THE KIDNEY IN SYSTEMIC VASCULITIS 639 Capillary Venule Arteriole Vein Small artery Large to medium- sized artery Cutaneous leucocytoclastic vasculitis Aorta Henoch \200\223Sch nlein purpura Cryoglobulinaemic vasculitis Microscopic polyangiltis Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis Polyarteritis nodosa Kawasaki disease Giant cell arteritis Takayasu arteritis Fig. 8.3 Chapel Hill classi \201 cation of vasculitis, based on the size of vessel. Modi \201 ed from Jeanette JC, Falk RJ, Andrassy K, et al . (1994) Nomenclature of systemic vasc ulitides. Proposal of an international consensus conference. Arthritis Rheum , 37: 187 \200\223 92. with permission from John Wiley and Sons. CHAPTER 8 The kidney in systemic disease 640 ANCA-associated vasculitis Introduction (ANCA)-associated vasculitis Anti-neutrophil cytopl asmic antibody includes granulomatosis with polyangiitis (GPA \200\224 previously known as Wegener \200\231 s granulomatosis), microscopic polyangiitis (MPA), and renal-limited vas culitis (RLV). GPA is differentiated pathologically by the presence of granulomatous in \202 ammation, bu t this may not always be apparent if a biopsy for histologi- cal examination is not underta ken. Clinical surrogates that point towards GPA, rather than MPA, include upper airways sym ptoms or lower respira- tory tract nodules and cavitation. Classi \201 cation Two classi \201 cation systems are used: (i) the Chapel Hill Consensus Conference (CHCC) criteria, and (ii) The European Medicines Agency (EMA) algorithm. Neithe r is perfect. The categorization of patients remains imprecise (and often clinically unnece ssary). It has been suggested that a more simple classi \201 cation, based on anti-PR3 or anti-MPO positivity, may be more expedient (see ANCA, b p. 642). Does discriminating GPA from MPA matter? Perhaps not \200\224 treatment is similar, and th e clinical and serological pres- entations overlap, often enough to suggest that they may r epresent a disease spectrum, rather than distinct entities (see Table 8.4). In the relevant literature, many studies group them together as a small vessel vasculitis. Table 8.4 GPA and MPA discrimination GPA MPA ENT involvement Yes No ANCA speci \201 city c-ANCA (PR3) p-ANCA (MPO) Yes (but not in the kidney) Granulomata No Likelihood of relapse Higher Lower Incidence The incidence of MPA/GPA/RLV is 10 \200\223 20 pmp per year (in Europe). This in creases with age (peak age 65 \200\223 74). It is rare in childhood. More common in Caucas ians. Slightly more common in \231\202 vs \231\200 . Prognosis Without treatment, mortality is 7 80%. However, this prognosis was dra- matically improved by treatment with cyclophosphamide and steroids. Even so, 1- and 5-year survival (in patients with renal involvement) remain 7 85% and 7 75%, respectively \200\224 in part , s to considerable treatment-related morbidity ( (cid:2) death in the \201 rst year is 3 x more likely to be s to treatment ANCA-ASSOCIATED VASCULITIS 641 than the disease itself on traditional regimens. In addition, >40% of mor- bidity is relate d to therapy). \200 Poor prognostic indicators: older age, pulmonary hemorrhage, and severe renal disease. Poor renal prognostic indicators: severe disease at presentation, age >65 years, resistance to cyclophosphamide therapy, and \201 brotic changes on renal biopsy. (cid:2) ESRD will result in up to 25%. Clinical presentation 2 Extremely variable and the early stages of the disease often missed . \200 Systemic symptoms are common: fever, weight loss, malaise, myalgia, and polyarthralgia. Other systems or organs that can be affected include: Upper respiratory tract ( 7 80% GPA, uncommon MPA): nasal discharge, epistaxis, sinusitis, oral or nasal ulcers, otitis media, deafness, cartilaginous involveme nt (collapse of nasal bridge and subglottic stenosis). Lung ( 7 70% GPA, 7 30% MPA): capillaritis, causing pulmonary hemorrhage (may present as frank haemoptysis but can be incipient), 2 Pulmonary hemorrhage is exacerbated by even mild pulmonary oedema, so any degree of \202 uid overload should b e avoided. Also lung nodules and cavities, pleuritis, and pleural effusions. \200 Kidney ( 7 80% GPA, 7 90% MPA): scenarios include: Microscopic haematuria or haematoproteinuria with a normal GFR. Proteinuria is usually subn ephrotic range. i BP ( 7 30%). Grumbling deterioration in GFR. \200 Fulminant AKI. \200 Patients with renal-limited va sculitis may develop additional organ involvement at a later stage. Skin: vasculitic rash, palpable purpura, ulceration. \200 Nervous system: mononeuritis mu ltiplex, peripheral neuropathy. \200 Eyes: conjunctivitis, episcleritis, uveitis, retro-o rbital mass. \200 Gut: abdominal pain, haemorrhagic ulceration, bloody diarrhea. \200 C ardiac: pericarditis, coronary vasculitis. \200 Circulation: venous thromboses are more c