Lupus nephritisrecent advices and slicc classifications

Presenter: Dr. Kushal.D.P

HOD: Prof. Dr. Gadwalkar Srikant. R

Moderator: Prof. Dr. Shashibhushan. J

Introduction• Systemic lupus erythematosis is an autoimmune disease in

which organs and cells undergo damage initially mediated by tissue binding autoantibodies and immune complexes.

• The term lupus means ‘wolf’.• The median age of onset in Indian SLE is 24.5 years and the

sex ratio (F:M) is 9:1. • Incidence and prevalence SLE is rare in India. A prevalence

study in India (carried out in a rural population near Delhi) found a point prevalence of 3 per 100,000. This is a much lower figure than reported from the west (varying from 12.5 per100,000 adults in England to 39 per 100,000 in Finland and 124 per 100,000 in USA).

Etiopathogenesis •

• Some polymorphisms influence clinical manifestations; such as single nucleotide polymorphisms (SNPs) of STAT 4 that associate with severe disease, anti-DNA, nephritis, and anti-phospholipid syndrome , and an allele of FCGRIIA encoding a receptor that binds immune complexes poorly and predisposes to nephritis.

• ECM components and cell surface glycoproteins act as autoantigens in lupus nephritis.

• Lupus nephritis is rare in drug induced lupus(DILE).

Antibody & Prevalence Clinical Utility

Antinuclear antibodies

98 Best screening test

Anti-dsDNA 70 SLE-specific and in some patients correlate with disease activity, nephritis, vasculitis

Anti-Sm 25 Specific for SLE

Anti-RNP 40 Not specific for SLEAnti-Ro (SS-A) 30 Not specific for SLE; associated with sicca syndrome, predisposes to

subacutecutaneous lupus, and to neonatal lupus with congenital heart block; associated with decreased risk for nephritis

Anti-La (SS-B) 10 Usually associated with anti-Ro; associated with decreased risk for nephritis

Antihistone 70 More frequent in drug-induced lupus than in SLE

Antiphospholipid 50 Three tests available—ELISAs for cardiolipin and 2G1, sensitive prothrombin time (DRVVT); predisposes to clotting, fetal loss, thrombocytopenia

Antierythrocyte 60 Measured as direct Coombs' test; a small proportion develops overt hemolysis

Antiplatelet 30 Associated with thrombocytopenia

Antineuronal 60 In some series a positive test in CSF correlates with active CNS lupus.

Antiribosomal P 20 In some series a positive test in serum correlates with depression or psychosis due to CNS lupus

Clinical features• At its onset, SLE may involve one or several organ systems;

over time, additional manifestations may occur . • Most of the autoantibodies characteristic of each person are

present at the time clinical manifestations appear . • Severity of SLE varies from mild and intermittent to severe

and fulminant. • Most patients experience exacerbations interspersed with

periods of relative quiescence; permanent complete remissions are rare.

Manifestation Prevalence, %

Systemic: Fatigue, malaise, fever, anorexia, weight loss 95Musculoskeletal 95 Arthralgias/myalgias 95 Nonerosive polyarthritis 60 Hand deformities 10 Myopathy/myositis 25/5 Ischemic necrosis of bone 15

