Unit 4 - Renal Flashcards
(309 cards)
1
Q
Describe in a single sentence the role of the kidney in total body homeostasis
A
The main physiological function of the kidneys is the maintenance of the composition and volume of the ECF
2
Q
State the volume of each of the major body compartments in a standard-sized, healthy, adult individual
A
- total body water = 42L
- ICF = 27L (noncirculating cell volume = 24L, RBCs = 3L)
- ## ECF = 15L (interstitial fluid = 12L, plasma = 3L)
3
Q
Describe the major components and volumes of daily water intake and loss
A
- 2L ingested
- .5L metabolically produced
- 1L through sweat, feces, skin
- 1.5L through urine
4
Q
Identify the processes of water intake and output that are regulated to achieve extracellular fluid homeostasis
A
- for most regulated substances, ingestion is in excess of incidental losses –> ECF constancy is achieved by regulating urinary output
- regulates volume, osmolarity, electrolytes, pH of ECF
5
Q
Identify the basic functional structures of the nephron
A
- blood supply and epithelial tube
- blood supply is two capillary beds in series (glomerular and peritubular capillaries)
- afferent arteriole –> glomerular capillary –> efferent arteriole –> peritubular capillary
6
Q
Describe the basic glomerular and tubular processes and how they interact to achieve ECF homeostasis
A
three processes
1) glomerular filtration
- filter plasma into initial part of tubule
- free passage of H2O and solutes into tubule
- bigger stuff like proteins, lipids, and RBCs stay in capillaries
2) tubular reabsorption
- transport filtered stuff that wants to regulate across epithelial cell layer using transporters
- regulate rate of reabsorption so that just enough ECF components are returned to plasma for ECF constancy
3) excretion
- substance in excess of required ECF balance amount pass through tubule through urine
4) secretion
- movement of substances from blood into tubular lumen
7
Q
For a normal sized healthy individual, state the magnitude of renal blood flow, renal plasma flow, glomerular filtration rate, filtration fraction, and urine flow rate
A
- RBF = 1.3L/min
- RPF = .65L/min
- GFR = 130mL/min
- FF = .2
- UFR = 1.5L/day
8
Q
Describe regulation of vascular resistance by angiotensin II via the baroreceptor-mediated renin-angiotensin axis
A
- regulate circulating levels of angiotensin
- dec BP –> sensed by baroreceptors to inc renin secretion –> converts angiotensinogen to AT1 –> AT1 goes to lungs –> ACE converts AT1 to AT2 –> causes arteriolar vasoconstriction and inc in MAP
- *level of renin is rate-limiting for the production of AT2 and thus determines the status of the axis
9
Q
Why is it beneficial for the kidneys to recycle almost 99.9% of filtered stuff?
A
- kidneys are sentinels of ECF
- large capacity of GI system to add stuff to ECF in short time
- renal system removes excess ingested substances to prevent buildup in ECF
- basically in standby mode for a lot of the time, but can respond rapidly to excessive ingestion
- waste removal is not hugely important
- basically high filtration allows kidneys to quickly remove waste
- high filtration and reabs allows kidneys to precisely and rapidly control the volume and composition of body fluids
10
Q
What are non-ECF functions of the renal system?
A
- produce EPO for RBC production –> renal failure can lead to anemia
- gluconeogenesis
11
Q
What are normal values for bicarb, Cl, Cr, osm, K, protein, Na, and BUN (don’t need to memorize)
A
- bicarb 18-23 mEg/L
- Cl 98-106 mEq/L
- Cr .6-1.2 mg/dL
- osm 280-296 mOsm/kg
- K 3.5-5 mEq/L
- protein 6-8.4 gm/dL
- Na 135-145 mEq/L
- BUN 7-8 mg/dL
12
Q
Describe the arteriolar, capillary, and epithelial components of the filtration apparatus
A
- filtration occurs across capillary loops into bowman’s capsule
- afferent and efferent arterioles control flow of plasma/blood and GFR
- granular cells (SMCs of afferent arteriole) secrete renin and are part of juxtoglomerular apparatus
13
Q
Describe the ultrastructural basis for molecular sieving during glomerular filtration
A
- cut-off size for filtration is about 60kDa (albumin is slightly larger)
- three layers of filtration
1) endothelium - fenestrated epithelium; excludes RBCs; holes are fairly large
2) *basal lamina - thick BM secreted by endo and epi cells; mucoproteins which are large acidic sugars attached to protein cores; meshwork for filtration; negatively charged so ~60kDa pos charged filter better;
3) *podocytes - tubular epithelial cells; intertwined feet with slit membranes that connect feet; acts as a molecular sieve
14
Q
Describe the Starling forces that drive and oppose glomerular filtration
A
- Pgc (hydrostatic pressure within glomerular capillary) drives fluid out; main driving force for filtration
- Pt is backflow from bowman’s capsule back into the glomerulus
- Pigc is flow into the glomerulus due to large dissolved proteins in the plasma like albumin
- Pit is fairly nonexistent since no large dissolved proteins there
15
Q
State the Starling equation for glomerular filtration rate
A
GFR = K*(Pgc-Pt-pigc)
16
Q
State the typical magnitude of each of the Starling forces and the resultant net filtration pressure
A
Pgc = 46mmHg Pt = 10mmHg pigc = 30mm NFP = 6mmHg out into bowman's capsule
- to get such a high GFR, K must be really high which is determined by conductivity and surface area
- surface area is about 1m^2
17
Q
Define the process of autoregulation of GFR and RBF, including the structures involved, the cellular mechanisms, and physiological context and limitations under which this process operates
A
- filtration process is nonspecific –> keeps GFR constant and changes tubular reabs/secretion of regulated substances to “fine tune”
- changes in MAP do not cause proportional changes to glomerular capillary pressure
- Pgc is autoregulated
Structures involved:
- afferent areriole is regulating valve to keep renal blood flow constant
- Pgc and GFR also stay constant
Cellular mechanisms:
- myogenic: MAP changes smooth muscle cells of arteriole to constrict or dilate to keep downstream capillary blood flow constant
Physiological context:
- short term inc in MAP –> afferent arteriole constricts –> GFR and RBF are maintained
- opposite for short term dec in MAP
Limitations:
- good from MAP 75-150mmHg pressure range
- some residual error so upward creep of RBF and GFR and Pgc
- outside of range they change a lot
18
Q
Define the process of hypovolemic regulation of GFR and RBF including the structures involved, the cellular mechanisms, and physiological context under which this process operates
A
- when sever vol dec, need to shunt blood to heart, brain, and lungs, so kidneys are underperfused, but want to keep some blood flow because important
- vasoconstricts afferent and efferent arterioles with severe dec in MAP
Structures involved:
- afferent and efferent arterioles constrict with severe hypotension
Cellular mechanisms:
- 1) normal baroreceptors sense dec in MAP –> renal sympathetic activity inc –> arteriolar constriction (AA and EA) –> dec RBF and constant/slight dec GFR
- 2) external baroreceptors –> RAAS system causes even more vasoconstriction of AA and EA
- 3) intrarenal baroreceptors activate
Physiological context:
- first AA constricts –> dec RBF but also dec Pgc and as a result GFR
- second EA constricts –> Pgc is restored and GFR as well but RBF dec even more
- generally GFR will still dec slightly, but not as much as RBF –> FF inc –> pigc inc –> dec GFR
19
Q
Describe the role of renal prostaglandins in the renal response to hypovolemia
A
- produced by renal interstitial cells in kidney medulla b/w renal pyramids
- secreted in response to AT2 and have a local dilatory effect on arterioles
- 1) maintain adequate RBF by blunting effects of AT2 (renal cells are sensitive to ischemia)
- 2) focuses more on AA –> brings GFR back up to normal
20
Q
What happens with severe hypovolemia in general?
A
- dec MAP –> 1 and 2
1) stimulate arterial baroreceptor reflex –> inc symp activity to kidneys –> constrict AA and EA (also happens through secretion of renin/AT2) –> dec RBF –> inc FF –> inc pigc and keep Pgc constant –> dec/constant GFR
2) JGA baroreceptor stimulation –> JGA renin secretion –> AT2 –> inc TPR –> restore MAP
21
Q
What is filtration equilibrium?
A
- lose NFP as you go along glomerular capillary bed, so NFP reaches 0 at some point before plasma exits capillary
22
Q
Describe the major anatomical regions of the kidney including the renal artery and vein, major and minor calyces, medulla, cortex, renal pyramids, and regions containing collecting ducts
A
- outer fibrous capsule
- cortex underneath capsule
- medullary pyramids under cortex
- pyramids have nephrons and collecting ducts
- collecting ducts empty urine at tips of pyramids into calyces
- minor calyx drains into major calyx into renal pelvis into hilum into ureter
- renal artery and vein are in hilum as well
23
Q
Outline the flow of blood into and within the kidney finishing with its exit in the renal vein
A
- renal arteries come off of abdominal aorta
- in hilum, split into anterior and posterior segments –> interlobar arteries between pyramids
- near boundary between cortex and medulla, branch into arcuate arteries parallel to outer capsule
- branch into interlobula arteries in cortex to capsul
- branch into afferent artetioles that go to glomeruli of nephrons
- filter plasma contents then go into efferent arterioles
- EAs form vasa recta that surrounds tubules of nephron
- blood from peritubular capillaries and EAs –> interlobular veins –> arcuate veins –> interlobar veins –> renal vein
24
Q
Describe the cellular disposition of Bowman’s capsule including the glomerulus and the cells and filtration barrier that comprise it and the visceral and parietal epithelia. Illustrate and describe the relationship between glomerular endothelial cells, the filtration barrier, the podocytes, and the mesangial cells. Why are the endothelial cells fenestrated?
A
- renal corpuscles are in cortex
- glomerulus is a capillary network and is surrounded by epithelial capsule called Bowman’s capsule
- you have an AA going into glomerulus and an EA leaving glomerulus
- mesangial cells is CT within capillary bed that provides support
- outside capillaries are podocytes (visceral epithelium of BC)
- basal lamina/filtration barrier between endothelium of capillaries and podocytes
- parietal epithelium of BC is simple squamous epithelium
- fenestrated endothelium prevents cells and platelets from passing
- BL prevents >65kDa sized molecules from passing, but positively charged easier to get through
- podocyte filtration is last layer of filtration; loss of podocytes –> excessive protein in filtrate
- mesangial cells are phagocytic and contractile
25
Describe the functions of later regions of the nephron after filtration through the glomerulus. Outline each region and give one example of specialized functions of the different portions of the nephron involved in resorption of solutes. Understand the relationship between the microscopic structure of different endothelial cells in the kidney and their function. Be able to describe where in the kidney (medulla or cortex) the different resorptive events occur
Proximal tubule:
- cuboidal epithelium and brush border of microvilli
- tight junctions between cells
- infolds on basolateral side that have Na/K ATPases to pump out Na so that Na is taken up on the lumenal side
- lots of mitochondria for ATP production
- 80% of filtrate is absorbed in this area
Loop of Henle:
- thick descending of proximal tubule --> thin loop of henle
- thin loops are simple squamous epithelium
- osmotic salt gradient maintained in medulla
- ascending loop are cuboidal cells and actively transport Na and have lots of mito and are similar to proximal tubule cells
Distal tubule:
- cuboidal and short microvilli
- acid base balance
- responde to aldosterone and ADH
- lots of mito, infolds, and ATPase for Na/K pump
Collecting tubules:
- clear cells (principal) and intercalated cells (fewer and darker)
- cuboidal cells and short microvilli and become columnar towards duct
- principal cells are active transporters and excrete K into lumen and take up Na into cell
- intercalated cells secrete H+ and reabsorb bicarb
- ADH inc permeability to H2O of collecting ducts --> more concentrated urine
26
Interstitial cells around tubules in medulla
- macrophages
- fibroblast-like cells
- stellate cells containing lipid droplets
- some contain mRNA for EPO production
27
Juxtaglomerular apparatus
- vascular pole of renal corpuscle
- connected to distal convoluted tubule through macula densa
- JG cells are smooth muscle cells in wall of AA that secrete renin
- lacis cells are in contact with macula densa and JG cells
- control BP
- response to Cl ions in urinary filtrate in distal tubules
28
Describe the unique epithelium of the ureters and
| bladder and know its functional significance
- bladder and ureters are lined with transitional epithelium
| - unique lamina propria with folded elastic CT that allows entire epithelium to stretch a lot
29
State the magnitude and regulated range of NaCl and water handling by the kidneys
- most of the filtered load of water and salt is obligatorily reabsorbed (a lot is filtered, little is excreted) with only a small fraction under homeostatic control
- most reabs occurs in PT and LOH
- fine tuning/homeostatically varied reabs in DT and CD
- what happens if you ingest a lot of H2O or Na? --> H2O is alright, because hard to ingest a lot of H2O, but if impaired GFR or excessive H2O reabs --> H2O intox; Na is harder because regulated/excreted amount is so small, you can exceed excretory limits --> volume expanding effect --> HTN?
