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An update on the treatment of glomerulonephritisa

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Glomerulonephritis (GN) is a common cause of end stage renal disease (ESRD). Some of these entities are responsive to immunosuppressive agents and other therapies. There have been recent advances in …

Glomerulonephritis (GN) is a common cause of end stage renal disease (ESRD). Some of these entities are responsive to immunosuppressive agents and other therapies. There have been recent advances in the treatment options, notably the benefit shown with the use of rituximab in some forms of GN. Moreover, the KDIGO guideline on the management of glomerulonephritis has recently been published which has consolidated the available evidence on the management of this heterogeneous group of disorders. Though there are significant risks and side-effects involved, the treatment of some of the forms of GN can be very gratifying while others progress relentlessly to ESRD. This review summarizes some of the key recommendations from the KDIGO guideline along with a brief discussion of the supporting evidence.

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  • 1. Anupdateonthetreatmentofglomerulonephritis
  • 2. Review ArticleAn update on the treatment of glomerulonephritisVadamalai VivekConsultant Nephrologist, Apollo Hospital, Greams Lane, Off Greams Road, Chennai 600006, Indiaa r t i c l e i n f oArticle history:Received 11 January 2013Accepted 17 January 2013Available online 23 January 2013Keywords:GlomerulonephritisTreatmentImmunosuppressionNephrotic syndromeProteinuriaa b s t r a c tGlomerulonephritis (GN) is a common cause of end stage renal disease (ESRD). Some ofthese entities are responsive to immunosuppressive agents and other therapies. Therehave been recent advances in the treatment options, notably the benefit shown with theuse of rituximab in some forms of GN. Moreover, the KDIGO guideline on the managementof glomerulonephritis has recently been published which has consolidated the availableevidence on the management of this heterogeneous group of disorders. Though there aresignificant risks and side-effects involved, the treatment of some of the forms of GN can bevery gratifying while others progress relentlessly to ESRD. This review summarizes some ofthe key recommendations from the KDIGO guideline along with a brief discussion of thesupporting evidence.Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.1. IntroductionGlomerulonephritis (GN) is the third most common cause ofend stage renal disease (ESRD). The incidence of some formsof primary GN, like IgA nephropathy, is increasing worldwide.Some of them respond well to treatment, hence avoiding themorbidity and cost associated with dialysis or renal trans-plantation. This article reviews the recent evidence for thetreatment of the common types of GN in adults. The KidneyDisease Improving Global Outcomes (KDIGO) clinical practiceguideline for glomerulonephritis has recently been pub-lished.1Newer drugs such as rituximab are now availablewhich has increased the options available to treat this chal-lenging group of disorders. Salient aspects of the KDIGO rec-ommendations are highlighted and a brief discussion of thesupporting evidence follows the recommendations.The grading of the recommendations stated and theirsupporting evidence is according to the KDIGO clinical prac-tice guideline for glomerulonephritis. The strength ofrecommendation followed by the level of supporting evidenceis mentioned within parenthesis after each guidance.The strength of recommendation is indicated as Level 1(“recommend”), Level 2 (“suggest”), or Not Graded, and thequality of the supporting evidence is shown as A, B, C, or D.Grade Quality ofevidenceMeaningA High We are confident that the true effect liesclose to that of the estimate of the effect.B Moderate The true effect is likely to be close to theestimate of the effect, but there isa possibility that it is substantiallydifferent.C Low The true effect may be substantiallydifferent from the estimate of the effect.D Very low The estimate of effect is very uncertain,and often will be far from the truth.E-mail address: vadamalaivivek@gmail.com.Available online at www.sciencedirect.comjournal homepage: www.elsevier.com/locate/apmea p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 40976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.http://dx.doi.org/10.1016/j.apme.2013.01.011
