Pediatrics

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.

Table I.

Drug Dose Side Effects
Prednisone Up to 2 mg/kg/day.Maximum dose 60-80 mg/day. weight gain, Cushingoid appearance, hypertension, striae, diabetes mellitus, osteopenia, growth suppression, cataracts, acne, peptic ulcer, muscle weakness
IVMethylprednisolone Pulse therapy:15-30 mg/kg/dose daily for three days.Maximum dose 1,000 mg. Same as prednisone.
Mycophenolate mofetil 600 mg/m2 BID abdominal pain, diarrhea, constipation, anemia, leukopenia, hypertension, infection
IVcyclophosphamide 500-1,000mg/m2. Monthly doses x 6, then every 3 months. Given along with mesna to protect the bladder. hemorrhagic cystitis, secondary malignancy, sterility, alopecia, nephrotoxicity, infection, anemia,leukopenia, thrombocytopenia, rash,amenorrhea
Rituximab 375 mg/m2, up to 4 doses infection, infusion reaction, rash, progressive multifocal leukoencephalopathy (rare)
Tacrolimus 0.1-0.3 mg/kg/day.Need to monitor levels. hypertension, nephrotoxicity, tremor, infection, diabetes mellitus, hyperkalemia
Azathioprine 0.5-2.5 mg/kg/day pancytopenia, infection, diarrhea

Induction:

- For moderate to severe disease, pulse IV methylprednisolone is given for 3 consecutive days followed by oral corticosteroids weaned to a lower dose over 6-8 weeks.

- Standard therapy (NIH protocol): Six pulses of IV cyclophosphamide monthly x 6 months, then every 3 months along with corticosteroids. This protocol is associated with a high rate of short-term and long-term side effects.

- Studies have looked at lower dose cyclophosphamide and have shown equivalent efficacy with reduced side effects.

- Recent controlled trials have shown that oral mycophenolate mofetil (MMF) is equivalent to the standard NIH protocol with reduced side effects and is now considered an alternative first-line treatment for lupus nephritis. MMF may be more effective than cyclophosphamide in African American and Hispanic populations.

- Rituximab, an anti-CD20 monoclonal antibody, has been shown to be effective in refractory cases that do not respond to cyclophosphamide. However, no additional benefit is seen when rituximab is added to standard treatment during induction.

Maintenance:

- The choice and dosage of maintenance therapy can be individualized to achieve the lowest dose and best tolerated agent. Maintenance therapy is usually required for 2-3 years and may be longer in some cases.

- Corticosteroids are typically utilized with the aim of limiting the dose to reduce side effects.

- Mycophenolate mofetil and azathioprine have shown efficacy in maintaining remission with a low side effect profile.

  • Class V: Mycophenolate mofetil, with or without a calcineurin inhibitor such as tacrolimus, is effective therapy for membranous nephropathy.

  • Acute kidney injury may require temporary dialysis. Patients who progress to end-stage kidney disease require renal replacement therapy with chronic dialysis or kidney transplantation.

What are the possible outcomes of SLE nephritis?

  • Median time to remission is 10-15 months.

  • Relapse rate is high, 25% at 5 years, 46% at 10 years.

  • 25%-30% develop end-stage kidney disease over 20 years of follow-up

  • Race, ethnicity, and presenting histologic class are the most important predictors for kidney outcome.

  • Children have more severe renal involvement compared with adults.

What will you tell the family about prognosis?

  • Patients with pure membranous nephropathy generally have a good long-term prognosis, with few patients progressing to end-stage kidney disease.

  • The recurrence rate of lupus nephritis after kidney transplantation is less than 10%.

  • The primary risk factor for mortality or poor outcomes in SLE is renal disease.

What causes this disease and how frequent is it?

  • Detailed epidemiology:

    • 60%-80% of pediatric patients with SLE will develop nephritis.

    • Up to 50% will have kidney disease upon presentation.

    • Recurrent renal flares are associated with increased risk of end-stage kidney disease.

    • African Americans have an increased incidence of SLE nephritis compared with Caucasians. Hispanics are not at increased risk for nephritis; however, African American and Hispanic patients have increased disease activity, increased risk of relapse, and decreased renal survival.

  • What’s known about the genetics? There are genetic linkages to the development of lupus nephritis. HLA-A1, B8-DR3, complement, and Fc receptor alleles are known genes associated with lupus nephritis.

What complications might you expect from the disease or treatment of the disease?

Hemorrhagic cystitis and long-term risk of bladder cancer is associated with cyclophosphamide treatment. Therefore, IV hydration and mesna should be utilized to protect the bladder.

Are additional laboratory studies available; even some that are not widely available?

Biomarkers of SLE disease activity is a new area of interest. A Lupus Nephritis Renal Panel, consisting of urine biomarkers (transferrin, ceruloplasmin, alpha-1 acid glycoprotein, neutrophil gelatinase-associated lipocalin (NGAL), prostaglandin-D synthase and monocyte chemotactic protein 1) is shown to increase three months prior to a renal flare and is correlated with renal disease activity.

How can SLE nephritis be prevented?

Prevention is aimed at proper immunotherapy to minimize disease activity.

Patients should be monitored for side effects of treatment and given supplementation with calcium and vitamin D.

Patients should avoid UV light, as it can trigger a relapse.

What is the evidence?

The evidence for management and treatment of pediatric lupus nephritis is not strong because large randomized controlled trials in children are lacking. Best practice management varies between centers because data is extrapolated from adult trials, small pediatric cohort studies, and case series/reports.

Bomback, A, Appel, G. "Updates on the treatment of lupus nephritis". J Am Soc Nephrol. vol. 21. 2010. pp. 2028-35.

Ongoing controversies regarding etiology, diagnosis, treatment

There is a need for evidence-based treatment guidelines and clinical trials specific to the pediatric population with SLE. Further research is needed with newer treatments, such as ocrelizumab, abatacept, belimumab, adrenocorticotropic hormone (ACTH), and laquinimod.

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