30
Describe the major epithelial transport mechanisms for NaCl and water reabsorption in each major tubular segment
- Na/K ATPase in BL membrane --> dec Na inside cell to allow for gradient of reabs
- Cl goes through tight junctions to maintain neutrality
- H2O follows because of osmotic gradient
- glucose can be paired with Na to become concentrated inside cell
Proximal tubule: reabs majority of filtered H2O and NaCl and most of important metabolites (glucose, amino acids, bicarb)
- 65% of H2O and NaCl reabs here
- captures important metabolites at first chance
Loop of Henle:
- create a hypERtonic interstitium
- 25% of NaCl reabs in asc loop --> osmotic gradient for H2O in desc limb bc no permeability to H2O in asc limb and opposite for desc limb; 15% of H2O reabs in desc limb
- Na/K/2Cl transporter reabs Na, K, and Cl in asc limb
- very concentrated as you go towards medulla
- vasa recta also in U shape to maintain concentration gradient; h2O leaves during descent but enters in ascent and vice versa for solutes
Distal tubule/Collecting duct:
- reabs of H2O and NaCl to fine tune
- only 20% of H2O and 10% of NaCl reach
- tight junctions, so mostly transcellular movement
- ADH and aldosterone play a major role here
- aldosterone --> inc # of Na channels and BL Na pumps
- ADH/vasopressin --> aquaporins fuse into apical membrane for water to flow from lumen to serosa
31
State the relative proportion of water and NaCl reabsorbed in each tubular segment
PT - 65% NaCl, 65% H2O
LOH - desc: 15% H2O; asc: 25% NaCl
DT/CD - 10% NaCl, 20% H2O
32
Describe the overall role of each major tubular segment in the regulation of NaCl and water reabsorption
PT: Taking an obligatory "big bite" of the filtered load of H2O and NaCl, and the recapture of important metabolites in the filtrate
LOH: creation of a hypertonic interstitium
DT/CD: reabsorption of H2O and NaCl in DT/CD "fine tuning"
33
Identify the major hormones that regulate tubular reabsorption of NaCl and water and their tubular and cellular site of action
DT/CD:
- aldosterone --> inc # of Na channels and BL Na pumps
- ADH/vasopressin --> aquaporins fuse into apical membrane for water to flow from lumen to serosa
34
Describe the molecular mechanism of action of aldosterone and ADH/vasopressin with respect to NaCl and water transport
DT/CD:
- aldosterone --> inc # of Na channels and BL Na pumps
- ADH/vasopressin --> aquaporins fuse into apical membrane for water to flow from lumen to serosa
35
State the Starling equation for the flow of solution from the renal interstitium to the peritubular capillaries
Fic = K’ (Pint + πcap– Pcap - πint)
36
Give values for each of the Starling forces and the net pressure driving the flow in the Starling equation
Fic = K’ (Pint + πcap– Pcap - πint)
```
Pint = 7mmHg
Pcap = 11mmHg
- 4mmHg out of cap
*Picap = 35mmHg
Piint = 6mmHg
- 29mmHg into cap
--> NFP = 25mmHg into cap
```
37
Describe qualitatively the effects of increasing and decreasing tubular flow on water and Na excretion
- faster flow = less time to be reabsorbed = greater proportion of substances excreted
- vice versa for slower flow
- diuretic inc flow by dec H2O reabs in part of tubule --> more vol excreted
- small changes in GFR can be significant
38
Define "glomerulotubular balance" and "tubuloglomerular feedback" and describe the roles these processes play in the regulation of NaCl and water reabsorption
Glomerulotubular balance:
- obligatory reabsorption mechanisms in PT to compensate for changes in a filtered load
- PT adjusts to that a fixed proportion of filtered load of H2O and NaCl is always reabsorbed (65%)
Tubuloglomerular feedback:
- regulates GFR in response to changes in NaCl at macula densa, which cause AA to constrict or dilate and monitor DT
- inc GFR --> inc flow --> dec NaCl reabs in asc limb of LOH --> NaCl conc inc when reaches macula densa --> AA contracts from JGA signaling and secretion of AT2/ADH --> dec Pgc --> dec GFR
39
State the qualitative effects of adding and subtracting Na from the ECF on ECF volume and the physicochemical bases for these changes
- Na is the major osmotic substance in the ECF
- ECF is in osmotic equilibrium with ICF
- loss or gains in ECF Na --> changes in ECF volume more than Na conc
- injestion of 10g of NaCl to ECF ultimately results in larger inc in volume in ECF than inc in [NaCl]
- due to 2x larger vol of ICF over ECF --> Na changes in ECF leads to 2x changes in ECF volume over Na conc
40
Describe the physiological feedback loops involved in the homeostasis of Na balance in the ECF
- Na regulation monitor ECF volume with baroreceptors in aortic arch and carotid sinus
- RAAS and SNS activate when low ECF --> Na reabs and vasoconstriction
Feedback loop:
- dec ECF Na --> water shift from ECF to ICF --> ECF and MAP dec --> activate RAAS --> AT2 and aldosterone inc --> aldosterone inc reabs of Na
41
Identify the dominant pathway involved in H2O regulation during normal variations in volume and capacity
- involves sensing of serum osmolarity and modifying renal handling of water
- ECF H2O content affects ECF osmolarity/[Na] more than ECF volume
- neurons in supraoptic nucleus detect osmolarity through changes in their cell volume (ECF osm inc --> cell shrink --> secrete ADH and stimulate thirst)
- ADH levels inc when osm >280 --> osm keep inc and ADH keep inc --> more H2O reabs in DT and urine osm inc until max of 1200 --> serum osm 290 because kidneys cannot concentrate urine anymore and stimulate thirst to get more H2O
42
Identify the dominant pathway involved in H2O regulation during severe hypovolemia
- a state of hypovolemia, SON are stimulated and synthesize ADH
- monitoring of ECH water involves monitoring ECF osmolarity and volume
- normally, it is ECF osmolarity, but in severe hypovolemia, ECF volume overrides osmotic control
- ADH is main effector
- ECF osm inc or ECF vol severe dec --> ADH released --> ADH binds to receptor on BL side of epithelial cells in DT/CD --> synthesis of aquaporin channels on apical membrane of DT/CD cells --> permit H2O reabs --> osm of the urine inc while osm of ECF dec/vol inc
- if serum Na inc --> inc thirst and inc ADH --> inc H2O intake and inc H2O reabs
- if serum Na dec --> dec thirst and suppress ADH --> dec H2O intake and inc H2O excretion
43
Describe the pathways involved in the regulation of ECF volume in a hypervolemic state by atrial natriuretic factor
- inc ECF volume --> inc distention of atria --> release of ANP granule contents from atrial cardiocytes --> pro-ANP cleaved to make active ANP --> active ANP reaches target in body --> does a lot of things:
1) dec secretion of ADH/block ADH acting on tubules --> dec H2O reabs --> inc H2O excretion
2) dilates AA and EA --> inc GFR --> inc H2O excretion and Na excretion
3) dec renin release --> dec AT2 --> dec aldosterone/block aldosterone action on tubules --> dec Na reabs --> dec gradient for H2O reabs --> dec H2O reabs
44
Hypovolemic patient, hyper/hyponatremic
- patient is hypovolemic (losing Na) from diuretics and little food
- if also not drinking then losing H2O due to diuretics and sweating --> [Na] inc so hypovolemic and hypernatremic
- if drank a lot --> [Na] dec so hypovolemic and hyponatremic
45
Euvolemic hyponatremia
- patients in normal Na balance but positive H2O balance
| - ADH secreted inappropriately and kidneys cannot excrete all of the water ingested
46
Hypervolemic hyponatremia
- seen in heart, liver, renal failure
- excretion of Na impaired --> hypervolemia
- EABV low --> ADH stimulated --> dec excretion of H2O
47
What happens in sever sweating?
1) dec ECF volume --> dec LA filling pressure --> inc baroreceptor reflex --> activate ADH --> inc H2O reabs
2) inc ECF osmolarity (bc losing hypotonic fluid) --> activate brain osmoreeptors in hypothalamus --> activate ADH --> inc H2O reabs
48
What happens in severe diarrhea?
- initial isotonic loss of ECF volume --> inc activation of ADH pathway --> inc H2O reabs
- when patient starts to recover by drinking water, drinks pure water --> overall osmolarity of ECF dec --> dec activation of ADH --> dec ADH secretion
- *changes in ECF osm are linear in ADH levels, but changes in ECF volume have no effect on ADH until volume dec significantly
- so what happens?
- first, have a severe isotonic loss, so lots of ADH secreted and osmolarity isn't changed so no effect from there
- after drinking pure water, correct volume change back to not having an effect on ADH levels, but this reduces osmolarity and would cause a dec in ADH levels so ultimately ADH suppression occurs and excretion would be maximized
- basically:
**
ECF water regulation is primarily an osmoregulatory system with an emergency low-volume override
**
49
Identify the physiologic determinants of GFR at a single nephron level as well as for the whole kidney
- SNGFR is determined by Starling forces:
SNGFR = K*[(Pgc-Pt)-(pigc-pit)]
- Pgc (cap hydrostatic pressure) --> largest factor
- pigc (cap oncotic pressure)
- Pt (tubular hydrostatic pressure)
- pit (tubular oncotic pressure) --> basically zero
- K factor to account for surface area and permeability of capillary
- basically:
SNGFR prop to Pgc
- Pgc influenced by AA and EA tone
- AA constr --> dec Pgc
- EA constr --> inc Pgc
- maintained by dilate AA (prostaglandins. NO) and constrict EA (AT2)
- constrict AA with NSAIDs and dilate EA with ARBs/ACEi
50
Identify the mechanisms operant in autoregulation of renal blood flow and glomerular filtration rate
- autoregulation is maintenance of RBF and GFR over wide range of MAP
- intrinsice to blood vessel endothelium and media
51
Demonstrate how to calculate and/or estimate glomerular filtration rate
GFR = Ux*V/Px
Ux = urine conc
V = urine flow rate
Px = plasma conc
- need something that is freely filtered and not reabs or secreted
- can use inulin, but need to infuse IV
- urea is freely filtered and not secreted, BUT is reabs and influenced by protein intake--> underestimation of GFR
- usually measured by creatinine --> breakdown product of muscles; freely filtered, not reabs, but secreted slightly --> overestimation by 15%, but still a fairly good measurement of GFR
52
Explain the concept of balance and the central role of the kidney in achieving Na, H2O, K, and acid balance
- what goes in must go out otherwise you will accumulate or the opposite
53
What is clearance?
- the clearance of X is defined as the volume of plasma from which all of X is removed
- if a substance is freely filtered at glomerulus and is not reabs or secreted, then its clearance = GFR
54
What are clinical measurement methods for GFR?
- measure plasma creatinine --> if inc, then not being excreted which indicates deteriorating renal function
***
Cr clearance = [(A)*(140-age)*weight]/(72*Scr)
- A = 1 if male, .85 if female
- age is age in years
- weight is in kg
- Scr is serum creatinine in mg/dL
* **
- can also measure using clearance:
- Clx = Ux*V/Px
- collect urine over 24hrs and get plasma creatinine
55
Define the pathophysiology of dec GFR in acute tubular necrosis
- vascular and tubular factors
- vascular: dec in RBF and dec in glomerular permeability
- tubular: tubular obstruction by cell debris and backleak of glomerular filtrate across incompetent tubular BM
- ischemia --> damage to tubular epithelial cells --> bare section of tubule for backleak --> cells clog up PT
56
What is the definition of acute kidney injury?
- a rapid reduction in GFR leading to an inc in plasma creatinine conc, urea, and other nitrogenous wastes leading to azotemia
- three types:
1) pre-renal: dec in GFR due to dec in renal plasma flow/perfusion
2) post-renal: dec in GFR due to obstruction of urine flow
3) intra-renal: dec in GFR due to direct injury to kidneys
57
What is uremia?
- multiple organ dysfunction due to retention of "uremic toxins", lack of renal hormones, due to acute/chronic kidney injury
- symptoms include NVD, abd pain, weakness, fatigue
58
Prerenal azotemia
- reduction in renal perfusion
- 60-70% of AKI cases
- try to restore intravascular volume to prevent ischemic injury
- prolonged prerenal azotemia may leads to ATN
- dec ECF vol: renal losses, GI losses, hemorrhage
- inc ECF vol --> dec CO (CHF, MI, etc.) or systemic arterial vasodilation (cirrhosis, sepsis, etc.)
- FENa is less than 1% with prerenal azotemia because Na reabsorbed a lot and Cr conc will be high
- treat by optimizing renal perfusion (improve CO in CHF or giving fluids)
59
What is the fractional excretion of Na?
FENa = CNa/Cr * 100
| - UNa/PNa / UCr/PCr * 100
60
Postrenal azotemia
- usually due to obstruction of urine flow
- inc in intratubular pressure causes low GFR acutely
- impairment of tubular Na reabs --> inc urine Na conc and low urine Cr conc
- FENa usually >2%
- check with renal ultrasound
- catheter can diagnose and treat at the same time
- prompt relief of acute obstruction is usually assoc with complete return of renal function, but prolong obstruction is often accompanied by incomplete return of renal function
- treat with relief of obstruction
61
Intrarenal azotemia
- 4 types:
1) vascular: cholesterol emboli, renal vein thrombosis
2) glomerular: acute GN, hemolytic uremic syndrome
3) interstitial: acute interstitial nephritis
4) tubular: ischemia, ATN
62
What is the clinical approach to AKI?
1) history and physical exam:
- intravascular vol depletion --> pre-renal
- cardia dysfunction --> pre-renal
- hypotension, surgey, hemorrhage, transfusion reactions, radiocontrast dye, cardiac cath --> can indicate ATN
- urinary obstruction
- rash, fever, etc.
2) urinalysis:
- high tonicity if reabs H2O --> pre-renal
- heme pigments without RBCs --> rhabdomyolysis or hemolysis
- RBC casts --> GN
- WBC casts --> AIN (allergic interstitial nephritis)
- pigmented, granular casts and renal tubular epithelial cells --> ATN
3) urine chemistries:
- low FENa --> prerenal
- high FENa --> other causes
63
What is the definition of nephrotic syndrome?
- excessive leak of protein through glomerular capillary into urinary space
- >3.5g/day of albuminuria --> hypoalbuminemia and edema
- hyperlipidemia (inc serum cholesterol)
- lipiduria (fat in urine)
1) Proteinuria (>3.5g/day):
- disruption of slit diaphragm
- nephrin defect, injury to podocyte
2) Hypoalbuminemia (serum albumin less than 3g/dL):
- proteinuria and inc catabolism of reabs protein in tubules
- liver inc protein synth but cannot compensate completely
3) Edema:
- dec serum albumin --> dec capillary oncotic pressure --> inc fluid in intersititium
4) Hyperlipidemia (cholesterol >250mg/dL):
- inc in serum cholesterol due to inc lipoprotein synth of liver
5) Lipiduria:
- inc capillary wall permeability and hyperlipidemia
- "maltese cross"
also see:
- inc risk of infection due to loss of IgG and complement in urine; pneumonia and bacterial peritonitis
- inc thrombosis risk due to inc in coag factor synth
- poor growth due to loss of vitamin D
- protein malnutrition
64
What is the definition of nephritic syndrome?
- active inflammation within glomerulus leads to damage to the glomerulus with subsequent loss of filtration and a dec DFR
presents with:
- microhematuria, leukocyturia, occasionally red cell casts, non-nephrotic proteinuria, dec GFR, HTN, edema
65
What are the major nephrotic syndrome diseases? both renal-only and systemic
Renal only:
- hereditary nephrotic syndrome
- minimal change disease
- focal segmental glomerular sclerosis
- membranous nephropathy
- membranoproliferative GN
systemic:
- diabetes
- amyloidosis
- light chain deposition disease
- lupus membranous type
66
What are the major nephritic diseases? both renal-only and systemic
Renal only:
- post strep GN
- IgA nephropathy
- rapidly progressive GN (anti-GBM nephritis, idiopathic RPGN)
systemic:
- ANCA-assoc vasculitis
- microscopic polyangiitis/granulomatous polyangiitis
- henoch-schonlein purpura
- HCV-assoc cryoglobulinemia
- SLE
67
Minimal Change Disease
Definition:
- common cause of nephrotic syndrome
- glomeruli appear normal under light microscopy
Epidemiology:
- 75% of cases in children
Pathology:
- normal LM
- no complement on IF
- EM find foot process fusion
Etiology:
- due to circulating permeability factor produced by T cells --> acts directly on podocyte --> disruption of filtration barrier leads to inc permeability
Presentation:
- nephrotic syndrome
- edema and weight gain
- normal GFR
- no HTN
- usually occurs with viral URTI
Treatment:
- steroids
- maybe add cyclophosphamide if relapses
Overall good prognosis
68
Hereditary Glomerular Disease
Etiology:
- mutations in nephrin, podocin, and WT-1
Presentation:
- steroid-resistant nephrotic syndrome
- nephrin mutation leads to proteinuria, edema, and failure to thrive
Pathology:
- lesion is similar to FSGS
Treatment:
- reduce proteinuria with ACEi and eventually renal transplant
69
What happens in asymptomatic proteinuria and/or hematuria?
