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A proposed histopathologic classification, scoring, and grading system for renal amyloidosis: standardization of renal amyloid biopsy report.

The histopathologic changes in a renal biopsy from a patient with systemic amyloidosis comprise a spectrum of vascular, glomerular, and tubulointerstitial amyloid deposition and associated nonamyloid lesions, such as secondary or age-related changes. (1-4) Histopathologic features of renal amyloidosis have evolved over the years as more lesions have been identified and diagnosed. (5-15) It has been an increasing challenge to apply new pathogenetic insights to the interpretation of the renal biopsy in amyloidosis and to correlate pathologic findings with clinical symptoms, choice of treatment, and prognosis. Clear relationships between the extent of amyloid deposition evident by renal biopsy and severity of clinical manifestations have not been demonstrated. Whether this lack of clinicopathologic correlation reflects sampling bias, different pathogenic mechanisms, or forms of amyloid deposition is not clear.15 Renal biopsy studies have revealed the need for standardization of the renal amyloid biopsy report, including biochemical classification (typing), histopathologic classification (class), scoring of renal amyloid deposition, and association with other histopathologic lesions and grading. The standardization of renal amyloid biopsy interpretation is critical to the issue of patient care and for the comparison of outcome results and therapeutic trials between different clinics. There is no standardized schema of renal biopsy interpretation for systemic amyloidosis like the Banff classification or the classification of glomerulonephritis in systemic lupus erythematosus. (1-4,16-20) It is necessary that pathologists reach a consensus concerning the definition of the different types, classes, and grades of renal amyloidosis and the meaning of the pathologic terminology applied in order to standardize the way biopsies are interpreted and reported between different nephropathology centers. With these objectives in mind, we proposed a histopathologic classification, scoring, and grading system for renal amyloidosis.

RENAL AMYLOIDOSIS

Amyloid is defined as an in vivo-deposited material that can be distinguished from nonamyloid deposits by characteristic fibrillar electron microscopic appearance, typical x-ray diffraction pattern, and specific staining reactions, particularly affinity for the dye Congo red (CR) with resulting green birefringence. (21,22) The main constituent of amyloid deposits is the precursor protein fibril. (21-23) At least 25 different precursor proteins are known and are associated with a variety of inflammatory, immune, infectious, and hereditary conditions. (21,24)

Clinically evident renal involvement occurs mainly in AA amyloidosis and AL amyloidosis and is presented as proteinuria or nephrotic syndrome and renal failure.22-25 Renal involvement can be found in some hereditary forms of amyloidosis. Eight precursor fibrils are particularly important for kidney (Table 1). The deposition of Ap2M occurs in patients on prolonged maintenance dialysis, but diagnosis on the kidney biopsy is unexpected.1,2 The incidence of amyloid in patients with nephrotic syndrome or proteinuria was found in 2% to 12% of native renal biopsies. (5,26-35) Annual average incidence of renal amyloidosis in our unit on native kidney biopsies is found 6.5% (range, 4%-12%), which is higher than usual for studies. Amyloidosis without therapy usually progresses to end-stage kidney disease, is a major source of morbidity, and also may be fatal with cardiac involvement. The deposition of amyloid is not irreversible. Progression of amyloidosis can be delayed or stopped by treatment of the underlying disease or specific therapy modalities; deposits may also regress. (36-45)

PATHOGENESIS OF RENAL INJURY IN AMYLOIDOSIS

With progressive amyloid fibril protein accumulation, disruption of glomerular and also whole-renal architecture is the underlying mechanism of renal dysfunction. A deleterious impact of amyloid on surrounding tissue is appreciated from histologic examination of kidneys that have extensive amyloid deposits. However, observations suggest that amyloidogenic proteins have toxicities that contribute to the disease manifestations as well. (15) Indirect support for a role of the amyloidogenic precursors in disease manifestations has been raised in several observations. Proteinuria decreases rapidly after treatment that eliminates or markedly reduces production of the amyloidogenic precursor protein. This observation has been made in AL and AA amyloidosis. (46-50) In small series of patients with AL amyloidosis who underwent serial kidney biopsies, the extent of amyloid deposition seemed to be similar in biopsies that were performed before treatment and after treatment-induced resolution of proteinuria. (51,52) A lack of biopsy improvement after proteinuria resolution in AA amyloidosis also has been reported. (53) Also consistent with a functional effect of amyloidogenic precursor proteins are in vitro demonstrations of specific phenotypic changes in cultured mesangial cells that are exposed to amyloidogenic light chains. These changes are not seen when the cells are exposed to nonamyloidogenic light chains. (54)

DIAGNOSIS OF RENAL AMYLOIDOSIS

The presence of amyloidosis may be suspected clinically, but the diagnosis is made by pathologists. Amyloidosis is commonly diagnosed by renal needle biopsy and other tissues, such as rectum, fat tissue, and liver. Diagnosis of renal amyloid is easier than rectum, bone marrow, skin, and liver, and it can be made on one glomerulus or, even if there are no glomeruli, perirenal soft tissue or spleen in the renal needle biopsy specimen. Amyloid deposition is found in different degrees in mesangium, capillary walls, interstitium, and blood vessels. The most common and often the earliest site of amyloid deposition in the kidney is the glomeruli, but the blood vessels, the interstitium, and the tubular basement membranes may be predominantly affected (Figure 1). Renal AA amyloid deposition is found in varying degrees between the glomeruli, blood vessels, and interstitium.

