LN Is Among the Most Severe and Dangerous Complications of Systemic Lupus Erythematosus (SLE)1,2
SLE Affects Approximately 200,000 to 300,000 Patients in the United States7-11
ONLY
42%
of patients with SLE are screened for LN12,a
UP TO
60%
of patients with SLE develop LN13
87%
of patients with LN are class III, IV, or V2
ONLY
42%
of patients with SLE are screened for LN12,a
UP TO
60%
of patients with SLE develop LN13
87%
of patients with LN are class III, IV, or V2
By the time LN is diagnosed, irreversible kidney damage may already be present.14
UP TO
30%
of patients with LN progress to end-stage
renal disease within 15 years of diagnosis3
45x
increased risk of kidney failure once
diagnosed with LN2,b,c
32.8
YEARS
mean age of patients with LN who
submitted to kidney transplantation15
aPatients with SLE without LN.
bAs compared with patients with SLE without LN.2
cAnalysis of Systemic Lupus International Collaborating Clinics inception cohort of newly diagnosed patients enrolled between 1999 and 2012, who were followed for a mean of 4.6 years. A total of 1827 patients were recruited, of whom 700 had LN over the course of follow-up.2
Proteinuria Is a Significant Risk Factor for Kidney Damage16,17
Even low levels of proteinuria may be associated with significant kidney damage14
- Patients with proteinuria <0.5 g/day had a median chronicity index of 2 (range: 0-4)14
- Proteinuria level at 12 months is a predictor of long-term renal outcomes18,d
- Levels of proteinuria 0.5-0.8 g/day predict long-term renal outcomes, including 15-year CKD-free survival18-20
Did you know? Even mild clinical presentations (eg, subnephrotic proteinuria) can be associated with active histological lesions21,22
Nearly 90%
of patients with proteinuria <0.5 g/day have been reported to have class III or IV (±V) LN on biopsy14
Histologic Findings at Biopsy in Patients With SLE14,e-g
Even a Single Flare of LN Can Reduce the Lifespan of the Kidney6
Nephron Loss and LN
Adapted with permission from Anders HJ et al. Nature Reviews Disease Primers. 2020;6(1):7.
- A single flare of LN can cause irreversible nephron loss, potentially shortening the lifespan of the kidneys by decades6
- Every subsequent flare contributes to the accrual of kidney damage, further shortening kidney lifespan and increasing the risk of adverse long-term outcomes such as ESKD6
- Nephron loss and podocyte damage often lead to protein leakage into the urine6,23
- Proteinuria as a marker of kidney damage routinely precedes eGFR decline6,16
Early and definitive treatment is crucial to preserving nephron loss6
dRetrospective analysis conducted to determine if proteinuria was a good predictor of renal outcomes in a racially diverse group of patients with severe LN. A total of 107 patients with biopsy-proven LN with at least 7 years of available longitudinal follow-up data were selected for the study, of which 94 patients diagnosed with end-stage renal disease after the first year of follow-up were enrolled. Poor long-term renal outcome was defined as serum creatinine ≥1.5 mg/dL at the 7-year follow-up, and good renal outcome was serum creatinine <1.5 mg/dL. Kaplan-Meier curves were used to assess renal survival using the proposed proteinuria cutoff of <0.8 g/24 hours at 12 months.18
eFrom a study of 222 patients with SLE who underwent kidney biopsy for suspicion of LN.14
fPercentage of patients with ISN/RPS class III or IV (± V), or V with proteinuria <0.5 g/day calculation: ([14 + 21 + 2 + 4 + 0]/46) x 100 = 89.1%.14
gPercentage of patients with ISN/RPS class III or IV (± V), or V with proteinuria ≥0.5 g/day calculation: ([18 + 135 + 3 + 19]/176) x 100 = 99.4%.14
Proteinuria Reduction Is Associated With Long-Term Renal Protection24
The larger the initial reduction in proteinuria in the first several months of management, the lower the risk of ESKD24
Kidney Survival Based on Proteinuria Response Status24,h
Adapted with permission from Chen YE et al. Clinical Journal of the American Society of Nephrology. 2008;3(1):46-53.
The Need Remains for Additional Treatment Options5
MMF + Steroids Induction Response at 24 Weeks25,i,j
MMF + steroidsk alone frequently fail to substantially reduce proteinuria, with only 20%-30% of patients achieving a complete response at 1-2 years5,26
hRetrospective analysis of patients (N=86) enrolled in the prospective controlled trial of plasmapheresis in severe LN to determine long-term prognosis of achieving partial response. Complete response was defined as SCr ≤1.4 mg/dL and proteinuria ≤0.33 g/day within 5 years of study entry, and partial response was defined as ≤25% increase in baseline SCr and ≥50% reduction in baseline proteinuria to ≤1.5 g/day (but >0.33 g/day) within 5 years of entering the study. Kidney survival was determined by kidney failure (≥6 mg/dL SCr or the initiation of kidney replacement therapy).24
iPercentage of patients with partial response calculations: 56.2% – 8.6% = 47.6%.25
jPercentage of patients with no response calculations: 100% – 56.2% = 43.8%.25
kIn the Aspreva Lupus Management Study, MMF (data presented here) and intravenous cyclophosphamide (data not shown) were compared, both with steroids, as induction treatment in patients with class III, IV, and V LN (N=370). Primary endpoint was response at 24 weeks. Response was defined as a decrease in UPCR to <3 mg/mg in patients with baseline nephrotic proteinuria (≥3 mg/mg), or by ≥50% in patients with subnephrotic baseline proteinuria (<3 mg/mg), and stabilization (±25%) or improvement in SCr as adjudicated by a blinded Clinical Endpoints Committee. Complete response was a secondary endpoint defined as return to normal SCr, urine protein ≤0.5 g/day, and inactive urinary sediment (≤5 WBC/hpf and ≤5 RBC/hpf, and a reading of lower than 2+ on dipstick and absence of red cell casts).25
Guideline Recommendations for LN
Vigilance Around Suspected Kidney Involvement
Strive for early LN identification, given the repercussions of delaying diagnosis
At every visit, implement vigilant screening and monitoring for kidney involvement
Once identified, consider early intervention with multitarget treatment regimen
Management Goals to Optimize Kidney Function
Treat to targetl:
- Reduce proteinuria by ≥25% at 3 months and ≥50% at 6 months
- Reduce urine protein <0.5-0.7 g/day at 12-24 months
Reduce steroid exposure: Quickly taper steroid dose to ≤5 mg/day
Management should be continued once complete response is achieved for at least 3 years
EULAR Guidelines: Recommended Management Targets for LN5
lAll with eGFR within 10% of baseline.5
ACR=American College of Rheumatology; CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate; ESKD=end-stage kidney disease; EULAR=European Alliance of Associations for Rheumatology; hpf=high-power field; ISN/RPS=International Society of Nephrology/Renal Pathology Society; MMF=mycophenolate mofetil; RBC=red blood cell; SCr=serum creatinine; SLE=systemic lupus erythematosus; UPCR=urine protein-to-creatinine ratio; WBC=white blood cell.
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