Pathophysiology: Renal

The Glomerulus ....................................................................................................................................................................... 2

The Tubules ............................................................................................................................................................................. 7
Sodium Balance ..................................................................................................................................................................... 11
Osmolality & Disorders of Sodium Concentration ................................................................................................................ 15
Disorders of Potassium Balance ............................................................................................................................................ 23
Acute Renal Failure ............................................................................................................................................................... 28
Metabolic Acidosis ................................................................................................................................................................ 33
Nephrolithiasis ...................................................................................................................................................................... 39
Metabolic Alkalosis ............................................................................................................................................................... 42
Chronic Kidney Disease ......................................................................................................................................................... 47
Pathogenesis of Hypertension .............................................................................................................................................. 52
Non-pharmacologic Treatment of Hypertension.................................................................................................................. 56
Management of End Stage Renal Disease ............................................................................................................................ 60
Genetic Renal Disease ........................................................................................................................................................... 62

1
 The Glomerulus
The Nephron (review)
1. Glomerular capillary network (capillary tuft)  By the numbers: the kidney
 625-700 mL/min plasma in to kidney
2. Bowman’s space 
 ≥ 90 ml/min fluid filtered (GFR)
3. PCT (proximal convoluted tubule) 
 180 L of glomerular ultrafiltrate made /day
4. Loop of Henle 
 1-1.5 million nephrons / kidney
5. DCT (distal convoluted tubule) 
 25-30 minutes: time it takes for the whole
6. Collecting duct plasma volume to be filtered at the glomeruli

The Glomerulus
Basic Idea: blood comes in via afferent arterioles; fluid filters out of capillaries, across epithelial
cells & filtration barrier, into Bowman’s space, which is part of the proximal tubule, and flows
down the PCT
 Filtrate just like plasma minus macromolecules

Afferent arterioles  glomerular capillaries  efferent arterioles

 Afferent / efferent can constrict / dilate to modulate glomerular function / GFR

Efferent arteriole  breaks up into peritublular capillaries

 Surround proximal tubule / distal tubule of same nephrons & surrounding nephrons
 Loops of Henle of juxtaglomerular nephrons (important in urinary concentration)
supplied by vasa recta

Glomerular Filtration Barrier

Fluid from the glomerular capillaries needs to pass through these layers to reach Bowman’s space en route to the PCT
1. Endothelial cells of glomerular capillaries
a. fenestrated; cells can’t pass but macromolecules can

2. Glomerular basement membrane

a. collagen, blocks large plasma proteins & slows small ones

3. Podocytes (glomerular epithelial cells)

a. with foot processes & filtration slits
b. Finest & final barrier; filters all but small proteins
c. Important for maintaining a relatively protein-free ultrafiltrate

Glomerular Filtration Rate (GFR)

Rate of filtration of plasma  initiate urine formation
 Measures kidney function
 Normal: ≥ 90 mL / min

Depends on Starling forces

 Hydraulic pressure (ΔP) is pushing fluid
out of capillary into Bowman’s Space
 Oncotic pressure (Δπ) is working against
it (more protein in capillaries)

2
Equation: 𝐺𝐹𝑅 = 𝐾𝑓 Δ𝑃 − 𝑠Δ𝜋 = 𝐾𝑓 [ 𝑃𝑔𝑐 − 𝑃𝑏𝑠 − 𝑠 𝜋𝑔𝑐 − 𝜋𝑏𝑠 ]
 where P is pressure, gc = glomerular capillary, bs = Bowman’s space.
 Kf is a filtration constant
(reflects surface area & permeability for fluid movement)
 s is a “reflection coefficient” of proteins across the capillary wall
(0=permeable, 1=impermeable)

Normally, the filtrate is essentially protein free: so πbs = 0 and s = 1

 𝑮𝑭𝑹simplified = 𝑲𝒇 𝑷𝒈𝒄 − 𝑷𝒃𝒔 − 𝝅𝒈𝒄

Puf: can combine terms

(think about GFR in terms of one net driving force / net filtration pressure)
 𝑮𝑭𝑹 = 𝑲𝒇 𝑷𝒖𝒇

As you travel along the capillary, ↓Puf (driving force decreases)

 ↑oncotic force driving fluid back into capillary (fluid left but not proteins)
 ↓hydrostatic force (fluid’s already left for bowman’s capsule)

Regulation of GFR
You can change either the driving force (Puf) or the filtration constant (Kf)

Changing glomerular hydrostatic pressure (Pgc) is most common way to alter GFR via Puf
 Regulate by constricting or dilation of afferent / efferent renal arterioles

aortic pressure− renal venous pressure

Renal plasma flow: 𝑅𝑃𝐹 = renal vascular resistance
 Basically: how much plasma’s flowing through the kidneys?
 Note that this is different from GFR (how much filtrate is being produced?)
 Renal vascular resistance is mostly determined by resistance at afferent / efferent arterioles
Constrict afferent arteriole:
 fluid can’t get through
 less hydrostatic pressure in glomerular capillary
 ↓Puf and ↓GFR
Constrict efferent arteriole:
 fluid backs up
 more hydrostatic pressure in glomerular capillary
 ↑Puf and ↑GFR
In both cases: ↓RBF
 You’re constricting something, so resistance in the kidney increases 
 flow decreases (blood’s being shunted away from it)

What affects this tone?

 Autoregulation mechanisms: Angiotensin II, Intrinsic myogenic control, tubuloglomerular feedback (TGF) – see below
 Norepinephrine: constrict both (afferent > efferent) so GFR↓
o Get blood to important organs!
 Prostaglandins: counteract NE to preserve GFR
o Dilate afferent > efferent

Kuf – the filtration coefficient - can be altered too (physiologically or in disease)

 Contraction of mesangial cells  close some capillaries  less surface area
 Inflammation / sclerosis: damage filtration barrier, ↓Kuf
3
 Autoregulation

Kidney can maintain RBF and GFR pretty well over a range of BP MECHANISMS OF AUTOREGULATION
1. Renin – angiotensin – aldosterone system
I. RAAS system 2. Myogenic mechanism
1. BP falls (e.g. you’re bleeding out) 3. Tubuloglomerular feedback
2. Volume sensors activated  ↑ renin release from juxtaglomerular
cells in macula densa
3. Renin cleaves angiotensingen → angiotensin I
4. AT I  AT II via ACE (lung, vascular endothelial cells, glomerulus)
5. AT II:
a. ↑ systemic vasoconstriction
b. ↑ aldosterone (along with AT II itself)  ↑ renal tubular Na reabsorption
i. Net effect: help restore extracellular fluid volume
c. KEY:ANGIOTENSIN II constricts EFFERENT > AFFERENT arteriole at glomerulus
i. increases Pgc to maintain GFR

II. Myogenic Mechanism

 If you stretch vascular smooth muscle, it contracts reflexively
 If ↑arterial pressure  would lead to ↑GFR / RBF (want to maintain!)
o But: ↑pressure  ↑stretch  contract afferent arteriole  increase resistance
o Brings RBF / GFR back down

III. Tubuloglomerular Feedback Mechanism adenosine

 If renal blood flow increases too much, you overwhelm Na reabsorption
mechanisms
 ↑NaCl at the juxtaglomerular (JG) apparatus –
where the thick ascending limb (TAL) meets the glomerulus
o TAL contacts afferent / efferent arterioles here
o TAL cells facing glomerulus = specialized (macula densa)
o Granular cells of arterioles (afferent & efferent) produce renin
 JGA says “whoa, we’re wasting NaCl: slow down!” to arterioles
by releasing adenosine
 Adenosine  constriction of afferent arteriole (of same nephron as TAL!)
o ↓GFR back towards normal
 Opposite happens if ↓blood pressure  ↓GFR  ↓NaCl

Why autoregulation? If GFR increased proportionally to arterial BP changes:

 Short-term: too much sodium would be
excreted  ↓ECV, many problems
 Long-term: really high Pgc is bad for the
glomerulus (damage capillaries)
Clinical example: Pt on ACEI & NSAID
 ↓AT II and ↓prostaglandins (from NSAID)
 If they get volume depleted:
o can’t increase AT II (no efferent > afferent constriction)
o can’t increase prostaglandin (no dilation of efferent arteriole)
 Net result: GFR drops severely (can’t autoregulate!)

Evaluating GFR
Need a substance: present in plasma, filtered freely at glomerulus, not reabsorbed / secreted / produced / metabolized by tubules

Inulin: polysaccharide, satisfies all above criteria: everything filtered shows up in urine
 Filtered inulin = excreted inulin
 𝑷inulin × 𝑮𝑭𝑹 = 𝑼inulin × 𝑽

4
 o where P = plasma inulin, GFR = glomerular filtration rate, U = urine inulin, V = urine flow rate
𝑼
 𝑮𝑭𝑹 = 𝑷inulin × 𝑽 = the ratio of urine to plasma inulin times the urine flow rate (mL / min)
inulin
𝑼
 More generally, the clearance of any substance is 𝑷 × 𝑽

Creatinine: used in clinical practice to estimate GFR

 Why? Inulin isn’t made endogenously, need to give IV (creatinine is normally around)
 From muscle breakdown of skeletal muscle creatine (endogenous)
Limitations:
 Secreted in proximal tubules (limitation for estimating GFR – makes GFR look 10-20% higher than it is)
o If GFR↓, secretion ↑ (not good – makes GFR look better than it is because more ends up in urine!)
 In plasma, there are some things that are falsely measured as creatinine (make GFR look 10-20% lower)
 (So we say the numerator & denominator errors mostly cancel each other out)

Calculating Creatinine Clearance (THIS IS IMPORTANT – KNOW HOW TO DO THIS)

1. Collect 24h urine & plasma sample
𝑼
2. Creatinine clearance = 𝑷 × 𝑽
a. Example: 1mg/dl plasma creatinine, 100mg/dL urine creatinine, 1440mL/ day 24h urine volume:
𝑼 100mg/dL 1440mL 1day mL
×𝑽= × × = 𝟏𝟎𝟎
𝑷 1mg/dL day 1440min min

Can also calculate from age, lean body weight, and plasma creatinine (Cockcroft-Gault equation)
140−age × lean body weight (kg)
 𝐶𝐶𝑟 = 𝑃𝐶𝑟 ×72
(don’t memorize this)
 (multiply by 0.85 if woman (lower muscle mass as % body mass)
 Note the factors at play: muscle mass decreases with age, bigger people have more muscle, etc.
 This is different for different people: bigger / more muscle will have bigger creatinine clearances

The relationship between plasma creatinine and GFR is EXPONENTIAL

 a little change in plasma CR can be a big change in GFR
 limitation of using plasma creatinine

BUN: Blood urea nitrogen

 made by liver; routinely measured in lab tests
 generally varies inversely with GFR but also ↑ with ↑protein intake, ↑tissue
breakdown, volume depletion; ↓ with liver disease
 marker of waste product accumulation from low GFR

More complicated ways to measure too (e.g. 4 variable MDRD formula – takes ethnicity, gender, age, serum Cr into account)

Glomerular Permeability & Permselectivity

 Size & charge are key
 Remember 3 layers: endothelium, GBM, podocytes(epithelium)
o Tons of molecules involved in slit diaphragm; mutations in any of
them can give hereditary protein wasting syndrome

Electrical charge:
 All 3 layers: glycoproteins with sialic acid moieties (negative charge)
 Positively charged molecules filter more freely
 Negatively charged molecules are blocked (e.g. albumin)
 Minimal change disease: decrease in charge; see albuminuria
5
Size:
 Big stuff doesn’t get through
 Albumin: big (small % gets through) but so much albumin & so much plasma
that about 7g/day filtered
 40 Å is about the cutoff

Shape plays a role too but isn’t talked about as much

Proteinuria
 Generally >2g/day suggests glomerular disease; tubular dz has less proteinuria

Glomerular proteinuria
 Lose protein into urine (200mg  >20g/day) via glomeruli

 Selective proteinuria: usually predominantly albumin (e.g.

minimal change disease: loss of – charge)
o Urine electrophoresis: see big albumin peak only

 Nonselective proteinuria: all plasma proteins appear in filtrate

(same proportion as plasma)
o Urine electrophoresis: see same distribution as in plasma

Tubular proteinuria
 Disease of proximal tubules
Non-selective
(usually reabsorb small filtered proteins + some albumin)

 Urine electrophoresis: see small proteins > albumin Selective

Overproduction proteinuria
 Making too much of a protein
(e.g. multiple myeloma  light chains into urine)

 DIPSTICK ONLY DETECTS ALBUMIN: don’t be fooled!

o If you need to see others, use sulfosalicylic acid (SSA) test

6
 The Tubules
What they do: reabsorb & secrete
 180 L ultrafiltrate; >25K mEq sodium / day: and about 99% of ultrafiltrate reabsorbed

The Basic Setup

 Directional transport is key: need polarity of cell

o what’s in apical membrane ≠ what’s in basolateral membrane

 Passive (channels) or active (transporters; coupling/ATP use)

ion movement

 ATP is generally ultimate energy source

Blood
Lumen
 Na/K ATPase provides gradients that fuel a lot of transport

The Tubule: Big Picture

Most reabsorption: in EARLY PARTS of tubule (PROXIMAL TUBULE and Loop of Henle)

7
 The Tubule

SECTION REABSORBS / SECRETES REGULATION OTHER PICTURE

Reabsorbs most
filtered:
 Sodium
 Water
If proximal tubule is
 Potassium Angiotensin II: broken, you can urinate
PROXIMAL TUBULE  Chloride ↑ sodium reabsorption out too much base (can
 Bicarbonate lead to acidosis)
(actually  ↑Na / H exchanger
+ +

“reclamation” since  Triggered when volume Using INTRACELLULAR

-
HCO3 is broken depleted SODIUM GRADIENT
down & re- (Na/K ATPase) for
assembled on other sodium reabsorption
side)
 Glucose
 Amino acids

Also plays a role in

urinary dilution &
concentration (macula
LOOP OF HENLE densa here, etc) – see
Reabsorbs: below.
 Sodium
 Chloride Using Na gradient to
 Potassium transport in K / Cl-

Some diuretics work

here (block Na
reabsorption)

8
 Aldosterone: By this point, Na
 ↑Na absorb/ K secretion in/out might be close
Reabsorbs:  (↑Na/K ATPase activity, to 1: can’t use

Principal Cells
 Sodium K+ channel opened too) concentration gradient
 Water (if ADH) to bring in Na
ADH (antidiuretic hormone,
Excretes: a.k.a. vasopressin: 3Na/2K ATPase makes
 Potassium  ↑aquaporin insertion inside a little negative;
into membrane facing charge is driving force
urine side for Na absorption

H+ ATPase on urinary
COLLECTING side is predominant
DUCT way acid excreted
Secretes:
H+/K+ ATPase
 Acid
Type A

Aldosterone: ↑ acid activated by

secretion hypokalemia; can
Can reabsorb K if
reabsorb K from
hypokalemic
Intercalated Cells

urinary space when

needed

“A” secretes ACID

Use Cl / HCO3
exchanger on apical
Type B

Secretes: membrane to secrete

 Base (if in excess) when needed

“B” secretes BASE

9
Remember the countercurrent exchange in the Loop of Henle (that it exists, not how it works)
 Sets up a salt gradient (more concentrated at bottom)

Descending Limb of LH: permeable to H2O, not Na+ Ascending Limb of LH: permeable to NaCl, not H2O
 Water flows out but not sodium  Recover salt (flows from high salt concentration
(high salt concentration in interstitium) in lumen to lower in interstitium)

Urinary Dilution
High water load  excrete by diluting urine!

