Narrative Review

Ten Common Mistakes in the Management of Lupus Nephritis

Bhadran Bose, MBBS, FRACP,1 Earl D. Silverman, MD, FRCPC,2 and
Joanne M. Bargman, MD, FRCPC1

Management of patients with lupus nephritis can be complex and challenging. We suggest that there are
some widely held misconceptions about lupus, and unfortunately, these underpin the treatment of many pa-
tients. There is little evidence to support the common assumption that intravenous pulse cyclophosphamide is
the best treatment for lupus nephritis. Although there is much focus on which immunosuppressive agent to
use, too little attention is paid to the proper dose and duration of corticosteroids and concomitant therapy with
antimalarial agents. Many clinicians reflexively perform kidney biopsies when these biopsies may be high risk
and not influence therapy. There is little emphasis on or awareness of nonadherence to therapy, which is an
underappreciated cause of treatment resistance. Resolution of proteinuria and hematuria can take a long time,
and immunotherapy should not be intensified based on urine sediment alone. Furthermore, the intensity of the
immunosuppression must be considered in the context of lupus nephritis class and duration of kidney damage.
Finally, clinicians are aware of the risks of pregnancy in the face of active lupus, but assume that their patients
also are aware of this and forget to discuss this with them. With a combined experience of more than 50 years
in managing children and adults with lupus, we offer our impression of recurrent mistakes in the management
of lupus in general, with a focus on treatment of lupus nephritis.
Am J Kidney Dis. 63(4):667-676. ª 2014 by the National Kidney Foundation, Inc.

INDEX WORDS: Antimalarial agents and nonadherence; azathioprine; cyclophosphamide; lupus nephritis.

Joanne M. Bargman, MD, FRCPC, was the Donald W. Seldin

Distinguished Award recipient at the 2013 National Kidney
Foundation Spring Clinical Meetings. This award was
established to recognize excellence in clinical nephrology in
the tradition of one of the foremost teachers and researchers
in the field, Dr Donald W. Seldin.
nephritis. Based on this study, the National Institutes
of Health (NIH) has promoted high-dose cyclophos-
phamide as a first-line induction agent for lupus
nephritis, and this regimen is used by many rheuma-
tologists and nephrologists. The cyclophosphamide
dosage is 0.5-1.0 g/m2 monthly for 6 months, fol-
lowed by repeat dosing every 3 months for 1 year,

K idney involvement in systemic lupus erythema-

tosus (SLE) can range from mild to severe and
occurs in 50%-70% of patients with lupus.1-3 Despite
advances in therapy, morbidity and mortality remain
high. In some studies, lupus nephritis leads to end-
stage renal failure in 17%-25% of patients4-6 and also
is associated with increased mortality.7,8 There are
some common misconceptions that are widely held
and may compromise optimal therapy of these
patients. If these misconception or myths are
addressed, we believe the outcome of these patients
might improve. These comments are based on our
experience over the past quarter century dealing with
a diverse ethnic lupus population in academically
based multidisciplinary lupus clinics in Toronto.
The following are the 10 most common mistakes
we have observed surrounding the management of
patients with lupus nephritis (Box 1).
1. ASSUMING THAT INTRAVENOUS
CYCLOPHOSPHAMIDE IS THE GOLD-STANDARD
INDUCTION AGENT FOR LUPUS NEPHRITIS
Following the initial publication by Austin et al9 in
1986, intravenous (IV) cyclophosphamide has been
considered the gold standard for treatment of lupus
followed by an additional 2 doses 6 months apart.
However, there are major concerns with this regimen,
especially in young patients with lupus, due to the
risks of gonadal toxicity and malignancy.
In 2002, the Euro-Lupus Nephritis Trial compared
low-dose IV cyclophosphamide (500 mg IV biweekly
for 6 doses) versus the high-dose NIH regimen in
90 patients.10 Renal response and relapse rate were
similar between the 2 groups. The long-term efficacy
of the Euro-Lupus Nephritis Trial regimen also was
shown in a 10-year follow-up study.11 However,
there was no statistical difference in adverse events
between groups. Limitations of the study are that most
patients in the study were white, 78% had preserved
From the 1University of Toronto, University Health Network/
Toronto General Hospital; and 2SickKids Hospital, Toronto,
Ontario, Canada.
Received August 12, 2013. Accepted in revised form October 8,
2013. Originally published online December 13, 2013.
Address correspondence to Joanne M. Bargman, MD, FRCPC,
University Health Network, Toronto General Hospital, 200 Eliz-
abeth Street, 8N-840, Toronto, ON M5G 2C4, Canada. E-mail:
joanne.bargman@uhn.ca
 2014 by the National Kidney Foundation, Inc.
0272-6386/$36.00
http://dx.doi.org/10.1053/j.ajkd.2013.10.056

