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Abstract Twenty-five children (20 girls and five boys) with lupus nephritis seen over last 12 years, were eval- uated. Twenty underwent renal biopsies. Cyclophos ...

Rheumatol Int (2006) 26: 604–607 DOI 10.1007/s00296-005-0036-9

O R I GI N A L A R T IC L E

Surjit Singh Æ Devidayal Æ Ranjana Minz Ritambhra Nada Æ Kusum Joshi

Childhood lupus nephritis: 12 years experience from North India

Received: 9 September 2004 / Accepted: 28 July 2005 / Published online: 24 September 2005  Springer-Verlag 2005

Abstract Twenty-five children (20 girls and five boys) with lupus nephritis seen over last 12 years, were evaluated. Twenty underwent renal biopsies. Cyclophosphamide pulse therapy was used in eight patients (median 14 pulses, range 6–16) with severe disease or histological class. Four of these eight patients became asymptomatic (class IV, 2; class II and V, one each) after 4–24 months. Two (class III and IV, one each) died after a stable chronic renal insufficiency for almost a decade; one died 9 months after diagnosis (class IV). Of the 12 patients who underwent biopsy but were not treated with cyclophosphamide, six became asymptomatic during follow up (class II, four patients; class VI and V, one each), two continued to have proteinuria (class II), one (class IV) had raised ESR but normal renal functions and two died (class IV). Three of the five patients who were not biopsied remained asymptomatic; two were lost to follow up. Mortality was seen only with class III (one patient) or class IV (five patients) lesions. Outcome in lupus nephritis depends largely on WHO histological class. Cyclophosphamide pulse therapy is associated with a favorable outcome. Keywords Lupus nephritis Æ Treatment Æ Children

S. Singh (&) Æ Devidayal Advanced Pediatric Centre, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India E-mail: [email protected] Tel.: +91-172-2747585 Fax: +91-172-2744401 R. Minz Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India R. Nada Æ K. Joshi Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India

Introduction Nephritis is an important cause of long-term morbidity and mortality in children with systemic lupus erythematosus (SLE). Therapy is mainly based on World Health Organization (WHO) histological class and includes immunosuppressive drugs like cyclophosphamide, azathioprine and cyclosporin in addition to corticosteroids and supportive care [1]. Intermittent cyclophosphamide pulse therapy, evaluated extensively in adults, has been shown to be associated with improved long-term outcomes [2–4]. There is paucity of literature from developing countries on childhood lupus nephritis especially on use of pulse cyclophosphamide therapy [5–7]. The mentioned studies also show rather mixed treatment outcomes. To add to this existing knowledge, we reviewed medical records of 25 children with lupus nephritis seen at our institute over last 12 years with a view to determine their clinical course.

Patients and methods Systemic lupus erythematosus was diagnosed in 40 children who attended Pediatric Rheumatology and Immunology Clinic of Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh between February 1991 and July 2003. The diagnosis of SLE was based on the revised 1982 American College of Rheumatology criteria [8]. All patients fulfilled a median of six (range 4–8) ACR criteria. Out of these 40 children, lupus nephritis was diagnosed in 25 (62%). Renal biopsies were done based on their urinary abnormalities i.e. proteinuria (>40 mg/m2/h), hematuria (10 RBCs/HPF) or azotemia (urea>40 mg/dl, creatinine>1.0 mg/dl). Those who had severe nephritis (eight patients, 32%) clinically and/or histologically and had received at least six cyclophosphamide pulses were evaluated separately.

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Renal biopsies Ultrasound guided percutaneous renal biopsies were performed in 20 patients. Milder urinary abnormalities or lack of consent were the reasons for not doing biopsies in the other five patients. Specimens were subjected to light microscopy and immunofluoresence examinations using standard fixation and staining procedures. Lesions were classified according to modified WHO classification system [9]. In addition activity (AI) and chronicity indices (CI) were allotted to each biopsy specimen as modified from Austin et al. [10]. This was done only for patients who received pulse cyclophosphamide therapy. The AI was graded on a scale of 0–24 by summing up the individual score (0–3+) for each of the following histological parameters: endocapillary hypercellularity, leukocyte infiltration, subendothelial deposits, fibrinoid necrosis/karyorrexis, cellular crescents and interstitial inflammation. Similarly, CI was obtained by adding the individual scores (0–3+) for each of the following: glomerular sclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis. Repeat biopsies were not done. Therapy protocol The initial evaluation included recording their clinical status and laboratory investigations including hemogram, urinalysis, urea, creatinine, 24 h urine protein and anti-nuclear factor (ANF). Anti-double stranded DNA (dsDNA) and serum complement titres could not be done in all patients. Treatment decisions were based on disease activity and histological class. All children received prednisolone (usually 1–2 mg/kg/day) for control of disease activity. This was tapered off slowly to the lowest possible dose required to sustain remission. Intravenous pulse therapy was used in 12 patients; only eight of these received six or more pulses. In the other four, pulse therapy could not be continued either due to their death (three patients) or inadequate follow up (one patient). A pulse consisted of intravenous infusion of cyclophosphamide in a dose of 500–750 mg/m2 given over 1–2 h. Adequate hydration was ensured over the next 24 h. These pulses of cyclophosphamide were given monthly for 6–12 months followed by quarterly pulses for 1 year. Two children also received oral azathioprine Table 1 Renal biopsy details of patients

