Cardiovascular, Respiratory and Renal Physiology

The heart, lungs and kidneys are a single team: the heart moves blood, the lungs load it with oxygen and unload carbon dioxide, and the kidneys decide how much water, salt and acid the body keeps. Board questions in this area reward students who can reason from a few relationships (flow equals pressure over resistance, Starling forces, clearance, Henderson Hasselbalch) rather than memorize isolated numbers. In practice, the same reasoning lets you recognize the patient whose fatigue, dyspnea, edema or back pain is really cardiopulmonary or renal.

Section 1The heart as a pump

Cardiac electrical activity

The heartbeat starts in the sinoatrial (SA) node, whose cells have no stable resting potential. Their pacemaker potential (phase 4) is driven by the funny current (I_f, an inward Na+ current through HCN channels that opens on hyperpolarization), then T type and finally L type calcium channels. The upstroke of nodal cells (phase 0) is carried by calcium, so it is slow, and repolarization (phase 3) by potassium. The SA node fires about 60 to 100 times per minute; the AV node about 40 to 60; Purkinje fibers about 20 to 40.

Sympathetic stimulation (norepinephrine on beta 1, raising cAMP) increases I_f and calcium current, steepening phase 4 and raising heart rate (positive chronotropy) and speeding AV conduction (positive dromotropy). Vagal stimulation (ACh on M2, Gi) opens ACh activated K+ channels, hyperpolarizes nodal cells and flattens phase 4, slowing rate and AV conduction. At rest, vagal tone dominates: the intrinsic rate of a denervated (transplanted) heart is about 100 per minute.

Conduction velocity is fastest in Purkinje fibers (about 2 to 4 m/s), so the ventricles contract nearly simultaneously, and slowest in the AV node (about 0.05 m/s). The AV nodal delay (about 0.1 s) lets the atria finish emptying before the ventricles contract.

ECG basics

The electrocardiogram records the summed extracellular currents of the heart from the body surface. Standard paper speed is 25 mm/s, so one small box is 0.04 s and one large box is 0.20 s; 10 mm equals 1 mV.

Heart rate estimate: 300 divided by the number of large boxes between R waves. A prolonged PR interval is first degree AV block; dropped QRS complexes indicate second degree block; complete dissociation is third degree block.

The cardiac cycle

At a heart rate of 75, each cycle lasts 0.8 s: about 0.3 s systole and 0.5 s diastole. Tachycardia shortens diastole far more than systole, reducing filling and coronary perfusion.

1. Atrial systole. Follows the P wave. Tops up ventricular filling (about 20 percent at rest, more at high heart rates or with a stiff ventricle). Produces the a wave of the jugular venous and atrial pressure tracing. Lost in atrial fibrillation.
2. Isovolumetric contraction. Begins with the QRS. Ventricular pressure exceeds atrial pressure, the mitral and tricuspid valves close (S1), and pressure rises steeply with all valves shut. The c wave appears as the tricuspid bulges back.
3. Rapid and reduced ejection. When left ventricular pressure exceeds aortic pressure (about 80 mm Hg), the aortic valve opens. Pressure peaks near 120 mm Hg. Stroke volume, about 70 mL, leaves; the T wave occurs late in ejection.
4. Isovolumetric relaxation. Ventricular pressure falls below aortic pressure, the aortic and pulmonic valves close (S2), and the brief backflow produces the dicrotic notch (incisura). Pressure plunges with all valves shut. The v wave reflects atrial filling against a closed AV valve.
5. Rapid and reduced filling. Ventricular pressure falls below atrial pressure, the AV valves open and blood rushes in (most filling occurs in this early phase). Slow filling (diastasis) follows.

Typical left heart values: end diastolic volume (EDV) about 120 to 140 mL, end systolic volume (ESV) about 50 to 70 mL, stroke volume (SV = EDV minus ESV) about 70 mL, ejection fraction (EF = SV/EDV) about 55 to 70 percent.

Pressure volume loops

Plotting left ventricular pressure against volume over one beat traces a counterclockwise loop. The width of the loop is stroke volume; the area inside is stroke work. The lower boundary is the end diastolic pressure volume relationship (passive compliance); the upper left corner lies on the end systolic pressure volume relationship (ESPVR), whose slope (elastance) is an index of contractility.

