Dialysis-related amyloidosis - CORE

Kidney International, Vol. 41(1992), pp. 1416—1429

NEPHROLOGY FORUM

Dialysis-related amyloidosisPrincipal discussant: KAa M. KOCH

Medizinische Hochschule Hannover, Hannover, Germany

A 38-year-old male required the initiation of regular hemodialysistreatment 19 years ago because of end-stage renal disease due tomesangioproliferative glomerulonephritis.

After an initial 3 months of center dialysis, during which an arterio-venous fistula was created in the left forearm, the patient was trainedfor home dialysis. At home, he was dialyzed overnight 3 x 10hours/week at a blood flow of 250 mI/mm and a dialysate flow of 500mi/mm using the Klll dialyzer with cellulosic membranes and a 1 m2surface area; a given dialyzer was used three times before being rebuilt.After 5 years, "reuse" KiiI dialysis was replaced by single-use dialysisemploying a 1 m2 commercial plate dialyzer with cellulosic membranes;dialysis time was reduced to 3 x 8 hours/week but blood and dialysateflow rates were unchanged. At that time the patient was totally anuric.His predialysis (first dialysis of the week) serum urea and creatinineconcentrations with the new dialysis regime ranged from 2 1—25 mmol/liter (120—150 mg/dl) and 1000—1100 mol/liter (11—12 mg/dl), respec-tively. The patient was unemployed but physically well; he refused tobe placed on the walting list for cadaveric transplantation.

Ten years after the start of hemodialysis, radiologic examination ofthe skeleton showed general osteoporosis without specific lesionsattributable to renal osteodystrophy. The serum levels of C-terminalPTH were moderately elevated. The patient was normocalcemic andhad intermittent mild hyperphosphatemia (< 6 mg/dl). Bone histologyfrom an iliac crest biopsy revealed only slight osteitis fibrosa, as well asminor evidence of defective mineralization. The dose of oral phosphatebinders and oral calcium carbonate was increased, and treatment withcalcitriol (0.25 pg/day) was initiated.

In the following years, clinical and neurophysiologic signs of carpal-

tunnel syndrome developed and increased in intensity; 13 years afterthe start of hemodialysis, bilateral carpal-tunnel release procedureswere required for relief of symptoms. Light and electron microscopyexamination of the excised tissue showed synovial amyloid depositswith positive immunoperoxidase staining for J2 microglobulin in theright carpal tunnel. Histologic search for amyloid in tissue obtainedfrom the left carpal tunnel was negative. In both carpal tunnels,synovial collagen was massively increased. Skeletal radiography per-formed at the time of the operation showed small cystic lesions in bothradial heads, a single cyst in the left navicular bone, several cystictrnnslucencies with a maximal diameter of 1.5 cm in both femoralheads, and one juxtaarticular cyst in the right os acetabulum.

Subsequently, increasing pain and limitation of movement in both hipjoints developed; 16 years after the start of hemodialysis, the patientcould walk only with the help of crutches because of severe pain in theleft hip. Radiography revealed fractures of both femoral necks (left side,complete; right side, incomplete) in areas of cystic transformation.Bilateral total hip replacement was performed. Histologic examinationdisclosed masses of $2 microglobulin-related amyloid within the syno-via as well as in cystic bone lesions. In comparison with the histologicfindings on an iliac crest biopsy obtained 6 years earlier, the extent ofosteitis fibrosa had increased; staining for aluminum was negative.

Postoperatively, the daily calcitriol dose was increased to 0.5 jig.Dialysis was performed with a 1.2 m2 polysulfone capillary membraneat a weekly dialysis prescription of 3 x 6 hours. The j32-microglobulinconcentrations decreased from an average predialysis level of 45mg/liter (during dialysis with the cellulosic membrane) to an average of30 mg/liter.

One year later, the patient developed hypercalcemia, which persistedafter calcitriol therapy was stopped. At the same time, serum alkalinephosphatase activity started to rise and C-terminal PTH was found to beextremely high; subtotal parathyroidectomy was performed.

During his 19th year of hemodialysis, the patient began to experiencesevere pain in the upper cervical vertebrae, which was induced bymovements of the neck and which spread to both shoulders and upperarms. Radiography showed massive destruction of the arcus of thesecond cervical vertebra and cystic lesions of the third cervical vertebra(Fig, I). A nuclear magnetic resonance scan revealed nodular masseswith reduced signal intensity overlying destroyed areas of the rightlateral pnrts of the second and third cervical vertebrae (Fig. 2). Thesefindings were interpreted as consistent with amyloid deposits. Therewas no indication of spinal cord compression.

The risks of cord damage from neurosurgical intervention wereunacceptable to the patient so that no operative procedure to stabilizethe cervical vertebrae was performed. He was provided with anexternal stabilizing cravatte to prevent palnful and dangerous move-ments. Now in his 19th year after hemodialysis, the patient hasexpressed willingness to receive a renal transplant and has been placedon a wailing list for a cadaveric graft.

Discussion

Presentation of this Forum is made possible by an educational grantfrom Merck Sharp & Dohmc International. This Forum was presentedin Talloires, France, in May 1991.

© 1992 by the International Society of Nephrology

PROF. DR. KARL M. KOCH (Professor of Medicine, Head,Division of Nephrology, Hannover Medical School, Hannover,Germany): This case, with its succession of osteoarticularlesions such as carpal-tunnel syndrome (CTS) and multiplefractures due to cystic bone transformation, unfortunately

1416

EditorsJORDAN J. COHENJOHN T. HARRLNGTONNICOLAOS E. MAmAS

Managing EditorCHERYL J. ZUSMAN

State University of New York at Stony Brookand

Tufts University School of Medicine

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Nephrology Forum: Dialysis-related amyloidosis 1417

were found in the carpal synovia and perineural tissue inlong-term, regular hemodialysis patients with CTS [1—4], and in1985 when Gejyo et al demonstrated that the lesions containeda new type of amyloid with beta-2-microglobulin (f32m) as theconstituent protein [5, 61. Because f32m amyloidosis associatedwith osteoarticular pathology appeared to be limited to thedialysis population, the term dialysis-related amyloidosis(DRA) was introduced.

The specific histologic diagnosis of 132m amyloid depends onimmunohistochemistry, because, like all types of amyloid, itexhibits nonspecific Congo-red staining with green birefrin-gence under polarized light; /32m amyloid deposits stain specif-ically with anti-132m antibodies [5, 6]. Also like other types ofamyloid [7], /32m amyloid deposits contain serum amyloid P(SAP) component [8] and therefore also stain with anti-SAP-antibodies [9]. Electron microscopy reveals, in contrast to thestraight, longer, and thinner fibrils seen in other types ofamyloid, shorter and thicker curvilinear fibrils aligned in paral-lel and aggregated in bundles [10—13].

