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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 5  |  Page : 756-760
A Clinicopathological Study of Lupus Nephritis in Children

1 Department of Pediatrics, Pediatric Nephrology Division, Abozar Children's Hospital, Jondishapour University of Medical Sciences, Ahvaz, Iran
2 Department of Pediatrics, Pediatric Nephrology Division, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
3 Department of Obstetrics and Gynecology, Emam Khomeini's Hospital, Jondishapour University of Medical Sciences, Ahvaz, Iran

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To assess clinical characteristics, pathological findings, and therapeutic response in children with lupus nephritis (LN), we retrospectively studied 25 children under 16 years of age with LN at the Abozar children's hospital from 1995 to 2006. The study included 13(65%) girls and 7(35%) boys. The mean age at the time of diagnosis of SLE was 10.2 (± 4.8) years. Eighteen patients (90%) were more than 8 years old. Sixty percent of the patients presented as nephritic-nephrotic syndrome. All the patients underwent percutaneous renal biopsy and were followed up for at least 36 months. The clinical and serologic parameters at the time of renal biopsy were recorded. Twenty patients were treated with the following regimens: one (class I) with low dose prednisone, 7 (class II, III) with high­dose of prednisone, 12 (class IV) with high-dose prednisone plus 13 intermittent intravenous cyclophosphamide (CTX) pulses (monthly for 6 months and then every 3 months), followed by mycophenolate mofetil (MMF) as maintenance therapy. Remission was achieved in 17 (85%) cases; one required hemodialysis and 2 died due to renal failure and central nervous system involvement. Among 12 cases with class IV, 11 responded to prednisone and intravenous CTX pulses. We conclude that i.v. pulses of CTX induced clinical remission of renal disease in the majority of children with severe LN. MMF maintenance therapy was effective after induction of remission in refractory cases. However, this study was performed in a small number of subjects, further studies to confirm the long­term efficacy and safety of CTX pulse therapy on larger numbers of patients are warranted.

Keywords: Lupus nephritis, Cyclophosphamide, Renal failure

How to cite this article:
Ahmadzadeh A, Derakhshan A, Ahmadzadeh A. A Clinicopathological Study of Lupus Nephritis in Children. Saudi J Kidney Dis Transpl 2008;19:756-60

How to cite this URL:
Ahmadzadeh A, Derakhshan A, Ahmadzadeh A. A Clinicopathological Study of Lupus Nephritis in Children. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2023 Jan 30];19:756-60. Available from: https://www.sjkdt.org/text.asp?2008/19/5/756/42449

   Introduction Top

Systemic lupus erythematousus (SLE) is a chronic inflammatory disease characterized by highly diverse clinical manifestations. [1] Over­all, 60–80% children with SLE have urinary or renal function abnormalities in the disease course. Clinically significant renal involvement ranges from asymptomatic urine findings to nephrotic syndrome and renal failure, and it is more common in children with SLE than in adults. [2],[3] Diagnosis of SLE is usually con­firmed if any four or more of the eleven criteria of American College of Rheumatology (ACR) are present. [4]

Lupus nephritis (LN) is the most common cause of morbidity and mortality in patients with SLE. Thus, kidney biopsy is crucial for determining prognosis and mode of treatment. Before 1970 the prognosis of patients with SLE was very poor. With aggressive therapy, the prognosis of LN has improved signifi­cantly. A majority of treated patients achieve complete or partial remission at 12–18 months and have stable renal function. Infection and end stage renal disease are the main causes of mortality. [1],[5],[6],[7]

To evaluate the clinical course and histo­pathological features as well as the efficacy and safety of intravenous (i.v.) cyclophos­phamide (CTX) pulses in children with LN, we retrospectively studied all patients admitted with LN in our center over 10 years.

