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Nephrosis and Nephrosis and NephritisNephritis
Dr M White, Paediatric SpRDr M White, Paediatric SpRTCD LectureTCD Lecture
Mon 11Mon 11thth May 2009 May 2009
1) Nephrotic Syndrome1) Nephrotic Syndrome2) Glomerulonephritis2) Glomerulonephritis
Nephrotic Nephrotic SyndromeSyndrome
Nephrotic SyndromeNephrotic Syndrome Characterised by proteinuria (3.5g Characterised by proteinuria (3.5g
per 24 hours), hypoalbuminemia per 24 hours), hypoalbuminemia (serum <30g/dL), oedema, (serum <30g/dL), oedema, hypercholesterolemiahypercholesterolemia
Almost always idiopathic in Almost always idiopathic in childhoodchildhood
ClassificationClassification Primary vs SecondaryPrimary vs Secondary HistologyHistology TherapeuticTherapeutic
Primary Nephrotic Primary Nephrotic SyndromeSyndrome
Post-infectious aetiologiesPost-infectious aetiologies Congenital Nephrotic SyndromeCongenital Nephrotic Syndrome Collagen vascular disorders (SLE/RA/PAN)Collagen vascular disorders (SLE/RA/PAN) Henoch-Schonlein PurpuraHenoch-Schonlein Purpura Hereditary NephritisHereditary Nephritis Sickle cell diseaseSickle cell disease Diabetes MellitusDiabetes Mellitus AmyloidosisAmyloidosis MalignancyMalignancy
Secondary Nephrotic Secondary Nephrotic SyndromeSyndrome
Group A beta-haemolytic strepGroup A beta-haemolytic strep SyphilisSyphilis MalariaMalaria TBTB Viral infections (varicella, HBV, HIV-1, Viral infections (varicella, HBV, HIV-1,
infectious mononucleosis)infectious mononucleosis)
Histological ClassificationHistological Classification Minimal-change nephrotic syndrome Minimal-change nephrotic syndrome
(MCNS) = 84.5%(MCNS) = 84.5% Focal Segmental glomerulosclerosis Focal Segmental glomerulosclerosis
(FSGS) = 9.5%(FSGS) = 9.5% Mesangial proliferation = 2.5%Mesangial proliferation = 2.5% Membranous nephropathy & others Membranous nephropathy & others
= 3.5%= 3.5%
Therapeutic ClassificationTherapeutic Classification Steroid sensitive (85-90%)Steroid sensitive (85-90%) Steroid resistant (10-15%)Steroid resistant (10-15%) Steroid dependent Steroid dependent Frequently relapsingFrequently relapsing
PathophysiologyPathophysiology Two important issues; 1)mechanism of Two important issues; 1)mechanism of
glomerular injury 2)proteinuriaglomerular injury 2)proteinuria Circulating non-immune factors in MCD Circulating non-immune factors in MCD
and FSGSand FSGS Circulating immune factors in disorders Circulating immune factors in disorders
membranoproliferative GN, membranoproliferative GN, poststreptococcal GN and SLE nephritispoststreptococcal GN and SLE nephritis
Mutations in podocyte or slit diaphragm in Mutations in podocyte or slit diaphragm in inherited form of congenital, infantile or inherited form of congenital, infantile or glucocorticoid resistant nephrotic glucocorticoid resistant nephrotic syndromesyndrome
Incidence = 2-7 cases per 100,00 Incidence = 2-7 cases per 100,00 per yearper year
15 times more common in 15 times more common in children than adultschildren than adults
Age of onset varies with type of Age of onset varies with type of diseasedisease
Mortality rate related to primary Mortality rate related to primary disease processdisease process
DefinitionsDefinitions RemissionRemission – negative urinalysis on 1 – negative urinalysis on 1stst
morning urine for 3 consecutive morning urine for 3 consecutive morningsmornings
RelapseRelapse – 3+ proteinuria on 3 or more – 3+ proteinuria on 3 or more consecutive 1consecutive 1stst morning urines morning urines
Frequently relapsingFrequently relapsing – 2 or more – 2 or more relapses within 6 months of diagnosis; or relapses within 6 months of diagnosis; or 4 or more relapses per year4 or more relapses per year
Steroid resistantSteroid resistant – no remission after 4 – no remission after 4 weeks of prednisolone 60mg/mweeks of prednisolone 60mg/m2/2/dayday
PresentationPresentation First sign usually facial swelling – First sign usually facial swelling –
periorbital oedemaperiorbital oedema Increasing oedema over days to Increasing oedema over days to
weeksweeks Lethargy, poor appetite, Lethargy, poor appetite,
weakness, abdominal painweakness, abdominal pain May follow an apparent viral URTIMay follow an apparent viral URTI Haematuria/hypertension unusualHaematuria/hypertension unusual
Differential DiagnosesDifferential Diagnoses
Congestive heart failureCongestive heart failure CirrhosisCirrhosis Protein losing statesProtein losing states
