Monotypic light or heavy chain deposits, > Nonorganized granular electron-dense depos its Monotypic light or heavy chain deposits, > Organized but randomly arranged \201 bri ls, 8 \200\22312 nm in diameter Polyclonal IgG deposits of 4 isotype Coarse granular mono- typic IgG (IgG1, or IgG2, or IgG3) and C3 deposits Immunohistochemistry Hollow microtubules, usually >30 nm in diameter, ordered in parallel Organized but randomly arranged \201 brils, usually 20 nm in diameter Electron microscopy GN, glomerulonephritis; MCGN, mesangiocapillary GN. The signs of ITG and FGN are usually those of the neph- rotic syndrome. generally yield de \201 nitive results, but AL deposits are stained with standard antisera to or light chains in only 50% of \201 xed biopsies. Confirmation of AL amyloidos is therefore commonly requires exclusion of other types through an immunohisto- chemical pa nel and sequencing of the genes associated with hereditary systemic amyloidosis. Differenti ating between the various immunoglobulin- related glomerulopathies can be dif \201 cult (T able 4.2.1). Renal biopsy Histological diagnosis of amyloid requires staining of the tissue deposits wit h Congo Red and demonstration of pathognomonic red \200\223green dichroism when viewed in c ross-polarized light. The lesions of ITG and FGN are Congo Red negative. A renal biopsy is the most frequent diagnostic test. Renal AL amyloid deposits are typically found in the mes an- gium, along the glomerular basement membrane (GBM) and in the blood vessels but are als o often present in the tubules and interstitium. However, there is a signi \201 cant rate of false-positive and false-negative diagnoses, owing to sampling errors and inadequate pre paration, staining and interpretation. The presence of SAP within deposits, identified by i mmunohistochemistry (optimally using frozen sections) and/or immunogold labeling, also dist inguishes amyloid (including AA and hereditary forms) from ITG and MIDD. The basis of a rep ort of SAP within the deposits of FGN is unclear. Amyloid deposits identi \201 ed histolog ically must be further characterized immunohistochemically to identify the par- ticular amy loid \201 bril type, of which there are 20. Renal involvement by amyloid occurs in amylo idosis associ- ated with the following amyloid \201 brils: \200 \200 \200 \200 \200 \200 \200 \200 Light microscopy ITG and FGN are characterized by atypical mem- branous GN lesions or lobul ar mesangiocapillary GN but there may be mesangial proliferation, crescents or sclerosing G N. MIDD is characterized by Congo Red-negative nodular glomerulosclerosis and deposition of periodic acid \200\223Schiff (PAS) positive material in the tubular basement mem- brane. Immuno \202 uorescence (IF) microscopy Immuno \202 uorescence in ITG should include not o nly stand- ard antisera to and light chains, but also antisera to IgG subclasses, in order to demonstrate clonality. IF will reveal coarse granular staining for IgG (IgG1, or I gG2, or IgG3) and C3 along the capillary basement membranes and in the mesangium. In both I TG and AL amyloidosis the Ig deposits are clonal and therefore always have a monotypic ligh t chain ( or ), although this is not always demonstrable by immunohistochemistry. In FG N, polyclonal IgG deposits of the 4 isotype are typical. In MIDD, IF reveals monotypic li ght or heavy chain deposits along glomerular and/or tubular basement membranes, more common ly than isotype. Electron microscopy In ITG there are typically large (>30 nm) (Fig. 4.2.1C) thick- walled microtubular (hollow) \201 brils with hollow, lucent centers arrang ed in parallel arrays, compared with small (8 \200\22312 nm) organized solid \201 brils w ithout a lucent core in amyloidosis (Fig. 4.2.1A) and organized but randomly arranged \201 brils of 12 \200\22330 nm in FGN (Fig. 4.2.1B). AL; AA; \201 brinogen AA chain; transthyretin; lysozyme; apolipoprotein AI; apolipoprotei n AII; gelsolin. Commercially available antibodies to serum amyloid A protein (SAA), transthyretin (TTR) and B2-micro-globulin J. GILLMORE AND P. HAWKINS 152 Electron microscopy in MIDD shows nonorganized granu- lar electron-dense deposits in the gl omerulus and along tubular basement membranes. Tests for cryoglobulins should be undertaken in all cases in which microtubular renal deposits are identi \201 ed. (a) General investigations Discovery of AL amyloid deposits should be followed by a careful ass essment of renal, hepatic, cardiac and peripheral and autonomic nerve function. ITG and FGN almost always have renal-limited manifestations. Imaging for soft tissue or lymph node inv olvement by amy- loid may be indicated by the clinical features. Special investigations All patients with AL amyloidosis or ITG should undergo comprehensive investigation for an underlying clonal B-cell dyscrasia, which may be extremely subtle. El ectrophoresis and immuno \201 xation of blood and