Managing Lupus Nephritis: The 2012 ACR Way

A third of patients with Systemic Lupus Erythematosus (SLE) may already have renal involvement by the the time the condition is diagnosed. And over the next 10 years, a total of 50-60% of patients would have lupus nephritis (i.e. an additional 20-30% of patients would develop it subsequently! That is why physicians should always evaluate renal function every clinic visit.) And as I always tell residents and patients alike, if lupus nephritis is not properly managed, the condition may progress to end stage renal disease in a span of two years. It therefore comes as no surprise that there would be separate guidelines on the screening and management of lupus nephritis from the American College of Rheumatology.
HOW TO WE DIAGNOSE LUPUS NEPHRITIS
Based on the ACR Classification Criteria for SLE, renal involvement is defined by the presence of (1) proteinuria detected by dipstick (at LEAST +3) or 24 hour urine collection (>0.5g/24 hours); or, (2) the presence of cellular casts including RBC, hemoglobin, granular, tubular or mixed. A review of ACR criteria has also lead to the acceptance of a spot urine protein/ creatinine ratio >0.5 as a surrogate for the 24 hour urine collection. Likewise, “active urinary sediment” has been defined as >5 RBC or WBC/hpf in the absence of infection (Pop Quiz! How would you then differentiate whether the pyuria or hematuria detected on urinalysis is due to infection or SLE?). Perhaps, the optimal way to diagnose lupus nephritis is via renal biopsy specimen demonstrating immune complex GN compatible with SLE. An interesting definition included in the 2012 ACR Guidelines is that a diagnosis of lupus nephritis (LN) should be considered valid if based on the opinion of a rheumatologist or nephrologist.
WHO SHOULD UNDERGO RENAL BIOPSY FOR LN
Based on the recommendations, all patients with clinical evidence of active LN (as defined above), previously untreated, should undergo renal biopsy unless strongly contraindicated (Level C). This is to allow classification of the type of renal involvement which would determine prognosis, disease course and appropriate treatment. Furthermore, renal biopsy would allow evaluation of activity and chronicity and to determine the presence of problems outside of the glomeruli – such as tubular and vascular pathologies. And likewise, the renal biopsy may reveal alternative or additional causes of renal disease such as drug-induced tubular necrosis, hypovolemia and hypotension.
Aside from determining the lupus nephritis classification, renal biopsies should also be performed in the following settings (all Level C):
  • Increasing serum creatinine without compelling alternative causes
  • Confirmed proteinuria >1g/24 hours
  • Combinations of the following, assuming the findings are confirmed in at least 2 tests done within a short period of time and in the absence of alternative causes: (a) proteinuria >0.5g/24 hours and >5 RBC/hpf or (b) proteinuria >0.5g/24 hours and >5 WBC/hpf