Manifestation Prevalence, %

Cutaneous 80

Photosensitivity 70

Malar rash 50

Oral ulcers 40

Alopecia 40

Discoid rash 20

Vasculitis rash 20

Other (e.g., urticaria, subacute cutaneous lupus) 15

Hematologic 85

Anemia (chronic disease) 70

Leukopenia (<4000/L) 65

Lymphopenia (<1500/L) 50

Thrombocytopenia (100,000/L) 15

Lymphadenopathy 15

Splenomegaly 15

Hemolytic anemia 10

Manifestation Prevalence, %

Neurologic 60

Cognitive disorder 50

Mood disorder 40

Headache 25

Seizures 20

Mono-, polyneuropathy 15

Stroke, TIA 10

Acute confusional state or movement disorder 2–5

Aseptic meningitis, myelopathy <1

Cardiopulmonary 60

Pleurisy, pericarditis, effusions 30–50

Myocarditis, endocarditis 10

Lupus pneumonitis 10

Coronary artery disease 10

Interstitial fibrosis 5

Pulmonary hypertension, ARDS, hemorrhage <5

Shrinking lung syndrome <5

Manifestation Prevalence, %

Renal 30–50

Proteinuria 500 mg/24 h, cellular casts 30–50

Nephrotic syndrome 25

End-stage renal disease 5–10

Gastrointestinal 40

Nonspecific (nausea, mild pain, diarrhea) 30

Abnormal liver enzymes 40

Vasculitis 5

Thrombosis 15

Venous 10

Arterial 5

Ocular 15

Sicca syndrome 15

Conjunctivitis, episcleritis 10

Vasculitis 5

Diagnosis• The Systemic Lupus International Collaborating Clinics (SLICC)

Classification 2012 criteria were derived for relatively simple classification rule.

Rule Sensitivity Specificity Misclassified cases(number)

1997 ACR criteria

267/310 (86%)

365/392 (93%)

70

SLICC criteria 292/310 (94%)

361/392 (92%)

49

1997 ACR criteria

Malar rash Fixed erythema, flat or raised, over the malar eminences

Discoid rash Erythematous circular raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur

Photosensitivity Exposure to ultraviolet light causes rash

Oral ulcers Includes oral and nasopharyngeal ulcers, observed by physician

Arthritis Nonerosive arthritis of two or more peripheral joints, with tenderness, swelling, or effusion

Serositis Pleuritis or pericarditis documented by ECG or rub or evidence of effusion

Renal disorder Proteinuria >0.5 g/d or 3+, or cellular casts

Neurologic disorder Seizures or psychosis without other causes

Hematologic disorder Hemolytic anemia or leukopenia (<4000/L) or lymphopenia (<1500/L) or thrombocytopenia(<100,000/L) in the absence of offending drugs

Immunologic disorder Anti-dsDNA, anti-Sm, and/or anti-phospholipid

Antinuclear antibodies An abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time in the absence of drugs known to induce ANAs

If 4 of these criteria, well documented, are present at any time in a patient's history, the diagnosis is likely to be SLE

Clinical and immunologic criteria used in the SLICC classification criteria

A. Clinical criteria

1.Acute cutaneous lupus

Including lupus malar rash (do not count if malar discoid); bullous lupus; toxic epidermal necrolysis variant of SLE; maculopapular lupus rash; photosensitive lupus rash in the absence of dermatomyositis; or subacute cutaneous lupus (nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory depigmentation or telangiectasia)

2.Chronic cutaneous lupus

Including classical discoid rash; localized (above the neck); generalized (above and below the neck); hypertrophic (verrucous) lupus; lupus panniculitis (profundus); mucosal lupus; lupus erythematosus tumidus; chillblains lupus; discoid lupus/lichen planus overlap

3.Oral ulcers Palate, buccal, tongue or nasal ulcers in the absence of other causes, such as vasculitis, Behçet’s, infection (herpes), inflammatory bowel disease, reactive arthritis and acidic foods

4.Nonscarring alopecia

Diffuse thinning or hair fragility with visible broken hairs in the absence of other causes such as alopecia areata, drugs, iron deficiency and androgenic alopecia

5.Synovitis Involving two or more joints, characterized by swelling, effusion or tenderness in two or more joints, and 30 minutes or more of morning stiffness

6.Serositis Typical pleurisy for more than 1 day or pleural effusions or pleural rub; typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day or pericardial effusion or pericardial rub or pericarditis by electrocardiography in the absence of other causes, such as infection, uremia and Dressler’s pericarditis

7.Renal Urine protein/creatinine (or 24-hour urine protein) representing 500 mg of protein/24 hour or red blood cell casts

8.Neurologic Seizures; psychosis; mononeuritis multiplex in the absence of other known causes such as primary vasculitis; myelitis; peripheral or cranial neuropathy in the absence of other known causes such as primary vasculitis, infection and diabetes mellitus; acute confusional state in the absence of other causes, including toxic-metabolic, uremia, drugs

