G L O M E R U L O P A T H I E SG L O M E R U L O P A T H I E S

Hasyim kasim MD

GlomerulopathiesGlomerulopathies

GlomerulopathyGlomerulopathy : a group of diverse conditions – including, but not limited : a group of diverse conditions – including, but not limited

to, glomerulonephritis – having in common the fact that the disease to, glomerulonephritis – having in common the fact that the disease

process begins in the glomerulus or that the glomerulus is the most process begins in the glomerulus or that the glomerulus is the most

importantly diseased part of the nephron.importantly diseased part of the nephron.

Glomerulopathies are the most common causes of end-stage renal diseaseGlomerulopathies are the most common causes of end-stage renal disease

Clinical presentation of glomerular diseaseClinical presentation of glomerular disease

I.I. Acute glomerulonephritisAcute glomerulonephritis

II.II. Rapidly progressive glomerulonephritisRapidly progressive glomerulonephritis

III.III. Chronic glomerulonephritisChronic glomerulonephritis

IV.IV. Persistent urinary abnormalities with few or no symptomsPersistent urinary abnormalities with few or no symptoms

V.V. Nephrotic syndromeNephrotic syndrome

Acute glomerulonephritisAcute glomerulonephritis

• OligouriaOligouria

• Hematuria : red blood castsHematuria : red blood casts

• Proteinuria : usually < 3 g/dayProteinuria : usually < 3 g/day

• EdemaEdema

• HypertensionHypertension

• Abrupt onset, usually self-limitingAbrupt onset, usually self-limiting

Rapidly progressive glomerulonephritisRapidly progressive glomerulonephritis

• Renal failure over days/weeksRenal failure over days/weeks

• Proteinuria : usually < 3 g/dayProteinuria : usually < 3 g/day

• Hematuria : red blood castsHematuria : red blood casts

• Blood pressure often normalBlood pressure often normal

• May have other features of vasculitisMay have other features of vasculitis

Chronic glomerulonephritisChronic glomerulonephritis

• Hypertension

• Renal insuficiency

• Proteinuria > 3g/day

• Shrunken smooth kidneys

Persisting urinary abnormalities with few or no symptomsPersisting urinary abnormalities with few or no symptoms

• Reccurent or persistent hematuria with or without

abnormal proteinuria

• Isolated non-nephrotic glomerular proteinuria

( asymptomatic proteinuria without hematuria ;

isolated proteinuria )

Nephrotic syndromeNephrotic syndrome

• Clinical entity having mClinical entity having muultiple causes and characterizedltiple causes and characterized

by increased glomerular permeability manifested by increased glomerular permeability manifested

by massive proteinuria and lipiduria.by massive proteinuria and lipiduria.

• Massive proteinuria > 3.5 g/day/1.73mMassive proteinuria > 3.5 g/day/1.73m22 body surface area body surface area

in the absence of a depressed GFR.in the absence of a depressed GFR.

Clinical Features of The Nephrotic SyndromeClinical Features of The Nephrotic Syndrome

Manifestations of the nephrotic syndrome itselfManifestations of the nephrotic syndrome itself

Signs and symptoms determined by the underlying disease Signs and symptoms determined by the underlying disease involving the kidneyinvolving the kidney

Differentiation between nephrotic and nephritic syndromeDifferentiation between nephrotic and nephritic syndrome

Typical Typical featuresfeatures

NephroticNephrotic NephriticNephritic

OnsetOnset InsidiousInsidious AbruptAbrupt

EdemaEdema ++++++++ ++++

Blood pressureBlood pressure NormalNormal RaisedRaised

Jugular venous Jugular venous pressurepressure

Normal/lowNormal/low RaisedRaised

ProteinuriaProteinuria ++++++++ ++++

HematuriaHematuria May/may not May/may not occuroccur

++++++

Red-cell castsRed-cell casts AbsentAbsent PresentPresent

Serum albuminSerum albumin lowlow Normal/slightly Normal/slightly reducereduce

Clinical manifestation of nephrotic syndrome :Clinical manifestation of nephrotic syndrome :

