Notes: PathologyNotetaker: Roy, S. pgs 20Term: Spring 2006Lecturer: FredericksonTopic: Kidney Part IVDate: Monday, May 15, 2006

Class Bulletin:

The notes enclosed include the intellectual property of Dr. Rich Fredrickson. For this reason, they may not be copied, reproduced, altered or used in any way for profit without the written consent of said lecturer. Dr. Fredrickson can be reached at 425 602 3155 or RFREDRIC@bastyr.edu for further questions.

Outline for this lectureTopic: Kidney Part IVPhysiology review

DISEASES THAT AFFECT THE TUBULES Acute Tubular Necrosis

DISEASES THAT AFFECT THE INTERSTITIUMPyleonephritis Acute PyleonephritisChronic Pyelonephritis and Reflux NephropathyDrug Induced NephritisAnalgesic NephritisMetabolic NephropathyNeoplasms

DISEASES OF RENAL BLOOD VESSELSBenign Hypertension and NephrosclerosisMalignant Hypertension and NephrosclerosisRenal Artery StenosisThrombotic MicroangiopathiesOther Vascular Diseases of the Kidney

URINARY OBSTRUCTIONUROLITHIASISNEOPLASMS OF THE KIDNEYBenignMalignant

Topic: Kidney Part IV

Physiology review:I don’t know about you but I am getting lost in all the terminology. I just want to make sure that I understand, when reviewing renal path, it is useless to memorize and far more important to understand the normal function and anatomy of the kidney and then piece out by the NAME of the pathology what may go wrong. For example, in studying “Acute Tubular Necrosis” I need to understand what renal tubules are, how they work and what they do. Then, piece out the name: Acute, sudden and severe onset. Tubular: dz occurring in the renal tubules. Necrosis: death of cells. “translation: suddenly, the cells in renal tubules begin to die.” From this, I know that the etiology has to be ischemia or toxic exposure, and that necrosis will lead to renal failure!

For my own sake, I am going to review the physiology in brief. This was mostly covered in Kidney Part I; feel free to skip this.

FUNCTIONS OF THE KIDNEYFiltration of wastes The kidney removes from the blood many organic wastes, ammonia, urea, and other metabolic byproducts that may otherwise be harmful to the body.

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Secretion of hormones 1. Secretion of erythropoietin, which regulates red blood cell production in the bone marrow.2. Secretion of renin, which is a key part of the renin-angiotensin-aldosterone system.3. Secretion of the active form of vitamin D, calcitriol, and prostaglandins.

Sodium and water homeostasis There is a stable balance of sodium and water in the body. The major homeostatic control point for maintaining this stable balance is renal excretion. The kidney is directed to excrete or retain sodium via the actions of:

1. aldosterone 2. antidiuretic hormone (ADH, or vasopressin)3. atrial natriuretic peptide (ANP)

on it.

Acid-base homeostasisThe body is very sensitive to its pH level. Outside the range of pH that is compatible with life, proteins are denatured and digested, enzymes lose their ability to function, and the body is unable to sustain itself.The kidneys maintain acid-base homeostasis by regulating the pH of the blood plasma. Gains and losses of acid and base must be balanced.

Sources of acid gain: Carbon dioxide (since CO2 and H2OH2CO3, carbonic acid, with catalyst: carbonic anhydrase) Metabolism of proteins and other organic molecules Production of nonvolatile acids Diarrhea or urine Loss of bicarbonate

Sources of acid loss:Metabolism of various organic anions Use of hydrogen ions Vomit or urine Loss of acid

When acid loss > acid gain alkalosis When acid gain >acid loss acidosis

Kidney Responses to acidosis:1. Bicarbonate is added to the blood plasma by tubular cells.2. Tubular cells reabsorb more bicarbonate from the tubular fluid3. Collecting duct cells secrete more hydrogen and generate more bicarbonate.4. Ammoniagenesis leads to increased buffer formation (in the form of NH3)

Kidney Responses to alkalosis:1. Excretion of bicarbonate in urine.

a. This is caused by lowered rate of hydrogen ion secretion from tubular epithelial cells.b. This is also caused by lowered rates of glutamine metabolism and ammonia excretion.

