Daniel A. Shoskes, MD, MSc, FRCSC, Alan W. McMahon, MD

Renal physiology impacts the urological care of patients in numerous ways. These can include the pathophysiology of surgical disease (renal tubular acidosis, malignant paraneoplastic syndromes), the modification of surgical technique (ischemia reperfusion injury and intrarenal surgery), or iatrogenic complications of surgery (hyponatremia, metabolic complications of urinary diversions). The purpose of this chapter is not to turn urologists into nephrologists, but rather to provide a firm fundamental knowledge of renal physiology and pathophysiology to provide the foundation for urologic specific conditions and therapies.

Renal Physiology

Vascular (Renal Blood Flow and Glomerular Flow Rate)

Renal Blood Flow (RBF)

RBF is regulated by changes in vascular resistance of all the arteries up to and including the efferent arteriole, which in turn is regulated by a variety of neurohormonal signals (see below).

Blood enters the kidney through the renal arteries and divides into progressively smaller arteries (interlobar, arcuate, and interlobular arteries) until it enters the glomerular capillary through the afferent arteriole. A portion of the plasma that enters the glomerulus is filtered across the glomerular membrane; this is called the filtration fraction. The rest of the blood exits the glomerular capillary through the efferent arteriole. In nephrons located in the renal cortex, these capillaries travel in close proximity to the tubules and modulate solute and water reabsorption. In juxtamedullary nephrons (located deeper in the medulla), the efferent arterioles branch out to form vasa recta, which participate in the countercurrent mechanism through which urine is highly concentrated and body water conserved (see later discussion).

Under normal resting conditions, RBF is 20% of total cardiac output. Total blood flow is different for men and women, averaging 982 ± 184 mL/min in women and 1209 ± 256 mL/min in men (Dworkin and Brenner, 2004). Renal plasma flow (RPF) is slightly less, averaging 592 mL/min in women and 659 mL/min in men, and varies with hematocrit (RPF = RBF × [1−Hct]). RBF is not evenly distributed to all parts of the kidney. Flow to the outer cortex is 2 to 3 times greater than that to the inner cortex, which in turn is two to four times greater than that to the medulla (Dworkin and Brenner, 2004).

Determinants of Glomerular Filtration

The most important function of the kidney is the process of glomerular filtration. Through the passive ultrafiltration of plasma across the glomerular membrane, the kidney is able to regulate total body salt and water content, electrolyte composition, and eliminate waste products of protein metabolism.

The process of filtration is analogous to fluid movement across any capillary wall, and is governed by Starling forces. The glomerular filtration rate (GFR) is thus determined by both hydraulic and oncotic pressure differences between the glomerular capillary and the Bowman space, as well as by the permeability of the glomerular membrane:

where Lp = glomerular permeability and S = glomerular surface area.

The rate at which filtration occurs within an individual nephron is termed the “single nephron GFR” (SN-GFR). A more relevant measurement is that of total GFR, which is the sum of all SN-GFR and is expressed in milliliters per minute. GFR is thus a reflection of overall renal function. Alterations in GFR can occur either with alterations in any aspect of Starling forces, or through a change in renal plasma flow (RPF).

1. Transglomerular (hydraulic) pressure (TGP)—the most significant determinant of GFR is the TGP. Although systemic arterial pressures impact on TGP, the glomerular capillary is unique in that it is interposed between two arterioles (the afferent and efferent arterioles) and thus can regulate intraglomerular capillary pressure (IGP) independent of systemic pressures through changes in afferent and efferent arteriolar tone. Under normal circumstances, the pressure within the Bowman space is essentially zero, and only in conditions of urinary obstruction does the pressure increase to clinically significant levels. Thus the TGP = IGP.

2. Renal plasma flow—increases in RPF lead to increases in GFR. Although the filtration fraction cannot exceed 20% under normal circumstances, an increase in RPF will lead to an increase in absolute GFR.

