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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
3.
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
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 CoMorbid 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.
2.
3.
4.
5.
6.
7.
8
9
Task Force Panelists
ISN/RPS 2003 Classification of Lupus Nephritis
Renal Pathology Scoring System
Studies of Poor Prognostic Findings based on Renal Biopsy
RCT Inclusion/Exclusion Criteria and Jadad Scores
Cohort Studies Inclusion/Exclusion Criteria and Newcastle-Ottawa Scale
End Stage Renal Disease/Renal Transplantation Articles
Summary of Commonly Used Medications’ Teratogenic Effects
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 (78-9). 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). Livingrelated 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 68.893.6%, 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 casecontrol 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 antidsDNA 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 antidsDNA 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 antidsDNA 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) (115116), 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 LDLcholesterol 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 socioeconomic 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 AfricanAmericans (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 costsavings 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**
Professor of Nephrology
Radboud University Nijmegen
Med Ctr
Nijmegen, THE NETHERLANDS
Jill P. Buyon, MD*
Professor of Medicine
NYU / Hospital for Joint Diseases
New York, NEW YORK
Gabriel Contreras, MD**
Associate Professor of Medicine
Rosalind Ramsey-Goldman,
MD*
Professor of Medicine
Northwestern University
Chicago, ILLINOIS
Frederic A. Houssiau, MD,
PhD*
Professor and Head
Rheumatology
Universite Catholique Louvain
Brussels BELGIUM
David A. Isenberg, MD, FRCP*
Professor
Miami, FLORIDA
Center for Rheumatology
Research
University College of London
London ENGLAND
Karen H. Costenbader, MD,
MPH*
Assistant Professor of Medicine
Kenneth C. Kalunian, MD*
Professor of Medicine
Div of Nephrology
University of Miami
Rheumatology Immunology &
Allergy
Harvard Med School / Brigham
Boston, MASSACHUSETTS
Mary Ann Dooley, MD*
Associate Professor of Medicine
Nephrology
University of North Carolina
Chapel Hill, NORTH CAROLINA
Chi-Chiu Mok, MD*
Chief of Rheumatology
Tuen Mun and Pok Oi Hospital
HONG KONG
Liz Shaw-Stabler
Executive Director
Center for Lupus Care, Inc.
Inglewood, CALIFORNIA
Brad Rovin, MD**
Professor of Medicine
Division of Nephrology
The Ohio State University
Columbus, OHIO
Murray B. Urowitz, MD,
FRCPC*
Professor in Medicine
Center for Innovative Therapy
UCSD School of Medicine
La Jolla, CALIFORNIA
The Toronto Western Hospital
Toronto, CANADA
Susan Manzi, MD, MPH*
Chair, Department of Medicine
David Wofsy, MD*
Professor of Rheumatology
West Penn Allegheny Health
System
Pittsburgh, PENNSYLVANIA
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
Glomerular Abnormallties
1. Cellular proliferation
2. Fibrinoid necrosis, karyorrhexis
3. Cellular crescents
4. Hyaline thrombi, wire loops
5. Leukocyte infiltration
Tubulointerstitial Abnormalities
1. Mononuclear-cell infiltration
Chronicity Index
1. Glomerular sclerosis
2. Fibrous crescents
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
Austin et al. (24)
Austin et al. (36)
Austin et al. (51)
Banfi et al (53)
Blanco et al. (48)
Contreras et al (141)
Esdaile et al (142)
Esdaile et al. (33)
Faurschou et al (35)
Hill et al. (143)
Kojo et al. (39)
Magil et al (144)
Makino et al. (30)
Miranda et al. (31)
Moroni et al (145)
Mosca et al. (26)
Nossent et al (38)
Parichatikanond et al
(37)
Yokoyama et al. (23)
Poor prognostic findings
50% renal failure at 8 years in high risk group (CI
1+ in pts age 8-23 or CI 5+ in pts 24-61)
25% of class IV developed renal failure at 10
years follow up. Chronicity markers are individual
risk factors for renal failure and very high risk
factor in combination.
>50% crescents or moderate/severe interstitial
fibrosis at high risk for doubling creatinine
Renal vascular lesions (Lupus vasculopathy,
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
Vascular hyalinosis, glomerular sclerosis, fibrous
crescents and CI >3
chronicity index >/= 2
Tubulointerstitial fibrosis/atrophy
Class IV LN Marked subendothelial immune
deposits
Class III, Class VI lupus nephritis
Presence of tubular macrophages,
karyorrhexis/fibrinoid necrosis, cellular crescents
Cellular crescents, fibrous crescents, segmental
sclerosis
Presence of karyorrhexis
Karyorrhexis associated with response to high
dose steroids
Glomerular thrombosis strongly associated with
crescents, glomerular necrosis and increased AI
CI > 2
AI 9+, CI 4+
AI 12+, CI 4+
>25% sclerotic glomeruli, >25% tubular atrophy,
>25% interstitital mononuclear, infiltrate
Class IV(S &G), ESRF in patients with IV(S or G)
vs I, II, III, V (40.9% vs 2.6%)
N
102
Year
1983
102
1984
64
1995
285
1991
85
1994
213
87
87
2005
1989
1991
100
71
2010
2001
99
2009
45
60
1988
1993
108
1994
93
81
116
81
2007
1997
1990
1997
60
2004
AI = activity index, CI = chronicity index, RVL = renal vascular lesion, LN = lupus nephritis
Treatment with CPH or Cyclosporin ever before,
treatment with other immunosuppressive drugs or
high-dose glucocorticoids within the last 3 months,
persistent elevation of serum creatinine
(>=140micromol/l), pregnancy or lactation, bone
marrow insufficiency with cytopenias not
Diagnosis of SLE (meeting 4 criteria of the ACR),
renal biopsy documenting lupus nephritis according
to WHO or ISN/RPS as proliferative
glomerulonephritis class III (focal) or IV (diffuse);
clinical activity as defined by presence of at least 2
of the following: abnormal proteinuria (more than
Zavada et al,
CYCLOFALUNE study,
Czech
Republic,
2010 (146)
Endocapillary proliferation or subendothelial
electron-dense deposits characteristic of
proliferative lupus nephritis, clinical or histologic
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.
Exclusion Criteria
Diagnosis of SLE by the ACR, a renal biopsy that
showed typical lupus membranous nephropathy
(LMN) by light and electron microscopy, >= 2g;/d
proteinuria, age >=12 year, informed consent
Cyclosporin (CSA) vs Cyclophosphamide (CYC) IV
Article
Inclusion Criteria
Austin et al,
NIH, USA
2009 (44)
Table 5. RCT Inclusion/Exclusion Criteria and Jadad Scores
Prednisone (Pred) vs Cyclophosphamid (CYC) IV vs Cyclosporin (CSA)
Article
Inclusion Criteria
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Jadad
Score
3
Jadad
Score
1
attributable to SLE, and severe coexisting
conditions, such as infection, liver disease, active
peptic ulcer, etc.
Exclusion Criteria
Diagnosis of SLE by criteria of ARA, one of the
criteria required was positive LE cell test in the
course of the disease, kidney disease unaccounted
for by other pathologic processes, with at least one
Steinberg and of the following: red cell casts in a fresh centrifuged
Decker,
urine sediment; cellular casts and either hematuria
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,
positive lupus erythematosus cell test, and kidney
disease unaccounted for by other pathologic
processes with at least one of the following: red
Carette et al, cell casts in a fresh centrifuged urine sediment;
NIH, USA,
cellular casts and either hematuria (ten
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
1
1
Creatinine clearance consistently less than 20ml
Jadad
Score
4
Jadad
Score
A major infection within the preceding 2 weeks,
pregnancy, immunosuppressive therapy within 2
months, severe liver disease, a history of
hypersensitivity to a study drug, or a serum
creatinine greater than 4.0mg% (creatinine
clearance <20ml/min)
A major infection within the preceding 2 weeks.
Pregnancy. Immunosuppressive therapy within 2
months. Severe liver disease. A history of
hypersensitivity to a study drug, or a serum
creatinine greater than 4.0mg% (creatinine
clearance <20ml/min)
Prednisone (Pred) vs Azathioprine (AZA) vs Cyclophosphamide (CYC)
Article
Inclusion Criteria
Exclusion Criteria
500mg of protein in a 24-h urine specimen),
abnormal microscopic hematuria, or C3
hypocomplementemia (the latter two were defined
according to the norms in the laboratories of the
participating center)
Cyclosporin (CSA) vs Cyclophosphamide (CYC) IV
Article
Inclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
histologic evidence of active lupus
glomerulonephritis, and informed consent to all
aspects of the study.
