Lupus Nephritis treatment-current consensus

Dr. Vishal GolayIPGME&R

FANA

Case Definition of Lupus NephritisACR definition:

– persistent proteinuria >0.5 g/d or >3+ by dipstick, and/or – cellular casts including RBCs, Hb, granular, tubular, or mixed).

Additional recommendations by ACR:– Urinary PCR >0.5– “active urinary sediment” (>5 RBCs/hpf, >5 WBCs/hpf in the

absence of infection, or cellular casts limited to RBC or WBC casts) can be substituted for cellular casts.

– Optimal would be a histological demonstration.– ACR Core Executive Panel- diagnosis of LN should also be

considered valid if based on the opinion of a rheumatologist or nephrologist.

Lupus 2004;13:857–60.

Indications of renal biopsy• Low threshold.• Any sign of renal involvement.• Lowering of GFR (formulas like CG, MDRD, Schwartz are not

fully validated in SLE).

• Biopsy within 1 month of disease onset preferably before immunosuppression.

• But, high dose GC should be given if there will be a delay in HPE.

ACR Recommendations

• The importance of early biopsy and start of treatment as a prognostic factor for LN has been shown in many studies.

• Data show that clinicians tend to wait for HPE of severe LN before initiating immunosuppression. This treatment delay is critical for the prognosis of LN.

J Rheumatol2006;33:1563–9.

Renal Biopsy in LN

• ISN/RPS 2003 classification is uniformly accepted.

• At least 8 g should be examined by LM with H&E, PAS, Masson’s Trichrome & Silver stains. IF for IgG, IgA, IgM, κ and λ.

• EM can be used(if possible) for recognition of prolif and membranous lesions.

• Chronicity and activity scoring to be done. Vascular lesions s/o APLA should be looked for.

Chronicity index (0 to 3+ each, total of 12)

1. Glomerulosclerosis, 2. Fibrous crescents, 3. Tubular atrophy, and 4. Interstitial fibrosis

Activity index (graded on a scale of 0 to 3+ for each); total of 241. Endocapillary

proliferation, 2. Glomerular leukocyte

infiltration, 3. Wire loop deposits, 4. Fibrinoid necrosis and

karyorrhexis (X2), 5. Cellular crescents (X2)6. Interstitial inflammation

AI >12 and CI >4 has poor 10 year renal survival

NIH Disease activity scoring system

Goals of immunosuppressive Rx

– Long-term preservation of renal function, – Prevention of flares, – Avoidance of treatment-related harms, and– Improved quality of life and survival.

• Treatment must be based on a shared decision between patient and doctor.

• Immunosuppressive treatment is generally not indicated in classes I and VI LN, unless necessitated by extra-renal lupus activity

Outcome definitionsComplete renal response:proteinuria <0.5 g/d(uPCR) (common) and normal or near-normal (within 10% of normal GFR if previously abnormal) GFR(return of sCr to previous baseline)

Partial renal response:≥50% reduction in proteinuria to subnephrotic levels (common) and normal or near-normal GFR by 6-12 months (Stabilization (±25%), or improvement of SCr, but not to normal)

EULAR/ERA-EDTA KDIGO

Deterioration: A sustained 25% increase in SCr is widely usedbut has not been validated.

Outcome definitions (Flares/relapse)

KDIGO

A fall in levels of serum complement components and a rise in anti–dsDNA antibody titers also support a diagnosis of relapse.

Outcome definitions (Flares/relapse)

Nephritic flares: • reproducible increase of sCr by ≥30% (or, decrease in

GFR by≥10%) and • active urine sediment with increase in glomerular

haematuria by ≥10 RBC/hpf, irrespective of changes in proteinuria;

Proteinuric flares: • Reproducible doubling of UPCR to >100 mg/mmol after

complete response or reproducible doubling of UPCR to >200 mg/mmol after partial response.

EULAR/ERA-EDTA

Adjunctive therapies

Hydroxychloroquine:• protects against the onset of LN, against relapses of LN,

ESRD, vascular thrombosis, and that it has a favourable impact on lipid profiles.

• Dosage of 6.5mg/kg/d or 400mg/d (whichever is lower) after ophthalmological exam.

• Dose modification for GFR <30ml/hr.• Yearly ophthal exam after 5 yrs of use (earlier if

increased risk).