as maintenance immunosuppressive therapy. Hypertension was managed with nifedipine, enalapril and propranolol used either singly or in combination. At each follow up visit, monitoring was done for therapy related complications in addition to reassessment of clinical and laboratory parameters. Mean duration of follow up was 6.5 years (range 9 months– 12 years). Outcome was defined using a modification of the schema given by Yang et al. [6] as follows: (a) Clinically improved or controlled: urinalysis, renal functions show improvement or no progression. (b) Progressed: deteriorating renal functions. (c) Chronic renal failure or ESRD: requiring repeated dialysis or transplanted. (d) Death: due to renal or non-renal cause. (e) Lost follow up: no visits for more than 1 year.

Results The series comprised of 25 patients; there were 20 girls and five boys (M:F::5:1). Their mean age was 9.9 years (range 4–12.5 years). Duration of their disease at presentation varied from 1 month to 4 years (mean, 11.5 months) and duration of nephritis 0 day (detected at admission) to 24 months (mean, 6.5 months). The interval between onset of lupus nephritis and renal biopsy varied from 1 week to 26 months (mean, 7 months). All patients had nephrotic range proteinuria; mean level was 222 mg/m2/h (range 40–560 mg/m2/h) in a 24 h urine specimen. All except three patients had microscopic hematuria. Mean serum urea was 76.6 mg/ dl (range 20–196) and creatinine 1.6 mg/dl (range 0.6– 4.2 mg/dl). Serum C3 levels ranged between 70 and 100 (mean, 78.5 mg/dl); normal level 77–195 mg/dl. Diffuse ANF positivity (4+) was seen in 12 patients while five had 3+ and eight had 2+ positivity. The degree of ANF positivity did not correlate with severity of nephritis. Anti-dsDNA titers were 10–12 times the normal values in ten patients; only two had normal levels. Class II nephritis was seen in eight patients (40%), class III in one patient (5%), class IV in nine (45%) while class V in two patients (10%). Average AI and CI per biopsy specimen were 5.6 and 2, respectively (Table 1). Eight children received a median of 14 pulses of cyclophosphamide (range 6–16). Two patients were given

S. no.

Duration from onset to biopsy

Total no. of glomeruli

Activity index

Chronicity index

WHO class

1. 2. 3. 4. 5. 6. 7. 8.

1 week 1 week 24 months 26 months 1 month 5 months 2 weeks 1 week

10 8 6 17 7 12 30 25

8 3 9 5 6 2 9 11

1 9 1 1 1 1 1 1

II III IV V IV II IV IV

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maintenance azathioprine for an average of 20 months. Table 2 summarizes the clinical and laboratory data of eight patients treated with cyclophosphamide pulses. Clinical course in follow up In eight patients who received pulse therapy, hematuria disappeared in all patients except one over an average of 4.6 months while proteinuria resolved in four patients after a mean duration of 8.2 months. Four of these became asymptomatic after duration varying between four and 24 months. Patient no. 6 also had become asymptomatic except mild proteinuria before being lost to follow up. After an initial 50% decrease in serum urea and creatinine and then stabilization for next 7 years, continuous worsening back to the pre-therapy levels occurred over the last 3 years in one patient with class III nephritis. She died recently on her way to hospital possibly due to hypertensive encephalopathy (poor adherence to therapy). Her serum creatinine had remained below 3.0 mg/dl throughout. Similarly, patient no. 3 remained asymptomatic except for proteinurea for initial 7 years, then had recurrence of azotemia and a stable renal insufficiency for almost 3 years before she died of an unascertained cause at home. However, both these patients had been offered renal transplantation, which could not be carried out. Uncontrolled disease activity resulted in one death in the treated group. Of the 12 patients who underwent biopsy but were not treated with cyclophosphamide, six became asymptomatic during follow up (class II, four patients; class VI and V, one each), two continued to have proteinuria (class II), one (class IV) had raised ESR but normal renal functions and three died during initial admission (class IV). Three of the five patients who were not biopsied remained asymptomatic; two were lost to follow up. Relapses: one patient who had relapsed twice, died during second relapse. Relapse of mild proteinuria resolving of its own occurred in another patient. Of the significant therapy related complications, leucopenia occurred twice in one patient (no. 3) requir-

ing temporary interruptions of therapy. Three developed reversible alopecia. None of our patients had hemorrhagic cystitis. There was no major episode of septicemia although recurrent urinary tract infections (E. coli) occurred in one patient (no. 2). Two patients developed bilateral subcapsular cataract; both had received corticosteroids for a mean duration of 3 years before cyclophosphamide pulses. The safety of pulse therapy on gonadal functions, however, remains unevaluated.

