verse events in the combination therapy group (renal failure, i K+, d BP, CV events). Other interventions \200 Treat dyslipidaemia: Aim fasting LDL <3.0mmol/L. Statins are usually necessary (and demonstrably reduce cardiac events in diabetic patients). X Statins may reduce proteinuria and preserve GFR in overt DN. \200 The role of aspirin a nd other antiplatelet agents for primary prevention of CV events in patients with DN is uncertain. However, if no contraindication, low-dose as pirin (75mg od) is often recommended. Smoking cessation. \200 Modest dietary protein restriction (0.8g/kg per day, b p. 208) ma y slow decline in GFR. X Some advocate a more stringent restriction to 0.6g/kg/day in selecte d patients. DIABETIC NEPHROPATHY: MANAGEMENT 2 617 Novel treatments for DN Better understanding of DN has informed novel therapeutic strategie s, particularly with respect to the downstream effects of hyperglycaemia (AGE formation, pr otein kinase C activity, production of pro- \201 brotic intermediates, endothelin activity , and in \202 ammatory pathways). Some show promise in both experimental models and clinic al trials. In all cases, larger studies will be necessary to determine if short-term improv e- ments (e.g. reduction in albuminuria) translate to overall improvements in DN outcomes. Pyridoxamine. Is a member of the vitamin B6 family that inhibits AGE formation. It reduces mesangial expansion, decreases albuminuria, and slows SCr rise in animal models. Clinical s tudies suggest promise for early intervention in DN. Experimental agents that prevent AGE cross-linkage or inhibit AGE and AGE receptor (RAGE) interaction are also under development. Ruboxistaurin. Is a selective protein kinase C inhibitor that reduces albuminuria (albeit w ith no signi \201 cant difference for other renal outcomes) in T2DM DN. Pirfenidone. Is an anti \201 brotic (via d TGF- B production) and a free radical scavenger under investigati on in several clinical contexts, including DN. It reduces mesangial expansion and collagen gene expression in animals. Clinical trials suggest it may improve GFR but not albuminuria. Tranilast is another anti \201 brotic agent that has shown bene \201 cial effects in ani mal models and clinical trials. Doxycycline may also have anti \201 brotic properties and has been shown to reduce proteinuria. Sulodexide. A glycosaminoglycan, inhibits TGF- B prod uction and causes dose-dependent reductions in albuminuria (persistent after discontinuatio n). Early clinical trials vs placebo have been disappointing. Avosentan. Is an ET-1 receptor antagonist that reduces urinary albumin excretion at the exp ense of increased CV events (CCF and volume overload). Atrasentan also reduces albuminuria and is more selective for the ET-A receptor. It is associated with peripheral oedema but is less likely to cause frank volume overload. Further trials are awaited. The transcription factor nuclear factor erythroid-related factor 2 (Nrf2) is involved in nu merous anti-in \202 ammatory and antioxidant path- ways. Nrf2 knockout mice suffer worse n ephropathy in experimental diabetes. Bardoxolone methyl , a synthetic triterpenoid, induces Nrf2 and improves GFR (but with no change in albuminuria). Unfortunately, the internationa l BEACON trial was stopped early, following excess adverse events in the treatment arm. Diabetic mice lacking vitamin D receptors demonstrate RAS upregu- lation, glomerulosclerosi s, and increased urinary albumin losses. The administration of an active vitamin D analog p aricalcitol has been shown to signi \201 cantly ameliorate this albuminuria. CHAPTER 8 The kidney in systemic disease 618 Other diabetes-related urinary tract disorders Papillary necrosis ( b p. 585) Occurs in 7 1 :20 with diabetic nephropathy. May be asymptomatic but can present as pain (recurrent renal colic) or infection. Haematuria, modest proteinuria (<2g/24h), and sterile pyuria are comm on. Renovascular disease ( b p. 586) Suspect if dif \201 cult to control BP, \202 uid re tention, or >20% rise in SCr (or fall in eGFR), following an ACE-I or ARB. Neurogenic bladder (diabetic cystopathy) A degree of bladder dysfunction is present in 7 40 % of patients with long-standing diabetes. It results from peripheral and autonomic neuropa - thy (characterized by segmental demyelination with impaired conduction). The \201 rst m anifestation is usually loss of sensation of bladder \201 lling, with subsequent progress ive loss of motor function. Incomplete emptying leads to a large-volume bladder, with a sig ni \201 cant post-micturition volume and urinary stasis. Recurrent UTIs and urinary incont inence are common. Investigation: MSU for M,C+S. USS bladder pre- and