Pesticide Excretion

Ernest Hodgson , in Hayes' Handbook of Pesticide Toxicology (Third Edition), 2010

41.2.3 Tubular Reabsorption

Tubular reabsorption is the second major step in urine formation. Most of the reabsorption of solutes necessary for normal body function such as amino acids, glucose, and salts takes place in the proximal part of the tubule. This reabsorption may be active, as in the case of glucose, amino acids, and peptides, whereas water, chloride, and other ions are passively reabsorbed. Reabsorption of water and ions also occurs in the distal tubule and in the collecting duct.

Reabsorption of xenobiotics is usually passive and controlled by the same principles that regulate their passage across any membrane. That is, lipophilic compounds cross cell membranes more rapidly than polar ones; hence, lipophilic toxicants will tend to be passively reabsorbed more than polar ones and, overall, elimination of polar toxicants and their polar metabolites will be facilitated.

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Pesticide Excretion

Ernest Hodgson , in Pesticide Biotransformation and Disposition, 2012

Tubular Reabsorption

Tubular reabsorption is the second major step in urine formation. Most of the reabsorption of solutes necessary for normal body function, such as amino acids, glucose, and salts, takes place in the proximal part of the tubule. This reabsorption may be active, as in the case of glucose, amino acids, and peptides, whereas water, chloride, and other ions are passively reabsorbed. Reabsorption of water and ions also occurs in the distal tubule and in the collecting duct.

Reabsorption of xenobiotics is usually passive and controlled by the same principles that regulate their passage across any membrane. That is, lipophilic compounds cross cell membranes more rapidly than polar compounds; hence, lipophilic toxicants will tend to be passively reabsorbed more than polar toxicants and, overall, elimination of polar toxicants and their polar metabolites will be facilitated.

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Nanoparticle Pharmacokinetics and Toxicokinetics

Ashok K. Singh PhD , in Engineered Nanoparticles, 2016

2.4.1 Excretion via the Kidney

Each kidney contains approximately 1   million nephrons, the structural and functional units of the kidneys that carry out processes that form urine (Figure 28). Nephrons consist of the glomerulus corpuscle (composed of capillaries) surrounded by a glomerular capsule (Bowman's capsule) and a renal tubule. The renal tubule begins at the glomerular capsule as the proximal convoluted tubule (PCT), continues through the loop of Henle, and turns into a distal convoluted tubule (DCT) before emptying into a collecting duct. The collecting ducts collect filtrate from many nephrons and empty into a minor calyx.

Figure 28. Microstructure of the glomerular apparatus. PCT, proximal convoluted tubules; DCT, distal convoluted tubules; CD, collecting duct.

Renal Glomerular Filtration: Glomerular filtration is a passive, nonselective process in which hydrostatic pressure (approximately 10   mm   Hg) forces fluids and small (<5   nm) hydrophilic particles through the glomerular membrane (Deen et al., 2001). Glomeruli restrict the passage of the hydrophobic or nanoparticles. The glomerular filtration rate (GFR) is the volume of filtrate formed each minute by all the glomeruli of the kidneys combined. The normal adult GFR is 120–125   mL/min. Changes in the GFR affect the rate of elimination of chemicals, which are primarily eliminated by filtration (e.g., digoxin, kanamycin). In addition to size, the filtration of molecules also depends on their charge. The filtration-size threshold for globular proteins has been accepted to be less than 5   nm in hydrodynamic diameter (HD). For example, inulin (HD: 3   nm) achieves 100% renal filtration with a blood half-life of only 9   min (Prescott et al., 1991).

Renal Tubular Reabsorption: The intertubular pressure allows filtration of all nonprotein bound hydrophilic components of plasma (nutrients: glucose, amino acids, and essential elements; particles <5   nm) in PCT. This involves near total reabsorption of organic nutrients and the hormonally regulated reabsorption of water and ions. Nonresorbed polar molecules remain in the renal filtrate and are excreted via urine. Urine pH plays an important role in the excretion of polar chemicals. For weak acids, urine alkalization favors the ionized form and promotes excretion. Different areas of the tubules have different absorptive capabilities.

