Renal Pathophysiology - Lectures Week 1

8/21/2019 Renal Pathophysiology - Lectures Week 1

1/23

Renal Pathophysiology Lecture w/ Dr. Kupin 19 September 211The Topic of This Lecture Is: Acute Kidney Injury (AKI)

!cute "i#ney in$uryis rapid deterioration in renal function that causes accumulation ofnitrogenous waste.

o It occurs within % months, but its generally reversible. The kidneys cant regulatesolute balance.

o There isnt a specic level of BU or !"#$. %e look for a rise in serum creatinine

&S&r' instead. If its a chronic "i#ney #isease&&KD', its for ( ) months and irreversible.

*+ is limited. 'n#(stage renal #isease&'SRD' is a subclass of -", so a kidney

replacement is needed.

In this case, clearance of creatinine is less than /0 m12min. That

necessitates #ialysis.o !)otemiais an elevation of BU, a key nitrogen3based waste product. It may be

asymptomatic. Build3up of nitrogenous waste causes a constellation of side e4ects termed

uremia.o 5"I caninvolve oliguria&6700 m12day' oranuria &6/00 m12day'. 8orethan 700

m12day is non3oliguric.

Typically patients that are oliguric or anuric are more ill. 59otemia is almostcertain.

:-r is an indirect predictor of *+, while 2* hour creatine clearanceis a betterestimator.

o -reatine is synthesi9ed as the liver and stored in muscle as &PK. It is metaboli9edto creatinine.

Its produced in a constant amount every day by muscles, and it undergoes

little transport.

Theres a certain amount of dietary creatine as well, since it is ingestedwith proteins.

But, theres a bit of secretion in the pro;imal tubule, so it slightly

o+erestimatesthe *+.

5bout /7< of urinary creatinine is from secretion by strong organicacid secretion.

o :-r varies based on muscle mass. %omen tend to have lower values, so their upper

limit of normal is /.= mg2d1, while men have an upper limit of /.7 mg2d1. :till, thatsa ma;imal value.

>ne must take a baseline measurement. If it goes up by .% mg/#L within% months, it-s !K.

This means that its possible to have an 5"I with a subnormal :-r.

It occurs in those with cirrhosis, pregnancy &volume e;pansion', or

e;tremes of age. If the baseline value is over the ma;imal value, its -". ?ou can have both

5"I and -"@o :-r is a poor predictor of *+ because initial changes reAect a greater loss of

kidney function than changes that occur later on. 5 rise from /.0 mg2d1 to =.0mg2d1 is more damaging than =.0 to ).0.

&reatinine clearanceoverestimates true kidney function by /7< in healthy folks and ()0< in kidney disease.

o Its measured with a = hour collection of urine. Then, one measures U-r, C, and D-r.

This value must be e;pressed in m12min &not 12day'. This is still Eust an

appro;imation@o 'stimate# 0Rtakes into account age, weight, and se;. These all relate to

production of creatinine.


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+or the same :-r, its worse to be older, lighter &in terms of lean body

weight', and a woman.o 5nother formula takes into account race, because blac"s ten# to ha+e greater

muscle #ensity. reais produced when F)from protein is metaboli9ed by the liver. Its measured in the

blood as 3.o There is a super important ratio with it and the :-r. 3/S&ris /03/7. 8emori9e

that shit.o

Urea itself is not to;ic, but other nitrogenous compounds, like ammonium, are&uremia'. remic syn#romeincludes confusion, nausea, pericarditis, myoclonus, and

sei9ures. If BU is elevated and pericarditis is present, its an emergency. 5void

tamponade@o BU can also be elevated by steroids &tissue breakdown', *I bleeding, and

e;cessive catabolism. It can be from increased protein intake. Its not an independent marker of

kidney function. Drotein intake should be limited in patients with kidney disease, who have a

lowered *+.

:-r is measured with a colorimetric assay. >ther chromogens can screw up thecomputers reading.

o In Eaundice, bilirubincauses yellowing of the plasma, so the machine gives falselylow :-r levels.

This e4ect is compounded by the fact that people with cirrhosis produce less

creatinine. -onversely, #iabetic "etoaci#osisgives falsely high levels as fats are

broken down. Two drugs prevent pro;imal tubule secretion. They cause a /73)7< increase in serum :-r.

o 4rimethoprim&halfofBactrim' does this, as doescimeti#ine, an F= antagonist&DDIs dont cause this'.

In rhab#omyolysis, trauma has caused damage to muscle membranes, leading torelease of creatinine.

o Statinshave a black3bo; warning that they might cause this, since they lowercholesterol availability.

:evere muscle irritants like cocainecan also cause rhabdomyolysis.o Its important to check creatine phospho"inase&&PK' levels, as its released in

muscle breakdown.o The best way to discern whether an elevated :-r is spurious is to look at the

BU2:-r ratio. It its 6 /0 and urine output is normal, then :-r is elevated independent of

*+.


