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Nephritis2008.

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Nephritis2008.

  1. 1. Glomerular Diseases in Children Lecturer Xin Yue TIANJIN MEDICAL UNIVERSITY PEDIATRIC DPT. GENERAL HOSPITAL
  2. 2. Anatomic and Structural Characteristics of Kidneys
  3. 10. The nephron and collecting duct 1. renal corpuscle 2. proximal convoluted tubule 3. proximal straight tubule 4. descending thin limb 5. ascending thin limb 6. distal straight tubule (thick ascending tubule) 7. macula densa 8. Distal convoluted tubule 9. Connecting tubule 10. Cortical collecting duct 11. Outer medullary collecting duct 12. inner medullary collecting duct
  4. 12. Glomerulus
  5. 13. AA afferent arteriole MD macula densa EGM extraglomerular mesangium EA efferent arteriole GC granular cells SMC vascular smooth muscle cells PE parietal epithelium PO podocyte M mesangium E endothelium F foot process GBM glomerular basement membrane US urinary space
  6. 16. Glomerulus
  7. 17. Functions of Kidneys <ul><li>Remove waste and excess water </li></ul><ul><li>Produce hormones: </li></ul><ul><li>Renin regulate BP </li></ul><ul><li>Erythropoietin production of RBC </li></ul><ul><li>1,25(OH) 2 D 3 uptake of Ca </li></ul>
  8. 18. <ul><li>primary glomerular disease : </li></ul><ul><li>glomerulonephritis </li></ul><ul><li>nephrotic syndrome </li></ul><ul><li>isolated hematuria or proteinuria </li></ul><ul><li>secondary glomerular disease: SLE, HSP </li></ul><ul><li>congenital or genetic glomerular disease: </li></ul><ul><li>congenital nephrotic syndrome </li></ul><ul><li>familial nephritis: </li></ul><ul><li>thin basement membrane disease </li></ul><ul><li>Alport’s syndrome </li></ul>Classification of Glomerular Diseases Clinical classification
  9. 19. Glomerulonephritis(GN) <ul><li>Acute GN : Hematuria, variable proteinuria, azotemia, and hypertension. </li></ul><ul><li>Rapidly progressive GN: Hematuria, oliguria and acute renal failure. </li></ul><ul><li>Prolonged GN : Hematuria and proteinuria without renal dysfunction and hypertension persist over 1 year in patients with definitive past history of acute GN, or ½ y in patients without past history of GN. </li></ul><ul><li>Chronic GN: Over 1 year of disease course with various degree of renal dysfunction and/or persistent hypertension. </li></ul>
  10. 20. <ul><li>minimal change (nephrotic syndrome ) </li></ul><ul><li>focal and/or Segmental glomerular lesion </li></ul><ul><li>focal -Segmental proliferative GN </li></ul><ul><li>focal -Segmental necrotizing GN </li></ul><ul><li>focal- Segmental glomerulosclerosis </li></ul><ul><li>diffuse glomerulonephritis </li></ul><ul><li>non- proliferative: membranous nephropathy </li></ul><ul><li>proliferative glomerulonephritis </li></ul><ul><li>mesangial proliferative GN </li></ul><ul><li>intracapillary proliferative GN </li></ul><ul><li>mesangiocapillary nephritis </li></ul><ul><li>dense deposit GN </li></ul><ul><li>extracapillary proliferative GN </li></ul><ul><li>sclerotic GN </li></ul>Pathologic classification of primary GD
  11. 21. Acute glomerulonephritis (AGN)
  12. 22. Introduction <ul><li>Synonyms: acute nephritis, </li></ul><ul><li>acute nephritic syndrome </li></ul><ul><li>An immunologic mechanism: is the result of </li></ul><ul><li>an immune process that injures the glomeruli </li></ul><ul><li>of the kidney. </li></ul><ul><li>Clinical features: a sudden onset of hematuria , </li></ul><ul><li>proteinuria , edema , hypertension , oliguria and </li></ul><ul><li>volume overload . Azotemia is another </li></ul><ul><li>common but inconstant finding. </li></ul>
  13. 23. Introduction <ul><li>Acute poststreptococcal GN (APSGN): </li></ul><ul><li>AGN that follows an infection with a nephritogenic strain of group A beta-hemolytic </li></ul><ul><li>streptococci . </li></ul><ul><li>One of the most common forms of renal parenchymal disease in childhood. </li></ul><ul><li>The classic example of the acute nephritic syndrome. </li></ul>
