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


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


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

Puf: can combine terms (think about GFR in terms of one net driving force / net filtration pressure)

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 Renal plasma flow:
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

Kidney can maintain RBF and GFR pretty well over a range of BP MECHANISMS OF AUTOREGULATION 1. Renin – angiotensin – aldosterone system 2. Myogenic mechanism 3. Tubuloglomerular feedback

I. RAAS system
1. 2. 3. 4. 5.

BP falls (e.g. you’re bleeding out) Volume sensors activated  ↑ renin release from juxtaglomerular cells in macula densa Renin cleaves angiotensingen → angiotensin I AT I  AT II via ACE (lung, vascular endothelial cells, glomerulus) 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
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 o o TAL contacts afferent / efferent arterioles here TAL cells facing glomerulus = specialized (macula densa) 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 4


where P = plasma inulin, GFR = glomerular filtration rate, U = urine inulin, V = urine flow rate

= the ratio of urine to plasma inulin times the urine flow rate (mL / min) More generally, the clearance of any substance is

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 2. Creatinine clearance = a. Example: 1mg/dl plasma creatinine, 100mg/dL urine creatinine, 1440mL/ day 24h urine volume:

Can also calculate from age, lean body weight, and plasma creatinine (Cockcroft-Gault equation) (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


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

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 (usually reabsorb small filtered proteins + some albumin) Urine electrophoresis: see small proteins > albumin 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

Non-selective Selective


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

The Tubule: Big Picture

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


The Tubule
Reabsorbs most filtered: Sodium Water Potassium Chloride Bicarbonate
(actually “reclamation” since HCO3 is broken down & reassembled on other side)





Angiotensin II: ↑ sodium reabsorption
↑Na / H exchanger Triggered when volume depleted
+ +

If proximal tubule is broken, you can urinate out too much base (can lead to acidosis) Using INTRACELLULAR SODIUM GRADIENT (Na/K ATPase) for sodium reabsorption

Glucose Amino acids Also plays a role in urinary dilution & concentration (macula densa here, etc) – see below. Using Na gradient to transport in K / ClSome diuretics work here (block Na reabsorption)

Reabsorbs: Sodium Chloride Potassium


Principal Cells

Reabsorbs: Sodium Water (if ADH) Excretes: Potassium

Aldosterone: ↑Na absorb/ K secretion (↑Na/K ATPase activity, K+ channel opened too) ADH (antidiuretic hormone, a.k.a. vasopressin: ↑aquaporin insertion into membrane facing urine side

By this point, Na in/out might be close to 1: can’t use concentration gradient to bring in Na 3Na/2K ATPase makes inside a little negative; charge is driving force for Na absorption

Type A Secretes: Acid
Can reabsorb K if hypokalemic

H+ ATPase on urinary side is predominant way acid excreted H+/K+ ATPase activated by hypokalemia; can reabsorb K from urinary space when needed “A” secretes ACID

Aldosterone: ↑ acid secretion

Intercalated Cells

Type B

Secretes: Base (if in excess)

Use Cl / HCO3 exchanger on apical membrane to secrete when needed “B” secretes BASE


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

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

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!


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 o o ↓stretch  ↑symp ↑Na retention & ↑vasoconstriction + ↑stretch  ↓symp ↓Na retention & ↓vasoconstriction 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

Sympathetic System

EFFECTORS & WHAT THEY DO Atrial Natriuretic Peptide
L. atrial distention increases release Inhibits Na reabsorption in collecting duct

Vasoconstriction (veins: more venous return, arteries: ↑BP) ↑ contractility ↑ renin  ↑(AT IAT II) + ↑ tubular Na absorption (direct effect)


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.


Edema: When Sodium Balance Goes Bad
Edema is the manifestation of excess extracellular volume Effective circulating volume actually DECREASES  ↑ sympathetics, ↑angiotensin II, ↑ADH Common causes of Edema 1. Congestive Heart Failure 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. Ascites (backup to splanchnic circ) & peripheral edema result
↓ albumin ↓oncotic pressure Venous pooling Nephrotic Syndrome CHF Cirrhosis

Nephrotic syndrome Protein lost in urine
↓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


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: 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)

Estimated osmolality = 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


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 ADH is primary driver • 1% rise in tonicity
(made in hypothalamus, stored in posterior pituitary & released)

Increased osmolality from increased Na (relative lack of water)  triggers osmolality receptors o Stimulates thirst (drink more)

• Pain • Nausea • ≥10% decrease in ECV

↓release of ADH • Fall in tonicity • Ethanol

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!)