ommon. Birmingham vasculitis activity score (BVAS) This is a validated clinical tool that quanti \201 es disease activity in systemic vasculitis. It has been adopted internationally and is now a staple in clini- cal vasculitis trials. The BVAS form is divided into nine sections. Eight are organ-based, each including symptoms and signs typical for involvement of that particu- lar organ in vasculitis, e.g. haematuri a, proteinuria, and different categories of SCr in the renal section. The ninth section is for systemic symptoms. The clinician only scores features they consider to be the result of active vasculitis. Completion of the form provides a numerical score (0 \200\223 68) that can be used to assess disease severity and response to treatment. Online BVAS calculators are available, although some training prior to their use is desirable. CHAPTER 8 The kidney in systemic disease 642 ANCA-associated vasculitis: investigations ANCA \200 During testing for ANCA, the patient \200\231 s serum is tested for IgG binding to ethanol- \201 xed neutrophils. Binding occurs in either: A cytoplasmic pattern (c-ANCA) (antibody usually con \201 rmed as anti-proteinase 3). A perinuclear pattern (p-ANCA) (antibody usually con \201 rmed as anti-myeloperoxidase). In fact, both PR3 and MPO are found in the same intracellular granules, so these staining patterns are actually useful artifacts of ethanol \201 xation. Positive ANCA staining is then followed by speci \201 c assays for IgG binding to MPO or PR3 antigens (via ELISA or bead assay). (cid:2) ANCA may also be positive in other in \202 ammatory and infective diseases, so always interpret in clinical context. \200 This is particularly true of p-AN CA. \200 Anti-MPO and anti-PR3 assays are usually negative or low titre (other neutrophil antigens, e.g. lactoferrin or cathepsin, are the source of binding). In \202 ammatory: SLE, rheumatoid arthritis, in \202 ammatory bowel disease, interstitial lung diseases, autoimmune liver disease. Infective: HIV, TB, infective endocarditis. 7 10 \200\223 15% of patients with clinical and/or histological evidence of GPA/ MPA/RLV a re ANCA-negative at presentation (although some will become positive over time). The positive predictive value of a positive ANCA is dependent on the clinical situation: \200 GPA: ANCA-positive in 80 \200\223 90% ( 7 75% c-ANCA or anti-PR 3). \200 MPA: ANCA-positive in 80 \200\223 90% ( 7 70% p-ANCA or anti-MPO). Other investigations \200 2 Urinalysis for haematuria (microscopic haematuria almost univ ersal) and proteinuria, microscopy for red cells and red cell casts, uPCR. \200 FBC (anem ia common, thrombocytosis, leucocytosis), SCr, U&E, LFTs, CRP (often raised). Consider blood cultures. ABGs if suspected lung involvement. \200 Other autoimmune serology: Anti - GBM: \200\230 double positive \200\231 ANCA and anti-GBM disease is well recognized and behaves like anti-GBM disease ( b p. 656). \200 Anti-dsDNA, ENAs, C3, C4, rheumatoid factor to help exclude alternative diagnoses ( b p. 40). Imaging: Renal USS for renal sizes and to exclude obstruction. \200 CXR or CT may show patchy or d iffuse alveolar shadowing. This could represent infection, pulmonary oedema, or pulmonary h emorrhage. Nodules, cavitation, pleural involvement, and reticulonodular shadowing may also be present in GPA. \200 Transfer factor may be raised in pulmonary hemorrhage. ANCA-ASSOCIATED VASCULITIS: INVESTIGATIONS 643 Bronchoscopy may be desirable if pulmonary hemorrhage suspected but no de \201 nite haemop tysis. Bronchoalveolar lavage may reveal frank blood or haemosiderin-laden macrophages. Renal biopsy is usually indicated. However, a positive anti-MPO or anti-PR3, in the context of rapidly progressive AKI, may mandate the immediate commencement of treatment prior to histological diagnosis. Renal histology A focal and segmental necrotizing crescentic glomerulonephritis is charac- teristic (see Fig. 8.4). If small vessels, e.g. interlobular arteries, are sampled, they ma y show in \202 ammation and necrosis. Associated interstitial in \202 am- mation is often present. Immunostaining reveals no, or very few, immune complex or complement deposits, 6 referred to as \200\230 pauci-immune \200\231 . Granulomatous in \202 ammation is not pr esent in the kidney in GPA (but often found in the upper airways and other tissues). Chronicity, particularly the degree of irreversible glomerulosclerosis and tubulointerstiti al \201 brosis, will offer useful prognostic information. This may help to guide therapy. For example, aggressive and sustained induc- tion therapy is not warranted in a patient wi th principally kidney limited disease where a biopsy has suggested that renal recovery is i mprobable. ANCA and pathogenesis There is now a large literature con \201 rming that ANCA can activat e neu- trophils in vitro , leading to: (i) tethering