SN Wong, KW Chan, MC Chiu, HK Paediatric Nephrology Study Group

Abstract

To study the role of renal biopsy in the evaluation of childhood glomerular diseases, we undertook a retrospective review of 150 renal biopsies performed for Chinese children below 16 years of age in nine major public hospitals in Hong Kong from January 1, 1991 to December 31, 1993. Among 75 children biopsied for nephrotic syndrome, pathological diagnosis included minimal change disease (MCD) (37), diffuse mesangial proliferation (DMP) (13), hepatitis B virus (HBV)-membranous nephropathy (7), focal segmental glomerulosclerosis (FSGS) (6). Diseases other than MCD-DMP-FSGS spectrum were diagnosed in 19 cases and all except 2 occurred in children presenting with nephritic-nephrotic features, positive serology for HBV, or steroid resistance. In 21 patients biopsied for persistent isolated hematuria, IgA nephropathy, Alport's syndrome, benign hematuria and proliferative endocapillary GN were diagnosed respectively in 10, 4, 6, and 1 patients. In 16 patients biopsied for persistent hematuria and proteinuria with or without other nephritic features, IgAN(5), proliferative endocapillary GN(5) and various other nephropathies(6) were found. Overall, the commonest primary glomerulonephritis were minimal change disease (MCD) (25%), IgA nephropathy (11%), and diffuse mesangial proliferation (DMP) (9%), while the commonest secondary glomerulonephritis were lupus nephritis (16%) and Schonlein-Henoch purpura (9%). The data showed local paediatric nephrologists performed renal biopsies only on selected patients and this was helpful in their diagnosis and treatment.

Introduction

Since its first introduction in 1951,¹ renal biopsy has revolutionized the study of glomerular diseases. With the help of light and electron microscopy and immunofluorescent examination of renal tissues, the renal pathologist has been able to classify glomerulonephritis, to describe their clinico-pathological correlation and natural history, and to study their pathogenesis.² The clinicians utilize the information for the diagnosis and monitoring of treatment of their patients. The pattern of glomerular diseases may differ in different population groups. There have been a few reports on childhood glomerulonephritis in Chinese.^3,4 We have undertook a retrospective review of renal biopsies in children among the major public hospitals in Hong Kong to find out the clinical indications for renal biopsy among the local pediatric nephrologists, the relative frequencies of different glomerular diseases in the Chinese children, and the clinico-pathological correlation of glomerular diseases in Chinese children.

Patients and Methods

From the biopsy records of Paediatric and Pathology Departments of the participating hospitals, patients below the age of 16 years, who underwent renal biopsy, during the period from January 1, 1991 to December 31, 1993 were retrieved. The case records of these patients were reviewed to collect demographic data, clinical features, indications of renal biopsy, pathological diagnosis, their treatment and outcome.

All renal biopsies were routinely processed in a standard technique for light microscopy, electron microscopy and immunofluorescence study. Renal tissues were considered adequate for diagnosis if they contain more than 6 glomeruli. They were reported by the pathologists of individual hospitals basing on WHO classification.⁵ The pathological findings were reviewed by a renal pathologist with no change in diagnostic classification in all cases.

Clinical features were recorded according to a set of predetermined criteria as follows: Haematuria was defined as morning urine haemastix 2+ or more and presence of >5 RBCs on microscopy. Proteinuria was defined as morning urine albustix 2+ or more, or protein excretion rate of more than 4 mg/m²/hr. Nephrotic syndrome was defined as massive proteinuria of > 40 mg/m²/hr and presence of edema and serum albumin concentration of <25 g/L. Nephritic-nephrotic syndrome was defined as nephrotic syndrome with the presence of atypical features such as hypertension, persistent microscopic or gross hematuria, impaired renal function, low complement C3 concentration. Suspected nephritis was considered in the presence of the above features but a normal serum albumin level of > 25 g/L. Renal insufficiency was defined as glomerular filtration rate, as determined by Schwartz formula, of < 50 ml/mm/1.73 m². Chronic renal failure was defined as a GFR of < 25 ml/mm/1.73 m², and end stage renal disease was defined as a GFR of < 5 ml/mm/1.73 m², or requiring dialysis. Steroid resistance was defined as proteinuria despite 4 weeks of prednisolone at dose of 60 mg/m²/day. Steroid dependence was defined as relapse of NS on decreasing prednisolone dose or within 2 weeks of stopping prednisolone therapy. Henoch-Schonlein purpura was diagnosed when 2 or more of the following were present: vasculitic purpura, abdominal pain or gastrointestinal bleeding, joint pain, and urinary abnormalities. Systemic lupus erythematosus was diagnosed by the criteria of American College of Rheumatology.

