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. The culpable antigens remain anonymous, although several environmental and infectious preci pitants have been proposed. In particular, mycobacterial species (with mycobacterial DNA is olated from 7 25% of sarcoid specimens), propionibacteria, and viruses. Various environment al triggers have also been postulated. It is unclear how this exposure results in such vari ed abnormalities of the immune response. CD4+ Th cell activation and cytokine production (e sp. IFN- G , IL-2, IL-12, and TNF- A ) appear crucial (patients with sarcoidosis who acquir e HIV do not progress their granulomatous disease). T cells exhibit a restricted TCR repert oire, suggesting oligoclonal expansion in response to a speci \201 c antigen. In addition, paradoxical peripheral immune anergy is evident during active disease, e.g. reduced delaye d type hypersensitivity reactions. Histology Characteristic, irrespective of site: non-case ating epithelioid granulomas, comprising a central area of macrophages that differentiate i nto epithelioid cells before fusion into multinucleate giant cells. These are surrounded by CD4+ T cells, with CD8+ cells and B cells located peripherally. Unlike TB, necrosis is min imal. The nidus for granuloma formation may be partly pro- cessed antigenic material (e.g. microbial debris), and they are an attempt to \200\230 seal off \200\231 such material to limit tissue injury. Symptoms and signs \200 Protean: sarcoidosis is the great clinical mimic of the post-syphilis era. \200 Classically presents with \211 1 of the following four: bilateral hilar adenopathy, pulmonary in \201 ltrates, skin lesions, and ocular involvement. Other: General: lymphadenopathy, fevers, weight loss, malaise. \200 Chest: stage I \200\224 bil ateral hilar adenopathy; stage II \200\224 adenopathy and in \201 ltrates; stage III \200\224 interstitial disease with regressing adenopathy; stage IV \200\224 pulmonary \201 brosis. Eyes: uveitis, keratoconjunctivitis sicca, retinal vasculitis. \200 Skin: pigmentary chan ges, lupus pernio, erythema nodosum. \200 Cardiac: conduction defects, arrhythmias, cardi omyopathy. \200 Neuro: mononeuritis multiplex, aseptic meningitis, pituitary in \201 ltr ation ( l cranial DI); neurosarcoid may present as an MS-like illness. Liver: granulomatous hepatitis. \200 Kidney: see b p. 671. SARCOIDOSIS 671 Investigations Usually rests on combined clinical, imaging, and histological \201 ndings. 50% of cases are found incidentally on chest imaging. Serum ACE +ve in 7 75% cases and use ful for disease monitoring. Renal involvement Exact prevalence unknown. CKD occurs in 7 1% of patients. Calcium metabol ism \200 Common. Activated macrophages within granulomas express 1 A -hydroxylase and convert 25-(OH) vitamin D 3 to active 1,25-(OH) 2 vitamin D 3 (calcitr iol), particularly during sunny months (increased substrate availability). This leads to i gut Ca 2+ uptake and l : \200 Hypercalcaemia (10 \200\223 20%). More common in older pat ients (esp. \231\202 ). \200 Hypercalciuria ( 7 50%). \200 Calcium oxalate nephrolithi asis ( 7 15%). \200 Nephrocalcinosis (which is associated with CKD). Management: rehydrate. Steroids d macrophage calcitriol production. Consider d calcium (and oxalate) intake ( b p. 723). Avoid calcium and vitamin D supplements. Bisphosphonates inhi bit osteoclastic release of skeletal calcium. Ketoconazole inhibits the conversion of 25-(O H) vitamin D 3 to 1,25-(OH) 2 vitamin D 3 . Tubular dysfunction s to i Ca 2+ or granulomatous TIN. Defective concentrating ability with polyuria common. Other defects: RTA, Na + wasting, and Fanconi \200\231 s. Glomerular disease Uncommon. Various histological patterns described, including FSGS, membr anous, mesangioproliferative, MCGN, IgAN, and crescentic GN (all may be steroid-responsive) . Immunoglobulin and complement deposition is usual. Underlying mechanisms unknown but pres umably a consequence of altered immune responses. Obstruction 2 to retroperitoneal lymphadenopathy and \201 brosis (See b p. 738.) Granul omatous interstitial nephritis 7 20% sarcoid patients have renal granulomatous in \202 amm ation, although it is symptomatic in a minority only. More common in \231\202 . 