  14. 24. <ul><li>Susceptibility to APSGN may be genetically determined as well as dependent on favorable host factors . </li></ul><ul><li>The disease occurs with greatest frequency among children and young adults. Seventy percent of patients are children between 5 and 10 years of age . It is quite rare before age 2 years . </li></ul><ul><li>A 2:1 preponderance of males is reported. </li></ul>Epidemiology
  15. 25. Etiology <ul><li>Many etiologic agents have been implicated in AGN. </li></ul><ul><li>Group A β-hemolytic streptococci are the most common organisms to be associated with AGN. More than 80 types exist, but only a few of them are nephritogenic. </li></ul><ul><li>Other infectious agents : </li></ul><ul><li>other bacteria, viruses, parasites and fungal agents have been implicated, and it is likely that there are diverse etiologies. </li></ul>
  16. 26. The difference of various APSGN <ul><li>Respiratory infection skin infection </li></ul><ul><li>Typical serotypes </li></ul><ul><li>in APSGN 1, 3, 4, 12 * , 25 2, 49 * , 55, 57, 60 </li></ul><ul><li>Areas temperate zone subtropical zone </li></ul><ul><li>Seasons winter & spring summer & autumn </li></ul><ul><li>Age school children young children </li></ul><ul><li>Precursory tonsillitis, scarlet fever, impetigo </li></ul><ul><li>infection Otitis media </li></ul><ul><li>Latent period 1~2 weeks 2~3weeks </li></ul>
  17. 27. Tonsillitis
  18. 28. <ul><li>Circulating immune complexes formation </li></ul><ul><li>In situ immune complexes formation </li></ul><ul><li>auto immune complexes formation </li></ul>Pathogenesis
  19. 29. Traditionally, streptococcal antigens have been considered to be the exogenous antigen stimulating antigen-antibody circulating immune complexes that are subsequently deposited along the glomerular basement membrane (GBM). The processes of immunologic injuries on the GBM are as follows : circulating immune complexes formation
  20. 30. Streptococcal infection immune complex formation immune injuries cellular proliferation GBM fracture capillary lumen narrowed hematuria glomerular blood flow decreased proteinuria oliguria GFR  azotemia retention of water & sodium blood volume  edema hypertension edema hypertension hematuria proteinuria
  21. 31. <ul><li>It is possible that streptococcal antigens bind to the glomerular capillary wall, forming the nidus for in situ immune complex formation. </li></ul><ul><li>Subepithelial deposits of immune proteins are now well known to be induced by exogenous antigens. These antigens are “planted” in the GBM by interaction with negatively charged GBM sites or by charge-independent processes. </li></ul><ul><li>The charge-dependent mechanism may be important in the pathogenesis of APSGN </li></ul>in situ immune complexes formation
  22. 32. Auto immune complexes formation <ul><li>It has been recently suggested that nephritogenic streptococci modify native IgG so that altered autologous IgG would then act as an endogenous neoantigen that would produce antigen-antibody circulating immune complexes . </li></ul>
  23. 33. <ul><li>The histological findings of APSGN are remarkably uniform in distribution in the glomeruli. </li></ul><ul><li>The process is diffuse and generalized in that all the observed glomeruli and all the lobules in each glomerulus are involved to a similar degree. </li></ul>Pathology
  24. 34. <ul><li>focal - segmental </li></ul>generalized - diffuse
  25. 35. <ul><li>All glomeruli appear enlarged and hypercellular . </li></ul><ul><li>Diffuse mesangial cell proliferation with an increase </li></ul><ul><li>in mesangial matrix . </li></ul><ul><li>Polymorphonuclear leukocytes are common in glomeruli during the early stage of the disease. </li></ul><ul><li>Severe endocapillary proliferation is often a poor prognostic sign. </li></ul><ul><li>Crescents are uncommon but may be seen in severe cases. </li></ul>By light microscopy
  26. 39. <ul><li>Subepithelial electron-dense deposits or “humps” are present which are observed on the epithelial side of the glomerular basement membrane (GBM). </li></ul><ul><li>Gaps or discontinuities of GBM, which is likely indicative of proteinuria and hematuria. </li></ul>By electron microscopy
  27. 42. Electron-dense deposits
