
of serum immunoglobulin D and often IgA concentrations.
In 1999, HIDS was reported to be associated with mutations
in the Mevalonate Kinase Gene (MVK), encoding the enzyme
mevalonate kinase, which is involved in cholesterol, farnesyl
and isoprenoid biosynthesis. The molecular mechanism by which
defective activity of mevalonate kinase may lead to fever attacks
are still unknown. To date, 39-HIDS-associated mutations have
been described of which the most common encode MVK V377I
and I268T. In contrast to the other periodic fever syndromes, the
risk of AA Amyloidosis in HIDS seems to be extremely low. Our
CONGRESSO aNNualE di aNatOmia patOlOGiCa SiapEC – iap • fiRENzE, 25-27 OttOBRE 2012
report contributes the evidence that AA Amyloidosis may occur
in association with HIDS, indicating the opportunity to envisage,
during the follow-up of patients with HIDS, the possible occurrence
of reactive Amyloidosis and to plan the appropriate laboratory
tests, including the assessment of systemic Amyloidosis, on
a regular basis.
references
Obici L, Manno C, Onetti Muda A, et al. First Report of Systemic Reactive
(AA) Amyloidosis in a Patient with the Hyperimmunoglobulinemia
D with Periodic Fever Syndrome. Arthritis & Rheumatism
2004;50:2966-9.
Lachmann HJ, Goodman HJB, Andrews PA, et al. AA Amyloidosis Complicating
Hyperimmunoglobulinemia D with Periodic Fever Syndrome.
A Report of Two Cases. Arthritis & Rheumatism 2006;54:2010-4.
Siewert R, Ferber J, Horstmann RD, et al. Hereditary Periodic Fever
with Systemic Amyloidosis: Is Hyper-IgD Syndrome Really a Benign
Disease? American Journal of Kidney Disease 2006; 48:E41-5.
Hopfer H, Thorsten W, Mihatsch MJ. Renal amyloidosis revisited:
amyloid distribution, dynamics and biochemical type. Nephrol Dial
Transplant 2011;26:2877-84.
Late antibody mediated rejection: correlation
between pathologic and clinical findings and posttransplant
de novo donor-specific HLA antibodies
in pediatric kidney recipients
A.R. Sementa1 , P. Ceriolo1 , F. Ginevri2 , G. Barbano2 , M.C. Coccia1
, G. Ghiggeri2 , C. Gambini1 1 2 Histopathology and Pediatric Nephrology, Giannina Gaslini Insitute
IRCCS, Genoa.
Introduction. Although in recent years short-term renal allograft
outcome has significantly and progressively improved, late failure
of kidney transplants remains a relevant clinical problem 1 .
Thus, clinical and pathological research is focusing its efforts
towards a better understanding of the mechanisms which lead to
chronic graft damage 2 , in order to identify markers able to predict
its onset and guide early or preemptive intervention. Renal biopsy
remains the most sensitive diagnostic tool for the diagnosis of
rejection and other causes of graft dysfunction. While the pathologic
features of graft rejection have been recognized for a long
time, the pathogenesis of both T cell-mediated rejection (TCMR)
and antibody-mediated rejection (ABMR) is not fully understood.
It is widely accepted that ABMR generally has a worse prognosis.
Recognition of the clinical relevance of alloantibodies (already
known as mediators of hyperacute rejection) rested on new
diagnostic techniques which showed that peritubular capillary
deposition of C4d in renal transplant biopsy is strongly associated
with a poor prognosis. C4d is a fragment of C4b, an activation
product of the classic complement pathway. C4d deposition is
strongly associated with circulating antibody to donor HLA class
I or class II antigen. The diagnostic criteria for ABMR rest on
morphological evidence of acute tissue injury; immunopathologic
evidence for antibody action in peritubular capillaries (C4d
deposition) and serologic evidence of circulating antibodies to
donor HLA or other anti-donor endothelial antigens. In response
to the emerging data and technologies, the 9 th Banff Conference
on Allograft Pathology up-dated the Banff schema for renal
allograft rejection 3 . As a result, inclusion of peritubular capillaritis
grading, C4d scoring and interpretation of C4d deposition
without morphological evidence of active rejection are among
the most important updates. A positive association between presence
of HLA antibodies prior to/after transplantation and poor
transplant outcome has been widely reported and significantly
contributed to elucidate the central role of humoral immunity
in the pathogenesis of chronic allograft damage. Nevertheless, a
number of patients in which the new solid-phase methods of detecting
alloantibodies had not demonstrated the presence of HLA