7 50% have an abnormal CXR and 7 50% an elevated serum ACE. Concomitant i Ca 2+ may be present (and c ontribute to i SCr). Presentation is variable: asymp- tomatic i SCr, active disease in othe r organs, loin pain. Urinalysis is typi- cally bland, with proteinuria mild, if present. \200 Diagnosis: renal biopsy (see Histology). Ca 2+ deposition not uncommon. \200 Differ ential diagnosis: AIN of any cause, esp. drug hypersensitivity ( b p. 580), infection, TINU ( b p. 581) and Sj gren \200\231 s syndrome ( b p. 669). Management: rehydrate if i Ca 2+ . Prednisolone 20 \200\223 40mg daily: SCr and Ca 2+ may improve rapidly. Taper once SCr stabilized \200\224 generally slowly (over >1 year). Many clinicians maintain a long-term maintenance dose, at the lowest possible dose. Monitor SCr and Ca 2+ (serum and urine), but predicting relapse is dif \201 cult, so maintain high ind ex of suspicion. CHAPTER 8 The kidney in systemic disease 672 Fabry \200\231 s disease Introduction Fabry \200\231 s disease is a rare, multisystem, X- linked lysosomal storage disease, resulting from a de \201 ciency of the enzyme A -galacto sidase A ( A -Gal A). This results in the widespread lysosomal accumulation of the glycosph in- golipid substrates of A -Gal A, particularly globotriaosylceramide (GL-3). Progressive GL-3 accumulation in vascular endothelial lysosomes leads to extensive and progressive occlusive small vessel disease. Genetics The second most common lysosomal storage disorder (after Gaucher \200\231 s disea se), with a prevalence of 7 1 in 100,000. The gene for A -Gal A is located on the long arm of the X chromosome (Xq22). More than 500 A -Gal A mutations have been identi \201 ed. Many lead to little, if any, A -Gal A activity (classic Fabry \200\231 s disease), whilst others allow for residual enzym e activity (typically late-onset disease). The sons of affected \231\202 will not have the disease, whereas all their daughters will be heterozygotes. 50% of the sons of heterozygotes will then be affected (whilst 50% of the ir daughters will also be heterozygotes). Heterozygous \231\200 have a wide range of clini cal manifestations, from asymptomatic to severely affected (although symptoms tend to manif est later in life). Genetic counseling should be offered. Clinical features Often begin in childhood and adolescence. \200 Skin: petechial-like ang iokeratomas (appear as clusters of small red spots; classically umbilical, swimsuit region, and on extremities). Histologically, these are small, dilated veins of the upper dermis, c overed by hyperkeratotic epidermis. Cardiac: occlusive coronary disease, conduction abnormalities, valvular disease, LVH. Lower extremity oedema (lymphatic glycosphingolipid accumulation). Neurological: painful acroparaesthesias (tingling, numbness, and stiffness of distal extremities \200\224 particularly during a febrile illness), neuropath ic pain, autonomic dysfunction, hyperhidrosis, TIAs, stroke, vertebrobasilar insuf \201 ci ency (ataxia, memory loss), tinnitus, hearing loss, depression. Ocular: corneal opacities (called verticillata) and dystrophy (visible on slit lamp examination). Pulmonary: cough, obstructive airways disease. \200 Renal involvement: glomerular damage with proteinuria 9 microscopic haematuria. Progressive CKD and ESRD (typically age 7 30 \200\223 50). Renal abnormalities may be milder in heterozygote \231\200 , e.g. isosthenur ia, asymptomatic proteinuria \200\224 however, 10% will progress to ESRD. FABRY \200\231S DISEASE 673 The underdiagnosed \200\230 renal variant \200\231 There is evidence that Fabry \200\231 s disease is an underestimated