OedemaOedema

HypertensionHypertension

DyslipidemiaDyslipidemia

Hypercoagulable stateHypercoagulable state

Hypoproteinemia / proteinuriaHypoproteinemia / proteinuria

Progressive renal failureProgressive renal failure

Trace metal deficienciesTrace metal deficiencies

Endocrine disturbancesEndocrine disturbances

Infectious / immunodeficiency statesInfectious / immunodeficiency states

Classification of the disease states associated with the development of Classification of the disease states associated with the development of nephrotic syndromenephrotic syndrome

I. Idiopathic nephrotic syndrome due to Primary Glomerular DiseaseI. Idiopathic nephrotic syndrome due to Primary Glomerular Disease

II.Nephrotic syndrome associated with spesific etiologic events or in which II.Nephrotic syndrome associated with spesific etiologic events or in which glomerular disease arises as a complication of other diseaseglomerular disease arises as a complication of other disease

1.1. MedicationsMedications

2.2. Allergens, venoms, immuizationAllergens, venoms, immuization

3.3. Infection ( bacterial, viral, protozoal, helminthic )Infection ( bacterial, viral, protozoal, helminthic )

4.4. Neoplasmic ( solid tumors, leukemia and lymphoma )Neoplasmic ( solid tumors, leukemia and lymphoma )

5.5. Multisystem diseaseMultisystem disease

6.6. Heredofamilial and metabolic diseaseHeredofamilial and metabolic disease

7.7. MiscellaneousMiscellaneous

Formation of nephrotic edemaFormation of nephrotic edema

UnderfillUnderfill

ProteinuriaProteinuria

HypoalbuminemiaHypoalbuminemia

Plasma colloidPlasma colloidOncotic pressure Oncotic pressure

Starling forcesStarling forces

Reduced plasma volumeReduced plasma volume

Vasopressin Vasopressin ANP normal/lowANP normal/low RAS activatedRAS activatedAldosterone Aldosterone

Water retentionWater retention

EdemaEdemaSodium retentionSodium retention

OverfillOverfill

Primary tubular defect Primary tubular defect causing sodium retentioncausing sodium retention

Normal/raised Normal/raised plasma volumeplasma volume

Vasopressin Vasopressin normalnormal

ANP ANP

Aldosterone Aldosterone

Management of oedema in nephrotic syndromeManagement of oedema in nephrotic syndrome

MildMildDietary NaCl restriction ( to 3-4 g NaCl per day )Dietary NaCl restriction ( to 3-4 g NaCl per day )Support stockingsSupport stockingsHydrochlorothiazide 12.5-50 mg/day ( if GFR > 50 ml/min )Hydrochlorothiazide 12.5-50 mg/day ( if GFR > 50 ml/min )Frusemide 40-80 mg/day ( if GFR < 70 ml/min )Frusemide 40-80 mg/day ( if GFR < 70 ml/min )

ModerateModerateContinue NaCl restrictionContinue NaCl restriction( Frusemide 160-480 mg/day or bumetamide 1-2 mg/day or torsemide( Frusemide 160-480 mg/day or bumetamide 1-2 mg/day or torsemide

40-160 mg/day )40-160 mg/day )SevereSevere

Continue NaCl restrictionContinue NaCl restrictionOral or IV frusemide 160-480 mg/day ( or bumetanide or torsemide ) plusOral or IV frusemide 160-480 mg/day ( or bumetanide or torsemide ) plus

metalozone 2.5-10 mg/daymetalozone 2.5-10 mg/dayRefractoryRefractory

Continuous IV infussion or frusemide ( 20 mg/h ) or bumetanide ( 1 mg/h ) Continuous IV infussion or frusemide ( 20 mg/h ) or bumetanide ( 1 mg/h ) after a loading doseafter a loading dose

ororHyperosmotic salt-poor albumin ( 25-50 g ) mixed with 120 mg of Hyperosmotic salt-poor albumin ( 25-50 g ) mixed with 120 mg of

furosemidefurosemideororSlow continuous veno-venous ultrafiltration using a highly permeable Slow continuous veno-venous ultrafiltration using a highly permeable

membranemembrane

Plasma lipid concentrations in nephrotic syndromePlasma lipid concentrations in nephrotic syndrome