  • 3. 2. Minimal change disease (MCD)2.1. Treatment of initial episode of adult MCDCorticosteroids are recommended for the initial treatment of neph-rotic syndrome (1C).The following treatment measures are suggested:Prednisolone as a daily single dose of 1 mg/kg (maximum 80 mg)or alternate-day single dose of 2 mg/kg (maximum 120 mg) (2C).The initial dose of prednisolone is to be maintained for a mini-mum period of 4 weeks in those achieving complete remission, andfor a maximum period of 16 weeks in those that don’t achievecomplete remission (2C).In patients who remit, taper steroids slowly over a period of up to6 months (2D).Cyclophosphamide or calcineurin inhibitors (CNIs) are to beconsidered in patients with contraindications or intolerance to high-dose corticosteroids (2D).Up to 3 relapses a year can be treated with corticosteroids (2D).There are no randomized controlled trials (RCTs) to guidethe therapy of relapse in adult MCD. But relapses can usuallybe managed with a more rapid taper of corticosteroids. Muchof the recommendations for the treatment of adults with MCDwith steroids is based on extrapolation from studies inchildren.2A complete remission (CR) is a reduction in proteinuria to300 mg/day. Glucocorticoid or steroid-resistance (SR) refers tolittle or no reduction in proteinuria after 16 weeks of adequatesteroid therapy. Patients are considered frequent relapsers(FR) if they have more than three relapses per year.2.2. In the frequent relapser (FR)/steroid dependant (SD)patient the following treatment measures are suggestedOral cyclophosphamide 2e2.5 mg/kg/d for 8 weeks (2C).CNI (cyclosporine 3e5 mg/kg/d or tacrolimus 0.05e0.1 mg/kg/d in divided doses) for 1e2 years for patients with FR/SD MCD whoelapsed despite cyclophosphamide, or for those concerned about therisk of infertility (2C).Mycophenolate mofetil (MMF) 500e1000 mg twice daily for 1e2years for patients intolerant of corticosteroids, cyclophosphamide,and CNIs (2D).Re-evaluate corticosteroid-resistant patients for other causes ofnephrotic syndrome (Not Graded).Response to steroids is usually abrupt with response beingof the “all or none type”. More than half of adult MCD patientswill relapse and up to a third of them may be frequent re-lapsers or corticosteroid-dependent. Corticosteroid therapyleads to complete remission in over 80% of adults with MCD.Adults with MCD take longer to respond compared to children,with only 50% responding by 4 weeks.3Many observationalstudies have reported the efficacy of cyclosporine withremission rates of 70e90%.4Cyclosporine may have theadditional benefit of lower exposure to corticosteroids as itpermits earlier steroid withdrawal.5Cyclosporine is a possiblealternative in patients who continue to relapse after an initialcourse of cyclophosphamide, who are steroid-dependent, orin whom avoidance of the toxicity of cyclophosphamide (eg,gonadal toxicity) is important.670 and 90 percent of glucocorticoid-dependent or fre-quently relapsing patients, respectively, could undergo com-plete or partial remission when treated with cyclosporine ata dose of 4e6 mg/kg per day in divided doses.7Tacrolimus issimilar in efficacy to cyclosporine in inducing completeremission.8All patients in this study were able to discontinuecorticosteroids. Therapeutic levels for CNI’s have not beendefined in adult patients with MCD. CNI dose should begradually reduced to the lowest level that maintainsremission.There is very scant evidence to recommend the use of MMFin adults. Other agents that have shown anecdotal benefit inMCD are levamisole, azathioprine and rituximab. In situationsof resource constraints, it is worthwhile remembering thatprednisone and cyclophosphamide are considerably lessexpensive than CNIs and MMF.3. Focal and segmental glomerulosclerosis3.1. Initial treatment of