Physical ExaminationPhysical Examination Overall inspectionOverall inspection Vital signsVital signs Physical ExaminationPhysical Examination
Periorbital oedemaPeriorbital oedema Pitting oedema of legsPitting oedema of legs Scrotal oedemaScrotal oedema Sacral oedemaSacral oedema AscitesAscites Loss of skin creasesLoss of skin creases
Laboratory studiesLaboratory studies Diagnosis based on history and clinical Diagnosis based on history and clinical
findingsfindings Urine dipstick Urine dipstick 24 hour urine collection 24 hour urine collection U&EU&E FBCFBC +/- Hepatitis serology, HIV, serum +/- Hepatitis serology, HIV, serum
complement, varicella serologycomplement, varicella serology Renal USRenal US Others – Antistreptolysin O titres, serum Others – Antistreptolysin O titres, serum
protein electrophoresis, antinuclear antibodiesprotein electrophoresis, antinuclear antibodies
Renal biopsyRenal biopsy RarelyRarely performed in Paediatric cases performed in Paediatric cases Consider if;Consider if; Congenital Nephrotic SyndromeCongenital Nephrotic Syndrome > 8 years at onset> 8 years at onset Steroid resistanceSteroid resistance Frequent relapsesFrequent relapses Significant nephritic manifestationsSignificant nephritic manifestations
TreatmentTreatment Prednisolone 60mg/mPrednisolone 60mg/m22/day x 4 weeks, /day x 4 weeks,
40mg/m2 alternate days for 4 weeks then 40mg/m2 alternate days for 4 weeks then STOPSTOP
For relapse – prednisolone 60mg/mFor relapse – prednisolone 60mg/m22/day until /day until remission, then 40mg/mremission, then 40mg/m22 alt doses for 3 doses, alt doses for 3 doses, and reduce alt day dose by 10mg/mand reduce alt day dose by 10mg/m22 every 3 every 3 days until 10mg/mdays until 10mg/m22 alt days – then 5mg/m alt days – then 5mg/m22 alt alt days for three doses then STOPdays for three doses then STOP
Consider antithrombotic agents, oral penicillinConsider antithrombotic agents, oral penicillin VZIG for varicella contacts, aciclovir for VZIG for varicella contacts, aciclovir for
varicella infectionvaricella infection
Frequently Relapsing or Frequently Relapsing or Steroid dependent NSSteroid dependent NS
Cyclosporin ACyclosporin A TacrolimusTacrolimus CyclophosphamideCyclophosphamide Mycophenolate mofetilMycophenolate mofetil
SRNSSRNS Should be referred to specialist unitShould be referred to specialist unit Full remission not achievedFull remission not achieved Aim to reduce proteinuria so not in Aim to reduce proteinuria so not in
nephrotic rangenephrotic range Significant chance of hypertension and Significant chance of hypertension and
progression to renal failureprogression to renal failure If histology shows FSGS – 20-40% chance If histology shows FSGS – 20-40% chance
of recurrence post transplantof recurrence post transplant
Clinical FeaturesClinical Features SSNSSSNS Toddler, pre-schoolToddler, pre-school No HTNNo HTN Mild, intermittent Mild, intermittent
haematuriahaematuria Normal renal functionNormal renal function Excellent prognosis, Excellent prognosis,
even if frequently even if frequently relapsingrelapsing
Usually not biopsiedUsually not biopsied
SRNSSRNS <1 year, > 8 years<1 year, > 8 years HTN commonHTN common Persistent haematuriaPersistent haematuria Renal function often Renal function often
abnormalabnormal Risk of long term HTN Risk of long term HTN
and renal failureand renal failure Usual histology FSGSUsual histology FSGS
ComplicationsComplications InfectionInfection – typically with Strep pneumoniae – typically with Strep pneumoniae
(pneumonia or peritonitis) (oedema (pneumonia or peritonitis) (oedema &peritoneal fluid, loss of immunoglobulins, &peritoneal fluid, loss of immunoglobulins, immunosupression)immunosupression)
ThrombosisThrombosis – loss of antithrombin III and – loss of antithrombin III and proteins S&C in urine, increased procoagulant proteins S&C in urine, increased procoagulant factors by liver, increased haematocrit, factors by liver, increased haematocrit, relative immobility, steroid therapyrelative immobility, steroid therapy
HypovolemiaHypovolemia – shift of fluid from – shift of fluid from intravascular space, symptoms – oliguria, abd intravascular space, symptoms – oliguria, abd pain, anorexia, postural hypotensionpain, anorexia, postural hypotension
Drug toxicityDrug toxicity – side effects of steroid – side effects of steroid treatment, nephrotoxcity from cyclosporin A treatment, nephrotoxcity from cyclosporin A or tacrolimusor tacrolimus
