15.1 Functions of the Kidney and Functional Anatomy
Functions of the Kidney
The kidneys perform three basic processes:
– Ultrafiltration (filtration across a semipermeable membrane that is driven by hydrostatic pressure) of large volumes of water and solutes from the blood into the renal tubular system
– Reabsorption of filtered substances that are needed by the body from the renal tubules into the bloodstream. These include water, Na+, glucose, and bicarbonate (HCO3−).
– Secretion of substances from the bloodstream into the renal tubules
By extension of these three processes, the kidneys are able to
– Adjust salt and water excretion to maintain a constant extracellular fluid (ECF) volume and osmolality. Blood pressure homeostasis is maintained in part via modulation of ECF volume.
– Maintain acid–base balance
– Remove waste substances and ingested toxins from the blood and excrete them as urine. Waste substances are produced from metabolism and include urea and ammonia from protein catabolism and uric acid from nucleic acid metabolism.
In addition to homeostatic and excretory functions, the kidneys produce several hormones, including erythropoietin, which stimulates the production of red blood cells in response to hypoxia (low partial pressure of oxygen [Po2]); calcitriol, which increases serum [Ca2+] and [Po43−] for the mineralization of new bone; and renin, which forms part of a system that helps to regulate Na+, ECF volume, and blood pressure.
Erythropoietin
Erythropoietin is a renal hormone that regulates the production of red blood cells in the bone marrow. Patients with chronic renal failure develop anemia secondary to inadequate levels of erythropoietin. Human recombinant erythropoietin has been shown to be effective in treatment of anemia associated with uremia (increased blood [urea]). There are no direct adverse effects of replacement therapy, although ~25% of patients experience hypertension during treatment (mechanism not understood). Patients on renal dialysis require erythropoietin.
Renal osteodystrophy
In chronic renal failure, the failing kidneys are unable to perform the necessary α1-hydroxylation reactions to produce calcitriol (the active form of vitamin D), and they have a reduced capacity to excrete phosphate. This leads to hyperparathyroidism due to hypocalcemia and hyperphosphatemia. Derangement of bone remodeling occurs, which is referred to as renal osteodystrophy. The symptoms of renal osteodystrophy include bone and joint pain, bone deformation, and increased likelihood of bone fractures. Chronic renal failure requires hemodialysis several times per week until renal transplantation can occur. Renal osteodystrophy is treated with calcium and calcitriol, restricting the dietary intake of phosphate, and by the administration of medications that bind phosphate, such as calcium carbonate and calcium acetate.
Functional Anatomy of the Kidney
Renal Cortex, Renal Medulla, and Renal Pelvis
The kidney is divided into three main anatomical areas: the cortex, the medulla, and the renal pelvis (Fig. 15.1).
– The renal cortex is the area where ultrafiltration occurs.
– The renal medulla is the area that serves to concentrate the urine.
– The renal pelvis collects urine and drains into the ureter and bladder.
Nephron
The functional unit of the kidney is the nephron (Fig. 15.2), where the three basic processes of ultrafiltration, reabsorption, and secretion occur. Substances that are filtered and secreted but not reabsorbed are excreted as final urine.
There are five parts of the nephron: the glomerulus, the proximal convoluted tubule, the loop of Henle, the distal convoluted tubule, and the collecting ducts.
Glomerulus
– The glomerulus is the site of plasma ultrafiltration, or glomerular filtration (Fig. 15.3). A rterial blood is delivered to the glomerular capillaries via afferent arterioles. Plasma then undergoes ultrafiltration across the glomerular barrier, and the ultrafiltrate passes into Bowman’s capsule and the renal tubular system. The fraction of plasma and substances that do not undergo filtration leave the glomerulus via efferent arterioles and flow into peritubular capillaries surrounding the nephron.
Fig. 15.1 
Midlongitudinal section through a right kidney, posterior view.
From Thieme Atlas of Anatomy, Neck and Internal Organs, © Thieme 2006, Illustration by Markus Voll.
–The glomerular barrier consists of capillary endothelial cells, the endothelial basement membrane, and the epithelial cells of Bowman’s capsule.