Hyponatremia (<135 mEq / L): General points
Fall in Na often but not always implies fall in tonicity Clinical symptoms of hyponatremia: o Need fall in TONICITY  (isoosmolar hypoNa is asymptomatic!) o MOVEMENT OF WATER (not Na) dictates symptoms [Na] 125-135 120-125 <120 Symptoms Nonspecific: Neuro sx start: BAD:

General Approach Hx / clinical status of pt Determine osmolality Evaluate volume status Evaluate urine osmolality & electrolytes (if needed) 5. Treat 1. 2. 3. 4.

Mild Moderate Severe

anorexia, apathy, restlessness, nausea, lethargy, muscle cramps agitation, disorientation, headache 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

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, 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!)


Etiologies: Renal Loss (diuretics, obstruction, RTA, etc.) Non-renal Loss (GI: vomit/diarrhea, etc)

Urine Na > 20 mEq / L < 10 mEq / L

Why? Can’t conserve Na via kidney mechanisms, so spill to urine 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: Renal Failure CHF, Cirrhosis Urine Na > 20 mEq / L < 10 mEq / L Why? Can’t fully excrete water load, losing some sodium RAAS activated big time - hang on to Na (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: Increased ADH Release Adrenal insufficiency, nausea, hypothyroidism, medications, pain SIADH (see below) Primary Polydipsia

Urine Na > 20 mEq / L

Why? Reabsorbing water but normal ECV: concentrating too much “reset osmostat”- decreased threshold for ADH secretion SIADH is diagnosis of exclusion Drinking too much water (e.g. psych problems) – dilute urine, ADH suppressed (hyponatremia with appropriately low urine osm) 19

< 10 mEq / L

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

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)

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 o Minimal [Na] change so very little osmotic shift happens large proportion remains in vasculature so BP increases & perfusion better

Lower [Na] the most? D5W (5% dextrose in water)
o o o Can’t just give pure water IV: RBC will lyse 5% dextrose: temporary osmotic gradient (moves into cells slowly with insulin secretion) 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)


Diabetes Insipidus
ADH system is messed up: DI is the opposite of SIADH in a lot of ways! Central DI not making enough ADH (hypothal / pituitary) Pituitary tumors (do visual field tests), Pituitary apoplexy (infarction post-partum)
Infections, idiopathic too

Nephrogenic DI 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 Give exogenous ADH (ddAVP) Treat cause Nephrogenic Treat cause when possible 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)


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?

Na/K ATPase
Na out, K in. Catechols, insulin, thyroid hormone, state of K+ balance all regulate activity. 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 (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


Insulin Plasma [K+] Exercise too

Promotes K+ entry (skeletal mm, liver) via ↑Na/K ATPase
Independent of glucose transport; physiologic role in K regulation (basal levels allow K entry)
+ +

By itself can promote K+ entry into cells (passive mechanisms?) Block symp & insulin deficient: can still get K+ entry (but impaired)

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)

Extracellular pH

Hyperosmolality Rate of cell breakdown

Excess H+ enters cell to be buffered  Cl- enters poorly, so electroneutrality 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) Increased K+ inside  gradient for passive exit via K+ channels Cells release K+ when broken down (trauma, crush injury) so K+ ↑ in plasma 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 1520% (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 o Lumen-negative gradient generated by Na + reabsorption (through Na channels) + Tubule flow constantly washes away secreted K

ALDOSTERONE regulates all these steps

Aldosterone ↑ # Na channels in apical membrane  more negative
lumen  more K secretion

Plasma [K+]

Distal flow rate Wash away secreted K+ (if

Sodium Reabsorption More Na+ reabsorbed ↑Na/K ATPase activity  more K+
inside  better gradient to secrete

Transepithelial potential difference If lots of poorly reabsorable anion (HCO3-), lumen more negative (so more K+ secreted)

Enhances basolateral Na/K ATPase (↑ *K+]in so bigger

Same changes as aldosterone (independently!)

