Web viewToday will discuss glomerular disease; constitute some of the major problems encountered in...

Noor Alsallaqpatho.20/2/2014

Today will discuss glomerular disease; constitute some of the major problems encountered in nephrology, the most common causes of chronic kidney disease in humans. They are one of most common causes of needed core peopsy referral for glomerulonephritis collectively they are called chronic glomerulo nephritis ,they can be primary that’s mean they start mainly in the kidney mainly , or they can be secondary to systemic illness like hypertension ,diabetes ,systemic lopuserthomatosis . all these disease at the end they affect kidney and they affect the glomeruli.Before discuss kidney we will discuss 2 syndrome:

1-nephrotic syndrome and what are the glomerular diseases that cause this syndrome.2 -Nephritic syndrome, and what glomerular disease that cause it.

Before that ,****l want to maintion some of the histology of the glomeruli .glomerular taft surrounded by bowmen capsule and glomeruli consist of multiple capillary size spaces "tuft of capillary" surrounded by endothelial cell and all these tuft are surrounded by visceral epithelial cell ,and partial epithelial cell lining of the bowmen capsule. There is partial epithelial on bowmen capsule and there is visceral epithelial cell surrounded glumerular tuft of the capillaries and there is between cells called mesengeal cell(producing mesengal matrix in between the capillary spaces.)enter afferent arteriol & getout efferent arteriole. This is the basic structure of the

glomeruli . any disease affect the glomeruli affect the mesenguim or on the endothelial specially basement membrane of the endothelial cell or effect partial epithelial cell lining bowmen capsule. You know that then is kidney barrier ,"because of the basement membrane of the glomeruli ,this barrier is impermeable for many material like large size and small size protein ,they cannot be execreted or can not be pass due to the large size or due to the negative charge because happen a repulsion between it and the membrane ,so it's important to know that the membrane of the glomeruli is act as a barrier that prevents the exchange of the protein to go to the urine.

In disease process, this permeability affect , become more permeable to different molecular specially protein , now we will see in nephrotic syndrome what will happen. Nephrotic syndrome it is a triad of the first three component, plus, minus the fourth component.

1-the first and more important in definition nephrotic syndrome is massive proteinuria (massive means in large amount) it should more than 3.5 g per day .they make 24 hour, urine collection all the day and they see the amount of protein if it was more than 3.5 g

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There is some picture in the end of the sheet can help u in understand the histo. Of the kidney******


this is called massive protein urea in the nephroitic range anything below this is called non nephrotic range protein urea .

2-the second component is called hypoalbuminea(expected because the protein is go out with urine and this protein in urine contain albumin and other proteins ,as albumin is secreted out of urine so the concentration in the blood will decrease so hypoalbuminemia with plasma albumin level less than 3g/dl ,the first component is 3.5g per 24hr of urine

collection .3-generalized edema in nephrotic syndrome is mainly due to the hypoalbuminemia(low

albumin concentration , osmetic pressure (oncotic pressure)inside bloode vessel is low so permit the fluid to go out from low oncotic pressure places to high oncotic pressure places ,so the intravascular volume of fluid decrease ,all fluid is going from inside vessel to the outside, it collect every where may be in lower limbs (because lower limb edema, because fill out legs)or in abdomen Ascites is the build up of fluid in the space between the lining of the abdomen and abdominal organs (the peritoneal cavity),or around the eyes(these pt. wake up,they have puffiness due to accumulation of fluid )or generalized edema that called Anasarca ,the other cause of edema is manily because by hypoalbuminemea But there is other cause when all fluid go out of intravascular to extravascular space so intravascular volume decrease , the blood flow to the kidney decrease so GFR (glomeruli filtration rate)decrease ,so the kidney response to produce more hormone called aldosterone to make water &Na retention ,so the body sense that there is low volume ,low fluid so the body compensate by more water and Na retention ,in fact there is no low fluid , or low volume but all fluid go out from inside vessel to outside of vessel .these 2 mechanism cause edema in nephrotic syndrome but its mainly due to

hypoalbuminemia. 4-can be present or not hyperlipidemia &lipiduria the cause of hyperlipidemia is not very

much stood, they said it could be when there is decrease albumin, the body(or the liver)will start produce more lipoprotein (component of it is the lipid so the lipid level in blood increase) this is cause of hyperlipidemia this a suggested mechanism lipiduria cause of the leakness of the basement membrane of the capillary tuft of the glomeruli ,they permit due leaky of albumin &protein in addition to lipid, so it will start the lipiduriea due to the permeability of the membrane.