In hematoxylin-eosin (H&E)-stained sections, amyloid is recognized as amorphous hyaline and eosinophilic extracellular material. Different histochemical stains, such as periodic acid-Schiff, Masson trichrome, and silver stains, are routinely used in nephropathology laboratories. Although Jones methenamine silver staining is not used for the demonstration of amyloid, we and others have observed that in some cases, amyloid deposits stain positively or show spicules (Figure 2). (11,55,56) Although useful for some amyloid-associated changes in brain, these methods may stain primarily nonamyloid structures. Amyloid deposits stain only weakly with periodic acid-Schiff, and this finding is important for differential diagnosis. (1-4)

Congo red staining continues to be the gold standard in the routine diagnosis of amyloidosis. Amyloid deposits stain with CR and show apple green birefringence under polarized light. Additional stains, such as crystal or methyl violet, sirius red, and alcian blue, and such techniques as ultraviolet light with CR staining or thioflavin T may be useful. (55,56)

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Congo red staining can technically be difficult.55,56 Diagnostic recommendations and differential diagnosis of amyloid deposition are covered elsewhere in this issue of the Archives. To increase the sensitivity of detecting amyloid, additional techniques have been investigated. Congo red staining and immunohistochemistry applied together have been shown to be more sensitive than CR alone. (57) It was suggested recently that CR fluorescence (Figure 3, A through C) is the most sensitive method for the direct detection of amyloid. (58,59) Congo red fluorescence gives red or pink fluorescence, depending on the filter set. Congo red fluorescence and thioflavin T are useful ancillary methods for the assessment of renal amyloidosis because immunofluorescence study is done routinely. The amyloid appears more distinct with the green filter (tetramethylrhodamine isothiocyanate; Figure 3, B), whereas the background fluorescence is more apparent with the blue filter (fluorescein isothiocyanate) set (Figure 3, C). Binding of thioflavin T to amyloid produces yellow-green fluorescence (Figure 3, D).

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NOMENCLATURE OF RENAL AMYLOIDOSIS

In the literature, the terms used for typing and classification of renal amyloidosis are frequently used interchangeably or synonymously. To accommodate the clinicopathologic and pathogenetic insights and to eliminate inconsistencies and ambiguities, standardization of the renal biopsy report is needed. We believe that biochemical classification (typing or subtyping) should be used for defining the precursor protein type or subtype based on immunohistochemical, biochemical, or genetic studies. Histopathologic classification of renal amyloidosis should be used principally to define glomerular amyloid deposition and also other histopathologic changes based on the light microscopic finding.

TYPING OF RENAL AMYLOIDOSIS (BIOCHEMICAL CLASSIFICATION)

After the diagnosis of amyloid, it is necessary to type the amyloid fibril protein. (60) Typing of amyloid deposits is important because of the difference in their pathogenesis and treatment strategies. Clinical aspects and genetics of amyloidosis are covered elsewhere in this issue of the ARCHIVES. Therapies are not successful in patients diagnosed at advanced stages of amyloidosis. In patients with renal failure, a supportive therapy with or without a transplantation (renal or renal and liver) is essential.

There are no conclusive glomerular histomorphologic features that clearly distinguish among the different biochemical forms by light microscopy. But predominantly vascular and interstitial amyloidosis in the kidney may be found frequently in hereditary amyloidosis. Different types of amyloid also are indistinguishable by electron microscopy. Congo red with potassium permanganate stain currently has no role in amyloid typing because certain types of non-AA amyloidosis (eg, A[[beta].sub.2]M and AApoA1) can be found to be negative. (56)

Typing of the amyloid deposits can be performed with various techniques. The most definitive method used in the clinical setting is immunofluorescence or immunohistochemical staining of tissue using antibodies that are directed against known amyloidogenic proteins.4,55,56,59-80 This is an easy and inexpensive technique that can be performed in every laboratory. Many studies have confirmed the suitability and use of immunohistochemical typing of amyloid. (4,55,56,59-80) Typing the most common systemic amyloidoses (ie, AA, AL, AApol, Afib, ALys, and ATTR amyloid) could be done in the kidney biopsies.