Buffering of hydrogen ionsAny substance that can reversibly bind hydrogen ions is called a buffer. Hydrogen ions are buffered by extracellular (e.g., bicarbonate) and intracellular buffers (including proteins and phosphate).

MECHANISMS OF THE KIDNEYThe kidney's ability to perform many of its functions depends on the three fundamental functions of filtration, reabsorption, and secretion.

Filtration The blood is filtered by nephrons, the functional units of the kidney. Each nephron begins in a renal corpuscle, which is composed of a glomerulus enclosed in a Bowman's capsule.

Cells, proteins, and other large molecules are filtered out of the glomerulus by a process of ultrafiltration, leaving an ultrafiltrate that resembles plasma (with negligible plasma proteins) to enter Bowman's space.

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Filtration is driven by Starling forces.

The ultrafiltrate is passed through, in turn, the proximal tubulethe loop of Henle the distal convoluted tubuleand a series of collecting ducts to form urine.

Reabsorption Tubular reabsorption is the process by which solutes and water are removed from the tubular fluid and transported into the blood. It is called reabsorption (and not absorption) because these substances have already been absorbed once (particularly in the intestines). Reabsorption is a two-step process beginning with the active or passive extraction of substances from the tubule fluid into the renal interstitium (the connective tissue that surrounds the nephrons), and then the transport of these substances from the interstitium into the bloodstream. These transport processes are driven by Starling forces, diffusion, and active transport.

In some cases, reabsorption is indirect. For example, bicarbonate (HCO3-) does not have a transporter, so

its reabsorption involves a series of reactions in the tubule lumen and tubular epithelium. It begins with the active secretion of a hydrogen ion (H+) into the tubule fluid via a Na/H exchanger:

And now for some Modell 3rd qtr Physio, or Littleton/ Biochem:

In the lumen The H+ combines with HCO3

- to form carbonic acid (H2CO3) Luminal carbonic anhydrase enzymatically converts H2CO3 into H2O and CO2

CO2 freely diffuses into the cell

In the epithelial cell Cytoplasmic carbonic anhydrase converts the CO2 and H2O into H2CO3

H2CO3 readily dissociates into H+ and HCO3-

HCO3- is facilitated out of the cell's basolateral membrane

Some key regulatory hormones for reabsorption include:1. aldosterone , which stimulates active sodium reabsorption, and 2. antidiuretic hormone , which stimulates passive water reabsorption

Both hormones exert their effects principally on the collecting ducts.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Secretion

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Tubular secretion is the transfer of materials from peritubular capillaries to renal tubular lumen. Tubular secretion is caused mainly by active transport.Usually only a few substances are secreted. These substances are present in great excess, or are natural poisons.

DISEASES THAT AFFECT THE TUBULES As we went over in Kidney Part I, in terms of disease, the kidney can be divided into four components:

1. Glomerulia. filtration dzb. these are the most critical

2. Tubulesa. dz of reabsorption

3. Interstituma. Dz of connective tissue

4. Blood vesselsa. Vascular disease

We covered the most critical type of kidney pathology, Glomerular Disease. in Part III, now we will briefly address the rest: tubular, interstitial and vascular dz

Acute Tubular NecrosisThis is an acute destruction of the renal tubular epithelial cells that is a major cause of acute renal failure and severe oliguria (scant urine production)

Major causes of ATN1. ischemia (esp after shock)2. bacterial septicemias3. large burns4. crushing injuries5. toxic exposure

a. any chemical that precipitates at a low pH is nephrotoxic bc it’s high concentration affects the tubules

The website: http://www.atsdr.cdc.gov/ from the CDC tells you where you find nephrotoxins and how to avoid them

The nephrotoxic chemicals that are esp damaging to PCTs are:1. heavy metals2. mercury

a. High: shark, bluefin tuna, orang roughyb. Low: salmon, canned tuna, shellfish

3. lead4. gold5. uranium

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6. chromium7. bismuth8. platinum

The nephrotoxic organic solvents are:1. carbon tetrachloride

a. It was used in the production of refrigeration fluid and propellants for aerosol cans, as a pesticide, as a cleaning fluid and degreasing agent, in fire extinguishers, and in spot removers. Because of its harmful effects, these uses are now banned and it is only used in some industrial applications. But it is still in the air, water and soil near industrial areas.