Boumpas et
al, NIH, USA
1992 (152)
Patients had 4 or more criteria for SLE and severe
lupus nephritis defined by a nephritic urine
sediment and impaired renal function with a
creatinine clearance between 25 and 80 ml per
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
Prednisone (Pred) vs Cyclophosphamide (CYC) IV
Article
Inclusion Criteria
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.
Diagnosis of systemic lupus erythematosus and
Steinberg and clinical/histologic evidence of active lupus
Steinberg,
glomerulonephritis.
NIH, USA,
1991 (150)
NIH, USA,
1986 (149)
Jadad
Score
Pregnancy or had received cytotoxic drug therapy
for more than 10 weeks at any time, active
infections, insulin-dependent diabetes, or previous
malignancy.
Exclusion Criteria
Jadad
Score
2
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.
Prednisone (Pred) vs Azathioprine (AZA) vs Cyclophosphamide (CYC)
Article
Inclusion Criteria
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Donadio et
al, Mayo,
USA,
1976 (154)
Clinical diagnosis of SLE and fulfilled 4 or more of
the criteria for the classification of SLE as
developed by the ARA Committee on Diagnostic
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
>= 1:32 – or if a positive LE-cell preparation was
not obtained, on finding two doubtful positive (for
example, rosettes of neutrophils or nucleolysis) and
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
Prednisone (Pred) vs Cyclophosphamide (CYC) PO
Article
Inclusion Criteria
Gourley et al,
NIH, USA,
1996 (153)
than 25% of glomeruli. Renal biopsies were
evaluated by light and electron microscopy.
Patients had to have both glomerulonephritis and a
diagnosis of systemic lupus erythematosus.
Glomerulonephritis was defined as a sediment on
two or more urianlyses that showed either 10 or
more erythrocytes per high-power field or
erythrocyte or leukocyte casts (without evidence of
infection) or both, plus histologic evidence of active
proliferative lupus glomerulonephritis on a renal
biopsy specimen obtained within 3 months of study
entry (provided that a biopsy could be done safely).
Cyclophosphamide had been used in the past or if
other immunosuppressive drugs had been used
within 6 months of entry into the study.
Exclusion Criteria
Receipt of cytotoxic drug treatment for more than 2
weeks during the 6 weeks before study entry or
receipt of cylophosphamide therapy for more than
10 weeks at any time; receipt of pulse therapy with
corticosteroids during the 6 weeks before study
entry; need (at the time of study entry_ for oral
corticosteroids in dosages greater than 0.5mg of a
prednisone equivalent per kilogram of body weight
per day to control extrarenal disease; active or
chronic infection; pregnancy; the presence of only
one kidney; insulin-dependent diabetes mellitus;
and allergy to methyprednisolone or
cylophosphamide.
Prednisone (Pred) vs Azathioprine (AZA) vs Cyclophosphamide (CYC)
Article
Inclusion Criteria
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Jadad
Score
2
2
Jadad
Score
Pohl et al,
Lupus
Clark et al,
Canada and
Jamaica,
1983 (156)
4 of the ARA criteria for the diagnosis of SLE and
had at least one episode of ANA positivity, elevated
DNA binding and complement depression. All had
renal biopsy with the diagnosis of diffuse
proliferative glomerulonephritis.
Diagnosis of SLE confirmed by at least 4 of the
ARA diagnostic criteria with some modifications; by
Serum creatinine concentration of more than 533
micromol/L (6.0mg/dL); previous plasmapheresis
Creatinine clerarance was less than 3mg/100ml.
Prednisone (Pred) + Cyclophosphamide (CYC) vs plasmapheresis
Article
Inclusion Criteria
Exclusion Criteria
Danadio et
al, Mayo
Clinic, USA
1978 (155)
Exclusion Criteria
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
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 mid1973, elevated levels of anti-nDNA, creatinine
clearance less than 80ml/min/1.73m2 or a
reduction of 25% in creatinine clearance as
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) vs Cyclophosphamide (CYC) PO
Article
Inclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
2
Jadad
Score
1
2
Jadad
Score
current renal biopsy evidence of severe lupus
glomerulonephritis (WHO Class III or IV with more
than 50% of glomeruli involved or class V with
superimposed diffuse or severe segmental
proliferation)
16 years of age or older; diagnosis of SLE as
defined by ARA and a qualifying renal biopsy.
Refused CYC treatment or in whom renal biopsy
showed significant sclerosis or chronic changes but
without activity were excluded.
Exclusion Criteria
Pregnancy, serum creatinine concentration above
530 micromol per liter (6mg/dL), previous treatment
with plasmapheresis, a history of primary
myocardial disease, a history of cancer within the
past 5 years, prednisone-associated psychosis,
peptic ulcer disase, and active liver disease.
for any reason; a history of steroid psychosis;
current pregnancy; a history of neoplasm within the
previous 5 years; a neutrophil count of less than
1500/mm3; or age of less than 16 years.
Houssiau et
al, EuroLupus
Nephritis
Trial, 2002
(160)
Diagnosis of SLE according to the ACR criteria,
age >= 14 years, biopsy proven proliferative lupus
glomerulonephritis (WHO Class II, IV, Vc, or Vd),
and proteinuria >= 500mg in 24 hours.
Patients who had taken CYC or AZA during the
previous year or had taken >=15mg/day prednisone
(or equivalent) during the previous month were
excluded (except for a course of glucocorticoids for
a maximum of 10 days before the referral). Other
exclusion criteria were renal thrombotic
microangiopathy, preexisting chronic renal failure,
pregnancy, previous malignancy (except skin and
cervical intraepithelial neoplasis), diabetes mellitus,
High-Dose Cyclophosphamide (CYC) IV vs Low Dose Cyclophosphamide (CYC) IV
Article
Inclusion Criteria
Exclusion Criteria
Mok et al,
Hong Kong,
2001 (159)
Fulfilled at least 4 of the ACR criteria for the
classification of SLE and had DPGN (WHO Class
IVa or IVb) diagnosed and treated in two large
regional hospitals in Hong Kong (Queen Mary and
Ten Mun Hospitals) between 1995 and 1998 were
included in this study.
Cyclophosphamide (CYC) IV vs Cyclophosphamide (CYC) PO
Article
Inclusion Criteria
Nephritis
Collaborative
Study Group,
NIH, USA,
1991 (157)
Lewis et al,
Lupus
Nephritis
Collaborative
Group, USA,
1992 (158)
Prednisone (Pred) + Cyclophosphamide (CYC) vs plasmapheresis
Article
Inclusion Criteria
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Jadad
Score
2
Jadad
Score
0
3
Jadad
Score
Ong et al,
Malaysia,
2005 (163)
Hu et al,
Nanjing,
2002 (162)
Patients has SLE diagnosis according to ARA
criteria; urinalysis showed active urine sediments,
proteinuria >2g/d; renal biopsy reviewed lupus
nephritis WHO IV within 3 months prior to the study
SLE fulfilling ARA criteria with WHO Class III or IV
lupus nephritis, aged 16 years or older
Mycophenolate Mofetil (MMF) vs Cyclophosphamide (CYC) IV
Article
Inclusion Criteria
Bao et al,
Nanjing,
2008 (161)
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,
immunofluorescence, and electron microscopy
within 3 wk before enrollment; and exhibited overt
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.
Serum creatinine more than 200 micromol/L, white
blood cell count < 3.5 x 10 9 L, evidence of major
infection, history of cancer, alcohol or substance
Severe complication such as infection, leucopenia,
heart failure or malfunction of the central nerve
system or liver
Exclusion Criteria
Serum creatinine > 3.0mg/dl (265.2 microlmol/L) or
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) + Tacrolimus vs Cyclophosphamide (CYC) IV
Article
Inclusion Criteria
Exclusion Criteria
previously documented severe toxicity to
immunosuppressive drugs, and anticipated poor
compliance with the protocol.
High-Dose Cyclophosphamide (CYC) IV vs Low Dose Cyclophosphamide (CYC) IV
Article
Inclusion Criteria
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
2
Jadad
Score
-1
Jadad
Score
2
Jadad
Score
Appel et al,
ALMS,
2009 (166)
Wang et al,
Nanjing,
2007 (165)
Ginzler et al,
USA, 2005
(164)
Exclusion Criteria
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
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
urine specimen), microscopic hematuria (defined
within the past 12 months, monoclonal antibody
as >5 red cells per high power-field) or the
therapy within the past 30 days, or pregnancy or
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
>= 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
Class IV with exception of superimposed
secondary immunodeficiency, especially leukocyte
membranous changes and NNV lesion shown in
count of <=2 x 19 9 L; any clinically significant
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
Aged 12 to 75 yrs, diagnosis of SLE, LN (active or
Treatment with MMF or IVC within the previous
active/chronic) conformed by kidney biopsy within
year, continuous dialysis for ?2 wk before
6 mo before randomization as ISN/RPS 2003
randomization or anticipated during longer than 8
Mycophenolate Mofetil (MMF) vs Cyclophosphamide (CYC) IV
Article
Inclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
3
3
2
Jadad
Score
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
Isenberg et al,
Sub Analysis
of ALMS trial,
2010 (167)
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
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.