Immunohistochemical typing of amyloidosis poses several problems and requires experience. Published series show a wide range of success in immunohistochemical amyloid typing, ranging from 38% to 87%.67,68,72,80 Immunohistochemical diagnosis of AA type is relatively reliable, but there is a problem in the differentiation of AL and hereditary amyloidoses. (69-80) Immunohistochemistry in amyloid typing is covered elsewhere in this issue of the ARCHIVES. In AL type, amyloid fibril proteins may be nonreactive with commercial antibodies. Therefore, negative light chain staining in association with amyloid does not rule out AL amyloidosis and may not be suggestive of AA amyloidosis in renal biopsies. In this situation, more precise chemical or molecular methodologies should be performed, if possible. (15,70)

Other antibody-based techniques, such as immunoelectron microscopy and Western blotting, have been shown to yield better results than immunohistochemistry. (81-83) The most direct method for identifying the amyloidogenic protein is mass spectrometry or amino acid sequencing of proteins that are extracted from amyloid deposits. (65,66,83-93) These extraction techniques can only be performed in specialized laboratories.

AA Amyloidosis

In Europe, approximately 45% of systemic amyloidoses are AA amyloidosis. (76) The AA amyloid proteins result from a proteolytic cleavage serum amyloid A protein, an acute-phase reactant produced by liver. (94) Acquired and hereditary diseases can lead to AA amyloidosis, including chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever (FMF) or other periodic fever syndromes, bronchiectasis, tuberculosis, and chronic osteomyelitis. (1,2,76) The kidney is the most frequently affected target organ in AA amyloidosis. (22,25) Progressive deposition of amyloid in the kidney results in proteinuria and progressive loss of renal function. Renal involvement is a major cause of morbidity and mortality. The underlying disease usually is longstanding, and active inflammation typically is present when amyloidosis becomes evident. The glomeruli are almost always involved. Interstitial deposits are inconstant, but they are found in the medulla. In some rheumatoid arthritis-associated AA amyloidosis patients, predominantly vascular involvement can be found. (13,14) Some of the predisposing diseases, such as rheumatoid arthritis and tuberculosis, are very prevalent in the adult population; therefore, immunohistochemical demonstration of AA protein in tissue amyloid or a careful evaluation for other types of amyloidosis should be performed before concluding that the type of amyloidosis is AA. (5,15)

AL Amyloidosis

In the United States and the Western world, AL amyloidosis is the most prevalent type of systemic amyloidosis. (1,15) AL amyloidosis is derived from the immunoglobulin light chain and is associated with various B-cell lymphoproliferative disorders encompassing the multiple myeloma-plasma cell dyscrasia spectrum and, on occasion, with malignant lymphomas and macroglobulinemia. Immunoreactivity of tissue amyloid for [kappa] or [lambda] light chain is evidence for AL amyloidosis. Demonstration of a monoclonal immunoglobulin (Ig) protein in the blood, in urine, or in clonal plasma cells in the bone marrow is also helpful for the diagnosis. Bone marrow biopsy is important for determining the plasma cell burden and also assessing the plasma cell clonality. Because of the frequency of clinically insignificant monoclonal gammopathies in elderly patients, the presence of a monoclonal gammopathy should not lead to the conclusion that the amyloid is AL unless there is immunohistochemical evidence of light chains in the amyloid deposits or there has been a thorough evaluation for other types of amyloidosis. (69,79,80)

Hereditary Amyloidoses

Hereditary amyloidosis is caused by deposition of genetically variant proteins and is associated with mutations in the genes for either transthyretin, apolipoprotein AI, apolipoprotein AII, lysozyme, or fibrinogen A.95-111 Until the amyloid fibril proteins and their precursors were identified, familial amyloidosis was classified by clinical and pathologic phenotype.96 Whereas several of the familial disorders are distinctly neuropathic or cardiopathic, virtually all of them can affect kidneys, although in some of these amyloidoses, renal deposits may be clinically silent. These are being diagnosed with increasing frequency; however, most of them may be underdiagnosed. Although ATTR is systemic, it is typically associated with polyneuropathy and cardiac involvement, whereas renal involvement may be clinically silent. In some ATTR mutants, however, nephropathy may be present, leading to renal failure. (98-101) Isolated glomerular involvement with no amyloid in the tubules, interstitium, or vessels has been found to be characteristic of fibrinogen Aa amyloidosis. (69,102,103) Renal failure develops rapidly. In patients presenting with renal, gastrointestinal, or bleeding complications, ALys should be considered. (104-106) In AApoAI, deposits are typically extraglomerular, medullary, and associated with renal failure rather than proteinuria. (107) Although some of the hereditary amyloidoses can affect the kidney, the development of renal injury varies, ranging from slow to rapid progression to renal insufficiency. (96)

AA amyloidosis also complicates 4 hereditary diseases with varying frequencies: FMF, the tumor necrosis factor receptor-associated periodic syndrome, Muckle-Wells syndrome, and hyperimmunoglobulinemia IgD with periodic fever. (112)