↓flow, K builds up in lumenless secretion) More flow  more Na+ delivered  see Sodium Reabsorption


↑ # open K channels in apical membrane (↑ K+ permeability)



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) 2. Pseudohyperkalemia: lab artifact a. Take blood sample  mechanical trauma during venipuncture b. RBCs damaged, release K+ in tube c. Can see ↑ K in serum samples (RBC removed from serum samples by MAJOR CATEGORIES OF HYPERKALEMIA ↑ Intake Pseudohyperkalemia Shift from inout of cells ↓ 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. 1. 2. Defects anywhere along the pathway can cause problems (see picture)

iii. #1 cause of hyperkalemia in adults: HYPORENINIMIC HYPOALDOSTERONISM (type IV RTA)
Mild-moderate renal insufficiency; 50% with diabetes, 85% with ↓ renin 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)


Hyperkalemia: Symptoms, Treatment

Muscle weakness
Abnormalities in cardiac conduction ( cardiac arrest)

o o

Peaked T-waves (see picture, ↑ with ↑ K) are key finding
Widened QRS, loss of P wave  sine wave pattern  Vfib / no activity! 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
+ + +


Decreased total body potassium, continued…

Potassium loss: hypokalemia usually from renal or GI loss
GI loss diarrhea (incl. laxative abuse) intestinal fistulas, other drainage
(vomiting is mostly renal loss!)


↓ Na reabsorption in loop of henle (loop diuretics) or distal tubule (thiazides) 

↑ Na delivered to distal nephron ↑K secretion NOT GI loss ↑ bicarb (vomitus has H+) Overwhelm reabsorption  bicarb delivered to distal nephron  ↑ K secretion (charge) Transient (↑ Na, HCO3 reabsorption because hypovolemic)  limit bicarb delivery Esp aldosterone  renal K loss
May have co-existent metabolic alkalosis, mild volume expansion, HTN (aldo effects) Think adrenal adenomas / carcinomas / hyperplasia (↑ mineralicorticoids) Cushing’s: ectopic ACTH produced  ↑↑ cortisol  overwhelms normal conversion to cortisone (can’t bind), cortisol can still bind mineralicorticoid receptor  effects Hyperreninism too

Vomiting Renal / urinary loss

Mineralicorticoid excess

Bartter’s & Gitelman’s syndromes (rare inherited disorders)

Nonabsorbable Anions
Ampho B Hypomagnesimia too

More K+ secreted in distal tubule (more negative lumen) HCO3- is most common, can see others too
Increased membrane permeability

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

EKG findings: primarily delayed ventricular repolarization
o o o

S-T segment depression Flattened T-waves ↑ U-waves
Can see PR prolongation/ wide QRS too


Predisposes to cardiac arrhythmias (esp with digitalis or Hx of coronary ischemia)

Renal dysfunction
o o o poor response to ADH, polydipsia & polyuria Urinary acidification (K+ exchanged for H+  intracellular acidosis  H+ loss by kidney) 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 relies on muscle mass (bigger more normal in big people)
can be falsely elevated by meds that interfere with tubular Cr secretion

ARF: PROBLEMS! Accumulation of toxins Azotemia: ↑ BUN
↑ nitrogenous end products of protein / AA metabolism in blood Uremia: signs & sx with azotemia (sleepy, confused, asterixis, pericarditis, etc)

Doubling of creatinine = 50% ↓ GFR Urine output in ARF Can be normal too! Oliguria: ↓ urine production (<500mL/day) Anuria: absence of urine (<50mL/day)

End result: ↑ morbidity & ↑mortality
6x risk mortality with hosp-acquired ARF 40-60% mortality for oliguric, 15-20% for nonoliguric

Fluid management problems Electrolyte abnormalities Acid/base disorders Medication dosing (if renally cleared!) Temp / long-term dialysis? Recovery is common (± sequelae)

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!


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) Diagnosis of prerenal ARF 1) History (HPI, PMH of cardiac disorders, bleeding; meds: diuretics, NSAIDs, oliguria) 2) PE: volume status (HR/BP, orthostatics), dry mouth, skin tenting, etc. 3) Should return to baseline with fluids FENa%: Fractional Excretion of Sodium
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

BUN / Cr ratio Urine Na FENa Uosm U/A Great key for prerenal ARF! > 20:1 < 20 mEq / L < 1% > 500 mosm/kg Normal
Kidney holding on to sodium, Na/BUN coupled so BUN ↑ vs Cr

Holding on to sodium! Non-osmotic ADH release!

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: Calyces / pelvis of each kidney generally only has 5-10 mL urine Obstruction  proximal dilatation of calyces / pelvis  destroy medulla & compress cortex Acute renal failure results: pressure atrophy intrarenal reflux ischemia 29

Children Young Adults Older adults Anatomic abnormalities Caliculi Prostatic hypertrophy / cancer Retroperitoneal / pelvic cancer Caliculi

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!