Am J Kidney Dis. 2014;63(4):667-676 667


Box 1. Ten Common Mistakes in the Management of Lupus
Nephritis
1. Assuming that intravenous cyclophosphamide is the
gold-standard induction agent for lupus nephritis
2. Improper dosing of corticosteroids
3. Not using antimalarial agents routinely
4. Using urinary sediment for response criteria
5. Not scaling the intensity of immunosuppression to the
different classes of lupus nephritis, especially class V
membranous lupus
6. Missing nonadherence to therapy as a cause of “treat-
ment failure”
7. Not reducing or minimizing immunosuppressive expo-
sure in patients with advanced kidney disease
8. Forgetting to monitor side effects of immunosuppression
and to use prophylaxis
9. Performing a biopsy on the kidney, especially in a high-
risk patient, when it will not affect therapy
10. Neglecting to address pregnancy
kidney function (creatinine , 1.3 mg/dL), and the
relatively small number (90) of patients treated.
Interestingly, few have commented on the role of
azathioprine, to which the low-dose IV cyclophos-
phamide group was transitioned after 3 months. Rather
than being a comparison of high- versus low-dose IV
cyclophosphamide, this study compared ongoing IV
cyclophosphamide (high-dose group) therapy with
low-dose IV cyclophosphamide followed by azathio-
prine past the 3-month point (low-dose group).
Therefore, this study could be considered to be one
comparing high-dose cyclophosphamide to azathio-
prine after the 3-month mark.
More recently, mycophenolate mofetil (MMF) has
been studied as alternative induction therapy to IV
cyclophosphamide and may prove particularly effec-
tive in patients of African-Caribbean descent.
Initially, MMF was compared to oral cyclophospha-
mide in 42 patients.12,13 Patients received either
12 months of MMF (2 g/d for 6 months and then
1 g/d for 6 months) or 6 months of oral cyclophos-
phamide (2.5 mg/kg/d) followed by 6 months of oral
azathioprine (1.5 mg/kg/d). Both groups received
corticosteroids. Complete remission, partial remis-
sion, relapse rates, and rate of chronic kidney disease
(CKD) or end-stage renal failure were similar be-
tween groups. There was a trend for more infections
in the cyclophosphamide group, but it was not sta-
tistically significant.
This trial was followed by 3 randomized controlled
trials comparing MMF versus IV cyclophospha-
mide.14-16 One of the trials was an open-label crossover
noninferiority trial and at 24 weeks showed significantly
improved complete and partial remission rates in the
MMF group (goal induction dose of 3 g/d) compared to
the cyclophosphamide group.16 There was an increased
rate of pyogenic infection in the cyclophosphamide
group. The ALMS (Aspreva Lupus Management
668
Bose, Silverman, and Bargman
Study) induction therapy study showed similar
cumulative remission rates between both groups. The
renal and nonrenal outcomes were equivalent at 6
months.14 The 2 large trials comparing MMF versus IV
cyclophosphamide are summarized in Table 1.
These studies suggest that MMF is as effective as
IV cyclophosphamide as an induction agent for lupus
nephritis, with fewer adverse events such as gonadal
toxicity and secondary malignancy. MMF should be
considered as a first-line agent for induction, espe-
cially in young patients with lupus. Another consid-
eration is that with only 6 months of follow-up, it is
unclear how much of the effect is the result of high-
dose corticosteroid therapy given in each arm.
Going back to the pioneering study of Donadio et al17
published in 1978, corticosteroids alone led to the
same early remission rate compared to corticosteroid
in combination with a second immunosuppressive
agent. Studies of different immunosuppressive regi-
mens that have such a short follow-up (including
trials up to 6 months) may have the same overarching
effect of the corticosteroid, diluting or negating any
potential difference among secondary agents.
The other drug that is underused as an induction
agent is azathioprine. A pooled analysis of 8 studies
of lupus nephritis including 250 patients (including
children) was published in 1984.18 In this analysis,
113 patients received only corticosteroids and the rest
received corticosteroid with either azathioprine or
cyclophosphamide. Analysis showed that patients
who received azathioprine or cyclophosphamide with
corticosteroid had less kidney deterioration, were less
likely to have end-stage renal disease, and were less
likely to die of kidney disease than patients receiving
corticosteroid alone. There were approximately 60
patients in each group (prednisone vs cyclophospha-
mide/prednisone and prednisone vs azathioprine/
prednisone), and hence results of the study did not
reach statistical significance. The number of deaths in
the azathioprine group was lower than that in the
other 2 groups. Unfortunately, none of these studies
was a head-to-head comparison of 2 immunosup-
pressive agents. However, within the limitations of
this kind of analysis, azathioprine appeared to be a
useful induction agent in the management of diffuse
proliferative lupus nephritis.
Another widely held belief is that if the biopsy
shows very aggressive lupus nephritis, it mandates
treatment with a more toxic agent (IV cyclophos-
phamide). There is no reason to believe that more
aggressive disease requires therapy with a more toxic
drug. The combination of the 2 may be a recipe for
serious treatment-related side effects. When appro-
priate, less toxic drugs such as MMF or azathioprine
should be considered for induction instead of cyclo-
phosphamide. Furthermore, treatment with pulse IV
Am J Kidney Dis. 2014;63(4):667-676
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Mistakes in Treating Lupus Nephritis

