Nephrosis 2009,


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Nephrosis 2009,

  1. 1. Glomerular Diseases in Children Lecturer Xin Yue TIANJIN MEDICAL UNIVERSITY PEDIATRIC DPT. GENERAL HOSPITAL
  2. 2. Nephrotic syndrome (NS)
  3. 3. Introduction The nephrotic syndrome (NS) is characterized by Edema Hypercholesterolemia (greater than 5.72 mmol/L) Hypoalbuminemia (less than 30 g/L ) Severe proteinuria (greater than 0.05/kg/24hr)
  4. 4. Secondary nephrosis Primary nephrotic syndrome(90%) Types of nephrotic syndrome Congenital nephrosis Simple nephrosis Nephritic nephrosis
  5. 5. Etiology <ul><li>Remains unknown </li></ul><ul><li>Several hypotheses </li></ul><ul><li>Abnormalities in the function of thymus- </li></ul><ul><li>derived (T-cell) lymphocytes </li></ul><ul><li>Specific HLA antigens </li></ul><ul><li>Complement deficiencies </li></ul><ul><li>Atopy </li></ul>
  6. 6. Pathology <ul><li>Five Morphologic Patterns: </li></ul><ul><li>Minimal-change disease (MCNS) (78%-85%) </li></ul><ul><li>Focal segmental glomerulosclerosis (FSGS) (6.7%-10%) </li></ul><ul><li>Mesangial proliferative glomerulonephritis (MsPGN) (5%) </li></ul><ul><li>Membranous glomerulopathy (MGN) (commonly occurs in adults) </li></ul><ul><li>Membranoproliferative glomerulonephritis </li></ul><ul><li>(MPGN) </li></ul>
  7. 7. <ul><li>Features of MCD: </li></ul><ul><li>LM - appear normal or show minimal increase in mesangial cells and matrix. </li></ul><ul><li>IF – typically negative. </li></ul><ul><li>EM - effacement of foot processes. </li></ul><ul><li>More than 95% of children with MCNS are sensitive to corticosteroid therapy. </li></ul>Minimal-change Disease
  8. 10. Normal Foot Processes Effacement of Foot Processes
  9. 14. MGN: Mildly Thickened Capillary Loops
  10. 18. Pathophysiology <ul><li>Proteinuria </li></ul><ul><li>Hypoproteinemia </li></ul><ul><li>Edema </li></ul><ul><li>Hyperlipidemia </li></ul>
  11. 19. <ul><li>Normally, the charge and size selective barrier of the glomerular capillary wall (GCW) prevents filtration of plasma proteins with negative charges or large molecular weight. </li></ul><ul><li>In patients with NS, the structural changes : </li></ul><ul><li>(1) damage to the endothelial surface, causing loss of </li></ul><ul><li>the negative charge. (2) damage to the GBM </li></ul><ul><li>(3) effacement of the foot processes. </li></ul><ul><li>leading to increased GCW permeability </li></ul><ul><li>large amounts of protein (primarily albumin) cross the barrier and are excreted. </li></ul>Proteinuria(1)
  12. 20. <ul><li>(Highly) selective proteinuria: </li></ul><ul><li>the damage of glomeruli is mild and the permeability of GBM would be selectively altered, </li></ul><ul><li>increasing capillary transport of anionically charged particles (albumin et al) </li></ul><ul><li>Non- selective proteinuria: </li></ul><ul><li>injuries of the glomeruli are severe both small(albumin, transferrin) and large proteins (α 2 - macroglobulin, et al) can pass through the GBM and appear in urine. </li></ul>Proteinuria(2)
  13. 21. <ul><li>Filtration slit membrane </li></ul><ul><li>fenestrations </li></ul><ul><li>Epithelial foot processes </li></ul><ul><li>lamina rara externa </li></ul><ul><li>lamina densa GBM </li></ul><ul><li>lamina rara interna </li></ul><ul><li>capillary endothelium </li></ul>glomerular filter membrane
