There have been some cases where abnormal histopathologic findings could not be found in the kidney could even with proper specimen collection through percutaneous renal biopsy (PRB) in accordance with its indication. We analyzed the incidence and clinical outcomes of children who showed normal histopathological findings in their PRBs.
The medical records of 552 pediatric subjects who underwent PRB between 2005 and 2016 were reviewed. Twenty-six subjects were excluded because allograft biopsy was performed in nine subjects, and the age at biopsy was greater than 18 years in 17 subjects. Finally, 526 subjects were enrolled in this study.
Of the 526 pediatric patients, 32 (6.1%) showed no histopathological abnormalities in their PRBs. The male-to-female ratio of the patients was 1.9:1, and the mean ages at the first visit and at biopsy were 10.6 ± 4.1 and 11.4 ± 3.8 years, respectively. In accordance with the biopsy indications, recurrent gross hematuria showed the highest incidence rate, but combined hematuria and proteinuria had the lowest incidence rate regarding normal renal histopathology among all the subjects. At a mean follow-up of 35.5 ± 23.6 months, urinary abnormalities had improved in more than 50% of the subjects with normal renal histopathology, and none of the patients showed progression to end-stage renal disease or required rebiopsy due to symptom worsening during the follow-up period.
The clinical outcomes of children with normal PRB histopathologic findings are generally good. Further studies to evaluate their long-term outcomes are needed.
Percutaneous renal biopsy (PRB) is an important and valuable procedure for the diagnosis of renal diseases. It provides valuable information to determine a treatment plan and predict prognosis. PRB using an aspiration biopsy needle was first introduced in 1951 by Iversen and Brun [
The general indications for renal biopsy include recurrent gross hematuria (RGH) of unknown origin, combined hematuria and proteinuria (CHP), and isolated proteinuria (IP). In addition, steroid-resistant nephrotic syndrome, acute kidney injury of unknown origin, unexplained chronic renal insufficiency, systemic disease with renal involvement, and renal transplant dysfunction are also common indications [
The medical records of 552 subjects who underwent PRB between 2005 and 2016 at the Department of Pediatrics, Kyungpook National University Hospital were reviewed, and 26 subjects were excluded due to previous allograft biopsy (n = 9) or age at biopsy greater than 18 years (n = 17). The patient’s age, sex, clinical symptoms, and laboratory findings at the first and last visits after PRB were retrospectively analyzed (
This study was conducted in accordance with the principles of the Declaration of Helsinki, and the requirement of informed consent was waived due to the retrospective nature of this study. This study was reviewed and approved by the Institutional Review Board of Kyungpook National University Hospital (No. 2021-04-003).
PRB was performed by a pediatric nephrologist using a portable ultrasonography unit for localization. The patients were placed in a prone position and received local anesthesia or sedation. The biopsy was performed using a 16-gage (G) automated biopsy needle (16 G×150 mm, Acecut; TSK Laboratory, Tochigi, Japan) and repeated until specimen adequacy was confirmed by the pathologist. In native renal biopsies, the adequate yield of glomeruli is considered to be 10 to 20 when 14- and 16-G needles are used [
Descriptive statistics were used to describe the data. Continuous variables were presented as mean ± standard deviation.
