Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of glomerulonephritis in adults.

CSN Commentary Canadian Society of Nephrology Commentary on the 2012 KDIGO Clinical Practice Guideline for Glomerulonephritis: Management of Glomerulonephritis in Adults Andrey V. Cybulsky, MD, FRCPC,1 Michael Walsh, MD, FRCPC,2 Greg Knoll, MD, FRCPC,3 Michelle Hladunewich, MSc, MD, FRCPC,4 Joanne Bargman, MD, FRCPC,4 Heather Reich, MD, FRCPC,4 Atul Humar, MD, FRCP,5 Susan Samuel, MD, FRCPC,6 Martin Bitzan, MD, FRCPC,7 Michael Zapitelli, MD, FRCPC,7 Allison Dart, MD, FRCPC,8 Cherry Mammen, MD, FRCPC,9 Maury Pinsk, MD, FRCPC,6 and Norman Muirhead, MD, FRCPC, FRCP (Ed)10 The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for management of glomerulonephritis was recently released. The Canadian Society of Nephrology convened a working group to review the recommendations and comment on their relevancy and applicability to the Canadian context. A subgroup of adult nephrologists reviewed the guideline statements for management of glomerular disease in adults and agreed with most of the guideline statements developed by KDIGO. This commentary highlights areas for which there is lack of evidence and areas in need of translation of evidence into clinical practice. Areas of controversy or uncertainty, including the choice of second-line agents, are discussed in more detail. Existing practice variation also is addressed. The relevance of treatment recommendations to the Canadian practitioner is discussed. Am J Kidney Dis. -(-):---. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Clinical practice guideline implementation; KDIGO (Kidney Disease: Improving Global Outcomes); Canadian Society of Nephrology (CSN); nephrotic syndrome; glomerulonephritis.

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he proliferation of clinical practice guidelines in a wide range of disciplines, including nephrology, speaks to a deep-rooted need for comprehensive assessment of the medical literature and the synthesis of that information into a practical and meaningful context for the practicing physician. Unfortunately, the proliferation of clinical practice guidelines has led at times to confusion or contradiction as national societies in many countries feel a need to provide their own comprehensive clinical practice guidelines. In this context, KDIGO (Kidney Disease: Improving Global Outcomes) was established in 2003 with the stated mission to “improve the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines.”1(pS1) In the period since the formation of KDIGO, comprehensive clinical practice guidelines have been developed and published for chronic kidney disease (CKD)–mineral and bone disorder,1 renal transplantation,2 blood pressure in CKD,3 acute kidney injury,4 anemia in CKD,5 and hepatitis C virus (HCV) infection in CKD.6 The KDIGO clinical practice guideline for glomerulonephritis (GN)7 represents a systematic review and synthesis of the literature available on the topic as of January 2011, with addition of new data available as of November 2011. Am J Kidney Dis. 2014;-(-):---

The Canadian Society of Nephrology (CSN) is supportive of the efforts of KDIGO to provide comprehensive and broadly applicable clinical practice guidelines for the international nephrology community. However, the CSN and other professional groups such as KDOQI (Kidney Disease Outcomes Quality Initiative) see a need to consider local factors in using clinical practice guidelines to guide care. In this context, the CSN therefore has established

From the 1Department of Medicine, McGill University, Montreal, Quebec; 2Division of Nephrology, Department of Medicine, McMaster University, Hamilton; 3Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa; 4Department of Medicine, University of Toronto, Toronto, Ontario; 5Transplant Infectious Diseases and 6Department of Pediatrics, University of Alberta, Edmonton, Alberta; 7 Montreal Children’s Hospital, Montreal, Quebec; 8Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba; 9Department of Pediatrics, University of British Columbia, Vancouver, British Columbia; and 10Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada. Address correspondence to Norman Muirhead, MD, FRCPC, FRCP (Ed), LHSC University Hospital, Western University, 339 Windermere Rd, London ON N6A 5A5, Canada. E-mail: norman. [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.12.001 1

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working groups to review KDIGO clinical practice guidelines and provide a perspective on their applicability in Canadian health care. This is particularly important for newer and/or more expensive therapies that may be affected by variable restrictions on use in different jurisdictions in the country.

REVIEW AND APPROVAL PROCESS FOR CSN COMMENTARIES The CSN guidelines committee, having decided that the KDIGO clinical practice guideline for GN was a priority for comment, established working groups in the summer of 2012 to develop 2 commentaries, one on the guideline statements relevant to adults and another regarding guideline statements relevant to children (see Samuel et al8). Individual members of CSN were solicited and selected for the working group based on their interest and expertise, taking due note of potential conflicts of interest. This commentary, focused on management of GN in adults, was developed during summer and fall of 2012, using the original KDIGO GN clinical practice guideline7 and materials referenced in the report as information sources. The working group conferred regularly by teleconference and all authors approved the final submitted text. All efforts were made to achieve consensus. When consensus was not possible, all viewpoints are discussed. The final document was sent out by CSN for peer review and revised according to the issues raised before final ratification by the CSN guidelines committee and CSN executive.

STRUCTURE OF THIS COMMENTARY This commentary does not attempt to discuss all the KDIGO recommendations for GN; rather, the focus is on areas for which there is more comprehensive evidence or an important clinical need. Implications for Canadian health care are discussed when applicable and important areas for future research also are identified. Individually, each of the GNs is relatively uncommon and frequently has a chronic course. These features make studying the GNs, particularly the conduct of adequately powered randomized controlled trials (RCTs), challenging. However, GNs collectively account for approximately one-quarter of end-stage renal disease (ESRD). Given this, global studies to determine optimal treatments are required and represent an opportunity for the nephrology community to work toward reducing a cause of ESRD that is uniquely its domain. Although the current KDIGO guideline represents a step forward in collating the existing knowledge on treating GNs, many chapters lack a research agenda. In order to advance our understanding of GNs, improve treatments, and reduce ESRD, the nephrology community 2

needs to establish clear research priorities and undertake large collaborative studies of these diseases. The endorsement of such an agenda by international groups such as KDIGO followed by the broader nephrology community will be a major advancement in the study and treatment of GN. In this commentary, numbered text within horizontal rules is quoted directly from the KDIGO document, using the same numbering scheme as in the original. All material is reproduced with permission of KDIGO.