Heart sounds and murmurs

S1 is closure of the mitral and tricuspid valves at the start of systole, loudest at the apex. S2 is closure of the aortic and pulmonic valves, loudest at the base. Inspiration increases venous return to the right heart and delays pulmonic closure, producing physiologic splitting of S2. Wide fixed splitting suggests an atrial septal defect; paradoxical splitting (split on expiration) suggests delayed aortic closure, as in left bundle branch block or aortic stenosis. S3, in early diastole during rapid filling, is normal in children and athletes but in older adults suggests volume overload or systolic heart failure. S4, just before S1, is atrial contraction against a stiff ventricle (hypertrophy, ischemia, long standing hypertension) and is never heard in atrial fibrillation.

Cardiac output and its determinants

Cardiac output (CO) = heart rate times stroke volume, about 5 L/min at rest (70 per minute times 70 mL), rising to 20 to 25 L/min in trained exercise or more in elite athletes. The Fick principle measures it: CO = oxygen consumption divided by the arteriovenous O2 content difference (about 250 mL/min divided by 50 mL O2 per liter = 5 L/min).

• Preload is the ventricular wall stress at end diastole, approximated by EDV or end diastolic pressure. It depends on venous return, blood volume, venous tone, atrial contraction and filling time.
• Afterload is the wall stress the ventricle must develop to eject, approximated by aortic pressure (or total peripheral resistance). By the law of Laplace, wall stress = pressure times radius divided by (2 times wall thickness), so a dilated ventricle faces higher afterload and a hypertrophied wall reduces it.
• Contractility (inotropy) is force generated at a given preload, reflecting calcium handling. It rises with sympathetic stimulation, catecholamines, digoxin and higher heart rate (the Bowditch staircase), and falls with ischemia, acidosis, hypoxia, beta blockers, calcium channel blockers and heart failure.

The Frank Starling mechanism

The Frank Starling law states that, within physiological limits, the heart pumps whatever blood returns to it: increasing EDV stretches sarcomeres toward optimal length and increases stroke volume. Cardiac muscle normally operates on the ascending limb of its length tension curve, below the optimal length (unlike skeletal muscle, which sits near the peak). Stretch also raises troponin C calcium sensitivity. The mechanism automatically matches the outputs of the right and left ventricles beat by beat. A family of Starling curves exists: positive inotropes shift the curve up and left; heart failure shifts it down and right, so a higher filling pressure (and congestion) is needed for the same output.

Section 2Hemodynamics and blood pressure control

Flow, pressure and resistance

The basic law of the circulation is the hydraulic version of Ohm's law: flow (Q) = pressure difference (ΔP) / resistance (R). For the whole systemic circulation, cardiac output = (mean arterial pressure minus right atrial pressure) / total peripheral resistance, usually simplified to MAP = CO times TPR. Mean arterial pressure is about diastolic plus one third of pulse pressure (for 120/80, about 93 mm Hg). Pulse pressure (systolic minus diastolic) rises with stroke volume and with stiffer arteries (reduced compliance in aging, isolated systolic hypertension) and widens in aortic regurgitation and hyperthyroidism.

Poiseuille's law describes resistance to laminar flow in a tube: R = 8ηL / πr⁴, where η is viscosity, L length and r radius. Because resistance varies with the fourth power of the radius, halving a vessel's radius raises its resistance 16 fold. This is why arterioles, whose smooth muscle changes radius, are the main resistance vessels and the site of the largest pressure drop. Viscosity depends mainly on hematocrit: polycythemia raises resistance, anemia lowers it.

• Series resistances add (R total = R1 + R2 + ...), as when blood passes artery, arteriole, capillary and vein.
• Parallel resistances combine reciprocally (1/R total = 1/R1 + 1/R2 + ...), so total resistance is lower than any single branch. Organs are arranged in parallel, so each can regulate its own flow.
• Velocity = flow / cross sectional area. Total capillary cross section is enormous, so velocity is slowest there, allowing exchange; it is fastest in the aorta.
• Turbulence is predicted by a high Reynolds number (high velocity, large diameter, low viscosity). Turbulent flow makes noise: murmurs, bruits and the Korotkoff sounds heard when measuring blood pressure.
• Compliance = ΔV / ΔP. Veins are about 20 to 24 times more compliant than arteries and hold about 60 to 70 percent of blood volume (the capacitance vessels).