3. Glomerular permeability—generally, an increase in permeability does not lead to an increase in GFR, because the glomerulus is already at maximal permeability for water and other relevant solutes. It may, however, lead to increased filtration of larger molecules not normally filtered, such as albumin. Reductions in permeability, or in glomerular surface area, can lead to reductions in GFR.

4. Oncotic pressure—the least relevant of all the variables. Under normal circumstances, plasma proteins are not filtered across the glomerular membrane and so oncotic pressure within the Bowman space is essentially zero.

and since

we can now see that

This is called the clearance of a substance and reflects the amount of plasma that is completely cleared of the substance per unit time. There are a number of substances that have been used clinically to estimate GFR.

1. Inulin—is a fructose polysaccharide that meets the necessary requirements, and inulin clearance is felt to be the best measure of GFR. However, it is not clinically useful because it is difficult to administer (requires an intravenous infusion of inulin), and difficult to measure.

2. Radiolabelled compounds—such as iothalamate or diethylenetriaminepentaacetic acid (DTPA). These clearances are also very accurate, but are again limited in clinical use by their cost and availability (Perrone et al, 1990).

3. Creatinine—the most widely used estimate of GFR is the 24-hour creatinine clearance (CrCl) (Levey, 1990). It uses endogenous creatinine, which is produced at a constant rate. The rate of production varies from individual to individual, but for a single individual daily variability is less than 10%. It has the advantage of being easy to perform (no intravenous [IV] infusion), is relatively cheap, and readily available. However, it is less accurate than inulin clearance, because some creatinine is cleared from plasma through proximal tubular secretion; thus a CrCl overestimates true GFR, on average, by 10% to 20%. This becomes even more important as GFR declines, because tubular secretion increases in response to increasing serum creatinine levels and may contribute up to 35% of all creatinine removal at GFR levels of 40 to 80 mL/min (Shemesh et al, 1985). At best, then, the CrCl should be considered the “upper limit” of the true GFR.

Plasma Markers

An even simpler method to estimate GFR is with the use of plasma levels of substances that can be used as surrogate markers of GFR. To be useful, the substance must fulfill the criteria outlined above. Three such substances have been used:

1. Plasma creatinine (PCr)—the most widely used plasma marker of GFR. While creatinine production is constant within an individual from day to day, there is marked variation in production rates between individuals. The absolute rate depends upon muscle mass, which in turn is influenced by age, sex, and body mass. Thus there is no single “normal” PCr that reflects a “normal” GFR; it must be individualized for every person. This can be accomplished through mathematical manipulation (see below). However, the relationship of PCr to GFR is relatively constant (Fig. 38–1), and thus changes in PCr can be used to predict corresponding changes in GFR. As a general rule of thumb, every 50% reduction in GFR results in a doubling of PCr. There are limitations to the use of the PCr that should be noted:

• As GFR falls, tubular secretion of creatinine increases; so, PCr may not change noticeably until there has been a significant drop in GFR (Shemesh et al, 1985).

• Creatinine production may increase in states of increased muscle breakdown (e.g., rhabdomyolysis) or with increased dietary protein intake or supplementation, leading to an underestimation of true GFR.

• Creatinine production may decrease with liver cirrhosis, leading to an overestimation of true GFR.

2. Plasma urea—another widely used plasma marker. Urea production and excretion is highly variable, influenced, for instance by dehydration, high-protein diets, and increased tissue breakdown. As a result, it is a much less reliable marker of GFR than is the PCr and should not be used as the sole determinant.

3. Plasma cystatin C—is an endogenous protein found in all nucleated cells. It has a constant rate of production unaffected by diet, and clearance is not influenced by tubular functions (Filler et al, 2005). This test is not widely available at present, but likely will replace PCr as the standard test in GFR assessment.

Figure 38–1 Relationship between serum creatinine and creatinine clearance. PCr, plasma creatinine.

Mathematical Correction

There are a number of mathematical formulas that have been developed to improve the accuracy of the PCr estimation of GFR (National Kidney Foundation, 2002). The two most widely used are the Cockcroft-Gault and “modification of diet in renal disease” (MDRD) formulas.

