OS 214: RenalGlomerulonephritis (GN) Dr. Agnes Mejia Exam 1&2 OUTLINE I. II. III. IV. V. A. B. C. VI. VII. VIII. Introduction Glomerulonephritis Pathogenesis of Glomerulonephritis Approach to Patient with Glomerulonephritis Forms of Glomerulonephritis IgA Nephropathy Poststreptococcal Glomerulonephritis Membranous Glomerulonephritis Summary Socioeconomic impact of Glomerulonephritis Figures O2sat 92%) Severe Uncompensated Metabolic acidosis (low pH, low HCO3; causes tachypnea) Heart not enlarged but with congestion Showed pulmonary edema Peaked T waves (denotes hyperkalemia) you have to give calcium gluconate as treatment Small shrunken kidney Cortex should at least be 4.5cm thick CXR To rule out pneumonia EKG Check for hyperkalemia UTZ Note: The lecturer did not provide a powerpoint. Thank you to Irving for sending pictures of the ppt for this trans. Please be reminded that the exam questions will come mainly from HPIM 17th ed.; topics included are general information on glomerular disease, GN, IgA nephropathy, PSGN and MGN. I. INTRODUCTION A. Case of ER, presented with: o high BP (160/100), HR 104, RR 30/min o pale, sallow (in between pallor and jaundice) o “peculiar fetor” – fruity smell o evidence of cardiac damage (Grade II Av block hypertensive) but not yet in CHF due to absence of s3 o no evidence of liver involvement o ++ bipedal edema o Dry skin, good and equal pulses o Basal crepitant rales B. Primary Impression: UREMIA (symptom diagnosis) Symptoms seen in the ER o Vomiting o Tremors o Anorexia o Weakness o SOB o Pruritus o Easy fatigability o Irritability Full blown Uremia (not seen in ER) o Somnolence o Seizures o Disorientation o Coma *Azotemia is a laboratory diagnosis Uremia a clinical diagnosis C. Labs Requested Lab CBC BUN *Creatinine Purpose Check for anemia due to pallor To asses kidney function, but creatinine is more important Single most important test for uremia (uremic if azotemic); if high, tells you that px likely has kidney disease To check for acidosis Finding in ER Low Hg (7) Elevated (60umol/L) Increased (1800 umol/L) Urinalysis Visualize the kidney: If enlarged (e.g. 12 cm)=acute GN, reversible If shrunken=ESRD,irreversi ble (Normal Filipino size:9.6 cm in length; Normal Caucasia:11-12 cm) *Normal globular, thick cortex “window to glomerular disease” -early morning urine expected to have a dark, intense color if kidney is able to concentrate urine - concentrated (Sp. gravity 1.020-1.030) -Acute GN – red cell casts; RBCs degenerate to fine/coarse granular casts reflects chronicity -Hyaline casts can be found in a normal person -Most common cause of pus cells non infective pyuria -low sp. gravity -granular casts -Increase RBC and WBC -mucus threads rare denotes that urine was well collected -px has no fever but high WBC may indicate sterile pyuria *if creatinine is high, BUN is expected to be abnormal; if BUN is high, creatinine is not necessarily high *the presence of protein in the urine is not correlated with the specific gravity of the urine since SG indicates the ability of the kidneys to concentrate. Even if this is intact, the kidneys can still spill out urine. *those in asterisks are the cheaper tests, so they are the most economical and efficient in terms of information. D. Final Diagnosis: o Uremia secondary to ESRD (CKD Stage secondary to Chronic Glomerulonephritis (CGN) V) Basis for diagnosis: CGN o young adult, hypertension at age 19 (hypertensive nephrosclerosis takes about 20 years to develop, and so it is an unlikely ddx) o hematuria, pyuria o small kidneys (denotes a chronic problem, not acute) ESRD o o o shrunken kidneys uremia, anemia, low Ca Inc phosphorus Electrolytes Ca Phosphorus **K ***ABG Decreased Elevated (6) Elevated (5.9) *Single most important determinant of chronicity shrunken kidneys *Severe renal failure Ca low, Phosphorus high **ER is a UP student; inc BP at age 19 (140/90). ER was erroneously treated as UTI for 3 years in a male with no symptoms and an abnormal urinalysis; ER passed engineering boards 3 days before he underwent hemodialysis! Needed if urgent action is required (can easily kill the patient) Needed if urgent action is required (pH7.2; pCO235; pO294; HCO311; March 