Without ADH:
 Sodium reabsorbed in ascending Loop
of Henle, distal tubule, leading to
dilute urine but…

 Water can’t escape (no aquaporins)

 End result: dilute urine excreted

o (↓↓ urine osmolality)

Urinary Concentration
Water deprivation  conserve by concentrating urine

 Collecting duct passes through

hypertonic medulla (from
gradient generated by
countercurrent multiplier)

 ADH: insert aquaporins

 Water can now follow the
sodium gradient & flow out into
interstitium

 End result: concentrated urine excreted

o (↑↑ urine osmolality)

Summary
Tubular Functions:
 Reabsorption of most of ultrafiltrate
o >99% with bulk early, fine tuning later
 Secretion of solutes
o K+, H+
 Regulation of above processes (Angiotensin, aldosterone, ADH)
10
 Sodium Balance
Distribution of total body water (60% weight)
 1/3 extracellular fluid (ECF)
 2/3 intracellular fluid (ICF)
 Vascular space & ECF generally equilibrate with regard to electrolytes

Whatever sodium you eat generally gets into your body

 Na/K pumps on basolateral surface of gut epithelium provide driving force
 Osmolality increases, brain sends signals, get thirsty & drink water to
return sodium to appropriate concentration

Compartments
If you add isotonic sodium, it stays in extracellular space (vasculature, etc)
If you add sodium only, decrease ICF and increase ECF
 (sodium stays outside of cells, draws water out)
If you add water only it distributes to ICF and ECF equally

Sodium quantity is reflected by ECF volume changes

Serum sodium concentration reflects osmolarity of the whole body
 Abnormal water balance = changes in serum Na

Sodium Intake vs. Excretion

Intake: 0.2 to >12g/day
Excretion: varies with intake
 Body tries to maintain excretion = intake
 Balance maintained unless large changes in intake

NA EXCRETION almost entirely via the KIDNEY

 Na+ reabsorption happens at various points along the
nephron – see diagram
 Proximal tubule: Majority (65%) of Na reabsorption
 Principal cells (collecting duct): fine tuning
o Only 3% of reabsorption, but a lot of sodium passes
through the kidney so 3% can be a big deal
 Blocking Na+ reabsorption  excretion

Fast changes: output lags behind intake

 Eat a ton of salt – takes longer to get output up to speed
o Gain body mass by H2O retention in the meantime
 Same is true for opposite situation: stop eating salt, takes a bit to get
your output back down to normal

Result: steady state ECF volume is determined by Na+ intake

 ↑Na+ intake  ↑ECF volume

Corollary: ↑ ECF volume  ↑ Na+ excretion

o Get rid of Na to get rid of volume!

11
 Edema
 Too much sodium  too much ECF  edema! (too little
sodium = low ECF = low intravascular volume too)

 Note that when you have CHF, you’re starting at a higher ECF
level with reduced ability to get rid of sodium (hang on to all
that you can)
o Smaller increases in Na intake can push you over
the line to edema
 The threshold for Na excretion is greater in edematous
states – e.g. start getting rid of Na at higher ECF volumes

Sodium Balance: How’s it Happen?

 Important to maintain ECF  vascular volume  blood pressure (for cardiac function)
o Sodium deficit ECF ↓  intravascular volume ↓ (not cool)
o Sodium excess  ECF ↑  edema

Basic idea:
 ECF reflects Na+
 To maintain balance, just sense volume & adjust Na accordingly
(@ kidney since it’s the main way Na+ can leave)

1. Effective circulating volume

a. The part of ECF that’s in the arterial system and effectively
perfusing tissues (doesn’t count edema fluid, etc)
b. This is what the sensors use to detect body sodium

2. Sensors
a. In both arterial & venous circulation
b. Sense stretch (direct relation to pressure)
c. Want ‘em close to brain (the important place; detect problems
before they arise)
d. Want redundancy (cause the brain is important)

Carotid Sinus, Great Vessels of the Chest, Atria

 Sympathetic stimulation:
+
o ↓stretch  ↑symp ↑Na retention & ↑vasoconstriction
+
o ↑stretch  ↓symp ↓Na retention & ↓vasoconstriction
o If you’re not stretching, volume is low:
+
try to get more Na and vasoconstrict to keep BP up

 ADH (vasopressin) released with volume depletion too

o (mostly osmotic regulation though – ADH responds more sensitively to isovolemic osmotic increases)

Renal afferent arteriole:

 Stretch receptors in afferent arteriole
 ↓ pressure  renin released  angiotensin II formed
 Opposite for high pressure and increase stretch (less renin)
(Hepatic sensors too but not as important)

12
3. Effectors: Two main mechanisms of regulation:
A. Systemic hemodynamics (cardiovascular)
 Sympathetics & angiotensin II:
vasoconstrict & shunt blood towards brain
o Clinically: cold extremities, etc.
B. Renal Na+ excretion / retention
 Sympathetics, angiotensin II, and
aldosterone
 Also GFR & atrial natriuretic peptide, but these
aren’t as important

EFFECTORS & WHAT THEY DO

Sympathetic System Atrial Natriuretic Peptide
 Vasoconstriction
(veins: more venous return, arteries: ↑BP)  L. atrial distention increases release
 ↑ contractility  Inhibits Na reabsorption in collecting duct
 ↑ renin  ↑(AT IAT II)
 ↑ tubular Na+ absorption (direct effect)
Aldosterone Angiotensin II
 Regulates Na reabsorption  Vasoconstriction too
+

 Principal cell of cortical  ↑ proximal sodium reabsorption

collecting duct is primary  ↑ renin  ↑(AT IAT II)
target  ↑ GFR
↑GFR
 ↑ Na/K exchange (constricts eff > aff arteriole)
 ↑Na channels in CCD & DT
Note: constrict both afferent & efferent arteriole  help maintain GFR but shunting blood away from kidney too (to brain, etc)

Tubuloglomerular Feedback
Happens at the single nephron level: another mechanism to control sodium balance

1. ↑ NaCl at macula densa (tubule cells - part of thick ascending limb) – there’s too much
NaCl getting through, so you need to slow down!
2. Macula densa feeds back on afferent arteriole by secreting adenosine (constrict: ↓GFR!)

The Big Picture

If ECV drops, ↓venous return  ↓CO  ↓BP drops

Restoration of blood pressure is goal(two ways)

 Volume: Hang on to Na (restore circulating volume)
 Hemodynamics: Pump more volume, faster,
harder against more resistance

Note from diagram:

 Sympathetics : direct effect on ↑tubular Na reabsorption
 Angiotensin II works on hemodynamic (vasoconstriction)
& volume (reabsorption of Na) mechanisms
 Increasing venous return, contractility, heart rate, &
resistance all help keep BP up
 Na is the key to increasing effective circulating volume

Manifestations: cold extremities (shunt blood to vital

organs), tachycardia, etc.

13
 Edema: When Sodium Balance Goes Bad

Edema is the manifestation of excess extracellular volume Common causes of Edema

 Effective circulating volume actually DECREASES  1. Congestive Heart Failure
 ↑ sympathetics, ↑angiotensin II, ↑ADH 2. Cirrhosis
3. Nephrotic Syndrome
Even if excess total volume, the kidneys can’t tell (just see effective circ. vol)
 Vicious cycle results because the volume is useless (not in circ)
The mechanisms are the same as before, just driven by different causes than bleeding out

Congestive Heart Failure

 Low CO  ↓baroreceptors  ↑Na & H2O retention, etc.
 Pulmonary & peripheral edema can result

Cirrhosis
 Portal hypertension (blood backs up in portal circulation)
 Also shunted from arterial to venous circulation
 ↓ECV  ↑ Na retention, etc.
↓ albumin
 Ascites (backup to splanchnic ↓oncotic pressure
circ) & peripheral edema result
Venous pooling Cirrhosis
Nephrotic syndrome Nephrotic
CHF
 Protein lost in urine Syndrome
 ↓albumin  ↓oncotic pressure
Can’t keep blood in circulation
 goes to interstitial space
 ↓ECV  ↓Na retention, etc.

 Peripheral edema (and even

ansarca: edema over whole
body) can result

Take Home Points

 Sodium is the primary determinant of ECF

 Sodium balance is achieved through responses to changes in effective circulating volume
 Responses require sensors and effectors
 The final common pathway = salt retention or excretion by the kidney
 Dysregulation of the system can result in volume overload with edema as an important feature

14
 Osmolality & Disorders of Sodium Concentration
Osmoles & Osmolality
Osmole: # moles of a substance dissolved in solution: a quantity
 (e.g. 1mmole glucose  1 mOsmole; 1mmol NaCl  2 mOsm)

Osmolality: osm / kg (temperature independent)

Osmolality: osm/L (temperature dependent – can freeze)

Osmotic pressure: hydrostatic pressure exerted by particles in solution

on opposite sides of semipermeable membrane

Tonicity
Tonicity: measure of effective osmolality
 Ineffective osmole: if the membrane is permeable, equilibrates & no gradient left
o Urea, glucose
 Effective osmoles: restricted to one compartment
o Only effective osmoles contribute to tonicity
o Na is major extracellular osmole; largest determinant of tonicity in humans (2Na ~osmolality b/c NaCl)

BUN glucose
Estimated osmolality = 𝟐 × [Na] + + (KNOW THIS EQUATION)
𝟐.𝟖 𝟏𝟖

Osmolal gap (OG)

OG = Measured – estimated osmolality (usually ≤10 mOsm/kg)
 >10 indicates presence of osmotically active particle – there’s something else in there!
 Need to think about poisoning (ethanol, methanol, ethylene glycol,isopropyl alcohol, mannitol)

Regulation of body fluid compartments

Remember these fractions:

 TBW (total body water) = 0.6* x wt (0.5 in women)
 ICF = 2/3 x TBW
 ECF = 1/3 x TBW
 Plasma ≈ 1/4 x ECF

If you change tonicity, water movement goes from

low osmolality  high

15
 Regulation of Osmolality
Osmolality is primarily regulated by gain or loss of WATER
 If you have too much Na or too little, the main mechanism is NOT gain / loss of Na
 Plasma osmolality ~ 280 -285 mOsm / kg
o Sodium = 140 mOsm (2xNa ~280)
↑release of ADH ↓release of ADH
ADH is primary driver • 1% rise in tonicity • Fall in tonicity
(made in hypothalamus, stored in posterior pituitary & released)
• Pain • Ethanol
 Increased osmolality from increased Na (relative lack of
• Nausea
water)  triggers osmolality receptors
• ≥10% decrease in ECV
o Stimulates thirst (drink more)

 Also released when >10% decrease in effective circulating volume

o Hypoperfusion (dehydration, heart failure, hypotension) will release ADH
o NON-Osmotic release – last-ditch method in rare circumstance to use ADH to conserve volume
 Serum [Na] will fall!
o Why not use ADH for volume regulation? Water is a poor volume expander – would shift to ICF!

ADH:
1) binds V2 receptors on basolateral surfaces of medullary
collecting duct cells  ↑ cAMP  ↑aquaporin-2
insertion into luminal side  allows water reabsorption

2) Conivaptan, tolvaptan inhibit V2 receptor: aquaresis

(serum Na will RISE but only because water is lost)

Normal kidney: can concentrate a lot!

 50 mOsm/kg (no ADH)1200 mOsm/kg (max ADH)
 14L max to 580 mL min of urine
 Big range: but what if you ate only 300 mOsm & drank 8L
water? You’d become hyponatremic
(can’t make it that dilute!)

OSMOREGULATION and
BLOOD PRESSURE / VOLUME REGULATION
are DIFFERENT!

OSMOLARITY IS CONTROLLED BY WATER

BALANCE! BLOOD PRESSURE IS CONTROLLED BY NA
BALANCE!

OSMOLARITY IS CONTROLLED BY WATER BALANCE!

BLOOD PRESSURE IS CONTROLLED BY NA BALANCE!

OSMOLARITY IS CONTROLLED BY WATER BALANCE!

BLOOD PRESSURE IS CONTROLLED BY NA BALANCE!

OSMOLARITY IS CONTROLLED BY WATER BALANCE!

BLOOD PRESSURE IS CONTROLLED BY NA BALANCE!
16
 Hyponatremia (<135 mEq / L): General points
General Approach
1. Hx / clinical status of pt
 Fall in Na often but not always implies fall in tonicity
2. Determine osmolality
 Clinical symptoms of hyponatremia:
3. Evaluate volume status
o Need fall in TONICITY
4. Evaluate urine osmolality
 (isoosmolar hypoNa is asymptomatic!)
& electrolytes (if needed)
o MOVEMENT OF WATER (not Na) dictates symptoms
5. Treat
[Na] Symptoms
Mild 125-135 Nonspecific: anorexia, apathy, restlessness, nausea, lethargy, muscle cramps
Moderate 120-125 Neuro sx start: agitation, disorientation, headache
Severe <120 BAD: seizures, coma, areflexia, Cheyne-Stokes breathing, incontinence, death

What happens to the brain?

1) Acute: brain swells
(water rushes in because *Na+ is ↓ outside)
2) Chronic: brain adapts (electrolytes shift from
inout; brain returns to normal size)

Clinical approach: Summary

First, assess osmolality:

 Isosmotic? Rare; could be lab
error or isotonic infusion. Some
other osmole must be taking
Na’s place
 Hyperosmotic? Hyperglycemia
(more glucose around) or
hypertonic infusions could do it

If hyposmotic (vast majority),

check volume:

 Hypovolemic? You’re losing

water & sodium, but more
sodium (hyponatremic). Give
isotonic saline

 Isovolemic? You’ve got too

much water, either because
you’re drinking too much
(polydipsia) or you’re holding on
to too much (ADH messed up,
like in SIADH). Water restrict.

 Hypervolemic? You’re gaining

water & sodium, but more
water (RAAS + non-osmotic ADH
release in CHF, for example).
Water restrict ± diuretics.
Isosmolar hyponatremia
17
  Fall in Na without change in tonicity: must have some other osmole to account for difference
 No water shift  no symptoms
Etiologies:
 Isotonic infusions (e.g. use isoosmotic glycine in prostate surgery; gets absorbed; isoosmotic but no Na )
o *Na+↓ (water added) but no fluid shifts (tonicity unchanged
 Pseudohyponatremia: lab artifact of flame photometer in pts with hyperlipidemia / hyperproteinemia (rare today)

Treatment: often doesn’t require intervention

Hyperosmolar hyponatremia
 Addition of non-Na osmoles at concentration greater than plasma osmolality
 Osmolality ↑ but Na ↓
o (volume added and/or water shifts from ICF to ECF due to ↑ extracellular osmolality, but no Na added)
Etiologies:
 Hyperglycemia: e.g. diabetic ketoacidosis
o Normally, glucose put into ECF equilibrates with ICF (via insulin)
o Diabetes: ↓insulin, so glucose becomes effective osmole (more volume sucked out of cell)
o [Na] falls 1.6 mEq/L for every 100 mg/dL rise in glucose above 100
 E.g. if you have a pt with Na = 130 and glc = 500, you can expect Na = 136.4 when you control glc to 100
 Hypertonic infusions: e.g. give mannitol

Treatment: treat underlying condition

Hypoosmolar hyponatremia: general points

Most common disorder of sodium concentration
 Need to make sure: check osmolality! (most hyponatremia pts will be hypoosmolar but some aren’t! see above!)
 Now that we’ve checked hyperosmolar & isoosmolar hyponatremias off of the list, nail down what kind of hypoosmolar
hyponatremia this is by using volume status

Key features of hypoosmolar hyponatremia:

 Plasma osm < 280 mOsm/kg
 Need to determine volume status for etiology (BP / osmolality regulated independently)
o Hypovolemic, euvolemic, hypervolemic: check clinically!
o Skin turgor, edema, rales, capillary refill, low BP, tachycardic, etc.to look for low volume
 Patient has too much water relative to sodium
o although absolute amounts of TBW & sodium can be high, nl, or low

Hypovolemic hypoosmolar hyponatremia

Dehydrated & hypovolemic
 loss of sodium > water but have lost both
o pt drinks water but doesn’t replace Na deficit
 ↓ECV  non-osmotic ADH release (trying to conserve volume)
o dilutes Na even more
o Body trying to maintain perfusion at expense of tonicity!
 Urine osm > plasma osm
o (concentrating: using ADH to try to conserve volume, so
concentrated urine!)

