NEPHROTIC SYNDROME -UG DISCUSSION

2 yr. old presents with puffiness of face. He has no hematuria.  His had uri 1 wk ago. his puffiness is more towards morning hours. Urine output is reduceded. No h/o liver disease or renal disease. No h/o suggestive of malnutrition

o/e  facial puffiness,b/l pedal edema bp nl, umbilicus stretched. No hsm   free fluid present . pleural effusion + ,other systems normal

what is edema?

Edema may be defined as the abnormal swelling of tissues from the accumulation of fluid in the extravascular space

What is the pathophysiology of edema?

The occurrence of edema in healthy individuals is usually prevented by the balance of oncotic and hydrostatic pressures between the intravascular and interstitial spaces, as well as the normal function of the lymphatic system. Any imbalance in this system may lead to increased interstitial fluid and resultant tissue swelling. Edema may occur as a result of decreased intravascular oncotic pressure, increased venous or lymphatic pressure, or from the loss of normal vascular permeability, as seen with vasculitis from an allergic or hypersensitivity reaction.

Tightly controlled serum levels of albumin and sodium maintain normal intravascular oncotic pressure. Hypoalbuminemia may arise from decreased production of proteins caused by hepatic disease, as a result of protein malnutrition or, more commonly from losses of protein through gastrointestinal (GI), renal, or dermal (e.g., burns) conditions. When the albumin level is less than 2.5 g/dL, the oncotic pressure in the vascular space is reduced enough for fluid to move freely into the soft tissues and, if not corrected, generalized edema may result.

When the intravascular albumin and sodium levels are within the normal range and vascular permeability is preserved, the formation of edema requires increased hydrostatic pressures to overcome the oncotic pressure, forcing fluid out of the vascular space. This can occur as a result of hypervolemia from cardiac failure, renal failure, salt retention, estrogen–progesterone excess, or renal tubular insensitivity to the natriuretic and diuretic actions of atrial natriuretic peptide

What are the causes of edema?

What are the common causes of edema?

How to evaluate generalized edema?

Generalized edema, with an otherwise normal exam, occurs most commonly in patients with renal disease, particularly nephrotic syndrome). Other forms of renal disease or vasculitis, including glomerulonephritis, hemolytic uremic syndrome, or Henoch-Schönlein purpura (HSP) may also be responsible.

In nephrotic syndrome 3+ or 4+ proteinuria,edema+, ascites or pleural effusion, normal bp,reduced serum proteins ,increased cholesterol, normal renal function and compliments are seen

In nephritis Tea- or cola-colored urine, facial or body edema, hypertension, and oliguria are classic symptoms of acute nephritic syndrome. Diseases commonly manifesting as acute nephritic syndrome include postinfectious glomerulonephritis.

In an infant or preschool child dietary history, h/o measles ,diarrhoea, h/o diluted weaning formula,irritable,apathetic child  may give clues to severe edematous malnutrition

A child with neonatal cholestasis or jaundice, failure thrive,gi bleeding,abdominal distension may be suffering from a liver disease. In an edematous patient with a normal cardiac exam and no proteinuria, further evaluation should include a search for hepatic and other GI diseases

what is your probable dx?

In view of generalized edema,normal bp,no hematuria,absent liver,cardiac or dietary problem ,this child has most probably a renal disease causing generalized edema. Of all renal disease causing generalized edema nepgrotic syndrome is the commonest

What is nephrotic syndrome?

Nephrotic syndrome, a manifestation of glomerular disease, is characterized by nephrotic range proteinuria and the triad of clinical findings associated with large urinary losses of protein: hypoalbuminemia, edema, and hyperlipidemia. Nephrotic range proteinuria is defined as protein excretion of > 40 mg/m²/hr or a first morning protein : creatinine ratio of >2 : 1

What is the aetiology?

Most children with nephrotic syndrome have a form of primary or idiopathic nephrotic syndrome. Glomerular lesions associated with idiopathic nephrotic syndrome include minimal change disease (the most common), focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, membranous nephropathy and diffuse mesangial proliferation. These etiologies have different age distributions

How do you define nephrotic syndrome?

