Keywords
systemic lupus erythematosus - childhood lupus nephritis - class IV lupus nephritis
Introduction
Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory disorder
of autoimmune origin predominately affecting the skin, joints, heart, lungs, and importantly
kidneys.[1] Childhood SLE (cSLE) shows wide variation in its incidence and prevalence. Based
on the demographic profile and age of the individuals, a comparatively higher frequency
of cSLE cases is being reported amongst Asians, African Americans, Hispanics, and
Native Americans.[2] It is a rare disease accounting for 15 to 20% of all the diagnosed cases of SLE,
with an incidence of 0.3 to 0.9/100,000 children per year and a prevalence of 3.3
to 8.8/100,000.[3]
[4]
[5] The predominance of cSLE in female pediatric patients increases gradually with age
to the values observed in adults.[6]
[7]
[8]
[9] Lupus nephritis in children is usually a severe manifestation of SLE and is associated
with high morbidity and mortality.[10]
The clinical presentation of lupus nephritis ranges from asymptomatic low-grade proteinuria
to end-stage renal disease (ESRD). Unlike adults, the clinical features of SLE are
often less conspicuous in the pediatric population with a significant proportion of
children presenting with severe renal manifestation at onset, lacking adequate criteria
to diagnose as SLE.[11] The International Society of Nephrology and Renal Pathology Society (ISN/RPS) graded
lupus nephritis into six histological grades.
Our study is the first study conducted in northeast India emphasizing the epidemiological,
clinical, immunological, and histopathological spectrum of cSLE. The relationship
between the clinical, biochemical, serological, and histopathological findings is
also studied in the present study.
Materials and Methods
This was a hospital-based retrospective descriptive study, spanning a period of 8
years (2012–2020) in the Department of Pathology. In all biopsy-proven cases with
lupus nephritis in patients below 18 years of age, a minimum of 10 glomeruli was considered
adequate. Only native kidney biopsies were included in the study. Clinical and laboratory
data were retrieved from the medical record department of the hospital. Hematoxylin
and eosin (H&E), Masson's trichrome (MT), periodic acid-Schiff (PAS), and Jones silver-stained
slides were reviewed from the slide library of the department of histopathology. Data
from immunofluorescence studies (IgA, IgG, IgM, C3, C1q, kappa, and lambda) were noted.
Both histopathological and immunofluorescence slides were evaluated independently
by two nephropathologists. A consensus was arrived after discussion in case of any
disconcordance. All cases were classified according to the ISN/RPS classification
system and statistical analysis was based on a chi-square test using the IBM SPSS
Statistics Version 20 software. A p-value < 0.05 was considered statistically significant. All cases had informed written
consent in their medical records about the use of individuals' data for academic purposes
and all the patients' caretakers had consented to it in the past.
Results
A total of 53 biopsy-proven cases of lupus nephritis were included in the study. The
patients' age ranged from 5 to 18 years. The mean age of presentation was 14.5 years.
Out of the 53 cases, 46 were female and 7 were male with a female:male of 6.5:1. Amongst
the clinical presentations, edema (n = 20) and hypertension (n = 20) were the most common presentation followed by skin lesions (n = 17) and serous cavity effusion (n = 16). Proteinuria (n = 31), graded as 3+ (n = 15), 2+ (n = 10) and1+ (n = 6) was the commonest laboratory parameters at presentation. Serum creatinine levels
ranged from 0.4 mg/dL to 4.4 mg/dL with a mean of 1.4 mg/dL and serum creatinine levels
were raised in 25 of the cases. Hematuria was seen in 23 of the cases, 21 cases showed
microscopic hematuria, whereas only two cases showed macroscopic hematuria at presentation.
Amongst all the immunological markers, dsDNA was the commonest presenting in 34 cases,
followed by ANA with 33 positive cases.
Predominantly, the study population was classified as class IV lupus nephritis (n = 34). No cases of class I and class V was noted. Histopathology showed mesangial
hypercellularity, endocapillary proliferation, and wire loop lesions representing
various classes of lupus nephritis ([Fig. 1]). Immunofluorescence showed full house pattern with IgA, IgG, IgM, C3, C1q, Kappa,
and lambda ([Fig. 2]).
Fig. 1 Histopathology of lupus nephritis showed (A) wire loop lesions and (B) mesangial hypercellularity (Hematoxylin and eosin, 200x and 400x).
Fig. 2 Immunofluorescence showing full house pattern for IgA, IgG, IgM, C3, C1q, kappa,
and lambda (FITC, 100x and 200x).
[Table 1] shows the relationship between the clinical, biochemical, serological, and histopathological
findings of the study group. No statistically significant correlation between advanced
histopathological class and age or gender in the study group was noted. However, significant
correlation was noted for class IV LN patients presenting with proteinuria and hematuria
at diagnosis. Moreover, ANA and anti-ds-DNA positivity were significantly associated
with advanced renal histopathology.
