Nine plasmapheresis treatments (removal of 1.5 plasma volumes with 4.5% albumin as replacem ent \202 uid): daily for 3 days then three times a week for 2 weeks. This page intentionally left blank J. BARRATT 100 Immunoglobulin A nephropathy and Henoch \200\223Sch nlein purpura Immunoglobulin A nephropathy (IgAN) is the common- est pattern of glomerulonephritis seen i n the Western world. It is an important cause of progressive kidney disease with 25 \200 \22330% of patients developing ESRD within 25 years of diagnosis. The diagnosis of IgAN alw ays requires a renal biopsy. Closely associated with IgAN is Henoch \200\223Sch nlein purp ura (HSP), a small vessel systemic vasculitis charac- terized by small blood vessel deposit ion of IgA predom- inantly within the skin, joints, gut and kidney. The nephritis of HSP is also characterized by mesangial IgA deposi- tion and may be histologically indistinguishab le from IgAN. It is generally accepted that: \200 <10% have complete resolution of urinary abnormalitie s; \200 episodes of macroscopic hematuria become less fre- quent with time after diagnosi s although the majority of patients will have persistent microscopic hematuria; 1.5% will reach ESRD per year; \200 25 \200\22330% will require renal replacement therapy within 20 \200\22325 years; Recurrence after renal transplantation: \200 This is assuming increasing importance as a cause of graft failure as control of rejection improves. It is typically slowly progressive although occasional patients will have a rapidly progressive course. At 5 years a 5% risk of graft failure due to recurrence, a 13% risk of signi \201 cant gra ft dysfunction, and a risk of IgA deposition of \211 50%. IgA nephropathy IgAN is de \201 ned by the predominant deposition of polymeric IgA1 in the glomerular mesangium. The risk of graft loss increases to 25% if \201 rst graft was lost to recurrence. Epidemiology There is a male predominance. Peak incidence is in the 2nd and 3rd decades. Th ere is wide geographic variation in the incidence, the highest being reported in the Paci \201 c rim (this may re \202 ect differing approaches to renal biopsy for minor urine abno rmalities). Prevalence of subclinical (asymptomatic and undiagnosed) IgAN may be as high as 16% of the general population. There is no consistent evidence that these risks differ between living and cadaveric donors. There is no evidence that the immunosuppressive regi- men alters the incidence of IgAN recu rrence or the prognosis of recurrence in the short term. Clinical features Symptoms 30 \200\22340% of patients present with macroscopic hematuria 12 \200\22372 h after the development of a mucosal infection (most commonly upper respiratory tract). 30 \200\22340% of patients are asymptomatic and are identi \201 ed following inci dental urine testing with microscopic hema- turia and/or proteinuria. 5% of patients develo p nephrotic syndrome. <5% of patients present with AKI. <5% of patients present with malign ant hypertension. Remaining patients are identi \201 ed following investigation of hyperte nsion, usually associated with microscopic hematu- ria and or proteinuria. Etiology <10% of cases have familial IgA nephropathy. \200 Genome-wide linkage analysis has demonstrated linkage of IgAN to 6q22 \200\22323 and the pu tative gene locus IGAN1. There are no obvious candidate genes within the linked interval. I t is not certain that genetic \201 ndings from these families will have direct bearing on more typical sporadic cases of IgAN. >90% of cases are sporadic and the etiology is unknown. \200 No evidence for involvement of a speci \201 c infectious agent despite association of macr oscopic hematuria with mucosal in \202 ammation. No evidence for hypersensitivity to food antigens in the majority of cases with exception of a small group of patients with celiac d isease. Abnormal O-glycosylation of IgA1 hinge region thought to promote formation of circu lating IgA immune com- plexes with propensity for mesangial deposition and mesangial cell a ctivation. Signs There are no speci \201 c physical signs diagnostic of IgAN. Occasionally patients m ay exhibit loin pain (unilateral or bilateral). The relationship of loin pain to active glo meru- lonephritis is ill-understood. Differential diagnosis The diagnosis of IgAN requires a renal biopsy. Primary IgAN must be distinguished from other secondary forms of IgAN associated with: \200 Chronic liver dise ase, particularly alcoholic cirrhosis (thought to be due to impaired IgA immune complex cle arance by the liver). Natural history The perceived overall cohort risk is heavily in \202 uenced by different d iagnostic approaches. Centers with a low threshold for renal biopsy for patients with mild urine abnormality, particularly those working in countries where urine screening programs a re established, will likely diagnose IgAN in a larger number of patients