Glomerulonephritis block a trans

8/14/2019 Glomerulonephritis block a trans

http://slidepdf.com/reader/full/glomerulonephritis-block-a-trans 1/7

Glomerulonephritis (GN)

OS 214: Renal Dr. Agnes Mejia

Exam 1&2

March 6, 2009/Friday Page 1 of 7

Seth, Ian

OUTLINEI. IntroductionII. GlomerulonephritisIII. Pathogenesis of Glomerulonephritis

IV. Approach to Patient withGlomerulonephritis

V. Forms of GlomerulonephritisA. IgA NephropathyB. Poststreptococcal GlomerulonephritisC. Membranous Glomerulonephritis

VI. SummaryVII. Socioeconomic impact of

GlomerulonephritisVIII. Figures

Note: The lecturer did not provide a powerpoint. Thank you toIrving for sending pictures of the ppt for this trans. Please bereminded that the exam questions will come mainly from HPIM 17 th ed.; topics included are general information on glomerular

disease, GN, IgA nephropathy, PSGN and MGN.

I. INTRODUCTIONA. 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 Seizureso Disorientation

o Coma

*Azotemia is a laboratory diagnosis

Uremia a clinical diagnosis

C. Labs Requested

Lab Purpose Finding in ER

CBC Check for anemia due topallor

Low Hg (7)

BUN To asses kidney function,but creatinine is moreimportant

Elevated (60umol/L)

*Creatinine Single most importanttest for uremia (uremic if azotemic); if high, tellsyou that px likely haskidney disease

Increased (1800 umol/L)

ElectrolytesCa

To check for acidosis Decreased

Phosphorus Elevated (6)**K Needed if urgent action is

required (can easily killthe patient)

Elevated (5.9)

***ABG Needed if urgent action isrequired

(pH7.2; pCO235;pO294; HCO311;

O2sat 92%) SevereUncompensatedMetabolic acidosis (lowpH, low HCO3;

causes tachypnea)CXR To rule out pneumonia Heart not enlarged but

with congestionShowed pulmonaryedema

EKG Check for hyperkalemia Peaked T waves(denotes hyperkalemia)

you have to givecalcium gluconate astreatment

UTZ Visualize the kidney:If enlarged (e.g. 12cm)=acute GN, reversibleIf shrunken=ESRD,irreversible(Normal Filipino size:9.6cm in length; NormalCaucasia:11-12 cm)

*Normal globular, thickcortex

Small shrunken kidneyCortex should at least be4.5cm thick

Urinalysis “window to glomerular disease”-early morning urineexpected to have a dark,intense color if kidney isable to concentrate urine- concentrated (Sp.gravity 1.020-1.030)-Acute GN – red cellcasts; RBCs degenerateto fine/coarse granular

casts reflects chronicity

-Hyaline casts can befound in a normal person-Most common cause of

pus cells non infectivepyuria

-low sp. gravity-granular casts-Increase RBC andWBC

-mucus threads raredenotes that urine waswell collected-px has no fever but high

WBC may indicatesterile pyuria

*if creatinine is high, BUN is expected to be abnormal; if BUNis high, creatinine is not necessarily high*the presence of protein in the urine is not correlated with thespecific gravity of the urine since SG indicates the ability of the kidneys to concentrate. Even if this is intact, the kidneyscan still spill out urine.*those in asterisks are the cheaper tests, so they are the mosteconomical and efficient in terms of information.

D. Final Diagnosis:o Uremia secondary to ESRD (CKD Stage V)

secondary to Chronic Glomerulonephritis (CGN)

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)

ESRDo shrunken kidneys

o

uremia, anemia, low Cao Inc phosphorus

*Single most important determinant of chronicity shrunkenkidneys

*Severe renal failure Ca low, Phosphorus high

**ER is a UP student; inc BP at age 19 (140/90). ER waserroneously treated as UTI for 3 years in a male with nosymptoms and an abnormal urinalysis; ER passedengineering boards 3 days before he underwent hemodialysis!