post-void. Ask the patient to complete a bladder diary. Urodynamic \201 ndings include decreased bladder sensation, impaired detr usor contractility, and eventual detrusor are \202 exia. Detrusor hyperre \202 exia is al so recognized. Screen for other manifestations of autonomic dysfunction, e.g. postural HR a nd BP. Exclude signi \201 cant prostatic disease. Interventions include regular voiding in the absence of urge (e.g. every 2h), anti-incontin ence aids to absorb urine losses and protect skin integ- rity, assisted voiding (e.g. supra pubic manual pressure), drugs (e.g. the parasympathomimetic agent bethanechol) (bene \201 ts inconsistent), inter- mittent self-catheterization, (also d bladder volume and may help partial recovery of detrusor function), long-term catheterization, urinary diver- sion, and treatment of associated infection. Urinary tract infection ( b p. 706) \231\200 with diab etes have twice the incidence of UTI, compared to those with- out diabetes. Diabetes is als o a risk factor for UTIs in \231\202 . There is also a higher incidence of pyelonephritis and renal abscess formation. 90% of cases of emphysematous pyelonephritis ( b p. 711) occur in patients with diabetes. Contrast induced-AKI ( b p. 148) Patients with diabetes, probab ly as a result of intrarenal microvascular disease, are more susceptible to CI-AKI. OTHER DIABETES-RELATED URINARY TRACT DISORDERS 619 Considerations in ESRD from diabetic nephropathy 2 Patients with T1DM (and selected patient s with T2DM) should be considered for combined kidney/pancreas transplantation ( b p. 446). Diabetic patients often need to initiate dialysis at an earlier stage than patients with ES RD from another cause, e.g. eGFR in the 10 \200\223 15mL/min range, as they are often more symptomatic, tolerate volume overload less well, and have a heightened propensity to hyper kalaemia. Survival and causes of death in diabetic patients on dialysis Diabetic patients with ESRD h ave a 5-year survival rate of 7 30% (com- pared with 7 60% in those without diabetes). This is largely a conse- quence of their comorbidity, particularly CV disease. A higher inciden ce of withdrawal from dialysis treatment is also reported. Dialysis modality: peritoneal dialysis vs haemodialysis No clear difference in outcome betw een PD and HD has been observed. USRDS data and Canadian studies have offered con \202 ict ing results (potentially explained by different patient demographics and comorbidi- ties). Overall, there is a suggestion that older diabetic patients survive longer on HD, and young er patients longer on PD. Renal transplantation in diabetics Renal transplantation is safe and effective. In appropri ately selected patients, it can offer improved survival and rehabilitation, compared to dia lysis. Studies have shown similar 1- and 5-year graft survival in dia- betic and non-diabet ic patients undergoing transplantation when data are censored for patients dying with a fun ctioning graft. Living donor graft survival is superior to deceased donor grafts (80% vs 64 % 5-year graft survival). CHAPTER 8 The kidney in systemic disease 620 Plasma cell dyscrasias Introduction In this related group of disorders, bone marrow-derived malignant plasma cells produce abnormal immunoglobulin proteins that can cause renal injur y by a number of mechanisms, including tubular blockage (e.g. mye- loma cast nephropathy), direct glomerular injury (e.g. light chain deposi- tion disease), immune complex formation (e.g. cryoglobulinaemia), and aggregation + accumulation (e.g. AL amyloidosis). The four most important syndromes are: Myeloma kidney (cast nephropathy) ( 7 30 \200\223 65%). \200 AL amyloid ( 7 20%). \200 Monoclonal immunoglobulin deposition disease (MIDD): Light chain deposition disease (LCDD) ( 7 10%). \200 Immunotactoid or \201 brillary glo merulopathy (rare). Cryoglobulinaemia (rare). Renal presentations of the plasma cell dyscrasias \200 AKI: cast nephropathy, dehydration , i Ca 2+ , sepsis, drug-induced. \200 CKD: cast nephropathy, AL amyloid, MIDD. \200 Pr oteinuria (or nephrotic syndrome): AL amyloid, MIDD. \200 Tubular dysfunction (acquired F anconi \200\231 s syndrome, partial proximal and distal tubular defects): cast nephropathy, plasma cell in \201 ltration. What is in an immunoglobulin (Ig)? An Ig comprises two heavy chains (with a complement- \201 xing site) and two light chains (with an antigen-binding site). Plasma cell dyscrasias may produce whole monoclonal Ig, whole light chains or heavy chains, or parts of either. T his leads to the slightly confusing terminology surrounding the speci \201 c diseases caus ed by each protein. Myeloma kidney Multiple myeloma is a hematological malignancy caused