18
Etiologies: Urine Na Why?
Renal Loss (diuretics, obstruction, RTA, etc.) > 20 mEq / L Can’t conserve Na via kidney mechanisms, so spill to urine
Non-renal Loss (GI: vomit/diarrhea, etc) < 10 mEq / L RAAS activated, so hang on to sodium

Treatment: give isotonic saline (replace Na & water, shut off non-osmotic ADH release)

Hypervolemic hypoosmolar hyponatremia

Volume overloaded: ↑total volume sodium & water, but more water than sodium (hypoNa)
 Gain of water > sodium
o Intense stimulation of RAAS: retain Na & H2O (CHF / cirrhosis)
 CHF: AT II, ADH, impaired renal perfusion
(so can’t excrete excess Na & water) all contributing
o Can’t excrete Na/H2O (renal failure)
o Both lead to volume overload
 DECREASED ECV (not effectively perfusing)  non-osmotic ADH release (ongoing retention despite hypoNa)
 Urine osm > plasma osm
(concentrating: using ADH to conserve water, so concentrated urine)

Etiologies: Urine Na Why?

Renal Failure > 20 mEq / L Can’t fully excrete water load, losing some sodium
RAAS activated big time - hang on to Na
CHF, Cirrhosis < 10 mEq / L
(hypoperfusing; trying to ↑ECV)

Treatment:
 Fluid restriction
 Treat underlying condition (CHF, etc.)
 Sodium / water removal: diuretics / aquaretics (V2 blockers, antagonize ADH) /
dialysis

Note: in both hyper- and hypo-volemic disorders, urine osm > plasma; ADH increased in both
 need to assess VOLUME status!
 Treatment is very different! Isotonic saline for hypovolemic, fluid restriction for hypervolemic!

Euvolemic hypoosmolar hyponatremia

 No clinical evidence of volume overload or hypovolemia (no edema, pulm edema, HF Sx, etc)
 Fairly normal sodium balance but DO have EXCESS WATER
o Impaired free WATER EXCRETION but normal ECV
o ADH can be high, normal, low

Etiologies: Urine Na Why?

Increased ADH Release
Reabsorbing water but normal ECV: concentrating too much
 Adrenal insufficiency, nausea,
> 20 mEq / L “reset osmostat”- decreased threshold for ADH secretion
hypothyroidism, medications, pain
SIADH is diagnosis of exclusion
 SIADH (see below)
Drinking too much water (e.g. psych problems) – dilute urine, ADH
Primary Polydipsia < 10 mEq / L
suppressed (hyponatremia with appropriately low urine osm)
19
Treatment
 Fluid restriction
 High solute diet (help excrete more)
 water removal (aquaretics: V2 blockers, block ADH function e.g. in SIADH)

Syndrome of Inappropriate ADH (SIADH) secretion

 Clinically euvolemic

 Serum osm < 270 mOsm / kg

 Urine osm >100 mOsm/kg (> serum osm)
o Net retention of water: you see a really
low serum osmolarity, so your urine
osmolarity should be really low (should be
trying to get rid of water with dilute urine
by shutting off ADH) – but you’re not
diluting enough (keep inserting some
aquaporins because ADH turn off)
 Normal dietary intake with UNa > 20
 No alternative diagnosis (thyroid, adrenal
problems) – diagnosis of exclusion
Causes of SIADH
 Idiopathic
 Pulmonary disease
 Postoperative
 Severe nausea / vomiting
 Drugs (SSRI, narcotics, cyclophos, others)
 Exctasy ingestion (aggravated by big fluid intake)
 Ectopic ADH production (e.g. small cell carcinoma of lung)
 Marathon runners / extreme endurance sports
 Also: infections, vascular problems, psychosis, HIV, oxytocin,
waldenstrom’s, head trauma, delirium tremens, others!

Treatment of Hyponatremia
Remember: severe hyponatremia  brain swells → seizures, other bad sx
 If you give a more hypertonic solution (3% is max), you’ll raise Na levels very quickly

Emergent therapy: for bad symptomatic hyponatremia

 GET Na UP! Raise until seizing stops or Na = 115/120 mEq/L
 ACUTE, SYMPTOMATIC HYPONATREMIA with CNS SX REQUIRES 3% NaCl (1-2 mg/kg/hr)
o Overwhelms ability of kidney to excrete Na

Routine therapy:
 Raise slowly (no more than 8-12 mEq/L in 24h: 0.5 mEq/L/hr)
 Once stable, can try aquaretic if too much ADH is problem (antagonize)
 3% NaCl is for emergent therapy only!

Central Pontine Myelinolysis: what happens if you correct hypoNa too quickly?
 ECF [Na] rises suddenly, water rushes out of cells & brain shrinks
 Osmotic demyelination can occur (especially in pons)
 Neuro sx: paraperesis, quadriparesis, dysarthria, dysphagia, coma, seizures
 Dx: CT/ MRI, may take 2-4 wks for lesions to develop
o More risk if post-partum, malnourished, alcoholics

Managing SIADH
 [Na]↓ with normal saline (0.9%)the Na will be excreted (RAAS working OK) but water will be retained (ectopic ADH).
 Salt tablets don’t work either (same reasoning)
 Aquaretics (conivaptan, tolvaptan): block V2 receptor for ADH in collecting duct (sodium excretion unchanged)
o Free water excretion (aquaresis, not diuresis)
o Don’t use if hypovolemic hypoosmolar hyponatremia: would lose volume!.
20
 Hypernatremia
Lack of water relative to Na
 Pts usually volume contracted; plasma osmolality always increased

 Water  out of brain down Na gradient (cerebral atrophy)

o Rapid correction bad: cerebral edema

(suddenly water flows back into brain
cells, expansion  poor results)

Causes:
Loss / inadequate water intake (water loss > Na loss)
 Hypernatremia makes you REALLY THIRSTY: have to ask “why wasn’t this person getting the water they need”?
o Sweating, diuretics, impaired thirst
o Lack of free access to fluid (elderly, nursing home, paralyzed)
o Urinary concentrating defect (DIABETES INSIPIDUS)
 usually OK with just drinking a lot of water (but can become hypernatremic if access cut off)

Administration of hypertonic saline (inpatients, will be hypervolemic)

Treatment: e.g. hypernatremic & hypotensive pt

 Best way to expand plasma volume without inducing cerebral dehydration? Normal saline
o Minimal [Na] change so very little osmotic shift happens
o large proportion remains in vasculature so BP increases & perfusion better

 Lower [Na] the most? D5W (5% dextrose in water)

o Can’t just give pure water IV: RBC will lyse
o 5% dextrose: temporary osmotic gradient (moves into cells slowly with insulin secretion)
o Like giving free water but safe & slow (gives cells time to adjust)

 Correct slowly (0.5 mEq/hr decrease in [Na], 8-12 mEq/L/day to avoid edema)

21
 Diabetes Insipidus
ADH system is messed up: DI is the opposite of SIADH in a lot of ways!

Central DI Nephrogenic DI

not making enough ADH (hypothal / pituitary)
 Pituitary tumors (do visual field tests),
 Pituitary apoplexy (infarction post-partum)
 Infections, idiopathic too
kidneys not responding to ADH (ADH production OK)
Can be complete or partial (more common)
 Drugs (lithium, others)
 Electrolytes (hypercalcemia, hypokalemia)
 Congenital mutations (e.g. V2 receptor)
 Disease (SCD, amyloid, sjogren’s, renal lymphoma, others)

How does lithium cause DI?

 Enters distal nephron via epithelial Na channel (blocked by K+ - sparing diuretics – good for treatment)
 Interferes with ADH-induced AQP2 upregulation
 Can stop Li to prevent more damage, but DI may persist

Treatment of DI:
Central Nephrogenic

 Give exogenous ADH (ddAVP)  Treat cause when possible

 Treat cause  K+-sparing diuretics (amiloride) if lithium use ongoing
(block Na channel that Li uses)
 Thiazide diuretics / low solute diet to decrease polyuria

DDx: pt with polyuria & drinking 5L fluid/ day: has ↑ plasma *Na+, ↑ Posm = 300, Uosm = 70, glc = nl
 Primary polydipsia: [Na] & urine osm are low in polydipsia (large water ingestion so [Na] drops; shut off ADH so
dilute urine) – here plasma [Na] is high
 Diuretics: not DM (glc normal), would think high Uosm (more salt excreted)
 Renal concentrating defect is cause here: insufficient fluid intake to account for losses (so [Na] is high in plasma)

22
 Disorders of Potassium Balance
Potassium:
 Major intracellular cation (98% in cells)
 3Na / 2K ATPase maintains gradients

Major physiologic functions of potassium:

1) Cell metabolism (regulates protein / glycogen synthesis)
2) Determines resting potential against cell membranes
a. Nernst formula, etc: ~-88mV

Membrane potential (Em) is proportional to [K]in /[K]out

 Hyper- and hypo-kalemia can result in muscle paralysis & arrhythmias

Normal K+ homeostasis
Excess potassium needs to be dealt with (can’t have it hanging out in ECF – would disrupt potential):
1) Distribute excess K+ into cells (quick, right after ingestion – maintain ratio)
2) Excrete excess K+ into urine (need to eliminate what you “hid” in the cells)

What influences ICF / ECF K+ ratio?

PHYSIOLOGIC STUFF
Na out, K in. Catechols, insulin, thyroid hormone, state of K+ balance all regulate activity.
Na/K ATPase
 Digitalis inhibits (can lead to fatal hyperkalemia)

α-2 receptors inhibit, β-2 receptors promote K+ entry

 β-2 receptor: stimulates at least partly by activating Na/K ATPase
Catecholamines (basal catecholamine levels permissive)

+
Give β-blocker: more increase in plasma K after ingest a bunch (can’t take up into ICF)
 Release of epinephrine during stress: acute ↓ of plasma K
+

Promotes K+ entry (skeletal mm, liver) via ↑Na/K ATPase

Insulin

+ +
Independent of glucose transport; physiologic role in K regulation (basal levels allow K entry)

By itself can promote K+ entry into cells (passive mechanisms?)

Plasma [K+]
 Block symp & insulin deficient: can still get K+ entry (but impaired)
Exercise too
PATHOLOGIC STUFF
Chronic disease
Metabolic acidosis has big effect (resp. acidosis has minor effect)
 More pronounced when not due to accumulation of organic acids (lactic/keto-acidosis)
 Excess H+ enters cell to be buffered  Cl- enters poorly, so electroneutrality
Extracellular pH maintained by kicking out K+ (and Na+) into ECF
 Plasma K+ ↑0.2-1.7 mEq / L for every 0.1↓ in pH
Net effect: depends on severity of acidemia & K+ balance
Water diffuses out of cells down gradient; K+ moves too (solvent drag through H2O channels)
Hyperosmolality
Increased K+ inside  gradient for passive exit via K+ channels
Cells release K+ when broken down (trauma, crush injury) so K+ ↑ in plasma
Rate of cell breakdown
Cells need K+ if rapidly proliferating (correction of megaloblastic anemia, etc): ↓ K+ in plasma

23
 Renal potassium excretion
KIDNEYS play major role in K+ balance
 Small amounts lost in stool/sweat (can maybe see changes in fecal excretion with mineralocorticoid level shifts, K +
balance changes, rates of stool excretion)

1) Proximal tubule reabsorbs 70-80% of

filtered K (passive, follows Na/H2O)

2) Thick ascending limb reabsorbs 15-

20% (Na/K/2Cl cotransporter)

3) By the early distal tubule: only 10%

left, so rate of K+ excretion depends
on K+ secretion (principal cells in
cortical collecting tubule & outer
medullary collecting tubule)

K+ Secretion (principal cell of CT)

 Na/K ATPase in basolateral side:
pumps K+ in using ATP (need to have K+ inside to get rid of it)

 K+ secreted passively via K+ channels in apical side: uses

favorable electrochemical gradient
+
o Lumen-negative gradient generated by Na
+
reabsorption (through Na channels)
+
o Tubule flow constantly washes away secreted K

 ALDOSTERONE regulates all these steps

REGULATION OF K+ SECRETION
Sodium Transepithelial
Aldosterone Plasma [K+] Distal flow rate
Reabsorption potential difference
 ↑ # Na channels in apical Wash away
membrane  more negative secreted K+ (if
+
lumen  more K secretion
+
↓flow, K builds up More Na+ If lots of poorly
in lumenless reabsorbed reabsorable anion
 Enhances basolateral Na/K Same changes as
secretion) ↑Na/K ATPase (HCO3-), lumen more
ATPase (↑ *K+]in so bigger aldosterone
(independently!) activity  more K+ negative
gradient) More flow  more inside  better
 ↑ # open K channels in apical
+ Na+ delivered  gradient to secrete (so more K+ secreted)
membrane (↑ K+ permeability) see Sodium
Reabsorption

24
 Hyperkalemia (serum K+> 5.5 mEq/L): Causes
1. Increased K+ Intake
a. Need accompanying defect in K+ excretion to be a problem
b. Body good at preventing K+ accumulation (taken into cells / excreted) MAJOR CATEGORIES
OF HYPERKALEMIA
2. Pseudohyperkalemia: lab artifact  ↑ Intake
a. Take blood sample  mechanical trauma during venipuncture  Pseudohyperkalemia
b. RBCs damaged, release K+ in tube  Shift from inout of cells
c. Can see ↑ K in serum samples (RBC removed from serum samples by  ↓ renal excretion
clotting, release some K when they clot)
i. See even more if WBC > 100k or plt > 400k (more clotting)
ii. Can use green top tube (has heparin so no clotting) to measure K in plasma to avoid

3. Shift out of cells

a. Catecholamines & insulin  ↑ Na/K ATPase as per above; deficiency in either leads to ↑ Kplasma
b. Normal pt: glucose load  insulin released  glucose into cells (& mild hypokalemia)

c. Type I Diabetics: glucose load  no insulin released  glucose stays outside; water rushes out because glc
is osmole now  K follows  hyperkalemia
i. Treat with insulin: K+ goes back into cells (and glucose too – double effect)
ii. Total body K ↓ (high glucose  osmotic diuresis, renal K+ loss)

d. Β-adrenergic blockade (using β-blockers)

i. Can interfere with K+ entry – usually OK unless renal failure or big K+ load superimposed
e. Digoxin: blocks Na/K ATPase; tends to ↑ K levels (insignificant @ therapeutic levels)
f. Tissue breakdown: trauma (e.g. crush injury), rhabdomyolysis, tumor lysis  ↑ K release

4. Decreased Renal Excretion

a. Renal failure
i. K+ OK if adequate urine output (compensates by ↑ K+ excretion @ each functioning nephron)
ii. Mediated by aldosterone & ↑ Na/K ATPase activity
iii. Oliguria: ↓ K+ excretion (↓ flow to distal secretory site)
b. ↓ Effective circulating volume
i. Fluid loss, heart failure, cirrhosis
ii. ↓ GFR, ↑ Na/H2O reabsorption proximally 
↓ distal flow & Na delivery  ↓ K secretion
iii. Happens despite 2° hypoaldosteronism
c. Hypoaldosteronism
i. Either ↓ effect or ↓ production of aldosterone
1. ± other forms of Na wasting, metabolic acidosis
ii. Major stimuli for aldosterone secretion:
↑ plasma K and angiotensin II
1. Defects anywhere along the pathway can cause problems (see picture)
iii. #1 cause of hyperkalemia in adults: HYPORENINIMIC HYPOALDOSTERONISM (type IV RTA)
1. Mild-moderate renal insufficiency; 50% with diabetes, 85% with ↓ renin
2. Typically Asx hyperK
iv. Cyclosporin, NSAIDs, ACEI can cause similar problems (interfere with aldosterone)
v. K-sparing diuretics (spironolactone: directly antagonizes all aspects of aldosterone, amiloride &
+
trimamterene block luminal Na channel) also impair excretion
vi. ↓ Adrenal Synthesis too (primary adrenal insufficiency, enzyme deficiencies, heparin may ↓ aldo)
25
 Hyperkalemia: Symptoms, Treatment
Symptoms:
 Muscle weakness
 Abnormalities in cardiac conduction ( cardiac arrest)
 EKG:
o Peaked T-waves (see picture, ↑ with ↑ K) are key finding

o Widened QRS, loss of P wave

 sine wave pattern  Vfib /
no activity!

o Variable levels of onset

between patients: must
monitor EKG!

