82 ‫محاضرة‬

‫ عبد اهلل مطر‬: ‫اجلزء األول‬

Slide 33 SLE:

I think you already know the criteria of diagnosis , you have to have four out of eleven criteria ( arthritis , hematuria ,
skin rash , anemia , ANA +ve … and so on ), so if the patient going to have four of this criteria then you can label him as
having systemic lupus erythromatosis and next step is actually is to assess kidney involvement .

- Renal involvement in lupus erythromatosis is very important cause of morbidity and mortality. ‫جزء كبٌر من‬
‫المرضى اللً عندهم‬SLE ‫ بموتوا او بصٌر عندهم‬renal failure ‫بعدها رح ٌموتوا تبعا ً للمضاعفات اللً صارت فً الكلٌة‬
- That’s why it is very important to assess the kidney involvement in any patient who have systemic lupus
erythromatosis even without manifestation of kidney involvement.
 Variety of changes are going to happen in the kidneys , and will have different morphologic and clinical range
, they’re classified according to WHO into SIX classes , these six classes are going to be correlated to the
expected clinical manifestation , so whenever you have SLE in the kidney , you can see anything and it will be
correct! so a patient can have lupus nephritis and we go for a biopsy and it might be :

I . NORMAL : this doesn’t mean that his kidneys are not involved or they aren’t going to be involved.
II . MESANGIAL EXPANSION : mesangial proliferation as well as expansion of the mesangial matrix.

Or that patient can have variety of proliferative disorders :

III . FOCAL PROLIFERATIVE : little amount of glomeruli with proliferation .

IV . DIFFUSE PROLIFERATIVE : All the glomeruli are going to display proliferation .

 Proliferation of what ?
 Proliferation of endothelial , mesangial or sometimes infiltration of inflammatory cells leading to exudation ,
maybe epithelial proliferation ( if forming crescent ) .
 So you are going to see proliferating glomeruli that can involve a portion of some glomeruli ( FOCAL ) or it can
be diffusely affecting all the glomeruli (DIFFUSE ).

Or these lesion can be non-proliferative but associated with thickening of the membrane:

V . MEMBRANOUS NEPHROPATHY PATTERN : here you get to see thickening of the membrane or glomeruli ,but without
any significant inflammation , without any significant necroinflammatory process or proliferation .

Or sometimes unfortunately we go for to a kidney biopsy , and we find :

VI . ADVANCED SCLEROSING GLOMERULONEPHRITIS : what are we get to see is end stage of glomerulosclerosis ( always
glomerulosclerosis is the end result actually of many of kidney diseases )

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  What is going to be expected in clinical presentation ?

 Now we have to assess kidney involvement , how do we do that ( before going for a biopsy ) ?

Urine Analysis ( Really Important ) - GOOD URINE ANALYSIS IS A LIQUID BIOPSY OF THE KIDNEY –
 A patient who has mesangial by electron microscopy , the normal glomeruli might have some proteinuria or some
hematuria , this applies also to class two.
glomeruli ‫ فً ال‬minimal change-like changes ‫ أو‬mesangial ‫ٌعنً المرٌض اللً عنده‬
- Where ( In glomeruli ) you don’t get to see any Light microscopic manifestation , these patients might have
some sort of proteinuria or mild hematuria ..
 But if the patient has proliferative lesion , what are we going to find ?
- Cast or in other words Nephritic syndrome ( absolutely right ) , If the patient is going to have proliferation that
means definitely this is going to be associated with Nephritic syndrome .
- Always we say that proliferation is a manifestation of injury , sometimes mild or focal necrosis , and that’s
usually going to be associated with proliferation ..
- So the Proliferation is really a bad news in glomeruli …
 So patients with proliferative lesions are going to have Nephritic syndrome that might actually advance to
RPGN ..
- Focal proliferative present to us as Nephritic syndrome
- Diffuse proliferative with epithelial crescent formation present to us as RPGN ( Rapidly Progressive
GlomeruloNephritis )
 Or this patient with proteinuria leading to Nephrotic syndrome, will have membranous nephropathy ( proteinuria
means that there is not much damage to the glomeruli but there is leakage through the basement membrane ) , or
theses patients in late stages are going to have renal failure.
‫ ٌا إمّا‬RPGN ‫ ٌا إمّا‬nephrotic ‫ ٌا إمّا‬nephritic ‫ ٌا إ ّما‬hematuria ‫ أو‬proteinuria ‫ ٌا إمّا شوٌة‬urine ‫ ٌا إمّا وال اشً فً ال‬: ‫المرٌض إجا‬
... chronic renal failure ‫ ٌا إمّا‬acute renal failure
‫أكثر من‬Roughly all the changes that we expect to see in glomerular disease can be associated with SLE nephritis .. -
‫ و هذا أمر سًء‬proliferative ‫نصهم رح ٌكونوا‬