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In 5"I, kidneys are ( /0 cm, which is normal. :carring causes contraction due to brosis,

so -" has 6 G cm.o ltrasoun#elicits the te;tures and lengths of the kidneys. "idneys are less

echogenic than the liver. The liver is homogenous, while there is corticome#ullary #i5erentiationin

a healthy kidney. In 5"I, the kidneys look like they should. +ibrosis diminishes that

di4erentiation in -".o

In -", the kidneys become more diHcult to see on ultrasound. Theyre small andlook like the liver. If 5"I is suspected, determine where the cause of the disease is. If from inadeuate

perfusion, its pre(renal.o In an outpatient setting, the most common etiology is pre(renal a)otemia, caused

by a loss of *+. %aste cannot be cleaned out of the blood, so to;ic nitrogenous compounds

build up. Underperfusion signals the kidney to reabsorb a#&pro;imally' and reabsorb

F=> &via 5F'.

If 85D is between J0 and =00 mmFg, then the kidneys can

autoregulate *+.o 6ypo+olemiacauses activation of a local myogenic response, baroreceptor

response, and the 55:. If the lesion is in the kidney itself, its renal. 1astly, it its from obstructed urinary Aow, its

post3renal.o In the hospital, a patient with 5"Imost likelyhas acute tubular necrosis&!43',

which is renal. 'n#othelial cellsare disrupted by minor 7enestra. +luid is ltered through the

basement membrane of those.o Po#ocytes&visceral epithelial cells' are the last impediment to the formation of

urine. These pores are so small that they generated an ultra8ltrateof solutes

under 6 K0k altons.o esangial cellsare smooth muscle cells that a4ect capillary tone. They nevertouch the urine.

o ntraglomerular pressure&P&' is critical forforcing Auidthrough the ltration slitsandforming urine.

Fypoperfusion reduces that pressure. !(causes e4erent vasoconstriction& 00'.

The a4erent arteriole dilates due to D*L=, D*I=, >, and 5.

+iltration fraction &*+2B+' is normally 2:. Fypoperfusion doesnta4ect it@

Fypoperfusion causes decreases in B+ and *+, while :-r and BU both

rise.o !utoregulationis dependent upon the M*5. The macula #ensain the distal tubule

senses diminished Aow and sends signals to M* cells in the a4erent arteriole. Thesesignals are the prostaglan#ins.

The M* cells respond by producing renin, which eventually leads to 53II andal#osterone.

o Colume depletion is caused by diarrhea, vomiting, hemorrhage, sweating, burns, or

diuresis. N4hir# spacingO is movement of Auid into the interstitial space. Dretty sure

thats Eust edema.

Thats caused by cirrhosis, nephrotic syndrome, malnutrition,

pancreatitis, or sepsis.


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1ow -> causes relati+e +olume #epletion. It can be from 8I, valve diseaseor renal stenosis.

o 5utoregulation can be disrupted by blocking 53II activity via !&'(sor !Rs. 5dditionally, cycloo;ygenase inhibitors&3S!Ds' inhibit prostaglandin

formation.

D*s are formed from membrane phospholipids arachidonic acid

D*s via ->P. :5Is shift the curve to the right, such that hypovolemia raises risk of pre3

renal a9otemia. ?oure ne taking them unless youre on diuretics or become volume

depleted@ :5Is disrupt both a4erent vasodilation via D*s and e4erent

vasoconstriction from 53II@

5-L3Is25Bs only have the latter e4ect. *+ and ++ fall, while ++ is

normal on :5Is.

This is why its terrible to ta"e an !&'(, #iuretic, an# aspirin.?our kidneys hate that.

:5Is are completely prohibited in -F+, cirrhosis, nephrosis, or bilateral

renal stenosis. %hile 5-L3Is25Bs can cause 5"I after hypovolemia, theyre reno3protective

in -". %LI.


5/23

Renal Pathophysiology Lecture w/ Dr. Kupin 2 September 211The Topic of This Lecture Is: Acute Kidney Injury (AKI), continued

5s said previously, most outpatient cases of 5"I are pre3renal a9otemia. In the hospital,

that is not the case.o 3osocomial !Kis not from volume depletion. Its damage directly to the kidneys.

This can be acute tubular necrosis&!43', glomerulonephritis, or interstitialnephritis.

o 5T is an intrinsic 5"I, caused by either ischemia &Q0=delivery than the medulla, which is unusual for an

organ. The inner medulla gets the least amount of blood, but it also has very little

metabolism.o The outer medulla receives less blood, but it has very high metabolic demands. It

uses n the whole, the kidney uses

less than /0


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To separate pre3renal a9otemia from 5T, look atS urine a#, +La#, +LUrea, BU2:-r, and

specic gravity.o rine 3a?means that theres volume depletion, since the kidneys are trying to

reabsorb all of it. 3a?a+i#ityis dened as urine a# 6 =0 mL21. That is diagnostic of pre3

renal a9otemia.