•

The PCT is most active and selective in reabsorption.

•

The descending limb of the loop of Henle is permeable to water, while the ascending limb is impermeable to water but permeable to electrolytes.

•

The DCT and collecting duct have Na+ and water permeability regulated by the hormones aldosterone, antidiuretic hormone, and atrial natriuretic peptide.

Renal Tubular Secretion: Tubular secretion disposes unwanted solutes and solutes that were reabsorbed, rids the body of excess K+, and controls blood pH. Tubular secretion is most active in the PCT, but it also occurs in the DCT and collecting ducts. The kidney can actively transport some filtered drugs (e.g., dicloxacillin) against a concentration gradient, even if the drugs are protein-bound, but dissociates rapidly. A drug called probenecid competitively inhibits the tubular secretion of the penicillin, and it may be used clinically to prolong the duration of effect of the antibiotics.

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Pathogenesis of Hypertension

Michael E. Hall , John E. Hall , in Hypertension: A Companion to Braunwald's Heart Disease (Third Edition), 2018

Obesity Increases Renal Sodium Reabsorption and Impairs Pressure Natriuresis

Increased renal sodium reabsorption and impaired renal-pressure natriuresis play a major role in initiating the rise in BP associated with excess weight gain. 160 At least three major factors increase renal sodium reabsorption and BP during rapid, excessive weight gain (Fig. 5.8): (1) Compression of the kidneys by increased visceral, retroperitoneal and renal sinus fat; (2) RAAS activation, including stimulation of MR independent of aldosterone; and (3) SNS activation and increased renal sympathetic nerve activity (RSNA). Also, CKD may, over a much longer time, amplify the BP effects of these mechanisms and, make obesity-associated hypertension more difficult to control and less easily reversed by weight loss. 2,161

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Thirst Physiology

J. Leiper , in Encyclopedia of Human Nutrition (Third Edition), 2013

Fluid Requirements

Renal reabsorption can reduce the volume of water and solute loss, and hence slow the rate of progress of a fluid deficit, but it cannot stop its development. Intake of fluid either as food or drink is required to restore a fluid deficit. Daily fluid intake is highly variable between individuals and the rate of loss is dependent on factors such as environmental temperature, physical activity, sweating rate, antidiuretic function, and dietary solute load. A representative normal daily water turnover in a sedentary individual living in a temperate climate and eating a typical western diet is approximately 2–3   l, and a minimum daily fluid intake of approximately 1.7   l is necessary to conserve fluid balance. The water content of the typical western diet approximates to approximately 1   l and metabolically derived water produces in the order of approximately 300   ml, which together almost offsets the daily obligatory water loss. Therefore, in many situations, the requirement for fluid intake can actually be very low.

There are conditions in which water loss is greater than that indicated above and replacement obviously requires a compensatory increase in the daily fluid intake (Figure 6). Urine volume is related to the solute content of the diet, with a minimum volume of approximately 500   ml being necessary to eliminate the usual daily solute load. Diets rich in protein or foods with a high sodium content require a greater obligatory urine output for excretion. The renal concentrating ability at maximum antidiuresis determines the minimum urinary water loss for a given dietary solute load. Normally, there is a wide range of urinary osmolality such that the same solute load can be excreted in 500   ml of urine with an osmolality of 1400   mosmol   kg–1 or in 23   l of urine with an osmolality of 30   mosmol   kg–1. This feature of renal excretion allows body water balance to be maintained while fluid intake volume is varied.

Prolonged relatively intense muscular activity, elevated ambient temperature, and fever all increase the rate of evaporative sweat loss. Individual sweat rates are highly variable, with average exercise-induced losses usually in the order of 1   l   h–1, but daily losses of between 10 and 15   l have been recorded. Daily fecal losses associated with a western diet are usually between 100 and 200   ml; however diarrhea, particularly infectious diarrhea, can produce prodigious fecal water losses that are potentially fatal.

