Nephrotic vs Nephritic syndrome
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1 Nephrotic vs Nephritic syndrome Hooman N.MD IUMS 3 y/o male presents to the ER with fever, abdominal pain, and has had puffy eyes for the past 2 days. 1
2 What is your diagnosis? 2
3 Type of Edema Non Pitting Edema 3
4 Measurement of Proteinuria Semiquantitative Dipstick Turbidometric SSA TCA - NA Quantitative Turbidometric methods+photometer/nephrometer Ultraviolate spectrophotometry Biuret method (more sensitive) Micro kjeldahl method ( research most accurate) Qualitative measures Electrophoresis Immunodiffusion ELIZA Dipstick Interpretation Negative0 = no Trace = < 30 mg/dl 1+ = 30 mg/dl 2+ = 100 mg/dl 3+ = 300 mg/dl 4+ = 2000 mg/dl 4
5 Method Interpretation Sulfosalicylic Acid turbidity ( 0 mg/dl) Trace = slight turbidity (1-10 mg/dl) 1+ = print can be read (15-30 mg/dl) 2+ = through which heavy black lines on white background can be seen 3+ = white cloud with fine precipitate through which heavy black lines cannot be seen ( mg/dl) 4+ = flocculent precipitate (> 500 mg/dl) Method Dipstick Turbidometric Concentrated urine False + False + Dilute urine False - False - Urine PH>8 False + False - Contamination antiseptic False + No effect Tolbutamide metabolites No effect False + Penicillin, Cephalosporin No effect False + Sulfisoxazole metabolites No effect False + Phenazopyridin False + No effect contrast media No effect False + Measurement of Proteinuria Quantitative Methods Timed Urine Collection Overnight 24- Hour Lack of consistency Activity Other factors Improper timing OVER COLLECTION, UNDER-COLLECTION Incomplete bladder emptying, Neurogenic bladder, Incontinency Radio contrast media (FP) 5
6 Measurement of Proteinuria Quantitative Methods UPr/UCr (T.Prot vs. albumin) Random First morning Lower creatinine excretion in» Female» Age Variable creatinine excretion in NB Hydration Total Urine Protein(g/m 2 /d)=0.063x(upr/cr) Up/Ucr = daily protein excretion in gram (Cr excretion is = 1 gr/day) adult Have to be corrected for age, sex, body weight Case 1: A previously well 3 yr F CC: facial puffiness (few days ago) PE: BP=92/55,PR 20,HR=90, T 37 HN-Heart- Lung & Abdomen= Nr Ext 2+ pulses U/A 4+ protein, SG 1.030, Blood ; Prot 2g/dl, S Alb 1.4 g/dl, Cholestrol 350 mg/dl BUN Cr nr WHAT IS THE DIAGNOSIS? 6
7 Definition Generalized edema Most commonly beginning as facial, particularly periorbital, and pretibial edema Hypoproteinemia (<2g/dL) albumin<<globulin Albumin:Globulin < 1.0 Proteinuria 3-4+ on urine dip Protein:Creatinine > 2.0 (first morning void) 24 hour protein > 50 mg/kg Hypercholesterolemia (>200mg/dL) VLDL and LDL Other Laboratory Findings Microscopic Hematuria if gross hematuria, must consider IgA nephropathy Hyponatremia Hypocalcemia Hyperkalemia - Hypokalemia Hypercoaguability increased thrombin and decreased platelet inhibitors PTT Normal complement levels 7
8 Additional Clinical Findings Abdominal Pain Ascites Oliguria Scrotal/Labial swelling Tachypnea Chest Pain Etiology Primary (Idiopathic) Nephrotic Syndrome (90%) Minimal Change Disease (80%) Focal Segmental Glomerulosclerosis (FSGS) (10%) Mesangial Proliferation (5%) Mebranoproliferative Glomerulonephritis (MPGN) (5%) Membranous Nephropathy (1%) Minimal Change Disease Younger age Glomeruli appear normal or show minimal mesangial increase Not usually associated with hematuria or hypertension No association with renal failure Majority (90%) respond to steroids 8
