NEPHROTIC SYNDROME IN PAEDIATRIC

Illustrated information about nephrotic syndrome in children

1. PEDIATRIC NEPHROTIC SYNDROME Presented by: Dr. Mona Mohammed Ali.

2. INTRODUCTION: Nephrotic syndrome, or nephrosis, is defined by the presence of nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia.

3. While nephrotic-range proteinuria in adults is characterized by protein excretion of 3.5 g or more per day, in children it is defined as protein excretion of more than 40 mg/m2/h or a first-morning urine protein/creatinine of 2-3 mg/mg creatinine or greater. INTRODUCTION:

4. Nephrotic syndrome is a constellation of clinical findings that is the result of massive renal losses of protein. Thus, nephrotic syndrome is not a disease itself, but the manifestation of many different glomerular diseases. These diseases might be acute and transient, such as post infectious glomerulonephritis, or chronic and progressive, such as focal segmental glomerulosclerosis (FSGS). Still other diseases might be relapsing and remitting, such as minimal change nephrotic syndrome (MCNS). INTRODUCTION:

5. The glomerular diseases that cause nephrotic syndrome generally can be divided into primary and secondary etiologies . Primary nephrotic syndrome (PNS), also known as idiopathic nephrotic syndrome (INS), is associated with glomerular diseases intrinsic to the kidney and not related to systemic causes . The subcategories of INS are based on histological descriptions, but clinical-pathological correlations have been made. C lassification:

6. Idiopathic Nephrotic Syndrome: A wide variety of glomerular lesions can be seen in INS. These include : Minimal change nephrotic syndrome (MCNS). focal segmental glomerulosclerosis ( FSGS). membranous nephropathy ( MN). membranoproliferative glomerulonephritis ( MPGN). C3 glomerulonephritis ( C3GN). IgA nephropathy, diffuse mesangial proliferation, and others.

7. By definition, secondary nephrotic syndrome refers to an etiology extrinsic to the kidney. Secondary causes of nephrotic syndrome include : ( 1) autoimmune and vasculitic diseases, such as Henoch-Schönlein purpura (HSP), systemic lupus erythematosus, and antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. (2) infectious diseases, such as congenital syphilis, malaria, human immunodeficiency virus (HIV), and hepatitis B and C. (2) infectious diseases, such as congenital syphilis, malaria, human immunodeficiency virus (HIV ), and hepatitis B and C. (3) malignancy . ( 4) environmental and drug exposure, such as heroin and mercury. (5 ) systemic diseases such as diabetes mellitus, among many other causes

8. Genetic Causes of NS: Finnish-type congenital nephrotic syndrome (NPHS1, nephrin ) Denys-Drash syndrome ( WT1) Frasier syndrome ( WT1) Diffuse mesangial sclerosis (WT1, PLCE1) Autosomal recessive, familial FSGS (NPHS2, podocin) Autosomal dominant, familial FSGS (ACTN4, α-actinin-4; TRPC6 ) Others.

9. Schematic drawing of the glomerular barrier: Podo = podocytes ; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx ). 

10. Physiology: . Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasm

11. S & S: Pitting edema is the presenting symptom in about 95% of children with nephrotic syndrome. It is typically found in the lower extremities, face and periorbital regions, scrotum or labia, and abdomen (ascites).

12. Pitting Edema:

13. S&S: A history of a respiratory tract infection immediately preceding the onset of nephrotic syndrome is frequent. Allergy - Approximately 30% of children with nephrotic syndrome have a history of allergy . Macrohematuria . Hypotension and signs of shock - Can be present in children presenting with sepsis Respiratory distress - Due to either massive ascites and thoracic compression or frank pulmonary edema, effusions, or both. Symptoms of infection - Such as fever, lethargy, irritability, or abdominal pain due to sepsis or peritonitis

14. S&S: Tachypnea - To compensate for mechanical restriction to breathing Seizure - Due to cerebral thrombosis Anorexia Irritability Fatigue Abdominal discomfort Diarrhea Hypertension

15. MCNS: Minimal-change disease (MCD), also known as lipoid nephrosis or nil disease, arises from a histopathologic lesion in the glomerulus and is characterized by intense proteinuria leading to edema and intravascular volume depletion. It is the most common single form of nephrotic syndrome in children, but it can also occur in adults.