- The more they have proliferation, more of glomeruli will be affected , and the worse is the prognosis (ending
with renal failure ) .
- With these patients we have to have very good assessments of the urine analysis , we go for BUN & creatinine
and if normal this doesn’t rule out kidney involvement in patients who have SLE .
In IF what we will find ?
- ( On light microscope  minimal like or normal or mesangial or focal , diffuse proliferative , membranous
nephropathy or advanced kidney disease )
- In IF we will find everything (( full-house pattern )) , so you get to see IgM , IgG , IgA and C3 everywhere ( in sub
endothelial , within the basement membrane and sub epithelial and also in mesangium ) and this advised for
electron microscopy where you get to see deposits everywhere .
- On top of that you going to see characteristic lesions of SLE in patients who have SLE nephropathy , what we
refer as WIRE LOOPS , so some of the glomeruli or some of the capillaries are going to be so thickened so as to
look like the wire loops in the patients who have SLE ( usually we don’t go to diagnosis based on these wire
loops , this will be later to assessing antibodies and urine analysis ) , so before we go for kidney biopsy in
patients who have nephritic or nephrotic you have to have that screening that we mentioned before.
 So most of the patients who have SLE nephritis are going to be previously diagnosed , yet you go for kidney
biopsy to assess the extent of the damage

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  All of these will be more characteristic of SLE nephritis in these patients :
- we may find wire loops , hematoxilyn bodies ( due to aggregation of inflammatory cells and crushing of their
DNA content ) , proliferation , membrane thickening , epithelial crescents .. so whatever you think of you can
find in a patient who has SLE nephritis .

 In Immunofluorescence ( IF ), we find granular deposits of Immunoglobulins (any type.. IgA, IgM ,IgG ) and
sometimes you get to see nuclear staining when you go for IF denoting that these patients have Anti-Nuclear
Antibody , this is how we actually test ANA, either you go for ELISA testing the circulating antibodies in the serum
or sometimes you fix those supposedly present in the patient serum antibodies to a hepatocyte slide , and if the
patient is going to have ANA they will attach there , then they are going to be labeled by anti-antibody .
‫ تاعٌنه رح ٌضووا لحالهم‬nuclei ‫ قاعدٌن على ال‬antibodies ً‫فإذا المرٌض عنده أصال‬
- So staining of the nuclei is going to be supportive that these patients are having Anti-Nuclear Antibody ( ANA
) in these cases .
In Electron Microscopy , you get to see remarkably and irregularly thickened capillary loops that represent
actually the wire loops ( by light microscopy) , and sometimes you get to see those deposits everywhere , and
sometimes we get to see also what we called microarrays ( microtubular arrays ) as well as other diagnostic things.
- In RPGN , these patients are going to have active sediment with elevated BUN & creatinine , so if patient with
elevated BUN & creatinine and active sediment, then we have casts ( granular cast ), we have proteinuria ,
hematuria .. usually an excess of + 2 ( at least +2 ) , and this is what we refer to as RBC cast , and if the patient
has elevated BUN & creatinine , then mostly he has RPGN ( the bad acute nephritic ).
- However, if the patient has nephrotic , he is going to have membranous with deposits sub epithelial , almost
this we will be classical of membranous nephropathy yet the patient is going to have SLE by lab and clinical
data.
membranous nephropathy‫ و‬SLE ‫ٌعنً المرٌض أصالً عنده‬
- Could be a part of SLE spectrum (nephritis) , and may be membranous nephropathy alone .

 Who will have the better prognosis ?

 With only membranous, because at least he doesn’t have damage , and they might respond later on . And if we
stain the basement membrane , we are going to see spikes and sub epithelial deposits, and if we go for electron
microscopy , sometimes you get to see these microtubular arrays which are going to be due to cytoskeletal
rearrangement in the endothelial cell ( rare ) .
- Actually you don’t have to go for electron microscopy for each patient who has some sort of kidney
involvement , so good light microscopy and good IF in most cases are enough.
- Electron microscopy will confirm what you know or it is going to confirm what you expect to see in these
patients .

-These ( normal , mesangial,…) are not stages , those were CLASSES .

 So a patient is going to have only nephrotic , may be on top of that he is going to have proliferative … But these
aren’t stages , they are classes according to the type of antibodies that are going to be seen and where it will
attack and according to the type of immune complexes ( depending on the outcome of immune complexes
formation and reaction ) .
 However , Just focal and diffuse proliferative we can consider as continuum of a single process as focal
proliferative can progress to diffuse proliferative leading to sometimes end stage kidney disease .

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Slide 57 Renal Transplant pathology

