1. Childhood nephrotic syndrome: Diagnosis and management Dr

2. Overview  Nephrotic syndrome in children Introduction, definition Clinical presentation Investigations  Referral to a paediatric nephrologist Management Conclusions (Practice points)

3. Introduction  Nephrotic syndrome (NS) Commonest glomerular disease affecting children Frequently encountered in general paediatrics Characterised by  Significant proteinuria (early morning urine protein to creatinine ratio > 200mg/mmol) leading to Hypoalbuminaemia (plasma albumin of < 25g/l) Paediatrics and child health 2010;20(1):36-42

4. Introduction  NS defined by the clinical triad of Oedema Nephrotic range proteinuria and Hypoalbuminaemia  Typically accompanied by Dyslipidaemia with elevated plasma cholesterol and triglycerides Paediatrics and child health 2010;20(1):36-42

5. Introduction  NS can be Congenital or acquired  Congenital disease May be due to a genetic mutation or secondary to a congenital infection  Acquired disease More common and is usually idiopathic Categorised according to the response to corticosteroid treatment as  Either steroid sensitive or steroid resistant disease Paediatrics and child health 2010;20(1):36-42

6. Introduction  Acquired nephrotic syndrome Idiopathic (primary) or Secondary (table hereunder) Paediatrics and child health 2010;20(1):36-42

7. Clinical presentation  History Typically children present because of oedema  Initially in a peri-orbital distribution and many children are initially diagnosed with an allergic reaction  the lower limbs and genital area swollen later in the day as extracellular fluid accumulates and edema develops in the dependent areas. Often history of a preceding viral infection The duration of symptoms variable and a past history of atopic disease is present in 30-60% of children The vaccination history and previous varicella infection should be noted About 3% of children will have an affected parent or sibling and  If there is a family history the disease is likely to follow a very similar pattern Paediatrics and child health 2010;20(1):36-42

8. Clinical presentation  History 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 Paediatrics and child health 2010;20(1):36-42

9. Clinical presentation  Examination Document  Height  Weight  Blood pressure,  Capillary refill time,  Heart rate  Evidence of pleural effusions, ascites, peripheral, scrotal or sacral oedema.  The assessment of intravascular volume is important since Hypovolaemia is a common finding and is the leading cause of mortality and morbidity in these children Paediatrics and child health 2010;20(1):36-42

10. Clinical presentation  Examination Document the following; height, weight, blood pressure, capillary refill time, heart rate, evidence of pleural effusions, ascites, peripheral, scrotal or sacral oedema.  The assessment of intravascular volume is important since hypovolaemia is a common finding and is the leading cause of mortality and morbidity in these children  The following are recognised markers of hypovolaemia: capillary refill time >2 seconds, toe-core temperature gap >2C, hypotension, persistent tachycardia and abdominal pain. Since assessment of hypovolaemia can be difficult a urinary sodium can be useful with a urine Na <10mmol/l being indicative of severe hypovolaemia Paediatrics and child health 2010;20(1):36-42

11. Clinical presentation  Differential diagnoses At presentation it is important to consider the differential diagnosis of a child presenting with oedema. These include  Acute nephritis (hypertension, oliguria, oedema) or  Renal failure (abnormal plasma creatinine) and  Non-renal causes of oedema such as Protein losing enteropathy, Severe cardiac failure, Chronic liver disease Paediatrics and child health 2010;20(1):36-42

12. NS: Investigations  The purpose of investigations in NS is (1) to confirm the clinical diagnosis; (2) to seek a possible cause; (3) to assess renal function; and (4) to identify biochemical disorders related to the nephrotic state Paediatrics and child health 2010;20(1):36-42

13. NS: Investigations  Children presenting with typical features of NS will require minimal investigations Paediatrics and child health 2008;18(8):369-374