In cases of nephritic syndrome , azotemia hematuria and hypertension ,they are little or absent. But in nephritic syndrome these 3 is important component or feature.Azotemia: functional impairment means increase keratinin and urea level in blood.

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-The relative frequencies of the several causes of the nephrotic syndrome vary according to age:

a. In children 1 to 7 years of age, the nephrotic syndrome is almost always caused by a lesion primary to the kidney, called primary GN or primary glomerulonephritis.

b. Whereas among adults it often is due to renal manifestations of a systemic disease The most frequent systemic causes of the nephrotic syndrome in adults are diabetes (affect the kidney so in beganing the leakness of protein is little until in the end it end with nephrotic range massive protenuriea), hypertension , amyloidosis (deposition of amyloid material in kidney)and systemic lupus erythematosus(SLE).

(slide 6:prevalance of cause of GN different from children &adult we will talk about those GN in a while ,but in children 65% of cases of Nephrotic syndrome are cause by disease called minimal change disease( most common cause of nephrotic syndrome in children) in adults in old day it was MCD but now it is focal segmental glomerulscloresis is more

common in 35% cause of nephrotic syndrome in adult).Minimal change disease :

•Means glumeruli not show much changes ,they appear almost normal unremarkable when examine under LM.its abenign disorder means as a sequelae in future it will not progretion in to chronic renal failure or chronic renal disease axcept in few or very rare cases .it is the most frequent cause of the nephrotic syndrome in children.as I said

• It is characterized by glomeruli that have a normal appearance by light microscopy but(the only change in this disease in EM means when examin by LM &immunofluresense M they look normal but in EM it will have effacement of podocyte when viewed in EM.) show diffuse effacement of podocyte foot processes when viewed with the electron microscope.

• Podocyte: vesciral epithelial cell covering glomerular tuft of capillaries. Although it may develop at any age, this condition is most common between ages 1 and 7 years.

Morphology:

LM: The glomeruli in minimal change disease appear normal. The GBM appears normal.(basement membrane appear normal ,it is leaky, abnormal structure functionally but his shape looks normal.

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EM: uniform and diffuse effacement of the foot processes of the podocytes(these pt. respond to corticosteroid very well once you give them steroid ,proteinuria reverse to normal podocyte effacement (means instead of having foot process separate ,they become effuse)is

also reversible upon corticosteroids treatment .

Clinical course:They are slow onset of nephritic syndrome, massive protienuriea in a previously heath

child (child have no previous disease). No hypertension, and renal function is preserved.Selective proteinuria confined to the smaller serum proteins, like albumin , globulin for example in MCD , they are not excreted , only the albumin .The prognosis in children with this disorder is good they have dramatic response to corticosteroid therapy when we give them corticosteroid they have quickly reverse of the condition however small no.

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Glumerular tuft under the LM it appear normally.

Glumerular tuft under EM (the arrow) is called effacement of foot process these should be separated like foot print but they all diffuse together,that why the barrier become leaky for protein.


of pt. have recurrent protienuria but they will still respond to corticosteroid ,there is subset of these pt. they will still corticosteroid dependent for along time because of recurrent of proteinuria . however it still recurrent for proteinuria it still benign proteinuria that is only less than 5% of these pt. progress will have at the end chronic renal failure so what (distinguish) or differ MCD in children glomeruli is normal under LM &massive proteinuria that is selective for albumin and response to corticosteroid is very effective &reversal of proteinurea &small amount of pt. become steroid dependent ,very rare pt. have chronic renal failure less than 5% of pt. adult with MCD have the same feature on LM and EM but the response to corticosteroid will be much less ,(children respond very good but adult response is less.). some children once have proteinuria when they take corticosteroid every thing will back to normal ,some of them this problem goes away for 1to2 years or 1to2 months then they have another proteinuria and if we give them and their corticosteroid ,they will become okey (on and off)but other they will have always proteinuria and will always take corticosteroid (corticosteroid depended). In adults it will not respond to corticosteroid (corticosteroid resistence).