This is really tough topic and ever changing one , the classification in slides is totally changed now , and the new
classification is not adopted everywhere , so the doctor said that he will not speak in details about this topic , but you
are going to see many transplanted kidneys because the price of the kidney is now more acceptable , transplantation in
Palestine is restricted to first degree relatives .
‫الدكتور ٌتحدّث عن قضٌة طبٌة أخالقٌة و إنه فً ناس بكونوا طبٌعٌن و ما بقربوا للمرٌض و بٌجوا ٌتبرّعوا بالكلٌة و بقول إنه دورنا كأطباء إنا ما نشجّع‬
 ‫ لألسف‬matching ‫هذه األمور و ما نفتحلها المجال مع العلم إنه ما منقدر نمنع المتبرّع الغرٌب من التبرع و منفحص ال‬
You will see much patients with transplanted kidneys and you are going to deal with such patients , and all patients
with transplanted kidneys are going to have some sort of rejection unless the kidney was from a homozygous twin :D
‫هذا هو المحل الوحٌد اللً ممكن ما ٌصٌر فً رٌجٌكشن غٌر هٌك إال ٌصٌر رٌجٌكشن‬
 And that rejection was classified in different ways , one of these ways is according to the acuity of the rejection
:
1-HYPERACUTE REJECTION : fortunately we don’t see nowadays anymore , the rejection starts during transplantation ,
the kidney become cyanotic and it won't perfused ( instead of being purple due to circulation it will become cyanotic )
and it will pass all amount of hemorrhagic blood then it will shut down ..
- The cause is preformed antibodies in recipient circulation ( from multiple blood transfusion so the recipient
has exposed to many antigens or it may be a lady with multiple children or a patient who has transplantation
before ) , so in these cases we have to be sure that the patient doesn’t have circulating antibodies.
- SO nowadays we don’t go for kidney transplantation before assessing the presence of these Panel Reactive
Antibodies (PRA) or circulating antibodies in the serum of that patient , If he has them we treat him we delay
to the biopsy until these antibodies are going to decrease in concentration , so you aren’t supposed to see
hyperacute rejection anymore .
2-ACUTE REJECTION ( MILD OR SEVERE ) : If that is severe enough to be seen clinically and in the laboratory we referred
to it as Acute Rejection , If that was not severe and if that was controlled by Immunotherapy , It will be very subclinical
acute which will become Chronic
3-CHRONIC REJECTION : it is the accumulation of multiple parts of mild acute rejection , so the chronic rejection is an
acute one.
 And depending on what we are going to see you will classify ( as the classifications are revised now ) , You will get
to see mostly inflammatory cells or cytotoxic lymphocytes attacking the blood vessels or they can attack the
tubules and the interstitium .
Blood vessel involvement  more in acute rejection
Tubulointerstitial Reaction  more in chronic rejection ( or in mild acute forms )
 So when we take a biopsy we assess the glomeruli , we assess the tubules, and we assess the extent of the
inflammatory cell infiltrate , sometimes we also go for the demonstration of certain cytotoxic antibodies and
then we will decide what type of rejection our patient is having , and we determine the treatment ( the drugs
we give to prevent rejection , might be associated with nephropathy- such as Tacrolimus- that looks like
rejection ) .
 Immunosuppressants will be administrated to these patient along their lives , because the patient is going to
have rejection episodes unless the donor was his homozygous twin.
 Many of these patients are going to have debilitating renal function after five to ten years of transplantation ,
e.g. the doctor knows a patient who has more years with transplanted kidneys , he got bad hepatocellular
carcinoma due to immunosuppression.

‫ لٌش المرضى بزرعوا كلٌة طالما خالل عشرة سنوات رح ٌردوا ٌفقدوا عمل الكلى ؟‬: ‫ سؤال‬

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 ‫ كل أسبوع أو أسبوعٌن ألنها‬dialysis ‫ إنه المرضى مستعدٌن ٌدفعوا عشرة آالف شٌكل و أكثر عشان ٌتج ّنبوا قعدة غسٌل الكلى‬: ‫ الجواب‬
. ‫أمر مزعج جد ًا لهؤالء المرضى‬
! ‫ ممكن الواحد ٌكون عاٌش مع كلٌة واحدة و هو مش داري و ٌتم اكتشاف ذلك صدفة‬: ‫معلومة عابرة‬
‫ لٌش لما ٌٌجوا ٌقٌموا الكلٌة عشان الزراعة بقٌموا الثنتٌن و بخلوا وحدة من األصلٌات ؟‬: ً‫ سؤال ثان‬
: ‫ الجواب‬
you don’t bother to go for end stage kidneys , we transplant in different anatomic sites ( In Right Iliac fossa not
retroperitonium ) , so you don’t have to go for two surgical approaches , so no problem , they are fibrotic tissue
having no harm to our body unless they get a tumor .

- So these Patients are going to have immunosuppression for their lives ( we go for biopsy to know the extent of
damage the reached )
 We see cortical inflammatory process : you get to see edema of the interstitium , vasculitis and you get to see
tubulitis ( inflammatory cells incursion in the epithelial cells of tubules and leading to their destruction ) , this is
a characteristic type of immune mediated tubular-interstitial nephritis.
 (Slide 61) this is a tubule and these are lymphocytes , eventually these cells are going to destroy more and
more tubules until these patients are going to have tubular atrophy , interstitial fibrosis and later on
glomerulosclerosis .
 Vascular Rejection may happen , you get to see cytotoxic lymphocytes within the intima , this can be
associated with accelerated atheromatous plaque formation eventually leading to thrombosis of that blood
vessel and again to ischemic damage to the kidney itself .
) ‫ اختلف فما بده ٌحكً عنهم كثٌر ( اقرأوهم قراءة‬approach ‫الدكتور بقول إنه كل ال‬

End of RENAL4 slides

 Renal 5 slides

Diseases affecting tubules and interstitium

Despite the kidney is one organ , despite the nephron is one functional unit , however , you are going to see different
diseases targeting different portions of the kidney specifically.As we mentioned before that glomerulonephritis is
glomerular diseases where we had targeting of the glomeruli before damaging the tubules and the interstitium , so the
disease starts with glomerulitis and that’s going to be associated with glomerulosclerosis, then tubules will be
impaired then end stage kidney disease .
OR that process might start within the tubules and interstitium sparing the glomeruli for late stages and all portions
are going to have damage and sclerosis . But the process actually might start within the interstitium or within the
tubules or within the parenchyma of the kidney itself not from the glomeruli , this is what we call Tubulointerstitial
nephritis , keeping in mind that these are parenchymal disease that affect both the cortex and the medulla ,the doctor
think that mostly they are medullary pelvic disease (we have inflammation of the interstitium in between the glomeruli
, in between the tubules and later on that might affect the blood vessels as well as the entire kidney itself ) .
 Now this process might be bacterial or it can be non-bacterial .
1- We call the bacterial one as Pyelonephritis ( again pyelonephritis doesn’t mean inflammation of renal pelvis or
inflammation specifically of medulla of the kidney , IT MEANS inflammation of parenchyma entirely but the process
start actually in the parenchyma between the glomeruli itself ).
2- Or this can be non-bacterial and we call it Tubulointerstitial Nephritis .