urine are mandatory. (b) Serum free light chain assay A high sensitivity serum free light chain assay has recently b een developed which can quantify circulating free immu- noglobulin light chains with a rema rkable sensitivity of <5 mg/L. The serum free light chain assay has increased identi \201 ca- tion of an underlying clonal B-cell dyscrasia from 80% to >95% in patients with system ic AL amyloidosis, and it is frequently the only quantitative measure of clonal response to treatment. [123I]SAP scintigraphy This was developed and is routinely available at the Nat ional Amyloidosis Center, UK. The scan identi \201 es the presence, distribution and exten t of amyloid deposits in systemic amyloidosis. Serial SAP scans monitor progress, and have shown that amyloid deposits often regress when the supply of the respective amyloid \201 bril precursor protein is suf \201 ciently reduced (Fig. 4.2.2). SAP scans are negative in Congo Red-negative \201 brillary glomerulopathies and nonorganized MIDD, providing valu- able corroborative support of this diagnosis. (c) Natural history Without treatment, AL amyloidosis is inexorably progres- sive and almost al ways fatal with a median survival of only 6 \200\22315 months. Diagnosis of renal AL amyloi dosis is associated with a median time to renal replacement therapy (RRT) of 1 year in the absence of effective chemotherapy, and median survival on dialysis is only 8 months. ITG a nd FGN are generally renal-limited and more slowly progressive diseases, with the median ti me from diagnosis to RRT >2 years and with a markedly better overall prog- nosis than AL am yloidosis. Approximately 20% of patients with kidney dysfunction due to renal AL amyloid de posits eventually develop ESRD. The outcome of AL amyloidosis can be dramatically improved by chemotherapy that suppresses monoclonal Ig production. This can halt disease progression and may facilitate regression of amyloid. There may be complete resolution of the nephroti c syndrome following effective chemotherapy in AL Fig. 4.2.1 Electron micrographs demonstrating the \201 brils of (a) amyloidosis (randomly arranged 8 \200\22312 nm in diameter), (b) \201 brillary glomerulonephritis (randomly ar ranged 12 \200\22330 nm in diameter), and (c) immunotactoid glomerulopathy (parallel arrays , hollow centered microtubules (arrowheads) >30 nm in diameter). amyloidosis, and progression of CKD may be substantially retarded. 50% of patients with ITG or FGN reach ESRD. However, marked improvement in nephrotic-range proteinuria and renal ex cretory function have been reported following chemotherapy in patients with ITG (or FGN). Recurrence after renal transplantation Amyloid deposits may recur in the renal allograft. S uppression of monoclonal light chain production by chemotherapy reduces the risk of graft a myloid. CHAPTER 4.2 Amyloid and immunotactoid glomerulopathy 153 However, patients with AL amyloidosis often tolerate chemotherapy poorly, some are refracto ry, and clinical bene \201 t after effective chemotherapy is always delayed. Oral melphalan and prednisolone This is well-tolerated but responses are slow and limited, and this treatment should be reserved for older, sicker patients. Oral intermediate dose combinations Includes cyclophosphamide, thalidomide and dexametha- s one (CTD), and melphalan and dexamethasone (Mel Dex). They induce swifter clonal responses in >50% of cases. High-dose melphalan chemotherapy with autologous peripheral stem-cell rescue This may achie ve even higher clonal response rates, but at the expense of TRM of 12 \200\22325%, limiting its appeal as \201 rst line treatment to highly selected, \201 tter patients. Fig. 4.2.2 Serial anterior whole body scintigraphs in a patient with AL amyloidosis treated with oral melphalan and corticosteroids: baseline scan (left) showed extensive amyloid dep osits in the liver and spleen obscuring the signal from the kidneys; follow-up scintigraphy 6 months later (right) showed complete regression of amyloid from the liver and marked reg ression from the spleen with a reciprocal increase in the blood-pool signal. Other agents Rituximab may be used in patients with CD20-positive (usually IgM) clones. The proteasome inhibitor, bortezomib, and lenalidomide have also been used. Frequent satisfact ory responses to intermediate intensity chemotherapy indicate that high dose treatment is u nnec- essary in many patients. However, there been very few comparative trials of chemother apy in AL amyloidosis. The fundamental objective of treatment in AL amyloidosis is to adequ ately suppress production of amyloidogenic free light chains without unacceptable toxicity. This requires tai- lored individual treatment and close monitoring. In ITG, chemotherapy a imed at suppressing the under- lying B-cell clone is also rational although there is a much smaller body of evidence than in AL amyloidosis. Renal bene \201 t has