Case discussionCase discussionExtern Theerawat NaksanguanExtern Theerawat Naksanguan

Case Case Patient profile: Patient profile: หญิ�งไทยโสดอาย หญิ�งไทยโสดอาย 46 46 ปี�ปี�Chief complaint: Chief complaint: ขา ขา 22 ข�างบวมมากข��นมา ข�างบวมมากข��นมา 1wk1wk

Present illness: Present illness:

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Case Case

►Past history : Past history : underlying DM 20 yr : Mixtard 30-0-20underlying DM 20 yr : Mixtard 30-0-20 HT : amlodipine 1x1, Enarapril 1x1, HT : amlodipine 1x1, Enarapril 1x1,

Propanolol 1x1 Propanolol 1x1 CRFCRF?? CataractCataract ปีฏิ�เสธปีระว%ตั�ด�'มส รา ปีฏิ�เสธปีระว%ตั�ด�'มส รา ,,การใช้�ยาหม�อยาล3กกลอน การใช้�ยาหม�อยาล3กกลอน

►Family history : Family history : ปีฏิ�เสธโรคทางกรรมพ%นธ )ปีฏิ�เสธโรคทางกรรมพ%นธ )►Drug allergy : -Drug allergy : -

Physical examinationPhysical examination

►Vital signs : Temp 37, BP 160/110 ,PR Vital signs : Temp 37, BP 160/110 ,PR 80 RR 2080 RR 20

►GA : a woman , mild pale ,no GA : a woman , mild pale ,no jaundice,no dyspneajaundice,no dyspnea

►HEENT :HEENT : Puffy face and ,not pale Puffy face and ,not pale conjuctivae , anicteric sclerae, JVP not conjuctivae , anicteric sclerae, JVP not engorged ,parotid gland not enlargeengorged ,parotid gland not enlarge , , no malar rash , no oral ulcer ,no malar rash , no oral ulcer ,

► LN. : can’t palpableLN. : can’t palpable► Skin : no petechiae , no ecchymosisSkin : no petechiae , no ecchymosis► Chest & Lung : Clear,equal breath sound ,no Chest & Lung : Clear,equal breath sound ,no

adventitious soundadventitious sound► Abdomen : soft not tender , no Abdomen : soft not tender , no

hepatosplenomegaly ,bimanual palpation –vehepatosplenomegaly ,bimanual palpation –ve► Extremities : Pitting edema 4+ ,no joint Extremities : Pitting edema 4+ ,no joint

swellingswelling► Neuro : grossly intactNeuro : grossly intact

Investigation Investigation

► CBC ; CBC ; Hb 8.47 Hct 25.6 WBC 7360 ; N91, L3.51Hb 8.47 Hct 25.6 WBC 7360 ; N91, L3.51 Plt 194000Plt 194000

► Electrolyte BUN/Cr ;Electrolyte BUN/Cr ; Na 142.6 ,K 4.41 ,Cl 109.3 ,CO2 27Na 142.6 ,K 4.41 ,Cl 109.3 ,CO2 27 BUN/Cr 71/2.0BUN/Cr 71/2.0 Blood glucose 220Blood glucose 220

► LFTs ;LFTs ; TP 5.3 , Glob 3.1 , Alb 2.2 , Chol 581TP 5.3 , Glob 3.1 , Alb 2.2 , Chol 581 Tbil 0.4, Dbil 0.1, AST/ALT 26/61 ,ALP 78Tbil 0.4, Dbil 0.1, AST/ALT 26/61 ,ALP 78

►UA : Sp.gr 1.015 , protein 3+ ,Sugar UA : Sp.gr 1.015 , protein 3+ ,Sugar 2+ WBC 0-1,RBC 0-1 , 2+ WBC 0-1,RBC 0-1 ,

►Urine protein 24 hr ; 9,492 mgUrine protein 24 hr ; 9,492 mg►VDRL = Non reactVDRL = Non react►ANA = +ve homogenous patternANA = +ve homogenous pattern►LE cell = negativeLE cell = negative