Clinical syndrome de fi ned by (1) large proteinuria of 3 to 4+ by dipstick or Upc >2 g/g creatinine

(>0.2 g/mmol) or >40 mg/m 2 /h in a timed urine specimen, (2) hypoalbuminemia <25 g/l, and (3)

generalized edema

What is relapse?

Relapse =Urine albumin 3+ or 4+ (or proteinuria >40 mg/m 2 /h) for three consecutive days,

having been in remission previously

what is frequent relapse?

Two or more relapses during 6 months, or more than three relapses during any 12-month period

What is steroid dependence?

Two consecutive relapses during alternate-day prednisone therapy or within 14 days of its

Discontinuation

What is steroid resistant ns?

Persistent proteinuria (>2 g/g creatinine) despite high-dose prednisone therapy with 60 mg/m 2

(2 mg/kg) daily for 4 weeks, in the absence of infection or nonadherence to medication

What is the pathology?

In minimal change nephrotic syndrome (MCNS) (approximately 85% of total cases of nephrotic syndrome in children), the glomeruli appear normal or show a minimal increase in mesangial cells and matrix. Findings on immunofluorescence microscopy are typically negative, and electron microscopy simply reveals effacement of the epithelial cell foot processes. More than 95% of children with minimal change disease respond to corticosteroid therapy.

Mesangial proliferation is characterized by a diffuse increase in mesangial cells and matrix on light microscopy. Immunofluorescence microscopy might reveal trace to 1+ mesangial IgM and/or IgA staining.

In focal segmental glomerulosclerosis (FSGS), glomeruli show lesions that are both focal (present only in a proportion of glomeruli) and segmental (localized to ≥1 intraglomerular tufts). The lesions consist of mesangial cell proliferation and segmental scarring on light microscopy

What are the clinical manifestations?

The idiopathic nephrotic syndrome is more common in boys than in girls (2 : 1) and most commonly appears between the ages of 2 and 6 yr(. However, it has been reported as early as 6 mo of ageand throughout adulthood. MCNS is present in 85-90% of patients <6 yr of age.

In contrast, only 20-30% of adolescents who present forthe first time with nephrotic yndrome have MCNS. The more common cause of idiopathic nephrotic syndrome in this older age group is FSGS. The incidence of FSGS may be increasing; it may be morecommon in African-American, Hispanic, and Asian patients.

The initial episode of idiopathic nephrotic syndrome, as well as subsequent relapses, usually follows minor infections and, uncommonly,reactions to insect bites, beestings, or poison ivy.

Children usually present with mild edema, which is initially notedaround the eyes and in the lower extremities. Nephrotic syndrome caninitially be misdiagnosed as an allergic disorder because of the periorbitalswelling that decreases throughout the day. With time, the edema becomes generalized, with the development of ascites, pleural effusions,and genital edema. Anorexia, irritability, abdominal pain, anddiarrhea are common. Important features of minimal change idiopathic nephrotic syndrome are the absence of hypertension and gross hematuria (the so-called nephritic features).

The differential diagnosis of the child with marked edema includes protein-losing enteropathy, hepatic failure, heart failure, acute or chronicglomerulonephritis, and protein malnutrition.

A diagnosis other thanMCNS should be considered in children <1 yr of age, with a positive family history of nephrotic syndrome, and/or the presence of extrarenal findings (e.g., arthritis, rash, anemia), hypertension or pulmonary edema, acute or chronic renal insufficiency, and gross hematuria

How to confirm the diagnosis?

The diagnosis of nephrotic syndrome is confirmed by urinalysis with first morning urine protein : creatinine ratio and serum electrolytes,blood urea nitrogen, creatinine, albumin, and cholesterol levels; evaluation to rule out secondary forms of nephrotic syndrome (children ≥10yr): complement C3 level, antinuclear antibody, double-stranded DNA and hepatitides B and C, and HIV in high-risk populations; and kidneybiopsy (for children ≥12 yr, who are less likely to have MCNS).The urinalysis reveals 3+ or 4+ proteinuria, and microscopic hematuriais present in 20% of children. A spot urine protein : creatinineratio should be >2.0. The serum creatinine value is usually normal, butit may be abnormally elevated if there is diminished renal perfusionfrom contraction of the intravascular volume. The serum albumin levelis <2.5 g/dL, and serum cholesterol and triglyceride levels are elevated.Serum complement levels are normal. A renal biopsy is not routinelyperformed if the patient fits the standard clinical picture of MCNS

What is the treatment?

