Nephrotic syndrome

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16.6 Nephrotic syndrome

1 Nephrotic syndrome refers to the clinical findings of hypoalbuminaemia, heavy proteinuria, oedema and hyperlipidaemia. Every child has albuminaemia but not all features are necessary for diagnosis.

2 Despite the presence of oedema, shock still needs to be treated with 20 mL kg^–1 0.9% saline or albumin boluses.

3 Renal function is usually normal though serum creatinine may be slightly elevated at presentation.

4 There is 1–2% mortality despite good long-term prognosis.

5 The physical findings of peritonitis in nephrotic syndrome may be very subtle, thus the emergency physician must have a very high index of suspicion for peritonitis.

6 Death from peritonitis and thrombosis can occur despite very good care.

7 All children with nephritic syndrome should receive pneumococcal vaccine.

8 All non-immune children on steroid therapy who are exposed to varicella require prompt administration of zoster immune globulin. Should they develop lesions, they require treatment with intravenous aciclovir.

Introduction

Definition

Nephrotic syndrome (NS) refers to the findings of heavy proteinuria, hypoalbuminaemia, oedema and hyperlipidaemia, which result from a massive loss of protein in the urine secondary to glomerular disease. All components of the disease do not need to be present for diagnosis. The protein lost in the urine includes plasma proteins of molecular weight up to and including albumin. Generalised glomerular leak to macro-molecules does not occur in most cases, but can occur in severe disease. In severe disease, as there is progressive loss of glomerular permselectivity, renal clearance of IgG approaches that of albumin. Protein selectivity is seen mainly in minimal change nephrotic syndrome. The determination of protein selectivity has little clinical value but does increase the likelihood of response to steroid therapy.

The hallmarks of nephrotic syndrome are hypoalbuminaemia (serum albumin <30 g L^–1), heavy proteinuria (>50 mg kg^–1 body weight per 24 hours, or >1000 mg m^–2 per 24 hours), generalised oedema and hyperlipidaemia (triglycerides and cholesterol).

Primary nephrotic syndrome (idiopathic) represents disease limited to the kidney. Disease is classified by responsiveness to steroid therapy (steroid sensitive, steroid dependent or steroid resistant) and histology on renal biopsy (minimal change, mesangial proliferative glomerulonephritis (GN) and focal segmental glomerulosclerosis, FSGS).

Secondary nephrotic syndrome represents multisystem disease that has kidney involvement, e.g. lupus nephritis, hereditary nephritis and Henoch–Schönlein purpura.

Certain drugs and chemicals can cause nephrotic syndrome, e.g. phenytoin, non-steroidal anti-inflammatory drugs, and captopril.

Epidemiology

Minimal change nephrotic syndrome (MCNS) is more common in males. Mean age of onset is <6 years for primary nephrotic syndrome, and >6 years for secondary. It is usually sporadic. A congenital form, inherited in an autosomal recessive manner, presents in the newborn period.

Aetiology

The cause of primary nephrotic syndrome is unknown and hence is referred to as idiopathic. The commonest form is minimal change disease (85%). Renal biopsy findings in this form show no abnormality of the glomeruli on light microscopy. Electron microscopy shows effacement of the epithelial foot processes. Biopsy findings of FSGS (10%) reveal normal appearing glomeruli but may show some mesangial proliferation. Some biopsy specimens may demonstrate segmental scarring. Mesangial proliferative disease (5%) shows diffuse increase in mesangial cells and matrix on biopsy.

Pathophysiology

An immune basis for MCNS was proposed in 1974 but no primary immune abnormality has been identified. Studies have shown increased levels of circulating soluble interleukin-2 receptor in patients with active MCNS and FSGS. This soluble interleukin-2 receptor is shed by activated lymphocytes and may therefore indicate generalised activation of the immune system. However, this circulating soluble interleukin-2 receptor could serve as a neutraliser of circulating interleukin-2. It is unknown whether circulating levels represent evidence of activation or an attempt to down-regulate the immune responses.

