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LUPUS AROUND THE WORLD

Childhood lupus nephritis in a developing country—24 years’ single-center experience from North India S Singh1, B Abujam1, A Gupta1, D Suri1, A Rawat1, B Saikia2, R Walker Minz2, K Joshi3 and R Nada3 1

Pediatric Allergy Immunology Unit, Advanced Pediatrics Centre; 2Department of Immunopathology; and 3Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Objective: Data on outcome of childhood lupus nephritis from developing countries are sparse. This study looks at outcome in children with lupus nephritis from a federal government-funded teaching hospital in North India. Methods: This study included children less than 14 years of age with lupus nephritis who presented to a single center during a period of 24 years (1991 to 2013). Data on clinical characteristics and outcome were extracted from medical records. The primary outcome was actuarial survival (time-to-death) and secondary outcome was actuarial renal survival using Kaplan-Meier analysis. A worst-case scenario that assumed children who were lost to follow-up as having either died or gone into end-stage renal disease was also calculated. Log-rank test and Cox-regression were used to assess difference in survival by histological class and predictors of poor outcome, respectively. Results: This study included 72 children, with a female:male ratio of 3:1, mean (SD) age at onset of lupus 9.3 (2.4) years and mean (SD) time from onset-to-nephritis being 9.4 (12.6) months. Renal biopsy was conducted in 53 children. The most common histological class was class IV (35 children). Mortality occurred in 22 children (30%), with half of these occurring at presentation. The two important causes of death were infection and end-stage renal disease. Actuarial survival was 81%, 67% and 59% at one, five and 10 years, respectively. In the worst-case scenario, actuarial survival was 72%, 53% and 38%, respectively. Renal survival was 96%, 89% and 78% (worst-case scenario 86%, 73% and 52%) at one, five and 10 years, respectively. There was no difference in survival by histological class. On univariate analysis, serum creatinine at presentation (hazard ratio ¼ 2.2 (95% CI 1.3–3.9)) and serious infection (hazard ratio 7.9 (95% CI 2.6–23.5)) were statistically significant predictors of time-todeath. Conclusion: Outcome of children with lupus nephritis from India is worse than developed countries. Nearly one-third of the children died, half at presentation, with common causes being infection and end-stage renal disease. Lupus (2015) 0, 1–7. Key words: Childhood systemic lupus erythematosus; lupus nephritis; disease activity

Introduction Childhood-onset systemic lupus erythematosus (cSLE) is the most common autoimmune disease leading to chronic kidney disease in children. Onset in childhood occurs in 10–15% of all cases of SLE. Onset in childhood compared to adults is associated with more frequent and severe renal and central nervous system involvement.2 Indeed, studies have found a worse

Correspondence to: Surjit Singh, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. E-mail: [email protected] Received 6 October 2014; accepted 7 January 2015

outcome of cSLE as compared to lupus in adults.3 In addition, ethnic factors also affect the severity and outcome of SLE. African Americans and Hispanics have poorer outcome as compared to Caucasian patients.4 There are some data that lupus nephritis in Indian patients also has a worse prognosis than developed countries.5 The aim of this study is to assess longterm outcome of lupus nephritis in Indian children (onset of lupus nephritis less than 14 years), followed up at a tertiary care center in North India over 24 (1991–2013) years. We had previously published outcome in 25 of these children followed up for a duration of 12 years.6

! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

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10.1177/0961203315570166

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Materials and methods This was a retrospective study that included children diagnosed with lupus nephritis in a tertiary-care university hospital in North India. This hospital is federal government funded and provides subsidized medical care to all patients and free care to below-poverty-line patients. This hospital subsidy (or free care) covers charges for outpatient consultation, admission and investigations. However, most drugs and consumables for dialysis have to be funded by the patients themselves or directly through a government scheme. This retrospective study was approved by the departmental review committee. Participants Children were included if they (1) fulfilled the American College of Rheumatology 1997 revised criteria for diagnosis of SLE,7 (2) had lupus nephritis, defined as persistent proteinuria (proteinuria  500 mg/day or urine protein/creatinine ratio  0.5) or active urine sediment (hematuria  5/ high-power field (hpf) or any cellular casts) and (3) had onset of lupus and nephritis before 14 years of age. Clinical features Information was extracted from the medical records and included age at first presentation, age at diagnosis of SLE, age at onset of nephritis, clinical features, immunological profile, renal biopsy reports, induction and maintenance therapy, the clinical and renal status at one year after nephritis, complications and outcome. Nephrotic syndrome was defined as the presence of edema, massive proteinuria (urine protein/creatinine  2) and hypoalbuminemia (serum albumin < 25 g/l). Nephritic syndrome was defined by presence of microscopic hematuria, hypertension and renal impairment. Hypertension was defined as elevation of blood pressure above the 95th percentile for age and gender, and those requiring antihypertensive medication. Laboratory tests and renal biopsy Antinuclear antibody (ANA) was measured by indirect-immunofluorescence and a titer of 1/80 or higher was reported as positive. Anti-doublestranded DNA (anti-dsDNA) antibodies were measured by enzyme-linked immunosorbent assay (ELISA). Complement levels were measured by nephelometry. All renal biopsy specimens were

examined by light microscopy and immunofluorescence. They were classified according to the World Health Organization (WHO): class II (mesangial glomerulonephritis); class III (focalproliferative glomerulonephritis); class IV (diffuseproliferative glomerulonephritis) and class V (membranous glomerulonephritis).8,9 In case of a renal biopsy not being performed, reasons for the same were extracted from records. Long-term outcome The primary outcome measure was actuarial survival (time to death). The secondary outcome measure was renal survival, i.e. time to end-stage renal disease (ESRD) (defined as requiring renal replacement therapy). When calculating renal survival, death due to a reason other than ESRD led to censoring. We additionally calculated the worstcase scenario by assuming all patients who had been lost to follow up as having had the event of interest (death or ESRD). Therapy for lupus nephritis The usual protocol for children with nephritis in our center is described. All children received steroids (1 mg/kg/d prednisolone equivalent) for one to two months followed by slow tapering over six months to one year. Among patients with proliferative nephritis (class III or IV), usual induction therapy included monthly pulses of intravenous cyclophosphamide (15 mg/kg) and in a minority mycophenolate mofetil. Induction was usually administered for six months to one year based on the physician’s assessment of response. The usual maintenance regimen included quarterly pulses of intravenous cyclophosphamide or oral azathioprine (1–2 mg/kg/day) for a minimum duration of two years. All children with lupus received hydroxychloroquine (6.5 mg per kg per day) unless contraindicated. Response to treatment/short-term outcome at one year The patients’ response to treatment in the short term was defined as either complete or partial remission, active disease, progression or ESRD as per the definitions below. (1) Complete remission (CR) was defined as normal renal function (creatinine  1.5 mg/dl), absence of proteinuria (Up/c < 0.2 or 24 hours urine protein < 200 mg) and absence of active sediments). (2) Partial remission (PR) was defined normal renal function (creatinine  1.5 mg/dl), at least a 50% reduction in

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proteinuria and absence of massive proteinuria (Up/c < 3 or 24-hour urine protein < 3 g) and absence of any active urinary sediments. (3) Nonresponse or progression or active disease (NR/P) was defined as < 50% reduction in proteinuria or the presence of massive proteinuria (Up/c>3 or 24-hour urine protein > 3 g) or presence of any active urinary sediments. (4) ESRD was defined as requiring renal replacement therapy. Relapses were defined as recurrence of clinical disease, requiring an increase in dose to high-dose steroid (prednisolone equivalent of 1 mg/kg/day) or addition of an additional immunosuppressive agent. Statistical analysis SPSS version 15 (Chicago, IL, USA) was used for statistical analysis. Data are presented as meanSD or median (interquartile range). Survival data were analyzed using Kaplan-Meier survival curves. Log-rank test was used to test difference in survival between different groups. Cox-regression was used to determine predictors and hazard ratios (HRs) were calculated.