by an excess of plasma cells. It is characterized by aberrant overproduction of monoclonal immunoglobulin (termed paraprotein or \200\230 M \200\231 protein) plus associated light chains, either kappa ( ) or lambda ( ). The most common class of whole immunoglobulin is IgG (followed by I gA then IgD). In some cases, only the associated or light chain will be identi \201 ed. The diagnosis of myeloma requires: A serum or urine paraprotein. \200 Clonal plasma cells occupy >10% of the bone marrow. \200 End-organ damage unexplained by other pathology, e.g. i Ca 2+ , i SCr, anemia, or lytic bone disease (remember: CRAB ( b p. 624)). Incidence 7 40 pmp/year. 80% pa tients present aged >60 (although the diagnosis may need to be considered in much younger p atients). \231\202 > \231\200 . Renal involvement is a major complication of myeloma, pre sent at (or preceding) diagnosis in 20 \200\223 50% of patients, and in 50% of patients du ring the course of the disease ( 7 10% require RRT). PLASMA CELL DYSCRASIAS 621 Myeloma and AKI Myeloma has a propensity to injure the renal tubules, leaving patients vuln erable to secondary insults that cause ATN, such as volume depletion and hypotension. In ad dition, reduced tubular \202 ow will increase tubular light chain concentrations and furt her enhance tubular damage. Common causes of AKI \200 Cast nephropathy (most common). \200 ATN from sepsis, d BP. \200 i Ca 2+ causes dehydration and vasoconstriction. \200 NSAIDs taken for skeletal pai n. \200 Contrast-induced AKI. \200 Drug-induced: diuretics, toxicity of myeloma therapy . When to suspect myeloma Any unexplained i SCr/ d eGFR, esp. if associated with disproportio nate anemia (or anemia that is refractory to ESA therapy). Also d Plt or d WCC (marrow fail ure s to plasma cell in \201 ltration), immune paresis (reduction in all Ig classes), skel etal pain (e.g. low back). Urinalysis may be relatively normal (light chains are not detect ed by dipstick). Investigations \200 FBC ( d Hb common; d Plt and d WCC less so), i ESR, i SCr, i Ca 2+ , i urate/LDH ( i cell turnover). Serum protein electrophoresis (SPEP) for paraprotein. Detects intact Ig but only high levels of light chain. Immuno \201 xation is more sensitive but is not quant itative. Immunoglobulins (? immune paresis), B 2 microglobulin (activity monitoring \200 \224 but accumulates in renal impairment). Bence \200\223 Jones proteinuria. These are urinary free light chains detected by urinary protein electrophoresis and immuno \201 xation. \200 Skeletal survey (osteoly tic lesions, osteoporosis, fractures). \200 Bone marrow aspirate and trephine. \200 Ren al biopsy ( b p. 80). Serum free light chain (SFLC) assay \200 New nephelometric/turbidimetric assays that meas ure free or light chains are superseding biochemical methods. They utilize polyclonal antibodies to epitopes that are sequestered when light chains are bound to heavy chains bu t exposed when they circulate freely. A rapid test, with excellent sensitivity and speci \201 city. \200 Combine with SPEP, as this characterizes the intact Ig component. \200 Can identify most patients with myeloma , amyloidosis, and MIDD. \200 Considered abnormal when or free light chain is incre ased and the ratio between the two is abnormal. SFLC accumulates if d GFR, so normal ranges are adjusted. \200 Serial measurements help t o monitor therapeutic response. \200 Advocated by the International Myeloma Working Group (IMWG) for initial screening of plasma cell dyscrasias. CHAPTER 8 The kidney in systemic disease 622 Myeloma: cast nephropathy Introduction The commonest form of renal involvement within the p lasma cell dyscra- sias ( 7 30 \200\223 65%) and virtually always the cause (or a contribu tor) to severe renal impairment. Casts develop when the excess \201 ltered load of light chains reacts with Tamm \200\223 Horsfall mucoprotein (THMP) in the more distal tubule and forms an insoluble proteinaceous plug. This obstructs tubular \202 ow, disrupts tubular architecture, and leads to progressive interstitial injury (which becomes rapidly irreversi ble). Cast formation is promoted by various properties of the light chain (e.g. charge in relatio n to tubular \202 uid pH, binding avidity for THMP, propensity to aggregate), their conce ntration and promoting factors, such as dehydra- tion. It is possible to have a very high l ight chain load without AKI. Pathogenesis and histology Cast nephropathy is characterized by eosinophilic acellular cast s that have a distinctive fractured appearance (see Fig. 8.1). These occur princi- pally in the distal nephron (distal tubules and collecting ducts), leading to tubular epithelial ce ll death and luminal distortion. Casts