6, 2009/Friday Page 1 of 7 Seth, Ian OS 214: Renal Glomerulonephritis (GN) Dr. Agnes Mejia Exam 1&2 *Immunofluorescence can be used to determine whether immune complexes are in-situ or circulating My Goals (which I guess have to be our goals) 1. To be aware 2. To be suspicious 3. To Set the Alarm II. Glomerulonephritis -inflammation of the glomerular capillaries a. Normal Kidneys: o smooth surface o pinkish cortex o reddish medulla o yellow calyces, pelvis o In GN: kidneys are pale *Kidney disease has 10 types but can manifest the same way. But if you look inside the kidneys, the pathology is actually different. They hit different parts of the kidney thus histology is important! b. Glomerulus o 600 thousand – 2 million (all in all) in a normal individual *prematures have less glomeruli higher tendency for hypertension higher tendency for renal disease at age 50 o is a ball of capillaries (“berries”) with afferent and efferent arterioles (histology: stalk – where efferent and afferent arterioles run) o glomerular capillaries filter 120-180 L/d of plasma water o filtration occurs through a physicochemical barrier governed by pore size and negative electrostatic charge o glomerulus is an imperfect barrier *e.g. albumin-despite its negativity, readily passes through due to its small radius (3.6nm vs. 4nm radius of glomerular basement mebrane (GBM) slit-pores); albumin is reabsorbed in the proximal tubules (urine normally contains only 8-10 mg) *Glomerulonephritis can affect any part of the glomerulus (mesangium, parietal epithelium, basement membrane, podocytes) and will manifest differently. In GN: the glomeruli are full of scars Pathogenesis: (1) Circulating immune complexes (2) In-situ immune complexes *Overlapping etiologies may produce similar glomerular lesions display common patterns of injury (syndrome); this is evident in microscopy: IgA paramesangial; can still see spaces in glomerulus; most common in Asians Poststrep GN (PSGN) – same pattern of injury can be seen in lupus; immune-complex GN; most common post infectious Membranous GN (MGN) –same pattern can be seen in idiopathic, Hepatitis, and drug-induced; just hits the basement membrane, causing it to thicken; most common in men IV. Approach to Patient with Glomerulonephritis A. History and PE (what to look at) o confined to the kidneys or systemic? acute or chronic? o signs and symptoms (what to ask the px) • dysuria – pain during urination? • nocturia – urination at night? • • hematuria – blood in the urine? (2 kinds gross and microscopic) o o o o o retention/incontinence – incomplete voiding? • frequency – urinating more often? • Sediments- may “latak” sa ilalim ang ihi? • frothy urine – like beer? • edema last known urinalysis/creatinine pregnancy status (preeclampsia); birth control pills last normal BP Blood pressure • must give exact value, not just saying normal or high, because what is high for one person may be normal for another Urinalysis • window to glomerular disease • Quality of urine: clear, cloudy or bloody (gross hematuria) *if with gross hematuria and is painless consider malignancy until proven otherwise; if painful, consider urethritis *Dilute urine yellow concentrated *Cloudy tea colored *Bloody gross hematuria Table 277-1. Urine assays for albumin/proteinuria (HPIM 17th ed) 24Hr Albumin/ Dipstick 24Hh Albumin creatinine proteinuri Urine (mg/24h) ratio a Protein (mg/G) (mg/24h) Normal 8-10 <30 <150 Microalbu 30-300 30-300 -/trace/1+ minuria Proteinuria >300 >300 Trace-3+ >150 V. Forms of Glomerulonephritis (Patterns of Clinical GN) Form Acute Nephritic Infectious Disease Associated; Nephritic Nephrotic Basement membrane Glomerular Vascular Disease Prototype Disease IgA Nephropathy PostStreptococcal (PSGN) Membranous GN Alport’s syndrome ANCA small vessel vasculits T-cells (CD 4/8) activation Loca activation of toll-like receptors on Glomerular Cells Deposition of Immune Complexes Complement injury Glomerular injury Mononuclear infiltration Cytokine release Attract more inflammatory cells Glomerular damage GN *In summary, GN may be caused by circulating or in situ immune complexes, but whichever the cause is, they both follow the path of