Second cause of nephritic syndrome is "more common in adult" focal segmental glomerularsclerosis. Sclerosis means fibrosis in glomeruli characterized histologically by sclerosis affecting some but not all glomeruli (focal involvement) , means may the biopsy come with all glomeruli of it is normal but that not exclude that there is disease process of other glumeruli ,that is not shown in biopsy. Segmental means even in the same glomerulas only one or 2 segment are sclerosied so not all segmental are sclerosid. This early in the disease ,and the disease progression more and more glomeruli are effected so may be all glomeruli are effected so may be all glomeruli in kidney become effected and more and more of the glomerulus it self is effected so you can found a glomeruli is totally effected and sclerosid .in the early of the visease it is focal and segmental.

1-20-30% of cases of FSGS are primary means iodopathic (no underlying cause). 2-the remainder of causes may be associated with other condition like they can occur with association with HIV (human immunodeficiency virus) or AIDS or pt. with drug abuser heroin abus or

3 -can occur as secondary event to other form of glumeronephritis(GN) like example IGA nephropathy

4-as a maladapration after nephron loss(like hypertension , they has nephron loss and FSGS , or some people who remove part of the kidney (partial nephroctomy) they remaining glomeruli may be as adaptive mechanism because of the pressure is high on them development of the hypertension ,also they have secondary FSGS .so it

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secondary to nephron loss . nephron means all glomerulus & tubules &all the unit of it.

5 -in inherited or congenital forms , it is not that much common in this state we see it in children resulting from mutation in protein forming the BM or podocyte

processes , so these can cause secondary FSGS . But in 20-30% of cases is unknown As we said more common in adult & it constitute the most common cause of nephrotic syndrome in adult . in children its imp. to distinguish from MCD because the biopsy due to the focal nature of the disease , all the biopsy in normal , so we say its MCD , pt. have nephrotic syndrome the same clinical presentation but if we give them corticosteroid he wont respond so don’t think the cause is not MCD , it is other disease FSGS because FSGS distinguish of respond to

corticosteroid is not pronounced . Difference between MCD &FSGS .in FSGS ,there is here incident of hematuria and hypertension . IN MCD ,these things are rare.the proteinurea is not selective means albumin in addition to other protein like globulin .

selective protein urea ,means just 1protien type like albumin like MCD. In general the third difference is corticosteroid therapy in FSGS is poor. and MCD is bengin disease 5% of pt. progress to renal failure. FSGS 50%of pt. progress to renal failure within 10 years to diagnosis. Adult do less fine /well than children . children in FSGS the complication is less than adult ,always disease is more worse.Pathogenesis in FSGS:Injury to the podocytes(reversal epithelial cell) is thought to represent the initiating event of primary FSGS.

The deposition of hyaline masses in the glomeruli represents the entrapment of plasma proteins and lipids in foci of injury where sclerosis develops(main feature histologically in FSGS is sclerosis is deposition of hyaline amorphous pink material in glomerular that represent entrapetment of plasma protein &lipids &secondary sclerosis.

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Morphology:Main glomeruli that affect disease start from juxtamedullary glomeruli you know that kidney have cortex &medulla so first glomeruli is affect are deep in the cortex close to the junction with medulla that why sometime may be biopsy from superficial part of cortex & all glomeruli are normal so are missed the disease glomeruli so the diagnosis of FSGS not

easy to diagnosis.by LM: increased mesangial matrix, obliterated capillary lumens, (cause mesengial matrix that increase that is pinkish ,sceloried &fibrosed press on capillary lumen that why increase pressure inside glomeruls &deposition of hyaline

masses &lipid droplet.)and deposition of hyaline masses (hyalinosis) and lipid droplets .

in IF non specific trapping of Ig see the biopsy shiny we target certain antibody or complement component for biopsy so there is disease that happened it deposition and bind these antibody so appear shiny green.&also other disease like MSD there is no any diposition . the distinguish of FSGS from MCD in IF these is by IGM (immounglopendeposition) on &complement deposition on areas that are hylanised

&scelorised. in EM same feature of MCD on foot process all of them are fused &faced.

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Patented capillary loop closed (not opened) & scelerosed &compressed.