– Capillary endothelial cells are fenestrated (have holes), thus increasing capillary permeability.
– The epithelial cells of Bowman’s capsule have podocytes with slitlike pores between them that are closed by a slit membrane.
– Both the endothelial basement membrane and the epithelial cells of Bowman’s capsule are lined by negatively charged glycoproteins. This makes the glomerular barrier relatively impermeable to negatively charged plasma proteins (e.g., albumin). In glomerular disease, these negatively charged proteins may be destroyed, allowing proteins to enter the urine (proteinuria).
– The glomerular barrier is most permeable to small, neutral or positively charged molecules.
Renal Tubular System
– The proximal convoluted tubule is the site of reabsorption of most of the filtered load from the tubular lumen into pericapillary blood.
– The loop of Henle that extends into the medulla is involved in the concentration or dilution of urine by changing the osmolality of the tissue surrounding it.
– The distal convoluted tubule and collecting ducts reabsorb Na+ and water as necessary to maintain ECF and electrolyte balance. The collecting duct also collects final urine and drains into the renal pelvis for excretion.
Urinary tract infections
Urinary tract infections (UTIs) are common, especially in women due to the proximity of the urethra to the vagina (allowing easier spread of sexually transmitted infections and diseases) and due to the short length of the urethra compared with men. UTIs present with any of the following symptoms: frequency of urination, urgency, strangury (frequent, painful expulsion of small amount of urine despite urgency), h ematuria (blood in the urine), cloudy urine, incontinence, fever with diarrhea and vomiting, and pain (usually suprapubic pain in women and anal pain in men). Trimethoprim with sulfamethoxazole is given to treat uncomplicated UTIs caused by susceptible bacteria (Escherichia coli, Staphylococcus spp., Streptococcus spp., Pseudomonas, and Proteus). In addition, patients are advised to drink plenty of fluids and urinate often.
Fig. 15.2 Anatomy of the nephron.
The smallest functional unit of the kidney is the nephron, which consists of the glomerulus, renal tubules, and collecting ducts.
From Thieme Atlas of Anatomy, Neck and Internal Organs, © Thieme 2006, Illustration by Markus Voll.
Fig. 15.3 Glomerulus and Bowman’s capsule.
Blood enters the glomerulus by an afferent arteriole and exits via an efferent arteriole from which the peritubular capillary network arises. The glomerular barrier separates the blood side from the Bowman capsular space. The glomerular barrier comprises the fenestrated endothelium of the glomerular capillaries, followed by the basement membrane as the second layer, and the visceral epithelial cells of Bowman’s capsule on the urine side. The latter is formed by podocytes with numerous interdigitating footlike processes (pedicels). The slitlike spaces between them are closed by the slit membrane, with pores of ~5 nm in diameter.
15.2 Body Fluid Compartments and Their Composition
Total Body Water
Total body water (TBW) accounts for ~60% of body weight. The percentage of TBW declines with increased age and increased amounts of body fat.
TBW is distributed between two major compartments within the body: intra- and extracellular fluid (ICF and ECF).
Intracellular Fluid
ICF is the fluid within the body’s cells (cytoplasm).
– It accounts for ~40% of body weight (two-thirds of TBW).
– K+ and Mg2+ are the major cations.
– Proteins and organic phosphates (e.g., adenosine triphosphate [ATP], adenosine diphosphate [ADP], and adenosine monophosphate [AMP]) are the major anions.
Extracellular Fluid
ECF is plasma and interstitial fluid (including lymph).
– ECF accounts for ~20% of body weight (one third of TBW), of which ~5% is attributed to plasma and ~15% of which is interstitial fluid.
– Plasma is the fluid portion of the blood that remains after blood cells are removed. It contains important proteins (e.g., albumin and globulins).
– Interstitial fluid is the fluid that occupies the spaces between cells. Its composition is the same as plasma except that it is relatively free of proteins.
– Na+ is the major cation.
– Cl− and HCO3− are the major anions.
