Niaudet P. Nephrotic syndrome in children. Curr Opin Pediatr 1993; 5: 174 \200\223179. Waldman M, Crew RJ, Valeri A, et al. Adult minimal-change disease: clinical characteristics , treatment, and outcomes. Clin J Am Soc Nephrol 2007; 2: 445 \200\223453. See also Urinalysis and microscopy, p. 8 Renal biopsy, p. 32 Nephrotic syndrome, p. 80 Foca l segmental glomerulosclerosis, p. 92 Internet resources Nephrotic syndrome in children support group: http://www.nephrotic.co.uk/ National Kidney Federation: http://www.kidney.org.uk/ Further reading Brodehl J. The treatment of minimal change nephrotic syndrome: lessons lear ned from multicentre co-operative studies. Eur J Pediatr 1991; 150: 380 \200\223387. This page intentionally left blank P. TOPHAM 92 Focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is not a single disease entity but rather a group of clinicopathological syn- dromes that present with similar histological appearances on r enal biopsy. Usually FSGS presents with proteinuria or nephrotic syn- drome. It accounts fo r up to 35% of nephrotic syndrome in adults but is uncommon in children. It is associated w ith progressive renal dysfunction with a risk that is proportional to the level of proteinu ria. FSGS can be classi \201 ed as primary (idiopathic) or secondary (to a wide variety of disease processes). Table 3.4.1 Causes of FSGS Primary (idiopathic) FSGS Secondary FSGS Familial FSGS due to mutations in: -Actinin 4 (autosomal dominant) \200 Podocin (autosomal recessive) \200 TRPC6 (autoso mal dominant) Virus-associated: HIV (HIV-associated nephropathy) \200 Parvovirus B19 Drugs: Pamidronate \200 Lithium \200 Interferon- \200 Heroin Epidemiology The prevalence of FSGS is increasing in both adults and children. Primary FSGS is marginally more common in males. The risk of progressing to ESRD is two times higher in males than in females. It is two to three times more common in Blacks than in Caucasians ( it accounts for up to 50% of nephrotic syndrome in adult Blacks in the USA). Progression to ESRD is also four times more likely in Blacks than in Caucasians. There is geographic vari ation in prevalence. For example: \200 in the USA, FSGS is the commonest cause of nephrot ic syndrome in adults (35 \200\22350%) and is the commonest pri- mary glomerular cause of E SRD (2.3% of all ESRD patients); Secondary FSGS due to adaptive responses: Reduced renal mass Oligomeganephronia \200 Unilateral renal agenesis \200 Renal dysplasia \200 Re \202 ux nephropathy \200 Chronic allograft nephropathy Normal renal mass \200 Hypertension \200 Obesity \200 Sickle cell anemia \200 Cyano tic congenital heart disease by contrast, in Spain FSGS accounts for 12% of adult Secondary FSGS Genetic disease -Actinin 4 \200 \200 nephrotic syndrome. Etiology The causes of FSGS are listed in Table 3.4.1. This is inherited in an autosomal dominant pattern. -Actinin 4 is an actin cross-linking protein the mutant form of which binds to actin with higher af \201 nity. It is postu- lat ed that this causes alterations to the podocyte cytoskeleton and dysfunction. It characteri stically causes subnephrotic proteinuria. Primary FSGS By de \201 nition the etiology of primary FSGS is unknown. The focus of injur y is the podocyte although the mediators of this injury are unknown. Some argue that primar y FSGS and minimal change dis- ease (MCD) may be part of the same disease spectrum and ther efore share a common etiology. This is sup- ported by: \200 the morphological similarity of MCD glomeruli with Podocin \200 \200 This is inherited in an autosomal recessive pattern. It characteristically causes steroid-r esistant disease in childhood. Sporadic cases have also been described in both children and adults. This is more common in children and 20 \200\22330% of sporadic FSGS in children ha ve podocin (NPHS2 gene) mutations. Podocin is an integral membrane protein that interacts w ith nephrin and CD2-associated protein (CD2-AP) and therefore has a critical role in mainta ining glomerular permselectivity. nonsclerosed glomeruli in FSGS; the observation in a small number of cases of MCD of apparent evolution with time into FSGS; the presence of a circulating factor in some patients with FSGS. This factor is thought to be responsible for the early recurrence of proteinuria after transplanta- tion in some pati ents. This factor has not yet been characterized. TRPC6 \200 This