Nephrotic Syndrome

Nephrotic Syndrome(NS) （肾病综合征） Department of pediatrics The third affiliated hospital of zhengzhou university 郑大三附院 儿科 杜开先 Email: [email protected] Telephone: 66903476

Purpose and requirement 1.To understand classification, path-physiology and pathogenesis of nephrotic syndrome 2.To master the differential diagnosis between the simple nephrotic syndrome and nephritic type NS

Purpose and requirement 3. To understand the complication of nephrotic syndrome 4. To master the principle of treatment and how to treatment nephrotic syndrome with corticosteroid and other immunosuppressive drugs

Teaching emphases 1. How to differentiate AGN from Primary nephrotic syndrome, 2. The differential diagnosis between the simple and nephritic NS 3. The manifestations and treatment of NS 4. How to treat nephrotic syndrome with corticosteroid

Introduction(1) 1.Nephrotic syndrome (NS) or Nephrosis is a condition that is often caused by any of a group of diseases that damage the kidneys filtering system, the glomeruli. The condition lead to hypoalbuminemia (low level of albumin in the blood) ,Edema (swelling)and Hypercholesterolemia (high level of cholesterol in the blood) .

Introduction(2) 2. An increased glomerular permeability resulting in proteinuria is the primary renal abnormality in NS 3. It is a common disease among chinese children and more in boys than in girls (2-4:1).Mean age at onset is 2 to 7 yr average at 2.5years of age.

Etiology NS can be divided into three groups: Primary (Idiopathic): 85 ~ 90%,associate with immune disorder, but unclear. Secondary: 10 ~ 15%,due to infections,drugs or toxins, autoimmunous diseases , tomors. Infantile (congenital ): rare

Pathology Most (90%)children with primary nephrotic syndrome have some form of idiopathic nephrotic syndrome: 1.Minimal-change diseases (MCD): 85% the glomeruli appear normal. the epithelial cell foot processes fused. More than 95% of children with MCD, and better responding to corticosteriod therapy.

Minimal-change disease: the glomeruli appear normal. the epithelial cell foot processes fused

Pathology 2. Focal segmental glomerulosclerosis (FSGS): 10%,sclerosis and hyalinosis involving a portion of glomerular tuft, even only of the glomeruli, accompanied tubular atrophy. IgM and C3(complement) within sclerotic areas.

Focal segmental glomerulo-sclerosis

Pathology 3. membranoproliferative glomerulonephritis (MPGN):  5% diffuse proliferation of mesangial cells and matrix, electronic density deposits and C3 desposit in mesangial and GBM.

系膜增生性肾小球肾炎 (HE× 400) membranoproliferative glomerulonephritis

Pathology 4. Membranous Glomerulonephritis (MGN): rare GBM (glomerular basement membranes) thicker, IgG and C3 deposits.

Pathophysiology(1) 1.Proteinuria: The underlying pathogenetic abnormality in NS is proteinuria, which increase in glomerular capillary wall permeability. Underlying defect is thought to be caused by the loss of charge selectivity of the glomerular basement membrane, which permits negatively charged proteins, primarily albumin to pass easily through the capillary walls into the urine.

Pathophysiology(2) 2.Hypoalbuminemia Excessive urinary loss of protein and catabolism by the kidney of circulating albumin leads to a decrease in serum protein . Hypoproteinemia is fundamentally a “hypoabluminemia”.

Pathophysiology(3) 3. Edema (1) The colloidal osmotic pressure is reduced because of the amount of serum albumin. (2) The renin-angiotensin system and the secretion of antidiuretic hormone and aldosterone is increased

Pathophysiology(4) 4. Hyperlipidemia (1).The hypoproteinemia stimulates generalized protein synthesis in the liver including the lipoproteins; (2). Lipid catabolism is diminished, pertaining to reduced plasma levels of lipoprotein lipase.

Sequence of Events in Nephrotic Syndrome Pathophysiology Glomerular injury

Clinical Manifestations

Increased permeability of glomerular basement membrane

Heavy Proteinuria Microhematuria(occasional)

Albuminurin

Decreased serum albumin Decreased plasma oncotic pressure Decreased peripheral capillary return

Increased renal Na reabsorbption

Increased interstitial fluid

Hypoproteinemia Hypercholestrolemia Urinary sodium Edema(Periorbital, peripheral, ascites)

Clinical manifestations(1) 1. Onset is insidious. 2. Edema is often the presenting symptom. Edema may be minimal or massive, and is usually first apparent around the eyes. Depressed edema may occurs in areas of the body, such as the hands, ankles, feet, and genitalia. Severe edema may give rise to ascites and/or pleural effusions.