Measuring the Volume of Body Fluid Compartments
Indicator Dilution Method
The indicator dilution method involves the administration of a known amount of a marker substance that will distribute within the body compartment under investigation.
– TBW can be measured using tritiated water or deuterium oxide (D2O), as its distribution is the same as water.
– ECF volume is measured using substances that will not enter cells (e.g., mannitol, inulin, sucrose, and thiosulfate).
– Plasma volume is measured using substances that neither leave the vasculature nor enter red blood cells (e.g., Evans blue dye or radioactive serum albumin).
The volume of the compartment is then found by determining the final concentration of the marker substance that has been added to the compartment using the following equation:
V = Q/C,
where V is the volume of the body fluid compartment or volume of distribution (L), Q is the quantity of the marker substance added to the compartment minus the amount lost from the compartment by excretion or metabolism during the measurement (mg), and C is the measured final concentration of marker substance (mg/L).
Note:
– Interstitial fluid volume is calculated as the difference between ECF volume and plasma volume.
– Intracellular volume is calculated as the difference between TBW and ECF volume.
Movement of Fluid between Compartments
Under normal circumstances, the osmolality (i.e., the concentration of osmotically active solutes) of the ECF compartment and ICF compartment are equal. The osmotic content of ICF is determined by the concentration of K+ and charged proteins, and the osmolality of ECF is primarily determined by its NaCl content.
Any alteration in the osmolality of the ECF will cause water movement between the ECF and ICF toward the compartment with the higher osmolality (i.e., higher solute concentration) until equilibrium is reached between the two compartments.
Table 15.1 summarizes circumstances/disease states that may cause fluid movement between the ECF and ICF, as well as the effects on hematocrit (percentage of blood volume composed of red blood cells [RBCs]), plasma protein concentration, and blood pressure (BP).
Hematocrit
The hematocrit is the percentage of blood volume that is RBCs. It is normally ~48% for men and ~38% for women. The hematocrit is elevated in polycythemia, a disorder in which the bone marrow produces excessive RBCs. This is driven by the increased secretion of erythropoietin by the kidneys in response to hypoxia (low Po2), for example, due to chronic obstructive pulmonary disease (COPD). It may also be elevated in dehydration due to loss of ECF volume, which concentrates RBCs. The hematocrit is lowered in hemorrhage (due to loss of RBCs) and iron-deficiency anemia (due to defective RBC synthesis).
Dextrose as an intravenous fluid
Hypovolemia (decreased blood volume) may require the administration of intravenous (IV) fluids to restore ECF volume. Distilled water given IV would lyse RBCs due to osmotic forces. This is prevented by giving a 5% dextrose solution with normal osmolality. The body metabolizes the glucose quickly, leaving an increase in water without ions.
Rhabdomyolysis
Rhabdomyolysis is the rapid breakdown of skeletal muscle due to injury to muscle tissue. The muscle breakdown product, myoglobin, is harmful to the kidney and can precipitate acute kidney failure. Signs and symptoms include pain, tenderness, and swelling of the affected muscle, as well as nausea, vomiting, confusion, arrhythmias, coma, anuria, and later disseminated intravascular coagulation (DIC). Treatment is primarily aimed at preventing acute kidney failure with the administration of fluid IV to increase ECF volume, increase the glomerular filtration rate (GFR) and oxygen delivery, and dilute myoglobin and any other toxins.
Syndrome of inappropriate antidiuretic hormone secretion
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) occurs when excessive amounts of antidiuretic hormone (ADH) are secreted from the posterior pituitary gland. This leads to hyponatremia (low blood sodium levels) and fluid overload. Causes include head injury, meningitis, cancer, and infections (e.g., brain abscess and pneumonia). Treatment involves management of the underlying cause and the use of demeclocycline or lithium carbonate (vasopressin [ADH] antagonists) for symptomatic control.
15.3 Renal Blood Flow, Renal Plasma Flow, and Glomerular Filtration Rate
– Renal blood flow (RBF) is the volume of blood entering the kidneys per minute. It is ~1 L/min (20% of cardiac output).
– Renal plasma flow (RPF) is the volume of plasma entering the kidneys per minute. The average RPF is ~600 mL/min.