FSGSIt is recommended that corticosteroid and immunosuppressivetherapy be used only in patients with idiopathic FSGS with thenephrotic syndrome (1C).The following measures have been suggested-Prednisolone be given at a daily single dose of 1 mg/kg (max-imum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg)(2C).The initial dose of steroids be given for a minimum of 4 weeks;and continued up to a maximum of 16 weeks, if tolerated, or untilcomplete remission has been achieved, whichever is earlier (2D).Corticosteroids are to be tapered slowly over a period of 6 monthsafter achieving complete remission (2D).CNIs are to be considered as first-line therapy for patients withrelative contraindications or intolerance to high-dose corticosteroids(e.g., uncontrolled diabetes, psychiatric conditions, severe osteopo-rosis) (2D).3.2. Treatment for relapseRelapse of nephrotic syndrome is treated as per the recommendationsfor relapsing MCD in adults (2D).3.3. Treatment for steroid-resistant FSGSThe following measures have been suggested:Cyclosporine use at 3e5 mg/kg/d in divided doses be given for atleast 4e6 months.If there is a partial or complete remission, cyclosporine could becontinued for at least 12 months, followed by a slow taper (2D).In patients with steroid-resistant FSGS, who do not toleratecyclosporine, a combination of mycophenolate mofetil and high-dosedexamethasone could be tried (2C).Partial remission refers to a reduction of proteinuria to0.3e3.5 g/d (300e3500 mg/g [30e350 mg/mmol]), urine crea-tinine and stable serum creatinine (change in creatinine <25%)OR Reduction of proteinuria to 0.3e3.5 g/d (300e3500 mg/g[30e350 mg/mmol]), urine creatinine and a decrease >50%a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 48
  • 4. from baseline, and stable serum creatinine (change in crea-tinine <25%).Focal and segmental glomerulosclerosis could occur with-out an identifiable cause (“primary”) or as a response to glo-merular injury or glomerular hypertension (“secondary”). Norandomized trial has compared prednisolone or other im-munosuppressives for the initial therapy of primary FSGS.In patients with patients with preserved GFR, prednisolonehas been shown to induce complete or partial remission in40e80 percent. It is probably beneficial to use immunosup-pressive therapy in patients who have nephrotic range pro-teinuria. Prednisolone is administered for a minimum of12e16 weeks.9Its efficacy is less in patients with reducedkidney function (Eg. GFR <25e35 mL/min per 1.73 m2). Theresponse to immunosuppressive drugs is perhaps less forthose with reduced kidney function. In the one study, the rateof remission was less in patients with a serum creatinine>1.4 mg/dL (124 mmol/L).10Overall course of treatment of at least six to eight monthsis required.11Shorter courses (two months) result in muchlower remission rates (20e30%) and may have led to theview held earlier that this condition was not steroidresponsive.12The following dosing recommendations are extrapolatedfrom doses used with apparent success in some of theobservational studies and in trials of other renal diseases:Prednisolone, 1 mg/kg per day (maximum dose 80 mg/day)OR 2 mg/kg every other day (maximum dose 120 mg/day).Patients who are steroid responsive show some reductionin protein excretion within the first 8e12 weeks of therapy.Steroid-resistance (SR) is defined as little or no reduction inprotein excretion with 16 weeks of therapy. Predisposingfactors for SR, in addition to reduced GFR, include AfricanAmerican race, patients with significant tubulointerstitialchange on renal biopsy, massive proteinuria and those withmutations in genes that code for podocyte proteins (Eg.NPHS2). Compliance with therapy should be ensured beforelabelling a patient steroid-resistant. Steroid-dependence isdefined as the development of two relapses during or within 2weeks of completing steroid therapy.Tacrolimus has been shown to be effective in patientswith steroid resistant or dependant FSGS.13Its superiorityover cyclosporine has not been established. MMF may havea role in patients who have not responded to steroid orcyclosporine treatment or who develop