9.Hemolytic anemia 10.Leukopenia < 4,000/mm3 at least once (in the absence of other known causes such as

Felty’s, drugs and portal hypertension); or Lymphopenia (< 1,000/mm3 at least once) in the absence of other known causes such as corticosteroids, drugs and infection

11.Thrombocytopenia

Thrombocytopenia (< 100,000/mm3) at least once (in the absence of other known causes such as drugs, portal hypertension, and TTP)

B. Immunologic criteria

1.ANA Above laboratory reference range

2.Anti-dsDNA Above laboratory reference range, except ELISA: twice above laboratory reference range

3.Anti-Sm

4.Antiphospholipid antibody

Any of the following lupus anticoagulant false-positive RPR medium or high titer anticardiolipin (IgA, IgG or IgM) anti-β2 glycoprotein I (IgA, IgG or IgM)

5.Low complement Low C3, low C4, low CH50

6.Direct Coombs test In the absence of hemolytic anemia

Classifying SLE as per SLICC criteria 2012 Classify a patient as having SLE if • The patient satisfies four of the criteria listed including at least one clinical criterion and one immunologic criterion; or • The patient has biopsy-proven nephritis compatible with SLE and with ANA or anti-dsDNA antibodies.

Subacute cutaneous lupus lesions

Discoid lupus erythematosus

Acute cutaneous lupus (malar rash )

Lupus nephritis• Renal involvement is a major cause of morbidity and

hospital admissions in SLE patients and occurs in 40% to 70% of all patients.

• Generally, renal involvement tends to occur within the first 2 years of SLE with its frequency decreasing significantly after the first 5 years of disease.

• Almost half of patients present with asymptomatic urine abnormalities, such as hematuria and proteinuria.

• Nephrotic or nephritic syndrome or both also may be observed in 30% of patients.

• Rarely (<5%), patients may present with chronic renal insufficiency, rapidly progressive glomerulonephritis, or a pulmonary-renal vasculitis syndrome.

• Higher in men than in women.• Survival with SLE - 95% at 5 years 92% at 10 years.• Lupus nephritis reduces survival 88% at 10 years.

Features %

Proteinuria 100

Miroscopic hematuria 80

Tubular abnormalities 60-80

Reduced renal function 40-80

Nephrotic syndrome 45-65Granular casts 30

Rapidly declining renal function 30

Hypertension 15-50

Hyperkalemia 15

Macroscopic hematuria 1-2

Acute renal failure 1-2

• Clinical features of patients with lupus.

American College of Rheumatology Guidelines for Screening, Treatment, and Management of Lupus Nephritis. 2012

Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.2012

KDIGO(Kidney disease improving global outcomes) Clinical Practice Guideline for Glomerulonephritis. 2012

ACR 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:• Spot urine protein/creatinine ratio of >0.5 can be

substituted for the 24-hour protein measurement.• “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

Renal biopsy• All patients with clinical evidence of active LN,

previously untreated, undergo renal biopsy (unless strongly contraindicated) so that glomerular disease can be classified by current ISN/RPS classification

• Evaluated for activity and chronicity and for tubular and vascular changes

• Biopsies may identify additional or alternative causes of renal disease, such as tubular necrosis related to medications, hypovolemia, or hypotension.

Indications for renal biopsy in patients with systemic lupus erythematosus• Increasing serum creatinine without compelling alternative

causes (such as sepsis, hypovolemia, or medication)• Confirmed proteinuria of 1.0 gm per 24 hours (either 24-hour

urine specimens or spot protein/creatinine ratios are acceptable)

• 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 0.5 gm per 24 hours plus hematuria, defined as 5 RBCs per hpf b. Proteinuria 0.5 gm per 24 hours plus cellular casts

• In cases of persisting isolated glomerular haematuria, isolated leucocyturia (after other causes, such as infection or drugs are excluded)

• Lowering of GFR • Biopsy within 1 month of disease onset preferably before

immunosuppression.

• At least 8 glomeruli 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

proliferative and membranous lesions.• Chronicity and activity scoring to be done. Vascular

lesions s/o APLA should be looked for.