Treatment
1) Stabilize membrane with calcium gluconate: short-acting – restores membrane potential / excitability
2) Shift K+ into cells by giving insulin & glucose: insulin  drives K into cells (glc prevents hypoglycemia)
a. Sodium bicarbonate helps too (bicarb helps with acidosis)
3) Remove extra K+ (shifting is only temporary – need to get that potassium out of the body!)
a. Cation exchange resins (sodium polystyrene sulfonate = Kayexelate®) – takes up K in exchange for Na in gut
b. Dialysis if diabetic / available / etc (but invasive)
c. Diuretics to help excretion (with diuresis)

Hypokalemia: K+ < 3.5 mEq/L

Low K is almost never spurious (only if something like ↑WBC in

leukemia, really metabolically active, take up K in tube)

Need to determine: ↓ total body K or just K shifted into cells?

Transcellular potassium shifts: shift K into cells!

 Metabolic alkalosis (K+ and H+ lost in diuretics / vomiting)
o Modest effect only
 Insulin & β-adrenergic receptors  K+ entry

Decreased total body potassium: really lost it!

 ↓ oral intake is rarely cause
o Principal cells good at downregulating K+ secretion
o Intercalated cells can reabsorb K+ if K+ depleted
+ + +
 ↑ # H / K ATPase pumps with ↓ K

26
Decreased total body potassium, continued…
 Potassium loss: hypokalemia usually from renal or GI loss
 diarrhea (incl. laxative abuse)
GI loss

 intestinal fistulas, other drainage

 (vomiting is mostly renal loss!)
↓ Na reabsorption in loop of henle (loop diuretics) or distal tubule (thiazides) 
Diuretics
↑ Na delivered to distal nephron ↑K secretion
NOT GI loss
 ↑ bicarb (vomitus has H+)
Vomiting
 Overwhelm reabsorption  bicarb delivered to distal nephron  ↑ K secretion (charge)
 Transient (↑ Na, HCO3 reabsorption because hypovolemic)  limit bicarb delivery
-
Renal / urinary loss

 Esp aldosterone  renal K loss

 May have co-existent metabolic alkalosis, mild volume expansion, HTN (aldo effects)
Mineralicorticoid  Think adrenal adenomas / carcinomas / hyperplasia (↑ mineralicorticoids)
excess  Cushing’s: ectopic ACTH produced  ↑↑ cortisol  overwhelms normal conversion to cortisone (can’t bind),
cortisol can still bind mineralicorticoid receptor  effects
 Hyperreninism too
Bartter’s & Gitelman’s syndromes (rare inherited disorders)
Nonabsorbable  More K+ secreted in distal tubule (more negative lumen)
Anions  HCO3- is most common, can see others too
Ampho B  Increased membrane permeability
Hypomagnesimia too

Symptoms
 Impaired neuromuscular function (weakness  paralysis, intestinal dilation, ileus)

 EKG findings: primarily delayed ventricular repolarization

o S-T segment depression
o Flattened T-waves
o ↑ U-waves
o Can see PR prolongation/ wide QRS too
o Predisposes to cardiac arrhythmias
(esp with digitalis or Hx of coronary
ischemia)

 Renal dysfunction
o poor response to ADH, polydipsia & polyuria
o Urinary acidification (K+ exchanged for H+  intracellular acidosis  H+ loss by kidney)
o Chronic K+ depletion  vacuolar lesions in PT/DT epithelial cells
 can see interstitial fibrosis & tubular dilatation (can be irreversible!)

 Rhabdomyolysis if severe K depletion (can’t regulate muscle blood flow)

Treatment
 K+ replacement
o Give as KCl oral or IV (oral is faster, can be dangerous IV)
o Prefer KCl to KHCO3 because Cl helps take care of metabolic acidosis that often comes with hypoK
 Also, bicarb is non-reabsorbable (could promote more K loss!)
27
 Acute Renal Failure
Routine lab panel (right): BUN & Cr are circled

ARF: Abrupt (<48hrs) decline in GFR

 serum creatinine ↑ ≥ 0.3 mg/dL from baseline, or
 serum creatinine ↑ ≥ 50%, or
 oliguria (↓ urine output) < 0.5 mL/kg/hr for > 6hrs
a.k.a “acute kidney injury” (AKI)

Creatinine ≥ 1.3mg/dL often used but has pitfalls ARF: PROBLEMS!

 relies on muscle mass (bigger more normal in big people)  Accumulation of toxins
 can be falsely elevated by meds that interfere with tubular Cr  Azotemia: ↑ BUN
secretion ↑ nitrogenous end products of protein /
 Doubling of creatinine = 50% ↓ GFR AA metabolism in blood
 Uremia: signs & sx with azotemia
Urine output in ARF (sleepy, confused, asterixis, pericarditis,
 Can be normal too! etc)
 Oliguria: ↓ urine production (<500mL/day)  Fluid management problems
 Anuria: absence of urine (<50mL/day)  Electrolyte abnormalities
 Acid/base disorders
 Medication dosing (if renally cleared!)
End result: ↑ morbidity & ↑mortality  Temp / long-term dialysis?
 6x risk mortality with hosp-acquired ARF  Recovery is common (± sequelae)
 40-60% mortality for oliguric, 15-20% for nonoliguric

Important & common (1-4% general med-surg admissions, 10-30% ICU admissions)

Classification: by anatomic site

For every patient with ↑ SCr, think:

 Is it prerenal (↓perfusion)?
 Is it postrenal (obstructive)?
 Is it renal (intrinsic)?

 If renal, think through the kidney: renal

vascular, glomerular, interstitial, tubular
(ischemic or toxic)?

Helps categorize the DDx and think of where to look

Prerenal ARF
Pathophysiology: need to get blood to glomerulus to form urine!
 Autoregulation: hold RBF / GFR constant over perfusion pressure range
o ↓ perfusion  dilate afferent (eicosanoids) & constrict efferent (angiotensin II) arterioles
 If you ↓ renal perfusion below autoregulatory range, can get sudden GFR drop!

28
Picture to right has causes of prerenal failure
In general: not getting blood to kidney!
 ↓ intravascular volume
(ECF loss or sequestration)

 ↓ cardiac output
(myocardial dysfunction)

 Renal vasoconstriction (drugs)

 Renal artery occlusion

(thrombus/embolus/trauma)
Labs
Diagnosis of prerenal ARF
BUN / Cr Great key for prerenal ARF!
> 20:1 Kidney holding on to sodium,
1) History (HPI, PMH of cardiac disorders, ratio
Na/BUN coupled so BUN ↑ vs Cr
bleeding; meds: diuretics, NSAIDs, oliguria) Urine Na < 20 mEq / L
2) PE: volume status (HR/BP, orthostatics), Holding on to sodium!
FENa < 1%
dry mouth, skin tenting, etc.
Uosm > 500 mosm/kg Non-osmotic ADH release!
3) Should return to baseline with fluids
U/A Normal
𝑈 ×𝑃
FENa%: Fractional Excretion of Sodium = 𝑃 𝑁𝑎 ×𝑈 𝐶𝑟
𝑁𝑎 𝐶𝑟
 What % of sodium is being excreted? (adjusts for other variables, not as simplistic as urine Na)
 Low FENa = salt avidity, FENa > 2%: acute tubular necrosis or other kidney disease (can’t reabsorb)
o Need oliguria to suggest prerenal disease, can’t interpret if on diuretics

Problems with BUN/Cr ratio

 ↑ urea formation: falsely ↑ (catabolic state: fever, tissue necrosis, corticosteroids, sepsis, GI bleeds)
 ↓ urea formation: falsely ↓ (protein malnutrition, advanced liver dz, hereditary syndromes of urea cycle)

Hepatorenal Syndrome (HRS)

 Pts with advanced chronic liver disease (18% of those with cirrhosis / ascites in 1 yr)
 Vasoconstriction of renal circulation with vasodilation of extrarenal circ  arterial hypotension
 No significant renal abnormalities on path, resolve renal function with liver tx!

Postrenal ARF (“obstructive uropathy”)

Block urine flow at any point along its journey; requires bilateral obstruction for ARF to develop

Pathogenesis: Causes
 Calyces / pelvis of each kidney Children Anatomic abnormalities
generally only has 5-10 mL urine Young Adults Caliculi
 Obstruction  proximal dilatation Prostatic hypertrophy / cancer
of calyces / pelvis  destroy Older adults Retroperitoneal / pelvic cancer
medulla & compress cortex Caliculi

Acute renal failure results:

 pressure atrophy
 intrarenal reflux
 ischemia

29
Clinically:
 hydronephrosis (dilate urinary tract proximal to obstruction)
 ↑ UTI frequency

Diagnosis: early is important!

 Renal U/S to look for obstruction / hydronephrosis
 CT if U/S doesn’t help
 Abdominal Xray for stones
 Intravenous pyelogram (IVP) but requires dye
 Bladder cath

Treatment:
 Address life-threatening issues first (sepsis, severe electrolyte abnormalities)
 Try to preserve renal function (relieve obstruction!)
 Direct therapy to cause of obstruction!

Renal ARF
Think renal after excluding prerenal & postrenal!
Categorization of renal ARF: ANATOMY
Vascular  Intrarenal vascular
Thrombotic micoangiopathies:  Glomerulonephritis
 vascular thrombosis  Interstitial
 2° endothelial cell injury + platelet activation  Tubular*
 Etiologies: malignant hypertension, scleroderma, TTP, HUS,
pregnancy-related (Acute Tubular Necrosis is most common cause of ARF)

Renal vein thrombosis bilateral or in a solitary kidney

Glomerulonephritis
Rapidly Progressive Glomerulonephritis (RPGN): Glomerular injury + extensive crescent formation
 Anti-GBM AB (e.g. Goodpasture’s)
 Immune complex formation / deposition (lupus, post-strep, IgA nephropathy, endocarditis, mixed cryoglobulinemia)
 Pauci-immune (“ANCA-associated GN”: Wegener’s & microscopic polyangitis)

RPGN: What happens?

 Nephritic syndrome with glomerular inflammation
 ↓ GFR, non-nephrotic proteinuria, edema, HTN, hematuria (+ RBC casts)

RPGN: diagnosis
 Renal insufficiency
 U/A: glomerular hematuria, RBC casts, mild proteinuria
 Systemic complaints: fatigue, edema, extrarenal involvement
o Multiorgan associations –
 each has characteristic multi-system manifestations
o Each has its own diagnostic test too
o Don’t have to memorize for this lecture,
but maybe a good chart anyway

30
Interstitial
Acute Interstitial Nephritis (AIN) CLINICAL PRESENTATION OF AIN
 Inflammatory infiltrates in interstitium Renal Extrarenal
 Rare but need to detect (treatable & reversible)  ARF Hypersensitivity!
 Drug rxn most commonly, but can be idiopathic or 2°  Mild proteinuria
(<1g/day,↑ if 2° to NSAIDs)  Low grade fever
to infection, dz, malignancy
 Abnormal U/A: RBC, WBC,  “Maculopapular” rash
o Methicillin & NSAIDs are big offenders, lots
WBC casts (see pic)  Arthralgias
of Abx & common infections, leukemia,
 Eosinophiluria  Eosinophilia
lymphoma, SLE too
 Flank pain
(2° to capsule distension)
Pathophysiology of AIN
 Immunological hypersensitivity rxn to antigen
(usually extrarenal, e.g. drug)
 Cell-mediated immunity key
(T-cell infiltrate, ± granulomas, Ab / immune complexes)

Treatment of AIN:
want to stop before it gets to fibrosis (can be irreversible)!
 Stop agent
 Ccontrol inflammation (corticosteroids, prednisone)

Tubular
Acute tubular necrosis: #1 CAUSE OF ARF in hospitalized patients (should always be #1 on DDx)
 Injury to renal parenchyma following:
o Renal ischemia (sepsis, surgery, bleeding)
o Exposure to nephrotoxins (endogenous or exogenous)

ATN outcomes: high mortality rate (esp with dialysis), up to 80% with MOF in ICU
 Ischemic ATN: from prolonged prerenal state (shock / sepsis)

ISCHEMIC ATN
 Proximal tubule & medullary TALH are most susceptible to ischemic & toxic
injury (don’t get much O2)
o Avid Na+ retention by S3 segment of PT & TALH  ↑O2 demand, ↓PO2
 Poor oxygenation  tubular injury (death or sloughing of normal cells into lumen)
o ↑ intracellular Ca, oxygen free radicals↑, ↓ ATP, apoptosis
 Other factors: C’ activation (alternative pathway), intracellular adhesion molecules involved, inflammatory cells (T-cells),
inflammatory mediators, etc.

TOXIC ATN: Can be either endogenous or exogenous nephrotoxins

1. Endogenous nephrotoxins that cause ATN

 myoglobinuria (rhabdomyolysis), hemoglobinuria
 light chains (myeloma)
 crystals, urate, hypercalcemia

31
Rhabdoymyolysis (endogenous nephrotoxin: myoglobin) Diagnosis of rhabdomyolysis
 Important cause of ATN (10-15% hosp pts with ARF in US)  Suggestive Hx
 Causes: trauma, esp crush injury, cocaine, exercise, statins, many others  Dipstick: heme + but no RBC
(tricking the dipstick: actually seeing Mb!)
Pathogenesis  Serum creatine kinase ↑↑
 Skeletal mm damage  myoglobin released  freely filtered @  Creatine ↑ disproportionate to BUN
glomerulus  PT reabsorption overwhelmed delivered to DT,  HyperK, hyperureicemia, HyperPO4
casts form (esp acid urine)  Metabolic acidosis
 HypoCa
(Ca/phos deposited in injured muscle)
Consequences:
 Intrarenal vasoconstriction (second hit) – scavenging of nitric oxide Tx of rhabdomyolysis
o Third-spacing of fluid in damaged muscle  hypovolemia  more
 Establish high urine flow rate
vasoconstriction
with saline infusion
 Proximal tubule iron toxicity (from Mb)  ± Supportive dialysis (but doesn’t
remove Mb, which is too big)
2. Exogenous nephrotoxins that cause ATN
Agent Effects
 Gent: direct tubular toxin
 Cationic: interacts with lipids in cell membranes
Aminoglycosides  ARF 5-10 days after start of Rx (if right away, not AG’s fault!)
Antimicrobials  Distal injury  polyuria (nonoliguiric ARF)
 Cr takes 3 wks to recover
Ampho B, vancomycin
Chemotherapy Cisplatin, 5-FU, others
Lithium
 Radiocontrast for CT, cardiac cath, etc.
 ATN via direct tubular toxicity
Other
Radioconstrast  Prerenal ARF too! (intense intrarenal vasoconstriction)
 Generally recover; avoid nephrotoxins while recovering
o No specific treatment

Diagnosis & Treatment of ATN

Diagnosis: H&P, often with multiple possible causes Treatment: no specific treatment; try to tx
(bacteremia + hypotension + gent) underlying cause, remove offending agents
 U/A: muddy brown, granular casts; ↑ Urine [Na+]  supportive care until / if renal function recovers
 Uosm > 350 (lose urine concentrating ability)
Finding Prerenal ATN
U/A Normal Muddy brown casts
+
ARF most commonly caused by ATN but prerenal ARF is 2nd! Urine [Na ] <2 >40
FENa < 1% > 2%
See table to right: remember in ATN can’t retain Na or concentrate well!
Uosm > 500 < 350

HIV-associated nephropathy (HIVAN)

 FAST – rapid onset  ESRD
 Mostly African Americans; 3rd leading cause of ESRD in AApts 40-65, most CD4 < 200
 Glomerular lesion (HIV pts also get ARF from infection, HTN, meds, intratubular obstruction from med crystallization, etc.)

Presentation: ARF + heavy proteinuria + bland UA, U/S shows large kidneys
Path: FSGS with collapsed basement membrane
Treatment: antiretrovirals, prednisone, ACEi
32
 Metabolic Acidosis
Acidemia: blood pH < 7.4 Alkalemia: blood pH > 7.4 Normal physiologic pH values*
Acidosis: processes that lower pH Alkalosis: processes that raise pH Extracellular fluids 7.37 – 7.43
3 HCO− Intracellular fluids 6.60 – 7.20
Henderson Hasselbach: 𝑝𝐻 = 6.10 + log(0.03 x PCO )
2 Range of extracellular pH 6.80 – 7.80
(Don’t memorize: (while still being alive)
just know you can calculate pH, bicarb, or PCO2 given the other two) * Biological processes run best at pH optima!

