NEPHROTIC SYNDROME

DR. R. KANDASAMY, MD, DCHPROFESSOR OF PEDIATRICS

ICH &HC

NEPHROTIC SYNDROME IN NEPHROTIC SYNDROME IN CHILDRENCHILDREN

According to ISKDC (International Study According to ISKDC (International Study of Kidney Disease in Children) it is defined of Kidney Disease in Children) it is defined as Proteinuria of more than 40 mg/M2/hr as Proteinuria of more than 40 mg/M2/hr and Hypoalbuminaemia less than 2.5g/dl. and Hypoalbuminaemia less than 2.5g/dl.

But for practical purposes it is defined But for practical purposes it is defined as proteinuria more than 50 mg/kg/24 hours, as proteinuria more than 50 mg/kg/24 hours, serum total protein less than 5 G/dl, serum serum total protein less than 5 G/dl, serum albumin less than 3 G/dl, albumin less than 3 G/dl, hypercholesterolemia more than 220 mg/dl hypercholesterolemia more than 220 mg/dl and with or without edema. and with or without edema.

Nephrotic Syndrome is classified as Nephrotic Syndrome is classified as Primary Glomerular disease and Secondary Primary Glomerular disease and Secondary Glomerular disease. Histopathologically primary Glomerular disease. Histopathologically primary or idiopathic Nephrotic Syndrome are classified or idiopathic Nephrotic Syndrome are classified as: as:

Minimal Change Nephrotic SyndromeMinimal Change Nephrotic Syndrome Focal Glomerular SclerosisFocal Glomerular Sclerosis Diffuse Glomerular SclerosisDiffuse Glomerular Sclerosis Membranous Glomerular nephrotisMembranous Glomerular nephrotis Mesangio Capillary Glomerular nephrotisMesangio Capillary Glomerular nephrotis Mesangial Proliferative Glomerular nephrotisMesangial Proliferative Glomerular nephrotis Endo capillary Proliferative Glomerular nephrotisEndo capillary Proliferative Glomerular nephrotis Other Chronic Sclerosing lesionOther Chronic Sclerosing lesion Other unclassified diseaseOther unclassified disease

The prevalence of primary nephrotic The prevalence of primary nephrotic syndrome due to primary glomerular disease syndrome due to primary glomerular disease according to Cameron and Co-workers is given according to Cameron and Co-workers is given below: below:

LESIONLESION % OF PREVALENCE% OF PREVALENCEMinimal ChangeMinimal Change 83%83%Focal Glomerular ScelerosisFocal Glomerular Scelerosis 8%8%Membranous Glomerular nephroticMembranous Glomerular nephrotic 1%1%Mesangiocapillary Glomerular nephroticMesangiocapillary Glomerular nephrotic 5%5%Other proliferative lesion including MesangialOther proliferative lesion including MesangialEndocapillary and crescentric Endocapillary and crescentric Glomerular nephritisGlomerular nephritis 3%3%

100%100%

SECONDARY GLOMERULAR SECONDARY GLOMERULAR

DISEASE:DISEASE: Infection :Infection : - Post Infectious Glomerular nephrotis- Post Infectious Glomerular nephrotis

- Infective Endocarditis- Infective Endocarditis - Hepatitis B Infection - Hepatitis B Infection

- Shunt nephrotis- Shunt nephrotis- Malaria- Malaria

Multisystem :Multisystem : - Henoch Schonlein purpura- Henoch Schonlein purpura- Systemic Lupus erythmatosus- Systemic Lupus erythmatosus- Polyarteritis Nodosa- Polyarteritis Nodosa

Heredo familial Heredo familial - Alport Syndrome- Alport SyndromeNeoplasm :Neoplasm : - Hodgkins’ disease- Hodgkins’ disease

- Leukemia- Leukemia- Wilm’s tumor- Wilm’s tumor

Medication : Medication : - Non steroidal anti inflammatory drugs- Non steroidal anti inflammatory drugs- Anti convulsants like phenytoin, - Anti convulsants like phenytoin,

trimethadionetrimethadione PencillaminePencillamine- Allergens, Serum sickness toxoid, food - Allergens, Serum sickness toxoid, food

allergensallergens- Insect bites- Insect bites

ETIOLOGY: ETIOLOGY: Etiology of Idiopathic Nephrotic Syndrome is obscure. Etiology of Idiopathic Nephrotic Syndrome is obscure.

