Patho sheet.urinary #4 - Abarar Sa3adeh

The 4th and the last patho lec in the kidney.
Written by : Abrar Sa’adeh .
Dr. Caramella .

Today we are gonna to talk about ATN…,and Tumors of the Kidney….so let’s start…



ATN is a clinic pathologic entity characterized morphologically by destruction of tubular epithelial cells and clinically by acute diminution or loss of renal function. It is the most common cause of acute renal failure,
which signifies rapid reduction of renal function and urine flow, falling within 24 hours to less than 400 mL per day.
ATN is a reversible renal lesion that arises in a variety of clinical settings. Most of these, ranging from severe trauma to acute pancreatitis, have in common a period of inadequate blood flow to the peripheral organs (such as kidney), usually accompanied by marked hypotension and shock This pattern of ATN is called ischemic ATN.
Mismatched blood transfusions and other hemolytic crises causing hemoglobinuria and skeletal muscle injuries causing myoglobinuria also produce a picture resembling ischemic ATN.
The second pattern, called nephrotoxic ATN, is caused by a multitude of drugs, such as gentamicin and other antibiotics and radiographic contrast agents, poisons, including heavy metals (e.g., mercury); and organic solvents (e.g., carbon tetrachloride).
In addition to its frequency, the potential reversibility of ATN adds to its clinical importance. Proper management means the difference between full recovery and death,,, means that it’s reversible,,


The critical events in both ischemic and nephrotoxic ATN are believed to be:
(1) Tubular injury and
(2) Persistent and severe disturbances in blood flow resulting in diminished O2 and substrate delivery to tubular cells.
• Tubule cell injury: Tubular epithelial cells are particularly sensitive to ischemia (anoxia )and are also vulnerable to toxins.
Several factors predispose the tubules to toxic injury, including :
A- a vast electrically charged surface for fluid reabsorption,
B- active transport systems for ions and organic acids,
C- a high metabolic rate and oxygen consumption requirement in order to perform these transport and reabsorption functions,
D- and the capability for effective concentration,, so even if the amount of toxins is small it has the ability to concentrate it.

These points explain why the epithelial cells are sensitive for toxins much more than other kinds of tissues ,,,
Ischemia causes numerous structural and functional alterations in epithelial cells,
Loss of cellular polarity seems to be functionally important but reversible (an early event)
This lead to redistribution of the membrane proteins (Na,K,ATPase) from the basolateral to the luminal surface of the tubular cells , resulting in decreased sodium reabsorption by proximal tubules and hence increased sodium delivery to the distal tubules.
The latter incites vasoconstriction via tubuloglomerular feedback, redistribution or alteration of integrins that anchor tubular cell to the underlying basement membranes result in shedding of the tubular cells into the urine .
In addition, ischemic tubular cells express cytokines and adhesion molecules such as P-selectin that help in recruiting leukocytes that appear to participate in the subsequent injury.
Injured cells detach from the basement membranes and cause luminal tubule obstruction, increased intratubular pressure,and decreased GFR.
In addition, fluid from the damaged tubules can leak into the interstitium,resulting in interstitial edema, increased interstitial pressure, and further damage to the tubules.
Ischemic renal injury is also characterized by hemodynamic alterations that cause reduced GFR. The major one is intrarenal vasoconstriction which is mediated by sublethal endothelial injury, leading to increased release of the vasoconstrictor endothelin and decreased production of the vasodilators nitric oxide and PGI2(prostaglandins).
Morphology :
Ischemic necrosis is characterized by Necrosis of the short segments of the tubules,
Most of the lesions are seen in The straight portion of the proximal tubule and the ascending thick limb in the renal medulla ,, but no segment of the proximal or distal tubules is spared .
This includes
attenuation or loss of proximal tubule brush borders,
simplification of cell structure,
cell swelling ,
vacuolization,
and sloughing of of non-necrotic tubular cells into the tubular lumina and then onto the Urine.
A stiking additional finding is is the presence of proteinaceous casts in the distal tubules and collecting ducts.
They consist of Tamm-Horsfall protein(which is secreted NORMALLY by tubular epithelium ) along with hemoglobin and other plasma proteins.
When crush have produced ATN the casts are composed of MYOGLOBIN .
The histologic picture in toxic ATN is basically similar with some differences ,, Necrosis is most prominent in the PROXIMAL tubules ..and the tubular basement membranes are generally spared .
IF the patient survives for a week ,epithelial regeneration becomes apparent in the form of LOW CUBOIDAL epithelial and prominent mitotic activity in the persisting TUBULAR epithelium cells.
EXCEPT where the basement membrane is destroyed regeneration is TOTALLY and COMPLETE ,, means in any area where the basement membrane is still intact and healthy ,, the regeneration is COMPLETE and TOTAL,,, BUT in the areas where the basement membrane is DESTROYED there is no regeneration :).
Clinical Course:
The clinical course of ATN is highly variable, but the classic case may be divided into :
1- initiation,
2- Maintenance,
3- and recovery stages.

