LUPUS NEPHRITIS

DR. TALHA-SAMI-UL-HAQUE

HMO

MU-VA

DHAKA MEDICAL COLLEGE HOSPITAL

In 1941, Klemperer, Pollack and Baehr first described systemic lupus erythematosus (SLE)

as one of the Connective Tissue Disease.

19th-century

• The term “lupus erythematosus” was introduced to describe skin lesions

almost 100 years

later

• the disease is systemic and spares no organ

SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus is an autoimmune disease in which organs and cells undergo damage initially mediated by tissue binding autoantibodies and immune complexes.

LUPUS NEPHRITIS

• Lupus nephritis is histologically evident in most patients with SLE.• One of the most serious manifestations of SLE.• Usually arises within 5 years of diagnosis.

PATHOPHYSIOLOGY

Autoimmunity plays a major role in the pathogenesis of lupus nephritis.

Immunologic mechanisms

Production of autoantibodies

Against nuclear elements

The characteristics of the nephritogenic autoantibodies associated with lupus nephritis are as follows :

i. Antigen specificity directed against nucleosome or double-stranded DNA (dsDNA) - Some anti-dsDNA antibodies cross-react with the glomerular basement membrane.

ii. Higher-affinity autoantibodies may form intravascular immune complexes, which are deposited in glomeruli.

iii. Cationic autoantibodies have a higher affinity for the anionic glomerular basement membrane.

iv. Autoantibodies of certain isotypes (immunoglobulin IgG 1 and IgG 3) readily activate complement.

Autoantibodies

Form pathogenic immune complexes intravascularly

Immune complexes deposited in glomeruli

Bind to antigens already located in the glomerular

basement membrane

Immune complexes in situ

Activating complement and attracting inflammatory cells, including lymphocytes, macrophages, and neutrophils

Promote an inflammatory response

The histologic type of lupus nephritis that develops depends on numerous factors, including the antigen specificity and other

properties of the autoantibodies and the type of inflammatory response that is determined by other host factors.

ETIOLOGY

There are multiple susceptibility factors, which result in abnormal immune responses, which vary among different patients. These factors include:• Genetic factors• Immunologic factors• Environmental factors

GENETIC FACTORSGenetic predisposition plays an important role in the development of both SLE and lupus nephritis. Multiple genes, many of which are not yet identified, mediate this genetic predisposition [Human leukocyte antigen (HLA) class II genes, Complement genes, FcγR genes and others]

IMMUNOLOGIC FACTORS• Patients with SLE have poor clearance mechanisms for

cellular debris. Nuclear debris from apoptotic cells induces plasmacytoid dendritic cells to produce interferon-α, which is a potent inducer of the immune system and autoimmunity.

• Autoreactive B lymphocytes, which are normally inactive, become active in SLE because of a malfunction of normal homeostatic mechanisms, resulting in escape from tolerance. This leads to the production of autoantibodies.

• Anti-dsDNA antibodies, develop through a process of epitope spreading.

ENVIRONMENTAL FACTOR

• UV light• EBV• Smoking• Alcohol• Silica dust

EPIDEMIOLOGY

50–60% developing nephritis during the first 10 years of disease.

35% adults having SLE have clinical evidence of nephritis at time of diagnosis.

African Americans and Hispanics

Whites

9 1

20-40

BANGLADESH

Lupus nephri tis was the most prevalent among secondary GN

common histological type was found Class IV [40%]

Female

73.2% 21-40 year age

ANA positive 63%

Anti-ds DNA was positive

100%

CLINICAL FEATURES: SYMPTOMS

1. Asymptomatic

2. Symptoms of active systemic lupus erythematosus (SLE), including fatigue, fever, rash, arthritis, serositis, or central nervous system (CNS) disease.

3. Symptoms related to active nephritis may include peripheral edema secondary to hypertension or hypoalbuminemia.

4. Other symptoms directly related to hypertension that are commonly associated with diffuse lupus nephritis include headache, dizziness, visual disturbances, and signs of cardiac decompensation.

• Focal and diffuse lupus nephritis: evidence of generalized active SLE with the presence of a rash, oral or nasal ulcers, synovitis, or serositis. Signs of active nephritis are also common.

• Active lupus nephritis: hypertension, peripheral edema, and, occasionally, cardiac decompensation.

• Membranous lupus nephritis: signs of an isolated nephrotic syndrome are common. These include peripheral edema, ascites, and pleural and pericardial effusions without hypertension.

CLINICAL FEATURES: SIGNS

• Several studies have focused on the discrepancy between clinical presentation and pathologic findings at renal biopsy in patients with SLE.• Silent LN has been reported not only in class

II but also in class IV. • Even patients with low-level proteinuria

(<1g/24h) have demonstrated significant renal involvement with proliferative LN (classes III or IV).