Thrombotic micoangiopathies: vascular thrombosis 2° endothelial cell injury + platelet activation
Etiologies: malignant hypertension, scleroderma, TTP, HUS, pregnancy-related

Categorization of renal ARF: ANATOMY Intrarenal vascular Glomerulonephritis Interstitial Tubular*
(Acute Tubular Necrosis is most common cause of ARF)

Renal vein thrombosis bilateral or in a solitary kidney

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 o o Multiorgan associations –  each has characteristic multi-system manifestations Each has its own diagnostic test too Don’t have to memorize for this lecture, but maybe a good chart anyway


Acute Interstitial Nephritis (AIN) Inflammatory infiltrates in interstitium Rare but need to detect (treatable & reversible) Drug rxn most commonly, but can be idiopathic or 2° to infection, dz, malignancy o Methicillin & NSAIDs are big offenders, lots of Abx & common infections, leukemia, lymphoma, SLE too Pathophysiology of AIN Immunological hypersensitivity rxn to antigen
(usually extrarenal, e.g. drug)

ARF Mild proteinuria
(<1g/day,↑ if 2° to NSAIDs)

Hypersensitivity! Low grade fever “Maculopapular” rash Arthralgias Eosinophilia

Abnormal U/A: RBC, WBC, WBC casts (see pic) Eosinophiluria Flank pain (2° to capsule distension)

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)

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)

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)
Important cause of ATN (10-15% hosp pts with ARF in US) Causes: trauma, esp crush injury, cocaine, exercise, statins, many others Pathogenesis Skeletal mm damage  myoglobin released  freely filtered @ glomerulus  PT reabsorption overwhelmed delivered to DT, casts form (esp acid urine) Consequences: Intrarenal vasoconstriction (second hit) – scavenging of nitric oxide
o Third-spacing of fluid in damaged muscle  hypovolemia  more vasoconstriction

Diagnosis of rhabdomyolysis
Suggestive Hx

Dipstick: heme + but no RBC
(tricking the dipstick: actually seeing Mb!) Serum creatine kinase ↑↑ Creatine ↑ disproportionate to BUN HyperK, hyperureicemia, HyperPO4 Metabolic acidosis HypoCa
(Ca/phos deposited in injured muscle)

Proximal tubule iron toxicity (from Mb)

Tx of rhabdomyolysis Establish high urine flow rate with saline infusion
± 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 ARF 5-10 days after start of Rx (if right away, not AG’s fault!) Distal injury  polyuria (nonoliguiric ARF) Cr takes 3 wks to recover




Ampho B, vancomycin Cisplatin, 5-FU, others Lithium
Radiocontrast for CT, cardiac cath, etc. ATN via direct tubular toxicity 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 (bacteremia + hypotension + gent) U/A: muddy brown, granular casts; ↑ Urine [Na+] Uosm > 350 (lose urine concentrating ability) Treatment: no specific treatment; try to tx underlying cause, remove offending agents
supportive care until / if renal function recovers Finding U/A + Urine [Na ] FENa Uosm Prerenal Normal <2 < 1% > 500 ATN Muddy brown casts >40 > 2% < 350

ARF most commonly caused by ATN but prerenal ARF is 2nd! See table to right: remember in ATN can’t retain Na or concentrate well!

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 Acidosis: processes that lower pH Henderson Hasselbach: (Don’t memorize: just know you can calculate pH, bicarb, or PCO2 given the other two) Alkalemia: blood pH > 7.4 Alkalosis: processes that raise pH
Normal physiologic pH values* Extracellular fluids 7.37 – 7.43 Intracellular fluids 6.60 – 7.20 Range of extracellular pH 6.80 – 7.80 (while still being alive) * Biological processes run best at pH optima!

Characteristics Fall in plasma HCO3Low arterial pH Compensatory hyperventilation
(blow off CO2  ↓ PCO2)

Etiology: REDUCTION OF HCO3↑ acid production ↓ renal acid excretion Loss of HCO3- (stool or kidney)

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+ + HCO3In 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


H+ into cells, K+ out of cells

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

HCO3- Reclamation

Proximal tubule : 90% of bicarb reclaimed
Na/H antiport on apical surface, H combines with bicarb, CO2 in, bicarb reformed inside, Na/bicarb symport on BM side

Collecting tubule: 10% bicarb reclaimed distally
Same idea, just no sodium gradient available now (most has been reabsorbed: have to use ATP to get the hydrogen into lumen & Cl / bicarb antiport to get bicarb into blood)


Acid Secretion

Proximal tubule: Titratable acids
Same Na/H antiport as before + Instead of combining with bicarb, H combines with titratable acid & excreted into urine;

Collecting tubule: Titratable acids
Same idea; need ATP to get H out because sodium isn’t around; combines with titratable acid & excreted

