Abstract | | |
Pediatric renal biopsy is an uncommon event, and the spectrum of the disease is evaluated and managed mostly on the clinical grounds. Compared to adults, the indications for renal biopsy in pediatric population are very few. We reviewed the pediatric renal biopsies received at our tertiary center in Mumbai, India, over a period of six years to study the incidence of various medical renal diseases, their spectrum on histology and its correlation with electron microscopy (EM). A total of 65 pediatric renal biopsies in the age group of 0−12 years were evaluated over a period of six years. The mean age of our patients was 7.9 years, with a median of 8.8 years with a male-to-female ratio of 1.3:1. The overall most common indication for biopsy was nephrotic syndrome (NS) including steroid-resistant NS, followed by proteinuria and nephritic syndrome. Majority of the lesions included in the study were primary glomerular disease (71%) while secondary glomerular disease amounted to 18%. The spectrum of disease includes minimal-change disease (MCD) (27.7%), followed by membranoproliferative glomerulonephritis (MPGN) (15.38%), focal segmental glomerulosclerosis (FSGS) (9.23%), lupus nephritis (7.7%), hemolytic uremic syndrome (7.7%), MPGN (6.15%), advanced renal disease (6.15%), membranous glomerulonephritis (3.07%), and crescentic glomerulonephritis (3.07%). This study is an important contribution to the epidemiology of pediatric renal disease spectrum in the Indian population. We conclude that MCD is the most common pathology seen in pediatric age group, with NS as the most common indication for biopsy. There is a steady increase in the incidence of FSGS in the pediatric population with frequent relapses and an increase in the incidence of steroid resistance. However, with the use of immunofluorescence and EM, an accurate diagnosis is possible, so an early renal biopsy should be planned in nonresponding cases and at times even before starting the treatment for appropriate treatment.
How to cite this article: Yadav S, Kandalkar B. Epidemiology of Pediatric Renal Diseases and its Histopathological Spectrum − A Single-Center Experience from India. Saudi J Kidney Dis Transpl 2021;32:1744-53 |
How to cite this URL: Yadav S, Kandalkar B. Epidemiology of Pediatric Renal Diseases and its Histopathological Spectrum − A Single-Center Experience from India. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2023 Feb 4];32:1744-53. Available from: https://www.sjkdt.org/text.asp?2021/32/6/1744/352437 |
Introduction | |  |
Since its first introduction in 1951, renal biopsy has revolutionized the study of glomerular diseases worldwide. With the help of light microscopy (LM) and electron microscopy (EM), and immunofluorescence (IF) examination of renal tissues, the renal pathologists have been able to classify glomerular disease, describe the clinicopathological correlation, study the pathogenesis, and predict the prognosis.[1] Renal biopsy is a decisive diagnostic procedure in patients with renal disease. However, the indications for renal biopsies have changed over the years. In pediatric population, the indications include persistent hematuria of unknown origin, persistent proteinuria of unknown origin, steroid-resistant nephrotic syndrome (NS), acute renal failure of unknown origin, familial nephritis, rapidly progressive glomerulonephritis, “atypical” acute glomerulonephritis, suspected tubulointerstitial nephritis, and nephropathies in systemic diseases [lupus erythematosus and Henoch-Schoenlein purpura (HSP)].[2]
Renal biopsy is relatively uncommon in children compared with adults. This difference is due to the fact that NS in children is assumed to be due to minimal-change disease (MCD), and hence, steroid therapy is instituted without biopsy confirmation. Furthermore, despite medical advancements, the technique is more challenging in pediatric population than adults. Renal biopsy in NS is done only when they have steroid-resistant or steroid-dependent NS.[3],[4]
There is little information on pediatric renal biopsies worldwide till now, and the reasons for this include lack of pediatric nephrologists, educated personnel, scientific workers, as well as modest investments in the health-care system and scientific projects.[5] Hence, we did a retrospective analysis of the pediatric renal biopsies received in surgical pathology department over a period of six years in order to study the incidences and the histopathological characteristics of various pediatric lesions in our country and then to correlate them clinically and with IF/EM studies wherever feasible.