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  Bacterial mostly is due to ascending infection or due to hematogenous , while other non-bacterial causes can
include different agents ( metabolic (hypokalemia , hypercalcemia ) , radiation , immunological mechanisms
and DRUGS ) .
ACUTE PYELONEPHRITIS

First one to be discussed is Acute Pyelonephritis ( it is like acute pneumonia , so this is a clinical term that you will see
in certain syndromatic presentation )
) Acute pyelonephritis ‫ٌعنً المرٌض الزم ٌكون عنده عدة شغالت مع بعض حتى نقول هذا المرٌض عنده‬
 What do you think ? what would these patients have ?
 Fever , Chills , dysuria , polyuria and FLANK PAIN

- These patients are going to have that symptoms complex which is mostly associated with acute pyelonephritis
.
 Causes :
A. Mostly ascending infection of urinary genital tract ( mostly gram –ve bacteria specially E.coli )
- This is can be more common in females ( because of the shorter urethra of females ) .
- Other gram –ve or gram +ve can be implicated in acute pyelonephritis ( E.coli , proteus , klebsiella , then gram
+ve )

 Why should a patient have acute pyelonephritis ?-

 If a patient has pyelonephritis we should know , and it is going to be more important if the patient has
recurrent attacks of urinary tract infections manifested as pyelonephritis .
‫ و هذا بسبب‬inflammation ‫ عادة ما بكون عنا‬bladder ‫ فً ال‬inflammation ‫ مش المفروض ٌكون عنا‬-
Different mechanisms of defense , immune system has very important role, in addition to that is the URODYNAMICS (
which is unidirectional continuous flow of the urine ) , urine is not going to be 100% sterile.
significant ‫ وحدة أو ثنتٌن هذا مش‬colony ‫ ٌعنً اذا زرعنا و طلع معنا‬-

- Even though we have passing of microbes in our urine these aren’t going to flourish because of continuous
voiding .
pyelonephritis ‫ ماشً لتحت مش لفوق فغالبا ما رح ٌصٌر عنا‬urine ‫ ٌعنً طالما ال‬-

- So the patient who is going to have pyelonephritis , especially the recurrent attack , this means that there is a
problem ( either due to stasis ( urodynamic abnormality ) or due to instrument )

 Whenever you going to use a catheter or any foreign body into a patient , it is a attractable for infections ( any
patient with Foley’s catheter is going to have a sort of infection ) , especially if using these catheters for a long
period of time
 Any patient who doesn’t have normal voiding is definitely going to have UTI ( such as prostate hyperplasia
patients , and diabetic patients ) , his is also common in children who have vesicoureteral reflux ( VUR) :
- So during voiding , when the pressure in the bladder increases , usually this cannot overcome the constricted
sphincter at the uretrovesical junction and the urine has to pass downward to urethra , if the patient has
abnormal junction this is going to be associated with back flow of the urine ( causing inflammation ).

 Another cause , if the ureter is relaxed ( doesn’t contract as normally like peristaltic ) but these diseases are
going to be very rare ( may be in pregnancy or progesterone excess (relaxant ) this can be associated with
dilatation and tortuosity )

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 Predisposes to acute UTI ‫ فهذا عادي لكنه‬urine ‫ فً ال‬WBCs ‫ٌعنً اذ ا مرأة حامل عندها‬

B. The other source of pyelonephritis is hematogenous spread (continuous bacteremia ) such as endocarditis
patients or patients with septicemia .
- Whenever we have pyelonephritis we have to consider why , not giving antibiotics and that’s it , we should ask
why that patient in particular developed acute UTI .

 The UTI and pyelonephritis are going to be more common in female ( shorter urethra ) , or during sexual
intercourse causing cystitis ( honey-moon cystitis ) and sometimes we get to see pyelonephritis in these
patients .

I repeat ! : whenever a patient has pyelonephritis, we should look for the cause !
1- instrumentation , traumatization , obstruction , vesicoureteral reflux , diabetes or paraplegia.
2- The most important cause in children is vesicoureteral reflux (VUR) specially females ( shorter urethra on top
of that ) .
 How can we diagnose that condition ?
1- Screening with contrast in bladder , ask the patient to go for the toilet ,
: ‫ مش المفروض ٌطلع لفوق و إذا طلع لفوق‬contrast ‫ هسا ال‬-
Then this is diagnostic that the patient has VUR . and if you don’t address that the patient is going to have recurrent
pyelonephritis leading to end stage kidney disease .

2- Ultrasound can be used in kidneys to see stone, dilatation , hydronephrosis ( when kidney are too damaged ) .

