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NDT Advance Access published online on March 29, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm041
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Renal involvement in systemic amyloidosis—an Italian retrospective study on epidemiological and clinical data at diagnosis

Franco Bergesio1, Anna Maria Ciciani2, Marisa Santostefano3, Rachele Brugnano4, Marco Manganaro5, Giovanni Palladini6, Anna Maria Di Palma7, Marco Gallo8, Pier Luigi Tosi2, Maurizio Salvadori1 on behalf of the Immunopathology Group of the Italian Society of Nephrology

1Renal Unit, Azienda Ospedaliero-Universitaria Careggi, 2Renal Unit, Nuovo Ospedale S. Giovanni di Dio, Firenze, 3Renal Unit, Ospedale S. Maria delle Croci, Ravenna, 4Renal Unit, Ospedale R. Silvestrini, Perugia, 5Renal Unit, Ospedale Mauriziano Umberto I°, Torino, 6Amyloid Centre, Ospedale Universitario S. Matteo, Pavia, 7Renal Unit, Ospedali Riuniti, Foggia and 8Dialysis Centre "Ulivella", Istituto Fiorentino di Cura e Assistenza, Firenze, Italy

Correspondence and offprint requests to: Franco Bergesio, Renal Unit – Azienda Ospedaliero-Universitaria Careggi, Villa Monna Tessa, Viale Pieraccini 18, 50139 Firenze Italy. Email: francobergesio{at}libero.it



   Abstract
Top
 Abstract
Introduction
 Aim of the study
 Study design
 Patients
 Methods
 Results
 Discussion
 Conclusion
 Appendix. List of participating...
 References
 
Background. Few data are available on epidemiology and clinical picture of renal involvement in different forms of systemic amyloidosis.

Methods. Patients with biopsy-proven systemic amyloidosis diagnosed in Italy between January 1995 and December 2000 were selected from 49 Nephrology and Internal Medicine Units provided they showed signs characteristic of renal involvement. Clinical and laboratory information were collected by using a specific data form for diagnosis integrated by a questionnaire on diagnostic tools. Collected data were matched both with the Italian Registry of Renal Biopsies (IRRB) and the Registry of the Italian Society of Amyloidosis (SIA) in order to approximate the incidence of the disease.

Results. Of all patients, 373 were finally selected throughout Italy with an estimated mean incidence of renal amyloidosis of 2.1 per million population (p.m.p.) per year. Of those, 237 were affected from AL (primary) amyloidosis, 104 from AA (secondary) amyloidosis and 6 from AF (heredofamilial) forms. In 26 cases the type of amyloidosis remained undetermined. Among patients with AL, 36 presented an associated multiple myeloma (MM). Rheumatoid arthritis (RA) was the commonest underlying disease in AA. Median age ranged between 63 and 65 years in all groups. Males were prevalent in AL and females in AA. The main clinical features of renal involvement were represented by nephrotic syndrome and renal failure observed in 59 and 54% of cases, respectively. The presence of a lambda light chain, either in serum or urine was significantly associated to a more elevated urinary protein loss and to a reduced renal function.

Patients with AA showed a worse renal function at presentation than patients with AL, possibly due to a late diagnosis and/or referral to nephrology units. Diagnosis was obtained by renal biopsy in 315 cases, by abdominal fat tissue (AFT) aspiration/biopsy in 156 patients and by other organ biopsies in 47 patients. Characterization of deposits was extremely variable among referring centres.

Conclusions. Our results point to an increased incidence of renal amyloidosis observed in Italy over the period 1996–2000 with AL as the prevalent type. Characterization of amyloid deposits still remains the major diagnostic challenge of the disease. The institution of networks dedicated to rare diseases is strongly recommended in order to effectively afford this challenge.

Keywords: AA amyloidosis; abdominal fat aspiration; AL amyloidosis; epidemiology; renal amyloidosis; renal biopsy



   Introduction
Top
 Abstract
 Introduction
Aim of the study
 Study design
 Patients
 Methods
 Results
 Discussion
 Conclusion
 Appendix. List of participating...
 References
 
The amyloidoses constitute a heterogeneous group of systemic or localized diseases, characterized by extracellular deposition of protein precursors, as insoluble fibrillar aggregates, able to induce both an organ dysfunction and/or cellular death [1]. Despite a common beta-fibrillar structure, the protein precursors and pathogenetic mechanisms of amyloid fibrils may vary according to the different type of amyloidosis: AL (primary or immunoglobulin light chain associated), AA (secondary or reactive to chronic inflammation) and AF or heredofamilial. Amyloidosis is classified under the group of rare diseases even if it has been and likely still remains largely under-diagnosed.

