Summary

The roles of general practitioners in management of childhood nephrotic syndrome:

• To recognize the presenting features of childhood nephrotic syndrome
• To detect atypical features at presentation
• To initiate medical treatment in children with typical presentation
• To provide education to the family
• To provide routine health maintenance care
• To monitor progress and complications
• To decide when to refer to paediatric nephrologist

摘要

全科醫生在診治兒童腎病綜合症的角色包括：

• 識別兒童腎病綜合症的病徵
• 察覺非典型的病徵表現
• 為有典型病徵的兒童開始治療程序
• 向家庭成員提供相關知識
• 提供日常疾病治療
• 監察腎病病情進度及併發症
• 決定何時轉介予兒童腎病專科醫生

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Introduction

Nephrotic syndrome is a kidney disorder characterized by oedema, heavy proteinuria, hypoalbuminaemia and hyperlipidaemia (Table 1). Untreated nephrotic syndrome is often associated with increased risks of life-threatening infection, thrombosis and dyslipidaemia. The aetiologies and management of nephrotic syndrome in children are different from their adult counterparts and general practitioners who manage patients in different age groups need to be aware of these differences. As clinical response to corticosteroids can give much more significant prognostic indications than the underlying histology can, and the majority of children with nephrotic syndrome are sensitive to corticosteroids, renal biopsy is not usually needed at the onset.

Table 1: Definitions used in nephrotic syndrome
Hypoalbuminaemia	serum albumin level less than 25 g/dL
Hyperlipidaemia	total cholesterol more than 200 mg/dL, and/or triglycerides more than 160 mg/dL
Proteinuria	urinary excretion of more than 40 mg/m2/hour, or random urine protein to creatinine ratio more than 2

Pathogenesis

The common primary and secondary causes of nephrotic syndrome are shown in Table 2. Although genetic mutations leading to disruption of the integrity of the podocyte cytoskeleton have been reported in some patients with nephritic syndrome,¹ the exact pathomechanism of nephrotic syndrome still remains uncertain. Circumstantial evidence suggests that perturbations of cell mediated immunity may play a significant role in the pathogenesis of nephritic syndrome.² Furthermore, there is also clinical and laboratory evidence that a circulating “permeability” factor exists and may be responsible for the increase in permeability of the glomerular basement membrane, but the factor has not yet been identified.³

Table 2: Common aetiologies of childhood nephrotic syndrome
Primary	Secondary
MCD	SLE
FSGS	MPGN
Diffuse mesangial proliferation	HSP
Membranous glomerulopathy	Hepatitis B and C
MCD: minimal change disease FSGS: focal segmental glomerulosclerosis SLE: systemic lupus erythematosus MPGN: membranoproloiferative glomerulonephritis HSP: Henoch-Schonlein Purpura

Epidemiology

The incidence of idiopathic nephrotic syndrome among children under the age of 16 has been reported to be between 2 to 7 per 100,000 children per year.⁴ According to the statistics report from the Hong Kong Government in the year of 2009, the number of children in Hong Kong with age under 15 was 865,000.⁵ Therefore, the annual incidence of nephrotic syndrome among Hong Kong children is expected to be between 17 to 61 children per year. This number is in line with the reported data from the Hong Kong Paediatric Nephrology Society. According to their database, the annual incidence of nephrotic syndrome among children in Hong Kong was 57 per year during the period of 1998 to 2000 (range 43 to 69).⁶

Roles of general practitioners

To recognize the presenting features of childhood nephrotic syndrome

The diagnostic criteria of nephrotic syndrome are:
1) oedema,
2) proteinuria,
3) hypoalbuminaemia, and
4) hyperlipidaemia

Oedema is the predominant presenting feature in children with nephrotic syndrome. Its pathogenesis remains controversial. Oedematous swelling usually develops around the eyes initially, which is often mistaken as allergy. If left alone, the swelling becomes generalized to involve the whole body. Patients and their families may also notice progressive abdominal distension, decrease in urine output and frothy urine. Physical examinations may reveal marked increase in body weight, pleural effusion and ascites. Urinalysis shows heavy proteinuria and occasionally haematuria. Laboratory investigations that are helpful at presentation are shown in Table 3. As twenty-four hour urine collections are not very practical with children and unnecessary in most children with nephrotic syndrome; proteinuria may be quantified as the protein to creatinine ratio on a randomly voided sample.