- >150mg protein/day
- selective or nonselective (loss of size barrier; more common)
- can lead to nephrotic syndrome
- RBC casts specific for glomerular bleeding
70
Focal Segmental Glomerular Sclerosis (FSGS)
Definition:
- LM shows normal appearance except segmental scarring in some glomeruli
- proteinuria caused by rest of glomeruli where capillary wall shows inc permeability
Epi:
- common in AfAms and 20-40yos
Pathology:
- segmental scarring in some glomeruli
- IF is usually negative but can show IgM and C3 in scarred areas
- EM shows diffuse foot process fusion with generalized capillary wall defect
Etiology:
- idiopathic FSGS caused by circulating factors that affects podocyte
- genetic mutations to podocin gene
- HIV nephropathy --> lesion of FSGS
- AfAms have polymorphisms in apoliprotein that provide protection against trypanosomiasis
- assoc with minimal change disease or heroin use or HIV infection
Presentation:
- idiopathic nephrotic syndrome
- maybe HTN or microhematuria
Treatment:
- reduce proteinuria with ACEi --> dec glomerular pressure
- corticosteroids can help and cyclosporines
- antiretroviral for HIV patients helps
Can progress to renal failure
71
Membranous Nephropathy
Definition:
- immune mediated with immune complex deposition in subepithelial space (between podocyte and GBM)
- GBM appears thickened under LM
Epi:
- most common cause in older adults
Pathology:
- thickening of GBM by LM
- spikes along BM after staining --> extensions of new BM material between immune complex deposits on subepithelial side of BM
- IF shows granular deposits of Ig and C3 along GBM
- EM shows electron dense subepithelial deposits of immune complexes
Etiology:
- autoimmune but antibody against antigen on podocyte (PLA2 receptor) --> complement/immune complex injury to podocyte --> capped and shed into subepithelial space and forms deposit
- assoc with hep B, lupus, drugs, and cancer
Presentation:
- nephrotic syndrome
- can have non nephrotic proteinuria early on
- HTN and renal failure can develop over time
- look for cancer
Treatment:
- steroids
- cytotoxic drugs (cyclophosphamide)
- ACEi to lower proteinuria
72
Membranoproliferative Glomerulonephritis (MPGN)
Definition:
- proliferation and thickening of GBM
- type 1 = immune complex deposition
- type 2 = complement activation in capillary wall w/o immune deposits
Epi:
- type 1 assoc with chronic hep c virus
- type 2 seen with defects in alternative complement pathway
Pathology:
- LM shows thickening of GBM, mesangial cell proliferation, lobulated glomerulus
- deposits of C3 and IgG prominent on capillary walls, mesangium,
- type 2 is similar but just not IgG
Pathogenesis:
- nephrotic/nephritic
- trapping of immune complexes in subendothelial and mesangial areas --> complement activation and leukocyte recruitment
- circulating nephritic factor
Presentation:
- acute nephritis
- HTN
- hep c infection
Treatment:
- anti HCV therapy
- immunosuppression
- steroids
73
Diabetic Nephropathy
- glycosylation of GBM inc permeability and thickening
- mesangial expansion from dec turnover of glycosylated proteins in mesangial matrix
- inc glucose (inc TGF)
- EA glycosylated (inc GFR)
- hyperfiltration injury
- *proteinuria --> nephrotic syndrome
- microhematuria, but no casts
- eosinophilic nodular GS, mesangial expansion, GM thicken
- control blood glucose and HTN via ACEi
74
SLE / Lupus nephritis
- endogenous Ab-Ag complex from ANAs
- nephritic presentation
- but also nephrotic
- treat with steroids
Pathology:
- immune complexes in mesangium, subendothelial space, subepithelial space
- IF shows C3, IgC, IgM, IgA, and C1q
- lumpy bumpy
Pathogenesis:
- autoantibodies to DNA, RNA, histone
Presentation:
- proteinuria, hematuria
- can be nephritic or nephrotic
Treatment:
- high dose corticosteroids
75
Amyloidosis
- multiple myeloma, TB, RA
- nephrotic syndrome
- systemic symptoms (enlarged spleen/liver, CHF, etc)
- look for plasma light chains
- amyloid deposits in renal biopsy
- congo red stain shows apple green birefringence
76
What happens in nephritic syndrome?
- hematuria
- dysmorphic RBCs
- RBC casts
- proteinuria
- HTN and edema
- dec GFR (inc serum Cr)
- RBCs, WBCs in urine
- inflammation of glomeruli
- orthopnea
- pulm edema
77
Clinical evaluation of suspected GN
- history and PE focus on rashes, lung disease, neuro problems, viral/bact infections, MSK or heme abnormalities
- labs: get a CBC, electrolytes, 24hr urine, LFTs
- serum complement levels
- tissue diagnosis
78
Pathophysiology of nephritic syndrome
- glomerular inflammation
- cells/casts in urine
- immune complexes deposit in mesangium or subendothelial space --> inflam mediators and bring in inflam cells
- auto-antibodies can cause glomerular endothelial injury
- ANCA mediate vasculitis causes necrotizing injury of glomerular capillaries
1) proteinuria:
- direct damage to glomerular capillary wall by immune mechanisms --> inc in protein filtration
- usually less than 3g/day (contrast to nephrotic syndrome)
2) dec GFR:
- acute inflammation --> vasoconstriction/occlusion/thrombosis of cap loops --> dec surface area
- azotemia
- hyperkalemia
3) urine sediment:
- RBCs, WBCs, RBC casts --> glomerular inflammation and disruption of GBM
4) edema:
- inc in reabs of Na and H2O due to dec glomerular perfusion --> inc ECF volume
5) HTN:
- Na and H2O retention
79
What is seen on histology of glomerulonephritis?
LM:
- look at glomeruli for hypercellularity, scarring, lesions
- crescents if proliferation of cells in BC (macrophages and parietal epithelial cells) --> RPGN
IF:
- if Igs present or complement proteins
EM:
- morphology of BM
- fusion of podocytes (nephrotic syndrome)
- immune deposit locations
80
Post-infectious Glomerulonephritis
- usually after group A strep infection; maybe after staph endocarditis
Epi:
- 2-3wks after infection
- can also occur with acute endocarditis
Etiology:
- antibody response to certain streptococcal antigens --> immune complexes lodging in flomeruli --> activating of complement
Pathology:
- LM shows proliferation with infiltration of neutrophils and monocytes
- IF shows *granular deposits of IgG and C3 in subendothelial, mesangial, and subepithelial areas;
- EM shows subendothelial and mesangial deposits and *"subepithelial humps"
- Cr and BUN inc
- WBC mild inc
Presentation:
- edema, weight gain
- hematuria, proteinuria
- dec GFR
- HTN
- inc antibodies to strep antigens
- inc alternate complement pathway (low C3, high C4)
- pulm edema (rales)
- fever
Diagnosis:
- nephritic snydrome
- positive streptozyme test
- low C3 levels
- if severe or persistent, get biopsy
- IF shows burning bush
Treatment:
- self-limiting; maybe steroids
81
IgA Nephropathy
- mesangial proliferative GN with IgA immune deposits in mesangium, but not so much in subendothelial areas
Epi:
- most common acute GN; 15-35yos
Etiology:
- IgA immune complexes in mesangium --> proliferation and matrix expansion
Pathology:
- LM shows inc in mesangial cells
- IF shows IgA, IgG, C3 in mesangium
- *burning bush on IF = mesangial IgA, C3
- EM shows mesangial immune deposits
Presentation:
- *asymptomatic microhematuria --> nephritic syndrome
- nonnephrotic proteinuria
- ok renal function
- occasional RBC casts
- onset of viral illness
- occasional fever, rash, GI issues, renal disease
- skin biopsy shows IgA deposits (Henoch Schonlein purpura)
Treatment:
- 25-50% progress to ESRD over 15yrs
- ACEi can slow progression
- steroids may help
82
Anti-GBM disease / Goodpasture's syndrome / Rapidly Progressive (Crescentic) GN
- sever GN with pulm hemorrhage
- goodpastures = pulm hemorrhage, Fe deficiency anemia, GN due to circulating antibody to GBM
Pathology:
- antibody to collagen in GBM --> IgG deposits by IF
- complement activation
- neutrophil infiltration
- crescent formation and loss of renal function (RPGN)
```
***
IF:
- linear = goodpastures, anti-GBM
- granular = IgA, SLE, endocarditis
- no staining = GPA
***
```
Presentation:
- rapidly progressive GN
- high fevers, nausea, vomiting, hemoptysis
- oliguria
- pulm hemorrhage from antibody deposition on alveolar BM
- smoking makes worse
- can be renal only
- anti-GBM antibodies detected using ELISA
Treatment:
- aggressive steroids
- immunosuppression
- plasma exchange
- kidney biopsy
83
Pauci-Immune Renal Vasculitis
- small vessel vasculitis of kidneys without evidence of immune complex deposition
Pathology:
- glomeruli demonstrate fibrinoid necrosis and crescents
Pathogenesis:
- anti-neutrophil cytoplasma antibodies (ANCA)
Presentation:
- multiple organs affected
- nephritic pattern of renal disease
- alveolar capillaritis and pulm hemorrhage
Treatment:
- immunosuppressive drugs
- steroids and cyclophosphamide
- plasma exchange
84
Cryoglobulinemia
- antibodies that ppt in cold --> immune complexes in small vessels --> vasculitis
Epi:
- hep c infection
Pathology:
- immune complex GN
- membranoproliferative pattern; subendothelial deposits
Pathogenesis:
- hep c infection
Presentation:
- palpable purpura
- arthralgia
- general weakness
- proteinuria, hematuria
Treatment:
- antiviral for hep c
- rituximab
85
Henoch Schonlein purpura
- skin lesions/palpable purpura
- arthritis
- GI involvement (colic and bleeding)
- GN
- focal proliferative necrotizing GN
- crescents
- mesangial and cap wall IgA deposits
86
Chronic Renal Failure
- nephron loss --> dec GFR
- uremia
- due to glomerular disease, vascular disease/HTN, infection, drugs, urinary tract obstruction
87
Define focal, diffuse, segmental, and global
- focal = few glomeruli
- diffuse = all glomeruli
- segmental = part of a single glomerulus
- global = all of a single glomerulus
88
Alport's Disease
- nephritis, deafness, ocular lesions
- mutation of collagen IV
- X-linked
89
Define the basic principles of urine collection
- 1-2L/day of urine produced usually
- must be tested w/in 2hrs of collection
- refrigerate if can't be examined w/in 2 hrs
- 24hr specimens are not acceptable for testing
- 24hr collection with container using preservatives
90
Describe the different types of urinalysis and understand their corresponding clinical-pathological correlation, including macroscopic examination and chemical analysis (use and interpretation of dipstick for: glucose; bilirubin; specific gravity; blood; pH; protein; urobilinogen; nitrite; leukocyte esterase; microscopic examination; and cytology)
Visual Inspection
1) volume
- polyuria = >2L/day; indicates defective reabs of Na/H2O
- oliguria = less than 500mL/day; indicates pre, infra, post renal disease
- anuria = less than 100mL/day
2) color
- yellow, green, brown: bile pigments (bilirubin)
- orange, red, brown: excreted urobilinogen
- pink, red: hematuria
- dark brown, black: methhemoglobin, rhabdo
3) turbidity = undissolved solid material (cells/crystals)
Chemical Screening
1) specific gravity:
- kidney's conc ability
- less than 1.001 --> less conc; polydipsia, diuretics, DI
- >1.035, more conc; dehydration, DM, proteinuria, CHF, addison's, SIADH
- osmolality is normally 500-850mOsm/kg
- if acute oliguria and >1.01 = pre-renal; if 1.008-1.012 = RTA
2) pH:
- 4.6-8
- acidic = met/resp acidosis, high protein diet,
- alkaline = RTA, UTI, excess bicarb ingested, met/resp alkalosis
3) proteinuria:
- usually less than .5g/day in urine
- nephrotic syndrom (>3.5g/day) or multiple myeloma if proteinuria
- proteinuria = >150mg/dL
4) glucose:
- normall undetectable in urine
- w/ hyperglycemia, glucose appears in urine when blood glucose >180-200mg/dL
5) ketones:
- positive in urine when inc in lipid metabolism
6) blood:
- no RBCs = free Hb = intravascular hemolysis
- RBC casts = glomerular hematuria = if renal dysfunction, then nephritic syndrome
- free RBCs = non-glomerular hematuria = kidney, ureter, bladder, urethra
7) nitrite:
- indicates UTI; usually gram neg bacteria
8) leukocyte esterase:
- made by neutrophils
- can indicate UTI, vaginal secretion, or glomerulonephritis
Microscopic Examination
- >3 RBCs/HPF is abnormal
- dysmorphic shape = glomerular origin (usually w/ RBC casts)
- normal shape = non-glomerular pattern w/ no casts
- >5 WBCs/HPF is abnormal (inflammation)
- renal tubula epithelial cells shed during renal parenchymal disease (+ lipid = nephrotic syndrome)
- hyaline casts: dehydration, fever, renal injury (lots) but otherwise nonspecific
- waxy casts: advanced chronic renal failure
- RBC casts: glomerular disease
- WBC casts: inflammation in kidney
- tubular cell casts: ATN, virus, drugs/toxins
- granular casts: immune complexes, fibrinogen
- fatty casts: nephrotic syndrome
91
Understand that hypo/hypernatremia refer to the concentration of Na in serum and not to the absolute amount of Na in the body
- concentration, so relative amounts of Na and H2O
| - hyponatremia is most commonly caused by excess of H2O (ADH)
92
Describe the pathophysiology of how hypo/hypernatremia can developed (importance of ADH)
- hyponatremia is most commonly caused by excess of H2O due to release of ADH
- tonicity of ECF reflects tonicity of cells
- serum osm = 2*Na + BUN/2.8 + glu/18
93
What are the 3 essential features of a normal diluting system?
1) tubular fluid is diluted in ascending LOH and DT by reabs of NaCl; Na/K/2cl contransporter in asc limb and NaCl cotransporter in DT
2) normal GFR and proximal reabs; if inc proximal reabs --> dec DT delivery --> vol of dilute urine excreted dec
* 3) absence of ADH; if ADH, then CD becomes H2O permeable --> lumen and interstitium equilibrate --> urine becomes concentrated (H2O leaves to interstitium) so dec H2O excretion
94
What are the 3 essential features of a normal concentrating system?
600mOsm waste needs to be excreted --> can be as little as .5 L if concentrating ability is ok
1) generate a hypertonic interstitium; asc LOH w/ Na/K/2Cl contransporter makes interstitium hypertonic and dilutes tubular fluid
2) secretion of ADH; CD permeable to H2O --> water reabs to make urine concentrated
3) if can't concentrate, then need to excrete more volume of urine --> need to replace these H2O losses
95
When is ADH released?
- change in serum osm (high) and changes in effective intravascular blood volume (low)
- initially controlled by inc osm but when volume depletion is really severe, then blood volume response dominates
- aka normally osmoregulatory, but during stress becomes volume regulatory
96
How does ADH work?
- ADH reacts with tubular cell membrane receptor --> activates adenylate cyclase --> cAMP --> cascade resulting in aquaporins to reabs H2O
97
What happens in hyponatremia, generally?
- bad at excreting H2O --> retain a lot of H2O --> ECF volume inc --> dilute serum Na --> hyponatremia
98
What are the 3 different types of hyponatremia?
- hypertonic (>300mOsm serum osm)
- isotonic (280-300mOsm serum osm)
- hypotonic (less than 280 mOsm serum osm)
99
Hypertonic hyponatremia
- inc in non-Na solute --> hyperglycemia, mannitol, glycerol
- inc glucose 100 mg/dL = serum Na dec 1.6 mEq/L
- high Sosm --> H2O shifts from ICF to ECF --> hypertonic hyponatremia
100
Isotonic hyponatremia
- normal Sosm
| - lab artifact caused by hyperlipidemia or hyperproteinemia (multiple myeloma)
101
Hypotonic hyponatremia
- 3 types: hypervolemic, euvolemic, hypovolemic
- hypervolemia: edema
- hypovolemia: high serum uric acid; hypotension, tachycardia, orthostasis)
- euvolemia: low serum uric acid
102
Hypovolemic hyponatremia
- low total body Na
- appropriate ADH release causes reabs of H2O to help ECF volume depletion
- causes can include: GI losses, diuretic use, salt losing nephritis, mineralocorticoid def, osmotic diuresis
- treat with normal saline
- if UNa > 20 --> renal loss (not reabs Na)
- if UNa less than 20 --> extrarenal loss
103
Hypervolemic hyponatremia
- high total body Na
- seen in CHF, cirrhosis, nephrotic syndrome --> EABV is dec (poor perfusion) --> ADH activation
- renal failure --> inability to lose free H2O due to dec GFR
- see edema
- caused by CHF, cirrhosis, nephrotic syndrome, and advanced/chronic/acute renal failure
- if UNa >20 --> ARF, CKD (kidneys not reabs Na)
- if UNa less than 20 --> CHF, cirrhosis, nephrotic syndrome
- treat underlying cause with loop diuretics
104
Euvolemic hyponatremia
- normal total body Na
- inc ADH secretion but no inc in Sosm or dec EABV (inappropriate)
Causes can include:
- hypothyroidism --> ADH secretion
- drugs
- adrenal insuff
- primary polydipsia (excessive thirst)
- SIADH (hypoosmolality, non-dilute urine and non CV, hepatic, renal disease) caused by carcinomas, pulm diseases, CNS disorders
105
What are signs of hyponatremia?