If its @ * m'A/Lin a setting of renal inEury, the tubules are physicallyinEured &5T'.

o

0'3a?measures reabsorptive ability as &-a#2--r' /00 are reabsorbed. Its &-Urea2--r' /00


7/23

59otemia

Urine a# &mL21' 6 =0 ( 0Urine osmolarity&m>sm'

6 700 W=J0

:pecic gravity &u' ( /.0/7 W/.0/

0

+La# 6 /< ( =ther than si9e and echogenicity, castsin the urine can di4erentiate 5"I and -".o 5 cast is an aggregation of 4amm(6ors7all glycoproteinsin the shape of a

cylinder. 6yaline castsare from regular turnover of cells. They are translucent and

totally normal@ Datients with pre3renal a9otemia have bland urine samples, lacking other

casts.o ranular castsare pathognomonic for 5T. They are full of particles released from

cell damage. They can be large and broad. They are always opaue. It is now too3late to

treat with Auids.o Ea;y castsindicate -". The granules are smooth and shiny and have coalesced

over time. These are older. They demonstrate chronicity. ?ou can have both wa;y and

granular ones. In patients with 5"I, the most important thing to regulate is "#, since theres often

dangerous hyper"alemia.o Tissue breakdown elevates plasma !"#$. Intake of "# must be restricted. 1ook for *I

bleeds. In a patientwith low *+, > >T give "# 3sparing drugs like 5-L3Is25Bs,

Bactrim, or :5Is@ 3S!Dslead to low levels of renin and aldosterone. These drugs take a long

time to wear o4.

!&'s/!Rslead to high levels of renin due to a lack of feedback.o 4rimethoprimimpairs pro;imal tubule -r secretion. Its like a "#3sparing diuretic in

the distal tubule.o Fyperkalemia causes sinus node failure &no D wave', spiked T waves, and a widened

X:. The resting membrane potentialis more positive at higher "# levels &3

Q0log&!"#$i2!"#$e''. If the 8D e;ceeds threshold, then repolari9ation is impossible. Thats when

its deadly@o Infusing -a=# raises the threshold potential. This doesnt a4ect "#clearance, but

halts symptoms.o 8oving "#into the intracellular environment can help as well. This is done by

insulinor F2 agonists. These increase activity of the a# 2"# 35TDase. In normal states, this can lead

to hypokalemia. Y= agonists are dangerous in patients with -5 due to hypotension and reAe;

tachycardia.

lucoseinfused alone is dangerous, but some should be given afterinsulin infusion.


8/23

o "#can be removed from the body by the *I tract if an e;change resin&Kaye;alate' is given.

It e;changes "#for a#in the colon. Its a rectal enema that does not a4ect

F->)3.o Dialysisis a last resort for uncontrolled hyperkalemia with Auid overload and

metabolic acidosis. +or treating pre3renal a9otemia, give isotonic saline, which is a plasma substitute.

o In 5T, dont give anything. The kidneys need to recover cells. 5 and diuretics >

>T FL1D. Must support the patient by keeping them hydrated and fed and watching

electrolytes.o D!binds to receptors in the kidney, dilating both a4erent and e4erent arterioles.

It doesnt change *+ or ++, but it does inhibit a little a#reabsorption,

causing natriuresis. In 5"I, there is an initiating phasein which there is a hemodynamic or to;ic insult.

o The dangerous and deadly phase is the oliguric phasewith urine volume 600m12day. Its /03/ days.

o e;t comes the #iuretic phase, since new cells are there, but they are immature. The reco+ery phaselasts )3/= months before full recovery, but there is

permanent scarring.

The outcome of 5T is rarely good. Falf of patients dieR 7< reuire dialysis. >nly /7 overload, which

causes -F+.o In 5"I, check BU, :-r, and hemodynamic status. 1ook for nephroto;ins, then do a

urine panel. uring therapy, follow the course of electrolytes and volume. Eatch 7or

hyper"alemia@@@


9/23

Renal Pathophysiology Lecture w/ Dr. Kupin 19 September 211The Topic of This Lecture Is: Hepatorenal and Cardiorenal Syndroes

Fepatorenal and cardiorenal syndromes are forms of 5"I. 8ore specically, pre3renal

a9otemia.o 6epatorenal syn#romeis a distinct disease state dened by criteria, not Eust liver

# kidney disease. These criteria are cirrhosis and portal FT, with S&r @ 1.B mg/#Land

proteinuria 6 700 mg2d1. There is no improvement in J hours following volume e;pansion via / g2kg

of IC albumin.o &irrhosisis irreversible parenchymal damage to the liver from Lt>F abuse,

hepatitis, obesity, etc. There is a loss of hepatic synthetic function and increased back pressure to

the portal vein. The portal +eindrains the intestines, stomach, spleen, pancreas, Z

gallbladder into the liver.o Portal 643is a portal pressure gradient @ 12 mm6g. Its associated with

varicosities and ascites. >aricescan be in the esophagus, the stomach, or the rectum. uptures are

life3threatening.

The build3up of pressure causes a reversal of :tarling forces, leading tointerstitial e;pansion.

!scitesappears as distended Aanks and everted umbilicus. ?ou canfeel Auid waves.

The abdomen lls up with transu#atedue to portal FT and low albumin.o Fepatorenal syndrome has two types. In type , its within = weeks. :-r rapidly

doubles &( =.7 mg2d1'. Type I occurs when e4ective circulating volume is reduced in the presence of

portal FT and cirrhosis[ diuretic therapy, *I bleed, paracentesis, orspontaneous bacterial peritonitis.

The longer that a person cirrhosis, the more likely it is that F: willdevelop.

In type , theres slow, insidious strangulation of the kidney over weeks ormonths.

o F: is a form of pre3renal 5"I that #oes not impro+e with Gui# therapy. The kidneys initiate compensation and reabsorb as much a#and F=> as

possible. Unlike patients with hypoperfusion, they have increase# &=and #ecrease#

S>R@@@

The back pressure from portal FT causes splanchnic arterial+aso#ilation.