16. History: Facial edema is noted first. Edema may be preceded by an upper respiratory tract infection, an allergic reaction to a bee sting, the use of certain drugs, or malignancies. Malaise and easy fatigability can occur. Weight gain often is an additional feature. The patient also may present with one or more of the following: Hypovolemia  Hypertension  Thromboembolism  Infection

17. Facial Edema:

18. Causes: Almost all cases are idiopathic, but a small percentage of cases (approximately 10-20%) may have an identifiable cause. Secondary cases may be due to any of the following: Drugs - Nonsteroidal anti-inflammatory drugs (NSAIDs), rifampin, interferon, ampicillin/penicillin, trimethadione , mercury-containing cosmetic skin cream. Toxins - Mercury, lithium, bee stings, fire coral exposure. Infection - Infectious mononucleosis, HIV, immunization. Tumor - Hodgkin lymphoma (most commonly), carcinoma, other lymphoproliferative diseases. Hematopoietic stem cell transplantation

19. Physical Examination: Blood pressure usually normal in children. Dependent edema is the most prominent sign. The retina has a wet appearance. Subungual edema with horizontal lines (called Muehrcke lines) also may occur. Hernias may be found, and the elasticity of the ears may be decreased. Heavy proteinuria over an extended period of time leads to a state of protein depletion with muscle wasting, thinning of the skin, and growth failure. Pleural and ascitic fluid can accumulate. Rarely, cellulitis, peritonitis, or pneumonia may be the first indication of an underlying nephrotic syndrome. Children may have growth failure.

20. D/D: Other problems to be considered include the following: C1q nephropathy. Focal segmental glomerulosclerosis. Immunoglobulin M (IgM) nephropathy. Membranous nephropathy.

21. Workup: Urinalysis findings are benign in minimal-change disease (MCD), but profound proteinuria and oval fat bodies may be observed. In children, the critical level for diagnosis is proteinuria of more than 40 mg/h/m2. In adults, the threshold is more than 3.5 g/d/1.73 m2. A random albumin-to-creatinine concentration ratio is in excess of 5. Urine specific gravity is high because of proteinuria. A 24-hour urine measurement should be obtained for protein and creatinine clearance.

22. Other laboratory findings are as follows : Hypoalbuminemia is an important marker if nephrotic syndrome. Hyperlipidemia is a feature of nephrotic state. Renal function is usually normal. Serologic workup (including antinuclear antibodies , complements , and cryoglobulins) is normal. Hyponatremia is often observed and is in part a spurious finding secondary to the hyperlipidemic state; it also occurs from water retention caused by hypovolemia and antidiuretic hormone release Elevated hemoglobin and hematocrit are consequences of plasma volume contraction. Renal sonogram results are normal in patients with MCD.

23. Because MCD accounts for 90% of all cases of idiopathic nephrotic syndrome in children, renal biopsy is not part of the initial workup for MCD in that age group. Instead , biopsy is performed only in those children who fail to achieve remission with an empiric course of corticosteroids, or in those with atypical presentation.

24. Indications of Renal Biopsy: Age younger than 1 year or older than 8 years. Presence of recurrent gross hematuria. Relevant family history of kidney disease . Symptoms of systemic disease. Positive viral screens. Additional criteria are laboratory findings p, such as the following: Sustained elevation in serum creatinine levels. Low C3/C4 levels. Positive ANA findings. Positive anti–double-stranded DNA antibody assay.

25. Histologic Findings in MCNS: Light Microscope : normal or near normal appearance. Irmmunohistology : No significant glomerular deposition of immunoglobulins or complement components in patients with MCD . Electron microscopy: Retraction of the epithelial foot processes is observed consistently in patients with MCD. This is, at times, erroneously described as foot-process fusion and results from disordered epithelial cell structure with withdrawal of the dendritic process .

26. Treatment: A trial of corticosteroids is the first step in treatment of idiopathic nephrotic syndrome (INS) in which kidney biopsy is not initially indicated. Thus, patients may be considered for steroid treatment prior to kidney biopsy if they meet all of the following criteria: Age 1-8 years. Normal kidney function. No macroscopic (gross) hematuria. No symptoms of systemic disease (fever, rash, joint pain, weight loss). Normal complement levels. Negative antinuclear antibody (ANA) assay. Negative viral screens (ie, HIV, hepatitis B and C). No family history of kidney disease. complement levels. Negative antinuclear antibody (ANA) assay. Negative viral screens (ie, HIV, hepatitis B and C). No family history of kidney disease.