DIFFERENTIAL DIAGNOSES

• Chronic Glomerulonephritis• Diffuse Proliferative Glomerulonephritis• Granulomatosis with Polyangiitis (Wegener

Granulomatosis)• Membranous Glomerulonephritis• Polyarteritis Nodosa• Rapidly Progressive Glomerulonephritis

INVESTIGATIONS

INVESTIGATIONS:

Evaluating renal function• To detect any renal involvement early.

Renal biopsy• Classification is based on light microscopy,

immunofluorescence, and electron microscopy findings from renal biopsy specimens.

LABORATORY TESTS

• Blood urea nitrogen (BUN)• Serum creatinine• Urine R/M/E (to check for protein, red blood cells [RBCs],

and cellular casts)• A spot urine test for creatinine and protein concentration

(normal creatinine excretion is 1000 mg/24 h/1.75 m 2; normal protein excretion is 150-200 mg/24 h/1.75 m 2; normal urinary protein-to-creatinine ratio is <0.2)

• A 24-hour urine test for creatinine clearance and protein excretion

• ANA [for diagnosis SLE]• Antibodies to double-stranded DNA (dsDNA), ↑• Complement (C3, C4, and CH50), ↓

• Erythrocyte sedimentation rate (ESR), ↑• C-reactive protein (CRP) levels. ↔• Anti-C1q antibodies ↑ [less sensitive then Anti

dsDNA, but more specific]

LABORATORY TESTS

Urinary biomarkers can accurately identify active lupus nephritis in children:• Alpha-1-acid glycoprotein (AGP)• Ceruloplasmin• Lipocalin-like prostaglandin D synthase (LPGDS)• Transferrin

LABORATORY TESTS

Features %Proteinuria 100Miroscopic hematuria 80Tubular abnormalities 60-80Reduced renal function 40-80Nephrotic syndrome 45-65Granular casts 30Rapidly declining renal function 30Hypertension 15-50Hyperkalemia 15Macroscopic hematuria 1-2Acute renal failure 1-2

ACR CRITERIA

ACR criteria

Persistent proteinuria >0.5 gm per day or greater than

3+ by dipstick, and/or

Cellular casts including red blood cells [RBCs],

hemoglobin, granular, tubular, or mixed

Review of the ACR criteria

Spot urine protein/creatinine ratio of

>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

RENAL BIOPSY All patients with clinical evidence of active LN, previously untreated, undergo renal biopsy (unless strongly contraindicated) for• Classified by current ISN/RPS classification• Disease evaluated for activity and chronicity• Identify additional or alternative causes of renal

disease• Determining prognosis and treatment

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:• Proteinuria 0.5 gm per 24 hours plus

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

casts

International Society of Nephrology/Renal Pathology Society 2003 classification of LN

Class I Minimal mesangial LN

Class II Mesangial proliferative LN

Class III Focal LN (50% of glomeruli)III (A): active lesionsIII (A/C): active and chronic lesionsIII (C): chronic lesions

Class IV Diffuse LN (50% glomeruli)Diffuse segmental (IV-S) or global (IV-G) LNIV (A): active lesionsIV (A/C): active and chronic lesionsIV (C): chronic lesions

Class V Membranous LN

Class VI Advanced sclerosing LN (90% globallysclerosed glomeruli without residualactivity)

CLASS I

Delicate mesangial positivity for IgG.

No structural changes by light microscopy

CLASS II

Mesangial cell proliferation, mesangial matrix expansion.

Granular mesangial positivity of all three immunoglobulins and both complements (C1q and C3) (“full house” pattern)

CLASS III

Less than 50% of all glomeruli, segmental or global, swelling and proliferation of endothelial and mesangial cells associated with leukocyte accumulation, capillary necrosis, and hyaline thrombi; extracapillary proliferation, crescents.

Full house pattern as in class II, immune deposits also identified in tubular basement membranes, interstitial capillary walls, interstitial collagen, arterial intima, and media, Fibrinogen positivity

CLASS IV

Lesions similar to Class III, but involves > 50% of glomeruli

WIRE LOOP LESIONS

HYALINE THROMBI

CLASS V

Diffuse thickening of the capillary walls due to deposition ofsubepithelial immune complexes, increased production of basement membrane-like material

There are delicate subepithelial immune deposits staining for IgG with or without mesangial deposits

CLASS VI

Sclerosis of more than 90% of the glomeruli, end stage renal disease, severe tubular atrophy, interstitial fibrosis, inflammation.

TREATMENT

TREATMENTThe principal goal of therapy in lupus nephritis is to normalize renal function or, at least, to prevent the progressive loss of renal function. Therapy differs depending on the pathologic lesion. It is important to treat extrarenal manifestations and other variables that may affect the kidneys.