and migration across endothe- lium; (i i) degranulation l proin \202 ammatory cytokines l recruitment of monocytes and macrophage s; (iii) augmentation of in \202 ammation and endothelial cell injury through free radical generation. This suggests that ANCAs are not an epiphenomenon (providing a useful clinical test), but t hat they contribute to pathogenesis. In vivo con- \201 rmation of this has been obtained with the demonstration of anti-MPO antibodies causing focal necrotizing crescentic GN follo wing injection into mice. In addition, neonatal disease following placental transfer of ant i-MPO antibodies has been described. It is likely that T cells speci \201 c for MPO and PR3 also contribute. Unanswered questio ns include: (i) how antibodies to MPO or PR3 arise; and (ii) how tolerance to self-antigens is broken. Transient induction of anti-PR3 antibodies has been shown during infection, and a possible infective association has been reinforced by the link between GPA and persisten t S. aureus nasal carriage. CHAPTER 8 The kidney in systemic disease 644 ANCA-associated vasculitis: treatment Both the disease and toxicity of therapy are associat ed with signi \201 cant morbidity and mortality. Risk vs bene \201 t should be assessed i n each indi- vidual case and discussed with the patient. There has been a recent expan- sio n in the literature regarding treatment of ANCA-associated vasculitis (see Table 8.5). For a full discussion on starting immunosuppression, particularly the necessary monitoring and preventative and protective measures (e.g. bone protection and PJP prophylaxis) that mu st be undertaken, see b p. 540. Induction therapy (to achieve remission) Corticosteroids: high-dose oral steroids (usually starting at around 1mg/kg prednisolone but rarely exceeding 60mg). Tapering regimens vary i n differ- ent centers; possible regimens are shown in Table 8.5. Table 8.5 Suggested regimen for steroid reduction Week Dose Week Dose Month Dose 0 60mg 6 20mg 3 12.5mg 1 45mg 7 20mg 4 12.5mg 2 30mg 8 15mg 5 10mg 3 25mg 9 15mg 6 10mg 4 25mg 10 15mg 12 7.5mg 5 20mg 11 15mg Cyclophosphamide: in addition to steroids. Daily oral therapy or intra- venous or oral puls ed therapy. Pulsed therapy is as effective at inducing remission but may be associated with a higher risk of relapse. Switch to maintenance therapy between 3 and 6 months when remiss ion achieved (minimum 3 months \200\231 therapy recommended). \200 Oral: 1.5 \200\223 2 mg/kg/day (1.5mg/kg if age >60) to a maximum of 200mg (round the dose to the nearest 25mg). Intravenous. Possible regimens: Ten pulses (15mg/kg) over 25 weeks, with age and GFR adjustments, or 0.75g/m 2 every 3 \200\223 4 weeks (initial dose to 0.5g/m 2 if age >60 years or GFR <20mL/min/1.73m 2 ). Doses are adjusted accordingly to maintain 2-week nadir leucocyte count >3,000/mm 3 . Rituximab: provides an alternative to cyclophosphamide and has been shown to be as effectiv e at inducing remission. Adverse events (perhaps surprisingly) appear comparable. The risk of relapse is yet to be clearly de \201 ned. It has the attraction of not affecting fertil ity. Note: much more expensive. Dose: 375mg/m 2 weekly x 4. ANCA-ASSOCIATED VASCULITIS: TREATMENT 645 Additional therapy for severe disease \200 Severe disease may be de \201 ned (arbitraril y) as rapidly i SCr, SCr >500 mol/L (or dialysis-dependent), or pulmonary hemorrhage. X Pulsed methylprednisolone: Three doses of 0.5 \200\223 1g IV over 3 days given initially. \200 No direct evidence o f bene \201 t and may increase complications. \200 The MEPEX trial suggested that plasma exchange is more effective than pulsed corticosteroids in severe disease (increased surviv al at 3 months, increased independent renal function at 3 months, less ESRD at 1 year), but the additive effect of both treatments is not known. Plasma exchange: Indications: severe disease or coexisting anti-GBM antibodies. \200 MEPEX regimen: seven exchanges (60mL/kg) over 14 days with 5% albumin. FFP or Octaplas may be needed at the e nd of the exchange if there has been a recent renal biopsy or there is pulmonary hemorrhage ( b p. 72). Ongoing PEXIVAS study should de \201 ne dosing/duration further. Resistant disease \200 Failure to induce remission occurs in 7 10%. \200 Therapeutic op tions: add rituximab to steroids and cyclophosphamide (or cyclophosphamide to steroids and rituximab). Commence plasma exchange. Consider IVIg (0.5mg/kg/day). Polyclonal ATG or alemtuzumab (Campath ) have been used b ut lack an evidence base. Maintenance therapy (to maintain remission) \200 Induction therapy usually moves to maint enance between 3 \200\223 6 months. Low-dose prednisolone (see Table 8.5). \200 Convert cyclophosphamide to azathioprine 1.5m g/kg/day (max 200mg). \200 MMF 1g bd is an alternative in patients intolerant of azathiop rine (but is associated with higher rates of relapse). It is not yet known whether MMF offers an alternative for induction therapy (MYCYC trial ongoing). The role of rituximab in maintenance therapy is not yet de \201 ned. \200 Methotrexate m ay also be used but has a higher relapse rate and is generally not favored for patients with renal or lung disease. \200 Co-trimoxazole may re duce upper respiratory tract relapses in GPA and is used, in addition to standard immunosuppression. Most clinicians continue maintenance therapy for at least 2 years, often longer in GPA, but the optimal duration is unknown. The risks and bene \201 ts of ongoing treatment will dep end on the individual clinical scenario and should be discussed with the patient. 