There is hypercoagulability resulting from serum protein abnormalities introduced by renal protein wasting. All children with acute NS have increased platelet aggregation. Blood viscosity is increased and blood flow is reduced. Fibrinogen concentration is increased and antithrombin III is lost in the urine. All these factors contribute to this problem in NS.

The cause of cholesterolaemia and hypertriglyceridaemia remains uncertain. One theory is that reduced plasma oncotic pressure may stimulate lipoprotein synthesis and perhaps lipolytic factors may be lost in the urine.

Oedema reflects retention of salt and water. Reduced serum albumin causes a reduction in plasma oncotic pressure. When plasma oncotic pressure falls, intravascular volume is reduced, which stimulates proximal tubular reabsorption of sodium. The renin–angiotensin system is also stimulated, raising the serum aldosterone, which further increases distal tubular reabsorption of sodium. There is an increase in filtration capacity in patients with nephrotic syndrome along with an increase in glomerular permeability, resulting in proteinuria.

There is also evidence in some patients for primary salt and water retention by the kidney.

History

The presence of the following may be noted on history:

• recent flu-like illness;

• abdominal pain;

• recent ant bites or bee stings.

Examination

Periorbital oedema is noted initially, but in time oedema becomes generalised. Oedema of the lower extremities is usually ‘pitting’ in type and accumulates in dependent sites. The rate and degree of oedema formation is directly related to salt intake and to the degree of hypoalbuminaemia and therefore can vary from child to child. Ascites may be present. Pleural effusions or pulmonary oedema may develop. Scrotal or perineal oedema may be very distressing to the patient. Blood pressure may be decreased when hypovolaemia exists or may be elevated if there is significant renal disease by activation of the renin–angiotensin system or primary salt retention.

Investigations

• Hypoalbuminaemia (serum albumin <30 g L^–1) occurs in every child with nephrotic syndrome.

• Reliably timed 24-hour urine collections are difficult to obtain in children (protein excretion exceeds 50 mg kg^–1 per 24 hours or 1000 mg m^–2 per 24 hours in nephrotic syndrome), so the proteinuria is generally quantified by the ratio of urine protein to urine creatinine. Spot urine protein:creatinine ratio is >300 mg nmol^–1 in nephrotic syndrome. Normal is <0.2 mg protein per mg creatinine (or protein per mmol creatinine).

• Microscopic haematuria is seen in < 15% but macroscopic haematuria is rare.

• Urinalysis by dipstick reveals + 3 or + 4 proteinuria.

• Urine specific gravity is usually high at >1.020, but may be lower.

• Haematocrit is often elevated due to intravascular depletion and can be followed to assess fluid status.

• Hyperlipidaemia is present with elevated serum cholesterol and triglyceride levels.

• Serum sodium can be low due to decreased free water excretion but is rarely symptomatic and does not require treatment. Total body sodium is high.

• Hypocalcaemia is a common finding and reflects the low serum albumin. The ionised calcium is usually normal, however, and the hypocalcaemia is asymptomatic.

• Plasma urea and creatinine are elevated in approximately 25% of patients.

• Serum complement levels are normal in MCNS, FSGS and mesangial proliferative glomerulonephritis.

Steroids can be used as a diagnostic tool in the management of NS. The patient is said to be steroid responsive when the urine becomes free of protein. If the child continues to have proteinuria (>2 +) after 4–8 weeks of compliance with continuous daily prednisone, the nephrosis is termed steroid resistant and renal biopsy is indicated to determine the precise cause, e.g. FSGS.

Renal biopsy is not indicated during the initial episode of acute nephrotic syndrome. The need for, and timing of a renal biopsy is determined by the subsequent disease course, e.g. poor or no response of initial episode to steroid therapy after 4–8 weeks of treatment or if other signs or symptoms are present that indicate a systemic disease.

Differential diagnosis

Other causes of oedema need to be excluded: congestive heart failure; starvation; protein-losing enteropathy; cystic fibrosis; hypothyroidism; vasculitis; and steroid therapy.

