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SYMPOSIUM: NEPHROLOGY

Management of nephrotic syndrome
Niamh M Dolan Denis Gill

Abstract
Children with nephrotic syndrome (NS) primarily present to their general practitioner or general paediatrician. Shared care with a paediatric nephrologist is recommended for all difficult cases of NS. This review discusses the approach to management of NS in childhood and it is hoped that it will provide primary care physicians with a useful reference when dealing with a child with NS. The focus will mainly be steroidsensitive NS.

Keywords corticosteroids; minimal change; nephrotic syndrome; steroid
sensitive

Introduction
Little has changed in the management of nephrotic syndrome (NS) in the past 20 years. Corticosteroids have been the mainstay of treatment for the past 50 years. Historically important dates in the management of childhood NS include the introduction of penicillin (1945) and steroids (1955), the International Study of Kidney Disease in Children (1970–1985) and the introduction of the pneumococcal vaccine (2000). Among the many reviews on this subject we would recommend those of the British Association for Paediatric Nephrology (1994),1 Hodson et al (2000),2 and a previous review in this journal (2002).3 New approaches to immunosuppressive and immune modulating agents are greatly needed. For the purpose of this review we will confine ourselves largely to standard regimens in primary and secondary paediatric care in the belief that children requiring long-term immunosuppression are best managed in specialist tertiary nephrology units. NS is defined as the combination of heavy proteinuria (protein:creatinine ratio greater than 200 mg/mmol), hypoalbuminemia (less than 25 g/L) and generalized oedema. Approximately 80% of cases of childhood NS have minimal change disease (MCD), the commonest glomerular disease of childhood with a median age at presentation of 4 years. It is more common in

males than females (ratio 3:2). Over 90% of cases with MCD will respond to steroid therapy, but 70% of these will develop a relapsing course. Steroid responsiveness is the most important determining factor in the long-term prognosis of NS (see below). Conditions such as focal segmental glomerulosclerosis (FSGS) and mesangiocapillary glomerulosclerosis (MCGN) account for the remaining 20% of cases of NS. These conditions tend to present in the older child and the majority do not respond to oral steroid therapy alone, making the outcome considerably less favourable. Any disease that alters glomerular function so as to cause a glomerular leak from Bowman’s space may lead to NS (Table 1).4 MCD is characterized by normal or near normal glomeruli on light microscopy, absence of immune deposits and fusion of foot processes on electron microscopy. By contrast, FSGS is characterized by focal (only in some glomeruli) and segmental scarring and immune deposits. It is assumed that MCD and FSGS are immune mediated; there is controversy as to whether they are part of a spectrum or separate disorders. Serum IgG levels are low and IgM levels are often raised. Children with NS are susceptible to bacterial infections (Streptococcus pneumoniae). All modes of effective treatment affect the immune system (steroids, cyclophosphamide, cyclosporin and tacrolimus). There is a recognized association with atopic disease and studies suggest abnormalities of T-cell function.5–7 In general, routine renal biopsy is not performed at presentation as the majority of children have MCD and are likely to respond to corticosteroids. The definitions used in this review are given in Table 2.

Clinical features and diagnosis
In NS the usual presenting feature is oedema which is generalized and affected by gravity. The face, particularly the periorbital area, is swollen in the morning, the lower limbs and genital area later in the day as extracellular fluid accumulates and develops in the dependent areas. Serous effusions (transudates) may be seen in more severe cases with the development of pleural effusions and ascites. There is often upper respiratory tract infection and, with onset of oedema, children will be lethargic, irritable and have poor appetite, and may have diarrhoea and abdominal pain. Blood pressure is usually normal or low. Persistent hypertension is rare in MCD or FSGS and should raise suspicion of some other form of glomerular disease such as membranoproliferative disease.

Causes of nephrotic syndrome in childhood
Primary glomerular disease Minimal change disease Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis

Niamh M Dolan MB BCh BAO MRCPI is Specialist Registrar, Paediatric Nephrology at the Department of Paediatric Nephrology, The Children’s University Hospital, Temple Street, Dublin, Ireland. Denis Gill MB BSc DCH FRCPI FRCPCH is Consultant Paediatric Nephrologist at the Department of Paediatric Nephrology, The Children’s University Hospital, Temple Street, Dublin, Ireland.