Congenital Nephrotic SyndromeCongenital Nephrotic Syndrome Onset in first 3 months of lifeOnset in first 3 months of life Large placenta – usually 40% of birth weightLarge placenta – usually 40% of birth weight Almost always resistant to drug treatmentAlmost always resistant to drug treatment High morbidity from protein malnutrition & sepsisHigh morbidity from protein malnutrition & sepsis Finnish type-Finnish type- most severe, AR most severe, AR Diffuse mesangial sclerosisDiffuse mesangial sclerosis – less severe, AR – less severe, AR Denys-Drash syndromeDenys-Drash syndrome – includes – includes
pseudohermaphroditism and Wilms tumourpseudohermaphroditism and Wilms tumour FSGSFSGS Secondary congenital nephrotic syndrome – Secondary congenital nephrotic syndrome –
congenital syphiliscongenital syphilis Intensive supportive care – 20% albumin, Intensive supportive care – 20% albumin,
nutritional support, early unilateral nephrectomynutritional support, early unilateral nephrectomy Dialysis and transplantationDialysis and transplantation
GlomerulonephritisGlomerulonephritis
GlomerulonephritisGlomerulonephritis Refers to a specific set of renal Refers to a specific set of renal
diseases in which an immunologic diseases in which an immunologic mechanism triggers inflammation mechanism triggers inflammation and proliferation of glomerular tissue and proliferation of glomerular tissue that result in damage to the that result in damage to the basement membrane, mesangium or basement membrane, mesangium or capillary endotheliumcapillary endothelium
GlomerulonephritisGlomerulonephritis Sudden onset of haematuria, proteinuria Sudden onset of haematuria, proteinuria
and red blood cell castsand red blood cell casts Often accompanied by hypertension, Often accompanied by hypertension,
oedema and impaired renal functionoedema and impaired renal function Represents 10-15% of glomerular Represents 10-15% of glomerular
diseasedisease Chronic GN may lead to scarring of the Chronic GN may lead to scarring of the
tubulo-interstitial areas of the kidney, tubulo-interstitial areas of the kidney, with progressive renal impairmentwith progressive renal impairment
PathophysiologyPathophysiology Lesions are the result of glomerular Lesions are the result of glomerular
deposition or immune complex deposition or immune complex formationformation
Kidneys may be enlarged up to 50%Kidneys may be enlarged up to 50% Histological appearance – swelling of Histological appearance – swelling of
glomerular tufts, infiltration with glomerular tufts, infiltration with polymorpholeucocytespolymorpholeucocytes
Immunoflouresence reveals deposition Immunoflouresence reveals deposition of immunoglobulins and complementof immunoglobulins and complement
CausesCauses Post infectious – most common, Strep, Post infectious – most common, Strep,
viral/fungal/parasiticviral/fungal/parasitic Systemic causes – vasculitis, collagen Systemic causes – vasculitis, collagen
vascular disease, hypersensitivity, HSP, vascular disease, hypersensitivity, HSP, Goodpasture, drugs (gold penicillamine)Goodpasture, drugs (gold penicillamine)
Renal disease – membranoproliferative Renal disease – membranoproliferative GN, Berger disease, Idiopathic rapidly GN, Berger disease, Idiopathic rapidly progressive glomerulonephritisprogressive glomerulonephritis
Morbidity/MortalityMorbidity/Mortality Up to 100% of post-streptococcal GN Up to 100% of post-streptococcal GN
recover completelyrecover completely Sporadic cases progress to chronic form in Sporadic cases progress to chronic form in
10% of children10% of children GN most common cause of chronic renal GN most common cause of chronic renal
failure (25%)failure (25%) Mortality 0-7%Mortality 0-7% Male : Female 2:1Male : Female 2:1 Most cases aged 5-15 yearsMost cases aged 5-15 years Can occur at any ageCan occur at any age
ClinicalClinical Most common- 2-14 year old boy, Most common- 2-14 year old boy,
presenting with peri-orbital pufffiness presenting with peri-orbital pufffiness after a strep infectionafter a strep infection
Urine is dark Urine is dark (‘Coca-Cola’ urine)(‘Coca-Cola’ urine) and and output is reducedoutput is reduced
BP may be elevatedBP may be elevated Abrupt onset of symptomsAbrupt onset of symptoms Weakness, fever, abd pain, malaiseWeakness, fever, abd pain, malaise
ClinicalClinical Most common- 2-14 year old boy, Most common- 2-14 year old boy,
