EVIDENCE REPORT

Guidelines for the Screening, Treatment and Monitoring of Lupus Nephritis in Adults

Working Group

UCLA Bevra H. Hahn, MD (Rheum) Jennifer M. Grossman, MD (Rheum) Maureen McMahon, MD (Rheum) W Dean Wallace, MD (Path) Karandeep Singh, MD (Nephrology) Soo-In Choi, MD (Rheum) Justin Peng, MD (Rheum) Mazdak Khalighi, MD (Path) Maneesh Gogia, MD (Rheum) John FitzGerald, MD (Rheum) Alan Wilkinson, MD (Renal) Suzanne Kafaja, MD (Rheum) William J Martin, MD (Rheum) Christine Lau, MD (Nephrology) Sefali Parikh, MD (Nephrology) Mohammad Kamgar, MD (Nephrology) Anjay Rastogi, MD (Nephrology) Weiling Chen, MA (Rheum) Cheryl C Lee, BA (Rheum) Rikke Ogawa (Librarian)

UCLA-Harbor George A. Karpouzas, MD (Rheum)

UCLA and Cedars-Sinai Daniel Wallace, MD (Rheum)

Oklahoma Joan T. Merrill, MD (Rheum)

UCSF Jinoos Yazdany, MD (Rheum) David Daikh, MD (Rheum)

Special thanks to Rosalind Ramsey-Goldman, MD and Niloo Nobkht, MD Table of Contents

Abbreviations

1. Introduction

2. Guideline Development Methods a. Methodology 1. Rationale and Development of a uniform Lupus Nephritis Definition 2. Search Strategy 3. Study Selection Based on Title and Abstracts 4. Selection of Studies Based on Full Text of Articles 5. Quality Assessment

b. Data Extraction and Synthesis 1. Rating the Strength of Evidence 2. RAND/UCLA Appropriateness Method Using the Task Force Panel (TFP)

c. Definition of Key Term

3. Evidence for Screening, Treatment and Monitoring of Lupus Nephritis in Adults

a. Screening Summary - Pathology 1. Role of the Renal Biopsy in Lupus Nephritis 2. Correlation of Outcome and Biopsy Findings 3. Vascular and Tubulointerstitial Disease in Lupus Nephritis

b. Treatment and Monitoring 1. Randomized Control Trials 2. Cohort Studies

c. End Stage Renal Disease 1. When to Consider Transplant 2. Graft and Patient Survival 3. Immunosuppressive Medications 4. Predictors of Outcome After Transplant 5. Summary

d. Pregnancy in Lupus Nephritis Patients 1. Maternal/Fetal Outcomes of Pregnancy in Women with SLE 2. Relationship of Drugs Used to Treat Nephritis and Outcome of Pregnancy in Lupus Nephritis

4. Biomarkers in SLE Nephritis a. Anti-dsDNA and Complement b. Anti-dsDNA c. Anti-C1Q d. Complement

5. Adjunctive Therapies to Delay Progression of Renal Damage and Development of Co- Morbid Conditions 6. Socio-Economic Costs and Impact of Lupus Nephritis a. Overview of incidence, economic impact and risk factors of lupus nephritis b. Cost of Lupus Nephritis c. Cost Effectiveness Analysis of Specific Treatments 1. IV Cyclophosphamide vs Steroids alone 2. Mycophenalate Mofetil vs IV Cyclophosphamide Tables 1. Task Force Panelists 2. ISN/RPS 2003 Classification of Lupus Nephritis 3. Renal Pathology Scoring System 4. Studies of Poor Prognostic Findings based on Renal Biopsy 5. RCT Inclusion/Exclusion Criteria and Jadad Scores 6. Cohort Studies Inclusion/Exclusion Criteria and Newcastle-Ottawa Scale 7. End Stage Renal Disease/Renal Transplantation Articles 8 Summary of Commonly Used Medications’ Teratogenic Effects 9 Use of Anti-DNA antibodies for prognosis among SLE patients

APPENDICES A. Search Strategy B. Abstraction Tool – Abstracts C. Abstraction Tool – RCT Articles D. Abstraction Tool – Cohort Articles E. Case Scenarios

REFERENCES ABBREVIATIONS

ACR American College of Rheumatology ANA Anti-nuclear antibody Anti-dsDNA Anti-double strand Deoxynucleic Acid ARA American Rheumatism Association AZA Azathioprine CPH Cr Creatinine CR Complete Response CrCl Creatinine Clearance CYC Cyclophosphamide DDay GGram Hpf High Power Field ISN/RPS KG Kilogram IV Intervenous LE Lupus Erythematosus MG Miligram MTX Methotrexate PO PR Partial Response Pred Prednisone Prot Protein RBC Red Blood Cell serCr Serum Creatinine SLE Systemic Lupus Erythematosus UUrine WBC White Blood Cell WHO Wk Week Yr Year 1. Introduction

Important clinical advances have been made since the last ACR guidelines on diagnosis and management of SLE were published in 1999 (1). Those advances include a) improved histologic classification of subsets in renal biopsies (2), b) better management strategies to reduce renal damage (3), c) improved instruments to measure disease activity, damage, flare, and response to therapies ACR response criteria 2004 (4-9) and d) introduction of new treatments with evidence for equal or better response rates and less toxicity compared to the “standard” therapies reviewed in the 1999 (1). The promise of biologic therapies is now on the near horizon with very recent reports of successful clinical trials in lupus (e.g. Belimumab (10)) and lupus nephritis (e.g. ALMS (11)). In addition, the methodology underlying guidelines for medical therapy has improved dramatically (see for example the 2008 ACR guidelines for treatment of rheumatoid arthritis (12). Therefore, it is timely for the ACR to issue updated guidelines for screening, treatment and monitoring in people with lupus nephritis.

The purpose of this systematic review generated evidence-based report is to help develop clinical scenarios to be used for guideline development utilizing a collaborative effort with a working group (WG) and core expert panel (CEP) of clinicians and methodologists.

2. Guideline Development Methods

a. Methodology

Rationale and Development of a uniform Lupus Nephritis Definition After many discussions, the working group defined diagnosis of Lupus Nephritis as one that meets ACR criteria (persistent proteinuria and/or cellular casts) or in the opinion of a trained rheumatologist or nephrologist.

Search Strategy We conducted a systematic review of randomized controlled trials and large cohort studies for the therapies identified by the CEP that have been used in treatment of Lupus Nephritis. The therapies chosen were selected on the basis of their availability to be used in treatment of lupus nephritis. Therapies currently in development and not yet available on the market were not reviewed. The search strategy is outlined in Appendix A, and briefly, used Medline (through PubMed) by applying MeSH headings and relevant keywords with references through 1/22/2010. The search was updated on August 8, 2010.

Study Selection Based on Titles and Abstracts Our search was limited to human studies, published in English, and having abstracts. We excluded all review articles. The initial literature search identified 10418 potential interest citations. Two reviewers screened each title and abstract for relevance to the specific aims.

The articles were excluded if: Study population not specific for lupus nephritis (e.g. lupus, autoimmune disease) Case series, Review articles, Meta-analysis Study population consists of all patients less than age 16 Study therapy is not currently commercially available

For randomized clinical trial, articles were excluded if total number of lupus nephritis patients in the study were less than 30. For cohort studies, articles were included using the following criteria: -if treatment has already been studied in randomized clinical trial, the cohort study must have either higher number of patients and/or longer study duration - if treatment has not been studied in randomized clinical trial but is or will anticipated to be commercially available (e.g. rituximab, stem cell)

Selection of Studies Based on Full Text of Articles At the screening phase, all articles identified through the searches for lupus nephritis were reviewed independently by two physicians using a structured form (Appendix B). A third reviewer reconciled discordant results and any disagreements between reviewers. For Randomized Clinical Trials and Cohort Studies, the principal investigators reviewed the results and made final acceptance.

Accepted Randomized Clinical Trials, articles were then reviewed and the relevant data abstracted using a standardized data abstraction forms (Appendix C). The full text of all the articles was reviewed and data abstracted by two reviewers. For Cohort Studies, full text of all the articles was reviewed and data abstracted by at least one reviewer with more than 50% of the articles undergoing duplicate independent data abstraction and reconciliation to ensure consistency and accuracy. (Appendix D – cohort study abstraction form). The principle investigator adjudicated discrepant results in both.

Accepted articles in pathology, renal transplant and end stage renal disease articles, pregnancy, biomarker, and socio-economic quality of life were sent to designated reviewers.

Data were entered into an Excel Spreadsheet.

Quality Assessment The quality of RCTs was assessed using the Jadad instrument (13). The Jadad scale ranges from 0-5 based on points given for randomization, blinding, and accounting for withdrawals and dropouts. The quality of the cohort Studies was assessed using the New Castle-Ottawa Quality Assessment Scale (14). The New Castle-Ottawa scale ranges from 0 – 9 stars based on points given for selection, comparability and exposure.

b. Data Extraction and Synthesis

Rating the Strength of Evidence For each recommendation, the strength of evidence will be assigned using the method from the American College of Cardiology (15) and/or EULAR/ESCIST (16-17) after the Task Force Panel meeting when the recommendations are developed.

RAND/UCLA Appropriateness Method using the Task Force Panel (TFP) The RAND/UCLA methodology (18-20) incorporates elements of the nominal and Delphi methods. The task force panelists received the evidence report and case scenarios (see Appendix E), illustrating the potential key permutations for each guidelines, instructions for grading scenarios and definitions of all variables and agreed upon thresholds and branch points by email. They were asked to use the evidence to rate the appropriateness of the clinical scenarios permutations. Using a 9-point Likert scale to rate each scenario permutation, the first set of ratings occurred before and a second set of ratings after a group meeting. Disagreement was defined when > 1/3 of the panelists rated a scenario in the lowest tertile of the appropriateness (1-2-3) and > 1/3 of the panelist rated the same scenario in the upper tertile (7- 8-9). In the absence of disagreement, a median rating in the lowest tertile classified a scenario permutation as “inappropriate” and a median rating in the upper tertile classified a scenario as appropriate. Those scenario permutations rating in 4-5-6 together with those with disagreement were classified as “uncertain.” Dispersion of the scores provided the degree of agreement

The anonymous ratings of the 1st round of ratings were reviewed with the panelists at each meeting. Through discussion of definitions and scenario, the reasons for the uncertain category were identified and resolution of discrepancies were attempted by modification of the scenarios, clarification of definitions, or acknowledgement of discordance between clinical practice experience and the medical literature.

Please see Table 1 for list of Task Force Panelists.

Definition of Key Term

DEFINITION OF LUPUS NEPHRITIS DIAGNOSIS Lupus Nephritis is defined as one that meets ACR criteria (persistent proteinuria and/or cellular casts) or in the opinion of a trained rheumatologist or nephrologist.

Evidence for the Screening, Treatment and Monitoring of Lupus Nephritis in Adults.

a. Screening Summary - Pathology

ROLE OF THE RENAL BIOPSY IN LUPUS NEPHRITIS The purpose of the renal biopsy and the significance of its findings in the treatment of lupus nephritis (LN) have been extensively debated despite, or because of, numerous studies evaluating renal biopsy findings in patients with systemic lupus erythematosus. In an effort to better characterize the specific pathologic findings in lupus-related renal disease, the World Health Organization (WHO) developed a classification system for lupus nephritis in 1974. Over the years this system has been modified and recently, in 2003, adapted into a new classification system under the auspices of the International Society of Nephrology and the Renal Pathology Society (2, 21). The lupus classification is based solely on glomerular disease and does not incorporate vascular or tubulointerstitial changes. As with the WHO system, the ISN/RPS classification has six classes: minimal mesangial LN (class I), mesangial LN (class II), focal LN (class III), diffuse LN (class IV), membranous LN (class V), and sclerosing LN (class IV). Classes III and IV are further characterized by the presence of active or chronic lesions and class IV is subdivided into segmental (IV-S) or global (IV-G) glomerular disease (see Table 2). Some studies have since shown improved interobserver reproducibility with this system (22-23). However the clinical significance of each of these classes and subclasses has been a source of investigation and debate. To evaluate acute and chronic changes a semi-quantitative activity and chronicity grading system was published by the National Institute of Health (NIH) and has been used in many studies (24) (see table 2). However, this grading system is not uniformly applied and has been shown to have poor reproducibility by some authors (25). With the wealth of literature from different cohorts of patients from all over the world over the last 30 years, it is not surprising that there are often contradictory findings in similarly structured studies (see Table 3).

The primary role of the renal biopsy is to provide information to guide treatment. Historically, the proliferative lesions (class III and IV LN) have been regarded as clinically more severe and require immunosuppressive therapy (26-28). It has been recognized that these classes have wide variability in activity and chronicity and the exact point at which immunosuppression should be started or increased has been widely investigated. A review of the literature demonstrates a lack of consensus regarding which lesions respond to therapy and at what point treatment should be initiated. Nevertheless, many studies have shown cellular crescents, glomerular necrosis with karyorrhectic debris, subendothelial deposits, and tubulointerstitial inflammation all correlate with acute renal insufficiency and demonstrate a response to immunosuppressive therapy (29-34).

The corollary to the activity index is the chronicity index. Beyond a certain point, it is futile to attempt aggressive therapy. The point at which renal scarring precludes improvement by treatment has been investigated and should always be an important consideration in the evaluation of the renal biopsy. Sclerosing lupus nephritis (class VI) with 90% or greater glomerular sclerosis has consistently been shown to have poor prognosis or no response to treatment (35). In one study, patients younger than 23 with any form of renal scarring have been found to be at 50% risk for renal failure at 8 years (24). Furthermore, numerous studies have found each chronicity marker, specifically global and/or segmental glomerulosclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis, to be individual risk factors for renal failure and in combination indicate very high risk (29, 36-40). Chronic lesions have poor prognostic implications even in the setting of normal renal function (41).

The specific lesions and threshold of activity that require treatment have been investigated. Studies have shown no or limited response to immunosuppressive treatment in patients with mesangial lupus nephritis (class I and class II). However this should be considered in light of data revealing 50% of patients with class II lupus nephritis have no evidence of renal disease (42). Patients with subepithelial deposits only (class V) have minimal improvement of serum creatinine when treated with immunosuppressive therapy, but may improve proteinuria (43-45). In the setting of combined proliferative LN (class III or IV) and membranous LN (class V), the proliferative process dominates the clinical picture and is a better indicator of response to treatment (46).

There are several findings on the renal biopsy that can strongly suggest lupus as the etiology of the glomerulonephritis. These include “full house” deposition of immunoglobulins and complements (IgG, IgA, IgM, C1q and C3) demonstrated by immunofluorescence microscopy and tubuloreticular structures in endothelial cells seen by electron microscopy (47). Nevertheless, there are no features that are pathognomonic for lupus nephritis and it is recommended in the ISN/RPS classification system to defer the diagnosis of lupus nephritis in the absence of collaborating clinical evidence (21). Of course, the renal biopsy is also an important diagnostic tool to detect non lupus-related renal diseases or, rarely, subclinical lupus nephritis (42).

CORRELATION OF OUTCOME AND BIOPSY FINDINGS The strongest risk factors for renal failure are primarily chronic changes, especially tubulointerstitial scarring and glomerular sclerosis. In some studies high activity indices especially the presence of cellular crescents, have also correlated with renal failure or death (32, 41, 48-50). However, mild to moderately active proliferative lesions have stronger correlation with acute renal insufficiency than chronic renal failure. This may be a reflection of treatment intervention and not a true picture of the natural disease course. One study found chronic renal insufficiency, as defined by doubling serum creatinine, was predicted by >50% crescents or moderate to severe tubulointerstitial scarring (51) (see Table 4 for composite data indicating poor renal prognosis from multiple studies).

VASCULAR AND TUBULOINTERSTITIAL DISEASE IN LUPUS NEPHRITIS Vascular lesions are not a component of the lupus nephritis classification systems. However, there are a variety of vascular injuries that may be concurrent with the glomerular disease and may or may not be associated with the underlying lupus. The vascular lesions include nephrosclerosis, uncomplicated immune complex deposits, non-inflammatory necrotizing vasculopathy (lupus vasculopathy), vasculitis and vascular thrombosis (52). Nephrosclerosis is more common in older patients or patients with hypertension. Different studies have found no change or mild reduction in renal survival in the setting of nephrosclerosis and concurrent LN in older patients. Uncomplicated immune complex deposits are due to deposition of circulating lupus-related immune complexes. This finding has not been shown to have clinical significance. Lupus vasculopathy is most commonly seen in active class III and class IV lupus nephritis. Lupus vasculopathy is a poor prognostic finding as demonstrated by one study that found 68.1% renal survival at 5 years in patients with this lesion (53). Concurrent vasculitis is rare and is frequently associated with ANCA antibodies. Vascular thrombosis may indicate thrombotic microangiopathy and in the setting of lupus is often associated with antiphospholipid antibodies. Studies evaluating vasculitis and vascular thromboses in the setting of lupus nephritis have demonstrated increase in glomerular sclerosis and reduced renal survival (31, 53).

Tubulointerstitial inflammation is most commonly present with class III or IV LN and associated with immune complex deposits in 73% of cases (54). This suggests immune complex deposits cause most but not all cases of tubulointerstitial inflammation. The role of tubulointerstitial scarring as an independent risk factor for chronic renal failure has previously been discussed (24, 41).

b. TREATMENT AND MONITORING

Randomized Controlled Trials (RCT) In Randomized Controlled Trials, 31 peer-reviewed articles and 3 abstracts were abstracted based on selection criteria. Treatments inclusion/exclusion criteria are listed in Table 5. Jadad score was calculated indicating the quality assessment of the article.