view is not universally held, however. The differential expression of cyclin-dependent kinase inhibitors, dystro- glycans, TGF- , and cytotoxic T-lymphocyte effectors in MCD an d FSGS argue that MCD and FSGS have divergent etiologies. Mutations of the transient receptor potential cation 6 channel cause autosomal dominant FSG S. TRPC6 localizes to the slit-diaphragm in association with podocin and nephrin. Alteratio ns in calcium \202 uxes caused by the TRPC6 muta- tions probably underlie the development of FSGS through alteration of podocyte cytoskeletal structure. CHAPTER 3.4 Focal segmental glomerulosclerosis 93 Complement levels and other soluble immunological investigations are normal. Tubular dysfun ction (aminoaciduria, phosphaturia, glycosuria) may develop as a consequence of proteinuria - induced injury. CD2-AP \200 CD2-AP interacts with nephrin and podocin and is prob- ably important for the maintenance o f slit-diaphragm integrity. CD2-AP mutations have been identi \201 ed in a small number of cases of FSGS, although causality has not been established. Pathology FSGS is classi \201 ed into a number of histological variants based on their lig ht microscopic appearances. This classi \201 cation is used for both primary and secondary forms but first requires exclusion of other glomeru- lopathies that may result in an FSGS pattern of injury (e.g. hereditary nephritis, healed in \202 ammatory GN) by immuno \202 uorescence and electron microscopy, and clinical correlation. In this classi \201 cation \201 ve variants have been descri bed (Table 3.4.2). In addition, other variants have been proposed to fall within the FSGS spectrum (e.g. C1q nephropathy, FSGS with diffuse mesangi al hypercellularity). It should be understood that these variants are simply pathological d escriptions and their clinical implications have not yet been tested prospectively. Viral-mediated FSGS Parvovirus B19 \200 This has been detected in 80% of biopsies and >85% of serum samples from patients with coll apsing FSGS. It is highly prevalent in the general population, and there- fore causality ha s not yet been established. Human immunode \201 ciency virus (HIV) \200 There is robust evidence that HIV causes collapsing FSGS. HIV can directly infect podocytes . A number of HIV gene products have been shown to disrupt podocytes: Nef induces dediffere ntiation and proliferation of podocytes and also disrupts the cytoskeleton; Tat suppresses nephrin expression; vpr synergizes with nef and enhances podocyte injury. \200 Drug-induced FSGS \200 Table 3.4.2 Morphologic variants of FSGS Heroin, pamidronate, lithium, and -interferon have been associated with FSGS. The mechani sm of injury is unclear but direct podocyte toxicity is likely. FSGS can remit following dr ug withdrawal. FSGS, not otherwise speci \201 ed (NOS) (classic FSGS) FSGS, perihilar variant FSGS, cellu lar variant FSGS, collapsing variant (collapsing glomerulopathy) FSGS, tip variant Structural maladaptive FSGS \200 Common forms of secondary FSGS are caused by adaptive glomerular responses. These usually r elate to: congenital renal mass reduction (renal dysplasia, oligomeganephronia, unilateral renal agenesis); acquired renal mass reduction (reflux nephropathy, surgical resection, chr onic allograft nephropathy); hemodynamic stress (obesity, hypertension, sickle cell disease ). FSGS not otherwise speci \201 ed (NOS) (classic FSGS) This is the common form of FSGS. It is de \201 ned by segmental sclerosis involving any portion of the tuft, in some, but not all, glomeruli. The other FSGS variants must be excluded \201 rst. Glomerular capillaries are occluded by hyaline deposits (insudation of plasma proteins into the permeable capilla ry wall) and foam cells (Fig. 3.4.1A) Juxtamedullary glomeruli are affected first, therefor e the sclerotic lesions may be missed in early disease if the corticomedullary junction is not sampled in the renal biopsy. Immunofluorescence microscopy reveals no immune deposits a lthough granular deposition of IgM, C3 and C1 may be seen in sclerotic lesions (thought to be due to pas- sive trapping). Electron microscopy demonstrates podocyte foot process effac ement both in sclerosed areas, and also in nonsclero- sed glomeruli. This indicates that al though at the light microscopic level this is a focal disease, it is in fact a diffuse podo cyte disease. In these conditions the unifying