cause of pro- gressive CKD and ESRD. Measurement of A -Gal A activity in \231\202 dialysis patients suggests 0.2 \200\223 1.0% have unrecognized dis ease. The majority of these patients do not exhibit current or historical \200\230 hallmark \200\231 Fabry \200\231 s symptoms, esp. angiokeratomas, acroparaesthesias, or corneal opa cities, which might have drawn attention to the diagnosis sooner. Many other features of cl assical disease remain absent, although cardiac involvement can often be found on closer sc rutiny. Theses individuals tended to have residual A -Gal A activity and 6 to have developed clinically overt disease later in life. Renal histology As well as in vascular endothelium, glycosphingolipid accumulation occurs i n podocytes, mesangial cells, and, to a lesser extent, tubular cells (lipid-laden distal tu bular cells are shed and can be seen on urine micros- copy). In later-onset variants, podoc ytes are more dominantly affected than other cell types. On microscopy, foamy inclusions may be seen in most cell types. Arteriolar sclerosis, glome rular atrophy and sclerosis, and tubulointersti- tial \201 brosis are common. Electron mi croscopy reveals characteristic lyso- somal lamellar cytoplasmic (termed myelin or zebra bo dies). Investigation \200 Slit lamp examination. \200 Lipid-laden epithelial cells on urine mi croscopy. \200 Reduced or absent plasma A -Gal A activity. \200 Elevated serum GL-3 lev el. \200 A -Gal A mutation analysis in equivocal cases. Treatment Enzyme replacement therapy (ERT) with recombinant A -Gal A has trans- formed mana gement. Two preparations are available: agalsidase alfa (Replagel ) and beta (Fabrazyme ). Usually delivered as an IV infusion at 2-weekly intervals. (cid:2) Extremely expensiv e. Infusion reactions are not uncommon. Neutralizing antibodies develop to the recombinant enzyme but do not usually appear to decrease ef \201 cacy. Treatment demonstrably stabilizes and slows progression of disease, with clearance of accum ulated GL-3 from capillary endothelial cells in kid- ney, skin, and heart. Progression of C KD is slowed. Initiate ERT at the time of diagnosis in adult \231\202 patients. Timing will depend on cl inical symptoms and evidence of organ involvement in heterozygote \231\200 . ERT should be continued in ESRD patients for its non-renal bene \201 ts. Transplantation i s feasible, as recurrent disease is also ameliorated by therapy. CHAPTER 8 The kidney in systemic disease 674 HIV and renal disease Introduction Almost 40 million people worldwide are infected with HIV -1, and 7 30% of patients with HIV infection have a degree of renal dysfunction. As a resul t, HIV-associated kidney disease has emerged as a relatively common cause of ESRD and HIV-a ssociated mortality. HIV is associated with almost every described renal lesion (as well as many electrolyte and acid \200\223 base disorders), either as a direct consequence of infection or as a result of the nephrotoxic pro \201 le of highly active antiret- roviral therapy (HAART) medicati ons (see Table 8.8). HIV-related renal lesions can be classi \201 ed according to histopat hological \201 ndings. The most frequent are: classic HIV-associated nephropathy (HIVAN), HIV immune complex kidney disease (HIVICK), and HIV-associated thrombotic micro- angiopath y (HIV-TMA). However, many more glomerular lesions can occur that sit outside this framewor k. In addition, patients may develop glomerular disease related to concomitant HCV or HBV i nfection. 