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Indian Pediatr 2020;57: 401-406 |
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Management of Lupus Nephritis in Children
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Rebecca Scobell1 and Madhura Pradhan2
From 1Pediatric Nephrology and
2Clinical Pediatrics, Perelman School of Medicine
University of Pennsylvania, Children’s Hospital of
Philadelphia, PA, United States of America.
Correspondence to: Dr Madhura Pradhan, Children’s Hospital
of Philadelphia, PA 19104, USA.
Email:
[email protected]
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Lupus nephritis affects 50-75% of all
children with systemic lupus erythematosus with a higher
prevalence in Asians. It remains a major contributor to morbidity
and mortality in childhood onset lupus. Proliferative lupus
nephritis (class III and class IV) warrants aggressive treatment
to prevent progression to end stage renal disease. Newer
immunosuppressive agents available in the last decade offer more
options to treat lupus nephritis. Despite guidelines from
professional bodies, there remains a lack of consensus on the
treatment of refractory disease and duration of maintenance
therapy. We review the treatment options for pediatric patients
with lupus nephritis based on studies and published guidelines in
the last decade, and highlight opportunities for continued
improvement in care.
Keywords:
Glomerulonephritis, Induction, Immunosuppression, Maintenance.
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Childhood-onset systemic lupus erythematosus (cSLE) has
an incidence of 0.3 to 0.9 per 100,000 children-years and a
prevalence of 3.3-8.8 per 100,000 children with higher
prevalence rates in non-white populations including Asians
[1]. About 10-20% of cases of SLE are diagnosed during
childhood with a median age of onset of 11-12 years, and
these patients have increased disease severity and lower
survival rates [2]. Renal disease occurs in 50-75% of all
cSLE patients, mostly within the first two years of
diagnosis [2,3]. As per the American College of Rheumatology
(ACR) criteria, lupus nephritis is defined as persistent
proteinuria (>0.5 g/day or >3+ by dipstick) and/or cellular
casts in the urine. A spot urine protein/creatinine ratio of
>0.5 can be substituted for the 24-hour urine protein
measurement and an ‘active urinary sediment’ (>5 RBC/high
power field (hpf), >5 WBC/hpf in the absence of infection,
or cellular casts limited to red blood cells or white blood
cell casts) can be substituted for cellular casts [4].
Initial manifestations of renal disease range from minimal
proteinuria and hematuria to nephrotic-range, rapidly
progressive glomerulonephritis, severe hypertension, and
acute kidney injury. The frequency of nephritis in patients
with SLE is significantly higher in African Americans,
Asians (40-82%) and Hispanics than in whites (29%) and is
higher in men [5]. Nephritis is a major risk factor for
morbidity and mortality in SLE and 10% of patients with
lupus nephritis will develop end stage renal disease (ESRD)
with a higher risk in patients with more severe histological
classi-fication (44% over 15 years) [5].
As there
may be a lack of clinico-pathologic correlation, a renal
biopsy is the gold standard for diagnosis. Histopathology is
valuable in guiding treat-ment and a renal biopsy is
strongly recommended for all patients with clinical evidence
of lupus nephritis for classification of nephritis and
evaluation of activity and chronicity [6,7]. The
recommendations of the Inter-national Society of Nephrology
(ISN) and the Renal Pathology Society (RPS) revised in 2018
are currently used as the basis for the classification of
lupus nephritis [8,9]. In general, class I (minimal
mesangial) and class II (mesangial proliferative) nephritis
are mild lesions and require little to no targeted
immunosuppressive treatment due to a favorable natural
history. The Kidney Disease Improving Global Outcomes
(KDIGO) clinical practice guidelines suggest that treatment
for class I/II lupus nephritis be dictated by extra renal
manifestations; except that patients with nephrotic range
proteinuria receive steroid or calcineurin inhibitor (CNI)
therapy [10]. Class III (focal proliferative) and class IV
(diffuse proliferative) lesions are the most frequent and
severe findings in childhood lupus nephritis [2,11].