adverse effects due tothe use of high-dose steroids or cyclosporine. Though MMFuse may not achieve complete remission may in the majorityof patients, it has been shown to induce partial remission inFSGS.14Only small observational studies have addressed the use ofalkylating agents, sirolimus and rituximab in primary FSGS.Though plasma exchange is of benefit in recurrent FSGS in therenal allograft, its role in the treatment of primary FSGS is yetto be established. Only one small uncontrolled study showedsome benefit with plasma exchange in addition to the use ofsteroids and an alkylating agent.15The role of the GVV-test forthe soluble permeability factor and that of LDL apheresis is yetto be determined. One uncontrolled study has shown somebenefit with the use of the orally active antifibrotic agent,pirfenidone.164. Idiopathic membranous nephropathy(IMN)4.1. When is initial therapy indicated?It is recommended that initial therapy be started only in patientswith nephrotic syndrome AND when at least one of the followingconditions is met. These patients are at a high risk of progressivedecline in renal function:Urinary protein excretion persistently >4 g/d AND remainsat over 50% of the baseline value, AND does not show pro-gressive decline, during antihypertensive and antiproteinurictherapy during an observation period of at least 6 months (1B).The presence of severe, disabling, or life-threatening symptomsrelated to the nephrotic syndrome (1C).Serum creatinine has risen by 30% or more within 6 to 12 monthsfrom the time of diagnosis but the eGFR is not less than 25e30 ml/min/1.73 m2(2C).Treatment is usually commenced after 6 months ofobservation as there is an up to 30% chance of spontaneousremission.174.2. Initial therapy of IMNInitial therapy consists of a 6-month course of alternating monthlycycles of oral and i.v. corticosteroids, and oral alkylating agents (1B).Cyclosporine or tacrolimus can be used for a period of at least 6months in patients who meet the criteria for initial therapy, but whorefuse or have contraindications to the cyclical corticosteroid/alkylating-agent regimen (1C).The dosage of CNI be reduced at intervals of 4e8 weeks to a levelof about 50% of the starting dosage, if remission is maintained andthere is no CNI-related nephrotoxicity, and continued for at least 12months (2C).Remission can be induced either with the use of a 6 monthregime of alternating months of corticosteroids and an alky-lating agent like chlorambucil or cyclophosphamide (“Ponti-celli regime”). Both alkylating agents are equally effective.18Many clinicians prefer cyclophosphamide because of its po-tential for less bone marrow toxicity than chlorambucil. Theregime can be summarised as follows:Months 1,3 & 5: i.v. methylprednisolone (1 g) daily for threedoses, then oral prednisolone (0.5 mg/kg/d) for 27 daysMonth 2,4 & 6: Oral chlorambucil (0.15e0.2 mg/kg/d) or oralcyclophosphamide (2.0 mg/kg/d) for 30 daysAn alternative to the use of an alkylating agent is cyclo-sporine. This agent should be the initial choice in patientsconcerned about the risk to fertility and adverse effects ofcorticosteroid use. Though the remission rates are similar tothe use of steroids and alkylating agents alternately, theduration of therapy is longer with the risk of cyclosporinenephrotoxicity.19Moreover, cyclosporine is expensive, it re-quires therapeutic drug level monitoring and there is a higherrisk of relapse on stopping this agent. Tacrolimus is associatedwith less side effects, such as hirsutism or gingival hypertro-phy than cyclosporine but has a higher risk of inducingdiabetes.a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 4 9