Collecting tubule: AMMONIUM BUFFERING
MAIN WAY that acid is excreted!
Ammonium can diffuse through to lumen, combine + with H , gets trapped (only uncharged things move through membranes) & excreted

Proximal tubule: another way to form ammonium
From glutamine (protein products) See diagram of ammonia recycling below

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


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 / HCO3Example: (~ normal values) 7.4 / 40 / 90 / 25

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

Normal AG value High anion gap metabolic acidosis Normal anion gap metabolic acidosis 5-11 > 11 5-11

Unmeasured anions: (phosphates, sulfates, proteins) Extra anions present but not measured! HCO3- out but replaced by Cl- in

Healthy people Exogenous acids, poisons Endogenous ketoacids or lactates GI bicarb Loss 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)


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


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 HCO3o 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 Type Picture Description
↓ bicarb reabsorption in proximal tubule
Can have pH < 5.3 (still have distal tubule working to acidify by secretion), bicarb can be OK (distal compensation), Fanconi syndrome: damage to proximal tubule  can’t reabsorb a lot of stuff hypophosphatemia, glucosuria, aminoaciduria
Plasma HCO3 K

Urine pH

Multiple myeloma Carbonic anhydrase inhibitors Other drugs

Type II
(proximal RTA)


nl or <5.3 ↓ Consequences:

rickets or osteomalacia (from phosphate wasting) Chronic kidney disease #1

Type I
(distal RTA)

↓ net H+ secretion in distal tubules
No distal nephron to compensate: urine pH rises, plasma bicarb can fall a lot


nl Drugs, autoimmune disorders or >5.3 (Sjogrens, RA) ↓
Anything that messes up the distal tubule Aldosterone deficiency

No response to aldosterone

Type IV

↓ H+ & K+ secretion in distal tubules 
mild metabolic acidosis + hyperK ↓ urinary NH4 excretion too


↑ <5.3 ↑ Aldosterone resistance

(adrenal insufficiency, heparin, diabetic nephropathy, HIV)

(amiloride, triamterene, spironolactone, trimethoprim)


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)
breathing too fast?) breathing too slow?)

If pCO2 < expected: simultaneous respiratory alkalosis (overcompensating: If pCO2 > expected: simultaneous respiratory acidosis (not compensating enough: 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


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 o o

E. coli doesn’t make urease (so E. coli UTI doesn’t cause struvite stones) Urease: urea  2NH3 + CO2 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


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 o o o Ca normally binds oxalate in gut Saponified Ca can’t bind oxalate ↑ oxalate load absorbed, delivered to kidney ↑ Urinary oxalate Calcium oxalate stones form



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

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 o Hit kidney with shock wave to break stones up into tiny little pieces, wash out without symptoms Non-invasive!


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 ↑ anaerobic glycolysis ↓ cerebral perfusion  tetany, seizures, lethargy, delirium ↑ organic acid production ↓ K+ ↓ plasma [Ca+]

CARDIOVASCULAR Vascular constriction ↓ coronary perfusion
↑ supraventricular & ventricular arrhythmias

H+, HCO3-, and the Nephron
Proximal tubule: net HCO3- reclamation Collecting duct: net H+ secretion Next page: more detail


Proximal Tubule: Reclaim HCO3Net 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 o o H comes with a Cl for electroneutrality To maintain Cl in cell for excretion, exchange Cl and bicarb at basolateral membrane 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!


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!

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

Metabolic Alkalosis: Generation Phase
To have metabolic acidosis need Generation phase: something to start it up Maintenance phase: something that keeps it going Vomiting: Normal: HCl (stomach) neutralized by NaHCO3 (pancreas) Vomiting: lose HCl  NaHCO3 stays in blood alkalosis! Diuretics ↑ NaCl delivery to collecting duct ↓ volume  ↑ aldosterone (the whole point of diuretics) GENERATION PHASE: WHAT STARTS MET ALKALOSIS? Loss of acid
Vomiting Diuretics ↑ aldosterone states

Hypokalemia: H+ shifts into cells Alkali load
Citrate from massive blood transfusion 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


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? Volume depletion ↓ ECV  ↓ renal perfusion ↑ AT II  ↑ aldosterone (see below) ↓ ECV  Cl- depletion too (see below) ↑ aldosterone  ↑ H+ secretion
↑ H ATPase ( type A cells) + ↑ Na/K ATPase  ↑ Na reabsorption (primary cells) more negative lumen