process is an increase in intraglomerular hydrostatic pres sure that causes glomeru- lar hyper \201 ltration (either to maintain GFR in the face of a reduced nephron number, or as a direct consequence of the underlying pathological process) . Whilst initially adaptive, these changes eventually become maladaptive with glomerular hy pertension and hyper \201 ltra- tion leading to glomerular scarring. Clinical presentation FSGS presents with nephrotic syndrome or asymptomatic proteinuria. In children with FSGS 70 \200\22390% will have nephrotic syndrome. In adults 50 \200\22370% w ill have nephrotic syndrome. Secondary FSGS due to hyper \201 ltration injury tends to pre sent with subnephrotic proteinuria and CKD. In adults and children with FSGS: \200 \200 \200 FSGS, perihilar variant This is de \201 ned as perihilar hyalinosis and sclerosis in >50% of the glomeruli with sclerotic lesions (Fig. 3.4.1B). The cellular, tip, and collapsing va riants must be excluded \201 rst. This variant is often seen in the secondary forms of FS GS mediated by hyper \201 ltration (although it can also be indica- tive of primary FSGS). hypertension is present in 30 \200\22350% at presentation; invisible hematuria is present i n 25 \200\22375%; reduced GFR is present in 20 \200\22330%. Proteinuria can vary from <1 g/day to >30 g/day, and is typically nonselective. P. TOPHAM 94 If caused by secondary FSGS, glomerular hypertrophy is often apparent. Immuno \202 uoresce nce microscopy reveals IgM and C3 in sclerosed areas only. Electron microscopy demonstrates variable foot process effacement. Other variants of FSGS C1q nephropathy This is an idiopathic glomerulopathy characterized b y FSGS or MCD morphology (with variable mesangial hypercellularity) and predominant deposit ion of C1q (with IgG, IgA, IgM and other complement components). Exclusion of immune-comple x-mediated disease (e.g. lupus nephritis, MCGN) is necessary to make the diagnosis. Electro n-dense deposits are found in a paramesangial distribution. There is variable foot process effacement. Although the morphology resembles FSGS, there is debate whether C1q nephropathy represents an FSGS variant or whether it should be regarded as a separate entity. FSGS, cellular variant This is de \201 ned by the presence of at least one glomerulus with segmental endocapillary hypercellularity that occludes the capillary lumen (Fig. 3.4.1C). Capillary occlusion is caused by foam cells, in \201 ltrating leukocytes, karyorrhectic de bris, and hyaline. Podocytes may be hyperplastic, and occasionally they form a pseudocresce nt. The tip and collapsing variants must be excluded. Immuno \202 uorescence microscopy de monstrates C3 and IgM in the sclerosed areas. Electron microscopy demonstrates widespread a nd severe podocyte foot process effacement. FSGS with diffuse mesangial hypercellularity This is de \201 ned by the identi \201 catio n of FSGS lesions on a background of diffuse mesangial hypercellularity. Immuno \202 uores cence microscopy demonstrates diffuse mesangial deposition of IgM, with variable amounts of C3. Electron microscopy demonstrates extensive foot process effacement without electron-de nse deposits. This variant is seen almost exclusively in children. FSGS, collapsing variant (collapsing glomerulopathy) This is de \201 ned by the presence o f at least one glomerulus with segmental or global tuft collapse and overlying hyper- troph y/hyperplasia of podocytes (Fig. 3.4.1D). The lesion is usually global rather than segmenta l. The hyperplastic/hypertrophied podocytes often contain protein resorption droplets and \201 ll Bowman \200\231s space form- ing pseudocrescents. There is no endocapillary prolif eration which differentiates it from the cellular variant. Collapsing variant changes may b e seen with FSGS NOS in the same biopsy. Tubulointerstitial disease with tubular atrophy an d intersti- tial \201 brosis is prominent. Immuno \202 uorescence microscopy demonstrate s IgM and C3 in sclerosed areas. Electron microscopy demonstrates severe and widespread foo t process effacement. Endothelial tubuloreticular inclusions are characteristic of HIV-asso ciated collapsing FSGS. Secondary FSGS Generally the appearances of secondary FSGS are the same as those of primary FSGS. A few additional pathological features may be identi \201 ed that help to determine the etiology: HIV-associated disease This causes