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
D Day
G Gram
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
U Urine
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
Radboud University Nijmegen
Med Ctr
Nijmegen, THE NETHERLANDS
MD*
Chief of Rheumatology
Professor of Medicine
Tuen Mun and Pok Oi Hospital
Northwestern University
Chicago, ILLINOIS HONG KONG

Frederic A. Houssiau, MD,

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

Gabriel Contreras, MD** David A. Isenberg, MD, FRCP*

Associate Professor of Medicine
Div of Nephrology
University of Miami
University College of London
Miami, FLORIDA
Brad Rovin, MD**
Professor
Professor of Medicine
Center for Rheumatology
Division of Nephrology
Research
The Ohio State University
Columbus, OHIO
London ENGLAND

Karen H. Costenbader, MD,

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

Mary Ann Dooley, MD*

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

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
NIH, USA, histologic evidence of active lupus
1986 (149) glomerulonephritis, and informed consent to all
aspects of the study.
Diagnosis of systemic lupus erythematosus and
Steinberg and clinical/histologic evidence of active lupus
Steinberg, glomerulonephritis.
NIH, USA,
1991 (150)
The presence of >=4 ACR criteria for SLE, age 18
to 60 years, creatinine clearance (Cockcroft-Gault)
>25ml/min, and biopsy-proven proliferative LN. For
patients already known to have proliferative LN, the
last renal biopsy had to be performed less than one
Grootscholten
year before. Patients with WHO-class IV or Vd LN
et al,
were eligible when they had signs of active
Netherlands
nephritis or a deterioration of renal function.
Nephrology,
Patients with WHO-class III or Vc LN had to meet
2006 (151)
both criteria.
Prednisone (Pred) vs Cyclophosphamide (CYC) IV
Article Inclusion Criteria
Patients had 4 or more criteria for SLE and severe
lupus nephritis defined by a nephritic urine
Boumpas et sediment and impaired renal function with a
al, NIH, USA creatinine clearance between 25 and 80 ml per
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
Jadad
Score
per minute, major infection within 2 week s of study
entry, pregnancy, a leukocyte count of less than
2000 per cubic millimeter, cytotoxic-drug therapy
within eight weeks, and sensitivity to the study drug
Creatinine clearance consistently <20ml/minute, 2
presence of a major infection within the previous 2
weeks, pregnancy, white blood cell count
<2000/mm3, treatment with a cytotoxic drug within
the previous 8 weeks, or known sensitivity to any
study drug.
Patients with membranous LN WHO-class Va or Vb 2
were excluded.. Decline in renal function (more
than 30% increase in serum creatinine) during
treatment with cytotoxic immunosuppressive agents
in the month before inclusion. Active infection.
Malignancy <5 years before randomization.
Pregnancy or refusal to use reliable contraceptives
during the first 2.5 years of treatment. Chronic
active or persisting hepatitis or cirrhosis of the liver,
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.
Exclusion Criteria Jadad
Score
Pregnancy or had received cytotoxic drug therapy 2
for more than 10 weeks at any time, active
infections, insulin-dependent diabetes, or previous
malignancy.
 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
Eligible patients were either gender and between
12 and 60 yr of age; provided written informed
consent; diagnosis of SLE according for ACR
(1997); showed an SLE disease activity index
>=12; had a diagnosis of Class V+IV LN according
to ISN/RPS 2003 classification of LN, with a
pathologic chronic index (CI) <4 proved by light,
Bao et al,
immunofluorescence, and electron microscopy
Nanjing,
within 3 wk before enrollment; and exhibited overt
2008 (161)
proteinuria (>=1.5g of protein in a 24-h urine
specimen) with or without active urinary sediment
(any of urine sediment RBC count >10 x 10 4/ml or
white blood cells > 5 per high-power field or red cell
casts in the absence of infection or other causes.
Jadad
Score
Serum creatinine > 3.0mg/dl (265.2 microlmol/L) or 2
estimated Creatinine clearance <30ml/min per
1.73m2 on repeated testing; liver function with ALT,
ASST, or bilirubin greater than twice the upper limit
of the reference range; abnormal glucose
metabolism, defined as a fasting (i.e., no caloric
intake for at least 8 h) plasema glucose level > 6.1
mmol/L and/or a 2-h plasma glucose level > 7.8
mmol/L; known hypersensitivity or contraindication
to any components of these regimens; use of CTX,
MMF, or tacrolimus within the past 12 wk;
pregnancy or lactation; life-threatening
complications such as cerebral lupus; or other
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
Class III, IV-S or IV-G, V, III+V, or IV+V. Patients
with class III or V LN must have had proteinuria (at
least 2g/d) which was considered clinically
significant level of proteinuria, and might indicate a
recent deterioration in renal function.
Aged 12 to 75 yrs, diagnosis of SLE, LN (active or
active/chronic) conformed by kidney biopsy within
6 mo before randomization as ISN/RPS 2003
Class III, IV-S or IV-G, V, III+V, or IV+V. Patients
Isenberg et al, with class III or V LN must have had proteinuria (at
Sub Analysis least 2g/d) which was considered clinically
of ALMS trial, significant level of proteinuria, and might indicate a
2010 (167) recent deterioration in renal function.
Pure Class V LN included in this analysis only.
ALMS - Aged 12 to 75 yrs, diagnosis of SLE, LN
Radhakrishnan (active or active/chronic) conformed by kidney
et al, ALMS + biopsy within 6 mo before randomization as
Ginzler et al, ISN/RPS 2003 Class III, IV-S or IV-G, V, III+V, or
2010 IV+V. Patients with class III or V LN must have
(NOTE had proteinuria (at least 2g/d) which was
COMBINED 2 considered clinically significant level of proteinuria,
studies) (43) and might indicate a recent deterioration in renal
function.
GINZLER - SLE meeting 4 classification criteria of
the ACR; renal biopsy documenting lupus nephritis
Exclusion Criteria Jadad
Score
wk, pancreatitis, gastronintestinal hemorrhage
within 6 mo or active peptic ulcer within 3 mo,
severe viral infection, severe cardiovascular
disease, bone marrow insufficiency with cytopenias
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.
Treatment with MMF or IVC within the previous
year, continuous dialysis for ?2 wk before
randomization or anticipated during longer than 8
wk, pancreatitis, gastronintestinal hemorrhage
within 6 mo or active peptic ulcer within 3 mo,
severe viral infection, severe cardiovascular
disease, bone marrow insufficiency with cytopenias
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.
ALMS - Treatment with MMF or IVC within the 2
previous year, continuous dialysis for ?2 wk before
randomization or anticipated during longer than 8
wk, pancreatitis, gastronintestinal hemorrhage
within 6 mo or active peptic ulcer within 3 mo,
severe viral infection, severe cardiovascular
disease, bone marrow insufficiency with cytopenias
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.
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
according to the classification of WHO III, IV, or V;
clinical activity as defined by one or more of the
following: incidence decrease in renal function
(serum creatinine, >1mg/dL (88.4 micromol/L),
proteinuria (defined as more than 500mg of protein
in a 24-h urine specimen), microscopic hematuria
(defined as >5 red cells per high power-field) or the
presence of cellular casts, increasing proteinuria
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.
SLE meeting 4 classification criteria of the ACR
with newly diagnosed active proliferative class III or
IV lupus nephritis and aged 15 years or older were
El Shafey et enrolled in the study.
al, Egypt,
2010 (168)
MMF + AZA vs CYC PO + AZA
Article Inclusion Criteria
SLE according to ARA including renal-biopsy
Chan et al,
evidence of diffuse proliferative lupus nephritis
Hong Kong,
(WHO IV), urinary protein excretion of 1g or more
2000 (169)
per 24 hours, serum albumin concentration of
Exclusion Criteria Jadad
Score
/min, serum creatinine on repeated testing greater
than 3mg/dL (265.2 microlmol /L), severe
coexisting conditions precluding
immunosuppressive therapy or conditions requiring
intravenous antibiotic therapy, prior treatment with
mycophenolate mofetil, treatment with intravenous
cyclophosphamide within the past 12 months,
monoclonal antibody therapy within the past 30
days, or pregnancy or lactation.
Estimated glomerular filtration rate (eGFR) of less 2
than 30ml per minute, serum cereatinine on
repeated testing more than 200 micromol/L, white
blood cell (WBC) count of less than 3.5 x 19 9/l,
evidence of major infection, history of cancer,
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.
Exclusion Criteria Jadad
Score
Serum creatinine concentration higher than 2
3.4mg/dL (300 micromol per liter); life-threatening
complications such as cerebral lupus or severe
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
Age >18 years who fulfilled ACR classification
criteria for SLE, moderately active lupus defined by
1 of the 2 sets of criteria. Criteria set 1 – presence
of chronic glomerulonephritis with an inadequate
response to at least 6 months of adequate
immunosuppressive therapy (with either
methylprednisolone pulse doses,
cylcophosphamide, azathioprine, cyclosporine,
mycophenolate mofetil, high-dose dialy
corticosteroids, methotrexate, or intravenous
Illei, et al,
immunoglobulin, plus the following 4 features: less
USA, 2010
than a 30% increase in serum creatinine levels as
(174)
compared with the lowest level achived during
treatment; proteinuria at levels <=1.5 times the
value at baseline (before treatment); <= 2+ cellular
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
Exclusion Criteria Jadad
Score
Pregnancy, any therapy with human, murine 0
antibodies, or any experimental therapy within 3
months, therapy with cyclophosphamide, pulse
methylprednisolone or IVIG within 4 weeks, or
azathioprine, mycophenolate mofetil, cyclosporine,
or methotrexate within 2 weeks of the first dose of
study medication. Serum creatinine level >3.0
mg/dl, white blood cell count <3500/microL,
absolute neutrophil count < 3000 microlL, absolute
lymphocyte count <= 500/microlL, hemoglobin
value <8.0 gm/dl, platelet count <50000/microlL,
AST or ALT levels >1.5 times the upper limits of
normal, or >1000 Epstein-Barr virus genome
equivalents/10 6 preipheral blood mononuclear
cells.
 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
Frappier J, transplantation in patients with SLE received 60 renal
Bedrossian J, patients with transplants in the different renal
Legendre C, Hiesse systemic lupus transplantation centers in Paris. All patients
C, Bitker MO, Sraer erythematosus: a met the criteria of the American
JD, Antoine C. multicenter study. Rheumatism Association for SLE, and
Hopital Henri diagnoses were confirmed by renal biopsy
Mondor, Creteil, specimens in all patients. The long-term
France. Transplant outcome of renal transplantation in these
Proc. 1997 patients was examined, including patient
Aug;29(5):2363-4. and graft survival, posttransplant lupus
activity, serum creatinine levels, rejection
episodes, and the causes of graft loss and
patient death. All charts were examined for
any evidence of recurrent lupus nephritis.
These 60 renal transplants were compared
with the patient and graft survival for 106
controls matched for age, gender, maximum
panel-reactive antibody level, and date of
transplant.
The population studied consisted mainly of young women (mean
age, 33.2 years; range, 21 to 54, n = 48 [90%]). The duration of
disease before transplant was 93.6 +- 6.2 months and the
duration of dialysis before transplant was 48 _~ 6 months. At the
time of transplant, none of the patients had clinically active SLE,
only four had hypocomplementemia, and 25 had positive anti-
DNA titers. Of the 60 transplants, 56 (93%) were cadaveric and 4
(7%) were from living related donors. Forty-six patients (86%)
had primary allografts, and 7 (14%) were given a second
allograft. Donor age was 38 _+ 2.4 years. The number of HLA
matches was 2.96 -+ 0.2. Panel-reactive antibody level was
>80% in 19 cases (31%). Overall graft survival rates for lupus
patients were 83% and 69% at 1 and 5 years, respectively,
similar to those of control graft survivals of 82.5% and 70% (P
= .60). Of the 60 kidneys transplanted in SLE patients during this
21.5-year period, 37 (62%) are still functioning, and the mean
serum creatinine level is 15 _+ 2.5 mg/L. Fifteen grafts were lost
due to chronic rejection, 3 to acute rejection, 3 to renal artery
thrombosis, 1 to ureteral necrosis, and 1 to thrombotic
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
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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
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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