IncreasedIncreasedVery low density lipoproteinsIntermediate density lipoproteinsLow density lipoproteinsApolipoprotein BApolipoprotein CIIIHigh density lipoproteinsLipoprotein (a)Total cholesterolTriglycerides ( when serum albumin < 2 g/dl)

UnchangedUnchangedApolipoprotein AIApolipoprotein AIIApolipoprotein CIII

DecreasedDecreasedHigh density lipoprotein 2

Therapy of dyslipidemia in nephrotic syndromeTherapy of dyslipidemia in nephrotic syndrome

• Only full successful when the underlying cause is remidied Only full successful when the underlying cause is remidied and long term complete remission of proteinuria are and long term complete remission of proteinuria are inducedinduced

• Reduced cholesterol and saturated fat intake Reduced cholesterol and saturated fat intake ( relatively ineffective )( relatively ineffective )

• Drugs : HMG co-enzyme A reductase inhibitorsDrugs : HMG co-enzyme A reductase inhibitors( lovastatin, simvastatin, fluvastatin, atorvastatin )( lovastatin, simvastatin, fluvastatin, atorvastatin )

Coagulation abnormalities in nephrotic syndromeCoagulation abnormalities in nephrotic syndrome

Increased ( prothrombotic )Increased ( prothrombotic )FibrinogenPlatelets ( and platelet adhesiveness )Plasma viscosity ( cholesterol, lipid )Lipoprotein (a)Plasminogen activator inhibitor

Decreased ( antithrombotic )Decreased ( antithrombotic )Active protein CActive protein SAntithrombin III

Prothrombotic state are correlated with serum albumin levelsProthrombotic state are correlated with serum albumin levels

Serum albumin < 2-2.5 g/dl appears to be associated with an Serum albumin < 2-2.5 g/dl appears to be associated with an increased risk of thromboembolism increased risk of thromboembolism

Diagnostic approach in nephrotic syndromeDiagnostic approach in nephrotic syndrome

I.I. ClinicalClinical

II.II. Laboratory studiesLaboratory studies

III.III. Renal biopsyRenal biopsy

I. ClincialI. Clincial

HistoryHistoryPreexisting diseasePreexisting diseasePrevious infectionPrevious infectionDrug ingestionDrug ingestionArthritis, rashArthritis, rashCurrent pregnancyCurrent pregnancyFamily history of renal diseaseFamily history of renal disease

Physical examinationPhysical examinationSevere obesitySevere obesityRash, arthritisRash, arthritisDiabetic retinopathyDiabetic retinopathyHypertensionHypertensionEvidence of malignancyEvidence of malignancyLipodystrophyLipodystrophyLymphoadenopathy/hepatosplenomegalyLymphoadenopathy/hepatosplenomegaly

II. Laboratory StudiesII. Laboratory Studies

Urinalysis

In all cases ( non-diagnostic )Creatinine clearanceSerum protein electrophoresisSerum total cholesterol, lipoproteinSerum ionized calciumParathyroid hormone

In selected cases ( to established the diagnosis )Complement levelAntinuclear antibody assay CryoglobulinsHepatitis and HIV serologySerum and urine immunoelectrophoresis

III. Renal biopsyIII. Renal biopsy

• Minimal change diseaseMinimal change disease• Focal segmental glomerulosclerosisFocal segmental glomerulosclerosis• Membranous nephropathyMembranous nephropathy• Membranoproliferative glomerulonephritisMembranoproliferative glomerulonephritis• Other glomerulonephritisOther glomerulonephritis

Suggested approach for initial treatmentSuggested approach for initial treatment( Minimal change disease )( Minimal change disease )

ChildrenChildrenPrednisone 60 mg/mPrednisone 60 mg/m22/day until remission, then 40 mg/m/day until remission, then 40 mg/m22/48 h for /48 h for 12 weeks, then reduce by 5-10 mg/m12 weeks, then reduce by 5-10 mg/m22/48 h every month./48 h every month.