Capillary exchange and Starling forces

Gases diffuse through endothelial cells; water and small solutes pass through clefts and fenestrations. Bulk fluid movement follows the Starling equation:

Net filtration = K_f [(P_c minus P_i) minus σ(π_c minus π_i)]

P_c is capillary hydrostatic pressure (pushes fluid out), P_i interstitial hydrostatic pressure (normally near zero or slightly negative), π_c plasma oncotic pressure (about 25 mm Hg, mainly from albumin; pulls fluid in), π_i interstitial oncotic pressure, K_f the filtration coefficient (permeability times area) and σ the reflection coefficient for protein. At the arterial end filtration predominates; toward the venous end absorption occurs, but slightly more fluid is filtered than reabsorbed overall (about 2 to 4 L per day systemically), and the lymphatics return the excess and any leaked protein to the blood.

Local control of blood flow

Each organ adjusts its own arteriolar resistance to match flow to need.

• Autoregulation keeps flow nearly constant across a range of perfusion pressures (roughly 60 to 150 mm Hg for brain and kidney). The myogenic mechanism (stretch of arteriolar smooth muscle triggers contraction) and the metabolic mechanism (washout or accumulation of metabolites) both contribute.
• Active (functional) hyperemia: increased metabolism raises local CO2, H+, K+, adenosine, lactate and temperature and lowers O2, all of which dilate arterioles. Adenosine is especially important in the coronary circulation.
• Endothelial factors: nitric oxide (from shear stress and ACh via eNOS, acting through cGMP) and prostacyclin dilate; endothelin and thromboxane A2 constrict.

The baroreceptor reflex

Short term blood pressure control is a negative feedback loop that acts within seconds.

1. Receptors: stretch receptors in the carotid sinus (afferents in the glossopharyngeal nerve, CN IX, via the sinus nerve of Hering) and the aortic arch (afferents in the vagus, CN X). The carotid sinus responds to both rises and falls in pressure and is more sensitive; the aortic arch responds mainly to rises.
2. Integration: the nucleus tractus solitarius in the medulla. Increased firing excites the vagal motor nuclei (nucleus ambiguus, dorsal motor nucleus) and inhibits the sympathetic vasomotor center in the rostral ventrolateral medulla.
3. Effectors: when pressure falls, baroreceptor firing falls, so vagal tone drops and sympathetic outflow rises: heart rate, contractility, arteriolar constriction (TPR) and venoconstriction all increase, restoring MAP.

The reflex buffers moment to moment changes, such as standing up, but it resets within days to a sustained new pressure, so it does not set long term blood pressure.

The renin angiotensin aldosterone system

Long term pressure control works through blood volume, and therefore through renal sodium handling. Renin is released by the juxtaglomerular (granular) cells of the afferent arteriole in response to three signals: reduced renal perfusion pressure (intrarenal baroreceptor), reduced NaCl delivery to the macula densa, and sympathetic stimulation via beta 1 receptors.

1. Renin cleaves angiotensinogen (from the liver) to angiotensin I.
2. Angiotensin converting enzyme (ACE), mainly on pulmonary endothelium, converts angiotensin I to angiotensin II. ACE also breaks down bradykinin, which is why ACE inhibitors cause cough and angioedema.
3. Angiotensin II acts on AT1 receptors: arteriolar vasoconstriction; constriction of the efferent arteriole more than the afferent (preserving GFR); stimulation of aldosterone release from the zona glomerulosa; increased proximal tubule Na+ reabsorption (Na+/H+ exchanger); ADH release and thirst; and enhanced sympathetic activity.
4. Aldosterone acts on principal cells of the late distal tubule and collecting duct to increase ENaC sodium channels and Na+/K+ ATPase, retaining sodium (and water) and secreting K+ and H+.