The epidemiology of amyloidosis is not well known [2] and mostly limited to case-series and mortality data for AL [2–4] and/or autopsy studies for AA [2,5–7]. Kyle et al. [8] in the attempt to determine incidence of AL amyloidosis in Olmstead County, Minnesota, during the period 1952–92, found that the overall age and sex-adjusted annual incidence rate was 8.9 cases per million population (p.m.p.) per year and estimated a global incidence of ~1275–3200 new cases per year in the USA.

AA epidemiological data, extrapolated from autopsy records in western nations, estimated a prevalence of about 0.5–0.86% varying according to environmental risk factors and geographic clustering [2,9]. Incidence and prevalence of heredofamilial forms of amyloidosis are not known, although some of them are particularly common in specific geographical areas [10].

The kidney is frequently involved in AL and almost invariably in AA.

Nephrotic syndrome and/or renal failure occur at presentation in about two-thirds of the patients with AL [3,4,11] and up to 91% of patients with AA [5].

Renal involvement is also common in some heredofamilial forms like those due to mutations in the genes for fibrinogen A {alpha} chain, apolipoprotein A1, A2, lysozyme or, less frequently, transthyretin (TTR) molecule [11].

On the other hand, renal amyloidosis characterized by vascular deposits [12] or tubulo-interstitial nephritis with mild progressive renal failure but without significant proteinuria has been recently described in apolipoprotein A1 [13] and TTR familial forms [10], as well as in some cases of AL and AA [12].

Renal amyloidosis, regardless of the type, accounted for 2.5 and 4% of all renal biopsies in the Italian (1987–93) [14] and Spanish registry (1994–99) [15], respectively.

Prevalence of amyloidosis among elderly non-diabetic patients with nephrotic syndrome increases to 12% in Italian and Spanish registries (URL http://www.irrb.net) and to 17.2% of all renal biopsies, respectively [16]. However, no data on the type of amyloid deposits are reported in either registry. Currently, the gold standard for diagnosis of amyloidosis is Congo red staining of tissue biopsies with typical apple-green birefringence when viewed under polarized light. Under the electron microscope, all amyloid deposits appear as rigid, non-branching and randomly arranged fibrils of 8–10 nm in diameter [1]. The amyloid biochemical composition is revealed either by immunofluorescence or immunohistochemical techniques and, more appropriately, by electron-immunohistochemistry [17]. DNA sequence analysis of amyloidogenic protein variants further contributes to define the nature of deposits in AF [1].

Kidney biopsy, like other parenchimatous organs, is usually being discouraged because of the risk of bleeding complications. Thanks to the widespread nature of the amyloid deposition, biopsy of salivary glands, skin, rectum, abdominal fat and bone marrow can easily reveal amyloid deposits in most cases of AL, so that only few patients need to perform a biopsy of the involved organ (kidney, heart, etc.) [4,18]. In a blind controlled study, abdominal fat tissue (AFT) aspiration revealed AL amyloidosis with a sensibility of 72% and a specificity of 99% [19]. AFT aspirate has a probative value in patients with high clinical suspicion of amyloidosis supported by consistent clinical and laboratory data [18–20].

The procedure proved to be a simple, safe and certainly an effective alternative to organ biopsy [21,22].



   Aim of the study
Top
 Abstract
 Introduction
 Aim of the study
Study design
 Patients
 Methods
 Results
 Discussion
 Conclusion
 Appendix. List of participating...
 References
 
Primary end-points:

  • to attempt a retrospective evaluation of the incidence of renal amyloidosis in Italy between January 1995 and December 2000,
  • to analyse demographic data and clinical characteristics of patients according to the different types of amyloidosis (AL, AA and AF).

A secondary end-point was represented by the evaluation of diagnostic procedures, and particularly of those employed for characterization of amyloid deposits.



   Study design
Top
 Abstract
 Introduction
 Aim of the study
 Study design
Patients
 Methods
 Results
 Discussion
 Conclusion
 Appendix. List of participating...
 References
 
We retrospectively evaluated a cohort of patients affected by biopsy-proven systemic amyloidosis with renal involvement diagnosed in Italy between January 1995 and December 2000. Patients were selected from among 45 major renal units representing the 35% of all nephrological centres associated to the Italian Society of Nephrology (SIN) and from three internal medicine units and one haematology unit associated to the Italian Society of Amyloidosis (SIA).

In addition, in order to attempt a retrospective evaluation of the incidence of renal amyloidosis, our data were matched for the period 1996–2000 with the two major data bases existing in Italy: the Italian Registry of Renal Biopsies (IRRB) and the Registry of SIA.



