Lupus Nephritis in Children
A Case Study
By Christy Sandborg, M.D.
Associate Professor of Pediatrics and Director of Pediatric Rheumatology
Stanford University School of Medicine, Stanford, CA
Introduction
At least 15 percent of all lupus patients have onset of their disease prior to age 18. Several studies suggest that lupus may cause more organ system involvement or be a more aggressive disease in children and adolescents. The reasons for this are not entirely clear and are likely to be a combination of delayed diagnosis and genetic and/or environmental predisposition.
Many healthcare providers may not recognize lupus in children and adolescents, simply because they do not think that a disease like lupus could occur in children, thus leading to a delay in treatment and an unrecognized progression of disease. As in other diseases that start in childhood, the manifestations may be more severe because the factors that cause early onset also may cause more intense disease expression. Early recognition of the condition as well as evaluation of the severity of the disease are essential to improving the outcome in this age group.
CASE HISTORY
Medical History
In August 2002, an 8-year-old Asian female developed fatigue, fevers, and joint pain with swelling of her wrists and knees. Her family practice physician diagnosed acute rheumatic fever and started her on a course of aspirin and penicillin for four weeks. Her fevers improved, but she continued to have marked fatigue and developed swelling of her eyelids and feet.
Laboratory tests were obtained that showed a sedimentation rate of 120, and urinalysis with 2+ protein and 10-20 red blood cells/hpf. She was referred to a nephrologist who obtained an ANA titer of 1:1260. She was then referred to a pediatric rheumatologist.
Physical Examination
- Vital Signs: temperature: 37.8 C (100.04 F), pulse 110, blood pressure 122/82
- Skin: no malar rash or other rash noted
- Eyes: periorbital edema
- Nose: normal
- Mouth: no lesions
- Nodes: increased cervical and axillary adenopathy
- Chest: clear to auscultation, no respiratory distress
- Heart: mild tachycardia, no murmurs, gallops, or rubs; pulses all full and equal
- Abdomen: non-tender, liver slightly enlarged
- Musculoskeletal: joint swelling and tenderness of wrists, left knee and right ankle; pitting edema of lower legs
- Neurological: normal reflexes, cranial nerves, and mental status
Laboratory Test Results
- White blood count 3.2 (normal >4)
- Hematocrit 25% (normal for age >36%)
- Platelets 250,000 (normal >150,000)
- Erythrocyte sedimentation rate 120 mm/hr (normal <20)
- Albumin 2.1 gm/dl (normal 3.5-4/3)
- Creatinine 0.9 mg/dl (age-matched normals 0.5-0.8)
- ANA 1:1260
- Anti-ds DNA 1:640
- C3 low at 25 ml/dl (normal 86-130)
- C4 low at 3.5mg/dl (normal 15-25)
- Urinalysis 2+ protein, 5-10 WBC/hpf, 10-20 RBC/hpf, 5-10 hyaline casts
- Urine protein-to-creatinine ratio 2.1 (normal <0.1)
Diagnostic Impression
The most likely diagnosis in this child is lupus with the major criteria of leukopenia, lymphopenia, positive ANA, positive anti-ds DNA, arthritis, and nephritis. The concerning aspects of this case are 1) that she has high blood pressure for her age and 2) that her creatinine, although normal for adults, is actually twice what it should be for a child her age. Both of these factors, in addition to her high urinary protein losses, suggest that she has significant renal disease. To better characterize the extent of her renal disease, a closed renal biopsy was performed. Microscopic evaluation showed Class IV-G (A) nephritis [based on the International Society of Nephrology/Renal Pathology Society (ISN/RPS) scoring system for lupus nephritis].
Management and Clinical Course
Based on the renal biopsy, which showed aggressive renal disease and decreased renal function, a course of IV pulse cyclophosphamide was recommended. She received seven monthly pulses of 750-1,000 mg/m2 (based on an endpoint of WBC of >2 but <4), followed by increasing intervals (6-12 weeks) of continued cyclophosphamide. Along with the cyclophosphamide she received IV methylprednisolone pulses of 30 mg/kg. Additional medicines included calcium and vitamin D, ranitidine (for decreasing stomach acid), lisinopril (for high blood pressure), and multivitamins.
Three months after cyclophosphamide treatments had started, her complement levels, ESR, WBC, and hematocrit had normalized. By five months, her creatinine had become 0.45, her urinalysis was normal without protein, RBCs, or casts, and her urine protein-to-creatinine ratio was almost normal at 0.17. She continued to do well, and one year after starting the cyclophosphamide she was switched to maintenance therapy with mycophenylate mofetil at 600 mg/m2 per dose twice daily. She remains on this regimen at this time, one year later.
The Pediatric Rheumatologist's View
- Lupus in children can occur as young as 4 years of age, with the majority of cases occurring after 12 years of age. Severe lupus nephritis (ISN/RPS Class III and IV) occurs in more than 60 percent of children with lupus, and renal biopsy is useful in determining appropriate treatment to prevent renal failure.
- Children have age-related levels of creatinine and blood pressure, and these levels need to be used to assess clinical status. Using adult norms can be misleading.
- Cyclophosphamide pulse therapy is the recommended treatment in pediatric lupus for severe lupus nephritis. Some providers are concerned about short- and long-term side effects of immunosuppressives in children, such as premature ovarian failure. Premature ovarian failure is less common in prepubertal and adolescent girls compared with adult women. In addition, progression to renal failure in a young person is a significant burden that will require dialysis and multiple renal transplants (each transplant typically lasts up to 15 years).
- Methylprednisolone pulse therapy in conjunction with cyclophosphamide pulse therapy has been shown to improve renal outcomes in one study in adults and is used by some pediatric rheumatologists.
- Calcium and vitamin D supplementation are important, as the majority of bone deposition occurs in adolescence and will be depleted by both lupus itself and the medications used in treatment.
Summary
Lupus can occur in children and adolescents, and the first step in making the diagnosis is thinking of the possibility. Early recognition of organ system involvement provides the best chance of improving outcomes with prompt intervention. Appropriately matching the severity of the disease with the intensity of treatment is essential to preventing organ system damage. Some physicians and healthcare providers worry about exposing children and adolescents to medications such as immunosuppressive agents and corticosteroids that have major side effects.
Unfortunately, there are no large, well-designed studies of treatment for childhood lupus, and most pediatric rheumatologists extrapolate as best they can from adult studies. However, in those cases where there is a real risk of renal failure, one must balance the benefits and burdens of treatment with these drugs and the long-term risk of renal failure, dialysis, and transplant.
Glossary
Adenopathy-swelling or enlargement of the lymph nodes Class IV-G (A) nephritis-a subclass of one of the five classes of lupus nephritis designated by the ISN/RPS; IV is diffuse proliferative nephritis, which is an advanced stage with loss of kidney function
Leukopenia -a lower-than-normal number of leukocytes in the blood, which means fewer of these white blood cells that act as scavengers to remove damaged and dying cells and help fight infection
Lymphopenia-a lower-than-normal number of lymphocytes in the blood, which means fewer of these white blood cells to help fight infection and mediate the immune response RBC/hpf and WBC/hpf-red blood cells and white blood cells per high power field (a microscopic exam)
References
Barbano G, Gusmano R, et al. Childhood-onset lupus nephritis: a single-center experience of pulse intravenous cyclophosphamide therapy. J Nephrol 2002; 15:123-129.
Illei GG, Austin HA, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001; 135:248-257.
Perfumo F and Martini A. Lupus nephritis in children. Lupus 2005; 14:83-88.
Weening JJ, D'Agati VD, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15:241-250.