Opened

This is amorphous pinkish material deposit this is segmental , the remaining glomerulus looks normal but the arrow is sclerosid sceloris means deposition of this pinkish material between capillary loop &press on them , this mean that capillary loops may become collapsed because of scelorsis or fibrosis that occur


Third caused of nephritic syndrome: membranous nephropathy membranous from its name the basement membrane of capillary loop are thickened instead of become thin they look thick they appear on LM&EM it is a slowly progressive disease it occur between

30-50 year of age unlikely to see in adolescent &child. a characterized morphologically by the presence of sub epithelial immunoglobulin-containing deposits along the

GBM(basement membrane). NOTE:GMB become deposition it IG so it begin thicken,mean material coming from outside &stay on this (BM)with time the (BM)become thicker .Well-developed cases show diffuse thickening of the capillary wall(this is the most important

feature of membranous GN fuse thickening of the (BM)).

Idiopathic in about 85% of cases.(underline cause unknown) Secondary in 15%, due to :

(1 )infections (chronic hepatitis B, syphilis, schistosomiasis, malaria) ;(2 )malignant tumors, particularly carcinoma of the lung and colon and melanoma;

(3 )SLE and other autoimmune conditions ;(4 )exposure to inorganic salts (gold, mercury); and

(5 )drugs (penicillamine, captopril, nonsteroidal anti-inflammatory agents(they can effect the kidney in variable ways analgesic nephropathy ,dryg induce interstitial nephritis so

they can induce membraneeous nephropathy)) .

Morphology;

LM: diffuse thickening of the GBM (more important thing ,diffuse all glomerular tuft).IF(deposition of IG but not traping as sceloris fossi as FSGS): typical granular deposits of immunoglobulins and complement along the GBM.

EM: subepithelial deposits(this IG deposite between epithelial cell &BM(we have endothelial cell lining lumen capillary ,under it BM from outside the epithelial cell appear &podocyte )between BM &podocyte we called them subepithellial deposite ,they come from Ig&they park there so they make as spike &dome pattern inaddition to effacement of foot processes.

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Clinical course:The proteinuria is nonselective (globulins and albumin)(in membraneous nephropathy as

FSGS). Does not usually respond to corticosteroid therapy. (as FSGS)only about 40%(as higher % asFSGS) suffer progressive disease terminating in renal failure after 2 to 20 years.

An additional 10% to 30% have a more benign course with partial or complete remission of proteinuria .

B) The Nephritic Syndrome(the main syndrome of the kidney): characterized bya. Hematuria (RBC casts),(RBC in the urine either gross hematuria or microscope hematuria and the presence of RBC cost because of the presence of RBC in the tubule they accumulate and take the shape of the tubule lumen& when they go out in urine in urine analysis , they appear as cast (like ( )like WBC when they are in pyelonephritis they accumulate in tubule and they made WBCcast seen

in urine analysis) .

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EM:these podocyte &this is the sub epithelial space" between podocyte or epithelial cell & BM"these are the deposite they accumulate under the epithelium ,and they are IG and BM start to built between them BM until BM surrounded them ,the end result the BM itself will become thick &the deposite

inside appear as spikes like (

)foot process as MCD &FSGS they are fused .

طالع بكون سيارة عجلspikesمنه

ال نفسشكل لها الشكل tubuleاسطوانية


b. Oliguria with azotemia ,means kidney function is effected in nephritic syndrome not like nephrotic syndrome,, Oliguria: decrease urine out put,, azotemia: keratinin & urea are

high in association of symptom of uremia in this pt .c. Hypertensiond. Proteinuria.(plus/minus )means Proteinuria may be present but not in the nephrotic range (non nephrotic range Proteinuria) ACUTE ONSET OF SYMPTOMS but in nephrotic syndrome is slowly onset of symptom. The main causes of nephritic syndrome:

One of the most cause is 1. Acute postinfectious glomerulonephritis

What distinguish its Diffuse proliferation and swelling of the glomerular cells and frequent infiltration glomerulus by neutrophils & inflammatory cell ,u look to the glomerulus u find its very cellular there is proliferation of cells native to the glomerulus itself & there is infiltration by inflammatory cell from outside.

the classic case a child come with(it usually happen in children ) history of 1to4weeks ago with streptococcal infection usually of the pharynx cause by group A B-hemolytic streptococcus or of the skin but most of the time it is in the pharynx .if pt. came with tonsillitis or pharyngitis before 4 weeks and then he come with hypertension ,hematuriea azotemia this is the classic case of Acute postinfectious glomerulonephritis. In most cases the initial infection is localized to the pharynx or skin.Morphology:

LM:the distinguish is the glomerulus is very cellular proliferation of cells ,,swelling ,edema of the cell in addition to infillitration by neutrophil &other inflammatory cell.