  • 5. 4.3. Treatment of IMN resistant to initial therapyPatients with IMN resistant to alkylating agent/steroid-based initialtherapy can be treated with a CNI (2C).Patients with IMN resistant to CNI-based initial therapy can betreated with an alkylating agent/steroid-based therapy (2C).4.4. Treatment for relapses of nephrotic syndrome inadults with IMNThey can be treated by reinstitution of the same therapy that resultedin the initial remission (2D).The risk of renal and deep vein thrombosis seems higher inIMN patients than those with other causes of the nephroticsyndrome. The exact reason is unknown. A serum albuminconcentration 2.8 g/dL (28 g/L) seems to be the thresholdlevel for increased risk in membranous nephropathy.20Anti-coagulation may be considered if there is an additional riskfactor for thrombosis, eg. Recent surgery.Great strides have been made in understanding the patho-genesis of IMN. The most notable being the discovery ofPhospholipase A2 receptor (PLA2R) as the possible target anti-gen in the development of this disorder. An assay has beendeveloped for the detection of the antibody directed againstPLA2R which could guide therapy.21The clinical utility of usingthe antibody assay for guiding therapy requires further study.IMN usually progresses very slowly and once remission isachieved, it can be maintained for a prolonged period with theuse of ACE inhibitors and/or angiotensin receptor blockers.5. Idiopathic membranoproliferativeglomerulonephritis (MPGN)5.1. Treatment of idiopathic MPGNAdults with presumed idiopathic MPGN accompanied by nephroticsyndrome AND progressive decline of kidney function could receiveoral cyclophosphamide or MMF plus low-dose alternate day or dailycorticosteroids with initial therapy limited to less than 6 months(2D).Type I MPGN is associated with subendothelial andmesangial electron-dense deposits containing immunoglo-bulin and/or C3, chronic hepatitis B or C infection are commoncauses. Type II MPGN with electron-dense intramembranousdeposits containing numerous complement components, butnot immunoglobulin, now known as ‘‘dense-deposit disease’’.Type III MPGN is characterized by the presence of sub-epithelial as well as subendothelial electron-dense deposits. Adiagnosis of idiopathic MPGN necessitates that all underlyingcauses of the MPGN pattern are excluded.Long-term use of prednisolone has been shown to be ofbenefit in children with MPGN.22Pulsed intravenous methyl-prednisolone may be better than oral steroids.23There are norandomized controlled trials of steroid use in adults withMPGN.Inpatientswithsignificantproteinuria, a regimesimilarto that used in focal and segmental glomerulosclerosis is used,starting with oral prednisolone at 1 mg/kg for 12e16 weeks. Ifthe patient responds, prednisone is gradually tapered toalternate day therapy over six to eight months. If there is aninadequate response, steroids are tapered and stopped. Con-vincing evidence does not exist to support the use of cytotoxicagents, MMF, cyclosporine or oral anticoagulants.Some studies have demonstrated a significant reduction inproteinuria with the use of anti-platelet agents. Platelet con-sumption has been shown to be increased in MPGN, suggest-ing a possible role for platelets in causing glomerular injury. Ifa combination of aspirin and dipyridamole is used, this has tobe continued for a prolonged period.24Rituximab has been shown to be beneficial in patients withMPGN and no underlying haematological disorder.25It alsoseems to help those with a monoclonal gammopathy.266. Immunoglobulin A nephropathy (IgAN)6.1. Antiproteinuric and antihypertensive therapyLong-term ACE-I or ARB treatment is recommended when protein-uria is >1 g/d, with dose titration based on blood pressure (1B).In IgAN, use blood pressure treatment goals of <130/80 mmHg inpatients with proteinuria <1 g/d, and <125/75 mmHg when initialproteinuria is >1 g/d (Not Graded).6.2. CorticosteroidsPatients with persistent proteinuria >1 g/d, despite 3e6 months ofoptimized supportive care (including ACE-I or ARBs and bloodpressure control), and GFR >50 ml/min per 1.73 m2, could receivea 6-month course of corticosteroid therapy (2C).Two options exist for the use of steroids:i.v. bolus injections of 1 g methylprednisolone for 3 dayseach at months 1, 3, and 5, followed by oral steroid 0.5 mg/kgprednisone on alternate days for 6 months.276-month regime of oral prednisolone starting with0.8e1 mg/kg/d for 2 months and then reduced by 0.2 mg/kg/d per month for the next 4 months.286.3. Fish oil treatmentFish oil is suggested in the treatment of IgAN in patients with per-sistent proteinuria >1 g/d, despite 3e6 