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Kidney International, Vol. 52 (1997), pp. 832—838
Dialysis-related amyloidosis of the tongue in long-term hemodialysis patients
KENZOMATSUO,MAsAHIK0 NAKAMOTO, CHIIo YASUNAGA, TADANOBU GOYA, and KEIzo SuGmtAdHI
Kidney Center, Saiseikai Yahata Hospital, Kitakyushu, and Department of Surgety II, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Dialysis-related amyloidosis of the tongue in long-term hemodialysis patients maintained on regular hemodialysis treatment (RDT) for patients. Dialysis-related amyloidosis (DRA) predominantly occurs in the more than 10 years. We describe the clinical and pathological ostcoarticular structures. However, according to studies in the increasing number of long-term hemodialysis patients, DRA has also been systemi- characteristics in these patients and their relation to systemic cally found to appear in the other tissues and organs as well. In this study, DRA. we investigated lingual amyloidosis in relation to systemic DRA. A total of 472 patients were studied who were on regular hemodialysis for more than METHODS 10 years, including 103 patients for more than 20 years. Eight of these patients (7 males and 1 female, mean age 59 8 years, range 46 to 68 Patients years) developed lingual amyloidosis, seemingly as a result of p2-micro- A total of 472 patients, 262 males and 210 females maintained globulin (,m) deposits. All patients demonstrating lingual amyloidosis had been treated with regular hemodialysis for more than 20 years (mean on regular hemodialysis treatment for more than 10 years were HD duration 23.6 t1.4years), and its morbidity was 7.8% in the 103 selected from the patients at Saiseikai Yahata Hospital and 25 patients and 20% (6 patients) in the 30 patients treated for more than 23 other affiliated hospitals. Among them, 103 patients (70 males and years with hemodialysis. Hemodialysis (HD) duration with bioincompat- ible unsubstituted cellulose membranes in the 8 patients was longer than 33 females; mean age 549 years; range 37 to 81 years) had been 1.6 that in the control group without lingual amyloidosis (P <0.05).Lingual treated for more than 20 years (mean HD duration 22.2 amyloid nodules were whitish-yellow in color and varied in size, at least years, range 20.0 to 26.4 years). All these patients were examined over 1 mm in diameter. Their consistency was firmer than the intact for the presence of lingual nodules. The patients underwent tongue. The location of the amyloid nodules could be classified into two regular hemodialysis for between four and five hours, three times types: (I) diffuse type (diffusely distributed over the tongue), and (2) lateral type (localized only in the lateral side of the tongue). Five of the a week with various types of dialysis membranes without reuse. eight patients with lingual amyloidosis complained of functional distur- The type of dialysate buffer was bicarbonate. bances in the tongue, such as abnormal taste, or difficulty in mobility and articulation. No macroglossia was observed in any of these cases. It was Dialysis membranes thus concluded that DRA of the tongue is a very rare complication, occurring in the late stage of long-term hemodialysis patients, that disturbs The types of dialysis membranes used for the patients were their quality of life. classified into three categories according to the established clas- sification [12]: (1) unsubstituted cellulose membranes (Cell), (2) modified cellulose membranes (Mod), (3) synthetic membranes (Syn) (Table 1). Ultrafiltration coefficients (defined as the water Dialysis-related amyloidosis (DRA) is a major complication influx ml/mm Hg/hr) were also classified into three groups: (1) low long-term hemodialysis patients that has been recognized as beingflux, less than 10 ml/mm Hg/hr; (2) moderate flux, greater than 10 caused by amyloid deposition and derived from /32-microglobulin ml/mm Hg/hr and less than 20 mI/mm Hg/hr; (3) high flux, greater (2m) [1].Itis also well known that DRA predominantly involves the osteoartieular system, and is less frequently related to thethan 20 mI/mm Hg/hr. other extraarticular systems [2—81. As the number of long-termPatients with lingual nodules hemodialysis patients continues to increase, DRA tends to sys- temically appear in the extra-articular system following the onset Lingual nodules were maeroscopically detected in 10 patients of osteoarticular DRA. In addition, systemic DRA-related lingualand biopsied under local anesthesia. The 10 patients had been amyloidosis has only been rarely reported [7—111. In this study, we treated by regular hemodialysis for more than 20 years. Lingual investigated eight patients with the lingual amyloidosis among 472nodules with whitish-yellow color were observed in 8 of 10 patients. Lingual dysfunction, especially about taste, mobility, and artic- ulation, were retrospectively studied in these 10 patients whether Key words: hemodialysis, amyloidosis, tongue, complication of dialysis. or not there were any differences in the patients' complaints Received for publication August 2, 1996 before or after the appearance of lingual nodules. Lingual artie- and in revised form March 31, 1997 ulatory imprecision was finally judged by an otorhinolaryngologist Accepted for publication April 14, 1997 after any laryngeal disease that potentially causes articulatory © 1997 by the International Society of Nephrology disorder was ruled out.
