nephritis nephrosis

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