Table 1. Two Large Studies Comparing MMF Versus IV Cyclophosphamide for Induction Treatment of Lupus Nephritis

Therapy Baseline SCr 24-h Urine

Study N (wk) Age (y) Race (%) Kidney Biopsy Class (%) (mg/dL) Protein (g/d) Intervention (n) Outcome

Ginzler15 140 24 31.5 6 9.5 White, 17; III, 15.5; IV, 54.5; 1.07 6 0.50 4.25 6 3.3 MMF, mean maximal MMF group:
(2005) black, 56.5; V, 19.5; mixed tolerated dose 2.6 g/d 1 CR, 22.5%;
Asian, 5.5; membranoproliferative, prednisone (71); IV CYC, PR, 29.6%; I
Hispanic, 20; 11.5 cumulative dose per V CYC group:
other, 1 patient 7,302 6 1,695 mg 1 CR, 5.8%;
prednisone (69) PR, 24.6%
Appel14 370 24 31.9 6 10.7 White, 39.7; III/III 1 V, 15.7; IV/IV 1 V, 1.13 6 0.90 4.1 6 3.7 MMF, median dose 2.6 g/d 1 Primary efficacy
(2009; Asian, 33.2; 68.1; V only, 16.2 prednisone (185); IV CYC, end point
ALMS) other, 27 median no. of doses, 6.0; achieveda in
median total dose per 56.2% of MMF
infusion, 0.75 g/m2 1 group; 53% of
prednisone (185) IV CYC group
Note: Conversion factor for SCr in mg/dL to mmol/L, 388.4.
Abbreviations and definitions: CR, complete remission defined as return to within 10% of normal serum creatinine levels, proteinuria, and urine sediment; CYC, cyclophosphamide; IV,
intravenous; MMF, mycophenolate mofetil; PR, partial remission defined as 50% improvement in all abnormal renal measurements without worsening (within 10%) of any measurement;
SCr, serum creatinine.
a
Primary efficacy end point: decrease in 24-hour urine protein to ,3 in patients with baseline nephrotic-range proteinuria ($3), or by $50% in patients with subnephrotic baseline
proteinuria (,3), and stabilization (625%) or improvement in SCr level at 24 weeks.
669