Therapies comparison include prednisone PO and IV, cyclosporine, cyclophosphamide PO and IV, azathioprine, plasmapheresis, mycophenolate mofetil, leflunomide, rituximab, belimumab, and tocilizumab. Data abstracted include therapies in which all study participants are on, biopsy data, duration of the study, average lupus and lupus nephritis duration, intervention arms, endpoints, and adverse reactions.

Data are compiled into an excel sheet that includes Intervention and Outcome (I-O) and a separate sheet including Adverse Events (AEs). Yellow highlights indicate statistically significant parameter within treatment arm from baseline to after treatment. Orange highlights indicate statistically significant parameter between treatment arms.

Cohort Studies In Cohort studies, 25 peer-reviewed articles were abstracted based on commercially available therapies, large # cohorts or long duration of the study. Newcastle-Ottawa Scale is calculated indicating the quality assessment of the article. Please see Table 6.

Therapies comparison include rituximab, stem cell, anti-malarial, cyclosporine, cytoxan, immunosuppressives, azathioprine, mycophenolate mofetil, leflunomide.

Data are compiled into an excel sheet that includes Intervention and Outcome (I-O) and a separate sheet including Adverse Events (AEs). Yellow highlights indicate statistically significant parameter within treatment arm from baseline to after treatment. Orange highlights indicate statistically significant parameter between treatment arms. c. End Stage Renal Disease

When to consider transplant Expert opinion suggests that clinical activity of lupus should be quiescient before transplantation, with quiescence achieved without cytotoxic agents or more than 10 mg of prednisone daily. Clinically active lupus typically improves with the development of chronic kidney disease but may not do so in some patients, particularly African American women. It is the degree of clinical activity, and not the presence or absence of serologic markers of disease activity, that should determine transplant candidacy. Patients who are heavily immunosuppressed during the course of their native kidney disease may be at increased risk for post-transplantation opportunistic infections, lymphoma, and avascular necrosis (55).

When lupus nephritis results in end stage renal disease, dialysis must be given consideration. There is some evidence to suggest that patients who receive peritoneal dialysis have better post-transplant graft outcomes as compared to those receiving hemodialysis (56). However, candidacy for peritoneal dialysis requires the presence of some residual kidney function, and as that is lost hemodialysis is usually required to achieve sufficient clearance.

The timing for transplantation is not an issue for those without donors. However, if there is ready access to a living related kidney donor, preemptive transplantation is generally a good option. One small study found that dialysis greater than 25 months may be associated with worse graft survival in transplant recipients (57), while other studies (58-59) found no association between duration of dialysis and graft outcomes. A study reviewing USRDS data over a several-year period (56) found no difference in recipient mortality in patients receiving hemodialysis prior to transplant versus no dialysis prior to transplant, although there was a trend towards worse graft outcomes in patients not receiving any dialysis (hazard ratio 1.3, p = 0.055).

Graft and patient survival Once a decision has been made to proceed with transplant, there is an abundance of data to suggest that kidney transplantation in patients with lupus nephritis is associated with outcomes generally equivalent to transplant recipients with other underlying etiologies (58-66). Living- related kidney transplants appear to be associated with better graft and recipient outcomes as compared to deceased donor kidney transplants (60).

One-, three-, and five-year rates of graft survival reported in the literature range from 68.8- 93.6%, 56-84%, and 33-89%, respectively. Weighted mean 1-, 3-, and 5-year graft survival based on number of transplants per study was 85.1%, 60.9%, and 43.9%, respectively. One-, three-, and five-year rates of kidney transplant recipient survival reported in the literature range from 86.5-99.2%, 61-97.2%, and 36-96%, respectively. Weighted mean 1-, 3-, and 5-year patient survival based on number of transplants per study was 93.3%, 70.1%, and 53.5%, respectively.

Though subclinical recurrence of lupus nephritis may be common on routine surveillance biopsies (67), the prevalence of recurrent lupus nephritis was found to be only 2.4% in analysis of multi-year UNOS data (68), with risk factors for recurrence including African American race, female gender, and younger age.

Immunosuppressive medications The use of calcineurin inhibitors, mycophenolate mofetil/mycophenolic acid, and azathioprine is considered the mainstay of immunosuppressive therapy in all kidney transplant recipients. Therefore, it is not surprising that the use of these drugs has been associated with improved outcomes in kidney transplant recipients with lupus nephritis. Recipients with lupus nephritis who were not treated with a calcineurin inhibitor had an 89% greater risk of graft failure and an 80% greater risk of death. Those who did not receive either mycophenolic acid or azathioprine had a 41% increased risk of graft failure and a 66% increased risk of death (56).

Predictors of outcome after transplant Risk factors for graft failure include multiple pregnancies, multiple blood transfusions, a greater comorbidity index, higher body weight, age, African American race of the donor or recipient, prior history of transplantation, greater PRA levels, lower level of HLA matching, deceased donors, and hemodialysis in pretransplant period. Risk factors for recipient death include higher recipient and donor age, prior transplantations, and higher rate of pretransplant transfusions (56).

Summary In summary, kidney transplantation for lupus nephritis should be treated similarly to kidney transplantation for other causes of renal failure. Ideally, lupus should be clinically quiescent at the time of transplant. Peritoneal dialysis should be chosen over hemodialysis as a bridge to transplantation if a living-related kidney donor is not readily available. Graft and patient survival in kidney transplant recipients with lupus nephritis are generally on par with non-lupus-related kidney transplant recipients. The presence of lupus should not influence choice of immunosuppressive medications. Certain factors can be predictive of worse graft and recipient outcomes. Please see Table 7 for Summary of End Stage Renal Disease/Renal Transplantation Articles. d. Pregnancy in Lupus Nephritis Patients

Maternal/Fetal outcomes of pregnancy in women with SLE. We identified one systematic review/ meta-analysis that examined pregnancy outcomes in patients with Systemic Lupus Erythematosus and Lupus Nephritis (69). This review yielded 37 studies which fulfilled study entry criteria, including 29 studies that were case series, five case- control studies, and three cohort studies. Twelve studies were prospective, and 25 studies were retrospective. 34 studies had data for active nephritis at the time of conception, whereas 33 reported data from patients with historic nephritis. Overall, the studies included a total of 1842 patients and 2751 pregnancies.

Random-effects analytic methods were used to evaluate pregnancy complication rates. Overall, the induced abortion rate was 5.9%; when these pregnancies were excluded, fetal complications included spontaneous abortion (16%), intra-uterine growth restriction (12.7%), stillbirth (3.6%), and neo-natal deaths (2.5%). Among live births, the preterm birth rate was 39.4%. The definitions used to determine these outcomes were not clarified in the manuscript.

The most frequent maternal complications included lupus flare (25.6%), hypertension (16.3%), nephritis (16.1%) (no specification given regarding frequency of new disease vs. recurrence), and pre-eclampsia (7.6%). Severe complications, including eclampsia, stroke, and maternal death were observed in <1% of subjects. Maternal deaths occurred because of opportunistic infections, sepsis, flares of lupus nephritis, and renal impairment. Random-effects meta-regression analysis was performed to assess the effects of nephritis on pregnancy outcomes. Active nephritis was significantly associated with maternal hypertension and preterm birth, whereas a history of nephritis was significantly associated with hypertension and pre-eclampsia. After controlling for hypertension, the association between active nephritis and preterm birth was still statistically significant.

Nine papers of thrity-seven correlated renal histology with maternal and/or fetal outcomes. Among these studies, there was no statistically significant association seen between histologic subclass and the rate of unsuccessful pregnancy or any pregnancy complication.

Relationship of Drugs Used to Treat Nephritis and Outcome of Pregnancy in Lupus Nephritis We did not identify any randomized controlled studies that examined the use of medications to treat lupus nephritis in pregnancy. We did identify one retrospective case series that correlated outcomes of pregnancy with treatments of lupus (70). In this study, there were no differences in outcome seen between patients treated with prednisolone alone, prednisolone plus azathioprine, and those who received no treatment. 21/23 pregnancies in women taking azathioprine were successful. A summary of data from MICROMEDEX regarding known information about the teratogenic effects of commonly used medications in lupus nephritis is presented in Table 8.

4. BIOMARKERS IN SLE NEPHRITIS

Biomarkers can be defined as a genetic, biological, biochemical or molecular events whose alternations correlate with disease development or manifestations and can be measured in the laboratory (71). Many different types of biomarkers have been, or are being evaluated, including but not limited to genetic tests, RNA microarray profiles, cytokine profiles, autoantibody profiles and flow cytometry assays of B cell subsets. This is an evolving field with numerous promising candidates (reviewed by Mok, CC (72). This evidence report will focus on anti-dsDNA, C3, C4 and anti-C1q as they are easily measured, readily available and frequently evaluated in patients with SLE. Recommendations for the use of biomarkers in SLE will require updating as additional scientific data and clinical feasibility is reported.

Articles for the evidence report came from four sources; recent reviews (72-74), the evidence report for Quality Measures in SLE, kindly provided by Jinoos Yazdani, MD, expert identified articles, and articles from the RCT, CCT and cohort searches as described in the methods section.

Anti-dsDNA and complement There is no direct evidence from prospective controlled trials that checking SLE specific laboratory tests, such as anti-dsDNA and complements (versus not checking these laboratories) will improve patient outcomes. However, several of these assays are part of the diagnostic criteria for SLE, have been shown to have prognostic significance, and may assist with disease monitoring (discussed under "indirect evidence" below).

With regard to monitoring of anti-dsDNA antibodies and complements, two randomized controlled trials have directly addressed the question of whether SLE flares can be decreased by responding to changing titers of these assays with escalation of immunosuppressive therapy (75-76). Although the morbidity associated with prophylactic escalations of corticosteroids have made enthusiasm for these trials somewhat limited, both trials (discussed below), did demonstrate that flares in a subset of patients can be decreased. The first study by Dutch investigators (76) performed block randomization of patients with anti- dsDNA antibodies by whether patients experienced a flare in the previous 2 years, and by two immunosuppression maintenance regimens (stable treatment with glucocorticoids and another immunosuppressive or decreasing glucocorticoid dosage versus no immunosuppressive agents). Early treatment with prednisone 30 mg/day when patients in the treatment arm experienced a 25% rise in anti-dsDNA titers reduced the incidence of major and minor flares.

A more recent randomized study by Tseng et al.(75) followed 154 patients monthly for up to 18 months. During follow-up, 41 patients were characterized as having serological flares (elevation of both anti-dsDNA level by 25% and the C3a level by 50% over the previous 1-2 monthly visits). Using a double-blind design, half of these patients received 30 mg/day of prednisone or a placebo for two weeks, followed by a taper over the ensuing 2 weeks. A statistically significant reduction in flares in the group receiving prednisone was observed. However, this study also illustrated that the positive predictive value for these biomarkers for clinical flares in SLE was suboptimal, and that many patients would be over-treated if the serological cutoffs used in this study were used.

Anti-dsDNA Anti-dsDNA antibodies have high specificity for SLE and are found in up to 70% of patients at some point in the course of the disease. Several lines of indirect evidence support the utility of checking anti-dsDNA antibodies at baseline (at a minimum) in patients with SLE. These include:

1) Evidence that these antibodies correlate with disease activity

2) Evidence that in a subset of patients, anti-dsDNA antibodies may precede disease exacerbations

3) Evidence that the presence of these antibodies may identify patients with an increased chance of specific severe disease manifestations over time, such as glomerulonephritis.

Each of these is discussed below.

Kavanaugh et al., as part of the American College of Rheumatology Ad Hoc Committee on Immunologic Testing, issued guidelines for the use of the anti-DNA antibody testing in 2002 (77). Using a systematic review of the literature, they calculated sensitivities, specificities, and likelihood ratios for anti-DNA testing in SLE. The results are adapted in Table 9.

As illustrated in Table 9, the positive likelihood ratios of 4.14 (disease activity), 1.7 (renal involvement), and 1.7 (renal activity) show that the presence of anti-DNA can influence the likelihood of important disease parameters. These overall effects are small, but significant. The general conclusion from these data is that anti-DNA antibodies remain an important clinical tool in the management of SLE. However, the specific weighted means are likely prone to error given the immense heterogeneity in studies given different definitions of disease activity and differing patient populations.

The systematic review of the literature performed by Yazdany and colleagues yielded a number of other relevant studies as well:

1) Additional studies demonstrating that anti-dsDNA antibodies correlate with disease activity in SLE were identified (78-86). However, clinical-serological discordance (i.e. clinical quiescence, but high anti-dsDNA antibodies or vice versa) has also been described in a subset of patients (87-89). 2) Many studies have shown that rising anti-dsDNA antibody titers may predict disease flares in a subset of SLE patients (83, 89-96), particularly renal flares(97-101). However, a few negative studies have also been reported (102-104), and some studies show anti- dsDNA antibody levels actually decrease in the midst of a flare (92-94). 3) A few studies have shown that anti-dsDNA antibodies early in disease increase the chance of the development of certain disease manifestations, such as glomerulonephritis (81, 105-107), and that these antibodies may be associated with poorer renal outcomes (108-110).

Not all studies support the use of routine antiDNA testing. Esdaile and colleagues found the sensitivity for anti-dsDNA detecting a flare as assessed by SLEDAI was 50% and the specificity was less than 75% with positive and negative likelihood ratios near 1.0 (111).

Anti-C1Q The use of anti-C1q as a biomarker in lupus nephritis was recently reviewed by Mok in 2010 (72). To summarize, anti-C1q antibodies are present in 20-44% of lupus patients with most studies showing an association of these antibodies with renal disease. A review by Sinico et al noted that anti-C1q correlated with active renal disease with a sensitivity ranging from 44%- 100% and a specificity of 70-92% (112).

Two recent prospective studies have been published. In one study of 70 patients with SLE prior to a diagnosis of SLE , 15 developed renal disease all with positive anti-C1q, 93% with anti- dsDNA while 45% without renal disease had anti-C1q and 73% were antiDNA positive (112). The median follow up for patients who had not developed nephritis was 13 years (range 2-17). In this study, anti-C1Q did not correlate with antiDNA.

Moroni and colleagues studied the relationship of antiC1q antibodies in SLE in 228 patients followed for an average of 6 years (113). Elevation of anti-C1q predicted renal flares with a sensitivity of 80.5% and specificity of 71%. This was only marginally better than antiDNA and complement levels. This study suggested that all four tests combined together had a good negative predictive value while antiC1q combined with C3 and C4 yielded the best results for positive predictive value. Anti-C1q was not as informative in patients with membranous GN as 46% of flares occurred in anti-C1q negative patients.

Not all studies support the use of routine antiC1Q testing. Esdaile and colleagues found the sensitivity for anti-C1q detecting a flare as assessed by SLEDAI was 50% and the specificity was less than 75% with positive and negative likelihood ratios near 1.0 (111).

Anti-C1q antibodies are not necessarily specific for SLE as they can be seen in 0-3% in children and up to 18% in elderly individuals (114). They can also be seen with infections.

Complement The relationship of complement to SLE is complex and research in this area is ongoing. Despite the limitations of applying this potential biomarker longitudinally to all SLE patients (such as variations in synthesis, genetic deficiencies and varied extravascular distribution) (115- 116), evidence supports obtaining baseline values for complements with available assays as a minimal standard of care. Although not part of the diagnostic criteria for SLE, depressed complement levels may add to the clinical information traditionally used to diagnose the disease. In addition, literature spanning several decades points to the following generalizations: 1) Depressed complements or complement split products roughly correlate with some aspects of disease activity in SLE (85, 115-116), such as renal disease (81, 117-119), 2) Decreasing complements and complement split products can predict flares in some patients (94-96, 99-101, 120-121) and 3) Hypocomplementemia may also be associated with poorer outcomes over time (99, 122).

Not all studies support the use of routine complement testing. Esdaile and colleagues found the sensitivity for C4 detecting a flare as defined by SLEDAI was 50% and the specificity was less than 75% with positive and negative likelihood ratios near 1.0 (111). For C3, the likelihood ratio for a positive test was near 2.0, suggesting that it may be more helpful.

5. ADJUNCTIVE THERAPIES TO DELAY PROGRESSION OF RENAL DAMAGE AND DEVELOPMENT OF CO-MORBID CONDITIONS

Several partly-preventable factors contribute to progressive renal damage, particularly in the setting of proteinuria. These include adaptive hyperfiltration (relatively normal glomeruli increase in size and function in response to damage in other glomeruli, which probably leads to glomerular sclerosis), systemic hypertension, accelerated atherosclerosis, hypovolemia and exposure to nephrotoxic drugs or dyes. Therefore, management of lupus nephritis includes not only the control of SLE but also attention to these other issues, particularly since lupus nephritis tends to flare and/or to persist, making progression to end stage renal disease fairly common over a course of 25 years. The recommendations discussed below are available from the National Kidney Foundation and UpToDate (123-124).

Treatment with an angiotensin converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB) is recommended for any patient with glomerular disease and proteinuria persistent beyond 3 months, and/or patients with glomerular renal disease who are hypertensive. ACE and ARB are more effective in delaying decline of renal function if initiated before serum creatinine levels reach 1.2 mg/dL in women and 1.5 mg/Dl in men. There are two goals of ACE/ARB treatment: a) proteinuria lower than 1000 mg per 24 hours, and b) blood pressure lower than 130/80, with some authorities encouraging an even lower number if proteinuria exceeds 1000 mg per 24 hours. Data are stronger for effectiveness of ACE/ARB therapies in slowing decline of renal function in chronic kidney disease, compared to low protein diets. However, if proteinuria cannot be reduced below 1000 mg/24 hours with ACE/ARB, diet intervention should be considered. A 60% reduction in proteinuria from baseline may be the best achievable outcome. If ACE/ARB are not adequate for control of hypertension, loop diuretics should be added. ACE/ARB reduce glomerular perfusion; an increase in serum creatinine is common after instituting these agents; an increase of 35% over 2 to 4 months is acceptable if stable. Hyperkalemia is also a potential adverse effect. Both serum Cr and K+ should be assayed at regular intervals after initiation of ACE/ARB therapies.