 Multisystem disease

Henoch-Schönlein purpura Systemic lupus erythematosus Table 1

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© 2008 Elsevier Ltd. All rights reserved.

(2) to seek a possible cause. instead proteinuria is usually measured on first morning spot voids. All rights reserved. partly responsible for increased risk of serious systemic infection ↑ Haemoglobin ↑ Cholesterol. ds. Such features would indicate referral to a paediatric nephrologist and the possible need for a renal biopsy. Estimation of dry weight. Does this child need diuretics or ACE inhibitors? 5. Atypical features • Age less than 12 months or greater than 12 years • Persistent hypertension or impaired renal function • Gross haematuria • Low plasma C3 • Hepatitis B or C positive These features suggest the possibility of an alternative diagnosis which is less likely to respond to steroid therapy. sensitivity and culture Serum electrolytes. The recommended investigations are listed in Table 3 and some relevant laboratory findings in Table 4. triglyceride and cholesterol. Proteinuria needs to be quantified as the protein: creatinine ratio or per litre of urine. calcium FBC Complement C3 and C4 levels Varicella zoster serology Hepatitis B and C serology ASO titre. Some important clinical questions 1. lupus antibody serology (ANA. and (4) to identify biochemical disorders related to the nephrotic state. The finding of heavy proteinuria (3–4+) on dipstick and oedema in a child in the developed world usually means a diagnosis of NS. albumin. . 3.SYMPOSIUM: NEPHROLOGY Definitions Remission Relapse Frequently relapsing nephritic syndrome Steroid-dependent nephrotic syndrome Urine protein dipstick 0 or trace for 3 consecutive days 2+ or more protein on urine dipstick for 3 consecutive days Two or more relapses within 6 months of initial response or four or more relapses within any 12-month period Two consecutive relapses during corticosteroid treatment or within 14 days of stopping corticosteroid treatment Failure to achieve response to steroids despite 28 days of corticosteroids 60 mg/m2/day Nephrotic syndrome: biochemical disorders ↓ Serum sodium 130–135 mmol/L ↓ Serum calcium level Common. Is the child’s weight known prior to onset of NS? How much oedema has the child? 1 kg = 1 L? 3 kg = 3 L? Or more? 2. Microscopic haematuria may be present in up to 25% of children with steroid-sensitive NS and should not be a contraindication to empirical steroid therapy. anti-DNAse B. Is the child euvolaemic or hypovolaemic? This simple question can be difficult to answer clinically. Methods of assessing circulating volume are listed in Table 5. triglyceride Steroid resistance ↓ Serum albumin ↓ Serum IgG Table 2 Table 4 Investigations The purpose of investigations in NS is (1) to confirm the clinical diagnosis. rarely causes tetany Corrects with remission. factitious secondary to hyperlipidaemia Do not correct Secondary to protein losses. Does this child need volume expansion? 4.DNA) if atypical presenting features Table 3 Core – toe temperature gradient Fingers/toes Capillary refill (s) Pulse rate Pulse volume Blood pressure Postural hypotension Urine output Spot urine sodium (mmol/L) Table 5 Probably normal <2°C Pink <2 Normal Normal Normal − Normal >20 Probably reduced >2°C Bluish > 3–4 Increased Reduced Reduced + Reduced <10 PAEDIATRICS AND CHILD HEALTH 18:8 370 © 2008 Elsevier Ltd. (3) to assess renal function. Do not use albumin to correct Due to urinary losses. Twenty-four hour urine collections are impractical and unnecessary in most children with NS. Does this child need antibiotic prophylaxis? Circulating volume: clinical assessment Recommended investigations Urine dipstick analysis (protein and blood) First morning urine for protein:creatinine ratio Urine for microscopy. Measure ionized calcium >14 g/dl may indicate hypovolaemia Usually corrects with remission. ENA. statins used only in chronic nephrotic syndrome Due to urinary losses.