PATHOGENESIS: PATHOGENESIS: - Lymphocytotoxins- Lymphocytotoxins

- Immune Complexes- Immune Complexes are responsible for are responsible for increasing the increasing the

- Lymphokines- Lymphokines glomerular permeability glomerular permeability and and

- Vasoactive Amines- Vasoactive Amines Proteinuria. Proteinuria.

T Cell – Dysfunction is the modern thinking. It is observed in T Cell – Dysfunction is the modern thinking. It is observed in Hodgkin’s disease. Hodgkin’s disease.

In Focal Glomerular Sclerosis – Immune Complexes, IgM and C have In Focal Glomerular Sclerosis – Immune Complexes, IgM and C have been identified.been identified.

MCNS – has been linked with HLA B12, HLA B8 and HLA DR7.MCNS – has been linked with HLA B12, HLA B8 and HLA DR7.In Membranopro liferative nephritis the role of Hepatitis B antigens In Membranopro liferative nephritis the role of Hepatitis B antigens

in have been demonstrated. in have been demonstrated. MCNS – Electron microscopy reveals the glomeruli appear normal on MCNS – Electron microscopy reveals the glomeruli appear normal on

Minimal increase in mesangial cell and matrixMinimal increase in mesangial cell and matrixRetraction of the epithelial cell foot processRetraction of the epithelial cell foot process

FGG – Focal Glomerular Sclerosis FGG – Focal Glomerular Sclerosis - Majority of glomerulo appear normal or manifest - Majority of glomerulo appear normal or manifest

mesangial proliferationmesangial proliferation

In children the commonest form of N.S. is primary nephrotic In children the commonest form of N.S. is primary nephrotic syndrome syndrome

Among these the MCNS is the most frequent. Among these the MCNS is the most frequent. Insidious onset of odemaInsidious onset of odema Mild fever and ColdMild fever and Cold Many children have recurrent episodes of such transient Many children have recurrent episodes of such transient

edema for many months. edema for many months. Physical examination shows Physical examination shows

Edema – The edema is initially noted around the eyes Edema – The edema is initially noted around the eyes and in the lower extremidies where it is pitting in and in the lower extremidies where it is pitting in nature, with time edema becomes generalized and nature, with time edema becomes generalized and may associate with weight gain and the development may associate with weight gain and the development of ascites, pleural effusion and decreased urinal of ascites, pleural effusion and decreased urinal output. output.

Pallor Pallor White nails with red bands (leukonychia) White nails with red bands (leukonychia) Normal Blood PressureNormal Blood Pressure No evidence of Renal failureNo evidence of Renal failure

CLINICAL FEATURES:CLINICAL FEATURES:

DIFFERENTIATION OF MCNS AND DIFFERENTIATION OF MCNS AND

OTHER TYPESOTHER TYPES

PATHOPHYSIOLOGYPATHOPHYSIOLOGY MASSIVE PROTEINURIA: MASSIVE PROTEINURIA:

Increased permeability to proteinsIncreased permeability to proteins Selective proeinuria occursSelective proeinuria occurs

- low molecular weight proteins are - low molecular weight proteins are excreted. excreted. Eg. Albine Eg. Albine

- high molecular weight proteins - high molecular weight proteins

Eg. Lipoproteins are not excreted. Eg. Lipoproteins are not excreted. HYPOALBUMINAENIA:HYPOALBUMINAENIA:

- - Because more proteins are lost in Because more proteins are lost in the urine. the urine.

EDEMAEDEMA Fluid movements across capillary is normally the Fluid movements across capillary is normally the

result of a balance between filteration and reabsorption, due result of a balance between filteration and reabsorption, due to changes in capillary and tissue hydrostatic and oncotic to changes in capillary and tissue hydrostatic and oncotic pressure. It is still the pathogenesis of edema in NS is not pressure. It is still the pathogenesis of edema in NS is not well understood. well understood.

Because of the hypoalbuminaenia there is reduction Because of the hypoalbuminaenia there is reduction in plasmo oncotic pressure leads to leak of fluid in to the in plasmo oncotic pressure leads to leak of fluid in to the interstitial compartment or accumulation of fluid secondary interstitial compartment or accumulation of fluid secondary to sodium due to internal defect. to sodium due to internal defect.

The major sites involved in the edema formation are: The major sites involved in the edema formation are: 1. Capillaries – where there is disruption of starling 1. Capillaries – where there is disruption of starling

equilibiria equilibiria 2. Kidney – where there is primary salt retension2. Kidney – where there is primary salt retension

According to the classical view According to the classical view 1. Vascular underfill hypothesis 1. Vascular underfill hypothesis 2. Vascular overfill hypothesis 2. Vascular overfill hypothesis

Vascular underfill hypothesis is responsible for the formation Vascular underfill hypothesis is responsible for the formation of edema. of edema.