Treatment

• It can be difficult to assess volume status in patients with NS. The patient may be in shock despite the presence of oedema. Attention to detail on clinical examination can assist with the assessment. Clues to hypovolaemia are: tachycardia; peripheral vasoconstriction with poor capillary refill time; and orthostatic hypotension, i.e. positive tilt test. Other clues to volume status include a history of oliguria and evidence of renal insufficiency on laboratory investigations.

• Albumin infusions transiently increase plasma volume and are most useful in patients with profound volume depletion. Plasma volume is increased using 4% albumin rather than 0.9% saline. It is important to note that this is only a temporising measure. The infused albumin is rapidly lost in the urine, especially when the original albumin level is very low because of high renal albumin clearance (rate of loss is proportional to albumin clearance and serum albumin level). The patient can develop acute pulmonary oedema requiring admission to an intensive-care unit.

• In a patient symptomatic from massive oedema, a trial of diuretics may be given, provided the patient is not hypovolaemic, and only after discussion with a nephrologist. Diuretics may induce hypotension, severe volume depletion, ARF and hyperkalaemia if there is already incipient hypovolaemia. An infusion of 20% salt-deficient albumin 0.5–1 g kg^–1, followed 30 minutes later by furosemide 0.5–1 mg kg^–1 intravenously can be effective. In occasional circumstances, ultrafiltration or haemofiltration may be used to manage fluid overload.

• The natriuretic effect of furosemide is thought to be diminished in NS. Increasing the dose or using furosemide in combination with a diuretic acting at another site, such as a thiazide diuretic (hydrochlorothiazide 1 mg kg^–1 day^–1 in two divided doses) is recommended to overcome the hyporesponsiveness. Metolazone (diuretic activity on the distal tubule) is a powerful diuretic and is occasionally employed but must be used with caution. If serum albumin is <15 g L^–1, diuretic therapy is ineffective.

• Oral fluids, when offered, should be given in small aliquots, especially in hyponatraemic patients, in whom any free water will tend to lower the plasma sodium further.

• Therapeutic paracentesis may be indicated for acute respiratory distress but is rarely necessary. Respiratory distress is due to reduced lung capacity secondary to the increased abdominal pressure. Paracentesis should only be used when there is no other way to support respiration, because of the association of complications with the procedure, e.g. infection and the re-accumulation of the fluid.

• Prednisolone is started at 2 mg kg^–1 day^–1 (60 mg m^–2 day^–1) in two divided doses. A divided daily dose is used in preference to a single dose as some children who fail to respond to a single daily dose respond to divided doses. Disappearance of proteinuria is seen in 90% within 4–6 weeks.

• If the child is unwell or peritonitis is suspected, antibiotics are commenced after appropriate cultures are taken. Prophylactic antibiotics are generally recommended for all patients whilst nephrotic and on high-dose steroids.

• Some units advocate routine use of low-dose aspirin, though this is not commonly done.

• Angiotensin-converting enzyme (ACE) inhibitors are good antihypertensive drugs in those patients who have hypertension from their primary disease or as a result of steroid therapy. ACE inhibitors are useful as most of the hypertension is due to activation of the renin–angiotensin system. If the hypertension is a result of steroid therapy, the patient may respond better to a β-blocker.

• Some children with MCNS who are steroid-responsive either relapse frequently or require a high daily dose of steroids to maintain remission. These children are at risk of development of serious side effects from the steroids, including growth failure, hypertension, osteoporotic bone disease and posterior sublenticular cataracts. The alkylating agents cyclophosphamide or chlorambucil can produce prolonged and sometimes permanent remission and are considered to be ‘steroid-sparing’. These alkylating agents are not commonly needed in patients with MCNS but when needed they are very effective. Some patients with MCNS may not respond to the alkylating agents and will respond to ciclosporin (<5.5 mg kg^–1 per 24 hours or <200 mg m^–2 per 24 hours) if there is steroid responsiveness. Dependence on ciclosporin is common, the effect lasting only as long as treatment continues. Some nephrologists consider the limited risk of ciclosporin nephrotoxicity in this population to be preferable to the side effects of chronic steroid toxicity or the risk of sterility from a second alkylating agent when one course of an alkylating agent is insufficient therapy.