months of optimized sup-portivecare(includingACE-IorARBsandbloodpressurecontrol)(2D).Low quality evidence supports its use in patients withsignificant proteinuria.29A dose of 3.3 g/d can be used in pa-tients who have proteinuria >1 g/d despite ACE-I or ARB use.6.4. MCD with mesangial IgA depositsTreatment is as for MCD in nephrotic patients showing pathologicalfindings of MCD with mesangial IgA deposits on kidney biopsy (2B).6.5. Crescentic IgANDefine crescentic IgAN as IgAN with crescents in more than 50% ofglomeruli in the renal biopsy with rapidly progressive renal deteri-oration (Not Graded).The use of steroids and cyclophosphamide is suggested in pa-tients with IgAN and rapidly progressive crescentic IgAN, analogousto the treatment of ANCA vasculitis (2D).a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 410
  • 6. This entity could result in rapid deterioration of renalfunction and is likely to respond to immunosuppression.Though there are no randomized controlled trials, observa-tional studies have shown benefit with the use of steroids andcyclophosphamide.30The ideal maintenance regime andduration of therapy is unclear. Only poor quality evidencesupports the use of plasma exchange in crescentic IgAN.There is no convincing evidence supporting the use of anti-platelet agents or tonsillectomy in patients with IgAnephropathy.Henoch-Schonlein nephritis is treated similar to IgAnephropathy.7. Lupus nephritis7.1. Class I LN (minimal-mesangial LN) & Class II LN(mesangial-proliferative LN)It has been suggested that these patients be treated as dictated by theextrarenal clinical manifestations of lupus. (2D) Patients with class IILN with proteinuria >3 g/d could be treated with corticosteroids orCNIs as described for MCD (2D).7.2. Class III LN (focal LN) and Class IV LN (diffuse LN)7.2.1. Initial therapyIt is recommend that corticosteroids (1A) be combined with eithercyclophosphamide (1B) or MMF (1B).Prednisolone is usually initiated at a dose of 1 mg/kg/d which is tapered over 6 months. Four options are availablefor the initial treatment, along with steroids:The NIH regime e i.v. cyclophosphamide 0.5e1 g/m2;monthly for 6 months.31Euro-Lupus regime e i.v. cyclophosphamide 500 mg; every2 weeks for 3 months.32Oral cyclophosphamide e 1.0e1.5 mg/kg/d (maximumdose 150 mg/d) for 2e4 months.33MMF e up to 3 g/d for 6 months.34Mycophenolate has been shown to be equivalent tocyclophosphamide in inducing remission in LN.35Combina-tion therapy with steroids, tacrolimus and mycophenolate hasbeen shown to be superior to steroids and cyclophosphamidein one study.36This strategy needs further study in differentpatient populations. Cyclosporine and azathioprine have beenshown to be effective in only small studies and their use is notrecommended as initial treatment of LN.7.2.2. Maintenance therapyAfter initial therapy is complete, patients with class III and IV LNshould receive maintenance therapy with azathioprine (1.5e2.5 mg/kg/d) or MMF (1e2 g/d in divided doses), and low-dose oral corti-costeroids (<10 mg/d prednisolone equivalent) (1B).CNIs with low-dose corticosteroids can be used for in patientswho are intolerant of MMF and azathioprine (2C).After complete remission is achieved, maintenance therapy becontinued for at least 1 year before consideration is given to taperingthe immunosuppression (2D).The MAINTAIN Nephritis trial found that MMF wasequivalent to azathioprine in maintaining remission in LNafter an initial induction regime of 6 months of IV cyclo-phosphamide.37The ALMS study extension phase found thatMMF was superior to azathioprine at maintaining remissionafter an initial induction regime of 6 months of MMF.38Theduration of maintenance treatment is not clearly defined. Aminimum duration of 1 year is recommended after completeremission has been achieved.7.3. Class V LN (membranous LN)It is recommended that patients with class V LN, normal kidneyfunction, and sub-nephrotic range proteinuria be treated with anti-proteinuric and antihypertensive medications, and only receive cor-ticosteroids and immunosuppressives as dictated by the extrarenalmanifestations of systemic lupus (2D).Patients with