METABOLIC ACIDOSIS
Characteristics Etiology: REDUCTION OF HCO3-
 Fall in plasma HCO3-
 ↑ acid production
 Low arterial pH
 ↓ renal acid excretion
 Compensatory hyperventilation  Loss of HCO3- (stool or kidney)
(blow off CO2  ↓ PCO2)

ACIDS: Two classes

Carbonic acids (carbohydrates & fat) Non-carbonic acids (proteins), a.k.a. “titratable acids”
 Much more around, most important buffer  Less around
 Carbonic anhydrase (CA):  H+ comes during breakdown to glucose + urea
CO2 + H2O (CA) H2CO3  H+ + HCO3-

In general, we produce acid overall (generates an acid load – how do we get rid of it?)
 Extracellular buffer (HCO3-): 600k times higher than H+ concentration
 Intracellular buffers (proteins, CHOs, phosphates in cells/bones)
o Cells/bones eventually buffer about 55-60% of acid loads
o H+ into cells, K+ out of cells

Kidney and Acid/Base

Basic principles
HCO3- is reclaimed Acid is secreted
 removed by secreting H+ from tubule lumen
 filtered bicarb  completely “reabsorbed”/reclaimed
 H+ combines with titratable acids or NH3
 90% proximal, 10% distal tubules
to buffer acid in urine

HCO3- Reclamation

Proximal tubule : 90% of bicarb reclaimed Collecting tubule: 10% bicarb reclaimed distally
 Na/H antiport on apical surface, H combines with  Same idea, just no sodium gradient available now (most
bicarb, CO2 in, bicarb reformed inside, Na/bicarb has been reabsorbed: have to use ATP to get the hydrogen
symport on BM side into lumen & Cl / bicarb antiport to get bicarb into blood)

33
 Acid Secretion

Proximal tubule: Titratable acids Collecting tubule: Titratable acids

 
+
Same Na/H antiport as before Same idea; need ATP to get H out because sodium isn’t
 +
Instead of combining with bicarb, H combines with around; combines with titratable acid & excreted
titratable acid & excreted into urine;

Collecting tubule: AMMONIUM BUFFERING Proximal tubule: another way to form ammonium
 MAIN WAY that acid is excreted!  From glutamine (protein products)
 Ammonium can diffuse through to lumen, combine  See diagram of ammonia recycling below
+
with H , gets trapped (only uncharged things move
through membranes) & excreted

Ammonia recycling:
 Ammonia is freely permeable (NH3)
 Ammonium gets trapped in collecting duct  out in urine
(taking that extra hydrogen with it!  acid secreted!)

Approaching Acid-Base Problems

1) Look at pH (acidotic / alkalotic?)

2) Look at serum [HCO3-] (metabolic or respiratory?)
3) Calculate serum anion gap
4) Determine underlying cause
5) Determine therapy

34
In metabolic acidosis
 ↓ HCO3- is the primary problem
 ↓ PCO2 to compensate
o Tachypnea (try to “blow off CO2”)
o Try to maintain pH (but can’t quite)

 H+ + HCO3-  H2O + CO2

 ↓ HCO3,  LeChatlier shift to left  ↑ H+
 That’s bad, so ↓ CO2 via ↑ RR to balance

Arterial blood gas is how you get this data

 Format: pH / PCO2 / PO2 / HCO3-
 Example: (~ normal values) 7.4 / 40 / 90 / 25

Serum Anion Gap

Measured cation – measured anion = Na+ - (Cl- + HCO3-)

AG Why? Examples
Unmeasured anions:
Normal AG value 5-11 Healthy people
(phosphates, sulfates, proteins)
High anion gap Exogenous acids, poisons
> 11 Extra anions present but not measured!
metabolic acidosis Endogenous ketoacids or lactates
Normal anion gap GI bicarb Loss
5-11 HCO3- out but replaced by Cl- in
metabolic acidosis Renal bicarb loss

High anion gap metabolic acidosis

SLUMPED (MEMORIZE THIS): DDx of High Anion Gap Met Acidosis

How to assess?
Salicylic acid overdose Blood salicylate level
Lactic acidosis (incl. D-lactate) Serum lactate level
Uremia (renal failure) BUN / Cr / phosphate
Methanol poisoning Serum tox screen
Paradehyde poisoning
Ethylene glycol poisoning Serum tox screen, urine oxalate crystals
Diabetic keotacidosis Blood / urine ketones

Lactic acidosis
 Lactic acid: chews up bicarb, leaves behind anion gap
 ↑ lactate production (seizure, shock, hypoxia, sepsis)
o altered redox state  ↑ lactate production
 ↓ lactate utilization (hypoperfusion, liver dz – blocks
gluconeogenesis in liver & shunts pyruvate to lactic acid
formation)

35
Ketoacidosis
 Acetoacetate, β-hydroxybuturate  chew up bicarb, leave
behind anion gap
 Uncontrolled DM (usually type 1) is #1 cause
 alcoholic ketoacidosis - #2 cause (↑ lipolysis, ↓
gluconeogenesis, ↓ calories with alcohol  ↑ ketones)
 fasting (using FA  ketones for fuel)

Aspirin (toxin): converted to salicylic acid (chews up bicarb, etc)

 tinnitus, vertigo, nausea, diarrhea, altered mental state, coma, death
 Respiratory alkalosis at first! Stimulates respiratory centers (↓ PCO2), then high anion gap met acidosis
 Tx: dialysis

Methanol (toxin): wood alcohol

 converted to formaldehyde by alcohol DH formic acid
 Weakness, nausea, headache, ↓ vision, blindness, coma, death
 Lethal dose: 50-100 mL (doesn’t take much)
 Treatment: Fomepizole (inhibits alcohol DH), dialysis,
ethanol (as a competitive inhibitor of alcohol DH)

Ethyene Glycol (toxin): antifreeze, solvents

 Metabolized: glycolic & oxalic acid
o Can see calcium oxalate “envelope” crystals in urine (Dx!)
 Drunkenness, coma, tachypnea, pulmonary edema, flank pain, renal failure
 Tastes sweet & gives you a buzz, but…
 Lethal dose: 100mL (doesn’t take much)
 Treatment: same as methanol (fomepizole, EtOH, dialysis)

Renal Failure: 2 possibilities

 ↓ GFR  ↓ titratable acid excretion  ↑ anion gap, metabolic acidosis
o High anion gap metabolic acidosis!
o Titratable acids building up!
 ↓ tubular function  ↓ ammonia generation  retention of HCl  normal anion gap
o Normal anion gap metabolic acidosis
o Cl retained as bicarb ↓ so anion gap doesn’t change

Normal anion gap metabolic acidosis

 -
Bicarb lost but Cl increases, so anion gap stays the same
 GI loss: Diarrhea (GI loss of bicarb) or uterosigmoidostomy (urinary Cl exchanges with bicarb in gut)
 Renal losses (renal tubular acidosis): types 1,2,4

GI losses
Diarrhea: gastroenteritis, E. coli, cholera, laxative abuse
 Intestinal fluids have 50-70 mEq/L bicarb  lose in diarrhea
 Volume depletion  ↑ NaCl reabsorption in kidney  ↑ Cl
o For every bicarb lost, Cl- is gained  normal anion gap

36
Uretrosigmoidostomy
 Implant ureters into sigmoid colon (old surgery for congenital bladder problems)
 Hyperchloremic metabolic acidosis results
 Urine: high Cl- and NH4+, colon:
o absorbs Cl- in exchange for HCO3-
o absorbs NH4+ with Cl- as anion
 Other (rather predictable) problems: ↑ pyelonephritis, bowel incontinence (leak mixture of urine & stool at night on occasion)

Renal losses: renal tubular acidosis

Plasma + Urine
Type Picture Description HCO3
- K
pH Causes
↓ bicarb reabsorption in proximal
tubule Multiple myeloma
Carbonic anhydrase inhibitors
Can have pH < 5.3 (still have distal Other drugs
tubule working to acidify by secretion), nl
Type II bicarb can be OK (distal compensation), 14-20 or <5.3
(proximal RTA) ↓ Consequences:
Fanconi syndrome: damage to proximal
tubule  can’t reabsorb a lot of stuff rickets or osteomalacia
hypophosphatemia, glucosuria, (from phosphate wasting)
aminoaciduria
Chronic kidney disease #1
↓ net H+ secretion in distal tubules nl Drugs, autoimmune disorders
Type I <10 or >5.3 (Sjogrens, RA)
(distal RTA) No distal nephron to compensate: urine
pH rises, plasma bicarb can fall a lot ↓
Anything that messes up the
distal tubule

No response to aldosterone
Type IV ↓ H+ & K+ secretion in distal tubules 
(hypoaldosteronism) mild metabolic acidosis + hyperK
+ (amiloride, triamterene,
↓ urinary NH4 excretion too
Aldosterone deficiency
(adrenal insufficiency, heparin,
diabetic nephropathy, HIV)
15-17
↑
<5.3
↑ Aldosterone resistance
spironolactone, trimethoprim)

37
 Urine anion gap
UAG = (Na + K) - Cl
 Different from serum AG!
 Urine electrolytes: NaCl, KCl, NH4Cl
o So Na + K + NH4 should equal Cl
 Urine AG therefore a measure of AMMONIUM: should be negative
o Negative UAG: ↑ ↑ NH4Cl
o + or near zero: ↓ ↓ NH4Cl

UAG: Diarrhea, proximal RTA normal (negative) UAG

 Large NH4 in urine (DT works fine) so negative UAG
 Proximal RTA will have normal UAG too (distal NH4 production is fine)
 More ammonia as % of ‘lytes: but each NH4 comes with a Cl so anion gap is still negative!
o Getting an “extra” chloride for each NH4  negative gap

UAG: Type I or Type IV RTA: positive or zero UAG

 Now NH4 production is impaired (either damaged DT or ↓ aldosterone)
 Urine mostly NaCl, KCl: so (Na+K) and Cl will be mostly balanced!
o UAG = zero or positive!

Lab value summary table for RTA

Respiratory Compensation: What should pCO2 be?

 Usually going to hyperventilate so expect ↓ PCO2 with metabolic acidosis: but how much?

 Winters formula: predicted pCO2 = 1.5 (HCO3-) + 8 (± 2)

 If pCO2 < expected: simultaneous respiratory alkalosis (overcompensating: breathing too fast?)
 If pCO2 > expected: simultaneous respiratory acidosis (not compensating enough: breathing too slow?)

 Example: HCO3- = 14, expect pCO2 to be (1.5x14)+8 ± 2 = 29 ± 2

o If your patient had a pCO2 of 27-31, they’re in the expected range

38
 Nephrolithiasis
 Common (13% males, 7% females) and more common (37% ↑ ’80-’94), and expensive ($2B in 2005)
 Can be a phenotypic expression of an underlying metabolic disorder
 Advances in technology: helical CT for Dx, minimally invasive interventions for Tx
Stone classification
INFECTION METABOLIC
Struvite Calcium (classic)
Carbonate apatite - calcium oxalate
- calcium phosphate
Cystine
Uric acid

Infection stones: Struvite

Struvite a.k.a. “staghorn stones”
 Magnesium ammonium phosphate
 Can occur only if ↑urine pH / ammonia

How to make struvite

 Urease-producing organism needed: Proteus, Klebsiella, also ureaplasma,
staphylococcus, providencia, pseudomonas
o E. coli doesn’t make urease (so E. coli UTI doesn’t cause struvite stones)
o Urease: urea  2NH3 + CO2
o NH3 + H2O  NH4+ + OH-, then ammonia can go into Mg NH4 PO4 stones

What’s important about struvite stones?

 Rapid growth & large size (staghorn configuration)
 Associated morbidity (chronic infection, sepsis, lost of renal function)
 Requires surgical removal (pay attention to microbiologic studies too)

Metabolic Stones
Metabolic stones: need abnormal urine physical chemistry as a consequence of renal pathophysiology
Metabolic Stones: Cystinuria
 RARE: <1% all stone formers
 KIDS: median age of onset 12 YEARS
o Aut recessive (hereditary)
 High rate of recurrence but can ↓ recurrence with tx

Mechanism:
 Impaired PT transporter
o reduces reabsorption of dibasic amino acids (cys, ornithine, lys, arg)
 Results in increased urinary cystine excretion
 Cystine insoluble @ physiologic urinary pH)
o Push urine pH ↑, can increase solubility of cysteine: can prevent
formation & eventually dissolve stones

39
 Metabolic Stones: Uric acid
 5-10% all stones
o Gout = ↑ risk, but most pts don’t have gout (but do have “purine gluttony”- lots of steaks)
o Also associated with: chronic diarrheal states, diabetes + metabolic syndrome
 RADIOLUCENT on PLAIN X-RAY (visible on CT)
o No calcium – so if a patient has pain & xray clear, could still have uric acid stones

Pathogenesis:
 ↑ urinary uric acid helpful but not mandatory
 Acid urine pH required
o H+ + Urate-  Uric Acid
o Drive soluble urate salt to insoluble uric acid (pKa 5.75)
 Again: alkalinize urine  make UA more soluble!

Metabolic stones: Calcium Oxalate

Idopathic calcium oxalate stone former: the typical kidneystone patient
 About 80% kidneystone patients

Supersaturation: 1° importance for struvite, cystine, uric acid (precipitation, etc.)

Calcium oxalate stone formation: more complex

o Supersaturation necessary
o Other factors may be as / more important
o We’re all supersaturated with calcium oxalate, but only some form stones!
 Balance between supersaturation & inhibitors of stone formation

Randall (JH grad @ Penn): studied cadavers, found papillary

calcification (“plaque”) with stones attached
 Randall’s plaque: White plaques at papillae
 big calcium phosphate plaques where calcium oxalate
stones start forming
 nidus for crystallization

Mechanism of crystallization (not for memorizing)

 initial crystal deposits: BM of loop of henle, crystals
accumulate (interstitial CaP)
 urothelium erodes, CaP exposed to urine, CaOx binds (CaOx
supersaturated in urine), stone can grow

Non-idiopathic calcium oxalate stone formers: Enteric hyperoxaluria

 short gut syndrome (bowel resection, IBD, or bariatric surgery) or
malabsorptive state
 Fat malabsorbed; fat-soluble vitamins & calcium are saponified
o Ca normally binds oxalate in gut
o Saponified Ca can’t bind oxalate
o ↑ oxalate load absorbed, delivered to kidney
o ↑ Urinary oxalate
o Calcium oxalate stones form

40
 Metabolic Stones: Calcium Phosphate

Calcium phosphate crystallization is pH dependent (unlike calcium oxalate)

 Prefers alkaline pH (unlike other stones – can be a consequence of over-treatment with alkali therapy!)

Renal tubular acidosis (Type 1 – distal)

 Inability of distal nephron to acidify urine
 Net acid excretion impaired, ↓ plasma bicarb, urinary pH can’t fall, chronic H+ retention
 Associated with stone formation (multi-factorial)
o Acidosis (↑ calcium phosphate release from bone – buffer to retained acid)
o ↑ pH (more calcium phosphate precipitation)
o ↓ urinary citrate (normally inhibits stone formation)

Primary hyperparathyroidism
 Bones, stones, abdominal moans, psychiatric overtones
 Disease of middle age, W>M
 All consequences from ↑ PTH
o Hypercalcemia (↑ gut absorption, ↑ load to kidney, hypercalciuria b/c of ↑ filtered load)
o ↑ calcium reabsorption by distal tubule (but overwhelmed by Ca load)
o ↑ bone resorption ( osteoporosis / osteopenia)

 Stones in 15-20% cases (calcium oxalate &

calcium phosphate occur most commonly)

 Clinical presentation: nothing distinguishing

about stone disease (serum Ca can be only
mildly elevated)

Idiopathic hypercalciuria: happens despite normal

serum calcium level
 Intestinal overabsorption
 Defective renal tubular Ca reabsorption

Treatment
 Surgery (minimally invasive)
o 1 cm incision, stick mini vacuum cleaner into kidney collecting system, break up stone & suck it out
 Uteroscopy: minimally invasive; grab it with a basket
 Shock wave lithotripsy
o Hit kidney with shock wave to break stones up into tiny little pieces, wash out without symptoms
o Non-invasive!