Exam 1&2


Seth, Ian

My Goals (which I guess have to be our goals)

1. To be aware2. To be suspicious3. 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 histologyis important!

b. Glomeruluso 600 thousand – 2 million (all in all) in a normal

individual

*prematures have less glomeruli higher tendency

for hypertension higher tendency for renal diseaseat age 50

o is a ball of capillaries (“berries”) with afferent and

efferent arterioles (histology: stalk – where efferentand 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 electrostaticcharge

o glomerulus is an imperfect barrier

*e.g. albumin-despite its negativity, readily passesthrough due to its small radius (3.6nm vs. 4nm radiusof glomerular basement mebrane (GBM) slit-pores);albumin is reabsorbed in the proximal tubules (urinenormally 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) (2)Circulating immune complexes In-situ immune complexes

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

*In summary, GN may be caused by circulating or in situimmune complexes, but whichever the cause is, they bothfollow the path of inflammation via T-cell activation

*Immunofluorescence can be used to determine whether immune complexes are in-situ or circulating

*Overlapping etiologies may produce similar glomerular

lesions display common patterns of injury (syndrome); this isevident in microscopy:

IgA paramesangial; can still see spaces in glomerulus; mostcommon in Asians

Poststrep GN (PSGN) – same pattern of injury can be seen inlupus; immune-complex GN; most common post infectious

Membranous GN (MGN) –same pattern can be seen inidiopathic, Hepatitis, and drug-induced; just hits the basementmembrane, 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)

• retention/incontinence – incomplete

voiding?

• frequency – urinating more often?

• Sediments- may “latak” sa ilalim ang ihi?

• frothy urine – like beer?

• edema

o last known urinalysis/creatinineo pregnancy status (preeclampsia); birth control pills

o last normal BP

o Blood pressure

• must give exact value, not just saying

normal or high, because what is high for one person may be normal for another

o 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(mg/24h)

Albumin/creatinineratio(mg/G)

Dipstickproteinuria

24HhUrineProtein(mg/24h)

Normal 8-10 <30 - <150

Microalbuminuria

30-300 30-300 -/trace/1+ -

Proteinuria >300 >300 Trace-3+ >150

V. Forms of Glomerulonephritis (Patterns of Clinical GN)

Form Prototype Disease

Acute Nephritic IgA Nephropathy

Infectious DiseaseAssociated; Nephritic

PostStreptococcal GN(PSGN)

Nephrotic Membranous GN

Basement membrane Alport’s syndrome

Glomerular Vascular Disease ANCA small vessel vasculits





Exam 1&2


Seth, Ian

Pumonary-Renal Goodpasture’s disease

*just focus on the first three as said by the lecturer, ayt?

A. IgA NephropathyCASE:

31 femaleRoutine annual Physical checkupUrinalysis

- RBC –TNTC - WBC – 0-3- Protein (-)- Casts (-)

BP 120/70

o immune complex mediated GN defined by the

presence of diffuse mesangial IgA deposits often

associated with mesangial hypercellularityo circulating immune complexes get deposited in the

mesangium or podocytes (not the basementmembrane [BM])

o IgM, IgG, C3, or immunoglobulin light chains can be

codistributed with IgAo Mild – do not undergo dialysis

o 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

• Pathogenesis: defective immune response formation of

immune complex proinflammatory, proproliferative,

proapoptotic, profibrotic + milieu in glomerulimesangial/podocyte injury, capillary hypertension, alteredperm 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 adultso between episodes, urinalysis is normal

o in persistent hematuria, increasing proteinuria is

found

• Differentials

o Henoch-Schonlein Purpura- can be

distinguished for IgA Nephropathy by prominent

systemic sx, younger onset (<20yrs old),preceding infection and abdominal complaintso Crohn’s disease, chronic lover disease, GI

adenocarcinoma, etc –also present with IgAdeposition in mesangium; can be differentiateddue 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

o sometimes recur post transplant

o risk factors for renal failure: HPN, proteinuria,

absence of episodic macroscopic hematuria,male, older age of onset, sever renal biopsychanges

o “Point of no return” – stage where treatment is

insufficient usually when creatinine is at least 2o the clinical prognostic index (CPI) of GN–made

in Verona, Italy; a scoring system that predictsthe 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

o Score of 0-2*: higher 10-year renal survival; 3-5:

lower 10-year renal survival; most likely to endup in dialysis; hence, creatinine is the single

most impt predictors of survival since itautomatically 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