are surrounded by in \202 ammatory cell in \201 lt rates (including macrophages and multinucle- ate giant cells), causing interstitial in \202 ammation, oedema and, inevitably, \201 brosis. Casts are polychromatic, with Masson \200\231 s trichrome positive for monoclonal light chain, and may stain with Congo red (al though are not birefringent under polarized light). Fig. 8.1 Fractured tubular casts characteristic of myeloma kidney. Reproduced with permissi on from Davison AMA, Cameron JS, Grunfeld J-P et al . (eds) (2005). Oxford Textbook of Clin ical Nephrology , 3rd edn. Oxford: Oxford University Press. MYELOMA: CAST NEPHROPATHY 623 Management of cast nephropathy 2 Correct associated reversible causes of AKI: dehydration, i Ca 2+ , sepsis, and hyperuricaemia. \200 Rehydrate: Crystalloid IV \200\224 may require large volumes (>5L) if i Ca 2+ . \200 (cid:2) Sodium bicarbonate can be used if there is a systemic acidosis, but alkaline diuresis does not alter outcomes. Strict monitoring of \202 uid balance. Encourage to drink 3L/day. \200 Increasing urina ry \202 ow will reduce urinary light chain concentration and help prevent further cast formation. Furosemide promotes cast formation, so its use should be avoided. \200 Expect Hb to fall \200\224 transfuse, as required. Correct i Ca 2+ ( b p. 806). If i Ca 2+ persists once euvolaemic, consider IV bisphosphonate ( b p. 807). Appropriate cultures and antimicrobials if concomitant sepsis. \200 Correct hyperuricaemi a ( b p. 160): \200 Start allopurinol 100mg daily. Stop NSAIDs and other nephrotoxic drugs. \200 If anemic, consider for an ESA ( b p. 222). High dose usually necessary. \200 Renal support: Initiate RRT for standard indication (required in 7 10%; recovery in 7 20%). Dialysate Ca 2+ may need reduction. No convincing evidence of a modality bene \201 t for HDF, HF, or PD. \200 X Extended fre quent haemodialysis, using a protein-leaking dialyser with very large pores and improved li ght chain clearance (termed a \200\230 high cut-off \200\231 or HCO dialyser), may be of bene \201 t and is currently under further investigation. X Plasma exchange (PEX): PEX can reduce plasma light chain load, but rebound is usual. \200 Appears less bene \201 cial than extended dialysis with HCO dialyser. \200 Bene \201 cial in hyperviscosit y syndromes (e.g. Waldenstr m macroglobulinaemia) ( b p. 635). Speci \201 c therapy: Myeloma is incurable. The goal is to reduce Ig or light chain burden, induce remission, and increase survival. High-dose corticosteroid, e.g. dexamethasone 20mg PO bd for 4 days, to induce plasma cell a poptosis (as soon as possible). \200 Subsequent chemotherapy is tailored to the individua l situation. \200 Bortezomib, a proteasomal inhibitor, appears bene \201 cial in patients with renal disease and does not require dose adjustment ( (cid:2) SE: neuropathy). It may be given alone or in combination with thalidomide (or its analog lenalidomide) ( (c id:2) SE: venous thrombosis) 9 doxorubicin. Alkylating agents, such as melphalan and cyclophosphamide, impair haemopoietic stem cell function and may be best avoided if autologous transplantatio n is feasible. Autologous stem cell transplantation (ASCT) offers the best prospect of complete remission in selected patients. CHAPTER 8 The kidney in systemic disease 624 When myeloma is not myeloma Finding a paraprotein in serum or urine does not always con \201 rm a diag- nosis of myeloma. Monoclonal gammopathy of uncertain signi \201 cance (MGUS) \200 Paraprotein <3g/dL. \200 <10% plasma cells in the bone marrow. \200 Usually does not have Bence \200\223 Jo nes proteinuria. \200 No evidence of end-organ damage ( \200\230 CRAB \200\231 ): Calcium: i Ca 2+ >0.25mmol/L (1mg/dL) above the upper limit of normal or >2.75mmol/L (11mg/L). Renal insuf \201 ciency: SCr >173 mol/L (1.96mg/dL). \200 Anemia: Hb 20g/L below lowe r limit of normal or <100g/L. \200 Bone lesions: lytic lesions or osteopenia with compres sion fractures. Other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episodes in 12 months). \200 7 3% of individuals aged >70 have MGUS. \200 7 1% progress to symp tomatic myeloma each year. \200 Risk factors for progression: higher paraprotein level, n on-IgG paraprotein, and an abnormal SFLC ratio. A monoclonal protein that can be characterized as a MGUS is not uncommonly found during the initial work-up of elderly patients with CKD. This mandates surveillance, usually 6 \200 \223 12-monthly, with considera- tion of either a bone marrow biopsy or a renal biopsy or b oth if there is diagnostic doubt or evidence of progression. Where renal involvement is the prime clinical concern in this context, the term monoclonal gam- mopathy of