Pathology

• Immune complex formation and deposition in the kidney results in intraglomerular inflammation with recruitment of leukocytes and activation and proliferation of resident renal cells.

• Intense inflammation may destroy resident renal cells by necrosis or apoptosis, resulting in fibrinoid necrosis.

• In a few patients, intense capillary inflammation results in rupture of the capillary wall and the capsule itself with epithelial cells, mononuclear cells, fibrin basement membrane material, and collagen accumulating in the urinary space of the glomerulus (crescentic glomerulonephritis).

• When injury is less intense, endocapillary cells respond by proliferating and producing extracellular matrix (proliferative lesions).

• Extreme injury or protracted inflammation activates a final common pathway of all types of glomerular injury, resulting in atrophy and scarring.

• In lupus nephritis, the location of immune complex deposition and formation is closely linked to histopathology and the intensity of the inflammatory response.

• Deposition of immune complexes in the mesangium is characteristic of mesangial lupus nephritis.

• Immune complex deposition in the subendothelial area of the capillary loops results in proliferative lupus nephritis (focal or diffuse) with exuberant glomerular hypercellularity. This hypercellularity is due to proliferation of mesangial and endothelial cells and leukocytic infiltrates, resulting in compromised capillary flow and renal function.

• Epimembranous (subepithelial) deposits along peripheral glomerular capillary loops that are diffusely thickened and the lack of inflammatory infiltrate are characteristic of membranous nephropathy

• In renal biopsies, the pattern and severity of injury are important in diagnosis and in selecting the best therapy.

• All the classification systems focus on glomerular disease, although the presence of tubular interstitial and vascular disease is important to clinical outcomes.

• The International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) have published a newer, similar classification that is replacing WHO standards.

International Society of Nephrology/ Renal Pathology Society (ISN/RPS) classification of lupus nephritis (2003)Class I Minimal mesangial lupus nephritis

Class II Mesangial proliferative lupus nephritis

Class III Focal lupus nephritis

Class IV Diffuse segmental (IV-S) or global (IV-G) lupus nephritis

Class V Membranous lupus nephritis

Class VI Advanced sclerosing lupus nephritis

• Class I: Minimal Mesangial Lupus NephritisNormal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence.

• Class II: Mesangial Proliferative Lupus NephritisPurely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposits. A few isolated subepithelial or subendothelial deposits may be visible by immunofluorescence or electron microscopy, but not by light microscopy.

• Class III: Focal Lupus NephritisActive or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations. Class III (A): Active lesions—focal proliferative lupus nephritis Class III (A/C): Active and chronic lesions—focal proliferative and sclerosing lupus nephritis Class III (C): Chronic inactive lesions with glomerular scars—focal sclerosing lupus nephritis

• Class IV: Diffuse Lupus Nephritis(most common & most severe form)Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving 50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) lupus nephritis when 50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when 50% of the involved glomeruli have global lesions. Segmental is defined as a glomerular lesion that involves less than one-half of the glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation.

Class IV-S (A): Active lesions—diffuse segmental proliferative lupus nephritis Class IV-G (A): Active lesions—diffuse global proliferative lupus nephritis Class IV-S (A/C): Active and chronic lesions—diffuse segmental proliferative and sclerosing lupus nephritis Class IV-G (A/C): Active and chronic lesions—diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C): Chronic inactive lesions with scars—diffuse segmental sclerosing lupus nephritis Class IV-G (C): Chronic inactive lesions with scars—diffuse global sclerosing lupus nephritis

• Class V: Membranous Lupus NephritisGlobal or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations. Class V lupus nephritis may occur in combination with class III or IV, in which case both will be diagnosed. Class V lupus nephritis may show advanced sclerosis.

• Class VI: Advanced Sclerotic Lupus Nephritis90% of glomeruli globally sclerosed without residual activity.