with mild disease and good prognosis, thus favorably influencing the overall outcome of the cohort. HIV and AIDS (associated with high serum IgA level). \200 Celiac disease (in a small prop ortion of patients adher- ence to a gluten-free diet can lead to reduced proteinu- ria and improvement of renal function). Henoch \200\223Sch nlein purpura (a small vessel vasculitis with renal biopsy appearances indistinguishable from IgA nephropathy). CHAPTER 3.5 Immunoglobulin A nephrophy and Henoch \200\223Sch nlein 101 Mesangial deposition of IgA, along with other immunoglob- ulin classes and complement may a lso be a feature of lupus nephritis but the clinical and serologic features usually present no diagnostic dif \201 culty. There have also been a number of reports of an IgA-domi- na nt post-infectious glomerulonephritis associated with methicillin-sensitive and -resistant Staphylococcus aureus infection. This disease is marked by severe glomerular changes on ren al biopsy, nephrotic range proteinuria and rapid decline in renal function with many patien ts develop- ing irreversible ESRD. Crescents are common in biopsies performed during epi- sodes of macroscopic hematuria with renal impairment. Tubulointerstitial changes do not differ from those seen in other forms o f progressive glomerulonephritis. Immunohistology IgA is the sole immunoglobulin in 15% of biopsies (Fig. 3.5.2). IgG is present in 50 \200\22370% and IgM in 31 \200\22366% of biopsi es although staining is usually less intense than IgA. Codeposition of IgG and IgM is unrel ated to the extent of glomerular injury or clinical outcome. C3 deposition is usual and has the same distribution as IgA. The pathological signi \201 cance is uncertain. IgA deposit s may extend beyond the mesangium to the periphery of the glomerular capillaries and this h as been associated with a worse prognosis. Electron microscopy Mesangial and paramesangial electron-dense deposits are the ultrastructural manifestation of mesangial IgA deposition ( Fig. 3.5.3). Capillary loop deposits are usually subendothelial but can be intramembranous or subepithelial and are associ- ated with a worse clinical outcome in adults. The quantity , size, shape and density of deposits vary from glomerulus to glomerulus and from one mesan gial zone to another. The glomerular basement membrane (GBM) shows localized abnormalities in 15 \200\22340% cases. GBM abnor- malities are associated with heavy proteinuria, more se vere glomerular changes and crescent formation. A proportion of patients have diffuse unifo rm global thinning of the GBM indistinguishable from thin mem- brane nephropathy. It is not clear whether this group of patients has any de \201 ning clinical or prognostic characte r- istics compared with most IgAN. Investigations General investigations Assessment of renal function, urinary protein leak an d renal size are mandatory for the investigation of suspected glomerulonephritis. Raised se rum IgA1 levels are found in 30 \200\22350% of all patients, but are less common in childre n and do not cor- relate with disease activity or severity. A high proportion of light c hain, rather than the normal predominance of the isotype, is also a distinctive feature of serum IgA in IgAN although the signi \201 cance of this is unknown. Complement componen ts C3 and C4, and CH50 in the serum are usually normal but there is some evidence of system ic complement activation with more specific testing. Circulating autoantibodies, IgA-rheuma toid factors and IgA-containing immune complexes have been reported in IgAN but none appear to be disease speci \201 c. Laboratory checks for liver function and hepatitis B status a re suf \201 cient to exclude the common causes of secondary IgAN. Special investigations The diagnosis of IgAN requires a renal biopsy. No accumulation of cl inical and laboratory evidence has suf \201 cient speci \201 city and sensitivity to avoi d the need for diagnostic biopsy. There has been a single report suggesting measurement of IgA1 O-glycosylation may in the future be used to diagnose IgAN but this remains speculativ e at present. A number of classi \201 cations of IgAN based on light micro- scopic findings are in use ( for example those of Lee and Haas), but there is little agreement about their rela- tive ut ility. The International IgA Nephropathy Network with the Renal Pathology Society are prese ntly develop- ing an international consensus on a pathological classi \201 - cation for Ig AN which is expected to be published in 2009. Renal biopsy features Mesangial IgA deposits are the de \201 ning hallmark of IgAN and can be identi \201 ed by immuno \202 uorescence or immu- noperoxidase techniques. IgA deposi ts are diffuse and global even if light microscopic changes are focal and segmental. Heavy mesangial IgA deposition may be seen with no light microscopic change. \200 Light microsc opy Risk strati \201 cation Many studies have identi \201 ed features at presentation which m ark a poor prognosis (Table 3.5.1). Although prognostic formulas using simple clinical and laboratory data have been proposed there is not yet suf \201 - cient consensus to recommen d them in clinical practice for the prediction of individual progression risk. Treatment General measures As with all causes of CKD, patients with IgAN and CKD 3, 4 and 5 must pay close attention to cardiovascular risk and: \200 \200 \200 Light microscopic abnormalities may be minimal, but the commonest appearance is mesangial h ypercellularity which is usually diffuse and global (Fig. 3.5.1). Progressive disease is as sociated with relentless accumu- lation of mesangial matrix. Crescentic change may be super imposed on diffuse mesangial proliferative glomerulonephritis with or with- out associated segmental necrosis. stop smoking; eat a healthy and balanced diet; take regular exercise. J. BARRATT 102 Table 3.5.1 Prognostic markers at presentation in IgA nephropathy Clinical Histopathologic Poor prognosis Poor prognosis Light microscopy Increasing age Capsular adhesions and crescents Duration of preceding symptoms Glomerular sclerosis Severity of proteinuria Tubule atrophy Hypertension Interstitial \201 brosis Renal impairment Vascular wall thickening Increased body mass index Immuno \202 uorescence Capillary-loop IgA deposits Ultrastructure Capillary wall electron-dense deposits Mesangiolysis GBM abnormalities Good prognosis Good prognosis Recurrent macroscopic hematuria Minimal light microscopic abnormalities No impact on prognosis No impact on prognosis Gender Intensity of IgA deposits Ethnicity Codeposition of mesangial IgG, IgM or C3 Serum IgA level Recurrent macroscopic hematuria No speci \201 c treatment required. No role for prophylact ic antibiotics. No role for tonsillectomy. Follow-up Patients with CKD 1 \200\2233 can be followed up in primary care (see algorithm i n Appendix). Patients with progressive renal decline and CKD 4 and 5 require continued neph ro- logical review on a 2 \200\2236-monthly basis dependent upon their eGFR. Microscopic hematuria and <1 g/24 h proteinuria No speci \201 c treatment required. Consid er ACEI and/or ARB. Pregnancy As with other chronic glomerulonephritides, pregnancy- related complications in I gAN are increased when there is: \200 \200 \200 Nephrotic syndrome Consider corticosteroids if the histological features are consistent wit h superimposed minimal change disease. Generic management of nephrotic syndrome. renal impairment (Cr >150 mol/l); proteinuria (>1 g/24 h); hypertension (either on treatm ent or >140/90). Patients with high-risk clinical pro \201 les should be offered preconception counseling a nd when pregnant careful monitoring in a combined renal \200\223obstetric clinic. Acute kidney injury A renal biopsy is almost always required. \200 \200 Acute tubular necrosis: provide supportive care. Crescentic IgAN: if there is active glomer ular in \202 amma- tion, deteriorating renal function and no significant chronic damage th en treat with cyclophosphamide and corticosteroids (as for small vessel vasculitis); otherw ise provide supportive management. Prognosis 25 \200\22330% of patients will require renal replacement therapy within 20 \200 \22325 years. Those at greatest risk of progressive renal failure are patients with signifi cant proteinuria, hypertension and impaired renal function at the time of renal biopsy (Tab le 3.5.1). Slowly progressive IgAN Blood pressure control: aim for <125/75 mmHg; greatest bene \201 t is with maximal renin \200\223angiotensin system blockade. Proteinuria >1 g/24 h: aim for maximal renin angiotensin system blockade. There is no conclusive evidence for: \200 \200 \200 \200 \200 Future prospects The International IgAN Network is shortly to report on an international co nsensus on a pathological classi \201 cation for IgAN. This will hopefully help with strat i \201 cation of patients according to the risk of progressive renal failure and help in t he development of new clinical trials where recruitment is based on renal biopsy features o f disease activity (as in lupus nephritis) rather than on blunt clinical parameters such as proteinuria which may re \202 ect both active disease and chronic irreversible parenchyma l damage. corticosteroids; mycophenolate mofetil; cyclophosphamide; \201 sh oil; anticoagulation or antiplatelet agents. CHAPTER 3.5 Immunoglobulin A nephrophy and Henoch \200\223Sch nlein 103 FP CL Fig. 3.5.1. Light microscopic changes in IgA nephropathy. An H&E- stained section demonstra ting mesangial expansion with mesangial cell proliferation. A capsular adhesion can also be seen (arrowed). Fig. 3.5.3. An electron micrograph demonstrating IgA immune complex deposition within the m esangium and paramesangium. Electron-dense IgA immune complexes (arrowed). Normal podocyte