RENAL INVOLVEMENT PATTERNS OF

SYSTEMIC AMYLOIDOSIS

The histomorphologic changes in a renal biopsy from a patient with systemic amyloidosis comprise a spectrum of glomerular, interstitial, and vascular amyloid deposition, with or without associated renal lesions, such as interstitial fibrosis, tubular atrophy, interstitial inflammation, global glomerular sclerosis, or proliferative glomerular lesions. Many histomorphologic studies have been performed to describe details of renal amyloidosis. Most of the patients have predominant glomerular deposition with or without vascular and interstitial amyloid depositions. Occasionally, patients may have a different renal pattern, because the amyloid deposits are predominantly or primarily limited to the vessels or interstitium. (1,2,13) Correlations between morphology, biochemical types, and clinical features of renal amyloidosis have never been adequately evaluated because of recently defined hereditary renal amyloidosis and misdiagnosis of AL amyloidosis. Prognosis for vascular and interstitial deposits seems better than for glomerular deposits. (1,2,13,14) The therapeutic options for amyloidosis have been defined, but standardized, detailed histopathologic classification, scoring schemas, and grades of renal amyloidosis have not yet been established. (36-54)

HISTOPATHOLOGIC CLASSIFICATION OF

RENAL AMYLOIDOSIS

History

Pathologists have been attempting to predict patient outcomes from the renal biopsy. It is well known that renal amyloid deposits vary in amount and location, early glomerular amyloid depositions tend to be spotty and segmental, and late amyloid deposits become more uniform and diffuse. Watanabe and Saniter, (6) Dikman et al, (7) Shiiki et al, (8,9) Nagata et al, (10) and others11-14 have attempted to define glomerular amyloid deposition pattern.

Watanabe and Saniter6 observed 2 types of glomerular distribution patterns of amyloid: nodular and diffuse. Dikman et al (7) divided glomerular patterns into 4 types, that is, segmental, diffuse, nodular, and mixed (nodular and diffuse). Shiiki et al (8,9) also defined 4 types of amyloid deposition pattern (types I-IV), that is, mesangial nodular, mesangiocapillary, perimembranous, and hilar patterns. (8,9) Later, Nagata et al (10) also added type v with minimal amyloid deposition. Six patterns of renal amyloidosis were proposed, similarly to the systemic lupus erythematosus glomerulonephritis classification based principally on glomerular deposits on light microscopy. (34,35) Recently, distribution of glomerular amyloid deposits was classified according to 6 different patterns: mesangial segmental type, mesangial nodular type, diffuse endomembranous type, mesangiocapillary or mixed type, predominant extramembranous or perimembranous type, and hilar type. (13)

Proposal

Renal amyloidosis can be defined according to the predominant distribution of amyloid deposits in renal parenchyma as a glomerular, interstitial, or vascular form of amyloidosis. Based on other studies, glomerular involvement is frequent, typical, and also clinically more important, determining histopathologic factors in development of renal failure in AA amyloidosis. (1,2,13) To eliminate inconsistencies and ambiguities, histopathologic classification of glomerular amyloid was proposed (Table 2). This classification was adopted and preserves the simplicity of the 2003 WHO/RPS systemic lupus erythematosus classification. (19,20) Like the systemic lupus erythematosus classification, histopathologic classification of renal amyloidosis (class) is based exclusively on glomerular pathology. Class of renal amyloidosis principally depends on glomerular amyloid pattern and the quantity of glomerular amyloid deposition with other additional histopathologic findings, and it is based on light microscopy (Figure 4). The system was first presented in a World Congress of Nephrology held in Singapore and later modified slightly. (34,35) Further modifications can be proposed with experiences of AL and hereditary amyloidosis (interstitial [Figure 1, B] or vascular [Figure 1, C] forms of amyloidosis), such as AApoAI or only middle-sized renal vascular amyloidosis.

CLASS I: MINIMAL AMYLOID DEPOSITION

Class I is defined as minimal renal amyloidosis with less than 10% extension of glomerular amyloid deposition. The minimal amyloid deposition is focal and segmental within the vascular pole or mesangium. Hematoxylin-eosin sections may be nearly normal; thus, histochemical and immunohistochemical techniques and electron microscopy might be necessary for a definitive diagnosis. A high level of suspicion is needed to avoid missing amyloid deposits. Congo red and other stains may not clearly identify small amyloid deposition; ultrastructural evaluation is the best way to obtain the diagnosis of amyloidosis. There is no concomitant amyloid-related tubulointerstitial alteration except on renal transplant biopsies with recurrence. In renal allograft patients, amyloid deposits may be found only on vessels without glomerular involvement (recurrence of AA amyloid) and should be classified as class I. In renal transplantation patients, arteriolar hyalinosis may be confused with amyloidosis because of the similar eosinophilic appearance.

In our experience, early AA amyloidosis shows amyloid deposits predominantly in hilar (vascular pole) and mesangial patterns, and AL amyloidosis may be focal and segmental and membranous. Only the focal, segmental form of vascular amyloidosis without interstitial amyloid deposits is seen in renal transplantation patients with AA recurrences, some FMF patients treated with colchicine, and hereditary amyloidoses without glomerular involvement, and all of these cases could be classified as class I.

CLASS II: MESANGIAL MINIMAL AMYLOID

DEPOSITION

Class II is defined as mesangial minimal amyloid deposition with 10% to 25% extension of glomerular amyloid deposition recognized by routine H&E sections and without concomitant amyloid-related tubulointerstitial alterations. Amyloid deposition is focal and segmental within the vascular pole and mesangial deposition. Sometimes, differentiation between class I and class II based on light microscopy and H&E sections might be difficult. If amyloid deposits cannot be suspected under the routine H&E sections, the biopsy should be classified as class I; otherwise, it should be classified as class II. Recurrence of AA amyloidosis in renal transplantation patients may be associated with chronic tubulointerstitial lesions.