832 Matsuo et a!: Dialysis-related amyloidosis of the tongue 833
Table1. Classification of dialysis membranes
Unsubstituted cellulose Modified cellulose Synthetic Water flux Low to high Low to high Low to high Complement activation High Moderate to low Low (Biocompatibility) (—) (+) (+) Unsubstituted cellulose Cellulose acetate Polymethylmethacrylate (PMMA) Saponified cellulose Cellulose diacetate Polyacrylonitrile (PAN) Cuprophane Cellulose triacetate Polysulfone (PS) Cuprammonium rayon Hemophan Polyamide (PAM) Ethylenevinylalcohol copolymer (EVAL) Polyester polymer alloy (PEPA) Water flux is defined as: low, less than 10 mI/mm Hg/hr; high, greater than 20 mI/mm Hg/hr.
Table 2. Clinical features and courses of DRA in the 8 patients with lingual aniyloidosis Tongue CTS Bone cyst GIA Location First Final dx. Location DSA Location (biopsy) appearance by biopsy Age Cause of First op. Frequency of op. Patient Years Sex renal failure 1-ID years LID years Location HD years LID years 1 53 M CGN 15.7 4 L, R, L, R 14.6 Wrist 18.2 C4/5 24.3 26.4 2 46 F CGN 13 2 R, L 14 Wrist — — 19.7 23.9 3 67 M CON 18 3 R, L, R 12.3 Hip op. — — 22 23.8 4 59 M CGN 16.3 3 L, R, R 16.3 Wrist — 23.9Rectum 22.3 23.5 5 65 M CON 15.7 2 R, L 15.7 Wrist, Hip — 23.5Rectum 23.5 23.5 6 58 M CON 10.8 3 R, L, L 16 Wrist 20 C3/4—5/6 — 20 23.3 21.7 op. 7 52 M CGN 16 2 L, R 16 Wrist — — 18 22.9 8 68 M CGN 11.5 2 L, R 16.2 Wrist — — 19.3 21.3 Abbreviations are: CTS, carpal tunnel syndrome; DSA, destructive spondylarthropathy; GIA, gastrointestinal amyloidosis; op., operation; M, male; F, female; CON, chronic glomerulonephritis; R, right; L, left; dx, diagnosis.
