| Abstract|| |
Context: Systemic lupus erythematosus is an autoimmune multisystem disease with a high predilection for renal involvement. Lupus nephritis develops in 20% to 75% within the first two years. Presentation varies from subnephrotic proteinuria to end-stage renal disease. Aims: To study clinical features, biochemical, and serological parameters and correlate with histological activity and chronicity score [modified National Institute of Health (NIH) score]. Settings and Design: Retrospective, cross-sectional, single-center based study in a tertiary care hospital of Eastern India. Subjects and Methods: We incuded 36 children with lupus nephritis diagnosed from February 2018 to March 2019. Laboratory data included were complete blood count (CBC), blood glucose, urine analysis, serum urea, creatinine, blood urea nitrogen (BUN), albumin, cholesterol, HBsAg, antihepatitis C virus (HCV) antibody, antistreptolysin O (ASO) titer, antinuclear antibody (ANA), myeloperoxidase antineutrophil cytoplasmic antibody (MPO ANCA), proteinase 3 antineutrophil cytoplasmic antibody (PR3 ANCA), double-stranded DNA (dsDNA), C3, and C4. Clinical parameters were age, sex, blood pressure (BP), skin lesions, arthralgia, edema, obesity. Renal biopsies examined with light microscopy, hematoxylin and eosin (H and E), periodic acid-Schiff (PAS), silver methanamine, Masson's trichrome (MT) stains. Immunofluorescence microscopy done with IgG, IgM, IgA, C3c, C1q, kappa, lambda antibodies. Statistical Analysis Used: Kruskal–Wallis and χ2 tests. Results: Mean age was 15.12 ± 3.49 and 12.5 ± 1.73 years for lupus nephritis (LN) with activity and LN without activity, respectively. Mean dsDNA was higher and mean C3 was lower (52.35 ± 22.21 mg/dl) in active LN. Mean 24-hour urinary protein was higher in LN without activity. Serum creatinine was raised in active LN. LN class III and IV showed higher activity than chronicity. Conclusions: Pediatric LN is proliferative and more active as compared with adult counterparts. Activity scores are much higher than chronicity scores.
Keywords: Activity, chronicity, lupus nephritis, pediatric, proliferative, systemic lupus erythematosus
|How to cite this article:|
Basu K, Karmakar S, Sengupta M, Roychowdhury A, Ghosh A, Bandopadhyay M. Pediatric lupus nephritis – An evil cousin of its adult counterpart: A single-center based experience from a tertiary care hospital of Eastern India. Indian J Pathol Microbiol 2020;63:397-404
|How to cite this URL:|
Basu K, Karmakar S, Sengupta M, Roychowdhury A, Ghosh A, Bandopadhyay M. Pediatric lupus nephritis – An evil cousin of its adult counterpart: A single-center based experience from a tertiary care hospital of Eastern India. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Sep 19];63:397-404. Available from: http://www.ijpmonline.org/text.asp?2020/63/3/397/291700
| Introduction|| |
Systemic lupus erythematosus (SLE) is an autoimmune disease with a frequent association of chronic inflammatory multisystem involvement both in adults and childhood population. SLE shows a high predilection for renal involvement. Lupus nephritis (LN) occurs in about 20% to 75% of all lupus patients, mostly within the first two years after diagnosis., Childhood SLE (cSLE) has got a higher prevalence of renal involvement than its adult counterpart, comprising about 40-80% of cSLE patients. In fact, pediatric LN has shown to cause more active lesions than adult LN. The presentation of pediatric LN remains highly variable ranging from subnephrotic range proteinuria to end-stage renal disease (ESRD). Practically incidence of proliferative glomerulonephritis (GN) is much higher in children. Recent advancement in therapeutic strategies has led to a greater improvement in short-term survival and prognosis., Nevertheless, diffuse proliferative GN is the most severe form and associated with progression to ESRD in many cases.,,,
Data regarding the correlation between clinical and biochemical parameters with the activity of the lesion following renal biopsy is sparse from Eastern India. We have conducted a retrospective study to analyze the spectrum of pediatric LN regarding its histological classification and its severity by histopathological and immunofluorescence microscopic study.
Aims of the study
- To study the clinical features, biochemical parameters, and serological features of childhood SLE patients
- To study, classify, and score [modified National Institute of Health (NIH) score] the renal biopsies obtained from childhood SLE patients after light and immunofluorescence microscopy
- To correlate clinical and biochemical parameters with the activity of the lesion following renal biopsy of childhood SLE patients.
| Subjects and Methods|| |
We have conducted a retrospective, cross-sectional, single-center based study at the Department of Pathology in collaboration with the Department of Nephrology and Rheumatology in a tertiary care hospital of Eastern India. We have included a total of 36 children of less than 18 years of age, who had presented with clinical features of LN.