Nephrotic Syndrome

Corticosteroids are the mainstay of therapy for MCNS. The treatment guidelines for corticosteroid use presented below are adapted from and based on the 2012 Kidney Disease: Improving Global Outcomes

(KDIGO) clinical practice guidelines on glomerulonephritis.Treatment of Initial Episode of Nephrotic SyndromeIn children with presumed MCNS, prednisone or prednisolone should be administered as a single daily dose of 60 mg/m2/day or 2 mg/kg/dayto a maximum of 60 mg daily for -6 wk followed by alternate-day prednisone (starting at 40 mg/m2 qod or 1.5 mg/kg qod) for a period ranging from 8 wk to 5 mo, with apering of the dose. When planning the duration of steroid therapy, the side effects of prolonged corticosteroid administration must be kept in mind.Approximately 80-90% of children respond to steroid therapy.

Response is defined as the attainment of remission within theinitial 4 wk of corticosteroid therapy. Remission consists of a urineprotein : creatinine ratio of <0.2 or <1+ protein on urine dipstick for 3 consecutive days. The vast majority of children who respond to prednisone therapy do so within the first 5 wk of treatment.

How to manage complications of Nephrotic Syndrome?

Edema. Children with severe symptomatic edema, including large pleural effusions, ascites, or severe genital edema, should be hospitalized. In addition to sodium restriction (<1500 mg daily),water/fluid restriction may be necessary if the child is hyponatremic.A swollen scrotum may be elevated with pillows to enhance fluidremoval by gravity. Diuresis may be augmented by the administrationof loop diuretics (furosemide), orally or intravenously, although extreme caution should be exercised. Aggressive diuresis can lead tointravascular volume depletion and an increased risk for acute renalfailure and intravascular thrombosis.When a patient has severe generalized edema with evidence of intravascular volume depletion (e.g., hemoconcentration, hypotension,tachycardia), IV administration of 25% albumin (0.5-1.0 galbumin/kg) as a slow infusion followed by furosemide (1-2 mg/kg/dose IV) is sometimes necessary. Such therapy should be used only incollaboration with a pediatric nephrologist and mandates close monitoringof volume status, blood pressure, serum electrolyte balance,and renal function. Symptomatic volume overload, with hypertension,heart failure, and pulmonary edema, is a potential complication ofparenteral albumin therapy, particularly when administered as rapid infusions.

How will you manage Dyslipidemia?

Dyslipidemia should be managed with a low-fat diet. Dietary fat intake should be limited to <30% of calories withsaturated fat intake <10% calories. Dietary cholesterol intake shouldbe <300 mg/day.

There are insufficient data to recommend the use of 3-hydroxy-3-methylgluataryl coenzyme A (HMG-CoA) reductaseinhibitors routinely in children with dyslipidemia.

How will you treat infections?

Families of children with nephrotic syndrome should be counseled regarding the signs and symptoms of infections such as cellulitis, peritonitis, and bacteremia. If there is suspicion of infection,a blood culture should be drawn prior to starting empiric antibiotic therapy. In the case of spontaneous bacterial peritonitis(abdominal pain diarrhea low bp), peritoneal fluid should be collected if there is sufficient fluid to perform a paracentesis and sent for cell count, Gram stain, and culture. The antibiotic provided must be of broad enough coverage to include Pneumococcusa nd Gram-negative bacteria. A 3rd-generation cephalosporin is a common choice of IV antibiotic.

How to treat Thromboembolism?

 Children who present with the clinical signs of thromboembolism should be evaluated by appropriate imagingstudies to confirm the presence of a clot. Studies to delineate a specificunderlying hypercoagulable state are recommended. Anticoagulationtherapy in children with thrombotic events appears to be effective—heparin, low-molecular-weight heparin, and warfarin are therapeuticoptions.