inflammation via T-cell activation March 6, 2009/Friday Page 2 of 7 Seth, Ian OS 214: Renal Glomerulonephritis (GN) Dr. Agnes Mejia Exam 1&2 Pumonary-Renal Goodpasture’s disease o o *just focus on the first three as said by the lecturer, ayt? A. IgA Nephropathy CASE: 31 female Routine annual Physical checkup Urinalysis RBC –TNTC WBC – 0-3 Protein (-) Casts (-) BP 120/70 o o o o o immune complex mediated GN defined by the presence of diffuse mesangial IgA deposits often associated with mesangial hypercellularity circulating immune complexes get deposited in the mesangium or podocytes (not the basement membrane [BM]) IgM, IgG, C3, or immunoglobulin light chains can be codistributed with IgA Mild – do not undergo dialysis RPGN (rapidly progessive)- end up in dialysis after 6 mos • POSTstrep GN - tea colored urine happens 2 weeks after infection • In IgA – happens with the infection o o o sometimes recur post transplant risk factors for renal failure: HPN, proteinuria, absence of episodic macroscopic hematuria, male, older age of onset, sever renal biopsy changes “Point of no return” – stage where treatment is insufficient usually when creatinine is at least 2 the clinical prognostic index (CPI) of GN–made in Verona, Italy; a scoring system that predicts the prognosis of GN • 2pts for Serum Creatinine> 1.4mg/dl • 1pt for Proteinuria> 1g/24 hrs • 1pt for presence of HPN • 1pt patient > 30 years old Score of 0-2*: higher 10-year renal survival; 3-5: lower 10-year renal survival; most likely to end up in dialysis; hence, creatinine is the single most impt predictors of survival since it automatically gives you 2pts if abnormal *Immunoflourescence positive for IgA • Treatment o Evidence-based: ACEI-ARB, Steroids, fish oil (severe only), sequential, cyclophosphamide: azathioprine (progressive only) o Non-evidence Based: azathioprine/MMF, CNI (CsA Tacro), IVIg, Leflunomide, heparin/warfarin/dipyridamole, tonsillectomy • *IgA GN is common, progressive, but treatable Pathogenesis: defective immune response formation of immune complex proinflammatory, proproliferative, proapoptotic, profibrotic + milieu in glomeruli mesangial/podocyte injury, capillary hypertension, altered perm selectivity, glomerulosclerosis, tubulo-interstitial fibrous hematuria, proteinuria, decreased GFR Epidemiology o most common form of GN worldwide o 30% in Asia and Pacific RimEast > West o 20% in southern Europe o low prevalence in N. Europe & N. America o Male > Female o peak incidence: 2nd-3rd decade of life o rare familial clustering Presentation o most common presentations are: • recurrent episodic macroscopic hematuria following a respiratory infection in children • asymptomatic microscopic hematuria seen in adults o between episodes, urinalysis is normal o in persistent hematuria, increasing proteinuria is found Differentials o Henoch-Schonlein Purpuracan be distinguished for IgA Nephropathy by prominent systemic sx, younger onset (<20yrs old), preceding infection and abdominal complaints o Crohn’s disease, chronic lover disease, GI adenocarcinoma, etc –also present with IgA deposition in mesangium; can be differentiated due to absence of significant glomerular inflammation. Progression o generally a benign disease, but 25-30% progress to renal failure over 20-25 yrs. o 5-30% go into complete remission B. PostStreptococcal Glomerulonephritis (PSGN) CASE: 22 male 1 month impetigo in L leg Pus, crust, swelling, redness, fever tea colored urine, dec outpu, puffy eyelids, anorexi, easy fatigability, inc BP o o o also known as Postinfectious GN prototype for acute endocapillary proliferative GN classically not a nephritic syndrome • • • • Pathogenesis: putative streptococcal antigens circulating 1-C, activation of complement with cell mediated injury deposition in GBM Epidemiology o typically sporadic o children between 2-14 yrs (10% in px>40yrs) o Males > Females o 10% pts>40yrs o familial/cohabitant incidence is high-40% o M types of Streptococci (nephritogenic strains) o impetigo- M types 2, 47, 49, 55, 57, 60; PSGN develops 2-6 wks after a skin infection o Pharyngitis (nephritogenic strain)- M types 1,2, 3, 4, 12, 25, 49; PSGN develops 1-3 wks after strep upper