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). Prognosis Almost uniformly fatal if untreated. Independent renal function in >90% at 1 year when presenting SCr <500 mol/L (5.6 mg/dL); 82% when SCr >500 mol/L (5.6 mg/dL), and just 8% if dialysis-dependent. Pulmonary hemorrhage signi \201 cantly increases early mor tality. Transplantation is not recommended until anti-GBM antibodies have been absent for 6 months. If they persist, then further treatment (e.g. rituximab) may be contemplated. CHAPTER 8 The kidney in systemic disease 658 Lupus nephritis Introduction Systemic lupus erythematosus (SLE) is a heterogeneous multisys tem dis- ease characterized by autoantibody production and a diverse range of clinical mani festations, as outlined in Table 8.7. SLE is more common in black patients, Hispanics, and Asians. It principally occurs in young adults and is more common in \231\200 by a factor o f 7 10. Lupus nephritis should form part of the differential diagnosis in any patient presenting wi th an active urinary sediment 9 renal dysfunction. The diagnosis of SLE will not already be established in many patients. Renal disease is common in SLE, developing to some degree in 7 50% of patients and usually occurring within the \201 rst 5 years of diagnosis. Surveillance is 6 important (and ofte n performed by non-nephrologists). Pathogenesis The pathogenesis of SLE is multifactorial, involving genetic, hormonal, and en vironmental factors. The strong genetic element is shown by 7 25 \200\223 50% concordance in monozygotic twins and the fact that \211 10% of patient rela- tives are affected. Nume rous abnormalities of the immune system have been described, although it is not universally understood whether these are epiphenomenon or causative. The hallmark of SLE is the production of a range of autoantibodies, in particular, to self- antigens that contain DNA and RNA. Factors that may promote autoimmunity include i IFN- A , increased levels of the B cell sur- vival factor Blys (BAFF), and stimulation of nuclei ac id-binding receptors TLR7 and TLR9. Immune complexes containing autoantibody cause tissue i njury by stimulation of leucocyte Fc receptors and complement activa- tion. However, comple ment appears to play a dual role, as it can also be protective \200\224 genetic de \201 c iency of the early classical pathway components C1q and C4 strongly predisposes to SLE, per haps through a defect in the clearance of apoptotic cells. Faulty apoptotic processes are a general feature of the disease, with early autoantibody responses directed against the nuc leosome (which arises from apoptotic cells). Common clinical manifestations \200 Systemic: fever, weight loss. \200 Skin: malar rash , photosensitivity, alopecia. \200 Joints/hands: arthralgia, arthritis, Raynaud \200\231 s. \200 Serositis: pleural effusion, peritonitis, pericarditis. \200 CNS: headaches, s troke, seizures, psychosis. \200 Renal: i SCr, haematuria, proteinuria (nephrotic syndrom e), i BP. \200 Hematological: anemia, leucopenia, thrombocytopenia. \200 Cardiovascular : myocarditis, pericardial effusion, sterile endocarditis, venous and arterial thromboses (antiphospholipid syndrome). LUPUS NEPHRITIS 659 Investigations Routine laboratory tests \200 Urinalysis for blood ( l suggests active glo merular disease) and protein, microscopy for red cell casts, uPCR or uACR. FBC, U&E, SCr, LFTs, CK, ESR (typically raised), d serum albumin (if nephrotic). CRP (typically not raised unless serositis; can be a useful discriminator). Immunological tests in patients suspected of having SLE \200 ANA (>95%; sensitive but not speci \201 c) Anti-dsDNA (increased speci \201 city), C3 and C4 (reduced), ENAs (including anti-Ro, anti \200\223 La, anti-Sm ) ( b p. 42). Anti-C1q antibodies have reasonable sensitivity and even better speci \201 city for active nephritis (particularly in combination with anti-DNA). ANCA (positive in a proportion; usually anti-MPO) ( b p. 642). \200 Anticardiolipin antib odies and lupus anticoagulant ( b p. 664). Radiology Renal USS: renal sizes; exclude obstru ction, and investigate possible renal vein thrombosis (esp. if nephrotic 9 antiphospholipid syndrome) ( b p. 590). Renal biopsy A renal biopsy is indicated in most patients with susp ected lupus nephritis. 