2 Patients with HIV infection are also more vulnerable to episodes of AKI (which has a high er mortality risk than non-HIV-associated AKI) as well as HIV-associated malignant lesions of the kidneys. Epidemiology Historically, HIVAN was the most common lesion associated with HIV infection i n the developed world. However, the incidence has decreased with HAART. The true prevalence of HIVAN is unknown, as many patients do not undergo a renal biopsy. In one series, HIVAN was seen in 40 \200\223 60% of biopsies. In another, the following lesions were found: HIV AN 27%; HIVICK 21%; membranous GN 13% ( 9 hep B); post-infectious dif- fuse proliferative G N 8%; mesangial hyperplasia (pure mesangial changes, immunostaining negative) 6%; IgAN 5%; others \200\224 malignant i BP, TMA, TIN, ATN, diabetic nephropathy, hep C-associated MCGN . The incidence of renal associated neoplasms is 7 4 \200\223 8% in patients with AIDS. Neop lastic processes include lymphomas and Kaposi \200\231 s sarcomas and usually occur as par t of widespread disease. HIV AND RENAL DISEASE 675 Table 8.8 Causes of renal failure in HIV AKI Sepsis Rhabdomyolysis Drug toxicity: Rifampicin Co-trimoxazole Aminoglycosides Acute glomerulonephritis Pyelonephritis Renal TB HIVAN ( 9 H IVICK) with: ATN Acute on chronic Drug nephrotoxicity Granulomatous disease Malignant i BP Lymphoma CKD HIVAN Other GN: Membranous MCGN IgAN Mesangioproliferative Idiopathic FSGS Hypertensive nephrosclerosis Diabetic nephropathy Adapted from Swanepoel, C, Am J Kidney Dis , 2012; 60 (4):668 \200\223678. CHAPTER 8 The kidney in systemic disease 676 HIV and renal disease: HIVAN Introduction As HIV infection has burgeoned globaly, HIVAN has become a signi \201 - cant cause of CKD and ESRD. It is almost exclusive to black adults. The University of Cape Town has developed a HIVAN classi \201 cation to enable standardiz ation of terminology (see Table 8.9). Prognostic indicators and outcomes have been evaluate d using this classi \201 cation. Pathogenesis Transgenic mouse models suggest that expression of HIV genes alone is not suf \201 cient to cause HIVAN. Genetic factors ( MYH9 , ApolL1 genes \200\224 two variants in the ApoL1 gene have been identi \201 ed as the susceptibil- ity alleles responsible for m ost of the increased risk in black patients), unknown environmental factors, and host facto rs (e.g. RAAS activation) are also important. Viral proteins, such as Nef, induce podocyte dysfunc- tion \200\224 characterized by increased proliferation, apoptosis, and dedifferen - tiation. Others, including Vpr, induce apoptosis of renal tubular epithelial cells. As re nal cells do not express classical CD4 HIV-1 receptors, it is unclear how virus enters the cells, although direct cell \200\223 cell transmission appears important for infection of renal tubular epithelial cells. Histopathology HIVAN is characterized by the so-called collapsing variant of FSGS (the capi llary tuft literally crumples), with microcystic tubular dilatation, tubular atrophy, inter stitial in \201 ltrates (often CD8+ cells), interstitial oedema, and \201 brosis. Immuno staining is non-speci \201 c. EM often reveals endothelial cell tubuloreticular inclusions and nuclear bodies. 2 These \201 ndings should prompt serological testing for HIV. Symptoms and signs Proteinuria \200\224 often with the nephrotic syndrome clinically. Rena l impair- ment (usually superadded ATN). BP is characteristically normal ( 7 80%), perhaps s to relative vasodilatation and renal salt loss. Oedema may be less marked than in other c ause of the nephrotic syndrome, a phenom- enon that is unexplained. Investigations \200 Urine microscopy \200\224 may show broad, waxy casts. \200 uPCR \200\224 proteinuria often heavy. \200 i SCr, U&E (SIADH), d albumin. \200 CD4+ T cell count: Usually <200 cells/ L (but HIVAN has been reported in patients with higher counts). Renal prognosis is worse in patients with AIDS, especially if their CD4 count <50 cells/ L. HIV viral load: typically high (>400 copies/mL). \200 Hepatitis B and C serology. \200 USS \200\224 often shows normal or large echogenic kidneys. \200 Renal biopsy: owing to diversity of potential lesions, biopsy is recommended in virtually all cases. HIV AND RENAL DISEASE: HIVAN 677 Table 8.9 The University of Cape Town classi \201 cation of HIVAN Glomerulus Glomerular variants of