NEPHROTIC SYNDROME Definition:
Nephrotic syndrome is defined by the associ-ation of a proteinuria higher than 3.5 g/24 hours, hypoalbuminaemia, oedema and dyslipidaemia.Remission: dyslipidaemia.Remission: Up/c <0.2 or Albustix-negative or trace for3 days. Relapse: After remission, an increase in t he first morning Up/c to >=2orAl-bustix reading of>=2 for 3 o f 5 consecutive days. Frequently relapsing: 2 or more re -lapses within 6 months after initial therapy or >=4 relapses in any 12 month period. Steroid dependent: Relapse during taper or within 2 weeks of discontinu-ation of steroid therapy. Steroid resistant: Inability to induce a remission with 4weeks of daily steroid therapy. Classification
Histologic classification of Nephrotic syndrome: 1. minimal change (MCNS) (77.1%), 2. focal segmental glomerulosclerosis (FSGS) (7.9%), 3. membranoproliferative glomerulonephritis (6.2%), 4. others (8.8%) Typical Features
Atypical Features
Age 1-10 years
<1yr, >10years
Normotensive
Hypertensive
Normal Adrenal Function
Elevated Creatinine
+/- microscopic haematuria
Macroscopic Haematuria
Pathophysiology
Classic hypothesis/Underfill hypothesis: classic hypothesis, also called the underfill hypothesis, postulates that sodium retention in NS is secondary to de creased effective arterial blood volume, hence the term underfill. The hypothesis suggests the following sequence of events: ur inary loss of proteins in NS, especially albumin, causing hypoalbuminaemia, which in turn causes a decrease in plasma oncotic pressure.
This decrease in plasma oncotic pressure would then cause an imbalance in Starling forces, movement of fluid from the intravascular space to the interstitial space, causing a decrease in effect ive arterial blood volume and consequently, relative hypovolaemia. This would then result in activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, increased antidiuretic hormone release and inhibition of atrial natriuretic peptide rele ase. Activation of these systems would cause sodium and water retention in the kidneys, with subsequent oedema. However, several experimental and clinical observations made over the years do not support this hypothesis. Nephrotic syndrome -> Albuminuria ->Hypoalbuminaemia ->Reduction in plasma oncotic pressure -> Translocation of fluid from the intravascular space to the interstitial space -> Decrease in effective arterial blood volume Classic or underfill hypothesis of oedema formation in nephrotic syndrome Albuminuria
Hypoalbuminaemia
Reduction in plasma oncotic pressure Translocation of fluid from the intravascular space to the interstitial s ace Decrease in effective arterial blood volume
↑ Renin-angiotensin-aldosterone system
↑ Sympathetic nervous system ↑ Arginine-vasopressin
Sodium and water retention by the kidney Oedema
Arguments against the underfill hypothesis of oedema formation in nephrotic syndrome: 1. Patients and laboratory rats with low serum albumin levels do not develop oedema or sodium retention. 2. Natriuresis in the recovery phase of nephrotic syndrome begins when proteinuria disappears but before serum albumin returns to normal levels. 3. The absolute decrease in plasma oncotic pressure does not affect the volume of t he intravascular space in nephritic syndrome. 4. Plasma and blood volumes are normal or increased in nephrotic syndrome. 5. Intravascular space expansion with albumin does not increase natriuresis in patients with nephrotic syndrome. 6. The activation of the renin-angiotensin-aldosterone system is not involved in the development of oedema in nephritic syndrome. 7. Bilateral adrenalectomy does not prevent sodium retention in nephrotic syndrome in laboratory rats.