1. Cockcroft-Gault—originally developed from data collected from individuals with normal renal function; it is a simple formula to estimate CrCl (not GFR) that corrects for age, sex, and body mass (Cockcroft and Gault, 1976). The formula is

It has the advantage of being very simple, but is not as accurate as other methods when renal function is impaired.

2. MDRD formulas—a series of formulas derived from data collected in patients with severe renal impairment; they are more complex but more accurate than the Cockcroft-Gault. The simplest estimate of GFR is the four-variable equation (PCr, age, sex, and ethnicity) (Manjunath et al, 2001):

In summary, the GFR is analogous to renal function. Total GFR is a summation of all SN-GFR, which in turn are determined primarily by TGP and glomerular permeability of the individual nephrons, and it is usually tightly regulated. A GFR estimate should be obtained in all patients with renal impairment (rather than a PCr alone), and the recommended method is through the use of the four-variable MDRD formula or Cockcroft-Gault formula.

Key Points: Renal Blood Flow and Glomerular Filtration Rate

• GFR reflects total renal function.

• GFR can be approximated by creatinine clearance.

• Formulas based on patient’s age, weight, and serum creatinine can best estimate GFR.

Hormonal

Control of Renal Vascular Tone

Vascular tone of the renal vessels, the net balance of vasoconstrictive and vasodilatory forces, is crucial to the maintenance of renal blood flow, GFR, tubular renal function, and systemic blood pressure. There is a complex network of hormones and vasoactive substances with both direct and indirect effects, resulting in a system that is pleiotropic and redundant. Although much has been learned from animal models about the function of individual molecules, the complexity of the total system can lead to unexpected outcomes when individual pathways are manipulated pharmacologically. A summary of substances known to impact vascular tone is given in Table 38–1.

Table 38–1 Vasoactive Substances That Control Renal Artery Tone

Atrial natriuretic peptide

Vasodilation

Vasoconstrictors

Angiotensin II

Angiotensin II is a potent vasoconstrictor. In the kidney, there is a more pronounced constrictive effect on the efferent than the afferent arteriole, due to inhibition of angiotensin II actions in the afferent arteriole by nitric oxide and prostaglandin (Arima, 2003). Elevated levels of angiotensin II are important for maintaining GFR in pathologic conditions that reduce RBF (e.g., renal artery stenosis, dietary sodium restriction). The classical effects of angiotensin II (vasoconstriction, aldosterone release, sodium retention) are mediated by the AT1 receptor (Kaschina and Unger, 2003). The AT2 receptor, however, may cause intrarenal dilation and be protective against renal ischemic injury (Carey, 2005).

Norepinephrine

Norepinephrine vasoconstricts all the major vascular beds in the kidney, mediated through the α₁ receptor. In patients who receive norepinephrine as a pressor agent in the face of systemic vasodilation, renal function is preserved and may actually improve (Albanese et al, 2004).

Endothelin

Endothelin is the most potent vasoconstrictor yet identified. There are three isoforms, with ET-1 being the most fully described. An endothelin precursor (big ET-1; 39 amino acids) is cleaved to ET-1 (21 amino acids) by an endothelin converting enzyme found on the endothelial cell membrane. The endothelin receptors are subclassified into ET (A), which are purely vasoconstrictive, and ET (B). The ET (B) receptors may cause either vasodilation by stimulating the release of nitric oxide from endothelial cells, or vasoconstriction of vascular smooth muscle cells (Fellner and Arendshorst, 2004). ET-1 release is stimulated by angiotensin II, antidiuretic hormone, thrombin, cytokines, reactive oxygen species, and shearing forces acting on the vascular endothelium. ET-1 release is inhibited by nitric oxide, as well as by prostacyclin and atrial natriuretic peptide. Blockade of the ET (A) receptor can reduce renal vasoconstriction seen in such ischemic conditions as ureteral obstruction (Bhangdia et al, 2003).