Discussion Our analysis shows that outcome in children with lupus nephritis generally depends on WHO histological class. Use of pulse therapy is associated with a favorable outcome. The effects of cyclophosphamide pulses on disease activity were significant. In majority of these patients, the disease flares remained suppressed allowing a near normal quality of life with little organ dysfunction. This is particularly so in two patients (numbers 2 and 3) who could carry on with normal daily activities for almost a decade despite having derangements of renal functions. The lower relapse rates as compared to other series is significant as relapses increase the risk of renal function deterioration secondary to cumulative damage as well as cumulative toxicities of additional immunosuppressive therapy [11]. However, the proportionate mortality (37%) as compared to rest of the cohort of children followed up at our clinic (33%) is similar [12]. Controversies regarding treatment of class II, III and IV lesions exist due to difficulties in prognosticating lupus nephritis [10]. Although some generalizations can be made based on WHO class, precise prognostication in a given patient is quite difficult. Moreover, transformations from one class to another are well known [13]. These transformations occur in all directions; majority (40%) from histological class III to IV [10]. One of our patients with class III nephritis did progress to chronic renal failure despite aggressive therapy. In the largest series on pediatric lupus nephritis, at least 21 of the 55 children with class II lesions were treated with

Table 2 Clinical and laboratory characteristics of patients and their clinical outcome S. no.

Age (years)

Duration of disease/nephritis (months)

Salient pre-therapy features Pr/Hem/Ur/Cr/HTN

Time taken to resolve (in months) Pr/Hem/Ur/Cr/HTN

Total no. of CP pulses

Duration of F/U (years)

Clinical outcome

1. 2. 3. 4. 5. 6. 7. 8.

10 8 10 6 11 9 10 8

48/at adm 2.5/ adm 24/24 24/24 1/1 4/at adm 4/at adm 3/3

1.2/+/12.5/2.5/+ 5.6/+/196/4.2/+ 4.5/+/132/3.2/+ 1.6/+/18/1.3/ 0.4/ /28/0.9/ 2.9/+/140/2.0/+ 0.4/+/30/1.0/+ 1.8/+/30/1.0/+

9/2/9/9/9 UR/6/UR/UR/UR UR/2/9/9/30 4/4/ / / 8/ / / / UR/2/2/2/4 UR/UR/ / /UR 12/12/ / /24

14 16 16 12 16 12 6 14

4 10 10 10 9.75 1.5 0.75 4

A D D A A E D A

Pr proteinuria; Hem hematuria; Ur urea; Cr creatinine; HTN hypertension; UR, unresolved; CP cyclophosphamide

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immunosuppressive therapy although it was not clear whether favorable outcome could be attributed to immunosuppressive agents used [6]. Again all 13 patients with class V lesions were treated on similar lines. Despite aggressive therapy, the outcome of class V patients was only marginally better as compared to class IV (62% vs 55%) [6]. The prognostic value of AI and CI is limited [10] but combined with WHO classification, are useful for overall assessment of kidney damage. The CI is more predictive of outcome than AI with a CI of £ 1 associated with a 100% 10-year survival and ‡4 indicating a 32% 10-year survival. Only one patient in the present series (no. 2) had a high CI and consequent poor outcome. The other patient with a poor renal outcome (no. 3) had a low CI but severe histological class. We used azathioprine as maintenance immunosuppressive therapy in two patients to prevent disease exacerbations as well as to allow a reduction in steroid dose and hence minimize steroid side effects on physical appearance in these young adolescent girls. Other workers have also used azathioprine as an alternative maintenance therapy and found it useful in preserving renal functions and preventing relapses [14, 15]. It is an established fact that meticulous follow up improves survival in SLE [16] but ensuring follow up itself is a great difficulty in our set up. This is possibly the reason that despite some large series on childhood lupus [17, 18], there is no information about their follow up, especially concerning therapy. Our study is the first one from India on long-term follow up. In conclusion, our experience with cyclophosphamide pulse therapy indicates that this therapy is associated with favorable outcome. However, oncogenecity and gonadal toxicity of cyclophosphamide will remain a concern on long-term follow up.

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