Pertinent findingsPertinent findings

►Generalized EdemaGeneralized Edema►HyperalbuminuriaHyperalbuminuria►HypoalbuminemiaHypoalbuminemia►HypercholesterolemiaHypercholesterolemia►Underlying DM HTUnderlying DM HT

Problem listProblem list

► Nephrotic syndrome DDx Lupus Nephrotic syndrome DDx Lupus nephritisnephritis

EdemaEdema► Definition ; Definition ;

increase volume of interstitial fluidincrease volume of interstitial fluid► Etiology ;Etiology ;

Localized edemaLocalized edema► Venous / lymphatic obstructionVenous / lymphatic obstruction

Generalized edemaGeneralized edema► CHFCHF► Pericardial diseasePericardial disease

Chronic constrictive pericarditisChronic constrictive pericarditis Pericarditis with effusionPericarditis with effusion

► Liver diseaseLiver disease► Hypoalbuminemic statesHypoalbuminemic states

Nephrotic syndromeNephrotic syndrome Protein-losing enteropathyProtein-losing enteropathy Malnutrition Malnutrition

Nephrotic SyndromeNephrotic Syndrome

►Characterized by Characterized by Heavy proteinuria (>3.5g/day)Heavy proteinuria (>3.5g/day) Hypoalbuminemia (<2.5g/dl)Hypoalbuminemia (<2.5g/dl) Generalized Edema Generalized Edema Hypercholesterolemia (>250mg/dl)Hypercholesterolemia (>250mg/dl) Normal renal functionNormal renal function

Secondary Nephrotic Secondary Nephrotic syndromesyndrome

► Postinfectious etiologies Postinfectious etiologies ► Collagen vascular disease (eg, systemic Collagen vascular disease (eg, systemic

lupus erythematosus [lupus erythematosus [SLESLE], rheumatoid ], rheumatoid arthritis, polyarteritis nodosa) arthritis, polyarteritis nodosa)

► Henoch-Schönlein purpura Henoch-Schönlein purpura ► Hereditary nephritis Hereditary nephritis ► Sickle cell disease Sickle cell disease ► Diabetes mellitus Diabetes mellitus

► Amyloidosis Amyloidosis ► Malignancy (eg, leukemia, lymphoma, Wilms Malignancy (eg, leukemia, lymphoma, Wilms

tumor, pheochromocytoma) tumor, pheochromocytoma) ► Toxins (eg, bee sting, poison ivy and oak, Toxins (eg, bee sting, poison ivy and oak,

snake venom) snake venom) ► Medications (eg, probenecid, fenoprofen, Medications (eg, probenecid, fenoprofen,

captopril, lithium, warfarin, penicillamine, captopril, lithium, warfarin, penicillamine, mercury, gold, trimethadione, mercury, gold, trimethadione, paramethadione) paramethadione)

► Heroin useHeroin use

Secondary Nephrotic Secondary Nephrotic syndromesyndrome

Post infectious causePost infectious cause

►Group A beta-hemolytic streptococci Group A beta-hemolytic streptococci ►Syphilis Syphilis ►Malaria Malaria ►Tuberculosis Tuberculosis ►Viral infections (eg, varicella, hepatitis Viral infections (eg, varicella, hepatitis

B, HIV type 1, infectious B, HIV type 1, infectious mononucleosis)mononucleosis)

Primary nephrotic syndromePrimary nephrotic syndrome

Histologic classificationHistologic classification► Focal segmental glomerulosclerosis*Focal segmental glomerulosclerosis*► Membranous nephropathyMembranous nephropathy► Minimal change diseaseMinimal change disease► Membranoproliferative glomerulonephritis*Membranoproliferative glomerulonephritis*► Fibrillary-immunotactoid glomerulopathyFibrillary-immunotactoid glomerulopathy► Mesangial proliferative GN(IgM Mesangial proliferative GN(IgM

nephropathy)*nephropathy)*► IgA nephropathy IgA nephropathy

Minimal steroid-responsed*

PathophysiologyPathophysiology

►concentration of heparan sulfate concentration of heparan sulfate mucopolysaccharide in the basement mucopolysaccharide in the basement membrane is lowermembrane is lower

►protein cross the barrier are excreted. protein cross the barrier are excreted. ►High glomerular permeability High glomerular permeability

hyperalbuminuria hyperalbuminuria hypoalbuminemia. hypoalbuminemia. greater transcapillary filtration of water greater transcapillary filtration of water

and the development of edema. and the development of edema.