Other preventable causes of decline in renal function include dehydration for any reason (vomiting, diarrhea, infections, over-diuresis) and administration of potentially nephrotoxic drugs (aminoglycoside antibiotics, NSAIDs, radiographic contrast materials including gadolinium, etc), and these should be avoided when possible.

Metabolic disorders can accompany chronic kidney disease and cause organ damage, such as metabolic acidosis, hyperphosphatemia, hyperparathyroidism, hyperkalemia, and malnutrition due to anorexia. Guidelines for detection and management of these problems are available (123-124).

Management of hyperlipidemia is also required as a measure to lower cardiovascular disease risk associated both with SLE and with chronic kidney disease CKD. The most common lipid abnormality in CKD is hypertriglyceridemia, which should be treated by diet and appropriate medication. CKD is considered an independent risk factor for coronary heart disease; thus the LDL-cholesterol should be kept below 100 mg/dL (2.6 mmol/L), and some authorities recommend a level less than 70 mg/dL. Statin therapies are usually required to reduce LDL- cholesterol levels. One randomized controlled study shows that patients with SLE who have undergone renal transplantation have significantly fewer cardiovascular events than similar patients on placebo (125).

Anemia of CKD may require treatment; see references (123) and (124).

Planning for renal replacement therapy, discussed in another section, should begin when GFR, falling steadily, reaches a level below 30 mL/min/1.73 M2. Planning for placement of shunts which require months to mature, for identifying and typing potential living donors, etc require time and participation of multiple medical teams. Uremic symptoms are common when GFR falls below 15 mL/min. Uremic symptoms usually requiring immediate dialysis include volume overload that cannot be controlled medically, pericarditis/pleurisy, hypertension that cannot be controlled medically, platelet dysfunction with active bleeding, acute peripheral neuropathy or encephalopathy, and hyperkalemia that cannot be controlled medically.

Prevention of infection and screening for malignancies are additional concerns in managing patients with lupus nephritis receiving chronic immunosuppression. Prospective studies of immunization with influenza or pneumococcal vaccines suggest that they are safe and relatively effective in terms of antibody titers induced (patients on high doses of immunosuppressives are less likely to respond than those on lower doses). Otherwise, systematic prospective studies addressing efficacy and safety of preventing infections and screening for malignancies in SLE patients are not available. A recent USA study (126) showed that administration of influenza/pneumococcal vaccines occurs in approximately 60% of SLE patients, as does routine screening for malignancy (mammograms, cervical smears, colon screening).

6. SOCIO-ECONOMIC COSTS AND IMPACT OF LUPUS NEPHRITIS There have been several studies that address the socio-economic costs of lupus nephritis. Pharmaceutical companies have sponsored many of these studies. However, the studies demonstrate similar findings that the additional cost of lupus nephritis over lupus without nephritis or non-lupus conditions is significant. Additional studies have examined the relative cost-effectiveness of different nephritis treatments with strong evidence supporting cycophosphamide over prednisone mono-therapy for the treatment of severe lupus nephritis (127) and mycophenalate mofetil to be more cost-effective than cyclophosphamide (128).

Overview of incidence, economic impact and risk factors of lupus nephritis Ward described the incidence of end stage renal disease (ESRD) due to systemic lupus ertythematosus using US Renal Data System, a national population-based registry of all patients receiving renal replacement therapy for ESRD (129). The 2004 incident rate was 4.9 per million in 2004. Women had higher rates than did men (7.6 vs. 2.0), African-American higher than either Hispanic or Caucasian (20.3 vs. 5.8 vs. 3.0). Patients with lower socio- economic status had higher rates than those with high socio-economic status (5.2 vs. 3.8). Other authors have supported the findings of higher rates of lupus nephritis among African- Americans (130-132). Poverty may account for some of this explanation (131, 133). In a population based ecological study, Ward reported that lower socio-economic areas had higher incidence of endstage renal disease due to SLE (129) suggesting that limited access to care results in poorer SLE renal outcomes. However, Petri attributed the race differences due to other factors including adherence (physician reported) and type of medical insurance (134). Contreras supported the association of poverty and lupus nephritis (132). In an interesting study on race using genetic markers and patient questionnaires from the LUMINA study (135), Fernandez portioned out the contribution of race and socio-economic factors on risk of lupus nephritis. Through logistic modeling, ethnicity explained 7.6% of the variation observed. The ethnicity component could be further broken down into admixture vs. socio-economic status variables. Ward reported that Lupus patients were as likely to get living related transplants but less likely to get cadaveric renal transplants and more likely to stay on transplant lists longer than other patients with ESRD. Female gender and African-American patients were more prevalent proportions than other causes of renal failure (136).

Cost of Lupus Nephritis Carls and colleagues described the direct and indirect costs of SLE and SLE nephritis using a large commercial database that contains data on medical and pharmaceutical claims to calculate direct medical costs (2005 US$) and data on employee absenteeism and short-term disability (137). The project was co-authored by the Health and Productivity Divisions, Thomas Healthcare and Bristol-Myers Squibb, UCSF Institute for Health and Productivity and Emory University, Rollins School of Public Health. Of the 17 million enrollees, 6269 patients with lupus were identified based on at least inpatient or at least 2 outpatient medical claims. Of these SLE patients 592 had nephritis. Lupus nephritis patients’ direct and indirect medical costs totaled $58,389 and $5,806 versus Lupus patients without nephritis $15,447 and $5,714 versus $6,819 and $5,093 (for controls matched to lupus patients without nephritis). Compared to 11 other chronic care conditions, lupus nephritis was associated with the highest medical costs (driven primarily by direct medical costs). Clarke and colleagues (138) used a cohort of 6 Canadian and US clinics that collected prospective self-reported patient data on health resource utilization and lost work. Patients’ direct and indirect medical expenditures were estimated using patient self reported health utilization and work reported absenteeism. All costs were expressed in terms of 2002 Canadian dollars. Bristol-Myers Squibb supported funding. Of the 715 patients, 89% had no renal disease. Stratifying patients by the SLICC renal damage count, patients with higher scores had higher direct and indirect medical costs. Patient with no renal disease had median direct and indirect costs of $14K and $46K versus patients whose SLICC renal damage = 3 with costs of $90K and $77K. Li and colleagues (139) conducted a similar study using Medicaid patients. The study was authored and supported by funding from Bristol-Myers Squibb. Using at least 2 outpatient claims or at least 1 inpatient claim, 20,125 SLE patients were identified and 2,298 patients with continuous enrollment during the 5-years follow-up. Patients with lupus nephritis had significantly higher direct medical costs ($27,463) than either lupus patients without nephritis ($13,014) or matched controls ($9,258). When nephritis patients were stratified by presence of ESRD, costs for patients with ESRD ($47,660) were significantly higher than costs for patients without ESRD ($18,002). Li also demonstrated that costs increased significantly over the years for lupus patients (particularly for those patients with ESRD). Pelletier and colleagues used a large US commercial insurance clams dataset to examine cost of lupus nephritis (140). The study was supported and co-authored by Genetech. Of the 15,590 SLE patients identified, 1068 had nephritis. One-third of the patients (30.3%) with nephritis were hospitalized during the year while only 13.6% of the SLE patients without nephritis were hospitalized. Costs across all medical areas of care (e.g. laboratory, outpatient, emergency department, infusions) were higher among patients with nephritis totaling $30,652 vs. $12,029 (in 2008 US$) per patient. Costs directly attributable to SLE were $6,991 and $2,489 respectively.

Cost effectiveness analyses of specific treatments

Intravenous Cyclophosphamide vs. Steroids alone In a 1994 NIAMS funded study, McInnes and colleagues reported that cyclophosphamide plus steroids was cost-savings compared to steroids alone, attributable to the significant costs of higher rates of ESRD for patients treated with steroids alone (127). All costs were reported in 1998 dollars. When looking at costs projected over 10 years for a hypothetical cohort of 1130 SLE nephritis patients (annual estimate of incident nephritis), the expected total costs of patients treated with steroids alone would be $65 million (more than 99% of that cost coming from the care for the 50% of patients projected with ESRD). In contrast, the cost of providing care for patients treated with cyclophosphamide was $14 million with only 5% of patients progressing to ESRD. Even though the analysis was over-simplified the magnitude of the cost- savings is clear. (As an example, they have all of the 5% of patients treated with cyclophosphamide progressing to ESRD in year 3.)

Mycophenalate Mofetil vs. Intravenous Cyclophosphamide In a study funded and co-authored by Aspreva, Wilson and colleagues analyzed quality adjusted life-years by treatment type (128). Based on 2.7 g of MMF vs. 750 mg/m2 of cyclophosphamide costs and quality of life were derived for a hypothetical cohort of 10,000 simulated patients. Algorithms were detailed to include crossover patients, expected outcomes, as well as major and some minor adverse infections. The expected cost in 2005 £ for MMF vs. cylophosphamide over 24-weeks was £1,388 vs. £2,994. MMF also had superior quality of life scores with 0.26 QALYs vs. 0.22 QALYs therefore resulting in cost-saving (dominance) of MMF yielding a cost-savings of £41,205 per QALY. The typical willingness to pay for a QALY is £25 - £35 thousand (equivalent to $50 – $70 thousand). Using sensitivity analyses to vary outcomes the confidence interval around the £41,205 per QALY even with poorer outcomes, there was 81% probability that the cost per QALY would be less than the willingness to pay for QALY. Table 1 – Task Force Panelists

Jo H. M. Berden, MD** Rosalind Ramsey-Goldman, Chi-Chiu Mok, MD* Professor of Nephrology MD* Chief of Rheumatology Radboud University Nijmegen Professor of Medicine Tuen Mun and Pok Oi Hospital Med Ctr Northwestern University HONG KONG Nijmegen, THE NETHERLANDS Chicago, ILLINOIS

Frederic A. Houssiau, MD, Jill P. Buyon, MD* PhD* Liz Shaw-Stabler Professor of Medicine Professor and Head Executive Director NYU / Hospital for Joint Diseases Rheumatology Center for Lupus Care, Inc. New York, NEW YORK Universite Catholique Louvain Inglewood, CALIFORNIA Brussels BELGIUM

Gabriel Contreras, MD** David A. Isenberg, MD, FRCP* Brad Rovin, MD** Professor Associate Professor of Medicine Professor of Medicine Center for Rheumatology Div of Nephrology Division of Nephrology Research The Ohio State University University of Miami University College of London Columbus, OHIO Miami, FLORIDA London ENGLAND

Karen H. Costenbader, MD, MPH* Kenneth C. Kalunian, MD* Murray B. Urowitz, MD, Assistant Professor of Medicine Professor of Medicine FRCPC* Rheumatology Immunology & Center for Innovative Therapy Professor in Medicine Allergy UCSD School of Medicine The Toronto Western Hospital Harvard Med School / Brigham La Jolla, CALIFORNIA Toronto, CANADA Boston, MASSACHUSETTS

Mary Ann Dooley, MD* Susan Manzi, MD, MPH* David Wofsy, MD* Associate Professor of Medicine Chair, Department of Medicine Professor of Rheumatology Nephrology West Penn Allegheny Health Arthritis-Immunology University of North Carolina System VA Medical Center / UCSF Pittsburgh, PENNSYLVANIA San Francisco, CALIFORNIA Chapel Hill, NORTH CAROLINA

Peng Thim Fan, MD* Rheumatologist, Community Practice North Hollywood, CALIFORNIA

* = Rheumatology ** = Nephrology *** = Pathology Table 2.

ISN/RPS 2003 Classification of Lupus Nephritis

Class I Minimal mesangial lupus nephritis Class II Mesangial proliferative lupus nephritis Class III Focal lupus nephritisa Class III (A) Active lesions: focal proliferative lupus nephritis Class III (A/C) Active and chronic lesions: focal proliferative and sclerosing lupus nephritis Class III (C) Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis Class IV Diffuse lupus nephritisb Class IV-S (A) Active lesions: diffuse segmental proliferative lupus nephritis Class IV-G (A) Active lesions: diffuse global proliferative lupus nephritis Class IV-S (A/C) Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis Class IV-G (A/C) Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C) Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis Class IV-G (C) Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis Class V Membranous lupus nephritis Class VI Advanced sclerotic lupus nephritis Adapted from Weening et al. (21) Table 3.

Renal Pathology Scoring System

Activity Index Chronicity Index Glomerular Abnormallties 1. Cellular proliferation 1. Glomerular sclerosis 2. Fibrinoid necrosis, karyorrhexis 2. Fibrous crescents 3. Cellular crescents 4. Hyaline thrombi, wire loops 5. Leukocyte infiltration

Tubulointerstitial Abnormalities 1. Mononuclear-cell infiltration 1. Interstitial fibrosis 2. Tubular atrophy

All parameters are scored from 1-3 in terms of severity. Fibrinoid necrosis and cellular crescents are weighted by factor of 2. Maximum score of activity index is 24, of chronicity index is 12 Adapted from Austin et al. (24) Table 4. Studies of Poor Prognostic Findings based on Renal Biopsy

Study Poor prognostic findings N Year Austin et al. (24) 50% renal failure at 8 years in high risk group (CI 102 1983 1+ in pts age 8-23 or CI 5+ in pts 24-61) Austin et al. (36) 25% of class IV developed renal failure at 10 102 1984 years follow up. Chronicity markers are individual risk factors for renal failure and very high risk factor in combination. Austin et al. (51) >50% crescents or moderate/severe interstitial 64 1995 fibrosis at high risk for doubling creatinine Banfi et al (53) Renal vascular lesions (Lupus vasculopathy, 285 1991 vasculitis, thrombosis, nephrosclerosis) 5 & 10 year survival of 74.3% and 58% in pts with RVL vs 92% and 83.3% in pts without RVL Blanco et al. (48) Vascular hyalinosis, glomerular sclerosis, fibrous 85 1994 crescents and CI >3 Contreras et al (141) chronicity index >/= 2 213 2005 Esdaile et al (142) Tubulointerstitial fibrosis/atrophy 87 1989 Esdaile et al. (33) Class IV LN Marked subendothelial immune 87 1991 deposits Faurschou et al (35) Class III, Class VI lupus nephritis 100 2010 Hill et al. (143) Presence of tubular macrophages, 71 2001 karyorrhexis/fibrinoid necrosis, cellular crescents Kojo et al. (39) Cellular crescents, fibrous crescents, segmental 99 2009 sclerosis Magil et al (144) Presence of karyorrhexis 45 1988 Makino et al. (30) Karyorrhexis associated with response to high 60 1993 dose steroids Miranda et al. (31) Glomerular thrombosis strongly associated with 108 1994 crescents, glomerular necrosis and increased AI Moroni et al (145) CI > 2 93 2007 Mosca et al. (26) AI 9+, CI 4+ 81 1997 Nossent et al (38) AI 12+, CI 4+ 116 1990 Parichatikanond et al >25% sclerotic glomeruli, >25% tubular atrophy, 81 1997 (37) >25% interstitital mononuclear, infiltrate Yokoyama et al. (23) Class IV(S &G), ESRF in patients with IV(S or G) 60 2004 vs I, II, III, V (40.9% vs 2.6%)

AI = activity index, CI = chronicity index, RVL = renal vascular lesion, LN = lupus nephritis GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS

Table 5. RCT Inclusion/Exclusion Criteria and Jadad Scores Prednisone (Pred) vs Cyclophosphamid (CYC) IV vs Cyclosporin (CSA) Article Inclusion Criteria Exclusion Criteria Jadad Score Austin et al, Diagnosis of SLE by the ACR, a renal biopsy that Endocapillary proliferation or subendothelial 1 NIH, USA showed typical lupus membranous nephropathy electron-dense deposits characteristic of 2009 (44) (LMN) by light and electron microscopy, >= 2g;/d proliferative lupus nephritis, clinical or histologic proteinuria, age >=12 year, informed consent evidence of nonlupus renal disease, cytotoxic drug or CsA use ruing the 30d period before study entry, cytotoxic drug or CsA use for >2wk during the 10 wk period before study entry, cytotoxic drug or CsA use for >10 wk at anytime in the past, requirement for corticosteroids in dosage >20 mg/m2 body surface area per day of prednisone (or equivalent) for control of extrarenal disease at the time of study entry, active or chronic infection (including HIV infection), preexistent malignancy, pregnancy in female patients, nursing mothers, female patients who were not practicing birth control, a single functioning kidney, insulin-treated diabetes, GFR <25ml/min per 1.73m2 body surface area at study entry, and history of allergy or toxicity to cyclophosphamide or CsA.