HOW DO WE CLASSIFY LUPUS NEPHRITIS

Where as previously we used the WHO Classification of Lupus Nephritis, the current guidelines recommend using the 2003 International Society of Nephrology/ Renal Pathology Society (ISN/ RPS) Classification (Level C).
  • Class I Minimal Mesangial LN (previously WHO Class IIA)
  • Class II Mesangial Proliferative LN (previously WHO Class IIB)
  • Class III Focal LN (previously WHO Class III)
  • Class IV Diffuse Proliferative LN (previously WHO Class IV)
  • Class V Membranous LN (previously WHO Class V)
  • Class VI Advanced Sclerosing LN (previous WHO Class VI)
There may be instances when renal biopsy may reveal features suggestive of different classes of LN (i.e. mixed Class III and V, Class IV and V, etc). In such cases, treatment should follow the more severe forms of LN (i.e. Class III and IV).
In general, the guidelines suggest that those with Class I and II LN generally do not require immunosuppresive treatment (i.e. steroids would suffice) (Level C).
ADJUNCTIVE MEASURES
Aside from treating LN, the clinician should also pay attention to the following concerns/ problems of the patient.
  • All patients with LN should be treated with hydroxychloroquine (HCQ) unless there is a contraindication (Level C). Controlled trials and recent cross-sectional and prospective data have shown that treatment with hydroxychloroquine resulted in lower rates of SLE flares, lower damage (including renal) accrual, and reduced risk of clotting events.
  • All LN patients with proteinuria >0.5g/24 hours (or equivalent measures) should have blockade of the renin-angiotensin system which drives intraglomerular pressure (Level A). Treatment with either ACE inhibitors or ARBs reduce proteinuria by 30% and may delay both the doubling of serum creatinine and the progression to ESRD.
  • In LN patients with hypertension, the target for BP control is <130/80 mm Hg (Level A). This helps delay progression of renal disease.
  • Statins should be given in all LN patients with LDL-cholesterol levels >100mg/dl (Level C). It has been shown that reduced GFR (<60ml/min) is a risk factor for accelerated atherosclerosis. Likewise, SLE by itself is an independent risk factor for accelerated atherosclerosis.
  • All LN patients of child-bearing potential should receive counseling regarding pregnancy risks conferred by the disease and its treatments (Level C).
STARTING TREATMENT FOR LUPUS NEPHRITIS CLASS III/IV
Induction treatment of Lupus Nephritis Class III/IV entails the use of either mycophenolate mofetil (MMF) or cyclophosphamide (CYC) along with glucocorticoids (GC). (Level A)
 
Glucocorticoids. The Task Force Panel (TFP) recommends initiating treatment with Pulse IV GC (methylprednisolone 500-1000mg daily for three doses) followed by daily oral GC (equivalent to prednisone 0.5-1.0 mg/kg/day) which will be eventually tapered to the minimal amount necessary to control disease activity. Here is where the biopsy results would be important. If crescents are present on biopsy, the higher dose (1 mg/kg/day) would be used following pulse GC. Otherwise, we may use prednisone 0.5 mg/kg/day.
 
Mycophenolate Mofetil. MMF has been shown in high quality studies, a meta-analysis and expert opinion to be equivalent to cyclophosphamide although long-term data are not as abundant. MMF may be preferred over CYC when fertility issues are a concern for young women with LN.
MMF should be started a total daily dose of 3 grams. Fortunately, for Asians, a lower dose of 2 grams/day may be used as induction therapy (Level C).  However, the exact scenarios wherein the different doses of MMF can be used are as follows: (1) For those with Class III/IV LN without cellular crescents OR for LN with proteinuria and stable creatinine but a biopsy could not be performed BOTH the 2g and 3g daily dose are acceptable. (2) For those with Class III/IV LN and cresents OR for LN with proteinuria and a recent significant rise in creatinine but a biopsy could not be done the 3g daily dose is preferred.
For those patients who develop nausea and diarrhea on MMF, mycophenolic acid (MPA) may be an alternative. The equivalent doses are 2g MMF = 1440 mg MPA and 3g MMF = 2160 mg MPA.
 
Cyclophosphamide. Two regimens of IV CYC are available: (1) The low dose “Euro-Lupus” protocol of 500 mg given every 2 weeks for 6 doses (Level B); and, (2) The high-dose “NIH” protocol of 500-1000 mg/m2 BSA given once a month for 6 doses (Level A). Both regimens are to be followed up with treatment with either MMF or azathioprine (AZA). There is a higher level of evidence for the NIH Protocol – it being the standard used for the longest period of time.
 