• Adjunctive Treatments• Primary disease management by immunosuppressive agents• Induction Therapy• Maintenance Therapy

• Lifestyle Changes

ADJUNCTIVE TREATMENTSDrugs Cause

Hydroxychloroquine[Max 6–6.5 mg/kg body weight]

All SLE patients with; unless there is a contraindication:• Lower rates of Flare• Reduced renal damage• Less clotting events

ACEi/ARBs Patients with proteinuria >0.5 gm/day• Reduces proteinuria by 30%, and • Significantly delays doubling of serum

creatinine • Delays progression to ESRD

Antihypertensive Target of ≤130/80 mmHg• Significant delay in progression of

renal disease

Statin therapy Patients with LDL >100 mg/dl• As GFR<60ml/min/1.73m2 & SLE itself

accelerated atherosclerosis

Calcium supplementation Prevent osteoporosis if the patient is on long-term corticosteroid therapy

IMMUNOSUPPRESSIVE AGENTS• Depends upon class of LN diagnosed on kidney

biopsy along with presence of extra-renal manifestations of SLE

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

CLASS I LN (MINIMAL-MESANGIAL LN)

Treatment as dictated by the extrarenal clinical manifestations of lupus• Class I LN has no clinical kidney manifestations.• Class I LN is not associated with long-term

impairment of kidney function

• May require treatment if proteinuria is greater than 1000 mg/day. • Consider prednisone in low-to-moderate

doses (ie, 20-40 mg/day) for 1-3 months, with subsequent taper.

CLASS II LN (MESANGIAL-PROLIFERATIVE LN)

CLASS III LN (FOCAL) AND CLASS IV LN (DIFFUSE)• At high risk of progressing to ESRD • Require aggressive therapy. • Therapy for class III and IV LN has 2 phases: • Initial/Induction phase: to rapidly decrease kidney

inflammation• Maintenance phase: to consolidate treatment over a

longer time.

INITIAL/INDUCTION THERAPY

INITIAL/INDUCTION PHASE

• Initial therapy with corticosteroids , combined with either cyclophosphamide or MMF.

• 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.

GLUCOCORTICOIDS

• Pulse IV glucocorticoids (500–1000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended.• Followed by daily oral glucocorticoids (0.5–1

mg/kg/day), followed by a taper to the minimal amount necessary to control disease.

REGIMENS FOR INITIAL THERAPY IN CLASS III/CLASS IV LN [INTERNATIONAL SOCIETY OF NEPHROLOGY- KIDNEY DISEASE IMPROVING GLOBAL OUTCOME]

MMF CYC

• Non Asian = 3gm/D• Asian = 2 gm/D• Class III/IV + crescents = 3gm/D• Proteinuria + recent significant

rise in creatinine = 3gm/D

• In severe class III/IV LN• In whites, low- and high-dose regimens were

equivalent in efficacy.• Serious infections were less frequent with the lower

doses• Low and high-dose regimens similar rates of LN

flares, end-stage renal disease, and doubling of the serum creatinine.

IMPORTANT CONSIDERATIONS FOR CYC• The use of sodium-2-mercaptoethane (mesna) will also minimize the

risk of hemorrhagic cystitis when cyclophosphamide is given as i.v. pulses.

• Lifetime maximum of 36 g cyclophosphamide in patients with systemic lupus as there is chance of hematologic malignancies later in life.

• The dose of cyclophosphamide should be decreased by 20% (CrCl 25-50ml/min) or 30% (10–25 ml/min)

• To minimize bladder toxicity with oral cyclophosphamide, suggest instructing patients to take cyclophosphamide in the morning, and to drink extra fluid.

• To protect fertility, women should be offered prophylaxis with leuprolide and men testosterone. Ovarian tissue cryopreservation/sperm banking are other options.

HOW CAN WE PREDICT OUTCOME??• After 8 week: ≥ 25% reduction in proteinuria

and/or normalization of C3 and/or C4 serum levels = likely to show good clinical renal responses• After 6 months: decrease in serum creatinine

and in proteinuria to <1 gm/D predicts a good long-term outcome

DEFINITIONS OF RESPONSE TO THERAPY• Complete response: Return of SCr to previous baseline, plus a

decline in the uPCR to <500 mg/g (<50 mg/mmol).• Partial response: 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 [≥300 mg/mmol]), improvement requires a ≥50% reduction in uPCR, and a uPCR <3000 mg/g [<300 mg/mmol].

• Deterioration: There is no definition of deterioration in LN to define treatment failure. A sustained 25% increase in SCr is widely used but has not been validated.

IF THE PATIENT NOT IMPROVED??