2 Note: severe disease may be seen histologically with a \200\230 m ild \200\231 clinical phenotype (e.g. normal SCr, mild proteinuria, and microscopic haemat u- ria). Histology is crucial for planning of treatment and also yields important prognosti c information. A complex range of light microscopic \201 ndings may be present and classi \201 ed as shown in Table 8.7. In all cases, immunostain- ing shows a \200\230 full hous e \200\231 , i.e. it is positive for IgG, IgM, IgA, C3, and C1q. Other renal pathologies a lso occur in SLE, including thrombotic microan- giopathy ( b p. 574), AIN ( b p. 580), mini mal change ( b p. 558), and ischaemic nephropathy from renal artery stenosis ( b p. 665). Table 8.7 ISN 2004 classi \201 cation of lupus nephritis I Normal light microscopy with immune deposits II Mesangial proliferation with immune deposits III Focal lupus nephritis: endo- or extracapillary GN in <50% of glomeruli IV Diffuse lupus nephritis: endo- or extracapillary GN in >50% of glomeruli, either segmentall y (IV \200\223 S) or globaly (IV \200\223 G) V Membranous change (subepithelial deposits) VI Advanced sclerosis with >90% glomeruli obsolete Class III and IV are additionally labeled as active (a), chronic (c), or both (a/c). Signs of activity: endocapillary hypercellularity with or without leucocyte in \201 ltrati on, karyorrhexis, \201 brinoid necrosis, GBM rupture, cellular or \201 brocellular cres cents, subendothelial deposits on light microscopy, intraluminal immune aggregates. Signs o f chronicity : segmental or global glomerulosclerosis, \201 brous adhesions, \201 brous crescents. CHAPTER 8 The kidney in systemic disease 660 Lupus nephritis: initial treatment Initial therapy For a discussion on starting and monitor ing immunosuppression, see b p. 540. Classes I and II Usually presents as mild renal diseas e, such as microscopic haematuria 9 proteinuria that does not usually warrant speci \201 c therapy. Classes III and IV (or III + V and IV + V) \200 Immunosuppression is required for these c ategories. \200 Class III typically presents as mild to moderate renal disease, with micr oscopic haematuria, moderate proteinuria, and (in a signi \201 cant number) deteriorating renal function. Extrarenal SLE is often active (see Fig. 8.6). Class IV typically presents as severe renal disease: i BP, oedema, active urinary sediment, deteriorating renal function ( (cid:2) often rapid), and nephrotic range proteinuria (extrarenal SLE is usually active). Class V typically presents as the nephrotic syndrome. The prognosis is worse if class V is found in combination with class III or IV. In the past, large doses of pulsed IV cyclophosphamide were used in addition to steroids (based on NIH evidence). More recent evidence has shown that: (ii) low-dose IV cyclophosphamide is just as effective, and (ii) MMF is as ef \201 cacious as cyclophospham ide for most patients. Standard initial therapy for most with classes III and IV disease is 6 high-dose oral steroids and oral MMF. Cyclophosphamide is generally reserved for patients w ho have failed initial treatment. Corticosteroids Most centers start with a high dose of oral prednisolone ( 7 1mg/kg, max 60 mg od). Protocols for subsequent tapering will vary. See b p. 540 for possible regimen. Pul sed IV methylprednisolone (0.5 \200\223 1g IV x 3) is often given initially, although ther e is no direct evidence of bene \201 t \200\224 although it may allow a lower dose of pre dnisolone to be used initially (e.g. 0.5mg/kg \200\224 the \200\230 Eurolupus protocol \200\231 ). Mycophenolate Given at a total dose of 2 \200\223 3g/day and normally continue d at the maximum dose for at least 6 months. It is important to titrate the dose to these l evels, as tolerated. Cyclophosphamide Usually reserved for patients who have failed MMF, al though some clinicians still favor as initial therapy in more fulminant disease. Usually gi ven as 6 x IV doses of 500mg at 2-weekly intervals. Rituximab Reserved for patients who hav e not responded to MMF or cyclophosphamide. Clinical trials in both extrarenal and renal lu pus disap- pointing, but clinical experience suggests bene \201 t in selected patients. Be limumab (Anti-BLyS) Clinical trials have shown bene \201 t in extrarenal lupus. Studies in lupus nephritis are ongoing. Class V \200 The optimal therapy for pure membranous