REFERENCES

1. Guidelines for referral and management of systemic lupus erythematosus in adults. American College
of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum.
1999;42(9):1785-96.

2. Markowitz GS, D'Agati VD. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3
years. Kidney Int. 2007;71(6):491-5.

3. Bomback AS, Appel GB. Updates on the treatment of lupus nephritis. J Am Soc Nephrol.
2010;21(12):2028-35.

4. Griffiths B, Mosca M, Gordon C. Assessment of patients with systemic lupus erythematosus and the
use of lupus disease activity indices. Best Pract Res Clin Rheumatol. 2005;19(5):685-708.

5. Gordon C, Sutcliffe N, Skan J, Stoll T, Isenberg DA. Definition and treatment of lupus flares measured
by the BILAG index. Rheumatology (Oxford). 2003;42(11):1372-9.

6. Isenberg DA, Gordon C. From BILAG to BLIPS--disease activity assessment in lupus past, present and
future. Lupus. 2000;9(9):651-4.

7. Gladman DD, Goldsmith CH, Urowitz MB, Bacon P, Fortin P, Ginzler E, et al. The Systemic Lupus
International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for
Systemic Lupus Erythematosus International Comparison. J Rheumatol. 2000;27(2):373-6.

8. Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J
Rheumatol. 2002;29(2):288-91.

9. Isenberg DA, Rahman A, Allen E, Farewell V, Akil M, Bruce IN, et al. BILAG 2004. Development and
initial validation of an updated version of the British Isles Lupus Assessment Group's disease activity index for
patients with systemic lupus erythematosus. Rheumatology (Oxford). 2005;44(7):902-6.

10. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al. A phase III, randomized,
placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients
with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918-30.

11. Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, et al. Mycophenolate versus
azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011;365(20):1886-95.

12. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College of
Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic
drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762-84.

13. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality
of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.

14. Wells G, Shea B, O'Connnell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale
(NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2010 [cited; Available from:
http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

15. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005
Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing
Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in
collaboration with the American College of Chest Physicians and the International Society for Heart and Lung
Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12):e154-235.

16. Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines: developing guidelines. BMJ.
1999;318(7183):593-6.

17. Zhang W, Doherty M, Arden N, Bannwarth B, Bijlsma J, Gunther KP, et al. EULAR evidence based
recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing
Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis.
2005;64(5):669-81.