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.
Mycophenolate Mofetil (MMF) vs Cyclophosphamide (CYC) IV
Article
Inclusion 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
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Chan et al,
Hong Kong,
2000 (169)
SLE according to ARA including renal-biopsy
evidence of diffuse proliferative lupus nephritis
(WHO IV), urinary protein excretion of 1g or more
per 24 hours, serum albumin concentration of
MMF + AZA vs CYC PO + AZA
Article
Inclusion Criteria
El Shafey et
al, Egypt,
2010 (168)
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
enrolled in the study.
Mycophenolate Mofetil (MMF) vs Cyclophosphamide (CYC) IV
Article
Inclusion Criteria
Serum creatinine concentration higher than
3.4mg/dL (300 micromol per liter); life-threatening
complications such as cerebral lupus or severe
infection, history of poor compliance with drug
Exclusion Criteria
Estimated glomerular filtration rate (eGFR) of less
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.
/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.
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Jadad
Score
2
2
Jadad
Score
Non-lupus related renal disease (such as
microthrombotic disease associated with
antiphospholipid syndrome),treatment with
glucocorticoids (GCs) (>15mg equivalent
prednisolone/day) in the last month before entry
intot he study (except a very short-course highdose oral GC treatment before referral), treatment
with CY, AZA, MMF, or cyclosporine A in the
Age >=14 years, SLE according to ACR
classification criteria, 24h proteinuria >= 500mg,
biopsy –proven WHO Class III, IV, Vc or Vd lupus
glomerulonephritis (biopsy performed less than 1
month before entry to protocol), contraception (or
sexual abstinence)
Houssiau et
al,
MAINTAIN
Nephritis
Trial, 2010
(different
cohort from
ELNT) (172)
Creatinine clearance that was consistently less
than 20ml/min, any clinically significant infection,
pregnancy, receipt of more than 7 doses of
intravenous cyclophosphamide, or the receipt of
azathioprine for longer than 8 weeks.
Exclusion Criteria
SLE according to ARA who had undergone a
kidney biopsy. 18 years of age or older. Histologic
diagnosis of proliferative lupus nephritis (WHO
Class III, IV, or Vb)
Exclusion Criteria
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.
Serum creatinine concentration >4.52 mg/dL
(400micromol/L), life-threatening complications
such as cerebral lupus or severe infection, poor
drug compliance, treatment with CTX or MMF
within 6 mo before baseline, or treatment with
prednisolone at dose >0.4mg/kg per d orally for >2
wk before baseline.
Exclusion Criteria
MMF vs AZA
Article
Inclusion Criteria
Contreras et
al,
USA, 2004
(171)
MMF vs AZA vs CYC IV
Article
Inclusion Criteria
Chan et al,
Hong Kong,
2005 (170)
SLE defined by 1982 ARA criteria, renal biopsy
showing diffuse proliferative lupus nephritis (WHO
Class IV) which corresponded to 2003 ISN/RPS
class IV-S or IV-G, urinary protein exretion of 1g/24
hours or above, and serum albumin concentration
<35g/L.
3.5g/dL or less.
MMF + AZA vs CYC PO + AZA
Article
Inclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Jadad
Score
3
Jadad
Score
2
3
Jadad
Score
Pts with Class III/IV LN and urine protein to
creatinine ratio >1
Inclusion Criteria
Rituximab
Article
ABSTRACT
- Furie et al,
LUNAR,
2009
SLE according to 1997 ACR criteria; SLEDAI >= 8;
clinically evident renal disease and biopsydocumented diffuse proliferative or focal
proliferative lupus nephritis (ISN/RPS 2003 Type IV
A or A/C and Type III A or A/C) with or without
coincident membranous nephropathy and
pathological activity index (AI) >=4.
Wang et al,
Leflunomid
Lupus
Nephritis
Study Group,
China, 2008
(173)
Leflunomide vs CYC IV
Article
Inclusion Criteria
Abstract
ALMS
Maintenance
(Wofsy et al,
2010)
MMF vs AZA
Article
Inclusion Criteria
Exclusion Criteria
Received cyclophosphamide within the previous 3
months. Cerebral lupus, severe infection, liver
disease, pregnancy, and anticipated poor
compliance with the protocol.
Exclusion Criteria
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.
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Jadad
Score
Jadad
Score
0
0
Jadad
Score
Illei, et al,
USA, 2010
(174)
Tocilizumab
Article
ABSTRACT
- Manzi et al,
BLISS
2010
Belimumab
Article
Exclusion Criteria
Pregnancy, any therapy with human, murine
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.
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
immunoglobulin, plus the following 4 features: less
than a 30% increase in serum creatinine levels as
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
No active LN
Exclusion Criteria
Inclusion Criteria
Seropositive (ANA >=1:30 and/or anti-dsDNA >=30
IU/mL) SLE with SELENA SLEDAI >=6 on stable
standard-of –care therapy ofr >=30d were enrolled
Inclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Jadad
Score
0
Jadad
Score
x
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.
Inclusion Criteria
Exclusion Criteria
Jadad
Score
Please see enclosed excel sheet for Randomized Controlled Trial (RCT) – Intervention-Outcome (I-O) and Adverse Event (AE)
data
Tocilizumab
Article
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
RANDOMIZED CLINICAL TRIALS
Liang et al,
Nanjing,
Jayne et al,
UK, 2004
(178)
Burt et al,
USA, 2006
(179)
Stem Cell
Article
Catapano et
al, UK and
Italy, 2010
(175)
Terrier et al,
France, 2010
(176)
Jonsdottir et
al, Europe,
2010 (177)
Retrospective data from the European Group for Blood and
Marrow Transplantation and European League against
Rheumatism Registry.
At least 4 of 11 ACR Criteria for SLE and required more than
20mg/d of prednisone or its equivalent despite use of
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.
SLE refractory to standard therapies. All patients had at least 4
of 11 ACR criteria for SLE. Eligibility criteria include one of the
Inclusion Criteria
Exclusion Criteria
Exclusion Criteria
SLE and active LN. Pooled data from 2 cohorts, WHO Class V and WHO
Class III or IV.
Data extracted from 2 electronic databases and patients’ note in Vasculitis
and Lupus Clinic at Addenbrooke’s Hospital, Cambridge, UK. Fulfill at least 4
ACR diagnostic criteria. Patients receiving rituximab for refractory or relapsing
SLE.
Data collected prospectively from 82 centers in the AIR registry. SLE
classified according to ACR 1982 revised criteria.
Table 6. Cohort Studies Inclusion/Exclusion Criteria and Newcastle-Ottawa Scale
Rituximab
Article
Inclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
COHORT STUDIES
1
4
Newcastle
Ottawa
Scale
4
1
6
Newcastle
Ottawa
Scale
3
Inclusion Criteria
Single center. Fulfilled 1997 revised criteria for SLE
classification. Biopsy proven LN. Renal biopsies reviewed by 2
pathologists and categorized according to ISN/RPS in 2004.
Longitudinal observational cohort. Patients were >= 16 years of
age and had disease duration of <= 5 years. Each patient had a
baseline or enrollment visit (T0) followed by a 6 month visit
(T0.5) and subsequently yearly visit. Time of diagnosis (TD)
Siso et al,
Spain, 2008
(182)
Pons-Estel
et al, USA
and Puerto
Rico, 2009
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.
All patients met at least 4 of the 11 ACR criteria for SLE.
SLEDAI socre >=8, lack of response to treatment with monthly
IV CYC 500-1000 mg/m2 for >= 6 months or lack of response to
treatment with oral MMF (2000 mg/day) for >=3 months, and
continued daily doses of >20mg of prednisone or its equivalent.
Also if they had refractory immune-mediated transfusiondependent 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.
Inclusion Criteria
Exclusion Criteria
Uncontrolled infection, mean
pulmonary artery pressure > 50mm
Hg, failure of one of the vital organs,
were pregnant or lactating.
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
Antimalarial
Article
Sun et al,
Nanjing
China, 2010
(181)
2010 (180)
Stem Cell
Article
4
Newcastle
Ottawa
Scale
5
3
Newcastle
Ottawa
Scale
Retrospective charge review. Patient meet the 1982 ACR
criteria for the diagnosis of SLE and have an active LN verified
and classified by a renal biopsy, treated with CsA.
Inclusion Criteria
was defined as the time when each patient met 4 ACR criteria.