foot processes (FP) and capillary loops (CL) can be seen. (All images courtesy of Dr Nick M ayer, Consultant Histopathologist, University Hospitals of Leicester, UK.) Fig. 3.5.2. Immuno \202 uorescence micrograph demonstrating mesangial IgA staining. J. BARRATT 104 Two ongoing trials will hopefully resolve the issue of whether immunosuppression is appropr iate in progressive IgAN: the STOP-IgAN trial comparing maximal supportive therapy with imm unosuppression; and an Italian-based study which is comparing ACEI and prednisolone versus ACEI alone. Signs Apart from the rash there are no other distinctive physical signs. Differential diagnosis In children HSP is the commonest form of vasculitis. A clinical diag nosis is often made from the characteristic rash and abdominal pain. A de \201 nitive diag nosis requires identi \201 cation of tissue IgA deposition which can be found in the vesse ls of affected skin as well as the kidney. In adults the differential diagnosis is wider in cluding many other forms of small vessel vasculitis which must be distin- guished on the ba sis of clinical, serological and histopatho- logical \201 ndings. Henoch \200\223Sch nlein purpura Henoch \200\223Sch nlein purpura (HSP) is a small-vessel sys- temic vasculitis characterized by IgA deposition in affected blood vessels. The purpu ric rash is a cutaneous vasculitis and the renal lesion (HSP nephritis) is a mesangial prol if- erative GN usually indistinguishable from IgAN. Epidemiology HSP can occur at any age but is commonest in the \201 rst decade of life. Th ere is a slight male predominance. Investigations General investigations Etiology There is much indirect evidence to suggest a close rela- tionship between IgAN and HSP: \200 Assessment of renal function, urinary protein leak and renal size are mandatory for the inv estigation of suspected glomerulonephritis. Serum IgA is raised in 50%, but complement C3 a nd C4 are normal. Monozygotic twins have been described: one who devel- oped IgAN and the other HSP at the sa me time. HSP developing on a background of proven IgAN has been described in both adults an d children. Many abnormalities of the IgA immune system, including abnormal IgA1 glycosylat ion, have been described in both IgAN and HSP. Special investigations The diagnosis of HSP nephritis requires a renal biopsy. No accumulat ion of clinical and laboratory evidence has suf \201 cient speci \201 city and sensitivit y to avoid the need for a diagnostic biopsy. Why some individuals suffer renal-limited disease (IgAN) and others a systemic disease (HSP ) is not known. Renal biopsy features HSP nephritis is de \201 ned by the presence of mesangial IgA detect ed by immuno \202 uorescence or immunoperoxidase. Renal biopsy features are the same as th ose for IgAN. Natural history Much of the renal disease in HSP is transient. Asymptomatic hematuria or pr oteinuria usually disappears within a few weeks of presentation. Of those with persistent e vidence of renal disease the most common feature is persistent asymptomatic hematu- ria and proteinuria. 20% will develop the nephrotic syndrome. 25% patients will develop CKD. AKI due to crescentic HSP nephritis usually occurs early and is more common than crescentic Ig AN. HSP nephritis can recur after renal transplantation. Overall transplant success and gra ft longevity do not differ between HSP and other forms of primary renal disease. Changes in immunosuppressive regimens over the last two decades have not altered the recurrence rate or its prognosis. Risk strati \201 cation There is limited information but case series suggest that, as with IgAN hypertension, the degree of proteinuria and impaired renal function at biopsy predict a poorer progno- sis. Treatment General measures As with all causes of CKD, patients with HSP and CKD3, 4 and 5 must pay close attention to cardiovascular risk and: \200 \200 \200 stop smoking; eat a healthy and balanced diet; take regular exercise. Speci \201 c treatment There is very little information to guide treatment of HSP nephriti s. There are no published randomized controlled trials and most studies in IgAN exclude tho se with HSP so it is unclear whether their conclusions can be extrapolated to HSP. Transien t early nephritis requires no speci \201 c treatment. There is no evidence that corticoste roids or other immu- nosuppressive regimens alter the natural history of neph- rotic syndro me or slowly progressive glomerular damage in HSP. Crescentic HSP nephritis is more common than crescentic IgAN. Regimens used for renal vasculitis have also been applied to crescent ic HSP nephritis with apparent bene \201 t, although there are no controlled trials. Clinical features Symptoms The presenting feature is a palpable purpuric rash caused by cut aneous vasculitis. The rash has a characteristic extensor surface distribution with sparing of the trunk and face. Crops of rash, often