Azathioprine. AZA has also been used as induction therapy for patients with LN. However, long term studies have shown AZA to be less effective than CYC in inducing improvement, in preventing flares of LN and in delaying progression of chronic lesions on renal biopsy.
STARTING TREATMENT FOR LUPUS NEPHRITIS CLASS V
For patients with pure Class V LN and nephrotic range proteinuria, treatment should be started with oral GC (prednisone 0.5 mg/kg/day) and MMF 2-3g/daily. This is to be given for at least 6 months. (Level A)
ASSESSING FOR RESPONSE
The TFP recommends that most patients be followed up for 6 months after initiating treatment with either MMF or CYC before making any major changes in treatment, other than altering the GC dose (Level A). Parameters that indicate improvement include (1) reduction or normalization of serum creatinine; (2) improvement of proteinuria to <1 g/24 hours; and, (3) normalization of C3 and/or C4 serum levels. Other parameters that indicate improvement as early as 2 months/ 8 weeks include: (1) >25% reduction in proteinuria and (2) normalization of serum C3 and C4 levels.
However, a decision to shift to another treatment may be made as early as 3 months if there is clear evidence of worsening such as 50% or more worsening of either the serum creatinine or proteinuria. (Level A)
CHANGING THERAPIES FOR THOSE WHO DON’T RESPOND
If after 6 months of treatment and there is no evidence of satisfactory response or there is worsening at 3 months or 6 months, the guidelines suggest a switch of immunosuppressive agent from either CYC to MMF or from MMF to CYC. This changes are to be accompanied by again giving IV pulses of GC for 3 days. (Level C)
Likewise, rituximab (RTX) can be used for patients who fail to improve or worsens after 6 months of one induction therapy, or after the patient has failed both CYC and MMF (Level C). Another alternative for those who fail treatment with both CYC and MMF is to use in combination MMF and calcineurin inhibitors.

MAINTAINING RESPONSE AFTER INDUCTION THERAPY

Whether the patient has Class III, IV or V LN, following satisfactory induction therapy, the guidelines recommend either AZA or MMF be used for maintenance therapy (Level A). MMF may be given as 1-2 g daily dose while AZA is given at 2 mg/kg/day. However, MMF is superior to AZA with regards to time to treatment failure (a composite index consisting of death, ESRD, doubling of creatinine and renal flare) and in each element of the composite score.  Furthermore, severe adverse events occurred more frequently in those receiving AZA than in those who were given MMF. Unfortunately, there is inadequate data as to how rapidly AZA or MMF can be tapered and withdrawn. But based on initial controlled trials, either drug were given for at least 2 years.
LUPUS NEPHRITIS IN THE PREGNANT PATIENT
There are several approaches to managing lupus nephritis in a pregnant patient (all Level C):
  • If with prior history of LN but no current evidence of systemic or renal disease activity, no nephritis medications are necessary.
  • If with prior history of LN and evidence of mild systemic activity, patients may be treated with HCQ.
  • If clinically active LN is present, and there is significant extra-renal disease activity, GC at doses necessary to control disease activity may be given. And if necessary, AZA may be added.
  • For those with persistently active LN with documented or suspected Class III or IV with crescents, consider early delivery once the fetus is viable.
MONITORING THE LUPUS PATIENT FOR NEPHRITIS
  • No prior or current LN – BP every 3 months, urinalysis, spot urine protein/ creatinine, serum creatinine, serum C3 and (quantitative) dsDNA every 6 months.
  • Active nephritis, at onset of treatment – BP, urinalysis, spot urine protein/ creatinine, serum creatinine every 1 month, serum C3 every 2 months and (quantitative) dsDNA every 3 months.
  • Previously active LN, none currently – BP, urinalysis, spot urine protein/ creatinine, serum creatinine, serum C3 every 3 months and (quantitative) dsDNA every 6 months.
  • Pregnant with active LN, at onset of treatment – BP, urinalysis, spot urine protein/ creatinine, serum creatinine, serum C3 and (quantitative) dsDNA every 1 month.
  • Pregnant with prior LN, none currently – BP, urinalysis every 1 month,  spot urine protein/ creatinine, serum creatinine, serum C3 and (quantitative) dsDNA every 3 months.
Reference:  Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology Guidelines for Screening, Treatment and Management of Lupus Nephritis. Arth Care and Res June 2012; 64 (6): 797-808.
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