9 Overview of Primary Nephrotic Syndrome Min. change FSGS MPGN Hematuria 10-20% 60-80% 80% HTN 10% 20% 35% Renal Failure None 10 years 5-20 years Microscopy Foot process fusion Sclerotic lesions Variable Immune None IgM Complement Steroid response 90% 15-20% Unknown Adjunctive therapy Diuretics (Lasix, thiazides) Albumin only if needed for volume resuscitation or severe hyponatremia Sodium restriction (3 gm/kg) Fluid restriction (if hyponatremic) Ace inhibitors (if hypertensive) Statins (if hyperlipidemia is severe) Immunization Pneumococcal, Varicella and Flu 9
10 Relapse and Resistance Most children (up to 80%) will go on to relapse several times = proteinuria >3d with edema Relapses are treated with a 2 nd course of steroids Frequent relapser 4 relapses in 1 year Steroid Dependent if the relapse is during taper or within 28 days of initial course Steroid resistant No initial response after 8 wks of steroid therapy. Most often FSGS. Other agents such as high dose methylprednisolone and cylcophosphamide may be used When to consider biopsy? If initial presentation includes: Hematuria Hypertension Renal Insufficiency Hypocomplementemia Age <1 yr or >8-10 yrs Steroid resistant Complications Infection Loss of immunoglobulins Immunosupressive therapy Protein malnutrition Edema / Ascites *spontaneous bacterial peritonitis is most common infection 10
11 More Complications Thromboembolic events (2-5%) Arterial and Venous Increase in prothrombotic factors: Fibrinogen Hemoconcentration Decrease in fibrinolytic factors: Antithrombin III Proteins C and S * Avoid aggressive diuresis and use of indwelling catheters Still more complications Hypothyroidism loss of thyroid binding globulin (TBG) Hypocalcemia loss of vitamin D binding globulin Steroid-associated Weight gain Gastritis Osteoporosis Cataracts Mood changes Diabetes 11
12 In the clinic 10 y/o boy with Gross Hematuria for 3 weeks With every void, with some frequency. Brownish red in color, now tea colored. Mild back pain for the past few days. No dysuria, no abdominal pain, no fever. 2 wks ago, Hx / of URI like picture, with sore throat, no meds taken. No Rash, no cough. Resolved on its own. mild edema Creatinine 1 mg/dl BUN 96 mg/dl CBC= normal, with Hgb 10 gm/dl Pt. has BP s 170/100 ASO elevated at 760 UA= large blood, and 3+ protein Multiple RBC casts on microscopic exam of urine. What is the diagnosis? 12
13 Nephritic Syndrome Differential Diagnosis Acute Postinfectious Glomerulonephritis IgA (±IgG) Deposition Systemic Lupus Erythematosus IgA Nephropathy - Berger's Disease Henoch-Schonlein Purpura (HSP) Ischemia/Infarction (ATN or papillary necrosis) Autoimmune Disease Membranoproliferative GN Etiology Following infections by nephritogenic strains of Group A ß hemolytic streptococci Pharyngitis (serotypes 1, 2, 4 and 12) Impetigo (serotypes 47,49, 57) Infection is uncommon in children <2 y/o Possibly due to decreased attachment of GABHS to nasopharyngeal epithelial cells Close contact with potentially infected individuals occurs in child care and grade school 13
14 Case definition for APSGN Clinical cases need 4 criteria, Subclinical cases, only criteria 2,3 and 4 Clinically compatible illness with one or more of : Oedema Macroscopic hematuria High blood pressure ( DPB>80 mmhg if 13 years of age or younger, or > 90 mmhg if older than 13 years) Microscopic glomerular hematuria RBC > 10/ml Dipstick : hematuria of 2+ or more Evidence of recent streptococcal infection Positive GAS culture from skin or throat, or elevated ASO or anti- DNase B Reduced serum complement level Hyaluronic acid capsule Hide its own Ag Prevent opsonized phagoctosis by neutrophils /macrphage Hyaluronidase Digest host connective tissue / own Capsule Streptokinases Fibrin lysis Streptodronase Streptolysin Deoxyribonuclease s/o activity oxigen stable/labile leukocidin protein M, F M Adhesins protein Colonization Resistance to phagocytosis LTA Adhesins Serology Anti-streptolysin O (ASO) Antibodies rise in ~75% of cases Titers of ASO rise within days; declines over 1-6 months Anti-DNase B and Anti-hyaluronidase rise more quickly Elevation in any of the titers will detect ~100% of persons with recent strep infection Note that ASO titers rise in pharangitis, not in cutaneous disease Streptococcal antigen M serotypes 12,1, and 4 are especially associated with GN Anti-Streptokinase, M-protein specific tests, and anti-nadase can also be determined 14