2 Maintenance therapy is not recommend in patients who are dialysis-dependent and have no extrarenal disease manifestations. Relapse rates are lower i n patients with ESRD on dialysis ( (cid:2) but infection rates are higher). CHAPTER 8 The kidney in systemic disease 646 ANCA-associated vasculitis: monitoring response and predicting relapse See Table 8.6 for re cent trials. Successful achievement and maintenance of remission may be monitored by: Clinical assessment: see Clinical presentation in ANCA-associated vasculitis ( b p. 641), b ut note that patients may not just have a recurrence of previous features \200\224 they ma y develop new ones. Changes in BVAS score ( b p. 641). \200 Presence/absence of urinary abnormalities: partic ularly haematuria (note: persistent proteinuria may not indicate persistent disease, rather irreversible glom erular damage). CRP: useful but non-speci \201 c. Poses a common clinical dilemma when raised; does it rep resent relapse or infection? (cid:2) Both must be taken seriously. Stable or improving renal function. \200 ANCA and anti-MPO or anti-PR3 levels. X Rising anti-MPO or anti-PR3 level may predict relapse, but this has not been consistent in all studies. There is currently no role for presumptively increasing immunosuppression in the absence of a change in clinical disease activity (although rising titres will usually mandate an increase in surveillance intensity). See Fig. 8.4 for renal biopsy. Treating relapse \200 Severe relapses should be treated, as per induction therapy. Howeve r, any decision to re-institute cyclophosphamide should be based, at least in part, on the cumulative dose to date, as there is evidence of a higher malignancy risk for cumulative do ses over 36g. The preservation of fertility may also be a prime concern. Rituximab may be p referred in this situation. Less severe relapses require careful clinical judgment. Most clinicians will opt to avoid r epeat cyclophosphamide therapy where possible. If relapse has occurred off maintenance ther apy, then the re-institution of steroids and azathioprine (or MMF) may be suf \201 cient. ANCA-ASSOCIATED VASCULITIS 647 Renal replacement therapy Standard AKI indications for IHD or CRRT apply during the treatme nt of vasculitis ( b p. 172). The development of irreversible ESRD will in \202 uence trea tment choices (see Treating relapse, b p. 646). Transplantation : it is generally recommended that patients wait for 6 \200\223 12 months post-remission prior to transplantation. Ongoing ANCA positivity per se is not signi \201 cantly associated with reduced graft survival. Recurrent disease can be expected in 15 \200\223 20% but causes graft loss in a minority. A recent series of 7 100 patients suggest ed 70% graft survival at 10 years. Rejection rates are similar to the general transplant po pulation, but there is an increased infection risk, presumably re \202 ecting cumulative i mmune suppression. Fig. 8.4 Renal biopsy in ANCA-associated vasculitis. The glomerulus is outlined by Bowman \200\231 s capsule, which is highlighted by the silver stain (as are the capillary loops). Most of the glomerulus has been obliterated by a crescent, with just a few remnant capillar y loops remaining open. CHAPTER 8 The kidney in systemic disease 648 Table 8.6 Recent trials in systemic vasculitis Trial Year Treatment n In brief 144 RCT. Renal patients. Aza as good CYCAZAREM 2003 Cyclophosphamide (CyC) vs Aza (maintenance) SOLUTION 2003 ATG (refractory disease) 15 Case series. Possible bene \201 t. (cid:2) in pulmonary hemorrhage 174 RCT. Etanercept had worse outcomes and i malignancy WGET 2005 Etanercept vs placebo (maintenance) MEPEX 2007 Plasma exchange (PEX) (induction) 137 RCT. PEX improved mortality and GFR (see text) 160 RCT. No difference CYCLOPS 2009 Daily oral CyC vs intermittent pulsed (induction) RITUXVAS 2008 Rituximab (RTX) vs CyC (induction) 44 RCT. RTX safe and comparable IMPROVE 2010 MMF vs azathioprine (Aza) (maintenance) 156 RCT. MMF less effective RAVE 2010 RTX vs CyC (induction) 197 RCT. Excluded pulmonary hemorrhage and severe renal disease. Comparable outcomes CycLowVas 2011 RTX x2 