Materials and Methods | |  |
The databases of surgical pathology department were searched for pediatric patients undergoing renal biopsy for indications other than malignancies over a period of six years. A total of 65 renal biopsies were received in the department during the study period. Ethical clearance was waived off as it was a retrospective study related to the audit of the entities and involved no patients. The data sheet was made which included age of the patients, symptoms, urinary findings, and routine hematological investigations. Renal biopsy cores were fixed in 10% buffered formalin and submitted for routine processing; paraffin sections were cut at 2−3-μ thickness and stained with hematoxylin and eosin stain, silver methenamine, and periodic acid−Schiff stain. Special stains for fibrin and Congo red stain were done wherever indicated. Examination was carried out under a light microscope to record histopathological features in various renal lesions. The histological diagnosis was correlated with the IF and EM findings wherever possible.
Definitions
NS was defined as edema, proteinuria >40 mg/m2/h, and hypoalbuminemia <2.5 g/dL.
Acute nephritic syndrome (ANS) was defined as hematuria, oliguria, edema, hypertension (≥95th centile for age), and glomerular filtration rate (GFR) <75 mL/min/1.73 m2. Rapidly progressive renal failure was defined as rapid worsening of kidney function (GFR <75 mL/min/1.73 m2) over a period of one to 12 weeks. Hematuria was defined as microscopic or gross persistent hematuria without proteinuria and with normal renal function.[6]
Results | |  |
A retrospective analysis of 65 pediatric renal biopsies was done during a period of six years. Total renal biopsies received during this period for medical renal diseases were around 1350. Thus, pediatric renal biopsies constitute only
0. 4% of the total renal biopsies at our center. The disease spanned over all the age groups including newborns and infants. The most common age bracket was seven to 12 years, and the overall male-to-female ratio was 1.3:1. The mean age of our patients was 7.9 years, with a median of 8.8 years. The most common clinical presentation in our patients was NS (n = 36, 55.38%) followed by ANS (n = 10, 15.38%). One patient even presented with congenital NS. Isolated hematuria and proteinuria were seen in five cases each (7.69%). Hypertension was noted in 15 patients as an isolated symptom or as a part of nephritic syndrome. The lesions were classified based on the World Health Organization 2004 classification [Table 1] and [Figure 1]. The gender-wise distribution of primary and secondary glomerular diseases is shown in [Table 2]. As expected, the most common primary glomerular disease in our study was MCD and the most common secondary glomerular disease was pediatric lupus nephritis (LN). Other lesions are enumerated in [Table 3]. | Table 1. Classification of the lesions as per the World Health Organization 2004 classification.
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 | Table 2. Gender distribution of primary and secondary glomerular diseases.
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 | Table 3. Distribution of primary and secondary glomerular diseases. MesPGN: Mesangioproliferative glomerulonephritis, FSGS: Focal segmental glomerulosclerosis, MGN: Membranoproliferative glomerulonephritis, MCD: Minimal-change disease.
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Similar to the literature and even in nephrology unit, most of the pediatric patients did not require a biopsy diagnosis. Biopsy diagnosis is advised only in cases of persistent symptoms on therapy, treatment failure, or treatment resistance. The most common indications for renal biopsies in our study were persistent NS, steroid-resistant NS, and persistent proteinuria and hematuria. The most common overall diagnosis in our study including primary and secondary glomerular diseases was MCD followed by membranoproliferative glomerulonephritis (MPGN) and focal segmental glomerulosclerosis (FSGS) [Table 4] and [Figure 2]. | Figure 2. Spectrum of renal diseases in Indian pediatric population. MPGN: Membranoproliferative glomerulonephritis, FSGS: Focal segmental glomerulosclerosis, HUS: Hemolytic uremic syndrome.
