Review

1. RENAL REVIEW

2. BODY COMPARTMENTS

3. Plasma osmolality is the concentration of
all the solutes (electrolytes and
nonelectrolytes) in plasma.
Plasma osmolality is normally between
285 and 295 mmol/L.

5. Water Distribution
• The distribution of water among the three body water
compartments (intracellular, interstitial and plasma
compartments) is determined by two forces:
• Osmotic pressure
• Hydrostatic pressure
• The balance of these forces determines the amount of
water in each compartment.
• Osmotic pressure is the force exerted by solutes
• Hydrostatic pressure is the force exerted by water

8. 60-40-20 Rule
The amount of water contained in the
body, total body water, is 60% of a
person's weight. Since 1 liter of water
weighs 1 kilogram, calculating totalbody
water (TBW) is simple.

9. Effects of Gender and Age on TBW
• Men are about 60% water by weight and women are 50-55% water by
weight.
• Women have a lower TBW because they have a higher proportion of
body fat, which contains little water.
• Age also affects total body water. Infants have a high percentage of
water by weight. The elderly have a lower percentage of water by
weight.
• Full-term in-fants are about 70% water which decreases to 60% after
6 months to a year.

10. Electrolyte Distribution
• The electrolyte compositions of the intracellular and extracellular
compartments are different. The intracellular compartment has a high
concentration of K+ (140 mEq/L) and the extracellular compartment
has a high concentration of Na+(135-145 mEq/L).
• Because the cell membrane is impermeable to sodium and
potassium, Na-K-ATPase pumps located in the cell membrane are
required to move these ions in and out of the cell.
• Although the intracellular and extracellular compartments have
different solute compositions, the two compartments have the same
osmolality because the cell membrane is permeable to water.

11. Electrolyte Distribution

13. Gibbs Donnan Effect
• Plasma and interstitial fluid composition differ by about 5% in
concentration of diffusible ions.
• The interstitial fluid contains little protein and no blood cells because
the capillary walls exclude the passage of larger protein molecules.
• Unequal distribution of proteins  Increased plasma concentration of
cations and slightly lower concentration of anions like Cl-
• Gibbs-Donnan Equilibrium:
• The movement of ions is governed by:
• 1. Concentration difference
• 2. Permeability of the membrane
• 3. Voltage gradient across the membrane

14. Intracellular vs. Extracellular
• Major extracellular cations: Na+
• Major extracellular anions: Cl-, HCO3-
• Major intracellular cations: K+, Mg2+
• Major intracellular anions: Organic phosphates, proteins
• The ionic composition of intracellular fluids differs from the
extracellular compartment due to the presence of a large lipid bilayer,
which prevents the diffusion of almost all solutes except for those that
are very small or non-polar.
• Most solutes move across the compartments via specific transporters,
such as Na+/K+ ATPase.

15. Water Loss and Expansion
• Water distributes to all compartments in the body so the gain in water
with intake or decrease in water with loss are all based on what
percentage of total body water is in that compartment.
• 2/3 will distribute to ICF
• 1/3 will distribute to ECF
• 1/4 of the ECF will distribute to Plasma

17. Normal Ranges
• Water intake:
• Water: 1200 ml
• Food: 1000 ml
• Metabolic: 300 ml
• Total: 2500 ml
• Water loss
• Insensible (mainly respiratory): 700 ml
• Sweat: 100 ml
• Feces: 200 ml
• Urine: 1500 ml
• Total: 2500 ml

19. Dextrose is used in in situations of solute
free fluid loss such as hypernatremia

20. D5W initially only distributes to the
extracellular compartment but over time it
distributes amongst all three fluid
compartments
Over time it is metabolized to CO2 and
Water and distributes across body
compartments

21. Saline Infusions

22. Effects of Saline Infusions
• Isotonic saline (0.9%) delivers NaCl and water to the plasma
and interstitial compartments.
• Used for dehydration and hypovolemia
• Hypotonic saline (0.45%) delivers water to all three body water
compartments and NaCl to the extracellular compartment.
• Used as maintenance IV
• Hypertonic saline (3%) removes water from the intracellular
compartment.
• Used in hyponatremia
• Lactated Ringer's is a more physiologic isotonic solution than
0.9% NaCl and remains in the plasma and interstitial
compartments

23. GLOMERULAR
FILTRATION

24. Clearance
• Clearance equation: C=UV/P
• Units of C are ml/min
• UV= rate of excretion (moles/min)
• [U]x = urine concentration of a substance X (mg/ml)
• V= urine flow rate per min (ml/min)
• P= plasma concentration (moles/ml)
• Renal clearance is the volume of plasma completely cleared of a
substance by the kidney per unit time
• “Virtual quantity” b/c the kidney does not completely clear the plasma
of any substance, though PAH comes close

25. GFR
• Glomerular filtration rate (GFR) is the flow rate of filtered fluid through
the kidney, i.e. the volume of fluid filtered from the glomerular
capillaries into Bowman's capsule per unit time.
• Typical value: ~125 mL/min
• 180L/day
• Filtration fraction represents the amount of plasma entering the
kidneys/nephrons that actually passes into the renal tubules
• It is equal to GFR/RPF
• Typical value: 0.15 - 0.2

26. Estimating GFR
• GFR can be measured by the clearance of inulin
• GFR = Cinulin = UinulinV/Pinulin
• Clearance of any substance can be compared with the
clearance of inulin and expressed as the clearance ratio:
• Cx/C=1: clearance of X equals the clearance of inulin - the
substance x must be filtered but neither reabsorbed nor secreted
• Cx/C<1: clearance of X is lower than clearance of inulin. Either the
substance is not filtered, or it is filtered and subsequently
reabsorbed
• Cx/C>1: clearance of X is higher than the clearance of inulin. The
substance is filtered and secreted

27. Inulin vs. Creatinine for GFR
• Inulin (the perfect glomerular marker)
• Not bound to plasma proteins, uncharged
• Freely filtered across the glomerular capillary wall
• Completely inert in the renal tubule
• Creatinine (not perfect, but it’s good)
• Freely filtered across the glomerular capillaries
• Secreted to a small extent
• Clearance of creatinine slightly overestimates the GFR.
• Creatinine is more convenient b/c it’s endogenous and you
don’t have to infuse it like you do for inulin
• Plasma level of creatinine is related to age, gender, and muscle
mass of the patient

28. Glomerular Filtration Rate Forces
• GFR = Kf [(PGC – PBS) – πGC]
• Kf is defined by water permeability per unit of surface area and the
total surface area. It is much higher in the glomerular capillaries
• PGC: Hydrostatic pressure in glomerular capillaries (45)
• PBS: Hydrostatic pressure in Bowman’s space (10)
• πGC : Oncotic pressure in glomerular capillaries
• Increases along capillaries

29. Changes in Oncotic Pressure
• As GFR increases, the oncotic pressure (colloid osmotic pressure) of
the peritubular capillary of that nephron will increase, while the
hydrostatic pressure will decrease.
• Both of these changes encourage water and solutes to move into the
peritubular capillaries.
• As GFR increases, there is more resorption in the proximal tubules
because peritubular capillary hydrostatic pressure decreases and
oncotic pressure increases.
• The major driving force is the high oncotic pressure.

30. Estimating RPF and RBF
• RPF can be estimated from the clearance of an organic acid para-aminophippuric
acid (PAH)
• RPF = UPAHV/PPAH
• RBF can be calculated from the RPF and the hematocrit
• RBF = RPF/(1-Hct)

31. On average RBF is 1800L per day

32. Cockcroft-Gault
• Cockcroft-Gault formula predicts the CrCl (creatinine clearance) from
the weight, age, and serum Creatinine
• CrCl=[(140-age) x Kg/(72*Cr)] * 0.85 for women
• Less accurate in weight extremes
• Derived from 24hr urine collection on hospitalized male veterans,
therefore multiplying by 0.85 is supposed to correct for lower muscle
mass in women.
• No empiric data was collected from women

33. MDRD
• MDRD: requires 3 demographic variables (age, race, and gender)
and one biochemical variable (creatinine). Uses regression analysis
to estimate the GFR (as opposed to CrCl used in the CG equation)

34. CKD-EPI
• Estimates GFR from serum creatinine, age, sex, and race for adults
>18years old.
• GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × (0.993*Age) ×
1.018 [if female] × 1.159 [if black]
• Scr is serum creatinine in mg/dL,
• κ is 0.7 for females and 0.9 for males,
• α is -0.329 for females and -0.411 for males,
• min indicates the minimum of Scr /κ or 1, and
• max indicates the maximum of Scr /κ or 1

35. Renal Handling of Glucose
• Glucose is filtered across glomerular capillaries and reabsorbed by
the epithelial cells of the proximal and convoluted tubule.
• Because there is a limited number of glucose transporters the
mechanism has a transport maximum, or Tmax.
• Splay: phenomenon where the Tmax for glucose is approached
gradually, rather than sharply. Splay is the portion of the titration curve
where reabsorption is approaching saturation, but is not fully
saturated and glucose is excreted in the urine before resorption levels
off at the Tmax value
• Explanations for Splay:
• Low affinity of Na+/glucose cotransporter.
• Nephron heterogeneity - Tm for whole kidney reflects average Tm of all
nephrons, yet all nephrons do NOT have the same Tm.

37. Glomerular Filtration Barrier
• Endothelium
• Pores 70-100nm in diameter- these are relatively large so fluid, dissolved solutes, and plasma
proteins are all filtered across this layer
• Pores are not large enough for RBCs to be filtered
• Basement membrane
• Composed of 3 layers
• lamina rara interna- fused to the endothelium
• lamina densa
• lamina rara externa- fused to the epithelial cell layer
• The multilayered basement membrane does not permit filtration of plasma proteins
• Epithelium
• Specialized cells called podocytes
• Filtration slits of 25-60nm in diameter
• small size of the filtration slits  important barrier to filtration
• Negatively charged glycoproteins on filtration barrier enhance filtration of cations
• Also create an electrostatic barrier to filtration of plasma proteins
• In certain glomerular diseases removal of these charges leads to proteinuria

38. Damage to endothelium would cause
hematuria while damage to basement
membrane would cause proteinuria

39. Renal Blood Flow
• Renal Vasculature
• Blood enters kidney via renal artery, which branches into interlobar
arteries, arcuate arteries, and then cortical radial arteries
• First set of arterioles = afferent arterioles
• Deliver blood to the glomerular capillaries, across which ultrafiltration
occurs
• Second set of arterioles = efferent arterioles
• Remove blood from the glomerular capillaries
• Deliver blood to the peritubular capillaries
• Solutes and water are reabsorbed into the peritubular capillaries.
• Typical values
• GFR: 125 mL/min (70 kg person)
• RBF: 1200 mL/min

41. Afferent and Efferent Arterioles
• Constriction of the afferent arteriole
• Decrease RPF
• Decrease PGC (less blood volume, less hydrostatic pressure)
• Decrease GFR
• Constriction of the efferent arteriole
• Decrease RPF
• Increase PGC (blood is blocked from leaving capillaries)
• Increase GFR

42. Myogenic Autoregulation
• Increased renal arterial pressure causes increased pressure in the
afferent arteriole.
• In the absence of autoregulation, the RBF and GFR would increase,
but in response to the increased pressure, the afferent arteriole
constricts, which prevents an increase in the RBF and GFR.
• The opposite response (dilation of afferent arteriole) occurs when the
arterial pressure decreases.
• Involves opening of stretch-activated calcium channels in the smooth
muscle cell membranes (inc. Ca2+ and contraction of SMC)

43. Tubuloglomerular Feedback
• The juxtaglomerular apparatus (located in the distal tubule) allows
each tubule to regulate its own glomerulus
• Increased delivery of NaCl to the macula densa leads to decreased
GFR  ATP and adenosine are released from cells in the JG
apparatus, which constrict afferent arterioles, reducing RBF and GFR
• Decreased delivery of NaCl to the macula densa leads to increased
GFR  PGI2 and NO are released, leading to vasodilation and
increased RPF and GFR
• Increased pressure on JG cells causes release of renin

44. Sympathetic NS Activity
• The sympathetic nerve activity is stimulated by decreased BP or
decreased ECF volume.
• Since RBF is determined by total resistance, the vasoconstriction of
both afferent and efferent arterioles will decrease the RBF.
• The GFR is influenced by the glomerular capillary pressure, so
constriction of the afferent arteriole will decrease GFR, while
constriction of the efferent arteriole will increase GFR.
• RBF decreases a lot while GFR decreases less in response to
sympathetic nerve activity.