   Patients
Top
 Abstract
 Introduction
 Aim of the study
 Study design
 Patients
Methods
 Results
 Discussion
 Conclusion
 Appendix. List of participating...
 References
 
Inclusion criteria
All patients with evidence of amyloid deposits on renal biopsy were enroled into the study. According to criteria for non-invasive diagnosis of amyloidosis, patients who underwent biopsies of other organs including AFT were enroled into the study provided they showed typical signs of renal involvement [urinary protein excretion (UPE) >0.5 g/day and/or renal insufficiency] and did not suffer from diabetic nephropathy [18].

Patients on dialysis at time of diagnosis were also included in the study provided they underwent a renal biopsy.

Data collection
Data were collected by using a form which included clinical and laboratory characteristics at presentation: type and site of biopsies, serum creatinine, 24 h UPE, monoclonal component (MC) in serum and/or urine, bone marrow plasma cell infiltration and heart involvement.

In addition, a questionnaire was sent out to all centres in order to collect further information on diagnostic tools employed for diagnosis and characterization of deposits. In particular we investigated the sampling and reading of AFT specimens as well as the immunoreactivity to commercially available antibodies specific for kappa and lambda light chains, amyloid A protein (AA) and TTR.



   Methods
Top
 Abstract
 Introduction
 Aim of the study
 Study design
 Patients
 Methods
Results
 Discussion
 Conclusion
 Appendix. List of participating...
 References
 
Diagnosis and classification of amyloidosis
Diagnosis was made by each participating centre in the presence of typical apple-green birefringence under a polarized light microscope after staining with Congo red.

Amyloid classification was carried out according to clinical, laboratory and histopathological criteria such as the presence of a suggestive family history, the type and number of organs involved, the presence of a MC either in serum and/or urine and the presence of clinical and laboratory features typical of a chronic inflammatory disease. Regarding histopathology, centres were asked which type of antibodies they usually employed: against kappa and lambda light chains, AA or TTR and whether they used immunofluorescence or immunohistochemistry.

Diagnosis of familial forms usually associated to renal involvement was made by DNA analysis searching for mutations in the genes encoding for apolipoprotein AI, apolipoprotein AII, lysozyme, fibrinogen A {alpha}-chain and TTR. DNA was obtained, using standard procedures, from peripheral blood mononuclear cells of affected patients. Mutations were detected by direct sequencing of the investigated genes as reported elsewhere [13].

Missing or conflicting data were explained by means of direct contacts with referring physicians. Supplementary information were requested in the absence of diagnosis of the type of amyloidosis or in the presence of conflicting data like, for instance, the presence of a MC in patients recorded as AA. Eventually, those cases in which the type of amyloidosis was not reported or available data were insufficient to reach a confident diagnosis were signed as ‘undetermined’ (UD) and were excluded from statistical evaluation.

Multiple myeloma (MM) was diagnosed according to Salmon and Durie criteria [23] when bone marrow plasma cells were ≥20% in the presence of hypercalcaemia and/or lytic bone lesions.

Because of the great variability of normal reference values adopted by different laboratories, we arbitrarily defined renal failure as a creatinine level ≥1.3 mg/dl. Serum creatinine levels were derived from laboratory data performed at the time of diagnosis. An UPE above 3.5 g/day was defined as nephrotic level proteinuria.

Cardiac involvement was recorded in all cases with low voltages in the standard leads and typical features of restrictive cardiomiopathy were associated with diastolic dysfunction, granular sparkling of myocardial texture and increased interventricular septum thickness on echocardiography, in the absence of other potential causes of left ventricular hypertrophy.

Statistical analysis
All data are presented as medians with range. Differences between groups were evaluated using Mann–Whitney U-test for unpaired data or {chi}2 analysis when necessary. The annual incidence was defined as the total number of new cases per year related to the mean total population of the year and it was expressed as p.m.p.

P < 0.05 was considered significant.



   Results
Top
 Abstract
 Introduction
 Aim of the study
 Study design
 Patients
 Methods
 Results
Discussion
 Conclusion
 Appendix. List of participating...
 References
 
Three hundred and seventy-three fulfilled inclusion criteria.

Distribution of patients according to different type of amyloid is shown in Figure 1. Clinical characteristics of patients are reported in Table 1.


Figure 1
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  		Fig. 1. Distribution according to different type of amyloidosis in 373 patients. UD, undetermined.

 

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  		Table 1. Demographic and laboratory data according to different type of amyloidosis

 
In keeping with the diagnostic criteria adopted, 237 patients (63.5%) were classified as AL of whom 36 (9.6%) were found to have an associated MM. One hundred and four (27.9%) were classified as AA and six (1.6%) as AF. Of these, four patients were affected by a recently reported new variant of apolipoprotein A1 (Leu75Pro) and were selected from a very restricted geographical area in Northern Italy (13). One patient showed a fibrinogen A {alpha} chain mutation (Glu526Val) and another one remained undetermined.