GUIDELINE STATEMENTS AND COMMENTARY Treating Minimal Change Disease in Adults 5.1.3: We suggest the initial high dose of corticoseroids, if tolerated, be maintained for a minimum period of 4 weeks if complete remission is achieved, and for a maximum period of 16 weeks if complete remission is not achieved. (2C) 5.1.5: For patients with relative contraindications or intolerance to high-dose corticosteroids (e.g., uncontrolled diabetes, psychiatric conditions, severe osteoporosis), we suggest oral cyclophosphamide or CNIs as discussed in frequently relapsing MCD. (2D) 5.1.6: We suggest using the same initial dose and duration of corticosteroids for infrequent relapses as in Recommendations 5.1.2, 5.1.3, and 5.1.4. (2D) 5.4.2: We suggest that, for the initial episode of nephrotic syndrome associated with MCD, statins not be used to treat hyperlipidemia, and ACE-I or ARBs not be used in normotensive patients to lower proteinuria. (2D)

Commentary The overall grade of evidence to guide the treatment of minimal change disease (MCD) in adults is poor and largely extrapolated from studies in children. Nonetheless, due to a severe paucity of controlled trial data, the CSN is in agreement with the general principles of management proposed by the KDIGO guideline. However, an understanding of the quality of available evidence as it pertains to adults is important for the practicing clinician who is balancing treatment response against the potential for treatmentrelated side effects. A recent systematic review that searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, reference articles, and abstracts from conference proceedings for RCTs or quasi-RCTs identified only 3 RCTs with 68 participants older than 18 years.9 These data proved inadequate to make any firm conclusions with respect to the utility of prednisone therapy in adults. The guideline notes that the response rate to steroid therapy is more variable in adults, who often respond more slowly, increasing the potential for significant steroid-related side effects, and make recommendations for use of steroid-sparing agents. However, there are inadequate Am J Kidney Dis. 2014;-(-):---

Canadian Perspective on KDIGO Glomerulonephritis CPGs

controlled data to draw firm conclusions on the superiority of any of the steroid-sparing treatment options. Finally, all available observational data come from short-term studies, yet nephrotic syndrome often is a remitting and relapsing chronic disease that requires a long-term approach to therapy. Although it may be reasonable to withhold blockade of the reninangiotensin system (RAS) in acutely nephrotic patients with the propensity to develop acute kidney injury, supportive therapy including statins should be considered in some adult patients given the variable response to therapy, the often prolonged time to response to therapy, and the potential relapsingremitting nature of MCD in adults. As such, the extrapolation of the pediatric literature to adults as quoted in the guideline may be inappropriate, and clinicians will need to exercise judgment given the significant morbidity and mortality due to coronary artery disease noted in patients with CKD. Overall, vigilant monitoring for side effects is warranted, irrespective of chosen therapy, with supportive care aimed at limiting ancillary damage from both nephrotic syndrome and the immunosuppressive agents. Implications Within Canadian Health Care Steroid therapy is inexpensive, whereas other potential therapeutic options are more costly, less proven, and may not be covered by all provincial health plans. Further controlled trials will be necessary to ensure similar coverage across all Canadian provinces. This may prove unrealistic.

Evaluation and Treatment of Focal Segmental Glomerulosclerosis 6.2.3: We suggest the initial high dose of corticosteroids be given for a minimum of 4 weeks; continue high-dose corticosteroids up to a maximum of 16 weeks, as tolerated, or until complete remission has been achieved, whichever is earlier. (2D) 6.2.4: We suggest corticosteroids be tapered slowly over a period of 6 months after achieving complete remission. (2D) 6.3.1: We suggest that a relapse of nephrotic syndrome is treated as per the recommendations for relapsing MCD in adults (see Chapters 5.1 and 5.2). (2D)

Commentary Focal segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome associated with glomerular injury that may be either idiopathic or secondary to one of a number of other disorders that typically result from decreased glomerular mass. As noted in the guideline, these secondary causes should be considered carefully because in these cases, the risks of immunosuppression are more likely to outweigh any potential benefit. As such, the guideline recommends immunosuppressive therapy only in cases of Am J Kidney Dis. 2014;-(-):---

nephrotic syndrome. Cardiovascular risk reduction (ie, RAS blockade and statin therapy) is recommended in patients presumed to have a secondary cause of FSGS. However, it should be noted that there is no absolute confirmatory test that can differentiate idiopathic from secondary FSGS. Consequently, clinicians must carefully assess for potential clinical and pathologic clues with respect to the cause of this disease while watching patients closely for worsening of proteinuria and kidney function so that the opportunity to provide immunosuppressive therapy is not missed. In patients with nephrotic syndrome, immunosuppression has been shown to improve proteinuria and slow progression to ESRD, but side effects of the current options, including high-dose prolonged corticosteroids and calcineurin inhibitors (CNIs), are significant and rates of treatment failure and relapses are common. Prednisone often is used as first-line therapy largely based on data from observational cohorts. The dose and duration of therapy are not clear and therefore have varied. As noted in the guideline, both daily regimens and alternate-day regimens have been used. As in MCD, adult patients can take much longer to respond, with poorer response rates compared with children. Steroid resistance even to prolonged treatment is present in .50% of adult patients. Further, intolerance to steroid therapy tends to be more significant, especially in the presence of advanced age and other comorbid conditions, such as obesity and diabetes. In patients with steroid resistance or intolerance, CNIs therefore have emerged as the therapeutic choice in many centers. In a multicenter prospective RCT, patients with steroid-resistant FSGS were randomly assigned to continue on low-dose prednisone either alone or in combination with cyclosporine. The therapy was continued for 26 weeks and then tapered over 4 weeks. The response rate in cyclosporinetreated patients was .70%, but relapses upon discontinuation of therapy were common, at .50%.10 As such, prolonged therapy likely is necessary, yet duration of therapy was not described in the current guideline. In smaller studies, tacrolimus also has demonstrated similar rates of complete and partial remission in patients with steroid-resistant or steroiddependent nephrotic syndrome and thus can be considered an alternative CNI guided by the side-effect profile. It should be noted that CNIs must be used with caution in patients with significant vascular or interstitial disease on renal biopsy and in those who have decreased estimated glomerular filtration rate (eGFR). Other therapeutic options include mycophenolate mofetil (MMF), dexamethasone, and rituximab. A recent RCT of children and adults with steroidresistant FSGS showed that the combination of a 12-month course of MMF and high-dose dexamethasone induced a 33% combined partial and complete 3