– RBF is calculated as follows:
RBF = RPF/(1-hematocrit)
where (1-hematocrit) is the fraction of total blood volume that is plasma and glomerular filtration rate (GFR) is the volume of plasma filtered per minute by all glomeruli in the kidneys. The average GFR for a healthy 70 kg man is 125 mL/min (~20% of RPF) and declines with age.
– The magnitude of the GFR is an index of general kidney function.
– Filtration fraction is the fraction of total plasma volume that is filtered across the glomerulus. It is expressed by the following equation:
Filtration fraction = GFR/RPF
– It is normally one-fifth (20%) of RPF. The other 80% flows into the peritubular capillaries from the efferent arterioles.
Nephrotoxic drugs
An example of a nephrotoxic drug is gentamicin, an aminoglycoside antibiotic used to treat severe infections. It is excreted in unchanged form, mostly by glomerular filtration, in the kidney. In renal impairment, gentamicin will accumulate in the kidney, causing destruction of kidney cells (nephrotoxicity). If used, the dosage and treatment period should be minimal and plasma concentration should be closely monitored.
Determinants of GFR
Ultrafiltration of plasma occurs as plasma moves from glomerular capillaries into Bowman’s capsule under the influence of Starling forces (Fig. 15.4). Glomerular filtration is the same mechanism as systemic capillary filtration, i.e., the balance between hydrostatic and oncotic forces across the glomerular membrane determines the direction of fluid movement.
Fig. 15.4 Starling forces across glomerular capillaries.
Glomerular capillary hydrostatic pressure is the main driving force for ultrafiltration across the glomerular membrane. It is opposed by the hydrostatic pressure in Bowman capsule and glomerular capillary oncotic pressure. (PBC, Bowman’s capsule hydrostatic pressure; PGC, glomerular capillary hydrostatic pressure; πGC, glomerular oncotic pressure)
Net ultrafiltration pressure is determined by the Starling equation:
where
Kf = filtration coefficient of the glomerular capillaries. It depends on the membrane permeability of the cells that comprise the glomerular barrier and their surface area.
PGC = glomerular capillary hydrostatic pressure. It is constant throughout the capillary (~45 mm Hg).
PBC = Bowman’s capsule hydrostatic pressure. It is analogous to interstitial hydrostatic pressure (Pi) in systemic capillaries and is usually ~10 mm Hg.
πGC = glomerular capillary oncotic pressure. It usually increases along the length of the capillary because as water is filtered out of capillaries, the proteins left behind become increasingly concentrated. It is ~28 mm Hg.
πBC= Bowman’s capsule oncotic pressure. It is usually zero because very little protein is filtered under normal conditions.
Table 15.2 summarizes the effects of changes in Starling forces on net ultrafiltration pressure and GFR.
Glomerular versus systemic capillaries
The glomerular capillaries are much more permeable than average systemic capillaries. Approximately 180 L/day of fluid are filtered across glomerular capillaries, whereas only 4 L/day of fluid would have been filtered if these were systemic capillaries. The ultrafiltration coefficient for glomerular capillaries is ~40 to 50 times greater than for systemic capillaries.
Nephrotic syndrome
Nephrotic syndrome results in severe proteinuria (loss of proteins into the urine), hypoalbuminemia (see box page 112), and edema due to the decrease in capillary oncotic pressure. Causes of nephrotic syndrome include glomerulonephritis (inflammation of the glomerulus), diabetes, neoplasia, and drugs. Signs include peripheral edema, ascites (accumulation of fluid in the peritoneal space), and swelling of the eyelids. Venous thrombosis and emboli may occur due to excretion of certain clotting factors and antithrombin III in the urine. Treatment involves the administration of a loop diuretic with a K+-sparing agent, plasma protein replacement, and anticoagulation (if necessary) to prevent thrombosis or emboli. The underlying cause should also be sought and treated appropriately.