Patients with proliferative lesions have the highest risk of
ESRD and, thus, are treated with aggressive
immunosuppression [2]. Combination of class III or IV with
class V (membranous) lupus nephritis is prevalent and
treatment strategies used for proliferative nephritis should
be followed [10]. With current treatment regimens, the
incidence of ESRD in patients with proliferative lupus
nephritis has improved and the 5-year renal survival of
children ranges from 77-93% [12].
Goals of
Therapy
Therapeutic goals for the treatment
of lupus nephritis include achieving prompt renal remission,
avoiding flares, preventing chronic renal impairment,
improving survival and quality of life, and minimizing
iatrogenic effects. As short-term outcomes improve, more
attention is needed on balancing the risks of long-term
immunosuppressive exposure. However, it is important to
remember that failure to achieve and maintain remission of
nephritis reduces the rates of renal survival and overall
survival.
The treatment of proliferative lupus nephritis
is commonly divided into two distinct phases: induction and
maintenance. The induction phase is composed of intense
immunosuppression aimed at achieving remission with
resolution of active inflammatory changes. Consensus renal
response definitions in pediatric LN define substantial
response (complete remission) as normalization of renal
function, inactive urine sediment (<5 WBC/hpf, <5 RBC/hpf,
and no casts), plus spot protein/creatinine ratio <0.2 [13].
Induction is followed by a longer maintenance phase, during
which less intense immunosuppressive regimens are used to
sustain remission while attempting to minimize side effects
associated with medications. The widely used KDIGO practice
guidelines are based on adult data, but suggest that
pediatric providers follow the same treatment algorithms
[10]. In the absence of robust clinical trial data in
pediatric patients with proliferative LN, consensus
treatment plans have been developed by CARRA (Childhood
Arthritis and Rheumatology Research Alliance) for induction
therapy based on available scientific evidence and pediatric
rheumatology group experience with the goal of improving
prognosis by standardizing treatment plans [13].
INDUCTION THERAPY
The consensus
treatment plans for induction therapy recommend either
intravenous cyclophosphamide (IV-CYC) or mycophenolate
mofetil (MMF) along with steroids for a duration of 6 months
(Table I). Consensus was reached to administer a total of 6
monthly IV-CYC dosages (starting with 500 mg/m2 and
increasing based on tolerance and WBC nadir to a maximum
dosage of 1,500 mg). In the adult literature, this standard
dosing regimen (designated the NIH regimen) has been
compared to a low dose (or Euro-lupus) regimen which
consists of 500 mg IV-CYC every 2 weeks for 6 treatments
followed by initiation of maintenance therapy. These
regimens have shown a similar efficacy in the populations
studied and the ACR recommends this regimen for IV-CYC
induction in patients who are white with European background
[7]. The KDIGO guidelines also include option for oral
cyclophosphamide (1.0-1.5 mg/kg/day, maximum 150 mg/day) for
2-4 months [10]. MMF is recommended at a dose of 600
mg/m2/dose (maximum 1,500 mg) twice daily. This is similar
to European pediatric consensus dosing regimens (1200
mg/m2/day, maximum 2000 mg/day; when poor response option to
increase to maximum of 1800 mg/m2/day, maximum dose 3000
mg/day) [11]. African-Americans and Hispanics with lupus
nephritis may respond less well to IV-CYC than patients of
white or Asian races; thus, MMF is the preferred agent for
these populations [7]. Observational studies and a recent
single center trial from India suggest a comparable rate of
response with either IV-CYC (both dosing regimens studied)
or oral MMF [14–16]. However, one pediatric study in the
Indian population detected better efficacy of MMF compared
with IV-CYC induction [17].
Despite dramatic
variability of glucocorticoid prescribing practices, CARRA
consensus guidelines for induction provided three regimens
(primarily oral, primarily IV, and mixed oral/IV) with the
goal to achieve a daily dosage of oral glucocorticoids
between 10 and 20 mg upon completion of induction therapy at
24 weeks [13]. High dose IV methylprednisolone pulses (30
mg/kg/dose IV for three consecutive days, maximum 1000
mg/dose), but not oral glucocorticoids, have the potential
to eliminate the interferon–a gene expression signature in
cSLE, by reducing the number of plasmacytoid dendritic cells
and hence all regimen allow the use of this therapy, which
is invariably used for severe disease [13]. Most studies in
cSLE report the use of oral prednisone 1-2 mg/kg/day
(maximum 60 mg/day) with tapering schedule by 10-20% at one-
or two-week intervals based on clinical improvement [11].