the collapsing variant of FSGS but in addition tubular m icrocysts and glomerular endothelial cell tubulo- reticular inclusions are characteristical ly seen. Structural maladaptive FSGS These usually have glomerulomegaly and perihilar scleros- ing l esions. Podocyte hyperplasia and hypertrophy are unusual. Podocyte foot process effacement is less severe than in other forms of FSGS and usually affects <50% of the glomerular capil lary surface. Diagnosis The diagnosis of FSGS requires a renal biopsy, and for the biopsy sample to conta in glomeruli with sclerosed lesions. In addition, the identi \201 cation of sclerosed lesi ons within a biopsy depends on the affected glomeruli being sectioned at the appropriate le vel. The chances of identifying the lesions of FSGS are increa- sed by: \200 \200 FSGS, tip variant This is de \201 ned by the presence of at least one segmen- tal lesion i nvolving the tip domain (the outer 25% of the tuft next to the origin of the proximal tubul e) (Fig. 3.4.1E). The affected segment may herniate into the tubular lumen. The lesions may be cellular or sclerosing. Foam cells and hyalinosis are common. The presence of perihilar sclerosis or collapsing sclerosis rules out the tip variant. Tip lesions occur in isolatio n in approximately one-fourth of cases, and in association with other peripheral FSGS lesio ns in the remainder. Immuno \202 uorescence microscopy changes are the same as seen with o ther lesions. Foot process effacement is severe and widespread. sampling the corticomedullary junction; obtaining a biopsy with a substantial number (>20) of glomeruli; sectioning the biopsy sample at multiple levels. In those with no sclerosing lesions on biopsy, a repeat biopsy may be prompted by failure t o respond to steroid therapy. The additional sampling in itself increases the likeli- hood of identifying sclerosing lesions. If FSGS lesions are identi \201 ed, primary and seconda ry forms need to be differentiated, since this will determine the sub- sequent management. CHAPTER 3.4 Focal segmental glomerulosclerosis 95 (a) (b) (c) (d) (e) Fig. 3.4.1 (a) FSGS not otherwise specified. Methanamine silver-stained glomerulus showing a segmental sclerotic lesion with hyalinosis and extracellular matrix accumulation. The non sclerosed capillary loops are otherwise normal. (b) FSGS perihilar variant. A segmental scl erosing lesion is located at the vascular pole (arrow). (c) FSGS cellular variant. The indi cated segment (arrows) demonstrates endocapillary occlusion with foam cells, inflammatory c ells, and pyknotic debris. The overlying podocytes are hypertrophied and hyperplastic. (d) FSGS collapsing variant. There is global collapse of the glomerular tuft with hypertrophy a nd hyperplasia of the overlying podocytes. (e) FSGS tip lesion variant. The arrow indicates an area of hyalinosis and adhesion to the tubular pole. This area has become detached from the remaining glomerular tuft. (Courtesy of Dr Nick Mayer, Consultant Histopathologist, Un iversity Hospitals of Leicester, UK.) P. TOPHAM 96 Secondary FSGS due to structural maladaptive changes is usually associated with less protei nuria, higher serum albu- min levels, and less foot process effacement on the biopsy. A fam ily history of proteinuria and young age at onset is suggestive of genetic forms of FSGS. A thorough drug history should be obtained and appropri- ate viral studies undertaken. Anticoagulation should be considered in those with severe nephrotic states (serum albumin < 20 \200\22325 g/l, proteinuria >10 g/day). Disease-speci \201 c treatment Until recently primary FSGS was regarded as a steroid- resi stant disease. However, longer courses of steroids at higher doses have been shown to induc e remission (complete or partial) in 50 \200\22370% of patients. There are no large-scale r andomized trials that help to guide the optimal therapy of FSGS. However, the available stu dies have highlighted some general principles: \200 Natural history This is very variable. However, most untreated patients (or treated patient s with no response) with primary FSGS will have a progres- sive rise in proteinuria and pro gression to ESRD. Only 5 \200\22325% of patients will have a spontaneous remission. ESRD de velops after 5 \200\22320 years of proteinuria (by 5 years in 50%). The risk of renal failu re is increased by: \200 \200 \200 \200 \200 \200 Given the poor prognosis