Kidney stones
Kidney stones in the renal pelvis and ureters will increase hydrostatic pressure in Bowman capsule and therefore greatly reduce GFR. Uric acid kidney stones may sometimes be dissolved by alkalinizing the urine with intake of potassium citrate. Kidney stones that are < 0.5 in. (1.27 cm) in diameter can be fragmented by applying focused ultrasound waves (lithotripsy).
Regulation of Renal Plasma Flow and Glomerular Filtration Rate
Regulation of GFR is linked to the regulation of RPF, because the flow of plasma to the kidneys influences the rate of filtration.
Autoregulation
Renal autoregulation ensures that RPF and GFR remain almost constant over a wide range of mean arterial blood pressures (BPs) (80−180 mm Hg). As blood pressure (BP) increases within this range, resistance in renal arterioles increases proportionately to minimize large increases in RPF and GFR by limiting changes in glomerular pressure (Fig. 15.5).
The two intrarenal mechanisms responsible for renal autoregulation are the myogenic mechanism and the tubuloglomerular feedback mechanism.
Myogenic Mechanism. Increases in renal arterial pressure cause stretching of the afferent arteriolar smooth muscle. This, in turn, causes the smooth muscle to contract, increasing resistance, which decreases RPF (and GFR) to their normal levels.
Tubuloglomerular Feedback Mechanism. Increases in renal arterial pressure increase the GFR and lead to an increased solute load to the macula densa cells in the distal tubule (Fig. 15.2). This activates these cells, and they stimulate the adjacent afferent arteriole to constrict. The arteriolar constriction increases resistance, thus decreasing RPF (and GFR) to their normal levels.
Fig. 15.5 Autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR).
Autoregulation of RBF ensures that minimal changes in renal plasma flow (RPF) and GFR occur when the systemic blood pressure (BP) fluctuates between 80 and 180 mm Hg. If the BP falls below ~80 mm Hg, however, renal circulation and filtration will ultimately fail. RBF and GFR can be regulated independently by making isolated changes in the resistances of the afferent and efferent arterioles.
Regulation by Modulation of Arteriolar Resistance
Even in the face of autoregulation, changes in RPF and GFR can occur by local changes in vascular resistance of afferent and efferent arterioles. These resistance changes can be caused by the actions of the autonomic nervous system and various vasoactive humoral agents.
– Sympathetic activation leads to vasoconstriction of both afferent and efferent renal arterioles. This will reduce RPF and GFR. Similarly, decreased sympathetic tone results in decreased renal vascular resistance and increased RPF and GFR.
– Vasoactive humoral agents that act as vasoconstrictors, for example, catecholamines, angiotensin II, ADH (vasopressin), prostaglandins, and endothelin, will reduce RPF and GFR.
– Vasoactive humoral agents that act as vasodilators, for example, atrial natriuretic peptide (ANP), acetylcholine, kinins, and nitric oxide (NO), will increase RPF and GFR.
Note: When resistance is altered in the afferent arteriole only, RPF and GFR change in the same direction. When resistance is altered in the efferent arteriole only, RPF and GFR change in opposite directions. Therefore, GFR tends to decrease less than RPF when sympathetic tone is increased, as both afferent and efferent arterioles are constricted.
Renal oxygen consumption and metabolism
Per unit of tissue weight, the kidneys are perfused by more blood, and they consume more oxygen (O2) than does any other organ except the heart. Yet the renal arteriovenous O2 content difference is lower than that of other organs. This unique feature reflects the high filtering capacity of the kidneys; consequently, RBF is far in excess of the kidneys’ basal O2 requirements. The high renal O2 consumption reflects the amount of energy required for the reabsorption of filtered Na+. Energy is derived from oxidative metabolism (mostly of fatty acids) in the renal cortex. In contrast, the renal medullary structures derive energy from anaerobic metabolism of glucose.
15.4 Renal Clearance
Renal clearance measures the efficiency of the kidneys in removing a substance from plasma. It is a useful concept in renal physiology because it can be used to quantitatively measure the intensity of several aspects of renal function (i.e., ultrafiltration, reabsorption, and secretion).