2. Chloroforma. Swimming pools

3. methyl alcohol4. phenol

a. You may be exposed to very low levels in your home because it is found in a number of products, including some medicines, lotions, and ointments. Low levels of phenol are found in some foods, including smoked summer sausage, fried chicken, mountain cheese, and some species of FARMED fish (eg salmon). Phenol enters the lungs when you inhale tobacco smoke. It can be present in low levels in air and drinking water.

The nephrotoxic drugs are:1. gentamycin2. neomycin3. aminoglycosides (abx against gram negative bacteria)4. cyclosporin A

1. anti-rejection transplant drug

Pathogenesis of ATN:Key: decreased renal perfusion from preglomerular vasoconstrictionleakage of tubular fluid into the tissue spaceoliguria. 50% of acute renal failure in hospitals due to ATN. It is a reversible renal lesion…

Caused by:1. ischemia, primarily2. nephrotoxic tubular obstruction due to casts or edema

Steps in ischemiaStep One ShockStep Two Volume of bld entering afferent arteriole dropsStep Three Afferent in kidneyreninStep Four Cleaves angiotensin from liverangiotensin IStep Five LungACE

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Step Six Cleaves angiotensin IIIStep Seven Angiotensin II causes systemic vasoconstriction of arteriolesStep Seven With afferent arteriole constricted, there is further decreased perfusionStep Eight Decreased renal blood flow to peritubular caps dropsStep Nine Tubular cells can’t make enough ATPStep Ten Loss of cell polarityStep Eleven Na rushes in distal tubulefeedback vasoconstrictionaggravates situStep Twelve Necrosis of epithelial cellsStep Thirteen Dead cells and protein slough off and “casts” plug up tubuleStep Fourteen The high P in the lumen forces fluid out into tissue spaceStep Fifteen Obstructional debris further decreases GFR and tubular flowStep Fifteen Oliguria

Steps in Tubular ObstructionStep One poisons directly interfere with ATPStep Two Loss of cell polarityStep Three Na rushes in distal tubulefeedback vasoconstrictionaggravates situStep Four Extensive necrosis of PCT cells because low ATP production

Step Thirteen Dead cells and protein slough off and “casts” plug up tubuleStep Fourteen The high P in the lumen forces fluid out into tissue spaceStep Fifteen Obstructional debris further decreases GFR and tubular flowStep Fifteen Oliguria

Figure 20-32 in the text, p994 is a really beautiful schematic that covers the entire pathogenesis in acute renal failure. P993-5 are a good read of the pathogenesis of ischemia. And Slides 103-4/163 give a diagram representation of tubular injury. It is important to note that ischemic injury causes patchy necrosis in PCT and Loop of Henle and casts from Loop through Collecting ducts. Whereas Toxic injury causes continous necrosis just distal to glomerulus through proximal tubule and proximally in PCT with casts from Loop through collecting ducts. This is easier to understand if you look at Alide 103.Four Clinical Phases of ATNPhase OneStage of onset (about 36 hours) with hypotension and shock

Phase Two1. Oliguric stage

a. down to 40 to 400mls per day2. uremia3. hyperkalemia

a. high potassium in the bloodstream4. elevated BUN not excreted in urine, so bldg up5. elevated serum creatinine not excreted in urine, so bldg up6. metabolic acidosis

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a. increase in total body acid induced by 2 basic mechanisms, as follows: an inability of the kidneys to excrete the dietary hydrogen (H+) load, and an increase in the generation of H+ that is due to the addition of H+ (lactic acid or ketoacids) or to the loss of bicarbonate (HCO3

-) due to inappropriate wasting by the kidney or the gastrointestinal tract.