  14. 22. The glomerular capillary wall: Charge selective filter The glomerular capillary wall: Size selective filter
  15. 23. <ul><li>Increased urinary loss of proteins is the main cause. </li></ul><ul><li>Other factors: </li></ul><ul><li>The capacity to increase hepatic synthesis </li></ul><ul><li>appears insufficient to compensate for the </li></ul><ul><li>large urinary losses. </li></ul><ul><li>Increaed protein catabolism. </li></ul><ul><li>Some plasma protein levels are actually increased in NS increased and relatively unregulated hepatic production of protein in response to hypoalbuminemia. </li></ul>Hypoproteinemia(1)
  16. 24. <ul><li>Like albumin, the concertration of other plasma proteins are decreased: </li></ul><ul><li>IgG and some components of complememt </li></ul><ul><li>decreased immunity </li></ul><ul><li>Some anti-coagulant factors </li></ul><ul><li>hypercoagulability state </li></ul><ul><li>Vitamin D combining protein </li></ul><ul><li>hypocalcemia </li></ul><ul><li>Transferrin </li></ul><ul><li>anemia </li></ul>Hypoproteinemia(2)
  17. 25. <ul><li>Hypoalbuminemia lowers the plasma colloid osmotic pressure with extravasation of plasma water into the interstitial space. </li></ul><ul><li>The reduction in intravascular volume leads to: </li></ul><ul><li>(1) A decrease in renal perfusion which stimulates </li></ul><ul><li>the renin-angiotensin-aldosterone system </li></ul><ul><li>(2) An increase in the synthesis and secretion of </li></ul><ul><li>antidiuretic hormone(ADH) </li></ul><ul><li>Retention of both sodium and water </li></ul>Edema(1) Traditional opinions:
  18. 26. <ul><li>a primary renal disturbance (reduced GFR) </li></ul><ul><li>primary renal retention of sodium and water </li></ul><ul><li>expansion of plasma suppression of the renin- </li></ul><ul><li>angiotensin-aldosterone system </li></ul><ul><li>increased capillary hydrostatic pressure </li></ul><ul><li>extravasation of fluid into the interstitial space </li></ul><ul><li>edema </li></ul><ul><li>Each explanation may be valid for some patients with </li></ul><ul><li>NS, depending on their underlying renal disease or the </li></ul><ul><li>stage of their disease at the time of study. </li></ul>Edema(2) Recent opinions:
  19. 27. <ul><li>Two factors offer at least partial explanation: </li></ul><ul><li>Hypoproteinemia results in generalized liver protein synthesis, including lipoproteins </li></ul><ul><li>Lipid catabolism is decreased </li></ul><ul><li>Two pathologic patterns: </li></ul><ul><li>hypercholesterolemia alone and </li></ul><ul><li>combined hypercholesterolemia and </li></ul><ul><li>hypertriglyceridemia </li></ul><ul><li>It plays a role in the hypercoagulable state , and may play a role in the progression of glomerulosclerosis . </li></ul>Hyperlipidemia
  20. 28. Clinical manifestations <ul><li>Age: 75% of pediatric patients <6y at onset </li></ul><ul><li>with peak age of onset between 2-3y. </li></ul><ul><li>Sex: male: female = 2:1-3:2 </li></ul><ul><li>Eedema the major clinical manifestation </li></ul><ul><li>Lethargy, poor appetite, weakness, pallor, diarrhea and occasional abdominal pain. </li></ul><ul><li>Hematuria and hypertension are unusual but manifest in a minority of patients. </li></ul>