Inclusion Criteria
Ioannidis et
al, USA and
Greece,
2000 (186)
Mok et al,
Hong Kong,
China, 2004
(187)
de Castro et
al, Brazil,
2007 (188)
Dooley et al,
USA, 1996
(185)
SLE patients with biopsy proven DPGN initially treated with
regimens that included CYC and corticosteroids between years
1988 and 2001. All fulfilled at least 4 of the ACR criteria for SLE
classification.
SLE classification by ACR classification criteria, treated and
followed from July 1988 to December 2003.
Renal biopsy diagnosis of SLE-DPGN from within the
Glomerular Disease Collaborative Network (GDCN) were eligible
for inclusion in this study. Patient fulfilled 4 or more criteria from
the 1982 ACR revised criteria for classification of SLE.
Documentation of treatment or intention to treat with CYC IV was
required for study entry.
All patients with biopsy-documented diagnosis of proliferative
lupus nephritis (WHO type III or IV) treated with IVC.
Histological class II or V according to
1995 WHO classification.
Exclusion Criteria
Exclusion Criteria
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
Cyclophosphamide (CYC)
Article
Inclusion Criteria
Rihova et al,
Czech
Republic,
2007 (184)
Cyclosporin
Article
LUMINA
study (183)
Antimalarial
Article
6
3
1
Newcastle
Ottawa
Scale
0
Newcastle
Ottawa
Scale
2
Newcastle
Ottawa
Scale
Renal biopsy proven diffuse proliferative lupus
glomerulonephritis (1995 WHO Class IV) treated in Hong Kong
identified by clinical registries or renal biopsy databases. All
patients fulfilled at least 4 ACR criteria for SLE classifications
and were initially treated with corticosteroids and CYC.
Prospective randomized trial with 1:1 randomization. SLE
patients met >= 4 of revised ACR criteria for SLE with moderate
to severe activity in an organ as defined as BILAG A or a high
score for that organ on the SLAM or hospitalization for
involvement of that organ. Lack of response or expected lack of
response to moderate- to high- dose corticosteroids, to the
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.
Cyclophosphamide (CYC) vs Azathioprine (AZA)
Urowitz et al,
Toronto,
Canada,
2007 (191)
SLE >= 4 ACR criteria or 3 ACR criteria plus a typical
histological lesion of SLE on renal or skin biopsy. Patients with
active renal disease treated with immunosuppressive/cytotoxic
medications in the year after diagnosis of active renal disease
were selected from clinic database. Active renal disease
defined as presence of 2 consecutive visits of one of: red blood
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.
Immunosuppressives vs Cyclophosphamide (CYC)
Article
Inclusion Criteria
Petri et al,
USA, 2010
(190)
Mok et al,
Hong Kong
China, 2006
(189)
Newcastle
Ottawa
Scale
3
Exclusion Criteria
Newcastle
Ottawa
Scale
3
Musculoskeletal lupus from the
4
category of eligible organ involvement.
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
Cyclophosphamide (CYC)
Article
Inclusion Criteria
Decker et al,
NIH, 1975
(192)
Serum creatinine exceeding
400micromol/L, treatment with
cyclophosphamide or mycophenolate
mofetil within 6 months, or
prednisolone dose exceeding
0.4mg/kg/d for more than 2 weeks prior
to baseline/
Houssiau et
al, Europe,
ELNT, 2004
Subanalysis
(193)
SLE patients according to ACR criteria, age 14 years or older
Patients who had taken CYC or AZA
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)
during the previous month were
excluded (except for a course of
glucocorticoids for a maximum of 10
days before the referral). Other
exclusion criteria were renal thrombotic
microangiopathy, preexisting chronic
renal failure, pregnancy, previous
malignancy (except skin and cervical
High dose cyclophosphamide (CYC) vs Low dose cyclophosphamide followed by Azathioprine (AZA)
Article
Inclusion Criteria
Exclusion Criteria
Chan et al,
Hong Kong,
China, 2005
(170)
Prospective cohort. Diagnosis of WHO Class IV lupus nephritis
confirmed by renal biopsy, baseline urinary protein excretion
exceeding 1g/24h, baseline serum albumin below 35g/L,
treatment with sequential immunosuppression. Patients with
superimposed membranous changes were included provided
that there were concomitant diffuse proliferative features.
Exclusion Criteria
Serum creatinine of greater than
4mg/100ml or creatinine clearance of
less than 20ml/min
Diagnosis of SLE by ARA criteria including a positive
erythematosus cell test; kidney disease with either erythrocyte
casts, celluar casts, and either hematuria (20 erythrocytes/hpf)
or high anti-DNA antibodies, low complement, and a positive
renal biopsy, and diffuse glomerulonephritis with at least a
portion of all glomeruli involved.
Cyclophosphamide (CYC) + Azathioprine (AZA)
Article
Inclusion Criteria
Exclusion Criteria
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
Inclusion Criteria
Article
Newcastle
Ottawa
Scale
3
Newcastle
Ottawa
Scale
3
Newcastle
Ottawa
Scale
3
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
Single center, retrospective. Patients fulfilled 1997 SLE
diagnosis criterion of ARA, presentation of clinical renal lesion,
crescent formation more than 50% and having undertaken
MMF or CTX therapy during their induction period.
Single center retrospective chart review of SLE patients with
biopsy ISN/RPS criteria Class II, III, IV,V, and VI. Patients
must be followed for at least 6 months.
SLE according to ACR criteria, class III/IV/V LN treated with
MMF.
Leflunomide
Mok et al,
Hong Kong,
China, 2004
(197)
Open label - Renal biopsy-proven pure membranous lupus
glomerulonephritis (WHO Va and Vb).
Azathioprine (AZA)
Article
Inclusion Criteria
CortezHernandez
et al, Spain,
2010 (196)
Rivera et al,
2009 (195)
Tang et al,
Nanjing
Chinca, 2008
(194)
Mycophenolate Mofetil (MMF)
Article
Inclusion Criteria
WHO Classification Vc and Vd.
Exclusion Criteria
Exclusion Criteria
intraepithelial neoplasis), diabetes
mellitus, previously documented severe
toxicity to immunosuppressive drugs,
and anticipated poor compliance with
the protocol.
High dose cyclophosphamide (CYC) vs Low dose cyclophosphamide followed by Azathioprine (AZA)
Article
Inclusion Criteria
Exclusion Criteria
Newcastle
Ottawa
Scale
3
3
3
Newcastle
Ottawa
Scale
5
Newcastle
Ottawa
Scale
x
Exclusion Criteria
Severe insufficiency of organs besides
kidney, including heart failure, liver
failure, severe psychosis, leukocyte and
platelet count less than 3 x 10 9/L and
50 x 10 9 respectively, pregnant
women, lactating women, children of
less than 16 age.
Fulfilled 1997 ACR classification criteria for SLE admitted as
inpatients undergoing kidney biopsy.
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
Inclusion Criteria
Please see enclosed excel sheet for Cohort Trial – Intervention-Outcome (I-O) and Adverse Event (AE) data
Zhang et al,
Harbin
China, 2009
(198)
Article
Newcastle
Ottawa
Scale
3
Goral S, Ynares C,
Shappell SB, Snyder
S, Feurer ID,
Kazancioglu R, Fogo
AB, Helderman JH.
University of
Pennsylvania School
of Medicine
Transplantation. 2003
Mar 15;75(5):651-6.
Authors
Hashemi V, Nadjafi I,
Azzordegan F,
Ghahramani N,
Broumand B. Shariati
Hospital, Tehran
University of Medical
Sciences, Iran.
Transplant Proc.
1999
Dec;31(8):3142-3.
Ward MM. Palo Alto
Health Care System,
Palo Alto, CA Kidney
Int. 2000
May;57(5):2136-43.
RESULTS: Among the 50 patients with at least 3 months of
follow-up, RLN was present in 15 (52% of patients who
underwent biopsy, 30% of total patients): mesangial lupus
nephritis (LN) (class II) in eight, focal proliferative LN (class III) in
four, and membranous LN (class Vb) in three patients. One
patient had graft loss because of RLN (class II) at 10.5 years.
The duration of dialysis before transplantation was not different
between patients with RLN compared to patients without RLN
(P=0.40). Overall patient survival (n=50) was 96% at 1 year and
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
RESULTS: In an unadjusted analysis, the risk of graft failure after
first cadaveric transplant was slightly but significantly greater
among patients with ESRD caused by lupus nephritis than
among those with ESRD caused by other causes [hazard ratio
(HR), 1.13; 95% CI, 1.01 to 1. 26, P = 0.04]. However, after
adjustment for potential confounding factors, the risk of graft
failure was not increased in patients with ESRD caused by lupus
nephritis (HR, 1.08; 95% CI, 0.94 to 1.23, P = 0.28). Mortality
after the first cadaveric transplantation did not differ between
groups. The adjusted risks of graft failure (HR, 1.06; 95% CI,
0.84 to 1.32, P = 0.62) and patient mortality (HR = 0. 69; 95% CI,
0.45 to 1.05, P = 0.09) after the first living-related renal transplant
were also not significantly higher among patients with ESRD
caused by lupus nephritis. CONCLUSIONS: Graft and patient
survival after first cadaveric and first living-related renal
transplants are similar in patients with ESRD caused by lupus
nephritis and patients with ESRD from other causes.