Table 3: Common laboratory investigations performed at first onset of nephrotic syndrome in children

Urinalysis

Random urine for protein to creatinine ratio

Serum electrolytes, albumin and cholesterol

Complete blood count

Complement C3 and C4 levels

Varicella zoster serology

Hepatitis B and C serology

Anti-streptolysin O titre,

Anti-nuclear antibody

To detect atypical features at presentation

Minimal change disease is by far the commonest childhood nephrotic syndrome.⁷ The presence of any of the clinical features, shown in Table 4, suggests a possibility of alternative diagnosis. These children are less likely to respond to corticosteroids therapy and should be referred to paediatric nephrologists. On the other hand, microscopic haematuria may be present in up to 25% of children with steroid sensitive nephrotic syndrome and should not be a contraindication to empirical corticosteroids therapy.⁸

Table 4: Atypical clinical feature for children with nephrotic syndrome

Age 12 years

Elevated blood pressure

Impaired renal function

Gross haematuria

Low plasma complement C3 level

Hepatitis B or C antigens positive

To initiate medical treatment in children with typical presentation  

Several studies in the past have determined that among children with nephrotic syndrome, 70 to 80% had histological diagnosis of minimal change disease.^{9, 10} Since we no longer perform renal biopsy on every child at presentation, we are not able to replicate those studies anymore. Nonetheless, the study from the Hong Kong Nephrology Study Group reported that, among 75 children with biopsy due to nephrotic syndrome between the years 1991 to 1993, 49% had minimal change disease.¹¹ Therefore the majority of children with nephrotic syndrome are still very likely to b e sensitive to corticosteroids treatment. In the absence of atypical features, and if family physicians are comfortable to assume the care, these children can be managed in a family practice setting with an empirical course of treatment without a renal biopsy.

The mainstay of treatment in children with nephrotic syndrome is corticosteroids. The protocol that we use at our centre is prednisone 2 mg/kg/day (maximum 60 mg per day in prepubertal and 80 mg in postpubertal children). A previous study from Germany showed that the risk of relapse was reduced by 40% during the first 6 months with a prolonged duration of treatment with corticosteroids.¹² Hence, for initial onset of nephrotic syndrome, the treatment is continued for 6 weeks and then converted to alternate day treatment. The optimal duration of alternate day treatment is still controversial and usually last for 8 to 12 weeks, depending on the personal experience of the individual paediatric nephrologist involved in the care. Although randomized trials have confirmed the benefits of reducing relapse by prolonging the duration of initial corticosteroid therapy for up to 6 months, children receiving such a long course of steroids might be at risk of side effects.¹³

Studies have shown that steroids can be given in once-daily dose or in divided doses without altering the efficacy.¹⁴ As gastric irritation is not common in children on steroid treatment, it is not an universal practice to put every child on H₂ antagonist for gastric protection at the author’s centre. Steroids have many side effects, and it is important to inform the family about this before initiation of treatment. Some children experience significant steroids side effects as depicted in Table 5. Besides an increase in appetite, emotional lability is also very commonly seen in children on high dose steroids. Side effects are usually minimal when the child is on alternate day regimen. Although most parent will worry about long-term side effects of steroids such as cosmetic disfigurements, cataract, diabetes and stunted growth, it is not common unless the child has been on the drug for a prolong period of time, for example in the situations of frequent relapses or treatment becoming steroid resistant. Hence, the family needs to be reassured that the side effects and complications of treatment will be monitored closely, and if necessary, the child should be referred to a specialist.

Response to steroid therapy is shown by the resolution of proteinuria (three consecutive days of zero or trace proteinuria on urinalysis). Approximately 80% will respond to steroid therapy within 14 days from the start of treatment.¹⁴ Those who fail to respond within four weeks will require referral to a paediatric nephrologist for further assessment and renal biopsy.

To provide education to the family

Numerous other practical aspects are important and needed to be addressed by the family physician involved. In most centres, it has been a common practice to admit children with first onset of nephrotic syndrome to the hospital, as other ancillary services, such as dietary consultants are more readily available there to provide education (see below) to the families. However, it is probably more convenient for those families in Hong Kong, who live nearby close to the clinic and have access to medical advice easily, especially those who are reliable, to receive the education as outpatient. Parents and caretakers (often the maid) need a clear explanation of the diagnosis of nephrotic syndrome, its implications for future prognosis and the significance of compliance with medication. Side effects of corticosteroids must also be clearly explained (Table 5). Provision of written information will be very helpful so that other family members may also become aware of the situation.

Table 5: Potential side effects of using corticosteroids in children with nephrotic syndrome

Increased appetite

Weight gain/obesity

Emotional lability

Acne

Cushingnoid features

Increased susceptibility to infection

Cataracts

Hypertension

Growth suppression

Adrenal suppression

Decrease in bone mineral density

Impaired glucose metabolism

Families need to be taught on how to perform urinalysis for home monitoring. They should keep a clear record of urinalysis, medications given and any medical symptoms experienced. It is important that the caretakers know how to contact the appropriate medical staff in the case of a relapse. A relapse is defined as recurrence of proteinuria (three consecutive days of 2+ or greater proteinuria on urinalysis).