Clinical observations

Fig. 1. The arcus of the 2nd cervical vertebra is nearly destroyed by alarge cyst (arrow). The arcus of the 3rd vertebra shows a number ofsmall cysts. In addition the dorsal part of the atlas is significantlynarrowed.

exemplifies a common clinical syndrome in patients with end-stage renal disease (ESRD) who survive for 10 or more yearswith regular dialysis treatment (RDT). This syndrome—dialy-sis-related amyloidosis—with its crippling consequences, isnow recognized as a very serious complication of RDT, one thatin fact may limit the duration of long-term RDT.

During the last decade, clinical investigators gradually real-ized that the syndrome might have no direct relationship withestablished pathogenetic mechanisms of osteoarticular diseasein RDT such as secondary hyperparathyroidism or aluminumaccumulation, but that it could have a specific pathogenesis ofits own. This hypothesis was confirmed when amyloid deposits

Carpal-tunnel syndrome and destructive arthropathy associ-ated with cystic bone lesions are the major clinical manifesta-tions of DRA [1—4, 6, 13—23]. Although some clinical studies[1—4, 12, 14, 15, 18, 19] of the then-putative entity wereperformed before Gejyo demonstrated that f32m was the amy-bid precursor protein [5, 6], it seems justified to attribute thereported cases also to f32m amyboidosis because the radiologicand clinical findings were indistinguishable from those reportedin well-established cases of J32m amyloidosis and because noneof the established causes of other types of amyboidosis wasfound.

The main clinical symptoms and electrophysiologic findingsof carnal-tunnel syndrome in dialysis patients are identical tothose of idiopathic CTS and CTS accompanying other diseasessuch as rheumatoid arthritis, old fractures, and diabetes melli-tus; these symptoms and findings include hypesthesia, hypal-gesia as well as pain (especially at night), thenar weakness andwasting, decreased motor nerve conluction velocity, and pro-longation or absence of distal moto latency. In hemodialysispatients, simultaneous or successi)e bilateral occurrence ofCTS is very common. In severe cases of CTS in regularhemodialysis patients, contraction of the hand and atrophy ofthe digital muscles—the so-called "amyloid hand"—can de-velop.

The occurrence of CTS in patients undergoing RDT wasknown before the association between CTS and 132m amyloiddeposits in the carpal tissue was recognized [24, 25], but thereported incidence of CTS increased in the years following thediscovery of f32m amyloidosis. This increase might have beendue to stimulated interest and better diagnosis, but it is alsopossible that it reflected the increasing number of patients withlonger duration of RDT. In a recent study in a large populationof RDT patients, the percentage of patients who requiredoperation for CTS increased steeply from almost zero before 8years of regular hemodialysis to 50% at 14 years and 100% at 20years [26]. In one multicenter retrospective study, age at theonset of dialysis correlated significantly with the developmentof CTS [27].

1418 Nephrology Forum: Dialysis-related amyloidosis

Fig. 2. TI weighted axial magnetic resonance image. Right-sided destruction of the lateral parts of the second and third cervical vertebra isapparent. The low-signal area (arrow) in place of the destructive lesion is compatible with an amyloid deposit ( marks spinal channel with myelon).

There is considerable variation in the number of amyloid-positive cases of CTS and in the mass of amyloid found in thecarpal tissue. Whereas in some studies 70% to 100% of theoperated cases were amyloid positive [3, 4, 21], other studiesreported a lower incidence of amyloid-positive eases [14, 15,18]. These differences might be explained in part by differencesin the methods or thoroughness of investigation, but they alsocould be interpreted as indicating pathogenetic mechanismsother than amyloidosis. This latter interpretation is supportedby the observation that the amyloid deposits in some patientswith CTS are scattered, patchy, and minute islets withinhyperplastic connective tissue [16, 17]. Nevertheless, in otherstudies the amyloid deposits were so massive that they alonecould account for median nerve entrapment [6, 28, 29].

In CTS, amyloid usually is deposited in the carpal synovia,finger flexor tendon sheaths, transverse carpal ligament, andperineural tissue [29, 30]. Histologically one finds a pericollag-enous distribution of the deposits [12, 17] associated withhyperplasia of the synovial tissue [28, 31]. When the depositionin the tendons and tendon sheaths of the fingers is excessive,these lesions cause "amyloid hand."

The main target of (32m amyloid-related destructivearthropathy is large and medium-sized joints. The pathologyranges from synovitis and effusions to erosions and destruction

[11, 20—23, 32] accompanied by stiffening and pain of theinvolved joints.

As in CTS, the lesions can start unilaterally but in many casesthe contralateral joint soon becomes affected. Symptoms due toinvolvement of shoulders and knees usually arise approxi-mately 8 to 10 years after the start of RDT and very oftencoincide with the manifestation of CTS. As a rule, the hipssubsequently become affected (that is, 12 to 15 years after thestart of RDT), culminating in pathologic fractures of the femoralneck.

Spinal symptoms—especially destructive spondyloat-thropa-thy—manifest at variable times. The spine can be affectedearly, but more often it begins to deteriorate many years afterthe start of RDT. Whether the thm amyloid found in affectedlocations [23, 33—36] is a primary factor in the pathogenesis ofspondyloarthropathy in regular dialysis patients is still contro-versial [37]. Kuntz et al have suggested that the deposition ofhydroxyapatite crystals in the intervertebral discs plays apathogenetic role in dialysis-related spondyloarthropathy [38].There is no doubt, however, that j32m amyloid deposits wereresponsible for the development of spinal neurologic complica-tions in 3 reported cases [36, 39, 40]. Finally, in many cases,fl2-microglobulin amyloidosis also affects the sternoclavicular


joint. The deposits can be asymptomatic [41] or accompaniedby painful joint swelling [42].

Radiologic examination in f32m-amyloid-associated arthropa-thy demonstrates erosions and marginal defects of the affectedbones, mainly at synovial insertion sites. A characteristicfinding is periarticular cystic bone lesions, which grow innumber and size with the continuation of RDT. Commonlyaffected sites include the carpal bones, femoral and humoralheads, acetabulum, tibial plateau, and distal radius [20—23, 29,32]. Subchondral cysts in the knee, hip, and shoulder canprecede articular narrowing by 2 to 4 years [21]. Progression ofcystic bone defects in the femoral neck results in pathologicfractures [11, 21, 32]. Extraosseous radiologic findings, whichinclude swelling of articular and periarticular soft tissue mainlyinvolving joint capsules, synovia, and tendons, can be visual-ized and quantified by ultrasonography [43].