18. Gordon T. The Delphi Project; 1994.

19. Fitch K, Bernstein S, Aguilar M, Burnand B, Lacalle JR, Lozaro P, et al. The RAND/UCLA
Appropriateness Method User's Manual. Santa Monica: RAND Corporation; 2001.

20. Shekelle PG, Chassin MR, Park RE. Assessing the predictive validity of the RAND/UCLA
appropriateness method criteria for performing carotid endarterectomy. Int J Technol Assess Health Care.
1998;14(4):707-27.

21. Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of
glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65(2):521-30.

22. Furness PN, Taub N. Interobserver reproducibility and application of the ISN/RPS classification of lupus
nephritis-a UK-wide study. Am J Surg Pathol. 2006;30(8):1030-5.

23. Yokoyama H, Wada T, Hara A, Yamahana J, Nakaya I, Kobayashi M, et al. The outcome and a new
ISN/RPS 2003 classification of lupus nephritis in Japanese. Kidney Int. 2004;66(6):2382-8.

24. Austin HA, 3rd, Muenz LR, Joyce KM, Antonovych TA, Kullick ME, Klippel JH, et al. Prognostic factors
in lupus nephritis. Contribution of renal histologic data. Am J Med. 1983;75(3):382-91.

25. Wernick RM, Smith DL, Houghton DC, Phillips DS, Booth JL, Runckel DN, et al. Reliability of histologic
scoring for lupus nephritis: a community-based evaluation. Ann Intern Med. 1993;119(8):805-11.

26. Mosca M, Pasquariello A, Tavoni A, Moriconi L, Moneta I, Innocenti M, et al. Predictors of renal
outcome in diffuse proliferative glomerulonephritis in systemic lupus erythematosus. Lupus. 1997;6(4):371-8.

27. Stamenkovic I, Favre H, Donath A, Assimacopoulos A, Chatelanat F. Renal biopsy in SLE irrespective
of clinical findings: long-term follow-up. Clin Nephrol. 1986;26(3):109-15.

28. Ayodele OE, Okpechi IG, Swanepoel CR. Predictors of poor renal outcome in patients with biopsy-
proven lupus nephritis. Nephrology (Carlton). 2010;15(4):482-90.

29. Whiting-O'Keefe Q, Henke JE, Shearn MA, Hopper J, Jr., Biava CG, Epstein WV. The information
content from renal biopsy in systemic lupus erythematosus. Ann Intern Med. 1982;96(6 Pt 1):718-23.

30. Makino H, Hayashi Y, Yamasaki Y, Shikata K, Kashihara N, Kira S, et al. Clinical significance of
necrosis in lupus nephritis. Intern Med. 1994;33(8):461-5.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

31. Miranda JM, Garcia-Torres R, Jara LJ, Medina F, Cervera H, Fraga A. Renal biopsy in systemic lupus
erythematosus: significance of glomerular thrombosis. Analysis of 108 cases. Lupus. 1994;3(1):25-9.

32. Esdaile JM, Joseph L, MacKenzie T, Kashgarian M, Hayslett JP. The pathogenesis and prognosis of
lupus nephritis: information from repeat renal biopsy. Semin Arthritis Rheum. 1993;23(2):135-48.

33. Esdaile JM, Federgreen W, Quintal H, Suissa S, Hayslett JP, Kashgarian M. Predictors of one year
outcome in lupus nephritis: the importance of renal biopsy. Q J Med. 1991;81(295):907-18.

34. Tang Z, Wang Z, Zhang HT, Hu WX, Zeng CH, Chen HP, et al. Clinical features and renal outcome in
lupus patients with diffuse crescentic glomerulonephritis. Rheumatol Int. 2009;30(1):45-9.

35. Faurschou M, Dreyer L, Kamper AL, Starklint H, Jacobsen S. Long-term mortality and renal outcome in
a cohort of 100 patients with lupus nephritis. Arthritis Care Res (Hoboken). 2010;62(6):873-80.

36. Austin HA, 3rd, Muenz LR, Joyce KM, Antonovych TT, Balow JE. Diffuse proliferative lupus nephritis:
identification of specific pathologic features affecting renal outcome. Kidney Int. 1984;25(4):689-95.

37. Parichatikanond P, Francis ND, Malasit P, Laohapand T, Nimmannit S, Singchoovong L, et al. Lupus
nephritis: clinicopathological study of 162 cases in Thailand. J Clin Pathol. 1986;39(2):160-6.

38. Nossent HC, Henzen-Logmans SC, Vroom TM, Berden JH, Swaak TJ. Contribution of renal biopsy
data in predicting outcome in lupus nephritis. Analysis of 116 patients. Arthritis Rheum. 1990;33(7):970-7.

39. Kojo S, Sada KE, Kobayashi M, Maruyama M, Maeshima Y, Sugiyama H, et al. Clinical usefulness of a
prognostic score in histological analysis of renal biopsy in patients with lupus nephritis. J Rheumatol.
2009;36(10):2218-23.

40. Yu F, Wu LH, Tan Y, Li LH, Wang CL, Wang WK, et al. Tubulointerstitial lesions of patients with lupus
nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system.
Kidney Int. 2010;77(9):820-9.

41. McLaughlin JR, Bombardier C, Farewell VT, Gladman DD, Urowitz MB. Kidney biopsy in systemic
lupus erythematosus. III. Survival analysis controlling for clinical and laboratory variables. Arthritis Rheum.
1994;37(4):559-67.

42. Gladman DD, Urowitz MB, Cole E, Ritchie S, Chang CH, Churg J. Kidney biopsy in SLE. I. A clinical-
morphologic evaluation. Q J Med. 1989;73(272):1125-33.

43. Radhakrishnan J, Moutzouris DA, Ginzler EM, Solomons N, Siempos, II, Appel GB. Mycophenolate
mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney
Int. 2010;77(2):152-60.

44. Austin HA, 3rd, Illei GG, Braun MJ, Balow JE. Randomized, controlled trial of prednisone,
cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol. 2009;20(4):901-
11.

45. Dujovne I, Pollak VE, Pirani CL, Dillard MG. The distribution and character of glomerular deposits in
systemic lupus erythematosus. Kidney Int. 1972;2(1):33-50.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

46. Najafi CC, Korbet SM, Lewis EJ, Schwartz MM, Reichlin M, Evans J. Significance of histologic patterns
of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int. 2001;59(6):2156-
63.

47. Ferluga D, Jerse M, Vizjak A, Hvala A, Rozman B, Kos-Golja M, et al. Correlation among WHO classes,
histomorphologic patterns of glomerulonephritis and glomerular immune deposits in SLE. Wien Klin
Wochenschr. 2000;112(15-16):692-701.

48. Blanco FJ, De la Mata J, Lopez-Fernandez JI, Gomez-Reino JJ. Light, immunofluorescence and
electron microscopy renal biopsy findings as predictors of mortality in eighty-five Spanish patients with
systemic lupus erythematosus. Br J Rheumatol. 1994;33(3):260-6.

49. Yu F, Tan Y, Liu G, Wang SX, Zou WZ, Zhao MH. Clinicopathological characteristics and outcomes of
patients with crescentic lupus nephritis. Kidney Int. 2009;76(3):307-17.

50. Tateno S, Kobayashi Y, Shigematsu H, Hiki Y. Study of lupus nephritis: its classification and the
significance of subendothelial deposits. Q J Med. 1983;52(207):311-31.