Results Patient characteristics Renal involvement (lupus nephritis) occurred in 72 (58%) of the 124 children who were diagnosed with SLE in our center from 1991 to 2013. This study included these 72 children (male (M):female (F) ¼ 17:55) with lupus nephritis. The mean (SD) age at onset of SLE was 9.4  2.4 years. Onset of SLE before 5 years of age occurred in four, onset between 5 and 10 years in 40 and onset between 10 and 14 years in 28. Mean (SD) duration between onset of SLE to detection of nephritis was 9.4  12.6 months. Lupus nephritis occurred within the first year after onset of SLE in 81% of the children and within six months in 61% of the children (Table 1). Common clinical features at presentation were fever, malar rash, oral ulcers and arthritis (Table 2). Proteinuria was the most common urinary abnormality at onset of nephritis, being present in 94.4%. At onset, 14 patients were in renal failure, including two patients with Class V nephritis (Table 3). Renal biopsy and histology was available for 53 children with lupus nephritis, and the most common histological class was class IV (present in 35 patients) (Table 1). The reasons for not performing biopsies were available in 14 patients; the most common reason being inability

Table 1 Baseline characteristics and demographic profile of childhood-onset lupus nephritis (n ¼ 72) included in this study. Characteristic Gender (male:female) Age at onset of SLE (years), meanSD Age at presentation (years), meanSD Onset to nephritis, duration (months), meanSD Lupus nephritis at presentation to our center, N (%) Antinuclear antibody positive, N (%) Anti-dsDNA antibody at presentation, N (%) Low C3 at presentation, N (%) Low C4 at presentation, N (%) Renal biopsy performed, N (%) Histological class on renal biopsy, N (%) Class II Class III Class IV Class V Thrombocytopenia Leukopenia Hemoglobin < 8 g/dl

17:55 9.4  2.4 10.5  2.1 9.4  12.6 55 (76.4) 68/72 (94.4) 42/48 (87.5) 36/44 (81.8) 24/28 (85.7) 53 (75) 10 (18.9) 1 (1.9) 35 (66.0) 7 (13.2) 16 (23.5) 4 (5.5) 21 (29.8)

SLE: systemic lupus erythematosus; anti-dsDNA: anti-doublestranded DNA.

Table 2 Clinical features in children with lupus nephritis at presentation (n ¼ 72). Clinical features

At onset

Cumulative (ever)

Fever Arthritis Malar rash Oral ulcers Photosensitivity Alopecia Serositis Hematological Central nervous system Renal

62 28 37 32 20 9 8 24 12 43

63 38 47 44 28 10 19 35 17 72

(86.1) (38.9) (51.4) (44.4) (27.8) (12.5) (11.1) (33.3) (16.6) (59.7)

(87.5) (52.8) (65.3) (61.1) (38.9) (13.9) (26.4) (48.6) (23.6) (100)

to bear the cost of the procedure (in eight patients). Other causes were poor general condition of the patient in three, ongoing anticoagulation in one, thrombocytopenia in one and refusal by caregivers in one child. Treatment regimens The most common agent used for induction and maintenance was intravenous pulses of cyclophosphamide. The mean (SD) number of cyclophosphamide pulses received was 10.4 (4.6). The induction regimens are summarized in Figure 1. Among patients with class II nephritis, many children received induction with cytotoxic drugs because of the presence of extra-renal disease. Only three of seven children with class V lupus Lupus

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Table 3

Renal histology and the renal manifestations at diagnosis of lupus nephritis.