All histopathological diagnoses in 526 patients are presented in
Thirty-two out of 526 patients showed normal renal histopathological findings, accounting for 6.1% of the entire subject pool. Of these patients, 21 were male, and 11 were female (male-to-female ratio, 1.9:1). The mean ages at the first visit and at biopsy were 10.6 ± 4.1 and 11.4 ± 3.8 years, respectively (
In the 32 patients with normal renal histopathology, the chief complaint at the first visit was RGH in nine patients (28.1%), PMH in 10 (31.3%), CHP in 6 (18.8%), IP in 4 (12.5%), and other renal insufficiencies in 3 (9.4%), all of which were suitable indications for renal biopsy. In all 10 patients with CHP and IP, the amount of proteinuria was not in the nephrotic range. The mean eGFR at the first visit was 105.6 ± 36.2 mL/min/1.73 m2. As a result of PRB, the mean glomeruli yield for the LM was 15.7 ± 12.2, and all specimens were determined to be properly collected. No diagnostic abnormalities were found with LM, IF, and EM among all subjects with normal renal histopathology (
The mean follow-up period was 35.5 ± 23.6 months after the first visit and 25.8 ± 20.5 months after the biopsy, excluding four subjects who were lost to follow-up, of whom one had RGH, two had PMH, and one had CHP. According to chief complaints of patients with normal PRB findings at their first visit, analysis at the last visit after biopsy finally confirmed the following symptoms and urine abnormalities. Among the eight subjects who presented RGH at the first visit, six (75.0%) had no gross or microscopic hematuria-related events during the follow-up period. Gross hematuria and microscopic hematuria were each confirmed in one subject (12.5% and 12.5%, respectively). Among the eight subjects that presented PMH, four (50.0%) showed improvement. Among the five subjects who presented CHP, four (80.0%) showed improvement in urine abnormalities, and one (20.0%) was subsequently diagnosed with PMH. Among the four subjects with IP at the time of their first visit, three (75.0%) were later found to have persistent IP. The mean UPCR of three subjects with persistent IP was 0.62 ± 0.30 at the first visit and 0.25 ± 0.17 after the biopsy. Among the three subjects who presented with renal insufficiency, there was no eGFR decline; their mean eGFR was 65.5 ± 10.6 mL/min/1.73 m2 at the first visit and 69.2 ± 4.9 mL/min/1.73 m2 after the biopsy. One had persistent renal insufficiency, but the other two showed improvement of symptoms (
Of the 28 subjects with normal renal histopathological findings, none showed progression to end-stage renal disease (ESRD) or required rebiopsy due to worsening of symptoms during the follow-up period.
PRB is a highly effective and relatively safe method for diagnosing renal disease and is widely used in children. As the PRB technique has gradually developed, the accuracy of sampling has increased, and the diagnostic rate has improved accordingly. The indications for PRB include RGH, PMH, CHP, IP, steroid-resistant nephrotic syndrome, unexplained renal insufficiency, systemic disease with renal involvement, and renal transplant dysfunction [
Several studies have reported the use of PRB in children with normal histopathological findings [
In this study, 32 of the 526 children (6.1%) who underwent PRB presented with normal pathological findings, and the indications for biopsy in these patients were as follows: RGH (9 of 32 patients, 28.1%), PMH with (6 of 32 patients, 18.8%) or without proteinuria (10 of 32 patients, 31.3%), IP (4 of 32 patients, 12.5%), and unexplained renal insufficiency (3 of 32 patients, 9.4%). In contrast, all the children with nephrotic syndrome and systemic disease with renal involvement presented significant histopathological PRB abnormalities. In this study, we explained the clinical manifestations and outcomes in children with normal renal PRB histopathology.
In this study, the most common indication for PRB in the children with normal kidney histopathology was isolated hematuria, RGH and/or PMH without other symptoms, such as proteinuria, edema, hypertension, or renal insufficiency (19 of 32 patients, 59.4%). In fact, many reports have presented evidence to support that the prognosis of isolated hematuria is good and that renal biopsy is not indicated for children with isolated hematuria [
In Korea, the number of children with microscopic hematuria has increased after annual school urine screening tests have been performed since 1998. Since then, the prevalence of TBMN has increased greatly and was reported to be the most common pathological finding in pediatric patients with asymptomatic hematuria [
In this study, 10 of the 32 patients (31.3%) with normal kidney histopathology had proteinuria with or without PMH as the indication for PRB. Although many clinicians no longer recommend isolated low-grade proteinuria (150–1,000 mg/day) as an indication for renal biopsy, persistent asymptomatic proteinuria as a criterion for renal biopsy in children is still controversial [
In this study, the clinical outcomes of children with normal histopathological PRB findings were favorable. During the follow-up period (means of 35.5 ± 23.6 months after the first visit and 25.8 ± 20.5 months after biopsy), six out of eight subjects (75.0%) with RGH, four out of eight subjects (50.0%) with PMH, four out of five subjects (80.0%) with CHP, and one out of four subjects (25.0%) with IP showed improvement in urinary abnormalities. In addition, among the three subjects who presented with renal insufficiency without abnormal urine, one developed persistent renal insufficiency, but the other two showed improvement of renal insufficiency. Of the 28 subjects with normal renal histopathological findings, none showed progression to ESRD or required rebiopsy due to worsening of symptoms during the follow-up period.