CLASS III: FOCAL MESANGIOCAPILLARY AMYLOID DEPOSITION (INCLUDING NODULAR AMYLOIDOSIS)

Class III is defined as focal mesangiocapillary amyloid deposition with 26% to 50% extension of glomerular amyloid deposition (segmental) and less than 50% glomeruli (focal) easily recognized on routine H&E sections. Insignificant cortical tubulointerstitial alterations may be present. Amyloid deposition in the vessels and medullary interstitium may accompany the glomerular lesions.

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CLASS IV: DIFFUSE MESANGIOCAPILLARY AMYLOID DEPOSITION

Class IV is defined as diffuse mesangiocapillary amyloid deposition with 51% to 75% extension of glomerular amyloid deposition easily recognized on routine H&E sections. If the affected glomeruli number more than 50%, the deposits may be segmental (less than 50% extension of glomeruli), similarly to diffuse global or segmental lupus nephritis. Cortical chronic tubulointerstitial alterations should be present, including cortical interstitial amyloid deposits, tubular atrophy, interstitial fibrosis and inflammation, and globally sclerotic glomeruli. Sometimes, differentiation of class Iv from class III renal amyloidosis may be difficult. If a case has significant tubulointerstitial lesion and diffuse glomerular involvement within capillary walls, this should also be classified as class IV.

CLASS V: MEMBRANOUS AMYLOID DEPOSITION

Class V is defined as a diffuse membranous pattern without prominent mesangial amyloid deposition that looks very similar to membranous glomerulonephritis. We and others observed that this pattern is generally associated with AL or non-AA amyloidosis. Minimal AL focal membranous deposition (early form) should be classified as class I. This pattern was described as perimembranous (type III) by Shiiki et al (8,9) and others. (11,13)

CLASS VI: ADVANCED AMYLOIDOSIS

Class VI is defined as advanced amyloid deposition with more than 76% extension of glomerular amyloid deposition, more than 50% glomeruli, and glomerular amyloid balls with or without global glomerular sclerosis. There should be prominent tubular loss with interstitial fibrosis and inflammation.

SCORING AND GRADING OF RENAL AMYLOIDOSIS

History

Watanabe and Saniter (6) graded glomerular amyloid deposits from 0 to 4. Vascular amyloid deposition was graded from 0 to 3. Shiiki et al (8,9) and Nagata et al (10) graded glomerular extension of amyloid depositions from 1 to 4

as less than 25%, 26% to 50%, 51% to 75%, and more than

76% of the glomeruli, respectively. The extent of amyloid in vessels as well as the degree of interstitial fibrosis also were assessed simultaneously: 0 indicates absent; 1, mild; 2, moderate; and 3, severe. A similar scoring system was also used by Verine et al. (13) Sasatomi et al (12,113) used semi-quantitative evaluation for amyloid deposition in glomeruli, interstitium, and vessels, which was also performed by computer-assisted morphometry. (12,113) Each lesion was scored from 1 to 3. The sum of damage (0-9) associated with amyloid deposition was calculated, indicating total numeric codes of renal pathologic damage. Verine (13) defined renal amyloid load similarly to Sasatomi et al. (12,113) Recently, computer-assisted morphometry was used by Oguchi et al. (98)

Proposal

More detailed histopathologic definitions and scoring systems are necessary for clinicopathologic or international comparative or collaborative studies. Scoring systems for renal allograft pathology (Banff classification) and lupus nephropathy were defined. We considered all histopathologic findings associated with amyloidosis that contribute to renal function and outcome. Renal amyloid deposition (glomerular, vascular, and interstitial amyloid deposition) and other additional histopathologic lesions, such as global glomerular sclerosis, inflammatory infiltration, interstitial fibrosis, and tubular atrophy, interfere with renal function and should also be scored. The scoring system is designed similarly to the Banff classification, but the scoring scheme shows a little difference (Table 3). Tubulointerstitial lesions are scored on 5 codes (0, 1, 2, 3, and 4; no, minimal, mild, moderate, and severe, respectively). Numeric code of Banff "ci," "ct," and "i" were divided into 2 codes--1% to 10% indicating minimal and 11% to 25% indicating mild--and the others are used similarly. (16-18)

Glomerular involvement is known to be more important for renal outcome. Glomerular amyloid scores were doubled. First glomerular score is the glomerular amyloid pattern and is closely similar to classes I to VI (score 1 to 6). Second glomerular score shows extension of glomerular amyloid deposition (percentage) and is divided to 5 scores: 1% to 10%, 11% to 25%, 26% to 50%, 51% to 75%, and more than 75%. The amyloid deposits observed in the kidney may show a great diversity. When significant variations are found between the glomerular amyloid deposits, the average amyloid accumulation should be estimated and considered.