C. In old patients , prostate hyperplasia is really important cause

‫ فبصٌر عندهم مشاكل و همً مش دارٌٌن‬abnormal voiding ‫ألنه بعض المرضى بتعوّ دوا ع ال‬

‫ اشطبوه‬، ‫ العنوان جاي بالغلط‬51 ‫سالٌد‬ -

 So If patient with UTI rule out :

o Obstruction
o Reflux
o Pregnancy
o Instrumentation
o Diabetes Mellitus
o Sex and age are also Important
o Pre-existing renal lesion ( kinked ureter )
o Immunosuppression

 Diabetes is going to affect the kidney in variety of ways :

o In glomeruli  diabetic nephropathy
o Blood vessels  atherosclerosis
o In large vessels  hyaline arteriolosclerosis
o IN PARENCHYMA  PYELONEPHRITIS
- Most of diabetic patients have pyelonephritis in association with neuropathy affecting urine flow , they can
have also necrotizing papillitis and they can have other source of inflammatory processes that can be
associated with more frequent bacteremia , not necessary to have septicemia. So these patients have higher
chances to have UTI
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  What are you going to see in patients of pyelonephritis clinically ?
Grossly : we don’t have to go to gross examination
Lab and clinical data : is going to be quiet characteristic .
 What’s the difference between pyelonephritis and ‫ل‬glomerulonephritis ‫؟؟‬
 glomerulonephritis affects both kidneys ( as immune mechanisms don’t distinguish between right and left
kidneys ) so all glomeruli are going to be affected in the right or the left kidneys in the same way , that’s why it
doesn’t matter where you go for biopsy. so glomerulonephritis is a diffuse bilateral usually symmetric process.
 WHILE Pyelonephritis is not necessarily so , it can be one kidney , it can be bilateral , but usually it's never
symmetric and it's never at the same stage ‫ٌعنً ٌمكن كلٌة قرّبت تخرب و تكون الثانٌة سلٌمة أو ممكن ٌكون فٌها شوٌة مشاكل‬
- So this doesn’t necessarily have to be the same progress , the both may be in the same stage or progress if the
obstruction is (for example) at the prostate level , but usually pyelonephritis might be unilateral , it might be
bilateral , BUT usually it is not that symmetry .
- And kidney that’s infected with that inflammatory process is usually going to be edematous , increased in size
with many white-yellowish nodules that represent micro abscesses.

Microscopically - usually we don’t have to go for biopsy to diagnose - , we will find expanded interstitium (
interstitium is barely seen in normal kidney and very tightly crowded tubules microscopically ) infiltrated by
inflammatory cells mostly neutrophils ( which will come from blood vessels of the interstitium ) and they
drained into tubules and doing that they are going to be more and more concentrated , you are going to have
continuous inflow of neutrophils , and then primary urine are going to be concentrated ( huge amount of
neutrophils drained ) then they will get molded into WBC casts .

- So if we see WBC cast in urine , this is equivocal of pyelonephritis .. so urine analysis is very valuable test , and
the technician shouldn’t tell us that there's WBCs in urine , he should tell us if there're casts or not .,this is
because neutrophils alone can be present due to cystitis and due to renal stones , BUT having neutrophil casts
is diagnostic of pyelonephritis .
- And these tubules might be distended , some of them might eventually rupture leading to formation of micro
abscesses within the glomeruli .
- SO THE DIAGNOSIS IS EASY : FLANK PAIN , CHILLS , FEVER , MALAISE , DYSURIA , PYURIA AND MOST IMPORTANTLY WBC
CAST .
In these cases do we have to go for ultrasound ?
- YES , not for the diagnosis but to look for underlying cause
‫ هل عند المرٌض‬، ‫ هل قاعدة بمحلها أو ال‬، ‫ هل الكلٌة خربانة أو ال‬congenital abnormality ً‫ أو هل ف‬stones ً‫ٌعنً عشان نشوف شو فً هل ف‬
.. ‫كلٌة وحدة وال ثنتٌن‬
- So yes we go for ultrasound to have an idea about the condition of that kidney , and the ultrasound will not
diagnose pyelonephritis , but it will tell us that the kidney is edematous or having stones and so on .
The amount of urine is going to be normal or sometimes with a little increase , with isosthenuria.
- Isothenuria : refers to the excretion of urine whose specific gravity (concentration) is neither greater (more
concentrated) nor less (more dilute) than that of protein-free plasma, typically . Isosthenuria reflects renal
tubular damage/failure of renal medullary function - Wikipedia ))
 So WBC start in the interstitium , they get into the tubules where they are going to be more and more
concentrated , some of these tubules will rupture leading to small tiny abscesses
 And then you get to treat your patient ( the good thing in the acute pyelonephritis that it is a clinical entity and
the patients are going to have their complains that are going to be diagnosed then treated and when you treat
properly these patients ( despite some portions of kidney will be completely damaged.. very minimal fibrosis ) ,
they will recover ( Good outcome ) .
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  The glomeruli are normal , no antigens and immune complexes that are going to target the glomeruli , so the
glomeruli are going to look normal .
 The problem will happen if the patient has repeated attacks of the acute and poorly controlled and badly
treated pyelonephritis , that will be associated with ongoing Tubulointerstitial destruction , so more tubular
destruction , more interstitial fibrosis and definitely the more of these we have , the secondary glomerular
sclerosis will take place leading after that to end stage kidney disease , where the tubules are going to be
atrophic and the interstitium are going to be fibrotic and the glomeruli are going to be sclerotic .

‫طولكرم_عنابٌة‬#

‫ بيان حممد‬: ‫اجلزء الثاني‬

Slide 20 Cont. Pyelonephritis

So Whenever you are going to see abnormal urine (WBCs, Hematuria, cast) we have to send the patient for US.
Sometimes you send the patient for US because of UTI and you find pyonephrosis.