   Patients and Methods Top

We enrolled patients less than 16 years of age who manifested 4 or more of ACR criteria for diagnosis of SLE, [4] and diagnosis was con­firmed with renal biopsy from 1995 to 2006. Using these criteria, 25 subjects were iden­tified, after exclusion of 5 patients due to short period of follow-up or inadequate laboratory data, 20 subjects were available for analysis. The percutaneous kidney biopsy was per­formed within 2–6 weeks of diagnosis. Each renal biopsy was processed for light and immunofluorescence microscopy using stan­dard methods of fixation and staining. An ade­quate biopsy specimen contained at least ten glomeruli. Each biopsy was classified accor­ding to the WHO classification system. [8]

At the time of biopsy, the following labo­ratory findings were recorded for each patient: white blood cell count, hemoglobin level, platelet count, albumin, C3, C4, antinuclear antibodies, anti-double-stranded DNA-binding activity, 24–hr urine protein excretion, urina­lysis, ESR, serum creatinine, and calculation of glomerular filtration rate (GFR) using the Schwartz formula. [9] Hypertension was defined as systolic and diastolic above the 95 th per­centile for age and height on 3 consecutive measurements. A hemoglobin concentration < 10 g/dL and GFR < 75 ml/min/1.73 m 2 were considered abnormal.

According to the disease activity, serologic values and histopathological data, patients were treated with the following regimens: class I with 1 mg/kg/day prednisone, class II and class III with high-dose (2 mg/kg/day) of predni­sone, diuretics and antihypertensive drugs, class IV with high-dose prednisolone and inter­mittent IV CTX pulses were administered monthly for 6 months and then every 3 months for the total period of 30 months. Informed consent was obtained from the parents after detailed explanation of the disease nature and possible side effects of CTX. Patients were treated with 750 mg/m 2 of IV CTX body surface areas as an initial dose. The drug was administered over one hour as a single intra­venous infusion in 100 ml of 5% dextrose solution followed by oral hydration for 24 hours. The patients received 2–mercaptoethane sulphonate sodium (MESNA) during the first 12 hours after IV CTX.

In patients with total leukocyte count of less than 3500/mm 3 2 weeks following CTX admi­nistration, the dose of CTX was reduced to one half of the previous dose at next dose. Conco­mitant high-dose daily oral prednisone was given in the first month. This dose was re­duced to 50% by the second month, and then gradually reduced according to the disease activity, to be maintained on a regimen of at least 0.25 mg/kg/day through the CTX the­rapy. Intravenous methylprednisolone pulse the­rapy (30 mg/kg/dose up to 1 g, given daily for 3 days) was administered prior to the first dose of CTX for patients who presented with LN and poor condition. Physical examinations and laboratory investigations were performed on each admission for CTX treatment and every 3 months after the last dose of CTX. All patients with class IV recieved mycophenolate mofetil (600 mg/m 2 /dose) twice daily and low-dose of prednisone (0.25/kg/day) after completion of IV CTX pulses.

   Results Top

Of the 20 children with biopsy proven LN, 13 (65%) were girls; the female to male ratio was 1.8:1. The mean age was 10.2 (± 4.8) years at the time of diagnosis. Eighteen patients (90%) were more than 8 years old. The most common clinical features at the time of diagnosis in­cluded edema (90%), fever (85%), weight loss (85%) and malar rash (55%) [Table 1].

The laboratory data at the time of diagnosis are shown in [Table 2]. Antinuclear antibodies, anti-double stranded DNA antibodies, hypo­complementemia, and proteinuria were detec­ted in all of the patients. The disease pre­sentation of the children included acute glo­merulonephritis (AGN) in 7 (35%), full-blown SLE in 3 (15%), prolonged fever in 4 (20%), severe anemia in 3 (15%), idiopathic thrombo­cypenic purpura (ITP) in 2 (10%) and typhoid fever in1 (5%). Seventy percent of the patients presented as nephritic-nephrotic syndrome.

The Pathological findings included minimal change (class I) in one patient, mesangial glo­merulonephritis (class II) in 5, focal segmental proliferative glomerulonephritis (class III) in 2, diffuse proliferative glomerulonephritis (class IV) in 12, and class V in none. The patholo­gical features, treatment methods, and outcome of the patients are shown in [Table 3].

