The kidney maintains the homeostasis of body fluids through the excretion of metabolic end products and toxins, the regulation of body fluid volume and blood pressure, and the regulation of mineral and acid-base balance. While the regulatory function of the kidney directly affects the one-third of the fluid that is located in the vascular compartment, because there is free movement of water between the intracellular and extracellular fluid (ECF) compartments, the latter containing two-thirds of the body fluid volume, renal function actually affects the composition of all body fluids.

The kidney consists of (1) an inner renal medulla and (2) an outer renal cortex (Fig. 2.1). The functional unit of the kidney is the nephron (Fig. 2.2). Each kidney contains approximately 1 million nephrons. Each nephron consists of a specialized capillary vascular network called the glomerulus, which is surrounded by Bowman capsule, a balloon-like structure into which the capillary tufts of the glomerulus protrude. Each glomerulus is connected to a series of specialized epithelial segments that collectively are known as the renal tubule.

The tubule is divided into several segments. The first segment, the proximal tubule, is subdivided into convoluted and straight portions; the second segment, the loop of Henle, is subdivided into the thin descending, the thin ascending, and the thick ascending limbs; and the third segment, the distal tubule, is subdivided into the distal convoluted tubule and the cortical, medullary, and papillary collecting ducts. The renal cortex contains the glomeruli, the proximal tubule, the distal tubule, and the cortical collecting duct. The renal medulla is made up of the loops of Henle, the medullary and papillary collecting ducts, and renal pyramids, the apices of which project into the minor calyces. The nephrons that are located close to the corticomedullary junction have larger glomeruli, and their loops of Henle descend deeper into the renal papilla than those located more superficially in the renal cortex.

The main renal artery branches into interlobar arteries that divide into the arcuate arteries located at the corticomedullary junction. These, in turn, become the interlobular arteries that finally divide into the afferent arterioles, each of which leads to a glomerulus. The glomerulus is drained by an efferent arteriole that subdivides to form a peritubular capillary network known as the vasa recta. The vasa recta then anastomose to form venous channels. This unique arrangement in the kidney, in which the glomerulus is located between two resistive capillary networks as opposed to the arteriole-capillary-venule arrangement of the other tissues of the body, helps to maintain constant hydrostatic pressure at the level of the glomerulus despite changes in blood pressure and is the driving force for glomerular filtration.

The macula densa is a distinctive portion of the tubule between the ascending loop of Henle and the distal convoluted tubule that courses between the afferent and efferent arterioles. It represents the tubular component of a specialized area of the nephron called the juxtaglomerular apparatus. The juxtaglomerular apparatus is the site of renin synthesis and plays a major role in blood pressure regulation.

The homeostatic functions of the kidney are achieved through two simultaneous processes: (1) glomerular filtration and (2) tubular resorption/secretion. The net filtration pressure (NFP) is equal to the sum of the glomerular hydrostatic pressure and the colloid osmotic pressure in Bowman capsule (which favors fluid movement from the capillary space into Bowman space) minus the sum of the mean glomerular capillary oncotic pressure and the hydrostatic pressure in Bowman space (the principal forces opposing ultrafiltration). Because protein is not filtered by the glomerulus, the fluid of Bowman space is protein free; thus, the colloid osmotic pressure in Bowman space is negligible. The glomerular filtration rate (GFR) is determined by the NFP and the surface area available for filtration, as well as by the permeability of the glomerular capillary bed. The average GFR in a human with normal renal function is approximately 125 mL/min, which is equal to 180 L/day or approximately 12 times the volume of the ECF.

Although 180 L of fluid is filtered in a day, only 1 to 2 L of urine is produced per day in which wastes may be concentrated 100- to 200-fold above their plasma concentration. This concentration of the final urine product is the result of a combination of tubular secretion and reabsorption. Under normal conditions, approximately two-thirds of the ultrafiltrate volume is reabsorbed in the proximal tubule by a process linked to the active secretion of hydrogen ions and the active reabsorption of sodium, glucose, amino acids, and other solutes. Isotonicity of the fluid in the proximal tubule with the plasma is maintained because the cells of the proximal tubule are freely permeable to water.

In the loop of Henle, which begins at the corticomedullary junction, differential absorption of sodium chloride occurs so that the fluid in the tubular lumen, initially isotonic with the interstitium, becomes progressively more concentrated in the descending limb, reaching its maximum concentration at the bend of the loop and then becomes progressively more hypotonic with respect to plasma as it reaches the thick ascending limb of the loop. This differential absorption of sodium chloride occurs because the cells in the descending limb have a high permeability for water but a low permeability for salt, whereas in the thick ascending limb, the cells are impermeable to water but have a high permeability for salt, which is actively reabsorbed. This process, known as the renal countercurrent mechanism, results in progressive interstitial hypertonicity in the medulla and is required for final concentration of the urine by the distal tubules.