 What happens in pyonephrosis?

 the ureter of kidney closes so the urine will be thrown back to the kidney itself along with bacteria, it will be
associated with ongoing inflammation
 and the high pressure of kidney will lead to cortical atrophy, the pelvicalyceal system will get distended and
filled by neutrophils, SO kidney will turn into a bag filled by pus (pyonephrosis)
 So there’s continuous obstruction, unilateral, if bilateral will have the pt. will present with ARF.
 So Obstruction- pyelonephritis –pyonephrosis
 What to do to kidney in this situation?
“Pyonephrosis means cortical atrophy, pelvicalyceal dilatation and the cortical changes are irreversible “. So
nth to do! That kidney is lost!
Remember: Pyelonephritis might be unilateral but it’s more common to be asymmetrically bilateral depending on
the cause. The BUN creatinine will be normal because there’s another functional kidney.

Slide 21 Necrotizing Papillitis

 Sometimes, some patients present with under diagnosed entity we call it Necrotizing Papillitis. The tips of the
papilla are at unprivileged situation. That area has High osmosis, low PH, less perfused and more subjected to
bacterial infection.so whenever there is contamination along with hypoxia this will be associated with papillary
tip necrosis and might get sluffed with the urine.
 So, Some patient start with UTI and suddenly they have Proteinuria ,hematuria , temporary elevated BUN
creatinine.so the probable cause is papillaritic necrosis that can be rarely associated with renal failure .
 There are many causes for papillaritic necrosis–slide23- and these include use of analgesics, DM, UTI and
obstruction. (Especially in combination). Other causes include: hemoglobinopathies, hemophilia, cirrhosis,
different types of dehydration.
Slide 25 Chronic pyelonephritis

If the patient is not going to have that clinically evident pyelonephritis then he is going to have subclinical ongoing
tubular interstitial inflammation that we refer to as chronic pyelonephritis the inflammation is going to subside but
won’t resolve totally and the underlying cause are still there (e.g. prostate, DM, child with vesicoureteral reflux all of
these conditions are still there).

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 So these patients will have chronic ongoing infection with gradual replacement of the acute inflammatory cells
with chronic inflammatory cells with proliferation of the fibroblast with tubular atrophy
 And these patients are going to end with chronic pyelonephritis that can be morphologically evident by irregular
scarring and shrinking of the kidney.
 Is it Unilateral or Bilateral!? It depends; if bilateral it won’t be strictly symmetric.
 manifestations
 In these conditions the patient is not going to have that evident picture of chills and fever ,
 he will have little dysuria
 some febrile temperature,
 on urine analysis he has pyuria- contamination of urine
 No glucocytosis or flank pain as you get to see in acute pyelonephritis. All of the manifestations will be
less prominent and unfortunately the destruction of kidneys will be more established until eventually
these kidneys end with total destruction of the functional units of the kidney.
The final pathway of all kidney diseases: *Tubules atrophy, *interstitial fibrosis, *glomerulo sclerosis.

 Remember: In glomerulonephritis it started from glomeruli so those patients are going to have glomerular
sclerosis and the Tubules draining those abnormal glomeruli will get atrophic , the interstitium will get
fibrotic
 HOWEVER- slide29- , in this condition the process started in the interstitium( interstitial inflammation ,
proliferation of fibroblast , interstitial fibrosis ) some of the tubules will become so atrophic that will get
distended ,dilated and filled by proteinous material ( follicle filled with red protein that resembles thyroid
tissue ). That’s why we refer to the condition as thyrodization of kidney.
‫فقط شكال ولٌس لها عالقة بهرمونات الثاٌروٌد‬

All kidneys will be lost gradually until that kidney will be totally nonfunctional.

Later on, glomerulosclerosis occurs that can be secondary or later on it might be nonspecific. that is because of
the loss of some glomeruli the remaining viable ones will get more flow and more pressure and this pressure can be
associated with proteinous exudation leading to focal segmental glomerular sclerosis like picture that can be
associated with nephrotic syndrome.

Remember: Focal segmental is one of the causes of nephrotic syndrome. It can be primary idiopathic or due to
ablation nephropathy.

So this can be one of the stations of the progression to chronic kidney disease and these patients are going to have
renal failure eventually.

 What to do in these cases?

 In these cases you have to assess the extent of renal damage and the functionality of each kidney.
 Creatinine might be normal, but if it’s elevated this means this is really bad and the patient is entering end
stage kidney disease!
 Then you assess which kidney is affected more than the other. This done by intravenous pyelogram, where we
inject a colorful substance and that substance must be excreted by the kidney and you assess how of these
kidneys is going to function. You assess the trajectory of that flow and then you decide what you are going to
do to these kidneys, if there is anything to be done!
 Unfortunately These patients usually come in late stages because they are not going to have anuria neither
oliguria. In fact its normal urea or polyuria (because of tubular loss, so no enough reabsorption, the
remaining glomeruli can’t have enough filtration that not going to be totally reabsorbed) leading to polyuria

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 of hypotonic urine (with low specific gravity). The patient thinks he has good urine and thinks he has good
kidneys.
 So these patients present with chronic renal failure and unfortunately you will see some of them in young
ages. When they present they have very high Creatinine, anemia, Characteristic discoloration of skin,
gastritis, pleural effusion, and serositis.
o Recently a young lady in her 20’s ,was presented with severe recurrent anemia that required multiple
transfusion no one bothered to do the creatinine tests .She was diagnosed with renal failure she thinks she has
good urine.
o However, patients in their 40’s 10’s usually come with hypertension, creatinine will be high and on US the
kidneys are small and shrunken. No need for biopsy, and if we do we will find interstitial fibrosis, tubular
atrophy, glomerulosclerosis and this is the final pathway of all kidney diseases. There is no point to go for kidney
biopsies because there is no value of it. However we go for it, if the patient is young (20’s) and the kidneys are
not massively shrunken and you want to give him another chance to find some functionality to save him from
kidney .transplantation because in these cases transplantation is the only solution.
Slide 32 Drug induced interstitial nephritis