In 26 patients, amyloidosis type remained undetermined (UD = 7%). Ten patients were on dialysis at the time of diagnosis. Five of them were AL, four AA and one remained undetermined. In this case diagnosis was made few months after beginning of renal replacement therapy (RRT).

Demographic data at presentation was as follows: 191 females (51%) and 182 males (49%) with a M/F ratio of about one. Median age at diagnosis was 63 years (range 19–88) with no significant differences between males (median 63) and females (median 66).

Male gender was prevalent in AL (M/F 112/89) and in MM (22/14), while females were more prevalent in AA (M/F 42/62). AF presented an equal gender distribution (3/3). Median age was similar, with a wide range of distribution, in all amyloid groups (Table 1).

Frequency of different types of amyloidosis according to age and gender distribution is reported in Figure 2: 62% of patients aged between 60 and 79 years; 30% between 40 and 59 years; 4% of patients aged <40 years and 4% >80 years.


Figure 2
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  		Fig. 2. Frequency of different types of amyloidosis according to age and gender distribution.

 
Incidence study
In the period 1996–2000, 13125 renal biopsies of native kidneys were referred to the IRRB. Renal amyloidosis was diagnosed in 380 cases for an overall incidence of 2.9% (URL http://www.irrb.net). After matching these cases with those diagnosed in our series as well as in series from SIA in the same period of time, a total number of 608 patients were finally collected. In this period the mean annual incidence of renal amyloidosis increased from 1.8 to 2.4 with an estimated median of 2.1 p.m.p. per year.

Site of diagnosis and characterization of deposits
Diagnosis of amyloidosis was carried out with renal biopsy in 315 cases (84.5%), while in the remaining 58 (15.5%) this was established on the basis either of AFT biopsy/aspiration (49 cases, 13.1%) or of other organ biopsies (nine cases, 2.4%) (Table 2).


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  		Table 2. Site of diagnosis according to amyloid typea

 
AFT specimens, either obtained by aspiration or biopsy, were performed in 33 centres (77%) for a total number of 156 patients (41.8%) using different modalities: 22 centres performed a fine needle aspiration, nine a surgical biopsy procedure and two a needle biopsy.

The histological specimen was evaluated by the pathologist in 26 centres and by the same operator in eight. One hundred and seven among 156 patients also received a renal biopsy allowing us to investigate AFT sensitivity. Overall sensitivity of AFT reached 78% with 82% in AL and 70% in AA (Table 3).


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  		Table 3. Abdominal fat tissue specimen (N 156)

 
Conventional immunohistochemical methods were routinely applied on renal biopsies by 44 centres: of these, 30 always employed commercially available antibodies for kappa and lambda light chains, whereas 14 did so only in doubtful cases. Twenty of them declared to employ immunofluorescence on frozen sections, while the others used the immunoperoxidase method on fixed samples. Six centres also declared to use antibodies against AA and one only against TTR (immunoperoxidase method). Five centres performed immunofluorescence on bone marrow plasma cells and four carried out electron microscope immunohistochemical analysis on biopsy samples. Only two centres employed DNA analysis for routine investigation of more common genetic variants associated to renal involvement.

AA amyloidosis
In our cohort of patients, AA appears to be less common than AL (29 vs 53%). Rheumatoid arthritis (RA) was the most frequent underlying cause (40 patients, 37%), followed by Crohn's disease (nine patients, 8.3%) and tuberculosis (six patients, 5.5%).

Cystic fibrosis, Castelman's disease, Muckle-Wells syndrome, psoriasis, SLE and chronic hepatic disease were among the rare causes (‘Miscellaneous’) associated to AA amyloidosis in our study (12 cases, 12%).

In 25 patients (20.4%) the underlying disease remained unknown (Figure 3). In two cases, two different coexisting diseases were diagnosed (tuberculosis associated to Crohn's disease and SLE associated to tuberculosis).


Figure 3
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  		Fig. 3. Percentage distribution of diseases associated to AA amyloidosis (N = 104). *Miscellaneous: Muckle–Wells syndrome (1), psoriasis (1), neoplasms (2), LES (1), Sjogren (1), sclerosis colangitis (1), ulcerous rectocolitis (2), chronic epatitis (1), recurrent infections (1), UTI (1).

 
Serum and urine MC
The presence of MC in serum and/or urine using immunoelectrophoresis or immunofixation was detected in 235 out of 356 investigated patients (66%).