provoked by intercurrent infection, may contin ue for some time but rarely beyond one year from \201 rst presentation. Polyarthralgia is common. Abdominal pain, due to gut vasculitis, is usually mild and transient but severe pa in and bloody diarrhea may develop due to intussusception. CHAPTER 3.5 Immunoglobulin A nephrophy and Henoch \200\223Sch nlein 105 Follow-up Follow-up should be the same as for patients with IgAN. Evidence from cohort stud ies of children with HSP sug- gests that all women with a history of HSP should be care- fu lly monitored during pregnancy, even if they had no evidence of renal disease at the time o f diagnosis. Feehally J, Barratt J, Coppo R, Cook T, Roberts I. International IgA nephropathy network cl inico-pathological classi \201 cation of IgA nephropathy. Contrib Nephrol 2007; 157: 13 \200\22318. Floege J Recurrent IgA nephropathy after renal transplantation. Semin Nephrol 2004; 24: 287 \200\223291. Ronkainen J, Nuutinen M, Koskimies O. The adult kidney 24 years after childhood Henoch Sch nlein purpura: a retrospective cohort study. Lancet 2002; 360: 666 \200\223670. Prognosis The long-term outcome of patients with HSP is generally considered to be very goo d unless they develop HSP nephritis. The risk of ESRD in children and adults with HSP nephr itis is unclear but appears low (<10%). Sano H, Izumida M, Shimizu H, et al. Risk factors of renal involve- ment and signi \201 ca nt proteinuria in Henoch Sch nlein purpura. Eur J Pediatr 2002; 161: 196 \200\223201. Internet resources The International IgA nephropathy network: http://www.igan-world.org IgA nephropathy factsheets for children and adults: Future prospects There is a clear need for randomized controlled trials of immunosuppressiv e regimens in HSP nephritis in both adults and children. In all likelihood, however, it wil l be advances in the under- standing of the pathogenesis and treatment of IgAN that will ma ke the most impact on the management of HSP nephritis. http://www.gosh.nhs.uk/factsheets/families/ F060415/index.html h t t p : / / w w w . e m r n . o r g . u k / d o c u m e n t s / IgANephropathy.pdf Henoch \200\223Sch nlein purpura factsheet for children and families: Further reading Barratt J, Feehally J. IgA nephropathy. J Am Soc Nephrol 2005; http://www.ich.ucl.ac.uk/factsheets/families/ F050244 16: 2088 \200\2232097. Barratt J, Feehally J. Treatment of IgA nephropathy. Kidney Int 2006; See also Proteinuria and/or hematuria, p. 76 Nephrotic syndrome, p. 80 Minimal change disea se, p. 86 69: 1934 \200\2231938. Barratt J, Feehally J. IgA nephropathy. Semin Nephrol 2008; 28: 1 \200\2233. Barratt J, Smi th AC, Molyneux KM, Feehally J. Immunopathogenesis of IgA nephropathy. Semin Immunopathol 2007; 29: 427 \200\223443. Davin JC, Ten Berge IJ, Weening JJ. What is the difference between IgA nephropathy and Heno ch \200\223Sch nlein purpura nephritis? Kidney Int 2001; 59: 823 \200\223834. A. SALMON AND S. HARPER 106 Membranous nephropathy Membranous nephropathy (MN) is the commonest cause of nephrotic syndrome in Caucasian adult s. Approximately one-fourth of patients have an underlying systemic dis- ease ( \200\230sec ondary MN \200\231). The routine use of immunosup- pressive therapies remains controversial . MN is the most common renal manifestation of HBV infection. MN typically develops in the ch ronic carrier state. HBV accounts for up to 40% of MN cases in endemic regions, and is part icularly common in young males. Hepatitis C virus infection and a number of tropical dis- e ases (including malaria) have been reported in association with MN. De \201 nition MN is a histological diagnosis, usually made in the context of nephrotic ra nge, or persistent nonnephrotic, proteinuria. Fine granular immune deposits of IgG and comp lement compo- nents are present in a diffuse pattern in the subepithelial space, resulting in thickening of the glomerular basement membrane (GBM). The absence of associated hypercel lular- ity or glomerular in \202 ammation con \201 rms the diagnosis. Drugs Penicillamine, gold and NSAIDs are the agents most com- monly associated with MN. MN usually appears in the \201 rst 6 \200\22312 months of treatment. Renal transplantation MN may recur in the renal transplant, typically in patients whose ini tial disease demonstrated rapid deterioration to end-stage renal failure (ESRF). Recurrence usually occurs in the \201 rst year after transplantation. De novo MN accounts for 30% o f cases of nephrotic syn- drome in renal transplant recipients. Epidemiology The UK incidence is 11 cases pmp per year. It is most commonly diagnosed in t he 5th \200\2236th decades of life, and is uncommon in children. Male:female ratio is 2:1. It is a more common cause of unexplained nephrotic syn- drome in Caucasian than Black indiv iduals. There is little variation in the incidence of idiopathic MN across geographical reg ions; variations