Graft failure and patient mortality after the
first cadaveric renal transplantation were
compared between 772 adults with ESRD
caused by lupus nephritis and 32,644 adults
with ESRD caused by other causes who
received a transplant between 1987 and
1994 and were included in the United States
Renal Data System. The median follow-up
times were 4.9 and 5.0 years in the two
groups, respectively. Multivariate Cox
regression models were used to adjust the
risks of graft failure and mortality for group
differences in recipient and donor
characteristics. Similar comparisons were
performed between 390 adults with ESRD
caused by lupus nephritis and 10,512 adults
with ESRD caused by other causes after
first living-related renal transplantation.
The records of 54 renal transplant recipients
with SLE were reviewed. Thirty-one patients
underwent biopsy because of worsening
renal function and proteinuria. All biopsy
specimens were evaluated by light
microscopy, immunofluorescence (IF), and
electron microscopy (EM).
Outcomes of renal
transplantation
among patients with
end-stage renal
disease caused by
lupus nephritis.
Recurrent lupus
nephritis in renal
transplant recipients
revisited: it is not
rare.
Results/Conclusions
Graft survival at 1 yr = 85.6%, 3 yr = 73%. No correlation w/
gender, age at transplant, and donor source. Causes of graft
loss: chronic graft rejection 11/37, acute rejection 2/37,
recurrence of LN 1/37. Patient survival at 1 yr 94.4%, at 3 yrs
91.7%. 2/37 died of MI, 1/37 died of pneumococcal
infection/sepsis, 1/37 died of opium toxicity.
Description/Methods
Looked at 37 pts with LN and ESRD who
had undergone renal transplantation. Posttransplant meds = CsA, aza, and pred,
except in 1 case aza+pred.
Title
Renal
transplantation in
systemic lupus
erythematosus: a
multicenter study
with 37 patients in
Iran.
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
One patient developed renal failure with serological evidence of
SLE activity at 61 months after transplantation. In the absence of
urine abnormalities we favored the diagnosis of rejection,
although recurrence of lupus nephritis could not formally be
excluded. This was the only case of a possible recurrence of
lupus nephritis. Two other patients developed extra-renal
manifestations of SLE at 6 and 17 months after transplantation.
Patient and graft survival rates at 5 years after transplantation
were 86% and 68%, respectively. Survival rates were not
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.
RESULTS: Mean follow-up after renal transplantation was 91 +/59 months for patients with lupus and 90 +/- 64 months for
controls. Actuarial 15-year patient (80% versus 83%) and deathcensored graft survival rates (69% versus 67%) were not
significantly different between patients with lupus and controls.
Risks for acute and chronic rejection, arterial hypertension, and
infection were not different between the 2 groups. Mean serum
creatinine levels also were similar in the 2 groups at the last
follow-up visit. Intravascular thrombotic events occurred in 9
patients with SLE (26%) and 6 controls (8.6%; P = 0.038). In the
SLE group, 6 of 7 antiphospholipid (aPL) antibody-positive
versus 3 of 17 aPL antibody-negative patients experienced
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
We studied the outcome of renal
transplantation in patients with SLE who
underwent transplantations in our center
between 1968 and 2001. Patient and graft
survival were compared with a matched
control group. We specifically looked for any
evidence of recurrent disease. There were
23 patients (two male, 21 female) with a
mean +/-SD age of 34+/-12 years at
transplantation.
Outcome of renal
transplantation in
patients with
systemic lupus
erythematosus.
The long-term
prognosis of renal
transplantation in
patients with lupus
nephritis.
Deegens JK, Artz
MA, Hoitsma AJ,
Wetzels JF.
University Medical
Center of Nijmegen,
The Netherlands.
Transpl Int. 2003
Jun;16(6):411-8.
Epub 2003 Mar 19.
Moroni G, Tantardini
F, Gallelli B, Quaglini
S, Banfi G, Poli F,
Montagnino G,
Meroni P, Messa P,
Ponticelli C. Centro
Trasfusionale e di
Immunologia dei
Trapianti IRCCS,
Ospedale Maggiore
Milano, Italy Am J
Kidney Dis. 2005
May;45(5):903-11.
Between June 1982 and 2004, a total of 33
adults with lupus nephritis received 35
kidney allografts. Outcomes of these grafts
and those of 70 controls matched for age,
sex, and donor source who underwent
transplantation during the same period were
compared.
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.
Description/Methods
Title
Authors
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
Results/Conclusions
with SLE and matched controls. The risk for thrombotic
complications was greater in patients with SLE, particularly aPLpositive patients. Nephritis recurred in less than 10% of patients
with SLE and did not influence graft survival.
Univariate analysis showed similar graft but better patient
survival rates for primary lupus and non-lupus transplant
recipients (5-year patient survival rates for lupus cohort 85.2% for
deceased donor transplants and 92.1% for living donor
transplants as opposed to 82.1% and 89.8% respectively for the
non-lupus cohort; P=0.05 and 0.03) but similar patient survival
rates for deceased donor retransplant patients. After controlling
for confounding factors, no differences in patient or graft survival
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 nonlupus transplant recipients.
RESULTS: The mean follow-up period of this study was 4.7 +/2.4 years. While unadjusted analysis using Kaplan-Meier curves
demonstrated an association between SLE and improved
allograft survival compared with DM, in multivariate analysis the
SLE group had worse allograft [hazard ratio (HR) 1.09, P < 0.05]
and recipient (HR 1.19, P < 0.05) survival compared with the DM
group. Subgroup analysis based on the type of donor showed
that SLE patients who received deceased donor allograft had
worse allograft and recipient survival (HR 1.14, P = 0.002 and
HR 1.30, P = 0.001, respectively) compared with non-SLE
deceased donor allograft recipients. Among living allograft
Description/Methods
Here, we compared patient and graft
outcomes in lupus and non-lupus recipients
transplanted between 1996 to 2000 using
the United Network of Organ Sharing/Organ
Procurement Transplant Network database.
We evaluated the impact of recipient and
donor demographic factors, time on dialysis
and the initial immunosuppression regimen
on rejection rates and transplant outcomes.
We conducted the retrospective analysis
using data from USRDS and UNOS
databases. Patients were divided into five
groups based on the cause of end-stage
renal disease (ESRD): diabetes mellitus
(DM), SLE, glomerulonephritis, hypertension
and other causes. Between 1990 and 1999,
2886 renal transplantation recipients with
ESRD due to SLE were identified from a
total of 92 844 patients.
Title
Outcomes of renal
transplantation for
recipients with lupus
nephritis: analysis of
the Organ
Procurement and
Transplantation
Network database.
The outcome of
renal transplantation
among systemic
lupus erythematosus
patients.
Authors
Bunnapradist S,
Chung P, Peng A,
Hong A, Chung P,
Lee B, Fukami S,
Takemoto SK, Singh
AK. Transplantation.
2006 Sep
15;82(5):612-8.
Chelamcharla M,
Javaid B, Baird BC,
GoldfarbRumyantzev AS.
University of Utah
Health Sciences
Center Nephrol Dial
Transplant. 2007
Dec;22(12):3623-30.
Epub 2007 Jul 19.
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
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.
RESULTS: The number of pretransplant pregnancies
incrementally increased the risk of graft failure [hazard ratio (HR)
1.54, p < 0.05] in the entire subgroup of females and in the
subgroup of recipients aged 25-35 yr. Recipient and donor age
had an association with both the risk of graft failure (HR 0.96, p <
0.001; HR 1.01, p < 0.005) and recipient death (HR 1.04, p <
0.001; HR 1.01, p < 0.05). Greater graft-failure risk accompanied
increased recipient weight (HR 1.01, p < 0.001); African
Americans compared with whites (HR 1.55, p < 0.001); greater
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
Description/Methods
Using the data from the United States Renal
Data System of patients transplanted
between January 1, 1995 through
December 31, 2002 (and followed through
December 31, 2003) (n = 2882), we
performed a retrospective analysis of factors
associated with long-term death-censored
graft survival and recipient survival.
Title
Factors affecting
kidney-transplant
outcome in
recipients with lupus
nephritis.
Authors
Tang H,
Chelamcharla M,
Baird BC, Shihab FS,
Koford JK, GoldfarbRumyantzev AS.