Distinguishing /32m-amyloid-related bone cysts from browntumors of secondary hyperparathyroidism is not always easy. Ifradiologic signs of subperiosteal bone erosion are missing, andbone cysts increase in size despite parathyroidectomy, one canprobably assume that DRA is present. Of further differentialdiagnostic value is that hyperparathyroid cysts often appear inthe metaphysis and epiphysis of tubular bones, jaws, and ribs,whereas the amyloid-related cysts are restricted to the vicinityof synovial joints [20, 21, 23, 44]. One also should take intoaccount that cysts attributable to secondary hyperparathyroid-ism rarely are located in carpal bones [45]. Finally, subchondralbone cysts appear to be very specific for f32m amyloidosis.Zingraaf and coworkers pointed out a close correlation betweenthe occurrence of subchondral bone cysts and histologic evi-dence of J32m amyloidosis in the sternoclavicular joint [41].

Immunohistologic evaluation of biopsy and autopsy speci-mens discloses f32m amloid deposits localized mainly in thesynovia of the affected joints. Amyloid also is detected inmaterial obtained from the bone cysts, either by cyst punctureor during surgery for repair of pathologic fractures from cysticbone lesions. In these patients with cystic bone lesions, theamyloid deposits were found to be especially massive [11, 21,32].

Using the radiologic and clinical criteria I have outlined, onecan conclude that the prevalence of osteoarticular lesionsattributable to /32m amyloid, like the prevalance of CTS,increases with the duration of RDT; beyond 15 years, virtually100% of hemodialysis patients have osteoarticular lesions [32].Older patients are at a higher risk of being affected [27].

The salient radiologic and clinical feature of DRA is theappearance of deposits in osteoarticular tissue. Deposition of/32m amyloid outside these sites, in locations such as abdominalfat, the gastrointestinal tract, lung, liver, heart, and endocrinetissue, has been demonstrated in a limited number of patients[28, 46—56]. Although the visceral amyloid deposits generallyare small and mainly perivascular, in a few patients, thesedeposits can have significant clinical consequences, such ascardiac or intestinal malfunction [47, 51—55]. Because of thelimitations in deposit size and distribution of extraskeletal j32mamyloid, easily accessible regions such as abdominal subcuta-neous fat and the rectum are not reliable biopsy target areas fordiagnosing 32m amyloidosis [22, 28, 48, 55—57].

Pat hophysiology

Beta,-microglobulin, an 11,800 dalton globular protein, con-sists of 100 amino acids arranged in a single polypeptide chain.As part of the human class-I major histocompatibility complex,2m is expressed on the surface of all nucleated cells [58—60].Also found as an intragranular protein within neutrophil gran-ulocytes, it is released from these cells during degranulation[61]. Experimental studies in hepatocytes showed that in thesecells f32m is a secretory protein; its synthesis and release aremodulated by alpha- and gamma-interferon [62].

After shedding from cellular surfaces or release from withincells, J32m can be detected in the plasma. Plasma f32m is notbound to other protein, and more than 90% circulates inmonomeric form [63]. Approximately 95% of f32m is eliminatedvia glomerular filtration [64], thereafter undergoing almostcomplete tubular absorption and metabolic degradation [65];the remaining 5% is cleared at unknown extrarenal sites. Notsurprisingly, a close negative correlation between glomerularfiltration rate and the serum level of J32m has been demonstrated[66]. The average daily synthesis of f32m in normal subjects isapproximately 200 mg. Measurements in 3 patients with variousdegrees of severe renal insufficiency showed values of the sameorder of magnitude [64].

Increased synthesis and release of /32m into the extracellularspace, as indicated by a rise in serum /32m levels, occurs ininflammatory and malignant lymphoproliferative disease [67].In vitro and in vivo studies indicate that increased synthesis andrelease of /32m are mediated by cytokines: stimulatory effectson synthesis and release in cultures of various cell types couldbe ascribed to tumor necrosis factor (TNF), interleukin-2 (IL-2), and interferon (INF) alpha and gamma [62, 68—70]. In vivoapplication of recombinant INF alpha and gamma as well as ofTNF increased 132m serum levels [70, 71]. Findings regarding anin vitro stimulatory effect of interleukin- 1 are controversial [62,69, 70, 72]. In vivo, however, a stimulatory effect of IL-l viainduction of release of other cytokines such as INF and IL-2 ispredictable [73].

Retention and synthesis of f32m in patients on RDT. Serumconcentrations of /32m, normally ranging from 1 to 3 mg/liter,can be elevated as high as 60-fold in patients receiving regularhemodialysis who have no residual renal function [63]. Theretention of the precursor protein in terminal renal failure is anabsolute prerequisite for the development of /32m amyloidosis.In view of the known effects of cytokines on /32m productionand with the growing evidence that hemodialysis induces aninflammatory response, it is conceivable that the process ofhemodialysis itself might increase f32m synthesis and release,thereby contributing to the accumulation of the amyloid precur-sor protein. Activation of cells and the release of inflammatorymediators during or following hemodialysis have been postu-lated since the early l980s as part of the interleukin hypothe-sis" [74]; the theory has been widely documented since. Duringhemodialysis, blood cells can release several mediators includ-ing IL-i [75—77], TNF [77], reactive oxygen species [78], andprostaglandins [79]. Furthermore, complement activation oc-curs on some dialysis membranes [80], which in turn inducescellular monokine mRNA production, thereby preconditioning


cells to an increased monokine release upon subsequent stim-ulation [81]. Besides the dialysis membrane, acetate (as dialy-sate buffer) and especially endotoxin in the dialysate inducecellular monokine release [82, 83]. Some of these mechanismsalso might be operative in CAPD patients. Two reports suggestthat peritoneal dialysis itself is sufficient stimulus to induceperitoneal activation of cells and cytokine release in asympto-matic patients treated with continous ambulatory peritonealdialysis (CAPD) [84, 851.

Direct, experimental in-vitro data indicate that the inflamma-tory response induced by hemodialysis could cause an in-creased production of f32m. Recent studies demonstrated thatisolated peripheral blood lymphocytes (PBL) and peripheralblood mononuclear cells (PBMC) harvested at the end ofhemodialysis with cellulosic membranes showed, respectively,an increased expression of f32m RNA in culture [861 or higherf32m concentrations in the culture supernatant [87] when com-pared with control cells harvested before dialysis. When poly-methylmethacrylate (PMNA) membranes were used, the /32mconcentration in PBMC supernatants did not increase. In addi-tion to the release of inflammatory mediators, hemodialysis caninduce degranulation of neutrophil polymorphonuclear leuko-cytes (PMNL) and release of proteases, depending on the typeof membrane used [88, 89]. It is conceivable but not yet provedthat the degranulation of neutrophil PMNL also involves /32m-containing granules [61] and thereby also results in cellularrelease of /32m.

