Clinicopathological findings and outcome of lupus nephritis in Tunisian children: a review of 43 patients

We report clinical and renal histological data, treatment modalities and outcome of 43 Tunisian children with biopsy-proven lupus nephritis seen over a 23-year period. There were 39 girls and 4 boys with a mean age of 12.5 years at diagnosis of lupus nephritis and followed for a mean period of 77 months. Renal symptoms included urinary abnormalities in all patients, hypertension in 40% of cases, nephrotic syndrome in 60% of cases and renal failure in 25% of cases. Class IV and class III nephritis were observed in 48.8 % and 30.2 % respectively. Corticosteroids were used in all cases, associated to immunosuppressive therapy in 23%. Overall survival was 86% at 5 years and 74% at 10 and 15 years. Renal survival was 83% at 5 and 10 years and 63% at 15 years. Initial renal failure and tubulointerstitial fibrosis were significantly increased risk for the development of end-stage renal disease in our study group. Renal histological findings provide the basis for treatment recommendations. Timely performed renal biopsy is greatly needed to accurately determine the prognosis and to guide treatment in children lupus nephritis.


Introduction
Systemic lupus erythematosus (SLE) presents throughout the age spectrum and one of its most severe manifestations, lupus nephritis (LN), may have devastating consequences at any age [1]. Renal disease occurs in 20 % to 75% of all SLE patients, mostly within the first 2 years after diagnosis [1,2]. SLE presenting in childhood (cSLE) accounts for 15 to 20% of all cases. It occurs in 15-20% before the age of 16 [1,3]. There are until now no studies about LN in Tunisian children. Therefore, we conducted a retrospective study describing epidemiological, clinical, biological and pathological features of LN and their correlations as well as prognostic factors.

Methods
The present study reports a cohort of 43 SLE patients with disease onset before the age of 16 year-old from January 1983 to December 2006. All patients fulfilled at least four of the American College of Rheumatology criteria for the classification of SLE [4]. We Hypertension was defined as blood pressure greater than the 95 th percentile for age and sex [5]. Estimated glomerular filtration rate (eGFR) was estimated by the formula of Schwartz et al. [6] for eGFR. Renal failure was defined as eGFR less than 60 ml/min per 1.73m 2 . Nephrotic syndrome was defined as proteinuria greater than 50 mg/kg in 24-h urin and serum albumin less than 3 g/dl.

Results
The study population consisted in 43 children with LN. There were 39 females and four males (The female to-male ratio: 9.75/1). The mean age at onset of lupus was 11.95 years (range: 6-16 years). Class III was associated with class V in 5 patients (11.6 %) and class IV was associated with class V in 8 patients (18.6%).
Proliferative lesions were found in 34 patients (79%). There was no significant difference in LN presentation between histopathological groups. In the other hand, there was no significant difference in chronicity and activity scores between proliferative classes. were more frequent in the deceased group but without significant correlations while the probability of developing ESRD was statistically higher in patient with renal failure at presentation or tubulointerstitial fibrosis in renal biopsy ( Figure 2 and Figure 3).  [2,8]. In Tunisia, S.Yaalaoui [9] has reported 16 patients with cSLE during a period of 9 years. In Egypt, several studies [10,11] have reported a relatively high prevalence of lupus in Egyptian children compared to Tunisian children. The disease was diagnosed before the age of 10 years in 17 % of patients. The majority of cSLE children were aged above 10 years [12,13]. Children with SLE are more susceptible than adults to nephritis [10,12]. In a study of S.Yaalaoui, renal involvement was found in 75 % of patients [9]. In Arab countries, pediatric lupus nephritis was noted in 29 to 80% of cases [13,14]. In western countries, renal involvement was reported also in 30 to 80 % [15,16].

Discussion
In our study, female to-male ratio was 9.75/1 while in the other reports, there was a lower predilection for female gender in childhood lupus [17,18]. Concerning renal manifestations, hematuria and proteinuria are the most commonly identified abnormalities, being reported in 67 to 100% of affected children in different series [8,16]. In our group, proteinuria was observed in 97.7%, and nephrotic syndrome was found in 62.7 % of patients and this is slightly higher than in other studies [17]. Hypertension varies significantly across different studies, from 30 to 50 % [18,19]. In our study, hypertension was found in 39 % of patients. The frequency of renal failure ranged from 20 to 70% [20]. In our study, renal failure at presentation was noted in 25.5% and this is significantly less common than in the study reported by S.Yaalaoui et al. (66.6%) [9]. When compared to Tunisian adult series of SLE [21], renal manifestations appear to be similar to our group. This result was also compatible with the findings reported by Mak et al [22].
In our study, The most frequent histopathological finding was class IV LN (48.8%), approaching the results from several reports, ranging from 37% to 46% [23,24]. In our study, proliferative lesions were observed in 79% of cases and this result was similar to an italian study [25]. Class V LN has been reported to have a lower incidence in children [26]. In our group, pure class V LN was found only in 11.6% of cases. In our group, patients with class IV LN have more hypertension and renal failure at presentation, while nephrotic syndrome was more common in class V LN.
The treatment recommendations for childhood lupus nephritis have been extrapolated from adult studies or derived from past reports of case series. Thereby, new regimens using steroids in addition to lower doses and shorter treatment durations of intravenous CYC or MMF can been used in children with low toxicity without sacrificing efficacy of therapy [27]. In the other hand, rituximab can improve disease activity but controlled studies are required [28]. All of our patients received a higher initial steroids or equal to 1mg / kg / day (97.4%). Immunosuppressive therapy was administered in 23 % of cases at induction therapy.
The outcome for pediatric lupus nephritis has improved over the last 30 years with the addition of corticosteroids to cytotoxic agents [8,17]. In our study group, complete remission and partial remission were observed in 45.7 % and 11.6% respectively after a mean were predictive of renal flares [15,22]. In our study, only increased creatinine at presentation was associated with renal relapse and estimated renal survival was lower than the majority of pediatric series [13,17,20]. There was no difference in renal survival between different histological classes. However, tubulointerstitial fibrosis was associated with a poor renal outcome. The mortality rate in our study group was 17.1%. The mortality rate in other studies has varied from 5% to 30% [27][28].

Conclusion
In conclusion, lupus nephritis is rare in children.  The high incidence of proliferative lesion (class III or IV LN) on renal biopsy. Table 1: Extra-renal manifestations