presenting with periorbital pufffiness presenting with periorbital pufffiness after a strep infectionafter a strep infection
Urine is dark Urine is dark (‘Coca-Cola’ urine(‘Coca-Cola’ urine) and ) and output is reducedoutput is reduced
BP may be elevatedBP may be elevated Abrupt onset of symptomsAbrupt onset of symptoms Weakness, fever, abd pain, malaiseWeakness, fever, abd pain, malaise
Clinical courseClinical course Latent period of up to 3 weeks after Latent period of up to 3 weeks after
infection(1-2 weeks postpharyngitis, 2-4 weeks infection(1-2 weeks postpharyngitis, 2-4 weeks postdermal inf)postdermal inf)
Haematuria Haematuria universaluniversal OliguriaOliguria OedemaOedema Headache (sec to hypertension)Headache (sec to hypertension) SOB or dyspnoea on exertionSOB or dyspnoea on exertion Possible flank pain (stretching of renal Possible flank pain (stretching of renal
capsule)capsule)
Laboratory studiesLaboratory studies FBC – dilutional anaemia, increased WCCFBC – dilutional anaemia, increased WCC U&E – ?Elevated urea U&E – ?Elevated urea ±± creatinine creatinine Urinalysis – haematuria, Red cell casts Urinalysis – haematuria, Red cell casts
present, 24 hour collection helpfulpresent, 24 hour collection helpful ASOT (increased in 60-80%), anti-DNAse bASOT (increased in 60-80%), anti-DNAse b ESR ?CRPESR ?CRP Cultures (throat, blood, urine)Cultures (throat, blood, urine) Complement (Decreased C3, normal C4)Complement (Decreased C3, normal C4)
Other testsOther tests Radiography – CXR if cough +/- Radiography – CXR if cough +/-
haemoptysishaemoptysis Echo if new murmur/repeated + Echo if new murmur/repeated +
blood cultureblood culture ANAANA Targeted testsTargeted tests
Renal BiopsyRenal Biopsy Acute GN self limited, good prognosisAcute GN self limited, good prognosis
Significant Renal Impairment, Significant Renal Impairment, atypical presentation, family history, atypical presentation, family history, massive proteinuria, nephrotic massive proteinuria, nephrotic syndromesyndrome
ManagementManagement Treatment mainly supportiveTreatment mainly supportive Correct electrolyte abnormalities if Correct electrolyte abnormalities if
presentpresent Post Streptococcal – penicillin therapyPost Streptococcal – penicillin therapy Admission if oliguria and renal failureAdmission if oliguria and renal failure Fluid restriction with significant Fluid restriction with significant
oedemaoedema
ComplicationsComplications Rare in post-strep GNRare in post-strep GN Microhaematuria may persist for Microhaematuria may persist for
yearsyears Marked decline in GFR is rareMarked decline in GFR is rare Chronic renal failureChronic renal failure Nephrotic SyndromeNephrotic Syndrome
Acute Post-streptococcal GNAcute Post-streptococcal GN Onset of reddish-brown (‘Coca-Cola’) urine Onset of reddish-brown (‘Coca-Cola’) urine
10-14 days after strep throat or skin 10-14 days after strep throat or skin infectioninfection
Deposition of immune complexes in Deposition of immune complexes in glomeruliglomeruli
Treatment mainly supportiveTreatment mainly supportive Excellent recoveryExcellent recovery Check C3/C4 after recovery – should Check C3/C4 after recovery – should
normalisenormalise
Henoch-Schonlein purpuraHenoch-Schonlein purpura 70% will have some degree of renal 70% will have some degree of renal
involvementinvolvement Usually microscopic haematuria +/- Usually microscopic haematuria +/-
proteinuriaproteinuria May have relapsing courseMay have relapsing course Refer if nephritic/nephrotic/sustained Refer if nephritic/nephrotic/sustained
hypertensionhypertension Severe cases – steroids, azathioprineSevere cases – steroids, azathioprine Histologically identical to IgA nephropathyHistologically identical to IgA nephropathy Follow until urinalysis normalFollow until urinalysis normal Accounts for 5-20% of children in ESRFAccounts for 5-20% of children in ESRF
SummarySummary Nephrotic SyndromeNephrotic Syndrome Minimal Change Disease most common, Minimal Change Disease most common,
majority steroid sensitive, peri-orbital majority steroid sensitive, peri-orbital oedema most common presenting oedema most common presenting featurefeature
GlomerulonephritisGlomerulonephritis Presents with haematuria, usually post Presents with haematuria, usually post
infectious in children, mainly self limiting, infectious in children, mainly self limiting, supportive treatmentsupportive treatment