Then, to explain abnormal urinalysis findings despite nondiagnostic renal pathology in children, we hypothesized two possible causes of these results: (1) pathological study was too early and (2) orthostatic proteinuria or nonglomerular causes such as idiopathic hypercalciuria or nutcracker syndrome were not ruled out in spite of evaluation before PRB. First, normal renal pathology in spite of abnormal urinalysis, so-called subpathological renal damage, would be possible during childhood. We suggest that school urinalysis screening, as in Korea, can provide early recognition of abnormal urinalysis; thus, it could contribute to the increase in subpathological status diagnosis rate by PRB. In addition, although examination of first morning urine samples to rule out orthostatic proteinuria and the measurement of spot urine calcium-to-creatinine ratio to rule out idiopathic hypercalciuria were performed, results sometimes fluctuated according to the sampling method used or the patient’s diet. Renal vein Doppler ultrasonography can also fail to diagnose nutcracker syndrome as a cause of RGH, especially in small children.
In summary, despite the appropriate application of renal biopsy, the incidence rate of normal renal histopathology in children was 6.1%, and clinical outcomes were good, as most urine abnormalities improved, and none of the patients showed progression to ESRD or required rebiopsy due to worsening of symptoms including aggravation of proteinuria, increase in frequency of gross hematuria and deterioration of renal function during the follow-up period. Further studies to evaluate the long-term outcomes of children with normal renal histopathology are needed.
All authors have no conflicts of interest to declare.
Conceptualization: MHC
Data curation: MJP, HMJ, HSB, SIL, MHH, YJK
Investigation: NK, MJP, HMJ, HSB, SIL, MHH, YJK, MHC
Writing–original draft: NK, MHC
Writing–review & editing: All authors
All authors read and approved the final manuscript.
CHP, combined hematuria and proteinuria; eGFR, estimated glomerular filtration rate; IP, isolated proteinuria; PMH, isolated persistent microscopic hematuria; PRB, percutaneous renal biopsy.
Incidence rate of normal renal histopathology according to indications for biopsy
The dashed line represents the total incidence rate of normal renal histopathology in the 526 subjects (32 of 526, 6.1%).
RGH, recurrent gross hematuria; PMH, isolated persistent microscopic hematuria; IP, Isolated proteinuria; CHP, combined hematuria and proteinuria.
Histopathological diagnoses in 526 patients
Diagnose | RGH (n = 39) | PMH (n = 149) | CHP (n = 216) | IP (n = 100) | Others (n = 22) | Total (n = 526) |
---|---|---|---|---|---|---|
IgAN | 13 | 16 | 60 | 1 | 2 | 92 (17.5) |
TBMN | 10 | 103 | 21 | 0 | 2 | 136 (25.9) |
MCD | 1 | 0 | 2 | 53 | 0 | 56 (10.6) |
MGN | 0 | 1 | 5 | 4 | 0 | 10 (1.9) |
MPGN | 0 | 1 | 5 | 1 | 0 | 7 (1.3) |
FSGS | 0 | 0 | 7 | 19 | 1 | 27 (5.1) |
PSGN | 1 | 0 | 2 | 0 | 0 | 3 (0.6) |
Alport disease | 1 | 1 | 13 | 0 | 0 | 15 (2.9) |
HSP nephritis | 1 | 8 | 60 | 4 | 0 | 73 (13.9) |
SLE nephritis | 0 | 2 | 13 | 4 | 6 | 25 (4.8) |
HUS | 0 | 0 | 2 | 0 | 1 | 3 (0.6) |
IgAN + TBMN | 3 | 5 | 7 | 1 | 0 | 16 (3.0) |
MCD+TBMN | 0 | 0 | 4 | 5 | 0 | 9 (1.7) |
HSP nephritis+TBMN | 0 | 1 | 5 | 0 | 0 | 6 (1.1) |
TINU syndrome | 0 | 0 | 0 | 2 | 0 | 2 (0.4) |
TIN | 0 | 0 | 0 | 0 | 4 | 4 (0.8) |
ESRD | 0 | 0 | 0 | 1 | 2 | 3 (0.6) |
Others | 0 | 1 | 4 | 1 | 1 | 7 (1.3) |
No diagnostic abnormality | 9 | 10 | 6 | 4 | 3 | 32 (6.1) |
Data are expressed as number only or number (%).