respiratory infection (pharyngitis) Labs o Decreased CH50, decreased C3 o Inconsistently positive culture (10-70%) o Increased ASO titers (30%) o Anti-DNase (70%) o Antihyaluronidone Ab (40%) Presentation • • • • March 6, 2009/Friday Page 3 of 7 Seth, Ian OS 214: Renal Glomerulonephritis (GN) Dr. Agnes Mejia Exam 1&2 o o o o o o classic presentation of acute nephritic px: HPN, hematuria, RBC casts, pyuria, mild to moderate proteinuria oliguric renal failure systemic symptoms include headache, malaise, anorexia, flank pain (swollen renal capsule) in 50% of cases in the 1st week of symptoms: 90% have depressed CH50, decreased C3 (because they are circulating and get deposited in the GBM) positive strep cultures are inconsistent • • heavy proteinuria (24h urine total protein > 3g), minimal hematuria, hypoalbuminemia, hypercholesterolemia, HPN if untreated leads to progressive glomerular injury, decline in GFR and renal failure Edema There are 2 theories for the cause of edema due to NS: 1. Underfill protein spillage low albumin (albumin acts as the magnet that attracts fluid) low oncotic pressure low intravascular volume secondary sodium retention EDEMA 2. Overfill low GFR low RPF and low FF primary Na retention Expanded ECF volume EDEMA Nephrotic syndrome (NS) is described as: 24hr total Pr>3gm, hypertension, hypercholesterolemia, hypoalbuminemia, edema/anasarca *therapy of edema in NS: low Na diet, oral loop diuretic, goal of 1-2lbs edema loss/day Renal Biopsy o LM: uniform thickening of the BM along the peripheral capillary loops o Immunoflorescence: diffuse granular deposits of IgG and C3 o EM: electron dense subepithelial deposits Renal Biopsy o diffuse proliferative: little bowman’s space seen o hypercellularity of mesangial and endothelial cells o glomerular infiltrates of PMN leukocytes o granular subendothelial immune deposits of IgG, IgM, C3, C4, C5-9 o subepithelial deposits-“humps” o RPGN – with crescents • • Diagnosis o renal biopsy is not necessary o subclinical cases are reported to be more common than clinical nephritis and characterized by asymptomatic microscopic hematuria and low serum complement levels Treatment o supportive • • for HTN o o o o for Edema • Dialysis if indicated (oliguric) antibiotic tx for strep infection for px and cohabitants no role for immunosuppressive tx even if crescents are present good prognosis, rare recurrence, permanent renal failure is very uncommon (1-3%) complete resolution of hematuria and proteinuria in children occur in 3- 6 weeks of onset of nephritis • C. Membranous Glomerulonephritis (MPGN/MGN) o also called Mebranous Nephropathy (MGN) o in situ formation of immune complexes with megalinreceptor associated protein as the putative agent • Progression o some reports suggest that degree of tubular atrophy or interstitial fibrosis are better predictors than the stage of glomerular disease o high recurrence rates o Abrupt onset of edema o spontaneous remission occur in 20-30% of patients and occur late in the course after year of NS o 1/3 have relapsing NS but maintain normal renal functions o 1/3 develop Renal failure of die of complications of NS o risk factors for worse prognosis: male, older age, HPN, persistent proteinuria o MGN has highest reported incidence of renal vein thrombosis, pulmonary embolism and DVT complications among NS Treatment o symptomatic treatment: edema (oral loop diuretics, low Na diet, target is loss of 1-2lbs or fluid per day), HPN, dyslipidemia, hypercholesterolinemia (lipid lowering agents to decrease risk for CVS disease), proteinuria (inhibition of RAS) o immunosuppresive drugs (steroids and cyclophosphamide, chlorambucil, cyclosporine, tacrolimus, rituximab) for primary MGN and persistent proteinuria (>3.0g/24hrs) o experience with mycophenolate mofetil or antiCD20 antibody is limited o prophylactic anticoagulation (controversial but recommended) in px with sever proteinuria Epidemiology o 30% of nephrotic syndrome (NS) in adults o rare in children but most common NS in the elderly o peak incidence between 30-50 years o Males > Females (2:1) o 25-30% secondary to malignancy (tumors of lung, breast, colon), infection (Hep B, malaria, schistosomiasis), rheumatologic