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remission. Following discontinuation of the MMF and dexamethasone, 18% experienced relapse.11 This study demonstrated a very modest improvement with prolonged dexamethasone exposure and MMF when given in combination. To date, evidence that rituximab might prove effective in patients with FSGS is limited. An important research recommendation in FSGS is the establishment of biomarkers of disease activity. It is hypothesized that a large number of circulating proteins have pro- or antiproteinuric effects on normal glomeruli, and that changes in the relative ratio of these circulating proteins could be a major determinant of proteinuria in disease states. Recent insights into podocyte biology have identified a urokinase receptor (uPAR [urokinase plasminogen activator receptor]) integral to the maintenance of the slit diaphragm through its ability to form signaling complexes with other transmembrane proteins, including lipid-dependent activation of avb3 integrin.12 A soluble cleavage product (suPAR) is elevated in FSGS,13 particularly with posttransplantation recurrence. These novel biomarkers may provide insights into the pathogenesis of the disease and its activity, predict remission more accurately, and may lead to mechanism-based therapeutics. Moreover, the biomarkers may define the appropriate timing and duration of treatments. Idiopathic Membranous Nephropathy 7.2.1: We recommend that initial therapy be started only in patients with nephrotic syndrome AND when at least one of the following conditions is met: Urinary protein excretion persistently exceeds 4 g/d AND remains at over 50% of the baseline value, AND does not show progressive decline, during antihypertensive and antiproteinuric therapy (see Chapter 1) during an observation period of at least 6 months; (1B) the presence of severe, disabling, or lifethreatening symptoms related to the nephrotic syndrome; (1C) SCr has risen by 30% or more within 6 to 12 months from the time of diagnosis but the eGFR is not less than 25–30 ml/min/1.73 m2 AND this change is not explained by superimposed complications. (2C) 7.3.1: We recommend that initial therapy consist of a 6month course of alternating monthly cycles of oral and i.v. corticosteroids, and oral alkylating agents (see Table 15). (1B) 7.3.3: We recommend patients be managed conservatively for at least 6 months following the completion of this regimen before being considered a treatment failure if there is no remission, unless kidney function is deteriorating or severe, disabling, or potentially lifethreatening symptoms related to the nephrotic syndrome are present (see also Recommendation 7.2.1). (1C)

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Commentary In chapter 7 of the KDIGO guideline, there are no grade 1A recommendations and only 3 grade 1B recommendations. There are 15 grade 1C, 2B, 2C, or 2D recommendations. The relatively low quality of evidence in this area reflects the absence of adequate idiopathic membranous nephropathy biomarkers and lack of established effectiveness of current treatments. The recommendations for therapy primarily involve cyclophosphamide/chlorambucil or CNIbased immunosuppression protocols, whereas there are no specific recommendations for newer agents, such as rituximab, due to lack of robust evidence. Nevertheless, a significant understanding of idiopathic membranous nephropathy pathogenesis has been achieved recently, biomarker studies are ongoing,14 and newer agents presently are being tested in RCTs (eg, rituximab vs cyclosporine; ClinicalTrials.gov identifier NCT01180036). These developments provide reason for optimism that therapy of idiopathic membranous nephropathy may undergo improvement and become more mechanism directed in future years. In guideline statement 7.2.1, it is recommended that specific therapy be instituted only if urinary protein excretion persistently is .4 g/d, remains at .50% of the baseline value, and does not show progressive decline during antihypertensive and antiproteinuric therapy during an observation period of at least 6 months. The recommendation is based on an algorithm developed at 6 months of observation.15 At the same time, the guideline states that remission may be delayed for as long as 18-24 months and that the mean time to remission was recently reported as 14.7 6 11.4 months.16 Moreover, spontaneous remission has been reported in .20% of patients with proteinuria with protein excretion of 8-12 g/d and even .12 g/d. Therefore, although the guideline recommends an observation period of at least 6 months, a significantly longer observation period could be considered. A conservative approach should be maintained in patients showing a progressive decline in proteinuria during the first year of followup (including patients with massive proteinuria), provided that renal function continues to be normal. By analogy, guideline statement 7.3.3 recommends that patients be managed conservatively for at least 6 months following the completion of a specific treatment regimen before being considered a treatment failure if there is no remission; however, spontaneous remission may involve a period as long as 12-18 months.16 A 6-month definition of treatment failure is relatively arbitrary compared with a longer period. We agree with research recommendations for further study of antiphospholipase A2 receptor antibodies and other biomarkers of disease activity, which may assist Am J Kidney Dis. 2014;-(-):---


in defining remission more accurately, as well as the appropriate periods of observation.14 In regard to the recommendation in guideline statement 7.3.1 that initial therapy consist of a 6-month course of alternating monthly cycles of oral and intravenous corticosteroids and oral alkylating agents, the published evidence for the efficacy of alkylation agents appears stronger compared with CNIs. Studies of alkylation agents have a longer duration of follow-up data, and treatment with CNIs, while effective in inducing remission, is associated with a high rate of relapse. However, the side effects of alkylating agents are perceived to be more substantial.17 On balance, a CNI-based regimen may be favored by some practitioners. It should be noted that results of a recently published study that compares an alkylating agent (chlorambucil) with cyclosporine and supportive therapy alone in patients with idiopathic membranous nephropathy and declining renal function are strongly in favor of the alkylating agent over both CNIs and supportive therapy in reducing renal functional decline.18 The trial involved patients with at least a 20% decline in renal function, but a serum creatinine (SCr) level , 300 mmol/L. Baseline proteinuria in the 3 treatment groups ranged from protein excretion of 6.8-10.1 g/24 h. Even in the chlorambucil-treated group, renal function continued to decline in w60% of patients over 3 years, but overall, renal function was significantly better preserved in this group. However, side effects were greater in patients receiving the alkylating agent.18 Idiopathic Membranoproliferative GN 8.2.1: We suggest that adults or children with presumed idiopathic MPGN accompanied by nephrotic syndrome AND progressive decline of kidney function receive oral cyclophosphamide or MMF plus low-dose alternate-day or daily corticosteroids with initial therapy limited to less than 6 months. (2D)

Commentary Membranoproliferative GN (MPGN) is a histologic pattern of injury and not a specific disease.19-23 The term MPGN therefore is obsolete and should be replaced with a mechanistic classification according to the presence of immunoglobulins (Igs) and/or complement, that is, Ig1C31 and Ig–C31. The former can be subclassified into the presence of polyclonal and/or monoclonal antibodies, and the latter, into dense deposit disease and C3 nephropathy. The key to optimal treatment of MPGN likely will depend on identification of the underlying cause and may include immunosuppression, chemotherapy of monoclonal gammopathy disorders, or complement-regulatory therapies directed at the C3 convertase or terminal complement pathway.22,24 Am J Kidney Dis. 2014;-(-):---

Implications Within Canadian Health Care There are no specific implications at the present time, but assuming complement-regulatory therapies are approved for Ig–C31 nephropathies in the future, the cost and coverage of these therapies will become major considerations. The substantial costs of such drugs, which are biologic reagents, presently are covered to a variable extent by provincial health plans and private insurers.