Causes
Nephrotic syndrome may result from either primary glomerular or systemic disease leading to renal insult. Primary glomerular diseases associated with nephrotic syndrome: 1. Primary glomerular diseases (frequent; rare) 2. Membranous glomerulopathy 3. Focal and segmental glomerulosclerosis 4. Minimal change disease (MCD) glomerulopathy 5. IgA nephropathy 6. Membranopoliferative glomerulonephritis 7. C1q glomerulopathy 8. Fibrillar glomerulopathy 9. Congenital podocyte anomaly
Causes of secondary Nephrotic syndrome (most frequent). 1. Medications (non exhaustive) Allergens, immunisations 2. NSAIDs, pamidronate, rifampicin, IFN alpha, gold, lithium, Pollens, seric illness, vaccines, bee stin 3. interferon alpha 4. Infections Systemic illnesses (most frequent) 5. Bacterial: Endocarditis, syphilis, tuberculosis, mycoplasma infections Systemic lupus erythematosus (SLE), 6. Viral: HIV, HBV, HCV, EBV, CMV,VZV Rheumatoid polyarthritis, 7. Protozoal:Toxoplasmosis, malaria Schonlein-Henoch purpura 8. Helminthic: Schisostomiasis, trypanosomiasis, filariasis MGUS, amyloidosis 9. Neoplasia Metabolic diseases and heredofamilia 10. Solid tumours Type I and II diabetes 11. Haemo- or lymphopathies Hypothyroidism 12. Multiple myeloma Alport syndrome 13. GVHD post marrow transplantation Graves disease 14. Fabry disease 15. Miscellanous (examples) 16. Pregnancy-associated 17. Chronic allograft failure 18. Nephronic reduction 19. Renal artery stenosis 20. Obesity 21. Heart failure (right/left) and pericarditis
Clinical Presentation
History The first sign of nephrotic syndrome in children is usually swelling of the face; this is followed by swelling of the entire body. Adults can prese nt with dependent edema. Foamy urine may be a presenting feature. A thrombotic complication, such as deep venous thrombosis of the c alf veins or even a pulmonary embolus, may be the first clue indicating nephrotic syndrome. Additional historical features can be related to the cause of nephrotic syndrome. Thus, the recent start of a nonsteroidal anti-inflammatory drug (NSAID) or a 10-year history o f diabetes may be very relevant. Physical Examination Edema is the predominant feature of nephrotic syndrome and initially develops around the eyes and legs. With time, the edema becomes generalized and may be associated with an incre ase in weight, the development of ascites, or pleural effusions.
Hematuria and hypertension manifest in a minority of patients. Additional features on exam will vary according to cause and as a result of whether or not renal function impairment exists. Thus, in the case of longstanding diabetes, there m ay be diabetic retinopathy, which correlates closely with diabetic nephropathy. If the kidney function is reduced, there may be hypertension and/or anemia.
Diagnosis and Lab
Recommendations for initial evaluation include: ●urinalysis; ●first morning Up/c; ●serum electrolytes, serum urea ni-trogen, creatinine, and glucose; ●cholesterol level; ●serum albumin level; ●complement 3 level; ●antinuclear antibody level (for children aged >=10 years or with any other signs of systemic lupus erythematosus);
●hepatitis B, hepatitis C, and HIV se-rology in high-risk populations; ●purified protein derivative level; and ●kidney biopsy for children aged >=12 years Treatment
On the basis of the ISKDC study, 95% of children with steroid-responsive nephrotic syndrome will demonstrate resolution of proteinuria with 4 weeks of daily glucocorticoid therapy and 100% after an additional 3 weeks of alternate-day therapy. This consensus guideline uses a 4-week oral glucocorticoid limit to define ste-roid resistance; however, t herapy may be continued during the subsequent evaluation for steroid-resistant ne-phrotic syndrome, allowing the capture of late r esponders. Initial Therapy for Childhood Nephrotic Syndrome ●prednisone 2 mg/kg per day for 6 weeks (maximum: 60 mg); ●thenprednisone1.5mg/kg on alternate days for 6weeks (maximum: 40mg); ●no steroid taper is required at the conclusion of this initial therapy.