Definitive in-vivo evidence for an increased synthesis of f32minduced by hemodialysis is not available. Increases of fJ,mserum levels ranging from 5% to 40% observed during hemodi-alysis with cellulosic membranes impermeable for /32m [90—92]were interpreted as an indication of increased production of/32m [90]. Subsequently, however, 2 separate studies, one usinginulin space measurements [93] and the other using comparativekinetics of myoglobin as a marker molecule of similar size [94],showed that in hemodialysis with celiulosic membranes, theintradialytic changes of serum concentrations of /32m are mainlyconsequences of concomitant changes of extracellular volume.Further support for this concept comes from the finding thatsham dialysis (without dialysate and hence without weight loss)using cellulosic membranes for 2 to 4 hours does not changef32m serum levels [94].

We determined overall f3.2m synthesis in 11 anuric chronichemodialysis patients and in S healthy volunteers in a kineticstudy using '31I-/32m [95]. The mean synthesis rate of 3.100.79 (SD) mg/kg/day of the patient group was higher than that of2.4 0.67 mg/kg/day in healthy controls; the difference was notsignificant, however. Within the patient group, those treatedwith /32m-impermeable, "less biocompatible" cuprophanemembranes (n 5) had a higher mean synthetic rate than didthose (n = 5) treated with /'32m-permeable, "more biocompati-ble" polysulfone membranes, 3.26 0.80 (SD) mg/kg/dayversus 2.66 0.46 mg/kg/day. The limited data preclude anymeaningful statistical analysis of the subgroups. More informa-tion regarding the effect of dialyzer membrane would be gainedby comparing rates of synthesis of /32m before and after the useof various membranes in the same individuals.

Processing of f32m and amyloido genesis. In addition toretention and possibly increased synthesis of the precursorprotein, further mechanisms appear to be involved in the

pathogenesis of fJ2m amyloidosis. Although amyloid fibril-likestructures can be created in vitro from intact f32m [96], severalobservations argue against simple precipitation as the solemechanism of amyloidogenesis in DRA: (1) the /32m serum leveldoes not correlate with the presence or absence of disease [96,97]; (2) fragmented and polymerized f32m next to monomeric-intact /32m was found to be a major constituent of the amyloid[8, 98, 99]; (3) the predilection of /32m amyloid for osteoarticulartissue with relative sparing of parenchymal organs, whichgenerally are involved in other types of amyloidosis, suggestsspecific local mechanisms predisposing to amyloid deposition;(4) the increased prevalence of DRA with age [27], and our ownobservation that occasional patients are spared from DRA eventhough they have had hemodialysis treatment with cellulosicmembranes for more than 15 years, suggests that additionalpathogenctic mechanisms of a more general nature exist.

In contrast to the initial findings of Gejyo [5, 6], Linke'sanalysis of the amino-acid sequence of J32m-amyloid fibrilsrevealed that these fibrils not only consisted of intact j32m, butto a significant degree, also of p2m fragments, most of themwith lysine-specific cleavage [98, 99]. Ogawa also showed bytwo-dimensional electrophoresis that in addition to intact fl2m,a "novel f32m" with a reduced molecular weight occurred insolubilized amyloid fibrils [100]. This "novel J32m" also wasdetected in the plasma of long-term hemodialysis patients withclinical manifestations of p2m-amyloid. These findings suggestthat alterations of the precursor molecule, such as limitedproteolysis, are involved in /32m amyloidogenesis; this hypoth-esis is consistent with current concepts of the patbogenesis ofseveral other types of amyloid [101]. The cellular activationwith subsequent release of inflammatory mediators and prote-ases induced by hemodialysis might be involved. Such cellularactivation preceding the limited proteolysis of /32m could takeplace on the dialyzer membrane itself. Alternatively, resident orblood-derived cells in the tissue (especially macrophages) acti-vated by mediators released from circulating cells during dial-ysis might participate in f32m proteolysis.

An intriguing modification of the proteolysis hypothesis wassuggested recently by Argues and colleagues [102]. They positthat incompleteness of proteolysis of f32m is the prerequisite foramyloid fibril formation and that complete proteolysis is pre-vented by "amyloid-enhancing factors" such as the anti-pro-tease amacroglobulin (a2m); further, they demonstrated thepresence of a2m in J32m amyloid deposits. If this hypothesis iscorrect, the modulation of proteolysis by a2m-macroglobulin istwofold; in addition to the proteolytic activity of enzymesalready synthesized, a2m also inhibits the protease productionof macrophages following specific receptor binding [104, 105].Adding credence to Argilés' concept is the observation that, inpatients receiving RDT who have CTS, serum levels of a2mwere higher than they were in patients without amyloidosis whohad had RDT for just as long [106].

The predilection of fl2m amyloid deposits for osteoarticulartissues, which are rich in collagen, and the close ultrastructuralassociation between 132m amyloid and collagen within thesetissues [12, 17, 31] suggest a high affinity of the precursor fJ2mfor collagen. Indeed, Homma et al showed that 132m binds tovarious collagens in a dose-dependent manner [107]. Whetherthis affinity for collagen is increased in hemodialysis patientsbecause of alterations in collagen composition is unknown.


According to experimental findings by Kisilevsky and Snow,the glycosaminoglycans (GAG) composition of the interstitialmatrix of the periarticular tissue also might be a local factorfavoring amyloid formation [1081. A relation between amyloiddeposition and GAGs also was suggested by ultrastructural andimmunohistochemical studies of J32m-amyloid deposits in he-modialysis patients [13]. Nishi et al demonstrated that theamyloid fiber bundles were surrounded by GAGs and con-cluded that GAGs regulate the distribution and arrangement offibrils.

If proteolytic processing of the precursor molecule is aprerequisite for fibril formation, one can reasonably assumethat the proteolytic processing takes place where the precursoraccumulates. Within the synovia, the predominant location ofarticular f32m amyloid deposits, amyloid is found with andwithout synovial infiltration by inflammatory cells [31]. Theprime suspects involved in f32m proteolysis therefore are thesynoviocytes. Their number in patients receiving long-termhemodialysis treatment is significantly increased [311, and asubtype (type A) morphologically and functionally displaysmacrophage-like features [109]. This potential involvement ofthe synoviocytes in fibril pathogenesis could be a furtherpredisposing factor for the preferential articular disposition of2m amyloid. Whether the synoviocytes are activated andproliferate because of the mere presence of f32m, or whetherinflammatory processes induced by hemodialysis are also in-volved is not known.

Aluminum [1101 and iron [111] also have been proposed aspredisposing factors to the intraarticular accumulation of f32m.The role of iron is controversial, and contradictory observa-tions exist [23, 32]. The issue is complicated by the possibilitythat the simultaneous increase of aluminum and iron deposits,on the one hand, and of amyloid deposits, on the other, mightbe a fortuitous association of two independent, time-relatedcomplications of long-term hemodialysis therapy.

Therapeutic considerations

The experimental investigation of dialysis-related amyloido-sis continues to pose many intriguing questions to the scientist.But how does our current knowledge aid the clinician who hasto care for these patients? Let us consider some importantpoints that can be useful in clinical decision-making.

(1) Dialysis-related amyloid would not exist without accumu-lation of the precursor.