Inappropriate fluid intake can be produced following lesions or development of tumors in regions of the brain associated with the thirst centers. Diabetes insipidus promotes an increase in the volume of fluid ingested, which is caused by a lowering of the basal threshold set point for osmotic thirst. A similar, although less pronounced, lowering of the osmotic thirst threshold occurs during pregnancy. In both the young and the elderly, the thirst response can be blunted and inappropriate drinking habits may occur. Psychogenic disturbances in the sensation of thirst and hence fluid intake have also been reported for a variety of clinical conditions.

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Structural Organization of the Mammalian Kidney

Wilhelm Kriz , Brigitte Kaissling , in Seldin and Giebisch's The Kidney (Fourth Edition), 2008

Endocytotic Apparatus

Tubular reabsorption of filtered proteins results from fluid phase or receptor-mediated endocytosis (69, 113). Receptor-mediated endocytosis is the most efficient. By multiphoton microscopy the passage of proteins across the different endocytotic compartments has been directly observed in vivo (430).

The first requirement for receptor-mediated endocytosis is binding of a ligand to a receptor protein on the surface of the tubular cell. The multireceptors megalin, cubilin, and amnionless (226, 427), binding to partially differential ligands, have all been located in the proximal tubule, mainly at the base of the microvillus plasma membrane, in the intermicrovillar membrane invaginations (clefts), and in subapical clathrin-coated pits. Megalin, belonging to the LDL-receptor family, is bound with its cytoplasmic tail to cytoplasmic adaptor proteins (443, 599), forms a tandem with the peripheral protein cubilin (642, 643) and is responsible for the internalization of its own ligands and of cubilin with its ligands (113). Amnionless protein is essential for the membrane association and trafficking of cubilin. The receptor–ligand complexes are gathered in the clathrin-coated membrane pits and are directed by clathrin-coated vesicles to larger, uncoated early and late endosomes, located slightly deeper in the cytoplasm. In the endosomes the receptors are cleaved from the ligands and travel back to the luminal membrane via uncoated DATs (114, 225, 406, 407). The DATs form an elaborate, moving dynamic network of anastomosing tubules (130, 225), which are transiently connected to the larger endosomes and display at their other end small clathrin-coated domains (129–131, 194). From the endosomes the ligands are sorted for degradation to lysosomes or for ubiquitination via the proteasome pathway. The trafficking of internalized material from the vacuolar apparatus to lysosomes critically depends on the microtubular system (382). Microtubules normally form a loose network across the proximal tubule cells and become highly oriented in an apicobasal direction during vesicular transport of endocytosed cargo to lysosomes (383).

The dimensions of the vacuolar apparatus (Fig. 44) and the location of megalin in proximal tubule cells are correlated with the rate of endocytosis. If endocytosis does not take place, either due to paucity of ligands in the tubular fluid (e.g., normally in S3) or lack or low levels of the endocytosis receptor (26, 28, 113), the vacuolar apparatus is barely developed.

The processing of material in the vesicular compartments of the endocytotic pathway relies on acidification. NHE3, the proton-ATPase, and the chloride channel ClC-5 are highly expressed and colocalized in the inter-microvillous clefts as well as in the vesicular membranes in the early endocytotic pathway (112, 205, 654). Dysfunction of one or several of these acidifying proteins may cause primary defects in endocytosis. Knockout of the ClC-5 channel, for instance, impairs the clearance of PTH from the tubular fluid, entailing hyperphosphaturia and hypercalciuria (112, 654). This mechanism can explain the high incidence of kidney stones in Dent disease, with functionally impaired ClC-5 channels (144, 260, 261).