SWITCH REGIMEN

OTHER INITIAL REGIMENSRegimens

Rituximab • When treatment failed with MMF/CYC

Azathioprine • 2nd line protocol• Less effective than CYC

MPA • Less nausea & diarrhea than MMF• Should measured 1 hour after a dose

Cyclosporine • (4–5 mg/ kg/d) was used for 9 months, and then tapered over the next 9 months.

• No differences in responses, relapse rate, Infections and leukopenia with CYC.

• ACR guideline preferred it for maintenance therapy.

Tacrolimus • Equivalent to high-dose IV CYC in inducing complete and partial remissions of LN

MAINTENANCE THERAPY

• Azathioprine (1.5–2.5 mg/kg/d) or • MMF (1–2 g/d in divided doses)

±Low-dose oral corticosteroids

Calcineurin inhibitors with low-dose corticosteroids be used for maintenance therapy in patients who are intolerant of MMF and azathioprine.

MAINTENANCE THERAPY

Complete remission is achieved

Repeat kidney biopsy

Change in therapy

Continued for at least 1 year

Consideration for tapering

Kidney function deteriorates and/or proteinuria worsens

Treatment be increased to the previous level of immunosuppression that controlled the LN

YESNO

After1 year

DURATION OF THERAPY

• There is no evidence to help determine the duration of maintenance therapy.

• The average duration of immunosuppression was 3.5 years in seven RCTs.

• Immunosuppressive therapy should usually be slowly tapered after patients have been in complete remission for a year.

CLASS V LN (MEMBRANOUS LN)• Generally treated with prednisone for 1-3 months,

followed by tapering for 1-2 years if a response occurs. If no response occurs, the drug is discontinued.

• Immunosuppressive drugs are generally not used unless renal function worsens or a proliferative component is present on renal biopsy samples.

CLASS VI LN (ADVANCED SCLEROSIS LN)

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

LIFESTYLE CHANGES FOR LUPUS NEPHRITIS• Drink enough fluids to stay well hydrated.• Eat a low-sodium diet, especially if hypertension is an

issue.• Avoid smoking and drinking alcohol.• Exercise regularly.• Maintain a healthy blood pressure.• Limit cholesterol.• Avoid medications that can affect the kidneys, such as

nonsteroidal anti-inflammatory drugs (NSAIDs).

RELAPSE OF LN

• Treated with the initial therapy followed by the maintenance therapy that was effective in inducing the original remission• Consider a repeat kidney biopsy during relapse if

there is suspicion that the histologic class of LN has changed, or there is uncertainty whether a rising SCr and/or worsening proteinuria represents disease activity or chronicity.

SYSTEMIC LUPUS AND THROMBOTIC MICROANGIOPATHY

• Antiphospholipid syndrome occurs when immune system mistakenly attacks some of the normal proteins in blood.

• The antiphospholipid anti-body syndrome (APS) involving the kidney in systemic lupus patients, with or without LN.

Blood tests for antiphospholipid syndrome look for at least one of the following three antibodies in your blood:• Lupus anticoagulant• Anti-cardiolipin• Beta-2 glycoprotein I

To confirm a diagnosis of antiphospholipid syndrome, the antibodies must appear in your blood at least twice, in tests conducted at least 12 weeks apart.

SYSTEMIC LUPUS AND THROMBOTIC MICROANGIOPATHY

• Heparin: Typically, first be given as injection, combined with another blood thinner in pill form, likely warfarin (Coumadin).

• Warfarin: After several days of combined heparin and warfarin, discontinue the heparin and continue the warfarin, possibly for the rest of life.

• Aspirin: In some cases, may recommend adding low-dose aspirin to treatment plan.

Target INR 2–3

SYSTEMIC LUPUS AND THROMBOTIC MICROANGIOPATHY

• Patients with systemic lupus and thrombotic thrombocytopenic purpura (TTP) receive plasma exchange as for patients with TTP without systemic lupus.

SYSTEMIC LUPUS AND THROMBOTIC MICROANGIOPATHY

SYSTEMIC LUPUS AND PREGNANCY• Women be counseled to delay pregnancy until a complete remission of LN has been achieved.

• 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

• Clinically active nephritis is present, or there is substantial extrarenal disease activity: glucocorticoids (at doses necessary to control disease activity) ± AZA

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

• Contraindicated: High-dose glucocorticoid [hypertension and diabetes mellitus]. MMF, CYC, and methotrexate should be avoided because they are teratogenic.

• Class III or IV with crescents: consideration of delivery after 28 weeks for a viable fetus.

• Administration of low-dose aspirin during pregnancy to decrease the risk of fetal loss.

SYSTEMIC LUPUS AND PREGNANCY

MONITORING ACTIVITY OF LN

PROGNOSIS

10 year

73%

5year

85%

5-year survival

rate was close to

0%

1950

THANK YOU