Serum and/or urinary MC was detected in 181 (90%) out of 201 AL patients. Thirteen out of 20 AL patients without a MC (10%) had evidence of monoclonal proliferation of plasma cells in the bone marrow. The remainder had a positive immunohistochemical staining for light chains on tissue biopsies. Serum and/or urinary MC was detected in 34 (94%) of patients with AL and an associated MM.

Two patients among these presented a non-secretory myeloma with typical features of the disease including bone marrow plasma cells infiltration (50 and 60%, respectively) and osteolytic lesions. The overall kappa/lambda ratio in these patients was around 1: 2.

Four patients with AA and 16 out of 26 who remained undetermined showed a serum and/or urinary MC.

In summary, a serum MC was identified in 194 patients (88%), with a high prevalence of IgG {lambda} (40%) followed by IgG {kappa} (20%) and isolated lambda light chains (14%). A urinary MC was identified in 162 patients (73%), with a high prevalence of lambda light chains (64%) followed by isolated kappa light chains (18%). On the basis of presence/absence of serum and/or urinary MC, three different patterns were distinguished: 142 patients (63%) revealed both a serum and urinary MC (kappa/lambda ratio 1: 3), 43 (26%) only showed a serum (kappa/lambda ratio 1: 1) and 25 (11%) an isolated urinary MC (kappa/lambda ratio 1: 4). The presence of a lambda light chain in serum and/or urine was associated to a significantly higher UPE (P = 0.004) and serum creatinine level (P = 0.006).

Bone marrow biopsy
Bone marrow biopsy was performed in 202 patients (53%) with a median of plasma cell infiltration of about 10%. Patients with an associated MM showed a markedly higher plasma cell infiltration (median value 29%) than patients without MM (median value 8%).

Renal involvement at diagnosis
After stratification of patients into three groups according to serum creatinine levels (<1.3; 1.3 ÷ 1.9; ≥1.9 mg/dl) and proteinuria (<1; 1 ÷ 3.5; >3.5 g/day), 64% of patients presented a nephrotic range proteinuria and 54% a renal insufficiency (serum creatinine levels ≥1.3 mg/dl) (Table 4).


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  		Table 4. Renal function and proteinuria according to different distribution values

 
Patients with AA showed at presentation a significantly higher serum creatinine than patients with AL or MM (Table 1).

A creatinine value below 1.3 mg/dl was recorded in 46% of patients, while a mild renal failure (sCr between 1.3 and 1.9 mg/dl) was detected in 21% of overall patients. One hundred and twenty-five patients (33%) showed a more severe renal failure (sCr > 1.9 mg/dl) and nine were already on RRT (four haemo- and five peritoneal dialyses) at presentation. Non-nephrotic proteinuria was detected in 129 patients (36%), while only 18 (5%) presented a UPE < 1 g/day. No remarkable differences were observed in proteinuria among different groups (Table 1).

Other organ involvement
One hundred and seven patients (28%) showed a concomitant involvement of another organ besides the kidney. Ninety-one of them (85%) suffered from heart involvement. Of these, 60 (30%) were found to have AL and 12 (11%) AA (Table 1). Seven patients with AL showed involvement of gastrointestinal (GI) tract, eight of the liver and four of soft tissues. Among patients with AA, seven showed involvement of GI tract and three of soft tissues. Three patients with MM showed involvement of soft tissues.



   Discussion
Top
 Abstract
 Introduction
 Aim of the study
 Study design
 Patients
 Methods
 Results
 Discussion
Conclusion
 Appendix. List of participating...
 References
 
To our knowledge this is the first time that data on the epidemiology of renal involvement in amyloidosis are reported in the literature according to the different type of deposits.

The estimated mean annual incidence of renal amyloidosis observed in Italy between 1996 and 2000 was 2.1 p.m.p. per year, less than 3.3 observed in Spain in the period 1994–99 [19] and much lower than 8.9 and 8.6 reported, by Kyle et al. [8] for AL and by Cazalets et al., respectively for all types of amyloidosis [25]. However, in our study we only considered amyloidosis with renal involvement diagnosed within the whole country where we mostly considered the greatest nephrological centres without including minor centres or other departments involved in the disease. Interestingly, the incidence increased between 1996 and 2000 from 1.81 to 2.41 p.m.p. per year. This could be due to both an increasing number of participating renal units (from 110 to 128) and/or to an improved awareness of the disease.

In our cohort, AL represented the more common type of renal amyloidosis with 62% of cases including 9% of patients with an associated MM. Other groups reported an incidence of MM associated to AL of 5 and 15% [3,4].

Among 1315 patients with amyloidosis, recorded at Mayo Clinic from January 1981 to December 1992, about two-thirds were found to have AL (70%), while only a minority of cases was found to have AA (3%) or familial forms (4%), the remainder being represented by localized (19%) and senile forms (4%) [3].