(2) The possibility that the dialytic process promotes thepathogenesis of DRA via regular induction of intermittentinflammatory reactions is too great to be disregarded.

(3) A large, retrospective multicenter study showed thatlong-term hemodialysis with a highly permeable acrylonitrilemembrane was superior to long-term hemodialysis with acuprophane membrane, in that the former was associated witha lesser prevalence of clinical and radiologic manifestations ofDRA [27]. Although this study is otherwise very thorough andcritical, it is limited because it relied mainly on clinical andradiologic criteria, and the number of patients at risk for 15years was small. Nevertheless, the study results do supportpoints (1) and (2) for the following reasons: In contrast tocuprophane, which is practically impermeable to 2m, acryloni-trile permits a weekly removal of 400—600 mg of f32m [1121.Even though this quantity is far less than the weekly synthesis

of approximately 1500 mg [95], its removal probably at leastslows the continous increase of the 2m burden. Furthermore,in comparison to cuprophane, acrylonitrile is more "biocom-patible," as it has a high adsorptive capacity for cytokines [113]as well as endotoxins [114], and its use is accompanied by littlerelease of proteases from blood cells [88], low complementactivation [115], and little induction of phagocytic oxidativemetabolism [78].

(4) The multicenter study I just mentioned showed that age atonset of RDT also affected the prevalence of chronic manifes-tations of DRA [27]. Patients over the age of 40 at the initiationof regular hemodialysis treatment carried a higher risk for thedevelopment of bone amyloidosis than did younger patients.

(5) Successful, early kidney transplantation certainly pre-vents DRA. Furthermore, in patients with already establishedDRA, renal transplantation arrests the progression of radiologicsigns of DRA [1161 and produces an almost immediate abate-ment of osteoarticular pain. The latter effect probably is mainlydue to the antiinflammatory action of steroids, but it also mightbe caused partly by the termination of the induction of inflam-matory activity by hemodialysis and the return of normal ornearly normal renal function.

Let me suggest a cautious but, I believe, justified set ofpolicies based on these five points. Patients older than fifty,whether or not they are candidates for transplantation, shouldbe dialyzed with the acrylonitrile membrane or a membranewith comparable qualities, such as polysulfone or polyamide.The same approach applies for younger patients who have littlechance of receiving a transplant. Patients with clinically estab-lished DRA should be given a high priority for transplantationso they won't become disabled. In view of the potential ofbacterial products to induce inflammatory processes duringhemodialysis, the dialysate should be sterile and pyrogen-free.This measure especially applies when membranes with lessresistance to the passage of bacterial products from dialysate toblood are used [117].

Should one use hemofiltration or continuous ambulatoryperitoneal dialysis (CAPD) to prevent or delay the manifesta-tions of DRA? Even though hemofilters with "biocompatible"membranes enable the weekly removal of approximately 1000mg of f32m [118], wide use of hemofiltration will be prevented byits prohibitive cost as long as commercial substitution fluid hasto be used. The weekly removal of approximately 300 mg off32m in CAPD patients is lower than that achieved with hemo-dialysis with high-flux membranes [112]. Like hemodialysis,CAPD can induce cellular activation and release inflammatorymediators [84, 85]. Clinical reports of continuous progression ofDRA bone lesions after a change from hemodialysis to CAPD[32] and of the occurrence of amyloid deposits in patientstreated exclusively by CAPD [119, 120] suggest that CAPDmight not be superior to hemodialysis in preventing DRA or indelaying its onset. A conclusive comparative evaluation of theprevalence of DRA in CAPD patients and regular hemodialysispatients does not exist because of the small number of patientswith long-term exposure to CAPD.

The rationale for my recommendations certainly would bestrengthened and additional preventive measures could beevaluated by prospective studies. So far, the prospective eval-uation of strategies for preventing DRA has been hampered by


the non-availability of an early and sensitive diagnostic proce-dure that would be acceptable to patients and that wouldindicate the presence of f32m amyloid anywhere in the body.Amyloid-related clinical symptoms or radiologic findings arelate occurrences in the development of DRA, and biopsies ofnon-selected, easily accessible tissues at best yield only chancefindings of amyloid [22, 28, 48, 55—57]. The two procedures thatmost often yield positive results, synovial biopsies and theaspiration of joint effusions [19, 22, 26], do not have thepotential of becoming routine diagnostic procedures in prospec-tive trials. However, two recent reports are very promising.They describe the diagnostic radionuclide tracing and imagingof f32m-amyloid deposits by injections of either '231-labeledserum amyloid P component (SAP) [1211 or 1311-labeled /32m[1221. A minor constituent of j32m-amyloid, SAP accounts forabout 5% to 15% of the total amyloid mass [123]. Injection ofthe radiolabeled molecule allowed the noninvasive detection ofamyloid deposits of the carpal-tunnel region and metacarpopha-langeal joints of two long-term hemodialysis patients [121]. It isnot known, however, whether the scan also will detect minor,asymptomatic, early stages of amyloid deposition. An alterna-tive to scanning with radiolabled SAP is offered by the injectionof the radiolabeled precursor molecule j32m [122]. Using thistechnique, we found localized tracer accumulation in the shoul-ders, hands, knees, pelvis, and vertebral column in 23 of 30patients on regular hemodialysis treatment longer than 5 years[122]. Correlation of scan findings with available immunohistol-ogy showed a very high sensitivity and specificity of the scanfor the detection of $2m-amyloid deposits. With the scan it ispossible to detect amyloid deposits before their presence isindicated by clinical symptoms and/or radiologic alterations ofbones. This is shown in Figure 3, which depicts our results todate in 49 patients.

Currently, this radiodiagnostic method offers a sensitive andnoninvasive way of demonstrating p2m deposits. It might notonly permit a more complete description of the prevalence off32m-amyloidosis but, by repeated scanning, it also might allowone to assess the influence of different therapeutic strategies onthe appearance of amyloid deposits or on the fate of existingdeposits.

Questions and answers

DR. F. JOHN GENNARI (Professor of Medicine and Director,Nephrology Division, University of Vermont College of Medi-cine, Burlington, Vermont): It seems to me that CAPD patientswould be the appropriate controls for chronic hemodialysispatients in studies on DRA. Are there comparisons? What arethe f32-microglobulin levels in CAPD patients? I am surprisedthat this population has not been studied more completely.

DR. KocH: The populations with long-term exposure toCAPD, that is, longer than 10 years, are very small, so noconclusive comparison of the prevalence of DRA in CAPDpatients and regular hemodialysis patients is available. Never-theless, the number of case reports with /32m-amyloid beingfound in CAPD patients are increasing. Actually there existsone study by Benz et al comparing the incidence of CTS in twolarge populations of regular hemodialysis and CAPD patients[124]. There were no significant differences, but no histologicexaminations for amyloid were performed. Regarding /32mplasma levels in CAPD patients, plasma j32m is in the range of

that in hemodialysis patients provided renal function is compa-rable.