doses, CyC x6 doses (induction) 23 Case series. Excluded pulmonary hemorrhage and severe renal disease Good remission, less st eroid MYCYC Ongoing MMF vs CyC (induction) RCT PEXIVAS Ongoing PEX (induction) RCT. Further info re dosing/timing of PEX and steroids RITAZAREM Ongoing RTX vs Aza (maintenance in relapsing disease) RCT ANCA-ASSOCIATED VASCULITIS 649 CHAPTER 8 The kidney in systemic disease 650 Henoch \200\223 Sch nlein purpura Introduction \200 Small vessel systemic vasculitis predominantly affecting children (20 per 100,000 population in the UK). Peak incidence age 4 \200\223 5 (range generally 2 \200\223 11). \200 2:1 \231\202 : \231\200 ratio. Caucasian > black patients. \200 More common in winter and early spring \200\224 associated with an upper respiratory tract infection (with accompanying fever and malaise) in 7 2/3. IgA plays a critical role in the pathogenesis of HSP ( l circulating IgA containing immune complexes, IgA deposition in vessel walls and renal mesangium). These abn ormalities are associated with IgA1, not IgA2. \200 IgA complexes and complement deposit in target organs l release of in \202 ammatory mediators. Serum IgA elevated in 7 50%. A small number are ANCA-positive. Clinical presentation \200 Presents as a tetrad of skin rash, abdominal pain, arthralgia, and renal involvement. \200 Rash: skin manifestations usually dominate the clinical picture. Purpur ic (usually symmetrical) rash, affecting legs, buttocks (and, less frequently, arms). Abdom en, chest, and face are typically spared. New lesions may develop over several months. Hist ology: leucocytoclastic vasculitis with vascular IgA and C3 deposition. Urticaria may also occur. Abdominal: GI manifestations in 7 3/4 patients. Nausea, vomiting, diarrhea (may be bloody), colicky pain (which may be severe), GI bleeding, ileus, infarctio n, perforation, intussusception, pancreatitis, cholecystitis. Arthralgia: joint manifestations in 7 2/3 patients. Usually symmetrical polyarthralgia, mai nly involving knees and ankles, wrists and \201 ngers less common. True arthritis and per manent damage extremely rare. Renal involvement: focal and segmental mesangial proliferative GN presenting as haematuria, proteinuria (which can be nephrotic range) 9 renal impairment and i BP. A renal biopsy is usually reserved for nephritic/nephrotic presentations, renal impairment, and persistent or heavy proteinuria. The severity of renal sequelae is often not related to the severity of other manifestations Other: pulmonary hemorrhage, cerebral vasculitis ( l headache, irritability, seizures, focal weakness, altered mental state), neuropathies, and orchitis. Prognosis \200 Usually self-limiting (usually <1 month; rarely >2 months). \200 Follow- up is recommended. Isolated microscopic (and intermittent macroscopic) haematuria may persist, but the prognosis is good in this situation. i BP is also probably more common. \200 The presence of proteinuria is an adverse prognos tic sign. HENOCH \200\223SCH \226NLEIN PURPURA 651 Nephritic and mixed nephritic/nephrotic presentations have the worse prognosis ( 7 1/3 will progress to ESRD). Estimated as the cause of ESRD in 7 1.5 \200\223 3% children overall. In adults, renal involvement is more common. Complete resolution is the norm, but persisten t urinary abnormalities ( (cid:2) proteinuria) predict a worse prognosis and mandate follow -up. Recurrence in 7 1/3 cases, particularly if renal involvement (usually within 6 months). Treatment \200 Usually symptomatic only, e.g. analgesia for arthralgia. \200 Severe ski n or GI manifestations may require corticosteroids. \200 Nephritis ( X no strong evidence base): Steroid treatment does not prevent renal involvement. \200 Heavy proteinuria, impaired re nal function, and crescents on renal biopsy often precipitate steroid treatment, e.g. 3 x d oses of IV methylprednisolone, followed by 4 weeks of PO prednisolone. If the response is f avorable, they are continued and weaned over 7 6 months. Some advocate the use of cyclophos phamide in this group. RPGN with >50% crescentic change is often treated as per other causes of systemic vasculiti s (e.g. steroids, cyclophosphamide, and plasma exchange). ACE-I for persistent proteinuria. HSP and IgAN: similar but (probably) not the same Whether HSP and IgA nephropathy are diffe rent faces of the same clinicopathological entity remains a matter for debate. \200 Simil arities: The extrarenal manifestations of both are similar. \200 IgAN can occur in patients with a history of HSP and the two have occurred in the same family. Patients with HSP who subsequently receive a kidney transplant may develop IgA deposits in the graft. Similar changes in the IgA system, e.g. aberrant glycosylation of circulating IgA, can be demonstrated in both. Differences: Age of onset is much younger in HSP. \200 Extrarenal