Phase Three1. early diuretic phase

b. increasing urine volume may reach 3 liters per dayc. loss of electolytes, now hypokalemiad. may cause death because of severe electrolyte loss

1. also increased vulnerability to infections

Phase Four1. late diuretic phasenow in the third week2. person survives shock, renal tubule cells start to regen3. tubule anatomy and function is restored4. BUN returns to normal5. complete recovery

DISEASES of THE RENAL INTERSTITIUM

Basic features of Renal Interstital DzTubular dz primarily affects reabsorption. Reabsorption is a two-step process beginning with the active or passive extraction of substances from the tubule fluid into the renal interstitium. The interstitium is the connective tissue that surrounds the nephrons, so renal interstitial disease occurs along with renal tubular disease.

Some glomerular involvement may be presentInvolves inflammation and fibrosis in tissue spaceresults in chronic renal failure

Pyleonephritis Let’s bk it down: “pyelo” comes from the Greek word for pelvis. “nephritis” , Nephros, Gk for kidney, and “itis”, inflammation. So “pyleonephritis” is inflammation of the renal pelvis. What can I assume? The renal pelvis is connected to the ureter which is connected to the bladder which is connected to the urethra. Etiology probably involves some exogenous bacterial agent. What else? The function of the renal pelvis is to collect the urine formed and dumped by the collecting ducts. The cortical collecting ducts receive filtrate from multiple connecting tubules and descend into the renal medulla medullary collecting ducts. The terminal portions of medullary ducts are papillary ducts renal papilla into a minor calyxmajor calycesrenal pelvis. So a disease of the pelvis can travel up the calyces to the papilla and even affect the renal tubules and tissue surrounding them.

General features of PNVery common disease affecting interstitial connective tissue, tubules and renal pelvis.

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Two main types of PN1. acute

a. always bacterialascending urinary tract infection

2. chronica. may be caused by chronic infectionb. may be associated with obvious obstruction

Etiology and pathogenesis PN1. gram negative bacilli

a. 85% of cases2. fecal flora

a. E colib. Proteusc. Klebsiellad. Enterobacteria

3. blood stream origina. for example during septicemiasb. esp seen if kidney is already compromised

4. obstructionsi. constriction along urethra

1. Benign Prostate Hyperplasiaii. tumors of bladder

iii. stones

Most common path Ascending infections from a UTI especially in females where 8 X more likely than male. This is due to:

1. shorter urethra2. no prostatic antimicrobial secretions3. hormonal cycles affect "bacterial adherence"4. "honeymoon" cystitis

a. aggressive, frequent or sex without psychological reception, sense of ‘owning it’, enjoyment/lubrication irritates urethra, and inflammation predisposes to infection

Aggravation to common pathanything contributing to urine retention predisposes to principles of "vesicoureteral" reflux. Normally, in an adult, the ureters pass obliquely into the bladder (in kids, the passage is more direct, perpendicular). The oblique passageway allows for a VU valve. When the bladder is full, the P inside pushes on the tissue and closes the bladder (in kids, there is a greater risk of reflux).

Least common pathobstructions and hematogenous infection. See Slide 112/163 for a digramatic representation of etiology in pyelo.

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See slide 113/163 for extra features of Pyelo

Acute PyleonephritisAcute pyelo is an acute pus-sy inflammation of the kidney caused by bacterial and sometimes viral infection, whether septic or ascending and associated with VU reflux.

Morphology acute interstitial suppurative inflammation plus tubular coagulation necrosis (and pus in tubules) focal abscesses especially on cortical surfaces+++++++ GLOMERULI SEEM RESISTENT TO INFECTION

Uncompliated APN usu benign course and S/Sx disappear in a few days after abx Tx.

