A. Total Body Water 60% of weight 42kg (70kg man)

1. Intracellular 40% (2/3) 28 L
2. Extracellular 20% (1/3) 14 L
   1. Interstitial 16.5% 11.5 L
   2. Plasma 3.5% 2.5 L

B. Plasma Oncotic Pressure

1. Total 28mm 7.3g/dL
2. Albumin 21mm 4.5g/dL
3. Globulins 6.5mm 2.5g/dL
4. Fibrinogen 0.3mm 0.3g/dL
5. Plasma Osmolality 280-300 mOsm

C. Electrolyte Distribution

1. Intracellular
   1. Potassium 160mM
   2. Magnesium 34mM
   3. Calcium 0.15mM
   4. Sodium 12mM
2. Plasma Values
   1. Sodium 135-145 mM
   2. Chloride 95-105 mM
   3. Bicarbonate 26-30 mM
   4. Potassium 3.5-5.0 mM
   5. Calcium (total) 8.5-10.5 mM
   6. Magnesium 1.6-2.6 mM
   7. Phosphates (Pi) 3.0-4.5 mM
   8. Proteins 7.3g/dL in plasma 2.5g/dL in ECF
   9. Uric Acid <7.2 mg/dL
   10. Anion Gap 12-18 mM

D. Blood pH

1. 7.35-7.45 [H+] = 45-35nM Intracellular pH ~6.9
2. Normal CO2 40mm Hg (arterial) with 1.2mM H2CO3
3. Normal HCO3- 24-30 mM
4. Normal pO2 104mm Hg (alveolar) Normal pO2 (arterial) 70-90mm Hg
5. Alveolar-Arterial Oxygen (A-a) Gradient: <15mm Hg (increases with age)
6. pH = pK + log{[HCO3-]/[H2CO3]} and the pK = 6.1 for carbonic acid
7. Note that [H2CO3] = pCO2 x a , where a = 0.031mM/mmHg (solubility product)
8. From this it follows that delta (pCO2)=10 causes delta (pH) = 0.08

E. Buffer Capacity of Blood

1. Total Buffer Capacity ~15mEq/kg body weight
2. Plasma Strong Ion Difference (SID) = ~42mEq/L Na+, K+, Cl-, Ca2+, Mg2+, SO42-
3. Nonvolatile Weak Acids (A-) : [PO4]~1mM [Prot]~16mM
4. Anion Gap = ([Na+]+[K+])-([Cl-]+[HCO3-]) ~ 15-16meq/liter

F. Renal Filtration Characteristics

1. Renal Blood Flow: 650 mL/min / kidney
2. Normal GFR: 125mL/min / kidney
3. Initial Filtrate: All Ions (not lactate <6mM), proteins < 30 kD MW, various catabolites
4. Protein Losses: Normally 150-200mg/24 hours

G. Fluid Losses

1. Total Normal Fluid Losses: ~2 L / day for adults
2. Urine
   1. Urine Output: 0.5L/day min, 15-20 L/day max
   2. Urine pH: 4.5-7.5 (pH >8.0 suggests a urea (base) splitting infection)
   3. Urine Osmolality: 5-50 mOsm minimum, and 800-1400 mOsm maximum
   4. Normal Creatinine Cleared 20-25mg/kg/24hrs male, 15-20mg/kg/24 hours female
   5. Normal Protein Lost in Urine 150-200mg / 24 hours
3. Other Losses: Insensible (Sweating, respirations) ~500ml/day, Stool ~150 mL/day

A. Anion Gap

1. Cation-anion difference: (Na++K+) - (Cl-+HCO3-) ~ 16mM
2. The remainder (electro-neutrality is required) is made up by:
   1. Proteins
   2. Phosphate
   3. Other non-volatile acids (eg. lactate, ßHB)
3. A simple view is that the normal anion gap is a measure of the plasma protein, the most significant contributor to the anion gap
4. For each 1gm/dL albumin, ~2 units of the gap are created
5. Abnormal gaps are usually due to increase in unmeasured anions
   1. Acetate and ß-hydroxybutyrate in diabetic ketoacidosis (DKA)
   2. Lactate in shock
   3. Acetate, organic acids in methanol and ethylene glycol poisoning

B. Donnan Equilibrium

1. Semipermeable membrane separates a non-diffusible substance from a diffusible substrate
2. Diffusible anions and cations are distributed on the two sides of the membrane so that:
   1. The products of their concentrations are equal, and
   2. The sum of the concentrations of diffusible and non-diffusible anions on either side of the membrane is equal to the sum of the concentrations of diffusible and non- diffusible cations
3. The unequal distribution of diffusible ions thus produced causes a potential difference between the two sides of the membrane.