Renal manifestations

Total (N ¼ 72)

Class II (N ¼ 10)

Class III (N ¼ 1)

Class IV (N ¼ 35)

Class V (N ¼ 7)

Non-biopsied (N ¼ 19)

Anasarca Oliguria Hypertension Proteinuria Creatinine > 1.5 mg/dl Nephrotic syndrome Hematuria Leukocyturia 24 hour urine protein (grams/24 hours) (meanSD)

39 16 27 68 14 50 45 24

6 0 5 9 0 7 5 2 2.2  2.2

1 0 0 1 0 1 1 0 2.5

21 10 15 34 10 31 26 14 3.3  2.4

3 2 3 7 2 5 2 2 4.4  4.3

8 4 4 17 2 6 11 6 2.2  1.9

(54.2) (22.2) (37.5) (94.4) (19.4) (69.4) (62.5) (33.3)

Figure 1 Flow diagram showing the various induction regimen and maintenance treatment of the 72 children with lupus nephritis. CYC: cyclophosphamide; MMF: mycophenolate mofetil; IVIG: intravenous immunoglobulin; LFU: Lost to follow-up.

nephritis received cytotoxic therapy. One child received rituximab for development of optic neuritis while on ongoing cyclophosphamide pulse therapy. Three children were on warfarin for pulmonary thromboembolism with lupus anticoagulant positivity. One patient who presented with active lupus nephritis and sepsis received intravenous immunoglobulin (IVIG). Follow-up and outcome The mean (SD) duration of follow-up was 4.0  4.4 years (range 0.2–20 years) with a total follow-up of 287 patient years. Among the 72 children with nephritis, 22 (30%) children died, with 11

(15%) of the deaths occurring at presentation. Common reasons for death was severe infections and complications related to ESRD (Table 4). At last follow-up, 41 patients were in CR, two in PR and seven had active disease. Primary outcome, i.e. the actuarial survival, was 81%, 67% and 59% at one, five and 10 years, respectively. In the worstcase scenario, the corresponding figures are 72%, 53% and 38%, respectively. Renal survival was 96%, 89% and 78% (worst-case scenario being 86%, 73% and 52%) at one, five and 10 years, respectively (Figure 2). There was no difference in actuarial survival or renal survival among children with class II, class IV, class V and those children who were not biopsied (Figure 3). In addition, there

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Table 4

Causes of death in children with lupus nephritis in our cohort (N ¼ 72).

Cause of death

Died at initial presentation (N ¼ 11)

Died later (N ¼ 11)

Severe infection

6 Sepsis 4 (polymicrobial 3, E. coli 1) Disseminated CMV þ Zygomycosis 1 Not specified 1 1

3 Disseminated tuberculosis 2 Invasive aspergillosis 1

Disease activity

End-stage renal disease/CKDa complications Pulmonary thromboembolism Cause not known

4 Hypertensive emergency 1 E. coli sepsis 1 Unknown 2 – –

1 Renal failure with hypertensive emergency 1 3 Hypertensive emergency 2 Unknown 1 1 3

a

End-stage renal disease ¼ renal failure requiring renal replacement therapy. CKD: chronic kidney disease, defined as elevation of serum creatinine above normal (>1.5 mg/dl) for more than three months; CMV: cytomegalovirus.

Figure 2 Kaplan-Meier survival curve showing comparison of overall survival and renal survival in our cohort of childhood-onset lupus nephritis (N ¼ 72).

was no difference in actuarial survival among children with nephritis at presentation compared to those who developed nephritis later (figure not shown). Among the predictors for the primary outcome, on univariate analysis, only baseline serum creatinine (HR ¼ 2.2 (95% confidence interval (CI) 1.3–3.9)) and serious infection (HR 7.9 (95% CI 2.6–23.5)) were statistically significant predictors of time-to-death.

Complications Among complications related to lupus de novo as well as related to treatment, infection was observed in one-fourth of children. The most common infection was pyoderma. Six children developed tuberculosis, two of whom died. Invasive fungal infection occurred in two patients and both succumbed to their illness. One-fifth of children Lupus

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Figure 3 Kaplan-Meier survival curve showing comparison of overall survival and renal survival of class II, IV, V and not biopsied children with lupus nephritis in our cohort. Actuarial renal survival.

developed a cataract, while one-fourth had stunted growth.