Complications of APN the three P’s1. papillary necrosis

a. esp in diabetics with decreased resistance2. pyelonephrosis

a. renal pelvis is a sac of pus3. perinephric abscess

a. rupture through capsule

See Slide 115/163 for a really horrible picture of APN. Slide 116 is a histo slide that shows how APN is marked by acute neutrophilic exudate within the renal tubules and the renal substance and Slide 117 shows papillary necrosis—it’s pretty extraordinarily focal and uniform!

Clinical course of APN1. costovertebral angle tenderness2. evidence of bladder irritation

a. dysuriab. frequencyc. urgency

3. systemic evidence of infection4. leukocyte casts in urine is diagnostic

Predisposing conditions for APN5. obstuctions6. instrumentation7. vesicoureteral reflux (VUR)8. pregnancy9. pre-existing renal lesions10. patients sex and age11. diabetes

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Chronic Pyelonephritis and Reflux NephropathyOf course, here we are talking about chronic inflammation of the renal pelvis extending to the calyces, tubules and interstitium renal scarring. In CPN, the role of bacteria is uncertain.

The two principle forms of CPN:1. chronic obstructive

a. obstruction (like a renal stone or cancer) causes high pressure backflowb. major and minor calyces are dilated like balloonsc. P backflow into collecting ducts

i. LEADS to:1. "thyroidization" of the tubules

a. pink debris or precipitated filtrate that can’t be removedtubules look like thyroid follicles: pathonumonic for CPN

b. expanded epithelium in tubule with flat, proliferating cells instead of neat, sharp cuboidals, lined up.

2. P atrophy around the inside surface of the kidney3. diffuse corticomedullary scars and atrophic cortex4. CHRONIC renal failure

2. Reflux Nephropathy (VUR)a. By far the more common form of CPN scarring; occurs in childhood as the

result of a superimposition of UTI, a short intramural ureter and congenital vesicouretral reflux. It is a common source of hypertension in kids.

b. RESULTS in:i. scars at upper and lower poles

ii. scars over dilated minor calycesiii. lymphoid follicles at edge of calyxiv. arcuate and interlobular arteries show damagev. thyroidization of tubules

c. EVENTUALLYi. Focal segmental glomerulonephritis

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Clinical features of CPN back pain fever pyuria

o pus-sy urine bacturia polyuria

o signifies tubular involvement proteinuria

o signifies glomerulonephritis

Drug Induced NephritisWhat I can deduce from the name? Kidney inflammation due to toxic metabolites and or immune reactions from/to drug use/ abuse. Has to be hematogenous in origin, no one is sticking a drug up their ureter…I hope!

Basic features Renal exposure to drugs is high because of intense blood supply Toxins insoluble at acid pH are precipitated in DCT and collecting ducts

How ToxinsRenal Injury1. interstitial immune reactions (hypersensitivity)2. direct tubule damage (e.g., mercuric chloride)3. subtle cumulative damage over many yearschronic renal insufficiency

Allergic or Drug-induced nephritisThese drugs:

1. nonsteroidal anti-inflammatory agents2. synthetic penicillin3. sulfonamides

BUT not dose dependent damage CAUSE interstitial inflammation

Clinical Signs and Symptoms:

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Skin rash eosinophilia IgEs in serum IgGs in tubular basement membrane sometimes granulomas hematuria sterile pyuria+++++++

o NO BUGS, just pus.

Clinical note: you want to drink LOTS of water when taking these drugs because you may be able to prevent tubular precipitation by dilution.

Analgesic nephritisThese DRUGS:

mixtures of analgesicso “coal tar analgesics”, antipyretics, usu mixtures of caffeine, aspirin,

acetominophen (a less toxic metabolite of phenacetin), and codeine. phenacetin (3 kg over 3 year span)

o since it was demo’d to be carcinogenic it has been reformulated since 1983, it is an antipyretic analgesic

RESULT in papillary necrosis first cortical-tubular-interstitial inflammation and fibrosis is

secondary

Pathogenesis of AN:Phenacetin metabolite acetominophen injures cells by:covalent bondingoxidative damage

Aspirin potentiates this effect by:inhibiting the vasodialatory effects of PGE, predisposing the papillae to ischemia.