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 | Table 4. Distribution of cases as per the diagnosis. MPGN: Membranoproliferative glomerulonephritis, FSGS: Focal segmental glomerulosclerosis, HUS: Hemolytic uremic syndrome, MCD: Minimal-change disease.
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Most patients of FSGS had steroid-resistant NS. EM findings were available in five cases of FSGS reported on LM. Two cases were confirmed as FSGS, two cases were reported as MCD, while one case was called focal proliferative glomerulonephritis. These findings suggest that steroid resistance in an otherwise MCD may indicate progression of MCD to FSGS or any other proliferative disease. We also had five cases of pediatric LN, and all were in the age group of seven to 12 years. Their most common presentation was proteinuria seen in all the patients, and on histology, all cases showed diffuse proliferative GN, class 4. Serological studies revealed antinuclear antibody in all the five patients. Among the vascular lesions in our study, there were five cases of hemolytic uremic syndrome (HUS); however, only one presented with diarrhea. We also had a clinical case of Alport’s syndrome with cola-colored urine, which on histology showed lipid-laden foam cells in the interstitium. This was confirmed with EM studies which showed lamellation of the glomerular basement membrane, a classical finding of Alport’s syndrome.
EM studies were available in 42/65 (64.61%) cases. Most of the cases were concordant on EM. There were six discordant cases, all of which showed either variable degree of mesangial proliferation or segmental sclerosis on LM, which on EM showed flattening of foot processes of podocytes without any deposits and were compatible with MCD. This also indicates the wide spectrum of MCD on histology [Figures 3 and 4]. | Figure 3. (a) A normal glomerulus in a case MCD (H&E stain), (b) EM showing flattening of foot process of podocytes seen in MCD, (c) Mesangial proliferation and sclerosis (black arrows) seen in FSGS, (d) PAS staining highlighting the sclerosis (black arrow) in FSGS as magenta color, (e) SM staining showing deposition of silver (black arrow) in the region of sclerosis, (f) Thickening of the basement membrane of capillaries seen in MPGN, (g) SM stain showing double contour/splitting of the basement membrane, (h) IF showing fluffy deposits, (i) EM reveals dense deposits highlighted by red arrow MCD: Minimal-change disease, H&E: Hematoxylin and eosin, EM: Electron microscopy, IF: Immunofluorescence, FSGS: Focal segmental glomerulosclerosis, PAS: Periodic acid�Schiff, MPGN: Membranoproliferative glomerulonephritis.
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 | Figure 4. (j) H&E stain showing thickened capillary walls in MGN, (k) PAS stain confirming the thickened capillary wall of MGN, (l) SM stain showing small spikes projecting from the epithelial side of the glomerular basement membrane in MGN, (m) EM showing continuous subepithelial deposits (red arrow), (n) Glomeruli showing many microthrombi on H and E stain in a case of HUS (black arrow), (o) Microthrombi confirmed by fibrin stain in case of HUS, (p and q) Core biopsy showing foamy cells in the interstitium in a case suggestive of Alport�s syndrome, (r) EM showing lamellation/zebra lines characteristic of Alport�s syndrome highlighted by red arrow H&E: Hematoxylin and eosin, MGN: Membranoproliferative glomerulonephritis, PAS: Periodic acid-Schiff, EM: Electron microscopy, HUS: Hemolytic uremic syndrome.