University of Utah
School of Medicine
Clin Transplant. 2008
May-Jun;22(3):26372.
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
Description/Methods
Patients age 15 years or older with incident
ESRD due to lupus nephritis in 1996-2004
and living in one of the 50 United States or
the District of Columbia were identified using
the US Renal Data System, a national
population-based registry of all patients
receiving renal replacement therapy for
ESRD. Incidence rates were computed for
each calendar year, using population
estimates of the US census as
denominators.
The archival records of all kidney transplant
recipients with a prior diagnosis of SLE
(according to the American College of
Rheumatology criteria) from June 1977 to
June 2007 were reviewed. Patients who had
died or lost the allograft within 90 days of
engraftment were excluded. Time-to-event
data were examined by univariable and
multivariable Cox proportional hazards
regression analyses.
Title
Changes in the
incidence of
endstage renal
disease due to lupus
nephritis in the
United States, 19962004.
Risk factors and
impact of recurrent
lupus nephritis in
patients with
systemic lupus
erythematosus
undergoing renal
transplantation: data
from a single US
institution.
Authors
Ward MM.
NIH/NIAMS/IRP J
Rheumatol. 2009
Jan;36(1):63-7.
Burgos PI, Perkins
EL, Pons-Estel GJ,
Kendrick SA, Liu JM,
Kendrick WT, Cook
WJ, Julian BA,
Alarcón GS, Kew CE
2nd. University of
Alabama at
Birmingham Arthritis
Rheum. 2009
Sep;60(9):2757-66.
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.
RESULTS: Over the 9-year study period, 9199 new cases of
ESRD due to lupus nephritis were observed. Incidence rates,
adjusted to the age, sex, and race composition of the US
population in 2000, were 4.4 per million in 1996 and 4.9 per
million in 2004. Compared to the pooled incidence rate in 19961998, the relative risk of ESRD due to lupus nephritis in 19992000 was 0.99 (95% CI 0.93-1.06), in 2001-2002 was 0.99 (95%
CI 0.92-1.06), and in 2003-2004 was 0.96 (95% CI 0.89-1.02).
Findings were similar in analyses stratified by sex, age group,
race, and socioeconomic status. CONCLUSION: There was no
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.
RESULTS: Two hundred twenty of nearly 7,000 renal
transplantations were performed in 202 SLE patients during the
30-year interval. Of the 177 patients who met the criteria for
study entry, the majority were women (80%) and African
American (65%), the mean age was 35.6 years, and the mean
disease duration was 11.2 years. Recurrent lupus nephritis was
noted in 20 patients (11%), allograft loss in 69 patients (39%),
and death in 36 patients (20%). African American ethnicity was
found to be associated with a shorter time-to-event for recurrent
lupus nephritis (hazard ratio [HR] 4.63, 95% confidence interval
[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
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.
There were no significant differences between patients with short
renal survival (<3 years) and long renal survival (>3 years) for the
various demographic variables such as age, sex, PD duration,
immunosuppressive drug administration, or exchange system (P
> 0.05). Interestingly, before PD, patients with short renal
survival had lower serum complement levels than patients with
long renal survival (C3, 40.2 +/- 14.4 vs 76.3 +/- 18.5 mg/dL, P <
0.001; and C4, 14.8 +/- 4.7 vs 22.4 +/- 8.1 mg/dL, P < 0.05).
However, the differences in complement levels between the
groups disappeared after PD (C3, 76.5 +/- 27.3 vs 84.2 +/- 27.8
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.
Description/Methods
This longitudinal study investigated whether
renal survival can affect the course and
outcome of systemic lupus erythematosus
(SLE) patients treated with chronic
peritoneal dialysis (PD). Thirty-five SLE
patients, out of 1115 end-stage renal
disease (ESRD) patients treated with
chronic PD, were seen between 1990 and
2007 at the Chang Gung Memorial Hospital.
Patients were followed up for a mean of
38.8 +/- 22.9 months.
Title
Impact of renal
survival on the
course and outcome
of systemic lupus
erythematosus
patients treated with
chronic peritoneal
dialysis.
Authors
Liang CC, Huang CC,
Wang IK, Chang CT,
Chen KH, Weng CH,
Lin JL, Hung CC,
Yang CW, Yen TH.
China Medical
University Hospital,
Taichung, Taiwan
Ther Apher Dial.
2010 Feb;14(1):3542.
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
However, since the long-term outcome after
transplantation in this group of patients is
not well established, we have examined the
long-term outcome in SLE patients who
underwent renal transplantation at the
University of Minnesota. Thirty-two SLE
patients receiving 33 transplants between
December 1969 and December 1987 were
studied retrospectively and compared with
controls matched for age, sex, donor
source, HLA match, date of transplant, and
diabetic status.
Single-center 1-15year results of renal
transplantation in
patients with
systemic lupus
erythematosus.
Dialysis and
transplantation in
patients with renal
failure due to
systemic lupus
erythematosus. The
Australian and New
Zealand experience.
Bumgardner GL,
Mauer SM, Payne W,
Dunn DL, Sutherland
DE, Fryd DS, Ascher
NL, Simmons RL,
Najarian JS.
University of
Minnesota,
Minneapolis
Transplantation. 1988
Nov;46(5):703-9.
Pollock CA, Ibels LS.
Royal North Shore
Hospital, NSW. Aust
N Z J Med. 1987
Jun;17(3):321-5.
Between 1977 and 1985, 5726 patients in
Australia and New Zealand entered end
stage renal failure programmes. Of these,
63 patients had renal failure due to systemic
lupus erythematosus (a prevalence of 1.1%
of patients entering renal replacement
programmes).
Description/Methods
All patients with SLE that had undergone
transplant with a functioning graft were
asked in 2008 to participate in a crosssectional study. The study included a
standardised clinical examination, laboratory
tests and a biopsy of the transplanted
kidney.
Title
Recurrent lupus
nephritis after kidney
transplantation: a
surveillance biopsy
study.
Authors
Norby GE, Strøm EH,
Midtvedt K, Hartmann
A, Gilboe IM,
Leivestad T,
Stenstrøm J, Holdaas
H. Oslo University
Hospital, Norway.
Ann Rheum Dis.
2010
Aug;69(8):1484-7.
Epub 2010 May 24.
Results/Conclusions
RESULTS: A total of 41 (93%) of a cohort of 44 patients with
SLE with renal transplants participated. Of the biopsies, 3 were
indication biopsies and 38 were surveillance biopsies. In all, 22
patients (54%) had biopsy-proven recurrence of LN. The majority
of the cases were subclinical and characterised as class I/class II
LN. Proteinuria (mg protein/mmol creatinine) was significantly
increased in patients with recurrence, 70.6 (104.9) mg/mmol
versus 11.9 (6.7) mg/mmol in patients without recurrence
(p=0.038). Lupus anticoagulant was found more frequently in the
patients with recurrence, nine versus two patients (p=0.033).
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.
A total of 69% (22/32) of patients underwent less than 1 year of
dialysis prior to transplantation, and 50% (16/32) experienced
biopsy-proved acute rejection, which was reversible in 67%
(11/16). Actuarial graft function and patient survival rate in SLE
patients were not significantly different from those in the matched
control group. Duration of prior dialysis did not affect outcome.
Surviving grafts have excellent function as measured by serum
creatinine (1.3 +/- 0.4 mg/dl, means +/- SD). Causes of death
were sepsis (5) and myocardial infarction (1). One patient lost the
graft from rejection after withdrawal of immunosuppression
because of a malignancy one month posttransplant. Three
patients lost graft function due to chronic rejection. To date no
patients have had evidence of recurrent SLE nephritis.
When compared with patients with other forms of
glomerulonephritis, there was a female preponderance and a
younger age distribution in patients with renal failure due to lupus
nephritis. Integrated patient, dialysis, and transplant survival data
showed that results in patients with renal failure due to lupus
nephritis were comparable with those in patients with other forms
of glomerulonephritis or in patients with renal failure due to any
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
This study is a retrospective evaluation of
each of these independent risk factors in 80
renal transplants for ESRD secondary to
SLE done at our institution between 1971
and 1994. Our entire non-diabetic cohort of
1,966 renal transplants is used as a
comparison group.
Long-term graft survival and graft function of
renal transplant recipients with SLE,
Wegener's granulomatosis, microscopic
polyangiitis, Goodpasture's syndrome, and
Henoch-Schonlein purpura were evaluated
in a single center. In addition, the incidence
of renal and extrarenal relapses and the
impact of the immunosuppressive therapy
on the course of the autoimmune disease
Risk factors for renal
allograft loss in
patients with
systemic lupus
erythematosus.
Renal
transplantation for
patients with
autoimmune
diseases: singlecenter experience
with 42 patients.