Discussion The present study is a retrospective analysis of 72 children with lupus nephritis from an Indian center. This study found an M:F ratio of 1:3, which is similar to previous studies on childhood lupus nephritis from India, Thailand, Taiwan, Egypt and some Caucasian studies.6,10–12 However, a majority of the children in our study were younger than 10 years of age, which is much higher than the previous Indian series10 and the Paediatric Rheumatology International Trials Organisation (PRINTO) series by Perfumo and Martini.13 This can be attributed to a strict division of patients in our hospital, with children above 14 years of age being managed by the adult renal physicians. Renal involvement was observed in 58% (72/124) of the children in our cohort of cSLE. Similar figures and incidence of renal involvement have been reported in cohorts from China (51%),14 United Kingdom (47%),15 the United States (56%)16 and Canada (55%).12 On biopsy, class IV lupus nephritis (64%) was found to be the most common histopathological class, similar to other cohorts. It was associated with higher prevalence of hypertension, anasarca, increased serum creatinine and hematuria

on urinalysis. We could not obtain data on how many renal biopsies showed a mixed pattern. Somewhat different from previous data, our study found nephrotic range proteinuria in more than 67% of children with nephritis, which is higher than previously reported figures of 18–51%.10,17 Survival of children in our study was 67% and 59% at 5 and 10 years, respectively. This is lower than developed countries and other parts of Asia. Indeed, many studies now report five-year survival rates of greater than 95%.17–21 The mortality rate in our study was 30%, which is in the higher range of 3–32.7% reported in various studies.22–24 Many of the deaths were related to serious infections. Indeed, occurrence of a serious infection was an important predictor of time-to-death. Studies from developing nations have also implicated infection to be responsible for half to two-thirds of deaths in SLE patients.10,23,25,26 The relatively high occurrence of tuberculosis in our study (leading to death in some cases) has also been found in previous Indian studies.10,23 This probably reflects the high prevalence and transmission rates of disease per se in our population with an annual risk of tuberculous infection being 1–2%. The deaths in children in our cohort were bimodal, with half of them occurring at initial presentation, which is different from the other major Indian study.10 The reason for the high number of deaths at initial presentation can be attributed to our institution being a referral center. Indeed, many

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children presented with severe infections, and even ESRD. The same reasons were also responsible for most of the deaths that occurred later. In our cohort, occurrence of ESRD always led to mortality. This is a reflection of the socio-economic conditions in the patient population our hospital caters to (being a government hospital), most of whom cannot afford renal replacement therapy. In this context, it is difficult to speculate on what is the contribution of other factors like ethnicity and genetics in the determination of prognosis of patients in our cohort. The limitations of our study are the retrospective collection of data, and number of patients lost to follow up. However our study is important because it gives an important perspective on the long-term outcome of lupus nephritis in a young lupus cohort from a developing country, in a resource-constrained setting.

Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.

Conflict of interest statement The authors have no conflicts of interest to declare.

References 1 Cassidy JT. Textbook of pediatric rheumatology, 6th ed. Philadelphia: Saunders, 2011, pp. xvi, 794. 2 Brunner HI, Gladman DD, Iban˜ez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adultonset systemic lupus erythematosus. Arthritis Rheum 2008; 58: 556–562. 3 Alarco´n GS, Friedman AW, Straaton KV, et al. Systemic lupus erythematosus in three ethnic groups: III. A comparison of characteristics early in the natural history of the LUMINA cohort. LUpus in MInority populations: NAture vs. Nurture. Lupus 1999; 8: 197–209. 4 Klein-Gitelman M, Reiff A, Silverman ED. Systemic lupus erythematosus in childhood. Rheum Dis Clin North Am 2002; 28: 561–577, vi-vii. 5 Kumar A, Malaviya AN, Singh RR, Singh YN, Adya CM, Kakkar R. Survival in patients with systemic lupus erythematosus in India. Rheumatol Int 1992; 12: 107–109.