C. Starling's Hypothesis

1. Forces which drive fluids out of the circulation are:
   1. Plasma hydrostatic pressure and the
   2. Osmotic pressure of interstitial fluid
2. Forces which drive fluids into the circulation are:
   1. Interstitial hydrostatic pressure and
   2. Plasma (protein) osmotic pressure
3. Flux out = Kf·[(Pc-Pi)-s·(,c-,i)]

A. Summary of FactorsFactors Effect Cause
B. Control of Volume

1. Thirst
   1. Main centers in hypothalamus
   2. Detection of increased osmolarity increases thirst sensation
2. ADH (Vasopressin) [1]
   1. ADH is nonapeptide hormone, 8-arginine vasopressin
   2. Normally, ADH is made by the hypothalamus, in the supraoptic nuclei
   3. Synthesized as a composite precursor with its carrier protein, neurophysin II (NP2)
   4. Most of the hormone is stored in vesicles in axons
   5. Axonal projections for hypothalamus lead to hypophysial portal system as well as to several brain areas
   6. ADH released in portal system, along with corticotropin releasing hormone (CRH), regulate secretion of adrenocorticotropic hormone (ACTH) by anterior pitiutary
   7. Secretion of ADH stimulated by signals from osmoreceptors and baroreceptors
3. ADH Receptors
   1. There are three vasopressin receptor subtypes: V1a, V1b, and V2
   2. The receptors are G-protein coupled proteins, 7 transmembrane helices
   3. ADH is secreted into the blood stream and acts on blood vessels, kidney, and platelets
4. ADH Functions
   1. ADH's primary function in humans is to increase water resorption in collecting ducts
   2. ADH binds to V2 receptors and influence water-channels (aquaporin) function [2]
   3. ADH also acts on distal tubule cells, thick descending loop of Henle
   4. ADH is a weak vasoconstrictor mediated by through V1a receptors
   5. V1a also mediates platelet aggregation and hepatic glycogenolysis
5. Osmolality and Intravascular Volume
   1. Playoff between electrolyte balance (aldosterone, ANF) and fluid volume levels (ADH)
   2. The most potent sensors are for plasma osmolality, at least in terms of ADH secretion
   3. Although the system is primarily MONITORED through osmolality, the system is MODULATED primarily through volume changes
   4. Thus, Na+ depletion (hyponatremia) is sensed more quickly than volume depletion
   5. However, if volume contraction is sufficiently severe, hypovolumemic stimulation of ADH secretion may override osmotic signals and cause water retention
   6. This can occur despite progressive dilution of body fluids and worsening hyponatremia
6. Regulation with Increased Salt Intake
   1. Increased salt intake results in volume expansion which is mediated by ADH secretion
   2. This prevents the development of hypernatremia
   3. Aldosterone is inhibited, ANP and BNP stimulated, and the Na+ is excreted
   4. Na+ excretion is mediated primarily by natriuretic peptides (ANP and BNP, see below)
   5. Water is lost in the urine with the Na+
7. Regulation with Decreased Volume (Salt) Intake
   1. In dehydration, vasopressin (ADH) plays a central role in volume regulation
   2. Decreased baroreceptor sensation leads to hypovolemia
   3. Hypovolemia stimulates ADH production
   4. Increased ADH leads to increased renal collecting duct water (and salt) retention
   5. Lack of volume leads to inhibition of atrial natriuretic factors
   6. Renin and aldosterone levels increase
   7. Renin increases angiotensin II, causing increased vasoconstriction
   8. Aldosterone increases causes sodium retention (potassium loss), and fluid retention