renal signi \201 cance has recently been coined. Asymptomatic (previously \200\230smoldering \200\231) myeloma \200 Refers to asymptomati c patients, with paraprotein >3g/dL and a plasma cell in \201 ltrate >10% but no end-organ damage. Evolves to symptomatic myeloma in 7 3% patients per year for the \201 rst 5 years, and then progression declines in incidence. Plasmacytomas \200 Solid tumors made up of clonal plasma cells found as solitary bone pla smacytoma (SBP) or solitary extramedullary plasmacytoma (EMP) (usually upper respiratory tr act). <50% produce a (usually low level) paraprotein. \200 Renal involvement is rare. \200 Pr ogression to myeloma in 7 50% (SBP > EMP). Treated with local radiotherapy. Median survival 10 years. ESRD in myeloma Mortality on dialysis depends mainly on progression of the underlying myelo ma, as patients survive as long as matched myeloma patients without renal failure. Early mo rtality is high ( 7 20% die within the \201 rst 2 months), but mean 3-year survival is 7 30%. Patients who respond to chemotherapy do much better. MYELOMA: CAST NEPHROPATHY 625 Both haemodialysis and peritoneal dialysis are feasible modalities. However, the main risk concerns susceptibility to infection (from the disease itself and its treatment), so CAPD-r elated peritonitis and dialysis catheter-related sepsis can be severe. For this reason, an AVF should be fashioned as soon as recovery of renal function is unlikely ( 7 20% recover r enal function with treatment, usually within the 3 months). The usual indications for commencement of dialysis in CKD/ESRD apply ( b p. 267), but patie nts may be symptomatic at a higher GFR in view of their comorbidities and 6 require an earl ier start. In addition, progression to ESRD can be swift, with limited time for RRT educati on or psychologi- cal adjustment. CHAPTER 8 The kidney in systemic disease 626 Monoclonal Ig deposition disease Introduction Monoclonal Ig deposition disease (MIDD) descr ibes another clinicopatho- logical variant of abnormal monoclonal light chain (or, less com monly, heavy chain) deposition, termed LCDD and HCDD, respectively. This is a similar condi tion to AL amyloid, but there are important structural differ- ences, as the proteins do no t organize into \201 brils. LCDD is more common and usually caused by an abnormal chai n, while or chains are usually responsible for HCDD. The clinical presentations of LCDD and HCDD are similar \200\224 usually with nephritic-ty pe glomerular injury: proteinuria (nephrotic range in 7 30%), microscopic haematuria, i BP, and renal impairment (which may rapidly progress). May also present as CKD. Renal involvem ent is often the \201 nding that prompts a search for an underlying dyscrasia (usually my eloma, but Waldenstr m macroglobulinaemia, chronic lymphocytic leukemia, and lymphoma ar e also associated). However, a malignant process may not fully declare itself despite prolo nged follow-up. Light chain deposition disease (LCDD) \200 A plasma cell dyscrasia causes tissue depositi on of a monoclonal Ig light chain ( in 65%). Differs from amyloid, as the light chain lacks hydrophilic residues so cannot organize into \201 brils (or stain positive for Congo red), forming granular depos its instead. The light chains have distinct properties, e.g. variants of the light chain variable reg ion (types I and IV), in \202 uencing their deposition. \200 Associated with overt myelo ma in 7 50% (myeloma may subsequently develop). Bone marrow plasma cell expansion not alway s present. \200 No monoclonal band on electrophoresis, and immuno \201 xation in 7 30% patients, but SFLC assays are signi \201 cantly more speci \201 c. Extrarenal features are less common than renal: cardiac (diastolic dysfunction, arrhythmias), hepatic (abnormal LFTs, hepatomegaly), and nerves (neuropathy). Histological features on renal biopsy: Extracellular matrix accumulation causes nodular glomerulosclerosis (Congo red negative ), with glomerular and tubular basement membrane thi ckening. This appears similar to diabetic Kimmelstiel \200\223 Wilson changes ( b p. 608). Can be an MCGN injury pattern. Immunostaining is positive for monoclonal light chains in capillary walls, basement membranes, and mesangium. EM demonstrates bands of amorphous, granular deposits, without \201 bril formation, in gl omerular and tubular basement membranes. Treatment is directed against the underlying plasma cell dyscrasia, generally using the sam e criteria and regimens as for myeloma. Response is monitored through measurement of SFLC. \200 Age and CKD are negative prognost ic indicators. 7 50% will eventually reach ESRD. Renal transplantation contraindicated unle ss complete remission. 