51. Austin HA, 3rd, Boumpas DT, Vaughan EM, Balow JE. High-risk features of lupus nephritis: importance
of race and clinical and histological factors in 166 patients. Nephrol Dial Transplant. 1995;10(9):1620-8.

52. Descombes E, Droz D, Drouet L, Grunfeld JP, Lesavre P. Renal vascular lesions in lupus nephritis.
Medicine (Baltimore). 1997;76(5):355-68.

53. Banfi G, Bertani T, Boeri V, Faraggiana T, Mazzucco G, Monga G, et al. Renal vascular lesions as a
marker of poor prognosis in patients with lupus nephritis. Gruppo Italiano per lo Studio della Nefrite Lupica
(GISNEL). Am J Kidney Dis. 1991;18(2):240-8.

54. Magil AB, Tyler M. Tubulo-interstitial disease in lupus nephritis. A morphometric study. Histopathology.
1984;8(1):81-7.

55. Kasiske BL, Cangro CB, Hariharan S, Hricik DE, Kerman RH, Roth D, et al. The evaluation of renal
transplantation candidates: clinical practice guidelines. Am J Transplant. 2001;1 Suppl 2:3-95.

56. Tang H, Chelamcharla M, Baird BC, Shihab FS, Koford JK, Goldfarb-Rumyantzev AS. Factors affecting
kidney-transplant outcome in recipients with lupus nephritis. Clin Transplant. 2008;22(3):263-72.

57. Lochhead KM, Pirsch JD, D'Alessandro AM, Knechtle SJ, Kalayoglu M, Sollinger HW, et al. Risk
factors for renal allograft loss in patients with systemic lupus erythematosus. Kidney Int. 1996;49(2):512-7.

58. Bunnapradist S, Chung P, Peng A, Hong A, Lee B, Fukami S, et al. Outcomes of renal transplantation
for recipients with lupus nephritis: analysis of the Organ Procurement and Transplantation Network database.
Transplantation. 2006;82(5):612-8.

59. Bumgardner GL, Mauer SM, Payne W, Dunn DL, Sutherland DE, Fryd DS, et al. Single-center 1-15-
year results of renal transplantation in patients with systemic lupus erythematosus. Transplantation.
1988;46(5):703-9.

60. Ward MM. Outcomes of renal transplantation among patients with end-stage renal disease caused by
lupus nephritis. Kidney Int. 2000;57(5):2136-43.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

61. Moroni G, Tantardini F, Gallelli B, Quaglini S, Banfi G, Poli F, et al. The long-term prognosis of renal
transplantation in patients with lupus nephritis. Am J Kidney Dis. 2005;45(5):903-11.

62. Deegens JK, Artz MA, Hoitsma AJ, Wetzels JF. Outcome of renal transplantation in patients with
systemic lupus erythematosus. Transpl Int. 2003;16(6):411-8.

63. Haubitz M, Kliem V, Koch KM, Nashan B, Schlitt HJ, Pichlmayr R, et al. Renal transplantation for
patients with autoimmune diseases: single-center experience with 42 patients. Transplantation.
1997;63(9):1251-7.

64. Grimbert P, Lang P, Frappier J, Bedrossian J, Legendre C, Hiesse C, et al. Renal transplantation in
patients with systemic lupus erythematosus: a multicenter study. Transplant Proc. 1997;29(5):2363-4.

65. Grimbert P, Frappier J, Bedrossian J, Legendre C, Antoine C, Hiesse C, et al. Long-term outcome of
kidney transplantation in patients with systemic lupus erythematosus: a multicenter study. Groupe Cooperatif
de Transplantation d'ile de France. Transplantation. 1998;66(8):1000-3.

66. Azevedo LS, Romao JE, Jr., Malheiros D, Saldanha LB, Ianhez LE, Sabbaga E. Renal transplantation
in systemic lupus erythematosus. A case control study of 45 patients. Nephrol Dial Transplant.
1998;13(11):2894-8.

67. Norby GE, Strom EH, Midtvedt K, Hartmann A, Gilboe IM, Leivestad T, et al. Recurrent lupus nephritis
after kidney transplantation: a surveillance biopsy study. Ann Rheum Dis. 2010;69(8):1484-7.

68. Contreras G, Mattiazzi A, Guerra G, Ortega LM, Tozman EC, Li H, et al. Recurrence of lupus nephritis
after kidney transplantation. J Am Soc Nephrol. 2010;21(7):1200-7.

69. Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM, Garovic VD. A systematic review and meta-
analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am
Soc Nephrol. 2010;5(11):2060-8.

70. Oviasu E, Hicks J, Cameron JS. The outcome of pregnancy in women with lupus nephritis. Lupus.
1991;1(1):19-25.

71. Illei GG, Tackey E, Lapteva L, Lipsky PE. Biomarkers in systemic lupus erythematosus. I. General
overview of biomarkers and their applicability. Arthritis Rheum. 2004;50(6):1709-20.

72. Mok CC. Biomarkers for lupus nephritis: a critical appraisal. J Biomed Biotechnol. 2010;2010:638413.

73. Liu CC, Ahearn JM. The search for lupus biomarkers. Best Pract Res Clin Rheumatol. 2009;23(4):507-
23.

74. Isenberg DA, Manson JJ, Ehrenstein MR, Rahman A. Fifty years of anti-ds DNA antibodies: are we
approaching journey's end? Rheumatology (Oxford). 2007;46(7):1052-6.

75. Tseng CE, Buyon JP, Kim M, Belmont HM, Mackay M, Diamond B, et al. The effect of moderate-dose
corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic
lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial. Arthritis
Rheum. 2006;54(11):3623-32.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

76. Bootsma H, Spronk P, Derksen R, de Boer G, Wolters-Dicke H, Hermans J, et al. Prevention of

relapses in systemic lupus erythematosus. Lancet. 1995;345(8965):1595-9.

77. Kavanaugh AF, Solomon DH. Guidelines for immunologic laboratory testing in the rheumatic diseases:
anti-DNA antibody tests. Arthritis Rheum. 2002;47(5):546-55.

78. Bardana EJ, Jr., Harbeck RJ, Hoffman AA, Pirofsky B, Carr RI. The prognostic and therapeutic
implications of DNA:anti-DNA immune complexes in systemic lupus erythematosus (SLE). Am J Med.
1975;59(4):515-22.

79. Alarcon GS, Calvo-Alen J, McGwin G, Jr., Uribe AG, Toloza SM, Roseman JM, et al. Systemic lupus
erythematosus in a multiethnic cohort: LUMINA XXXV. Predictive factors of high disease activity over time.
Ann Rheum Dis. 2006;65(9):1168-74.

80. Cortes-Hernandez J, Ordi-Ros J, Labrador M, Bujan S, Balada E, Segarra A, et al. Antihistone and anti-
double-stranded deoxyribonucleic acid antibodies are associated with renal disease in systemic lupus
erythematosus. Am J Med. 2004;116(3):165-73.

81. Huong DL, Papo T, Beaufils H, Wechsler B, Bletry O, Baumelou A, et al. Renal involvement in systemic
lupus erythematosus. A study of 180 patients from a single center. Medicine (Baltimore). 1999;78(3):148-66.

82. Ignat GP, Rat AC, Sychra JJ, Vo J, Varga J, Teodorescu M. Information on diagnosis and management
of systemic lupus erythematosus derived from the routine measurement of 8 nuclear autoantibodies. J
Rheumatol. 2003;30(8):1761-9.