Da. CHARLEs VAN YPER5ELE (Professor of Medicine, RenalUnit, Cliniques Universitaires, St. Luc Universite de Louvain,Louvain, Belgium): In our hands, adequate radiologic examina-tion of the wrists and, more recently, ultrasonic quantitativeassessment of tendon thickness in the shoulders and the hipsprovide early specific evidence for the diagnosis of DRA. Underthe circumstances, what is the place of isotopic imaging tech-niques?

Da. KOCH: I totally agree regarding the usefulness of x-raysand ultrasonography in the clinical situation. The isotopicimaging techniques, since they are highly sensitive and specificand in our hands enable us to prove the existence of amyloidbefore characteristic skeletal alterations are visible, are excel-lent research tools. This especially applies for their use inprospective trials comparing the effect of different dialytictreatment modalities on the development and progression ofDRA.

DR. VAN YPERSELE: 131I-3microglobu1in entails a 2 to 3 mCiload that has radiation hazards unacceptable to Belgian ethicscommittees. We should not forget that /32-microglobulin amy-bid was demonstrated prior to the onset of dialysis [125]. It isworth pointing out that the synovial deposition of amyboid is notlimited to /32-microglobulin amyloidosis but is a characteristic ofamyloidosis due to AL amyloid as well. Further, spleen depos-its have been identified by Pepys and his colleagues, who reliedon 1231 serum amyloid P component imaging techniques [126].

DR. KOCH: At present the radiation dose of the '31I-f32m scantechnique is comparable to that of a barium enema x-rayinvestigation of the colon. We therefore apply this techniquevery restrictively but hope to be able to reduce the radiationexposure by employing other isotopes. The serum amyloid P(SAP) component scan developed by Pepys and coworkersimparts less radiation exposure because the imaging of theamyloid deposits takes place after 24 hours instead of 72 hourswith the 1311-f32m scan.

To my knowledge, there exists only a single reported patientwith proven /32m-amyloid prior to the onset of dialysis [125].The patient was 69 years old and had long-standing, severerenal insufficiency due to cortical necrosis. Histologicallyproven splenic deposition of f32m-amyloid so far has beenreported in only 4 patients. In view of this very rare incidence,the frequent positive splenic imaging with the SAP scan (12/35RDT patients) reported by Pepys and coworkers is very sur-prising [126].

DR. ANDREW REE5 (Professor of Nephrology, Royal Post-graduate Medical School, London, United Kingdom): I wouldlike to focus on the specificity of the /32-microglobulin scans.The SAP scan has been shown to be highly specific for amyloidboth by autoradiography and by the use of appropriate controls.Is the same true for the 132m on scans? My second questionrelates to the increase in RNA for IL-lfi. It appeared to betransient, as there appears to be no increase in cells tested after3 hours of dialysis. Was the increase in IL-1j3 message associ-ated with synthesis of the protein, or were you just showingchanges in mRNA?

DR. KOCH: The WI/32m scan also is highly specific regardingthe imaging of f32m amyloid deposits. In all cases we have so farinvestigated histologically, we have found J32m amyboid in sites

CocC0,

00)0C.)

with prior positive imaging. Inflammatory lesions of othercauses, such as active chronic polyarthritis and abscesses,when they were present in the investigated hemodialysis pa-tients, showed no positive imaging.

Regarding the demonstration of mRNA for IL-1/3 in mono-nuclear cells of samples taken at the venous blood line of acellulosic dialyzer, this indeed was a transient phenomenon.The disappearance of mRNA in samples taken during the latercourse of hemodialysis suggests that the induction of mRNA forIL-l13 is due to CSa, which preferably is generated during theearly part of hemodialysis, when the membrane is not yetcoated by protein. So far we only have looked for mRNA in

mononuclear cells lyzed after they had been kept for 30 minutesat room temperature following harvesting. We are in the pro-cess of studying whether these cells also synthesize and releaseIL-lp.

DR. MICHEL GOLDMAN (Head, Department of Immunology,Hôpital Erasme, Université Libre de Bruxelles, Brussels, Bel-gium): If we consider the clinical data of Charles van Yperseletogether with your own laboratory data, it appears that theincidence of amyloidosis is lower with the use of syntheticmembranes that are permeable to cytokine-inducing sub-stances. The important factor therefore could be the comple-ment activation induced by cellulosic membranes. Since this

%ofpts. N=13 N=21 N=9 N=6


100

80

60

40

20

0

100 -

80 -

60 -

40 -

20 -

0-0-5

Grade 0

0)CC)Co

C)C)00CO

C0

I r5-10 10-15 15-20

Time on hemodialysis, years

Fig. 3. '311-p2m accumulation in hemodialysis patients versus clinical and/or radiologic findings compatible with the diagnosis of J32m-amyloidosis.Tracer accumulation and clinical/radiologic symptoms were graded according to the number of sites involved: 0, none; I, one or two sites; II, threeor four sites; III, five or six sites; and IV, more than six sites.

II III liv


phenomenon can be prevented by reusing the membranes, doesthe reuse procedure have any influence on the development ofdialysis-related amyloidosis?

DR. KOCH: I do not know of any study of the effect ofdialyzer reuse on the development of dialysis-related amyloi-dosis. Whether complement is activated in a reused dialyzerdepends on the membrane-cleansing procedure applied beforereuse. Of course we have to realize that cell-membrane contactand complement activation might not be the only mechanismsinvolved in cytokine induction. We also have to consider thatbacteria-derived substances contained in the dialysate mightpermeate the dialyzer membrane and induce cytokines on theblood side.

DR. MICHAEL J. MIHATSCH (Chairman, Department of Pa-thology, University of Basel, Base!, Switzerland): What isknown about the turnover and disappearance rate of 132mamyloid in transplant patients?

DR. KOCH: So far there exists no direct evidence that f32mamyloid deposits are reduced or disappear after successfultransplantation in RDT patients. The immediate and impressivereduction in amyloid-related symptoms after transplantationprobably is due to the antiinflammatory effects of steroids.Studies by Dr. van Ypersele also showed that there is no furtherprogression of the radiologic manifestations of DRA but also noregression after successful transplantation. Pepys and cowork-ers reported negative SAP scans in patients after transplanta-tion despite histologically proven DRA before transplantation[1261. This observation indeed suggests reduction of amyloidmass after transplantation. An alternative explanation could bea lack of newly formed amyloid fibrils with free ligands for SAPbinding.

DR. CHARLES M. MION (Professor of Nephro!ogy and Head,Division of Nephrology, University of Montpellier, School ofMedicine, Montpellier, France): I believe that the residual renalfunction in CAPD patients probably is extremely important inretarding the development of Ø2m amyloidosis. Second, I haveseen carpal-tunnel syndrome with equal frequency in patientstreated with and without cuprophane membranes. Would youcomment?