manifestations, especially cutaneous , are much more common in HSP. Glomerular, particularly mesangial, sclerosis is more common in IgAN, while endothelial pro liferation is more common in HSP. \200 On EM, deposits are mostly limited to the mesangiu m in IgAN but more widely distributed in HSP. IgA deposits may be relatively weak in HSP, compared to IgAN. \200 IgG immune deposits ar e found more commonly in HSP. \200 Persistent haematuria, proteinuria, and CKD are more c ommon in IgAN. CHAPTER 8 The kidney in systemic disease 652 Polyarteritis nodosa Introduction Polyarteritis nodosa (PAN) is a rare (<10 PMP) medium-ves sel necrotizing transmural arteritis, involving principally the skin, nerves, gut, and kidn ey. Most cases are idiopathic, but 7 30% may be secondary (hepatitis B, hepati- tis C, SLE, RA, Sj gren \200\231 s, hairy cell leukemia). Onset is usually age 40 \200\223 60. Symptoms and signs Usually presents with systemic symptoms (fever, weight loss, arthralgia, and myalgia). Skin disease includes nodules, livedo reticularis, or pur- pura (indicating small vessel involvement). Medium vessel involvement in the gut presents as abdominal pain (often postprandial), perforation, or bloody stool. Other features include testicular pain (epididymo-orchitis), mononeuritis multiplex (peripheral neuropathy), stroke, and myocardia l ischaemia. Renal ischaemia causes i BP 9 renal impairment. There may be loin pain from segmental renal infarcts. Unlike the ANCA-associated vasculitides, glomerular disease is not a feature of PAN. Investigations Urinalysis Inactive \200\224 generally no microscopic haematuria (as no glo merular in \202 amma- tion), although proteinuria may be present ( i BP). An exception mig ht be the haematuria (often visible) that occurs with renal infarction with PAN). Routine laboratory tests FBC, biochemistry pro \201 le with muscle enzymes. CRP is usually raised and may be used to monitor disease. Tests to exclude an underlying cause or alternative diagnosis Hepatitis B and C serology, C 3, C4, RhF, ENAs, anti-dsDNA, cryoglobu- lins, blood cultures (exclude infection). 2 PAN is not associated with ANCA. Diagnostic tests Diagnosis is made, following tissue biopsy or angiography. The classical \201 nding is of microaneurysms or beading, with vascular occlusion in the renal or mesent eric vascular tree (see Fig. 8.5). Renal biopsy may show segmental transmural \201 brinoi d necrosis in medium-sized arteries 9 down- stream ischaemic changes or frank infarction. Management and natural history \200 The prognosis of untreated disease is extremely poor. \200 Treat underlying cause in secondary disease. \200 In primary PAN, mild disease is generally treated with corticosteroids alone. Moderate to severe disease is treated with corticosteroids and cyclophosphamide for at least 3 \200\223 6 months, followed by azathioprine in a similar m anner to ANCA-associated vasculitis. Relapses are infrequent. POLYARTERITIS NODOSA 653 Fig. 8.5 Medium-vessel aneurysms in the kidneys at ateriography. Reproduced with permission from Wu K and Throssell D (2006) Nephrol Dial Transplant , 21 (6): 1710 \200\223 12. Takayasu \200\231 s disease \200 Chronic in \202 ammatory condition associated with gra nulomatous arteritis, intimal proliferation, and medial and adventitial \201 brosis ( l a rterial occlusion, post-stenotic dilatation, and frank aneurysm formation). Atherosclerosis supervenes as patients age. Affects large vessels \200\224 principally the aorta (and branches) and pulmonary vessels. Etiology unknown. Most common in young \231\200 . Relatively common in Asia (esp. Japan). Rare in Caucasians (<3 pmp). Classically described as a triphasic disease: (i) \200\230 pre-pulseless \200\231 phase w ith systemic symptoms; (ii) a vascular in \202 ammatory phase; and (iii) a quiescent occlu sive phase. Presentation: systemic symptoms (weight loss, fatigue, fever), claudication, angina, CVA, vertebrobasilar insuf \201 ciency, steal syndromes, aneurysms, asymmetrical BP in limbs, bruits, aortic incompetence (if ascending aorta involved). 7 50% develop renovasular i BP. Investigations: acute phase response ( i CRP, ESR) and normochromic anemia. Autoantibodies, including ANCA, are negative. Angiography is diagnostic (MR angiography and PET scanning may identify areas of active in \202 ammation). Treatment: steroids are the mainstay, but many patients relapse as they are tapered. Eviden ce base for \200\230 steroid-sparing \200\231 agents is poor. Methotrexate, azathioprine, and anti-TNF therapy have been used. Revascularization is often necessary. Relatively poor results from angioplasty (reocclusion) and stenting (restenosis). Surgery may be necessary (but high inc idence of graft restenosis). CHAPTER 8 The kidney in systemic disease 654 Churg \200\223 Strauss syndrome Introduction Now referred to as eosinophilic