Anasarca of NS

Ascites of NS

Depressed edema of NS

Severe swelling of the ankles in nephrotic syndrome

Clinical manifestations(2) 3. Decreased urine output 4. General condition: pallor, irritability, lethargy, fatigue. 5. Gastrointestinal disturbances: Vomiting, diarrhea, anorexia.

Clinical Manifestations (summary) Four character of clinical manifestations •Heavy Proteinuria ： urine protein +++ ~ ++++, 24 hrs urine protein is more than 0.1g/kg. •Hypoalbuminaemia: (low level of albumin in the blood) albumin concentration less than 30 g/L ; •Hypercholestrolemia: due to hypoalbuminaemia, but detail is not clear. •Severe Edema : Edema usually begin around eyes and face, severe in morning and decrease in afternoon.With the developing of the edema, ankles swelling, swelling foot, swollen abdomen might occur. even entire body swelling.

Laboratory tests(1) 1.Urinalysis Protein ﹢﹢﹢or greater, 24 hour urine protein: frequently greater than 0.05-0.1g/kg per day; Hematuria: absent or transient.

Laboratory tests(2) 2.Blood Examination Total protein: decreased Albumin: less than 3g/dl; Cholesterol: greater than 5.7mmol/L Erythrocyte sedimentation rate (ESR): accelerated C3 normal Different level of azotemia

Laboratory tests(3) 3. Renal Biopsy Renal biopsy is indicated if patient is steroid resistant (has failed to achieve remission after 28 days of steroid therapy) or relapse and frequently relapse or nephritic Type NS

Diagnosis Have the following condition (1) Massive Proteinuria UP≥ +++ ； or 〉 50mg/kg/d (2) Hypoproteinemia Albumin: less than 30g/L (3) Edema (4) Hyperlipemia Cholesterol ＞ 5.7mmol/L

Differential diagnosis 1. Simple NS and Nephritic NS 2. Acute Glomerulonephritis and Nephrotic Syndrome

1.Simple NS and Nephritic NS Simple NS Pathol clinic

MCD Depressed edema Massive proteinuria Hypoalbuminemia Hyperlipemia

Nephritic NS non-MCD simple NS plus: ① Persistent hematuria ， RBC>10/HP ② Azotemia ③ Hypertension ④ persistent low complement

2.Acute Glomerulonephritis and Nephrotic Syndrome Assessment Factors Cause

AGN Immune reaction to

NS Idiopathic; possibly

group A beta hemolytic

a hypersensitivity

streptococcal infection

reaction

Onset

Abrupt

Insidious

Hematuria

Profuse

Rare

Edema

Mild

Extreme

Hypertension

Marked

Mild

Hyperlipemia

Rare or Mild

Marked

5-10 year

2-3 year

Peak Age Incident

Acute Glomerulonephritis and Nephrotic Syndrome Interventions

Bed rest for

Administration

3-4 weeks,

of prednisone,

Antihypertensives

Possibly diuretic

as needs;

supplements

Symptomatic therapy for congestive heart fature Diet

Normal for age

Prevention

Prevention or thorough treatment or group A beta streptococcal infections

High-protein, low-salt None known

Complication(1) 1.Infections major complication reason: ① Decreased immunoglobulin levels

② The edema fluid acting as a culture medium

③ Decreased bactericidal activity of the leukocytes ④ Immunosuppressive therapy

Complication(2) Common sits infections: Respiratory tract Pneumonia Sepsis Cellulitis Urinary tract infection (UTI) Primary peritonitis

Complication(3) 2.Hypercoagulation and Thrombosis Reason: (1) Elevated plasma levels of certain coagulation factors (2) Inhibitors of fibrinolysis (3) Decreased plasma level of anti-thrombin Ⅲ (4) Elevated viscosity due to hyperlipemia (5) Increased platelet aggregation

Complication(4) 3. Acute Renal Failure Manifestation: Oliguria (urine output less than 0.5-1ml/kg/hr), hematuria, headache, edema, severe hypertension, lethargy, nausea and vomiting

Complication(5) 4. Electrolyte Imbalance The long-term use of diuretics, steroids and diet limits can result in electrolyts imbalance, including hypokalemia, hyponatremia, hypocalcemia. 5. Development Retardation

Complications (summary) Hypovolemic shock (shock due to low blood volume):usually occur after diuresis, Electrolyte disturbance : results from salt-free foods,diuresis,diarrhea . Acute renal failure (ARF): majority associate with low blood volume. Infections :respiratory infections,skin infections, peritonitis.