been reported when hematological remission is achieved. Microscopic amyloid deposits frequently develop within the graft when monoclonal light chai n production is not completely suppressed, but often these do not impair graft function. Fi ve-year patient and renal allograft survival among patients with AL amyloidosis visiting th e UK National Amyloidosis Center is 70%, probably re \202 ecting careful selection of pat ients for transplantation. There is very little literature on renal transplantation in ITG or FGN. Early recurrence in a renal allograft with subsequent response to chemotherapy has been reported. Risk strati \201 cation Poor prognostic features in AL amyloidosis include: \200 \200 \200 \200 Follow-up The underlying clonal dyscrasia and amyloidotic organ function require regular mo nitoring following chemother- apy in patients with AL amyloidosis and ITG, with the expecta tion that the disease is likely to relapse at some stage. cardiac involvement; extensive liver involvement; peripheral neuropathy; symptomatic autono mic neuropathy. Median survival with predominant cardiac disease is <1 year from diagnosis. Creatinine clea rance at the time of diagnosis of amy- loidosis or ITG in \202 uence the renal prognosis. Risk of treatment-related mortality (TRM) with high-dose melphalan and autologous stem cell transplantation (SCT) in AL amyloidosis is strongly in \202 uenced by: \200 AA amyloidosis Epidemiology The prevalence of AA amyloidosis in postmortem studies is 0.50 \200\2230.86%. In developed countries 70% of cases are found in patients with autoimmune i n \202 ammatory diseases (most commonly juvenile and adult rheumatoid arthritis). Heredofa milial forms account for 10% of cases. In developing countries chronic infection still acco unts for the majority of cases. ECOG (Eastern Cooperative Oncology Group) performance status; the number of organs involved by amyloid; the extent of cardiac involvement. \200 Pharmacological treatment In many patients with systemic AL amyloidosis, suppression of the B-cells producing amyloidogenic monoclonal immu- noglobulin light chains through chemother apy is associated with: \200 \200 \200 \200 Etiology AA protein is a proteolytic fragment of serum amyloid A (SAA) protein. SAA has sev eral isoforms of which SAA1 and SAA2 are the acute phase isoforms. They are apolipoproteins that associate with HDL and are thought to enhance the af \201 nity of HDL for macrophage s during an acute phase response. reduction of new amyloid formation; regression of existing deposits; preservation of organ function; enhanced survival. J. GILLMORE AND P. HAWKINS 154 Persistence of an acute phase response causes persistent production and elevated serum leve ls of SAA1 and SAA2 (probably via proin \202 ammatory cytokines IL-1, IL-6 and TNF-A). Sub sequent proteolytic cleavage of SAA by macrophages generates amyloidogenic peptides (AA) wh ich then aggre- gate to form \201 brils. Although elevated serum SAA levels are required for the development of AA amyloidosis, it is unclear why only \210 5% of patients with a p ersistent inflammatory response develop AA amyloidosis. There is speculation that polymorph isms in SAA genes may determine the risk of developing AA amyloidosis. This may partially e xplain the geographical variability in AA amyloidosis risk in patients with chronic in \202 ammatory dis- ease. For instance the SAA1.3 allele has been shown to be associated wit h the development of AA amyloidosis and is a predictor of poor outcome for Japanese patient s with rheumatoid arthritis. The major causes of AA amyloidosis are listed in Table 4.2.2. The heredofamilial forms of AA amyloidosis will be described later. A small minority have predominantly vascular deposits and present with progressive renal dy sfunction and little pro- teinuria. Extra-renal Amyloid deposition in other sites can be clinically impor- tant. These other si tes include: \200 spleen always involved \201 rst but usually asymptomatic (occasional functional hyposplen ism); gastrointestinal tract 20% (diarrhea, constipation, malab- sorption, GI bleeding). A feature of advanced disease; liver 15% (hepatomegaly) in advanced disease. adrenal glands 5 0 \200\22360% (abnormal synacthen test in 50% of patients); heart (extremely rarely clinic ally signi \201 cant). \200 Skin, tongue, and nerve involvement is rare in AA amy- loidosis (in contrast to AL amyloido sis). Investigations The best approach for diagnosing AA amyloidosis remains controversial. Renal biopsy is diagnostic in virtually all patients with renal manifestations. The renal biopsy features of amyloidosis have been described previously. However, renal biopsy involves a s mall but de \201 nite risk and therefore less invasive biopsy options have been advo- cate d. Biopsies of salivary glands, abdominal fat, and rectal mucosa (full thickness biopsy is required) have a diagnostic yield of up to 