7 25% 10-year survival. MONOCLONAL IG DEPOSITION DISEASE 627 Heavy chain deposition disease (HCDD) A rare disorder. Abnormal heavy chains deposit in the glomerulus and cause a similar disease to LCDD. Underlying myeloma is identi \201 ed in 7 25%. Extrarenal disease is less common. Monoclonal Ig-derived material in the kidney Can arise from any part of an immunoglobulin ( b p. 620) and can be classi \201 ed (see Table 8.3) according to the appearance of the de posits on biopsy (including EM). Immunoglobulin and Ig-derived fragments have an af \201 nity for basement membranes, perha ps explaining the strong association with renal disease (particularly as 7 20% of cardiac o utput passes through the kidneys). Table 8.3 Classi \201 cation Organized Crystalline Cast nephropathy Fanconi \200\231 s syndrome ( b p. 825) AA or AL amyloidosis Fibrillar Microtubular Immunotactoid GN Cryoglobulinaemia Disorganized Granular LCDD HCDD Immunotactoid and \201 brillary glomerulonephritis Rare disorders characterized by the de position of non-amyloid (i.e. Congo red negative) proteinaceous \201 brils derived from i mmunoglobu- lin. Usually very similar glomerulopathic presentation to that of MIDD. They ar e almost always con \201 ned to the glomeruli, with no extrarenal disease. Progression to ESRD is frequent. No speci \201 c diagnostic test, so renal biopsy (with EM) is key. Investigate for parapro tein, HCV, hematological malignancy, and autoimmune disease. Fibrillary GN. Does not usually associate with a paraprotein. Deposition of polyclonal IgG in mesangium and glomerulus. Appears as mesangial proliferation or MCGN on light microscopy . EM: randomly arranged \201 brils, usually 7 20nm in diameter. There is no treatment proven to slow progression. Small trials of immunosuppressive therapy have been disappointing (except in patients with crescentic changes on renal biopsy where prednisolone + cyclo- phosphamide may be effective). Immunotactoid GN. Often associated with hematological disease (esp. CLL, B cell NHL). Whole monoclonal IgG and C3 deposits. Light microscopy appears as an atypical membranous or lobu lar MCGN. EM: rod-like, hollow, microtubular structures, usually >30nm in diameter, ordered in parallel. Treat underlying disease. CHAPTER 8 The kidney in systemic disease 628 Renal amyloid: AL amyloid Introduction Amyloidosis is a multisystem disorder caused by extr acellular deposition of abnormal (misfolded and insoluble) \201 brils resulting from the aggrega- tion of an aberrant protein. When this aberrant protein is an immuno- globulin or light chain (usually ), it is known as primary or AL amyloidosis. In secondary amyloidos is, the protein is serum amyloid A (SAA), which is overproduced in chronic in \202 ammatio n. In less common hereditary forms, a variety of proteins are involved, including \201 br inogen A A chain, tran- sthyretin, and apolipoproteins AI and AII. Amyloid \201 brils of all types are 8 \200\223 12nm in diameter and always bound to the normal plasma protein serum amyloid P (SAP). SAP appears to render the \201 brils extreme ly resistant to degradation. Classically, amyloid deposits appear an apple-green color on C ongo red staining if viewed under birefringent light. AL amyloid The \201 brils in AL amyloid are derived from either whole monoclonal Ig or, m ore commonly, from light chain (usually ). There is an underlying plasma cell dyscrasia, but this will be clinically overt in only 25% (usually myeloma \200\224 amyloid deposits will be found in 10 \200\223 20% myeloma patients). AL amyloid may be deposited in virtual ly any tissue in the body, depend- ing, to an extent, on the particular physicochemical cha racteristics of the involved Ig or light chain. Annual incidence 7 10 pmp. Median age at diagnosis 7 65. Clinical features Depend on speci \201 c organ involvement, but systemic symptoms, such as malaise and weight loss, are common. \200 Cardiac: restrictive cardiomyopathy ( 7 30%) a nd arrhythmias (these are the main cause of death). Liver: hepatomegaly (and splenomegaly) from in \201 ltration. Hyposplenism causes susceptibility to sepsis (the other main cause of death). Gut: motility disorders, GI bleeding, macroglossia (tongue in \201 ltration). \200 Nerve s: sensorimotor neuropathy (may be painful), autonomic neuropathy (e.g. orthostatic hypotension, bladder dysfunction), and compression syndromes ( e.g. carpal tunnel). Hematological: bleeding diathesis, associated with factor X or IX de \201 ciency. May manifest as easy bruising \200\224 but measurement of PT, APTT, and o ften bleeding time are necessary prior to organ biopsy ( (cid:2) esp. renal). Skin: purpura (esp. recurrent periorbital), papules. \200 Joints: synovitis and polyarthr opathy. \200 Adrenal: hypoadrenalism. \200 Thyroid: hypothyroidism. \200 Renal: invol vement in 7 50%. Normally proteinuria (often nephrotic range, with severe oedema) and variable degrees of renal impairment. Microscopic haematuria is uncommon. Tubular defects, including RTA, may occur. 