  21. 29. <ul><li>A presenting symptom in 95% of children with NS </li></ul><ul><li>Usually begins insidiously with unexpected weight gain and early morning periorbital swelling dependent areas (lower extremities, genitals and feet). </li></ul><ul><li>It can develop into generalized and marked edema (anasarca): inability to open the eyes. </li></ul><ul><li>ascites and pleural effusion respiratory distress. </li></ul><ul><li>marked swelling in the abdomen, scrotal or labial </li></ul><ul><li>areas prevents walking. </li></ul><ul><li>decreased urine output. </li></ul><ul><li>The edema is soft and pitting in nature. </li></ul>Edema
  22. 34. <ul><li>Clinical classification </li></ul><ul><li>Simple nephrosis hematuria </li></ul><ul><li>Nephritic nephrosis azotemia </li></ul><ul><li>hypertension </li></ul><ul><li>C 3  </li></ul><ul><li>Response to steroid therapy (prednisone 1.5~2mg/kg.d) </li></ul><ul><li>Complete response: urinary protein negative </li></ul><ul><li>No response: + + + ~ + + + + </li></ul><ul><li>Partial response: + ~ + + </li></ul>Classification
  23. 35. <ul><li>Only has the 4 major features of NS: </li></ul><ul><li>massive proteinuria, </li></ul><ul><li>hypoalbuminemia, </li></ul><ul><li>marked edema, </li></ul><ul><li>hypercholesterolemia. </li></ul>Simple nephrosis
  24. 36. <ul><li>Besides the 4 major features of NS, also has one or more of the following features: </li></ul><ul><li>Hematuria: Increased RBCs (>10/HP) in urine are detected for several times (at least in 3 centrifuged urine specimens within 2 weeks) </li></ul><ul><li>Repeated hypertension: BP>130/90mmHg in shchool-aged patients, and >120/80 in preshchool-aged patients (not caused by corticosteroids) </li></ul><ul><li>Persistent azotemia: BUN>10.7mmol/L (not caused by hypovolemia) </li></ul><ul><li>Repeated or prolonged low serum levels of total complement(CH 50 )or C 3 </li></ul>Nephritic nephrosis
  25. 37. Differential between simple and nephritic nephrosis Typical features Simple nephrosis Nephritic nephrosis Age 2~7 yr, peak age is 3 yr School age Edema Severe (ascites) Mild or moderate Hyperlipidemia ↑↑ ↑ Proteinuria + + + ~ + + + + ++ ~ +++ >50~100mg/kg/24hr <50mg/kg/24hr Serum albumin ↓↓ Normal/slightly ↓ Hematuria RBC < 10/HP RBC > 10/HP Blood pressure Normal Raised Complement C 3 Normal Normal/low Renal function Normal Abnormal Histological type MCNS FSGS, MPGN Prognosis well Bad
  26. 38. Complications <ul><li>Infections </li></ul><ul><li>Hypovolemia </li></ul><ul><li>Electrolyte disturbances </li></ul><ul><li>Hypercoagulability states and </li></ul><ul><li>thrombosis </li></ul><ul><li>Acute renal failure </li></ul>
  27. 39. <ul><li>The major complication </li></ul><ul><li>Causes: </li></ul><ul><li> decreased immunity (urinary loss of Ig and C) </li></ul><ul><li> edema fluid acting as a culture medium </li></ul><ul><li> immunosuppressive therapy </li></ul><ul><li> protein deficiency </li></ul><ul><li>The common infectious complications: </li></ul><ul><li>bacterial sepsis, cellulitis, pneumonia, urinary tract infections and primary peritonitis. </li></ul>Infections
  28. 40. <ul><li>Causes: </li></ul><ul><li> Hypoalbuminemia the plasma oncotic pressure loss of plasma water into the interstitial space and causing a decrease in circulating blood volume. </li></ul><ul><li> Diuresis </li></ul><ul><li>Symptoms and signs: restlessness, cold hands and feet, delayed capillary filling, oliguria, tachycardia and Hypotension. </li></ul>Hypovolemia
  29. 41. <ul><li>Causes: </li></ul><ul><li> Limitations of diet </li></ul><ul><li> Poor intake </li></ul><ul><li> GI loss (vomiting and diarrhea) </li></ul><ul><li> Diuresis </li></ul><ul><li>hyponatremia, hypokalemia, hypocalcemia </li></ul>Electrolyte disturbances
