Nephrosis and Nephritis Dr M White, Paediatric SpR TCD Lecture Mon 11th May 2009

1) Nephrotic Syndrome 2) Glomerulonephritis

Nephrotic Syndrome

Nephrotic Syndrome Characterised by proteinuria (3.5g per 24 hours), hypoalbuminemia (serum <30g/dL), oedema, hypercholesterolemia Almost always idiopathic in childhood

Classification Primary vs Secondary Histology Therapeutic

Primary Nephrotic Syndrome Post-infectious aetiologies Congenital Nephrotic Syndrome Collagen vascular disorders (SLE/RA/PAN) Henoch-Schonlein Purpura Hereditary Nephritis Sickle cell disease Diabetes Mellitus Amyloidosis Malignancy

Secondary Nephrotic Syndrome Group A beta-haemolytic strep Syphilis Malaria TB Viral infections (varicella, HBV, HIV-1, infectious mononucleosis)

Histological Classification Minimal-change nephrotic syndrome (MCNS) = 84.5% Focal Segmental glomerulosclerosis (FSGS) = 9.5% Mesangial proliferation = 2.5% Membranous nephropathy & others = 3.5%

Therapeutic Classification Steroid sensitive (85-90%) Steroid resistant (10-15%) Steroid dependent Frequently relapsing

Pathophysiology Two important issues; 1)mechanism of glomerular injury 2)proteinuria Circulating non-immune factors in MCD and FSGS Circulating immune factors in disorders membranoproliferative GN, poststreptococcal GN and SLE nephritis Mutations in podocyte or slit diaphragm in inherited form of congenital, infantile or glucocorticoid resistant nephrotic syndrome

Incidence = 2-7 cases per 100,00 per year 15 times more common in children than adults Age of onset varies with type of disease Mortality rate related to primary disease process

Definitions Remission – negative urinalysis on 1st morning urine for 3 consecutive mornings Relapse – 3+ proteinuria on 3 or more consecutive 1st morning urines Frequently relapsing – 2 or more relapses within 6 months of diagnosis; or 4 or more relapses per year Steroid resistant – no remission after 4 weeks of prednisolone 60mg/m2/day

Presentation First sign usually facial swelling – periorbital oedema Increasing oedema over days to weeks Lethargy, poor appetite, weakness, abdominal pain May follow an apparent viral URTI Haematuria/hypertension unusual

Differential Diagnoses Congestive heart failure Cirrhosis Protein losing states

Physical Examination Overall inspection Vital signs Periorbital oedema Pitting oedema of legs Scrotal oedema Sacral oedema Ascites Loss of skin creases

Laboratory studies Diagnosis based on history and clinical findings Urine dipstick 24 hour urine collection U&E FBC +/- Hepatitis serology, HIV, serum complement, varicella serology Renal US Others – Antistreptolysin O titres, serum protein electrophoresis, antinuclear antibodies

Renal biopsy Rarely performed in Paediatric cases Consider if; Congenital Nephrotic Syndrome > 8 years at onset Steroid resistance Frequent relapses Significant nephritic manifestations

Treatment Prednisolone 60mg/m2/day x 4 weeks, 40mg/m2 alternate days for 4 weeks then STOP For relapse – prednisolone 60mg/m2/day until remission, then 40mg/m2 alt doses for 3 doses, and reduce alt day dose by 10mg/m2 every 3 days until 10mg/m2 alt days – then 5mg/m2 alt days for three doses then STOP Consider antithrombotic agents, oral penicillin VZIG for varicella contacts, aciclovir for varicella infection

Frequently Relapsing or Steroid dependent NS Cyclosporin A Tacrolimus Cyclophosphamide Mycophenolate mofetil

SRNS Should be referred to specialist unit Full remission not achieved Aim to reduce proteinuria so not in nephrotic range Significant chance of hypertension and progression to renal failure If histology shows FSGS – 20-40% chance of recurrence post transplant

Clinical Features SSNS Toddler, pre-school No HTN Mild, intermittent haematuria Normal renal function Excellent prognosis, even if frequently relapsing Usually not biopsied SRNS <1 year, > 8 years HTN common Persistent haematuria Renal function often abnormal Risk of long term HTN and renal failure Usual histology FSGS

Complications Infection – typically with Strep pneumoniae (pneumonia or peritonitis) (oedema &peritoneal fluid, loss of immunoglobulins, immunosupression) Thrombosis – loss of antithrombin III and proteins S&C in urine, increased procoagulant factors by liver, increased haematocrit, relative immobility, steroid therapy Hypovolemia – shift of fluid from intravascular space, symptoms – oliguria, abd pain, anorexia, postural hypotension Drug toxicity – side effects of steroid treatment, nephrotoxcity from cyclosporin A or tacrolimus