Cyclosporin (CSA) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score Zavada et al, Diagnosis of SLE (meeting 4 criteria of the ACR), Treatment with CPH or Cyclosporin ever before, 3 CYCLOFA- renal biopsy documenting lupus nephritis according treatment with other immunosuppressive drugs or LUNE study, to WHO or ISN/RPS as proliferative high-dose glucocorticoids within the last 3 months, Czech glomerulonephritis class III (focal) or IV (diffuse); persistent elevation of serum creatinine Republic, clinical activity as defined by presence of at least 2 (>=140micromol/l), pregnancy or lactation, bone 2010 (146) of the following: abnormal proteinuria (more than marrow insufficiency with cytopenias not GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS Cyclosporin (CSA) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score 500mg of protein in a 24-h urine specimen), attributable to SLE, and severe coexisting abnormal microscopic hematuria, or C3 conditions, such as infection, liver disease, active hypocomplementemia (the latter two were defined peptic ulcer, etc. according to the norms in the laboratories of the participating center)

Prednisone (Pred) vs Azathioprine (AZA) vs Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Jadad Score Diagnosis of SLE by criteria of ARA, one of the A major infection within the preceding 2 weeks. 4 criteria required was positive LE cell test in the Pregnancy. Immunosuppressive therapy within 2 course of the disease, kidney disease unaccounted months. Severe liver disease. A history of for by other pathologic processes, with at least one hypersensitivity to a study drug, or a serum Steinberg and of the following: red cell casts in a fresh centrifuged creatinine greater than 4.0mg% (creatinine Decker, urine sediment; cellular casts and either hematuria clearance <20ml/min) NIH, USA, (20 RBC/hpf) or pyruia (20 WBC/hpf), proteinuria of 1974 (147) at least 1g/24 hr, or the combination of high serum titers of anti-DNA binding activity, low serum complement and a positive renal biopsy, renal biopsy demonstrating diffuse glomerulonephritis with at least a portion of all glomeruli involved. Diagnosis of SLE by ARA preliminary criteria, A major infection within the preceding 2 weeks, 1 positive lupus erythematosus cell test, and kidney pregnancy, immunosuppressive therapy within 2 disease unaccounted for by other pathologic months, severe liver disease, a history of processes with at least one of the following: red hypersensitivity to a study drug, or a serum Carette et al, cell casts in a fresh centrifuged urine sediment; creatinine greater than 4.0mg% (creatinine NIH, USA, cellular casts and either hematuria (ten clearance <20ml/min) 1983 (148) erythrocytes per high power field) or pyuria (ten leukocytes per high power field) in the absence of infection; proteinuria of at least 1 g/d or the combination of high serum DNA binding activity, low serum complement and renal biopsy results consistent with lupus glomerulonephritis Austin et al, Diagnosis of SLE as defined by ARA, clinical or Creatinine clearance consistently less than 20ml 1 GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS Prednisone (Pred) vs Azathioprine (AZA) vs Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Jadad Score NIH, USA, histologic evidence of active lupus per minute, major infection within 2 week s of study 1986 (149) glomerulonephritis, and informed consent to all entry, pregnancy, a leukocyte count of less than aspects of the study. 2000 per cubic millimeter, cytotoxic-drug therapy within eight weeks, and sensitivity to the study drug Diagnosis of systemic lupus erythematosus and Creatinine clearance consistently <20ml/minute, 2 Steinberg and clinical/histologic evidence of active lupus presence of a major infection within the previous 2 Steinberg, glomerulonephritis. weeks, pregnancy, white blood cell count NIH, USA, <2000/mm3, treatment with a cytotoxic drug within 1991 (150) the previous 8 weeks, or known sensitivity to any study drug. The presence of >=4 ACR criteria for SLE, age 18 Patients with membranous LN WHO-class Va or Vb 2 to 60 years, creatinine clearance (Cockcroft-Gault) were excluded.. Decline in renal function (more >25ml/min, and biopsy-proven proliferative LN. For than 30% increase in serum creatinine) during patients already known to have proliferative LN, the treatment with cytotoxic immunosuppressive agents last renal biopsy had to be performed less than one in the month before inclusion. Active infection. Grootscholten year before. Patients with WHO-class IV or Vd LN Malignancy <5 years before randomization. et al, were eligible when they had signs of active Pregnancy or refusal to use reliable contraceptives Netherlands nephritis or a deterioration of renal function. during the first 2.5 years of treatment. Chronic Nephrology, Patients with WHO-class III or Vc LN had to meet active or persisting hepatitis or cirrhosis of the liver, 2006 (151) both criteria. active peptic ulcer, leukocytopenia (<3.0x10 9 /l) or thrombocytopenia (<100 x 10 9/l), with suppressed bone marrow (as shown in a bone marrow aspirate). Known allergy for azathioprine or cyclophosphamide. Prednisone (Pred) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score Patients had 4 or more criteria for SLE and severe Pregnancy or had received cytotoxic drug therapy 2 lupus nephritis defined by a nephritic urine for more than 10 weeks at any time, active Boumpas et sediment and impaired renal function with a infections, insulin-dependent diabetes, or previous al, NIH, USA creatinine clearance between 25 and 80 ml per malignancy. 1992 (152) min. If creatinine clearance was higher than 80 ml per min, the candidate had to have very active renal histology with crescents or necrosis in more GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS Prednisone (Pred) vs Azathioprine (AZA) vs Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Jadad Score than 25% of glomeruli. Renal biopsies were evaluated by light and electron microscopy. Patients had to have both glomerulonephritis and a Receipt of cytotoxic drug treatment for more than 2 2 diagnosis of systemic lupus erythematosus. weeks during the 6 weeks before study entry or Glomerulonephritis was defined as a sediment on receipt of cylophosphamide therapy for more than two or more urianlyses that showed either 10 or 10 weeks at any time; receipt of pulse therapy with more erythrocytes per high-power field or corticosteroids during the 6 weeks before study Gourley et al, erythrocyte or leukocyte casts (without evidence of entry; need (at the time of study entry_ for oral NIH, USA, infection) or both, plus histologic evidence of active corticosteroids in dosages greater than 0.5mg of a 1996 (153) proliferative lupus glomerulonephritis on a renal prednisone equivalent per kilogram of body weight biopsy specimen obtained within 3 months of study per day to control extrarenal disease; active or entry (provided that a biopsy could be done safely). chronic infection; pregnancy; the presence of only one kidney; insulin-dependent diabetes mellitus; and allergy to methyprednisolone or cylophosphamide.

Prednisone (Pred) vs Cyclophosphamide (CYC) PO Article Inclusion Criteria Exclusion Criteria Jadad Score Clinical diagnosis of SLE and fulfilled 4 or more of Cyclophosphamide had been used in the past or if 2 the criteria for the classification of SLE as other immunosuppressive drugs had been used developed by the ARA Committee on Diagnostic within 6 months of entry into the study. and Therapeutic Criteria. Serologic confirmation of the disease was also required, based on finding of a positive LE-cell preparation and an ANA in a titer Donadio et >= 1:32 – or if a positive LE-cell preparation was al, Mayo, not obtained, on finding two doubtful positive (for USA, example, rosettes of neutrophils or nucleolysis) and 1976 (154) an ANA titer >= 1:32. In addition, working criteria defining progressive lupus glomerulonephritis on the basis of renal insufficiency based either on reduced initial creatinine clearance to less than 80ml/min per 1.73m2 or on a 25% reduction in creatinine clearance as compared to initial GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS Prednisone (Pred) vs Cyclophosphamide (CYC) PO Article Inclusion Criteria Exclusion Criteria Jadad Score clearance over a maximum period of 3 months, and on a renal morphologic diagnosis of active glomerulonephritis. Arbitrarily established a 25% change in creatinine clearance as indicting an important change in renal function so as to take into consideration the biologic variability of creatinine excretion that influences creatinine clearance. Patients previously untreated or treated with adrenocorticoids were considered to be eligible for the study Clinical diagnosis of systemic lupus erythematosus Cyclophosphamide had been used in the past or if 2 and have fulfilled 4 or more of the criteria used for other immunosuppressive drugs had been used the classification of the disease. A positive LE-cell within 6 months of entry into the study. preparation or rosettes of neutrophils or nucleolysis, a positive ANA >= 1:32 or since mid- Danadio et 1973, elevated levels of anti-nDNA, creatinine al, Mayo clearance less than 80ml/min/1.73m2 or a Clinic, USA reduction of 25% in creatinine clearance as 1978 (155) compared with the initial clearance over a maximal period of 3 months, and adequate renal biopsy showing diffuse proliferative glomerulonephritis. Patients previously untreated or treated with steroid agents were eligible.

Prednisone (Pred) + Cyclophosphamide (CYC) vs plasmapheresis Article Inclusion Criteria Exclusion Criteria Jadad Score 4 of the ARA criteria for the diagnosis of SLE and Creatinine clerarance was less than 3mg/100ml. 1 Clark et al, had at least one episode of ANA positivity, elevated Canada and DNA binding and complement depression. All had Jamaica, renal biopsy with the diagnosis of diffuse 1983 (156) proliferative glomerulonephritis. Pohl et al, Diagnosis of SLE confirmed by at least 4 of the Serum creatinine concentration of more than 533 2 Lupus ARA diagnostic criteria with some modifications; by micromol/L (6.0mg/dL); previous plasmapheresis GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS Prednisone (Pred) + Cyclophosphamide (CYC) vs plasmapheresis Article Inclusion Criteria Exclusion Criteria Jadad Score Nephritis current renal biopsy evidence of severe lupus for any reason; a history of steroid psychosis; Collaborative glomerulonephritis (WHO Class III or IV with more current pregnancy; a history of neoplasm within the Study Group, than 50% of glomeruli involved or class V with previous 5 years; a neutrophil count of less than NIH, USA, superimposed diffuse or severe segmental 1500/mm3; or age of less than 16 years. 1991 (157) proliferation) Lewis et al, 16 years of age or older; diagnosis of SLE as Pregnancy, serum creatinine concentration above 3 Lupus defined by ARA and a qualifying renal biopsy. 530 micromol per liter (6mg/dL), previous treatment Nephritis with plasmapheresis, a history of primary Collaborative myocardial disease, a history of cancer within the Group, USA, past 5 years, prednisone-associated psychosis, 1992 (158) peptic ulcer disase, and active liver disease.

Cyclophosphamide (CYC) IV vs Cyclophosphamide (CYC) PO Article Inclusion Criteria Exclusion Criteria Jadad Score Fulfilled at least 4 of the ACR criteria for the Refused CYC treatment or in whom renal biopsy 0 classification of SLE and had DPGN (WHO Class showed significant sclerosis or chronic changes but Mok et al, IVa or IVb) diagnosed and treated in two large without activity were excluded. Hong Kong, regional hospitals in Hong Kong (Queen Mary and 2001 (159) Ten Mun Hospitals) between 1995 and 1998 were included in this study.

High-Dose Cyclophosphamide (CYC) IV vs Low Dose Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score Diagnosis of SLE according to the ACR criteria, Patients who had taken CYC or AZA during the 2 age >= 14 years, biopsy proven proliferative lupus previous year or had taken >=15mg/day prednisone Houssiau et glomerulonephritis (WHO Class II, IV, Vc, or Vd), (or equivalent) during the previous month were al, Euro- and proteinuria >= 500mg in 24 hours. excluded (except for a course of glucocorticoids for Lupus a maximum of 10 days before the referral). Other Nephritis exclusion criteria were renal thrombotic Trial, 2002 microangiopathy, preexisting chronic renal failure, (160) pregnancy, previous malignancy (except skin and cervical intraepithelial neoplasis), diabetes mellitus, GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS High-Dose Cyclophosphamide (CYC) IV vs Low Dose Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score previously documented severe toxicity to immunosuppressive drugs, and anticipated poor compliance with the protocol.

Mycophenolate Mofetil (MMF) + Tacrolimus vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score Eligible patients were either gender and between Serum creatinine > 3.0mg/dl (265.2 microlmol/L) or 2 12 and 60 yr of age; provided written informed estimated Creatinine clearance <30ml/min per consent; diagnosis of SLE according for ACR 1.73m2 on repeated testing; liver function with ALT, (1997); showed an SLE disease activity index ASST, or bilirubin greater than twice the upper limit >=12; had a diagnosis of Class V+IV LN according of the reference range; abnormal glucose to ISN/RPS 2003 classification of LN, with a metabolism, defined as a fasting (i.e., no caloric pathologic chronic index (CI) <4 proved by light, intake for at least 8 h) plasema glucose level > 6.1 Bao et al, immunofluorescence, and electron microscopy mmol/L and/or a 2-h plasma glucose level > 7.8 Nanjing, within 3 wk before enrollment; and exhibited overt mmol/L; known hypersensitivity or contraindication 2008 (161) proteinuria (>=1.5g of protein in a 24-h urine to any components of these regimens; use of CTX, specimen) with or without active urinary sediment MMF, or tacrolimus within the past 12 wk; (any of urine sediment RBC count >10 x 10 4/ml or pregnancy or lactation; life-threatening white blood cells > 5 per high-power field or red cell complications such as cerebral lupus; or other casts in the absence of infection or other causes. severe coexisting conditions precluding immunosuppressive therapy or conditions requiring intravenous antibiotic therapy.

Mycophenolate Mofetil (MMF) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score Patients has SLE diagnosis according to ARA Severe complication such as infection, leucopenia, -1 Hu et al, criteria; urinalysis showed active urine sediments, heart failure or malfunction of the central nerve Nanjing, proteinuria >2g/d; renal biopsy reviewed lupus system or liver 2002 (162) nephritis WHO IV within 3 months prior to the study Ong et al, SLE fulfilling ARA criteria with WHO Class III or IV Serum creatinine more than 200 micromol/L, white 2 Malaysia, lupus nephritis, aged 16 years or older blood cell count < 3.5 x 10 9 L, evidence of major 2005 (163) infection, history of cancer, alcohol or substance GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS Mycophenolate Mofetil (MMF) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score abuse, active peptic ulcer disease, pregnant or lactating women, known allergy to MMF or cyclophosphamide and use of study drugs in the preceding 6 months. SLE meeting 4 classification criteria of the ACR; Creatinine clearance of less than 30ml /min, serum 2 renal biopsy documenting lupus nephritis according creatinine on repeated testing greater than 3mg/dL to the classification of WHO III, IV, or V; clinical (265.2 microlmol /L), severe coexisting conditions activity as defined by one or more of the following: precluding immunosuppressive therapy or incidence decrease in renal function (serum conditions requiring intravenous antibiotic therapy, creatinine, >1mg/dL (88.4 micromol/L), proteinuria prior treatment with mycophenolate mofetil, (defined as more than 500mg of protein in a 24-h treatment with intravenous cyclophosphamide Ginzler et al, urine specimen), microscopic hematuria (defined within the past 12 months, monoclonal antibody USA, 2005 as >5 red cells per high power-field) or the therapy within the past 30 days, or pregnancy or (164) presence of cellular casts, increasing proteinuria lactation. with rising levels of serum creatinine, active urine sediment (hematuria or celluar casts), or serologic abnormality (anti-DNA antibodies or hypocomplementemia). Those with Class III or V lupus nephritis were required to have a serum creatinine level greater than 1mg/dL or proteinuria greater than 2g in a 24-h urine specimen. ARA criteria of SLE, 18-50 yrs of age; urine protein Serum creatinine >=3 mg/dL or creatinine 3 >= 1g/24h with active urine sediment; serum clearance <30mL/min; proportion of glomerular creatinine <3mg/dL (265microlmol/L) or creatinine sclerosis >=50%, chronicity index >=4 with several clearance >=30mL/min, biopsy proven ISN/RPS renal tubule-interstitial fibrosis; primary or Wang et al, Class IV with exception of superimposed secondary immunodeficiency, especially leukocyte Nanjing, membranous changes and NNV lesion shown in count of <=2 x 19 9 L; any clinically significant 2007 (165) arterioles and interlobular arteries and the infection, pregnancy or lactation, active type B or C proportion of glomerular sclerosis <50% and hepatitis, tuberculosis and the receipt of CTX, chronic index <4. MMF, or other cytotoxic drugs within the past 3 months Appel et al, Aged 12 to 75 yrs, diagnosis of SLE, LN (active or Treatment with MMF or IVC within the previous 3 ALMS, active/chronic) conformed by kidney biopsy within year, continuous dialysis for ?2 wk before 2009 (166) 6 mo before randomization as ISN/RPS 2003 randomization or anticipated during longer than 8 GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS Mycophenolate Mofetil (MMF) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score Class III, IV-S or IV-G, V, III+V, or IV+V. Patients wk, pancreatitis, gastronintestinal hemorrhage with class III or V LN must have had proteinuria (at within 6 mo or active peptic ulcer within 3 mo, least 2g/d) which was considered clinically severe viral infection, severe cardiovascular significant level of proteinuria, and might indicate a disease, bone marrow insufficiency with cytopenias recent deterioration in renal function. not attributable to SLE, or current infection requiring intravenous antibiotics. Pulse intravenous corticosteroids were prohibited within 2 wk before first randomization and throughout the study. Aged 12 to 75 yrs, diagnosis of SLE, LN (active or Treatment with MMF or IVC within the previous active/chronic) conformed by kidney biopsy within year, continuous dialysis for ?2 wk before 6 mo before randomization as ISN/RPS 2003 randomization or anticipated during longer than 8 Class III, IV-S or IV-G, V, III+V, or IV+V. Patients wk, pancreatitis, gastronintestinal hemorrhage Isenberg et al, with class III or V LN must have had proteinuria (at within 6 mo or active peptic ulcer within 3 mo, Sub Analysis least 2g/d) which was considered clinically severe viral infection, severe cardiovascular of ALMS trial, significant level of proteinuria, and might indicate a disease, bone marrow insufficiency with cytopenias 2010 (167) recent deterioration in renal function. not attributable to SLE, or current infection requiring intravenous antibiotics. Pulse intravenous corticosteroids were prohibited within 2 wk before first randomization and throughout the study. Pure Class V LN included in this analysis only. ALMS - Treatment with MMF or IVC within the 2 previous year, continuous dialysis for ?2 wk before ALMS - Aged 12 to 75 yrs, diagnosis of SLE, LN randomization or anticipated during longer than 8 Radhakrishnan (active or active/chronic) conformed by kidney wk, pancreatitis, gastronintestinal hemorrhage et al, ALMS + biopsy within 6 mo before randomization as within 6 mo or active peptic ulcer within 3 mo, Ginzler et al, ISN/RPS 2003 Class III, IV-S or IV-G, V, III+V, or severe viral infection, severe cardiovascular 2010 IV+V. Patients with class III or V LN must have disease, bone marrow insufficiency with cytopenias (NOTE had proteinuria (at least 2g/d) which was not attributable to SLE, or current infection COMBINED 2 considered clinically significant level of proteinuria, requiring intravenous antibiotics. Pulse studies) (43) and might indicate a recent deterioration in renal intravenous corticosteroids were prohibited within 2 function. wk before first randomization and throughout the GINZLER - SLE meeting 4 classification criteria of study. the ACR; renal biopsy documenting lupus nephritis GINZLER - Creatinine clearance of less than 30ml GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS Mycophenolate Mofetil (MMF) vs Cyclophosphamide (CYC) IV Article Inclusion Criteria Exclusion Criteria Jadad Score according to the classification of WHO III, IV, or V; /min, serum creatinine on repeated testing greater clinical activity as defined by one or more of the than 3mg/dL (265.2 microlmol /L), severe following: incidence decrease in renal function coexisting conditions precluding (serum creatinine, >1mg/dL (88.4 micromol/L), immunosuppressive therapy or conditions requiring proteinuria (defined as more than 500mg of protein intravenous antibiotic therapy, prior treatment with in a 24-h urine specimen), microscopic hematuria mycophenolate mofetil, treatment with intravenous (defined as >5 red cells per high power-field) or the cyclophosphamide within the past 12 months, presence of cellular casts, increasing proteinuria monoclonal antibody therapy within the past 30 with rising levels of serum creatinine, active urine days, or pregnancy or lactation. sediment (hematuria or celluar casts), or serologic abnormality (anti-DNA antibodies or hypocomplementemia). Those with Class III or V lupus nephritis were required to have a serum creatinine level greater than 1mg/dL or proteinuria greater than 2g in a 24-h urine specimen. SLE meeting 4 classification criteria of the ACR Estimated glomerular filtration rate (eGFR) of less 2 with newly diagnosed active proliferative class III or than 30ml per minute, serum cereatinine on IV lupus nephritis and aged 15 years or older were repeated testing more than 200 micromol/L, white El Shafey et enrolled in the study. blood cell (WBC) count of less than 3.5 x 19 9/l, al, Egypt, evidence of major infection, history of cancer, 2010 (168) alcohol or substance abuse, active peptic ulcer disease, pregnant or lactating women, known allergy to MMF or cyclophosphamide, and the use of study drugs in the preceding 6 months.