   Discussion Top

Renal disease is frequent in children with SLE. Clinical symptoms of renal involvement occur in 30–70% of patients. [2],[3],[10] In the absence of aggressive treatment, the child may die or progress to renal failure. [11] During the past 20 years, new therapeutic approaches, including the use of cytotoxic agents have further im­proved renal survival. However, there is still some controversy regarding the best treatment. In the studies performed by the National Ins­titutes of Health, the incidence of renal failure was significantly higher in patients treated with prednisone alone compared with patients given i.v. CTX. Also, there was a trend for a better outcome in patients who received i.v. CTX compared with those with oral CTX alone or in combination with azathioprine. [12]

The most common clinical manifestations in our patients were edema, prolonged fever and weight loss. SLE is a protean disease and it is the great masquerader. Therefore, children with SLE can present with various manifestations, so only 50% of our patients were directly ad­mitted in pediatric nephrology division with the diagnosis of glomerular disease. Five pa­tients had been initially admitted in infectious division and five in hematologic division (3 with severe anemia and 2 with purpura). All the patients manifested the clinical and sero­logical evidence of active SLE with lupus nephritis at the time of renal biopsy.

Our study disclosed that treatment of severe lupus nephritis (class IV) with a drug regimen that includes i.v. CTX resulted in a significant improvement in renal function during the treat­ment period and follow-up as has been ob­served in other studies. [13],[14] Data presented here reveals that 11 out of 12 patients with class IV of lupus nephritis responded well to i.v. CTX therapy. An 11–year-old boy who initially res­ponded, subsequently developed lupus cereb­ritis and progressed to semi-comatose state for 13 days and recovered after addition of myco­phenolate mofetil (MMF). Another, 9–year-old girl with class IV did not respond to i.v. CTX and progressed to end-stage renal disease (ESRD). She is now on maintenance hemodia­lysis and on the waiting list for renal transplan­tation. Two female patients (7 and 9 years of age) with class III did not receive CTX deve­loped ESRD and died. One of them had presented with chronic anemia, intractable hypertension and seizures. The causes of the worse response to treatment were probably due to the delayed diagnosis and chronicity of the disease. The study of Lehman et al. demons­trated improvement in the clinical features of SLE, serological activity, and renal function in 16 children treated with i.v. CTX regimen and followed for 12 months. [13] Later, this author and his colleagues reported a dramatic im­provement in renal function, a decrease in 24­hr urine protein excretion, and a decrease in the prednisone dosage, following 36 months of IV CTX therapy. [14]

Al Salloum performed a study and followed nine patients with severe lupus nephritis with a similar regimen for 5 years. [15] In this study CTX therapy was associated with significant improvement in renal function during treat­ment, but 56% of the patients progressed to chronic renal failure and 22% required dialysis 2 years after discontinuation of CTX. He con­cluded that this regimen was not effective in his patients in the long-term, especially those presenting with high serum creatinine and hypertension.

A prolonged duration between the onset of renal disease and renal biopsy has been found to predict a higher frequency of renal insuffi­ciency, renal failure and death attributed to renal involvement in patients with lupus neph­ritis. [16] The question of timing of renal biopsy in patients with LN is always difficult. Patients in the present study underwent renal biopsy early after the clinical diagnosis of LN was made. This suggests that early intervention treatment in our patients may be one of the causes of better response than the patients of Al Salloum's study of the use of MMF after i.v. CTX pulses might be the other reason.

Ovarian toxicity is a serious complication of CTX therapy, the risk of amenorrhea depends on the age of the patients at the time of ini­tiating treatment and the total numbers of pulses. When the total number of pulses exceeds 15, the likelihood of developing ame­norrhea is 17% for patients less than 25 years of age. [11],[17] Among our patients receiving i.v. CTX pulses, four girls were pre-pubertal and 3 of them had their normal menstruation during 36 months of follow-up. Infection is another serious complication of CTX pulse, which may be life- threatening. [18] None of our patients had serious infection during treatment or later follow-up.

In conclusion, it seems that i.v. pulses of CTX does induce clinical remission in the majority of patients with severe LN especially those with earlier diagnosis. It also appears that MMF is an appropriate drug for maintaining therapy and induction of remission in refrac­tory cases. We suggest multi-center studies on a larger number of subjects to better evaluate the therapeutic options in these patients.

   Acknowledgment Top

The authors thank Mr. Asghar Hamedi for his help in the study and Mrs. Nabi-Dawoodi for typing the manuscript.

