New Recommendations for the Management of Lupus Nephritis

VBCR - September 2012, Volume 1, No 4 - Lupus

By Mary Mosley

New recommendations for the management of lupus nephritis (LN) call for a renal biopsy at the earliest sign of kidney dysfunction to guide the use of immunosuppressive treatment in patients with systemic lupus erythematosus (SLE). The goal for treatment is a complete renal response, defined as proteinuria <0.5 g per 24 hours, with normal or near-normal renal function.

Nearly one half of patients with SLE will develop LN, and the presence of LN increases the risk for renal failure, cardiovascular (CV) disease, and death.

The recommendations were issued jointly by the European League Against Rheumatism and European Renal Association and the European Dialysis and Transplant Association (EULAR/ERA-EDTA) for the management of adult and pediatric LN (Bertsias GK, et al. Ann Rheum Dis. Epub 2012 Jul 31).

The 32-member panel that developed the recommendations included internists, rheumatologists, and ne­phrologists, all of whom are involved in the care of patients with LN, as well as renal pathologists and pediatricians with LN expertise.

The 28 final recommendations are based on the results of a systemic literature review and expert opinion. The literature review included English-language articles published up to December 2011, including some recent controlled clinical trials that prompted this new set of recommendations related to the diagnosis, monitoring, prognosis, and treatment recommendations for patients with LN. The mean and median ratings by the committee for each recommendation are detailed in the article, in addition to the level of evidence and the strength of the recommendation.

Indications for First Renal Biopsy
There is a low threshold for performing a renal biopsy in patients with SLE, according to the new recommendations, because of the “po­ten­tially aggressive nature of LN.” The panel states that this should be done within a month of disease onset, and preferably before immunosuppressive therapy is initiated, but that high-dose glucocorticoid treatment should not be delayed if the biopsy must be delayed.

Clinical, serologic, and laboratory tests should not be relied on, because of their inability to predict histologic findings.

Indications for biopsy are the sign of any renal involvement, including reproducible proteinuria ≥0.5 g per
24 hours, especially in the presence of glomerular hematuria, cellular casts, or both. Other settings for which biopsy could be considered include persisting isolated glomerular hematuria, isolated leukocyturia, and unexplained renal insufficiency with normal urinary findings. Of note, the panel states that the renal biopsy should be performed in the first month after disease onset.

The pathologic assessment of the renal biopsy should include active and chronic changes of the glomerulus and the renal and interstitial tubules, as well as vascular lesions that are associated with antiphospholipid antibodies or the antiphospholipid syndrome. The 2003 classification system from the International Society of Nephrology/Renal Pathol­ogy Society should be used.

Immunosuppressive Therapy
Treatment decisions should be made jointly by the patient and physician. The treatment goal is a complete renal response, with a partial renal response—≥50% reduction in proteinuria to subnephrotic levels, and a normal or near-normal glomerular filtration rate (GFR)—achieved preferably by 6 months, and at least by 12 months.

The panel provides detailed information for defining and managing nephritic and proteinuric flares, which can occur after a renal re­sponse; nephritic flares have a more negative effect on renal outcomes.

Initial Agents in Adults
Experienced clinical centers are preferred for treating and managing patients with LN. Immuno­suppres­sive treatments discussed in the recommendations include myco­phenolic acid sodium (MPA), myco­phenolate mofetil (MMF), enteric-coated myco­phenolic acid sodium (eMPA), cyclo­phos­phamide (CY), azathioprine (AZA), and intravenous methylprednisolone (MP).

The major recommendations for initial therapy in adults are:

  • MPA or low-dose CY is recommended as initial therapy for most cases of class III to IV LN, based on the results of the Aspreva Lupus Man­agement Study (ALMS), the largest study in patients with LN. The panel notes, however, that long-term efficacy and safety data (>5 years) are lacking for MPA. The ALMS study showed that the response rates for 6 months of MPA (target MMF dose, 3 g/day) and intra­venous CY (monthly pulses, 0.5-1 g/m2) were comparable.
  • MMF and eMPA are “likely to be equally efficacious,” according to the panel, and either MPA formulation can be used until the limited data for this recommendation are validated. An eMPA dose of 720 mg is roughly equivalent to a 1-g dose of MMF.
  • There are some differences in efficacy and toxicity related to ethnicity. For Caucasians with class III to IV LN, and perhaps class V LN, low-dose intravenous CY (total dose, 3 g over 3 months) combined with glucocorticoids (0.5 mg/kg daily) is recommended for initial therapy. MPA may be more effective in patients of African descent, based on subgroup analyses of 2 studies; however, the panel stated that more evidence is needed to make a recommendation in this regard.
  • For pure class V LN, with proteinuria in the nephrotic range, MPA combined with oral glucocorticoids is recommended as initial therapy for most patients (MMF target dose, 3 g daily for 6 months). MPA was shown to have an antiproteinuric effect that is similar to the effect of high-dose intravenous CY, based on the combined analysis of 2 clinical trials. MPA also has a better gonadal toxicity profile.
  • In patients with impaired renal function or crescents, MPA can be used, based on evidence from post hoc analysis (in patients with baseline GFR <30 mL/min/1.73 m2) from the ALMS study and 2 studies in severe histologic forms of LN.
  • AZA is recommended only for pa­tients with class III or IV LN with preserved renal function and no evi­dence of adverse histologic findings.
  •  Intravenous MP pulses to decrease the cumulative dose of glucocor­ticoids are recommended, based on ex­tra­polation from controlled studies.

Subsequent Therapy in Adults
MPA is recommended for continued therapy if the patient responded to initial therapy with this drug. For selected patients with preserved renal function, calcineurin inhibitors may be considered.

The lack of data beyond 3 years requires physicians to individualize treatment, “with an effort first to withdraw glucocorticoids before immunosuppressive agents,” the panel stated.

Monitoring, Prognosis of Lupus Nephritis
LN requires lifetime monitoring, approximately every 3 to 6 months. After LN is initially diagnosed or flares occur, patients should schedule office visits every 2 to 4 weeks for the first 2 to 4 months; thereafter, the frequency should be based on the re­sponse to treatment.

The parameters to be assessed at each visit include:

  • Serum creatinine
  • Estimated GFR
  • Serum albumin
  • Proteinuria
  • Urinary sediment
  • Serum complement component 3 (C3) and C4
  • Serum anti–double-stranded DNA antibodies.

Predictors of long-term outcomes in LN are changes in serum creatinine, proteinuria, hemoglobin levels, and blood pressure. Repeat renal biopsy should be reserved for selected cases.

Other Guidance
The diagnosis, management, and monitoring of LN children are similar to that for adults. However, LN is more severe in children, who in gen­eral have more renal damage and receive more intensive immunosuppressive treatment.

End-stage renal disease will develop within 15 years in approximately 10% to 30% of patients with LN, even with immunosuppressive treatment. Patients with LN can be candidates for renal transplantation if lupus activity is absent or is at a low level for 3 to 6 months.

The EULAR/ERA-EDTA recommendations also include guidance for refractory LN, LN in pregnant women and women who are planning to be­come pregnant, and adjunctive therapy for any CV disease or CV risk factors.

The panel also presents a 9-item research agenda, including the need for evidence supporting the long-term efficacy and safety of MPA, evidence for switching regimens after treatment failure, and the need for randomized controlled trials in children with LN.

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Last modified: May 21, 2015
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