How to tackle Obesity and Growth disturbance?

Glucocorticoids may increase the body mass index in children who are overweight when steroid therapy isinitiated, and these children are more likely to remain overweight. Anticipatory dietary counseling is recommended. Growth may be affected in children who require long-erm corticosteroid therapy.Steroid-sparing strategies may improve linear growth in children who require prolonged courses of steroids.

How to treat Relapse of Nephrotic Syndrome?

Relapse of nephrotic syndrome is defined as a urine protein : creatinine ratio of >2 or ≥3+protein on urine dipstick testing for 3 consecutive days. Relapses arecommon, especially in younger children, and are often triggered by upper respiratory or gastrointestinal infections. Relapses are usuallytreated in a manner similar to the initial episode, except that dailyprednisone courses are shortened. Daily high-dose prednisone is given until the child has achieved remission, and the regimen is then switched to alternate-day therapy. The duration of alternate day therapy varies depending on the frequency of relapses of the individual child. Children are classified as infrequent relapsers or frequent relapsers, and as being steroid dependent based on the number of relapses in a 12 mo period or their inability to remain in remission following discontinuation of steroid therapy.

What is Steroid Resistance?.

Steroid resistance is defined as the failureto achieve remission after 8 wk of corticosteroid therapy. Childrenwith steroid-resistant nephrotic syndrome require further evaluation,including a diagnostic kidney biopsy, evaluation of kidneyfunction, and quantitation of urine protein excretion (in addition tourine dipstick testing). Steroid-resistant nephrotic syndrome is usually caused by FSGS (80%), MCNS, or membrano proliferative glomerulonephritis.

Implications of Steroid-Resistant Nephrotic Syndrome.

Steroid-resistant nephrotic syndrome, and specificallyFSGS, is associated with a 50% risk for end-stage kidney disease within5 yr of diagnosis if patients do not achieve a partial or complete remission.

Persistent nephrotic syndrome is associated with poor patient reported quality of life, hypertension, serious infections, andthromboembolic events. Children reaching end-stage kidney diseasehave a greatly reduced life expectancy compared to their peers.

What are the Alternative Therapies to Corticosteroids in theTreatment of Nephrotic Syndrome?.

Steroid-dependent patients, frequent relapsers, and steroid-resistant patients are candidatesfor alternative therapies, particularly if they have severe corticosteroid toxicity (cushingoid appearance, hypertension, cataracts, and/or growth failure).

Cyclophosphamide prolongs the duration of remission and reduces the number of relapses in children with frequentlyrelapsing and steroid-dependent nephrotic syndrome. The potentialside effects of the drug (neutropenia, disseminated varicella, hemorrhagiccystitis, alopecia, sterility, increased risk of future malignancy) should be carefully reviewed with the family before initiating treatment.

Cyclophosphamide (2 mg/kg) is given as a single oral dose fora total duration of 8-12 wk. Alternate-day prednisone therapy is often continued during the course of cyclophosphamide administration.During cyclophosphamide therapy, he white blood cell count must be monitored weekly and the drug should be withheld if the count falls below 5,000/mm3. The cumulative threshold dose above which oligospermiaor azoospermia occurs in boys is >250 mg/kg.

Calcineurin inhibitors (cyclosporine or tacrolimus) are recommendedas initial therapy for children with steroid-resistant nephrotic syndrome. Children must be monitored for side effects, including hypertension, nephrotoxicity, hirsutism, and gingival hyperplasia.

Mycophenolate can maintain remission in children with steroid-dependent or frequently relapsing nephrotic syndrome.

Levamisole, an antihelmintic agent with immunomodulating effects that has been shown to reduce the risk of relapse in comparison to prednisone, is not available in the United States. There are also uncontrolled preliminary data regarding prolonged remissions achieved with rituximab, the chimeric monoclonal antibody against CD20, in children with steroid-dependent and/or steroid-resistant nephrotic syndrome. There are no data from randomized clinical trials directly comparing the various corticosteroid-sparing agents. Most children who respond to cyclosporine, tacrolimus, or mycophenolate therapy tend to relapse when the medication is discontinued. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may be helpful as adjunct therapy to reduce proteinuria in steroid-resistant patients.