- GI issues (anorexia, nausea, vomiting)
- altered sensorium
- seizures
106
How do you treat hyponatremia?
- restrict H2O
- correct underlying disease
- give hypertonic NaCl with/out furosemide (which inc free H2O excretion)
- raise the serum Na slowly to avoid neuro problems (central pontine myelinolysis)
107
When does hypernatremia occur?
- ADH is dec or ineffective
- H2O intake is less than required to compensate for GI losses
- common causes are dec thirst, inability to obtain water
- see inc in Sosm
108
What are the causes of hypernatremia?
- dec total body Na --> body water loss > body salt loss --> GI loss, burns, diuretic use w/o water intake
- inc total body Na --> rare; hypertonic fluid received
- normal total body Na --> either ADH def (central DI) or ADH resistance (nephrogenic DI)
109
Describe the causes of hypernatremia with normal total body Na
Central diabetes insipidus
- ADH deficiency
- usually idiopathic, maybe head trauma, surgery, neoplasma
- treat with ADH (DDAVP)
Nephrogenic DI:
- ADH resistant (renal duct is unresponsive)
- congenital (rare) or acquired from CKD, hypercalcemia, hypokalemia, drugs, sickle cell anemia, polycystic kidney disease, urinary obstruction; pregnancy release of vasopressinase
- does NOT respond to ADH --> treat with lots of fluids and thiazide diuretics (dec urine flow by causing Na loss and volume depletion)
110
What are signs of hypernatremia?
- neuromuscular irritability (twitches, hyperreflexive, seizures, coma, death)
111
How do you treat hypernatremia?
- restore Sosm to normal
- give water according to .6*weight*[(current Na/140)-1]
- give water slowly to avoid sudden shifts in brain cell water
112
Discuss the concept of EABV and the hormonal mechanisms involved in its maintenance. Must also understand how these systems interact when one (or several) components are diseased
- EABV is the vol of blood detected by volume sensors in arterial circulation
- afferent limb detects changes in EABV and efferent limb regulates rate of Na excretion
113
Describe the distribution of the total body water
- 42L TBW
- 2/3 (28L) ICF
- 1/3 (14L) ECF
- out of 14L ECF --> 10.5 is extravascular, 3.5 is intravascular
114
What are the volume sensors?
1) low pressure baroreceptors
- cardiac atria, LV, pulm vasculature
- venous side
- protect against ECF vol expansion and contraction
- inc vol --> inc venous return --> stretch receptors signal hypothalamus and medulla --> dec renal SNS activity --> dec Na and H2O (excreted) --> dec ECF vol
2) high pressure baroreceptors
- carotid sinus
- aortic body
- arterial side
- protect against vol depletion
- dec EABV --> signal brain --> inc renal SNS activity --> retain Na and H2O --> inc ECF vol
- also release NE --> inc BP by inc HR and TPR
3) intrarenal sensors
- in JGA
- release renin
- dec in arterial pressure --> inc in intracellular Ca --> inc in renin secretion --> Na reabs with aldosterone
115
What are factors that regulate renal Na excretion?
1) GFR
- 23g usually filtered/hr
- autoregulated
- TGF: inc distal delivery of NaCl --> inc AA tone --> RBF and GFR dec
- GTB: changes in GFR = change in rate of PT Na reabs so that it stays ~65%
2) PT physical forces
3) Humoral effector mech
- vol dec --> AT2, aldosterone, and catecholamines retain Na
- vol inc --> PGs, BK, ANP excrete Na
4) Renal symp nerve
- vol dec --> retain Na and release renin
116
What parts of the nephron handle Na?
1) proximal tubule
- PT reabs ~60% of Na
- electrochemical gradient to go inside cell maintained by Na/K ATPase
- coupled to Cl, PO4, glucose, amino acids, etc.
- Na/H antiporter brings Na in and H out
2) LOH
- 30% Na reabs in thick asc limb, which is impermeable to H2O
- Na/K/2Cl transporter (loop diuretics block) brings into cell caused by Na/K pump gradient
3) DT
- 1) Na enters cell through Na channels (amiloride blocks) and Cl ions go between cells
- 2) NaCl reabs occurs by NaCl cotransport (thiazides block)
- 3) Na goes in and H goes out
4) CD
- intercalated cells secrete H (A) and bicarb (B)
- Na enters principal cells (amiloride blocks) and K leaves
117
What are the causes of extracellular volume contraction?
- renal or extra-renal
- renal: salt and water loss due to loss of effector mechanism (diuresis, adrenal insuff, aldosterone def, Na transporter defects) or intrinsic renal disease
- extra-renal: GI loss, skin, hemorrhage, accumulation into areas outside ECF and ICF
118
What are Bartter's and Gitelman's syndrome?
- they are renal losses of Na and H2O
- Bartter's: mutation in Na/K/2Cl cotransporter in TALOH; hypokalemia (K is excreted), hypomagnesemia, metabolic alkalosis, inc renin and aldosterone, inc Ca excretion, and normal BP (kind of like loop diuretics)
- Gitelman's: mutation in NaCl cotransporter in DT --> hypokalemia, hypomagnesemia, metabolic alkalosis, dec urine Ca
119
What are extrarenal losses of volume?
- when extra renal loses are not replaced
- vomiting, nasogastric suction --> metabolic alkalosis
- diarrhea --> loss of bicarb = metabolic acidosis
- excessive sweating --> loss of hypotonic fluids
120
What is the physiologic response of the body to ECF volume depletion?
- baroreceptors detect dec EABV --> inc SNS activity --> inc HR, inotropy, TPR; also inc AT2, ADH, and endothelin
- renal response is to replenish fluids and conserve salt
- dec GFR = dec Na filtered/inc reabs of Na
- activate renal SNS --> constrict AA (dec GFR) = inc reabs of Na
- inc oncotic pressure/dec hydrostatice pressure = inc fluid reabs into vessels
- RAAS --> AT2 acts on Na/H in PT to inc Na reabs; aldosterone in DT creates more Na/K pumps to reabs more Na
- ADH = inc H2O reabs
- ANP = inc Na reabs
121
What shows up on history and PE for volume depletion?
- thirst, postural dizziness, weakness --> mild
- worsened lightheadedness/dizziness --> severe
- palpitations
- dec urine output
- confusion
- orthostatic hypotension
- tachycardia
- dry mucous membranes
- hypotension
- dec RA pressure and CVP and LA pressure
- dec CO
122
What serum values show up in volume contraction?
- inc BUN/Cr ratio --> normally 10-15:1; if vol dec --> kidney reabs Na in PT --> urea follows Na --> BUN inc
- metabolic alkalosis if vomiting
- metabolic acidosis if diarrhea
- inc hematocrit and serum albumin
123
What urine values show up in vol contraction?
- UNa is low because trying to reabs Na
- if UNa is high, then probably ATN or kidney damage leading to inability to reabs Na
- FENa = UNa/PNa / UCr/PCr * 100; less than 1% if prerenal azotemia, >2% if acute renal failure
- Sosm inc --> kidney reabs Na and H2O to produce concentrated urine
- Sosm dec --> excrete free H2O to produce dilute urine
124
How do you treat ECF volume contraction?
- expand ECF volume
- if hemorrhage, give blood or albumin/dexrtan
- isotonic saline expands ECF volume
- give KCl if loss of K
- hypovolemic shock --> rapidly give fluids
- D5W spreads 2/3 to ICF and 1/3 to ECF
- saline spreads 3/4 to interstitium and 1/4 to intravascular
- plasma goes all into intravascular
125
What causes ECF volume expansion?
- renal/extrarenal fluid losses do not match H2O and salt intake --> edema
1) Starling forces:
- CHF --> inc venous pressure --> inc hydrostatic pressure
- nephrotic syndrome --> protein loss --> dec oncotic pressure
- cirrhosis --> dec albumin and inc vasodilation --> dec oncotic and inc hydrostatic
- basically dec CO --> activation of ventricular/atrial receptors --> SNS stimulation --> RAAS and ADH stimulation --> ADH reabs H2O, SNS inc TPR, RAAS inc Na reabs --> inc BP
- nephrotic syndrome caused by DM, SLE, amyloidosis, hep B, syphilis, NSAIDs, etc.
2) overproduction of ADH or mineralocorticoids --> hyperaldosteronism or SIADH --> inc Na and H2O reabs
3) primary renal Na retention in acute GN
126
How do you treat volume expansion?
- treat underlying condition
- restrict Na
- diuretics
- treat CHF with inc inotropy, dec afterload, dec preload
- normal BP, glycemic control, proteinuria in DM with ACEI
- cirrhosis treated with paracentesis, albumin, spironolactone
127
Describe the different diuretics and their site of actions
PT:
- acetazolamide
- block carbonic anhydrase action --> excrete bicarb in urine
- causes metabolic acidosis and can treat metabolic alkalosis when vol expanded
LOH:
- furosemide, bumetanide, torsemide
- inhibit Na/K/2Cl transporter at TALOH --> blocks 25% of reabs Na
- can cause metabolic alkalosis, hypokalemia, hypocalcemia, and hypomagnesemia
DT:
- thiazides
- inhibit NaCl transporter
- limit diluting ability of distal nephron
- inc Ca reabs and dec urine Ca excretion, but similar side effects as loop diuretics
CD:
- triamterene and amiloride
- block Na channels
- spironolactone competitive inhibitor of aldosterone
- excrete Na and retain K
128
Describe the cellular mechanisms for K reabs and secretion and their tubular location
- 30g K filtered by glomerulus each day
- excretion ranges from 0 to 45g (can reabs really well but also means that we secrete K)
- almost complete (80%) reabs in PT
- fine tuning in DT and CD
- in PT, K reabs is between cells (paracellular) and passive; Na builds up in serosa and H2O follows and so does K
- in LOH, reabs of K is transcellular with Na/K/2Cl cotransporter (Na pumped out with Na/K pump to cause gradient for Na); then K goes into serosa down conc gradient and is reabs
- *almost all K is reabs in PT and LOH and fine tuned secretion in distal parts
- in principal cells of distal nephron, K comes into cell from Na/K pump and then goes down its gradient into lumen
129
Describe the feedback pathways that regulate ECF K levels via K secretion
- mass action effects: inc ECF K --> inc ATPase pumping K into cell --> inc K movement down gradient into lumen
- hormone mediated via aldosterone: inc ECF K --> inc stimulation of adrenal cortex cells --> inc aldosterone --> inc Na/K pumps on BL and K channels on apical side--> inc intracellular K --> inc K secretion
130
Describe the effects of inc and dec tubular flow on K secretion
- inc GFR --> lumenal K doesn't get a chance to inc greatly because it is "washed away" by flow
- dec GFR --> lumenal K builds up and dec gradient for K secretion
- loop diuretics inc K secretion
- inc aldosterone --> inc K secretion but also inc Na reabs --> more H2O reabs --> dec tubular flow --> dec K secretion
- in hyperaldosteronism, inc in ECF volume and inc in MAP maintains filtration rate/tubular flow --> K secretion inc
- CHF --> inc aldosterone levels from dec MAP and potentially inc AT2 --> dec GFR --> K secretion dec
131
State the effects of acid/base imbalances on K levels
- *alkalosis inc K secretion and produces hypokalemia
| - inc ECF pH (dec H+) --> shift K into cells (hypokalemia) --> inc intracellular K --> K secretion --> hypokalemia
132
Describe the cellular mechanisms by which acid/base abnormalities can cause hypokalemia and hyperkalemia
- alkalosis causes hypokalemia (shift of K into cells and low pH allows more K to be secreted)
- in acidosis, shift of K from cells to ECF (hyperkalemia) and apical K channels are inhibited (dec secretion) --> dec K secretion
- however acidosis also inhibits Na reabs --> H2O stays in tubule --> inc tubular flow --> inc K secretion
- basically it depends in acidosis
133
What effect do loop diuretics have on K secretion?
- blocks Na/K/2Cl transporter, so have K secretion, but even more of an effect than that
- without that transporter, interstitium is not as hypertonic --> more water remains in lumen and not reabs in desc limb or DT --> inc tubular flow where K is secreted --> inc secretion of K
134
What are factors regulating internal balance (plasma K)?
1) blood pH
- generally, hyperkalemia with acidemia and hypokalemia with alkalemia
2) insulin
- hyperkalemia --> insulin release --> moves K into cells
3) adrenergic activity
- beta2 agonists --> inc K entry into cells (similar to insulin)
- beta blockers can have opposite effect
- alpha agonists can impair K entry into cell
4) exercise
- injury to muscle cells --> leakage of K into ECF
- athletes can have hypokalemia
5) Na/K ATPase
- inhibited --> K leaves cells --> hyperkalemia
6) hyperosmolality
- shift K out of cells
135
Discuss how to diagnostically approach a case of hypokalemia
1) is there an internal shift of K? alkalemia, insulin, beta agonist, etc.
2) is there a low K intake?
3) GI loss of K? diarrhea, vomiting
4) excessive renal loss of K? diuretics
136
Describe the physiologic effects of hypo and hyperkalemia, particularly as they relate to excitable tissues
Hypokalemia
a) metabolic effects
- dec K --> dec insulin --> glucose intolerance
- dec K --> inc intracellular acidosis --> inc renal ammonia production (bad for cirrhosis)
b) CV effects
- atrial and ventricular arrhythmias
c) neuromuscular effects
- weakness, rhabdomyolysis
d) renal effects
- inc thirst, defect in concentration --> polyuria
- can cause proteinuria, and dec GFR
Hyperkalemia
a) CV effects
- inc plasma K --> inc Ki/Ke --> raise membrane potential towards threshold
- EKG shows peaked T wave, wide QRS, flat P waves, "sine wave"
b) neuromuscular effects
- weakness; due to depolarization
137
Discuss how to diagnostically and therapeutically approach a case of hyperkalemia
1) is this a medical emergency (K>6 --> perform an EKG)?
2) is there an internal shift of K into ECF? (acidemia, digitalis, adrenergic block, hyperosmolar state)
3) is there dec renal K excretion? (renal failure with GFR less than 10, hypoaldosteronism, K sparing diuretics)
4) is there a major inc in K input? (IV infusions, diet)
138
What are the factors regulating body potassium content (external balance)?
a) renal excretion of K
- can excrete lots of K without a change in plasma K
- 100% filtered at glomerulus --> 50% reabs in PT --> secreted in DLOH to 100% --> reabs in TALOH by Na/K/2Cl so 10% left by CCT --> secreted in CCT to 100% through K channels --> reabs in CD by KCl cotransporter left with 50%
- *hypo or hyperkalemia almost always result from alterations in K secretion/reabs from CD because 10% of K reaches CCT
b) GI K excretion
- excretes 10-15% of k normally
- diarrhea inc K losses
c) skin K excretion
- sweating can lead to major K losses
139
What are the major determinants of urinary K excretion?
1) normal DT function
- normal epithelium
- adequate delivery of Na to distal nephron
2) aldosterone activity
- aldo stimulates secretion of K
- if no aldo --> hyperkalemia
- excess aldo --> hypokalemia
- inc K stimulates aldo secretion to lower it
3) urine flow rate
- inc flow rate --> inc K excretion
4) delivery of non-reabs anions to distal nephron
- excretion of sulfates, bicarb, etc. will bring K along with it
140
What are the potential causes of hypokalemia?