Patients were included according to the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria for SLE classification fulfilling at least four criteria, with at least one clinical criterion and one immunologic criterion or LN as the sole clinical criterion in the presence of antinuclear antibodies (ANA) or anti-dsDNA antibodies.
We have excluded the patients with any other diagnosis, transplanted kidney, any primary neoplastic conditions, and inconclusive results. The total study period was 1 year from February 2018 to March 2019.
We have collected the following laboratory data for each of the subjects of this study: Complete blood count, blood glucose, urine analyses, serum urea, serum creatinine, blood urea nitrogen (BUN), serum albumin, serum cholesterol, serum hepatitis B surface antigen (HBs Ag), antihepatitis C antibody (anti-HCV Ab), antistreptolysin O (ASO) titer, serum antinuclear antibody (ANA), serum myeloperoxidase antineutrophil cytoplasmic antibody, (MPO ANCA), serum proteinase 3 antineutrophil cytoplasmic antibody (PR3 ANCA), serum double-stranded DNA (dsDNA), serum C3 and C4 levels. Clinical parameters (age, sex, blood pressure, skin lesions, arthralgia, edema, obesity) were also documented for each of the subjects.
Depending on the laboratory parameters and serological findings, all patients were categorized into four clinical syndromes:
Occult nephritis: Hematuria and/or mild proteinuria (0.5 g/d < quantitative urinary protein <1 g/d), or proteinuria (1 g/d ≤ quantitative urinary protein ≤3.5 g/d) without hematuria and eGFR ≥ 60 mL/min/1.73 m2.
Nephritic syndrome: Mild to moderate proteinuria (1 g/d ≤ urinary protein excretion ≤ 3.5 g/d) with hematuria, may be accompanied by edema and hypertension and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2.
Nephrotic syndrome: High proteinuria (urinary protein >3.5 g/d), low serum albumin (<30 g/L), hyperlipidemia, high degree of edema, and eGFR ≥60 mL/min/1.73 m2.
Renal failure: Decrease in GFR (eGFR <60 mL/min/1.73 m2), may be accompanied by anemia, hypertension, or edema.
Renal biopsies were done by Tru-cut semi-automated renal biopsy gun. All renal biopsy specimens were examined by the trained pathologists at our institute using a light microscope and immunofluorescence microscope. Hematoxylin and eosin (H and E), periodic acid Schiff (PAS), silver methamine, Masson's Trichrome (MT) stains were used for light microscopy. Specimens for immunofluorescence microscopy were received in Michelle's medium and were stained using fluorescein isothiocyanate (FITC) conjugated polyclonal rabbit antisera against human IgG, IgM, IgA, C3c, C1q, kappa, lambda. Immunofluorescence findings were categorized based on location and intensity from (+) to (++++). Control slides were also examined simultaneously.
We performed the Kruskal–Wallis test for comparisons between multiple groups, succeeded by an analysis of the χ2 test for categorical evaluation. Correlations were evaluated using Spearman's rank correlation. P value <0.05 was considered as significant. We used statistical software (GraphPad PRISM 5) for analysis.
| Results|| |
[Table 1] shows the baseline characteristics of the whole study cohort. We have studied a total of 36 cases of pediatric LN and divided them into two broad categories – LN with activity (88.88%) and LN without any activity (11.11%). The mean ages of presentation were 15.12 ± 3.49 years and 12.5 ± 1.73 years for proliferative and non-proliferative GN, respectively. Overall, 35 cases were female and only one case was male (M:F = 1:35). Mean dsDNA value was found to be higher in active LN than that in inactive LN (P value = 0.0203). Mean serum C3 value was typically low in active LN (52.35 ± 22.21 mg/dL), which was statistically significant (P value < 0.0001). Mean 24-hour urinary protein was higher in LN without activity than that in active LN (P value < 0.0001). Hypertension was associated with 4 cases out of which 3 (75%) cases were under LN with activity category. Serum creatinine was found to be raised only in active LN (18.75%).
[Table 2] represents the histopathological characteristics of different classes of LN. We have found 5 cases of LN class II (13.88%), 9 cases of LN class III (25%), 13 cases of LN class IV (36.11%), 3 cases of LN class V (8.33%), 1 case of LN class II + V (2.77%), 3 cases of LN class III + V (8.33%), and 2 cases of LN class IV + V (5.55%). Therefore, the most frequently found histological type was LN class IV followed by LN class III. Another significant finding was all class II LN cases were associated with activity in the form of interstitial inflammatory cell infiltration [Figure 1], [Figure 2], [Figure 3], [Figure 4].