Blood builds up in the rest of the abdomen and remains captive there.

o The locali9ed splanchnic vasodilation is from local e;cess of nitric o;ide and

glucagon. lucagonis not metaboli9ed when theres cirrhosis, and shear stress causes

> release.

It desensiti9es the mesenteric circulation to L Z 53II, and it increases

> synthesis. The kidney does everything it does in pre3renal a9otemia, but it cant

overcome third spacing.o Casodilation of splanchnic beds leads to +asoconstriction elsewhere. >ther

organs are less perfused. *+ cannot be maintained because of severe vasoconstriction of the a4erent

arteriole.


10/23

o In cirrhosis, the heart fails too, since bilirubin and bile acids poison it, causing

decompensation. >nce there is cirrhotic car#iomyopathy, -> becomes decreased, and L5BC

drops further.o Datients with F: have lower than normal :-r and BU, so BU2:-r is a less

sensitive measurement. Baseline :-r for patients with cirrhosis is like .H mg/#L. 1ook for changes of

0.) or more@o

Dersistently low blood Aow can induce apoptosis and brosis from local cytokineupregulation. This occurs more in Type II F:, which causes permanent kidney failure if left

untreated.o The only di4erence between the urine panelof pre3renal a9otemia and F: is the

response to Auids. Datients will develop 5T unless splanchnic vasodilation is corrected.

o Treatment issplanchnic +asoconstrictionby \/3agonists, C/ agonists,orglucagonantagonism.

In addition, plasma volume is increased via infusion of albumin &oncotic

pressure'.

This treatment is successful in 2/% o7 cases, but its not without risks.

%hile these agents divert blood to the systemic circulation, they constrictother vessels.

This can lead to an 8I or a stroke. Its a gamble, but its the only hope

they have. Dhysical treatments include trans$ugular intrahepatic portosystemic

shunt&4PS'.

The hepatic vein is connected to the portal vein, so the liver is totally

bypassed.

Its a temporary bypass that buys time for a li+er transplant. Theresstill cirrhosis.

o There absolutely will be relapse into F: unless the patient gets

a new liver.


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&ar#iorenal syn#romebegins with reduced eEection fraction, leading to increasedsympathetic activation.

o There is reduced renal perfusion, so theres 5"I and reversible pre3renal a9otemia.

If its persistent, there is irreversible inEury and nephrosclerosisfromchronic hypo;ia.

o There are ele+ate# natriuretic pepti#es. BD has a longer half3life, so its bloodlevels are diagnostic.

:ystemically, !3Pand 3Pcause vasodilation and venodilation, which

reduce afterload and decrease venous return, respectively. The latterprevents over3stretching of the heart.o In the kidney, they cause e4erent vasoconstriction and a4erent vasodilation, like

autoregulation. That increases ++ by improving *+. They cause natriuresisby acting on

the inner me#ullary collecting #uct&&D', where they reduce c*8D andblock a# reabsorption.

The diuretic e4ect is pretty poor, so high levels dont e4ectively reduce blood

volume.

5lso, all of the bodys e4orts to increase perfusion dont increase renal

levels of 5D.o In -:, gi+ing Gui#s worsens the &60. Instead, they reuire positi+e

inotropes. 1eft ventricular function must be improved before the kidneys can be helped.

1oop diuretics may improve these patients as well.


12/23

Renal Pathophysiology Lecture w/ Dr. Roth 21 September 211The Topic of This Lecture Is: !pideiolo"y and Adaptations of Chronic Kidney #isease (CK#)

&hronic "i#ney #isease&&KD' refers to abnormalities with or without lowered *+lasting at least ) months.

o There may be pathological abnormalities or markers of damage, like compounds in

urine or blood. Lven if there arent markers, if the 0R is I H mL/min, then the person

has -". Deriod. 5"I is dened by a rapid 0.) mg2d1 increase in :-r. -" is a decrease in *+

or sign of inEury.o :tructural problems include polycystic #isease, or more grossly, loss of an entire

kidney. +unctional problems include microalbuminuria &small losses', proteinuria, and

hematuria. 5gain, 0R is estimate#using :-r and formulas that take into account age, weight,

gender, and race.o +or a given :-r, a higher *+ is e;pected in someone male, young, heavily3

muscled, or black. -" is put into stages based on *+. In stage 1, theres chronic damage, while *+ is (

G0 m12min.

o :tage = *+ is Q03J0R stage ) is )037G, and stage is /73=G. I dunno if we need tomemori9e that.

o Ki#ney 7ailureis stage 7 -", such that *+ is 6 /7 m12min, or the person is ondialysis.

isk factors -" include FT, diabetes, autoimmune diseases, family history, being black,

and being old.o *+ declines at about / m12min. :o, one can have -" Eust from senescencesenescence &what

a great word'. Datients with -" are not immune to reversible causes of renal dysfunction, which can

lead to 5"I.o :o, avoid complications and slow progression of the disease while preparing for

transplant.