80%. The identi \201 cation of amyloid on a bio psy requires further characterization to differentiate it from other forms of amyloidosis. Immunohistochemical staining for SAA protein using com- mercially available antibodies is d iagnostic in nearly all cases of AA amyloidosis. [123I]SAP scintigraphy can also be used to assess the distri- bution and extent of AA amyloid deposits, and to monitor the response t o treatment. Table 4.2.2 Conditions associated with AA amyloidosis Chronic in \202 ammatory disease Rheumatoid arthritis Juvenile rheumatoid arthritis Ankylosing spondylitis Reiter syndrome Beh et syndrome Crohn \200\231s disease Chronic infection Tuberculosis Leprosy Osteomyelitis Bronchiectasis Cystic \201 brosis Malignant disease Lymphoma Castleman disease Renal cell carcinoma Hairy cell leukemia Natural history Patients with AA amyloidosis usually survive longer than those with AL amyl oidosis (40% 3 year survival, median survival 24 \200\22350 months). Causes of death includ e infection (currently the major cause accounting for 40 \200\22350% of deaths), dialysis-r elated complications, bowel perforation, GI bleeding, and myocar- dial infarction. Poor pro gnostic factors include: \200 \200 \200 \200 Heredofamilial disease Familial Mediterranean fever Muckle \200\223Wells syndrome TRAPS low serum albumin; signi \201 cant proteinuria; raised serum SAA; raised CRP. Clinical features Renal The kidney is affected in almost all patients with AA amy- loidosis . Approximately 95% of patients with renal AA amyloidosis will have glomerular involvement but amyloid deposition within the interstitium is equally common. The presenta- tion may va ry from low grade proteinuria to severe neph- rotic syndrome. Invisible hematuria is presen t in about one-third of patients. The level of SAA predicts outcome. Estimated 10 year survivals are: \200 \200 90% if median serum SAA levels <10 mg/L; 40% if median serum SAA levels >10 mg/L. Recurrence after renal transplantation Renal transplantation is reasonably successful in th ose with AA amyloidosis. CHAPTER 4.2 Amyloid and immunotactoid glomerulopathy 155 Features of an attack include: \200 Recurrent amyloid deposition can occur in up to 33% of cases, although graft loss due to re current disease is uncommon. Recurrent amyloid can be avoided if serum SAA concentration is maintained at <10 mg/L. Graft survival is comparable to that seen with nonamyloid recipien ts, but patient survival at 3 years is reduced (50% versus 80%) mainly due to infectious an d cardiovascular disease. severe pain (due to serositis (peritonitis, pleuritis, syno- vitis)) \200\231 fever (which typically persists for 1 \200\2233 days). Attacks are accompanied by a substantial increase in acute phase reactants. Usually patient s will have recurrent attacks although the frequency can be very variable. FMF is complicat ed by AA amyloidosis in up to 60% of patients. There is a substantial ethnic in \202 uence on this risk (Turks 60%, non-Ashkenazi Jews 30%, Armenians 2%). Amyloidosis predominantly affects the kidneys, spleen, liver and gut. Colchicine is the mainstay of treatment for FMF . Over 80% of patients respond to 1 \200\2232 mg/day (i.e. a reduc- tion in the frequency o f attacks), and it has been shown to substantially reduce the risk of developing AA amyloid osis. It may also permit amyloid regression and reversal of neph- rotic syndrome and/or pre vent renal function decline in patients with established AA amyloidosis. Treatment The goal of treatment is suppression of SAA synthesis by treatment of the underlying cause of chronic in \202 ammation. This prevents further amyloid deposition and may lead to regr ession of existing deposits. As indicated above, suppression of SAA synthesis improves outc ome. For infectious and malignant causes de \201 nitive treatment of the underlying diseas e (where possible) is clearly the most appropriate treatment. For chronic in \202 ammatory disease a number of treatment options appear to be effective. Alkylating agents In juvenile and adult rheumatoid arthritis, cyclophospha- mide and chlora mbucil have been shown to improve patient survival. In general these studies have demon- st rated a 5 year survival of >70% with treatment compared to <30% without. Others Other familial in \202 ammatory diseases that can underlie AA amyloidosis include: \200 \200 \200 \200 TNF receptor-1-associated periodic syndrome (TRAPS); hyper IgD syndrome; Muckle \200\223Wel ls syndrome; familial cold autoin \202 ammatory syndrome. Colchicine This has become accepted treatment for patients with familial Mediterranean feve r (FMF) (see below). It has never been formally studied in nonfamilial in \202 amma- tory AA amyloidosis although anecdotal reports have sug- gested benefit in patients with ankylos ing spondylitis, ulcerative colitis, and Beh et disease. The bene \201 t of colchicine is almost certainly due to its