Losing volume

Losing volume

Losing volume ↑ RAAS ↑ aldo

Losing volume ↑ RAAS ↑ aldo


Aldosterone: good for fixing ECV but bad for alkalosis!
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 Why ↓K? Not from direct loss (vomit): in both cases, ↓ volume ↓ 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

Losing volume ↑ RAAS ↑ aldo

Losing volume ↑ RAAS ↑ aldo

↓ Cl- in lumen by the time you get to collecting tubule Type A intercalated cells export H+ with Cl along (maintain electroneutrality) Chloride depletion
Bigger gradient for Cl to flow blood  cell  lumen, easier to drag + H along to keep electroneutrality

Losing volume ↑ RAAS ↓ Cl in urine

Losing volume ↑ RAAS ↓ Cl in urine

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


(Later: volume considerations win out, ↓Na) 45

Cl- “sensitive” (UCl < 25 mEq / L) Example GI loss (vomiting, NG suction) Diuretics (late-remote use) ↑ distal Na+ delivery  ↑H+ / K+ loss ↓ ECF, ↑ aldo, hypoK, ↓ Cl maintain alkalosis Low with remote use
(can be high with current use: losing lots of fluid!)

Cl- “resistant” (UCl > 25 mEq / L) Mineralocorticoid excess 1° hyperaldosteronism Cushing’s syndrome ↑ aldosterone  “aldosterone escape” (kidney senses too much aldosterone  excrete NaCl!) Unclear mechanism High (both UNa and UCl)
Apparent mineralocorticoid excess (licorice, 11-β-OHsteroid-DH deficiency, LIddle’s syndrome), Glucocorticoid-remedial HTN, adrenogenital syndromes, Bartter’s & Gitelman’s syndromes

↓ HCl generates alkalosis What happens? ↓ ECF, ↑ aldo, hypoK, ↓ Cl maintain alkalosis Low

Urine Cl-

Other examples


IV NaCl + KCl
Treatment NaCl: restore volume (less Na retention, ↓ aldosterone, lets kidney excrete NaHCO3, ↑ Cl delivery to distal nephron)
+ + +

KCl + fix underlying problem
Not NaCl: actually have ↑ total body NaCl (HTN)! ↑ aldo is problem: high aldo w/o ↑ ECV! Fix hypoK – still causes problems Remove adrenal adenoma, use aldo antagonist like spironolactone

KCl: replete K deficit (hypokalemia), ↑K  ↓ H secretion

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-]


Chronic Kidney Disease
Measuring GFR
Inulin Clearance: gold standard, don’t really use clinically Serum Creatinine: 1st line (good or bad?) Creatinine Clearance: UV/P & match units o Hard to get urine, lots of problems, etc. Definition of CKD Kidney damage for ≥ 3 months
o Structural or functional abnormalities of kidney, ± ↓ GFR

↓ GFR for ≥ 3 months New staging for CKD: primarily based on kidney function Abbreviated MDRD study equation 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) Cockcroft-Gault equation: 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: If GFR < 5-25 cc/min: can increase your FeNa to still get rid of salt start retaining sodium

(no symptoms!) (edema, HTN, pulmonary congestion)

Kidney can keep up – to a point! 47

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

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!

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
Inhibits Na/K/2Cl cotransport Inhibits NO synth in Mϕ 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 o o o


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


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

Earlier: when GFR > 20, (↑ snGFR)

Phosphorus: goes up in long-standing kidney disease (eventually) Later: when GFR < 20
Still have blocked transporter but ↑ serum phosphorus (weird – why aren’t you still peeing it out if you can’t absorb it?) GFR very low: not getting phosphorus excreted  builds up

↓ serum phosphorus have ↑ phosphorus in tubule vs. to normal Block phosphate transporter via PTH  pee it out

How long as CKD been going on? Check PTH and hemoglobin! o Very elevated PTH - ↓ GFR (higher stage CKD) o Low Hb (anemic! ↓ Epo


Can’t rely on calcium or phosphate levels
o o o as calcium↓, PTH ↑, driving ↓ phosphate and ↓ Ca Maintains a pretty constant level of Ca and phosphate 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!)