in the incidence of secondary causes in different parts of the world re \202 ect variations in the incidence of the underlying (particularly infectious) causes. HL A-DR3 confers a three-fold increased risk. Progressive renal dysfunction is more common in individu- als with HLA-DR3 and HLA-DR5. Pathogenesis A number of lines of evidence indicate an autoimmune pathogenesis of idiopathi c MN: \200 the association with autoimmune diseases such as SLE and diabetes; case series in which tra nsplacental transfer of maternal antibodies directed against a podocyte cell membrane antig en (neutral endopeptidase: NEP) caused membra- nous nephropathy in the fetus; the observati on of comparable histology in animal mod- els, following induction of synthesis of antibodi es directed against the rat podocyte surface antigen mega- lin by injection of brush border proteins ( \200\230Heymann nephritis \200\231). Etiology Primary ( \200\230idiopathic \200\231) MN Classi \201 cation of MN as idiopathic indicates, by de \201 nition, an unknown etiology. Primary MN accounts for 75% of cases i n adults, but only 25% of cases in children. Studies of Heymann nephritis suggest that: \200 \200 immune deposits form in situ; antipodocyte antibodies induce complement activation, leading to podocyte cell activation and secretion of oxidants, proteases and other molecules that impair the function of the glomerular filtration barrier; alterations in podocytes and the composition of the GBM lead to loss of size- and charge-molecular selectivity, and to decre ased hydraulic conductance; ongoing proteinuria initiates interstitial \201 brosis, which further impairs excretory renal function. Secondary MN MN can occur with a wide variety of underlying diseases and treatments. It is most commonly associated with the following. Malignancy Malignancy accompanies MN in 7 \200\2238% of cases, although the incidence is re ported to be as high as 22% in patients aged >60 years. Tumors of lung, breast and gastroin testinal tract are most common. MN may precede evidence of malignancy in 40% of patients, a nd by up to 12 \200\22318 months. Immune complexes in secondary MN are specific to the underlying disease (e.g. HBeAg and HBe Ab in HBV infection). Systemic lupus erythematosis (SLE) Natural history Traditionally known as the \200\230disease of thirds \200\231; epidemi- ol ogical studies indicate likely outcomes for patients with MN: \200 MN accounts for 20% of nephrotic syndrome in patients with SLE. Anti-DNA and antinuclear a ntibodies are typically of low titer and low avidity, whereas complement levels are fre- qu ently normal. One-third exhibit spontaneous remission of disease, usually in the \201 rst 2 years after diagnosis, although remis- sion can occur at any time. One-third exhibit chronic persisten t proteinuria with preservation of renal function. Infection Hepatitis B virus (HBV) infection is the most common infectious disease associate d with MN. CHAPTER 3.6 Membranous nephropathy 107 One-third progress slowly to ESRF. For patients with nephrotic syndrome in the presence of solid-organ malignancy: \200 MN i s the histological diagnosis in 60 \200\22380% of cases; \200 the need for renal biopsy u nder these circumstances should be carefully balanced against tumor prognosis, and the poss ibility of alternative glomerular diagnosis (more common in hematological malignancies). Outcome variability contributes to the different conclu- sions reached by therapeutic trial s and meta-analyzes, par- ticularly when small numbers and short follow-up are employed. Symptoms and signs There are no speci \201 c clinical features of MN. 80% of patients pres ent with nephrotic syndrome; asymp- tomatic non-nephrotic proteinuria is detected in the re maining 20%. 50% of adult patients have microscopic hematuria at pres- entation. Additional clinical features of underlying associated dis- eases (see \200\230Secondary MN \200\231) , or complications of MN (see \200\230Special investigations \200\231), should be sought. Renal biopsy \201 ndings IgG-positive deposits limited to the subepithelial space are cha racteristic of MN. Fig. 3.6.1 shows the characteristic his- tological appearances of MN. Light microscopy This can be normal in early disease. Later changes are characterized by: \200 glomerular capillary wall thickening; \200 GBM projections evident on silver-methan amine staining Differential diagnosis Prior to renal biopsy, the differential diagnoses are the causes of unexplained nephrotic syndrome, including: \200 \200 \200 \200 \200 ( \200\230silver spikes \200\231); absence of glomerular hypertrophy. Mesangial hypercellularity may indicate underlying SLE. Renal function is best predicted by the magnitude of inter- stitial (rather than glomerular ) changes. These are: \200 diffuse in \201 ltrate (mononuclear cells); \200 tubular at rophy; \200 interstitial \201 brosis. Immunohistology