45. Angiotensin II
• Angiotensin II is a potent vasoconstrictor of both afferent and efferent
arterioles.
• The efferent arteriole is more sensitive to angiotensin II than the
afferent arteriole, and this difference in sensitivity has consequences
for its effect on GFR
• Low levels of angiotensin II produce an increase in GFR by
constricting efferent arterioles, while high levels of angiotensin II
produce a decrease in GFR by constricting both afferent and efferent
arterioles.

46. Prostaglandin Formation
• Prostaglandins (E2 and I2 ) are produced locally in the kidneys and cause
vasodilation of both afferent and efferent arterioles.
• The same stimuli that activate the sympathetic nervous system and
increase angiotensin II levels in hemorrhage also activate local renal
prostaglandin production.
• The vasodilatory effects of prostaglandins are clearly protective for RBF.
• Thus, prostaglandins modulate the vasoconstriction produced by the
sympathetic nervous system and angiotensin II.
• Unopposed, this vasoconstriction can cause a profound reduction in RBF,
resulting in renal failure. Nonsteroidal antiinflammatory drugs
• (NSAIDs ) inhibit synthesis of prostaglandins and, therefore, interfere
with the protective effects of prostaglandins on renal function following a
hemorrhage.

47. Renal Artery Stenosis
• Renal artery stenosis will lead to a decrease in renal blood flow. GFR
is dependent on renal plasma flow.
• In the normal range the dependence isn’t very significant.
• When the RPF is low, in the dashed box, the GFR is heavily
influenced by the RPF.
• The RPF can decrease significantly in renal artery stenosis leading to
a significantly decreased GFR as well.
• This can lead to renal failure.

48. OSMOLALITY

49. Sodium and Osmolality
• Normal range of dietary Na+ intake: <2.5g/d
• Low Na+ diet: .05g/d
• Major routes of Na+ loss from the body: Kidneys
• Sodium is the major determinant of plasma osmolality (Posm)
• Increased sodium leads to increased plasma osmolality  osmotic
movement of water into the extracellular space
• Retention of water w/o sodium lowers PNa and Posm, so water will
move into the intracellular compartment until osmotic equilibrium is
reached.
• Administration of isotonic saline leads to no change in Posm. That
means no net movement of water into the intracellular compartment
and ECF is increased more effectively than with just water

51. Renin Release
• Factors that can promote renin release:
• Decreased afferent arteriolar pressure sensed by baroreceptors in
the wall of the afferent arteriole
• Increased SNA regulated by cardiac and arterial baroreceptors
• Increased circulating catecholamines regulated by cardiac and
arterial baroreceptors
• Decreased macula densa NaCl delivery

52. Angiotensin stimulates sodium
reabsorption in the proximal tubules
Aldosterone stimulates sodium
reabsorption in the TAL, DCT and
collecting ducts.
ANP blocks ENAC and decreases sodium
reabsorption in DCT and collecting ducts.

53. Renin Angiotensin System
• Renin converts angiotensinogen (from liver) to angiotensin I
• Angiotensin converting enzyme (from lungs) converts ATI  ATII
• ATII stimulates AT1 and AT2 receptors
• AT1 receptor stimulation:
• Increased aldosterone (in the adrenal gland)
• Vasoconstriction
• Increased proximal tubule Na+ reabsorption
• Increased thirst
• Increased ADH release
• Decreased RBF, but maintains GFR
• AT2 receptor stimulation:
• Vasodilation

54. Aldosterone
• 1. Increases number of Na-K-ATPase pumps in basolateral
membrane
• 2. Increases sodium channels and sodium resorption
• 3. Increased sodium resorption increases electrical gradient for
potassium secretion
• 4. Increases number of potassium channels
• Increased sodium reabsorption and potassium excretion!

55. ADH
• The osmoreceptors of the hypothalamus are very sensitive to
changes in osmolality. A change in plasma osmolality of only 1% is
detectable by the hypothalamus.
• An increase in plasma osmolality stimulates ADH and thirst. A
decrease in plasma osmolality suppresses ADH and thirst
• In the absence of ADH, the collecting tubules are impermeable to
water.
• In the presence of ADH, the collecting tubules are unlocked and water
inthe collecting tubules is resorbed. ADH causes aquaporin channels
to be inserted into the tubular membrane, allowing the resorption of
water.
• Water flows through the channels into the concentrated medullary
interstitium

56. Osmolality is the most sensitive stimulus
for ADH release.

57. 3 Actions of ADH
• (1) It increases the water permeability of the principal cells of the late
distal tubule and collecting ducts.
• (2) It increases the activity of the Na-K-2Cl cotransporter of the thick
ascending limb, enhancing countercurrent multiplication and the size
of the corticopapillary osmotic gradient.
• (3) It increases urea permeability in the inner medullary collecting
ducts, enhancing urea recycling and the size of the corticopapillary
osmotic gradient.

58. Effective circulating volume is the fraction
of the blood volume that is effectively
perfusing tissues at a particular time.

60. Secondary Hypertension
• The RAAS is activated in volume depleted states but can
also be activated in particular pathologies:
• Renal artery stenosis
• Hyperaldosteronism
• Glucocorticoid excess
• Coarctation of aorta
• Sleep apnea
• Pheochromocytoma
• Genetic diseases

61. Glomerulotubular Balance
• Glomerulotubular balance = a mechanism for coupling reabsorption to
the GFR; ensures that a constant fraction of the filtered load is
reabsorbed by the proximal tubule (67%)
• Mechanism: Increased filtration means more water was lost in the
glomerulus. This leads to increased oncotic pressure in the
peritubular capillary. This leads to a starling force that favors
reabsorption into the capillaries.

62. Volume is regulated by changing Na+
reabsorption; osmolality is regulated by
changing water reabsorption.
Volume: Angiotensin II, Aldosterone,
Catecholamines
Osmolarity: ADH

63. Hypovolemia

64. Hypervolemia

66. Symptoms of Hypovolemia
• Orthostatic hypotension/lightheadedness on standing
• Tachycardia
• Decreased skin turgor
• Cool, pale skin

67. Pressure Natriuresis
• Compensatory mechanism in which increased blood pressure causes
decreased reabsorption of Sodium and Water to normalize blood
pressure
• Liddle’s Syndrome and Renal artery stenosis disrupt this mechanism

69. ACUTELY
Hyponatremia  Cerebral Edema
Hypernatremia  Cerebral Shrinkage
Be careful in treating compensated
hypo/hypernatremia

70. Hyponatremia
• Hyponatremia is a plasma sodium concentration less than 135
mEq/L. Since sodium is the major contributor to plasma
osmolality, a low sodium concentration is usually associated
with hypoosmolality
• In all cases hyponatremia is due to a relative EXCESS of
water.
• IMPAIRED WATER EXCRETION, INCREASED ADH
• Causes
• Psychogenic polydipsia is a disorder of compulsive water drinking.
• Renal failure decreases urine output so that even modest water intake
cannot be excreted by the kidney.
• Increased ADH activity causes hyponatremia in two settings:
appropriate and inappropriate ADH release.
• Appropriate: diarrhea, vomiting, burns, CHF, cirrhosis
• Inappropriate: SIADH, hypothyroidism, adrenal insufficiency

71. Loop diuretics are less likely than thiazide
diuretics to cause hyponatremia because
loop diuretics disrupt the interstitial
gradient and oppose water reabsorption in
the distal tubule.

72. Pseudohyponatremia
• Hyponatremia in the face of a normal or elevated plasma osmolality
• Can be due to hyperproteinemia, hyperlipidemia or increased levels
of osmotically active solutes such as glucose or mannitol in the
plasma.

73. Urine Sodium for Diagnosis
• The urine sodium can give important details on the volume status of
the patient. Hyponatremia could be either associated with volume
depletion or SIADH.
• In either case, the urine osmolality would be elevated indicating the
presence of ADH.
• However, in one case (volume depletion) the stimulus for ADH
secretion is physiological and in the other case (SIADH) it is
inappropriate.
• In SIADH, the patient is volume expanded and the urine sodium
levels approximate intake (usually about 40-60 mEq/L).
• In a volume depleted state, the urine sodium is usually very low and
reflects avid sodium reabsorption by the renal tubules in an effort to
maintain vascular volume.

74. ADH Release
• Osmolality is sensed by hypothalamic osmoreceptors
• Supraoptic & paraventricular nuclei cause stimulation of release of
ADH from the pituitary (activated in cases of HIGH osmolality/volume
depletion) → increase water reabsorption → low volume/high
osmolality urine → restore plasma osmolality
• Lateral pre-optic area regulates thirst (suppression in response to
volume expansion, increased thirst in response to volume depletion)

75. SIADH
• In SIADH, circulating levels of the hormone ADH are abnormally high
owing to either excessive secretion from the posterior pituitary
following head injury or secretion of ADH from abnormal sites such as
lung tumors.
• In these conditions, ADH is secreted autonomously, without an
osmotic stimulus; in other words, ADH is secreted when it is not
needed. In SIADH, the high levels of ADH increase water
reabsorption by the late distal tubule and collecting ducts, making the
urine hyperosmotic and diluting the plasma osmolarity
• Normally, a low plasma osmolarity would inhibit secretion of ADH;
however, in SIADH, this feedback inhibition does not occur because
ADH is secreted
• Treatment: IV hypertonic saline, fluid restriction, demeclocycline

76. Diagnosis of SIADH
• SIADH is recognized by four characteristics:
• 1. Hypotonic hyponatremia
• Low plasma osmolality and low plasma sodium concentration
• 2. Euvolemia
• 3. High urine sodium (>20 mEq/L)
• 4. High urine osmolality (>200 mmol/L)

77. Oversecretion vs. Undersecretion of ADH
• Oversecretion: SIADH, Adrenal Insufficiency
• Undersecretion: Diabetes Insipidus

78. Hypernatremia
• Hypernatremia is a plasma sodium concentration greater
than 145 mEq/L. Since sodium is the major contributor to
plasma osmolality, hypernatremia always causes
hyperosmolality
• Due to an excess of sodium or a loss of water

80. Only osmostic diarrhea predisposes to
hypernatremia, most GI secretions are
iso-osmotic!

81. Maintenance of hypernatremia is due to
inability to ingest water

84. A plasma sodium concentration of greater
than 150 mEq/L is virtually never seen in
an alert patient who has access to water.
Thus, the patient must have a
hypothalamic lesion affecting the thirst
center, resulting in diminished sensation
of thirst (hypodipsia).