15 Pathogenesis Formation of immune complexes including antibodies and streptococcal antigens Localization (deposition) on subepithelial portion of glomerular basement membrane Initiate inflammatory response, including Complement deposition (reduced serum levels) This leads to localized mesangial and endothelial cell proliferation Clinical Manifestation Rare before age 3 Initial pharyngitis MAY present with: Fever, tonsillopharyngeal erythema, exudate, swollen/tender adenopathy. Absence of rhinorrhea and cough 60-70% of children will present as such. Clinical Manifestation Later Malaise, Lethargy, Abdominal/Flank Pain, Fever are common. Typically an acute nephritic syndrome develops 1-2 wk after a strep pharyngitis Or 3-6 wks after strep pyoderma Nephritic Syndrome: Tea colored urine Only 1/3 rd present with gross hematuria 2/3 rd could be microscopic Facial/body edema HTN Oliguria Renal involvement ranges from asymptomatic microscopic hematuria to ARF. 15
16 Further Manifestations Encephalopathy Hypertension is the commonest cause Toxic effects of strep on the CNS-rare Heart Failure Secondary to HTN, and hypervolemia Nephrotic Syndrome may develop in 10-20% of cases. Heavy proteinuria (40mg/m 2 /hr) Hypoalbuminemia (<2.5g/dL) Edema Acute Phase resolves anywhere from 3 weeks to 2 months after onset. Hematuria (gross or microscopic) can continue for up to a year Diagnosis UA RBC s RBC Casts Proteinuria Leukocytes From inflammation, not a response to infection!! Normochromic Anemia Low grade hemolysis and Hemodilution Serum C3 is reduced Returns to normal 6-8 wks after onset 16
17 Confirmation of Diagnosis Positive Throat Culture Can represent the carrier state Limited by: Poor culture technique Surreptitious abx use Rapid Strep: 76-87% sensitive 90-96% specific Elevated ASO Rarely elevated after strep skin infections Can indicate recent infection Anti-DNase B antigen Elevated in both pharygitis and pyoderma Your best bet More tests Anti-Zymogen titers Shown to be 88% sensitive, and 85% specific in the diagnosis of strep infection with glomerulonephritis. Hardly used Streptozyme test Detects ab to streptolysin O, DNase B, hyaluronidase, streptokinase, nicotinamideadenine dinucleotidase When to consider a Renal Biopsy? Usually not done, unless Symptoms point towards SLE ARF Low C3 level for more than 3 mos after onset Clinical features do not resolve in 6-8 wks. REMEMBER: asymptomatic microscopic hematuria can be expected for up to one year) 17
18 18
19 Complications ARF Volume overload Heart Failure HTN - 60% of patients Hyperkalemia Hyperphosphatemia Hypocalcemia Acidosis Seizures Uremia Treatment 10 day course of ABX If throat culture positive, not for pyoderma Does not affect course or risk of GN Does limit the spread of nephritogenic organisms Na + restricted diet Anti Hypertensive Meds Ca + channel blockers Vasodilators ACE inhibitors Management of ARF complications Prognosis 95% children with complete recovery. Recurrence is rare. 19
20 NS APSGN HTN -ve +ve Urine Color dark yellow Cola color Proteinuria Severe Moderate Pulmonary Edema -ve +ve Edema Pitting nonpitting pale pink cold warm Size of Heart small Large Hematuria not persist Macro/Micro micro C3 Nr Low Renal Failure -ve +ve ECF Low High 20
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