A control group comprised 24 patients (21 males and 3 females;Blood chemistry mean age 57 7 years, range 44 to 70 years) matched for age, sex, Predialysis serum concentration of 2-microglobulin was mea- HD duration (mean HD duration 23.2 1.4 years, range 20.8 to sured by an enzyme immunoassay (IMX 2-microdainapack; 25.7 years) with no lingual nodules. DAINABOT, Tokyo, Japan), and that of Apo E by a turbidimetry immunoassay in the 8 patients with amyloid lingual nodules and in Pathological investigations the control group. The resected specimens of the tongue were collected from the ten patients including two for the control. Formalin-fixed andStatistical analysis paraffin-embedded tissue sections were prepared for hematoxylin Comparison between the 8 patients with amyloid lingual nod- and eosin (H&E), and for Congo red stainings. An immunohis- ules and a control group was done using Mann-Whitney U-test. A tochemical study was performed on formalin-fixed and paraffin- P value of < 0.05 was considered statistically significant. embedded tissue specimens using the labeled streptavidin biotin method (DAKO LSAB''° Kit) [131. Rabbit anti-human /32-micro-RESULTS globulin, anti-human P component, anti-human apolipoprotein E (Apo E), anti-human kappa light chains, anti-human lambda lightPatient profiles chains, anti-human prealbumin, monoclonal mouse anti-human Lingual nodules were observed in 10 patients, all of whom on amyloid A component, and anti-human macrophage (CD68)RDT for more than 20 years. Biopsy disclosed j32m amyloid antibodies were purchased from Dakkopatts, Inc., and were useddeposits in 8 of the 10 patients. The color of the amyloid lingual as the primary antibodies. The primary antibodies were applied innodules was characteristically whitish-yellow in the 8 patients. 1:100 and 1:400 dilutions, respectively. Negative controls were The 8 patients with amyloid lingual nodules (7 males and 1 obtained by omitting the primary antibodies and replacing themfemale; mean age 59 8 years, range 46 to 68 years) had with nonimmune serum. The peroxidase was visualized withundergone chronic HD for an average of 23.6 1.4 years (range 0.001% (wt/vol) H202 and 0.005% diaminobenzidine in phos-21.3 to 26.4 years) at the time of diagnosis (Table 2). the phate-buffered saline, pH 7.4, and then the sections were coun-prevalence was nil for patients dialyzed for less than 20 years, terstained with hematoxylin. For electron microscopy, the tissuesreached 8% (8 of 103) in patients dialyzed for more than 20 years were fixed in 2% glutaraldehyde, postfixed in 1% osmium tetrox-and 20% (6 of 30) in patients treated for more than 23 years. ide, and embedded in epoxy resin. Some of the tissues were Individual characteristics are listed in Table 2. A retrospective processed from paraffin blocks. assessment of the 8 patients demonstrates osteoarticular evidence 834 Matsuoet air Dialysis-related amyloidosis of the tongue
Table3.Duration of dialysis membranes used in the 8 patients with lingual amyloidosis
Membranes years Cell Total of Cell Mod Total of Mod & Syn Water flux Low Moderate High Low to high Moderate Low High Low to high Biocompatibility — + + + + Patient 1 17.4 1.8 5.7 24.9 1.5 1.5 2 14.5 4.3 1.6 20.4 2.1 1.4 3.5 3 18.5 2.3 1.6 22.4 1.4 1.4 4 18.1 0.1 18.2 2.8 2.5 5.3 5 19.4 19.4 4.1 4.1 6 18.8 18.8 0.8 3.1 0.7 4.6 7 22.9 22.9 8 19.4 19.4 1.8 1.8 Abbreviations are:Cell, unsubstitutedcellulose;Mod, modifiedcellulose; Syn, synthetic.