Lochhead KM, Pirsch
JD, D'Alessandro
AM, Knechtle SJ,
Kalayoglu M,
Sollinger HW, Belzer
FO. University of
Wisconsin Hospital
and Clinics Kidney
Int. 1996
Feb;49(2):512-7.
Haubitz M, Kliem V,
Koch KM, Nashan B,
Schlitt HJ, Pichlmayr
R, Brunkhorst R.
Medical School
Hannover, Germany.
Transplantation. 1997
May 15;63(9):1251-7.
Description/Methods
Title
Authors
Our results showed equivalent graft survival rates between lupus
patients and the cohort at 1, 5 and 10 years (P = 0.56). However,
an analysis of cyclosporine-era cadaver grafts revealed that the
lupus group had poorer 5-year graft survival than the cohort
(41% vs. 71%, P = 0.02). Evaluation of cyclosporine-era lupus
graft survival showed significantly improved outcome in livingrelated lupus recipients over cadaver grafts at five years (89%
vs. 41%, P = 0.003). The majority of grafts lost in the lupus
cadaver recipients were due to chronic rejection. Rejection was
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.
RESULTS: Renal transplant recipients with autoimmune
diseases such as vasculitis and SLE had a patient survival rate
(94% after 5 years) and a graft survival rate (65% after 5 years)
comparable to those of patients with other causes of end-stage
renal disease (patient survival 88% and graft survival 71% after 5
years). Graft losses due to the underlying disease were rare.
Extrarenal relapses occurred in three patients with Wegener's
granulomatosis, one patient with microscopic polyangiitis, and
three patients with SLE, but were less frequent compared with
Results/Conclusions
acceptable forms of treatment for patients with end stage renal
failure due to systemic lupus erythematosus.
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
Description/Methods
were studied.
Between October 1971 and August 1993, 53
patients with SLE received 60 renal
transplants in the different renal
transplantation centers in Paris. All patients
met the criteria of the American
Rheumatism Association for SLE, and
diagnoses were confirmed by renal biopsy
specimens in all patients. The long-term
outcome of renal transplantation in these
patients was examined, including patient
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.
Title
Renal
transplantation in
patients with
systemic lupus
erythematosus: a
multicenter study.
Authors
Grimbert P, Lang P,
Frappier J,
Bedrossian J,
Legendre C, Hiesse
C, Bitker MO, Sraer
JD, Antoine C.
Hopital Henri
Mondor, Creteil,
France. Transplant
Proc. 1997
Aug;29(5):2363-4.
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 antiDNA 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.
Results/Conclusions
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.
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
Title
Frequency of
recurrent lupus
nephritis among
ninety-seven renal
transplant patients
during the
cyclosporine era.
Outcome of renal
transplantation in
ninety-seven
cyclosporine-era
patients with
systemic lupus
erythematosus and
matched controls.
Authors
Stone JH, Millward
CL, Olson JL, Amend
WJ, Criswell LA.
University of
California, San
Francisco Arthritis
Rheum. 1998
Apr;41(4):678-86.
Stone JH, Amend
WJ, Criswell LA.
Johns Hopkins
University Arthritis
Rheum. 1998
Aug;41(8):1438-45.
A total of 97 SLE patients who underwent
renal transplantation between January 1984
and September 1996 were selected for
study and were matched with a group of
non-SLE controls (1 control for each SLE
patient) who also received transplants
during that period. SLE patients and controls
were matched on 6 covariates: age, sex,
race, type of allograft (cadaveric versus
living-related), number of previous
transplants, and year of transplantation. All
study subjects received either cyclosporine
or FK-506/tacrolimus as part of their
immunosuppressive regimen. In a rigorous
medical records review, the status of each
allograft and the cause of each graft loss
Description/Methods
We reviewed the posttransplant clinical
course and renal biopsy results in 97
consecutive SLE patients who underwent a
total of 106 renal transplantation procedures
at our center from January 1984 to
September 1996.
Results/Conclusions
RESULTS: There were 81 female and 16 male patients, with a
mean age of 35 years. Mean duration of dialysis prior to
transplantation was 33.5 months; 9 patients were never dialyzed.
In all patients, the disease was clinically and serologically
quiescent at the time of transplantation. The mean
posttransplantation followup period was 62.6 months. Patients
underwent a total of 143 posttransplant biopsies. Nine patients
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.
RESULTS: The control group included patients with 20 different
causes of end-stage renal disease (ESRD). The mean followup
times for the SLE patients and controls were 323 weeks and 320
weeks, respectively. During the followup period, 52 SLE patients
and 37 controls lost their allografts. The 1-, 2-, 5-, and 10-year
allograft survival probabilities for the 2 groups (SLE versus
controls) were as follows: 81.7% versus 88.2% (1-year); 74.7%
versus 84.4% (2-year); 45.9% versus 75.0% (5-year); and 18.5%
versus 34.8% (10-year). In the multivariate model, the relative
hazard of allograft loss associated with SLE as the cause of
ESRD was 2.1 (95% confidence interval 1.06-4.06, P = 0.0328).
The total number of HLA mismatches, smoking status, and
delayed allograft function were also associated with allograft loss
in the multivariate model. CONCLUSION: Compared with
matched controls, renal transplant patients with SLE had inferior
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
RESULTS: No patient had clinically active systemic lupus
erythematosus (SLE) at the time of transplantation. The 1-year
graft and patient survival rates were 83% and 98%, and the 5year graft and patient survival rates were 69% and 96%.
Actuarial graft and patient survival rates in SLE patients were not
significantly different from those of the matched control group.
Chronic rejection was the major risk factor for graft loss. Lupus
nephritis recurred in the graft of one patient 3 months after
transplantation, and there were extrarenal manifestations of SLE
in four others. CONCLUSIONS: The present study confirms that
patients with SLE can receive transplants with excellent graft and
patient survival rates and a low rate of clinical recurrent lupus
nephritis.
The patients received their transplants over
a 260-month period (21.5 years) between
October 1971 and August 1993. The
population was predominantly women
(90%), and the mean age at the time of the
transplantation was 33.2 years (range: 2154 years). Fifty-six transplants (93%) were
from cadaveric donors, and 4 (7%) were
from living-related donors; 46 patients (86%)
had primary allografts, and 7 (14%) received
a second allograft. The duration of disease
before transplantation was 93.6+/-6.2
months, and the duration of dialysis before
transplantation was 48+/-6 months.
Forty-five patients with systemic lupus
erythematosus subjected to 48 kidney
transplants were studied. For comparative
purposes, a case-control population was
selected, matched for gender, race, type of
donor, age, and time of transplantation.
Patients with non-glomerulonephritis
diseases were excluded.
Long-term outcome
of kidney
transplantation in
patients with
systemic lupus
erythematosus: a
multicenter study.
Groupe Cooperatif
de Transplantation
d'île de France.
Renal
transplantation in
systemic lupus
erythematosus. A
case control study of
45 patients.
Grimbert P, Frappier
J, Bedrossian J,
Legendre C, Antoine
C, Hiesse C, Bitker
MO, Sraer JD, Lang
P. Hôpital Henri
Mondor, Créteil,
France.
Transplantation. 1998
Oct 27;66(8):1000-3.
Azevedo LS, Romão
JE Jr, Malheiros D,
Saldanha LB, Ianhez
LE, Sabbaga E.
University of São
Paulo Medical
School, SP, Brazil.
Nephrol Dial
Transplant. 1998
Nov;13(11):2894-8.
RESULTS: No differences in acute episodes of rejection, causes
of kidney loss or patient death were observed. General as well as
infectious complications were similar. Pregnancy rates and
outcomes were similar with no deleterious effect on patients or
grafts. Actuarial 1- and 5-year patient survivals (97.7 and 91.1%
for SLE and 95.4 and 87% for controls, respectively) and graft
survivals (93.1 and 80.7% for SLE and 88.8 and 70.2% for
controls, respectively) were similar. Long-term renal function
expressed by serum creatinine was the same. No differences in
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
Results/Conclusions
allograft loss.
Description/Methods
was determined.
Title
Authors
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
The frequency and outcome of recurrent
lupus nephritis (RLN) among recipients of a
kidney allograft vary among single-center
reports. From the United Network for Organ
Sharing files, we estimated the period
prevalence and predictors of RLN in
recipients who received a transplant
between 1987 and 2006 and assessed the
effects of RLN on allograft failure and
recipients' survival.
Recurrence of lupus
nephritis after kidney
transplantation.
Lupus nephritis
outcome with and
without renal biopsy:
a 5-year
comparative study.
Contreras G,
Mattiazzi A, Guerra
G, Ortega LM,
Tozman EC, Li H,
Tamariz L, Carvalho
C, Kupin W, Ladino
M, LeClercq B,
Jaraba I, Carvalho D,
Carles E, Roth D.