The papillary necrosis is distinguished from the acute necrosis in diabetics in that it is not uniform, one papillae can be necrotic and another fine.

Morphology Analgesic Nephritis1. Although most glomeruli are normal2. We see early patchy necrosis of loops of Henle3. eventually the collecting ducts and entire pyramid4. reaches the papillae5. detached or sloughed papillae (into urine)6. dystrophic calcification is common

o non systemic mineralization of soft tissue

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7. Finallycortical atrophy and DIFFUSE INTERSTITIAL FIBROSIS

8. We also see analgesic microangiopathyo BM in blood vessel wall is split

Clinical features of Analgesic Nephritis "middle-aged women with chronic headaches" inability to concentrate the urine renal stones pyuria sloughed papillae may obstruct ureter increased risk of papillary carcinoma of renal pelvis

Metabolic NephropathyMetabolic cause of renal interstitial disease

Urate nephropathyo urate crystals in interstitium and/or tubuleso due to conditions leading to elevated levels of uric acid in blood like:

primary gout polycythemia or leukemia chemotherapy for cancer

causes sudden increase in uric acid from necrosis of cancer cells acute urate nephropathy

chronic lead poisoning

URIC ACID METABOLISMThree types of nephropathy can occur in pats with hyperuremic disorders:1. Acute urate nephropathy is assoc with

acid pH precipitation of uric acid in collecting ducts leading to obstructions acute renal failure

mostly seen in cancer patsSee slide 133/163 for a picture of urate crystals

2. Chronic urate nephropathy is assoc with deposition of crystals of monosodium urate in distal tubules, collecting ducts and

interstitiumlook needle-like in histo slide. Mostly seen in protracted gout

3. Nephrolithiasis Uric acid stones in 20% of patients with chronic gout Uric acid stones in 40% of patients with acute urate nephropathy

See slide 135/163 for a disturbing pic of the gross kidney with nephrolithiasis. Staghorn calculi (struvite stones) are a type of kidney stone that may occur with frequent kidney

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infections. They are called "staghorn" calculi because on X-rays they look like deer (stag) horns. Fewer than 10% of the people who have kidney stones have this type of stone.

Struvite stones can be more serious because they are large stones and an infection may be present. Medical treatment, including antibiotics and surgical removal of the stone, is usually needed. Women are affected more than men because of their higher risk for urinary tract infections.

CALCIUM/ POTASSIUM METABOLISMNephrocalcinosisDz char by hypercalcemia like:hyperparathyroidismmultiple myelomaVitamin D intoxicationmetastatic bone dzexcess calcium intake

RESULTs in:calcium phosphate in renal tubulescalcium stones. Basement membranes calcify in tubules and glomerulus

Hypokalemic nephropathyDz char by low potassium:GI tract diseaseadrenal overactivitychronic use of diuretics

RESULTs in:interference with countercurrent exchange system in loops disturbed tubular concentration of urine

NeoplasmsNeoplastic causes of renal interstitial disease

1. nonrenal malignant tumors, esp. hemopoietic impact the kidney interstituma. via paraneoplastic syndromesb. via therapy for cancer

2. multiple myelomaa. renal involvement occurs in 59% of patients with multiple myelomab. tubules toxic to Bence-Jones proteinsc. BJ proteins combine with certain glycoprotein to form castsd. progression to chronic renal failure or sometimes acute RFe. associated amyloidosis is common

See slide 138/163 for a picture of myeloma kidney casts. Read more about this condition on p1005-6 of text.

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DISEASES OF RENAL BLOOD VESSELSWe breezed through this in class. I am just pasting the notes here, I am going to just review pgs 1006-1012 for details.