Opposing the system, atrial and brain natriuretic peptides (ANP from atria, BNP from ventricles, released by stretch) dilate the afferent arteriole, raise GFR, inhibit renin, aldosterone and collecting duct sodium reabsorption, and cause natriuresis. BNP is a useful blood marker of heart failure. Pressure natriuresis, the direct increase in renal salt and water excretion as arterial pressure rises, is the ultimate long term set point for blood pressure.

Section 3Respiratory physiology

Mechanics of breathing

Air flows down a pressure gradient, so to inhale the alveolar pressure must fall below atmospheric pressure. The diaphragm (phrenic nerve, C3 to C5) is the main inspiratory muscle; contraction flattens its dome and enlarges the thorax vertically, while the external intercostals raise the ribs (pump handle in upper ribs, bucket handle in lower ribs). Expansion makes intrapleural pressure more negative (from about -5 to about -8 cm H2O), alveoli expand, alveolar pressure falls slightly below atmospheric and air enters. Quiet expiration is passive, driven by elastic recoil of lung and chest wall. Forced expiration and coughing use the internal intercostals and abdominal muscles.

Intrapleural pressure is negative at rest because the lung tends to recoil inward while the chest wall tends to spring outward; the thin pleural fluid layer couples them. At functional residual capacity (FRC) these opposing recoils balance. If air enters the pleural space (pneumothorax), intrapleural pressure becomes atmospheric, the lung collapses inward and the chest wall springs outward.

Compliance and surface tension

Compliance = ΔV / ΔP, a measure of distensibility (the inverse of elastance). Compliance is reduced in pulmonary fibrosis, pulmonary edema, atelectasis and surfactant deficiency (stiff lungs, low volumes) and increased in emphysema, where destruction of elastic tissue makes lungs easy to inflate but poor at recoil, trapping air. About two thirds of lung recoil comes from surface tension at the air liquid interface of alveoli. By the law of Laplace (P = 2T / r), small alveoli would collapse into large ones without help. Surfactant (mainly dipalmitoylphosphatidylcholine, made by type II pneumocytes) lowers surface tension, more so in smaller alveoli, stabilizing them, increasing compliance and keeping alveoli dry. Premature infants lacking it develop neonatal respiratory distress syndrome.

Lung volumes and capacities

A capacity is a sum of two or more volumes. Any capacity containing RV (FRC, TLC) requires helium dilution, nitrogen washout or body plethysmography. FEV1/FVC distinguishes patterns: in obstructive disease (asthma, COPD, bronchiectasis) FEV1 falls more than FVC, so the ratio is below about 0.70, and TLC and RV rise (air trapping). In restrictive disease (fibrosis, chest wall deformity such as severe kyphoscoliosis or ankylosing spondylitis, neuromuscular weakness, obesity) both fall proportionally, the ratio is normal or high, and TLC is reduced.

Ventilation and dead space

Minute ventilation = tidal volume times respiratory rate (about 500 mL times 12 = 6 L/min). Not all of it reaches gas exchange surfaces. Anatomic dead space (conducting airways, about 150 mL, or roughly 1 mL per pound of ideal body weight) plus alveolar dead space (ventilated but unperfused alveoli) equals physiologic dead space. Alveolar ventilation = (TV minus dead space) times rate, about 4.2 L/min. Rapid shallow breathing wastes more ventilation on dead space than slow deep breathing at the same minute ventilation. Alveolar PCO2 is inversely proportional to alveolar ventilation: double the ventilation and PaCO2 halves.

Ventilation and perfusion

Both ventilation and perfusion are greater at the base of the upright lung than at the apex, but perfusion increases more steeply with gravity. So the apex has a high V/Q ratio (about 3; high PO2, low PCO2) and the base has a low V/Q (about 0.6). The overall average is about 0.8 to 1.0.

• V/Q = 0 (shunt): perfusion without ventilation (airway obstruction, pneumonia filling alveoli, atelectasis, right to left cardiac shunt). Hypoxemia does not correct with 100 percent oxygen.
• V/Q = infinity (dead space): ventilation without perfusion (pulmonary embolism). Wasted ventilation.
• Hypoxic pulmonary vasoconstriction diverts blood away from poorly ventilated regions to limit mismatch.