Active and chronic glomerular lesionsActive lesions• Endocapillary hypercellularity with or without leukocyte

infiltration and with substantial luminal reduction• Karyorrhexis• Fibrinoid necrosis• Rupture of glomerular basement membrane• Crescents, cellular or fibrocellular• Subendothelial deposits identifiable by light microscopy

(wireloops)• Intraluminal immune aggregates (hyaline thrombi)Chronic lesions• Glomerular sclerosis (segmental, global)• Fibrous adhesions• Fibrous crescents

Treatment

• NSAIDs, antimalarials, glucocorticoids, and, in severe, refractory cases, immunosuppressive agents (azathioprine, mycophenolate mofetil, methotrexate) are used in the treatment of SLE patients without major organ involvement.

General

• Involvement of major organs or extensive involvement of nonmajor organs (i.e., skin) refractory to first-line agents

• Failure to respond to or inability to taper corticosteroids to acceptable doses for long-term use

• Indications for Cytotoxic Drug Use in Systemic Lupus Erythematosus

Specific Organ Involvement Renal: Proliferative or membranous nephritis (nephritic or nephrotic syndrome) Hematologic:

Severe thrombocytopenia (platelets <20 × 103/μL) Thrombotic thrombocytopenic purpura–like syndrome Severe hemolytic or aplastic anemia, or immune neutropenia not responding to corticosteroids

Pulmonary:Lupus pneumonitis or alveolar hemorrhage

Cardiac: Myocarditis with depressed left ventricular function, pericarditis with impending tamponade

Gastrointestinal: Abdominal vasculitis

Nervous system: Transverse myelitis, cerebritis, psychosis refractory to corticosteroids, mononeuritis multiplex, severe peripheral neuropathy

Mild disease:Induction Therapy• High-dose corticosteroids (i.e., 0.5-1 mg/kg/day prednisone

for 4-6 wk with gradual tapering to 0.125 mg/kg every other day within 3 mo) alone or in combination with azathioprine (1-2 mg/kg/day)

• If no remission within 3 mo, treat as moderately severeMaintenance Therapy• Low-dose corticosteroids (i.e., prednisone ≤0.125 mg/kg on

alternate days) alone or with azathioprine (1-2 mg/kg/day)

• Moderate diseaseInduction Therapy• MMF (2 g/day) (or azathioprine) with corticosteroids as

above; if no remission after the first 6-12 mo, advance to next therapy or

• Pulse cyclophosphamide alone or in combination with pulse corticosteroids for the first 6 mo (background corticosteroids 0.5 mg/kg/day for 4 wk, then taper) for 7 pulses

Maintenance Therapy• If remission after first 6-12 mo, MMF may be tapered to 1.5

g/day twice a day for 6-12 mo and then to 1 g/day; consider further tapering at the end of each year in remission or

• Quarterly pulses of cyclophosphamide or• Azathioprine (1-2 mg/kg/day)

SevereInduction Therapy• Monthly pulses of cyclophosphamide combined with

pulse corticosteroids for 6-12 mo• If no response, consider adding rituximab or switch to

MMFMaintenance Therapy• Quarterly pulses of cyclophosphamide for at least 1 yr

beyond remission• Azathioprine (1-2 mg/kg/day)• MMF (1-2 g/day)

Treatment of lupus nephritis• Depends upon class of LN diagnosed on kidney biopsy

along with presence of extra-renal manifestations of SLE• Goal of treatment is to normalize kidney function,

reduce proteinuria, and prevent progressive loss of kidney function.

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

Adjunctive therapy• All SLE patients with nephritis be treated with a background HCQ

unless there is a contraindication Rationale:1. Lower rates of Flares2. Reduced renal damage3. Less clotting events

• LN patients with proteinuria >0.5 gm per 24 hours should have blockade of the renin–angiotensin system Rationale:

1. Reduces proteinuria by 30%2. Significantly delays doubling of serum creatinine3. Delays progression to end-stage renal disease4. Control of hypertension, with a target of <130/80 mm Hg

• Statin therapy be introduced in patients with low-density lipoprotein cholesterol >100 mg/dl

• Acetyl-salicylic acid in patients with anti-phospholipid antibodies, calcium and vitamin D supplementation, and immunisations with non-live vaccines may reduce treatment or disease-related comorbidities and should be considered

• Consider anticoagulant treatment in nephrotic syndrome with serum albumin <20 g/litre, especially if persistent or in the presence of anti-phospholipid antibodies

Class I and class II

• Conservative (Non-immunomodulatory) treatment is appropriate for Class I and II LN

• RAAS Blockade with ACE/ARB delays progression of Lupus Nephritis

• Spironolactone significantly reduces proteinuria and lowers levels of anti ds DNA and anti ss DNA

• Class I and II LN be treated as dictated by the extrarenal clinical manifestations of lupus

• EXCEPTION: II LN with proteinuria >3 g/d be treated with corticosteroids or CNIs as described for MCD.