Pathogenesis of Hypertension
Definition: a persistent elevation of the systolic blood pressure and/or diastolic blood pressure in the systemic arteries repeated measurements Classification of BP for adults 18yo or older Cutoff point is arbitrary: BP classification SBP (mm Hg) DBP (mm Hg) o Resting SBP ≥ 140 and/or Normal <120 and <80 o Resting DBP ≥ 90 Prehypertension 120-139 or 80-89 Stage 1 hypertension 140-159 or 90-99 Stage2 hypertension ≥160 or ≥100 Epidemiology: major public health problem 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 ↑ tubular reabsorption (mineralocorticoids) system to accommodate CO

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

Cardiac Output & PVR

Most hypertensives: NORMAL CO but ↑ PVR
PVR: determined by small arterioles, which have smooth muscle cells in walls 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))


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) ↑ aldo synthesis / release ↑ vascular cell hyperplasia & hypertrophy

↑ thirst

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


Sympathetic Nervous System

↑ SNS  ↑ BP: Heart: ↑ CO (↑ contractility & ↑HR) Vasculature: ↑ PVR Kidneys: ↑ fluid retention

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”?)


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

Nitric Oxide

Short-lived, highly permeable gas, released by endothelial cells in response to… o BP changes, shear stress, pulsatile stretch 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 Factors

Transplanted kidney from donor with HTN  ↑ BP, ↑ need for antihypertensive Rx Donor without HTN: no ↑ BP in recipient 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)

Intrauterine differences

Low birth weight is the big one (poor fetal nutrition) ↓ birth weigh  ↓ # nephrons  HTN Also ↑ with ↓ social status of father


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 ↑ Systolic BP with ↑ Na excretion (measuring Na intake) and ↓ potassium excretion 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

Environmental Factors

Secondary Causes of Hypertension
Can be renal, endocrine, cardiovascular, neurologic, other (drugs, genetics, etc.) Renal causes
Renal parenchymal disease (glomerulonephrits, chornic pyelonephritis, PKD) Renal vascular disease (renal artery stenosis from atherosclerosis or fibromuscular dysplasia) Renin-secreting tumors (really rare)

Cardiovascular causes
Congenital coarctaion of the aorta (just distal to L. subclavian a.) Polyarteritis nodosa or other vasculitis that affects kidneys

Neurological causes
↑ intra-cranial pressure Sleep apnea

Endocrine causes:
Adrenal gland: adrenal cortical hyperfunction (Cushing’s, Conn’s, CAH) Pituitary gland: acromegaly, basophilic adenoma (↑ ACTH) Thyroid gland (thyrotoxicosis)

Pheochromocytoma Drug-induced or related 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


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

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 Non-adherence Inadequate doses Inappropriate combinations Volume overload:
o Excess sodium intake o Kidney disease o Inadequate diuretic therapy

Associated conditions:
o Obesity o Excess alcohol intake

o o o o o o o Illicit drugs: cocaine, amphetamines, … Sympathomimetics: decongestants, … Oral contraceptives Steroids Cyclosporine, tacrolimus Erythropoietin 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


Non-pharmacologic Treatment of Hypertension
BP measurement history Harvey (1616): circulation Hales (18th c): cannulated artery (horse) Kortokoff: observed sounds made by constriction of artery at certain
points in inflation / deflation of cuff that correspond to SBP & DBP

Benefits of “lifestyle” therapies
Non-hypertensives ↓ BP Prevent HTN Prevent age-related rise in BP Always initial therapy 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)


Blood pressure classification (JNC VII)
“pre-hypertension” – have 90% risk of developing HTN Try to motivate to change lifestyle! Prevalence: most people are abnormal HTN: 27%, PreHTN: 31%, HTN: 42% Category Normal Pre-hypertension Hypertension Stage 1 Stage 2 Systolic BP < 120 120-139 140-159 ≥ 160 and or or or Diastolic BP <80 80-89 90-99 ≥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!

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. 2. 3. 1. bigger effect if your diet was high sodium before Difference maintained throughout day & night Bigger effect in AA vs non-AA pts Issues: no clinical test for salt sensitivity, use groups

c. BP response to change in salt intake is heterogeneous: AA & older pts are more “salt sensitive” 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) 57

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. 2. Was tested with outpatients, fed them everything, isocaloric (wt constant) & Na similar in all diets Tested vs. typical American, DASH, typical American with more fruits & vegetables


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


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.) d. 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) 58

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


Management of End Stage Renal Disease
GFR < 15 - need to start renal replacement therapy (dialysis or transplant) Scope of the problem 600K pts with ESRD, 100k/yr and growing, $28B/yr Minorities over-represented: AA, Hispanics, Native Americans Leading causes: DM, HTN, chronic glomerulonephritis, HIV-associated nephropathy (HIVAN), hereditary dz (polycystic kidney or alport's) Treatment options: (often switch modalities) Peritoneal dialysis
Continuous ambulatory peritoneal dialysis (CAPD) Continuous cycling peritoneal dialysis (CCPD)