1- The initiation phase: The only indication of renal involvement is a slight decline in urine output with a rise in serum creatinine.

2- The Maintenance phase : begins when the urine output falls markedly usually to between 50 and 400 ml per day (oliguria) .
The clinical picture of is dominated by the signs and symptoms of uremia and fluid overload ,, in the absence of careful supportive treatment or dialysis ,, the patient may die during this phase .
3- The recovery phase : is ushered in by a steady increase in urine volume that may reach up to 3 L/day, because the tubular function is still deranged serious electrolyte may occur during this phase ,, there also seems to be increases vulnerability to infection ,,
For these reasons about 25% of deaths of AYN occur during this phase .
During the final phase there is gradual return of the person’s well-being ,,
Patients who do not die from the underlying precipitating problem have a 90% to 95% chance of recovering from ANT .





TUMORS:
In general benign tumors such as small cortical papillary adenomas or medullary fibromas ,, have NO clinical significance .
The most common of malignant tumors of the kidney is renal cell carcinoma, followed by Wilms tumor(nephroblastoma), which is found in children,primary tumors of the calyces and pelvis.
Tumors of the lower urinary tract are about TWICE as common as renal cell carcinoma .
Renal Cell Carcinoma :
Renal carcinoma represent 80%-85% of all primary malignant tumors of the kidney , and 2%-3% of all cancers in adult.
40% of patients die of this disease.
Carcinomas of the kidney are most common from the sixth to the seventh decades.
And Men are affected TWICE as commonly as women ,
the risk of developing these tumors is higher in
SMOKERS ,
HYPERTENSIVE
or OBESE patients .And those who have had occupational exposure to cadmium .
Smokers who are exposed to cadmium have a particularly high incidence of renal cell carcinomas,, the risk of developing renal cell carcinoma is increased 30 fold in individuals who develop acquired polycystic disease as a complication of chronic dialysis (synergistic effect).




Clear Cell Carcinoma :
These are the most common type accounting for 70% to 80% of renal cell cancers.
Histologically .. they are made up with cells with clear or granular cytoplasm whereas are sporadic they also occur in familial forms or in association with von Hippel-Lindau (VHL) disease.
VHL..is an autosomal dominant disease and is characterized by predisposition to a varet of noeplasms ,but particularly to Hemangioblastomas of bilateral renal cysts and bilateral and often multiple clear cell carcinomas develop in 40% to 60% of individuals.
Those with VHL syndrome inherit a germ-line mutation of the VHL gene on chromosome 3p25 and lose the second allele by SOMATIC mutation .
The VHL protein is involved in limiting the angiogenic response to hypoxia thus its absence may lead to increased angiogenesis and tumor growth.
Papillary Renal Cell Carcinomas:
These compromise 10% to 15% of all renal cancers,,as the name indicates they show a papillary growth pattern .
These tumors are frequently multifocal and bilateral and appear as early-stage tumors .
The culprit in this case (المتهم في هذه الحالة) is MET proto-oncogene located on chromosome 7q31 .
The MET gene is tyrosin kinase receptor for the growth factor called Hepatocyte growth factor.
Its an increased dosage of the MET gene on chromosome 7 that seems to spur abnormal growth in the proximal tubular epithelilial cell precursors of papillary carcinoma.
In keeping with this trisomy of chromosome 7 is seen commonly in familial cases, in these individuals along with the increase gene dosage there are activating mutations of the MET gene .


Chromophobe Renal Carcinomas :
These are the least common representing 5% of all renal cell carcinomas. They arise from intercalated cells of collecting ducts their name denotes the observation that the tumor stain more Darkly (they are less clear than cells in clear cell carcinoma .).
These tumors are unique in having multiple losses of entire chromosomes, including chromosome:
1
2
6
10
13
17
And 21
Thus they show extreme hypodiploidy, because of multiple losses the ”critical hit”
Has not been determined .in general chromophobe renal cancers have A Good Prognosis.