41
 Metabolic Alkalosis
Compensation is part of metabolic acidosis
Has: generation phase (starts) and maintenance phase (persists)

What is metabolic alkalosis?

1. excess serum HCO3- ≫ 24 mEq/L (pathological process responsible)
2. ↑ plasma pH (≫7.4)
o To make ↑ plasma pH closer to normal: RR↓, PaCO2↑ (compensation)
o PaCO2 ≫ 40 (if 40 or less, something else is going on!)

For every 1 mEq/L rise in bicarb above 24, get a 0.7 mm Hg rise in PaCO2

Approaching acid/base status:

Can’t just tell from serum bicarb

1) Look @ serum pH (> 7.4?)

2) Look @ bicarb (>24?)
3) Determine expected compensation for PaCO2
-
a. 0.7 mm Hg x (Δ *HCO3 ] from 24) = expected change
b. Add expected change to 40 mmHg to see if another
process present as well
-
c. Example: if HCO3 = 31, expect (7x0.7)=4.9 increase in PaCO2

Consequences of metabolic acidosis: What’s the big deal?

Metabolic acidosis can KILL you!

↓ respiration  ↓ O2 delivery to tissues

 O2 dissociation curve of Hb shifts left ↓ O2 release to peripheral tissue

o “Bohr effect” – remember, if acidic (e.g. lactic acid ↑ in muscles), then the body wants to dump off more oxygen.
If alkalotic, will hang on to O2

 Vasoconstriction (↓ perfusion of vital organs)

CEREBRAL METABOLIC CARDIOVASCULAR
↓ cerebral perfusion  ↑ anaerobic glycolysis Vascular constriction
tetany, seizures, lethargy, delirium ↑ organic acid production
↓ coronary perfusion
↓ K+
↑ supraventricular & ventricular arrhythmias
↓ plasma [Ca+]

H+, HCO3-, and the Nephron

Proximal tubule: net HCO3- reclamation

Collecting duct: net H+ secretion

Next page: more detail

42
 Proximal Tubule: Reclaim HCO3-
Net movement: dotted line (reclaim bicarb)
 90% of filtered bicarb reclaimed here!

Proximal acidification linked to proximal HCO3- reclamation

 H+ secreted (Na exchange)  bicarb buffers  CO2 diffuses, etc.
 Weak acids, NH4+ also buffer secreted H+

Collecting duct: type A intercalated cells

Reabsorb last 10% of bicarb
 H+ ATPase pump secretes H+ (no more Na gradient)
+ -
o H comes with a Cl for electroneutrality
-
o To maintain Cl in cell for excretion, exchange Cl and bicarb at
basolateral membrane
o Result: reclamation of bicarb
 Aldosterone: ↑ H+ pump activity

Secrete acid
 H+ ATPase pump secretes H+ (↑ with aldosterone)
 Same thing as before, the H+ just doesn’t combine with bicarb
o H+ buffered in lumen by / excreted as:
 NH4Cl (most secreted this way)
 H2PO4 (titratable acid), HCl
 Note that Cl- still exchanges with bicarb on basolateral surface
o For every H+ secreted, a bicarb gets reabsorbed

In hypoK+
 H+/K+ ATPase (exchanger): second way to secrete H+
o Activated when ↓ K+

 Hypokalemia: ↑ acid excretion in type A cells

o BAD for alkalosis
 (for every H+ you secrete, you absorb a bicarb!)
 Bicarb is the last thing you need! You’re alkalotic!

Collecting duct: type B intercalated cells

Secrete base

 Requires Cl- in urinary space‼ (key)

 Bicarb and chloride exchanged!

43
 Collecting duct: principal cells

Acid secretion
 Generate a negative charge in lumen

 3Na / 2K ATPase (↑ with aldosterone) on basolateral side

o more of a drive for Na to come in from lumen than for K
to go out (3 Na / 2 K)
o slight negative charge generated in lumen

 Negative charge in lumen  easier for H+ to be secreted from

type A intercalated cell (bottom)
o Means more bicarb reabsorbed too!

COLLECTING DUCT IN ACID-BASE: SUMMARY TABLE

 H+ secretion (luminal H+/K+ ATPase)
Type A intercalated
 HCO3- regeneration (basolateral HCO3- / Cl- exchanger)
Type B intercalated  Secrete HCO3- (luminal HCO3- / Cl- exchanger)
Principal  Na+ influx  negative lumen  indirectly ↑ H+ secretion
 ↑ H+-ATPase activity (type A cells)
Aldosterone
 ↑ Na+ into principal cells (↑ lumen negativity  ↑ H+ secretion

Metabolic Alkalosis: Generation Phase

To have metabolic acidosis need
 Generation phase: something to start it up GENERATION PHASE: WHAT STARTS MET ALKALOSIS?
 Maintenance phase: something that keeps it going Loss of acid
 Vomiting
Vomiting:  Diuretics
 Normal: HCl (stomach) neutralized by NaHCO3 (pancreas)  ↑ aldosterone states
 Vomiting: lose HCl  NaHCO3 stays in blood alkalosis!
Hypokalemia: H+ shifts into cells
Diuretics Alkali load
 ↑ NaCl delivery to collecting duct  Citrate from massive blood transfusion
 ↓ volume  ↑ aldosterone (the whole point of diuretics)  NaHCO3 administration
 Milk alkali syndrome (e.g. antacid use)
 Combination: More Na absorption (principal cell) Volume contraction
o more Na in lumen = ↑ gradient to enter cell
o ↑ aldo  ↑ Na/K ATPase in principal cell
o ↑ Na absorption  lumen more negative 
o ↑ H+ secretion from type A intercalated cell met alkalosis

44
 Metabolic Alkalosis: Maintenance Phase
What keeps alkalosis going? Need impaired renal HCO3- excretion
 ↓ GFR: can’t get rid of extra bicarb
 ↑ tubular reabsorption
o Volume depletion, hyperaldosteronism, hypokalemia, chloride depletion
o All these keep kidney from getting rid of extra bicarb
 Target maintenance for treatment!

What happens? Vomiting? Diuretics?

Volume depletion
↓ ECV  ↓ renal perfusion ↑ AT II  ↑ aldosterone (see below)  
↓ ECV  Cl- depletion too (see below) Losing volume Losing volume

↑ aldosterone  ↑ H+ secretion
 ↑ H+ ATPase ( type A cells)
 ↑ Na/K ATPase  ↑ Na+ reabsorption (primary cells) more  
Aldosterone negative lumen Losing volume Losing volume
↑ RAAS ↑ RAAS
Aldosterone: good for fixing ECV but bad for alkalosis! ↑ aldo ↑ aldo
 Last thing you want to do is pee acid: H+ lost  bicarb is retained!

↑ H+/K+ ATPase (type A cells)

 Acid excreted, maintains alkalosis
 Good for fixing hypoK, bad for alkalosis!  
Hypokalemia Losing volume Losing volume
↑ RAAS ↑ RAAS
Why ↓K? Not from direct loss (vomit): in both cases, ↓ volume
↑ aldo ↑ aldo
 ↓ volume  ↑ aldo  ↑ Na/K exchange (principal cell) 
 retain Na (try to maintain volume) but excrete K  hypoK

 Volume depletion  ↑ RAAS,  ↑ Na reabsorption 

+

Cl follows paracellularly
 ↓ Cl- in lumen by the time you get to collecting tubule

Type A intercalated cells export H+ with Cl along

(maintain electroneutrality)  
 Bigger gradient for Cl to flow blood  cell  lumen, easier to drag
-
Chloride depletion Losing volume Losing volume
+
H along to keep electroneutrality ↑ RAAS ↑ RAAS
- -
 ↑ H+ excretion  maintain alkalosis ↓ Cl in urine ↓ Cl in urine

Type B intercalated cells secrete base

 Need luminal Cl- to pump in (exchanger for HCO3 excretion)
 Low urine Cl  can’t exchange for HCO3-  maintain alkalosis

Chloride sensitive vs resistant metabolic alkalosis

+
Normally, use urine Na to assess volume status
In metabolic alkalosis, use urine Cl-: why?
 Early (volume depletion + metabolic acidosis): two competing forces
+
o Want to raise volume  retain Na  urine Na should be low
o Want to dump bicarbonate  fight alkalosis  bicarb secreted proximally as NaHCO3  ↑ urine Na
o Can make urine Na look normal, even if ↓ volume!
 (Later: volume considerations win out, ↓Na)

45
 Cl- “sensitive” (UCl < 25 mEq / L) Cl- “resistant” (UCl > 25 mEq / L)

Mineralocorticoid excess
GI loss Diuretics
Example  1° hyperaldosteronism
(vomiting, NG suction) (late-remote use)
 Cushing’s syndrome

↑ distal Na+ delivery

↓ HCl generates alkalosis ↑ aldosterone  “aldosterone escape” (kidney
 ↑H+ / K+ loss
What senses too much aldosterone  excrete NaCl!)
happens? ↓ ECF, ↑ aldo, hypoK, ↓ Cl
↓ ECF, ↑ aldo, hypoK,
maintain alkalosis Unclear mechanism
↓ Cl maintain alkalosis
Low with remote use
Urine Cl- Low (can be high with current High (both UNa and UCl)
use: losing lots of fluid!)
Apparent mineralocorticoid excess (licorice, 11-β-OH-
Other steroid-DH deficiency, LIddle’s syndrome),
Post-hypercapnia
examples Glucocorticoid-remedial HTN, adrenogenital
syndromes, Bartter’s & Gitelman’s syndromes

IV NaCl + KCl KCl + fix underlying problem

Not NaCl: actually have ↑ total body NaCl (HTN)!
↑ aldo is problem: high aldo w/o ↑ ECV!
Treatment NaCl: restore volume (less Na- retention, ↓ aldosterone, lets
kidney excrete NaHCO3, ↑ Cl delivery to distal nephron)  Fix hypoK – still causes problems
+ + +  Remove adrenal adenoma, use aldo
KCl: replete K deficit (hypokalemia), ↑K  ↓ H secretion
antagonist like spironolactone

More on mineralocorticoid excess & other causes

Primary hyperaldosteronism & Cushing’s syndrome
 HTN, metabolic alkalosis, hypokalemia
 ↑ H+ secretion (directly through type A intercalated cells’ H+ ATPase & via principal cells / negative lumen)
 ↓ K+ and ↑ aldosterone maintain alkalosis

Syndromes of real & apparent mineralocorticoid excess (all of those listed above)
 Normally: cortisol  cortisone (inactive) by 11-β-OH-steroid-DH
o Cortisol can bind mineralocorticoid receptor just as well as aldosterone & provoke same effects
o Just normally inactivated in tissue where it would hit those MRs
 Enzyme deficiency, inhibitors (licorice / chewing tobacco), or just a ton of cortisol (Cushing’s) 
o Cortisol binds MR, aldosterone-like effects

Bartter’s Syndrome: acts like a loop diuretic Gitelman’s syndrome: acts like thiazide diuretic
 Genetic defect of Na+ reabsorption in TALH  Genetic defect of Na+ reabsorption in DCT
Both: ↑ distal Na delivery  H+ & K+ wasting
+

Both: can be exacerbated by volume depletion

Contraciton alkalosis
 E.g. CHF pt treated with diuretic
 Lose NaCl, KCl, HCl in ECF with diuretics
 Don’t lose bicarb: same amt bicarb, less volume  ↑ *HCO3-]

46
 Chronic Kidney Disease
Measuring GFR
 Inulin Clearance: gold standard, don’t really use clinically Definition of CKD
 Serum Creatinine: 1st line (good or bad?)  Kidney damage for ≥ 3 months
 Creatinine Clearance: UV/P & match units o Structural or functional abnormalities of
o Hard to get urine, lots of problems, etc. kidney, ± ↓ GFR
 ↓ GFR for ≥ 3 months
Abbreviated MDRD study equation New staging for CKD: primarily based on kidney function
 Better approximation, easier (no urine collection)
 SCr, age, gender, race – but didn’t include older people in study (does it apply?)
 Given to you on labs (hard to calculate – lab does it)

140−age × lean body weight (in kg)

Cockcroft-Gault equation: 𝐶𝐶𝑟 = × (0.85 𝑓𝑜𝑟 𝑤𝑜𝑚𝑒𝑛)
𝑃𝐶𝑟 ×72
 Easier to calculate, useful, not as accurate as MDRD

CKD: Epidemiology
20M with CKD in US, many more at risk
 Staging: see picture (higher is worse: based on GFR)

Diabetes is #1 cause, HTN #2, Glomerulonephritis #3

What are we looking at? GFR is the total GFR!

 Takes whole kidney into account
 Single nephrons: snGFR

Progression of CRD
Injury to a single nephron (glomerular, tubulessclerosis)
 Initially ↓ GFR
 Then ↑ GFR: residual nephrons start working harder!
o Can even take out a kidney and get GFR recovering
 But ↑ snGFR  ↑ injury to remaining nephrons!
o Downward spiral

What does the kidney do?

• Fluid and Electrolyte Homeostasis
– Sodium and Volume , Water Balance and Tonicity
– Potassium, Calcium/phosphate and Magnesium
• Acid/Base Balance
• Elimination of toxic waste
• Blood Pressure Regulation
• Endocrine (EPO, 1:25-OH-Vit-D)

Sodium in CRD
+
If GFR > 25 cc/min: can increase your FeNa to still get rid of salt (no symptoms!)
If GFR < 5-25 cc/min: start retaining sodium (edema, HTN, pulmonary congestion)

Kidney can keep up – to a point!

47
 Water
Normally: concentrate or dilute urine
 Loop of Henle: generates medullary concentration gradient, reabsorb Na+ to dilute urine
 Countercurrent mechanism is intact, adequate distal delivery of salt & water

CRD:
 Scarring, not a lot of space to do the exchange: all of this messed up
 Limits both concentration & dilution:
o Normal range for urine: 50-1200 mOsm/L
o CKD has an upper range of 600 mOsm/L

Potassium
 If aldosterone production is normal: you can handle potassium until
GFR < 20 mL/min (then you start hyperK)
 Deficient in aldosterone: develop hyperkalemia earlier(with higher GFRs!)
o ↓ aldo: primary adrenal problem, 2° adrenal problem to diabetes, HIV, or ACEi

Acid/Base Balance
Acid load: 1mEq/kg/day
 Sulfuric acid: sulfur-containing amino acids
 Excreted as H+ (titratible acids) & ammonium

In CKD:
 GFR > 40 ml/min: ↑ ammonium excretion per nephron
o (can be 3-4x normal excretion per nephron because they’re
compensating)

 GFR below 40: can’t keep compensating with remaining nephrons

o ↓ Total ammonium excretion (see graph: can’t get rid of it!)

Why is this a problem?

 Body starts using hydroxyapatite as base  bones dissolving  fractures!

Uremia
Multiple functions of kidney deteriorate in parallel  complex symptoms

Kidney needs to eliminate poisons but we don’t know what they are!
 Small water soluble molecules? Urea? But we used to give it as a diuretic! Not convincing
o Inhibits Na/K/2Cl cotransport
o Inhibits NO synth in Mϕ
o Precursor of guanidines: inhibits PMN superoxide production, may induce seizures, etc.
 Protein bound compounds? if you eat less protein, less symptoms of CRD!
o P Cresol: multiple cell functions incl. oxygen uptake, drug protein binding, growth, permeability of cell membranes
 Phenol is end product of protein metabolism
o Indoles: product of liver metabolism, ↑ levels  ↓ endothelial cell prolif / repair
 Middle molecules? (MW > 500 Da)
o These middle weight fractions of dialysis can inhibit various things – but we still don’t know

48
 Blood Pressure Regulation
Increased blood pressure:

 Need less when giving a pressor! Decreased threshold

 In chronic kidney disease:

o Can’t get rid of sodium: ↑ effective arterial blood volume
o ↑ renin, ↑ NE: more vasoconstriction
o Exacerbates HTN, causes more damage, etc.