Infection-Related GN 9.2.1: For HCV-infected patients with CKD Stages 1 or 2 and GN, we suggest combined antiviral treatment using pegylated interferon and ribavirin as in the general population. (2C) [based on KDIGO HCV Recommendation 2.2.1] 9.2.2: For HCV-infected patients with CKD Stages 3, 4, or 5 and GN not yet on dialysis, we suggest monotherapy with pegylated interferon, with doses adjusted to the level of kidney function. (2D) [based on KDIGO HCV Recommendation 2.2.2] 9.3.1: We recommend that patients with HBV infection and GN receive treatment with interferon-a or with nucleoside analogues as recommended for the general population by standard clinical practice guidelines for HBV infection. (1C)

Commentary The working group noted that the majority of the suggestions in chapter 9 were based on low- or very low-quality data. The working group agrees with most of the recommendations presented in this section of the KDIGO guideline. Most of the suggestions and recommendations are common sense statements directed at treatment of the underlying infection. The only level 1 recommendations in this chapter were made in reference to the treatment of hepatitis B virus (HBV)-related GN. The guideline stated that patients should receive treatment with interferon alfa or a nucleoside analogue. Both treatments would be acceptable, but in Canada, it would be much more common for a patient to receive one of the nucleoside analogues such as tenofovir or entecavir as initial therapy based on safety profile and ease of administration.25 In contrast to potential cure with interferon, drug therapy with a nucleoside analogue would be required for life. Although the working group agreed with the recommendations for the treatment of HCV infection, it was noted that the referenced KDIGO HCV guideline was published in 2008. Since that time, protease inhibitors such as boceprevir and telaprevir have become available for the treatment of HCV infection. International guidelines now recommend that one of the protease inhibitors (boceprevir or telaprevir) be added to pegylated interferon and ribavirin for genotype I patients. These newer regimens increase 5

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response rates from 40%-50% up to 70%-80%.26,27 However, there are no data for the use of the agents in patients with CKD. Unfortunately, Canadian guidelines on the treatment of HCV were last published in 2007 and make no reference to the novel protease inhibitors.28 Drug coverage for protease inhibitors is variable across Canada. HCV therapy overall is evolving rapidly due to the development of new agents. The working group agrees that human immunodeficiency virus (HIV)-associated nephropathy should be treated with antiretroviral therapy. Because a wide variety of treatment options are available, recent Canadian recommendations should be used to select the most appropriate regimen.29 Implications Within Canadian Health Care 1. In contrast to other chapters in this guideline, several of the disorders discussed in this section would occur rarely in the Canadian population. Nonetheless, given increased immigration and international travel, Canadian physicians will need to be aware of renal issues related to certain infections (eg, schistosomiasis and lymphatic filariasis) discussed in this chapter. 2. Therapies to treat infection-related GN for the most part are available in Canada. The cost of medications, especially potentially expensive agents such as lifelong antiviral therapy, is covered by a mix of government funding and private insurance. However, the level of government funding is under provincial jurisdiction and varies somewhat between the provinces, especially for new HCV therapies. In addition, eligibility for funding based on clinical criteria (eg, viral load and renal function) may vary in different jurisdictions throughout the country.

IgA Nephropathy 10.1: Initial evaluation including assessment of risk of progressive kidney disease 10.1.2: Assess the risk of progression in all cases by evaluation of proteinuria, blood pressure, and eGFR at the time of diagnosis and during follow-up. (Not Graded) 10.1.3: Pathological features may be used to assess prognosis. (Not Graded) 10.2: Antiproteinuric and antihypertensive therapy 10.2.4: In IgAN, use blood pressure treatment goals of ,130/80 mm Hg in patients with proteinuria ,1 g/d, and ,125/75 mm Hg when initial proteinuria is .1 g/d (See Chapter 2). (Not Graded) 10.3: Corticosteroids 10.3.1: We suggest that patients with persistent proteinuria $1 g/d, despite 3–6 months of optimized supportive care (including ACE-I or ARBs and blood pressure control), and GFR . 50 ml/min per 1.73 m2, receive a 6-month course of corticosteroid therapy. (2C) 10.4: Immunosuppressive agents (cyclophosphamide, azathioprine, MMF, cyclosporine) 6

10.4.1: We suggest not treating with corticosteroids combined with cyclophosphamide or azathioprine in IgAN patients (unless there is crescentic IgAN with rapidly deteriorating kidney function; see Recommendation 10.6.3). (2D) 10.4.3: We suggest not using MMF in IgAN. (2C) 10.5: Other treatments 10.5.1: Fish oil treatment 10.5.1.1: We suggest using fish oil in the treatment of IgAN with persistent proteinuria .1 g/d, despite 3–6 months of optimized supportive care (including ACE-I or ARBs and blood pressure control). (2D) 10.6: Atypical forms of IgAN 10.6.1: MCD with mesangial IgA deposits 10.6.1.1: We recommend treatment as for MCD (see Chapter 5) in nephrotic patients showing pathological findings of MCD with mesangial IgA deposits on kidney biopsy. (2B) 10.6.3: Crescentic IgAN 10.6.3.1: Define crescentic IgAN as IgAN with crescents in more than 50% of glomeruli in the renal biopsy with rapidly progressive renal deterioration. (Not Graded) 10.6.3.2: We suggest the use of steroids and cyclophosphamide in patients with IgAN and rapidly progressive crescentic IgAN, analogous to the treatment of ANCA vasculitis (see Chapter 13). (2D)

Commentary Prognosis. Clinicians cannot fully account for the variability in outcome based on clinical features alone. The KDIGO guideline alludes to the fact that the new Oxford MEST (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis) score adds independent prognostic information at the time of diagnosis.30,31 This finding now has been validated in independent pediatric and adult populations.32-36 However, although information obtained from the pathology score is statistically independent of the usual prognostic markers, the incremental value of pathologic findings in predicting outcome remains unknown. The impact of histologic variant on therapeutic response also is not known. Conservative therapy. Data suggest that reduction in proteinuria to protein excretion , 1 g/d is associated with a favorable outcome, whether this is achieved through conservative or immunomodulatory treatment strategies.37 The incorporation of proteinuria into the target blood pressure goals reflects a trend toward improved outcomes in proteinuric patients receiving more aggressive blood pressure control in a recent meta-analysis,38 but there are no RCTs to compare blood pressure targets. Therefore, the targeting of 130/80 versus 125/75 mm Hg is opinion based. The guideline does not address the risk of cardiovascular complications in patients with IgA nephropathy (IgAN). Sub–nephrotic-range proteinuria now is a well-recognized risk factor for cardiovascular Am J Kidney Dis. 2014;-(-):---