1) spurious
- high WBC count
2) dec total body K
- check urine K
- if UK less than 20 --> kidneys are ok and reabs K --> GI loss --> if dec pH then diarrhea causing metabolic acidosis; if normal pH then dec intake
- if UK >20 --> renal problem --> look at pH
- - if alkalosis --> look at UCl --> >20 means BP too high or too low (Cushings, Bartters, Gittelmans) --> treat with K sparing diuretic, KCl, vol replacement; less than 20 means diuretics --> treat with KCl and vol replacement
- - if normal pH --> low Mg
- - if acidosis --> DKA, RTA, treat with citrate or bicarb
3) transcellular shift
- stress leads to inc cortisol --> binds to mineralocorticoid receptors and mimics aldosterone --> inc Na reabs and K secretion
141
What are causes of hyperkalemia?
1) spurious
- inc platelet count
2) transcellular shift
- DKA or hyperglycemia
- beta2 blockade
- digitalis
3) dec renal excretion of K
- look at GFR
- - if less than 20 --> exogenous K ingestion or endogenous K production or drugs
- - if >20 --> look at aldosterone
- --- dec aldosterone --> look at renin
- ----- low renin = DM
- ----- high renin = adrenal insufficiency
- --- inc aldosterone --> look at urine K
- ----- low urine K = dec Na delivery
- ----- high urine K = drugs (PHA)
142
How do you treat hypokalemia?
- restore plasma and total body K
- give KCl
- diuretics that dec renal K excretion (spironolactone, amiloride)
143
How do you treat hyperkalemia?
- reversible depol with Ca infusion
- shift K into cells with insulin, beta2 agonists, NaHCO3
- remove K from body with kayexalate, diuretics, hemodialysis
CBIGK
- Calcium gluconate (stabilize cardiac membrane)
- Beta2 agonist - drive K into cells
- bicarb - drive K into cells with alkalemia?
- insulin + glucose - drive K into cells
- kayexalate - resin that binds K in gut and removes it
144
Define the prevalence of HTN in the U.S.
- +50mil in US, +1bil worldwide
- inc prevalence w/ age
- normotensive at 55 --> 90% risk of HTN lifetime
- 115/75 --> CV risk doubles with each increment of 20/10
- dec BP = dec stroke, MI, HF incidence
- 34% of people with HTN have BP under control (less than 140/90)
145
Define the incidence of CV and renal complications of HTN
- dec BP = dec stroke, MI, HF incidence
| - parenchymal disease, renovascular HTN
146
Discuss the pathophysiology of essential and secondary HTN
Essential HTN:
- not completely understood
- HTN caused by inc in CO or TPR
- inc Na and H2O retention --> inc ECF vol --> inc SV --> HTN
- this inc ECF volume tends to be acutely normalized, but what happens over time is an inc in TPR at level of arterioles --> inc HTN
- basically, inc vol leads to CO and HTN in early phases and then transformed into state of inc TPR over time
- Na is reabs really well and must excrete excess Na to prevent ECF vol expansion
- if these Na excretion mechanisms are messed up --> HTN
- *predisposition to genetic HTN resides in the kidney, at least partially and not caused by neurohormonal abnormalities or intrinsic differences in blood vessels
- *inc Na reabs --> inc ECF vol --> inc CO --> inc perfusion to organs --> autoregulation vasoconstriction to dec blood flow --> thickened vessel walls --> persistent inc in TPR
Secondary HTN:
a) renovascular HTN
- abnormal activation of renin release by kidney which can be a result of activated beta sympathetic nerves, stimulation of renal baroreceptors by dec MAP, or activation of macula densa chemoreceptor by dec delivery of NaCl to distal nephron
- renin --> AT2 release --> *vasoconstriction, *Na reabs in PT, aldosterone release, mitogenesis
- dec RBF --> activation of renal baroreceptors --> inc PT Na reabs --> activates macula densa --> dec delivery of Na to macula densa --> renin secreted --> AT2 --> inc BP --> suppress PT reabs of Na --> excrete Na
- less than 30yo, renal artery stenosis due to fibromuscular dysplasia --> treat with percutaneous balloon dilatation
- >50yo, male, smoker, usually due to atherosclerosis
b) renal parenchymal HTN
- dec in vasodepressor (PGs) effect
- *inc in ADH effect
- 10% have inc renin levels
- 90% have volume overload
- causes can include GN, polycystic KD, diabetic nephropathy
c) hyperaldosteronism
- secondary: aldo secretion caused by inc in plasma renin which can happen in renal artery stenosis or volume depletion
- primary: pathological defect in adrenal cortex due to adenoma or hyperplasia of adrenal glands
- inc ECF volume, suppress renin activity
- rare, not progressive, and no edema
d) pheochromocytoma
- benign tumor of adrenal medulla
- excess catecholamines
- inc in vascular resistance
147
Discuss the role of non-pharmacological therapy of HTN
- reduce CVD and renal morbidity and mortality
- treat to BP less than 140/90 or 130/80 if DM or CKD
- achieve SBP goal
- lifestyle modifications --> drugs (thiazides, ACI/ARB/BB/CCB) --> optimize dosages
148
Describe the mechanics of anti-HTN drug actions
A
- ACEI - inhibit RAAS --> dec TPR
- ARB - inhibit RAAS --> dec TPR
B
- BB - dec CO
C
- CCB - dec TPR, CO
D
- diuretics - natriuresis, dec CO, dec TPR
149
What is HTN defined (arbitrarily) as?
SBP > 140
DBP > 90
goal is less than 130/80 for anyone with DM or CKD
150
What is the difference between essential and secondary HTN?
- essential HTN: single reversible cause of inc BP cannot be IDed (90-95%)
- secondary HTN: mechanism is known (5-10%)
- essential: genetic and environmental factors, esp genetic
- environmental factors are: inc Na diet, obesity, alcohol, stress, sedentary, smoking, low K or Ca
- secondary HTN: usually hormonal imbalances
151
What are the mechanisms of impaired natriuresis?
a) loss of nephron mass
- dec surface area of GFR --> dec capacity to excrete a salt load --> salt sensitive HTN
b) activations of SNS and neurohormonal axis
- RAAS and SNS --> act to reabs Na with AT2
c) abnormal blood vessel response to vasoconstrictors
- if constrict AA too much then dec RBF dec natriuresis
152
What is Guyton's hypothesis?
- inc perfusion to kidneys = inc Na excretion
- higher perfusion pressure inc hydrostatic pressure of peritubular capillaries --> dec reabs ability out of tubule --> more excreted
- autoregulation causes ultimate inc in TPR
153
How do thiazide diuretics cause anti-HTN?
- incompletely understood
- acute effect of diuretics is a dec in ECF and plasma volume --> dec CO
- over time though, Na balance attenuates and plasma volume and CO are normalized, but also a dec in TPR long term
- proposed that natriuresis ability means that HTN is no longer necessary to maintain Na balance
154
What are the clinical implications of HTN?
- look at end organ damage of eyes, cerebral vessels, heart, kidneys, etc.
- 90% of HTN cases are due to essential HTN
- a hypertensive crisis is where acute management of the elevated BP plays an important role in outcome
- differentiate between benign and malignant hypertension with fundoscopic exam; look for HTN neuroretinopathy (malignant HTN) --> striate hemorrhage and cotton wool spots with/out papilledema --> indicates systemic HTN vasculopathy
- non-malignant HTN --> absence of HNR; retinal arteriosclerosis, retinopathy
155
What is malignant HTN?
- inc BP with widespread acute arteriolar injury (hypertensive vasculopathy)
- flame shaped hemorrhages (failure of autoregulation)
- cotton wool spots (ischemic infarction of retinal nerve fiber bundles)
- papilledema (large cotton wool spot from ischemia of optic nerve)
- HTN induced arteriolitis
- characterized by necrotizing arteriolitis in kidneys; fibrinoid necrosis of AA
- proliferative endarteritis - narrowing of vessel lumen due to intimal thickening and superimposed fibrin thrombi
156
State the production rate of metabolic, nonvolatile acid in a healthy, average-sized individual
- 1mmol/kg/day of nonvolatile acid --> ~60mEq of H+ added to ECF/day
157
State the major acid buffering mechanisms in the ECF
- *bicarb buffer system
- albumin and Igs
- bone --> osteoblasts are suppressed and osteoclasts stimulated in acidosis --> H+ absorption into bone --> release of Na, K, CO3, PO4 (dec bone health)
- amino acid side groups
-
158
Describe the chemical reaction scheme and role of bicarb in the buffering of nonvolatile acid
H+ + HCO3- |--> H2CO3 |--> CO2 + H2O
- converts nonvolatile acid to a gaseous volatile form that can be eliminated by exhaling
- reaction is reversible
- inc CO2 can shift reaction other way; inc metabolic demand but dec blood flow
159
State the role of the kidney in the maintenance of bicarb levels
- maintenance of ECF bicarb
- bicarb use up to mop H+ that is created by HSO4 and HPO4
- bicarb is also freely filtered at glomerulus, so it needs to be reabs
- kidneys make bicarb
160
Describe the cellular mechanisms, tubular localization, and daily magnitude of bicarb reabs
- most reabs of bicarb happens in PT
- have Na/H exchanger that brings Na in and H out --> H and bicarb combine to make H2CO3 --> breaks down to CO2 and H2O --> CO2 goes into cell --> remakes H2CO3 with H2O inside cell --> splits into H and HCO3 --> HCO3 reabs with a Na/HCO3 contransporter and the H is recycled
- acid/base ECF balance is not changed (H is recycled)
- charge balanced with Na
161
Describe the cellular mechanisms, tubular localization, and daily magnitude of bicarb synthesis
- epithelial intercalated cells in DT
- CO2 from ECF --> combines with H2O to make H2CO3 --> splits to H and HCO3 --> H is secreted into lumen and bicarb transported into ECF with Cl exchanged in
- with all the H being secreted into the lumen, kidney neutralizes it with urinary buffers (titratable acids and ammonia trapping)
- titratable acids (HPO4, Cr, urate): H complexed to acid anion like HPO4; HPO42- combines with H to make H2PO4-
- ammonia trapping: tubular cells break down glutamine to NH3 --> NH3 combines with secreted H to form NH4+ that is excreted
- ammonia trapping is up or downregulated in response to H secretion, but titratable acids are just incidental
- both reabs and secretion of bicarb require apical secretion of H, BL extrusion of bicarb from inside
162
Describe the renal response to metabolic acidosis
- primary problem of metabolic overproduction of H
- bicarb buffers H --> produces CO2 --> exhaled out
- this dec filtered load of bicarb --> less H secretion needed to reabs bicarb --> excess secretory capacity to allow inc bicarb synth to replace what is lost
163
Describe the long term effects of primary changes in ECF K levels on plasma pH
- alkalosis --> inc K excretion and hypokalemia
- vice versa
- hypokalemia --> H into tubular cells --> inc in H transporters --> inc H secretion --> alkalosis
- acidosis --> take in H and dec secretion of K and hyperkalemia
- vice versa
- hyperkalemia --> K into cells --> dec H apical secretion --> inc K secretion --> acidosis
- K can also inhibit NH3 production --> dec NH3 trapping --> pH dec in tubular fluid --> secretion of H into tubule dec because of weaker gradient --> more acidosis
- hyperkalemia --> dec rate of H secretion --> acidosis
164
Describe the regulatory pathway for bicarb
- reabs much larger process than synth of bicarb
- 60mmol of bicarb need to by synthesized each day to neutralize 60mmol of H produced
- however need to reabs a lot more bicarb; 4320mmol of bicarb need to be transported
- no bicarb synth can occur until bicarb reabs is complete
- this happens because if bicarb in lumen (meaning enough so that synth not required) then you have bicarb reabs and H recycling and continued presence of CO2 inside cell --> CO2 cannot come in and synthesize bicarb;
- bicarb in tubular fluid is so large that only DT segment actually ends up synthesizing bicarb
- metabolic acidosis has up to 200 mmol/day of H so bicarb can compensate by synth more bicarb
- metabolic alkalosis where can excrete up to 80mmol of bicarb/day
- H secretion and bicarb reabs are rate limiting
- these rates (H secretion apically and bicarb reabs BL) depend on ECF pH and CO2; inc in CO or H causes cell to insert more transporter into apical and BL membranes
165
What is the renal response to respiratory acidosis?
- ventilation dec --> CO2 inc --> acidemia
- inc CO2 in ECF --> bicarb inc due to shift and inc in H (rapid) --> not compensatory because creating acid and bicarb
- kidneys respond to acidosis via inc H pumps in apical membrane of tubular cells (CD) (slow over days) --> inc H secretion from CO2 entering ECF from synthesis of bicarb and compensates for primary acidosis
- inc filtered load of bicarb; inc H secreted reabsorbs this newly added bicarb and H excretion returns to normal
- SUMMARY: kidneys respond in short term by inc excretion of H through bicarb; this becomes limited by inc filtered load of bicarb
- prolonged RA see a partial renal compensation with inc bicarb
166
Discuss the concept (and rules) of compensation
- the compensation is in the same direction as the primary change
167
Respiratory alkalosis
- primary dec in PCO2
- breathing too much
- compensate by dec bicarb from 1) H release acutely and 2) renal H retention chronically
- expected dec in bicarb: 2 for 10 PCO2 = acute; 4 for 10 = chronic
- can see dec K, neurologic problems, dec intracranial pressure, cardiac arrhythmias
- treat underlying cause; depress ventilation with a sedative
168
Respiratory acidosis
- primary inc in PCO2
- inadequate breathing from 1) sensing/signaling in brain, 2) muscles/motion, 3) free flow, or 4) gas exchange
- compensate by inc bicarb with 1) cell buffering acutely or 2) renal H excretion/bicarb resorption
- expected inc in bicarb: 1 for 10 PCO2 = acute; 4 for 10 PCO2 = chronic
- can see neuro problems, inc intracranial pressure, cardiac arrhythmias, hypotension from vasodilation
- treat underlying cause; watch PO2 make sure doesn't go too low
169
Metabolic alkalosis
- primary inc in bicarb
- generation: 1) add bicarb, 2) lose H (vomiting, diuretics), 3) lose Cl rich fluids (diuretics, diarrhea, sweat), 4) post-hypercapnea (met alk with chronic resp acid after ventilating --> dec CO2 but bicarb still high), 5) hypokalemia
- maintenance: always kidneys fault; dec ability to excrete excess bicarb due to Cl or K dec which affects ion channels in kidney --> dec bicarb excretion
- Cl depletion --> reabs of bicarb
- K depletion --> inc aldosterone release ??
- mineralocorticoid activity may be increased in vol depletion --> act on H ATPase of intercalated cell of DT --> secrete H and reabs bicarb --> maintain alkalosis
- hypovolemia: Cl depletion; release of aldosterone
- diagnose as Cl responsive or unresponsive --> if UCl less than 20 = Cl responsive because reabs Cl due to Cl depletion
- causes of Cl responsive metabolic alkalosis: diuretics, vomiting, diarrhea, CF, post hypercapnea
- causes of Cl unresponsive metabolic alkalosis: hyperaldosteronism, Cushing's, licorice
- compensate inc in bicarb with dec in ventilation to inc PCO2
- change in CO2 = (.25 to 1) * change in bicarb
- need to watch out for cardiac arrhythmias and hypocalcemia
- treat with hypoventliation; infusions of NaCl if Cl responsive; block mineralocorticoid effect if Cl unresponsive with spironolactone or amiloride
170
Metabolic acidosis
- primary decrease in bicarb
- caused by loss of bicarb of addition of acid
- look at anion gap: if normal then due to loss of bicarb; if inc then due to addition of acid
- AG = Na-Cl-bicarb = 9+-3
nonAG metabolic acidosis
- no AG because loss of bicarb is replaced by inc in Cl (not other anions)
- hyperchloremic acidosis
- GI losses (diarrhea) of kidney problems (defect in reabs/handling --> RTA)
AG metabolic acidosis
- anions that accompany added acid make up for bicarb being lost to neutralize acid --> inc anion gap
- can be due to production of organic acids or failure to excrete H and anions due to renal failure
- urine pH should dec if metabolic acidosis exists
- if urine pH >5.5 (not acidic) in setting of nonAG metabolic acidosis --> RTA because kidneys not excreting H like they should
- if urine H is less than 5.3 --> kidneys are normal and GI loss of bicarb/diarrhea exists
- urine anion gap: if negative --> NH3 production is okay and that nonAG metabolic acidosis is due to GI loss
- if positive, then NH3 prod is impaired and RTA exists
- urine anion gap = UNa + UK - UCl
- if NH3 prod inc in state of metabolic acidosis, then UCl should also increase --> UAG becomes negative
171
Describe normal acid and bicarb handling by the kidney
1) bicarb reabs mostly in PT
- if defect, then bicarb excreted and you have proximal RTA
2) H excretion in DT that makes more bicarb
- 60mEq of H is made every day
- this consumes 60mEq of bicarb so need to synth new bicarb
172
What are the 3 mechanisms of H excretion?