83. Mirzayan MJ, Schmidt RE, Witte T. Prognostic parameters for flare in systemic lupus erythematosus.
Rheumatology (Oxford). 2000;39(12):1316-9.

84. Urowitz MB, Feletar M, Bruce IN, Ibanez D, Gladman DD. Prolonged remission in systemic lupus
erythematosus. J Rheumatol. 2005;32(8):1467-72.

85. Yee CS, Farewell V, Isenberg DA, Rahman A, Teh LS, Griffiths B, et al. British Isles Lupus Assessment
Group 2004 index is valid for assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum.
2007;56(12):4113-9.

86. Forger F, Matthias T, Oppermann M, Becker H, Helmke K. Clinical significance of anti-dsDNA antibody
isotypes: IgG/IgM ratio of anti-dsDNA antibodies as a prognostic marker for lupus nephritis. Lupus.
2004;13(1):36-44.

87. Gladman DD, Urowitz MB, Keystone EC. Serologically active clinically quiescent systemic lupus
erythematosus: a discordance between clinical and serologic features. Am J Med. 1979;66(2):210-5.

88. Gladman DD, Hirani N, Ibanez D, Urowitz MB. Clinically active serologically quiescent systemic lupus
erythematosus. J Rheumatol. 2003;30(9):1960-2.

89. Ng KP, Manson JJ, Rahman A, Isenberg DA. Association of antinucleosome antibodies with disease
flare in serologically active clinically quiescent patients with systemic lupus erythematosus. Arthritis Rheum.
2006;55(6):900-4.

90. ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CG. Measurement of increases in anti-
double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus.
A long-term, prospective study. Arthritis Rheum. 1990;33(5):634-43.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

91. Bootsma H, Spronk PE, Ter Borg EJ, Hummel EJ, de Boer G, Limburg PC, et al. The predictive value
of fluctuations in IgM and IgG class anti-dsDNA antibodies for relapses in systemic lupus erythematosus. A
prospective long-term observation. Ann Rheum Dis. 1997;56(11):661-6.

92. Ho A, Magder LS, Barr SG, Petri M. Decreases in anti-double-stranded DNA levels are associated with
concurrent flares in patients with systemic lupus erythematosus. Arthritis Rheum. 2001;44(10):2342-9.

93. Swaak AJ, Groenwold J, Aarden LA, Statius van Eps LW, Feltkamp EW. Prognostic value of anti-
dsDNA in SLE. Ann Rheum Dis. 1982;41(4):388-95.

94. Swaak AJ, Aarden LA, Statius van Eps LW, Feltkamp TE. Anti-dsDNA and complement profiles as
prognostic guides in systemic lupus erythematosus. Arthritis Rheum. 1979;22(3):226-35.

95. Swaak AJ, Groenwold J, Bronsveld W. Predictive value of complement profiles and anti-dsDNA in
systemic lupus erythematosus. Ann Rheum Dis. 1986;45(5):359-66.

96. Zonana-Nacach A, Salas M, Sanchez ML, Camargo-Coronel A, Bravo-Gatica C, Mintz G.

Measurement of clinical activity of systemic lupus erythematosus and laboratory abnormalities: a 12-month
prospective study. J Rheumatol. 1995;22(1):45-9.

97. Bastian HM, Alarcon GS, Roseman JM, McGwin G, Jr., Vila LM, Fessler BJ, et al. Systemic lupus
erythematosus in a multiethnic US cohort (LUMINA) XL II: factors predictive of new or worsening proteinuria.
Rheumatology (Oxford). 2007;46(4):683-9.

98. Bastian HM, Roseman JM, McGwin G, Jr., Alarcon GS, Friedman AW, Fessler BJ, et al. Systemic
lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus.
2002;11(3):152-60.

99. Cortes-Hernandez J, Ordi-Ros J, Labrador M, Segarra A, Tovar JL, Balada E, et al. Predictors of poor
renal outcome in patients with lupus nephritis treated with combined pulses of cyclophosphamide and
methylprednisolone. Lupus. 2003;12(4):287-96.

100. Linnik MD, Hu JZ, Heilbrunn KR, Strand V, Hurley FL, Joh T. Relationship between anti-double-
stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus.
Arthritis Rheum. 2005;52(4):1129-37.

101. Wada Y, Ito S, Ueno M, Nakano M, Arakawa M, Gejyo F. Renal outcome and predictors of clinical renal
involvement in patients with silent lupus nephritis. Nephron Clin Pract. 2004;98(4):c105-11.

102. Abrass CK, Nies KM, Louie JS, Border WA, Glassock RJ. Correlation and predictive accuracy of
circulating immune complexes with disease activity in patients with systemic lupus erythematosus. Arthritis
Rheum. 1980;23(3):273-82.

103. Cameron JS, Lessof MH, Ogg CS, Williams BD, Williams DG. Disease activity in the nephritis of
systemic lupus erythematosus in relation to serum complement concentrations. DNA-binding capacity and
precipitating anti-DNA antibody. Clin Exp Immunol. 1976;25(3):418-27.

104. El Hachmi M, Jadoul M, Lefebvre C, Depresseux G, Houssiau FA. Relapses of lupus nephritis:
incidence, risk factors, serology and impact on outcome. Lupus. 2003;12(9):692-6.

105. van den Berg L, Nossent H, Rekvig O. Prior anti-dsDNA antibody status does not predict later disease
manifestations in systemic lupus erythematosus. Clin Rheumatol. 2006;25(3):347-52.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

106. Arbuckle MR, James JA, Kohlhase KF, Rubertone MV, Dennis GJ, Harley JB. Development of anti-
dsDNA autoantibodies prior to clinical diagnosis of systemic lupus erythematosus. Scand J Immunol.
2001;54(1-2):211-9.

107. Alba P, Bento L, Cuadrado MJ, Karim Y, Tungekar MF, Abbs I, et al. Anti-dsDNA, anti-Sm antibodies,
and the lupus anticoagulant: significant factors associated with lupus nephritis. Ann Rheum Dis.
2003;62(6):556-60.

108. Mosca M, Chimenti D, Pratesi F, Baldini C, Anzilotti C, Bombardieri S, et al. Prevalence and clinico-
serological correlations of anti-alpha-enolase, anti-C1q, and anti-dsDNA antibodies in patients with systemic
lupus erythematosus. J Rheumatol. 2006;33(4):695-7.

109. Manger K, Manger B, Repp R, Geisselbrecht M, Geiger A, Pfahlberg A, et al. Definition of risk factors
for death, end stage renal disease, and thromboembolic events in a monocentric cohort of 338 patients with
systemic lupus erythematosus. Ann Rheum Dis. 2002;61(12):1065-70.

110. Esdaile JM, Abrahamowicz M, MacKenzie T, Hayslett JP, Kashgarian M. The time-dependence of long-
term prediction in lupus nephritis. Arthritis Rheum. 1994;37(3):359-68.

111. Esdaile JM, Joseph L, Abrahamowicz M, Li Y, Danoff D, Clarke AE. Routine immunologic tests in
systemic lupus erythematosus: is there a need for more studies? J Rheumatol. 1996;23(11):1891-6.

112. Sinico RA, Rimoldi L, Radice A, Bianchi L, Gallelli B, Moroni G. Anti-C1q autoantibodies in lupus
nephritis. Ann N Y Acad Sci. 2009;1173:47-51.