|Table 2: Individual Histopathological Lesion And Their Correlation According To ISN-RPS Class|
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|Figure 1: Upper left: Lupus Nephritis Class III A, Focal proliferative lesion. Upper right: Lupus Nephritis Class III A, Focal interstitial inflammation and minimal fibrosis. Lower left: Lupus Nephritis Class IV A, Diffuse proliferative lesion. Lower right: Lupus Nephritis Class IV A, Diffuse interstitial inflammation|
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|Figure 2: Upper left: Lupus Nephritis combined class (III + V). Focal proliferative lesion and diffuse global thickening of the glomerular basement membrane (GBM). Upper right: Lupus Nephritis combined class (III + V). Interstitial inflammation and fibrosis. Lower left: Lupus Nephritis combined class (IV + V). Diffuse proliferative lesion. Wire loop lesions present. Lower right: Lupus Nephritis combined class (IV + V). Acute tubular injury.|
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|Figure 3: Upper two rows: Lupus Nephritis Class IV A. Immunofluorescence shows diffuse full house positivity for immunoglobulin (IgG, IgA, IgM) complements (C3c, C1q) and light chains (kappa and lambda) in the mesangium. Lower two rows: Lupus Nephritis Class III A. Immunofluorescence show segmental full house positivity for immunoglobulin (IgG, IgA, IgM) complements (C3c, C1q) and light chains (kappa and lambda) in the mesangium.|
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|Figure 4: Upper two rows: Lupus Nephritis combined class (III + V). Immunofluorescence shows segmental full house positivity for immunoglobulin (IgG, IgA, IgM) complements (C3c, C1q) and light chains (kappa and lambda) in the mesangium and diffuse positivity along the glomerular basement membrane. Lower two rows: Lupus Nephritis combined class (IV + V). Immunofluorescence shows diffuse full house positivity for immunoglobulin (IgG, IgA, IgM) complements (C3c, C1q) and light chains (kappa and lambda) in the mesangium and along the glomerular basement membrane.|
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We have compared the following activity and chronicity parameters among the obtained LN classes [according to modified National Institute of Health (NIH) activity and chronicity score]: endocapillary hypercellularity, cellular crescent, fibrous crescent, neutrophilic infiltration, fibrinoid necrosis, segmental sclerosis, and global glomerulosclerosis. We have found endocapillary hypercellularity in 27 (75%) cases, which was statistically significant (P value- <0.0001). Cellular crescent was present in 4 (11.11%) cases but fibrous crescent was present in a single case only (P value- 0.007). Neutrophilic infiltration was present in total 14 (38.88%) cases among which 69.23% cases of LN class IV and 50% cases of LN class III showed this feature. Fibrinoid necrosis was present in 46.15% cases of LN class IV. None of the cases showed diffuse global glomerulosclerosis.
We have compared interstitial inflammation and tubular atrophy/interstitial fibrosis (IFTA) among the obtained classes of LN. Interstitial inflammation and IFTA were graded as—minimal: <10%, mild: 11–25%, moderate: 26–50%, severe: >50%. Three (8.33%) cases showed minimal interstitial inflammation, 20 (55.55%) cases showed mild interstitial inflammation, 12 (33.33%) cases showed moderate interstitial inflammation and only a single case showed severe interstitial inflammation along with lymphoid follicle formation.
Arterial sclerosis was found in total 14 (38.88%) cases among which 12 (85.71%) cases were found in proliferative GN category.
[Figure 5] and [Figure 6] show the semi-quantitative distribution of previously mentioned activity and chronicity variables. The bar chart shows that moderate to severe degrees are associated with the activity variables only whereas minimal to mild degrees are associated with the chronicity variables.
|Figure 5: Distribution of semi-quantitative severity scores for each of the|
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The Box Whisker plots for activity and chronicity score in LN class III and IV also show that the activity is higher than chronicity. Therefore, from the histopathological point of view, pediatric LN is mostly proliferative and active in nature.
| Discussion|| |
Adult SLE (aSLE) is about 10 times commoner than cSLE in the United States. Children with cSLE have more severe disease than their adult counterparts. LN has a profound negative impact on survival with high healthcare expenditure of both children and adults. During the preceding 5 years, there has been a move towards identifying differences between cSLE and aSLE on a biological level but clear explanations are still lacking.
Our study is a retrospective analysis of 36 cases of biopsy-proven pediatric LN. Most of the cases were younger than 15 years of age at the time of presentation and there was a strong female preponderance, similar to the other studies., The clinical, biochemical, and serological markers were in parallel with other recent Indian and western study cohorts [Table 3]. In our study, the most frequent clinical finding was skin rash followed by arthritis and the most prevalent histological type was LN class IV followed by class III, similar to what was reported by Srivastava et al. and Lee et al. [Table 3]., Disease manifestations in children are somewhat different than those in adults. Previous studies have shown that young patients are prone to show a tendency for more internal organ involvement at disease onset, in contrast to an increased incidence of musculoskeletal or cutaneous involvement in adults. Young patients have a strong tendency to show an aggressive disease course as compared to adult patients. Previous studies show a frequency of hypertension and nephrotic syndrome at presentation ranging from 40–55% and 18–40%, respectively; while in this study, 11% were hypertensive and 45% were nephrotic.,, Patients with normal initial serum creatinine levels have a low risk of renal failure. The presence of hypertension at the time of diagnosis and persistent hypertension lasting greater than four months is considered the most important poor prognostic clinical finding in LN in children. Also, severe nephrotic syndrome and anemia are considered as predictors of poor renal outcome in cSLE.