1) excretion of titratable acids
- filtered at glomerulus and then bind to H
- phosphate binds with H to make H2PO4 which is excreted
- incidental and not compensatory for acidemia
2) excretion of nontitratable acid (ammonium)
- NH3 is made by PT and binds to H to make NH4
- can inc in response to acidemia through glutamine breakdown
- NH3 production is inhibited by hyperkalemia --> RTA
3) free H excretion by DT
173
What are causes of nonAG metabolic acidosis
- GI loss of bicarb from diarrhea --> loss of bicarb rich and K rich fluid --> pH less than 5.3 and UAG is negative
- RTA: proximal --> dec ability to reabs bicarb; distal --> can't excrete H with NH3 --> synth more bicarb --> pH >5.3 and UAG is positive; hyperkalemia --> inc K inhibits NH3 prod --> UAG is positive and pH > 5.3
174
What are the causes of AG metabolic acidosis
KARL
K - ketoacidosis: inc oxidation of fatty acids
- diabetic: not enough insulin
- alcoholic: ketoacids, lactic acids, acetic acids
- starvation: use fatty acids for energy when low insulin
A- aspirin and other toxins
- generate lactic acid
- methanol: formic acid
- ethylene glycol: glycolic acid
R - renal failure
- retain organic anions and don't generate NH3
L - lactic acidosis
- ischemia
- mitochondrial derangement
MUDPILES
175
What are the physiologic effects of metabolic acidosis?
- heart contractility is depressed and peripheral resistance dec --> hypotension
- Kussmaul breathing
- hypercalcuria
- bone disease
176
Respiratory compensation in metabolic acidosis
change in PCO2 = (1to1.5) * change in bicarb
177
How do you treat metabolic acidosis
- correct underlying disorder (fix low bicarb)
- oral NaHCO3 therapy chronically
- IV bicarb acutely
178
Describe the rules of compensation for simple acid base disorders
Metabolic acidosis
- winter's formula
1. 5*bicarb+8+/-2
Metabolic alkalosis
change in PCO2 = (.25to1) * change in bicarb
Respiratory acidosis:
- acute: bicarb inc 1 = PCO2 inc 10
- chronic: bicarb inc 4 = PCO2 inc 10
Respiratory alkalosis:
- acute: bicarb dec 2 = PCO2 dec 10
- chronic: bicarb dec 4 = PCO2 dec 10
179
Mixed acid base disorders
- if PCO2 and bicarb in opposite directions --> mixed disorder
- metabolic acidosis + metabolic alkalosis
- - presence of large inc in AG that is out of proportion to dec in bicarb seen in metabolic acidosis (e.g. AG = 50 and bicarb = 15)
- - some other process that is getting rid of H (probably vomiting)
180
What is the clinical approach to acid base disturbances?
1) is it acidemia or alkalemia? (look at pH)
2) is it respiratory of metabolic? (look at PCO2 and bicarb)
3) if resp, is it acute or chronic? (compare pH with expected)
4) if metabolic, is AG or nonAG? (AG=Na-Cl-bicarb)
4a) if nonAG, what is urine AG (UNa+UK-UCl)
4b) is resp compensation adequate? (winter's or .25to1)
5) other acid/base metabolic disturbances? (delta/delta rule --> deltaHCO3/deltaAG = 1 if no other metabolic disturbances; if >1 then something else causing bicarb consumption and additional metabolic acidosis; if less than 1 then underlying metabolic alkalosis to start with)
181
Describe the effects of diuretics on Ca2+ metabolism and, where possible, describe the mechanisms causing these effects.
- loop diuretics dec plasma Ca
| - thiazides inc plasma Ca
182
Identify the factors that regulate blood pressure and know the definition of hypertension.
- BP = CO * PVR
- CO is affected by inotropy of heart, HR, filling pressure
- PVR is affected by SNS and PNS activity, blood volume/viscosity, heart function
183
What is the mechanism of action of Mannitol?
- induce diuresis by elevating osmolarity of glomerular filtrate --> hinder reabs of H2O
- inc excretion of H2O, Na, and Cl
- mannitol is not metabolized and not reabs in PT
184
What are the pharmacokinetics of Mannitol?
- IV
- distributes in ECF
- excreted by glomerular filtration
185
What are the uses of Mannitol?
- prevent AKI secondary to vascular surgery
- glaucoma (dec IOP)
- cerebral edema (dec ICP)
- preserve renal function in rhabdomyolysis
186
What are adverse effects of Mannitol?
- acute inc in ECF
- nausea, headache
- prolonged use --> H2O loss and hypernatremia
- HF
187
What is the mechanism of action of Acetazolamide?
- carbonic anhydrase inhibitor --> inhibit regeneration/reabs of bicarb in PT --> excrete bicarb --> alkaline diuresis
- basically induce a metabolic acidosis
188
What are the pharmacokinetics of Acetazolamide?
- oral
- 90% bound by plasma proteins
- not metabolized
- excreted by glomerular filtration
- PT secretion
- 1/2 life 5hrs
189
What are the uses of Acetazolamide?
- NOT as diuretic
- NOT in HF
- glaucoma
- metabolic alkalosis
- mountain sickness
190
What are the adverse effects of Acetazolamide?
- metabolic acidosis
- fatigue
- CNS depression
- paresthesias
191
What is the mechanism of action of Furosemide?
- inhibit Na/K/2Cl transporter in ALOH --> excrete Na and K and Cl --> dec Na reabs
- dec tonicity of interstitium --> dec reabs of H2O in CD
- dec Mg and Ca
192
What are the pharmacokinetics of Furosemide?
- oral or IV
- rapid onset
- metabolized and renally excreted
193
What are the uses of Furosemide?
- HTN
- CV or pulm edema
- hypercalcemia
- CHF
194
What are the adverse effects of Furosemide?
- hypokalemia
- metabolic alkalosis (hypokalemia --> shift K out of cell --> H into cell and secreted)
- ototoxicity/deafness
- uric acid retention --> gout
195
What is the mechanism of action of thiazide diuretics?
- Na/Cl contransporter in DT inhibited --> diuresis of about 5% of filtered Na
- initial diuresis senses that high filtered load of Na reaching distal tubule --> inc in renin and aldosterone activation --> reabs Na and secrete K
- weaker diuretic than loop diuretics
196
What are the pharmacokinetics of thiazides?
- oral
- secrete in PT
- not metabolized
- excreted by glomerular filtration and secretion
- renal excretion
197
What are the uses of thiazides?
- HTN
- edema
- CHF
- hypercalcuria
198
What are adverse effects of thiazides?
- hyperuricemia --> gout
- hypokalemia
- 2ndary hyperaldosteronism
- hyperglycemia
- hyperlipidemia
- hypercalcemia
199
What is the mechanism of action of spironolactone?
- antagonist of aldosterone
| - competitive binding of receptors at Na/K exchanger in CT --> dec reabs of Na and excretion of K
200
What are the pharmacokinetics of spironolactone?
- oral
- metabolized to active metabolite canrenone
- renal and biliary excretion
- slow onset
- long half life
201
What are the uses of spironolactone?
- resistant HTN
- HF
- hyperaldosteronism
202
What are the adverse effects of spironolactone?
- hyperkalemia
- gynecomastia (switch to epleronone)
- amenorrhea
203
What is the mechanism of action of Na channel blockers (triamterone, amiloride)
- block luminal Na channels in DT/CD
- dec Na reabs and H2O reabs
- dec driving force for K and H secretion
204
What are the pharmacokinetics of Na channel blockers?
- oral
- secreted as organic bases
- metabolized in liver and renal and biliary excretion
205
What are the uses of Na channel blockers
- weak diuretic
| - use with other diuretics
206
What are adverse effects of Na channel blockers?
- hyperkalemia
- hyperuricemia
- glucose intolerance in DM
207
What is the mechanism of action of ACE inhibitors (-pril)
- inhibits conversion of AT1 to AT2 --> prevents AT2 mediated vasoconstriction and stimulation of aldosterone release
- blocks degradation of bradykinin --> causes cough; causes vasodilation
208
What are the pharmacokinetics of ACEIs?
- less than 1hr to onset
- oral
- most renally excreted
209
What are the adverse effects of ACEIs?
- cough
- hyperkalemia
- contraind in pregnancy
210
What are the uses of ACEIs?
- HTN
- HF
- CKD
- diabetic nephropathy
- polycythemia
211
What is the mechanism of action of ARBs? (-sartan)
- block AT2 action on AT receptor --> prevents AT2 mediated vasoconstriction and aldosterone release
212
What are the adverse effects of ARBs?
- hyperkalemia
| - contraind in pregnancy
213
What are the uses of ARBs?
- HTN
- HF
- CKD
- diabetic nephropathy
- polycythemia
- no cough/edema like in ACEI
- no bradykinin vasodilation
- more expensive
214
What is the mechanism of action of Ca Channel Blockers
- -dipines = DHP
- diltiazem and verapamil = NDHP
Mechanism of action:
- vasodilate and dec PVR by blocking L type Ca channels
- LTCC blockers inhibit influx of extracellular Ca through Ca channels --> loss of extracellular Ca influx inhibits phosphodiesterase --> inc GMP --> inhibit smooth muscle contraction
- DHPs more selective to blocking LTCCs in blood vessels (mainly vascular)
- verapamil equal between cardiac and vascular LTCCs
- NDHP dec conduction through AV node and dec chronotropy and inotropy (mainly heart)
215
What are the pharmacokinetics of CCBs?
- readily absorbed
- metabolized by liver to inactive metabolites
- NDHP inhibit CYP3A4 (watch with statins, warfarin, amiodarone; more DDIs)
- prolonged half life
216
What are the adverse effects of CCBs?
- NDHP: nausea, headache, constipation, conduction defects
| - DHP: peripheral edema, reflex tachycardia, headache; AVOID USING NIFEDIPINE IN ARRHYTHMIAS b/c fast --> reflect tachy
217
What are the uses of CCBs?
- NDHP: HTN, migraine, angina, afib rate control
| - DHP: HTN, migraine
218
What is the mechanism of action for beta blockers?
- non-selective or selective for beta1 and beta2: block cardiac receptors to dec CO (dec HR and inotropy) and suppress renin activity
- selective for beta1, beta2, and alpha1 --> dec HR, inotropy, and also have vasodilation and dec renin activation
219
What are the pharmacokinetics of beta blockers?
- metoprolol and labetalol are excreted by liver
- atenolol is excreted by kidney
- start at low dose and uptitrate
220
What are adverse effects of beta blockers?
- fatigue
- negative inotropy --> hypotension, fluid retention
- bronchoconstriction
- dec sexual function
- hyperglycemia/lipidemia
221
What are the uses of beta blockers?
- HTN
- angina
- post MI/CAD
- HF
- migraine
222
What is the mechanism of action of direct vasodilators?
- peripheral vasodilation through relaxing vascular smooth muscle
- venodilators (nitroglycerin) --> dec preload,
- arterial dilators (hydralazine, minoxidil) --> release NO, open Na channels to hyperpolarize --> dec afterload
223
What are the adverse effects of direct vasodilators?
- hydralazine can have SLE-like symptoms
- minoxidil can cause reflex tachycardia, Na and H2O retention
- headache, anorexia, NVD
224
What are the uses of direct vasodilators?
- HTN
| - HF
225
What is the mechanism of action of alpha1 blockers?
- dec systemic vascular resistance
| - block alpha1 adrenergic receptors --> vasodilation
226
What are the adverse effects of alpha1 blockers
- orthostatic HTN
- headache
- peripheral edema
227
What are the uses of alpha1 blockers
- HTN
| - BPH
228
What is the mechanism of action of centrally acting agents?
- clonidine stimulates alpha2 adrenergic receptors --> vasodilation
- methyldopa is an alpha2 adrenergic agonist (but lots of adverse effects)
229
What are adverse effects of centrally acting agents?
- orthostatic HTN
- dry mouth
- sedation
- rebound HTN
230
What are the uses of centrally acting agents?
- HTN
- ADHD
- smoking cessation
- alcohol withdrawal
231
What is the general approach to HTN treatment?
1) loop diuretic + thiazide
2) add ACEI or ARB
3) spironolactone or epleronone
4) add other HTN drugs
232
What are drugs used for HTN crisis?
sodium nitroprusside
- NO donor --> smooth muscle relaxation
- arterial and venous dilation --> preload and afterload dec
- immediate onset
- can cause NVD, reflex tachy
nicardipine/clevidipine
- DHP blocker --> smooth muscle relaxation
- quick onset
- tachy, dizziness
fenoldopam
- peripheral dopamine agonist --> vasodilation
- quick onset
- reflex tachy
233
Identify the stages of CKD and the utility of this classification system
- purpose is to guide interventions and early detection
- progression occurs due to hyperfiltration injury
1) kidney damage, normal GFR >90 --> treat
2) kidney damage, GFR 60-90 --> estimate progression
3) GFR 30-60 --> treat complications
4) GFR 15-30 --> prepare for renal replacement therapy
5) GFR less than 15 --> kidney failure; dialysis or transplant
234
Describe how balance is maintained for Na, H2O, K, and H in CKD
Creatinine/urea
- excretion rates are constant but have diminished clearance
- concentration inc, GFR dec --> constant excretion
H2O
- fraction of H2O reabs dec --> inc flow per nephron --> hyperfiltration progression
- urine conc ability is limited (300mOsm) --> prone to water excess from dec H2O excretion (can only excrete 3L max compared to 12L with max dilution so holding onto water) and water deficiency because can't concentrate urine so need to excrete more water to keep BUN excretion constant (need at least 2L to concentrate urine compared to .5L, so losing water)
Na
- fraction of Na reabs dec, fraction excreted inc
- inc in Na intake --> edema
- dec in Na intake --> extrarenal losses/vol depletion
- dec GFR = inability to respond quickly to Na changes and have to excrete more to maintain same body Na
- see vol expansion, inc tubular flow rate --> hyperfiltration, natriuretic peptides
K
- inc K excretion/secretion due to dec GFR --> inc CCT excretion/secretion
- inc tubular flow --> inc solute load per nephron --> inc Na delivery --> inc aldosterone --> inc K excretion
H
- kidneys make more NH4 to balance acid up to a point (GFR ~20) --> H accumulates and is retained --> dec bicarb --> nonAG metabolic acidosis
Ca and P
- dec GFR --> inc Pi --> inc FGF23 --> dec 1,25 vitamin D --> dec Ca and inc Pi --> inc PTH --> inc Ca and dec Pi --> osteitis fibrosa
235
Define the definition of uremic syndrome and the major theories of the pathogenesis of uremia
- retention of toxins that are normally excreted in urine
- inc PTH du to dec Ca, dec EPO, dec 1,25 vit D --> bone disease and 2ndary hyperparathyroidism
- leads to anemia (dec EPO, dec RBC lifespan, marrow fibrosis, dec Fe absorption, bloodloss), pericarditis, HTN (inc volume, inc RAAS, dec baroreceptor sensitivity, dec vasodilators), hyperphosphatemia, hypocalcemia, 2ndary hyperparathyroidism, osteomalacia, pruritus, difficulty concentrating, glucose intolerance
- retained nitrogenous products?