Class III and IV LN • Patients with proliferative classes of lupus nephritis

need immunomodulatory treatment to turn off the immune system.

• Induction therapy: It is initial intense treatment given to induce remission of active disease

• Maintenance therapy: continued to keep patient in remission and prevent relapses

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

Induction therapy: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).

Regimen A. NIH B. Euro-Lupus C. Oral cyclophosphamide

D. MMF

Cyclophosphamide

i.v. cyclophosphamide 0.5–1 g/m2; monthlyfor 6 months

i.v. cyclophosphamide500 mg; every 2 weeksfor 3 months

Oral cyclophosphamide1.0–1.5 mg/kg/d (maximumdose 150 mg/d) for 2–4 months

-

MMF - - - MMF up to 3 g/d for 6 months

All regimens include corticosteroids: Oral prednisone, initial dose up to 0.5–1 mg/kg/d, tapering over 6–12 months according to clinical response. i.v. methylprednisolone is sometimes added initially for severe disease.

• Maintenance therapy:• MMF at lower doses (initial target MMF dose 2 g/day)

or AZA (2 mg/kg/day) for at least 3 years, in combination with low dose prednisone (5–7.5 mg/day). Gradual drug withdrawal, glucocorticoids first, can then be attempted.

• Patients who responded to initial treatment with MMF should remain on MMF unless pregnancy is contemplated, in which case they should switch to AZA at least 3 months prior to conception.

• CNIs with low-dose corticosteroids be used in patients who are intolerant of MMF and azathioprine.

• After complete remission is achieved, maintenance therapy be continued for at least 1 year before tapering the immunosuppression.

• If complete remission 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.

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

• Monitoring

• 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.

• 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.

• Lifetime maximum of 36 g cyclophosphamide in patients with systemic lupus..

Outcome definitionsEULARrecommendations

KDIGOrecommendations

Complete response

urine protein:creatinine ratio (UPCR) <50 mg/mmol (roughly equivalent to proteinuria <0.5 g/24 h) and normal or nearnormal (within 10% of normal GFR if previously abnormal) GFR.

proteinuria <0.5 g/d(uPCR) and return of sCr to previous baseline

Partial response

50% reduction in proteinuria to subnephrotic levels and normal or near-normal GFR, should be achieved preferably by 6 months and no later than12 months following treatment initiation

Stabilization (±25%), or improvement of SCr, but not to normal, plus a ≥50% decrease in uPCR. If there was nephrotic-range proteinuria (uPCR>3000 mg/g), improvement requires ≥50% reduction in uPCR, and a uPCR <3000 mg/g.

Deterioration: A sustained 25% increase in SCr is widely used

Flares and relapses• Nephritic flares include reproducible increase of serum

creatinine by ≥30% (or, decrease in GFR by ≥10%) and active urine sediment with increase in glomerular haematuria by ≥10 red blood cells per high power field.

• proteinuric flares include reproducible doubling of UPCR to >100 mg/mmol after complete response or reproducible doubling of UPCR to >200 mg/mmol after partial response

Mild kidney relapse Moderate kidney relapse Severe kidney relapse

Increase in glomerular hematuria from <5 to >15 RBC/hpf, with ≥2 acanthocytes/hpf ≥1 RBC cast, WBCcast (no infection), or both

If baseline creatinine is:-- <2.0 mg/dl , an increase of0.20–1.0 mg/dl -- ≥2.0 mg/dl, an increase of0.40–1.5 mg/dl and/orIf baseline uPCR is:-- <500 mg/g, an increase to1000 mg/g -- 500–1000 mg/g , an increase to2000 mg/g, but less than absoluteincrease of >5000 mg/g -- >1000 mg/g , an increase of ≥2-fold with absolute uPCR <5000 mg/g

If baseline creatinine is:-- <2 mg/dl , an increase of >1.0 mg/dl-- ≥2 mg/dl, an increase of ≥1.5 mg/dl And/oran absolute increase of uPCR >5000 mg/g

Resistant lupus • For patients who fail treatment with MMF or CY,

treatment is switched from MMF to CY, or CY to MPA, or rituximab be given.