anti- in \202 ammatory effect although there have previously been suggestions of a direct effect on \201 bril formation. Hereditary amyloidosis Hereditary renal amyloidosis is rare. Mutations in a number of precu rsor proteins can result in relatively selective renal amyloid deposition. Fibrinogen A alpha-chain This is the commonest type of hereditary amyloidosis associated wi th nephropathy. Four mutations of this gene have been identi \201 ed, all of which are ass ociated with renal disease. The renal disease is exclusively glomerular with sparing of the interstitium and vessels. Patients have been successfully managed with combined liver and kidney transplantation. Anticytokine therapy Given the role of cytokines in the induction of SSA protein synthesis, inhibition of IL-1 and TNF-A is an attractive ther- apeutic option. Although not yet forma lly studied, small series suggest that biologics with activity against proin \202 ammatory cytokines suppress SAA production thereby permitting amyloid regression. Transthyretin More than 100 mutations have been identi \201 ed in the tran- sthyretin gene and most of these produce an amyloidog- enic protein. Different mutations result in differ ent phenotypes: pre- dominantly cardiomyopathic, neuropathic, and ocular forms have been de scribed. Clinically signi \201 cant renal amy- loid is unusual. Successful treatment with orthotopic liver transplantation has been described. Heredofamilial disease causing AA amyloidosis Familial Mediterranean fever (FMF) FMF causes AA amyloidosis and is the commonest familial amyloidosis. It is an autosomal recessive dis order most commonly found in Sephardic Jews and Armenians, but has been iden- ti \201 ed i n a wide variety of ethnic groups. It is caused by mutation of the gene encoding pyrin/ mar enostrin. This is an intranuclear regulator of transcrip- tion of in \202 ammatory mediato rs, and also appears to regu- late the activity of the inflammasome (a complex of proteins that triggers the release of IL-1B). In \202 ammasome dysregulation also underlies other a utoin \202 ammatory dis- eases including Muckle \200\223Wells syndrome. Patients typically have their \201 rst attack before the age of 20 years. Gelsolin Mutations in the gelsolin gene produce familial amyloidosis, Finnish type, which c lassically presents with corneal dystro- phy, cranial neuropathy, and cutis laxa. Renal and cardiac involvement can also occur, but is rarely clinically signi \201 cant. J. GILLMORE AND P. HAWKINS 156 delay the onset of ESRD in AA amyloidosis in a randomized placebo-controlled trial. Small m olecule ligands that stabilize amyloid precursor proteins in the blood and inhibit their pr opensity to form \201 brils are in clinical trial. Other approaches to destabilizing and disrupting estab- lished amyloid deposits using antibodies and small mole- cule drugs are p oised for study in man. Apolipoprotein AI and AII Apo AI mutations produce dominant nephropathy and/or cardiomyopat hy. Liver, skin laryngeal, and nerve involve- ment may also appear. A successful outcome fr om combined liver and kidney transplant has been described. Apo AII mutations result in slo wly progressive renal dis- ease with both glomerular and interstitial involvement. Lysozyme Mutations in this gene produce predominant renal and GI/ liver disease. The renal phenotype can be very variable even within families. The only available treatment is suppor tive care. The diagnosis of hereditary amyloidosis can be dif \201 cult since monoclonal g ammopathy can be identi \201 ed in 3% and 5% of patients above the age of 50 and 70 years respec- tively. Such patients may therefore be labeled as having AL amyloidosis. 10% of pat ients with a diagnosis of AL amyloidosis have been shown to have hereditary forms of amyloi dosis. Characterization of the amyloid type is of paramount importance therefore. This ofte n requires both immuno- histochemical and genetic analysis to rule out hereditary amyloidos is. This potentially may allow unnecessary chemotherapy to be avoided. Further reading Bridoux F, Hugue V, Coldefy O, et al. Fibrillary glomerulonephritis and imm unotactoid (microtubular) glomerulopathy are associ- ated with distinct immunologic feature s. Kidney Int 2002; 62: 1764 \200\2231775. Ivanyi B, Degrell P. Fibrillary glomerulonephritis and immunotactoid glomerulopathy. Nephro l Dial Transplant 2004; 19: 2166 \200\2232170. Lin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immu- noglobulin deposition disease: the disease spectrum. J Am Soc Nephrol 200 1; 12: 1482 \200\2231492. Markowitz GS. Dysproteinemia and the kidney. Adv Anat Pathol 2004; 11: 49 \200\22363. Pepys MB. Amyloidosis. Annu Rev Med 2006; 57: 223 \200\223241. Internet resources Amyloidosis Support Network: http://www.amyloidosis.org/ UK National Amyloid Center: http://www.ucl.ac.uk/medicine/amyloidosis/nac/ Future prospects Elucidation of aspects