ET-1 has a number of other actions besides vasoconstriction. ET-1 stimulates aldosterone secretion, produces positive inotropy and chronotropy in the heart, decreases renal blood flow and GFR, and releases atrial natriuretic peptide. Despite reduction in RBF, sodium excretion is increased, suggesting that ET may be responsible for maintaining sodium balance when the renin-angiotensin system is depressed (Perez del Villar et al, 2005). Medullary blood flow is preserved in the face of endothelin induced vasoconstriction, which may explain the relative stimulation of tubular functions (Evans et al, 2004).

Vasopressin

Vasopressin acts directly on blood vessels through the vasopressin V1 receptor but does not directly change RBF at low doses (Malay et al, 2004). Vasopressin does potentiate the vasoconstrictive effects of norepinephrine (Segarra et al, 2002) and can induce renal ischemia at high doses. At the low doses typically employed in the management of septic shock, renal function is preserved (Holmes et al, 2001).

Atrial Natriuretic Peptide

Atrial natriuretic peptide (ANP) is a vasoactive hormone synthesized primarily by the atria in response to stretching, as occurs during physiologic levels of volume expansion (Fig. 38–2). The primary actions of ANP on the kidney are increased GFR and natriuresis. ANP can increase GFR without a change in renal blood flow (Sward et al, 2005) by the combination of afferent arteriolar vasodilatation and efferent arteriolar vasoconstriction. In addition, ANP dilates vessels that have been preconstricted by norepinephrine, angiotensin II, or vasopressin. ANP production increases during bilateral obstructive uropathy, which may be one mechanism of preserving GFR (Kim et al, 2002).

Figure 38–2 Schematic representation of the fundamental biologic processes of atrial natriuretic peptide (ANP). AII, angiotensin II.

ANP increases natriuresis mainly through inhibition of sodium reabsorption in the medullary collecting duct (Zeidel et al, 1988); decreased renin and decreased aldosterone production may also play a role (Laragh, 1985). Clinically, however, infusion of low-dose ANP during surgery increases water and electrolyte excretion without measured systemic changes in cortisol, angiotensin II, or aldosterone (Koda et al, 2005). This approach has also been used to prevent ischemic renal damage in high-risk cardiac surgery (Sward et al, 2004).

Vasodilators

Nitric Oxide

Nitric oxide (NO) is a highly reactive gas that participates in multiple physiologic and pathophysiologic reactions in the body. NO is synthesized from the reaction between arginine, reduced nicotinamide adenine dinucleotide phosphate (NADPH), and oxygen to produce citrulline, NADP, water, and NO. This reaction is catalyzed by a family of enzymes called nitric oxide synthase (NOS). Although all NOS enzymes catalyze the same reaction, they differ in distribution, expression, and stimuli. Neuronal (nNOS, NOS-1) and endothelial (eNOS, NOS-3) are constitutively expressed, and iNOS (NOS-2) is inducible. eNOS is found in the vascular endothelium, and the NO produced there plays a key role in vasodilation and vascular remodeling (Rudic et al, 1998). eNOS expression is stimulated by shear stress by activation of the tyrosine kinase c-SRC (Davis et al, 2004), by heat shock protein 90 (Harris et al, 2003), by oxidant stress (Cai et al, 2001), and by vascular mediators such as bradykinin, serotonin, adenosine, ADP/ATP, histamine, and thrombin (Arnal et al, 1999).

After its formation by vascular endothelial cells, NO diffuses to vascular smooth muscle cells where it activates soluble guanylyl cyclase (sGC), producing 3′,5′-cyclic guanosine monophosphate (cGMP). Subsequently, cGMP activates both cGMP- and 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent protein kinases (PKG and PKA, respectively) leading to smooth muscle relaxation. eNOS blockade increases renal vascular resistance and decreases the glomerular ultrafiltration coefficient (Gabbai, 2001). NO also helps maintain vascular integrity, with increased expression being linked to decreased neointimal formation and medial thickening (Kawashima et al, 2001). Indeed, the degenerative changes seen in chronic allograft nephropathy related to cyclosporine use can be mitigated by increased nitric oxide expression (Chander et al, 2005). Increased eNOS activity is also associated with protection from renal ischemia-reperfusion injury (Shoskes et al, 1997).