cyclophosphamide leads to an unpredictable nadir in
white blood cell count a week or 2 later. The leuko-
penia puts the patient at risk for infectious compli-
cations. This can be particularly fraught in the patient
with diminished glomerular filtration rate, for whom
even dose-adjusted IV cyclophosphamide can lead
to severe prolonged leukopenia. At least with cyclo-
phosphamide given as daily oral therapy, there is more
control over therapy dose and consequent leuko-
penia.19 However, these patients should be monitored
closely for bladder toxicity secondary to daily exposure
of oral cyclophosphamide.
2. IMPROPER DOSING OF CORTICOSTEROIDS
The National Kidney Foundation’s KDIGO (Kidney
Disease: Improving Global Outcomes) and other
guidelines (American College of Rheumatology and
the European League Against Rheumatism/European
Dialysis and Transplantation Association) recommend
an initial prednisone dosage of 1 mg/kg, with a slow
taper over 6-12 months.20 The guidelines also recom-
mend using low-dose prednisone (#10 mg/d) for
maintenance therapy, and for relapse, the same dose of
prednisone that was effective in inducing original
remission. Although the dose and duration of oral
corticosteroids have never been subject to evaluation
by randomized controlled trials, these current recom-
mendations seem to be effective in inducing and
maintaining remission.
However, it is our impression that most clinicians
focus their attention more on the second agent than on
the dose and duration of prednisone, and as a result,
many patients are treated with lower dose prednisone
that is tapered off quickly. This is due to concerns
related to the multiple side effects of prednisone.
Rapid tapering and/or discontinuation of prednisone
put patients at high risk for relapse. Some patients,
despite having a second agent, may need a prolonged
or even life-long course of low-dose prednisone to
maintain remission.
Similarly, in refractory lupus nephritis, more
attention is given to the second agent instead of the
prednisone dose. There are patients who, despite
changing their second agent, continue to be refractory
to therapy. These patients potentially could benefit
from increasing the dose of prednisone. (See also
nonadherence, discussed later.)
3. NOT USING ANTIMALARIAL AGENTS
ROUTINELY
Antimalarial agents such as hydroxychloroquine
have been used to treat mucocutaneous, musculo-
skeletal, serosal, and constitutional manifestations
of SLE. In randomized controlled trials and post
hoc analyses, hydroxychloroquine has been shown
to reduce the risk of damage accrual,21 improve
670
Bose, Silverman, and Bargman
survival,22,23 and decrease the frequency of lupus
flare.24,25 It also has been shown to improve kidney
outcomes. There is an increased probability of remis-
sion in patients with membranous nephritis treated with
MMF when combined with hydroxychloroquine26 and
also a lowered probability of decrease in kidney func-
tion if used prior to the onset of lupus nephritis.27
It retards the development of kidney damage in estab-
lished lupus nephritis28 and is safe to continue during
pregnancy.29
Despite all this evidence, the role of antimalarial
medications in the treatment of patients with SLE
is underappreciated in the nephrology community.
The probability of a patient with SLE receiving
an antimalarial agent is substantially decreased (odds
ratio, 0.51; 95% confidence interval [CI], 0.31-0.84)
if their primary lupus physician is a nephrologist
rather than a rheumatologist.30 Certainly in the
nephrology community, there has been a great deal of
discussion about what second agent to use, such that
insufficient emphasis has been given to ancillary
therapy, including long-term high-dose corticosteroid
therapy and antimalarial agents.
4. USING URINARY SEDIMENT FOR RESPONSE
CRITERIA
The panel convened by the American College of
Rheumatology to examine outcome markers in lupus
nephritis recommends using urinary sediment for
assessing response.31 According to the committee,
improvement was defined as changing from active
urinary sediment to inactive urinary sediment (eg, #5
red blood cells, #5 white blood cells, and no red blood
cell or white blood cell casts). They defined worsening
as active sediment in a patient who previously had
inactive urinary sediment and for which there were
no viable alternative explanations. The committee
defined active urinary sediment as .5 red blood cells
and .5 white blood cells per high-power field and/or
cellular casts where none existed previously.
However, in reality, the quantity of cells or casts
observed can be influenced by the duration of centri-
fuge time and how vigorously the pellet at the bottom
of the centrifuge tube is resuspended in the superna-
tant. We also know that some more benign processes
such as mesangial proliferation (class II nephritis)
can be associated with red blood cells and red blood
cell casts in urine, and these lesions do not require
immunosuppressive agents. Hence, using urinary
sediment for response criteria can be misleading and
can result in unnecessary use of potentially toxic
therapies. In our experience, this is recognized more
often by nephrologists than by rheumatologists.
However, guideline panels setting criteria for kidney
involvement in lupus unfortunately have a dearth of
nephrologists.32
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Mistakes in Treating Lupus Nephritis
5. NOT SCALING THE INTENSITY OF