disease in the general population, independent of renal function.39 It is not known whether the association between low-grade proteinuria and cardiovascular risk is consistent in young and otherwise healthy patients with proteinuria due to primary kidney disease, and this is an important area for future research. If there is a higher risk of cardiovascular morbidity and mortality in this population, blood pressure targets should take into account prevention of cardiovascular complications and lipid-lowering agents may be an important cornerstone of long-term care. Immunotherapy. There are 2 RCTs referenced in this recommendation that support the benefit of corticosteroids compared to conservative therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs),40,41 and both these studies included patients with relatively preserved renal function. A larger multicenter RCT currently is underway in a population with a broad range of renal function (GFR, 20-70 mL/min/1.73 m2) to evaluate the benefits of corticosteroids in patients with persistent proteinuria with protein excretion . 1 g/d despite optimal conservative therapy.42 As in other forms of GN, the relative potential benefits of corticosteroids must be evaluated at the level of the individual patient and relative contraindications (eg, obesity, glucose intolerance, and poorly controlled hypertension) to steroid therapy must be considered. The duration of therapy recommended in this guideline is 6 months. However, this does not mean that a full 6-month trial of corticosteroids is required prior to determining if the patient is likely to “respond” and benefit from this medication. It is worth noting that with time, proteinuria frequently recurs following cessation of corticosteroid therapy.43 This is not addressed in the guideline. The role of adjunctive steroid-sparing therapy for patients with a relapse following a good antiproteinuric response to corticosteroids remains unclear and requires further investigation. Future work also should include the evaluation of whether the histologic pattern of IgAN may identify patients who are more likely to benefit from corticosteroids. The addition of azathioprine to prednisone does not result in a benefit with respect to clinical outcomes according to a well-designed randomized prospective study.44 However, it has not been studied as a steroidsparing agent in patients who have a relapse following withdrawal of corticosteroid therapy. The guideline advises explicitly against the use of MMF. Although it has been suggested that the lack of effect of MMF reflected the fact that the drug was administered initially to patients with very advanced disease,45 RCTs in patients with more moderate disease risk demonstrate conflicting findings.46,47 In addition, observational studies in IgAN should remind us that Am J Kidney Dis. 2014;-(-):---

MMF is not without toxicity48 and is not necessarily a superior therapy in all forms of proliferative GN.49 Fish oil. The recommendation to use fish oil for prevention of renal disease progression is acceptable largely due to the lack of observed harm of this intervention because study findings regarding benefit are conflicting. However, it must be recognized that 3 g/d of purified polyunsaturated fatty acid was the lowest dose associated with beneficial renal outcomes compared with ACE inhibitors or ARBs alone.50 Therefore, the composition of the fish oil formulation is important, and it may be a challenge for individual patients to meet and maintain this target. IgAN variants. The role for combination immunosuppression in crescentic (.50% of glomeruli) IgAN accompanied by rapidly progressive renal deterioration is supported by only low-grade evidence, with retrospective data supporting potentially improved outcome compared with historical controls.51,52 Even less is known about the therapeutic implications of crescents in the absence of rapidly progressive changes in renal function. The lack of inclusion of crescents in the Oxford MEST score should not lead clinicians to conclude that they have no clinical importance; the independent impact of crescents on outcome (above information from clinical parameters) simply is not known. There were insufficient numbers of patients with crescents in the multinational Oxford studies to evaluate the independent prognostic value of crescents or the percentage of glomeruli with crescents associated with adverse prognosis. Further, a very rapidly progressive clinical course would have precluded inclusion in the Oxford cohort. Limited observational data suggest that .50% crescents indicates high risk of progression, and more guidance is required to guide therapeutic decisions in patients with preserved renal function. Henoch-Schönlein Purpura 11.4.1: We suggest that HSP nephritis in adults be treated the same as in children. (2D)

Commentary In Canada, immunosuppressant medication choices appear to be center specific and a unanimous practice algorithm does not exist. There is a preference to use immunosuppressant therapy for Henoch-Schönlein purpura (HSP) that combines steroid therapy with one of azathioprine, cyclosporine, tacrolimus, or MMF/ mycophenolic acid. Cyclophosphamide is used less frequently, particularly because there is no evidence suggesting increased efficacy and due to side effects of infertility and malignancy. Cost has a significant impact on the choice of immunosuppressant therapy. 7

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Newer medications generally are not approved for use in children by Health Canada or provincial formularies and thus are not eligible for provincial drug coverage programs. These practice patterns suggest that the current state of knowledge for treatment of HSP nephritis shows areas requiring active research that include: (1) determination of the severity of histologic disease that requires therapy, and (2) whether any immunosuppressive therapy alone or in combination is effective in inducing remission and preserving kidney function. Although most clinicians would consider performing a biopsy in the presence of persistent proteinuria, hypertension, or azotemia, there currently are no data to inform how long a patient should be observed for spontaneous remission before intervening with therapy or biopsy. Lupus Nephritis 12.3: Class III LN (focal LN) and class IV LN (diffuse LN) —initial therapy 12.3.1: We recommend initial therapy with corticosteroids (1A), combined with either cyclophosphamide (1B) or MMF (1B). 12.3.2: We suggest that, if patients have worsening LN (rising SCr, worsening proteinuria) during the first 3 months of treatment, a change be made to an alternative recommended therapy, or a repeat kidney biopsy be performed to guide further treatment. (2D) 12.5.2: We suggest that patients with pure class V LN and persistent nephrotic proteinuria be treated with corticosteroids plus an additional immunosuppressive agent: cyclophosphamide (2C), or CNI (2C), or MMF (2D), or azathioprine (2D). 12.8: Relapse of LN 12.8.1: We suggest that a relapse of LN after complete or partial remission be treated with the initial therapy followed by the maintenance therapy that was effective in inducing the original remission. (2B) 12.9: Treatment of resistant disease 12.9.1: In patients with worsening SCr and/or proteinuria after completing one of the initial treatment regimens, consider performing a repeat kidney biopsy to distinguish active LN from scarring. (Not Graded) 12.9.2: Treat patients with worsening SCr and/or proteinuria who continue to have active LN on biopsy with one of the alternative initial treatment regimens (see Section 12.3). (Not Graded) 12.9.3: We suggest that nonresponders who have failed more than one of the recommended initial regimens may be considered for treatment with rituximab, i.v. immunoglobulin, or CNIs. (2D) 12.11: Systemic lupus and pregnancy 12.11.1: We suggest that women be counseled to delay pregnancy until a complete remission of LN has been achieved. (2D) 12.11.3: We suggest that hydroxychloroquine be continued during pregnancy. (2B) 12.11.4: We suggest that LN patients who become pregnant while being treated with MMF be switched to azathioprine. (1B)