MMF + AZA vs CYC PO + AZA Article Inclusion Criteria Exclusion Criteria Jadad Score SLE according to ARA including renal-biopsy Serum creatinine concentration higher than 2 Chan et al, evidence of diffuse proliferative lupus nephritis 3.4mg/dL (300 micromol per liter); life-threatening Hong Kong, (WHO IV), urinary protein excretion of 1g or more complications such as cerebral lupus or severe 2000 (169) per 24 hours, serum albumin concentration of infection, history of poor compliance with drug GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS MMF + AZA vs CYC PO + AZA Article Inclusion Criteria Exclusion Criteria Jadad Score 3.5g/dL or less. regimens, women who were pregnant or unwilling to use contraception. Patients who had received cyclophosphamide within the previous 6 months or who had taken oral prednisolone at a dose of 0.8mg/kg of body weight per day or more for more than 2 weeks. SLE defined by 1982 ARA criteria, renal biopsy Serum creatinine concentration >4.52 mg/dL 3 showing diffuse proliferative lupus nephritis (WHO (400micromol/L), life-threatening complications Chan et al, Class IV) which corresponded to 2003 ISN/RPS such as cerebral lupus or severe infection, poor Hong Kong, class IV-S or IV-G, urinary protein exretion of 1g/24 drug compliance, treatment with CTX or MMF 2005 (170) hours or above, and serum albumin concentration within 6 mo before baseline, or treatment with <35g/L. prednisolone at dose >0.4mg/kg per d orally for >2 wk before baseline.

MMF vs AZA vs CYC IV Article Inclusion Criteria Exclusion Criteria Jadad Score SLE according to ARA who had undergone a Creatinine clearance that was consistently less 2 Contreras et kidney biopsy. 18 years of age or older. Histologic than 20ml/min, any clinically significant infection, al, diagnosis of proliferative lupus nephritis (WHO pregnancy, receipt of more than 7 doses of USA, 2004 Class III, IV, or Vb) intravenous cyclophosphamide, or the receipt of (171) azathioprine for longer than 8 weeks.

MMF vs AZA Article Inclusion Criteria Exclusion Criteria Jadad Score Houssiau et Age >=14 years, SLE according to ACR Non-lupus related renal disease (such as 3 al, classification criteria, 24h proteinuria >= 500mg, microthrombotic disease associated with MAINTAIN biopsy –proven WHO Class III, IV, Vc or Vd lupus antiphospholipid syndrome),treatment with Nephritis glomerulonephritis (biopsy performed less than 1 glucocorticoids (GCs) (>15mg equivalent Trial, 2010 month before entry to protocol), contraception (or prednisolone/day) in the last month before entry (different sexual abstinence) intot he study (except a very short-course high- cohort from dose oral GC treatment before referral), treatment ELNT) (172) with CY, AZA, MMF, or cyclosporine A in the GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS MMF vs AZA Article Inclusion Criteria Exclusion Criteria Jadad Score previous year, pre-existing chronic renal failure (defined as a serum creatinine value above the upper normal value for the local laboratory) due to a previous episode of LN or other cause, pregnancy, breast feeding, previous malignancy (except for skin and cervical intraepithelial neoplasias), diabetes mellitus, previously documented severe toxicity of immunosuppressants, anticipated non-compliance with the protocol. Abstract 0 ALMS Maintenance (Wofsy et al, 2010)

Leflunomide vs CYC IV Article Inclusion Criteria Exclusion Criteria Jadad Score Wang et al, SLE according to 1997 ACR criteria; SLEDAI >= 8; Received cyclophosphamide within the previous 3 0 Leflunomid clinically evident renal disease and biopsy- months. Cerebral lupus, severe infection, liver Lupus documented diffuse proliferative or focal disease, pregnancy, and anticipated poor Nephritis proliferative lupus nephritis (ISN/RPS 2003 Type IV compliance with the protocol. Study Group, A or A/C and Type III A or A/C) with or without China, 2008 coincident membranous nephropathy and (173) pathological activity index (AI) >=4.

Rituximab Article Inclusion Criteria Exclusion Criteria Jadad Score ABSTRACT Pts with Class III/IV LN and urine protein to - Furie et al, creatinine ratio >1 LUNAR, 2009 GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS

Belimumab Article Inclusion Criteria Exclusion Criteria Jadad Score ABSTRACT Seropositive (ANA >=1:30 and/or anti-dsDNA >=30 No active LN - Manzi et al, IU/mL) SLE with SELENA SLEDAI >=6 on stable BLISS standard-of –care therapy ofr >=30d were enrolled 2010

Tocilizumab Article Inclusion Criteria Exclusion Criteria Jadad Score Age >18 years who fulfilled ACR classification Pregnancy, any therapy with human, murine 0 criteria for SLE, moderately active lupus defined by antibodies, or any experimental therapy within 3 1 of the 2 sets of criteria. Criteria set 1 – presence months, therapy with cyclophosphamide, pulse of chronic glomerulonephritis with an inadequate methylprednisolone or IVIG within 4 weeks, or response to at least 6 months of adequate azathioprine, mycophenolate mofetil, cyclosporine, immunosuppressive therapy (with either or methotrexate within 2 weeks of the first dose of methylprednisolone pulse doses, study medication. Serum creatinine level >3.0 cylcophosphamide, azathioprine, cyclosporine, mg/dl, white blood cell count <3500/microL, mycophenolate mofetil, high-dose dialy absolute neutrophil count < 3000 microlL, absolute corticosteroids, methotrexate, or intravenous lymphocyte count <= 500/microlL, hemoglobin Illei, et al, immunoglobulin, plus the following 4 features: less value <8.0 gm/dl, platelet count <50000/microlL, USA, 2010 than a 30% increase in serum creatinine levels as AST or ALT levels >1.5 times the upper limits of (174) compared with the lowest level achived during normal, or >1000 Epstein-Barr virus genome treatment; proteinuria at levels <=1.5 times the equivalents/10 6 preipheral blood mononuclear value at baseline (before treatment); <= 2+ cellular cells. casts in the urinary sediments; and extrarenal disease activity not exceeding a score of 10 on the nonrenal components of the SELENA version of SLEDAI. Creiteria set 2 consisted of moderately active extrarenal lupus, defined as extrarenal SELENA-SLEDAI score in the range of 3-10. SELENA-SLEDAI score must have been stable for GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS RANDOMIZED CLINICAL TRIALS Tocilizumab Article Inclusion Criteria Exclusion Criteria Jadad Score at least 2 weeks prior to screening. Required presence of at least 1 serological marker of autoantibody production or systemic inflammation, therefore 1 or more of the following 4 features had to be present: serum anti-dsDNA antibody level >= 30IU, an IgG anticardiolipin antibody level >=20 igG phospholipid units/ml, a C-reactive protein level (CRP) > 0.8mg/dl, or an erythrocyte sedimentation rate (ESR) >25 mm/h in men and >42 mm/h in women. Stable dose of Prednisone <=0.3 mg/kg/d for at least 2 weeks before the first dose of study medication. Effective form f contraception.

x Please see enclosed excel sheet for Randomized Controlled Trial (RCT) – Intervention-Outcome (I-O) and Adverse Event (AE) data GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS COHORT STUDIES

Table 6. Cohort Studies Inclusion/Exclusion Criteria and Newcastle-Ottawa Scale Rituximab Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Catapano et Data extracted from 2 electronic databases and patients’ note in Vasculitis 3 al, UK and and Lupus Clinic at Addenbrooke’s Hospital, Cambridge, UK. Fulfill at least 4 Italy, 2010 ACR diagnostic criteria. Patients receiving rituximab for refractory or relapsing (175) SLE. Terrier et al, Data collected prospectively from 82 centers in the AIR registry. SLE 6 France, 2010 classified according to ACR 1982 revised criteria. (176) Jonsdottir et SLE and active LN. Pooled data from 2 cohorts, WHO Class V and WHO 1 al, Europe, Class III or IV. 2010 (177)

Stem Cell Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Jayne et al, Retrospective data from the European Group for Blood and 4 UK, 2004 Marrow Transplantation and European League against (178) Rheumatism Registry. Burt et al, At least 4 of 11 ACR Criteria for SLE and required more than 4 USA, 2006 20mg/d of prednisone or its equivalent despite use of (179) cyclophosphamide. WHO Class III or IV glomerulonephritis, involvement of lthe lung, involvement of the central nervous system, vasculitis, myositis, transfusion-dependent autoimmune cytopenias, severe serositiis, ulcerative mucocutaneous disease, or antiphospholipid syndrome (definied by Sapporo criteria). Nephritis required failure of 6 or more monthly pulse of cylcophosphamide. Nonrenal visceral organ involvement required failure of at least 3 months of cyclophosphamide. Liang et al, SLE refractory to standard therapies. All patients had at least 4 1 Nanjing, of 11 ACR criteria for SLE. Eligibility criteria include one of the GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Stem Cell Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale 2010 (180) following features: progressive and active disease with SELENA SLEDAI score >=8 despite continuous treatment with IV pulse CYC with a total dosage of 400-800 mg every month for at least 6 months or oral MMF 1000-2000 mg/d for at least 3 months and continued daily dosage of more than 20mg of prednisone or its equivalent; refractory immune-mediated thrombocytopenia; refractor LN defined either as proteinuria >=1000mg/24 h, sercum creatinine >=1.5mg/dL or decreased Creatinine clearance without end-stage renal failure in patients with WHO Class IV/V glomerulonephritis despite 6 months of CYC or MMF. Sun et al, All patients met at least 4 of the 11 ACR criteria for SLE. Uncontrolled infection, mean 3 Nanjing SLEDAI socre >=8, lack of response to treatment with monthly pulmonary artery pressure > 50mm China, 2010 IV CYC 500-1000 mg/m2 for >= 6 months or lack of response to Hg, failure of one of the vital organs, (181) treatment with oral MMF (2000 mg/day) for >=3 months, and were pregnant or lactating. continued daily doses of >20mg of prednisone or its equivalent. Also if they had refractory immune-mediated transfusion- dependent thrombocytopenia or refractory lupus nephritis defined as either proteinuria >= 1000mg/24 h or serum creatinine >= 1.5mg/dL or decreased creatinine clearance without end-stage renal failure in patients with WHOC IV/V glomerulonephritis despite 6 months treatment of CYC or 3 months of treatment with MMF.

Antimalarial Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Siso et al, Single center. Fulfilled 1997 revised criteria for SLE 5 Spain, 2008 classification. Biopsy proven LN. Renal biopsies reviewed by 2 (182) pathologists and categorized according to ISN/RPS in 2004. Pons-Estel Longitudinal observational cohort. Patients were >= 16 years of 4 et al, USA age and had disease duration of <= 5 years. Each patient had a and Puerto baseline or enrollment visit (T0) followed by a 6 month visit Rico, 2009 (T0.5) and subsequently yearly visit. Time of diagnosis (TD) GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Antimalarial Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale LUMINA was defined as the time when each patient met 4 ACR criteria. study (183)

Cyclosporin Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Rihova et al, Retrospective charge review. Patient meet the 1982 ACR 2 Czech criteria for the diagnosis of SLE and have an active LN verified Republic, and classified by a renal biopsy, treated with CsA. 2007 (184)

Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Renal biopsy diagnosis of SLE-DPGN from within the 0 Glomerular Disease Collaborative Network (GDCN) were eligible Dooley et al, for inclusion in this study. Patient fulfilled 4 or more criteria from USA, 1996 the 1982 ACR revised criteria for classification of SLE. (185) Documentation of treatment or intention to treat with CYC IV was required for study entry. Ioannidis et All patients with biopsy-documented diagnosis of proliferative 1 al, USA and lupus nephritis (WHO type III or IV) treated with IVC. Greece, 2000 (186) Mok et al, SLE patients with biopsy proven DPGN initially treated with 3 Hong Kong, regimens that included CYC and corticosteroids between years China, 2004 1988 and 2001. All fulfilled at least 4 of the ACR criteria for SLE (187) classification. de Castro et SLE classification by ACR classification criteria, treated and Histological class II or V according to 6 al, Brazil, followed from July 1988 to December 2003. 1995 WHO classification. 2007 (188) GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Renal biopsy proven diffuse proliferative lupus 3 Mok et al, glomerulonephritis (1995 WHO Class IV) treated in Hong Kong Hong Kong identified by clinical registries or renal biopsy databases. All China, 2006 patients fulfilled at least 4 ACR criteria for SLE classifications (189) and were initially treated with corticosteroids and CYC. Prospective randomized trial with 1:1 randomization. SLE Musculoskeletal lupus from the 4 patients met >= 4 of revised ACR criteria for SLE with moderate category of eligible organ involvement. to severe activity in an organ as defined as BILAG A or a high score for that organ on the SLAM or hospitalization for Petri et al, involvement of that organ. Lack of response or expected lack of USA, 2010 response to moderate- to high- dose corticosteroids, to the (190) equivalent degree of immunosuppression, or to appropriate other treatment. Combination therapy of both hydroxychorologuine and quinacrine as well as immunosuppression had to have failed for SLE patients with cutaneous lupus.

Immunosuppressives vs Cyclophosphamide (CYC) Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale SLE >= 4 ACR criteria or 3 ACR criteria plus a typical 3 histological lesion of SLE on renal or skin biopsy. Patients with active renal disease treated with immunosuppressive/cytotoxic Urowitz et al, medications in the year after diagnosis of active renal disease Toronto, were selected from clinic database. Active renal disease Canada, defined as presence of 2 consecutive visits of one of: red blood 2007 (191) cell casts or hemegranular casts, hematuria or pyruia in the absence of other causes, or proteinuria (>500mg/24h or >= 3+ on dipstick) or an abnormal kidney biopsy showing active lupus nephritis.

Cyclophosphamide (CYC) vs Azathioprine (AZA) GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Diagnosis of SLE by ARA criteria including a positive Serum creatinine of greater than 3 erythematosus cell test; kidney disease with either erythrocyte 4mg/100ml or creatinine clearance of Decker et al, casts, celluar casts, and either hematuria (20 erythrocytes/hpf) less than 20ml/min NIH, 1975 or high anti-DNA antibodies, low complement, and a positive (192) renal biopsy, and diffuse glomerulonephritis with at least a portion of all glomeruli involved.