6 Singh S, Devidayal, Minz R, Nada R, Joshi K. Childhood lupus nephritis: 12 years experience from North India. Rheumatol Int 2006; 26: 604–607. 7 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725. 8 Appel GB, Silva FG, Pirani CL, Meltzer JI, Estes D. Renal involvement in systemic lupus erythematosus (SLE): A study of 56 patients emphasizing histologic classification. Medicine (Baltimore) 1978; 57: 371–410. 9 Sommers SC, Bernstein J. Kidney pathology decennial, 1966–1975. New York: Appleton-Century-Crofts, 1975, pp. x, 687. 10 Hari P, Bagga A, Mahajan P, Dinda A. Outcome of lupus nephritis in Indian children. Lupus 2009; 18: 348–354. 11 Huang JL, Yeh KW, Yao TC, et al. Pediatric lupus in Asia. Lupus 2010; 19: 1414–1418. 12 Hiraki LT, Benseler SM, Tyrrell PN, Harvey E, Hebert D, Silverman ED. Ethnic differences in pediatric systemic lupus erythematosus. J Rheumatol 2009; 36: 2539–2546. 13 Perfumo F, Martini A. Lupus nephritis in children. Lupus 2005; 14: 83–88. 14 Lee PY, Yeh KW, Yao TC, Lee WI, Lin YJ, Huang JL. The outcome of patients with renal involvement in pediatric-onset systemic lupus erythematosus—a 20-year experience in Asia. Lupus 2013; 22: 1534–1540. 15 Watson L, Leone V, Pilkington C, et al. Disease activity, severity, and damage in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort. Arthritis Rheum 2012; 64: 2356–2365. 16 Pineles D, Valente A, Warren B, Peterson MG, Lehman TJ, Moorthy LN. Worldwide incidence and prevalence of pediatric onset systemic lupus erythematosus. Lupus 2011; 20: 1187–1192. 17 Bogdanovic´ R, Nikolic´ V, Pasic´ S, et al. Lupus nephritis in childhood: A review of 53 patients followed at a single center. Pediatr Nephrol 2004; 19: 36–44. 18 Yang LY, Chen WP, Lin CY. Lupus nephritis in children—a review of 167 patients. Pediatrics 1994; 94: 335–340. 19 Wong SN, Tse KC, Lee TL, et al. Lupus nephritis in Chinese children—a territory-wide cohort study in Hong Kong. Pediatr Nephrol 2006; 21: 1104–1112. 20 Lee BS, Cho HY, Kim EJ, et al. Clinical outcomes of childhood lupus nephritis: A single center’s experience. Pediatr Nephrol 2007; 22: 222–231. 21 Hiraki LT, Feldman CH, Liu J, et al. Prevalence, incidence, and demographics of systemic lupus erythematosus and lupus nephritis from 2000 to 2004 among children in the US Medicaid beneficiary population. Arthritis Rheum 2012; 64: 2669–2676. 22 Hagelberg S, Lee Y, Bargman J, et al. Longterm followup of childhood lupus nephritis. J Rheumatol 2002; 29: 2635–2642. 23 Dhir V, Aggarwal A, Lawrence A, Agarwal V, Misra R. Longterm outcome of lupus nephritis in Asian Indians. Arthritis Care Res 2012; 64: 713–720. 24 Bakr A. Epidemiology treatment and outcome of childhood systemic lupus erythematosus in Egypt. Pediatr Nephrol 2005; 20: 1081–1086. 25 Lee PP, Lee TL, Ho MH, Wong WH, Lau YL. Recurrent major infections in juvenile-onset systemic lupus erythematosus—a close link with long-term disease damage. Rheumatology (Oxford) 2007; 46: 1290–1296. 26 Vachvanichsanong P, Dissaneewate P, McNeil E. Diffuse proliferative glomerulonephritis does not determine the worst outcome in childhood-onset lupus nephritis: A 23-year experience in a single centre. Nephrol Dial Transplant 2009; 24: 2729–2734.

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Childhood lupus nephritis in a developing country-24 years' single-center experience from North India.

Data on outcome of childhood lupus nephritis from developing countries are sparse. This study looks at outcome in children with lupus nephritis from a...
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