236
Identify the most important management principles of CKD
- treat the HTN with ACEI or ARBs
- maintain serum Pi with diet counseling and phosphate binders
- treat uremia with dialysis or transplantation
237
What is the definition of chronic kidney disease?
- permanent reduction in GFR
| - symptoms do not occur until about GFR less that 15
238
What are the most common causes of CKD?
- diabetic nephropathy*
- HTN nephrosclerosis & renal vascular disease
- GN
- PCKD
- interstitial nephritis
- obstruction
239
What are the clinical features of uremia?-
Anemia
- dec EPO production
- RBC survival is shortened due to toxins in blood
- blood loss due to abnormal coagulation and dec platelet function
- marrow space fibrosis with osteitis fibrosa of secondary hyperparathyroidism
Hypertension
- in ECF volume due to inability to excrete Na
- inc RAAS
- dysfunction of ANS --> insensitive baroreceptors and inc symp tone
- dec vasodilators; dec renal production of PGs or bradykinin
Ca and P metabolism
- dec GFR --> inc Pi --> inc FGF23 --> dec 1,25 vit D --> dec Ca and inc Pi --> inc PTH to inc Ca and dec Pi --> bone destruction
240
Recognize the indications for starting dialysis
- goals are to remove toxins that are normally cleared by kidney and to maintain euvolemia
- start if life-threatening conditions like severe hyperkalemia, severe vol overload, uremic pericarditis
- if mild cognitive changes due to uremia then consider dialysis if proper access; if no access, then benefits weighed against risk of catheter infection
- no specific GFR that mandates dialysis
- no difference between starting dialysis early or late (better or worsened GFR)
- if reduced life expectancy, dialysis may worsen chances of living
241
Describe the different modalities of dialysis
Hemodialysis
- most common
- at outpatient or at home
- 3x/week; 3-4hrs/session at hospital
- 5-6x/week; shorter sessions at home
- can do longer sessions at night
- blood leaves fistula/catheter and enters a tube with a semi-permeable membrane
- outside of tube is dialysate; solutes in blood move into dialysate (low conc) by diffusion down conc gradient and then returned to body
- can remove fluid by applying positive pressure to blood compartment
- preferred access through AV fistula: anastomose artery to vein; usually in nondom arm; take time to mature and grow muscle to take multiple injections;
- can have AV grafts but have higher infection risk and can get blocked more easily
- dual lumen catheters in internal jugular vein but have high infection rate
- pros: fairly quick, fluid control
- cons: large volumes of fluid to remove, can't remove large molecules or solutes that are protein bound
- complications: infections with gram neg (staph aureus), hypotension, angina, ischemia
Peritoneal dialysis
- rarer than hemodialysis, but common worldwide
- catheter in peritoneal cavity
- dialysate infused into peritoneal cavity with high dextrose conc --> high oncotic pressure --> fluid moves from bloodstream to peritoneal cavity
- drain peritoneal cavity
- cont ambulatory peritoneal dialysis is manual and 3-4x daily
- cont cycling peritoneal dialysis is automated and many times overnight
- lower cost, no need for vascular access, easier to do at home and manage on your own
- can cause hernias, infectious peritonitis
242
Discuss the complications of dialysis
- dialysis does not fully replace kidneys
- mortality rate >20% in first year and 50% after 5yrs
- usually die from CV disease and infections
- frequent dialysis, beta blockers, ACEIs may improve mortality
243
Discuss the risks and benefits of undergoing kidney transplantation vs. dialysis
- comorbidities with dialysis: advanced age, diabetes, CAD, COPD, cancer
- transplant improves long term patient survival vs. dialysis but not to that of general population
- higher mortality shortly after transplantation due to surgery and immunosuppression, but long term survival benefit
- better QOL and less expensive
244
Discuss the role of the human HLA system in kidney transplantation
- donor HLA antigens will be recognized by recipients immune system as non-self --> immune response/rejection unless immunosuppressed
- basically have HLA antigens that present peptides to T cells
- T cells recognize donor HLA antigens on donor APCs or host APCs --> activate T cells --> cytotoxic T cells and Th1 response with delayed type hypersensitivity --> B cell activation
- 6/6 HLA match vs 0/6 HLA match improves long term survival but doesn't change acute rejection
245
Describe the main classes of immunosuppression utilized in clinical kidney transplantation
- standard is triple therapy with a calcineurin inhibitor, a proliferation signal inhibitor, and prednisone
- side effects are inc risk of infection and malignancy and potential toxicity
Calcineurin inhibitors:
- cyclosporine and tacrolimus (prograf)
- can cause nephrotoxicity, HTN, DM
- inhibits T cell receptor activation
Proliferation inhibitors
1) mycophenolate mofetil
- inhibit purine synth
- GI and heme problems
2) mTOR inhibitors
- inhibit mTOR proliferation signaling
- nephrotoxicity
- cytopenias
Prednisone
- immunosuppression
- HTN, hyperlipidemia, weight gain
246
Describe the basic approach to kidney transplant AKI
- pre, intra, post-renal azotemias
- surgical, immunological, infectious complications
Pre-renal
- vol depletion from post-op fluid shifts and blood loss
- thrombosis of renal artery or vein
- calcineurin inhibitor effects on AA
Post-renal
- transplant ureter obstruction due to fluid collection (lymph or blood)
- urine leak from break down of transplant ureter; Cr inc due to absorption through peritoneal membrane
Intra-renal
- FSGS, MPGN2, atypical HUS, membranous nephropathy, IgA nephropathy, SLE, diabetic nephropathy
- infection: UTI and pyelonephritis
- CMV and BK virus
- rejection: T-cell --> tubular inflammation; B-cell --> peritubular capillary and glomerular inflammation
Steps:
1) history and PE: focus on hemodynamic events and findings (NVD, volume status)
2) imaging and lab: US for obstruction or fluid collection; calcineurin inhibitor level; UA for infection/proteinuria; bacterial/virus or antibodies against donor HLA antigens
3) renal transplant biopsy
247
Describe how the pathophysiological changes that occur in chronic kidney disease (CKD) can alter the pharmacokinetic disposition of, and the pharmacodynamic response to, drugs administered to CKD patients.
Absorption
- GI problems can have an effects on bioavailability
- lots of drugs taken by a CKD patient --> potential for DDIs
- esp with phosphate binders and bile acid sequestrants --> reduce bioavailability by binding drugs
Distribution
- inc in levels of free unbound drug and Cp
- DOSE/Vd = Cp
- Vd is smaller in CKD patients because of dec tissue binding
- greater levels of free phenytoin and greater ability to distribute outside of the plasma and greater potential for toxicity
Elimination
- MD/T = Cpss*CL
- insulin metabolism dec in CKD
- hepatic metabolism leads to active metabolites and can accumulate in CKD
- renal excretion dec in CKD and half life inc --> dosage adjustments
- C-G equation for CLCr to assess kidney function
CLCr = [(140-age)*body weight]/SCr * 72
- dosing changes not really required until GFR less than 50 so stage 1 and 2 CKD don't need a change in maintenance dose
- thiazides have dec efficacy in CKD because less reaches site of action in nephron
- need to use thiazide and loop diuretic
248
Describe changes in the pharmacotherapeutic regimen that may be necessary to manage changes in plasma drug levels and drug response that occur as a result of these alterations in pharmacokinetics and pharmacodynamics in CKD patients.
- slow progression of CKD by treating diabetes, HTN, and hyperlipidemias
Diabetes
- glyburine: 1/2 life inc
- metformin: use NOT recommended if SCr > 1.5
- insulin: 1/2 life inc
HTN
- thiazides may lose efficacy
- avoid K sparing diuretics
- ACEI/ARB: used in all stages, monitor for hyperkalemia, may cause ARF
- BBs: atenolol 1/2 life inc
Hyperlipidemia
- fibrates: gemfibrozil recommended for stage 5
249
Relate the pathophysiological changes in CKD that result in anemia, renal osteodystrophy, and hyperkalemia TO the pharmacologic strategies that are used in their management.
Anemia
- kidney function dec --> EPO production dec --> anemia
a) Epoetin and darbepoeitn
- MOA: glycoproteins with recomb DNA identical to EPO
- PK: given parenterally every week or two weeks
- SE: HTN maybe
b) Fe supplement
- MOA: Fe for production of Hb
- PK: oral, poor absorption, IV better
- SE: constipation, nausea, abd pain, hypotension, headaches
- DDI: absorption dec by Ca and drugs that inc gastric pH
Renal Osteodystrophy
- dec kidney function --> dec Pi eliminary --> inc Pi --> inc FGF23 --> dec 1,25 vit d --> dec Ca --> inc PTH --> bone destruction
a) phosphate binders
- Ca compounds
- MOA: bind Pi in GI tract to form insoluble Mg, Ca, or Al phosphate --> excreted --> dec Pi absorption and serum levels
- PK: orally with meals
- SE: GI - constipation, diarrhea, nausea, vomiting, abd pain, hypercalcemia, hyperphosphatemia, CNS toxicity
b) vitamin D compounds
- calcitriol (1,25 dihydroxy vit D)
- MOA: suppress PTH secretion by stimulating Ca absorption
- PK: oral and IV
- SE: hypercalcemia and hyperphosphatemia
- DDI: absorption dec with cholestyramine
c) calcimimetics
- alternative to vit D if hypercalcemic
- MOA: bind to Ca sensing receptors on parathyroid cells --> inc sensitivity to plasma Ca levels --> dec release of PTH
- PK: orally, metab by CYP450
- SE: hypocalcemia
- DDI: inhibitors of CYP2D6
Hyperkalemia
- failing kidney cannot excrete enough K
- there are drugs that cause hyperkalemia like K sparing diuretics (spironolactone, amiloride); ACE/ARBs; digoxin
- treat with CBIG K
- acutely (Ca gluconate, Na bicarb, beta agonists (albuterol), insulin + glucose)
- MOA: shift K into cell to be excreted
- use kayexalate for chronic
- MOA: cation resin that binds K for Na in intestines
- PK: oral and rectal
- SE: constipation, NV
250
What dilate and constrict the AA?
Dilate (inc GFR, inc RBF):
- NO, PG (endogenous)
- dopamine (renal protective by inc RBF)
- caffeine blocks adenosine; also diuretic effect
Constrict (dec GFR, dec RBF):
- AT2, NE (blocked by dopamine)
- NSAIDs
251
What dilate and constrict the EA?
Dilate (dec GFR, inc RBF):
- nothing endogenous
- ACEI/ARBs
Constrict (inc GFR, dec RBF)
- AT2
- NE
252
Describe the pathogenesis of UTI in terms of routes of infection, organism virulence factors, host defense mechanisms, predisposing factors, clinical manifestations, and complications
- UTIs mostly remain confined to lower urinary tract (bladder and urethra) and may involve upper UT (ureter, pelvis, kidney)
Routes of infection:
- ascending: most common; fecal flora; e coli; proteus, klebsiella, enterobacter
- blood borne: less common; sepsis or endocarditis; usually with ureteral obstruction, IS therapy; non-enteric bacteria (staph, fungi, viruses)
Virulence factors:
- bacterial adhesion: adhesive molecules on pili
- O antigens
- endotoxin (dec ureteric peristalsis)
Host defense mechanisms:
- mechanical (hydrokinetic): bladder emptying/urine flow, ureteric peristalsis
- chemical (urine): antibx prostatic secretions, urine osmolality/pH, ammonia
- inc UTI risk with P1 strains of blood group Ags
- immunological: IgA, complement
- cellular: PMNs, shedding urothelial cells
Predisposing factors:
- females: shorter urethra, lack of prostatic fluid, urethral trauma
- pregnancy
- diabetes
- instrumentation
- stasis: obstruction, etc.
- vesicoureteral reflux
- immune compromise
- kidney/UT disease
Clinical manifestations:
- bacteriuria, symptomatic UTI, lab findings
Complications:
- acute pyelonephritis, perinephric abscess, scarring, recurrence, stones
253
Compare and contrast the features and pathogenesis of the 2 major causes of chronic pyelonephritis (UT obstruction and vesicoureteral reflux)
UT obstruction
- causes (intrinsic, extrinsic)
- intrinsic: tumors of UT, calculi, clots
- stricture
- extrinsic: pelvic, retroperitoneal tumors, fibrosis, hemorrhage
- obst predisposes to infection and recurrence; interferes with eradication;
- obst + infection = chronic pyelonephritis
- inc pressure, inflammation, ischemia, injury
- consequences; hydronephrosis, hydroureter, infection, chronic obst PN, RF, HTN
- clinical manifestations: acute PN (fever, malaise, NV, abd pain); lower UT infection (dysuria, frequency, hematuria); pyelonephrosis or perinephric abscess (rigors, pain, scoliosis, swelling, weight loss, night sweats)
Vesicoureteral reflux
- retrograde flow of urine from bladder into ureter and renal pelvis during micturition
- reflux nephropathy
- no valve at ureterovesicle junction
- compressed when intravesicle pressure inc
- enter perpendicularly and functionality is lost
- congenital abnormality; common in infants
- spontaneous remission
- polar scarring
Recurrent infections w/o obstruction, reflux or some other underlying UT disease (stones, DM) rarely if ever cause pyelonephritis
254
Nephrolithiasis
- males > females
- hypercalcemia, inc uric acid, low pH, dec vol, bacteria = predisp factors
- can occur in tubules, calices, pelvis, UB
- struvite: bacterial infection (proteus/staph) convert urea to ammonia --> alkaline urine
- staghorn calculus --> alkalotic urine; chronic obst PN; gross irreg scarred atrophied tubules with chronic inflam and acute inflam; casts in tubules
255
List the incidence, gross and microscopic features of Renal Papillary Adenoma
- benign
- well circumscribed in cortex
- small (5mm diameter)
- surgically removed
256
For clear cell carcinoma list their: incidence, clinical features, imaging features, gross pathology, microscopic pathology
Incidence:
- 70-80% of all RCCs
- M>F
Clinical features:
- hematuria
- renal mass on imaging
- renal cortex, invade renal vein and up IVC into heart
- enlarged lymph nodes
- hematogenous spread to lungs
Imaging:
- mass in renal cortex
Gross pathology:
- usually single tumor, spherical, yellow gray mass, focal hemorrhage, 20% are cystic
Histology:
- 3 cell types: clear, granular, and spindle
Genetics:
- VHL gene encodes a protein that is part of ubiquitin ligase complex
- most cases are sporadic
Prognosis:
- 5yr survival rate is 45-70% if no metastases
- if renal vein or fat involvement, then 15-20%
- treat with nephrectomy, maybe partial nephrectomy
257
Describe the basic genetic differences between spontaneous and familial renal tumors
- uhh one is spontaneous and the other is familial/genetic idk
258
Describe the gross and histologic findings of transitional cell carcinoma
Incidence:
- 80% of patients b/w 50-80yo
- M>F
- smokers
Clinical:
- >90% of tumors in UT
- hematuria, irritative bladder symptoms like dysuria, frequency, urgency
- may arise from calyces, pelvis, ureters, bladder, urethra, or urothelium lined ducts in prostate
- can extend to pelvic sidewalls and metastasize to lungs, bones, and liver
- obstruction can lead to hydronephrosis
Imaging:
- filling defects in UT
Pathology:
- vary from purely papillary to nodular or flat
- noninvasive or invasive tumors involving lamina propria, muscularis propria, peri-cystic fat tissue, or other organs
- papillary lesions are red, elevated excrescences with varied size 1cm-5cm
- may have multiple separate tumors
- benign papilloma to highly aggressive
- majority are low grade
- arise from later or posterior walls at bladder base usually
- treat with BCG, electrocautery, surgery
259
incidence, gross and microscopic features of Angiomyolipoma
- vessels
- smooth muscle
- fat
- tuberous sclerosis
260
incidence, gross and microscopic features of Oncocytoma
- eosinophilic epithelial cells
- lots of mitochondria
- within family groups usually
261
For papillary carcinoma list their: incidence, clinical features, imaging features, gross pathology, microscopic pathology
Incidence:
- 10-15% of RCC
Clinical features:
-
Imaging:
Gross pathology:
- frequently multifocal
Histology:
- papillary growth pattern
Genetics:
- familial and sporadic
- trisomy 7, 16, 17
Prognosis:
- better than clear cell RCC
262
For chromophobe carcinoma list their: incidence, clinical features, imaging features, gross pathology, microscopic pathology
Incidence:
- 5% of RCCs
Clinical features:
Imaging:
Gross pathology:
- cells with prominent cell membranes and pale eosinophilic cytoplasm
- halo around nucleus
Histology:
- difficult to distinguish from oncocytoma
Genetics:
- multiple chr losses and extreme hypodiploidy
- intercalated cells of CDs
Prognosis:
- excellent
263
For collecting/bellini duct carcinoma list their: incidence, clinical features, imaging features, gross pathology, microscopic pathology
Incidence:
- 1% of renal neoplasms
Clinical features:
Imaging:
Gross pathology:
- nests of malignant cells enmeshed w/in a prominent fibrotic stroma
- medullary
Histology:
Genetics:
Prognosis:
- aggressive and poor
264
For familial RCC list their: incidence, clinical features, imaging features, gross pathology, microscopic pathology
Incidence:
- 4%
Clinical features:
- VHL syndrome
- - hemangioblastomas of cerebellum and retins
- - develop renal cysts and bilateral, multiple RCCs
- hereditary familial clear cell carcinoma
- - confined to kidney
- hereditary papillary carcinoma
- - AD
- - multiple bilateral tumors
- - papillary histology
265
Define the two primary functions of the urinary bladder.
idk store urine i guess
266
Detail the parasympathetic and sympathetic innervation to the lower urinary tract.