disorders (lupus) o other etiologies are Drug-induced MGN o Unknown/Idiopathic is still the most common MGN Causes: • Idiopathic • • • Secondary: malignancy,infective Hep B, Rheumatology (SLE), Drugs (Gold) 25-30% is secondary Presentation o 80% with nephrotic syndrome (NS)* and nonselective proteinuria o 50% with microscopic hematuria Nephrotic Syndrome Low risk Normal renal function Protein <4 Medium Normal fxn March 6, 2009/Friday Page 4 of 7 Seth, Ian OS 214: Renal Glomerulonephritis (GN) Dr. Agnes Mejia Exam 1&2 Protein >=4 <8 High Abnormal fxn Protein >= 8 VI. SUMMARY Be aware o Family History: HTN, DM, CVD, Gout, Dialysis, ESRD Be suspicious o BP > 140/90 o Frothy/cloudy urine o Crea > 1.5 mg/dL or 132 umol/L o GFR < 60 o Nocturia o Dysuria Set the Alarm o Urinalysis o BP >130/80 o Crea 1.5mg/dl, 132 mmol/L 3 Syndromes and their signs Form Prototype Disease Acute IgA Nephropathy Nephritic Infectious PSGN Disease Associated; Nephritic Nephrotic MGN Proteinuria +/++ +/++ Albuminuria +++ +++ ++++ + *the GFR should be greatly decreased before creatinine manifests with an abnormality. Hence, be suspicious agad! *A normal creatinine doesn’t mean there’s normal kidney function, so always compute! Therapeutic Intervention o AntiInflammatory: Prednisone, tacrolimus, MMF, ritazimab o Reduce Proteinuria: ACEI, ARB e.g. FSGS-progression, remission, relapse if mainatained on prednisone, but if given combination therapy of prednisone and mycophenolate, disease is kept in remission VII. Socioeconomic impact of Glomerulonephritis o Dialysis: Php40,000 per month o Kidney transplant: Php1.2 M o Maintenance medications: Php60,000 per month *Hence: set the alarm! Because GN is a TREATABLE disease; if treated early, there’s no need for these expensive interventions. VIII. Figures Postinfectious (poststreptococcal) glomerulonephritis.The glomerular tuft shows proliferative changes with numerous PMNs, with a crescentic reaction in severe cases (A1). These deposits localize in the mesangium and along the capillary wall in a subepithelial pattern and stain dominantly for C3 and to a lesser extent for IgG (A2). Subepithelial hump-shaped deposits are seen by electron microscopy (A3). March 6, 2009/Friday Page 5 of 7 Seth, Ian OS 214: Renal Glomerulonephritis (GN) Dr. Agnes Mejia Exam 1&2 IgA nephropathy There is variable mesangial expansion due to mesangial deposits, with some cases also showing endocapillary proliferation or segmental sclerosis (C1). By immunofluorescence, deposits are evident (C2). Membranous glomerulopathy. Membranous glomerulopathy is due to subepithelial deposits, with resulting basement membrane reaction, resulting in the appearance of spike-like projections on silver stain (B1). The deposits are directly visualized by fluorescent anti IgG, revealing diffuse granular capillary loop staining (B2). By electron microscopy, the subepithelial location of the deposits and early surrounding basement membrane reaction is evident, with overlying foot process effacement (B3) Hyaline Cast Berry-like configuration of the glomeruli. March 6, 2009/Friday Page 6 of 7 Seth, Ian OS 214: Renal Glomerulonephritis (GN) Dr. Agnes Mejia Exam 1&2 Immunofluorescent staining of glomeruli with labeled antiIgG demonstrating linear staining (D1) from a patient with antiGBM disease or immune deposits from a patient with membranous glomerulonephritis compared to IgG lumpybumpy staining (D2). Preformed immune deposits can preciptate from the circulation and collect along the glomerular basement membrane (GBM) in the subendothelial space or can form in situ along the subepithelial space. The mechanisms of glomerular injury have a complicated pathogenesis. Immune deposits and complement deposition classically draw macrophages and neutrophils into the glomerulus. T lymphocytes may follow to participate in the injury pattern as well. *Amplification mediators such as locally derived oxidants and proteases expand this inflammation, and depending on the location of the target antigen and the genetic polymorphisms of the host, basement membranes are damaged with either endocapillary or extracapillary proliferation March 6, 2009/Friday Page 7 of 7 Seth, Ian