The distal tubule continues the water dilution of urine through the active transport of sodium and chloride coupled with relative water impermeability. The collecting ducts are the primary site of action of antidiuretic hormone (ADH). The final 15% of water absorption is achieved within the collecting ducts. The collecting ducts are virtually impermeable to water in the absence of ADH, but when ADH is present, water passes freely across the tubular wall, allowing the tubular fluid to achieve the same tonicity as the fluid in the surrounding interstitium. Thus, hypertonic urine is produced without the active transport of water. The distal nephron also reabsorbs sodium and secretes hydrogen ions and potassium under the influence of aldosterone. Parathyroid hormone also acts on the distal tubule to conserve calcium.

The rate at which a substance is removed from the plasma in a given period is termed the clearance of that substance. For a substance that is freely filtered and not reabsorbed or secreted by the tubule, the rate of clearance is equal to the GFR. The polysaccharide, inulin, meets this requirement and, therefore, can be used to determine GFR. Creatinine, an endogenous product of muscle metabolism, is produced in relatively constant amounts each day.
Creatinine is present in the plasma, and is excreted by glomerular filtration. Measurement of creatinine clearance is therefore convenient, although it is not as exact as the inulin clearance, because a small amount of creatinine is also secreted by the tubules. Because creatinine clearance tends to underestimate renal dysfunction, particularly with mild impairment, the National Kidney Foundation has suggested that the estimated glomerular filtration rate (eGFR) may be a better model for predicting renal dysfunction than relying solely on serum creatinine determinations. eGFR is generally calculated from the serum creatinine by either the Cockcroft-Gault formula or, more commonly, one of the modified diet in renal disease (MDRD) formulae. All of these formulae are calculated using a combination of the serum creatinine level, patient age, and patient gender. The Cockcroft-Gault formula also utilizes patient weight, while the MDRD formulae also accounts for patient race.

The most common of the abovementioned eGFR estimation formulae is the 4-variable MDRD formula, which is listed as follows: eGFR (mL/min/1.73 m²) = 175 × [serum creatinine (µmol/L) × 0.0113]^-1.154 × age (years)^-0.203 (× 0.742 if female). There are many eGFR calculators available on the Internet.

Although attempts at radiography of the urinary tract began shortly after Roentgen’s discovery in 1895, the first report of opacification of the urinary tract was in 1923, when researchers at the Mayo Clinic discovered opacification of the bladder in patients being treated with sodium iodide. It is remarkable that in the more than 80 years since this discovery, no intravascular element other than iodine has proven suitable for imaging with x-rays.

Attempts at developing an injectable radiopaque iodinated contrast media were initially made in Germany under the direction of Moses Swick, an American urologist, who ultimately focused on linking the iodine to a 6-carbon benzene ring in an attempt to increase water solubility and decrease toxicity.

In 1955, Hoppe et al. at Sterling Winthrop Research Institute produced sodium diatrizoate (Fig. 2.3), a fully substituted derivative of 2,4,6-triiodobenzoic acid, which became the first modern iodinated contrast media. This agent was ionic in that the anionic benzene cation had to be conjugated with a positively charged sodium (cation), with the sodium diatrizoate molecule dissociating into two particles in solution (ratio of three iodine atoms to two particles in solution). This product and its derivatives, including sodium/meglumine diatrizoate and meglumine iothalmate, became the standard urographic contrast media for the next 30 years.

Although these ionic contrast media, which are still commonly used for enteric procedures today, including cystograms, some esophagograms, and some enemas, were safer than the previously used materials, much of the remaining toxicity of the compounds was related to their high osmolality (>1,500 mOsm/kg of water or approximately five times greater than plasma at standard contrast concentrations).

In 1968, Torsten Almen of Malmö, Sweden, theorized that the high osmolality of ionic contrast (with osmolality basically being a measure of the number of particles in solution) could be reduced by synthesizing a product that would be nondissociating. He demonstrated that the ionizing carboxyl group of conventional contrast media could be replaced with a nondissociating hydrophilic group such as an amide, resulting in a ratio of three iodine atoms per one particle in solution. This would theoretically decrease the osmolality by 50%, reducing the number of particles in solution without loss of iodine content. The first nonionic contrast media, metrizamide, was never used in the United States as a urographic agent, because of its considerable cost and the necessity to package it as a freeze-dried lyophilized powder that needed to be reconstituted with water immediately before use.