granulomatosi s with polyangiitis (EGPA). This is an ANCA-associated vasculitis (50% positive), but patie nts are gen- erally younger patients than MPA/GPA/RLV (mean age 40). \231\202 = \231\200 . Characterized classically by rhinitis, asthma, and eosinophilia and primar- ily affects the lung and skin. However, it may affect any organ. The incidence of renal involvement in EGP A is dif \201 cult to estimate (probably 7 30%). Symptoms and signs Disease typically evolves in stages (with some overlap): \200 Atopic p rodrome: \200 2nd/3rd decade. \200 Allergic rhinitis or other atopic conditions. \200 Asthma (often severe/steroid-requiring). Eosinophilic stage: Peripheral eosinophilia (>1.5 x 10 9 /L). \200 Eosinophilic in \201 ltration of organs ( esp. lung and gut). Vasculitic stage: 3rd/4th decade. \200 Severe systemic vasculitis/extravascular granulomatosis. \200 Pres ents as fever, malaise, weight loss. \200 Widespread organ involvement includes: \210\222 Lungs: i severity of asthma, dyspnoea, haemoptysis, pulmonary opacities/nodules, pleural effusions. \210\222 Kidneys ( 7 30%): 50% with rapidly progressive AKI, 50% with isolated proteinuria/haematuria. i BP is common (presumably renal ischaemia). \210\222 Gut: eosinophilic gastroenteritis, ischaemic bowel, abdominal pain, bloody diarrhea. \210\222 Skin: tender subcutaneous nodules, palpable purpura, urticaria. \210\222 ENT: na sal obstruction, polyps, otitis media, hearing loss. \210\222 Cardiac: coronary vasculitis (angina), myocarditis (LVF), or pericarditis ( (cid:2) tamponade). \210\222 Neuro: mononeuritis multiplex, painful polyneuropathy. \210\222 Musculoskeletal: myalgia, migratory polyarthritis. \210\222 Lymphadenopathy: eosinophilic LN seen in 30 \200\223 40%. Investigations \200 Urinalysis, (microscopic haematuria, proteinuria), microscopy for red cells and red cell casts, uPCR. FBC ( d Hb) and prominent eosinophilia (often >10% total WCC, or absolute count >1.5 x 10 9 /L). i ESR, u i CRP, immunoglobulins ( i IgE \200\224 common and may vary with disease activity , polyclonal hypergammaglobulinaemia). U&E, Alb, LFT, CK. ANCA (usually anti-MPO) positive in 7 50% (particularly during vasculitis phase). RhF often positive at low titre. CHURG \200\223STRAUSS SYNDROME 655 CXR ( \202 itting, patchy in \201 ltration) 9 ABG. \200 ECG, echo (consider cardiac MR with gadolinium if either abnormal). \200 Lung \200\224 transfer factor, HRCT, PFT (obst ructive picture with d lung volume), BAL/lung biopsy. Tissue biopsy classically shows eosinophil-rich granulomatous in \202 ammation. If sampled, vessels show a small to medium vessel necrotizing vasculitis . Renal biopsy may show vasculitis 9 focal and segmental necrotizing GN though usually with a n eosinophilic in \201 ltrate and granuloma formation throughout the interstitium. A large series of 7 115 patients (all ANCA-positive) showed >50% had necrotizing GN on biopsy. Diagnostic criteria Lanham criteria (three criteria) vs American College of Rheumatology cr iteria (six criteria) from: \200 Asthma. \200 >10% eosinophils. \200 Mono-/polyneurop athy. \200 Migratory/transient CXR opacities. \200 Paranasal sinus abnormalities. \200 Biopsy containing a blood vessel, with eosinophils in extravascular areas. Treatment Assess for severity using the \201 ve factor score (FFS): (1) cardiac involve- ment; (2) SCr >141 mol/L (1.6mg/dL); (3) proteinuria >1g/day; (4) GI disease; (5) CNS in volvement. Score 0 (no factors), 1 (1 factor), or 2 (2+ factors). \200 Prednisolone: PO 1 mg/kg/day for 6 \200\223 12 weeks (or until remission (consider initial pulsed IV if multi-organ involvement). Treat asthma and i BP with standar d therapy. >90% remission with steroids alone if FFS score 0. Eosinophilia is exquisitely s teroid-sensitive and may resolve rapidly on treatment. Cyclophosphamide: PO or IV for 3 \200\223 6 months, followed by maintenance therapy simila r to ANCA-associated vasculitis ( b p. 640). Use for refractory disease or if FFS 2+, FFS 1 plus cardiac involvement, or FFS 0 but ANCA-positive. Other: azathioprine and methotrexate (not if GFR <50mL/min) have been used to maintain of remission. Limited data for MMF, rituximab, and others. Plasma exc hange appears to confer no additional bene \201 t. Monitor for relapse using clinical symptoms, eosinophil count, and acute phase reactants (E SR, CRP). ANCA positivity does not predict disease activity. Relapse can be expected in 7 2 5% of cases. Survival is 70% at 5 years. Most deaths occur during the vasculitic phase. CHAPTER 8 The kidney in systemic disease 656 Anti-GBM (Goodpasture \200\231 s) disease Introduction A rare disease (<1 pmp) that presen ts as RPGN 9 pulmonary haemor- rhage. Occurs in older children and adults of all ages but w ith peaks at age 20 \200\223 30 and 60 \200\223 70. More common in Caucasians. \231\202 > \231\200 (slightly). Pathogenesis