PNS
- innervate the detrusor muscle --> activation = detrusor muscle contraction and leads to urination
- pelvic nerves from S2-S4 go to detrusor muscle
SNS
- activations of SNS inhibits detrusor contraction and inc tension in smooth muscle of bladder neck and proximal urethra --> prevent urination until PNS activation
- T10-L2 hypogastric nerve goes to detrusor and smooth muscle
Motor (somatic) innervation
- bladder, pelvic floor, urethral sphincter
- sense bladder fullness
- S2-S4 pudendal nerve goes to external rhabdosphincter
267
Describe the micturition cycle.
1) inc in wall tension of bladder
- pressure in bladder inc and cannot tolerate anymore
2) afferent input overcomes pontine micturition center threshold and provides cortical egress micturition begins
3) pudendal nerve activity ceases --> external sphincter relaxes --> detrusor neurons are non-inhibited and activated
4) proximal urethra opens
5) bladder contracts
268
Categorize the types of urinary incontinence.
Overflow incontinence
- overactive outflow dysfunction
- underactive bladder dysfunction
* *Stress incontinence
- underactive outflow dysfunction
- involuntary sudden loss of urine during inc in abd pressure (physical stress) like laughing, sneezing, coughing, exercising
* *Urge incontinence
- overactive bladder dysfunction
269
Compare/contrast the causes of incontinence in men and women.
- stress incontinence common in women
- pelvic muscle strain
- childbirth
- pelvic muscle tone loss
- estrogen loss/menopause
- in men, due to prostatectomy, radiation, neurogenic
270
Discuss the common causes of lower urinary tract obstruction in men.
- BPH most often
- prostate/bladder cancer
- stricture after surgery
271
Describe lesions to NS and the effect it has on micturition
cortical/brainstem lesion --> hyperactive detrusor; normal external sphincter --> incontinence
spinal cord injury --> hyperactive detrusor; hyperactive external sphincter --> dyssinergia
OAB --> hyperactive detrusor; normal external sphincter --> OAB
sacral cord, nerve root, nerve lesion --> complete areflexia of detrusor; normal/hyper external sphincter --> inability to void
272
Describe the early stages of development of the kidney: the position of the urogenital ridge, the nephrogenic cord, the formation of the nephrotomes, and the origin of the pronephric/mesonephric duct
- pronephros (3-4wks)
- mesonephros (4-8wks)
- metanephros (5wks-maturity)
- initially form from nephrogenic cord within urogenital ridge (tisse running laterally and ventrally to the dorsal aorta lengthwise along coelom of embryo)
- starts out as mesodermal cells along length of nephrogenic cord --> group into nephrotomes within each somite which form a duct
273
Outline the temporal and spatial relationships of the pronephros, the mesonephros, the mesonephric (Wolffian) duct, the paramesonephric (Mullerian) duct, and the metanephros
- pronephros degenerates at about 4wks
- at 5wks, have mesonephric duct and paramesonephric duct coming off of cloaca
- 6wks have formation of collecting tubules and malphigian pyramids
- 10-11wks have formation of metanephric tubules and rest of nephron
274
Describe the development of the collecting system from the ureteric bud through various stages until the appearance of collecting tubules
a) ureteric bud
- starts out as bud of epithelial cells pouching out from the mesonephric duct
- it is enveloped by the metanephric blastema
b) collecting ducts and tubules
- bud branches into calcyces and forms primitive collecting ducts as these finger like projections in groups called Malphigian pyramids
275
Describe the location and development of the metanephric vesicles and their elongation to form metanephric tubules. Be able to detail the relationship of the ends of these tubules with the collecting system and with the glomerulus and to describe the portions of the nephron derived from regions of the metanephric tubules
a) ureteric bud
- starts out as bud of epithelial cells pouching out from the mesonephric duct
- it is enveloped by the metanephric blastema
b) collecting ducts and tubules
- bud branches into calcyces and forms primitive collecting ducts as these finger like projections in groups called Malphigian pyramids
c) glomeruli and rest of nephron (10-11wks)
- metanephric spheroid induced to differentiate at tip of collecting tubules
- they become metanephric vesicles
- they elongate and form an S shape called metanephric tubules
- these form the rest of the nephron
- collecting tubule merges with end and the other end envelopes glomerular capillaries
-
276
Outline the formation of the urogenital sinus and describe its development to the bladder and urethra. What happens to the allantois and cloaca of the early embryo?
- have allantois forming cloaca
- have mesonephric duct with ureteric bud, paramesonephric duct, and then hindgut
- hindgut becomes its own thing
- urogenital sinus in same area with allantois and paramesonephric duct
- have ureter, mesonephric duct, then paramesonephric duct coming off of primitive bladder then hindgut doin its thang
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Describe the ascent of the kidney. Know the resultant structures that the Wolffian and Mullerian ducts give rise to in males and females respectively
- mesonephric duct becomes a part of epidydimis and ductus deferens in males and degenerates in females
- mullerian duct becomes oviducts and uterus in females but degenerates in males
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Be aware, although the specific molecular mechanisms of inductive processes will not be discussed in classes, that kidney development involves a complex series of mutual mesodermal inductive events and that mutations in molecules involved in these processes can have profound effects on kidney development, several effects of which can be observed clinically in neonates
k
279
Define hydronephrosis,
Hydronephrosis
| - dilation of the renal pelvis by accumulated urine due to obstruction
280
Discuss the pathophysiologic events and consequences of UT obstruction in the fetus
- fetus swallows amniotic fluid and produces urine
- if urine production is diminished, then have less amniotic fluid and that can be detrimental to development
Potter syndrome
- UT obstruction --> dec amniotic fluid --> pulm hypoplasia, deformation of face and limbs, placental amnion nodosum (nodules on fetus due to dec conc of amniotic fluid)
Prune belly (eagle barrett syndrome)
- male with thin abd wall with megalocystis and tortuous, dilated ureters
- dilated Ut may cause pressure atrophy of abd wall
- lack of descent of testicles because urinary bladder blocking them
- can have pulm hypoplasia with oligohydramnios
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Ureteropelvic junction obstruction
Ureteropelvic junction obstruction
- *most common cause of pediatric hydronephrosis
- *M>F
- left>right; bilateral
- due to incomplete canalization of ureteric bud a 12wks gestations or local abnormality of smooth muscle fibers and inc fibrosis --> impeding peristalsis
- presents with abd mass, pain, UTI
- *usually with other congenital abnormalities
- surgically repaired
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, hydroureter,
Hydroureter
| - dilation of the ureter by accumulated urine due to obstruction
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reflux
Reflux
| - backflow of urine up the UT upon contraction of the detrusor muscle during micturition
284
, and megalocystis
Megalocystis
| - abnormal distention of the bladder by urine due to bladder outlet obstruction
285
Ureteral duplication
- *most common renal abnormality
- *F>M
- 2 ureters ipsilaterally enter bladder
- *propensity for vesicoureteral reflux into lower pole and obstruction of upper pole
- *may end in ureterocoele
- *signs include failure to potty train and continuous drop incontinence
286
Ureterocoele
- *a cystic dilation of the terminal intravesical (portion within the bladder wall) ureter
- ectopic ureterocoele is at the bladder neck or urethra
- *70% ectopic, 80% with upper pole ureter
- can be obstructive is stenotic; can cause reflux
- *diagnosed prenatally with hydronephrosis or UTI or prolapse through urethra causing bladder outlet obstruction
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Urachal remnant
- *urachus connects dome of fetal bladder to allantois in umbilical cord
- *normally forms median umbilical ligament
- *signs are pain and retraction of umbilicus during micturition
- cyst forms 30% of time between umbilicus and suprapubic area
- *sinus or fistula leads to drainage of clear or purulent urine at umbilicus; sometimes UTI
- *can form a polyp
288
Posterior urethral valves
- *congenital obstructing membrane in posterior male urethra
- abnormal insertion of mesonephric duct on cloaca prior to dividing into urogenital sinus and rectal canal
- *abnormal development of upstream structures due to inc intraluminal pressure
- most common cause of bladder outlet obstruction in boys
- *presents with anuria or bladder distention prenatally
- *poor urine stream, UTI, or incontinence when older
289
Hypospadias
- *orifice of penile urethra is along ventral aspect of penis instead of tip
- *due to abnormal fusion of urogenital folds in males
290
Chordee
- *fibrous band causing the penis to curve
| - usually with hypospaidus or epispadius
291
Epispadius
- *urethral opening on dorsal aspect of penis
292
Exstrophy
- exposure of bladder mucosa due to absence of abd wall
293
Renal agenesis/aplasia
- usually left kidney affected
- opposite kidney gets larger/hypertrophies to compensate
- if bilateral, incompatible with life
- usually due to ureteric bud not forming
294
Renal hypoplasia
- underdevelopment of a kidney with contralateral compensatory hypertrophy
295
Renal dysplasia
- abnormal metanephric tissue differentiation of the kidney tissue with cysts and hetertropic tissues such as cartilage due to pleuripotent potential of renal anlage
296
Renal ectopia
- *failure of kidney to rise out of the pelvis or to rotate medially
- may cause ureteral obstruction
- kidneys are discoid or flat
297
Horseshoe kidney
- *kidneys are fused at lower pole
- ectopic and fail to rotate medially
- *inc incidence of urolithiasis
298
What are the 3 cystic kidney diseases?
1) simple cysts
2) medullary sponge kidney
3) acquired renal cystic disease
299
Simple cysts
- *most common renal lesion
- 1/4 by 50yo
- usually asymptomatic, may be up to a few cm large
300
Medullary sponge kidney
- 20% of patients with nephrolithiasis
- *normal sized kidneys with enlarged and pale renal pyramid(s)
- bilateral 70% of the time
- *1-3mm cysts are dilated collecting ducts lined by cuboidal or flattened epithelium in papillary portions of the pyramids
301
Acquired renal cystic disease
- *occurs in ESRD patients
- *inc #, size, incidence of cysts with duration of dialysis
- *M>F
- usually asymptomatic, but hematuria, flank pain, renal colic, palpable renal mass possible
- *cortical cysts with clear fluid
302
ADPKD
- autosomal dominant polycystic kidney disease
- *mutations in PDK1 (90%) and PKD2 --> encode polycystin
- *25% have no family history
- *100% penetrance with large cysts
- *bilaterally enlarged kidneys with multiple cysts throughout medulla and cortex and clear hemorrhagic fluid
- hepatic cysts common with age
- also see mitral valve prolapse, diverticulosis, cerebral aneurysms, pancreatic cysts
- *presents in 40s with chronic flank pain and intermittent hematuria
- *HTN CKD in 50s
- *some progress to ESRD in 60s
- 10% of all ESRD cases
303
ARPKD
- autosomal recessive polycystic kidney disease
- *PKHD1 --> encodes fibrocystin
- kidneys are enlarged, but still maintain normal shape
- kidneys may be much larger in neonates
- radial cysts are less than 3mm in diameter and extend from papillary tips to surface of the cortex
- *cysts are dilated collecting tubules lined by cuboidal epithelium
- *liver is enlarged with bile duct proliferation and congenital hepatic fibrosis (periportal fibrosis); always there*
- *HTN in first few years of life, dec urine conc ability, renal insuff
- growth retardation
- can progress to renal failure; 5% of ESRD cases
304
Nephronophthisis-medullary cystic kidney disease complex
- *autosomal recessive
- *most common genetic cause of ESRD in first 20yrs
- 5-15% of ESRD cases
- *bilateral small kidneys with cortical atrophy; thick, pitted, granular, capsular surface
- spherical cysts in corticomedullary junction
- 25% do not have cysts
- cysts lined by single layers of cuboidal epithelium and thickened BM
305
Von Hippel Lindau
- mutation in VHL gene
- *retinal and cerebellar hemangioblastomas, pheochromocytomas, RCC in 40% of patients
- 2/3 have renal cysts, and pancreatic, hepatic, and epididymal cysts
- *renal cysts with glycogen rich cells bilaterally in 75% of patients
306
Tuberous sclerosis
- mutations in TSC1 and TSC2
- *facial nevi, cardiac rhabdomyomas, epilepsy, angiofibromas, mental retardation, multiple renal angiomyolipomas
- renal cysts in 25%
- varied size of cysts; lined by eosinophilic cells and large, hyperchromatic nuclei
307
Multicystic dysplasia of the kidney (MCDK)
- *most common cause of abd mass in newborn period
- most common cystic malformation of kidney in infancy
- ureteral or ureteropelvic atresia
- *nonfunctional and involuted kidney
- usually asymptomatic
- *kidney is abnormally shaped; looks like a bunch of grapes
- primitive epithelial ducts and nests of metaplastic cartilage and fibrovascular structures
- abnormal induction of metanephric blastema by ureteric bud
308
Congenital mesoblastic nephroma
- *most common kidney tumor from birth to 6mos
- *ring sign on prenatal sonogram
- solitary firm round infiltrating fibrous mass made of bland spindle cells
- benign if resected, but aggressive variant exists
309
Wilms tumor (nephroblastoma)
- *most common malignant kidney tumor of childhood (80% of pediatric renal tumors)
- *presents b/w 4-6yo as a solitary abdominal mass
- *claw sign on imaging
- *triphasic histology: stromal (fibroblastic), blasternal (small round blue cells), and epithelial (tubules)
- treat with resection and chemo
- *anaplasia (large, hyperchromatic nuclei and multipolar mitoses) means resistance to chemo
- *bilateral wilms tumor associated with beckwith-weidemann syndrome --> gigantism, macroglossia, exompalmos
- *WAGR --> wilms, aniridia, GU malformation, and mental retardation: deletion of PAX6 and WT1