Finally, similarly to the renal amyloid load, the renal amyloid prognostic score (RAPS) is defined. When the sum of the amyloid scores, global glomerular sclerosis, inflammatory infiltration, interstitial fibrosis, and tubular atrophy is considered, RAPS is determined (Table 4). RAPS is further divided into 3 grades (early, late, and advanced renal amyloidosis; Figure 5).

Sometimes, concomitant glomerular crescents can be found within renal amyloidosis, and these are excluded from the scoring system. (10)

Recently, amyloid A protein quantification was made in abdominal fat tissue of patients with AA amyloidosis.114 Renal biopsy is thought to be an invasive, risky procedure. Based on experience with more than 400 renal biopsies with amyloidosis and more than 100 other tissue biopsies with amyloidosis, renal biopsy is the most suitable and easiest tissue for the diagnosis and assessment of amyloid deposition intensity.115 Concern sometimes is raised about the risk for procedure-related bleeding as a result of vascular fragility. However, there is little evidence suggesting that rate of bleeding complications is higher in these patients. (15)

RENAL AMYLOIDOSIS EXPERIENCE IN TURKEY

Recently, in our department, a total of 305 renal bio-psyproven amyloidoses from 288 patients were reevaluated for classification and scoring (292 native and 13 transplant needle biopsies; time period 1990-2007). Amyloid was diagnosed using the stringent, alkaline, alcoholic CR staining method of Puchtler et al. (56) The characteristic green birefringent polarization was taken as proof of the presence of amyloid deposits. AA amyloidosis was identified by using the peroxidase-antiperoxidase method using an antibody against AA protein (M 0759; Dako, Carpinteria, California). Non-AA cases were also searched for [kappa] and [lambda] light chains, plasma cell dyscrasia, and multiple myeloma.

Proteinuria was the main clinical manifestation in the native biopsies, but it was not evident in renal allograft biopsies. AA amyloidosis was detected in 91% of the patients. Most of the cases were FMF-related amyloidosis (Table 5). Other renal studies from Turkey defined similar involvement of AA amyloidosis. (116-119) A few non-AA cases have properties of hereditary amyloidosis. In AA amyloidosis, the average age is 36 [+ or -] 17 years, nearly 2 decades younger than the non-AA cases (average age, 53 [+ or -] 11 years).

Biopsies of 9 cases (3%) were inadequate for classification and grading. Glomerular involvement by amyloid was present in all cases mainly in the mesangium except the 3 renal transplant recurrences. Depositions were evaluated as 10%, 16%, 21%, 38%, 4%, and 8%, respectively, for classes I, II, III, IV, V, and VI. The RAPS grades were found to be 13%, 53%, and 31%, respectively, for grades I, II, and III. Comparison of class and grading is given in Table 6. Positive correlations between class I and grade I, class VI and grade III, and class III and grade II were observed. Also, a positive correlation was identified between extension of glomerular amyloid depositions, interstitial fibrosis, and inflammation scores.

The correlation and prognostic importance of a histopathologic classification, scoring, and grading system with interval time for renal failure and renal outcome, patient outcome, and recurrence rate for renal transplantation were planned. Because of the long-term biopsy period, inadequacy of the patients' records and outcomes, different therapy regimes, and etiologies, clinical validation of this study has not yet been completed. We only compared class and grade of renal amyloidosis. Further study with subgroups of AA amyloidosis, FMF, and chronic rheumatoid diseases will be completed. Because of our AA/AL amyloidosis ratio and predisposition toward FMF-related AA, there is a need for further international collaborative studies using this histopathologic classification, scoring, and grading system.

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RECOMMENDATIONS FOR EVALUATING AND REPORTING A RENAL BIOPSY FROM A PATIENT WITH SYSTEMIC AMYLOIDOSIS

Histopathologic techniques are mandatory for a reliable classification and typing of renal amyloidosis. For accurate pathologic analysis, it is important that the tissue be optimally preserved, processed by a skilled technician, and sectioned at multiple levels and thicker than usual. Proper tissue handling and use of special histochemical and immunohistochemical stains are essential for accurate and complete assessment of amyloid depositions.

To diagnose renal amyloidosis, there are no limitations on tissues on the needle biopsy, such as including only renal medulla or nonrenal tissue (eg, perirenal tissue or spleen). To classify amyloidosis, the renal biopsy should contain a minimum of 10 glomeruli for light microscopic analysis. (16,19) Immunofluorescence study is required for complete renal biopsy analysis and should include staining for IgG, IgA, and IgM isotypes, [kappa] and [lambda] light chains, and complement components C3 and C1q with fresh tissue. Glomerular immune deposits attributable to immune complex nephritis as detected by immunofluorescence may be associated with systemic amyloidosis. The role of electron microscopy in the diagnosis of amyloidosis cannot be underestimated and may be essential in class I.