8

Commentary There are 6 recommendations in the chapter about lupus nephritis: 2 concerning induction and maintenance therapy for class III and IV lupus nephritis; 2 concerning avoidance of immunosuppression for patients with either membranous lupus with sub– nephrotic-range proteinuria or sclerosing lesions; and 2 recommendations that involve the management of lupus nephritis in pregnancy. When strong RCT evidence does not exist, the KDIGO guideline provides expert opinion, to the great potential benefit of clinicians seeking practical advice. Inappropriate immunosuppression in lupus nephritis likely accounts for much of the morbidity and perhaps mortality that is seen with this illness. It thus is useful that the guideline statements for lupus nephritis include advice regarding overtreatment of patients with more benign disease (mesangial lupus nephritis and membranous lupus nephritis with lowgrade proteinuria) or in whom treatment is unlikely to be of benefit (sclerosing lupus nephritis).The guideline also appropriately does not distinguish between focal proliferative and diffuse proliferative disease because the difference between the classifications often is arbitrary (,50% vs .50% involvement).53 Advice to avoid escalation of therapy unless there is evidence of deterioration rather than persistence of urinary abnormalities alone is welcome, particularly because problems such as microscopic hematuria may persist for months or years after attaining remission. Although one earlier study suggested a poor outcome for patients with lupus nephritis who attained only a partial remission,54 more recent data suggest that the long-term outcome of these patients is excellent.55 The CSN working group believes it is important to emphasize 2 aspects of therapy: the importance of corticosteroid dose and duration in the management of lupus nephritis, and second, nonadherence to therapy as perhaps one of the most important causes of treatment failure (12.9). Dose and duration of corticosteroid. There is a tendency in treating lupus nephritis to worry more about choice of immunosuppressive (eg, cyclophosphamide vs MMF) than the dose and duration of corticosteroid therapy. The guideline appropriately recommends high-dose corticosteroids during initial therapy, but then “tapering according to clinical response over 6 to twelve months.” Although there is little evidence concerning what to do after the initial high-dose corticosteroid therapy, a rapid steroid taper, especially aiming to have the patient off corticosteroid therapy by 6 months, can increase the risk for relapse.56 Similarly, although a maintenance dose , 10 mg/d is suggested, some patients may Am J Kidney Dis. 2014;-(-):---


require a higher dose to maintain remission. A recent survey of practice patterns in the management of lupus nephritis indicated that Canadian physicians were more likely than their counterparts in the United Kingdom or in recommended clinical practice guidelines to reduce or eliminate steroids in most patients with lupus nephritis.57 Nonadherence to therapy and “resistant” disease. The proclivity of lupus is to affect young female patients. Corticosteroid side effects can be devastating for this demographic cohort. It is understandable that patients experiencing side effects may modify or abandon therapy altogether. Therefore, in a patient with “resistant” or quickly “relapsing” disease (guideline statements 12.3.2 and 12.9), rather than switching to alternative therapy, it is crucial to explore adherence to the current prescription. Nonadherence to oral therapy probably is the best reason to choose a parenteral cyclophosphamidebased regimen. Given the reduction in serious side effects with the Euro Lupus regimen (500 mg intravenously every 2 weeks for 6 doses total),58 it is recommended over the National Institutes of Health (NIH) protocol,59 particularly if there is reduced GFR. Induction regimens. The guideline suggests that induction studies using MMF included patients with “milder” renal disease compared with those in studies of high-dose cyclophosphamide and conclude that because MMF is unproven for more serious renal involvement, perhaps cyclophosphamide in the NIH protocol would be preferred. It is difficult to say which studies had patients with more, rather than less, severe renal involvement when these reports span continents and decades in time. However, it is worth noting that in the NIH report first using intravenous pulse cyclophosphamide, median SCr level was 1.0 mg/dL.59 There is no a priori reason to believe that patients with more severe involvement with lupus nephritis will respond better to a more toxic regimen. Further, a subgroup analysis of patients with eGFR , 30 mL/min/1.73 m2 in the ALMS (Aspreva Lupus Management Study) did not find evidence that MMF was inferior to intravenous pulse cyclophosphamide.60 Azathioprine also is given little attention in the section on initial therapy, most likely because there is little evidence for its efficacy in class III and IV lupus nephritis. However, lack of evidence of efficacy is not the same as evidence of lack of efficacy. The interesting Dutch study and its follow-up reports are quoted in this section. Purported to be a trial of azathioprine versus intravenous cyclophosphamide, azathioprine was used with pulse corticosteroid, whereas the cyclophosphamide was used with daily oral corticosteroid. Nonetheless, the azathioprine induction group did well with fewer side effects.61 Am J Kidney Dis. 2014;-(-):---

However, a follow-up report noted a higher relapse rate and doubling of SCr level (and chronicity on renal biopsy) with the azathioprine regimen.62 The second renal biopsies were performed in only half the original study cohort, and the most recent report from this trial shows that at close to 10 years of follow-up, the incidence of doubling of SCr level, ESRD, and mortality were not different between the 2 groups.63 The authors themselves note that the biopsy data from their previous report did not help predict deterioration of renal function.63 Maintenance therapy. Most clinicians agree that long-term maintenance therapy with cyclophosphamide should be avoided and maintenance therapy be with either MMF or azathioprine, combined with low-dose corticosteroid (recommendation 12.4.1). The CSN working group concurs that the recommendation did not advocate too strongly for MMF over azathioprine. In a US study comparing therapy with intravenous cyclophosphamide, azathioprine, and MMF, there was a suggestion of fewer relapses with MMF compared to azathioprine.64 However, by 6 years of follow-up, the numbers were small. Two more recent studies have compared maintenance treatment with these 2 drugs. In the MAINTAIN Nephritis Euro Lupus trial, the Euro Lupus patients were randomly assigned to azathioprine versus MMF after 6 months. The patients did not have to be in complete or partial remission to enter this phase of the trial. After more than 4 years’ follow-up, there was no difference between the MMF and azathioprine groups with respect to relapse or doubling of SCr level.65 The second study was the maintenance study of ALMS. In contrast to the MAINTAIN study, patients had to be in complete or partial remission at the time of randomization to azathioprine or MMF in doses similar to those used in MAINTAIN. In this study, the relapse rate in the MMF group was half as much as those being maintained with azathioprine (16% vs 32%; P , 0.005).66 Potential benefits of MMF over azathioprine need to be offset by consideration of costs and the potential for pregnancy. Membranous lupus nephritis. The CSN working group agrees with the recommendations that patients with subnephrotic proteinuria have a good long-term prognosis and should be managed with antiproteinuric therapy, such as renin-angiotensin-aldosterone system (RAAS) inhibitors only. Membranous lupus with sustained nephrotic-range proteinuria certainly carries a better renal prognosis than focal or diffuse proliferative lupus nephritis. However, there is still a small subset of patients with sustained heavy proteinuria who may progress to CKD. Furthermore, there is sizable morbidity associated with sustained nephrosis, including hyperlipidemia and associated accelerated 9

