Summary

Although most children with the incidental finding of proteinuria do not have kidney disease and the proteinuria disappears on repeat testing, persistent asymptomatic proteinuria may be the first presenting feature of an underlying renal disorder. It is important to repeat the urinalysis and to rule out orthostatic proteinuria, as this will alleviate the anxiety of most patients and parents. In a minority group of patients, referral to a paediatric nephrologist is recommended.

摘要

雖然在兒童偶然發現的蛋白尿多數並非由腎病引起，而在重復測試時，蛋白尿往往自然消失，可是持續無症狀的蛋白尿也可能是腎病的初期徵兆。替病人重復測試小便和排除直立性蛋白尿可減輕病人和父母的憂慮。但仍有少數病人，需要轉介到兒童腎病專科作進一步跟進。

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Introduction

The normal rate of protein excretion is considered to be less than 4 mg/m²/hour. Asymptomatic proteinuria refers to proteinuria discovered during evaluation of an asymptomatic child.¹ The patient does not have fever, oedema, or haematuria. Epidemiological studies for asymptomatic proteinuria showed that transient proteinuria can occur up to 6% in children, but persistent proteinuria is less common.^2-4 Although the presence of protein in urine may suggest serious underlying renal pathology, initial evaluation can be done in a general practitioner's office. Depending on the findings, the patients can either be managed by the general practitioners or be referred to a paediatric nephrologist for further treatment. The management of paediatric patients with nephrotic syndrome is different and will not be discussed here.

The role of the general practitioner

According to the 2001 Census and Statistics report, 16.5% (1.11 million) of the Hong Kong population was between 0 and 14 years old.⁵ Data from various sources indicated that the prevalence of isolated asymptomatic proteinuria in children has been estimated to be between 0.6% and 6%.^2-4 Although epidemiological data for asymptomatic proteinuria is not available in Hong Kong, it is reasonable to assume that incidental finding of proteinuria in children is quite common. The majority of children with proteinuria are likely to be discovered and managed by the general practitioner. The principal goals of asymptomatic proteinuria management are:

1) To detect and confirm the presence of proteinuria

2) To differentiate between transient and persistent proteinuria

3) To provide management in a primary care clinic

4) To decide when to refer to a paediatric nephrologist

Detection and confirmation of proteinuria

In the primary care clinic, proteinuria is most commonly discovered by a positive dipstick (Multistix or Albustix) of urine test. Proteins present in urine cause a change in the colour of the specific patch for protein on the dipstick that is impregnated with tetrabromphenol blue. Tetrabromphenol blue is a pH colour dye that reacts preferentially to albumin and it is relatively insensitive to other proteins. Depending on the colour change, the results can be read as trace, 1+ to 4+. One plus indicates a concentration of albumin of 30 mg/dl and 4+ indicates a concentration of at least 1,000 mg/dl. False positive results may occur especially in alkaline urine and in the presence of some common drugs and chemicals such as chlorhexidine and benzalkonium chloride. In offices that are still using sulphosalicylic acid to detect proteinuria, penicillin, cephalosporin and radio-contrast medium can lead to a false positive dipstick result.⁶ Samples containing urease-producing bacteria may also have an elevated pH resulting in false positive results. As the reaction depends on the concentration rather than the amount of protein in the urine, patients with persistent proteinuria (see below) should have the amount of protein in urine quantified in either a timed collection or a random sample for protein to creatinine ratio. The normal rate of protein excretion is less than 4 mg/m²/hr. This rate is approximately equal to a urine protein to creatinine ratio of 0.2 or urine albumin to creatinine excretion of less than 30 mg/g of creatinine.

Heavy proteinuria occurs in children with nephrotic syndrome, which is rare in children and is defined by the occurrence of generalized oedema, heavy proteinuria, hypoalbuminaemia and hyperlipidaemia. The amount of protein in urine is usually high with an excretion of more than 40 mg/m²/hr or urine protein to creatinine ratio of more than 3. Since children with nephrotic syndrome will present with other symptoms and the management is different, it will not be discussed here.

Differentiation between transient and persistent proteinuria

Although asymptomatic proteinuria may be the first presentation of significant renal diseases, benign conditions need to be ruled out before carrying out extensive or invasive investigations. Transient proteinuria rarely associates with significant underlying renal diseases and may occur in children after heavy exercise, when under stress or during fever and bladder infection. If bladder infection is suspected, the infection should be confirmed and appropriately treated before repeating the urinalysis. As many as 30 to 50% of children with proteinuria have transient rather than persistent proteinuria, and most of the proteinuria disappears after repeat testing. Therefore it is recommended to repeat the urine analysis for two more times, at least a week apart, to confirm that it is persistent before the initiation of extensive work up.⁷

After the patient is confirmed to have persistent proteinuria, orthostatic or postural proteinuria should be excluded before carrying out extensive investigations. Orthostatic proteinuria is a common benign condition defined as abnormal excretion of protein that happens only when the subject is upright but not during recumbence. This condition occurs more commonly in adolescents and young adults. Proteinuria may result in a dipstick of 3+ to 4+ protein, but the 24-hour urine collection seldom exceeds 40 mg/m²/hr. The condition can be diagnosed by the "6 cups test". The patient is asked to void and discard the urine just before going to bed and remain recumbent throughout the night before obtaining a morning specimen. Another specimen is also collected during the day after the patient has resumed normal activities. The sample collections should be repeated for 2 more days. If the properly collected morning samples have trace or negative for protein on dipstick test or the urine protein to creatinine ratios are less than 0.2, it is quite reassuring that the diagnosis is orthostatic proteinuria. If the first morning sample is still positive for protein, further investigations are indicated. Long term follow up studies have suggested that this is a benign condition and the individuals are not at greater risk of developing renal diseases in later life than the general population.^8-10