IMMUNOSUPPRESSION TO THE DIFFERENT
CLASSES OF LUPUS NEPHRITIS, ESPECIALLY
CLASS V MEMBRANOUS LUPUS
Membranous lupus nephritis (MLN) accounts for
approximately 10%-20% of cases of lupus nephritis.33
Although the risk of decrease in kidney function is not
as great as that with the endocapillary proliferative
variants, up to 20% of patients with MLN require
dialysis or kidney transplantation within 10 years of
diagnosis.34-36 Kidney survival is only 50% in pa-
tients with MLN at 20 years,36 but a recent study
demonstrated kidney survival . 80% at 15 years.37
Furthermore, there is a sizable incidence of thrombo-
embolic events in patients with MLN.36,38 Thrombotic
events are associated with antiphospholipid anti-
bodies38 and nephrotic syndrome.36
High-dose alternate-day corticosteroid has been
used widely as the first-line agent. However, this
treatment regimen was derived from studies of
idiopathic membranous nephropathy and there is
little evidence that it works.39 Still, that does not
mean that daily corticosteroid therapy is not effec-
tive. A small (42-patient) randomized controlled trial
compared adjunctive immunosuppressive drugs with
prednisone alone.40 Adjunctive regimens included
either cyclosporine for 11 months or alternate-month
IV cyclophosphamide for 6 doses; the control group
received alternate-day prednisone alone. The study
showed that regimens containing cyclosporine or
IV cyclophosphamide were each more effective
than alternate-day prednisone alone in inducing
remission of proteinuria in patients with MLN. At
1 year, the cumulative probability of remission
of proteinuria was 27% with prednisone (4 of 15
patients), 60% with IV cyclophosphamide (9 of 15
patients), and 83% with cyclosporine (10 of 12
patients). Eight of the 10 patients who did not
respond to prednisone or cyclosporine or who
experienced a relapse after cyclosporine therapy was
stopped subsequently achieved remission when
treated with IV cyclophosphamide.
It is well known that the antiproteinuric effect of
calcineurin inhibitors tends to dissipate when the
calcineurin-inhibitor treatment is stopped. In the
aforementioned study, the agents were given for 11
months. Therefore, it is not surprising that there
were relapses at the 1-year mark in the group
receiving cyclosporine. Furthermore, although it is
widely recognized that corticosteroids alone were not
effective in this study, the steroid regimen was alter-
nate day. We have observed many patients with
membranous lupus enter remission on daily modest
(0.5-mg/kg) doses of corticosteroid, obviating the
need for more toxic therapy.
Am J Kidney Dis. 2014;63(4):667-676
A recent pooled analysis of 2 large, multicenter,
randomized, controlled trials in pure class V MLN
compared MMF versus IV cyclophosphamide for 24
weeks as induction therapy.41 Both groups received
high-dose daily prednisone. Patients in both groups
showed significant improvement in urinary protein
excretion and stabilization of serum creatinine levels.
Based on this finding, it was concluded that MMF
was as effective as IV cyclophosphamide to induce
remission in patients with class V MLN. However, it
is conceivable that the remissions were obtained
because of the sizable dose of corticosteroid, negating
an effect of a second agent. The authors concluded
that one second agent was as effective as the other,
but it may be the case that the corticosteroid regimen
was solely responsible for the remission. However,
meta-analysis of 24 studies of class V lupus nephritis
and nephrotic-range proteinuria showed that the
addition of an immunosuppressive agent to predni-
sone resulted in a significantly higher complete or
partial response rate than prednisone alone. However,
there was no statistically significant difference in
response rates among azathioprine, MMF, cyclo-
phosphamide, or cyclosporine.42
Class I and II lupus nephritis have minor abnor-
malities and excellent kidney outcomes and should
not by themselves be an indication for immunosup-
pressive treatment. Similarly, “burnt-out” class IV
lupus nephritis should be managed as in any patient
with CKD, focusing on blood pressure control and
other measures to delay progression.
6. MISSING NONADHERENCE TO THERAPY AS A
CAUSE OF TREATMENT FAILURE
A common concern in the medical field is whether
patients adhere to the regimen of care recommended
by the physician and the extent of their persistence
over time. According to research, the highest estimate
is that 50% of individuals with chronic disease comply
with the recommendations of their physicians, irre-
spective of disease, treatment, or age.43 Adherence and
persistence are low, even for patients who have dis-
eases that carry a high or moderate risk of death.44-46
Similarly, in SLE, nonadherence has been a critical
issue, especially when patients are exposed to medi-
cations such as corticosteroids that lead to cosmetic
side effects. Nonadherence should be strongly ex-
plored before escalating therapy in patients when they
are not responding to treatment. Suspicion should
arise when patients do not develop visible side effects
from steroids, such as cushingoid features, acne, and
weight gain, or cannot immediately state how many
pills they are taking every day. (As an example, if a
patient is taking 40 mg of prednisone every day, he or
she is counting out 8 tablets of 5 mg and therefore
should be able to immediately recall how many
671