For typing of the amyloid deposits, additional or conformational immunohistochemical staining can be done on paraffin sections. These are easy and inexpensive techniques and can be performed in every laboratory. As a rule, the most common systemic amyloidoses--amyloid P, AA, and AL--must be screened, and in addition, hereditary amyloidoses AApoAI, AFib, ALys, and ATTR also should be searched. We should remember false-negatives and false-positives can occur in 25% to 35% of cases. To increase the sensitivity, the antisera from multiple vendors may be used. The diagnostic approach of amyloidosis is multidisciplinary and demands careful clinical evaluation in addition to detailed histochemical and immunohistochemical studies.

The kidney is one of the most important and common sites for amyloid deposition, with evidence of clinical renal disease in most patients. Although most of the systemic amyloidoses affect the kidney, there is significant variability in the degree of renal involvement between patients. Severity of renal involvement also affects clinical presentation and prognosis adversely. A renal histopathologic classification, scoring, and grading system can distinguish the candidate patients with a good response to old or new amyloid-specific medical therapies and also allow standardization at different nephropathology centers for the comparison of outcome results and therapeutic trials. In our study, the AA/non-AA amyloidosis ratio was 9:1. However, the ratio was 2:1 in Western Europe versus 1:17 in the United States. Familial Mediterranean fever was found to be a major etiologic factor in AA amyloidosis in our study. However, the ratio is different in other countries, such as chronic inflammatory diseases or rheumatoid diseases. Because of these differences, standardized, international clinicopathologic collaborative studies on renal amyloidosis are needed.

Standardized pathology reports of renal biopsy--proven amyloidosis should include type of precursor protein, predominant involvement of renal compartment, histopathologic classification of renal amyloidosis, renal amyloid prognostic score, and grade (eg, amyloidosis AA with predominant glomerular involvement, class IV, RAPS score 13, grade 2). The histopathologic classification and grading system of renal amyloidosis has been applied successfully and is easy and practical, but our experience relies mainly on AA amyloidosis (91%) and FMF. Further studies assessing intraobserver and interobserver agreement and including different types of amyloidosis (non-AA types) are required. Like the classification of Banff and lupus glomerulonephritis, a histopathologic classification, scoring, and grading system of renal amyloidosis might be changed and improved during routine renal pathology practice.

This study was supported by a grant from the Ege University Research Projects (03 TIP 008). We thank Goksen Ertutar, Hasibe Konuir, Hayriye Koktas, and Dilek Pehlivan for technical assistance, and Dr Mine Hekimgil for her comments on reviewing the manuscript.

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Sait Sen, MD; Banu Sarsik, MD

Accepted for publication February 5, 2009.

From the Pathology Department, Ege University School of Medicine, Bornova Izmir, Turkey.

The authors have no relevant financial interest in the products or companies described in this article.

Presented at the 4th Annual Renal Pathology Society/Kidney and Urology Foundation of America satellite meeting, Update on amyloidoses from the XI International Symposium on Amyloidosis by Members of The International Society of Amyloidosis and The Renal Pathology Society, Istanbul, Turkey, September 13, 2007. A portion of this work was presented at the World Congress of Nephrology in Singapore, June 2005, and was published in abstract form (Nephrology. 2005; 10(suppl):A331). A portion of this work was presented at the 21st European Congress of Pathology in Istanbul, Turkey, September 13, 2007, and was published in abstract form (Vircows Arch. 2007;451:516-517).

Reprints: Sait Sen, MD, Pathology Department, Ege University School of Medicine, Bornova Izmir, Turkey (e-mail: sait.sen@ege.edu.tr).
Table 1. Important Amyloid Precursor Fibrils for Renal Pathology

                                               Renal
Amyloid Protein    Precursor Protein        Involvement

AL                 Monoclonal immuno-       G, V, I
                     globulin light chain
AA                 Serum amyloid A          G, V, I
AFib               Fibrinogen Aa chain      G
AApoAI             Apolipoprotein AI        I, G
AApoAII            Apolipoprotein AII       G, V
ALys               Lysozyme                 G, V, I
ATTR (Val30Met)    Transthyretin            I, G
AGel               Gelsolin                 G
A[[beta].sub.2]M   [beta]-Microglobulin     Unknown

Amyloid Protein    Other Organ Involvement

AL                 Heart, liver, gastrointestinal tract, spleen,
                     nervous system, soft tissue, thyroid, adrenal
                     gland
AA                 Liver, gastrointestinal tract, spleen, autonomic
                     nervous system, thyroid, heart
AFib               Liver, spleen
AApoAI             Liver, heart, skin, larynx
AApoAII            Liver, heart, skin, adrenals, bone marrow
ALys               Liver, gastrointestinal tract, spleen, lymph
                     nodes, lung, thyroid, salivary glands
ATTR (Val30Met)    Liver, autonomic nervous system
AGel               Nervous system
A[[beta].sub.2]M   Dialysis-related amyloidosis; osteoarticular
                     tissue; less common sites are gastrointestinal
                     tract, blood vessels, and heart

Abbreviations: G, glomerular; I, interstitial; V, vascular.