DR. KOCH: I agree; residual renal function is generally betterpreserved during the first years of CAPD, so the accumulationof /32m, the amyloid precursor protein, might be reduced andthe development of 2m amyloidosis might be retarded.

Your observation of an equal frequency of CTS in patientstreated with cellulosic membranes and those treated with non-cellulosic membranes does not disagree with the results of theEuropean multicenter study: Whereas there was a significanteffect of the choice of membrane on bone amyloidosis, radio-logically determined, there was no effect on the prevalence ofCTS sufficiently severe to require surgery. A cautious interpre-tation of these findings is that, in hemodialysis patients, thmamyloid might not be the only cause of CTS.

DR. ARTURO BORSATTI (Professor of Nephro!ogy, Instituteof Internal Medicine, University of Padova, Padova, Italy):Can a steady state of j32-microglobulin be achieved in dialysispatients, or is there a constant increase of f32-microglobulin inthe blood? Can one remove the f32-microglobulin synthesized?

DR. KOCH: If you define a constant 132m plasma level asindicative of a steady state, then chronic hemodialysis patientsare in a steady state as long as residual renal function and /32m

removal by dialytic treatment do not change. Accordingly, acontinuous increase of plasma fl2m is seen during the earlyperiod of regular hemodialysis treatment when residual functionshows pronounced changes. In patients with very long timesspent on regular hemodialysis treatment, plasma levels tend todecrease again, as shown by Charra et al [261 and supported byour own experience. This finding has been interpreted as apossible indication of increased j32m amyloid formation. Re-garding your question whether 132m synthesis can be balancedby removal, our own data suggest that this is not possible evenwith high-flux hemodialysis or hemofiltration [95]. On the otherhand, it is conceivable that even a moderate reduction of 132maccumulation might retard the development of DRA.

DR. CHRISTOPHER 0. WINEARLS (Consultant Nephrologist,Renal Unit, Churchill Hospital, Oxford, United Kingdom): Youshowed intriguing data on IL-1f3 in RNA expression in cellsharvested from the venous return of the dialyzer. Could youcomment on the synthesis rates, and on any differences pre- andpost-membrane?

DR. KOCH: We did not quantify the synthesis rate for IL-lj3mRNA. The cells harvested from the arterial line contained noor negligible amounts of mRNA, whereas there was a verystrong signal for mRNA in the cells taken from the venousblood line at the same time.

DR. WINEARL5: Can you reassure us that the cell populationswere the same in the arterial and venous lines?

DR. KOCH: The assayed cell populations of the venous andarterial sample were different. The mononuclear cells harvestedfrom the venous sample by Ficolllllypaque centrifugation sep-aration were contaminated by as much as 40% with granulo-cytes, whereas by the same technique we gained almost puremononuclear cells from the arterial sample. We attribute thisdifference to a change of specific gravity of the granulocytesafter they pass the dialyzer. However, since granulocytes canonly express very small amounts of IL-l/3, we are very sure thatwe measured the mRNA of mononuclear cells in the venoussample.

DR. WINEARLS: What explains the speed with which theRNA was expressed?

DR. KOCH: Before lysis of the cells for mRNA measurement,the samples were kept for 30 minutes at room temperature. Sothere was some time allotted for mRNA synthesis. The speed ofsynthesis might not have been exceptionally high.

DR. ALEX M. DAVISON (Consultant and Renal Physician,Department of Renal Medicine, St. James's University Hospi-tal, Leeds, United Kingdom): You mentioned some of thepossible reasons for the distribution of p2m amyloid. Would youexpand your thoughts on this?

DR. KOCH: The predilection of /32m amyloid for synovialtissue is very striking. This affinity might be due to a highaffinity of J32m for collagen. When one studies synovial /32mamyloid deposits with the electron microscope, one almostalways finds the amyloid fibrils very closely arranged to colla-gen fibrils. In this context it may be of importance that Hommarecently showed that f32m binds to various collagens in adose-dependent manner [107]. Some cells within the synoviadisplay macrophage-like functions and therefore might be in-volved in proteolytic processing of 32m, which could be aprerequisite for local amyloid fibril formation.


Another local predisposing factor might be glycosoaminogly-cans (GAGs) which, according to experimental findings ofKisilevsky and Snow, are operative in amyloid fibril formation[1081. Using tissue obtained from hemodialysis patients withDRA, Nishi et al showed that 32m amyloid fibni bundles oftenare surrounded by GAGs [13]. These researchers concludedthat GAGs exert a regulatory effect on the distribution andarrangement of amyloid fibrils.

DR. JORDAN J. COHEN (Dean, School of Medicine, StateUniversity of New York at Stony Brook, Stony Brook, NewYork): You noted that there is a poor correlation between theamount of /32-microglobulin amyloid and the amount of collagenseen histologically. In fact, even in the patient presented today,carpal-tunnel tissue from one side contained 32-microglobulinamyloid, but on the other side /32m-amyloid was undetectable.This discrepancy raises the possibility that the presence of 132-microglobulin is an epiphenomenon. Is it possible that /2-microglobulin is not involved in the pathogenesis but is some-how being captured by the collagen, and that something elsetriggers the mass of collagen that produces the symptoms ofcarpal-tunnel syndrome?

DR. KOCH: This is a very good point. Whereas in somepatients the amyloid deposits are very massive and withoutdoubt cause local damage, for instance compression of themedian nerve, in other cases one finds only minute amounts ofamyloid but masses of collagen within the carpal tunnel tissue.So there is the suspicion that the pathogenesis not only involves132m-amyloid but also alterations of collagen metabolism.

DR. NICOLAOS E. MADIAS (Chief, Division of Nephrology,New England Medical Center, Boston, Massachusetts): Re-garding pathogenesis, an IL-i receptor antagonist recently hasbeen developed and is being used in animal and human inves-tigation. Has this antagonist been used in an effort to evaluatethe effects of dialysis-induced IL-i release on f32-microglobulinproduction? Also, is there an animal model for the syndrome?Recognizing the long time required for the syndrome to developin humans, one could employ exogenous administration of132-microglobulin in association with dialysis to study the patho-genesis of the syndrome.

DR. KocH: I do not know of any experiments studying theeffect of IL- 1 receptor antagonists on IL-i induction duringhemodialysis. So far there also do not exist animal models with132m amyloidosis. I assume it would be necessary to dialyzeanuric animals for prolonged times. The additional infusion ofgrams of f32m might speed up the development of f32m amyloi-dosis.

DR. MICHEL OLMER (Chief, Nephrology Unit, Hôpital de IaConception, Marseille, France): I am interested in whether theuse of pyrogen-free dialysate is associated with /32-microglob-ulin deposition. In Marseille, we find amyloid deposits only inpatients treated with nonsterile dialysate.