prednisone tablets are taken). With the start of corti-
costeroid therapy, there is almost always a gratifying
improvement in hemoglobin level and lupus-related
serologic test results, much before improvements
in urinary indexes. If there is no change in hemoglobin
level early or in double-stranded DNA titers and com-
plement levels within 3-4 months, nonadherence
should be considered. The otherwise excellent KDIGO
guidelines discuss switching therapies for “treatment
failure” without addressing the possibility of non-
adherence as the cause.20
7. NOT REDUCING OR MINIMIZING
IMMUNOSUPPRESSIVE EXPOSURE IN PATIENTS
WITH ADVANCED KIDNEY DISEASE
In a patient with stage 4 or 5 CKD secondary to
lupus nephritis, a renal-limited flare might not warrant
another course of aggressive immunosuppressive
therapy. There will be significant scarring in the
kidney and the patient will have very little or no
benefit from another course of aggressive therapy.
The intensity of immunotherapy should be guided by
extrarenal manifestations.
For patients who are on dialysis therapy, the
immunosuppressive dose should be minimized, if
possible, because they are at a high risk of infection.
Immunosuppression is a risk factor for peritonitis in
peritoneal dialysis patients47 and also in hemodialysis
patients dialyzing through tunneled cuffed catheters.48
Although most patients with lupus have diminished
clinical and serologic activity after starting dialysis
therapy, some of them continue to have persistent
disease activity.49,50 Most flares in these patients are
extrarenal. Immunosuppressive dose should be altered
based on the clinical situation and, when possible,
minimized.
We strongly recommend that pulse cyclophospha-
mide therapy be avoided in patients with CKD
because of the unpredictable risk of severe leuko-
penia, even with reduced dose.
8. FORGETTING TO MONITOR SIDE EFFECTS
OF IMMUNOSUPPRESSION AND TO USE
PROPHYLAXIS
All the immunosuppressants used in managing
lupus nephritis have side effects that need close
monitoring and use of appropriate prophylaxis. Un-
fortunately, some of this recommended monitoring
gets overlooked and patients end up with significant
preventable health care problems.
The following are the commonly missed side
effects.
Osteoporosis
The prevalence of osteoporosis has been reported
to range from 4%-24% in patients with SLE and
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Bose, Silverman, and Bargman
10%-20% in premenopausal patients. The reported
prevalence of vertebral fractures in patients with SLE
has been reported to be as low as 7.6% and as high as
37%.51 The risk of fracture depends on the cortico-
steroid dosage and duration. The use of prednisone
for 3 months or more with up to just 2.5 mg/d leads to
a significantly increased fracture relative risk (RR)
of 1.55. Similarly, significantly increased fracture
risks for a dosage of 2.5-7.5 mg/d (RR, 2.59) and
dosages . 7.5 mg/d (RR, 5.18) have been reported.52
One study reported that there was a 7-fold increase in
hip fractures and 17-fold increase in vertebral frac-
tures when 10 mg/d of prednisone was used for more
than 90 days.53
Spinal bone mineral density is a significant pre-
dictor of new fractures in patients on corticosteroid
treatment. Thus, for each reduction point in T score,
the RR of fracture is 1.85 (95% CI, 1.06-3.21).52
New American College of Rheumatology recom-
mendations have suggested performing densitometry
in any patient who will use corticosteroids (preven-
tion) and in patients already on corticosteroid (treat-
ment) regardless of the dose and duration of
corticosteroid use.54 There currently are no guidelines
for the frequency of follow-up dual-energy x-ray
absorptiometry.
When supplemented with vitamin D, calcium has
been shown to significantly reduce the risk of verte-
bral fracture with no effect on nonvertebral frac-
tures.55 Although not currently in the American
College of Rheumatology guidelines, use of
bisphosphonates has been widely advocated in the
first 1-2 years of prolonged corticosteroid therapy.
However, after 2 years, there is a low-bone-turnover
state and bisphosphonates are not likely to be help-
ful and may be harmful.56 Relatively short-acting
oral bisphosphonates such as alendronate and risedr-
onate weekly are the drugs of choice for women
of child-bearing age. However, due to lack of suffi-
cient data, the safety of this drug is questionable in
this age group. Long-acting IV medications, such as
zolindronate, can be used in men or postmenopausal
women.
Patients with lupus using corticosteroids should
have regular bone mineral density scans obtained and
should be supplemented routinely with calcium and
vitamin D (1,000 IU/d). Bisphosphonates should be
added when appropriate. Other agents, such as ter-
iparatide (recombinant parathyroid hormone), should
be considered when bisphosphonates fail or are
contraindicated.
Patients with lupus with active disease may be at
particularly high risk for osteoporosis because active
SLE and corticosteroid therapy are important factors
leading to the high incidence of osteoporosis and
fractures in patients with SLE.
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Mistakes in Treating Lupus Nephritis
Ocular toxicity of antimalarial agents