Structural change lead to proteinuriaStructural change lead to proteinuria►endothelial surface damage, causing endothelial surface damage, causing

loss of the negative chargeloss of the negative charge►glomerular basement membrane glomerular basement membrane

damage and damage and ►effacement of the foot processeseffacement of the foot processes

►Recently, congenital nephrotic Recently, congenital nephrotic syndrome of the Finnish type has been syndrome of the Finnish type has been determined to be caused by mutations determined to be caused by mutations in the gene known as in the gene known as NPHS1.NPHS1. This This gene codes for a cell adhesion protein gene codes for a cell adhesion protein called nephrin, which is synthesized by called nephrin, which is synthesized by podocytes. podocytes.

Pathophysiology Pathophysiology

► Urinary Ig losses lower the patient's Urinary Ig losses lower the patient's resistance to infections and increase the risk resistance to infections and increase the risk of serious sepsis and peritonitis. of serious sepsis and peritonitis.

► The loss of antithrombin III and plasminogen The loss of antithrombin III and plasminogen via urine and the simultaneous increase in via urine and the simultaneous increase in clotting factors, especially factors I, VII, VIII, clotting factors, especially factors I, VII, VIII, and X, increases the risk for arterial and X, increases the risk for arterial thrombosis, venous thrombosis, and thrombosis, venous thrombosis, and pulmonary embolism, which occurs in 5% of pulmonary embolism, which occurs in 5% of children with nephrotic syndrome. children with nephrotic syndrome.

►vitamin D–binding protein and vitamin D–binding protein and complexes excretion leading to complexes excretion leading to (1) malabsorption of calcium and (1) malabsorption of calcium and

development of bone disease (eg, osteitis development of bone disease (eg, osteitis fibrosa cystica) because of enhanced fibrosa cystica) because of enhanced parathyroid hormone production parathyroid hormone production

(2) osteomalacia because of impairment (2) osteomalacia because of impairment in mineralization. in mineralization.

Two pathogenic processes are Two pathogenic processes are operative, including operative, including

(1) hypoproteinemia stimulating (1) hypoproteinemia stimulating generalized protein synthesis in the generalized protein synthesis in the liver, including the lipoproteins liver, including the lipoproteins

(2) diminution of lipid catabolism (2) diminution of lipid catabolism caused by reduced plasma levels of caused by reduced plasma levels of lipoprotein lipase.lipoprotein lipase.

► In adults, the most common form of In adults, the most common form of glomerulopathy glomerulopathy membranous glomerulonephritis, membranous glomerulonephritis, FSGS. FSGS. diabetic nephropathy is emerging as a diabetic nephropathy is emerging as a

major cause of nephrotic syndrome. major cause of nephrotic syndrome.

Signs and symptoms Signs and symptoms ►Facial swelling or anasarca Facial swelling or anasarca ►Edema of dependent parts ; ankles or Edema of dependent parts ; ankles or

legs.legs.►A hypercoagulable state leading to A hypercoagulable state leading to

thrombotic complications thrombotic complications ► lethargy, poor appetite, weakness, lethargy, poor appetite, weakness,

and occasional abdominal pain.and occasional abdominal pain.

►A quantitative estimation of 24-hour urine A quantitative estimation of 24-hour urine protein excretion is the standard method protein excretion is the standard method (>3.5 g/day)(>3.5 g/day)

Nephrotic levels of proteinuria are Nephrotic levels of proteinuria are associated with a ratio of urinary protein associated with a ratio of urinary protein to urinary creatinine of greater than 2to urinary creatinine of greater than 2

►Blood: serum creatinine, urea nitrogen, Blood: serum creatinine, urea nitrogen, serum albumin, and serum lipids. serum albumin, and serum lipids.

