Gn Trans

OS 214: Renal

Dr. Agnes Mejia Exam 1

Glomerulonephritis

OUTLINE I. II. III. IV. V.

VI. VII. VIII.

Introduction Glomerulonephritis Pathogenesis of Glomerulonephritis Approach to Patient with Glomerulonephritis Forms of Glomerulonephritis A. IgA Nephropathy B. Poststreptococcal Glomerulonephritis C. Membranous Glomerulonephritis Summary Socioeconomic impact of Glomerulonephritis Figures

Note: The lecturer did not provide the transcribers with a copy of her ppt so the contents of this trans are based on the transcribers (and Gerard’s ) notes. Please read chapter 277 of Harrison’s on Glomerular Disease, especially the general information on Glomerular disease, Glomerulonephritis, and the topics IgA nephrotpathy, PSGN, MGN. Other specific topics not discussed (e.g minimal change disease, etc) are not included in the exam DAW. Questions in the exam will mainly come from Harrison’s. I. INTRODUCTION A. Case of ER, presented with:  high BP (140/90), high HR, RR 30/min  pale, sallow (in between pallor and jaundice)  “peculiar fetor” – fruity smell  evidence of cardiac damage (Grade II Av block) but not yet in CHF due to absence of s3  no evidence of liver involvement B. Primary Impression: UREMIA Symptoms seen in ER Full-blown uremia: (not seen in ER) vomiting somnolence tremors seizures anorexia disorientation weakness coma SOB Pruritus Easy fatigability restlessness C. Labs Requested Lab CBC BUN Creatinine Electrolytes Ca

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); To check for acidosis

P

Finding in ER Low Hg elevated increased Decreased Elevated

K

Needed if urgent action is required

Elevated

ABG

Needed if urgent action is required

CXR

To rule out pneumonia

EKG

Check for hyperkalemia Visualize the kidney: If enlarged (e.g. 12 cm)=acute GN,

Uncompensated Metabolic acidosis (low pH, low HCO3; causes tachypnea) Heart not enlarged but with congestion Peaked T waves (hyperkalemia) Small shrunken kidney

UTZ

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Urinalysis

reversible If shrunken=ESRD,irrev ersible (Normal Filipino size:9.6 cm in length; Normal Caucasia:1112 cm) “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

-low sp. gravity -granular casts

*if creatinine is high, BUN is expected to be abnormal; if BUN is high, creatinine is not necessarily high D. Final Diagnosis: Uremia secondary to ESRD (CKD Stage V) secondary to Chronic Glomerulonephritis (CGN) Basis for diagnosis: CGN - young adult, hypertension at age 19 - hematuria, pyuria - small kidneys ESRD - shrunken kidneys **thus, ER was erroneously treated as UTI for 3 years in a male with no symptoms and an abnormal urinalysis II. Glomerulonephritis -inflammation of the glomerular capillaries a. Normal Kidneys: - smooth surface - pinkish cortex - reddish medulla - yellow calyces, pelvis -In GN: kidneys are pale b. Glomerulus - 600 thousand – 2 million *prematures have less glomeruli  higher tendency for hypertension  higher tendency for renal disease at age 50 - ball of capillaries (“berries”) with afferent and efferent arterioles (histology: stalk – where efferent and afferent arterioles run) - glomerular capillaries filter 120-180 L/d of plasma water -filtration occurs through a physicochemical barrier governed by pore size and negative electrostatic charge -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: glomeruli are full of scars

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OS 214: Renal

Dr. Agnes Mejia Exam 1

Glomerulonephritis

Pathogenesis: (1) Circulating immune complexes

V. Forms of Glomerulonephritis (2) In-situ immune complexes

T-cells (CD 4/8) Glomerular injury

Form Acute Nephritic Infectious Disease Associated; Nephritic Nephrotic

Prototype Disease IgA Nephropathy PostStreptococcal GN (PSGN) Membranous GN

Mononuclears Cytokine release Attract more inflammatory cells Glomerular damage *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 *Immunofluorescence can be used to determine whether immune complexes are in-situ or circulating *Overlapping etiologies may display common patterns of injury (syndrome); this is evident in microscopy:

A. IgA Nephropathy -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 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

•

IgA Nephropathy

Poststrep GN (PSGN) – same pattern of injury can be seen in lupus, immune-complex GN

• Membranous GN (MGN) –same pattern can be seen in idiopathic, Hepatitis, drug-induced IV. Approach to Patient with Glomerulonephritis A. History and PE - confined to the kidneys or systemic? acute or chronic? - signs and symptoms dysuria – pain during urination? nocturia – urination at night? hematuria – blood in the urine? retention/incontinence – incomplete voiding? frequency – urinating more often? sediments frothy urine – like beer edema - last known urinalysis/creatinine - pregnancy status (preeclampsia); birth control pills - 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 hemturia) *painless gross hemturia suggests malignancy; if it is painful, then it suggests urethritis Table 277-1. Urine assays for albumin/proteinuria (HPIM) 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

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Epidemiology -most common form of GN worldwide -30% in Asia and Pacific RimEast > West 20% in southern Europe low prevalence in N. Europe & N. America -Male > Female - -peak incidence: 2nd-3rd decade of life -rare familial clustering Presentation -most common presentations are: a. recurrent episodic macroscopic hematuria following a respiratory infection in children b. asymptomatic microscopic hematuria seen in adults -between episodes, urinalysis is normal -in persistent hematuria, increasing proteinuria is found Differentials -Henoch-Schonlein Purpura- can be distinguished for IgA Nephropathy by prominent systemic sx, younger onset (<20yrs old), preceding infection and abdominal complaints -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 -generally a benign disease, but 25-30% progress to renal failure over 20-25 yrs. -5-30% go into complete remission -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 prgnosis 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

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OS 214: Renal

Dr. Agnes Mejia Exam 1

Glomerulonephritis

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-25-30% secondary to malignancy (tumors of lung, breast, colon), infection (Hep B, malaria, schistosomiasis), rheumatologic disorders like lupus -other etiologies are Drug-induced MGN -Unknown/Idiopathic is still the most common MGN

Treatment Evidence-based: ACEI-ARB, Steroids, fish oil Non-evidence Based: tonsillectomy 2. PostStreptococcal Glomerulonephritis (PSGN)

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also known as Postinfectious GN prototype for acute endocapillary proliferative GN Epidemiology typically sporadic children between 2-14 yrs (10% in px>40yrs) Males > Females familial/cohabitant incidence is high-40% M types of Streptococci (nephritogenic strains) impetigo- M types 2, 47, 49, 55, 57, 60 -PSGN develops 2-6 wks after a skin infection

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Renal Biopsy -LM: uniform thickening of the BM along the peripheral capillary loops -Immunolorescence: diffuse granular deposits of IgG and C3 -EM: electron dense subepithelial deposits

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Diagnosis -renal biopsy is not necessary -subliclinical cases are reported to be more common than clinical nephritis and characterized by asymptomatic microscopic hematuria and low serum complement levels

3. Membranous Glomerulonephritis -also called Mebranous Nephropathy (MGN) -in situ formation of immune complexes with megalin-receptor associated protein as the putative agent

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Edema -There are 2 theories for the cause of edema due to NS: underfill and overfill 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  primary Na retention  Expanded ECF volume  EDEMA

Presentation -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

Treatment - supportive HTN 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 heamturia and proteinuria in children occur in 3- 6 weeks of onset of nephritis

Epidemiology -30% of nephrotic syndrome (NS) in adults -rare in children but most common NS in the elderly -peak incidence between 30-50 years - Males > Females (2:1)

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Presentation -80% with nephrotic syndrome (NS)* and nonselective proteinuria -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

pharyngitis- M types 1,2, 3, 4, 12, 25, 49 -PSGN develops 1-3 wks after pharyngitis