Ocular side effects of antimalarial agents include
keratopathy, ciliary body involvement, lens opacities,
and retinopathy.57 There are a number of factors that
may contribute to the development of antimalarial
retinopathy, including daily and cumulative dosage,
length of treatment, whether there also is kidney or
liver disease, patient age, and concomitant retinal
disease. Daily dosage and cumulative dose are the
most important factors. The recommended dosage
is ,6.5 mg/kg/d, and this is in patients with normal
kidney function.58 It has been suggested that a
cumulative dosage . 100 g carries a significant risk
of retinopathy.59
Patients using these medications should have an
annual retinal examination. The only treatment for
ocular toxicity is cessation of treatment with the drug.
Pneumocystis jiroveci pneumonia prophylaxis
Patients who are on high-dose steroid therapy are at
higher risk of developing P jiroveci pneumonia
(pneumocystis pneumonia) because of depletion of
CD41 T cells.60 Human immunodeficiency virus
(HIV)-positive patients with pneumocystis pneumonia
(86%-92%) have better survival rates compared with
HIV-negative patients with pneumocystis pneumonia
with various underlying conditions (51%-80%).61
HIV-negative patients with pneumocystis pneumonia
appear to rapidly develop fulminant pneumonia with
severe oxygenation impairment, diffuse alveolar dam-
age, and respiratory failure.
Prophylaxis for pneumocystis pneumonia has been
shown to decrease mortality and morbidity signifi-
cantly. HIV-infected patients and kidney transplant
recipients have clear guidelines about when to start
prophylaxis and for how long. Unfortunately, there
are no clear guidelines for pneumocystis pneumonia
prophylaxis in patients with SLE on immunosup-
pression therapy. Hence, this easily can be missed,
putting these patients at risk of developing pneumo-
cystis pneumonia. We recommend following local
health care guidelines with regard to the prophylactic
agent of choice.
9. PERFORMING A BIOPSY ON THE KIDNEY,
ESPECIALLY IN A HIGH-RISK PATIENT,
WHEN IT WILL NOT AFFECT THERAPY
Diagnosis of lupus nephritis based on only clinical
features is not very reliable, emphasizing the need for
kidney biopsy. Histopathologic findings in lupus
nephritis can be very diverse and kidney biopsy not
only determines the diagnosis and prognosis, but
guides the management. Kidney biopsy also helps
rule out other kidney disease that may affect patients
of similar age and sex. These include renal thrombotic
Am J Kidney Dis. 2014;63(4):667-676
microangiopathy, acute tubular necrosis, drug-induced
interstitial nephritis, focal segmental glomerulo-
sclerosis, and immunoglobulin A kidney disease.
However, kidney biopsy has its own risk and
bleeding remains of foremost concern following a
kidney biopsy. Major complications, those requiring
blood transfusion or invasive intervention, have been
reported in 0%-6.4% of biopsies. Low hematocrit
and high creatinine values are predictors of compli-
cations. Patients with SLE have additional risks of
bleeding due to platelet dysfunction, hypertension,
and decrease in kidney function, although this has not
been proved in studies. Hence, biopsy should be
deferred if it is not going to change the present
management and also in situations in which the risk of
bleeding is very high (eg, in patients with elevated
serum creatinine levels or receiving anticoagulation).
A common scenario is the patient with lupus, either at
first presentation or with a major flare, presenting
with hypertension, pancytopenia (including throm-
bocytopenia), elevated serum creatinine level, hema-
turia, and nephrotic-range proteinuria in the context
of positive lupus serologic test results. Many clini-
cians feel compelled to perform a kidney biopsy,
although the comorbid conditions may render the
procedure high risk. It is obvious that the diagnosis is
lupus nephritis and mandates aggressive immuno-
suppression (measurement of serum antiphospholipid
antibody can help rule out renal thrombotic micro-
angiopathy). The kidney biopsy therefore is not going
to change the initial approach to therapy. Similarly, if
the patient presents with some extrarenal manifesta-
tion that mandates aggressive immunotherapy, such
as pulmonary hemorrhage, there is little to gain and a
lot to risk by performing a kidney biopsy when the
patient is going to receive aggressive therapy in any
case.
We do not see the value of repeat kidney biopsy
in patients with no significant change in clinical
parameters. A study by Arends et al62 confirmed that
a protocol repeat kidney biopsy does not offer much
additional information regarding long-term kidney
outcome after immunosuppressive treatment in pa-
tients with proliferative lupus nephritis. Not surpris-
ingly, a decrease in activity index from baseline to
biopsy at 2 years was associated inversely with time
to occurrence of renal relapse after 2 years, but the
chronicity index and activity index from repeat kid-
ney biopsies could not predict long-term renal
outcome. Therefore, repeat biopsy added very little to
clinical observation.
10. NEGLECTING TO ADDRESS PREGNANCY
Approximately 90% of patients with lupus are
women. When given the diagnosis of lupus, many are
concerned about becoming pregnant. Advising these
673