Causes of hypoxemia: hypoventilation (normal A-a gradient, high PaCO2), low inspired O2 such as altitude (normal A-a gradient), V/Q mismatch (raised A-a gradient, corrects with O2), shunt (raised gradient, does not correct) and diffusion limitation (raised gradient, worse with exercise). The alveolar gas equation estimates alveolar PO2: PAO2 = FiO2 (Patm minus PH2O) minus PaCO2 / R = 0.21 (760 minus 47) minus 40/0.8, which is about 100 mm Hg at sea level. The normal A-a gradient is about 5 to 15 mm Hg and widens with age.

Gas exchange

Gas diffuses across the alveolar capillary membrane according to Fick's law: rate is proportional to area, the partial pressure difference and the gas's diffusion coefficient (solubility over the square root of molecular weight), and inversely proportional to thickness. CO2 is about 20 times more soluble than O2, so it diffuses about 20 times faster and its exchange is rarely limited. Thickening (fibrosis) or loss of surface area (emphysema) impairs O2 transfer first, measured as reduced DLCO. Normally blood equilibrates with alveolar O2 within the first third of its 0.75 s transit, leaving a reserve for exercise; O2 uptake is perfusion limited in health and becomes diffusion limited in fibrosis, strenuous exercise and at altitude.

Oxygen transport

Each deciliter of arterial blood carries about 20 mL O2: about 0.3 mL dissolved (0.003 mL per mm Hg PO2 per dL) and the rest bound to hemoglobin (1.34 mL O2 per gram of saturated Hb, at 15 g/dL). Oxygen content = (1.34 times Hb times SaO2) + (0.003 times PaO2). Anemia lowers content but not PaO2 or saturation; carbon monoxide lowers content and saturation measured by co-oximetry while PaO2 stays normal.

The oxyhemoglobin dissociation curve is sigmoidal because of cooperative binding: each O2 bound increases the affinity of the remaining hemes (the shift from tense to relaxed state). The flat upper part means saturation stays above 90 percent until PaO2 falls below about 60 mm Hg, protecting loading. The steep middle part means small falls in tissue PO2 release large amounts of O2. Key points: PaO2 100 gives about 98 percent saturation; PO2 40 (mixed venous) about 75 percent; P50, the PO2 at 50 percent saturation, about 26 to 27 mm Hg.

The Bohr effect is the rightward shift caused by CO2 and H+; it helps unload O2 in metabolically active tissue. 2,3-BPG, made by red cells in glycolysis, binds deoxyhemoglobin and rises with chronic hypoxia, altitude and anemia. Fetal hemoglobin (alpha 2 gamma 2) binds 2,3-BPG poorly, so it has higher affinity and draws O2 from maternal blood. Carbon monoxide binds hemoglobin about 200 to 250 times more avidly than O2, lowers carrying capacity and shifts the remaining curve left, causing severe tissue hypoxia despite a normal PaO2 and often misleadingly normal pulse oximetry.

Carbon dioxide transport

CO2 travels in three forms: about 70 percent as bicarbonate, about 20 to 23 percent as carbamino compounds (bound to hemoglobin's amino groups) and about 7 to 10 percent dissolved. In red cells, carbonic anhydrase converts CO2 and H2O to H2CO3, which dissociates to H+ and HCO3-. Hemoglobin buffers the H+; HCO3- leaves the cell in exchange for Cl- (the chloride shift, via band 3). In the lungs the process reverses. The Haldane effect describes how deoxygenated hemoglobin binds more CO2 and H+, so oxygenation in the lungs releases CO2.

Control of breathing

The rhythm generator is in the medulla. The dorsal respiratory group (in the nucleus tractus solitarius) drives mainly inspiration and receives afferents from CN IX and X. The ventral respiratory group, including the pre-Botzinger complex (the core rhythm generator), handles forced expiration and inspiration. Pontine centers fine tune the pattern, and the cortex allows voluntary control.