If left untreated, its almost a guarantee that -" will devolve into L:.o Things that can lead to 5"I are volume depletion &perhaps from diuretics' and

accelerated FT. Feart failure can also lead to poor perfusion, as can nephroto;ic substances

and UTIs.o The initial evaluation should include a S&r&and e*+', as well as a protein/S&r

ratio. 5 urine se#iment e;amlooks for B-s, %B-s, and cellular casts &wa;y

casts@'. The most non3invasive, cheap imaging is ultrasound. It should always be

done@

:erum levels of electrolytes, hemoglobin, -a

=#

and Di, and DTF shouldbe obtained. "idneys are pretty awesome at adapting to -" and maintaining volume and a#balance.

o This is accomplished by nephron hypertrophy and hyperfunction. ew nephrons

-5>T be made.o egardless of the disease that initiates -", theres a common nal pathway.

:hort3term adaptive changes have long3term maladaptive conseuences.

o Its e;plained by the intact nephron hypothesis. +or every nephron that dies,another compensates.

:inge nephrons increase their *+ via compensatory hyper8ltration.


13/23

That involves increased F# secretion &F#generation' with increased

a# 2F=> e;cretion.

5ll of these secretory adaptations occur through tubularhypertrophy.

5t the level of the glomerulus, *+ is increased to prevent a9otemia via urea

e;cretion.o >ne would e;pect BU to double if half of ones nephrons are lost, and for *+ to

drop by 70. Casoconstriction is done by

53II, of course.

Both of those increase P&&the latter also decreases ]*-', so sn*+goes up too@

The cost of these changes is intraglomerular 643, which stretches andcauses hypertrophy of glomerular capillaries. That increases the wall stresson the vessels and the mesangium.

-ollagen production is increased to prevent over3stretching, leading to

scarring. -" leads to metabolic aci#osisfrom increased generation of F#and reduced

ltration of titratable acids.o This is why each nephron is reuired to secrete more 6?as -" progresses.o 5s a long3term e4ect, F# causes inAammation of the renal interstitium and

deposition of collagen. >nce the cycle of intraglomerular FT, glomerular hypertrophy, and

increased renal ammoniagenesis starts, renal function declines even if theoriginal disease is treated.

5s for tubular adaptations, elevated 5D will increase 0'3a?, so it cant be used to detectvolume depletion.

o The ability to concentrate urine is diminished, so solute losses are balanced. Thus, CJ 1.1&normal'.

:ince these patients cannot concentrate urine, they often have nocturia.


14/23

Renal Pathophysiology Lecture w/ Dr. Roth 21 September 211The Topic of This Lecture Is: $ro"ression and Coplications of CK#

-ase /S 7Q y2o 8 w2 =0 year h2o 8 and FT. Llevated :-r, BU, phosphorous, and DTF

&which is cra9y high'.o e0R 2< mL/min. BU2:-rS /K.=. F->)3, Fb, and -a=#are all low. 5ll of these are

signs of -". Lvery person with -" has a di4erent rate of decline in *+. But, it generally tends to be

uite steady.o This allows us to predict how long itll be until someone needs dialysis, unless

progression is slowed.o %e cant modify race2gender, but we can control FT, diabetes, and compensatory

hyperltration. 5 study found that lowering P pre+ents renal complicationsin 511

patients with diabetes@ Lven in patients with marked proteinuria, aggressive blood pressure control

helps a lot.o Datients in -" stages /3 with proteinuria or diabetes should have their P I

12B/B mm6g. This should 8rst be attempte# by !&'(s or !Rswith reduction in

dietary salt.

8ost -" patients will reuire multiple anti3hypertensive drugs, D1U: adiuretic. Lesh.

>nly a few drugs a4ect both systemic intraglomerular blood pressures.

o %e really want to block 53II, since thats the agent causing e5erent arteriolar+asoconstriction.

o 53II causes glomerular capillary 643, increases permeability, causes mesangialcell proliferation, induces an increase in T*+3Y, and stimulates aldosteroneproduction. That all leads to brosis.

5ntagoni9ing the 55: blunts hypertrophy of the glomerulus and lowers D *-.

o 5-L3Is25Bs slow the progression of -" in patients with and without diabetes.

Booyah. :till, they dont halt the disease process. They Eust make the decline less

severe. In addition to decreasing BD, these drugs can reduce baseline proteinuria by

more than 70 reduce *+ in the short3term. Fowever, it diminishes long3term

conseuences@ In the long run, there is less scarring, and *+ is maintained for a much

longer time.

-ompensatory hyperinAationS *+ drops by 7 m12min2yr. 5-L3IsS only =

m12min2yr@ Its important to check serum K?Min patients on an 5-L3I, since there will be less

aldosterone.o

5 lowered *+ in addition to diminished "

#

secretion may lead to hyper"alemia.o These patients shoul# 3=4 ta"e 3S!Ds or K?(sparing #iuretics. Theyre more

likely to be on 1asi;. Be aware of which drugs are e;creted by the kidneys, since the dosage must

be lowered.o :-r is e;pected to rise a little with these drugs. If it spikes rapidly, suspect a

vascular abnormality. 0i;e# stenosis o7 the renal arterydiminishes *+ unless theres e4erent

vasoconstriction.

*iving an 5-L3I25B to these patients can lead to 5"I. Foly lawsuit

Batman.


15/23

>ther complications of -" include volume overload, metabolic acidosis, hyper3DTF, FT,

and anemia.o 8any of these are secondary to dysfunction of the endocrine kidney.