85. Nephrogenic/Central Diabetes Insipidus
• Central diabetes insipidus is characterized by the inability of the brain
to release ADH.
• Nephrogenic diabetes insipidus is characterized by the inability of the
kidney to respond to ADH.
• The urine of patients with diabetes insipidus is dilute with a low
concentration of sodium. Because of the large amount of dilute fluid
lost in the urine, patients are predisposed to hypernatremia.

86. Distinguishing DI and Polydipsia
• The plasma sodium concentration tends to be in the high-normal
range in diabetes insipidus (142-146 mEq/L) due to tendency toward
water loss and the need to keep up with the water loss by thirst.
• In primary polydipsia, the sodium is in the low-normal range (136-139
mEq/L) due to the continuing excess water intake.
• Thus, a finding at either extreme is helpful diagnostically, whereas a
plasma sodium concentration of 140 mEq/L is of little help.

87. Water Deprivation Test with administration
of ddAVP to distinguish Central DI from
Nephrogenic DI

88. Aldosterone acts at principle and
intercalated cells.
The action of aldosterone at the principle
cell is important in volume regulation and
potassium balance (causes K+ secretion);
Its action at the intercalated cell is
important in acid-base balance (can
cause metabolic acidosis)

89. The two primary stimuli for release of
aldosterone are volume depletion and
hyperkalemia

90. Effects of Aldosterone
• Increased serum sodium
• Decreased serum potassium
• Blood pressure and volume increased

91. TUBULAR FUNCTION

93. Early Proximal Tubule Overview
• (1) The entire proximal tubule reabsorbs 67% of the filtered Na
• (2) The entire proximal tubule also reabsorbs 67% of the filtered
water. The tight coupling between Na and water reabsorption is called
isosmotic reabsorption.
• (3) This bulk reabsorption of Na and water is critically important for
maintaining ECF volume.
• (4) The proximal tubule is the site of glomerulotubular balance, a
mechanism for coupling reabsorption to the GFR.

95. Early Proximal Tubule Transport
• Cotransport mechanisms: Na-glucose(SGLT), Na–amino acid, Na -
phosphate, Na –lactate, and Na-citrate
• Countertransport mechanism: Na-H+ exchange
• SITE OF ANGIOTENSIN II ACTION
• Contraction alkalosis!!!
• Na-K+-ATP Transporter
• 100% of glucose is absorbed
• 85% of filtered HCO3- is absorbed

96. Late Proximal Tubule
• Filtrate has high Cl- concentration
• This drives Na-H+ exchange and Cl-Formate exchange on the
luminal side.
• The high Cl- gradient allows for paracellular diffusion into the blood
• The Na-K+-ATP exchanger moves sodium into the blood

98. Loop of Henle
• The thin descending limb is passively permeable to small solutes and
water while the thin ascending limb is passively permeable to small
solutes but not to water and creates a hyposmotic tubular fluid
• The thick ascending limb absorbs 25% of sodium by means of the
Na-K+-2Cl- transporter.
• Diffusion of K+ backwards creates a lumen positive potential
difference that drives absorption of Mg2+ and Ca2+
• Impermeable to water  Dilution
• Site of Loop Diuretics and Bartter’s Syndrome

100. Early Distal Tubule
• Absorbs 5% of filtered Na via the Na-Cl- transporter
• Na-K+-ATP transporter moves Na into blood
• Cl- diffuses into the blood
• Site of Thiazide diuretics and Gittelman’s Syndrome
• Impermeable to water  Dilution

102. Late Distal Tubule and Collecting Ducts
• The principal cells are involved in Na+ reabsorption, K+ secretion,
and water reabsorption
• The intercalated cells are involved in K+ reabsorption and H+
secretion.
• Absorb 3% of Na
• ENAC Na channels
• Site of K+ sparing Diuretics, Aldosterone
• Water permeability is controlled by ADH

104. Transport ATPases
• Na+/K+ ATPase
• Generates Na+ gradient by pumping Na out of the cell which allows
many other solutes to be reabsorbed along with it
• Basolateral side of the glomerulus and nephron
• H+/K+ ATPase
• Secretes H+ and reabsorbs K+
• Mostly in the collecting duct (also distal tubule) on the lumenal side
of the intercalated cells
• H+ ATPase
• Secretes H+ into the lumen, stimulated by aldosterone
• Collecting duct and distal tubule

105. Ion and Water Channels
• (ROMK)
• Potassium recycling in thick ascending limb and potassium secretion in cortical
collecting duct, located on lumenal side
• Mutations lead to Bartter Syndrome
• ENaC
• Principal cells of collecting tubule and late distal tubule on lumenal surface
• Makes lumen electronegative by reabsorbing Na+, allowing for K+ secretion
• Target of potassium sparing diuretics (amiloride)
• Liddle’s Syndrome: mutation leads excess channels and Na+ reabsorption
causing increased ECF volume and hypertension
• Aquaporins
• Selectively conduct water into cell
• Placed in late distal tubule and collecting duct in response to ADH

106. Coupled Transporters
• Na+ glucose- Early proximal tubule
• Na+/H+ antiporter- Late proximal tubule
• Na+ K+ 2Cl symporter (NKCC)- TAL
• Na+ phosphate symporter- Early proximal tubule
• Na+ Cl symporter- Early distal tubule
• Na+ HCO3 symporter- Intercalated cells of collecting duct and late
distal tubule
• Cl/HCO3 antiporter- Intercalated cells of collecting duct and late distal
tubule, some in proximal tubule

107. CONCENTRATION AND
DILUTION

108. Urine osmolality can vary from 50 to 1200
mosmole/kg water and urine volume can
range from 0.5 to 20 liter/day

109. ADH
• ADH is released in response to increased osmolality or decreased
volume
• Osmolality is a much more sensitive stimulus
• Significant release of ADH in response to tiny (1%) increases in plasma osmolality
(280 –290 mosmole/kg water is normal)
• ADH release in response to decreased volume or pressure is not as sensitive (5-
10% change)
• In presence of high ADH, urine is low in volume, high in osmolality
• Rapid onset and termination of ADH responses
• ADH elevates cAMP which causes insertion into luminal membrane of
vesicles containing aquaporin-2, a water channel protein
• ADH also increases urea permeability of inner medullary collecting tubule
and may increase NaCl reabsorption in TAL

110. There is a gradient of osmolality in the
medulla: 300 mosmolal at cortico-medullary
border and 1200 mosmolal at
the tips of the papillae in the presence of
high ADH

111. Countercurrent Multiplier
• Ion transport in the TAL is the engine of the countercurrent
multiplier
• Na-K+-2Cl- transporter
• Na-K+-ATP transporter keeps intracellular Na+ low
• K+ recycles across membrane (ROMK)
• + Charge in tubular lumen pushes Ca2+ and Mg+ across junctions
• SITE OF LOOP DIURETICS
• Wasting of magnesium, calcium and potassium
• But LESS likely to cause hyponatremia

112. CONCENTRATION occurs in the thin
descending limb
DILUTION occurs in the thick ascending
limb and early distal tubule

113. Osmolar Clearance
• Total solute excretion (in osmoles/min) is UosmV (osmole/ml x ml/min =
osmole/min)
• Osmolar clearance (Cosm) is then defined as (UosmV)/Posm; the units
are ml/min
• This is equal to the ml of plasma that would have to be cleared each
minute of all solute to account for the rate of solute excretion

114. When urine is iso-osmolar to plasma,
osmolar clearance equals urine flow rate

115. Water Clearance
• Cwater = V – Cosm
• If Cwater is positive, osmolality of body fluids increases due to urine
formation
• If Cwater is negative, osmolarity of body fluids decreases due to urine
formation

116. POTASSIUM

117. Normal Values
• 3.5-5.0 mEq/L
• 98% of Potassium is intracellular
• Small changes have dramatic clinical consequences

118. What determines Renal Potassium
Excretion?
• Aldosterone
• K+ in diet
• Sodium Delivery to distal tubule
• Diuretics increase K+ secretion
• Tubular Flow Rate
• Non-reabsorbable negative charge
• Acid base changes
• Acidosis decreases K+ secretion
• Alkalosis increases K+ secretion
• H+-K+ ATPASE at basolateral membrane

119. Potassium Handling
• Compensation
• A potassium load is buffered by the movement of potassium into cells
by Na-K-ATPase.
• This immediate defense against hyperkalemia is stimulated by:
• Catecholamines
• Insulin
• Increased plasma potassium
• Plasma pH
• Cellular destruction/synthesis
• Correction
• Hyperkalemia is corrected by renal excretion of excess potassium
• This long-term defense against hyperkalemia is stimulated by:
• Elevated plasma potassium
• Aldosterone
• Increased flow through the distal tubules

120. Potassium Buffering
• Acutely, Potassium is taken into cells
• Electroneutrality is maintained by pushing H+ out of cells
• This produces an intracellular alkalosis  less of a gradient to
secrete H+ ions in intercalated cells
• The major stimulus for ammonium secretion is an intracellular
acidosis
• Alkalosis reduces excretion of ammonium which prevents excretion
of acid load

121. Potassium Secretion in Distal Tubule
• Step one
• Na-K-ATPase pump maintains a low concentration of sodium and a
high concentration of potassium in the cells.
• Step two
• Low intracellular sodium concentration allows sodium to flow down
its concentration gradient into the tubular cells. The flow of sodium
into the tubular cell is the rate-limiting step in potassium secretion.
• Step three
• Movement of positively charged sodium into tubular cell without an
associated anion creates an electrical gradient between the tubule
and the tubular cells. The tubular lumen is negatively charged.
• Step four
• Potassium passively flows down both electrical and chemical
(concentration) gradients into the tubular fluid

122. 1. Elevation in plasma potassium
concentration tends to increase excretion
by direct effects
AND
2. Hyperkalemia causes aldosterone
secretion

123. Increased Plasma Potassium Effects
• 1. Increased number of Na-K-ATPase pumps
• 2. Increased sodium channels and sodium resorption
• 3. Increased electrical gradient for potassium secretion
• 4. Weaker than aldosterone’s effect!

124. Increased Flow to Distal Tubule
• Increased distal flow enhances the chemical gradient by quickly
washing away any secreted potassium. This prevents the
accumulation of potassium in the tubule which would decrease the
chemical gradient.
• Increased delivery of sodium to the distal nephron increases sodium
re-sorption and enhances the electrical gradient, favoring potassium
excretion

125. Nonresorbable Anions
• Normally, the tubule fluid is negatively charged and attracts the
positively charged potassium. The negative charge is created by the
resorption of sodium without chloride by the tubular cell.
• As the movement of sodium causes the tubule fluid to become more
electronegative, some of this negative charge is lost as chloride slips
between the tubule cells and is resorbed.
• If the predominant anion in the tubules is not chloride, but rather a
nonresorbable anion, none of the negative charge is lost. If none of
the negative charge is lost, the tubule will attract more potassium!

126. Aldosterone Effects on Potassium
• 1. Increases number of Na-K-ATPase pumps in basolateral
membrane
• 2. Increases sodium channels and sodium resorption
• 3. Increased sodium resorption increases electrical gradient for
potassium secretion
• 4. Increases number of potassium channels

127. How is potassium maintained in a high
salt diet?
• Volume expansion induced by high-salt diet will decrease activity of
renin-angiotensin-aldosterone system
• Reduction of aldosterone secretion, diminishes potassium secretion,
counteracting the effect of the increased distal flow.