• Central chemoreceptors on the ventral medulla respond to the pH of CSF, which reflects arterial PCO2 because CO2 crosses the blood brain barrier freely while H+ and HCO3- do not. They provide about 70 to 80 percent of the drive at rest. PaCO2 is the main minute to minute stimulus.
• Peripheral chemoreceptors in the carotid bodies (CN IX) and aortic bodies (CN X) respond to low PaO2 (strongly below about 60 mm Hg), high PaCO2 and low pH. The carotid bodies are the only receptors that drive ventilation in response to hypoxemia and the main responders to metabolic acidosis.
• Lung receptors: pulmonary stretch receptors (Hering Breuer inflation reflex, vagal), irritant receptors (cough, bronchoconstriction) and juxtacapillary (J) receptors (rapid shallow breathing in pulmonary edema).

Section 4Renal physiology

Renal blood flow and glomerular filtration

The kidneys receive about 20 to 25 percent of cardiac output (renal blood flow about 1.1 to 1.2 L/min; renal plasma flow about 600 to 650 mL/min) despite making up less than 1 percent of body weight. Blood passes through two capillary beds in series: the glomerulus, a high pressure bed between the afferent and efferent arterioles that filters, and the peritubular capillaries (and vasa recta in the medulla), a low pressure bed that reabsorbs.

The filtration barrier has three layers: fenestrated capillary endothelium, the glomerular basement membrane (negatively charged heparan sulfate) and the filtration slits between podocyte foot processes, bridged by nephrin. Filtration depends on size (molecules below about 7,000 Da filter freely; albumin at about 69,000 Da and negatively charged is largely held back) and charge.

Glomerular filtration rate follows the Starling equation: GFR = K_f [(P_GC minus P_BS) minus π_GC]. Glomerular capillary hydrostatic pressure (about 45 to 60 mm Hg) favors filtration; Bowman's space pressure (about 10 to 15) and glomerular oncotic pressure (about 25 rising to 35 along the capillary) oppose it. Normal GFR is about 125 mL/min, or 180 L/day; the filtration fraction (GFR / RPF) is about 20 percent.

GFR is autoregulated between mean arterial pressures of about 80 and 180 mm Hg by the myogenic response of the afferent arteriole and by tubuloglomerular feedback: when GFR and NaCl delivery to the macula densa rise, the macula densa releases adenosine, constricting the afferent arteriole and bringing GFR back down. The macula densa, juxtaglomerular cells and extraglomerular mesangial cells together form the juxtaglomerular apparatus.

Clearance

Clearance is the volume of plasma completely cleared of a substance per unit time: C = (U times V) / P, where U is urine concentration, V urine flow rate and P plasma concentration. It is the key tool for measuring kidney function.

• Inulin is freely filtered and neither reabsorbed nor secreted, so its clearance equals GFR exactly (the gold standard).
• Creatinine is freely filtered and slightly secreted, so its clearance slightly overestimates GFR; it is the routine clinical estimate. Serum creatinine rises as GFR falls: halving GFR roughly doubles serum creatinine at steady state. Because creatinine production reflects muscle mass, the same serum value means a lower GFR in a small elderly woman than in a muscular young man.
• Para-aminohippuric acid (PAH) is filtered and almost completely secreted in one pass, so its clearance estimates effective renal plasma flow.
• If clearance of a substance is less than GFR, it is net reabsorbed (glucose, normally zero; urea, about half); if greater than GFR, it is net secreted (PAH, many drugs, K+ under some conditions).

A BUN to creatinine ratio above 20 suggests prerenal azotemia, because slow tubular flow increases urea reabsorption.

Tubular reabsorption and secretion along the nephron

Of the 180 L filtered daily, about 99 percent of water and sodium is reabsorbed. Each segment has a characteristic set of transporters, all ultimately powered by the basolateral Na+/K+ ATPase.

Glucose reabsorption is a transport maximum (T_m) system. Below a plasma glucose of about 200 mg/dL (the renal threshold, where the first nephrons saturate) none appears in urine; above about 375 mg/dL all nephrons are saturated (T_m about 375 mg/min). Glucosuria with polyuria is a classic sign of uncontrolled diabetes.