CHP, combined hematuria and proteinuria; ESRD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; HSP, Henoch-Schönlein purpura; HUS, hemolytic uremic syndrome; IgAN, immunoglobulin A nephropathy; IP, isolated proteinuria; MCD, minimal change disease; MGN, membranous glomerulonephritis; MPGN, membranoproliferative glomerulonephritis; PMH, isolated persistent microscopic hematuria; PSGN, poststreptococcal glomerulonephritis; RGH, recurrent gross hematuria; SLE, systemic lupus erythematosus; TBMN, thin basement membrane nephropathy; TIN, tubulointerstitial nephritis; TINU, tubulointerstitial nephritis and uveitis.
Baseline characteristics of the patients with normal histopathological findings
Characteristic | Data |
---|---|
Demographic | |
Patients with normal PRB findings | 32 (6.1) |
Sex, male/female | 21 (65.6)/11 (34.4) |
Age at initial visit (yr) | 10.6 ± 4.1 |
Age at renal biopsy (yr) | 11.4 ± 3.8 |
Indication for PRB | |
RGH | 9 (28.1) |
PMH | 10 (31.3) |
CHP | 6 (18.8) |
IP | 4 (12.5) |
Other renal insufficiencies | 3 (9.4) |
Laboratory investigation | |
Hemoglobin (g/dL) | 13.5 ± 1.5 |
Platelet (×103/μL) | 283.4 ± 64.8 |
Serum albumin (g/dL) | 4.6 ± 0.3 |
Creatinine (mg/dL) | 0.6 ± 0.2 |
eGFR (mL/min/1.73 m2) | 105.6 ± 36.2 |
Histopathological finding | |
No. of glomeruli | 15.7 ± 12.2 |
Data are expressed as number (%) or mean ± standard deviation.
CHP, combined hematuria and proteinuria; eGFR, estimated glomerular filtration rate; IP, isolated proteinuria; PMH, isolated persistent microscopic hematuria; PRB, percutaneous renal biopsy; RGH, recurrent gross hematuria.
Results of follow-up observations according to major urine abnormalities
Follow-up results by urine abnormality at the first visit | Follow-up patient |
---|---|
RGH | 8 |
Gross hematuria | 1 (12.5) |
Microscopic hematuria | 1 (12.5) |
No hematuria | 6 (75.0) |
PMH | 8 |
Isolated microscopic hematuria | 4 (50.0) |
No microscopic hematuria | 4 (50.0) |
CHP | 5 |
Hematuria and proteinuria | 0 (0) |
Hematuria | 1 (20.0) |
No abnormality in urine analysis | 4 (80.0) |
IP | 4 |
Proteinuria | 3 (75.0) |
No abnormality in urine analysis | 1 (25.0) |
Other renal insufficiencies | 3 |
Persistent renal insufficiency | 1 (33.3) |
Improved symptoms and no abnormality in urine analysis | 2 (66.7) |
Data are expressed as number only or number (%). Follow-up duration, 35.5 ± 23.6 months.
CHP, combined hematuria and proteinuria; IP, isolated proteinuria; PMH, isolated persistent microscopic hematuria; RGH, recurrent gross hematuria.