– Renal clearance is the volume of plasma from which a given substance is completely cleared by the kidneys and excreted in the urine per unit time. It can be calculated using the following equation (a modification of the Fick equation):
C = UV/P
where C is the renal clearance (mL/min), U is the urine concentration (mg/mL), P is the plasma concentration (mg/mL), and V is urine output (mL/min).
Example:
Over a 12-hour (720-minute) collection period, a patient produces 504 mL of urine with a creatinine concentration of 0.11 mg/mL. The plasma creatinine is 0.001 mg/mL. The clearance (of creatinine) is
– A substance that is freely filtered (i.e., that has the same concentration in the filtrate as in plasma) and does not undergo net reabsorption or secretion in the renal tubules (e.g., inulin) will have a clearance value that is equal to GFR.
– A substance that undergoes net reabsorption from the tubules into pericapillary blood (e.g., urea) will have a clearance value that is lower than GFR.
– A substance that undergoes net secretion from pericapillary blood into the tubules (e.g., p-aminohippuric acid [PAH]) will have a clearance value that is higher than GFR.
Measurement of Glomerular Filtration Rate Using Inulin Clearance
Inulin is a nontoxic polysaccharide that is not bound to plasma proteins. It is freely filtered at the glomerulus and is neither reabsorbed nor secreted by renal tubules; therefore, the volume of plasma cleared of inulin per minute is equal to the GFR and may be calculated as follows:
GFR = Cinulin = [U]inulin × V/[P]inulin
Example:
Urine flow rate = 1 mL/min, plasma inulin = 0.15 mg/mL, urine inulin = 15 mg/mL
Measurement of Glomerular Filtration Rate Using Creatinine Clearance
Creatinine is an end product of skeletal muscle creatine metabolism and has a fairly constant concentration in plasma under normal conditions.
– Creatinine is freely filtered by the glomerulus and is not reabsorbed. However, small amounts are secreted into the renal tubules, so creatinine clearance gives a slightly greater estimate of GFR than inulin clearance. Despite this, creatinine clearance is used to measure GFR rather than inulin clearance because creatinine is endogenously produced.
– There is an inverse relationship between plasma creatinine level and the magnitude of GFR; for example, if GFR decreases to half of normal, and creatinine production remains constant, plasma creatinine will double.
Measurement of Glomerular Filtration Rate Using Urea Clearance
Urea is filtered and reabsorbed. Under conditions when urea reabsorption is approximately a constant fraction of the filtered load, urea clearance can be used to estimate GFR. Plasma levels of urea are used to estimate renal function by the same inverse relationship as serum creatinine. Plasma urea level is expressed as blood urea nitrogen (BUN) concentration. When GFR falls, BUN usually rises in parallel to serum creatinine. However, urea clearance or BUN is usually not a reliable indicator of the magnitude of GFR, as plasma urea concentration varies widely, depending on protein intake, protein catabolism, and variable renal resorption of urea under different states of hydration.
Measurement of Renal Plasma Flow Using p-aminohippuric Acid Clearance
PAH is both filtered and secreted into renal tubules; therefore, the renal clearance of PAH is greater than GFR and is not used for its quantitative measurement. However, the renal clearance of PAH can be used to estimate the magnitude of RPF because PAH is completely cleared from the plasma by renal excretion during a single circuit of plasma flow through the kidney. Normally, 85 to 90% of plasma flowing through the kidney reaches the nephron and is cleared of PAH, therefore PAH clearance is a measure of effective renal plasma flow (ERPF) (thus accounting for the 10 to 15% of plasma that does not supply the nephron) and can be calculated using the equation for renal clearance.
ERPF = CPAH = [U]PAH × V/[P]PAH
Renal Clearance of Glucose
The renal clearance of glucose is zero at normal plasma glucose concentration (80 mg/100 mL) and up to 300 mg/100 mL because all filtered glucose is reabsorbed by renal tubules. If plasma glucose levels increase above 3 times normal, the renal reabsorptive rate of glucose will reach its maximum tubular transport capacity, and glucose excretion will increase until its clearance approaches GFR. That is, at high plasma glucose concentrations, the majority of excreted glucose comes from its unreabsorbed filtered load.