The countercurrent mechanism

To concentrate urine to as much as 1,200 mOsm/kg, the kidney builds a gradient of interstitial osmolality from 300 mOsm/kg at the corticomedullary junction to about 1,200 at the papilla.

1. Countercurrent multiplier (loop of Henle). The thick ascending limb pumps NaCl into the interstitium without water, creating a single effect of about 200 mOsm/kg between tubule and interstitium at each level. The descending limb loses water to the concentrated interstitium, so its fluid becomes concentrated and is then carried deeper. Flow in opposite directions in the two limbs multiplies the small horizontal gradient into a large vertical one.
2. Urea recycling. ADH increases urea permeability (UT-A1 transporters) in the inner medullary collecting duct; urea diffuses into the interstitium and contributes about half of inner medullary osmolality. Protein malnutrition lowers concentrating ability.
3. Countercurrent exchanger (vasa recta). The hairpin, slow flowing vasa recta capillaries passively exchange solute and water so blood leaving the medulla does not wash out the gradient. Very high medullary blood flow reduces concentrating ability.

Fluid leaving the thick ascending limb is hypo-osmotic (about 100 mOsm/kg) regardless of hydration. Whether final urine is dilute (as low as 50 mOsm/kg) or concentrated then depends on ADH.

ADH and aldosterone

In nephrogenic diabetes insipidus the collecting duct does not respond to ADH (lithium, demeclocycline, hypercalcemia, hypokalemia, V2 receptor mutations), so desmopressin does not help.

Micturition

Urine moves down the ureters by peristalsis into the bladder, whose detrusor muscle is single unit smooth muscle. Stress relaxation lets the bladder fill to about 300 to 400 mL with little rise in pressure; the first urge appears around 150 mL. Control involves three systems.

Stretch afferents travel in the pelvic nerves to the sacral cord and up to the pontine micturition center, which coordinates detrusor contraction with sphincter relaxation. The frontal cortex inhibits the pons until voiding is socially appropriate. Lesions produce predictable patterns: a suprapontine lesion (stroke, dementia) causes urge incontinence with coordinated voiding; a spinal cord lesion above the sacral segments causes a spastic, small capacity bladder with detrusor sphincter dyssynergia; a sacral or cauda equina lesion causes a flaccid, overfilled bladder with retention and overflow incontinence.

Section 5Body fluids, electrolytes and acid base balance

Fluid compartments

Total body water is about 60 percent of body weight in a lean adult man (about 42 L in a 70 kg man), lower in women and older adults (more fat, which holds little water) and higher in infants. The 60-40-20 rule: total body water 60 percent of weight, intracellular fluid (ICF) 40 percent, extracellular fluid (ECF) 20 percent. ECF is divided into interstitial fluid (about three quarters of ECF) and plasma (about one quarter, roughly 3 L), plus small transcellular volumes (CSF, synovial, pleural fluid).

Osmolality and water shifts

Osmolality is solute particles per kilogram of water. Plasma osmolality is normally about 285 to 295 mOsm/kg and can be estimated as 2 times Na+ + glucose/18 + BUN/2.8 (mg/dL units). Because water crosses most cell membranes freely (through aquaporins), ICF and ECF osmolality are always equal at steady state; water moves to wherever solute concentration is higher. Sodium is effectively confined to the ECF and potassium to the ICF, so ECF volume is determined by total body sodium and plasma sodium concentration reflects water balance. Urea is an ineffective osmole because it crosses membranes.

Sodium and water balance

Normal plasma Na+ is 135 to 145 mEq/L. Hyponatremia almost always means relative water excess. It is classified by volume status: hypovolemic (diuretics, vomiting, adrenal insufficiency), euvolemic (SIADH, hypothyroidism, primary polydipsia) and hypervolemic (heart failure, cirrhosis, nephrotic syndrome, in which low effective arterial volume drives ADH). Correcting chronic hyponatremia too quickly risks osmotic demyelination. Hypernatremia means water deficit (inadequate access to water, diabetes insipidus, osmotic diuresis), most often in infants and frail elderly people who cannot drink; brain cells shrink.