of the molecular pathogenesis of amyloid and amyloi dosis is leading to the development of novel treatments. A small molecule glycosaminoglycan analog, eprodisate, designed to inhibit the amyloidogenic interaction between SAA and glyc osaminoglycans, has lately been reported to See also Immunological investigation of renal disease, p. 36 Infection-related glomerulonep hritis, p. 128 Plasma cell dyscrasias, p. 158 Mixed cryoglobulinemia and hepatitis C infect ion, p. 176 This page intentionally left blank C. WINEARLS 158 Plasma cell dyscrasias Malignant plasma cells produce abnormal immunoglobulin proteins which cause renal injury by a number of mecha- nisms (Table 4.3.1). Table 4.3.2 Renal effects of myeloma Clinical presentation Cause Acute kidney injury Dehydration Hypercalcemia Infection Cast nephropathy Table 4.3.1 Mechanisms of immunoglobulin-related renal injury Primary mechanism Secondary mechanism Example Chronic kidney disease Cast nephropathy Excess IgM Hyperviscosity Waldenstrom \200\231s AL amyloid macroglobulinemia Cast nephropathy MIDD Abnormal LC binding to THP Binding to BM Blockage of distal tubule Glomerular injury Monoclonal Ig Deposition disease Cryoglobulinem ia Proteinuria AL amyloid MIDD IgM RhF binding to IgG Immune complex formation This is often a consequence of dehydration, hypercalcemia or infection. Aggregation and binding Tissue deposition AL amyloid Clinical presentation, investigation and immediate management Patients may be found to have renal dysfunction at the time myeloma is \201 rst diagnosed or when it relapses. They us ually present with the systemic effects of the plasma cell malignancy (malaise, weight loss , anemia, symp- toms of hypercalcemia, or bone pain). A number will present with isolated a cute renal failure without obvious manifestations of myeloma. The diagnosis is made on rena l biopsy or from the routine tests performed in patients with unexplained acute renal failu re. The diagnostic and staging investigations should include: \200 \200 \200 LC, light chain; THP, Tamm \200\223Horsfall protein; BM, basement membrane; Ig, immunoglobu lin; RhF, rheumatoid factor; AL, light chain amyloid. Disease syndromes There are four important disease states driven by plasma cell dyscrasias: \200 \200 \200 \200 myeloma kidney; light chain (AL) amyloid; cryoglobulinemia; monoclonal immunoglobulin depos ition disease (MIDD) and immunotactoid glomerulopathy (ITG). FBC to assess marrow failure; bone marrow to assess in \201 ltration; skeletal survey to d etermine the sites and extent of bone deposits; serum paraprotein and immunoglobulin concen trations; serum free LC concentrations; urine LC concentration. These clinical syndromes result from the combination of the tumor load of the underlying pl asma cell malignancy, and the secondary effects of the abnormal immunoglobulin protein. The contribution of each to the illness varies. In patients with myeloma the illness is domina ted by the effects of the malignant plasma cell clone, whereas in the AL amyloid the clone may be hard to detect and the illness is largely a consequence of the tissue deposition of the amyloid pro- tein containing the abnormal light chain (LC). \200 \200 Immediate management should include: \200 \200 \200 \200 rehydration; antibiotics for infection; intravenous bisphosphonates for hypercalcemia; bloo d transfusion for anemia. Myeloma kidney Myeloma is characterized by expansion of a malignant clone of plasma cells w hich: \200 \200 \200 \200 Severe renal failure (eGFR <30 mL/min) This occurs in 10% of patients with myeloma and is usually an early manifestation. The caus e is almost always cast nephropathy (Fig. 4.3.1). Cast nephropathy develops when the excess ive load of \201 l- tered abnormal LCs reacts with Tamm \200\223Horsfall protein (THP) in the distal tubule to produce an insoluble plug. This blocks tubular \202 ow, disrupts th e tubule, and leads to interstitial injury which is usually permanent and seldom reversible . This reaction depends on the property of the LC (i.e. whether it has an af \201 nity for THP), the LC concentration, and a trigger which favors the reaction, e.g. hypercalcemia an d dehydration. Although cast nephropathy can only be con \201 rmed from a renal biopsy the investigation is not essential if the diagnosis occupy >10% of the bone marrow; produce a paraprotein >30 g/L; suppress the production of n ormal immunoglobulins; cause damage by local effects on the skeleton and the bone marrow, a nd distally on the kidney. It is an incurable disease with an incidence of 40 cases pmp per year. It is more common in the elderly, males and Blacks. Effects on the kidney (Table 4.3.2) 10% of patients who develop myeloma will suffer severe renal injury but 50% of newly diagno sed cases will have a degree of transient and reversible renal dysfunction at the time of d iagnosis. CHAPTER 4.3 Plasma cell dyscrasias 159 The issue of renal transplantation seldom arises but should only be undertaken if remission has been achieved. This will usually have required a stem cell autograft or a bone marrow allograft. 