• In FSGS ciclosporin is more effective in steroid-dependent rather than in steroid-resistant disease and may even be more nephrotoxic in this latter group.

• Whilst on steroid therapy, non-immune children exposed to chickenpox require prompt administration of zoster immune globulin.

• Immunisations: Live-virus vaccines should not be administered to children on high-dose corticosteroid therapy. Children receiving <2 mg kg^–1 per 24 hours of prednisolone or its equivalent, can be immunised. Those children receiving >2 mg kg^–1 per 24 hours daily or alternate daily prednisolone or its equivalent for more than 14 days, should have live-virus vaccine administration deferred for at least 1 month after discontinuation of the steroids. Resonse to treatment – see Table 16.6.1.

Remission Urine protein excretion <4 mg hr⁻¹ m⁻² or urine protein negative/trace for 3 consecutive days Relapse Urine protein on Dipstix 2+ for 3 consecutive days having previously been in remission. This occurs in up to 75% of patients Frequent relapse 2 more relapses within 6 months or >4 relapses in 12 months Steroid dependence 2 consecutive relapses occurring during steroid treatment or within 14 days of its cessation Steroid resistance Failure to achieve response after 28 days of steroid at 60 mg m⁻² day⁻¹

Disposition

Outpatient management is appropriate for children with the first presentation of NS, if the oedema is not massive and there is no suspicion of infection or life-threatening complications and the physician can be assured of close follow up. The rest are best managed as inpatients to permit further work up and treatment and to provide education and support for the patient and family.

Admission is warranted in a child with known history of nephrotic syndrome if there are signs of severe dehydration, unexplained fever, renal insufficiency (i.e. elevation in serum creatinine), refractory oedema (e.g. respiratory distress) or suspected peritonitis. Discuss admission of frequent relapsers, or > 1st relapse, with the nephrologist.

Prognosis

Long-term prognosis is good for children with steroid-responsive primary nephrotic syndrome, though 1–2% mortality is associated. Most deaths are due to peritonitis or sepsis (pneumonia), and thrombus, which may occur despite good care. Relapses may recur for many years, often until puberty, with a small number continuing to relapse through to adulthood. These relapses are not usually severe and can be treated with short courses of oral steroids. Though these children with steroid-responsive disease may require steroid therapy intermittently throughout childhood, serious sequelae of steroid toxicity are uncommon.

When in remission, the child should have unrestricted diet and activity.

Recovery is considered permanent if the child remains asymptomatic and has no requirement for medications for more than 2 years.

Complications

As MCNS is a self-limited disease in most children, a distinction must be made between the complications of the disease itself and those that are related to the treatment. Major complications of the disease itself are infection, dislipidaemia and thrombosis. Treatment with steroids may increase body mass index and impair growth.

Acute complications occur in two groups of patients:

Those who present de novo or in relapse but not taking steroids.

Those who present in relapse or remission while still receiving pharmacological doses of steroids.

The tendency to develop infections is a true complication of the disease.

Hypogammaglobulinaemia

Is a factor in the reduced defences against bacterial infections. IgG is the immunoglobulin most severely depleted. This may be a consequence of it being the smallest of the immunoglobulins and the one with the greatest renal excretion.

Bacterial infections

occur in both groups but are more common in the steroid-treated group

Spontaneous bacterial peritonitis

is a major source of morbidity in children with NS. Main causative organisms are Streptococcus pneumoniae and Escherichia coli. Diagnosis of peritonitis should always be considered in a child with nephrotic syndrome who complains of abdominal pain. The physical findings of peritonitis in NS may be very subtle. The patient does not necessarily have a rigid abdomen. The physician must have a high index of suspicion when assessing these patients. Steroid therapy, especially high dose (2 mg kg^–1 day^–1 of prednisolone) can mask the typical signs and symptoms of infection. Children with NS can develop other infections such as pneumonia, cellulitis and sepsis.