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vascular disease. Important also is the thrombotic risk that can lead to significant morbidity. There is only one RCT comparing corticosteroid alone to corticosteroid plus cyclophosphamide or cyclosporine. Furthermore, that study took decades to complete.67 As in nonlupus glomerular disease, cyclosporine led to complete or partial remission only for as long as it was used; there was a high relapse rate upon its discontinuation. However, the length of therapy was limited to only 11 months. Furthermore, the corticosteroids in this trial were given in an alternate-day regimen, which although sparing many side effects, has not been commonly used since the publication of the Coggins study of alternate-day steroids for idiopathic membranous nephropathy.68 The addition of cyclophosphamide led to a more sustained remission. A recent meta-analysis found that the response to steroids alone was 60% compared to 81% with the addition of another immunosuppressive agent.69 Although the guideline recommends a study of steroid monotherapy for class V lupus nephritis, this particular nephritis can take months to years to remit. For example, one study showed that it took up to 3 years for these patients to enter remission.70 This delay in response poses a number of challenges: First, it makes a good trial very difficult to undertake, particularly because lupus membranous is less commonly encountered than the proliferative forms, and the duration of the trial would pose numerous problems. Systemic lupus in pregnancy. As in all CKDs, renal insufficiency and chronic hypertension factor toward poor pregnancy outcomes, but lupus is unique in that active nephritis predicts an especially poor pregnancy outcome. Furthermore, pregnancy itself has been shown to increase the potential of a disease flare during any trimester and in the early postpartum.71 As such, the guideline appropriately recommends delaying pregnancy until a complete remission of lupus nephritis has been achieved (guideline statement 12.11.1) and not to taper pregnancy-safe immunosuppression until at least 3 months postdelivery (guideline statement 12.11.6) to prevent a flare in pregnancy or the early postpartum, when the risk is deemed to be the highest. However, the guideline does not comment on the appropriate timing of pregnancy, definition of remission, and provides insufficient detail with respect to the management of potentially teratogenic medications.

that these patients might encounter in other countries. However, drug costs often are not covered by provincial health plans and so these must be taken into consideration. Newer agents such as the biologics remain prohibitively expensive, but for most patients do not add much therapeutic benefit over the conventional drugs discussed in this chapter.

Implications for Canadian Health Care Given the relatively high rate of immigration from Asia and the Caribbean, many centers in Canada are now seeing sizable numbers of high-risk patients with lupus and lupus nephritis. The universal access to health care blurs some of the socioeconomic barriers

Commentary Guideline section 13.1 has 2 level-1 recommendations. Both deserve comment. Recommending only cyclophosphamide or rituximab in addition to glucocorticoids may be overly restrictive. There is evidence to suggest that early or limited cases of antineutrophil

10

Pauci-immune focal and segmental necrotizing GN 13.1: Initial treatment of pauci-immune focal and segmental necrotizing GN 13.1.1: We recommend that cyclophosphamide and corticosteroids be used as initial treatment. (1A) 13.1.2: We recommend that rituximab and corticosteroids be used as an alternative initial treatment in patients without severe disease or in whom cyclophosphamide is contraindicated. (1B) 13.2: Special patient populations 13.2.1: We recommend the addition of plasmapheresis for patients requiring dialysis or with rapidly increasing SCr. (1C) 13.2.2: We suggest the addition of plasmapheresis for patients with diffuse pulmonary hemorrhage. (2C) 13.2.3: We suggest the addition of plasmapheresis for patients with overlap syndrome of ANCA vasculitis and anti-GBM GN, according to proposed criteria and regimen for anti-GBM GN (see Chapter 14). (2D) 13.3: Maintenance therapy 13.3.3: We recommend no maintenance therapy in patients who are dialysis-dependent and have no extrarenal manifestations of disease. (1C) 13.4: Choice of agent for maintenance therapy 13.4.1: We recommend azathioprine 1–2 mg/kg/d orally as maintenance therapy. (1B) 13.4.2: We suggest that MMF, up to 1 g twice daily, be used for maintenance therapy in patients who are allergic to, or intolerant of, azathioprine. (2C) 13.4.3: We suggest trimethoprim-sulfamethoxazole as an adjunct to maintenance therapy in patients with upper respiratory tract disease. (2B) 13.4.4: We suggest methotrexate (initially 0.3 mg/kg/wk, maximum 25 mg/wk) for maintenance therapy in patients intolerant of azathioprine and MMF, but not if GFR is ,60 ml/min per 1.73 m2. (1C) 13.4.5: We recommend not using etanercept as adjunctive therapy. (1A) 13.6: Treatment of resistant disease 13.6.1: In ANCA GN resistant to induction therapy with cyclophosphamide and corticosteroids, we recommend the addition of rituximab (1C), and suggest i.v. immunoglobulin (2C) or plasmapheresis (2D) as alternatives. 13.8: Transplantation 13.8.1: We recommend delaying transplantation until patients are in complete extrarenal remission for 12 months. (1C)

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cytoplasmic antibody (ANCA)-associated vasculitis, approximately one-third of which have some degree of renal involvement, in which SCr level is ,150 mmol/L may be treated safely with methotrexate.72 However, the risks and benefits of alternative agents, as well as optimal duration of use, vary when compared to cyclophosphamide.73 Data supporting the use of rituximab as an alternative to cyclophosphamide largely come from 2 RCTs.74,75 These trials focus on early outcomes. Although the data are encouraging, unresolved issues remain regarding optimal treatment after induction with rituximab (eg, ongoing use of an immunosuppressive for maintenance, redosing of rituximab) that those prescribing rituximab for pauci-immune GN must be aware of. Furthermore, although longterm evidence from the lymphoma experience and medium-term evidence from rheumatoid arthritis suggest rituximab is safe in the longer term, there are few data for the long-term safety of rituximab in vasculitis or for patients with chronic repeated exposures (such as happens when it is used for recurrent disease or as maintenance therapy). One level 1 recommendation and 3 level 2 suggestions are made for management of specific subpopulations. Three of these points pertain to the use of plasmapheresis. There is insufficient evidence to support a recommendation that plasmapheresis be used in all patients with a rapidly increasing SCr level or that require dialysis. A recent meta-analysis found that the number of patients randomly assigned was insufficient to make robust conclusions (ie, high risk of type I and type II errors) and that there was an important discrepancy between the apparent risk reduction in dialysis dependency and mortality.76 Specifically, although the risk of ESRD appears to decrease in plasmapheresis-treated patients, the risk of death is unchanged. Furthermore, the estimated risk reduction in ESRD appears implausibly large, suggesting serious overestimation of effect. The suggested use of plasmapheresis in all patients with alveolar hemorrhage or overlap syndromes of ANCA vasculitis and anti–glomerular basement membrane (anti-GBM) disease is based on uncontrolled case series. Given the heterogeneity of presentations of alveolar hemorrhage, the potential variability in prognostic significance of different severities of hemorrhage, and the unproven role of plasmapheresis and its associated side effects and cost, it is difficult to support its use uniformly. Furthermore, the potential for plasmapheresis to deplete immunoglobulins and clotting factors and therefore potentially predispose patients to infection and further hemorrhage require its prescription and monitoring to be considered carefully. Further evidence is required and may be available in the Am J Kidney Dis. 2014;-(-):---