Caused by antibodies (usually IgG) against two adjacent regions in the NC1 dom ain of the A 3 chain of type IV collagen ( \200\230 Goodpasture \200\231 s epitopes \200 \231 ). This A 3 chain is limited to the BM of the glomerulus and alveolus (also choroid pl exus, testis, and cochlear \200\224 although clinically irrelevant). The epitopes are usua lly structurally sequestered and 6 protected but become more accessible in the disease. It is now recognized that cell-mediated immunity is also important, with strong evidence fr om animal models and clinical studies that T cells reac- tive with type IV collagen contrib ute to in \202 ammatory responses. Genetic (e.g. HLA DR15, particularly the DRB1*1501 allele) and envi- ronmental (e.g. hydrocarbon exposure) factors in \202 uence susceptibility. Others risk factors include smoking and membranous GN (anti-GBM disease can occur before, d uring, or after this GN). Such factors appear to damage either the glomerular or alveolar B M l epitope exposure and autoimmune responses. There is no strong association with infectio n. Symptoms and signs \200 Usually presents acutely with rapidly progressive AKI (with haema turia and subnephrotic proteinuria) 9 pulmonary hemorrhage ( 7 60%). \200 Some patients r eport loin pain and haematuria during early stages. \200 No renal involvement is very rar e. \200 Pulmonary hemorrhage may present as frank haemoptysis but is often more incipient, e.g. cough, dyspnoea, blood- \202 ecked sputum. Pulmonary hemorrhage occurs almost exclusively in smokers and, more commonly, in younger patients. 2 Note: pulmonary hemorrhage is exacerbated by even mild pulmonary oedema, so \202 uid overload must be avoided. Systemic symptoms, such as fever and weight loss, are usually absent and may suggest an alternative diagnosis, such as vasculitis. Investigations Routine laboratory tests \200 Urinalysis for blood and protein, uPCR (prot einuria usually non-nephrotic). FBC, U&E, SCr, CRP (often raised). Autoimmune serology \200 Anti-GBM antibodies: request urgently if suspected. Titres broad ly correlate with disease activity. False positives: viral infections, esp. HIV, hep C. False negatives unusual (diagnosis then rests on biopsy). ANCA: important differential diagnosis, and 25% are \200\230 double positive \200\231 for both anti-GBM and ANCA (usually anti-MPO). Such patients usually behave like anti-GBM d isease but may have rashes and arthralgia. ANTI-GBM (GOODPASTURE \200\231S) DISEASE 657 Imaging and investigation of pulmonary hemorrhage \200 CXR 9 CT (diffuse alveolar shadowi ng). ABGs. \200 Renal USS to measure renal sizes and exclude obstruction. \200 Transfer factor (KCO) may be raised if pulmonary hemorrhage. \200 Bronchoalveolar lavage: frank b lood or haemosiderin-laden macrophages. Renal biopsy \200 2 Usually indicated but should not delay treatment if anti-GBM positive in the appropriate clinical context. Histology: focal and segmental necrotizing, crescentic GN. The light microscopic \201 ndings are similar to those in ANCA-associated vasculitis, except that a ll crescents are usually at the same stage of development (termed \200\230 synchronous \200\231 ). Immunostaining demonstrates linear capillary wall staining for IgG and C3 (also seen in diabetic nephropathy and \201 brillary GN). EM will show frequent breaks in the GBM. The biopsy may also yield helpful prognostic information. Signi \201 cant potentially reve rsible acute tubular injury may suggest a good chance of recovery despite advanced renal fa ilure. Management Initial treatment is similar to ANCA-associated vasculitis, although mainte- nan ce therapy is generally not necessary, as relapse is very rare (anti-GBM is often referred to as a \200\230 one-hit \200\231 disease). For a discussion on starting and monitoring immunosuppression, see b p. 540. \200 Corticosteroids: prednisolone (1mg/kg to max 60mg/day), and taper over 6 months, then stop (regimen will vary between centers). Initial pulsed methylpredniso lone (three doses x 0.5 \200\223 1g IV) although limited direct evidence of bene \201 t. Cyclophosphamide: given in combination with steroids. Usually 3 months daily oral therapy ( b p. 541). If anti-GBM remains positive, some clinicians then favor sw itching to azathioprine for a further period. \200 Plasma exchange: should be given to al l patients. Usually daily for 2 \200\223 3 weeks, but duration can be tailored to clinical response and anti-GBM titre (aim: undetectable) ( b p. 950). Once dialysis \200\223 dependent, renal recovery is very unusual. Potentially toxic treatm ent may not be warranted in this situation (unless there is pulmo- nary hemorrhage), but fe atures on the renal biopsy (see \200\230Investigations \200\231) should also inform this d ecision, as should potential future transplantation (see \200\230Prognosis \200\231).