113. Moroni G, Radice A, Giammarresi G, Quaglini S, Gallelli B, Leoni A, et al. Are laboratory tests useful for
monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus
nephritis. Ann Rheum Dis. 2009;68(2):234-7.

114. Tsirogianni A, Pipi E, Soufleros K. Relevance of anti-C1q autoantibodies to lupus nephritis. Ann N Y
Acad Sci. 2009;1173:243-51.

115. Porcel JM, Ordi J, Castro-Salomo A, Vilardell M, Rodrigo MJ, Gene T, et al. The value of complement
activation products in the assessment of systemic lupus erythematosus flares. Clin Immunol Immunopathol.
1995;74(3):283-8.

116. Nagy G, Brozik M, Varga L, Fust G, Kirschfink M, Kiss E, et al. Usefulness of detection of complement
activation products in evaluating SLE activity. Lupus. 2000;9(1):19-25.

117. Ramos-Casals M, Campoamor MT, Chamorro A, Salvador G, Segura S, Botero JC, et al.
Hypocomplementemia in systemic lupus erythematosus and primary antiphospholipid syndrome: prevalence
and clinical significance in 667 patients. Lupus. 2004;13(10):777-83.

118. Sullivan KE, Wisnieski JJ, Winkelstein JA, Louie J, Sachs E, Choi R, et al. Serum complement
determinations in patients with quiescent systemic lupus erythematosus. J Rheumatol. 1996;23(12):2063-7.

119. Ho A, Barr SG, Magder LS, Petri M. A decrease in complement is associated with increased renal and
hematologic activity in patients with systemic lupus erythematosus. Arthritis Rheum. 2001;44(10):2350-7.

120. Buyon JP, Tamerius J, Belmont HM, Abramson SB. Assessment of disease activity and impending flare
in patients with systemic lupus erythematosus. Comparison of the use of complement split products and
conventional measurements of complement. Arthritis Rheum. 1992;35(9):1028-37.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

121. Hopkins P, Belmont HM, Buyon J, Philips M, Weissmann G, Abramson SB. Increased levels of plasma
anaphylatoxins in systemic lupus erythematosus predict flares of the disease and may elicit vascular injury in
lupus cerebritis. Arthritis Rheum. 1988;31(5):632-41.

122. Laitman RS, Glicklich D, Sablay LB, Grayzel AI, Barland P, Bank N. Effect of long-term normalization of
serum complement levels on the course of lupus nephritis. Am J Med. 1989;87(2):132-8.

123. Foundation NK. NKF-KDOQI Guidelines. 1997 [cited; Available from:

http://www.kidney.org/professionals/kdoqi/guidelines_commentaries.cfm#guidelines

124. Post TW, Rose BD. Overview of the management of chronic kidney disease in adults. UpToDate 182;
2010.

125. Norby GE, Holme I, Fellstrom B, Jardine A, Cole E, Abedini S, et al. Effect of fluvastatin on cardiac
outcomes in kidney transplant patients with systemic lupus erythematosus: a randomized placebo-controlled
study. Arthritis Rheum. 2009;60(4):1060-4.

126. Yazdany J, Tonner C, Trupin L, Panopalis P, Gillis JZ, Hersh AO, et al. Provision of preventive health
care in systemic lupus erythematosus: data from a large observational cohort study. Arthritis Res Ther.
2010;12(3):R84.

127. McInnes PM, Schuttinga J, Sanslone WR, Stark SP, Klippel JH. The economic impact of treatment of
severe lupus nephritis with prednisone and intravenous cyclophosphamide. Arthritis Rheum. 1994;37(7):1000-
6.

128. Wilson EC, Jayne DR, Dellow E, Fordham RJ. The cost-effectiveness of mycophenolate mofetil as
firstline therapy in active lupus nephritis. Rheumatology (Oxford). 2007;46(7):1096-101.

129. Ward MM. Access to care and the incidence of endstage renal disease due to systemic lupus
erythematosus. J Rheumatol. 2010;37(6):1158-63.

130. Hopkinson ND, Jenkinson C, Muir KR, Doherty M, Powell RJ. Racial group, socioeconomic status, and
the development of persistent proteinuria in systemic lupus erythematosus. Ann Rheum Dis. 2000;59(2):116-9.

131. Ward MM. Medical insurance, socioeconomic status, and age of onset of endstage renal disease in
patients with lupus nephritis. J Rheumatol. 2007;34(10):2024-7.

132. Contreras G, Lenz O, Pardo V, Borja E, Cely C, Iqbal K, et al. Outcomes in African Americans and
Hispanics with lupus nephritis. Kidney Int. 2006;69(10):1846-51.

133. Barr RG, Seliger S, Appel GB, Zuniga R, D'Agati V, Salmon J, et al. Prognosis in proliferative lupus
nephritis: the role of socio-economic status and race/ethnicity. Nephrol Dial Transplant. 2003;18(10):2039-46.

134. Petri M, Perez-Gutthann S, Longenecker JC, Hochberg M. Morbidity of systemic lupus erythematosus:
role of race and socioeconomic status. Am J Med. 1991;91(4):345-53.

135. Fernandez M, Alarcon GS, Calvo-Alen J, Andrade R, McGwin G, Jr., Vila LM, et al. A multiethnic,
multicenter cohort of patients with systemic lupus erythematosus (SLE) as a model for the study of ethnic
disparities in SLE. Arthritis Rheum. 2007;57(4):576-84.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

136. Ward MM. Access to renal transplantation among patients with end-stage renal disease due to lupus
nephritis. Am J Kidney Dis. 2000;35(5):915-22.

137. Carls G, Li T, Panopalis P, Wang S, Mell AG, Gibson TB, et al. Direct and indirect costs to employers of
patients with systemic lupus erythematosus with and without nephritis. J Occup Environ Med. 2009;51(1):66-79.

138. Clarke AE, Petri M, Manzi S, Isenberg DA, Gordon C, Senecal JL, et al. The systemic lupus
erythematosus Tri-nation Study: absence of a link between health resource use and health outcome.
Rheumatology (Oxford). 2004;43(8):1016-24.

139. Li T, Carls GS, Panopalis P, Wang S, Gibson TB, Goetzel RZ. Long-term medical costs and resource
utilization in systemic lupus erythematosus and lupus nephritis: a five-year analysis of a large medicaid
population. Arthritis Rheum. 2009;61(6):755-63.

140. Pelletier EM, Ogale S, Yu E, Brunetta P, Garg J. Economic outcomes in patients diagnosed with
systemic lupus erythematosus with versus without nephritis: results from an analysis of data from a US claims
database. Clin Ther. 2009;31(11):2653-64.

141. Contreras G, Pardo V, Cely C, Borja E, Hurtado A, De La Cuesta C, et al. Factors associated with poor
outcomes in patients with lupus nephritis. Lupus. 2005;14(11):890-5.

142. Esdaile JM, Levinton C, Federgreen W, Hayslett JP, Kashgarian M. The clinical and renal biopsy
predictors of long-term outcome in lupus nephritis: a study of 87 patients and review of the literature. Q J Med.
1989;72(269):779-833.

143. Hill GS, Delahousse M, Nochy D, Remy P, Mignon F, Mery JP, et al. Predictive power of the second
renal biopsy in lupus nephritis: significance of macrophages. Kidney Int. 2001;59(1):304-16.