Although these findings may be the result of a bias due to the prevalent attention paid by the Mayo Clinic group to AL forms, Buxbaum also reported AL to be the commonest form of amyloidosis found in the USA [24] and a similar result was also reached in a recent study from Cazalets in France [25].

In our group, RA was the prevalent cause leading to AA, but tuberculosis was still the underlying disease in 5.5% of cases. The underlying inflammatory disease remained unknown in 23% of all AL cases and, despite a substantial progress in the molecular diagnosis of rare causes, even in 6% of patients with AA recently evaluated at the National Amyloidosis Centre in London (7). Joss et al. [6], reviewing all patients with diagnosis of AA during the period 1985–99, reported a calculated incidence in western Scotland of 3–4 new cases p.m.p. per year, half of the figure reported by Kyle et al. [8] in AL.

In the last two decades, Joss and Kyle observed a changed pattern of the underlying diseases responsible for AA with a marked decrease of infectious diseases and a distinct increase (about 70%) of chronic rheumatological conditions [5,6]. At the moment, infectious diseases are still the main cause of AA amyloidosis in developing countries, while in western countries rheumatic diseases have taken their place [9].

In spite of the lack of specific epidemiological data, it is possible to presume that AL is the more common form of systemic amyloidosis in western countries, whereas AA is likely to be prevalent in developing ones [2,9]. In contrast, the Combined Report on Regular Dialysis and Transplantation in Europe in 1989 still reported that 76% out of 784 patients with amyloidosis alive on RRT suffered from secondary amyloidosis due to a chronic inflammatory disease [26]. Some other data on epidemiology of renal amyloidosis are also obtainable from national registries of renal biopsies. Schena et al. [14] reported in Italy a frequency of 2.9% among 13,125 native renal biopsies collected over the period between 1996 and 2000 (URL http://www.irrb.net) while the Spanish Registry of GN reported a frequency of 4% from 1994 to 1999 [19].

The end-stage renal disease (ESRD) due to renal amyloidosis accounted for 1.6% of all causes responsible for RRT in Europe in 1989 [26] and for 1.29% in 2003 [27].

Prevalence of amyloidosis among patients on RRT in Europe in 2003 was 0.76%. In the same year renal amyloidosis accounted in Italy for 0.78% of all causes responsible for RRT with a prevalence of ~0.5% (data from 75% for the Italian uraemic population) (URL http://www.sin.ridt.org).

Demographic data observed in our study are mainly confirmatory of those reported by Kyle and Gertz [3]. The age-specific distribution rates increased in both series in each decade of life after the age of 40 years either in men or women, except for a significant decrease after the eighth decade. The relatively low fraction of patients older than 80 years probably reflects in both series an under-diagnosed disease in the elderly. Most patients in our study (62%) were aged between 60 and 79 years, but a significant group (14%) were aged <50 years. Of these, 26 patients were affected by AA and 21 by AL amyloidosis. This is likely the result of an earlier clinical onset of AA, which in turn depends on the age, duration and activity of the underlying disease.

Unfortunately, no information on disease duration could be obtained in our patients with AA. The gender distribution of our cohort of patients showed ~60% of male prevalence in AL, while females were prevalent in AA (59%). This is in agreement with reports that women are more commonly affected than men by rheumatic diseases. Our results confirmed in patients with amyloidosis the overall prevalence of lambda light chains (kappa:lambda ratio about 1:3). In agreement with Gertz et al. [20], the presence of a lambda MC either in serum or urine was significantly associated to a higher proteinuria and a reduced renal function. Proteinuria, either nephrosic or not, was by far the major presenting symptom, being present in over 90% of all patients. Renal insufficiency was diagnosed in 54% of patients, similarly to what was observed by Kyle et al. [3] and slightly more prevalent than previously reported by Schena et al. [14]. In addition, a worse renal function was found in patients with AA at the time of presentation. This could be due to a late referral of these patients and call for a more strict cooperation among different specialists, for diagnosis and treatment of the disease. Heart involvement was the other most relevant clinical picture found in 24% of the overall patients. In particular, a cardiac involvement occurred in 30% of AL as compared with 58% reported by the Pavia Amyloid Centre [4], to 17% by Kyle and Gertz [3] and to 20% by UK Registry [22]. Noteworthy heart involvement was also observed in 12 patients with AA (11%), a particularly high figure especially if compared with 2% recently reported from the National English Registry by Lachmann et al. [7]. Diagnosis and characterization of amyloidosis showed a wide lack of standardized approach among referring centres. The impossibility to characterize the type of amyloidosis in 26 patients (7% overall cases) well outlines the difficulties encountered in the typing process. If renal amyloidosis was mainly diagnosed by renal biopsy, characterization of deposits by immunohistochemical analysis was extremely variable. Most centres only used kappa and lambda light chain antibodies with very few centres systematically employing a complete panel for tissue immunohistochemistry (antibodies against AA in addition to anti-kappa and anti-lambda light chains). Almost occasional was the use of immunohistochemistry on electron microscope and of genetic testing of amyloidogenic protein precursors. As a consequence, the amyloid-typing process showed widely variable and heterogeneous results. A particular challenge was represented by patients with a negative immunofluorescence microscopy for kappa and lambda light chains. While immunohistochemistry of renal tissue is usually an important diagnostic tool, commercially available antibodies to kappa and lambda light chains are not sufficiently reliable to detect light chains in amyloid deposits in the kidney. Therefore, a negative result for light chains in association with a positive Congo red staining does not rule out the diagnosis of AL-amyloidosis [28].