  28. 43. Electron-dense deposits
  29. 44. <ul><li>Lumpy-bumpy deposits of immunoglobulin G and complement 3 along the capillary loops and within the mesangium. </li></ul><ul><li>It is helpful in the differential diagnosis of other entities that may mimic APSGN clinically, particularly IgA nephropathy. </li></ul>Immunofluorescence microscopy
  30. 48. Clinical manifestations Atypical cases Typical cases severe cases
  31. 49. Typical manifestations
  32. 50. <ul><li>Edema </li></ul><ul><li>The most frequent presenting symptom (85% of the patients) </li></ul><ul><li>First involves the eyelids or periorbital area </li></ul><ul><li>lower extremities generalized (ascites, pleural effusions) </li></ul><ul><li>Nonpitting edema </li></ul><ul><li>Decreased urinary output ( oliguria , anuria) may coexist. </li></ul>Edema and oliguria
  33. 53. <ul><li>urinary output < 250ml/m 2 /24hr </li></ul><ul><li>school child < 400ml/day </li></ul><ul><li>preschool child < 300ml/day </li></ul><ul><li>infant & toddler < 200ml/day </li></ul><ul><li>urinary output < 30 - 50ml/24hr </li></ul>oliguria anuria
  34. 54. <ul><li>Gross hematuria (30-50% of patients) </li></ul><ul><li>The urine is visibly bloody (smoky, tea-colored, cola-colored, or fresh bloody urine). </li></ul><ul><li>The different colors of urine are related to its PH: fresh color neutral or less alkaline </li></ul><ul><li>dark color acid </li></ul><ul><li>Microscopical hematuria (almost all patients) </li></ul><ul><li>The urine appears normal, but >3 RBCs/HP are found in centrifuged urine sediment examined microscopically. </li></ul>Hematuria
  35. 55. <ul><li>Reported in 30-70% of patients </li></ul><ul><li>Pathogenesis: related to ECF expansion in </li></ul><ul><li>part or vasospasm. </li></ul><ul><li>The magnitude of the increase in Bp is </li></ul><ul><li>highly variable. </li></ul><ul><li>mild-moderate: 120-150/80-110mmHg </li></ul><ul><li>severe: >200/120 mmHg </li></ul><ul><li>h ypertensive encephalopathy </li></ul>Hypertension
  36. 56. <ul><li>Nonspecific symptoms: </li></ul><ul><li>such as anorexia, vomiting, general malaise, abdominal or flank pain, low-grade fever and lethargy are uncommon. </li></ul>Others
  37. 57. <ul><ul><ul><li>Acute </li></ul></ul></ul><ul><ul><ul><li>renal </li></ul></ul></ul><ul><ul><ul><li>failure </li></ul></ul></ul>Hypertensive encephalopathy Circulatory congestion Severe manifestations <ul><ul><ul><li>The early phase of acute nephritis in children is </li></ul></ul></ul><ul><ul><ul><li>perilous because of three possible complications </li></ul></ul></ul>
  38. 58. <ul><li>Cause: an increase in blood volume secondary to </li></ul><ul><li>retention of sodium and water. </li></ul><ul><li>Features: </li></ul><ul><li>dyspnea, orthopnea, and cough </li></ul><ul><li>pulmonary rales </li></ul><ul><li>increased HR, gallop rhythm, venous </li></ul><ul><li>engorgement, enlarged liver </li></ul><ul><li>Chest radiograph: cardiomegaly and pulmonary </li></ul><ul><li>edema. </li></ul>Circulatory congestion
  39. 59. <ul><li>The most serious early complication. </li></ul><ul><li>Pathophysiology: </li></ul><ul><li>An acute rise in systemic Bp exceeds the </li></ul><ul><li>individual cerebral autoregulatory </li></ul><ul><li>range </li></ul><ul><li>Increased cerebral perfusion </li></ul><ul><li>Exudation of fluid into the brain (cerebral </li></ul><ul><li>edema) </li></ul><ul><li>Clinical featurs: headache, vomiting, depressed </li></ul><ul><li>sensorium, confusion, visual disturbance, </li></ul><ul><li>aphasia, memory loss, coma, convulsion, </li></ul><ul><li>papilledema. </li></ul>Hypertensive encephalopathy
  40. 60. <ul><li>Sudden loss of the ability of the kidney to excrete excess water and wastes, and conserve electrolyte. </li></ul><ul><li>Features </li></ul><ul><li>Oliguria or anuria </li></ul><ul><li>Azotemia </li></ul><ul><li>Hyperkalemia </li></ul><ul><li>Metabolic acidosis </li></ul>Acute renal failure
  41. 61. Atypical manifestations