Table 1
Relationship between clinical, biochemical, serological and histopathological findings
|
Histopathological class
|
II
|
III
|
IV
|
VI
|
p-Value
|
|
Age (y)
|
<12
|
2
|
0
|
6
|
0
|
0.3
|
|
>12
|
5
|
11
|
28
|
1
|
|
Sex
|
Male
|
1
|
2
|
4
|
0
|
0.9
|
|
Female
|
6
|
9
|
30
|
1
|
|
S. creatinine
|
<1 mg/dL
|
5
|
5
|
18
|
0
|
0.5
|
|
>1 mg/dL
|
2
|
6
|
16
|
1
|
|
Proteinuria
|
3+
|
0
|
2
|
12
|
1
|
0.01
|
|
2+
|
0
|
2
|
8
|
0
|
|
1+
|
0
|
4
|
2
|
0
|
|
Nil
|
7
|
3
|
12
|
0
|
|
Hematuria
|
Present
|
2
|
9
|
12
|
0
|
0.03
|
|
Absent
|
5
|
2
|
22
|
1
|
|
Hypertension
|
Present
|
2
|
6
|
12
|
0
|
0.5
|
|
Absent
|
5
|
5
|
22
|
1
|
|
ANA
|
Positive
|
1
|
7
|
24
|
1
|
0.003
|
|
Negative
|
6
|
4
|
10
|
|
|
ds DNA
|
Positive
|
2
|
10
|
21
|
1
|
0.04
|
|
Negative
|
5
|
1
|
13
|
0
|
Discussion
Our study illustrated clinical, biochemical, serological, and histopathological findings
of LN in northeastern children of India. The etiopathogenesis of LN in children and
adults is similar; however, the disease is more severe in pediatric populations. In
our study, the prevalence of pediatric and adolescent lupus nephritis was found to
be 11.3%, which was slightly higher than the prevalence seen in other studies[3]
[4]
[5] Patients' ages ranged from 5 to 18 years of age, which was similar to other studies
that have found that LN is rare in children less than 5 years of age.[12] Female:male ratio was 6.5:1 in our study population, a finding almost similar to
the study done by Samanta et al.[13] The prevalence of hypertension varies significantly across different studies, ranging
from 30 to 50%.[14]
[15]
[16] In our study, hypertension was found in 37.7% of patients. In our study group, proteinuria
was observed in 58.49% of cases (n = 31) at presentation, microscopic hematuria and proteinuria are the most commonly
identified abnormalities as seen in other Indian series.[17]
[18]
Edema was the commonest presentation followed by skin lesions and serous cavity effusion
in our study population. Most children clinically presented with serous cavity effusion,
arthritis, and skin lesion. Despite a large number of clinical manifestations, the
signs and symptoms of lupus nephritis do not always reflect the severity of the disease.
Additionally, clinical findings do not predict the clinical development or the prognosis
of patients with the disease. Therefore, kidney biopsy becomes an essential measure
for assessing tissue involvement, categorizing lupus nephritis, and choosing the course
of therapy
The current study showed class IV lupus nephritis was the most common histopathological
finding (64.15%), similar to the results of a study done by Emre et al and Mittal
et al.[19]
[20] We did not find any cases with class I or class V lupus nephritis in our study population
a finding partially attributed to the lack of awareness among the caretakers of the
patients and also to the unavailability of adequate health care facilities for prompt
diagnosis. However medical literature notes a lower incidence of Class V LN in children.[21] In our study group, patients presenting with class IV LN were significantly associated
with proteinuria, hematuria, and positivity for ANA and ds DNA, a finding consistent
with a study done by Nandi et al and Jebali et al, where patients with Class IV LN
were associated significantly with positive ds DNA.[14]
[17]
Conclusion
SLE in the pediatric and adolescent population is a severe, chronic condition, and
the overall mortality is high all over the world. Renal involvement is an important
risk factor for mortality in patients with cSLE. A timely performed renal biopsy helps
determine an accurate class of childhood lupus nephritis, which aids in better supportive
care, selection of aggressive therapy, and use of newer drugs in selected cases. The
current study helps in the documentation of various clinicopathologic spectra of childhood
lupus nephritis in northeast India. The authors of the present study conclude that
cSLE patients presenting as lupus nephritis in northeast India usually present with
a higher histological grade with a statistically significant correlation concerning
proteinuria and hematuria amongst the laboratory parameters, which points toward an
aggressive clinical laboratory picture at presentation. There is an urgent need to
improve aspects regarding clinical care and our understanding of various aspects associated
with this disease, in particular regarding the evaluation of novel therapies as adjuncts
to current treatment regimes.