lupus nephritis is uncertain, as most trials have included only small numbers of such patients. LUPUS NEPHRITIS: INITIAL TREATMENT 661 If renal function is normal and proteinuria subnephrotic, immunosuppression may not be indicated initially. \200 Spontaneous remission of class V d isease may occur. \200 Patients should be treated with ACE-I or ARBs, as for any proteinu ric renal disease. If nephrotic range proteinuria, most clinicians would institute similar therapy to classes III and IV, as described previously. Calcineurin inhibitors are an alternative. Additional therapy \200 All patients with lupus nephritis should receive ACE-I/ARBs, if s igni \201 cant proteinuria, plus BP treatment, as needed (aim <130/80mmHg). Treat complications of CKD, e.g. anemia and SHPT ( (cid:2) often neglected. SLE patients have high incidence of CV disease, so CV risk factors much be given appropriate attention. Hydroxychloroquine (200 \200\223 400mg PO od) for all patients, unless contraindicated (demonstrably lowers disease \202 are rates). Fig. 8.6 Image from a renal biopsy of a patient with lupus nephritis. The glomerulus shows segmental proliferation and is outlined by Bowman \200\231 s capsule, which picks up the s ilver stain, as do the capillary loops. The left hand half of the glomerulus shows endocapi llary proliferation, and the right half is almost normal. This biopsy would be classi \201 ed as class III or class IV, depending on the percentage of glomeruli affected (see Table 8.7). CHAPTER 8 The kidney in systemic disease 662 Lupus nephritis: further treatment Maintaining remission There is no clear demarcation betw een induction and remission phases. Evidence of an initial response to treatment, with impr oving renal function and reducing proteinuria, can continue for many months. Nonetheless, a lthough it is somewhat arbitrary, patients are categorized after 6 months \200\231 treatme nt: \200 Complete remission: uPCR <50mg/mmol, with a normalized or stable SCr. Partial remission: uPCR improved 50% on baseline and <300mg/mmol, with a normalized or stable SCr. Non-responders. Complete remission \200 If MMF has been used, the dose may be reduced, although it is advisable to maintain a dose of around 2g/day for at least 2 years. Low-dose prednisolone (e.g. 5 \200\223 10mg daily) is often continued. \200 Azathioprine can be an alternative to MMF for remission maintenance if the latter is not tolerated (alt hough recent trial evidence suggests that MMF is superior). Partial remission or non-responders \200 The clinical decision-making process in partial responders can be challenging; options include continued observation (especially if paramet ers are improving), a further renal biopsy, or an escalation in therapy. Cyclophosphamide or rituximab may be considered. Cessation of immunosuppression There is no strong evidence to guide the decision to withdra w mainte- nance therapy. Case series suggest that the risk of relapse is inversely proporti onal to length of prior treatment. Therapy for at least 5 years is advisable. Monitoring Patients require close long-term surveillance. Monitoring for renal disease \200 Urinalysis (particularly microscopic haematuria), uPCR or uACR. \200 SCr, serum albumin. If there is signi \201 cant proteinuria, serum albumin can be a more precise marker than uPCR and uACR (providing no other factors that depress a lbumin, such as infection, are present). Repeat renal biopsy. Monitoring lupus serology \200 Anti-dsDNA, C3, C4, ESR, anti-C1q are useful for disease a ctivity. \200 One or more may be known to be particularly useful in an individual patient , but no single marker, or combination, has suf \201 cient sensitivity or speci \201 city to be used in isolation. LUPUS NEPHRITIS: FURTHER TREATMENT 663 (cid:2) Some patients may have active serology but no clinical disease activity. However, those in whom the serological markers are negative are unlikely to have signi \201 cant activity (especially if previously positive). Prognosis Outcomes are variable and depend on disease severity and response to treatment. O verall mortality 7 10% at 10 years for lupus nephritis (approxi- mately double that of non- renal disease). Chronic in \202 ammation, organ damage, toxicity of therapy, and increased CV disease all contribute to this. Renal