Congenital Nephrotic Syndrome Onset in first 3 months of life Large placenta – usually 40% of birth weight Almost always resistant to drug treatment High morbidity from protein malnutrition & sepsis Finnish type- most severe, AR Diffuse mesangial sclerosis – less severe, AR Denys-Drash syndrome – includes pseudohermaphroditism and Wilms tumour FSGS Secondary congenital nephrotic syndrome – congenital syphilis Intensive supportive care – 20% albumin, nutritional support, early unilateral nephrectomy Dialysis and transplantation

Glomerulonephritis

Glomerulonephritis Refers to a specific set of renal diseases in which an immunologic mechanism triggers inflammation and proliferation of glomerular tissue that result in damage to the basement membrane, mesangium or capillary endothelium

Glomerulonephritis Sudden onset of haematuria, proteinuria and red blood cell casts Often accompanied by hypertension, oedema and impaired renal function Represents 10-15% of glomerular disease Chronic GN may lead to scarring of the tubulo-interstitial areas of the kidney, with progressive renal impairment

Pathophysiology Lesions are the result of glomerular deposition or immune complex formation Kidneys may be enlarged up to 50% Histological appearance – swelling of glomerular tufts, infiltration with polymorpholeucocytes Immunoflouresence reveals deposition of immunoglobulins and complement

Causes Post infectious – most common, Strep, viral/fungal/parasitic Systemic causes – vasculitis, collagen vascular disease, hypersensitivity, HSP, Goodpasture, drugs (gold penicillamine) Renal disease – membranoproliferative GN, Berger disease, Idiopathic rapidly progressive glomerulonephritis

Morbidity/Mortality Up to 100% of post-streptococcal GN recover completely Sporadic cases progress to chronic form in 10% of children GN most common cause of chronic renal failure (25%) Mortality 0-7% Male : Female 2:1 Most cases aged 5-15 years Can occur at any age

Clinical Most common- 2-14 year old boy, presenting with peri-orbital pufffiness after a strep infection Urine is dark (‘Coca-Cola’ urine) and output is reduced BP may be elevated Abrupt onset of symptoms Weakness, fever, abd pain, malaise

Clinical Most common- 2-14 year old boy, presenting with periorbital pufffiness after a strep infection Urine is dark (‘Coca-Cola’ urine) and output is reduced BP may be elevated Abrupt onset of symptoms Weakness, fever, abd pain, malaise

Clinical course Latent period of up to 3 weeks after infection(1-2 weeks postpharyngitis, 2-4 weeks postdermal inf) Haematuria universal Oliguria Oedema Headache (sec to hypertension) SOB or dyspnoea on exertion Possible flank pain (stretching of renal capsule) Latent period of up to 3 weeks after infection(1-2 weeks postpharyngitis, 2-4 weeks postdermal inf)

Laboratory studies FBC – dilutional anaemia, increased WCC U&E – ?Elevated urea ± creatinine Urinalysis – haematuria, Red cell casts present, 24 hour collection helpful ASOT (increased in 60-80%), anti-DNAse b ESR ?CRP Cultures (throat, blood, urine) Complement (Decreased C3, normal C4)

Other tests Radiography – CXR if cough +/- haemoptysis Echo if new murmur/repeated + blood culture ANA Targeted tests

Renal Biopsy Acute GN self limited, good prognosis Significant Renal Impairment, atypical presentation, family history, massive proteinuria, nephrotic syndrome

Management Treatment mainly supportive Correct electrolyte abnormalities if present Post Streptococcal – penicillin therapy Admission if oliguria and renal failure Fluid restriction with significant oedema

Complications Rare in post-strep GN Microhaematuria may persist for years Marked decline in GFR is rare Chronic renal failure Nephrotic Syndrome

Acute Post-streptococcal GN Onset of reddish-brown (‘Coca-Cola’) urine 10-14 days after strep throat or skin infection Deposition of immune complexes in glomeruli Treatment mainly supportive Excellent recovery Check C3/C4 after recovery – should normalise

Henoch-Schonlein purpura 70% will have some degree of renal involvement Usually microscopic haematuria +/- proteinuria May have relapsing course Refer if nephritic/nephrotic/sustained hypertension Severe cases – steroids, azathioprine Histologically identical to IgA nephropathy Follow until urinalysis normal Accounts for 5-20% of children in ESRF

Summary Nephrotic Syndrome Minimal Change Disease most common, majority steroid sensitive, peri-orbital oedema most common presenting feature Glomerulonephritis Presents with haematuria, usually post infectious in children, mainly self limiting, supportive treatment