  42. 62. <ul><li>No edema, hypertension, or gross hematuria </li></ul><ul><li>Is discovered by examination of urine </li></ul><ul><li>Moderate-severe symptoms </li></ul><ul><li>Normal urinalysis or minor urinary change </li></ul>Asymptomatic acute nephritis The prodromes of streptococcal infection and low level of C 3 is helpful in diagnosis. Acute nephritis with minimal urinary findings Acute nephritis with severe proteinuria
  43. 63. Laboratory findings <ul><li>Urinalysis </li></ul><ul><li>Blood routine test and ESR </li></ul><ul><li>Serum concentration of complement 3 </li></ul><ul><li>Evidences of a prior streptococcal infection (ASO) </li></ul><ul><li>Renal function </li></ul>
  44. 64. <ul><li>Hematuria (Gross or microscopic) </li></ul><ul><li>Proteinuria: ranging from 1 + to 3 + qualitatively. There is usually not more than 1 gram of protein in a 24-hour collection quantitatively . </li></ul><ul><li>Centrifuged urinary sediment: RBCs, WBCs, epithelial cells, casts( RBC-, WBC-, hyaline-, granular-) </li></ul><ul><li>Contrast- phase microscopy: Dysmorphic RBCs are indicative of glomerular hematuria. </li></ul>Urinalysis
  45. 66. Red blood cell cast in a patient with glomerular hematuria
  46. 67. Granular cast
  47. 70. <ul><li>Anemia </li></ul><ul><li>Normocytic, normochromic in the early </li></ul><ul><li>phase </li></ul><ul><li>Mild-moderate (parallel the degree of </li></ul><ul><li>ECF volume expansion) </li></ul><ul><li>PLT is normal </li></ul><ul><li>WBCs is normal or increased </li></ul><ul><li>ESR may be accelerated in the acute phase </li></ul>Blood routine test and ESR
  48. 71. <ul><li>Reduced serum C 3 levels in at least 90% of patients examined in the early phase of their nephritis. </li></ul><ul><li>Serum C 3 returns to normal concentrations 10 days to 8 weeks after presentation, so serial examination of C 3 is particularly helpful in substantiating the diagnosis. </li></ul><ul><li>The level of reduction of C 3 does not have prognostic significance. </li></ul><ul><li>Prolonged hypocomplementemia suggests alternative diagnosis. </li></ul><ul><li>Follow up to check the C 3 level is important. </li></ul>Serum concentration of complement C 3
  49. 72. <ul><li>Antibodies to a variety of streptococcal antigens </li></ul><ul><li>Antistreptolysin O (ASO) </li></ul><ul><li>Anti-diphosphopyridine nucleotidase(ADPNase) </li></ul><ul><li>Anti-hyaluronidase (AHase) </li></ul><ul><li>Anti-deoxyribonuclease B(ADNase B) </li></ul><ul><li>ASO The ASO titer is usually elevated from 1 to 3 weeks after the infection, reaching the highest level of titer from 3 to 5 weeks, and returning to normal 3~6months after the streptococcal infection. </li></ul>Evidences of a prior streptococcal infection
  50. 73. <ul><li>Elevated BUN and creatinine values </li></ul><ul><li>This reflects the decrease in the glomerular filtration rate that occurs in the acute phase </li></ul><ul><li>The elevations are usually transient. </li></ul><ul><li>Acute renal failure is rare in children with APSGN </li></ul>Renal function
  51. 74. Diagnosis <ul><li>Acute onset </li></ul><ul><li>Symptoms: edema, oliguria, dark urine, </li></ul><ul><li>hypertension </li></ul><ul><li>Urinalysis: RBCs, protein, casts </li></ul><ul><li>Evidences of streptococcal infection: </li></ul><ul><li>Prodromes </li></ul><ul><li>Elavated serum titers of Abs to streptozymes(ASO) </li></ul><ul><li>Reduction of serum concentration of C3 </li></ul>
  52. 75. Differential diagnosis <ul><li>Urinary tract infection </li></ul><ul><li>Membranoproliferative disease </li></ul><ul><li>Benign recurrent hematuria </li></ul><ul><li>Primary nephrotic syndrome </li></ul>
  53. 76. Treatment <ul><li>Nursing and diet </li></ul><ul><li>Antibiotic therapy </li></ul><ul><li>Symptomatic therapy </li></ul><ul><li>Treatment of severe complications </li></ul>
  54. 77. <ul><li>Bed rest is indicated as long as there are clinical manifestations of active disease, such as edema, hypertension, or gross hematuria (usually subside within 2-3w). </li></ul><ul><li>Dietary limitations of sodium and water may be necessary during the early stage. </li></ul><ul><li>Protein needs to be restricted if azotemia occurs during the initial stage of acute nephritis (protein intake<0.5g/kg/day). </li></ul>Nursing and diet