!nemia o7 &KDis from 'po #e8ciency. Lpo is usually made by peritubular capillaryendothelial cells.

o These cells become brotic in -". The B-s look normalR there are Eust fewer of

them.o Datients have lower uality of life and may get L>6. They may end up needing

blood transfusions.o 5s *+ decreases, as does Fb. 1ook for other causes like low +e, low B/=, or low

folic acid &BG'.o These patients often respond well to Lpo therapy, but if Fb goes too high, there can

be thrombosis. This doesnt ; the problem, since costly inEections must be done routinely.

-" can cause secon#ary hyperparathyroi#ism, which a4ects -a=#, Di, calcitriol, and+*+3=).

o Citamin is metaboli9ed to calcitriolin the kidney by N1(hy#ro;ylase. Thatincreases serum !-a=#$.

\/3hydro;ylase is inhibited by high !D i$ and +*+3=) and stimulated by DTF.

o Datients on dialysis have no renal e;cretion of Pi, so e;cess levels precipitate into

vessels with -a=#. 00(2%is made by osteocytes if !Di$ is high. It regulates both -a=#and Di

metabolism.o P46release is stimulated mainly by low !-a=# $ &also, high !Di$'. It works to correct

both those issues. The tra#e(o5 hypothesisis that alterations in bodyhomeostasis maycorrect the

imbalance in the short3term.o Fowever, these have detrimental e4ects over time, as seen with elevated !DTF$ in

-".o 5s *+ decreases, serum !-a=#$ gets lower, but not appreciably.

:erum !Di$ rises, but it doesnt become a problem until the patient gets to

L:.o -alcitriol levels fall before changes in DTF become noticeable. %hat we do see is

00(2% ele+ation. :o, DTF doesnt rise from a loss of kidney tissue. There must be some other

inAuence. Datients should be given Citamin early in the course of -", rather than

waiting.

They can also be given calcitriol directly. oth keeps calling it 1,2B(O=62D%.

o Larly in -" &stages )2', Dilevels are normal, but DTF and +*+3=) are both very

high.


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The parathyroid gland undergoes hyperplasia, then becomes more nodular as it produces

DTF in e;cess.o :ometimes, it stops being secondary hyper3DTF as the gland ends up autonomously

secreting DTF. In secondary hyper3DTF, the high DTF levels are a response to a stimulus.

!-a=#$ remains low.o 5s DTF remains elevated, there is increased bone turnover, termed osteitis 8brosa

cystica.

But, reduced calcitriol levels cause osteomalacia&reduced bone volume andminerali9ation'. Datients with -" may have a mi;ture of both types of bone disease.

o Datients should have restricted Diintake. ntestinal Pibin#erscan increasee;cretion in the stool.

:ome binders are -a=# 3based, others are not. arely, we use aluminum3based

antacids.o 5t this time, theres no available assay for +*+3=). %e Eust look at DTF, -a=#, and Di.

Its important to monitor these three, since e;tremes of them are associated

with mortality.o &alcimimeticsact as agonists at -a=# receptors, signaling to the parathyroid to

stop producing DTF.

5n e;ample of a calcimimetic is cinacalcet&:ensipar'. &>Dis the leading cause of death in patients with -". Its associated with FT, diabetes,

dyslipidemia, etc.o angerous vascular calcication &arteriosclerosis' occurs secondary to

precipitation of -a=# and Di.o There is deposition in the wall of the vessel ^ the me#ia, rather than the intima &in

atherosclerosis'. The likelihood of a vascular event increases as -" becomes more severe.

8ost patients in stages /3 die from a cardiovascular event rather than L:.

etabolic aci#osisoccurs when renal ammoniagenesis is overwhelmed.

o The body responds to chronic acidemia by dissolving bone to mobili9e F->)3and Di.

o

*iving these patients 6&=%(

tablets&or citrate' works to bring F->)3

closer to =mL21. >f course, giving the F->)3with a salt can lead to a#accumulation,

necessitating diuresis. 5s -" progresses, a#retention occurs, leading to positi+e 3a?balance&intake

e;ceeds output'.o Increased L-+C can generate edema, so patients with -" must be on a a# 3

restricted diet.o In the early stages, thia9ides are e4ective, but they are dependent upon *+ for

their activity. :ince loop #iureticsare secreted by tubules, they remain e4ective in late3

stage -".

In stage 7 -", patients get uremiaS anore;ia, nausea, vomiting, pericarditis, andperipheral neuropathy.

o There is no direct correlation between absolute levels of BU and :-r and uremic

symptoms. %hile the 55: attempts to correct for decreased *+, it ultimately causes progression of

-".o Because of this, it must be inhibite# by !&'(s/!Rs, which are proven to reduce

rate of *+ decline. 5ggressive control of systemic FT adds to this e4ect.

o >ur patient at the beginning doesnt need dialysis yet, but probably will in the ne;t

few years.


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%ith an e*+ of =J, he has stage -". Fe reuires an 5-L3I and a few

other interventions.