►Other tests: In adult's, testing Other tests: In adult's, testing cryoglobulins and performing serum cryoglobulins and performing serum protein electrophoresis or urine protein electrophoresis or urine protein electrophoresis can be useful protein electrophoresis can be useful for detecting the etiology of nephrotic for detecting the etiology of nephrotic syndrome.syndrome.

Others tests (secondary Others tests (secondary causes)causes)

►DM ; HbA1c , retinopathyDM ; HbA1c , retinopathy►SLE ; ANA , anti-dsDNA ,Anti-SLE ; ANA , anti-dsDNA ,Anti-

Sm ,others..Sm ,others..►Post infectious process ; Complement , Post infectious process ; Complement ,

HBV,HCV,HIV,HBV,HCV,HIV,

Renal biopsy Renal biopsy

► Indicated in the following Indicated in the following circumstances:circumstances: Congenital nephrotic syndromeCongenital nephrotic syndrome Children older than 8 years at onsetChildren older than 8 years at onset Steroid resistanceSteroid resistance Frequent relapses or steroid dependencyFrequent relapses or steroid dependency Significant chronic nephritic Significant chronic nephritic

manifestationsmanifestations

Adult nephrotic syndrome: Note that a Adult nephrotic syndrome: Note that a renal biopsy is not indicated in adults renal biopsy is not indicated in adults when the nephrotic syndrome is due to an when the nephrotic syndrome is due to an obvious cause such as diabetes mellitus, obvious cause such as diabetes mellitus, ie, when the patient has other diabetes-ie, when the patient has other diabetes-related overt complications.related overt complications.

Renal biopsy Renal biopsy

Medical CareMedical Care

Acute managementAcute management Hospitalization should be considered if a Hospitalization should be considered if a

patient has generalized edema severe patient has generalized edema severe enough to cause respiratory distress enough to cause respiratory distress

An effective regimen is to give salt-poor An effective regimen is to give salt-poor albumin at 1 g/kg, followed by albumin at 1 g/kg, followed by intravenous furosemide intravenous furosemide

A cornerstone of treatment of nephrotic A cornerstone of treatment of nephrotic syndrome in adults is ACE inhibitors syndrome in adults is ACE inhibitors and/or adrenergic receptor binders. and/or adrenergic receptor binders.

►MedicationMedication Prednisone (Deltasone, Orasone, Prednisone (Deltasone, Orasone,

Meticorten, Sterapred) Meticorten, Sterapred) ►60 mg/m2/d PO, titrate to a maximum 80 60 mg/m2/d PO, titrate to a maximum 80

mg/m2/d until remission; then, 40 mg/m2/d, mg/m2/d until remission; then, 40 mg/m2/d, titrate to 60 mg/m2 qod for 4 wk titrate to 60 mg/m2 qod for 4 wk

ImmunomodulatorsImmunomodulators ►Cyclophosphamide (Cytoxan) Cyclophosphamide (Cytoxan)

40-50 mg/kg IV in 1 divided dose over 3 d 40-50 mg/kg IV in 1 divided dose over 3 d ►Cyclosporine (Sandimmune) Cyclosporine (Sandimmune)

5-15 mg/kg PO qd or divided bid; IV dose is one 5-15 mg/kg PO qd or divided bid; IV dose is one third total oral dose via infusion over 6 h third total oral dose via infusion over 6 h

Medical treatmentMedical treatment

►Prednisolone 60 mg/m2/d PO Prednisolone 60 mg/m2/d PO (2mg/kg/day) divide tid x 4-6 Wks(2mg/kg/day) divide tid x 4-6 Wks

►Then taper off by once daily day-Then taper off by once daily day-another day x 4-6 Wksanother day x 4-6 Wks

► If not response (persistent edema If not response (persistent edema proteinuria 2+) called “Steroid proteinuria 2+) called “Steroid resistant” that need Renal biopsy resistant” that need Renal biopsy

► In frequent relapser, steroid dependent In frequent relapser, steroid dependent may be immunosuppressant is indicated may be immunosuppressant is indicated

General managementGeneral management

► The diet should provide adequate energy The diet should provide adequate energy (caloric) intake and adequate protein (1-2 (caloric) intake and adequate protein (1-2 g/kg/d).g/kg/d).