A study by Basu et al. on adult-onset LN showed similar outcomes except that we have got proliferative GN a lot more than non-proliferative GN in pediatric LN. The activity scores were much higher than the chronicity scores in almost all the cases, which demonstrate that these lesions are more active than their adult counterparts as compared with the study by Basu et al. [Figure 6]. Diffuse proliferative GN (Class IV LN) is associated with a poor prognosis. A positive correlation was observed between the presence of chronic lesions like glomerulosclerosis and tubulointerstitial chronicity (high chronicity index) on renal biopsy and a poor renal outcome. The presence of a high degree of interstitial fibrosis (IF) in the first renal biopsy is associated with the development of ESRD. The combination of a cellular crescent and interstitial chronicity is particularly ominous. Rate of renal survival is significantly dismal in some races like American blacks despite more aggressive treatment.
The occurence of acute renal flares characterized by a rapid increase in plasma creatinine and decreased eGFR after cessation of treatment is a strong predictor of the development of irreversible deterioration of renal functions. It is recommended that all patients with LN, particularly those with hypertension should be closely monitored to catch and treat early and vigorously any possible deterioration of renal function  caused by LN flares.
The risk of progression to ESRD in children  with LN is 18 to 50%. This complication occurs after a mean period of five years. However, the progression of LN severe enough to the stage of dialysis requirement does not necessarily indicate that it is “end-stage”. Ten percent to 28% of patients with LN who require dialysis with renal failure will recover enough function to come off dialysis.
Dialysis, either hemodialysis or peritoneal dialysis, can be started, and these patients perform as well as nonlupus patients with end-stage renal disease.
Clinical and biological manifestations of the disease most often improve in patients on chronic dialysis, thus allowing discontinuation of corticosteroids and immunosuppressive therapy. However, clinical manifestations can sometimes persist or even get exaggerated at this stage  secondary to stress factors. Renal transplantation is the treatment of choice for those with renal failure. Patients with ESRD secondary to LN are excellent candidates for renal allograft transplantation as the recurrence of LN is rare. Graft and patient survival after the first cadaveric and first living-related renal transplantations are similar in patients with ESRD caused by LN and patients with ESRD from other causes. The outcome of 100 renal transplantations in children with LN reported by Batrosh, were comparable to those seen in an age, race, and gender-matched control group. This is despite the fact that SLE patients have an underlying disease with multiorgan involvement and have received immunosuppression for prolonged periods before transplantation.
The treatment outcome of LN has been one of the success stories of nephrology during the past three decades, despite being a cause of significant mortality and morbidity. Improvement in survival has come at the expense of long-term complications of therapy, with profound consequences in the pediatric age group. Diffuse proliferative GN requires vigorous treatment. There are still some questions on the duration of treatment, the physician should keep in mind that inadequate treatment of severe nephritis exposes the patient to the risk of progressive renal failure. LN requires long-term and careful follow-up of affected patients and meticulous attention is required to optimize patient outcomes.
Compared to adults, children and adolescents with SLE have higher mortality rates and are perceived to encounter more disease damage. Remission is exceedingly rare in cSLE in North America. Major causes of death in cSLE and aSLE include renal disease, severe disease flares, and infections., There is an ongoing controversy as to whether age at SLE onset constitutes a risk factor for poor disease outcome. Degree of hypocomplementemia and degree of ANA positivity are not associated with progression to renal failure. Male sex, Black race, low socioeconomic status, thrombocytopenia, disease damage, and non-adherence to treatment, have all been linked with poor survival.
| Conclusions|| |
There is a paucity of studies from Eastern India regarding the correlation between histological class and activity/chronicity scoring in childhood LN. We have shown the prevalence of histological subclass as well as a good correlation between the histological subclass and the activity/chronicity scoring in pediatric patients. Therefore, we concluded that pediatric LN happens to be proliferative and more active in nature as compared with their adult counterpart. Standardization of treatment of LN in children has been done and measures of quality of medical care have been defined. We hope that this will result in improved health outcomes with cSLE. Nonetheless, there remains a dire need for more efficacious and less toxic therapies.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Associate Professor, Department of Pathology, Institute of Post Graduate Medical Education and Research, 244 A J C Bose Road, Kolkata- 700 020, West Bengal
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]