Miller School of
Medicine, University
of Miami J Am Soc
Nephrol. 2010
Jul;21(7):1200-7.
Epub 2010 May 20.
Jakez-Ocampo J,
Arreola-Zavala R,
Richaud-Patin Y,
Romero-Díaz J,
Llorente L. Instituto
Nacional de Ciencias
Médicas y Nutrición
Salvador Zubirán,
México City J Clin
Rheumatol. 2004
The no-biopsy group consisted of 30
patients with lupus with strong clinical and
laboratory suspicion of proliferative
glomerulonephritis in whom a renal biopsy
was unavailable either because of medical
contraindication or the patient's refusal. The
biopsy group included 30 patients
undergoing biopsy and a histologic
diagnosis of DPGN. Patients were followed
from the onset of nephritis and at 18, 36,
Description/Methods
Title
Authors
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.
Among 6850 recipients of a kidney allograft with systemic lupus
erythematosus, 167 recipients had RLN, 1770 experienced
rejection, and 4913 control subjects did not experience rejection.
The period prevalence of RLN was 2.44%. Non-Hispanic black
race, female gender, and age <33 years each independently
increased the odds of RLN. Graft failure occurred in 156 (93%) of
those with RLN, 1517 (86%) of those with rejection, and 923
(19%) of control subjects without rejection. Although recipients
with RLN had a fourfold greater risk for graft failure compared
with control subjects without rejection, only 7% of graft failure
episodes were attributable to RLN compared and 43% to
rejection. During follow-up, 867 (13%) recipients died: 27 (16%)
in the RLN group, 313 (18%) in the rejection group, and 527
(11%) in the control group. In summary, severe RLN is
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.
RESULTS: At onset, the no-biopsy group showed lower C3
levels and higher proteinuria, although both groups showed
evident deterioration of the renal function. No significant
differences were found in treatment, outcome, survival, renal
function tests, or in the development of kidney failure.
CONCLUSIONS: Proliferative glomerulonephritis deserves
prompt diagnosis and treatment. This study demonstrates that
experience in the management of lupus nephropathy, together
with clinical and laboratory data, are often enough information to
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
Results/Conclusions
absence of a renal biopsy.
Patient survival did not differ, but graft survival at 6 and 12
months post transplantation was significantly reduced in SLE
patients (p less than 0.001). When divided into groups using
either azathioprine and steroids or combinations including
cyclosporin A (14 and 17 SLE patients in each group), graft
survival was significantly reduced for the azathioprine-treated
SLE patients, 36% vs. 82% for their controls at one year. For
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.
For all 64 patients combined, the 1-year graft and patient survival
rates are 68.8 and 86.5%, respectively, whereas 5-year graft and
patient survival rates are 60.9 and 85.9%, respectively. Patients
whose immunosuppressive regimen was CsA-based had a 1year graft survival of 71.5 versus 63.6% in the AZA group.
However, this 7.9% difference did not reach statistical
significance (p = 0.95). The 5-year graft survival of the CsAbased group was 69.1 versus 45.5% for the AZA group, p < 0.05.
One-year patient survival was 77.3% for the AZA group and
92.9% for the CsA group, p < 0.05). The data show that patients
with ESRD secondary to lupus nephritis can undergo renal
transplantation with satisfactory outcome. Immunosuppression
based upon CsA improves first-year patient and allograft survival
by 15.6 and 7.9%. respectively.
Description/Methods
and 60 months.
The outcome of primary renal
transplantation in 31 SLE patients was
evaluated in relation to two contemporary
controls per patient, matched for age, sex
and immunosuppressive therapy. The
proportion of living donors was one third in
both groups.
The outcome of renal transplantation in 64
patients with end-stage renal disease
(ESRD) secondary to lupus nephritis is the
subject of this report. The patients were
transplanted over a 150-month (12.5-year)
period (between July 5, 1979, and January
30, 1992). The study population is
predominantly made up of young females
(mean age, 34.7 +/- 9 years, n = 54, 81.3%).
Fifty-one transplants (79.7%) are cadaveric,
and 13 (20.3%) are from living-related
donors. Fifty-eight patients (90.6%) had
primary (first) allografts, and 6 (9.4%)
received a second allograft.
Title
Renal
transplantation in
patients with
systemic lupus
erythematosus:
increased risk of
early graft loss.
Renal
transplantation in
systemic lupus
erythematosus: a
single-center
experience with
sixty-four cases.
Authors
Dec;10(6):289-94.
Nyberg G, Karlberg I,
Svalander C,
Hedman L, Blohmé I.
Sahlgrenska
Hospital, Göteborg,
Sweden. Scand J
Urol Nephrol.
1990;24(4):307-13.
el-Shahawy MA,
Aswad S, Mendez
RG, Bangsil R,
Mendez R, Massry
SG. University of
Southern California
School of
MedicineAm J
Nephrol.
1995;15(2):123-8.
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
Authors
Title
Description/Methods
Posttransplantation immunosuppression
consisted of azathioprine and prednisone
(AZA group, n = 22, 34.3%) or AZA,
prednisone and cyclosporine (CsA group, n
= 42, 65.6%).
Results/Conclusions
GUIDELINES FOR THE SCREENING, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
END STAGE RENAL DISEASE / RENAL TRANSPLANTATION ARTICLES
D
D
D
Azathioprine
MMF
Pregnan
cy
Categor
y
Cyclophosphami
de
Treatment
Teratogenic
Teratogenic
Yes (but fetal
liver lacks
enzyme
which
converts
drug to
active
metabolites)
Unknown
Teratogenic
Animal
Studies
yes
Crosses
Placenta?
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
malformations, but when given during the second or third trimesters are believed
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
been identified which is attributable to this drug. Retrospective review of
pregnancy outcomes revealed that infants exposed to azathioprine may develop
the following adverse effects: thymic atrophy, leukopenia, anemia,
thrombocytopenia, chromosome aberrations, reduced immunoglobulin levels,
and infections. Adjustment of azathioprine dosage to maintain normal maternal
leukocyte counts may decrease or prevent neonatal leukopenia and
thrombocytopenia (Armenti et al, 1998). Current guidelines regarding pregnant
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
(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,
Human Studies
PREGNANCY AND LUPUS NEPHRITIS
Table 8. Summary of Commonly Used Medications’ Teratogenic Effects
GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
Pregnan
cy
Categor
y
X
D
C
Treatment
Leflunomide
Chlorambucil
Tacrolimus
Yes
Yes
Unknown
Crosses
Placenta?
Teratogenic
Teratogenic
Animal
Studies
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
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
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
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).
Human Studies
GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
PREGNANCY AND LUPUS NEPHRITIS
Pregnan
cy
Categor
y
C
Treatment
Cyclosporine
Yes
Crosses
Placenta?
No
Animal
Studies
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,
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).
Human Studies
GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN ADULTS
PREGNANCY AND LUPUS NEPHRITIS
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
inactive
present vs. absent
Reference
Technique Sen Spec +LR -LR
Sen Spec +LR
Renal disease active
vs. inactive
-LR Sen Spec +LR
-LR
0.92 0.55
2.1
0.14
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
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
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
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
Bootsma, et al. (204) Crithidia
1.00
0.13 1.15 0.38
0.89
0.4
0.82
0.18
1.0
0.97 0.91 0.33
1.4
0.26
0.95 14.8 0.27 0.88
0.41
1.5
0.29
0.85
0.33
2.6
0.45
1.2
0.56
Chubick et al. (202) ELISA
Kalmin, et al. (203)
Farr
Pincus, et al. (205)
Farr
Ballou, et al. (206)
Crithidia
Garcia, et al. (207)
Crithidia
Weitzman, et al.
Farr
0.74
1.8
0.5
0.44
1.48 0.28
0.76
0.66 2.28 0.36
0.68
0.82 3.76 0.39
0.82 0.32
(208)
Miniter, et al. (209) RIA
Ballou,et al. (210)
Crithidia
Isenberg, et al.
ELISA
0.53
0.64
1.46
0.73
0.44
0.57
1.02
0.98
0.76
0.54 1.65 0.44
Abrass, et al. (102) RIA
0.33
0.68 1.03 0.97
Davis, et al. (212)
RIA
0.93
0.78 3.48
0.1
Feldman, et al.
Farr
0.2
0.88
0.9
0.25
0.93
3.6
0.8
NA
NA
NA
0.66
0.66 4.14 0.51
0.65
0.41
1.7
0.76 0.86 0.45
1.7
0.3
(211)
1.6
NA
(213)
Weighted means
GUIDELINES FOR THE SCREENING, DIAGNOSIS, TREATMENT AND MONITORING OF LUPUS NEPHRITIS IN
ADULTS
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