Endocytosis contributes also to acute regulation of transport rates by selective retraction of transport proteins from the microvillous membrane. For instance, the drastic decrease of the brush border protein NaPi-IIa protein, occurring within minutes after an injection of PTH (383, 441), soon after acute high phosphate intake (359), or following activation of dopamine receptors (27), relies on withdrawal of NaPi-IIa, first, from its anchoring NHERF1/2 and PDZ proteins in the apical scaffold (63, 141) and, second, by subsequent endocytotic uptake of the protein by endocytosis (358, 382, 383). Absence or reduced expression of megalin markedly slows down the endocytosis of NaPi-IIa (26, 28).

The passage of NaPi-IIa across the successive endocytotic compartments, namely, the megalin-containing clefts, the clathrin-coated-vesicle compartment (614), through the early and late endosomal compartment, and finally its disposal in lysosomes, where NaPi-IIa is degraded (29–31) has been tracked by immunofluorescence (29). The shifting of the protein through the early endocytotic compartments goes along with a dramatic, rapidly transient expansion and remodeling of the vacuolar apparatus in the subapical compartment (Fig. 44) (383).

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Disorders of Bone Mineral Metabolism: Normal Homeostasis

ALLEN W. ROOT MD , in Pediatric Endocrinology (Third Edition), 2008

Phosphate

Eighty-five percent of body phosphate is deposited in bone as hydroxyapatite. The remainder is intracellular (in the cytosol or mitochondria in the form of inorganic phosphate esters or salts, membrane phospholipids, and phosphorylated metabolic intermediate compounds) or in interstitial fluid or serum (0.1%), where it circulates as free orthophosphate anions HPO4 2− and H2PO4 − (55%), bound to proteins (10%), or complexed to calcium, magnesium, or sodium (35%). 1,22 At pH 7.4, serum HPO4 2− and H2PO4 − are present in a molar ratio of 4:1. In alkalotic states, the ratio increases—and with acidosis it declines. (At pH 7.4, 1 mmol/L of orthophosphate 5 1.8 mEq/L 5 3.1 mg/dL.) Intracellularly, cytosolic free phosphate concentrations approximate those in serum (i.e., 3–6 mg/dL). Phosphate is an integral and absolutely essential component of cellular and intracellular membrane phospholipids, ribonucleic (RNA) and deoxyribonucleic (DNA) acids, energy-generating ATP, and intracellular signal transduction systems. 2,37

The serum phosphate concentration is regulated by intake, intestinal absorption, excretion, and renal tubular reabsorptive mechanisms and fluctuates with age, gender, growth rate, diet, and serum calcium levels. 1,38 Inasmuch as phosphate is found in all cells and foods, dietary deficiency is unusual. Dietary phosphate is absorbed across the intestinal brush border as HPO4 2− in direct proportion to its intake, principally in the duodenum and jejunum. It is absorbed by both passive paracellular diffusion related to the luminal concentration of this anion and by an active transcellular mechanism stimulated by calcitriol.

The latter is an energy-requiring transport process with sodium through a Na+-HPO4 2− cotransporter protein (SLC34A2, solute carrier family 34, member 2) maintained by a calcitriol-dependent Na+, K+-ATPase. Phosphate is also secreted into the intestinal tract. When dietary phosphate intake falls below 310 mg/day in the adult, net phosphate absorption is negative. At low phosphate intakes, absorption is active in the duodenum, jejunum, and distal ileum—whereas at high intakes 60% to 80% of ingested phosphate is absorbed primarily by diffusion. Phosphate absorption can be impaired by its intraluminal precipitation as an aluminum or calcium salt and by intestinal malabsorption disorders.

Phosphate is filtered in the renal glomerulus and reabsorbed in the proximal (85%) and distal convoluted tubules. It is actively transported across the luminal membrane against an electrochemical gradient through specific Na+-HPO4 2− cotransporter proteins with the aid of Na+, K+-ATPase. 1,22 Expression of the renal Na+-HPO4 2− cotransporter protein (SLC34A1) is regulated by serum phosphate levels (hypophosphatemia increases expression), PTH, PTHrP, and fibroblast growth factor (FGF)-23. Phosphate exits the renal tubular cell with sodium through cation exchange for potassium. The maximal tubular reabsorption of phosphate approximates the filtered load.