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Discussion | |  |
The literature review was carried out with the help of Medline, US National Library of Medicine, and was compared to other similar published studies. The prevalence of pediatric renal disease varies in different parts of the world due to difference in the socioeconomic, demographic, and genetic factors.[7] Primary glomerulopathy was seen in 46 cases (70.71%), secondary glomerulopathy in 12 cases (18.46%), and vascular lesions were seen in five patients (7.69%) in our study. The ratio of primary-to-secondary glomerular disease in our study was 3.83:1, with a male-to-female ratio of 1.36:1. Ali et al studied 415 pediatric renal biopsies in northern Pakistan, of which 378 (91.08%) children had primary GN, while only 37 (8.92%) children had secondary GN, similar to our study.[4] Our study was also comparable to studies done by Abdullah in Saudi Arabia, Jalalah and Jamal in Saudi Arabia, and Coppo et al in the Italian pediatric population.[7],[8],[9] Jalalah and Jamal reported a primary:secondary glomerular disease ratio of 3.3:1.[8] The mean age and male-to-female ratio of our patients were 7.9 years and 1.3:1, respectively. This was comparable to Sadaf et al who had studied 108 pediatric patients in Pakistan, with a male-to-female ratio of 1.3:1 and a mean age of 7 years.[10]
Distribution of the primary glomerular lesions in our study revealed MCD as the most common primary glomerular lesion (30.4%), followed by mesangial proliferative glomerulonephritis (MesPGN) (17.3%), FSGS (13.04%), MPGN (13.04%), advanced renal disease/ crescentic GN (10.8%), and other lesions[Table 2]. In a similar study done by Wu et al in China in children of <15 years, they had reported a higher incidence of MCD (43.7%), followed by IgA nephropathy (18.7%), MesPGN (12.5%), FSGS (12.5%), membranous GN (MGN) (6.3%), and endocapillary proliferative GN (6.3%).[11] Although the spectrum and frequencies of the renal lesions are same as in our study, some variations are attributed to the socioeconomic, genetic, and demographic factors. [Table 5][12],[13],[14],[15],[16] shows the incidence of primary glomerular lesions presenting as NS in the various studies reported in literature and its comparison with our study. Our results were comparable with most of the reported literature except for the study by Kumar et al[17] who had a lower incidence of MCD and higher incidence of FSGS than our study. This may be due to sampling bias, as pediatric renal biopsies are usually avoided unless the child becomes steroid dependent or steroid resistant to study the spectrum of disease.{Table 2}
The most common secondary glomerular disease in our study was LN, with an incidence of 7.6%. Ali et al reported an incidence of 0. 96% of LN in Saudi Arabia, while Garg et al reported an incidence of 3.8% of LN in India, which is very low than the present study; however, our sample size of LN was small. Coppo et al reported an incidence of 5% of LN in the Italian pediatric population. Another study done by Mohapatra et al in South Asian children revealed MCD in 21.2% and LN in 16.2% as the most common primary and secondary glomerulopathies. However, their age group for the cases was 0−18 years, causing selection bias.[1],[4],[6],[9] Although our cases ranged from two months to 12 years, the mean age in our study was 8.25 years for LN, which is similar to other studies in the literature.[3],[18],[19],[20]
Wang et al[21] studied the spectrum of disease in the plateau region of China and compared them to the non-plateau group. They reported a higher incidence of secondary glomerular disease both in boys and girls in the plateau group as compared to the nonplateau group which had primary glomerulopathy incidence higher than secondary glomerulopathy. The most common secondary glomerular disease in their study was also HSP in contrast to LN in most of the other studies, including our study indicating geographical variations.[17] Hepatitis B-related GN is the most common secondary glomerular disease in the sub-Saharan region due to high endemicity.[6] Thus, this indicates that LN is more common in the Indian population as compared to Caucasians. The most common indication of biopsy was steroid-resistant NS and steroid-dependent, NS which is comparable to other cohorts of Pakistan, Egypt, Turkey, Serbia, and China.[10]
Congenital NS is a rare disease present since birth but manifests in the first three months of life with proteinuria, microscopic hematuria, and mild degrees of aminoaciduria and glycosuria, presumably owing to tubular changes. The glomerular pathology is very subtle and not diagnostic of congenital NS, and the most common pathologic finding is tubular dilatation which goes unnoticed many times. EM shows widespread effacement of the glomerular epithelial cell foot processes.[12],[22] We also had a suspected case of congenital NS presenting at the age of two months with massive proteinuria. LM findings revealed normal glomeruli with tubular dilatation and tubular damage. However, EM and genetic studies were not done in this case for confirmation. The patient responded well to the steroid therapy.