128. Acid Base Balance and Potassium
• In alkalosis, there is a deficit of H+ in the ECF. H+ leaves the cells to
aid in buffering, and K+ enters the cells to maintain electroneutrality.
The increased intracellular K+ concentration increases the driving
force for K+ secretion, causing HYPOKALEMIA.
• In acidosis, there is an excess of H+ in the ECF. H+ enters the cells
for buffering, and K+ leaves the cells to maintain electroneutrality. The
intracellular K+ concentration decreases, which decreases the driving
force for K+ secretion, causing HYPERKALEMIA.

129. Potassium Regulation
• Potassium can be reabsorbed by intercalated cells and the H+-K+
ATPase
• OR
• Potassium can be secreted by principal cells

130. Hypokalemia

132. Disorders of excess mineralocorticoid
activity are all characterized by
hypokalemia, metabolic alkalosis,
hypertension and mild hypernatremia

133. If urine potassium is high in patients with
hypokalemia, think of a renal cause
• Hypertension with Hypokalemia
• In renal stenosis, renin is high
• In hyperaldosteronism, renin is low
• Also vomiting

134. Nonresorbable Anions
• Etiology of hypokalemia Anion
• Diabetic ketoacidosis...............................ßhydroxybutyrate
• Vomiting...................................................Bicarbonate
• Renal tubular acidosis (proximal)..............Bicarbonate
• Penicillin derivatives.................................Penicillin deriv.
• Toluene (glue sniffing)..............................Hippurate

135. Vomiting causes a metabolic alkalosis due
to loss of HCl and hypokalemia due to
increased quantities of nonresorbable
anions.
Urine potassium should be high.

136. Diarrhea causes a normal anion gap
hyperchloremic metabolic acidosis
and hypokalemia from loss of potassium
in stool.

137. Type I Renal Tubular Acidosis causes a
normal anion gap hyperchloremic
metabolic acidosis with hypokalemia due
to renal loss of potassium

138. The most common symptom of
hypokalemia is muscle weakness and
cardiac arrythmias

139. Hypokalemia Treatment
• Potassium Chloride
• Potassium Bicarbonate (if metabolic acidosis)
• If patient is on a diuretic: Potassium-sparing diuretic

140. Hyperkalemia Etiology
• Increased K+ intake from diet or medications
• IV fluid, penicillin, blood transfusions
• Movement of K+ out of cells
• Cell death
• Metabolic acidosis
• Lack of insulin
• Hypertonic plasma and solute drag
• Beta-blockers and digoxin
• Severe exercise
• Impaired renal excretion
• Renal failure
• Effective volume depletion  Sympathetic/RAAS decrease GFR
• Hypoaldosteronism
• NSAIDS, ACE inhibitors, ARBs, Cyclosporine
• Addisons: (TB and HIV associated)
• Spironolactone

141. If a patient has persistent hyperkalemia,
then there is a defect in the renal
excretion of potassium

142. Symptoms of Hyperkalemia
• Muscle weakness
• Cardiac
• Peaked T waves
• Increased P-R interval
• Widened QRS complex
• Lost P wave
• Sinusoidal EKG

143. Hyperkalemia treatment
• CHECK EKG  if there is an EKG change then give IV calcium
immediately
• Glucose and Insulin
• Bicarbonate
• Beta agonist (inhaled), causes tachycardia
• Binding resin to increase GI excretion
• Dialysis

144. CALCIUM, MAGNESIUM
AND PHOSPHATE

146. Filtered load of Ca and P
• Filtered Ca2+ load = (GFR) x (plasma concentration of Ca2+) x 0.6
• Filtered Phosphate load = (GFR) x (plasma concentration of
phosphate) x 0.9

147. Reabsorption of Ca2+ and P
• Calcium
• 70% is reabsorbed in the proximal tubule and 20% is reabsorbed in the thick
ascending limb
• Loop diuretics cause increased Calcium excretion by inhibiting Na reabsorption
in the TAL
• 8% is reabsorbed in the distal tubule and collecting duct by an active process
• <1% is normally excreted
• PTH increases Ca reabsorption in the distal tubule
• Thiazide diuretics increase Ca2+ reabsorption in the distal tubule and can be
used to treat Kidney Stones.
• Phosphate
• 85% of fitered phospate is reabsorbed in proximal tubule by Na+-phosphate
cotransport. Distal segments of the nephron do not reabsorb phospate so 15%
is excreted in the urine.
• PTH inhibits phosphate reabsorption in proximal tubule via cAMP inhibition of
transporter  phosphaturia

148. PTH
• PTH is secreted in response to low calcium levels, as sensed by the
calcium sensing receptors in the thick ascending loop of henle and the
chief cells in the parathyroid gland
• Bones:
• PTH receptors are located on osteoblasts. Initially, administering PTH will cause an
increase in bone formation. However, the long-lasting effect of PTH causes an
increase in bone resorption. The long-lasting effect is mediated by cytokines
released from osteoblasts.
• Kidneys:
• 1) Inhibit phosphate reabsorption by inhibiting Na+-phosphate cotransport in the
proximal convoluted tubule. Leads to phosphaturia and increase in urinary cAMP.
• 2). PTH acts on the distal convoluted tubule to stimulate Ca2+ reabsorption.
• Intestine:
• PTH stimulates renal 1alpha-hydroxylase. 1,25-dihydroxycholecalciferol (active
vitamin D) will stimulate intestinal Ca2+ and P absorption.

149. Rapid PTH Secretion
• Parathyroid cell membrane has Ca2+ sensing receptors that
are linked, via a G protein to phospholipase C.
• Increased Ca2+
• When extracellular Ca2+ is increased, Ca2+ binds to the receptor and
activates phospholipase C
• Activated phospholipase C leads to increased levels of IP3/Ca2+,
which inhibits PTH secretion.
• Decreased Ca2+
• When extracellular Ca2+ is decreased, there is decreased Ca2+
binding to the receptor
• Phospholipase C is not activated, so there are not increased levels of
IP3/Ca2+. This lack of inhibition then allows for PTH secretion.

150. Calcium and Acid Base Balance
• During acidemia more H+ will bind to albumin which leaves less sites
for Ca2+ to bind ⇒ Increase in free ionized Ca2+ concentration.
• During alkalemia: less H+ will bind which allows Ca2+ to bind to
albumin ⇒ Decrease in the free ionized Ca2+ concentration.

151. Vitamin D
• Human skin-derived VD3 is produced from 7-dehydroxycholesterol
upon exposure to ultraviolet B radiation (UVB, wavelength 290–315
nm)
• As a fat-soluble vitamin, dietary vitamin D is incorporated into
chylomicrons and transported via lymphatics into the venous
circulation
• Exogenous and endogenous Vitamin D is transported to the liver.
Here, it is metabolized by the cytochrome P450 enzymes vitamin D
25-hydroxylases to 25-hydroxy vitamin D (25(OH)D)
• In classical calcium-related responses, another cytochrome P450
enzyme, 1α-hydroxylase (CYP27B1), converts 25(OH)D to the
biologically active form of vitamin D, 1,25-hydroxy vitamin D
(1,25(OH)2D) in the proximal tubule of the kidneys

152. Vitamin D
• PTH stimulates renal 1alpha-hydroxylase (enzyme used to convert 25-
hydroxycholecalciferol—> 1,25-dihydroxycholecalicferol)
• Vitamin D is going to promote mineralization of new bone, and its actions
are coordinated to increase both [Ca2+] and [phosphate] in plasma so
that these can be deposited into new bone material.
• Vitamin D has opposite effects on phosphate, than PTH, on the kidney.
PTH stimulates Ca2+ reabsorption and inhibits phosphate reabsorption,
and 1, 25-dihydroxycholecalciferol (Vit D) stimulates the reabsorption of
both ions.
• Vitamin D also increases absorption of Ca2+ and phosphate in the
intestine via induced synthesis of calbindin D28K
• In children, vitamin D deficiency→ Rickets
• In adults, vitamin D deficiency→ Osteomalacia

153. Sources of Vitamin D
• Sun - D3 is synthesized in skin by UV exposure
• Food (Vitamin D3): Cod liver oil, swordfish, salmon, tuna fish, milk
• Supplements (Vitamin D2): vitamin D fortified milk, vitamin tablets

155. Calcitonin
• Hormone secreted by parafollicular cells of thyroid
• Acts directly on osteoclasts
• Inhibits bone resorption (in the setting of high plasma Ca++), thus
LOWERS plasma Ca++
• Inhibits bone resorption thus LOWERS plasma phosphate

156. Symptoms of Hypocalcemia
• Hyperreflexia
• Spontaneous twitching
• Muscle Cramps
• Tingling and numbness
• Chvostek sign
• Trousseau sign

157. Symptoms of Hypercalcemia
• Stones, bones, groans and psychiatric overtones
• Constipation
• Polyuria (excessive urine)
• Polydipsia (excessive thirst)
• Hyporeflexia
• Lethargy
• Coma
• Death
• TREAT WITH IV FLUIDS

158. Familial hypocalciuric hypercalcemia
• Autosomal dominant inactivating mutation of calcium sensing
receptors in PT glands and ascending limb of kidney
• High PTH
• High Vitamin D
• Hypercalcemia
• Hypocalciuria
• Hypophosphatemia
• Hyperphosphaturia
• Usually asymptomatic

159. Humoral hypercalcemia of malignancy
• Some malignant tumors secrete PTH-related peptide
• Low PTH
• High Vitamin D
• Hypercalcemia
• Hypophosphatemia
• Hyperphosphaturia

160. Pseudohypoparathyroidism
• Autosomal dominant mutation of Gs protein in kidney and bone
• High PTH
• Low Vitamin D
• Hypocalcemia
• Hyperphosphatemia
• Hypophosphaturia
• Short stature, short neck, obesity, subcutaneous calcification, and
shortened 4th metatarsals and metacarpals

161. Hypoparathyroidism
• Common consequence of parathyroid/thyroid surgery
• less common is autoimmune and congenital
• Low PTH
• Low Vitamin D
• Hypocalcemia
• Hyperphosphatemia
• Hypophosphaturia
• Paresthesia, muscle cramps and tetany (severe spasms)
• Chvostek’s sign and Trousseau’s sign
• Fatigue, headaches, bone pains

162. Secondary hyperparathyroidism
• Chronic hypocalcemia from Vitamin D deficiency or chronic renal
failure
• High PTH
• Low Vitamin D
• Hypocalcemia/normal [but never high]
• *Hypophosphatemia
• *Hyperphosphaturia

163. Primary Hyperparathyroidism
• Parathyroid adenoma
• High PTH
• High Vitamin D
• Hypercalcemia
• Hypercalciuria (due to overload)
• Hypophosphatemia
• Hyperphosphaturia
• “Stones, bones, and groans”
• Stones from hypercalciuria
• Bones from increased bone resorption
• Groans from constipation

164. Distinguish Primary hyperparathyroidism
from Familial Hypercalciuric
Hypercalcemia based upon urine calcium

165. TUBULAR DYSFUNCTION

166. Bartter’s syndrome
• Bartter’s syndrome is an autosome recessive disorder characterized
by a mutation of the Na-K-2Cl cotransporter (loss of function of the
NKCC2 gene) or ROMK channel which are in the thick ascending
LOOP OF HENLE.
• In children, it presents as failure to thrive.
• Bartter’s syndrome is associated with renal stones and has an
electrolyte picture identical to chronic loop diuretic use: hyponatremia,
hypokalemia, metabolic alkalosis and hypercalcuria (which causes
the stones).
• Magnesium deficiency tends to be mild.