HIVAN \210\222 FSGS collapsing variant \210\222 FSGS non-collapsin g variant with additional features \210\222 Global sclerosis with epithelial cell involvem ent ( \200\230 fetal \200\231 variant) Additional features to glomerular variants of HIVAN: \210\222 Parietal 9 visceral epitheli al cell hypertrophy and hyperplasia \210\222 Presence of pseudocrescents Fibrosis Interstitium Lymphocytic in \201 ltrate Plasma cells within the lymphocytic in \201 ltrate Diffuse in \202 ammatory lymphocytic syndrome Tubules Presence of microcysts Epithelial cell hyperplasia and hypertrophy HIV and immune complex GN With additional features of HIVAN (as described above): \210\222 MCGN \210\222 Ball in cup: very large subepithelial immune deposits \210\222 Any other GN Without additional features of HIVAN (immune complex alone) Others Diseases unrelated to HIV, e.g. granulomas, ATN, drug reactions, lymphoma Adapted from Swanepoel, C, Am J Kidney Dis , 2012; 60 (4):668 \200\223 678. Management of HIVAN HAART, a three-drug regimen of two reverse transcriptase inhibitors plu s a protease inhibitor, has completely transformed the outlook for HIV-infected individuals . A diagnosis of HIVAN is considered as an indica- tion for HAART, regardless of CD4 count. Continuous therapy is impor- tant to gain maximal bene \201 t: there is a high incidence of ESRD in patients whose treatment is interrupted through poor compliance. HAART exerts the following effects on HIVAN: Reduced proteinuria \200\224 with full or partial remission of nephrotic syndrome. Delayed progression of renal impairment. \200 Potential renal recovery and dialysis indep endence ACE-I/ARBs should be prescribed, as for any proteinuric renal disease (note: avoid calcium channel blockers if on protease inhibitors). Prednisolone has been used with some success, particularly when prominent interstitial in \202 ammation and i SCr, but there is an absence of well-controlled trials. Ciclosporin has been studied in children. CHAPTER 8 The kidney in systemic disease 678 HIV and renal disease: other lesions HIVICK Immune complex-related lesions are gathered und er the term HIVICK. These resemble IgA nephropathy and diffuse proliferative glomerulone- p hritis (lupus-like). Pathogenesis As the immune complexes are generated by an HIV-induced immune response, an ac tive viraemia is required. It is not clear why some patients develop HIVICK and some patien ts develop HIVAN, but both appear to be the consequence of a dysregulated immune response t o HIV infection. In IgA type, IgA and viral antigen complexes deposit in the kidney. Histopathology Mesangial change with mild/moderate hyperplasia and immune deposits. Large s ubepithelial deposits are seen with a \200\230 ball-in-cup \200\231 appearance. The diffu se proliferative GN (described as \200\230 lupus-like \200\231 ) has IgG, IgM, C3, and C1 q immune deposits. Symptoms and signs Presentation can vary, although haematuria and low-grade proteinuria are most common. Rapidly progressive glomerulonephritis and nephrotic syn- drome are also reco gnized. Unlike HIVAN, the vast majority of patients are Caucasian or Hispanic, although aff ected Asians and black patients are described. Investigations Investigations, such as ANA and ANCA, must be interpreted with caution becau se false positives are more common in HIV-infected patients. Management Whilst HAART is established as the main treatment for HIVAN, it is unclear if ot her types of HIV-related kidney disease derive as much bene \201 t from its use. The Strat egic Timing of Antiretroviral Treatment (START) study is an ongoing trial investigating the impact of early HAART therapy on AIDS and non-AIDS conditions, including CKD, and should h elp to answer this question in the near future. HIV-associated thrombotic microangiopathy HIV-TMA is associated with more advanced HIV dise ase and AIDS. It is another example of a renal lesion that has declined in