of untreated nephrotic FSGS, such patients should be offered corti costeroid treat- ment. When corticosteroids are used, they should be adminis- tered at an a ppropriately high dose (1 mg/kg/day of prednisolone). Corticosteroids should be given for a n appropriate length of time. Four months of treatment may be neces- sary before remission is induced. nephrotic range proteinuria; elevated serum creatinine; Black race; collapsing variant; tub ulointerstitial \201 brosis; failure to respond to treatment. Who to treat There is no way to predict in advance who will respond to steroids. Steroids s hould be offered to those with primary FSGS and nephrotic range proteinuria. Signi \201 ca nt renal function impairment (GFR <35 mL/min) predicts a poorer response to steroids unless it is due to AKI, and the renal biopsy demonstrates little tubulointer- stitial \201 bro sis. The risk of steroid side-effects in individual cases needs to be considered and weighe d against the potential bene \201 t given the necessity for high dose and prolonged steroi d treatment. Steroid treatment is usually not given to those with: \200 The histological variant also determines outcome. \200 The NOS, cellular, and tip variants have a 50% to almost 80% chance of complete or partial remission with treat- ment. The collapsing variant is the least responsive to therapy and p rogresses most rapidly to ESRD. Raised serum creatinine and tubulointerstitial \201 brosi s at presentation heralds a particularly poor prognosis. In those that develop ESRD due to primary FSGS, recur- rence can occur following renal tran splantation (see below). Treatment General treatment General measures to deal with consequences of nephrotic syndrom e are described in Chapter 3.2. For patients with FSGS and CKD 3, 4 and 5 close attention s hould be paid to cardiovascular risk management. Patients should be encouraged to: \200 \200 \200 subnephrotic proteinuria and preser ved renal function since the prognosis in this setting is usually good; subnephrotic proteinuria and impaired renal function since the response to therapy is poor (may indicate sec- ondary FSGS or primary FSGS of long duration). These patients should be managed primarily with general treatment measures, particularly RA S blockade. stop smoking; eat a healthy and balanced diet; take regular exercise. Initial treatment approach There is no consensus about the optimal steroid regimen to be us ed in the treatment of FSGS. A typical regimen is: Prednisolone 1 mg/kg/day (or 2 mg/kg on alternate days) for up to 12 \200\22316 weeks. Several outcomes may be observed: \200 Hypertension should be treated to national guidelines using: \200 \200 \200 dietary sodium restriction; diuretics; renin \200\223angiotensin system blockade. Secondary hyperlipidemia should be managed using: \200 \200 Complete remission (<300 mg proteinuria/day) within 12 weeks. Continue prednisolone at full dose for 2 weeks after remission, then gradually taper to stop over 2 \200\2233 months. Pa rtial remission (>50% fall in proteinuria to <3.5 g/day) within 12 weeks. Taper the prednis olone dose over 6 \200\2239 months. An alternate-day steroid regimen can be used in this si tuation. If proteinuria increases during the taper (de \201 ned as steroid dependence) sec ond-line treatments can be used (see below). dietary measures; HMG CoA reductase inhibitors (aim LDL-cholesterol <3 mmol/l, total choles terol <5 mmol/l, or a 30% reduc- tion from baseline for either parameter; extrapolated from national targets). Proteinuria should be minimized using renin \200\223angiotensin sys- tem (RAS) blockade wit h ACEIs and/or ARB titrated to a maximal dose (alone or in combination) as long as there ar e no adverse effects on systemic BP, GFR or serum potassium. CHAPTER 3.4 Focal segmental glomerulosclerosis 97 Reduction in proteinuria at 12 \200\22316 weeks but fall <50% and proteinuria still >3.5 g/ day. If proteinuria is still falling and if steroid side-effects are minimal, high-dose pre d- nisolone may be continued (or an alternate-day regimen used). If proteinuria has plateau ed or if steroid side- effects are signi \201 cant, second-line agents can be consid- ered . No signi \201 cant improvement in proteinuria by 12 \200\22316 weeks. These patients are de \201 ned as steroid resistant. A trial of second-line therapy can be used with brisk w ith- drawal of steroids (over 4 \200\2236 weeks). Cyclophosphamide (2 mg/kg/day) should be given for 8 \200\22312 weeks, while the patient is still taking steroids. Mycophenolate mofetil In uncontrolled studies mycophenolate has induced com- plete or parti al remission in 40% of patients with steroid- resistant or steroid-dependent FSGS. An Nati onal Institutes of Health/NIDDK-sponsored pro- spective randomized trial comparing ciclospo rin and myc- ophenolate in steroid-resistant patients is currently underway. It can be cons idered in those with no response to pred- nisolone and/or ciclosporin, contraindications to ciclosporin use, or evidence of ciclosporin nephrotoxicity. A dose of 750 \200\2231000 mg/ bd should be given for 4 \200\2236 months. Relapsing disease If after a complete or partial remission is induced, a relapse occurs aft er 1 year, the steroid course is repeated. If relapse occurs either within 1 year of remiss ion, or while on a steroid taper, or after a previous relapse, second-line agents should be considered. Tacrolimus There is some evidence, albeit from uncontrolled studies, that tacrolimus may be of bene \201 t in patients with FSGS. Although it has not been directly compared with cic losporin, case reports have described response to tac- rolimus in patients who have had no response to ciclosporin. It should be primarily reserved for patients in whom side- effects (excluding nephrotoxicity) preclude the use of ciclosporin. Second-line treatment Second-line agents should be considered in those patients with: \200 unacceptable steroid side-effects (or likelihood of poor tolerance of steroids e.g. morbid obesity, diabetes mellitus); incomplete remission (i.e. <50% reduction in proteinu- ria, or >3.5 g/day proteinuria after treatment); steroid-dependent FSGS; relapsing disease (i.e. m ore than one relapse); steroid-resistant FSGS. \200 \200 Sirolimus A small number of reports have described a variable out- come with sirolimus. Two studies have described episodes of AKI, deteriorating renal function, and no remissions. A further study has described a 50% remission rate. A further concern is that the use of sir olimus in proteinuric renal transplant recipients is associated with worsening of proteinur ia and the development of focal sclerosing lesions on biopsy. For these reasons there is cu rrently insuf \201 cient evidence to support the use of sirolimus in the treatment of FSGS . Ciclosporin This is the most commonly used second-line agent. It is able to induce remissio n in 20 \200\22370% of patients with steroid-resistant FSGS, although the longer-term ef \201 cacy is unknown. Ciclosporin should be given at a dose of 3 \200\2234 mg/kg/day in 2 d oses, with low dose prednisolone (0.15 mg/kg/day). Target ciclosporin trough levels are 100 \200\223200 ng/mL. Remission usually occurs within 3 months. Relapse is common after early withdrawal therefore many clinicians continue for \211 6 months (perhaps ideally >1 year) after remission is achieved followed by a slow taper. The prednisolone dose can be halved after 6 months and then continued for the duration of the ciclosporin treat- ment (or withd rawn if steroid side-effects are signi \201 cant). Because of the potential nephrotoxic ef fects of ciclosporin, alternative agents (e.g. mycophenolate or cyclophosphamide) should be considered in those with GFR <40 mL/min. Rituximab The use of rituximab (monoclonal anti-CD20 antibody) in the treatment of childhoo d and adult FSGS in native and transplant kidneys has been described in a few case reports. The outcome has been variable and its use in the treat- ment of FSGS cannot be recommended . Plasmapheresis The role of plasmapheresis in the treatment of primary FSGS has only been ev aluated in a small number of uncon- trolled studies in patients with steroid- and cytotoxic - resistant disease. Its use is based upon the bene \201 t seen in patients with early rec urrence of FSGS post-transplantation, and the identi \201 cation of a circulating permeabi lity factor in some patients with primary FSGS. The reported remission rate has varied from 25 to 75%. It is currently not possible to identify patients who may bene \201 t from pla smapheresis. An assay for the permeability factor is not widely available, and the relation ship between the presence of permeability factor and proteinuria is not strong. Based on th is evidence plasmapheresis should only be