Factors which may precipitate hypovolaemia include diarrhoea. e. Routine nursing management includes: • Semi-quantification of urine protein losses (dipsticking all urine specimens) • Daily weighing • Pulse and blood pressure monitoring • Prevention of infection and appropriate isolation • Careful fluid balance with recording of oral/parenteral input and measurement of urine output • Parental information. Hypertension may also occur in the acute phase. They should keep a clear record of daily urinalysis and medications given. The child should be weighed regularly and have regular clinical assessment of capillary refill time. There is no evidence for use of a high protein diet. A ‘no added salt’ diet is therefore an appropriate measure. Sodium retention will cause further extracellular fluid expansion with exacerbation of generalized oedema. Prophylactic oral phenoxymethylpenicillin (12. peripheral temperature.0 g/kg of 20% albumin can be given slowly over 4–6 h and 0. Complications of NS include: • Hypovolaemia. resulting in maximal salt and water retention.8 The oedematous nephrotic child is at significant risk of hypovolaemia. It is important that parents know to contact the appropriate medical staff in the case of a relapse. Hypoalbuminaemia leads to an imbalance of Starling equilibrium by reducing the oncotic pressure.5–1. Infection Streptococcus pneumoniae and Gram-negative organisms are the commonest pathogens causing possible peritonitis. A live vaccine can however be given if the child is on a low dose alternate day regimen. Diet As mentioned above. Children should be encouraged to have a normal healthy diet.5–1 mg/kg of frusemide given at the end or mid way through the infusion.5% albumin. Those with only mild oedema do not need to have fluid restriction. PAEDIATRICS AND CHILD HEALTH 18:8 © 2008 Elsevier Ltd. and parental education. Persistence of hypertension in the absence of hypovolaemia warrants referral to a paediatric nephrologist. Hypovolaemia should be promptly corrected with appropriate fluids. Parents need to be taught how to do urinalysis for home testing.6 371 Management All children presenting with their first episode of NS should be admitted to hospital for diagnostic assessment. the pathogenesis of which remains incompletely understood. Hypotension is a sign of severe hypovolaemia and should be quickly addressed. Children with steroid-sensitive nephrotic syndrome are considered immunosuppressed if they have received daily steroids for greater than 1 week in the previous 3 months. Families should be provided with written information. • Thrombosis.SYMPOSIUM: NEPHROLOGY Complications Before the introduction of appropriate medical treatment as many as 30% of patients died from NS. thrombosis or serious infection. frusemide at 2 mg/kg/24 h. The oedematous nephrotic child is at significant risk of hypovolaemia due to rapid urinary loss of protein and maldistribution of extracellular fluid. intercurrent illness or exposure to varicella infection (when nonimmune).e. This may lead to acute renal failure and increases the risk of thrombosis. Children should be encouraged to mobilize as normal. . Twenty per cent albumin should never be used to correct low serum albumin levels. Varicella zoster and measles infection may be life threatening in the nonimmune child with NS. 10–20 ml/kg 4. • Infection. Side effects of medications must also be clearly explained. Twenty per cent albumin in combination with diuretics is used in centres to relieve severe symptomatic oedema: 0. nursing and medical management. septicaemia and cellulitis. dizziness. Mobilization Bed rest may increase the risk of venous thrombosis. causing retained fluid to escape from the circulation into the interstitial space and leading to progressive oedema. support and reassurance • Maintaining child mobility and morale Fluid balance. vomiting and inappropriate use of diuretics.5 mg/kg twice daily) administration is recommended while the child is oedematous and any suspected infection should be promptly treated with broad-spectrum antibiotics while awaiting culture. We will first cover general management and then the use of prednisolone or equivalent. If hypovolaemia is present it should be promptly corrected with administration of 10–20 ml/kg of 4.5% albumin. Parent information Parents need a clear explanation of the diagnosis of NS. oliguria. Diuretics are used in some cases to help control the oedema until remission begins. its implications for the future and the importance of compliance with medication.g. Rapid administration should be avoided to prevent intravascular volume overload. The use of diuretics should be reviewed on a daily basis and the patient’s electrolytes should be checked regularly. Symptoms may include abdominal pain. education. Some children with NS are hyperviscotic and in a hypercoagulable state with raised plasma fibrinogen levels and urinary losses of antithrombin III. hypovolaemia and blood pressure The main clinical manifestation of NS is oedema. Children with NS are at increased risk of bacterial infection. poor peripheral perfusion and hypertension→hypotension. a ‘no added salt’ diet is advisable in view of the salt and water overload. This fall in oncotic pressure also causes a contraction of the circulating blood volume. With careful modern management most children should expect not to experience hypovolaemia. All rights reserved. i. This increased susceptibility is due to urinary loss of immunoglobulins and complement components. tachycardia. most commonly with Streptococcus pneumoniae. Immunization Live vaccines should not be given to immunosuppressed children. Treatment with corticosteroids and immunosuppressant therapy will also leave children susceptible to infection. pulse rate and blood pressure. thus parents must be advised to report any contact as a matter of urgency. The child who is fluid restricted and/or who is on diuretics should be kept under close review to avoid inducing hypovolaemia.

