Pediatr Nephrol (2004) 19:36–44 DOI 10.1007/s00467-003-1278-y
ORIGINAL ARTICLE
Radovan Bogdanovic´ · Vesna Nikolic´ · Srdjan PaÐic´ · Jovan Dimitrijevic´ · Jasmina Lipkovska-Markovic´ · Jelena Eric´-Marinkovic´ · MiloÐ Ognjanovic´ · Aleksandra Minic´ · NataÐa Stajic´
Lupus nephritis in childhood: a review of 53 patients followed at a single center Received: 15 November 2002 / Revised: 3 July 2003 / Accepted: 7 July 2003 / Published online: 22 November 2003 IPNA 2003
Abstract We retrospectively evaluated the clinical and histopathological features, treatment modalities, and outcome of 53 children and adolescents with biopsy-proven lupus nephritis (LN), followed between September 1983 and September 2001. The mean age (€SD) at the time of diagnosis of systemic lupus erythematosus (SLE) was 12.9€2.6 years and the mean follow-up from the time of biopsy was 4.8€3.4 years. At the time of biopsy, all 53 patients had proteinuria, 21 (40%) had nephrotic syndrome, and 14 (26%) had impaired renal function. Class IV nephritis, observed in 34 (64%) patients, was the most frequent histopathology on initial renal biopsy. The patients with class IV LN had a significant tendency to develop hypertension (P=0.04) and nephrotic syndrome (P=0.027), and a lower mean glomerular filtration rate In memory of Professor Miodrag Sindjic´ (1927–2000), nephropathologist, our teacher and friend R. Bogdanovic´ ()) · V. Nikolic´ · M. Ognjanovic´ · N. Stajic´ Department of Nephrology, Institute of Mother and Child Health Care ˇ upic´”, of Serbia “Dr Vukan C Radoja Dakica 8, 11070 Belgrade, Serbia, Serbia and Montenegro e-mail:
[email protected] Tel.: +381-11-31081050 Fax: +381-11-3108160 S. PaÐic´ · A. Minic´ Department of Clinical Immunology, Institute of Mother and Child Health Care ˇ upic´”, of Serbia “Dr Vukan C Belgrade, Serbia, Serbia and Montenegro J. Dimitrijevic´ Institute of Pathology, Military Medical Academy, Belgrade, Serbia, Serbia and Montenegro J. Lipkovska-Markovic´ Institute of Pathology, School of Medicine, University of Belgrade, Belgrade, Serbia, Serbia and Montenegro J. Eric´-Marinkovic´ Institute of Medical Statistics and Informatics, School of Medicine, University of Belgrade, Belgrade, Serbia, Serbia and Montenegro
(P=0.000). Based on the renal histopathology and clinical presentation, patients were treated with corticosteroids alone or combined with azathioprine or with intravenous cyclophosphamide. Plasmapheresis or cyclosporine was used in 4 and 1 patient, respectively. Follow-up biopsies, performed in 13 patients, showed no change in 6 patients, were progressive in 4, and regressive in 3. On final clinical evaluation, renal disease was in complete or partial remission in 42 of 53 patients (80%), 4 had clinically active disease but with normal renal function, and 7 (13%), all with WHO class IV LN, were classified as having an adverse outcome, i.e., either preterminal (2) or terminal (4) renal failure or death (1). Five-year kidney and patient survival rates from the time of biopsy to the endpoints of terminal renal failure or death were 88.6% and 98.1%, respectively, in the whole group, and 82.4% and 97.1%, respectively, in the WHO class IV group. Nephrotic syndrome and class IV nephritis at initial biopsy were the only parameters significantly associated with adverse outcome in our study group. There was no association with gender, age, hypertension, impaired renal function, anemia, increased morphological index scores, and treatment modalities. We conclude that clinical and histopathological features of LN and treatment regimens in our study do not differ markedly from those in most pediatric series. However, the 5-year kidney and patient survival rates are among the best reported in recent pediatric series. The prognosis of LN is primarily dependent on the histopathological lesions. Keywords Lupus nephritis · Clinical and morphological features · Treatment · Outcome · Prognostic factors
Introduction Lupus nephritis (LN) is one of the main clinical presentations determining the course and outcome in patients with systemic lupus erythematosus (SLE) [1, 2, 3, 4, 5]. Clinically overt nephropathy is more often a presenting clinical manifestation of SLE in children than