Although raised local levels of NO from eNOS can be beneficial to renal function, induction of iNOS and overproduction of NO from inflammatory cells can be deleterious. In the face of free oxygen radicals at the site of inflammation, NO can interact with reactive oxygen species to form peroxynitrite, which induces protein damage by formation of nitrotyrosine. Increased iNOS has been related to damage from nitrotyrosine in glomerular disease (Trachtman, 2004), lupus nephritis (Takeda et al, 2004), and transplant rejection (Albrecht et al, 2002). Increased iNOS activity has direct renal effects as well, including upregulation of sodium and bicarbonate tubular transport (Wang, 2002).

Carbon Monoxide

Carbon monoxide (CO) gas is another reactive diffusible mediator with multiple effects throughout the body, especially in the kidney. Heme oxygenase (HO), an essential enzyme in heme catabolism, catalyzes the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin (Hill-Kapturczak et al, 2002). Biliverdin is subsequently converted to bilirubin by biliverdin reductase. HO is expressed in two forms, constitutive HO-2 and inducible HO-1. Increased CO production produces vasodilation in the kidney and can counteract catecholamine induced vasoconstriction (Mustafa and Johns, 2001). In particular, both HO-1 and HO-2 are highly expressed in the medulla and help maintain renal medullary blood flow (Zou et al, 2000). In cirrhosis, decreased renal expression of HO-1 is linked to renal dysfunction (Miyazono et al, 2002). CO also regulates sodium transport in the loop of Henle, with HO-2 blockade inhibiting sodium excretion (Wang et al, 2003) and stimulation increasing natriuresis and diuresis (Rodriguez et al, 2003).

The other primary effect of CO in the kidney is renoprotection from oxidant injury. CO has documented anti-inflammatory, antioxidant, and cytoprotective actions (Sikorski et al, 2004). Indeed, a patient with a genetic HO-1 deficiency had significant tubular and vascular endothelial injury (Ohta et al, 2000). Increased CO is protective against ischemia-reperfusion injury in native and transplant kidneys (Nakao et al, 2005). Induction of HO-1 through agents such as bioflavonoids protects against tubular damage and improves renal transplant function (Shoskes et al, 2003).

Key Points: Hormonal

• Multiple chemical mediators act on renal vascular tone, which controls renal blood flow.

• Endothelin is the most potent vasoconstrictor.

• Nitric oxide and carbon monoxide are potent vasodilators.

Erythropoiesis

Red blood cell (RBC) production is a tightly regulated process. Basal RBC production is roughly 10 RBCs/hr, but this rate can be greatly increased during times of anemia or hypoxia. The kidney is the major organ involved in this process, and is responsible for monitoring RBC levels and increasing RBC output through the production of the hormone erythropoietin.

Erythroid Progenitor Cells

Mature RBCs are produced from a small pool of multipotent progenitor cells (Suda et al, 1984), which in turn are derived from the fetal liver. The earliest committed cell is the erythroid burst-forming unit (BFU-E), which, under appropriate stimulation, divides to produce erythroid colony-forming units (CFU-E). Further differentiation leads to the production of proerythroblasts, reticulocytes, and, ultimately (after extrusion of the nucleus), mature RBCs. The entire process requires about 2 weeks.

Erythropoietin

Maturation of the BFU-E and CFU-E depends on the appropriate growth factors. The most important of these factors is erythropoietin (EPO). The kidney is responsible for the majority of EPO production (90%), while the liver may contribute a smaller amount (10%). Kidney-derived EPO is produced by a subpopulation of interstitial fibroblasts, and possibly proximal tubular cells, in response to decreased O₂ tension.

EPO-deficient mice die in utero with a marked reduction in erythropoiesis (Munugalavadla and Kapur, 2005). Additional growth factors such as interleukin-3, GM-CSF, stem cell factor, activin, insulin-like growth factor (IGF-I), and, possibly, hepatic growth factor act synergistically with EPO to reduce apoptosis and thus promote proliferation of erythroid cells (Muta and Krantz, 1993).