Adjunctive therapies

RAS blockade:• Recommended in all patients with HTN or proteinuria >0.5g/d

with target BP of <130/80 mmHg

• Recommendation based on– Evidence for their antiHTN, antiproteinuric and renoprotective

effect, and – Lack of data on the comparative efficacy of other classes of antiHTN

agents in LN.

• The use of combination ACE inhibitors/ARB therapies is controversial.

Adjunctive therapies

Statins (ACR, Level C evidence):• statin therapy in patients with LDL>100 mg/dl.• Those with GFR <60ml/min is a risk factor for acc.

atherosclerosis.• SLE is itself a risk factor for acc. atherosclerosis.

Pre-pregnancy counseling in women of child bearing age (ACR, Level C evidence).

Treatment of Lupus Nephritis

Analyzing available data

• “Hard outcome measures”: doubling of serum creatinine, ESRD death. Usually seen only in very long term follow up.

• “Intermediate outcome measures”: renal response and flares/relapses. Usually seen within 2 years and has been found to correlate well with the hard outcomes.

• However, correlation does not guarantee surrogacy.

Lupus Nephritis Class II

• No prospective studies in this group of patients. • If nephrotic-range proteinuria is found with class II LN,

this may be due to a concomitant podocytopathy.

KDIGO 2012:1. Treat patients with class II LN and proteinuria <1 g/d as

dictated by the extrarenal clinical manifestations of lupus. (2D)

2. We suggest that class II LN with proteinuria >3g/d be treated with corticosteroids or CNIs as described for MCD. (2D)

Lupus Nephritis Class III/IV (Initial therapy)

• There are differences between the various guidelines regarding the choice of the initial therapy.

• This is predominantly due to the racial differences and response rates seen according to the place of origin of these guidelines.

Major differences

• The European guidelines recommend either MMF/low dose “Euro lupus protocol” as the first choice. MMF/ high dose iv CYC can be tried in those with adverse prognostic factors (acute deterioration in renal function, substantial cellular crescents and/or fibrinoid necrosis).

• KDIGO guidelines however favour use of CYC (high dose) in those with severe disease and MMF in those with less severe disease/ favourable ethnicity (although the levels of evidence for both is 1B).

Major differences

• EULAR/ERA-EDTA guidelines recommend a lower starting dose of steriods @0.5mg/kg/d after an initial pulse of 500-750mg iv for 3 days reducing to ≤10mg/d by 4-6 months.

• Steroids are recommended at starting dose of 1mg/kg/d in the KDIGO guidelines, tapering over 6-12 months.

Interestingly though, the dosing and duration of corticosteroids has never been subjected to evaluation by RCTs.

Some relevant trials on Prolif Lupus

Compared with the NIH trials, much lower proportions of patients in the Euro Lupus Nephritis Trial were Afro Caribbean, had nephrotic syndrome or impaired renal function. The mean serum creatinine of the patients was only 1.15 ± 0.66mg/dl

Euro Lupus Nephritis Trial

Some relevant trials on Prolif Lupus

CYC treatment advice

• Bladder toxicity found to be greater with oral CYC. Lifetime maximum should be 36 g CYC in patients SLE.

• Dose of CYC decreased by 20% or 30% in patients with CrCl 25–50 and 10–25 ml/min, respectively.

• Monitor TLC after 10-14 days of iv CYC and keep nadir counts ≥3000/µl.

• Monitor TLC weekly when on oral CYC and keep nadir counts ≥3000/µl.

CYC treatment advice

• Take oral CYC in the morning, and drink extra fluid at each meal and at bed time.

• Use of sodium-2-mercaptoethane (mesna) will minimize the risk of hemorrhagic cystitis in those on iv CYC.

• Fertility prophylaxis with leuprolide and testosterone.

• Other options for fertility-Ovarian tissue cryopreservation and sperm banking.

KDIGO 2012:• We suggest that, if patients have worsening LN

(rising SCr, worsening proteinuria) during the first 3 months of treatment, a change be made to an alternative recommended initial therapy, or a repeat kidney biopsy be performed to guide further treatment. (2D)

Lupus Nephritis Class III/IV (Maintenance therapy)

MAINTAIN Trial

MMF superior to Aza for maintenance?• A total of 227 patients across sites in the US, Western Europe,

China, Argentina, and Mexico, who improved after 6 months of either high-dose CYC or MMF were randomly assigned to maintenance treatment (116 to MMF and 111 to Aza)

• Over 3 years of follow up, MMF was statistically better than AZA in time to treatment failure (a composite including death, end-stage renal disease, doubling of serum creatinine, and renal flare), and in each element of the composite score.