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Renal Pathophysiology Lecture w/ Dr. Kupin 22 September 211The Topic of This Lecture Is: %enal %eplaceent Therapy: #ialysis

Datients with 'SRDreuire hemodialysis, peritoneal dialysis, or transplantation, unlessthey want to die.

o The time that patients spend waiting for a transplant is getting longer, reuiring

more dialysis.o The prevalence of L: increases with age due to senescence and comorbid

conditions. The number one cause of kidney failure is #iabetes, followed by FT. ace is an important factor in determining susceptibility. Blacks are at higher

risk. Dlanning for dialysis begins when patients have stage -" ^ a 0R I % mL/min.

o :ome form of renal replacement therapy is typically begun when *+ drops below

/0 m12min.o Indications for T are hyperkalemia, metabolic acidosis, pericardial friction rub,

uremic syndrome, or unmanageable volume overload. There is no specic BU or*+ level, Eust signs and symptoms@

6emo#ialysisreuires vascular access to the blood, a lter, a machine, and a sta4available for monitoring.

o 5ccess is obtained either through a surgical !> 8stulaor a synthetic gra7t&5C*

made of TeAon. The 5C+ is the radial artery to cephalic vein or brachial artery to

brachiocephalic vein. The graft can be placed in the forearm, upper arm, or thigh &anywhere,

really'.o These procedures arteriali9e the veins, in that pressure causes them to become

engorged. epending on collateral Aow, the 5C+25C* can be side3to3side or end3to3side.

o +or every round of dialysis, two needles must be inserted &an arterial and a venous

line'. The arterial lineis still venous blood, but thats what is being drawn out. These become cosmetically disguring as the stulas become permanently

distended.o If an 5C+ or 5C* isnt possible, dialysis is done with a tunnele# catheterinto the

IMC. This is not desirable, as its ineHcient with risks of infection and thrombosis.

It must stay in for months@ The catheter is two tubes that run parallel to one

another.

The catheter has a double lumen. >ne of them is porous so blood is

pulled out. +iltering in dialysis reuires di4usion and convection &ultraltration'. Di5usion is much

more important.o Theres a semi3permeable membrane that permits removal of to;ins into the

dialysate. :ubstances move between blood and dialysate down their concentration

gradient. Dialysateis a synthetically3created sterile solution that contains particular

solutes.

It has normal a-l and glucose, high F->)3, very little "#, and no urea.

o This allows for alkali9ation of the blood and removal of e;tra "#.

o +or con+ection, substances are removed in bulk. -learance is directly related toremoved volume.

o 5 hollow 8ber #ialy)eracts as an articial kidney. Blood is ltered through 70,000little bers.


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The material, made from cellulose, naturally has microscopic pores, so

solutes freely di4use.o ialysate is puri8e# city waterthats warmed and mi;ed with the appropriate

solutes.o ialysis works mostly by di4usion, while the normal human kidney works by

convection. *+ is maintained only by ultraltration, so its important to know that

dialysis is di4erent.o

ialysis is done for )3 hours a day at least thrice per week. %e should do it moreoften. BU spikes whenever dialysis isnt done. It can be reduced by Q7< with each

treatment. >nce a patient begins dialysis, we cannot use :-r as a marker of function

&and its non3to;ic'. 5 few patients will choose peritoneal #ialysisfor T. The peritoneal cavity is infused

with =1 of Auid.o ialysate is inserted into the peritoneal space, which is a virtual space in the

absence of ascites. This increases the surface area for di4usion while Auid chills out in the

abdomen.

i4usion occurs between vessels in the peritoneal membrane and thedialysate.

That Auid is drained and replaced every. single. day. That sounds awful.

o 5s in hemodialysis, the tube is tunneled to make a deeper track that minimi9es

infections.o !mbulatory #ialysiscan be done multiple times per day with smaller volumes of

e;change &-5D'. -5D doesnt reuire a machine, and it takes about )030 minutes to do each

e;change.o 8ost people prefer &&PD&cycling', in which the cycling of /01 occurs while

sleeping.

Datents are disconnected during the day, but hooked up to a ltering machineat night.o This is$ust as e5ecti+e. It doesnt reuire clean water and allows for more

independence. The person must follow strict sterile techniue and can never have had

abdominal surgery. There is also less of a restriction on diet or Auid intake. Dlus, theres no

driving to centers.o Bags of peritoneal dialysate will be delivered to the persons home on a regular

basis.


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ialysis #oes not return patients to normal 0R, nor does it return BU to normallevels.

o Datients are basically in stage -". It doesnt replace the functionality of the

kidney. Datients in L: are e;pected to lose Q03K0< of their years of survival thanks

to &>D. 1ots of folks have FT, hyperlipidemia, arteriosclerosis, and concomitant

diabetes.o 8aintenance dialysis doesnt replace endocrine function, nor can it remove high 8%

to;ins. :ince therapy is intermittent, there are huge Auctuations in BU, pF, "#, etc.

Renal Pathophysiology Lecture w/ Dr. Kupin 22 September 211The Topic of This Lecture Is: %enal %eplaceent Therapy: #ialysis

The denitive treatment for L: is kidney transplantation. It impro+es Auality o7 li7ean# sur+i+al.

o 4ransplantationstill leaves you with a =03)0< lower survival rate, but its doublethat of dialysis.

o 5 ca#a+er "i#neyhas a lifespan of /03/7 years, while a li+ing #onorwill last at

least 7 years longer.o Transplants are done in people of all ages. Its better to do them pre3emptively

&before dialysis'. Datients should be caught with a 0R o7 1(1B mL/min.