167. Bartter’s Syndrome Signs
• SIGNS:
• NOT HYPERTENSIVE
• Metabolic alkalosis
• Hypokalemia
• Hypomagnesemia
• Hypocalcemia (hypercalciuria)
• Hyperaldosteronism (because body detects low sodium)
• Elevated Plasma Renin Activity (PRA)
• Resistance to angiotensin II infusion
• Renal salt wasting
• JGA hyperplasia
• SYMPTOMS:
• Mental and growth retardation
• Seizures, paresthesias
• Muscle weakness
• Polyuria and polydipsia
• Kidney stones

168. Bartter’s syndrome has a clinical
presentation very similar to
Diuretic/laxative abuse and vomiting

169. Gitelman’s syndrome
• Gitelman’s syndrome is a autosomal recessive disorder characterized
by a defect in the Na+-Cl- transporter in the distal tubule. It often
presents in adulthood, but it is a life-long congenital disorder. The
electrolyte picture is consistent with chronic thiazide diuretic use.
These patients have hypocalcuria and do not develop renal stones.
• Patients with Gitelman’s syndrome have profound hypomagnesemia.

170. Gittelman’s Syndrome Signs and Sx
• Signs
• NOT HYPERTENSIVE
• Hypokalemia
• Metabolic Alkalosis
• Hypercalcemia
• Hypocalciuria
• Hypomagnesemia
• Symptoms
• Muscle cramps
• Fatigue
• Chondrocalcinosis

171. Patients with Bartter syndrome tend to
have a blunted response to a loop
diuretic, while patients with Gittelman’s
syndrome tend to have a blunted
response to a thiazide diuretic.

172. Measurement of urinary calcium can help
distinguish between the two disorders
Bartter’s: Hypercalciuria
Gittelman’s: Hypocalciuria

173. Think of Bartter’s and Gittelman’s as
equivalen to being constituitively on a
diuretic… so patients are NOT
hypertensive.
Whereas Liddle’smimic primary
hyperaldosteronism  hypertension

174. Liddle Syndrome
• Liddle's syndrome is a rare autosomal dominant condition in which
there is a primary increase in collecting tubule sodium reabsorption
and, in most cases, potassium secretion.
• A truncated or missense mutation in the ENaC channel leads to a
CONSTITUTIVELY ACTIVE Na channel.
• The mutation increases the number of channels, and increases
probability that a given channel is open.
• Affected patients typically present with hypertension, hypokalemia,
and metabolic alkalosis, findings that are similar to those seen in
other disorders caused by mineralocorticoid excess. Most patients
present at a young age.

175. Liddle Syndrome Signs and Sx
• Signs
• Hypertension
• Hypokalemia
• Metabolic Acidosis
• Young Age
• Hypoaldosteronism

176. Therapy in Liddle's syndrome consists of
prescribing amiloride or triamterene,
potassium-sparing diuretics that directly
block the collecting tubule sodium
channels and can correct both the
hypertension and, if present, the
hypokalemia

177. ACID BASE BALANCE

178. Acid-Base
Normal Arterial Plasma Values
• pH: 7.35-7.45; Mean: 7.40
• Limits compatible with life: 6.8 - 8.0
• PCO2: 35-45 mmHg: Mean: 40 mmHg
• [HCO3-]: 22-26 mEq/L: Mean: 24 mEq/L

179. Normal Acid Base Dynamics
• The typical American diet generates net H+ from protein catabolism -
for each H+ buffered, one HCO3- is consumed! The kidney can’t
afford to lose all this HCO3-, so the kidneys:
• Reabsorb almost all filtered HCO3-
• Metabolically generate new HCO3-
• Actively excrete H+ in an amount equal to the H+ generated
metabolically and ingested

180. Acid Production
• 2 types of acid are produced in the body
• Volatile acid: CO2
• CO2 + H2O  H2CO3 which dissociates into H+ and HCO3-
• This reaction is catalyzed by carbonic anhydrase
• Fixed acids: Sulfuric and Phosphoric (40-60mmol/day)
• Volatile acid = 13,000 mEq of carbonic acid /day (H2CO3)
• Excreted by lungs as CO2
• Non-volatile acid = 40-80 mEq of fixed acid/day (H+ and HCO3-)
• Excreted by kidneys

181. Henderson Hasselbalch
• A- is the base form of the buffer (H+ acceptor)
• HA is the acid form of the buffer
• When A- = HA the pH = pKa of the buffer

182. Bicarbonate is the major buffer of the
extracellular fluid.
[HCO ]
3
0.03P
CO2
pH 6.1 log

 

183. Carbonic Anhydrase
• Luminal membrane Na+/H+ exchanger secretes H+ into the lumen
• H+ in lumen combines with filtered HCO3- to form H2CO3 and
decomposes into CO2 and H2O, catalyzed by a brush border
carbonic anhydrase.
• The CO2 & H2O cross the luminal membrane and enter cell.
• Inside cell, CO2 and H2O recombine to form H2CO3, catalyzed by
intracellular carbonic anhydrase.
• H2CO3 decomposes back to H+ and HCO3-.
• HCO3- is transported across the basolateral membrane into the blood
by Na+/HCO3- cotransport and Cl-/HCO3- exchange.

184. Reabsorption of HCO3-
• Reabsorption occurs primarily in the proximal tubule
• There is net reabsorption of HCO3- but NOT net secretion of H+
• Increases in the filtered load result in increases of reabsorption until the
capacity is exceeded [40mEq/L] and HCO3- will be excreted in the urine
• Increases in PCO2 result in increased HCO3 reabsorption
• RENAL COMPENSATION FOR RESPIRATORY ACIDOSIS
• Decreases in PCO2 result in decreased HCO3 reabsorption
• RENAL COMPENSATION FOR RESPIRATORY ALKALOSIS
• ECF Volume expansion  decreased reabsorption
• ECF Volume contraction  Increased reabsorption
• Contraction alkalosis
• Angiotensin II  increased reabsorption

185. There is no net excretion of H+ in the
proximal tubule.

186. Mechanisms of H+ Excretion
• In the intercalated cells H+ is secreted into the lumen by an
H+-ATPase and HCO3- is absorbed into the blood.
• The H+-ATPase is increased by aldosterone resulting in net secretion
of H+ and net resorption of HCO3-
• METABOLIC ALKALOSIS IN EXTREME CASES
• The amount of H+ secreted as NH4+ depends on the amount
of NH3 synthesized by renal cells and the urine pH.
• In the intercalated cell, H+ is secreted into the lumen and combines
with NH3 to form NH4+ which is excreted (diffusion trapping)
• The lower the pH of the urine, the greater the NH4+ excretion
(gradient for NH3 diffusion is increased as well)
• In acidosis an adaptive increase in NH3 synthesis occurs
• Hyperkalemia inhibits NH3 synthesis (SEEN IN
HYPOALDOSTERONISM and Type 4 Tubular Acidosis)

187. Greater delivery of K+, lumenal neg.
potential, and higher flow rate all promote
increased secretion of H+ by intercalated
cell.

188. Serum Anion Gap
• [Na+] – ([Cl-] + [HCO3-])
• Represents unmeasured anions in serum
• (phospate, citrate, sulfate, protein)
• Normal value 12mEq/L (range 8-16)
• In metabolic acidosis an anion must increase to maintain
electroneutrality and replace los HCO3-
• If the anion is chloride  Normal Anion Gap
• If the anion is unmeasured  Increased Anion gap

189. Anion gap acidoses must be recognized
quickly as they can be life-threatening.

190. Metabolic Acidosis
• Normal Anion Gap
• Diarrhea
• Type 1 Renal Tubular Acidosis
• Type 2 Renal Tubular Acidosis
• Type 4 Renal tubular acidosis
• High Anion Gap
• Ketoacidosis
• Lactic acidosis
• Chronic renal failure
• Salicylate intoxication
• Methanol, formaldehyde intoxication
• Ethylene glycol intoxication

191. In response to sustained acidosis, the
kidney increases excretion of titratable
acid and dramatically increases
metabolism of glutamine and excretion of
NH4+. The latter response begins in
days, but may take a few weeks to reach
its maximum

192. Metabolic Alkalosis
• Vomiting
• Loss of gastric H+; leaves HCO3- behind in blood, worsened by
volume contraction, hypokalemia, high urine potassium
• Hyperaldosteronism
• Increased H+ secretion by distal tubule; increased HCO3-
absorption  METABOLIC ALKALOSIS
• Loop or Thiazide diuretics
• Volume contraction alkalosis
• Bartter, Gitelman and Liddle

193. All diuretics except those that act on
principal cells cause enhanced secretion
of H+ and K+
ALKALOSIS
HYPOKALEMIA

194. Respiratory Acidosis
• Opiates
• Sedatives
• Anesthetics
• Guillain-Barre syndrome
• Polio
• ALS
• Multiple Sclerosis
• Airway obstruction
• COPD

195. Respiratory Alkalosis
• Pneumonia
• Pulmonary Embolus
• High Altitude
• Psychogenic
• Salicylate Intoxication

196. Mixed Disorders
• Calculate the starting bicarbonate
• Delta gap + bicarbonate = Starting bicarbonate
• In cases of a pure anion gap metabolic acidosis, the rise in the anion
gap from 12 should equal the fall in bicarbonate from 24 (a
bicarbonate was lost for each additional acid).
• If there is a significant discrepancy, then another metabolic disorder is
present:
• If the starting bicarbonate is too high: metabolic alkalosis
• If the starting bicarbonate is too low: non-gap metabolic acidosis

197. Winter’s Formula for Metabolic Acidosis
• Expected pCO2 = (1.5 x serum bicarbonate) + 8 (+/-2)

199. Tubular Acidosis

200. Chloride and Metabolic Alkalosis
• Chloride-responsive metabolic alkalosis involves urine chloride levels
of less than 10 mEq/L and is characterized by decreased ECF volume
and low serum chloride levels, such as occurs with vomiting. This
type responds to administration of chloride salt.
• Chloride-resistant metabolic alkalosis involves urine chloride levels of
more than 20 mEq/L and is characterized by increased ECF volume.
As the name implies, this type resists administration of chloride salt.
Primary aldosteronism is an example of chloride-resistant metabolic
alkalosis.

201. The 2 major divisions of Metabolic Alkalosis
Chloride responsive’ group (urine chloride < 10 mmol/l)
Key Feature: Chloride Deficiency
Typical causes in the low urine chloride group are:
•Loss of gastric juice (eg vomiting esp if pyloric obstruction,
or nasogastric suction)
•Diuretic therapy
‘Chloride resistant’ group (urine chloride > 20 mmol/l)
Key Feature: Excess Steroids or Current Diuretic Use
Typical causes:
•Excess adrenocortical activity (eg primary aldosteronism,
Bartter’s syndrome, Cushing’s syndrome, other causes of
excess adrenocortical activity)
•Current diuretic therapy
•‘Idiopathic’ group

202. Alkalosis may cause symptoms of
hypocalcemia because H+ and Ca2+
compete for binding on plasma proteins
and decreased H+  increased Ca2+
binding

203. GLOMERULAR
HISTOLOGY AND INJURY

204. Glomerulus

205. The Glomerular Filtration Barrier
• A thin layer of fenestrated endothelial cells, each fenestra being 70 to 100 nm in
diameter.
• A glomerular basement membrane (GBM) with a thick, electron-dense central
layer, the lamina densa, and thinner, electron-lucent peripheral layers, the lamina
rara interna and lamina rara externa. The GBM consists of collagen (mostly type
IV), laminin, polyanionic proteoglycans, fibronectin, and several other
glycoproteins.
• Podocytes, which are structurally complex cells that possess interdigitating
processes embedded in and adherent to the lamina rara externa of the basement
membrane. Adjacent foot processes are separated by 20- to 30-nm-wide filtration
slits, which are bridged by a thin slit diaphragm composed in large part of nephrin.
• The glomerular tuft is supported by mesangial cells lying between the capillaries.
Basement membrane–like mesangial matrix forms a meshwork through which the
mesangial cells are scattered. These cells, of mesenchymal origin, are contractile
and are capable of proliferation, of laying down collagen and other matrix
components, and of secreting a number of biologically active mediators.