Cyclophosphamide (CYC) + Azathioprine (AZA) Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Prospective cohort. Diagnosis of WHO Class IV lupus nephritis Serum creatinine exceeding 3 confirmed by renal biopsy, baseline urinary protein excretion 400micromol/L, treatment with Chan et al, exceeding 1g/24h, baseline serum albumin below 35g/L, cyclophosphamide or mycophenolate Hong Kong, treatment with sequential immunosuppression. Patients with mofetil within 6 months, or China, 2005 superimposed membranous changes were included provided prednisolone dose exceeding (170) that there were concomitant diffuse proliferative features. 0.4mg/kg/d for more than 2 weeks prior to baseline/

High dose cyclophosphamide (CYC) vs Low dose cyclophosphamide followed by Azathioprine (AZA) Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale SLE patients according to ACR criteria, age 14 years or older Patients who had taken CYC or AZA 3 with biopsy proven proliferative lupus glomerulonephritis (WHO during the previous year or had taken Class III, IV, Vc, or Vd) and proteinuria >= 500mg/24 h. >=15mg/day prednisone (or equivalent) Houssiau et during the previous month were al, Europe, excluded (except for a course of ELNT, 2004 glucocorticoids for a maximum of 10 Subanalysis days before the referral). Other (193) exclusion criteria were renal thrombotic microangiopathy, preexisting chronic renal failure, pregnancy, previous malignancy (except skin and cervical GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS High dose cyclophosphamide (CYC) vs Low dose cyclophosphamide followed by Azathioprine (AZA) Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale intraepithelial neoplasis), diabetes mellitus, previously documented severe toxicity to immunosuppressive drugs, and anticipated poor compliance with the protocol.

Mycophenolate Mofetil (MMF) Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Tang et al, Single center, retrospective. Patients fulfilled 1997 SLE 5 Nanjing diagnosis criterion of ARA, presentation of clinical renal lesion, Chinca, 2008 crescent formation more than 50% and having undertaken (194) MMF or CTX therapy during their induction period. Single center retrospective chart review of SLE patients with 3 Rivera et al, biopsy ISN/RPS criteria Class II, III, IV,V, and VI. Patients 2009 (195) must be followed for at least 6 months. Cortez- SLE according to ACR criteria, class III/IV/V LN treated with 3 Hernandez MMF. et al, Spain, 2010 (196)

Azathioprine (AZA) Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Mok et al, Open label - Renal biopsy-proven pure membranous lupus WHO Classification Vc and Vd. 3 Hong Kong, glomerulonephritis (WHO Va and Vb). China, 2004 (197)

Leflunomide GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS Article Inclusion Criteria Exclusion Criteria Newcastle Ottawa Scale Fulfilled 1997 ACR classification criteria for SLE admitted as Severe insufficiency of organs besides 3 inpatients undergoing kidney biopsy. kidney, including heart failure, liver Zhang et al, failure, severe psychosis, leukocyte and Harbin platelet count less than 3 x 10 9/L and China, 2009 50 x 10 9 respectively, pregnant (198) women, lactating women, children of less than 16 age.

x Please see enclosed excel sheet for Cohort Trial – Intervention-Outcome (I-O) and Adverse Event (AE) data GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS

END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions Hashemi V, Nadjafi I, Renal Looked at 37 pts with LN and ESRD who Graft survival at 1 yr = 85.6%, 3 yr = 73%. No correlation w/ Azzordegan F, transplantation in had undergone renal transplantation. Post- gender, age at transplant, and donor source. Causes of graft Ghahramani N, systemic lupus transplant meds = CsA, aza, and pred, loss: chronic graft rejection 11/37, acute rejection 2/37, Broumand B. Shariati erythematosus: a except in 1 case aza+pred. recurrence of LN 1/37. Patient survival at 1 yr 94.4%, at 3 yrs Hospital, Tehran multicenter study 91.7%. 2/37 died of MI, 1/37 died of pneumococcal University of Medical with 37 patients in infection/sepsis, 1/37 died of opium toxicity. Sciences, Iran. Iran. Transplant Proc. 1999 Dec;31(8):3142-3. Ward MM. Palo Alto Outcomes of renal Graft failure and patient mortality after the RESULTS: In an unadjusted analysis, the risk of graft failure after Health Care System, transplantation first cadaveric renal transplantation were first cadaveric transplant was slightly but significantly greater Palo Alto, CA Kidney among patients with compared between 772 adults with ESRD among patients with ESRD caused by lupus nephritis than Int. 2000 end-stage renal caused by lupus nephritis and 32,644 adults among those with ESRD caused by other causes [hazard ratio May;57(5):2136-43. disease caused by with ESRD caused by other causes who (HR), 1.13; 95% CI, 1.01 to 1. 26, P = 0.04]. However, after lupus nephritis. received a transplant between 1987 and adjustment for potential confounding factors, the risk of graft 1994 and were included in the United States failure was not increased in patients with ESRD caused by lupus Renal Data System. The median follow-up nephritis (HR, 1.08; 95% CI, 0.94 to 1.23, P = 0.28). Mortality times were 4.9 and 5.0 years in the two after the first cadaveric transplantation did not differ between groups, respectively. Multivariate Cox groups. The adjusted risks of graft failure (HR, 1.06; 95% CI, regression models were used to adjust the 0.84 to 1.32, P = 0.62) and patient mortality (HR = 0. 69; 95% CI, risks of graft failure and mortality for group 0.45 to 1.05, P = 0.09) after the first living-related renal transplant differences in recipient and donor were also not significantly higher among patients with ESRD characteristics. Similar comparisons were caused by lupus nephritis. CONCLUSIONS: Graft and patient performed between 390 adults with ESRD survival after first cadaveric and first living-related renal caused by lupus nephritis and 10,512 adults transplants are similar in patients with ESRD caused by lupus with ESRD caused by other causes after nephritis and patients with ESRD from other causes. first living-related renal transplantation. Goral S, Ynares C, Recurrent lupus The records of 54 renal transplant recipients RESULTS: Among the 50 patients with at least 3 months of Shappell SB, Snyder nephritis in renal with SLE were reviewed. Thirty-one patients follow-up, RLN was present in 15 (52% of patients who S, Feurer ID, transplant recipients underwent biopsy because of worsening underwent biopsy, 30% of total patients): mesangial lupus Kazancioglu R, Fogo revisited: it is not renal function and proteinuria. All biopsy nephritis (LN) (class II) in eight, focal proliferative LN (class III) in AB, Helderman JH. rare. specimens were evaluated by light four, and membranous LN (class Vb) in three patients. One University of microscopy, immunofluorescence (IF), and patient had graft loss because of RLN (class II) at 10.5 years. Pennsylvania School electron microscopy (EM). The duration of dialysis before transplantation was not different of Medicine between patients with RLN compared to patients without RLN Transplantation. 2003 (P=0.40). Overall patient survival (n=50) was 96% at 1 year and Mar 15;75(5):651-6. 82% at 5 years, and graft survival was 87% at 1 year and 60% at 5 years. Graft survival was worse in patients who underwent biopsy compared with patients who never underwent biopsy (P<0.01). CONCLUSIONS: RLN is more common than GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions previously reported, but in our series, graft loss because of RLN was rare. Aggressive use of allograft biopsies and morphologic evaluation with IF and EM are important factors in the diagnosis of RLN. The impact of new immunosuppressive agents on the incidence of RLN remains to be seen.

Deegens JK, Artz Outcome of renal We studied the outcome of renal One patient developed renal failure with serological evidence of MA, Hoitsma AJ, transplantation in transplantation in patients with SLE who SLE activity at 61 months after transplantation. In the absence of Wetzels JF. patients with underwent transplantations in our center urine abnormalities we favored the diagnosis of rejection, University Medical systemic lupus between 1968 and 2001. Patient and graft although recurrence of lupus nephritis could not formally be Center of Nijmegen, erythematosus. survival were compared with a matched excluded. This was the only case of a possible recurrence of The Netherlands. control group. We specifically looked for any lupus nephritis. Two other patients developed extra-renal Transpl Int. 2003 evidence of recurrent disease. There were manifestations of SLE at 6 and 17 months after transplantation. Jun;16(6):411-8. 23 patients (two male, 21 female) with a Patient and graft survival rates at 5 years after transplantation Epub 2003 Mar 19. mean +/-SD age of 34+/-12 years at were 86% and 68%, respectively. Survival rates were not transplantation. significantly different from those of a matched control group, 95% and 78%, respectively. Recurrence of SLE after transplantation is rare. The results of renal transplantation in patients with SLE do not differ significantly from a matched control group. Renal transplantation is a good alternative for renal replacement therapy in patients with lupus nephritis. Moroni G, Tantardini The long-term Between June 1982 and 2004, a total of 33 RESULTS: Mean follow-up after renal transplantation was 91 +/- F, Gallelli B, Quaglini prognosis of renal adults with lupus nephritis received 35 59 months for patients with lupus and 90 +/- 64 months for S, Banfi G, Poli F, transplantation in kidney allografts. Outcomes of these grafts controls. Actuarial 15-year patient (80% versus 83%) and death- Montagnino G, patients with lupus and those of 70 controls matched for age, censored graft survival rates (69% versus 67%) were not Meroni P, Messa P, nephritis. sex, and donor source who underwent significantly different between patients with lupus and controls. Ponticelli C. Centro transplantation during the same period were Risks for acute and chronic rejection, arterial hypertension, and Trasfusionale e di compared. infection were not different between the 2 groups. Mean serum Immunologia dei creatinine levels also were similar in the 2 groups at the last Trapianti IRCCS, follow-up visit. Intravascular thrombotic events occurred in 9 Ospedale Maggiore patients with SLE (26%) and 6 controls (8.6%; P = 0.038). In the Milano, Italy Am J SLE group, 6 of 7 antiphospholipid (aPL) antibody-positive Kidney Dis. 2005 versus 3 of 17 aPL antibody-negative patients experienced May;45(5):903-11. thrombotic events ( P = 0.015). Recurrence of lupus nephritis was documented in 3 renal grafts (8.6%), but no graft was lost because of recurrent lupus nephritis. CONCLUSION: Long-term patient and graft survival probabilities were similar in patients GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions with SLE and matched controls. The risk for thrombotic complications was greater in patients with SLE, particularly aPL- positive patients. Nephritis recurred in less than 10% of patients with SLE and did not influence graft survival.

Bunnapradist S, Outcomes of renal Here, we compared patient and graft Univariate analysis showed similar graft but better patient Chung P, Peng A, transplantation for outcomes in lupus and non-lupus recipients survival rates for primary lupus and non-lupus transplant Hong A, Chung P, recipients with lupus transplanted between 1996 to 2000 using recipients (5-year patient survival rates for lupus cohort 85.2% for Lee B, Fukami S, nephritis: analysis of the United Network of Organ Sharing/Organ deceased donor transplants and 92.1% for living donor Takemoto SK, Singh the Organ Procurement Transplant Network database. transplants as opposed to 82.1% and 89.8% respectively for the AK. Transplantation. Procurement and We evaluated the impact of recipient and non-lupus cohort; P=0.05 and 0.03) but similar patient survival 2006 Sep Transplantation donor demographic factors, time on dialysis rates for deceased donor retransplant patients. After controlling 15;82(5):612-8. Network database. and the initial immunosuppression regimen for confounding factors, no differences in patient or graft survival on rejection rates and transplant outcomes. were seen between the two groups. No difference in acute rejection rates were observed in deceased donor transplants, but there was a small but significant increase in the risk of acute rejection in living donor lupus transplant recipients (hazard ratio=1.19, P=0.05). Risk of graft failure was lower for deceased donor recipients receiving MMF (five-year graft loss rate=29.6% for MMF vs. 40.2% for those not receiving MMF, P<0.0001), but no differences were seen among living donor recipients. Outcomes were similar regardless of type of calcineurin inhibitor, induction therapy, and time on dialysis. We conclude that lupus transplant recipients have outcomes generally equivalent to non- lupus transplant recipients. Chelamcharla M, The outcome of We conducted the retrospective analysis RESULTS: The mean follow-up period of this study was 4.7 +/- Javaid B, Baird BC, renal transplantation using data from USRDS and UNOS 2.4 years. While unadjusted analysis using Kaplan-Meier curves Goldfarb- among systemic databases. Patients were divided into five demonstrated an association between SLE and improved Rumyantzev AS. lupus erythematosus groups based on the cause of end-stage allograft survival compared with DM, in multivariate analysis the University of Utah patients. renal disease (ESRD): diabetes mellitus SLE group had worse allograft [hazard ratio (HR) 1.09, P < 0.05] Health Sciences (DM), SLE, glomerulonephritis, hypertension and recipient (HR 1.19, P < 0.05) survival compared with the DM Center Nephrol Dial and other causes. Between 1990 and 1999, group. Subgroup analysis based on the type of donor showed Transplant. 2007 2886 renal transplantation recipients with that SLE patients who received deceased donor allograft had Dec;22(12):3623-30. ESRD due to SLE were identified from a worse allograft and recipient survival (HR 1.14, P = 0.002 and Epub 2007 Jul 19. total of 92 844 patients. HR 1.30, P = 0.001, respectively) compared with non-SLE deceased donor allograft recipients. Among living allograft GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions recipients, there were no significant differences in either allograft or recipient survival compared with non-SLE recipients. CONCLUSIONS: SLE as a cause of ESRD in renal transplant recipients is associated with worse allograft and recipient survival compared with DM; this association is true for the entire population and for the recipients of deceased donor (but not living donor) transplant. Deceased donor allograft recipients have worse outcomes compared with living allograft recipients.

Tang H, Factors affecting Using the data from the United States Renal RESULTS: The number of pretransplant pregnancies Chelamcharla M, kidney-transplant Data System of patients transplanted incrementally increased the risk of graft failure [hazard ratio (HR) Baird BC, Shihab FS, outcome in between January 1, 1995 through 1.54, p < 0.05] in the entire subgroup of females and in the Koford JK, Goldfarb- recipients with lupus December 31, 2002 (and followed through subgroup of recipients aged 25-35 yr. Recipient and donor age Rumyantzev AS. nephritis. December 31, 2003) (n = 2882), we had an association with both the risk of graft failure (HR 0.96, p < University of Utah performed a retrospective analysis of factors 0.001; HR 1.01, p < 0.005) and recipient death (HR 1.04, p < School of Medicine associated with long-term death-censored 0.001; HR 1.01, p < 0.05). Greater graft-failure risk accompanied Clin Transplant. 2008 graft survival and recipient survival. increased recipient weight (HR 1.01, p < 0.001); African May-Jun;22(3):263- Americans compared with whites (HR 1.55, p < 0.001); greater 72. Charlson comorbidity index (HR 1.17, p < 0.05); and greater panel reactive antibody (PRA) levels (HR 1.06, p < 0.001). Pretransplant peritoneal dialysis as the predominant modality had an association with decreased risk of graft failure (HR 0.49, p < 0.001), while prior transplantation was associated with greater risk of graft failure and recipient death (HR 2.29, p < 0.001; HR 3.59, p < 0.001, respectively) compared with hemodialysis (HD). The number of matched human leukocyte antigens (HLA) antigens and living donors (HR 0.92, p < 0.05; HR 0.64, p < 0.001, respectively) was associated with decreased risk of graft failure. Increased risk of graft failure and recipient death was associated with nonuse of calcineurin inhibitors (HR 1.89, p < 0.005; HR 1.80, p < 0.005) and mycophenolic acid (MPA) (including mycophenolate mofetil and MPA) or azathioprine (HR 1.41, p < 0.05; HR 1.66, p < 0.01). Using both cyclosporine and tacrolimus was associated with increased risk of graft failure (HR 2.09, p < 0.05). Using MPA is associated with greater risk of recipient death compared with azathioprine (HR 1.47, p < 0.05). CONCLUSION: In renal transplant recipients with lupus nephritis, multiple pregnancies, multiple blood transfusions, greater comorbidity index, higher body weight, age and African American race of the donor or recipient, prior history of GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions transplantation, greater PRA levels, lower level of HLA matching, deceased donors, and HD in pretransplant period have an association with increased risk of graft failure. Similarly, higher recipient and donor age, prior transplantations, and higher rate of pretransplant transfusions are associated with greater risk of recipient mortality. Using neither cyclosporine nor tacrolimus or using both (compared with tacrolimus) and neither MPA nor azathioprine (compared with azathioprine) was associated with increased risk of graft failure and recipient death. Using MPA is associated with greater risk of recipient death compared with azathioprine. Testing these results in a prospective study might provide important information for clinical practice. Ward MM. Changes in the Patients age 15 years or older with incident RESULTS: Over the 9-year study period, 9199 new cases of NIH/NIAMS/IRP J incidence of ESRD due to lupus nephritis in 1996-2004 ESRD due to lupus nephritis were observed. Incidence rates, Rheumatol. 2009 endstage renal and living in one of the 50 United States or adjusted to the age, sex, and race composition of the US Jan;36(1):63-7. disease due to lupus the District of Columbia were identified using population in 2000, were 4.4 per million in 1996 and 4.9 per nephritis in the the US Renal Data System, a national million in 2004. Compared to the pooled incidence rate in 1996- United States, 1996- population-based registry of all patients 1998, the relative risk of ESRD due to lupus nephritis in 1999- 2004. receiving renal replacement therapy for 2000 was 0.99 (95% CI 0.93-1.06), in 2001-2002 was 0.99 (95% ESRD. Incidence rates were computed for CI 0.92-1.06), and in 2003-2004 was 0.96 (95% CI 0.89-1.02). each calendar year, using population Findings were similar in analyses stratified by sex, age group, estimates of the US census as race, and socioeconomic status. CONCLUSION: There was no denominators. decrease in the incidence of ESRD due to lupus nephritis between 1996 and 2004. This may reflect the limits of effectiveness of current treatments, or limitations in access, use, or adherence to treatment. Burgos PI, Perkins Risk factors and The archival records of all kidney transplant RESULTS: Two hundred twenty of nearly 7,000 renal EL, Pons-Estel GJ, impact of recurrent recipients with a prior diagnosis of SLE transplantations were performed in 202 SLE patients during the Kendrick SA, Liu JM, lupus nephritis in (according to the American College of 30-year interval. Of the 177 patients who met the criteria for Kendrick WT, Cook patients with Rheumatology criteria) from June 1977 to study entry, the majority were women (80%) and African WJ, Julian BA, systemic lupus June 2007 were reviewed. Patients who had American (65%), the mean age was 35.6 years, and the mean Alarcón GS, Kew CE erythematosus died or lost the allograft within 90 days of disease duration was 11.2 years. Recurrent lupus nephritis was 2nd. University of undergoing renal engraftment were excluded. Time-to-event noted in 20 patients (11%), allograft loss in 69 patients (39%), Alabama at transplantation: data data were examined by univariable and and death in 36 patients (20%). African American ethnicity was Birmingham Arthritis from a single US multivariable Cox proportional hazards found to be associated with a shorter time-to-event for recurrent Rheum. 2009 institution. regression analyses. lupus nephritis (hazard ratio [HR] 4.63, 95% confidence interval Sep;60(9):2757-66. [95% CI] 1.29-16.65) and death (HR 2.47, 95% CI 0.91-6.71), although, with the latter, the association was not statistically significant. Recurrent lupus nephritis and chronic rejection of the kidney transplant were found to be risk factors for allograft loss (HR 2.48, 95% CI 1.09-5.60 and HR 2.72, 95% CI 1.55-4.78, respectively). In patients with recurrent lupus nephritis, the lesion GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions in the engrafted kidney was predominantly mesangial, compared with a predominance of proliferative or membranous lesions in the native kidneys. CONCLUSION: African American ethnicity was independently associated with recurrent lupus nephritis. Allograft loss was associated with chronic transplant rejection and recurrence of lupus nephritis. Recurrent lupus nephritis is infrequent and relatively benign, without influence on a patient's survival.