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in adults [2, 6]. Overt renal abnormalities are found in about 80% of children and adolescents later in the course of the disease [1, 2, 4]. Although at the time of biopsy, clinical features correlate better with histopathology than serological tests, renal histology cannot be predicted with certainty from the clinical picture [1, 4, 7]. However, the more severe histological forms of nephritis tend to have more severe renal manifestations [1, 2, 4, 7]. With recent advances in diagnosis and treatment, the prognosis for both children and adults with LN has improved remarkably [2, 4, 6, 7, 8]. The clinical course and outcome can no longer be considered separately from the results of treatment [9]. While it is generally accepted that the addition of immunosuppressive drugs to prednisone has improved outcome [10, 11], there is no agreement on the superior effect of one immunosuppressive regimen over another [7, 8, 12]. A number of studies have attempted to establish the prognostic criteria for LN in adults, but there has been more controversy than agreement [7]. In childhood LN, several studies have been performed to investigate clinicopathological correlation, efficacy of different treatment modalities, and the prognostic relevance of demographic, clinical, and histopathological features [13, 14, 15, 16, 17, 18, 19, 20, 21]. Although the results of these studies regarding factors affecting outcome remain controversial, male sex, black race, age at onset before puberty, persistent hypertension, impaired renal function, nephrotic syndrome, anemia, class IV LN, and increased histological index scores have been identified as significant prognostic parameters [15, 16, 18, 19, 20, 21]. In this retrospective analysis we evaluated the clinical and histopathological features, clinical course, and outcome of LN in 53 children and adolescents followed at our hospital over 18 years. Our aim was to identify the risk factors for renal failure and mortality and to share our experience in treating LN in children.
Patients and methods Patient selection The patients selected for this study were 18 years old or younger, were initially seen between September 1983 and September 2001, and fulfilled four or more of the 1982 Revised American Rheumatism Association criteria for the diagnosis of SLE [22]. Patients with drug-induced lupus, discoid lupus, or mixed connective tissue disease were excluded. The clinical diagnosis of LN required the presence of an active urinary sediment, proteinuria with or without nephrotic syndrome, and/or raised serum creatinine levels. All patients had undergone renal biopsies between January 1986 and September 2001. All patients’ data were entered with the terminal date being the date last seen before the study was undertaken. Eighteen patients from the present study have been included in our previous reports [23, 24, 25]. Clinical and laboratory data The clinical and laboratory features at the time of renal biopsy included clinical manifestations, blood pressure, nephrotic status, urinalysis, serum creatinine concentrations, 24-h urine protein and/
or first-morning urine protein and creatinine. Hypertension was defined as systolic and/or diastolic blood pressure above the 95th percentile for sex and age [26]. Abnormal urinalysis was considered when there were >10 red blood cells (RBC) or white blood cells per high-power field (hpf), urine protein >1 g/l, and/or casts. Heavy (nephrotic) proteinuria was defined as protein >50 mg/kg (>40 mg/ m2 per hour) in 24-h urine or as first-morning urine protein/ creatinine ratio >200 mg/mmol [27]. A glomerular filtration rate (GFR) 1 mg/dl (88 mmol/l) were considered abnormal. We did not perform systematic investigation of double-stranded (ds) DNA or antiphospholipid antibodies throughout the study period. Anti-DNA positivity was defined as a titer >7 IU/ml. Criteria for the diagnosis of antiphospholipid syndrome evolved over time [29]. Renal biopsy All children underwent percutaneous renal biopsy within 1 year of LN, except 