  30. 42. <ul><li>Causes: </li></ul><ul><li> Urinary loss of anti-coagulant proteins </li></ul><ul><li> Hemoconcentration and hypovolemia </li></ul><ul><li> Hyperlipidemia (increased viscosity) and increased platelet aggregation </li></ul><ul><li> Elevated coagulation factors </li></ul><ul><li>Renal vein thrombosis is more common </li></ul><ul><li>Pulmonary or cerebral embolism life-threatening </li></ul><ul><li>Avoidance of bed rest, volume depletion, diuretics and deep venous or arterial punctures to prevent embolism. </li></ul>Hypercoagulability states and thrombosis
  31. 43. <ul><li>Is more often precipitated by hypovolemia </li></ul><ul><li>Reduction in the glomerular filtration rate has also been hypothesized </li></ul>Acute renal failure
  32. 44. Laboratory findings <ul><li>1. Urinalysis </li></ul><ul><li>Proteinuria: </li></ul><ul><li> Protein: qualitatively +++~++++ </li></ul><ul><li>quantitatively >0.1g/kg.d. </li></ul><ul><li> The ratio of urinary protein to urinary </li></ul><ul><li>creatinine: >2 </li></ul><ul><li>Hematuria </li></ul><ul><li> RBC may be increased in nephritic- </li></ul><ul><li>nephrotic syndrome </li></ul><ul><li> Occasionally appears in simple nephrosis </li></ul>
  33. 45. <ul><li>2. Blood: </li></ul><ul><li>Hypoalbuminemia: albumin < 10g~20g/L </li></ul><ul><li>Hyperlipidemia: cholesterol > 5.7mmol/L </li></ul><ul><li>ESR > 100mm/h </li></ul><ul><li>In nephritic-nephrotic syndrome, renal </li></ul><ul><li>functions and serum complement 3 may </li></ul><ul><li>be reduced. </li></ul><ul><li>Serum electrolyte determination: to </li></ul><ul><li>evaluate hyponatremia, hypokalemia, </li></ul><ul><li>hypocalcemia </li></ul>
  34. 46. Diagnosis <ul><li>The criteria of diagnosis: </li></ul><ul><li>Massive proteinuria: Urinalysis reveals 3+ or 4+. Protein excretion exceeds 100mg/kg.d. </li></ul><ul><li>Hypoalbuminemia: The serum albumin level is generally less than 30g/L (usually 10g~20g/L) </li></ul><ul><li>Hypercholesterolemia: the serum concentration of cholesterol is > 5.7mmol/L </li></ul><ul><li>Edema with various degrees </li></ul><ul><li>The first two items are the most necessary for diagnosis </li></ul><ul><li>The diagnosis of different clinical types of NS </li></ul>
  35. 47. Differential diagnosis <ul><li>Primary NS should be differentiated from secondary NS or GN with nephrotic picture, such as HSP nephritis, SLE nephritis, APSGN. </li></ul>
  36. 48. Treatment(1) <ul><li>General measures </li></ul><ul><li> Activity </li></ul><ul><li> Diet </li></ul><ul><li> Diuretic therapy </li></ul><ul><li> Treatment of complications </li></ul>
  37. 49. <ul><li>Do not restrict activity unless the patient is severely edematous or with severe hypertention or infections. </li></ul><ul><li>To prevent thrombosis, patients restricted to bed rest should change position frequently. </li></ul>Activity
  38. 50. <ul><li>The diet should provide adequate energy (calorie) intake and adequate protein (1-2 g/kg/d). </li></ul><ul><li>Sodium restriction (Low sodium or no sodium diet) is indicated for patients with edema or hypertension, but should be adjusted according to the serum levels of sodium. Long-term sodium restriction is not recommended. </li></ul><ul><li>Fluid restriction is required when the edema is severe with oliguria. </li></ul><ul><li>Replacement of vitamins and minerals. </li></ul>Diet