27. Corticosteroids: KDIGO clinical practice guidelines recommend prednisone dosed at 60 mg/m2/day (2 mg/kg/day) given daily for 4–6 weeks, followed by 40 mg/m2 (1.5 mg/kg) given on alternate days for 2–5 months, with a minimum total duration of treatment of 12 week

28. Treatment Of Infrequent Relapses: For infrequent relapses (one relapse within 6 months of initial response, or 1-3 relapses in any 12-month period), steroids are resumed, although for a shorter duration than treatment during initial presentation. Prednisone , 2 mg/kg/d (60 mg/m2/d), is given as a single morning dose until the patient has been free of proteinuria for at least 3 days. Following remission of proteinuria, prednisone is reduced to 1.5 mg/kg (40 mg/m2) given as a single dose on alternate days for 4 weeks. Steroids may then be gradually tapered.

29. Frequently Relapsing and Steroid-Dependent Disease: Frequently relapsing nephrotic syndrome (FRNS) is defined as steroid-sensitive nephrotic syndrome (SSNS) with 2 or more relapses within 6 months, or 4 or more relapses within a 12-month period . Steroid-dependent nephrotic syndrome (SDNS) is defined as SSNS with 2 or more consecutive relapses during tapering or within 14 days of stopping steroids. 

30. Treatment Of FRNS & SDNS : The current KDIGO 2012 guidelines recommend that in FRNS and SDNS, prednisone treatment be prescribed at 2 mg/kg/d (60 mg/m2/d) as a single morning dose until the patient has been free of proteinuria for at least 3 days. Following remission of proteinuria, prednisone is reduced to 1.5 mg/kg (40 mg/m2) given as a single dose on alternate days and tapered over 3 or more months. A steroid-sparing agent, such as those listed below, can be considered once proteinuria is in remission .

31. S teroid-sparing A gents: Alkylating agents (e.g., cyclophosphamide [CYP], chlorambucil, nitrogen mustard) Calcineurin inhibitors (e.g., cyclosporin A [CSA], tacrolimus [TAC ] Levamisole Mycophenolate mofetil (MMF) Rituximab

32. Steroid-Resistant Disease and Focal Segmental GS The most frequently recommended treatment for FSGS and SRNS is CSA. Approximately 36% of children with SRNS may achieve remission with this agent. TAC may be effective as well Others.

33. Indications for Hospital Admission Anasarca , especially when resistant to outpatient therapy and/or accompanied by respiratory compromise, massive ascites or scrotal/perineal or penile edema. Significant hypertension. Anuria or severe oliguria. Peritonitis , sepsis, or other severe infection. Significant respiratory infection. social reasons. often is useful on initial presentation of idiopathic nephrotic syndrome (INS) in order to provide intensive education of the family regarding INS and long-term management at home.

34. Diet: A sodium-restricted diet should be maintained while a patient is edematous and until proteinuria remits. Thereafter, a normal diet can be followed. During severe edema, careful and modest fluid restriction may be appropriate, but the patient must be monitored closely for excessive intravascular volume depletion. Protein restriction is not indicated, except in cases of acute or chronic kidney failure when severe azotemia is present. Even then, protein restriction should be done carefully as to avoid impaired somatic growth.

35. Activity: A normal activity plan is recommended. Because viral respiratory illnesses are often associated with relapses of nephrotic syndrome, keeping children with INS away from those who have obvious respiratory tract infections may be beneficial. However, children should not be kept out of school and should have as normal a routine as possible.

36. Vaccination: Routine childhood vaccines with live virus strains are contraindicated during steroid therapy and for a minimum of 1 month afterward.  Yearly influenza vaccination is recommended Pneumococcal vaccination should be administered to all patients with INS upon presentation postexposure prophylaxis with varicella-zoster immune globulin is recommended in the nonimmune patient. Patient with varicella-zoster infection should be treated with acyclovir and carefully monitored. Routine non-live viral vaccines should be administered according to their schedules .

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