Table 4.Statistical analysis between the 8 patients with lingual 0.01), while no difference was observed in total number of years of amyloidosis and the control group low flux dialysis membranes (Cell, Mod, Syn). Patients with lingual amyloidosis Controlgroup Clinical characteristics (N= 8) (N=24) Pvalue Age years 59 8 58 7 NS The amyloid nodules of the tongue were whitish-yellow in color Gender male/female 7/1 21/3 NS and appeared in various sizes greater than 1 mm in diameter HD duration years 23.6 1.4 23.2 1.4 1 and 2). The nodules was firmer in consistency than other Cell duration years 20.8 2.4 17.04.5 (Figs. Low flux cell 18.62.3 14.73.4 <001 intact area of the tongue. The locations were classified into two duration years types: the lateral type (Fig. 1) and the diffuse type (Fig. 2). There Duration of low flux 19.62.2 17.7±3.1 NS was no difference in the hemodialysis duration of these two types. membranes (Cell, No macroglossia was seen even in the diffuse type. DRA of the Mod, Syn) years 132m mg/liter 28.78.3 27.68.4 NS tongue induced the following lingual dysfunctions: (1) loss of ApoE mg/dl 4.8 1.0 4.92.2 NS feeling or abnormal taste; (2) disturbed mobility; (3) lingual articulatory imprecision (Table 5). Four (Patients 4, 5, 6, 7) of the Abbreviations are: Cell, unsubstituted cellulose membrane; Mod, mod- 8 patients complained of a taste disturbance, and were all diffuse ified cellulose membrane; Syn, synthetic membrane; 13,m, /37-microglobu- lin; ApoE, apolipoprotein E; NS, not significant. type. Two (Patients 2 and 7) of them presented a disturbed lingual mobility. Only patient 7, the most severe case of all, developed inaccurate lingual articulation (Table 5). The other two patients of DRA in each patient as demonstrated by CTS operation (10.8with 2m non-related lingual nodules didn't complain of lingual to 18 years after the onset of dialysis), typical bone cysts accordingdysfunction. Though we measured the predialysis serum levels of to established criteria (12.3 to 16.3 years after onset of dialysis)f37m and Apo E, no difference was found between the 8 patients [141. In addition, two patients (Patients 1 and 6) suffered fromand the control group (Table 4). destructive spondylarthropathy (DSA) (18.2 to 21.7 yeas after onset of dialysis) while the other 2 (Patients 4 and 5) demon-Histological characteristics strated gastrointestinal amyloidosis confirmed by rectal biopsy (23.5 to 23.9 years after onset of dialysis). These 8 patients had A histological characteristic of the lingual amyloidosis was already noticed their lingual nodules before final diagnosis wasmassive arnyloid depositions distributed from the subepithelium made by lingual biopsy. The mean duration of hemodialysis wasto the deeper muscle layer in all tongue specimens, which were 21.1 2.2 years when they became aware of lingual nodules.confirmed to react with antibodies to human 13,m. In the light Lingual amyloidosis appeared after CTS and bone cysts. microscopic study, the specimens showed amorphous, eosino- philic deposits diffusely from the suhepithelium to the deeper Dialysis membranes muscle layer (Fig. 3), strongly stained for Congo red, and showed The types of dialysis membranes used for the entire duration ofan apple-green birefringence under crossed polarized light. These hemodialysis in the 8 patients with lingual amyloidosis are shownall specimens were thus diagnosed as amyloid deposits. An in Table 3 according to the classification of dialysis membranesimmunohistoehemical study, using the labeled streptavidin biotin (Table 1). The total duration of unsubstituted cellulose (Cell) wasmethod (DAKO LSAB Kit), demonstrated amyloid deposits that longer than those of modified cellulose (Mod) and syntheticwere confirmed to react with antibodies to human amyloid P (Syn). The mean duration of Cell was 20.82.4 years (Table 4),component, Apo E, and 2m as well. However, no immunoreac- most of which utilizing low flux Cell (mean duration: 18.62.3tivity was observed to the amyloid A