followed by prednisolone 40 mg/m2/day (maximum 60 mg) on alternate days for 28 days (14 doses). A response to steroid therapy is indicated by the resolution of proteinuria (3 consecutive days of zero or trace proteinuria on urinalysis).10 • Alkylating agents. however. In these cases.1 Alternative immunomodulatory agents If a child cannot be maintained in remission on a low dose of alternate-day steroids or if they are experiencing significant side effects. unless they develop peripheral oedema. been recommended that the accumulative dose and duration of corticosteroid therapy should exceed that used in this standard regimen. alternative agents should be used.1. The large majority of children are given an empirical course of corticosteroids as greater than 90% of those with MCD and 20% of those with FSGS will respond to corticosteroid therapy. (2) to maintain remission. The diagnosis of steroid-responsive NS is made if the child goes into remission within the first 28 days of steroid therapy. especially in relation to behaviour. Infrequently relapsing children can be managed with repeated courses of this regimen. which is still largely in use.6 Intravenous methylprednisolone. 50% of children will follow a frequently relapsing course or will become steroid dependent. It is not necessary to perform a renal biopsy before changing to these alternative agents as the histological findings do not influence the clinical decision. When children first present with NS there are no predictive factors determining the risk of subsequent relapses. There are multiple potential side effects with steroid therapy and if problematic side effects develop (Table 6).9 Children who relapse frequently in the first 6 months are at a higher risk of relapsing over the subsequent 18 months. Prednisolone is rapidly absorbed in the gastrointestinal tract and peak plasma concentrations are reached within 2 h of administration. The objectives of steroid therapy are (1) to induce remission. These children should be referred to a paediatric nephrologist for further management. however. consists of prednisolone 60 mg/m2 (maximum dose 80 mg) for 28 days. Some centres use a H2 antagonist for gastric protection. in an equivalent dose to oral prednisolone. however. aggressive.1–0. The number of relapses within the first 6 months of presentation is. Cyclophosphamide is preferred in Ireland and the UK. the child can be observed for longer prior to recommencing steroids. cantankerous and emotionally labile.3 It is not unusual for a child with NS to develop significant proteinuria during an intercurrent viral infection. The growth and blood pressure of a child on long-term steroids should be reviewed every 3 months. Cyclophosphamide has been shown to induce a 2-year relapse-free rate in approximately 70% of children with steroid-sensitive NS and 25% of children with steroid-dependent 372 Corticosteroid side effects Behavioural problems Increased appetite Weight gain/obesity Acne Hirsutism Increased susceptibility to infection Posterior subcapsular cataracts Hypertension Growth suppression Pubertal delay Adrenal suppression Acute pancreatitis Osteoporosis Impaired glucose metabolism Table 6 PAEDIATRICS AND CHILD HEALTH 18:8 © 2008 Elsevier Ltd. they should have an annual ophthalmology assessment to check for cataracts. is useful in the vomiting child. Steroids are given in a once-daily dose. Chlorambucil is given at a dose of 0. a great need for a large randomized controlled trial comparing longer and shorter courses of corticosteroid therapy. followed by prednisolone 40 mg/m2 (maximum 40 mg) on alternate days for 28 days. immunosuppressive or both. Approximately 80% will respond to steroid therapy. There is. The dose of cyclophosphamide is 2–3 mg/kg/day for a total of 8 weeks and is commenced following induction of remission with prednisolone. and pubertal status should be monitored and bone age checked if there is any delay. The International Study of Kidney Disease (ISKD) regimen. and (3) to minimize side effects. usually between 7 and 14 days from the start of this regimen. the dose of corticosteroids is weaned to 0. whereas chlorambucil is used more commonly in the US and Europe. A relapse is characterized by 3 consecutive days of 2+ or more proteinuria and is usually detected on routine daily urinalysis at home (Table 2). highly predictive of the subsequent course.5 mg/kg/day for a period of 6–12 months. Many preschool children on high-dose steroids become overactive. children should be maintained on a relatively low-dose alternate-day regimen. It is unclear whether their mode of action is antiinflammatory. Some children experience significant steroid side effects. After the first month of therapy. appetite and acne form rash (Table 6). It has. Those who fail to respond will require referral to a specialist paediatric nephrologist for further assessment and renal biopsy. All rights reserved. A longer course of alternate-day maintenance therapy can be considered for those children with a frequently relapsing course.2 mg/kg for the same period of time. and this change in behaviour needs to be explained to parents. then alternative immunomodulatory agents should be considered (Table 7). while those who relapse infrequently in the first 6 months are less likely to develop a frequently relapsing course. Relapsing steroid-sensitive nephrotic syndrome More than 70% of children with steroid-sensitive NS will relapse. Randomized controlled trials have shown an increased benefit if children are treated for at least 3 months during their first nephrotic episode. After remission is achieved. . though acute or chronic gastric ulceration is extremely uncommon in children on steroid treatment. The stage at which alternate agents to corticosteroids are introduced should be decided by a paediatric nephrologist. However. The current ISKD relapse regimen is prednisolone 60 mg/m2/ day (maximum 80 mg) until urinary remission (Table 2).SYMPOSIUM: NEPHROLOGY Steroid therapy – first presentation Corticosteroids have been used in the treatment of NS since the 1950s. These agents work by binding to purine bases and impairing normal DNA transcription.