pure class V LN and persistent nephrotic protein-uria could be treated with corticosteroids plus an additional immu-nosuppressive agent: cyclophosphamide (2C), or CNI (2C), or MMF(2D), or azathioprine (2D).Only one small study compared cyclophosphamide withcyclosporine in the treatment of patients with class V LN andnephrotic range proteinuria. They were both equivalent inefficacy with a higher risk of relapse associated with cyclo-sporine use.39Small studies have shown benefit with the useof MMF, azathioprine and tacrolimus.7.4. General treatment of LNIt has been suggested that all patients with LN of any class aretreated with hydroxychloroquine (maximum daily dose of 6e6.5 mg/kg ideal body weight), unless there is a specific contraindication (2C).7.5. Class VI LN (advanced sclerosis LN)Patients with class VI LN could be treated with corticosteroids andimmunosuppressives only as dictated by the extrarenal manifesta-tions of systemic lupus (2D).7.6. Relapse of LNIt has been suggested that a relapse of LN after complete or partialremission be treated with the same regime as that which achievedthe initial response (2B).If resuming the original therapy would put the patient at risk forexcessive lifetime cyclophosphamide exposure, then a non-cyclophosphamide-based initial regimen can be used (2B).7.7. Treatment of resistant diseaseTreat patients with worsening serum creatinine and/or proteinuriawho continue to have active LN on biopsy with one of the alternativeinitial treatment regimens (Not Graded).Non-responders who have failed more than one of the recom-mended initial regimens may be considered for treatment with rit-uximab, i.v. immunoglobulin, or CNIs (2D).Rituximab has been shown to be beneficial in refractory LNonly in small open-label studies.40Very limited evidencesupports the use of i.v immunoglobulin and cyclosporine inthis situation. Plasma exchange could be considered, espe-cially with other organ involvement eg. CNS.a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 4 11
  • 7. 7.8. Systemic lupus and thrombotic microangiopathyAntiphospholipid antibody syndrome (APS) involving the kidney insystemic lupus patients, with or without LN, can be treated byanticoagulation (target international normalized ratio [INR] 2e3)(2D).Patients with systemic lupus and thrombotic thrombocytopenicpurpura (TTP) could receive plasma exchange as for patients withTTP without systemic lupus (2D).8. Pauci-immune focal and segmentalnecrotizing glomerulonephritis8.1. Initial treatment of pauci-immune focal andsegmental necrotizing GNIt is recommended that cyclophosphamide and corticosteroids beused as initial treatment (1A).Rituximab and corticosteroids are recommended as an alter-native initial treatment in patients without severe disease or inwhom cyclophosphamide is contraindicated (1B).Both i.v and oral cyclophosphamide are equally effective ininducing remission but for the same duration of therapy, pa-tients in the i.v. pulse arm received about half the cumulativeamount of cyclophosphamide as in the daily oral arm.41Theconsequence is a lower risk of leucopoenia and infections buta higher relapse rate in patients treated with i.v cyclo-phosphamide.42There is no convincing evidence supportingthe use of i.v pulsed methylprednisolone which is widely usedbecause of the rapidity of action. A dose of 500 mg daily for 3days is probably as effective as the 1 g dose and associatedwith less side effects.Two randomized controlled studies, RITUXVAS and RAVE,have shown rituximab to be as effective as cyclophosphamidein inducing remission.43Both trials used a dosage of 375 mg/m2weekly for 4 weeks. The long-term adverse effect profile ofrituximab is unknown. Its expense may also limit its use.8.2. Special patient populationsThe addition of plasmapheresis is recommended for patientsrequiring dialysis or with rapidly increasing SCr. (1C) It can also beused in diffuse pulmonary haemorrhage. (2C), combined ANCAvasculitis and anti-GBM GN (2D).Discontinue cyclophosphamide therapy after 3 months in pa-tients who remain dialysis dependent and who do not have anyextrarenal manifestations of disease (2C).Plasma exchange should