Tubular phosphate reabsorption is increased by low phosphate intake and hypophosphatemia (due to decrease in filtered load), hypercalcemia (by decrease in the glomerular filtration rate), depletion of extracellular fluid volume, and metabolic alkalosis (Table 3-4). Renal tubular reabsorption of phosphate is depressed by high phosphate intake and by PTH- and PTHrP-mediated down-regulation of SLC34A1. Calcitriol, glucocorticoids, and thiazide diuretics decrease renal tubular reabsorption of phosphate. Phosphate is deposited in bone as hydroxyapatite dependent on local levels of calcium, phosphate, and alkaline phosphatase activity and is reabsorbed by osteoclasts whose activity is stimulated by PTH, calcitriol, and other osteoclast-activating factors. Serum concentrations of phosphate are highest in infancy and early childhood (4–7 mg/dL) and then decline during mid-childhood and adolescence to adult values (2.5–4.5 mg/dL).

PHOSPHATONINS

Renal tubular reabsorption of phosphate is regulated by several substances collectively termed phosphatonins (Figure 3-1). Phosphaturic agents have been identified in the serum of normal subjects and in patients with X-linked hypophosphatemic rickets (XHR), which is due to loss-of-function mutations in the membrane-bound 749-aa endopeptidase encoded by PHEX (phosphate-regulating gene with homologies to endopeptidases located on the X chromosome). They have also been identified in patients with autosomal-dominant hypophos-phatemic rickets (ADHR-OMIM 193100), due to activating mutations in FGF23, and in patients with tumor-induced osteomalacia in which increased production of FGF23 and other phosphaturic agents has been identified. 38,39

By inhibition of phosphate transport in the kidney, phosphatonins lead to hyperphosphaturia and hypophosphatemia. They also inhibit activity of 25-hydroxyvitamin D-1a hydroxylase, resulting in decreased synthesis and thus inappropriately normal or low serum concentrations of calcitriol and in impaired intestinal absorption of phosphate. 40 Among the best characterized of the phosphatonins is FGF23, generated as a 251-aa with a 24-aa signal sequence that is post-translationally glycosylated. It is expressed primarily by osteoblasts and osteocytes and to a lesser extent by the brain, thyroid, PTG, thymus, cardiac/skeletal muscle, liver, and intestines. In osteoblasts, expression of FGF23 is enhanced by calcitriol acting through the VDR and modified by a chondrocyte-derived secreted factor yet to be characterized. 41,42

FGF23 induces renal phosphate wasting by down-regulating expression of SLC34A1, the Na+-HPO4 2− cotransporter expressed in the apical or luminal membrane of the proximal renal tubule. It also down-regulates expression of a related renal tubular Na+-HPO4 2− cotransporter encoded by SLC34A3, and of 25-hydroxyvitamin D-1a hydroxylase encoded by CYP27B1. FGF23 acts through binding to the c isoform of tyrosine kinase FGF receptors (FGFR) 1, 2, and 3. The genes encoding the FGFRs consist of 19 exons that may be alternatively spliced to include or to exclude exon 8 or exon 9 (encoding the third extracellular immunoglobulin-like domain of the FGF receptor, which helps to specify the ligand bound by the receptor). When exon 8 is included in the mRNA transcript, the β isoform of the FGFR is formed. When exon 9 is included in the transcript, the c isoform is produced. Although it is likely that FGF23 binds to multiple FGFR c isoforms, the multifunctional protein klotho has been reported to convert FGFR1(IIIc) into a specific FGF23 receptor in renal tissue. 38,43 Highly sulfated glycosaminoglycans facilitate ligand-receptor interaction.