protein, kappa light chain, years). Hemodialysis duration of Cell was significantly longer (P Fig. 1. The diffuse type of the lingual amyloidosis (Patient 7 in Table 2). Amyloid nodules of various size are diffusely observed on the tongue of our most severe case. Fig. 2. The lateral type of the lingual amyloidosis (Patient 2 in Table 2). Aniyloid nodules are observed on the lateral side of the tongue. microscopic study revealed the typical fibrillar structure of amy- Table 5. Clinical characteristics of lingual amyboidosis bid. The fibrils were arranged in parallel and nonbranching, curvilinear bundles (Fig. 4). Location of Functianal disturbance of the amyboid nodules tongue DISCUSSION Patient Lateral DorsumMacroglossiaTasteMobility Articulation In this study, we investigated the clinical and pathological I L,R - - - - - characteristics of lingual amyloidosis in relation to systemic DRA. 2 L,R — — + — Among our 472 patients undergoing RDT for more than 10 years, 3 L,R - — — - - — — — including 103 patients for more than 20 years, eight patients 4 L,R + + 5 L,R + — + — whose HD duration was more than 20 years developed lingual 6 L,R + - + - — amyloidosis (Table 2). The HD duration was at least 18 years 7 L,R + — + + + before the nodules were found by patients themselves, although it 8 L,R - - - - - was not obvious whether or not they were lingual amyboidosis. In Abbreviations are: Lateral, lateral side of the tongue; Dorsum, dorsum the previous case reports (Table 6) [7-11], the shortest duration ofof the tongue; L, left; R, right. DRA. DRAcanthusbeclassified intotwostages,namelythe intestinal tractandthetongue appearedlaterthanosteoarticular osteoarticular lesions[16j.In our8patients,DRAofthegastro- Beyond 15years,virtually100% ofhemodialysispatientsdevelop CTS, isreportedtoincrease withthedurationofRDT[15]. lar lesionsattributableto2m amyloid,liketheprevalenceof system (Table2).Intheliterature,prevalenceofosteoarticu- cannot directlycompareour8patientswiththembecause of the 836 initial andthelate stages.Theformeriswell knownasosteoar- tion system. dialysis membrane,dialysate,reuseofdialyzer,orwaterpurifica- lack ofinformationabouttheirHDconditionssuchastype of HD was12years,lessthanthatofourstudygroups.However, we All ofour8patientsexperiencedDRAtheosteoarticular I Matsuo et al:Dialysis-relatedamyloidosisofthetongue Atrt .,c, •• '. .dt prolonged HD durationofcellulosemembranes (Cell)formore remains highforaprolonged period[151. DRA maybegrosslyelevatedserum concentrationsofJ32m,which factors areinvolved,thechief prerequisite forthedevelopmentof accelerated theproductionof j32m[15,17].Althoughmany compared tothecontrolgroup (Table4),whichmayhave considerably longperiod(mean duration20.8 patible, unsubstitutedcellulosemembraneshadbeenused fora treatment formorethan20years. regular hemodialysis,suchasthoseundergoinghemodialysis since ittendstopredominantlyoccurinpatientswithlonger that DRAofthetongueshouldbeincludedinlatestage group ticular DRAwhilethelatterisextraarticularDRA.Weconsider ,1 Regarding thedialysismembranesinour8patients,bioincom- bundles (x25,000). fibrils werearrangedinparallelandcurvilinear tongue (Patient6inTable2).Theamyloid Fig. 4.Theelectronmicroscopicfindingsofthe stain, X40). infiltrated betweenthem(hematoxylin&eosin muscle layer.Mononuclearcellsscatteredly seen betweenthesubepitheliumanddeeper eosinophilic amyloiddepositionsarediffusely tongue (Patient7inTable2).Amorphousand Fig. 3.Thelightmicroscopicfindingsofthe We thus suggestthat 2.4 years) Matsuo et al: Dialysis-related amyloidosis of the tongue 837 Table6. Previous case reports of lingual amyloidosis of DRA Patients . Authors Cause of Duration Dialysis Case [referencel AgeSexrenal failureof HD membrane Symptoms Nodules Macroglossia 1 Fuchs et al [10] 56 M CGN 18Y CuprophaneOdynophagia Rt side — 2 Ogawa et al [71 54 M CGN 12Y ND — — — Autopsy 3 Guccion et al [8] 50 M CGN 12Y ND — Dorsal, lateral, — Nodule size: pale-yellowish 0.2—0.6 cm 4 Sethi et al [9] 48 M Crescentic 18Y CuprophaneUnpleasant