Thromboembolism

from hypercoagulability is the second major contributor to morbidity and mortality. The thrombus is usually venous and is located in the deep vessels of the extremities, renal vein, pulmonary venous system and cerebral cortical system. For this reason, it is recommended that femoral or deep venepuncture is avoided if possible in children with nephrotic syndrome. The risk of thromboembolus is real and exists even in the first acute presentation with NS. This is due to increased platelet aggregation, and in part also due to the urinary loss of several proteins that inhibit blood coagulation, especially antithrombin-III, protein C and protein S. Increased blood viscosity and reduced blood flow also play a role. Renal vein thrombosis should be suspected if flank pain, haematuria and decreased renal function occur. Occlusion of the arterial system is uncommon.

Hyperlipidaemia

associated with NS rarely gives rise to clinical complications as it usually reverses with steroid therapy. It may become problematic in patients with chronic NS.

Symptomatic hypovolaemia

Despite the presence of oedema, symptomatic hypovolaemia leading to shock can develop if fluids are restricted injudiciously with or without diuretic therapy

Respiratory compromise

can rarely be caused by massive ascites, warranting emergency paracentesis in some cases

Hypertensive encephalopathy

Acute increase in blood pressure may occur in steroid-treated children at any stage of their illness. The diagnosis of hypertensive encephalopathy is based on the degree of change in the blood pressure and rate of increase rather than on a specific level of systolic and/or diastolic blood pressure.

Benign intracranial hypertension

can be precipitated by abrupt reduction in steroid doses

Growth

can be impaired in nephrotic syndrome. Insulin-like growth factor (IGF-1)-binding protein is lost in the urine, which may account for the reduced serum levels of IGF-1 and IGF-2. Growth impairment is also a consequence of steroid therapy.

Prevention

As the primary causes of idiopathic nephrotic syndrome are unknown, there is no means of prevention.

There is some evidence supporting a role of the immune system in paediatric minimal change disease. Relapses can be triggered by minor infections.

Vaccination against varicella, influenza and pneumococcus would seem prudent, given the relapsing nature of nephrotic syndrome. Some susceptibility to infection may result from loss of opsonising factors in the urine so even if the child has been immunised, vigilance is warranted against the possibility of any bacterial infection.

Controversies and future directions

Cyclo-oxygenase inhibitors are a class of drugs that may be of assistance in reducing proteinuria in patients with NS, although, unlike ACE inhibitors, they generally cause a reduction in GFR.

Further reading

Bergstein J. Conditions particularly associated with proteinuria. In: Behrman R., Kliegman R., Jenson H., editors. Nelson’s textbook of pediatrics. 16th ed. Philadelphia: WB Saunders; 2000:1592-1596.

Cronan K., Norman M. Renal and electrolyte emergencies. In: Fleisher G., Ludwig S., editors. Textbook of pediatric emergency medicine. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2000:832-835.

Falk R.J., Charles Jennette J., Nachman P.H. Nephrotic syndrome. Brenner B., editor. The kidney, 6th ed, vol. 2. Philadelphia: WB Saunders, 2000;1266-1283.

Gipson D.S., Massengill S.F., Yaol L., et al. Management of childhood onset nephrotic syndrome. Pediatrics. 2009;124:747-757.

Grimbert P., Audard V., Remy P., et al. Recent approaches to the pathogenesis of minimal-change nephrotic syndrome. Nephrol Dial Transpl. 2003;18:245-248.

Kaysen G.A. Proteinuria and the nephrotic syndrome. In: Schrier R.W., editor. Renal and electrolyte disorders. 6th ed. Philadelphia: Lippincott, Williams & Wilkins; 2003:580-614.

Roth K.S., Amaker B.H., Chan J.CM. Nephrotic syndrome: Pathogenesis and management. Pediatr Rev. 2002;23:237-247.

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