patients about pregnancy and managing them during
pregnancy can be challenging. It is important to
involve a high-risk obstetrician and a rheumatologist
who have experience in managing pregnant patients
with lupus.
Many patients with active lupus have no idea that
pregnancy at this time is fraught with risk for both
mother and fetus. It is incumbent upon the physicians
caring for the patient to counsel strongly against
conception during a lupus flare or persistently active
disease. Relatedly, practical advice about contracep-
tion also should be offered. Patients should be
screened for the presence of lupus anticoagulant prior
to the use of estrogen-containing birth control pills
because this combination is associated with a signif-
icant risk of thrombosis.
Many patients with lupus are able to have a suc-
cessful pregnancy. However, patients with lupus are
more likely to develop pregnancy complications
compared to the general population. The disease
needs to be in remission before the patient becomes
pregnant. A general recommendation is to avoid
pregnancy until at least 6 months after the lupus
disease activity, especially kidney disease, has been
completely brought under control.63 Appropriate
contraceptive advice should be given to patients when
their disease is not under control and while they are
receiving teratogenic medications such as MMF. A
switch from MMF to azathioprine should be made
well in advance, and then the go-ahead for pregnancy
should be given only if the patient still continues to be
in remission after the switch. Patients also should
come off treatment with medications that are not
safe in pregnancy, such as angiotensin-converting
enzyme inhibitors and angiotensin receptor blockers.
Corticosteroids, hydroxychloroquine, azathioprine, and
cyclosporine are acceptably safe to use during preg-
nancy, and their use must be weighed against the risk
of relapse during the pregnancy. It is recommended
that hydroxychloroquine treatment be continued during
pregnancy because there is a risk of flare upon its
cessation.
Patients also need be counseled about the potential
risk of stillbirth, fetal loss, intrauterine growth re-
striction, and prematurity. Women of child-bearing
age with lupus also should be screened for anti-
phospholipid antibody because it is associated with
fetal loss. We suggest referring these patients to ex-
perts who manage high-risk pregnant patients with
SLE.
ACKNOWLEDGEMENTS
Support: None.
Financial Disclosure: Dr Silverman is a consultant for Eli Lilly
and Glaxo Smith Kline. The remaining authors declare that they
have no relevant financial interests.
674
Bose, Silverman, and Bargman
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