incidence in the HAART era (<1% of HIV-infected patients). The pathogenesis of HIV-associated TMA is poorly understood. ADAMTS-13 levels are generally not decreased, suggesting an uncon- ventional mechanism for TMA in this group ( b p. 576). However, with adequate treatment, it generally carries a better prognosis than idiopathic TMA. Suspect if AKI, thrombocytopenia, and evidence of microangiopathic haemolytic anemia. De \201 nitive diagnosis requires a renal biopsy. Patients with a high viral load (VL) require longer PEX therapy, compared to patients with a lower VL. HIV AND RENAL DISEASE: OTHER LESIONS 679 HAART-related renal side effects There has been a de \201 nite reduction in the incidence of HIVAN since the introduction of HAART medications; however, signi \201 cant evidence of nephrotoxicity associated with HAART has emerged. Common problems include: Protease inhibitors: Examples: indinavir, nel \201 navir, ritonavir. \200 Problems: crystalluria (may cause m icrotubular obstruction and ATN or lead to nephrolithiasis), interstitial nephritis. Nucleotide reverse transcriptase inhibitors: Examples: zidovudine, didanosine, adefovir, tenofovir. \200 Problems: proximal tubular ce ll injury ( l Fanconi-like syndrome), lactic acidosis (often severe \200\224 probably the consequence of mitochondrial DNA damag e), AKI (ATN). Also associated with CKD (itself the consequence of interstitial \201 bros is). ESRD in patients with HIV infection In the USA and elsewhere, HIV-associated ESRD is an epi demic among black patients. The risk of ESRD in black HIV-infected individuals is 7 3 \200 \223 6 x higher than in Caucasian HIV-infected patients. Concomitant IVDU and HCV infection are important additional risk factors for ESRD. Despite the successes of HAART, longer ove rall survival in both black and Caucasian patients with HIV-associated CKD has meant that t he prevalence of ESRD is still increasing \200\224 and remains associated with poorer surv ival (although this is improving). Dialysis Survival on either HD or CAPD appears comparable. HIV-infected patients undergoing haemodialysis do not require isolation. Transplantation Transplanting patients with HIV infection is a challenge in terms of infec- tion rates, rejection rates, and attaining therapeutic and non-toxic levels of immunosuppr ession. However, in appropriate cases, it is thought to improve survival in comparison to d ialysis. Patient selection is crucial. Criteria: stable disease and antiviral regi- men, compliant w ith medication, undetectable viral load, and preserved CD4 counts >200 cells/ L). In add ition, drug interactions and toxicities are a major challenge. The largest series of HIV kidney transplantations was published in 2010, with 150 performed over a 6-year period (including both live-related and deceased donor). Regimens were tacro limus- or ciclosporin-based, and some patients had ATG induction; 3 years \200\231 follow- up. Rejection rates were high \200\224 31% at year 1, 41% at year 3. Graft survival was wo rse in comparison to the non-HIV transplant population, and increased numbers of neoplasms were seen. CHAPTER 8 The kidney in systemic disease 680 Hepatitis B Introduction Approximately 1/3 of the world \200\231 s population have been in fected with HBV, and 7 350 million are chronic carriers. The majority of these are in the d eveloping world, especially Africa and South East Asia where perina- tal transmission is th e dominant route of infection. The prevalence in the USA and Western Europe is 7 0.1 \200 \223 0.5% (placing them in the lowest WHO category), although this will vary considerably b etween particular commu- nities. In the USA, it is estimated that there are 7 1.3 million c arriers (some estimates are much higher). The majority of these infections are acquired as adults, principally via sexual activity or IVDU. Although acute HBV infec- tion rates have fallen ( l d IVDU, needle exchanges, behavioral