Results

Patient demographic pattern

From January 1, 1991 to December 31, 1993, a total of 150 children underwent renal biopsy in the nine public hospitals participating in the review. All were Chinese children. Their age at biopsy ranged from 1 month to 15.9 years, with 23 patients below 5 years of age, 48 patients between 5 and 10 years, and 79 patients above 10 years. There were 84 boys and 67 girls. A strong male predominance occurred in the younger patients. The male:female ratio was 3.4 : 1, 1.5:1, and 0.9:1 for the age groups below 5 years, 5 to 10 years, and above 10 years respectively.

Clinical indications for biopsy

A total of 75 children who suffered from nephrotic syndrome were biopsied. Thirty-five patients were biopsied at presentation because of atypical age of onset (after 10 years in 11 cases; below 1 year in 2 cases), presence of nephritic-nephrotic features including persistent hypertension, gross hematuria, impaired renal function, and low complement C3 concentrations (6 cases), presence of HBsAg and HBeAg in serum (7 cases), initial steroid resistance (9 cases). The remaining forty patients were biopsied at a later stage of their illness, when their nephrotic syndrome was steroid dependent (34 cases) or steroid resistant after relapses (6 cases). Within the same period, a total of 132 children presented with primary nephrotic syndrome to the participating hospitals.

In 39 cases, renal biopsy was performed for diagnosis of suspected glomerulonephritis. Sixteen of these 39 cases had hematuria and proteinuria with or without other nephritic features such as hypertension and azotaemia. Isolated hematuria was the reason for biopsy in 21 cases (recurrent gross hematuria in 12 cases, persistent microscopic hematuria for 1 - 5 years in 7 cases, hematuria and sensorineural deafness or family history of Alport's syndrome in 2 cases). Isolated heavy proteinuria (more than 1 gram/day) without other nephrotic features occurred in the remaining 2 cases.

Renal biopsies were performed in 35 children for the assessment of systemic diseases with renal involvement. Twenty-two patients were diagnosed to have systemic lupus erythematosus before the renal biopsy. They had nephrotic syndrome (14 cases), nephritic-nephrotic syndrome (2 cases), proteinuria and hematuria (6 cases) and isolated proteinuria (2 cases). In 13 patients, Schonlein-Henoch purpura was diagnosed clinically and renal biopsy was performed for evaluation of massive proteinuria (> 40 mg/m²/hour) and hematuria without oedema or hypoalbuminemia in 10 cases, and of nephrotic syndrome in 3 cases.

Overall frequency of renal pathology

As shown in Table I, the commonest primary renal pathology in our population were minimal change disease (MCD) (25%), IgA nephropathy (11%), diffuse mesangial proliferation(DMP) (9%), diffuse endocapillary proliferative glomerulonephritis (6%), and focal segmental glomerulosclerosis (FSGS) (5%). The commonest secondary glomerulonephritis were lupus nephritis (16%), Schonlein-Henoch nephritis (9%), and HBV-associated membranous nephropathy(MGN) (5%).

Pattern of renal pathology in nephrotic children

Table II shows the renal pathology diagnosed in the nephrotic children in relation to the indications of biopsy. In this group, 64 cases (85%) had primary glomerulopathy including MCD in 37, DMP in 13, FSGS in 6, IgA nephropathy in 3, diffuse endocapillary proliferative GN in 3, MPGN in 2. The remaining 11 cases (15%) had secondary GN due to HBV-associated MGN in 7, lupus nephritis in 2, Alport's syndrome in 1 case, and congenital nephrotic syndrome due to CMV infection in 1 case.

Pathologies other than the MCD-DMP-FSGS spectrum were mainly diagnosed in patients biopsied at presentation for the presence of nephritic-nephrotic features, positive HBV markers, and early steroid resistance. 1gM deposits were identified in 6 cases of DMP but because of the small number of cases, no difference in clinical features and outcomes could be identified in these cases as compared with those without 1gM deposits.

Pattern of renal pathology for other non-nephrotic indications

Table III shows the renal pathology in patients biopsied for other indications. Patients with isolated hematuria had IgA nephropathy (10 out of 21 cases), Alport's syndrome (4 out of 21 cases), diffuse endocapillary proliferative glomerulonephritis (1 out of 21 cases). In the remaining 6 cases, no renal pathology was identified in the renal biopsy specimens, including electron microscopy examination for thickness of the glomerular basement membrane. A diagnosis of benign hematuria was given to these 6 cases.

For patients with hematuria and proteinuria and other nephritic features, a variety of glomerulonephritis were identified, including IgA nephropathy in 5 cases, diffuse endocapillary proliferative glomerulonephritis in 5 cases, and MGN, MPGN, and anti-GBM nephritis in 1 each.

Renal pathology in lupus nephritis (Table IV)

Systemic lupus erythematosus (SLE) was diagnosed before biopsy in 22 patients. Biopsy was performed in these patients because of urinary abnormalities, to assess the severity of nephritis and to guide treatment. In two patients, SLE was first discovered by renal biopsy for nephrotic syndrome and was subsequently confirmed by the clinical course and other features. Table IV shows the clinical features at the time of biopsy and outcome at last follow up in relation to their renal pathology. In these Chinese children with lupus nephritis, the most frequent presentation was nephrotic syndrome and commonest pathology is Class IV nephritis. Most were responsive to treatment, with all except 4 patients in complete remission or with asymptomatic haematuria or proteinuria when last followed up at a mean of 25 months.