Benign Hypertension and NephrosclerosisDefinitionsIn looking at benign vs malignant pay attn to arterioles

Benign hypertensionLong term developing hypertensionhyaline arteriolosclerosis (from leakage of plasma proteins ) appears in renal vessels, loweres lumen size a tad and causes BENIGN NEPHROSCLEROSIS.

Benign NephrosclerosisBenign nephrosclerosis is the term used for the renal path assoc with sclerosis of renal arterioles and small arteries. The result is focal ischemia to tubules, glom and b membrane, narrow lumen and duplication of internal elastic membrane

Note: benign nephrosclerosis rarely causes uremia

Ischemic changes in nephrosclerosis atrophy of tubules glomerular ischemia and changes collagen in Bowman's space damage to GBM possible total sclerosis of glomeruli

Malignant Hypertension220-240/13-140 mmHg

Malignant nephrosclerosis is the form of renal dz assoc with the accelerated phase of HT. It is a Frequent cause of death by uremia. It occurs in chronic renal failure and results in:hyperplastic arteriolosclerosis (onion-skin layers)fibrinoid necrosis in vesselshigh renin activityextrarenal complications.

Extra renal Complications of Malignant HT:1. LEFT VENTRICULAR FAILURE

increased intracranial pressure headaches nausea and vomiting

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scotomas in visual fields microaneurysms in retinal vessels

2. HYPERTENSIVE CRISIS loss of consciousness convulsions medical emergency

See slide 140 and 141 to compare hyaline to hyperplastic AS.

Essential HTThere are Two Etiology “classes” for Hypertension:1. Essential or Primary2. Secondary

A person with HT 2ndary to Renal, Endocrine, Vascular, or Neurogenic probs will A person who has idiopathic high BP (140/90) and it is creeping up has essential HT. If left untreated, it will be expressed as arteriosclerosis in the kidney.

90-95% of those with malignant HT started out with essential HT.

characteristics of essential HT:(1) females more(2) blacks more(3) about 50% of population over 50(4) slow progression(5) leads to cardiovascular and cerebrovascular complications(6) is expressed as arteriolosclerosis even in kidney(7) possibly due to a defect in sodium excretion

Pathogenesis of HT:Review slides 145-148: Important review of the pathogenesis of HT

Renal Artery Stenosisa) most often caused by an atheroma at origin of renal arteryb) which causes increased renin secretion

This is the most curable form of hypertension, remove the stenosis, remove the HT.

Thrombotic MicroangiopathiesI’ll sound this title out: An occlusive (thrombotic) event in small bld vessels—this would result in hemolytic anemias in small vessels, thrombocytopenia and possibly renal failure…

The text classifies thrombotic microangiopathies as follows:

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1. Classic childhood HUS2. Adult HUS3. Familial HUS4. Idopathic TTP

There is considerable overlap between HUS and TTP, in fact, sometimes they are referred to as HUS/TTP.

Childhood hemolytic uremic syndromeUncommon but causes acute renal failure in kids

S/Sx: sudden severe oliguria sudden severe hemolytic anemia

Pathogenesis of these disorders is basically the same:Although these disorders may have diverse causes, two processes dominate the pathogenetic sequence of events:

1. endothelial injury and activation with subsequent intravascular thrombosis

2. platelet aggregationBoth of these events cause:

1. vascular obstruction or microthrombi in glom caps2. vasoconstriction

ischemia

Causes have been:1. a strain of E coli from Jack-in-the-Box2. or a Shiga toxin from Shigella

Complications can include: other thrombotic and bleeding problems neurological damage cardiovascular damage

Adult hemolytic uremic syndromeCan occur in a variety of settings by mechanisms that are not clear

1. Pregnancy with complicationsa. postpartum renal failure

2. Infectiona. typhoid fever

3. oral contraceptives4. vascular renal dz

a. malignant HT5. chemotherapeutic and immunosuppressive drugs

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Thrombotic thrombocytopenia purpura (TTP)It is caused by an acquired or genetic defect in a protease that cleaves large vWF multimers. The abnormal forms of vWF promote platelet aggregation.