  39. 51. <ul><li> Diuretic is indicated when edema is severe, esp. with ascites. </li></ul><ul><li> It can be used for symptomatic relief until steroid diuresis occurs </li></ul><ul><li> Hydrochlorothiazide(HCT): 2-4mg/kg.d </li></ul><ul><li> Antisterone: may be added if HCT is not effective. </li></ul><ul><li> Salt-poor albumin at 0.5~1g/kg iv, over 1 hr (when serum albumin<20g/L), followed by iv injection furosemide 1-2mg/kg.dose . Multiple use is not recommended. </li></ul><ul><li> A renal blood vessel dilator should be given (dopamine 2~4 μg/kg.min) in patients with refractory edema, combined with furosemide. </li></ul><ul><li> Hypovolemic shock or postural hypotension should be monitored during diuresis. </li></ul>Diuretic therapy
  40. 52. <ul><li>Anti-infection: antibiotics that cover both gram-positive and negative organisms should be given; But continuous prophylactic antibiotics are not recommended. </li></ul><ul><li>Anti-coagulation therapy: heparin, persantin, exercise of extremities, et al. </li></ul><ul><li>Therapy for electrolyte disturbance. </li></ul>Treatment of complications
  41. 53. Treatment(2) <ul><li>Specific therapy </li></ul><ul><li> Glucocorticoid therapy </li></ul><ul><li> Cytotoxic agent therapy </li></ul><ul><li> Pulse therapy </li></ul>
  42. 54. <ul><li>At initial diagnosis, Prednisone or Prednisolone oral therapy is the first line: </li></ul><ul><li>Before starting steroid therapy, a tuberculin skin test should be done. </li></ul><ul><li>Medium-long term prednisone therapy </li></ul><ul><li>Short term prednisone therapy </li></ul><ul><li>NS types classified by response to steroid therapy </li></ul><ul><li>Adverse effects of long term corticosteroid treatment </li></ul>Glucocorticoid therapy
  43. 55. Medium-long term prednisone therapy <ul><li>Commonly used in China, including 3 phases: </li></ul><ul><li>2mg/kg/d (maximum 60 mg/day) tid, until the proteinuria has dissappeared for 2 weeks </li></ul><ul><li> Remission can be achieved during this phase in most children with PNS, then entered the next phase </li></ul><ul><li> If remission isn’t achieved, continue the initial dosage, but not over 8 weeks before entered the next phase. </li></ul><ul><li>2. 1.5- 2mg/kg, qod (single dose, every other morning, alternate-day therapy) for another 4 weeks. </li></ul><ul><li>3. Reduced by 2.5~5 mg q2-4w until stopped. </li></ul><ul><li>Medium term therapy: total course is 6m </li></ul><ul><li>Long term therapy: total course is 9~12m </li></ul>
  44. 56. Short term prednisone therapy <ul><li>Prednisone dosage at: </li></ul><ul><li>2mg/kg/d (maximum 60 mg/day) tid, for 4 weeks </li></ul><ul><li>Regardless of the responses, entered the next phase. </li></ul><ul><li>2. 1.4mg/kg, qod for another 4 weeks, then stopped. </li></ul><ul><li>The total therapy course is 8~12 weeks. </li></ul><ul><li>May be associated with a higher rate of early recurrence or relapse. </li></ul>
  45. 57. <ul><li>Steroid sensitive NS: Complete remission is achieved within the first 8 w of the initial steroid therapy. </li></ul><ul><li>Partialy steroid sensitive NS: After 8w of the initial steroid therapy, edema subsides, but urinary protein is still +~++. </li></ul><ul><li>Steroid resistant NS: Failure to achieve remission (urinary protein  +++) in spite of 8 weeks of standard prednisone therapy. </li></ul>NS types classified by response to steroid therapy(1)