VASCULAR OVERFILL VASCULAR OVERFILL

HYPOTHESISHYPOTHESIS Primary intra renal defect in sodium handling is Primary intra renal defect in sodium handling is

responsible for occurrence of edemaresponsible for occurrence of edema

This results in decreased filteration per nephron, This results in decreased filteration per nephron, increase in tubular reabsorption and decreased increase in tubular reabsorption and decreased sensitivity to atrial netriuretic peptide leading to sensitivity to atrial netriuretic peptide leading to fluid retension. fluid retension.

Finally the human body is equipped with Finally the human body is equipped with defence mechanism that limits excessive capillary defence mechanism that limits excessive capillary fluid filteration. fluid filteration.

These defense mechanism includes These defense mechanism includes increased interstitial hydrostatic pressure and increased interstitial hydrostatic pressure and lymph flow, decreased interstitial oncotic pressure lymph flow, decreased interstitial oncotic pressure and reduced permeability of the capillaries to and reduced permeability of the capillaries to protein. protein.

Edema results when these adoptive mechanism Edema results when these adoptive mechanism are inadequate. are inadequate.

It is suggested that vascular underfill is It is suggested that vascular underfill is responsible for most cases of edema in MCNS. responsible for most cases of edema in MCNS. Other mechanisms might be important in patients Other mechanisms might be important in patients with non MCNS. with non MCNS.

There is increasing evidence of hypoalbumia and There is increasing evidence of hypoalbumia and the inability of the renal distal tubules to excret the inability of the renal distal tubules to excret sodium are not the only factor responsible for the sodium are not the only factor responsible for the occurrence of edema. occurrence of edema.

Internal vascular capillary permeability related to Internal vascular capillary permeability related to the release of vascular permeability factor and the release of vascular permeability factor and other cytokines may also play a important role in other cytokines may also play a important role in the pathogenisis of NS. the pathogenisis of NS.

INVESTIGATIONSINVESTIGATIONS

Hb %Hb %TCTCDCDCMxMxUrine ExaminationUrine ExaminationUrine Culture and Sensitivity Urine Culture and Sensitivity X Ray ChestX Ray ChestUSG AbdomenUSG AbdomenSerum Proteins Serum Proteins Urinary Proteins Urinary Proteins Spot Urine Test Spot Urine Test Serum Cholesterol Serum Cholesterol Calculation of selective Protenoria Calculation of selective Protenoria

= Urinary IgG /dl= Urinary IgG /dl XX Serum Albumin / dl = Serum Albumin / dl =

Less than 0.1 Less than 0.1

Serum IgG / dlSerum IgG / dl Urinary Albumin / dl Urinary Albumin / dl

indicate MCNSindicate MCNS

Kidney BiopsyKidney Biopsy

COMPLICATIONS DUE TO DISEASECOMPLICATIONS DUE TO DISEASE A. Loss of Proteins: A. Loss of Proteins: AlbuminAlbumin EdemaEdemaTransferrinTransferrin AnemiaAnemiaTMGTMG Biochemical hypothyroidismBiochemical hypothyroidismVit.D Binding Globulin Vit.D Binding Globulin Hypocalcemia (Along with loss of 1,25 Hypocalcemia (Along with loss of 1,25

diOH diOH chole calciferol)chole calciferol)ImmunoglobulinImmunoglobulin Infection Infection Coagulation factorsCoagulation factors Hypercoagulable stateHypercoagulable state

B. Infection:B. Infection:Loss of ImmunoglobulinLoss of Immunoglobulin AcuteAcuteDepressed CMIDepressed CMI Chronic Chronic

C. Hypercoagulable State: C. Hypercoagulable State: - due to alteration in coagulation factors, associated - due to alteration in coagulation factors, associated

infections, sepsis, Hypovolemiainfections, sepsis, Hypovolemiai) Renal Vein Thrombosisi) Renal Vein Thrombosisii) Peripheral Vein Thrombosisii) Peripheral Vein Thrombosisiii) Cerebral Vein Thrombosis iii) Cerebral Vein Thrombosis

D. Renal Failure: D. Renal Failure: i) Chronic renal failurei) Chronic renal failure

- as a part of disease process.- as a part of disease process.ii) Acute renal failureii) Acute renal failure

a)a) Hypovolemia induced ATNHypovolemia induced ATNb)b) Septicemia leading to shock and ATNSepticemia leading to shock and ATNc)c) Septicemia causing bacterimia and AINSepticemia causing bacterimia and AINd)d) Other drugs causing AINOther drugs causing AINe)e) Bilateral renal vein thrombosis Bilateral renal vein thrombosis f)f) Crescentic GN on existing glomerular disease like Crescentic GN on existing glomerular disease like

FSGS, MGN and MPGN. FSGS, MGN and MPGN.