EPO has also been shown to have effects outside of the bone marrow. EPO receptors have been demonstrated in kidney, brain, retina, heart, skeletal muscle, and endothelial cells (Juul et al, 1998). In the kidney, pretreatment with high-dose EPO has been shown to reduce ischemia-reperfusion injury in animal models, due to decreased apoptosis (Patel et al, 2004).

Regulation of EPO Production and Erythropoiesis

Production of EPO, and hence erythropoiesis, is closely associated with circulating O₂ tension. Under hypoxic conditions, the alpha subunit of the regulatory protein hypoxia-inducible factor-1 (HIF-1) is exposed (Wang et al, 1995). Binding of HIF-1 alpha with HIF-1 beta, hepatic nuclear factor-4 (HNF-4), and p300 turns on erythropoietin transcription (Arany et al, 1996). Once the hypoxia has been corrected, HIF-1 alpha is ubiquinated and rapidly degraded by proteosomes, thus shutting down erythropoietin production. There is also in-vitro evidence that hypoxia itself may directly increase erythropoiesis through HIF-1–mediated increases in autocrine motility factor (AMF) production and subsequent decrease in apoptosis (Mikami et al, 2005).

In states of chronic inflammation, erythropoiesis is decreased. Apoptosis of erythroid progenitor cells occurs in the presence of the tumor-associated antigen RCAS1, which is also produced by macrophages under inflammatory conditions (Suehiro et al, 2005).

In certain malignancies, such as renal cell carcinoma, erythropoiesis is enhanced due to a mutation in the von Hippel-Lindau (VHL) gene. As a result, there are constitutively increased levels of HIF-1 and polycythemia (Wiesener et al, 2002).

Erythropoiesis is also decreased in most forms of chronic renal failure, and subsequently anemia is common in the later stages of the disease. This is due to decreased EPO levels as a result of a reduction in the number of functional EPO-producing cells within the kidney. Recombinant human erythropoietin (rHuEPO) has been shown to be an effective treatment for this type of anemia.

rHuEPO has also been used to treat anemia associated with malignancy but must be used with caution in these conditions because its use may be associated with an increased risk of venous thromboembolism and higher mortality (Bennett et al, 2008).

Bone Mineral Regulation

Normal regulation of bone mineralization, through maintenance of serum calcium and phosphorus levels, is achieved through the actions of vitamin D and parathyroid hormone (PTH). The actions of both hormones are exerted largely through the kidney (Fig. 38–3).

Figure 38–3 Effects of vitamin D and parathyroid hormone (PTH) on calcium homeostasis. ECF, extracellular fluid.

(From Yu SLY. Renal transport of calcium, magnesium, and phosphate. In: Brenner BM, editor. Brenner and Rector’s the kidney. 7th ed. Philadelphia: WB Saunders; 2004. p. 536.)

Vitamin D Regulation

The kidney plays an important role in the regulation of vitamin D activity. The major source of vitamin D is through dermal synthesis of the precursor compound cholecalciferol (vitamin D₃), or through dietary intake of vitamin D₃–fortified foods. Vitamin D₃ has minimal biological activity and requires two hydroxylations to become active. The first occurs in the liver through the action of 25-hydroxylase to form 25-hydroxycholecalciferol (calcidiol). The calcidiol molecule is bound to vitamin D binding protein and transported to the kidney, where it is filtered and reabsorbed by renal tubular cells. A second hydroxylation occurs within the tubular cell. Because these cells contain both 1α-hydroxylase and 24α-hydroxylase, hydroxylation will produce either inactive 24,25-dihydroxycholecalciferol or 1,25-dihydroxycholecalciferol (calcitriol), the biologically active form that is one hundred times more potent than calcidiol. Calcitriol production is regulated by calcidiol levels as well as the 1α-hydroxylase levels. These are, in turn, determined by PTH and plasma phosphate levels (increased enzyme activity) and serum calcitriol levels (decreased enzyme activity) (Portale et al, 1989). However, unregulated calcitriol synthesis can occur in macrophages in granulomatous conditions such as sarcoidosis and tuberculosis, and in prostate epithelial and cancer cells (Young et al, 2004).