AdultsAdultsPrednisone 1mg/kg/day until remission or for 6 weeks, then 1.6 mg/kg/48 hPrednisone 1mg/kg/day until remission or for 6 weeks, then 1.6 mg/kg/48 hfor 1 month, then reduce by 0.2-0.4 mg/kg/48 h.for 1 month, then reduce by 0.2-0.4 mg/kg/48 h.

ElderlyElderlyPrednisone 1 mg/kg/day until remission or for 4 weeks, then 0.8 mg/kg/day Prednisone 1 mg/kg/day until remission or for 4 weeks, then 0.8 mg/kg/day for 2 weeks, then 1.6 mg/kg/48 h for 2 weeks. Then reduce by 0.4 mg/kg/48 hfor 2 weeks, then 1.6 mg/kg/48 h for 2 weeks. Then reduce by 0.4 mg/kg/48 hevery 2 weeks. If no remission continue with 1.2 mg/kg/48 h for another every 2 weeks. If no remission continue with 1.2 mg/kg/48 h for another 4 weeks then reduce.4 weeks then reduce.

Contraindications to prednisoneContraindications to prednisoneCyclophosphamide 2 mg/kg/day or chlorambucil 0.15mg/kg/day for 8-12 Cyclophosphamide 2 mg/kg/day or chlorambucil 0.15mg/kg/day for 8-12 weeksweeks

Definitions used to describe responses and relapses in patients with minimalDefinitions used to describe responses and relapses in patients with minimalChange nephropathyChange nephropathy

Complete remissionComplete remission Proteinuria lower than 4 mg/m2/day in children or Proteinuria lower than 4 mg/m2/day in children or lower than 0.2 g/day in adults for three consecutive lower than 0.2 g/day in adults for three consecutive

daysdays

Partial remissionPartial remission Proteinuria between 4 and 40 mg/m2/dayin children Proteinuria between 4 and 40 mg/m2/dayin children or between 0.21 and 3.5 g/day in adults for three or between 0.21 and 3.5 g/day in adults for three

consecutive daysconsecutive days

Relapse of proteinuriaRelapse of proteinuria Proteinuria excreeding 4 mg/m2/day in children or Proteinuria excreeding 4 mg/m2/day in children or 0.2 g/day in adults for at least 1 week, in patients 0.2 g/day in adults for at least 1 week, in patients

who were in complete remissionwho were in complete remission

Relapse of nephrotic Relapse of nephrotic syndromesyndrome

Proteinuria exceeding 40 mg/m2/day in children or Proteinuria exceeding 40 mg/m2/day in children or 3.5 g/day in adults for at least 1 week, in patients 3.5 g/day in adults for at least 1 week, in patients

who were in complete or partial remmisionwho were in complete or partial remmision

Frequent relapsesFrequent relapses Patients with 2 or more episodes of the nephrotic Patients with 2 or more episodes of the nephrotic syndrome in 6 months or 3 or more episodes of the syndrome in 6 months or 3 or more episodes of the

nephrotic syndrome in 12 monthnephrotic syndrome in 12 month

Steroid-dependent Steroid-dependent nephrotic syndromenephrotic syndrome

Reappearance of the nephrotic syndrome within 2 Reappearance of the nephrotic syndrome within 2 weeks after reduction or discontinuation of weeks after reduction or discontinuation of

glucocorticoidsglucocorticoids

Steroid-resistant nephrotic Steroid-resistant nephrotic syndromesyndrome

ControversialControversial

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