Another cause, very common and undiagnosed for end stage kidney disease is drug induced interstitial nephritis
especially analgesics and antibiotics. Ampicillins, especially the semisynthetic of them are very bad! Most of people
take NSAIDs and antidiuretic that are associated with interstitial nephritis that can be acute (associated with heavy
inflammation of interstitium and tubules) or chronic.

o Drug induced nephritis differs from pyelonephritis in that the drug induced is more diffused , bilateral and
symmetric and if severe can be associated with acute renal failure because these drugs will be concentrated in
those tubules.
Clinical manifestation:

 These patients will have fever,

 Skin rash because most of these are immune mediated.
 They can have eosinophilia , hematuria, proteinuria
 But more important eosinophiluria. If you suspect drug induced nephropathy you have to ask your lab
technician to look for eosinophils they must be specifically looked for it.
In urine analysis we check for the Physical characteristics: Color, weight, specific gravity to assess tubular function.
You pay attention to the color when it’s (red and brown), turbidity. Then you go for chemistry, dry chemistry all of
these are chemically or dry chemical reagents that replace the tubes that we used to do chemical tests before. Then
microscopic examination of the urine.

Slide 35 Morphology

 Nephritis Targeting of the interstitum and tubules by inflammatory cells , the inflammatory infiltrate here is
lymphocytes along with plasma cells and eosinophils
 Most of these inflammatory cells are going to encroach on the tubules leading to tubulolitis (inflammatory cells
on top of the basement membrane attacking the tubular epithelial cells. sometimes leading to their shedding
into tubular lumina leading to formation of cellular cast).
Cellular Cast when the tubular epithelial cells die, found in acute tubular necrosis (ATN). Sometimes you get to see
granulomas.

 Microscopically, you get to see dramatically expanded interstitium by inflammatory cells, mostly small looking
dark cells lymphocytes along with few eosinophils forming tubulolitis.

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  Slide37Drug induced might be due to anaphylactic type reaction (type one) or it might be cytotoxic mediated
(type 4) that can be sometimes associated with granulomatous formation.
 It can be so mild to be associated with mild fever , mild dysuria , mild eosinophiluria or can be so severe to lead
to acute renal failure or chronic tubular interstitial nephritis leading eventually to tubular atrophy fibrosis,
glomerular sclerosis and sometimes with or without papillartic necrosis .
Slide 41 These patients are going to have CRF” chronic renal failure”, hypertension, anemia and more importantly
transitional cell carcinoma.

Acute tubular necrosis (ATN)

Types of nephritis:

 Tubular interstitial nephritis. If it’s bacterial its pyelonephritis and its more unilateral not symmetric. If not
bacterial associated, it will be Bilateral and symmetric especially drugs as well as analgesics.
 Along with tubular interstitial nephritis, there will be Inflammation of the interstitium as well as shedding or
necrosis of some tubular epithelial cells. So if we are speaking about ACUTE tubular interstitial nephritis, and
even if a lot of cells die, eventually these patients are going to regenerate their dead tubular epithelial cells
with full recovery of the kidney function. But some sort of other causes might be associated with more necrosis
“more than inflammation “this will lead to acute tubular necrosis that can be associated with acute renal
failure (one of the most common causes).
Slide 43 Acute renal failure

In Acute renal failure Creatinine is high and progressively elevated.

 ARF causes :
 prerenal : shock (septicemic hypovolemic cardiogenic, dehydration )
 renal : rapidly progressive, ATN
 post renal : total complete obstruction ( e.g. stones in both kidneys )

 ARF when we use that term to differentiate it from acute nephritic syndrome?
Both are associated with elevated creatinine. So, Elevated creatinine and most importantly oliguria which
denotes decrease urine output (less than 400 ml per 24 hours) that’s why these patients must be put on
catheters.
Note: “Anuria is a surgical term, no urine at all”
Slide47: ARF could result from:

 Glomerular causes.
 Tubular causes. e.g. ATN
 Vasculitis: poly arthritis nodosa, thrombotic thrombocytopenic purpura.
 acute cortical causes
 It can be due to acute papillary necrosis especially if that’s going to affect more than one of the pyramids
and it will be transient ,can be treatable but if it’s not treated will be associated with lethal outcome.
 Obstruction
Slide 49 ATN again

 What causes acute tubular necrosis?

Tubules are cells that require continuous energy supply because they have too much of subcellular organelles
,mitochondria , continuously reabsorbing water and all of these process are energy demanding, so usually the
cause that is going to be associated with ATN is going to be ischemic or toxic . They will be bilateral and diffuse.

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  Ischemic include hypotension, trauma, sepsis, pancreatitis all lead to shock.
o The first organ to be affected by hypo perfusion is kidney. So kidneys are going to initiate compensatory
mechanisms (renin aldosterone), vasoconstriction, and if these fail to enough perfuse the kidneys the tubules
will be hypo perfused leading to their hypoxia and then necrosis. If the kidney is hypo perfused, the tubules are
totally blocked so necrosis and sluffing of the tubular epithelial cells into the Lumina occur and the lumen is
closed, so these patients are going to have oliguria patients (not anuria) and elevated creatinine.
o Sometimes you get to see that in rhabdomyolysis ( crushing massive trauma )
o and In intravascular hemolysis( incompatible blood transfusion ,severe fauvism ) .
 Toxic substances include - aminoglycosides like gentamicin ( before giving the patient gentamicin we have to
do creatinine test and if we are in urge to give gentamicin and creatinine is abnormal we cut the dose to the
half).
 Aminoglycosides and Radiocontrast agents can also be associated ARF.
 Poisoning with heavy metals, CCL4, is associated with acute tubular necrosis.