As bed rest may increase th e risk of venous thrombosis, children should be encouraged to be mobile as normal.

A “no added salt” diet is mandatory since the oedema will worsen when the disease is active. As most children on corticosteroids will have increased appetite, it is also very important to encourage a healthy normal diet and having regular physical activities. 

To provide routine health maintenance care

Children with steroid sensitive nephrotic syndrome are considered immunosuppressed if they have received daily steroids for more than one week in the previous three months, and live vaccines should not be given until at least one month after discontinuation of the corticosteroids. According to the newly revised vaccine schedule for children in Hong Kong, the only live vaccine that are contraindicated in children with active nephrotic syndrome is the MMR.¹⁵ Although no guidelines are available, and there are some concerns regarding suboptimal sero-con version, there is no absolute contraindication to giving “non-live vaccines” while the child is on steroid. At our centre, we emphasize immunization for every child; we encourage all our patients with nephrotic syndrome to receive their regular vaccination while they are in remission, including immunizations against varicella and pneumococcus.

Although most children suffering from the influenza virus infections will have uneventful recovery, children with active nephrotic syndrome on treatment, as well as those who have been on steroid or other immunosuppressive treatments within the last three and six months respectively, are more prone to suffer complications of their illnesses. Therefore children with nephrotic syndrome should be offered influenza vaccination before the influenza season arrives. During an outbreak, if they develop signs and symptoms of lower respiratory tract disease, especially with clinical deterioration, they should be offered antiviral treatment, ideally within 48 hours of symptoms onset.

To monitor progress and complications

According to a recent study from Hong Kong with a mean follow-up duration of 10 ± 3 years, only 17% of children with steroid sensitive nephrotic syndrome did not have any relapse,¹⁶ and up to one third of the relapsers still continued to have active disease at the end of the study. It cannot be overemphasized that families should be informed about the likelihood of relapses in children with nephrotic syndrome, thus they will not feel guilty and have the impression that they have not done enough to prevent it. Other studies also showed that approximately 80% of children with steroid sensitive nephrotic syndrome will relapse one or more times, while some relapse frequently or become steroid dependent. These children should be referred to a paediatric nephrologist for further management. Nevertheless, even children with steroid sensitive nephrotic syndrome are prone to have complications. This is related to the perturbation of the innate system and medication side effects. They have increased predisposition to common infections including cellulitis, upper respiratory tract infections and pneumonia. Another major infectious complication is peritonitis. Families should be instructed to seek medical attention if the child is sick. Although it may be due to gastric irritation secondary to corticosteroids, peritonitis should be considered in every child presenting with an acute abdominal pain, especially if accompanied with fever. They are also at an increased risk of thrombosis but current literatures do not support routine use of anticoagulants. However, immobilization, volume depletion and diuretics should be avoided because of the increased predisposition to thrombosis. Hyperlipidaemia in most children with steroid sensitive nephrotic syndrome is usually transient, although it persists in children with resistant nephrotic syndrome, which may potentially contribute to cardiovascular morbidity in adulthood. Therefore, children with nephrotic syndrome should be encouraged to adopt a low fat diet.

To decide when to refer to paediatric nephrologist

The short- and long-term prognosis of children with steroid sensitive nephrotic syndrome is excellent. If the general practitioner feels comfortable, it is not necessary to refer every child to a specialist. However, under certain circumstances, especially if the nephrotic syndrome becomes difficult to manage, the care should be shared with a paediatric nephrologist. Figure 1 depicts an algorithm on when a child should be referred to a paediatric nephrologist.

Conclusion

Childhood nephrotic syndrome is not an uncommon condition, and general practitioners should be aware that the management of such condition in children is different from adults. In most instances, children with nephrotic syndrome can be given a course of corticosteroids without a renal biopsy. However, in the presence of atypical features and if the management becomes difficult, it is always prudent to share the care with a paediatric nephrologist.

Key messages

1. Outpatient management of nephrotic syndrome is feasible and probably more convenient for families in Hong Kong.
2. Children with nephrotic syndrome often have low intravascular volume and diuretics are not indicated.
3. Abdominal pain, especially if severe and associated with fever, may be a warning sign of peritonitis.
4. Parents should be informed of the side effects of corticosteroids.
5. Children requiring long-term corticosteroids and/or other immunosuppressive drugs are best managed by paediatric nephrologists.

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References