SLE glomerulonephritis

OVERVIEW: What every practitioner needs to know

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder characterized by production of autoantibodies and deposition of immune complexes, with ensuing inflammation and tissue damage. Renal involvement of SLE with lupus nephritis affects 60%-80% of pediatric patients and is associated with significant morbidity and mortality. Kidney biopsy is necessary for staging to guide treatment and prognosis. Proliferative nephritis is the most severe form of lupus nephritis.

Are you sure your patient has SLE nephritis? What are the typical findings for this disease?

Renal manifestations of SLE nephritis include microscopic/gross hematuria, proteinuria, nephrotic syndrome, nephritic syndrome, hypertension, and renal dysfunction. The most common findings include:

Variable proteinuria – may be in nephrotic range

Microscopic hematuria or gross hematuria (tea-colored)

Edema – may be due to fluid overload in nephritic syndrome or due to decreased oncotic pressure in nephrotic syndrome.

Hypertension

How is SLE nephritis classified?

SLE nephritis is classified based on histologic findings on kidney biopsy. The World Health Organization (WHO) classification of lupus nephritis was replaced by that of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) in 2004. This grading system is useful for determining treatment course and prognosis. Proliferative lupus nephritis (Class III and IV) is the most severe form of lupus nephritis.

Classification of lupus nephritis:

Class I: Minimal mesangial lupus nephritis. Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence

Class II: Mesangial proliferative lupus nephritis. Mesangial hypercellularity or mesangial matrix expansion with mesangial immune deposits

Class III: Focal lupus nephritis. Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations. Further divided by active (A) vs. chronic lesions (C), III-A, III-A/C, III-C.

Class IV: Diffuse lupus nephritis. 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. Further divided by segmental (IV-S) vs. global lesions (IV-G) and active vs. chronic lesions (A, A/C, C).

Class V: Membranous lupus nephritis. Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations. This may occur in combination with Class III and IV nephritis.

Class VI: Advanced sclerosis lupus nephritis. ≥90% of glomeruli globally sclerosed without residual activity.

(Adapted from Weening et al. J Am Soc Nephrol 2004;15:241-50.)

What are findings of SLE nephritis on physical exam?

• Hypertension

• Periorbital edema

• Rales, retractions

• Ascites

• Pedal edema

• Other findings of SLE: malar or discoid rash, oral ulcers, arthritis, pericardial rub, seizures, or psychosis

What other disease/condition shares some of these symptoms?

Patients with SLE may also present with other renal manifestations, such as tubulointerstitial nephritis, renal arterial or venous thrombosis, thrombotic microangiopathy, and antiphospholipid syndrome.

Differential diagnosis of SLE nephritis:

• IgA nephropathy

• Henoch-Schönlein purpura

• Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis

• Alport syndrome

• Membranoproliferative glomerulonephritis (MPGN)

• Membranous nephropathy

• Focal segmental glomerulosclerosis (FSGS)

Kidney diseases associated with a low complement C3, include: poststreptococcal acute glomerulonephritis (PSAGN), MPGN, SLE nephritis and shunt/endocarditis nephritis. SLE nephritis activates both the classical and alternative complement pathway and usually has low C3 and C4.

What caused this disease to develop at this time?

The etiology and pathogenesis of SLE is not completely understood. A combination of genetic, environmental, and immunoregulatory factors are thought to trigger onset of the disease. The development of autoantibodies is postulated to arise from the loss of self-tolerance, dysregulated apoptosis, and inadequate removal of apoptotic cells, leading to prolonged exposure of the immune system to nuclear and cell membrane components.

Kidney injury in lupus nephritis may be due to binding of autoantibodies to intrinsic antigens in the glomerulus (e.g., cell surface glycoproteins, extracellular matrix components), deposition of preformed immune complexes, or binding of autoantibodies to antigens deposited in the glomerulus from the circulation. Binding of Fc receptor and complement to these immune complexes then sets off the cytotoxic and inflammatory response.

Predisposing factors for SLE:

Genetic factors:

• Monozygotic twins have a 25% concordance rate, and there is familial clustering of SLE.

• HLA haplotypes DR2 and DR3 are associated with SLE.

• There are genetic linkages to development of lupus nephritis because there is familial clustering of end-stage kidney disease in certain ethnic groups (i.e., African American). HLA-A1, B8-DR3, complement, and Fc receptor alleles are known genes associated with lupus nephritis.

Environmental factors:

• UV light

• Silica dust

• Hair dyes

• Solvents

• Uncooked L-canavanine found in alfalfa sprouts

Hormonal: Estrogen (85% female)

Race: African American (Incidence two times more common than in Caucasian)

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

• CBC: anemia, thrombocytopenia, leukopenia, hemolytic anemia

• Anti-double stranded DNA: elevated

• Complement C3 and C4: low

• Urinalysis with microscopy: red blood cell casts and dysmorphic red blood cells

• Urinary protein:creatinine ratio in a first morning sample. Proteinuria may reach nephrotic range (Pr/Cr >2).

• Comprehensive metabolic panel: may present with elevated serum creatinine and BUN, electrolyte disturbance and hypoalbuminemia.

• PT/PTT, fibrinogen and lupus anti-coagulants are needed prior to renal biopsy.

• Consultation with Rheumatology for further testing: anti-Smith, anti-Ro, anti-La antibodies, lupus anticoagulants

Would imaging studies be helpful? If so, which ones?

• In general, imaging studies are not required for the diagnosis of SLE nephritis. Renal ultrasound may show enlarged, echogenic kidneys.

Confirming the diagnosis

• Renal biopsy is necessary to diagnose SLE nephritis and guide treatment.

• Renal biopsy is indicated in SLE when there are features of nephrotic syndrome, nephritic syndrome, significant proteinuria (protein:creatinine ratio >1) or elevated serum creatinine. Patients with SLE commonly have elevated PTT with inhibitors, and may need to be evaluated by Hematology prior to biopsy. NSAIDs and aspirin should also be discontinued prior to biopsy.

• Light microscopy findings vary from mild mesangial proliferation to segmental proliferative lesions to crescentic proliferative necrotizing glomerulonephritis. Capillary obliteration, necrosis, proliferation, and scarring may be present. Extra-glomerular findings include interstitial inflammation and sclerosis, tubular dropout, and vascular changes. Immunofluorescence may show deposition of IgG, IgM, IgA, C3, and C1q. When all are present, this represents a ‘full house’ pattern that is highly suggestive of SLE nephritis. Electron microscopy reveals the presence of immune deposits.

• Membranous nephropathy is found in 14% of cases. Principal features include uniform thickening of the glomerular basement membrane, creating a ‘wire loop’ appearance, and intramembranous immune complex deposition, the ‘spike and dome’ pattern.

If you are able to confirm that the patient has SLE nephritis, what treatment should be initiated?

• Treatment of lupus nephritis is guided by the histologic ISN/RSP class and clinical presentation. Table I gives a list of drugs used for lupus nephritis, their doses, and their side effects.

• Class I and Class II: There is no specific immunotherapy to treat kidney manifestations. Treatment is aimed at optimal blood pressure control with ACE inhibitors or angiotensin receptor blockers. Renin-angiotensin-aldosterone system blockade is renoprotective, reduces proteinuria, and may delay the progression of lupus nephritis. Renal function and potassium should be monitored.

• Class III and Class IV: Treatment of proliferative nephritis is divided into two phases: induction and maintenance. Induction therapy is intense therapy aimed at controlling disease activity and inducing remission of the flare. This is followed by maintenance therapy, which has the goal of preventing relapse and controlling inflammation.