Endocrine: Anemia
EPO deficiency is primary cause
 ↓ GFR  ↓ EPO so ↑ anemia prevalence (see graph)
Secondary causes too:
 Fe deficiency
 Nutritional deficiencies
 Occult GI bleeds
Anemia from any cause can happen in pts with CKD
 need to do full evaluation first

Endocrine: PTH, Calcium & Phosphorus

Parathyroid hormone is key in control of vitamin D, calcium, and phosphorus balance

Calcium Homeostasis: Get back to set point (10 mg/dL)

 ↓ blood *Ca+2]  ↑ PTH 

o Bones: release Ca+2
o Kidneys: take up more Ca+2 & make more
1,25OHD3
 More active vit D  more uptake in
intestines

 ↑ blood *Ca+2]  ↑ calcitonin (thyroid)

o Bones: deposit Ca+2
o Kidneys: take up less Ca+2

So if kidney is messed up, so is calcium homeostasis!

Phosphorus:
 Proximal tubule reabsorbs (2Na+ / H2PO4 cotransport)
o 15-20% gets through, excreted in urine
 So phosphate would also be out of balance in kidney disease

49
Vitamin D:

Normal synthesis:
1. Make Vitamin D3 by exposure to sun
2. Precursor binds to D-binding protein

3. Hepatic: D3  25(OH)D3
(storage form)

4. Renal: 25(OH)D3  1,25(OH)D3

(active form)

 No kidney  active vitamin D3 ↓

 Most vitamin D deficiency: Middle East (stay out of sun & veils for women)

In chronic renal failure: Bone problems in CKD

 ↓ Ca+2  ↑ PTH  Acidosis  use hydroxyapatite as base to buffer
 But kidneys are messed up:  Calcium homeostasis disturbed
o can’t reabsorb & o ↓ reabsorption
o can’t make active vitamin D to get from diet! o ↓ active vitamin D  ↓ GI absorption
 Chew up bones in order to maintain calcium homeostasis! o ↑ bone breakdown to release more calcium
 CHRONIC HYPOCALCEMIA

Phosphorus: goes up in long-standing kidney disease (eventually)

Earlier: when GFR > 20, (↑ snGFR) Later: when GFR < 20
 ↓ serum phosphorus  Still have blocked transporter but
 have ↑ phosphorus in tubule vs. to normal  ↑ serum phosphorus
 Block phosphate transporter via PTH  pee it (weird – why aren’t you still peeing it out if you can’t absorb it?)
out  GFR very low: not getting phosphorus excreted  builds up

How long as CKD been going on?

 Check PTH and hemoglobin!
o Very elevated PTH - ↓ GFR (higher stage CKD)
o Low Hb (anemic! ↓ Epo

50
  Can’t rely on calcium or phosphate levels
o as calcium↓, PTH ↑, driving ↓ phosphate and ↓ Ca
o Maintains a pretty constant level of Ca and
phosphate
o but PTH itself is elevated (keeps increasing with ↓
GFR as each new drop in calcium happens)

↑ Calcium and ↑ phosphate also deposit (CaPO4)

 Skin: patients often itch
 Arteries, mitral valve  arterial/valvular calcification
o Basically getting CAD!  ↑ heart disease risk

Parathyroid hyperplasia
 Need to crank up PTH so parathyroid grows
 Eventually develops nodularity  single nodule
 Doesn’t respond to normal feedback
o Making PTH no matter what!
o Even if you correct Ca+2 levels, doesn’t help:
o e.g. transplant, might have to remove parathyroid
(↑↑ PTH persists!)

51
 Pathogenesis of Hypertension
Definition: a persistent elevation of the systolic blood pressure and/or diastolic blood pressure in the systemic arteries
 repeated measurements
 Cutoff point is arbitrary: Classification of BP for adults 18yo or older
o Resting SBP ≥ 140 and/or BP classification SBP (mm Hg) DBP (mm Hg)
o Resting DBP ≥ 90 Normal <120 and <80
Prehypertension 120-139 or 80-89
Stage 1 hypertension 140-159 or 90-99
Epidemiology: major public health problem Stage2 hypertension ≥160 or ≥100
 High prevalence (24% all US adults, ↑ in Blacks)
 ↑ risk CVD (MI & stroke) & ESRD
 Awareness is low (72% pts aware they have ↑ BP)
 Treatment & control are lower (61% get Tx, 35% under control!)

Pathogenesis of Hypertension
BP = CO x PVR (need to keep them balanced)
HTN: ↑ CO and/or ↑ PVR
 ↑ CO: ↑ preload, ↑ contractility, ↑ HR
 ↑ PVR: ↑ arteriolar vasoconstriction, or structural alterations (remodeling)
↑ preload = ↑ECVF (extracellular fluid volume) ↑ contractility or ↑ HR ↑ PVR
↑ ECFV = Na, H2O retention
 Arteriolar vasoconstriction
(alteration in kidney’s ability to regulate Na balance)
 ↑ sympathetics  Vascular structural remodeling
 ↓ Na excretion & ↑total body Na
 ↑ catecholamines o ↓ elasticity, capacity of circulatory
 ↓ Na excretion: from ↓ GFR (CKD) and/or ↑
system to accommodate CO
tubular reabsorption (mineralocorticoids)

Primary / Essential HTN (95% of hypertensives)

 Most patients = no definable cause (“primary” / “essential” HTN)
o Big variety of systems involved: CO, PVR, RAAS, sympathetics;
o Other factors: endothelin, NO, ANP, bradykinin

Most hypertensives: NORMAL CO but ↑ PVR

Cardiac Output
 PVR: determined by small arterioles, which have smooth muscle cells in walls
& PVR
 Prolonged smooth mm constriction  structural changes in vessel walls  irreversible rise in BP

Renin: secreted from JGA cells of aff. arteriole if:

 ↓ glomerular perfusion, ↓ salt intake, symp. stimulation via
o stretch receptors in aff. Arteriole
o symp. nerve endings in JGA cells
o composition of macula densa fluid (TALH))

RAAS  Many HTN pts have LOW RENIN & AT II levels (elderly, AAs)
 See other lectures for full/better summary of RAAS
AT II effects via ATII type I receptor:
 vasoconstriction  ↑ tubular Na reabsorption (direct & via aldo)  ↑ thirst
 ↑ aldo synthesis / release  ↑ vascular cell hyperplasia & hypertrophy

Remember: non-circulating, local RAAS systems too (brain, heart, kidneys, arterial tree); regulate regional blood flow

52
 ↑ SNS  ↑ BP:
 Heart: ↑ CO (↑ contractility & ↑HR)
 Vasculature: ↑ PVR
Sympathetic  Kidneys: ↑ fluid retention
Nervous
System
Contributes to development of HTN but not maintenance of HTN as much
 Can induce vascular changes (smooth muscle hypertrophy)  maintain
HTN although symp activity ↓

Most potent endogenous vasoconstrictor

 Released from endothelial cells  bind ET-A receptors (vascular smooth mm)  vasoconstriction
 Plasma levels normal in HTN subjects (↑ sensitivity in “essential HTN”?)
Endothelin-1
Possible evidence for role in HTN:
 excise endothelin-secreting tumor cure HTN
 Bosentan (ET receptor blocker) has equivalent BP reduction as enalapril (ACEi)
 Endothelin antagonist: ↓ BP, ↓ PVR in normotensive people: maybe tonic role in BP?

Potent vasodilator
 Short-lived, highly permeable gas, released by endothelial cells in response to…
o BP changes, shear stress, pulsatile stretch
Nitric Oxide  Also: ↓ platelet adhesion / aggregation, ↓ migration/proliferation of vascular smooth mm cells

Tonic role? Animal models: NO inhibitors  sustained HTN

 NO -mediated relaxation diminished in HTN pts, but don’t know if this is cause or consequence of HTN

Multiple genes, may account for ≈ 30% variation in population BP

 HTN 2x as common if one or both parents have HTN

Inherited HTN component: primarily in the KIDNEY(abnormal Na HANDLING)

Genetic  Transplanted kidney from donor with HTN  ↑ BP, ↑ need for antihypertensive Rx
 Donor without HTN: no ↑ BP in recipient
Factors
Specific mutations can cause HTN too
 Liddle’s : HTN (mutation  activate ENaC in DCT, low plasma renin / aldosterone, responds to amiloride)
 Congenital adrenal hyperplasia: 11-β-OHase deficiency, ↓ cortisol  ↑ ACTH  HTN (↑ secretion of
11-deoxycorticosterone)

Low birth weight is the big one (poor fetal nutrition)

Intrauterine  ↓ birth weigh  ↓ # nephrons  HTN
differences
Also ↑ with ↓ social status of father

53
 Many factors: SALT INTAKE, obesity, occupation, alcohol intake, family size, crowding

Salt intake: strong association

 “salt sensitivity” – may be interaction between genetic predisposition & environmental exposure
Environmental  ↑ Systolic BP with ↑ Na excretion (measuring Na intake) and ↓ potassium excretion
Factors
The western diet:
 ↑ Na intake  ↓ renal adaptation  ↑ Na retention & ↓ K retention
 ↑ Na/K ATPase activity  ↑ cellular sodium ; ↓ cellular potassium
 Vascular smooth mm constriction, ↑ PVR, HTN

Secondary Causes of Hypertension

Can be renal, endocrine, cardiovascular, neurologic, other (drugs, genetics, etc.)

Renal causes Cardiovascular causes

 Renal parenchymal disease  Congenital coarctaion of the aorta
(glomerulonephrits, chornic pyelonephritis, PKD) (just distal to L. subclavian a.)
 Renal vascular disease  Polyarteritis nodosa
(renal artery stenosis from atherosclerosis or or other vasculitis that affects kidneys
fibromuscular dysplasia)
 Renin-secreting tumors (really rare) Neurological causes
 ↑ intra-cranial pressure
Endocrine causes:  Sleep apnea
 Adrenal gland:
adrenal cortical hyperfunction (Cushing’s, Conn’s, CAH) Others:
 Pituitary gland:  Pheochromocytoma
acromegaly, basophilic adenoma (↑ ACTH)  Drug-induced or related
 Thyroid gland (thyrotoxicosis)  Genetic: Little’s

A few specific examples:

Renal artery stenosis

 ↓ renal perfusion  ↑ RAAS  HTN

 Can be caused by atherosclerosis, or

fibromuscular dysplasia

Pheochromocytoma
 See IVC displaced anteriorly on sagittal MRI (finding for adrenal tumors)
 CATECHOLAMINE-SECRETING (unregulated & excessive)
o ↑ CO, ↑ PVR  HTN

Primary hyperaldosteronism
 Adrenal enlargement on T1-weighted MRI
 Unregulated, excessive tumor production of aldosterone
o ↑ mineralocorticoid effect  ↑ Na reabsorption in DT
o Na retention  volume expansion  HTN
o Renin: chronically suppressed

54
 Risk factors for HTN
• Genetic predisposition or family history • Excessive alcohol intake
• Black race • Low socioeconomic status
• Diagnosis of prehypertension • Sleep apnea
• Increasing age • Use of certain illegal drugs or over the counter
• Obesity medications
• High sodium – low potassium intake

Resistant HTN
If you see a patient with HTN and can’t control despite multiple Rx’s (resistant), think of this list

 Improper BP measurement  Associated conditions:

 Non-adherence o Obesity
 Inadequate doses o Excess alcohol intake
 Inappropriate combinations
 Drug-induced:
o Illicit drugs: cocaine, amphetamines, …
 Volume overload:
o Sympathomimetics: decongestants, …
o Excess sodium intake
o Oral contraceptives
o Kidney disease
o Steroids
o Inadequate diuretic therapy
o Cyclosporine, tacrolimus
o Erythropoietin
o Licorice

Hypercoagulability and Hypertension: a mystery wrapped in a riddle

The thrombotic paradox of hypertension, a.k.a. the Birmingham paradox

 Blood vessels exposed to HIGH PRESSURE in HTN
 But the main complications of HTN are THROMBOTIC (stroke & MI) rather than HEMORRHAGIC

55
 Non-pharmacologic Treatment of Hypertension
BP measurement history Benefits of “lifestyle” therapies
 Harvey (1616): circulation ↓ BP
 Hales (18th c): cannulated artery (horse) Non-hypertensives Prevent HTN
Prevent age-related rise in BP
Kortokoff: observed sounds made by constriction of artery at certain Always initial therapy
points in inflation / deflation of cuff that correspond to SBP & DBP Hypertensives Adjunct to drug therapy
Substitute for meds

Accurate BP measurement in office

 Properly calibrated & validated instrument
 Seated measurement (5 minutes in chair with feet on floor, legs not crossed, arm supported at heart level)
 Cuff: right size (should cover at least 80% of arm)

Inflate cuff  occlude blood flow 

1st Kortokoff sound @ SBP
5th Kortokoff sound @ DBP

Waveform: maximum amplitude of pulse in

cuff (used in oscillometric)

Ascultory: listen to BP
Aneroid (dial measures pressure)
 Less accurate than mercury
 Mercury banned now though

Oscillometric (machine)
 Less accurate
 Measure amplitude of pulse waveform at
maximum, algorithm  estimate SBP &
DBP
 Underestimate higher BPs, overestimate lower BPs

Who cares about blood pressure?

 SBP ↑ with age (target in elderly)

 DBP ↑ with age until about 60
 ↑ Pulse Pressure with age

↑ HTN with ↑ BMI

Hypertension is #1 for burden of disease / death in developed world!
↑ risk of stroke (at all ages)

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 Blood pressure classification (JNC VII)

“pre-hypertension” – have 90% risk of developing HTN Category Systolic BP Diastolic BP

 Try to motivate to change lifestyle! Normal < 120 and <80
Pre-hypertension 120-139 or 80-89
Prevalence: most people are abnormal Hypertension
HTN: 27%, PreHTN: 31%, HTN: 42% Stage 1 140-159 or 90-99
Stage 2 ≥ 160 or ≥100
Pretty much everybody develops HTN if you live to be 85
 But some studies: less in farmers than city dwellers in China
 Lifestyle could make a difference!

Treatment
Always encourage lifestyle: even if they’re normal; add drugs depending on stage (HTN stage 1 or 2)

LIFESTYLE THERAPIES TO ↓ BP
 Weight loss (among those who are overweight or obese)
 ↓ salt (sodium chloride) intake
 ↑ potassium intake
 Certain dietary patterns
o DASH diet
o Vegetarian diets
 Increased physical activity
 Moderation of alcohol intake (among those who drink)

Don’t see: smoking (doesn’t ↑ risk HTN on its own), trans-fats, saturated fat, cholesterol etc!
 Hypertensives should still reduce these things (CVD/stroke risk!)

Calcium & Mg supplements, fish oil, fiber don’t seem to work in isolation
Studies in isolation: see table for ↓ SBP/DBP

1) Choose & prepare foods with Little or No Salt

a. ↑ NaCl  ↑ BP, we eat way more than basic needs (150
mmol vs 10 mmol)
b. DASH DIET: lowers blood pressure (10mm – like taking a pill)
1. bigger effect if your diet was high sodium before
2. Difference maintained throughout day & night
3. Bigger effect in AA vs non-AA pts
c. BP response to change in salt intake is heterogeneous: AA & older pts are more “salt sensitive”
1. Issues: no clinical test for salt sensitivity, use groups
d. Where does salt come from? Processed foods (not much at the table)
e. Goal: < 1,500 mg/day (65mmol)
1. interim target (<2,300 mg / 100 mmol/day) –hard to hit real goal with current food supply

2) Increase your intake of foods rich in potassium

a. Diet rich in potassium  lower BP
b. Hard to take KCl pills (really big)  diet is the best way to go
1. ↓ BP, reduces “salt sensitivity”
c. Food: preferred (usually KCitrate, a bicarb precursor: also helps with ↓ bone turnover, ↓ risk kidney stones)

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 1. fruits (bananas, oranges, orange juice)
2. vegetables (broccoli, tomatoes/tomato juice, potatoes)
3. others (beans, yogurt, dairy)
d. At least 4,700 mg per day (should be lower if impaired K excretion)
e. Impaired excretion:
1. Drugs: ACEi, ARB, K+-sparing diuretics
2. Medical conditions: diabetes with kidney damage, CKD, HF

3) Consume the DASH Diet

a. This is the recommended diet – not Atkins, etc.
1. Was tested with outpatients, fed them everything, isocaloric (wt constant) & Na similar in all diets
2. Tested vs. typical American, DASH, typical American with more fruits & vegetables

b. What is it?
1. Emphasizes: fruits, vegetables, low-fat dairy products
2. Includes: whole grains, nuts, poultry, fish
3. Reduced: sat fat, total fat, cholesterol, red
meat, sweets, and sugar-containing beverages

c. What does it do?