change in the HIV era, vaccination of the a t-risk), the frequency of chronic infection is actually increasing because of migration fro m areas of high prevalence. The virus The HBV genome comprises partially double-stranded ci rcular DNA linked to a DNA polymerase and surrounded by nucleocapsid and lipid envelopes. E mbedded within these outer layers are the numerous antigens familiar from serological ident i \201 cation of the disease. The illness In adults, an acute seroconversion illness follo ws 1 \200\223 6 months after expo- sure. This ranges from asymptomatic (usual), through a non-speci \201 c viral illness, to a more severe illness with frank jaundice. Most adults develop immunity and clear the virus. The remainder become chronic carri- ers. Patients may alternate between active disease, where the immune responses cause liver in \202 ammation , and an inactive carrier state. Carriers are at risk of hepatic (chronic hepatitis, cirrho sis, and hepatocellular car- cinoma) and extra-hepatic (e.g. GN, vasculitis, and reactive a rthritis) com- plications. If HBV is acquired in childhood, chronic carriage is the norm ( 7 90%). This falls to 7 5 \200\223 10% in adults (higher in the elderly). HBV serology explained \200 The diagnosis and monitoring of HBV is based on the collectiv e interpretation of several serologic markers (+ HBV DNA + liver enzymes) (see Table 8.10). HBsAg may appear \211 1 week post-exposure but usually \211 4 \200\223 6 weeks. \200 HBsAg positivity indicates that an individual is infected ( (cid:2) and 6 potentially infectious). HBsAg persistence (>6 months) separates acute infection from chronic \200\230 carrier \200\231 status. Quantitative HBsAg testing is available, with lower levels associated with better host immu ne HBV control. Its utility for monitoring of therapy (esp. nucleoside/nucleotide analogs) is increasing. The immune response to HBsAg produces anti-HBs (as does vaccination). This usually persists inde \201 nitely. The \201 rst antibody identi \201 ed is actually anti-HBc. IgM anti-HBc indicates acute infection \200\224 and it may be the evidence of HBV acutely, before HBsAg and anti-HBs ap pear. Subsequent IgG anti-HBc persists inde \201 nitely (signifying either historical or o ngoing infection). HEPATITIS B 681 HBeAg is a marker of viral replication ( (cid:2) and 6 infectivity). Although HBeAg is often present acutely (suggesting i infectivity), that is not its main clinical utility. HBV within liver cells may be in a replicating (i.e. virus-producing) and non-replicating ( host DNA-integrated) form. As HBeAg is produced only during viral replication, it is an ext remely useful marker of viral activity during surveillance of chronic HBV carriers. HBeAg disappearance and appearance of anti-HBe is termed seroconversion. This may occur during acute HBV or years later in chronic carriers. Serocon version is good news \200\224 associated with d HBV replication, HBV clearance, clinical i mprovement, and favorable response to treatment. 2 General rule: +ve HBeAg = infectivity; +ve anti-HBs = immunity. \200 HBV DNA estimates viral burden and viral replication. It can be quantitatively measured via sensitive PCR assays. \200 HBV DNA helps: (i) to determine re covery from acute infection; (ii) to distinguish inactive carriers from those with active d isease; and (iii) to assess the appropriateness of antiviral therapy. Table 8.10 Interpretation of HBV serology Serology Status Implication HBsAg Anti-HBc Anti-HBs Negative Negative Negative Susceptible HBsAg Anti-HBc Anti-HBs Negative Positive Positive Immune due to natural infection HBsAg Anti-HBc Anti-HBs Negative Negative Positive Immune due to HBV vaccination HBsAg Anti-HBc IgM anti-HBc Anti-HBs Positive Positive Positive Negative Acutely infected HBsAg Anti-HBc IgM anti-HBc Anti-HBs Positive Positive Negative Negative Chronically infected HBsAg Anti-HBc Anti-HBs Negative Positive Negative