Complications (summary) Thrombosis(Blood clot occurring in a blood vessel) : Blood abnormally overclots due to thick blood, hypercholestrolemia . It is easy to develop a blood clot in the legs and renal veins. Development Retardation

Therapy 1. general therapy (1) Rest No restrictions are placed on the activity, but some limitations are advisable because of infection.

Therapy (2) Diet .The diet should provide high quality of protein ,low in fat , adequate carbon -hydrate ,high vitamins , easy to digest A diet with no added salt is advised if the patient is edematous. Fluid restriction is not usually required unless the edema is severe

Therapy (3) Antibiotics Antibodies can not be used for prevention, but for treatment . (4) Diuresis Hydrochlorothiazide Spironolactone Furosemide Albumin

1-3mg/kg/d 1-2mg/kg/d 1-2mg/kg/d 0.5-1g/kg/d

Therapy

2. Corticosteroids:

Purpose: to stop the loss of protein in the urine (1) Short term 8W Prednisone 2mg/kg/d (maximum daily dose 60mg) divided into three doses over the day for 4w , After 4w changed to 1.5-2mg/kg/d taken every other day as a single dose with breakfast . Continues 4w later ---abrupt cease

(2) Middle 6-9M Prednisone 2mg/kg/d (maximum daily dose 60mg) divided into three doses over the day , If urine protein become negative within 4w; 2w after the urine become protein free prednisone is changed to 2mg/kg/d taken every other day as a single dose with breakfast, continued for 4w, later per 2-4w subtract 2.5-5mg until cessation Total duration :6 months

(3) Long term 9-12M Prednisone 2mg/kg/d divided into three doses over the day, If urine protein is not become negative within 4w;continued the doses until 2w after the urine become protein free (not over 8w ), prednisone is changed to 2mg/kg/d taken every other day as a single dose with breakfast, continued for 4w, later per 2-4w subtract 2.5-5mg until cessation Total duration : 9 months

Steroid response Prednisone 2mg/kg/d (Maxdosage:60mg/d) divided into three doses (1) Steroid sensitive : Achieving a remission within 28 days of the start of prednisone therapy for the initial presentation of NS

Steroid response (2) Steroid resistance : Failure to achive response inspite of 8 weeks of prednisone therapy at 60mg/m2 per day (3) Steroid dependent: two consecutive relapses, occuring during prednisone therapy, or within 14 days after its cessation

prednison treatment ： weight ） Urine protein is negative (steroid sensitive) 10mg t.i.d

30mg g.o.d

（ a sample of child of 15kg Short-time protocol stops here, but long-time protocol begins to reduce dose by 2.5 ~ 5mg/time every 2 ~4W.

weeks

Urine protein is positive(steroid 10mg 30mg unsensitive) t.i.d

q.o.d

weeks

Urine protein is still positive （ teroid 30mg resistance ） q.o.d

weeks

add immunosuppression ( CTX 2mg/kg/d)

Therapy 3. Immunosuppressive drugs should be done in Frequent relapses , teroid resistance, or steroid dependency. (1) Cyclophosphamide ( cytoxan ,CTX ) oral: 2mg/kg/d,divice to 3 times , 8 ~ 12 weeks; high dose: 10 ~ 12mg/kg/d + 5%Glucose 100 ~200ml, ivdrip, successive 2 days, every 2 weeks. (2) Cyclosporin A (CSA) 5mg/(kg.d)

Total duration: 3m-6m

Therapy 4. Anti-Coagulation: Heparin 1mg/kg/d ivgtt qd 2-4w Urokinase 30000-60000U/d ivgtt qd 1-2w Dipyridamole 5-10mg/kg/d tid po 6m

Therapy 5. ACEI (angiotensin converting enzyme inhibitors) Captopril 0.3-0.5mg/kg/d tid po Enalapril 0.08-0.1mg/kg/d bid po

Prognosis Most children with steroid-respond nephrosis have repeated relapses until the disease resolves spontaneously toward the end of the 2nd decade of life. It is important to indicate to the family that the child will have no residual renal dysfunction, that the disease is generally not hereditary, and that the child( in the absence of cyclophosphamide or chlorambucil therapy) will remain fertile.

Prognosis To minimize the psychologic effects of the nephrosis, it should be emphasized that when in remission the child is normal and may have unrestricted diet and activity. While a child is in remission, it is generally unnecessary to test the urine for protein.