7 20% develop ESRD. Kidneys often appear large on USS. RENAL AMYLOID: AL AMYLOID 629 Renal histology \200 Light microscopy: widespread amorphous extracellular amyloid deposit s are seen in the mesangium, along the glomerular basement membrane and in blood vessels. T hey appear less frequently in the tubules and interstitium. Characteristic Congo red staini ng. Immunostaining: for (occasionally ) and SAP may be positive, but is unreliable. Other types of amyloid deposits are differentiated with special stains, e.g. to SAA. EM: demonstrates \201 brils (see Fig. 8.2) but will not distinguish types. Investigations \200 Tissue biopsy to con \201 rm diagnosis. If no renal involvement, the n salivary gland, subcutaneous abdominal fat, or rectum are favored sites (positive in >80%). Serum and urine protein electrophoresis 9 immuno \201 xation. Positive in 7 90% and 75%, r espectively. (cid:2) Beware a coincidental MGUS, and consider other, including hereditary, forms. Serum free light chains (electrophoresis + SFLC positive in 7 99%). \200 Bone marrow exam ination ( i plasma cells in 7 50 \200\223 60%). \200 Echocardiography. \200 123 I SAP scintigraphy: not widely available. Radiolabelled SAP protein is injected to locate areas o f amyloid deposition. Demonstrates distribution and extent of deposits and can be used to m onitor response to treatment. Prognosis Very poor outlook without treatment \200\224 usually progressive and fatal withi n 1 \200\223 2 years. Cardiac involvement is a particularly poor prognostic indicator. Dia gnosis of renal AL amyloid is associated with a median time to RRT of 7 1 year (with median time to death within a further year). Happily, the prognosis is greatly improved with effective therapy of the underlying plasma cell dyscrasia \200\224 with amyloid regression in many cases. For renal involvement, reso lution of the nephrotic syndrome, with stabi- lization of renal function and retarded progr ession to ESRD, is the goal of treatment. Management Treatment aims to decrease, or eliminate, the culpable plasma cell clone. Patien ts are often elderly, so therapy must be tailored accord- ingly. Regimens include cyclophos phamide, thalidomide, and dexametha- sone (CTD), or melphalan plus dexamethasone (M/Dex). R esponses in 7 30 \200\223 50%. Lenalidomide and bortezomib are increasingly used, based on experiences in myeloma. High-dose chemotherapy with autologous stem cell transplantation i n selected patients. Dialysis for standard indications. Renal transplantation is only possible if the plasma cel l dyscrasia is in complete remission (recurrence in the graft is inevitable otherwise) and cardiac function remains acceptable. CHAPTER 8 The kidney in systemic disease 630 Renal amyloid: AA amyloidosis AA amyloidosis AA amyloidosis results from the sustained elev ation of the acute phase reactant serum amyloid A protein (SAA). In developing countries, c hronic infections account for the majority of cases. In developed nations, chronic in \202 ammatory autoimmune conditions, particularly rheumatoid arthritis, are now much more impor tant. Prevalence is linked to that of underlying conditions, which vary accord- ing to geography. The overall post-mortem incidence of AA amyloidosis in western nations is 0.5 \200\223 0. 86%. Pathogenesis There are several isoforms of SAA: SAA1 and SAA2 appear to be most important f or acute phase responses. They are HDL-bound apolipopro- teins that i macrophage HDL uptake during in \202 ammation (through the displacement of apolipoprotein A1). The persistence of SAA is probably s to pro-in \202 ammatory cytokines, such as IL-1, IL-6, and TNF- A . P roteolytic cleavage of SAA then generates peptide fragments that aggregate into mis- folded AA \201 brils via an interaction with the glycosaminoglycan heparan sulfate. It remains unknown why only 7 5% of patients with persistent in \202 ammation develop AA amyloidosis; other factors (e.g. genetic, includ- ing SAA1 polymorphisms) are clearly important. Causes \200 Chronic in \202 ammatory disease: Rheumatoid arthritis and juvenile rheumatoid arthritis ( 7 40%). \200 Psoriatic arthropat hy, ankylosing spondylitis ( 7 30%). \200 Reiter \200\231 s syndrome. \200 Beh et \200\231 s syndrome. \200 In \202 ammatory bowel disease. Chronic infections: \200 TB, leprosy. \200 Osteomyelitis. \200 Cystic \201 brosis, bronchiectasis. \200 Chronic