207. H&E (hematoxylin and eosin)

208. PAS (periodic acid Schiff) stain

209. Jones methenamine silver stain

210. Trichrome stain (fibrosis/sclerosis)

211. Immunofluorescence
Granular = immune complexes
Linear = autoantibodies to GBM

212. Diffuse, Focal, Segmental, Global Injury
• Focal: < 50% of glomeruli damaged
• Diffuse: > 50% of glomeruli damaged
• Segmental: Glomerulus is partially damaged
• Global: Entire glomerulus is damaged

213. Electron Dense Deposits
• Injury of the glomerulus from immune complex deposition or
destruction of tissue
• Supepithelial: Membranous glomerulonephropathy
• Subendothelial and Intramembranous: MPGN

214. Localization of immune
complexes in the glomerulus:
(1) Subepithelial humps, as in
acute glomerulonephritis
(2) Epimembranous deposits, as
in membranous nephropathy
and Heymann nephritis
(3) Subendothelial deposits, as
in lupus nephritis and
membranoproliferative
glomerulonephritis
(4) Mesangial deposits, as in IgA
nephropathy.

215. Podocyte Effacement

216. Mesangial Expansion Pattern
Nodular/lobular
Diabetic glomerulosclerosis
Amyloidosis
LCDD
Branching
IgA nephropathy
Lupus nephritis

217. Mesangial Hypercellularity
• More than 2 cells per tuft

218. Endocapillary Hypercellularity
• Obliteration of the capillary, loops by swollen endothelial cells and
inflammatory cells
• Often described as proliferative glomerulonephritis
• MPGN and Lupus

219. Extracapillary Hypercellularity
• A cellular crescent is defined as a
proliferation of parietal epithelial
cells and inflammatory cells, more
than 2 cell layers thick
• Always associated with fibrin
which indicates active necrosis
• Always implies a Rapidly
Progressive Glomerulonephritis

220. FSGS
• Segmental and Focal
• Histology: Increased mesangial
matrix, obliterated capillary
lumina, hyalinosis, and lipid
droplets.
• On EM, podocytes exhibit
effacement of foot processes.

221. IHC Staining
• Deposition of circulating immune
complexes gives a granular
pattern.
• Anti-GBM antibody
glomerulonephritis displays a
linear pattern.

222. Primary vs. Secondary GN

223. Mechanisms of Glomerular Injury
• 1. Injury by antibodies reacting in situ within the glomerulus, either
binding to insoluble fixed (intrinsic) glomerular antigens or extrinsic
molecules planted within the glomerulus  Electron dense deposits
• Membranous nephropathy (PLA2)
• Granular IF staining
• Anti-GBM  Goodpasture syndrome
• Linear IF staining
• 2. Injury resulting from deposition of circulating antigen-antibody
complexes in the glomerulus.
• Infectious Glomerulonephritis
• Lupus nephritis
• IgA Nephropathy

225. Complement and Glomerular Injury
• Antibody-mediated immune injury is an important mechanism of
glomerular damage, mainly via complement- and leukocyte-mediated
pathways. Antibodies may also be directly cytotoxic to cells in the
glomerulus.
• Alternative complement pathway activation occurs in the
clinicopathologic entity called dense-deposit disease, until recently
referred to as membranoproliferative glomerulonephritis (MPGN type
II), and in an emerging diagnostic category of diseases broadly
termed C3 glomerulopathies.
• Low Complement GN: MPGN, Post-streptococcal
glomerulonephritis, SLE

226. Podocyte Injury
• The podocyte is crucial to the maintenance of glomerular
barrier function. Podocyte slit diaphragms are important
diffusion barriers for plasma proteins, and podocytes are also
largely responsible for synthesis of GBM components.
• Podocyte injury can be induced by:
• Antibodies to podocyte antigens
• Toxins (i.e. ribosome poison puromycin)
• Cytokines
• Circulating factors (i.e. focal segmental glomerulosclerosis)
• Morphologic changes of podocyte injury:
• Effacement of foot processes
• Vacuolization
• Retraction and detachment of cells from GBM
• PROTEINURIA

227. ELECTROLYTE
DISORDERS

228. CHF and Cirrhosis in Hyponatremia
• Conditions such as liver cirrhosis congestive heart failure are
associated with third spacing and low effective circulating volume
• This leads to an increase in ADH secretion because the body thinks it
is hypovolemic. The increased ADH leads to water retention which in
turn dilutes the sodium concentration and therefore causes
hyponatremia.
• Clinical clues: presence of peripheral edema, pleural effusion,
pulmonary edema or ascites, low blood pressure, rapid hear rate,
drop of BP when standing from supine position

229. Assessing volume state

230. Reduced effective circulating volume is
associated with low urinary sodium
concentration (<20 mmol/L)

234. Diagnostic Work up
• 1. Check urine osmolality
• if < 100 → no ADH (primary polydipsia)
• 2. Check serum osmolality
• If low → true hyponatremia
• If elevated --> hyperglycemia etc. (dilutional hyponatremia)
• If normal → pseudohyponatremia (high protein or lipid levels)
• 3. Check urine Na+
• If < 20 → RAA activated → heart failure or cirrhosis
• If > 40 euvolemic hyponatremia (SIADH, adrenal insufficiency,
hypothyroidism)

235. Sosm
• Calculated Sosm = 2 x Na+ + glucose/18 + BUN/2.8
• Example; [Na+] = 140, Glucose = 90, BUN = 14
• Sosm = 2 x 140 + 90/18 + 14/2.8 = 290
• You should check the difference between calculated and measure
Sosm (osmolal gap) to see if there unusual osmoles in the blood
(occurs in alcohol intoxication, mannitol infusion)
• Normal osmolal gap <9

236. Serum osmolality is high in dilutional
hyponatremia and normal in
pseudohyponatremia

237. Dilutional Hyponatremia
• Dilutional hyponatremia occurs in the case of diabetes
(hyperglycemia causes water to come out of the cells) OR in
transurethral resection of the prostate or bladder OR in hysterectomy
(sorbitol or glycine may be used during the surgery to irrigate which
are absorbed and cause a shift in water outside of the cells).
• In the case of dilutional hyponatremia caused by diabetes, serum
osmolality is usually high. However, the osmolal gap is normal
because glucose is accounted for in that formula. For every 100
mg/dL increase in glucose, expect a 1.6 mmol/L drop in [Na+].

238. Psuedohyponatremia
• Pseudohyponatremia is rare and occurs in the presence of
hyperlipidemia and hyperprotinemia. Normally, water makes up 93%
of the plasma, and proteins and lipids make up 7% of the plasma. The
increase in proteins and lipids upsets this balance and therefore the
apparent concentration of Na+.
• To test for this, look at lipid and protein levels in the plasma. Also look
at serum osmolality, which should be normal.

239. Thiazide diuretics are more likely to cause
hyponatremia than loop diuretics

240. Pain and nausea may cause increased
secretion of ADH

241. SIADH
• Diagnostic Criteria for SIADH:
• Low serum osmolality
• High unregulated ADH secretion leads to a constant high rate of water
reabsorption in the CD causing dilution of the serum despite euvolemia
• High urine osmolality (greater than 100 mosm/kg) and high urine
sodium concentration
• The high rate of water reabsorption means that the kidney is constantly
concentrating urine
• Low urine uric acid
• Uric acid tends to follow the water in the kidney (it maintains a constant
concentration between compartments). So by reabsorbing a lot of water, the
tubular water compartment is small and very little uric acid can be excreted
• Euvolemia
• SIADH is a Diagnosis of exclusion!- hormones, heart, liver
function, GFR must all be normal

242. Medical Conditions SIADH
• Pulmonary infections: TB, lung abscesses, bacterial/viral pneumonia
• CNS problems (cause disruption of the normal inhibitory mechanisms
of ADH release from the posterior pituitary)
• Infection: meningitis, encephalitis, abscess
• Injury: stroke, trauma, subarachnoid hemorrhage
• Malignancies (certain tumors/ cancers have ectopic ADH production)
• Small cell carcinoma of lung (most common)
• Rarely other lung cancers
• Less common: other head/neck cancers, extrapulmonary small cell carcinomas

243. *Medications causing SIADH*
IMPORTANT
• Thiazide diuretics (lots of NaCl excretion)
• Carbamazepine (increases ADH secretion)
• Vincristine- chemotherapy (increases ADH secretion)
• Ifosfamide- chemotherapy (increases ADH secretion)
• Antipsychotics/antidepressants (increase ADH secretion)
• Oxytocin and dDAVP (ADH analogs)
• Cyclophosphamide (potentiate renal action of ADH)
• NSAIDs (potentiate renal action of ADH)
• SSRIs (unknown mechanism)

244. Endocrine Disorders
• SIADH
• LOW serum osmolality
• HIGH urine osmolality
• HIGH urine sodium concentration
• LOW serum uric acid
• Euvolemia
• Adrenal Insufficiency
• LOW serum osmolality
• Very HIGH urine osmolality
• HIGH urine sodium concentration
• LOW serum uric acid
• Euvolemia
• Hypothyroidism
• LOW serum osmolality
• HIGH urine osmolality
• HIGH urine sodium concentration
• LOW serum uric acid
• Euvolemia

245. Management of Hyponatremia
• Fluid restriction: for everyone with hyponatremia
• Hypertonic 3% NaCl solution
• For symptomatic patients (seizures, altered mental status)
• Hypertonic saline increases ECV osmolality acutely
• Furosemide: Loop diuretic (you could use another loop diuretic too)
• Reduces medullary gradient
• DO NOT CORRECT TOO QUICKLY
• Avoid correction faster than 0.5-1mmmol/hr or >10-12 mmol/day

246. Risks of Sodium Correction
• Edema due to acute hyponatremia safely corrects when Na+ is added
to the ECF.
• Chronic hyponatremia is usually asymptomatic because the body has
adapted by moving solute into the cells, thereby decreasing ECF
volume. Adding Na+ too quickly results in overcorrection, pulling too
much water out of the cells.
• Appropriate correction: 0.5-1.0 mmol/hr, or 10-12 mmol/day
• Risk of rapid correction: Central Pontine Myelinolysis
• Delayed neurological symptoms: dysarthria, altered mental status show up
about a week later with MRI signs (hyperintensity in the pons).

247. Osmotic Demyelination Syndrome
• Osmotic demyelination syndrome (ODS) was first described in
alcoholism, but myelin loss may also be present in other conditions such
as liver transplantation, malnutrition, and AIDS.
• It may occur, in the context of rapid restoration or overcorrection of the
serum Na+ concentration. Thus patients inadvertently subjected to rapid
correction must be monitored carefully.
• Majority of cases are asymptomatic and the onset of symptoms may be
delayed (usually taking 24-48 hours to manifest) which is why you should
check Na+ often to ensure you’re not replenishing too quickly
• Classical clinical features: quadriparesis (weakness in all four limbs) and
pseudobulbar palsies (inability to control facial movements)
• Classic findings on T2- weighted image MRI are hyperdense (white
areas) in the central pons. This lesion reflects increased water content in
the area.