replacement therapy SLE represents 7 1 \200\223 2% of patients on an ESRD program. S urvival is comparable to patient without SLE. Lupus is generally quiescent once on dialysis (a state of relevant immune suppression), although extrarenal disease \202 ares may occu r and require treatment. Interestingly, the better the quality of dialysis (e.g. longer hou rs), the higher the risk of relapse. Patients are usually good candidates for transplantati on. It is recom- mended that disease has been inactive for 3 \200\223 6 months at the time of transplantation. There is con \202 icting evidence concerning graft out- comes, with a historical suggestion that these may be poorer. However, this is probably not the case. Re current disease is relatively uncommon. Concurrent antiphospholipid antibody syndrome with graft loss from thrombotic events may contribute to the inferior outcomes seen in some seri es. CHAPTER 8 The kidney in systemic disease 664 Antiphospholipid syndrome (APS) Introduction Antiphospholipid antibodies may occur as a pri mary entity ( 7 50%) or in association with connective tissue diseases, e.g. SLE ( 7 30 \200\223 40%), Sj gren \200\231 s ( 7 40%), RA ( 7 30%), systemic sclerosis ( 7 25%). T hey are also present in 7 5% of the normal population. As well as autoimmune diseases, antiphospholipid antibodies are asso- ciated with infection s (e.g. HIV, hepatitis C, and syphilis) and drugs (e.g. hydralazine, procainamide, IFN- A ) . APS is de \201 ned as antiphospholipid antibodies plus one or more clinical episodes of ar terial, venous, or small vessel thrombosis in any organ (con- \201 rmed on imaging or his tologically). APS occurs at all ages and is more common in \231\200 . It is more frequent in relatives of affected patients. APS and fetal loss De \201 nition used in pregnancy is antiphospholipid antibodies plus: \200 One or more spontaneous abortion (>10 weeks). \200 One or more births <34 weeks, wi th severe pre-eclampsia, eclampsia, or placental insuf \201 ciency. Three or more unexplained, consecutive, spontaneous abortions <20 weeks \200\231 gestation. Pathogenesis Dysregulation of coagulation l thrombosis. Exact mechanisms are unclear. Howev er, it appears that aberrant apoptosis may expose membrane phos- pholipids for binding by p lasma proteins. These complexes then stimulate autoantibody production. Thrombosis is initiated by antibodies to coagulation factors (e.g. protein C and S) 9 platelet and endothelial activation 9 complement activation. Clinical features Some patients are asymptomatic. In others, an associated disease will dom inate clinical presentation, e.g. SLE. The presentation of APS essen- tially re \202 ects a multi-organ disorder, characterized by hypercoagulability and recurrent thrombosis: \200 Vascular: DVT, PE, pulmonary hypertension, MI, digital ischaemia. \200 Obstetric: fetal loss, pre-eclampsia. \200 Neurological: CVA, sinus thrombosis. \200 Hematological: thr ombocytopenia ( 7 30%), haemolytic anemia. \200 Skin: livedo reticularis, cutaneous infar cts, ulceration. \200 Eyes: retinal vein thrombosis, amaurosis fugax. \200 Other: adren al infarction, avascular necrosis, Libmann \200\223 Sacks endocarditis. Catastrophic APS (CAPS) is a rare, fulminant form, with rapid multisystem involvement and o rgan infarction. Mortality is high. ANTIPHOSPHOLIPID SYNDROME (APS) 665 Renal involvement \200 Thrombotic microangiopathy ( b p. 574). \200 Renal artery thromb osis and ischaemic nephropathy ( b p. 586). \200 Hypertension (including accelerated phas e). \200 Proteinuria. \200 Increased risk of vascular thrombosis post-transplantation. \200 Increased risk of vascular access thrombosis in haemodialysis patients. Laboratory tests for antiphospholipid antibodies \200 Elevated levels of antibodies again st anionic membrane phospholipids or their associated plasma proteins. Persistence is important for diagnosis of APS \200\224 one or more of the following must t o be present on at least two occasions, at least 12 weeks apart: \200 IgG 9 IgM anticardi olipin antibody (IgG more commonly associated with thrombosis). Causes false positive syphilis serology. Anti- B 2GP-I. \200 Lupus anticoagulant ( (cid:2) strongest risk for thrombosis). The lupus anticoagulant (LA) is directed against various plasma coagula- tion molecules and results in