Theyre contraindicated in patients with active malignancies &within = years',

an active infection, or active ischemic heart disease &they wont survive thesurgery'.

Datients with autoimmune kidney disease can get a kidney as long as its in

remission.

Fell, we even give kidneys to people with FIC or hepatitis - if theyre

well3controlled.o The average wait time on the kidney transplant list is %(B years, and its worse in

some communities.o Lvery citi9en of the United :tates has an eual opportunity for a transplant.

8edicare pays for it. Fowever, patients that are able to travel have a better chance since lists go

by states.o The ideal donor is 6L! i#entical&a sibling'. e;t best is someone with a one3

haplotype match. "idneys are not placed where the original organ was. Theyre heterotopic, not orthotopic

like the heart.o The new kidney is placed in the inguinal region &1X', attached to the iliac vessels.

o The anastomosis is end3to3side. The ureter is connected to the bladderR the native

ones are atrophic. The artery, vein, and ureter are the only things that hold the kidney where it

is. >ur biggest fear after getting a transplant is re$ection. Its less likely if theres matching

of the 8F-2F15.o There are histocompatibility leu"ocyte antigens&6L!' that are found on

chromosome H. >f the three specic regions, class I is F15 5 Z F15 BR class is 6L! D

&structurally di4erent'.

>ne of these co3dominant alleles is inherited from each parent.


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:o, a sibling can either have 0, /, or = matched haplotypes &70 hypersensiti+ity responseof

cytoto;ic T3cells.o The response is delayed as T3cells are recruited to attack the F15 comple;es on the

new kidney. The interstitial space and tubules become inltrated with T3cells. Its

tubulitis. arely, there is catastrophic antibo#y(me#iate# re$ectionbecause antibodies against

F15s are present.o This is seen in patients who have had a blood transfusion, pregnancy, or previous

transplant. The response is hyperacute&type '. 5ntibodies inltrate immediately &like,

in the >'. This is usually an Ig* antibody to a particular F15. There are no immune

comple;es.o Thankfully, this doesnt occur anymore because we do a crossmatch test.

It tests for the presence of pre3formed Ig* antibodies directed against those

F15s.o It is possible for F15 antibodies to form slowly over time, but this is less important.


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mmunosuppression tries to neutrali9e T3cells, beginning with in#uction therapythatwipes out T3cells.

o This is accomplished by Ig* antibodies against mature T3cells, termed

thymoglobulinor =K4%.o >ral maintenance therapies prevent repopulation of T3cells, keeping the number

low. -orticosteroids, calcineurin inhibitors, purine synthesis inhibitors, or mT>

inhibitors.

r. "upin made a huge deal about knowing each of these, along withe;amples.o T3cells produce calcineurin, signaling a release of I13=, which would induce

proliferation. That proliferation involves mT> and synthesis of purines &needed for 5

replication'.o L(1is released after T3cell proliferation. Its responsible for inAammation.

&orticosteroi#sinhibit it. Pre#nisone, etc. cause FT, weight gain, diabetes, and osteoporosis

&inhibits vitamin '.o The most powerful drugs to prevent reEection are calcineurin inhibitors

&cyclosporine, tacrolimus'.

These drugs do not block I13=, but they prevent its production. That inhibitsproliferation.

The maEor side e4ect has nothing to do with bone marrow. 46'Q !R'3'P6R=4=&.

This is the reason why transplant kidneys die@ %ere actively poisoningthem.

>bviously this is a huge problem, since interstitial 8brosisis a form of -".o Purine synthesis inhibitors&a9athioprine, mycophenolic acid' prevent cell

replication. This prevents reEection, but it cannot treat it. Dyrimidine inhibitors are not

very useful.

5ny cell that replicates is a4ected by this, as there is bone marrowsuppression.o m4=R inhibitors&rapamycin' block an intracellular signal that stimulates

proliferation. It only has one maEor side e4ectS it leads to hyperlipi#emiafrom cholesterol

accumulation.o 8ost everyone gets a calcineurin inhibitor and a purine synthesis inhibitor

&mycophenolic acid'. :teroids and mT> inhibitors are second lines. These tend to have the worst

side e4ects. Immunosuppression increases the risk of viral and fungal infections, which reuire cell3

mediated immunity.

o The most important one of these is cytomegalo+irus&&>'. Its the scourge oftransplant surgery.

It can lead to potentially fatal fever, pneumonia, hepatitis, and colitis.

o Bacterial infections are less of a problem, but everyone receives prophyla;is for

pneuococcus.o The most common malignancies that we see are skin cancer and (cell

lymphoma. This is often related to LBC, since B3cells with the virus propagate without

inhibition.o :till, most transplant patients dont die of infections or malignancy, 46'Q D' =0

&>D.


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ew kidneys are a4ected by whatever damaged the previous kidney, like diabetes and

FT.o 5 uniue problem is 7ocal segmental sclerosis&0S', leading to post3transplant

nephrotic syndrome. 4ransplant tourismhas a risk of hepatitis, FIC, malaria, etc. Its -5_? 5*L>U:.

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Renal Pathophysiology - Lectures Week 1