Findings Urinary abnormalities GFR > 90 mL / min GFR 60-89 GFR 30-59 GFR 25-39 GFR < 15

Hemodialysis (in center or home)

Renal transplantation
Deceased donor Living donor (related or unrelated)

Dialysis = "to separate": separating crystalloid from colloid by a semi-permeable membrane Dialyzer: biocompatible membrane with parallel hollow fibrils
o o o blood flows inside fibrils, rapid blood flow rate (450mL/min) solute drawn off by diffusion, fluid drawn off by convection Fast flow replenishes gradient

Dialysate: bathes blood with countercurrent flow 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 o Large central venous cath (not good - invasive, endocarditis, etc) 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
Rapid, performed by staff Nutritionally safe (not losing protein) Can give IV meds (procrit, iron, VitD, Abx) Easy to monitor Social interaction, supportive environment Access complications (infection, clotting, thromboses, high-output HF because of A/V fistula) Accelerated atherosclerosis (more AGEs, not cleared) Hyperparathyroidism Depression & suicide (passive, via withdrawal of Tx mostly) Inflexible schedule Rapid fluid shifts (hypotension, cramping weakness) "Sawtooth" labs & BP shifts


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
Personal freedom Better BP control Higher Hgb/Hct (less blood loss) No a/v access problems (clotting, infection) Smoother uremic control (avoid saw-tooth chemistries, big volume expansion/contraction)

PD disadvantages
Personal responsibility / time committment Protein wasting - big complication! K wasting Potential for cath-related bacterial peritonitis 4-6wk lead time (surgical visit, cath placement, cath maturation, education) "cycler claustrophobia" - have to be hooked up toa machine at night Need: space for supplies, visual acuity +/- helper

Dialysis is management, transplant is cure Transplant: remember that kidney does more than fluid / electrolyte balance
o o Mineral balance, EPO secretion, drug metabollism all taken care of with transplant but not dialysis 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
• Freedom from dialysis • Avoids accelerated CV syndrome with dialysis • Better overall survival • • • • •

Perioperative risks (morbidity & mortality) Lifelong need for immunosuppression Risk of rejection Risk of allograft nephropathy Side effects of therapy

Side effects of therapy: • HTN, infection, malignancy (skin, lymphoma, other), steroid toxicity (cataracts, bones, joints, diabetes) 61

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

Alport syndrome (hereditary nephritis): a GBM disorder
X-linked and autosomal forms

X-linked form
Epidemiology 85% of Alport’s Males more severely affected • Glomerular hematuria (from birth) • Proteinuria (develops in childhood) • Hearing loss (55%) – progressive, sensorineural • Anterior lenticonus: cone-like lens deformation (in 15-30%, pathognomonic) • Variable presentation in females (random X-inactivation) o Intermittent microscopic hematuria, no significant proteinuria, ↓↓ESRD • ESRD common in males (most young adulthood < 30, subset later) α5 subunit of type IV collagen (+α6 for subset with leiomyomatosis)

Autosomal forms
Recessive 15%
Severity: M=F

Dominant Rare
Overlap with familial benign hematuria?

• Hearing loss

Signs & symptoms

• Hematuria
(common in heterozygous “carriers”)

Course Mutations

ESRD early

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)

• EM: •

Can be diagnostic 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 62

Congenital Nephrotic Syndrome (NPHS1): a podocyte disorder
Epidemiology • Rare (Finland: 1/8000; Lancaster County, PA (Groffdale Mennonites): 1/500) – founder effects • Autosomal recessive 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 Clinical Presentation
Early fetal presentation (Heavy proteinuria) Premature birth Proteinuria (± RBC/WBC) Often die in first years of life (complications of nephrotic syndrome, 1° infection)

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

Various mutations: in the end, affecting TALH NaCl transport (like loop diuretic – Na/K/2Cl cotransporter) Mutation NKCC2 ROMK Target Na/K/2Cl transporter ATP-sensitive K channel Why is Na transport messed up?
Inactivates, so no NaCl absorption 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 Need to get rid of Cl to keep Na/K/2Cl transport going


Basolateral Cl channel

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 acidosis?
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
+ +


Liddle Syndrome: a salt-wasting tubular disorder
Autosomal dominant Rx: amiloride/triamterine (sodium channel blockers) in early stages Transplantation cures HTN in early stage, may have irreversible vessel changes in later stages 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)

Clincal Presentation
Childhood / early adulthood presentation (with HYPERTENSION) “Pseudohyperaldosteronism” o HTN, HypoK, Metabolic alkalosis o ↓renin / aldo! (not hyperaldo!)

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)? 64