   References Top

1.Niadet P, Salmon R. Systemic lupus erythema­tosus. In: Avner ED, Harmon WE, Niadet P. Pediatric Nephrology, 5th eds, Philadelphia, Lippincott Williams & Wilkins. 2004; 865- 88.  Back to cited text no. 1    
2.Perfume F, Martini A. Lupus nephritis in children. Lupus 2005;14(1): 83-88.  Back to cited text no. 2    
3.Gloor JM. Lupus nephritis in children. Lupus 1998;7(9):639-43.  Back to cited text no. 3    
4.Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of SLE. Arthritis Rheum 1982;25(11):1271-4.  Back to cited text no. 4    
5.Cameron JS. Lupus nephritic in childhood and adolescence. Pediatr Nephrol 1994;8:230-49.  Back to cited text no. 5    
6.Baqi N, Moazami S, Singh A, Ahmad H, Bala­chandra S, Tejani A. Lupus nephritis in children: a longitudinal study of prognostic factors and therapy. J Am Soc Nephrol 1996;7(6):924-9.  Back to cited text no. 6    
7.Hagelberg S, Lee Y, Bargman J, et al. Long-term follow-up of childhood lupus nephritis. J Rheumatol 2002;29(12):2635-42.  Back to cited text no. 7    
8.Churg J, Sobin LH. Lupus nephritis. In: Renal diseases: Classification and atlas of glomerular disease. Tokyo: Igaku-Shoin Ltd, 1982;127-49.  Back to cited text no. 8    
9.Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children and adolescents. Pediatr Clin North Am 1987;34(3): 571-90.  Back to cited text no. 9    
10.Ponticelli C, Banfi G, Moroni G. Systemic lupus erythmatosus. In: Davidson AM, Cameron JS, Grunfeld JP, Kerr DN, Ritz E, Winearls CG. Clinical nephrology. 2nd ed, Oxford, Oxford Medical Publication, 1998: 935-54.  Back to cited text no. 10    
11.Niadet P. Treatment of lupus nephritis in children. Pediatr Nephrol 2000;14(2):156-66.  Back to cited text no. 11    
12.Steinberg AD, Steinberg SC. Long-term pre­servation of renal function in patients with lupus nephritis receiving treatment that includes cyclo­phosphamide versus those treated with pred­nisone only. Arthritis Rheum 1991;34(8): 945-95.  Back to cited text no. 12    
13.Lehman TJ, Sherry DD, Wagner Weiner L, et al. Intermittent intravenous, cyclophosphamide therapy for lupus nephritis. J Pediatr 1989;114 (6):1055-60.  Back to cited text no. 13    
14.Lehman TJ, Onel K. Intermettinet intravenous cyclophosphomide arrests progression of the renal chronicity index in childhood systemic lupus nephritis. J Pediatr 2000;136(2):243-7.  Back to cited text no. 14    
15.Al Salloum AA. Cyclophosphamide therapy for lupus nephritis: Poor renal survival in Arab children. Pediatr Nephrol 2003;18(4):357-61.  Back to cited text no. 15    
16.Esdaile JM, Joseph L, Mackenzie T, Kashgarium M, Hayslent J. The benefit of early treatment with immunosuppressive agents in lupus nephritis. J Rheumatol 1994;21(11):2046-51.  Back to cited text no. 16    
17.Boumpas DT, Austin HA, Vaughan EM, Yarboro CH, Kippel JH, Balow JE. Risk for sustained amenorrhea in patients with lupus nephritis receiving intermittent cyclophosphamide therapy. Ann Intern Med 1993;119(5):366-9.  Back to cited text no. 17    
18.Opastirakul S, Chartapisak W. Infection in children with lupus nephritis receiving pulse and oral cyclophosphamide therapy. Pediatr Nephrol 2005;20(12):1750-5.  Back to cited text no. 18    

Correspondence Address:
Ali Ahmadzadeh
Department of Pediatrics, Pediatric Nephrology Division, Abozar Children's Hospital, Jondishapour University of Medical Sciences, Ahvaz
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Source of Support: None, Conflict of Interest: None

PMID: 18711291

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  [Table 1], [Table 2], [Table 3]

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