____________
 What happens to glomeruli?
The glomeruli will not be affected because they will not consume any energy, so hypoxia will not damage them and
toxins are not going to be reabsorbed within the glomeruli so damage will be minimal.

Slide 51 Pathogenesis

Here the damage is synergistic meaning we have to have hypoxic and toxic conditions at the same time to cause
damage. The process is going to be mostly on tubules not glomeruli.

Slide 52- Because of very active metabolism in the kidneys, their large surface areas with active transport, active
counter current, relatively hypoxic acidic all that will favor predominantly tubular injury in patients who have
tubular necrosis.

Slide53 More compensatory mechanism will begin that can actually contribute to more tubular damage, e.g. In
hypoxia the kidney induces vasoconstriction that will lead to decrease GFR more and more kidney damage , switch
from cortical to medullary blood flow , so less blood getting through the glomeruli and subsequently less blood
getting through the arcuate arteries

 So hypoxia and toxins will play a synergistic effect that will lead to Remarkable reduction of the GFR as well as
tubular injury and all of that will be associated with oliguria because of massive tubular injury, tubular cell
sluffing into tubules themselves, no reabsorption, much decreased GFR. No urine, so metabolites will get into
blood leading to elevated creatinine and the manifestation of acute renal failure. Ischemia does vasoconstriction
and Loss of polarity, abnormal reabsorption, detachment and necrosis and apoptosis of the tubular epithelial
cells, all of that will contribute to sluffing of epithelial cells and decreased flow into tubules which is very
important to maintain their viability and subsequently sluffing of epithelial cast. In tubular interstitial nephritis
we will not see many of them because we will have inflammation more than necrosis so in tubular interstitial
you can see eosinophilic cast not cellular. So if we see cellular cast you think about ATN.
Slide55 Morphologically, These cells will cease to function, variable individual cell necrosis, the tubules will get
dilated, in some areas the basement membrane will get ruptured and some areas will have more damage
manifested by sluffing of the tubular epithelial cells, tubulorrhexis (fragmentation of the basement membrane with
accumulation of proteinous fluid in tubular lamina as well as inflammatory infiltrate in the interstitium).

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 However the functional damage is far more than that. Although Tubular cell necrosis is present but the remaining
viable ones are not functional. And along with the increased GFR which we can’t see in the biopsies all of that will
contribute to significant injury in patients who have ATN.

Slide Clinical
57-59
 What stages we are going to see in ATN?
Three continuous stages:

1-Initiating 2- maintenance 3- recovery

1. Initiating in the first 2 days of injury depending on severity and type of ischemia or toxin.
o The tubules won’t die at once unless the patient gets into severe shock, and in these cases the patients
die of brain hypoxia more than ATN.
o So we normally see this in hypovolemia esp. in home deliveries and in surgeries where blood loss that
cannot be well substantiated.
o So these patients are going to have ongoing increase in creatinine and BUN a decrease in urine output
along with ongoing tubular necrosis so the patient is getting into ATN .
o At this stage it’s very hard to diagnose .We can diagnose due to hypo perfusion and hypoxia or most
of cases if the cause is hypo perfusion or hypoxia ,
o If going to correct that, you will cease the development of ATN because that stage is still reversible!!
((We still don’t have too much necrotic epithelial cells ))
o no Hematuria
o So because elevation of creatinine some other medical cause going on and this is the idea – there is
other medical problem in this pt.
o So when pf in first shock stage ,we have to take care of kidney that might get into ATN if you don’t
reverse or control it
2. Maintenance:
o We have enough tubular epithelial cell necrosis and enough decrease of GFR to account for remarkable
elevation of creatinine and oliguria.
o So hypertension is probably present as well. (Cellular cast +oliguria = ATN).
o It takes 2-3 weeks in this stage but it can last sometimes for 1 or 1.5 months.
o Diagnosis: Oliguria, if the patient is not hypertensive, good pressure and circulation yet no enough urine
output, this means he is having ATN which might go on for a long period of time.
o And these get into ARF if you not going to support them by dialysis they will die ,this is a case of acute
well established renal failure due to massive tubular epithelial necrosis and tubulorrhexis of some of the
basement membrane, the interstitium is not yet fibrotic, the glomeruli are not ye sclerotic ,the tubules
are not yet atrophic. However a lot of necrosis is present.
o Theoretically these patients can regenerate their tubules if they have enough time to do that (if this
situation doesn’t cause death), if patients on dialysis and you control their medical or surgical situation
they are going to slowly recover.
3. Recovery:
o at first there is no output in this stage pt. will start regeneration of the tubular epithelial cells ,
o the kidney circulation will improve and so the GFR,
o But the renal and tubular reabsorption will not and now we get into a stage of polyuria and the problem
here is polyuria with remarkable loss of electrolytes so the patient might die of electrolyte imbalance. We
still have to control the fluid intake and output and control his electrolyte and these patients are going to
gradually improve.

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o These patients might recover after weeks and months, mortality is still high though!

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