DR. KocH: Bacteria-derived substances contained in thedialysate can permeate certain dialyzer membranes and therebycould induce cytokines such as IL-1f3 and tumor necrosis factor(TNF) on the blood side. The involvement of such a chain ofevents in the pathogenesis of DRA is conceivable but notproven. The only clinical report supporting this concept is yourown work, which showed that the use of a dialysate with a verylow endotoxin content was accompanied by a lower incidence

of CTS [127]. However, as we discussed before, CTS is notdefinite proof of the presence of amyloid.

Da. JOHN T. HARRINGTON (Chief of Medicine, Newton-Wellesley Hospital, Newton, Massachusetts): Are there exper-imental data regarding the pharmacologic inhibition of f2-microglobulin synthesis?

DR. KOCH: Considering our own studies in uremic patients,one has to assume that at least 75% of their /32m synthesis is dueto normal cell turnover. To inhibit 132m synthesis significantly,one would have to suppress normal cell turnover. This wouldnecessitate the application of cytostatic drugs. I do not thinkthis is advisable in RDT patients who already suffer from amultitude of immune defects.

DR. BRUNO BAGGIO (Associate Professor of Nephrology,Institute of Internal Medicine, Division of Nephrology, Pa-dova, Italy): Do you think that the plasma oxalate level and, inparticular, its abrupt variation during the interdialytic periodcould play a role in dialysis-related amyloid syndrome?

DR. KOCH: I do not know of any data suggesting a relationbetween plasma or tissue oxalate levels and DRA. We used the1311-J32m scan to study a patient being treated with regularhemodialysis who suffered from primary oxalosis. None of hismassive tissue oxalate deposits appeared positive with the scan.

Da. MIHATSCH: Beta2-microglobulin amyloid is always de-posited in close association with collagen. The specificity of the132 deposition might be related to the specific type of collagen.Are there data regarding cytokines in synovial fluid and howthey might influence this binding?

DR. KocH: Your question concerning a preference of 132m fora specific collagen certainly merits investigation. The sameapplies for cytokine levels in joints with synovial f32m amyloiddeposits. Elevated levels would indicate local inflammatoryprocesses. I am sorry that I cannot be more specific.

DR. MICHAEL H. RAMBAUSEK (Department of Nephrology,University of Heidelberg, Heidelberg, Germany): Beta2-micro-globulin is part of the HLA system. This fact raises the questionof whether there is any genetic predisposition for the develop-ment of dialysis-related amyloid disease.

DR. KocH: So far no data suggest a genetic predisposition forDRA. The very high prevalence of DRA in long-term hemodi-alysis patients actually argues against a major role for geneticfactors.

DR. JOHN F. DONOHOE (Consultant Nephrolo gist, Depart-ment of Nephrology, Beaumont Hospital, Dublin, Ireland):What is known of the relative prevalence or incidence of DRAbetween the United States and Europe? Are there knowndifferences within Europe, that is, north versus south? If thesedata are available, what are the implications regarding thepathogenesis of DRA?

DR. KOCH: I am afraid that currently no representative dataare available that permit a comparison between the incidence ofDRA in the United States and Europe. The major obstaclesobviously are the lack of standardization of diagnostic criteriaand incomplete information concerning possibly relevant back-ground conditions such as dialysate quality, application ofreuse, etc.

DR. LEENDERT A. VAN Es (Professor of Medicine, Depart-ment of Nephrology, Leiden University Hospital, Leiden, TheNetherlands): Is the magnitude of the renal elimination of


/3.2-microglobulin based on the measurement of arteriovenousdifferences across the kidney in humans?

Dx. KOCH: Yes; by measuring renal arteriovenous differ-ences of f32m concentrations in patients with normal renalfunction, we have found that this difference is equal to orslightly higher than that of inulin. This suggests that /32m isfreely filterable in the glomerulus. Similar findings are knownfrom animal studies.

Dx. MADIAS: Has your scanning technique with radiolabeledfl2m suggested a greater systemic (that is, non-osteoarticular)deposition of /3microglobulin than clinically suspected?

Dx. KOCH: No, our experience with the "I-j32m scan doesnot suggest a very significant systemic deposition of /32mamyloid outside osteoarticular tissues. Histologically provennon-osteoarticular deposits in the majority of reported patientswere found to be minute and therefore might not be detected bythe scan.

Dx. MION: Would you comment on recent observationsshowing early synovial deposits in dialysis patients [128]? Whatis the sensitivity of the various scans in the detection of theseearly deposits?

Dx. KOCH: Obviously, our scan is not able to detect micro-scopic amyloid deposits. Nevertheless, it enabled us to spotamyloid deposits in patients who had been treated with dialysisfor less than 6 years and who had no clinical or radiologicindications of DRA.

Dx. WINEARLS: MayI comment on the SAP scans? ProfessorPepys' group at the Hammersmith Hospital recently completedan evaluation of this technique in hemodialysis patients [126].The principal findings were: (I) there is focal localization oftracer at sites where histologic examination confirms amyloiddeposition but, apart from the spleen, no evidence of visceralinvolvement; (2) the scans do not always detect fJ2m-amyloid indeep sites; and (3) scans in four patients with a history ofdialysis amyloid proven histologically, who had had successfulrenal transplants, were negative, suggesting that accumulationof amyloid had at least been arrested.

Dx. KOCH: I agree regarding the very limited systemicaccumulation of j32m amyloid. Regarding f32m amyloid in deepsites, the 1311-f32m scan proved to be very effective in imagingamyloid deposits located in the hip joints. We have no post-transplant experience with the scan, because administered j32mis eliminated too rapidly by glomerular filtration when renalfunction is restored; thus our scan cannot be applied in thissetting.

Dx. COHEN: How practical is it to maintain sterile dialysate?Does it increase the cost of the procedure excessively? Wouldyou recommend using sterile dialysate routinely for all patients?

Dx. KOCH: In our experience with a well-designed andcarefully serviced reverse-Osmosis unit and good machine ster-ilization, we can produce dialysate with a very low endotoxincontent, as low as 50 to 100 pg/mi.

A further improvement could be achieved by placing polysul-fone or polyamide hemofilters in the dialysate line downstreamfrom the machine. Hemofilters made of these membranes rejectand adsorb bacteria-derived products and can be reused as longas the cleaning procedure is performed with sterile and pyro-gen-free water and also includes back-filtration.

Acknowledgments

The NMR image and the radiograph were kindly supplied by Profes-sor Dr. H. Hundeshagen, Department of Nuclear Medicine and Bio-physics, and Professor Dr. M. Galanski, Department of DiagnosticRadiology I, both at Hannover Medical School, Hannover, Germany.

Reprint requests to Prof K. Koch, Medizinische Hochschule Han-nover, Abteilung Nephrologie, Konstanty-Gutschow Sir. 8, D-3000Hannover 61, Germany

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