Immune deposits consist of IgG (p redominantly IgG4) and complement components (C3 and the C5b-9 \200\230membrane attack com plex \200\231). Fine, granular, diffuse staining is present in all capillary loops. Positiv e staining for IgA or IgM, or staining in mesangial areas, suggests underlying SLE. minimal change disease; FSGS; mesangiocapillary glomerulonephritis (types I and II); amyloi dosis; light chain deposition disease. Following renal biopsy, the differential diagnosis lies between idiopathic and secondary MN . General investigations Assessment of renal function, blood pressure, urinary pro- tein excr etion and serum albumin, urinalysis and renal size are mandatory for the investigation of s uspected glomeru- lonephritis. Special investigations The diagnosis of MN requires a renal biopsy. A number of additional investigations directed at the most frequent underlying causes of secondary MN should inclu de: \200 \200 \200 \200 \200 \200 Electron microscopy Electron-dense deposits (responsible for IgG-positive staining) are obs erved in the subepithelial space. Foot process effacement overlies the deposits. GBM projec ts between electron-dense deposits (responsible for silver spikes). GBM becomes thickened a nd engulfs the electron-dense deposits. anti-dsDNA and antinuclear antibodies; complement levels; hepatitis B serology; fasting glu cose; thyroid function tests; CXR. Staging Electron microscopy \201 ndings are used to categorize MN into four stages: \200 stage I: subepithelial deposits with podocyte foot proc- For patients aged >50 years, recommended investigations for malignancy include: \200 \200 \200 \200 \200 ess effacement and normal GBM thickness; \200 stage II: GBM projection between deposits; \200 stage III: new GBM surrounds deposits; \200 stage IV: highly thickened GBM, with l oss of clear \200\230spike \200\231 pattern of GBM projections and with increasing deposit lucency. CXR. mammography (in women). stool for fecal occult blood. colonoscopy. measurement of tumo r markers, such as prostate- speci \201 c antigen (PSA). These biopsy stages do not correlate with clinical disease severity, treatment response, or outcome. For patients with acutely deteriorating renal function and an active urinary sediment, anti -GBM antibodies should be sought. Development of these antibodies is a rare but well- recog nized complication of MN. For patients with suspected thromboembolic events, including thos e with flank pain and hematuria, renal venography should be considered to look for renal ve in thrombosis. Important histological variants Focal sclerosis This \201 nding predicts rapid progressio n to ESRF. Glomerular crescents The presence of anti-GBM antibodies is associated with the development of crescentic glomerulonephritis on a background of MN. A. SALMON AND S. HARPER 108 (a) (b) (c) Fig. 3.6.1 (a) Glomerulus stained with methanamine silver showing \200\230spike \200\231 f ormation. (b) Immuno \202 uorescence microscopy showing granular deposition of IgG around capillary loops. (c) Electron micrograph showing numerous subepithelial electron-dense depo sits and foot process effacement. (Courtesy of Dr Nick Mayer, Consultant Histopathologist, University Hospitals of Leicester, UK.) Patient advice General As with all causes of chronic kidney disease, patients with MN and C KD 3, 4 and 5 must pay close attention to cardio- vascular risk and: \200 stop smoking; \200 eat a healthy and balanced diet; \200 take regular exercise. Atypical deposits IgA- or C1q-positive immuno \202 uorescence, mesangial cell proliferatio n and mesangial or subendothelial deposits indicate an increased likelihood of underlying m alignancy. Panimmunoreactivity Positive immuno \202 uorescence for IgM and/or IgA, along- side IgG, p articularly in mesangial areas, indicates underly- ing SLE. Pregnancy ACEIs or A2R blockers should be avoided in women con- sidering pregnancy When pre gnant, patients should be monitored in a renal \200\223 obstetric clinic. 90% of pregnancie s in patients with MN result in live births. Repeated pregnancies do not alter the outcome of MN. Risk strati \201 cation Older age and male gender adversely affects prognosis. Persistent proteinuria (>8 g/day for >6 months, >6 g/day for >9 months, or >4 g/day for >1 year) has a high (>65%) positive predictive value for progression to ESRF. Impaired renal function is a useful index (positive predic- tive value >60%) of progression to ESRF. The rate of chang e of creatinine clearance over time is a better index of disease severity than creatinine a t presentation. Published algorithms augment the speci \201 city and positive predictive v alue of prognostically important clinical factors. The use of published methods of risk str atification is variable, both in practice and in therapeutic trials. Pharmacological treatment Nonspeci \201 c measures Blood pressure: treat to National