communication with parents and rapid access to hospital when required. Early identification of frequent relapses among children with minimal change nephrotic syndrome. The vast majority of children with MCD will outgrow NS with normal kidney function. Blood count and MMF level should be routinely monitored. Arch Dis Child 1994. Royal College of Physicians.and long-term prognosis of NS associated with MCD should be excellent. While on MMF therapy a 50% or more reduction in relapse rate has been Side effects of cyclophosphamide Bone marrow suppression Reversible hair loss Gastrointestinal upset Haemorrhagic cystitis Impaired fertility Malignancy Table 8 ReFeReNCeS 1 Report of a workshop by the British Association for Paediatric Nephrology and Research Unit. Webb NJ.SYMPOSIUM: NEPHROLOGY Indications for use of alternate immunomodulatory agents 1. Pediatr Nephrol 1989. Medical advice should be sought if the child becomes unwell. 5 Ritz E. The immune system in minimal change nephrotic syndrome. It is given at a dose of 0. Relapse on prednisolone dosage >1 mg/kg on alternate days Table 7 demonstrated and treatment continuation beyond 12 months has resulted in steroid sparing and a reduced need for alternative treatments while maintaining low relapse rates. 101: 514–518. support their parents.14 Prognosis The short. A full blood count should be checked on a weekly basis and if neutropenia develops the dose should be reduced or discontinued until the level returns to a normal range. 4 Haycock G.g. MMF has been found to be effective in reducing relapse rates and steroid requirements in children with frequently relapsing NS or steroid-dependent NS. 2: 556–560.g. Management of nephrotic syndrome in childhood. ◆ NS. 7 Schnaper HW. However.cell proliferation. Arch Dis Child 2000. Mortality with NS is now unusual in the developed world. relapse is almost inevitable when cyclosporin is withdrawn. hypovolaemia. Cyclosporin can be continued in patients with steroid-sensitive NS if there is no histological evidence of chronic nephrotoxicity. Cyclosporin is a potentially nephrotoxic drug and it is accepted practice to perform a renal biopsy after 18–24 h of treatment or if there is microalbuminuria. p. e. Serious complications are infrequent and most can be prevented by meticulous care and attention to fluid balance. 8 Vande Walle JG. 330: 61–62. 2003. thrombosis • 2. In some circumstances it is used earlier than cyclophosphamide. identification of the ‘nephrotic factor’ and improved immune modulation will further enhance prognosis. 6 Shaloub RJ. Studies to date have shown best results in steroid-resistant NS. acne and leukopenia.13. peripubertal boys at risk of cyclophosphamide-related gonadal toxicity. e. eds. In the interim. It is hoped that a better understanding of nephrotic triggers (viruses are temporally associated with primary presentation and relapse induction). Children usually respond well to low doses of cyclosporin and steroid therapy can be withdrawn without relapse in most cases. diabetes Unusually severe relapses. Willis NS. • Tacrolimus has a similar mode of action to cyclosporin and similar side effects. Knight JF. Curr Paediatr 2002. Postlewaite R.11 The side effects (Table 8) of cyclophosphamide need to be discussed in detail with the parents prior to commencing therapy. PAEDIATRICS AND CHILD HEALTH 18:8 373 © 2008 Elsevier Ltd. N Engl J Med 1994.2–0. e. .5 mg/kg/alternate day plus one or more of following: • Unacceptable side effects of corticosteroid therapy • High risk of toxicity. Lancet 1974. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. hypertrichosis and gum hyperplasia.and B. In: Webb N. Donkenwolcke RA. Pediatr Nephrol 2001. Current morbidity in NS is often related to medications. It is recommended that the care of all children with difficult NS be shared with a paediatric nephrologist. The child with idiopathic nephrotic syndrome. et al. After induction with prednisolone. boys approaching puberty. 341–366. 12: 551–560. paediatricians need appropriately to care for these children. J Pediatr 1982. Pathogenesis of “idiopathic” nephrotic syndrome. drug dosages. 16: 283–293. and ensure that NS does not metamorphose into the ‘neurotic syndrome’. • Cyclosporin is often used after a previous course of cyclophosphamide.g. All rights reserved. 2 Hodson EM. • Mycophenolate mofetil (MMF) strongly inhibits both T. 9 International Study of kidney disease in children. Clinical paediatric nephrology. Pathogenesis of oedema formation in the nephrotic syndrome.12 The side effects on MMF include gastrointestinal discomfort. These side effects are dose dependent and can be prevented or adjusted according to blood levels. diarrhoea. Relapse on prednisolone dosage >0. 83: 45–51. Consensus statement on management and audit potential for steroid responsive nephrotic syndrome. There is no agreement about the appropriate therapeutic level of cyclosporin but most centres would aim for the lowest therapeutic level that maintains remission. 3 Holt RC. 3: 101–110. blood volume parameters. The side effects of cyclosporin include tremor. Oxford: Oxford University Press. 70: 151–157.3 mg/kg/day in two divided doses. cyclosporin is commenced at a dose of 4–6 mg/kg/day in two divided doses. Most centres will aim for a target level of 5–10 μg/L. malaise. Cyclosporin levels should be checked every 2 months. Corticosteroid therapy in nephrotic syndrome: a meta-analysis of randomised controlled trials.