ulceration. Malignancies: Renal cell carcinoma. \200 Lymphoma, Castleman \200\231 s disease. Familial: Familial Mediterranean fever (FMF). Clinical features \200 Renal: unlike AL amyloid, renal involvement is universal. Proteinu ria (often nephrotic range) is typical, although a minority (<10%) present with progressive CKD , with no proteinuria (predominantly vascular amyloid deposition). Renal biopsy demonstrate s both glomerular and tubulointerstitial involvement. Note: microscopic haematuria is prese nt in 7 30% so is a much more common feature than in AL amyloid. Spleen: always involved ( l hyposplenism l infection). \200 Adrenals: abnormal adrenal fu nction in 7 50%. RENAL AMYLOID: AA AMYLOIDOSIS 631 Liver: hepatomegaly. \200 GI tract: present in more advanced disease ( l motility disorde rs, malabsorption, bleeding). Cardiac ( 7 10%), skin, tongue, and nerve: much less common than in AL. Investigations \200 Tissue biopsy is necessary to con \201 rm diagnosis. This is often a renal biopsy, but less invasive alternatives include salivary gland, subcutaneous abdominal fat, or rectum (positive in >80%). Immunostaining tissue for SAA protein differentiates AA from other forms of amyloidosis in virtually all cases. CRP and ESR were used to monitor disease and response to treatment, but SAA is increasingly used for this purpose. 123 I SAP scintigraphy ( b p. 629). Prognosis Outcomes depend heavily on the control of und erlying disease processes. Prognosis is better than AL amyloid but still guarded: 7 40% sur vival at 3 years, overall. Infection is the major cause of death. SAA concentration helps p redict outcomes, as risk of death rises with the median SAA (10-year survival 7 90% if medi an SAA <10mg/L and only 7 40% if >10mg/dL). Outcomes have improved for those with ESRD (previously a signi \201 cant cause of death), although patients still have worse dialysis outcomes than those with unrelated conditions. Renal transplantation can be considered if underlying disease is consistently controlled, a s recurrent amyloid is surprisingly uncommon in this context. However, 3-year patient survi val post-transplant is reduced (principally s to infectious and CV causes). Treatment Treat the underlying in \202 ammatory or infectious condition to prevent further amyloid deposi tion. Existing amyloid appears to regress in 7 50%, especially if SAA is maintained <10mg/L . \200 Infectious disease: antimicrobials and or surgical intervention, as indicated. Chronic in \202 ammatory disease: several treatments have shown ef \201 cacy in the in \202 ammatory arthritides and may be applicable to other situations. \200 Alkylating agen ts, such as cyclophosphamide and chlorambucil, have been shown to improve survival. Anti-TNF therapy, with in \202 iximab, etanercept, and adalimumab, are effective at lowering SAA production. Experience is growing with the anti-IL6 receptor antibody tocilizumab. Colchicine has demonstrable ef \201 cacy in FMF, reducing febrile episodes and renal involvement. Mechanism of action is unclear but appears related to suppr ession of in \202 ammatory responses. X It has also been used, with variable success, in n on-FMF patients with renal disease. Novel approaches: there is increasing interest in therapies that can interfere with \201 bril aggregation and deposition, e.g. agents that disrupt the int eraction of SAA with glycosaminoglycan or induce dimerization of SAP to provoke improved sy stemic clearance. CHAPTER 8 The kidney in systemic disease 632 Renal amyloid: other forms Other forms of amyloidosis with renal involvement Inherited fever syndromes Familial Mediterranean fever (FMF): causes AA amyloidosis and is the most common inherited form. Inheritance is autosomal recessive, most commonly affecting Sephardic Jews, Armenians, and Turks. It is caused by a mutation in the MEFV gene encoding pyrin, a regulator of transcription for in \202 ammatory mediators, including IL-1. Perio dic acute attacks (of variable frequency) pre- sent before the age of 20, with fever ( 7 25 % have fever alone) and serositis ( l peritonitis, pleurisy, synovitis) lasting 48 \200 \223 72 hours before spontaneous reso- lution. During the \202 are: i WCC and i CRP. AA a myloid complicates 7 60% (Turks are at highest risk), and renal involvement is common. Colc hicine 1 \200\223 2mg/day is highly successful at reducing both \202 are frequency and A A amy- loidosis risk. It may also stabilize already established renal disease. Others: TNF receptor-associated periodic syndrome (TRAPS) is autoso- mal dominant, with onset in childh ood. Colchicine is less effective. Muckle Wells syndrome presents soon after birth, with da ily episodes of rash, red eyes, and fever.