Lupus Nephritis

Prof. Hafiz Ijaz AhmadDepartment of Nephrology

Allama Iqbal Medical College Lahore

Systemic Lupus Erythematosus

• Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease of unknown cause that can affect virtually any organ of the body.

• Immunologic abnormalities, especially the production of a number of antinuclear antibodies (ANA), are a prominent feature of the disease.

• Prevalence in USA: 10-400 / 100,000• Blacks > Asians > whites• F:M – 10:1• Multigenic Disease• Highest in Black women, Lowest in white men• OCP/hormone replacement: 1.2 – 2 fold↑• Environmental Stimuli: UV, EBV, Tobacco

Diagnostic Criteria forSystemic Lupus Erythematosus

• Malar Rash• Discoid Rash• Photosensitivity• Oral ulcers• Arthritis• Serositis

• Renal disorder– Proteinuria, cellular

casts• Neurologic Disorder• Hematologic Disorder• Immunologic Disorder• Antinuclear antibodiesIf ≥4 any time in Pt Hx

Clinical Manifestations

• Fever• Fatigue• Weight loss• Malar Rash– Fixed erythema, flat/raised, over malar eminences

• Discoid Rash– Erythematous circular raised patches, scaling, scarring

• Photosensitivity– Exposure to UV light causes rash

• Oral Ulcers– Oral/nasopharyngeal ulcers

• Arthritis– Non erosive , 2 or more peripheral joints, tenderness, swelling

• Serositis– Pleuritis, pericarditis (ECG / Rub)

• Renal Disorder– Proteinuria > 0.5 g/d or 3+, cellular casts

• Neurological disorder– Seizures / psychosis without other cause

• Hematological disorder– Hemolytic anemia, leukopenia, lymphopenia,

thrombocytopenia• Immunologic disorder– Anti-dsDNA, anti-sm, and/or anti-phospholipid

• Antinuclear antibodies– ANA, IF or ther assay

Lupus NephritisACR Criteria

• Proteinuria > 0.5 g/d OR• 3 + proteinuria• Active urinary sediments: dysmorphic RBCs,

RBC casts`

Renal Manifestations in patients with Lupus

• Proteinuria 100%– Nephrotic syndrome 45-65%

• Hematuria– Microhematuria 80%– Macrohematuria 1-2%

• Cellular casts 30%• Reduced renal function 40-80%

– RPGN 10-20%– AKI 1-2%

• Hypertension 15-50%• Tubular abnormalities 60-80%

Histological Classification

• Minimal mesangial lupus nephritis (class I) • Mesangial proliferative lupus nephritis (class

II)• Focal lupus nephritis (class III)• Diffuse lupus nephritis (class IV) • Membranous lupus nephritis (class V)• Advanced sclerosing lupus nephritis (class VI)

Why renal biopsy is important

• Two Lesions: Membranous LN but may also have a proliferative GN

• Patients with less severe clinical disease but Biopsy shows severe

• Patients with more severe disease may have additional findings to alter the choice of therapy: diffuse proliferative LN & marked crescent formation

• In addition to its role in patients with established lupus, renal biopsy may aid the diagnosis in patients for whom the diagnosis of lupus is uncertain

Indications for renal biopsy

●Protein excretion greater than 500 mg/day.●An active urinary sediment with hematuria

(five or more red blood cells per high-power field, most of which are dysmorphic) and cellular casts. Red cells are dysmorphic.

●A rising serum creatinine that is not clearly attributable to another mechanism.

Treatment of Lupus Nephritis

Conclusions

• In this 24-week trial, mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile.

Exclusion criteria

• creatinine clearance of less than 30 ml per minute • serum creatinine on repeated testing greater than 3.0 mg per

deciliter (265.2 µmol per liter)• severe coexisting conditions precluding immunosuppressive

therapy • conditions requiring intravenous antibiotic therapy• prior treatment with mycophenolate mofetil• treatment with intravenous cyclophosphamide within the past

12 months • monoclonal antibody therapy within the past 30 days • pregnancy or lactation.

Conclusions

• a 36-month, randomized, double-blind, double-dummy, phase 3 study comparing oral mycophenolate mofetil (2 g/d) and oral azathioprine (2 mg/kg/d)

• Mycophenolate mofetil was superior to azathioprine in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy.

(N engl j med 365;20 nejm.org november 17, 2011)

Belimumab for Systemic Lupus Erythematosus

(N Engl J Med 2013; 368:1528-1535)

• A 20-year-old woman with SLE presents with disease flares and receives belimumab, a monoclonal antibody that binds to B-cell activating factor, inhibiting B-cell stimulation. Belimumab is considered for patients who do not have a response or have adverse effects with first-line therapies.

Conclusions

• We used double immunostaining to evaluate pathway activation in the mammalian target of rapamycin complex (mTORC) and the nature of cell proliferation in the vessels of patients with primary or secondary antiphospholipid syndrome nephropathy.

• Our results suggest that the mTORC pathway is involved in the vascular lesions associated with the antiphospholipid syndrome.

Treatment of Lupus Nephritis

• Class I & II : No specific Therapy• Class III & IV:– Induction Phase– Maintenance Phase

• Class V:– Nephrotic Syndrome– Subnephrotic Proteinuria

• Class VI

Treatment of Proliferative LN

• Induction Phase– Methylprednisolone1g IV X 3d or 1mg/kg oral– MMF 1-1.5 g bid or– IV cyclophosphamide or oral cyclophosphamide

3-6 Months

Treatment of Proliferative LN

• Maintenance Phase–Low dose steroids + MMF 0.5 -1 g bid–OR low dose steroids + AZA 1-2mg/kg• Supportive Treatment•ACE-I, ARBs, osteoporosis

prophylaxis, CV prevention)

Prognosis

• A curable/managable disease with modern treatment

• Overall 5 year survival - >90%• ESRD 8 – 15%• Late improvement – termination of Dialysis• LN - 1-2% of ESRD population

Prognosis

• Severe infections– Immuno-compromised status– Medicines

• AV fistula clotting• Premature Myocardial Ischemia (APL)

Predictors of poor outcome

• Race – Black, South asians

• Male gender• Younger age <24• Poor socio-economic

status• Higher baseline Creat.• Higher baseline

Proteinuria

• Severe anemia, throbocytopenia

• Hypocomplementemia• Elevated anti dsDNA• Delay in initiation of

treatment• Relapse of Nephritic

syndrome

LN & Renal Transplant

• Outcome is the same as other patients• False positive “cross match”• Immunosuppression, rejection episodes, graft

loss same• Wait on dialysis ?• Pre-amptive immunosuppression• Disease recurrence 1-30%, graft loss rare

772 adults with ESRD caused by lupus nephritis and 32,644 adults with ESRD caused by other causes who

received a transplant between 1987 and 1994

Conclusions

• Graft and patient survival after first cadaveric and first living-related renal transplants are similar in patients with ESRD caused by lupus nephritis and patients with ESRD from other causes.

THANKS