22: 2059–2065. Tacrolimus: a new therapy for steroid resistant nephrotic syndrome in children. Ehrich JH. 23: 910–913. 14 Gulati S. Treatment with mycophenolate mofetil and prednisolone for steroid-dependent nephrotic syndrome. 16: 271–282. Bagga A. Lewis MA. et al. 13 Sinha MD. A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. et al. 21: 1848–1854. . Prasad N. Pediatr Nephrol 2001. et al. 12 Afzal K. Nephrol Dial Transplant 2006. especially if severe. et al. 11 Latta K. Menon S.SYMPOSIUM: NEPHROLOGY 10 Webb NJ. Childhood steroid sensitive nephrotic syndrome: does the histology matter? Am J Kidney Dis 1996. Iqbal J. 27: 484–488. Rigby E. may be a warning of hypovolaemia or peritonitis Intravenous albumin should never be used to correct serum albumin Children requiring long-term immunosuppression are best managed in specialist tertiary nephrology units Parents should be fully informed of the behavioural side effects of corticosteroids as these are often underemphasized PAEDIATRICS AND CHILD HEALTH 18:8 374 © 2008 Elsevier Ltd. Practice points • • • • • • All children with their first episode of NS should be admitted to hospital for diagnostic assessment The child with NS is at significant risk of hypovolaemia Abdominal pain. All rights reserved. Nephrol Dial Transplant 2008. Von Schnackenburg C. Sharma RK. Treatment of severe steroiddependent nephrotic syndrome in children with tacrolimus. Pediatr Nephrol 2007. MacLeod R.