con- sidered in those with severe FSGS-related ne phrosis that is resistant to all other treatment modalities. Cytotoxic agents The use of cyclophosphamide and chlorambucil in the treatment of FSGS has only been reported in retrospec- tive, uncontrolled studies. In children with steroid-depen dent or relapsing idiopathic nephrotic syndrome, cyclophosphamide induces remission in 75%, but in only 25% of those with steroid-resistant disease. In the treatment of FSGS, cycloph osphamide should be reserved for those with an incomplete response to ster- oids in whom ci closporin is contraindicated (e.g. extensive tubulointerstial \201 brosis, GFR <40 mL/min ). In this setting, however, many would prefer to use mycophenolate mofetil because of its better side-effect pro \201 le. P. TOPHAM 98 Follow-up Routine blood chemistries, including eGFR, and the urine PCR should be measured a t 2 \200\2234 week intervals during the \201 rst 2 \200\2233 months of treatment. Before reducing immunosuppression, the level of pro- teinuria should be confirmed with two urine P CR measurements. Once drug therapy is stabilized and/or is being tapered, monitoring at 1 \200\2232 month intervals is appropriate. Standard immunosuppression regimen (steroid, cal- cineurin inhibitor, mycophenolate). Avoid mTOR (mam- malian target of rapamycin) inhibitors. RAS blockade. If remission is induced (urine PCR <100), monitor pro- teinuria monthly. If remission is no t induced: \200 \200 continue plasmapheresis (weekly for 6 weeks); consider switching the immunosuppression regi men to cyclophosphamide (1 \200\2232 mg/kg/day) and prednisolone 0.5 \200\2231 mg/kg/day fo r up to 3 months, then revert to standard transplant regimen. Recurrent FSGS post-transplantation Primary FSGS can recur in a renal allograft. It is thou ght to be due to the presence of a circulating permeability factor (or possibly to the loss of a normal serum component). The overall risk of recurrence is 20%; however, an increased risk of recurrence can be seen in those: \200 \200 \200 \200 Although recurrent FSGS can cause graft loss, the inci- dence of allograft loss at 10 years due to recurrent FSGS is only 12%. Further reading Burgess E. Management of focal segmental glomerulosclerosis: evidence-based recommendations. Kidney Int 1999; 70(Suppl): S26. aged <20 years; with a rapid course from diagnosis to ESRD (<3 years); with previous recurr ence in a transplant; with mesangial proliferation on native renal biopsy. D \200\231Agati V. The many masks of focal segmental glomerulosclerosis. Kidney Int 1994; 46: 1223. D \200\231Agati V. Pathologic classi \201 cation of focal segmental glomerulo- The onset of recurrence may be very rapid (within hours of the transplant), the nephrosis m ay be severe, and allo- graft dysfunction is common. Most cases present within 1 month post -transplant (median 14 days in children) although late recurrence can also occur. The diagn osis is made by detecting increasing proteinuria (a baseline measurement of protein excreti on form the native kidneys is helpful in this regard), and from a renal biopsy. The renal b iopsy in the early stages may just dem- onstrate foot process effacement. Given the associa tion of FSGS with viral infection, polymerase chain reaction for Parvovirus B19, CMV, EBV, BK virus, and hepatitis C virus should be performed. sclerosis. Semin Nephrol 2003; 23: 117 \200\223134. Matalon A, Valeri A, Appel GB. Treatment of focal segmental glomerulosclerosis. Semin Nephrol 2000; 20: 309. Meyrier A. Nephrotic focal segmental glomerulosclerosis in 2004: an update. Nephrol Dial Transplant 2004; 19: 2437. Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am J Kidney Dis 1995; 25: 534. Internet resources NIH/NIDDK cyclosporin/mycophenolate trial information: http://www.fsgstrial.org/welcome.htmL See also Urinalysis and microscopy, p. 8 Renal biopsy, p. 32 Nephrotic syndrome, p. 80 Mini mal change disease, p. 86 Infection-related glomerulonephritis, p. 128 Recurrent disease an d de novo disease postrenal trans- plantation, p. 572 Treatment Although never subjected to randomized prospective study, plasmapheresis is the t reatment of choice for recur- rent FSGS. Retrospective studies have shown that most people who commence plasmapheresis within 2 weeks of disease onset will remit. A typical treatment regimen would be: \200 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.