Review analysis of our 65 cases revealed the most common diagnoses on light microscopy being MCD (27.7%) followed by MPGN (15.38%), FSGS (9.23%), LN (7.7%), HUS (7.7%), MesPGN (6.15%), advanced renal disease (6.15%), MGN (3.07%), crescentic glomerulonephritis (3.07%) and Alport’s syndrome (1.5%). Similarly, a 10-year study done by Absar et al[3] in Pakistan on 41 biopsies revealed that the most common histopatho-logical diagnosis was MCD (37%) followed by FSGS (12%) patients and MPGN (10%). Ali et al[4] also reported similar incidences.
Nie et al[23] highlighted very well the changing pattern of pediatric glomerular disease in Chinese cohorts. In their study, IgA nephropathy (17%) was the most common diagnosis followed by MCD (14%) and FSGS (14%) during 2004−2007. However, in the year 2008−2011, MCD surpassed IgA by a big margin and became the predominant pattern in pediatric population.[23] Changing trend in patterns was also observed in the Indian data, wherein there were gradual decline in MCD and constant increase in FSGS cases. This may be keeping in with the data from the western countries; however, the authors cannot entirely exclude a referral bias.[6]
Among the vascular lesions, we had five cases of HUS with the age range of five months to 12 years. Although HUS is usually associated with diarrhea, we had only one case with a history of diarrhea. Diarrhea-associated HUS usually occurs in younger children (our patient was 5 months old) compared to those without associated diarrhea. The renal manifestations include oliguria, anuria, hematuria, hemoglobinuria, proteinuria, various types of casts in the urine, hyperkalemia, and elevated blood urea nitrogen and serum creatinine level. Approximately half of pediatric patients require dialysis. The clinical presentation in the present study was nephritic syndrome (3 cases), acute renal failure (1 case), and proteinuria (1 case).[12]
Conclusion | |  |
Pediatric renal biopsy is a rare event as most of the time an empirical steroid therapy is started before biopsy. This study is an important contribution to the epidemiology of pediatric renal disease spectrum in the Indian population. We conclude that MCD is the most common pathology seen in pediatric age group, with NS as the most common indication for biopsy. There is a constant steady increase in the incidence of FSGS in the pediatric age group and also an increase in the incidence of steroid resistance in patients of MCD. However, with the use of IF and EM, an accurate diagnosis is possible, so an early renal biopsy should be planned in nonresponding cases and at times even before starting the treatment for appropriate treatment. Furthermore, renal biopsy helps in assessing the course of the disease in cases of LN. Thus, a renal biopsy is advocated to diagnose the lesion, assess the progress of the lesion, and to decide the treatment plan.
Conflict of interest: None declared.
References | |  |
1. | Garg AK, Kanitkar M, Venkateshwar V. Clinicopathological spectrum of renal biopsies in children. Med J Armed Forces India 2010; 66:216-9. |
2. | Skálová S, Podhola M, Rejtar P. Paediatric renal biopsies in East Bohemia. Single centre experience in the years 1997-2008. Acta Medica (Hradec Kralove) 2009;52:141-7. |
3. | Absar A, Diamond M, Sonia Y, et al. Ten year experience of pediatric kidney biopsies from a single center in Pakistan. Indian J Nephrol 2010;20:190-2.  [ PUBMED] [Full text] |
4. | Ali A, Ali MU, Akhtar SZ. Histological pattern of paediatric renal diseases in northern Pakistan. J Pak Med Assoc 2011;61:653-8. |
5. | Bazina M, Glavina-Durdov M, Scukanec-Spoljar M, et al. Epidemiology of renal disease in children in the region of southern Croatia: A 10-year review of regional renal biopsy databases. Med Sci Monit 2007;13:R172-6. |