• In patients with worsening SCr and/or proteinuria after completing one of the initial treatment regimens, consider performing a repeat kidney biopsy to distinguish active LN from scarring.

• Treat patients with active LN on biopsy with one of the alternative initial treatment regimens.

• Nonresponders who have failed more than one of the recommended initial regimens may be considered for treatment with rituximab, i.v. immunoglobulin, or CNIs.

• Relapses• A relapse of LN after complete or partial remission

be treated with the initial therapy followed by the maintenance therapy that was effective in inducing the original remission.

• If resuming the original therapy would put the patient at risk for excessive lifetime cyclophosphamide exposure, then a non–cyclophosphamide- based initial regimen be used

• Consider a repeat kidney biopsy during relapse.

Predictors for not achieving remission:• SCr at the start of treatment• Magnitude of increase in SCr during relapse• Delay in starting therapy for more than 3 months after a

clinical diagnosis of LN.• Severity of proteinuria• Failure to achieve complete remission a major risk factor for

kidney relapse

Pure Class V• Non-nephrotic proteinuria, with normal renal function:

antiproteinuric and antiHTN medications with steroids and immunosuppressants depending on the extrarenal manifestations.

• Nephrotic range proteinuria: corticosteroids plus an additional immunosuppressive agent: cyclophosphamide , or CNI , or MMF, or azathioprine .

• However, ACR and EULAR/ERA-EDTA recommends MMF as the first line therapy and alternatives given are CYC/CNIs/rituximab.

ESRD• All methods of renal replacement treatment can be used in

patients with lupus, but there may be increased risk of infections in patients on peritoneal dialysis still on immunosuppressive agents and vascular access thrombosis in patients with anti-phospholipid antibodies

• Transplantation should be performed when lupus activity has been absent, or at a low level, for at least 3– 6 months, with superior results obtained with living donor and pre-emptive transplantation. Anti-phospholipid antibodies should be sought during transplant preparation because they are associated with an increased risk of vascular events in the transplanted kidney.

• Treated with corticosteroids and immunosuppressives only as dictated by the extrarenal manifestations of systemic lupus.

• Lupus nephritis in pregnancy • In patients with prior LN but no current evidence of

systemic or renal disease activity, no nephritis medications are necessary.

• Patients with mild systemic activity may be treated with HCQ

• If clinically active nephritis is present, or there is substantial extrarenal disease activity, the clinician may prescribe glucocorticoids at doses necessary to control disease activity, and if necessary AZA can be added

• Persistently active nephritis with documented or suspected class III or IV with crescents, consideration of delivery after 28 weeks for a viable fetus is recommended.

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

• The intensity of treatment should not be reduced in anticipation of pregnancy.

• During pregnancy, acetylsalicylic acid should be considered to reduce the risk of pre-eclampsia and fetal loss.

• Patients should be assessed at least every 4 weeks, preferably by a specialist physician and obstetrician.

• Flare of LN during pregnancy can be treated with acceptable medications stated above depending on severity of flare

• If pregnant patients are receiving corticosteroids or azathioprine, these drugs not be tapered during pregnancy or for at least 3 months after delivery.

References

• Harrison's Principles of Internal Medicine. 18th edition • Kelley's Textbook of Rheumatology. 8th ed.• American College of Rheumatology Guidelines for Screening,

Treatment, and Management of Lupus Nephritis. 2012• Joint European League Against Rheumatism and European

Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.2012

• KDIGO Clinical Practice Guideline for Glomerulonephritis. 2012

• Derivation and Validation of the Systemic Lupus International Collaborating Clinics Classification Criteria for Systemic Lupus Erythematosus.2012

Thank you