prolongation of clotting assays, including APTT, kaolin clotting time, and dilu te Russell viper venom time (DRVVT). The presence of LA is con \201 rmed by mixing normal plasma with patient plasma. If there is a clotting factor de \201 ciency, mixing should co rrect the clotting time; when it does not, it suggests an inhibitor is present. Treatment Tailored according to presentation and prior history of thrombotic events. Asympt omatic individuals who are found to have antiphospholipid anti- bodies do not require speci \201 c treatment. However: \200 Prophylactic therapy: Modify other risk factors: smoking, i BP, i lipid. Avoid oral contraceptive. X Aspirin 75mg daily. Widely used in this context but bene \201 t unproven. Clopidogrel is an alternative if aspirin-intolerant. If SLE, consider hydroxychloroquine 200 \200\223 400mg daily. Thrombosis: Full anticoagulation with IV or SC heparin, followed by (lifelong) warfarin therapy (target INR 2.0 \200\223 3.0 for venous and 3.0 \200\223 4.0 for arterial thrombosis or recurren t thrombotic events). Consider warfarin plus aspirin if refractory. APS in pregnancy: Aspirin and LMWH prophylaxis for those with no previous history of thrombosis or prior fetal loss. Continue 6 \200\223 12 weeks post-partum. Full anticoagulation with LMWH for those with thrombosis history. CAPS: meticulous anticoagulation. Plasma exchange, corticosteroids, and IVIg may be of bene \201 t. Consider immune suppression (e.g. cyclophosphamide, esp. i f associated connective tissue disorder). CHAPTER 8 The kidney in systemic disease 666 Systemic sclerosis Introduction Systemic sclerosis (SSc) is a heterogeneous autoimmune conn ective tissue disorder characterized by in \202 ammation, \201 brosis, and vasomotor abn or- malities. It is 7 5 x more common in \231\200 , with peak age 30 \200\223 40. On the basis of clinical presentation, organ involvement, and outcomes, it is subclassi \201 ed as follows. Diffuse cutaneous systemic sclerosis Skin involvement is proximal to elbows and knees, and solid organ involve- ment is frequent. Characteristic autoantibodies: anti-Scl-70 and anti-RNP. More equal sex distribution. Limited cutaneous sy stemic sclerosis Skin involvement is more distal, and solid organ involvement is unusual. C REST syndrome is an example. Characteristic autoantibodies: anti-centromere. Pathophysiolog y Dysregulated collagen synthesis and degradation, associated with multi- ple immunological (e.g. anti-endothelial cell antibodies) and vascular (e.g. aberrant vasomotor control) irr egularities, leads to collagen accumula- tion and \201 brotic cutaneous and visceral dama ge. Many cell types (includ- ing endothelial, \201 broblasts, T and B cells, and macropha ges), as well as cytokines (particularly pro- \201 brotic IL-4, TGF- B , and PDGF), contri bute to progressive changes in the extracellular matrix and its constituents, includ- ing \201 bronectin, proteoglycans, and various forms of collagen. Clinical presentation Patchy skin oedema, with eventual \201 brosis and calcinosis, digital ulcera- tion, periorbital tethering and microstomia, nasal beaking and tapering of the \201 ngers (sclerodactyly), Raynaud \200\231 s phenomenon, facial and limb telangi- ectasia, non-erosive arthritis, m yalgia, oesophageal (and intestinal) dysmo- tility, pulmonary \201 brosis, and pulmonary hypertension. Renal involvement Clinical presentations: i BP and scleroderma renal crisis, CKD (relatively common \200\224 s to \201 brotic renal change), drug-related, e.g. NSAID s, sys- temic vasculitis (<2%), SSc + SLE overlap with lupus-type nephritis. SCr, eGFR, urinalysis ( 9 uPCR), and BP should be regularly monitored in patients with SSc (e.g. 3 \200\223 6 months). Patients should be encouraged to undertake home BP monitoring. Scleroderma renal crisis A syndrome of AKI and accelerated i BP in the context of SSc. It occurs in 5% of all SSc patients (15% diffuse disease; 1 \200\223 2% limited disease). It is the \201 rst presentation of SSc in 7 20%. Pathogenesis Remains poorly understood, but endothelial injury with intimal thickening of intrarenal arteries l d renal perfusion and hyperreninaemia. Subsequent changes (including epithelial to mesenchymal transdifferentiati on) within the glomeruli and tubulointerstitium promote renal injury. Endothelin-1 