Liang CC, Huang CC, Impact of renal This longitudinal study investigated whether There were no significant differences between patients with short Wang IK, Chang CT, survival on the renal survival can affect the course and renal survival (<3 years) and long renal survival (>3 years) for the Chen KH, Weng CH, course and outcome outcome of systemic lupus erythematosus various demographic variables such as age, sex, PD duration, Lin JL, Hung CC, of systemic lupus (SLE) patients treated with chronic immunosuppressive drug administration, or exchange system (P Yang CW, Yen TH. erythematosus peritoneal dialysis (PD). Thirty-five SLE > 0.05). Interestingly, before PD, patients with short renal China Medical patients treated with patients, out of 1115 end-stage renal survival had lower serum complement levels than patients with University Hospital, chronic peritoneal disease (ESRD) patients treated with long renal survival (C3, 40.2 +/- 14.4 vs 76.3 +/- 18.5 mg/dL, P < Taichung, Taiwan dialysis. chronic PD, were seen between 1990 and 0.001; and C4, 14.8 +/- 4.7 vs 22.4 +/- 8.1 mg/dL, P < 0.05). Ther Apher Dial. 2007 at the Chang Gung Memorial Hospital. However, the differences in complement levels between the 2010 Feb;14(1):35- Patients were followed up for a mean of groups disappeared after PD (C3, 76.5 +/- 27.3 vs 84.2 +/- 27.8 42. 38.8 +/- 22.9 months. mg/dL; and C4, 26.7 +/- 11.3 vs 22.6 +/- 10.8 mg/dL, both P > 0.05). Patients with short renal survival were more likely to have a high peritoneal solute transporter rate (PSTR) than their long renal survival counterparts (chi(2)-test, P = 0.02, and AUROC = 0.744 and P = 0.040); however, there were no significant differences for other variables such as cardiothoracic ratio (CTR), Kt/V, residual renal function, exit site infection, and peritonitis (P > 0.05). Finally, Kaplan-Meier analysis revealed that the two groups did not differ in patient and technical survival (P > 0.05). Therefore it was concluded that renal survival might be associated with PSTR, but not with patient and technical survival in SLE patients treated with PD. GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions Norby GE, Strøm EH, Recurrent lupus All patients with SLE that had undergone RESULTS: A total of 41 (93%) of a cohort of 44 patients with Midtvedt K, Hartmann nephritis after kidney transplant with a functioning graft were SLE with renal transplants participated. Of the biopsies, 3 were A, Gilboe IM, transplantation: a asked in 2008 to participate in a cross- indication biopsies and 38 were surveillance biopsies. In all, 22 Leivestad T, surveillance biopsy sectional study. The study included a patients (54%) had biopsy-proven recurrence of LN. The majority Stenstrøm J, Holdaas study. standardised clinical examination, laboratory of the cases were subclinical and characterised as class I/class II H. Oslo University tests and a biopsy of the transplanted LN. Proteinuria (mg protein/mmol creatinine) was significantly Hospital, Norway. kidney. increased in patients with recurrence, 70.6 (104.9) mg/mmol Ann Rheum Dis. versus 11.9 (6.7) mg/mmol in patients without recurrence 2010 (p=0.038). Lupus anticoagulant was found more frequently in the Aug;69(8):1484-7. patients with recurrence, nine versus two patients (p=0.033). Epub 2010 May 24. Recurrence of LN was associated with receiving a kidney from a living donor (p=0.049). In all, 83% (34 of 41) had chronic allograft nephropathy in the transplanted kidneys with no difference between patients with recurrence or without. CONCLUSIONS: Subclinical recurrence of LN is common in patients with renal transplants with SLE. The majority of the patients have chronic allograft nephropathy. Bumgardner GL, Single-center 1-15- However, since the long-term outcome after A total of 69% (22/32) of patients underwent less than 1 year of Mauer SM, Payne W, year results of renal transplantation in this group of patients is dialysis prior to transplantation, and 50% (16/32) experienced Dunn DL, Sutherland transplantation in not well established, we have examined the biopsy-proved acute rejection, which was reversible in 67% DE, Fryd DS, Ascher patients with long-term outcome in SLE patients who (11/16). Actuarial graft function and patient survival rate in SLE NL, Simmons RL, systemic lupus underwent renal transplantation at the patients were not significantly different from those in the matched Najarian JS. erythematosus. University of Minnesota. Thirty-two SLE control group. Duration of prior dialysis did not affect outcome. University of patients receiving 33 transplants between Surviving grafts have excellent function as measured by serum Minnesota, December 1969 and December 1987 were creatinine (1.3 +/- 0.4 mg/dl, means +/- SD). Causes of death Minneapolis studied retrospectively and compared with were sepsis (5) and myocardial infarction (1). One patient lost the Transplantation. 1988 controls matched for age, sex, donor graft from rejection after withdrawal of immunosuppression Nov;46(5):703-9. source, HLA match, date of transplant, and because of a malignancy one month posttransplant. Three diabetic status. patients lost graft function due to chronic rejection. To date no patients have had evidence of recurrent SLE nephritis. Pollock CA, Ibels LS. Dialysis and Between 1977 and 1985, 5726 patients in When compared with patients with other forms of Royal North Shore transplantation in Australia and New Zealand entered end glomerulonephritis, there was a female preponderance and a Hospital, NSW. Aust patients with renal stage renal failure programmes. Of these, younger age distribution in patients with renal failure due to lupus N Z J Med. 1987 failure due to 63 patients had renal failure due to systemic nephritis. Integrated patient, dialysis, and transplant survival data Jun;17(3):321-5. systemic lupus lupus erythematosus (a prevalence of 1.1% showed that results in patients with renal failure due to lupus erythematosus. The of patients entering renal replacement nephritis were comparable with those in patients with other forms Australian and New programmes). of glomerulonephritis or in patients with renal failure due to any Zealand experience. cause. Age at entry significantly affected survival, with significant differences being found in those patients under as opposed to over 50 years of age. Causes of death in patients with lupus nephritis were similar to those in patients with renal failure due to other causes. It is concluded that dialysis and transplantation are GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions acceptable forms of treatment for patients with end stage renal failure due to systemic lupus erythematosus.

Lochhead KM, Pirsch Risk factors for renal This study is a retrospective evaluation of Our results showed equivalent graft survival rates between lupus JD, D'Alessandro allograft loss in each of these independent risk factors in 80 patients and the cohort at 1, 5 and 10 years (P = 0.56). However, AM, Knechtle SJ, patients with renal transplants for ESRD secondary to an analysis of cyclosporine-era cadaver grafts revealed that the Kalayoglu M, systemic lupus SLE done at our institution between 1971 lupus group had poorer 5-year graft survival than the cohort Sollinger HW, Belzer erythematosus. and 1994. Our entire non-diabetic cohort of (41% vs. 71%, P = 0.02). Evaluation of cyclosporine-era lupus FO. University of 1,966 renal transplants is used as a graft survival showed significantly improved outcome in living- Wisconsin Hospital comparison group. related lupus recipients over cadaver grafts at five years (89% and Clinics Kidney vs. 41%, P = 0.003). The majority of grafts lost in the lupus Int. 1996 cadaver recipients were due to chronic rejection. Rejection was Feb;49(2):512-7. increased in lupus recipients: 69% of lupus patients experienced rejection in the first year compared to 58% of controls (P = 0.01). Stratified for age, sex, race and cyclosporine use, this difference remained significant (P = 0.003, relative risk 1.7). Nephrectomy, splenectomy and 3 to 6 months of pretransplant dialysis did not improve graft survival. A dialysis duration of greater than 25 months predicted worse graft survival (P = 0.01). Among lupus patients, PRA did not correlate with graft outcome (P = 0.5), and HLA-identical cadaver grafts had improved outcomes compared to cadaver grafts. We conclude that acute and chronic rejection are the major risk factors for graft loss in lupus patients. The superior outcome of living-related over cadaver grafts in lupus patients suggests an increased role for living-related grafts. Pretransplant dialysis, nephrectomy and splenectomy are not indicated. Haubitz M, Kliem V, Renal Long-term graft survival and graft function of RESULTS: Renal transplant recipients with autoimmune Koch KM, Nashan B, transplantation for renal transplant recipients with SLE, diseases such as vasculitis and SLE had a patient survival rate Schlitt HJ, Pichlmayr patients with Wegener's granulomatosis, microscopic (94% after 5 years) and a graft survival rate (65% after 5 years) R, Brunkhorst R. autoimmune polyangiitis, Goodpasture's syndrome, and comparable to those of patients with other causes of end-stage Medical School diseases: single- Henoch-Schonlein purpura were evaluated renal disease (patient survival 88% and graft survival 71% after 5 Hannover, Germany. center experience in a single center. In addition, the incidence years). Graft losses due to the underlying disease were rare. Transplantation. 1997 with 42 patients. of renal and extrarenal relapses and the Extrarenal relapses occurred in three patients with Wegener's May 15;63(9):1251-7. impact of the immunosuppressive therapy granulomatosis, one patient with microscopic polyangiitis, and on the course of the autoimmune disease three patients with SLE, but were less frequent compared with GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions were studied. the period with chronic dialysis therapy. Autoantibody levels in patients with SLE, Wegener's granulomatosis, or microscopic polyangiitis did not seem to influence the outcome. CONCLUSIONS: Renal transplantation should be offered to patients with autoimmune diseases. Follow-up should include the short-term control of renal and extrarenal disease activity.

Grimbert P, Lang P, Renal Between October 1971 and August 1993, 53 The population studied consisted mainly of young women (mean Frappier J, transplantation in patients with SLE received 60 renal age, 33.2 years; range, 21 to 54, n = 48 [90%]). The duration of Bedrossian J, patients with transplants in the different renal disease before transplant was 93.6 +- 6.2 months and the Legendre C, Hiesse systemic lupus transplantation centers in Paris. All patients duration of dialysis before transplant was 48 _~ 6 months. At the C, Bitker MO, Sraer erythematosus: a met the criteria of the American time of transplant, none of the patients had clinically active SLE, JD, Antoine C. multicenter study. Rheumatism Association for SLE, and only four had hypocomplementemia, and 25 had positive anti- Hopital Henri diagnoses were confirmed by renal biopsy DNA titers. Of the 60 transplants, 56 (93%) were cadaveric and 4 Mondor, Creteil, specimens in all patients. The long-term (7%) were from living related donors. Forty-six patients (86%) France. Transplant outcome of renal transplantation in these had primary allografts, and 7 (14%) were given a second Proc. 1997 patients was examined, including patient allograft. Donor age was 38 _+ 2.4 years. The number of HLA Aug;29(5):2363-4. and graft survival, posttransplant lupus matches was 2.96 -+ 0.2. Panel-reactive antibody level was activity, serum creatinine levels, rejection >80% in 19 cases (31%). Overall graft survival rates for lupus episodes, and the causes of graft loss and patients were 83% and 69% at 1 and 5 years, respectively, patient death. All charts were examined for similar to those of control graft survivals of 82.5% and 70% (P any evidence of recurrent lupus nephritis. = .60). Of the 60 kidneys transplanted in SLE patients during this These 60 renal transplants were compared 21.5-year period, 37 (62%) are still functioning, and the mean with the patient and graft survival for 106 serum creatinine level is 15 _+ 2.5 mg/L. Fifteen grafts were lost controls matched for age, gender, maximum due to chronic rejection, 3 to acute rejection, 3 to renal artery panel-reactive antibody level, and date of thrombosis, 1 to ureteral necrosis, and 1 to thrombotic transplant. icroangiopathy caused by cyclosporine. Fortyone (68%) of the kidney transplants had at least one biopsy-documented episode of acute rejection, and there was histological evidence of chronic rejection in 36 (60%) kidney transplants. The survival of the lupus patients was similar to the controls: it was 98% at 1 year and 96% at 5 years in the lupus group, and 97% and 93% at 1 and 5 years in the controls (P = .96). Two of the lupus patients died from sepsis. GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions Stone JH, Millward Frequency of We reviewed the posttransplant clinical RESULTS: There were 81 female and 16 male patients, with a CL, Olson JL, Amend recurrent lupus course and renal biopsy results in 97 mean age of 35 years. Mean duration of dialysis prior to WJ, Criswell LA. nephritis among consecutive SLE patients who underwent a transplantation was 33.5 months; 9 patients were never dialyzed. University of ninety-seven renal total of 106 renal transplantation procedures In all patients, the disease was clinically and serologically California, San transplant patients at our center from January 1984 to quiescent at the time of transplantation. The mean Francisco Arthritis during the September 1996. posttransplantation followup period was 62.6 months. Patients Rheum. 1998 cyclosporine era. underwent a total of 143 posttransplant biopsies. Nine patients Apr;41(4):678-86. had pathologic evidence of recurrent LN. Six of the patients with recurrence had cadaveric grafts, 2 had living-related grafts, and 1 had a living-unrelated graft. Recurrence occurred an average of 3.1 years after transplantation; the longest interval was 9.3 years and the shortest, 5 days. Histopathologic diagnoses on recurrence included diffuse proliferative glomerulonephritis, focal proliferative glomerulonephritis, membranous glomerulonephritis, and mesangial glomerulonephritis. In 4 patients, recurrent LN contributed to graft loss. Three of the patients with recurrence had serologic evidence of active lupus, but only 1 had symptoms of active lupus (arthritis). Three patients who lost their grafts secondary to recurrent LN underwent second renal transplantation procedures and had functioning grafts at 7, 30, and 35 months, respectively. CONCLUSION: In the largest single medical center series of renal transplant patients with SLE, recurrent LN was more common than reported in the literature, but was not always associated with allograft loss. Recurrent LN was often present in the absence of clinical and serologic evidence of active SLE. Stone JH, Amend Outcome of renal A total of 97 SLE patients who underwent RESULTS: The control group included patients with 20 different WJ, Criswell LA. transplantation in renal transplantation between January 1984 causes of end-stage renal disease (ESRD). The mean followup Johns Hopkins ninety-seven and September 1996 were selected for times for the SLE patients and controls were 323 weeks and 320 University Arthritis cyclosporine-era study and were matched with a group of weeks, respectively. During the followup period, 52 SLE patients Rheum. 1998 patients with non-SLE controls (1 control for each SLE and 37 controls lost their allografts. The 1-, 2-, 5-, and 10-year Aug;41(8):1438-45. systemic lupus patient) who also received transplants allograft survival probabilities for the 2 groups (SLE versus erythematosus and during that period. SLE patients and controls controls) were as follows: 81.7% versus 88.2% (1-year); 74.7% matched controls. were matched on 6 covariates: age, sex, versus 84.4% (2-year); 45.9% versus 75.0% (5-year); and 18.5% race, type of allograft (cadaveric versus versus 34.8% (10-year). In the multivariate model, the relative living-related), number of previous hazard of allograft loss associated with SLE as the cause of transplants, and year of transplantation. All ESRD was 2.1 (95% confidence interval 1.06-4.06, P = 0.0328). study subjects received either cyclosporine The total number of HLA mismatches, smoking status, and or FK-506/tacrolimus as part of their delayed allograft function were also associated with allograft loss immunosuppressive regimen. In a rigorous in the multivariate model. CONCLUSION: Compared with medical records review, the status of each matched controls, renal transplant patients with SLE had inferior allograft and the cause of each graft loss transplantation outcomes, with more than twice the risk of GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions was determined. allograft loss.