3 patients who were biopsied from 1.7 to 2.3 years after diagnosis of LN. The procedure was performed with the consent of the patient’s parents, under X-ray or ultrasonographic guidance, using a Tru-cut needle (Travenol). The specimens were processed for light and immunofluorescent microscopy. Renal lesions were classified according to the WHO classification criteria for LN [30]. For scoring of the activity (from 1 to 24) and chronicity (from 0 to 12) indices, the presence of active and chronic lesions was assessed using the parameters of the National Institutes of Health (NIH) group reports [31, 32]. Renal vascular damage from a thrombotic microangiopathy was classified as antiphospholipid syndrome or hemolytic uremic-like syndrome depending on whether or not it was associated with antiphospholipid antibodies [33]. During the study, 13 children (25%) received a control biopsy for therapeutic monitoring or because of flare-up of nephritis or progressive deterioration in renal function. Treatment Treatment was determined by disease activity and renal pathology. In patients with class Ib LN, treatment was given for extrarenal manifestations of SLE. Patients with class II LN who had proteinuria 1 g/day or with serum creatinine >1 mg/dl (88 mmol/l), azathioprine at a dose of 2–3 mg/kg per day was added to prednisone. Patients with WHO class IV LN were generally treated with high-dose intravenous methylprednisolone (MP) pulses (10– 30 mg/kg, maximum 1 g, on alternate days, 3–6 doses) followed by oral prednisone (1–2 mg/kg daily, maximum 60 mg/day) over 1– 2 months, which was then gradually tapered over the next 3– 4 months to a maintenance dose of 0.5–0.75 mg/kg on alternate days. Patients with clinically severe disease, after completion of three or six doses of MP pulses, were treated with cyclophosphamide (CY), given monthly for 6 months as a single i.v. bolus at a maximum dose of 1 g/m2. If renal disease was clinically active after 6 monthly CY boluses, it was continued every 3 months for a total period of 24–30 months if the patient did not reach end-stage renal disease before that. Most but not all patients receiving CY were given 2-mercaptoethane sulfonate sodium (MESNA) after CY infusion. Oral prednisone was maintained at 0.5–0.75 mg/kg on alternate days throughout the course of CY and azathioprine (1–2 mg/kg per day) was added after completion of the first 6 months of CY. Class III patients and class IV LN patients with clinically less severe disease were treated with corticosteroids alone or with corticosteroids and azathioprine. Plasmapheresis was instituted in those patients with class IV LN who were refractory to other treatments or who experienced thrombotic microangiopathies, either antiphospholipid syndrome or hemolytic uremic-like syndrome, when aspirin, at a dose of 2 mg/kg on alternate days for at
38 least 6 months was also added. Patients with class V LN received prednisone and azathioprine or cyclosporine. The treatment strategy for individual patients varied over the course of treatment. Drug doses were adjusted according to clinical response or to maintain the C3 complement and anti-DNA antibody titer levels as near to normal as possible. Discontinuation of treatment was attempted when stable renal function, proteinuria absent or less than 0.5 g/day, and normal immunological tests continued for at least 3 years. Symptomatic therapy consisted of diuretics and/or antihypertensive drugs or depended on extrarenal manifestations of SLE or complications. Outcome All patients were followed during the treatment period on a monthly or 3-monthly basis, and at 3- to 6-month intervals thereafter. The duration of follow-up was calculated from the date when a diagnosis of LN was established by renal biopsy to the last date when the patient was seen, or was known to have developed renal failure. The clinical course and outcome were classified and defined as follows: (1) remission, (2) clinically active renal disease, or (3) adverse outcome. Remission of LN was defined as (a) complete, blood pressure, urinalysis and serum creatinine level within normal limits or (b) partial, proteinuria