Renal Biopsy -diffurse proliferative: little bowma’s space seen -hypercellularity of mesangial and endothelial cells -glomerular infiltrates of PMN leukocytes -granular subendothelial immune deposits of IgG, IgM, C3, C4, C5-9 -subepthelial deposits-“humps” -RPGN – with crescents

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Progression -some reports suggest that degree of tubular atrophy or interstitial fibrosis are better predictors than the stage of glomerular disease -high recurrence rates -spontaneous remission occur in 20-30% of patients and occur late in the course after year of NS -1/3 have relapsing NS but maintain normal renal fcns -1/3 develop Renal failure of die of complications of NS -risk factors for worse prognosis: male, older age, HPN, persistent proteinuria -MGN has highest reported incidence of renal vein thrombosis, pulmonary embolism and DVT complications among NS Treatment -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) -immunosuppresive drugs (steroids and cyclophosphamide, chlorambucil, cyclosporine) for primary MGN and persistent protyeinuria (>3.0g/24hrs) -experience with mycophenolate mofetil or anti-CD20 antibody is limited -prophylactic anticoagulation (controversial but recommended) in px with sever proteinuria

VI. SUMMARY Be aware - Family History: HTN, DM, CVD, Gout, Dialysis Be suspicious - BP > 140/90 - Frothy/cloudy urine - Crea > 1.5 mg/dL or 132 umol/L - GFR < 60

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OS 214: Renal

Dr. Agnes Mejia Exam 1

Glomerulonephritis

- Nocturia - Dysuria Set the Alarm Urinalysis

3 Syndromes and their signs Form Prototype Disease Acute IgA Nephropathy Nephritic Infectious PSGN Disease Associated; Nephritic Nephrotic MGN

Proteinuria +/++

Albuminuria +++

+/++

+++

++++

+

G F R

Creatinine, *the GFR should be greatly decreased before creatinine manifests with an abnormality. hence, be suspicious agad! Therapeutic Intervention AntiInflammatory: Prednisone, tacrolimus, MMF, ritazimab 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 Dialysis: Php40,000 per month Kidney transplant: Php1.2 M Maintenance medications: Php60,000 per month

Postinfectious   (poststreptococcal)   glomerulone­ phritis.The glomerular tuft shows proliferative changes with  numerous PMNs, with a crescentic reaction in severe cases  (Top). 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 (Middle).  Subepithelial   hump­shaped   deposits   are   seen  by   electron  microscopy (Bottom). 

*hence: set the alarm! because GN is a TREATABLE disease; if treated early, there’s no need for these expensive interventions VIII. Figures

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OS 214: Renal

Dr. Agnes Mejia Exam 1

Glomerulonephritis

IgA nephropathy There is variable mesangial expansion due to mesangial  de  posits,   with   some   cases   also   showing   endocapillary  proliferation

 

or  

segmental

 

sclerosis

 

(Top).By 

immunofluorescence, deposits are evident ( Middle).

  Membranous glomerulopathy. Membranous glomeru­  lopathy   is   due   to   subepithelial   deposits,   with   resulting  basement membrane reaction, resulting in the appearance of  spike­like projections on  silver stain (Top). The deposits are 

Hyaline Cast

directly   visualized   by   fluorescent   anti   IgG,   revealing   diffuse  granular capillary loop staining (Middle). By elec­  tron microscopy, the subepithelial location of the deposits and  early   surrounding   basement   membrane   reaction   is   evident,  with overlying foot process effacement (Bottom)

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.

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OS 214: Renal

Dr. Agnes Mejia Exam 1

Glomerulonephritis

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 extracaillary proliferation. 

Immunofluorescent   staining   of   glomeruli   with   labeled   anti­IgG  demonstrating linear staining (mid) from a patient with anti­GBM disease  or immune deposits from a patient with membranous glomerulonephritis  compared to IgG lumpy­bumpy staining (bottom). 

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.

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