It should be kept in mind that in some cases the differential diagnosis among AL, AA and AF can be very difficult. The presence of a serum MC does not necessarily mean that amyloidosis is of AL type, as it was recently reported by Lachmann et al. [29] who detected low levels of intact monoclonal immunoglobulin light chains in 24% of patients with hereditary amyloidosis.

Hereditary forms are more common than previously thought and may coexist with an MC. A monoclonal protein may also be observed in patients with reactive amyloidosis.

On the other hand, our data confirmed that electrophoresis and immunofixation cannot detect serum or urinary monoclonal protein in about 10% of AL patients. Gertz et al. [20] found a serum MC in 89% of AL patients in whom both immunoelectrophoresis and immunofixation were performed. Lachmann et al. [30] demonstrated circulating monoclonal free light chains in the majority of patients with AL amyloidosis using a sensitive nephelometric immunoassay. The assay gives a positive result in 92% of patients with systemic AL amyloidosis, including those in whom monoclonal immunoglobulin cannot be demonstrated by conventional methods. This new immunoassay can detect and quantify free light chains in serum and urine with remarkable specificity and sensitivity [31]. When employed together with serum and urinary immunofixation, diagnostic sensitivity rises to 99% [18]. Until recently the finding of amyloid deposits in tissue biopsies of patients with nephrotic syndrome and/or renal failure not referable to other diseases together with an MC either in serum or urine, was sufficient to make the diagnosis of renal involvement in AL amyloidosis [20]. In recent years, however, it has become ever more evident the need to screen most of the patients suspected to have AL also for the presence of familial forms of amyloidosis, and in particular for TTR mutations in order to exclude the possibility of MC incidentally associated with a familial, reactive or senile amyloidosis [18,29,32]. DNA sequence analysis for genetically variant proteins further contributes to define the nature of tissue deposits and is now strongly recommended for screening diagnosis [1,18,32]. Immuno-electron microscopy, which unequivocally characterizes the amyloid deposits by co-localizing the specific proteins within the fibrils, can eventually be employed in doubtful cases even on AFT samples [33].

In patients who underwent both AFT and renal biopsy, sensitivity of AFT confirmed to be good for AL but relatively poor for AA. Our patients with AL showed a higher AFT sensitivity than that reported by Gertz et al. [19] in a blind and controlled study for diagnosis of AL.

Nephrologists did not show much confidence on AFT collection and in the majority of cases preferred to do a renal biopsy, which in our cohort of cases, did not lead to severe adverse events. In addition, in those cases secondary to ApoA1 variants, renal disease presented without proteinuria [13] and it is possible that in other cases the disease may present with a prevalent interstitial or vascular involvement [13,14]. Consequently, in our opinion, a renal biopsy should always be performed after an accurate investigation of the bleeding risk in order to allow diagnosis also in atypical forms. However, when renal biopsy cannot be safely performed, diagnosis may still be made in the presence of nephrotic syndrome and/or renal failure by using a non-renal tissue-sample, provided a diabetic nephropathy and a light chain depostiton disease (LCDD) have been previously excluded. Although LCDD usually concerns {kappa} rather than {lambda} light chains and rarely occur in patients with amyloidosis, the disease cannot be easily ruled out in the absence of a renal biopsy.



   Conclusion
Top
 Abstract
 Introduction
 Aim of the study
 Study design
 Patients
 Methods
 Results
 Discussion
 Conclusion
Appendix. List of participating...
 References
 
In summary, our data point to an increased incidence of renal amyloidosis in Italy from 1996 to 2000, with AL as the prevalent form. Cardiac involvement is frequent in patients with AL but is not unusual in AA. Although AFT samples may be important for the diagnosis of the disease, our findings confirmed the essential role of renal biopsy and call attention to the urgent need for a shared diagnostic methodology concerning typing.