Vitamin D Activity

Calcitriol functions through a single intracellular vitamin D receptor (VDR) to regulate gene transcription (Lowe et al, 1992). Its primary function is the maintenance of serum calcium and phosphorus levels. The four main target organs are the intestine (increases intestinal absorption of calcium, and to a lesser extent, phosphorus), the bones (regulates osteoblast activity, and in combination with PTH, allows for osteoclast activation and bone resorption), the kidney (increases reabsorption of calcium) and the parathyroid gland (suppresses PTH release). Recent evidence suggests that both calcidiol and calcitriol may also function as antiproliferative agents. Prostate epithelial and cancer cells demonstrate VDR, and vitamin D may suppress the growth of these cells, especially in combination with androgens (Tuohimaa et al, 2005).

In summary, vitamin D contributes to normal bone mineralization by maintaining normal serum calcium and phosphorus levels through increased intestinal absorption of calcium and phosphorus and increased renal reabsorption of calcium.

Parathyroid Hormone Regulation

Synthesis, secretion, and degradation of PTH are influenced directly by serum calcium levels through calcium sensing receptors located on parathyroid cells. During periods of hypocalcemia, PTH synthesis and secretion are increased while degradation is decreased. The opposite occurs during hypercalcemia. In addition, calcitriol has a suppressive effect on PTH synthesis and parathyroid cell proliferation, mediated through vitamin D receptors located on the surface of parathyroid cells. Hyperphosphatemia also directly stimulates PTH release, primarily in advanced renal insufficiency. Finally, other cations such as magnesium and aluminum have slight stimulatory effects, likely mediated through the calcium sensing receptors.

Parathyroid Hormone Activity

PTH exerts its activity through PTH/PTHrP receptors, which are localized primarily in the kidneys and bone.

Bone

Its effect on bone metabolism depends upon its administration; if given continuously, it stimulates bone resorption and increases serum calcium and phosphorus levels. Given intermittently, it leads to increased bone formation and mineral density.

Kidney

The renal effects of PTH are threefold. First, it increases active calcium reabsorption at the level of the distal tubule (Friedman and Gesek, 1993). Second, it decreases phosphate reabsorption in the proximal convoluted tubule (and the distal tubule, to a lesser degree) through its action on the sodium phosphorus cotransporter (Pfister et al, 1997). Third, it stimulates calcitriol production by increasing 1α-hydoxylase levels while decreasing 24α-hydroxylase levels (Broadus et al, 1980).

In summary, PTH functions to maintain normal serum calcium and phosphorus levels by increasing bone resorption, increasing renal reabsorption of calcium and excretion of phosphorus, and stimulating production of calcitriol.

Antidiuretic Hormone

Antidiuretic hormone (ADH), or arginine vasopressin as it is called in humans, is a polypeptide secreted by the posterior pituitary gland. It functions to maintain serum osmolality and volume through the regulation of free-water excretion in the kidney.

ADH Actions

ADH increases the passive reabsorption of water at the level of the collecting duct. Through interaction with the V2 receptor, it facilitates the insertion of preformed water channels, known as aquaporin-2 (AQP-2), into the luminal membrane of the principal cells (Agre et al, 2002). This allows luminal water to enter the cell and then diffuse back into the systemic circulation through the basolateral membrane of the cell (Fig. 38–4). ADH increases urea reabsorption in the medullary collecting tubule through specific urea transporters, which helps maintain the high interstitial osmolality required for water reabsorption. ADH also increases systemic vascular resistance through interaction with the V1 receptor; this is of minor physiologic importance. Other effects of ADH include increased sodium reabsorption and potassium excretion, increased prostaglandin synthesis, increased ACTH secretion (through V3 receptors), and release of both factor VIII and von Willebrand factor from vascular endothelium.