Guide lines. \200 Dietary sodium restriction. \200 Diuretics. \200 Renin \200\223angiotensi n system blockade. CHAPTER 3.6 Membranous nephropathy 109 Secondary hyperlipidemia \200 Dietary measures. \200 HMG CoA reductase inhibitors (aim LDL-cholesterol <3 mmol/L, total cholesterol <5 mmol/L, or a 30% reduction from baseline fo r either parameter; extrapo- lated from national targets). The use of immunosuppression should be balanced against the risk of worsening the malignant disease. Systemic lupus erythematosis Evidence-based recommendations for therapy speci \201 c to SL E-related MN are lacking. The natural history and therapeutic approaches are similar to idi opathic MN. Anticoagulation \200 Decision analysis models predict bene \201 t from prophy- lactic wa rfarin therapy. Recommendations are for treatment in severe nephrotic states (serum albumin <20 g/l). HBV In the minority of children in whom MN does not spontaneously remit, interferon- ther apy is effective and well-tolerated. Successful therapy with interferon- and lamivudine h as been reported in adult patients with HBV-associated MN. Decrease urinary protein excretion \200 Renin \200\223angiotensin system blockade with AC EIs or A2R blockers should be titrated to a maximal dose (alone or in combination) as long as there are no adverse effects on systemic BP, GFR or serum potassium. Drugs Withdraw any drug therapy considered to be causative. De novo MN in renal allografts No formal evidence supports changes to immunosuppres- sive t herapy although, if accompanied by deteriorating graft function, use of calcineurin inhibit ors can be minimized. In individuals with well-maintained serum albumin the above measures may be all that is req uired. For those who are overtly nephrotic corticosteroids alone are often suf \201 cient to induce clinical remission, although the use and enthusiasm for such treatment varies bet ween centers and countries. Prognosis and follow-up Idiopathic MN Patients with partial remissions or normal renal func tion after 3 years have an excellent prognosis. Of the one-third of patients who progress t o ESRF, the proportion who are dead or dialysis dependent is 30% at 5 years, 70% at 10 year s and 80% at 15 years. Disease-speci \201 c measures Routine use of cytotoxic therapies is still controversial an d these are often reserved for those at the highest risk of progression to ESRF (usually th ose with severe and/or resistant nephrosis and those with deteriorating renal function). Th ere is often considerable delay between the start of therapy and a reduction in urinary pro tein excre- tion. Several treatment regimens have been described: Secondary MN Malignancy Nephrotic syndrome frequently, though not invariably, resolves with treatment of the malignant disease given time (6 \200\22318 months). Tumor prognosis deter mines outcome, but is often poor (75% mortality 3 months after the diagnosis of malignancy) . Corticosteroids plus chlorambucil Methylprednisolone 1 g IV for 3 days, then 0.5 mg/kg pred - nisolone orally for 1 month, alternating with 1 month of chlorambucil 0.1 \200\2230.2 mg/ kg/day for 6 months. Outcome: Decreased proteinuria, slower rate of decline of renal functi on, and decreased progression to ESRF. Systemic lupus erythematosis Monitoring for transformation into the more aggressive forms o f lupus nephritis (e.g. proliferative nephritis) is important. Corticosteroids + cyclophosphamide Methylprednisolone 1 g IV for 3 days, then 0.5 mg/kg pre d- nisolone orally for 1 month, alternating with 1 month of cyclophosphamide 2.5 mg/kg/day for a total of 6 months. Comparable ef \201 cacy to the corticosteroid + chlorambucil regi men, with a better adverse effect pro \201 le. HBV The course is more benign than idiopathic MN. Most children exhibit spontaneous remissi on within 5 years. 50 \200\22375% of patients treated with anti-HBV therapy experi- ence su stained remission. Ciclosporin 3.5 \200\2235 mg/kg/day Higher rates of complete or partial remission of nephro tic syndrome, and short-term preservation of renal function, when compared with placebo. Sh ort (<12 \200\22324 month) courses are associated with a higher relapse rate. Drugs Drug discontinuation leads to resolution of nephrotic syn- drome within 12 \200\22336 months. Progressive renal failure is very uncommon in this setting. Renal transplantation De novo MN in renal transplant recipients does not adversely affect g raft survival and is not considered a con- trainduction to retransplantation. Alternative third-line strategies Some preliminary evidence supports the consideration of m ycophenolate mofetil, IV immunoglobulin, pentoxyfylline, rituximab, and eculizumab. Further clinical trials are necessary to evaluate the utility of these agents. Further reading Burstein DM, Korbet SM, Schwartz MM. Membranous glomeru- lonephritis and malignancy. Am J Kidney Dis 1993; 22: 5 \200\22310.