14. NS: Investigations  The finding of heavy proteinuria (3–4+) on dipstick and oedema in a child usually means a diagnosis of NS  Proteinuria needs to be quantified as the protein: creatinine ratio or per litre of urine Twenty-four hour urine collections are impractical and unnecessary in most children with NS; instead proteinuria is usually measured on first morning spot voids Paediatrics and child health 2008;18(8):369-374

15. NS: Investigations Some relevant laboratory findings Paediatrics and child health 2008;18(8):369-374

16. NS: Investigations  Indications for kidney biopsy Revised guidelines for management of steroid-sensitive nephrotic syndrome. Indian J Nephrol 2008;18:31-9

17. Referral to a paediatric nephrologist  Most children with MCNS will respond to steroids and not require a renal biopsy at presentation\  However, if any of the following features are present, there is the possibility of an alternative diagnosis (less likely to respond to steroid therapy)and children should be referred to a paediatric nephrologist: Age 12yr Hypertension Renal impairment Macroscopic haematuria Decreased C3 complement Rash or arthropathy Primary steroid resistance (failure to go into initial remission with 60mg/m2 steroids for 28 days)

18. Referral to a paediatric nephrologist Revised guidelines for management of steroid-sensitive nephrotic syndrome. Indian J Nephrol 2008;18:31-9

19. Referral to a paediatric nephrologist  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

20. Some important clinical questions 1. Estimation of dry weight. 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. Is the child euvolaemic or hypovolaemic? This simple question can be difficult to answer clinically. Methods of assessing circulating volume are listed in Table in next slide.

21. Some important clinical questions

22. 3. Does this child need volume expansion? 4. Does this child need diuretics or ACE inhibitors? 5. Does this child need antibiotic prophylaxis?

23. Complications  Before the introduction of appropriate medical treatment as many as 30% of patients died from NS Complications of NS include: Hypovolaemia Infection Thrombosis  With careful modern management most children should expect Not to experience hypovolaemia, thrombosis or serious infection Paediatrics and child health 2010;20(1):36-42

24. Management  All children presenting with their first episode of NS should be admitted to hospital for Diagnostic assessment Nursing and medical management, and Parental education  We will first cover General management and then the use of prednisolone or equivalent Paediatrics and child health 2010;20(1):36-42

25. Management  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, education, support and reassurance Maintaining child mobility and morale

26. Management  Fluid balance, hypovolaemia and blood pressure A ‘no added salt’ diet is appropriate measure If hypovolaemia is present it should be promptly corrected with administration of 10–20 ml/kg of 4.5% albumin Diuretics are used in some cases to help control the oedema until remission begins, e.g. frusemide at 2 mg/kg/24 h The use of diuretics should be reviewed on a daily basis and the patient’s electrolytes should be checked regularly

27. Management  Fluid balance, hypovolaemia and blood pressure Twenty per cent albumin in combination with diuretics is used in centres to relieve severe symptomatic oedema: 0.5–1.0 g/kg of 20% albumin can be given slowly over 4– 6 h and 0.5–1 mg/kg of frusemide given at the end or mid way through the infusion Rapid administration should be avoided to prevent intravascular volume overload Twenty per cent albumin should never be used to correct low serum albumin levels

28. Management  Fluid balance, hypovolaemia and blood pressure Hypotension is a sign of severe hypovolaemia and should be quickly addressed Hypertension may also occur in the acute phase Persistence of hypertension in the absence of hypovolaemia warrants referral to a paediatric nephrologist

29. Management of edema in patients with nephrotic syndrome Patients requiring high-dose frusemide or addition of other diuretics should be under close supervision, preferably in a hospital Monitoring of serum electrolytes is necessary in all patients receiving diuretics Patients showing hypokalemia require potassium supplements or coadministration of spironolactone. The medications are reduced stepwise once diuresis ensues. *Management of hypovolemia consists of rapid infusion of normal saline at a dose of 15-20 ml/kg over 20-30 min; this may be repeated if clinical features of hypovolemia persist. Infusion of 5% albumin (10-15 ml/kg) or 20% albumin (0.5-1 g/kg) may be used in subjects who do not respond despite two boluses of saline Revised guidelines for management of steroid-sensitive nephrotic syndrome. Indian J Nephrol 2008;18:31-9