Other immunosuppressive agents with some evidence
for efficacy include azathioprine, abatacept (in conjunction
with CYC), calcineurin inhibitors (CNI), (cyclosporine,
tacrolimus), and rituximab. CNI-based regimens have been
studied in Asia, and often combine MMF and steroids with a
CNI (‘multitarget therapy’). A large Chinese randomized
trial reported improved rates of complete and partial renal
remission at 24-weeks in patients treated with low-dose MMF,
tacrolimus, and steroids compared to monthly IV-CYC and
steroids for induction of proliferative LN [18].
Rituximab has generally been reserved as an adjunctive
therapy in patients with relapsed or refractory disease. To
date, prospective randomized controlled trials have failed
to show a significant benefit in clinical outcomes with the
addition of rituximab to standard of care induction therapy
[19]. However, one study in pediatric population
demonstrated significantly improved flare-free survival in
patients who received rituximab as induction therapy, as
compared to patients treated with CYC or MMF [17].
Furthermore, a systematic review of studies that documented
outcomes for patients with refractory lupus nephritis
suggests that rituximab effectively induced remission in
patients who had not achieved remission with standard
therapies [20]. There are clinical trials underway which
include children using rituximab as an induction agent.
Additionally, there are several other B cell directed
therapies which have recently shown promise in the treatment
of LN including other B cell depletion agents targeting
CD-20 (obinutuzumab, ocrelizumab), proteasome inhibitors
(bortezomib, ixazomib) which particularly affect plasma
cells, and B-cell activating factor (BAFF, also known as
B-lymphocyte stimulator (BLyS)) antagonists (belimumab,
tabalumab) [21].
ADJUNCTIVE THERAPY
The ACR and EULAR/ERA-EDTA recommend that all SLE
patients with nephritis be treated with a background of
hydroxychloroquine to improve outcomes by reducing renal
flares and limiting the accrual of renal and cardiovascular
damage [6,7]. Additionally, all patients with proteinuria
>0.5 g/day (or >0.5 urine protein/creatinine ratio) should
have blockade of the renin-angiotensin system to reduce
intraglomerular pressure unless otherwise contraindicated
[7,11]. Up to 80% of patients with SLE are treated with
non-steroidal anti-inflammatory drugs (NSAIDs) for extra
renal manifestations, mainly arthritis and serositis. These
medications can induce sodium retention and reduction in
GFR, and lupus nephritis is a risk factor for
hemo-dynamically mediated, NSAID-induced acute renal failure
[22]. However, while a safe dosing and duration of NSAID use
for extra renal manifestations in patients with lupus
nephritis has not been established, it is reasonable for
most patients to receive these medications if needed with
close monitoring of renal function and re-evaluation for
ongoing therapy on a regular basis.
MAINTENANCE THERAPY
The goal of maintenance
therapy is to prevent relapse and control the disease by
limiting inflammation and damage. Up to 50% of patients with
proliferative lupus nephritis relapse following
reduction/cessation of immuno-suppressive therapy. In the
adult population, the relapse rates range from 5 to 15 per
100 patient-years for the first five years of follow up
[22]. Incidence of flares in the Indian pediatric population
has been reported to be about 0.16 episodes/person/year with
median duration to onset of first flare of 29 months [23].