► A diet with no added salt is advised if the A diet with no added salt is advised if the patient is edematous.patient is edematous.

► Management of hyperlipidemia is Management of hyperlipidemia is controversial and could be of some controversial and could be of some importance if the nephrotic state is prolonged.importance if the nephrotic state is prolonged.

► Fluid restriction is not usually required unless Fluid restriction is not usually required unless the edema is severe.the edema is severe.

ComplicationsComplications

1.Infection (major complication) 1.Infection (major complication) susceptibility to susceptibility to Streptococcus pneumoniaeStreptococcus pneumoniae Haemophilus influenzae Haemophilus influenzae Escherichia coli,Escherichia coli, other Gram -ve other Gram -ve Varicella infection Varicella infection

-bacterial sepsis-cellulitis, -pneumonia - peritonitis

Factors precipitateFactors precipitate

-Decreased immunoglobulin levels -Decreased immunoglobulin levels -Edema fluid acting as a culture -Edema fluid acting as a culture

medium medium -Protein deficiency-Protein deficiency -Decreased bactericidal activity of the -Decreased bactericidal activity of the

leukocytesleukocytes -Immunosuppressive therapy-Immunosuppressive therapy

-Decreased perfusion of the spleen -Decreased perfusion of the spleen caused by hypovolemiacaused by hypovolemia

-Urinary loss of a complement factor -Urinary loss of a complement factor (properdin factor B) opsonizes certain (properdin factor B) opsonizes certain bacteriabacteria

Factors precipitateFactors precipitate

2. Thromboembolism2. Thromboembolism

MN>FSGS >diabetic glomerulopathyMN>FSGS >diabetic glomerulopathy

►The factors includeThe factors include Thrombocytosis ; plt aggregation Thrombocytosis ; plt aggregation Antithrombin III, Protein C ,S decrease Antithrombin III, Protein C ,S decrease Procoagulant factor(fibrinogen ,factor VII) Procoagulant factor(fibrinogen ,factor VII)

increaseincrease

-Renal vein thrombosis -Pulmonary embolism

ComplicationsComplications

3. Hypovolemia 3. Hypovolemia (hypoalbuminemia<1.5 (hypoalbuminemia<1.5 g/dL) g/dL) Symptoms and Signs : Symptoms and Signs :

Vomiting Vomiting Abdominal pain Abdominal pain DiarrheaDiarrhea Cold hands and feetCold hands and feet Delayed capillary filling Delayed capillary filling Oliguria Oliguria Tachycardia ,HypotensionTachycardia ,Hypotension

ComplicationsComplications

4. Acute renal failure4. Acute renal failure Factors Factors

GN GN Hypovolemia Hypovolemia Sepsis Sepsis Edema of the kidneys Edema of the kidneys pressure- pressure-

mediated reduction in the GFRmediated reduction in the GFR

ComplicationsComplications

Hypertension Hypertension

-Acute nephritis -Acute nephritis

-Hyperreninemic state of nephrotic -Hyperreninemic state of nephrotic syndrome induced by hypovolemia and syndrome induced by hypovolemia and reduced perfusion of the kidneysreduced perfusion of the kidneys

ComplicationsComplications

OthersOthers►Tetany (hypocalcemia)Tetany (hypocalcemia)►Adverse effects of treatment Adverse effects of treatment

Corticosteroids and other Corticosteroids and other immunosuppressive drugs (eg, immunosuppressive drugs (eg, cyclophosphamide, levamisole, cyclophosphamide, levamisole, cyclosporin)cyclosporin)