30. Management  Infection Streptococcus pneumoniae and Gram-negative organisms are the commonest pathogens causing possible peritonitis, septicaemia and cellulitis Prophylactic oral phenoxymethylpenicillin (12.5 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

31. Clinical features and management of infections Revised guidelines for management of steroid-sensitive nephrotic syndrome. Indian J Nephrol 2008;18:31-9

32. Management  Mobilization Bed rest may increase the risk of venous thrombosis Encouraged to mobilize as normal  Diet As mentioned above, a ‘no added salt’ diet is advisable in view of the salt and water overload No evidence for use of a high protein diet Encouraged to have a normal healthy diet

33. Management  Parent information Parents need a clear explanation of the diagnosis of NS, its implications for the future and the importance of compliance with medication. Side effects of medications must also be clearly explained. Families should be provided with written information

34. Management  Parent information Parents need to be taught how to do urinalysis for home testing. They should keep a clear record of daily urinalysis and medications given It is important that parents know to contact the appropriate medical staff in the case of a relapse, intercurrent illness or exposure to varicella infection (when nonimmune)

35. Management  Immunization Live vaccines should not be given to immunosuppressed children 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 A live vaccine can however be given if the child is on a low dose alternate day regimen

36. Management  Corticosteroid therapy The International Study of Kidney Disease in Children (ISKDC) demonstrated that in MCNS the majority of children will respond to steroids with 95% of children going into complete remission following an 8 week course of high dose steroids Paediatrics and child health 2010;20(1):36-42

37. Definitions related to NS Revised guidelines for management of steroid-sensitive nephrotic syndrome. Indian J Nephrol 2008;18:31-9

38. Definitions related to NS Paediatrics and child health 2010;20(1):36-42

39. Management  ISKDC regimen of steroids – gold standard for three decades An eight week course of oral steroids (prednisolone) starting at  60mg/m 2 daily for 4 weeks followed by  40mg/m 2 on alternate days for the next 4 weeks Paediatrics and child health 2010;20(1):36-42

41. Revised guidelines for management of steroid-sensitive nephrotic syndrome. Indian J Nephrol 2008;18:31-9

42. Management

44. Guidelines:Management of Steroid Resistant Nephrotic Syndrome Indian society of pediatric nephrology Indian Pediatrics. 2009; 46(1): 35-47

45. Management  In view of lack of consensus regarding the most appropriate therapy, the Expert Group accepts that the choice of initial treatment shall continue to depend on the preference of the physician and the cost of medications There is a lack of consensus on the most appropriate first line therapy for children with SRNS, with many of the regimens extrapolated from studies in adults. Guidelines:Management of Steroid Resistant Nephrotic Syndrome Indian society of pediatric nephrology Indian Pediatrics. 2009; 46(1): 35-47

46. Management

47.  The wide range of options available for the pharmacotherapeutic management of NS and the lack of evidence about the comparative efficacy and safety of the different therapeutic strategies, make its positioning rather difficult  Therefore each hospital needs to draw up protocols based not only on the small amount of evidence available, but also on the Authorized indications, availability of the drugs, clinical experience, associated costs, and patient preferences with regard to the duration of treatment, incidence and type of adverse effects

48. Management  Development of new randomized controlled trials should be encouraged and setting up national plans for the treatment of this pathology might be a good approach for this problem

49. Pediatrics 2009;124;747-757

50. Management  The vast majority of children with MCD will outgrow NS with normal kidney function  In the interim, Paediatricians need appropriately to care for these children, support their parents, and ensure that NS does not metamorphose into the ‘neurotic syndrome’

51. Conclusions