E. Convulsions: E. Convulsions:

i) Hypocalcemia due to loss of Ca, 1, 25 di OH Cholecalciferol, i) Hypocalcemia due to loss of Ca, 1, 25 di OH Cholecalciferol, Vit.D, binding protein in urine.Vit.D, binding protein in urine.

ii) Hypertensionii) Hypertensioniii) Renal failure – unemiciii) Renal failure – unemiciv) Hyponatremiaiv) Hyponatremiav) Cerebral Vein thrombosis v) Cerebral Vein thrombosis

TREATMENTTREATMENT 1.1. Hospitalization is necessary in the presence ofHospitalization is necessary in the presence of

- gross oedema,- gross oedema,- respiratory distress- respiratory distress- pleural effusion- pleural effusion- peritonitis- peritonitis- unexplained fever- unexplained fever

2.2. Bed rest is essential in gross edemaBed rest is essential in gross edema3.3. Salt and fluid restriction depend upon oedemaSalt and fluid restriction depend upon oedema4.4. Diuretic is a double edged weapon, so it should Diuretic is a double edged weapon, so it should

be used with cautionbe used with caution5.5. Hydrochlorthizide would suffice in mild and Hydrochlorthizide would suffice in mild and

moderate edema given as 4 mg/kg in a single moderate edema given as 4 mg/kg in a single dose. dose.

6.6. Spiranolactone should be combined with these Spiranolactone should be combined with these diuretics. diuretics.

DIET: DIET: Salt restriction is important to reduce edema. Salt restriction is important to reduce edema.

Idli, idiyappam, rice puttu, sweet pongal, coconut Idli, idiyappam, rice puttu, sweet pongal, coconut rice, curd rice, lemon rice, beet-root, chappathi, rice, curd rice, lemon rice, beet-root, chappathi, dhall, sugar candy, boiled potato, carrot, cabbage, dhall, sugar candy, boiled potato, carrot, cabbage, tomato and onion are accepted. Start with salt free tomato and onion are accepted. Start with salt free diet in the presence of edema and then slowly add diet in the presence of edema and then slowly add salt. salt.

WATER: WATER: Along with salt restriction water restriction is Along with salt restriction water restriction is

necessary to prevent dilutional hyponatremia. In necessary to prevent dilutional hyponatremia. In mild edema intake is restricted to the urine output. mild edema intake is restricted to the urine output. In moderate edema intake is restricted to In moderate edema intake is restricted to insensible water loss. In massive edema fluid insensible water loss. In massive edema fluid intake is restricted to milk only equivalent to intake is restricted to milk only equivalent to insensible water loss. insensible water loss.

POTASSIUM: POTASSIUM:

Serum potassium abnormalities are infrequent in NS Serum potassium abnormalities are infrequent in NS without renal failure. without renal failure.

Hypokalemia is the consequence of indiscriminate Hypokalemia is the consequence of indiscriminate diuretics. diuretics.

Add oral potassium in the presence of excessive Add oral potassium in the presence of excessive tiredness or muscle weakness. tiredness or muscle weakness.

Periodic serum potassium level estimation will be Periodic serum potassium level estimation will be useful. useful.

PROTEIN: PROTEIN: Normal protein diet is advised. In case of malnutrition Normal protein diet is advised. In case of malnutrition increased protein is recommended. increased protein is recommended.

CALORIES: CALORIES: In the acute phase of Nephrotic Syndrome nutritional In the acute phase of Nephrotic Syndrome nutritional intake is reduced. In malnutrition caloric intake is reduced. In malnutrition caloric supplementation is necessary.supplementation is necessary.

LIPID: LIPID: HDL levels are elevated in MCNS. Abnormal HDL levels are elevated in MCNS. Abnormal

coagulability and glomerulus recrosis are consequence of lipid coagulability and glomerulus recrosis are consequence of lipid abnormalities. Weight control is essential. Diet should abnormalities. Weight control is essential. Diet should contain cholesterol less than 250 mg/day. contain cholesterol less than 250 mg/day.