Discussion

The present study attempted to survey the role of renal biopsy in diagnostic evaluation of children with renal diseases in Hong Kong, by describing the clinical indications that paediatric nephrologists in Hong Kong had performed renal biopsies, and by reporting the relative frequencies of various pathological findings in relation to the clinical indications. The data did not represent a true incidence of glomerular diseases in Hong Kong children over this 3-year period. Firstly not all children with renal diseases underwent renal biopsy, such as those with typical post-Streptococcal nephritis, typical nephrotic syndrome or isolated microscopic haematuria. Secondly some biopsy cases in private hospitals will be missed in the survey, although this is minimal because the public hospital system care for more than 80% of the population in Hong Kong,⁶ and because of financial reasons, the more complicated renal cases will be referred to public hospitals.

From our survey, renal biopsy were not considered necessary by paediatric nephrologists in the following situations. For nephrotic syndrome, no biopsy were performed for children aged one to ten years, without atypical features such as gross haematuria, hypertension, impaired renal function and low complement levels, and if they respond to empirical steroid therapy. Similarly no children with typical acute nephritic syndrome with evidence of recent streptococcal infection were biopsied in the public hospitals. The same was true for children with mild proteinuria (< 1 gram/day), or with single episode of isolated gross hematuria, or with transient microscopic hematuria.

Expectedly from our selective approach to biopsy, among children biopsied for nephrotic syndrome, we had a smaller percentage of minimal change disease (49%) compared to 76% of unselected cases in the report of the International Study of Kidney Disease in Childhood,⁷ or 57% of referred patients in a French report.⁸ On the other hand, we had a higher percentage of diffuse mesangial proliferative glomerulonephritis (1 3%) compared to 2.5% reported in ISKDC⁷ or 6.8% reported by Habib et al.⁸ We also had a higher percentage (9%) of membranous nephropathy which were mostly associated with chronic HBV infection. Because immunostaining for hepatitis B virus antigens was not a routine study in our laboratories, a direct causal relationship cannot be proven. Our finding was in agreement with the incidence of mesangial nephropathy (26.9%) and HBV membranous GN (9.8%) from a report from Taiwan.⁹ However, only 50% of our cases of DMP had predominant 1gM deposits whereas all of the cases of DMP reported by Chen et M9 were classified as 1gM nephropathy.

As shown in Table II, most patients biopsied for an age of onset of > 10 years or for steroid dependence or late steroid resistance have either MCD or DMP or FSGS, whereas other renal pathologies occurred in patients biopsied for the presence of nephritic features, positive serology of HBV or early steroid resistance. Since the treatment strategy for the MCD-DMP-FSGS spectrum is similar (that is, trial of steroid followed by use of levamisole or cyclophosphamide or cyclosporine A for the steroid intolerant patients), our results support the argument that a renal biopsy is not mandatory in the nephrotic children above 10 years of age, before steroid treatment, or those children with steroid sensitive but dependent nephrotic syndrome before receiving cyclophosphamide.¹⁰

Our overall incidence of IgA nephropathy was 11%. This was comparable to the incidence of 2-10% reported from studies in USA¹¹ and UK,¹² but lower than those of 18-40% reported from Japan¹³ and Italy.¹⁴ This was again because of our selective approach to do biopsy only in children with recurrent gross hematuria. We offered renal biopsy to children with microscopic hematuria only after a long period of observation and if parents were anxious to know the cause. We did not have universal urinary screening programs for school children as in Japan.

From Table III, the most likely causes in our patients with recurrent gross hematuria were IgA nephropathy, benign recurrent hematuria or Alport's syndrome. There is at present no specific therapy for mild IgA nephropathy or benign recurrent hematuria. For Alport's syndrome, no therapy can alter the progressive course. Therefore renal biopsy in this situation only provides information for the prediction of prognosis for the anxious parents.

On the other hand, when our patients with proteinuria and hematuria with or without other nephritic features were biopsied, a variety of glomerulonephritis were found. Some of these, such as anti-GBM crescentic nephritis, membranoproliferative glomerulonephritis, need early specific treatment. A renal biopsy is definitely indicated early in the course of this group of patients.

In conclusion, pediatric nephrologists in Hong Kong adopt a selective approach in performing renal biopsies. While minimal change disease is the commonest pathology, our population has a higher prevalence of DMP and HBV-associated membranous nephropathy among the nephrotic children in Hong Kong. The commoner causes of persistent hematuria are IgA nephropathy, Alport's syndrome and benign hematuria. Lupus nephritis and Henoch-Schonlein nephritis are the two commonest systemic diseases causing secondary glomerulonephritis.

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