near future with currently enrolling RCTs (eg, ISRCTN07757494). The guideline makes one recommendation and 2 suggestions regarding maintenance therapy. The second suggestion bears comment because it is based on relatively small numbers of patients in observational studies. Some caution must be taken that diagnosing extrarenal manifestations in dialysisdependent patients often is difficult. For example, malaise, fevers, fatigue, or difficult-to-control hypertension may be manifestations of either ESRD or inadequately controlled vasculitis. The decision to withdraw or reinstitute immunosuppression based on extrarenal symptoms must be weighed against the risk of infection and the potential benefits of immunosuppression.77 In general, we agree with these recommendations and suggestions regarding choice of agent for maintenance therapy. However, the best studied starting dose for azathioprine is 2 mg/kg to a maximum of 150 mg/d and reduced by 25 mg/d for patients older than 60 years.78 Furthermore, despite suggesting MMF over methotrexate, neither direct nor formal indirect comparisons of the efficacy of methotrexate compared to MMF exist. Given that one RCT demonstrated that MMF is inferior to azathioprine and another demonstrated similar results between azathioprine and methotrexate, one might surmise that methotrexate should be favored over MMF in patients intolerant of azathioprine and with preserved renal function.79,80 The guideline does not comment on glucocorticoids. There are few data to guide the optimal use of glucocorticoids in either initial or maintenance treatment. Observational data suggest that discontinuation of glucocorticoids within the first 6-12 months may be associated with an increased risk of relapse, but also may be associated with reduced adverse events.81,82 Note should be made that given the ubiquity and heterogeneity of its use and its potential short- and long-term consequences, optimal use of glucocorticoids should be a research priority. The recommendation for treating resistant disease merits 2 comments. First, resistant disease (ie, persistent or worsening disease activity despite adequate immunosuppressive therapy) must be differentiated from inadequately treated disease (which may be amenable to optimized doses of initial therapy) and manifestations of organ scarring (ie, damage from vasculitis such as impaired GFR secondary to glomerulosclerosis and fibrosis rather than ongoing necrosis) or superimposed disease (eg, infections, prerenal azotemia, or acute tubular necrosis). Only the first of these scenarios is likely to merit adjuvant therapy. The second comment is regarding the recommendation for rituximab while suggesting intravenous 11

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immunoglobulins (IVIgs) or plasma exchange. The role of rituximab is based largely on small uncontrolled case series with heterogeneous definitions of resistance.83 There is arguably better evidence for the addition of IVIg. There also is evidence from uncontrolled studies to support the use of agents such as deoxyspergualin or alemtuzumab for refractory cases.84,85 The recommendation to delay transplantation until patients are free of extrarenal manifestations for 12 months deserves comment. This recommendation is based on a single observational study that included only 26 deaths in the analysis. However, there was no association between timing of transplantation and transplant outcomes. There is a significant risk of misestimating the association between duration of remission and death given the limited sample size and ability to adjust for important confounders in this study design. Given the discrepancy in the relationship between death and transplant outcomes, the uncertain causal mechanism underpinning the association, and the potential benefits of not delaying transplantation, further research is required to determine the relationship between clinical manifestations of the disease and timing of transplantation. Implications for Canadian Health Care The relative cost-effectiveness of rituximab is not discussed, but in the Canadian health care system, the cost of the drug and its coverage by regional programs or insurance plans will be an important determinant of its use. Cost also must be considered when MMF is contemplated as a therapy. Reimbursement programs for MMF are heterogeneous across the provinces and across insurance programs. Mycophenolic acid may be covered by in some provinces when MMF is not. Extrapolating from the transplantation literature, there is little suggestion that mycophenolic acid is inferior to MMF and therefore may serve as a cost-effective substitute. The use of adjuvant therapies such as IVIg or plasmapheresis is expensive, but the cost is borne by the health care/hospital system rather than by the individual patient, and access to these therapies also may be controlled by the hospital system.

Treatment of Anti-GBM GN 14.1: Treatment of anti-GBM GN 14.1.1: We recommend initiating immunosuppression with cyclophosphamide and corticosteroids plus plasmapheresis (see Table 31) in all patients with anti-GBM GN except those who are dialysis-dependent at presentation and have 100% crescents in an adequate biopsy sample, and do not have pulmonary hemorrhage. (1B)

Commentary The recommendation to not initiate therapy in patients who are dialysis dependent at presentation 12

and have 100% crescents merits discussion. This recommendation is based on several small cohort studies in which the natural history of anti-GBM GN did not appear modified by aggressive therapy. However, patients with anti-GBM GN often are relatively young and therefore may be the most likely to tolerate aggressive therapy and have the largest long-term gains from even marginal preservation of renal function. Although patients with advanced glomerulosclerosis and tubulointerstitial fibrosis seem unlikely to recover, those with predominantly cellular crescents have improved in other studies of immunosuppression and plasma exchange.86 More data are required to make firm recommendations, particularly in the current era of improved availability of antiGBM diagnostic tests and physician awareness of the disease, as well as increasing knowledge regarding the safe use of immunosuppression. Implications for Canadian Health Care Access to plasmapheresis is limited in Canada. Given the probability that time to diagnosis is a major determinant of both SCr level and the degree of glomerulosclerosis and tubulointerstitial fibrosis prior to treatment (and therefore associated with the probability of effective treatment), patients with suspected anti-GBM disease should have the time it will take to access plasmapheresis factored into the expediency of their diagnostic workup.

SUMMARY AND CONCLUSIONS The KDIGO clinical practice guideline for GN represents an excellent summary of the current state of knowledge regarding glomerular disease and as such provides a useful framework for the practicing physician seeking advice on management of these often challenging patients. At the same time, the guideline emphasizes the lack of concrete evidence for many of the treatment and management decisions that need to be made on a daily basis. This is not the fault of the KDIGO review panel; rather, it serves to emphasize how difficult it is to study relatively uncommon diseases for which the clinical course can run a relapsing and remitting course over several decades before finally resulting in end-stage renal failure. For Canadian clinicians, the challenge will be how to incorporate some of the management suggestions into their everyday practice, given the somewhat fragmented nature of our individual provincial health plans that leads to variable access, particularly for newer agents or biologics, across the country. Additionally, having an approved indication for a medication does not always ensure ready access, particularly for patients without a drug plan who rely on access through provincial formularies. As an Am J Kidney Dis. 2014;-(-):---


example, rituximab is approved for management of ANCA vasculitis, but obtaining access to payment for this drug in the public or private system can be challenging. The gaps in our knowledge regarding management of GN are readily evident when reading the guideline. What is less evident is how those knowledge gaps can be closed and in what time frame. Canadian nephrologists will need to engage with colleagues throughout the world in collaborative research ventures if there is to be any hope of improving our state of knowledge. In the past decade, considerable progress has been made on understanding the molecular basis of some of the glomerular diseases that are either more common or have a poorer prognosis. These improvements of our understanding of the pathogenesis of FSGS, membranous nephropathy, and IgAN, as examples, should lead to therapies that are more directed. It is hoped that future clinical trials using targeted therapy might yield results more rapidly and with a greater degree of precision.

ACKNOWLEDGEMENTS Support: No financial support was required for the development of this commentary. Financial Disclosure: The authors declare that they have no relevant financial interests.

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