CALCIUM: CALCIUM: Secondary to hypoalbuminemia there is low ionic Secondary to hypoalbuminemia there is low ionic

calcium, which is responsible for cramps and tetany. Hence calcium, which is responsible for cramps and tetany. Hence calcium intake of 800 mg/day either by diet or tablet with calcium intake of 800 mg/day either by diet or tablet with Vit.D is necessary. Vit.D is necessary.

IRON & ZINC: IRON & ZINC: Iron supplementation is necessary in microcytic Iron supplementation is necessary in microcytic

hypochromic anaemia. Rarely Zinc may be needed in the hypochromic anaemia. Rarely Zinc may be needed in the presence of deficiency symptoms. presence of deficiency symptoms.

Glucocorticoid has some influence on glomerular Glucocorticoid has some influence on glomerular permeability. It blocks the action of migratory inhibiting permeability. It blocks the action of migratory inhibiting factor (MIF) and chemotactic factor, inhibits the endothelial factor (MIF) and chemotactic factor, inhibits the endothelial adherence of macrophages and leukocytes, blocks the adherence of macrophages and leukocytes, blocks the antigen processing function of macrophage, stabilizes antigen processing function of macrophage, stabilizes lysosomal membrane and prevents the increase in capillary lysosomal membrane and prevents the increase in capillary permeability and diapedesis. permeability and diapedesis.

INITIAL THERAPYINITIAL THERAPY Prednisolone 2 mg/kg as a single or divided doses for Prednisolone 2 mg/kg as a single or divided doses for

4 weeks then give 2mg/kg as single dose in the morning on 4 weeks then give 2mg/kg as single dose in the morning on alternate days for the next 4 weeks. Then taper prednisolone alternate days for the next 4 weeks. Then taper prednisolone by 10mgm every 2 weeks. If there Is persistent proteinuria by 10mgm every 2 weeks. If there Is persistent proteinuria even after four weeks of daily therapy of steroid, continue even after four weeks of daily therapy of steroid, continue the same dose for the next 4 weeks. If there is no remission the same dose for the next 4 weeks. If there is no remission even after 8 weeks of full dose of steroids, then lable the even after 8 weeks of full dose of steroids, then lable the child as steroid resistant. In this type of cases steroids should child as steroid resistant. In this type of cases steroids should be tapered to 0.5 mg/kg. Simultaneously add be tapered to 0.5 mg/kg. Simultaneously add cyclophosphamide in a dose of 2 mg/kg/day. Care should be cyclophosphamide in a dose of 2 mg/kg/day. Care should be taken to have weekly W.B.C. count. taken to have weekly W.B.C. count.

In case of steroid response but when there is frequent In case of steroid response but when there is frequent relapse prednisolone is to be given as 2 mg/kg for 4 weeks relapse prednisolone is to be given as 2 mg/kg for 4 weeks and then as a single dose in the morning on alternate day for and then as a single dose in the morning on alternate day for 4 weeks. After 8 weeks of steroid therapy, it should be 4 weeks. After 8 weeks of steroid therapy, it should be tapered but slowly so that the entire course lasts for 6 tapered but slowly so that the entire course lasts for 6 months. When the child is resistant to Predinosolone and months. When the child is resistant to Predinosolone and Cyclophosphamise, Chlorambucil, 2-3 mg/kg is given for 10 Cyclophosphamise, Chlorambucil, 2-3 mg/kg is given for 10 weeks. weeks.

COMPLICATIONS OFCOMPLICATIONS OF DRUGSDRUGSA. Steroids:A. Steroids:

Pseudo tumor cerebriPseudo tumor cerebriCataractCataractCushingoid faciesCushingoid faciesUnmasking of tuberculous focusUnmasking of tuberculous focusPeptic ulcerPeptic ulcerDiabetes mellitusDiabetes mellitusHypertensionHypertensionAseptic necrosis of femoral headAseptic necrosis of femoral head

B. Frusemide: B. Frusemide: HypokalemiaHypokalemiaHyponatremiaHyponatremiaHyperuricemiaHyperuricemiaHypercalciuriaHypercalciuriaHypocalcemiaHypocalcemiaHypovolemiaHypovolemiaTinnitusTinnitusDeafness - permanentDeafness - permanent

- temporary - temporary Acute interstitial nephritisAcute interstitial nephritis

C. Cyclophosphamide:C. Cyclophosphamide: Haemorrhagic Cystitis, Bone marrow Haemorrhagic Cystitis, Bone marrow depression, Alopecia. depression, Alopecia.