Potassium balance

About 98 percent of body potassium is intracellular; plasma K+ is only 3.5 to 5.0 mEq/L, so small shifts across membranes change plasma levels greatly. Internal balance (shift into cells) is promoted by insulin, beta 2 agonists (epinephrine, albuterol), alkalosis and aldosterone. Shift out of cells is caused by insulin deficiency, beta blockers, acidosis (H+ enters cells in exchange for K+), hyperosmolality, cell lysis (rhabdomyolysis, hemolysis, tumor lysis) and strenuous exercise. External balance is set by renal secretion in the late distal tubule and collecting duct principal cells, which increases with aldosterone, high K+ intake, high tubular flow and sodium delivery (why loop and thiazide diuretics waste potassium) and alkalosis.

Calcium and phosphate balance

Total plasma calcium is about 8.5 to 10.5 mg/dL: about 40 percent bound to albumin, about 10 percent complexed with anions and about 50 percent ionized, the physiologically active form. Total calcium falls with low albumin (correct by adding about 0.8 mg/dL per 1 g/dL drop in albumin below 4). Alkalosis increases binding of calcium to albumin (fewer H+ competing for negative sites) and lowers ionized calcium; this is why hyperventilation causes perioral tingling, carpopedal spasm and tetany even though total calcium is normal.

The parathyroid calcium sensing receptor detects ionized calcium; a fall stimulates PTH secretion within minutes. Magnesium is required for PTH release and action, so severe hypomagnesemia causes refractory hypocalcemia. Hypercalcemia (primary hyperparathyroidism, malignancy) causes "stones, bones, groans, thrones and psychiatric overtones": kidney stones, bone pain, abdominal pain and constipation, polyuria and confusion, with a shortened QT. Hypocalcemia causes neuromuscular irritability (Chvostek and Trousseau signs), tetany, laryngospasm and a long QT.

Buffers

Normal arterial pH is 7.35 to 7.45 ([H+] about 40 nmol/L), maintained despite daily production of about 15,000 mmol of volatile acid (CO2) and about 50 to 100 mEq of nonvolatile (fixed) acid from protein and phospholipid metabolism. Three lines of defense act in sequence: chemical buffers (seconds), respiratory compensation (minutes to hours) and renal compensation (hours to days).

• Bicarbonate/CO2 is the main extracellular buffer. Although its pK (6.1) is far from 7.4, it is powerful because it is an open system: the lungs adjust CO2 and the kidneys adjust HCO3-.
• Hemoglobin (histidine imidazole groups) and plasma proteins buffer within blood; deoxyhemoglobin is the better buffer.
• Phosphate (pK 6.8) is an important intracellular and urinary buffer (titratable acid).

The Henderson Hasselbalch equation: pH = 6.1 + log ([HCO3-] / (0.03 times PCO2)). With HCO3- 24 mEq/L and PCO2 40 mm Hg, the ratio is 24/1.2 = 20, log 20 is 1.3, and pH is 7.4. pH depends on the ratio of bicarbonate to CO2, not on either value alone, which is the basis of compensation.

The kidneys handle acid in two ways: reabsorbing filtered bicarbonate (mostly in the proximal tubule, using Na+/H+ exchange and carbonic anhydrase) and generating new bicarbonate by excreting H+ as titratable acid (H2PO4-) and ammonium (NH4+, from glutamine metabolism in the proximal tubule). Ammonium excretion is the main adaptive response to chronic acidosis. Each H+ excreted adds one new HCO3- to the blood.

Acid base disorders and compensation

Compensation never fully returns pH to 7.40 and never overshoots. If PCO2 or HCO3- falls outside the expected range, a second (mixed) disorder is present.

The anion gap

The anion gap = Na+ minus (Cl- + HCO3-), normally about 8 to 12 mEq/L, represents unmeasured anions, mostly albumin (lower the expected gap by about 2.5 for each 1 g/dL fall in albumin). In metabolic acidosis, if an unmeasured acid is added, bicarbonate falls and the gap rises (high anion gap). If bicarbonate is lost and replaced by chloride, the gap stays normal (normal anion gap acidosis, with chloride rising in place of bicarbonate).

Words worth knowing