Interpretation unclear; four possibilities 1. Resolved infection (most common) 2. False pos itive anti-HBc, 6 susceptible 3. \200\230 Low level \200\231 chronic infection 4. Resolvi ng acute infection Adapted, with permission, from the CDC. See M www.cdc.gov/hepatitis/HBV/PDFs/SerologicChart v8.pdf . CHAPTER 8 The kidney in systemic disease 682 HBV-related renal disease Introduction Three common nephropathies are described: membranous GN, MCGN, and polyarteritis nodosa (PAN). An association between HBV and IgAN has also bee n reported but may be coincidental, as IgAN is common in many populations. Minimal change, FSGS, and amyloid are also described. Pathogenesis Direct HBV renal tissue invasion does not occur (unlike HIV). Instead, viral a nd host factors (including genetic predisposition) play a role in glomeru- lar immune compl ex deposition. These complexes comprise viral anti- gens and host antibodies, either formin g in situ in the kidney or becoming trapped after circulation. The location of the immune d eposit depends on its size, which, in turn, depends on the involved antigen. Investigations Full HBV serology and HBV DNA PCR ( b p. 680). HCV and HIV serol- ogy. U&E, SCr, LFT. uPCR or uACR. FBC, INR. Full immunological screen may be required ( b p. 40). USS liver and kidneys. Renal biopsy. Membranous glomerulonephritis (MN) HBeAg \200\223 antibo dy immune complexes are small enough to pass through the capillary basement membrane and de posit in the subepithelial space and cause MN. The clinical course of HBV-associated MN dif fers between children and adults. MN is common in children aged 2 \200\223 12 years ( \231\202 > \231\200 ), presenting with proteinuria. Usually HBeAg +ve. Tends to remit spon tane- ously with seroconversion (i.e. clearance of HBeAg and development of anti-HBe). Prot einuria may persist for >1 year. Adults often present with a more chronic nephrotic syndrom e and progressive CKD in association with liver disease. >50% will reach ESRD in 3 years. Mesangiocapillary glomerulonephritis (MCGN) Immune complexes involving HBsAg are too large to traverse the base- ment membrane so settle in the subendothelial space. MCGN is more com mon in adults (>MN in that age group), presenting with i BP, heavy proteinuria, microhaemat uria, and progressive CKD (i.e. a more nephritic presentation than MN). Histology is simila r to type I MCGN ( b p. 550), with a \200\230 streetcar track \200\231 pattern \200\224 some normal capillary loops with thin BM, oth- ers with split BM. Unlike MCGN with HCV, cry oglobulins are not present. Polyarteritis nodosa (PAN) Occurs within 4 months of HBV infection in adults, presenting as a medium-vessel vasculitis attributed to immune complex deposition ( b p. 652). ANCA \200 \223 ve. Relapse rare \200\224 never once viral replication has stopped/seroconversion has occurred. Incidence appears to be falling along with the incidence of acute HBV. IgAN The liver metabolizes IgA, so serum IgA levels increase in hepatic disease of any caus e, potentially ending up secondarily deposited within the renal mesangium and capillary loo ps. Clinically signi \201 cant disease is rare. HBV-RELATED RENAL DISEASE 683 Treatment of HBV-associated disease in adults Cessation of immune complex formation require s treatment of HBV. Remission should follow seroconversion from HBeAg to anti-HBe and a red uction in, or disappearance of, HBV DNA. Long-term nucleoside analogs are often used for th is purpose (see below). Response rates are higher in MN than MCGN. Standard treatment of pr oteinuric disease with ACE-I/ARB to achieve BP <130/80mmHg and reduce urinary protein excre tion also applies. Immunosuppression should be avoided ( l i viral replication 9 hepatic de compensation \200\224 may occur on treatment with- drawal). PAN is a possible exception wh ere severity of disease may neces- sitate steroid and cytotoxic therapy, with concomitant a ntivirals.