  55. 78. <ul><li>All patients should receive a 10-day course of penicillin or other antistreptococcal antibiotic if APSGN is considered. </li></ul><ul><li>It is recommended to ensure eradication of the streptococcus. </li></ul><ul><li>This has no influences on the course or prognosis of the nephritis. </li></ul>Antibiotic therapy
  56. 79. <ul><li>Major goal: control edema and blood pressure. </li></ul><ul><li>Based on the clinical severity of the illness. </li></ul><ul><li>Restriction of salt and water is the most important and the first measure. </li></ul><ul><li>Diuretic and antihypertensive therapy. </li></ul>Symptomatic therapy
  57. 80. <ul><li>Dihydrochlorothiazide (DHCT) : </li></ul><ul><li>2-3 mg/kg.d, P.O. </li></ul><ul><li>Furosemide: </li></ul><ul><li>1-2 mg/kg orally, or 1mg/kg im/iv, repeated at 6- to 8-hour intervals until the desired diuresis is obtained. </li></ul>Diuretics
  58. 81. <ul><li>Diastolic value exceeds 90 mm Hg (12.0kPa), antihypertensive therapy should be given. </li></ul><ul><li>Nifedipine , a calcium channel blocker, 0.25 to 0.5 mg/kg.d, P.O. The ease of sublingual dosing is advantageous. </li></ul><ul><li>Reserpine , 0.07 mg/kg.dose i.m. The maximum dose should not exceed 2.0 mg. </li></ul><ul><li>Captopril , an angiotensin-converting enzyme inhibitor, 0.3 mg/kg.d, t.i.d, P.O. </li></ul>Antihypertensives
  59. 82. Treatment of severe complications
  60. 83. <ul><li>Anti-convulsion </li></ul><ul><li>Reduce Bp as rapidly as possible (fast-acting vasodilators) </li></ul><ul><li>Sodium nitroprusside: </li></ul><ul><li>25mg+5%GS500ml (50  g/ml) /iv drip at </li></ul><ul><li>0.02ml(1  g)/kg.min slowly increased </li></ul><ul><li>(max: 0.16ml (8  g)/kg.min ) </li></ul><ul><li>Diazoxide: </li></ul><ul><li>3-5 mg/kg intravenously; May be repeated in </li></ul><ul><li>15-30 min </li></ul><ul><li>Reduce cerebral edema diuretics (furosemide) </li></ul>Hypertensive encephalopathy
  61. 84. <ul><li>Restriction of water and salt is the first management. </li></ul><ul><li>Diuretics : furosemide 1mg/kg/dose, IV or </li></ul><ul><li>2mg/kg/dose, P.O </li></ul><ul><li>Sodium nitroprusside </li></ul><ul><li>Low-dosage of fast-acting digitalis (cedilanid) </li></ul><ul><li>Peritoneal dialysis or hemodialysis </li></ul>Severe circulatory congestion
  62. 85. <ul><li>Strict restriction of fluid intake </li></ul><ul><li>Furosemide can be increased to 5mg/kg/dose, if still no effect on diuresis, no need for further use. </li></ul><ul><li>Control hyperkalemia: IV calcium, glucose/insulin, and oral or rectal administration of potassium exchange resin </li></ul><ul><li>Dialysis: Persistent anuria, severe fluid overload, hyperkalemia, azotemia, metabolic acidosis. </li></ul>Acute renal failure
  63. 86. Disease course and prognosis (1) <ul><li>Most children (95%) with APSGN has an excellent prognosis. </li></ul><ul><li>The clinical course is largely predictable: </li></ul><ul><li>1. Resolutions of the main symptoms: </li></ul><ul><li>Edema, hypertension and gross </li></ul><ul><li>hematuria resolve within 2 </li></ul><ul><li>weeks. </li></ul><ul><li>The C3 returns to normal by 6-8w </li></ul><ul><li>(95%) </li></ul>
  64. 87. <ul><li>2. Abnormalities on urinalysis resolve </li></ul><ul><li>at a slower pace: </li></ul><ul><li>Proteinuria disappear within 2-3m </li></ul><ul><li>6m 1-2y (intermittent or postural </li></ul><ul><li>proteinuria) </li></ul><ul><li>Microscopic hematuria disappear </li></ul><ul><li>after 6m 1y 1-3y </li></ul><ul><li>Chronic phase: both hematuria and </li></ul><ul><li>proteinuia persist for more than 12m. </li></ul>(2)
  65. 88. Keys to be remembered <ul><li>Definition of AGN, APSGN, </li></ul><ul><li>The table: The difference of various APSGN; </li></ul><ul><li>Pathogenesis </li></ul><ul><li>Clinical manifestations </li></ul><ul><li>Laboratory findings </li></ul><ul><li>Diagnosis </li></ul>
  66. 89. <ul><li>1. Write down the beneficial hemodynamic effects of squatting position that adopted by patients with TOF. </li></ul><ul><li>2. Definition of Eisenmenger's syndrome </li></ul>quiz

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