Initial or Infrequent-Relapse Therapy ●prednisone 2 mg/kg per day until urine protein test results are nega-tive or trace for 3 consecutive days; ●then prednisone 1.5 mg/kg on alter-nate days for 4 weeks Frequently Relapsing Nephrotic Syndrome Therapy Options ●prednisone 2 mg/kg per day until proteinuria normalizes for 3 days, 1.5 mg/kg on alternate days for 4 weeks, and then taper over 2 months by 0.5 mg/kg on alternate days (total: 3 –4 months); ●oral cyclophosphamide 2mg/kg per day for 12 we eks (cumulative dose: 168 mg/kg) based on ideal body weight started during prednisone (2 mg/kg per day) induced remis-sion, decrease prednisone dose to 1.5 mg/kg on alternate days for 4 weeks, and then taper over 4weeks; ●mycophenolate mofetil 25 to 36 mg/kg per day (maximum: 2 g/day) divided twice daily (BID) for 1 to 2 years with a taperingdoseof prednisone; and ●cyclosporineA3to5mg/kg per day di-videdBID for anaverageof 2 to5 years.
Steroid-Dependent NephroticSyndrome Therapy ●glucocorticoidsarepreferred in theab-senceof significant steroid toxicity; ●secondary alternatives should be cho-senon thebasis of risk/benefit ratio; ●cyclosporineA3to5mg/kg per daydivided BID; ●tacrolimus 0.05 to 0.1mg/kg per daydivided BID; and ●mycophenolate mofetil 24 to 36 mg/kg per day or 1200 mg/m2 per day divided BID (maximum: 2 g/day)
Steroid-Resistant Nephrotic Syndrome Management ●kidney biopsy; ●tailor therapeutic regimen accord-ing to kidney histology; and ●provide optimal supportive therapy
ACE-I and ARB Therapy ●ACE-I or ARB therapy is recom-mended for steroid-resistant ne-phrotic syndrome; ●consider use of ACE-Is or ARBs with steroid-dependent or frequently re-lapsing nephrotic syndrome; ●counsel regarding contraindications of ACE-I or ARB therapy duringpregnancy
Edema Management ●counsel caregivers regarding po-tential complications of edema; and ●consider treatment with low-sodium diet, modest fluid restriction, diuretics, andalbumin infusions.
Hypertension Management ●control blood pressure to <90th percentile of normal
●recommend low-salt diet, exercise, and weight reduction if obesity is present; and ●ACE-Is and/or ARBs for chronic pharmacologic management
Complications
The complications of childhood ne-phrotic syndrome are associated with disease activity and therapy. Active ne-phrotic syndrome increases the risk for therapy-associated growth compli-cations, dyslipidemia, infections, and thromboembolism. Obesity and Growth ●monitor BMI and linear growth; ●provide counseling on weight con-trol; and ●consider glucocorticoid alterna-tives when short stature or obesity is pre sent.
Dyslipidemia ●low-fat diet; ●consider low-density lipoprotein cholesterol-lowering drug therapy when fasting low-density lipoprotein cholesterol levels are persistently 160 to 19 0 mg/dL; and ●counsel regarding contraindica-tions of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during pregnancy
Infection ●counsel regarding signs and symp-toms of infections such as cellulitis, peritonitis, and bacteremia; and ●provide empiric therapy for peritonitis until culture results areavailable
Thromboembolism ●evaluate children with a thromboembolism for an underlying hypercoagulopathy; and
●provide anticoagulation therapy forchildren with nephrotic syndrome and thromboembolism
Vaccinations ●immunize with the 23-valent and heptavalent conjugated pneumo-coccal vaccines; ●immunize the immunosuppressed or actively nephrotic patient and household contacts with inactivated influenza vaccine yearly; ●defer immunization with live vaccines: ● until prednisone dose is2 mg/kg per day (maximum: 20mg); ● for 3 months from completion of ther apy with cytotoxic agents; or ● for 1 month from completion of other daily immunosuppression; ●provide varicella immunization if nonimmune, on the basis of immu-nization history, disease history, or serologic evaluation; ●provide postexposure immunoglob-ulin for nonimmune immunocom-promised patients; and ●consider intravenous acyclovir for immunosuppressed children at the onset of chicken pox lesions.