FGF23 is measurable in normal adult sera with a mean concentration of 29 pg/mL that does not correlate with age or gender. Its concentration is inversely related to that of phosphate, and values rise when dietary phosphate increases and decline with phosphate restriction. 38 Serum values of FGF23 are increased in patients with XHR, ADHR, tumor-induced osteomalacia, and fibrous dysplasia associated with hypophosphatemia. In patients with ADHR, gain-of-function mutations (e.g., Arg179Trp) in FGF23 result in resistance to degradation of the protein that is normally cleaved between Arg179 and Ser180. In subjects with tumor-induced osteomalacia, the production of FGF23 is greatly increased.

Serum FGF23 concentrations are also elevated in the Hyp mouse model of XHR. FGF23 may be a substrate for PHEX enzymatic activity, but it is unclear if it is the endogenous substrate for this enzyme. 40,44 In the Hyp mouse, biallelic "knockout" of Fgf23 reverses the hypophosphatemia and relative calcitriol deficiency—suggesting that FGF23 is of fundamental pathogenic importance in XHR. In familial tumoral calcinosis (OMIM 211900), loss-of-function mutations in FGF23 lead to accelerated intracellular degradation of FGF23 that prevents secretion of intact protein—resulting in decreased renal excretion of phosphate, in hyperphosphatemia, in relatively increased calcitriol levels, and in diffuse ectopic calcification. 38,45

Tumors associated with hypophosphatemic osteomalacia also express FRP4 (frizzled related protein-4), MEPE (matrix extracellular phosphoglycoprotein), and FGF7—all of which have phosphaturic properties. 38,46 FRP4 is a secreted 346-aa glycosylated protein that shares the structure of the extracellular domain of transmembrane frizzled receptors. The natural ligands of frizzled receptors are Wnt proteins, and their coreceptors are the cell surface low-density lipoprotein receptor-related proteins (LRP-5/6). These heterotrimeric complexes stabilize intracellular β-catenin and the attendant signal transduction systems and are essential for bone formation (vide infra).

Secreted FRP4 serves as a "decoy" receptor competing with the frizzled receptor for binding to Wnt, thus inhibiting the function of this receptor. FRP4 is expressed in bone cells and in large amounts by tumors with associated osteomalacia. In normal adults, the mean serum FRP4 concentration is 34 ng/mL. FRP4 inhibits sodium-dependent renal tubular phosphate reabsorption by inhibition of Wnt signaling, leading to hypophosphatemia. It also reduces expression of the gene encoding 25-hydroxyvitamin D3-1α.hydroxylase. 40 MEPE is primarily expressed by osteoblasts, osteocytes, and odontoblasts—as well as by tumors associated with hypophosphatemic osteomalacia. It encodes a 525-aa 58-kDa protein, a member of the short-integrin-binding ligand-interacting glycoprotein family that also includes osteopontin. MEPE modulates osteoblast and osteoclast function and may both inhibit and support bone mineralization. 38 Although MEPE is able to inhibit sodium-dependent renal tubular phosphate reabsorption, its role in phosphate metabolism may be more complex inasmuch as knockout of MEPE in mice results in increased bone mass without altering serum phosphate or calcitriol values. 47 MEPE is associated with and may serve as a substrate for PHEX on the osteoblast surface. 44

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DEVELOPMENT OF GLOMERULAR AND TUBULAR FUNCTION IN FETAL AND NEWBORN PIGS AND THEIR RESPONSE TO HYPOTONIC SALINE LOAD

J.M. Alt , ... U. Biermann , in Kidney and Body Fluids, 1981

Tubular reabsorption and secretion

Table 1 summarizes the fractional reabsorption of creatinine, urea, glucose and fructose.

Table 1. Tubular reabsorption in % of filtered load.

creatinine urea glucose fructose
fetal pigs (10) 58±25 31±46 1) 99.6±0.3 84±10
neonatal pigs (6) 25±32 1) 66±8 99.2±0.4 −55±113 1)
1)
The substance was secreted by some of the animals.