6. | Mohapatra A, Kakde S, Annapandian VM, et al. Spectrum of biopsy proven renal disease in South Asian children: Two decades at a tropical tertiary care centre. Nephrology (Carlton) 2018; 23:1013-22. |
7. | Abdullah LS. Histopathological pattern of pediatric renal diseases: A study from a university hospital in western Saudi Arabia. Saudi J Kidney Dis Transpl 2012;23:377-84.  [ PUBMED] [Full text] |
8. | Jalalah SM, Jamal AA. Childhood primary glomerular diseases in the western region of Saudi Arabia. Saudi J Kidney Dis Transpl 2009; 20:608-12.  [ PUBMED] [Full text] |
9. | Coppo R, Gianoglio B, Porcellini MG, Maringhini S. Frequency of renal diseases and clinical indications for renal biopsy in children (report of the Italian National Registry of Renal Biopsies in Children). Group of Renal Immunopathology of the Italian Society of Pediatric Nephrology and Group of Renal Immunopathology of the Italian Society of Nephrology. Nephrol Dial Transplant 1998;13:293-7. |
10. | Sadaf A, Khemchand MN, Lateef Fouzia ZA. Clinicopathological profile of pediatric renal biopsies at a tertiary care hospital, Pakistan. Saudi J Kidney Dis Transpl 2018;29:1403-9.  [ PUBMED] [Full text] |
11. | Wu YQ, Wang Z, Xu HF, Jin XM, Zhou HZ. Frequency of primary glomerular disease in northeastern China. Braz J Med Biol Res 2011; 44:810-3. |
12. | Jennette J, Olson J, Schwartz M, Silva F. Heptinstall’s Pathology of the Kidney. 6th ed.: Philadelphia Lippincott Williams and Wilkins; 2007. |
13. | Habib R, Kleinknecht C, eds. The primary nephrotic syndrome of childhood: Classification and clinicopathologic study of 406 cases. New York: Appleton-Century-Crofts, 1971. |
14. | Anonymous. Nephrotic syndrome in children: Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report from the International Study of Kidney Disease in Children. Kidney Int 1978;13:159. |
15. | Chen WP, Lin CY, Hsu HC, et al. Childhood nephrotic syndrome and heavy proteinuria in Taiwan: A retrospective clinicopathologic study. Child Nephrol Urol 1988;9:57. |
16. | Gulati S, Sharma AP, Sharma RK, et al. Do current recommendations for kidney biopsy in nephrotic syndrome need modifications? Pediatr Nephrol 2002;17:404. |
17. | Kumar J, Gulati S, Sharma AP, Sharma RK, Gupta RK. Histopathological spectrum of childhood nephrotic syndrome in Indian children. Pediatr Nephrol 2003;18:657-60. |
18. | Abdelraheem MB, Ali EM, Mohamed RM, et al. Pattern of glomerular diseases in Sudanese children: A clinico-pathological study. Saudi J Kidney Dis Transpl 2010;21:778-83.  [ PUBMED] [Full text] |
19. | Demircin G, Deliba? A, Bek K, et al. A one-center experience with pediatric percutaneous renal biopsy and histopathology in Ankara, Turkey. Int Urol Nephrol 2009;41:933-9. |
20. | Yap YC, Wan J, Lee ML, Liaw L, Pee S, Lim YN. The Malaysia Registry of Paediatric Renal Biopsy; Nephrology 2008;13:(Suppl.),A72. |
21. | Wang N, Zhu T, Tao Y. Clinicopathological features of pediatric renal biopsies in the plateau regions of China. J Int Med Res 2018;46:4539- 46. |
22. | Iitaka K, Motoyama O, Hojo M, et al. Two cases of congenital nephrotic syndrome. Clin Exp Nephrol 2004;8:146-9. |
23. | Nie S, He W, Huang T, et al. The spectrum of biopsy-proven glomerular diseases among children in China: A national, cross-sectional survey. Clin J Am Soc Nephrol 2018;13:1047- 54. |

Correspondence Address: Subhash Yadav Department of Pathology, Tata Memorial Centre, A CI of Homi Bhabha National Institute, Parel, Mumbai - 400 012,Maharashtra, India. India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/1319-2442.352437

[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5] |