Immunohistochemical analysis should always be performed by using a complete antibody panel together (even in the absence of a family history) with a genetic testing of the more common amyloidogenic proteins. It is advisable that the establishment in the future of regional and national registries will greatly facilitate the epidemiological research and will improve diagnosis and treatment of rare diseases and of amyloidosis in particular.

Conflict of interest statement. None declared.



   Appendix. List of participating centres
Top
 Abstract
 Introduction
 Aim of the study
 Study design
 Patients
 Methods
 Results
 Discussion
 Conclusion
 Appendix. List of participating...
References
 

City Hospital Chief Referring
Ancona Umberto I V Mioli E Fanciulli
Aosta Ospedale Regionale S Aloatti A Gaiter
Arezzo S. Maria M Sasdelli D Bizzarri
Avellino S. Giuseppe Moscati W De Simone S Iannaccone
Bagno a Ripoli (FI) Ospedale S. Maria Annunziata F Pizzarelli S Nigrelli
Bari Policlinico FP Schena C Manno
Bassano del Grappa (VI) Ospedale Civile S. Bassiano A Fabris MV Pellanda
Bergamo Ospedali Riuniti G Remuzzi T Bertani
Bologna Malpighi A Santoro S Pasquali
Bologna S. Orsola S Stefoni GM Frascà
Bolzano Azienda Sanitaria di Bolzano W Huber P Riegler
Brescia Ospedali Civili P Maiorca G Gregorini
Cagliari G. Brotzu P Altieri A Pani
G Dessì
Castelfranco Veneto (TV) Presidio Ospedaliero C Cascone C Abaterusso
Cremona Istituti Ospitalieri F Malberti P Pecchini
Cuneo S. Croce M Formica C Pino
Firenze Azienda Ospedaliero-Universitaria Careggi M Salvadori F Bergesio
Firenze Nuovo Ospedale S. Giovanni di Dio PL Tosi G Monzani
F Manescalchi
Genova S. Martino G Cannella D Mulas
Genova Ospedale Universitario G De Ferrari S Garibotto
Lecco A. Manzoni F Locatelli C Pozzi
Lodi Ospedale Maggiore E Imbasciati M Farina
Lucca Ospedale Campo di Marte A Antonelli R Giusti
Milano S. Carlo Borromeo G Colasanti F Ferrario
Milano Ospedale Maggiore C Ponticelli G Banfi
Milano Istituto Clinico Humanitas G Graziani G Graziani
Modena Policlinico A Albertazzi L Furci
Montefiascone (VT) Ospedale di Montefiascone U.O. Ematologia M Montanaro M Montanaro
L Scaramucci
Napoli Università Federico II VE Andreucci B Cianciaruso
Palermo Dipartimento di Medicina Interna G Cerasola M Li Vecchi
Pavia Fondazione S. Maugeri A Salvadeo L Semeraro
Perugia R. Silvestrini U Buoncristiani R Brugnano
Pisa S. Chiara P Rindi V Batini
Ravenna S. Maria delle Croci M Fusaroli M Santostefano
A Fabbri
Reggio Calabria Melacrino C Zoccali C Martorano
Reggio Emilia Arcispedale S. Maria Nuova PP Borgatti R Rustichelli
Rimini Ospedale Infermi L Cagnoli L Cagnoli
Roma Policlinico Umberto I G Stirati G Pecci
Roma Fatebenefratelli - Isola Tiberina MG Chiappini M Di Girolamo
Roma S. Pertini A Paone M Galliani
Torino Don Bosco F Quarello G Rollino
Torino Mauriziano Umberto I M Bruno M Manganaro
Torino Molinette GP Segoloni L Besso
Torino CMID Ospedale L. Einaudi D Roccatello
Trento S. Chiara C Rovati C Comotti
Trieste Ospedale di Cattinara GO Panzetta S Savoldi
M Carraro
Udine S. Maria Misericordia D Montanaro G Boscutti
Verona Civile Maggiore G Maschio P Bernich
Vimercate (MI) Ospedale di Vimercate A Sessa M Righetti



   References
Top
 Abstract
 Introduction
 Aim of the study
 Study design
 Patients
 Methods
 Results
 Discussion
 Conclusion
 Appendix. List of participating...
 References
 

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Received for publication: 3. 8.06
Accepted in revised form: 12. 1.07


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F. Bergesio, A. M. Ciciani, M. Manganaro, G. Palladini, M. Santostefano, R. Brugnano, A. M. Di Palma, M. Gallo, A. Rosati, P. L. Tosi, et al.
Renal involvement in systemic amyloidosis: An Italian collaborative study on survival and renal outcome
Nephrol. Dial. Transplant., March 1, 2008; 23(3): 941 - 951.
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