• Severe adverse events occurred in significantly more patients receiving AZA than receiving MMF.

Dooley et al. NEJM 2011;365:1886–95.

• Thus, although maintenance therapy with Aza (1.5–2.5 mg/kg/d) or MMF (1–2 g/d in divided doses), and low-dose oral corticosteroids (≤10 mg/d prednisone equivalent) are both given equal levels of recommendation(1B) by KDIGO as well as the ACR(Level A) & EULAR/ERA-EDTA(Level A), it seems more prudent to choose MMF over Aza considering the present literature specially if the initial therapy was with higher dose MMF.

CNIs with low-dose corticosteroids can be used for maintenance therapy in patients who are intolerant of MMF and azathioprine. (2C-KDIGO)

Duration of maintenance therapy• There is a very low–quality evidence to guide the

duration of maintenance therapy after CR.• The average duration of immunosuppression was 3.5

years in seven RCTs.

• KDIGO recommends (2D) that immunosuppression should be tapered only after 1 year of achieving CR.

• Immunosuppression should be continued for patients who achieve only a partial remission.

• EULAR/ERA-EDTA recommends a total duration of Maintenance therapy of at least 3 years (Level C).

• KDIGO guidelines also state If CR has not been achieved after 12 months of maintenance therapy, consider performing a repeat kidney biopsy before determining if a change in therapy is indicated. (Not Graded)

• While maintenance therapy is being tapered, if kidney function deteriorates and/or proteinuria worsens, it is suggested that treatment be increased to the previous level of immunosuppression that controlled the LN. (2D)

Predictors of poor outcomeFactors that are found to have a role in predicting poor remission

rates are:– SCr at the start of treatment (RR 0.21 per 1 mg/dl),– the magnitude of increase in SCr during relapse, – a delay in starting therapy for more than 3 months

after a clinical diagnosis of LN, and – severity of proteinuria (HR 0.86 per 1 g/d

proteinuria.

• failure to achieve complete remission is a major risk factor for kidney relapse.

Resolution of proteinuria is the strongest predictor of kidney survival.

Monitoring therapy

ACR Recommendations

Treatment of pure LN Class V• Very poor available literature (only 1 small RCT).

• In those with non-nephrotic proteinuria, with normal renal function, KDIGO recommends antiproteinuric and antiHTN medications with steroids and immunosupp depending on the extrarenal manifestations.

• In those with nephrotic range proteinuria KDIGO recommends corticosteroids plus an additional immunosuppressive agent: cyclophosphamide (2C), or CNI (2C), or MMF(2D), or azathioprine (2D).

Treatment of pure LN Class V• However, ACR and EULAR/ERA-EDTA recommends

MMF as the first line therapy and alternatives given are CYC/CNIs/rituximab.

Treatment of Relapse

• KDIGO guidelines suggest that relapses should be treated with the same treatment that was used for initial and maintenance therapy which induced remission previously. If there is a chance of cumulative CYC toxicity, non-CYC Rx should be used.

• Renal biopsy can be considered if there is a suspicion of class switch or if there is uncertainty on the activity/chronicity contribution to the worsening.

Treatment of refractory diseaseThere is no consensus definition for refractory LN.• KDIGO arbitrarily defines refractory LN if

conventional CYC regimens have been tried without success, and non-CYC regimens have not worked.

• Biopsy should be done in these case to determine the level of activity and chronicity.

• “Salvage therapies” that may be considered are rituximab, i.v. immunoglobulin, or CNIs. (2D)

LN and pregnancy

• Pregnancy may be planned in patients with inactive lupus and UPCR <50 mg/mmol for the preceding 6 months, with GFR that should preferably be >50 ml/min.

• They should be Rx with drugs recommended as acceptable during prepregnancy counselling (HCQ, prednisone, Aza).

• Immunosuppresants should not be tapered during pregnancy or for at least 3 months postpartum.

• Low dose aspirin is beneficial.

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