144. Magil AB, Puterman ML, Ballon HS, Chan V, Lirenman DS, Rae A, et al. Prognostic factors in diffuse
proliferative lupus glomerulonephritis. Kidney Int. 1988;34(4):511-7.

145. Moroni G, Quaglini S, Gallelli B, Banfi G, Messa P, Ponticelli C. The long-term outcome of 93 patients
with proliferative lupus nephritis. Nephrol Dial Transplant. 2007;22(9):2531-9.

146. Zavada J, Pesickova S, Rysava R, Olejarova M, Horak P, Hrncir Z, et al. Cyclosporine A or intravenous
cyclophosphamide for lupus nephritis: the Cyclofa-Lune study. Lupus. 2010;19(11):1281-9.

147. Steinberg AD, Decker JL. A double-blind controlled trial comparing cyclophosphamide, azathioprine
and placebo in the treatment of lupus glomerulonephritis. Arthritis Rheum. 1974;17(6):923-37.

148. Carette S, Klippel JH, Decker JL, Austin HA, Plotz PH, Steinberg AD, et al. Controlled studies of oral
immunosuppressive drugs in lupus nephritis. A long-term follow-up. Ann Intern Med. 1983;99(1):1-8.

149. Austin HA, 3rd, Klippel JH, Balow JE, le Riche NG, Steinberg AD, Plotz PH, et al. Therapy of lupus
nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986;314(10):614-9.

150. Steinberg AD, Steinberg SC. Long-term preservation of renal function in patients with lupus nephritis
receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis
Rheum. 1991;34(8):945-50.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

151. Grootscholten C, Ligtenberg G, Hagen EC, van den Wall Bake AW, de Glas-Vos JW, Bijl M, et al.
Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized
controlled trial. Kidney Int. 2006;70(4):732-42.

152. Boumpas DT, Austin HA, 3rd, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, et al. Controlled trial
of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet.
1992;340(8822):741-5.

153. Gourley MF, Austin HA, 3rd, Scott D, Yarboro CH, Vaughan EM, Muir J, et al. Methylprednisolone and
cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann
Intern Med. 1996;125(7):549-57.

154. Donadio JV, Jr., Holley KE, Ferguson RH, Ilstrup DM. Progressive lupus glomerulonephritis. Treatment
with prednisone and combined prednisone and cyclophosphamide. Mayo Clin Proc. 1976;51(8):484-94.

155. Donadio JV, Jr., Holley KE, Ferguson RH, Ilstrup DM. Treatment of diffuse proliferative lupus nephritis
with prednisone and combined prednisone and cyclophosphamide. N Engl J Med. 1978;299(21):1151-5.

156. Clark WF, Cattran DC, Balfe JW, Williams W, Lindsay RM, Linton AL. Chronic plasma exchange in
systemic lupus erythematosus nephritis. Proc Eur Dial Transplant Assoc. 1983;20:629-35.

157. Pohl MA, Lan SP, Berl T. Plasmapheresis does not increase the risk for infection in immunosuppressed
patients with severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. Ann Intern Med.
1991;114(11):924-9.

158. Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM. A controlled trial of plasmapheresis therapy in
severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. N Engl J Med. 1992;326(21):1373-9.

159. Mok CC, Ho CT, Siu YP, Chan KW, Kwan TH, Lau CS, et al. Treatment of diffuse proliferative lupus
glomerulonephritis: a comparison of two cyclophosphamide-containing regimens. Am J Kidney Dis.
2001;38(2):256-64.

160. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, et al.
Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose
versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121-31.

161. Bao H, Liu ZH, Xie HL, Hu WX, Zhang HT, Li LS. Successful treatment of class V+IV lupus nephritis
with multitarget therapy. J Am Soc Nephrol. 2008;19(10):2001-10.

162. Hu W, Liu Z, Chen H, Tang Z, Wang Q, Shen K, et al. Mycophenolate mofetil vs cyclophosphamide
therapy for patients with diffuse proliferative lupus nephritis. Chin Med J (Engl). 2002;115(5):705-9.

163. Ong LM, Hooi LS, Lim TO, Goh BL, Ahmad G, Ghazalli R, et al. Randomized controlled trial of pulse
intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus
nephritis. Nephrology (Carlton). 2005;10(5):504-10.

164. Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, et al. Mycophenolate mofetil or
intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353(21):2219-28.

165. Wang J, Hu W, Xie H, Zhang H, Chen H, Zeng C, et al. Induction therapies for class IV lupus nephritis
with non-inflammatory necrotizing vasculopathy: mycophenolate mofetil or intravenous cyclophosphamide.
Lupus. 2007;16(9):707-12.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

166. Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Mycophenolate mofetil
versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20(5):1103-12.

167. Isenberg D, Appel GB, Contreras G, Dooley MA, Ginzler EM, Jayne D, et al. Influence of race/ethnicity
on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford). 2010;49(1):128-40.

168. El-Shafey EM, Abdou SH, Shareef MM. Is mycophenolate mofetil superior to pulse intravenous
cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients? Clin Exp Nephrol.
2010;14(3):214-21.

169. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in
patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J
Med. 2000;343(16):1156-62.

170. Chan TM, Tse KC, Tang CS, Lai KN, Li FK. Long-term outcome of patients with diffuse proliferative
lupus nephritis treated with prednisolone and oral cyclophosphamide followed by azathioprine. Lupus.
2005;14(4):265-72.

171. Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O'Nan P, et al. Sequential therapies for
proliferative lupus nephritis. N Engl J Med. 2004;350(10):971-80.

172. Houssiau FA, D'Cruz D, Sangle S, Remy P, Vasconcelos C, Petrovic R, et al. Azathioprine versus
mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN
Nephritis Trial. Ann Rheum Dis. 2010;69(12):2083-9.

173. Wang HY, Cui TG, Hou FF, Ni ZH, Chen XM, Lu FM, et al. Induction treatment of proliferative lupus
nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study. Lupus.
2008;17(7):638-44.

174. Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, et al. Tocilizumab in systemic lupus
erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label
phase I dosage-escalation study. Arthritis Rheum. 2010;62(2):542-52.

175. Catapano F, Chaudhry AN, Jones RB, Smith KG, Jayne DW. Long-term efficacy and safety of rituximab
in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant. 2010;25(11):3586-92.

176. Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, et al. Safety and efficacy of
rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and
Rituximab registry. Arthritis Rheum. 2010;62(8):2458-66.

177. Jonsdottir T, Gunnarsson I, Mourao AF, Lu TY, van Vollenhoven RF, Isenberg D. Clinical
improvements in proliferative vs membranous lupus nephritis following B-cell depletion: pooled data from two
cohorts. Rheumatology (Oxford). 2010;49(8):1502-4.

178. Jayne D, Passweg J, Marmont A, Farge D, Zhao X, Arnold R, et al. Autologous stem cell
transplantation for systemic lupus erythematosus. Lupus. 2004;13(3):168-76.

179. Burt RK, Traynor A, Statkute L, Barr WG, Rosa R, Schroeder J, et al. Nonmyeloablative hematopoietic
stem cell transplantation for systemic lupus erythematosus. JAMA. 2006;295(5):527-35.

180. Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, et al. Allogenic mesenchymal stem cells transplantation
in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis. 2010;69(8):1423-9.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

181. Sun L, Wang D, Liang J, Zhang H, Feng X, Wang H, et al. Umbilical cord mesenchymal stem cell
transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum. 2010;62(8):2467-75.

182. Siso A, Ramos-Casals M, Bove A, Brito-Zeron P, Soria N, Munoz S, et al. Previous antimalarial therapy
in patients diagnosed with lupus nephritis: influence on outcomes and survival. Lupus. 2008;17(4):281-8.

183. Pons-Estel GJ, Alarcon GS, McGwin G, Jr., Danila MI, Zhang J, Bastian HM, et al. Protective effect of
hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort.
Arthritis Rheum. 2009;61(6):830-9.

184. Rihova Z, Vankova Z, Maixnerova D, Dostal C, Jancova E, Honsova E, et al. Treatment of lupus
nephritis with cyclosporine - an outcome analysis. Kidney Blood Press Res. 2007;30(2):124-8.

185. Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal
survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int. 1997;51(4):1188-95.

186. Ioannidis JP, Boki KA, Katsorida ME, Drosos AA, Skopouli FN, Boletis JN, et al. Remission, relapse,
and re-remission of proliferative lupus nephritis treated with cyclophosphamide. Kidney Int. 2000;57(1):258-64.

187. Mok CC, Ying KY, Tang S, Leung CY, Lee KW, Ng WL, et al. Predictors and outcome of renal flares
after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis. Arthritis Rheum.
2004;50(8):2559-68.

188. de Castro WP, Morales JV, Wagner MB, Graudenz M, Edelweiss MI, Goncalves LF. Hypertension and
Afro-descendant ethnicity: a bad interaction for lupus nephritis treated with cyclophosphamide? Lupus.
2007;16(9):724-30.

189. Mok CC, Ying KY, Ng WL, Lee KW, To CH, Lau CS, et al. Long-term outcome of diffuse proliferative
lupus glomerulonephritis treated with cyclophosphamide. Am J Med. 2006;119(4):355 e25-33.

190. Petri M, Brodsky RA, Jones RJ, Gladstone D, Fillius M, Magder LS. High-dose cyclophosphamide
versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomized
trial. Arthritis Rheum. 2010;62(5):1487-93.

191. Urowitz MB, Ibanez D, Ali Y, Gladman DD. Outcomes in patients with active lupus nephritis requiring
immunosuppressives who never received cyclophosphamide. J Rheumatol. 2007;34(7):1491-6.

192. Decker JL, Klippel JH, Plotz PH, Steinberg AD. Cyclophosphamide or azathioprine in lupus
glomerulonephritis. A controlled trial: results at 28 months. Ann Intern Med. 1975;83(5):606-15.

193. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, et al. Early
response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-
term followup of patients in the Euro-Lupus Nephritis Trial. Arthritis Rheum. 2004;50(12):3934-40.

194. Tang Z, Yang G, Yu C, Yu Y, Wang J, Hu W, et al. Effects of mycophenolate mofetil for patients with
crescentic lupus nephritis. Nephrology (Carlton). 2008;13(8):702-7.

195. Rivera TL, Belmont HM, Malani S, Latorre M, Benton L, Weisstuch J, et al. Current therapies for lupus
nephritis in an ethnically heterogeneous cohort. J Rheumatol. 2009;36(2):298-305.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

196. Cortes-Hernandez J, Torres-Salido MT, Medrano AS, Tarres MV, Ordi-Ros J. Long-term outcomes--
mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol Dial
Transplant. 2010;25(12):3939-48.

197. Mok CC, Ying KY, Lau CS, Yim CW, Ng WL, Wong WS, et al. Treatment of pure membranous lupus
nephropathy with prednisone and azathioprine: an open-label trial. Am J Kidney Dis. 2004;43(2):269-76.

198. Zhang FS, Nie YK, Jin XM, Yu HM, Li YN, Sun Y. The efficacy and safety of leflunomide therapy in
lupus nephritis by repeat kidney biopsy. Rheumatol Int. 2009;29(11):1331-5.

199. Froelich CJ, Wallman J, Skosey JL, Teodorescu M. Clinical value of an integrated ELISA system for the
detection of 6 autoantibodies (ssDNA, dsDNA, Sm, RNP/Sm, SSA, and SSB). J Rheumatol. 1990;17(2):192-
200.

200. Emlen W, Jarusiripipat P, Burdick G. A new ELISA for the detection of double-stranded DNA antibodies.
J Immunol Methods. 1990;132(1):91-101.

201. Isenberg DA, Ehrenstein MR, Longhurst C, Kalsi JK. The origin, sequence, structure, and
consequences of developing anti-DNA antibodies. A human perspective. Arthritis Rheum. 1994;37(2):169-80.

202. Chubick A, Sontheimer RD, Gilliam JN, Ziff M. An appraisal of tests for native DNA antibodies in
connective tissue diseases. Clinical usefulness of Crithidia luciliae assay. Ann Intern Med. 1978;89(2):186-92.

203. Kalmin ND, Bartholomew WR, Wicher K. Relative values of laboratory assays in systemic lupus
erythematosus. Am J Clin Pathol. 1981;75(6):846-51.

204. Bootsma H, Spronk PE, Hummel EJ, de Boer G, ter Borg EJ, Limburg PC, et al. Anti-double stranded
DNA antibodies in systemic lupus erythematosus: detection and clinical relevance of IgM-class antibodies.
Scand J Rheumatol. 1996;25(6):352-9.

205. Pincus T, Schur PH, Rose JA, Decker JL, Talal N. Measurement of serum DNA-binding activity in
systemic lupus erythematosus. N Engl J Med. 1969;281(13):701-5.

206. Ballou SP, Kushner I. Anti-native DNA detection by the Crithidia luciliae method: an improved guide to
the diagnosis and clinical management of systemic lupus erythematosus. Arthritis Rheum. 1979;22(4):321-7.

207. Garcia CO, Molina JF, Gutierrez-Urena S, Scopelitis E, Wilson WA, Gharavi AE, et al. Autoantibody
profile in African-American patients with lupus nephritis. Lupus. 1996;5(6):602-5.

208. Weitzman RJ, Walker SE. Relation of titred peripheral pattern ANA to anti-DNA and disease activity in
systemic lupus erythematosus. Ann Rheum Dis. 1977;36(1):44-9.

209. Miniter MF, Stollar BD, Agnello V. Reassessment of the clinical significance of native DNA antibodies in
systemic lupus erythematosus. Arthritis Rheum. 1979;22(9):959-68.

210. Ballou SP, Kushner I. Lupus patients who lack detectable anti-DNA: clinical features and survival.
Arthritis Rheum. 1982;25(9):1126-9.

211. Isenberg DA, Shoenfeld Y, Schwartz RS. Multiple serologic reactions and their relationship to clinical
activity in systemic lupus erythematosus. Arthritis Rheum. 1984;27(2):132-8.
 GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS

212. Davis P, Percy JS, Russell AS. Correlation between levels of DNA antibodies and clinical disease
activity in SLE. Ann Rheum Dis. 1977;36(2):157-9.

213. Feldman MD, Huston DP, Karsh J, Balow JE, Klima E, Steinberg AD. Correlation of serum IgG, IgM,
and anti-native-DNA antibodies with renal and clinical indexes of activity in systemic lupus erythematosus. J
Rheumatol. 1982;9(1):52-8.