receptor dysregulation has also been observed. SYSTEMIC SCLEROSIS 667 Risk factors Recent onset of diffuse disease, active skin disease, steroid use, positive an ti-RNA polymerase. Clinical features and investigation \200 New-onset signi \201 cant i BP (e.g. >150/80mmHg) or BP that is signi \201 cantly higher than a patient \200\231 s ow n baseline. Can be asymptomatic, but accelerated BP with multisystem involvement may be pre sent ( b p. 518). Urinalysis, urine microscopy, and uPCR. Urinalysis is surprisingly bland but may reveal mild proteinuria 9 microscopic haematuria. i SCr, d Hb, d Plt, \201 lm (? fragments), i LDH, d haptoglobins (micro- angiopathic haemolytic anemia (MAHA) and thrombocytopenia in 7 50%). Autoantibodies: ANA ( 7 60% +ve in speckled pattern), anti-RNA polymerase antibodies. USS kidneys, ECG 9 echocardiogram (pericardial effusion in 7 5%). Renal histology May be ne cessary if the diagnosis is in doubt. Also yields important prog- nostic information. 2 BP must be controlled prior to biopsy ( b p. 80). Characteristic \201 ndings are \200\230 o nion skin \200\231 intimal proliferation and thicken- ing, \201 brin thombi, \201 brin oid necrosis, thrombotic microangiopathy, ischae- mic and collapsed glomeruli, variable deg rees of ATN. Management (see also Hypertensive emergency b p. 518) \200 Admit to a high d ependency environment. \200 Continuous cardiac monitoring, and consider invasive monitori ng, particularly invasive arterial BP monitoring. Meticulous \202 uid balance. Chart input and output. Catheterize. Patients have i vascula r resistance, so cautious \202 uid challenges, as appropriate. 2 Antihypertensive treatment. Aims: reduce SBP by 20mmHg and DBP by 10mmHg every 24h. (cid:2) Avoid d BP. ACE-I are the mainstay of therapy \200\224 they have been shown to signi \201 cantly reduce mortality (from 80% to 15%). Good BP control can prevent further renal deterioration and assist renal recovery. However, there is no evidence that ACE-I pre vent renal crises. \200 Captopril (12.5 \200\223 50mg PO tds) has a short half-life and is easy to titrate to BP. Switch to a longer-acting agent as soon as stable. \200 Add an ARB as second line. Additional agents, e.g. calcium channel blockers, may be required. 7 25% will require renal replacement therapy at presentation. \200 Unproven interventions include: epoprostenol infusion for 24 \200\223 48h ( l i renal perfusion), \201 sh oils ( b p. 547), and plasma exchange if severe TMA. Prognosis Progression to ESRD in 7 20 \200\223 50%. However, 7 50% will discontinue RRT wi thin 1 \200\223 2 years (transplantation should 6 rarely be considered during this period) . The degree of irreversible damage on renal biopsy may provide useful prognostic informati on to aid decision-making. Mortality remains signi \201 cant ( 7 30% at 3 years). Poor pro gnostic features include: permanent ESRD, older age (age >55), and low or normal BP at pres entation (pre- sumably a marker of signi \201 cant cardiac involvement). Recurrence is rar e, but compliance with treatment is crucial. CHAPTER 8 The kidney in systemic disease 668 Rheumatoid arthritis Introduction RA is a chronic multisystem autoimmune disorder of unknow n etiology, characterized by synovial hypertrophy, joint in \202 ammation, joint erosion, and many extra-articular manifestations. The annual incidence of RA is 7 3 cases per 10,000 population, with a prevalence of 7 1%. Incidence increases with age (peaking age 35 \200 \223 50), and the disease is more common in \231\200 . Renal conditions complicating RA \200 Drug toxicity (esp. NSAIDs). \200 Renal amyloidos is (AA amyloid). \200 Secondary membranous nephropathy (MN). \200 Other glomerular lesi ons. \200 Rheumatoid vasculitis. Drug toxicity \200 NSAIDs: see b p. 902. \200 Methotrexate (see b p. 899): now the most commonly prescribed disease-modifying anti-rheumatic drug (DMARD). Usually not nephrotoxic per se at the doses used for RA. However, it is primarily renally excreted, and the need f or dose adjustment is often underestimated. Best avoided if GFR <30mL/min. Gold (sodium aurothiomalate): now rarely used. Caused proteinuria in 7 10% and associated with membranous GN. Penicillamine: now rarely used; associated with membranous GN in 7 15%. Anti-TNF biological agents (e.g. etanercept): use has rapidly