The ACR recommends either MMF (1-2 g/day) or azathioprine
(AZA) (2 mg/kg/day) and low dose steroid for the maintenance
phase of treatment [7]. European evidence-based
recommen-dations for treatment of childhood-onset lupus
nephritis also advise use of MMF or AZA as maintenance
therapy [11]. The KDIGO guidelines additionally suggest that
a CNI be used for maintenance therapy in a patient
intolerant of MMF or AZA [10]. Low dose oral prednisone is
continued to attain the minimum dose required for control of
extrarenal symptoms. Across different trials, the
maintenance prednisone dose ranged from 0 to 0.2 mg/kg/day
[24-26]. Two recent meta-analyses evaluating treatment for
proliferative lupus nephritis found that MMF was the best
therapy for maintaining remission and preventing kidney
failure during maintenance treatment [27,28]. AZA should be
used when MMF is contraindicated or following failure of MMF
therapy. Additionally, patients maintained on multitarget
therapy (tacrolimus and MMF) had similar rates of relapse to
the group that had received IV-CYC who were then maintained
on AZA therapy [29].
The ideal length of this
therapy phase is unknown, and regimens reported in the
literature vary from one to five years. In older literature,
stopping cyclophos-phamide abruptly was associated with a
rapid deterioration of renal function [30], but evidence
supporting timeline and withdrawal of currently accepted
maintenance regimens remains limited. The majority of
patients in trials were adults and the duration of the
maintenance phase varied widely, with a mean follow-up time
ranging from 18-36 months. The usual extended therapy dose
of MMF in adult patients is 1000 mg twice daily (or 1200
mg/m2/day with a maximum dose of 1000 mg twice daily)
[6,7,11]. The dose may be tapered in stable patients, but
there are no specific guidelines on the timeline of this
taper.
Common end points of trials evaluating
maintenance therapy include time to disease flare, doubling
of serum creatinine, or development of ESRD, and these
studies are designed to compare medication regimens. There
are no published randomized controlled trials designed to
prospectively evaluate duration of maintenance therapy;
however, a randomized clinical trial is underway to address
this specific question (Clinicaltrials.gov identifier
NCT01946880). Relatively small retrospective studies have
shown that some patients with proliferative lupus nephritis
who enter stable remission can be maintained without
immunosuppressive treatment for years [22,25]. One of the
larger studies to date evaluating duration of maintenance
therapy included 32 patients in whom therapy was
successfully withdrawn with a subsequent median follow up
period of 203 months. This study found that longer median
duration of treatment (57 months vs 30 months) and longer
duration of remission before withdrawal of therapy (median
24 months vs 12 months) were associated with decreased risk
of disease flare [25]. Thus, these authors recommended at
least five years of treatment prior to withdrawal of
therapy. However, when the decision to stop therapy was
made, four patients were receiving only low dose AZA (25-50
mg/day) and the other 28 were taking only low dose
prednisone, which is less therapy than the standard
maintenance regimens at this time.
In the most
recent ACR guidelines, the task force panel did not vote on
the rate of medication taper during the maintenance phase
given the lack of adequate data [7]. Consensus documents
have indicated a minimum duration of three years [6,11].
Beyond this time period, there is little data to guide
treatment and consensus statements suggest that continuing
treatment for longer should be individualized with an effort
first to withdrawal glucocorticoids [6]. A re-biopsy has
been suggested in those patients with sustained remission to
verify histologic remission prior to discontinuing
immuno-suppression [5]. Most of the published studies in
which immunosuppression was either minimized or stopped
originated in Europe, therefore these findings cannot
necessarily be extrapolated to patient groups with different
ethnic backgrounds [22].
CONCLUSION
Advances in immunosuppressive medications have
resulted in improved renal survival and quality of life in
pediatric patients with lupus nephritis. Newer agents such
as MMF are effective as induction therapy, though with
variation amongst different ethnic groups. The duration of
maintenance therapy is a particularly important question in
pediatric onset lupus nephritis given the potential for
cumulative immunosuppressive medication exposure over time.
Currently, there is little data to guide duration of
treatment beyond three years in patients with
well-controlled disease. Consensus statements support
tapering medication around this time point with the initial
goal of withdrawal of glucocorticoids. Although reducing
rates of renal flares is important in preventing
disease-related morbidity and mortality in patients with
cSLE and lupus nephritis, a period without corticosteroids
and immunosuppressive therapy could be particularly useful
for preventing iatrogenic morbidity.
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