3. General support: Anemia can be managed with ESAs (erythopoiesis-stimu- lating agents), there being no evidence that the plasma cell dyscrasias are \200\230driven \200 \231 by erythropoietin. Response will be poor if there is marrow failure in which case regu lar blood transfusions will be needed. Pain control, especially of skeletal deposits, requi res careful administration of opiate analgesia and, in the absence of residual renal functi on, NSAIDs can be used. Local myeloma deposits respond well to radiotherapy. The prognosis of patients with myeloma and renal failure is poor \200\223 median survival is 12 months so plans for palliative care should be put in place in advance of the inevitable irreversib le complications or relapse. Fig. 4.3.1 Renal biopsy of cast nephropathy. The tubular casts have a \200\230fractured \200\231 appearance. can be inferred and management decisions will not be affected by the lack of histological c on \201 rmation. AL amyloid Amyloidosis is the disease caused by the systemic deposi- tion of an insoluble p rotein consisting of a \200\230rogue \200\231 protein which has misfolded into \201 bril s and associated with serum amyloid P protein (SAP). Certain LCs ( in 70% of cases), prod uced by plasma cell dyscrasias have this rogue property and give rise to AL amyloid. Renal biopsy will reveal abnormal glomeruli and/or blood vessels with featureless amorphous depos its that are Congo Red positive and have a \201 brillary appearance on electron microscop y (Fig. 4.3.2). Although AL amyloid is the most common form of systemic amyloid, 20% of cas es have a different origin. A specific diagnosis is essential to plan appropriate managemen t. Unfortunately immunocytochemistry of renal biopsy mate- rial is unreliable in that the o ffending LC may not be stained. Similarly, the \201 nding of a serum paraprotein is not d iagnos- tic as the patient may have an incidental MGUS. Amyloidosis is more common in the e lderly (median age of presentation is 60 years) and in men. The most important affected sy stems are: kidney, heart, gut, liver, and peripheral nerves. Heart and gut involvement pred ict a poor prognosis. Patients come to the attention of nephrologists when they develop hea vy proteinuria or the nephrotic syndrome. The plasma cell dyscrasia is not usually prominen t and only a minority of patients have overt myeloma. Diagnosis should not therefore rely o n bone marrow examination or conventional evidence of the presence of a paraprotein. Diagno sis and monitoring of response to treatment now relies on estimates of serum free LC concen trations. Initial treatment The immediate aim is to reverse the renal failure or stop it progressing. This treatment is therefore urgent. 1. Counter the precipitants and aggravants. \200 \200 \200 2. Redu ce the load of light chains. \200 Rehydration. Treat hypercalcemia. Stop NSAIDs. Prescribe dexamethasone to suppress the malignant plasma cell clone. Consider plasma exchan ge. One clinical trial has shown no bene \201 t but another is in progress. Light chain concentrations can be reduced more effectively with a high \202 ux dialysis t echnique. This treatment is being tested in a randomized trial. Subsequent treatment Once attempts at renal rescue have been made a medium and long-term ma nagement plan is needed. 1. Chemotherapy: The treatment choice will be made by hematooncolo gists and will depend on whether the aim is palliation or remis- sion induction. (Cure is r arely possible unless a bone mar- row allograft is feasible.) Melphalan doses should be red uced but cyclophosphamide and dexamethasone are used in conventional doses. Thalidomide and its analogs can be used without dose reduction. High dose chemotherapy with stem cell resc ue is offered to selected, usually younger patients without major comor- bidity but higher treatment-related mortality has to be expected. 2. Renal support: Patients whose renal fail ure is complete and irreversible will require dialysis. Because the presentation is usually acute, most patients will be treated by hemodialysis but there is no contraindi- cation to peritoneal dialysis. Both modalities carry an infection risk and myeloma patients are espe cially vulnerable because of hypogamma- globulinemia and leukopenia. Treatment This is generally aimed at neutralizing the abnormal plasma cell clone in the hop e of reducing the amount of precursor LC available to produce further amyloid deposits. Des pite the insolubility of amyloid, tissue damage can be stabilized by halting the production of the offending LC. Hematological remission is associated with an improved prognosis. C. WINEARLS 160 In practice the choice of treatment will be tailored to the individual patient