Management in the clinic

Positive protein results must be evaluated in the light of the history and physical examination. The evaluation algorithm of proteinuria is depicted in Figure 1. The initial evaluation of an incidental finding of proteinuria in children should therefore include a complete history that includes any recent history of infections, associated urine abnormality such as gross haematuria or change in urine output, other symptoms suggestive of systemic or rheumatic illnesses such as rash, weight loss, joint pain and swelling. Past medical history should include previous history of proteinuria, kidney disease and injury. History of drug usage is also important because some of the medications can be nephrotoxic. Family history should include any kidney diseases and early onset diabetes mellitus. Family history of deafness may suggest the possibility of Alport's disease, which may present as asymptomatic proteinuria and haematuria. The physical examination should consist of all the growth parameters, blood pressure, presence of oedema, ascites and palpation for kidneys. Transient proteinuria, with positive dipstick tests that disappeared on subsequent testing, is considered to be a benign condition and rarely indicates an underlying kidney disease. A yearly urinalysis to detect any recurrence of proteinuria and/or other urine abnormality, with a physical examination to detect any new onset of hypertension, is probably adequate management. Similarly, patients with orthostatic proteinuria have no increased risk of kidney disease than the general population; they should be followed by yearly urinalysis on the first morning urine specimen.

If transient proteinuria and orthostatic proteinuria have been ruled out, the urine protein needs to be quantified by urine protein to creatinine ratio and the cause should be determined. The presence of other abnormalities such as haematuria or abnormal sediments would strongly suggest an underlying kidney disease. Depending on the clinical suspicion of other systemic illness, supplemental laboratory investigations may include complete blood counts, renal function tests, serum protein and albumin levels, Complement 3 levels, ultrasound and voiding cystourethrogram (VCUG).

Although patients with orthostatic proteinuria have excellent long term outcomes, the prognosis of other patients with persistent proteinuria remain unclear. Since there is evidence showing that proteinuria itself can induce further renal injury and be associated with cardiovascular disease, persistent proteinuria needs to be treated.¹¹ Management depends on the severity of the proteinuria. Although avoidance of excessive protein intake may be beneficial, restriction of dietary intake of protein is not indicated and may be harmful.¹² On the other hand, a reduction of salt intake is usually recommended for patients with kidney diseases. Any consumption of nephrotoxic medication should be discontinued. Commonly used medications in children that are potentially renal toxic include non-steroidal anti-inflammatory drugs such as ibuprofen. Hypertension and diabetes, if present, should be treated. For those "diabetic prone" patients with micro-albuminuria, early treatment with angiotensin converting enzyme (ACE) inhibitor may be beneficial (see below).

There is increasing evidence that adjunctive therapy with ACE inhibitor and/or angiotensin receptor blocker (ARB) can reduce the amount of protein in urine and is probably renal "protective".¹³ Side effects of ACE inhibitors include dry cough due to increase production of kallikrein, reduction of glomerular filtration rate and hyperkalaemia. Its regular use in patients with proteinuria is still not universal. The physician should also stress that ACE inhibitors are teratogenic. Female patients need to be warned about this side effect and the medicines need to be discontinued in the future as they plan to become pregnant. Regardless of the treatment, frequent monitoring to assess the progression of severity of proteinuria or response to treatment is an indispensable part of the management.

Proteinuria, unlike haematuria, is often less alarming and usually not perceived as a severe disease to parents. However, persistent proteinuria of various degrees of severity in children should be regarded seriously, as recent studies suggested that this abnormality is associated with chronic kidney disease.¹⁴ The implication of this condition should be explained to the family and include them as part of the team in monitoring the progress of the situation.

Decision when to refer to paediatric nephrologist

Each child with proteinuria should be assessed individually. Patients with renal insufficiency, progressive renal disease and history or examination suggestive of systemic diseases should be referred to paediatric nephrologists for further work up. Although there are no evidence based guidelines, children with more severe proteinuria, i.e. urine protein to creatinine ratio of more than 0.5 (or lower if there is physician or parental anxiety) and presence of other co-existing urine abnormality such as haematuria, should probably be referred to paediatric nephrologist for management. A renal biopsy may be performed in order to rule out severe underlying diseases. Nevertheless, since proteinuria has been recognized as both a marker and a cause of progressive renal insufficiency, it is prudent to involve paediatric nephrologists who are specialized in management of persistent proteinuria in the management.

Conclusion

The finding of asymptomatic proteinuria is quite common in general practice, and most of the time, a careful history, physical examination and simple laboratory tests are usually enough to make a diagnosis. The finding suggestive of orthostatic proteinuria is reassuring for good long term prognosis. Extensive and invasive investigations are not indicated. However, patients with persistent proteinuria other than orthostatic proteinuria may have less favourable outcome. Until more information is available, it is still advisable to refer the patient to a paediatric nephrologist for further evaluation. In most instances, optimal care will be provided by the joint efforts of the general practitioners and the paediatric nephrologists.

Key messages

1. Proteinuria should be confirmed by repeat testing.
2. Coexistence of haematuria and abnormal sediments strongly suggests glomerular disease.
3. Proteinuria found by dipstick test should be quantified by either a timed collection of urine sample or a random sample for urine protein to creatinine ratio.
4. Orthostatic or postural proteinuria needs to be ruled out before extensive investigations.
5. Coexistence of other signs and symptoms such as hypertension, gross haematuria and abnormal renal function tests should prompt an immediate referral to a paediatric nephrologist.

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References