The tubular reabsorption of creatinine is linearly correlated to the reabsorption of urea (p < 0.00l) in fetuses as well as in newborns, the slope, however, is different in both groups. The fetusus reabsorb more creatinine than urea and the neonatal pigs retain more creatinine and excrete more urea. The fetal fructose excretion allowed the calculation of the tubular transport maximum (Tm) of fructose which is 0.1 µmol/min/g kidney weight (KW). The renal threshold is 1.88 mmol/l. The plasma fructose concentration in the fetuses is 3.5±0.8 mmol/l. The plasma fructose concentration in the newborns is 0.16±0.1 mmol/l. The renal handling of fructose by the newborns also differ from the fetuses in so far as they reabsorb only little or none and 3 out of 6 newborns secret fructose.

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Obesity in Hypertension

F. Xavier Pi-Sunyer , Panagiotis Kokkoris , in Hypertension, 2007

Renal Mechanisms

The increased renal sodium reabsorption in obese individuals can contribute to sodium retention and to an increase in extracellular and blood volume. The increase in blood volume is necessary to maintain sodium balance, but this results in elevation of BP. 13, 14 Another renal factor contributing to the development of obesity-related hypertension is compression of the kidneys caused by visceral fat accumulation. The result is increased intrarenal pressure, which leads to increased renal sodium reabsorption, water retention, and, finally, elevated BP. Additionally, fat tissue not only compresses the kidney, but also may penetrate the renal capsule and thus elevate intrarenal pressure further. 15, 16

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The assessment of parathyroid function

P.A. Lucas , J.S. Woodhead , in Calcium Disorders, 1982

PHOSPHATE EXCRETION

The renal reabsorption of filtered phosphate occurs primarily in the proximal tubule 69, the process being regulated by parathyroid hormone. Many attempts have been made over the years to use phosphate excretion as a monitor of parathyroid function including such derivations as the phosphate excretion index 60 . However, indices such as this are subject to variations in phosphate intake, urine volume and glomerular filtration rate (GFR). The most useful index of phosphate handling is the derived maximum tubular reabsorption capacity for phosphate relative to the glomerular filtration rate (TmP/GFR). This derivation may be calculated from a plot of phosphate clearance relative to the plasma phosphate concentration 11, obtained during a phosphate infusion. This procedure, which involves frequent blood samples and urine collections, may be difficult to carry out in practice. We have found that the nomogram derived by Walton and Bijvoet 80 provides a satisfactory alternative. The nomogram relates TmP/GFR to plasma phosphate and its excretion relative to creatinine (Figure 4.2) and enables the parameter to be derived from data based on a single urine collection, and a mid-collection plasma measurement.

Figure 4.2. Nomogram for the derivation of the maximum renal tubular reabsorption capacity for phosphate (TmP/GFR). Note: Tubular reabsorption of phosphate (TRP) = 1– Cp/Ccr. (From Walton and Bijvoet 80, courtesy of the Editor and Publishers, Lancet)

In practice a 2-hour collection is sufficient for clearance to be calculated from the formula:

Urine phosphate ×  plasma creatinine Plasma phosphate ×  urine creatinine =  Clearance of phosphate (C p ) Clearance of creatinine (C cr )

In normal subjects TmP/GFR ranges from 0.75–1.4mmol/l of glomerular filtrate. It is usually low in primary hyperparathyroidism 79 and may therefore provide diagnostic information. It has been possible to show that the nomogram may be used to detect small changes in phosphate reabsorption in response to near physiological doses of exogenous parathyroid hormone by sequential monitoring of urine and plasma 79 . The major drawback of TmP/GFR as a diagnostic test is the fact that it does not differentiate between malignancy and hyperparathyroidism, being low in both 76, and that its setting can be influenced by other factors such as oestrogens, growth hormone and glucocorticoids 11 . Thus, while a low TmP/GFR may provide additional evidence in a patient suspected of having hyperparathyroidism, as an independent observation it may be of relatively little value.

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