taste + + GN difficulty swallowing 5 Yuonai et al [11] 66 M ND ND ND — Dorsum — Abbreviations are: M, male; CGN, chronic glomeruloneprhitis; Y, years; ND, no data. than 20 years is one of the contributing factors that may induceApo E antibodies. The amyloid P component is known to be DRA of the tongue. In patients in which DRA is alreadycommonly associated with all types of systemic amyloidosis [26— established, biocompatible "high-flux" synthetic membranes29], although its role in the process of amyloidogenesis still should be used for hemodialysis, since they can significantlyremains to be clarified. Recently, Apo E was demonstrated to reduce the prevalence of DRA [14, 18, 19] and thereby improvehave an affinity to f3-amyloid protein, which forms amyloid fibrils such symptoms [20, 21]. in Alzheimer's disease [30]. In addition, recent studies showed In regard to the clinical signs and symptoms of lingual amyloid-that Apo E peptides are commonly associated with amyloid osis in our cases (Table 5), the location of the amyloid nodules wasdeposits in cases of systemic amyloidosis [31, 32]. The potential classified into two types: the lateral type (Fig. I) and the diffuserole of the amyloid P component and Apo E in amyloidogenesis type (Fig. 2). No lingual amyloidosis was found in the amyloidneeds to be investigated further. In our study, the predialysis nodules deposited only in the dorsum of the tongue, while Yuonaiserum levels of 132n1 and Apo E were compared between our 8 and Sciubba reported that amyloid nodules deposited on thepatients and the control group (Table 4). No difference was dorsum of the tongue [111. It is doubtful whether they preciselydiscovered between the two groups, which seemed compatible checked the lateral side of the tongue as well, because patients 6with those in previous studies [33, 34]. and 7 of the diffuse type in our cases initially noticed the nodules In conclusion, dialysis-related amyloidosis of the tongue is a only on the lateral side. We thus speculate that amyloid depositionvery rare complication in the late stage of long-term hemodialysis, predominantly starts on the lateral side of the tongue due tohowever, this problem may cause serious lingual dysfunction, frequent contact with the teeth and related stimulation. affecting the patients' quality of life. There was no macroglossia, although macroglossia is frequently seen as a sign of arnyloidosis in primary and myeloma-relatedACKNOWLEDGMENTS amyloidosis (AL amyloidosis). Macroglossia is estimated to occur We thank Dr. Takao Tanaka and Mr. Brian Quinn for their critical in 20% to 27% of such amyloidosis patients [22—251. Lingualreview, and Dr. Morimichi Miyagi for his cooperation. This study was amyloid lesions, macroglossia in particular is less frequent inpresented in part at the XIII International Congress of Nephrology, secondary amyloidosis (AA amyloidosis, etc.) than in the primaryMadrid, Spain, in July 1995. or myeloma associated types. Although only one case of macro- Reprint requests to Kenzo Matsuo, M.D., Kidney Center, Saiseikai Yahata glossia has been previously reported by Sethi et al [9] as a case ofHospital, 5-9-27 Harunomachi, Yahata Higashi-ku, Kitakyushu 805, Japan. systemic DRA (Table 6), it has yet to be clarified as to whether or not the tongue was enlarged. For clinical diagnosis of macroglos-REFERENCES sia, the following conditions are required: (1) increased firmness 1. GEJYO F, YAMADAT,ODANI5,NAKAGAWA Y, ARAKAWA M, KUNI- of the enlarged tongue, (2) enlargement of the submandibular 1OMO T, KATAOKA H, SUZUKI M, HIRASAWA Y, SFIIRAHAMA T, CoHEN structures, and (3) dental indentations on the tongue. When these AS, SHUMID K: A new form of amyloid protein associated with chronic hemodialysis was identified as 132-microglobulin. Biochem Biophys Res clinical appearances are present, then the diagnosis of macroglos- Commun 129:701—706, 1985 sia can be made. Lingual dysfunctions in mobility and articulation 2. 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