Figure 38–4 Action of antidiuretic hormone on aquaporin (AQP) transport. AC, adenylate cyclase; AP1, transcription factor; AVP, arginine vasopressin; cAMP, cyclic adenosine monophosphate; CRE, cAMP response element; CREB-P, CRE binding protein; EP₃, prostaglandin receptor; PGE₂, prostaglandin E₂.

(From Brown D, Nielsen S. The cell biology of vasopressin action. In: Brenner BM, editor. Brenner and Rector’s the kidney. 7th ed. Philadelphia: WB Saunders; 2004. p. 574.)

Control of ADH Secretion

There are two major stimuli for ADH release, hyperosmolality and decreased effective circulating volume (ECV), as well as a number of less common factors (Table 38–2).

Table 38–2 Physiologic and Pathologic Factors Affecting the Release of Antidiuretic Hormone

STIMULI	INHIBITORS
Hyperosmolality	Hypo-osmolality
Hypovolemia	Hypervolemia
Stress (e.g., pain)	Ethanol
Nausea	Phenytoin
Pregnancy
Hypoglycemia
Nicotine
Morphine
Other drugs

Hyperosmolality

The major extracellular osmole is sodium; so, for practical purposes ADH release is governed by changes in serum sodium concentrations. Serum osmolality is monitored by osmoreceptors in the hypothalamus, and changes as little as one percent are enough to affect ADH release (Robertson, 1987).

Decreased ECV

Circulating volume is monitored by pressure (baro-) receptors in the carotid sinus, which stimulate ADH release in response to reductions in ECV. These receptors are much less sensitive than the osmoreceptors, and, as such, ADH release is not affected until there is a noticeable drop in mean arterial pressures (usually around 10% to 15% blood volume loss) and after other vasoconstrictive hormones, such as renin and norepinephrine, have been activated.

Other Stimuli

There are a number of other factors that can increase ADH secretion (see Table 38–2). Nausea and pain are probably the most clinically relevant, and, as a result, postsurgical hyponatremia due to excessive ADH release is a potentially life-threatening problem.

When both decreased ECV and hyponatremia coexist, the pressure receptors usually override the osmoreceptors and prevent the inhibition of ADH secretion that is usually seen with hyponatremia (Baylis, 1987). This is clinically relevant in conditions of decreased ECV and hyponatremia, such as congestive heart failure where ADH secretion persists despite significant hyponatremia.

Renal Tubular Function

Basic Functions

The renal tubule has two basic functions: reabsorption (transport of substances from lumen to blood) and secretion (transport of substances from blood to lumen). Transport can involve one of two pathways: either transcellular (across the luminal and basolateral membrane) or paracellular (between cells) (Fig. 38–5). Each section of the tubule (Fig. 38–6) is specialized to facilitate absorption and secretion of certain substances through a variety of transport mechanisms.

Figure 38–5 Example of transcellular transport between the tubule cell and the basolateral membrane.

(From Moe OW, Baum M, Berry CA, Rector FC Jr. Renal transport of glucose, amino acids, sodium, chloride, and water. In: Brenner BM, editor. Brenner and Rector’s the kidney. 7th ed. Philadelphia: WB Saunders; 2004. p. 425.)

Figure 38–6 Organization of the renal tubule.

(From Knepper MA, Gamba F. Urine concentration and dilution. In: Brenner BM, editor. Brenner and Rector’s the kidney. 7th ed. Philadelphia: WB Saunders; 2004. p. 601.)

Proximal Convoluted Tubule (PCT)

The PCT is responsible for reabsorption of 60% of the glomerular filtrate. Under normal circumstances it reabsorbs 65% of the filtered sodium, potassium, and calcium; 80% of filtered phosphate, water, and bicarbonate; and 100% of the filtered glucose and amino acids (Moe et al, 2004). The PCT is able to increase or decrease reabsorption in response to changes in GFR to maintain constant reabsorptive fractions through the process of glomerulotubular balance. This is accomplished mainly by the early (S1 and S2) segments of the PCT. The later (S3) segment is responsible for secretion of numerous drugs and toxins that are too large, or protein bound, to be filtered. As well, the PCT is responsible for the generation of ammonia from glutamine, which is necessary for urinary acidification.