Morphology:
Clear cell carcinoma: (the most common form)
usually solitary and largr
its yellow to orange OR grey to white with prominent areas of cystic softening OR of hemorrhage,,,
small satellite nodules are found in the surrounding substance providing clear evidence of the aggressiveness of these lesions.
Invades the renal Vein
Extending in serpentine fashion as far as the inferior vena cava and even into the right side of the heart.
٭٭Depending on on the amounts of lipid and glycogen present the tumor cells of clear renal cell carcinoma may appear almost vacuolated or may be solid.
The classic vacuolated (lipid laden) or clear cells are demarcated only by their cell membranes. (the dr read some words then she said that they are not important and she is not gonna to ask us about them. )
Papillary Renal Cell Carcinoma:
exhibit varying degrees of papilla formation with fibrovascular cores.
They tend to be bilateral and multiple.
Chromophobe-type renal carcinoma :
the NUCLEI is surrounded by halos of cleared cytoplasm.


Clinical Course:
The most frequent presenting manifestation is Hematuria , occurring in more than 50% of cases.
Macroscopic hematuria tends to be intermittent and fleeting superimposed on a steady microscopic hematuria ,, less commonly produce flank pain and a palpable mass. External renal effects are fever and polycythemia.
Polycythemia affects 5% to 10% of persons with this disease.
Uncommonly ,,these tumors produce a variety of hormone-like substances resulting in Hypocalcaemia , Hypertension, Cushing syndrome Or feminization or masculinization.
The prevalent locations for metastases are the LUNGS and the BONES.
Tumors of the Urinary Bladder and Collecting System (Renal Calyces, Renal pelvis , Ureter and Urethra):
Tumors in the collecting system above the bladder are relatively UNCOMMON those in the bladder are an even more frequent cause of death than are kidney tumors.




Morphology :
Tumors arising in the urinary bladder range from small benign papillomas to large invasive cancers.
These tumors are classified into a rare benign papilloma , a group of papillary urothelial neoplasm of low malignant potential and two grades of urothelial carcinoma (low and high grade).
The very rare benign papillomas are
FRONDLIKE structure
having a delicate fibrovascular core coverd by multilayered , well-differentiated transitional epithelium .
such lesions are usually
solitary ,
they almost invariably noninvasive and benign
and they are rarely recure once removed .
Urothelial (transitional) cell carcinoma :
range from papillary to flat.
noninvasive to invasive .
and lwo grade to high grade.
(in situ stage of bladder carcinoma  always high grade , flat.)
Clinical Course :
Painless Hematuria is the most dominant presentation of all these tumors.
Because most arise in the bladder we willl consider these first .
They affect men 3 times as frequently as women and bladder tumors are 50 times more common in those who had been exposed to beta-naphthylamine.

Cigarette smoking
Chronic cystitis
Schistosomiasis of the bladder
Certain drugs (cyclophophamide)
All who are exposed to the listed points above are believed to have higher rates of incidence to this cancer.
A wide variety of genetic abnormalities are seen in bladder cancers ,, of these.. mutations involving several genes on chromosome 9 (including p16) ,p53 and FGFR3 (fibro blast growth facto receptor 3) Are the most common .
The clinical significance of bladder tumors dependes on
their histologic grade and differentiation and most IMPORTANTLY ,, ON the DEPTH of invasion of the lesion.
EXEPT for the clearly benign papillomas all tend to recur after removal.
In general with low grade shallow lesions the prognosis after removal is good , but when deep penetration of the bladder wall has occurred the 5-year survival is 58%.
Although papillary and cancerous neoplasms of the lining epithelium of the collecting system occur much less frequently un the renal pelvis than in the bladder they nonetheless make up 5% to 10% of primary renal tumors .
Painless hematuria is the MOST characteristic .
Infiltration of the walls of the pelvis ,calyces and renal vein worsens the prognosis .
Despite of removal the tumor by nephrectomy,, fewer than 50% of patients survive for 5 years..Cancer of the ureter is fortunately the RAREST of the tumors of the collecting system ,the 5-year survival rate is less than 10%....
To conclude ,,, cancers of the urinary bladder has much better prognosis than the tumors of renal pelvis and ureter …..♣♣
“There are three ingredients in the good life: learning, earning and yearning."
Best wishes from your colleague : Abrar Sa’adeh,,,,,
Corrections and additions are more than welcomed.