1. Fast & significant BP lowering (10 mm Hg)
2. Effective in broad segments of pop
3. Especially effective in:
1. Hypertensives
2. African-Americans
4. Also: ↓ LDL, meets all major nutrient / food recommendations, consistent with US dietary guidelines

4) Maintain a healthy body weight

a. BMI↑, HTN↑
b. BMI↑, also other ↑ CVD risk (HTN, DM type 2, cholesterol)
c. Weight loss  ↓ risk factors (BP, etc.)
Weight (lbs)×703
d. 𝐵𝑀𝐼 =
height (in2 )
e. To lose weight: cut calories: ↓ intake, ↑ exercise
1. 500 cal/day  4 lb / month
2. Hard – people tend to go back to weight

5) Be physically active
a. As you exercise, ↑ BP; with training, less increase in BP with exercise (good!)
1. Sedentary lifestyle: ↑ BP, ↑ BMI, ↑ CVD risk
2. Moderate activity: can lower BP (brisk walking, swimming) - recommended
3. Vigorous activity: also lowers BP but ↑ risk orthopedic problems
b. Shoot for: 30 min most days in a week

6) Moderation of Alcohol Intake (among those who drink)

a. Drink  ↓ BP; rebound ↑ BP after binge
b. J-shaped relationship: moderate drinking = ↓ risk of dying
1. Above 2 alcohol drinks / day, BP↑ with ↑ alcohol
c. Recommend: for those who drink, do so moderately
1. (≤2 drinks/day for M, ≤1 for women)
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 2. (↑ HDL, so don’t start if you don’t drink)
7) Macronutrients also affect BP
a. Reduce carbs, increase protein, increase good fats
b. 16 mm reduction (especially high protein) – DASH-like diets are good

How can docs help?

Public health approach: a 5mm reduction in SBP would lead to 15% less coronary heart disease, 27% less stroke
 Individual level – hard to maintain over time

Exercise advice:
 43% pts reported getting advice to ↑ exercise; 75% of those reported exercising
 42%: got advice to ↓ fatty foods, 88% reported trying

If you focus on sodium reduction, you can lower by 50% (confirmed by 24h urine!)
 Great chance for success – be encouraging

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 Management of End Stage Renal Disease
Stage Findings
GFR < 15 - need to start renal replacement therapy (dialysis or transplant)
Urinary abnormalities
I
GFR > 90 mL / min
Scope of the problem
II GFR 60-89
 600K pts with ESRD, 100k/yr and growing, $28B/yr
III GFR 30-59
 Minorities over-represented: AA, Hispanics, Native Americans
IV GFR 25-39
V (ERSD) GFR < 15
Leading causes: DM, HTN, chronic glomerulonephritis, HIV-associated
nephropathy (HIVAN), hereditary dz (polycystic kidney or alport's)

Treatment options: (often switch modalities)

Hemodialysis Peritoneal dialysis Renal transplantation
(in center or home)  Continuous ambulatory peritoneal dialysis (CAPD)  Deceased donor
 Continuous cycling peritoneal dialysis (CCPD)  Living donor (related or unrelated)

Hemodialysis
Dialysis = "to separate": separating crystalloid from colloid by a semi-permeable membrane
 Dialyzer: biocompatible membrane with parallel hollow fibrils
o blood flows inside fibrils, rapid blood flow rate (450mL/min)
 Dialysate: bathes blood with countercurrent flow
o solute drawn off by diffusion, fluid drawn off by convection
o Fast flow replenishes gradient
Inadequate dialysis:
 Delay: pan-serositis can result (pericarditis especially common if severe fluid load, advanced uremia)
 Inadequate: recurrent uremic symptoms & poor surival
 Access failure is life-limiting problem (if you keep clotting, can run out of access sites)

Requirements for hemodialysis

 Access to blood stream
o Large central venous cath (not good - invasive, endocarditis, etc)
o A-V fistula or graft for access, can cause HF problems if too large
 Fistula preferable to graft: use own blood vessels, "matures" in 8-16 wks
 Graft: more tendency to clot / infection
Facility placement, transport 3x/wk
o 3-4hrs per treatment + 1 hr pre-post preparation
o Fixed schedule - MWF or TThSa
 Compliance with diet, medication
Advantages Disadvantages
 Access complications (infection, clotting, thromboses,
high-output HF because of A/V fistula)
 Rapid, performed by staff
 Accelerated atherosclerosis (more AGEs, not cleared)
 Nutritionally safe (not losing protein)
 Hyperparathyroidism
 Can give IV meds (procrit, iron, VitD, Abx)
 Depression & suicide (passive, via withdrawal of Tx mostly)
 Easy to monitor
 Inflexible schedule
 Social interaction, supportive environment
 Rapid fluid shifts (hypotension, cramping weakness)
 "Sawtooth" labs & BP shifts

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 Peritoneal dialysis
 Uses peritoneal membrane as "dialyzer" membrane
 Slower blood rate than hemodialysis, do it every day
 Dialysate in via catheter with perforated tip in lower abd
 CCPD: continuous cycling PD (4-6 exchanges at night)
 CAPD: continuous ambulatory PD (4-6 exchanges in 24h)

Cath-related peritonitis: 0.5 episodes per pt/yr (fever, abd pain, nausea)
 Signs: abd tenderness +/- rebound, cloudy dialysate, elevated peritoneal WBC with PMNs
 50% gram + (coag - Staph, Staph aureus, VRE, Group B strep) - think skin organisms
 15% gram - (pseudomonas), 5% polymicrobial, <2% fungal

PD vs hemodialysis
PD advantages PD disadvantages
 Personal freedom  Personal responsibility / time committment
 Better BP control  Protein wasting - big complication!
 Higher Hgb/Hct (less blood loss)  K wasting
 No a/v access problems (clotting, infection)  Potential for cath-related bacterial peritonitis
 Smoother uremic control (avoid saw-tooth  4-6wk lead time (surgical visit, cath placement, cath maturation, education)
chemistries, big volume  "cycler claustrophobia" - have to be hooked up toa machine at night
expansion/contraction)  Need: space for supplies, visual acuity +/- helper

Transplantation
 Dialysis is management, transplant is cure
 Transplant: remember that kidney does more than fluid / electrolyte balance
o Mineral balance, EPO secretion, drug metabollism all taken care of with transplant but not dialysis
o Can reverse all signs & symptoms of uremia
Types :
 Cadaveric: brain-dead donor
 Living
o related donor
o unrelated donor
 Cross-match negative (unrelated donor better than cadaveric as long as they're blood type compatible)
 Cross-match positive (will do higher risk transplants in some exceptional situations)

"Most perfect" renal replacement therapy

 Rejection / chronic allograft nephropathy: limit long-term survival
o 10-20 yrs graft survival can occur
 Complications of immunosuppression therapy are big
Pre-transplant preparation needed:plasma exchange & immunosuppression

Advantages Disadvantages
• Perioperative risks (morbidity & mortality)
• Freedom from dialysis • Lifelong need for immunosuppression
• Avoids accelerated CV syndrome with dialysis • Risk of rejection
• Better overall survival • Risk of allograft nephropathy
• Side effects of therapy

Side effects of therapy:

• HTN, infection, malignancy (skin, lymphoma, other), steroid toxicity (cataracts, bones, joints, diabetes)

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 Genetic Renal Disease
Glomerular disorders Tubular disorders
Salt wasting Tubular structure
Alport Syndrome (hereditary nephritis)
Bartters syndrome
Congenital Nephrotic Syndrome Autosomal dominant polycystic kidney disease
Liddle syndrome

Alport syndrome (hereditary nephritis): a GBM disorder

X-linked and autosomal forms
Autosomal forms
X-linked form
Recessive Dominant
85% of Alport’s 15%
Epidemiology Rare
Males more severely affected Severity: M=F
• Glomerular hematuria (from birth) • Hearing loss
• Proteinuria (develops in childhood) common Overlap
Signs & • Hearing loss (55%) – progressive, sensorineural • Hematuria with familial
symptoms • Anterior lenticonus: cone-like lens deformation (in 15-30%, pathognomonic) (common in benign
• Variable presentation in females (random X-inactivation) heterozygous hematuria?
o Intermittent microscopic hematuria, no significant proteinuria, ↓↓ESRD “carriers”)
• ESRD common in males ESRD early
Course
(most young adulthood < 30, subset later) (teens-20s)
Mutations α5 subunit of type IV collagen (+α6 for subset with leiomyomatosis) α3 + α4 α3 + α4

Pathology
Bright-field: non-diagnostic (benign early  sclerotic glomeruli later)
IF: loss of Goodpasture epitope in GBM (males/AR forms)
• (can see staining / non-staining alteration in females)
• Can be diagnostic
EM:
• Early: GBM thinning (non-diagnostic)
• Late: basket-weave pattern (pathognomonic) (areas of thinning and
thickening, breaks in GBM on close-up, looks moth-eaten, holey, patchy)

What’s Wrong?
Type IV Collagens
• α1-α6 subunits, 3 combine  protamer
o 2 classes: (α1,3,5 | α2,4,6)
• α1-2 / α3-4 / α5-6 paired up on different
chromosomes (head-to-head)
• Goodpasture epitope is in globular domain of α3 subunit
• X-linked: α5 mutation, Autosomal: α3 + α4 mutation
Skin biopsy: can use for Dx
• α3,4,5 normally in GBM
• α5 is in skin too: see if it
stains! (near right)
• X-linked: no staining (males)
alternating stain (females)
IF of glomerulus:
• see all 3 (α3/4/5) are missing
• If you disrupt one, the whole collagen trimeric protamer can’t assemble
• Picture: far right
• This is why Goodpasture epitope (α3) lost in X-linked pt with α5 mutation

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 Congenital Nephrotic Syndrome (NPHS1): a podocyte disorder

Epidemiology Clinical Presentation

• Rare (Finland: 1/8000; Lancaster County, PA (Groffdale  Early fetal presentation (Heavy proteinuria)
Mennonites): 1/500) – founder effects  Premature birth
• Autosomal recessive  Proteinuria (± RBC/WBC)
 Often die in first years of life (complications
of nephrotic syndrome, 1° infection)
Pathology:
• Grossly enlarged kidneys with ↑# nephrons
• LM: non-diagnostic (normal glomeruli)
• EM: GBM ok, FOOT PROCESS FUSION of podocytes (see EM)

What’s wrong?
Mutation: Autosomal recessive (19q13.1,29) – NPHS1
 Expressed in kidney (fetal & adult), encodes adhesive protein
 Nephrin: the gene product, localized to slit diaphragm
o Slit diaphragm messed up, ↑ permeability  proteinuria

Bartter’s syndrome: a salt-wasing tubular disorder

Autosomal recessive, present at:
Presentation: like a LOOP DIURETIC OD
 birth/infancy (dehydration, severe salt wasting
 Hypokalemic metabolic alkalosis
 early childhood (failure to thrive)
 ↑ urine Cl excretion
 ↑ plasma renin & aldosterone activity
What’s wrong?  HypoNa (volume contraction ↑ ADH)
Rule out: 1° hyperaldo (no HTN), 2° hyperaldo (extrarenal NaCl losses  HyperCa  nephrocalcinosis
unlikely because so much Cl being secreted)

Various mutations: in the end, affecting TALH NaCl transport (like loop diuretic – Na/K/2Cl cotransporter)

Mutation Target Why is Na transport messed up?

NKCC2 Na/K/2Cl transporter Inactivates, so no NaCl absorption
ROMK ATP-sensitive K channel ROMK is backleak K channel: K is usually
low outside of cells, so to have 1:1:2
Na:K:Cl stoichiometry in cotransporter,
need to let K leak out into lumen
ClC-Kb Basolateral Cl channel Need to get rid of Cl to keep Na/K/2Cl
transport going

Barttin: another mutation, but causes hearing loss too!

 β-subunit for ClC-Ka and ClC-Kb chloride channels, required for membrane localization
 In cochlea, there are both ClC-Ka and ClC-Kb chloride channels (kidney: -Kb only)
o Knock out ClC-Kb, get: Bartter’s without hearing loss (cochlea still has Ka channel)
o Knock out barttin, get: Bartter’s + hearing loss (can’t localize Kb or Ka channels)

Why hypokalemia? ↑ distal flow to collecting duct  ↑ Na reabsorption (aldosterone)  ↑ negative lumen  ↑ K secretion
Why metabolic alkalosis?

+ +
HypoK  ↑ NH3 synth in PT; ↑ H /K ATPase in intercalated CD cells
 Negative lumen effect like above
Why hypercalciuria? Less positive lumen, so less force driving paracellular reabsorption of Ca & Mg out of lumen
Why not hypomagnesemia? More salt wasting, hypoaldo  ↑ Mg reabsorption in DCT

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 Liddle Syndrome: a salt-wasting tubular disorder

Autosomal dominant Clincal Presentation

 Childhood / early adulthood presentation
Rx: amiloride/triamterine (sodium channel blockers) in early stages (with HYPERTENSION)
 Transplantation cures HTN in early stage, may have  “Pseudohyperaldosteronism”
irreversible vessel changes in later stages o HTN, HypoK, Metabolic alkalosis
o ↓renin / aldo! (not hyperaldo!)
What’s wrong?

Mutations: ACTIVATING ENaC

 β or γ subunits or C-terminus of ENaC (sodium channel) in DCT
 ↑ cell surface expression or ↑ open channel probability
o Remember: ↓ volume  ↑ renin  ↑ AT II  ↑ aldo  ↑ ENaC
insertion into apical membrane in DCT  ↑ Na reabsorption (along with
↑ Na/K ATPase activity)

 ENaC constitutively on: as if aldosterone were working all the time!

(pseudohyperaldosteronism)

Polycystic Kidney Disease - disorder of tubular morphology

Tubules must be properly patterned (appropriate luminal diameter to match work)
 Too wide: inefficient processing; Too narrow: ↓ flow rate; Correct polarity needed too

PKD: group of disorders with altered tubular morphology

 Renal tubules don’t form properly or “forget” correct diameter

Autosomal dominant PKD:

 Common (1/500-1/1000), responsible for 4-5% ERSD in USA!
Systemic disorder
 GI cysts: hepatic in 80%; pancreatic in 10%
 Vascular abnormalities: intercranial aneuyrisms in 7%, aortic aneyurisms too
 Other complications: HTN (70-80%), cardiac valve abnormalities, kidney stones
(20-25%), UTI, hernias, diverticuli

HUGE KIDNEYS (see picture)

Genetics: PKD1 (85%) or PKD2 (15%), all probably membrane proteins / channels
 Two hit model (cysts are focal) – a germline mutation, then a somatic one

Possibilities for what PKD proteins do:

 Maybe related to cilia dysfunction? (non-motile, sensory cilia, role unknown in regulation)
 Maybe related to planar orientation? (for the cell: who’s in front of me or behind me? How should I be arranged)
 PKD inactivated: ↑ cAMP in cystic tissue, ↑ cAMP growth response – who knows?
o V-2 receptor blockers (aquaretics): ↓ cAMP signaling, some good response in mouse models?

ESRD in African Americans

 ↑↑ risk ESRD (except PKD) for AA pts (7x higher!), clearly multifactorial cause for discrepancy, but…
 Maybe a genetic factor? AA kidney dz pts have ↑↑ African heritage in chromosome 22
 May be related to dystrophin-type complex, regulating podocyte structure (hold together GBM)?

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