B. PostStreptococcal Glomerulonephritis (PSGN)

CASE:

22 male1 month impetigo in L leg

Pus, crust, swelling, redness, fever tea colored urine, dec outpu, puffy eyelids, anorexi, easy fatigability, inc BP

o also known as Postinfectious GN

o prototype for acute endocapillary proliferative GN

o 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 wksafter 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





Exam 1&2


Seth, Ian

o classic presentation of acute nephritic px: HPN,

hematuria, RBC casts, pyuria, mild to moderateproteinuria

o oliguric renal failure

o systemic symptoms include headache, malaise,

o anorexia, flank pain (swollen renal capsule) in 50%

of cases

o in the 1st week of symptoms: 90% have depressed

CH50, decreased C3 (because they are circulatingand get deposited in the GBM)

o positive strep cultures are inconsistent

Renal Biopsyo 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, C5-9o 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 andcharacterized by asymptomatic microscopichematuria and low serum complement levels

• Treatment

o supportive

• for HTN

• for Edema

• Dialysis if indicated (oliguric)

o antibiotic tx for strep infection for px and

cohabitantso no role for immunosuppressive tx even if

crescents are presento good prognosis, rare recurrence, permanent

renal failure is very uncommon (1-3%)o 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 megalin-

receptor associated protein as the putative agent

• 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% issecondary

• Presentation

o 80% with nephrotic syndrome (NS)* and

nonselective proteinuriao 50% with microscopic hematuria

Nephrotic Syndrome

• 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

EdemaThere 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

EDEMANephrotic syndrome (NS) is described as: 24hr totalPr>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 Biopsyo LM: uniform thickening of the BM along the

peripheral capillary loopso Immunoflorescence: diffuse granular deposits of

IgG and C3o EM: electron dense subepithelial deposits

• 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

functionso 1/3 develop Renal failure of die of complications

of NSo risk factors for worse prognosis: male, older age,

HPN, persistent proteinuriao MGN has highest reported incidence of renal

vein thrombosis, pulmonary embolism and DVTcomplications 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 todecrease 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 anti-

CD20 antibody is limitedo prophylactic anticoagulation (controversial but

recommended) in px with sever proteinuria

Low riskNormal renal functionProtein <4

MediumNormal fxn





Exam 1&2


Seth, Ian

Protein >=4 <8

HighAbnormal fxn

Protein >= 8

VI. SUMMARY

Be awareo Family History: HTN, DM, CVD, Gout, Dialysis,

ESRD

Be suspiciouso BP > 140/90

o Frothy/cloudy urine

o Crea > 1.5 mg/dL or 132 umol/L

o GFR < 60o 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 Proteinuria Albuminuria

AcuteNephritic

IgA Nephropathy +/++ +++

Infectious

DiseaseAssociated;Nephritic

PSGN +/++ +++

Nephrotic MGN ++++ +

*the GFR should be greatly decreased before creatininemanifests with an abnormality. Hence, be suspicious agad!

*A normal creatinine doesn’t mean there’s normal kidneyfunction, so always compute!Therapeutic Intervention

o AntiInflammatory: Prednisone, tacrolimus, MMF,

ritazimabo Reduce Proteinuria: ACEI, ARB

e.g. FSGS-progression, remission, relapse if

mainatained on prednisone, but if given combinationtherapy of prednisone and mycophenolate, diseaseis kept in remission

VII. Socioeconomic impact of Glomerulonephritiso 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 TREATABLEdisease; if treated early, there’s no need for these expensiveinterventions.

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).





Exam 1&2


Seth, Ian

Membranous glomerulopathy. Membranous glomerulopathy is dueto 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)

IgA nephropathy

There is variable mesangial expansion due to mesangialdeposits, with some cases also showing endocapillary proliferation or

segmental sclerosis (C1). By immunofluorescence, deposits are

evident (C2).

Hyaline Cast

Berry-like configuration of the glomeruli.





Exam 1&2


Seth, Ian

Immunofluorescent staining of glomeruli with labeled anti-

IgG demonstrating linear staining (D1) from a patient with anti-

GBM disease or immune deposits from a patient with

membranous glomerulonephritis compared to IgG lumpy-

bumpy 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 theglomerulus. 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

Documents

Glomerulonephritis block a trans