Slide: 152/163: Fibrin stain showing platelet-fibrin thrombi (red) in the glom caps, characteristic of microangiopathic disorders. On micro exam, the glomeruli show thickening and sometimes splitting of cap walls due to endothelial swelling and deposits of fibrin-related materials in the capillary lumen.

Other Vascular Diseases of the KidneyEmbolifrom atheromatous plaques in aorta or renal arterythe elderly with severe atherosclerosis

Sickle cell nephropathyviscosity of blood through vasa rectahypoxia in renal medulla from too many sickled cellspapillary necrosis

Clinical note: papillary necrosis is seen in: diabetics pyelonephritis analgesic nephropathy

Renal infarctionThe kidney are favored sites for the development of infarcts. Contributing to this predisposition is the extensive bld flow to the kidneys (1/4) of cardiac output; but more important is the “end-organ” nature of the bld supply with limited collateral circulation from extra renal sites.

Keys to remember:1. no dual blood supply2. wedge-shaped infarcts3. emboli from heart4. thrombosis because of PAN

See Slide 155/163 for a nice pic of this.

URINARY OBSTRUCTIONDefinition: "hydronephrosis" Abnormal enlargement of a kidney, which may be caused by blockage of the ureter (such as by a kidney stone) or chronic kidney disease that prevents urine from draining into the bladder.

Causes dilation of renal pelvis and calyces due to obstruction of outflow along with

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atrophy of renal tissue. May be unilateral or bilateral. May cause acute renal failure if bilateral.

UROLITHIASISA. in renal pelvis and calycesB. calcium oxalateC. calcium phosphateD. uric acid stones E. magnesium ammonium phosphate stones from urea-splitting bacteria

also called struvite stonesF. Cystine stones in kids with hereditary cystinuria

NEOPLASMS OF THE KIDNEYBenign1. cortical adenomas2. interstitial cells tumors (probably hamartomas)

MalignantTwo types of renal cell carcinoma1. clear cell2. papillary

See slide 160/163: the first histo prep is the clear cell adenocarcinoma and the second is the papillary type. The third slide, ignore. Clear cell has rounded polygonal shapes with abundant, clear or granular cytoplasm. Papillary is full of foamy macrophages in papillae.

General features(1) older persons (60 to 70 yo)(2) more in males(3) notorious for paraneoplastic endocrinopathies

(a) hypercalcemia(b) may cause nephrocalcinosis too

Morphology often multiple sites most at poles of kidneys invades renal vein usu only one kidney affected

See slide 159/163: kidney is split longitudinally, the white is the tumor, the red, the way the normal kidney looks.

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Clinical features(1) costovertebral pain(2) palpable mass(3) hematuria(4) bizarre growth patterns

(a) silent for a long while(b) then explosive growth

(5) however because of paraneoplastic state(a) polycythemia (from increased EPO)(b) hypercalcemia (from PTH)(c) hypertension (from ADH)(d) feminization (from estrogen)(e) Cushings syndrome (from ACTH)

(6) metastasis to (a) lungs and liver(b) bone(c) brain(d) opposite kidney

(7) late detection bc(a) no peritoneum, kidney is surrounded by a lot of fatswimming in perirenal fat, and minimal feeling with no compromise of renal function.

Wilm's tumor (nephroblastoma)1. common in kids under 102. 2nd most common tumor in kids3. It’s a mix of primitive cells like a teratoma, it could be made up of:

a. epitheliumb. musclec. boned. cartilage

4. Could be due to a deletion of the short arm of chromosome #11 (sometimes trisomy)

5. Can be very massive tumors with distended abdomen (up to 30 lbs)6. Usually unilateral7. Often see pulmonary metastasis but with chemotherapy and radiation has a 90%

long term survival

End:wk7PathMPart III.Sp06Roy

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