C. Natriuretic Peptides [10,12]

1. Natrually occurring peptides with renal natriuretic and diuretic activity
   1. Atrial natriuretic peptide (ANP)
   2. B-type or Brain derived natriuretic peptide (BNP; previously BDNP)
   3. C-type natriuretic peptide (CNP)
   4. Guanylin and uroguanylin are related peptides which act in GI tract
2. ANP
   1. Produced primarily by cardiac atria and stored primarily in granules
   2. Production is stimulated by endothelin, arginine vasopressin, and catecholamines
   3. Increased atrial wall tension (increased preload) stimulate secretion
   4. Infusions reduce blood pressure and induce a natriuresis
   5. Mature peptide is a 28 residue C-terminal fragment from a 126 residue precursor
   6. ANP stimulates natriuresis, diuresis, and renal afferent vasodilation
   7. Increased vasodilation can increase glomerular filtration rate (through urodilatin ?)
   8. ANP can block the effects of angiotensin II and may reduce its production
   9. Urodilatin is a unique renal natriuretic peptide with diuretic and natriuretic activity
   10. ANP derivative anaritide did not improve acute renal failure [11]
3. BNP
   1. Produced primarily by cardiac ventricles, not stored in granules
   2. Originally described in porcine brain; also made in human brain
   3. Produced in cardiac myocytes but is not stored
   4. Regulated primarily by altering mRNA levels in response to acute and chronic insults
   5. Plasma half-life is greater than ANP
   6. Plasma BNP levels correlate very well with degree of left ventricular dysfunction
   7. Plasma levels <18pg/mL have a negative predictive value of >97% for heart failure
   8. Degraded by plasma neutral endopeptidases
4. CNP
   1. There are 22 and 53 residue forms of the peptide hormone
   2. Plasma concentration of CNP is very low
   3. The 22 residue form predominants in CNS, anterior pituitary, kidney, and vascular endothelial cells, and plasma
   4. Synthesized by endothelium
   5. Local vasodilatory and antiproliferative effects on vascular smooth muscle
5. There are three receptors for the natriuretic peptide receptors (A, B, C)
   1. The A receptor binds ANP preferentially to BNP
   2. CNP binds to the B receptor
   3. Receptors A and B are linked ot cGMP-dependent signalling
   4. The C receptor is involved in clearance of all three natriuretic peptides
   5. Clearance is also carried out by degradation by plasma neutral endopeptidases
   6. Inhibitors of endopeptidases such as candoxatrilat increase Na+ excretion

A. Serum Creatinine (Cr) [2]

1. Creatinine is produced in kidneys, small intestine, pancreas and liver
2. About 98% of it is stored in the muscle cells
3. Thus, total body content of creatinine is proportional to the muscle mass
4. Creatinine in the blood stream is filtered by kidney and not resorbed
5. Therefore, serum [Cr] is an overall measure of glomerular filtering rate (GFR)
6. Some creatinine is secreted also (inhibited by various drugs)
7. Normal serum [Cr] range is 0.5-1.5mg/dL

B. Creatinine Clearance Rate (CCR)

1. Cr is not resorbed by the kidney
2. Therefore, serum [Cr] is an indirect measures GFR
3. The normal rate is ~125mL/min
4. Range is 110±20mL/min/1.73m2 body surface area
5. CCR ~ UV÷ [Cr]plasma where UV is urine creatinine excretion in 24 hours

C. Blood Urea Nitrogen (BUN) [2]

1. Urea is the major end product of protein and amino acid metabolism
2. Produced mainly by the liver and dumped into the blood
3. Blood or serum urea nitrogen is filtered and resorbed in the kidney
4. Filtration occurs through glomeruli; resorption at proximal tubules
5. Normal plasma range is 8-15 mg/dL
6. Reduction in normal BUN levels due to:
   1. Abnormal liver function
   2. Malnutrition
   3. Hereditary deficiency of urea cycle enzymes
7. Elevation in BUN levels due to:
   1. Renal failure - inability to filter BUN
   2. Increased proximal tubular resorption of BUN (hypovolemic state)
   3. Excessive production of BUN (uncommon cause)
8. Normally, the ratio of BUN to Cr in blood is ~10-15
   1. If ratio <10, then proximal tubules are defective
   2. This occurs in acute tubular necrosis
   3. If ratio >15, then the kidney is underperfused
   4. Underperfusion usually due to hypovolemia, heart failure, or renal artery stenosis

D. Fractional Excretion of Sodium (FE-Na)

1. Urine Na/Serum Na ÷ Urine Creatinine / Serum Creatinine
2. This is a very useful measurement for differentiating:
   1. prerenal azotemia (FE-Na <1) from
   2. acute renal failure (FE-Na ~2)
3. The FE-Na corrects for glomerular filtration rate (GFR) changes

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References

1. Bichet DG. 1998. Am J Med. 105(5):431
2. Jurado R and Mattix H. 1998. Arch Intern Med. 158(22):2509
3. Levin ER, Gardner DG, Samson WK. 1998. NEJM. 339(5):321
4. Cheung BMY and Kumana CR, et al. 1998. JAMA. 280(23):1983