EM: sub epithelial deposit the same appearance in membrane between epithelial cell &basement but in post streptococcus glomeronephritis,the deposition is very large so

called sub epithelial hump .

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Clinical Course: Sudden onset ,nephritic syndrome always come out of sudden onset of malaise, a slight

fever, nausea.Oliguria, azotemia, and hypertension are only mild to moderate.

Most important feature is hematuria: usually is gross hematuria,urine color is cola like or dark brown urine due to the presence of RBC it self's.

Proteinuria is present but is not in the nephrotic range proteinuria . Complement are on low in the blood because of deposition of IG & complement in the kidney in glomeruli the complement conc. In the blood decrease mean consumption of complement.

Serum antistreptolysin antibody it indicate there is a previous streptoco. infection. This is the antibody of the streptoco. means the body have previous infection with the strep. the form antistreptolysin antibody they can be detected in the serum in pt. with post infection glomerular nephritis . recovery is always almost complete in most children the disease they carries benign course . some children develop rapidly progressive glomerular nephritis.

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Cellular, notice the neutrophile cell, is the most segmented nuclei this post streptococcus nephritis

IN EXAM: subepithelial hump characteristic of what GN ?

Sub epithelial hump very large hump al l of it is IG deposition.


After awhile we will take RBGN & severe injury on the acute renal failure in adult from 15-50% of individual progress to chronic renal failure disease so in poststrep. glomerular nephritis the children usually complete recovery & adult usually the course is less well usually progress to renal failure or to GN in contrast, in children, the prevalence of chronicity after sporadic cases of acute postinfectious GN is much lower, always in children the disease much better in all disease we talked about its much better course in children than adult .Treatment corticosteroid therapy because its immune mediated process not infection the infection not present now but was present previously 4 weeks age & the immune reaction mediated not infection . -----------

2. IgA nephropathy It’s the most common glomerular nephritis world wide means either

causes nephritic syndrome but if u asked what is the most common

nephropathy world wide between all GN ? its IGA nephropathy . it usually affect children & children as an episode of gross hematuria within 1or2 days of upper respiratory tract infection . usually viral . the pt. have flu or cold after few days start gross hematuria suddenly the color of urine is dark brown or cola urine. typically the hematuria lasts several days and then subsides, only to recur every few months,its on &off recurrent hematuria the main clinically symptom of igA nephropathy. IgA nephropathy is one of the most common causes of recurrent microscopic or gross hematuria and is the most common glomerular disease revealed by renal biopsies worldwide. Hematuria is not associated with hypertensive or azotemia it a benign hematuria that is recurrent so the IgA nephropathy properly have no that much effect apart from the recurrent hematuria very few of cases they can progress of FSGS cause of FSGS is IgA nephropathay.

The pathogenic hallmark is the deposition of IgA in the glomeruli.

MorphologyLM: variable. The glomeruli may be normal or show mesangial widening deposition of IgA in mesangial ( mesangial mean space between capillary loop) become bigger and segmental inflammation confined to some glomeruli (focal proliferative GN because of

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presence of inflammatory cell.) always when is a inflammatory cell the disease is proliferative; (mesangioproliferative because of proliferation of mesengial cell ); or (rarely) overt crescentic GN. IF: mesangial deposition of IgA most imp. feature (&main Ig present is IgA) , often with C3 and smaller amounts of IgG or IgM Early components of the classical complement pathway are usually absent. EM: electron-dense deposits that we see on IF also appear in EM .Clinical Coursegross hematuria most imp. feature/ sign which is recurrent most of the time infection children & adult,, gross hematuria occur after an upper respiratory infection which usually viral . 30% to 40% have only microscopic hematuria, with or without proteinuria(without change color of urine & may pass un notice) 5% to 10% develop a typical (classical)acute nephritic syndrome. Hematuria& HT & azotemia this is can be seen in only 5-10% of cases IgA nephropathy is a benign disease .The hematuria typically lasts for several days and then subsides,it’s a recurrent problem after each upper respiratory tract infection after 2 days he will have gross hematuria, only to return every few months. Slow progression to chronic renal failure occurs in 25% to 50% of cases during a period of 20 years.

***Imp to know LM,EM,IF in each GN& to know if it nephritic or nephrotic.

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Many thanks to mais abdullah

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