Table 2. Histopathologic Classification of Renal
Amyloidosis Based on Glomerular Involvement

Class   Definition

0       No amyloid deposition
I       Minimal amyloid deposition
II      Mesangial minimal amyloid deposition
III     Focal mesangiocapillary amyloid deposition (includ-
          ing nodular amyloidosis)
IV      Diffuse mesangiocapillary amyloid deposition
V       Membranous amyloid deposition (observed generally
          in non-AA amyloidosis, especially AL amyloidosis)
VI      Advanced renal amyloidosis

Table 3. Scoring of Histopathologic Findings, Numeric Codes

                Definition                    Abbreviation

Class of glomerular amyloid deposition            GAP
Percentage of glomerular amyloid deposition       GA%
Vascular amyloid deposition                        VA
Interstitial amyloid deposition                    IA
Interstitial fibrosis and tubular atrophy         Ifib
Interstitial inflammatory infiltration            Iinf

Glomerular sclerosis                               GS

                Definition                    Definition

Class of glomerular amyloid deposition        Absent, hilar, minimal
                                                mesangial, focal
                                                mesangial,
                                                mesangiocapillar,
                                                membranous, global
                                                sclerotic
Percentage of glomerular amyloid deposition   0, 1%-10%, 11%-25%,
                                                26%-50%, 51%-75%,
                                                76%-100%
Vascular amyloid deposition                   Absent, minimal, focal,
                                                moderate, severe
                                                amyloid deposition
Interstitial amyloid deposition               Absent, minimal, focal,
                                                moderate, severe
                                                amyloid deposition
Interstitial fibrosis and tubular atrophy     0, 1%-10%, 11%-25%,
                                                26%-50%, 51%-100%
Interstitial inflammatory infiltration        0, 1%-10%, 11%-25%,
                                                26%-50%, 51%-100%
Glomerular sclerosis                          0, 1%-10%, 11%-25%,
                                                26%-50%, 51%-100%

                Definition                    Score

Class of glomerular amyloid deposition         0-6
Percentage of glomerular amyloid deposition    0-5
Vascular amyloid deposition                    0-4
Interstitial amyloid deposition                0-4
Interstitial fibrosis and tubular atrophy      0-4
Interstitial inflammatory infiltration         0-4
Glomerular sclerosis                           0-4

Table 4. Renal Amyloid Prognostic Score (RAPS) and
Grade

Definition                       Grade         RAPS

RAPS                                       0-31
  RAPS = GAP + GA% + VA + IA
    + Ifib + Iinf + GS
Grades of renal amyloidosis
  No renal amyloidosis         Grade 0     0
  Early renal amyloidosis      Grade I     1-7
  Late renal amyloidosis       Grade II    8-15
  Advanced renal amyloidosis   Grade III   16 or higher

Abbreviations: GA%, percentage of glomerular amyloid deposition;
GAP, class of glomerular amyloid deposition; GS, glomerular
sclerosis; IA, interstitial amyloid deposition; Ifib, interstitial
fibrosis and tubular atrophy; Iinf, interstitial inflammatory
infiltration; VA, vascular amyloid deposition.

Table 5. Etiologic Factors Associated With
Renal Amyloidosis

                                          No.   Percent

AA cases                                  263     91
  FMF phenotype 1                          73     25
  Recurrence of FMF in renal transplant     5      2
  Chronic infections                       32     11
    Tuberculosis                           16      6
    Bronchiectasis and chronic obstruc-
      tive lung disease                    11      4
    Other infections                        5      2
  Chronic inflammatory diseases            34     12
    RA and juvenile RA                     22      8
    Spondylarthropathy                     10      3
    Crohn disease                           2      1
  Others (tumors, POEMS syndrome,
    Behcet disease, other infections)      14      5
  Unknown (probably mostly FMF, phe-
    notype 2)                             105     36
Non-AA cases                               25      9
  Multiple myeloma                          8      3
  Probably hereditary amyloidosis           5      2
  Undetermined factors                     12      4

Abbreviations: AA, serum A amyloidosis; FMF, familial Mediterranean
fever; RA, rheumatoid arthritis.

Table 6. Comparison of Histopathologic Classification and Grade of
Renal Amyloidosis in Our Patients

                         Grade I,   Grade II,   Grade III,
Renal Amyloid            No. (%)     No. (%)     No. (%)

Class I                  23 (8)       9 (3)       0
Class II                 14 (5)      35 (11)      1 (0.3)
Class III                 3 (1)      58 (19)      2 (0.6)
Class IV                  0          52 (17)     64 (21)
Class V                   0           7 (2)       4 (1)
Class VI                  0           0          24 (8)
Inadequate for scoring    0           0           0
Total                    40 (13)    162 (53)     94 (31)

                          Inadequate for    Total Biopsy,
Renal Amyloid            Scoring, No. (%)      No. (%)

Class I                       0                32 (10)
Class II                      0                50 (16)
Class III                     0                63 (21)
Class IV                      0               116 (38)
Class V                       0                11 (4)
Class VI                      0                24 (8)
Inadequate for scoring        9 (3)             9 (3)
Total                         9 (3)           305 (100)
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Date:Apr 1, 2010
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