248. Hypernatremia
• GI: Severe diarrhea, vomiting, or adenomas
• Renal: Diabetes insipidus or osmotic diuresis
• Insensible and sweat losses: Burns, fever, respiratory infections
• Impaired thirst or inability to consume water

249. Diagnosing Hypernatremia
• Urine osmolality
• Isolated thirst disturbance
• Urine will be appropriately concentrated (>800 (600) mOsm/kg H2O)
• Diabetes Insipidus
• A urine osmolality of <150 (300) mOsm/kg H2O)
• Osmotic Diuresis
• If urine osmolality is persistently at or near 300mOsm/kg H2O an osmotic diuresis is likely
• Grey zone
• Urine osmolality 150-800 mOsm/kg H2O, Consider:
• Partial variants of diabetes insipidus
• Impaired countercurrent multiplication (CCM) (usually caused by tubulointerstitial kidney injury)
• Response to ADH:
• Response to ADH can help one to differentiate between central diabetes insipidus
(CDI) or nephrogenic diabetes insipidus (NDI)
• Only CDI will respond to exogenous ADH

250. Free Water Deficit
• The free water deficit is used to estimate the amount of water needed
to correct hypernatremia.
• Water Deficit = TBW x ([Plasma Na+/ 140]-1)
• TBW= total body water (weight in kg x 0.6 for men/ weight in kg x 0.5
for women)

251. Free Water Clearance
• Cwater = V – Cosm
• Cosm = (UosmV)/Posm

252. Management of Hypernatremia
• Treatment Complications
• Rapidly lowering Na+ concentration in plasma may precipitate
cerebral edema as water redistributes into intracellular
compartment. Thus one has to reduce the serum Na+
concentration gradually (over 48-72 hours)
• Guidelines for patients with hypernatremia:
• First restore volume contraction with normal saline before initiating
therapy with dilute solutions
• Can give ½ of water deficit back in 24 hours.
• Water deficit = TBW ([Na/140]- 1)
• Replace ongoing water and sodium losses (e.g urine, sweat) with an
intravenous solution of comparable tonicity

253. In metabolic alkalosis associated with
vomiting - use urine chloride to check
volume instead of sodium
Chloride will be low in volume depleted
states.

254. Considerations in Assessment
• Volume State
• Urine osmolality
• Urine sodium
• Medical Conditions
• Drugs

255. Na+ and K+ in Collecting Tubules
• Sodium reabsorbed by ENaC or the NaCl symporter
• Pumped out of the cell with Na/K ATPase
• K is pumped out by ROMK to help rectify the inward Na
• More Na uptake drives out more K
• Aldosterone binds to a mineralocorticoid receptor to increase the
uptake of Na and the excretion of K
• If Na isn’t delivered to that portion of the tubule, K won’t be
exchanged for it
• If Na is highly delivered (increased absolute presence, increased flow,
loop/thiazide diuretics), K will be highly exchanged
• If Na is highly taken up (lots of aldosterone, mutations in Liddle’s), K
will be highly exchanged

256. Factors Affecting Potassium Uptake
• Drugs:
• Insulin
• Beta-2 adrenergic agonists
• Alpha adrenergic antagonists
• Alkalosis (Base and Beta agonists)
• Hyposmolarity

257. Factors Increasing Potassium Excretion
• High K+ diet
• Hyperaldosteronism
• Alkalosis
• Thiazide diuretics
• Loop diuretics
• Luminal anions
• High urinary flow

258. Causes of Hyperkalemia
• Movement out of cells
• Insulin Deficiency
• Beta-2 adrenergic antagonists
• Alpha adrenergic agonists
• Acidosis (Acid and Alpha agonists)
• Hyperosmolarity
• Cell lysis (tumor cells, rhabdomyolysis, hemolysis)
• Exercise
• Impaired renal excretion
• Renal failure
• Effective volume depletion  Sympathetic/RAAS decrease GFR
• Hypoaldosteronism
• NSAIDS, ACE inhibitors, ARBs, Cyclosporine
• Addisons: (TB and HIV associated)
• Spironolactone

259. Acid Base Balance and Potassium
• The plasma membrane of some cells contain a K+/H+ ATPase
(exchanger; e.g. intercalated cells of late distal tubule, parietal cells of
the stomach). This exchanger is utilized to internally balance K+ in
response to acid-base disturbances
• Acidemia- too much H+ in the blood causes the H+ to be shifted in (in
order to utilize our intracellular buffering mechanisms) in exchange for
K+ shifting out, which leads to hyperkalemia
• Alkalemia- too little H+ in the blood causes intracellular H+ to be
shifted out of the cell in exchange for K+. Less K+ extracellularly
leads to hypokalemia

260. Insulin, Hyperglycemia, and Potassium
• Insulin stimulates the Na+/K+ pump, resulting in K+ being taken up by
the cell. With insulin deficiency, lower Na+/K+ pump activity leads to
hyperkalemia.
• Hyperglycemia → High ECF osmolarity compared to ICF. Water flows
out of the cell due to the osmotic gradient to equalize osmolarity
across the two compartments. As water leaves the cell, the
intracellular K+ concentration increases, which then drives its
diffusion out of the cell (think of it as water dragging K+ with it)

261. Hyporeninemic Hypoaldosteronism
• Also known as type IV renal tubular acidosis- caused by a deficiency
in the adrenal glands leading to a decrease in aldosterone.
• Characterized by a mild-normal anion gap metabolic acidosis
• Serum bicarbonate: 15-20 mmol/L
• Hypoaldosteronism  less K+ secretion
• Hyperkalemia  limits NH3 synthesis  decrease in H+ excretion
• It is usually associated with reduced GFR
• Most commonly associated with diabetes mellitus

262. GFR and Hyperkalemia
• Severely reduced GFR (GFR < 20 mL/ min) leads to hyperkalemia
because at this point, tubular flow is so low that the kidney is unable
to excrete adequate amounts of potassium.
• Remember that the rate of K+ is secretion is affected by:
• Delivery of Na+ to the distal tubule
• Low tubular flow delivers less Na+ to the distal tubule, and less K+ is
transported into the lumen for excretion
• The driving force on K+ that makes it want to leave cells
• Low tubular flow can cause K+ already secreted into the lumen of the
cortical collecting duct (CCD) to accumulate, reducing the gradient that
favors K+ excretion in that part of the nephron
• Low tubular flow → lower K+ excretion

263. Reduced Renal Excretion
• Obstructive uropathy can cause reduced excretion and hyperkalemia
which is higher than the degree expected for the degree of GFR
reduction
• Drugs such as trimethoprim, pentamidine , cyclosporin and tacrolimus
• Potassium sparing diuretics, ACE inhibitors and ARB, NSAIDs
• Reduced delivery of sodium to distal nephron (severe dehydration)

264. Symptoms of Hyperkalemia
• Ascending muscle weakness that starts in the legs and
progresses to the trunk and arms
• Can progress to a flaccid paralysis that mimics Guillain-Barre
• Cardiac conduction abnormalities
• Bundle branch blocks
• AV block
• Arrhythmias (specifically bradycardia and V-fib)
• Hyperkalemia raises the resting membrane potential leading to
ECG changes:
• Tall, peaked T waves
• Wide QRS complexes
• Severe hyperkalemia can lead to life threatening tachyarrhythmias

265. Workup of Hyperkalemia
• Check GFR
• (if GFR >20 look for additional causes)
• If GFR<15 and K+ >6 Dialysis may be needed)
• Drugs:
• Beta blockers
• Potassium sparing diuretics
• NSAIDs
• Ace Inhibitors or ARBs
• Check blood glucose
• Status of RAAS
• Hypoaldosteronism causes hyperkalemia

266. Management of Hyperkalemia
• In mild to moderate hyperkalemia in a severely volume depleted
patient, volume expansion with normal saline may be the only
treatment needed
• Assess severity by checking for ECG changes (K > 6 mmol/L)
• If ECG changes are present, stabilize the heart with IV calcium gluconate
• Lower Potassium levels
• Shift K+ into the cells by administering:
• Insulin w/ glucose (fast action: effects within 30 mins)
• Beta-2 agonist (albuterol)
• Remove excess K+
• Loop diuretics
• Potassium-binding resin (sodium polystyrene sulfonate)
• Dialysis
• Reserved for those with intractable kidney disease

267. In cases with severe volume depletion
and reduced Na deliver to distal nephron,
volume expansion with intravenous
normal saline may be the only treatment
required for mild to moderate
hyperkalemia

268. Causes of Hypokalemia
• K+ shift into the cell
• Drugs
• insulin
• beta-2 agonists
• Alkalosis
• [H+] is low, so intracellular H+ moves out of cells in exchange for K+
• Renal Loss
• Diuretics
• Genetic Defects that affect transport
• Bartter’s Syndrome (TAL)
• Gitelman’ Syndrome (DCT)
• Liddle’s Syndrome (CCD)
• Polyuria
• Hyperaldosteronism
• Mineralocorticoid excess (aldosterone, progesterone → sodium retention)
• Hypomagnesemia
• Mg+ blocks ROMK, so low Mg+ → high K+ excretion
• GI Loss
• diarrhea (K+ concentration is high in the colon)
• laxatives

269. Renal Loss
• Diuretics (osmotic, loop and thiazide)
• Bartter, Gitelman and Liddle syndromes
• Polyuria
• High aldosterone state
• Primary
• Secondary
• Apparent mineralocorticod excess
• Hypomagnesemia

270. Assessing the History
• A history of:
• Diarrhea → K+ loss from the gut
• Vomiting → alkalosis, high urine potassium
• High urine output → polyuria
• Medications: insulin, albuterol, laxatives, diuretics
• High blood pressure → hyperactive RAAS → hyperaldosteronism

271. High urine potassium (> 25 mmol/ L) →
Renal loss, Vomiting
Low urine potassium (< 25 mmol/ L) →
Most likely GI loss

272. Symptoms of Hypokalemia
• Severe muscle weakness or rhabdomyolysis (similar to ascending
pattern in hyperkalemia
• Muscle cramping
• ECG abnormalities—presence of a U wave
• Cardiac conduction abnormalities
• Metabolic alkalosis
• Renal dysfunction—structural and functional changes in the kidney
• Glucose intolerance—via reduced insulin secretion

273. Potassium Depletion- Metabolic Alkalosis
• Chronic potassium depletion increases urinary acid excretion.
• Ammonium production and absorption are enhanced and bicarbonate
reabsorption is stimulated.
• Chronic depletion also upregulates H, K-ATPase to increase
potassium absorption at the expense of enhanced hydrogen ion loss.
• Hypovolemia
• Vomiting
• Diuretic Use
• Bartter and Gittelman Syndromes
• Hypervolemia
• Hyperaldosteronism
• Mineralocorticoid Excess
• Liddle Syndrome

274. AME
• Cortisol can have activate aldosterone receptors (mineralocorticoid
receptor)
• A local enzyme, 11-HSD, breaks down cortisol to cortisone, which
cannot activate MR
• Congenital deficiency of this enzyme  AME
• Acquired deficiency occurs with high amount of licorice ingestion

275. The presence of distal or proximal RTA
should be considered in any patient with
an otherwise unexplained normal anion
gap (hyperchloremic) metabolic acidosis

276. Type I Renal Tubular Acidosis
• The primary defect in distal (Type 1) RTA is impaired distal
acidification. Diminished H-ATPase activity is probably the most
common cause of distal RTA. This defect impairs the ability to
maximally acidify the urine, and in most patients, the urine pH cannot
be reduced below 5.5. Patients present with a normal anion gap
metabolic acidosis and hypokalemia.
• ELEVATED URINE PH
• Commonly associated with hypokalemia

277. Sodium that is reabsorbed in the
collecting tubules must, to maintain
electroneutrality, be reabsorbed with an
anion, such as chloride or bicarbonate, or
in exchange for a cation, such as
potassium or hydrogen.
If hydrogen ion secretion is impaired,
potassium secretion generally increases.