  46. 58. <ul><li>Steroid dependent NS: Patients who has 2~3 consecutive relapses occurring during the period of steroid taper or within 14 days of its cessation is defined as… </li></ul><ul><li>Relapse or recurrence: Patients who has urinary protein  ++ after 4w of steroid cessation or during maintenance </li></ul><ul><li>Frequent relapses or recurrences: Patients who has 2 or more relapses or recurrences within 6 months, or  3 within 12 months is said to have … </li></ul><ul><li> </li></ul>NS types classified by response to steroid therapy(2)
  47. 59. Adverse effects of long term corticosteroid treatment <ul><li>Cushingoid features (obesity, round face, striae) </li></ul><ul><li>Increased susceptibility to infections </li></ul><ul><li>Hypertension </li></ul><ul><li>Osteoporosis </li></ul><ul><li>Hypokalemia </li></ul><ul><li>retarded growth </li></ul><ul><li>Cataracts </li></ul><ul><li>Peptic ulcer disease </li></ul><ul><li>Diabetes mellitus </li></ul>
  48. 60. <ul><li>Cyclophosphamide , cyclosporine, chlorambucil, nitrogen mustard… </li></ul><ul><li>Indication: </li></ul><ul><li> Intractable NS (steroid resistance, frequent relapses or recurrences) </li></ul><ul><li> Steroid dependent NS with signs of steroid toxicity. </li></ul><ul><li>The adverse effects : sexual gland damage; bone marrow depression; hemorrhagic cystitis; nausea, vomitting, gastritis; alopecia; liver damage. </li></ul>Cytotoxic agent therapy
  49. 61. <ul><li>Methylprednisolone : </li></ul><ul><li>15~30 mg/kg.d (<1.0g/d) add 10% glucose 100~250 ml in drip, for 3 days. Repeated same as above every 1~2 weeks if necessary. </li></ul><ul><li>CTX: </li></ul><ul><li>0.5~0.75g/m 2 in drip, once monthly, for 6 months if necessary. </li></ul>Pulse therapy
  50. 62. Prognosis(1) <ul><li>Varies depending on the histological type </li></ul><ul><li>>90% of MCNS respond to corticosteroid therapy </li></ul><ul><li> Only 30% of children never have a relapse after the initial remission </li></ul><ul><li> approximately 50% have 1-2 relapses within 5 years </li></ul><ul><li> 20% continue to relapse 10 years after diagnosis </li></ul><ul><li> Approximately 3% of patients who initially responded to steroids become steroid resistant. </li></ul>
  51. 63. <ul><li>Only approximately 20% of patients with FSGS undergo remission of proteinuria </li></ul><ul><li>Approximately 50% of patients with MsPGN undergo complete remission of proteinuria during steroid therapy </li></ul><ul><li>MPGN has the most worse prognosis. no difference was evident in the outcome between treated and untreated patients; </li></ul>Prognosis(2)
  52. 64. Indications of renal biopsy <ul><li>Unsuccessful therapeutic trial of steroids : </li></ul><ul><li> Steroid resistance </li></ul><ul><li> Frequent relapses or steroid dependency </li></ul><ul><li>A child >10y at onset </li></ul><ul><li>Coexistence of significant hematuria, hypertension, azotemia and depressed serum C3 at onset. </li></ul><ul><li>Secondary causes of nephrotic syndrome. </li></ul>
  53. 65. Keys to be remembered <ul><li>Type of NS </li></ul><ul><li>Five morphologic patterns of PNS </li></ul><ul><li>Pathophysiology of 4 fetures </li></ul><ul><li>Classification including the table of differential between simple and nephritic nephrosis </li></ul><ul><li>Complications </li></ul><ul><li>The criteria of diagnosis </li></ul>