depending on age, the number and extent of organ involvement and the presence or absence of mye- loma. Indeed in some patients it is appropriate to do no more than provide support for organ fail ure. In patients without extensive organ involvement the treat- ment choice is between high dose melphalan and PBSCT (peripheral blood stem cell support), or high dose combi- nation chemotherapy, e.g. VAD (vincristine, adriamycin and dexamethasone). Whether the higher trea tment-related mortality of high dose melphalan is justi \201 ed remains to be established. Those patients who develop end-stage renal failure have a two-fold greater annual risk of death than the general dial- ysis population. Renal transplantation is seldom a realistic o ption but there are cases of successful outcomes in individuals fortunate enough to receive both a marrow and a renal allograft. A quick screening test is the \201 nding of a high titer rheuma- toid factor and a low C4 level (evidence of activation of the classic complement pathway by the immune complexes). A bone marrow examination may reveal clusters of mono- clonal IgM (usually )-positive pla sma cells. Treatment is directed against the clone and the in \202 amma- tion but because the condition is chronic and often indo- lent, corticosteroids, alkylating agents and plasm a exchange/cryo \201 ltration are only deployed during nephritic \202 ares. Patients wit h hepatitis C virus-associated disease are treated with interferon-A and those with underly ing lym- phomas with conventional chemotherapy. Monoclonal Ig deposition disease and immunotactoid glomerulopathy The deposition of monoclo nal light or heavy chains on basement membranes is dependent on their particular physicoche mical properties. Cryoglubulinemia Cryoglobulins are so-called because of their tendency to precipitate at lo wer than body temperature: a dramatic in vitro phenomenon and a partial explanation of the micro- circulatory problems that occur in the periphery. They are classi \201 ed according to their constituents (Table 4.3.3). Types 1 and 2 are associated with plasma cell dyscras ias but the abnormal clone is recognized more from its prod- uct than its expansion. It is type 2 that causes renal injury by the deposition of IgM/IgG complexes manifesting usually as a mesangiocapil- lary glomerulonephritis causing the nephritic and/or neph- rotic syndro mes. The extrarenal manifestations are: lower limb purpura and ulceration, arthritis and a multifocal ischemic neuropathy (mononeuritis multiplex) caused by occlusion of the vasa ner vorum. The diagnosis will be suspected from the clinical presenta- tion and con \201 rmed by identi \201 cation of the cryoglobulin in serum extracted from a blood sample allowed t o clot at 37 C. The constituents are identi \201 ed by immunochemistry. Monoclonal Ig deposition disease LC deposition disease (LCDD), which is more common, is usu ally caused by an abnormal chain, and heavy chain deposition disease (HCDD) by either or chains. The disease presents with the classic signs and symptoms of glomerular injur y: proteinuria, hematuria, nephritic syndrome and renal impairment which often progresses r apidly. The diagnosis is usually made with a renal biopsy. The histological appearances are of a nodular glomerulo- sclerosis with both glomerular and tubular basement membrane thick ening (Fig. 4.3.3). The electron microscopic and immunohistochemical \201 nd- ings of rib bon-like deposits with chain-restricted reactivity are diagnostic (Fig. 4.3.3). A plasma ce ll dyscrasia is obvious in 50% of cases but the majority will have an identi \201 able pa raprotein in the urine or blood. The heart, liver and nerves can also be affected by the de position of the abnormal light or heavy chains. Treatment is directed against the plasma ce ll dyscrasia using the same regimens and criteria applied to myeloma. Some patients will re spond but the majority are refrac- tory. Response to treatment is monitored by measurement of the serum concentration of the free LC in LCDD. To avoid recurrent disease, transplantat ion should not be performed unless there is complete remission of the plasma cell dyscrasia . Table 4.3.3 Classi \201 cation of cryoglobulins Type Constituent Cause 1 Monoclonal IgG, IgM or IgA Lymphoma Myeloma Waldenstr m \200\231s Immunotactoid glomerulopathy This is a rare condition caused by deposition of whole monoclo nal IgG ( or ). Deposition is confined to glomeruli. Patients present with proteinuria or renal impairment and may have an underlying lymphoma or chronic leukemia. The light micr oscopic appearances are of an atypical mem- branous glomerulopathy but electron microscopy reveals microtubular deposits (Fig. 4.3.3). These are Congo Red negative. The condition is refractory to treatment and patients progress rapidly to renal failure. \200\230Essential \200\231 Lymphoma Hepatitis C Sj gren \200\231s syndrome 2