How to Immunize in Children with Nephrotic Syndrome?.

To reduce the risk of serious infections in children withnephrotic syndrome, give full pneumococcal vaccination (with the13-valent conjugant vaccine and 23-valent polysaccharide vaccine) and influenza vaccination annually to the child and their household contacts;defer vaccination with live vaccines until the prednisone dose is below either 1 mg/kg daily or 2 mg/kg on alternate days.

Live virus vaccines are contraindicated in children receiving corticosteroid sparingagents such as cyclophosphamide or cyclosporine. Following close contact with varicella infection, give immunocompromised children on immunosuppressive agents varicella-zoster immune globulin if available; immunize healthy household contacts with live vaccines tominimize the risk of transfer of infection to the immunosuppressedchild, but avoid direct exposure of the child to gastrointestinal or

respiratory secretions of vaccinated contacts for 3-6 wk aftervaccination.

How will you follow up a child with nephrotic syndrome?

Ensure compliance

Ht wt monitoring,urinalysis

Bone age prolonged steroids,lipid profile

Look for infections especially resp ,skin, abdominal

Look for bp

Drug related complication

What is the Prognosis?

Most children with steroid-responsive nephrotic syndrome have repeated relapses, which generally decrease in frequency as the childgrows older. Although there is no proven way to predict an individualchild’s course, children who respond rapidly to steroids and those who have no relapses during the first 6 mo after diagnosis are likely to follow an infrequently relapsing course. It is important to indicate tothe family that the child with steroid-responsive nephrotic syndrome is unlikely to develop chronic kidney isease, that the disease is rarely hereditary, and that the child (in the absence of prolonged cyclophosphamide therapy) will remain fertile.

To minimize the psychologic effects of the condition and its therapy, children with idiopathic nephrotic syndrome should not be considered chronically ill and should participate in all age-appropriate childhood activities and maintain an unrestricted diet when in remission.

Children with steroid-resistant nephrotic syndrome, ost often caused by FSGS, generally have a much poorer prognosis. These children develop progressive renal insufficiency, ultimately leading to end stage renal disease requiring dialysis or kidney transplantation.Recurrent nephrotic syndrome develops in 30-50% of transplant recipients with FSGS

How do you test urine?

Urine Dipstick

• Primarily detects albumin and test is highly specifi c, but not very sensitive for the detection of proteinuria (protein excretion must be more than 100 mg/day).
• Principle: strips are impregnated with a reagent called tetrabromophenol blue, buffered to an acidic pH of 3, which reacts with albumin in the urine in 30–60 s, forming a chromogen, which yields a color change.
• Color change: pale green → green → blue.
• Correlation: trace, <20 mg/dl; 1+, 30 mg/dl; 2+, 100 mg/dl; 3+, 300 mg/dl; 4+,>2,000 mg/dl.
• False positive in alkaline urine, concentrated urine, pyuria, bacteriuria.
• False negative in dilute urine, low-molecular-weight proteinuria.

Turbidimetric Method

Heat Coagulation Test

Less reliable as a result of many false-positive and false-negative results. Method: semiquantitative. A test tube containing about 10 ml of urine is heated in the upper part until it boils. The precipitate which does not disappear after addition of three drops of concentrated acetic acid suggests proteinuria.

Sulfosalicylic Acid (SSA) Test

Method: 5 ml or urine +5–10 drops of 20 % SSA → look for turbidity Interpretation (parentheses represent the approximate protein concentration):

• No or slight turbidity, 0 (0–10 mg/dl)
• Turbidity without granule formation (through which print can be read), 1+ (15– 30 mg/dl)

Turbidity with granule formation (through which heavy black lines on a white background can be seen), 2+ (40–100 mg/dl)

• Turbidity with granule formation and fl occulation (through which heavy black lines on a white background cannot be seen), 3+ (150–350 mg/dl)
• Flocculent precipitation, 4+ (>500 mg/dl)

– False positive—concentrated urine, gross hematuria, contrast media, penicillin, sulfonamides, miconazole, cephalosporins, tolbutamide