Several years after the introduction of metrizamide, second-generation low-osmolality contrast media were introduced into clinical practice. These products developed along two general lines. In the first group, hydrophilic nonionizing radicals were again introduced in positions one, three, and five of the benzene ring, whereas, positions two, four, and six remained the position of the iodine atoms. Because the radical at position number one did not dissociate, the number of iodine atoms relative to the number of particles in solution remained 3:1 rather than 3:2, as noted with ionic contrast media. Compounds in this category, which remain widely used today, include iohexol (Fig. 2.4; Omnipaque; GE Healthcare Inc., Princeton, NJ), iopamidol (Fig. 2.5; Isovue; Bracco Diagnostics Inc., Monroe, NJ), iopromide (Ultravist, Bayer Health Care, Wayne, NJ), and ioversol (Fig. 2.6; Optiray; Mallinckrodt Imaging, Hazelwood, MO). All of these products are generically known as nonionic monomers. Studies have demonstrated that the incidence of adverse events is greatly reduced (by a factor of about
five) when nonionic monomers are injected intravenously, in comparison to ionic monomers, a difference that is likely the result of their lower osmolality.

The second line of development of low osmolality contrast was directed toward the linkage of two triiodinated benzene rings together sharing only one ionizing carboxyl group (at position one of one of the benzene rings). These compounds have a ratio of six iodine atoms to two molecules in solution and also produce a ratio of 3:1. These contrast particles are generally known as ionic dimers and have a similar osmolality to nonionic monomers.

Further development involved the linkage of two nonionic monomeric compounds to form a nonionic dimer, which has a ratio of six iodine atoms to one particle in solution, and, therefore, has a ratio of 6:1. This modification has further reduced the osmolality of the resulting contrast media, such that nonionic dimers have an osmolality equal to plasma. Iodixanol (Fig. 2.7; Visipaque; GE Healthcare, Princeton, NJ) is the only one of these agents to be approved for use in the United States. Interestingly, the incidence of acute adverse events after nonionic dimer injection has not been seen to be significantly lower than that encountered after nonionic monomer injection.

Another property of contrast media is viscosity. This property describes the relative adhesiveness of the molecules of the contrast media for one another and is important because the viscosity of the contrast determines how rapidly the contrast may be injected. In general, more concentrated solutions of contrast material are more viscous than less concentrated solutions. Also, larger molecules tend to have higher viscosity than smaller molecules at the same concentrations. So, it is not surprising that nonionic dimers are considerably more viscous than are nonionic monomers. The viscosity of contrast media decreases with increasing temperature. For this reason, warming of viscous contrast material makes injection easier.

As can be seen, a variety of physical and chemical properties may be used to describe the contrast media in general use in the United States, the most important of which are ionicity and osmolality. With the older, ionic contrast media, the strength of the contrast media was frequently expressed in terms of percent contrast molecule concentration. This number represents the number of grams of the total contrast molecule per 100 mL of water. This designation does not, per se, describe the amount of iodine in solution, but in general, the higher the percent concentration, the more radiopaque the contrast media. Currently, many commonly used contrast media use a numerical designation to denote the amount of iodine in milligrams per milliliter of the contrast media. Thus, Conray 325 (Mallinckrodt Imaging, Hazelwood, MO), an ionic monomer,
contains 325 mg of iodine per mL of solution. Isovue 370 (Bracco, Monroe, NJ), a nonionic monomer, contains 375 mg of iodine per mL of solution.

Reactions to contrast media, although uncommon, continue to constitute a significant hazard to patients despite considerable research into their nature, incidence, and mechanisms. Fortunately, most adverse reactions are mild and self-limited, with symptoms including a metallic taste in the mouth, a sensation of warmth, and, occasionally, a few hives.

Adverse effects of contrast media can be divided into two groups: (1) allergic-like reactions, those which mimic an allergic response to contrast media, and (2) physiologic or chemotoxic effects, those thought to be secondary to a direct toxic effect of the contrast media. Because many of the allergic-like reactions to contrast media mimic those produced by true known allergens (i.e., urticaria or bronchospasm), but are not mediated by immunoglobulins, these reactions are sometimes referred to as “anaphylactoid” or “allergic-like” rather than anaphylactic.

Allergic-like reactions to nonionic contrast material are rare, in one series of more than 80,000 patients reported by Wang et al, occurring in 0.6% of patients injected for CT. Allergic-like reactions can be classified as (1) mild, (2) moderate, or (3) severe, with the vast majority of reactions being mild. Mild reactions are defined as those having only minor effects requiring no therapy. Moderate reactions are those that are transient and not life-threatening but usually requiring therapy. Severe reactions are defined as those that are life-threatening and that require intensive therapy. The more commonly encountered symptoms of these different types of allergic-like reactions are listed in Table 2.1.