278. Type II Renal Tubular Acidosis
• Proximal (Type 2) RTA is characterized by a reduction in proximal
bicarbonate reabsorptive capacity that leads to bicarbonate wasting in
the urine until the serum bicarbonate concentration has fallen to a
level low enough to allow all of the filtered bicarbonate to be
reabsorbed.
• It is often associated with diffuse proximal tubular dysfunction, known
as Fanconi syndrome.
• Sign of proximal tubule dysfunction in the urine (glucosuria, phosphaturia,
uricosuria, aminoaciduria)
• Mild hypokalemia may be seen

279. In the kidney, the resulting intracellular
acidosis stimulates both hydrogen
secretion and ammonia production. As
ammonia (NH3) diffuses into the tubular
lumen, it mostly combines with hydrogen
ions to form ammonium (NH4+). The
reduction in the free hydrogen ion
concentration elevates the urine pH.

280. Workup of Hypokalemia
• Rule out cellular shift: insulin, beta 2 agonist
• Check urine [K+]
• Low: diarrhea
• High: Renal Loss
• Check serum Mg (hypomagnesemia)
• If normal gap metabolic acidosis  Type 1 or 2 RTA
• Check BP
• Low: vomiting, Gitelman, Bartter
• High: PRA
• High  Renal artery stenosis, renin secreting tumor
• Low  Primary hyperaldosteronism, Liddle syndrome, AME

281. Hyperchloremic Metabolic Acidosis
• Two common causes of hyperchloremic (ie, normal anion gap)
metabolic acidosis and hypokalemia are diarrhea and renal tubular
acidosis (RTA). Diarrhea generates potassium loss in the stool, while
RTA produces potassium loss in the urine.
• Measurement of urinary potassium excretion may help to distinguish
between gastrointestinal and renal losses of potassium

282. Management of Hypokalemia
• Treat the underlying cause
• No treatment if mild and asymptomatic
• Give potassium chloride supplement
• Cannot be infused any faster than 10 mmol an hour or in concentrations >40
mmol/L in a peripheral vein
• Need a central vein catheter placed if higher rates or concentrations needed

283. URINALYSIS

284. Urinalysis
• Urine Dipstick Test
• Only measures albumin
• 24 hour urine collection
• Spot morning urine protein to creatinine ratio
• Depends on the constancy of serum creatinine

285. Urine Color

286. Red Urine
• If clear (a substance is dissolved in the urine)
• Rifampin (antibiotic): orange to red
• Phenytoin (antiepileptic): red
• Chloroquine (antimalarial), Nitrofurantoin (antibiotic): brown
• Food dye, beets, rhubarb
• Hemoglobin or myoglobin: pink to red
• Bilirubin (jaundice): dark yellow to brown
• If turbid:
• Red blood cells: red to brown

287. Turbid Urine
• Cloudy
• Causes:
• Pathologic
• Phosphaturia
• Pyuria
• Chyluria
• Lipiduria
• Hyperoxaluria
• Food and Drug
• Diet high in purine rich foods

289. Normal Values
Component Normal
Specific Gravity
(SG)
1.003 – 1.030
pH
5.0 – 5.5 (range: 4.5 –
8)
Leukocyte (LE) negative
Blood negative
Nitrite negative
Ketones negative
Bilirubin negative
Urobilinogen negative
Protein negative
Glucose negative

290. Specific Gravity
• The osmolality of the urine can be inferred by measuring the urine
specific gravity, which is defined as the weight of the solution compared
with the weight of an equal volume of distilled water.
• Normal value of SG: 1.003 - 1.030
• The urine specific gravity generally varies with the osmolality, rising by
approximately 0.001 for every 35 to 40 mosmol/kg increase in urine
osmolality.
• Thus, a urine osmolality of 280 mosmol/kg (which is isosmotic to normal
plasma) is usually associated with a urine specific gravity of 1.008 or
1.009.
• In presence of volume depletion  maximum ADH secretion 
increased water reabsorption  max SG = 1.030
• If above 1.030 then another substance is in the urine.

291. The specific gravity gives an indication of
the weight of the solute in the urine

292. When specific gravity is high, proteinuria
does not necessarily indicate nephrotic
syndrome

293. Urine pH
Normal range of urinary pH: 5.0 – 5.5 (range: 4.5 – 8)
Causes of high urine pH:
• UTI with urea splitting bacteria (e.g. proteus) (drives NH3 + H+ to
NH4+, causing decline in free H+)
• Ingestion of alkali
• Defect in urinary acidification in the collecting tubules (distal renal
tubular acidosis)

294. Normal Urinary Protein and Albumin
• Normal urinary protein excretion
• 40-80 mg/day
• upper limit of normal = 150 mg/day
• Normal urinary albumin excretion
• about 20 mg/day
• upper limit of normal = 30 mg/day

295. If urine dipstick protein is lower than
protein creatinine ratio, then there are two
possibilities:
1. Urine is dilute
2. Protein is not albumin and not
recognized by dipstick

296. Heme on Urine Dipstick
• Causes of positive blood on dipstick:
• Presence of intact red blood cells (hematuria)
• Presence of hemoglobin in urine from lysis of RBC in the
vasculature
• Presence of myoglobin in the urine from breakdown of skeletal
muscle cells (rhabdomyolysis)
• Differentiating between these causes:
• Urine microscopy
• Only in true hematuria red blood cells are seen in the urine
• With hemoglobinuria and myoglobinuria, microscopy does not show any
RBCs
• Look for clues in the pt history

297. False Positives and Negatives
• Dipstick blood is based on the reaction of heme moiety of hemoglobin
with peroxide and a chromogen to produce a change in color.
• False Positive:
• High number of bacteria such as enterobacter, staphylococci and streptococci can
cause false positive (pseudoperoxidase activity)
• False negative:
• Ascorbic acid (strong reducing agent) can cause a false negative

298. Protein Excretion via Urine Dipstick
• The reagent on most dipstick tests is sensitive to albumin
• Best at detecting glomerular proteinuria
• Results are affected by the urine concentration/specific gravity
• Concentrated sample (SG > 1.025) would OVERESTIMATE the albumin excretion
• Dilute sample (SG < 1.005) would UNDERESTIMATE albumin excretion
• In normal conditions small amount of albumin is filtered
into the urine, but it gets reabsorbed almost entirely in the
proximal tubules (PT)

300. Nephrotic Proteinuria
• Excretion of 3.5 or more grams of protein (PCR greater than 3) in
urine a day, caused by an increase in permeability of the capillary
walls of the glomerulus
• 3+ - 4+ protein with SG: 1.015 or lower usually suggests nephrotic
range

301. Positive Urinary Glucose
• Check a plasma glucose if you see glycosuria
• Elevated plasma glucose
• Inadequately controlled diabetes mellitus
• The filtered glucose load is increased to a level that exceeds proximal glucose
reabsorptive capacity
• Normal plasma glucose
• Indicative of proximal tubular defect and may be seen in combination with other
proximal tubular defects (bicarbonaturia)
• Think Fanconi, Type I Tubular Acidosis

302. Urinary Ketones and Nitrites
• Ketones
• Testing for ketones on the urinary dipstick is based on nitroprusside reaction with
acetoacetate and acetone
• Products of body fat metabolism, normally not found in the urine
• Most commonly associated with uncontrolled diabetes
• Can also occur during pregnancy, carbohydrate-free diets, and starvation
• Glucose is unavailable, so fatty acids break down into ketones.
• Nitrites
• Result when bacteria reduce nitrates to nitrites
• Seen in UTIs (proteus)
• Staph Aureus, Psuedomonas and Enterococcus do not cause positive nitrites

303. If case is associated with high serum
glucose, high anion gap metabolic
acidosis and positive blood and or urine
ketone, think about diabetic ketoacidosis

304. Leukocyte Esterase
• Leukocyte esterase (LE) on dipstick is based on indoxyl esterase activity
released from lysed neutrophils and macrophages
• May signal pyuria associated with UTI
• Organisms such as chlamydia and ureaplasma urealyticum should be considered in
patients with with pyuria and negative cultures
• Other causes of sterile pyuria include balanitis, nephrolithiasis, foreign bodies, exercise,
glomerulonephritis, and corticosteroid and cyclophosphamide (cytoxan) use
• Needs confirmation with urine microscopy to see the actual leukocytes
• False positive:
• Alkaline pH and low SG
• False negative:
• High SG prevents leukocyte lysis
• High glucose and protein in urine

305. Proteinurias
• Glomerular proteinuria
• Most common type
• Albumin is the primary urinary protein
• Increase in the permeability of the glomerular capillary wall that leads to abnormal filtration and
excretion of larger, normally unfiltered proteins
• Can be seen with any form of glomerular disease
• Large amount of albumin is seen (filtration barrier damage)
• Tubular proteinuria
• Results when malfunctioning tubule cells no longer metabolize or reabsorb filtered protein
• Low-molecular weight proteins predominate over albumin and rarely exceed 2g per day
• Not clinically important disorder unless accompanied by other defects in proximal function
• Mild albuminuria seen with proximal tube damage.
• Overflow proteinuria
• Increased production of smaller proteins leads to a rate of filtration that exceeds normal proximal
reabsorptive capacity
• Low-molecular weight proteins overwhelm the ability of the tubule to reabsorb filtered proteins

306. Microalbuminuria
• The excretion of abnormal quantities of albumin below the level
detectable by the urine dipstick
• Measured as 30-300 mg of albumin in a 24-hour period
• (normal albumin secretion < 30 mg/day)
• Earliest clinically detectable stage of diabetic nephropathy

307. RBCs
• May originate from infrarenal vessels, glomeruli, tubules, or anywhere
in the GU tract
• Dysmorphic RBCs have been transformed by transit through
abnormal glomerulus
• Suggests glomerular disease (e.g. glomerulonephritis)

308. WBCs
• UTIs (most common)
• Acute interstitial nephritis
• Legionella
• Leptospira
• Chronic infections (e.g., TB)
• Allergic interstitial nephritis
• Atheroembolic disease
• Granulomatous disease (e.g., sarcoidosis)
• Tubulointerstitial nephritis uveitis syndrome
• Men typically have < 2 WBCs per HPF
• Women < 5

309. Tubular Cells
• Tubulointerstitial disease
• Ischemic and nephrotoxic injury

310. Eosinophils
• Allergic interstitial nephritis
• Atheroembolic disease
• Prostatitis
• Vasculitis

311. Squamous Epithelial Cells
• Contamination

312. Urinary Casts
• Tamm-Horsfall mucoproteins are produced in distal parts of the
nephron
• When urine flow is reduced, they get compacted and take the shape
of the tubule
• The tubular content (cellular debries, intact RBC, WBC, tubular cells,
fat droplets), if any, can get trapped in the mucoproteins and excreted
as casts

313. Hyaline
• Increased numbers after exercise
• Suggests dehydration (low urine flow)
• Seen in prerenal AKI