Grimbert P, Frappier Long-term outcome The patients received their transplants over RESULTS: No patient had clinically active systemic lupus J, Bedrossian J, of kidney a 260-month period (21.5 years) between erythematosus (SLE) at the time of transplantation. The 1-year Legendre C, Antoine transplantation in October 1971 and August 1993. The graft and patient survival rates were 83% and 98%, and the 5- C, Hiesse C, Bitker patients with population was predominantly women year graft and patient survival rates were 69% and 96%. MO, Sraer JD, Lang systemic lupus (90%), and the mean age at the time of the Actuarial graft and patient survival rates in SLE patients were not P. Hôpital Henri erythematosus: a transplantation was 33.2 years (range: 21- significantly different from those of the matched control group. Mondor, Créteil, multicenter study. 54 years). Fifty-six transplants (93%) were Chronic rejection was the major risk factor for graft loss. Lupus France. Groupe Cooperatif from cadaveric donors, and 4 (7%) were nephritis recurred in the graft of one patient 3 months after Transplantation. 1998 de Transplantation from living-related donors; 46 patients (86%) transplantation, and there were extrarenal manifestations of SLE Oct 27;66(8):1000-3. d'île de France. had primary allografts, and 7 (14%) received in four others. CONCLUSIONS: The present study confirms that a second allograft. The duration of disease patients with SLE can receive transplants with excellent graft and before transplantation was 93.6+/-6.2 patient survival rates and a low rate of clinical recurrent lupus months, and the duration of dialysis before nephritis. transplantation was 48+/-6 months. Azevedo LS, Romão Renal Forty-five patients with systemic lupus RESULTS: No differences in acute episodes of rejection, causes JE Jr, Malheiros D, transplantation in erythematosus subjected to 48 kidney of kidney loss or patient death were observed. General as well as Saldanha LB, Ianhez systemic lupus transplants were studied. For comparative infectious complications were similar. Pregnancy rates and LE, Sabbaga E. erythematosus. A purposes, a case-control population was outcomes were similar with no deleterious effect on patients or University of São case control study of selected, matched for gender, race, type of grafts. Actuarial 1- and 5-year patient survivals (97.7 and 91.1% Paulo Medical 45 patients. donor, age, and time of transplantation. for SLE and 95.4 and 87% for controls, respectively) and graft School, SP, Brazil. Patients with non-glomerulonephritis survivals (93.1 and 80.7% for SLE and 88.8 and 70.2% for Nephrol Dial diseases were excluded. controls, respectively) were similar. Long-term renal function Transplant. 1998 expressed by serum creatinine was the same. No differences in Nov;13(11):2894-8. immunosuppressive drug (azathioprine, prednisone, and cyclosporin) requirements were found. Clinical SLE recurrence was suspected only once (a patient with thrombocytopenia, hypocomplementaemia with low complement levels and positive antiplatelet antibodies). Two SLE patients showed mesangial proliferative glomerulonephritis compatible with recurrence. Both grafts were lost. Two further patients showed membranous glomerulonephritis with an immunofluorescence pattern GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions compatible with recurrence. A fifth patient had necrotizing arteritis which recovered after treatment with cyclophosphamide and another patient showed focal and segmental glomerulosclerosis. Histology of biopsies from five patients in the control group showed signs compatible with recurrence of focal and segmental glomerulosclerosis and membranous glomerulonephritis. There was a wide variation in serum levels of antinuclear antibodies. A wide variation in complement levels was also observed, but with a tendency towards low C4 levels. CONCLUSIONS: The safety of renal transplantation in SLE patients is equivalent to a matched case-control group with a similar rate of recurrence of disease. Contreras G, Recurrence of lupus The frequency and outcome of recurrent Among 6850 recipients of a kidney allograft with systemic lupus Mattiazzi A, Guerra nephritis after kidney lupus nephritis (RLN) among recipients of a erythematosus, 167 recipients had RLN, 1770 experienced G, Ortega LM, transplantation. kidney allograft vary among single-center rejection, and 4913 control subjects did not experience rejection. Tozman EC, Li H, reports. From the United Network for Organ The period prevalence of RLN was 2.44%. Non-Hispanic black Tamariz L, Carvalho Sharing files, we estimated the period race, female gender, and age <33 years each independently C, Kupin W, Ladino prevalence and predictors of RLN in increased the odds of RLN. Graft failure occurred in 156 (93%) of M, LeClercq B, recipients who received a transplant those with RLN, 1517 (86%) of those with rejection, and 923 Jaraba I, Carvalho D, between 1987 and 2006 and assessed the (19%) of control subjects without rejection. Although recipients Carles E, Roth D. effects of RLN on allograft failure and with RLN had a fourfold greater risk for graft failure compared Miller School of recipients' survival. with control subjects without rejection, only 7% of graft failure Medicine, University episodes were attributable to RLN compared and 43% to of Miami J Am Soc rejection. During follow-up, 867 (13%) recipients died: 27 (16%) Nephrol. 2010 in the RLN group, 313 (18%) in the rejection group, and 527 Jul;21(7):1200-7. (11%) in the control group. In summary, severe RLN is Epub 2010 May 20. uncommon in recipients of a kidney allograft, but black recipients, female recipient, and younger recipients are at increased risk. Although RLN significantly increases the risk for graft failure, it contributes far less than rejection to its overall incidence; therefore, these findings should not keep patients with lupus from seeking a kidney transplant. Jakez-Ocampo J, Lupus nephritis The no-biopsy group consisted of 30 RESULTS: At onset, the no-biopsy group showed lower C3 Arreola-Zavala R, outcome with and patients with lupus with strong clinical and levels and higher proteinuria, although both groups showed Richaud-Patin Y, without renal biopsy: laboratory suspicion of proliferative evident deterioration of the renal function. No significant Romero-Díaz J, a 5-year glomerulonephritis in whom a renal biopsy differences were found in treatment, outcome, survival, renal Llorente L. Instituto comparative study. was unavailable either because of medical function tests, or in the development of kidney failure. Nacional de Ciencias contraindication or the patient's refusal. The CONCLUSIONS: Proliferative glomerulonephritis deserves Médicas y Nutrición biopsy group included 30 patients prompt diagnosis and treatment. This study demonstrates that Salvador Zubirán, undergoing biopsy and a histologic experience in the management of lupus nephropathy, together México City J Clin diagnosis of DPGN. Patients were followed with clinical and laboratory data, are often enough information to Rheumatol. 2004 from the onset of nephritis and at 18, 36, adequately treat proliferative glomerulonephritis even in the GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions Dec;10(6):289-94. and 60 months. absence of a renal biopsy.

Nyberg G, Karlberg I, Renal The outcome of primary renal Patient survival did not differ, but graft survival at 6 and 12 Svalander C, transplantation in transplantation in 31 SLE patients was months post transplantation was significantly reduced in SLE Hedman L, Blohmé I. patients with evaluated in relation to two contemporary patients (p less than 0.001). When divided into groups using Sahlgrenska systemic lupus controls per patient, matched for age, sex either azathioprine and steroids or combinations including Hospital, Göteborg, erythematosus: and immunosuppressive therapy. The cyclosporin A (14 and 17 SLE patients in each group), graft Sweden. Scand J increased risk of proportion of living donors was one third in survival was significantly reduced for the azathioprine-treated Urol Nephrol. early graft loss. both groups. SLE patients, 36% vs. 82% for their controls at one year. For 1990;24(4):307-13. cyclosporin-treated SLE patients, one-year graft survival was 59% vs. 85% for their controls, and 6 out of 17 grafts in the cyclosporin-treated group were lost within the first month vs. only 4 out of 34 controls. These differences were, however, not statistically different. Most failed grafts were lost from rejection, with a high proportion of acute vascular rejection, isolated or in combination with cellular rejection. There was no apparent association between rejection and HLA-matched or presence of HLA antibodies. Retransplantation was successful in 6 out of 7 cases. We conclude that SLE patients have an increased risk of early graft rejection, but that this may be overcome by more powerful immunosuppressive therapy. el-Shahawy MA, Renal The outcome of renal transplantation in 64 For all 64 patients combined, the 1-year graft and patient survival Aswad S, Mendez transplantation in patients with end-stage renal disease rates are 68.8 and 86.5%, respectively, whereas 5-year graft and RG, Bangsil R, systemic lupus (ESRD) secondary to lupus nephritis is the patient survival rates are 60.9 and 85.9%, respectively. Patients Mendez R, Massry erythematosus: a subject of this report. The patients were whose immunosuppressive regimen was CsA-based had a 1- SG. University of single-center transplanted over a 150-month (12.5-year) year graft survival of 71.5 versus 63.6% in the AZA group. Southern California experience with period (between July 5, 1979, and January However, this 7.9% difference did not reach statistical School of sixty-four cases. 30, 1992). The study population is significance (p = 0.95). The 5-year graft survival of the CsA- MedicineAm J predominantly made up of young females based group was 69.1 versus 45.5% for the AZA group, p < 0.05. Nephrol. (mean age, 34.7 +/- 9 years, n = 54, 81.3%). One-year patient survival was 77.3% for the AZA group and 1995;15(2):123-8. Fifty-one transplants (79.7%) are cadaveric, 92.9% for the CsA group, p < 0.05). The data show that patients and 13 (20.3%) are from living-related with ESRD secondary to lupus nephritis can undergo renal donors. Fifty-eight patients (90.6%) had transplantation with satisfactory outcome. Immunosuppression primary (first) allografts, and 6 (9.4%) based upon CsA improves first-year patient and allograft survival received a second allograft. by 15.6 and 7.9%. respectively. GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES

Authors Title Description/Methods Results/Conclusions Posttransplantation immunosuppression consisted of azathioprine and prednisone (AZA group, n = 22, 34.3%) or AZA, prednisone and cyclosporine (CsA group, n = 42, 65.6%). GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS

Table 8. Summary of Commonly Used Medications’ Teratogenic Effects

PREGNANCY AND LUPUS NEPHRITIS

Treatment Pregnan Crosses Animal Human Studies cy Placenta? Studies Categor y Teratogenic effects have been reported in association with the use of cyclophosphamide. In general, alkylating agents when given during the first trimester are believed to cause slight increases in the risk of congenital Cyclophosphami malformations, but when given during the second or third trimesters are believed D yes Teratogenic de to only increase the risk of growth retriction (Glantz, 1994). In one case series of 4 patients treated with cyclophosphamide for lupus during pregnancy (2 during first trimester, 2 during 2nd trimester), all 4 resulted in pregnancy loss (Clowse Lupus 2005) Azathioprine has been used during pregnancy in organ transplant recipients. During over 40 years of experience with azathioprine as an immunosuppressant in organ transplant patients, no predominant or specific malformation pattern has Yes (but fetal been identified which is attributable to this drug. Retrospective review of liver lacks pregnancy outcomes revealed that infants exposed to azathioprine may develop enzyme the following adverse effects: thymic atrophy, leukopenia, anemia, which Azathioprine D Teratogenic thrombocytopenia, chromosome aberrations, reduced immunoglobulin levels, converts and infections. Adjustment of azathioprine dosage to maintain normal maternal drug to leukocyte counts may decrease or prevent neonatal leukopenia and active thrombocytopenia (Armenti et al, 1998). Current guidelines regarding pregnant metabolites) renal transplant patients state that immunosuppressive therapy with or without steroids and azathioprine may be continued during pregnancy (EBPG Expert Group on Renal Transplantation, 2002). The National Transplantation Pregnancy Registry (NTPR) reports 24 female kidney recipients with 33 pregnancies exposed to mycophenolate mofetil. There were 15 spontaneous abortions (45%) and 18 live births, with structural abnormalities were present in 4 of these 18 infants (22%). Based on postmarketing data collected by the NTPR from 1995 to 2007 among women MMF D Unknown Teratogenic (n=77) with systemic exposure to mycophenolate mofetil during pregnancy, spontaneous abortions occurred in 25 women and fetal/infant malformations occurred in 14 offspring. Ear abnormalities were present in 6 of the 14 malformed infants. With doses below equivalent human clinical doses, fetal resorptions and/or malformations in the absence of maternal toxicity have occurred in rats and rabbits (Prod Info CellCept(R) oral capsules, tablets, GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS PREGNANCY AND LUPUS NEPHRITIS

Treatment Pregnan Crosses Animal Human Studies cy Placenta? Studies Categor y suspension, IV injection, 2009). Note that in 2007, the pregnancy category was changed from C to D because of the noted pattern of abnormalities Leflunomide use is contraindicated in women who are or may become pregnant. Based on animal data, leflunomide may increase the risk of fetal death or teratogenic effects in pregnant women. Prior to initiation of leflunomide, pregnancy must be excluded and the use of reliable contraception must be confirmed. P Of 168 pregnant women evaluated as of January 2004 in a controlled, cohort study (OTIS Rheumatoid Arthritis in Pregnancy), women with rheumatoid arthritis (RA) exposed to leflunomide early in pregnancy (n=43) and those with RA not exposed to leflunomide during pregnancy (n=78) were a significant 12 times (95% confidence interval (CI) 2.5, 59.2) and a significant 10.1 times (95% CI 2.2, 47.3), respectively, more likely to deliver preterm infants Leflunomide X Unknown Teratogenic compared with those in the non-diseased control group (n=47). The adjusted mean birth weight of full term infants was also significantly lower in the RA leflunomide group (3158 g, 95% CI 2979, 3336) and the RA control group (3250 g, 95% CI 3124, 3375) compared with the non-diseased control group (3618 g, 95% CI 3487, 3748; p less than 0.001). Overall, all groups had the same proportion of infants born with major and/or minor malformations (Chambers et al, 2004). However, in a follow-up study published in 2010, among 64 women who were exposed to leflunomide early in pregnancy, but stopped the drug and were treated with cholestyramine, there was no substantial increase in adverse pregnancy outcomes (Chambers Arthritis Rheum 2010). Teratogenic effects have been reported in association with the use of chlorambucil. The teratogenic effects of chlorambucil may be potentiated by caffeine (Bermas & Hill, 1995). In general, alkylating agents, when given during Chlorambucil D Yes Teratogenic the first trimester, are believed to cause slight increases in the risk of congenital malformations, but when given during the second or third trimesters are believed to only increase the risk of growth restriction (Glantz, 1994a).. Retrospective case analysis: 100 pregnancies (84 women) 71 pregnancies progressed to delivery, resulting in 68 live births and 24 pregnancies that were spontaneously or electively aborted. Four of the 68 surviving neonates had Tacrolimus C Yes congenital malformations, whereas none of the 24 aborted fetuses exhibited detectable malformations. Prematurity rate of 59% ;only 10% of the infants were outside of the 10th to 90th percentile range for birth weight when considering the gestational age of the neonate (Kainz et al, 2000). GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS PREGNANCY AND LUPUS NEPHRITIS

Treatment Pregnan Crosses Animal Human Studies cy Placenta? Studies Categor y In a study of 48 pregnant women being treated with therapeutic doses of cyclosporine, no evidence of direct hazard to the fetus was demonstrated. (Cockburn et al, 1989). No specific birth defect has been associated with CSA, Cyclosporine C Yes No although many sporadic congenital anomalies have been reported (Petri Autoimmunity 2003). In post-marketing surveillance of 166 pregnancies, 45% were pre-term, and the median birthweight was 2300 g (Arellano Med Clin 1991). GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS

Table 9 . Use of anti-DNA antibodies for prognosis among SLE patients. Overall SLE active vs. Renal involvement Renal disease active inactive present vs. absent vs. inactive

Reference Technique Sen Spec +LR -LR Sen Spec +LR -LR Sen Spec +LR -LR

Froelich, et al. (199). ELISA 0.75 0.75 3.0 0.33 Emlen, et al.(200) ELISA 0.69 0.77 3.05 0.4 Farr 0.98 0.97 25.2 0.02 Crithidia 0.56 0.97 24.1 0.45 Isenberg, et al.(201) Crithidia 0.62 0.75 1.8 0.5 0.92 0.55 2.1 0.14 Ter Borg, et al. (90) ELISA 0.32 0.64 0.88 1.06 Crithidia 0.14 0.91 1.55 0.94 Farr 0.41 0.73 1.5 0.81 Chubick et al. (202) ELISA 0.92 0.44 1.6 0.18 0.97 0.44 1.7 0.07 Farr 0.73 0.72 2.6 0.38 0.76 0.72 2.7 0.33 Kalmin, et al. (203) ELISA 0.71 0.33 1.05 0.88 0.91 0.08 0.99 1.12 Crithidia 0.43 0.6 1.07 0.95 0.46 0.6 1.15 0.9 Cameron, et al. (103) Farr 0.89 0.25 1.2 0.44 Bootsma, et al. (204) Crithidia 1.00 0.13 1.15 0.38 Farr 0.89 0.4 1.48 0.28 Pincus, et al. (205) Farr 0.82 0.18 1.0 0.97 0.91 0.33 1.4 0.26 Ballou, et al. (206) Crithidia 0.74 0.95 14.8 0.27 0.88 0.41 1.5 0.29 Garcia, et al. (207) Crithidia 0.85 0.33 2.6 0.45 Weitzman, et al. Farr 0.76 0.66 2.28 0.36 0.82 0.32 1.2 0.56 (208) Miniter, et al. (209) RIA 0.68 0.82 3.76 0.39 Ballou,et al. (210) Crithidia 0.53 0.64 1.46 0.73 Isenberg, et al. ELISA 0.76 0.54 1.65 0.44 (211) Abrass, et al. (102) RIA 0.33 0.68 1.03 0.97 0.44 0.57 1.02 0.98 Davis, et al. (212) RIA 0.93 0.78 3.48 0.1 Feldman, et al. Farr 0.2 0.88 1.6 0.9 0.25 0.93 3.6 0.8 NA NA NA NA (213) Weighted means 0.66 0.66 4.14 0.51 0.65 0.41 1.7 0.76 0.86 0.45 1.7 0.3 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS

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