be considered as an adjunct toconventional agents in inducing remission in patients withsevere renal disease (creatinine > 5.66 mg/dL) or alveolarhaemorrhage.44Plasma exchange may have a role in thosewith ANCA and Anti-GBM antibody positivity. There is insuf-ficient evidence to recommend MMF as initial therapy ofvasculitis.8.3. Maintenance therapyMaintenance therapy is recommended in patients who have achievedremission (1B).Maintenance therapy could be continued for at least 18 months inpatients who remain in complete remission (2D).Maintenance therapy is not to administered in patients who aredialysis-dependent and have no extrarenal manifestations of disease(1C).8.4. Choice of agent for maintenance therapyAzathioprine 1e2 mg/kg/d orally is recommended as maintenancetherapy (1B).MMF, up to 1 g twice daily, can be used in patients who areallergic to, or intolerant of, azathioprine (2C).It has been suggested that trimethoprim-sulfamethoxazole beused as an adjunct to maintenance therapy in patients with upperrespiratory tract disease (2B).Methotrexate (initially 0.3 mg/kg/wk, maximum 25 mg/wk)could be used for maintenance therapy in patients intolerant of aza-thioprine and MMF, but not if GFR is <60 ml/min per 1.73 m2(1C).Maintenance therapy with azathioprine (2 mg/kg/d) hasbeen clearly shown to be superior to mycophenolate.45Eta-nercept is not recommended as maintenance therapy.8.5. Treatment of relapseTreat patients with severe relapse of ANCA vasculitis (life- or organ-threatening) according to the same guidelines as for the initialtherapy (1C).Other relapses could be treated by reinstituting immunosup-pressive therapy or increasing its intensity with agents other thancyclophosphamide, including instituting or increasing dose of corti-costeroids, with or without azathioprine or MMF (2C).It is probably unsafe to exceed a cumulative dose of 36 g ofcyclophosphamide to avoid the risk of malignancies.46Rituximab-based regimes may be safer in patients who havebeen exposed to significant doses of cyclophosphamide in thepast.8.6. Treatment of resistant diseaseIn ANCA GN resistant to induction therapy with cyclophosphamideand corticosteroids, the addition of rituximab (1C) is recommended.i.v. immunoglobulin (2C) or plasmapheresis (2D) have been sug-gested as alternatives.In patients with resistant disease adjunctive therapy withi.v. immunoglobulin (single course of a total of 2 g/kg) waseffective in an RCT.47Several small studies have demon-strated a possible role for rituximab (375 mg/m2i.v. weekly x 4,or 500 mg i.v. weekly x 4 fixed doses) in this scenario. Plasmaexchange may also be beneficial.9. General measures in the management ofall patients with glomerulonephritisMeasures to manage symptoms and those to retard the pro-gression to ESRD should be instituted along with the specificmanagement of the GN. Patients with significant oedema willrequire dietary salt and fluid restriction and perhaps the use ofdiuretics. Moreover, the antiproteinuric effect of ACE inhibitoris potentiated by dietary salt restriction.48Adequate dietarya p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 412
  • 8. protein (0.8e1.0 g/kg daily) should be ensured. The nephroticstate results in complications such as coagulopathy andhyperlipidemia which may necessitate the use of anticoagu-lants and lipid lowering medication. Treatment of hyper-lipidemia should be in accordance with the guidelines for thoseat high risk for the development of cardiovascular disease.Statins(HMG CoAreductase inhibitors)aretheagentsofchoice.The major predictors of progression of nephropathy areproteinuria and hypertension. The target blood pressure inproteinuric patients should be 125/75 mm Hg and 130/80 inthose with proteinuria <1 g/d49ACE inhibitors (ACEI) and/or angiotensin receptor blockers(ARB) are the drugs of choice.50Some patients may not toler-ate higher doses of ACEI and/or ARB due to hypotension,hyperkalaemia or worsening azotemia (>30% above baseline).Although these agents can be used at any level of GFR, cautionshould be exercised in patients with advanced renal insuffi-ciency. 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