expanded. They appear safe, b ut case reports of an association with glomerular lesions and vasculitis have emerged. Renal amyloidosis ( b p. 628) Usually a long history of poorly controlled active RA, with j oint deformi- ties. Often seropositive (RhF +ve), with a grumbling acute phase response. Pr esentation is with proteinuria \200\224 often in the nephrotic range. Membranous GN Presents with proteinuria (less commonly, nephrotic syndrome) and his- torica lly associated with DMARDs, particularly gold and penicillamine. Usually occurred within 6 \200\223 12 months of commencement of therapy. Drug withdrawal usually leads to remission, but this may take up to a year. There are reports of MN in association with etanercept the rapy. Other glomerular lesions Mesangioproliferative GN is the most common renal lesion in RA pat ients who have undergone a renal biopsy ( 7 35%). An association with IgAN is also well rec ognized. These present with an active urinary sediment and (less commonly) renal impairment . A crescentic proliferative GN has been described in association with anti-TNF therapy. RHEUMATOID ARTHRITIS 669 Rheumatoid-associated vasculitis A small and medium vessel vasculitis, usually in RhF and a nti-CCP (cyclic citrullinated) antibody +ve patients with long-standing disease. Other risk factors include \231\202 sex and smoking. About 1 in 10 \231\202 and 1 in 40 \231\200 w ith RA developed vasculitis, although it is thought that this incidence is decreasing with improved treatment of severe RA. It is a severe mul- tisystem disorder, associated with a h igh mortality. Clinical presentation may be with cutaneous leucocytoclastic vasculitis, mon oneuritis multiplex, digital ischaemia, and ulceration, or with gut, cardiac, or cerebral v asculitis. Renal involvement manifests as an active urinalysis with a rising SCr. The renal lesion is a pauci-immune necrotizing GN ( b p. 643). Investigations include i CRP, i RhF, i anti-CCP antibodies. and d C3, d C4. 7 30% are p-ANCA-positive. Anti-TNF therapy has been successfully used for treatment, although it has also been implicated as a trigger in some cases (mechanisms unclear). Many clinicians treat as for ANCA-associated vasculitis ( b p. 644). Renal disease in other connective tissue disorders Renal disease is not uncommon, and monit oring of urinalysis, SCr, eGFR, and BP are an important consideration during follow-up. Sj gren s syndrome A multisystem autoimmune disorder that may be primary or arise in assoc iation with other connective tissue disorders, e.g. SLE, RA, or sys- temic sclerosis. Lymph ocytic in \201 ltration of exocrine glands, particularly the lacrimal and salivary glands, causes sicca symptoms, such as dry eyes and dry mouth. Anti-Ro and anti-La antibodies are typical. Renal involve- ment in 7 20%. Manifestations: \200 Distal (type 1) renal tubular acidosis ( b p. 824): May be partial or complete, with a tendency to nephrolithiasis. Impaired concentrating ability, with polyuria. \200 AKI s to acute interstitial nephritis ( b p. 580): Generally steroid-responsive. CKD (and ESRD) rare. Glomerular disease is uncommon. Mixed connective tissue disorder Associated with: \200 Membranous nephropathy ( b p. 564) and MCGN ( b p. 550). \200 Lupus nephritis or scleroderma renal crisis may develop. Polymyositis and dermatomyositis \200 Myositis and myoglobinuria may lead to false positi ve haematuria or, less commonly, AKI s to rhabdomyolysis ( b p. 152). Glomerular disease associations, e.g. mesangial proliferation, have been reported. CHAPTER 8 The kidney in systemic disease 670 Sarcoidosis Introduction A multisystem granulomatous disease of unknown cause, usually affe cting the respiratory system of young adults and characterized by non-caseating granulomas in involved organs. Renal disease complicates up to 40% of cases, although it is often subc linical. Pathogenesis Remains esoteric, although unidenti \201 ed antigen(s) appear to fue l dysregu- lated immune responses in susceptible individuals. Genetic predisposition is sug gested by i incidence in monozygotic twins, family aggregation, and race distribution ( i A frican Americans + Scandinavians). Many immune response genes have been incriminated (e.g. cytokine polymorphisms), with speci \201 c alleles associated with particular clinical phe notypes.